WO2022152019A1 - 一种手性噁嗪类化合物的制备方法 - Google Patents
一种手性噁嗪类化合物的制备方法 Download PDFInfo
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- WO2022152019A1 WO2022152019A1 PCT/CN2022/070278 CN2022070278W WO2022152019A1 WO 2022152019 A1 WO2022152019 A1 WO 2022152019A1 CN 2022070278 W CN2022070278 W CN 2022070278W WO 2022152019 A1 WO2022152019 A1 WO 2022152019A1
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- compound
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- alkyl
- heteroalkyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 40
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- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 12
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000005182 global health Effects 0.000 description 1
- 230000001553 hepatotropic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- XMBWDFGMSWQBCA-YPZZEJLDSA-N iodane Chemical compound [125IH] XMBWDFGMSWQBCA-YPZZEJLDSA-N 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 238000006400 oxidative hydrolysis reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- 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
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention relates to a preparation method of a chiral oxazine compound, in particular to a preparation method of the compound of formula (I) and its intermediate compound of formula (II).
- Hepatitis B is a disease caused by the infection of the body by the hepatitis B virus (Hepatitis B Virus, referred to as HBV).
- Hepatitis B virus is a hepatotropic virus that mainly exists in liver cells and damages liver cells, causing inflammation, necrosis and fibrosis of liver cells.
- HBV hepatitis B virus
- chronic hepatitis B (CHB) has become a great challenge to global health care, and is also the main cause of chronic liver disease, cirrhosis and liver cancer (HCC).
- HBsAg hepatitis B virus surface antigen
- Patent WO2018214875 found that a surface antigen inhibitor can effectively reduce HBsAg.
- the currently approved anti-HBV drugs are mainly immunomodulators (interferon- ⁇ and peginterferon- ⁇ -2 ⁇ ) and antiviral drugs (lamivudine, adefovir dipivoxil, entecavir, Bivudine, Tenofovir, Clavudine, etc.).
- antiviral drugs belong to nucleotide drugs, and their mechanism of action is to inhibit the synthesis of HBV DNA, and cannot directly reduce the level of HBsAg.
- nucleotide drugs show HBsAg clearance rates similar to those observed in nature (Janssen et al.
- the present invention provides the preparation method of the compound of formula (I),
- T is selected from CH and N;
- R 1 is selected from H, OH, CN, NH 2 , C 1-5 alkyl, C 1-5 heteroalkyl, C 2-5 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkane group, the C 1-5 alkyl, C 1-5 heteroalkyl, C 2-5 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally replaced by 1, 2 or 3 R substitutions;
- R 2 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 heteroalkyl, and the C 1-3 alkyl and C 1-3 heteroalkyl are optionally 2 or 3 R substitutions;
- n is selected from 0, 1, 2, 3, 4 and 5;
- A is selected from phenyl and 5-6 membered heteroaryl, and said phenyl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R;
- the preparation method of the compound of above-mentioned formula (I), also comprises the following steps:
- R 1 , R 2 and m are as defined in the present invention.
- the preparation method of the compound of above-mentioned formula (I), also comprises the following steps:
- R 1 , R 2 , m and A are defined in the present invention.
- R 1 is selected from H, OH, CH 3 , CHF 2 , CH 3 O, Other variables are as defined in the present invention.
- R 2 is selected from H, F, Cl, Br, CH 3 , CH 3 CH 2 , CH 3 O, CH 3 CH 2 O and The CH 3 , CH 3 CH 2 , CH 3 O, CH 3 CH 2 O and Optionally substituted with 1, 2 or 3 R, other variables are as defined herein.
- T, A and R 3 are as defined in the present invention.
- the present invention also provides compounds of formula (II)
- T and A are as defined in the present invention.
- the compound of formula (II) above is selected from
- the present invention also provides the preparation method of the compound of formula (II), comprising the following steps:
- T, R3 and A are as defined in the present invention.
- the present invention also provides a preparation method of the compound of formula (I), comprising the following steps:
- R 1 , R 2 , R 3 , T and A are as defined in the present invention.
- the invention adopts a chiral induction synthesis strategy, and can obtain a target product of a single configuration without chiral resolution.
- the process route of the present invention has the following advantages:
- the preparation method of the present invention has obvious advantages: raw materials are cheap and easy to obtain, reaction conditions are mild and controllable, intermediates and final products are easy to separate and purify, and the reaction scale is very suitable for industrialization.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
- the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
- the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or exists in two forms of formula (B-1) and formula (B-2) exists as a mixture of isomers.
- the following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2) exists in the form of a mixture.
- tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
- a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
- proton tautomers also called prototropic tautomers
- Valence tautomers include interconversions by recombination of some bonding electrons.
- keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
- the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
- the diastereoisomers were resolved and the pure enantiomers recovered.
- separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond, and -C 0 alkyl-A means that the structure is actually -A.
- substituents When the listed substituents do not specify through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine rings. The carbon atom is attached to the substituted group.
- the substituent can bond to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene.
- the direction of attachment is arbitrary, for example,
- the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
- Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- any one or more sites in the group can be linked to other groups by chemical bonds.
- connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
- the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
- a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
- the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
- the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
- the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” arranged around 5-7 atoms.
- C 1-5 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 5 carbon atoms.
- the C 1-5 alkyl group includes C 1-4 , C 1-3 , C 1-2 , C 2-5 , C 2-4 and C 5 alkyl group, etc.; it can be monovalent (eg methyl) , divalent (eg methylene) or polyvalent (eg methine).
- C 1-5 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), etc.
- C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
- Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 2-5 alkynyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 5 carbon atoms containing at least one carbon-carbon triple bond, a carbon-carbon triple bond can be located anywhere in the group.
- the C 2-5 alkynyl groups include C 2-4 , C 2-3 , C 5 , C 4 , C 3 and C 2 alkynyl groups and the like. It can be monovalent, bivalent or multivalent.
- Examples of C 2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
- C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, said C 3-6 cycloalkyl including C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
- Examples of C3-6 cycloalkyl groups include, but are not limited to , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- a heteroatom may occupy the position of attachment of the heterocycloalkyl to the rest of the molecule.
- the 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl and the like.
- Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
- a 5- to 6-membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
- the 5- to 6-membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
- Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H
- heteroalkyl by itself or in combination with another term means a stable straight or branched chain alkyl radical or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom.
- the heteroatoms are selected from the group consisting of B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized.
- the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-5 heteroalkyl; in other embodiments, the heteroalkyl Heteroalkyl is C 1-3 heteroalkyl.
- a heteroatom or group of heteroatoms can be located at any internal position within a heteroalkyl group, including where the alkyl group is attached to the rest of the molecule, except that the terms "alkoxy,”"alkylamino,” and “alkylthio” (or thioalkyl) Oxygenyl) is a customary expression referring to those alkyl groups attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively.
- Up to two heteroatoms may be consecutive, eg -CH2
- the solvent used in the present invention is commercially available.
- the present invention adopts the following abbreviations:
- aqueous phase was adjusted to pH 4-5 with concentrated hydrochloric acid, extracted with ethyl acetate (85 L), and the organic phase was concentrated to dryness under reduced pressure to obtain compound 2 (22.7 kg, purity: 99.4%, yield: 90.0%) as a brown oil.
- the crude compound 6 (5700 g) was dissolved in 20.37 L of methanol, and the temperature was turned on, and the internal temperature dropped to 5°C to 10°C. 8.92L aqueous hydrochloric acid solution (2M) was slowly added to the reaction kettle, and the internal temperature was controlled at 20°C-25°C during the dropwise addition. After the dropwise addition, the reaction was continued for 17 hours. Two pots were cast in parallel for this reaction, and the other pot was 3400g. The two pots of reaction solutions were combined, filtered, and dried. The dried crude product was transferred to a 50L reaction kettle, 23.5L of ethanol was added, the temperature was raised to 60°C, and the stirring was continued for 2 hours, and then naturally cooled to room temperature (20°C-25°C).
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Abstract
Description
DMF-DMA | N,N-二甲基甲酰胺二甲基缩醛 |
DCM | 二氯甲烷 |
THF | 四氢呋喃 |
PMB | 对甲氧基苄基,是一种保护基团 |
DMF | N,N-二甲基甲酰胺 |
TFA | 三氟乙酸 |
DCM | 二氯甲烷 |
PIFA | [双(三氟乙酰氧基)碘]苯 |
DMSO | 二甲亚砜 |
EtOH | 乙醇 |
MeOH | 甲醇 |
SOCl 2 | 二氯亚砜 |
DIPEA | 二异丙基乙基胺 |
SiO 2 | 100-200目硅胶粉,用于柱层析 |
SFC | 超临界流体色谱 |
p-HPLC | 制备高效液相色谱,用于化合物的纯化 |
Claims (18)
- 式(I)化合物的制备方法,其特征在于,包含如下步骤:其中,T选自CH和N;R 1选自H、OH、CN、NH 2、C 1~5烷基、C 1~5杂烷基、C 2~5炔基、C 3~6环烷基和3~6元杂环烷基,所述C 1~5烷基、C 1~5杂烷基、C 2~5炔基、C 3~6环烷基和3~6元杂环烷基任选被1、2或3个R取代;R 2选自H、F、Cl、Br、I、C 1~3烷基和C 1~3杂烷基,所述C 1~3烷基和C 1~3杂烷基任选被1、2或3个R取代;R 3选自H、F、Cl、Br、I、CN、-C(=O)-O-C 1~3烷基、-C(=O)-NH-C 1~3烷基、-C(=O)-N(C 1~3烷基) 2;m选自0、1、2、3、4和5;A选自苯基和5~6元杂芳基,所述苯基和5~6元杂芳基任选被1、2或3个R取代;R选自H、F、Cl、Br、I、OH、CN、NH 2、=O、CH 3、CH 3CH 2、CH 3O、CF 3、CHF 2、CH 2F;所述C 1~5杂烷基、3~6元杂环烷基、C 1~3杂烷基、5~6元杂芳基分别独立地包含1、2或3个分别独立地选自N、-O-、=O、-S-、-NH-、-(C=O)-、-(S=O)-和-(S=O) 2-的杂原子或杂原子团。
- 根据权利要求1或2所述的式(I)化合物的制备方法,其中,R 1选自H、OH、CN、NH 2、CH 3、CH 3CH 2、CH 3CH 2CH 2、CH 3CH 2CH 2CH 2、CH 3O、CH 3CH 2O、CH 3S、CH 3S(=O)、CH 3S(=O) 2、CH 3SCH 2、CH 3CH 2S、CH 3NH、 吡咯烷基、哌啶基、四氢吡喃基、吗啉基、2-吡咯烷酮基和3-吡咯烷酮基,所述CH 3、CH 3CH 2、CH 3CH 2CH 2、CH 3CH 2CH 2CH 2、CH 3O、CH 3CH 2O、CH 3S、CH 3S(=O)、CH 3S(=O) 2、CH 3SCH 2、CH 3CH 2S、CH 3NH、 吡咯烷基、哌啶基、四氢吡喃基、吗啉基、2-吡咯烷酮基和3-吡咯烷酮基任选被1、2或3个R取代。
- 根据权利要求6所述的式(I)化合物的制备方法,其中,R 2选自Cl和CH 3O。
- 根据权利要求1或2所述的式(I)化合物的制备方法,其中,A选自苯基、噻吩基、噻唑基、异噻唑基、恶唑基和异恶唑基,所述苯基、噻吩基、噻唑基、异噻唑基、恶唑基和异恶唑基任选被1、2或3个R取代。
- 根据权利要求1或2所述的式(I)化合物的制备方法,其中,R 3选自-C(=O)-N(CH 3) 2、-C(=O)-O-CH 3、Cl和CN。
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WO2019169539A1 (en) * | 2018-03-05 | 2019-09-12 | Pharmaresources (Shanghai) Co., Ltd. | Novel oxa-and aza-tricyclic 4-pyridone-3-carboxylic acid for treatment and prophylaxis of hepatitis b virus infection |
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WO2019169539A1 (en) * | 2018-03-05 | 2019-09-12 | Pharmaresources (Shanghai) Co., Ltd. | Novel oxa-and aza-tricyclic 4-pyridone-3-carboxylic acid for treatment and prophylaxis of hepatitis b virus infection |
Non-Patent Citations (4)
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BELEN'KII, L.I. PODDUBNYI, I.S. KRAYUSHKIN, M.M.: "A New Redox System: Trichloromethylarene - Pyridine Base. On the Mechanism of the Synthesis of N-(4-Pyridyl)pyridinium Dichloride", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM , NL, vol. 36, no. 28, 10 July 1995 (1995-07-10), Amsterdam , NL , pages 5075 - 5078, XP004027741, ISSN: 0040-4039 * |
BELENKII, LEONID I. ET AL.: "Quantum-chemical investigation of the mechanism of reaction between, pyridines and (trichloromethyl)arenes", KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII- CHEMISTRY OF HETEROCYCLIC COMPOUNDS, LATVIJSKIJ INSTITUT ORGANICESKOGO SINTEZA, RIGA, LV, no. 11, 31 December 1995 (1995-12-31), LV , pages 1551 - 1558, XP009538359, ISSN: 0132-6244 * |
DATABASE HCAPLUS 1 January 1900 (1900-01-01), GRIMMETT M R: "PRODUCT CLASS 4: BENZIMIDAZOLES", XP002412825, Database accession no. 2002-855869 * |
MAQUESTIAU ANDRÉ, ET AL.: "Rate-determining effects in the formation of N-(1-haloalkyl) heteroarylium halides", CHEMISCHE BERICHTE, vol. 124, no. 9, 30 September 1991 (1991-09-30), XP055951094, DOI: 10.1002/cber.19911240922 * |
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