CN1319593A - 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]硫氮杂䓬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]硫氮杂䓬的新方法及其合成噻萘普丁的应用 Download PDFInfo
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- JICJBGPOMZQUBB-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid Chemical compound O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21 JICJBGPOMZQUBB-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims abstract description 13
- 229960005138 tianeptine Drugs 0.000 title claims abstract description 13
- WSXNRJXPTNQJBH-UHFFFAOYSA-N 5,6-dihydro-4h-thiazine Chemical compound C1CSN=CC1 WSXNRJXPTNQJBH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 239000005864 Sulphur Substances 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 6
- 159000000000 sodium salts Chemical class 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 5
- 230000000996 additive effect Effects 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract 2
- 238000003786 synthesis reaction Methods 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 235000020057 cognac Nutrition 0.000 description 2
- VBPPJUXIEMSWDT-UHFFFAOYSA-N ethyl 7-aminoheptanoate Chemical compound CCOC(=O)CCCCCCN VBPPJUXIEMSWDT-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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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
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。
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．根据权利要求1或2得到的式(Ⅰ)化合物在合成噻萘普丁或其可药用盐中的应用。
4．根据权利要求1、2或3中任一项得到的式(Ⅰ)化合物在合成噻萘普丁的钠盐中的应用。
5．根据权利要求4的式(Ⅰ)化合物的应用，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的式(Ⅰ)化合物的应用，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4-6中任一项的式(Ⅰ)化合物的应用，其特征在于所得噻萘普丁的钠盐不含式(Ⅵ)的杂质：
Applications Claiming Priority (2)
| 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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| Publication Number | Publication Date |
|---|---|
| CN1319593A true CN1319593A (zh) | 2001-10-31 |
| CN1157387C CN1157387C (zh) | 2004-07-14 |
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| CNB011120835A Expired - Fee Related CN1157387C (zh) | 2000-03-31 | 2001-03-30 | 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 |
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| KR (1) | KR100464180B1 (zh) |
| CN (1) | CN1157387C (zh) |
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| AU (1) | AU777616B2 (zh) |
| BR (1) | BR0101230B1 (zh) |
| CA (1) | CA2342950C (zh) |
| DE (1) | DE60100321T2 (zh) |
| DK (1) | DK1138677T3 (zh) |
| EA (1) | EA003770B1 (zh) |
| ES (1) | ES2201019T3 (zh) |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105254587A (zh) * | 2015-10-21 | 2016-01-20 | 济南诚汇双达化工有限公司 | 一种噻萘普汀钠中间体的制备方法 |
| 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 |
| 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 |
| 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 |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| ES2570597T3 (es) * | 2005-10-17 | 2016-05-19 | Generics Uk Ltd | Proceso e intermedios para la preparación de Salmeterol |
| US9314469B2 (en) | 2008-05-05 | 2016-04-19 | Tonix Pharma Holdings Limited | Method for treating neurocognitive dysfunction |
| US8198268B2 (en) | 2008-10-31 | 2012-06-12 | Janssen Biotech, Inc. | Tianeptine sulfate salt forms and methods of making and using the same |
| WO2010070667A2 (en) * | 2008-11-19 | 2010-06-24 | Biophore India Pharmaceuticals Pvt. Ltd. | Novel process for the preparation of 7-((3-chloro-6-methyl-5,5-dioxo-6,11-dihydrodibenzo(c,f)(1,2) thiazepin-11-yl)amino)heptanoate |
| KR101136976B1 (ko) * | 2011-09-06 | 2012-05-30 | 건일제약 주식회사 | 티아넵틴 또는 그의 염을 포함하는 탈모증의 예방 또는 치료용 약학 조성물 |
| GB201208315D0 (en) | 2012-05-11 | 2012-06-27 | Numedicus Ltd | Pharmaceutical methods and compositions |
| AU2016323977B9 (en) | 2015-09-16 | 2021-03-04 | The Trustees Of Columbia University In The City Of New York | Carboxylic diarylthiazepineamines as mu-opioid receptor agonists |
| WO2017165738A1 (en) | 2016-03-25 | 2017-09-28 | The Trustees Of Columbia University In The City Of New York | Mitragynine alkaloids as opioid receptor modulators |
| WO2018170275A1 (en) * | 2017-03-15 | 2018-09-20 | The Trustees Of Columbia University In The City Of New York | Carboxylic diarythiazepineamines as mixed mu-and delta-opioid receptor agonists |
| 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 |
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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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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105254587A (zh) * | 2015-10-21 | 2016-01-20 | 济南诚汇双达化工有限公司 | 一种噻萘普汀钠中间体的制备方法 |
| CN105254587B (zh) * | 2015-10-21 | 2018-01-09 | 济南诚汇双达化工有限公司 | 一种噻萘普汀钠中间体的制备方法 |
| 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 |
| 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 |
| 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 |
| 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 |
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