CN113563318A - 一种恩格列净的合成方法 - Google Patents
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
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- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种恩格列净的合成方法。该方法采用(S)‑3‑(4‑(5‑溴‑2‑氯苄基)苯氧基)四氢呋喃为起始原料,在Pd2(dba)3催化下,在对甲苯磺酰肼、Xphos和叔丁醇锂共同作用下与2,3,4,6‑四苄基‑D‑吡喃葡萄糖酸‑1,5‑内酯偶联生成中间体I,中间体I经雷尼镍加氢还原双键同时脱苄基得到恩格列净。该方法不需丁基锂、格式试剂等危险物料,反应路线短,反应及后处理简单,安全性高,副反应少,产品收率高,纯度高,特别适合于工业化生产。
Description
技术领域
本发明涉及一种恩格列净的合成方法,属于有机合成技术领域。
背景技术
恩格列净是由勃林格殷格翰和礼来共同开发的一款新型、口服、高选择性钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂,可以选择性地抑制肾脏近曲小管上皮细胞膜管腔侧的SGLT-2,减少葡萄糖重吸收并促进尿糖排泄,进而发挥降低血糖的作用。恩格列净于2014年5月22日首先获得欧洲药物管理局(EMA)批准上市,又在2014年8月1日获得FDA批准,之后2017年9月27日恩格列净(国内商品名为欧唐静)获原国家食药监总局批准上市。凭借显著的降糖效果以及心血管效果获益,自上市以来,恩格列净的销售额快速增长,2019年,恩格列净全球销售额达到33.54亿美元,2020年达38.5亿美元,显示出强大的市场潜力和增长空间。
恩格列净,化学名称:(1S)-1,5-脱水-1-(4-氯-3-{4-[(3S)-四氢呋喃-3-氧基]苄基}苯基]-D-葡萄糖醇,分子量450.91,结构式如下所示。
关于恩格列净的合成,目前已有多篇文献及专利报道,其难点在于关键中间体与葡萄糖内酯的偶联,具体合成方法如下:
合成路线1:专利WO2006120208A以(3S)-3-[4-[(5-溴-2-氯苯基)甲基]苯氧基]四氢呋喃或者(3S)-3-[4-[(5-碘-2-氯苯基)甲基]苯氧基]四氢呋喃为原料,在无水无氧-75℃左右的超低温条件下先与正丁基锂或格式试剂反应,然后与TMS保护的葡萄糖酸内酯偶联,偶联产物经甲磺酸催化下与甲醇反应,在苄位引入甲氧基,然后经三乙基硅烷还原得到粗品后引入乙酰基纯化,最后水解得到产品。目前大部分国内外专利和文献都采用了该路线类似的方法。
该路线具有以下缺点:(1)路线较长:(2)使用正丁基锂、正丁基氯化镁等物质,使用条件极其苛刻需严格无水无氧,又极具有危险性;(3)该反应需要极低的温度来保证内酯不会开环,TMS保护基不稳定,且该路线可能有差向异构体杂质的生成,导致反应收率低;(4)后续需要引入乙酰基等保护基提高产品的结晶性加以纯化,反应操作繁琐且产业化过程中产品质量不易控制。
合成路线2:专利CN105399735A以特戊酰基保护的溴代吡喃葡萄糖与(3S)-3-[4-[(5-碘-2-氯苯基)甲基]苯氧基]四氢呋喃进行对接,一步得到恩格列净的特戊酸酯衍生物,经水解得到恩格列净,极大的缩短合成路线。但是该方法存在以下不足:(1)仍然需要使用正丁基锂拔除卤素,反应要求苛刻,操作不便;(2)所用有机锌试剂需要在280℃的高温下活化,使用不便;(3)使用的溴代吡喃葡萄糖成本很高,限制了该方法的应用。
合成路线3:专利CN102574829A和CN101193903A以(3S)-3-[4-[(5-碘-2-氯苯基)甲基]苯氧基]四氢呋喃为原料,采用异丙基氯化镁/氯化锂经格式交换后与TMS保护的葡萄糖酸内酯偶联,HCl催化下引入甲氧基,最后经三乙基硅烷还原得到产品。该反应路线较短,反应温度提高到-15℃,比较适合工业化生成,但是异丙基氯化镁/氯化锂等格式试剂使用条件苛刻,危险性较高,且引入甲氧基之前需要10%柠檬酸淬灭反应,并用甲苯除去体系中的水分,操作繁琐。
合成路线4:专利CN106905305A以(3S)-3-[4-[(5-溴-2-氯苯基)甲基]苯氧基]四氢呋喃或者(3S)-3-[4-[(5-碘-2-氯苯基)甲基]苯氧基]四氢呋喃为原料,与葡萄糖内酯衍生物反应,在碱的作用下水解得到产物。该路线较短,收率较高,但是偶联时依然采用格式试剂或丁基锂,操作条件苛刻,危险性较高;所用葡萄糖内酯衍生物价格高不易制得,产品成本很高,不适合工业化生产。
合成路线5:专利CN112194655A以镁屑和(3S)-3-[4-[(5-碘-2-氯苯基)甲基]苯氧基]四氢呋喃为原料,加碘引发反应制得格式试剂,再与TMS保护的葡萄糖酸内酯偶联,滴加HCl-甲醇溶液得到甲氧基产物,再经还原得到产品。此路线较短,杂质含量较少,但是自己做格式试剂危险性很高,破解时需要-30℃以下的低温,且依然存在格式试剂使用条件苛刻,危险性高的问题,不适宜工业化生产。
合成路线6:专利CN106117192A以2,3,4,6-四苄基-D-吡喃葡萄糖酸-1,5-内酯和对氯碘苯为原料,在-78℃下用正丁基锂拔碘后反应得到偶联物,经还原脱掉羟基,然后与多聚甲醛,(S)-3-苯氧基四氢呋喃反应得到苄基保护的恩格列净,最后经钯炭或氢氧化钯加氢脱除苄基得到产品。该路线较短,收率高,但是偶联时依然采用正丁基锂,操作条件苛刻,危险性很高,且采用昂贵的钯炭或氢氧化钯脱苄基的同时产生大量脱氯杂质,导致产品纯度不高。
发明内容
本发明克服了上述现有技术的不足,提供了一种恩格列净的合成方法。该方法采用(S)-3-(4-(5-溴-2-氯苄基)苯氧基)四氢呋喃为起始原料,在Pd2(dba)3催化下,在对甲苯磺酰肼、Xphos和叔丁醇锂共同作用下与2,3,4,6-四苄基-D-吡喃葡萄糖酸-1,5-内酯偶联生成中间体I,中间体I经雷尼镍加氢还原双键同时脱苄基得到恩格列净。该方法不需丁基锂、格式试剂等危险物料,反应路线短,反应及后处理简单,安全性高,副反应少,产品收率高,纯度高,特别适合于工业化生产。
本发明的技术方案是:一种恩格列净的合成方法,其特征是,包括以下步骤:
1)(S)-3-(4-(5-溴-2-氯苄基)苯氧基)四氢呋喃在Pd2(dba)3催化下,在对甲苯磺酰肼、XPhos和叔丁醇锂的共同作用下与2,3,4,6-四苄基-D-吡喃葡萄糖酸-1,5-内酯偶联生成中间体I;
2)中间体I经雷尼镍加氢还原双键,脱苄基得到恩格列净。
反应方程式如下所示:
备注:Pd2(dba)3:三(二亚苄基丙酮)二钯;Xphos:2-二环己基磷-2',4',6'-三异丙基联苯;t-BuOLi:叔丁基醇锂;TosNHNH2:对甲苯磺酰肼。
优选的,所述步骤1)的反应温度为80~110℃;步骤2)在压力0.7~0.9Mpa,温度60~80℃下进行反应。
优选的,所述步骤1)采用的反应溶剂为二氧六环、2-甲基四氢呋喃中的一种或二种的混合溶剂,更优选为二氧六环。
优选的,所述步骤2)的反应溶剂为甲醇、乙醇、异丙醇中的一种或多种的混合溶剂,更优选为异丙醇。
具体包括以下步骤:
1)氮气保护下,将(S)-3-(4-(5-溴-2-氯苄基)苯氧基)四氢呋喃、Pd2(dba)3、对甲苯磺酰肼,Xphos、叔丁醇锂和2,3,4,6-四苄基-D-吡喃葡萄糖酸-1,5-内酯加入到反应溶剂中,控温80~110℃,反应20~24h,经后处理得到中间体I;
2)氮气保护下,将中间体I和雷尼镍加入到反应溶剂中,氮气置换,通入氢气,保持压力0.7~0.9Mpa,温度60~80℃反应18~20h,经后处理得到恩格列净。
进一步的,所述步骤1)的后处理为:加水淬灭后,经萃取、洗涤、干燥、减蒸得到中间体I。其中萃取溶剂为:异丙醚、甲基叔丁基醚、二氯甲烷、乙酸乙酯中的一种或多种的混合溶剂,更优选为甲基叔丁基。
进一步的,所述步骤2)的后处理为:降温,滤除雷尼镍,减蒸至干,加溶剂重结晶,降至-5~0℃析晶,抽滤,烘干,得到恩格列净。其中重结晶用溶剂为:甲醇、乙醇、乙酸乙酯、醋酸异丙酯和异丙醇中的一种或多种的混合溶剂,更优选为乙醇。
优选的,所述步骤1)(S)-3-(4-(5-溴-2-氯苄基)苯氧基)四氢呋喃与2,3,4,6-四苄基-D-吡喃葡萄糖酸-1,5-内酯的摩尔投料比为1:1~1.5。
优选的,所述步骤1)(S)-3-(4-(5-溴-2-氯苄基)苯氧基)四氢呋喃与对甲苯磺酰肼、Xphos、Pd2(dba)3和叔丁醇锂的摩尔投料比为1:1~1.5:0.03~0.05:0.005~0.007:2.5~3.5。
优选的,所述步骤2)以中间体I的使用量计,雷尼镍的使用量为1-6%,优选5%。
本发明的有益效果是:该方法不需丁基锂、格式试剂等危险物料,反应路线短,反应及后处理简单,安全性高,副反应少,产品收率高(≥83%),纯度高(≥99.5%),特别适合于工业化生产。
具体实施方式
以下实施例是对本发明的进一步说明,但是本发明并不局限于此。
实施例1:
在500ml单口瓶中,依次加入对甲苯磺酰肼9.8g、Xphos 787mg、Pd2(dba)3 265mg、叔丁醇锂9.6g、2,3,4,6-四苄基-D-吡喃葡萄糖酸-1,5-内酯27.9g、(S)-3-(4-(5-溴-2-氯苄基)苯氧基)四氢呋喃15.2g、二氧六环350ml,氮气气保护下加热至110℃反应20h,加水200ml淬灭反应,甲基叔丁基醚300ml稀释分层,取甲基叔丁基醚层,水相继续萃取两次,合并萃取液,饱和食盐水洗,硫酸镁干燥,过滤,蒸干得30.3g中间体I,收率91.0%,纯度98.5%。
氮气保护下将30.3g中间体I,1.5g雷尼镍,300ml异丙醇加入到1L高压釜中,氮气置换3次,通入氢气,搅拌保持压力0.8~0.9Mpa,温度75~80℃反应18h,降温至30℃以下,滤除雷尼镍,减蒸至干,加入45ml乙醇重结晶,降至-5~0℃,析晶1h,抽滤,烘干得到产品15.7g,收率93.0%,纯度99.6%。
实施例2:
在500ml单口瓶中,依次加入对甲苯磺酰肼10.2g、Xphos 791mg、Pd2(dba)3 266mg、叔丁醇锂10.3g、2,3,4,6-四苄基-D-吡喃葡萄糖酸-1,5-内酯27.9g、(S)-3-(4-(5-溴-2-氯苄基)苯氧基)四氢呋喃15.2g、2-甲基四氢呋喃400ml,氮气气保护下加热至80℃反应20h,加水200ml淬灭反应,乙酸乙酯250ml稀释分层,取乙酸乙酯层,水相继续萃取两次,合并萃取液,饱和食盐水洗,硫酸镁干燥,过滤,蒸干得29.5g中间体I,收率88.6%,纯度98.7%。
氮气保护下将29.5g中间体I,1.5g雷尼镍,300ml乙醇加入到1L高压釜中,氮气置换3次,通入氢气,搅拌保持压力0.8~0.9Mpa,温度75~80℃反应20h,降温至30℃以下,滤除雷尼镍,减蒸至干,加入50ml醋酸异丙酯重结晶,降至-5~0℃,析晶1h,抽滤,烘干得到产品15.4g,收率93.7%,纯度99.4%。
Claims (10)
2.如权利要求1所述的一种恩格列净的合成方法,其特征是,所述步骤1)的反应温度为80~110℃。
3.如权利要求1所述的一种恩格列净的合成方法,其特征是,所述步骤2)在压力0.7~0.9Mpa,温度60~80℃下进行反应。
4.如权利要求1所述的一种恩格列净的合成方法,其特征是,所述步骤1)的反应溶剂为二氧六环、2-甲基四氢呋喃中的一种或二种的混合溶剂。
5.如权利要求1所述的一种恩格列净的合成方法,其特征是,所述步骤2)的反应溶剂为甲醇、乙醇、异丙醇中的一种或多种的混合溶剂。
6.如权利要求1-5中任一项所述的一种恩格列净的合成方法,其特征是,具体包括以下步骤:
1)氮气保护下,将(S)-3-(4-(5-溴-2-氯苄基)苯氧基)四氢呋喃、Pd2(dba)3、对甲苯磺酰肼,Xphos、叔丁醇锂和2,3,4,6-四苄基-D-吡喃葡萄糖酸-1,5-内酯加入到反应溶剂中,控温80~110℃,反应20~24h,经后处理得到中间体I;
2)氮气保护下,将中间体I和雷尼镍加入到反应溶剂中,氮气置换,通入氢气,保持压力0.7~0.9Mpa,温度60~80℃反应18~20h,经后处理得到恩格列净。
7.如权利要求6所述的一种恩格列净的合成方法,其特征是,所述步骤1)的后处理为:加水淬灭后,经萃取、洗涤、干燥、减蒸得到中间体I。
8.如权利要求7所述的一种恩格列净的合成方法,其特征是,所述萃取使用的萃取溶剂为:异丙醚、甲基叔丁基醚、二氯甲烷、乙酸乙酯中的一种或多种的混合溶剂。
9.如权利要求6所述的一种恩格列净的合成方法,其特征是,所述步骤2)的后处理为:降温,滤除雷尼镍,减蒸至干,加溶剂重结晶,降至-5~0℃析晶,抽滤,烘干,得到恩格列净。
10.如权利要求9所述的一种恩格列净的合成方法,其特征是,所述重结晶用溶剂为:甲醇、乙醇、乙酸乙酯、醋酸异丙酯、异丙醇中的一种或多种的混合溶剂。
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