TWI387601B - 方法及中間物 - Google Patents
方法及中間物 Download PDFInfo
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- TWI387601B TWI387601B TW096117466A TW96117466A TWI387601B TW I387601 B TWI387601 B TW I387601B TW 096117466 A TW096117466 A TW 096117466A TW 96117466 A TW96117466 A TW 96117466A TW I387601 B TWI387601 B TW I387601B
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- alkyl
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- 238000000034 method Methods 0.000 title claims description 38
- 230000008569 process Effects 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 55
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
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- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
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- 229940079593 drug Drugs 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- GBJVVSCPOBPEIT-UHFFFAOYSA-N AZT-1152 Chemical compound N=1C=NC2=CC(OCCCN(CC)CCOP(O)(O)=O)=CC=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 GBJVVSCPOBPEIT-UHFFFAOYSA-N 0.000 claims 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 37
- 239000000243 solution Substances 0.000 description 32
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- -1 Aurora-A Proteins 0.000 description 27
- QYZOGCMHVIGURT-UHFFFAOYSA-N AZD-1152 Chemical compound N=1C=NC2=CC(OCCCN(CCO)CC)=CC=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 QYZOGCMHVIGURT-UHFFFAOYSA-N 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 206010028980 Neoplasm Diseases 0.000 description 17
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 102100032306 Aurora kinase B Human genes 0.000 description 11
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- 101000798306 Homo sapiens Aurora kinase B Proteins 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
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- 125000004494 ethyl ester group Chemical group 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
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- IRDFFAPCSABAGK-UHFFFAOYSA-N tert-butyl dihydrogen phosphate Chemical compound CC(C)(C)OP(O)(O)=O IRDFFAPCSABAGK-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
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- 108091000080 Phosphotransferase Proteins 0.000 description 4
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- 201000010099 disease Diseases 0.000 description 4
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Classifications
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Description
本發明係關於一種適用於製備諸如磷酸二氫2-{乙基[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H
-吡唑-3-基)胺基]喹唑啉-7-基}氧基)丙基]胺基}乙酯(本文中稱為AZD1152)之醫藥化合物的新方法,該化合物為適用於治療諸如癌症之過度增殖性疾病的極光(aurora)激酶抑制劑。詳言之,本發明係關於一種用於製備某些極光激酶抑制劑之磷酸酯前藥形式之方法。本發明亦係關於用於該方法之新穎中間物。
癌症(及其他過度增殖性疾病)之特徵為在對細胞增殖之正常調節喪失時所發生的非受控式細胞增殖。此喪失常常似乎為對細胞路徑之遺傳損害所致的結果(細胞路徑控制細胞經由其細胞週期之進程)。
在真核生物體內,據稱蛋白質磷酸化之有序級聯控制細胞週期。已鑑別在此級聯中起關鍵作用之若干個蛋白質激酶家族。當與正常組織相比較時,許多此等激酶之活性在人類腫瘤中增加。此可藉由蛋白質之表現量增加(例如由於基因擴增),或藉由共活化劑或抑制蛋白之表現變化而發生。
此等細胞週期調節劑中最先鑑別且為最廣泛研究者為細胞週期蛋白(cyclin)依賴性激酶(或CDK)。近年來,已鑑別在結構上與CDK家族不同之蛋白質激酶且發現其在調節細胞週期中起關鍵作用。此等激酶亦顯現在腫瘤形成中起重要作用且包括果蠅屬(Drosophila
)極光及釀酒酵母(S.cerevisiae
)Ipll蛋白質之人類同源物。此等基因之三種人類同源物極光-A、極光-B及極光-C(亦分別稱為極光2、極光1及極光3)編碼細胞週期調節之絲胺酸-蘇胺酸蛋白質激酶(在Adams等人,2001,Trends in CellBiology.11(2):49-54中有概述)。此等同源物經由G2及有絲分裂展示峰值表現及激酶活性。若干種觀察結果暗示人類極光蛋白在癌症中有所牽連。極光-A基因定位於染色體20q13-經常在包括乳房腫瘤與結腸腫瘤之人類腫瘤中擴增之區域。由於在多於50%之原發性人類結腸直腸癌中極光-ADNA擴增且mRNA過度表現,因此極光-A可為此擴增子之主要靶基因。在此等腫瘤中,與鄰近正常組織相比較而言,極光-A蛋白含量顯現大大升高。此外,用人類極光-A轉染齧齒動物成纖維細胞引起轉型,從而賦予在軟瓊脂中生長之能力且在裸小鼠體內形成腫瘤(Bischoff等人,1998,The EMBO Journal.17(11):3052-3065)。其他研究(Zhou等人,1998,Nature Genetics.20(2):189-93)已展示極光-A之模擬過度表現引起中心體數目增加及非整倍性增加,其為在癌症發展過程中發生之已知事件。
亦已展示當與正常細胞相比較時在腫瘤細胞中極光-B(Adams等人,2001,Chromsoma.110(2):65-74)及極光C(Kimura等人,1999,Journal of Biological Chemistry,274(11):7334-40)之表現增加。極光-B在癌細胞中過度表現且已展示極光-B之含量增加與結腸直腸癌之晚期階段有關(Katayama等人(1999)J.Natl.Cancer Inst.91:1160)。此外,一份報導提出極光-B之過度表現經由在絲胺酸10處之組蛋白H3磷酸化增加來誘發非整倍性且過度表現極光-B之細胞形成出現轉移、更具侵襲性之腫瘤(Ota,T.等人,2002,Cancer Res.62:5168-5177)。極光-B為以與至少三種其他乘客蛋白(passenger protein)Survivin、INCENP及Borealin一起形成之穩定複合物的形式存在之染色體乘客蛋白(Carmena M.等人2003,Nat.Rev.Mol.Cell Biol.4:842-854)。Survivin在癌症中亦被上調且含有BIR(細胞凋亡蛋白(IAP)複製之桿狀病毒抑制劑)域,且因此可能在保護腫瘤細胞免於細胞凋亡及/或有絲分裂災變中起作用。
對於極光-C,據信其表現限於睾丸中但已發現其在多種癌細胞株中過度表現(Katayama H等人,2003,Cancer and Metastasis Reviews 22:451-464)。
重要的是,亦已證明藉由用反義寡核苷酸處理人類腫瘤細胞株去除極光-A表現及功能(WO 97/22702及WO 99/37788)引起細胞週期停滯且在此等腫瘤細胞株中產生抗增殖效應。另外,已證明當藉由siRNA處理選擇性單獨去除極光-B表現時(Ditchfield等人2003,journal of Cell Biology,161(2):267-280),極光-A及極光-B之小分子抑制劑在人類腫瘤細胞中具有抗增殖效應(Keen等人2001,Poster #2455,美國癌症研究協會年會(American Association of Cancer Research annual meeting))。此表明抑制極光-A及/或極光-B之功能將具有抗增殖效應,其可適用於治療人類腫瘤及其他過度增殖性疾病。抑制極光激酶作為此等疾病之治療方法可明顯優於靶向細胞週期之信號轉導路徑上游(例如彼等經諸如表皮生長因子受體(EGFR)或其他受體之生長因子受體酪胺酸激酶活化者)。由於細胞週期為所有此等不同信號轉導事件之最終下游,因此,將預測諸如抑制極光激酶的針對細胞週期之療法在所有增殖性腫瘤細胞中具有活性,同時將預測針對於特異性信號轉導分子(例如EGFR)之方法僅在表現彼等受體之腫瘤細胞子集中具有活性。亦咸信明顯"串話(cross talk)"存在於此等信號轉導路徑之間,此意謂抑制一種組分可由另一種組分來補償。
極光激酶之抑制劑描述於國際專利申請案WO 03/55491及WO 2004/058781中,且詳言之WO 2004/058781揭示一種具有以下結構式(IA)之化合物(於此稱為AZD1152)。
AZD1152為可快速及完全轉化(在人血漿中)成具有以下結構式(IVA)之活性部分(於此稱為AZD1152 HQPA)的前藥:
AZD1152 HQPA為具有對抗極光A、B-INCENP及C-INCENP之有效活性(Ki值分別為1369±419.2 nM,0.359±0.386 nM及17.03±12.2 nM)的ATP-競爭性及可逆性極光激酶抑制劑。已發現AZD1152抑制一組人類結腸直腸(SW620、HCT116、Colo205)及肺(A549、Calu-6)腫瘤異種移植物中之腫瘤生長,該抑制具有統計顯著性。
WO 2004/058781揭示一種用於製備類似於AZD1152類型之化合物之通用方法途徑。WO 2004/058781亦揭示一種用於製備AZD1152之方法途徑。此方法之概述展示於流程1中。
本發明係關於一種用於製備AZD1152及類似化合物之改良方法。詳言之,本發明係關於一種用於由AZD1152 HQPA製備AZD1152之改良方法。由於此方法特定言之係關於AZD1152,因此其概要展示於流程2中。此方法與先前所揭示之方法的不同之處在於其包括新穎的式(IIA)中間物:
吾人已發現此中間物可易於被分離,且令人驚訝地為,與先前所揭示之式(IIIA)中間物相比其更易於被分離:
因此,本發明之方法允許以較少雜質及改良產率來製備諸如AZD1152之化合物。
為此,本發明提供一種用於製備式(II)中間化合物之方法,
其中A
為含有一個氮原子且視情況含有1、2或3個另外之氮原子之5員雜芳基;X
為-NH-或-N(C1-4
烷基)-;m
為0、1、2或3;R 1
為經-OP(O)(OH)(OR)取代且視情況進一步經1或2個C1-4
烷氧基取代之C1-6
烷基;R 2
為氫或視情況經1、2或3個C1-4
烷氧基或-S(O)p
R8
(其中p為0、1或2)取代之C1-6
烷基或,R2
為選自C2-6
烯基、C2-6
炔基、C3-6
環烷基及C3-6
環烷基C1-4
烷基之基團;或R 1
及R 2
連同其所連接之氮形成可為飽和、不飽和或部分飽和之5員至7員環,其中該環經選自-OP(O)(OH)(OR)及C1-4
烷基之基團取代,該C1-4
烷基經-OP(O)(OH)(OR)取代,且其中該環視情況進一步經1、2或3個C1-4
烷基取代;R 3
為選自氫、鹵基、氰基、硝基、C1-6
烷氧基、C1-6
烷基之基團;R 4
為氫或選自C1-4
烷基、雜芳基、雜芳基C1-4
烷基、芳基及芳基C1-4
烷基之基團,該基團視情況經1、2或3個選自甲基、乙基、環丙基及乙炔基之取代基取代;R 5
係選自氫、C1-4
烷基、C2-4
烯基、C2-4
炔基、C3-6
環烷基及C3-6
環烷基C1-4
烷基;R 6
及R 7
係獨立地選自氫、C1-4
烷基、C3-6
環烷基及C1-4
烷氧基;R 8
為氫或C1-4
烷基;其中R
為酸不穩定性保護基,諸如第三丁基、三苯甲基、對甲氧苯基、苄基或苯基;該方法包含在-10℃至40℃之溫度下調整以下式(III)化合物之溶液之pH值為pH 5至pH 6.5,
其中A、X、m、R 3 、R 4 、R 5 、R 6
及R 7
係如對式(II)所定義;R 1'
為經-OP(O)(OR)2
取代且視情況進一步經1或2個C1-4
烷氧基取代之C1-6
烷基;R 2'
為氫或視情況經1、2或3個C1-4
烷氧基或-S(O)p
R8
(其中p為0、1或2)取代之C1-6
烷基,或R2'
為選自C2-6
烯基、C2-6
炔基、C3-6
環烷基及C3-6
環烷基C1-4
烷基之基團;或R 1'
及R 2'
連同其所連接之氮形成可為飽和、不飽和或部分飽和之5員至7員環,其中該環經選自-OP(O)(OR)2
及C1-4
烷基之基團取代,該C1-4
烷基經-OP(O)(OR)2
取代,且其中該環視情況進一步經1、2或3個C1-4
烷基取代;R 8
為氫或C1-4
烷基。
合適地,R為第三丁基。
合適地,在介於10℃與25℃之間的溫度下將該pH值調整為pH 5至pH 6.5範圍內之pH值。更合適地,將該pH值調整為在諸如約20℃之周圍溫度下pH 5至pH 6.5範圍內之pH值。
形成式(III)化合物之溶液所用之合適溶劑一般而言包括偶極性非質子性液體,諸如二甲基乙醯胺(DMA)及N-甲基吡咯啶酮(NMP)或其混合物。該等溶劑可能含有各種比例之水。
本發明之此態樣之一實施例提供一種用於製備式(IIA)中間化合物之方法,
其中R為酸不穩定性保護基,諸如第三丁基、三苯甲基、對甲氧苯基、苄基或苯基;該方法包含在-10℃至周圍溫度之溫度下調整以下式(IIIA)化合物之溶液之pH值為pH 5至pH 6.5,
其中R係如對於式(IIA)所定義。
合適地,R為第三丁基。
合適地,在介於10℃與25℃之間的溫度下將該pH值調整為pH 5至pH 6.5範圍內之pH值。更合適地,將該pH值調整為在諸如約20℃之周圍溫度下pH 5至pH 6.5範圍內之pH值。
形成式(IIIA)化合物之溶液所用之合適溶劑一般而言包括偶極性非質子性液體,諸如二甲基乙醯胺(DMA)及N-甲基吡咯啶酮(NMP)或其混合物。該等溶劑可能含有各種比例之水。
本發明亦提供一種用於由如本文中所述之式(II)化合物製備式(I)化合物或其醫藥學上可接受之鹽的方法:
其中A
為含有一個氮原子且視情況含有1、2或3個另外之氮原子之5員雜芳基;X
為-NH-或-N(C1-4
烷基)-;m
為0、1、2或3;R 1
為經-OP(O)(OH)2
取代且視情況進一步經1或2個C1-4
烷氧基取代之C1-6
烷基;R 2
為氫或視情況經1、2或3個C1-4
烷氧基或-S(O)p
R8
(其中p為0、1或2)取代之C1-6
烷基,或R2
為選自C2-6
烯基、C2-6
炔基、C3-6
環烷基及C3-6
環烷基C1-4
烷基之基團;或R 1
及R 2
連同其所連接之氮形成可為飽和、不飽和或部分飽和之5員至7員環,其中該環經選自-OP(O)(OH)2
及C1-4
烷基之基團取代,該C1-4
烷基經-OP(O)(OH)2
取代,且其中該環視情況進一步經1、2或3個C1-4
烷基取代;R 3
為選自氫、鹵基、氰基、硝基、C1-6
烷氧基、C1-6
烷基之基團;R 4
為氫或選自C1-4
烷基、雜芳基、雜芳基C1-4
烷基、芳基及芳基C1-4
烷基之基團,該基團視情況經1、2或3個選自甲基、乙基、環丙基及乙炔基之取代基取代;R 5
係選自氫、C1-4
烷基、C2-4
烯基、C2-4
炔基、C3-6
環烷基及C3-6
環烷基C1-4
烷基;R 6
及R 7
係獨立地選自氫、C1-4
烷基、C3-6
環烷基及C1-4
烷氧基;R 8
為氫或C1-4
烷基;該方法包含以下步驟:1)將合適酸添加至如本文中所定義之式(II)化合物之溶液中;2)將pH值調整至pH 4.5至pH 5.5範圍內;及此後若有必要或若需要,則3)使式(I)化合物轉化成其醫藥學上可接受之鹽。
形成式(II)化合物之溶液所用之合適溶劑包括偶極性非質子性液體,諸如二甲基乙醯胺(DMA)及N-甲基吡咯啶酮(NMP)或其混合物。該等溶劑可能含有各種比例之水。
合適地,步驟1)中所用之酸係選自鹽酸、反丁烯二酸、三氟乙酸、乙烷二磺酸、甲烷磺酸、硫酸氫鈉或任何其他具有足以便於移除酸不穩定性保護基之pKa的酸。
合適地,在步驟2)中,藉由添加適當之鹼將pH值調整為pH 4.5至pH 5.5範圍內。該鹼可選自諸如鈉、鉀或鋰之鹼金屬之氫氧化物。
合適地,步驟2)係在反應混合物保持溶液狀態,諸如介於15℃與60℃之間的溫度下進行。
用於步驟2)之適當溶劑可為四氫呋喃(THF)與水(較佳為等體積)之混合物。
本發明之此態樣之一實施例提供一種用於由式(IIA)化合物
(其中R為第三丁基)
製備AZD1152(式(IA))之方法,
該方法包含以下步驟:1)將合適酸添加至式(IIA)化合物之溶液中;及2)將所得混合物之pH值調整為pH 4.5至pH 5.5;及隨後視情況3)形成AZD1152之醫藥學上可接受之鹽。
形成式(IIA)化合物之溶液所用之合適溶劑包括偶極性非質子性液體,諸如二甲基乙醯胺(DMA)及N-甲基吡咯啶酮(NMP)或其混合物。該等溶劑可能含有各種比例之水。
合適地,步驟1)中所用之酸係選自鹽酸、反丁烯二酸、三氟乙酸、乙烷二磺酸、甲烷磺酸、硫酸氫鈉或任何其他具有足以便於移除酸不穩定性保護基之pKa的酸。
合適地,在步驟2)中,藉由添加適當之鹼將pH值調整為pH 4.5至pH 5.5範圍內。該鹼可選自諸如鈉、鉀或鋰之鹼金屬之氫氧化物。
合適地,步驟2)係在反應混合物保持溶液狀態,諸如介於15℃與60℃之間的溫度下,且尤其在室溫下進行。
用於步驟2)之適當溶劑可為四氫呋喃(THF)與水(較佳為等體積)之混合物。
式(II)化合物為新穎中間物且構成本發明之另一特徵。
式(IIA)化合物亦為新穎中間物且構成本發明之又一特徵。
本發明之另一態樣提供一種用於由式(IIIA)化合物
製備AZD1152(式(IA))之方法,
其中該方法包含以下步驟:(i)在-10℃至周圍溫度之溫度下將式(IIIA)化合物(其中R係如上文對於式(IIA)所定義)之溶液的pH值調整為pH 5至pH 6.5以形成式(IIA)化合物;
(ii)將合適酸添加至式(IIA)化合物之溶液中;(iii)將所得混合物之pH值調整為pH 4.5至pH 5.5以形成AZD1152(式(IA));及隨後視情況形成AZD1152之醫藥學上可接受之鹽。對於以上步驟(i)而言:合適地,R為第三丁基。
合適地,在介於10℃與25℃之間的溫度下將該pH值調整為pH 5至pH 6.5範圍內之pH值。更合適地,將該pH值調整為在諸如約20℃之周圍溫度下pH 5至pH 6.5範圍內之pH值。
形成式(IIIA)化合物之溶液所用之合適溶劑一般而言包括偶極性非質子性液體,諸如二甲基乙醯胺(DMA)與N-甲基吡咯啶酮(NMP)或其混合物。該等溶劑可能含有各種比例之水。
對於以上步驟(ii)而言:形成式(II)化合物之溶液所用之合適溶劑包括偶極性非質子性液體,諸如二甲基乙醯胺(DMA)及N-甲基吡咯啶酮(NMP)或其混合物。該等溶劑可能含有各種比例之水。
合適地,步驟(ii)中所用之酸係選自鹽酸、反丁烯二酸、三氟乙酸、乙烷二磺酸、甲烷磺酸、硫酸氫鈉或任何其他具有足以便於移除酸不穩定性保護基之pKa的酸。
對於以上步驟(iii)而言:藉由添加適當之鹼將pH值調整為pH 4.5至pH 5.5範圍內。該鹼可選自諸如鈉、鉀或鋰之鹼金屬之氫氧化物。
合適地,步驟(iii)係在反應混合物保持溶液狀態,諸如介於15℃與60℃之間的溫度下,且尤其在室溫下進行。
用於步驟(iii)之適當溶劑可為四氫呋喃(THF)與水(較佳為等體積)之混合物。
在本發明內,應瞭解就本文中所述且定義之某些化合物可由於一或多個不對稱碳原子而以光學活性形式或外消旋形式存在而言,本發明包括在其定義內之任何如此之光學活性形式或外消旋形式。光學活性形式之合成可藉由此項技術中熟知之有機化學標準技術,例如藉由自光學活性起始物質合成或藉由外消旋形式之解析來進行。類似地,上文所提及之活性可使用標準實驗室技術來評估。
在本發明內,應瞭解本文中所述之化合物可展現互變異構現象且在此說明書內之結構式圖示可僅表示可能互變異構形式中之一者。應瞭解,本發明涵蓋任何互變異構形式且並不僅限於結構式圖示內所用之任一互變異構形式。
亦應瞭解,本文中所述之某些化合物可以溶劑化形式以及非溶劑化形式(諸如水合形式)存在。應瞭解,本發明涵蓋所有該等溶劑化形式。
本發明係關於如本文中所定義之式(I)化合物以及其鹽。用於醫藥組合物中之鹽應為醫藥學上可接受之鹽,但其他鹽可適用於產生式(I)化合物及其醫藥學上可接受之鹽。本發明之醫藥學上可接受之鹽可例如包括如本文中所定義之式(I)化合物之酸加成鹽,該等式(I)化合物具有足夠之鹼性以形成該等鹽。該等酸加成鹽包括(但不限於)反丁烯二酸鹽、甲烷磺酸鹽、鹽酸鹽、氫溴酸鹽、檸檬酸鹽、乙烷二磺酸鹽及順丁烯二酸鹽以及與磷酸及硫酸形成之鹽。另外,在式(I)化合物具有足夠酸性之狀況下,鹽為鹼鹽且實例包括(但不限於)例如鈉或鉀之鹼金屬鹽,例如鈣或鎂之鹼土金屬鹽,或例如三乙胺、乙醇胺、二乙醇胺、三乙醇胺、嗎啉、N
-甲基哌啶、N
-乙基哌啶、二苄胺或胺基酸(諸如離胺酸)之有機胺鹽。
在本說明書中,通用術語"烷基"包括直鏈烷基與支鏈烷基。然而,對諸如"丙基"之個別烷基的提及係特定性的,其僅為直鏈形式,且對諸如"第三丁基"之個別支鏈烷基的提及係特定性的,其僅為支鏈形式。類似約定適用於其他通用術語,例如"烯基"及"炔基"。
"環烷基"為單環飽和烷基環,且"芳基"為單環或雙環芳族環。
除非另作說明,否則"雜芳基"為含有5至10個環原子之單環或雙環芳族環,其中1、2、3或4個環原子係選自氮、硫或氧,其中環氮或環硫可被氧化。
若視情況之取代基係選自"1或2"個或選自"1、2或3"個基團或取代基,則應瞭解此定義包括所有取代基係選自指定基團中之一者,亦即所有取代基相同;或該等取代基係選自指定基團中之兩者或兩者以上,亦即取代基不相同。
本發明之化合物已借助於電腦軟體(ACD/命名版本6.6或ACD命名批處理版本6.0)命名。
任何R基團(R及R1
至R8
)或該等基團之任何部分或取代基的合適涵義包括:對於C1-4
烷基而言:甲基、乙基、丙基、異丙基、丁基、2-甲基丙基及第三丁基;對於C1-6
烷基而言:C1-4
烷基、戊基、2,2-二甲基丙基、3-甲基丁基及己基;對於C2-4
烯基而言:乙烯基、烯丙基及1-丙烯基;對於C2-6
烯基而言:C2-4
烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基及4-己烯基;對於C2-4
炔基而言:乙炔基、1-丙炔基、2-丙炔基及3-丁炔基;對於C2-6
炔基而言:C2-4
炔基、2-戊炔基、己炔基及1-甲基戊-2-炔基;對於C3-6
環烷基而言:環丙基、環丁基、環戊基及環己基;對於C3-6
環烷基C1-4
烷基而言:環丙基甲基、環丙基乙基、環丁基甲基、環戊基甲基及環己基甲基;對於芳基而言:苯基及萘基;對於芳基C1-4
烷基而言:苄基、苯乙基、萘基甲基及萘基乙基;對於鹵基而言:氟基、氯基、溴基及碘基;對於C1-4
烷氧基而言:甲氧基、乙氧基、丙氧基及異丙氧基;對於C1-6
烷氧基而言:C1-4
烷氧基、戊氧基、1-乙基丙氧基及己氧基;對於雜芳基而言:吡啶基、咪唑基、喹啉基、啉基、嘧啶基、噻吩基、吡咯基、吡唑基、噻唑基、三唑基、噁唑基、異噁唑基及吡嗪基,且較佳為噻唑基、吡啶基、咪唑基及嘧啶基;對於雜芳基C1-4
烷基而言:吡啶基甲基、吡啶基乙基、嘧啶基乙基、嘧啶基丙基、嘧啶基丁基、咪唑基丙基、咪唑基丁基、喹啉基丙基、1,3,4-三唑基丙基及噁唑基甲基。
應注意對於本說明書中所用之術語給定之實例並不具有限制性。
在本文中藉由非限制性實例、數據及反應流程來說明本發明,其中除非另作說明,否則:(i)產率僅為達成說明之目的而給定且並不必定為可得到之最大值;(ii)若產物用於接種,則其可藉由諸如WO 2004/058781中所述之彼等先前已知的方法獲得;(iii)如本文中所述製備之化合物之特性一般係由1
H NMR以400 MHz,在添加有四甲基矽烷(TMS)(作為參考,TMS=0.00 ppm)、三氟乙酸(助於溶解)及內標(諸如順丁烯二酸)之六氘化二甲亞碸中加以確證。
如本文中所述,AZD1152及AZD1152 HQPA揭示於WO2004/058781中。WO2004/058781中所提供之關於AZD1152、AZD1152 HQPA之方法細節以及該等化合物製備途徑中之所有中間物係以引用的方式全部併入本文中。
7-(3-羥基丙氧基)喹唑啉-4(3H)-酮之製備
將2-胺基-4-氟苯甲酸及1,3-丙二醇攪拌在一起且加熱至120℃。添加乙酸甲脒且將混合物攪拌3.5小時以得到7-氟喹唑啉-4-酮。隨後經2小時又50分鐘將氫氧化鉀於1,3-丙二醇中之溶液添加至該混合物中,隨後使其冷卻至15℃。此後,將混合物加熱至125℃歷時5小時,隨後冷卻至75℃。將稀鹽酸(約6% w/w)逐漸添加至反應混合物中直至達到pH 4.5。經6小時使混合物冷卻至0℃且維持在彼溫度下歷時又一小時,隨後藉由離心來分離粗產物。將粗物質以水洗滌且在真空中乾燥,隨後在溫和回流下溶解於甲醇中且在減壓下於42℃之溫度下部分濃縮。隨後經3小時使此溶液冷卻至0℃且藉由過濾分離所得產物,隨後在真空中乾燥。回收得到7-(3-羥基丙氧基)喹唑啉-4(3H)-酮,產率為73%。
1
H-NMR(DMSO d6
):11.90(br s,1H),8.04(s,1H),8.00(d,1H),7.10(m,2H),4.17(t,2H),3.58(t,2H),1.92(m,2H):MS(+ve ESI):221(M+H)+
。
4-氯-7-(3-氯丙氧基)喹唑啉之製備
將7-(3-羥基丙氧基)喹唑啉-4(3H)-酮、甲苯及N,N-二異丙基-甲醯胺(DIPF)混合在一起且加熱至76℃,隨後在76℃下經1小時添加亞硫醯氯。隨後經1小時添加另外之亞硫醯氯,其後將溫度維持在76℃下歷時1小時。使混合物回流11小時以得到澄清溶液,使該溶液冷卻至38℃且經受真空蒸餾以移除甲苯及亞硫醯氯。隨後添加甲苯且將溶液保持在35℃下,同時用助濾劑(矽藻土或鈉磷鋁石及活性碳)將其淨化。將所得溶液部分濃縮,隨後添加庚烷且使混合物冷卻至0℃且攪拌23小時。將所形成之淺棕色懸浮液藉由過濾分離,以冷庚烷洗滌,隨後在真空中在30℃下乾燥以得到4-氯-7-(3-氯丙氧基)喹唑啉(63.6%)。
1
H-NMR(DMSO d6
):13.25(br s,1H),8.34(s,1H),8.06(d,1H),7.17(m,2H),4.21(t,2H),3.83(t,2H),2.23(m,2H):MS(+ve ESI):257,259(M+H)+
。
(3-{[7-(3-氯丙氧基)喹唑啉-4-基]胺基}-1H-吡唑-5-基)乙酸之製備
將4-氯-7-(3-氯丙氧基)喹唑啉添加至1莫耳當量之(3-胺基-1H
-吡唑-5-基)乙酸於N
-甲基吡咯啶酮(NMP)中之溶液中且隨後置放12小時。在接種及不接種之情況下且在添加及不添加乙腈作為反溶劑之情況下觀察到產物產生結晶。將所得固體藉由過濾分離,以N-甲基吡咯啶酮及乙腈洗滌且隨後在真空中乾燥以得到呈灰白色固體狀、含有1莫耳當量NMP之(3-{[7-(3-氯丙氧基)喹唑啉-4-基]胺基}-1H
-吡唑-5-基)乙酸鹽酸鹽:1
H-NMR(DMSO d6
):8.92(s,1H),8.79(d,1H),7.45(pr of d,1H),7.38(d,1H),6.7(s,1H),6.67(s,1H),4.31(t,2H),3.85(t,2H),3.72(s,2H),3.3(t),2.7(s,),2.27(m,2H),2.18(t),1.9(m):MS(+ve ESI):362.1015(M+H)+
。
2-(3-{[7-(3-氯丙氧基)喹唑啉-4-基]胺基}-1H-吡唑-5-基)-N-(3-氟苯基)乙醯胺之製備
向(3-{[7-(3-氯丙氧基)喹唑啉-4-基]胺基}-1H
-吡唑-5-基)乙酸鹽酸鹽於N,N-二甲基乙醯胺(DMA)中之懸浮液中添加4-二甲胺基吡啶(DMAP),同時維持15-25℃(理想地為15℃)之溫度,繼而添加N-甲基嗎啉,同時亦維持該溫度。以為了使溫度維持在25℃以下之速率添加3-氟苯胺(大大過量,其理想地為介於10-15莫耳當量之間的量)。其間將1-乙基-3-(3-二甲基胺基丙基)碳化二醯亞胺鹽酸鹽(EDCI.HCl)溶解於水中以得到約42% w/v之溶液(水之存在量對該方法中稍後結晶之結果而言係很重要的)。以受控方式經8小時將此溶液添加至漿料中以便將反應物維持在20-25℃之間的溫度;隨後用較佳形式之產物之晶體(理想地為預期產量之約1%之量)接種該混合物。將混合物攪拌約16小時,同時維持該溫度(理想地為20-25℃),隨後以受控方式添加反溶劑乙腈,繼而添加水,且為將溫度維持在20-25℃之間,繼而延長攪拌約21小時;此將使產物之回收率及形式最佳化。藉由過濾分離該物質且將濾餅以N,N
-二甲基乙醯胺:水:乙腈(體積比為5:3:2)之混合物、乙腈洗滌,且隨後乾燥(在真空中或在氮氣流下)以得到含有少許DMA之2-(3-{[7-(3-氯丙氧基)喹唑啉-4-基]胺基}-1H
-吡唑-5-基)-N-(3-氟苯基)乙醯胺,產率為約76-78%。
1
H-NMR(DMSO d6
;含有殘餘DMA):10.4(s,1H),8.9(s,1H),8.8(d,1H),7.59(dm,1H),7.46(dd,1H),7.33(m,2H),7.29(d,1H),6.85(m,1H),6.75(s,1H),4.35(t,2H),3.85(t,4H),2.95(s),2.83(s),2.56(s),2.25(m,2H),1.95(s):MS(+ve):455(M+H)+
。
2-{3-[(7-{3-[乙基(2-羥基乙基)胺基]丙氧基}-喹唑啉-4-基)胺基]-1H-吡唑-5-基}-N-(3-氟苯基)乙醯胺(AZD1152 HQPA)之製備
在惰性氣氛(諸如由氮氣提供)下,將2-(3-{[7-(3-氯丙氧基)喹唑啉-4-基]胺基}-1H
-吡唑-5-基)-N-(3-氟苯基)乙醯胺及2-(乙基胺基)乙醇(理想地為12莫耳當量)添加至N,N
-二甲基乙醯胺中且在攪拌下將混合物加熱至90℃。在12-16小時(理想地為12小時)之後,使反應物冷卻至約85℃且以受控方式添加水以將溫度維持在80-85℃之間。將該批料調整至80℃且用較佳形式之產物之晶體(理想地為預期產量之約1%之量)接種。以小心控制之方式經約20小時使混合物冷卻至20℃,以便使產物結晶成所需形式且具有足以提供良好過濾速率之尺寸。隨後將產物過濾且以水/N,N
-二甲基乙醯胺之混合物及乙腈洗滌,且適當地加以脫液(deliquor)以得到產物之水合形式。此後,用溫乙腈(理想地在40℃之溫度下)將濾餅原位製成漿料歷時一段時間(理想地為2小時),隨後過濾,以較多之乙腈洗滌且隨後乾燥(在真空中或在氮氣流下)以得到呈灰白色固體狀、幾乎無水之2-{3-[(7-{3-[乙基(2-羥基乙基)胺基]丙氧基}-喹唑啉-4-基)胺基]-1H
-吡唑-5-基}-N
-(3-氟苯基)乙醯胺,產率為85-90%。
1
H-NMR(DMSO d6
):10.55(s,1H),9.45(br s,1H),8.98(s,1H),8.8(d,1H),7.63(dm,1H),7.47(dd,1H),7.37(m,2H),7.32(d,1H),6.9(m,1H),6.77(s,1H),4.32(t,2H),3.83(br s,2H),3.76(t,2H),3.35(m,2H),3.25(m,4H),2.25(m,2H),1.25(t,3H):MS(+ve ESI):508.4(M+H)+
。
磷酸單(第三丁基)2-[[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H-吡唑-3-基)胺基]-喹唑啉-7-基}氧基)丙基](乙基)胺基]乙酯[AZD1152 t-Bu P(5)酯]之製備
將2-{3-[(7-{3-[乙基(2-羥基乙基)胺基]丙氧基}-喹唑啉-4-基)胺基]-1H
-吡唑-5-基}-N-(3-氟苯基)乙醯胺及鹽酸吡啶於N,N-二甲基乙醯胺中混合且使溶液冷卻至-15℃。隨後添加二乙基胺基磷酸二第三丁酯(1.5-2.1莫耳當量),同時維持該溫度。用30% w/w過氧化氫(約4.2莫耳當量)原位處理該反應混合物,同時將溫度保持在周圍溫度以下。藉由添加焦亞硫酸鈉(呈10% w/v溶液形式)來去除殘留過氧化氫,同時將溫度維持在40℃以下。隨後將所得之磷酸二-第三丁基2-[[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H
-吡唑-3-基)胺基]喹唑啉-7-基}氧基)丙基](乙基)胺基]乙酯之溶液加熱至40℃且添加氫氧化鈉溶液(2 M)以調整至pH 5-6.5。在接種之情況下,維持該溫度及該pH值歷時約90分鐘。隨後饋入水且進一步將pH值調整至pH 8-9之範圍內以使回收率最佳化。將溫反應混合物直接過濾以得到磷酸單-第三丁基2-[[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H
-吡唑-3-基)胺基]-喹唑啉-7-基}氧基)丙基](乙基)胺基]乙酯,將其以N,N-二甲基乙醯胺/水之混合物及水洗滌且最後乾燥(在真空中或在合適惰性氣體氣流中)以得到呈灰白色固體狀之磷酸單(第三丁基)2-[[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H
-吡唑-3-基)胺基]-喹唑啉-7-基}氧基)丙基](乙基)胺基]乙酯,產率介於86-93%之間。
1
H-NMR(DMSO d6
):10.48.(s,1H),9.75(br s,1H),8.98(s,1H),8.85(d,1H),7.67(dm,1H),7.48(dd,1H),7.37(m,2H),7.3(d,1H),6.87(m,1H),6.83(s,1H),4.34(t,2H),4.28(m,2H),3.88(s,2H),3.53(m,2H),3.43(m,2H),3.33(m,2H),2.3(m,2H),1.47(s,9H),1.32(t,3H):MS(+ve ESI):(M+H)+
644.2761片段(較少丁基)588.2147。
磷酸單(第三丁基)2-[[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H-吡唑-3-基)胺基]-喹唑啉-7-基}氧基)丙基](乙基)胺基]乙酯[AZD1152 t-Bu P(5)酯]之製備-替代途徑
經延長之時段(理想地為3小時)向鹽酸吡啶於N,N-二甲基乙醯胺中之漿料中饋入2-{3-[(7-{3-[乙基(2-羥基乙基)胺基]丙氧基}-喹唑啉-4-基)胺基]-1H
-吡唑-5-基}-N-(3-氟苯基)乙醯胺及二乙基胺基磷酸二第三丁酯(理想地為1莫耳當量)於N,N-二甲基乙醯胺中之溶液,且將溫度維持在-20℃至-10℃之間(理想地為-15℃)。此後,在1小時期間進一步添加二乙基胺基磷酸二第三丁酯(理想地為0.5莫耳當量),亦將溫度維持在-20℃至-10℃之間(理想地為-15℃)。
用30% w/w過氧化氫(約4.2莫耳當量)原位處理該反應混合物,同時將溫度保持在-10℃以下(理想地為-12℃至-8℃),且在此溫度下保持一段時間(理想地為16小時)。藉由添加焦亞硫酸鈉(呈10% w/v水溶液形式)來去除殘留過氧化氫,同時將溫度維持在40℃以下。
隨後將所得之磷酸二-第三丁基2-[[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H
-吡唑-3-基)胺基]喹唑啉-7-基}氧基)丙基](乙基)胺基]乙酯之溶液加熱至40℃且添加氫氧化鈉溶液(理想地為2 M)以調整至pH 5.5-6.5(理想地為pH 6),之後用合適結晶物質接種。保持該溫度且藉由添加額外氫氧化鈉溶液維持pH 5-6之範圍歷時至少2小時。隨後饋入水且將pH值進一步調整至pH 8-9範圍內(理想地為pH 8.8),同時將溫度(理想地為40℃但在35-45℃之範圍內)維持16小時以便使回收率最佳化。將溫反應混合物直接過濾以得到磷酸單-第三丁基2-[[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H
-吡唑-3-基)胺基]喹唑啉-7-基}氧基)丙基](乙基)胺基]乙酯,將其以水洗滌若干次且最後乾燥(在真空中或在合適惰性氣體氣流中)以得到呈灰白色固體狀之磷酸單(第三丁基)2-[[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H
-吡唑-3-基)胺基]-喹唑啉-7-基}氧基)丙基](乙基)胺基]乙酯,產率介於86-93%之間。
1
H-NMR(DMSO d6
):10.48(s,1H),9.75(br s,1H),8.98(s,1H),8.85(d,1H),7.67(dm,1H),7.48(dd,1H),7.37(m,2H),7.3(d,1H),6.87(m,1H),6.83(s,1H),4.34(t,2H),4.28(m,2H),3.88(s,2H),3.53(m,2H),3.43(m,2H),3.33(m,2H),2.3(m,2H),1.47(s,9H),1.32(t,3H):MS(+ve ESI):(M+H)+
644.2761片段(較少丁基)588.2147。
磷酸二氫2-{乙基[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H-吡唑-3-基)胺基]喹唑啉-7-基}氧基)丙基]胺基}乙酯(AZD1152)之製備
使磷酸單(第三丁基)2-[[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H
-吡唑-3-基)胺基]-喹唑啉-7-基}氧基)丙基](乙基)胺基]乙酯懸浮於水/四氫呋喃(THF)之混合物中且用介於1.5莫耳當量與3.0莫耳當量之間的過量鹽酸(理想地為2M之濃度且含有1.5莫耳當量)加以處理。將混合物加熱至55-65℃(理想地為60℃)且在60℃下保持約1小時。隨後使用氫氧化鈉(較佳具有2M濃度且含有1.7莫耳當量)鹼化該熱溶液以得到在pH 5.0-5.5範圍內之pH值,且隨後在55-65℃(理想地為60℃)下用較佳形式之產物之晶體(理想地為預期產量之約0.05% w/w之量)接種。將混合物在此溫度下攪拌至少1小時,隨後添加水,且將漿料攪拌並以受控方式經約12小時使其冷卻,之後在周圍溫度下攪拌至少4小時且隨後藉由過濾分離產物。將濾餅相繼用水隨後用THF洗滌且在真空中或使用濕化程序(藉由使經水蒸汽濕潤之惰性氣體通過固體直至獲得恆重)進行乾燥。在真空中乾燥之後,使固體磷酸二氫2-{乙基[3-({4-[(5-{2-[(3-氟苯基)胺基]-2-側氧基乙基}-1H
-吡唑-3-基)胺基]喹唑啉-7-基}氧基)丙基]胺基}乙酯在周圍條件下平衡至恆重以得到呈淺黃色針狀物質之水合形式。獲得產率為約81%之產物。
1
H-NMR(DMSO d6
):MS(+ve ESI):587.8(M+H)+ 1
H-NMR(DMSO d6
):10.53(s,1H),8.57(s,1H),8.54(d,1H),7.62(d,1H),7.37(m,2H),7.27(s,1H),7.21(d,1H),6.88(m,1H),6.65(s,1H),4.27(t,2H),4.05(m,2H),3.75(s,2H),3.24(m,2H),3.21(t,2H),3.13(q,2H),2.18(m,2H),1.24(t,3H):MS(+ve ESI):588(M+H)+
。
C26
H31
FN7
O6
P+3.0 H2
O需要C,48.7%;H,5.8%;N,15.3%;實驗值C,48.8%;H,5.35%;N,15.15%。
Claims (7)
- 一種用於製備式(II)中間化合物之方法,
- 一種用於製備式(IIA)中間化合物之方法,
- 一種用於由如請求項1所述之式(II)化合物製備式(I)化合物或其醫藥學上可接受之鹽的方法,
- 一種用於由式(IIA)化合物
- 一種用於由式(IIIA)化合物
- 一種式(II)化合物,其係如請求項1中所定義。
- 一種式(IIA)化合物,其係如請求項2中所定義。
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