CN116396265A - 一种替卡格雷中间体的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims description 14
- PYEJQVYISBUGDU-UHFFFAOYSA-N 2-(3,4-difluorophenyl)cyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1C1=CC=C(F)C(F)=C1 PYEJQVYISBUGDU-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 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 18
- -1 ticagrelor intermediate compound Chemical class 0.000 claims abstract description 13
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 11
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 9
- 238000001308 synthesis method Methods 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- 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 claims description 9
- 229960002528 ticagrelor Drugs 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims 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 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000007529 inorganic bases Chemical group 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 239000003638 chemical reducing agent Substances 0.000 abstract description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 26
- 235000019270 ammonium chloride Nutrition 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 7
- 238000010791 quenching Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 239000012071 phase Substances 0.000 description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 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 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 201000011244 Acrocallosal syndrome Diseases 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 208000019905 acrocephalosyndactyly Diseases 0.000 description 1
- 206010051895 acute chest syndrome Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013176 antiplatelet therapy Methods 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- 229940086777 brilinta Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- YSNXOQGDHGUKCZ-UHFFFAOYSA-N n-benzylhydroxylamine;hydron;chloride Chemical class Cl.ONCC1=CC=CC=C1 YSNXOQGDHGUKCZ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于有机合成领域，具体涉及一种替卡格雷中间体化合物I的合成方法，包括以下步骤：
Description
技术领域
本发明涉及替卡格雷中间体的制备方法，属于有机合成领域。
背景技术
替卡格雷(通用名：Ticagrelor，商品名为BRILINTA)，化学名为(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-二氟苯基)环丙烷氨基]-5-(丙烷巯基)-3H-[1,2,3]三氮唑[4,5-d]吡啶-3-基]-5-(2-羟基乙烷氧)环戊烷-1,2-二醇。替卡格雷的分子量：522.57；CAS登记号：274693-27-5；结构式为如下所示：
替卡格雷由AstraZeneca AB研发。2015年9月FDA批准的一种血小板聚集抑制剂，替卡格雷在美国被批准用于ACS患者的抗血小板治疗。
由于替卡格雷结构巨大的市场潜力，迄今已有众多合成方法相继被开发出来。通过分析可以发现，无论选用何种合成路线，大多使用一种关键中间体N-[(3aS,4R,6S,6aR)-四氢-6-(2-羟基乙氧基)-2,2-二甲基-4H-环戊烯并-1,3-二氧杂环戊烷-4-基]氨基甲酸苯甲酯(化合物I)。
原研专利WO2001092263A1中报道了化合物I的制备方法，化合物III在叔丁醇钾的作用下在有机溶剂中与溴乙酸乙酯反应的得到化合物II，化合物II用硼氢化锂还原的到化合物I，一锅反应，两步反应收率为86％；WO2013023511A1公开了相同条件的反应，两步反应收率为41.9％，其具体合成路线如下：
专利WO2012142983A1中报道了化合物I的制备方法，专利中未公开反应收率纯度数据，其具体合成路线如下：
专利CN103539773B中报道了化合物I的制备方法，化合物III在有机溶剂中一锅反应得到化合物I,反应收率为25％，其具体合成路线如下：
综上所述，目前对替格瑞洛中间体N-[(3aS,4R,6S,6aR)-四氢-6-(2-羟基乙氧基)-2,2-二甲基-4H-环戊烯并-1,3-二氧杂环戊烷-4-基]氨基甲酸苯甲酯(化合物I)的合成已有较多研究报道，但均存在诸多缺陷，如合成步骤过长、合成工艺不稳定、收率低等，这些不利因素限制了替格瑞洛中间体N-[(3aS,4R,6S,6aR)-四氢-6-(2-羟基乙氧基)-2,2-二甲基-4H-环戊烯并-1,3-二氧杂环戊烷-4-基]氨基甲酸苯甲酯(化合物I)的工业化生产。
本发明提供了一种新颖的合成路线，该合成路线缩短了反应步骤，反应温和，收率高，安全性好，不需要柱层析，得到的产品质量好，非常适合工业化生产。
发明内容
本发明提供了一种替卡格雷中间体N-[(3aS,4R,6S,6aR)-四氢-6-(2-羟基乙氧基)-2,2-二甲基-4H-环戊烯并-1,3-二氧杂环戊烷-4-基]氨基甲酸苯甲酯(化合物I)的制备方法，该方法为一种全新合成路线且适合工业化生产。
本发明提供了一种替卡格雷中间体化合物I的合成方法，包括以下步骤：
化合物III和环氧乙烷，在催化剂四丁基溴化铵和碱作用下，经过开环反应得到化合物I。
进一步的，所述化合物III与四丁基溴化铵的摩尔投料比为1:0.01～2，优选1:0.03～1。
进一步的，所述碱选自无机碱或有机碱，所述无机碱选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯、碳酸锂或钠氢，优选为碳酸钠、碳酸钾；所述有机碱选自叔丁醇钠、叔丁醇钾、叔戊醇钠、甲醇钠、乙醇钠、乙醇钾、三乙胺、吡啶、二异丙基乙基胺或N，N-二甲基苯胺；优选为叔丁醇钠、叔丁醇钾、三乙胺、吡啶、二异丙基乙基胺或N，N-二甲基苯胺，更优选为叔丁醇钠、叔丁醇钾。
进一步的，所述化合物III与碱的摩尔投料比为1:1～5，优选1：1～3；
进一步的，所述化合物III与碱(例如碳酸钠、碳酸钾、叔丁醇钠、叔丁醇钾、三乙胺、吡啶、二异丙基乙基胺或N，N-二甲基苯胺)的摩尔投料比为1:1～5，优选1：1～3；
进一步的，所述化合物III与环氧乙烷的摩尔投料比为1:3～10，优选1：4～6；
进一步的，所述开环反应在有机溶剂进行，有机溶剂选自四氢呋喃、二氯甲烷、乙腈、二氧六环、2-甲基四氢呋喃、甲苯、N,N-二甲基甲酰胺、甲基叔丁基醚、乙醚、二甲亚砜或甲醇一种或其任意组合，优选甲苯；
进一步的，所述开环反应时间为1～24h，优选为1～6h；
进一步的，所述开环反应温度为-50～60℃，优选为-20～0℃。
进一步的，本发明可选择性地，反应完全，滴加氯化铵溶液淬灭反应，搅拌，静置分液，有机相浓缩制备得到化合物I。
本发明还提供一种替卡格雷的合成方法，包含使用上述一种替卡格雷中间体化合物I的合成方法制备化合物I。
本发明方法的优点主要在于：
1.本发明提供了一种一步反应合成替卡格雷中间体I的制备方法；
2.该合成路线：路线短，收率高，总收率可高达80％，避开了使用还原剂，无需过柱子处理，产品纯度高。
具体实施例
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件进行。
实施例中所用的原料或试剂除特别说明之外，均市售可得。
实施例中除非特别指出，所述的试剂不经纯化直接使用。所有溶剂均购自商业化供应商，例如奥德里奇(Aldrich)，并且不经处理就可使用。
实施例1
将100g的化合物III(0.325mol)，500g的甲苯，4.84g四丁基溴化铵(0.015mol)加入到反应釜中；氮气置换3次，降温-10～-15℃。控温-10～-15℃，分批加入55.05g叔丁醇钠和71.58g环氧乙烷，间隔0.5h；-10～-15℃搅拌反应2h。控温T≤0℃滴加氯化铵溶液(20.18g氯化铵+200g水)淬灭，搅拌0.5h。静置分液，有机相60℃下浓缩，得到94.55g化合物I，收率80.4％，纯度97.22％。
实施例2
将100g的化合物III(0.325mol)，500g的甲苯，4.84g四丁基溴化铵(0.015mol)加入到反应釜中；氮气置换3次，降温-10～-15℃。控温-10～-15℃，分批加入64.30g叔丁醇钾和71.58g环氧乙烷，间隔0.5h；-10～-15℃搅拌反应2h。控温T≤0℃滴加氯化铵溶液(20.18g氯化铵+200g水)淬灭，搅拌0.5h。静置分液，下层水相保留，有机相60℃下浓缩，得到93.75g化合物I，收率79.6％，纯度97.01％。
实施例3
将100g的化合物III(0.325mol)，500g的甲苯，4.84g四丁基溴化铵(0.015mol)加入到反应釜中；氮气置换3次，降温-10～-15℃。控温-10～-15℃，分批加入63.10g叔戊醇钠和71.58g环氧乙烷，间隔0.5h；-10～-15℃搅拌反应2h。控温T≤0℃滴加氯化铵溶液(20.18g氯化铵+200g水)淬灭，搅拌0.5h。静置分液，下层水相保留，有机相60℃下浓缩，得到63.31g化合物I，收率53.7％，纯度96.96％。
实施例4
将100g的化合物III(0.325mol)，500g的甲苯，4.84g四丁基溴化铵(0.015mol)加入到反应釜中；氮气置换3次，降温-10～-15℃。控温-10～-15℃，分批加入60.73g碳酸钠和71.58g环氧乙烷，间隔0.5h；-10～-15℃搅拌反应4h。控温T≤0℃滴加氯化铵溶液(20.18g氯化铵+200g水)淬灭，搅拌0.5h。静置分液，下层水相保留，有机相60℃下浓缩，得到48.02g化合物I，收率40.4％，纯度96.34％。
实施例5
将100g的化合物III(0.325mol)，500g的甲苯，4.84g四丁基溴化铵(0.015mol)加入到反应釜中；氮气置换3次，降温-10～-15℃。控温-10～-15℃，分批加入79.19g碳酸钾和71.58g环氧乙烷，间隔0.5h；-10～-15℃搅拌反应3h。控温T≤0℃滴加氯化铵溶液(20.18g氯化铵+200g水)淬灭，搅拌0.5h。静置分液，下层水相保留，有机相60℃下浓缩，得到49.16g化合物I，收率41.2％，96.20％。
实施例6
将100g的化合物III(0.325mol)，500g的甲苯，4.84g四丁基溴化铵(0.015mol)加入到反应釜中；氮气置换3次，降温-10～-15℃。控温-10～-15℃，分批加入55.05g叔丁醇钠和100.8g乙二醇，间隔0.5h；-10～-15℃搅拌反应2h。控温T≤0℃滴加氯化铵溶液(20.18g氯化铵+200g水)淬灭，搅拌0.5h。静置分液，下层水相保留，有机相60℃下浓缩，未得到目标化合物I。
Claims (10)
1.一种替卡格雷中间体化合物I的合成方法，包括以下步骤：
化合物III和环氧乙烷，在催化剂四丁基溴化铵和碱作用下，经过开环反应得到化合物I。
2.根据权利要求1所述的制备方法，其特征在于，所述化合物III与四丁基溴化铵的摩尔投料比为1:0.01～2，优选1:0.03～1。
3.根据权利要求1或2所述的制备方法，其特征在于，所述碱选自无机碱或有机碱，所述无机碱选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯、碳酸锂或钠氢，优选为碳酸钠、碳酸钾。
4.根据权利要求3所述的制备方法，其特征在于，所述有机碱选自叔丁醇钠、叔丁醇钾、叔戊醇钠、甲醇钠、乙醇钠、乙醇钾、三乙胺、吡啶、二异丙基乙基胺或N，N-二甲基苯胺；优选为叔丁醇钠、叔丁醇钾、三乙胺、吡啶、二异丙基乙基胺或N，N-二甲基苯胺，更优选为叔丁醇钠、叔丁醇钾。
5.根据权利要求1或2所述的制备方法，其特征在于，所述化合物III与碱的摩尔投料比为1:1～5，优选1：1～3。
6.根据权利要求1或2所述的制备方法，其特征在于，所述化合物III与环氧乙烷的摩尔投料比为1:3～10，优选1：4～6。
7.根据权利要求1或2所述的制备方法，其特征在于，所述开环反应在有机溶剂进行，有机溶剂选自四氢呋喃、二氯甲烷、乙腈、二氧六环、2-甲基四氢呋喃、甲苯、N,N-二甲基甲酰胺、甲基叔丁基醚、乙醚、二甲亚砜或甲醇一种或其任意组合，优选甲苯。
8.根据权利要求1或2所述的制备方法，其特征在于，所述开环反应时间为1～24h，优选为1～6h。
9.根据权利要求1或2所述的制备方法，其特征在于，所述开环反应温度为-50～60℃，优选为-20～0℃。
10.一种替卡格雷的合成方法，其特征在于，包含权利要求1或2所述的一种替卡格雷中间体化合物I的合成方法。
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