CN112174966B - 一种制备盐酸吡西卡尼的新方法 - Google Patents
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Abstract
本发明公开了一种盐酸吡西卡尼的制备方法，以2,6‑二甲基苯胺为原料，与化合物Ⅰ进行酰胺化反应，制得酰胺化合物；酰胺化合物与化合物Ⅱ在氨的作用下，制得氮杂环化合物；氮杂环化合物经水解、脱羧，制得吡西卡尼碱基；吡西卡尼碱基经成盐制得盐酸吡西卡尼。该制备路线生产条件温和环保，易于操作，适宜工业化放大生产。
Description
技术领域
本发明涉及一种盐酸吡西卡尼的合成方法。
背景技术
盐酸吡西卡尼为口服有效的Ⅰc类抗心律失常药，适用于室性或室上性心律失常，特别适用于其他抗心律失常药无效或不能耐受的室性心动过速的治疗，很少引起中枢神经系统不良反应和抗胆碱效应。本品由日本第一制药厂研发，于1991年在日本首次上市。
目前文献中报道的盐酸吡西卡尼制备路线较少，主要以1-氮杂双环[3.3.0]-4-辛烯与高氯酸成盐，得到1-氮杂双环[3.3.0]-1(5)-辛烯高氯酸盐，然后与丙二酸单乙酯缩合得到（1-氮杂双环[3.3.0]-5-基）乙酸乙酯，水解生成（1-氮杂双环[3.3.0]-5-基）乙酸后，再与2,6-二甲基苯胺酰化得到盐酸吡西卡尼。
1-氮杂双环[3.3.0]-4-辛烯的制备以吡咯烷酮为原料，与γ-丁内酯反应后，在钠石灰的作用下干馏得到产品。
干馏温度高至300℃以上，一般生产设备无法满足要求；干馏后的产物也较为复杂，成高氯酸盐时收率在20%-30%，相对偏低。同时1-氮杂双环[3.3.0]-1(5)-辛烯高氯酸盐为有机物高氯酸盐，易燃易爆，具有一定的危险性，高氯酸盐的使用过程中常有爆炸事故发生，已经引起人们的极大关注。
发明内容
鉴于目前盐酸吡西卡尼制备工艺中的缺点，本发明人开发了一条全新的制备路线，本发明的合成路线如下：
。
本发明以2,6-二甲基苯胺为原料，与化合物Ⅰ进行酰胺化反应，制得酰胺化合物；酰胺化合物与化合物II在氨的作用下，制得氮杂环化合物；氮杂环化合物经水解、脱羧，制得吡西卡尼碱基；碱基经成盐制得盐酸盐半水合物。其中化合物Ⅰ中R1为C1至C4的直链或支链烷基或氢，R2为氰基或C1至C4烷基羧酸酯；酰胺化合物中R2为氰基或C1至C4烷基羧酸酯；化合物Ⅱ中X为卤族元素氯、溴、碘中的任一元素；氮杂环化合物中R2为氰基或C1至C4烷基羧酸酯。
本发明所采用的原料2,6-二甲基苯胺、化合物Ⅰ均为基本化工原料，价格便宜，易于工业化应用。
本发明所用的原辅料毒害作用小，反应条件温和，无需高温干馏，无危险化学品的加入和产出；制备操作简单，更易于工业化生产。
具体实施例
下面通过具体实施例，进一步阐明本发明，应理解这些实施例仅用于说明本发明而不用于限制本发明的范围，在阅读了本发明之后，本领域技术人员对本发明的各种等价形式的修改均落于本申请所附权利要求所限定的范围。
实施例1
步骤一：向反应釜中加入DMF 1L，2,6-二甲基苯胺0.243Kg，氰乙酸乙酯0.271Kg，加热至回流，搅拌回流反应12小时，反应结束后，冷却反应液至室温，倒入8L冰水中，搅拌半小时，抽滤，乙醇洗涤滤饼。
将滤饼加入到2L无水乙醇中，加热回流后冷却至0℃-10℃析晶2小时，抽滤，滤饼干燥，制得酰胺化合物0.313Kg，收率83%。
步骤二：-5℃左右，向3.5L浓氨水中通入氨气，以使氨水浓度达到40%-50%，加入甲醇2L，二氯庚酮0.366Kg，酰胺化合物0.376Kg，缓慢升温至12℃-18℃反应15小时，减压蒸馏未反应的氨和溶剂，加乙醇重结晶，抽滤，滤饼干燥，制得氮杂环化合物0.368Kg，收率62%。
步骤三：向反应釜中加入氮杂环化合物0.595Kg，水4L，甲醇3L，氢氧化钾0.135Kg，加热至50℃反应6小时，降至室温，用甲苯3L提取一次，水相调节pH至中性，升温至60℃-65℃脱羧2小时，减压蒸馏掉约2/3的溶剂，补加水4L，用乙酸乙酯3L提取三次，合并有机层，无水硫酸钠干燥，抽滤，滤液浓缩至干，得吡西卡尼碱基0.388Kg，收率71%。
步骤四：向反应釜中加入吡西卡尼碱基0.545Kg，95%乙醇4L，用10%盐酸调节pH=2-3，搅拌半小时，加入活性炭，脱色半小时，抽滤，蒸馏乙醇，加入乙酸乙酯5L，0℃-5℃搅拌析晶3小时，抽滤，滤饼干燥，制得盐酸吡西卡尼0.521Kg，收率82%。
实施例2
步骤一：向反应釜中加入DMF 1L，2,6-二甲基苯胺0.243Kg，丙二酸二乙酯0.385Kg，加热至回流，搅拌回流反应9小时，反应结束后，冷却反应液至室温，倒入8L冰水中，搅拌半小时，抽滤，乙醇洗涤滤饼。
将滤饼加入到2L无水乙醇中，加热回流后冷却至0℃-10℃析晶2小时，抽滤，滤饼干燥，制得酰胺化合物0.344Kg，收率73%。
步骤二：将3.5L浓氨水冷却至-5℃左右，通入氨气，以使氨水浓度达到40%-50%，加入甲醇2L，二氯庚酮0.366Kg，酰胺化合物0.471Kg，缓慢升温至12℃-18℃反应19小时，减压蒸馏未反应的氨和溶剂，加乙醇重结晶，抽滤，滤饼干燥，制得氮杂环化合物0.331Kg，收率48%。
步骤三：向反应釜中加入氮杂环化合物0.689Kg，水4L，甲醇3L，氢氧化钾0.124Kg，加热至50℃反应3小时，降至室温，用甲苯3L提取一次，水相调节pH至中性，升温至60℃-65℃脱羧2小时，减压蒸馏掉约2/3的溶剂，补加水4L，用乙酸乙酯3L提取三次，合并有机层，无水硫酸钠干燥，抽滤，滤液浓缩至干，得吡西卡尼碱基0.43Kg，收率79%。
步骤四：向反应釜中加入吡西卡尼碱基0.545Kg，95%乙醇4L，用10%盐酸调节pH=2-3，搅拌半小时，加入活性炭，脱色半小时，抽滤，蒸馏乙醇，加入乙酸乙酯5L，0℃-5℃搅拌析晶3小时，抽滤，滤饼干燥，制得吡西卡尼0.509Kg，收率80%。
Claims (1)
1.一种盐酸吡西卡尼的合成方法，其特征是通过如下化学反应合成盐酸吡西卡尼：
；
步骤一：2,6-二甲基苯胺与化合物Ⅰ进行酰胺化反应，制得酰胺化合物；化合物Ⅰ中R1为C1至C4烷基或氢，R2为氰基或C1至C4烷基羧酸酯；酰胺化合物中R2为氰基或C1至C4烷基羧酸酯；
步骤二：酰胺化合物与化合物Ⅱ在氨的作用下，制得氮杂环化合物；化合物Ⅱ中X为卤族元素氯、溴、碘中的任一元素，氮杂环化合物中R2为氰基或C1至C4烷基羧酸酯；
步骤三：氮杂环化合物经水解、脱羧，制得吡西卡尼碱基；
步骤四：吡西卡尼碱基经成盐制得盐酸吡西卡尼。
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| JPH05286975A (ja) * | 1992-04-10 | 1993-11-02 | Sanwa Kagaku Kenkyusho Co Ltd | １−アザビシクロ［３．３．０オクタン誘導体の製法 |
| EP0703233A2 (en) * | 1994-07-29 | 1996-03-27 | Sanwa Kagaku Kenkyusho Co., Ltd. | Process for the preparation of 5-substituted-1-azabicyclo (3.3.0) octanes |
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2019
- 2019-07-03 CN CN201910593720.6A patent/CN112174966B/zh active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05286975A (ja) * | 1992-04-10 | 1993-11-02 | Sanwa Kagaku Kenkyusho Co Ltd | １−アザビシクロ［３．３．０オクタン誘導体の製法 |
| EP0703233A2 (en) * | 1994-07-29 | 1996-03-27 | Sanwa Kagaku Kenkyusho Co., Ltd. | Process for the preparation of 5-substituted-1-azabicyclo (3.3.0) octanes |
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| PYRIDINE BASED PYRAZOLINES : SYNTHESIS AND ITS IMPACT ON CYTOTOXIC ENVIRONMENT IN SPLEENOCYTES;Alka Pradhan，等;Journal of Environmental Researh And Development;第1卷(第1期);16-21 * |
| Seiji Miyano，等.New Antiarrhythmic Agents. N-Aryl-8-pyrrolizidinealkanamides.Journal of Medicinal Chemistry.1985,第28卷(第6期),714-717. * |
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