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CN108976163B - 一种多奈哌齐双羟萘酸盐新的制备方法 - Google Patents

一种多奈哌齐双羟萘酸盐新的制备方法 Download PDF

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CN108976163B
CN108976163B CN201710413010.1A CN201710413010A CN108976163B CN 108976163 B CN108976163 B CN 108976163B CN 201710413010 A CN201710413010 A CN 201710413010A CN 108976163 B CN108976163 B CN 108976163B
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donepezil
shuang
hydroxynaphthoate
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CN108976163A (zh
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许炜
陈茜
顾虹
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Shanghai Aobo Biomedical Co ltd
Zhejiang Huahai Pharmaceutical Co Ltd
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Zhejiang Huahai Pharmaceutical Co Ltd
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Priority to EP18813380.5A priority patent/EP3620450B1/en
Priority to US16/618,896 priority patent/US11014885B2/en
Priority to PCT/CN2018/089999 priority patent/WO2018223971A1/zh
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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Abstract

本发明涉及一种多奈哌齐双羟萘酸盐(1‑苄基‑4‑[(5,6‑二甲氧基茚满酮‑2‑基)甲基]哌啶双羟萘酸盐)新的制备方法，采用所述方法制得的多奈哌齐双羟萘酸盐纯度高，具有良好的流动性。

Description

一种多奈哌齐双羟萘酸盐新的制备方法
技术领域
多奈哌齐双羟萘酸盐(1-苄基-4-[(5,6-二甲氧基茚满酮-2-基)甲基]哌啶双羟萘酸盐)新的制备方法，属于化学医药领域。
技术背景
多奈哌齐(Donepezil)化学名为1-苄基-4-[(5,6-二甲氧基茚满酮-2-基)甲基]哌啶，是一种阿尔茨海默病(Alzheimer's disease)的治疗药物。分子量为379.49，熔点为207℃。
阿尔茨海默病(Alzheimer's disease)会导致患者产生痴呆症状，包括记忆衰退、思维迟钝、日常活动受限等。阿尔茨海默病患者经常是非顺从性的，难以评价患者是否接受了药物的准确剂量。因此，通过成盐手段将多奈哌齐配制成缓释制剂是十分必要的。
专利CN201280058819公开了多奈哌齐双羟萘酸盐晶型A、B及其制备方法，采用的溶剂是DMSO与水，起始物料为多奈哌齐游离碱或多奈哌齐盐酸盐、双羟萘酸或双羟萘酸二钠盐。
专利WO2013005094公开了多奈哌齐双羟萘酸盐晶型T1，T2，T3及其制备方法，采用的溶剂包括甲醇、异丙醇、DMF与水，起始物料为多奈哌齐游离碱与双羟萘酸。
采用上述方法制备的多奈哌齐双羟萘酸盐粉体性质存在技术问题，团聚现象严重，流动性差，对后续药物的开发造成困难。本发明人通过不断的研究，发现一种新的多奈哌齐双羟萘酸盐的制备方法，克服了现有技术存在的问题。
发明内容
本发明提供了一种多奈哌齐双羟萘酸盐(式I化合物)的制备方法。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于，所述方法为将式I化合物溶解于有机溶剂中，滴加另一种溶剂使其析出。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于其中所述的反应溶剂选自醇类、醚类、酯类、酮类、腈类、烷烃类、水一种或者组合。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于，其中所述的反应溶剂选自酮类。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于，其中所述的反应溶剂为丙酮。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于，其中所述的溶解温度为0-50℃。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于，其中所述的溶解温度为15-30℃。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于，其中所述的滴加溶剂选自醇类、醚类、酯类、酮类、腈类、烷烃类、水一种或者组合。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于，其中所述的滴加溶剂为水。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于，其中所述的滴加溶剂时的温度为0-50℃。
更进一步，本发明提供了一种多奈哌齐双羟萘酸盐的制备方法，其特征在于，其中所述的滴加溶剂时的温度为15-30℃。
本发明所述的式I化合物，根据使用Cu-Kα辐射的X-射线粉末衍射光谱(见图1)与DSC-TGA谱图确定，为晶型A。
本发明所述的式I化合物，具有<30°的休止角，流动性良好。
附图说明
图1为多奈哌齐双羟萘酸盐的XRPD谱图。
图2为多奈哌齐双羟萘酸盐的DSC-TGA谱图。
具体实施实例：
以下将结合实施例对本发明的实施方式做详细说明。本发明的实施方式包括但不局限于下述实施例，其不应当被视为对本发明保护范围的限制。
本发明所述的X-射线粉末衍射数据是使用德国布鲁克公司的BRUKER D8Advance测定的，电压电流：40kV,40mA；测角仪：立式测角仪，半径280mm；狭缝：DS＝2°,SS＝1/2°,mask＝15mm,RS＝5.0mm；探测器：LYNXEYE检测器；扫描模式：连续扫描；扫描范围：3-40°；每步计数时间：0.2s；扫描总时间：390s。
本发明所述的差示扫描量热图谱是使用瑞士METTLER公司的TGA/DSC 2测定，温度范围30-300℃,升温速度10℃/min。
实施实例1：多奈哌齐双羟萘酸盐的制备
称取多奈哌齐双羟萘酸盐样品200mg，加入5ml丙酮，常温下使之完全溶解；常温下滴加15ml水溶液。滴加过程中立即出现固体，分散良好。滴加完毕继续搅拌2h后过滤。滤饼以50ml水洗涤，抽滤10min，真空干燥。得到180mg多奈哌齐双羟萘酸盐样品，晶型为Form A。
实施实例2：多奈哌齐双羟萘酸盐的制备
称取多奈哌齐双羟萘酸盐样品2g，加入50ml丙酮，常温下使之完全溶解；常温下滴加150ml水溶液。滴加过程中立即出现固体，分散良好。滴加完毕继续搅拌2h后过滤。滤饼以50ml水洗涤，抽滤10min，真空干燥。得到1.8g多奈哌齐双羟萘酸盐样品，晶型为Form A。
实施实例3：多奈哌齐双羟萘酸盐的制备
称取多奈哌齐双羟萘酸盐样品20g，加入500ml丙酮，常温下使之完全溶解；常温下滴加1.5L水溶液。滴加过程中立即出现固体，分散良好。滴加完毕继续搅拌2h后过滤。滤饼以500ml水洗涤，抽滤10min，真空干燥。得到18g多奈哌齐双羟萘酸盐样品，晶型为Form A。

Claims (1)

1.一种式I化合物晶型A的制备方法，其特征在于将式I化合物溶解于有机溶剂中，滴加另一种溶剂使其析出，得到式I化合物晶型A；
其中所述的有机溶剂为丙酮，溶解温度为15-30℃，滴加溶剂为水，滴加溶剂时的温度为15-30℃。
CN201710413010.1A 2017-06-05 2017-06-05 一种多奈哌齐双羟萘酸盐新的制备方法 Active CN108976163B (zh)

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CN201710413010.1A CN108976163B (zh) 2017-06-05 2017-06-05 一种多奈哌齐双羟萘酸盐新的制备方法
CN201880025218.9A CN110603247B (zh) 2017-06-05 2018-06-05 一种多奈哌齐双羟萘酸盐新的制备方法
EP18813380.5A EP3620450B1 (en) 2017-06-05 2018-06-05 New method for preparing donepezil pamoate
US16/618,896 US11014885B2 (en) 2017-06-05 2018-06-05 Method for preparing donepezil pamoate
PCT/CN2018/089999 WO2018223971A1 (zh) 2017-06-05 2018-06-05 一种多奈哌齐双羟萘酸盐新的制备方法

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US20080076928A1 (en) * 2004-06-29 2008-03-27 Tarur Venkatasubramanian Radha Novel pharmaceutical salts of 1-benzyl-4-&lsqb; (5,6-dimethoxy-1-indanone)-2-yl&rsqb; methyl piperidine ( Donepezil)
WO2013005094A1 (en) * 2011-07-05 2013-01-10 Torrent Pharmaceuticals Ltd Acid addition salt of donepezil and pharmaceutical composition thereof
CN104039765A (zh) * 2011-11-29 2014-09-10 顾自强 多奈哌齐双羟萘酸盐、制备方法及其应用
US20140315952A1 (en) * 2011-11-29 2014-10-23 Ziqiang Gu Donepezil pamoate, method of preparation and use thereof

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US7439365B2 (en) * 2003-11-17 2008-10-21 Usv, Ltd. Pharmaceutical salt of (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl] methyl piperidine (Donepezil)
CN101906066B (zh) * 2010-08-08 2015-03-11 浙江华海药业股份有限公司 一种制备盐酸奈哌齐晶型i的方法
EP3051977B1 (en) * 2013-10-01 2018-11-07 SPG International LLC Shelving system
WO2018153315A1 (zh) * 2017-02-23 2018-08-30 上海华汇拓医药科技有限公司 一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法

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US20080076928A1 (en) * 2004-06-29 2008-03-27 Tarur Venkatasubramanian Radha Novel pharmaceutical salts of 1-benzyl-4-&lsqb; (5,6-dimethoxy-1-indanone)-2-yl&rsqb; methyl piperidine ( Donepezil)
WO2013005094A1 (en) * 2011-07-05 2013-01-10 Torrent Pharmaceuticals Ltd Acid addition salt of donepezil and pharmaceutical composition thereof
CN104039765A (zh) * 2011-11-29 2014-09-10 顾自强 多奈哌齐双羟萘酸盐、制备方法及其应用
US20140315952A1 (en) * 2011-11-29 2014-10-23 Ziqiang Gu Donepezil pamoate, method of preparation and use thereof

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EP3620450B1 (en) 2022-05-11
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CN110603247B (zh) 2023-08-22
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