CN113801027A - 一种盐酸达泊西汀的合成工艺 - Google Patents

一种盐酸达泊西汀的合成工艺 Download PDF

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CN113801027A
CN113801027A CN202010551231.7A CN202010551231A CN113801027A CN 113801027 A CN113801027 A CN 113801027A CN 202010551231 A CN202010551231 A CN 202010551231A CN 113801027 A CN113801027 A CN 113801027A
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dapoxetine
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戴志成
夏承龙
徐斌
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Yangtze River Pharmaceutical Group Jiangsu Zilong Pharmaceutical Co ltd
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Abstract

本发明属于药物化学领域，具体涉及一种达泊西丁的生成工艺，其工艺特点反应步骤简单，原料价格低廉，D‑樟脑磺酸是对映异构体的拆分试剂。该工艺解决了目前达泊西汀产率低的难题，有良好的工业化前景。

Description

一种盐酸达泊西汀的合成工艺
一、技术领域
本发明属于药物化学，具体涉及盐酸达泊西汀的合成工艺。
二、背景技术
达泊西汀化学名为(S)-N，N-二甲基-3-(萘基-1-氧基)-苯丙氨基盐酸盐，是目前唯一获得国家食品药品监督管理局批准的治疗早泄的药物，被全球公认为治疗早泄最有效的药物，也曾作为抗抑郁药被广泛应用。它不是激素类药物，也没有依赖性，成药形式为盐酸盐。
三、发明内容
国内外报道的合成达泊西汀的文献较多，本研究在参考文献的基础上，对其合成工艺进行优化。以3-氯代苯丙酮为原料，与1-萘酚经醚化反应得到化合物a，a与二甲胺盐酸盐通过还原性氨基化反应产生到化合物b，化合物b经D-(+)-樟脑磺酸拆分获得D-樟脑磺酸盐c，c 再被碱中和产生手性中间体d，最后用氯化氢气体成酸盐得到目标化合物达泊西汀，合成路线见图1。经醚化反应制备化合物a时，我们采用丙酮做溶剂，碳酸铯做缚酸剂，在室温条件下就能获得理想的产率(95％以上)。关键中间体b的合成依赖还原性氨基化反应，经过筛选溶剂和还原剂，我们发现在甲醇中，硼氢化钠做还原剂，能实现二甲胺与化合物a的C-N 键偶联，产率在80％以上。我们用价格更低的D-樟脑磺酸做拆分试剂在室温条件下，用乙醚做溶剂，收率在40％左右。达泊西汀的D-樟脑磺酸盐经氢氧化钠溶液中和，捕获达泊西汀的游离碱。在制备盐酸盐的这一步骤中，向药物游离碱的乙醚溶液中通乳氯化氢气体，在室温条件下产品以晶体析出，产率达90％以上，纯度达到98％以上，重复性很好。该工艺原料易得，成本低廉，操作简便，合成步骤简洁，全程无须层析的纯化步骤，更利于工业化生产。
四、附图说明
图1为达泊西汀的合成路线
五、具体实施方式
1)3-(1-萘氧基)-苯丙酮(a)的制备
在250mL烧瓶中加入3-氯代苯丙酮(8.4g，50mmol)、1-萘酚(8.0g，55mmol mmol)、丙酮250mL，搅拌溶解。在室温条件下，加入碳酸铯(16.25g，55mmol)，搅拌12h。抽滤，除去固体；将液相减压蒸馏，除去丙酮，加入氯仿，1％氢氧化钠溶液洗至水相无色；饱和食盐水洗1次；无水硫酸钠干燥；抽滤；浓缩得到13.2g化合物a。收率：95.6％，纯度：98.1％。
2)N，N-二甲基-1-苯基-3-(1-萘氧基)丙胺(b)的制备
将13.8克的化合物a溶于200mL甲醇，然后加入硼氢化钠(5.0克，0.14mol)中，室温搅拌反应12h。滴加盐酸，调pH至3～4，旋蒸除去甲醇；用乙酸乙酯萃取3次；碳酸氢钠溶液洗涤2次；水洗2次；饱和食盐水洗涤1次；经无水硫酸钠干燥；抽滤；浓缩得到10.02 g化合物b。收率：87.0％，纯度：98.3％
3)达泊西汀樟脑磺酸盐(c)的制备
室温条件下，将化合物b(7.60g，32.74mmol)溶于250mL二氯甲烷中。加入D-(+)-樟脑磺酸(12.65g，32.74mmol)，搅拌0.5h，抽滤，白色固体用二氯甲烷洗涤三次，将固体在空气中干燥得到10.42g化合物c粗品。收率：42％，纯度：98.6％。
4)达泊西汀游离碱(d)的制备
将化合物c(10g，14.46mmol)、200mL二氯甲烷和100mL水加入500毫升的烧瓶中，室温搅拌。加10％氢氧化钠溶液调pH至10，继续搅拌1h。静置分层，水层用二氯甲烷萃取2次，合并有机相。将有机相水洗2次；饱和食盐水洗1次；无水硫酸钠干燥；抽滤；浓缩得到4.26g化合物d。收率：96.5％
5)盐酸达泊西汀的制备
将化合物d(6.1g，20mmol)溶于乙酸乙酯100mL中。室温通入氯化氢气体直到饱和，抽滤，用乙酸乙酯洗涤固体3次，室温干燥，得到6.5g终成品。收率：95.6％，纯度：98.91％。

Claims (5)

1.一种达泊西汀的生成工艺，其特征在于使用下述的工艺路线。
Figure FSA0000211533660000011
2.根据权利要求1，关键中间体a的合成，特征是：碳酸盐或叔胺做缚酸剂，萘酚和3-氯代苯丙酮，反应在丙酮或甲醇或乙醇中进行。
3.根据权利要求1，关键中间体b的合成，特征是：硼氢化钠做还原剂，二甲胺或它的盐酸盐做胺化试剂，甲醇、乙醇或丙酮做溶剂，室温条件。
4.根据权利要求1，化合物b对映异构体的拆分试剂是D-樟脑磺酸，所用溶剂是无水二氯甲烷或其他的乙腈、四氢呋喃和二氧六环等常见溶剂。
5.根据权利要求1，达泊西丁的合成方法，其特征是：将氯化氢气体通入到达泊西汀的游离碱d中，溶剂是二氯甲烷、氯仿、乙醚、四氢呋喃、乙腈和二氧六环，控制温度在-0℃～室温。
CN202010551231.7A 2020-06-16 2020-06-16 一种盐酸达泊西汀的合成工艺 Pending CN113801027A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112159328A (zh) * 2020-06-28 2021-01-01 石家庄市度智医药科技有限公司 一种达泊西汀的拆分方法

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Publication number Priority date Publication date Assignee Title
CN1821212A (zh) * 2006-03-15 2006-08-23 上海玛耀化学技术有限公司 一种达泊西汀的合成方法
WO2008035358A2 (en) * 2006-06-05 2008-03-27 Cadila Healthcare Limited Process for preparing dapoxetine
CN102229538A (zh) * 2011-05-11 2011-11-02 中南大学 一种达泊西汀的合成方法
CN102746170A (zh) * 2012-07-28 2012-10-24 湖南尔文生物科技有限公司 一种达泊西汀的制备方法
CN106242980A (zh) * 2016-08-03 2016-12-21 广安凯特医药化工有限公司 N,n‑二甲基‑3‑(萘‑1‑氧基)‑1‑苯丙胺或其盐酸盐的合成工艺
CN106748817A (zh) * 2016-12-06 2017-05-31 安徽省金楠医疗科技有限公司 一种盐酸达泊西汀制备方法
CN106748825A (zh) * 2016-11-29 2017-05-31 聊城大学 一种达泊西汀的合成、拆分纯化和成盐方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1821212A (zh) * 2006-03-15 2006-08-23 上海玛耀化学技术有限公司 一种达泊西汀的合成方法
WO2008035358A2 (en) * 2006-06-05 2008-03-27 Cadila Healthcare Limited Process for preparing dapoxetine
CN102229538A (zh) * 2011-05-11 2011-11-02 中南大学 一种达泊西汀的合成方法
CN102746170A (zh) * 2012-07-28 2012-10-24 湖南尔文生物科技有限公司 一种达泊西汀的制备方法
CN106242980A (zh) * 2016-08-03 2016-12-21 广安凯特医药化工有限公司 N,n‑二甲基‑3‑(萘‑1‑氧基)‑1‑苯丙胺或其盐酸盐的合成工艺
CN106748825A (zh) * 2016-11-29 2017-05-31 聊城大学 一种达泊西汀的合成、拆分纯化和成盐方法
CN106748817A (zh) * 2016-12-06 2017-05-31 安徽省金楠医疗科技有限公司 一种盐酸达泊西汀制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112159328A (zh) * 2020-06-28 2021-01-01 石家庄市度智医药科技有限公司 一种达泊西汀的拆分方法

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