TW202310838A - Glucagon-like peptide 1 receptor agonists - Google Patents
Glucagon-like peptide 1 receptor agonists Download PDFInfo
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- TW202310838A TW202310838A TW111118381A TW111118381A TW202310838A TW 202310838 A TW202310838 A TW 202310838A TW 111118381 A TW111118381 A TW 111118381A TW 111118381 A TW111118381 A TW 111118381A TW 202310838 A TW202310838 A TW 202310838A
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- pharmaceutically acceptable
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- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 495
- 150000003839 salts Chemical class 0.000 claims abstract description 90
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- -1 C 1 -C 3 haloalkyl Chemical group 0.000 claims description 149
- 229910052757 nitrogen Inorganic materials 0.000 claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 16
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- 125000001424 substituent group Chemical group 0.000 claims description 16
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- GZPHSAQLYPIAIN-DOMIDYPGSA-N pyridine-3-carbonitrile Chemical compound N#[14C]c1cccnc1 GZPHSAQLYPIAIN-DOMIDYPGSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Inorganic materials [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- JOKPITBUODAHEN-UHFFFAOYSA-N sulfanylideneplatinum Chemical compound [Pt]=S JOKPITBUODAHEN-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 231100000583 toxicological profile Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- BMDAASXALYXZSG-UHFFFAOYSA-M zinc;ethyl acetate;bromide Chemical compound Br[Zn+].CCOC([CH2-])=O BMDAASXALYXZSG-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Abstract
Description
本發明係關於類升糖素肽-1受體促效劑及該等化合物用於治療II型糖尿病之治療用途。The present invention relates to glucagon-like peptide-1 receptor agonists and the therapeutic use of these compounds for treating type II diabetes.
類升糖素肽-1 (GLP-1)係由腸內分泌L細胞分泌之肽激素之腸促胰液素家族成員。GLP-1誘導以葡萄糖依賴性方式自β細胞釋放胰島素。然而,GLP-1會快速代謝,從而僅一小部分GLP-1可用於誘導胰島素分泌。為彌補這一點,已研發GLP-1受體(GLP-1R)促效劑來增強胰島素分泌以治療II型糖尿病。Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by enteroendocrine L cells. GLP-1 induces the release of insulin from β cells in a glucose-dependent manner. However, GLP-1 is rapidly metabolized such that only a small portion of GLP-1 is available to induce insulin secretion. To compensate for this, GLP-1 receptor (GLP-1R) agonists have been developed to enhance insulin secretion for the treatment of type II diabetes.
已批準用於治療II型糖尿病之大部分GLP-1R促效劑係可注射劑。患者通常偏好於經口投與之藥物,此乃因注射涉及諸多缺點,例如不方便、疼痛及可能之注射部位刺激性。Most of the GLP-1R agonists approved for the treatment of type II diabetes are injectables. Patients often prefer drugs that are administered orally because injection involves disadvantages such as inconvenience, pain and possible injection site irritation.
WO2018/109607揭示闡述為GLP-1R促效劑之某些苯并咪唑衍生物。其他GLP-1促效劑化合物揭示於WO2019/239371、WO2019/239319、WO2020/103815、WO2020/207474、WO2020/263695、WO2021/018023、WO2021/081207、WO2021/096284、WO2021/096304、WO2021/112538、WO2021/154796、WO2021/160127、WO2021/187886、WO2021/197464、CN113480534、WO2021/219019、WO2021/244645、WO2021/249492、CN113801136、WO2021/254470、WO2021/259309、WO2022/007979、WO2022/031994、WO2022/028572、WO2022/040600、WO2022/042691、WO2022/068772、WO2022/078407、WO2022/078380及WO2022/078152中。WO2018/109607 discloses certain benzimidazole derivatives described as GLP-1R agonists. Other GLP-1 agonist compounds are disclosed in WO2019/239371, WO2019/239319, WO2020/103815, WO2020/207474, WO2020/263695, WO2021/018023, WO2021/081207, WO2021/096284, 1038, WO2021/09252 WO2021/154796、WO2021/160127、WO2021/187886、WO2021/197464、CN113480534、WO2021/219019、WO2021/244645、WO2021/249492、CN113801136、WO2021/254470、WO2021/259309、WO2022/007979、WO2022/031994、WO2022/ 028572, WO2022/040600, WO2022/042691, WO2022/068772, WO2022/078407, WO2022/078380 and WO2022/078152.
然而,需要替代GLP-1R促效劑。特定而言,需要可經口投與之GLP-1R促效劑。尤其需要具有有益毒理特徵及/或支持每天一次之投藥之藥物動力學特徵之強效GLP-1R促效劑。However, alternative GLP-1R agonists are needed. In particular, there is a need for GLP-1R agonists that can be administered orally. In particular, there is a need for potent GLP-1R agonists with beneficial toxicological profiles and/or pharmacokinetic profiles that support once-daily dosing.
因此,本發明提供下式之化合物: 式IX 其中-A-係-CR aR bCR aR bCR bR bO-、-OCR bR bCR aR bCR aR b-、-OCR bR bCR bR bO-、-CR aR bCR bR bOCR bR b-、-CR bR bOCR bR bCR aR b-、-CR bR bOCR bR b-、-CR aR bCR bR bO-或-OCR bR bCR aR b-; R a在每次出現時獨立地係H、鹵基、C 1-C 2烷基、OH或C 1-C 3烷氧基; R b在每次出現時獨立地係H、鹵基或C 1-C 2烷基; 係 或 ,其中a係與連接體A之連接點;b係連接體B之連接點; X 1、X 2、X 3及X 4獨立地係N、CH或CR 1,其中X 1、X 2、X 3及X 4中之不超過兩者係N且X 1、X 2、X 3及X 4中之不超過兩者係CR 1; X 5係N、CH或CR 1a,X 6、X 7及X 8獨立地係N、CH或CR 1,其中X 5、X 6、X 7及X 8中之不超過兩者係N且X 5、X 6、X 7及X 8中之不超過兩者係CR 1a或CR 1; R 1在每次出現時獨立地係CN;鹵基;視情況經OH取代之C 1-C 3烷基;C 1-C 3鹵代烷基;C 1-C 3烷氧基;C 3-C 5環烷基;-SO 2C 1-C 3烷基; , 或 ,其中每一X 9獨立地係CH或N且環中不超過一個X 9係N,每一R e獨立地選自:H、C 1-C 3鹵代烷基、鹵基、C 3-C 5環烷基及視情況經OH取代之C 1-C 3烷基,R h係H、C 1-C 3鹵代烷基、鹵基、C 3-C 5環烷基、OH、-NR cR d或視情況經OH取代之C 1-C 3烷基; 5-或6員雜芳基或苯基,其中雜芳基或苯基視情況經一或兩個獨立地選自以下之取代基取代:C 1-C 3烷氧基、C 3-C 5環烷基、-CH 2-C 3-C 5環烷基、-SO 2C 1-C 3烷基、C 4-C 5雜環基、-CH 2-C 4-C 5雜環基、鹵基、C 1-C 3鹵代烷基、C 1-C 3鹵代烷氧基、CN、-CONR cR d、-NR cR d或視情況經OH取代之C 1-C 3烷基; R 1a係CN;鹵基;視情況經OH取代之C 1-C 3烷基;C 1-C 3鹵代烷基;或C 1-C 3烷氧基; -B-係-CH 2O-、-OCH 2-或-CH 2NH-; Y 1、Y 2及Y 7獨立地係N、CH或CR 2,其中Y 1、Y 2及Y 7中之不超過一者係N且Y 1、Y 2及Y 7中之不超過兩者係CR 2; Y 3、Y 4、Y 5及Y 6獨立地係N、CH或CR 2,其中Y 3、Y 4、Y 5及Y 6中之不超過兩者係N且Y 3、Y 4、Y 5及Y 6中之不超過兩者係CR 2; R 2在每次出現時獨立地係鹵基或甲基; Z 1、Z 2及Z 3獨立地係N、CH或CR 3,其中Z 1、Z 2及Z 3中之不超過兩者係N且Z 1、Z 2及Z 3中之不超過兩者係CR 3; R 3在每次出現時獨立地係鹵基;C 1-C 4烷基;-OC 4-C 6環烷基,其視情況經C 1-C 2烷氧基、OH、C 1-C 3烷基或C 1-C 3鹵代烷基取代;-OC 4-C 6雜環基,其視情況經C 1-C 2烷氧基、OH、C 1-C 3烷基或C 1-C 3鹵代烷基取代;或C 1-C 4烷氧基,其視情況經一或兩個選自以下之取代基取代:C 1-C 2烷氧基、OH、-NR fR g、-CONR cR d、CN、鹵基或視情況經C 1-C 3烷基取代之5-或6員雜芳基; R 4係 、 或 ; R 5係-CO 2H、 或 ; R c及R d各自獨立地係H或C 1-C 3烷基; R f係H或C 1-C 3烷基;且 R g係H、C 1-C 3烷基、C 1-C 3鹵代烷基、C 3-C 5環烷基、C(O)C 1-C 3烷基或C 1-C 3烷基C 3-C 5環烷基; 或其醫藥上可接受之鹽。 Accordingly, the present invention provides compounds of the formula: Formula IX wherein -A-is -CR a R b CR a R b CR b R b O-, -OCR b R b CR a R b CR a R b -, -OCR b R b CR b R b O-, -CR a R b CR b R b OCR b R b -, -CR b R b OCR b R b CR a R b -, -CR b R b OCR b R b -, -CR a R b CR b R b O- or -OCR b R b CR a R b -; R a independently at each occurrence is H, halo, C 1 -C 2 alkyl, OH or C 1 -C 3 alkoxy; R b independently at each occurrence is H, halo or C 1 -C 2 alkyl; Tie or , wherein a is the connection point with the linker A; b is the connection point of the linker B; X 1 , X 2 , X 3 and X 4 are independently N, CH or CR 1 , wherein X 1 , X 2 , X No more than two of 3 and X 4 are N and no more than two of X 1 , X 2 , X 3 and X 4 are CR 1 ; X 5 is N, CH or CR 1a , X 6 , X 7 and X 8 is independently N, CH or CR 1 , wherein not more than two of X 5 , X 6 , X 7 and X 8 are N and not more than two of X 5 , X 6 , X 7 and X 8 is CR 1a or CR 1 ; R 1 is independently in each occurrence CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 -C 3 haloalkyl; C 1 -C 3 alkane Oxygen; C 3 -C 5 cycloalkyl; -SO 2 C 1 -C 3 alkyl; , or , wherein each X 9 is independently CH or N and no more than one X 9 is N in the ring, and each R e is independently selected from: H, C 1 -C 3 haloalkyl, halo, C 3 -C 5 Cycloalkyl and C 1 -C 3 alkyl optionally substituted by OH, Rh is H, C 1 -C 3 haloalkyl, halo, C 3 -C 5 cycloalkyl, OH, -NR c R d or C 1 -C 3 alkyl optionally substituted by OH; 5- or 6-membered heteroaryl or phenyl, wherein heteroaryl or phenyl is optionally substituted by one or two substituents independently selected from : C 1 -C 3 alkoxy, C 3 -C 5 cycloalkyl, -CH 2 -C 3 -C 5 cycloalkyl, -SO 2 C 1 -C 3 alkyl, C 4 -C 5 heterocycle base, -CH 2 -C 4 -C 5 heterocyclyl, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, CN, -CONR c R d , -NR c R d or depending C 1 -C 3 alkyl optionally substituted by OH; R 1a is CN; halo; C 1 -C 3 alkyl optionally substituted by OH; C 1 -C 3 haloalkyl; or C 1 -C 3 alkane Oxygen; -B- is -CH 2 O-, -OCH 2 - or -CH 2 NH-; Y 1 , Y 2 and Y 7 are independently N, CH or CR 2 , wherein Y 1 , Y 2 and Y Not more than one of 7 is N and not more than two of Y 1 , Y 2 and Y 7 are CR 2 ; Y 3 , Y 4 , Y 5 and Y 6 are independently N, CH or CR 2 , wherein Not more than two of Y 3 , Y 4 , Y 5 and Y 6 are N and not more than two of Y 3 , Y 4 , Y 5 and Y 6 are CR 2 ; R 2 is independently at each occurrence is halo or methyl; Z 1 , Z 2 and Z 3 are independently N, CH or CR 3 , wherein not more than two of Z 1 , Z 2 and Z 3 are N and Z 1 , Z 2 and Z Not more than two of 3 are CR 3 ; R 3 independently at each occurrence is halo; C 1 -C 4 alkyl; -OC 4 -C 6 cycloalkyl, which is optionally modified by C 1 -C 2 alkoxy, OH, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; -OC 4 -C 6 heterocyclyl, optionally substituted by C 1 -C 2 alkoxy, OH, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; or C 1 -C 4 alkoxy, optionally substituted by one or two substituents selected from: C 1 -C 2 alkoxy , OH, -NR f R g , -CONR c R d , CN, halo or 5- or 6-membered heteroaryl optionally substituted by C 1 -C 3 alkyl; R 4 is , or ; R 5 series -CO 2 H, or ; R c and R d are each independently H or C 1 -C 3 alkyl; R f is H or C 1 -C 3 alkyl; and R g is H, C 1 -C 3 alkyl, C 1 - C 3 haloalkyl, C 3 -C 5 cycloalkyl, C(O)C 1 -C 3 alkyl or C 1 -C 3 alkyl C 3 -C 5 cycloalkyl; or a pharmaceutically acceptable salt thereof .
式IX包含所有個別對映異構體及其混合物以及外消旋物。Formula IX includes all individual enantiomers and their mixtures as well as racemates.
在一實施例中,提供下式之化合物: 式V 或其醫藥上可接受之鹽。 In one embodiment, compounds of the formula are provided: Formula V or a pharmaceutically acceptable salt thereof.
在一實施例中,提供下式之化合物: 式Va 或其醫藥上可接受之鹽。 In one embodiment, compounds of the formula are provided: Formula Va or a pharmaceutically acceptable salt thereof.
在一實施例中,提供下式之化合物: 式VI 或其醫藥上可接受之鹽。 In one embodiment, compounds of the formula are provided: Formula VI or a pharmaceutically acceptable salt thereof.
在式V、Va及VI之一實施例中,Y 4、Y 5、Y 6及Y 7皆係CH。 In one embodiment of formulas V, Va and VI, Y 4 , Y 5 , Y 6 and Y 7 are all CH.
在一實施例中, 係 。在一實施例中, 係 ;X 1、X 3及X 4係CH;且X 2係CR 1。在一替代實施例中, 係 ;X 1係N;X 2係CR 1;且X 3及X 4係CH。在另一替代實施例中, 係 ;X 1、X 3及X 4係CH;且X 2係N。在另一替代實施例中, 係 ;X 1及X 4係CH;X 2係CR 1;且X 3係N。在另一替代實施例中, 係 ;X 1及X 3係CH;X 2係CR 1;且X 4係N。在另一替代實施例中, 係 ;X 1及X 3係CH;且X 2及X 4係CR 1。 In one embodiment, Tie . In one embodiment, Tie ; X 1 , X 3 and X 4 are CH; and X 2 is CR 1 . In an alternate embodiment, Tie ; X 1 is N; X 2 is CR 1 ; and X 3 and X 4 are CH. In another alternative embodiment, Tie ; X 1 , X 3 and X 4 are CH; and X 2 is N. In another alternative embodiment, Tie ; X 1 and X 4 are CH; X 2 is CR 1 ; and X 3 is N. In another alternative embodiment, Tie ; X 1 and X 3 are CH; X 2 is CR 1 ; and X 4 is N. In another alternative embodiment, Tie ; X 1 and X 3 are CH; and X 2 and X 4 are CR 1 .
在一實施例中,X 1、X 2、X 3及X 4中之僅一者係N。 In one embodiment, only one of X 1 , X 2 , X 3 and X 4 is N.
在一替代實施例中, 係 。在一實施例中, 係 ;X 5、X 7及X 8係CH;且X 6係CR 1。在一替代實施例中, 係 ;X 5係N;X 6係CR 1;且 X7及X 8係CH。 In an alternate embodiment, Tie . In one embodiment, Tie ; X 5 , X 7 and X 8 are CH; and X 6 is CR 1 . In an alternate embodiment, Tie ; X5 is N; X6 is CR1 ; and X7 and X8 are CH.
在一實施例中,X 5、X 6、X 7及X 8中之僅一者係N。 In one embodiment, only one of X 5 , X 6 , X 7 and X 8 is N.
在一實施例中,R 1係CN;鹵基;視情況經OH取代之C 1-C 3烷基;C 1-C 3鹵代烷基; 或 ,其中每一R e獨立地選自:H、C 1-C 3烷基或鹵基,且R h係H或鹵基; 5-或6員雜芳基或苯基,其中雜芳基或苯基視情況經一個選自以下之取代基取代:C 1-C 3烷氧基、C 3-C 5環烷基、-SO 2C 1-C 3烷基、C 4-C 5雜環基、-CH 2-C 4-C 5雜環基、鹵基、-CONR cR d、-NR cR d或視情況經OH取代之C 1-C 3烷基,其中R c及R d各自獨立地係H或C 1-C 3烷基。 In one embodiment, R is CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 -C 3 haloalkyl; or , wherein each R e is independently selected from: H, C 1 -C 3 alkyl or halo, and Rh is H or halo; 5- or 6-membered heteroaryl or phenyl, wherein heteroaryl or Phenyl is optionally substituted with one substituent selected from: C 1 -C 3 alkoxy, C 3 -C 5 cycloalkyl, -SO 2 C 1 -C 3 alkyl, C 4 -C 5 heterocycle -CH 2 -C 4 -C 5 heterocyclyl, halo, -CONR c R d , -NR c R d or optionally OH substituted C 1 -C 3 alkyl, wherein R c and R d Each is independently H or C 1 -C 3 alkyl.
在一實施例中,R 1係CN、鹵基、CF 3、-CH 2OH、 或 。較佳地,R 1係CN、Cl、F、CF 3、 或 。在一實施例中,R 1係CN;鹵基;視情況經OH取代之C 1-C 3烷基;C 1-C 3鹵代烷基; ,其中每一R e獨立地選自:H或C 1-C 3烷基;5-或6員雜芳基或苯基,其中雜芳基或苯基視情況經一個選自以下之取代基取代:C 1-C 3烷氧基、C 3-C 5環烷基、-SO 2C 1-C 3烷基、-CH 2-C 4-C 5雜環基、-CONR cR d或視情況經OH取代之C 1-C 3烷基,其中R c及R d各自獨立地係H或C 1-C 3烷基。在一實施例中,R 1係CN、鹵基、CF 3、-CH 2OH、 或 。較佳地,R 1係CN、Cl、F、CF 3、 或 。在另一實施例中,R 1係CN、鹵基、C 1-C 3烷基或C 1-C 3鹵代烷基。在一實施例中,R 1係CN、鹵基或CF 3。在一實施例中,R 1係CN或鹵基。 In one embodiment, R 1 is CN, halo, CF 3 , -CH 2 OH, or . Preferably, R 1 is CN, Cl, F, CF 3 , or . In one embodiment, R is CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 -C 3 haloalkyl; , wherein each R e is independently selected from: H or C 1 -C 3 alkyl; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl optionally undergoes a substituent selected from Substitution: C 1 -C 3 alkoxy, C 3 -C 5 cycloalkyl, -SO 2 C 1 -C 3 alkyl, -CH 2 -C 4 -C 5 heterocyclyl, -CONR c R d or Optionally OH substituted C 1 -C 3 alkyl, wherein R c and R d are each independently H or C 1 -C 3 alkyl. In one embodiment, R 1 is CN, halo, CF 3 , -CH 2 OH, or . Preferably, R 1 is CN, Cl, F, CF 3 , or . In another embodiment, R 1 is CN, halo, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In one embodiment, R 1 is CN, halo or CF 3 . In one embodiment, R 1 is CN or halo.
在一實施例中, 係 ;X 1、X 3及X 4係CH;X 2係CR 1;且R 1係CN;鹵基;視情況經OH取代之C 1-C 3烷基;C 1-C 3鹵代烷基; 或 ,其中每一R e獨立地選自:H、C 1-C 3烷基或鹵基,且R h係H或鹵基; 5-或6員雜芳基或苯基,其中雜芳基或苯基視情況經一個選自以下之取代基取代:C 1-C 3烷氧基、C 3-C 5環烷基、-SO 2C 1-C 3烷基、C 4-C 5雜環基、-CH 2-C 4-C 5雜環基、鹵基、-CONR cR d、-NR cR d或視情況經OH取代之C 1-C 3烷基,其中R c及R d各自獨立地係H或C 1-C 3烷基。較佳地,R 1係CN、鹵基、CF 3、-CH 2OH、 或 。更佳地,R 1係CN、Cl、F、CF 3、 或 。 In one embodiment, Tie ; X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is CN; halo; optionally OH-substituted C 1 -C 3 alkyl; C 1 -C 3 haloalkyl; or , wherein each R e is independently selected from: H, C 1 -C 3 alkyl or halo, and Rh is H or halo; 5- or 6-membered heteroaryl or phenyl, wherein heteroaryl or Phenyl is optionally substituted with one substituent selected from: C 1 -C 3 alkoxy, C 3 -C 5 cycloalkyl, -SO 2 C 1 -C 3 alkyl, C 4 -C 5 heterocycle -CH 2 -C 4 -C 5 heterocyclyl, halo, -CONR c R d , -NR c R d or optionally OH substituted C 1 -C 3 alkyl, wherein R c and R d Each is independently H or C 1 -C 3 alkyl. Preferably, R 1 is CN, halo, CF 3 , -CH 2 OH, or . More preferably, R 1 is CN, Cl, F, CF 3 , or .
在一實施例中, 係 ;X 1、X 3及X 4係CH;X 2係CR 1;且R 1係CN;鹵基;視情況經OH取代之C 1-C 3烷基;C 1-C 3鹵代烷基; ,其中每一R e獨立地選自:H或C 1-C 3烷基;5-或6員雜芳基或苯基,其中雜芳基或苯基視情況經一個選自以下之取代基取代:C 1-C 3烷氧基、C 3-C 5環烷基、-SO 2C 1-C 3烷基、-CH 2-C 4-C 5雜環基、-CONR cR d或視情況經OH取代之C 1-C 3烷基,其中R c及R d各自獨立地係H或C 1-C 3烷基。較佳地,R 1係CN、鹵基、CF 3、-CH 2OH、 或 。更佳地,R 1係CN、Cl、F、CF 3、 或 。在另一實施例中,X 1、X 3及X 4係CH;X 2係CR 1;且R 1係CN。在另一實施例中,X 1、X 3及X 4係CH;X 2係CR 1;且R 1係Cl。在另一實施例中,X 1、X 3及X 4係CH;X 2係CR 1;且R 1係CF 3。 In one embodiment, Tie ; X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is CN; halo; optionally OH-substituted C 1 -C 3 alkyl; C 1 -C 3 haloalkyl; , wherein each R e is independently selected from: H or C 1 -C 3 alkyl; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl optionally undergoes a substituent selected from Substitution: C 1 -C 3 alkoxy, C 3 -C 5 cycloalkyl, -SO 2 C 1 -C 3 alkyl, -CH 2 -C 4 -C 5 heterocyclyl, -CONR c R d or Optionally OH substituted C 1 -C 3 alkyl, wherein R c and R d are each independently H or C 1 -C 3 alkyl. Preferably, R 1 is CN, halo, CF 3 , -CH 2 OH, or . More preferably, R 1 is CN, Cl, F, CF 3 , or . In another embodiment, X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is CN. In another embodiment, X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is Cl. In another embodiment, X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is CF 3 .
在一替代實施例中, 係 ;X 1係N;X 2係CR 1;X 3及X 4係CH;且R 1係CF 3。 In an alternate embodiment, Tie ; X 1 is N; X 2 is CR 1 ; X 3 and X 4 are CH; and R 1 is CF 3 .
在一替代實施例中, 係 ;X 1及X 4係CH;X 2係CR 1;X 3係N;且R 1係CF 3。 In an alternate embodiment, Tie ; X 1 and X 4 are CH; X 2 is CR 1 ; X 3 is N; and R 1 is CF 3 .
在一替代實施例中, 係 ;X 1及X 3係CH;X 2係CR 1;X 4係N;且R 1係CN。 In an alternate embodiment, Tie ; X 1 and X 3 are CH; X 2 is CR 1 ; X 4 is N; and R 1 is CN.
在一替代實施例中, 係 ;X 1及X 3係CH;X 2及X 4係CR 1;且每一R 1獨立地選自鹵基及CN。較佳地,每一R 1獨立地選自F、Cl及CN。 In an alternate embodiment, Tie ; X 1 and X 3 are CH; X 2 and X 4 are CR 1 ; and each R 1 is independently selected from halo and CN. Preferably, each R 1 is independently selected from F, Cl and CN.
在一替代實施例中, 係 ;X 5、X 7及X 8係CH;X 6係CR 1;且R 1係CN或Cl。特定地,R 1係CN。 In an alternate embodiment, Tie ; X 5 , X 7 and X 8 are CH; X 6 is CR 1 ; and R 1 is CN or Cl. Specifically, R 1 is CN.
在一替代實施例中, 係 ;X 5係N;X 6係CR 1;X 7及X 8係CH;且R 1係CN。 In an alternate embodiment, Tie ; X 5 is N; X 6 is CR 1 ; X 7 and X 8 are CH; and R 1 is CN.
在一實施例中,-A-係-CH 2CH 2CH 2O-、-OCH 2CH 2O-、-CH 2CH 2OCH 2-、-CH 2OCH 2CH 2-、-CH 2OCH 2-、-CH 2CH 2O-、-OCH 2CH 2-或-CF 2CH 2OCH 2-。在一特定實施例中,-A-係-CH 2CH 2CH 2O-、-CH 2OCH 2-、-CH 2CH 2OCH 2-、CH 2OCH 2CH 2-或-CF 2CH 2OCH 2-。 In one embodiment, -A- is -CH 2 CH 2 CH 2 O-, -OCH 2 CH 2 O-, -CH 2 CH 2 OCH 2 -, -CH 2 OCH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 CH 2 O-, -OCH 2 CH 2 -, or -CF 2 CH 2 OCH 2 -. In a particular embodiment, -A- is -CH 2 CH 2 CH 2 O-, -CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 -, CH 2 OCH 2 CH 2 -, or -CF 2 CH 2 OCH 2 -.
在一實施例中,-A-係-CHR aCHR aCHR bO-、-CHR bOCHR b-或-OCHR bCHR bO-。在另一實施例中,-A-係-CHR aCHR aCHR bO-。在一特定實施例中,-A-係-CHR aCHR aCHR bO-且每一R a及R b係H。在一替代實施例中,-A-係-CHR bOCHR b-。在一特定實施例中,-A-係-CHR bOCHR b-且每一R b係H。在一替代實施例中,-A-係-OCHR bCHR bO-。在一特定實施例中,-A-係-OCHR bCHR bO-且每一R b係H。在一特定實施例中,-A-係-CH 2CH 2CH 2O-、-OCH 2CH 2O-、-CH 2CH 2OCH 2-、-CH 2OCH 2-或-CH 2CH 2O-;較佳地,A-係-CH 2CH 2CH 2O-或-CH 2OCH 2-。 In one embodiment, -A- is -CHR a CHR a CHR b O-, -CHR b OCHR b - or -OCHR b CHR b O-. In another embodiment, -A- is -CHR a CHR a CHR b O-. In a particular embodiment, -A- is -CHR a CHR a CHR b O- and each of R a and R b is H. In an alternative embodiment, -A- is -CHRbOCHRb- . In a particular embodiment , -A- is -CHRbOCHRb- and each Rb is H. In an alternative embodiment, -A- is -OCHR b CHR b O-. In a particular embodiment , -A- is -OCHRbCHRbO- and each Rb is H. In a particular embodiment, -A- is -CH 2 CH 2 CH 2 O-, -OCH 2 CH 2 O-, -CH 2 CH 2 OCH 2 -, -CH 2 OCH 2 - or -CH 2 CH 2 O-; preferably, A- is -CH 2 CH 2 CH 2 O- or -CH 2 OCH 2 -.
在一實施例中,-B-係-CH 2O-或-CH 2NH-。在一替代實施例中,B係-CH 2O-或-OCH 2-。在另一實施例中,-B-係-CH 2O-。 In one embodiment, -B- is -CH 2 O- or -CH 2 NH-. In an alternative embodiment, B is -CH2O- or -OCH2- . In another embodiment, -B- is -CH2O- .
在一實施例中,Y 3係N或CH。在一實施例中,Y 3係N。在一替代實施例中,Y 3係CH。 In one embodiment, Y3 is N or CH. In one embodiment, Y3 is N. In an alternative embodiment, Y3 is CH.
在一實施例中,Y 4係CH。 In one embodiment, Y4 is CH.
在一實施例中,Y 5係CH。 In one embodiment, Y5 is CH.
在一實施例中,Y 6係CH或CR 2。 In one embodiment, Y 6 is CH or CR 2 .
在一實施例中,Y 3係N;且Y 4、Y 5係CH;且Y 6係CH或CR 2。在另一實施例中,Y 3係N;且Y 4、Y 5係CH;且Y 6係CH。在又一實施例中,Y 3係N;且Y 4、Y 5係CH;且Y 6係CR 2,較佳地,R 2係F。在一替代實施例中,Y 3、Y 4、Y 5及Y 6皆係CH。在另一替代實施例中,Y 3及Y 6係N;且Y 4及Y 5係CH。 In one embodiment, Y 3 is N; and Y 4 and Y 5 are CH; and Y 6 is CH or CR 2 . In another embodiment, Y 3 is N; and Y 4 , Y 5 are CH; and Y 6 is CH. In yet another embodiment, Y 3 is N; and Y 4 and Y 5 are CH; and Y 6 is CR 2 , preferably, R 2 is F. In an alternative embodiment, Y3 , Y4 , Y5 and Y6 are all CH. In another alternative embodiment, Y3 and Y6 are N; and Y4 and Y5 are CH.
在一實施例中,Y 1係CH或CR 2。 In one embodiment, Y 1 is CH or CR 2 .
在一實施例中,Y 2係CH。 In one embodiment, Y2 is CH.
在一實施例中,Y 7係CH。 In one embodiment, Y7 is CH.
在一實施例中,R 2係F或甲基。 In one embodiment, R 2 is F or methyl.
在一實施例中,Y 1、Y 2及Y 7皆係CH。在一替代實施例中,Y 1係CR 2;Y 2係CH;Y 7係CH;且R 2係F。在另一替代實施例中,Y 1係CR 2;Y 2係CH;Y 7係CH;且R 2係甲基。 In one embodiment, Y 1 , Y 2 and Y 7 are all CH. In an alternative embodiment, Y1 is CR2 ; Y2 is CH; Y7 is CH; and R2 is F. In another alternative embodiment, Y1 is CR2 ; Y2 is CH; Y7 is CH; and R2 is methyl.
在一實施例中,Y 1及Y 2皆係CH。在一替代實施例中,Y 1係CR 2,Y 2係CH且R 2係F。在另一替代實施例中,Y 1係CR 2,Y 2係CH且R 2係甲基。 In one embodiment, both Y1 and Y2 are CH. In an alternative embodiment, Y1 is CR2 , Y2 is CH and R2 is F. In another alternative embodiment, Y1 is CR2 , Y2 is CH and R2 is methyl.
在一實施例中,Y 4、Y 5、Y 6及Y 7皆係CH。 In one embodiment, Y 4 , Y 5 , Y 6 and Y 7 are all CH.
在一實施例中,Z 1係CH或CR 3。 In one embodiment, Z 1 is CH or CR 3 .
在一實施例中,Z 2係CH。 In one embodiment, Z 2 is CH.
在一實施例中,Z 3係CH。在一替代實施例中,Z 3係N。 In one embodiment, Z3 is CH. In an alternative embodiment, Z3 is N.
在一特定實施例中,Z 2及Z 3皆係CH。 In a particular embodiment, both Z2 and Z3 are CH.
在一實施例中,R 3係鹵基;-OC 4-C 6雜環基,其視情況經C 1-C 3烷基取代 ;或C 1-C 4烷氧基,其視情況經一或兩個選自以下之取代基取代:C 1-C 2烷氧基、OH、-NR fR g、-CONR cR d或視情況經C 1-C 3烷基取代之5-或6員雜芳基;其中R c及R d各自獨立地係H或C 1-C 3烷基,R f係H或C 1-C 3烷基,且R g係H、C 1-C 3烷基或C 1-C 3鹵代烷基。在一特定實施例中,R 3係鹵基或視情況經一或兩個選自以下之取代基取代之C 1-C 4烷氧基:C 1-C 2烷氧基、OH或-NR fR g,其中R f及R g皆係CH 3;較佳地,R 3係F、-OCH 3、-OCH 2CH 2OCH 3、OCH 2CH 2OH或OCH 2CH 2N(CH 3) 2。 In one embodiment, R 3 is halo; -OC 4 -C 6 heterocyclyl, which is optionally substituted by C 1 -C 3 alkyl; or C 1 -C 4 alkoxy, which is optionally substituted by a Or substituted by two substituents selected from: C 1 -C 2 alkoxy, OH, -NR f R g , -CONR c R d or 5- or 6 optionally substituted by C 1 -C 3 alkyl Member heteroaryl; wherein R c and R d are each independently H or C 1 -C 3 alkyl, R f is H or C 1 -C 3 alkyl, and R g is H, C 1 -C 3 alkane group or C 1 -C 3 haloalkyl. In a specific embodiment, R 3 is halo or C 1 -C 4 alkoxy optionally substituted with one or two substituents selected from: C 1 -C 2 alkoxy, OH or -NR f R g , wherein both R f and R g are CH 3 ; preferably, R 3 is F, -OCH 3 , -OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 ) 2 .
在一實施例中,R 3係鹵基、C 1-C 4烷氧基或-C 1-C 3烷氧基C 1-C 2烷氧基;較佳地,R 3係F、-OCH 3或-OCH 2CH 2OCH 3。在一替代實施例中,R 3係鹵基、C 1-C 2烷基或甲氧基。 In one embodiment, R 3 is halogen, C 1 -C 4 alkoxy or -C 1 -C 3 alkoxy C 1 -C 2 alkoxy; preferably, R 3 is F, -OCH 3 or -OCH2CH2OCH3 . In an alternative embodiment, R 3 is halo, C 1 -C 2 alkyl or methoxy.
在一實施例中,Z 1係CR 3且R 3係鹵基;-OC 4-C 6雜環基,其視情況經C 1-C 3烷基取代;或C 1-C 4烷氧基,其視情況經一或兩個選自以下之取代基取代:C 1-C 2烷氧基、OH、-NR fR g、-CONR cR d或視情況經C 1-C 3烷基取代之5-或6員雜芳基;其中R c及R d各自獨立地係H或C 1-C 3烷基,R f係H或C 1-C 3烷基,且R g係H、C 1-C 3烷基或C 1-C 3鹵代烷基。在另一實施例中,Z 1係CR 3且R 3係鹵基或視情況經一或兩個選自以下之取代基取代之C 1-C 4烷氧基:C 1-C 2烷氧基、OH或-NR fR g,其中R f及R g皆係CH 3;較佳地,R 3係F、-OCH 3、-OCH 2CH 2OCH 3、OCH 2CH 2OH或OCH 2CH 2N(CH 3) 2。在一實施例中,Z 1係CR 3且R 3係F。在一替代實施例中,Z 1係CH。在另一替代實施例中,Z 1係CR 3且R 3係甲氧基。 In one embodiment, Z 1 is CR 3 and R 3 is halo; -OC 4 -C 6 heterocyclyl, optionally substituted by C 1 -C 3 alkyl; or C 1 -C 4 alkoxy , which is optionally substituted by one or two substituents selected from C 1 -C 2 alkoxy, OH, -NR f R g , -CONR c R d or optionally by C 1 -C 3 alkyl Substituted 5- or 6-membered heteroaryl; wherein R c and R d are each independently H or C 1 -C 3 alkyl, R f is H or C 1 -C 3 alkyl, and R g is H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In another embodiment, Z 1 is CR 3 and R 3 is halo or C 1 -C 4 alkoxy optionally substituted with one or two substituents selected from: C 1 -C 2 alkoxy Group, OH or -NR f R g , wherein both R f and R g are CH 3 ; preferably, R 3 is F, -OCH 3 , -OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH or OCH 2 CH2N ( CH3 ) 2 . In one embodiment, Z 1 is CR 3 and R 3 is F. In an alternative embodiment, Z is CH. In another alternative embodiment, Z1 is CR3 and R3 is methoxy.
在一實施例中,R 5係-CO 2H。在一替代實施例中,R 5係 。 In one embodiment, R 5 is -CO 2 H. In an alternative embodiment, R is .
在一實施例中,提供下式之化合物: 式VIII 其中-A-係-CH 2CH 2CH 2O-、-OCH 2CH 2O-、-CH 2CH 2OCH 2-、-CH 2OCH 2CH 2-、-CH 2OCH 2-、-CH 2CH 2O-、-OCH 2CH 2-或-CF 2CH 2OCH 2-; 係 或 ,其中a係與連接體A之連接點;b係連接體B之連接點; X 1、X 2、X 3及X 4獨立地係N、CH或CR 1,其中X 1、X 2、X 3及X 4中之不超過一者係N且X 1、X 2、X 3及X 4中之不超過兩者係CR 1; X 5係N或CH,X 6、X 7及X 8獨立地係N、CH或CR 1,其中X 5、X 6、X 7及X 8中之不超過一者係N且X 6、X 7及X 8中之不超過一者係CR 1; R 1在每次出現時獨立地係CN;鹵基;視情況經OH取代之C 1-C 3烷基;C 1-C 3鹵代烷基; 或 ,其中每一R e獨立地選自:H、C 1-C 3烷基或鹵基,且R h係H或鹵基; 5-或6員雜芳基或苯基,其中雜芳基或苯基視情況經一個選自以下之取代基取代:C 1-C 3烷氧基、C 3-C 5環烷基、-SO 2C 1-C 3烷基、C 4-C 5雜環基、-CH 2-C 4-C 5雜環基、鹵基、-CONR cR d、-NR cR d或視情況經OH取代之C 1-C 3烷基; -B-係-CH 2O-或-CH 2NH-; Y 1係CH或CR 2; Y 3係N或CH; Y 6係N、CH或CR 2; R 2在每次出現時獨立地係鹵基或甲基; Z 1係CH或CR 3; Z 3係N或CH; R 3係鹵基;-OC 4-C 6雜環基,其視情況經C 1-C 3烷基取代;或C 1-C 4烷氧基,其視情況經一或兩個選自以下之取代基取代:C 1-C 2烷氧基、OH、-NR fR g、-CONR cR d或視情況經C 1-C 3烷基取代之5-或6員雜芳基; R 4係 或 ; R 5係-CO 2H、 或 ; R c及R d各自獨立地係H或C 1-C 3烷基; R f係H或C 1-C 3烷基;且 R g係H、C 1-C 3烷基或C 1-C 3鹵代烷基; 或其醫藥上可接受之鹽。 In one embodiment, compounds of the formula are provided: Formula VIII where -A- is -CH 2 CH 2 CH 2 O-, -OCH 2 CH 2 O-, -CH 2 CH 2 OCH 2 -, -CH 2 OCH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 CH 2 O-, -OCH 2 CH 2 - or -CF 2 CH 2 OCH 2 -; Tie or , wherein a is the connection point with the linker A; b is the connection point of the linker B; X 1 , X 2 , X 3 and X 4 are independently N, CH or CR 1 , wherein X 1 , X 2 , X No more than one of 3 and X 4 is N and no more than two of X 1 , X 2 , X 3 and X 4 are CR 1 ; X 5 is N or CH, X 6 , X 7 and X 8 are independent It is N, CH or CR 1 , wherein not more than one of X 5 , X 6 , X 7 and X 8 is N and not more than one of X 6 , X 7 and X 8 is CR 1 ; R 1 independently at each occurrence is CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 -C 3 haloalkyl; or , wherein each R e is independently selected from: H, C 1 -C 3 alkyl or halo, and Rh is H or halo; 5- or 6-membered heteroaryl or phenyl, wherein heteroaryl or Phenyl is optionally substituted with one substituent selected from: C 1 -C 3 alkoxy, C 3 -C 5 cycloalkyl, -SO 2 C 1 -C 3 alkyl, C 4 -C 5 heterocycle -CH 2 -C 4 -C 5 heterocyclyl, halo, -CONR c R d , -NR c R d or C 1 -C 3 alkyl substituted by OH as appropriate; -B- is -CH 2 O- or -CH 2 NH-; Y 1 is CH or CR 2 ; Y 3 is N or CH; Y 6 is N, CH or CR 2 ; R 2 is independently halo or methyl at each occurrence ; Z 1 is CH or CR 3 ; Z 3 is N or CH; R 3 is halo; -OC 4 -C 6 heterocyclyl, which is optionally substituted by C 1 -C 3 alkyl; or C 1 -C 4 alkoxy, which is optionally substituted by one or two substituents selected from the group consisting of C 1 -C 2 alkoxy, OH, -NR f R g , -CONR c R d or optionally by C 1 - 5- or 6-membered heteroaryl substituted by C 3 alkyl; R 4 or ; R 5 series -CO 2 H, or ; R c and R d are each independently H or C 1 -C 3 alkyl; R f is H or C 1 -C 3 alkyl; and R g is H, C 1 -C 3 alkyl or C 1 - C 3 haloalkyl; or a pharmaceutically acceptable salt thereof.
在式VIII之一實施例中,-A-係-CH 2CH 2CH 2O-、-CH 2OCH 2-、-CH 2CH 2OCH 2-、CH 2OCH 2CH 2-或-CF 2CH 2OCH 2-。 In one embodiment of formula VIII, -A- is -CH 2 CH 2 CH 2 O-, -CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 -, CH 2 OCH 2 CH 2 - or -CF 2 CH2OCH2- .
在式VIII之一實施例中, 係 ;X 1、X 3及X 4係CH;且X 2係CR 1。在式VIII之一替代實施例中, 係 ;X 1係N;X 2係CR 1;且X 3及X 4係CH。在式VIII之另一替代實施例中, 係 ;X 1、X 3及X 4係CH;且X 2係N。在式VIII之另一替代實施例中, 係 ;X 1及X 4係CH;X 2係CR 1;且X 3係N。在式VIII之另一替代實施例中, 係 ;X 1及X 3係CH;X 2係CR 1;且X 4係N。在式VIII之另一替代實施例中, 係 ;X 1及X 3係CH;且X 2及X 4係CR 1。 In one embodiment of formula VIII, Tie ; X 1 , X 3 and X 4 are CH; and X 2 is CR 1 . In an alternative embodiment of Formula VIII, Tie ; X 1 is N; X 2 is CR 1 ; and X 3 and X 4 are CH. In another alternative embodiment of Formula VIII, Tie ; X 1 , X 3 and X 4 are CH; and X 2 is N. In another alternative embodiment of Formula VIII, Tie ; X 1 and X 4 are CH; X 2 is CR 1 ; and X 3 is N. In another alternative embodiment of Formula VIII, Tie ; X 1 and X 3 are CH; X 2 is CR 1 ; and X 4 is N. In another alternative embodiment of Formula VIII, Tie ; X 1 and X 3 are CH; and X 2 and X 4 are CR 1 .
在式VIII之一實施例中, 係 ;X 5、X 7及X 8係CH;且X 6係CR 1。在式VIII之一替代實施例中, 係 ;X 5係N;X 6係CR 1;且X 7及X 8係CH。 In one embodiment of formula VIII, Tie ; X 5 , X 7 and X 8 are CH; and X 6 is CR 1 . In an alternative embodiment of Formula VIII, Tie ; X 5 is N; X 6 is CR 1 ; and X 7 and X 8 are CH.
在式VIII之一實施例中,R 1係CN、鹵基、CF 3、-CH 2OH、 或 。較佳地,R 1係CN、Cl、F、CF 3、 或 。 In one embodiment of formula VIII, R 1 is CN, halo, CF 3 , -CH 2 OH, or . Preferably, R 1 is CN, Cl, F, CF 3 , or .
在式VIII之一實施例中, 係 ;X 1、X 3及X 4係CH;X 2係CR 1;且R 1係CN、鹵基、CF 3、-CH 2OH、 或 。較佳地,R 1係CN、Cl、F、CF 3、 或 。 In one embodiment of formula VIII, Tie ; X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is CN, halo, CF 3 , -CH 2 OH, or . Preferably, R 1 is CN, Cl, F, CF 3 , or .
在式VIII之一替代實施例中, 係 ;X 1係N;X 2係CR 1;X 3及X 4係CH;且R 1係CF 3。 In an alternative embodiment of Formula VIII, Tie ; X 1 is N; X 2 is CR 1 ; X 3 and X 4 are CH; and R 1 is CF 3 .
在式VIII之一替代實施例中, 係 ;X 1、X 3及X 4係CH,且X 2係N。 In an alternative embodiment of Formula VIII, Tie ; X 1 , X 3 and X 4 are CH, and X 2 is N.
在式VIII之一替代實施例中, 係 ;X 1及X 4係CH;X 2係CR 1;X 3係N;且R 1係CF 3。 In an alternative embodiment of Formula VIII, Tie ; X 1 and X 4 are CH; X 2 is CR 1 ; X 3 is N; and R 1 is CF 3 .
在式VIII之一替代實施例中, 係 ;X 1及X 3係CH;X 2係CR 1;X 4係N;且R 1係CN。 In an alternative embodiment of Formula VIII, Tie ; X 1 and X 3 are CH; X 2 is CR 1 ; X 4 is N; and R 1 is CN.
在式VIII之一替代實施例中, 係 ;X 1及X 3係CH;X 2及X 4係CR 1;且每一R 1獨立地選自鹵基及CN。較佳地,每一R 1獨立地選自F、Cl及CN。 In an alternative embodiment of Formula VIII, Tie ; X 1 and X 3 are CH; X 2 and X 4 are CR 1 ; and each R 1 is independently selected from halo and CN. Preferably, each R 1 is independently selected from F, Cl and CN.
在式VIII之一替代實施例中, 係 ;X 5、X 7及X 8係CH;X 6係CR 1;且R 1係CN或Cl。特定地,R 1係CN。 In an alternative embodiment of Formula VIII, Tie ; X 5 , X 7 and X 8 are CH; X 6 is CR 1 ; and R 1 is CN or Cl. Specifically, R 1 is CN.
在式VIII之一替代實施例中, 係 ;X 5係N;X 6係CR 1;X 7及X 8係CH;且R 1係CN。 In an alternative embodiment of Formula VIII, Tie ; X 5 is N; X 6 is CR 1 ; X 7 and X 8 are CH; and R 1 is CN.
在式VIII之一實施例中,-B-係-CH 2O-。 In one embodiment of formula VIII, -B- is -CH 2 O-.
在式VIII之一實施例中,Y 6係CH或CR 2。 In one embodiment of formula VIII, Y 6 is CH or CR 2 .
在式VIII之一實施例中,R 2係F或甲基。 In one embodiment of formula VIII, R 2 is F or methyl.
在式VIII之一實施例中,Y 3係N且Y 6係CH或CR 2。在式VIII之另一實施例中,Y 3係N且Y 6係CH。在又一實施例中,Y 3係N且Y 6係CR 2,較佳地,R 2係F。在一替代實施例中,Y 3及Y 6皆係CH。在另一替代實施例中,Y 3及Y 6皆係N。 In one embodiment of formula VIII, Y3 is N and Y6 is CH or CR2 . In another embodiment of Formula VIII, Y3 is N and Y6 is CH. In yet another embodiment, Y 3 is N and Y 6 is CR 2 , preferably, R 2 is F. In an alternative embodiment, both Y3 and Y6 are CH. In another alternative embodiment, both Y3 and Y6 are N.
在式VIII之一實施例中,Z 3係CH。 In one embodiment of Formula VIII, Z 3 is CH.
在式VIII之一實施例中,R 3係鹵基或視情況經一或兩個選自以下之取代基取代之C 1-C 4烷氧基:C 1-C 2烷氧基、OH或-NR fR g,其中R f及R g皆係CH 3;較佳地,R 3係F、-OCH 3、-OCH 2CH 2OCH 3、OCH 2CH 2OH或OCH 2CH 2N(CH 3) 2。 In one embodiment of formula VIII, R 3 is halo or C 1 -C 4 alkoxy optionally substituted by one or two substituents selected from: C 1 -C 2 alkoxy, OH or -NR f R g , wherein both R f and R g are CH 3 ; preferably, R 3 is F, -OCH 3 , -OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH or OCH 2 CH 2 N( CH 3 ) 2 .
在式VIII之一實施例中,R 4係 或 。 In one embodiment of formula VIII, R is or .
某些式VIII化合物具有下列特徵: i. -A-係-CH 2CH 2CH 2O-、-CH 2OCH 2-、-CH 2CH 2OCH 2-、CH 2OCH 2CH 2-或-CF 2CH 2OCH 2-; ii. 係 其中X 1、X 3及X 4係CH,X 2係CR 1,且R 1係CN、Cl、F、CF 3、 或 ;或其中X 1係N,X 2係CR 1,X 3及X 4係CH,且R 1係CF 3;或其中X 1、X 3及X 4係CH,且X 2係N;或其中X 1及X 4係CH,X 2係CR 1,X 3係N且R 1係CF 3;或其中X 1及X 3係CH,X 2係CR 1,X 4係N且R 1係CN;或其中X 1及X 3係CH,X 2及X 4係CR 1,且每一R 1獨立地選自F、Cl及CN; 或 係 ,其中X 5、X 7及X 8係CH,X 6係CR 1,且R 1係CN或Cl;或其中X 5係N,X 6係CR 1,X 7及X 8係CH,且R 1係CN; iii. -B-係-CH 2O-; iv. Y 1係CH或CR 2,且R 2係F或甲基; v. Y 6係CH或CR 2,且R 2係F; vi. Z 3係CH; vii. Z 1係CH或CR 3,且R 3係F、-OCH 3、-OCH 2CH 2OCH 3、OCH 2CH 2OH或OCH 2CH 2N(CH 3) 2;且 viii. R 4係 或 。 Certain compounds of formula VIII have the following characteristics: i. -A- is -CH 2 CH 2 CH 2 O-, -CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 -, CH 2 OCH 2 CH 2 -or- CF2CH2OCH2- ; ii . Tie Wherein X 1 , X 3 and X 4 are CH, X 2 is CR 1 , and R 1 is CN, Cl, F, CF 3 , or or wherein X 1 is N, X 2 is CR 1 , X 3 and X 4 are CH, and R 1 is CF 3 ; or wherein X 1 , X 3 and X 4 are CH, and X 2 is N; or wherein X 1 and X 4 are CH, X 2 is CR 1 , X 3 is N and R 1 is CF 3 ; or wherein X 1 and X 3 are CH, X 2 is CR 1 , X 4 is N and R 1 is CN or wherein X 1 and X 3 are CH, X 2 and X 4 are CR 1 , and each R 1 is independently selected from F, Cl and CN; or Tie , wherein X 5 , X 7 and X 8 are CH, X 6 is CR 1 , and R 1 is CN or Cl; or wherein X 5 is N, X 6 is CR 1 , X 7 and X 8 are CH, and R 1 is CN; iii. -B- is -CH 2 O-; iv. Y 1 is CH or CR 2 , and R 2 is F or methyl; v. Y 6 is CH or CR 2 , and R 2 is F vi. Z 3 is CH; vii. Z 1 is CH or CR 3 , and R 3 is F, -OCH 3 , -OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 ) 2 ; and viii. R 4 series or .
在一實施例中,提供下式之化合物: 式VII 或其醫藥上可接受之鹽。 In one embodiment, compounds of the formula are provided: Formula VII or a pharmaceutically acceptable salt thereof.
在一較佳實施例中,提供下式之化合物: 式VIIa 或其醫藥上可接受之鹽。 In a preferred embodiment, a compound of the following formula is provided: Formula VIIa or a pharmaceutically acceptable salt thereof.
在式VII及VIIa之一實施例中,X 2係CR 1且R 1係CN。在式VII及VIIa之一替代實施例中,X 2係CR 1且R 1係CF 3。 In one embodiment of formulas VII and VIIa, X 2 is CR 1 and R 1 is CN. In an alternative embodiment of formulas VII and VIIa, X 2 is CR 1 and R 1 is CF 3 .
在式VII及VIIa之一實施例中,Y 3係N。在一替代實施例中,Y 3係CH。 In one embodiment of formulas VII and VIIa, Y3 is N. In an alternative embodiment, Y3 is CH.
在式VII及VIIa之一實施例中,Y 1係CH。在一替代實施例中,Y 1係CR 2且R 2係甲基。 In one embodiment of formulas VII and VIIa, Y is CH. In an alternative embodiment, Y 1 is CR 2 and R 2 is methyl.
在式VII及VIIa之一實施例中,R 5係-CO 2H。在一替代實施例中,R 5係 。 In one embodiment of formulas VII and VIIa, R 5 is -CO 2 H. In an alternative embodiment, R is .
在一實施例中,提供下式之化合物: 式IV 其中-A-係-CHR aCHR aCHR bO-、-OCHR bCHR aCHR a-、-OCHR bCHR bO-、-CHR aCHR bOCHR b-、-CHR bOCHR bCHR a-、-CHR bOCHR b-、-CHR aCHR bO-或-OCHR bCHR a-; R a在每次出現時獨立地係H、鹵基、C 1-C 2烷基或OH; R b在每次出現時獨立地係H、鹵基或C 1-C 2烷基; 係 或 ,其中a係與連接體A之連接點;b係連接體B之連接點; X 1、X 2、X 3及X 4獨立地係N、CH或CR 1,其中X 1、X 2、X 3及X 4中之不超過兩者係N且X 1、X 2、X 3及X 4中之不超過兩者係CR 1; R 1係CN;鹵基;視情況經OH取代之C 1-C 3烷基;C 1-C 3鹵代烷基;C 1-C 3烷氧基;C 3-C 5環烷基;-SO 2C 1-C 3烷基; 或 ,其中每一R e獨立地選自:H、視情況經OH取代之C 1-C 3烷基、C 1-C 3鹵代烷基、鹵基及C 3-C 5環烷基; 5-或6員雜芳基或苯基,其中雜芳基或苯基視情況經一或兩個獨立地選自以下之取代基取代:視情況經OH取代之C 1-C 3烷基、C 1-C 3烷氧基、C 3-C 5環烷基、-CH 2-C 3-C 5環烷基、-SO 2C 1-C 3烷基、-CH 2-C 4-C 5雜環基、鹵基、C 1-C 3鹵代烷基、C 1-C 3鹵代烷氧基、CN或-CONR cR d,其中R c及R d各自獨立地係H或C 1-C 3烷基; -B-係-CH 2O-、-OCH 2-或-CH 2NH-; Y 1及Y 2獨立地係N、CH或CR 2,其中Y 1及Y 2中之僅一者可為N; Y 3係N或CH; R 2係鹵基或甲基; Z 1係N、CH或CR 3; Z 2係CH或CR 3; Z 3係N、CH或CR 3; R 3係鹵基、C 1-C 4烷基、C 1-C 4烷氧基或-C 1-C 3烷氧基C 1-C 2烷氧基; R 4係 或 ;且 R 5係-CO 2H或 ; 或其醫藥上可接受之鹽。 In one embodiment, compounds of the formula are provided: Formula IV where -A- is -CHR a CHR a CHR b O-, -OCHR b CHR a CHR a -, -OCHR b CHR b O-, -CHR a CHR b OCHR b -, -CHR b OCHR b CHR a -, -CHR b OCHR b -, -CHR a CHR b O- or -OCHR b CHR a -; R a independently at each occurrence is H, halo, C 1 -C 2 alkyl or OH; R b independently at each occurrence is H, halo or C 1 -C 2 alkyl; Tie or , wherein a is the connection point with the linker A; b is the connection point of the linker B; X 1 , X 2 , X 3 and X 4 are independently N, CH or CR 1 , wherein X 1 , X 2 , X Not more than two of 3 and X4 are N and not more than two of X1 , X2 , X3 and X4 are CR1 ; R1 is CN; halo; C1 optionally substituted by OH -C 3 alkyl; C 1 -C 3 haloalkyl; C 1 -C 3 alkoxy; C 3 -C 5 cycloalkyl; -SO 2 C 1 -C 3 alkyl; or , wherein each R e is independently selected from: H, C 1 -C 3 alkyl optionally substituted by OH, C 1 -C 3 haloalkyl, halo and C 3 -C 5 cycloalkyl; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted by one or two substituents independently selected from: C 1 -C 3 alkyl optionally substituted by OH, C 1 - C 3 alkoxy, C 3 -C 5 cycloalkyl, -CH 2 -C 3 -C 5 cycloalkyl, -SO 2 C 1 -C 3 alkyl, -CH 2 -C 4 -C 5 heterocycle radical, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, CN or -CONR c R d , wherein R c and R d are each independently H or C 1 -C 3 alkyl; -B- is -CH 2 O-, -OCH 2 - or -CH 2 NH-; Y 1 and Y 2 are independently N, CH or CR 2 , wherein only one of Y 1 and Y 2 can be N ; Y 3 is N or CH; R 2 is halo or methyl; Z 1 is N, CH or CR 3 ; Z 2 is CH or CR 3 ; Z 3 is N, CH or CR 3 ; R 3 is halo , C 1 -C 4 alkyl, C 1 -C 4 alkoxy or -C 1 -C 3 alkoxy C 1 -C 2 alkoxy; R 4 series or ; and R 5 is -CO 2 H or ; or a pharmaceutically acceptable salt thereof.
在一實施例中,提供式IV化合物,其中-A-係-CHR aCHR aCHR bO-、-OCHR bCHR aCHR a-、-OCHR bCHR bO-、-CHR aCHR bOCHR b-、-CHR bOCHR bCHR a-、-CHR bOCHR b-、-CHR aCHR bO-或-OCHR bCHR a-; R a在每次出現時獨立地係H、鹵基、C 1-C 2烷基或OH; R b在每次出現時獨立地係H、鹵基或C 1-C 2烷基; 係 或 ,其中a係與連接體A之連接點;b係連接體B之連接點; X 1、X 2、X 3及X 4獨立地係N、CH或CR 1,其中X 1、X 2、X 3及X 4中之不超過兩者可為N且X 1、X 2、X 3及X 4中之不超過兩者可為CR 1; R 1係CN、鹵基、C 1-C 3烷基或C 1-C 3鹵代烷基; -B-係-CH 2O-、-OCH 2-或-CH 2NH-; Y 1及Y 2獨立地係N、CH或CR 2,其中Y 1及Y 2中之僅一者可為N; Y 3係N或CH; R 2係鹵基或甲基; Z 1係N、CH或CR 3; Z 2係CH或CR 3; Z 3係N、CH或CR 3; R 3係鹵基、C 1-C 4烷基、C 1-C 4烷氧基或-C 1-C 3烷氧基C 1-C 2烷氧基; R 4係 或 ;且 R 5係-CO 2H或 ; 或其醫藥上可接受之鹽。 In one embodiment, a compound of formula IV is provided, wherein -A-is -CHR a CHR a CHR b O-, -OCHR b CHR a CHR a -, -OCHR b CHR b O-, -CHR a CHR b OCHR b -, -CHR b OCHR b CHR a -, -CHR b OCHR b -, -CHR a CHR b O-, or -OCHR b CHR a -; R a independently at each occurrence is H, halo, C 1 -C 2 alkyl or OH; R b independently at each occurrence is H, halo or C 1 -C 2 alkyl; Tie or , wherein a is the connection point with the linker A; b is the connection point of the linker B; X 1 , X 2 , X 3 and X 4 are independently N, CH or CR 1 , wherein X 1 , X 2 , X No more than two of 3 and X 4 can be N and no more than two of X 1 , X 2 , X 3 and X 4 can be CR 1 ; R 1 is CN, halo, C 1 -C 3 alkane or C 1 -C 3 haloalkyl; -B- is -CH 2 O-, -OCH 2 - or -CH 2 NH-; Y 1 and Y 2 are independently N, CH or CR 2 , wherein Y 1 and Only one of Y 2 may be N; Y 3 is N or CH; R 2 is halo or methyl; Z 1 is N, CH or CR 3 ; Z 2 is CH or CR 3 ; Z 3 is N, CH or CR 3 ; R 3 is halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or -C 1 -C 3 alkoxy C 1 -C 2 alkoxy; R 4 is or ; and R 5 is -CO 2 H or ; or a pharmaceutically acceptable salt thereof.
在一替代實施例中,提供下式之化合物: 式I 其中 -A-係-CHR aCHR aCHR bO-、-OCHR bCHR aCHR a-、-OCHR bCHR bO-、-CHR aCHR bOCHR b-、-CHR bOCHR bCHR a-、-CHR bOCHR b-、-CHR aCHR bO-或-OCHR bCHR a-; R a在每次出現時獨立地係H、鹵基、C 1-C 2烷基或OH; R b在每次出現時獨立地係H、鹵基或C 1-C 2烷基; X 1、X 2、X 3及X 4獨立地係N、CH或CR 1,其中X 1、X 2、X 3及X 4中之僅一者可為N且X 1、X 2、X 3及X 4中之不超過兩者可為CR 1; R 1係CN或鹵基; -B-係-CH 2O-或-OCH 2-; Y 1及Y 2獨立地係N、CH或CR 2,其中Y 1及Y 2中之僅一者可為N; R 2係鹵基或甲基; Z 1係N、CH或CR 3; Z 2係CH或CR 3; Z 3係N、CH或CR 3;且 R 3係鹵基、C 1-C 2烷基或甲氧基; 或其醫藥上可接受之鹽。 In an alternative embodiment, compounds of the formula are provided: Formula I wherein -A- is -CHR a CHR a CHR b O-, -OCHR b CHR a CHR a -, -OCHR b CHR b O-, -CHR a CHR b OCHR b -, -CHR b OCHR b CHR a -, -CHR b OCHR b -, -CHR a CHR b O- or -OCHR b CHR a -; R a independently at each occurrence is H, halo, C 1 -C 2 alkyl or OH; R b independently at each occurrence is H, halo or C 1 -C 2 alkyl; X 1 , X 2 , X 3 and X 4 are independently N, CH or CR 1 , wherein X 1 , X 2 , Only one of X 3 and X 4 can be N and no more than two of X 1 , X 2 , X 3 and X 4 can be CR 1 ; R 1 is CN or halo; -B- is -CH 2 O- or -OCH 2 -; Y 1 and Y 2 are independently N, CH or CR 2 , wherein only one of Y 1 and Y 2 can be N; R 2 is halo or methyl; Z 1 N, CH or CR 3 ; Z 2 is CH or CR 3 ; Z 3 is N, CH or CR 3 ; and R 3 is halogen, C 1 -C 2 alkyl or methoxy; The salt of acceptance.
在一實施例中,提供下式之化合物: 式Ia 或其醫藥上可接受之鹽。 In one embodiment, compounds of the formula are provided: Formula Ia or a pharmaceutically acceptable salt thereof.
在一實施例中,提供下式之化合物: 式II 或其醫藥上可接受之鹽。 In one embodiment, compounds of the formula are provided: Formula II or a pharmaceutically acceptable salt thereof.
在一較佳實施例中,提供下式之化合物: 式IIa 或其醫藥上可接受之鹽。 In a preferred embodiment, a compound of the following formula is provided: Formula IIa or a pharmaceutically acceptable salt thereof.
在一實施例中,提供下式之化合物: 式III 或其醫藥上可接受之鹽。 In one embodiment, compounds of the formula are provided: Formula III or a pharmaceutically acceptable salt thereof.
在一較佳實施例中,提供下式之化合物: 式IIIa 或其醫藥上可接受之鹽。 In a preferred embodiment, a compound of the following formula is provided: Formula IIIa or a pharmaceutically acceptable salt thereof.
在一實施例中,-A-係-CHR aCHR aCHR bO-。在另一實施例中,每一R a及R b係H。 In one embodiment, -A- is -CHR a CHR a CHR b O-. In another embodiment, each R a and R b is H.
在一實施例中,X 1、X 3及X 4係CH且X 2係CR 1。在一實施例中,R 1係CN。在一替代實施例中,R 1係Cl。 In one embodiment, X 1 , X 3 and X 4 are CH and X 2 is CR 1 . In one embodiment, R 1 is CN. In an alternative embodiment, R 1 is Cl.
在一實施例中,-B-係-CH 2O-。 In one embodiment, -B- is -CH 2 O-.
在一實施例中,Y 1及Y 2皆係CH。在一替代實施例中,Y 1係CR 2,Y 2係CH且R 2係F。 In one embodiment, both Y1 and Y2 are CH. In an alternative embodiment, Y1 is CR2 , Y2 is CH and R2 is F.
在一實施例中,Z 2及Z 3皆係CH。 In one embodiment, both Z2 and Z3 are CH.
在一實施例中,Z 1係CH或CR 3。在一實施例中,Z 1係CH。在一替代實施例中,Z 1係CR 3且R 3係F。 In one embodiment, Z 1 is CH or CR 3 . In one embodiment, Z 1 is CH. In an alternative embodiment, Z 1 is CR 3 and R 3 is F.
在一實施例中,提供選自以下之化合物: 及 或其醫藥上可接受之鹽。 In one embodiment, a compound selected from the group consisting of: and or a pharmaceutically acceptable salt thereof.
在連接體A中,所寫左手側端基連接至X環且右手側端基連接至含有Y 1、Y 2及Y 7之環。舉例而言,在基團-CR aR bCR aR bCR bR bO-中,氧連接至含有Y 1、Y 2及Y 7之環。在連接體B中,左手側端基連接至X環且右手側端基連接至含有Y 3之環。 In Linker A, it is written that the left hand end group is attached to the X ring and the right hand end group is attached to the ring containing Y1 , Y2 and Y7 . For example, in the group -CR a R b CR a R b CR b R b O-, the oxygen is attached to a ring containing Y 1 , Y 2 and Y 7 . In linker B, the left-hand end group is attached to the X ring and the right-hand end group is attached to the ring containing Y3 .
術語「鹵素」或「鹵基」係指氟、氯、溴或碘。The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
術語「C 1-C n烷基」係指含有1至n個碳原子之直鏈或具支鏈飽和烴。C 1-C 4烷基之實例包含(但不限於)甲基、乙基、丙基、丁基及第三丁基。C 1-C 3烷基之實例包含(但不限於)甲基、乙基及丙基。C 1-C 2烷基係甲基或乙基。 The term "C 1 -C n alkyl" refers to a straight chain or branched chain saturated hydrocarbon containing 1 to n carbon atoms. Examples of C 1 -C 4 alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. Examples of C 1 -C 3 alkyl include, but are not limited to, methyl, ethyl and propyl. C 1 -C 2 alkyl is methyl or ethyl.
術語「C 1-C n鹵代烷基」係指經一或多個鹵素取代之如本文所定義之C 1-C n烷基。C 1-C 3鹵代烷基之實例包含(但不限於)三氟甲基、二氟甲基及五氟乙基。 The term "C 1 -C n haloalkyl" refers to a C 1 -C n alkyl group, as defined herein, substituted with one or more halogens. Examples of C 1 -C 3 haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl and pentafluoroethyl.
術語「C 1-C n烷氧基」係指在鏈中含有1至n個碳原子且含有末端「O」之直鏈或具支鏈飽和烴,亦即-O(烷基)。C 1-C 4烷氧基之實例包含(但不限於)甲氧基、乙氧基、丙氧基及丁氧基。 The term "C 1 -C n alkoxy" refers to a linear or branched saturated hydrocarbon having 1 to n carbon atoms in the chain and a terminal "O", ie -O(alkyl). Examples of C 1 -C 4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.
術語「C 1-C n鹵代烷氧基」係指經一或多個鹵素取代之如本文所定義之C 1-C n烷氧基。C 1-C 3鹵代烷氧基之實例包含(但不限於)三氟甲氧基、二氟甲氧基及五氟乙氧基。 The term "C 1 -C n haloalkoxy" refers to a C 1 -C n alkoxy as defined herein substituted with one or more halogens. Examples of C 1 -C 3 haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy and pentafluoroethoxy.
術語「C 3-C 5環烷基」係指含有3至5個碳原子之單環飽和碳環。具體而言,其係指環丙基、環丁基或環戊基。 The term "C 3 -C 5 cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing 3 to 5 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl or cyclopentyl.
術語「C 4-C 6環烷基」係指含有4至6個碳原子之單環飽和碳環。具體而言,其係指環丁基、環戊基或環己基。 The term "C 4 -C 6 cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing 4 to 6 carbon atoms. Specifically, it refers to cyclobutyl, cyclopentyl or cyclohexyl.
術語「雜芳基」係指含有一或多個較佳地選自N、S及O之雜原子之單環芳香族環。5員雜芳基之實例包含(但不限於)吡唑、三唑及噻唑。6員雜芳基之實例包含(但不限於)吡啶及噠嗪。The term "heteroaryl" refers to a monocyclic aromatic ring containing one or more heteroatoms preferably selected from N, S and O. Examples of 5-membered heteroaryl groups include, but are not limited to, pyrazole, triazole, and thiazole. Examples of 6-membered heteroaryl groups include, but are not limited to, pyridine and pyridazine.
術語「C 4-C 6雜環基」係指含有一或多個雜原子之4、5或6員單環飽和環,例如吡咯啶。 The term "C 4 -C 6 heterocyclyl" refers to a 4-, 5- or 6-membered monocyclic saturated ring containing one or more heteroatoms, such as pyrrolidine.
術語「C 4-C 5雜環基」係指含有一或多個雜原子之4或5員單環飽和環,例如環氧丙烷。 The term "C 4 -C 5 heterocyclyl" refers to a 4- or 5-membered monocyclic saturated ring containing one or more heteroatoms, such as propylene oxide.
式IX涵蓋式I、Ia、Ib、II、IIa、IIb、III、IIIa、IIIb、IV、V、Va、Vb、VI、VII、VIIa及VIIb且提及下文(例如)之治療方法及治療用途中之式IX,其亦應理解為提及該等子式中之每一者及所有者。Formula IX encompasses formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, V, Va, Vb, VI, VII, VIIa, and VIIb and refers to methods of treatment and therapeutic uses below, for example In formula IX, it should also be understood as referring to each of these sub-formulas and owners.
在另一實施例中,提供一種醫藥上可接受之組合物,其包括式IX化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑、稀釋劑或賦形劑中之至少一者。在一較佳實施例中,醫藥上可接受之組合物經調配用於經口投與。In another embodiment, a pharmaceutically acceptable composition is provided, which includes a compound of formula IX or a pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier, diluent or excipient . In a preferred embodiment, the pharmaceutically acceptable composition is formulated for oral administration.
在另一實施例中,提供治療患者之II型糖尿病之方法,該方法包括需要治療之患者投與醫藥上可接受之組合物,該組合物包括有效量之式IX化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑、稀釋劑或賦形劑中之至少一者。在一實施例中,醫藥上可接受之組合物經調配用於經口投與。較佳地,患者係人類。In another embodiment, there is provided a method of treating type 2 diabetes in a patient, the method comprising administering to a patient in need of treatment a pharmaceutically acceptable composition comprising an effective amount of a compound of formula IX or a pharmaceutically acceptable salt and at least one of pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, pharmaceutically acceptable compositions are formulated for oral administration. Preferably, the patient is a human.
在另一實施例中,提供治療患者之II型糖尿病之方法,該方法包括向需要治療之患者投與有效量之式IX化合物或其醫藥上可接受之鹽。在一較佳實施例中,患者係人類。In another embodiment, there is provided a method of treating type II diabetes in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula IX, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.
在另一實施例中,提供降低患者之血糖含量之方法,該方法包括向需要治療之患者投與有效量之式IX化合物或其醫藥上可接受之鹽。在一較佳實施例中,患者係人類。In another embodiment, there is provided a method of lowering blood glucose levels in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of formula IX or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.
在另一實施例中,提供治療患者之高血糖症之方法,該方法包括向需要治療之患者投與有效量之式IX化合物或其醫藥上可接受之鹽。在一較佳實施例中,患者係人類。 In another embodiment, there is provided a method of treating hyperglycemia in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of Formula IX or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.
在另一實施例中,提供治療哺乳動物之肥胖症之方法,該方法包括向需要治療之患者投與有效量之式IX化合物或其醫藥上可接受之鹽。在一較佳實施例中,患者係人類。In another embodiment, there is provided a method of treating obesity in a mammal, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula IX or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.
在另一實施例中,提供治療患者之非酒精性脂肪性肝炎(NASH)之方法,該方法包括向需要治療之患者投與有效量之式IX化合物或其醫藥上可接受之鹽。在一較佳實施例中,患者係人類。In another embodiment, there is provided a method of treating nonalcoholic steatohepatitis (NASH) in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of Formula IX or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.
在一實施例中,提供用於療法中之式IX化合物或其醫藥上可接受之鹽。In one embodiment, there is provided a compound of formula IX, or a pharmaceutically acceptable salt thereof, for use in therapy.
在另一實施例中,提供用於治療II型糖尿病之式IX化合物或其醫藥上可接受之鹽。In another embodiment, there is provided a compound of formula IX or a pharmaceutically acceptable salt thereof for use in the treatment of type II diabetes.
在另一實施例中,提供用於降低血糖含量之式IX化合物或其醫藥上可接受之鹽。In another embodiment, there is provided a compound of formula IX or a pharmaceutically acceptable salt thereof for use in lowering blood sugar levels.
在另一實施例中,亦提供用於治療高血糖症之式IX化合物或其醫藥上可接受之鹽。 In another embodiment, a compound of formula IX or a pharmaceutically acceptable salt thereof for treating hyperglycemia is also provided.
在另一實施例中,提供用於治療肥胖症之式IX化合物或其醫藥上可接受之鹽。In another embodiment, there is provided a compound of formula IX or a pharmaceutically acceptable salt thereof for use in the treatment of obesity.
在另一實施例中,亦提供用於治療NASH之式IX化合物或其醫藥上可接受之鹽。In another embodiment, a compound of formula IX or a pharmaceutically acceptable salt thereof for treating NASH is also provided.
在一實施例中,提供式IX化合物或其醫藥上可接受之鹽之用途,其用以製造用於治療II型糖尿病之藥劑。In one embodiment, use of the compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating type II diabetes is provided.
在一實施例中,提供式IX化合物或其醫藥上可接受之鹽之用途,其用以製造用於降低血糖含量之藥劑。In one embodiment, use of the compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for lowering blood sugar levels is provided.
在一實施例中,提供式IX化合物或其醫藥上可接受之鹽之用途,其用以製造用於治療高血糖症之藥劑。 In one embodiment, use of the compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating hyperglycemia is provided. the
在一實施例中,提供式IX化合物或其醫藥上可接受之鹽之用途,其用以製造用於治療肥胖症之藥劑。 In one embodiment, the use of the compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating obesity is provided. the
在一實施例中,提供式IX化合物或其醫藥上可接受之鹽之用途,其用以製造用於治療NASH之藥劑。 In one embodiment, use of the compound of formula IX or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating NASH is provided. the
式IX化合物可與一或多種治療劑同時、分開或依序地組合使用。其他治療劑之實例包含(但不限於)二甲雙胍(metformin)、噻唑啶二酮、磺醯脲、二肽基肽酶4抑制劑、鈉葡萄糖協同轉運蛋白抑制劑及己酮糖激酶抑制劑。Compounds of formula IX may be used in combination with one or more therapeutic agents simultaneously, separately or sequentially. Examples of other therapeutic agents include, but are not limited to, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporter inhibitors, and ketohexokinase inhibitors.
在一較佳實施例中,經口投與式IX化合物。在一較佳實施例中,每天投與式IX化合物一次。在另一較佳實施例中,治療用途係在人類中。In a preferred embodiment, the compound of formula IX is administered orally. In a preferred embodiment, the compound of formula IX is administered once daily. In another preferred embodiment, the therapeutic use is in humans.
本申請案在35 U.S.C. §119(e)下主張2021年5月20日提出申請之美國臨時申請案第63/191,034號及202年10月12日提出申請之第63/254,564號之益處;其亦主張2021年12月21日提出申請之歐洲申請案EP21383172.0之優先權;該等申請案之揭示內容以引用方式併入本文中。 This application claims the benefit of U.S. Provisional Application Nos. 63/191,034, filed May 20, 2021, and 63/254,564, filed October 12, 202, under 35 U.S.C. §119(e); Priority is also claimed to European application EP21383172.0 filed on 21 December 2021; the disclosures of these applications are incorporated herein by reference.
本文所用之術語「醫藥上可接受之鹽」係指可視為可接受用於臨床及/或獸醫學應用之本發明化合物之鹽。醫藥上可接受之鹽及其常用製備方法之實例可參見「Handbook of Pharmaceutical Salts: Properties, Selection and Use」 P. Stahl等人,第2修訂版,Wiley-VCH, 2011及S.M. Berge等人,「Pharmaceutical Salts」, Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19。The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present invention which may be considered acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methods of preparation thereof can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P. Stahl et al., 2nd revised edition, Wiley-VCH, 2011 and S.M. Berge et al., " Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
術語「有效量」係指式IX化合物或其醫藥上可接受之鹽在單一劑量或多個劑量投與患者時在診斷或治療下於患者中提供期望效應的量。作為熟習此項技術者,主治醫師可易於藉由使用習用技術並藉由觀察在類似情況下所獲得之結果來確定有效量。在確定化合物之有效量或劑量時應考慮之因素包含:將投與化合物抑或其鹽;共投與之其他藥劑(若使用);患者之個頭、年齡及一般健康狀況;病症之累及程度或嚴重程度;個別患者之反應;投與模式;所投與製劑之生物可用性特性;所選劑量方案;及其他相關情況。本發明化合物在每天約0.01 mg/kg體重至約15 mg/kg體重範圍內之劑量下係有效的。The term "effective amount" refers to the amount of a compound of formula IX or a pharmaceutically acceptable salt thereof that provides a desired effect in a patient under diagnosis or treatment when administered to a patient in single or multiple doses. The attending physician, being one skilled in the art, can readily determine the effective amount by using conventional techniques and by observing results obtained under similar circumstances. Factors that should be considered in determining an effective amount or dosage of a compound include: the compound or a salt thereof to be administered; other co-administered agents (if used); the size, age and general health of the patient; the extent or severity of the condition individual patient response; mode of administration; bioavailability characteristics of the administered formulation; selected dosage regimen; and other relevant circumstances. The compounds of the present invention are effective at dosages ranging from about 0.01 mg/kg body weight to about 15 mg/kg body weight per day.
如本文中所使用,術語「治療(treating、to treat或treatment)」係指降低、減小或逆轉現有症狀、病症或病狀(例如高血糖症)之進展或嚴重程度,其可包含增加胰島素分泌。As used herein, the term "treating, to treat, or treatment" refers to reducing, reducing, or reversing the progression or severity of an existing symptom, disorder, or condition (eg, hyperglycemia), which may include increasing insulin secretion.
如本文中所使用,術語「患者」包含哺乳動物。患者較佳係人類。As used herein, the term "patient" includes mammals. The patient is preferably a human.
可將式IX化合物調配為可藉由使得該化合物生物可利用之任一途徑投與之醫藥組合物。較佳地,該等組合物用於經口投與。較佳地,將醫藥組合物調配為錠劑、膠囊或溶液。錠劑、膠囊或溶液可包含有效治療需要治療患者之量之式IX化合物。該等醫藥組合物及其製備製程在業內已眾所周知(例如參見「Remington: The Science and Practice of Pharmacy」, A. Adejare編輯,第23版,2020, Elsevier Science)。Compounds of formula IX can be formulated into pharmaceutical compositions that can be administered by any route that renders the compound bioavailable. Preferably, these compositions are for oral administration. Preferably, the pharmaceutical composition is formulated as a tablet, capsule or solution. Tablets, capsules or solutions may contain an amount of a compound of formula IX effective to treat a patient in need thereof. Such pharmaceutical compositions and their preparation processes are well known in the art (see, for example, "Remington: The Science and Practice of Pharmacy", edited by A. Adejare, 23rd edition, 2020, Elsevier Science).
式IX化合物及其醫藥上可接受之鹽可用於本發明之治療用途中,其中某些構形較佳。Compounds of formula IX and pharmaceutically acceptable salts thereof are useful in the therapeutic uses of the present invention, with certain configurations being preferred.
本發明化合物包含: 式Ia, 式Ib, 式IIa, 式IIb, 式IIIa, 式IIIb, 式Va, 式Vb, 式VIIa, 式VIIb, 或其醫藥上可接受之鹽。 Compounds of the present invention include: Formula Ia, Formula Ib, Formula IIa, Formula IIb, Formula IIIa, Formula IIIb, Formula Va, Formula Vb, Formula VIIa, Formula VIIb, or a pharmaceutically acceptable salt thereof.
儘管發明考慮所有個別對映異構體、其混合物及外消旋物,但式Ia、IIa、IIIa、Va及VIIa之化合物及其醫藥上可接受之鹽尤佳。Although the invention contemplates all individual enantiomers, mixtures and racemates thereof, the compounds of formula Ia, IIa, IIIa, Va and VIIa and their pharmaceutically acceptable salts are especially preferred.
熟習此項技術者可在合成本發明化合物之任一便利點處藉由各種方法來分離或拆分個別對映異構體,例如選擇性結晶技術、對掌性層析(例如參見J. Jacques等人,「 Enantiomers, Racemates, and Resolutions」, John Wiley and Sons, Inc., 1981以及E.L. Eliel及S.H. Wilen, 「 Stereochemistry of Organic Compounds」, Wiley-Interscience, 1994)或超臨界流體層析(SFC) (例如參見T. A. Berger; 「 Supercritical Fluid Chromatography Primer,」 Agilent Technologies,2015年7月)。 Those skilled in the art can separate or resolve individual enantiomers at any convenient point in the synthesis of the compounds of the invention by various methods, such as selective crystallization techniques, chiral chromatography (see for example J. Jacques et al., " Enantiomers, Racemates, and Resolutions ", John Wiley and Sons, Inc., 1981 and EL Eliel and SH Wilen, " Stereochemistry of Organic Compounds ", Wiley-Interscience, 1994) or supercritical fluid chromatography (SFC) (See eg TA Berger; " Supercritical Fluid Chromatography Primer ," Agilent Technologies, July 2015).
可(例如)藉由使式IX化合物及醫藥上可接受之適當鹼在業內熟知之標準條件下於適宜溶劑中進行反應來形成本發明化合物之醫藥上可接受之鹽(例如參見Bastin, R.J.等人, Org. Process. Res. Dev., 4, 427-435, 2000及Berge, S.M.等人, J. Pharm. Sci., 66, 1-19, 1977)。 Pharmaceutically acceptable salts of compounds of the invention can be formed, for example, by reacting a compound of formula IX with a suitable pharmaceutically acceptable base in a suitable solvent under standard conditions well known in the art (see for example Bastin, RJ et al. People, Org. Process. Res. Dev ., 4, 427-435, 2000 and Berge, SM et al., J. Pharm. Sci. , 66, 1-19, 1977).
本文所用之某些縮寫係根據Daub G.H.等人,「The Use of Acronyms in Organic Chemistry」 Aldrichimica Acta, 1984, 17(1), 6-23所定義。某些縮寫定義如下:「ACN」係指乙腈;「Boc」係指第三丁基氧基羰基;「cAMP」係指環狀腺苷-3’,5’-單磷酸酯;「DCM」係指二氯甲烷或氯化甲烷;「DEAD」係指偶氮二甲酸二乙酯;「DIAD」係指偶氮二甲酸二異丙酯;「DIPEA」係指N,N-二異丙基乙基胺;「DMF」係指N,N-二甲基甲醯胺;「DMSO」係指二甲基亞碸;「EC 50」係指與預定陽性對照化合物相比產生50%之靶活性反應之藥劑濃度(絕對EC 50);「EDC」係指N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽;「ES/MS」係指電噴霧質譜;「EtOAc」係指乙酸乙酯;「HATU」係指六氟磷酸1-[雙(二甲基胺基)亞甲基]-1 H-1,2,3-三唑并[4,5- b]吡啶鎓3-氧化物;「HEK」係指人類胚胎腎;「HEPES」係指4-(2-羥乙基)-1-六氫吡嗪乙磺酸;「h」分別係指小時數或小時;Ir[dF(CF3)ppy]2(dtbpy))PF6係指六氟磷酸[4,4′-雙(1,1-二甲基乙基)-2,2′-聯吡啶-N1,N1′]雙[3,5-二氟-2-[5-(三氟甲基)-2-吡啶基-N]苯基-C]銥(III);「KOAc」係指乙酸鉀;「MeOH」係指甲醇或甲基醇;「min」係指分鐘或分鐘數;「MTBE」係指甲基第三丁基醚;「Pd(dppf)Cl 2」係指[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II);PdCl 2(dtbpf)係指[1,1'-雙(二-第三丁基膦基)二茂鐵]二氯鈀(II);「RT」係指室溫;「S NAr」係指親核性芳香族取代;「TBAF」係指四丁基氟化銨;「TBS」係指第三丁基二甲基矽基;「TEA」係指三乙胺;「TFA」係指三氟乙酸;「THF」係指四氫呋喃;「TMAD」係指四甲基偶氮二甲醯胺;且「TMSCN」係指三甲基矽基氰化物。 Certain abbreviations used herein are defined according to Daub GH et al., "The Use of Acronyms in Organic Chemistry" Aldrichimica Acta , 1984, 17(1), 6-23. Certain abbreviations are defined as follows: "ACN" means acetonitrile; "Boc" means tert-butyloxycarbonyl; "cAMP" means cyclic adenosine-3',5'-monophosphate;"DCM" means refers to dichloromethane or methyl chloride; "DEAD" refers to diethyl azodicarboxylate; "DIAD" refers to diisopropyl azodicarboxylate; "DIPEA" refers to N,N-diisopropyl ethyl "DMF" refers to N,N-dimethylformamide; "DMSO" refers to dimethyl sulfide; "EC 50 " refers to the reaction that produces 50% of the target activity compared with the predetermined positive control compound The drug concentration (absolute EC 50 ); "EDC" refers to N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; "ES/MS" refers to electrospray Mass spectrum; "EtOAc" refers to ethyl acetate; "HATU" refers to hexafluorophosphate 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4, 5- b ] pyridinium 3-oxide; "HEK" refers to human embryonic kidney; "HEPES" refers to 4-(2-hydroxyethyl)-1-hexahydropyrazineethanesulfonic acid; "h" refers to Refers to hours or hours; Ir[dF(CF3)ppy]2(dtbpy))PF6 refers to [4,4′-bis(1,1-dimethylethyl)-2,2′-linked hexafluorophosphate Pyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III);"KOAc" means Potassium acetate; "MeOH" means methanol or methyl alcohol; "min" means minutes or minutes; "MTBE" means methyl tertiary butyl ether; "Pd(dppf)Cl 2 " means [1, 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PdCl 2 (dtbpf) refers to [1,1'-bis(di-tert-butylphosphino)ferrocene] Dichloropalladium(II); "RT" refers to room temperature; "S N Ar" refers to nucleophilic aromatic substitution; "TBAF" refers to tetrabutylammonium fluoride; "TBS" refers to tertiary butyl Dimethylsilyl; "TEA" means triethylamine; "TFA" means trifluoroacetic acid; "THF" means tetrahydrofuran; "TMAD" means tetramethylazodiformamide; and "TMSCN" Refers to trimethylsilyl cyanide.
可藉由各種程序來製備本發明化合物,一些程序闡釋於下文之製備及實例中。所闡述各途徑之特定合成步驟可以不同方式組合以製備本發明化合物或其鹽。可藉由習用方法(包含萃取、蒸發、沈澱、層析、過濾、研磨及結晶)回收下文每一步驟之產物。熟習此項技術者易於獲得各種試劑及起始材料。熟習此項技術者可在合成中之任一便利點處藉由諸如選擇性結晶技術或對掌性層析等方法分離或拆分個別異構體、對映異構體及非對映異構體(例如參見J. Jacques等人,「 Enantiomers, Racemates, and Resolutions」, John Wiley and Sons, Inc., 1981;以及E.L. Eliel及S.H. Wilen, 「 Stereochemistry of Organic Compounds」, Wiley-Interscience, 1994)。並不限制本發明範圍,提供下列製備及實例以進一步闡釋本發明。 The compounds of the invention can be prepared by a variety of procedures, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps of each of the pathways described may be combined in different ways to prepare the compounds of the invention or salts thereof. The product of each of the following steps can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration and crystallization. Various reagents and starting materials are readily available to those skilled in the art. Individual isomers, enantiomers and diastereoisomers may be separated or resolved by methods such as selective crystallization techniques or chiral chromatography at any convenient point in the synthesis by those skilled in the art (see, eg, J. Jacques et al., " Enantiomers, Racemates, and Resolutions ", John Wiley and Sons, Inc., 1981; and EL Eliel and SH Wilen, " Stereochemistry of Organic Compounds ", Wiley-Interscience, 1994). Without limiting the scope of the present invention, the following preparations and examples are provided to further illustrate the present invention.
反應圖 1 反應圖1展示用於製備本發明化合物之中間體7、8及9之合成。在步驟1中,在高溫下使用碘甲烷及碳酸鹽鹼對中間體1之羥基實施甲基化以得到甲氧基中間體2。在步驟2中,然後使用NaBH 4還原中間體2之酯基以得到醇中間體3。在步驟3中使用PBr 3將中間體3之醇轉化成溴化物中間體4,然後在步驟4中與TMSCN及TBAF進行反應以得到中間體5。在步驟5中於醇溶液中在高溫下使用硫酸處理中間體5之氰基以得到酯中間體6,然後在步驟6中使用BBr 3對甲氧基實施去甲基化以得到中間體7。視情況,可在步驟7中使用KOAc及Pd(dppf)Cl 2以及雙(頻哪醇)二硼或雙(新戊二醇)二硼在高溫下將中間體7轉化成酸酯以分別得到酸酯8或9。 Reaction Chart 1 Scheme 1 shows the synthesis of intermediates 7, 8 and 9 for the preparation of compounds of the invention. In step 1, the hydroxyl group of intermediate 1 was methylated using iodomethane and carbonate base at high temperature to obtain methoxyl intermediate 2. In step 2, the ester group of intermediate 2 is then reduced using NaBH 4 to give alcohol intermediate 3. The alcohol of intermediate 3 is converted to the bromide intermediate 4 using PBr 3 in step 3, which is then reacted with TMSCN and TBAF in step 4 to give intermediate 5. Treatment of the cyano group of intermediate 5 with sulfuric acid at elevated temperature in alcoholic solution in step 5 gives ester intermediate 6, followed by demethylation of the methoxy group with BBr 3 in step 6 to give intermediate 7. Optionally, intermediate 7 can be converted to esters to obtain Ester 8 or 9.
反應圖 2 反應圖2展示亦用於製備本發明化合物之中間體15、18、22及23之合成。在步驟1中使用氰化鋅及鈀觸媒在高溫下將溴化物10轉化成腈11。在步驟2a中使用亞硫醯氯在高溫下於醇溶液中將腈中間體11轉化成酯中間體12,然後在步驟3a中使用胺13及碳酸鹽鹼在高溫下於S NAr反應中置換氟以得到中間體14。然後在步驟4a中於氫氣氛下使用林德拉觸媒(Lindlar catalyst) (5% Pd)在甲醇中還原硝基以得到中間體15。可使用三級胺鹼使中間體15與2-氯乙醯氯進行反應以得到2-氯甲基咪唑中間體23。 為獲得四唑中間體,在步驟2b中使用胺鹼使中間體11與胺13進行S NAr反應以得到中間體16,然後在步驟3b中使用三丁基疊氮化錫在高溫下轉化成四唑中間體17。然後在步驟4b中於氫壓(4巴)下使用碳載鈀觸媒還原硝基以得到中間體18。或者,在步驟2c中使中間體11與三丁基疊氮化錫在高溫下進行反應以得到四唑中間體19,然後在步驟3c中使用諸如SEM (三甲基矽基乙氧基甲基)等基團對四唑氮實施保護以得到中間體20。在步驟4c中使用胺13及三級胺鹼在S NAr反應中置換氟以得到中間體21,然後在步驟5c中使用鐵在高溫下於乙酸中還原硝基以得到經保護四唑中間體22。 Reaction Image 2 Scheme 2 shows the synthesis of intermediates 15, 18, 22 and 23 which are also used to prepare compounds of the invention. Bromide 10 was converted to nitrile 11 at elevated temperature using zinc cyanide and palladium catalysts in step 1. Conversion of nitrile intermediate 11 to ester intermediate 12 in step 2a using thionyl chloride in alcoholic solution at elevated temperature followed by displacement in step 3a in S N Ar reaction using amine 13 and carbonate base at elevated temperature Fluorine to give intermediate 14. The nitro group was then reduced in methanol under hydrogen atmosphere using Lindlar catalyst (5% Pd) to give intermediate 15. Intermediate 15 can be reacted with 2-chloroacetyl chloride using a tertiary amine base to give 2-chloromethylimidazole intermediate 23. To obtain the tetrazole intermediate, intermediate 11 is subjected to a S N Ar reaction with amine 13 in step 2b using an amine base to give intermediate 16, which is then converted in step 3b using tributyltin azide at elevated temperature to Tetrazole intermediate 17. The nitro group is then reduced in step 4b under hydrogen pressure (4 bar) using a palladium on carbon catalyst to afford intermediate 18. Alternatively, intermediate 11 is reacted with tributyltin azide at elevated temperature in step 2c to give tetrazole intermediate 19, which is then used in step 3c using a method such as SEM (trimethylsilylethoxymethyl ) etc. to protect the tetrazole nitrogen to give intermediate 20. Displacement of fluorine in a S N Ar reaction using amine 13 and a tertiary amine base in step 4c gives intermediate 21, followed by reduction of the nitro group in step 5c using iron in acetic acid at elevated temperature to give the protected tetrazole intermediate twenty two.
反應圖 3 反應圖3展示合成用於製備本發明化合物之中間體32之三種途徑。在第一途徑中之步驟1a中,在高溫下使用乙酸鈀及碳酸鹽鹼使鹵化物中間體24與丙烯酸乙酯進行赫克偶合(Heck coupling)以得到中間體25,然後在步驟2a中於氫(40 psi)下進行烯烴還原以得到中間體26。在步驟3a中,使用PBr 3將中間體26之醇基轉化成溴化物,然後在高溫下與中間體27及Ag 2CO 3進行反應以得到中間體29。在步驟4a中使用LiBH 4還原酯基以得到中間體32。 在第二途徑中,首先在步驟1c中在高溫下使用Ag 2CO 3使中間體33 (其可使用PBr 3自中間體24製得)與中間體27進行反應以得到中間體34,然後在步驟2c中使用溴-[3-[第三丁基(二甲基)矽基]氧基丙基]鋅及鈀觸媒在高溫下進行根岸偶合(Negishi coupling)以得到中間體35。然後在步驟3c中使用TBAF實施去保護以得到中間體32。 在第三途徑中,在步驟1b中使用鈀觸媒及三級胺鹼使中間體24與第三丁基二甲基(2-丙炔基氧基)矽烷進行薗頭偶合(Sonogashira coupling)以得到中間體28,然後與中間體27進行光延反應(Mitsunobu reaction)以得到中間體30。在步驟3b中使用TBAF實施去保護且然後在步驟4b中使用氧化鉑在氫氣氛下對炔烴實施氫化以得到中間體32。 Reaction Image 3 Scheme 3 shows three routes for the synthesis of intermediate 32 for the preparation of compounds of the invention. In step 1a in the first pathway, Heck coupling of halide intermediate 24 with ethyl acrylate at elevated temperature using palladium acetate and a carbonate base affords intermediate 25, which is then obtained in step 2a at Olefin reduction under hydrogen (40 psi) gave intermediate 26. In step 3a, the alcohol group of intermediate 26 was converted to bromide using PBr 3 , and then reacted with intermediate 27 and Ag 2 CO 3 at high temperature to give intermediate 29. Reduction of the ester group using LiBH4 in step 4a gave intermediate 32. In the second route, intermediate 33 (which can be prepared from intermediate 24 using PBr 3 ) is first reacted with intermediate 27 using Ag2CO3 at elevated temperature in step 1c to give intermediate 34, and then in In step 2c, intermediate 35 was obtained by Negishi coupling using bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc and palladium catalyst at high temperature. Deprotection was then carried out using TBAF to give intermediate 32 in step 3c. In the third route, intermediate 24 is subjected to Sonogashira coupling with tert-butyldimethyl(2-propynyloxy)silane using a palladium catalyst and a tertiary amine base in step 1b to Intermediate 28 was obtained, which was then subjected to a Mitsunobu reaction with intermediate 27 to obtain intermediate 30 . Deprotection using TBAF in step 3b and then hydrogenation of the alkyne using platinum oxide under hydrogen atmosphere gives intermediate 32 in step 4b.
反應圖 4 反應圖4展示用於製備本發明化合物之中間體42之合成。在步驟1中,使溴化物中間體36與酞醯亞胺鉀在高溫下進行反應以得到中間體37。在步驟2中,與炔丙醇進行薗頭偶合以得到炔烴中間體38。在步驟3中,在高溫及氫力(90 psi)下使用銠觸媒還原中間體38之炔烴以得到中間體39。在步驟4中使酞醯亞胺基團與肼在高溫下進行反應以得到胺40,然後在步驟5中使用DIPEA在高溫下與中間體41進行S NAr反應以得到中間體42。 React Chart 4 Scheme 4 shows the synthesis of intermediate 42 for the preparation of compounds of the invention. In step 1, bromide intermediate 36 is reacted with potassium phthalimide at elevated temperature to afford intermediate 37. In step 2, a sono-coupling with propargyl alcohol affords alkyne intermediate 38. In step 3, the alkyne of intermediate 38 is reduced to obtain intermediate 39 using a rhodium catalyst at elevated temperature and hydrogen force (90 psi). Reaction of the phthalimide group with hydrazine at elevated temperature in step 4 affords amine 40, followed by S N Ar reaction with intermediate 41 using DIPEA at elevated temperature in step 5 to afford intermediate 42.
反應圖 5 反應圖5展示用於製備本發明化合物之中間體47之合成。在步驟1中,在高溫下使用碳酸鹽鹼使中間體43與(2-溴乙氧基)-第三丁基二甲基矽烷進行反應。在步驟2中使用硼氫化鈉還原中間體44之醛以得到醇45,然後在步驟3中與中間體27進行光延反應以得到中間體46。在步驟4中使用TBAF去除第三丁基二甲基矽基以得到中間體47。 Reaction Image 5 Scheme 5 shows the synthesis of intermediate 47 for the preparation of compounds of the invention. In Step 1, intermediate 43 is reacted with (2-bromoethoxy)-tert-butyldimethylsilane using carbonate base at elevated temperature. Reduction of the aldehyde of intermediate 44 with sodium borohydride in step 2 gives alcohol 45, followed by Mitsunobu reaction with intermediate 27 in step 3 to give intermediate 46. The tert-butyldimethylsilyl group was removed using TBAF in step 4 to give intermediate 47.
反應圖 6 可藉由反應圖6中所展示之替代途徑來製備如反應圖3中所闡述之中間體32。在步驟1a中,在高溫下使用溴-[3-[第三丁基(二甲基)矽基]氧基丙基]鋅及鈀觸媒使中間體48進行根岸偶合以得到中間體49,然後在步驟2a中使用氫化鋰鋁還原成醇中間體50。在步驟3a中,使中間體50與中間體27在光延條件下進行反應以得到中間體32。 或者,在步驟1b中使中間體24與中間體27在光延條件下進行反應或與第三丁醇鉀及芳基氟中間體41進行反應以得到中間體34。步驟2b及3b係如反應圖3中所闡述(與溴-[3-[第三丁基(二甲基)矽基]氧基丙基]鋅進行根岸偶合,隨後去保護以得到中間體32)。 Reaction Image 6 Intermediate 32 as illustrated in Scheme 3 can be prepared by an alternative route shown in Scheme 6. In step 1a, intermediate 48 was subjected to Negishi coupling using bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc and palladium catalyst at elevated temperature to give intermediate 49, This is then reduced to alcohol intermediate 50 using lithium aluminum hydride in step 2a. In step 3a, intermediate 50 is reacted with intermediate 27 under Mitsunobu conditions to obtain intermediate 32 . Alternatively, intermediate 24 is reacted with intermediate 27 under Mitsunobu conditions or with potassium tert-butoxide and aryl fluoride intermediate 41 to give intermediate 34 in step 1b. Steps 2b and 3b were as illustrated in Reaction Scheme 3 (Negishi coupling with bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc followed by deprotection to give intermediate 32 ).
反應圖 7 反應圖7展示合成用於製備本發明化合物之中間體55之兩種途徑。在第一途徑中,在步驟1a中使中間體51與中間體8或9進行光延反應以得到中間體52。在步驟2a中,然後使用鈀觸媒使中間體52進行分子內交叉偶合以形成大環中間體54。在第二途徑中,在步驟1b中使中間體51與中間體7進行光延反應以得到中間體53,然後在步驟2b中在高溫下實施鈀催化之分子內施蒂勒偶合(Stille coupling)以得到中間體54。在步驟3中使用LiOH水溶液或於ACN/水中之胍鹼水解中間體54之酯基以得到中間體55。 React Chart 7 Scheme 7 shows two routes for the synthesis of intermediate 55 for the preparation of compounds of the invention. In the first route, intermediate 51 is subjected to a Mitsunobu reaction with intermediate 8 or 9 to give intermediate 52 in step 1a. In step 2a, intermediate 52 is then subjected to intramolecular cross-coupling to form macrocyclic intermediate 54 using a palladium catalyst. In the second route, intermediate 51 is subjected to Mitsunobu reaction with intermediate 7 in step 1b to obtain intermediate 53, followed by palladium-catalyzed intramolecular Stiller coupling at elevated temperature in step 2b to Intermediate 54 was obtained. The ester group of intermediate 54 is hydrolyzed in step 3 using aqueous LiOH or guanidine base in ACN/water to afford intermediate 55.
反應圖 8 反應圖8展示用於製備本發明化合物之中間體64之合成。在步驟1中,使中間體56與3-溴-1-丙醇在高溫下進行還原偶合以得到中間體57,然後在步驟2中使用TBS基團實施保護以得到中間體58。然後在步驟3中使用硼氫化鋰還原酯以得到醇中間體59,然後在步驟4中與中間體27進行光延反應以得到中間體60。在步驟5中使用TBAF去除TBS保護基團以得到中間體61,然後在步驟6中與中間體8進行光延反應以得到中間體62。在步驟7中,使用鈀觸媒及磷酸鉀對中間體62實施環化以得到中間體63,然後在步驟8中使用LiOH水溶液或於ACN/水中之胍鹼進行水解以得到酸中間體64。 Reaction Chart 8 Scheme 8 shows the synthesis of intermediate 64 for the preparation of compounds of the invention. In step 1, intermediate 56 is reductively coupled with 3-bromo-1-propanol at elevated temperature to give intermediate 57, which is then protected with a TBS group in step 2 to give intermediate 58. The ester is then reduced using lithium borohydride in step 3 to give alcohol intermediate 59, followed by Mitsunobu reaction with intermediate 27 in step 4 to give intermediate 60. Removal of the TBS protecting group using TBAF in step 5 gave intermediate 61, followed by Mitsunobu reaction with intermediate 8 in step 6 to give intermediate 62. In step 7, intermediate 62 was cyclized using palladium catalyst and potassium phosphate to give intermediate 63, followed by hydrolysis in step 8 using aqueous LiOH or guanidine base in ACN/water to give acid intermediate 64.
反應圖 9 反應圖9展示用於製備本發明化合物之中間體77之合成,且展示公共中間體74之兩種合成途徑。 在獲得中間體74之第一途徑中,在步驟1a中,使用硼烷-二甲硫醚複合物還原酸中間體65以得到醇中間體66,然後在步驟2a中與氫化鈉及溴化物中間體67進行反應以得到中間體68。在步驟3a中,使用硼氫化鋰還原酯以得到中間體73,然後在步驟4a中與中間體27進行光延反應以得到中間體74。 在獲得中間體74之第二途徑中,在步驟1b中,在高溫下使用碳酸銀使烷基溴中間體69與中間體27進行反應以得到中間體70。在步驟2b中,使用硼氫化鋰還原中間體70之酯以得到醇71,然後在步驟3b中使用第三丁醇鉀與烷基溴72進行反應以得到中間體74。 在步驟5中,在高溫下使用鈀觸媒使中間體74與重氮乙酸乙酯進行偶合以得到中間體75。在步驟6中,在高溫下使用鈀觸媒實施分子內施蒂勒偶合以得到中間體76。或者,藉由一鍋式偶合(利用雙(新戊二醇)二硼使用鈀觸媒及新戊酸鉀)及分子內交叉偶合來達成步驟6以得到環狀中間體76。然後在步驟7中使用LiOH水溶液或於ACN/水中之胍鹼水解中間體76以得到酸中間體77。 Reaction Image 9 Scheme 9 shows the synthesis of intermediate 77 for the preparation of compounds of the invention and shows two synthetic routes to common intermediate 74. In a first route to intermediate 74, in step 1a, acid intermediate 65 is reduced using borane-dimethylsulfide complex to give alcohol intermediate 66, which is then intermediated with sodium hydride and bromide in step 2a Compound 67 is reacted to give intermediate 68. In step 3a, the ester is reduced using lithium borohydride to give intermediate 73, which is then subjected to Mitsunobu reaction with intermediate 27 to give intermediate 74 in step 4a. In a second route to intermediate 74, alkyl bromide intermediate 69 is reacted with intermediate 27 using silver carbonate at elevated temperature to give intermediate 70 in step 1b. In step 2b, the ester of intermediate 70 is reduced using lithium borohydride to give alcohol 71, followed by reaction with alkyl bromide 72 using potassium tert-butoxide to give intermediate 74 in step 3b. In step 5, intermediate 74 is coupled with ethyl diazoacetate at elevated temperature using a palladium catalyst to give intermediate 75. In step 6, intramolecular Stiller coupling was performed at elevated temperature using a palladium catalyst to afford intermediate 76. Alternatively, step 6 was achieved by one-pot coupling (using bis(neopentyl glycol) diboron using a palladium catalyst and potassium pivalate) and intramolecular cross-coupling to give cyclic intermediate 76 . Intermediate 76 is then base hydrolyzed in step 7 using either aqueous LiOH or guanidine in ACN/water to give acid intermediate 77.
反應圖 10 反應圖10展示用於製備本發明化合物之中間體83之製備。展示獲得公共中間體81之兩種途徑。在第一途徑中,在步驟1a中使用鈀觸媒及碳酸鹽鹼在高溫下使中間體78與2-[( E)-2-乙氧基乙烯基]-4,4,5,5-四甲基-1,3,2-二氧硼㖦進行偶合以得到中間體79。在步驟2a中,使用還原劑(例如二異丁基氫化鋁)處理酯以得到醇80,然後使用強有機鹼(例如第三丁醇鉀)與芳基氟41進行反應以得到中間體81。在第二途徑中,首先在步驟1b中使用鈀觸媒及無機鹼在高溫下使中間體34 (參見反應圖3)與(E)-1-乙氧基乙烯-2-酸頻哪醇酯進行偶合以得到中間體81。 在步驟4中,使用HCl在有機溶劑中處理中間體81以得到醛82,然後在步驟3中使用NaBH 4還原以得到醇中間體83。或者,可在一個步驟中使用乙酸汞及NaBH 4將中間體81轉化成中間體83。 React Chart 10 Scheme 10 shows the preparation of intermediate 83 for the preparation of compounds of the invention. Two routes to the common intermediate 81 are shown. In the first route, intermediate 78 is reacted with 2-[( E )-2-ethoxyvinyl]-4,4,5,5- Coupling with tetramethyl-1,3,2-dioxaboronium affords intermediate 79. In step 2a, treatment of the ester with a reducing agent such as diisobutylaluminum hydride gives alcohol 80, followed by reaction with aryl fluoride 41 using a strong organic base such as potassium tert-butoxide to give intermediate 81. In the second approach, intermediate 34 (see Reaction Scheme 3) and (E)-1-ethoxyethylene-2- Acid pinacol esters were coupled to afford intermediate 81. In step 4, intermediate 81 is treated with HCl in an organic solvent to give aldehyde 82, which is then reduced with NaBH4 in step 3 to give alcohol intermediate 83. Alternatively, intermediate 81 can be converted to intermediate 83 using mercuric acetate and NaBH4 in one step.
反應圖 11 反應圖11展示用於製備本發明化合物之中間體86之製備。在步驟1中,在高溫下使用(2-乙氧基-2-側氧基乙基)溴化鋅(II)及鈀觸媒使芳基碘84進行根岸偶合。在步驟2中,在流動反應器中使用N-溴琥珀醯亞胺使中間體85進行光化學溴化以得到溴化物中間體86。 React Chart 11 Scheme 11 shows the preparation of intermediate 86 for the preparation of compounds of the invention. In Step 1, aryl iodide 84 was subjected to Negishi coupling using (2-ethoxy-2-oxoethyl)zinc(II) bromide and a palladium catalyst at elevated temperature. In step 2, intermediate 85 was photochemically brominated using N-bromosuccinimide in a flow reactor to give bromide intermediate 86.
反應圖 12 反應圖12展示製備用於製備本發明化合物之中間體92之多種途徑。在步驟1a中,使用2,6-二-第三丁基吡啶及三氟甲磺酸銀使中間體83與中間體86進行反應以得到中間體89。或者,可首先在步驟1b中使中間體83與烷基溴87在類似於步驟1a之條件下進行反應以得到中間體88,然後在步驟1c中使用(2-乙氧基-2-側氧基乙基))溴化鋅及鈀觸媒在高溫下進行根岸偶合以得到中間體89。在步驟2a中,使中間體89在高溫下進行鈀催化之分子內施蒂勒偶合以得到中間體91。或者,在步驟2b中,藉由使用雙(頻哪醇)二硼、Pd(dppf)Cl 2及乙酸鉀在高溫下進行交叉偶合來將溴化物89轉化成酸酯中間體90,然後在步驟2c中經由分子內交叉偶合使用鈀觸媒實施環化以形成大環中間體91 (步驟2b及2c可實施為單一反應步驟)。最後,在步驟3中,使用LiOH水溶液或於ACN/水中之胍鹼水解酯以得到酸中間體92。 React Chart 12 Scheme 12 shows various routes for the preparation of intermediate 92 useful in the preparation of compounds of the invention. In step 1a, intermediate 83 is reacted with intermediate 86 using 2,6-di-tert-butylpyridine and silver triflate to give intermediate 89. Alternatively, intermediate 83 can be first reacted with alkyl bromide 87 in step 1b to give intermediate 88 under conditions similar to step 1a, and then used (2-ethoxy-2-oxo Negishi coupling with ethyl ethyl)) zinc bromide and palladium catalyst at elevated temperature afforded intermediate 89. In step 2a, intermediate 89 is subjected to a palladium-catalyzed intramolecular Stiller coupling at elevated temperature to afford intermediate 91 . Alternatively, in step 2b , bromide 89 was converted to Ester intermediate 90 is then cyclized via intramolecular cross-coupling using a palladium catalyst to form macrocyclic intermediate 91 in step 2c (steps 2b and 2c can be performed as a single reaction step). Finally, in step 3, the ester is base hydrolyzed using aqueous LiOH or guanidine in ACN/water to afford acid intermediate 92.
反應圖 13 反應圖13展示用於製備本發明化合物之中間體100之製備。首先在步驟1中使用光延條件使中間體93與中間體27進行偶合以得到中間體94。在步驟2中,使用鎳及銥觸媒使中間體94與溴乙醇進行偶合並使用藍光(456 nm)輻照反應液以得到中間體95。或者,以類似於在反應圖10中製備中間體83所展示之合成途徑之方式自中間體93 (代替中間體78)開始來製備中間體95。在步驟3中,使用2,6-二-第三丁基吡啶及三氟甲磺酸銀使中間體95與中間體96進行反應以得到中間體97。在步驟4中,藉由交叉偶合使用雙(頻哪醇)二硼、Pd(dppf)Cl 2及乙酸鉀在高溫下來將溴化物中間體97轉化成酸酯中間體98。在步驟5中,然後使用鈀觸媒使中間體98進行分子內交叉偶合以形成大環中間體99。或者,在一個步驟中經由分子內施蒂勒偶合使用六甲基二錫及鈀觸媒在高溫下將中間體97轉化成中間體99。然後在步驟6中使用LiOH水溶液或於ACN/水中之胍鹼水解中間體99以得到酸中間體100。 React Figure 13 Scheme 13 shows the preparation of intermediate 100 for the preparation of compounds of the invention. First, intermediate 93 is coupled with intermediate 27 using Mitsunobu conditions in step 1 to obtain intermediate 94 . In step 2, intermediate 94 was coupled with bromoethanol using nickel and iridium catalysts and the reaction solution was irradiated with blue light (456 nm) to obtain intermediate 95 . Alternatively, intermediate 95 was prepared starting from intermediate 93 (instead of intermediate 78) in a manner similar to the synthetic pathway shown for the preparation of intermediate 83 in Reaction Scheme 10. In step 3, intermediate 95 is reacted with intermediate 96 using 2,6-di-tert-butylpyridine and silver triflate to give intermediate 97. In step 4 , bromide intermediate 97 was converted to Ester intermediate 98. In step 5, intermediate 98 is then subjected to intramolecular cross-coupling to form macrocyclic intermediate 99 using a palladium catalyst. Alternatively, intermediate 97 was converted to intermediate 99 via intramolecular Stiller coupling using hexamethylditin and palladium catalysts at elevated temperature in one step. Intermediate 99 is then base hydrolyzed in step 6 using either aqueous LiOH or guanidine in ACN/water to give acid intermediate 100.
反應圖 14 反應圖14展示用於製備本發明化合物之中間體109之製備。在步驟1中,在高溫下使用N-溴琥珀醯亞胺使中間體101進行自由基溴化,然後與三甲基矽基氰化物及TBAF進行反應,然後使用硫酸在高溫下於EtOH水溶液中進行處理以得到酯中間體102。在步驟2中,使用鈀觸媒及碳酸鹽鹼使中間體102與(E)-1-乙氧基乙烯-2-酸頻哪醇酯進行偶合以得到中間體103,然後在步驟3中使用乙酸汞及硼氫化鈉轉化成醇104。單獨地,首先(例如)使用SEM基團對醛中間體43實施保護且然後在步驟4中使用硼氫化鈉進行還原以得到中間體105。在步驟5中,使中間體105與中間體27進行光延反應以得到中間體106。經由光延反應使中間體104及106偶合以得到中間體107,然後在步驟7中以類似於反應圖12中步驟2a (一鍋式施蒂勒偶合)或步驟2b及2c (硼化,隨後進行Pd催化之交叉偶合)之方式進行分子內環化以得到中間體108。然後在步驟8中使用LiOH水溶液或於ACN/水中之胍鹼實施酯水解以得到中間體109。 React Figure 14 Scheme 14 shows the preparation of intermediate 109 for the preparation of compounds of the invention. In Step 1, intermediate 101 is subjected to free radical bromination using N-bromosuccinimide at elevated temperature, followed by reaction with trimethylsilyl cyanide and TBAF, followed by sulfuric acid in aqueous EtOH at elevated temperature Work-up gives ester intermediate 102. In step 2, intermediate 102 is reacted with (E)-1-ethoxyethylene-2- Acid pinacol esters were coupled to give intermediate 103, which was then converted to alcohol 104 in step 3 using mercuric acetate and sodium borohydride. Separately, aldehyde intermediate 43 is first protected (for example) with a SEM group and then reduced in step 4 with sodium borohydride to give intermediate 105 . In step 5, intermediate 105 is subjected to a Mitsunobu reaction with intermediate 27 to obtain intermediate 106 . Intermediates 104 and 106 were coupled via the Mitsunobu reaction to give intermediate 107, which was then followed in Step 7 in a manner similar to Step 2a (one-pot Stiller coupling) or Steps 2b and 2c (borylation, followed by boronation) in Reaction Scheme 12. Pd-catalyzed cross-coupling) for intramolecular cyclization to afford intermediate 108. Ester hydrolysis was then carried out in step 8 using aqueous LiOH or guanidine base in ACN/water to give intermediate 109.
反應圖 15 反應圖15展示用於製備本發明化合物之中間體115之製備。在步驟1a中,在高溫下使用碳酸銀使烷基溴中間體144與中間體27進行反應,隨後在步驟2a中使用Red-Al ®還原酯以得到中間體112。或者,在步驟1b中使用甲酸鉀及鈀觸媒對中間體34實施羰基化以得到中間體111,隨後在步驟2b中使用NaBH 4還原醛以得到中間體112。在步驟3中,使用CBr 4及三苯基膦將中間體112之醇轉化成烷基溴以得到中間體113。在步驟4中,使中間體113及104與三氟甲磺酸銀進行反應以得到中間體114。然後在步驟5中以類似於反應圖12中步驟2a (一鍋式施蒂勒偶合)之方式或在步驟5及6中以類似於反應圖12中步驟2b及2c (硼化,隨後進行Pd催化之交叉偶合)之方式使中間體114發生分子內環化。在步驟7中使用LiOH水溶液或於ACN/水中之胍鹼水解所得酯以得到中間體115。 React Figure 15 Scheme 15 shows the preparation of intermediate 115 for the preparation of compounds of the invention. In step 1a, alkyl bromide intermediate 144 is reacted with intermediate 27 using silver carbonate at elevated temperature, followed by reduction of the ester using Red- Al® to give intermediate 112 in step 2a. Alternatively, intermediate 34 was carbonylated using potassium formate and palladium catalysts in step 1b to give intermediate 111, followed by reduction of the aldehyde with NaBH4 to give intermediate 112 in step 2b. In step 3, the alcohol of intermediate 112 is converted to alkyl bromide using CBr 4 and triphenylphosphine to give intermediate 113. In step 4, intermediates 113 and 104 are reacted with silver triflate to give intermediate 114. Then in step 5 in a manner similar to step 2a in Reaction Scheme 12 (one-pot Stiller coupling) or in steps 5 and 6 in a manner similar to steps 2b and 2c in Reaction Scheme 12 (borylation followed by Pd Intramolecular cyclization of intermediate 114 was achieved by means of catalyzed cross-coupling. The resulting ester is hydrolyzed in step 7 using aqueous LiOH or guanidine base in ACN/water to afford intermediate 115.
反應圖 16 反應圖16展示用於製備本發明化合物之中間體123之製備。在步驟1中,使中間體116與溴二氟乙酸甲酯及銅進行反應以得到中間體117,然後在步驟2中使用N-溴琥珀醯亞胺在流動反應器中以光化學方式實施溴化以得到烷基溴中間體118。在步驟3中,在高溫下使用磷酸鹽鹼使中間體118與中間體27進行反應以得到中間體119,然後在步驟4中進行LiBH 4還原以得到醇中間體120。在步驟5中,使用NaH處理中間體120並與中間體124進行反應以得到中間體121。在步驟6中,在高溫下使用(2-乙氧基-2-側氧基-乙基)溴化鋅及鈀觸媒使中間體121進行根岸偶合以得到中間體122。然後在步驟7中以類似於反應圖12中步驟2a (一鍋式施蒂勒偶合)或步驟2b及2c (硼化,隨後進行Pd催化之交叉偶合)之方式使中間體122進行分子內環化。然後在步驟8中使用LiOH水溶液或於ACN/水中之胍鹼水解酯以得到中間體123。 React Figure 16 Scheme 16 shows the preparation of intermediate 123 for the preparation of compounds of the invention. In step 1, intermediate 116 is reacted with methyl bromodifluoroacetate and copper to give intermediate 117, which is then brominated photochemically in a flow reactor using N-bromosuccinimide in step 2. to give the alkyl bromide intermediate 118. In step 3, intermediate 118 was reacted with intermediate 27 using a phosphate base at elevated temperature to give intermediate 119, followed by LiBH4 reduction in step 4 to give alcohol intermediate 120. In step 5, intermediate 120 is treated with NaH and reacted with intermediate 124 to obtain intermediate 121 . In step 6, intermediate 121 was subjected to Negishi coupling using (2-ethoxy-2-oxo-ethyl)zinc bromide and palladium catalyst at elevated temperature to obtain intermediate 122 . Intermediate 122 is then subjected to intramolecular cyclization in Step 7 in a manner similar to Step 2a (one-pot Stiller coupling) or Steps 2b and 2c (boration followed by Pd-catalyzed cross-coupling) in Scheme 12. change. The ester is then base hydrolyzed in step 8 using aqueous LiOH or guanidine in ACN/water to afford intermediate 123.
反應圖 17 反應圖17展示用於製備本發明化合物之酸酯中間體128之製備。在步驟1中,使用三氟甲磺酸銀使中間體83與烷基溴中間體125進行反應以得到中間體126,然後在步驟2中以類似於反應圖12中步驟2a (一鍋式施蒂勒偶合)或步驟2b及2c (硼化,隨後進行Pd催化之交叉偶合)之方式進行分子內環化。最後,在步驟3中在高溫下使用鈀觸媒及乙酸鉀使中間體127與雙(頻哪醇)二硼進行偶合以得到酸酯中間體128。 React Figure 17 Reaction Scheme 17 shows the reaction scheme used to prepare the compounds of the present invention Preparation of ester intermediate 128. In step 1, intermediate 83 is reacted with alkyl bromide intermediate 125 using silver triflate to give intermediate 126, which is then followed in step 2 in a manner similar to step 2a in Reaction Scheme 12 (one pot Thiele coupling) or steps 2b and 2c (borylation followed by Pd-catalyzed cross-coupling) for intramolecular cyclization. Finally, intermediate 127 is coupled with bis(pinacol)diboron using a palladium catalyst and potassium acetate at elevated temperature in step 3 to give Ester intermediate 128.
反應圖 18 反應圖18展示經由諸多不同途徑自中間體129 (涵蓋中間體128之通式)或中間體130 (涵蓋中間體55、64、77、92、100、109、115及123之通式)來製備本發明化合物。 為製備式IX’之酸化合物,在步驟1a中使用鈀觸媒及磷酸鹽鹼在高溫下使中間體129與氯甲基咪唑中間體23進行偶合以得到中間體143,然後在步驟3a中使用LiOH水溶液或於ACN/水中之胍鹼在高溫下水解酯以得到式IX’酸。或者,在步驟1c中使用醯胺偶合試劑(例如EDC或HATU)使酸中間體130與中間體15進行偶合以得到中間體132。然後在步驟2a中使用乙酸在高溫下對中間體132實施環化以得到中間體143,然後如步驟3a中所闡述將酯水解。 在步驟4a中藉由使用EDC及4-二甲基胺基吡啶使式IX’酸與環丙基甲磺醯胺進行偶合來製備式IX’’化合物。 藉由以下方式來來製備式IX’’’化合物:在步驟1b中使用HATU使中間體130與中間體18 (不含四唑氮保護基團,例如SEM)或22 (含有四唑氮保護基團)進行偶合以得到中間體131,然後在步驟2b中使用乙酸在高溫下實施環化(然後視需要步驟3b –使用例如TBAF實施四唑去保護以去除SEM基團)以得到式IX’’’之四唑化合物。 React Figure 18 Scheme 18 shows the preparation from Intermediate 129 (covering the general formula of Intermediate 128) or Intermediate 130 (covering the general formula of Intermediates 55, 64, 77, 92, 100, 109, 115 and 123) via a number of different routes Compounds of the invention. To prepare the acid compound of formula IX', intermediate 129 is coupled with chloromethylimidazole intermediate 23 at high temperature using palladium catalyst and phosphate base in step 1a to obtain intermediate 143, which is then used in step 3a Aqueous LiOH or guanidine base in ACN/water hydrolyzes the ester at elevated temperature to give the acid of formula IX'. Alternatively, acid intermediate 130 is coupled with intermediate 15 using an amide coupling reagent such as EDC or HATU to give intermediate 132 in step 1c. Intermediate 132 is then cyclized using acetic acid at elevated temperature in step 2a to give intermediate 143, followed by hydrolysis of the ester as described in step 3a. Compounds of formula IX'' are prepared in step 4a by coupling acids of formula IX' with cyclopropylmethanesulfonamide using EDC and 4-dimethylaminopyridine. Compounds of formula IX''' are prepared by combining intermediate 130 with intermediate 18 (without a tetrazolium nitrogen protecting group, such as SEM) or 22 (with a tetrazolium nitrogen protecting group) using HATU in step 1b. ) to give intermediate 131, followed by cyclization using acetic acid at elevated temperature in step 2b (then optionally step 3b - tetrazole deprotection using eg TBAF to remove the SEM group) to give formula IX''' Tetrazole compounds.
反應圖 19 反應圖19展示式IX’’’’之本發明化合物之製備。在步驟1a中使用醇中間體136使中間體133進行光延反應以得到135,然後在步驟2中使用胺13及三級胺鹼在高溫下進行S NAr反應以得到中間體138。或者,首先在步驟1b中使用醇136使二氟芳基中間體134進行S NAr反應,首先使用NaH處理且然後與中間體134在高溫下進行反應以得到中間體135。第二替代方式在步驟1c中藉由使用中間體137及136以類似於步驟1b之方式進行S NAr反應來得到中間體138。在步驟3中使用(例如)氫氣及碳載鈀還原中間體138之硝基以得到苯胺中間體139。然後,以類似於反應圖18中步驟1c、2a及3a之方式,以三個步驟自中間體139及130來製備式IX’’’’化合物。若反應圖19中所示之「-O-R」基團具有保護基團(例如氮上之Boc基團或氧上之第三丁基二甲基矽基),則作為最後步驟可去除該保護基團(例如使用TFA去除Boc基團或使用TBAF去除第三丁基二甲基矽基)。 React Figure 19 Reaction Scheme 19 shows the preparation of compounds of the invention of formula IX''''. Intermediate 133 was subjected to Mitsunobu reaction using alcohol intermediate 136 in step 1a to give 135, followed by SNAr reaction in step 2 using amine 13 and a tertiary amine base at elevated temperature to give intermediate 138. Alternatively, difluoroaryl intermediate 134 is first subjected to SNAr reaction with alcohol 136 in step 1b, treated first with NaH and then reacted with intermediate 134 at elevated temperature to give intermediate 135. A second alternative provides intermediate 138 in step 1c by performing a SNAr reaction using intermediates 137 and 136 in a similar manner to step 1b. The nitro group of intermediate 138 is reduced in step 3 using, for example, hydrogen and palladium on carbon to give aniline intermediate 139 . Compounds of formula IX'''' are then prepared from intermediates 139 and 130 in three steps in a manner similar to steps 1c, 2a and 3a in Scheme 18. If the "-OR" group shown in Reaction Scheme 19 has a protecting group (such as a Boc group on the nitrogen or a tert-butyldimethylsilyl group on the oxygen), then this protecting group can be removed as a final step groups (eg TFA for removal of Boc groups or TBAF for removal of tertiary butyldimethylsilyl groups).
反應圖 20 反應圖20展示自鹵化物中間體140來製備本發明化合物。在高溫下使用鈀觸媒及無機鹼使中間體140與視情況經取代之5-或6員芳基或雜芳基酸或酸酯進行交叉偶合反應(例如鈴木(Suzuki)偶合)以得到141。或者,可(例如)使用四羥基二硼及鈀觸媒在高溫下將140轉化成酸酯142,從而得到呈酸形式之142,然後與視情況經取代之5-或6員芳基或雜芳基鹵化物進行交叉偶合反應(例如鈴木偶合)以得到141。可在經保護或未保護形式之R 5上實施該等步驟,舉例而言,酯可用作經保護官能基且可水解以得到R 5= -CO 2H。 Reaction Chart 20 Scheme 20 shows the preparation of compounds of the invention from halide intermediate 140 . Intermediate 140 is reacted with an optionally substituted 5- or 6-membered aryl or heteroaryl group using a palladium catalyst and an inorganic base at elevated temperature sour or The ester is subjected to a cross-coupling reaction (eg Suzuki coupling) to give 141. Alternatively, 140 can be converted to Ester 142, so as to obtain 142 in the acid form, followed by a cross-coupling reaction (eg Suzuki coupling) with an optionally substituted 5- or 6-membered aryl or heteroaryl halide to give 141. These steps can be performed on R5 in protected or unprotected form, for example, esters can be used as protected functional groups and can be hydrolyzed to give R5 = -CO2H .
製備及實例在AGILENT ®HP1200液相層析系統上實施LC-ES/MS。在界接至可或可不具有ELSD之HPLC之質量選擇性檢測器/四極質譜儀上實施電噴霧質譜量測(以正及/或負模式獲得)。LC-ES/MS條件(低pH):管柱:PHENOMENEX ®GEMINI ®NX C18 2.0 × 50 mm 3.0 µm, 110 Å;梯度:在1.5 min內5-95% B,然後在0.5 min內95% B;管柱溫度:50℃ +/-10℃;流速:1.2 mL/min;1 µL注入體積;溶劑A:含有0.1% HCOOH之去離子水;溶劑B:含有0.1%甲酸之ACN;波長:200-400 nm及212-216 nm。若HPLC配備有ELSD,則設置為45℃蒸發儀溫度、40℃噴霧器溫度及1.6 SLM氣體流速。替代LC-MS條件(高pH):管柱:Waters xBridge ®C18管柱,2.1×50 mm, 3.5 µm;梯度:在1.5 min內5-95% B,然後在0.50 min內95% B;管柱溫度:50℃ +/-10℃;流速:1.2 mL/min;1μL注入體積;溶劑A:10 mM NH 4HCO 3,pH 9;溶劑B:ACN;波長:200-400 nm及212-216nm;若具有ELSD,則:45℃蒸發儀溫度、40℃噴霧器溫度及1.60 SLM氣體流速。 Preparation and Examples LC-ES/MS was performed on an AGILENT ® HP1200 liquid chromatography system. Electrospray mass spectrometry (acquired in positive and/or negative mode) was performed on a mass selective detector/quadrupole mass spectrometer interfaced to an HPLC that may or may not have an ELSD. LC-ES/MS conditions (low pH): Column: PHENOMENEX ® GEMINI ® NX C18 2.0 × 50 mm 3.0 µm, 110 Å; Gradient: 5-95% B in 1.5 min, then 95% B in 0.5 min ;Column temperature: 50℃ +/-10℃; Flow rate: 1.2 mL/min; 1 µL injection volume; Solvent A: deionized water containing 0.1% HCOOH; Solvent B: ACN containing 0.1% formic acid; Wavelength: 200 -400 nm and 212-216 nm. If the HPLC is equipped with an ELSD, the settings are 45 °C evaporator temperature, 40 °C nebulizer temperature and 1.6 SLM gas flow rate. Alternative LC-MS conditions (high pH): Column: Waters xBridge ® C18, 2.1×50 mm, 3.5 µm; Gradient: 5-95% B in 1.5 min, then 95% B in 0.50 min; tube Column temperature: 50°C +/-10°C; Flow rate: 1.2 mL/min; 1 μL injection volume; Solvent A: 10 mM NH 4 HCO 3 , pH 9; Solvent B: ACN; Wavelength: 200-400 nm and 212-216nm ; if with ELSD: 45°C evaporator temperature, 40°C nebulizer temperature and 1.60 SLM gas flow rate.
製備 14-溴-5-氟-2-甲氧基-苯甲酸甲酯 向4-溴-5-氟-2-羥基-苯甲酸甲酯(10.0 g, 40.1 mmol)及碳酸鉀(13.8 g, 100 mmol)於ACN (200 mL)中之混合物中添加碘甲烷(5.0 mL, 80.2 mmol)。將反應液在60℃下攪拌15 h。使用水(150 mL)稀釋反應混合物並使用DCM (3 × 60 mL)萃取。使用水(50 mL)洗滌合併之有機層。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮以得到10.3 g標題化合物(98%),其以粗製形式用於製備2。 1H-NMR (400 MHz, CDCl 3) δ 7.60 (d, J= 9 Hz, 1H), 7.15 (d, J= 5 Hz, 1H), 3.90 (s, 6H)。 Preparation 1 4-Bromo-5-fluoro-2-methoxy-benzoic acid methyl ester To a mixture of methyl 4-bromo-5-fluoro-2-hydroxy-benzoate (10.0 g, 40.1 mmol) and potassium carbonate (13.8 g, 100 mmol) in ACN (200 mL) was added methyl iodide (5.0 mL , 80.2 mmol). The reaction solution was stirred at 60 °C for 15 h. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were washed with water (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 10.3 g of the title compound (98%), which was used in Preparation 2 in crude form. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 9 Hz, 1H), 7.15 (d, J = 5 Hz, 1H), 3.90 (s, 6H).
製備 2(4-溴-5-氟-2-甲氧基-苯基)甲醇 向4-溴-5-氟-2-甲氧基-苯甲酸甲酯(14 g, 53.2 mmol)及MeOH (30 mL)於THF (300 mL)中之溶液中添加硼氫化鈉(10.7 g, 272 mmol)。將反應液在50℃下攪拌4 h。在減壓下濃縮反應混合物。將殘餘物溶於EtOAc (300 mL)中並使用鹽水(2 × 100 mL)洗滌。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於己烷中之0 - 20% EtOAc之梯度來純化殘餘物以得到11.5 g標題化合物(92%)。 1H-NMR (400 MHz, CDCl 3) δ 7.14 (d, J= 8 Hz, 1H), 7.0 (d, J= 6 Hz, 1H), 4.63 (s, 2H), 3.85 (s, 3H)。 Preparation of 2 (4-bromo-5-fluoro-2-methoxy-phenyl)methanol To a solution of methyl 4-bromo-5-fluoro-2-methoxy-benzoate (14 g, 53.2 mmol) and MeOH (30 mL) in THF (300 mL) was added sodium borohydride (10.7 g, 272 mmol). The reaction solution was stirred at 50 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL) and washed with brine (2 x 100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-20% EtOAc in hexanes to afford 11.5 g of the title compound (92%). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.14 (d, J = 8 Hz, 1H), 7.0 (d, J = 6 Hz, 1H), 4.63 (s, 2H), 3.85 (s, 3H).
製備 31-溴-4-(溴甲基)-2-氟-5-甲氧基-苯 向(4-溴-5-氟-2-甲氧基-苯基)甲醇(11.5 g, 48.9 mmol)於DCM (200 mL)中之溶液中添加三溴化磷(5.6 mL, 59 mmol)。將在室溫下反應液攪拌1 h。藉由添加冰水(50 mL)來終止反應並使用飽和碳酸氫鈉水溶液鹼化至pH 7。使用水(100 mL)洗滌有機層。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮以得到12.5 g標題化合物(86%),其以粗製形式用於製備4。 1H-NMR (400 MHz, CDCl 3) δ 7.13 (d, J= 8 Hz, 1H), 7.03 (d, J= 6 Hz, 1H), 4.46 (s, 2H), 3.89 (s, 3H)。 Preparation 3 1-Bromo-4-(bromomethyl)-2-fluoro-5-methoxy-benzene To a solution of (4-bromo-5-fluoro-2-methoxy-phenyl)methanol (11.5 g, 48.9 mmol) in DCM (200 mL) was added phosphorus tribromide (5.6 mL, 59 mmol). The reaction was stirred for 1 h at room temperature. The reaction was quenched by the addition of ice water (50 mL) and basified to pH 7 using saturated aqueous sodium bicarbonate. The organic layer was washed with water (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 12.5 g of the title compound (86%), which was used in Preparation 4 in crude form. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.13 (d, J = 8 Hz, 1H), 7.03 (d, J = 6 Hz, 1H), 4.46 (s, 2H), 3.89 (s, 3H).
製備 42-(4-溴-5-氟-2-甲氧基-苯基)乙腈 向1-溴-4-(溴甲基)-2-氟-5-甲氧基-苯(12.5 g, 42.0 mmol)及TMSCN (6.8 mL, 50.5 mmol)於ACN (250 mL)中之溶液中添加TBAF溶液(1.0 M於THF中,50 mL, 50 mmol)。將反應液在室溫下攪拌4 h。在減壓下濃縮反應液。將殘餘物溶於EtOAc (200 mL)中並使用飽和氯化鈉水溶液(2 × 50 mL)洗滌。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之0 - 10% EtOAc之梯度來純化殘餘物以得到8.0 g標題化合物(78%)。 1H-NMR (400 MHz, CDCl 3) δ 7.19 (d, J= 8 Hz, 1H), 7.04 (d, J= 5 Hz, 1H), 3.86 (s, 3H), 3.64 (s, 2H)。 Preparation 4 2-(4-bromo-5-fluoro-2-methoxy-phenyl)acetonitrile To a solution of 1-bromo-4-(bromomethyl)-2-fluoro-5-methoxy-benzene (12.5 g, 42.0 mmol) and TMSCN (6.8 mL, 50.5 mmol) in ACN (250 mL) A solution of TBAF (1.0 M in THF, 50 mL, 50 mmol) was added. The reaction solution was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous sodium chloride (2 x 50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-10% EtOAc in petroleum ether to afford 8.0 g of the title compound (78%). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.19 (d, J = 8 Hz, 1H), 7.04 (d, J = 5 Hz, 1H), 3.86 (s, 3H), 3.64 (s, 2H).
製備 52-(4-溴-5-氟-2-甲氧基-苯基)乙酸乙酯 向2-(4-溴-5-氟-2-甲氧基-苯基)乙腈(8.0 g, 32.8 mmol)於乙醇(100 mL)中之溶液中添加濃硫酸(25 mL)。將反應液在80℃下攪拌18 h。使用飽和碳酸氫鈉水溶液將反應液中和至pH 7。使用DCM (2 × 100 mL)萃取反應混合物。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮以得到9.3 g標題化合物(97%),其以粗製形式用於製備6。1H-NMR (400 MHz, CDCl3) δ 7.02-6.99 (m, 2H), 4.16 (q, J= 7 Hz, 2H), 3.80 (s, 3H), 3.56 (s, 2H), 1.26 (t, J= 7 Hz, 3H)。 Preparation 5 Ethyl 2-(4-bromo-5-fluoro-2-methoxy-phenyl)acetate To a solution of 2-(4-bromo-5-fluoro-2-methoxy-phenyl)acetonitrile (8.0 g, 32.8 mmol) in ethanol (100 mL) was added concentrated sulfuric acid (25 mL). The reaction solution was stirred at 80 °C for 18 h. The reaction solution was neutralized to pH 7 using saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with DCM (2 x 100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 9.3 g of the title compound (97%), which was used in crude form in Preparation 6. 1H-NMR (400 MHz, CDCl 3 ) δ 7.02-6.99 ( m, 2H), 4.16 (q, J = 7 Hz, 2H), 3.80 (s, 3H), 3.56 (s, 2H), 1.26 (t, J = 7 Hz, 3H).
製備 62-(4-溴-5-氟-2-羥基-苯基)乙酸乙酯 將2-(4-溴-5-氟-2-甲氧基-苯基)乙酸乙酯(5.0 g, 17.2 mmol)於DCM (100 mL)中之溶液冷卻至-78℃。添加三溴化硼(8.0 mL, 84.8 mmol)並將反應液在室溫下攪拌2 h。將反應混合物冷卻至0℃並使用冰水(40 mL)終止反應。使用飽和碳酸氫鈉水溶液將溶液鹼化至pH 7。使用水(20 mL)洗滌有機層。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮以得到4.0 g標題化合物(84%),其以粗製形式用於製備10、54及60。 1H-NMR (400 MHz, CDCl 3) δ 7.69 (s, 1H), 7.14 (d, J= 6 Hz, 1H), 6.90 (d, J= 4 Hz, 1H), 4.22 (q, J= 7 Hz, 2H), 3.61 (s, 2H), 1.31 (t, J= 8 Hz, 3 H)。 Preparation 6 Ethyl 2-(4-bromo-5-fluoro-2-hydroxy-phenyl)acetate A solution of ethyl 2-(4-bromo-5-fluoro-2-methoxy-phenyl)acetate (5.0 g, 17.2 mmol) in DCM (100 mL) was cooled to -78 °C. Boron tribromide (8.0 mL, 84.8 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C and quenched with ice water (40 mL). The solution was basified to pH 7 using saturated aqueous sodium bicarbonate. The organic layer was washed with water (20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4.0 g of the title compound (84%), which was used in preparations 10, 54, and 60 in crude form. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.69 (s, 1H), 7.14 (d, J = 6 Hz, 1H), 6.90 (d, J = 4 Hz, 1H), 4.22 (q, J = 7 Hz, 2H), 3.61 (s, 2H), 1.31 (t, J = 8 Hz, 3H).
製備 72-(4-溴-2-羥基-5-甲基-苯基)乙酸甲酯 基本上如製備6中所闡述使用2-(4-溴-2-甲氧基-5-甲基-苯基)乙酸甲酯來製備標題化合物。ES-MS m/z259及261 (M+H)。 Preparation 7 Methyl 2-(4-bromo-2-hydroxy-5-methyl-phenyl)acetate The title compound was prepared essentially as described in Preparation 6 using methyl 2-(4-bromo-2-methoxy-5-methyl-phenyl)acetate. ES-MS m/z 259 and 261 (M+H).
製備 82-[2-羥基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 向2-(4-溴-2-羥基-苯基)乙酸甲酯(1.30 g, 5.30 mmol)、雙(頻哪醇)二硼(1.98 g, 7.72 mmol)、KOAc (2.23 g, 22.5 mmol)及Pd(dppf)Cl 2(420 mg, 0.57 mmol)之混合物中添加1,4-二噁烷(24 mL)。將反應混合物在氮氣氛及80℃下攪拌60 h。經由Celite ®墊過濾混合物,並使用EtOAc沖洗。在減壓下濃縮濾液。將殘餘物溶於DCM中,吸附於二氧化矽上,並經由矽膠急速層析使用於己烷中之0 - 55% EtOAc之梯度純化以得到748 mg標題化合物(48%)。ES-MS m/z293 (M+H)。 Preparation 8 2-[2-Hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester Methyl 2-(4-bromo-2-hydroxy-phenyl)acetate (1.30 g, 5.30 mmol), bis(pinacol)diboron (1.98 g, 7.72 mmol), KOAc (2.23 g, 22.5 mmol) and Pd(dppf) Cl2 (420 mg, 0.57 mmol) was added 1,4-dioxane (24 mL). The reaction mixture was stirred under nitrogen atmosphere at 80 °C for 60 h. The mixture was filtered through a pad of Celite® and rinsed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed on silica, and purified by flash chromatography on silica gel using a gradient of 0-55% EtOAc in hexanes to afford 748 mg of the title compound (48%). ES-MS m/z 293 (M+H).
製備 92-[2-羥基-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 基本上如製備8中所闡述使用2-(4-溴-2-羥基-5-甲基-苯基)乙酸甲酯來製備標題化合物。經由矽膠急速層析使用於己烷中之5 - 80% EtOAc之梯度進行純化。ES-MS m/z304 (M-H)。 Preparation 9 2-[2-Hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester The title compound was prepared essentially as described in Preparation 8 using methyl 2-(4-bromo-2-hydroxy-5-methyl-phenyl)acetate. Purification was performed by flash chromatography on silica gel using a gradient of 5-80% EtOAc in hexanes. ES-MS m/z 304 (MH).
製備 102-[4-(5,5-二甲基-1,3,2-二氧雜硼雜環己烷-2-基)-5-氟-2-羥基苯基]乙酸乙酯 使用氮吹掃含有2-(4-溴-5-氟-2-羥基-苯基)乙酸乙酯(2.43 g, 8.16 mmol)、雙(新戊二醇)二硼(2.82 g, 12.2 mmol)及KOAc (2.04 g, 20.4 mmol)之燒瓶。添加無水1,4-二噁烷(33 mL)並在攪拌的同時使用氮吹掃5 min。添加二氯雙(三環己基膦)鈀(II) (0.31 g, 0.41 mmol)並在攪拌的同時使用氮吹掃5 min。在90℃下攪拌6 h,然後使用1,4-二噁烷(15 mL)洗掉固體並在室溫下攪拌過夜。添加矽藻土並使用MTBE (0.1 L)稀釋。攪拌30 min,經由Celite ®墊過濾並使用MTBE (0.1 L)沖洗。在減壓及50℃下濃縮濾液。將殘餘物溶於甲苯(0.1 L)中並在50℃下再次濃縮。藉由經由矽膠墊使用EtOAc及庚烷之1:1混合物洗脫來純化殘餘物。將含有標題化合物之級分濃縮至最終體積為30 mL並將所得漿液在環境溫度下攪拌1 h。藉由過濾收集固體,使用庚烷(0.1 L)洗滌並在減壓及50℃下乾燥19 h以提供1.77 g淺橙色固體形式之標題化合物(64%)。ES-MS m/z243 (酸之M+H)。 1H-NMR (400 MHz, CDCl 3) δ 7.28 (s, 1H), 7.27 (d, J = 5.2 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.80 (s, 4H), 3.65 (s, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.05 (s, 6H)。 Preparation 10 Ethyl 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-2-hydroxyphenyl]acetate A nitrogen purge containing ethyl 2-(4-bromo-5-fluoro-2-hydroxy-phenyl)acetate (2.43 g, 8.16 mmol), bis(neopentyl glycol)diboron (2.82 g, 12.2 mmol) and a flask of KOAc (2.04 g, 20.4 mmol). Anhydrous 1,4-dioxane (33 mL) was added and purged with nitrogen for 5 min while stirring. Dichlorobis(tricyclohexylphosphine)palladium(II) (0.31 g, 0.41 mmol) was added and purged with nitrogen for 5 min while stirring. Stir at 90 °C for 6 h, then wash off the solid with 1,4-dioxane (15 mL) and stir at room temperature overnight. Add Celite and dilute with MTBE (0.1 L). Stir for 30 min, filter through a pad of Celite® and rinse with MTBE (0.1 L). The filtrate was concentrated under reduced pressure at 50 °C. The residue was dissolved in toluene (0.1 L) and concentrated again at 50 °C. The residue was purified by eluting through a pad of silica gel with a 1:1 mixture of EtOAc and heptane. Fractions containing the title compound were concentrated to a final volume of 30 mL and the resulting slurry was stirred at ambient temperature for 1 h. The solid was collected by filtration, washed with heptane (0.1 L) and dried under reduced pressure at 50 °C for 19 h to afford 1.77 g of the title compound (64%) as a pale orange solid. ES-MS m/z 243 ( Acid M+H). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.28 (s, 1H), 7.27 (d, J = 5.2 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.80 (s, 4H), 3.65 (s, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.05 (s, 6H).
製備 112-[5-氟-2-羥基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯 基本上如製備10中所闡述使用雙(頻哪醇)二硼來製備標題化合物,將混合物在90℃下攪拌2 h,然後在100℃下攪拌18 h。經由矽膠急速層析使用於環己烷中之0 - 50% EtOAc之梯度來純化標題化合物,然後經由矽膠急速層析使用於環己烷中之0 - 40% EtOAc之梯度再純化。ES-MS m/z325 (M+H)。 Preparation 11 2-[5-Fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]ethyl acetate The title compound was prepared using bis(pinacol)diboron essentially as described in Preparation 10, and the mixture was stirred at 90 °C for 2 h and then at 100 °C for 18 h. The title compound was purified by silica gel flash chromatography using a gradient of 0-50% EtOAc in cyclohexane, then repurified by silica gel flash chromatography using a gradient of 0-40% EtOAc in cyclohexane. ES-MS m/z 325 (M+H).
製備 12(5-溴-4-氟-2-碘苯基)甲醇 向5-溴-4-氟-2-碘-苯甲酸(6.3 g, 18.2 mmol)於THF (55 mL)中之溶液中添加硼烷二甲硫醚複合物(2 M於THF中,27 mL, 54 mmol)。將反應混合物在室溫下攪拌21 h。濃縮反應混合物並將殘餘物溶於EtOAc中。使用飽和氯化銨水溶液洗滌溶液。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之10 - 30% EtOAc之梯度來純化殘餘物以得到5.1 g標題化合物(85%)。ES-MS m/z313及315 (M-H 2O)。 Preparation of 12 (5-bromo-4-fluoro-2-iodophenyl)methanol To a solution of 5-bromo-4-fluoro-2-iodo-benzoic acid (6.3 g, 18.2 mmol) in THF (55 mL) was added borane dimethyl sulfide complex (2 M in THF, 27 mL , 54 mmol). The reaction mixture was stirred at room temperature for 21 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The solution was washed with saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 10-30% EtOAc in heptane to afford 5.1 g of the title compound (85%). ES-MS m/z 313 and 315 ( MH2O ).
製備 133,5-二氟-4-硝基-苯甲酸甲酯 將亞硫醯氯(37 mL, 74 mmol)於MeOH (110 mL)中之溶液冷卻至-10℃並添加3,5-二氟-4-硝基-苯甲腈(2.8 g, 15 mmol)。在室溫下攪拌3 h,然後在2 h內將溫度逐漸升至65℃。過濾混合物並在減壓下濃縮。將殘餘物溶於EtOAc (150 mL)中。使用飽和碳酸氫鈉水溶液(50 mL)及鹽水(50 mL)洗滌。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之10% EtOAc來純化殘餘物以得到2.24 g標題化合物(66%)。 1H-NMR (400 MHz, CDCl 3) δ 7.78 (d, 2H), 4.0 (s, 3H)。 Preparation 13 3,5-Difluoro-4-nitro-benzoic acid methyl ester A solution of thionyl chloride (37 mL, 74 mmol) in MeOH (110 mL) was cooled to -10 °C and 3,5-difluoro-4-nitro-benzonitrile (2.8 g, 15 mmol) was added . Stir at room temperature for 3 h, then gradually increase the temperature to 65 °C over 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL). Wash with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using 10% EtOAc in petroleum ether to afford 2.24 g of the title compound (66%). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.78 (d, 2H), 4.0 (s, 3H).
製備 143-氟-4-硝基-5-[[(2S)-環氧丙烷-2-基甲基]胺基]苯甲酸甲酯 將[(2S)-環氧丙烷-2-基]甲胺(545 mg, 6.13 mmol, CAS 2091328-57-1)、 3,5-二氟-4-硝基-苯甲酸甲酯(1.4 g, 6.1 mmol)及碳酸鉀(1.7 g, 12 mmol)於ACN (14 mL)中之混合物在70℃下攪拌16 h。使用水(14 mL)稀釋反應混合物並使用EtOAc (3 × 14 mL)萃取。使用鹽水(14 mL)洗滌合併之有機層。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之0 - 30% EtOAc之梯度來純化殘餘物以得到1.68 g標題化合物(79%)。ES-MS m/z285 (M+H)。 Preparation 14 Methyl 3-fluoro-4-nitro-5-[[(2S)-epoxypropan-2-ylmethyl]amino]benzoate [(2S)-Oxiran-2-yl]methylamine (545 mg, 6.13 mmol, CAS 2091328-57-1), 3,5-difluoro-4-nitro-benzoic acid methyl ester (1.4 g , 6.1 mmol) and potassium carbonate (1.7 g, 12 mmol) in ACN (14 mL) was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (14 mL) and extracted with EtOAc (3 x 14 mL). The combined organic layers were washed with brine (14 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-30% EtOAc in petroleum ether to afford 1.68 g of the title compound (79%). ES-MS m/z 285 (M+H).
製備 15(S)-3-甲氧基-4-硝基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備14中所闡述使用3-氟-5-甲氧基-4-硝基-苯甲酸甲酯來製備標題化合物。經由矽膠層析使用於DCM中之5至30% EtOAc之梯度來純化殘餘物以得到標題化合物。ES-MS m/z296 (M+H)。 Preparation of 15 (S)-methyl 3-methoxy-4-nitro-5-((epoxypropylene-2-ylmethyl)amino)benzoate The title compound was prepared essentially as described in Preparation 14 using 3-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester. The residue was purified by silica gel chromatography using a gradient of 5 to 30% EtOAc in DCM to afford the title compound. ES-MS m/z 296 (M+H).
製備 164-胺基-3-氟-5-[[(2S)-環氧丙烷-2-基甲基]胺基]苯甲酸甲酯 向3-氟-4-硝基-5-[[(2S)-環氧丙烷-2-基甲基]胺基]苯甲酸甲酯(1.68 g, 4.84 mmol)於MeOH (17 mL)中之溶液中添加含有5%鈀之林德拉觸媒(600 mg, 0.28 mmol)。在室溫及氫氣氣氛下攪拌16 h。過濾反應混合物並在減壓下濃縮濾液以得到1.4 g標題化合物(100%),其以粗製形式用於製備86及91。ES-MS m/z255 (M+H)。 Preparation 16 Methyl 4-amino-3-fluoro-5-[[(2S)-epoxypropan-2-ylmethyl]amino]benzoate To methyl 3-fluoro-4-nitro-5-[[(2S)-epoxypropan-2-ylmethyl]amino]benzoate (1.68 g, 4.84 mmol) in MeOH (17 mL) Lindella catalyst (600 mg, 0.28 mmol) containing 5% palladium was added to the solution. Stir at room temperature under hydrogen atmosphere for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 1.4 g of the title compound (100%) which was used in the preparations 86 and 91 in crude form. ES-MS m/z 255 (M+H).
製備 174-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 基本上如製備16中所闡述使用(S)-3-甲氧基-4-硝基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯來製備標題化合物。標題化合物以粗製形式用於製備89、93、99及100。ES-MS m/z267 (M+H)。 Preparation 17 Methyl 4-amino-3-methoxy-5-[[(2S)-epoxypropan-2-yl]methylamino]benzoate The title compound was prepared essentially as described in Preparation 16 using (S)-methyl 3-methoxy-4-nitro-5-(((oxiran-2-ylmethyl)amino)benzoate. The title compound was used in the preparations 89, 93, 99 and 100 in crude form. ES-MS m/z 267 (M+H).
製備 183-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-4-硝基苯甲酸甲酯 向3-氟-4-硝基苯甲酸甲酯(300 mg, 1.5 mmol)及TEA (1.1 mL, 8.1 mmol)於THF (6 mL)及DMF (3 mL)中之溶液中添加(1-乙基-1H-咪唑-5-基)甲胺二鹽酸鹽(339 mg, 1.6 mmol)。在35℃下攪拌2 h,然後在50℃下攪拌16 h。使用水稀釋粗製反應混合物並使用EtOAc (3 × 15 mL)萃取。使用水及飽和NaCl水溶液洗滌合併之有機層,藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0 - 100% EtOAc且隨後於DCM中之5% MeOH之梯度來純化殘餘物以得到395 mg標題化合物(88%)。ES-MS m/z305 (M+H)。 Preparation 18 Methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate To a solution of methyl 3-fluoro-4-nitrobenzoate (300 mg, 1.5 mmol) and TEA (1.1 mL, 8.1 mmol) in THF (6 mL) and DMF (3 mL) was added (1-Ethyl (1H-imidazol-5-yl)methanamine dihydrochloride (339 mg, 1.6 mmol). Stir at 35 °C for 2 h, then at 50 °C for 16 h. The crude reaction mixture was diluted with water and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water and saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel using a gradient of 0-100% EtOAc in heptane followed by 5% MeOH in DCM to afford 395 mg of the title compound (88%). ES-MS m/z 305 (M+H).
製備 194-胺基-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)苯甲酸甲酯 將鐵(193 mg, 3.5 mmol)、氯化銨(10 mg, 0.19 mmol)及乙酸(46 mg, 0.77 mmol)於水(3 mL)中之溶液在50℃下攪拌15 min。添加3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-4-硝基苯甲酸甲酯(117 mg, 0.38 mmol)於DMF (1 mL)中之溶液。在50℃下攪拌15 min。使用碳酸鈉水溶液終止反應(至pH 8)並經由Celite ®過濾。使用水(2 × 20 mL)洗滌殘餘物並使用EtOAc (2 × 20 mL)反萃取水層。藉由硫酸鎂乾燥合併之有機相,過濾,並在減壓下濃縮以得到106 mg標題化合物(100%),其以粗製形式用於製備95。ES-MS m/z275 (M+H)。 Preparation 19 Methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate A solution of iron (193 mg, 3.5 mmol), ammonium chloride (10 mg, 0.19 mmol) and acetic acid (46 mg, 0.77 mmol) in water (3 mL) was stirred at 50°C for 15 min. Add a solution of methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (117 mg, 0.38 mmol) in DMF (1 mL) . Stir at 50 °C for 15 min. The reaction was quenched with aqueous sodium carbonate (to pH 8) and filtered through Celite® . The residue was washed with water (2 x 20 mL) and the aqueous layer was back extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 106 mg of the title compound (100%), which was used in Preparation 95 in crude form. ES-MS m/z 275 (M+H).
製備 203-氟-5-甲氧基-4-硝基苯甲腈 向5-溴-1-氟-3-甲氧基-2-硝基苯(700 mg, 2.7 mmol)、氰化鋅(226 mg, 1.9 mmol)及四(三苯基膦)鈀(0) (317 mg, 0.27 mmol)之混合物中添加DMF (17.8 mL)。在100℃下攪拌1.5 h。使用水稀釋粗製反應混合物並使用EtOAc萃取。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0 - 15% EtOAc之梯度來純化殘餘物以得到479 mg標題化合物(89%)。ES-MS m/z197 (M+H)。 Preparation of 20 3-fluoro-5-methoxy-4-nitrobenzonitrile To 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (700 mg, 2.7 mmol), zinc cyanide (226 mg, 1.9 mmol) and tetrakis (triphenylphosphine) palladium (0) (317 mg, 0.27 mmol) was added DMF (17.8 mL). Stir at 100 °C for 1.5 h. The crude reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0-15% EtOAc in heptane to afford 479 mg of the title compound (89%). ES-MS m/z 197 (M+H).
製備 21(S)-3-甲氧基-4-硝基-5-((環氧丙烷-2-基甲基)胺基)苯甲腈 將TEA (1.07 mL, 7.7 mmol)及(S)-環氧丙烷-2-基甲胺(235 mg, 2.56 mmoL)添加至3-氟-5-甲氧基-4-硝基苯甲腈(457 mg, 2.3 mmol)於DMF (7 mL)中之溶液中。在35℃下攪拌過夜。使用水稀釋粗製反應混合物並使用EtOAc萃取。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0 - 30% EtOAc之梯度來純化殘餘物以得到471 mg標題化合物(77%)。ES-MS m/z264 (M+H)。 Preparation of 21 (S)-3-methoxy-4-nitro-5-((epoxypropylene-2-ylmethyl)amino)benzonitrile To 3-fluoro-5-methoxy-4-nitrobenzonitrile ( 457 mg, 2.3 mmol) in DMF (7 mL). Stir overnight at 35°C. The crude reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient of 0-30% EtOAc in heptane to afford 471 mg of the title compound (77%). ES-MS m/z 264 (M+H).
製備 22(S)-3-甲氧基-2-硝基-N-(環氧丙烷-2-基甲基)-5-(1H-四唑-5-基)苯胺 將三丁基疊氮化錫(1.96 mL, 7.0 mmol)添加至(S)-3-甲氧基-4-硝基-5-((環氧丙烷-2-基甲基)胺基)苯甲腈(217 mg, 0.82 mmol)於甲苯(9.3 mL)中之溶液中。在微波中於攪拌下加熱至150℃並保持2.5 h。經由於二氧化矽中之10% w/w KF之塞過濾粗製反應混合物。濃縮並使用DCM研磨殘餘物以得到194 mg標題化合物(62%)。ES-MS m/z307 (M+H)。 Preparation of 22 (S)-3-methoxy-2-nitro-N-(epoxypropylene-2-ylmethyl)-5-(1H-tetrazol-5-yl)aniline Tributyltin azide (1.96 mL, 7.0 mmol) was added to (S)-3-methoxy-4-nitro-5-(((epoxypropan-2-ylmethyl)amino)benzene A solution of formylnitrile (217 mg, 0.82 mmol) in toluene (9.3 mL). Heat to 150 °C with stirring in microwave for 2.5 h. The crude reaction mixture was filtered through a plug of 10% w/w KF in silica. Concentrate and triturate the residue with DCM to give 194 mg of the title compound (62%). ES-MS m/z 307 (M+H).
製備 23(S)-3-甲氧基-N1-(環氧丙烷-2-基甲基)-5-(1H-四唑-5-基)苯-1,2-二胺 將碳載鈀(20 mg, 0.009 mmol)添加至(S)-3-甲氧基-2-硝基-N-(環氧丙烷-2-基甲基)-5-(1H-四唑-5-基)苯胺(160 mg, 0.42 mmol)及MeOH (3 mL)之混合物中。在室溫及4巴氫壓下攪拌8 h。經由Celite ®過濾粗製反應混合物並濃縮以得到120 mg標題化合物(52%),其以粗製形式用於製備96。ES-MS m/z277 (M+H)。 Preparation of 23 (S)-3-methoxy-N1-(epoxypropylene-2-ylmethyl)-5-(1H-tetrazol-5-yl)benzene-1,2-diamine Palladium on carbon (20 mg, 0.009 mmol) was added to (S)-3-methoxy-2-nitro-N-(epoxypropylene-2-ylmethyl)-5-(1H-tetrazole- 5-yl)aniline (160 mg, 0.42 mmol) and MeOH (3 mL). Stir for 8 h at room temperature under 4 bar hydrogen pressure. The crude reaction mixture was filtered through Celite® and concentrated to give 120 mg of the title compound (52%), which was used in Preparation 96 in crude form. ES-MS m/z 277 (M+H).
製備 244-[(6-溴-2-吡啶基)氧基甲基]-3-碘-苯甲腈 向4-(溴甲基)-3-碘-苯甲腈(2.88 g, 8.93 mmol)、6-溴吡啶-2-醇(1.10 g, 6.30 mmol)及碳酸銀(5.1 g, 18.0 mmol)之混合物中添加1,4-二噁烷(50 mL)。將反應混合物在60℃下攪拌15 h。使用EtOAc (50 mL)稀釋反應液並經由矽藻土過濾。使用水(2 × 50 mL)及飽和氯化鈉水溶液(50 mL)洗滌濾液。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由使用於己烷中之5 - 30% EtOAc之梯度洗脫之矽膠急速層析來純化殘餘物以得到2.8 g標題化合物(76%)。ES-MS m/z415及417 (M+H)。 Preparation 24 4-[(6-bromo-2-pyridyl)oxymethyl]-3-iodo-benzonitrile To 4-(bromomethyl)-3-iodo-benzonitrile (2.88 g, 8.93 mmol), 6-bromopyridin-2-ol (1.10 g, 6.30 mmol) and silver carbonate (5.1 g, 18.0 mmol) 1,4-Dioxane (50 mL) was added to the mixture. The reaction mixture was stirred at 60 °C for 15 h. The reaction was diluted with EtOAc (50 mL) and filtered through celite. The filtrate was washed with water (2 x 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5 - 30% EtOAc in hexanes to afford 2.8 g of the title compound (76%). ES-MS m/z 415 and 417 (M+H).
製備 254-氰基-3-(3-羥丙基)苯甲酸乙酯 在使用氮鼓泡的同時,將溴化鎳(II) (167 mg, 0.76 mmol)及4,4'-二-第三丁基-2,2'-聯吡啶(210 mg, 0.77)於無水1,4-二噁烷(40 mL)中之混合物在室溫下攪拌15 min。添加3-溴-4-氰基苯甲酸乙酯(2 g, 7.71 mmol)、3-溴-1-丙醇(1.7 mL, 18 mmol)及酞菁鈷(II) (441 mg, 0.77 mmol)。在使用氮鼓泡的同時,將混合物在室溫下攪拌5 min。添加四(二甲基胺基)乙烯(2.5 mL, 11 mmol)並在使用氮鼓泡的同時將混合物在室溫下繼續攪拌5 min。密封容器並將混合物在85℃下攪拌過夜。將混合物冷卻至室溫,經由Celite ®過濾並在減壓下濃縮。經由矽膠急速層析使用於環己烷中之20 - 50% EtOAc之梯度來純化殘餘物以得到綠色固體形式之標題化合物(863 mg, 46%)。ES-MS m/z251 (M+NH 4 +)。 Preparation 25 Ethyl 4-cyano-3-(3-hydroxypropyl)benzoate While bubbling with nitrogen, nickel(II) bromide (167 mg, 0.76 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (210 mg, 0.77) were dissolved in anhydrous The mixture in 1,4-dioxane (40 mL) was stirred at room temperature for 15 min. Add ethyl 3-bromo-4-cyanobenzoate (2 g, 7.71 mmol), 3-bromo-1-propanol (1.7 mL, 18 mmol) and cobalt(II) phthalocyanine (441 mg, 0.77 mmol) . While bubbling with nitrogen, the mixture was stirred at room temperature for 5 min. Tetrakis(dimethylamino)ethylene (2.5 mL, 11 mmol) was added and the mixture was stirred at room temperature for 5 min while bubbling with nitrogen. The vessel was sealed and the mixture was stirred overnight at 85 °C. The mixture was cooled to room temperature, filtered through Celite® and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 20-50% EtOAc in cyclohexane to give the title compound (863 mg, 46%) as a green solid. ES-MS m/z 251 (M+ NH4 + ).
製備 263-[3-[第三丁基(二甲基)矽基]氧基丙基]-4-氰基-苯甲酸乙酯 在室溫下,將三丁基二甲基氯矽烷(615 mg, 3.96 mmol)及咪唑(298 mg, 4.33 mmol)添加至4-氰基-3-(3-羥丙基)苯甲酸乙酯(863 mg, 3.59 mmol)於DCM (15 mL)中之溶液中。將混合物攪拌1 h並在減壓下濃縮。經由矽膠急速層析使用於環己烷中之0%至50% EtOAc之梯度來純化殘餘物以提供無色油狀物形式之標題化合物(1.24 g, 94%)。ES-MS m/z348 (M+H)。 Preparation 26 3-[3-[tert-Butyl(dimethyl)silyl]oxypropyl]-4-cyano-benzoic acid ethyl ester Tributyldimethylsilyl chloride (615 mg, 3.96 mmol) and imidazole (298 mg, 4.33 mmol) were added to ethyl 4-cyano-3-(3-hydroxypropyl)benzoate at room temperature (863 mg, 3.59 mmol) in DCM (15 mL). The mixture was stirred for 1 h and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0% to 50% EtOAc in cyclohexane to afford the title compound (1.24 g, 94%) as a colorless oil. ES-MS m/z 348 (M+H).
製備 272-[3-[第三丁基(二甲基)矽基]氧基丙基]-4-(羥甲基)苯甲腈 在0℃及氮氣氛下,將於THF中之硼氫化鋰(2.0 M, 3.9 mL, 7.8 mmol)添加至3-[3-[第三丁基(二甲基)矽基]氧基丙基]-4-氰基-苯甲酸乙酯(1.24 g, 3.39 mmol)於無水THF (9 mL)中之溶液中。在5 min之後去除冷卻浴並在室溫下攪拌過夜。濃縮以去除大部分反應溶劑並在0℃下小心添加檸檬酸(5%)。使用DCM萃取水層,合併有機層,藉由無水硫酸鈉乾燥,過濾並在減壓下濃縮。經由矽膠急速層析使用於環己烷中10%至50% EtOAc之梯度之來純化殘餘物以提供無色蠟狀固體形式之標題化合物(935 mg, 90%)。ES-MS m/z306 (M+H)。 Preparation 27 2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-(hydroxymethyl)benzonitrile Lithium borohydride (2.0 M, 3.9 mL, 7.8 mmol) in THF was added to 3-[3-[tert-butyl(dimethyl)silyl]oxypropyl ]-4-cyano-benzoic acid ethyl ester (1.24 g, 3.39 mmol) in anhydrous THF (9 mL). After 5 min the cooling bath was removed and stirred overnight at room temperature. Concentrate to remove most of the reaction solvent and add citric acid (5%) carefully at 0 °C. The aqueous layer was extracted with DCM, the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient of 10% to 50% EtOAc in cyclohexane to afford the title compound (935 mg, 90%) as a colorless waxy solid. ES-MS m/z 306 (M+H).
製備 284-[(6-溴-2-吡啶基)氧基甲基]-3-[3-[第三丁基(二甲基)矽基]氧基丙基]苯甲腈 向4-[(6-溴-2-吡啶基)氧基甲基]-3-碘-苯甲腈(2.6 g, 6.3 mmol)及四(三苯基膦)鈀(0) (0.27 g, 0.23 mmol)於1,4-二噁烷(50 mL)中之混合物中添加溴-[3-[第三丁基(二甲基)矽基]氧基丙基]鋅(0.50 M於THF中,25 mL, 12.5 mmol)。在60℃下攪拌1 h。使用EtOAc (100 mL)稀釋反應混合物,然後使用飽和氯化銨水溶液(100 mL)及鹽水(100 mL)洗滌。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由使用於己烷中之5 - 50% EtOAc之梯度洗脫之矽膠急速層析來純化殘餘物以得到1.07 g標題化合物(37%)。ES-MS m/z461及463 (M+H)。 Preparation 28 4-[(6-bromo-2-pyridyl)oxymethyl]-3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile 4-[(6-Bromo-2-pyridyl)oxymethyl]-3-iodo-benzonitrile (2.6 g, 6.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.23 mmol) in 1,4-dioxane (50 mL) was added bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc (0.50 M in THF , 25 mL, 12.5 mmol). Stir at 60 °C for 1 h. The reaction mixture was diluted with EtOAc (100 mL), then washed with saturated aqueous ammonium chloride (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5-50% EtOAc in hexanes to afford 1.07 g of the title compound (37%). ES-MS m/z 461 and 463 (M+H).
製備 294-[(6-溴-2-吡啶基)氧基甲基]-3-(3-羥丙基)苯甲腈 向4-[(6-溴-2-吡啶基)氧基甲基]-3-[3-[第三丁基(二甲基)矽基]氧基丙基]苯甲腈(1.32 g, 2.86 mmol)於THF (50 mL)中之混合物中添加TBAF溶液(1.0 M於THF中,2.9 mL, 2.9 mmol)。將反應混合物在室溫下攪拌1 h。使用EtOAc (50 mL)稀釋並使用飽和氯化銨水溶液(50 mL)及鹽水(50 mL)洗滌。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由使用於己烷中之5 - 75% EtOAc之梯度洗脫之矽膠急速層析來純化殘餘物以得到0.90 g標題化合物(92%)。ES-MS m/z347及349 (M+H)。 Preparation 29 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(3-hydroxypropyl)benzonitrile To 4-[(6-bromo-2-pyridyl)oxymethyl]-3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile (1.32 g, 2.86 mmol) in THF (50 mL) was added TBAF solution (1.0 M in THF, 2.9 mL, 2.9 mmol). The reaction mixture was stirred at room temperature for 1 h. Diluted with EtOAc (50 mL) and washed with saturated aqueous ammonium chloride (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5-75% EtOAc in hexanes to afford 0.90 g of the title compound (92%). ES-MS m/z 347 and 349 (M+H).
製備 304-[(6-溴-2-吡啶基)氧基甲基]-2-[3-[第三丁基(二甲基)矽基]氧基丙基]苯甲腈 在0℃及氮氣氛下,將DIAD (915 μL, 4.5 mmol)緩慢添加至三苯基膦(1.21 g, 4.61 mmol)於無水THF (15 mL)中之溶液中。將混合物攪拌30 min且然後添加2-[3-[第三丁基(二甲基)矽基]氧基丙基]-4-(羥甲基)苯甲腈(925 mg, 3.03 mmol)於無水THF (6 mL)中之溶液及2-溴-6-羥基吡啶(610 mg, 3.33 mmol)。去除冷卻浴,在室溫下攪拌2h,並在減壓下濃縮混合物。經由矽膠急速層析使用於環己烷中之0 - 30% EtOAc之梯度來純化殘餘物以提供1.12g標題化合物(78%)。ES-MS m/z461及463 (M+H)。 Preparation 30 4-[(6-bromo-2-pyridyl)oxymethyl]-2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile DIAD (915 μL, 4.5 mmol) was slowly added to a solution of triphenylphosphine (1.21 g, 4.61 mmol) in anhydrous THF (15 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred for 30 min and then 2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-(hydroxymethyl)benzonitrile (925 mg, 3.03 mmol) was added to Solution in anhydrous THF (6 mL) and 2-bromo-6-hydroxypyridine (610 mg, 3.33 mmol). The cooling bath was removed, stirred at room temperature for 2 h, and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0-30% EtOAc in cyclohexane to afford 1.12 g of the title compound (78%). ES-MS m/z 461 and 463 (M+H).
製備 314-[(6-溴-2-吡啶基)氧基甲基]-2-(3-羥丙基)苯甲腈 在室溫下,將TBAF溶液(1.0 M於THF中,2.7 mL, 2.7 mmol)緩慢添加至4-[(6-溴-2-吡啶基)氧基甲基]-2-[3-[第三丁基(二甲基)矽基]氧基丙基]苯甲腈(1.12 g, 2.43 mmol)於THF (24 mL)中之溶液中。將混合物攪拌1h。濃縮反應混合物並使用MTBE及水稀釋殘餘物。分離有機層並使用水及飽和NaCl水溶液洗滌,藉由無水Na 2SO 4乾燥,然後過濾並在減壓下濃縮。經由矽膠急速層析使用於環己烷中之25 - 50% EtOAc之梯度來純化殘餘物以提供白色固體形式之標題化合物(790 mg, 89%)。ES-MS m/z347及349 (M+H)。 Preparation 31 4-[(6-bromo-2-pyridyl)oxymethyl]-2-(3-hydroxypropyl)benzonitrile A solution of TBAF (1.0 M in THF, 2.7 mL, 2.7 mmol) was slowly added to 4-[(6-bromo-2-pyridyl)oxymethyl]-2-[3-[ In a solution of tributyl(dimethyl)silyl]oxypropyl]benzonitrile (1.12 g, 2.43 mmol) in THF (24 mL). The mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was diluted with MTBE and water. The organic layer was separated and washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4 , then filtered and concentrated under reduced pressure . The residue was purified by flash chromatography on silica gel using a gradient of 25-50% EtOAc in cyclohexane to afford the title compound (790 mg, 89%) as a white solid. ES-MS m/z 347 and 349 (M+H).
製備 323-(2-((第三丁基二甲基矽基)氧基)乙氧基)-4-甲醯基苯甲腈 向4-甲醯基-3-羥基苯甲腈(3.0g, 18.8 mmol)於DMF (56 mL)中之溶液中添加碘化鈉(1.4 g, 9.3 mmol)、碳酸鉀(3.8 g, 38 mmol)及(2-溴乙氧基)-第三丁基二甲基矽烷(6.1 mL, 28 mmol)。將混合物在70℃下攪拌24 h。使用水及EtOAc稀釋粗製反應混合物並使用EtOAc萃取水層。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0 - 30% EtOAc之梯度來純化殘餘物以得到5.68 g標題化合物(99%)。ES-MS m/z306 (M+H)。 Preparation 32 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-formylbenzonitrile To a solution of 4-formyl-3-hydroxybenzonitrile (3.0 g, 18.8 mmol) in DMF (56 mL) was added sodium iodide (1.4 g, 9.3 mmol), potassium carbonate (3.8 g, 38 mmol ) and (2-bromoethoxy)-tert-butyldimethylsilane (6.1 mL, 28 mmol). The mixture was stirred at 70 °C for 24 h. The crude reaction mixture was diluted with water and EtOAc and the aqueous layer was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0-30% EtOAc in heptane to afford 5.68 g of the title compound (99%). ES-MS m/z 306 (M+H).
製備 333-(2-((第三丁基二甲基矽基)氧基)乙氧基)-4-(羥甲基)苯甲腈 將3-(2-((第三丁基二甲基矽基)氧基)乙氧基)-4-甲醯基苯甲腈(450 mg, 1.47 mmol)於MeOH (4.6 mL)中之溶液冷卻至0℃。添加硼氫化鈉(112 mg, 2.96 mmol)並將混合物在0℃下攪拌15 min。將混合物升溫至室溫並攪拌1 h。使用水稀釋混合物並使用1 M HCl水溶液調節至pH 7,然後使用EtOAc萃取。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。使殘餘物通過矽膠墊以得到350 mg標題化合物(77%)。 1H-NMR (400 MHz, CDCl 3) δ 7.32 (d, J= 7.7 Hz, 1H), 7.15 (d, J= 7.7 Hz, 1H), 7.02 (d, J= 1.0 Hz, 1H), 4.60 (s, 2H), 4.0 (m, 2H), 3.8 (m, 2H), 3.03 (s, 1H), 0.81 (s, 9H), 0.0 (s, 6H)。 Preparation 33 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(hydroxymethyl)benzonitrile A solution of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-formylbenzonitrile (450 mg, 1.47 mmol) in MeOH (4.6 mL) Cool to 0 °C. Sodium borohydride (112 mg, 2.96 mmol) was added and the mixture was stirred at 0 °C for 15 min. The mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with water and adjusted to pH 7 with 1 M aqueous HCl, then extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was passed through a pad of silica gel to give 350 mg of the title compound (77%). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.32 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 1.0 Hz, 1H), 4.60 ( s, 2H), 4.0 (m, 2H), 3.8 (m, 2H), 3.03 (s, 1H), 0.81 (s, 9H), 0.0 (s, 6H).
製備 344-(((6-溴吡啶-2-基)氧基)甲基)-3-(2-((第三丁基二甲基矽基)氧基)乙氧基)苯甲腈 向3-(2-((第三丁基二甲基矽基)氧基)乙氧基)-4-(羥甲基)苯甲腈(350 mg, 1.14 mmol)、6-溴吡啶-2-醇(1.4 g, 8.0 mmol)及三苯基膦(2.35 g, 8.96 mmol)於THF (50 mL)中之溶液中添加DIAD (1.76 mL, 8.94 mmol)。將混合物在50℃下攪拌4 h且然後濃縮粗製反應混合物。使用EtOAc稀釋殘餘物,然後使用水(3×)及鹽水洗滌。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0 - 20% EtOAc之梯度來純化殘餘物以得到247 mg標題化合物(47%)。ES-MS m/z463及465 (M+H)。 Preparation 34 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzonitrile To 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(hydroxymethyl)benzonitrile (350 mg, 1.14 mmol), 6-bromopyridine-2 - To a solution of alcohol (1.4 g, 8.0 mmol) and triphenylphosphine (2.35 g, 8.96 mmol) in THF (50 mL) was added DIAD (1.76 mL, 8.94 mmol). The mixture was stirred at 50 °C for 4 h and then the crude reaction mixture was concentrated. The residue was diluted with EtOAc, then washed with water (3x) and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient of 0-20% EtOAc in heptane to afford 247 mg of the title compound (47%). ES-MS m/z 463 and 465 (M+H).
製備 354-(((6-溴吡啶-2-基)氧基)甲基)-3-(2-羥基乙氧基)苯甲腈 基本上如製備31中所闡述使用4-(((6-溴吡啶-2-基)氧基)甲基)-3-(2-((第三丁基二甲基矽基)氧基)乙氧基)苯甲腈來製備標題化合物,將反應液在室溫下攪拌2 h。經由矽膠急速層析使用於DCM中之0 - 20% EtOAc之梯度純化標題化合物。ES-MS m/z349及351 (M+H)。 Preparation 35 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-(2-hydroxyethoxy)benzonitrile Essentially as described in Preparation 31 using 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-(2-((tert-butyldimethylsilyl)oxy) Ethoxy)benzonitrile to prepare the title compound, and the reaction was stirred at room temperature for 2 h. The title compound was purified by flash chromatography on silica gel using a gradient of 0-20% EtOAc in DCM. ES-MS m/z 349 and 351 (M+H).
製備 36(E)-3-[5-氯-2-(羥甲基)苯基]丙-2-烯酸乙酯 向(2-溴-4-氯-苯基)甲醇(17.5 g, 79.0 mmol)、四丁基氯化銨(26.1 g, 93.9 mmol)、碳酸鉀(16.7 g, 121 mmol)及乙酸鈀(1.47 g, 6.55 mmol)於DMF (400 mL)中之混合物中添加丙烯酸乙酯(10.3 mL, 94.8 mmol)。將反應混合物在氮氣氛及90℃下攪拌6 h。經由Celite ®墊過濾反應混合物,然後使用EtOAc (200 mL)沖洗。使用EtOAc (200 mL)稀釋濾液並使用水(800 mL)洗滌。使用EtOAc (250 mL)反萃取水層。藉由硫酸鎂乾燥合併之有機相,過濾,並在減壓下濃縮。將殘餘物溶於DCM中,吸附於二氧化矽上,並經由矽膠層析使用於己烷中之15 - 40% EtOAc之梯度純化以得到6.14 g標題化合物(32%)。ES-MS m/z258 (M+NH 4 +)。 Preparation of 36 (E)-3-[5-Chloro-2-(hydroxymethyl)phenyl]prop-2-enoic acid ethyl ester To (2-bromo-4-chloro-phenyl)methanol (17.5 g, 79.0 mmol), tetrabutylammonium chloride (26.1 g, 93.9 mmol), potassium carbonate (16.7 g, 121 mmol) and palladium acetate (1.47 g, 6.55 mmol) in DMF (400 mL) was added ethyl acrylate (10.3 mL, 94.8 mmol). The reaction mixture was stirred under nitrogen atmosphere at 90 °C for 6 h. The reaction mixture was filtered through a pad of Celite® , then rinsed with EtOAc (200 mL). The filtrate was diluted with EtOAc (200 mL) and washed with water (800 mL). The aqueous layer was back extracted with EtOAc (250 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed on silica, and purified via silica gel chromatography using a gradient of 15-40% EtOAc in hexanes to afford 6.14 g of the title compound (32%). ES-MS m/z 258 (M+ NH4 + ).
製備 373-[5-氯-2-(羥甲基)苯基]丙酸乙酯 向碳載硫化鉑(5%, 220 mg, 0.056 mmol)於EtOAc (20 mL)中之混合物中添加於EtOAc (30 mL)中之(E)-3-[5-氯-2-(羥甲基)苯基]丙-2-烯酸乙酯(2.21 g, 9.18 mmol)。在室溫及40 psi氫氣壓下於帕爾振盪器(Parr shaker)中振盪1 h。經由Celite ®墊過濾並在減壓下濃縮濾液以提供1.91 g標題化合物(86%),其以粗製形式用於製備38。ES-MS m/z225 (M-H 2O)。 Preparation 37 Ethyl 3-[5-chloro-2-(hydroxymethyl)phenyl]propionate To a mixture of platinum sulfide on carbon (5%, 220 mg, 0.056 mmol) in EtOAc (20 mL) was added (E)-3-[5-chloro-2-(hydroxymethyl) in EtOAc (30 mL) yl)phenyl]prop-2-enoic acid ethyl ester (2.21 g, 9.18 mmol). Shake in a Parr shaker (Parr shaker) at room temperature and 40 psi hydrogen pressure for 1 h. Filtration through a pad of Celite® and concentration of the filtrate under reduced pressure provided 1.91 g of the title compound (86%) which was used in crude form in Preparation 38. ES-MS m/z 225 ( MH2O ).
製備 383-[2-(溴甲基)-5-氯-苯基]丙酸乙酯 向3-[5-氯-2-(羥甲基)苯基]丙酸乙酯(1.90 g, 7.80 mmol)於二乙醚(40 mL)中之混合物中逐滴添加三溴化磷(0.80 mL, 8.5 mmol)。在氮氣氛及室溫下攪拌1 h。藉由緩慢、逐滴添加飽和碳酸氫鈉水溶液(5 mL)來驟冷。分離各層且並使用乙酸乙酯(5 mL)萃取水層。藉由硫酸鎂乾燥合併之有機相,過濾,並在減壓下濃縮以提供2.40 g標題化合物(100%),其以粗製形式用於製備45。ES-MS m/z322及324 (M+NH 4 +)。 Preparation 38 Ethyl 3-[2-(bromomethyl)-5-chloro-phenyl]propionate To a mixture of ethyl 3-[5-chloro-2-(hydroxymethyl)phenyl]propionate (1.90 g, 7.80 mmol) in diethyl ether (40 mL) was added phosphorus tribromide (0.80 mL) dropwise , 8.5 mmol). Stir under nitrogen atmosphere at room temperature for 1 h. Quench by slow, dropwise addition of saturated aqueous sodium bicarbonate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 2.40 g of the title compound (100%), which was used in crude form in Preparation 45. ES-MS m/z 322 and 324 (M+ NH4 + ).
製備 394-[(1,3-二側氧基異二氫吲哚-2-基)甲基]-3-碘-苯甲腈 向4-(溴甲基)-3-碘苯甲腈(10 g, 30.13 mmol)於DMF (100mL)中之溶液中添加酞醯亞胺鉀(6.14 g, 33.14 mmol)。將反應混合物在80℃下加熱2 h且然後在室溫下攪拌16 h。去除溶劑並在500 mL水中將固體殘餘物研磨30 min。過濾白色固體,使用水洗滌並在真空及45℃下將固體乾燥20 h以提供白色固體形式之標題化合物(11.5 g, 88%)。ES-MS m/z405 (M+OH -)。 Preparation 39 4-[(1,3-Dioxoisoindolin-2-yl)methyl]-3-iodo-benzonitrile To a solution of 4-(bromomethyl)-3-iodobenzonitrile (10 g, 30.13 mmol) in DMF (100 mL) was added potassium phthalimide (6.14 g, 33.14 mmol). The reaction mixture was heated at 80 °C for 2 h and then stirred at room temperature for 16 h. The solvent was removed and the solid residue was triturated in 500 mL of water for 30 min. The white solid was filtered, washed with water and dried under vacuum at 45 °C for 20 h to afford the title compound (11.5 g, 88%) as a white solid. ES-MS m/z 405 (M+ OH- ).
製備 404-[(1,3-二側氧基異二氫吲哚-2-基)甲基]-3-(3-羥基丙-1-炔基)苯甲腈 向4-[(1,3-二側氧基異二氫吲哚-2-基)甲基]-3-碘-苯甲腈(5.0 g, 11.7 mmol)於THF (50 mL)及TEA (50 mL)中之懸浮液中添加雙(三苯基膦)二氯化鈀(0.33 g, 0.47 mmol)、碘化亞銅(0.18 g, 0.94 mmol)及炔丙醇(2.05 mL, 35.2 mmol)。將反應混合物在40℃下加熱3 h。冷卻至室溫,使用EtOAc (50 mL)及水(50 mL)稀釋並經由Celite ®過濾混合物。分離各相並使用額外EtOAc (2 × 50 mL)萃取水相。合併有機物,藉由硫酸鎂乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於環己烷中之30% EtOAc至100% EtOAc之梯度來純化殘餘物以得到3.2g (79%)奶油色固體形式之標題化合物。ES-MS m/z315 (M-H)。 Preparation of 40 4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-(3-hydroxyprop-1-ynyl)benzonitrile To 4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-iodo-benzonitrile (5.0 g, 11.7 mmol) in THF (50 mL) and TEA ( 50 mL) was added bis(triphenylphosphine)palladium dichloride (0.33 g, 0.47 mmol), cuprous iodide (0.18 g, 0.94 mmol) and propargyl alcohol (2.05 mL, 35.2 mmol) . The reaction mixture was heated at 40 °C for 3 h. Cool to room temperature, dilute with EtOAc (50 mL) and water (50 mL) and filter the mixture through Celite® . The phases were separated and the aqueous phase was extracted with additional EtOAc (2 x 50 mL). The organics were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 30% EtOAc to 100% EtOAc in cyclohexane to afford 3.2 g (79%) of the title compound as a cream solid. ES-MS m/z 315 (MH).
製備 414-[(1,3-二側氧基異二氫吲哚-2-基)甲基]-3-(3-羥丙基)苯甲腈 在250 mL Buchi® Miniclave反應器中,向4-[(1,3-二側氧基異二氫吲哚-2-基)甲基]-3-(3-羥基丙-1-炔基)苯甲腈(3 g, 9.48 mmol)於MeOH (60 mL)中之懸浮液中添加1,1'-雙(二-異丙基膦基)二茂鐵(1,5-環辛二烯)四氟硼酸銠(I) (0.34 g, 0.47 mmol)。向反應器中裝填90 psi氫並在50℃下加熱2 h。將反應混合物冷卻至室溫,蒸發溶劑並經由二氧化矽塞使用EtOAc作為溶劑來純化殘餘物以提供2.4g (75%)淺奶油色固體形式之標題化合物。ES-MS m/z321 (M+H)。 Preparation of 41 4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-(3-hydroxypropyl)benzonitrile In a 250 mL Buchi® Miniclave reactor, to 4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-(3-hydroxyprop-1-ynyl) To a suspension of benzonitrile (3 g, 9.48 mmol) in MeOH (60 mL) was added 1,1'-bis(di-isopropylphosphino)ferrocene(1,5-cyclooctadiene) Rhodium(I) tetrafluoroborate (0.34 g, 0.47 mmol). The reactor was charged with 90 psi hydrogen and heated at 50 °C for 2 h. The reaction mixture was cooled to room temperature, the solvent was evaporated and the residue was purified through a plug of silica using EtOAc as solvent to afford 2.4 g (75%) of the title compound as a pale cream solid. ES-MS m/z 321 (M+H).
製備 424-(胺基甲基)-3-(3-羥丙基)苯甲腈 向4-[(1,3-二側氧基異二氫吲哚-2-基)甲基]-3-(3-羥丙基)苯甲腈(2.4 g, 7.49 mmol)於MeOH (45 mL)中之懸浮液中添加單水合肼(1.90 mL, 37.6 mmol)並在60℃下攪拌20 h。將反應混合物冷卻至室溫並過濾固體。蒸發濾液,使用水(30 mL)稀釋殘餘物並使用DCM/MeOH 9:1 (3 × 20 mL)萃取。合併有機物,藉由硫酸鎂乾燥,過濾,並在減壓下濃縮以得到微紅色油狀物形式之標題化合物(880 mg, 49%)。ES-MS m/z191 (M+H)。 Preparation 42 4-(aminomethyl)-3-(3-hydroxypropyl)benzonitrile To 4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-(3-hydroxypropyl)benzonitrile (2.4 g, 7.49 mmol) in MeOH (45 mL) was added hydrazine monohydrate (1.90 mL, 37.6 mmol) and stirred at 60°C for 20 h. The reaction mixture was cooled to room temperature and the solid was filtered. The filtrate was evaporated, the residue was diluted with water (30 mL) and extracted with DCM/MeOH 9:1 (3 x 20 mL). The organics were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (880 mg, 49%) as a reddish oil. ES-MS m/z 191 (M+H).
製備 432-(((5-溴-4-氟-2-碘苄基)氧基)甲基)-4-氰基苯甲酸甲酯 在0℃下,向(5-溴-4-氟-2-碘苯基)甲醇(1.5 g, 4.5 mmol)於THF (24 mL)中之溶液中添加氫化鈉(60%,於礦物油中,362 mg, 9.1 mmol)。在0℃下攪拌30 min。添加2-(溴甲基)-4-氰基-苯甲酸甲酯(2.3 g, 9.1 mmol)並在室溫下攪拌1 h。使用EtOAc稀釋反應液並使用水及飽和NaCl水溶液洗滌有機層。使用EtOAc反萃取水層。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用DCM來純化殘餘物以得到2.5 g標題化合物(67%,61%純),且未經進一步純化即用於製備44中。ES-MS m/z504及506 (M+H)。 Preparation 43 Methyl 2-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-cyanobenzoate To a solution of (5-bromo-4-fluoro-2-iodophenyl)methanol (1.5 g, 4.5 mmol) in THF (24 mL) at 0 °C was added sodium hydride (60% in mineral oil , 362 mg, 9.1 mmol). Stir at 0 °C for 30 min. Add 2-(bromomethyl)-4-cyano-benzoic acid methyl ester (2.3 g, 9.1 mmol) and stir at room temperature for 1 h. The reaction was diluted with EtOAc and the organic layer was washed with water and saturated aqueous NaCl. The aqueous layer was back extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using DCM to give 2.5 g of the title compound (67%, 61% pure), which was used in Preparation 44 without further purification. ES-MS m/z 504 and 506 (M+H).
製備 443-(((5-溴-4-氟-2-碘苄基)氧基)甲基)-4-(羥甲基)苯甲腈 基本上如製備27中所闡述使用2-(((5-溴-4-氟-2-碘苄基)氧基)甲基)-4-氰基苯甲酸甲酯(製備43)及THF:MeOH之10:1混合物(作為反應溶劑)來製備標題化合物。在將反應液在室溫下攪拌20 h之後,添加另一部分之硼氫化鋰(0.5當量)並在室溫下攪拌2 h。使用EtOAc稀釋反應混合物並使用水及飽和NaCl水溶液洗滌有機層。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0 - 50% EtOAc之梯度來純化殘餘物以得到標題化合物。ES-MS m/z476及478 (M+H)。 Preparation 44 3-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-(hydroxymethyl)benzonitrile Using methyl 2-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-cyanobenzoate (Preparation 43) and THF essentially as described in Preparation 27: A 10:1 mixture of MeOH (as the reaction solvent) was used to prepare the title compound. After the reaction was stirred at room temperature for 20 h, another portion of lithium borohydride (0.5 equiv) was added and stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and saturated aqueous NaCl. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0-50% EtOAc in heptane to give the title compound. ES-MS m/z 476 and 478 (M+H).
製備 453-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氯-苯基]丙酸乙酯 向3-[2-(溴甲基)-5-氯-苯基]丙酸乙酯(2.40 g, 7.85 mmol)、6-溴吡啶-2-醇(1.98 g, 11.4 mmol)及碳酸銀(4.34 g, 15.7 mmol)之混合物中添加1,4-二噁烷(40 mL)。將反應混合物在40℃下攪拌15 h。經由Celite ®墊過濾並在減壓下濃縮濾液。將殘餘物溶於DCM中,吸附於二氧化矽上,並經由矽膠層析使用於己烷中之0 - 40% EtOAc之梯度純化以得到1.16 g標題化合物(37%)。ES-MS m/z398、400及402 (M+H)。 Preparation 45 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propionic acid ethyl ester To ethyl 3-[2-(bromomethyl)-5-chloro-phenyl]propionate (2.40 g, 7.85 mmol), 6-bromopyridin-2-ol (1.98 g, 11.4 mmol) and silver carbonate ( 4.34 g, 15.7 mmol) was added 1,4-dioxane (40 mL). The reaction mixture was stirred at 40 °C for 15 h. Filter through a pad of Celite® and concentrate the filtrate under reduced pressure. The residue was dissolved in DCM, adsorbed on silica, and purified via silica gel chromatography using a gradient of 0-40% EtOAc in hexanes to afford 1.16 g of the title compound (37%). ES-MS m/z 398, 400 and 402 (M+H).
製備 463-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氯-苯基]丙烷-1-醇 向3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氯-苯基]丙酸乙酯(1.16 g, 2.90 mmol)於THF (12 mL)中之混合物中逐滴添加硼氫化鋰(2.0 M於THF中,3.2 mL, 6.4 mmol)。將反應混合物在室溫下攪拌6 h。添加另一部分之硼氫化鋰(2.0 M於THF中,2.0 mL, 4.0 mmol)。將反應混合物在室溫下再攪拌17 h。藉由逐滴添加水來終止反應。使用EtOAc (50 mL)稀釋混合物並使用水(40 mL)洗滌。使用EtOAc (25 mL)反萃取水層。藉由硫酸鎂乾燥合併之有機相,過濾,並在減壓下濃縮。將殘餘物溶於DCM中,吸附於二氧化矽上,並經由使用於己烷中之0 - 55% EtOAc之梯度洗脫之矽膠急速層析純化以得到461 mg標題化合物(35%)。ES-MS m/z356、358及360 (M+H)。 Preparation 46 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propan-1-ol To a mixture of ethyl 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propanoate (1.16 g, 2.90 mmol) in THF (12 mL) Lithium borohydride (2.0 M in THF, 3.2 mL, 6.4 mmol) was added dropwise in . The reaction mixture was stirred at room temperature for 6 h. Another portion of lithium borohydride (2.0 M in THF, 2.0 mL, 4.0 mmol) was added. The reaction mixture was stirred for another 17 h at room temperature. The reaction was stopped by adding water dropwise. The mixture was diluted with EtOAc (50 mL) and washed with water (40 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed on silica, and purified by flash chromatography on silica gel eluting with a gradient of 0-55% EtOAc in hexanes to afford 461 mg of the title compound (35%). ES-MS m/z 356, 358 and 360 (M+H).
製備 474-[[(6-溴-2-吡啶基)胺基]甲基]-3-(3-羥丙基)苯甲腈 向4-(胺基甲基)-3-(3-羥丙基)苯甲腈(800 mg, 3.36 mmol)於DMSO (16 mL)中之溶液中添加2-溴-6-氟吡啶(610 mg, 3.36 mmol)及DIPEA (1.17 mL, 6.72 mmol)並在100℃下攪拌18 h。將反應混合物冷卻至室溫,使用水(40 mL)稀釋,並使用EtOAc (3 × 20 mL)萃取。合併有機物,藉由硫酸鎂乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於環己烷中之30% EtOAc至100% EtOAc之梯度來純化殘餘物以提供稠褐色油狀物形式之標題化合物(400 mg, 33%)。ES-MS m/z346及348 (M+H)。 Preparation 47 4-[[(6-bromo-2-pyridyl)amino]methyl]-3-(3-hydroxypropyl)benzonitrile To a solution of 4-(aminomethyl)-3-(3-hydroxypropyl)benzonitrile (800 mg, 3.36 mmol) in DMSO (16 mL) was added 2-bromo-6-fluoropyridine (610 mg, 3.36 mmol) and DIPEA (1.17 mL, 6.72 mmol) and stirred at 100°C for 18 h. The reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with EtOAc (3 x 20 mL). The organics were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 30% EtOAc to 100% EtOAc in cyclohexane to afford the title compound (400 mg, 33%) as a thick brown oil. ES-MS m/z 346 and 348 (M+H).
製備 484-[(3-溴苯氧基)甲基]-3-碘-苯甲腈 向4-(溴甲基)-3-碘-苯甲腈(2.0 g, 6.2 mmol)、3-溴苯酚(1.10 g, 6.4 mmol)及碳酸鉀(2.6 g, 19.0 mmol)之混合物中添加1,4-二噁烷(20 mL)。將反應混合物在室溫下攪拌15 h。使用EtOAc (100 mL)稀釋反應液並經由Celite ®過濾。使用水(2 × 50 mL)及飽和NaCl水溶液(50 mL)洗滌濾液。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由使用於己烷中之0 - 30% EtOAc之梯度洗脫之矽膠急速層析來純化殘餘物以提供2.4 g標題化合物(93%)。 1H NMR (400.13 MHz, CDCl 3) δ 8.16 (d, J= 1.5 Hz, 1H), 7.71 (dd, J= 1.5, 8.0 Hz, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.23-7.17 (m, 3H), 6.92 (dt, J= 7.5, 2.1 Hz, 1H), 5.05 (s, 2H)。 Preparation 48 4-[(3-bromophenoxy)methyl]-3-iodo-benzonitrile To a mixture of 4-(bromomethyl)-3-iodo-benzonitrile (2.0 g, 6.2 mmol), 3-bromophenol (1.10 g, 6.4 mmol) and potassium carbonate (2.6 g, 19.0 mmol) was added 1 , 4-dioxane (20 mL). The reaction mixture was stirred at room temperature for 15 h. The reaction was diluted with EtOAc (100 mL) and filtered through Celite® . The filtrate was washed with water (2 x 50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0-30% EtOAc in hexanes to afford 2.4 g of the title compound (93%). 1 H NMR (400.13 MHz, CDCl 3 ) δ 8.16 (d, J = 1.5 Hz, 1H), 7.71 (dd, J = 1.5, 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.23 -7.17 (m, 3H), 6.92 (dt, J = 7.5, 2.1 Hz, 1H), 5.05 (s, 2H).
製備 494-[(3-溴苯氧基)甲基]-3-[3-[第三丁基(二甲基)矽基]氧基丙基]苯甲腈 基本上如製備28中所闡述使用4-[(3-溴苯氧基)甲基]-3-碘-苯甲腈來製備標題化合物。ES-MS m/z460及462 (M+H)。 Preparation 49 4-[(3-bromophenoxy)methyl]-3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile The title compound was prepared essentially as described in Preparation 28 using 4-[(3-bromophenoxy)methyl]-3-iodo-benzonitrile. ES-MS m/z 460 and 462 (M+H).
製備 504-[(3-溴苯氧基)甲基]-3-(3-羥丙基)苯甲腈 基本上如製備29中所闡述使用4-[(3-溴苯氧基)甲基]-3-[3-[第三丁基(二甲基)矽基]氧基丙基]苯甲腈來製備標題化合物。ES-MS m/z344及346 (M-H)。 Preparation of 50 4-[(3-bromophenoxy)methyl]-3-(3-hydroxypropyl)benzonitrile Using 4-[(3-bromophenoxy)methyl]-3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile essentially as described in Preparation 29 to prepare the title compound. ES-MS m/z 344 and 346 (MH).
製備 512-溴-6-[[2-碘-4-(三氟甲基)苯基]甲氧基]吡啶 向[2-碘-4-(三氟甲基)苯基]甲醇(2.0 g, 6.6 mmol)、2-溴-6-氟-吡啶(1.2 g, 6.6 mmol)及1,4-二噁烷(25 mL)之混合物中添加第三丁醇鉀(0.98 g, 8.6 mmol)。將反應混合物在50℃下攪拌2 h。使用EtOAc (100 mL)稀釋反應液並經由Celite ®過濾。使用水(2 × 50 mL)及飽和氯化鈉水溶液(50 mL)洗滌濾液。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由使用於己烷中之10 - 50% EtOAc之梯度洗脫之矽膠急速層析來純化殘餘物以得到2.0 g標題化合物(66%)。ES-MS m/z458及460 (M+H)。 Preparation 51 2-Bromo-6-[[2-iodo-4-(trifluoromethyl)phenyl]methoxy]pyridine To [2-iodo-4-(trifluoromethyl)phenyl]methanol (2.0 g, 6.6 mmol), 2-bromo-6-fluoro-pyridine (1.2 g, 6.6 mmol) and 1,4-dioxane (25 mL) was added potassium tert-butoxide (0.98 g, 8.6 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction was diluted with EtOAc (100 mL) and filtered through Celite® . The filtrate was washed with water (2 x 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 10 - 50% EtOAc in hexanes to afford 2.0 g of the title compound (66%). ES-MS m/z 458 and 460 (M+H).
製備 523-[2-[(6-溴-2-吡啶基)氧基甲基]-5-(三氟甲基)苯基]丙氧基-第三丁基-二甲基-矽烷 基本上如製備28中所闡述使用2-溴-6-[[2-碘-4-(三氟甲基)苯基]甲氧基]吡啶來製備標題化合物。經由使用於己烷中之0 - 10% EtOAc之梯度洗脫之矽膠急速層析來純化標題化合物。其未經進一步表徵即直接用於製備53中。 Preparation 52 3-[2-[(6-Bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propoxy-tert-butyl-dimethyl-silane The title compound was prepared essentially as described in Preparation 28 using 2-bromo-6-[[2-iodo-4-(trifluoromethyl)phenyl]methoxy]pyridine. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 0-10% EtOAc in hexanes. It was used directly in the preparation of 53 without further characterization.
製備 533-[2-[(6-溴-2-吡啶基)氧基甲基]-5-(三氟甲基)苯基]丙烷-1-醇 基本上如製備29中所闡述使用3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-(三氟甲基)苯基]丙氧基-第三丁基-二甲基-矽烷來製備標題化合物。ES-MS m/z390及392 (M+H)。 Preparation 53 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propan-1-ol Essentially as described in Preparation 29 using 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propoxy-tert-butyl -Dimethyl-silane to prepare the title compound. ES-MS m/z 390 and 392 (M+H).
製備 542-[4-溴-2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]丙氧基]-5-氟-苯基]乙酸乙酯 向4-[(6-溴-2-吡啶基)氧基甲基]-3-(3-羥丙基)苯甲腈(550 mg, 1.58 mmol)及2-(4-溴-5-氟-2-羥基-苯基)乙酸乙酯(0.40 g, 1.4 mmol)於THF (10 mL)中之混合物中添加三-正丁基膦(0.90 mL, 4.0 mmol)。逐滴添加DEAD (於甲苯中之40%溶液,1.1 mL, 2.8 mmol)於DCM (1.1 mL)中之溶液。將反應混合物在室溫下攪拌15 h。使用MeOH (5 mL)終止反應並在減壓下濃縮。經由使用於己烷中之5 - 40% EtOAc之梯度洗脫之矽膠急速層析來純化殘餘物以得到1.1 g標題化合物(92%)。ES-MS m/z605、607及609 (M+H)。 Preparation 54 2-[4-Bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propoxy]-5-fluoro -Phenyl]ethyl acetate 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(3-hydroxypropyl)benzonitrile (550 mg, 1.58 mmol) and 2-(4-bromo-5-fluoro To a mixture of ethyl 2-hydroxy-phenyl)acetate (0.40 g, 1.4 mmol) in THF (10 mL) was added tri-n-butylphosphine (0.90 mL, 4.0 mmol). A solution of DEAD (40% solution in toluene, 1.1 mL, 2.8 mmol) in DCM (1.1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 15 h. The reaction was quenched with MeOH (5 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5-40% EtOAc in hexanes to afford 1.1 g of the title compound (92%). ES-MS m/z 605, 607 and 609 (M+H).
製備 552-[2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氯-苯基]丙氧基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 向3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氯-苯基]丙烷-1-醇(420 mg, 1.18 mmol)、2-[2-羥基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯(422 mg, 1.45 mmol)及三苯基膦(460 mg, 1.75 mmol)於THF (8 mL)中之混合物中逐滴添加DIAD (0.35 mL, 1.80 mmol)。將反應混合物在室溫下攪拌1.5 h。將混合物吸附於二氧化矽上並經由使用於己烷中之0 - 30% EtOAc之梯度洗脫之矽膠急速層析純化以得到306 mg標題化合物(41%)。ES-MS m/z630及632 (M+H)。 Preparation 55 2-[2-[3-[2-[(6-Bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propoxy]-4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaboron-2-yl)phenyl]acetic acid methyl ester To 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propan-1-ol (420 mg, 1.18 mmol), 2-[2-hydroxy- 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester (422 mg, 1.45 mmol) and triphenylphosphine (460 mg, 1.75 mmol) in THF (8 mL) was added dropwise DIAD (0.35 mL, 1.80 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The mixture was adsorbed on silica and purified by flash chromatography on silica gel eluting with a gradient of 0-30% EtOAc in hexanes to afford 306 mg of the title compound (41%). ES-MS m/z 630 and 632 (M+H).
製備 562-[2-[3-[2-[[(6-溴吡啶-2-基)氧基]甲基]-5-氰基苯基]丙氧基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 向4-[(6-溴-2-吡啶基)氧基甲基]-3-(3-羥丙基)苯甲腈(14.5 g, 41.9 mmol)及2-[2-羥基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯(18.7 g, 63.9 mmol)於THF (250 mL)中之混合物中添加三-正丁基膦(21 mL, 84 mmol)。在冰浴中冷卻溶液並逐滴添加DIAD (17 mL, 86 mmol)。將反應混合物在45℃下攪拌14 h且然後在減壓下濃縮。將殘餘物懸浮於EtOAc (100 mL)中並藉由過濾收集固體。使用EtOAc (3 × 25 mL)洗滌固體以得到19.7 g標題化合物(76%)。ES-MS m/z621, 623 (M+H)。 Preparation 56 2-[2-[3-[2-[[(6-Bromopyridin-2-yl)oxy]methyl]-5-cyanophenyl]propoxy]-4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester To 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(3-hydroxypropyl)benzonitrile (14.5 g, 41.9 mmol) and 2-[2-hydroxy-4-( In a mixture of methyl 4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetate (18.7 g, 63.9 mmol) in THF (250 mL) Tri-n-butylphosphine (21 mL, 84 mmol) was added. Cool the solution in an ice bath and add DIAD (17 mL, 86 mmol) dropwise. The reaction mixture was stirred at 45 °C for 14 h and then concentrated under reduced pressure. The residue was suspended in EtOAc (100 mL) and the solid was collected by filtration. The solid was washed with EtOAc (3 x 25 mL) to give 19.7 g of the title compound (76%). ES-MS m/z 621, 623 (M+H).
製備 572-[2-[3-[2-[[(6-溴-2-吡啶基)胺基]甲基]-5-氰基-苯基]丙氧基]-4-(5,5-二甲基-1,3,2-二氧雜硼雜環己烷-2-基)-5-氟-苯基]乙酸乙酯 在4℃下,向4-[[(6-溴-2-吡啶基)胺基]甲基]-3-(3-羥丙基)苯甲腈(380 mg, 1.04 mmol)及2-[4-(5,5-二甲基-1,3,2-二氧雜硼雜環己烷-2-基)-5-氟-2-羥基苯基]乙酸乙酯(0.38 g, 1.15 mmol)於THF (5.2 mL)中之溶液中添加三苯基膦(0.30g, 1.15 mmol)及偶氮二甲酸二-第三丁基酯(0.27 g, 1.15 mmol)。在室溫下攪拌22 h,濃縮反應混合物並經由矽膠層析使用於環己烷中10 - 70% EtOAc之梯度來純化殘餘物以得到淺褐色固體形式之標題化合物(500 mg, 60%)。ES-MS m/z570及572 (酸之M+H)。 Preparation 57 2-[2-[3-[2-[[(6-bromo-2-pyridyl)amino]methyl]-5-cyano-phenyl]propoxy]-4-(5, 5-Dimethyl-1,3,2-dioxaborin-2-yl)-5-fluoro-phenyl]ethyl acetate At 4°C, 4-[[(6-bromo-2-pyridyl)amino]methyl]-3-(3-hydroxypropyl)benzonitrile (380 mg, 1.04 mmol) and 2-[ 4-(5,5-Dimethyl-1,3,2-dioxaborin-2-yl)-5-fluoro-2-hydroxyphenyl]ethyl acetate (0.38 g, 1.15 mmol ) in THF (5.2 mL) were added triphenylphosphine (0.30 g, 1.15 mmol) and di-tert-butyl azodicarboxylate (0.27 g, 1.15 mmol). Stirring at room temperature for 22 h, the reaction mixture was concentrated and the residue was purified by silica gel chromatography using a gradient of 10 - 70% EtOAc in cyclohexane to give the title compound (500 mg, 60%) as a beige solid. ES-MS m/z 570 and 572 ( Acid M+H).
製備 582-[2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 基本上如製備55中所闡述使用4-[(6-溴-2-吡啶基)氧基甲基]-3-(3-羥丙基)苯甲腈及2-[2-羥基-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯來製備標題化合物。使用三-正丁基膦代替三苯基膦,使用DEAD代替DIAD,且使用二噁烷作為溶劑代替THF。經由矽膠急速層析使用於己烷中之80-100% DCM之梯度進行純化。ES-MS m/z635及637 (M+H)。 Preparation 58 2-[2-[3-[2-[(6-Bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propoxy]-5-methyl-4- Methyl (4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetate Using 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(3-hydroxypropyl)benzonitrile and 2-[2-hydroxy-5- Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester to prepare the title compound. Tri-n-butylphosphine was used instead of triphenylphosphine, DEAD was used instead of DIAD, and dioxane was used as solvent instead of THF. Purification was performed by flash chromatography on silica gel using a gradient of 80-100% DCM in hexanes. ES-MS m/z 635 and 637 (M+H).
製備 592-[2-[3-[5-[(6-溴-2-吡啶基)氧基甲基]-2-氰基-苯基]丙氧基]-5-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯 在室溫下,將偶氮二甲酸二-第三丁基酯(390 mg, 1.7 mmol)於無水THF (2 mL)中之溶液緩慢添加至三苯基膦(435mg, 1.66mmol)、4-[(6-溴-2-吡啶基)氧基甲基]-2-(3-羥丙基)苯甲腈(400 mg, 1.09 mmol)及2-[5-氟-2-羥基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯(480 mg,83%純度,1.23 mmol)於無水THF (8 mL)中之溶液中。將混合物在室溫下攪拌1 h。添加三苯基膦(170mg, 0.65mmol),且在5min之後緩慢添加偶氮二甲酸二-第三丁基酯(157 mg, 0.65 mmol)於無水THF (2 ml)中之溶液。濃縮反應混合物並經由矽膠急速層析使用於環己烷中之10 - 50% EtOAc之梯度來純化殘餘物以得到褐色蠟狀固體形式之標題化合物(689 mg,90%純度,86%)。ES-MS m/z653及655 (M+H)。 Preparation 59 2-[2-[3-[5-[(6-bromo-2-pyridyl)oxymethyl]-2-cyano-phenyl]propoxy]-5-fluoro-4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]ethyl acetate At room temperature, a solution of di-tert-butyl azodicarboxylate (390 mg, 1.7 mmol) in anhydrous THF (2 mL) was slowly added to triphenylphosphine (435 mg, 1.66 mmol), 4- [(6-Bromo-2-pyridyl)oxymethyl]-2-(3-hydroxypropyl)benzonitrile (400 mg, 1.09 mmol) and 2-[5-fluoro-2-hydroxy-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]ethyl acetate (480 mg, 83% purity, 1.23 mmol) in anhydrous THF (8 mL) in solution. The mixture was stirred at room temperature for 1 h. Triphenylphosphine (170 mg, 0.65 mmol) was added and after 5 min a solution of di-tert-butyl azodicarboxylate (157 mg, 0.65 mmol) in anhydrous THF (2 ml) was added slowly. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel using a gradient of 10-50% EtOAc in cyclohexane to give the title compound (689 mg, 90% purity, 86%) as a brown waxy solid. ES-MS m/z 653 and 655 (M+H).
製備 602-(4-溴-2-(2-(2-(((6-溴吡啶-2-基)氧基)甲基)-5-氰基苯氧基)乙氧基)-5-氟苯基)乙酸乙酯 向4-(((6-溴吡啶-2-基)氧基)甲基)-3-(2-羥基乙氧基)苯甲腈(640 mg, 1.83 mmol)、 2-(4-溴-5-氟-2-羥基-苯基)乙酸乙酯(506 mg, 1.83 mmoL)及TMAD (671 mg, 3.70 mmol)於THF (9 mL)中之溶液中添加三-正丁基膦(0.91 mL, 3.65 mmol)。在35℃下攪拌2 h。使用MeOH終止反應並濃縮粗製混合物。經由矽膠急速層析使用於庚烷中之0 - 30% EtOAc之梯度來純化殘餘物以得到876 mg標題化合物(79%)。ES-MS m/z607、609及611 (M+H)。 Preparation 60 2-(4-Bromo-2-(2-(2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyanophenoxy)ethoxy)-5 -Ethyl fluorophenyl)acetate 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-(2-hydroxyethoxy)benzonitrile (640 mg, 1.83 mmol), 2-(4-bromo- To a solution of ethyl 5-fluoro-2-hydroxy-phenyl)acetate (506 mg, 1.83 mmol) and TMAD (671 mg, 3.70 mmol) in THF (9 mL) was added tri-n-butylphosphine (0.91 mL , 3.65 mmol). Stir at 35 °C for 2 h. The reaction was quenched with MeOH and the crude mixture was concentrated. The residue was purified by flash chromatography on silica gel using a gradient of 0-30% EtOAc in heptane to afford 876 mg of the title compound (79%). ES-MS m/z 607, 609 and 611 (M+H).
製備 613-(((5-溴-4-氟-2-碘苄基)氧基)甲基)-4-(((6-溴吡啶-2-基)氧基)甲基)苯甲腈 基本上如製備34中所闡述使用3-(((5-溴-4-氟-2-碘苄基)氧基)甲基)-4-(羥甲基)苯甲腈來製備標題化合物。經由矽膠急速層析使用於庚烷中之0 - 10% EtOAc之梯度來純化標題化合物。ES-MS m/z631、633及635 (M+H)。 Preparation 61 3-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-(((6-bromopyridin-2-yl)oxy)methyl)benzyl Nitrile The title compound was prepared essentially as described in Preparation 34 using 3-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-(hydroxymethyl)benzonitrile. The title compound was purified by flash chromatography on silica gel using a gradient of 0-10% EtOAc in heptane. ES-MS m/z 631, 633 and 635 (M+H).
製備 622-(4-溴-2-(((2-(((6-溴吡啶-2-基)氧基)甲基)-5-氰基苄基)氧基)甲基)-5-氟苯基)乙酸乙酯 向3-(((5-溴-4-氟-2-碘苄基)氧基)甲基)-4-(((6-溴吡啶-2-基)氧基)甲基)苯甲腈(2.69 mg, 4.3 mmol)於ACN (75 mL)中之溶液中添加雙(三苯基膦)二氯化鈀(II) (305 mg, 0.43 mmol)、TEA (1.48 mL, 10.6 mmol)及甲酸(0.24 mL, 6.4 mmol)。在70℃下攪拌反應液並經10 min添加重氮乙酸乙酯(2 M於DCM中,8.5 mL, 17 mmol)於ACN (25 mL)中之溶液。在70℃下攪拌2 h。添加第二部分(初始添加量之一半)之所有試劑並進一步加熱1.5 h。使用EtOAc稀釋反應混合物並使用水洗滌有機層。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0至10% EtOAc之梯度來純化殘餘物以得到898 mg標題化合物(36%)。ES-MS m/z591、593及595 (M+H)。 Preparation 62 2-(4-Bromo-2-(((2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyanobenzyl)oxy)methyl)-5 -Ethyl fluorophenyl)acetate To 3-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-(((6-bromopyridin-2-yl)oxy)methyl)benzonitrile (2.69 mg, 4.3 mmol) in ACN (75 mL) was added bis(triphenylphosphine)palladium(II) dichloride (305 mg, 0.43 mmol), TEA (1.48 mL, 10.6 mmol) and formic acid (0.24 mL, 6.4 mmol). The reaction was stirred at 70 °C and a solution of ethyl diazoacetate (2 M in DCM, 8.5 mL, 17 mmol) in ACN (25 mL) was added over 10 min. Stir at 70 °C for 2 h. A second portion (half of the initial addition) of all reagents was added and heated for a further 1.5 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 10% EtOAc in heptane to afford 898 mg of the title compound (36%). ES-MS m/z 591, 593 and 595 (M+H).
製備 632-[2-[3-[2-[(3-溴苯氧基)甲基]-5-氰基-苯基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 基本上如製備54中所闡述使用4-[(3-溴苯氧基)甲基]-3-(3-羥丙基)苯甲腈及2-[2-羥基-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯、使用1,4-二噁烷作為反應溶劑來製備標題化合物,其中添加DEAD於甲苯中之40%溶液。經由使用於己烷中之80 - 100% DCM之梯度洗脫之矽膠急速層析來純化標題化合物。ES-MS m/z651及653 (M+NH 4 +)。 Preparation 63 2-[2-[3-[2-[(3-Bromophenoxy)methyl]-5-cyano-phenyl]propoxy]-5-methyl-4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester Essentially as described in Preparation 54 using 4-[(3-bromophenoxy)methyl]-3-(3-hydroxypropyl)benzonitrile and 2-[2-hydroxy-5-methyl-4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester, using 1,4-dioxane as reaction solvent to prepare the title Compound to which a 40% solution of DEAD in toluene was added. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 80-100% DCM in hexanes. ES-MS m/z 651 and 653 (M+ NH4 + ).
製備 642-[2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-(三氟甲基)苯基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 基本上如製備54中所闡述使用3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-(三氟甲基)苯基]丙烷-1-醇及2-[2-羥基-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯來製備標題化合物,其中向反應液中添加DEAD於甲苯中之40%溶液。經由使用於己烷中之85 - 100% DCM之梯度洗脫之矽膠急速層析來純化標題化合物。ES-MS m/z678及680 (M+H)。 Preparation 64 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propoxyl]-5-methyl -4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester Using 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propan-1-ol and 2- [2-Hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester to prepare the title compound , wherein a 40% solution of DEAD in toluene was added to the reaction solution. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 85-100% DCM in hexanes. ES-MS m/z 678 and 680 (M+H).
製備 652-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃(cyclononaphane)-1 4-基)乙酸乙酯 向2-[4-溴-2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]丙氧基]-5-氟-苯基]乙酸乙酯(1.1 g, 0.92 mmol)於1,4-二噁烷(40 mL)中之溶液中添加六甲基二錫(0.71 g, 2.2 mmol)。添加四(三苯基膦)鈀(0) (0.20 g, 0.20 mmol)。將反應混合物在90℃下攪拌60 h。在減壓下濃縮並經由使用於己烷中之5 - 45% EtOAc之梯度洗脫之矽膠急速層析來純化殘餘物以得到303 mg標題化合物(47%)。ES-MS m/z447 (M+H)。 Preparation of 65 2-(5 4 -cyano-1 6 -fluoro-3,9-dioxa-2 (2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Cyclonaphane-1 4 -yl) ethyl acetate To 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propoxy]-5-fluoro- To a solution of ethyl phenyl]acetate (1.1 g, 0.92 mmol) in 1,4-dioxane (40 mL) was added hexamethylditin (0.71 g, 2.2 mmol). Tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.20 mmol) was added. The reaction mixture was stirred at 90 °C for 60 h. Concentrate under reduced pressure and purify the residue by flash chromatography on silica gel eluting with a gradient of 5 - 45% EtOAc in hexanes to afford 303 mg of the title compound (47%). ES-MS m/z 447 (M+H).
製備 662-(5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯 向2-[2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氯-苯基]丙氧基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯(306 mg, 0.49 mmol)、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II) (XPhos Gen 2, 28.9 mg, 0.036 mmol)及磷酸鉀(420 mg, 1.94 mmol)之混合物中添加THF (48 mL)及水(5.4 mL)。將反應混合物在氮氣氛及40℃下攪拌15 h。在減壓下濃縮混合物。將殘餘物溶於DCM中,吸附於Celite ®上,並經由使用於己烷中之0 - 40% EtOAc之梯度洗脫之矽膠急速層析純化以得到152 mg標題化合物(74%)。ES-MS m/z424及426 (M+H)。 Preparation 66 2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-1 4 - base) methyl acetate To 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propoxy]-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester (306 mg, 0.49 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Gen 2, 28.9 mg, 0.036 mmol ) and potassium phosphate (420 mg, 1.94 mmol) were added THF (48 mL) and water (5.4 mL). The reaction mixture was stirred under nitrogen atmosphere at 40 °C for 15 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM, absorbed on Celite® , and purified by flash chromatography on silica gel eluting with a gradient of 0-40% EtOAc in hexanes to afford 152 mg of the title compound (74%). ES-MS m/z 424 and 426 (M+H).
製備 672-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯 向2-[2-[3-[2-[[(6-溴吡啶-2-基)氧基]甲基]-5-氰基苯基]丙氧基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯(19.7 g, 31.7 mmol)、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II) (XPhos Gen 2, 1.3 g, 1.6 mmol)及磷酸鉀(28.5 g, 132 mmol)之混合物中添加THF (500 mL)及水(52 mL)。將反應混合物在氮氣氛及45℃下攪拌2 h 15 min。使用EtOAc (200 mL)稀釋反應液並使用半飽和鹽水(400 mL)洗滌。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮。將殘餘物懸浮於EtOAc (100 mL)中並藉由過濾收集固體。使用EtOAc (3 × 30 mL)洗滌固體以得到10.7 g標題化合物(82%)。ES-MS m/z415 (M+H)。 Preparation 67 2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 -yl) methyl acetate To 2-[2-[3-[2-[[(6-bromopyridin-2-yl)oxy]methyl]-5-cyanophenyl]propoxy]-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester (19.7 g, 31.7 mmol), chloro(2-dicyclohexylphosphino-2', 4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Gen 2, 1.3 g, 1.6 mmol) and potassium phosphate (28.5 g, 132 mmol) were added THF (500 mL) and water (52 mL). The reaction mixture was stirred under nitrogen atmosphere at 45 °C for 2 h 15 min. The reaction was diluted with EtOAc (200 mL) and washed with half saturated brine (400 mL). The organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was suspended in EtOAc (100 mL) and the solid was collected by filtration. The solid was washed with EtOAc (3 x 30 mL) to give 10.7 g of the title compound (82%). ES-MS m/z 415 (M+H).
製備 682-(5 4-氰基-1 6-氟-9-氧雜-3-氮雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯 向2-[2-[3-[2-[[(6-溴-2-吡啶基)胺基]甲基]-5-氰基-苯基]丙氧基]-4-(5,5-二甲基-1,3,2-二氧雜硼雜環己烷-2-基)-5-氟-苯基]乙酸乙酯(460 mg, 0.57 mmol)於1,4-二噁烷(11.5 mL)中之溶液中添加PdCl 2(dtbpf) (77 mg, 0.11 mmol)及1M磷酸鉀水溶液(1.73 mL, 1.73 mmol)。在70℃下攪拌2 h,冷卻至室溫並使用飽和氯化銨溶液(15 mL)及EtOAc (10 mL)稀釋反應混合物。分離各相,使用EtOAc (2 × 5 mL)萃取水相。合併有機物,藉由硫酸鎂乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於環己烷中之30% EtOAc作為洗脫劑系統來純化殘餘物以提供淺黃色固體形式之標題化合物(125 mg, 49%)。ES-MS m/z446 (M+H)。 Preparation of 68 2-(5 4 -cyano-1 6 -fluoro-9-oxa- 3 -aza-2(2,6)-pyridine-1(1,3),5(1,2)-di phenylcyclononafin-1 4 -yl) ethyl acetate To 2-[2-[3-[2-[[(6-bromo-2-pyridyl)amino]methyl]-5-cyano-phenyl]propoxy]-4-(5,5 -Dimethyl-1,3,2-dioxaborin-2-yl)-5-fluoro-phenyl]ethyl acetate (460 mg, 0.57 mmol) in 1,4-dioxane To a solution in (11.5 mL) was added PdCl2 (dtbpf) (77 mg, 0.11 mmol) and 1M aqueous potassium phosphate (1.73 mL, 1.73 mmol). Stir at 70 °C for 2 h, cool to room temperature and dilute the reaction mixture with saturated ammonium chloride solution (15 mL) and EtOAc (10 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 5 mL). The organics were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30% EtOAc in cyclohexane as the eluent system to afford the title compound (125 mg, 49%) as a pale yellow solid. ES-MS m/z 446 (M+H).
製備 692-(5 4-氰基-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯 基本上如製備66中所闡述使用2-[2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯來製備標題化合物。經由矽膠急速層析使用於DCM中之0 - 20% EtOAc之梯度進行純化。ES-MS m/z429 (M+H)。 Preparation 69 2-(5 4 -cyano-1 6 -methyl-3,9-dioxa-2 (2,6)-pyridine-1(1,3),5(1,2)-diphenyl Methyl cyclononafin-1 4 -yl)acetate Essentially as described in Preparation 66 using 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propoxy]- The title compound was prepared from methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetate. Purification was performed by flash chromatography on silica gel using a gradient of 0-20% EtOAc in DCM. ES-MS m/z 429 (M+H).
製備 702-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸乙酯 向2-[2-[3-[5-[(6-溴-2-吡啶基)氧基甲基]-2-氰基-苯基]丙氧基]-5-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯(650 mg,90%純度,0.89 mmol)於1,4-二噁烷(30 mL)中之溶液中添加PdCl 2(dtbpf) (119 mg, 0.18 mmol)及1M磷酸鉀水溶液(2.7 mL, 2.7 mmol)。將混合物在50℃及氮氣氛下攪拌15 min,然後冷卻至室溫並使用DCM稀釋。藉由無水Na 2SO 4乾燥,過濾,並在減壓下濃縮。經由矽膠急速層析使用於環己烷中之10 - 30% EtOAc之梯度來純化殘餘物以提供極淺褐色固體形式之標題化合物(150 mg, 38%)。ES-MS m/z447 (M+H)。 Preparation 70 2-(5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona-1 4 -yl) ethyl acetate To 2-[2-[3-[5-[(6-bromo-2-pyridyl)oxymethyl]-2-cyano-phenyl]propoxy]-5-fluoro-4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]ethyl acetate (650 mg, 90% purity, 0.89 mmol) in 1,4-diox To a solution in alkanes (30 mL) was added PdCl2 (dtbpf) (119 mg, 0.18 mmol) and 1M aqueous potassium phosphate (2.7 mL, 2.7 mmol). The mixture was stirred at 50 °C under nitrogen atmosphere for 15 min, then cooled to room temperature and diluted with DCM. Dry over anhydrous Na2SO4 , filter, and concentrate under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 10-30% EtOAc in cyclohexane to afford the title compound (150 mg, 38%) as a very beige solid. ES-MS m/z 447 (M+H).
製備 712-(5 4-氰基-1 6-氟-3,6,9-三氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯 向2-(4-溴-2-(2-(2-(((6-溴吡啶-2-基)氧基)甲基)-5-氰基苯氧基)乙氧基)-5-氟苯基)乙酸乙酯(400 mg, 0.66 mmol)、KOAc (0.2 g, 2.0 mmol)、雙(頻哪醇)二硼(187 mg, 0.72 mmol)於1,4-二噁烷(2.2 mL)中之溶液中添加Pd(dppf)Cl 2-DCM複合物(27 mg, 0.032 mmol)。將混合物在85℃下攪拌1 h,然後使用水稀釋並使用EtOAc萃取三次。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。向殘餘物中添加THF (66 mL)、磷酸三鉀(0.6 g, 3.0 mmol)、水(7.3 mL)及氯化鈀(II) (6.0 mg, 0.033 mmol)及2-二環己基膦-2’,4’,6’-三異丙基聯苯(32 mg, 0.066 mmol)於THF (1 mL)中之預製溶液。在45℃下攪拌16 h。使用水稀釋粗製混合物並使用EtOAc (3×)萃取三次。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0 - 30% EtOAc之梯度來純化殘餘物以得到94 mg標題化合物(32%)。ES-MS m/z449 (M+H)。 Preparation of 71 2-(5 4 -cyano-1 6 -fluoro-3,6,9-trioxa-2 (2,6)-pyridine-1(1,3),5(1,2)-di phenylcyclononafin-1 4 -yl) ethyl acetate To 2-(4-bromo-2-(2-(2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyanophenoxy)ethoxy)-5- Fluorophenyl) ethyl acetate (400 mg, 0.66 mmol), KOAc (0.2 g, 2.0 mmol), bis(pinacol) diboron (187 mg, 0.72 mmol) in 1,4-dioxane (2.2 mL ) was added Pd(dppf)Cl 2 -DCM complex (27 mg, 0.032 mmol). The mixture was stirred at 85 °C for 1 h, then diluted with water and extracted three times with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the residue was added THF (66 mL), tripotassium phosphate (0.6 g, 3.0 mmol), water (7.3 mL) and palladium(II) chloride (6.0 mg, 0.033 mmol) and 2-dicyclohexylphosphine-2 A pre-prepared solution of ',4',6'-triisopropylbiphenyl (32 mg, 0.066 mmol) in THF (1 mL). Stir at 45 °C for 16 h. The crude mixture was diluted with water and extracted three times with EtOAc (3x). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient of 0-30% EtOAc in heptane to afford 94 mg of the title compound (32%). ES-MS m/z 449 (M+H).
製備 722-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸乙酯 基本上如製備65中所闡述使用2-(4-溴-2-(((2-(((6-溴吡啶-2-基)氧基)甲基)-5-氰基苄基)氧基)甲基)-5-氟苯基)乙酸乙酯、使用1.1當量六甲基二錫且使用Pd(dppf)Cl 2-DCM作為觸媒來製備標題化合物,其中將反應液在100℃下攪拌3.5 h。使用水稀釋粗製反應混合物並使用EtOAc萃取。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0 - 80% EtOAc之梯度來純化殘餘物以得到標題化合物。ES-MS m/z433 (M+H)。 Preparation of 72 2-(5 4 -cyano-1 6 -fluoro-3,7-dioxa-2 (2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Octan-1 4 -yl) ethyl acetate Using 2-(4-bromo-2-((((2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyanobenzyl)oxy) essentially as described in Preparation 65 base)methyl)-5-fluorophenyl)ethyl acetate, using 1.1 equivalents of hexamethylditin and using Pd(dppf)Cl 2 -DCM as catalyst to prepare the title compound, wherein the reaction solution was heated at 100°C Stir for 3.5 h. The crude reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0-80% EtOAc in heptane to give the title compound. ES-MS m/z 433 (M+H).
製備 732-(5 4-氰基-1 6-甲基-3,9-二氧雜-1,2(1,3),5(1,2)-三苯環壬蕃-1 4-基)乙酸甲酯 基本上如製備66中所闡述使用2-[2-[3-[2-[(3-溴苯氧基)甲基]-5-氰基-苯基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯來製備標題化合物,其中將反應混合物在40℃下攪拌1 h。經由使用於DCM中之0 - 20% EtOAc之梯度洗脫之矽膠急速層析來純化混合物以提供標題化合物。ES-MS m/z428 (M+H)。 Preparation 73 2-(5 4 -cyano-1 6 -methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylcyclonona-1 4 - base) methyl acetate Using 2-[2-[3-[2-[(3-bromophenoxy)methyl]-5-cyano-phenyl]propoxy]-5-methyl essentially as described in Preparation 66 -4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester to prepare the title compound, wherein the reaction mixture was heated at 40°C Stir for 1 h. The mixture was purified by flash chromatography on silica gel eluting with a gradient of 0-20% EtOAc in DCM to provide the title compound. ES-MS m/z 428 (M+H).
製備 742-(1 6-甲基-5 4-(三氟甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯 基本上如製備66中所闡述使用2-[2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-(三氟甲基)苯基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯來製備標題化合物,其中將反應液在40℃下攪拌1 h。經由使用於DCM中之0 - 20% EtOAc之梯度洗脫之矽膠急速層析來純化標題化合物。ES-MS m/z472 (M+H)。 Preparation 74 2-(1 6 -methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-Diphenylcyclonafin-1 4 -yl)methyl acetate Using 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propoxyl) essentially as described in Preparation 66 base]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester to prepare the title compound, wherein The reaction solution was stirred at 40 °C for 1 h. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 0-20% EtOAc in DCM. ES-MS m/z 472 (M+H).
製備 752-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 向2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯(290 mg, 0.649 mmol)於ACN:水(5 mL:0.5 mL)中之混合物中添加1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(0.30 g, 2.0 mmol)。將反應混合物在室溫下攪拌15 h。使用1.0 M檸檬酸水溶液將反應混合物之pH調節至pH 7並在減壓下濃縮以去除揮發物。使用EtOAc (100 mL)稀釋殘餘物並使用水(50 mL)及飽和NaCl水溶液(50 mL)洗滌。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮以得到238 mg標題化合物(88%),其以粗製形式用於製備85及86。ES-MS m/z419 (M+H)。 Preparation of 75 2-(5 4 -cyano-1 6 -fluoro-3,9-dioxa-2 (2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring nonafin-1 4 -yl)acetic acid To 2-(5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclone 1,3,4,6,7,8 - Hexahydro-2H- Pyrimido[1,2-a]pyrimidine (0.30 g, 2.0 mmol). The reaction mixture was stirred at room temperature for 15 h. The pH of the reaction mixture was adjusted to pH 7 using 1.0 M aqueous citric acid and concentrated under reduced pressure to remove volatiles. The residue was diluted with EtOAc (100 mL) and washed with water (50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 238 mg of the title compound (88%), which was used in preparations 85 and 86 in crude form. ES-MS m/z 419 (M+H).
製備 762-(5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 向2-(5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯(152 mg, 0.36 mmol)於ACN (3.6 mL)及THF (3 mL)中之混合物中添加氫氧化鋰水溶液(1.0 M, 1.1 mL, 1.1 mmol)。將混合物在40℃下攪拌2 h。使用檸檬酸水溶液(1.0 M, 2.2 mL)終止反應且然後使用EtOAc稀釋。去除水層並使用EtOAc (2 × 3 mL)萃取。藉由硫酸鎂乾燥合併之有機相,過濾,並在減壓下濃縮以得到150 mg標題化合物(100%),其以粗製形式用於製備87。ES-MS m/z410 (M+H)。 Preparation 76 2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-1 4 - base) acetic acid To 2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclononan- 1 4 -yl ) methyl acetate (152 mg, 0.36 mmol) in ACN (3.6 mL) and THF (3 mL) was added aqueous lithium hydroxide (1.0 M, 1.1 mL, 1.1 mmol). The mixture was stirred at 40 °C for 2 h. The reaction was quenched with aqueous citric acid (1.0 M, 2.2 mL) and then diluted with EtOAc. The aqueous layer was removed and extracted with EtOAc (2 x 3 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 150 mg of the title compound (100%), which was used in Preparation 87 in crude form. ES-MS m/z 410 (M+H).
製備 772-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 基本上如製備75中所闡述自2-(5 4氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯開始來製備標題化合物。在反應完成之後,冷卻至室溫並使用檸檬酸水溶液中和。過濾所得沈澱物並在真空下乾燥所得濾餅以得到標題化合物(100%)。ES-MS m/z401 (M+H)。 Preparation 77 2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 -yl)acetic acid From 2-( 54cyano -3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylene essentially as described in Preparation 75 Cyclononafin- 14 -yl)methyl acetate was used to prepare the title compound. After the reaction was complete, it was cooled to room temperature and neutralized with aqueous citric acid. The resulting precipitate was filtered and the resulting filter cake was dried under vacuum to give the title compound (100%). ES-MS m/z 401 (M+H).
製備 782-(5 4-氰基-1 6-氟-9-氧雜-3-氮雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 向2-(5 4-氰基-1 6-氟-9-氧雜-3-氮雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯(122 mg, 027 mmol)於ACN (3 mL)、THF (1 mL)及水(1 mL)中之懸浮液中添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(116 mg, 0.81 mmol)。在45℃下攪拌2 h,冷卻至室溫並使用1M檸檬酸溶液(2 mL)驟冷。使用EtOAc (3 × 3 mL)進行萃取。合併有機物,使用水及鹽水洗滌,藉由硫酸鎂乾燥,過濾,並在減壓下濃縮以得到蠟狀淺黃色固體(115 mg, 100%)。ES-MS m/z418 (M+H)。 Preparation of 78 2-(5 4 -cyano-1 6 -fluoro-9-oxa- 3 -aza-2(2,6)-pyridine-1(1,3),5(1,2)-di phenylcyclononafin-1 4 -yl)acetic acid To 2-(5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl To a suspension of ethyl cyclononafin- 14 -yl)acetate (122 mg, 027 mmol) in ACN (3 mL), THF (1 mL) and water (1 mL) was added 1,5,7-tris Azabicyclo[4.4.0]dec-5-ene (116 mg, 0.81 mmol). Stir at 45 °C for 2 h, cool to room temperature and quench with 1M citric acid solution (2 mL). Extraction was performed with EtOAc (3 x 3 mL). The organics were combined, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a waxy light yellow solid (115 mg, 100%). ES-MS m/z 418 (M+H).
製備 792-(5 4-氰基-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 基本上如製備75中所闡述使用2-(5 4-氰基-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物。ES-MS m/z415 (M+H)。 Preparation 79 2-(5 4 -cyano-1 6 -methyl-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl Cyclonona-1 4 -yl)acetic acid Using 2-( 54 -cyano- 16 -methyl-3,9-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononan-1 4 -yl)methyl acetate to prepare the title compound. ES-MS m/z 415 (M+H).
製備 802-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸 基本上如製備78中所闡述使用2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸乙酯來製備標題化合物。ES-MS m/z419 (M+H)。 Preparation 80 2-(5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona-1 4 -yl)acetic acid Using 2-(5 4 -cyano- 1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1,5(1,3)-di phenylcyclononan- 14 -yl) ethyl acetate to prepare the title compound. ES-MS m/z 419 (M+H).
製備 812-(5 4-氰基-1 6-氟-3,6,9-三氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 基本上如製備75中所闡述使用2-(5 4-氰基-1 6-氟-3,6,9-三氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯來製備標題化合物,其中將反應液在45℃下攪拌3 h。使用甲酸終止反應(至pH 7)並使用水稀釋。使用EtOAc萃取三次且然後使用3:1氯仿:異丙醇萃取三次。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於DCM中之10 - 80% EtOAc之梯度來純化殘餘物以得到標題化合物。ES-MS m/z421 (M+H)。 Preparation of 81 2-(5 4 -cyano-1 6 -fluoro-3,6,9-trioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di phenylcyclononafin-1 4 -yl)acetic acid Using 2-(5 4 -cyano- 1 6 -fluoro-3,6,9-trioxa-2(2,6)-pyridine-1(1,3), 5 (1,2)-Diphenylcyclononan-1 4 -yl) ethyl acetate to prepare the title compound, wherein the reaction solution was stirred at 45°C for 3 h. The reaction was quenched (to pH 7) with formic acid and diluted with water. Extracted three times with EtOAc and then three times with 3:1 chloroform:isopropanol. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 10-80% EtOAc in DCM to give the title compound. ES-MS m/z 421 (M+H).
製備 822-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸 基本上如製備75中所闡述使用乙基2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)來製備標題化合物,將反應液在45℃下攪拌1 h。使用甲酸終止反應(至pH 6-7)並使用EtOAc萃取,隨後使用3:1氯仿:2-丙醇萃取。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮以得到標題化合物(95%),其以粗製形式用於製備98。ES-MS m/z405 (M+H)。 Preparation of 82 2-(5 4 -cyano-1 6 -fluoro-3,7-dioxa-2 (2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Cinfan-1 4 -yl)acetic acid Essentially as described in Preparation 75 using ethyl 2-( 54 -cyano- 16 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-diphenylcyclooctane-1 4 -yl) to prepare the title compound, and the reaction solution was stirred at 45°C for 1 h. The reaction was quenched with formic acid (to pH 6-7) and extracted with EtOAc followed by 3:1 chloroform:2-propanol. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (95%), which was used in Preparation 98 in crude form. ES-MS m/z 405 (M+H).
製備 832-(5 4-氰基-1 6-甲基-3,9-二氧雜-1,2(1,3),5(1,2)-三苯環壬蕃-1 4-基)乙酸 基本上如製備75中所闡述使用2-(5 4-氰基-1 6-甲基-3,9-二氧雜-1,2(1,3),5(1,2)-三苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物,其中將反應混合物在45℃下攪拌1 h。標題化合物以粗製形式用於製備99。ES-MS m/z412 (M-H)。 Preparation 83 2-(5 4 -cyano-1 6 -methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylcyclonona-1 4 - base) acetic acid Using 2-( 54 -cyano- 16 -methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylene essentially as described in Preparation 75 Cyclononan- 14 -yl)acetic acid methyl ester to prepare the title compound, wherein the reaction mixture was stirred at 45 °C for 1 h. The title compound was used in Preparation 99 in crude form. ES-MS m/z 412 (MH).
製備 842-(1 6-甲基-5 4-(三氟甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 基本上如製備75中所闡述使用2-(1 6-甲基-5 4-(三氟甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物,將反應液在50℃下攪拌1 h。標題化合物以粗製形式用於製備100。ES-MS m/z458 (M+H)。 Preparation 84 2-(1 6 -methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-Diphenylcyclononafin-1 4 -yl)acetic acid Using 2-(1 6 -methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3 ), 5(1,2)-diphenylcyclonafin- 1 4 -yl)methyl acetate to prepare the title compound, and the reaction solution was stirred at 50°C for 1 h. The title compound was used in Preparation 100 in crude form. ES-MS m/z 458 (M+H).
製備 85(S)-4-(2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(粗製物,0.170 g, 0.361 mmol)及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得;100 mg, 0.423 mmol)於吡啶(3 mL)中之混合物中添加EDC (125 mg, 0.639 mmol)。將反應混合物在室溫下攪拌15 h。使用飽和氯化銨水溶液終止反應(至pH 6)。使用水(5 mL)稀釋混合物並使用EtOAc (3 × 10 mL)萃取。使用飽和氯化鈉水溶液(10 mL)洗滌合併之有機物。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由使用於石油醚中之0 - 50% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到225 mg標題化合物(71%)。ES-MS m/z637 (M+H)。 Preparation of 85 (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclononarfin-1 4 -yl)acetamido)-3-(((epoxypropane-2-ylmethyl)amino)benzoic acid methyl ester To 2-(5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclone Fan-1 4 -yl)acetic acid (crude, 0.170 g, 0.361 mmol) and 4-amino-3-[[(2S)-epoxypropane-2-yl]methylamino]benzoic acid methyl ester ( Prepared essentially as described in WO 2020/263695; to a mixture of 100 mg, 0.423 mmol) in pyridine (3 mL) was added EDC (125 mg, 0.639 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction was quenched (to pH 6) using saturated aqueous ammonium chloride. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed with saturated aqueous sodium chloride (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in petroleum ether to afford 225 mg of the title compound (71%). ES-MS m/z 637 (M+H).
製備 86(S)-4-(2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-氟-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(238 mg, 0.568 mmol)及4-胺基-3-氟-5-[[(2S)-環氧丙烷-2-基甲基]胺基]苯甲酸甲酯(0.20 g, 0.79 mmol)於DMF (5 mL)中之混合物中添加DIPEA (0.15 mL, 0.86 mmol)。添加HATU (0.20 g, 0.53 mmol)。在室溫下攪拌4 h。使用EtOAc (100 mL)稀釋反應液並使用水(50 mL)及飽和NaCl水溶液(50 mL)洗滌。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮以得到0.46 g標題化合物(99%),其以粗製形式用於製備102。ES-MS m/z655 (M+H)。 Preparation 86 (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclononafin-1 4 -yl)acetamido)-3-fluoro-5-(((epoxypropane-2-ylmethyl)amino)benzoic acid methyl ester To 2-(5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclone Fan-1 4 -yl)acetic acid (238 mg, 0.568 mmol) and methyl 4-amino-3-fluoro-5-[[(2S)-epoxypropan-2-ylmethyl]amino]benzoate (0.20 g, 0.79 mmol) in DMF (5 mL) was added DIPEA (0.15 mL, 0.86 mmol). Add HATU (0.20 g, 0.53 mmol). Stir at room temperature for 4 h. The reaction was diluted with EtOAc (100 mL) and washed with water (50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 0.46 g of the title compound (99%), which was used in preparation 102 in crude form. ES-MS m/z 655 (M+H).
製備 87(S)-4-(2-(5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得)來製備標題化合物,其中在後處理之前將反應液攪拌16 h。標題化合物以粗製形式用於製備104。ES-MS m/z628 (M+H)。 Preparation 87 (S)-4-(2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl Methyl cyclononafin-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate Using 2-( 54 -chloro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylene essentially as described in Preparation 86 Cyclononafin- 14 -yl)acetic acid and methyl 4-amino-3-[[(2S)-epoxypropan-2-yl]methylamino]benzoate (essentially as in WO 2020/263695 Prepared as described) to prepare the title compound by stirring the reaction for 16 h before working up. The title compound was used in Preparation 104 in crude form. ES-MS m/z 628 (M+H).
製備 88(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得)來製備標題化合物。獲得粗製標題化合物且未經純化即用於製備105。ES-MS m/z619 (M+H) Preparation of 88 (S)-4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Methyl phenylcyclononafin-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate Using 2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 86 Phenylcyclonafin- 14 -yl)acetic acid and methyl 4-amino-3-[[(2S)-epoxypropan-2-yl]methylamino]benzoate (essentially as described in WO 2020/263695 prepared as described in ) to prepare the title compound. The crude title compound was obtained and used in the preparation of 105 without purification. ES-MS m/z 619 (M+H)
製備 89(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(製備17)來製備標題化合物。經由矽膠層析使用於DCM中之5 - 80% EtOAc之梯度來純化殘餘物以得到標題化合物。ES-MS m/z649 (M+H)。 Preparation 89 (S)-4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Methyl phenylcyclononafin-1 4 -yl)acetamido)-3-methoxy-5-(((epoxypropylene-2-ylmethyl)amino)benzoate Using 2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 86 Phenylcyclononyl- 14 -yl)acetic acid and methyl 4-amino-3-methoxy-5-[[(2S)-epoxypropane-2-yl]methylamino]benzoate (Preparation 17) to prepare the title compound. The residue was purified by silica gel chromatography using a gradient of 5-80% EtOAc in DCM to give the title compound. ES-MS m/z 649 (M+H).
製備 90(S)-5-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-14-基)乙醯胺基)-6-((環氧丙烷-2-基甲基)胺基)吡啶甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(0.3g, 0.75 mmol)及(S)-5-胺基-6-((環氧丙烷-2-基甲基)胺基)吡啶甲酸甲酯來製備標題化合物。標題化合物未經純化即用於下一步驟中(製備107)。ES-MS m/z620 (M+H)。 Preparation of 90 (S)-5-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Phenylcyclononan-14-yl)acetamido)-6-(((epoxypropan-2-ylmethyl)amino)picolinate methyl ester Using 2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 86 Phenycyclononyl-1 4 -yl)acetic acid (0.3g, 0.75 mmol) and (S)-5-amino-6-(((epoxypropylene-2-ylmethyl)amino)picolinate methyl ester Preparation of the title compound. The title compound was used in the next step without purification (Preparation 107). ES-MS m/z 620 (M+H).
製備 91(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-氟-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-氟-5-[[(2S)-環氧丙烷-2-基甲基]胺基]苯甲酸甲酯來製備標題化合物。標題化合物未經純化即用於下一步驟中(製備108)。ES-MS m/z637 (M+H)。 Preparation 91 (S)-4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Methyl phenylcyclononafin-1 4 -yl)acetamido)-3-fluoro-5-(((epoxypropan-2-ylmethyl)amino)benzoate Using 2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 86 The title compound was prepared from phenylcyclononan- 14 -yl)acetic acid and methyl 4-amino-3-fluoro-5-[[(2S)-epoxypropan-2-ylmethyl]amino]benzoate . The title compound was used in the next step without purification (Preparation 108). ES-MS m/z 637 (M+H).
製備 92(S)-4-(2-(5 4-氰基-1 6-氟-9-氧雜-3-氮雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氰基-1 6-氟-9-氧雜-3-氮雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(115 mg, 0.27 mmol)於DMF (3.0 mL)中之溶液中添加 4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如 WO 2020/263695中所闡述製得) (75 mg, 0.32 mmol)、HATU (160 mg, 0.42 mmol)及DIPEA (0.15 mL, 0.86 mmol)。在室溫下攪拌2 h,使用水(10 mL)稀釋並使用EtOAc (4 × 5 mL)萃取。合併有機物,使用水及鹽水洗滌,藉由硫酸鎂乾燥,過濾,並在真空下濃縮以得到褐色固體形式之標題化合物(160 mg, 79%)。ES-MS m/z636 (M+H)。 Preparation 92 (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-9 -oxa-3-aza-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononan-1 4 -yl)acetamido)-3-(((epoxypropylene-2-ylmethyl)amino)benzoic acid methyl ester To 2-(5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl To a solution of cyclononafin-1 4 -yl)acetic acid (115 mg, 0.27 mmol) in DMF (3.0 mL) was added 4-amino-3-[[(2S)-epoxypropan-2-yl]methanol Methylamino]benzoate (prepared essentially as described in WO 2020/263695) (75 mg, 0.32 mmol), HATU (160 mg, 0.42 mmol) and DIPEA (0.15 mL, 0.86 mmol). Stir at room temperature for 2 h, dilute with water (10 mL) and extract with EtOAc (4 x 5 mL). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum to give the title compound (160 mg, 79%) as a tan solid. ES-MS m/z 636 (M+H).
製備 93(S)-4-(2-(5 4-氰基-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(製備17)來製備標題化合物。標題化合物未經純化即以粗產物形式用於下一步驟中(製備103)。ES-MS m/z663 (M+H)。 Preparation of 93 (S)-4-(2-(5 4 -cyano-1 6 -methyl-3,9-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononafin-1 4 -yl)acetamido)-3-methoxy-5-(((oxypropylene-2-ylmethyl)amino)benzoic acid methyl ester Using 2-( 54 -cyano- 16 -methyl-3,9-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononarfin-1 4 -yl)acetic acid and 4-amino-3-methoxy-5-[[(2S)-epoxypropane-2-yl]methylamino] Methyl benzoate (Preparation 17) to prepare the title compound. The title compound was used crude in the next step without purification (Preparation 103). ES-MS m/z 663 (M+H).
製備 94(S)-4-(2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得)來製備標題化合物。標題化合物未經純化即以其粗製形式用於製備110。ES-MS m/z637 (M+H)。 Preparation of 94 (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1,5(1,3)-di Methyl phenylcyclononafin-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate Using 2-(5 4 -cyano- 1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1,5(1,3)-di Phenylcyclonafin- 14 -yl)acetic acid and methyl 4-amino-3-[[(2S)-epoxypropan-2-yl]methylamino]benzoate (essentially as described in WO 2020/263695 prepared as described in ) to prepare the title compound. The title compound was used in Preparation 110 in its crude form without purification. ES-MS m/z 637 (M+H).
製備 954-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(100 mg, 0.25 mmol)及4-胺基-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)苯甲酸甲酯(製備19)來製備標題化合物。將反應液在室溫下攪拌18 h,然後使用水及EtOAc稀釋,然後使用EtOAc將水層萃取4次。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮以得到標題化合物,其以粗製形式用於製備111。ES-MS m/z657 (M+H)。 Preparation of 95 4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononene -1 4 -yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate methyl ester Using 2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 86 Phenylnonafin-1 4 -yl)acetic acid (100 mg, 0.25 mmol) and 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoic acid Methyl ester (Preparation 19) to prepare the title compound. The reaction was stirred at room temperature for 18 h, then diluted with water and EtOAc, and then the aqueous layer was extracted 4 times with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound, which was used in crude form in Preparation 111. ES-MS m/z 657 (M+H).
製備 96(S)-2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)-N-(2-甲氧基-6-((環氧丙烷-2-基甲基)胺基)-4-(1H-四唑-5-基)苯基)乙醯胺 基本上如製備86中所闡述使用2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及(S)-3-甲氧基-N1-(環氧丙烷-2-基甲基)-5-(1H-四唑-5-基)苯-1,2-二胺來製備標題化合物。在室溫下攪拌67 h。使用水及EtOAc稀釋混合物並使用EtOAc萃取水層。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於庚烷中之0 - 100% EtOAc且隨後於DCM中之0 - 10% MeOH之梯度來純化殘餘物。ES-MS m/z659 (M+H)。 Preparation 96 (S)-2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononyl Fan-1 4 -yl)-N-(2-methoxy-6-((epoxypropylene-2-ylmethyl)amino)-4-(1H-tetrazol-5-yl)phenyl) Acetamide Using 2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 86 Phenylcyclononan-1 4 -yl)acetic acid and (S)-3-methoxy-N1-(epoxypropylene-2-ylmethyl)-5-(1H-tetrazol-5-yl)benzene- 1,2-diamine to prepare the title compound. Stir at room temperature for 67 h. The mixture was diluted with water and EtOAc and the aqueous layer was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0-100% EtOAc in heptane followed by 0-10% MeOH in DCM. ES-MS m/z 659 (M+H).
製備 97(S)-4-(2-(5 4-氰基-1 6-氟-3,6,9-三氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-1 6-氟-3,6,9-三氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得)來製備標題化合物,其中將反應液在室溫下攪拌24 h。使用水稀釋粗製反應液並使用EtOAc萃取三次。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮以提供標題化合物,其以粗製形式用於製備112。ES-MS m/z639 (M+H)。 Preparation 97 (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-3,6,9-trioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononan-1 4 -yl)acetamido)-3-(((epoxypropylene-2-ylmethyl)amino)benzoic acid methyl ester Using 2-( 54 -cyano- 16 -fluoro-3,6,9-trioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononarfin-1 4 -yl)acetic acid and methyl 4-amino-3-[[(2S)-epoxypropane-2-yl]methylamino]benzoate ( The title compound was prepared essentially as described in WO 2020/263695), wherein the reaction was stirred at room temperature for 24 h. The crude reaction was diluted with water and extracted three times with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound, which was used in crude form in Preparation 112. ES-MS m/z 639 (M+H).
製備 98(S)-4-(2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得)來製備標題化合物,其中將反應液在室溫下攪拌2 h。使用水及EtOAc稀釋反應液並使用EtOAc萃取水層。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮以得到標題化合物,其以粗製形式用於製備113。ES-MS m/z623 (M+H)。 Preparation of 98 (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclooctane-1 4 -yl)acetamido)-3-(((epoxypropylene-2-ylmethyl)amino)benzoate methyl ester Using 2-( 54 -cyano- 16 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclooctane-1 4 -yl)acetic acid and methyl 4-amino-3-[[(2S)-epoxypropan-2-yl]methylamino]benzoate (essentially The title compound was prepared as described in WO 2020/263695), wherein the reaction was stirred at room temperature for 2 h. The reaction solution was diluted with water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound, which was used in the preparation of 113 in crude form. ES-MS m/z 623 (M+H).
製備 99(S)-4-(2-(5 4-氰基-1 6-甲基-3,9-二氧雜-1,2(1,3),5(1,2)-三苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備85中所闡述使用2-(5 4-氰基-1 6-甲基-3,9-二氧雜-1,2(1,3),5(1,2)-三苯環壬蕃-1 4-基)乙酸(製備83)及4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(製備17)來製備標題化合物。標題化合物未經純化即用於製備114。ES-MS m/z662 (M+H)。 Preparation of 99 (S)-4-(2-(5 4 -cyano-1 6 -methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenyl Methyl cyclononafin-1 4 -yl)acetamido)-3-methoxy-5-(((epoxypropan-2-ylmethyl)amino)benzoate Using 2-( 54 -cyano- 16 -methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylene essentially as described in Preparation 85 Cyclononafin- 14 -yl)acetic acid (Preparation 83) and 4-amino-3-methoxy-5-[[(2S)-epoxypropan-2-yl]methylamino]benzoic acid ester (Preparation 17) to prepare the title compound. The title compound was used in Preparation 114 without purification. ES-MS m/z 662 (M+H).
製備 100(S)-3-甲氧基-4-(2-(1 6-甲基-5 4-(三氟甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備85中所闡述使用2-(1 6-甲基-5 4-(三氟甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(製備84)及4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(製備17)來製備標題化合物。標題化合物未經純化即以粗產物形式用於製備115。ES-MS m/z706 (M+H)。 Preparation of 100 (S)-3-methoxy-4-(2-(1 6 -methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridine -1(1,3),5(1,2)-diphenylcyclononarfin-1 4 -yl)acetamido)-5-(((epoxypropylene-2-ylmethyl)amino)benzene Methyl formate Using 2-(1 6 -methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3 ), 5(1,2)-diphenylcyclonafin- 1 4 -yl)acetic acid (preparation 84) and 4-amino-3-methoxy-5-[[(2S)-propylene oxide-2 -yl]methylamino]methylbenzoate (Preparation 17) to prepare the title compound. The title compound was used crude in the preparation of 115 without purification. ES-MS m/z 706 (M+H).
製備 101(S)-2-((5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將(S)-4-(2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(220 mg, 0.295 mmol)於乙酸(3.0 mL)中之溶液在80℃下攪拌2 h。過濾反應混合物並在減壓下濃縮以得到200 mg標題化合物(87%),其以粗製形式用於實例1。ES-MS m/z619 (M+H)。 Preparation 101 (S)-2-((5 4 -cyano-1 6 -fluoro-3,9-dioxa- 2 (2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (S)-4-(2-(5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1, 2)-Diphenylcyclononarfin-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)methyl benzoate (220 mg, 0.295 mmol) in acetic acid (3.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give 200 mg of the title compound (87%), which was used in Example 1 in crude form. ES-MS m/z 619 (M+H).
製備 102(S)-2-((5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將於乙酸(5.0 mL)中之(S)-4-(2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-氟-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(0.46 g, 0.56 mmol)在55℃下攪拌15 h。濃縮反應混合物並將殘餘物溶於EtOAc (100 mL)中。使用飽和碳酸氫鈉水溶液及鹽水洗滌有機相。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於己烷中之5至60% EtOAc之梯度來純化殘餘物以得到0.24 g標題化合物(67%)。ES-MS m/z637 (M+H)。 Preparation 102 (S)-2-((5 4 -cyano-1 6 -fluoro-3,9-dioxa- 2 (2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononafin-1 4 -yl)methyl)-4-fluoro-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1(1 ,3),5(1,2)-diphenylcyclononarfin-1 4 -yl)acetamido)-3-fluoro-5-(((epoxypropane-2-ylmethyl)amino)benzene Methyl formate (0.46 g, 0.56 mmol) was stirred at 55 °C for 15 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 5 to 60% EtOAc in hexanes to afford 0.24 g of the title compound (67%). ES-MS m/z 637 (M+H).
製備 103(S)-2-((5 4-氰基-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備93)及1:1 DCM :乙酸來製備標題化合物。經由矽膠急速層析使用於DCM中之5 - 60% EtOAc之梯度進行純化。ES-MS m/z645 (M+H)。 Preparation 103 (S)-2-((5 4 -cyano-1 6 -methyl-3,9-dioxa- 2 (2,6)-pyridine-1(1,3), 5(1, 2)-Diphenylcyclononafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano- 16 -methyl-3,9-dioxa-2(2,6)-pyridine-1( 1,3),5(1,2)-diphenylcyclononarfin-1 4 -yl)acetamido)-3-methoxy-5-((epoxypropane-2-ylmethyl)amine base) methyl benzoate (Preparation 93) and 1:1 DCM:acetic acid to prepare the title compound. Purification was performed by flash chromatography on silica gel using a gradient of 5-60% EtOAc in DCM. ES-MS m/z 645 (M+H).
製備 104(S)-2-((5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯來製備標題化合物,其中將反應混合物在55℃下攪拌3.5 h且然後在65℃下攪拌2 h。在減壓下濃縮混合物並使用ACN共沸。將殘餘物溶於DCM中,吸附於Celite ®上,並經由使用於己烷中之0 - 100% EtOAc之梯度洗脫之矽膠層析進行純化。ES-MS m/z610 (M+H)。 Preparation of 104 (S)-2-((5 4 -Chloro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclone Fan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-(5 4 -chloro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononan- 14 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoic acid methyl ester to prepare the title compound, wherein The reaction mixture was stirred at 55°C for 3.5 h and then at 65°C for 2 h. The mixture was concentrated under reduced pressure and azeotroped using ACN. The residue was dissolved in DCM, absorbed on Celite® , and purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in hexanes. ES-MS m/z 610 (M+H).
製備 105(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備88)在1:1二氯乙烷:乙酸中來製備標題化合物。經由矽膠層析使用於DCM中之5 - 60% EtOAc之梯度來純化殘餘物以得到標題化合物。ES-MS m/z601 (M+H)。 Preparation of 105 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononafran-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate (Preparation 88) in 1 :1 dichloroethane:acetic acid to prepare the title compound. The residue was purified by silica gel chromatography using a gradient of 5-60% EtOAc in DCM to give the title compound. ES-MS m/z 601 (M+H).
製備 106(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯在1:1二氯乙烷:乙酸中來製備標題化合物。經由矽膠層析使用於DCM中之5 - 60% EtOAc之梯度來純化殘餘物以得到標題化合物。ES-MS m/z631 (M+H)。 Preparation of 106 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononafin-1 4 -yl)acetamido)-3-methoxy-5-(((epoxypropylene-2-ylmethyl)amino)benzoic acid methyl ester The title compound was prepared in 1:1 dichloroethane:acetic acid. The residue was purified by silica gel chromatography using a gradient of 5-60% EtOAc in DCM to give the title compound. ES-MS m/z 631 (M+H).
製備 107(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-3-(環氧丙烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-甲酸甲酯 基本上如製備102中所闡述使用(S)-5-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-14-基)乙醯胺基)-6-((環氧丙烷-2-基甲基)胺基)吡啶甲酸甲酯在1:1二氯乙烷:乙酸中來製備標題化合物,其中將反應時間增至48 h。經由矽膠層析使用於DCM中之5 - 60% EtOAc之梯度來純化殘餘物以得到標題化合物。ES-MS m/z602 (M+H)。 Preparation of 107 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-3-(epoxypropan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Using (S)-5-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononan-14-yl)acetamido)-6-(((epoxypropylene-2-ylmethyl)amino)picolinate methyl ester in 1:1 dichloroethyl Alkanes:acetic acid to prepare the title compound, wherein the reaction time was increased to 48 h. The residue was purified by silica gel chromatography using a gradient of 5-60% EtOAc in DCM to give the title compound. ES-MS m/z 602 (M+H).
製備 108(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-氟-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(0.38 g, 0.48 mmol)在1:1 二氯乙烷及乙酸中來製備標題化合物。經由矽膠層析使用於DCM中之5 - 60% EtOAc之梯度來純化殘餘物以得到0.24 g標題化合物(67%)。ES-MS m/z619 (M+H)。 Preparation of 108 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-4-fluoro-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononan-1 4 -yl)acetamido)-3-fluoro-5-(((epoxypropan-2-ylmethyl)amino)benzoic acid methyl ester (0.38 g, 0.48 mmol) in 1:1 dichloroethane and acetic acid to prepare the title compound. The residue was purified via silica gel chromatography using a gradient of 5-60% EtOAc in DCM to afford 0.24 g of the title compound (67%). ES-MS m/z 619 (M+H).
製備 109(S)-2-((5 4-氰基-1 6-氟-9-氧雜-3-氮雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將(S)-4-(2-(5 4-氰基-1 6-氟-9-氧雜-3-氮雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(160 mg, 0.20 mmol)於1,2-二氯乙烷(1.5 mL)及乙酸(1.25 mL)中之溶液在50℃下加熱6 h。將反應混合物冷卻至室溫,在減壓下濃縮溶劑,並經由矽膠層析使用於DCM中之10 - 50% EtOAc之梯度來純化殘餘物以提供70 mg (53%)白色固體形式之標題化合物。ES-MS m/z618 (M+H)。 Preparation of 109 (S)-2-((5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (S)-4-(2-(5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononafran-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate methyl ester (160 mg, 0.20 mmol) A solution in 1,2-dichloroethane (1.5 mL) and acetic acid (1.25 mL) was heated at 50 °C for 6 h. The reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 10-50% EtOAc in DCM to afford 70 mg (53%) of the title compound as a white solid . ES-MS m/z 618 (M+H).
製備 110(S)-2-((5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備109中所闡述使用(S)-4-(2-(5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯來製備標題化合物,其中將反應混合物在60℃下攪拌5.5 h。將混合物冷卻至室溫並在減壓下濃縮。經由矽膠層析使用於DCM中之10 - 30% EtOAc之梯度來純化殘餘物。ES-MS m/z619 (M+H)。 Preparation of 110 (S)-2-((5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclo Nonafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano- 16 -fluoro-3,9-dioxa-2(2,6)-pyridine-1,5) essentially as described in Preparation 109 (1,3)-Diphenylcyclononafran-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate methyl ester to prepare the title compound, wherein The reaction mixture was stirred at 60 °C for 5.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10-30% EtOAc in DCM. ES-MS m/z 619 (M+H).
製備 1112-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備101中所闡述使用4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)苯甲酸甲酯(製備95)來製備標題化合物,其中將反應液在65℃下攪拌5 h且然後在80℃下攪拌17 h。濃縮溶液並使用ACN共沸。經由矽膠層析使用於庚烷中之0 - 100% EtOAc之梯度然後使用於DCM中之0 - 10% MeOH之梯度來純化殘餘物。ES-MS m/z639 (M+H)。 Preparation 111 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclonona-1 4 -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using 4-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononafin- 14 -yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate methyl ester (Preparation 95 ) to prepare the title compound, wherein the reaction was stirred at 65 °C for 5 h and then at 80 °C for 17 h. The solution was concentrated and azeotroped using ACN. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in heptane and then a gradient of 0-10% MeOH in DCM. ES-MS m/z 639 (M+H).
製備 112(S)-2-((5 4-氰基-1 6-氟-3,6,9-三氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備101中所闡述使用(S)-4-(2-(5 4-氰基-1 6-氟-3,6,9-三氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯來製備標題化合物,其中將反應液在65℃下攪拌3 h。濃縮反應液並使用ACN共沸。經由使用於庚烷中之0 - 100% EtOAc之梯度然後使用於DCM中之0 - 2% MeOH之矽膠急速層析之梯度來純化殘餘物以得到標題化合物。ES-MS m/z621 (M+H)。 Preparation of 112 (S)-2-((5 4 -cyano-1 6 -fluoro-3,6,9-trioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano- 16 -fluoro-3,6,9-trioxa-2(2,6)-pyridine-1 essentially as described in Preparation 101 (1,3),5(1,2)-Diphenylcyclononarfin-1 4 -yl)acetamido)-3-((epoxypropylene-2-ylmethyl)amino)benzoic acid methyl The title compound was prepared from the ester by stirring the reaction at 65 °C for 3 h. The reaction was concentrated and azeotroped using ACN. The residue was purified by flash chromatography on silica gel using a gradient of 0-100% EtOAc in heptane, then 0-2% MeOH in DCM to give the title compound. ES-MS m/z 621 (M+H).
製備 113(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如述製備101中所闡使用(S)-4-(2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯來製備標題化合物,其中將反應液在65℃下攪拌1.5 h。濃縮溶液並使用ACN共沸,然後經由使用於庚烷中之0 - 60% EtOAc之梯度之矽膠急速層析來純化殘餘物以得到標題化合物。ES-MS m/z605 (M+H)。 Preparation 113 (S)-2-((5 4 -cyano-1 6 -fluoro-3,7-dioxa- 2 (2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclooctane-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano- 16 -fluoro-3,7-dioxa-2(2,6)-pyridine-1( 1,3),5(1,2)-Diphenylcyclooctafan-1 4 -yl)acetamido)-3-(((epoxypropylene-2-ylmethyl)amino)benzoic acid methyl ester The title compound was prepared by stirring the reaction at 65 °C for 1.5 h. The solution was concentrated and azeotroped using ACN, then the residue was purified by flash chromatography on silica gel with a gradient of 0-60% EtOAc in heptane to give the title compound. ES-MS m/z 605 (M+H).
製備 114(S)-2-((5 4-氰基-1 6-甲基-3,9-二氧雜-1,2(1,3),5(1,2)-三苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-1 6-甲基-3,9-二氧雜-1,2(1,3),5(1,2)-三苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備99)在1:1二氯乙烷:乙酸中來製備標題化合物。ES-MS m/z645 (M+H)。 Preparation of 114 (S)-2-((5 4 -cyano-1 6 -methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylcyclononyl Fan-1 4 -yl)methyl)-4-methoxy-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano- 16 -methyl-3,9-dioxa-1,2(1,3),5( 1,2)-Triphenylcyclononan-1 4 -yl)acetamido)-3-methoxy-5-(((epoxypropan-2-ylmethyl)amino)benzoate methyl ester ( Preparation 99) The title compound was prepared in 1:1 dichloroethane:acetic acid. ES-MS m/z 645 (M+H).
製備 115(S)-4-甲氧基-2-((1 6-甲基-5 4-(三氟甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-3-甲氧基-4-(2-(1 6-甲基-5 4-(三氟甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備100)在1:1 二氯乙烷:乙酸中來製備標題化合物。經由矽膠層析使用於己烷中之80 - 100% DCM之梯度來純化標題化合物。ES-MS m/z688 (M+H)。 Preparation 115 (S)-4-Methoxy-2-((1 6 -methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridine-1 (1,3),5(1,2)-Diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole -6-methyl carboxylate Using (S)-3-methoxy-4-(2-( 16 -methyl- 54- (trifluoromethyl)-3,9-dioxa-2) essentially as described in Preparation 102 (2,6)-Pyridine-1(1,3),5(1,2)-Diphenylcyclononan-1 4 -yl)acetamido)-5-((epoxypropylene-2-yl Methyl)amino)benzoate (Preparation 100) in 1:1 dichloroethane:acetic acid to prepare the title compound. The title compound was purified by silica gel chromatography using a gradient of 80-100% DCM in hexanes. ES-MS m/z 688 (M+H).
製備 1162-(4-溴-2-甲基苯基)乙酸甲酯 經15 min將亞硫醯氯(2.5 mL, 34.3 mmol)逐滴添加至2-(4-溴-2-甲基苯基)乙酸(5 g, 20.74 mmol)於MeOH (42 mL)中之4℃溶液中。將反應液攪拌3 h,然後在減壓下蒸發溶劑。向殘餘物中添加水(50 mL)及飽和NaHCO 3水溶液以溶液之pH = 7-8,然後使用EtOAc (3 × 30 mL)萃取。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,然後過濾並在減壓下濃縮以得到橙色油狀物形式之標題化合物(5.06g, 100%)。標題化合物在LCMS中並不離子化且未經進一步表徵即用於製備117。 Preparation of 116 2-(4-bromo-2-methylphenyl)methyl acetate Thionyl chloride (2.5 mL, 34.3 mmol) was added dropwise to a solution of 2-(4-bromo-2-methylphenyl)acetic acid (5 g, 20.74 mmol) in MeOH (42 mL) over 15 min. ℃ solution. The reaction was stirred for 3 h, then the solvent was evaporated under reduced pressure. Water (50 mL) and saturated aqueous NaHCO 3 were added to the residue to bring the solution to pH=7-8, then extracted with EtOAc (3×30 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , then filtered and concentrated under reduced pressure to give the title compound (5.06 g, 100%) as an orange oil. The title compound did not ionize in LCMS and was used in Preparation 117 without further characterization.
製備 1174-溴-2-(溴甲基)苯基乙酸甲酯 將2-(4-溴-2-甲基苯基)乙酸甲酯(4.03 g, 15.7 mmol)及N-溴琥珀醯亞胺(2.66 g, 14.9 mmol)於ACN (85 mL)中之溶液轉移通過配備有4 × 370 nm燈及4 × 440 nm燈之光化學流動反應器(反應器大小= 52mL,滯留時間= 1.3mL/min, 40℃)。經2 h收集溶液,蒸發溶劑,然後將水(20 mL)及MTBE (20 mL)添加至殘餘物中。分離各層並使用MTBE (2 × 20 mL)萃取水相。合併有機物,使用20% NaHSO 3水溶液、水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾並在減壓下濃縮。經由矽膠層析使用於環己烷中之10 - 40% DCM之梯度來純化殘餘物以得到白色蠟狀固體形式之標題化合物(5.1 g,85%純度,75%產率)。ES-MS m/z338/340/342 (M+NH 4 +)。 Preparation 117 4-Bromo-2-(bromomethyl)phenylacetic acid methyl ester A solution of methyl 2-(4-bromo-2-methylphenyl)acetate (4.03 g, 15.7 mmol) and N-bromosuccinimide (2.66 g, 14.9 mmol) in ACN (85 mL) was transferred Pass through a photochemical flow reactor equipped with 4 x 370 nm lamps and 4 x 440 nm lamps (reactor size = 52 mL, residence time = 1.3 mL/min, 40 °C). The solution was collected over 2 h, the solvent was evaporated, then water (20 mL) and MTBE (20 mL) were added to the residue. The layers were separated and the aqueous phase was extracted with MTBE (2 x 20 mL). The combined organics were washed with 20% aq. NaHSO 3 , water and sat. aq. NaCl, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 10-40% DCM in cyclohexane to give the title compound (5.1 g, 85% purity, 75% yield) as a white waxy solid. ES-MS m/z 338/340/342 (M+ NH4 + ).
製備 1183-氟-5-甲氧基-4-硝基-苯甲酸甲酯 向3,5-二氟-4-硝基-苯甲酸甲酯(0.3g, 1.38mmol)於MeOH (4 mL)中之溶液中添加甲醇鈉溶液(25質量%,於MeOH中,0.33 mL, 1.44 mmol),並將反應液在65℃下加熱2.5 h。將反應混合物冷卻至室溫,然後添加水並使用EtOAc (3 × 5 mL)萃取。合併有機物,使用飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,然後過濾並在真空中濃縮。經由矽膠層析來使用於庚烷中之EtOAc (0 - 10%)之梯度純化殘餘物以得到245 mg (76%)黃色油狀物形式之標題化合物。ES-MS m/z230 (M+H)。 Preparation of 118 3-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester To a solution of methyl 3,5-difluoro-4-nitro-benzoate (0.3 g, 1.38 mmol) in MeOH (4 mL) was added a solution of sodium methoxide (25 mass % in MeOH, 0.33 mL, 1.44 mmol), and the reaction solution was heated at 65 °C for 2.5 h. The reaction mixture was cooled to room temperature, then water was added and extracted with EtOAc (3 x 5 mL). The organics were combined, washed with saturated aqueous NaCl, dried over MgSO 4 , then filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of EtOAc (0-10%) in heptane to afford 245 mg (76%) of the title compound as a yellow oil. ES-MS m/z 230 (M+H).
製備 1193-氟-5-甲氧基-4-硝基-苯甲酸乙酯 將硫酸(2 mL, 3.1 g, 31 mmol)添加至3-氟-5-甲氧基-4-硝基-苯甲酸(0.67 g, 3.1 mmol)於EtOH (10 mL)中之溶液中,且將混合物加熱至80℃並保持1 h。使用飽和NaHCO 3水溶液將反應混合物驟冷並使用DCM萃取。藉由MgSO4乾燥有機層,過濾,並濃縮以得到標題化合物(0.73 g, 96%),其未經進一步純化即用於製備121。ES-MS m/z244 (M+H)。 Preparation of 119 3-fluoro-5-methoxy-4-nitro-benzoic acid ethyl ester Sulfuric acid (2 mL, 3.1 g, 31 mmol) was added to a solution of 3-fluoro-5-methoxy-4-nitro-benzoic acid (0.67 g, 3.1 mmol) in EtOH (10 mL), and The mixture was heated to 80 °C for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO 3 and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated to give the title compound (0.73 g, 96%), which was used in the preparation of 121 without further purification. ES-MS m/z 244 (M+H).
製備 1203-氟-5-(2-甲氧基乙氧基)-4-硝基-苯甲酸酯甲酯 將氫化鈉(92 mg, 2.30 mmol)懸浮於THF (10 ml)中,然後添加2-甲氧基乙醇(0.18 mL, 2.31 mmol)並在室溫下攪拌30 min。接下來,添加3,5-二氟-4-硝基-苯甲酸甲酯(0.5g, 2.30 mmol)並將混合物在60℃下攪拌16 h。使用水(100 mL)稀釋反應液並使用EtOAc (3 × 50 mL)萃取。藉由Na 2SO 4乾燥有機物,過濾,並濃縮。藉由矽膠層析使用於庚烷中之0 - 20% EtOAc之梯度進行純化以得到黃色油狀物形式之標題化合物(225 mg, 40%)。ES-MS m/z274 (M+H)。 Preparation of 120 3-fluoro-5-(2-methoxyethoxy)-4-nitro-benzoate methyl ester Sodium hydride (92 mg, 2.30 mmol) was suspended in THF (10 ml), then 2-methoxyethanol (0.18 mL, 2.31 mmol) was added and stirred at room temperature for 30 min. Next, methyl 3,5-difluoro-4-nitro-benzoate (0.5 g, 2.30 mmol) was added and the mixture was stirred at 60 °C for 16 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The organics were dried over Na2SO4 , filtered, and concentrated. Purification by silica gel chromatography using a gradient of 0-20% EtOAc in heptane afforded the title compound (225 mg, 40%) as a yellow oil. ES-MS m/z 274 (M+H).
製備 1213-甲氧基-4-硝基-5-(噁唑-2-基甲基胺基)苯甲酸乙酯 基本上如述製備14中所闡使用3-氟-5-甲氧基-4-硝基-苯甲酸乙酯(0.30 g, 1.0 mmol)及1-(1,3-噁唑-2-基)甲胺鹽酸鹽(0.20 g, 1.0 mmol)來製備標題化合物。經由矽膠層析使用於庚烷中之0 - 50% EtOAc之梯度來純化標題化合物。ES-MS m/z322 (M+H)。 Preparation 121 Ethyl 3-methoxy-4-nitro-5-(oxazol-2-ylmethylamino)benzoate 3-Fluoro-5-methoxy-4-nitro-benzoic acid ethyl ester (0.30 g, 1.0 mmol) and 1-(1,3-oxazol-2-yl) were used essentially as described in Preparation 14 ) methylamine hydrochloride (0.20 g, 1.0 mmol) to prepare the title compound. The title compound was purified by silica gel chromatography using a gradient of 0-50% EtOAc in heptane. ES-MS m/z 322 (M+H).
製備 1224-胺基-3-甲氧基-5-(噁唑-2-基甲基胺基)苯甲酸乙酯 將鐵粉(0.33g, 5.8 mmol)及NH 4Cl (0.015 g, 0.28 mmol懸浮於水(4.4 mL)中並添加乙酸(0.07 mL, 1.18 mmol)。在50℃下攪拌15 min,然後添加3-甲氧基-4-硝基-5-(噁唑-2-基甲基胺基)苯甲酸乙酯(0.165 g, 0.514 mmol)於DMF (1.45 mL)中之溶液。將混合物在50℃下攪拌20 min,冷卻至室溫,經由Celite ®過濾混合物並使用EtOAc (100 mL)沖洗。使用飽和NaHCO 3溶液(100 mL)洗滌有機物並藉由MgSO 4乾燥。過濾並濃縮以提供黃色油狀物形式之標題化合物(0.11 g, 74%),其未經純化即用於製備169。ES-MS m/z292 (M+H)。 Preparation of 122 4-amino-3-methoxy-5-(oxazol-2-ylmethylamino)ethyl benzoate Iron powder (0.33 g, 5.8 mmol) and NH 4 Cl (0.015 g, 0.28 mmol) were suspended in water (4.4 mL) and acetic acid (0.07 mL, 1.18 mmol) was added. Stirred at 50°C for 15 min, then added 3 -A solution of ethyl methoxy-4-nitro-5-(oxazol-2-ylmethylamino)benzoate (0.165 g, 0.514 mmol) in DMF (1.45 mL). The mixture was heated at 50° C. Stirred at 20 min, cooled to room temperature, filtered the mixture through Celite® and rinsed with EtOAc (100 mL). The organics were washed with saturated NaHCO solution (100 mL) and dried over MgSO 4 . Filtered and concentrated to afford a yellow oil The title compound (0.11 g, 74%) was used in the preparation of 169 without purification. ES-MS m/z 292 (M+H).
製備 1233-(2-甲氧基乙氧基)-4-硝基-5-[[(2S)-環氧丙烷-2-基]-甲基胺基]苯甲酸甲酯 基本上如製備14中所闡述使用3-氟-5-(2-甲氧基乙氧基)-4-硝基-苯甲酸甲酯及[(2S)-環氧丙烷-2-基]甲胺來製備標題化合物。經由矽膠層析使用於庚烷中之0 - 30% EtOAc之梯度來純化標題化合物。ES-MS m/z341 (M+H)。 Preparation 123 Methyl 3-(2-methoxyethoxy)-4-nitro-5-[[(2S)-epoxypropylene-2-yl]-methylamino]benzoate Using 3-fluoro-5-(2-methoxyethoxy)-4-nitro-benzoic acid methyl ester and [(2S)-epoxypropan-2-yl]methanol essentially as described in Preparation 14 amine to prepare the title compound. The title compound was purified by silica gel chromatography using a gradient of 0-30% EtOAc in heptane. ES-MS m/z 341 (M+H).
製備 1244-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 基本上如製備122中所闡述使用3-(2-甲氧基乙氧基)-4-硝基-5-(環氧丙烷-2-基-甲基胺基)苯甲酸甲酯來製備標題化合物。產物未經進一步純化即用於製備170。ES-MS m/z311 (M+H)。 Preparation 124 Methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-epoxypropane-2-yl]methylamino]benzoate The title was prepared essentially as described in Preparation 122 using methyl 3-(2-methoxyethoxy)-4-nitro-5-(epoxypropan-2-yl-methylamino)benzoate compound. The product was used in the preparation of 170 without further purification. ES-MS m/z 311 (M+H).
製備 1254-[(6-溴-2-吡啶基)氧基甲基]-3-[(E)-2-乙氧基乙烯基]苯甲腈 在氮鼓泡下,向4-[(6-溴-2-吡啶基)氧基甲基]-3-碘-苯甲腈(6 g, 14.45 mmol)於1,4二噁烷(100 mL)中之溶液中添加Cs 2CO 3(9.5 g, 29 mmol)、四(三苯基膦)鈀(0) (835 mg, 0.72 mmol)及(E)-1-乙氧基乙烯-2-酸頻哪醇酯(4.2 mL, 18.8 mmol)。將反應混合物在氮及90℃下加熱1天,然後添加額外之四(三苯基膦)鈀(0) (835 mg, 0.72 mmol)及(E)-1-乙氧基乙烯-2-酸頻哪醇酯(1 mL, 4.48 mmol)。將混合物在90℃下加熱加熱2天。冷卻混合物,添加水(100 mL)並使用EtOAc (3 × 60 mL)萃取。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於環己烷中之0 - 10% EtOAc之梯度來純化殘餘物以得到3.6 g (60%產率)淺黃色固體形式之標題化合物。ES-MS m/z359/361 (M+H)。 Preparation of 125 4-[(6-bromo-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile Under nitrogen bubbling, 4-[(6-bromo-2-pyridyl)oxymethyl]-3-iodo-benzonitrile (6 g, 14.45 mmol) in 1,4 dioxane (100 mL ) were added Cs 2 CO 3 (9.5 g, 29 mmol), tetrakis(triphenylphosphine)palladium(0) (835 mg, 0.72 mmol) and (E)-1-ethoxyethylene-2- Acid pinacol ester (4.2 mL, 18.8 mmol). The reaction mixture was heated under nitrogen at 90 °C for 1 day, then additional tetrakis(triphenylphosphine)palladium(0) (835 mg, 0.72 mmol) and (E)-1-ethoxyethylene-2- Acid pinacol ester (1 mL, 4.48 mmol). The mixture was heated at 90°C for 2 days. The mixture was cooled, water (100 mL) was added and extracted with EtOAc (3 x 60 mL). The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-10% EtOAc in cyclohexane to afford 3.6 g (60% yield) of the title compound as a pale yellow solid. ES-MS m/z 359/361 (M+H).
製備 1264-[(6-溴-2-吡啶基)氧基甲基]-3-(2-側氧基乙基)苯甲腈 向4-[(6-溴-2-吡啶基)氧基甲基]-3-[(E)-2-乙氧基乙烯基]苯甲腈(3.6 g, 8.5 mmol)於THF (54 mL)中之溶液中添加於1,4-二噁烷中之4M HCl (21 mL, 85 mmol)。將混合物在室溫下攪拌20 h。濃縮混合物,添加水(50 mL)及2M碳酸鈉水溶液直至pH = 8,且然後使用EtOAc (3 × 40 mL)萃取。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮以提供淺橙色固體形式之標題化合物(3.9 g, 97%)。ES-MS m/z331/333 (M+H)。 Preparation of 126 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile To 4-[(6-bromo-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile (3.6 g, 8.5 mmol) in THF (54 mL ) was added 4M HCl in 1,4-dioxane (21 mL, 85 mmol). The mixture was stirred at room temperature for 20 h. The mixture was concentrated, water (50 mL) and 2M aqueous sodium carbonate were added until pH = 8, and then extracted with EtOAc (3 x 40 mL). The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure to afford the title compound (3.9 g, 97%) as a light orange solid. ES-MS m/z 331/333 (M+H).
製備 1274-[(6-溴-2-吡啶基)氧基甲基]-3-(2-羥乙基)苯甲腈 向4-[(6-溴-2-吡啶基)氧基甲基]-3-(2-側氧基乙基)苯甲腈(3.9 g, 8.24 mmol)於MeOH (60 mL)中之溶液中分批添加硼氫化鈉(550 mg, 14.53 mmoL)。將混合物在室溫下攪拌1 h,蒸發溶劑,添加DCM (30 mL)及1M NaOH溶液(10 mL)並攪拌10 min。分離各相並使用額外DCM (2 × 5 mL)萃取水相。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾並在減壓下濃縮。經由矽膠層析使用於環己烷中之10 - 40% EtOAc之梯度來純化殘餘物以得到白色蠟狀固體形式之標題化合物(1.71 g, 60%)。ES-MS m/z333/335 (M+H)。 Preparation of 127 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile To a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile (3.9 g, 8.24 mmol) in MeOH (60 mL) Sodium borohydride (550 mg, 14.53 mmol) was added in portions. The mixture was stirred at room temperature for 1 h, the solvent was evaporated, DCM (30 mL) and 1M NaOH solution (10 mL) were added and stirred for 10 min. The phases were separated and the aqueous phase was extracted with additional DCM (2 x 5 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10-40% EtOAc in cyclohexane to give the title compound (1.71 g, 60%) as a white waxy solid. ES-MS m/z 333/335 (M+H).
製備 1282-溴-4-(羥甲基)苯甲腈 在0℃及氮氣氛下,將於THF中之硼氫化鋰(7.7 mL, 15.4 mmol, 2.0 mol/L)添加至3-溴-4-氰基苯甲酸乙酯(2 g, 7.71 mmol)於無水THF (20 mL)中之溶液中。使混合物達到室溫並攪拌過夜。去除大部分THF並在0℃下小心添加檸檬酸(5%水溶液)。使用EtOAc萃取水層,合併有機層,使用水及飽和NaCl水溶液洗滌,藉由無水Na 2SO 4乾燥,過濾並在減壓下濃縮。經由矽膠層析使用於環己烷中之30 - 100% EtOAc之梯度來純化殘餘物以提供白色固體形式之標題化合物(1.56 g,92%純度,88%)。 1H NMR (400 MHz, DMSO) δ 7.91 (d, J= 7.9 Hz, 1H), 7.80 (s, 1H), 7.51 (d, J= 7.5 Hz, 1H), 5.57 (t, J= 5.8 Hz, 1H), 4.59 (d, J= 5.9 Hz, 2H)。 Preparation of 128 2-bromo-4-(hydroxymethyl)benzonitrile Lithium borohydride (7.7 mL, 15.4 mmol, 2.0 mol/L) in THF was added to ethyl 3-bromo-4-cyanobenzoate (2 g, 7.71 mmol) at 0 °C under nitrogen atmosphere solution in anhydrous THF (20 mL). The mixture was allowed to reach room temperature and stirred overnight. Most of the THF was removed and citric acid (5% in water) was added carefully at 0 °C. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by silica gel chromatography using a gradient of 30 - 100% EtOAc in cyclohexane to afford the title compound (1.56 g, 92% purity, 88%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 7.91 (d, J = 7.9 Hz, 1H), 7.80 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 5.57 (t, J = 5.8 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H).
製備 1292-溴-4-[(6-氯-2-吡啶基)氧基甲基]苯甲腈 基本上如製備30中所闡述使用2-溴-4-(羥甲基)苯甲腈及6-氯吡啶-2-醇來製備標題化合物。經由矽膠層析使用於環己烷中之10 - 30% EtOAc之梯度來純化標題化合物。ES-MS m/z323, 325, 327 (M+H)。 Preparation of 129 2-bromo-4-[(6-chloro-2-pyridyl)oxymethyl]benzonitrile The title compound was prepared essentially as described in Preparation 30 using 2-bromo-4-(hydroxymethyl)benzonitrile and 6-chloropyridin-2-ol. The title compound was purified by silica gel chromatography using a gradient of 10-30% EtOAc in cyclohexane. ES-MS m/z 323, 325, 327 (M+H).
製備 1304-[(6-氯-2-吡啶基)氧基甲基]-2-(2-羥乙基)苯甲腈 向小瓶中裝填氯化鎳(II)乙二醇二甲基醚複合物(34 mg, 0.15 mmol)及4,4'-二-第三丁基-2,2'-聯吡啶(48 mg, 0.17 mmol)。使用氮吹掃小瓶並添加無水1,2-二甲氧基乙烷(3 mL)。將混合物攪拌15min。 向另一小瓶中裝填Na 2CO 3(335 mg, 3.13 mmol)、2-溴-4-[(6-氯-2-吡啶基)氧基甲基]苯甲腈(502 mg, 1.55 mmol)及(Ir[dF(CF 3)ppy] 2(dtbpy))PF 6(18 mg, 0.016 mmol)。使用氮吹掃小瓶並添加無水1,2-二甲氧基乙烷(12 mL)、2-溴乙醇(1.1 mL, 15 mmol)、參(三甲基矽基)矽烷(740 µL, 2.33 mmol)及預製Ni觸媒。使用氮將混合物鼓泡5 min並在EvoluChem TM光氧化還原箱中使用456 nm Kessil LED光與風扇將其輻照過夜。過濾掉固體,使用DCM洗滌並濃縮濾液。經由矽膠層析使用於DCM中之0 - 10% EtOAc之梯度作為洗脫劑系統來純化殘餘物以提供黃色蠟狀固體形式之標題化合物(190 mg, 42%)。ES-MS m/z289, 291 (M+H)。 Preparation of 130 4-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)benzonitrile Fill the vial with nickel(II) ethylene glycol dimethyl ether complex (34 mg, 0.15 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (48 mg, 0.17 mmol). The vial was purged with nitrogen and dry 1,2-dimethoxyethane (3 mL) was added. The mixture was stirred for 15 min. Charge another vial with Na 2 CO 3 (335 mg, 3.13 mmol), 2-bromo-4-[(6-chloro-2-pyridyl)oxymethyl]benzonitrile (502 mg, 1.55 mmol) and (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 (18 mg, 0.016 mmol). The vial was purged with nitrogen and anhydrous 1,2-dimethoxyethane (12 mL), 2-bromoethanol (1.1 mL, 15 mmol), ginseng(trimethylsilyl)silane (740 µL, 2.33 mmol ) and prefabricated Ni catalyst. The mixture was bubbled with nitrogen for 5 min and irradiated overnight in an EvoluChem ™ photoredox chamber using 456 nm Kessil LED light and a fan. The solid was filtered off, washed with DCM and the filtrate was concentrated. The residue was purified by silica gel chromatography using a gradient of 0-10% EtOAc in DCM as the eluent system to afford the title compound (190 mg, 42%) as a yellow waxy solid. ES-MS m/z 289, 291 (M+H).
製備 1312-溴-6-[(4-氟-2-碘-苯基)甲氧基]吡啶 向(4-氟-2-碘-苯基)甲醇(2.0 g, 7.9 mmol)、2-溴-6-氟-吡啶(1.4 g, 7.9 mmol)及1,4-二噁烷(25 mL)之混合物中添加第三丁醇鉀(1.20 g, 10.0 mmol)。將反應混合物在60℃下攪拌16 h。使用EtOAc (100 mL)稀釋反應液並經由Celite ®過濾。使用水(2 × 50 mL)及飽和氯化鈉水溶液(50 mL)洗滌濾液。藉由Na 2SO 4乾燥有機相,過濾,並在減壓下濃縮。經由使用於己烷中之5 - 50% DCM之梯度洗脫之矽膠急速層析來純化殘餘物以得到2.16 g標題化合物(67%)。ES-MS m/z408及410 (M+H)。 Preparation 131 2-bromo-6-[(4-fluoro-2-iodo-phenyl)methoxy]pyridine To (4-fluoro-2-iodo-phenyl)methanol (2.0 g, 7.9 mmol), 2-bromo-6-fluoro-pyridine (1.4 g, 7.9 mmol) and 1,4-dioxane (25 mL) Potassium tert-butoxide (1.20 g, 10.0 mmol) was added to the mixture. The reaction mixture was stirred at 60 °C for 16 h. The reaction was diluted with EtOAc (100 mL) and filtered through Celite® . The filtrate was washed with water (2 x 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by flash chromatography on silica gel eluting with a gradient of 5-50% DCM in hexanes to afford 2.16 g of the title compound (67%). ES-MS m/z 408 and 410 (M+H).
製備 1323-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氟-苯基]丙氧基-第三丁基-二甲基-矽烷 基本上如製備28中所闡述使用2-溴-6-[(4-氟-2-碘-苯基)甲氧基]吡啶來製備標題化合物。經由使用於己烷中之0 - 10% EtOAc之梯度洗脫之矽膠急速層析來純化標題化合物以得到在ES-MS中不離子化之油狀物,其未經進一步鑑別即直接用於製備133。 Preparation of 132 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propoxy-tert-butyl-dimethyl-silane The title compound was prepared essentially as described in Preparation 28 using 2-bromo-6-[(4-fluoro-2-iodo-phenyl)methoxy]pyridine. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 0-10% EtOAc in hexanes to give an oil that did not ionize in ES-MS, which was used directly in the preparation 133.
製備 1333-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氟-苯基]丙烷-1-醇 基本上如製備29中所闡述使用3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氟-苯基]丙氧基-第三丁基-二甲基-矽烷(製備132)來製備標題化合物。ES-MS m/z340及342 (M+H)。 Preparation 133 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propan-1-ol Essentially as described in Preparation 29 using 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propoxy-tert-butyl-dimethyl - Silane (Preparation 132) to prepare the title compound. ES-MS m/z 340 and 342 (M+H).
製備 1342-[3-[第三丁基(二甲基)矽基]氧基丙基]-6-(三氟甲基)吡啶-3-甲酸甲酯 基本上如製備28中所闡述使用2-溴-6-(三氟甲基)吡啶-3-甲酸甲酯來製備標題化合物。經由矽膠層析使用於DCM中之0 - 10% EtOAc之梯度來純化標題化合物。ES-MS m/z378 (M+H)。 Preparation 134 2-[3-[tertiary butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)pyridine-3-carboxylic acid methyl ester The title compound was prepared essentially as described in Preparation 28 using methyl 2-bromo-6-(trifluoromethyl)pyridine-3-carboxylate. The title compound was purified by silica gel chromatography using a gradient of 0-10% EtOAc in DCM. ES-MS m/z 378 (M+H).
製備 135[2-[3-[第三丁基(二甲基)矽基]氧基丙基]-6-(三氟甲基)-3-吡啶基]甲醇 在冰/鹽浴中將2-[3-[第三丁基(二甲基)矽基]氧基丙基]-6-(三氟甲基)吡啶-3-甲酸甲酯(2.0 g, 5.3 mmol)及THF (40 mL)之混合物冷卻至-10℃。向此混合物中添加氫化鋰鋁(0.20 g, 5.3 mmol)並在冷卻下攪拌1 h。藉由逐滴添加水(1 mL)來終止反應,然後使用EtOAc (50 mL)稀釋。經由Celite ®過濾所得混合物並使用EtOAc (100 mL)沖洗。使用水(100 mL)及飽和NaCl水溶液(100 mL)洗滌濾液,然後藉由Na 2SO 4乾燥。過濾並濃縮以得到淺棕色油狀物形式之標題化合物(1.66 g, 84%),其未經進一步純化即用於製備136。ES-MS m/z350 (M+H)。 Preparation of 135 [2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)-3-pyridyl]methanol Methyl 2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)pyridine-3-carboxylate (2.0 g, 5.3 mmol) and THF (40 mL) was cooled to -10°C. To this mixture was added lithium aluminum hydride (0.20 g, 5.3 mmol) and stirred under cooling for 1 h. The reaction was quenched by the dropwise addition of water (1 mL), then diluted with EtOAc (50 mL). The resulting mixture was filtered through Celite® and rinsed with EtOAc (100 mL). The filtrate was washed with water (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na 2 SO 4 . Filtration and concentration gave the title compound as a light brown oil (1.66 g, 84%) which was used in the preparation of 136 without further purification. ES-MS m/z 350 (M+H).
製備 1363-[3-[(6-溴-2-吡啶基)氧基甲基]-6-(三氟甲基)-2-吡啶基]丙氧基-第三丁基-二甲基-矽烷 基本上如製備51中所闡述使用[2-[3-[第三丁基(二甲基)矽基]氧基丙基]-6-(三氟甲基)-3-吡啶基]甲醇及2-溴-6-氟-吡啶來製備標題化合物,其中將反應液在60℃下攪拌16 h。經由使用於己烷中之5 - 50% DCM之梯度洗脫之矽膠急速層析來純化標題化合物。ES-MS m/z506及508 (M+H)。 Preparation 136 3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propoxy-tert-butyl-dimethyl - Silane Essentially as described in Preparation 51 using [2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)-3-pyridyl]methanol and 2-Bromo-6-fluoro-pyridine to prepare the title compound, wherein the reaction was stirred at 60 °C for 16 h. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 5-50% DCM in hexanes. ES-MS m/z 506 and 508 (M+H).
製備 1373-[3-[(6-溴-2-吡啶基)氧基甲基]-6-(三氟甲基)-2-吡啶基]丙烷-1-醇 基本上如製備29中所闡述使用3-[3-[(6-溴-2-吡啶基)氧基甲基]-6-(三氟甲基)-2-吡啶基]丙氧基-第三丁基-二甲基-矽烷來製備標題化合物。經由使用於己烷中之5 - 50% EtOAc之梯度洗脫之矽膠急速層析來純化標題化合物。ES-MS m/z390及392 (M+H)。 Preparation 137 3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propan-1-ol Essentially as described in Preparation 29 using 3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propoxy-th Tributyl-dimethyl-silane to prepare the title compound. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 5-50% EtOAc in hexanes. ES-MS m/z 390 and 392 (M+H).
製備 138(3-碘-4-吡啶基)甲醇 使用冰/鹽浴將3-碘吡啶-4-甲酸甲酯(5.0 g, 19 mmol)於THF (40 mL)及MeOH (10 mL)中之混合物冷卻至-10℃,然後添加硼氫化鈉(1.52 g, 40.2 mmol)並在冷卻下攪拌1 h。藉由逐滴添加水(1 mL)來終止反應,然後使用EtOAc (50 mL)稀釋。經由Celite ®過濾所得混合物並使用EtOAc (100 mL)沖洗。使用水(100 mL)及飽和NaCl水溶液(100 mL)洗滌濾液,然後藉由Na 2SO 4乾燥。經由矽膠層析使用於DCM中之5 - 50% (1:4 MeOH : EtOAc)之梯度來純化殘餘物以得到淺棕色固體形式之標題化合物(1.63 g, 36%)。ES-MS m/z236 (M+H)。 Preparation of 138 (3-iodo-4-pyridyl)methanol A mixture of methyl 3-iodopyridine-4-carboxylate (5.0 g, 19 mmol) in THF (40 mL) and MeOH (10 mL) was cooled to -10 °C using an ice/salt bath, then sodium borohydride ( 1.52 g, 40.2 mmol) and stirred for 1 h under cooling. The reaction was quenched by the dropwise addition of water (1 mL), then diluted with EtOAc (50 mL). The resulting mixture was filtered through Celite® and rinsed with EtOAc (100 mL). The filtrate was washed with water (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na 2 SO 4 . The residue was purified by silica gel chromatography using a gradient of 5-50% (1:4 MeOH:EtOAc) in DCM to afford the title compound (1.63 g, 36%) as a light brown solid. ES-MS m/z 236 (M+H).
製備 1392-溴-6-[(3-碘-4-吡啶基)甲氧基]吡啶 基本上如製備51中所闡述使用(3-碘-4-吡啶基)甲醇及2-溴-6-氟-吡啶來製備標題化合物,其中將反應液在60℃下攪拌16 h。經由矽膠層析使用於DCM中之5 - 50% EtOAc之梯度來純化標題化合物。ES-MS m/z390及392 (M+H)。 Preparation 139 2-bromo-6-[(3-iodo-4-pyridyl)methoxy]pyridine The title compound was prepared using (3-iodo-4-pyridyl)methanol and 2-bromo-6-fluoro-pyridine essentially as described in Preparation 51, wherein the reaction was stirred at 60 °C for 16 h. The title compound was purified by silica gel chromatography using a gradient of 5-50% EtOAc in DCM. ES-MS m/z 390 and 392 (M+H).
製備 1403-[4-[(6-溴-2-吡啶基)氧基甲基]-3-吡啶基]丙氧基-第三丁基-二甲基-矽烷 基本上如製備28中所闡述使用2-溴-6-[(3-碘-4-吡啶基)甲氧基]吡啶來製備標題化合物。經由矽膠層析使用於己烷中之0 - 80% EtOAc之梯度來純化標題化合物,且其未經進一步表徵即用於製備141。 Preparation 140 3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy-tert-butyl-dimethyl-silane The title compound was prepared essentially as described in Preparation 28 using 2-bromo-6-[(3-iodo-4-pyridyl)methoxy]pyridine. The title compound was purified by silica gel chromatography using a gradient of 0-80% EtOAc in hexanes and used in the preparation of 141 without further characterization.
製備 1413-[4-[(6-溴-2-吡啶基)氧基甲基]-3-吡啶基]丙烷-1-醇 基本上如製備29中所闡述使用3-[4-[(6-溴-2-吡啶基)氧基甲基]-3-吡啶基]丙氧基-第三丁基-二甲基-矽烷(製備140)來製備標題化合物。經由使用於DCM中之5 - 75% (1:4 MeOH : EtOAc)之梯度洗脫之矽膠層析來純化標題化合物。ES-MS m/z322及324 (M+H)。 Preparation 141 3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propane-1-ol Using 3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy-tert-butyl-dimethyl-silane essentially as described in Preparation 29 (Preparation 140) to prepare the title compound. The title compound was purified by silica gel chromatography eluting with a gradient of 5-75% (1:4 MeOH:EtOAc) in DCM. ES-MS m/z 322 and 324 (M+H).
製備 1422-[4-溴-2-[2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]乙氧基甲基]苯基]乙酸甲酯 在4℃下,向4-[(6-溴-2-吡啶基)氧基甲基]-3-(2-羥乙基)苯甲腈(1 g, 2.85 mmol)及4-溴-2-(溴甲基)苯基乙酸甲酯(1.65 g, 4.10 mmol)於DCM (15 mL)中之溶液中添加2,6-二-第三丁基吡啶(0.93 mL, 4.24 mmol)及三氟甲磺酸銀(1.10g, 4.24 mmol)。將混合物在低溫下攪拌1 h,然後在室溫下攪拌。在5 h之後,添加額外三氟甲磺酸銀(220 mg, 0.85 mmol)。在20 h之後,經由Celite ®過濾反應混合物,使用DCM沖洗。蒸發濾液並藉由矽膠層析使用10 - 100% DCM/環己烷之梯度來純化以得到白色固體形式之標題化合物(570 mg,75%純度,26%產率)。ES-MS m/z573/575/577 (M+H)。 Preparation 142 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]phenyl ] Methyl acetate At 4°C, 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (1 g, 2.85 mmol) and 4-bromo-2 To a solution of methyl (bromomethyl)phenylacetate (1.65 g, 4.10 mmol) in DCM (15 mL) was added 2,6-di-tert-butylpyridine (0.93 mL, 4.24 mmol) and trifluoro Silver methanesulfonate (1.10 g, 4.24 mmol). The mixture was stirred at low temperature for 1 h, then at room temperature. After 5 h, additional silver triflate (220 mg, 0.85 mmol) was added. After 20 h, the reaction mixture was filtered through Celite® , rinsing with DCM. The filtrate was evaporated and purified by silica gel chromatography using a gradient of 10 - 100% DCM/cyclohexane to give the title compound (570 mg, 75% purity, 26% yield) as a white solid. ES-MS m/z 573/575/577 (M+H).
製備 1432-[2-[2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]乙氧基甲基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 在氮下,向2-[4-溴-2-[2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]乙氧基甲基]苯基]乙酸甲酯(630 mg, 0.83 mmol,75%純度)於無水1,4-二噁烷(8.2 mL)中之溶液中添加雙(頻哪醇)二硼(260 mg, 1 mmol)及KOAc (202 mg, 2.01 mmol)。在5 min之後,添加Pd(dppf)Cl 2DCM複合物(40 mg, 0.048 mmol)並在80℃下加熱反應混合物。在3 h之後,將反應混合物冷卻至室溫,然後添加水(10 mL)及EtOAc (10 mL)。分離各層並使用EtOAc (2 × 5 mL)萃取水相。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾並在減壓下濃縮以提供褐色油狀物形式之標題化合物(850 mg, 60%純度),其未經進一步純化即用於製備150。ES-MS m/z621/623 (M+H)。 Preparation 143 2-[2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester Under nitrogen, to 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]ethoxymethyl To a solution of methyl ]phenyl]acetate (630 mg, 0.83 mmol, 75% purity) in anhydrous 1,4-dioxane (8.2 mL) was added bis(pinacol)diboron (260 mg, 1 mmol ) and KOAc (202 mg, 2.01 mmol). After 5 min, Pd(dppf)Cl 2 DCM complex (40 mg, 0.048 mmol) was added and the reaction mixture was heated at 80°C. After 3 h, the reaction mixture was cooled to room temperature, then water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (2 x 5 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered and concentrated under reduced pressure to afford the title compound (850 mg, 60% purity) as a brown oil which was used without further purification 150 in preparation. ES-MS m/z 621/623 (M+H).
製備 1442-[4-溴-2-[2-[5-[(6-氯-2-吡啶基)氧基甲基]-2-氰基-苯基]乙氧基甲基]苯基]乙酸甲酯 基本上如製備142中所闡述使用4-[(6-氯-2-吡啶基)氧基甲基]-2-(2-羥乙基)苯甲腈來製備標題化合物,其中向反應混合物中添加活化3 Å分子篩。經由矽膠層析使用於環己烷中之50 - 100% DCM之梯度來純化標題化合物。ES-MS m/z529, 531, 533 (M+H)。 Preparation 144 2-[4-bromo-2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]phenyl ] Methyl acetate The title compound was prepared essentially as described in Preparation 142 using 4-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)benzonitrile by adding to the reaction mixture Add activated 3 Å molecular sieves. The title compound was purified by silica gel chromatography using a gradient of 50-100% DCM in cyclohexane. ES-MS m/z 529, 531, 533 (M+H).
製備 1452-[2-[2-[5-[(6-氯-2-吡啶基)氧基甲基]-2-氰基-苯基]乙氧基甲基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 基本上如製備143中所闡述使用2-[4-溴-2-[2-[5-[(6-氯-2-吡啶基)氧基甲基]-2-氰基-苯基]乙氧基甲基]苯基]乙酸甲酯來製備標題化合物。在完成反應後,冷卻至室溫,添加飽和NaHCO 3及EtOAc並經由Celite ®過濾混合物。分離水層並使用水及飽和NaCl水溶液洗滌有機層,藉由無水Na 2SO 4乾燥,過濾並去除溶劑。經由矽膠層析使用於DCM中之0 - 2% EtOAc之梯度來純化殘餘物以提供無色蠟狀固體形式之標題化合物。ES-MS m/z577及579 (M+H)。 Preparation 145 2-[2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester Using 2-[4-bromo-2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethyl essentially as described in Preparation 143 Oxymethyl]phenyl]acetic acid methyl ester to prepare the title compound. After completion of the reaction, cooled to room temperature, saturated NaHCO 3 and EtOAc were added and the mixture was filtered through Celite® . The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4 , filtered and the solvent was removed . The residue was purified by silica gel chromatography using a gradient of 0-2% EtOAc in DCM to afford the title compound as a colorless waxy solid. ES-MS m/z 577 and 579 (M+H).
製備 1462-[2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氟-苯基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 基本上如製備54中所闡述使用3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氟-苯基]丙烷-1-醇及2-[2-羥基-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯且使用DEAD於甲苯中之40%溶液來製備標題化合物。經由使用於己烷中之85 - 100% DCM之梯度洗脫之矽膠急速層析來純化標題化合物。ES-MS m/z628及630 (M+H)。 Preparation 146 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propoxy]-5-methyl-4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester Using 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propan-1-ol and 2-[2-hydroxyl] essentially as described in Preparation 54 -5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester and use DEAD in toluene 40 % solution to prepare the title compound. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 85-100% DCM in hexanes. ES-MS m/z 628 and 630 (M+H).
製備 1472-[2-[3-[3-[(6-溴-2-吡啶基)氧基甲基]-6-(三氟甲基)-2-吡啶基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 基本上如製備55中所闡述使用3-[3-[(6-溴-2-吡啶基)氧基甲基]-6-(三氟甲基)-2-吡啶基]丙烷-1-醇及2-[2-羥基-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯在1,4-二噁烷(作為溶劑)中來製備標題化合物。將反應混合物在室溫下攪拌15 h,然後使用MeOH終止反應並在減壓下濃縮。經由使用於己烷中之85 - 100% DCM之梯度洗脫之矽膠急速層析來純化標題化合物。ES-MS m/z678及680 (M+H)。 Preparation 147 2-[2-[3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propoxyl]-5 -Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester Using 3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propan-1-ol essentially as described in Preparation 55 and methyl 2-[2-hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetate in 1,4-Dioxane (as solvent) to prepare the title compound. The reaction mixture was stirred at room temperature for 15 h, then quenched with MeOH and concentrated under reduced pressure. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 85-100% DCM in hexanes. ES-MS m/z 678 and 680 (M+H).
製備 1482-[2-[3-[4-[(6-溴-2-吡啶基)氧基甲基]-3-吡啶基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 基本上如製備55中所闡述使用3-[4-[(6-溴-2-吡啶基)氧基甲基]-3-吡啶基]丙烷-1-醇及2-[2-羥基-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯在1,4-二噁烷(作為溶劑)中來製備標題化合物,其中將反應液在室溫下攪拌15 h。使用MeOH終止反應並在減壓下濃縮。經由矽膠層析使用於己烷中之85 - 100 % DCM之梯度來純化殘餘物以得到標題化合物。ES-MS m/z611及613 (M+H)。 Preparation 148 2-[2-[3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy]-5-methyl-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester Using 3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propan-1-ol and 2-[2-hydroxy-5 -Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester in 1,4-dioxane (as solvent) to prepare the title compound, wherein the reaction was stirred at room temperature for 15 h. The reaction was quenched with MeOH and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 85-100% DCM in hexanes to give the title compound. ES-MS m/z 611 and 613 (M+H).
製備 1492-(5 4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯 將雙(頻哪醇)二硼(3.93 g, 15.2 mmol)及KOAc (3.04 g, 30.4 mmol)添加至2-(5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯(4.33 g, 10.1 mmol)於1,4-二噁烷(0.2 L)中之漿液中。使用氮將混合物吹掃5 min且然後添加[氯(2-二環己基膦基-2',4',6'-三-異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)] (0.25 g, 0.31 mmol)。將混合物在85℃及正氮壓下攪拌2.5 h,然後冷卻並在減壓下濃縮以去除大部分揮發物。將殘餘物分配於DCM (0.15 L)與水(0.15 L)之間,分離各相並使用額外DCM (50 mL)萃取水相。使用2 M K 2CO 3水溶液(50 mL)洗滌合併之有機相,然後使用鹽水(50 mL)洗滌,然後藉由MgSO 4乾燥並過濾。將濾液濃縮至30 mL體積,添加MeOH (0.2 L)且然後濃縮至60 mL體積。將混合物在環境溫度下攪拌3 h,藉由過濾收集固體並使用MeOH (30 mL)洗滌。將濾餅在減壓及50℃下乾燥13 h以提供4.95 g灰色固體形式之標題化合物(94%)。ES-MS m/z515及516 (M+H)。 Preparation 149 2-(5 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,9-dioxa-2(2,6 )-Pyridine-1(1,3),5(1,2)-diphenylcyclononafin-1 4 -yl)methyl acetate Bis(pinacol)diboron (3.93 g, 15.2 mmol) and KOAc (3.04 g, 30.4 mmol) were added to 2-(5 4 -chloro-3,9-dioxa-2(2,6)- Pyridine-1(1,3),5(1,2)-diphenylcyclononan- 14 -yl)methyl acetate (4.33 g, 10.1 mmol) in 1,4-dioxane (0.2 L) in the slurry. The mixture was purged with nitrogen for 5 min and then [chloro(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amine yl-1,1'-biphenyl-2-yl)palladium(II)] (0.25 g, 0.31 mmol). The mixture was stirred at 85 °C under positive nitrogen pressure for 2.5 h, then cooled and concentrated under reduced pressure to remove most of the volatiles. The residue was partitioned between DCM (0.15 L) and water (0.15 L), the phases were separated and the aqueous phase was extracted with additional DCM (50 mL). The combined organic phases were washed with 2 M aqueous K2CO3 (50 mL), then brine (50 mL), then dried over MgSO4 and filtered. The filtrate was concentrated to a volume of 30 mL, MeOH (0.2 L) was added and then concentrated to a volume of 60 mL. The mixture was stirred at ambient temperature for 3 h, the solid was collected by filtration and washed with MeOH (30 mL). The filter cake was dried under reduced pressure at 50 °C for 13 h to afford 4.95 g of the title compound (94%) as a gray solid. ES-MS m/z 515 and 516 (M+H).
製備 1502-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯 基本上如製備68中所闡述使用2-[2-[2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]乙氧基甲基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯(製備143)來製備標題化合物。ES-MS m/z415 (M+H)。 Preparation of 150 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-1 4 -yl) methyl acetate Using 2-[2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]ethoxymethyl essentially as described in Preparation 68 ]-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester (Preparation 143) to prepare the title compound. ES-MS m/z 415 (M+H).
製備 1512-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸乙酯 在氮氣氛下向圓底燒瓶中添加4-[(6-溴-2-吡啶基)氧基甲基]-3-(2-羥乙基)苯甲腈(400 mg, 1.20 mmol)、三苯基膦(473 mg 1.80 mmol)及2-[5-氟-2-羥基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯(563 mg, 1.44 mmol)於無水THF (10 mL)中之溶液。攪拌混合物直至固體溶解並在冰浴中冷卻。向混合物中添加偶氮二甲酸二-第三丁基酯(423 mg, 1.80 mmol)於THF (1.6 mL)中之溶液。去除冰浴並將反應液在室溫下保持2 h。向反應液中添加THF (26 mL)及磷酸鉀水溶液(1 M, 7.2 mL)並將混合物攪拌5 min。將Pd(dtbpf)Cl 2(80 mg, 0.12 mmol)添加至反應液中,使用氮吹掃若干次,且將反應液加熱至80℃並保持3 h。將反應液冷卻至室溫,使用EtOAc稀釋並添加Celite ®。 將混合物攪拌10 min,經由Celite ®墊過濾混合物,並使用EtOAc洗滌Celite ®墊。藉由MgSO 4乾燥濾液,過濾,並在減壓下濃縮濾液。經由矽膠層析使用於環己烷中之0 - 100% EtOAc之梯度來純化殘餘物以得到白色固體形式之標題產物(150 mg, 28.9%)。ES-MS m/z433 (M+H)。 Preparation of 151 2-(5 4 -cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Octan-1 4 -yl) ethyl acetate Add 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (400 mg, 1.20 mmol), tris Phenylphosphine (473 mg 1.80 mmol) and 2-[5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl ) A solution of phenyl]ethyl acetate (563 mg, 1.44 mmol) in anhydrous THF (10 mL). The mixture was stirred until the solids dissolved and cooled in an ice bath. To the mixture was added a solution of di-tert-butyl azodicarboxylate (423 mg, 1.80 mmol) in THF (1.6 mL). The ice bath was removed and the reaction solution was kept at room temperature for 2 h. THF (26 mL) and potassium phosphate aqueous solution (1 M, 7.2 mL) were added to the reaction solution and the mixture was stirred for 5 min. Pd(dtbpf)Cl 2 (80 mg, 0.12 mmol) was added to the reaction solution, purged several times with nitrogen, and the reaction solution was heated to 80° C. for 3 h. The reaction was cooled to room temperature, diluted with EtOAc and Celite® was added. The mixture was stirred for 10 min, the mixture was filtered through a pad of Celite® , and the pad of Celite® was washed with EtOAc. The filtrate was dried over MgSO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in cyclohexane to give the title product (150 mg, 28.9%) as a white solid. ES-MS m/z 433 (M+H).
製備 1522-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸甲酯 使用氮將2-[2-[2-[5-[(6-氯-2-吡啶基)氧基甲基]-2-氰基-苯基]乙氧基甲基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯(132 mg, 0.20 mmol,88質量%)、THF (5 mL)及磷酸三鉀水溶液(1.0 M, 1 mL, 1.0 mmol)之混合物鼓泡5 min。添加XPhos Pd(巴豆基)Cl (Pd-170觸媒,CAS編號:1798782-02-1, 6 mg, 0.009 mmol)並將混合物在50℃下攪拌50min。將反應混合物冷卻至室溫並添加水及EtOAc。分離水層並使用水及飽和NaCl水溶液洗滌有機層,藉由無水Na 2SO 4乾燥,過濾並濃縮。經由矽膠層析使用DCM來純化殘餘物以提供白色固體形式之標題化合物(51 mg, 61%)。ES-MS m/z415 (M+H)。 Preparation of 152 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononan-1 4 -yl)acetic acid methyl ester 2-[2-[2-[5-[(6-Chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester (132 mg, 0.20 mmol, 88% by mass), THF (5 mL) and A mixture of aqueous tripotassium phosphate (1.0 M, 1 mL, 1.0 mmol) was bubbled for 5 min. XPhos Pd(crotyl)Cl (Pd-170 catalyst, CAS number: 1798782-02-1, 6 mg, 0.009 mmol) was added and the mixture was stirred at 50°C for 50 min. The reaction mixture was cooled to room temperature and water and EtOAc were added. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4 , filtered and concentrated. The residue was purified by silica gel chromatography using DCM to afford the title compound (51 mg, 61%) as a white solid. ES-MS m/z 415 (M+H).
製備 1532-(5 4-氟-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯 基本上如製備66中所闡述使用2-[2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氟-苯基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯來製備標題化合物,其中將反應混合物在氮氣氛及40℃下攪拌1 h。經由使用於DCM中之0 - 20% EtOAc之梯度洗脫之矽膠急速層析來純化標題化合物。ES-MS m/z422 (M+H)。 Preparation of 153 2-(5 4 -fluoro-1 6 -methyl-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl acetate Using 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propoxy]-5 essentially as described in Preparation 66 -Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester to prepare the title compound, wherein the reaction mixture was Stir under nitrogen atmosphere at 40 °C for 1 h. The title compound was purified by flash chromatography on silica gel eluting with a gradient of 0-20% EtOAc in DCM. ES-MS m/z 422 (M+H).
製備 1542-(1 6-甲基-5 6-(三氟甲基)-3,9-二氧雜-2(2,6),5(3,2)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸甲酯 基本上如製備66中所闡述使用2-[2-[3-[3-[(6-溴-2-吡啶基)氧基甲基]-6-(三氟甲基)-2-吡啶基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯來製備標題化合物,其中將反應液在40℃下攪拌1 h。經由矽膠層析使用於DCM中之0 - 20% EtOAc之梯度來純化標題化合物。ES-MS m/z473 (M+H)。 Preparation of 154 2-(1 6 -methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-bipyridine-1(1, 3)-Phenycyclononafin-1 4 -yl)methyl acetate Using 2-[2-[3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl) essentially as described in Preparation 66 ]propoxy]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester to prepare the title Compound, where the reaction solution was stirred at 40°C for 1 h. The title compound was purified by silica gel chromatography using a gradient of 0-20% EtOAc in DCM. ES-MS m/z 473 (M+H).
製備 1552-(1 6-甲基-3,9-二氧雜-2(2,6),5(4,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸甲酯 基本上如製備66中所闡述使用2-[2-[3-[4-[(6-溴-2-吡啶基)氧基甲基]-3-吡啶基]丙氧基]-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯來製備標題化合物,其中將反應液在40℃下攪拌1 h。經由矽膠層析使用於DCM中之5 - 35% EtOAc之梯度來純化標題化合物。ES-MS m/z405 (M+H)。 Preparation of 155 2-(1 6 -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridine-1(1,3)-phenylcyclonona- 1 4 -yl) methyl acetate Using 2-[2-[3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy]-5-methanol essentially as described in Preparation 66 base-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester to prepare the title compound, wherein the reaction solution was heated at 40°C Stir for 1 h. The title compound was purified by silica gel chromatography using a gradient of 5-35% EtOAc in DCM. ES-MS m/z 405 (M+H).
製備 1562-(5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 將MeOH (20 mL)及水(5 mL)添加至2-(5 4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯(4.45 g, 8.55 mmol)及溴化銅(5.73 g, 25.7 mmol)之混合物中。將混合物在80℃下攪拌30 h。將混合物冷卻至環境溫度,添加30% NH 4OH水溶液並使用水稀釋至最終體積為大約0.5 L。將混合物攪拌0.5 h,藉由過濾收集固體並使用10% NH 4OH水溶液(0.1 L)洗滌,然後使用水(0.1 L)洗滌。將THF (0.14 L)、MeOH (70 mL)及1 M LiOH水溶液(35 mL)添加至潮濕固體中並在60℃下攪拌3.5 h。將1 M KH 2PO 4水溶液(0.1 L)添加至混合物中且然後使用水稀釋至最終體積為大約1 L。使混合物在攪拌下自然冷卻1 h,藉由過濾收集固體並使用1:4水:MeOH (0.2 L)及水(0.1 L)洗滌。將濾餅在減壓及50℃下乾燥16 h以提供3.66 g灰白色固體形式之標題化合物(92%)。ES-MS m/z454及456 (M+H)。 Preparation of 156 2-(5 4 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-1 4 - base) acetic acid Add MeOH (20 mL) and water (5 mL) to 2-(5 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3 , 9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl acetate (4.45 g, 8.55 mmol ) and copper bromide (5.73 g, 25.7 mmol). The mixture was stirred at 80 °C for 30 h. The mixture was cooled to ambient temperature, 30% aqueous NH 4 OH was added and diluted with water to a final volume of approximately 0.5 L. The mixture was stirred for 0.5 h, the solid was collected by filtration and washed with 10% aqueous NH 4 OH (0.1 L) followed by water (0.1 L). THF (0.14 L), MeOH (70 mL) and 1 M aqueous LiOH (35 mL) were added to the wet solid and stirred at 60 °C for 3.5 h. Aqueous 1 M KH 2 PO 4 (0.1 L) was added to the mixture and then diluted with water to a final volume of approximately 1 L. The mixture was allowed to cool naturally with stirring for 1 h, the solid was collected by filtration and washed with 1:4 water:MeOH (0.2 L) and water (0.1 L). The filter cake was dried under reduced pressure at 50 °C for 16 h to afford 3.66 g of the title compound (92%) as an off-white solid. ES-MS m/z 454 and 456 (M+H).
製備 1572-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 基本上如製備78中所闡述使用2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物。ES-MS m/z401 (M+H)。 Preparation 157 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 -yl)acetic acid Using 2-( 54 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 78 phenylcyclononan-1 4 -yl)acetic acid methyl ester to prepare the title compound. ES-MS m/z 401 (M+H).
製備 1582-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸 基本上如製備78中所闡述使用2-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸乙酯來製備標題化合物。ES-MS m/z418 (M+H)。 Preparation of 158 2-(5 4 -cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Cinfan-1 4 -yl)acetic acid Using 2-(5 4 -cyano- 1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclooctafan-1 4 -yl) ethyl acetate to prepare the title compound. ES-MS m/z 418 (M+H).
製備 1592-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸 基本上如製備78中所闡述使用2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物。ES-MS m/z401 (M+H)。 Preparation of 159 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononarene-1 4 -yl)acetic acid Using 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononane- 1 4 -yl)methyl acetate to prepare the title compound. ES-MS m/z 401 (M+H).
製備 1602-(1 6-甲基-5 4-(氟)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 基本上如製備75中所闡述使用2-(1 6-甲基-5 4-(氟)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物,其中將反應液在50℃下攪拌1 h。標題化合物未經純化即用於製備168。ES-MS m/z408 (M+H)。 Preparation of 160 2-(1 6 -methyl-5 4 -(fluoro)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di phenylcyclononafin-1 4 -yl)acetic acid Using 2-( 16 -methyl- 54- (fluoro)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononan- 1 4 -yl)acetic acid methyl ester to prepare the title compound, wherein the reaction solution was stirred at 50°C for 1 h. The title compound was used in Preparation 168 without purification. ES-MS m/z 408 (M+H).
製備 161甲基2-(1 6-甲基-5 6-(三氟甲基)-3,9-二氧雜-2(2,6),5(3,2)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸 基本上如製備75中所闡述使用2-(1 6-甲基-5 6-(三氟甲基)-3,9-二氧雜-2(2,6),5(3,2)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物,其中將反應液在50℃下攪拌1 h。標題化合物未經進一步純化即用於製備171。ES-MS m/z459 (M+H)。 Preparation of 161 methyl 2-(1 6 -methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-bipyridine-1( 1,3)-Phenycyclononafin-1 4 -yl)acetic acid Using 2-( 16 -methyl- 56- (trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-, essentially as described in Preparation 75, Dipyridine-1(1,3)-phencyclononan- 1 4 -yl)acetic acid methyl ester to prepare the title compound, wherein the reaction solution was stirred at 50°C for 1 h. The title compound was used in Preparation 171 without further purification. ES-MS m/z 459 (M+H).
製備 1622-(1 6-甲基-3,9-二氧雜-2(2,6),5(4,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸 基本上如製備75中所闡述使用2-(1 6-甲基-3,9-二氧雜-2(2,6),5(4,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物,其中將反應液在50℃下攪拌1 h。標題化合物未經進一步純化即用於製備172。ES-MS m/z391 (M+H)。 Preparation 162 2-(1 6 -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridine-1(1,3)-phenylcyclonona-1 4 -yl)acetic acid Using 2-(1 6 -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridine-1(1,3)-essentially as described in Preparation 75 The title compound was prepared from methyl phenylcyclononan-1 4 -yl)acetate, wherein the reaction was stirred at 50°C for 1 h. The title compound was used in Preparation 172 without further purification. ES-MS m/z 391 (M+H).
製備 163( S)-4-(2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸及4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯來製備標題化合物,其中將反應液攪拌16 h。標題化合物未經純化即用於下一步驟(製備173)中。ES-MS m/z653 (M+H)。 Preparation of 163 ( S )-4-(2-(5 4 -cyano- 1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclooctane-1 4 -yl)acetamido)-3-methoxy-5-(((epoxypropylene-2-ylmethyl)amino)benzoic acid methyl ester Using 2-( 54 -cyano- 16 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-diphenylcyclooctane-1 4 -yl)acetic acid and 4-amino-3-methoxy-5-[[(2S)-epoxypropane-2-yl]methylamino]benzene Methyl formate was used to prepare the title compound, where the reaction was stirred for 16 h. The title compound was used in the next step (Preparation 173) without purification. ES-MS m/z 653 (M+H).
製備 164( S)-4-(2-(5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 將DMF (33 mL)及吡啶(6 mL)添加至2-(5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(3.10 g, 6.69 mmol)及4-胺基-3-[[(2 S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得;1.75 g, 7.41 mmol)之混合物中並攪拌30 min。添加2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷-2,4,6-三氧化物(1.68 mol/L於EtOAc中,10 mL, 16.8 mmol)並將混合物攪拌50 min。使用水將反應混合物稀釋至最終體積為0.2 L並攪拌20 min。藉由過濾收集固體並使用水(0.1 L)洗滌。將濾餅在減壓及50℃下乾燥24 h以得到4.64 g淺粉紅色固體形式之標題化合物(99%)。ES-MS m/z672及674 (M+H)。 Preparation of 164 ( S )-4-(2-(5 4 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl Methyl cyclononafin-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate DMF (33 mL) and pyridine (6 mL) were added to 2-(5 4 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1, 2)-Diphenylcyclononarfin-1 4 -yl)acetic acid (3.10 g, 6.69 mmol) and 4-amino-3-[[( 2S )-epoxypropan-2-yl]methylamino] Methyl benzoate (prepared essentially as described in WO 2020/263695; 1.75 g, 7.41 mmol) in a mixture and stirred for 30 min. Add 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.68 mol/L in EtOAc , 10 mL, 16.8 mmol) and the mixture was stirred for 50 min. The reaction mixture was diluted with water to a final volume of 0.2 L and stirred for 20 min. The solid was collected by filtration and washed with water (0.1 L). The filter cake was dried under reduced pressure at 50 °C for 24 h to afford 4.64 g of the title compound (99%) as a pale pink solid. ES-MS m/z 672 and 674 (M+H).
製備 165(S)-4-(2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得)來製備標題化合物。標題化合物未經純化即用於下一步驟(製備175)中。ES-MS m/z619 (M+H)。 Preparation of 165 (S)-4-(2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Methyl phenylcyclononafin-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate Using 2-( 54 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 86 Phenycyclononafin- 14 -yl)acetic acid and methyl 4-amino-3-[[(2S)-epoxypropan-2-yl]methylamino]benzoate (essentially as described in WO 2020/263695 prepared as described in ) to prepare the title compound. The title compound was used in the next step (Preparation 175) without purification. ES-MS m/z 619 (M+H).
製備 166(S)-4-(2-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得)來製備標題化合物。標題化合物以粗製形式用於製備176。ES-MS m/z623 (M+H)。 Preparation of 166 (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclooctane-1 4 -yl)acetamido)-3-(((epoxypropylene-2-ylmethyl)amino)benzoate methyl ester Using 2-(5 4 -cyano- 1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-diphenylcyclooctane-1 4 -yl)acetic acid and methyl 4-amino-3-[[(2S)-epoxypropan-2-yl]methylamino]benzoate (essentially The title compound was prepared as described in WO 2020/263695). The title compound was used in Preparation 176 in crude form. ES-MS m/z 623 (M+H).
製備 167(S)-4-(2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(基本上如WO 2020/263695中所闡述製得)來製備標題化合物。標題化合物以粗製形式用於製備177。ES-MS m/z619 (M+H)。 Preparation 167 (S)-4-(2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona- 1 4 -yl)acetamido)-3-((epoxypropylene-2-ylmethyl)amino)methyl benzoate Using 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononane- 1 4 -yl)acetic acid and methyl 4-amino-3-[[(2S)-epoxypropan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695 ) to prepare the title compound. The title compound was used in Preparation 177 in crude form. ES-MS m/z 619 (M+H).
製備 168(S)-3-甲氧基-4-(2-(1 6-甲基-5 4-(氟)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(1 6-甲基-5 4-(氟)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(製備160)及4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯來製備標題化合物。標題化合物未經純化即用於製備178。ES-MS m/z656 (M+H)。 Preparation of 168 (S)-3-methoxy-4-(2-( 16 -methyl- 54- (fluoro)-3,9-dioxa-2(2,6)-pyridine-1( 1,3),5(1,2)-Diphenylcyclononarfin-1 4 -yl)acetamido)-5-(((epoxypropylene-2-ylmethyl)amino)benzoic acid methyl ester Using 2-( 16 -methyl- 54- (fluoro)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononarfin-1 4 -yl)acetic acid (Preparation 160) and 4-amino-3-methoxy-5-[[(2S)-epoxypropan-2-yl] Methylamino]benzoate to prepare the title compound. The title compound was used in Preparation 178 without purification. ES-MS m/z 656 (M+H).
製備 1694-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((噁唑-2-基甲基)胺基)苯甲酸乙酯 基本上如製備85中所闡述使用2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及-4-胺基-3-甲氧基-5-(噁唑-2-基甲基胺基)苯甲酸乙酯(製備122)來製備標題化合物。標題化合物未經純化即用於製備179。ES-MS m/z674 (M+H)。 Preparation of 169 4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononane -1 4 -yl)acetamido)-3-methoxy-5-((oxazol-2-ylmethyl)amino)ethyl benzoate Using 2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 85 The title compound was prepared from phenylcyclononan- 14 -yl)acetic acid and ethyl-4-amino-3-methoxy-5-(oxazol-2-ylmethylamino)benzoate (Preparation 122) . The title compound was used in Preparation 179 without purification. ES-MS m/z 674 (M+H).
製備 170(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備85中所闡述使用2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(製備124)來製備標題化合物。標題化合物未經進一步純化即用於製備180。ES-MS m/z693 (M+H)。 Preparation 170 (S)-4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Methyl phenylcyclononafin-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-(((oxypropylene-2-ylmethyl)amino)benzoate Using 2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 85 Phenylcyclononyl-1 4 -yl)acetic acid and 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-epoxypropane-2-yl]methylamino ] methyl benzoate (Preparation 124) to prepare the title compound. The title compound was used in Preparation 180 without further purification. ES-MS m/z 693 (M+H).
製備 171(S)-3-甲氧基-4-(2-(1 6-甲基-5 6-(三氟甲基)-3,9-二氧雜-2(2,6),5(3,2)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用甲基2-(1 6-甲基-5 6-(三氟甲基)-3,9-二氧雜-2(2,6),5(3,2)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸(製備161)及4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯來製備標題化合物。標題化合物未經進一步純化即用於製備183。ES-MS m/z707 (M+H)。 Preparation 171 (S)-3-Methoxy-4-(2-(1 6 -methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5 (3,2)-dipyridin-1(1,3)-phencyclononafin-1 4 -yl)acetamido)-5-((epoxypropylene-2-ylmethyl)amino)benzene Methyl formate Using methyl 2-(1 6 -methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6), 5(3,2 )-bipyridine-1(1,3)-phencyclononarfin- 1 4 -yl)acetic acid (preparation 161) and 4-amino-3-methoxy-5-[[(2S)-propylene oxide -2-yl]methylamino]benzoic acid methyl ester to prepare the title compound. The title compound was used in Preparation 183 without further purification. ES-MS m/z 707 (M+H).
製備 172(S)-3-甲氧基-4-(2-(1 6-甲基-3,9-二氧雜-2(2,6),5(4,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(1 6-甲基-3,9-二氧雜-2(2,6),5(4,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸(製備162)及4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯來製備標題化合物。標題化合物未經進一步純化即用於下一步驟(製備184)中。ES-MS m/z639 (M+H)。 Preparation 172 (S)-3-Methoxy-4-(2-(1 6 -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridine-1 (1,3)-Phenencyclononafran-1 4 -yl)acetamido)-5-(((epoxypropan-2-ylmethyl)amino)benzoic acid methyl ester Using 2-( 16 -methyl-3,9-dioxa-2(2,6),5(4,3)-bipyridine-1(1,3)- Phenycyclononafin- 14 -yl)acetic acid (Preparation 162) and 4-amino-3-methoxy-5-[[(2S)-epoxypropan-2-yl]methylamino]benzoic acid methyl ester to prepare the title compound. The title compound was used in the next step (Preparation 184) without further purification. ES-MS m/z 639 (M+H).
製備 173(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(來自製備163)來製備標題化合物,其中將反應液在65℃下加熱9h。將混合物冷卻至室溫並在減壓下蒸發溶劑,添加ACN以幫助去除乙酸。經由矽膠層析使用於DCM中之0 - 40% EtOAc且然後於DCM中之10% MeOH之梯度來純化殘餘物以得到淺橙色固體形式之標題化合物。ES-MS m/z635 (M+H)。 Preparation 173 (S)-2-((5 4 -cyano-1 6 -fluoro-3,7-dioxa- 2 (2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclooctane-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ester Using (S)-4-(2-( 54 -cyano- 16 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1) essentially as described in Preparation 102 ,3),5(1,2)-diphenylcyclooctane- 1 4 -yl)acetamido)-3-methoxy-5-((epoxypropan-2-ylmethyl)amino ) methyl benzoate (from Preparation 163) to prepare the title compound by heating the reaction at 65 °C for 9 h. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure, ACN was added to help remove acetic acid. The residue was purified by silica gel chromatography using a gradient of 0-40% EtOAc in DCM and then 10% MeOH in DCM to give the title compound as a pale orange solid. ES-MS m/z 635 (M+H).
製備 174( S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用( S)-4-(2-(5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯且使用1:1 乙酸:2-氯甲苯作為溶劑來製備標題化合物。將反應液在60℃及正氮壓下攪拌32 h。在減壓下濃縮反應混合物。將殘餘物溶於DCM中,濃縮於矽藻土上並藉由矽膠層析使用於DCM中之0-50% EtOAc之梯度純化以得到白色固體形式之標題化合物。ES-MS m/z654及656 (M+H)。 Preparation of 174 ( S )-2-((5 4 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononium Fan- 14 -yl)methyl)-1-(epoxypropan-2-ylmethyl) -1H -benzo[ d ]imidazole-6-carboxylic acid methyl ester Using ( S )-4-(2-( 54 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononafran- 14 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate methyl ester and using 1:1 acetic acid: 2-Chlorotoluene was used as solvent to prepare the title compound. The reaction solution was stirred at 60 °C for 32 h under positive nitrogen pressure. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM, concentrated on Celite and purified by silica gel chromatography using a gradient of 0-50% EtOAc in DCM to give the title compound as a white solid. ES-MS m/z 654 and 656 (M+H).
製備 175(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯在1:1 1,2-二氯乙烷:乙酸(作為溶劑)中來製備標題化合物,其中將反應液在50℃下加熱5 h。將反應混合物冷卻至室溫,在減壓下濃縮溶劑,並經由矽膠層析使用於DCM中之10 - 50% EtOAc之梯度來純化殘餘物以得到白色固體形式之標題化合物。ES-MS m/z601 (M+H)。 Preparation of 175 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononan-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)benzoate methyl ester at 1:1 1, 2-dichloroethane: acetic acid (as solvent) to prepare the title compound, wherein the reaction solution was heated at 50 °C for 5 h. The reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 10-50% EtOAc in DCM to give the title compound as a white solid. ES-MS m/z 601 (M+H).
製備 176(S)-2-((5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯在1:1 1,2-二氯乙烷:乙酸(作為溶劑)中來製備標題化合物,其中加熱至52℃並保持4 h。將反應液冷卻至室溫並在減壓下去除溶劑。經由矽膠層析使用於DCM中之0 - 100% EtOAc之梯度來純化殘餘物以得到黃色固體形式之標題化合物。ES-MS m/z605 (M+H)。 Preparation 176 (S)-2-((5 4 -cyano-1 6 -fluoro-3,8-dioxa- 2 (2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclooctane-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano- 16 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1) essentially as described in Preparation 102 ,3),methyl 5(1,2)-diphenylcyclooctafan-1 4 -yl)acetamido)-3-(((epoxypropylene-2-ylmethyl)amino)benzoate in 1:1 1,2-dichloroethane:acetic acid (as solvent) to prepare the title compound, which was heated to 52 °C for 4 h. The reaction solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in DCM to afford the title compound as a yellow solid. ES-MS m/z 605 (M+H).
製備 177(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯在1:1 1,2-二氯乙烷:乙酸(作為溶劑)中來製備標題化合物,其中將反應液在60℃下加熱5 h。將反應混合物冷卻至室溫,在減壓下濃縮溶劑,並經由矽膠層析使用於DCM中之25 - 50% EtOAc之梯度來純化殘餘物以得到白色固體形式之標題化合物。ES-MS m/z601 (M+H)。 Preparation 177 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3) essentially as described in Preparation 102 -Diphenylcyclononafin-1 4 -yl)acetamido)-3-(((epoxypropan-2-ylmethyl)amino)methyl benzoate in 1:1 1,2-dichloroethyl Alkanes: acetic acid (as solvent) to prepare the title compound, where the reaction was heated at 60 °C for 5 h. The reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 25-50% EtOAc in DCM to give the title compound as a white solid. ES-MS m/z 601 (M+H).
製備 178(S)-4-甲氧基-2-((1 6-甲基-5 4-(氟)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-3-甲氧基-4-(2-(1 6-甲基-5 4-(氟)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯在1:1 二氯乙烷:乙酸中來製備標題化合物。經由矽膠層析使用於己烷中之80 - 100% DCM之梯度來純化標題化合物。ES-MS m/z638 (M+H)。 Preparation 178 (S)-4-methoxy-2-(( 16 -methyl- 54- (fluoro)-3,9-dioxa-2(2,6)-pyridine-1(1, 3), 5(1,2)-diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- Methyl formate Using (S)-3-methoxy-4-(2-( 16 -methyl- 54- (fluoro)-3,9-dioxa-2(2, 6)-Pyridine-1(1,3), 5(1,2)-diphenylcyclononafran-1 4 -yl)acetamido)-5-((epoxypropylene-2-ylmethyl) Amino)methylbenzoate in 1:1 dichloroethane:acetic acid to prepare the title compound. The title compound was purified by silica gel chromatography using a gradient of 80-100% DCM in hexanes. ES-MS m/z 638 (M+H).
製備 1792-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(噁唑-2-基甲基)-1H-苯并[d]咪唑-6-甲酸乙酯 基本上如製備101中所闡述使用4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((噁唑-2-基甲基)胺基)苯甲酸乙酯在乙酸中來製備標題化合物。濃縮反應混合物並在庚烷中沈澱標題化合物,其未經進一步純化即用於實例23。ES-MS m/z656 (M+H)。 Preparation 179 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-1 4 -yl)methyl)-4-methoxy-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester Using 4-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononafin-1 4 -yl)acetamido)-3-methoxy-5-((oxazol-2-ylmethyl)amino)ethyl benzoate was prepared in acetic acid title compound. The reaction mixture was concentrated and the title compound was precipitated in heptane, which was used in Example 23 without further purification. ES-MS m/z 656 (M+H).
製備 180(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備101中所闡述使用(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯在乙酸中來製備標題化合物。經由矽膠層析使用於庚烷中之0 - 80% EtOAc之梯度來純化標題化合物。ES-MS m/z675 (M+H)。 Preparation of 180 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- Methyl formate Using (S)-4-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononafran-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-(((epoxypropane-2-ylmethyl) Amino)methyl benzoate in acetic acid to prepare the title compound. The title compound was purified by silica gel chromatography using a gradient of 0-80% EtOAc in heptane. ES-MS m/z 675 (M+H).
製備 181( S)-2-((5 4-甲醯基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸甲酯 向舒倫克管(Schlenk tube)中裝填雙(乙腈)二氯鈀(II) (11 mg, 0.042 mmol)及丁基二-1-金剛烷基膦(48 mg, 0.13 mmol)。使用氮吹掃管(3 ×真空/氮循環),並添加4-甲基嗎啉(3 mL, 27.24 mmol)。在攪拌下使用氮再次吹掃管(5 ×真空/氮循環)。封閉管並在環境溫度下攪拌1h。向玻璃壓力容器中裝填( S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸甲酯(290 mg, 0.42 mmol)及4-甲基嗎啉(9 mL, 81.73 mmol,100質量%)。蓋上隔片並在攪拌下使用氮將混合物鼓泡。在30 min之後,將觸媒懸浮液轉移至壓力容器中並使用合成氣將其吹掃三次直至80 psi,然後使用合成氣再填充至80 psi。攪拌混合物並在105℃下加熱過夜。將反應混合物冷卻至室溫並去除溶劑。將殘餘物分配於DCM (20 mL)與2 M K 2CO 3水溶液(20 mL)之間。分離有機層並使用DCM (10 mL)萃取水層。合併有機層,使用飽和NaCl水溶液(10 mL)洗滌,過濾並濃縮以提供320 mg橙色殘餘物。經由矽膠層析使用於DCM中之0 - 50% EtOAc之梯度來純化殘餘物以得到白色固體形式之標題化合物(250 mg, 89%)。ES-MS m/z604 (M+H)。 Preparation of 181 ( S )-2-((5 4 -formyl-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl Cyclononafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl ester A Schlenk tube was charged with bis(acetonitrile)dichloropalladium(II) (11 mg, 0.042 mmol) and butyldi-1-adamantylphosphine (48 mg, 0.13 mmol). The tube was purged with nitrogen (3 x vacuum/nitrogen cycle) and 4-methylmorpholine (3 mL, 27.24 mmol) was added. The tube was purged again with nitrogen (5 x vacuum/nitrogen cycle) with stirring. The tube was closed and stirred at ambient temperature for 1 h. Fill the glass pressure vessel with ( S )-2-((5 4 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)- Diphenylcyclononan- 14 -yl)methyl)-1-(epoxypropan-2-ylmethyl) -1H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (290 mg, 0.42 mmol ) and 4-methylmorpholine (9 mL, 81.73 mmol, 100% by mass). The septum was capped and the mixture was bubbled under stirring using nitrogen. After 30 min, the catalyst suspension was transferred to a pressure vessel and it was purged three times with syngas up to 80 psi, then refilled with syngas to 80 psi. The mixture was stirred and heated at 105°C overnight. The reaction mixture was cooled to room temperature and the solvent was removed. The residue was partitioned between DCM (20 mL) and 2 M aqueous K2CO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), filtered and concentrated to afford 320 mg of an orange residue. The residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in DCM to afford the title compound (250 mg, 89%) as a white solid. ES-MS m/z 604 (M+H).
製備 182( S)-2-((5 4-甲醯基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸 將1 M LiOH水溶液(1.25 mL, 1.25 mmol)添加至( S)-2-((5 4-甲醯基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸甲酯(0.25 g, 0.37 mmol,90質量%)於THF (5 mL)及MeOH (2.5 mL)中之經攪拌懸浮液中。密封反應容器並在60℃下攪拌2 h。使用1 M K 2HPO 4水溶液(5 mL)終止反應,使用水稀釋至60 mL體積並將混合物在環境溫度下攪拌過夜。藉由添加5%檸檬酸水溶液來將反應液pH調節至4,使用飽和NaCl水溶液(50 mL)稀釋,並使用DCM (50 mL)萃取,然後使用1:4異丙醇: DCM (50 mL, 25 mL, 25 mL)萃取三次。合併有機萃取物並在減壓及50℃下濃縮。將殘餘物溶於1:1 DCM : MeOH中,濃縮於矽藻土上且然後藉由矽膠層析使用於DCM中之0 - 20% MeOH之梯度進行純化。在減壓及50℃下濃縮適當級分以提供白色殘餘物,然後將殘餘物在EtOAc (5 mL)中攪拌0.5 h。藉由過濾收集固體並使用EtOAc (5 mL)洗滌。將固體在45℃及減壓下乾燥21 h以提供白色固體形式之標題化合物(125 mg, 51%)。ES-MS m/z590 (M+H)。 Preparation of 182 ( S )-2-((5 4 -formyl-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl Cyclononafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid 1 M aqueous LiOH (1.25 mL, 1.25 mmol) was added to ( S )-2-(( 54 -formyl-3,9-dioxa-2(2,6)-pyridine-1(1, 3), 5(1,2)-diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1 H -benzo[ d ]imidazole-6 - a stirred suspension of methyl formate (0.25 g, 0.37 mmol, 90 mass%) in THF (5 mL) and MeOH (2.5 mL). The reaction vessel was sealed and stirred at 60 °C for 2 h. The reaction was quenched with 1 M aqueous K2HPO4 (5 mL), diluted to a volume of 60 mL with water and the mixture was stirred at ambient temperature overnight. The pH of the reaction was adjusted to 4 by adding 5% aqueous citric acid, diluted with saturated aqueous NaCl (50 mL), and extracted with DCM (50 mL), followed by 1:4 isopropanol:DCM (50 mL, 25 mL, 25 mL) and extracted three times. The organic extracts were combined and concentrated under reduced pressure at 50 °C. The residue was dissolved in 1:1 DCM:MeOH, concentrated on Celite and then purified by silica gel chromatography using a gradient of 0-20% MeOH in DCM. The appropriate fractions were concentrated under reduced pressure at 50 °C to afford a white residue, which was then stirred in EtOAc (5 mL) for 0.5 h. The solid was collected by filtration and washed with EtOAc (5 mL). The solid was dried at 45 °C under reduced pressure for 21 h to afford the title compound (125 mg, 51%) as a white solid. ES-MS m/z 590 (M+H).
製備 183(S)-4-甲氧基-2-((1 6-甲基-5 6-(三氟甲基)-3,9-二氧雜-2(2,6),5(3,2)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-3-甲氧基-4-(2-(1 6-甲基-5 6-(三氟甲基)-3,9-二氧雜-2(2,6),5(3,2)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯在1:1 DCM :乙酸(作為溶劑)中來製備標題化合物。經由矽膠層析使用於己烷中之80 - 100% DCM之梯度來純化標題化合物。ES-MS m/z689 (M+H)。 Preparation 183 (S)-4-Methoxy-2-((1 6 -methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3 ,2)-dipyridine-1(1,3)-phencyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H-benzo[d]imidazole -6-methyl carboxylate Using (S)-3-methoxy-4-(2-( 16 -methyl- 56- (trifluoromethyl)-3,9-dioxa-2) essentially as described in Preparation 102 (2,6),5(3,2)-bipyridine-1(1,3)-phencyclononan-1 4 -yl)acetamido)-5-((epoxypropane-2-yl Methyl)amino)benzoate in 1:1 DCM:acetic acid (as solvent) to prepare the title compound. The title compound was purified by silica gel chromatography using a gradient of 80-100% DCM in hexanes. ES-MS m/z 689 (M+H).
製備 184(S)-4-甲氧基-2-((1 6-甲基-3,9-二氧雜-2(2,6),5(4,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-3-甲氧基-4-(2-(1 6-甲基-3,9-二氧雜-2(2,6),5(4,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備172)在1:1二氯乙烷:乙酸(作為溶劑)中來製備標題化合物。經由矽膠層析使用於DCM中之80 - 100% EtOAc之梯度來純化標題化合物。ES-MS m/z621 (M+H)。 Preparation of 184 (S)-4-methoxy-2-((1 6 -methyl-3,9-dioxa-2(2,6),5(4,3)-bipyridine-1(1 ,3)-Phenencyclononafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-3-methoxy-4-(2-( 16 -methyl-3,9-dioxa-2(2,6),5(4, 3)-Dipyridin-1(1,3)-phencyclononafin-1 4 -yl)acetamido)-5-(((epoxypropylene-2-ylmethyl)amino)benzoic acid methyl ester (Preparation 172) The title compound was prepared in 1:1 dichloroethane:acetic acid as solvent. The title compound was purified by silica gel chromatography using a gradient of 80-100% EtOAc in DCM. ES-MS m/z 621 (M+H).
製備 1855-(3-氟-4-硝基-苯基)-1H-四唑 向3-氟-4-硝基-苯甲腈(470 mg, 2.8 mmol)及TMSCN (4.5 mL, 33 mmol)於甲苯(9 mL)中之溶液中添加三丁基疊氮化錫(2 mL, 7 mmol),然後在微波反應器中於150℃下加熱2 h。使用飽和 NaHCO 3水溶液終止反應並使用EtOAc萃取。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮。經由矽膠層析使用DCM/MeOH/甲酸(9:1:0.1)之混合物來純化殘餘物以得到586 mg標題化合物(99%)。ES-MS m/z210 (M+H)。 Preparation of 185 5-(3-fluoro-4-nitro-phenyl)-1H-tetrazole To a solution of 3-fluoro-4-nitro-benzonitrile (470 mg, 2.8 mmol) and TMSCN (4.5 mL, 33 mmol) in toluene (9 mL) was added tributyltin azide (2 mL , 7 mmol), and then heated at 150 °C for 2 h in a microwave reactor. The reaction was quenched with saturated aqueous NaHCO 3 and extracted with EtOAc. The organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of DCM/MeOH/formic acid (9:1:0.1) to afford 586 mg of the title compound (99%). ES-MS m/z 210 (M+H).
製備 1862-[[5-(3-氟-4-硝基-苯基)四唑-1-基]甲氧基]乙基-三甲基-矽烷 在0℃下,向5-(3-氟-4-硝基-苯基)-1H-四唑(860 mg, 4.1 mmol)於THF (12 mL)中之溶液中添加氫化鈉(60%,於礦物油中,180 mg, 4.5 mmol)。將2-(氯甲氧基)乙基-三甲基-矽烷(0.79 mL, 4.5 mmol)添加至混合物中並在室溫下攪拌16 h。使用水終止反應並使用EtOAc萃取。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮。經由使用庚烷: EtOAc (8:2)洗脫之矽膠層析來純化殘餘物以得到240 mg標題化合物(17%)。ES-MS m/z377 (M+H)。 Preparation 186 2-[[5-(3-fluoro-4-nitro-phenyl)tetrazol-1-yl]methoxy]ethyl-trimethyl-silane To a solution of 5-(3-fluoro-4-nitro-phenyl)-1H-tetrazole (860 mg, 4.1 mmol) in THF (12 mL) was added sodium hydride (60%, in mineral oil, 180 mg, 4.5 mmol). 2-(Chloromethoxy)ethyl-trimethyl-silane (0.79 mL, 4.5 mmol) was added to the mixture and stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with heptane:EtOAc (8:2) to afford 240 mg of the title compound (17%). ES-MS m/z 377 (M+H).
製備 187富馬酸;[(2S)-環氧丙烷-2-基]甲胺 將[(2S)-環氧丙烷-2-基]甲胺(3.6 wt%,於EtOH中,1500 g, 620 mmol)及富馬酸(72 g, 620 mmol)在25℃及氮下混合36 h。過濾掉固體並在減壓下乾燥固體以得到白色固體形式之標題化合物(65 g, 52%)。 1H NMR (400.21 MHz, MeOH- d 4) δ 6.72 (s, 2H), 5.02 (ddd, J= 14.8, 7.0, 3.7 Hz, 1H), 4.77-4.70 (m, 1H), 4.61 (dt, J= 9.0, 6.1 Hz, 1H), 3.27 (dd, J= 7.1, 13.4 Hz, 1H), 3.16 (dd, J= 3.7, 13.4 Hz, 1H), 2.87-2.81 (m, 1H), 2.60-2.54 (m, 1H)。 Preparation of 187 fumaric acid; [(2S)-epoxypropan-2-yl]methylamine [(2S)-Oxiran-2-yl]methylamine (3.6 wt% in EtOH, 1500 g, 620 mmol) and fumaric acid (72 g, 620 mmol) were mixed at 25 °C under nitrogen for 36 h. The solid was filtered off and dried under reduced pressure to give the title compound (65 g, 52%) as a white solid. 1 H NMR (400.21 MHz, MeOH- d 4 ) δ 6.72 (s, 2H), 5.02 (ddd, J = 14.8, 7.0, 3.7 Hz, 1H), 4.77-4.70 (m, 1H), 4.61 (dt, J = 9.0, 6.1 Hz, 1H), 3.27 (dd, J = 7.1, 13.4 Hz, 1H), 3.16 (dd, J = 3.7, 13.4 Hz, 1H), 2.87-2.81 (m, 1H), 2.60-2.54 ( m, 1H).
製備 1882-硝基- N-[[(2R)-環氧丙烷-2-基]甲基]-5-[1-(2-三甲基矽基乙氧基甲基)四唑-5-基]苯胺 將富馬酸;[(2S)-環氧丙烷-2-基]甲胺(160 mg, 0.79 mmol)及TEA (0.39 mL, 2.8 mmol)於 N, N-二甲基乙醯胺(2 mL)中之溶液在室溫下攪拌1 h。添加2-[[5-(3-氟-4-硝基-苯基)四唑-1-基]甲氧基]乙基-三甲基-矽烷(240 mg, 0.7 mmol)並將混合物在35℃下攪拌16 h。使用水終止反應並使用EtOAc萃取。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮。經由使用庚烷: EtOAc (1:1)洗脫之矽膠層析來純化殘餘物以得到200 mg標題化合物(70%)。ES-MS m/z429 (M+Na)。 Preparation of 188 2-nitro- N -[[(2R)-epoxypropan-2-yl]methyl]-5-[1-(2-trimethylsilylethoxymethyl)tetrazole-5 -yl]aniline Fumaric acid; [(2S)-epoxypropan-2-yl]methanamine (160 mg, 0.79 mmol) and TEA (0.39 mL, 2.8 mmol) in N , N -dimethylacetamide (2 mL ) solution was stirred at room temperature for 1 h. 2-[[5-(3-Fluoro-4-nitro-phenyl)tetrazol-1-yl]methoxy]ethyl-trimethyl-silane (240 mg, 0.7 mmol) was added and the mixture was Stir at 35°C for 16 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with heptane:EtOAc (1:1) to afford 200 mg of the title compound (70%). ES-MS m/z 429 (M+Na).
製備 189N2-[[(2R)-環氧丙烷-2-基]甲基]-4-[1-(2-三甲基矽基乙氧基甲基)四唑-5-基]苯-1,2-二胺 將鐵(100 mg, 2 mmol)、氯化銨(7 mg, 0.1 mmol)及乙酸(30 µL, 0.5 mmol)於水(3 mL)中之混合物在50℃下劇烈攪拌15 min。添加於DMF (1 mL)中之2-硝基- N-[[(2R)-環氧丙烷-2-基]甲基]-5-[1-(2-三甲基矽基乙氧基甲基)四唑-5-基]苯胺(100 mg, 0.2 mmol)並將混合物在50℃下攪拌1 h。經由Celite ®墊過濾反應混合物,然後使用水驟冷並使用EtOAc萃取。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮以得到98 mg標題化合物(99%)。ES-MS m/z377 (M+H)。 Preparation of 189 N2-[[(2R)-Oxiran-2-yl]methyl]-4-[1-(2-Trimethylsilylethoxymethyl)tetrazol-5-yl]benzene- 1,2-diamine A mixture of iron (100 mg, 2 mmol), ammonium chloride (7 mg, 0.1 mmol) and acetic acid (30 µL, 0.5 mmol) in water (3 mL) was vigorously stirred at 50°C for 15 min. 2-Nitro- N -[[(2R)-epoxypropan-2-yl]methyl]-5-[1-(2-trimethylsilylethoxy in DMF (1 mL) Methyl)tetrazol-5-yl]aniline (100 mg, 0.2 mmol) and the mixture was stirred at 50°C for 1 h. The reaction mixture was filtered through a pad of Celite® , then quenched with water and extracted with EtOAc. The organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure to give 98 mg of the title compound (99%). ES-MS m/z 377 (M+H).
製備 190(S)-2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)-N-(2-((環氧丙烷-2-基甲基)胺基)-4-(1-((2-(三甲基矽基)乙氧基)甲基)-1H-四唑-5-基)苯基)乙醯胺 向2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(100 mg, 0.25 mmol)、N2-[[(2R)-環氧丙烷-2-基]甲基]-4-[1-(2-三甲基矽基乙氧基甲基)四唑-5-基]苯-1,2-二胺(98 mg, 0.26 mmol)及TEA (104 µL, 0.75 mmol)於DMF (2 mL)中之溶液中添加HATU (142 mg, 0.37 mmol)。將混合物在室溫下攪拌1 h。使用水終止反應並使用EtOAc萃取。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮以得到190 mg標題化合物(99%)。LC-MS滯留時間= 2.17 min。 Preparation 190 (S)-2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononyl Fan-1 4 -yl)-N-(2-(((epoxypropylene-2-ylmethyl)amino)-4-(1-((2-(trimethylsilyl)ethoxy)methyl Base)-1H-tetrazol-5-yl)phenyl)acetamide To 2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 - base) acetic acid (100 mg, 0.25 mmol), N2-[[(2R)-epoxypropane-2-yl]methyl]-4-[1-(2-trimethylsilylethoxymethyl) To a solution of tetrazol-5-yl]benzene-1,2-diamine (98 mg, 0.26 mmol) and TEA (104 µL, 0.75 mmol) in DMF (2 mL) was added HATU (142 mg, 0.37 mmol) . The mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure to give 190 mg of the title compound (99%). LC-MS retention time = 2.17 min.
製備 191(S)-1 4-((1-(環氧丙烷-2-基甲基)-6-(1-((2-(三甲基矽基)乙氧基)甲基)-1H-四唑-5-基)-1H-苯并[d]咪唑-2-基)甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-甲腈 基本上如製備102中所闡述使用(S)-2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)-N-(2-((環氧丙烷-2-基甲基)胺基)-4-(1-((2-(三甲基矽基)乙氧基)甲基)-1H-四唑-5-基)苯基)乙醯胺在1:1 1,2-二氯乙烷:乙酸(作為溶劑)中來製備標題化合物,其中將反應液在85℃下加熱16 h。在減壓下濃縮混合物。經由矽膠層析使用於庚烷中之0 - 100% EtOAc之梯度來純化殘餘物以得到標題化合物。ES-MS m/z741 (M+H)。 Preparation 191 (S)-1 4 -((1-(epoxypropan-2-ylmethyl)-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H -tetrazol-5-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclonazone-5 4 -carbonitrile Using (S)-2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1, 2)-Diphenylcyclononafin-1 4 -yl)-N-(2-(((epoxypropylene-2-ylmethyl)amino)-4-(1-((2-(trimethylsilyl base)ethoxy)methyl)-1H-tetrazol-5-yl)phenyl)acetamide in 1:1 1,2-dichloroethane:acetic acid (as solvent) to prepare the title compound, wherein The reaction solution was heated at 85 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in heptane to afford the title compound. ES-MS m/z 741 (M+H).
製備 1921-溴-4-(溴甲基)-2-氟-5-碘-苯 將N-溴琥珀醯亞胺(26.84 g, 150.8 mmol)添加至4-溴-5-氟-2-碘甲苯(25 g, 75.4 mmol)於氯仿(30 mL)中之溶液中;然後,添加2,2'-偶氮雙(2-甲基丙腈) (1.26 g, 7.54 mmol)並將反應液在80℃下加熱5 h。冷卻至室溫,添加NaHCO 3飽和溶液(300 mL)並使用DCM (200 mL)萃取。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用庚烷作為洗脫劑來純化殘餘物以得到16.04 g (54%產率)標題化合物。 1H NMR (400.13 MHz, CDCl 3) δ 8.05 (d, J= 6.8 Hz, 1H), 7.29 (d, J= 9.00, 1H), 4.51 (s, 2H)。 Preparation of 192 1-bromo-4-(bromomethyl)-2-fluoro-5-iodo-benzene N-Bromosuccinimide (26.84 g, 150.8 mmol) was added to a solution of 4-bromo-5-fluoro-2-iodotoluene (25 g, 75.4 mmol) in chloroform (30 mL); then, 2,2'-Azobis(2-methylpropionitrile) (1.26 g, 7.54 mmol) and the reaction solution was heated at 80°C for 5 h. Cooled to room temperature, added saturated NaHCO 3 solution (300 mL) and extracted with DCM (200 mL). The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using heptane as eluent to afford 16.04 g (54% yield) of the title compound. 1 H NMR (400.13 MHz, CDCl 3 ) δ 8.05 (d, J=6.8 Hz, 1H), 7.29 (d, J=9.00, 1H), 4.51 (s, 2H).
製備 1932-(4-溴-5-氟-2-碘-苯基)乙腈 向1-溴-4-(溴甲基)-2-氟-5-碘-苯(16.04 g, 40.74 mmol)及TMSCN (7.24 mL, 53 mmol)於ACN (110 mL)中之溶液中緩慢添加TBAF (1 M於THF中,53 mL, 53 mmol)。將反應液在40℃下加熱3 h。在減壓下蒸發溶劑,將殘餘物溶於EtOAc (150 mL)中並使用飽和NaCl水溶液(3 × 50 mL)洗滌有機物。藉由MgSO 4乾燥有機物,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 15% EtOAc之梯度來純化殘餘物以提供橙色油狀物形式之標題化合物(10.34 g, 69%)。ES-MS m/z340/342 (M+H)。 Preparation of 193 2-(4-bromo-5-fluoro-2-iodo-phenyl)acetonitrile To a solution of 1-bromo-4-(bromomethyl)-2-fluoro-5-iodo-benzene (16.04 g, 40.74 mmol) and TMSCN (7.24 mL, 53 mmol) in ACN (110 mL) was added slowly TBAF (1 M in THF, 53 mL, 53 mmol). The reaction solution was heated at 40 °C for 3 h. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc (150 mL) and the organics were washed with saturated aqueous NaCl (3 x 50 mL). The organics were dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-15% EtOAc in heptane to afford the title compound (10.34 g, 69%) as an orange oil. ES-MS m/z 340/342 (M+H).
製備 1942-(4-溴-5-氟-2-碘-苯基)乙酸乙酯 在室溫下,向2-(4-溴-5-氟-2-碘-苯基)乙腈(10.34 g, 30.43 mmol)於8 M EtOH/水(92 mL)中之溶液中添加硫酸(24 mL)。將反應混合物在80℃下加熱18 h。將混合物冷卻至室溫,藉由添加飽和NaHCO 3水溶液來鹼化反應液直至pH >7,並使用DCM (3 × 50 mL)萃取。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 10% EtOAc之梯度來純化殘餘物以得到8.88 g (75%)白色固體形式之標題化合物。ES-MS m/z387/389 (M+H)。 Preparation of 194 2-(4-bromo-5-fluoro-2-iodo-phenyl) ethyl acetate To a solution of 2-(4-bromo-5-fluoro-2-iodo-phenyl)acetonitrile (10.34 g, 30.43 mmol) in 8 M EtOH/water (92 mL) was added sulfuric acid (24 mL). The reaction mixture was heated at 80 °C for 18 h. The mixture was cooled to room temperature, the reaction was basified by adding saturated aqueous NaHCO 3 until pH >7, and extracted with DCM (3×50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-10% EtOAc in heptane to afford 8.88 g (75%) of the title compound as a white solid. ES-MS m/z 387/389 (M+H).
製備 1952-[4-溴-2-[2-乙氧基乙烯基]-5-氟-苯基]乙酸乙酯 在氮下,將四(三苯基膦)鈀(0) (1.3 g, 1.1 mmol)、Cs 2CO 3(7.4 g, 23 mmol)及2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧硼㖦(3.3 mL, 15 mmol)添加至2-(4-溴-5-氟-2-碘-苯基)乙酸乙酯(4.37g, 11.31 mmol)於1,4-二噁烷(80 mL)中之溶液中。將混合物在90℃下加熱5 h。使用水(100 mL)稀釋混合物並使用EtOAc (100 mL)萃取。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 10% EtOAc之梯度來純化殘餘物以得到2.51g (67%)黃色油狀物形式之標題化合物。ES-MS m/z331/333 (M+H)。 Preparation of 195 ethyl 2-[4-bromo-2-[2-ethoxyvinyl]-5-fluoro-phenyl]acetate Under nitrogen, tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.1 mmol), Cs 2 CO 3 (7.4 g, 23 mmol) and 2-(2-ethoxyvinyl)-4, 4,5,5-Tetramethyl-1,3,2-dioxaboronium (3.3 mL, 15 mmol) was added to ethyl 2-(4-bromo-5-fluoro-2-iodo-phenyl)acetate (4.37g, 11.31 mmol) in a solution in 1,4-dioxane (80 mL). The mixture was heated at 90 °C for 5 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-10% EtOAc in heptane to afford 2.51 g (67%) of the title compound as a yellow oil. ES-MS m/z 331/333 (M+H).
製備 1962-[4-溴-5-氟-2-(2-羥乙基)苯基]乙酸乙酯 在0℃下向2-[4-溴-2-[2-乙氧基乙烯基]-5-氟-苯基]乙酸乙酯(2.51g, 7.59 mmol)於THF (45 mL)中之溶液中添加乙酸汞(6.3 g, 19 mmol)並在0℃下攪拌2 h。同時,將硼氫化鈉(520 mg, 13.75 mmol)添加至K 2CO 3(60 g)於水(56 mL)中之溶液中,並將此混合物添加至含有起始材料之先前反應液中。將反應液在室溫下攪拌40 min,然後使用水(50 mL)稀釋並使用EtOAc (3 × 50 mL)萃取。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 25% EtOAc之梯度來純化殘餘物以提供無色油狀物形式之標題化合物(1.31 g,40%產率)。ES-MS m/z305/307 (M+H)。 Preparation of 196 2-[4-bromo-5-fluoro-2-(2-hydroxyethyl)phenyl]ethyl acetate To a solution of ethyl 2-[4-bromo-2-[2-ethoxyvinyl]-5-fluoro-phenyl]acetate (2.51g, 7.59 mmol) in THF (45 mL) at 0°C Mercury acetate (6.3 g, 19 mmol) was added and stirred at 0°C for 2 h. Simultaneously, sodium borohydride (520 mg, 13.75 mmol) was added to a solution of K2CO3 (60 g) in water (56 mL), and this mixture was added to the previous reaction containing the starting material. The reaction was stirred at room temperature for 40 min, then diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-25% EtOAc in heptane to afford the title compound (1.31 g, 40% yield) as a colorless oil. ES-MS m/z 305/307 (M+H).
製備 1974-甲醯基-3-羥基-苯甲腈 在-10℃下,向4-氰基-2-甲氧基苯甲醛(13 g, 79.86 mmol)於DCM (480 mL)中之溶液中分批添加三溴化硼(100 g, 399.16 mmol)。將反應液在室溫下攪拌3天,冷卻至0℃,並緩慢添加水(21 mL)。使用水(100 mL)稀釋反應液並使用DCM (3 × 100 mL)萃取。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 20% EtOAc之梯度來純化殘餘物以得到7.61g (65%)標題化合物。ES-MS m/z148 (M+H)。 Preparation of 197 4-formyl-3-hydroxy-benzonitrile To a solution of 4-cyano-2-methoxybenzaldehyde (13 g, 79.86 mmol) in DCM (480 mL) was added boron tribromide (100 g, 399.16 mmol) in portions at -10 °C . The reaction was stirred at room temperature for 3 days, cooled to 0 °C, and water (21 mL) was added slowly. The reaction was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-20% EtOAc in heptane to afford 7.61 g (65%) of the title compound. ES-MS m/z 148 (M+H).
製備 1984-甲醯基-3-(2-三甲基矽基乙氧基甲氧基)苯甲腈 將DIPEA (9.5 mL, 54 mmol)及2-(三甲基矽基)乙氧基甲基氯(5.3 mL, 30 mmol)添加至4-甲醯基-3-羥基-苯甲腈(4 g, 27.18 mmol)於DCM (68 mL)及二乙醚(30 mL)中之溶液中。將反應混合物在室溫下攪拌3 h。使用飽和NH 4Cl水溶液稀釋反應液並使用DCM (3 × 50 mL)萃取。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 20% EtOAc之梯度來純化殘餘物以提供標題化合物(5.67 g, 75%)。ES-MS m/z278 (M+H)。 Preparation of 198 4-formyl-3-(2-trimethylsilylethoxymethoxy)benzonitrile DIPEA (9.5 mL, 54 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (5.3 mL, 30 mmol) were added to 4-formyl-3-hydroxy-benzonitrile (4 g , 27.18 mmol) in DCM (68 mL) and diethyl ether (30 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction was diluted with saturated aqueous NH4Cl and extracted with DCM (3 x 50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-20% EtOAc in heptane to afford the title compound (5.67 g, 75%). ES-MS m/z 278 (M+H).
製備 1994-(羥甲基)-3-(2-三甲基矽基乙氧基甲氧基)苯甲腈 在0℃下,向4-甲醯基-3-(2-三甲基矽基乙氧基甲氧基)苯甲腈(5.67 g, 20.4 mmol)於THF (30mL)及MeOH (30 mL)中之溶液中分批添加硼氫化鈉(1.6 g, 42 mmol)。將反應混合物攪拌1 h,然後添加水(50 mL)並使用EtOAc (3 × 50 mL)萃取。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮以得到5.55g (97%)標題化合物。ES-MS m/z280 (M+H)。 Preparation of 199 4-(hydroxymethyl)-3-(2-trimethylsilylethoxymethoxy)benzonitrile Add 4-formyl-3-(2-trimethylsilylethoxymethoxy)benzonitrile (5.67 g, 20.4 mmol) in THF (30 mL) and MeOH (30 mL) at 0°C Sodium borohydride (1.6 g, 42 mmol) was added portionwise to the solution in . The reaction mixture was stirred for 1 h, then water (50 mL) was added and extracted with EtOAc (3 x 50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure to give 5.55 g (97%) of the title compound. ES-MS m/z 280 (M+H).
製備 2004-[(6-溴-2-吡啶基)氧基甲基]-3-(2-三甲基矽基乙氧基甲氧基)苯甲腈 在室溫下,將氫化鈉(60%於礦物油中,500 mg, 12.5 mmol)添加至4-(羥甲基)-3-(2-三甲基矽基乙氧基甲氧基)苯甲腈(2.65 g, 9.48 mmol)於THF (60 mL)中之溶液中。將混合物攪拌30 min,然後添加2-溴-6-氟吡啶(1.7g, 9.5 mmol)並將反應液在60℃下加熱3 h。將反應液冷卻至環境溫度,使用水(50 mL)稀釋並使用EtOAc (3 × 50 mL)萃取。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 10% EtOAc之梯度來純化殘餘物以得到3.18 g (77%)標題化合物。 1H NMR (400.13MHz, CDCl 3) δ 7.57 (d, J= 7.6 Hz, 1H), 7.46 (m, 2H), 7.32 (d, J= 8 Hz, 1H), 7.11 (d, J= 7.2 Hz, 1H), 6.77 (d, J= 8 Hz, 1H), 5.44 (s, 2H), 5.31 (s, 2H);3.78 (t, J= 8.4 Hz, 2H), 0.98 (t, J= 8.4Hz, 2H)。0.02 (s, 9H)。 Preparation of 200 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-trimethylsilylethoxymethoxy)benzonitrile Sodium hydride (60% in mineral oil, 500 mg, 12.5 mmol) was added to 4-(hydroxymethyl)-3-(2-trimethylsilylethoxymethoxy)benzene at room temperature A solution of forminonitrile (2.65 g, 9.48 mmol) in THF (60 mL). The mixture was stirred for 30 min, then 2-bromo-6-fluoropyridine (1.7 g, 9.5 mmol) was added and the reaction was heated at 60 °C for 3 h. The reaction was cooled to ambient temperature, diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-10% EtOAc in heptane to afford 3.18 g (77%) of the title compound. 1 H NMR (400.13MHz, CDCl 3 ) δ 7.57 (d, J = 7.6 Hz, 1H), 7.46 (m, 2H), 7.32 (d, J = 8 Hz, 1H), 7.11 (d, J = 7.2 Hz , 1H), 6.77 (d, J = 8 Hz, 1H), 5.44 (s, 2H), 5.31 (s, 2H); 3.78 (t, J = 8.4 Hz, 2H), 0.98 (t, J = 8.4Hz , 2H). 0.02 (s, 9H).
製備 2014-[(6-溴-2-吡啶基)氧基甲基]-3-羥基-苯甲腈 將四溴化碳(364 mg, 1.1 mmol)添加至4-[(6-溴-2-吡啶基)氧基甲基]-3-(2-三甲基矽基乙氧基甲氧基)苯甲腈(3.18 g, 7.31mmol)於2-丙醇(75 mL)中之溶液中。將反應混合物在80℃下加熱10 h,然後在減壓下濃縮溶劑並經由矽膠層析使用於庚烷中之0 - 20% EtOAc之梯度來純化殘餘物以提供白色固體形式之標題化合物(1.72 g, 57%)。ES-MS m/z305/307 (M+H)。 Preparation of 201 4-[(6-bromo-2-pyridyl)oxymethyl]-3-hydroxy-benzonitrile Add carbon tetrabromide (364 mg, 1.1 mmol) to 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-trimethylsilylethoxymethoxy) A solution of benzonitrile (3.18 g, 7.31 mmol) in 2-propanol (75 mL). The reaction mixture was heated at 80 °C for 10 h, then the solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0 - 20% EtOAc in heptane to afford the title compound as a white solid (1.72 g, 57%). ES-MS m/z 305/307 (M+H).
製備 2022-[4-溴-2-[2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯氧基]乙基]-5-氟-苯基]乙酸乙酯 在0℃下,向2-[4-溴-5-氟-2-(2-羥乙基)苯基]乙酸乙酯(519 mg, 1.70 mmol)、4-[(6-溴-2-吡啶基)氧基甲基]-3-羥基-苯甲腈(500 mg, 1.64 mmol)及三苯基膦(645 mg, 2.46 mmol)於THF (17 mL)中之溶液中添加稀釋於THF (1 mL)中之DEAD (40%,於甲苯中,0.97 mL, 2.46 mmol)。將反應混合物在室溫下攪拌過夜。在14 h之後,在0℃下添加稀釋於THF (1 mL)中之額外DEAD (40%,於甲苯中,0.53 mL, 1.36 mmol)。在在室溫下20 h之後,使用水(25 mL)稀釋反應混合物並使用EtOAc (3 × 10 mL)萃取。合併有機物,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之10 - 30% EtOAc之梯度來純化殘餘物以得到444 mg (44%)白色固體形式之標題化合物。ES-MS m/z591/593/595 (M+H)。 Preparation of 202 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenoxy]ethyl]-5-fluoro -Phenyl]ethyl acetate At 0°C, 2-[4-bromo-5-fluoro-2-(2-hydroxyethyl)phenyl] ethyl acetate (519 mg, 1.70 mmol), 4-[(6-bromo-2- A solution of pyridyl)oxymethyl]-3-hydroxy-benzonitrile (500 mg, 1.64 mmol) and triphenylphosphine (645 mg, 2.46 mmol) in THF (17 mL) was added and diluted in THF ( 1 mL) of DEAD (40% in toluene, 0.97 mL, 2.46 mmol). The reaction mixture was stirred overnight at room temperature. After 14 h, additional DEAD (40% in toluene, 0.53 mL, 1.36 mmol) diluted in THF (1 mL) was added at 0 °C. After 20 h at room temperature, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 10 mL). The organics were combined, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10-30% EtOAc in heptane to afford 444 mg (44%) of the title compound as a white solid. ES-MS m/z 591/593/595 (M+H).
製備 2032-(5 4-氰基-1 6-氟-3,6-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸乙酯 在兩個不同批次中,使氮鼓泡通過2-[4-溴-2-[2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯氧基]乙基]-5-氟-苯基]乙酸乙酯(299 mg, 0.50 mmol)於1,4-二噁烷(10 mL)中之溶液,然後添加六甲基二錫(0.16 mL, 0.76 mmol)及Pd(dppf)Cl 2DCM複合物(100 mg, 0.12 mmol)。將各反應混合物批次在100℃下加熱3h。將兩個批次冷卻至室溫並將其合併。使用水稀釋並使用EtOAc萃取三次。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之10 - 20% EtOAc之梯度來純化殘餘物以提供白色固體形式之標題化合物(90 mg, 41%)。ES-MS m/z433 (M+H)。 Preparation of 203 2-(5 4 -cyano-1 6 -fluoro-3,6-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Octan-1 4 -yl) ethyl acetate In two different batches, nitrogen was bubbled through 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano- A solution of phenoxy]ethyl]-5-fluoro-phenyl]ethyl acetate (299 mg, 0.50 mmol) in 1,4-dioxane (10 mL) was then added with hexamethylditin (0.16 mL, 0.76 mmol) and Pd(dppf)Cl 2 DCM complex (100 mg, 0.12 mmol). The reaction mixture batches were heated at 100 °C for 3 h. The two batches were cooled to room temperature and combined. Diluted with water and extracted three times with EtOAc. The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10-20% EtOAc in heptane to afford the title compound (90 mg, 41%) as a white solid. ES-MS m/z 433 (M+H).
製備 2042-(5 4-氰基-1 6-氟-3,6-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸 基本上如製備75中所闡述使用2-(5 4-氰基-1 6-氟-3,6-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸乙酯來製備標題化合物,其中將反應液在45℃下加熱3 h。將甲酸添加至混合物中直至pH = 5-6,使用水稀釋,並使用3:1 DCM :異丙醇萃取三次。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮以提供白色固體形式之標題化合物。ES-MS m/z405 (M+H)。 Preparation of 204 2-(5 4 -cyano-1 6 -fluoro-3,6-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Cinfan-1 4 -yl)acetic acid Using 2-(5 4 -cyano-1 6 -fluoro-3,6-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclooctafan-1 4 -yl)ethyl acetate to prepare the title compound, wherein the reaction solution was heated at 45°C for 3 h. Formic acid was added to the mixture until pH = 5-6, diluted with water, and extracted three times with 3:1 DCM:isopropanol. The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure to afford the title compound as a white solid. ES-MS m/z 405 (M+H).
製備 205(S)-4-(2-(5 4-氰基-1 6-氟-3,6-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氰基-1 6-氟-3,6-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸(82 mg, 0.20 mmol)及4-胺基-3-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(48 mg, 0.20 mmol)於DMF (2 mL)中之溶液中添加DIPEA (0.10 mL, 0.58 mmol)及HATU (115 mg, 0.30 mmol)。在室溫下攪拌24 h之後,添加額外DIPEA (0.055 mL, 0.31 mmol)及HATU (60 mg, 0.15 mmol)。在30 h之後,添加水及EtOAc,並使用EtOAc將混合物萃取三次。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮以得到標題化合物(200 mg, >100%),其未經進一步純化即用於製備206。ES-MS m/z623 (M+H)。 Preparation of 205 (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-3,6-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclooctane-1 4 -yl)acetamido)-3-(((epoxypropylene-2-ylmethyl)amino)benzoate methyl ester To 2-(5 4 -cyano-1 6 -fluoro-3,6-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclooctyl Fan-1 4 -yl)acetic acid (82 mg, 0.20 mmol) and methyl 4-amino-3-[[(2S)-epoxypropan-2-yl]methylamino]benzoate (48 mg, 0.20 mmol) in DMF (2 mL) was added DIPEA (0.10 mL, 0.58 mmol) and HATU (115 mg, 0.30 mmol). After stirring at room temperature for 24 h, additional DIPEA (0.055 mL, 0.31 mmol) and HATU (60 mg, 0.15 mmol) were added. After 30 h, water and EtOAc were added, and the mixture was extracted three times with EtOAc. The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the title compound (200 mg, >100%), which was used in Preparation 206 without further purification. ES-MS m/z 623 (M+H).
製備 206(S)-2-((5 4-氰基-1 6-氟-3,6-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將乙酸(6 mL)添加至(S)-4-(2-(5 4-氰基-1 6-氟-3,6-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙醯胺基)-3-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備205,200mg, 0.32 mmol)中,並在65℃下攪拌2 h。將混合物冷卻至室溫,在減壓下蒸發溶劑並經由矽膠層析使用於DCM中之0 - 20% EtOAc之梯度來純化殘餘物以得到92 mg (47%)標題化合物。ES-MS m/z605 (M+H)。 Preparation of 206 (S)-2-((5 4 -cyano-1 6 -fluoro- 3,6 -dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclooctane-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Acetic acid (6 mL) was added to (S)-4-(2-( 54 -cyano- 16 -fluoro-3,6-dioxa-2(2,6)-pyridine-1(1, 3), methyl 5(1,2)-diphenylcyclooctane-1 4 -yl)acetamido)-3-(((epoxypropylene-2-ylmethyl)amino)benzoate (preparation 205, 200mg, 0.32 mmol), and stirred at 65°C for 2 h. The mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-20% EtOAc in DCM to afford 92 mg (47%) of the title compound. ES-MS m/z 605 (M+H).
製備 2073-胺基-5-溴-吡啶-2-甲酸乙酯 將硫酸(52 mL, 927 mmol)緩慢添加至3-胺基-5-溴吡啶-2-甲酸(15 g, 65.66 mmol)於8M乙醇/水(197 mL)中之溶液中。將反應液在80℃下加熱18 h。將混合物冷卻至室溫,然後緩慢添加NaOH (2 M水溶液)直至pH = 8,並使用EtOAc (3 × 100 mL)萃取。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮以得到淺黃色固體形式之標題化合物(13.93 g, 86%)。ES-MS m/z245/247 (M+H)。 Preparation 207 3-Amino-5-bromo-pyridine-2-carboxylic acid ethyl ester Sulfuric acid (52 mL, 927 mmol) was slowly added to a solution of 3-amino-5-bromopyridine-2-carboxylic acid (15 g, 65.66 mmol) in 8M ethanol/water (197 mL). The reaction solution was heated at 80 °C for 18 h. The mixture was cooled to room temperature, then NaOH (2 M aq) was added slowly until pH = 8, and extracted with EtOAc (3 x 100 mL). The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the title compound (13.93 g, 86%) as a light yellow solid. ES-MS m/z 245/247 (M+H).
製備 208(3-胺基-5-溴-2-吡啶基)甲醇 在0℃下,向3-胺基-5-溴-吡啶-2-甲酸乙酯(13.93 g, 56.84 mmol)於THF (230 mL)及MeOH (23 mL)中之溶液中逐份添加硼氫化鋰(3.75 g, 172 mmol)。將反應液在室溫下攪拌1 h。添加NaHCO 3飽和溶液並使用EtOAc (5 × 100 mL)萃取。合併有機物,藉由硫酸鎂乾燥,過濾,並在減壓下濃縮。將ACN添加至殘餘物中並過濾所得漿液,使用ACN洗滌固體,然後在真空下乾燥固體以提供9.87 g (81%)灰棕色固體形式之標題化合物。ES-MS m/z203/205 (M+H)。 Preparation of 208 (3-amino-5-bromo-2-pyridyl)methanol To a solution of ethyl 3-amino-5-bromo-pyridine-2-carboxylate (13.93 g, 56.84 mmol) in THF (230 mL) and MeOH (23 mL) was added portionwise at 0 °C for hydroboration. Lithium (3.75 g, 172 mmol). The reaction was stirred at room temperature for 1 h. A saturated solution of NaHCO 3 was added and extracted with EtOAc (5×100 mL). The organics were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. ACN was added to the residue and the resulting slurry was filtered, the solid was washed with ACN and then dried under vacuum to afford 9.87 g (81%) of the title compound as a beige solid. ES-MS m/z 203/205 (M+H).
製備 209(5-溴-3-碘-2-吡啶基)甲醇 將水合4-甲基苯磺酸(27.81 g, 146.2 mmol)添加至(3-胺基-5-溴-2-吡啶基)甲醇(9.87 g, 48.63 mmol)於ACN (170 mL)中之懸浮液中。將混合物攪拌10 min,然後冷卻至0℃。將於水(20 mL)中之亞硝酸鈉(6.72 g, 97.4 mmol)添加至混合物中,然後添加於水(20 mL)中之碘化鉀(20.48 g, 123.4 mmol)。將反應液在0℃下攪拌10 min,然後在室溫下攪拌2 h。將NaHCO 3飽和水溶液添加至混合物中並使用EtOAc (3 × 100 mL)萃取。合併有機物,使用5%亞硫酸氫鈉水溶液、水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,然後過濾並在減壓下濃縮。使用ACN研磨所得固體,然後過濾並在真空下乾燥固體以得到微褐色固體形式之標題化合物(10.31 g, 61%)。ES-MS m/z314/316 (M+H)。 Preparation of 209 (5-bromo-3-iodo-2-pyridyl)methanol Add 4-methylbenzenesulfonic acid hydrate (27.81 g, 146.2 mmol) to a suspension of (3-amino-5-bromo-2-pyridyl)methanol (9.87 g, 48.63 mmol) in ACN (170 mL) in the liquid. The mixture was stirred for 10 min, then cooled to 0 °C. Sodium nitrite (6.72 g, 97.4 mmol) in water (20 mL) was added to the mixture, followed by potassium iodide (20.48 g, 123.4 mmol) in water (20 mL). The reaction was stirred at 0 °C for 10 min, then at room temperature for 2 h. Sat. aq. NaHCO 3 was added to the mixture and extracted with EtOAc (3×100 mL). The organics were combined, washed with 5% aqueous sodium bisulfite, water and saturated aqueous NaCl, dried over MgSO 4 , then filtered and concentrated under reduced pressure. The resulting solid was triturated with ACN, then filtered and dried under vacuum to give the title compound (10.31 g, 61%) as a brownish solid. ES-MS m/z 314/316 (M+H).
製備 210[5-溴-3-[3-[第三丁基(二甲基)矽基]氧基丙-1-炔基]-2-吡啶基]甲醇 在氮及室溫下,將雙(三苯基膦)二氯化鈀(II) (2.64 g, 3.73 mmol)、碘化亞銅(0.71 g, 3.76 mmol)及TEA (31 mL, 225 mmol)添加至(5-溴-3-碘-2-吡啶基)甲醇(11.78 g, 37.53 mmol)之溶液中。添加第三丁基二甲基(2-丙炔基氧基)矽烷(10 mL, 48 mmol),然後將反應液在40℃下加熱20 h。將反應液冷卻至室溫,添加水及鹽水,然後使用EtOAc將混合物萃取三次。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 20% EtOAc之梯度來純化殘餘物以得到9.03 g (67%)褐色油狀物形式之標題化合物。ES-MS m/z356/358 (M+H)。 Preparation of 210 [5-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-2-pyridyl]methanol Bis(triphenylphosphine)palladium(II) dichloride (2.64 g, 3.73 mmol), cuprous iodide (0.71 g, 3.76 mmol) and TEA (31 mL, 225 mmol) were mixed under nitrogen at room temperature Add to a solution of (5-bromo-3-iodo-2-pyridyl)methanol (11.78 g, 37.53 mmol). Tert-butyldimethyl(2-propynyloxy)silane (10 mL, 48 mmol) was added, and the reaction solution was heated at 40° C. for 20 h. The reaction was cooled to room temperature, water and brine were added, and the mixture was extracted three times with EtOAc. The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-20% EtOAc in heptane to afford 9.03 g (67%) of the title compound as a brown oil. ES-MS m/z 356/358 (M+H).
製備 2115-[3-[第三丁基(二甲基)矽基]氧基丙-1-炔基]-6-(羥甲基)吡啶-3-甲腈 在氮下,將氰化鋅(2.09 g, 17.85 mmol)添加至[5-溴-3-[3-[第三丁基(二甲基)矽基]氧基丙-1-炔基]-2-吡啶基]甲醇(9.03 g, 25.26 mmol)於DMF (180 mL)中之溶液中,然後添加四(三苯基膦)鈀(0) (2.93 g, 2.54 mmol)。將反應液在100℃下加熱2 h。將混合物冷卻至室溫,添加水及飽和NaCl水溶液並使用EtOAc將混合物萃取三次。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 25% EtOAc之梯度來純化殘餘物以提供4.6 g (60%)褐色油狀物形式之標題化合物。ES-MS m/z303 (M+H)。 Preparation of 211 5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-6-(hydroxymethyl)pyridine-3-carbonitrile Under nitrogen, zinc cyanide (2.09 g, 17.85 mmol) was added to [5-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]- 2-Pyridyl]methanol (9.03 g, 25.26 mmol) in DMF (180 mL) was then added tetrakis(triphenylphosphine)palladium(0) (2.93 g, 2.54 mmol). The reaction solution was heated at 100 °C for 2 h. The mixture was cooled to room temperature, water and saturated aqueous NaCl were added and the mixture was extracted three times with EtOAc. The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-25% EtOAc in heptane to afford 4.6 g (60%) of the title compound as a brown oil. ES-MS m/z 303 (M+H).
製備 2126-[(6-溴-2-吡啶基)氧基甲基]-5-[3-[第三丁基(二甲基)矽基]氧基丙-1-炔基]吡啶-3-甲腈 基本上如製備34中所闡述使用5-[3-[第三丁基(二甲基)矽基]氧基丙-1-炔基]-6-(羥甲基)吡啶-3-甲腈來製備標題化合物。在完成後,將反應液冷卻至室溫,在減壓下蒸發溶劑並經由矽膠層析使用於庚烷中之0 - 15% EtOAc之梯度來純化殘餘物以得到淺黃色固體形式之標題化合物。ES-MS m/z458/460 (M+H)。 Preparation 212 6-[(6-bromo-2-pyridyl)oxymethyl]-5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]pyridine- 3-carbonitrile Using 5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-6-(hydroxymethyl)pyridine-3-carbonitrile essentially as described in Preparation 34 to prepare the title compound. After completion, the reaction was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-15% EtOAc in heptane to give the title compound as a pale yellow solid. ES-MS m/z 458/460 (M+H).
製備 2136-[(6-溴-2-吡啶基)氧基甲基]-5-(3-羥基丙-1-炔基)吡啶-3-甲腈 將於THF中之1M TBAF (16.1 mL, 16.1 mmol)添加至6-[(6-溴-2-吡啶基)氧基甲基]-5-[3-[第三丁基(二甲基)矽基]氧基丙-1-炔基]吡啶-3-甲腈(6.15 g, 13.42 mmol)於THF (40 mL)中之溶液中。將混合物在室溫下攪拌7 h。添加NaHCO 3飽和水溶液並使用EtOAc將混合物萃取三次。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於庚烷中之0 - 50% EtOAc之梯度來純化殘餘物以提供3.04 g (66%)無色油狀物形式之標題化合物。ES-MS m/z344/346 (M+H)。 Preparation of 213 6-[(6-bromo-2-pyridyl)oxymethyl]-5-(3-hydroxyprop-1-ynyl)pyridine-3-carbonitrile 1M TBAF (16.1 mL, 16.1 mmol) in THF was added to 6-[(6-bromo-2-pyridyl)oxymethyl]-5-[3-[tert-butyl(dimethyl) A solution of silyl]oxyprop-1-ynyl]pyridine-3-carbonitrile (6.15 g, 13.42 mmol) in THF (40 mL). The mixture was stirred at room temperature for 7 h. Sat. aq. NaHCO 3 was added and the mixture was extracted three times with EtOAc. The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in heptane to afford 3.04 g (66%) of the title compound as a colorless oil. ES-MS m/z 344/346 (M+H).
製備 2146-[(6-溴-2-吡啶基)氧基甲基]-5-(3-羥丙基)吡啶-3-甲腈 將氧化鉑(0.06 g, 0.26 mmol)添加至6-[(6-溴-2-吡啶基)氧基甲基]-5-(3-羥基丙-1-炔基)吡啶-3-甲腈(0.65 g, 1.88 mmol)於MeOH (18 mL)及兩滴乙酸中之溶液中。向反應容器中裝填氫氣氛(15 psi)並將混合物在室溫下攪拌5 h。經由Celite ®墊過濾反應液,使用MeOH及EtOAc洗滌。在真空下蒸發濾液並經由矽膠層析使用於庚烷中之0 - 30% EtOAc之梯度來純化殘餘物以得到標題化合物(0.33 g, 51%)。ES-MS m/z348/350 (M+H)。 Preparation of 214 6-[(6-bromo-2-pyridyl)oxymethyl]-5-(3-hydroxypropyl)pyridine-3-carbonitrile Platinum oxide (0.06 g, 0.26 mmol) was added to 6-[(6-bromo-2-pyridyl)oxymethyl]-5-(3-hydroxyprop-1-ynyl)pyridine-3-carbonitrile (0.65 g, 1.88 mmol) in MeOH (18 mL) and two drops of acetic acid. A hydrogen atmosphere (15 psi) was charged to the reaction vessel and the mixture was stirred at room temperature for 5 h. The reaction was filtered through a pad of Celite® , washing with MeOH and EtOAc. The filtrate was evaporated under vacuum and the residue was purified by silica gel chromatography using a gradient of 0-30% EtOAc in heptane to give the title compound (0.33 g, 51%). ES-MS m/z 348/350 (M+H).
製備 2152-[4-溴-2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-3-吡啶基]丙氧基]-5-氟-苯基]乙酸乙酯 基本上如製備60中所闡述使用6-[(6-溴-2-吡啶基)氧基甲基]-5-(3-羥丙基)吡啶-3-甲腈(1.01 g, 2.9 mmol)來製備標題化合物,其中去除MeOH驟冷步驟且得到白色固體形式之標題化合物。ES-MS m/z606/608 (M+H)。 Preparation of 215 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-3-pyridyl]propoxy]-5 -Fluoro-phenyl] ethyl acetate Using 6-[(6-bromo-2-pyridyl)oxymethyl]-5-(3-hydroxypropyl)pyridine-3-carbonitrile (1.01 g, 2.9 mmol) essentially as described in Preparation 60 to prepare the title compound where the MeOH quench step was removed and the title compound was obtained as a white solid. ES-MS m/z 606/608 (M+H).
製備 2162-(5 5-氰基-1 6-氟-3,9-二氧雜-2(2,6),5(2,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸乙酯 在氮下,向2-[4-溴-2-[3-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-3-吡啶基]丙氧基]-5-氟-苯基]乙酸乙酯(0.75 g, 1.23 mmol)、氟化銫(203 mg, 1.33 mmol)及六甲基二錫(321 mg, 0.98 mmol)於1,4-二噁烷(55 mL)中之混合物中添加氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd G2, 75.2 mg, 0.094 mmol)。將反應混合物在100℃下加熱18 h。將混合物冷卻至室溫,經由Celite ®墊過濾,使用EtOAc (2 × 100 mL)及MeOH (2 × 100 mL)洗滌。蒸發濾液並經由矽膠層析使用於庚烷中之0 - 50% EtOAc之梯度來純化殘餘物以提供0.27 g (49%)淺黃色固體形式之標題化合物。ES-MS m/z448 (M+H)。 Preparation of 216 2-(5 5 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridine-1(1,3)-benzene ring nonafin-1 4 -yl) ethyl acetate Under nitrogen, to 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-3-pyridyl]propoxy ]-5-fluoro-phenyl]ethyl acetate (0.75 g, 1.23 mmol), cesium fluoride (203 mg, 1.33 mmol) and hexamethylditin (321 mg, 0.98 mmol) in 1,4-diox To the mixture in alkanes (55 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amine yl-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 75.2 mg, 0.094 mmol). The reaction mixture was heated at 100 °C for 18 h. The mixture was cooled to room temperature, filtered through a pad of Celite® , washed with EtOAc (2 x 100 mL) and MeOH (2 x 100 mL). The filtrate was evaporated and the residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in heptane to afford 0.27 g (49%) of the title compound as a pale yellow solid. ES-MS m/z 448 (M+H).
製備 2172-(5 5-氰基-1 6-氟-3,9-二氧雜-2(2,6),5(2,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸 向2-(5 5-氰基-1 6-氟-3,9-二氧雜-2(2,6),5(2,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸乙酯(0.12 g, 0.27 mmol)於ACN (3.2 mL)、THF (0.8 mL)及水(0.5 mL)中之混合物中添加1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(0.075 g, 0.54 mmol)。將懸浮液在45℃下加熱2 h。將混合物冷卻至室溫,添加甲酸直至pH = 4,並使用EtOAc (3 × 5 mL)萃取。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮以得到白色固體形式之標題化合物(0.11 g, 98%)。ES-MS m/z420 (M+H)。 Preparation of 217 2-(5 5 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6),5(2,3)-bipyridine-1(1,3)-benzene ring nonafin-1 4 -yl)acetic acid To 2-(5 5 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6), 5(2,3)-bipyridine-1(1,3)-phencyclone To a mixture of fen- 14 -yl)ethyl acetate (0.12 g, 0.27 mmol) in ACN (3.2 mL), THF (0.8 mL) and water (0.5 mL) was added 1,3,4,6,7, 8-Hexahydro-2H-pyrimido[1,2-a]pyrimidine (0.075 g, 0.54 mmol). The suspension was heated at 45 °C for 2 h. The mixture was cooled to room temperature, formic acid was added until pH = 4, and extracted with EtOAc (3 x 5 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the title compound (0.11 g, 98%) as a white solid. ES-MS m/z 420 (M+H).
製備 218(S)-4-(2-(5 5-氰基-1 6-氟-3,9-二氧雜-2(2,6),5(2,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 5-氰基-1 6-氟-3,9-二氧雜-2(2,6),5(2,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸(0.11 g, 0.26 mmol)及4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(0.077 g, 0.29 mmol)於DMF (1.3 mL)中之溶液中添加DIPEA (0.13 mL, 0.74 mmol)及HATU (0.16 g, 0.40 mmol)。將反應液在室溫下攪拌16 h。添加飽和NaHCO 3水溶液並使用EtOAc (2 × 40 mL)萃取。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮以得到灰棕色固體形式之標題化合物(0.22g),其未經進一步純化即用於製備219。ES-MS m/z668 (M+H)。 Preparation of 218 (S)-4-(2-(55-cyano- 16 - fluoro-3,9-dioxa-2(2,6),5(2,3)-bipyridine-1( 1,3)-Phenencyclononan-1 4 -yl)acetamido)-3-methoxy-5-(((epoxypropan-2-ylmethyl)amino)benzoic acid methyl ester To 2-(5 5 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridine-1(1,3)-phencyclononium Fan-1 4 -yl)acetic acid (0.11 g, 0.26 mmol) and 4-amino-3-methoxy-5-[[(2S)-epoxypropan-2-yl]methylamino]benzoic acid To a solution of the methyl ester (0.077 g, 0.29 mmol) in DMF (1.3 mL) was added DIPEA (0.13 mL, 0.74 mmol) and HATU (0.16 g, 0.40 mmol). The reaction solution was stirred at room temperature for 16 h. Sat. aq. NaHCO 3 was added and extracted with EtOAc (2×40 mL). The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the title compound as a beige solid (0.22 g), which was used in the preparation of 219 without further purification. ES-MS m/z 668 (M+H).
製備 219(S)-2-((5 5-氰基-1 6-氟-3,9-二氧雜-2(2,6),5(2,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 5-氰基-1 6-氟-3,9-二氧雜-2(2,6),5(2,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備218)來製備標題化合物,其中將反應液在100℃下加熱2 h。在完成後,將反應液冷卻至室溫,添加ACN並蒸發。重複此操作三次以確保去除乙酸。經由矽膠層析使用於庚烷中之0 - 100% EtOAc之梯度來純化殘餘物以得到淺褐色固體形式之標題化合物。ES-MS m/z650 (M+H)。 Preparation of 219 (S)-2-(( 55 -cyano-16-fluoro-3,9-dioxa- 2 (2,6),5(2,3)-bipyridine-1(1, 3)-Phenencyclononafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ester Using (S)-4-(2-( 55 -cyano- 16 -fluoro-3,9-dioxa-2(2,6),5(2,3) essentially as described in Preparation 102 )-bipyridine-1(1,3)-phencyclononafin- 1 4 -yl)acetamido)-3-methoxy-5-((epoxypropane-2-ylmethyl)amino ) methyl benzoate (Preparation 218) to prepare the title compound by heating the reaction at 100 °C for 2 h. After completion, the reaction was cooled to room temperature, ACN was added and evaporated. Repeat this three times to ensure removal of acetic acid. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in heptane to afford the title compound as a beige solid. ES-MS m/z 650 (M+H).
製備 2204-[(6-氯-2-吡啶基)氧基甲基]-3-碘-苯甲腈 將4-(溴甲基)-3-碘-苯甲腈(20.0 g, 62.1 mmol)、6-氯吡啶-2-醇(8.45 g, 65.2 mmol)及碳酸銀(17.1 g, 62.0 mmol)於1,4-二噁烷(400 mL)中之混合物在70℃下攪拌20 h。添加額外之6-氯吡啶-2-醇(1.61 g, 12.4 mmol)及碳酸銀(3.5 g, 13 mmol)並將混合物在70℃下攪拌5 h。將混合物冷卻至室溫並經由矽膠塞使用DCM作為洗脫劑來過濾以產生淺黃色固體形式之標題化合物(24.6 g, 107%)。ES-MS m/z371.0/373.0 (M+H)。 Preparation of 220 4-[(6-chloro-2-pyridyl)oxymethyl]-3-iodo-benzonitrile 4-(bromomethyl)-3-iodo-benzonitrile (20.0 g, 62.1 mmol), 6-chloropyridin-2-ol (8.45 g, 65.2 mmol) and silver carbonate (17.1 g, 62.0 mmol) in The mixture in 1,4-dioxane (400 mL) was stirred at 70 °C for 20 h. Additional 6-chloropyridin-2-ol (1.61 g, 12.4 mmol) and silver carbonate (3.5 g, 13 mmol) were added and the mixture was stirred at 70°C for 5 h. The mixture was cooled to room temperature and filtered through a silica gel plug using DCM as eluent to give the title compound (24.6 g, 107%) as a light yellow solid. ES-MS m/z 371.0/373.0 (M+H).
製備 2214-[(6-氯-2-吡啶基)氧基甲基]-3-甲醯基-苯甲腈 向4-[(6-氯-2-吡啶基)氧基甲基]-3-碘-苯甲腈(15.0 g, 40.5 mmol)、1,4-二氮雜雙環[2.2.2]辛烷(460 mg, 4.06 mmol)及甲酸鉀(6.90 g, 81.2 mmol)於DMF (180 mL)中之混合物中添加第三丁基異氰化物(5.52 mL, 48.6 mmol)、甲烷磺酸根基(三-第三丁基膦基)(2'-甲基胺基-1,1'-聯苯-2-基)鈀(II) [P(t-Bu)3 Pd G4, 775 mg, 1.29 mmol]及四氟硼酸三-第三丁基鏻(360 mg, 1.22 mmol)。將混合物在75℃下攪拌23 h。將混合物冷卻至室溫並經由矽膠塞使用DMF作為洗脫劑來過濾。將濾液冷卻至0℃,添加1N HCl (120 mL)並在0℃下攪拌15 min。使用水(200 mL)稀釋反應混合物並在室溫下攪拌30 min。過濾所得固體以產生淺綠色固體形式之標題化合物(5.4 g,77%純度,37%產率)。ES-MS m/z273.0/275.0 (M+H)。 Preparation of 221 4-[(6-chloro-2-pyridyl)oxymethyl]-3-formyl-benzonitrile To 4-[(6-chloro-2-pyridyl)oxymethyl]-3-iodo-benzonitrile (15.0 g, 40.5 mmol), 1,4-diazabicyclo[2.2.2]octane (460 mg, 4.06 mmol) and potassium formate (6.90 g, 81.2 mmol) in DMF (180 mL) were added tert-butyl isocyanide (5.52 mL, 48.6 mmol), methanesulfonate (tri- tert-butylphosphino)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) [P(t-Bu)3PdG4, 775 mg, 1.29 mmol] and Tri-tert-butylphosphonium tetrafluoroborate (360 mg, 1.22 mmol). The mixture was stirred at 75 °C for 23 h. The mixture was cooled to room temperature and filtered through a silica gel plug using DMF as eluent. The filtrate was cooled to 0°C, 1N HCl (120 mL) was added and stirred at 0°C for 15 min. The reaction mixture was diluted with water (200 mL) and stirred at room temperature for 30 min. The resulting solid was filtered to yield the title compound (5.4 g, 77% purity, 37% yield) as a pale green solid. ES-MS m/z 273.0/275.0 (M+H).
製備 2224-[(6-氯-2-吡啶基)氧基甲基]-3-(羥甲基)苯甲腈 將4-[(6-氯-2-吡啶基)氧基甲基]-3-甲醯基-苯甲腈(1.0 g, 3.67 mmol)於MeOH (20 mL)中之溶液冷卻至0℃並逐份添加硼氫化鈉(290 mg, 7.26 mmol)。將混合物在室溫下攪拌30 min,然後冷卻至0℃。向混合物中添加水(25 mL),然後添加5%檸檬酸水溶液直至pH = 5,然後添加額外水(50 mL)。將反應混合物在室溫下攪拌30 min。過濾所得固體以產生白色固體形式之標題化合物(901 mg, 89%)。ES-MS m/z275.0/277.0 (M+H)。 Preparation of 222 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(hydroxymethyl)benzonitrile A solution of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-formyl-benzonitrile (1.0 g, 3.67 mmol) in MeOH (20 mL) was cooled to 0 °C and Sodium borohydride (290 mg, 7.26 mmol) was added in portions. The mixture was stirred at room temperature for 30 min, then cooled to 0 °C. Water (25 mL) was added to the mixture, followed by 5% aqueous citric acid until pH = 5, then additional water (50 mL). The reaction mixture was stirred at room temperature for 30 min. The resulting solid was filtered to yield the title compound (901 mg, 89%) as a white solid. ES-MS m/z 275.0/277.0 (M+H).
製備 2233-(溴甲基)-4-[(6-氯-2-吡啶基)氧基甲基]苯甲腈 在0℃下,冷卻4-[(6-氯-2-吡啶基)氧基甲基]-3-(羥甲基)苯甲腈(870 mg, 3.17 mmol)及三苯基膦(932 mg, 3.52 mmol)於DCM (20 mL)中之溶液。添加四溴化碳(920 mg, 2.77 mmol)並將反應混合物在室溫下攪拌30 min。經由二氧化矽塞使用DCM作為洗脫劑來過濾反應混合物以產生淺褐色固體形式之化合物(1.25 g;116%產率)。ES-MS m/z337.0/339.0/341.0 (M+H)。 Preparation of 223 3-(bromomethyl)-4-[(6-chloro-2-pyridyl)oxymethyl]benzonitrile At 0°C, cool 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(hydroxymethyl)benzonitrile (870 mg, 3.17 mmol) and triphenylphosphine (932 mg , 3.52 mmol) in DCM (20 mL). Carbon tetrabromide (920 mg, 2.77 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through a plug of silica using DCM as eluent to yield the compound as a beige solid (1.25 g; 116% yield). ES-MS m/z 337.0/339.0/341.0 (M+H).
製備 2242-[4-溴-2-[2-[[2-[(6-氯-2-吡啶基)氧基甲基]-5-氰基-苯基]甲氧基]乙基]-5-氟-苯基]乙酸乙酯 在室溫下攪拌2-[4-溴-5-氟-2-(2-羥乙基)苯基]乙酸乙酯(750 mg, 2.46 mmol)、3-(溴甲基)-4-[(6-氯-2-吡啶基)氧基甲基]苯甲腈(1.24 g, 3.67 mmol)及2,6-二-第三丁基吡啶(2.3 mL, 9.9 mmol)於DCM (13.0 mL)中之溶液。逐份添加三氟甲磺酸銀(2.60 g, 10.0 mmol)並將反應混合物在室溫下攪拌2 h。過濾混合物並使用DCM (50 mL)洗滌固體。在減壓下濃縮濾液溶劑。經由矽膠層析使用於DCM中之0 - 100% EtOAc之梯度來純化殘餘物以得到黃色固體形式之標題化合物(480 mg, 34%)。ES-MS m/z561/563 (M+H)。 Preparation 224 2-[4-bromo-2-[2-[[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]methoxy]ethyl] -5-Fluoro-phenyl] ethyl acetate 2-[4-Bromo-5-fluoro-2-(2-hydroxyethyl)phenyl]ethyl acetate (750 mg, 2.46 mmol), 3-(bromomethyl)-4-[ (6-Chloro-2-pyridyl)oxymethyl]benzonitrile (1.24 g, 3.67 mmol) and 2,6-di-tert-butylpyridine (2.3 mL, 9.9 mmol) in DCM (13.0 mL) solution in. Silver triflate (2.60 g, 10.0 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 2 h. The mixture was filtered and the solid was washed with DCM (50 mL). The filtrate solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in DCM to afford the title compound (480 mg, 34%) as a yellow solid. ES-MS m/z 561/563 (M+H).
製備 2252-[2-[2-[[2-[(6-氯-2-吡啶基)氧基甲基]-5-氰基-苯基]甲氧基]乙基]-5-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯 在氮鼓泡下,向2-[4-溴-2-[2-[[2-[(6-氯-2-吡啶基)氧基甲基]-5-氰基-苯基]甲氧基]乙基]-5-氟-苯基]乙酸乙酯(150 mg, 0.27 mmol)、雙(頻哪醇)二硼(60 mg, 0.23 mmol) KOAc (54 mg, 0.54 mmol)於1,4-二噁烷(2.5 mL)中之混合物中添加二氯雙(三環己基膦)鈀(II) (30 mg, 0.04 mmol)並將反應混合物在90℃下攪拌30 min。將反應混合物冷卻至室溫,在減壓下濃縮並經由過濾且經由矽膠塞使用於DCM中之0 - 100% EtOAc之梯度作為洗脫劑來純化殘餘物以得到淺白色固體形式之標題化合物(101 mg, 65%)。ES-MS m/z609/611 (M+H)。 Preparation of 225 2-[2-[2-[[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]methoxy]ethyl]-5-fluoro -4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]ethyl acetate 2-[4-Bromo-2-[2-[[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]methoxyl Base]ethyl]-5-fluoro-phenyl]ethyl acetate (150 mg, 0.27 mmol), bis(pinacol)diboron (60 mg, 0.23 mmol) KOAc (54 mg, 0.54 mmol) in 1, To the mixture in 4-dioxane (2.5 mL) was added dichlorobis(tricyclohexylphosphine)palladium(II) (30 mg, 0.04 mmol) and the reaction mixture was stirred at 90°C for 30 min. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was purified by filtration and through a silica gel plug using a gradient of 0-100% EtOAc in DCM as eluent to afford the title compound as an off-white solid ( 101 mg, 65%). ES-MS m/z 609/611 (M+H).
製備 2262-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯 向2-[2-[2-[[2-[(6-氯-2-吡啶基)氧基甲基]-5-氰基-苯基]甲氧基]乙基]-5-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯(160 mg, 0.26 mmol)於THF (9.0 mL)中之混合物中添加1N磷酸三鉀/水(1.30 mL, 1.30 mmol)及氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd G2, 21 mg, 0.03 mmol)且使氮鼓泡通過混合物,並將反應液在70℃下攪拌30 min。將反應混合物冷卻至室溫,然後添加MTBE (25 mL)及水(25 mL)。分離各相並使用MTBE (3 × 20 mL)萃取水相。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由硫酸鈉乾燥,過濾,並在減壓下濃縮。藉由矽膠層析使用於DCM中之0 - 100% EtOAc之梯度作為洗脫劑來純化殘餘物以得到白色固體形式之標題化合物(45 mg, 34%)。ES-MS m/z447.0 (M+H)。 Preparation of 226 2-(5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring nonafin-1 4 -yl) ethyl acetate To 2-[2-[2-[[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]methoxy]ethyl]-5-fluoro- Ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetate (160 mg, 0.26 mmol) in THF (9.0 mL) To the mixture was added 1N tripotassium phosphate/water (1.30 mL, 1.30 mmol) and chlorine (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-Amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 21 mg, 0.03 mmol) and nitrogen was bubbled through the mixture and the reaction was heated at 70°C Stir for 30 min. The reaction mixture was cooled to room temperature, then MTBE (25 mL) and water (25 mL) were added. The phases were separated and the aqueous phase was extracted with MTBE (3 x 20 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in DCM as eluent to afford the title compound (45 mg, 34%) as a white solid. ES-MS m/z 447.0 (M+H).
製備 2272-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 在氮鼓泡下,向2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯(91 mg, 0.24 mmol)於ACN (2.7 mL)、THF (0.90 mL)及水(0.90 mL中之混合物中逐份添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(96 mg, 0.67 mmol)並將反應液在45℃下攪拌1 h。將反應混合物冷卻至室溫,添加水(5 mL)、5%檸檬酸水溶液直至pH = 5並將混合物在室溫下攪拌15 min。過濾所得固體以產生白色固體形式之標題化合物(72 mg, 85%)。ES-MS m/z419.0 (M+H)。 Preparation of 227 2-(5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring nonafin-1 4 -yl)acetic acid 2-(5 4 -cyano-1 6 -fluoro-3,7-dioxa- 2 (2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclonafin-1 4 -yl)ethyl acetate (91 mg, 0.24 mmol) was added in portions to a mixture of ACN (2.7 mL), THF (0.90 mL) and water (0.90 mL) in 1,5 ,7-Triazabicyclo[4.4.0]dec-5-ene (96 mg, 0.67 mmol) and the reaction solution was stirred at 45°C for 1 h. The reaction mixture was cooled to room temperature, and water (5 mL) was added , 5% aqueous citric acid until pH = 5 and the mixture was stirred at room temperature for 15 min. The resulting solid was filtered to yield the title compound (72 mg, 85%) as a white solid. ES-MS m/z 419.0 (M+ h).
製備 228(S)-4-(2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-2-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(70 mg, 0.167 mmol)於DMF (2.5 mL)中之溶液中添加 4-胺基-3-甲氧基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(50 mg, 0.19 mmol)、HATU (96 mg, 0.25 mmol)及DIPEA (0.1 mL, 0.60 mmol,)。將混合物在室溫下攪拌2 h,然後添加水(10 mL)及EtOAc (10 mL)。分離各相並使用EtOAc (3 × 10 mL)萃取水相。合併有機物,使用2 M Na 2CO 3水溶液、水及飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮以得到褐色固體形式之標題化合物(193 mg,48%純度,83%產率),其未經進一步純化即用於製備229。ES-MS m/z667.2 (M+H)。 Preparation of 228 (S)-4-(2-(5 4 -cyano- 1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclononarfin-1 4 -yl)acetamido)-2-methoxy-5-(((epoxypropane-2-ylmethyl)amino)benzoic acid methyl ester To 2-(5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclone To a solution of fen- 14 -yl)acetic acid (70 mg, 0.167 mmol) in DMF (2.5 mL) was added 4-amino-3-methoxy-5-[[(2S)-propylene oxide-2 -yl]methylamino]benzoate (50 mg, 0.19 mmol), HATU (96 mg, 0.25 mmol) and DIPEA (0.1 mL, 0.60 mmol,). The mixture was stirred at room temperature for 2 h, then water (10 mL) and EtOAc (10 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The organics were combined, washed with 2 M aq. Na2CO3 , water and saturated aq. NaCl , dried over Na2SO4 , filtered and concentrated under reduced pressure to give the title compound as a brown solid (193 mg, 48% purity, 83% yield), which was used in the preparation of 229 without further purification. ES-MS m/z 667.2 (M+H).
製備 229(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將(S)-4-(2-(5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-2-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備228,190 mg, 0.28 mmol)於1,2-二氯乙烷(3.0 mL)及乙酸(1.5 mL)中之溶液在60℃下加熱6 h。將反應混合物冷卻至室溫,在減壓下濃縮溶劑,並經由矽膠層析使用於DCM中之0 - 100% EtOAc之梯度來純化殘餘物以得到白色固體形式之標題化合物(58 mg, 31%)。ES-MS m/z649.2/650.2 (M+H)。 Preparation of 229 (S)-2-((5 4 -cyano- 1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ester (S)-4-(2-(5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1, 2)-Diphenylcyclononarfin- 14 -yl)acetamido)-2-methoxy-5-(((epoxypropan-2-ylmethyl)amino)methyl benzoate (Preparation 228 , 190 mg, 0.28 mmol) in 1,2-dichloroethane (3.0 mL) and acetic acid (1.5 mL) was heated at 60°C for 6 h. The reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in DCM to give the title compound as a white solid (58 mg, 31% ). ES-MS m/z 649.2/650.2 (M+H).
製備 2302-溴-4-氯-6-氟-苯甲醛 在-45℃下向1,2-二溴-5-氯-3-氟苯(50 g, 170 mmol)於庚烷(130 mL)及THF (210 mL)中之溶液中逐滴添加異丙基氯化鎂(於THF中之2 M溶液,94 mL, 188 mmol)且保持內部反應溫度介於-40℃與-45℃之間。在-40℃下攪拌30 min,然後逐滴添加DMF (66 mL, 853 mmol)並在-20℃下攪拌1 h。將反應混合物升溫至0℃,添加1 N HCl直至pH = 7並使用EtOAc (3 × 300 mL)萃取。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之0 - 12% EtOAc之梯度來純化殘餘物以得到黃色固體形式之標題化合物(22.70 g, 52%)。ES-MS m/z238 (M+H)。 Preparation 230 2-Bromo-4-chloro-6-fluoro-benzaldehyde To a solution of 1,2-dibromo-5-chloro-3-fluorobenzene (50 g, 170 mmol) in heptane (130 mL) and THF (210 mL) was added isopropyl dropwise at -45 °C Magnesium chloride (2 M solution in THF, 94 mL, 188 mmol) and maintain the internal reaction temperature between -40 °C and -45 °C. Stir at -40°C for 30 min, then add DMF (66 mL, 853 mmol) dropwise and stir at -20°C for 1 h. The reaction mixture was warmed to 0 °C, 1 N HCl was added until pH = 7 and extracted with EtOAc (3 x 300 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-12% EtOAc in petroleum ether to afford the title compound (22.70 g, 52%) as a yellow solid. ES-MS m/z 238 (M+H).
製備 231(2-溴-4-氯-6-氟-苯基)甲醇 在0℃下,將硼氫化鈉(5.16 g, 134 mmol)添加至2-溴-4-氯-6-氟-苯甲醛(22.70 g, 89.88 mmol)於MeOH (240 mL)中之溶液中。在室溫下攪拌2 h。冷卻至0℃並添加1N HCl直至pH = 7,濃縮大部分溶劑並使用EtOAc (3 × 150 mL)萃取混合物。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮以提供橙色固體形式之標題化合物(22.3 g, 88%)。ES-MS m/z263 (M+Na)。 Preparation of 231 (2-bromo-4-chloro-6-fluoro-phenyl)methanol Sodium borohydride (5.16 g, 134 mmol) was added to a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde (22.70 g, 89.88 mmol) in MeOH (240 mL) at 0 °C. Stir at room temperature for 2 h. Cooled to 0 °C and added 1N HCl until pH = 7, concentrated most of the solvent and extracted the mixture with EtOAc (3 x 150 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford the title compound (22.3 g, 88%) as an orange solid. ES-MS m/z 263 (M+Na).
製備 2321-溴-2-(溴甲基)-5-氯-3-氟-苯 在0℃下,向(2-溴-4-氯-6-氟-苯基)甲醇(22.3 g, 79.2 mmol)於DCM (220 mL)中之溶液中逐滴添加三溴化磷(7.51 mL, 79.2 mmol)。使反應混合物達到室溫並攪拌2 h。在減壓下濃縮溶劑並經由矽膠層析使用於石油醚中之0 - 2% EtOAc之梯度來純化殘餘物以得到無色油狀物形式之標題化合物(26.83 g, 95%)。 1H-NMR (400 MHz, DMSO- d 6) δ 7.75 (t, J= 2 Hz, 1H), 7.63 (dd, J= 9.5, 2 Hz, 1H), 4.70 (d, J= 2 Hz, 2H)。 Preparation of 232 1-bromo-2-(bromomethyl)-5-chloro-3-fluoro-benzene To a solution of (2-bromo-4-chloro-6-fluoro-phenyl)methanol (22.3 g, 79.2 mmol) in DCM (220 mL) was added phosphorus tribromide (7.51 mL) dropwise at 0 °C. , 79.2 mmol). The reaction mixture was allowed to reach room temperature and stirred for 2 h. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-2% EtOAc in petroleum ether to give the title compound (26.83 g, 95%) as a colorless oil. 1 H-NMR (400 MHz, DMSO- d 6 ) δ 7.75 (t, J = 2 Hz, 1H), 7.63 (dd, J = 9.5, 2 Hz, 1H), 4.70 (d, J = 2 Hz, 2H ).
製備 2332-[(2-溴-4-氯-6-氟-苯基)甲氧基]-6-氯-吡啶 向1-溴-2-(溴甲基)-5-氯-3-氟-苯(34.1 g, 107 mmol)及2-氯-6-羥基吡啶(57 g, 431 mmol)於ACN (1000 mL)中之溶液中添加碳酸銀(180 g, 653 mmol)。將反應混合物在40℃下攪拌36 h。將混合物冷卻至室溫,然後過濾並在減壓下濃縮濾液。經由矽膠層析使用於石油醚中之0 - 5% EtOAc之梯度來純化殘餘物以提供白色固體形式之標題化合物(22.8 g, 52%)。ES-MS m/z350/352 (M+H)。 Preparation 233 2-[(2-Bromo-4-chloro-6-fluoro-phenyl)methoxy]-6-chloro-pyridine Add 1-bromo-2-(bromomethyl)-5-chloro-3-fluoro-benzene (34.1 g, 107 mmol) and 2-chloro-6-hydroxypyridine (57 g, 431 mmol) in ACN (1000 mL ) was added to the solution in silver carbonate (180 g, 653 mmol). The reaction mixture was stirred at 40 °C for 36 h. The mixture was cooled to room temperature, then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-5% EtOAc in petroleum ether to afford the title compound (22.8 g, 52%) as a white solid. ES-MS m/z 350/352 (M+H).
製備 2342-氯-6-[[4-氯-2-[(E)-2-乙氧基乙烯基]-6-氟-苯基]甲氧基]吡啶 在氮下,向2-[(2-溴-4-氯-6-氟-苯基)甲氧基]-6-氯-吡啶(20.8 g, 50.4 mmol)及碳酸銫(33 g, 101 mmol)於1,4-二噁烷(200 mL)中之混合物中添加2-[(E)-2-乙氧基乙烯基]-4,4,5,5-四甲基-1,3,2-二氧硼㖦(11.8 mL, 55.4 mmol),然後添加四(三苯基膦)鈀(0) (6.13 g, 5.0 mmol)。將反應液在90℃下加熱12 h,然後添加額外之2-[(E)-2-乙氧基乙烯基]-4,4,5,5-四甲基-1,3,2-二氧硼㖦(5.4 mL, 25 mmol)及四(三苯基膦)鈀(0) (3.1 g, 2.5 mmol)。將混合物在90℃下再攪拌4 h。將混合物冷卻至室溫並在減壓下濃縮,然後添加水(150 mL)並使用EtOAc (3 × 150 mL)萃取。合併有機物,藉由Na 2SO 4乾燥,過濾,並在減壓下蒸發。經由矽膠層析使用於石油醚中之0 - 20% DCM之梯度來純化殘餘物以得到白色固體形式之標題化合物(13.71 g, 70%)。ES-MS m/z342 (M+H)。 Preparation 234 2-chloro-6-[[4-chloro-2-[(E)-2-ethoxyvinyl]-6-fluoro-phenyl]methoxy]pyridine Under nitrogen, 2-[(2-bromo-4-chloro-6-fluoro-phenyl)methoxy]-6-chloro-pyridine (20.8 g, 50.4 mmol) and cesium carbonate (33 g, 101 mmol ) to a mixture in 1,4-dioxane (200 mL) was added 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3, 2-Dioxaboronium (11.8 mL, 55.4 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (6.13 g, 5.0 mmol). The reaction solution was heated at 90°C for 12 h, and then additional 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-di Oxyboron (5.4 mL, 25 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.1 g, 2.5 mmol). The mixture was stirred at 90 °C for another 4 h. The mixture was cooled to room temperature and concentrated under reduced pressure, then water (150 mL) was added and extracted with EtOAc (3 x 150 mL). The organics were combined, dried over Na2SO4 , filtered, and evaporated under reduced pressure . The residue was purified by silica gel chromatography using a gradient of 0-20% DCM in petroleum ether to afford the title compound (13.71 g, 70%) as a white solid. ES-MS m/z 342 (M+H).
製備 2352-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]-3-氟-苯基]乙醇 在0℃下,向2-氯-6-[[4-氯-2-[(E)-2-乙氧基乙烯基]-6-氟-苯基]甲氧基]吡啶(12.7 g, 35.3 mmol)於THF (280 mL)及水(280 mL)中之溶液中添加乙酸汞(37.53 g, 117.8 mmol)並在0℃下攪拌3 h。在0℃下將50% K 2CO 3水溶液(190 mL)及硼氫化鈉(6 g, 158.59 mmol)添加至混合物中,然後在0℃下攪拌3 h。將水(200mL)添加至混合物中並使用EtOAc (3 × 500 mL)萃取。合併有機物,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之0 - 25% EtOAc之梯度來純化殘餘物以得到無色油狀物形式之標題化合物(9.46 g, 78%)。ES-MS m/z316 (M+H)。 Preparation of 235 2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-fluoro-phenyl]ethanol At 0°C, 2-chloro-6-[[4-chloro-2-[(E)-2-ethoxyvinyl]-6-fluoro-phenyl]methoxy]pyridine (12.7 g, To a solution of 35.3 mmol) in THF (280 mL) and water (280 mL) was added mercuric acetate (37.53 g, 117.8 mmol) and stirred at 0°C for 3 h. Aqueous 50% K 2 CO 3 (190 mL) and sodium borohydride (6 g, 158.59 mmol) were added to the mixture at 0°C, then stirred at 0°C for 3 h. Water (200 mL) was added to the mixture and extracted with EtOAc (3 x 500 mL). The organics were combined, dried over Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-25% EtOAc in petroleum ether to afford the title compound (9.46 g, 78%) as a colorless oil. ES-MS m/z 316 (M+H).
製備 2361-溴-5-(溴甲基)-2-氟-4-碘苯 製備5-溴-4-氟-2-碘甲苯(50.2 g, 156 mmol)及N-溴琥珀醯亞胺(29.2 g, 164 mmol)於ACN (0.8 L)中之溶液。以介於2 mL/min與3 mL/min之間之流速流經由盤繞PFA反應管(1/8’’ o.d.,52 mL體積)組成之光化學反應器,該反應管維持在40℃下且由4個Kessil PR160-370 nm (40 W)燈及4個Evoluchem 450 nm (30 W)燈之陣列環繞。在完成後,使ACN (60 mL)以相同速率流經反應器。攪拌反應器輸出物,並添加20%亞硫酸氫鈉水溶液(0.2 L)且然後添加水直至最終體積為2 L。將所得漿液在環境溫度下攪拌30 min。藉由過濾收集固體並使用水(0.5 L)洗滌。將濾餅溶於EtOAc (0.1 L)及庚烷(0.4 L)之混合物中並使用50 mL份量之水、NaHCO 3飽和水溶液及飽和NaCl水溶液洗滌有機層,然後藉由MgSO 4乾燥並過濾。在減壓及50℃下濃縮濾液以提供35.19 g奶油色固體形式之標題化合物(53%,93%純度)。 1H-NMR (400 MHz, CDCl 3) δ 7.65 (d, J= 6.8 Hz, 1H), 7.60 ( J= 7.6 Hz, 1H), 4.51 (s, 2H)。 19F{1H}-NMR (386.5 MHz, CDCl3) -105.55 (s)。 Preparation of 236 1-bromo-5-(bromomethyl)-2-fluoro-4-iodobenzene A solution of 5-bromo-4-fluoro-2-iodotoluene (50.2 g, 156 mmol) and N-bromosuccinimide (29.2 g, 164 mmol) in ACN (0.8 L) was prepared. Flow through a photochemical reactor consisting of a coiled PFA reaction tube (1/8'' od, 52 mL volume) at a flow rate between 2 mL/min and 3 mL/min, which is maintained at 40°C and Surrounded by an array of 4 Kessil PR160-370 nm (40 W) lamps and 4 Evoluchem 450 nm (30 W) lamps. Upon completion, ACN (60 mL) was flowed through the reactor at the same rate. The reactor output was stirred and 20% aqueous sodium bisulfite (0.2 L) was added and then water was added to a final volume of 2 L. The resulting slurry was stirred at ambient temperature for 30 min. The solid was collected by filtration and washed with water (0.5 L). The filter cake was dissolved in a mixture of EtOAc (0.1 L) and heptane (0.4 L) and the organic layer was washed with 50 mL portions of water, saturated aqueous NaHCO 3 and saturated aqueous NaCl, then dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure at 50°C to afford 35.19 g of the title compound (53%, 93% purity) as a cream solid. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.65 (d, J = 6.8 Hz, 1H), 7.60 ( J = 7.6 Hz, 1H), 4.51 (s, 2H). 19 F{1H}-NMR (386.5 MHz, CDCl3) -105.55 (s).
製備 2372-[[2-[2-[(5-溴-4-氟-2-碘-苯基)甲氧基]乙基]-4-氯-6-氟-苯基]甲氧基]-6-氯-吡啶 將三氟甲磺酸銀(8.30 g, 32 mmol)添加至2-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]-3-氟-苯基]乙醇(5.5 g, 16.0 mmol)、1-溴-5-(溴甲基)-2-氟-4-碘苯(10.85 g, 24.80 mmol)及2,6-二第三丁基-4-甲基吡啶(5 g, 24 mmol)於DCM (30 mL)中之溶液中。將反應液在室溫下攪拌5 h。經由Celite ®過濾反應混合物,使用水(100 mL)稀釋並使用EtOAc (3 × 100 mL)萃取。合併有機物,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之0 - 6% EtOAc之梯度來純化殘餘物以得到無色油狀物形式之標題化合物(8.51 g, 76%)。ES-MS m/z628/630 (M+H)。 Preparation 237 2-[[2-[2-[(5-bromo-4-fluoro-2-iodo-phenyl)methoxy]ethyl]-4-chloro-6-fluoro-phenyl]methoxy ]-6-chloro-pyridine Silver triflate (8.30 g, 32 mmol) was added to 2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-fluoro-phenyl]ethanol (5.5 g, 16.0 mmol), 1-bromo-5-(bromomethyl)-2-fluoro-4-iodobenzene (10.85 g, 24.80 mmol) and 2,6-di-tert-butyl-4-methyl In a solution of pyridine (5 g, 24 mmol) in DCM (30 mL). The reaction solution was stirred at room temperature for 5 h. The reaction mixture was filtered through Celite® , diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organics were combined, dried over Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-6% EtOAc in petroleum ether to afford the title compound (8.51 g, 76%) as a colorless oil. ES-MS m/z 628/630 (M+H).
製備 2382-[4-溴-2-[2-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]-3-氟-苯基]乙氧基甲基]-5-氟-苯基]乙酸乙酯 在氮下,向2-[[2-[2-[(5-溴-4-氟-2-碘-苯基)甲氧基]乙基]-4-氯-6-氟-苯基]甲氧基]-6-氯-吡啶(1.49 g, 1.94 mmol)及氯[(4,5-雙(二苯基膦基)-9,9-二甲基呫噸)-2-(2′-胺基-1,1′-聯苯)]鈀(II) (Xantphos-Pd-G2, 0.2 g, 0.2 mmol)於THF (7 mL)中之混合物中添加(2-乙氧基-2-側氧基乙基))溴化鋅(0.5 M於THF中,8 mL, 4 mmol)。將混合物在微波反應器中於65℃下加熱2 h。將混合物冷卻至室溫,添加飽和NH 4Cl水溶液(30 mL),然後使用水(30 mL)稀釋並使用EtOAc (3 × 50 mL)萃取。合併有機物,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之0 - 15% EtOAc之梯度來純化殘餘物以提供0.57 g (45%)無色油狀物形式之標題化合物。ES-MS m/z588/590 (M+H)。 Preparation of 238 2-[4-bromo-2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-fluoro-phenyl]ethoxymethyl ]-5-Fluoro-phenyl] ethyl acetate Under nitrogen, to 2-[[2-[2-[(5-bromo-4-fluoro-2-iodo-phenyl)methoxy]ethyl]-4-chloro-6-fluoro-phenyl] Methoxy]-6-chloro-pyridine (1.49 g, 1.94 mmol) and chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′ -Amino-1,1′-biphenyl)]palladium(II) (Xantphos-Pd-G2, 0.2 g, 0.2 mmol) in THF (7 mL) was added (2-ethoxy-2- Oxyethyl)) zinc bromide (0.5 M in THF, 8 mL, 4 mmol). The mixture was heated at 65 °C for 2 h in a microwave reactor. The mixture was cooled to room temperature, saturated aqueous NH4Cl (30 mL) was added, then diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The organics were combined, dried over Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-15% EtOAc in petroleum ether to afford 0.57 g (45%) of the title compound as a colorless oil. ES-MS m/z 588/590 (M+H).
製備 2392-(5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯 在氮下,向2-[4-溴-2-[2-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]-3-氟-苯基]乙氧基甲基]-5-氟-苯基]乙酸乙酯(1.43 g, 2.19 mmol)、2,2-二甲基丙酸鉀(0.78 g, 5.49 mmol)及雙(頻哪醇)二硼(0.8 g, 3 mmol)於THF (85 mL)中之溶液中添加氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd G2, 176 mg, 0.21 mmol)。將反應液在55℃下加熱4 h。將於水(6.57 mL)中之磷酸三鉀(1.42 g, 6.57 mmol)添加至反應液中並在55℃下加熱2 h。將混合物冷卻至室溫,添加水(30 mL),並使用EtOAc (3 × 100 mL)萃取。合併有機物,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之0 - 15% EtOAc之梯度來純化殘餘物以得到灰棕色固體形式之標題化合物(308 mg, 27%)。ES-MS m/z474 (M+H)。 Preparation 239 2-(5 4 -chloro-1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)- Diphenylcyclonafin-1 4 -yl) ethyl acetate Under nitrogen, to 2-[4-bromo-2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-fluoro-phenyl]ethoxy Methyl]-5-fluoro-phenyl] ethyl acetate (1.43 g, 2.19 mmol), potassium 2,2-dimethylpropionate (0.78 g, 5.49 mmol) and bis(pinacol) diboron ( To a solution of 0.8 g, 3 mmol) in THF (85 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[ 2-(2'-Amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 176 mg, 0.21 mmol). The reaction solution was heated at 55 °C for 4 h. Tripotassium phosphate (1.42 g, 6.57 mmol) in water (6.57 mL) was added to the reaction and heated at 55 °C for 2 h. The mixture was cooled to room temperature, water (30 mL) was added, and extracted with EtOAc (3 x 100 mL). The organics were combined, dried over Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-15% EtOAc in petroleum ether to give the title compound (308 mg, 27%) as a beige solid. ES-MS m/z 474 (M+H).
製備 2402-(5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 基本上如製備227中所闡述使用2-(5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯來製備標題化合物。ES-MS m/z446 (M+H)。 Preparation 240 2-(5 4 -chloro-1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)- Diphenylcyclonafin-1 4 -yl)acetic acid Using 2-(5 4 -chloro-1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3) essentially as described in Preparation 227, 5(1,2)-Diphenylcyclononan-1 4 -yl) ethyl acetate to prepare the title compound. ES-MS m/z 446 (M+H).
製備 241(S)-4-(2-(5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 在氮下,向2-(5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(245 mg, 0.54 mmol)及HATU (356 mg, 0.91 mmol)於DMF (5.4 mL)中之溶液中添加 4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(242 mg, 0.70 mmol)及DIPEA (0.28 mL, 1.62 mmol)。將混合物在室溫下攪拌2 h,然後添加水(10 mL)並使用EtOAc (3 × 25 mL)萃取。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮以提供白色固體形式之標題化合物(594 mg,34%純度),其未經進一步純化即用於製備242。ES-MS m/z738 (M+H)。 Preparation of 241 (S)-4-(2-(5 4 -chloro-1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclononafin-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-((epoxypropan-2-ylmethyl ) amino) methyl benzoate Under nitrogen, to 2-(5 4 -chloro-1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1, 2) To a solution of -diphenylcyclonafin-1 4 -yl)acetic acid (245 mg, 0.54 mmol) and HATU (356 mg, 0.91 mmol) in DMF (5.4 mL) was added 4-amino-3-( Methyl 2-methoxyethoxy)-5-[[(2S)-epoxypropan-2-yl]methylamino]benzoate (242 mg, 0.70 mmol) and DIPEA (0.28 mL, 1.62 mmol ). The mixture was stirred at room temperature for 2 h, then water (10 mL) was added and extracted with EtOAc (3 x 25 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over Na2SO4 , filtered, and concentrated under reduced pressure to afford the title compound (594 mg, 34% purity) as a white solid which was obtained without further purification. Used in the preparation of 242. ES-MS m/z 738 (M+H).
製備 242(S)-2-((5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯在1:1 1,2-二氯乙烷:乙酸(作為溶劑)中來製備標題化合物,其中將反應液在60℃下加熱6 h。將反應混合物冷卻至室溫,在減壓下蒸發溶劑,添加EtOAc/甲苯(1:1)以幫助去除濃縮物中之乙酸。經由矽膠層析使用於DCM中之0 - 5% MeOH之梯度來純化殘餘物以得到淺黃色固體形式之標題化合物(64%純度)。ES-MS m/z720 (M+H)。 Preparation of 242 (S)-2-((5 4 -chloro- 1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropan-2-ylmethyl)-1H-benzene And[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-(5 4 -chloro-1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine- 1(1,3),5(1,2)-Diphenylcyclononafin-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-((epoxy The title compound was prepared from propan-2-ylmethyl)amino)methyl benzoate in 1:1 1,2-dichloroethane:acetic acid (as solvent), where the reaction was heated at 60 °C for 6 h . The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, EtOAc/toluene (1:1) was added to help remove acetic acid from the concentrate. The residue was purified by silica gel chromatography using a gradient of 0-5% MeOH in DCM to afford the title compound (64% purity) as a pale yellow solid. ES-MS m/z 720 (M+H).
製備 2432-溴-6-(溴甲基)菸鹼甲腈 將2-溴-6-甲基菸鹼甲腈(23 g, 113.2 mmol)及N-溴琥珀醯亞胺(30.8 g, 170 mmol)於ACN (560 mL)中之溶液轉移通過配備有440-460 nM、200W燈之光化學流動反應器(反應器大小= 15 m,15 mL,流速= 1 mL/min,25℃)。蒸發反應溶劑並將殘餘物分配於水與DCM之間。分離有機層,使用飽和NaCl水溶液洗滌,藉由無水Na 2SO 4乾燥,過濾並去除溶劑。將殘餘物溶於THF (400 mL)中,在N 2及0℃下添加亞磷酸二乙酯(8.63 mL, 65.8 mmol)及DIPEA (17.8 mL, 99.0 mmol)並保持0.5 h。將反應混合物升溫至室溫並攪拌過夜以得到黑色溶液。將反應混合物分配於水與EtOAc之間。分離有機層,使用飽和NaCl水溶液洗滌,藉由無水Na 2SO 4乾燥,過濾並在減壓下濃縮。藉由矽膠層析使用於石油醚中之0 - 25% EtOAc之梯度來純化殘餘物以提供白色固體形式之標題化合物(28.45 g, 84%)。ES-MS m/z275, 277, 279 (M+H)。 Preparation of 243 2-bromo-6-(bromomethyl)nicotine carbonitrile A solution of 2-bromo-6-methylnicotinecarbonitrile (23 g, 113.2 mmol) and N-bromosuccinimide (30.8 g, 170 mmol) in ACN (560 mL) was transferred through a 440- Photochemical flow reactor with 460 nM, 200W lamp (reactor size = 15 m, 15 mL, flow rate = 1 mL/min, 25°C). The reaction solvent was evaporated and the residue was partitioned between water and DCM. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4 , filtered and the solvent was removed. The residue was dissolved in THF (400 mL), diethyl phosphite (8.63 mL, 65.8 mmol) and DIPEA (17.8 mL, 99.0 mmol) were added under N 2 at 0 °C for 0.5 h. The reaction mixture was warmed to room temperature and stirred overnight to give a black solution. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by silica gel chromatography using a gradient of 0-25% EtOAc in petroleum ether to afford the title compound (28.45 g, 84%) as a white solid. ES-MS m/z 275, 277, 279 (M+H).
製備 2442-溴-6-[(6-氯-2-吡啶基)氧基甲基]吡啶-3-甲腈 在室溫下,將碳酸銀(10.5 g, 37.3 mmol)添加至2-溴-6-(溴甲基)菸鹼甲腈(1.84 g, 6.33 mmol)及2-氯-6-羥基吡啶(3.35 g, 25.3 mmol)於ACN (150 mL)中之溶液中。將混合物在60℃下攪拌48 h。過濾掉固體並在減壓下濃縮濾液。藉由矽膠層析使用於石油醚中之0 - 23% EtOAc之梯度來純化殘餘物以提供白色固體形式之標題化合物(957 mg,91 wt%純,42%)。ES-MS m/z324, 326, 328 (M+H)。 Preparation of 244 2-bromo-6-[(6-chloro-2-pyridyl)oxymethyl]pyridine-3-carbonitrile Silver carbonate (10.5 g, 37.3 mmol) was added to 2-bromo-6-(bromomethyl)nicotinecarbonitrile (1.84 g, 6.33 mmol) and 2-chloro-6-hydroxypyridine (3.35 g, 25.3 mmol) in ACN (150 mL). The mixture was stirred at 60 °C for 48 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-23% EtOAc in petroleum ether to afford the title compound (957 mg, 91 wt% pure, 42%) as a white solid. ES-MS m/z 324, 326, 328 (M+H).
製備 2456-[(6-氯-2-吡啶基)氧基甲基]-2-[(E)-2-乙氧基乙烯基]吡啶-3-甲腈 將2-[(E)-2-乙氧基乙烯基]-4,4,5,5-四甲基-1,3,2-二氧硼㖦(13.5 mL, 63.4 mmol)及1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II) DCM複合物(4.7 g, 5.65 mmol)添加至2-溴-6-[(6-氯-2-吡啶基)氧基甲基]吡啶-3-甲腈(20.4 g, 56.6 mmol,91 wt%純)及磷酸三鉀(24.5 g, 113 mmol)於1,4-二噁烷(200 mL)及水(60 mL)中之混合物中。使用氮吹掃混合物並在90℃下攪拌4 h。將混合物冷卻至室溫,使用水(250mL)稀釋並使用EtOAc (250 mL × 4)萃取。合併有機層,藉由無水Na 2SO 4乾燥,過濾並去除溶劑。藉由矽膠層析使用於石油醚中之0 - 20% EtOAc之梯度來純化殘餘物以提供黃色固體形式之標題化合物(15.7g,83 wt%純度,73%)。ES-MS m/z316, 318 (M+H)。 Preparation of 245 6-[(6-chloro-2-pyridyl)oxymethyl]-2-[(E)-2-ethoxyvinyl]pyridine-3-carbonitrile 2-[(E)-2-Ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaboroxane (13.5 mL, 63.4 mmol) and 1,1 '-Bis(diphenylphosphino)ferrocene-palladium(II) chloride DCM complex (4.7 g, 5.65 mmol) was added to 2-bromo-6-[(6-chloro-2-pyridyl) Oxymethyl]pyridine-3-carbonitrile (20.4 g, 56.6 mmol, 91 wt% pure) and tripotassium phosphate (24.5 g, 113 mmol) in 1,4-dioxane (200 mL) and water (60 mL) in the mixture. The mixture was purged with nitrogen and stirred at 90 °C for 4 h. The mixture was cooled to room temperature, diluted with water (250 mL) and extracted with EtOAc (250 mL x 4). The organic layers were combined, dried over anhydrous Na2SO4 , filtered and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0-20% EtOAc in petroleum ether to afford the title compound (15.7 g, 83 wt% purity, 73%) as a yellow solid. ES-MS m/z 316, 318 (M+H).
製備 2466-[(6-氯-2-吡啶基)氧基甲基]-2-(2-羥乙基)吡啶-3-甲腈 基本上如製備235中所闡述使用6-[(6-氯-2-吡啶基)氧基甲基]-2-[(E)-2-乙氧基乙烯基]吡啶-3-甲腈來製備標題化合物。在完成反應後,過濾掉固體並使用EtOAc洗滌。對於濾液而言,分離有機層並使用EtOAc將水層萃取三次。合併有機層,藉由無水Na 2SO 4乾燥,然後過濾並在減壓下濃縮。藉由矽膠層析使用於石油醚中之0 - 45% EtOAc之梯度來純化殘餘物以提供淺黃色固體形式之標題化合物。ES-MS m/z290, 292 (M+H)。 Preparation of 246 6-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)pyridine-3-carbonitrile Using 6-[(6-chloro-2-pyridyl)oxymethyl]-2-[(E)-2-ethoxyvinyl]pyridine-3-carbonitrile essentially as described in Preparation 235 Preparation of the title compound. After completion of the reaction, the solid was filtered off and washed with EtOAc. For the filtrate, the organic layer was separated and the aqueous layer was extracted three times with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 , then filtered and concentrated under reduced pressure . The residue was purified by silica gel chromatography using a gradient of 0-45% EtOAc in petroleum ether to afford the title compound as a pale yellow solid. ES-MS m/z 290, 292 (M+H).
製備 2472-[4-溴-2-[2-[6-[(6-氯-2-吡啶基)氧基甲基]-3-氰基-2-吡啶基]乙氧基甲基]苯基]乙酸甲酯 基本上如製備224中所闡述使用6-[(6-氯-2-吡啶基)氧基甲基]-2-(2-羥乙基)吡啶-3-甲腈及2-[4-溴-2-(溴甲基)苯基]乙酸甲酯來製備標題化合物,其中將反應液在40℃下攪拌過夜。在完成反應後,在減壓下去除ACN,使用水稀釋殘餘物並使用EtOAc萃取。藉由無水Na 2SO 4乾燥有機物,過濾,並濃縮。藉由製備型HPLC [管柱:Phenomenex Luna C18 250 × 50 mm, 10 µm;移動相:於甲酸水溶液(0.225%)中之40 - 85% ACN]純化殘餘物以提供淺黃色蠟狀固體形式之標題化合物。ES-MS m/z530, 532, 534 (M+H)。 Preparation 247 2-[4-bromo-2-[2-[6-[(6-chloro-2-pyridyl)oxymethyl]-3-cyano-2-pyridyl]ethoxymethyl] Methyl phenyl]acetate Using 6-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)pyridine-3-carbonitrile and 2-[4-bromonitrile essentially as described in Preparation 224 -2-(Bromomethyl)phenyl]acetic acid methyl ester to prepare the title compound, wherein the reaction solution was stirred at 40° C. overnight. After completion of the reaction, ACN was removed under reduced pressure, the residue was diluted with water and extracted with EtOAc. The organics were dried over anhydrous Na2SO4 , filtered, and concentrated. The residue was purified by preparative HPLC [column: Phenomenex Luna C18 250 × 50 mm, 10 µm; mobile phase: 40 - 85% ACN in aqueous formic acid (0.225%)] to afford the product as a pale yellow waxy solid. title compound. ES-MS m/z 530, 532, 534 (M+H).
製備 2482-(5 5-氰基-3,8-二氧雜-2,5(2,6)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸甲酯 基本上如述製備216中所闡使用2-[4-溴-2-[2-[6-[(6-氯-2-吡啶基)氧基甲基]-3-氰基-2-吡啶基]乙氧基甲基]苯基]乙酸甲酯作為起始材料且使用(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]甲磺酸鈀(II) (XPhos Pd G3)作為觸媒來製備標題化合物,其中將反應液加熱至110℃過夜。在反應完成時,濃縮反應混合物,添加水,並使用EtOAc萃取三次。藉由Na 2SO 4乾燥合併之有機物,過濾,並濃縮。藉由HPLC [管柱:Welch Xtimate C18 150 × 40 mm, 10 µm;移動相:於甲酸水溶液(0.225%)中之40 - 80% ACN]來純化殘餘物以提供白色固體形式之標題化合物。ES-MS m/z416 (M+H)。 Preparation of 248 2-(5 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridine-1(1,3)-phenylcyclononan-1 4 -yl)acetic acid methyl ester Using 2-[4-bromo-2-[2-[6-[(6-chloro-2-pyridyl)oxymethyl]-3-cyano-2-pyridine essentially as described in Preparation 216 base]ethoxymethyl]phenyl]acetate as starting material and using (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl )[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3) was used as catalyst to prepare the title compound, wherein the reaction solution was heated to 110°C overnight. When the reaction was complete, the reaction mixture was concentrated, water was added, and extracted three times with EtOAc. The combined organics were dried over Na2SO4 , filtered, and concentrated . The residue was purified by HPLC [column: Welch Xtimate C18 150 x 40 mm, 10 µm; mobile phase: 40-80% ACN in aqueous formic acid (0.225%)] to afford the title compound as a white solid. ES-MS m/z 416 (M+H).
製備 2492-(5 5-氰基-3,8-二氧雜-2,5(2,6)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸 基本上如製備78中所闡述使用2-(5 5-氰基-3,8-二氧雜-2,5(2,6)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物。在反應完成時,去除有機溶劑並添加水及檸檬酸水溶液(1 M)以使pH達到5-6。過濾所得固體並使用水洗滌以提供白色固體形式之標題化合物。ES-MS m/z402 (M+H)。 Preparation of 249 2-(5 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridine-1(1,3)-phenylcyclononan- 1 4 -yl)acetic acid Using 2-( 55 -cyano-3,8-dioxa-2,5(2,6)-bipyridine-1(1,3)-phenylcyclonazone- 1 4 -yl)methyl acetate to prepare the title compound. When the reaction was complete, the organic solvent was removed and water and aqueous citric acid (1 M) were added to bring the pH to 5-6. The resulting solid was filtered and washed with water to afford the title compound as a white solid. ES-MS m/z 402 (M+H).
製備 250(S)-4-(2-(5 5-氰基-3,8-二氧雜-2,5(2,6)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 5-氰基-3,8-二氧雜-2,5(2,6)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙酸及4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯來製備標題化合物,其中將反應液在室溫下攪拌過夜。使用水稀釋反應混合物並使用EtOAc萃取三次。合併有機層,使用水及飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾,並在真空下濃縮以得到橙色蠟狀固體形式之標題化合物(其為54 wt%純)。ES-MS m/z694 (M+H)。 Preparation of 250 (S)-4-(2-(5 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridine-1(1,3)-phencyclonona- 1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-(((epoxypropylene-2-ylmethyl)amino)methyl benzoate Using 2-( 55 -cyano-3,8-dioxa-2,5(2,6)-dipyridine-1(1,3)-phenylcyclononane- 1 4 -yl)acetic acid and methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-epoxypropane-2-yl]methylamino]benzoate The title compound was prepared by stirring the reaction overnight at room temperature. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with water and saturated aqueous NaCl, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the title compound (54 wt% pure) as an orange waxy solid. ES-MS m/z 694 (M+H).
製備 251(S)-2-((5 5-氰基-3,8-二氧雜-2,5(2,6)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備109中所闡述使用(S)-4-(2-(5 5-氰基-3,8-二氧雜-2,5(2,6)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(54 wt%純)來製備標題化合物,其中在氮氣氛及60℃下攪拌6 h。藉由矽膠層析使用於DCM中之0 - 6% MeOH之梯度來純化以提供橙色蠟狀固體形式之標題化合物(其為63 wt%純)。ES-MS m/z676 (M+H)。 Preparation of 251 (S)-2-((5 5 -cyano-3,8-dioxa-2,5(2,6)-bipyridine-1(1,3)-phenylcyclonona-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 55 -cyano-3,8-dioxa-2,5(2,6)-bipyridine-1(1,3) essentially as described in Preparation 109 )-Phenencyclononan-1 4 -yl)Acetamido)-3-(2-Methoxyethoxy)-5-((Oxiran-2-ylmethyl)amino)benzoic acid Methyl ester (54 wt% pure) was used to prepare the title compound, which was stirred at 60 °C under nitrogen atmosphere for 6 h. Purification by silica gel chromatography using a gradient of 0-6% MeOH in DCM afforded the title compound (which was 63 wt% pure) as an orange waxy solid. ES-MS m/z 676 (M+H).
製備 2522-氯-5-(((6-氯吡啶-2-基)氧基)甲基)苯甲酸甲酯 向5-(溴甲基)-2-氯苯甲酸甲酯(25 g, 95 mmol)於1,4-二噁烷(600 mL)中之溶液中添加6-氯吡啶-2-醇(14.2 g, 110 mmol)及碳酸銀(53.2 g, 193 mmol)。將混合物在60℃下攪拌23 h。經由Celite ®過濾反應懸浮液並使用EtOAc沖洗。在減壓下濃縮濾液以得到29.4 g標題化合物(99%),其未經進一步純化即用於製備253。ES-MS m/z312, 314 (M+H)。 Preparation of 252 2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzoic acid methyl ester To a solution of methyl 5-(bromomethyl)-2-chlorobenzoate (25 g, 95 mmol) in 1,4-dioxane (600 mL) was added 6-chloropyridin-2-ol (14.2 g, 110 mmol) and silver carbonate (53.2 g, 193 mmol). The mixture was stirred at 60 °C for 23 h. The reaction suspension was filtered through Celite® and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to afford 29.4 g of the title compound (99%), which was used in the preparation of 253 without further purification. ES-MS m/z 312, 314 (M+H).
製備 253(2-氯-5-(((6-氯吡啶-2-基)氧基)甲基)苯基)甲醇 將2-氯-5-(((6-氯吡啶-2-基)氧基)甲基)苯甲酸甲酯(來自製備252,22 g, 71 mmol)於THF (200 mL)中之溶液冷卻至0℃,然後逐滴添加Red-Al ®(60 wt%,於甲苯中,30 mL, 92 mL)。將混合物在0℃下攪拌10 min,然後使用EtOAc (10 mL)終止反應。將混合物在室溫下攪拌2 h,然後使用水(200 mL)及EtOAc (200 mL)稀釋反應液。使用EtOAc (2 × 100 mL)萃取水層。藉由MgSO 4乾燥合併之有機相,過濾,並在減壓下濃縮以得到20.7 g標題化合物(100%),其未經進一步純化即用於製備254。ES-MS m/z284, 286 (M+H)。 Preparation of 253 (2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)methanol A solution of methyl 2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzoate (from Preparation 252, 22 g, 71 mmol) in THF (200 mL) was cooled to 0 °C, then Red-Al ® (60 wt% in toluene, 30 mL, 92 mL) was added dropwise. The mixture was stirred at 0 °C for 10 min, then quenched with EtOAc (10 mL). The mixture was stirred at room temperature for 2 h, then the reaction was diluted with water (200 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over MgSO 4 , filtered, and concentrated under reduced pressure to give 20.7 g of the title compound (100%), which was used in the preparation of 254 without further purification. ES-MS m/z 284, 286 (M+H).
製備 2542-((3-(溴甲基)-4-氯苄基)氧基)-6-氯吡啶 將(2-氯-5-(((6-氯吡啶-2-基)氧基)甲基)苯基)甲醇(來自製備253,1.5 g, 5.3 mmoL)及三苯基膦(2.0 g, 7.5 mmoL)於DCM (35 mL)中之溶液冷卻至0℃。添加四溴化碳(1.9 g, 5.7 mmoL),將反應混合物在0℃下攪拌10 min然後在室溫下攪拌30 min。經由矽膠墊過濾反應溶液並使用DCM沖洗。在減壓下濃縮濾液以得到1.8 g標題化合物(100%),其未經進一步純化即用於製備255。ES-MS m/z345/347/349 (M+H)。 Preparation of 254 2-((3-(bromomethyl)-4-chlorobenzyl)oxy)-6-chloropyridine (2-Chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)methanol (from Preparation 253, 1.5 g, 5.3 mmol) and triphenylphosphine (2.0 g, 7.5 mmol) in DCM (35 mL) was cooled to 0 °C. Carbon tetrabromide (1.9 g, 5.7 mmoL) was added and the reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 30 min. The reaction solution was filtered through a pad of silica gel and rinsed with DCM. The filtrate was concentrated under reduced pressure to give 1.8 g of the title compound (100%) which was used in the preparation of 255 without further purification. ES-MS m/z 345/347/349 (M+H).
製備 2552-(4-溴-2-(2-((2-氯-5-(((6-氯吡啶-2-基)氧基)甲基)苄基)氧基)乙基)-5-氟苯基)乙酸乙酯 基本上如製備224中所闡述使用2-((3-(溴甲基)-4-氯苄基)氧基)-6-氯吡啶(來自製備254)及2-[4-溴-5-氟-2-(2-羥乙基)苯基]乙酸乙酯來製備標題化合物,其中將反應液在室溫下攪拌1 h 15 min。過濾反應混合物並在減壓下濃縮,然後經由矽膠層析使用於己烷中之0 - 20% EtOAc之梯度來純化以得到標題化合物。ES-MS m/z570/572/574 (M+H)。 Preparation of 255 2-(4-bromo-2-(2-((2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzyl)oxy)ethyl)- 5-Fluorophenyl) ethyl acetate Using 2-((3-(bromomethyl)-4-chlorobenzyl)oxy)-6-chloropyridine (from Preparation 254) and 2-[4-bromo-5- The title compound was prepared from ethyl fluoro-2-(2-hydroxyethyl)phenyl]acetate, which was stirred at room temperature for 1 h 15 min. The reaction mixture was filtered and concentrated under reduced pressure, then purified by silica gel chromatography using a gradient of 0-20% EtOAc in hexanes to afford the title compound. ES-MS m/z 570/572/574 (M+H).
製備 2562-(2-(2-((2-氯-5-(((6-氯吡啶-2-基)氧基)甲基)苄基)氧基)乙基)-5-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基)乙酸乙酯 向2-(4-溴-2-(2-((2-氯-5-(((6-氯吡啶-2-基)氧基)甲基)苄基)氧基)乙基)-5-氟苯基)乙酸乙酯(855 mg, 1.5 mmoL)、雙(頻哪醇)二硼(480 mg, 1.87 mmoL)、KOAc (450 mg, 4.5 mmoL)及二氯雙(三環己基膦)鈀(II) (225 mg, 0.30 mmoL)之混合物中添加1,4-二噁烷(15 mL)。將混合物在90℃下攪拌5 h,然後添加Pd(dppf)Cl 2(125 mg, 0.17 mmoL)並將混合物在90℃下攪拌15 h。經由矽膠墊過濾粗製混合物並使用EtOAc沖洗。在減壓下濃縮濾液以得到標題化合物,其未經進一步純化即用於製備257。ES-MS m/z536 (酸之M+H)。 Preparation 256 2-(2-(2-((2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzyl)oxy)ethyl)-5-fluoro- 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)ethyl acetate To 2-(4-bromo-2-(2-((2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzyl)oxy)ethyl)-5 -fluorophenyl) ethyl acetate (855 mg, 1.5 mmoL), bis(pinacol) diboron (480 mg, 1.87 mmol), KOAc (450 mg, 4.5 mmoL) and dichlorobis(tricyclohexylphosphine) To the mixture of palladium(II) (225 mg, 0.30 mmol) was added 1,4-dioxane (15 mL). The mixture was stirred at 90°C for 5 h, then Pd(dppf)Cl 2 (125 mg, 0.17 mmoL) was added and the mixture was stirred at 90°C for 15 h. The crude mixture was filtered through a pad of silica gel and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound which was used in the preparation of 257 without further purification. ES-MS m/z 536 ( Acid M+H).
製備 2572-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸乙酯 向2-(2-(2-((2-氯-5-(((6-氯吡啶-2-基)氧基)甲基)苄基)氧基)乙基)-5-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基)乙酸乙酯(來自製備256,925 mg, 1.5 mmoL)及XPhos Pd G2 (145 mg, 0.18 mmoL)於THF (50 mL)中之溶液中添加磷酸鉀(1.6 g, 7.4 mmoL)於水(5 mL)中之溶液。將反應混合物在60℃下攪拌1.5 h。使用EtOAc (50 mL)及1:1水:飽和NaCl水溶液(50 mL)稀釋粗製反應混合物,並使用EtOAc (50 mL)萃取水層。藉由MgSO 4乾燥合併之有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於己烷中之0 - 40% EtOAc之梯度來純化殘餘物以得到140 mg標題化合物(20%)。ES-MS m/z456 (M+H)。 Preparation of 257 2-(5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona-1 4 - base) ethyl acetate To 2-(2-(2-((2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzyl)oxy)ethyl)-5-fluoro-4 -Ethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)acetate (from Preparation 256, 925 mg, 1.5 mmoL) and XPhos Pd G2 (145 mg, 0.18 mmol) in THF (50 mL) was added a solution of potassium phosphate (1.6 g, 7.4 mmol) in water (5 mL). The reaction mixture was stirred at 60 °C for 1.5 h. The crude reaction mixture was diluted with EtOAc (50 mL) and 1:1 water:saturated aqueous NaCl (50 mL), and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were dried over MgSO4 , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-40% EtOAc in hexanes to afford 140 mg of the title compound (20%). ES-MS m/z 456 (M+H).
製備 2582-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸 基本上如製備75中所闡述使用2-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸乙酯且使用3:3:1 ACN : 1,4-二噁烷:水作為溶劑來製備標題化合物,其中將反應液在50℃下加熱1 h 20 min。使用水稀釋反應液並使用1 M檸檬酸水溶液驟冷。藉由過濾收集沈澱材料並使用水沖洗以得到標題化合物。ES-MS m/z428 (M+H)。 Preparation of 258 2-(5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona-1 4 - base) acetic acid Using 2-(5 4 -chloro- 1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylene essentially as described in Preparation 75 The title compound was prepared from ethyl cyclononafin- 14 -yl)acetate and using 3:3:1 ACN:1,4-dioxane:water as solvent, where the reaction was heated at 50 °C for 1 h 20 min . The reaction was diluted with water and quenched with 1 M aqueous citric acid. The precipitated material was collected by filtration and rinsed with water to give the title compound. ES-MS m/z 428 (M+H).
製備 259(S)-4-(2-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯來製備標題化合物,其中將反應液在室溫下攪拌17 h。使用EtOAc及水稀釋反應液,使用水洗滌有機層並使用EtOAc將水層反萃取兩次。藉由MgSO 4乾燥合併之有機相,過濾,並在減壓下濃縮以提供標題化合物,其未經進一步純化即用於製備260。ES-MS m/z720 (M+H)。 Preparation of 259 (S)-4-(2-(5 4 -chloro- 1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenyl Methyl cyclononafin-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-(((oxypropylene-2-ylmethyl)amino)benzoate Using 2-(5 4 -chloro- 1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylene essentially as described in Preparation 86 Cyclononafin-1 4 -yl)acetic acid and 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-epoxypropane-2-yl]methylamino] The title compound was prepared from methyl benzoate by stirring the reaction at room temperature for 17 h. The reaction was diluted with EtOAc and water, the organic layer was washed with water and the aqueous layer was back extracted twice with EtOAc. The combined organic phases were dried over MgSO 4 , filtered, and concentrated under reduced pressure to provide the title compound, which was used in the preparation of 260 without further purification. ES-MS m/z 720 (M+H).
製備 260(S)-2-((5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備109中所闡述使用(S)-4-(2-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(來自製備259)來製備標題化合物。經由矽膠層析使用於己烷中之0 - 100% EtOAc之梯度來純化以得到標題化合物。ES-MS m/z702 (M+H)。 Preparation 260 (S)-2-((5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononium Fan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -chloro- 16 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5( 1,3)-Diphenylcyclononafran-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-((epoxypropane-2-ylmethyl)amine base) methyl benzoate (from Preparation 259) to prepare the title compound. Purification via silica gel chromatography using a gradient of 0-100% EtOAc in hexanes gave the title compound. ES-MS m/z 702 (M+H).
製備 2614-[(6-溴-5-氟-2-吡啶基)氧基甲基]-3-碘-苯甲腈 如下所述以相等規模製備兩個批次:將Na 2CO 3添加至4-(溴甲基)-3-碘-苯甲腈(22.4 g, 62.6 mmol)於丙酮(340 mL)及水(340 mL)中之溶液中。將兩個批次在80℃下攪拌過夜,然後合併兩個批次。濃縮混合物以去除丙酮,然後過濾掉固體並使用水洗滌。在真空下乾燥固體,然後將其在DCM (70 mL)中攪拌30 min。過濾固體,使用DCM沖洗,並在真空下乾燥以得到白色固體形式之4-(羥甲基)-3-碘-苯甲腈(23.6 g, 72%)。 1H-NMR (400 MHz, DMSO-d 6) δ 8.28 (d, J= 1.6 Hz, 1H), 7.88 (dd, J= 8.0, 1.6 Hz, 1H), 7.62 (d, J= 8.0 Hz, 1H), 5.71 (t, J= 5.6 Hz, 1H), 4.44 (d, J= 5.2 Hz, 2H)。 在0℃及氮下,向4-(羥甲基)-3-碘-苯甲腈(11.5 g, 43.5 mmol)、2-溴-3,6-二氟-吡啶(7.08 g, 35.8 mmol)於1,4-二噁烷(80 mL)中之溶液中添加第三丁醇鉀(1 M於THF中,43 mL, 43 mmol)。將反應液在0℃下攪拌1 h,然後將反應液在室溫下攪拌7 h。使用NH 4Cl飽和水溶液(50 mL)稀釋反應液,然後添加水(100 mL)並使用EtOAc (250 mL × 3)萃取。合併有機層,使用飽和NaCl水溶液(60 mL)洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮。藉由矽膠層析使用於石油醚中之0 - 45% DCM之梯度來純化殘餘物以得到白色固體形式之標題化合物(14.28g, 88%)。ES-MS m/z432 (M+H)。 Preparation 261 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-iodo-benzonitrile Two batches were prepared on equal scale as follows: Na2CO3 was added to 4-(bromomethyl)-3-iodo-benzonitrile (22.4 g, 62.6 mmol) in acetone (340 mL) and water ( 340 mL). Both batches were stirred overnight at 80°C and then the two batches were combined. The mixture was concentrated to remove acetone, then the solid was filtered off and washed with water. The solid was dried under vacuum, then stirred in DCM (70 mL) for 30 min. The solid was filtered, rinsed with DCM, and dried under vacuum to give 4-(hydroxymethyl)-3-iodo-benzonitrile (23.6 g, 72%) as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.28 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H ), 5.71 (t, J = 5.6 Hz, 1H), 4.44 (d, J = 5.2 Hz, 2H). 4-(hydroxymethyl)-3-iodo-benzonitrile (11.5 g, 43.5 mmol), 2-bromo-3,6-difluoro-pyridine (7.08 g, 35.8 mmol) To a solution in 1,4-dioxane (80 mL) was added potassium tert-butoxide (1 M in THF, 43 mL, 43 mmol). The reaction was stirred at 0 °C for 1 h, then at room temperature for 7 h. The reaction was diluted with saturated aqueous NH 4 Cl (50 mL), then added water (100 mL) and extracted with EtOAc (250 mL×3). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-45% DCM in petroleum ether to afford the title compound (14.28 g, 88%) as a white solid. ES-MS m/z 432 (M+H).
製備 2624-[(6-溴-5-氟-2-吡啶基)氧基甲基]-3-[(E)-2-乙氧基乙烯基]苯甲腈 基本上如製備245中所闡述使用4-[(6-溴-5-氟-2-吡啶基)氧基甲基]-3-碘-苯甲腈作為起始材料且使用K 2CO 3作為鹼來製備標題化合物,其中將反應液在90℃下攪拌1.5 h。在完成後,在減壓下濃縮反應混合物,然後添加水並使用EtOAc萃取三次。合併有機層,使用飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮。藉由矽膠層析使用於石油醚中之0 - 60% EtOAc之梯度來純化以得到白色固體形式之標題化合物。ES-MS m/z377 (M+H)。 Preparation of 262 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile Essentially as described in Preparation 245 using 4-[ ( 6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-iodo-benzonitrile as starting material and K2CO3 as Base, the title compound was prepared by stirring the reaction at 90 °C for 1.5 h. After completion, the reaction mixture was concentrated under reduced pressure, then water was added and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over Na2SO4 , filtered and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-60% EtOAc in petroleum ether gave the title compound as a white solid. ES-MS m/z 377 (M+H).
製備 2634-[(6-溴-5-氟-2-吡啶基)氧基甲基]-3-(2-側氧基乙基)苯甲腈 基本上如製備126中所闡述使用4-[(6-溴-5-氟-2-吡啶基)氧基甲基]-3-[(E)-2-乙氧基乙烯基]苯甲腈來製備標題化合物,將反應液在室溫下攪拌20 h。在完成後,使用水稀釋反應液並使用EtOAc萃取三次。合併有機層,使用飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮以得到淺黃色固體形式之標題化合物,其未經進一步純化即用於製備264。ES-MS m/z349, 351 (M+H)。 Preparation of 263 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile Using 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile essentially as described in Preparation 126 To prepare the title compound, the reaction was stirred at room temperature for 20 h. After completion, the reaction was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid, which was used in the preparation of 264 without further purification. ES-MS m/z 349, 351 (M+H).
製備 2644-[(6-溴-5-氟-2-吡啶基)氧基甲基]-3-(2-羥乙基)苯甲腈 在0℃下,向4-[(6-溴-5-氟-2-吡啶基)氧基甲基]-3-(2-側氧基乙基)苯甲腈(來自製備263,8.54 g, 22.0 mmol)於MeOH (80 mL)中之溶液中添加硼氫化鈉(3.59 g, 93.9 mmol)並將反應液在室溫下攪拌4 h。使用NH 4Cl飽和水溶液終止反應並在室溫下攪拌20 min。在減壓下濃縮反應混合物以去除溶劑。使用水(50 mL)稀釋殘餘物並使用EtOAc (200 mL × 3)萃取。合併有機層,使用飽和NaCl水溶液(60 mL)洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮。藉由矽膠層析使用於石油醚中之0 - 30% EtOAc之梯度來純化殘餘物以得到黃色油狀物形式之標題化合物(7.1g, 87%)。ES-MS m/z351/353 (M+H)。 Preparation of 264 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile At 0°C, 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile (from Preparation 263, 8.54 g , 22.0 mmol) in MeOH (80 mL) was added sodium borohydride (3.59 g, 93.9 mmol) and the reaction was stirred at room temperature for 4 h. The reaction was quenched with saturated aqueous NH4Cl and stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (50 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-30% EtOAc in petroleum ether to afford the title compound (7.1 g, 87%) as a yellow oil. ES-MS m/z 351/353 (M+H).
製備 2652-(4-溴-2-((2-(((6-溴-5-氟吡啶-2-基)氧基)甲基)-5-氰基苯乙氧基)甲基)苯基)乙酸甲酯 基本上如製備224中所闡述使用4-[(6-溴-5-氟-2-吡啶基)氧基甲基]-3-(2-羥乙基)苯甲腈及2-[4-溴-2-(溴甲基)苯基]乙酸甲酯作為起始材料且使用2,6-二-第三丁基-4-甲基吡啶代替2,6-二-第三丁基吡啶來製備標題化合物,其中將反應液在室溫下攪拌過夜。在完成後,濃縮反應混合物,然後添加水並使用EtOAc萃取三次。合併有機層,使用飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾並濃縮。藉由矽膠層析使用於石油醚中之0 - 100% DCM之梯度來純化以得到淺黃色油狀物形式之標題化合物。ES-MS m/z592 (M+H)。 Preparation 265 2-(4-bromo-2-((2-(((6-bromo-5-fluoropyridin-2-yl)oxy)methyl)-5-cyanophenethoxy)methyl) phenyl) methyl acetate Using 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile and 2-[4- Bromo-2-(bromomethyl)phenyl]acetic acid methyl ester as starting material and using 2,6-di-tert-butyl-4-methylpyridine instead of 2,6-di-tert-butylpyridine to The title compound was prepared by stirring the reaction overnight at room temperature. After completion, the reaction mixture was concentrated, then water was added and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over Na2SO4 , filtered and concentrated. Purification by silica gel chromatography using a gradient of 0-100% DCM in petroleum ether afforded the title compound as a pale yellow oil. ES-MS m/z 592 (M+H).
製備 2662-(5 4-氰基-2 3-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯 基本上如製備216中所闡述使用2-(4-溴-2-((2-(((6-溴-5-氟吡啶-2-基)氧基)甲基)-5-氰基苯乙氧基)甲基)苯基)乙酸甲酯作為起始材料且使用(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]甲磺酸鈀(II) (XPhos Pd G3)作為觸媒來製備標題化合物,其中在加熱期間使反應混合物避光。在完成後,在減壓下濃縮反應混合物以去除溶劑。使用水稀釋殘餘物並使用EtOAc萃取三次。合併有機層,使用飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮。藉由矽膠層析使用於石油醚中之0 - 33% EtOAc之梯度來純化以得到褐色固體形式之標題化合物。ES-MS m/z433 (M+H)。 Preparation of 266 2-(5 4 -cyano-2 3 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl acetate Using 2-(4-bromo-2-((2-(((6-bromo-5-fluoropyridin-2-yl)oxy)methyl)-5-cyanobenzene essentially as described in Preparation 216 Ethoxy)methyl)phenyl)methyl acetate as starting material and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-Amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3) was used as catalyst to prepare the title compound, wherein the reaction mixture was protected from light during heating. After completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over Na2SO4 , filtered and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-33% EtOAc in petroleum ether afforded the title compound as a tan solid. ES-MS m/z 433 (M+H).
製備 2672-(5 4-氰基-2 3-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 基本上如製備78中所闡述使用2-(5 4-氰基-2 3-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物。在完成後,使用1 M檸檬酸水溶液終止反應直至pH = 4.5。過濾沉墜固體,使用水洗滌,收集並在減壓下乾燥以得到白色固體形式之標題化合物,其未經進一步純化即用於製備268。ES-MS m/z419 (M+H)。 Preparation of 267 2-(5 4 -cyano-2 3 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring nonafin-1 4 -yl)acetic acid Using 2-( 54-cyano-23 -fluoro-3,8-dioxa- 2 (2,6)-pyridine-1(1,3),5(1 ,2)-Diphenylcyclononan-1 4 -yl)methyl acetate to prepare the title compound. Upon completion, the reaction was quenched using 1 M aqueous citric acid until pH = 4.5. The precipitated solid was filtered, washed with water, collected and dried under reduced pressure to give the title compound as a white solid which was used in the preparation of 268 without further purification. ES-MS m/z 419 (M+H).
製備 268(S)-4-(2-(5 4-氰基-2 3-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-2 3-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(製備267)及4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯來製備標題化合物,其中將反應液在室溫下攪拌過夜。在完成後,使用水稀釋反應液並使用EtOAc萃取三次。合併有機層,使用飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮以得到淺褐色油狀物形式之標題化合物,其未經進一步純化即用於製備269。ES-MS m/z711 (M+H)。 Preparation of 268 (S)-4-(2-(5 4 -cyano- 2 3 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclononarfin-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-((epoxypropane-2-ylmethyl)amino ) methyl benzoate Using 2-( 54-cyano-23 -fluoro-3,8-dioxa- 2 (2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclononarfin-1 4 -yl)acetic acid (preparation 267) and 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-propylene oxide -2-yl]methylamino]benzoic acid methyl ester to prepare the title compound, wherein the reaction was stirred at room temperature overnight. After completion, the reaction was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound as a light brown oil, which was used in the preparation of 269 without further purification. ES-MS m/z 711 (M+H).
製備 269(S)-2-((5 4-氰基-2 3-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-2 3-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備268)及1:1 1,2-二氯乙烷:乙酸來製備標題化合物,其中將反應液在55℃下加熱5 h。在完成反應後,在減壓下去除溶劑,然後將1:1 EtOAc :甲苯添加至殘餘物中並在真空中濃縮。藉由矽膠層析使用於DCM中之0 - 6% MeOH之梯度來純化以得到橙色油狀物形式之標題化合物。ES-MS m/z693 (M+H)。 Preparation of 269 (S)-2-((5 4 -cyano-2 3 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d ]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano- 23 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1) essentially as described in Preparation 102 ,3),5(1,2)-Diphenylcyclononafran-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-((propylene oxide-2 -ylmethyl)amino)methylbenzoate (Preparation 268) and 1:1 1,2-dichloroethane:acetic acid to prepare the title compound by heating the reaction at 55°C for 5 h. After completion of the reaction, the solvent was removed under reduced pressure, then 1:1 EtOAc:toluene was added to the residue and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0-6% MeOH in DCM gave the title compound as an orange oil. ES-MS m/z 693 (M+H).
製備 2702-(5-氰基-2-甲基-苯基)-2,2-二氟-乙酸甲酯 在THF (30 mL)及DMSO (80 mL)中攪拌3-碘-4-甲基苯甲腈(5 g, 19.96 mmol)及銅(12 g, 179.4 mmol)。向此漿液中添加溴二氟乙酸甲酯(6 mL, 51.9 mmol)並將此混合物在30℃及氮下繼續攪拌18 h。此後,添加100 mL飽和NaHCO 3水溶液,隨後添加100 mL EtOAc。過濾此混合物並使用EtOAc (3 × 50 mL)洗滌固體。然後分離濾液,並使用飽和NH 4Cl水溶液洗滌有機層。藉由MgSO 4乾燥有機物,過濾,並濃縮。經由矽膠層析(於己烷中之0-25% EtOAc)純化此殘餘物以得到透明結晶固體形式之產物(3.3 g, 73%)。 1H NMR (DMSO- d 6) ( 2.41 (s, 3H), 3.33 (s, 3H), 7.61 (d, J=8.0 Hz, 1H), 7.99 (d, J=7.9 Hz, 1H), 8.04 (d, J=1.2 Hz, 1H)。 Preparation 270 2-(5-cyano-2-methyl-phenyl)-2,2-difluoro-acetic acid methyl ester 3-Iodo-4-methylbenzonitrile (5 g, 19.96 mmol) and copper (12 g, 179.4 mmol) were stirred in THF (30 mL) and DMSO (80 mL). To this slurry was added methyl bromodifluoroacetate (6 mL, 51.9 mmol) and the mixture was stirred at 30 °C under nitrogen for an additional 18 h. After this time, 100 mL of saturated aqueous NaHCO 3 was added, followed by 100 mL of EtOAc. This mixture was filtered and the solid was washed with EtOAc (3 x 50 mL). The filtrate was then separated, and the organic layer was washed with saturated aqueous NH4Cl . The organics were dried over MgSO 4 , filtered, and concentrated. The residue was purified via silica gel chromatography (0-25% EtOAc in hexanes) to give the product as a clear crystalline solid (3.3 g, 73%). 1 H NMR (DMSO- d 6 ) ( 2.41 (s, 3H), 3.33 (s, 3H), 7.61 (d, J= 8.0 Hz, 1H), 7.99 (d, J= 7.9 Hz, 1H), 8.04 ( d, J= 1.2 Hz, 1H).
製備 2712-[2-(溴甲基)-5-氰基-苯基]-2,2-二氟-乙酸甲酯 將2-(5-氰基-2-甲基-苯基)-2,2-二氟-乙酸甲酯(4.4 g, 20 mmol)及N-溴琥珀醯亞胺(4 g, 22.47 mmol)溶於ACN (100 mL)中。經由流動條件(1.0 mL/min;72英尺之1/8’’外徑反應管,纏繞燒杯;維持於30℃下)使此溶液經受4100K白色燈泡兩次。在此處理之後,將反應液濃縮至乾燥且然後經由矽膠層析(於己烷中之0-10% EtOAc)純化此殘餘物以得到澄清稠油狀物形式之產物(3.7 g, 62%)。 1H NMR (DMSO- d 6) ( 3.41 (s, 3H), 3.89 (s, 2H), 7.61 (d, J=7.9 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 8.03 (s, 1H)。 Preparation 271 2-[2-(bromomethyl)-5-cyano-phenyl]-2,2-difluoro-acetic acid methyl ester 2-(5-cyano-2-methyl-phenyl)-2,2-difluoro-acetic acid methyl ester (4.4 g, 20 mmol) and N-bromosuccinimide (4 g, 22.47 mmol) Dissolve in ACN (100 mL). This solution was subjected to a 4100K white bulb twice via flow conditions (1.0 mL/min; 72 feet of 1/8'' OD reaction tube wrapped around the beaker; maintained at 30°C). After this workup, the reaction was concentrated to dryness and the residue was then purified via silica gel chromatography (0-10% EtOAc in hexanes) to give the product as a clear thick oil (3.7 g, 62%) . 1 H NMR (DMSO- d 6 ) ( 3.41 (s, 3H), 3.89 (s, 2H), 7.61 (d, J= 7.9 Hz, 1H), 7.99 (d, J= 8.0 Hz, 1H), 8.03 ( s, 1H).
製備 2722-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]-2,2-二氟-乙酸 將2-[2-(溴甲基)-5-氰基-苯基]-2,2-二氟-乙酸甲酯(6.2 g, 20 mmol)及2-溴-6-羥基吡啶(4.5 g, 2 5 mmol)溶於DMSO (50 mL)中。將磷酸三鉀(6.6 g, 30 mmol)添加至此溶液中,且加熱至60℃並保持2 h。此後,使用1N HCl終止反應(至pH ~6)並使用EtOAc萃取。藉由MgSO 4乾燥合併之有機物,過濾,並濃縮以得到厚褐色油狀物形式之產物(7.8 g, 100%)。ES-MS m/z( 79Br/ 81Br) 382.8/384.8 [M+H] +。 Preparation 272 2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetic acid 2-[2-(Bromomethyl)-5-cyano-phenyl]-2,2-difluoro-acetic acid methyl ester (6.2 g, 20 mmol) and 2-bromo-6-hydroxypyridine (4.5 g , 25 mmol) was dissolved in DMSO (50 mL). Tripotassium phosphate (6.6 g, 30 mmol) was added to this solution and heated to 60 °C for 2 h. After this time, the reaction was quenched with 1N HCl (to pH~6) and extracted with EtOAc. The combined organics were dried over MgSO 4 , filtered, and concentrated to give the product as a thick brown oil (7.8 g, 100%). ES-MS m/z ( 79 Br/ 81 Br) 382.8/384.8 [M+H] + .
製備 2732-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]-2,2-二氟-乙酸甲酯 在MeOH (100 mL)中攪拌2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]-2,2-二氟-乙酸(7.8 g, 20 mmol)。添加濃硫酸(0.1 mL, 2 mmol),且加熱至回流並保持30 h。將反應混合物濃縮至乾燥且然後經由矽膠層析(於己烷中之0-100% EtOAc)純化殘餘物以得到白色結晶固體形式之產物(8 g, 99%)。ES-MS m/z( 79Br/ 81Br) 396.8/398.8 [M+H] +。 Preparation of 273 2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetic acid methyl ester 2-[2-[(6-Bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetic acid (7.8 g , 20 mmol). Concentrated sulfuric acid (0.1 mL, 2 mmol) was added and heated to reflux for 30 h. The reaction mixture was concentrated to dryness and the residue was then purified via silica gel chromatography (0-100% EtOAc in hexanes) to give the product as a white crystalline solid (8 g, 99%). ES-MS m/z ( 79 Br/ 81 Br) 396.8/398.8 [M+H] + .
製備 2744-[(6-溴-2-吡啶基)氧基甲基]-3-(1,1-二氟-2-羥基-乙基)苯甲腈 將2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]-2,2-二氟-乙酸甲酯(8 g, 20.14 mmol)溶於THF (100 mL)中。向此溶液中添加硼氫化鋰(0.88 g, 40.4 mmol)並在環境溫度及氮下攪拌2 h。此後,使用飽和NH 4Cl溶液終止反應,並使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並濃縮。經由矽膠層析(於己烷中之0-50% EtOAc)純化此殘餘物以得到稠澄清油狀物形式之產物(4.7 g, 63%)。ES-MS m/z( 79Br/ 81Br) 368.8/370.8 [M+H] +。 Preparation of 274 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(1,1-difluoro-2-hydroxyl-ethyl)benzonitrile 2-[2-[(6-Bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetic acid methyl ester (8 g, 20.14 mmol) was dissolved in THF (100 mL). To this solution was added lithium borohydride (0.88 g, 40.4 mmol) and stirred at ambient temperature under nitrogen for 2 h. After this time, the reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated. The residue was purified via silica gel chromatography (0-50% EtOAc in hexanes) to give the product as a thick clear oil (4.7 g, 63%). ES-MS m/z ( 79 Br/ 81 Br) 368.8/370.8 [M+H] + .
製備 2753-[2-[(5-溴-2-碘-苯基)甲氧基]-1,1-二氟-乙基]-4-[(6-溴-2-吡啶基)氧基甲基]苯甲腈 將4-[(6-溴-2-吡啶基)氧基甲基]-3-(1,1-二氟-2-羥基-乙基)苯甲腈(4.5 g, 12 mmol)溶於THF (60 mL)及DMF (10 mL)中。向此溶液中添加氫化鈉(0.6 g, 15 mmol;60%質量,於礦物油中)並在環境溫度及氮下攪拌5 min。然後添加4-溴-2-(氯甲基)-1-碘苯(4.8 g, 14 mmol)並在環境溫度及氮下繼續攪拌18 h。此後,使用飽和NH 4Cl水溶液終止反應,並使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並濃縮。經由矽膠層析(於己烷中之0-30% EtOAc)純化此殘餘物以得到稠澄清油狀物形式之產物(3.9 g, 48%)。ES-MS m/z( 79Br/ 81Br) 663.0/665.0 [M+H] +。 Preparation of 275 3-[2-[(5-bromo-2-iodo-phenyl)methoxy]-1,1-difluoro-ethyl]-4-[(6-bromo-2-pyridyl)oxy Methyl]benzonitrile 4-[(6-Bromo-2-pyridyl)oxymethyl]-3-(1,1-difluoro-2-hydroxy-ethyl)benzonitrile (4.5 g, 12 mmol) was dissolved in THF (60 mL) and DMF (10 mL). To this solution was added sodium hydride (0.6 g, 15 mmol; 60% by mass in mineral oil) and stirred at ambient temperature under nitrogen for 5 min. 4-Bromo-2-(chloromethyl)-1-iodobenzene (4.8 g, 14 mmol) was then added and stirring was continued for 18 h at ambient temperature under nitrogen. After this time, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated. The residue was purified via silica gel chromatography (0-30% EtOAc in hexanes) to give the product as a thick clear oil (3.9 g, 48%). ES-MS m/z ( 79 Br/ 81 Br) 663.0/665.0 [M+H] + .
製備 2762-[4-溴-2-[[2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]-2,2-二氟-乙氧基]甲基]苯基]乙酸乙酯 將3-[2-[(5-溴-2-碘-苯基)甲氧基]-1,1-二氟-乙基]-4-[(6-溴-2-吡啶基)氧基甲基]苯甲腈(3.9 g, 5.9 mmol)及[(4,5-雙(二苯基膦基)-9,9-二甲基呫噸)-2-(2′-胺基-1,1′-聯苯)]甲磺酸鈀(II) (XantPhos Pd G3, 0.6 g, 0.6 mmol)溶於THF (30 mL)中。向此溶液中添加(2-乙氧基-2-側氧基-乙基)溴化鋅(0.5 M於乙醚中) (18 mL, 9.0 mmol),且將此混合物在氮下加熱至60℃並保持18 h。此後,將反應液冷卻至環境溫度,使用飽和NaHCO 3水溶液終止反應,並使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並濃縮。經由矽膠層析(於己烷中之0-30% EtOAc)純化此殘餘物以得到稠淺褐色油狀物形式之產物(1.6 g, 44%)。ES-MS m/z( 79Br/ 81Br) 623.2/625.2 [M+H] +。 Preparation 276 2-[4-bromo-2-[[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro -Ethoxy]methyl]phenyl]ethyl acetate 3-[2-[(5-bromo-2-iodo-phenyl)methoxy]-1,1-difluoro-ethyl]-4-[(6-bromo-2-pyridyl)oxy Methyl]benzonitrile (3.9 g, 5.9 mmol) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1 ,1′-biphenyl)]palladium(II) methanesulfonate (XantPhos Pd G3, 0.6 g, 0.6 mmol) was dissolved in THF (30 mL). To this solution was added (2-ethoxy-2-oxo-ethyl)zinc bromide (0.5 M in diethyl ether) (18 mL, 9.0 mmol), and the mixture was heated to 60 °C under nitrogen And keep it for 18 h. After this time, the reaction was cooled to ambient temperature, quenched with saturated aqueous NaHCO 3 , and extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated. The residue was purified via silica gel chromatography (0-30% EtOAc in hexanes) to give the product as a thick beige oil (1.6 g, 44%). ES-MS m/z ( 79 Br/ 81 Br) 623.2/625.2 [M+H] + .
製備 2772-(5 4-氰基-6,6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯 將2-[4-溴-2-[[2-[2-[(6-溴-2-吡啶基)氧基甲基]-5-氰基-苯基]-2,2-二氟-乙氧基]甲基]苯基]乙酸乙酯(1.6 g, 2.9 mmol)溶於1,4-二噁烷(30 mL)中。向此溶液中添加KOAc (0.64 g, 6.39 mmol)及雙(頻哪醇)二硼(0.8 g, 3.09 mmol)並使氮鼓泡通過此溶液10 min。此後,添加1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II) DCM複合物(0.11 g, 0.132 mmol),且將此混合物在氮下加熱至80℃並保持18 h。此後,將反應液冷卻至環境溫度,使用飽和NaCl水溶液稀釋,並使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並濃縮。將此殘餘物溶於1,4-二噁烷(50 mL)及水(3 mL)中並添加磷酸三鉀(1.4 g, 6.5 mmol),隨後添加氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd G2, 0.1 g, 0.125 mmol)。將此混合物加熱至60℃並保持2 h。此後,將反應液冷卻至環境溫度,使用飽和NH 4Cl水溶液終止反應,並使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並濃縮。經由矽膠層析(於己烷中之0-50% EtOAc)純化此殘餘物以得到白色固體形式之產物(249 mg, 21%)。ES-MS ( m/z) 465.2 (M+H)。 Preparation of 277 2-(5 4 -cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di phenylcyclonafin-1 4 -yl) ethyl acetate 2-[4-bromo-2-[[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro- Ethoxy]methyl]phenyl]ethyl acetate (1.6 g, 2.9 mmol) was dissolved in 1,4-dioxane (30 mL). To this solution was added KOAc (0.64 g, 6.39 mmol) and bis(pinacol)diboron (0.8 g, 3.09 mmol) and nitrogen was bubbled through the solution for 10 min. After this time, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride DCM complex (0.11 g, 0.132 mmol) was added, and this mixture was heated to 80 °C under nitrogen and Keep for 18 h. After this time, the reaction was cooled to ambient temperature, diluted with saturated aqueous NaCl, and extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated. This residue was dissolved in 1,4-dioxane (50 mL) and water (3 mL) and tripotassium phosphate (1.4 g, 6.5 mmol) was added followed by chloro(2-dicyclohexylphosphino-2 ',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 0.1 g, 0.125 mmol). This mixture was heated to 60 °C for 2 h. After this time, the reaction was cooled to ambient temperature, quenched with saturated aqueous NH4Cl , and extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated. The residue was purified via silica gel chromatography (0-50% EtOAc in hexanes) to give the product as a white solid (249 mg, 21%). ES-MS ( m/z ) 465.2 (M+H).
製備 278(S)-2-((5 4-氰基-6,6-二氟-3.8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸甲酯 將2-(5 4-氰基-6,6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯(249 mg, 0.54 mmol)溶於ACN (5 mL)、THF (1.8 mL)及水(1.8 mL)中。向此溶液中添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(0.23 g, 1.62 mmol)並將此混合物在環境溫度下攪拌2 h。此後,使用飽和NH 4Cl水溶液終止反應並使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並濃縮。將此殘餘物溶於DMF (2 mL)中並添加4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(0.055 g, 0.18 mmol)、DMF (0.09 mL, 0.5 mmol)及HATU (0.09 g, 0.24 mmol),且在環境溫度下攪拌18 h。此後,使用飽和NH 4Cl水溶液終止反應,並使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並濃縮。將此殘餘物溶於1,2-二氯乙烷(1 mL)中,添加乙酸(1 mL),且將此混合物加熱至50℃並保持18 h。將混合物濃縮至乾燥並經由矽膠層析(於己烷中之0-100% EtOAc)純化殘餘物以得到灰白色固體形式之標題化合物(61 mg, 52.5%)。ES-MS ( m/z) 711.4 (M+H)。 Preparation of 278 (S)-2-((5 4 -cyano-6,6-difluoro-3.8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ] imidazole-6-methyl carboxylate 2-(5 4 -cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl Ethyl cyclononafin-1 4 -yl)acetate (249 mg, 0.54 mmol) was dissolved in ACN (5 mL), THF (1.8 mL) and water (1.8 mL). To this solution was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.23 g, 1.62 mmol) and the mixture was stirred at ambient temperature for 2 h. After this time, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated. This residue was dissolved in DMF (2 mL) and 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-epoxypropan-2-yl]methyl was added Amino]methylbenzoate (0.055 g, 0.18 mmol), DMF (0.09 mL, 0.5 mmol) and HATU (0.09 g, 0.24 mmol), and stirred at ambient temperature for 18 h. After this time, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated. This residue was dissolved in 1,2-dichloroethane (1 mL), acetic acid (1 mL) was added, and the mixture was heated to 50 °C for 18 h. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound (61 mg, 52.5%) as an off-white solid. ES-MS ( m/z ) 711.4 (M+H).
製備 2794-[(2-氯嘧啶-4-基)氧基甲基]-3-碘-苯甲腈 向2-氯嘧啶-4-醇(8.50 g, 65.1 mmol)於DMF (150 mL)中之溶液中添加Cs 2CO 3(42.5 g, 130 mmol)及4-(溴甲基)-3-碘-苯甲腈(21.04 g, 65.35 mmol)。將反應混合物在環境溫度下攪拌16 h。將粗製反應液傾倒至水中並經由過濾收集沈澱物。將固體材料溶於DCM中並使用水洗滌兩次。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮以得到淺橙色固體形式之標題化合物(20.3 g, 84%),其未經進一步純化即用於製備280。ES/MS m/z372 (M+H)。 Preparation of 279 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-iodo-benzonitrile To a solution of 2-chloropyrimidin-4-ol (8.50 g, 65.1 mmol) in DMF (150 mL) was added Cs2CO3 (42.5 g, 130 mmol) and 4-(bromomethyl)-3-iodo - Benzonitrile (21.04 g, 65.35 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The crude reaction was poured into water and the precipitate was collected by filtration. The solid material was dissolved in DCM and washed twice with water. The organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the title compound (20.3 g, 84%) as a light orange solid, which was used in the preparation of 280 without further purification. ES/MS m/z 372 (M+H).
製備 2804-[(2-氯嘧啶-4-基)氧基甲基]-3-[( E)-2-乙氧基乙烯基]苯甲腈 向4-[(2-氯嘧啶-4-基)氧基甲基]-3-碘-苯甲腈(10.1 g, 27.2 mmol)於THF (150 mL)中之溶液中添加磷酸三鉀(40 mL, 80 mmol,於水中之2 M溶液)、2-[( E)-2-乙氧基乙烯基]-4,4,5,5-四甲基-1,3,2-二氧硼㖦(7.5 mL, 35 mmol)及雙(三苯基膦)二氯化鈀(II) (953 mg, 1.36 mmol)。使用氮將溶液吹掃15 min,然後在55℃下攪拌4 h。使用水稀釋反應混合物並使用EtOAc萃取。使用MgSO 4乾燥有機相,過濾,並在減壓下濃縮。將殘餘物溶於 EtOAc中並使用水洗滌以去除頻哪醇。使用MgSO 4乾燥有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於己烷中之0 - 30% EtOAc之梯度來純化殘餘物以得到標題化合物(5.97 g, 70%)。ES/MS m/z( 35Cl/ 37Cl) 315/317 [M+H] +。 Preparation of 280 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-[( E )-2-ethoxyvinyl]benzonitrile To a solution of 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-iodo-benzonitrile (10.1 g, 27.2 mmol) in THF (150 mL) was added tripotassium phosphate (40 mL, 80 mmol, 2 M solution in water), 2-[( E )-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaboron (7.5 mL, 35 mmol) and bis(triphenylphosphine)palladium(II) dichloride (953 mg, 1.36 mmol). The solution was purged with nitrogen for 15 min, then stirred at 55 °C for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried using MgSO 4 , filtered, and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water to remove pinacol. The organic phase was dried using MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-30% EtOAc in hexanes to afford the title compound (5.97 g, 70%). ES/MS m/z ( 35 Cl/ 37 Cl) 315/317 [M+H] + .
製備 2814-[(2-氯嘧啶-4-基)氧基甲基]-3-(2-羥乙基)苯甲腈 向4-[(2-氯嘧啶-4-基)氧基甲基]-3-[( E)-2-乙氧基乙烯基]苯甲腈(5.75 g, 18.2 mmol)於THF (85 mL)中之溶液中添加鹽酸(46 mL, 184 mmol,於二噁烷中之4M溶液)。在環境溫度下攪拌2.5 h。在減壓下濃縮反應液,然後使用DCM稀釋殘餘物。使用飽和NaHCO 3水溶液將混合物調節至pH = 8,然後使用DCM萃取。使用MgSO 4乾燥有機相,過濾,並在減壓下濃縮。將殘餘物溶於MeOH (100 mL)中,在冰浴中冷卻至0℃,然後逐漸添加硼氫化鈉(1.28 g, 33.7 mmol)。將混合物在0℃下攪拌30 min。使用1 M NaOH水溶液將反應混合物驟冷,然後使用水及DCM進一步稀釋溶液,並使用DCM萃取。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於己烷中之0 - 50% EtOAc之梯度來純化殘餘物以得到標題化合物(2.86 g, 44%)。ES/MS m/z( 35Cl/ 37Cl) 289/291 [M+H] +。 Preparation of 281 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile To 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-[( E )-2-ethoxyvinyl]benzonitrile (5.75 g, 18.2 mmol) in THF (85 mL ) was added hydrochloric acid (46 mL, 184 mmol, 4M solution in dioxane). Stir at ambient temperature for 2.5 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM. The mixture was adjusted to pH = 8 with saturated aqueous NaHCO 3 , then extracted with DCM. The organic phase was dried using MgSO 4 , filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL), cooled to 0 °C in an ice bath, then sodium borohydride (1.28 g, 33.7 mmol) was gradually added. The mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with 1 M aqueous NaOH, then the solution was further diluted with water and DCM, and extracted with DCM. The organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-50% EtOAc in hexanes to afford the title compound (2.86 g, 44%). ES/MS m/z ( 35 Cl/ 37 Cl) 289/291 [M+H] + .
製備 2822-[4-溴-2-[2-[2-[(2-氯嘧啶-4-基)氧基甲基]-5-氰基-苯基]乙氧基甲基]苯基]乙酸甲酯 在冰浴中將4-[(2-氯嘧啶-4-基)氧基甲基]-3-(2-羥乙基)苯甲腈(200 mg, 0.69 mmol)於無水DCM (4.6 mL)中之溶液冷卻0℃,添加2-[4-溴-2-(溴甲基)苯基]乙酸甲酯(556 mg, 1.73 mmol),然後添加2,6-二-第三丁基吡啶(0.31 mL, 1.38 mmol)及三氟甲磺酸銀(354 mg, 1.38 mmol)。將混合物在0℃下攪拌1 h,然後在環境溫度下攪拌16 h。經由矽藻土墊過濾反應混合物並使用DCM沖洗墊。在減壓下濃縮濾液並經由矽膠層析使用於己烷中之0 - 40% EtOAc之梯度來純化殘餘物以得到標題化合物(128 mg, 35%)。ES/MS m/z( 79Br/ 81Br) 529/531 [M+H] +。 Preparation of 282 2-[4-bromo-2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]phenyl ] Methyl acetate 4-[(2-Chloropyrimidin-4-yl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (200 mg, 0.69 mmol) was dissolved in anhydrous DCM (4.6 mL) in an ice bath The solution in was cooled to 0°C, and methyl 2-[4-bromo-2-(bromomethyl)phenyl]acetate (556 mg, 1.73 mmol) was added, followed by 2,6-di-tert-butylpyridine ( 0.31 mL, 1.38 mmol) and silver triflate (354 mg, 1.38 mmol). The mixture was stirred at 0 °C for 1 h, then at ambient temperature for 16 h. The reaction mixture was filtered through a pad of celite and the pad was rinsed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-40% EtOAc in hexanes to afford the title compound (128 mg, 35%). ES/MS m/z ( 79 Br/ 81 Br) 529/531 [M+H] + .
製備 2832-[2-[2-[2-[(2-氯嘧啶-4-基)氧基甲基]-5-氰基-苯基]乙氧基甲基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯 向2-[4-溴-2-[2-[2-[(2-氯嘧啶-4-基)氧基甲基]-5-氰基-苯基]乙氧基甲基]苯基]乙酸甲酯(566 mg, 0.715 mmol)於1,4-二噁烷(7.5 mL)中之溶液中添加雙(頻哪醇)二硼(222 mg, 0.86 mmol)、KOAc (177 mg, 1.80 mmol)及1,1`-雙(二苯基膦基)二茂鐵二氯化鈀(II)二氯甲烷複合物(30 mg, 0.036 mmol)。使用氮將溶液吹掃10 min,然後加熱至80℃。攪拌19 h。將反應液冷卻至環境溫度並經由矽膠塞過濾,使用DCM洗滌矽膠塞。在減壓下濃縮濾液以獲得標題化合物,其未經進一步純化即用於製備284。ES/MS m/z( 35Cl/ 37Cl) 496/498 [M+H] +(關於酸)。 Preparation of 283 2-[2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester To 2-[4-bromo-2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]phenyl] To a solution of methyl acetate (566 mg, 0.715 mmol) in 1,4-dioxane (7.5 mL) was added bis(pinacol)diboron (222 mg, 0.86 mmol), KOAc (177 mg, 1.80 mmol ) and 1,1`-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (30 mg, 0.036 mmol). The solution was purged with nitrogen for 10 min and then heated to 80 °C. Stir for 19 h. The reaction was cooled to ambient temperature and filtered through a silica gel plug, which was washed with DCM. The filtrate was concentrated under reduced pressure to obtain the title compound, which was used in the preparation of 284 without further purification. ES/MS m/z ( 35 Cl/ 37 Cl) 496/498 [M+H] + (about acid).
製備 2842-(5 4-氰基-3,8-二氧雜-2(2,4)-嘧啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯 向2-[2-[2-[2-[(2-氯嘧啶-4-基)氧基甲基]-5-氰基-苯基]乙氧基甲基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸甲酯(製備283, 130 mg, 0.225 mmol)於THF (5.6 mL)中之溶液中添加磷酸三鉀(0.68 mL, 0.68 mmol,1 M水溶液)。使用氮將溶液吹掃10 min,然後添加氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd G2, 8.9 mg, 0.011 mmol)並再繼續吹掃5 min。將溶液在50℃下加熱6 h。將反應液冷卻至環境溫度,然後添加水並使用EtOAc萃取。藉由MgSO 4乾燥合併之有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於己烷中之0 - 40% EtOAc梯度來純化粗製殘餘物以得到標題化合物(21 mg, 22%)。ES/MS m/z416 (M+H)。 Preparation of 284 2-(5 4 -cyano-3,8-dioxa-2(2,4)-pyrimidine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 -yl) methyl acetate To 2-[2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetic acid methyl ester (Preparation 283, 130 mg, 0.225 mmol) in THF (5.6 mL) Tripotassium phosphate (0.68 mL, 0.68 mmol, 1 M in water) was added. The solution was purged with nitrogen for 10 min, then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'- Amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.9 mg, 0.011 mmol) and purging was continued for another 5 min. The solution was heated at 50 °C for 6 h. The reaction was cooled to ambient temperature, then water was added and extracted with EtOAc. The combined organic phases were dried over MgSO4 , filtered and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography using a gradient of 0-40% EtOAc in hexanes to give the title compound (21 mg, 22%). ES/MS m/z 416 (M+H).
製備 2852-(5 4-氰基-3,8-二氧雜-2(2,4)-嘧啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 基本上如製備217中所闡述使用2-(5 4-氰基-3,8-二氧雜-2(2,4)-嘧啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸甲酯來製備標題化合物,其中將反應液在環境溫度下攪拌2 h。在完成後,使用5%檸檬酸水溶液終止反應(使pH達到4),然後使用EtOAc稀釋混合物。分離各層並使用EtOAc萃取水層。使用飽和NaCl水溶液洗滌合併之有機相。藉由MgSO 4乾燥有機相,過濾,並在真空下濃縮。使用水研磨所得固體以得到標題化合物。ES/MS m/z402 (M+H)。 Preparation of 285 2-(5 4 -cyano-3,8-dioxa-2(2,4)-pyrimidine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 -yl)acetic acid Using 2-( 54 -cyano-3,8-dioxa-2(2,4)-pyrimidine-1(1,3),5(1,2)-bis, essentially as described in Preparation 217 The title compound was prepared from methyl phenylcyclonafin-1 4 -yl)acetate, where the reaction was stirred at ambient temperature for 2 h. Upon completion, the reaction was quenched with 5% aqueous citric acid (to bring the pH to 4), and the mixture was diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl. The organic phase was dried over MgSO 4 , filtered and concentrated in vacuo. The resulting solid was triturated with water to give the title compound. ES/MS m/z 402 (M+H).
製備 286( S)-4-(2-(5 4-氰基-3,8-二氧雜-2(2,4)-嘧啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如述製備164中所闡使用2-(5 4-氰基-3,8-二氧雜-2(2,4)-嘧啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-甲氧基-5-[[(2 S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯作為起始材料來製備標題化合物,其中添加2,4,6-三丙基-1,3,5,2,4,6-三三磷雜環己烷-2,4,6-三氧化物於DMF中之50%溶液,且將溶液加熱至42℃並保持24 h。將反應液冷卻至環境溫度且然後添加水。使用EtOAc萃取水層,然後使用飽和NaHCO 3水溶液洗滌有機物。藉由MgSO 4乾燥有機物,過濾,並在減壓下濃縮以得到標題化合物,其未經進一步純化即用於製備287 (23.6 mg, 83%)。ES/MS m/z650 (M+H)。 Preparation of 286 ( S )-4-(2-(5 4 -cyano-3,8-dioxa-2(2,4)-pyrimidine-1(1,3),5(1,2)-di Methyl phenylcyclononafin-1 4 -yl)acetamido)-3-methoxy-5-(((epoxypropylene-2-ylmethyl)amino)benzoate Using 2-( 54 -cyano-3,8-dioxa-2(2,4)-pyrimidine-1(1,3),5(1,2)- Diphenylcyclononan-1 4 -yl)acetic acid and methyl 4-amino-3-methoxy-5-[[(2 S )-epoxypropane-2-yl]methylamino]benzoate As starting material to prepare the title compound, 2,4,6-tripropyl-1,3,5,2,4,6-tritriphosphorinane-2,4,6-trioxide was added 50% solution in DMF, and the solution was heated to 42 °C for 24 h. The reaction was cooled to ambient temperature and then water was added. The aqueous layer was extracted with EtOAc, and the organics were washed with saturated aqueous NaHCO 3 . The organics were dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the title compound, which was used in the preparation of 287 (23.6 mg, 83%) without further purification. ES/MS m/z 650 (M+H).
製備 287(S)-2-((5 4-氰基-3,8-二氧雜-2(2,4)-嘧啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[ d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用( S)-4-(2-(5 4-氰基-3,8-二氧雜-2(2,4)-嘧啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-甲氧基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備286)且使用1,2-二氯乙烷:乙酸之5:1混合物作為溶劑來製備標題化合物,其中將反應液加熱至53℃並保持22 h。在完成後,將反應混合物冷卻至環境溫度,使用DCM稀釋,並在減壓下濃縮。將殘餘物溶於EtOAc中並在減壓下濃縮兩次。經由矽膠層析使用於DCM中之0 - 5% MeOH之梯度來純化殘餘物以得到標題化合物。ES/MS m/z632 (M+H)。 Preparation of 287 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,4)-pyrimidine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropan-2-ylmethyl)-1H-benzo[ d ]imidazole-6-carboxylic acid methyl ester Using ( S )-4-(2-( 54 -cyano-3,8-dioxa-2(2,4)-pyrimidine-1(1,3),5 ) essentially as described in Preparation 102 (1,2)-Diphenylcyclononafin-1 4 -yl)acetamido)-3-methoxy-5-(((epoxypropylene-2-ylmethyl)amino)benzoic acid methyl ester (Preparation 286) and the title compound was prepared using a 5:1 mixture of 1,2-dichloroethane:acetic acid as solvent, where the reaction was heated to 53 °C for 22 h. After completion, the reaction mixture was cooled to ambient temperature, diluted with DCM, and concentrated under reduced pressure. The residue was dissolved in EtOAc and concentrated under reduced pressure twice. The residue was purified by silica gel chromatography using a gradient of 0-5% MeOH in DCM to give the title compound. ES/MS m/z 632 (M+H).
製備 2884-[( E)-2-乙氧基乙烯基]-6-(三氟甲基)吡啶-3-甲酸乙酯 向4-氯-6-(三氟甲基)菸鹼酸乙酯(15 g, 57.4 mmol)及Cs 2CO 3(37 g, 112.4 mmol)於1,4-二噁烷(130 mL)及水(45 mL)中之溶液中添加2-[( E)-2-乙氧基乙烯基]-4,4,5,5-四甲基-1,3,2-二氧硼㖦(13.4 mL, 62.9 mmol),然後添加四(三苯基膦)鈀(0) (7 g, 5.75 mmol)。使用氮吹掃溶液,然後將混合物加熱至90℃並攪拌16 h。在減壓下濃縮反應混合物,然後使用水稀釋。使用EtOAc萃取水層,藉由Na 2SO 4乾燥合併之有機物,過濾,並在減壓下濃縮。經由使用於石油醚中之0 - 23% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到標題化合物(14.5 g, 84%)。ES/MS m/z290 (M+H)。 Preparation of 288 4-[( E )-2-ethoxyvinyl]-6-(trifluoromethyl)pyridine-3-carboxylic acid ethyl ester To ethyl 4-chloro-6-(trifluoromethyl)nicotinate (15 g, 57.4 mmol) and Cs 2 CO 3 (37 g, 112.4 mmol) in 1,4-dioxane (130 mL) and To a solution in water (45 mL) was added 2-[( E )-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborol (13.4 mL, 62.9 mmol), followed by the addition of tetrakis(triphenylphosphine)palladium(0) (7 g, 5.75 mmol). The solution was purged with nitrogen, then the mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure, then diluted with water. The aqueous layer was extracted with EtOAc, the combined organics were dried over Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-23% EtOAc in petroleum ether to afford the title compound (14.5 g, 84%). ES/MS m/z 290 (M+H).
製備 289[4-[( E)-2-乙氧基乙烯基]-6-(三氟甲基)-3-吡啶基]甲醇 在-78℃及惰性氣氛下,向4-[( E)-2-乙氧基乙烯基]-6-(三氟甲基)吡啶-3-甲酸乙酯(14.5 g, 48.1 mmol)於THF (100 mL)中之溶液中添加二異丁基氫化鋁(150 mL, 150 mmol,於甲苯中之1M溶液)。自冷卻浴取出反應容器並在環境溫度下攪拌5 h。藉由在0℃下添加酒石酸鉀鈉飽和水溶液(200 mL)來終止反應,然後添加DCM (100 mL)。使用DCM萃取混合物,然後使用飽和NaCl水溶液洗滌合併之有機相。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮。經由使用於石油醚中之0 - 30% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到標題化合物(11 g, 90%)。ES/MS m/z247 (M +)。 Preparation of 289 [4-[( E )-2-ethoxyvinyl]-6-(trifluoromethyl)-3-pyridyl]methanol 4-[( E )-2-ethoxyvinyl]-6-(trifluoromethyl)pyridine-3-carboxylic acid ethyl ester (14.5 g, 48.1 mmol) in THF at -78°C under inert atmosphere To a solution in (100 mL) was added diisobutylaluminum hydride (150 mL, 150 mmol, 1M solution in toluene). The reaction vessel was removed from the cooling bath and stirred at ambient temperature for 5 h. The reaction was quenched by the addition of saturated aqueous potassium sodium tartrate (200 mL) at 0 °C, followed by DCM (100 mL). The mixture was extracted with DCM, and the combined organic phases were washed with saturated aqueous NaCl. The organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc in petroleum ether to afford the title compound (11 g, 90%). ES/MS m/z 247 (M + ).
製備 2905-[(6-溴-2-吡啶基)氧基甲基]-4-[( E)-2-乙氧基乙烯基]-2-(三氟甲基)吡啶 在0℃下,向[4-[( E)-2-乙氧基乙烯基]-6-(三氟甲基)-3-吡啶基]甲醇(10.5 g, 40.4 mmol)及2-溴-6-氟吡啶(5.4 mL, 51 mmol)於1,4-二噁烷(100 mL)中之溶液中添加第三丁醇鉀(52 mL, 52 mmol,於THF中之1M溶液)。將反應液在0℃下攪拌30 min,然後在環境溫度下攪拌2 h。使用飽和NH 4Cl水溶液(100 mL)終止反應,然後使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之0 - 30% EtOAc之梯度來純化殘餘物以得到標題化合物(17 g, 96%)。ES/MS m/z( 79Br/ 81Br) 402/404 [M+H] +。 Preparation of 290 5-[(6-bromo-2-pyridyl)oxymethyl]-4-[( E )-2-ethoxyvinyl]-2-(trifluoromethyl)pyridine At 0°C, [4-[( E )-2-ethoxyvinyl]-6-(trifluoromethyl)-3-pyridyl]methanol (10.5 g, 40.4 mmol) and 2-bromo- To a solution of 6-fluoropyridine (5.4 mL, 51 mmol) in 1,4-dioxane (100 mL) was added potassium tert-butoxide (52 mL, 52 mmol, 1M solution in THF). The reaction was stirred at 0 °C for 30 min, then at ambient temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL), then extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-30% EtOAc in petroleum ether to afford the title compound (17 g, 96%). ES/MS m/z ( 79 Br/ 81 Br) 402/404 [M+H] + .
製備 2912-[5-[(6-溴-2-吡啶基)氧基甲基]-2-(三氟甲基)-4-吡啶基]乙醇 在0℃下,向5-[(6-溴-2-吡啶基)氧基甲基]-4-[( E)-2-乙氧基乙烯基]-2-(三氟甲基)吡啶(16.5 g, 39.3 mmol)於THF (300 mL)及水(500 mL)中之溶液中添加乙酸汞(14.45 g, 44.89 mmol)。將混合物在0℃下攪拌30 min,然後添加50% K 2CO 3水溶液(210 mL)及硼氫化鈉(6.31 g, 165 mmol)。將混合物在0℃下攪拌2.5 h。過濾反應混合物,使用EtOAc洗滌濾液。將濾液轉移至分液漏斗中並使用EtOAc萃取。使用Na 2SO 4乾燥合併之有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於石油醚中之0 - 25% EtOAc之梯度來純化殘餘物以得到標題化合物(12.1 g, 81%)。ES/MS m/z( 79Br/ 81Br) 376/378 [M+H] +。 Preparation 291 2-[5-[(6-bromo-2-pyridyl)oxymethyl]-2-(trifluoromethyl)-4-pyridyl]ethanol At 0°C, to 5-[(6-bromo-2-pyridyl)oxymethyl]-4-[( E )-2-ethoxyvinyl]-2-(trifluoromethyl)pyridine (16.5 g, 39.3 mmol) in THF (300 mL) and water (500 mL) was added mercuric acetate (14.45 g, 44.89 mmol). The mixture was stirred at 0 °C for 30 min, then 50 % aqueous K2CO3 (210 mL) and sodium borohydride (6.31 g, 165 mmol) were added. The mixture was stirred at 0 °C for 2.5 h. The reaction mixture was filtered and the filtrate was washed with EtOAc. The filtrate was transferred to a separatory funnel and extracted with EtOAc. The combined organic phases were dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified via silica gel chromatography using a gradient of 0-25% EtOAc in petroleum ether to afford the title compound (12.1 g, 81%). ES/MS m/z ( 79 Br/ 81 Br) 376/378 [M+H] + .
製備 2924-[2-[(5-溴-2-氯-苯基)甲氧基]乙基]-5-[(6-溴-2-吡啶基)氧基甲基]-2-(三氟甲基)吡啶 在環境溫度及惰性氣氛下,向2-[5-[(6-溴-2-吡啶基)氧基甲基]-2-(三氟甲基)-4-吡啶基]乙醇(5.46 g, 14.3 mmol)、4-溴-1-氯-2-(氯甲基)苯(5.19 g, 21.4 mmol)及2,6-二-第三丁基-4-甲基吡啶(6 g, 28.64 mmol)於1,2-二氯乙烷(100 mL)中之溶液中添加三氟甲磺酸銀(12 g, 46.24 mmol)。將反應液加熱至70℃並攪拌18 h。在減壓下濃縮粗製反應液,然後使用水稀釋所得殘餘物。使用EtOAc萃取水相,然後使用飽和NaCl水溶液洗滌合併之有機相。藉由Na 2SO 4乾燥有機相,過濾,並在減壓下濃縮。經由使用於石油醚中之0 - 20% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到標題化合物(3.3 g, 37%)。ES/MS m/z580 (M+H)。 Preparation 292 4-[2-[(5-bromo-2-chloro-phenyl) methoxy] ethyl] -5-[(6-bromo-2-pyridyl) oxymethyl] -2-( Trifluoromethyl)pyridine 2-[5-[(6-bromo-2-pyridyl)oxymethyl]-2-(trifluoromethyl)-4-pyridyl]ethanol (5.46 g, 14.3 mmol), 4-bromo-1-chloro-2-(chloromethyl)benzene (5.19 g, 21.4 mmol) and 2,6-di-tert-butyl-4-methylpyridine (6 g, 28.64 mmol ) in 1,2-dichloroethane (100 mL) was added silver triflate (12 g, 46.24 mmol). The reaction solution was heated to 70 °C and stirred for 18 h. The crude reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with water. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated aqueous NaCl. The organic phase was dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in petroleum ether to give the title compound (3.3 g, 37%). ES/MS m/z 580 (M+H).
製備 2931 4-氯-5 6-(三氟甲基)-3,8-二氧雜-2(2,6),5(3,4)-二吡啶-1(1,3)-苯環壬蕃 基本上如製備216中所闡述使用4-[2-[(5-溴-2-氯-苯基)甲氧基]乙基]-5-[(6-溴-2-吡啶基)氧基甲基]-2-(三氟甲基)吡啶作為起始材料且使用(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]甲磺酸鈀(II) (XPhos Pd G3)作為觸媒來製備標題化合物,其中將反應液在110℃下加熱15 h。在減壓下濃縮粗製反應液,然後使用水稀釋殘餘物。使用EtOAc萃取水相,然後使用飽和氯化鈉水溶液洗滌合併之有機相。藉由Na 2SO 4乾燥有機相,過濾,並在減壓下濃縮。經由反相HPLC層析使用於甲酸水溶液中之30-100% ACN之梯度來純化殘餘物以得到白色固體形式之標題化合物(403 mg, 14%)。ES/MS m/z421 (M+H)。 Preparation of 293 1 4 -Chloro-5 6- (trifluoromethyl)-3,8-dioxa-2(2,6),5(3,4)-bipyridine-1(1,3)-benzene Ring Renfan Using 4-[2-[(5-bromo-2-chloro-phenyl)methoxy]ethyl]-5-[(6-bromo-2-pyridyl)oxy essentially as described in Preparation 216 Methyl]-2-(trifluoromethyl)pyridine as starting material and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-Amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3) was used as a catalyst to prepare the title compound, wherein the reaction solution was heated at 110°C for 15 h . The crude reaction solution was concentrated under reduced pressure, and the residue was diluted with water. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated aqueous sodium chloride. The organic phase was dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified via reverse phase HPLC chromatography using a gradient of 30-100% ACN in aqueous formic acid to afford the title compound (403 mg, 14%) as a white solid. ES/MS m/z 421 (M+H).
製備 2941 4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-5 6-(三氟甲基)-3,8-二氧雜-2(2,6),5(3,4)-二吡啶-1(1,3)-苯環壬蕃 向1 4-氯-5 6-(三氟甲基)-3,8-二氧雜-2(2,6),5(3,4)-二吡啶-1(1,3)-苯環壬蕃(275 mg, 0.62 mmol)、KOAc (155 mg, 1.56 mmol)及雙(頻哪醇)二硼(321 mg, 1.24 mmol)於1,4-二噁烷(6.5 mL)中之溶液中添加氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd G2, 50 mg, 0.06 mmol)。使用氮吹掃溶液,然後加熱至80℃並攪拌18 h。在減壓下濃縮反應混合物,然後使用水稀釋殘餘物。使用EtOAc萃取水相,然後使用飽和NaCl水溶液洗滌合併之有機相。藉由Na 2SO 4乾燥有機相,過濾,並在減壓下濃縮。經由使用於石油醚中之0 - 30% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到標題化合物(274 mg, 70%)。ES/MS m/z513 (M+H)。 Preparation of 294 1 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-5 6 -(trifluoromethyl)-3,8-diox Hetero-2(2,6),5(3,4)-bipyridine-1(1,3)-phenylcyclononidine To 1 4 -chloro-5 6 -(trifluoromethyl)-3,8-dioxa-2(2,6),5(3,4)-bipyridine-1(1,3)-benzene A solution of nonafin (275 mg, 0.62 mmol), KOAc (155 mg, 1.56 mmol) and bis(pinacol) diboron (321 mg, 1.24 mmol) in 1,4-dioxane (6.5 mL) Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl )] Palladium(II) (XPhos Pd G2, 50 mg, 0.06 mmol). The solution was purged with nitrogen, then heated to 80 °C and stirred for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated aqueous NaCl. The organic phase was dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc in petroleum ether to give the title compound (274 mg, 70%). ES/MS m/z 513 (M+H).
製備 2952-(氯甲基)-7-(2-甲氧基乙氧基)-3-[[(2 S)-環氧丙烷-2-基]甲基]苯并咪唑-5-甲酸甲酯 在環境溫度下,向4-胺基-3-(2-甲氧基乙氧基)-5-[[(2 S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(310 mg, 0.93 mmol)於EtOH (6 mL)中之溶液中添加2-氯-1,1,1-三甲氧基乙烷(710 mg, 4.50 mmol)。將混合物加熱至90℃並保持2 h,然後在減壓下濃縮反應液。經由使用於DCM中之0 - 5% MeOH之梯度洗脫之矽膠層析來純化殘餘物以得到標題化合物(360 mg, 94%)。ES/MS m/z369 (M+H)。 Preparation of 295 2-(chloromethyl)-7-(2-methoxyethoxy)-3-[[(2 S )-epoxypropane-2-yl]methyl]benzimidazole-5-carboxylic acid methyl ester At ambient temperature, methyl 4-amino-3-(2-methoxyethoxy)-5-[[( 2S )-epoxypropan-2-yl]methylamino]benzoate (310 mg, 0.93 mmol) in EtOH (6 mL) was added 2-chloro-1,1,1-trimethoxyethane (710 mg, 4.50 mmol). The mixture was heated to 90 °C for 2 h, then the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford the title compound (360 mg, 94%). ES/MS m/z 369 (M+H).
製備 296( S)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-2-((5 6-(三氟甲基)-3,8-二氧雜-2(2,6),5(3,4)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-1 H-苯并[ d]咪唑-6-甲酸甲酯 向1 4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-5 6-(三氟甲基)-3,8-二氧雜-2(2,6),5(3,4)-二吡啶-1(1,3)-苯環壬蕃(160 mg, 0.25 mmol, 81 wt%)、2-(氯甲基)-7-(2-甲氧基乙氧基)-3-[[(2 S)-環氧丙烷-2-基]甲基]苯并咪唑-5-甲酸甲酯(256 mg, 0.62 mmol,89質量%)及磷酸三鉀(172 mg, 0.79 mmol)於2-甲基四氫呋喃(1.6 mL)及水(0.32 mL)中之溶液中添加氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd G2, 26 mg, 0.03 mmol)。使用氮吹掃溶液,然後將反應液加熱至80℃並保持18 h。在減壓下濃縮反應混合物,然後使用水稀釋殘餘物。使用EtOAc萃取混合物,然後使用飽和NaCl水溶液洗滌合併之有機相。藉由Na 2SO 4乾燥有機相,過濾,並在減壓下濃縮。經由使用於石油醚中之0 - 60% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以獲得標題化合物(100 mg, 53%)。ES/MS m/z719 (M+H)。 Preparation of 296 ( S )-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-2-((5 6 -(trifluoromethyl)-3,8 -Dioxa-2(2,6),5(3,4)-bipyridine-1(1,3)-phencyclononan-1 4 -yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl ester To 1 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-5 6 -(trifluoromethyl)-3,8-dioxa -2(2,6),5(3,4)-dipyridine-1(1,3)-phenylcyclonazone (160 mg, 0.25 mmol, 81 wt%), 2-(chloromethyl)-7 -(2-Methoxyethoxy)-3-[[(2 S )-epoxypropan-2-yl]methyl]benzimidazole-5-carboxylic acid methyl ester (256 mg, 0.62 mmol, 89 mass %) and tripotassium phosphate (172 mg, 0.79 mmol) in 2-methyltetrahydrofuran (1.6 mL) and water (0.32 mL) were added chlorine (2-dicyclohexylphosphino-2',4', 6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 26 mg, 0.03 mmol) . The solution was purged with nitrogen, and then the reaction solution was heated to 80 °C for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The mixture was extracted with EtOAc, and the combined organic phases were washed with saturated aqueous NaCl. The organic phase was dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by silica gel chromatography eluting with a gradient of 0-60% EtOAc in petroleum ether to afford the title compound (100 mg, 53%). ES/MS m/z 719 (M+H).
製備 2972-(2-甲基噁唑-4-基)乙酸乙酯 在室溫下,將4-氯-3-側氧基-丁酸乙酯(40 g, 243 mmol)添加至乙醯胺(15 g, 254 mmol)於甲苯(80 mL)中之溶液中。加熱至130℃並攪拌12 h。過濾反應混合物並在減壓下濃縮濾液。經由使用於石油醚中之10 - 15% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到黃色油狀物形式之標題化合物(30%純度,19 g, 13%)。ES/MS m/z170 (M+H)。 Preparation of 297 2-(2-methyloxazol-4-yl) ethyl acetate 4-Chloro-3-oxo-butyric acid ethyl ester (40 g, 243 mmol) was added to a solution of acetamide (15 g, 254 mmol) in toluene (80 mL) at room temperature. Heat to 130 °C and stir for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 10-15% EtOAc in petroleum ether to give the title compound (30% purity, 19 g, 13%) as a yellow oil. ES/MS m/z 170 (M+H).
製備 2982-(2-甲基噁唑-4-基)乙醇 將氯化鈣(26 g, 234 mmol)添加至2-(2-甲基噁唑-4-基)乙酸乙酯(20 g, 35.5 mmol)於EtOH (400 mL)中之溶液中。將混合物攪拌20 min,冷卻至0℃,且然後添加硼氫化鈉(10 g, 265 mmol)。將反應混合物在室溫下攪拌12 h且然後使用1 M HCl水溶液將pH調節至7。使用DCM (3 × 200 mL)萃取混合物,藉由Na 2SO 4乾燥合併之有機物,過濾,並濃縮。經由使用於石油醚中之50 - 100% EtOAc之梯度、隨後於DCM中之0 - 15% MeOH之梯度洗脫之矽膠層析來純化殘餘物以得到黃色油狀物形式之標題化合物(70%純度,5 g, 78%)。ES/MS m/z128 (M+H)。 Preparation of 298 2-(2-methyloxazol-4-yl)ethanol Calcium chloride (26 g, 234 mmol) was added to a solution of ethyl 2-(2-methyloxazol-4-yl)acetate (20 g, 35.5 mmol) in EtOH (400 mL). The mixture was stirred for 20 min, cooled to 0 °C, and then sodium borohydride (10 g, 265 mmol) was added. The reaction mixture was stirred at room temperature for 12 h and then the pH was adjusted to 7 using 1 M aqueous HCl. The mixture was extracted with DCM (3 x 200 mL), the combined organics were dried over Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 50-100% EtOAc in petroleum ether followed by a gradient of 0-15% MeOH in DCM to give the title compound as a yellow oil (70% purity, 5 g, 78%). ES/MS m/z 128 (M+H).
製備 2993-氟-5-羥基-4-硝基-苯甲酸甲酯 在-40℃下,將三溴化硼(於DCM中之2 M溶液,65.4 mL, 131 mmol)逐滴添加至3-氟-5-甲氧基-4-硝基-苯甲酸甲酯(30 g, 131 mmol)於DCM (500 mL)中之溶液中。將混合物在-40℃下攪拌30 min且然後在環境溫度下攪拌16 h。將混合物傾倒至冰水(2 L)中並使用DCM (3 × 800 mL)萃取。使用飽和NaCl水溶液(2 × 300 mL)洗滌合併之有機層,藉由Na 2SO 4乾燥,過濾,並濃縮。經由使用於石油醚中之0 - 30% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到黃色固體形式之標題化合物(16.5 g, 59%)。 1H NMR (CDCl 3) ( 10.31 (s, 1H), 7.63 (s, 1H), 7.41 (d, 1H, J = 11), 3.98 (s, 3H)。 19F NMR (CDCl 3) δ -113.37 (s)。 Preparation of 299 3-fluoro-5-hydroxy-4-nitro-benzoic acid methyl ester Boron tribromide (2 M solution in DCM, 65.4 mL, 131 mmol) was added dropwise to methyl 3-fluoro-5-methoxy-4-nitro-benzoate ( 30 g, 131 mmol) in DCM (500 mL). The mixture was stirred at -40 °C for 30 min and then at ambient temperature for 16 h. The mixture was poured into ice water (2 L) and extracted with DCM (3 x 800 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x 300 mL), dried over Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc in petroleum ether to give the title compound (16.5 g, 59%) as a yellow solid. 1 H NMR (CDCl 3 ) ( 10.31 (s, 1H), 7.63 (s, 1H), 7.41 (d, 1H, J = 11), 3.98 (s, 3H). 19 F NMR (CDCl 3 ) δ -113.37 (s).
製備 3003-氟-5-[2-(2-甲基噁唑-4-基)乙氧基]-4-硝基-苯甲酸甲酯 在0℃下,將偶氮二甲酸二異丙基酯(5.6 g, 28 mmol)添加至3-氟-5-羥基-4-硝基-苯甲酸甲酯(3 g, 13.9 mmol)及2-(2-甲基噁唑-4-基)乙醇(3 g, 16.5 mmol)於THF (30 mL)中之溶液中。將混合物升溫至環境溫度並攪拌12 h。使用水(30 mL)稀釋混合物並使用EtOAc (3 × 50 mL)萃取。使用飽和NaCl水溶液(100 mL)洗滌合併之有機物,藉由Na 2SO 4乾燥,過濾,並濃縮。經由使用於石油醚中之0 - 50% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到淺黃色固體形式之標題化合物(17%純度,6 g, 23%)。ES/MS m/z325 (M+H)。 Preparation of 300 3-fluoro-5-[2-(2-methyloxazol-4-yl)ethoxy]-4-nitro-benzoic acid methyl ester Diisopropyl azodicarboxylate (5.6 g, 28 mmol) was added to 3-fluoro-5-hydroxy-4-nitro-benzoic acid methyl ester (3 g, 13.9 mmol) and 2 In a solution of -(2-methyloxazol-4-yl)ethanol (3 g, 16.5 mmol) in THF (30 mL). The mixture was warmed to ambient temperature and stirred for 12 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with saturated aqueous NaCl (100 mL), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in petroleum ether to give the title compound (17% purity, 6 g, 23%) as a pale yellow solid. ES/MS m/z 325 (M+H).
製備 3013-[2-(2-甲基噁唑-4-基)乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 將(S)-環氧丙烷-2-基甲胺(15 g, 6.29 mmol)及TEA (1 mL, 7.17 mmol)添加至3-氟-5-[2-(2-甲基噁唑-4-基)乙氧基]-4-硝基-苯甲酸甲酯(6 g, 3.15 mmol)於DMSO (150 mL)中之溶液中。將混合物在80℃下攪拌12 h,冷卻至環境溫度,使用水(300 mL)稀釋,並使用EtOAc (3 × 400 mL)萃取。使用飽和NaCl水溶液(3 × 500 mL)洗滌合併之有機層,藉由Na 2SO 4乾燥,過濾,並濃縮。經由使用於石油醚中之0 - 60% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以提供黃色油狀物形式之標題化合物(24%純度,2 g, 39%)。ES/MS m/z392 (M+H)。 Preparation 301 3-[2-(2-Methyloxazol-4-yl)ethoxy]-4-nitro-5-[[(2S)-epoxypropylene-2-yl]methylamino] methyl benzoate (S)-Oxiran-2-ylmethylamine (15 g, 6.29 mmol) and TEA (1 mL, 7.17 mmol) were added to 3-fluoro-5-[2-(2-methyloxazole-4 -yl)ethoxy]-4-nitro-benzoic acid methyl ester (6 g, 3.15 mmol) in DMSO (150 mL). The mixture was stirred at 80 °C for 12 h, cooled to ambient temperature, diluted with water (300 mL), and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with saturated aqueous NaCl (3 x 500 mL), dried over Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-60% EtOAc in petroleum ether to afford the title compound (24% purity, 2 g, 39%) as a yellow oil. ES/MS m/z 392 (M+H).
製備 3024-胺基-3-[2-(2-甲基噁唑-4-基)乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 將碳載鈀(1 g, 10wt% Pd)添加至3-[2-(2-甲基噁唑-4-基)乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(2 g, 1.23 mmol)於EtOAc (150 mL)中之溶液中。使用氫氣吹掃反應容器並抽真空三次。將氫氣氣囊連接至容器並攪拌2 h。過濾混合物並在減壓下濃縮。藉由使用於石油醚中之0 - 100% EtOAc之梯度洗脫之矽膠層析來純化殘餘物,且然後藉由製備型HPLC [管柱:Phenomenex C18 75 × 40 mm, 3 µm;移動相:於NH 4HCO 3水溶液(10 mM)中之18 - 48% ACN]進一步純化以得到白色固體形式之標題化合物(88 mg, 19%)。ES/MS m/z362 (M+H)。 Preparation 302 4-amino-3-[2-(2-methyloxazol-4-yl)ethoxy]-5-[[(2S)-epoxypropylene-2-yl]methylamino] methyl benzoate Palladium on carbon (1 g, 10 wt% Pd) was added to 3-[2-(2-methyloxazol-4-yl)ethoxy]-4-nitro-5-[[(2S)-cyclo A solution of methyl oxypropan-2-yl]methylamino]benzoate (2 g, 1.23 mmol) in EtOAc (150 mL). The reaction vessel was purged with hydrogen and evacuated three times. A hydrogen balloon was attached to the vessel and stirred for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient elution of 0-100% EtOAc in petroleum ether, and then by preparative HPLC [column: Phenomenex C18 75×40 mm, 3 μm; mobile phase: 18-48% ACN] in aqueous NH4HCO3 (10 mM) was further purified to give the title compound (88 mg, 19%) as a white solid. ES/MS m/z 362 (M+H).
製備 303(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-(2-甲基噁唑-4-基)乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 基本上如製備86中所闡述使用4-胺基-3-[2-(2-甲基噁唑-4-基)乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(80 mg, 0.215 mmol)及2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸來製備標題化合物,且產物未經進一步純化即用於製備304。ES/MS m/z744 (M+H)。 Preparation 303 (S)-4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Phenylcyclononafin-1 4 -yl)acetamido)-3-(2-(2-methyloxazol-4-yl)ethoxy)-5-((epoxypropylene-2-ylmethyl base) amino) methyl benzoate Essentially as described in Preparation 86 using 4-amino-3-[2-(2-methyloxazol-4-yl)ethoxy]-5-[[(2S)-propylene oxide-2- Methyl]methylamino]benzoate (80 mg, 0.215 mmol) and 2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3 ), 5(1,2)-diphenylcyclononan- 1 4 -yl)acetic acid to prepare the title compound and the product was used in the preparation of 304 without further purification. ES/MS m/z 744 (M+H).
製備 304(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(2-甲基噁唑-4-基)乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-(2-甲基噁唑-4-基)乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備303)及使用1,2-二氯乙烷:乙酸之1:1混合物來製備標題化合物。在完成後,將反應液冷卻至環境溫度並在真空下去除揮發物。添加1:1 EtOAc/甲苯并濃縮三次以去除殘餘乙酸。經由使用於DCM中之0 - 6% MeOH之梯度洗脫之矽膠層析來純化殘餘物以得到橙色固體形式之標題化合物。ES/MS m/z726 (M+H)。 Preparation of 304 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-4-(2-(2-methyloxazol-4-yl)ethoxy)-1-(epoxypropylene-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononafran-1 4 -yl)acetamido)-3-(2-(2-methyloxazol-4-yl)ethoxy)-5-((cyclo Oxypropan-2-ylmethyl)amino)benzoic acid methyl ester (Preparation 303) and a 1:1 mixture of 1,2-dichloroethane:acetic acid were used to prepare the title compound. Upon completion, the reaction was cooled to ambient temperature and volatiles were removed under vacuum. Added 1:1 EtOAc/toluene and concentrated three times to remove residual acetic acid. The residue was purified by silica gel chromatography eluting with a gradient of 0-6% MeOH in DCM to afford the title compound as an orange solid. ES/MS m/z 726 (M+H).
製備 305N-(2-羥乙基)-N-(2,2,2-三氟乙基)胺基甲酸第三丁基酯 在微波反應器中,將2-溴乙醇(5 g, 38.8 mmol)及2,2,2-三氟乙基胺(9.66 g, 97.0 mmol)於乙醇(50 mL)中之混合物在60℃下於密封管中加熱3 h,然後濃縮反應混合物。向殘餘物中添加TEA (5.2 mL, 3.7 g, 37 mmol)及焦碳酸二-第三丁基酯(5.6 mL, 5.3 g, 24 mmol)且將混合物在55℃及N2下攪拌過夜。將反應混合物分配於EtOAc與水之間,且在減壓下濃縮有機相。藉由矽膠層析使用於石油醚中之0 - 38% EtOAc之梯度來純化殘餘物以得到黃色油狀物形式之標題化合物(2.5 g, 50%)。 1H NMR (400 MHz, DMSO) δ 4.76 (m, 1H), 4.06 (q, J= 9.5 Hz, 2H), 3.67 (m, 2H), 3.30 (q, J= 6 Hz, 2H), 1.41 (s, 9H)。 Preparation of 305 tert-butyl N-(2-hydroxyethyl)-N-(2,2,2-trifluoroethyl)carbamate In a microwave reactor, a mixture of 2-bromoethanol (5 g, 38.8 mmol) and 2,2,2-trifluoroethylamine (9.66 g, 97.0 mmol) in ethanol (50 mL) was heated at 60°C After heating in a sealed tube for 3 h, the reaction mixture was concentrated. To the residue were added TEA (5.2 mL, 3.7 g, 37 mmol) and di-tert-butyl dicarbonate (5.6 mL, 5.3 g, 24 mmol) and the mixture was stirred at 55°C under N2 overnight. The reaction mixture was partitioned between EtOAc and water, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-38% EtOAc in petroleum ether to afford the title compound (2.5 g, 50%) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 4.76 (m, 1H), 4.06 (q, J = 9.5 Hz, 2H), 3.67 (m, 2H), 3.30 (q, J = 6 Hz, 2H), 1.41 ( s, 9H).
製備 3063-[2-[第三丁氧基羰基(2,2,2-三氟乙基)胺基]乙氧基]-5-氟-4-硝基-苯甲酸甲酯 在0℃下,向3-氟-5-羥基-4-硝基-苯甲酸甲酯(1.5 g, 6.6 mmol)、 N-(2-羥乙基)-N-(2,2,2-三氟乙基)胺基甲酸第三丁基酯(2.1 g, 7.8 mmol)及三苯基膦(3.5 g, 13 mmol)於THF (10 mL)中之溶液中添加DIAD (2.8 mL, 13 mmol)。在添加之後,將混合物在20℃下攪拌18 h。使用水(50 mL)稀釋混合物並使用EtOAc (3 × 50 mL)萃取。藉由Na 2SO 4乾燥合併之有機層,過濾,並在減壓下濃縮。藉由使用0 - 20% EtOAc/石油醚之梯度洗脫之矽膠層析來純化以得到黃色油狀物形式之標題化合物(3.2 g, 93%)。ES/MS m/z340.9 (M-Boc+H)。 Preparation of 306 3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5-fluoro-4-nitro-benzoic acid methyl ester At 0°C, 3-fluoro-5-hydroxy-4-nitro-benzoic acid methyl ester (1.5 g, 6.6 mmol), N-(2-hydroxyethyl)-N-(2,2,2- To a solution of tert-butyl trifluoroethyl)carbamate (2.1 g, 7.8 mmol) and triphenylphosphine (3.5 g, 13 mmol) in THF (10 mL) was added DIAD (2.8 mL, 13 mmol ). After the addition, the mixture was stirred at 20 °C for 18 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 , filtered, and concentrated under reduced pressure . Purification by silica gel chromatography eluting with a gradient of 0-20% EtOAc/petroleum ether gave the title compound (3.2 g, 93%) as a yellow oil. ES/MS m/z 340.9 (M-Boc+H).
製備 3073-[2-[第三丁氧基羰基(2,2,2-三氟乙基)胺基]乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 基本上如製備301中所闡述使用3-[2-[第三丁氧基羰基(2,2,2-三氟乙基)胺基]乙氧基]-5-氟-4-硝基-苯甲酸甲酯及富馬酸;(S)-環氧丙烷-2-基甲胺來製備標題化合物,其中將反應液在微波反應器中於100℃下加熱3 h。ES/MS m/z508.1 (M+H)。 Preparation 307 3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-4-nitro-5-[[(2S)-propylene oxide -2-yl]methylamino]benzoic acid methyl ester Essentially as described in Preparation 301 using 3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5-fluoro-4-nitro- Methyl benzoate and fumaric acid; (S)-epoxypropylene-2-ylmethylamine were used to prepare the title compound, wherein the reaction solution was heated in a microwave reactor at 100 °C for 3 h. ES/MS m/z 508.1 (M+H).
製備 3084-胺基-3-[2-[第三丁氧基羰基(2,2,2-三氟乙基)胺基]乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 向3-[2-[第三丁氧基羰基(2,2,2-三氟乙基)胺基]乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(1.1 g, 1.8 mmol)於MeOH (10 mL)中之溶液中添加Pd/C (810 mg,10質量%)。將混合物在環境溫度及氫(15 psi)下攪拌2 h。添加矽藻土,過濾,並在減壓下濃縮濾液。藉由使用於DCM中之0 - 9% MeOH之梯度洗脫之矽膠層析來純化殘餘物以得到標題化合物(940 mg, >99%)。ES/MS m/z478.1 (M+H)。 Preparation of 308 4-amino-3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5-[[(2S)-propylene oxide -2-yl]methylamino]benzoic acid methyl ester To 3-[2-[tertiary butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-4-nitro-5-[[(2S)-propylene oxide- To a solution of methyl 2-yl]methylamino]benzoate (1.1 g, 1.8 mmol) in MeOH (10 mL) was added Pd/C (810 mg, 10% by mass). The mixture was stirred at ambient temperature under hydrogen (15 psi) for 2 h. Celite was added, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0 - 9% MeOH in DCM to afford the title compound (940 mg, >99%). ES/MS m/z 478.1 (M+H).
製備 309(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-[2-[第三丁氧基羰基(2,2,2-三氟乙基)胺基]乙氧基]- 5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 基本上如製備86中所闡述使用2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸及4-胺基-3-[2-[第三丁氧基羰基(2,2,2-三氟乙基)胺基]乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯來製備標題化合物。ES/MS m/z860.2 (M+H)。 Preparation of 309 (S)-4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Benzenecyclononyl-1 4 -yl)acetamido)-3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5- Methyl [[(2S)-epoxypropan-2-yl]methylamino]benzoate Using 2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-dioxa, essentially as described in Preparation 86 Phenylcyclononafin-1 4 -yl)acetic acid and 4-amino-3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5 -[[(2S)-Oxiran-2-yl]methylamino]benzoic acid methyl ester to prepare the title compound. ES/MS m/z 860.2 (M+H).
製備 310(S)-4-(2-((第三丁氧基羰基)(2,2,2-三氟乙基)胺基)乙氧基)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-[2-[第三丁氧基羰基(2,2,2-三氟乙基)胺基]乙氧基]- 5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯及1:1 DCM :乙酸之混合物(作為溶劑)來製備標題化合物,其中將反應液在55℃下加熱18 h。在完成後,將反應液冷卻至環境溫度,使用甲苯稀釋,並在減壓下濃縮。藉由使用於DCM中之0 - 14% MeOH之梯度洗脫之矽膠層析來純化殘餘物以得到褐色油狀物形式之標題化合物。ES/MS m/z842.2 (M+H)。 Preparation 310 (S)-4-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)ethoxy)-2-((5 4 -cyano- 3,9-Dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononafin-1 4 -yl)methyl)-1-(cyclo Oxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using (S)-4-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononafran-1 4 -yl)acetamido)-3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino] The title compound was prepared from methyl ethoxy]-5-[[(2S)-epoxypropan-2-yl]methylamino]benzoate and a 1:1 mixture of DCM:acetic acid as solvent, wherein The reaction solution was heated at 55 °C for 18 h. After completion, the reaction was cooled to ambient temperature, diluted with toluene, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-14% MeOH in DCM to give the title compound as a brown oil. ES/MS m/z 842.2 (M+H).
製備 311(S)-4-(2-((第三丁氧基羰基)(2,2,2-三氟乙基)胺基)乙氧基)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例5中所闡述使用(S)-4-(2-((第三丁氧基羰基)(2,2,2-三氟乙基)胺基)乙氧基)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯、1,5,7-三氮雜雙環[4.4.0]癸-5-烯在3:1:1 ACN : THF :水之混合物中來製備標題化合物,其中將反應液在55℃下加熱2 h。在完成後,將反應液冷卻至環境溫度並使用1 M甲酸水溶液驟冷以得到沈澱物。過濾並收集沈澱物以得到標題化合物,其未經進一步純化即用於實例54。ES/MS m/z828.2 (M+H)。 Preparation 311 (S)-4-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)ethoxy)-2-((5 4 -cyano- 3,9-Dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononafin-1 4 -yl)methyl)-1-(cyclo Oxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-4-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)ethoxy)-2-( (5 4 -Cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan- 1 4 -yl)methanol Base)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester, 1,5,7-triazabicyclo[4.4.0]decane-5 -ene in a 3:1:1 ACN:THF:water mixture to prepare the title compound, where the reaction was heated at 55 °C for 2 h. Upon completion, the reaction was cooled to ambient temperature and quenched with 1 M aqueous formic acid to give a precipitate. The precipitate was filtered and collected to give the title compound which was used in Example 54 without further purification. ES/MS m/z 828.2 (M+H).
製備 3122-氯-6-[(4-氯-2-碘-苯基)甲氧基]吡啶 製備4-氯-2-碘-1-甲基-苯(40 g, 158 mmol)及N-溴琥珀醯亞胺(27.3 g, 153 mmol)於ACN (500 mL)中之溶液。流經由環繞4100K白色燈泡(42W、150W等效)之盤繞PFA反應管(1/8’’外徑,53 mL體積)組成之光化學反應器,其中流速為1.3 mL/min且維持系統溫度介於30℃與40℃之間。在完成後,使ACN (100 mL)以相同速率流經反應器。將輸出液滴注至含有6-氯吡啶-2-醇(21.8 g, 168 mmol)及K 2CO 3(44.1 g, 319 mmol)於ACN (400 mL)中之懸浮液之燒瓶中。在完全添加溴化材料之後,在室溫下攪拌1 h。過濾粗製反應混合物並在減壓下濃縮。經由矽膠層析使用於己烷中之0 - 10% EtOAc來純化殘餘物以得到45.8 g標題化合物(76%)。ES-MS m/z380及382 (M+H)。 Preparation of 312 2-chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine A solution of 4-chloro-2-iodo-1-methyl-benzene (40 g, 158 mmol) and N-bromosuccinimide (27.3 g, 153 mmol) in ACN (500 mL) was prepared. Flow through a photochemical reactor consisting of a coiled PFA reaction tube (1/8'' outer diameter, 53 mL volume) surrounding a 4100K white bulb (42W, 150W equivalent), where the flow rate is 1.3 mL/min and the system temperature is maintained at Between 30°C and 40°C. Upon completion, ACN (100 mL) was flowed through the reactor at the same rate. The output was instilled dropwise into a flask containing a suspension of 6-chloropyridin-2-ol (21.8 g, 168 mmol) and K 2 CO 3 (44.1 g, 319 mmol) in ACN (400 mL). After complete addition of brominated material, stir at room temperature for 1 h. The crude reaction mixture was filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using 0-10% EtOAc in hexanes to afford 45.8 g of the title compound (76%). ES-MS m/z 380 and 382 (M+H).
製備 3132-氯-6-[[4-氯-2-[2-乙氧基乙烯基]苯基]甲氧基]吡啶 在N 2下,向2-氯-6-[(4-氯-2-碘-苯基)甲氧基]吡啶(5.0 g, 13 mmol)於THF (70 mL)中之溶液中添加磷酸鉀水溶液(2 M, 150 mL, 300 mmol)及1-乙氧基乙烯-2-酸頻哪醇酯(1/1.3異構體混合物,3.81 mL, 17.1 mmol)並將混合物攪拌5 min。添加雙(三苯基膦)二氯化鈀(II) (470 mg, 0.663 mmol),且將混合物加熱至65℃並保持21 h。將混合物冷卻至室溫並添加水(100 mL)及EtOAc (100 mL)。將混合物在室溫下攪拌5 min,分離有機層並使用EtOAc (2 × 100 mL)萃取水層。合併有機層並使用水(100 mL)、飽和NaCl水溶液(100 mL)洗滌。濃縮有機物並藉由經由矽膠塞過濾使用DCM洗脫劑來純化殘餘物以得到褐色固體形式之標題化合物(4.37 g, 100%)。ES/MS m/z324 (M+H)。 Preparation of 313 2-chloro-6-[[4-chloro-2-[2-ethoxyvinyl]phenyl]methoxy]pyridine To a solution of 2-chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine (5.0 g, 13 mmol) in THF (70 mL) was added potassium phosphate under N Aqueous solution (2 M, 150 mL, 300 mmol) and 1-ethoxyethylene-2- Acid pinacol ester (1/1.3 isomer mixture, 3.81 mL, 17.1 mmol) and the mixture was stirred for 5 min. Bis(triphenylphosphine)palladium(II) dichloride (470 mg, 0.663 mmol) was added and the mixture was heated to 65 °C for 21 h. The mixture was cooled to room temperature and water (100 mL) and EtOAc (100 mL) were added. The mixture was stirred at room temperature for 5 min, the organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined and washed with water (100 mL), saturated aqueous NaCl (100 mL). The organics were concentrated and the residue was purified by filtration through a silica gel plug using DCM eluent to give the title compound (4.37 g, 100%) as a tan solid. ES/MS m/z 324 (M+H).
製備 3142-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]乙醛 向2-氯-6-[[4-氯-2-[2-乙氧基乙烯基]苯基]甲氧基]吡啶(54.2 g, 161.1 mmol)於丙酮(525 mL)及水(175 mL)中之溶液中添加鹽酸(35 mL, 407 mmol,36.5%於水中),且加熱至65℃並保持一小時。將反應液冷卻至室溫並使用水(250 mL)及MTBE (250 mL)稀釋。分離有機相並使用MTBE (3 × 250 mL)萃取水相。使用2M Na 2CO 3水溶液(250 mL)、水(250 mL)、飽和NaCl水溶液(250 mL)洗滌合併之有機層,藉由Na 2SO 4乾燥並在真空中去除溶劑以得到44.5 g標題化合物(93%),其未經進一步純化即用於製備315。ES-MS m/z296.0, 298.0 (M+H)。 Preparation of 314 2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]acetaldehyde To 2-chloro-6-[[4-chloro-2-[2-ethoxyvinyl]phenyl]methoxy]pyridine (54.2 g, 161.1 mmol) in acetone (525 mL) and water (175 mL ) was added hydrochloric acid (35 mL, 407 mmol, 36.5% in water) and heated to 65 °C for one hour. The reaction was cooled to room temperature and diluted with water (250 mL) and MTBE (250 mL). The organic phase was separated and the aqueous phase was extracted with MTBE (3 x 250 mL). The combined organic layers were washed with 2M aqueous Na2CO3 ( 250 mL), water ( 250 mL), saturated aqueous NaCl (250 mL), dried over Na2SO4 and the solvent was removed in vacuo to give 44.5 g of the title compound (93%), which was used in the preparation of 315 without further purification. ES-MS m/z 296.0, 298.0 (M+H).
製備 3152-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]乙醇 在5℃下,向2-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]乙醛(製備314,44.5 g, 150.3 mmol)於EtOH (400 mL)中之溶液中逐份添加硼氫化鈉(11.85 g, 300.7 mmol)並在室溫下攪拌一小時。將反應液冷卻至0℃並使用水(250 mL)驟冷,且使用5%檸檬酸水溶液將pH調節至6。添加MTBE (400 mL),分離有機相並使用MTBE (3 × 250 mL)萃取水相。合併有機層並使用水(250 mL)、飽和NaCl水溶液(250 mL)洗滌,藉由Na 2SO 4乾燥並在真空中去除溶劑。藉由矽膠層析使用於環己烷中之20 - 40% EtOAc之梯度來純化粗製材料以得到31.95 g標題化合物(71%),其在靜置時發生結晶。ES-MS m/z298.0, 300.0 (M+H)。 Preparation of 315 2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]ethanol 2-[5-Chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]acetaldehyde (Preparation 314, 44.5 g, 150.3 mmol) was dissolved in EtOH (400 mL) was added sodium borohydride (11.85 g, 300.7 mmol) in portions and stirred at room temperature for one hour. The reaction was cooled to 0 °C and quenched with water (250 mL), and the pH was adjusted to 6 using 5% aqueous citric acid. MTBE (400 mL) was added, the organic phase was separated and the aqueous phase was extracted with MTBE (3 x 250 mL). The organic layers were combined and washed with water (250 mL), saturated aqueous NaCl (250 mL), dried over Na 2 SO 4 and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography using a gradient of 20-40% EtOAc in cyclohexane to afford 31.95 g of the title compound (71%) which crystallized on standing. ES-MS m/z 298.0, 300.0 (M+H).
製備 3162-[[2-[2-[(5-溴-2-碘-苯基)甲氧基]乙基]-4-氯-苯基]甲氧基]-6-氯-吡啶 在0℃下,向2-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]乙醇(31.80 g, 106.6 mmol)於THF (360 mL)中之溶液中添加氫化鈉(60 wt%,於礦物油中,8.14 g, 203 mmol)並攪拌20 min。向其中逐份添加4-溴-2-(溴甲基)-1-碘-苯(49.4 g, 131 mmol)並使混合物升溫至室溫,且攪拌18 h。向其中添加額外氫化鈉(60 wt%,於礦物油中,1.25g, 31.3 mmol),隨後添加額外4-溴-2-(溴甲基)-1-碘-苯(4.9 g, 13 mmol)並將混合物在室溫下再攪拌5 h。將反應液冷卻至0℃並使用5%檸檬酸水溶液(250 mL)驟冷,且添加MTBE (200 mL)。分離有機相並使用MTBE (3 × 250 mL)萃取水相。合併有機層並使用水(200 mL)、飽和NaCl水溶液(200 mL)洗滌,藉由Na 2SO 4乾燥並在真空中去除溶劑。藉由矽膠層析使用於環己烷中之40 - 100% DCM之梯度來純化殘餘物以得到45.05 g黃色油狀物形式之標題化合物(71%)。ES-MS m/z593.8 (M+H)。 Preparation of 316 2-[[2-[2-[(5-bromo-2-iodo-phenyl)methoxy]ethyl]-4-chloro-phenyl]methoxy]-6-chloro-pyridine Add 2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]ethanol (31.80 g, 106.6 mmol) in THF (360 mL) at 0°C Sodium hydride (60 wt% in mineral oil, 8.14 g, 203 mmol) was added to the solution and stirred for 20 min. To this was added 4-bromo-2-(bromomethyl)-1-iodo-benzene (49.4 g, 131 mmol) in portions and the mixture was allowed to warm to room temperature and stirred for 18 h. To this was added additional sodium hydride (60 wt % in mineral oil, 1.25 g, 31.3 mmol), followed by additional 4-bromo-2-(bromomethyl)-1-iodo-benzene (4.9 g, 13 mmol) And the mixture was stirred for another 5 h at room temperature. The reaction was cooled to 0 °C and quenched with 5% aqueous citric acid (250 mL), and MTBE (200 mL) was added. The organic phase was separated and the aqueous phase was extracted with MTBE (3 x 250 mL). The organic layers were combined and washed with water (200 mL), saturated aqueous NaCl (200 mL), dried over Na 2 SO 4 and the solvent was removed in vacuo. The residue was purified by silica gel chromatography using a gradient of 40 - 100% DCM in cyclohexane to afford 45.05 g of the title compound (71%) as a yellow oil. ES-MS m/z 593.8 (M+H).
製備 3172-[4-溴-2-[2-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]乙氧基甲基]苯基]乙酸乙酯 在室溫及N 2下,攪拌2-[[2-[2-[(5-溴-2-碘-苯基)甲氧基]乙基]-4-氯-苯基]甲氧基]-6-氯-吡啶(13.11 g, 22.1 mmol)及氯[(4,5-雙(二苯基膦基)-9,9-二甲基呫噸)-2-(2'-胺基-1,1'-聯苯)]鈀(II)] (XantPhos Pd G2, 1.100 g, 1.107 mmol)於THF (50 mL)中之溶液。向此混合物中逐滴添加溴-(2-乙氧基-2-側氧基-乙基)鋅(0.4 M於THF中,103 mL, 40 mmol),且將混合物加熱至65℃並保持3 h。將反應混合物冷卻至0℃並使用5%檸檬酸水溶液(200 mL)驟冷,且添加MTBE (200 mL)。分離有機相並使用MTBE (3 × 100 mL)萃取水相。使用水(200 mL)、飽和NaCl水溶液(200 mL)洗滌合併之有機層,藉由Na 2SO 4乾燥並在真空下去除溶劑。藉由矽膠層析使用於環己烷中之20 - 100% DCM之梯度來純化殘餘物以得到9.15 g深褐色油狀物形式之標題化合物(75%)。ES-MS m/z552.0, 554.0 (M+H)。 Preparation 317 2-[4-Bromo-2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]ethoxymethyl]phenyl]acetic acid ethyl ester 2-[[2-[2-[(5-Bromo-2-iodo-phenyl)methoxy]ethyl]-4-chloro-phenyl]methoxy] was stirred at room temperature under N -6-chloro-pyridine (13.11 g, 22.1 mmol) and chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino- A solution of 1,1'-biphenyl)]palladium(II)] (XantPhos Pd G2, 1.100 g, 1.107 mmol) in THF (50 mL). To this mixture was added bromo-(2-ethoxy-2-oxo-ethyl)zinc (0.4 M in THF, 103 mL, 40 mmol) dropwise, and the mixture was heated to 65 °C for 3 h. The reaction mixture was cooled to 0 °C and quenched with 5% aqueous citric acid (200 mL), and MTBE (200 mL) was added. The organic phase was separated and the aqueous phase was extracted with MTBE (3 x 100 mL). The combined organic layers were washed with water (200 mL), saturated aqueous NaCl (200 mL), dried over Na 2 SO 4 and the solvent was removed in vacuo. The residue was purified by silica gel chromatography using a gradient of 20-100% DCM in cyclohexane to afford 9.15 g of the title compound (75%) as a dark brown oil. ES-MS m/z 552.0, 554.0 (M+H).
製備 3182-[2-[2-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]乙氧基甲基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯 使N 2氣鼓泡通過2-[4-溴-2-[2-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]乙氧基甲基]苯基]乙酸乙酯(7.50g, 13.6 mmol)、雙(頻哪醇)二硼(4.39 g, 16.9 mmol)及KOAc (4.1 g, 41 mmol)於二噁烷(270 mL)中之溶液15 min。向此混合物中添加二氯雙(三環己基膦)鈀(II) (1.02 g, 1.35 mmol),且加熱至90℃並保持20 h。向此混合物中添加額外之雙(頻哪醇)二硼(0.439 g, 1.69 mmol)、二氯雙(三環己基膦)鈀(II) (0.10 g, 0.13 mmol)及KOAc (0.410g, 4.1 mmol)。將混合物加熱至90℃並保持4 h。將混合物冷卻至室溫並經由使用DCM洗脫之矽膠塞過濾以得到9.11 g粗製深褐色油狀物形式之標題化合物(112%),其未經進一步純化即用於製備319。ES-MS m/z600.2, 602.2 (M+H)。 Preparation of 318 2-[2-[2-[5-chloro-2-[(6-chloro-2-pyridyl) oxymethyl] phenyl] ethoxymethyl] -4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaboron-2-yl)phenyl]ethyl acetate Bubble N gas through 2-[4-bromo-2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]ethoxymethyl A solution of ]phenyl]ethyl acetate (7.50 g, 13.6 mmol), bis(pinacol)diboron (4.39 g, 16.9 mmol) and KOAc (4.1 g, 41 mmol) in dioxane (270 mL) 15 min. To this mixture was added dichlorobis(tricyclohexylphosphine)palladium(II) (1.02 g, 1.35 mmol) and heated to 90 °C for 20 h. To this mixture was added additional bis(pinacol)diboron (0.439 g, 1.69 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (0.10 g, 0.13 mmol) and KOAc (0.410 g, 4.1 mmol). The mixture was heated to 90 °C for 4 h. The mixture was cooled to room temperature and filtered through a plug of silica gel eluting with DCM to afford 9.11 g of the title compound (112%) as a crude dark brown oil, which was used in the preparation of 319 without further purification. ES-MS m/z 600.2, 602.2 (M+H).
製備 3192-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯 使N 2氣鼓泡通過2-[2-[2-[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]乙氧基甲基]-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯(9.10g, 15.2 mmol)及磷酸三鉀水溶液(1 M, 91 mL, 91 mmol)於THF (610 mL)中之溶液15 min。向此混合物中添加[氯(2-二環己基膦基-2',4',6'-三-異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)] (XPhos-Pd-G2, 1.22 g, 1.52 mmol),且加熱至65℃並保持一小時。將反應液冷卻至室溫,使用水(300 mL)稀釋並使用MTBE (3 × 250 mL)萃取。使用水(250 mL)、飽和NaCl水溶液(250 mL)洗滌合併之有機物,藉由MgSO 4乾燥,過濾,並在真空中濃縮。藉由矽膠層析使用於環己烷中之80 - 100% DCM之梯度來純化殘餘物以得到1.6 g白色固體形式之標題化合物(24.1%)。ES-MS m/z438.2 (M+H)。 Preparation of 319 2-(5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-1 4 - base) ethyl acetate Bubble N gas through 2-[2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]ethoxymethyl]-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]ethyl acetate (9.10g, 15.2 mmol) and tripotassium phosphate aqueous solution (1 M, 91 mL, 91 mmol) in THF (610 mL) for 15 min. To this mixture was added [chloro(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1' -biphenyl-2-yl)palladium(II)] (XPhos-Pd-G2, 1.22 g, 1.52 mmol), and heated to 65 °C for one hour. The reaction was cooled to room temperature, diluted with water (300 mL) and extracted with MTBE (3 x 250 mL). The combined organics were washed with water (250 mL), saturated aqueous NaCl (250 mL), dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 80-100% DCM in cyclohexane to afford 1.6 g of the title compound (24.1%) as a white solid. ES-MS m/z 438.2 (M+H).
製備 3202-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 向2-(54-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-14-基)乙酸乙酯(900 mg, 2.06 mmol)於ACN (5 mL)、1,4-二噁烷(5 mL)及水(5 mL)中之溶液中添加1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(500 mg, 3.52 mmol),且加熱至50℃並保持3 h。將反應液冷卻至室溫,使用1N HCl (2 mL)驟冷,使用水稀釋並使用EtOAc (2 × 250 mL)萃取。合併有機物,使用飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾並在真空中濃縮以得到835 mg淺黃色固體形式之標題化合物(99%)。ES-MS m/z410.9 (M+H)。 Preparation 320 2-(5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-1 4 - base) acetic acid To 2-(54-chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-14-yl)acetic acid To a solution of ethyl ester (900 mg, 2.06 mmol) in ACN (5 mL), 1,4-dioxane (5 mL) and water (5 mL) was added 1,3,4,6,7,8- Hexahydro-2H-pyrimido[1,2-a]pyrimidine (500 mg, 3.52 mmol), and heated to 50°C for 3 h. The reaction was cooled to room temperature, quenched with 1N HCl (2 mL), diluted with water and extracted with EtOAc (2 x 250 mL). The organics were combined, washed with saturated aqueous NaCl, dried over MgSO 4 , filtered and concentrated in vacuo to give 835 mg of the title compound (99%) as a pale yellow solid. ES-MS m/z 410.9 (M+H).
製備 3213-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-5-氟-4-硝基-苯甲酸甲酯 向3-氟-5-羥基-4-硝基-苯甲酸甲酯(2 g, 9.3 mmol)、2-((第三丁基二甲基矽基)氧基)乙醇(2.6 g, 14 mmol)及三苯基苯基膦(3.5 g, 13 mmol)於THF (30 mL)中之0℃溶液中添加DIAD (3.8 g, 19 mmol)。升溫至20℃並攪拌12 h。使用水(50 mL)稀釋並使用EtOAc (3 × 80 mL)萃取。使用飽和氯化鈉水溶液(100 mL)洗滌合併之有機層,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮。藉由使用0-20% EtOAc/石油醚洗脫之矽膠層析來純化殘餘物以得到無色油狀物形式之標題化合物(4 g, 92%)。 1H NMR (CDCl 3) δ 7.59 (s, 1H), 7.51 (d, J= 24 Hz, 1H), 4.25 (t, J= 5 Hz, 2H), 3.98 (t, J = 5 Hz, 2H), 3.97 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H)。 Preparation 321 3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-fluoro-4-nitro-benzoic acid methyl ester To 3-fluoro-5-hydroxy-4-nitro-benzoic acid methyl ester (2 g, 9.3 mmol), 2-((tert-butyldimethylsilyl)oxy) ethanol (2.6 g, 14 mmol ) and triphenylphenylphosphine (3.5 g, 13 mmol) in THF (30 mL) at 0 °C was added DIAD (3.8 g, 19 mmol). Warm up to 20 °C and stir for 12 h. Diluted with water (50 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with saturated aqueous sodium chloride (100 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc/petroleum ether to give the title compound (4 g, 92%) as a colorless oil. 1 H NMR (CDCl 3 ) δ 7.59 (s, 1H), 7.51 (d, J = 24 Hz, 1H), 4.25 (t, J = 5 Hz, 2H), 3.98 (t, J = 5 Hz, 2H) , 3.97 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H).
製備 3223-(2-羥基乙氧基)-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 向3-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-5-氟-4-硝基-苯甲酸甲酯(2 g, 4.32 mmol)於DMSO (200 mL)中之溶液中添加TEA (2.5 mL, 18 mmol)及(S)-環氧丙烷-2-基甲胺(21 g, 8.7 mmol)。在80℃下攪拌12 h。使用水(200 mL)稀釋並使用EtOAc (3 × 300 mL)萃取。使用飽和氯化鈉水溶液(400 mL)洗滌合併之有機層,藉由Na 2SO 4乾燥,過濾,並在真空中濃縮。藉由使用0-50% EtOAc/石油醚洗脫之矽膠層析來純化殘餘物以得到標題化合物(320 mg, 18%)。 1H NMR (CDCl 3) δ 7.16 (s, 1H), 6.93 (s, 1H), 6.39 (s, 1H), 5.11 (m, 1H), 4.72 (m, 1H), 4.59 (m, 1H), 4.24 (t, j= 4 Hz, 2H), 3.97 – 3.93 (m, 5H), 3.50 (t, j= 4 Hz, 2H), 2.73 (m, 1H), 2.58 (m, 1H)。 Preparation 322 Methyl 3-(2-hydroxyethoxy)-4-nitro-5-[[(2S)-epoxypropane-2-yl]methylamino]benzoate To 3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-fluoro-4-nitro-benzoic acid methyl ester (2 g, 4.32 mmol) in DMSO (200 mL) was added TEA (2.5 mL, 18 mmol) and (S)-epoxypropylene-2-ylmethylamine (21 g, 8.7 mmol). Stir at 80 °C for 12 h. Diluted with water (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with saturated aqueous sodium chloride (400 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/petroleum ether to give the title compound (320 mg, 18%). 1 H NMR (CDCl 3 ) δ 7.16 (s, 1H), 6.93 (s, 1H), 6.39 (s, 1H), 5.11 (m, 1H), 4.72 (m, 1H), 4.59 (m, 1H), 4.24 (t, j = 4 Hz, 2H), 3.97 – 3.93 (m, 5H), 3.50 (t, j = 4 Hz, 2H), 2.73 (m, 1H), 2.58 (m, 1H).
製備 3233-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 向3-(2-羥基乙氧基)-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(320 mg, 0.78 mmol)於DCM (10 mL)中之溶液中添加第三丁基二甲基氯矽烷(200 mg, 1.29 mmol)及咪唑(130 mg, 1.90 mmol)。將混合物在20℃下攪拌2 h。使用水(20 mL)稀釋並使用DCM (3 × 30 mL)萃取。使用飽和氯化鈉水溶液(50 mL)洗滌合併之有機層,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮。藉由使用0-20% EtOAc/石油醚洗脫之矽膠層析來純化殘餘物以得到標題化合物(400 mg, 93%)。ES/MS ( m/z): 441.1 (M+H)。 Preparation 323 3-[2-[tertiary butyl(dimethyl)silyl]oxyethoxy]-4-nitro-5-[[(2S)-epoxypropane-2-yl]methyl Amino]benzoic acid methyl ester Add 3-(2-hydroxyethoxy)-4-nitro-5-[[(2S)-epoxypropane-2-yl]methylamino]benzoate (320 mg, 0.78 mmol) to To a solution in DCM (10 mL) was added tert-butyldimethylsilyl chloride (200 mg, 1.29 mmol) and imidazole (130 mg, 1.90 mmol). The mixture was stirred at 20 °C for 2 h. Diluted with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc/petroleum ether to give the title compound (400 mg, 93%). ES/MS ( m/z ): 441.1 (M+H).
製備 3244-胺基-3-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 向3-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(670 mg, 1.22 mmol)於EtOAc (100 mL)中之溶液中添加Pd/C (300 mg,10質量%)。使用氫氣吹掃三次並在20℃及填氫氣囊下攪拌一小時。過濾混合物且在減壓下濃縮濾液。藉由使用0-10% MeOH/DCM洗脫之矽膠層析來純化殘餘物以得到標題化合物(475 mg, 95%)。ES/MS ( m/z): 411.4 (M+H)。 Preparation 324 4-Amino-3-[2-[tertiary butyl(dimethyl)silyl]oxyethoxy]-5-[[(2S)-epoxypropane-2-yl]methyl Amino]benzoic acid methyl ester To 3-[2-[tertiary butyl(dimethyl)silyl]oxyethoxy]-4-nitro-5-[[(2S)-epoxypropylene-2-yl]methylamine To a solution of methyl]benzoate (670 mg, 1.22 mmol) in EtOAc (100 mL) was added Pd/C (300 mg, 10 mass %). It was purged three times with hydrogen and stirred for one hour at 20 °C under a hydrogen balloon. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give the title compound (475 mg, 95%). ES/MS ( m/z ): 411.4 (M+H).
製備 325(S)-3-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-4-(2-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(80 mg, 0.20 mmol)及4-胺基-3-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(87 mg, 0.21 mmol)於DMF (3 mL)中之溶液中添加DIEA (0.07 mL, 0.4 mmol),隨後添加HATU (124 mg, 0.32 mmol)。將混合物在20℃下攪拌2 h,然後使用水(20 mL)稀釋以形成固體。過濾掉固體並在真空下乾燥以得到標題化合物(132 mg, 84%)。ES/MS m/z( 35Cl/ 37Cl) 802.4/804.4 [M+H]。 Preparation of 325 (S)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-(2-(5 4 -chloro-3,8-dioxa- 2(2,6)-Pyridine-1(1,3),5(1,2)-Diphenylcyclononafin- 1 4 -yl)acetamido)-5-(((propylene oxide-2- Methyl (methyl) amino) benzoate To 2-(5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan- 1 4 -yl ) acetic acid (80 mg, 0.20 mmol) and 4-amino-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-[[(2S)-epoxy To a solution of propan-2-yl]methylamino]methylbenzoate (87 mg, 0.21 mmol) in DMF (3 mL) was added DIEA (0.07 mL, 0.4 mmol) followed by HATU (124 mg, 0.32 mmol). The mixture was stirred at 20 °C for 2 h, then diluted with water (20 mL) to form a solid. The solid was filtered off and dried under vacuum to give the title compound (132 mg, 84%). ES/MS m/z ( 35 Cl/ 37 Cl) 802.4/804.4 [M+H].
製備 326(S)-4-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將(S)-3-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-4-(2-(54-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-14-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(132 mg, 0.165 mmol)於乙酸(3 mL)中之溶液加熱至80℃並保持1.5 h,然後冷卻至環境溫度並在減壓下濃縮。藉由使用50 - 100% EtOAc/甲苯及隨後2 - 5% MeOH/EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到標題化合物(62 mg, 48%)。藉由LC-ES/MS測得,產物在1.8 min時洗脫出,但不離子化。LCMS分析之條件:2 × 50 Xbridge C18 3.5 µm,在50℃下,在1.5分鐘內於10 mM NH 4HCO 3水溶液中之5-95% ACN (pH 9),然後在0.5 min內95% ACN。 Preparation of 326 (S)-4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-2-((5 4 -chloro-3,8-dioxa-2( 2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylic acid methyl ester (S)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-(2-(54-chloro-3,8-dioxa-2( 2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-14-yl)acetamido)-5-((epoxypropylene-2-ylmethyl A solution of )amino)methylbenzoate (132 mg, 0.165 mmol) in acetic acid (3 mL) was heated to 80 °C for 1.5 h, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 50 - 100% EtOAc/toluene followed by 2 - 5% MeOH/EtOAc to afford the title compound (62 mg, 48%). The product eluted at 1.8 min, but was not ionized, as determined by LC-ES/MS. Conditions for LCMS analysis: 2 × 50 Xbridge C18 3.5 µm, 5-95% ACN (pH 9) in 10 mM NH 4 HCO 3 aqueous solution in 1.5 min at 50°C, then 95% ACN in 0.5 min .
製備 3273-[2-(二甲基胺基)乙氧基]-5-氟-4-硝基-苯甲酸甲酯 向3-氟-5-羥基-4-硝基-苯甲酸甲酯(2 g, 9.30 mmol)於THF (20 mL)中之溶液中添加N,N-二甲基乙醇胺(994 mg, 11.15 mmol)、三苯基膦(2.92 g, 11.15 mmol)及DIAD (2.25 g, 11.15 mmol)。將反應液在環境溫度下攪拌18 h。過濾反應混合物並在減壓下濃縮濾液。經由使用於DCM中之0 - 10% MeOH之梯度洗脫之矽膠急速層析來純化殘餘物以得到黃色油狀物形式之標題化合物(690 mg, 26%)。ES/MS m/z287 (M+H)。 Preparation 327 3-[2-(Dimethylamino)ethoxy]-5-fluoro-4-nitro-benzoic acid methyl ester To a solution of methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (2 g, 9.30 mmol) in THF (20 mL) was added N,N-dimethylethanolamine (994 mg, 11.15 mmol ), triphenylphosphine (2.92 g, 11.15 mmol) and DIAD (2.25 g, 11.15 mmol). The reaction was stirred at ambient temperature for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to afford the title compound (690 mg, 26%) as a yellow oil. ES/MS m/z 287 (M+H).
製備 3283-[2-(二甲基胺基)乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 向3-[2-(二甲基胺基)乙氧基]-5-氟-4-硝基-苯甲酸甲酯(690 mg, 2.41 mmol)於DMSO (8 mL)中之溶液中添加(2S)-環氧丙烷-2-基-甲胺(420 mg, 4.8 mmol)及TEA (1.46 g, 14.4 mmol)。將反應混合物在80℃下攪拌18 h。將混合物冷卻至環境溫度,使用水(50 mL)稀釋並使用EtOAc (2 × 50 mL)萃取。合併有機物,使用水及飽和NaCl水溶液(2 × 50 mL)洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下蒸發。經由使用於DCM中之0 - 20% MeOH之梯度洗脫之矽膠急速層析來純化殘餘物以得到無色油狀物形式之標題化合物(1.03 g, 72%)。ES/MS m/z354 (M+H)。 Preparation of 328 3-[2-(Dimethylamino)ethoxy]-4-nitro-5-[[(2S)-epoxypropylene-2-yl]methylamino]benzoic acid methyl ester To a solution of methyl 3-[2-(dimethylamino)ethoxy]-5-fluoro-4-nitro-benzoate (690 mg, 2.41 mmol) in DMSO (8 mL) was added ( 2S)-Oxiran-2-yl-methylamine (420 mg, 4.8 mmol) and TEA (1.46 g, 14.4 mmol). The reaction mixture was stirred at 80 °C for 18 h. The mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organics were combined, washed with water and saturated aqueous NaCl (2 x 50 mL), dried over Na2SO4 , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0-20% MeOH in DCM to afford the title compound (1.03 g, 72%) as a colorless oil. ES/MS m/z 354 (M+H).
製備 3294-胺基-3-[2-(二甲基胺基)乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 向3-[2-(二甲基胺基)乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(1.03 g, 1.75 mmol)於EtOAc (100 mL)中之溶液中添加10% Pd/C (200 mg, 0.18 mmol)。將混合物在氫氣(14.5 psi)及環境溫度下攪拌2 h,然後經由矽藻土過濾並在減壓下濃縮濾液。藉由製備型HPLC純化殘餘物以得到白色固體形式之標題化合物(102 mg, 17%)。[管柱:Welch Xtimate C18 75 × 40mm, 3 μm;移動相A:含有NH 3H 2O+NH 4HCO 3之H 2O;移動相B:ACN;梯度:22%至52% B)。ES/MS m/z324 (M+H)。 Preparation of 329 4-amino-3-[2-(dimethylamino)ethoxy]-5-[[(2S)-epoxypropylene-2-yl]methylamino]benzoic acid methyl ester To 3-[2-(dimethylamino)ethoxy]-4-nitro-5-[[(2S)-epoxypropane-2-yl]methylamino]benzoate (1.03 g, 1.75 mmol) in EtOAc (100 mL) was added 10% Pd/C (200 mg, 0.18 mmol). The mixture was stirred under hydrogen (14.5 psi) at ambient temperature for 2 h, then filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (102 mg, 17%) as a white solid. [Column: Welch Xtimate C18 75 × 40mm, 3 μm; Mobile phase A: H 2 O containing NH 3 H 2 O+NH 4 HCO 3 ; Mobile phase B: ACN; Gradient: 22% to 52% B). ES/MS m/z 324 (M+H).
製備 330(S)-4-(2-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-(二甲基胺基)乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(75 mg, 0.18 mmol)及4-胺基-3-[2-(二甲基胺基)乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(60 mg, 0.18 mmol)於DMF (2 mL)中之溶液中添加HATU (115 mg, 0.3 mmol)及DIPEA (0.10 mL, 0.5 mmol)。將混合物在環境溫度下攪拌17 h。使用水終止反應並過濾沈澱之白色固體。濃縮濾液並使用EtOAc萃取。合併有機層,藉由MgSO 4乾燥有機物,過濾,並濃縮以得到固體殘餘物。合併第一白色固體與殘餘物以得到白色固體形式之標題化合物(173 mg, 132%)。ES/MS m/z715 (M+H)。 Preparation 330 (S)-4-(2-(5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl Cyclononafin-1 4 -yl)acetamido)-3-(2-(dimethylamino)ethoxy)-5-(((epoxypropylene-2-ylmethyl)amino)benzene Methyl formate To 2-(5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclononan- 1 4 -yl ) acetic acid (75 mg, 0.18 mmol) and 4-amino-3-[2-(dimethylamino)ethoxy]-5-[[(2S)-epoxypropane-2-yl]methyl To a solution of methylamino]benzoate (60 mg, 0.18 mmol) in DMF (2 mL) was added HATU (115 mg, 0.3 mmol) and DIPEA (0.10 mL, 0.5 mmol). The mixture was stirred at ambient temperature for 17 h. The reaction was quenched with water and the precipitated white solid was filtered. The filtrate was concentrated and extracted with EtOAc. The organic layers were combined, dried over MgSO 4 , filtered, and concentrated to give a solid residue. The first white solid and residue were combined to give the title compound (173 mg, 132%) as a white solid. ES/MS m/z 715 (M+H).
製備 331(S)-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(二甲基胺基)乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將(S)-4-(2-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-(二甲基胺基)乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(130 mg; 0.18 mmol)於乙酸(2 mL)及1,2-二氯乙烷(1.5 mL)中之混合物在55℃下加熱21 h。將混合物冷卻至環境溫度並在減壓下濃縮。經由使用於DCM中之0 - 10% MeOH之梯度洗脫之矽膠急速層析來純化殘餘物以得到白色固體形式之標題化合物(89 mg, 70%)。ES/MS m/z697 (M+H)。 Preparation 331 (S)-2-((5 4 -Chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclone Fan-1 4 -yl)methyl)-4-(2-(dimethylamino)ethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole -6-methyl carboxylate (S)-4-(2-(5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)acetamido)-3-(2-(dimethylamino)ethoxy)-5-(((oxypropylene-2-ylmethyl)amino)benzoic acid A mixture of the methyl ester (130 mg; 0.18 mmol) in acetic acid (2 mL) and 1,2-dichloroethane (1.5 mL) was heated at 55 °C for 21 h. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to afford the title compound (89 mg, 70%) as a white solid. ES/MS m/z 697 (M+H).
製備 3323-[2-[第三丁氧基羰基(甲基)胺基]乙氧基]-5-氟-4-硝基-苯甲酸甲酯 向3-氟-5-羥基-4-硝基-苯甲酸甲酯(2 g, 9.30 mmol)及胺基甲酸第三丁基-(2-羥乙基)甲基酯(3.43 g, 18.6 mmol)於THF (20 mL)中之溶液中添加三苯基膦(3.7 g, 14 mmol)及DIAD (2.82 g, 13.9 mmol)。將反應液在環境溫度下攪拌12 h。在減壓下濃縮混合物並經由使用於石油醚中之0 - 20% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到黃色油狀物形式之標題化合物(2.3 g, 66%)。ES/MS ( m/z): 373 (M+H)。 Preparation of 332 3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5-fluoro-4-nitro-benzoic acid methyl ester To 3-fluoro-5-hydroxy-4-nitro-benzoic acid methyl ester (2 g, 9.30 mmol) and tertiary butyl-(2-hydroxyethyl) methyl carbamate (3.43 g, 18.6 mmol ) in THF (20 mL) was added triphenylphosphine (3.7 g, 14 mmol) and DIAD (2.82 g, 13.9 mmol). The reaction was stirred at ambient temperature for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in petroleum ether to give the title compound (2.3 g, 66%) as a yellow oil. ES/MS ( m/z ): 373 (M+H).
製備 3333-[2-[第三丁氧基羰基(甲基)胺基]乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 向3-[2-[第三丁氧基羰基(甲基)胺基]乙氧基]-5-氟-4-硝基-苯甲酸甲酯(1 g, 2.68 mmol)於DMSO (60 mL)中之溶液中添加(2S)-環氧丙烷-2-基-甲胺於EtOH (13.0g, 5.4 mmol)及TEA (1.6 g, 16 mmol)中之3.6% w/w溶液。將反應混合物在80℃下攪拌12 h。將混合物冷卻至環境溫度,使用水(100 mL)稀釋並使用EtOAc (3 × 100 mL)萃取。合併有機物,使用水及飽和NaCl水溶液(3 × 100 mL)洗滌,藉由Na 2SO 4乾燥,過濾,並在減壓下濃縮。經由使用於石油醚中之0 - 20% EtOAc之梯度洗脫之矽膠層析來純化殘餘物以得到黃色油狀物形式之標題化合物(750 mg, 62%)。ES/MS ( m/z): 440 (M+H-Boc)。 Preparation of 333 3-[2-[tertiary butoxycarbonyl (methyl)amino]ethoxy]-4-nitro-5-[[(2S)-epoxypropane-2-yl]methylamine Methyl]benzoate Add 3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5-fluoro-4-nitro-benzoic acid methyl ester (1 g, 2.68 mmol) in DMSO (60 mL ) was added a 3.6% w/w solution of (2S)-epoxypropan-2-yl-methylamine in EtOH (13.0 g, 5.4 mmol) and TEA (1.6 g, 16 mmol). The reaction mixture was stirred at 80 °C for 12 h. The mixture was cooled to ambient temperature, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organics were combined, washed with water and saturated aqueous NaCl (3 x 100 mL), dried over Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in petroleum ether to give the title compound (750 mg, 62%) as a yellow oil. ES/MS ( m/z ): 440 (M+H-Boc).
製備 3344-胺基-3-[2-[第三丁氧基羰基(甲基)胺基]乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯 向3-[2-[第三丁氧基羰基(甲基)胺基]乙氧基]-4-硝基-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(700 mg, 1.59 mmol)於EtOAc (50 mL)中之溶液中添加10% Pd/C (200 mg, 0.18 mmol)。將混合物在氫氣(15 psi)及環境溫度下攪拌2 h。經由矽藻土過濾反應混合物並在減壓下濃縮濾液以得到標題化合物(536 mg, 82%)。ES/MS ( m/z): 410 (M+H)。 Preparation of 334 4-amino-3-[2-[tertiary butoxycarbonyl (methyl) amino]ethoxy]-5-[[(2S)-epoxypropane-2-yl]methylamine Methyl]benzoate To 3-[2-[3-butoxycarbonyl (methyl)amino]ethoxy]-4-nitro-5-[[(2S)-epoxypropylene-2-yl]methylamino ] To a solution of methyl benzoate (700 mg, 1.59 mmol) in EtOAc (50 mL) was added 10% Pd/C (200 mg, 0.18 mmol). The mixture was stirred under hydrogen (15 psi) at ambient temperature for 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound (536 mg, 82%). ES/MS ( m/z ): 410 (M+H).
製備 335(S)-3-(2-((第三丁氧基羰基)(甲基)胺基)乙氧基)-4-(2-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(80 mg, 0.19 mmol)及4-胺基-3-[2-[第三丁氧基羰基(甲基)胺基]乙氧基]-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(82 mg, 0.19 mmol)於DMF (2 mL)中之溶液中添加HATU (130 mg, 0.33 mmol)及DIEA (0.11 mL, 0.62 mmol)。將混合物在環境溫度下攪拌15 h,然後使用水驟冷並使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並在減壓下濃縮以得到固體形式之標題化合物(155 mg, 80%),其未經進一步純化即用於製備336。ES/MS ( m/z): 801 (M+H)。 Preparation 335 (S)-3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-4-(2-(5 4 -chloro-3,8-dioxa -2(2,6)-Pyridine-1(1,3),5(1,2)-Diphenylcyclononan- 1 4 -yl)acetamido)-5-((propylene oxide-2 -ylmethyl)amino)methyl benzoate To 2-(5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclononan- 1 4 -yl ) acetic acid (80 mg, 0.19 mmol) and 4-amino-3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5-[[(2S)-propylene oxide To a solution of methyl-2-yl]methylamino]benzoate (82 mg, 0.19 mmol) in DMF (2 mL) was added HATU (130 mg, 0.33 mmol) and DIEA (0.11 mL, 0.62 mmol). The mixture was stirred at ambient temperature for 15 h, then quenched with water and extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the title compound as a solid (155 mg, 80%), which was used in the preparation of 336 without further purification. ES/MS ( m/z ): 801 (M+H).
製備 336(S)-4-(2-((第三丁氧基羰基)(甲基)胺基)乙氧基)-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將(S)-3-(2-((第三丁氧基羰基)(甲基)胺基)乙氧基)-4-(2-(5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備335,155 mg, 0.19 mmol)於乙酸(1.5 mL)及1,2-二氯乙烷(1.5 mL)中之混合物在55℃下加熱18 h。將反應液冷卻至環境溫度並在減壓下濃縮。經由使用於DCM中之0 - 10% MeOH之梯度洗脫之矽膠層析來純化殘餘物以得到白色固體形式之標題化合物(150 mg, 99%)。ES/MS ( m/z): 783 (M+H)。 Preparation 336 (S)-4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-((5 4 -chloro-3,8-dioxa-2 (2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylic acid methyl ester (S)-3-(2-((tertiary butoxycarbonyl)(methyl)amino)ethoxy)-4-(2-(5 4 -chloro-3,8-dioxa- 2(2,6)-Pyridine-1(1,3),5(1,2)-Diphenylcyclononafin- 1 4 -yl)acetamido)-5-(((propylene oxide-2- A mixture of methyl (methyl)amino)benzoate (preparation 335, 155 mg, 0.19 mmol) in acetic acid (1.5 mL) and 1,2-dichloroethane (1.5 mL) was heated at 55 °C for 18 h . The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to afford the title compound (150 mg, 99%) as a white solid. ES/MS ( m/z ): 783 (M+H).
製備 337(S)-4-(2-((第三丁氧基羰基)(甲基)胺基)乙氧基)-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-4-(2-((第三丁氧基羰基)(甲基)胺基)乙氧基)-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(150 mg, 0.19 mmol)於ACN (2 mL)、1,4-二噁烷(2 mL)及水(0.4 mL)中之氮脫氣混合物中添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(86 mg, 0.60 mmol),且將混合物加熱至55℃並保持36 h。將反應混合物冷卻至環境溫度,在減壓下濃縮,並經由反相層析使用於水中之10 - 90% ACN (向兩種溶劑中添加0.1%甲酸)之梯度來純化殘餘物以得到白色固體形式之標題化合物(64 mg, 43%)。ES/MS ( m/z): 769 (M+H)。 Preparation 337 (S)-4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-((5 4 -chloro-3,8-dioxa-2 (2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylic acid To (S)-4-(2-((tertiary butoxycarbonyl)(methyl)amino)ethoxy)-2-((5 4 -chloro-3,8-dioxa-2( 2,6)-Pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)- Nitrogen degassing of methyl 1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.19 mmol) in ACN (2 mL), 1,4-dioxane (2 mL) and water (0.4 mL) To the mixture was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (86 mg, 0.60 mmol), and the mixture was heated to 55 °C for 36 h. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure, and the residue was purified by reverse phase chromatography using a gradient of 10 - 90% ACN in water (0.1% formic acid was added to both solvents) to give a white solid form of the title compound (64 mg, 43%). ES/MS ( m/z ): 769 (M+H).
製備 3382-(4-溴-5-氟-2-甲基-苯基)乙酸乙酯 在室溫下向1-溴-2-氟-4-碘-5-甲基-苯(11 g, 34 mmol)及氯[(4,5-雙(二苯基膦基)-9,9-二甲基呫噸)-2-(2'-胺基-1,1'-聯苯)]鈀(II) (XantPhos-Pd-G2, 3.5 mg, 3.4 mmol)於THF (45 mL)中之溶液中添加(2-乙氧基-2-側氧基乙基)溴化鋅(II) (0.50 M於THF中,110 mL, 60 mmol)並將混合物在65℃及N 2下攪拌過夜。藉由添加1N HCl (100 mL)來終止反應,然後使用EtOAc (3 × 100 mL)萃取混合物。合併有機層並使用K 2CO 3水溶液(100 mL)洗滌,藉由Na 2SO 4乾燥並在真空中濃縮。藉由矽膠層析使用於石油醚中之0 - 20% EtOAc之梯度來純化殘餘物以得到淺黃色油狀物形式之標題化合物(9.73 g, 98%)。ES/MS m/z 274.8 (M+H)。 Preparation of 338 ethyl 2-(4-bromo-5-fluoro-2-methyl-phenyl)acetate To 1-bromo-2-fluoro-4-iodo-5-methyl-benzene (11 g, 34 mmol) and chloro[(4,5-bis(diphenylphosphino)-9,9 -Dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (XantPhos-Pd-G2, 3.5 mg, 3.4 mmol) in THF (45 mL) To a solution of (2-ethoxy-2-oxoethyl)zinc(II) bromide (0.50 M in THF, 110 mL, 60 mmol) was added and the mixture was stirred overnight at 65 °C under N . The reaction was quenched by adding 1N HCl (100 mL), and the mixture was extracted with EtOAc (3 x 100 mL). The organic layers were combined and washed with aqueous K 2 CO 3 (100 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0-20% EtOAc in petroleum ether to afford the title compound (9.73 g, 98%) as a light yellow oil. ES/MS m/z 274.8 (M+H).
製備 3392-[4-溴-2-(溴甲基)-5-氟-苯基]乙酸乙酯 製備2-(4-溴-5-氟-2-甲基-苯基)乙酸乙酯(5.9 g, 21 mmol)及N-溴琥珀醯亞胺(3.6 g, 20 mmol)於ACN (110 mL)中之溶液。使溶液流經由環繞4100K白色燈泡(42W、150W等效)之盤繞PFA反應管(1/8’’外徑,53 mL體積)組成之光化學反應器,其中流速為1.3 mL/min且維持系統溫度介於30℃與40℃之間。在完成後,使ACN (100 mL)以相同速率流經反應器。使用水(500 mL)及庚烷 (200 mL)稀釋輸出混合物。使用庚烷(200 mL)萃取水層並使用飽和硫代硫酸鈉水溶液(2 × 100 mL)洗滌合併之有機層。藉由MgSO 4乾燥有機層,過濾,並在真空下濃縮。經由矽膠層析使用於己烷中之0 - 10% EtOAc之梯度來純化殘餘物以得到7.0 g標題化合物(92%產率,90%純)。 1H-NMR (400 MHz, CDCl 3) δ 7.59 (d, J= 7 Hz, 1H), 7.09 (d, J= 9 Hz, 1H), 4.50 (s, 2H), 4.20 (q, J= 7.5 Hz, 2H), 3.75 (s, 2H), 1.29 (t, J= 7.5 Hz, 3H)。 Preparation of 339 2-[4-bromo-2-(bromomethyl)-5-fluoro-phenyl]ethyl acetate Preparation of ethyl 2-(4-bromo-5-fluoro-2-methyl-phenyl)acetate (5.9 g, 21 mmol) and N-bromosuccinimide (3.6 g, 20 mmol) in ACN (110 mL ) solution. Let the solution flow through a photochemical reactor composed of a coiled PFA reaction tube (1/8'' outer diameter, 53 mL volume) surrounding a 4100K white bulb (42W, 150W equivalent), where the flow rate is 1.3 mL/min and the system is maintained The temperature is between 30°C and 40°C. Upon completion, ACN (100 mL) was flowed through the reactor at the same rate. The output mixture was diluted with water (500 mL) and heptane (200 mL). The aqueous layer was extracted with heptane (200 mL) and the combined organic layers were washed with saturated aqueous sodium thiosulfate (2 x 100 mL). The organic layer was dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography using a gradient of 0-10% EtOAc in hexanes to afford 7.0 g of the title compound (92% yield, 90% pure). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 7 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 4.50 (s, 2H), 4.20 (q, J = 7.5 Hz, 2H), 3.75 (s, 2H), 1.29 (t, J = 7.5 Hz, 3H).
製備 3402-[4-溴-2-[2-[5-[(6-氯-2-吡啶基)氧基甲基]-2-氰基-苯基]乙氧基甲基]-5-氟-苯基]乙酸乙酯 向反應容器中裝填4-[(6-氯-2-吡啶基)氧基甲基]-2-(2-羥乙基)苯甲腈(700 mg, 2.4 mmol)、2-[4-溴-2-(溴甲基)-5-氟-苯基]乙酸乙酯(1.3 g, 3.2 mmol,88質量%)、無水DCM (20 mL)及2,6-二-第三丁基吡啶(835 μL, 3.61 mmol)。在氮氣氛下將混合物冷卻至0℃並添加三氟甲磺酸銀(878 mg, 3.38 mmol)。使混合物達到室溫並攪拌過夜。經由Celite ®過濾反應混合物,濃縮濾液並藉由矽膠層析使用於環己烷中之20 - 100% DCM之梯度來純化殘餘物以得到無色蠟狀固體形式之標題化合物(369 mg,67 wt%純,18%)。ES-MS m/z561, 563, 565 (M+H)。 Preparation of 340 2-[4-bromo-2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-5 -Fluoro-phenyl] ethyl acetate Charge the reaction vessel with 4-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)benzonitrile (700 mg, 2.4 mmol), 2-[4-bromo -2-(bromomethyl)-5-fluoro-phenyl] ethyl acetate (1.3 g, 3.2 mmol, 88% by mass), anhydrous DCM (20 mL) and 2,6-di-tert-butylpyridine ( 835 μL, 3.61 mmol). The mixture was cooled to 0 °C under nitrogen atmosphere and silver triflate (878 mg, 3.38 mmol) was added. The mixture was allowed to reach room temperature and stirred overnight. The reaction mixture was filtered through Celite® , the filtrate was concentrated and the residue was purified by silica gel chromatography using a gradient of 20 - 100% DCM in cyclohexane to afford the title compound (369 mg, 67 wt% pure, 18%). ES-MS m/z 561, 563, 565 (M+H).
製備 3412-[2-[2-[5-[(6-氯-2-吡啶基)氧基甲基]-2-氰基-苯基]乙氧基甲基]-5-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯 向反應容器中裝填2-[4-溴-2-[2-[5-[(6-氯-2-吡啶基)氧基甲基]-2-氰基-苯基]乙氧基甲基]-5-氟-苯基]乙酸乙酯(340 mg, 0.41 mmol,67 wt%純)、KOAc (140 mg, 1.40 mmol)、雙(頻哪醇)二硼(190 mg, 0.73 mmol)及無水1,4-二噁烷(4 mL)。使用氮將混合物鼓泡,添加二氯雙(三環己基膦)鈀(II) (61 mg, 0.081mmol)並在90℃下於預加熱浴中攪拌5 h。將反應混合物冷卻至室溫,添加飽和NaHCO 3水溶液及EtOAc並經由Celite ®過濾混合物。分離水層並使用水及飽和NaCl水溶液洗滌有機層,藉由Na 2SO 4乾燥,過濾並濃縮。經由矽膠層析使用於DCM中之0 - 100% EtOAc之梯度來純化殘餘物以得到黃色蠟狀固體形式之標題化合物(275 mg,75 wt%純,84%) 。ES-MS m/z609及611 (M+H)。 Preparation 341 2-[2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-5-fluoro-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]ethyl acetate Charge the reaction vessel with 2-[4-bromo-2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl ]-5-fluoro-phenyl] ethyl acetate (340 mg, 0.41 mmol, 67 wt% pure), KOAc (140 mg, 1.40 mmol), bis(pinacol) diboron (190 mg, 0.73 mmol) and Anhydrous 1,4-dioxane (4 mL). The mixture was sparged with nitrogen, dichlorobis(tricyclohexylphosphine)palladium(II) (61 mg, 0.081 mmol) was added and stirred at 90 °C in a preheating bath for 5 h. The reaction mixture was cooled to room temperature, saturated aqueous NaHCO 3 and EtOAc were added and the mixture was filtered through Celite® . The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over Na2SO4 , filtered and concentrated . The residue was purified via silica gel chromatography using a gradient of 0-100% EtOAc in DCM to afford the title compound (275 mg, 75 wt% pure, 84%) as a yellow waxy solid. ES-MS m/z 609 and 611 (M+H).
製備 3422-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸乙酯 向反應容器中裝填2-[2-[2-[5-[(6-氯-2-吡啶基)氧基甲基]-2-氰基-苯基]乙氧基甲基]-5-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基]乙酸乙酯(190 mg, 0.23 mmol,75 wt%純)及THF (7.8 mL)。使用氮將混合物鼓泡,然後添加磷酸三鉀(1.0 M於水中,1.2 mL, 1.2 mmol)及氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd G2, 20 mg, 0.025 mmol)。將混合物在70℃下於預加熱浴中攪拌30 min。將反應混合物冷卻至室溫並添加水及EtOAc。分離水層並使用水及飽和NaCl水溶液洗滌有機層,藉由Na 2SO 4乾燥,過濾並去除溶劑。經由矽膠層析使用於DCM中之0 - 5% EtOAc之梯度來純化殘餘物以提供淺褐色固體形式之標題化合物(49 mg,90 wt%純,42%)。ES-MS m/z447 (M+H)。 Preparation 342 2-(5 4 -cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona-1 4 -yl) ethyl acetate Fill the reaction vessel with 2-[2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-5- Ethyl fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]acetate (190 mg, 0.23 mmol, 75 wt% pure) and THF (7.8 mL). The mixture was sparged with nitrogen, then tripotassium phosphate (1.0 M in water, 1.2 mL, 1.2 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 20 mg, 0.025 mmol). The mixture was stirred at 70 °C for 30 min in a preheating bath. The reaction mixture was cooled to room temperature and water and EtOAc were added. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over Na2SO4 , filtered and the solvent was removed. The residue was purified via silica gel chromatography using a gradient of 0-5% EtOAc in DCM to afford the title compound (49 mg, 90 wt% pure, 42%) as a beige solid. ES-MS m/z 447 (M+H).
製備 3432-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸 將1,5,7-三氮雜雙環[4.4.0]癸-5-烯(62 mg, 0.44 mmol)添加至2-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸乙酯(72 mg, 0.145 mmol,90質量%)於ACN (1.5 mL)、THF (500 μL)及水(500 μL)之混合物中之懸浮液中。使用N 2吹掃混合物並在50℃下攪拌15 min。在氮流下去除有機溶劑。添加EtOAc及檸檬酸水溶液(5%)。分離水層並使用水及飽和NaCl水溶液洗滌有機層,藉由Na 2SO 4乾燥,過濾並去除溶劑以提供白色固體形式之標題化合物(65mg, 97%,91質量%)。ES-MS m/z419 (M+H)。 Preparation 343 2-(5 4 -cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona-1 4 -yl)acetic acid 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (62 mg, 0.44 mmol) was added to 2-(5 4 -cyano-1 6 -fluoro-3,8-diox Hetero-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononan-1 4 -yl)ethyl acetate (72 mg, 0.145 mmol, 90% by mass) in ACN (1.5 mL ), THF (500 μL) and water (500 μL) in a suspension. The mixture was purged with N2 and stirred at 50 °C for 15 min. Organic solvents were removed under nitrogen flow. EtOAc and aqueous citric acid (5%) were added. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over Na 2 SO 4 , filtered and the solvent removed to afford the title compound (65 mg, 97%, 91 mass %) as a white solid. ES-MS m/z 419 (M+H).
製備 344(S)-2-((5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 在氮氣氛下,向2-(5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸(65 mg, 0.14 mmol, 91質量%)及4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(45 mg, 0.145 mmol)於無水DMF (1.4 mL)中之溶液中添加HATU (70 mg, 0.18 mmol)及DIPEA (74 μL, 0.42 mmol)。將混合物在室溫下攪拌3 h並使用水及EtOAc稀釋。分離水層並使用水及飽和NaCl水溶液洗滌有機層,藉由Na 2SO 4乾燥,過濾並去除溶劑。將殘餘物溶於1,2-二氯乙烷(0.9 mL)及乙酸(0.9 mL)中並將混合物在60℃及N 2下加熱8 h。將反應混合物冷卻至室溫,在減壓下濃縮溶劑,在真空及35-40℃下乾燥並經由矽膠層析使用於DCM中之25 - 100% EtOAc之梯度來純化殘餘物以提供白色固體形式之標題化合物(50 mg, 49%)。ES-MS m/z693 (M+H)。 Preparation 344 (S)-2-((5 4 -cyano-1 6 -fluoro-3,8-dioxa- 2 (2,6)-pyridine-1,5(1,3)-diphenylcyclo Nonafin-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- Methyl formate Under nitrogen atmosphere, to 2-(5 4 -cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononium Fan-1 4 -yl)acetic acid (65 mg, 0.14 mmol, 91% by mass) and 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-propylene oxide- To a solution of methyl 2-yl]methylamino]benzoate (45 mg, 0.145 mmol) in anhydrous DMF (1.4 mL) was added HATU (70 mg, 0.18 mmol) and DIPEA (74 μL, 0.42 mmol). The mixture was stirred at room temperature for 3 h and diluted with water and EtOAc. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over Na2SO4 , filtered and the solvent was removed. The residue was dissolved in 1,2-dichloroethane (0.9 mL) and acetic acid (0.9 mL) and the mixture was heated at 60 °C under N2 for 8 h. The reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, dried under vacuum at 35-40 °C and the residue was purified by silica gel chromatography using a gradient of 25-100% EtOAc in DCM to afford a white solid The title compound (50 mg, 49%). ES-MS m/z 693 (M+H).
製備 3453-氟-5-((1-甲基吡咯啶-3-基)氧基)-4-硝基苯甲酸甲酯 將3-氟-5-羥基-4-硝基苯甲酸甲酯(2.0 g, 9.3 mmol)、1-甲基吡咯啶-3-醇(1.13 g, 11.2 mmol)、三苯基膦(2.93 g, 11.2 mmol)及DIAD (2.26 g, 11.2 mmol)於THF (80 mL)中之溶液在室溫下攪拌12 h。過濾並濃縮反應混合物,且經由矽膠層析使用於DCM中之0 - 10% MeOH之梯度來純化殘餘物以得到1.03 g標題化合物(37%)。ES-MS m/z299 (M+H)。 Preparation of 345 3-fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-4-nitrobenzoic acid methyl ester Methyl 3-fluoro-5-hydroxy-4-nitrobenzoate (2.0 g, 9.3 mmol), 1-methylpyrrolidin-3-ol (1.13 g, 11.2 mmol), triphenylphosphine (2.93 g , 11.2 mmol) and DIAD (2.26 g, 11.2 mmol) in THF (80 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered and concentrated, and the residue was purified by silica gel chromatography using a gradient of 0-10% MeOH in DCM to afford 1.03 g of the title compound (37%). ES-MS m/z 299 (M+H).
製備 3463-((1-甲基吡咯啶-3-基)氧基)-4-硝基-5-((((S)-環氧丙烷-2-基)甲基)胺基)苯甲酸甲酯 將3-氟-5-(1-甲基吡咯啶-3-基)氧基)-4-硝基苯甲酸甲酯(1.03 g, 3.45 mmol)、[(2S)-環氧丙烷-2-基]甲胺(20 g, 8.3 mmol)及TEA (2.1 g, 21 mmol)於DMSO (150 mL)中之溶液在80℃下攪拌12 h。使用水(50 mL)稀釋反應液並使用EtOAc (2 × 200 mL)萃取。使用飽和NaCl水溶液(5 × 40 mL)洗滌合併之有機層。藉由MgSO 4乾燥有機層,過濾,並濃縮。經由矽膠層析使用於DCM中之0 - 20% MeOH之梯度來純化殘餘物,隨後經由反相層析使用於氫氧化銨水溶液(0.05%)中之30 - 60% MeCN之梯度來純化以得到520 mg黃色油狀物形式之標題化合物(41%)。ES-MS m/z366 (M+H)。 Preparation of 346 3-((1-methylpyrrolidin-3-yl)oxy)-4-nitro-5-((((S)-epoxypropylene-2-yl)methyl)amino)benzene Methyl formate Methyl 3-fluoro-5-(1-methylpyrrolidin-3-yl)oxy)-4-nitrobenzoate (1.03 g, 3.45 mmol), [(2S)-propylene oxide-2- A solution of methylamine (20 g, 8.3 mmol) and TEA (2.1 g, 21 mmol) in DMSO (150 mL) was stirred at 80°C for 12 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with saturated aqueous NaCl (5 x 40 mL). The organic layer was dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-20% MeOH in DCM, followed by reverse phase chromatography using a gradient of 30-60% MeCN in aqueous ammonium hydroxide (0.05%) to give 520 mg of the title compound (41%) as a yellow oil. ES-MS m/z 366 (M+H).
製備 3474-胺基-3-((1-甲基吡咯啶-3-基)氧基)-5-((((S)-環氧丙烷-2-基)甲基)胺基)苯甲酸甲酯 將3-((1-甲基吡咯啶-3-基)氧基)-4-硝基-5-((((S)-環氧丙烷-2-基)甲基)胺基)苯甲酸甲酯(500 mg, 1.37 mmol)及碳載鈀(10%, 200 mg, 0.19 mmol)於EtOAc (100 mL)中之溶液在室溫及氫氣氣氛下攪拌2 h。過濾反應混合物並濃縮以得到358 mg淺黃色固體形式之標題化合物(78%)。ES-MS m/z336 (M+H)。 Preparation of 347 4-amino-3-((1-methylpyrrolidin-3-yl)oxy)-5-((((S)-epoxypropylene-2-yl)methyl)amino)benzene Methyl formate 3-((1-methylpyrrolidin-3-yl)oxy)-4-nitro-5-((((S)-epoxypropane-2-yl)methyl)amino)benzoic acid A solution of methyl ester (500 mg, 1.37 mmol) and palladium on carbon (10%, 200 mg, 0.19 mmol) in EtOAc (100 mL) was stirred at room temperature under hydrogen atmosphere for 2 h. The reaction mixture was filtered and concentrated to give 358 mg of the title compound (78%) as a pale yellow solid. ES-MS m/z 336 (M+H).
製備 3484-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((1-甲基吡咯啶-3-基)氧基)-5-((((S)-環氧丙烷-2-基)甲基)胺基)苯甲酸甲酯 向2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(75 mg, 0.18 mmol)及HATU (100 mg, 0.26 mmol)於DMF (1.8 mL)中之溶液中添加4-胺基-3-((1-甲基吡咯啶-3-基)氧基)-5-((((S)-環氧丙烷-2-基)甲基)胺基)苯甲酸甲酯(67 mg, 0.20 mmol)及DIPEA (0.08 mL, 0.45 mmol)。在20℃下攪拌2 h。使用水(10 mL)稀釋混合物並使用EtOAc (2 × 10 mL)萃取。使用飽和NaCl水溶液(10 mL)洗滌合併之有機層,藉由Na 2SO 4乾燥,過濾,並濃縮以得到425 mg標題化合物,其未經進一步純化即用於製備349。ES-MS m/z718 (M+H)。 Preparation of 348 4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononane -1 4 -yl)acetamido)-3-((1-methylpyrrolidin-3-yl)oxy)-5-((((S)-epoxypropane-2-yl)methyl ) amino) methyl benzoate To 2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 - 4-amino-3-((1-methylpyrrolidin-3-yl) to a solution of acetic acid (75 mg, 0.18 mmol) and HATU (100 mg, 0.26 mmol) in DMF (1.8 mL) Oxy)-5-((((S)-epoxypropan-2-yl)methyl)amino)benzoate (67 mg, 0.20 mmol) and DIPEA (0.08 mL, 0.45 mmol). Stir at 20 °C for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over Na 2 SO 4 , filtered, and concentrated to give 425 mg of the title compound, which was used in the preparation of 349 without further purification. ES-MS m/z 718 (M+H).
製備 3492-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-((1-甲基吡咯啶-3-基)氧基)-1-(((S)-環氧丙烷-2-基)甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-((1-甲基吡咯啶-3-基)氧基)-5-((((S)-環氧丙烷-2-基)甲基)胺基)苯甲酸甲酯(製備348,425 mg, 0.528 mmol)於1,2-二氯乙烷(4 mL)及乙酸(4 mL)中之溶液在55℃下攪拌12 h。使用1:1甲苯:ACN (10 mL)稀釋並濃縮溶液。經由矽膠層析使用於DCM中之0 - 10% MeOH之梯度來純化殘餘物以得到100 mg白色固體形式之標題化合物(27%)。ES-MS m/z700 (M+H)。 Preparation 349 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclonona-1 4 -yl)methyl)-4-((1-methylpyrrolidin-3-yl)oxy)-1-(((S)-epoxypropylene-2-yl)methyl)-1H-benzene And[d]imidazole-6-carboxylic acid methyl ester 4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 -yl)acetamido)-3-((1-methylpyrrolidin-3-yl)oxy)-5-((((S)-epoxypropane-2-yl)methyl) A solution of methyl amino)benzoate (preparation 348, 425 mg, 0.528 mmol) in 1,2-dichloroethane (4 mL) and acetic acid (4 mL) was stirred at 55 °C for 12 h. Dilute and concentrate the solution with 1:1 toluene:ACN (10 mL). The residue was purified by silica gel chromatography using a gradient of 0-10% MeOH in DCM to afford 100 mg of the title compound (27%) as a white solid. ES-MS m/z 700 (M+H).
製備 3502-(4-溴-2-((2-(((6-溴-5-氟吡啶-2-基)氧基)甲基)-5-氰基苯乙氧基)甲基)-5-氟苯基)乙酸乙酯 在20℃下,向4-[(6-溴-5-氟-2-吡啶基)氧基甲基]-3-(2-羥乙基)苯甲腈(4 g, 10.59 mmol)、2-[4-溴-2-(溴甲基)-5-氟-苯基]乙酸乙酯(8.3 g, 21 mmol)及2,6-二-第三丁基-4-甲基吡啶(4.45 g, 21.2 mmol)於DCM (60 mL)中之溶液中添加三氟甲磺酸銀(8.3 g, 32 mmol)。將反應液在室溫下攪拌過夜,然後在減壓下濃縮反應混合物以去除溶劑。使用水(100 mL)稀釋殘餘物並使用EtOAc (100 mL × 2)萃取。合併有機層,使用飽和NaCl水溶液(60 mL)洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮。藉由矽膠層析使用於石油醚中之0% - 100% DCM之梯度來純化殘餘物以得到淺黃色固體形式之標題化合物(2.15g, 25%)。ES-MS m/z625 (M+H)。 Preparation 350 2-(4-bromo-2-((2-(((6-bromo-5-fluoropyridin-2-yl)oxy)methyl)-5-cyanophenethoxy)methyl) -5-Fluorophenyl) ethyl acetate At 20°C, 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (4 g, 10.59 mmol), 2 -[4-Bromo-2-(bromomethyl)-5-fluoro-phenyl]ethyl acetate (8.3 g, 21 mmol) and 2,6-di-tert-butyl-4-methylpyridine (4.45 g, 21.2 mmol) in DCM (60 mL) was added silver triflate (8.3 g, 32 mmol). The reaction was stirred at room temperature overnight, then the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% - 100% DCM in petroleum ether to give the title compound (2.15 g, 25%) as a pale yellow solid. ES-MS m/z 625 (M+H).
製備 3512-(5 4-氰基-1 6,2 3-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯 在氮及室溫下,向2-(4-溴-2-((2-(((6-溴-5-氟吡啶-2-基)氧基)甲基)-5-氰基苯乙氧基)甲基)-5-氟苯基)乙酸乙酯(2.15 g, 2.63 mmol)及氟化銫(795 mg, 5.18 mmol)於1,4-二噁烷(230 mL)中之混合物中添加(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]甲磺酸鈀(II) (XPhos Pd G3, 450 mg, 0.521 mmol)及六甲基二錫(1.34 g, 4.05 mmol)。使反應液避光,將反應液加熱至110℃並攪拌15 h,然後在減壓下濃縮反應混合物以去除溶劑。使用水(100 mL)稀釋殘餘物並使用EtOAc (100 mL × 3)萃取。合併有機層,使用飽和NaCl水溶液(60 mL)洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮。藉由製備型HPLC [管柱:Xtimate C18 150 × 40 mm, 10µm;移動相:於水中之50 - 90% ACN之梯度(含有NH 3H 2O+NH 4HCO 3)]來純化粗製殘餘物以得到白色固體形式之標題化合物。(360.1 mg, 29%) ES-MS m/z465 (M+H)。 Preparation 351 2-(5 4 -cyano- 1 6 ,2 3 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2) -Diphenylcyclononafin-1 4 -yl) ethyl acetate Under nitrogen and room temperature, 2-(4-bromo-2-((2-(((6-bromo-5-fluoropyridin-2-yl)oxy)methyl)-5-cyanophenethyl In a mixture of oxy)methyl)-5-fluorophenyl)ethyl acetate (2.15 g, 2.63 mmol) and cesium fluoride (795 mg, 5.18 mmol) in 1,4-dioxane (230 mL) Add (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) ] Palladium(II) methanesulfonate (XPhos Pd G3, 450 mg, 0.521 mmol) and hexamethylditin (1.34 g, 4.05 mmol). The reaction solution was protected from light, and the reaction solution was heated to 110 °C and stirred for 15 h, then the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by preparative HPLC [column: Xtimate C18 150 × 40 mm, 10 µm; mobile phase: gradient of 50 - 90% ACN in water (containing NH 3 H 2 O+NH 4 HCO 3 )] to give the title compound as a white solid. (360.1 mg, 29%) ES-MS m/z 465 (M+H).
製備 3522-(5 4-氰基-1 6,2 3-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸 使用氮輕輕吹掃2-(5 4-氰基-1 6,2 3-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸乙酯(345 mg, 0.74 mmol)於THF (2.47 mL)、水(2.47 mL)及ACN (7.41 mL)中之溶液並添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(320 mg, 2.25 mmol)。密封反應容器並使用氮吹掃。將反應混合物加熱至45℃並在此溫度下攪拌2 h,然後在減壓下濃縮反應液以得到白色固體形式之標題化合物(385 mg, 100%),其未經進一步純化即用於製備353。ES-MS m/z437 (M+H)。 Preparation of 352 2-(5 4 -cyano-1 6 ,2 3 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2) -Diphenylcyclonona-1 4 -yl)acetic acid 2-(5 4 -cyano- 1 6 ,2 3 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononarfin- 1 4 -yl) ethyl acetate (345 mg, 0.74 mmol) in THF (2.47 mL), water (2.47 mL) and ACN (7.41 mL) was added and 1 , 5,7-Triazabicyclo[4.4.0]dec-5-ene (320 mg, 2.25 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated to 45 °C and stirred at this temperature for 2 h, then the reaction was concentrated under reduced pressure to give the title compound (385 mg, 100%) as a white solid, which was used in the preparation of 353 without further purification. . ES-MS m/z 437 (M+H).
製備 353(S)-4-(2-(5 4-氰基-1 6,2 3-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氰基-1 6,2 3-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(製備352,250 mg, 0.48 mmol)及HATU (378 mg, 0.97 mmol)於DMF (6 mL)中之溶液中添加4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(260 mg, 0.75 mmol),然後將DIPEA (300 μL, 1.72 mmol)添加至混合物中並在20℃及N 2下攪拌過夜。使用水(20 mL)稀釋反應液並使用EtOAc (20 mL × 2)萃取。合併有機層,使用飽和NaCl水溶液(20 mL)洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮以得到淺黃色固體形式之標題化合物(1.2 g, 100%),其未經進一步純化即用於製備354。ES-MS m/z729 (M+H)。 Preparation 353 (S)-4-(2-(5 4 -cyano- 1 6 ,2 3 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3) ,5(1,2)-diphenylcyclononafin-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-(((propylene oxide-2-ylmethyl base) amino) methyl benzoate To 2-(5 4 -cyano-1 6 ,2 3 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)- To a solution of diphenylcyclonafin-1 4 -yl)acetic acid (Preparation 352, 250 mg, 0.48 mmol) and HATU (378 mg, 0.97 mmol) in DMF (6 mL) was added 4-amino-3-( 2-Methoxyethoxy)-5-[[(2S)-epoxypropan-2-yl]methylamino]benzoic acid methyl ester (260 mg, 0.75 mmol), then DIPEA (300 μL, 1.72 mmol) was added to the mixture and stirred overnight at 20 °C under N2 . The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (1.2 g, 100%) as a light yellow solid which was not further used. Purification was used to prepare 354. ES-MS m/z 729 (M+H).
製備 354(S)-2-((5 4-氰基-1 6,2 3-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 在室溫及N 2下,向(S)-4-(2-(5 4-氰基-1 6,2 3-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(製備353,1.2 g, 0.49 mmol)於1,2-二氯乙烷(5 mL)中之溶液中添加乙酸(5 mL)。在55℃下加熱反應液並攪拌過夜。使用甲苯/ACN 1:1 (5 mL)稀釋反應液,在減壓下去除溶劑並藉由矽膠層析使用於DCM中之0 - 5% MeOH之梯度純化殘餘物以得到白色固體形式之標題產物(270 mg, 35%)。ES-MS m/z711 (M+H)。 Preparation 354 (S)-2-((5 4 -cyano- 1 6 ,2 3 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropane-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylic acid methyl ester At room temperature and N 2 , to (S)-4-(2-(5 4 -cyano-1 6 ,2 3 -difluoro-3,8-dioxa-2(2,6)-pyridine -1(1,3),5(1,2)-diphenylcyclononafin-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-((cyclo To a solution of methyl oxypropan-2-ylmethyl)amino)benzoate (Preparation 353, 1.2 g, 0.49 mmol) in 1,2-dichloroethane (5 mL) was added acetic acid (5 mL). The reaction was heated at 55°C and stirred overnight. The reaction was diluted with toluene/ACN 1:1 (5 mL), the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-5% MeOH in DCM to give the title product as a white solid (270 mg, 35%). ES-MS m/z 711 (M+H).
製備 355(S)-2-(氯甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將4-胺基-3-氟-5-[[(2S)-環氧丙烷-2-基甲基]胺基]苯甲酸甲酯(2.0 g, 7.9 mmol)及TEA (1.1 mL, 7.9 mmol)於1,2-二氯乙烷(22 mL)中之溶液冷卻至0℃並添加2-氯乙醯氯(0.63 mL, 7.9 mL)。將混合物在室溫下攪拌2 h。使用DCM稀釋反應混合物並使用水洗滌。藉由MgSO 4乾燥有機層,過濾,並濃縮。將所得殘餘物溶於乙酸(40 mL)中並在70℃下攪拌2 h。濃縮粗製反應液並經由矽膠層析使用於DCM中之0 - 4% MeOH之梯度來純化殘餘物以得到1.76 g黃色油狀物形式之標題化合物(72%)。ES-MS m/z313 (M+H)。 Preparation of 355 (S)-2-(Chloromethyl)-4-fluoro-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Methyl 4-amino-3-fluoro-5-[[(2S)-epoxypropan-2-ylmethyl]amino]benzoate (2.0 g, 7.9 mmol) and TEA (1.1 mL, 7.9 mmol ) in 1,2-dichloroethane (22 mL) was cooled to 0°C and 2-chloroacetyl chloride (0.63 mL, 7.9 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over MgSO 4 , filtered, and concentrated. The resulting residue was dissolved in acetic acid (40 mL) and stirred at 70 °C for 2 h. The crude reaction was concentrated and the residue was purified by silica gel chromatography using a gradient of 0-4% MeOH in DCM to afford 1.76 g of the title compound (72%) as a yellow oil. ES-MS m/z 313 (M+H).
製備 3563-(2-((5-溴-2-氯苄基)氧基)乙基)-4-(((6-溴吡啶-2-基)氧基)甲基)苯甲腈 將4-[(6-溴-2-吡啶基)氧基甲基]-3-(2-羥乙基)苯甲腈(2.3 g, 6.8 mmol)、4-溴-2-(溴甲基)-1-氯-苯(2.7 g, 9.5 mmol)及2,6-二-第三丁基吡啶(2.2 mL, 9.7 mmol)於DCM (36 mL)中之溶液冷卻至0℃。將三氟甲磺酸銀(3.0 g, 11.8 mmol)添加至反應混合物中並在0℃下攪拌15 min,然後在室溫下攪拌18 h。將額外三氟甲磺酸銀(0.53 g, 2.1 mmol)添加至反應混合物中並在室溫下攪拌22 h。經由Celite ®過濾粗製反應混合物,濃縮,並經由矽膠層析使用於庚烷中之0 - 100% DCM之梯度來純化殘餘物以得到2.3 g無色黏性固體形式之標題化合物(62%)。ES-MS m/z535/537/539 (M+H)。 Preparation of 356 3-(2-((5-bromo-2-chlorobenzyl)oxy)ethyl)-4-(((6-bromopyridin-2-yl)oxy)methyl)benzonitrile 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (2.3 g, 6.8 mmol), 4-bromo-2-(bromomethyl A solution of )-1-chloro-benzene (2.7 g, 9.5 mmol) and 2,6-di-tert-butylpyridine (2.2 mL, 9.7 mmol) in DCM (36 mL) was cooled to 0 °C. Silver triflate (3.0 g, 11.8 mmol) was added to the reaction mixture and stirred at 0 °C for 15 min, then at room temperature for 18 h. Additional silver triflate (0.53 g, 2.1 mmol) was added to the reaction mixture and stirred at room temperature for 22 h. The crude reaction mixture was filtered through Celite® , concentrated, and the residue was purified by silica gel chromatography using a gradient of 0-100% DCM in heptane to afford 2.3 g of the title compound (62%) as a colorless sticky solid. ES-MS m/z 535/537/539 (M+H).
製備 3571 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-甲腈 基本上如製備216中所闡述使用3-(2-((5-溴-2-氯苄基)氧基)乙基)-4-(((6-溴吡啶-2-基)氧基)甲基)苯甲腈來製備標題化合物,經由矽膠層析使用於庚烷中之0 - 25% EtOAc之梯度來純化標題化合物以得到灰棕色固體形式之標題化合物。ES-MS m/z377 (M+H)。 Preparation of 357 1 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-5 4 -carbonitrile Using 3-(2-((5-bromo-2-chlorobenzyl)oxy)ethyl)-4-(((6-bromopyridin-2-yl)oxy) essentially as described in Preparation 216 Methyl)benzonitrile to prepare the title compound, which was purified by silica gel chromatography using a gradient of 0-25% EtOAc in heptane to afford the title compound as a beige solid. ES-MS m/z 377 (M+H).
製備 3581 4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-甲腈 將1 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-甲腈(170 mg, 0.45 mmol)、(S)-1,2-丙二醇(0.2 mL, 3 mmol)、2-二環己基膦基-2',4',6'-三異丙基聯苯(XPhos, 44 mg, 0.09 mmol)、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd Gen 2, 35 mg, 0.045 mmol)、雙(頻哪醇)二硼(0.34 g, 1.3 mmol)及KOAc (0.13 g, 1.3 mmol)於2-甲基四氫呋喃(14 mL)中之溶液在80℃下攪拌3 h。過濾反應溶液並濃縮。將殘餘物溶於EtOAc中並使用水洗滌。藉由MgSO 4乾燥有機層,過濾,並濃縮以得到210 mg標題化合物(99%),其未經進一步純化即用於製備359。ES-MS m/z469 (M+H)。 Preparation of 358 1 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,8-dioxa-2(2,6)-pyridine -1(1,3),5(1,2)-diphenylcyclonazone-5 4 -carbonitrile 1 4 -Chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclonenona-5 4 -carbonitrile (170 mg, 0.45 mmol), (S)-1,2-propanediol (0.2 mL, 3 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 44 mg, 0.09 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1, 1'-biphenyl)] palladium(II) (XPhos Pd Gen 2, 35 mg, 0.045 mmol), bis(pinacol) diboron (0.34 g, 1.3 mmol) and KOAc (0.13 g, 1.3 mmol) in 2 - A solution in methyltetrahydrofuran (14 mL) was stirred at 80 °C for 3 h. The reaction solution was filtered and concentrated. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO 4 , filtered, and concentrated to give 210 mg of the title compound (99%), which was used in the preparation of 359 without further purification. ES-MS m/z 469 (M+H).
製備 359(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將1 4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-甲腈(0.12 g, 0.26 mmol)、(S)-2-(氯甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(0.12 g, 0.38 mmol)、2-二環己基膦基-2',4',6'-三異丙基聯苯(XPhos, 25 mg, 0.05 mmol)、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II) (XPhos Pd Gen 2 20 mg, 0.025 mmol)及磷酸三鉀(67 mg, 0.31 mmoL)於2-甲基四氫呋喃(3 mL)及水(0.3 mL)中之溶液在90℃下攪拌7 h。過濾反應溶液並使用EtOAc稀釋,使用水洗滌,藉由MgSO 4乾燥有機層,過濾,並濃縮。經由矽膠層析使用於DCM中之0 - 50% EtOAc之梯度來純化殘餘物以得到20 mg黃色固體形式之標題化合物(10%)。ES-MS m/z619 (M+H)。 Preparation 359 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-4-fluoro-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 1 4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,8-dioxa-2(2,6)-pyridine- 1(1,3),5(1,2)-diphenylcyclonona- 5 4 -carbonitrile (0.12 g, 0.26 mmol), (S)-2-(chloromethyl)-4-fluoro-1 -(Oxiranyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0.12 g, 0.38 mmol), 2-dicyclohexylphosphino-2',4',6 '-triisopropylbiphenyl (XPhos, 25 mg, 0.05 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-Amino-1,1'-biphenyl)]palladium(II) (XPhos Pd Gen 2 20 mg, 0.025 mmol) and tripotassium phosphate (67 mg, 0.31 mmol) in 2-methyl A solution in THF (3 mL) and water (0.3 mL) was stirred at 90°C for 7 h. The reaction solution was filtered and diluted with EtOAc, washed with water, the organic layer was dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in DCM to afford 20 mg of the title compound (10%) as a yellow solid. ES-MS m/z 619 (M+H).
製備 360(S)-3-(2-(二甲基胺基)-2-側氧基乙氧基)-4-硝基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 在0℃下,將於礦物油中之氫化鈉(60 wt%, 211 mg, 5.28 mmol)添加至2-羥基- N, N-二甲基乙醯胺(730 mg, 7.08 mmol)於THF (10 mL)中之溶液中,然後去除冷卻浴並將混合物攪拌1 h。將混合物再冷卻至0℃並添加3-氟-4-硝基-5-[[(2 S)-環氧丙烷-2-基甲基]胺基]苯甲酸甲酯(1 g, 3.52 mmol)。去除冷卻浴並將混合物攪拌48 h。使用飽和NH 4Cl溶液(30 mL)終止反應並使用EtOAc (3 × 50 mL)萃取。分離有機層,藉由Na2SO4乾燥,過濾並濃縮。藉由矽膠層析使用於石油醚中之0 - 60% EtOAc之梯度來純化殘餘物以提供黃色油狀物形式之標題化合物(800 mg, 61%)。ES-MS m/z368 (M+H)。 Preparation 360 (S)-3-(2-(Dimethylamino)-2-oxoethoxy)-4-nitro-5-(((propylene oxide-2-ylmethyl)amino ) methyl benzoate Sodium hydride (60 wt%, 211 mg, 5.28 mmol) in mineral oil was added to 2-hydroxy- N , N -dimethylacetamide (730 mg, 7.08 mmol) in THF ( 10 mL), the cooling bath was removed and the mixture was stirred for 1 h. The mixture was recooled to 0 °C and methyl 3-fluoro-4-nitro-5-[[( 2S )-epoxypropan-2-ylmethyl]amino]benzoate (1 g, 3.52 mmol ). The cooling bath was removed and the mixture was stirred for 48 h. The reaction was quenched with saturated NH4Cl solution (30 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-60% EtOAc in petroleum ether to afford the title compound (800 mg, 61%) as a yellow oil. ES-MS m/z 368 (M+H).
製備 361(S)-4-胺基-3-(2-(二甲基胺基)-2-側氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 使用氫氣吹掃含有(S)-3-(2-(二甲基胺基)-2-側氧基乙氧基)-4-硝基-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(800 mg, 2.13 mmol)、Pd/C (200 mg, 10 wt%)及EtOAc (60 mL)之容器三次。將混合物在一大氣壓H 2及環境溫度下攪拌4 h。過濾混合物並在減壓下濃縮。藉由矽膠層析使用於石油醚中之0 - 100% EtOAc之梯度來純化產物以提供黃色油狀物形式之標題化合物(636.4 mg, 88%)。ES-MS m/z338 (M+H)。 Preparation 361 (S)-4-Amino-3-(2-(Dimethylamino)-2-oxoethoxy)-5-((Oxiranyl-2-ylmethyl)amino ) methyl benzoate Use hydrogen to purging the )amino)methylbenzoate (800 mg, 2.13 mmol), Pd/C (200 mg, 10 wt%) and EtOAc (60 mL) in three containers. The mixture was stirred under one atmosphere of H2 at ambient temperature for 4 h. The mixture was filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography using a gradient of 0-100% EtOAc in petroleum ether to afford the title compound (636.4 mg, 88%) as a yellow oil. ES-MS m/z 338 (M+H).
製備 362(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-(二甲基胺基)-2-側氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 在環境溫度下,將1-丙烷膦酸酐(於DCM中之50 wt%溶液,225 μL, 0.378 mmol)添加至2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(75 mg, 0.187 mmol)及(S)-4-胺基-3-(2-(二甲基胺基)-2-側氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(69 mg, 0.20 mmol)於DMF (1 mL)及吡啶(150 μL, 1.85 mmol)中之溶液中。攪拌20 h且然後添加額外1-丙烷膦酸酐(225 μL, 0.378 mmol)。在再攪拌23 h之後,藉由添加水(2 mL)來終止反應。將混合物攪拌10 min,過濾並收集固體,然後在60℃及真空下將固體乾燥2 h以得到灰棕色固體形式之標題化合物(75.1 mg, 56%)。ES-MS m/z720 (M+H)。 Preparation 362 (S)-4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Phenylcyclononafin-1 4 -yl)acetamido)-3-(2-(dimethylamino)-2-oxoethoxy)-5-((epoxypropylene-2-yl Methyl)amino)benzoate 1-Propanephosphonic anhydride (50 wt% solution in DCM, 225 μL, 0.378 mmol) was added to 2-( 54 -cyano-3,9-dioxa-2(2, 6)-Pyridine-1(1,3), 5(1,2)-diphenylcyclononafin-1 4 -yl)acetic acid (75 mg, 0.187 mmol) and (S)-4-amino-3- (2-(Dimethylamino)-2-oxoethoxy)-5-((epoxypropylene-2-ylmethyl)amino)methyl benzoate (69 mg, 0.20 mmol) in DMF (1 mL) and pyridine (150 μL, 1.85 mmol). Stir for 20 h and then add additional 1-propanephosphonic anhydride (225 μL, 0.378 mmol). After stirring for another 23 h, the reaction was quenched by adding water (2 mL). The mixture was stirred for 10 min, filtered and the solid was collected, then dried under vacuum at 60 °C for 2 h to give the title compound (75.1 mg, 56%) as a beige solid. ES-MS m/z 720 (M+H).
製備 363(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(二甲基胺基)-2-側氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將(S)-4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-(二甲基胺基)-2-側氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(75 mg, 0.104 mmol)於乙酸(3 mL)中之溶液在60℃下攪拌20 h。在真空下去除乙酸並經由矽膠層析使用於氯仿中之0 - 20%異丙醇之梯度來純化殘餘物以得到70 mg標題化合物(70%純度,72%)。ES-MS m/z703 (M+H)。 Preparation 363 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-4-(2-(dimethylamino)-2-oxoethoxy)-1-(epoxypropylene-2-ylmethyl)-1H -Benzo[d]imidazole-6-carboxylic acid methyl ester (S)-4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl Cyclononafin-1 4 -yl)acetamido)-3-(2-(dimethylamino)-2-oxoethoxy)-5-(((propylene oxide-2-ylmethyl) A solution of methyl (amino)amino)benzoate (75 mg, 0.104 mmol) in acetic acid (3 mL) was stirred at 60°C for 20 h. Acetic acid was removed under vacuum and the residue was purified by silica gel chromatography using a gradient of 0-20% isopropanol in chloroform to afford 70 mg of the title compound (70% purity, 72%). ES-MS m/z 703 (M+H).
製備 3643-[(3-乙基咪唑-4-基)甲基胺基]-5-甲氧基-4-硝基-苯甲酸甲酯 將TEA (2.2 mL, 16 mmol)添加至3-氟-5-甲氧基-4-硝基-苯甲酸甲酯(900 mg, 3.93 mmol)及(1-乙基-1H-咪唑-5-基)甲基胺二鹽酸鹽(900 mg, 4.32 mmol)於DMF (20 mL)中之經攪拌溶液中。將混合物在60℃下攪拌16 h。使混合物冷卻至環境溫度並傾倒至飽和NH 4Cl水溶液(100 mL)中。使用DCM (3 × 100 mL)萃取混合物並使用飽和NaCl水溶液(3 × 50 mL)洗滌。藉由Na 2SO 4乾燥有機物,過濾,並在減壓下濃縮。藉由急速層析使用於EtOAc中之0 - 10% MeOH之梯度來純化殘餘物以得到黃色油狀物形式之標題化合物(800 mg, 61%)。ES-MS m/z335 (M+H)。 Preparation 364 3-[(3-Ethylimidazol-4-yl)methylamino]-5-methoxy-4-nitro-benzoic acid methyl ester TEA (2.2 mL, 16 mmol) was added to 3-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester (900 mg, 3.93 mmol) and (1-ethyl-1H-imidazole-5- in a stirred solution of methylamine dihydrochloride (900 mg, 4.32 mmol) in DMF (20 mL). The mixture was stirred at 60 °C for 16 h. The mixture was cooled to ambient temperature and poured into saturated aqueous NH4Cl (100 mL). The mixture was extracted with DCM (3 x 100 mL) and washed with saturated aqueous NaCl (3 x 50 mL). The organics were dried over Na2SO4 , filtered, and concentrated under reduced pressure . The residue was purified by flash chromatography using a gradient of 0-10% MeOH in EtOAc to give the title compound (800 mg, 61%) as a yellow oil. ES-MS m/z 335 (M+H).
製備 3654-胺基-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-5-甲氧基苯甲酸甲酯 將鐵(801 mg, 14.34 mmol)及NH 4Cl (768 mg, 14.4 mmol)添加至3-[(3-乙基咪唑-4-基)甲基胺基]-5-甲氧基-4-硝基-苯甲酸甲酯(960 mg, 2.87 mmol)於MeOH (30 mL)及水(10 mL)中之溶液中。在80℃下攪拌2 h,冷卻至環境溫度,然後藉由Celite ®墊過濾並使用MeOH (30 mL)洗滌墊。在減壓下濃縮濾液並藉由急速層析使用於EtOAc中之0 - 15% MeOH之梯度進行純化。藉由矽膠層析使用於EtOAc中之0 - 10% MeOH之梯度來再純化以得到褐色固體形式之標題化合物(504 mg, 55%)。ES-MS m/z305 (M+H)。 Preparation of 365 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-methoxybenzoic acid methyl ester Iron (801 mg, 14.34 mmol) and NH 4 Cl (768 mg, 14.4 mmol) were added to 3-[(3-ethylimidazol-4-yl)methylamino]-5-methoxy-4- A solution of methyl nitro-benzoate (960 mg, 2.87 mmol) in MeOH (30 mL) and water (10 mL). Stir at 80 °C for 2 h, cool to ambient temperature, then filter through a pad of Celite® and wash the pad with MeOH (30 mL). The filtrate was concentrated under reduced pressure and purified by flash chromatography using a gradient of 0-15% MeOH in EtOAc. Repurification by silica gel chromatography using a gradient of 0-10% MeOH in EtOAc gave the title compound (504 mg, 55%) as a tan solid. ES-MS m/z 305 (M+H).
製備 3664-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-5-甲氧基苯甲酸甲酯 在環境溫度下,將1-丙烷膦酸酐(於DMF中之50 wt%溶液,170 μL, 0.28 mmol)添加至2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(76 mg, 0.1898 mmol)及4-胺基-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-5-甲氧基苯甲酸甲酯(63 mg, 0.207 mmol)於DMF (600 μL)及吡啶(400 μL, 5 mmol)中之溶液中。將反應液在室溫下攪拌72 h,然後使用EtOAc (100 mL)稀釋,使用飽和NaHCO 3(100 mL)洗滌有機物,藉由Celite ®過濾,並使用額外EtOAc將濾液萃取三次。合併有機物,使用飽和NaCl水溶液洗滌兩次,藉由MgSO 4乾燥,過濾,並在減壓下濃縮以提供標題產物(136 mg),其未經進一步純化即用於製備367。ES-MS m/z688 (M+H)。 Preparation of 366 4-(2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononane -1 4 -yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-methoxybenzoic acid methyl ester 1-Propanephosphonic anhydride (50 wt% solution in DMF, 170 μL, 0.28 mmol) was added to 2-( 54 -cyano-3,9-dioxa-2(2, 6)-pyridine-1(1,3), 5(1,2)-diphenylcyclononan-1 4 -yl)acetic acid (76 mg, 0.1898 mmol) and 4-amino-3-(((1 -Ethyl-1H-imidazol-5-yl)methyl)amino)-5-methoxybenzoic acid methyl ester (63 mg, 0.207 mmol) in DMF (600 μL) and pyridine (400 μL, 5 mmol) in solution. The reaction was stirred at room temperature for 72 h, then diluted with EtOAc (100 mL), the organics were washed with saturated NaHCO 3 (100 mL), filtered through Celite® , and the filtrate was extracted three times with additional EtOAc. The organics were combined, washed twice with saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure to afford the title product (136 mg), which was used in the preparation of 367 without further purification. ES-MS m/z 688 (M+H).
製備 3672-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-4-甲氧基-1H-苯并[d]咪唑-6-甲酸甲酯 基本上如製備102中所闡述使用4-(2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-5-甲氧基苯甲酸甲酯(製備366)在1:1乙酸: 1,2-二氯乙烷(作為溶劑)之混合物中來製備標題化合物,其中將反應液在70℃下加熱16 h。將混合物冷卻至室溫並在真空下濃縮。添加1:1 EtOAc/甲苯并濃縮以去除殘餘乙酸(兩次)。將所得黃色固體在真空下乾燥2 h。藉由矽膠層析使用於DCM中之90 - 100% EtOAc之梯度純化固體,隨後使用MeOH純化以得到灰白色固體形式之標題化合物,其未經進一步純化即用於實例63。ES-MS m/z670 (M+H)。 Preparation 367 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclonona-1 4 -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Using 4-(2-( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2) essentially as described in Preparation 102 )-diphenylcyclononafin-1 4 -yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-methoxybenzene The title compound was prepared from methyl formate (Preparation 366) in a 1:1 mixture of acetic acid: 1,2-dichloroethane (as solvent) and the reaction was heated at 70 °C for 16 h. The mixture was cooled to room temperature and concentrated under vacuum. Added 1:1 EtOAc/toluene and concentrated to remove residual acetic acid (twice). The resulting yellow solid was dried under vacuum for 2 h. The solid was purified by silica gel chromatography using a gradient of 90-100% EtOAc in DCM, followed by MeOH to give the title compound as an off-white solid, which was used in Example 63 without further purification. ES-MS m/z 670 (M+H).
製備 368(S)-4-(2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯 向2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙酸(44 mg, 0.103 mmol)於DMF (1.2 mL)中之溶液中添加4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(32 mg, 0.103 mmol)、HATU (59 mg, 0.155 mmol)及DIPEA (0.055 mL, 0.32 mmol)。將混合物在室溫下攪拌2 h,然後使用水(10 mL)稀釋並使用EtOAc (4 × 5 mL)萃取。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在真空下濃縮以得到淺褐色固體形式之標題化合物 (80 mg,80%純度,88%產率)。ES-MS m/z693 (M+H)。 Preparation of 368 (S)-4-(2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Methyl phenylcyclononafin-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-(((oxypropylene-2-ylmethyl)amino)benzoate To 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 - To a solution of acetic acid (44 mg, 0.103 mmol) in DMF (1.2 mL) was added 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-propylene oxide -2-yl]methylamino]benzoate (32 mg, 0.103 mmol), HATU (59 mg, 0.155 mmol) and DIPEA (0.055 mL, 0.32 mmol). The mixture was stirred at room temperature for 2 h, then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated in vacuo to give the title compound (80 mg, 80% purity, 88% yield) as a beige solid. ES-MS m/z 693 (M+H).
製備 369(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 將(S)-4-(2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)乙醯胺基)-3-(2-甲氧基乙氧基)-5-((環氧丙烷-2-基甲基)胺基)苯甲酸甲酯(80 mg,80%純度,0.092 mmol)於1,2-二氯乙烷(0.7 mL)及乙酸(0.7 mL)中之溶液在58℃下加熱6 h。將反應混合物冷卻至室溫,在減壓下濃縮,並經由矽膠層析使用於DCM中之30 - 100% EtOAc之梯度來純化殘餘物以提供25 mg (40%)白色固體形式之標題化合物。ES-MS m/z675 (M+H)。 Preparation 369 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclo Nonafin-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- Methyl formate (S)-4-(2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl Cyclononafin-1 4 -yl)acetamido)-3-(2-methoxyethoxy)-5-(((epoxypropylene-2-ylmethyl)amino)methyl benzoate ( 80 mg, 80% purity, 0.092 mmol) in 1,2-dichloroethane (0.7 mL) and acetic acid (0.7 mL) were heated at 58°C for 6 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 30-100% EtOAc in DCM to afford 25 mg (40%) of the title compound as a white solid. ES-MS m/z 675 (M+H).
製備 370(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 在氮氣氛下,向2-(5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)乙酸(60 mg, 0.15 mmol)及4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(47 mg, 0.15)於無水DMF (1.5 mL)中之溶液中添加HATU (74 mg, 0.19 mmol)及DIPEA (0.08 mL, 0.45 mmol)。將混合物在室溫下攪拌2.5 h,然後添加水及EtOAc。分離水層並使用水及飽和NaCl水溶液洗滌有機層,藉由Na 2SO 4乾燥,過濾並濃縮。將殘餘物於1,2-二氯乙烷(0.9 mL)及乙酸(0.9 mL)中之溶液在氮氣氛及60℃下加熱8 h。將反應混合物冷卻至室溫,在減壓下濃縮溶劑,在真空及35-40℃下乾燥並經由矽膠層析使用於DCM中之25 - 100% EtOAc之梯度作為洗脫劑系統來純化殘餘物以提供白色固體形式之標題化合物(72 mg, 71%)。ES-MS m/z675 (M+H)。 Preparation 370 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Under nitrogen atmosphere, to 2-(5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona-1 4 - base) acetic acid (60 mg, 0.15 mmol) and 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-epoxypropylene-2-yl]methylamino] To a solution of methyl benzoate (47 mg, 0.15) in dry DMF (1.5 mL) was added HATU (74 mg, 0.19 mmol) and DIPEA (0.08 mL, 0.45 mmol). The mixture was stirred at room temperature for 2.5 h, then water and EtOAc were added. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over Na2SO4 , filtered and concentrated . A solution of the residue in 1,2-dichloroethane (0.9 mL) and acetic acid (0.9 mL) was heated under nitrogen atmosphere at 60 °C for 8 h. The reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure, dried under vacuum at 35-40 °C and the residue was purified by silica gel chromatography using a gradient of 25-100% EtOAc in DCM as the eluent system This afforded the title compound (72 mg, 71%) as a white solid. ES-MS m/z 675 (M+H).
製備 371(S)-(1 4-((6-(甲氧基羰基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-2-基)甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-基)酸 向反應容器中裝填(S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(500 mg, 0.72 mmol)、無水THF (5 mL)及MeOH (10 mL)。使用N 2將混合物鼓泡10 min,添加無水乙二醇(610 μL, 10.9 mmol)及DIPEA (315 μL, 1.82 mmol)。使用N 2將混合物鼓泡5 min,添加四羥基二硼(139 mg, 1.47 mmol)、三環己基膦(5 mg, 0.018 mmol)及[(三環己基膦)-2-(2′-胺基聯苯)]甲磺酸鈀(II) [P(Cy3) Pd G3, 26 mg, 0.039 mmol),密封容器並在50℃下於預加熱浴中攪拌2.5h。濃縮反應混合物,然後添加飽和NaHCO 3水溶液並攪拌5 min。過濾掉固體,然後使用水、ACN及MeOH洗滌固體以提供灰色固體形式之標題化合物(500 mg,90 wt%純,100%)。ES-MS m/z620 (M+H)。 Preparation 371 (S)-(1 4 -((6-(methoxycarbonyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)methyl )-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononafin-5 4 -yl) acid Fill the reaction vessel with (S)-2-((5 4 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di phencyclononafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (500 mg, 0.72 mmol), Anhydrous THF (5 mL) and MeOH (10 mL). The mixture was bubbled with N 2 for 10 min, and anhydrous ethylene glycol (610 μL, 10.9 mmol) and DIPEA (315 μL, 1.82 mmol) were added. The mixture was bubbled with N for 5 min, and tetrahydroxydiboron (139 mg, 1.47 mmol), tricyclohexylphosphine (5 mg, 0.018 mmol) and [(tricyclohexylphosphine)-2-(2′-amine) were added diphenyl)]palladium(II) methanesulfonate [P(Cy3)PdG3, 26 mg, 0.039 mmol), seal the vessel and stir at 50°C in a preheating bath for 2.5h. The reaction mixture was concentrated, then saturated aqueous NaHCO 3 was added and stirred for 5 min. The solid was filtered off, then washed with water, ACN and MeOH to afford the title compound (500 mg, 90 wt% pure, 100%) as a gray solid. ES-MS m/z 620 (M+H).
製備 372(S)-2-((5 4-(4-氟-1H-咪唑-1-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 向反應容器中裝填(S)-(1 4-((6-(甲氧基羰基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-2-基)甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-基)酸(21 mg, 0.03 mmol,90 wt%純)、4-氟-1H-咪唑(14 mg, 0.15 mmol)、乙酸銅(II) (5.8 mg, 0.032 mmol)、MeOH (245 μL)及吡啶(6 μL, 0.07 mmol)。密封反應容器並將懸浮液在60℃下攪拌10 h。添加EtOAc及氨水溶液(28%),分離有機層並使用氨水溶液(28%)、水及飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾並濃縮。經由矽膠層析使用於DCM中之20 - 100% EtOAc之梯度作為洗脫劑系統來純化殘餘物以提供白色固體形式之標題化合物(8 mg, 10%)。ES-MS m/z660 (M+H)。 Preparation 372 (S)-2-((5 4- (4-fluoro-1H-imidazol-1-yl)-3,9-dioxa-2(2,6)-pyridine-1(1,3) ,5(1,2)-diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ester Charge the reaction vessel with (S)-(1 4 -((6-(methoxycarbonyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazol-2-yl )methyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-5 4 -yl) acid (21 mg, 0.03 mmol, 90 wt% pure), 4-fluoro-1H-imidazole (14 mg, 0.15 mmol), copper(II) acetate (5.8 mg, 0.032 mmol), MeOH (245 μL) and pyridine ( 6 μL, 0.07 mmol). The reaction vessel was sealed and the suspension was stirred at 60 °C for 10 h. EtOAc and aqueous ammonia (28%) were added, the organic layer was separated and washed with aqueous ammonia (28%), water and saturated aqueous NaCl, dried over Na2SO4 , filtered and concentrated . The residue was purified by silica gel chromatography using a gradient of 20 - 100% EtOAc in DCM as the eluent system to afford the title compound (8 mg, 10%) as a white solid. ES-MS m/z 660 (M+H).
製備 3732-(溴甲基)-5-氯苯甲酸甲酯 基本上如製備236中所闡述使用5-氯-2-甲基苯甲酸甲酯來製備標題化合物。使用水及亞硫酸氫鈉水溶液攪拌反應器輸出液,分離各層,然後使用庚烷將水相萃取兩次。合併有機物,使用水(3 ×)、飽和NaHCO 3水溶液及然後飽和NaCl水溶液洗滌。藉由MgSO 4乾燥有機物,過濾並濃縮以得到黃色油狀物形式之標題化合物(67.99 g, 87%)。 1H NMR (400.21 MHz, CDCl 3) δ 7.98 (d, J= 2.2 Hz, 1H), 7.49 (dd, J= 2.3, 8.3 Hz, 1H), 7.43 (d, J= 8.3 Hz, 1H), 4.94 (s, 2H), 3.97 (s, 3H)。 Preparation 373 Methyl 2-(bromomethyl)-5-chlorobenzoate The title compound was prepared essentially as described in Preparation 236 using methyl 5-chloro-2-methylbenzoate. The reactor output was stirred with water and aqueous sodium bisulfite, the layers were separated, and the aqueous phase was extracted twice with heptane. The combined organics were washed with water (3x), saturated aqueous NaHCO 3 and then saturated aqueous NaCl. The organics were dried over MgSO 4 , filtered and concentrated to give the title compound (67.99 g, 87%) as a yellow oil. 1 H NMR (400.21 MHz, CDCl 3 ) δ 7.98 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 2.3, 8.3 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 4.94 (s, 2H), 3.97 (s, 3H).
製備 3745-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯甲酸甲酯 將2-(溴甲基)-5-氯-苯甲酸甲酯(20.0 g, 67.5 mmol)於甲苯(200 mL)中之溶液添加至6-氯吡啶-2-醇(10.9 g, 84.1 mmol)及碳酸銀(14.9 g, 54.0 mmol)之混合物中。將混合物在N 2下加熱至65℃並保持48 h,使用鋁箔使反應容器避光並添加額外甲苯(100 mL)。將DCM (200 mL)添加至反應液中並經由Celite ®墊過濾,使用DCM (100 mL)沖洗墊。將濾液濃縮至體積為100 mL,過濾掉第一批固體材料。使用1:1甲苯/庚烷(50 mL)及庚烷(2 × 50 mL)洗滌固體。將100 mL庚烷添加至濾液中且然後過濾掉第二批固體材料,如前所述使用1:1甲苯/庚烷(50 mL)及庚烷(2 × 50 mL)洗滌。濃縮濾液並經30 min將殘餘物在50℃下於庚烷(200 mL)中製成漿液,然後在環境溫度下攪拌過夜。過濾掉第三批固體並使用庚烷(2 × 50 mL)洗滌固體。合併第一、第二及第三批固體材料並在減壓及50℃下乾燥5.5 h以得到白色固體形式之標題化合物(18.85 g, 89%)。ES/MS m/z312, 314 (M+H)。 Preparation 374 Methyl 5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]benzoate A solution of 2-(bromomethyl)-5-chloro-benzoic acid methyl ester (20.0 g, 67.5 mmol) in toluene (200 mL) was added to 6-chloropyridin-2-ol (10.9 g, 84.1 mmol) And silver carbonate (14.9 g, 54.0 mmol) in the mixture. The mixture was heated to 65 °C under N2 for 48 h, the reaction vessel was shielded from light with aluminum foil and additional toluene (100 mL) was added. DCM (200 mL) was added to the reaction and filtered through a pad of Celite® , using DCM (100 mL) to rinse the pad. The filtrate was concentrated to a volume of 100 mL and the first solid material was filtered off. The solid was washed with 1:1 toluene/heptane (50 mL) and heptane (2 x 50 mL). 100 mL of heptane was added to the filtrate and then a second crop of solid material was filtered off, washing with 1:1 toluene/heptane (50 mL) and heptane (2 x 50 mL) as previously described. The filtrate was concentrated and the residue was slurried in heptane (200 mL) at 50 °C over 30 min, then stirred at ambient temperature overnight. The third crop of solids was filtered off and washed with heptane (2 x 50 mL). The first, second and third crops of solid material were combined and dried under reduced pressure at 50 °C for 5.5 h to afford the title compound (18.85 g, 89%) as a white solid. ES/MS m/z 312, 314 (M+H).
製備 375[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]甲醇 在N 2下,向5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯甲酸甲酯(14.78 g, 46.87 mmol)於THF (75 mL)中之混合物中添加LiBH 4(2 M於THF中,35 mL, 70 mmol)。將反應混合物在環境溫度下攪拌5 min,然後經1 h逐份添加MeOH (2.9 mL, 72 mmol)。將EtOAc (5 mL)、水(10 mL)、HCl (1 M水溶液,100 mL)及MTBE (300 mL)添加至混合物中並分離各層。分離各層,使用水(50 mL)、K 2CO 3水溶液(2 M, 50 mL)及飽和NaCl水溶液(50 mL)洗滌有機物。藉由MgSO 4乾燥有機物,過濾並濃縮濾液以得到蠟狀固體形式之標題化合物(13.54 g, 97%)。ES/MS m/z284, 286 (M+H)。 Preparation of 375 [5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]methanol To a mixture of methyl 5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]benzoate (14.78 g, 46.87 mmol) in THF (75 mL) was added under N LiBH4 (2 M in THF, 35 mL, 70 mmol). The reaction mixture was stirred at ambient temperature for 5 min, then MeOH (2.9 mL, 72 mmol) was added portionwise over 1 h. EtOAc (5 mL), water (10 mL), HCl (1 M aq, 100 mL) and MTBE (300 mL) were added to the mixture and the layers were separated. The layers were separated and the organics were washed with water (50 mL), aqueous K2CO3 (2 M, 50 mL), and saturated aqueous NaCl (50 mL). The organics were dried over MgSO 4 , filtered and the filtrate was concentrated to give the title compound (13.54 g, 97%) as a waxy solid. ES/MS m/z 284, 286 (M+H).
製備 3762-[[2-[(5-溴-4-氟-2-碘-苯基)甲氧基甲基]-4-氯-苯基]甲氧基]-6-氯-吡啶 在N 2下,將THF (7.5 mL)添加至[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]甲醇(0.50 g, 1.7 mmol)及1-溴-5-(溴甲基)-2-氟-4-碘苯(0.89 g, 2.1 mmol)之混合物中,然後逐份添加第三丁醇鉀(於第三丁醇中之1 M溶液,2.2 mL, 2.2 mmol)。將混合物在室溫下攪拌30 min,然後添加水(30 mL)並將混合物在室溫下攪拌過夜,從而產生具有黏性下部相之混合物。傾析掉上清液,添加水並傾析掉水。將其他部分溶於MeOH (55 mL)中並在60℃下加熱,且添加SiliaMetS三胺(1 g)並在60℃下繼續加熱3.5 h。經由Celite ®墊趁熱過濾反應液,使用熱MeOH (15 mL)沖洗墊,並濃縮濾液。將殘餘物溶於MTBE (20 mL)中,過濾,並濃縮。藉由矽膠層析使用於環己烷中之0 - 20% EtOAc之梯度來純化殘餘物以得到無色油狀物形式之標題化合物(0.75 g, 68%)。ES/MS m/z595, 597, 599(M+H)。 Preparation 376 2-[[2-[(5-bromo-4-fluoro-2-iodo-phenyl)methoxymethyl]-4-chloro-phenyl]methoxy]-6-chloro-pyridine THF ( 7.5 mL) was added to [5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]methanol (0.50 g, 1.7 mmol) and 1- To a mixture of bromo-5-(bromomethyl)-2-fluoro-4-iodobenzene (0.89 g, 2.1 mmol), potassium tert-butoxide (1 M solution in tertiary butanol, 2.2 mL, 2.2 mmol). The mixture was stirred at room temperature for 30 min, then water (30 mL) was added and the mixture was stirred at room temperature overnight, resulting in a mixture with a viscous lower phase. The supernatant was decanted off, water was added and the water was decanted off. The other portion was dissolved in MeOH (55 mL) and heated at 60 °C, and SiliaMetS triamine (1 g) was added and heating was continued at 60 °C for 3.5 h. The reaction was filtered hot through a pad of Celite® , the pad was rinsed with hot MeOH (15 mL), and the filtrate was concentrated. The residue was dissolved in MTBE (20 mL), filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-20% EtOAc in cyclohexane to give the title compound (0.75 g, 68%) as a colorless oil. ES/MS m/z 595, 597, 599 (M+H).
製備 3772-[4-溴-2-[[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]甲氧基甲基]-5-氟-苯基]乙酸乙酯 在N 2下,將溴-(2-乙氧基-2-側氧基-乙基)鋅 (0.4 M in THF, 3.4 mL, 1.4 mmol)添加至2-[[2-[(5-溴-4-氟-2-碘-苯基)甲氧基甲基]-4-氯-苯基]甲氧基]-6-氯-吡啶(0.58 g, 0.91 mmol)及氯[(4,5-雙(二苯基膦基)-9,9-二甲基呫噸)-2-(2'-胺基-1,1'-聯苯)]鈀(II) (Pd-179, Xantphos Pd G2, 45 mg, 0.045 mmol)於THF (1 mL)中之混合物中。將反應混合物加熱至60℃並保持10 h。將反應混合物分配於水(15 mL)、檸檬酸水溶液(5%, 5 mL)與MTBE之間。使用5 mL份量之水、K 2CO 3水溶液(2 M)及飽和NaCl水溶液洗滌有機相。將有機物濃縮於Celite ®上並藉由矽膠層析使用於環己烷中之5 - 40% EtOAc之梯度來純化以得到無色油狀物形式之標題化合物(311 mg, 58%)。 1H NMR (400.13 MHz, CDCl 3) δ 7.56-7.52 (m, 2H), 7.46-7.44 (m, 2H), 7.32 (dd, J= 2.2, 8.1 Hz, 1H), 7.07 (d, J= 9.0 Hz, 1H), 6.94 (d, J= 6.8 Hz, 1H), 6.66 (d, J= 7.6 Hz, 1H), 5.36 (s, 2H), 4.66 (s, 2H), 4.57 (s, 2H), 4.11 (q, J= 7.1 Hz, 2H), 3.68 (s, 2H), 1.22 (t, J= 7.1 Hz, 3H)。 Preparation 377 2-[4-bromo-2-[[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]methoxymethyl]-5-fluoro-benzene base] ethyl acetate Bromo-(2-ethoxy-2-oxo-ethyl)zinc (0.4 M in THF, 3.4 mL, 1.4 mmol) was added to 2-[[2-[(5-bromo -4-fluoro-2-iodo-phenyl)methoxymethyl]-4-chloro-phenyl]methoxy]-6-chloro-pyridine (0.58 g, 0.91 mmol) and chloro[(4,5 -Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd-179, Xantphos Pd G2, 45 mg, 0.045 mmol) in THF (1 mL). The reaction mixture was heated to 60 °C for 10 h. The reaction mixture was partitioned between water (15 mL), aqueous citric acid (5%, 5 mL) and MTBE. The organic phase was washed with 5 mL portions of water, aqueous K2CO3 (2 M) and saturated aqueous NaCl. The organics were concentrated on Celite® and purified by silica gel chromatography using a gradient of 5-40% EtOAc in cyclohexane to give the title compound (311 mg, 58%) as a colorless oil. 1 H NMR (400.13 MHz, CDCl 3 ) δ 7.56-7.52 (m, 2H), 7.46-7.44 (m, 2H), 7.32 (dd, J = 2.2, 8.1 Hz, 1H), 7.07 (d, J = 9.0 Hz, 1H), 6.94 (d, J = 6.8 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 5.36 (s, 2H), 4.66 (s, 2H), 4.57 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.68 (s, 2H), 1.22 (t, J = 7.1 Hz, 3H).
製備 3782-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸乙酯 使用N 2將2-[4-溴-2-[[5-氯-2-[(6-氯-2-吡啶基)氧基甲基]苯基]甲氧基甲基]-5-氟-苯基]乙酸乙酯(0.59 g, 1.0 mmol)、雙(新戊二醇)二硼(0.28 g, 1.2 mmol)及新戊酸鉀(0.36 g, 2.5 mmol)於無水THF (40 mL)中之混合物鼓泡10 min,然後添加氯(2-二環己基膦基-2',4',6'-三-異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II) (X-Phos-Pd-G2, 42 mg, 0.052 mmol)。將反應混合物在45℃下加熱1.5 h,然後在55℃下加熱1 h,然後添加額外雙(新戊二醇)二硼(46 mg, 0.20 mmol)並在55℃下繼續加熱45 min。添加磷酸三鉀(於水中之1.0 M溶液,3 mL, 3.0 mmol)並在55℃下繼續加熱2 h。將反應混合物分配於K 2CO 3水溶液(2 M, 25 mL)與DCM (100 mL)之間並分離各層。使用DCM (25 mL)萃取水層,合併有機物並經由Celite ®過濾。濃縮濾液並藉由矽膠層析使用DCM來純化殘餘物。使用DCM (5 mL)及庚烷(20 mL)之混合物研磨產物並在真空及40℃下乾燥固體以得到白色固體形式之標題化合物(144 mg, 32%)。ES/MS m/z442, 444 (M+H)。 Preparation 378 2-(5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclooctane Fan-1 4 -yl) ethyl acetate 2-[4-Bromo-2-[[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]methoxymethyl]-5-fluoro using N -Phenyl]ethyl acetate (0.59 g, 1.0 mmol), bis(neopentyl glycol) diboron (0.28 g, 1.2 mmol) and potassium pivalate (0.36 g, 2.5 mmol) in anhydrous THF (40 mL) The mixture was bubbled for 10 min, and then chloro(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino- 1,1'-biphenyl-2-yl)palladium(II) (X-Phos-Pd-G2, 42 mg, 0.052 mmol). The reaction mixture was heated at 45°C for 1.5 h, then at 55°C for 1 h, then additional bis(neopentyl glycol)diboron (46 mg, 0.20 mmol) was added and heating was continued at 55°C for 45 min. Tripotassium phosphate (1.0 M solution in water, 3 mL, 3.0 mmol) was added and heating was continued at 55 °C for 2 h. The reaction mixture was partitioned between aqueous K 2 CO 3 (2 M, 25 mL) and DCM (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (25 mL), and the organics were combined and filtered through Celite® . The filtrate was concentrated and the residue was purified by silica gel chromatography using DCM. The product was triturated with a mixture of DCM (5 mL) and heptane (20 mL) and the solid was dried under vacuum at 40 °C to give the title compound (144 mg, 32%) as a white solid. ES/MS m/z 442, 444 (M+H).
製備 3792-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸 將LiOH (1M水溶液,2.1 mL, 2.1 mmol)添加至2-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸乙酯(227 mg, 0.51 mmol)於THF (7 mL)及MeOH (3.4 mL)之混合物中之懸浮液中。將混合物在60℃下加熱1 h。濃縮反應混合物並添加檸檬酸水溶液(5%)。過濾掉固體,使用水洗滌並在真空及40℃下乾燥以獲得白色固體形式之標題化合物(246 mg,90質量%,100%)。ES-MS m/z414, 416 (M+H)。 Preparation 379 2-(5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclooctane Fan-1 4 -yl)acetic acid LiOH (1M in water, 2.1 mL, 2.1 mmol) was added to 2-(5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3) , a suspension of ethyl 5(1,2)-diphenylcyclooctafan-1 4 -yl)acetate (227 mg, 0.51 mmol) in a mixture of THF (7 mL) and MeOH (3.4 mL). The mixture was heated at 60 °C for 1 h. The reaction mixture was concentrated and aqueous citric acid (5%) was added. The solid was filtered off, washed with water and dried under vacuum at 40°C to obtain the title compound (246 mg, 90% by mass, 100%) as a white solid. ES-MS m/z 414, 416 (M+H).
製備 380(S)-2-((5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯 在氮氣氛下,向2-(5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)乙酸(246 mg, 0.535 mmol, 90質量%)及4-胺基-3-(2-甲氧基乙氧基)-5-[[(2S)-環氧丙烷-2-基]甲基胺基]苯甲酸甲酯(183 mg, 0.59 mmol)於無水DMF (6 mL)中之溶液中添加吡啶(492 μL, 6.08 mmol)及2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷-2,4,6-三氧化物(1.68 M於EtoAc中,800 μL, 1.34 mmol)。將混合物在室溫下攪拌30 min,然後添加水。過濾掉固體,使用水洗滌,並在40℃下乾燥過夜。將固體於1,2-二氯乙烷(6.4 mL)及乙酸(6.4 mL)中之懸浮液在N 2氣氛及60℃下加熱過夜。冷卻反應混合物,使用EtOAc及水稀釋並過濾掉固體。分離有機層,藉由Na 2SO 4乾燥,過濾有機物並在減壓下濃縮。經由矽膠層析使用於DCM中之0 - 50% EtOAc之梯度來純化殘餘物以提供白色固體形式之標題化合物(291 mg, 75%)。ES-MS m/z688, 690 (M+H)。 Preparation 380 (S)-2-((5 4 -chloro- 1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3),5(1,2) -Diphenylcyclooctane-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d] Methyl imidazole-6-carboxylate Under nitrogen atmosphere, to 2-(5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)- Diphenylcyclooctane-1 4 -yl)acetic acid (246 mg, 0.535 mmol, 90 mass%) and 4-amino-3-(2-methoxyethoxy)-5-[[(2S)- To a solution of propylene oxide-2-yl]methylamino]benzoate (183 mg, 0.59 mmol) in anhydrous DMF (6 mL) was added pyridine (492 μL, 6.08 mmol) and 2,4,6 - Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.68 M in EtoAc, 800 μL, 1.34 mmol). The mixture was stirred at room temperature for 30 min, then water was added. The solid was filtered off, washed with water, and dried overnight at 40°C. A suspension of the solid in 1,2-dichloroethane (6.4 mL) and acetic acid (6.4 mL) was heated under N2 atmosphere at 60 °C overnight. The reaction mixture was cooled, diluted with EtOAc and water and the solid was filtered off. The organic layer was separated, dried over Na2SO4 , the organics were filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in DCM to afford the title compound (291 mg, 75%) as a white solid. ES-MS m/z 688, 690 (M+H).
實例 1(S)-2-((5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 將(S)-2-((5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(200 mg, 0.257 mmol)及1,5,7-三氮雜雙環[4.4.0]癸-5-烯(300 mg, 2.11 mmol)於ACN:水(4.0 mL:1.0 mL)中之混合物在60℃下攪拌5 h。使用1.0 M鹽酸水溶液將混合物調節至pH 6。經由使用於0.225%甲酸水溶液中之40 - 70% ACN之梯度洗脫之C18反相層析來純化整個反應混合物以得到33 mg標題化合物(21%)。ES-MS m/z605 (M+H)。 Example 1 (S)-2-((5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (S)-2-((5 4 -cyano-1 6 -fluoro-3,9-dioxa- 2 (2,6)-pyridine-1(1,3),5(1,2) -Diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (200 mg, 0.257 mmol ) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (300 mg, 2.11 mmol) in ACN:water (4.0 mL:1.0 mL) was stirred at 60°C for 5 h . The mixture was adjusted to pH 6 using 1.0 M aqueous hydrochloric acid. The entire reaction mixture was purified via C18 reverse phase chromatography eluting with a gradient of 40-70% ACN in 0.225% aqueous formic acid to afford 33 mg of the title compound (21%). ES-MS m/z 605 (M+H).
實例 2(S)-2-((5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-2-((5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(0.24 g, 0.38 mmol)於ACN:水(5.0 mL:1.0 mL)中之溶液中添加1,3,4,6,7,8-六氫-2h-嘧啶并[1,2-a]嘧啶(50 mg, 0.40 mmol)。在室溫下攪拌15 h,然後在60℃下攪拌4 h。將反應混合物濃縮至一半體積並使用1 M檸檬酸水溶液中和至pH 7。使用水(100 mL)稀釋混合物並使用DCM (3 × 50 mL)萃取。使用飽和氯化鈉水溶液(50 mL)洗滌合併之有機層。藉由硫酸鈉乾燥有機相,過濾,並在減壓下濃縮。經由矽膠層析使用於溶劑A中之5 - 100%溶劑B之梯度來純化殘餘物,其中溶劑B係於EtOAc中之20% MeOH且溶劑B係DCM。經由C18反相層析使用於10 mM碳酸氫銨水溶液中之25 - 40% ACN (含有5% MeOH)之梯度來進一步純化產物以得到40 mg標題化合物(17%)。ES-MS m/z623 (M+H)。 Example 2 (S)-2-((5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononafin-1 4 -yl)methyl)-4-fluoro-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid To (S)-2-((5 4 -cyano-1 6 -fluoro-3,9-dioxa- 2 (2,6)-pyridine-1(1,3),5(1,2) -Diphenylcyclononafin-1 4 -yl)methyl)-4-fluoro-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0.24 g, 0.38 mmol) in ACN:water (5.0 mL:1.0 mL) was added 1,3,4,6,7,8-hexahydro-2h-pyrimido[1,2-a]pyrimidine (50 mg, 0.40 mmol). Stir at room temperature for 15 h, then at 60 °C for 4 h. The reaction mixture was concentrated to half volume and neutralized to pH 7 using 1 M aqueous citric acid. The mixture was diluted with water (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 5-100% solvent B in solvent A where solvent B was 20% MeOH in EtOAc and solvent B was DCM. The product was further purified via C18 reverse phase chromatography using a gradient of 25 - 40% ACN (containing 5% MeOH) in 10 mM aqueous ammonium bicarbonate to afford 40 mg of the title compound (17%). ES-MS m/z 623 (M+H).
實例 3(S)-2-((5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-2-((5 4-氯-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(45 mg, 0.074 mmol)於ACN:THF:MeOH (0.80 mL:0.50 mL:0.50 mL)中之混合物中添加氫氧化鋰水溶液(1.0 M, 0.75 mL)。將混合物在40℃下攪拌6 h並在55℃下攪拌30 min。將混合物吸附於Celite ®上並經由使用於10 mM碳酸氫銨水溶液中之0 - 100% ACN (含有5% MeOH)之梯度洗脫之C18反相層析來純化以得到22 mg標題化合物(49%)。ES-MS m/z596 (M+H)。 Example 3 (S)-2-((5 4 -chloro-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclone Fan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid To (S)-2-((5 4 -chloro-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona -1( 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (45 mg, 0.074 mmol) in ACN:THF: To a mixture in MeOH (0.80 mL:0.50 mL:0.50 mL) was added aqueous lithium hydroxide (1.0 M, 0.75 mL). The mixture was stirred at 40 °C for 6 h and at 55 °C for 30 min. The mixture was adsorbed on Celite® and purified by C18 reverse phase chromatography eluting with a gradient of 0 - 100% ACN (containing 5% MeOH) in 10 mM aqueous ammonium bicarbonate to afford 22 mg of the title compound (49 %). ES-MS m/z 596 (M+H).
實例 4(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 將(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(240 mg, 0.40 mmol)及1,5,7-三氮雜雙環[4.4.0]癸-5-烯(170 mg, 1.20 mmol)於1,4-二噁烷: ACN :水(5:5:1, 11 mL)中之混合物在60℃下攪拌3h,在25℃下攪拌16 h,然後在50℃下攪拌72 h。將混合物濃縮至四分之一體積並經由使用於10 mM碳酸氫銨水溶液中之10 - 80% ACN (含有5% MeOH)之梯度洗脫之C18反相層析來純化以得到160 mg標題化合物(68%)。ES-MS m/z587 (M+H)。 Example 4 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononium Fen-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (240 mg, 0.40 mmol) and 1,5 , a mixture of 7-triazabicyclo[4.4.0]dec-5-ene (170 mg, 1.20 mmol) in 1,4-dioxane:ACN:water (5:5:1, 11 mL) in Stir at 60 °C for 3 h, at 25 °C for 16 h, then at 50 °C for 72 h. The mixture was concentrated to a quarter volume and purified by C18 reverse phase chromatography eluting with a gradient of 10 - 80% ACN (containing 5% MeOH) in 10 mM aqueous ammonium bicarbonate to give 160 mg of the title compound (68%). ES-MS m/z 587 (M+H).
實例 5(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 將(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(230 mg, 0.28 mmol)及1,5,7-三氮雜雙環[4.4.0]癸-5-烯(170 mg, 1.20 mmol)於1,4-二噁烷: ACN :水(5 : 5 : 1, 11 mL)中之混合物在50℃下攪拌16 h,在65℃下攪拌4 h,然後在50℃下攪拌 72 h。將混合物濃縮至四分之一體積並經由使用於10 mM碳酸氫銨水溶液中之10 - 80% ACN (含有5% MeOH)之梯度洗脫之C18反相層析來純化以得到標題化合物(170 mg, 72%)。ES-MS m/z617 (M+H)。 Example 5 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclone Fan- 14 -yl)methyl)-4-methoxy-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (230 mg, 0.28 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (170 mg, 1.20 mmol) in 1,4-dioxane: ACN : water (5 : 5 : 1, 11 mL) was stirred at 50°C for 16 h, at 65°C for 4 h, then at 50°C for 72 h. The mixture was concentrated to a quarter volume and purified by C18 reverse phase chromatography eluting with a gradient of 10 - 80% ACN (containing 5% MeOH) in 10 mM aqueous ammonium bicarbonate to give the title compound (170 mg, 72%). ES-MS m/z 617 (M+H).
實例 6(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-3-(環氧丙烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-甲酸 基本上如述實例5中所闡使用(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-3-(環氧丙烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-甲酸甲酯來製備標題化合物。ES-MS m/z588 (M+H)。 Example 6 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-3-(epoxypropan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using (S)-2-(( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononafran-1 4 -yl)methyl)-3-(epoxypropan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester to prepare the title compound. ES-MS m/z 588 (M+H).
實例 7(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例5中所闡述使用(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物。ES-MS m/z605 (M+H)。 Example 7 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-fluoro-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1 ,2)-Diphenylcyclononafin-1 4 -yl)methyl)-4-fluoro-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ester to prepare the title compound. ES-MS m/z 605 (M+H).
實例 8(S)-2-((5 4-氰基-1 6-氟-9-氧雜-3-氮雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例5中所闡述使用(S)-2-((5 4-氰基-1 6-氟-9-氧雜-3-氮雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯在ACN : THF :水(1 : 1 : 0.4)中來製備標題化合物。將混合物在50℃下加熱4 h,冷卻至室溫並使用1M檸檬酸溶液驟冷。使用EtOAc將混合物萃取三次。合併有機物,使用水及鹽水洗滌,藉由硫酸鎂乾燥,過濾,並在減壓下濃縮。藉由C18反相層析使用於20 mM碳酸氫銨水溶液中之35 - 70% ACN之梯度來純化殘餘物以得到白色固體形式之標題化合物。ES-MS m/z604 (M+H)。 Example 8 (S)-2-((5 4 -cyano-1 6 -fluoro-9-oxa-3-aza-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano- 16 -fluoro-9-oxa-3-aza-2(2,6)-pyridine-1(1) essentially as described in Example 5 ,3),5(1,2)-Diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6 -Methyl formate in ACN:THF:water (1:1:0.4) to prepare the title compound. The mixture was heated at 50 °C for 4 h, cooled to room temperature and quenched with 1M citric acid solution. The mixture was extracted three times with EtOAc. The organics were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography using a gradient of 35 - 70% ACN in 20 mM aqueous ammonium bicarbonate to give the title compound as a white solid. ES-MS m/z 604 (M+H).
實例 9(S)-2-((5 4-氰基-16-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-14-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例5中所闡述使用(S)-2-((5 4-氰基-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物。ES-MS m/z631 (M+H)。 Example 9 (S)-2-((5 4 -cyano-16-methyl-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononan-14-yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano- 16 -methyl-3,9-dioxa-2(2,6)-pyridine-1(1, [ d] imidazole-6-carboxylic acid methyl ester to prepare the title compound. ES-MS m/z 631 (M+H).
實例 10(S)-2-((5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例5中所闡述使用(S)-2-((5 4-氰基-1 6-氟-3,9-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物。將混合物在60℃及氮氣氛下加熱2 h,然後冷卻至室溫並使用檸檬酸(5%水溶液)驟冷。過濾固體,然後使用水及ACN洗滌以得到白色固體形式之標題化合物。ES-MS m/z605 (M+H)。 Example 10 (S)-2-((5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenyl ring Nonafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano- 16 -fluoro-3,9-dioxa-2(2,6)-pyridine-1,5(1 The title compound. The mixture was heated at 60 °C under nitrogen atmosphere for 2 h, then cooled to room temperature and quenched with citric acid (5% in water). The solid was filtered, then washed with water and ACN to give the title compound as a white solid. ES-MS m/z 605 (M+H).
實例 112-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-甲酸 向2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(39.7 mg, 0.06 mmol)於ACN (0.75 mL)、THF (0.19 mL)及水(0.12 mL)中之溶液中添加1,3,4,6,7,8-六氫-2h-嘧啶并[1,2-a]嘧啶(35 mg, 0.25 mmol)。將混合物在45℃下攪拌3 h。添加額外1,3,4,6,7,8-六氫-2h-嘧啶并[1,2-a]嘧啶(7.5 mg, 0.05 mmol)並將反應液在50℃下攪拌1 h。使用甲酸終止反應(至pH 6-7)並使用EtOAc萃取。使用水稀釋並使用EtOAc萃取。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。藉由C18反相層析使用於(65 mM乙酸銨水溶液:ACN 90:10溶液)中之28 - 64% (1:1 ACN:MeOH)之梯度來純化殘餘物以得到11.8 mg標題化合物(30%)。ES-MS m/z625 (M+H)。 Example 11 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclonnona-1 4 -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid To 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona- 1 4 -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (39.7 mg, 0.06 mmol) in To a solution in ACN (0.75 mL), THF (0.19 mL) and water (0.12 mL) was added 1,3,4,6,7,8-hexahydro-2h-pyrimido[1,2-a]pyrimidine ( 35 mg, 0.25 mmol). The mixture was stirred at 45 °C for 3 h. Additional 1,3,4,6,7,8-hexahydro-2h-pyrimido[1,2-a]pyrimidine (7.5 mg, 0.05 mmol) was added and the reaction was stirred at 50°C for 1 h. The reaction was quenched with formic acid (to pH 6-7) and extracted with EtOAc. Diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography using a gradient of 28 - 64% (1:1 ACN:MeOH) in (65 mM aqueous ammonium acetate: ACN 90:10 solution) to give 11.8 mg of the title compound (30 %). ES-MS m/z 625 (M+H).
實例 12(S)-1 4-((4-甲氧基-1-(環氧丙烷-2-基甲基)-6-(1H-四唑-5-基)-1H-苯并[d]咪唑-2-基)甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-甲腈 將於乙酸(1.0 mL)中之(S)-2-(5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)-N-(2-甲氧基-6-((環氧丙烷-2-基甲基)胺基)-4-(1H-四唑-5-基)苯基)乙醯胺(56 mg, 0.05 mmol)在65℃下攪拌12 h。濃縮溶液並使用ACN共沸。藉由C18反相層析使用於25 mM碳酸銨水溶液中之41 - 83% 1:1 ACN:MeOH之梯度來純化殘餘物以得到9.4 mg標題化合物(28%)。ES-MS m/z641 (M+H)。 Example 12 (S)-1 4 -((4-methoxy-1-(epoxypropylene-2-ylmethyl)-6-(1H-tetrazol-5-yl)-1H-benzo[d ]imidazol-2-yl)methyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-5 4 -Formonitrile (S)-2-(5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1, 2)-Diphenylcyclononafin-1 4 -yl)-N-(2-methoxy-6-((epoxypropylene-2-ylmethyl)amino)-4-(1H-tetrazole- 5-yl)phenyl)acetamide (56 mg, 0.05 mmol) was stirred at 65°C for 12 h. The solution was concentrated and azeotroped using ACN. The residue was purified by C18 reverse phase chromatography using a gradient of 41 - 83% 1:1 ACN:MeOH in 25 mM aqueous ammonium carbonate to afford 9.4 mg of the title compound (28%). ES-MS m/z 641 (M+H).
實例 13(S)-2-((5 4-氰基-1 6-氟-3,6,9-三氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例1中所闡述使用(S)-2-((5 4-氰基-1 6-氟-3,6,9-三氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物,其中將反應液在45℃下攪拌2 h。在完成時,使用甲酸終止反應(至pH 7)並使用水稀釋粗製混合物。使用EtOAc將混合物萃取三次。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。經由矽膠急速層析使用於DCM中之0 - 40% 9:1 DCM:MeOH (含有1%甲酸)之梯度來純化殘餘物以得到標題化合物。ES-MS m/z607 (M+H)。 Example 13 (S)-2-((5 4 -cyano- 1 6 -fluoro-3,6,9-trioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano- 16 -fluoro-3,6,9-trioxa-2(2,6)-pyridine-1(1) essentially as described in Example 1 ,3),5(1,2)-diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6 -methyl formate to prepare the title compound, wherein the reaction was stirred at 45 °C for 2 h. Upon completion, the reaction was quenched with formic acid (to pH 7) and the crude mixture was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of 0-40% 9:1 DCM:MeOH in DCM containing 1% formic acid to give the title compound. ES-MS m/z 607 (M+H).
實例 14(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如針對實例2所闡述使用(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物,將反應液在45℃下攪拌19 h,然後添加1,4-二噁烷並在45℃下攪拌23 h。使用甲酸終止反應(終止pH 6-7)並使用EtOAc萃取,隨後使用3:1氯仿:2-丙醇萃取。藉由硫酸鎂乾燥有機相,過濾,並在減壓下濃縮。藉由C18反相層析使用於25 mM碳酸銨水溶液中之30 - 73% 1:1 ACN:MeOH之梯度來純化殘餘物以得到標題化合物。ES-MS m/z591 (M+H)。 Example 14 (S)-2-((5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclooctane-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano- 16 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3) essentially as described for Example 2 ), 5(1,2)-diphenylcyclooctane-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid To prepare the title compound, the reaction was stirred at 45°C for 19 h, then 1,4-dioxane was added and stirred at 45°C for 23 h. The reaction was quenched with formic acid (stop pH 6-7) and extracted with EtOAc, followed by 3:1 chloroform:2-propanol. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography using a gradient of 30 - 73% 1:1 ACN:MeOH in 25 mM aqueous ammonium carbonate to give the title compound. ES-MS m/z 591 (M+H).
實例 15(S)-2-((5 4-氰基-1 6-甲基-3,9-二氧雜-1,2(1,3),5(1,2)-三苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例4中所闡述使用(S)-2-((5 4-氰基-1 6-甲基-3,9-二氧雜-1,2(1,3),5(1,2)-三苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物。在完成後,將反應混合物濃縮至四分之一體積,使用檸檬酸溶液中和並經由使用於10 mM碳酸氫銨水溶液中之10 - 80% ACN (含有5% MeOH)之梯度洗脫之C18反相層析來純化以得到標題化合物。ES-MS m/z630 (M+H)。 Example 15 (S)-2-((5 4 -cyano-1 6 -methyl-3,9-dioxa-1,2(1,3),5(1,2)-triphenylcyclone Fan-1 4 -yl)methyl)-4-methoxy-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano- 16 -methyl-3,9-dioxa-1,2(1,3),5(1, 2)-Triphenylcyclononafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester to prepare the title compound. Upon completion, the reaction mixture was concentrated to a quarter volume, neutralized with citric acid solution and eluted through a C18 gradient of 10 - 80% ACN (containing 5% MeOH) in 10 mM aqueous ammonium bicarbonate. Purify by reverse phase chromatography to give the title compound. ES-MS m/z 630 (M+H).
實例 16(S)-4-甲氧基-2-((1 6-甲基-5 4-(三氟甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例1中所闡述使用(S)-4-甲氧基-2-((1 6-甲基-5 4-(三氟甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯且使用二噁烷:ACN:水(6:6:1)作為溶劑來製備標題化合物,其中將反應液在50℃下攪拌2h。在完成時,使用檸檬酸中和並濃縮反應混合物。使用EtOAc稀釋殘餘物並使用水及飽和NaCl水溶液洗滌。藉由硫酸鈉乾燥有機相,過濾,並濃縮。經由矽膠層析使用於DCM中之10 - 80% (於EtOAc中之20% MeOH)之梯度來純化殘餘物以得到標題化合物。ES-MS m/z674 (M+H)。 Example 16 (S)-4-methoxy-2-(( 16 -methyl- 54- (trifluoromethyl)-3,9-dioxa-2(2,6)-pyridine-1 (1,3),5(1,2)-Diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole -6-Formic acid Using (S)-4-methoxy-2-(( 16 -methyl- 54- (trifluoromethyl)-3,9-dioxa-2(2) essentially as described in Example 1 ,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H - Methyl benzo[d]imidazole-6-carboxylate and the title compound was prepared using dioxane:ACN:water (6:6:1 ) as solvent, where the reaction was stirred at 50 °C for 2 h. Upon completion, the reaction mixture was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and washed with water and saturated aqueous NaCl. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 10-80% (20% MeOH in EtOAc) in DCM to give the title compound. ES-MS m/z 674 (M+H).
實例 17(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例2中所闡述使用(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物。將反應液在45℃下攪拌4 h。將混合物冷卻至室溫,過濾,並蒸發濾液。藉由反相層析使用於溶劑A中之30 - 73%溶劑B (溶劑A = [65mM NH4OAc + ACN (90:10)];溶劑B = ACN])之梯度來純化殘餘物以得到白色固體形式之標題化合物。ES-MS m/z621 (M+H)。 Example 17 (S)-2-((5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclooctane-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano- 16 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3) essentially as described in Example 2 ), 5(1,2)-diphenylcyclooctane-1 4 -yl)methyl)-4-methoxy-1-(epoxypropan-2-ylmethyl)-1H-benzo[d ] imidazole-6-carboxylic acid methyl ester to prepare the title compound. The reaction solution was stirred at 45 °C for 4 h. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by reverse phase chromatography using a gradient of 30 - 73% solvent B in solvent A (solvent A = [65 mM NHOAc + ACN (90:10)]; solvent B = ACN]) to give a white solid form of the title compound. ES-MS m/z 621 (M+H).
實例 18( S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸 基本上如實例3中所闡述使用( S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸甲酯且使用2:1 THF:MeOH作為溶劑來製備標題化合物。在65℃下攪拌1.5 h並添加1 M KH 2PO 4水溶液。使用水將反應液稀釋2.5倍並在攪拌下冷卻45 min。藉由過濾收集固體並使用1:3 MeOH:水洗滌,隨後使用水洗滌。在減壓及50℃下將濾餅乾燥20 h以提供白色固體形式之標題化合物。ES-MS m/z640及642 (M+H)。 Example 18 ( S )-2-((5 4 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclone Fan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid Using ( S )-2-(( 54 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1, 2 ) . :1 THF:MeOH was used as solvent to prepare the title compound. Stir at 65 °C for 1.5 h and add 1 M aqueous KH2PO4 . The reaction solution was diluted 2.5 times with water and cooled for 45 min under stirring. The solid was collected by filtration and washed with 1:3 MeOH:water followed by water. The filter cake was dried under reduced pressure at 50 °C for 20 h to afford the title compound as a white solid. ES-MS m/z 640 and 642 (M+H).
實例 19(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例1中所闡述使用(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯在3:1:1 ACN : THF :水中來製備標題化合物。將混合物在55℃下加熱3 h,冷卻至室溫並使用5%檸檬酸水溶液驟冷直至pH = 4-5以沈澱白色固體。過濾固體,使用水(3次)及ACN洗滌,並在真空及45℃下乾燥過夜以得到白色固體形式之標題化合物。ES-MS m/z587 (M+H)。 Example 19 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1) essentially as described in Example 1 , 2)-diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester in 3: 1:1 ACN:THF:water to prepare the title compound. The mixture was heated at 55 °C for 3 h, cooled to room temperature and quenched with 5% aqueous citric acid until pH = 4-5 to precipitate a white solid. The solid was filtered, washed with water (3 times) and ACN, and dried under vacuum at 45°C overnight to give the title compound as a white solid. ES-MS m/z 587 (M+H).
實例 20(S)-2-((5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例1中所闡述使用(S)-2-((5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯在3:1:1 ACN : 1,4-二噁烷:水(作為溶劑)中來製備標題化合物。將反應液加熱至60℃並保持3 h,然後冷卻至室溫並使用檸檬酸溶液(5%,於水中)驟冷。使用EtOAc稀釋,分離各相並使用EtOAc將水相萃取兩次。合併有機相,使用水及飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,過濾並在減壓下濃縮。藉由SFC [管柱:Chiralpak 20×250mm, 5 µm;等梯度移動相:於(MeOH + 0.5%二甲基乙基胺)中之35% CO 2,在100巴下,流速:65 mL/min]純化殘餘物以得到白色固體形式之標題化合物。ES-MS m/z591 (M+H)。 Example 20 (S)-2-((5 4 -cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclooctane-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano- 16 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3) essentially as described in Example 1 ), 5(1,2)-diphenylcyclooctane-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Methyl ester in 3:1:1 ACN:1,4-dioxane:water (as solvent) to prepare the title compound. The reaction was heated to 60 °C for 3 h, then cooled to room temperature and quenched with citric acid solution (5% in water). It was diluted with EtOAc, the phases were separated and the aqueous phase was extracted twice with EtOAc. The organic phases were combined, washed with water and saturated aqueous NaCl, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. By SFC [column: Chiralpak 20×250mm, 5 µm; isocratic mobile phase: 35% CO 2 in (MeOH + 0.5% dimethylethylamine), at 100 bar, flow rate: 65 mL/ min] The residue was purified to give the title compound as a white solid. ES-MS m/z 591 (M+H).
實例 21(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例1中所闡述使用(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(90 mg, 0.14 mmol)在3:1:1 ACN : 1,4-二噁烷:水(作為溶劑)中來製備標題化合物。將反應液加熱至60℃並保持1h,冷卻至室溫並使用檸檬酸水溶液(5%)驟冷。過濾固體並使用水洗滌,且然後使用ACN洗滌以提供白色固體形式之標題化合物。ES-MS m/z587 (M+H)。 Example 21 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona- 1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-bis) essentially as described in Example 1 Phenycyclononafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (90 mg, 0.14 mmol) in 3:1:1 ACN:1,4-dioxane:water (as solvent) to prepare the title compound. The reaction was heated to 60 °C for 1 h, cooled to room temperature and quenched with aqueous citric acid (5%). The solid was filtered and washed with water and then ACN to afford the title compound as a white solid. ES-MS m/z 587 (M+H).
實例 22(S)-4-甲氧基-2-((1 6-甲基-5 4-(氟)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例4中所闡述使用(S)-4-甲氧基-2-((1 6-甲基-5 4-(氟)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物,其中將反應液在50℃下攪拌2h。濃縮反應,使用檸檬酸水溶液中和並經由C18反相層析使用於10 mM NH 4HCO 3水溶液中之10 - 80% ACN (含有5% MeOH)之梯度進行純化。ES-MS m/z624 (M+H)。 Example 22 (S)-4-methoxy-2-(( 16 -methyl- 54- (fluoro)-3,9-dioxa-2(2,6)-pyridine-1(1, 3), 5(1,2)-diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- formic acid Using (S)-4-methoxy-2-(( 16 -methyl- 54- (fluoro)-3,9-dioxa-2(2,6) essentially as described in Example 4 -Pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo [d] imidazole-6-carboxylic acid methyl ester to prepare the title compound, wherein the reaction solution was stirred at 50 ° C for 2h. The reaction was concentrated, neutralized with aqueous citric acid and purified by C18 reverse phase chromatography using a gradient of 10-80% ACN with 5% MeOH in 10 mM aqueous NH4HCO3 . ES-MS m/z 624 (M+H).
實例 232-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(噁唑-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例1中所闡述使用2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(噁唑-2-基甲基)-1H-苯并[d]咪唑-6-甲酸乙酯來製備標題化合物,其中將反應液在65℃下攪拌72 h。將混合物濃縮至四分之一體積並使用甲酸調節至pH = 5。收集所得沈澱物並經由使用於10 mM NH 4HCO 3水溶液中之10 - 80% ACN (含有5% MeOH)之梯度洗脫之C18反相層析來純化以得到無色固體形式之標題化合物。ES-MS m/z628 (M+H)。 Example 23 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclonona-1 4 -yl)methyl)-4-methoxy-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 2-(( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)- Diphenylcyclononafin-1 4 -yl)methyl)-4-methoxy-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester to prepare The title compound, wherein the reaction solution was stirred at 65 °C for 72 h. The mixture was concentrated to a quarter volume and adjusted to pH=5 using formic acid. The resulting precipitate was collected and purified by C18 reverse phase chromatography eluting with a gradient of 10 - 80% ACN (containing 5% MeOH) in 10 mM aqueous NH4HCO3 to give the title compound as a colorless solid. ES-MS m/z 628 (M+H).
實例 24(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例1中所闡述使用(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯使用5:5:1 1,4-二噁烷: ACN :水作為溶劑來製備標題化合物,其中將反應液在45℃下攪拌16 h。將混合物濃縮至四分之一體積並使用甲酸調節至pH = 5。使用水稀釋混合物並使用氯仿/異丙醇(3:1)萃取有機物。藉由MgSO 4乾燥有機物,過濾並濃縮。經由使用於DCM中之0 - 40% (於MeOH中之10%甲酸)之梯度洗脫之急速層析來純化標題化合物。ES-MS m/z661 (M+H)。 Example 24 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- formic acid Using (S)-2-(( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1) essentially as described in Example 1 ,2)-Diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo [d] Methyl imidazole-6-carboxylate The title compound was prepared using 5:5:1 1,4-dioxane:ACN:water as solvent, and the reaction solution was stirred at 45°C for 16 h. The mixture was concentrated to a quarter volume and adjusted to pH=5 using formic acid. The mixture was diluted with water and the organics were extracted with chloroform/isopropanol (3:1). The organics were dried over MgSO4 , filtered and concentrated. The title compound was purified by flash chromatography eluting with a gradient of 0 - 40% (10% formic acid in MeOH) in DCM. ES-MS m/z 661 (M+H).
實例 25( S)-2-((5 4-(羥甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸 在0℃下,將硼氫化鈉(5.3 mg, 0.14 mmol)添加至( S)-2-((5 4-甲醯基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸(30 mg, 0.051 mmol)於MeOH (460 µL)及THF (1 mL)之混合物在之漿液中。將混合物攪拌5 min且然後升溫至室溫。將反應液攪拌 20 min且然後在室溫下使用氮流去除揮發物。添加檸檬酸水溶液(5%),攪拌5 min,過濾固體並使用水及MeOH洗滌。經由矽膠層析使用於DCM中之10% MeOH來純化固體以提供白色固體形式之標題化合物(8 mg, 25%)。ES-MS m/z592 (M+H)。 Example 25 ( S )-2-((5 4- (hydroxymethyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)- Diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid Sodium borohydride (5.3 mg, 0.14 mmol) was added to ( S )-2-((5 4 -formyl-3,9-dioxa-2(2,6)-pyridine- 1(1,3),5(1,2)-Diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ] imidazole-6-carboxylic acid (30 mg, 0.051 mmol) in a slurry of a mixture of MeOH (460 µL) and THF (1 mL). The mixture was stirred for 5 min and then warmed to room temperature. The reaction was stirred for 20 min and then volatiles were removed using a nitrogen stream at room temperature. Aqueous citric acid (5%) was added, stirred for 5 min, the solid was filtered and washed with water and MeOH. The solid was purified by silica gel chromatography using 10% MeOH in DCM to afford the title compound (8 mg, 25%) as a white solid. ES-MS m/z 592 (M+H).
實例 26(S)-4-甲氧基-2-((1 6-甲基-5 6-(三氟甲基)-3,9-二氧雜-2(2,6),5(3,2)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸;1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶 基本上如實例4中所闡述使用(S)-4-甲氧基-2-((1 6-甲基-5 6-(三氟甲基)-3,9-二氧雜-2(2,6),5(3,2)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物,其中將反應液在45℃下攪拌16 h。使用檸檬酸水溶液中和反應液,濃縮混合物,並經由C18反相層析使用於10 mM NH 4HCO 3水溶液中之10 - 80% ACN (含有5% MeOH)之梯度進行純化。ES-MS m/z675 (M+H)。 Example 26 (S)-4-methoxy-2-(( 16 -methyl- 56- (trifluoromethyl)-3,9-dioxa-2(2,6),5(3 ,2)-dipyridine-1(1,3)-phencyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H-benzo[d]imidazole -6-Formic acid; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine Using (S)-4-methoxy-2-((1 6 -methyl-5 6 -(trifluoromethyl)-3,9-dioxa-2(2) essentially as described in Example 4 ,6),5(3,2)-bipyridine-1(1,3)-phencyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H -Benzo[d]imidazole-6-carboxylic acid methyl ester to prepare the title compound, wherein the reaction solution was stirred at 45°C for 16 h. The reaction was neutralized with aqueous citric acid, the mixture was concentrated, and purified by C18 reverse phase chromatography using a gradient of 10-80% ACN (containing 5% MeOH ) in 10 mM aqueous NH4HCO3 . ES-MS m/z 675 (M+H).
實例 27(S)-4-甲氧基-2-((1 6-甲基-3,9-二氧雜-2(2,6),5(4,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例4中所闡述使用(S)-4-甲氧基-2-((1 6-甲基-3,9-二氧雜-2(2,6),5(4,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物,其中將反應液在50℃下攪拌2h。濃縮反應液,使用檸檬酸水溶液中和並經由C18反相層析使用於10 mM NH 4HCO 3水溶液中之10 - 80% ACN (含有5% MeOH)之梯度進行純化。將純化產物再溶於DCM中並使用檸檬酸水溶液中和。使用水及飽和NaCl水溶液洗滌有機物。基於Na 2SO 4乾燥,過濾並濃縮以得到標題化合物。ES-MS m/z607 (M+H)。 Example 27 (S)-4-methoxy-2-(( 16 -methyl-3,9-dioxa-2(2,6),5(4,3)-bipyridine-1(1 ,3)-Phenencyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-4-methoxy-2-(( 16 -methyl-3,9-dioxa-2(2,6),5(4,3) essentially as described in Example 4 -Dipyridin-1(1,3)-phencyclononafin-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- The title compound was prepared from methyl formate, where the reaction was stirred at 50 °C for 2 h. The reaction was concentrated, neutralized with aqueous citric acid and purified by C18 reverse phase chromatography using a gradient of 10-80% ACN with 5% MeOH in 10 mM aqueous NH4HCO3 . The purified product was redissolved in DCM and neutralized with aqueous citric acid. The organics were washed with water and saturated aqueous NaCl. Dry over Na2SO4 , filter and concentrate to give the title compound. ES-MS m/z 607 (M+H).
實例 28( S)-1-(環氧丙烷-2-基甲基)-2-((5 4-(1-(環氧丙烷-3-基甲基)-1 H-吡唑-4-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1 H-苯并[ d]咪唑-6-甲酸 將DMF (0.43 mL)及磷酸三鉀(1 M水溶液,0.13 mL, 0.13 mmol)添加至含有( S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸(30 mg, 0.0436 mmol)、1-(環氧丙烷-3-基甲基)-4-(四甲基-1,3,2-二氧硼㖦-2-基)-1 H-吡唑(19 mg, 0.0698 mmol)及1,1'-雙(二-第三丁基膦基)二茂鐵二氯化鈀(1.4 mg, 0.0021 mmol)之容器中。使用氮吹掃容器,密封容器,並將混合物在60℃下攪拌2 h。冷卻至環境溫度,且然後經由C18反相層析使用ACN/10 mM NH 4HCO 3水溶液作為洗脫劑來直接純化混合物。 與來自第二類似反應之材料合併,將所得固體懸浮於1:1 DCM : EtOAc中,並在減壓下部分地濃縮以去除DCM。在環境溫度下將懸浮液攪拌10 min,然後藉由過濾收集固體並使用EtOAc洗滌。在減壓及50℃下乾燥16 h以提供28 mg白色固體形式之標題化合物(兩個反應中之每一者之平均產率為41%)。ES-MS m/z698。 Example 28 ( S )-1-(epoxypropylene-2-ylmethyl)-2-(( 54- (1-(epoxypropylene-3-ylmethyl) -1H -pyrazole-4- Base)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-1 4 -yl)methyl)-1 H -Benzo[ d ]imidazole-6-carboxylic acid DMF (0.43 mL) and tripotassium phosphate (1 M in water, 0.13 mL, 0.13 mmol) were added to a solution containing ( S )-2-((5 4 -bromo-3,9-dioxa-2(2,6 )-pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1 H - Benzo[ d ]imidazole-6-carboxylic acid (30 mg, 0.0436 mmol), 1-(epoxypropan-3-ylmethyl)-4-(tetramethyl-1,3,2-dioxaboronium- Container of 2-yl) -1H -pyrazole (19 mg, 0.0698 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (1.4 mg, 0.0021 mmol) middle. The vessel was purged with nitrogen, sealed, and the mixture was stirred at 60 °C for 2 h. Cooled to ambient temperature, and then directly purified the mixture via C18 reverse phase chromatography using ACN/10 mM aqueous NH4HCO3 as eluent. Combined with material from a second similar reaction, the resulting solid was suspended in 1:1 DCM:EtOAc and partially concentrated under reduced pressure to remove DCM. The suspension was stirred at ambient temperature for 10 min, then the solid was collected by filtration and washed with EtOAc. Drying under reduced pressure at 50 °C for 16 h afforded 28 mg of the title compound as a white solid (41% average yield for each of the two reactions). ES-MS m/z 698.
實例 29(
S)-2-((5
4-(6-甲氧基吡啶-3-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1
4-基)甲基)-1-(環氧丙烷-2-基甲基)-1
H-苯并[
d]咪唑-6-甲酸
使用攪拌棒將(
S)-2-((5
4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1
4-基)甲基)-1-(環氧丙烷-2-基甲基)-1
H-苯并[
d]咪唑-6-甲酸(30 mg, 0.0436 mmol)、2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)吡啶(22 mg, 0.094 mmol)及1,1'-雙(二-第三丁基膦基)二茂鐵二氯化鈀(3 mg, 0.0045 mmol)添加至玻璃管中。使用氮吹掃管並添加磷酸三鉀(1 M水溶液,0.13 mL, 0.13 mmol)及DMF (0.5 mL)。將混合物在60℃下攪拌16 h。將額外1,1'-雙(二-第三丁基膦基)二茂鐵二氯化鈀(3 mg, 0.0045 mmol)添加至反應液中並在60℃下加熱3 h,然後在90℃下加熱16 h。將混合物冷卻至環境溫度,且然後使用C18反相層析使用ACN/10 mM NH
4HCO
3水溶液作為洗脫劑來直接純化反應混合物以得到固體形式之標題化合物(4.7 mg, 14%)。ES-MS
m/z669。
基本上如實例29中所闡述使用適當酸或酸酯酯來製備下列實例。
實例 40( S)-2-((5 4-(1-甲基-1 H-吡唑-4-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸 基本上如實例29中所闡述使用1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)吡唑來製備標題化合物,其中將反應液在60℃下攪拌2 h並省略第二觸媒添加。將粗製反應混合物加載於疏水親脂平衡(HLB)樹脂上並使用10 mM NH 4HCO 3水溶液緩衝液洗脫,然後使用1:1 DCM : MeOH洗脫。濃縮含有標題化合物之級分且然後使用C18反相層析且使用於10 mM NH 4HCO 3水溶液中之ACN之梯度進一步純化。ES-MS m/z642。 Example 40 ( S )-2-((5 4- (1-methyl-1 H -pyrazol-4-yl)-3,9-dioxa-2(2,6)-pyridine-1(1 ,3),5(1,2)-Diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ]imidazole- 6-Formic acid The title compound was prepared essentially as described in Example 29 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole , wherein the reaction solution was stirred at 60 °C for 2 h and the addition of the second catalyst was omitted. The crude reaction mixture was loaded onto a hydrophobic lipophilic balance (HLB) resin and eluted with 10 mM NH4HCO3 aqueous buffer followed by 1:1 DCM:MeOH. Fractions containing the title compound were concentrated and then further purified using C18 reverse phase chromatography with a gradient of ACN in 10 mM aq . NH4HCO3 . ES-MS m/z 642.
實例 41(S)-1 4-((1-(環氧丙烷-2-基甲基)-6-(1H-四唑-5-基)-1H-苯并[d]咪唑-2-基)甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-甲腈 向(S)-1 4-((1-(環氧丙烷-2-基甲基)-6-(1-((2-(三甲基矽基)乙氧基)甲基)-1H-四唑-5-基)-1H-苯并[d]咪唑-2-基)甲基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-5 4-甲腈(100 mg, 0.1 mmol)於THF (2 mL)中之溶液中添加TBAF (1 M於THF中,0.3 mL, 0.3 mmol)。將混合物在60℃下攪拌16 h。使用水終止反應並使用EtOAc稀釋。藉由MgSO 4乾燥有機相,過濾,並在減壓下濃縮。將殘餘物懸浮於氨水溶液中並在50℃下攪拌6 h。在減壓下濃縮並藉由C18反相層析使用於乙酸銨水溶液中之30 - 70% ACN之梯度來純化固體以得到93 mg標題化合物(10%)。ES-MS m/z611 (M+H)。 Example 41 (S)-1 4 -((1-(epoxypropylene-2-ylmethyl)-6-(1H-tetrazol-5-yl)-1H-benzo[d]imidazol-2-yl )methyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-5 4 -carbonitrile To (S)-1 4 -((1-(epoxypropylene-2-ylmethyl)-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Tetrazol-5-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5 To a solution of (1,2)-diphenylcyclonafin- 54 -carbonitrile (100 mg, 0.1 mmol) in THF (2 mL) was added TBAF (1 M in THF, 0.3 mL, 0.3 mmol). The mixture was stirred at 60 °C for 16 h. The reaction was quenched with water and diluted with EtOAc. The organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was suspended in aqueous ammonia and stirred at 50 °C for 6 h. Concentrate under reduced pressure and purify the solid by C18 reverse phase chromatography using a gradient of 30-70% ACN in aqueous ammonium acetate to afford 93 mg of the title compound (10%). ES-MS m/z 611 (M+H).
實例 42(S)-2-((5 4-氰基-1 6-氟-3,6-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-2-((5 4-氰基-1 6-氟-3,6-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(92 mg, 0.15 mmol)於ACN (8.4 mL)及水(4.8 mL)中之溶液中添加1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(87 mg, 0.61 mmol)。在45℃下攪拌過夜。將混合物冷卻至室溫,使用水稀釋並使用3:1 DCM :異丙醇萃取三次。合併有機物,使用水及飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於DCM中之30% EtOAc且然後使用於DCM中之0 - 5% (10:1 MeOH :甲酸)之梯度來純化殘餘物。藉由反相層析使用於0.1%甲酸水溶液中之41 - 83% [1:1 ACN : MeOH] (pH3)來再純化以得到白色固體形式之標題化合物(12 mg, 13%)。ES-MS m/z591 (M+H)。 Example 42 (S)-2-((5 4 -cyano-1 6 -fluoro-3,6-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclooctane-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid To (S)-2-((5 4 -cyano-1 6 -fluoro-3,6-dioxa-2(2,6)-pyridine-1(1,3),5(1,2) -Diphenylcyclooctane-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (92 mg, 0.15 mmol ) in ACN (8.4 mL) and water (4.8 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (87 mg, 0.61 mmol). Stir overnight at 45°C. The mixture was cooled to room temperature, diluted with water and extracted three times with 3:1 DCM:isopropanol. The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 30% EtOAc in DCM and then a gradient of 0-5% (10:1 MeOH:formic acid) in DCM. Repurification by reverse phase chromatography using 41 - 83% [1:1 ACN:MeOH] in 0.1% aqueous formic acid (pH 3) gave the title compound (12 mg, 13%) as a white solid. ES-MS m/z 591 (M+H).
實例 43(S)-2-((5 5-氰基-1 6-氟-3,9-二氧雜-2(2,6),5(2,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸二甲酸鹽 向(S)-2-((5 5-氰基-1 6-氟-3,9-二氧雜-2(2,6),5(2,3)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(66 mg, 0.10 mmol)於ACN (1.2 mL)、THF (0.3 mL)及水(0.2 mL)中之懸浮液中添加1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(0.032 g, 0.23 mmol)。將懸浮液在45℃下攪拌6 h。將混合物冷卻至室溫,添加甲酸直至pH = 4,並使用EtOAc (3 × 5 mL)萃取。合併有機物,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。經由矽膠層析使用於溶劑A中之0 - 50%溶劑B之梯度(其中溶劑B = (DCM / MeOH /甲酸,9:0.9:0.1)且溶劑A = DCM)來純化殘餘物以得到灰棕色固體形式之標題化合物(15 mg, 24%)。ES-MS m/z636 (M+H-甲酸鹽)。 Example 43 (S)-2-((5 5 -cyano- 1 6 -fluoro-3,9-dioxa-2(2,6), 5(2,3)-bipyridine-1(1, 3)-Phenycyclononafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid di Formate To (S)-2-((5 5 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6),5(2,3)-bipyridine-1(1,3 )-phencyclononafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (66 mg, 0.10 mmol) to a suspension in ACN (1.2 mL), THF (0.3 mL) and water (0.2 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a]pyrimidine (0.032 g, 0.23 mmol). The suspension was stirred at 45 °C for 6 h. The mixture was cooled to room temperature, formic acid was added until pH = 4, and extracted with EtOAc (3 x 5 mL). The organics were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 - 50% solvent B in solvent A (where solvent B = (DCM/MeOH/formic acid, 9:0.9:0.1) and solvent A = DCM) to give a beige The title compound as a solid (15 mg, 24%). ES-MS m/z 636 (M+H-formate).
實例 44(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(57 mg, 0.09 mmol)於脫氣ACN (0.9 mL)、1,4-二噁烷(0.3 mL)及水(0.3 mL)中之懸浮液中添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(38 mg, 0.27 mmol)。將反應混合物在60℃下加熱2 h,冷卻至室溫,添加5%檸檬酸水溶液直至pH = 5,然後添加水(2.0 mL)並將混合物在室溫下攪拌15 min。過濾所得固體,使用水(5 mL)洗滌並在真空及45℃下乾燥過夜。將固體懸浮於MeOH (1.0 mL)中並將混合物在室溫下攪拌15 min。過濾所得固體,使用MeOH (0.5 mL)、EtOAc (1.5 mL)洗滌並在真空及45℃下乾燥過夜以得到淺褐色固體形式之標題化合物(19 mg, 34%)。ES-MS m/z635.2/636.2 (M+H)。 Example 44 (S)-2-((5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid To (S)-2-((5 4 -cyano-1 6 -fluoro-3,7-dioxa- 2 (2,6)-pyridine-1(1,3),5(1,2) -Diphenylcyclononafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (57 mg, 0.09 mmol) to a suspension in degassed ACN (0.9 mL), 1,4-dioxane (0.3 mL) and water (0.3 mL) was added 1,5,7-triazabicyclo[ 4.4.0] Dec-5-ene (38 mg, 0.27 mmol). The reaction mixture was heated at 60 °C for 2 h, cooled to room temperature, 5% aqueous citric acid was added until pH = 5, then water (2.0 mL) was added and the mixture was stirred at room temperature for 15 min. The resulting solid was filtered, washed with water (5 mL) and dried under vacuum at 45 °C overnight. The solid was suspended in MeOH (1.0 mL) and the mixture was stirred at room temperature for 15 min. The resulting solid was filtered, washed with MeOH (0.5 mL), EtOAc (1.5 mL) and dried under vacuum at 45 °C overnight to give the title compound (19 mg, 34%) as a beige solid. ES-MS m/z 635.2/636.2 (M+H).
實例 45(S)-2-((5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 在55℃下,向(S)-2-((5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(245 mg,64%純度,0.21 mmol)於ACN (2.4 mL)、水(0.8 mL)及THF (0.8 mL)中之溶液中添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(210 mg, 1.47 mmol)。將混合物在55℃下攪拌2 h,冷卻至室溫,添加5%檸檬酸水溶液直至pH = 4-5,然後過濾沈澱之白色固體。將固體溶於ACN/MeOH中並藉由製備型HPLC [管柱:Welch Xtimate C18 150 × 30 mm × 5 µm;移動相:於甲酸水溶液(0.225%)中之30 - 70% ACN]純化以提供白色固體形式之標題化合物(31 mg, 20%)。ES-MS m/z706 (M+H)。 Example 45 (S)-2-((5 4 -chloro- 1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropan-2-ylmethyl)-1H-benzene And[d]imidazole-6-carboxylic acid At 55°C, to (S)-2-((5 4 -chloro- 1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3 ), 5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl) To a solution of 1H-benzo[d]imidazole-6-carboxylic acid methyl ester (245 mg, 64% purity, 0.21 mmol) in ACN (2.4 mL), water (0.8 mL) and THF (0.8 mL) was added 1 , 5,7-Triazabicyclo[4.4.0]dec-5-ene (210 mg, 1.47 mmol). The mixture was stirred at 55 °C for 2 h, cooled to room temperature, 5% aqueous citric acid was added until pH = 4-5, and the precipitated white solid was filtered. The solid was dissolved in ACN/MeOH and purified by preparative HPLC [column: Welch Xtimate C18 150 × 30 mm × 5 µm; mobile phase: 30 - 70% ACN in aqueous formic acid (0.225%)] to provide The title compound (31 mg, 20%) was in the form of a white solid. ES-MS m/z 706 (M+H).
實例 46(S)-2-((5 5-氰基-3,8-二氧雜-2,5(2,6)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例5中所闡述使用(S)-2-((5 5-氰基-3,8-二氧雜-2,5(2,6)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(63 wt%純)在ACN : THF :水(3:1:1)之混合物中來製備標題化合物,其中將反應液在55℃及氮氣氛下加熱2h。將反應混合物冷卻至室溫並使用檸檬酸水溶液(5%)驟冷,然後過濾固體並使用水洗滌。藉由製備型HPLC [管柱:Welch Xtimate C18 150 × 30 mm, 5 µm;移動相:於甲酸水溶液(0.225%)中之25 - 65% ACN]純化以得到白色固體形式之標題化合物。ES-MS m/z662 (M+H)。 Example 46 (S)-2-((5 5 -cyano-3,8-dioxa-2,5(2,6)-bipyridine-1(1,3)-benzenecyclonona-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 55 -cyano-3,8-dioxa-2,5(2,6)-bipyridine-1(1,3)- Benzenecyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole- The title compound was prepared from methyl 6-carboxylate (63 wt% pure) in a mixture of ACN:THF:water (3:1:1), where the reaction was heated at 55°C under nitrogen atmosphere for 2h. The reaction mixture was cooled to room temperature and quenched with aqueous citric acid (5%), then the solid was filtered and washed with water. Purification by preparative HPLC [column: Welch Xtimate C18 150 x 30 mm, 5 µm; mobile phase: 25 - 65% ACN in aqueous formic acid (0.225%)] gave the title compound as a white solid. ES-MS m/z 662 (M+H).
實例 47(S)-2-((5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例2中所闡述使用(S)-2-((5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯在10:5:3 ACN : 1,4-二噁烷:水(作為溶劑)中來製備標題化合物,其中將反應混合物在55℃下攪拌6 h 30 min。將粗製反應混合物濃縮於Celite ®上並藉由C18反相層析使用於NH 4HCO 3水溶液(10 mM + 5% MeOH)中之10 - 73% ACN之梯度來純化以得到標題化合物。ES-MS m/z688 (M+H)。 Example 47 (S)-2-((5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclone Fan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -chloro- 16 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1, [ d] The title compound was prepared from methyl imidazole-6-carboxylate in 10:5:3 ACN:1,4-dioxane:water (as solvent), and the reaction mixture was stirred at 55 °C for 6 h 30 min. The crude reaction mixture was concentrated on Celite® and purified by C18 reverse phase chromatography using a gradient of 10 - 73% ACN in aqueous NH4HCO3 (10 mM + 5% MeOH) to afford the title compound. ES-MS m/z 688 (M+H).
實例 48(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-2-((5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(15 mg, 0.022 mmoL)、三水合亞鐵氰化鉀(14.5 mg, 0.039 mmoL)、XPhos Pd(巴豆基)Cl (Pd-170, 5.5 mg, 0.008 mmoL)及KOAc (5.6 mg, 0.056 mmoL)之混合物中添加1,4-二噁烷(1.0 mL)及水(0.4 mL)。將混合物在90℃下攪拌4 h。將反應混合物濃縮於Celite ®上並藉由C18反相層析使用於NH 4HCO 3水溶液(10 mM + 5% MeOH)中之10 - 73% ACN之梯度來純化以得到8.2 mg標題化合物(55%)。ES-MS m/z679 (M+H)。 Example 48 (S)-2-((5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- formic acid To (S)-2-((5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononene -1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( 15 mg, 0.022 mmoL), potassium ferrocyanide trihydrate (14.5 mg, 0.039 mmoL), XPhos Pd (crotyl) Cl (Pd-170, 5.5 mg, 0.008 mmoL) and KOAc (5.6 mg, 0.056 mmoL) To the mixture were added 1,4-dioxane (1.0 mL) and water (0.4 mL). The mixture was stirred at 90 °C for 4 h. The reaction mixture was concentrated on Celite® and purified by C18 reverse phase chromatography using a gradient of 10 - 73% ACN in aqueous NH4HCO3 (10 mM + 5% MeOH) to afford 8.2 mg of the title compound (55 %). ES-MS m/z 679 (M+H).
實例 49(S)-2-((5 4-氰基-2 3-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例45中所闡述使用(S)-2-((5 4-氰基-2 3-氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯來製備標題化合物。藉由製備型HPLC [管柱:Welch Xtimate C18 150 × 25 mm, 5 µm;移動相:於TFA水溶液(0.1%)中之25 - 70% ACN]進行純化。在減壓下去除有機溶劑並凍乾殘餘水溶液以得到白色固體形式之標題產物。ES-MS m/z679 (M+H)。 Example 49 (S)-2-((5 4 -cyano-2 3- fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d ]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano- 23 -fluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3) essentially as described in Example 45 ), 5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylic acid methyl ester to prepare the title compound. Purification was performed by preparative HPLC [column: Welch Xtimate C18 150 × 25 mm, 5 µm; mobile phase: 25 - 70% ACN in aqueous TFA (0.1%)]. The organic solvent was removed under reduced pressure and the residual aqueous solution was lyophilized to give the title product as a white solid. ES-MS m/z 679 (M+H).
實例 50(S)-2-((5 4-氰基-6,6-二氟-3.8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸 將(S)-2-((5 4-氰基-6,6-二氟-3.8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸甲酯(61 mg, 0.086 mmol)溶於ACN (1 mL)、1,4-二噁烷(0.3 mL)及水(0.3 mL)中。向此溶液中添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(0.04 g, 0.28 mmol)並將此混合物在環境溫度下攪拌18 h。此後,使用1N HCl終止反應(至pH 5),並使用EtOAc萃取。藉由MgSO 4乾燥有機物,過濾,並濃縮。使用反相HPLC [管柱:Phenomenex Kinetex EVO C18 100 × 30 mm, 5 µm;移動相:於NH 4HCO 3水溶液(10 mM + 5% MeOH)中之23 - 58% ACN]純化此材料以得到白色固體形式之標題化合物(14.5 mg, 24.1%)。ES-MS ( m/z) 697.4 (M+H)。 Example 50 (S)-2-((5 4 -cyano-6,6-difluoro-3.8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ] imidazole-6-carboxylic acid (S)-2-((5 4 -cyano-6,6-difluoro-3.8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2) -Diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1 H -benzo[ d ] Methyl imidazole-6-carboxylate (61 mg, 0.086 mmol) was dissolved in ACN (1 mL), 1,4-dioxane (0.3 mL) and water (0.3 mL). To this solution was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.04 g, 0.28 mmol) and the mixture was stirred at ambient temperature for 18 h. After this time, the reaction was quenched with 1N HCl (to pH 5) and extracted with EtOAc. The organics were dried over MgSO 4 , filtered, and concentrated. This material was purified using reverse phase HPLC [column: Phenomenex Kinetex EVO C18 100 × 30 mm, 5 µm; mobile phase: 23 - 58% ACN in aqueous NH4HCO3 (10 mM + 5% MeOH)] to give The title compound (14.5 mg, 24.1%) was in the form of a white solid. ES-MS ( m/z ) 697.4 (M+H).
實例 51( S)-2-((5 4-氰基-3,8-二氧雜-2(2,4)-嘧啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[ d]咪唑-6-甲酸 基本上如實例2中所闡述使用(S)-2-((5 4-氰基-3,8-二氧雜-2(2,4)-嘧啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[ d]咪唑-6-甲酸甲酯作為起始材料且使用5:2:1 ACN : 1,4-二噁烷:水作為溶劑來製備標題化合物,其中將反應液加熱至40℃並保持21 h。在完成後,將反應液冷卻至環境溫度並使用5%檸檬酸水溶液驟冷(使pH達到4)。過濾所得沈澱物並使用水洗滌固體。在減壓下乾燥所收集固體以得到標題化合物。ES/MS m/z618 (M+H)。 Example 51 ( S )-2-((5 4 -cyano-3,8-dioxa-2(2,4)-pyrimidine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropan-2-ylmethyl)-1H-benzo[ d ]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano-3,8-dioxa-2(2,4)-pyrimidine-1(1,3),5(1) essentially as described in Example 2 ,2)-Diphenylcyclononafin-1 4 -yl)methyl)-4-methoxy-1-(epoxypropylene-2-ylmethyl)-1H-benzo[ d ]imidazole-6- The title compound was prepared using methyl formate as starting material and 5:2:1 ACN:1,4-dioxane:water as solvent, where the reaction was heated to 40 °C for 21 h. Upon completion, the reaction was cooled to ambient temperature and quenched with 5% aqueous citric acid (to bring the pH to 4). The resulting precipitate was filtered and the solid was washed with water. The collected solids were dried under reduced pressure to give the title compound. ES/MS m/z 618 (M+H).
實例 52( S)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-2-((5 6-(三氟甲基)-3,8-二氧雜-2(2,6),5(3,4)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-1 H-苯并[ d]咪唑-6-甲酸 基本上如實例2中所闡述使用( S)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-2-((5 6-(三氟甲基)-3,8-二氧雜-2(2,6),5(3,4)-二吡啶-1(1,3)-苯環壬蕃-1 4-基)甲基)-1 H-苯并[ d]咪唑-6-甲酸甲酯及2.8:1:1 ACN : THF :水(作為溶劑)來製備標題化合物,其中將反應液在45℃下加熱2 h。使用1 M檸檬酸水溶液終止反應且使pH達到4.5。過濾所得無色固體並在真空下乾燥。經由反相層析在C18管柱上使用於甲酸水溶液(0.225%)中之42% - 75% ACN之梯度來純化以得到標題化合物。ES/MS m/z705 (M+H)。 Example 52 ( S )-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-2-((5 6 -(trifluoromethyl)-3,8 -Dioxa-2(2,6),5(3,4)-bipyridine-1(1,3)-phencyclononan-1 4 -yl)methyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid Using ( S )-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-2-((5 6 -(trifluoro Methyl)-3,8-dioxa-2(2,6),5(3,4)-bipyridine-1(1,3)-phenylcyclononan-1 4 -yl)methyl)- 1 H -Benzo[ d ]imidazole-6-carboxylic acid methyl ester and 2.8:1:1 ACN:THF:water (as solvent) to prepare the title compound, wherein the reaction solution was heated at 45°C for 2 h. The reaction was quenched using 1 M aqueous citric acid and the pH was brought to 4.5. The resulting colorless solid was filtered and dried under vacuum. Purification via reverse phase chromatography on a C18 column using a gradient of 42% - 75% ACN in aqueous formic acid (0.225%) gave the title compound. ES/MS m/z 705 (M+H).
實例 53(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(2-甲基噁唑-4-基)乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例5中所闡述使用(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(2-甲基噁唑-4-基)乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯且使用3:1:1 ACN : THF :水之混合物作為溶劑來製備標題化合物,其中將反應液在35℃下攪拌6 h。在完成後,濃縮混合物並將殘餘物溶於最少DMSO中。過濾DMSO溶液並藉由製備型HPLC [管柱:Welch Xtimate C18 150 × 30 mm, 5 µm;移動相:於NH 4HCO 3水溶液(10mM)中之10 - 45% ACN之梯度]純化濾液以得到白色固體形式之標題化合物。ES/MS m/z712 (M+H)。 Example 53 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-(2-(2-methyloxazol-4-yl)ethoxy)-1-(epoxypropylene-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylic acid Using (S)-2-(( 54 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1 ,2)-Diphenylcyclononafin-1 4 -yl)methyl)-4-(2-(2-methyloxazol-4-yl)ethoxy)-1-(propylene oxide-2- The title compound was prepared using methyl methyl)-1H-benzo[d]imidazole-6-carboxylate and using a 3:1:1 ACN:THF:water mixture as solvent, wherein the reaction was stirred at 35°C for 6 h. Upon completion, the mixture was concentrated and the residue was dissolved in minimal DMSO. The DMSO solution was filtered and the filtrate was purified by preparative HPLC [column: Welch Xtimate C18 150 × 30 mm, 5 µm; mobile phase: gradient of 10 - 45% ACN in aqueous NH 4 HCO 3 (10 mM)] to obtain The title compound as a white solid. ES/MS m/z 712 (M+H).
實例 54(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-4-(2-((2,2,2-三氟乙基)胺基)乙氧基)-1H-苯并[d]咪唑-6-甲酸 向(S)-4-(2-((第三丁氧基羰基)(2,2,2-三氟乙基)胺基)乙氧基)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(製備311,75 mg, 0.058 mmol)於甲苯(7 mL)中之溶液中添加矽膠(750 mg),且將混合物加熱至120℃並保持18 h。將混合物冷卻至環境溫度,過濾,並在真空中濃縮。經由製備型HPLC [管柱: Xtimate C18 100 × 30 mm, 10 µm;移動相:於甲酸水溶液(0.2%)中之35 - 65% ACN之梯度]純化殘餘物以得到無色固體形式之標題化合物(2.5 mg, 5.7%)。ES/MS m/z728.6 (M+H)。 Example 54 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-4-(2-((2,2,2-trifluoroethyl)amino)ethoxy )-1H-Benzo[d]imidazole-6-carboxylic acid To (S)-4-(2-((tertiary butoxycarbonyl)(2,2,2-trifluoroethyl)amino)ethoxy)-2-((5 4 -cyano-3 ,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxy To a solution of propan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Preparation 311, 75 mg, 0.058 mmol) in toluene (7 mL) was added silica gel (750 mg), and the The mixture was heated to 120 °C for 18 h. The mixture was cooled to ambient temperature, filtered, and concentrated in vacuo. The residue was purified via preparative HPLC [column: Xtimate C18 100 x 30 mm, 10 µm; mobile phase: gradient of 35 - 65% ACN in aqueous formic acid (0.2%)] to give the title compound as a colorless solid ( 2.5 mg, 5.7%). ES/MS m/z 728.6 (M+H).
實例 55(S)-4-[2-羥基乙氧基]-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-4-[2-[第三丁基(二甲基)矽基]氧基乙氧基]-2-((54-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-14-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(62 mg, 0.079 mmol)於THF (5 mL)及MeOH (2 mL)中之溶液中添加溶於水(2 mL)中之LiOH (10 mg, 0.42 mmol),且加熱至45℃並保持1.5 h。添加溶於水(1 mL)中之額外LiOH (12 mg, 0.050 mmol)並在45℃下再加熱一小時,冷卻0至環境溫度,並在減壓下濃縮。將粗製材料懸浮於水(20 mL)中並使用1N HCl將pH調節至5。過濾固體,收集,並在減壓下乾燥。經由使用於10mM碳酸氫銨水溶液中之30-60% ACN (含有5% MeOH)洗脫之C18反相層析來純化以得到標題化合物(7.5 mg, 14%)。ES/MS ( m/z): 656.4 (M+H)。 Example 55 (S)-4-[2-hydroxyethoxy]-2-((5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-Diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid To (S)-4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-2-((54-chloro-3,8-dioxa-2(2, 6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-14-yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzene To a solution of methyl[d]imidazole-6-carboxylate (62 mg, 0.079 mmol) in THF (5 mL) and MeOH (2 mL) was added LiOH (10 mg, 0.42 mmol), and heated to 45°C for 1.5 h. Additional LiOH (12 mg, 0.050 mmol) dissolved in water (1 mL) was added and heated at 45 °C for an additional hour, cooled to ambient temperature, and concentrated under reduced pressure. The crude material was suspended in water (20 mL) and the pH was adjusted to 5 using 1 N HCl. The solid was collected by filtration and dried under reduced pressure. Purification via C18 reverse phase chromatography eluting with 30-60% ACN (containing 5% MeOH) in 10 mM aqueous ammonium bicarbonate gave the title compound (7.5 mg, 14%). ES/MS ( m/z ): 656.4 (M+H).
實例 56(S)-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(二甲基胺基)乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(二甲基胺基)乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(89 mg, 0.12 mmol)於ACN (2 mL)、1,4-二噁烷(1 mL)及水(0.22 mL)中之氮吹掃混合物添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(60 mg, 0.42 mmol)。將反應混合物在60℃下加熱16 h。將混合物冷卻至環境溫度,在減壓下濃縮,並經由反相層析使用於水中之10 - 80% ACN (向ACN及水中添加0.1%甲酸)之梯度來純化殘餘物以得到無色固體形式之標題化合物(42 mg, 48%)。ES/MS m/z683 (M+H)。 Example 56 (S)-2-((5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclone Fan-1 4 -yl)methyl)-4-(2-(dimethylamino)ethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole -6-Formic acid To (S)-2-((5 4 -chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclononyl -1 4 -yl)methyl)-4-(2-(dimethylamino)ethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole- A nitrogen-purged mixture of methyl 6-carboxylate (89 mg, 0.12 mmol) in ACN (2 mL), 1,4-dioxane (1 mL) and water (0.22 mL) was added with 1,5,7-tris Azabicyclo[4.4.0]dec-5-ene (60 mg, 0.42 mmol). The reaction mixture was heated at 60 °C for 16 h. The mixture was cooled to ambient temperature, concentrated under reduced pressure, and the residue was purified by reverse phase chromatography using a gradient of 10 - 80% ACN in water (0.1% formic acid was added to ACN and water) to give methionine as a colorless solid. The title compound (42 mg, 48%). ES/MS m/z 683 (M+H).
實例 57(S)-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(甲基胺基)乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向於DCM (2 mL)中之(S)-4-(2-((第三丁氧基羰基)(甲基)胺基)乙氧基)-2-((5 4-氯-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(12.3 mg, 0.016 mmol)中添加TFA (0.1 mL, 1 mmol)。將混合物在環境溫度下攪拌15 min,然後在減壓下濃縮反應液並藉由反相層析使用於水中之10 - 90% ACN之梯度(向兩種溶劑中添加0.1%甲酸)來純化殘餘物以得到標題化合物(2.2 mg, 21%)。ES/MS ( m/z): 669 (M+H)。 Example 57 (S)-2-((5 4 -Chloro-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclone Fan-1 4 -yl)methyl)-4-(2-(methylamino)ethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole- 6-Formic acid To (S)-4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-((5 4 -chloro-3, 8-Dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(propylene oxide -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (12.3 mg, 0.016 mmol) was added TFA (0.1 mL, 1 mmol). The mixture was stirred at ambient temperature for 15 min, then the reaction was concentrated under reduced pressure and the residue was purified by reverse phase chromatography using a gradient of 10 - 90% ACN in water (0.1% formic acid was added to both solvents). to give the title compound (2.2 mg, 21%). ES/MS ( m/z ): 669 (M+H).
實例 58(S)-2-((5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 將1,5,7-三氮雜雙環[4.4.0]癸-5-烯(29 mg, 0.20mmol)添加至(S)-2-((5 4-氰基-1 6-氟-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(50 mg, 0.069 mmol)於ACN (1.4 mL)、1,4-二噁烷(0.5 mL)及水(0.5 mL)之混合物中之脫氣懸浮液中。將混合物在60℃及N 2下加熱1.5 h,冷卻至室溫並使用檸檬酸水溶液(5%)驟冷。過濾固體並使用水洗滌,且然後使用ACN洗滌以提供無色固體形式之標題化合物(34 mg, 70%)。ES-MS m/z679 (M+H)。 Example 58 (S)-2-((5 4 -cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- formic acid 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (29 mg, 0.20 mmol) was added to (S)-2-((5 4 -cyano-1 6 -fluoro-3 ,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononafin-1 4 -yl)methyl)-4-(2-methoxyethoxy yl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (50 mg, 0.069 mmol) in ACN (1.4 mL), 1,4-bis A degassed suspension in a mixture of oxane (0.5 mL) and water (0.5 mL). The mixture was heated at 60 °C under N2 for 1.5 h, cooled to room temperature and quenched with aqueous citric acid (5%). The solid was filtered and washed with water and then ACN to afford the title compound (34 mg, 70%) as a colorless solid. ES-MS m/z 679 (M+H).
實例 592-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-((1-甲基吡咯啶-3-基)氧基)-1-(((S)-環氧丙烷-2-基)甲基)-1H-苯并[d]咪唑-6-甲酸 將2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-((1-甲基吡咯啶-3-基)氧基)-1-(((S)-環氧丙烷-2-基)甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(90 mg, 0.12 mmol)及1,5,7-三氮雜雙環[4.4.0]癸-5-烯(55 mg, 0.39 mmol)於1,4-二噁烷(0.4 mL)、水(0.4 mL)及ACN (0.4 mL)之氮吹掃混合物中之溶液在25℃下攪拌6 h。使用甲酸將混合物調節至pH 7並濃縮。經由反相層析使用於氫氧化銨水溶液(0.04%) + NH 4HCO 3(10 mM)中之6 - 46% MeCN 之梯度來純化殘餘物以得到30.5 mg標題化合物(35%)。ES-MS m/z686 (M+H)。 Example 59 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclonnona-1 4 -yl)methyl)-4-((1-methylpyrrolidin-3-yl)oxy)-1-(((S)-epoxypropylene-2-yl)methyl)-1H-benzene And[d]imidazole-6-carboxylic acid 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclonona-1 4 -yl)methyl)-4-((1-methylpyrrolidin-3-yl)oxy)-1-(((S)-epoxypropylene-2-yl)methyl)-1H-benzo [d] Methyl imidazole-6-carboxylate (90 mg, 0.12 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (55 mg, 0.39 mmol) in 1,4- A solution of dioxane (0.4 mL), water (0.4 mL) and ACN (0.4 mL) in a nitrogen purged mixture was stirred at 25 °C for 6 h. The mixture was adjusted to pH 7 using formic acid and concentrated. The residue was purified via reverse phase chromatography using a gradient of 6 - 46% MeCN in aqueous ammonium hydroxide (0.04%) + NH 4 HCO 3 (10 mM) to afford 30.5 mg of the title compound (35%). ES-MS m/z 686 (M+H).
實例 60(S)-2-((5 4-氰基-1 6,2 3-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-2-((5 4-氰基-1 6,2 3-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(250 mg, 0.16 mmol)於THF (1.17 mL)、水(1.17 mL)及ACN (3.51 mL)中之脫氣溶液中添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(150 mg, 1.06 mmol)。密封反應容器並使用氮吹掃。將反應混合物加熱至45℃並在此溫度下攪拌2 h。使用1 M檸檬酸水溶液終止反應直至pH = 4.5,然後過濾無色固體並在減壓下乾燥。藉由製備型HPLC (管柱:Welch Xtimate C18 150 × 25 mm, 5 µm;移動相:於甲酸水溶液中之25 - 60% ACN之梯度)純化固體以得到無色固體形式之標題化合物(53.9 mg, 49%) ES-MS m/z697 (M+H)。 Example 60 (S)-2-((5 4 -cyano- 1 6 ,2 3 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylic acid To (S)-2-((5 4 -cyano- 1 6 ,2 3 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5( 1,2)-Diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropan-2-ylmethyl)-1H-benzene To a degassed solution of methyl[d]imidazole-6-carboxylate (250 mg, 0.16 mmol) in THF (1.17 mL), water (1.17 mL) and ACN (3.51 mL) was added 1,5,7-tris Azabicyclo[4.4.0]dec-5-ene (150 mg, 1.06 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated to 45 °C and stirred at this temperature for 2 h. The reaction was quenched with 1 M aqueous citric acid until pH = 4.5, then the colorless solid was filtered and dried under reduced pressure. The solid was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm, 5 µm; mobile phase: gradient of 25 - 60% ACN in aqueous formic acid) to give the title compound as a colorless solid (53.9 mg, 49%) ES-MS m/z 697 (M+H).
實例 61(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 將(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-氟-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(20 mg, 0.03 mmol)及1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-A]嘧啶(20 mg, 0.1 mmol)於ACN (6 mL)及水(4 mL)中之溶液在45℃下攪拌7 h。使用甲酸調節至pH 6並使用3:1氯仿:異丙醇萃取。藉由硫酸鎂乾燥有機層,過濾,並濃縮。經由矽膠層析使用於DCM中之0 - 10% (MeOH + 10%甲酸)之梯度來純化殘餘物以得到4 mg標題化合物(20%)。ES-MS m/z605 (M+H)。 Example 61 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-fluoro-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononium Fan- 14 -yl)methyl)-4-fluoro-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (20 mg, 0.03 mmol) and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-A]pyrimidine (20 mg, 0.1 mmol) in ACN (6 mL) and water (4 mL) Stir at 45 °C for 7 h. Adjust to pH 6 with formic acid and extract with 3:1 chloroform:isopropanol. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography using a gradient of 0 - 10% (MeOH + 10% formic acid) in DCM to afford 4 mg of the title compound (20%). ES-MS m/z 605 (M+H).
實例 62(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(二甲基胺基)-2-側氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 將(S)-2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-(二甲基胺基)-2-側氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(50 mg, 0.0356 mmol)與三甲基氫氧化錫(34 mg, 0.178630 mmol)於1,2-二氯乙烷(1 mL)中之溶液在80℃下攪拌16 h。將溫度增至90℃並保持7 h,且然後增至100℃並保持72 h。添加額外三甲基氫氧化錫(34 mg, 0.179 mmol),且加熱至105℃並保持18 h。使反應混合物冷卻至環境溫度並在真空下濃縮。添加15%檸檬酸水溶液(1 mL)以形成膠狀物,藉由燒結漏斗緩慢過濾。使用水(2 mL)洗滌膠狀物並在60℃下於真空烘箱中乾燥。藉由製備型HPLC [管柱:Phenomenex Kinetex EVO C18 250 × 30 mm, 5 µm;移動相:於NH 4HCO 3水溶液(10 mM + 5% MeOH)中之0 - 100% ACN之梯度]純化粗產物以得到無色固體形式之標題化合物(12.5 mg, 51%)。ES-MS m/z688 (M+H)。 Example 62 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-(2-(dimethylamino)-2-oxoethoxy)-1-(epoxypropylene-2-ylmethyl)-1H -Benzo[d]imidazole-6-carboxylic acid (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononium Fan-1 4 -yl)methyl)-4-(2-(dimethylamino)-2-oxoethoxy)-1-(epoxypropylene-2-ylmethyl)-1H- A solution of methyl benzo[d]imidazole-6-carboxylate (50 mg, 0.0356 mmol) and trimethyltin hydroxide (34 mg, 0.178630 mmol) in 1,2-dichloroethane (1 mL) was Stir at 80°C for 16 h. The temperature was increased to 90°C and held for 7 h, and then increased to 100°C and held for 72 h. Additional trimethyltin hydroxide (34 mg, 0.179 mmol) was added and heated to 105 °C for 18 h. The reaction mixture was cooled to ambient temperature and concentrated under vacuum. Aqueous 15% citric acid (1 mL) was added to form a gum which was slowly filtered through a sintered funnel. The gum was washed with water (2 mL) and dried in a vacuum oven at 60 °C. The crude was purified by preparative HPLC [column: Phenomenex Kinetex EVO C18 250 × 30 mm, 5 µm; mobile phase: gradient of 0 - 100% ACN in aqueous NH 4 HCO 3 (10 mM + 5% MeOH)] The product was obtained as the title compound (12.5 mg, 51%) as a colorless solid. ES-MS m/z 688 (M+H).
實例 632-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-4-甲氧基-1H-苯并[d]咪唑-6-甲酸 使用氮將1,5,7-三氮雜雙環[4.4.0]癸-5-烯(28 mg, 0.197 mmol)於ACN (0.4 mL)、1,4-二噁烷(0.4 mL)及水(0.15 mL)之混合物中之溶液吹掃10 min。將無氧溶液添加至含有2-((5 4-氰基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-4-甲氧基-1H-苯并[d]咪唑-6-甲酸甲酯(44 mg, 0.065 mmol)之反應容器中。將混合物在環境溫度下攪拌24 h。將反應混合物分配於EtOAc與0.1 M HCl水溶液之間。分離有機層並使用飽和NaCl水溶液洗滌,藉由MgSO 4乾燥,過濾,並在減壓下濃縮。藉由製備型HPLC [管柱:Phenomenex Kinetex® EVO C18 100 × 30 mm, 5 µm;移動相:於甲酸水溶液(0.1%)中之14 - 48% ACN之梯度]純化殘餘物以提供標題化合物(8.2 mg, 19%)。ES-MS m/z655 (M+H)。 Example 63 2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenylcyclonenona-1 4 -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (28 mg, 0.197 mmol) was dissolved in ACN (0.4 mL), 1,4-dioxane (0.4 mL) and water using nitrogen (0.15 mL) of the solution in the mixture was purged for 10 min. Add the anaerobic solution to the Cyclononafin-1 4 -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6 - Methyl formate (44 mg, 0.065 mmol) in a reaction vessel. The mixture was stirred at ambient temperature for 24 h. The reaction mixture was partitioned between EtOAc and 0.1 M aqueous HCl. The organic layer was separated and washed with saturated aqueous NaCl, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: Phenomenex Kinetex® EVO C18 100 x 30 mm, 5 µm; mobile phase: gradient of 14 - 48% ACN in aqueous formic acid (0.1%)] to afford the title compound ( 8.2 mg, 19%). ES-MS m/z 655 (M+H).
實例 64(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(23 mg, 0.033 mmol)於脫氣ACN (0.5 mL)、THF (0.2 mL)及水(0.2 mL)中之懸浮液中添加1,5,7-三氮雜雙環[4.4.0]癸-5-烯(15 mg, 0.11 mmol)。將混合物加熱至55℃並保持3 h,然後冷卻至室溫並添加5%檸檬酸水溶液以使pH = 4-5。過濾所得固體,使用水(3次)及ACN洗滌固體,然後在真空及45℃下乾燥過夜以得到灰棕色固體形式之標題化合物(15 mg, 63%)。ES-MS m/z661 (M+H)。 Example 64 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2)-diphenyl ring Nonafin-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6- formic acid To (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononium Fan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid To a suspension of the methyl ester (23 mg, 0.033 mmol) in degassed ACN (0.5 mL), THF (0.2 mL) and water (0.2 mL) was added 1,5,7-triazabicyclo[4.4.0] Dec-5-ene (15 mg, 0.11 mmol). The mixture was heated to 55 °C for 3 h, then cooled to room temperature and 5% aqueous citric acid was added to bring pH = 4-5. The resulting solid was filtered, washed with water (3 times) and ACN, then dried under vacuum at 45 °C overnight to give the title compound (15 mg, 63%) as a beige solid. ES-MS m/z 661 (M+H).
實例 65(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 將1,5,7-三氮雜雙環[4.4.0]癸-5-烯(26 mg, 0.18mmol)添加至(S)-2-((5 4-氰基-3,8-二氧雜-2(2,6)-吡啶-1,5(1,3)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(45 mg, 0.067 mmol)於ACN (1.4 mL)、1,4-二噁烷(0.5 mL)及水(0.5 mL)之混合物中之脫氣懸浮液中。將混合物在60℃及N 2下加熱1.5 h,冷卻至室溫並使用檸檬酸水溶液(5%)驟冷。過濾固體並使用水洗滌,且然後使用ACN洗滌以提供白色固體形式之標題化合物(26mg, 59%)。ES-MS m/z661 (M+H)。 Example 65 (S)-2-((5 4 -cyano-3,8-dioxa-2(2,6)-pyridine-1,5(1,3)-diphenylcyclonona- 1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (26 mg, 0.18 mmol) was added to (S)-2-((5 4 -cyano-3,8-diox Hetero-2(2,6)-pyridine-1,5(1,3)-diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1- (Oxiran-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (45 mg, 0.067 mmol) in ACN (1.4 mL), 1,4-dioxane (0.5 mL ) and water (0.5 mL) in a degassed suspension. The mixture was heated at 60 °C under N2 for 1.5 h, cooled to room temperature and quenched with aqueous citric acid (5%). The solid was filtered and washed with water and then ACN to afford the title compound (26 mg, 59%) as a white solid. ES-MS m/z 661 (M+H).
實例 66(S)-2-((5 4-(4-氟-1H-咪唑-1-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 將LiOH水溶液(1M, 120 μL, 0.12 mmol)添加至 (S)-2-((5 4-(4-氟-1H-咪唑-1-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(30 mg, 0.045 mmol)於MeOH (300 μL)及THF (600 μL)之混合物中之懸浮液中並在60℃下攪拌12 h。濃縮反應混合物並添加檸檬酸水溶液(5%)。過濾掉固體,使用水、ACN及MeOH洗滌以提供淺褐色固體形式之標題化合物(11 mg, 47%)。ES-MS m/z646 (M+H)。 Example 66 (S)-2-((5 4- (4-fluoro-1H-imidazol-1-yl)-3,9-dioxa-2(2,6)-pyridine-1(1,3) ,5(1,2)-Diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Aqueous LiOH (1M, 120 μL, 0.12 mmol) was added to (S)-2-(( 54- (4-fluoro-1H-imidazol-1-yl)-3,9-dioxa-2(2 ,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropane-2-ylmethyl)-1H - A suspension of methyl benzo[d]imidazole-6-carboxylate (30 mg, 0.045 mmol) in a mixture of MeOH (300 μL) and THF (600 μL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated and aqueous citric acid (5%) was added. The solid was filtered off, washed with water, ACN and MeOH to afford the title compound (11 mg, 47%) as a beige solid. ES-MS m/z 646 (M+H).
實例 67(S)-2-((5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 將LiOH水溶液(1 M, 1.6 mL, 1.6 mmol)添加至(S)-2-((5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(285 mg, 0.39 mmol)於THF (8.5 mL)及MeOH (4.3 mL)之混合物中之懸浮液中。將混合物在60℃下加熱3 h。濃縮反應混合物,添加檸檬酸水溶液(5%),然後過濾掉固體並使用水及ACN洗滌。在真空及40℃下乾燥固體以獲得白色固體形式之標題化合物(285 mg, 100%)。ES-MS m/z674, 676 (M+H)。 Example 67 (S)-2-((5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2) -Diphenylcyclooctane-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d] Imidazole-6-carboxylic acid Aqueous LiOH (1 M, 1.6 mL, 1.6 mmol) was added to (S)-2-((5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine- 1(1,3),5(1,2)-diphenylcyclooctane-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(propylene oxide-2 In a suspension of methyl -1H-benzo[d]imidazole-6-carboxylate (285 mg, 0.39 mmol) in a mixture of THF (8.5 mL) and MeOH (4.3 mL). The mixture was heated at 60 °C for 3 h. The reaction mixture was concentrated, aqueous citric acid (5%) was added, then the solid was filtered off and washed with water and ACN. The solid was dried under vacuum at 40 °C to obtain the title compound (285 mg, 100%) as a white solid. ES-MS m/z 674, 676 (M+H).
實例 68(S)-2-((5 4-氰基-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向反應容器中裝填(S)-2-((5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(61 mg, 0.087 mmol)、三水合六氰基鐵酸四鉀(57 mg, 0.135 mmol)、KOAc (19 mg, 0.19 mmol)及氯(巴豆基)(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)鈀(II) (Pd-170,XPhos Pd(巴豆基)Cl,6.2 mg, 0.009 mmol]。使用N 2吹掃反應混合物並添加DMF (1.7 mL)及水(0.9 mL)。使用N 2再次吹掃混合物5 min,密封容器並在90℃下攪拌過夜。將混合物冷卻至室溫,添加檸檬酸水溶液(5%),過濾掉固體並使用水及ACN洗滌。藉由製備型HPLC [管柱:XBridge C18 19 × 150 mm, 5 µm,移動相:於NH 4HCO 3水溶液(20 mM, pH9)中之30 - 50% ACN之梯度]純化固體以提供白色固體形式之標題化合物(9 mg, 16%)。ES-MS m/z665 (M+H)。 Example 68 (S)-2-((5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1,2 )-diphenylcyclooctane-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d ]imidazole-6-carboxylic acid Charge (S)-2-((5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclooctane-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo [d] imidazole-6-carboxylic acid (61 mg, 0.087 mmol), tetrapotassium hexacyanoferrate trihydrate (57 mg, 0.135 mmol), KOAc (19 mg, 0.19 mmol) and chloro(crotyl) (2- Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) (Pd-170, XPhos Pd(crotyl)Cl, 6.2 mg, 0.009 mmol ]. The reaction mixture was purged with N2 and DMF (1.7 mL) and water (0.9 mL) were added. The mixture was purged again with N2 for 5 min, the vessel was sealed and stirred overnight at 90 °C. The mixture was cooled to room temperature, Aqueous citric acid (5%) was added, the solid was filtered off and washed with water and ACN. By preparative HPLC [column: XBridge C18 19 × 150 mm, 5 µm, mobile phase: NH 4 HCO 3 aqueous solution (20 mM , gradient of 30-50% ACN in pH 9)] Purification of the solid gave the title compound (9 mg, 16%) as a white solid. ES-MS m/z 665 (M+H).
實例 69(S)-N-((環丙基甲基)磺醯基)-2-((5 4-氟-1 6-甲基-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-甲氧基-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲醯胺 向(S)-4-甲氧基-2-((1 6-甲基-5 4-(氟)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(100 mg, 0.16 mmol)於DCM (2 mL)中之溶液中添加4-二甲基胺基吡啶(20 mg, 0.16 mmol)、環丙基甲磺醯胺(35 mg, 0.26 mmol)、TEA (0.1 mL, 0.7 mmol)並使用N 2將混合物輕輕吹掃10 min。將EDC (50 mg, 0.26 mmol)添加至反應混合物中,在室溫下攪拌過夜,然後將反應液在40℃下加熱4 h。使用檸檬酸水溶液(5%)終止反應並使用DCM稀釋。分離各相並使用DCM將取水層萃兩次。合併有機相,使用飽和NaCl水溶液洗滌,藉由Na 2SO 4乾燥,藉由過濾過濾掉固體並在減壓下去除溶劑。藉由製備型HPLC [管柱:Xbridge C18 150 × 19mm, 5 µm,移動相:於NH 4CO 3水溶液(20 mM, pH = 9)中之50 - 80% ACN之梯度]純化殘餘物以得到白色固體形式之標題產物(28 mg, 23.6%) ES-MS m/z741(M+H)。 Example 69 (S)-N-((cyclopropylmethyl)sulfonyl)-2-((5 4 -fluoro-1 6 -methyl -3,9-dioxa-2(2,6) -Pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-4-methoxy-1-(epoxypropane-2-ylmethyl )-1H-Benzo[d]imidazole-6-carboxamide To (S)-4-methoxy-2-((1 6 -methyl-5 4 -(fluoro)-3,9-dioxa-2(2,6)-pyridine-1(1,3 ), 5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (100 mg, 0.16 mmol) in DCM (2 mL) was added 4-dimethylaminopyridine (20 mg, 0.16 mmol), cyclopropylmethanesulfonamide (35 mg, 0.26 mmol), TEA (0.1 mL, 0.7 mmol) and the mixture was gently purged with N for 10 min. EDC (50 mg, 0.26 mmol) was added to the reaction mixture, stirred overnight at room temperature, and then the reaction solution was heated at 40°C for 4 h. The reaction was quenched with aqueous citric acid (5%) and diluted with DCM. The phases were separated and the aqueous layer was extracted twice with DCM. The organic phases were combined, washed with saturated aqueous NaCl, dried over Na2SO4 , the solids were filtered off by filtration and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC [column: Xbridge C18 150 × 19mm, 5 µm, mobile phase: gradient of 50 - 80% ACN in aqueous NH 4 CO 3 (20 mM, pH = 9)] to obtain The title product as a white solid (28 mg, 23.6%) ES-MS m/z 741 (M+H).
實例 70(S)-2-((5 4-氰基-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 基本上如實例68中所闡述使用(S)-2-((5 4-氯-1 6,5 6-二氟-3,8-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸作為起始材料且使用1,4-二噁烷:水之2.5:1混合物作為溶劑來製備標題化合物,其中將反應液加熱至90℃並保持4 h。藉由製備型HPLC [管柱:C18 100 × 30 mm, 5 µm;移動相:於甲酸水溶液(0.225%)中之15 - 85% ACN之梯度]純化以提供白色固體形式之標題化合物。ES-MS m/z697 (M+H)。 Example 70 (S)-2-((5 4 -cyano- 1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1(1,3),5 (1,2)-Diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropane-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylic acid Using (S)-2-((5 4 -chloro-1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridine-1( 1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropane-2-yl The title compound was prepared using methyl)-1H-benzo[d]imidazole-6-carboxylic acid as starting material and a 2.5:1 mixture of 1,4-dioxane:water as solvent, where the reaction was heated to 90 ℃ and keep for 4 h. Purification by preparative HPLC [column: C18 100 x 30 mm, 5 µm; mobile phase: gradient of 15 - 85% ACN in aqueous formic acid (0.225%)] afforded the title compound as a white solid. ES-MS m/z 697 (M+H).
實例 71(S)-2-((5 4-(3-氟-4-側氧基吡啶-1(4H)-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向反應容器中裝填(S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(51 mg, 0.079 mmol)、3-氟吡啶-4-醇(14 mg, 0.12 mmol)、碘化銅(I) (1.6 mg, 0.008 mmol)及K 2CO 3(22 mg, 0.156 mmol)。使用N 2吹掃反應容器,然後添加無水DMSO (80 μL)及2,2,6,6-四甲基-3,5-庚二酮(7 μL, 0.033 mmol)。將反應混合物在120℃下攪拌9 h。將混合物冷卻至室溫,添加檸檬酸水溶液(5%),然後過濾掉固體並使用水洗滌。藉由製備型HPLC [管柱:XBridge C18 19 × 150 mm, 5 µm;移動相:於NH 4HCO 3水溶液(20 mM, pH9)中之30 - 60% ACN之梯度]純化以提供白色固體形式之標題化合物(10 mg, 18%)。ES-MS m/z673 (M+H)。 Example 71 (S)-2-((5 4- (3-fluoro-4-oxopyridin-1(4H)-yl)-3,9-dioxa-2(2,6)-pyridine- 1(1,3),5(1,2)-Diphenylcyclononafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d] Imidazole-6-carboxylic acid Fill the reaction vessel with (S)-2-((5 4 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-di Benzenenonafin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (51 mg, 0.079 mmol), 3- Fluopyridin-4-ol (14 mg, 0.12 mmol), copper(I) iodide (1.6 mg, 0.008 mmol) and K 2 CO 3 (22 mg, 0.156 mmol). The reaction vessel was purged with N2 , then anhydrous DMSO (80 μL) and 2,2,6,6-tetramethyl-3,5-heptanedione (7 μL, 0.033 mmol) were added. The reaction mixture was stirred at 120 °C for 9 h. The mixture was cooled to room temperature, aqueous citric acid (5%) was added, and the solid was filtered off and washed with water. Purification by preparative HPLC [column: XBridge C18 19 × 150 mm, 5 µm; mobile phase: gradient of 30 - 60% ACN in aqueous NH4HCO3 (20 mM, pH9)] to afford a white solid The title compound (10 mg, 18%). ES-MS m/z 673 (M+H).
實例 72( S)-2-((5 4-(4-甲基-1H-咪唑-1-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸 將無水DMSO (0.06 mL)添加至( S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸(20 mg, 0.031 mmol)、4-甲基咪唑(10 mg, 0.119 mmol)、磷酸三鉀(13 mg, 0.059 mmol)、N 1,N 2-雙(呋喃-2-基甲基)草醯胺(3 mg, 0.012 mmol)及氧化銅(I) (5 mg, 0.034 mmol)之混合物中。使用氬吹掃反應容器,密封容器,且在攪拌下加熱至120℃並保持19 h。合併於DCM (20 mL)中之反應混合物與在類似條件下使用雙(四丁基銨碘化物)碘化銅(I) (7 mg, 0.006 mmol)代替氧化銅(I)所製備之第二混合物。添加水(5 mL)、2-丙醇(5 mL)、檸檬酸水溶液(5%, 5 mL)及飽和NaCl水溶液(20 mL),然後振盪混合物並分離各相。使用4:1 DCM : 2-丙醇(50 mL,以兩份)萃取水相。使用磷酸三鉀水溶液將水溶液pH調節至3並使用4:1 DCM : 2-丙醇(15 mL)再次萃取。合併有機萃取物並在減壓下濃縮。藉由反相層析使用於NH 4HCO 3水溶液(10 mM, pH = 9)中之30 - 60% ACN之梯度來純化殘餘物以得到固體形式之標題化合物(6 mg, 15%)。ES-MS m/z642 (M+H)。 Example 72 ( S )-2-((5 4- (4-methyl-1H-imidazol-1-yl)-3,9-dioxa-2(2,6)-pyridine-1(1,3 ), 5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ]imidazol-6- formic acid Anhydrous DMSO (0.06 mL) was added to ( S )-2-(( 54 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1, 2)-Diphenylcyclononan- 14 -yl)methyl)-1-(epoxypropan-2-ylmethyl) -1H -benzo[ d ]imidazole-6-carboxylic acid (20 mg, 0.031 mmol), 4-methylimidazole (10 mg, 0.119 mmol), tripotassium phosphate (13 mg, 0.059 mmol), N 1 , N 2 -bis(furan-2-ylmethyl)oxamide (3 mg, 0.012 mmol) and copper(I) oxide (5 mg, 0.034 mmol). The reaction vessel was purged with argon, sealed, and heated to 120 °C with stirring for 19 h. The reaction mixture combined in DCM (20 mL) was mixed with the second compound prepared under similar conditions using bis(tetrabutylammonium iodide) copper(I) iodide (7 mg, 0.006 mmol) instead of copper(I) oxide. mixture. Water (5 mL), 2-propanol (5 mL), aqueous citric acid (5%, 5 mL) and saturated aqueous NaCl (20 mL) were added, then the mixture was shaken and the phases were separated. The aqueous phase was extracted with 4:1 DCM:2-propanol (50 mL in two portions). The aqueous pH was adjusted to 3 with aqueous tripotassium phosphate and re-extracted with 4:1 DCM:2-propanol (15 mL). The organic extracts were combined and concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a gradient of 30 - 60% ACN in aqueous NH 4 HCO 3 (10 mM, pH=9) to give the title compound (6 mg, 15%) as a solid. ES-MS m/z 642 (M+H).
實例 73( S)-2-((5 4-(1H-咪唑-1-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸 將無水DMSO (0.20 mL)添加至( S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1 H-苯并[ d]咪唑-6-甲酸(30 mg, 0.046 mmol)、咪唑(13 mg, 0.189 mmol)、磷酸三鉀(20 mg, 0.091 mmol)、N 1,N 2-雙(呋喃-2-基甲基)草醯胺(5 mg, 0.02 mmol)及氧化銅(I) (3 mg, 0.02 mmol)之混合物中。使用氬吹掃容器,密封容器,且然後在攪拌下加熱至120℃並保持20 h。將反應混合物轉移至經MeOH洗滌之強陰離子交換樹脂柱(Isolute ®SAX)中並使用7:3 MeOH/水、MeOH、DCM及含有3%乙酸之1:1 DCM : MeOH依序洗脫。合併含有標題化合物之級分並在減壓下濃縮。將殘餘物溶於DMSO中且然後藉由反相層析使用於NH 4HCO 3水溶液(10 mM, pH = 9)中之30 - 60% ACN之梯度來純化混合物。在減壓下濃縮適當級分。在1:1 DCM : EtOAc (4 mL)中研磨固體殘餘物並部分地濃縮混合物以去除DCM。離心懸浮液,去除上清液且然後將殘餘物在50℃及減壓下乾燥24 h以提供9.4 mg白色固體形式之標題化合物(29%產率)。ES-MS m/z628 (M+H)。 Example 73 ( S )-2-((5 4- (1H-imidazol-1-yl)-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1 ,2)-Diphenylcyclononarfin-1 4 -yl)methyl)-1-(epoxypropan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid Anhydrous DMSO (0.20 mL) was added to ( S )-2-(( 54 -bromo-3,9-dioxa-2(2,6)-pyridine-1(1,3),5(1, 2)-Diphenylcyclononan- 14 -yl)methyl)-1-(epoxypropan-2-ylmethyl) -1H -benzo[ d ]imidazole-6-carboxylic acid (30 mg, 0.046 mmol), imidazole (13 mg, 0.189 mmol), tripotassium phosphate (20 mg, 0.091 mmol), N 1 , N 2 -bis(furan-2-ylmethyl)oxamide (5 mg, 0.02 mmol) and Copper(I) oxide (3 mg, 0.02 mmol) in mixture. The vessel was purged with argon, sealed, and then heated to 120 °C with stirring for 20 h. The reaction mixture was transferred to a strong anion exchange resin column ( Isolute® SAX) washed with MeOH and eluted sequentially with 7:3 MeOH/water, MeOH, DCM and 1:1 DCM:MeOH containing 3% acetic acid. Fractions containing the title compound were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and the mixture was then purified by reverse phase chromatography using a gradient of 30-60% ACN in aqueous NH 4 HCO 3 (10 mM, pH=9). Appropriate fractions were concentrated under reduced pressure. The solid residue was triturated in 1:1 DCM:EtOAc (4 mL) and the mixture was partially concentrated to remove DCM. The suspension was centrifuged, the supernatant removed and the residue was then dried at 50 °C under reduced pressure for 24 h to afford 9.4 mg of the title compound as a white solid (29% yield). ES-MS m/z 628 (M+H).
實例 74(S)-1-(環氧丙烷-2-基甲基)-2-((5 4-(4-側氧基吡啶-1(4H)-基)-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1H-苯并[d]咪唑-6-甲酸 將無水DMSO (80 µL)及2,2,6,6-四甲基-3,5-庚烷二酮(7 μL, 0.033 mmol)添加至(S)-2-((5 4-溴-3,9-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環壬蕃-1 4-基)甲基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(50 mg, 0.078 mmol)、4-羥基吡啶(10 mg, 0.102 mmol)、碘化銅(I) (1.6 mg, 0.008 mmol)及K 2CO 3(22 mg, 0.156 mmol)之氮吹掃混合物中。密封容器並在120℃下攪拌16 h。將混合物冷卻至室溫,添加檸檬酸水溶液(5%),過濾掉固體並使用水洗滌。藉由製備型HPLC [管柱:XBridge C18 19 × 150 mm, 5 µm;移動相:於NH 4HCO 3水溶液(20 mM, pH = 9)中之25 - 55% ACN之梯度]純化固體,然後使用MeOH及ACN洗滌固體產物以得到無色固體形式之標題化合物(11 mg, 18%)。ES-MS m/z655 (M+H)。 Example 74 (S)-1-(epoxypropylene-2-ylmethyl)-2-(( 54- (4-oxopyridin-1(4H)-yl)-3,9-dioxa -2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononan-1 4 -yl)methyl)-1H-benzo[d]imidazole-6- formic acid Anhydrous DMSO (80 µL) and 2,2,6,6-tetramethyl-3,5-heptanedione (7 µL, 0.033 mmol) were added to (S)-2-((5 4 -bromo- 3,9-Dioxa-2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclononafin-1 4 -yl)methyl)-1-(cyclo Oxypropan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.078 mmol), 4-hydroxypyridine (10 mg, 0.102 mmol), copper(I) iodide (1.6 mg, 0.008 mmol) and K 2 CO 3 (22 mg, 0.156 mmol) in a nitrogen-purged mixture. The vessel was sealed and stirred at 120 °C for 16 h. The mixture was cooled to room temperature, aqueous citric acid (5%) was added, the solid was filtered off and washed with water. The solid was purified by preparative HPLC [column: XBridge C18 19 × 150 mm, 5 µm; mobile phase: gradient of 25 - 55% ACN in aqueous NH 4 HCO 3 (20 mM, pH = 9)], then The solid product was washed with MeOH and ACN to give the title compound (11 mg, 18%) as a colorless solid. ES-MS m/z 655 (M+H).
實例 75(S)-2-((1 6-氟-5 4-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基)-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸 向反應容器中裝填(S)-2-((5 4-氯-1 6-氟-3,7-二氧雜-2(2,6)-吡啶-1(1,3),5(1,2)-二苯環辛蕃-1 4-基)甲基)-4-(2-甲氧基乙氧基)-1-(環氧丙烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(61 mg, 0.087 mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)吡啶-2(1H)-酮(43 mg, 0.174 mmol)及氯(巴豆基)(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)鈀(II) (Pd-170,XPhos Pd(巴豆基)Cl,6.2 mg, 0.009 mmol)。使用N 2吹掃容器,添加DMF (860 μL)及磷酸三鉀水溶液(1 M, 260 μL, 0.26 mmol),並將混合物在90℃下攪拌2.5 h。將混合物冷卻至室溫,添加檸檬酸水溶液(5%),過濾掉固體並使用水及ACN洗滌。藉由製備型HPLC [管柱:XBridge C18, 19 × 150 mm, 5 µm;移動相:於NH 4HCO 3(20 mM, pH = 9)中之30 - 60% ACN之梯度]純化固體以提供淺褐色固體形式之標題化合物(9.5 mg, 14%)。ES-MS m/z747 (M+H)。 Example 75 (S)-2-((1 6 -fluoro-5 4 -(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3,7-dioxa -2(2,6)-pyridine-1(1,3),5(1,2)-diphenylcyclooctane-1 4 -yl)methyl)-4-(2-methoxyethoxy )-1-(epoxypropylene-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Charge (S)-2-((5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridine-1(1,3), 5(1 ,2)-Diphenylcyclooctane-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(epoxypropylene-2-ylmethyl)-1H-benzo [d] Imidazole-6-carboxylic acid (61 mg, 0.087 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl )pyridin-2(1H)-one (43 mg, 0.174 mmol) and chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- Biphenyl)palladium(II) (Pd-170, XPhos Pd(crotyl)Cl, 6.2 mg, 0.009 mmol). The vessel was purged with N 2 , DMF (860 μL) and aqueous tripotassium phosphate (1 M, 260 μL, 0.26 mmol) were added, and the mixture was stirred at 90 °C for 2.5 h. The mixture was cooled to room temperature, aqueous citric acid (5%) was added, the solid was filtered off and washed with water and ACN. The solid was purified by preparative HPLC [column: XBridge C18, 19 × 150 mm, 5 µm; mobile phase: gradient of 30 - 60% ACN in NH 4 HCO 3 (20 mM, pH = 9)] to provide The title compound (9.5 mg, 14%) as a beige solid. ES-MS m/z 747 (M+H).
生物分析 人類 GLP-1 受體 HEK293 細胞 cAMP 分析使用cAMP形成在以581 ± 94 (n=6)及104 ± 12 (n=5) fmol/mg蛋白質之表現密度(使用[
125I]GLP-1(7-36)NH
2同源競爭結合分析測得)表現人類GLP-1R (NCBI登錄號:NP_002053)之HEK293純系細胞系中來測定GLP-1受體功能活性。使用化合物(於DMSO中之20點濃度-反應曲線,2.75倍Labcyte Echo直接稀釋液,384孔板Corning目錄號:3570)在補充有1X GlutaMAX
TM(Gibco目錄號:35050)、0.1%牛酪蛋白(Sigma C4765-10ML)、250 µM IBMX (3-異丁基-1-甲基黃嘌呤,Acros目錄號:228420010)及20 mM HEPES (Gibco目錄號:15630)之DMEM (Gibco目錄號:31053)中處理hGLP-1R受體表現細胞,分析體積為20 µL (最終DMSO濃度為0.5%)。在37℃下培育30 min之後,使用CisBio cAMP Dynamic 2 HTRF分析套組(62AM4PEJ)定量測定細胞內cAMP之所致增加。簡言之,藉由添加於細胞溶解緩衝液(10 µL)中之cAMP-d2偶聯物且隨後添加亦於細胞溶解緩衝液(10 µL)中之抗體抗cAMP-Eu
3+-穴狀化合物來檢測細胞內之cAMP含量。將所得競爭性分析液在室溫下培育至少60 min,然後使用PerkinElmer Envision
®儀器在320 nm激發及665 nm與620 nm發射下進行檢測。Envision單位(665nm/620nm下發射*10,000)與cAMP之存在量成反比且使用cAMP標準曲線轉換成nM cAMP/孔。將每一孔中之所生成cAMP量(nM)轉換成使用人類GLP-1(7-36)NH
2所觀察之最大反應之百分比。藉由非線性回歸分析使用最大反應百分比對所添加化合物之濃度(擬合至4參數邏輯方程式)來推導相對EC
50值及最高百分比(E
max)。在上述cAMP分析中使用表現581及104 fmol/mg GLP-1R之HEK293細胞中測試實例1至80之化合物之EC
50及E
max數據分別展示於表1及2中。該等數據指示,實例1至80之化合物係人類GLP-1受體之促效劑。
表 1. 具有 581 fmol/mg 之 GLP-1R 表現密度之 HEK293 細胞系、細胞內 cAMP 反應、相對 EC
50 及 E
max
GLP-1R CHO 細胞 β - 抑制蛋白募集分析經活化G蛋白偶合受體可與β-抑制蛋白家族之信號傳導蛋白相互作用。使用PathHunter酶片段互補方式實質上如文獻所闡述(von Degenfeld等人,FASEB J., 2007 (14):3819-26及Hamdouchi等人,J. Med Chem., 2016 59(24):10891-10916)來測定化合物針對GLP-1R誘導之抑制蛋白募集之功效。可自DiscoveRx獲得表現加Pro-Link標籤之人類GLP-1R及加酶受體標籤之β-抑制蛋白-2之CHO-K1細胞並製備為備用於分析之冷凍細胞。將測試化合物溶於DMSO中且使用Echo聲學分配器(LabCyte)實施連續稀釋。分析培養基係含有0.1% w/v水解酪蛋白(Sigma)之PathHunter細胞分析緩衝液(DiscoveRx)。將100 nL測試化合物溶液分配至384孔板中之10 μL分析培養基中,且然後添加於分析培養基中之10 μL細胞以達成5000個細胞/孔。將板在37℃/5% CO
2培育器中培育90 min且添加10 μL PathHunter檢測試劑(DiscoveRx),並將板在室溫下培育60 min。量測發光信號。將化合物濃度-反應曲線擬合至4參數邏輯模型以計算功效(以EC
50及最高百分比(E
max)形式)。使用DMSO及GLP-1(7-36)作為最小及最大對照將數據正規化至刺激% (Campbell等人,Assay Guidance Manual 2017)。試樣化合物刺激GLP-1R誘導之β-抑制蛋白募集之功效報告於表3中。
表 3. hGLP1R 誘導之 β - 抑制蛋白 -2 募集之相對 EC
50 及 E
max
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MX2023002108A (en) | 2020-08-21 | 2023-07-11 | Terns Pharmaceuticals Inc | Compounds as glp-1r agonists. |
WO2022042691A1 (en) | 2020-08-28 | 2022-03-03 | Gasherbrum Bio, Inc. | Heterocyclic glp-1 agonists |
TW202220985A (en) | 2020-09-01 | 2022-06-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | Fused imidazole derivative, preparation method thereof, and medical use thereof |
CN115515956A (en) | 2020-09-29 | 2022-12-23 | 深圳信立泰药业股份有限公司 | Benzimidazole derivative and preparation method and medical application thereof |
EP4227299A1 (en) | 2020-10-12 | 2023-08-16 | Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd. | Benzimidazolone glp-1 receptor agonist and use thereof |
JP2023546054A (en) | 2020-10-13 | 2023-11-01 | ガシャーブラム・バイオ・インコーポレイテッド | Heterocyclic GLP-1 agonist |
WO2022078407A1 (en) | 2020-10-13 | 2022-04-21 | Gasherbrum Bio, Inc. | Heterocyclic glp-1 agonists |
CN113480534B (en) | 2021-07-23 | 2022-05-13 | 广州必贝特医药股份有限公司 | Benzimidazole or azabenzimidazole-6-carboxylic acid compounds and application thereof |
-
2022
- 2022-05-17 TW TW111118381A patent/TW202310838A/en unknown
- 2022-05-19 AU AU2022275931A patent/AU2022275931A1/en active Pending
- 2022-05-19 EP EP22729392.5A patent/EP4341255A1/en active Pending
- 2022-05-19 KR KR1020237039778A patent/KR20230173166A/en active Search and Examination
- 2022-05-19 WO PCT/US2022/029958 patent/WO2022246019A1/en active Application Filing
- 2022-05-19 BR BR112023022851A patent/BR112023022851A2/en unknown
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- 2022-05-19 CA CA3218345A patent/CA3218345A1/en active Pending
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CA3218345A1 (en) | 2022-11-24 |
EP4341255A1 (en) | 2024-03-27 |
WO2022246019A1 (en) | 2022-11-24 |
BR112023022851A2 (en) | 2024-01-23 |
AU2022275931A1 (en) | 2023-11-02 |
KR20230173166A (en) | 2023-12-26 |
IL308397A (en) | 2024-01-01 |
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