CN110092738B - 维格列汀的制备方法 - Google Patents
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- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 title claims abstract description 38
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种维格列汀的制备方法,通过在咪唑并噻唑作为手性配体和钯催化剂存在下,以丁烯二酸二乙酯和氨基保护的(S)‑3‑氨基‑3‑氰基‑丙酸乙酯为起始原料,经环合、脱保护、偶联等步骤,获得高产率高纯度的维格列汀产物,反应路线短,产率高,副产物少,降低了生产成本,有利于工业化生产。
Description
技术领域
本申请涉及一种治疗糖尿病的药物维格列汀的制备方法,属于西药合成领域。
背景技术
近年来糖尿病发病率逐年提高,糖尿病已成为继心血管类疾病恶性肿瘤后又一严重威胁人类健康的非传染性疾病。而糖尿病的II型发病率占90%,II型糖尿病的发病机制主要是因为人机体对胰岛素的抗性和胰岛素,细胞的功能缺陷所引发的。临床上用于II型糖尿病治疗药主要有胰岛素分泌促进剂,磺酰脲类、氯茴苯酸类、胰岛素增敏剂类、胰岛素及胰岛素受体激动剂和二肽基肽酶-4 抑制剂。
维格列汀(vildagliptin),化学名为(2S)-1-[[(3-羟基-1-金刚烷基)氨基]乙酰基)]-2-氰基-吡咯烷,是由诺华公司开发的一种强效选择性二肽基肽酶-抑制剂,用于II型糖尿病的治疗,化学结构式如下式所示。
维格列汀可以与磺酰脲类、吡格列酮、二甲双胍、胰岛素等药物联合用药,降血糖效果明显。维格列汀的开发前景良好,其合成工艺的研究引起了市场上的广泛关注。
维格列汀的的合成方法按照反应原料不同,可以分为三类。其一,以L-脯氨酰胺为原料,和氯乙酰氯反应,经取代反应和脱水缩合,再与3-氨基-1-羟基- 金刚烷反应,得到维格列汀,后续研发人员在此基础上多有改进,但总反应步骤长,收率较低;其二,以(S)-2-氰基-吡咯烷为反应原料,与酰氯和3-氨基-1- 羟基-金刚烷反应,得到维格列汀,该路线反应步骤短,操作方便,但(S)-2-氰基 -吡咯烷价格昂贵,生产成本较高;其三,以L-脯氨酸为原料,和氯乙酰氯反应,经取代反应、缩合反应、脱水反应,再与3-氨基-1-羟基-金刚烷反应,得到维格列汀,虽然步骤有所缩短,但产物纯度低,总收率不高。
为解决上述技术问题,本申请提供一种新的制备维格列汀的方法。基于第二种制备方法,利用有机小分子合成领域中钯催化剂与手性配体在环状手性化合物合成中的应用,通过不断筛选反应条件,发现在特定咪唑并噻唑配体和钯催化剂存在下,以丁烯二酸二乙酯和氨基保护的(S)-3-氨基-3-氰基-丙酸乙酯为起始原料,能够高产率、高选择性获得反应原料(S)-2-氰基-吡咯烷,进而降低了生产成本,有利于工业化生产。另外,重结晶过程进一步提升了产物纯度,获得的产品HPLC显示纯度大于99.9%。
发明内容
本发明要解决的技术问题是针对现有技术中,维格列汀反应路线较为繁琐,反应原料(S)-2-氰基-吡咯烷价格昂贵,产物纯度不高等问题。
为了解决上述技术问题,本发明提供的技术方案为:
一种维格列汀的合成方法,其合成路线如下:
具体反应过程包括:
在四氢呋喃中,加入丁烯二酸二乙酯和(S)-N-Boc-3-氨基-3-氰基-丙酸乙酯,在催化剂三氟乙酸钯和手性配体L1及醋酸铜存在下,通入空气,30-50℃下搅拌 3-5小时,TLC监测反应进程,待反应完毕,加水分层,有机相无水硫酸镁干燥过夜,减压浓缩,甲苯溶解,加入固体氢氧化钠,氮气保护下封管加热至180℃,反应10-12小时,冷至室温,过滤,减压除去溶剂,经柱层析,获得化合物 (S)-N-Boc-2-氰基-吡咯烷;
催化剂三氟乙酸钯和手性配体L1的摩尔用量是丁烯二酸二乙酯的0.5-5%;醋酸铜的摩尔用量是丁烯二酸二乙酯的1-3倍;丁烯二酸二乙酯和(S)-N-Boc-3- 氨基-3-氰基-丙酸乙酯的摩尔用量比为1-2:1;氢氧化钠的摩尔用量是 (S)-N-Boc-3-氨基-3-氰基-丙酸乙酯的1-5倍。
在二氯甲烷中,加入(S)-N-Boc-2-氰基-吡咯烷,1-3倍摩尔量的甲磺酸,加热至40℃-60℃,反应1-4小时,降至室温,加入蒸馏水,分液,有机相浓缩,经柱层析获得(S)-2-氰基-吡咯烷。
在二氯甲烷中,加入(S)-2-氰基-吡咯烷,1-2倍摩尔量的氯乙酰氯,1-3倍摩尔量的三乙胺,回流反应0.5-2小时,冷至室温,加入蒸馏水,分液,有机相浓缩,经柱层析得(S)-N-氯乙酰基-2-氰基-吡咯烷。
在二氯甲烷中,加入(S)-N-氯乙酰基-2-氰基-吡咯烷和1-1.5倍摩尔量的3- 氨基-1-羟基-金刚烷、1-3倍摩尔量的K2CO3,40℃-60℃下反应3-8小时,加入蒸馏水,分液,有机相浓缩,经柱层析,获得维格列汀。
将维格列汀粗品溶于二氯甲烷,滴加甲酸水溶液至体系pH为4-4.5,加热至40℃-50℃搅拌10-20分钟,分层,水相用碳酸钠水溶液调节pH至7.5-8,搅拌10-20分钟,二氯甲烷萃取,有机相浓缩,干燥,得纯品,HPLC纯度大于99.9%。
本发明的有益效果为:
本发明提供了一种全新的制备维格列汀的合成路线,反应路线较短,采用的原料更加廉价易得,降低了原料(S)-2-氰基-吡咯烷的成本,反应过程容易操作,各步骤产率高,降低了生产成本,重结晶过程显著提高了产物纯度,有利于工业化生产。
附图说明
图1为维格列汀的合成路线。
具体实施方式
本发明公开了一种维格列汀的制备方法,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。需要特别指出的是,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,并且相关人员明显能在不脱离本发明内容、精神和范围的基础上对本文所述内容进行改动或适当变更与组合,来实现和应用本发明技术。
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。
为了使本领域的技术人员更好地理解本发明的技术方案,下面结合具体实施例对本发明作进一步的详细说明。
实施例1:(S)-2-氰基-吡咯烷的制备
在150mL四氢呋喃中,加入8.25g(48mmol)丁烯二酸二乙酯和12.11g (50mmol)(S)-N-Boc-3-氨基-3-氰基-丙酸乙酯,在0.20g(0.6mmol)催化剂三氟乙酸钯和0.15g(0.8mmol)2-叔丁基咪唑并噻唑手性配体(L1)及17.01g (85mmol)醋酸铜存在下,通入空气,50℃下搅拌3小时,TLC监测反应进程,待反应完毕,加水分层,有机相无水硫酸镁干燥过夜,减压浓缩,50mL甲苯溶解,加入固体氢氧化钠4.37g,氮气保护下封管加热至180℃,反应10小时,冷至室温,过滤,减压除去溶剂,经柱层析,获得化合物(S)-N-Boc-2-氰基-吡咯烷8.93g(45.5mmol),产率为95%,e.e.>99.9%。
在120mL二氯甲烷中,加入8.93g(45.5mmol)(S)-N-Boc-2-氰基-吡咯烷, 5.77g(60mmol)甲磺酸,加热至回流,反应2小时,降至室温,加入蒸馏水,分液,有机相浓缩,经柱层析获得(S)-2-氰基-吡咯烷4.23g(44mmol),产率为 97%。
实施例2:(S)-2-氰基-吡咯烷的制备
在120mL四氢呋喃中,加入5.16g(30mmol)丁烯二酸二乙酯和7.99g (33mmol)(S)-N-Boc-3-氨基-3-氰基-丙酸乙酯,在0.17g(0.5mmol)催化剂三氟乙酸钯和0.33g(0.6mmol)2-叔丁基咪唑并噻唑手性配体(L1)及13.98g (70mmol)醋酸铜存在下,通入空气,40℃下搅拌5小时,TLC监测反应进程,待反应完毕,加水分层,有机相无水硫酸镁干燥过夜,减压浓缩,50mL甲苯溶解,加入固体氢氧化钠4.31g,氮气保护下封管加热至180℃,反应10小时,冷至室温,过滤,减压除去溶剂,经柱层析,获得化合物(S)-N-Boc-2-氰基-吡咯烷 5.63g(28.7mmol),产率为96%,e.e.>99.9%。
在100mL二氯甲烷中,加入5.63g(28.7mmol)(S)-N-Boc-2-氰基-吡咯烷, 3.17g(33mmol)甲磺酸,加热至回流,反应2小时,降至室温,加入蒸馏水,分液,有机相浓缩,经柱层析获得(S)-2-氰基-吡咯烷2.66g(27.7mmol),产率为97%。
实施例3:(S)-N-氯乙酰基-2-氰基-吡咯烷
在100mL二氯甲烷中,加入2.88g(30mmol)(S)-2-氰基-吡咯烷,4.08g (36mmol)氯乙酰氯,6.08g(60mmol)三乙胺,回流反应2小时,冷至室温,加入蒸馏水,分液,有机相浓缩,经柱层析得(S)-N-氯乙酰基-2-氰基-吡咯烷4.83g (28mmol),产率为93%。
实施例4:维格列汀的制备
在100mL二氯甲烷中,加入4.32g(25mmol)(S)-N-氯乙酰基-2-氰基-吡咯烷和4.68g(28mmol)3-氨基-1-羟基-金刚烷、6.91g(50mmol)K2CO3,回流反应5小时,加入蒸馏水,分液,有机相浓缩,经柱层析,获得维格列汀6.89g (22.7mmol),产率为91%,HPLC纯度98.8%。
实施例5:维格列汀的精制
将5.21g维格列汀粗品溶于80mL二氯甲烷,滴加甲酸水溶液至体系pH为 4.5,加热至45℃搅拌15分钟,分层,水相用碳酸钠水溶液调节pH至7.8,搅拌15分钟,二氯甲烷萃取,有机相浓缩,干燥,得纯品5.07g,HPLC纯度大于 99.9%。
实施例6:维格列汀的精制
将4.55g维格列汀粗品溶于50mL二氯甲烷,滴加甲酸水溶液至体系pH为 4.5,加热至50℃搅拌10分钟,分层,水相用碳酸钠水溶液调节pH至8.0,搅拌15分钟,二氯甲烷萃取,有机相浓缩,干燥,得纯品4.41g,HPLC纯度大于 99.9%。
Claims (7)
2.根据权利要求1所述维格列汀的制备方法,其特征在于:
在四氢呋喃中,加入丁烯二酸二乙酯和(S)-N-Boc-3-氨基-3-氰基-丙酸乙酯,在催化剂三氟乙酸钯和手性配体L1及醋酸铜存在下,通入空气,30-50℃下搅拌3-5小时,TLC监测反应进程,待反应完毕,加水分层,有机相无水硫酸镁干燥过夜,减压浓缩,甲苯溶解,加入固体氢氧化钠,氮气保护下封管加热至180℃,反应10-12小时,冷至室温,过滤,减压除去溶剂,经柱层析,获得化合物(S)-N-Boc-2-氰基-吡咯烷;
催化剂三氟乙酸钯和手性配体L1的摩尔用量是丁烯二酸二乙酯的0.5-5%;醋酸铜的摩尔用量是丁烯二酸二乙酯的1-3倍;丁烯二酸二乙酯和(S)-N-Boc-3-氨基-3-氰基-丙酸乙酯的摩尔用量比为1-2:1;氢氧化钠的摩尔用量是(S)-N-Boc-3-氨基-3-氰基-丙酸乙酯的1-5倍。
3.根据权利要求1所述维格列汀的制备方法,其特征在于:在二氯甲烷中,加入(S)-N-Boc-2-氰基-吡咯烷,1-3倍摩尔量的甲磺酸,加热至40℃-60℃,反应1-4小时,降至室温,加入蒸馏水,分液,有机相浓缩,经柱层析获得(S)-2-氰基-吡咯烷。
4.根据权利要求1所述维格列汀的制备方法,其特征在于:在二氯甲烷中,加入(S)-2-氰基-吡咯烷,1-2倍摩尔量的氯乙酰氯,1-3倍摩尔量的三乙胺,回流反应0.5-2小时,冷至室温,加入蒸馏水,分液,有机相浓缩,经柱层析得(S)-N-氯乙酰基-2-氰基-吡咯烷。
5.根据权利要求1所述维格列汀的制备方法,其特征在于:在二氯甲烷中,加入(S)-N-氯乙酰基-2-氰基-吡咯烷和1-1.5倍摩尔量的3-氨基-1-羟基-金刚烷、1-3倍摩尔量的K2CO3,40℃-60℃下反应3-8小时,加入蒸馏水,分液,有机相浓缩,经柱层析,获得维格列汀。
6.根据权利要求1所述维格列汀的制备方法,其特征在于:获得维格列汀产品后,还包含重结晶纯化步骤。
7.根据权利要求6所述维格列汀的制备方法,其特征在于:将维格列汀粗品溶于二氯甲烷,滴加甲酸水溶液至体系pH为4-4.5,加热至40℃-50℃搅拌10-20分钟,分层,水相用碳酸钠水溶液调节pH至7.5-8,搅拌10-20分钟,二氯甲烷萃取,有机相浓缩,干燥,得纯品,HPLC纯度大于99.9%。
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