CN107141236A - 替卡格雷中间体(1r,2r)‑2‑(3,4‑二氟代苯基)环丙烷腈的新合成方法 - Google Patents
替卡格雷中间体(1r,2r)‑2‑(3,4‑二氟代苯基)环丙烷腈的新合成方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/20—Preparation of carboxylic acid nitriles by dehydration of carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H13/06—Fatty acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
-
- 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
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- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开替卡格雷中间体(1R,2R)‑2‑(3,4‑二氟代苯基)环丙烷腈的新合成方法。将葡萄糖分子手性辅助试剂与(2E)‑3‑(3,4‑二氟苯基)丙烯酰氯进行酰胺化反应;然后与硫叶立德试剂进行还丙烷化反应,得到N‑葡萄糖基(1R,2R)‑2‑(3,4‑二氟苯基)环丙基甲酰胺;将N‑葡萄糖基(1R,2R)‑2‑(3,4‑二氟苯基)环丙基甲酰胺,在PPh3、CBr4、AgOTf和NH3水的作用下,进行β‑N‑糖苷化反应。该方法具有工艺路线较短、起始物料廉价易得,产率高,立体选择性和对映选择性好等特点,很大程度上降低了生产成本,在经济性方面更优秀。
Description
技术领域
本发明属于有机合成和化学医药制备技术领域,涉及一种(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的合成方法,具体是一种用于制备抗凝血药物替卡格雷的重要中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的合成方法。
技术背景
替卡格雷(Ticagrelor/Brilinta)是由阿斯利康公司研发的一种新型、小分子抗血凝药,是第一个可逆结合的、直接起效的、口服给药的血小板二磷酸腺苷P2Y12受体拮抗剂。新近发表的PLATO(43个国家862个中心进行的随机、双盲、多中心平行对照临床试验)结果显示,与氯吡格雷相比,替卡格雷使心血管死亡、心肌梗死或卒中组成的主要复合终点相对危险度显著降低16%,同时未增加主要安全性终点—大出血的发生率。尤其是替卡格雷停药后血小板功能很快得到恢复,用药更加灵活。因此,在欧洲心脏病协会公布的ESC2010年指南中,替卡格雷已被推荐(I级推荐,B类证据)作为氯吡格雷抵抗患者的重要替代治疗药。如今替卡格雷已在41个国家获准上市,并纳入其中7个国家的医疗补偿范围。据分析师预计,2015年之前该药的总销售额将达到20亿美元。在这种形势下,对替卡格雷及其相关的具有战略意义中间体的研发及产业化已成为业界关注的焦点。
如式IV所示的(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈是合成抗凝血药物替卡格雷的关键手性中间体,目前为止,已有文献报道(1R,2R)-2-(3,4-二氟苯基)环丙烷腈的合成路线主要有以下三种:第一种、以1,2-二氟苯为起始原料,通过酰化合、取代、还原、环丙烷化反应以及手性拆分获得目标化合物[WO,2013124280A1];第二种、樟脑锍叶立德camphor-derived sulfonium ylide与丙烯腈的环丙烷化反应,不对称合成[Kun Huang,Zhi-Zhen Huang,A Practical and Controllable Enantioselective Synthesis of 2-Phenyl-1-cyclopropanecarboxylates via a Camphor-Derived Sulfonium YlideSYNLETT 2005,10:1621–1623];第三种、以3,4-二氟苯甲醛为起始原料,通过缩合、环丙烷化反应及手性拆分获得目标化合物[WO2013144295A1]。
上述工艺路线经过数年的发展和改进,虽已成为目前(1R,2R)-2-(3,4-二氟苯基)环丙烷腈制备的主要方法,但还是存在其自身难以克服的缺点。主要体现在以下两点:1).制备成本较高。上述工艺路线存在路线较长、收率较低、手性产物需要拆分以及使用昂贵的手性物质为手性诱导中心等不足,这导致(1R,2R)-2-(3,4-二氟苯基)环丙烷腈的生产成本大大提高,且原有工艺路线技术改进的空间有限。2).制备过程环保性欠佳,原子经济性差。上述工艺路线中的副产品难于回收再利用、三废产生量大、生产过程环境污染大。因此,迫切需要发展及建立一种高效、环保、低成本替卡格雷关键手性中间体(1R,2R)-2-(3,4-二氟苯基)环丙烷腈的合成新方法。
随着人们对复杂手性分子对映体不同生理作用的深入了解,不对称合成的研究得到了迅速发展,目前已成为化学化工研究的热门领域之一。糖类是自然界大量存在、廉价、易得的天然产物,结构和种类丰富且对环境友好的有价值的手性源,糖分子结构中具有多个手性中心和官能团,通过选择性的羟基保护和去保护可以调控所在分子的电子云密度和空间结构排布,因此近年来糖作为天然手性源越来越多地受到化学家们的青睐。
发明内容
本发明的目的是针对现有技术的不足,对(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈合成工艺进行了更加深入的研究,并为其提供一种操作简单,产物收率高、反应立体选择性好、生产成本低和环境友好的不对称合成新方法。
本发明的目的在于公开了糖分子手性辅助试剂诱导新型抗血凝药物合成的关键手性中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈(IV)的合成方法。该制备方法包括以下步骤:
步骤(1)、将式I所示的葡萄糖分子手性辅助试剂与(2E)-3-(3,4-二氟苯基)丙烯酰氯溶于甲苯中,在碱A的作用下,一定温度下进行酰胺化反应,即得式II所示的葡萄糖基α,β-不饱和酰胺化合物,反应过程如下所示:
所述的碱A为三乙胺或吡啶,优选为吡啶;
作为优选,酰胺化反应中反应温度为60~65℃;
作为优选,酰胺化反应的反应时间为3~4h;
所述的葡萄糖分子手性辅助试剂、(2E)-3-(3,4-二氟苯基)丙烯酰氯、碱A的摩尔比为1:(1.1~1.2):(1.5~1.8);
步骤(2)、将步骤(1)得到的式II所示N-葡萄糖基α,β-不饱和酰胺化合物与硫叶立德试剂,以DMSO为溶剂,在碱B的作用下,在一定温度下进行还丙烷化反应,即得式III所示的N-葡萄糖基(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺,反应过程如下所示:
作为优选,环丙烷化反应溶剂为DMSO;
作为优选,环丙烷化反应碱B为NaH;
所述的环丙烷化反应中反应温度为0℃~20℃,优选15℃~20℃;
作为优选,环丙烷化反应的反应时间为4~6h;
所述的N-葡萄糖基α,β-不饱和酰胺化合物、锍叶立德、NaH的摩尔比为1:(1.2~1.5):(1.5~2.0);
步骤(3)、将步骤(2)得到的式III所示N-葡萄糖基(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺,在PPh3、CBr4、NH3水和AgOTf的作用下,进行β-N-糖苷化反应,即得式IV所示的(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈和I所示的葡萄糖分子手性辅助试剂。
作为优选,N-糖苷化反应的溶剂为无水乙腈;
作为优选,N-糖苷化反应的反应温度为20℃~25℃;
作为优选,N-糖苷化反应的的反应时间为10~16h;
所述的N-(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺、PPh3、CBr4、AgOTf和NH3水的摩尔比为1:2:3:2:2。
本发明通过对(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的合成方法进行了进一步的研究,发明了一种利用葡萄糖分子手性辅助试剂不对称合成(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新方法,该发明的方法与现有方法对比具有以下优点:
1)该方法具有工艺路线较短、起始物料廉价易得,产率高,立体选择性和对映选择性好等特点,很大程度上降低了生产成本,在经济性方面更优秀。
2)该方法反应条件温和,操作简便,产品及副产物易于分离纯化,改善了生产环境,适合规模化生产。
3)葡萄胺手性辅助试剂无需任何修饰即可回收再利用,环境友好。
具体实施方式
下面结合实施例进一步说明本发明,但不限制本发明。
首先,葡萄糖基α,β-不饱和酰胺化合物II的具体合成实施例如下:实施例1-1.N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(2E)-3-(3,4-二氟苯基)丙烯酰胺的合成
于500mL的四口瓶中依次加入N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]胺I(36.1g,0.02mol),甲苯(200mL)和吡啶(2.37g,0.03mol),置于0℃条件下,缓慢滴加(2E)-3-(3,4-二氟苯基)丙烯酰氯甲苯溶液(4.44g(2E)-3-(3,4-二氟苯基)丙烯酰氯溶于甲苯100mL),滴加完后升温至65℃并保温反应,TLC检测反应,反应结束后,冷却至室温,分别用5%的NaCl溶液,6%的NaHCO3溶液和纯化水洗涤,减压蒸馏得淡黄色固体38.83g。产品收率98.5%,HPLC含量99.5%。
实施例1-2.N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(2E)-3-(3,4-二氟苯基)丙烯酰胺的合成
于500mL的四口瓶中依次加入N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]胺I(36.1g,0.02mol),甲苯(200mL)和三乙胺(3.03g,0.03mol),置于0℃条件下,缓慢滴加(2E)-3-(3,4-二氟苯基)丙烯酰氯甲苯溶液(4.44g(2E)-3-(3,4-二氟苯基)丙烯酰氯溶于甲苯100mL),滴加完后升温至65℃并保温反应,TLC检测反应,反应结束后,冷却至室温,分别用5%的NaCl溶液,6%的NaHCO3溶液和纯化水洗涤,减压蒸馏得淡黄色固体37.64g。产品收率95.5%,HPLC含量99.0%。实施例1-3.N-(2,3,4,6-四-O-特戊酰基-β-D-吡喃葡萄糖基)-(2E)-3-(3,4-二氟苯基)丙烯酰胺的合成
于500mL的四口瓶中依次加入N-[2,3,4,6-四-O-特戊酰基-β-D-吡喃葡萄糖基]胺I(10.3g,0.02mol),甲苯(200mL)和吡啶(2.37g,0.03mol),置于0℃条件下,缓慢滴加(2E)-3-(3,4-二氟苯基)丙烯酰氯甲苯溶液(4.44g(2E)-3-(3,4-二氟苯基)丙烯酰氯溶于甲苯100mL),滴加完后升温至65℃并保温反应,TLC检测反应,反应结束后,冷却至室温,分别用5%的NaCl溶液,6%的NaHCO3溶液和纯化水洗涤,减压蒸馏得类白色固体13.35g。产品收率98.0%,HPLC含量99.6%。
实施例1-4.N-(2,3,4,6-四-O-特戊酰基-β-D-吡喃葡萄糖基)-(2E)-3-(3,4-二氟苯基)丙烯酰胺的合成
于500mL的四口瓶中依次加入N-[2,3,4,6-四-O-特戊酰基-β-D-吡喃葡萄糖基]胺I(10.3g,0.02mol),甲苯(200mL)和吡啶(2.84g,0.036mol),置于0℃条件下,缓慢滴加(2E)-3-(3,4-二氟苯基)丙烯酰氯甲苯溶液(0.024mol(2E)-3-(3,4-二氟苯基)丙烯酰氯溶于甲苯100mL),滴加完后升温至60℃并保温反应,TLC检测反应,反应结束后,冷却至室温,分别用5%的NaCl溶液,6%的NaHCO3溶液和纯化水洗涤,减压蒸馏得类白色固体13.28g。产品收率97.5%,HPLC含量99.5%。
然后利用上述任一实施例1-1~1-4制备得到的葡萄糖基α,β-不饱和酰胺化合物II用于合成葡萄糖基(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺III,具体实施例如下:
实施例2-1.N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺
N2保护下,于500ml四口瓶中加入三甲基碘化亚砜TMSOI(2.64g,0.012mol)和DMSO(100mL),加热搅拌溶清。然后降温至15℃,分批加入60%NaH(0.80g,0.02mol),加完后,控温15~20℃,将N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(2E)-3-(3,4-二氟苯基)丙烯酰胺DMSO溶液(19.71g N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(2E)-3-(3,4-二氟苯基)丙烯酰胺溶于80mL DMSO),缓慢滴加到上述四口瓶中,滴加完后保温反应,TLC检测约16h反应完成。反应结束后,将反应液缓慢加入到冷的饱和氯化铵溶液(200mL)中,再用乙酸乙酯(400mL)萃取,将有机层用饱和食盐水(2×200mL)洗涤两次,再用无水硫酸钠干燥,将有机层减压浓缩得粗产物,再经正己烷打浆便得17.46g浅黄色固体目标产物,收率为88.0﹪。
实施例2-2.N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺
N2保护下,于500mL四口瓶中加入三甲基碘化亚砜TMSOI(3.3g,0.015mol)和DMSO(100mL),加热搅拌溶清。然后降温至15℃,分批加入60%NaH(0.80g,0.02mol),加完后,控温15~20℃,将N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(2E)-3-(3,4-二氟苯基)丙烯酰胺DMSO溶液(19.71gN-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(2E)-3-(3,4-二氟苯基)丙烯酰胺溶于80mL DMSO),缓慢滴加到上述四口瓶中,滴加完后保温反应,TLC检测约16h反应完成。反应结束后,将反应液缓慢加入到冷的饱和氯化铵溶液(200mL)中,再用乙酸乙酯(400ml)萃取,将有机层用饱和食盐水(2×200mL)洗涤两次,再用无水硫酸钠干燥,将有机层减压浓缩得粗产物,再经正己烷打浆便得17.86g浅黄色固体目标产物,收率为90.0﹪。
实施例2-3.N-(2,3,4,6-四-O-特戊酰基-β-D-吡喃葡萄糖基)-(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺
N2保护下,于500mL四口瓶中加入三甲基碘化亚砜TMSOI(6.6g,0.03mol)和DMSO(100mL),加热搅拌溶清。然后降温至15℃,分批加入60%NaH(1.60g,0.04mol),加完后,控温15~20℃,将N-(2,3,4,6-四-O-特戊酰基-β-D-吡喃葡萄糖基)-(1R,2R)-2-(3,4-二氟苯基)丙烯酰胺DMSO溶液(13.62g N-(2,3,4,6-四-O-特戊酰基-β-D-吡喃葡萄糖基)-(1R,2R)-2-(3,4-二氟苯基)丙烯酰胺溶于80mL DMSO),缓慢滴加到上述四口瓶中,滴加完后保温反应,TLC检测约16h反应完成。反应结束后,将反应液缓慢加入到冷的饱和氯化铵溶液(200mL)中,再用乙酸乙酯(400mL)萃取,将有机层用饱和食盐水(2×200mL)洗涤两次,再用无水硫酸钠干燥,将有机层减压浓缩得粗产物,再经正己烷打浆便得12.18g类白色固体目标产物,收率为87.5﹪。
实施例2-4.N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺
N2保护下,于500mL四口瓶中加入三甲基碘化亚砜TMSOI(0.013mol)和DMSO(100mL),加热搅拌溶清。然后降温至15℃,分批加入60%NaH(0.015mol),加完后,控温0℃,将N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(2E)-3-(3,4-二氟苯基)丙烯酰胺DMSO溶液(19.71gN-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(2E)-3-(3,4-二氟苯基)丙烯酰胺溶于80mL DMSO),缓慢滴加到上述四口瓶中,滴加完后保温反应,TLC检测约16h反应完成。反应结束后,将反应液缓慢加入到冷的饱和氯化铵溶液(200mL)中,再用乙酸乙酯(400mL)萃取,将有机层用饱和食盐水(2×200mL)洗涤两次,再用无水硫酸钠干燥,将有机层减压浓缩得粗产物,再经正己烷打浆便得17.56g浅黄色固体目标产物,收率为88.5﹪。
然后利用上述任一实施例2-1~2-4制备得到的N-葡萄糖基-(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺III用于合成(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈IV,具体实施例如下:
实施例3-1.
氩气保护下,于500mL四口瓶中依次加入N-(2,3,4,6-四-O-特戊酰基-β-D-吡喃葡萄糖基)-(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺(13.91g,0.02mol)、PPh3(10.48g,0.04mol)和无水乙腈200mL,搅拌溶清,接着室温下缓慢滴加CBr4的乙腈溶液(19.8g CBr4溶于100mL乙腈),滴加完后20℃保温反应4小时,接着加入浓氨水(70mL)和AgOTf的乙腈溶液(AgOTf 10.27g溶于50mL乙腈),加完后继续保温反应6-16h。反应结束后过滤去除沉淀并加入二氯甲烷100mL。所得溶液经盐酸水溶液洗涤、静置分层,有机层经无水Na2SO4干燥,减压蒸馏得3.40g无色油状产物IV,收率为95.0%。产品经过结构确认,为我们的目标产物。水层经NaOH调至碱性,二氯甲烷萃取、无水Na2SO4干燥产减压蒸去溶剂,再经正己烷重结晶得19.78g白色固体产物I,回收率为96.0%,可直接再利用。
实施例3-2.
氩气保护下,于500mL四口瓶中依次加入N-[2,3,4,6-四-O-(3,4,5-三苄氧基)苯甲酰基-β-D-吡喃葡萄糖基]-(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺(39.70g,0.02mol)、PPh3(10.48g,0.04mol)和无水乙腈200mL,搅拌溶清,接着室温下缓慢滴加CBr4的乙腈溶液(19.8g CBr4溶于100mL乙腈),滴加完后25℃保温反应4小时,接着加入浓氨水(70mL)和AgOTf的乙腈溶液(AgOTf 10.27g溶于50mL乙腈),加完后继续保温反应6-16h。反应结束后过滤去除沉淀并加入二氯甲烷100mL。所得溶液经盐酸水溶液洗涤、静置分层,有机层经无水Na2SO4干燥,减压蒸馏得3.44g无色油状产物IV,收率为96.0%。产品经过结构确认,为我们的目标产物。水层经NaOH调至碱性,二氯甲烷萃取、无水Na2SO4干燥产减压蒸去溶剂,再经正己烷重结晶得34.47g白色固体产物I,回收率为95.5%,可直接再利用。
Claims (10)
1.替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于该方法包括以下步骤:
步骤(1)、将式I所示的葡萄糖分子手性辅助试剂与(2E)-3-(3,4-二氟苯基)丙烯酰氯溶于甲苯中,在碱A的作用下,一定温度下进行酰胺化反应,即得式II所示的葡萄糖基α,β-不饱和酰胺化合物,反应过程如下:
步骤(2)、将步骤(1)得到的式II所示N-葡萄糖基α,β-不饱和酰胺化合物与硫叶立德试剂,以DMSO为溶剂,在碱B的作用下,一定温度下进行还丙烷化反应,即得式III所示的N-葡萄糖基(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺,反应过程如下:
步骤(3)、将步骤(2)得到的式III所示N-葡萄糖基(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺,在PPh3、CBr4、NH3水和AgOTf的作用下,进行β-N-糖苷化反应,即得式IV所示的(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈和I所示的葡萄糖分子手性辅助试剂:
2.如权利要求1所述的替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于步骤(1)所述的碱A为三乙胺或吡啶;步骤(2)环丙烷化反应碱B为NaH。
3.如权利要求2所述的替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于步骤(1)所述的碱A为吡啶。
4.如权利要求1所述的替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于步骤(1)酰胺化反应中反应温度为60~65℃,反应时间为3~4h;步骤(2)所述的环丙烷化反应中反应温度为0℃~20℃,反应时间为4~6h。
5.如权利要求1所述的替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于步骤(1)所述的葡萄糖分子手性辅助试剂、(2E)-3-(3,4-二氟苯基)丙烯酰氯、吡啶的摩尔比为1:1.1~1.2:1.5~1.8。
6.如权利要求4所述的替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于步骤(2)所述的环丙烷化反应中反应温度为15℃~20℃。
7.如权利要求1所述的替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于步骤(2)所述的N-葡萄糖基α,β-不饱和酰胺化合物、锍叶立德、NaH的摩尔比为1~1.2~1.5:1.5~2.0。
8.如权利要求1所述的替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于步骤(3)N-糖苷化反应的溶剂为无水乙腈。
9.如权利要求1所述的替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于步骤(3)N-糖苷化反应的反应温度为20℃~25℃,反应时间为10~16h。
10.如权利要求1所述的替卡格雷中间体(1R,2R)-2-(3,4-二氟代苯基)环丙烷腈的新合成方法,其特征在于步骤(3)所述的N-(1R,2R)-2-(3,4-二氟苯基)环丙基甲酰胺、PPh3、CBr4、NH3水和AgOTf的摩尔比为1:2:3:2:2。
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