CN102229581B - 非布司他中间体的制备方法 - Google Patents
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Abstract
本发明涉及药物化学领域，具体涉及治疗痛风药物非布司他的中间体2-(3-甲酰基-4-羟基苯基)-4-甲基-噻唑-5-羧酸乙酯的制备方法。其特征是以3-甲基-4-羟基苯甲醛为起始原料，经氰基化、成醚、羰基化、硫代酰胺化以及环合制得。本发明的制备方法避免了氰化钠等剧毒试剂以及强腐蚀性试剂三氟乙酸和乌洛托品的使用，反应条件温和，操作简便。
Description
技术领域
本发明涉及药物化学领域，具体涉及治疗痛风药物非布司他的重要中间体2-(3-甲酰基-4-羟基苯基)-4-甲基-噻唑-5-羧酸乙酯的制备方法。
背景技术
非布司他是日本帝人公司研发的非嘌呤类黄嘌呤氧化酶抑制剂，能有效阻断尿酸形成，临床主要用于预防和治疗高尿酸血症及其引发的痛风。非布司他于2008获欧盟批准在法国上市，非，与原有治疗痛风的常用药别嘌呤醇相比，该药的治疗效果更显著。国内外主要相关合成方法：
1.专利US5614520非布司他的合成工艺如下：
此工艺路线使用剧毒的氰化钾和氰化亚铜，且反应条件较苛刻不易工业化。
2.专利JP1994329647非布司他的合成路线如下：
此工艺中制备2-(3-甲酰基-4-羟基苯基)-4-甲基-噻唑-5-羧酸乙酯使用了三氟乙酸，对设备腐蚀较大。
发明内容
本发明的目的是提供了一条新的合成非布司他中间体2-(3-甲酰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯的工艺路线。工艺路线如下：
2-(3-甲酰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯的制备方法，选用3-甲基-4-羟基苯甲醛为起始原料，包括原料氰基化、成醚、羰基化、硫代酰胺化以及环合即得2-(3-甲酰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯。
本发明中3-甲基-4-羟基苯腈合成步骤为：3-甲基-4-羟基苯甲醛在甲酸钠存在下，与盐酸羟胺反应，溶剂选用甲酸。
本发明中醚合成反应步骤为：在碘化钾存催化下，溴代异丁烷与3-甲基-4-羟基苯腈反应，其中溶剂选用N，N-二甲基甲酰胺。3-甲基-4-羟基苯腈与溴代异丁烷的摩尔比为1∶2到1∶4，优选为1∶3。
本发明中2-异丁氧基-5-氰基苯甲醛合成步骤为：3-甲基-4-异丁氧基苯腈在溶剂中，经N-溴代丁二酰亚胺以及过氧化二苯甲酰催化反应制得，反应溶剂选用四氯化碳。
本发明中硫代酰胺化反应步骤为：在溶剂中，2-异丁氧基-5-氰基苯甲醛与硫氢化钠反应，反应溶剂选用乙醇。2-异丁氧基-5-氰基苯甲醛与硫氢化钠的摩尔数为1∶1.1到1∶1.5，优选为1∶1.2。
本发明避开了剧毒性试剂，不使用强腐蚀性试剂，反应条件温和，操作简便，适合工业化生产。
本发明制备的非布司他中间体2-(3-甲酰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯经氰基化和水解反应可制备非布司他。
具体实施方式
1.3-甲基-4-羟基苯腈的合成
将3-甲基-4-羟基苯甲醛13.6g溶解于适量甲酸中，并在室温下加入9.6g盐酸羟胺和二水合甲酸钠21.1g，然后升温至甲酸回流5～6小时反应结束，将反应液降至室温，过滤固体，滤饼用水洗涤，过滤得产物3-甲基-4-羟基苯腈8.7g，收率为65％。
2.3-甲基-4-异丁氧基苯腈的合成
500mL烧瓶中加入3-甲基-4-羟基苯腈7g，搅拌溶于150mL DMF，加入14.5g碳酸钾和14.8g碘化钾，50℃搅拌反应10分钟，13.6g溴代异丁烷缓慢滴加进反应液，50℃搅拌反应10小时。反应液冷却至室温，加水250mL，乙醚100mL萃取3次。有机层使用饱和氯化铵及饱和氯化钠洗涤后经硫酸镁干燥，减压蒸除溶剂得到3-甲基-4-异丁氧基苯腈8.8g。收率为89％。
3.2-异丁氧基-5-氰基苯甲醛的合成
3-甲基-4-异丁氧基苯腈6g，N-溴代丁二酰亚胺128.8g溶于600mL四氯化碳中，加热至回流反应20分钟，加入0.4g过氧化二苯甲酰，回流反应8小时。反应液冷却后过滤除去不溶物。溶液加入70％甲醇溶液中，加热回流反应10小时。反应液冷却后，减压蒸除溶剂，乙醚萃取，无水硫酸镁干燥后减压蒸除溶剂得2-异丁氧基-5-氰基苯甲醛4.1g，收率为63％。
4.3-甲酰基-4-异丁氧基硫代苯甲酰胺的合成
2.2g硫氢化钠，4g六水合氯化镁溶于DMF中，滴加溶于10mlDMF的2-异丁氧基-5-氰基苯甲醛4g，室温反应4小时，加水搅拌，乙酸乙酯萃取，有机层分别使用饱和氯化钠溶液、1N盐酸洗涤，无水硫酸镁干燥，抽虑，滤液减压蒸除溶剂得产物3-甲酰基-4-异丁氧基硫代苯甲酰胺4.2g。收率为89％。
5.2-(3-甲酰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯的合成
3-甲酰基-4-异丁氧基硫代苯甲酰胺4g溶解于DMF中，加入3.88g氯代乙酰乙酸乙酯，60℃反应4小时，停止反应，反应液冷却后过滤得到固体，乙酸乙酯重结晶得到白色固体2-(3-甲酰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯4.5g，收率为77％。
6.2-(3-氰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯的合成
将2-(3-甲酰基-4-羟基苯基)-4-甲基-噻唑-5-甲酸乙酯4g溶解于甲酸中，并在室温加入0.96g盐酸羟胺和2.15g二水合甲酸钠，然后升温至甲酸回流。5～6小时反应结束，将反应液降至室温，过滤固体，滤饼用水洗涤，得2-(3-氰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯2.6g，收率为65％。
7.2-(3-氰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸的合成
将2-(3-氰基--4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯2g加入50％乙醇溶液中，并在室温加入0.28g氢氧化钠，然后反应液升温50℃搅拌至溶液澄清。5～6小时反应结束后，用稀盐酸调节至酸性(PH＝2～3)，析出固体，过滤固体，滤饼用水洗涤得非布司他粗品，乙醇重结晶得固体1.4g，收率为87％。
Claims (6)
1.一种制备如下结构式(I)的非布司他中间体的方法
该方法包括以下步骤：将式(II)所示的3-甲基-4-羟基苯甲醛
与盐酸羟胺发生氰基化反应得到式(III)所示的3-甲基-4-羟基苯腈；
将式(III)化合物在碳酸钾和碘化钾存在下，与溴代异丁烷反应获得式(IV)所示的化合物3-甲基-4-异丁氧基苯腈；
式(IV)化合物在过氧化二苯甲酰催化下与N-溴代丁二酰亚胺反应得到式(V)所示的化合物2-异丁氧基-5-氰基苯甲醛；
式(V)化合物在六水合氯化镁催化下与硫氢化钠反应得到式(VI)所示的化合物3-甲酰基-4-异丁氧基硫代苯甲酰胺；
式(VI)化合物与氯代乙酰乙酸乙酯环合得到式(I)化合物。
2.如权利要求1所述的方法，其特征在于将式(II)化合物氰基化获得式(III)化合物过程中选用甲酸做溶剂。
3.如权利要求1所述的方法，其特征在于将式(III)化合物醚化获得(IV)化合物过程，选用N，N-二甲基甲酰胺做溶剂。
4.如权利要求1所述的方法，其特征在于将式(III)化合物醚化获得(IV)化合物过程，3-甲基-4-羟基苯腈与溴代异丁烷的摩尔比为1∶2到1∶4。
5.如权利要求1所述的方法，其特征在于将式(IV)化合物氧化生成式(V)所示的化合物过程，选用四氯化碳做溶剂。
6.如权利要求1所述的方法，其特征在于式(V)化合物加成得到式(VI)所示化合物过程中，2-异丁氧基-5-氰基苯甲醛与硫氢化钠的摩尔数为1∶1.1到1∶1.5。
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