CN104592309B - 一种手性氨基酸的制备方法 - Google Patents
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/04—Nickel compounds
- C07F15/045—Nickel compounds without a metal-carbon linkage
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
本发明涉及一种制备化合物(OMLT‑01)的方法,其包括:在酰胺溶剂中,化合物(OMLT‑A)与氢氧化钠溶液混合,冷却至0‑10℃,滴加氯丙炔进行亲核取代反应
Description
技术领域
本发明涉及药物化学领域,具体涉及一种L-炔丙基甘氨酸的制备方法。
背景技术
Omarigliptin是一种每周一次的DPP-4抑制剂,开发用于2型糖尿病的治疗。在今年9月公布的首个III期临床中,Omarigliptin疗效媲美默沙东自身热销的每日一次口服糖尿病药物Januvia(捷诺维,sitagliptin,西他列汀)。
PCT申请WO2010056708报道了Omarigliptin的合成方法,化合物OMLT03是其中一个关键的中间体,其结构如下所示:
现有技术如Tetrahedron:Asymmetry,9(12),2121-2131;1998等报道了化合物OMLT03的制备方法,但存在如下缺点:或存在使用试剂污染大,或存在无手性,或存在成本高的缺陷,针对这些问题,我们提出了一个成本较低,且关键物料能回收利用的新方案,解决环境污染问题,及成本高问题,同时直接构建目标手性氨基酸。
发明内容
本发明一方面提供一种制备化合物OMLT01的方法,
其包括:在酰胺溶剂中,化合物OMLT-A与氢氧化钠溶液混合,冷却至0-10℃,滴加氯丙炔进行亲核取代反应,
所述酰胺溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、或组合。
所述氢氧化钠溶液的浓度为25%wt至45%wt,在某些实施例中,氢氧化钠溶液的浓度为约35%wt。
在一些实施例中,所述制备化合物OMLT01的方法,其包括:室温下,将5g化合物OMLT-A加入30ml的N,N-二甲基甲酰胺,搅拌,加入约35%wt的氢氧化钠溶液,冷却至-10℃,缓慢滴加1.05g氯丙炔,滴加完毕后继续反应1小时至24h。
在一些实施例中,所述的亲核取代反应,反应结束后,向反应液中加入50ml冰水,-10℃下保温2h,过滤并洗涤固体,干燥,得到浅红色固体。
本发明另一方面提供一种化合物OMLT01的水解方法,其包括:室温下,化合物OMLT01与甲醇、水以及浓盐酸混合,将混合物升温至60至70℃,反应1小时至24h。
在一个实施方案中,所述的水解方法,其包括:室温下,将150g化合物OMLT01与400ml甲醇、61.6ml水以及112g浓盐酸混合,将混合物升温至65℃进行水解反应。
在一个实施方案中,水解反应结束后,将反应液降至室温,加入螯合剂,45℃下减压蒸干有机溶剂,得到一浓缩物,加入二氯甲烷和水、搅拌,用20%wt的氢氧化钠溶液调节pH值至9-10,分液,水相用二氯甲烷萃取两次,得到含有化合物OMLT02的水溶液,合并上步二氯甲烷溶液,于室温下搅拌,缓慢滴加浓盐酸,于0.5h滴加完毕,滴加完毕后于室温下继续搅拌3-5h,析出化合物OMLT02-01固体,
所述的螯合剂为乙二胺四乙酸二钠、乙二胺、2,2'-联吡啶、1,10-邻二氮杂菲或草酸根,在某些实施例中,所述的螯合剂为乙二胺四乙酸二钠。
所述二氯甲烷和水,其体积比为2:1-1:1。
在一个实施方案中,室温下,往含有化合物OMLT02的水溶液中,缓慢滴加Boc酸酐,约1-2h滴加完毕,滴加完毕反应16-24h,得到化合物OMLT03,
在一个实施方案中,所述化合物OMLT02的水溶液其pH为9-10,反应过程中,保持反应液的pH为9-10,当pH低于9时,添加氢氧化钠溶液,确保反应液的pH为9-10。
在一个实施方案中,.反应完毕后,加入二氯甲烷萃取两次,水相降温至10-20℃,用30%硫酸氢钠调节pH至3-5,然后水相再用二氯甲烷萃取两次,合并有机相,35℃真空除去溶剂,得到化合OMLT03。
本发明取得以下有益效果:
1.针对重金属污染问题,我们采用镍配体作为起始物料,虽然也引进了重金属,但是我们采用EDTA络合重金属后,脱掉的(S)-N-(2-苯甲酰基-4-氯苯基)-1-苄基吡咯-2-甲酰胺可以回收再利用,进一步降低成本。
2.文献中大多采用溴丙炔或其他试剂来合成氨基酸,其成本相对较高,本技术采用氯丙炔,其价格和毒副性均比溴丙炔小很多。
3.亲核取代反应采用酰胺溶剂,优选N,N-二甲基甲酰胺作为溶剂可以提高立体选择性,减少副反应,原料反应彻底,从而提高收率和纯度。
本发明上下文中,所述反应完毕是指采用TLC监测反应原料点消失或采用高效液相(HPLC)监控反应终点,原料的HPLC纯度小于或等于1.0%时即视为反应完毕,反应时间通常在12小时以下。
本发明上下文中,术语“室温”是指事物所处位置周围的自然温度,所述环境温度可以依据所处地区、所处季节、所处时间有所不同,一般在-20℃-45℃之间或在大约18℃-30℃,或大约20℃-25℃或大约22℃。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案,下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得,化合物OMLT-A按照Tetrahedron:Asymmetry,9(12),2121-2131;1998的方法制备。
本发明中,DCM表示二氯甲烷,Boc表示叔丁氧羰基。
实施例1化合物OMLT01的制备
1.0.57g氢氧化钠加入1ml水溶解后冷却至室温待用;
2.室温下,5.00g化合物OMLT-A加入30ml的表一所示的溶剂、搅拌,加入上述氢氧化钠溶液,冷却至-10℃,缓慢滴加1.05g氯丙炔,滴加完毕后继续反应1-2h,取样送HPLC检测,当化合物OMLT-A的含量(峰面积)小于1.0%时,视为反应完毕;
3.反应完毕后加入50ml冰水,-10℃下保温2h,过滤并洗涤产品,干燥,得到浅红色固体,收率90%以上。
表一:在不同溶剂中反应的HPLC检测结果
其中,OMLT-A、异构体和二取代的结构分别如下式所示:
实施例2化合物OMLT02的合成
1.室温下,150.00g OMLT01加入400ml甲醇61.6ml水以及112.00g盐酸溶液。
2.升温至65℃反应3-5h。
3.降至室温,加入119.00gEDTA·4Na·4H2O,45℃减压蒸干有机溶剂。
4.加入150ml水,260ml DCM搅拌,用20%氢氧化钠溶液调节pH值至9-10,分液,水相用210ml DCM萃取两次,确保水相pH值=9-10,得到化合物OMLT02水溶液待用。
化合物OMLT02-01配体回收方案:
合并上步DCM溶液,于室温下搅拌,缓慢滴加41.15g 36%盐酸溶液,于0.5h滴加完毕,滴加完毕后于室温下继续搅拌3-5h。抽滤,滤饼用适量DCM洗涤,干燥得到类白色固体,收率80%以上,纯度99.90%。
实施例3化合物OMLT03的合成:
1.确保实施例2得到的化合物OMLT02水溶液pH=9-10,于室温下缓慢滴加79.80gBoc酸酐,约1-2h滴加完毕,滴加完毕反应16-24h,反应过程中确保pH=9-10。
2.反应完毕,加入260ml DCM萃取,再用150ml DCM萃取,水相降温至10-20℃,用30%硫酸氢钠调节PH=3-5,加入300ml DCM萃取,水相再用200ml DCM萃取,合并有机相,35℃真空除去溶剂,得到浅黄色油状物,收率85%。
本发明的方法已经通过较佳实施例进行了描述,相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。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内。
Claims (5)
1.一种制备化合物OMLT01的方法,
其包括:室温下,将5g化合物OMLT-A加入30ml的N,N-二甲基甲酰胺,搅拌,加入氢氧化钠溶液,该氢氧化钠溶液由0.57g氢氧化钠溶于1ml水制备获得,体系冷却至-10℃,缓慢滴加1.05g氯丙炔,滴加完毕后继续反应1.5小时,取样送HPLC检测,当化合物OMLT-A的含量小于1%时,视为反应完毕;反应完毕后加入50ml冰水,-10度下保温搅拌2h,过滤并洗涤产品,干燥,得到浅红色固体。
2.一种化合物OMLT01的水解方法,其包括以下步骤:
a)根据权利要求1所述的制备化合物OMLT01的方法制备获得OMLT01;
b)将步骤a)中制备获得的OMLT01与甲醇、水以及浓盐酸混合,将混合物升温至60至70℃,反应1h至24h。
3.根据权利要求2所述的水解方法,其包括:室温下,将150g化合物OMLT01与400ml甲醇、61.6ml水以及112g浓盐酸混合,将混合物升温至65℃进行水解反应。
4.根据权利要求2所述的水解方法,水解反应结束后,将反应液降至室温,加入螯合剂,45℃下减压蒸干有机溶剂,得到一浓缩物,加入二氯甲烷和水、搅拌,用20%wt的氢氧化钠溶液调节pH值至9-10,分液,水相用二氯甲烷萃取两次,得到含有化合物OMLT02的水溶液,合并上步二氯甲烷溶液,于室温下搅拌,缓慢滴加浓盐酸,于0.5h滴加完毕,滴加完毕后于室温下继续搅拌3-5h,析出化合物OMLT02-01固体,
所述的螯合剂为乙二胺四乙酸二钠、乙二胺、2,2'-联吡啶、1,10-邻二氮杂菲或草酸根,或者为乙二胺四乙酸二钠,所述二氯甲烷和水,其体积比为2:1-1:1。
5.一种制备化合物OMLT03的方法,包括:根据权利要求4所述的水解方法,得到含有OMLT02的水溶液;然后在室温下,往所得含有化合物OMLT02的水溶液中,缓慢滴加Boc酸酐,1-2h滴加完毕,滴加完毕,反应16-24h,得到化合物OMLT03,
反应过程中,保持反应液的pH为9-10。
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