CN107365268B - 一种降压药福辛普利钠及其关键中间体的制备方法 - Google Patents
一种降压药福辛普利钠及其关键中间体的制备方法 Download PDFInfo
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- CN107365268B CN107365268B CN201610307339.5A CN201610307339A CN107365268B CN 107365268 B CN107365268 B CN 107365268B CN 201610307339 A CN201610307339 A CN 201610307339A CN 107365268 B CN107365268 B CN 107365268B
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- acetone
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- fosinopril sodium
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- 238000002360 preparation method Methods 0.000 title abstract description 19
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Classifications
-
- 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
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Abstract
本发明涉及适用于工业化生产的一种降压药福辛普利钠及其关键中间体反式‑4‑苯基‑L‑脯氨酸的制备方法，其中关键中间体反式‑4‑苯基‑L‑脯氨酸的合成手性选择性高，方法简便易操作。
Description
技术领域
本发明涉及医药领域，具体涉及一种降压药福辛普利钠（式Ⅰ）及其关键中间体反式-4-苯基-L-脯氨酸（式Ⅴ）的制备方法。
背景技术
血管紧张素转化酶抑制剂（ACEI）是一类高效、安全的心血管系统药物，在高血压和心力衰竭治疗中有卓著的临床疗效和良好的耐受性。自1977年第一个血管紧张素转化酶抑制剂（ACEI）类药物卡托普利（Captopril）问世以来，相继出现了第一代ACEI药物，其代表性药物为卡托普利；第2代ACEI药物，其代表性药物有依那普利（Enalapril）；福辛普利（Fosinopril）是第三代ACEI药物中第1个代表性药物。
福辛普利是唯一含次膦酸酯基的ACEI，亲脂性强，起效缓慢，易透过细胞膜进入组织，从而减少局部ATⅡ,使微血管舒张，因而具有最好的心脏和血管保护作用。福辛普利单药具有最大降压效果，但谷峰比值>50%，所以降压作用缓慢而平稳。福辛普利钠是由美国百时美施贵宝（Bristol-Myers Squibb）公司研制开发，于1991年首次在英国投入市场，1991年和1992年相继在美国和意大利上市。
血管紧张素转化酶将血管紧张素Ⅰ转化为血管紧张素Ⅱ，后者引起高血压。福辛普利钠（反式-4-环己基-1-[[[2-甲基-1-(1-氧代丙氧基)丙氧基](4-苯基丁基)氧膦基]乙酰基-L-脯氨酸钠盐）是一种已知作为血管紧张素转换酶抑制剂(ACE)的药物，主要用于治疗高血压。
福辛普利钠的合成途径有多种，美国专利US4337201和US4873356以及美国专利申请US2006/0160772A1、国际申请WO2002/088149对其中的一些进行了描述。其中，福辛普利钠的合成途径如下:
在合成路线1中，中间体L6具有两个手性中心，但是经过异丙醚重结晶和辛可尼定拆分可以得到单一构型的L6，其拆分途径操作简单,并且拆分后所得产品的ee值高；在合成路线2中，涉及到后拆分且收率低，成本高难以实现工业化生产。
发明内容
本发明提供一种合成条件优化的福辛普利钠的制备方法，通过质量比为甲醇/丙酮=1/4的溶剂精制方法，获得产品纯度更高的福辛普利钠，易于工业化生产；本发明中通过手性合成的方法获得高纯度的中间体反式-4-苯基-L-脯氨酸（式Ⅴ），能有效减少不需要异构体的生成，且方法简便易操作，本发明以偶氮二甲酸二异丙酯和三苯基膦为催化剂；本发明的合成路线如下：
本发明涵盖的内容包括以下方面
1.提供一种化合物反式-4-苯基-L-脯氨酸（式Ⅴ）的制备方法。
化合物Ⅶ的制备：
将甲烷磺酸溶解于惰性溶剂中，在催化剂三苯基膦和偶氮二甲酸二异丙酯条件下，与化合物Ⅷ在有机碱条件下进行光延反应，产生瓦尔登翻转，再经一定量氢氧化钠溶液水解得到化合物Ⅶ；惰性溶剂为甲苯、苯、氯苯、二甲苯、四氯化碳、DMF和DMSO,优选甲苯；有机碱为三乙胺、二乙胺、吡啶、哌啶和4-二甲氨基吡啶（DMAP），优选三乙胺。
化合物Ⅵ的制备：
在惰性气体保护下将化合物Ⅶ和反应物苯，在催化量的路易斯酸下反应生成化合物Ⅵ，再经精制溶剂纯化得到高纯度的化合物Ⅵ；惰性气体为氩气、氮气，优选氮气；路易斯酸为无水氯化铝、无水氯化锌、无水氯化铁和三氟化硼，优选无水氯化铝；催化量是化合物Ⅶ摩尔量的1-5倍；精制溶剂为乙酸乙酯、二氯甲烷、丙酮和乙酸丁酯，优选乙酸丁酯。
化合物Ⅴ的制备：
在惰性气体保护下将化合物Ⅵ溶解于惰性溶剂中，加入无机酸，回流反应水解得到化合物Ⅴ,再经精制溶剂纯化得到高纯度的化合物Ⅴ；惰性气体为氩气、氮气，优选氮气；惰性溶剂为二氧六环、甲苯、DMF、四氯化碳，优选二氧六环；无机酸为浓盐酸、浓硫酸、6N盐酸和3N盐酸，优选浓盐酸；精制溶剂为乙酸乙酯、乙酸丙酯、丙酮、二氯甲烷、乙醇和异丙醇，优选乙酸乙酯。
提供一种福辛普利钠（式Ⅰ）的制备方法
化合物Ⅳ的制备：
将化合物Ⅴ溶于惰性溶剂中，加入酸和催化剂，于氢气体系下，氢化反应得到化合物Ⅳ；惰性溶剂为甲醇、乙醇、水、乙酸乙酯，优选甲醇；酸为盐酸、醋酸、三氟乙酸、硫酸、硝酸，优选盐酸；催化剂为5%钯炭、10%钯炭、氧化铂、5%铑炭和10%铑炭，优选5%铑炭。
化合物Ⅱ的制备：
将化合物Ⅲ溶于惰性溶剂中，在有机碱催化下，与一定量新戊酰氯反应得混合酸酐，再与化合物Ⅳ反应，最终得到化合物Ⅱ；惰性溶剂为二氯甲烷、三氯甲烷、DMF和丙酮，优选二氯甲烷；有机碱为吡啶、三乙胺、二乙胺和哌啶，优选吡啶和三乙胺；新戊酰氯用量为1-2倍摩尔当量。
化合物Ⅰ的制备：
将化合物Ⅱ溶于惰性溶剂中，经成盐试剂成盐得到化合物Ⅰ,再经精制溶剂纯化得到高纯度的化合物Ⅰ；惰性溶剂为二氯甲烷、乙酸乙酯、DMF和丙酮，优选乙酸乙酯；成盐试剂为异辛酸钠、碳酸氢钠和碳酸钠，优选异辛酸钠；精制溶剂为乙酸乙酯、丙酮、乙醇、异丙醇、甲醇/丙酮=1/4（质量比）、甲醇/丙酮=1/3（质量比）、甲醇/丙酮=1/5（质量比）、甲醇/乙酸乙酯=1/4（质量比）、乙醇/丙酮=1/4（质量比），优选甲醇/丙酮=1/4（质量比）。
具体实施方式
实施例
1）化合物Ⅶ的制备：
在反应瓶中加入甲烷磺酸（3.24 g），三苯基膦（9.21 g）和甲苯（70 ml），开启搅拌，溶液为悬浮液，将悬浮液控温至20℃，加入偶氮二甲酸二异丙酯（7.95 g），保持体系温度在35℃以下。将化合物Ⅷ（7.0 g）加入反应瓶中，然后加入三乙胺（1.14 g）,搅拌10min。加热、升温至65℃，薄层色谱点板跟踪。反应3h，向反应液中加入水（100 ml）、乙酸乙酯（100ml）,萃取两次,合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏得11.2g油状物。将油状物（11.2 g）、氢氧化钠（1.68 g）的水溶液（25 ml）加入250ml反应瓶中，在5℃下剧烈搅拌2h，通过6N盐酸调节pH至6-7。悬浮液在5℃下搅拌1h，过滤掉固体物，用50ml冰水洗涤滤饼两次，滤液用3.6ml冰醋酸在25℃下调节pH至3.8-3.9，搅拌30min，开始有晶体形成，继续用2ml冰醋酸调节pH至4，混合物通过缓慢滴加6N盐酸调节pH至2，搅拌30min。最后降至0℃，搅拌1h有大量白色固体析出，经过滤、干燥得白色固体7.04g，收率：81.9%。
2）化合物Ⅵ的制备：
在氮气保护下向三口反应瓶中加入化合物Ⅶ（6.0 g）、苯（60ml）和无水氯化铝（9.19g），开启搅拌，保持体系温度不超过15℃ ，此时溶液为非均相，剧烈搅拌4h，然后升温至20℃，搅拌1.5h，溶液呈均相体系。薄层色谱跟踪，反应5.5h，将反应液冷却至7℃，慢慢加入6N盐酸（34ml）。溶液用14ml食盐水处理后，室温下搅拌45min，静置过夜。第二天过滤，滤饼用40ml水洗四次，真空干燥，固体投入50ml乙酸丁酯中，加热至沸，产物溶解。加入无水硫酸钠（5g），继续沸腾5min，趁热用硅藻土过滤，滤液经减压浓缩干得无色油状物4.73g，收率78.9%。
3）化合物Ⅴ的制备：
在氮气保护下向反应瓶中加入化合物Ⅵ（4.0 g）、浓盐酸（15 ml）和二氧六环（40ml），开启搅拌，加热、升温至回流。薄层色谱跟踪反应，反应约12h，将反应液减压浓缩干，加入正己烷（40 ml），再减压浓缩干，得浅黄色固体，固体用乙酸乙酯（100 ml）溶解，产品不溶，室温搅拌打浆1h，静置有白色固体析出，过滤得白色固体（1.74 g），收率：67.0%。
4）化合物Ⅳ的制备：
在反应瓶中加入化合物Ⅴ（1.2 g）、5%铑炭（0.24 g）、浓盐酸（1.2 ml）和甲醇（12ml），开启搅拌，通2.0MPa氢气进行氢化反应，加热、升温至30℃。薄层色谱跟踪，反应2h，将反应液减压过滤，滤液经减压浓缩得白色固体（1.11 g），收率：90.0%。
5）化合物Ⅱ的制备：
在反应瓶中将化合物Ⅲ（0.71 kg）溶于二氯甲烷（13 L）中，搅拌下加入吡啶（6.23g）和三乙胺（204.4 g），冰盐浴下将反应液降温至-10～-15℃，滴加新戊酰氯（243.6 g），在2h内滴加完毕。滴加完毕，维持体系温度在-10℃～-15℃搅拌2h，然后加入化合物Ⅳ（362.2g），搅拌下加热升温至20～25℃， 薄层色谱点板监测，搅拌反应2h，向反应液中加入纯化水（15.5 L），用盐酸（6N ，500 mL）调节pH=1.0～2.0，搅拌10min，静置10min，萃取分出有机相，重复水洗两次。有机相经真空减压浓缩得到油状物福辛普利（温控在25～30℃），重594g，收率57.1%。
6）化合物Ⅰ的制备：
在反应瓶中将福辛普利（5.3kg）溶于乙酸乙酯（20L）中，搅拌下加入溶有异辛酸钠（3.5g）的乙酸乙酯溶液（20L），控制体系温度在25～30℃，搅拌6h，有大量白色固体析出。经过滤，滤饼用少量乙酸乙酯洗涤，得白色固体，于真空减压烘箱中，30～35℃干燥2～3h，得到FX粗品（5.22g），收率：94.8%。
如本发明所述的精制纯化方法如下：将福辛普利钠粗品（1.8 kg）溶解于甲醇（7kg）中，通过真空负压转移至反应釜中，开启48℃水浴，反应液在25min完全溶解澄清，然后加入活性炭（360g），维持体系温度48℃，脱色30min，将反应液经减压抽滤，滤液通过真空转移至反应釜中，然后将丙酮（28kg）抽入到高位槽中，开启搅拌，转速60rpm，滴加丙酮，在1h内滴完，滴毕控制体系温度在25℃，搅拌析晶6h，停止搅拌，开启底阀，将物料转移至离心机，离心甩滤，滤饼先用甲醇：丙酮=1:4（质量比）（2kg）进行漂洗，再用丙酮（4kg）离心洗涤，将滤饼转移至真空干燥箱中，保持温度30～40℃，真空干燥2h，福辛普利钠固体通过60目不锈钢筛过筛，得颗粒均匀的固体，然后将控制粒径的固体继续于温度30～40℃，真空度控制在0.085 MPa以上，真空干燥20小时，得福辛普利钠精制品（1.65kg），收率：91.7，含量99.6%（HPLC）。
Claims (1)
1.一种福辛普利钠的制备方法，将1.8kg福辛普利钠粗品，溶解于7kg甲醇中，通过真空负压转移至反应釜中，开启48℃水浴，反应液在25min完全溶解澄清，然后加入360g活性炭，维持体系温度48℃，脱色30min，将反应液经减压抽滤，滤液通过真空转移至反应釜中，然后将28kg丙酮，抽入到高位槽中，开启搅拌，转速60rpm，滴加丙酮，在1h内滴完，滴毕控制体系温度在25℃，搅拌析晶6h，停止搅拌，开启底阀，将物料转移至离心机，离心甩滤，滤饼先用甲醇：丙酮的质量比为1:4进行漂洗，再用4kg丙酮离心洗涤，将滤饼转移至真空干燥箱中，保持温度30～40℃，真空干燥2h，福辛普利钠固体通过60目不锈钢筛过筛，得颗粒均匀的固体，然后将控制粒径的固体继续于温度30～40℃，真空度控制在0.085MPa以上，真空干燥20小时，得1.65kg福辛普利钠精制品，收率91.7％，HPLC含量99.6％,其中离心甩滤使用甲醇和丙酮的用量为2kg。
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