CN1157387C - 制备11-氨基-3-氯-6,11-二氢-5,5-二氧代-6-甲基-二苯并[c,f][1,2]硫氮杂�的新方法及其合成噻萘普丁的应用 - Google Patents
制备11-氨基-3-氯-6,11-二氢-5,5-二氧代-6-甲基-二苯并[c,f][1,2]硫氮杂�的新方法及其合成噻萘普丁的应用 Download PDFInfo
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- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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Abstract
本发明涉及工业合成式(I)化合物及其加成盐的方法：还涉及式(I)化合物在合成噻萘普丁及其可药用盐中的应用。
Description
本发明涉及工业合成式(I)的11-氨基-3-氯-6，11-二氢-5，5-二氧代-6-甲基-二苯并[c，f][1，2]硫氮杂(thiazepine)及其加成盐的新方法：
式(I)化合物是合成式(II)的噻萘普丁及其可药用盐的重要中间体：
式(II)化合物及其加成盐具有有价值的药理性能。它们是5-羟色胺摄取的刺激剂，这使得它们可用于治疗抑郁和焦虑。
式(II)化合物、其制备及其在治疗剂中的应用已描述于专利说明书FR 2 104 728中。
鉴于其药用价值，能够使用可得的无问题原料且使用易于转化为工业规模的合成方法以最佳产率和纯度生产该化合物是重要的。
专利说明书FR 2 104 728描述了通过使3，11-二氯-6，11-二氢-5，5-二氧代-6-甲基-二苯并[c，f][1，2]硫氮杂与7-氨基庚酸乙酯反应制备式(II)化合物。
然而，该方法不能以令人满意的产率和纯度得到式(II)化合物，特别是由于7-氨基庚酸乙酯在反应混合物中不稳定。
专利说明书EP 0 671 173描述了通过使式(I)的胺与7-溴庚酸乙酯反应制备式(II))化合物的异构体。该方法由于以好得多的产率和纯度提供式(II)的噻萘普丁而非常有价值。
然而该文献并未提及如何得到式(I)的起始胺。
鉴于没有合成该中间体的方法，本发明的发明人进行了详细的研究，结果开发出一种尤其有价值的工业合成方法，该方法能以优异产率和纯度以使用无问题的原料的两步得到式(I)化合物。
更具体而言，本发明涉及一种制备式(I)化合物的方法，该方法的特征在于使式(III)的酮：
与硼氢化钠在N-十二烷基-N-甲基-二乙醇溴化铵存在下于两相介质(氯代溶剂如氯仿、二氯甲烷或二氯乙烷/氢氧化钠水溶液)中反应，得到式(IV)的醇，
将该式(IV)醇以在氯代溶剂如氯仿或二氯甲烷中的悬浮液用氯化氢气体处理，得到式(V)的氯化物：
然后不加分离地将式(V)氯化物用氨气处理，同时维持温度为25-35℃，得到式(I)化合物，若需要，将其转化为加成盐如盐酸盐。
该方法因下列原因而尤为有价值：
·式(III)的酮由硼氢化钠在甲醇介质中还原是已知的且尤其描述于专利说明书FR 1 566 191中。然而该类反应混合物在工业规模上的处理是费力的，尤其要求蒸发大量甲醇。申请人已发现尤为有利的是在氯代溶剂如二氯乙烷、二氯甲烷或氯仿中进行所述还原，因为这样可以通过过滤直接分离所形成的醇。
·当在非羟基化溶剂中进行时，由硼氢化钠还原酮要求使用相转移催化剂。申请人发现以对应于所用酮的1-3％重量的量使用N-十二烷基-N-甲基-二乙醇溴化铵可以完全且非常快速地(2-3小时)还原式(III)的酮。作为对比，使用常规相转移催化剂-四丁基硫酸氢铵要求两倍长的反应时间。
·通过氯化氢气体的作用将所得式(IV)的醇转化为式(V)的氯代化合物，然后在脱气后用氨就地处理该氯代化合物，得到式(I)的伯胺。
该程序的优点在于避免分离中间体氯代化合物，从而限制了操作数目。
·通过使卤代化合物与氨反应制备伯胺通常产生相当不令人满意的结果：产率低且形成大比例的副产物(仲胺和叔胺)。申请人发现了惊人地允许以良好产率由相应的式(V)氯化物得到式(I)的伯胺的操作条件。这些条件包括将氨流通过式(V)氯化物在氯代溶剂如氯仿或二氯甲烷中的悬浮液，同时维持反应介质的温度为约30℃。然后以盐酸盐形式从反应介质中有利地分离产物。在这些条件下，由式IV的醇开始的产率大于75％且所得产物含有低于0.3％的式(VI)仲胺：
所得盐酸盐具有非常好的纯度，使得其在合成式(II)噻萘普丁中的应用尤为有利。
作为举例，使根据本发明得到的11-氨基-3-氯-6，11-二氢-5，5-二氧代-6-甲基-二苯并[c，f][1，2]硫氮杂盐酸盐与7-溴庚酸乙酯在碳酸氢钠存在下于回流的乙醇介质中反应允许以高度令人满意的产率和纯度得到式(II)的噻萘普丁。
若需要，随后将后一化合物通过加入氢氧化钠转化为其钠盐。所得噻萘普丁的钠盐具有优异的纯度且含有低于0.4％的杂质(由C18柱上的液相色谱测量)。
具体而言，其含有低于0.1％的式(VII)二取代产物：
且不含式(VI)的杂质。
下列实施例说明本发明且决不限制本发明。
实施例1：3-氯-6，11-二氢-5-二氧代-11-羟基-6-甲基-二苯并[c，f][1，2]硫氮杂。
将100kg3-氯-6，11-二氢-6-甲基-5，5，11-三氧代-二苯并[c，f][1，2]硫氮杂、1.8kg N-十二烷基-N-甲基-二乙醇溴化铵和100升氯仿导入搅拌反应器中。然后将混合物加热至回流并加入4.6kg硼氢化钠在140升水和0.7kg 30％氢氧化钠溶液中的溶液。气体的挥发停止后，使反应混合物达到室温并将所得沉淀滤出、用水洗涤和干燥。以97％的产率得到标题化合物。
熔点：199-200℃
实施例2：11-氨基-3-氯-6，11-二氢-5，5-二氧代-6-甲基-二苯并[c，f][1，2]硫氮杂盐酸盐
将实施例1所述醇(100kg)在氯仿中的悬浮液在5℃下用氯化氢气流处理，然后在通过用氮气脱气除去过量氯化氢之后，将所得氯化物的悬浮液用氨气流处理，同时维持反应介质的温度为30℃。然后用氮气流除去过量氨；再加入水，分离混合物并用水洗涤有机相，然后用30kg浓盐酸处理。过滤收集所得沉淀，用氯仿洗涤，然后干燥。以79％的产率得到标题化合物。
熔点：193-197℃
Claims (7)
1.工业合成式(I)的11-氨基-3-氯-6，11-二氢-5，5-二氧代-6-甲基-二苯并[c，f][1，2]硫氮杂及其加成盐的方法：
其特征在于使式(III)的酮：
与硼氢化钠在N-十二烷基-N-甲基-二乙醇溴化铵存在下于由氯代溶剂和氢氧化钠水溶液组成的两相介质中反应，得到式(IV)的醇：
将该式(IV)醇以在氯代溶剂如氯仿或二氯甲烷中的悬浮液用氯化氢气体处理，得到式(V)的氯化物：
然后不加分离地将式(V)氯化物用氨气处理，同时维持温度为25-35℃，得到式(I)化合物，
若需要，将其转化为加成盐如盐酸盐。
2.根据权利要求1的方法，其特征在于式(IV)的仲胺在所形成的式(I)化合物的盐酸盐中的含量低于0.3％：
3.由11-氨基-3-氯-6，11-二氢-5，5-二氧代-6-甲基-二苯并[c，f][1，2]硫氮杂作为起始化合物合成噻萘普丁或其可药用盐的方法，其特征在于所述起始化合物根据权利要求1或2的方法制备。
4.由11-氨基-3-氯-6，11-二氢-5，5-二氧代-6-甲基-二苯并[c，f][1，2]硫氮杂作为起始化合物合成噻萘普丁的钠盐的方法，其特征在于所述起始化合物根据权利要求1或2的方法制备。
5.根据权利要求4的的方法，其特征在于所得噻萘普丁的钠盐中杂质含量低于0.4％。
6.根据权利要求4或5的方法，其特征在于所得噻萘普丁的钠盐中式(VII)的杂质含量低于0.1％：
7.根据权利要求4或5的方法，其特征在于所得噻萘普丁的钠盐不含式(VI)的杂质：
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0004111A FR2807039A1 (fr) | 2000-03-31 | 2000-03-31 | NOUVEAU PROCEDE DE PREPARATION DE LA 11-AMINO-3-CHLORO-6,11- DIHYDRO-5,5-DIOXO-6-METHYL-DIBENZO[c,f][1,2]-THIAZEPINE ET APPLICATION A LA SYNTHESE DE LA TIANEPTINE |
| FR0004111 | 2000-03-31 |
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| CN1319593A CN1319593A (zh) | 2001-10-31 |
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| US6683072B1 (en) * | 2003-02-04 | 2004-01-27 | Vela Pharmaceuticals, Inc. | Compositions and methods for treatment of irritable bowel syndrome and nonulcer dyspepsia |
| PL1937626T3 (pl) * | 2005-10-17 | 2016-08-31 | Generics Uk Ltd | Sposób i związki do otrzymywania salmeterolu |
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| US10961244B2 (en) | 2016-03-25 | 2021-03-30 | The Trustees Of Columbia University In The City Of New York | Mitragynine alkaloids as opioid receptor modulators |
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| CN110790723A (zh) * | 2018-08-02 | 2020-02-14 | 北京万全德众医药生物技术有限公司 | 噻奈普汀钠的合成方法 |
| KR20180101307A (ko) | 2018-09-04 | 2018-09-12 | 지엘팜텍주식회사 | 티아넵틴 또는 이의 약제학적으로 허용되는 염을 포함하는 경구투여용 서방성 정제 |
| KR102199871B1 (ko) | 2018-12-21 | 2021-01-08 | 주식회사 한서켐 | 3,11-디클로로-6-메틸-6,11-디하이드로디벤조[c,f][1,2]티아제핀 5,5-디옥시드의 제조방법 |
| KR20200104265A (ko) | 2020-08-21 | 2020-09-03 | 지엘팜텍주식회사 | 티아넵틴 또는 이의 약제학적으로 허용되는 염을 포함하는 경구투여용 서방성 정제 |
| CN112062733A (zh) * | 2020-10-30 | 2020-12-11 | 南京法恩化学有限公司 | 一种噻萘普汀钠的制备方法 |
| CN115872951A (zh) * | 2022-12-25 | 2023-03-31 | 山东诚汇双达药业有限公司 | 一种噻奈普汀钠中间体甲氧基取代物的合成方法 |
| CN115819375A (zh) * | 2022-12-25 | 2023-03-21 | 山东诚汇双达药业有限公司 | 噻奈普汀钠关键中间体的制备方法 |
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| GB1179108A (en) * | 1966-12-19 | 1970-01-28 | Science Union & Cie | New Derivatives of Dibenzo (c,f) Thiazepine (1,2) and processes for manufacturing them |
| GB1269551A (en) | 1969-03-27 | 1972-04-06 | Science Union & Cie | New tricyclic derivatives and process for their manufacture |
| CA995213A (fr) * | 1972-03-16 | 1976-08-17 | Charles Malen | Procede de preparation de derives tricycliques |
| PL106752B1 (pl) * | 1976-02-25 | 1980-01-31 | Politechnika Gdanska | Sposob otrzymywania nowych 1-nitro-9-alkiloaminoalkiloaminoakrydyn lub ich soli |
| US4564612A (en) * | 1983-04-22 | 1986-01-14 | Takeda Chemical Industries, Ltd. | Condensed, seven-membered ring compounds and their use |
| KR890002073A (ko) * | 1987-07-01 | 1989-04-07 | 원본미기재 | 나프토티아제핀온 |
| RU2024509C1 (ru) * | 1991-05-07 | 1994-12-15 | Всероссийский научный центр по безопасности биологически активных веществ | Производные 9-аминоакридина или их соли с органическими или неорганическими кислотами, проявляющие психотропную, антиамнестическую и липидрегулирующую активность |
| JPH05255290A (ja) * | 1992-03-17 | 1993-10-05 | Fujisawa Pharmaceut Co Ltd | 腫瘍壊死因子産生阻害剤 |
| FR2716623B1 (fr) * | 1994-02-25 | 1996-08-23 | Adir | Utilisation d'un dérivé tricyclique pour l'obtention de médicaments destinés au traitement des troubles mnémo-cognitifs. |
| US5783584A (en) * | 1995-12-11 | 1998-07-21 | Mayo Foundation For Medical Education And Research | THA analogs useful as cholinesterase inhibitors |
| US5886185A (en) * | 1997-11-20 | 1999-03-23 | Development Center For Biotechnoloy | Polyamine-linked acridine dimers |
| GB2339778A (en) * | 1998-07-17 | 2000-02-09 | Secr Defence | Terphenyl Liquid Crystals |
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