CN107266488A - 一种替卡格雷中间体及其制备方法 - Google Patents
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- 229960002528 ticagrelor Drugs 0.000 title claims abstract description 20
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title claims abstract description 19
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- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 3
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- -1 alkali metal nitrites salts Chemical class 0.000 claims description 3
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- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
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- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
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- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- 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 1
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
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- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
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- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical class [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
本发明公开了一种替卡格雷中间体,其结构如式I所示;一种结构式如式I所示的化合物的制备方法,由化合物II与化合物III进行取代反应制得化合物I,
Description
技术领域
本发明涉及药物化学领域,具体涉及一种抗血小板凝集药替卡格雷的新型中间体及其制备方法。
背景技术
美国专利US6251910和US6525060公开了一系列新的三唑并(4,5-D)嘧啶化合物,其中,替卡格雷是一种新型的,具有选择性的小分子抗凝血药。该药能可逆性地作用于血管平滑肌细胞上的嘌呤2受体亚型P2Y12,对ADP引起的血小板聚集有明显的抑制作用,且口服使用后起效迅速,因此能有效改善急性冠心病患者的症状。
替卡格雷化学名为(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-二氟苯基)环丙氨基]-5-(硫丙基)-3H-[1,2,3]三唑[4,5-d]嘧啶-3-基]-5-(2-羟基乙氧基)环戊烷-1,2-二醇,其化学结构如式(VII)所示:
美国专利US6525060首次报道了替卡格雷的制备方法,专利中所报道的制备方法需要使用危险和爆炸性试剂如DIBAL-H、NaH,以及昂贵的四氧化锇,后处理步骤需要用柱层析方法,不适合工业化生产;PCT申请WO2001092263报道了通过2-{[(3aR,4S,6R,6aS)-6-氨基-2,2-二甲基四氢-3aH-环戊二烯并[d][1,3]-二氧杂环戊-4-基]氧基}-1-乙醇与4,6-二氯-2-(丙硫烷基)-5-嘧啶胺发生取代反应生成一种新型中间体[3aR-(3aα,4α,6α,6aα)]-2-[[6-[[5-氨基-6-氯-2-(丙硫基)-4-嘧啶基]氨基]四氢-2,2-二甲基-3aH-环戊并[d][1,3]二氧杂环戊-4-基]氧基]乙醇,新型中间体在适当酸和亚硝酸盐催化下发生环合反应,环合产物与(1R,2S)-2-(3,4-二氟苯基)-环丙胺发生偶合反应,偶合产物在酸性条件下发生去保护反应得到式(A)所示的替卡格雷化合物。随后PCT申请WO2010030224报道了WO2001092263改进方法。用这种新型中间体制备替卡格雷的方法,涉及的取代反应、环合反应、偶合反应和去保护反应,所述的反应时间长,过程操作冗长而繁琐,不利于工业化生产。
发明内容
本发明提供一种用于制备替卡格雷的新型的中间体,所述新型的中间体为如式(I)所示的化合物:
其中,R表示含硅原子的羟基保护基,如三甲基硅基,叔丁基二甲基硅基。
本发明另一方面提供新型中间体(I)所示化合物的制备方法,在碱存在下,由化合物II与化合物III在溶剂中进行取代反应:
其中,化合物II中R表示含硅原子的羟基保护基,如三甲基硅基,叔丁基二甲基硅基。
所述的取代反应所用的溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、四氢呋喃、乙醚、二氧六环、甲基叔丁基醚、二乙二醇二甲醚、二氯甲烷、氯仿、乙酸乙酯、乙酸异丙酯、丙酮、丁酮、苯、甲苯、二甲苯中的一种或几种的混合物。
所述的取代反应的反应温度为室温至溶剂的回流温度。
所述的取代反应所使用的碱为氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钙、氢氧化镁、碳酸钠、碳酸钾、三乙胺、二乙胺、二异丙胺中的一种或几种的混合物。
本发明还提供新型中间体式(I)所示化合物用于制备式(A)所示的替卡格雷化合物的方法,其方法包括以下步骤:
a)由化合物I与碱金属亚硝酸盐或有机亚硝酸盐发生环合反应制备得到化合物IV,化合物IV的结构式如下:
其中,化合物IV中的R表示含硅原子的羟基保护基,如三甲基硅基,叔丁基二甲基硅基。
b)由化合物IV与化合物V进行缩合反应,制得化合物VI,化合物VI结构式如下:
c)由化合物VI进行脱保护反应制备得到替卡格雷,结构如式VII所示,
用本发明所提供的新型中间体制备替卡格雷的方法,反应时间短,后处理简便,产率高纯度高。
具体实施方式
本发明实施例公开了一种替卡格雷的新型中间体,这种中间体的制备方法以及用这种新型中间体制备替卡格雷的方法。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法进行改动或适当变更与组合,来实现和应用本发明技术。为了进一步理解本发明,下面结合实施例对本发明进行详细说明。
实施例1
化合物I的合成
将15g化合物II与10g化合物III加入到四氢呋喃中,再加入4g氢氧化钾,加热回流搅拌2小时,TLC点板监控反应完全,加入水和乙酸乙酯,萃取分液,收集有机相,加入无水硫酸钠干燥,过滤,减压浓缩,剩余物经层析硅胶柱分离得到17g化合物I,经LCMS确认,ESI M+1=491。
实施例2
化合物IV的合成
将17g化合物I加入到甲苯中,再加入15ml冰醋酸,冷却至16℃,缓慢加入5g亚硝酸钠的水溶液,室温搅拌6小时,TLC点板监控反应完全,静置分层,收集有机层,用饱和碳酸钾水溶液洗2遍,直接用于下步反应。
实施例3
化合物VI的合成
将11g化合物V加入到制备化合物IV所得的反应液中,保持体系温度为16℃,加入8g碳酸钾的水溶液,搅拌10小时,TLC点板监控反应完全,收集有机层,用醋酸水溶液洗2遍,再用饱和食盐水洗两遍,直接用于下步反应。
实施例4
化合物VII的合成
将化合物VI的反应液加入到150ml甲醇中,再加入35ml盐酸,室温搅拌4小时,TLC点板反应完全,静置分液,收集水层,加入碳酸钠至Ph=8,再加入乙酸乙酯萃取,收集有机层,加入无水硫酸钠干燥,过滤,减压浓缩。浓缩剩余物加入到120ml四氢呋喃中,加入18g四丁基氟化铵,室温搅拌过夜,TLC点板反应完全,加入水和乙酸乙酯萃取分液,收集有机层,加入无水硫酸钠干燥,过滤,减压浓缩。浓缩剩余物经层析硅胶柱分离得到5.6g黄色化合物VII,即替卡格雷,HPLC大于99.5%。
Claims (7)
1.一种如式I所示的化合物:
其中,R表示含硅原子的羟基保护基,如三甲基硅基,叔丁基二甲基硅基。
2.一种制备如式I所示的化合物的方法,在碱存在下,由化合物II与化合物III在溶剂中进行取代反应:
其中,化合物II中R表示含硅原子的羟基保护基,如三甲基硅基,叔丁基二甲基硅基。
3.根据权利要求2所述的方法,所述的取代反应所用的溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、四氢呋喃、乙醚、二氧六环、甲基叔丁基醚、二乙二醇二甲醚、二氯甲烷、氯仿、乙酸乙酯、乙酸异丙酯、丙酮、丁酮、苯、甲苯、二甲苯中的一种或几种的混合物。
4.根据权利要求2所述的方法,所述的取代反应的反应温度为室温至溶剂的回流温度。
5.根据权利要求2所述的方法,所述的取代反应所使用的碱为氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钙、氢氧化镁、碳酸钠、碳酸钾、三乙胺、二乙胺、二异丙胺中的一种或几种的混合物。
6.一种由中间体I制备替卡格雷的方法,包括以下步骤:
a)由化合物I与碱金属亚硝酸盐或有机亚硝酸盐发生环合反应制备得到化合物IV,化合物IV的结构式如下:
其中,化合物IV中的R表示含硅原子的羟基保护基,如三甲基硅基,叔丁基二甲基硅基。
b)由化合物IV与化合物V进行缩合反应,制得化合物VI,化合物VI结构式如下:
c)由化合物VI进行脱保护反应制备得到替卡格雷,结构如式VII所示,
7.一种如式II所示的化合物,
其中,R表示含硅原子的羟基保护基,如三甲基硅基,叔丁基二甲基硅基。
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