CN101481321B - 阿戈美拉汀卤化氢复合物及其制备方法 - Google Patents
阿戈美拉汀卤化氢复合物及其制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B7/00—Halogens; Halogen acids
- C01B7/01—Chlorine; Hydrogen chloride
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B7/00—Halogens; Halogen acids
- C01B7/09—Bromine; Hydrogen bromide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及阿戈美拉汀的一种复合物及其制备方法。本发明方法得到的阿戈美拉汀卤化氢复合物，溶解性比阿戈美拉汀有显著提高，适合成品药物制剂时的应用需要；且产品稳定性好、纯度高。在制备工艺上也非常简便，无需特殊的操作，即可得到高纯度的产品。
Description
技术领域
本发明涉及阿戈美拉汀的一种复合物及其制备方法技术领域。
背景技术
阿戈美拉汀(agomelatine，1)，化学名为N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺，其结构式如下式II所示。其商品名为Valdoxan，是法国Servier公司研发的褪黑激素激动剂，兼有拮抗5HT2C受体作用。它是第一个褪黑激素类抗抑郁药，能有效治疗抑郁症，改善睡眠参数和保持性功能。
鉴于该化合物的药学价值，获得纯度优良、溶解度更好、具有很确定且重现性极好的化合物或复合物是及其重要的。
发明内容
本发明的目的就是提供一种阿戈美拉汀卤化氢复合物，该新的化合物溶解度高，稳定性好，纯度高，利于阿戈美拉汀做成药物制剂的实际应用。
本发明的另一目的是提供上述阿戈美拉汀卤化氢复合物的制备方法。
本申请的发明人在进行阿戈美拉汀产品纯化时，惊喜的发现阿戈美拉汀能与如下的无机酸，如盐酸、氢溴酸或氢碘酸混合形成物理化学性质稳定的复合物，此复合物适用于药物制剂的制备。使用其它常用的多种无机酸(如：硫酸、磷酸、过氯酸等)或有机酸(如：乙酸、草酸、酒石酸、富马酸等)，均不易得到复合物。
上述的阿戈美拉汀卤化氢复合物，如下式所示：
其中X代表卤素。X优选Cl或Br。
阿戈美拉汀卤化氢复合物的制备方法，该方法是将阿戈美拉汀与各种形式的HX反应形成复合物。具体操作时，既可以先将阿戈美拉汀溶解于有机溶剂，然后通入HX气体，将结晶析出的固体洗涤、干燥；也可以是将阿戈美拉汀加入到含有HX的有机溶液中，结晶析出后洗涤、干燥。HX浓度的控制是以能析出复合物为最低浓度要求为准。经过多次的实验结果比较，盐酸乙酸乙酯中析出的阿戈美拉汀盐酸复合物收率比较高，所以最优选的方法是将阿戈美拉汀加入到盐酸乙酸乙酯中，结晶析出后洗涤、干燥得到目标产物。
上述阿戈美拉汀卤化氢复合物的制备方法，其有机溶剂的选择没有特别限制，只要是能够溶解反应原料阿戈美拉汀及卤化氢，同时又能使阿戈美拉汀卤化氢复合物析出即可。可使用的溶剂包括：乙酸乙酯、乙酸甲酯、乙酸正丁酯、丙酮、乙腈等，优选乙酸乙酯。像极性较低的溶剂，如醇类(乙醇，甲醇等)、DMF、DMSO等都不太合适。
本发明的有益效果：
本发明在众多常用酸中发现阿戈美拉汀仅能与氢卤酸反应生产稳定的复合物，且无论是在稳定性、溶解度、吸湿性等物理性质，以及制取难度上显著优于其它的常用酸与阿戈美拉汀的反应产物。
本发明制备的阿戈美拉汀卤化氢复合物，溶解性比阿戈美拉汀有显著提高，适合成品药物制剂时的应用需要；且产品稳定性好、纯度高。在制备工艺上也非常简便，无需特殊的操作，即可得到高纯度的产品。
具体实施方式
下面通过几个优选的具体实施例进一步说明本发明，对于实施例中涉及的具体数据和操作等并不构成本发明要求保护范围的限制。
实施例1：
将1.0g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，室温下缓慢通入干燥的氯化氢气体直至溶液不再增重，过滤，固体用乙酸乙酯2ml*2洗涤，30℃下干燥得到白色固体1.05g；纯度：99.7％。
分析结果(C15H17NO2·HCl)
计算值：Cl％(12.69％)
实测值：Cl％(12.44％)
熔点：64-66℃
实施例2：
将3.0g阿戈美拉汀搅拌溶解于30ml乙酸乙酯中，室温下通入干燥的氯化氢气体直至溶液不再增重，过滤，固体用乙酸乙酯5ml*2洗涤，30℃下干燥得到白色固体3.2g；纯度：99.8％。
分析结果(C15H17NO2·HCl)
计算值：Cl％(12.69％)
实测值：Cl％(12.60％)
熔点：64-66℃
实施例3：
将10g阿戈美拉汀搅拌溶解于100ml乙酸乙酯中，室温下通入干燥的氯化氢气体直至溶液不再增重，过滤，固体用乙酸乙酯10ml*2洗涤，30℃下干燥得到白色固体10.8g。
分析结果(C15H17NO2·HCl)；纯度：99.8％
计算值：Cl％(12.69％)
实测值：Cl％(12.21％)
熔点：64-66℃
实施例4：
将10g阿戈美拉汀加入到饱和的100ml氯化氢乙酸乙酯溶液中，室温下搅拌1h，过滤，固体用乙酸乙酯10ml*2洗涤，30℃下干燥得到白色固体10.9g；纯度：99.8％。
分析结果(C15H17NO2·HCl)
计算值：Cl％(12.69％)
实测值：Cl％(12.39％)
熔点：64-66℃
实施例5：
根据专利CN1680284A制备阿戈美拉汀的方法，将17.3g 2-(7-甲氧基-1-萘基)乙胺盐酸盐和6.6g乙酸钠的乙醇溶液加入反应器中，搅拌混合物，然后加入7.9g乙酸酐。对反应混合物加热回流，加入60ml水。将反应混合物回复至室温，滤出所获沉淀物，母液用20ml×3乙酸乙酯萃取，蒸干溶剂，所获固体搅拌溶解于100ml乙酸乙酯中，室温下通入干燥的氯化氢气体直至溶液不再增重，过滤，固体用乙酸乙酯10ml*2洗涤，30℃下干燥得到白色固体18.5g。
收率：91％，纯度：99.1％。
分析结果(C15H17NO2·HCl)
计算值：Cl％(12.69％)
实测值：Cl％(12.57％)
熔点：64-66℃
实施例6：
根据专利CN1680284A制备阿戈美拉汀的方法，将17.3g 2-(7-甲氧基-1-萘基)乙胺盐酸盐和6.6g乙酸钠的乙醇溶液加入反应器中，搅拌混合物，然后加入7.9g乙酸酐。对反应混合物加热回流，加入60ml水。将反应混合物回复至室温，滤出所获沉淀物，母液用20ml×3乙酸乙酯萃取，蒸干溶剂，所获固体加入到100ml饱和氯化氢乙酸乙酯溶液中，室温下搅拌1h，过滤，固体用乙酸乙酯10ml*2洗涤，30℃下干燥得到白色固体18.7g，收率：92％，纯度：99.8％。
分析结果(C15H17NO2·HCl)
计算值：Cl％(12.69％)
实测值：Cl％(12.70％)
熔点：64-66℃
实施例7：
将10g阿戈美拉汀搅拌溶解于100ml乙酸乙酯中，室温下干燥的溴化氢气体直至溶液不再增重，过滤，固体用乙酸乙酯10ml*2洗涤，30℃下干燥得到白色固体11.2g；纯度：99.3％。
分析结果(C15H17NO2·HBr)
计算值：Br％(24.6％)
实测值：Br％(23.8％)
熔点：85-87℃
实施例8：
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，室温下逐滴滴入浓硫酸，始终无沉淀析出。
实施例9：
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，在-10度下逐滴滴入浓硫酸，始终无沉淀析出。
实施例10
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，在-10度下逐滴滴入冰醋酸，始终无沉淀析出。
实施例11
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，在-10度下逐滴滴入富马酸，始终无沉淀析出。
测试方法：
分别将阿戈美拉汀的氯化氢和溴化氢复合物放入40℃的恒温箱中，放置30天，通过高效液相色谱法对这些晶型的稳定性进行研究。
1、样品纯度测定
色谱条件：用十八烷基硅烷键合硅胶为填充剂；以10mM/L磷酸缓冲盐(用氢氧化钠调节pH至7.0)和乙腈体积比为2∶7的混合溶液作为流动相；柱温为40℃；检测波长为220nm。通过内标法测定纯度。
用流动相分别配置成1mg/mL的溶液，各取10μL注入液相色谱仪，记录色谱图。
2、样品含量测定
测定方法参考样品纯度测定的方法，用外标法进行测定。结果如下表1：
表1
| 阿戈美拉汀复合物 | 0天 | 5天 | 10天 | 30天 |
| 氯化氢复合物 | 99.8％ | 99.8％ | 99.8％ | 99.8％ |
| 溴化氢复合物 | 99.3％ | 99.3％ | 99.3％ | 99.3％ |
3、水溶性测定
测定方法采用HPLC方法，用外标法进行测定。结果如下表2：
表2
| 样品名称 | 阿戈美拉汀 | 阿戈美拉汀HBr复合物 | 阿戈美拉汀HCl复合物 |
| 纯度 | 99.79％ | 99.77％ | 99.82％ |
| 溶解度(mg/ml) | 1.11 | 2.14 | 1.60 |
Claims (5)
1.如下式所示的阿戈美拉汀卤化氢复合物：
其中X代表卤素。
2.如权利要求1所述的阿戈美拉汀卤化氢复合物，其特征在于：X为Cl或Br。
3.权利要求1或2所述阿戈美拉汀卤化氢复合物的制备方法，该方法是先将阿戈美拉汀溶解于有机溶剂，然后通入HX气体，结晶析出复合物。
4.权利要求1或2所述阿戈美拉汀卤化氢复合物的制备方法，该方法是将阿戈美拉汀加入到含有HX的有机溶液中，结晶析出复合物。
5.如权利要求3所述阿戈美拉汀卤化氢复合物的制备方法，其特征在于：通入HX气体直至饱和。
Priority Applications (36)
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| CN2009100467821A CN101481321B (zh) | 2009-02-27 | 2009-02-27 | 阿戈美拉汀卤化氢复合物及其制备方法 |
| BRPI1008767-2A BRPI1008767B1 (pt) | 2009-02-27 | 2010-02-26 | Complexo de haleto de hidrogênio de agomelatina e preparação do mesmo |
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| PT107458366T PT2418195E (pt) | 2009-02-27 | 2010-02-26 | Complexo de hidrohalogeneto de agomelatina e método para a sua preparação |
| PCT/CN2010/070780 WO2010097052A1 (zh) | 2009-02-27 | 2010-02-26 | 阿戈美拉汀卤化氢复合物及其制备方法 |
| EP10745836.6A EP2418195B1 (en) | 2009-02-27 | 2010-02-26 | Agomelatine hydrohalide complex and preparation method thereof |
| MA34120A MA33063B1 (fr) | 2009-02-27 | 2010-02-26 | Complexe d'hydrohalogenure d'agomelatine et procede de preparation de celui-ci |
| AU2010217082A AU2010217082B2 (en) | 2009-02-27 | 2010-02-26 | Agomelatine hydrohalide complex and preparation method thereof |
| EA201101208A EA021939B1 (ru) | 2009-02-27 | 2010-02-26 | Гидрогалогенидный комплекс агомелатина и его получение |
| MX2011008946A MX2011008946A (es) | 2009-02-27 | 2010-02-26 | Un complejo de haluro de hidrogeno de agomelatina y la preparacion del mismo. |
| SG2011058542A SG173691A1 (en) | 2009-02-27 | 2010-02-26 | Agomelatine hydrohalide complex and preparation method thereof |
| NZ594773A NZ594773A (en) | 2009-02-27 | 2010-02-26 | Agomelatine hydrohalide complex and preparation method thereof |
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| CA2753449A CA2753449C (en) | 2009-02-27 | 2010-02-26 | Agomelatine hydrohalide complex and preparation method thereof |
| PE2011001512A PE20120652A1 (es) | 2009-02-27 | 2010-02-26 | Un complejo de haluro de hidrogeno de agomelatina y la preparacion del mismo |
| ES10745836T ES2530730T3 (es) | 2009-02-27 | 2010-02-26 | Complejo hidrohalogenuro-agomelatina y preparación del mismo |
| UAA201111232A UA97619C2 (ru) | 2009-02-27 | 2010-02-26 | Гидрогалогенидный комплекс агомелатина и способ его получения |
| KR1020117021812A KR101284202B1 (ko) | 2009-02-27 | 2010-02-26 | 아고멜라틴 할로겐산염 복합체 및 이의 제조 방법 |
| AP2011005845A AP3048A (en) | 2009-02-27 | 2010-02-26 | Agomelatine hydrohalide complex and preparation method thereof |
| PL10745836T PL2418195T3 (pl) | 2009-02-27 | 2010-02-26 | Kompleks halogenowodorowy agomelatyny i sposób jego wytwarzania |
| MYPI2011003884A MY154015A (en) | 2009-02-27 | 2010-02-26 | A hydrogen halide complex of agomelatine and preparation thereof |
| US13/138,511 US8524949B2 (en) | 2009-02-27 | 2010-02-26 | Agomelatine hydrohalide complex and preparation method thereof |
| JP2011551399A JP5426693B2 (ja) | 2009-02-27 | 2010-02-26 | アゴメラチンハロゲン化水素複合体及びその製造方法 |
| DK10745836T DK2418195T3 (en) | 2009-02-27 | 2010-02-26 | Agomelatinhydrogenhalogenidkompleks and manufacturing method thereof |
| SI201030872T SI2418195T1 (sl) | 2009-02-27 | 2010-02-26 | Agomelatin halogenovodikov kompleks in njegov postopek priprave |
| IL214682A IL214682A (en) | 2009-02-27 | 2011-08-16 | Agomalatine hydrohydric linkage and method of preparation thereof |
| ZA2011/06048A ZA201106048B (en) | 2009-02-27 | 2011-08-17 | Agomelatine hydrohalide complex and preparation method thereof |
| CR20110446A CR20110446A (es) | 2009-02-27 | 2011-08-19 | Un complejo de haluro de hidrógeno de agomelatina y la preparación del mismo |
| CU20110163A CU20110163A7 (es) | 2009-02-27 | 2011-08-23 | Un complejo de haluro de hidrógeno de agomelatina y la preparación del mismo |
| CO11109274A CO6420335A2 (es) | 2009-02-27 | 2011-08-26 | Un complejo de haluro de hidrogeno de agomelatina y la preparación del mismo |
| NI201100163A NI201100163A (es) | 2009-02-27 | 2011-08-26 | Un complejo de haluro de hidrógeno de agomelatina y la preparación del mismo |
| HN2011002291A HN2011002291A (es) | 2009-02-27 | 2011-08-26 | Un complejo de haluro de hidrogeno de agomelatina y la preparacion del mismo |
| CL2011002090A CL2011002090A1 (es) | 2009-02-27 | 2011-08-26 | Complejo de haluro de agomelatina, que corresponde a un derivado de naftaleno; procedimiento de preparacion del mismo. |
| EC2011011290A ECSP11011290A (es) | 2009-02-27 | 2011-08-26 | Un Complejo de Haluro de Hidrógeno de Agomelatina y la Preparación del Mismo |
| HRP20150072AT HRP20150072T1 (en) | 2009-02-27 | 2015-01-20 | Agomelatine hydrohalide complex and preparation method thereof |
| CY20151100070T CY1117100T1 (el) | 2009-02-27 | 2015-01-22 | Συμπλοκο υδραλογονου της αγομελατινης και μεθοδος παρασκευης του |
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| JP (1) | JP5426693B2 (zh) |
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| SI (1) | SI2418195T1 (zh) |
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| CN102106806B (zh) * | 2009-12-29 | 2013-04-17 | 上海中西制药有限公司 | 一种固体制剂的制备方法及所得固体制剂 |
| CN102190594A (zh) * | 2010-03-17 | 2011-09-21 | 上海医药工业研究院 | 阿戈美拉汀氯化氢水合物及其制备方法 |
| CN102190595A (zh) * | 2010-03-17 | 2011-09-21 | 上海医药工业研究院 | 阿戈美拉汀溴化氢水合物及其制备方法 |
| CN101870662B (zh) * | 2010-05-21 | 2013-03-20 | 中山大学 | 结晶型阿戈美拉汀溶剂化物及其制备方法 |
| WO2012046253A2 (en) * | 2010-10-08 | 2012-04-12 | Msn Laboratories Limited | Process for the preparation of n-[2- (7-methoxy-l-naphthyl) ethyl] acetamide and its novel crystalline forms |
| EP2517700B1 (en) * | 2011-04-28 | 2013-07-17 | Zentiva, k.s. | Pharmaceutically acceptable cocrystals of N-[2-(7-methoxy-1-naphthyl]acetamide and methods of their preparation |
| EP2551257A1 (en) * | 2011-07-28 | 2013-01-30 | Laboratorios Del. Dr. Esteve, S.A. | Co-crystals of agomelatine with co-crystal-formers |
| FR2978916B1 (fr) | 2011-08-10 | 2013-07-26 | Servier Lab | Composition pharmaceutique solide pour administration buccale d'agomelatine |
| CN102718675B (zh) * | 2012-06-07 | 2015-03-25 | 上海右手医药科技开发有限公司 | 阿戈美拉汀甲磺酸复合物及其制备方法 |
| EP2851363B1 (en) * | 2012-05-14 | 2018-01-03 | Shanghai Righthand Pharmtech. Co., Ltd. | Agomelatine acid radical composite, and preparation method and application thereof |
| CN102702041B (zh) * | 2012-05-14 | 2013-08-14 | 上海右手医药科技开发有限公司 | 阿戈美拉汀苯磺酸类复合物及其制备方法 |
| CN102702008B (zh) * | 2012-06-03 | 2014-05-28 | 上海右手医药科技开发有限公司 | 阿戈美拉汀硫酸复合物及其制备方法 |
| ES2590908T3 (es) * | 2012-12-17 | 2016-11-24 | Dr. Reddy's Laboratories Ltd. | Cocristal de agomelatina con ácido fosfórico |
| WO2014096373A1 (en) | 2012-12-21 | 2014-06-26 | Laboratorios Lesvi, S. L. | Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof |
| FR3001894A1 (fr) | 2013-02-08 | 2014-08-15 | Servier Lab | Composition pharmaceutique solide pour administration buccale d'agomelatine |
| US9573891B2 (en) * | 2013-07-29 | 2017-02-21 | Les Laboratoires Servier | Complexes of agomelatine and sulphonic acids, a process for their preparation and pharmaceutical compositions containing them |
| RU2695609C2 (ru) * | 2013-07-31 | 2019-07-24 | Ле Лаборатуар Сервье | НОВЫЕ ФОРМЫ СОКРИСТАЛЛОВ АГОМЕЛАТИНА И n-ТОЛУОЛСУЛЬФОНОВОЙ КИСЛОТЫ, СПОСОБ ИХ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ, КОТОРЫЕ ИХ СОДЕРЖАТ |
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Effective date of registration: 20121226 Address after: Inside France Patentee after: Service Lab Address before: 200040 Beijing West Road, Shanghai, No. 1320, No. Patentee before: Shanghai Institute of pharmaceutical industry |
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