CN102827019B - 一组新的苯并环丁烷化合物及其在化学合成中的应用 - Google Patents
一组新的苯并环丁烷化合物及其在化学合成中的应用 Download PDFInfo
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Abstract
本发明鉴于目前伊伐布雷定巨大的药用价值以及其合成的较大难度，提供了一组新的苯并环丁烷化合物和制备它们的方法以及由他们制备伊伐布雷定的方法，亦即提供了伊伐布雷定新的制备方法，该方法合成路线短，操作简单，大大降低伊伐布雷定的合成难度，且成本低廉，产品收率高，具有很好的产业化基础和应用价值。
Description
技术领域
本发明属于医药化工领域，具体涉及到一组新的苯并环丁烷化合物及其在伊伐布雷定制备中的应用。
背景技术
伊伐布雷定，化学名为：7,8-二甲氧基-3-(3-[[(1S)(4,5-二甲氧基苯并环丁烷-1-基)甲基]-甲氨基]丙基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮，其结构如下式所示：
伊伐布雷定临床上可以用于治疗各种心肌缺血，例如心绞痛、心肌梗塞和相关的节律紊乱，是一种治疗前景非常广阔的新一代心血管类药物。
目前，伊伐布雷定的合成主要有以下几种：
方法一：
其中：R基团代表卤素、二氧戊环、二氧己环等。
方法二：
其中：R基团代表卤素、二氧戊环、二氧己环等。
方法三：
其中R表示取代或者未取代的、任选被全氟代的直链或支链烷基，取代或者未取代的芳基、苄基或者CH2COOEt。
从现有的伊伐布雷定合成方法中可以看出，无论哪种方法，伊伐布雷定的制备成本都较高以及制备难度大，操作繁琐并且收率较低，工业放大生产存在一定的瓶颈。
发明内容
鉴于目前伊伐布雷定巨大的药用价值以及其合成的较大难度，本发明提供了一组新的苯并环丁烷化合物和制备它们的方法以及由他们制备伊伐布雷定的方法，亦即提供了伊伐布雷定新的制备方法，该方法合成路线短，操作简单，大大降低伊伐布雷定的合成难度，且成本低廉，产品收率高，具有很好的产业化基础和应用价值。
本发明提供了一组新的苯并环丁烷化合物，其结构式分别为：
化合物III
化合物I
化合物V。
所述的新的苯并环丁烷化合物的制备方法，包括如下步骤：
化合物II
A、 化合物II即(1S)-[N-(3-卤丙基)-N-甲基]氨甲酰基-4,5-二甲氧基苯并环丁烷在溶剂中与氨基乙醛缩二甲醇在缚酸剂存在的条件下进行N烷基化反应，生成化合物III；
化合物III
B、 化合物III在还原剂存在的条件下进行还原反应生成化合物IV；
化合物IV
C、 化合物IV与3,4-二甲氧基苯乙酸进行酰胺化反应，生成化合物V。
化合物V
所述的步骤A中的溶剂为二氯甲烷、四氢呋喃、1,4-二氧六环、二甲基亚砜、富马酸二甲酯或甲基乙酰胺。
所述的步骤A中的缚酸剂为有机碱或无机碱，优选三乙胺或碳酸钾。
所述的步骤B是在醚类溶剂中进行，所述醚类溶剂优选四氢呋喃或1,4-二氧六环。
所述的步骤B中的还原剂为金属硼氢化物或者金属氢化物，优选硼氢化钠、硼氢化钾或四氢铝锂。
所述的步骤C中3,4-二甲氧基苯乙酸先生成酰氯再与化合物进行酰胺化反应。
所述的步骤C是在二氯亚砜中进行。
所述的新的苯并环丁烷化合物在制备伊伐布雷定中的应用：化合物V在酸存在条件下进行成环反应可以制得化合物，化合物I进行还原反应得到伊伐布雷定。
化合物I
所述的酸为盐酸、氢溴酸或乙酸。
伊伐布雷定可以任选地转化为其可药用酸加成盐，所述可药用酸选自盐酸、氢溴酸、硫酸、磷酸、乙酸、琥珀酸、富马酸、酒石酸、马来酸、柠檬酸、甲磺酸、苯甲酸，并可转化为其水合物。
本发明所提供的化合物III、化合物和化合物是新化合物，其可以用作化学或制药工业的合成用中间体，尤其是用于合成伊伐布雷定及其与药用酸的加成盐和其水合物，合成伊伐布雷定的工艺操作简单，成本低廉，产品收率高，大大降低伊伐布雷定的合成难度。
具体实施方式
一下结合具体实施方式对本发明进行详细说明。
实施例1：化合物III即(1S)-[N-(3-(2,2-二甲氧基乙胺)-丙基)-N-甲基]氨甲酰基-4,5-二甲氧基苯并环丁烷的制备
将35mL的氨基乙醛缩二甲醇，50mL三乙胺溶于300mL二氯甲烷中，将反应瓶置于冰浴中，将89.3g (1S)-[N-(3-氯丙基)-N-甲基]氨甲酰基-4,5-二甲氧基苯并环丁烷溶于450mL的二氯甲烷中形成溶液，将溶液滴入前述置于冰浴中的反应液中，室温下搅拌，饱和300mL NaHCO3洗涤有机层2次，再加入300mL水洗涤2次，收集有机层，无水硫酸钠干燥，减压浓缩得棕黄色油状物质即化合物III98.9g，收率为90%。
实施例2：化合物即(1S)-[N-(3-(2,2-二甲氧基乙胺)-丙基)-N-甲基]氨甲基-4,5-二甲氧基苯并环丁烷的制备
向装有73.3 g实施例1制备的化合物III的反应瓶中通入氮气保护，加入350 mL无水四氢呋喃，搅拌溶解，冰浴下分批向反应液中加入10.0g四氢铝锂，加料毕，于室温下搅拌5小时，取样点板原料反应完全，向反应液中缓慢滴加50mL水淬灭反应，向反应液加入500 mL乙酸乙酯，再加入无水硫酸钠搅拌干燥2 小时，滤除干燥剂，滤液减压浓缩得剩余物即化合物61.3 g，收率87%。
实施例3：化合物即N-(3-(N-(((S)-1,2-二氢-4,5-二甲氧基苯并环丁烷-2-基)甲基)-N-甲酰胺)丙基)-N-(2,2-二甲氧基乙基)-2-(3,4-二甲氧基苯基)乙酰胺的制备
于1 L反应瓶中加入400 mL二氯甲烷，搅拌下加入39.2 g 的3,4-二甲氧基苯乙酸，冰浴降温至0℃~5℃，开始滴加28.5 g氯化亚砜，控制滴加速度使反应液温度不超过10℃，滴毕撤掉冰水浴，于室温搅拌反应2 小时，减压蒸干溶剂得棕色油状物，加200 mL二氯甲烷溶解，备用；
将350mL含有35.2g实施例2制备的化合物的二氯甲烷溶液用三乙胺调节PH至8~9，滴加上步备用的含棕色油状物的二氯甲烷溶液，控制滴加速度使反应液温度不超过25℃，滴毕室温反应4小时，反应液用200 mL水洗3次，收集二氯甲烷层，无水硫酸钠干燥，滤除干燥剂，滤液减压浓缩得剩余物即化合物 41.4g，收率78%。
实施例4：化合物I即7,8-二甲氧基-3-(3-[[(1S)(4,5-二甲氧基苯并环丁烷-1-基)甲基]-甲氨基]丙基)-1,3,-二氢-2H-苯并氮杂卓-2-酮的制备
将53.1g实施例3制备的化合物溶于250mL浓盐酸后，再加入250mL冰醋酸混合，室温下搅拌24小时，将混合物倒入500mL冰水中，析出白色粉末，抽滤，滤饼用水洗至中性，干燥得白色粉末即得化合物I 32.2g，收率69%。
实施例5：伊伐布雷定（7,8-二甲氧基-3-(3-[[(1S)(4,5-二甲氧基苯并环丁烷-1-基)甲基]-甲氨基]丙基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮）的制备
将10.0g实施例4所制备的化合物I加入到1L的氢化釜中，相继加入5.0g的10%钯炭、200mL乙醇、20mL乙酸，室温下于2个大气压下反应8个小时，反应完，过滤，适量乙醇洗涤滤饼，收集滤液，减压浓缩得剩余物即伊伐布雷定9.5g，收率95%。
实施例6：盐酸伊伐布雷定的制备
将6.6mL 3N氯化氢乙醇溶液滴加到90mL 含有9.0g实施例5制备的伊伐布雷定的乙腈溶液中，室温搅拌反应12小时，过滤，适量乙醇洗涤滤饼，滤饼干燥即得盐酸伊伐布雷定8.2g，收率85%。
Claims (8)
1.一种苯并环丁烷化合物的制备方法，包括如下步骤：
A. 化合物II即(1S)-[N-(3-卤丙基)-N-甲基]氨甲酰基-4,5-二甲氧基苯并环丁烷在溶剂中与氨基乙醛缩二甲醇在缚酸剂存在的条件下进行N烷基化反应，生成化合物III；
化合物II 化合物III
B. 化合物III在还原剂存在的条件下进行还原反应生成化合物IV；
化合物I
C. 化合物IV与3,4-二甲氧基苯乙酸进行酰胺化反应，生成化合物V
化合物V。
2.根据权利要求1所述的制备方法，其特征在于：所述的步骤A中的溶剂为二氯甲烷、四氢呋喃、1,4-二氧六环、二甲基亚砜、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
3.根据权利要求1所述的制备方法，其特征在于：所述的步骤A中的缚酸剂为有机碱或无机碱。
4.根据权利要求1所述的制备方法，其特征在于：所述的步骤B是在醚类溶剂中进行。
5.根据权利要求1所述的制备方法，其特征在于：所述的步骤B中的还原剂为金属硼氢化物或者金属氢化物。
6.根据权利要求1所述的制备方法，其特征在于：所述的步骤C中3,4-二甲氧基苯乙酸先生成酰氯再与化合物进行酰胺化反应。
7.根据权利要求1所述的制备方法，其特征在于：所述的步骤C是在二氯亚砜中进行。
8.一种如式a所示的化合物III，
式a。
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