[go: up one dir, main page]

CN114105862A - 盐酸多奈哌齐杂质及其制备方法 - Google Patents

盐酸多奈哌齐杂质及其制备方法 Download PDF

Info

Publication number
CN114105862A
CN114105862A CN202010890593.9A CN202010890593A CN114105862A CN 114105862 A CN114105862 A CN 114105862A CN 202010890593 A CN202010890593 A CN 202010890593A CN 114105862 A CN114105862 A CN 114105862A
Authority
CN
China
Prior art keywords
impurity
donepezil
sodium
quaternary ammonium
ammonium salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202010890593.9A
Other languages
English (en)
Inventor
刘岳
蓝俊亮
胡佳兴
黄文锋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Huahai Pharmaceutical Co Ltd
Zhejiang Huahai Licheng Pharmaceutical Co Ltd
Original Assignee
Zhejiang Huahai Pharmaceutical Co Ltd
Zhejiang Huahai Licheng Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Huahai Pharmaceutical Co Ltd, Zhejiang Huahai Licheng Pharmaceutical Co Ltd filed Critical Zhejiang Huahai Pharmaceutical Co Ltd
Priority to CN202010890593.9A priority Critical patent/CN114105862A/zh
Publication of CN114105862A publication Critical patent/CN114105862A/zh
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及如下所示的盐酸多奈哌齐的新杂质及其制备方法，所述方法包括将多奈哌齐和氯苄或者溴苄反应生成季铵盐，再经重排反应、分离得到目标化合物。本发明得到的杂质对于研究杂质来源以及新的分析方法开发非常有用。

Description

盐酸多奈哌齐杂质及其制备方法
技术领域
本发明涉及盐酸多奈哌齐的新杂质及其制备方法。
背景技术
盐酸多奈哌齐是一种治疗老年痴呆治疗药物，属于第二代胆碱酯酶抑制剂，临床上用于轻度或中度阿尔茨海默型痴呆症状的治疗，结构如下所示：
Figure BDA0002656842240000011
药物杂质与药品质量、安全性及效能密切相关，杂质控制在药物开发研究中的重要性也越来越受到重视。
发明内容
在盐酸多奈哌齐成品检测时，申请人发现在第二次进样检测时会出现2个单杂，调查发现由于杂质出峰时间较晚(60分钟后才出峰)，而现有检测方法条件下该杂质不出峰，等第二针进样检测时，第一针残留的杂质就会在第二个样品出峰，经结构鉴定是两个文献从未报道的全新杂质，结构式如下所示：
Figure BDA0002656842240000012
鉴于目前分析方法的局限性，为了更好地控制该杂质，保证产品质量，需要提供杂质标准品用于开发新的分析方法。
因此，本发明的另一方面，是提供了一种制备杂质I和杂质II的方法，包括以下步骤：
1)将游离后的多奈哌齐和卤代烃反应生成式III所示的季铵盐，
2)式III所示季铵盐在碱性条件下在有机溶剂中经重排反应生成杂质I和杂质II，
3)分离得到杂质I和杂质II，合成路线如下所示:
Figure BDA0002656842240000021
上述结构式中，X为氯或溴。
上述制备方法的优选方案为：
其中步骤1中所用的溶剂选自二氯甲烷，乙腈，氯仿，丙酮或乙酸乙酯，进一步优选二氯甲烷；卤代烃优选为氯苄或者溴苄；氯苄或者溴苄与多奈哌齐的摩尔比为1:1-2:1，优选1.2:1；反应温度优选为25-80℃，进一步优选为溶剂回流温度。
步骤2中所用的溶剂为四氢呋喃，甲基叔丁醚，甲基四氢呋喃，乙二醇二甲醚等醚类溶剂，进一步优选四氢呋喃；碱为甲醇钠，甲醇钠钾，叔丁醇钠，叔丁醇钾，乙醇钠，乙醇钾等有机碱。
步骤3的分离方法优选为柱层析。
本发明提供了两种全新的多奈哌齐杂质化合物，这对于寻找杂质的来源以及进一步研究从源头上降低该杂质的方法非常有用；另一方面本发明制备得到的杂质可以作为标准品用于多奈哌齐分析方法的开发，从而有效控制该杂质和保证药品质量。
具体实施方式
称取41.6g盐酸多奈哌齐粗品，加入300ml二氯甲烷，搅拌，称取4g氢氧化钠，加入150ml水，配成氢氧化钠水溶液，然后滴加氢氧化钠水溶液，滴加完毕，搅拌0.5-1小时，静止15分钟，分层，二氯甲烷层中加入20.5克苄溴，升温回流8-10h，降温过滤，二氯甲烷洗涤滤饼，得季铵盐50.6g，收率92％，纯度99％。
称取36g的季铵盐加入到500ml三口烧瓶中，加入350ml四氢呋喃，加入11g叔丁醇钠，室温下反应15-20h，反应结束后抽滤，滤饼用四氢呋喃洗涤，滤液用硅胶拌样上柱，过柱之前需要用三乙胺润柱再进行分离。通过分离分别得到杂质I和杂质II，收率分别为25.8％和36.9％，HPLC纯度分别为98％和99％，ESI-MS[M+H+]＝470.1。
杂质I:1H NMR(400MHz,CDCl3)7.20～7.12(3H,m),7.11～6.99(6H,m),6.94～6.92(2H,d),6.76(1H,s),3.88(3H,s),3.82(3H,s),3.59(1H,s),3.29～3.27(1H,m),3.15～3.08(1H,dd),3.00～2.94(3H,t),2.63～2.55(2H,m),1.99～1.97(1H,m),1.84～1.74(2H,m),1.70～1.51(3H,m),1.35～1.17(4H,m)
13C NMR(100MHz,CDCl3)206.7,154.4,148.3,147.7,128.3,128.2,127.9,126.8,126.7,126.0,124.7,106.3,103.3,70.9,55.1,55.0,51.3,47.9,47.9,44.3,38.1,37.6,33.4,32.2,32.2,30.9,25.8
杂质II:1H NMR(400MHz,CDCl3)7.78～7.76(1H,d),7.36～7.35(2H,d),7.24～7.19(3H,m),7.17～7.12(2H,m),7.07～7.02(2H,m),6.82(1H,s),4.34(1H,s),3.88(3H,s),3.83(3H,s),3.17～3.11(1H,m),2.91～2.87(1H,m),2.72～2.60(3H,m),2.26(3H,s),1.89～1.74(3H,m),1.61(1H,s),1.55～1.52(1H,m),1.42～1.39(1H,m),1.31～1.17(3H,m)
13C NMR(100MHz,CDCl3)207.9,155.4,149.4,148.8,142.2,141.5,135.7,130.4,129.3,128.6,128.2,127.2,126.6,126.2,126.1,107.3,104.3,56.2,56.1,52.8,52.7,52.6,45.5,45.5,38.6,34.8,34.7,33.4,33.3,32.1,32.0,26.9,19.9。

Claims (10)

1.多奈哌齐杂质化合物，选自以下化合物：
Figure FDA0002656842230000011
2.一种制备杂质I和杂质II的方法，包括以下步骤：
1)将多奈哌齐和氯苄或者溴苄反应生成式III所示的季铵盐，
2)式III所示的季铵盐在碱性条件下在有机溶剂中经重排反应生成杂质I和杂质II，
3)分离得到杂质I和杂质II，合成路线如下所示:
Figure FDA0002656842230000012
上述结构式中，X为氯或溴。
3.根据权利要求2所示的方法，其中步骤1中所用的溶剂选自二氯甲烷，乙腈，氯仿，丙酮或乙酸乙酯。
4.根据权利要求2所示的方法，其中步骤1中氯苄或者溴苄与多奈哌齐的摩尔比为1:1-2:1。
5.根据权利要求4所示的方法，其中步骤1中氯苄或者溴苄与多奈哌齐的摩尔比为1.2:1。
6.根据权利要求2所示的方法，其中步骤1中反应温度优选为25-80℃。
7.根据权利要求6所示的方法，其中步骤1中反应温度为溶剂回流温度。
8.根据权利要求2所示的方法，其中步骤2中所用的溶剂为四氢呋喃，甲基叔丁基醚，甲基四氢呋喃或乙二醇二甲醚。
9.根据权利要求2所示的方法，其中步骤2中所用碱为甲醇钠，甲醇钠钾，叔丁醇钠，叔丁醇钾，乙醇钠或乙醇钾。
10.根据权利要求2所示的方法，其中步骤3的分离方法为柱层析。
CN202010890593.9A 2020-08-29 2020-08-29 盐酸多奈哌齐杂质及其制备方法 Pending CN114105862A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010890593.9A CN114105862A (zh) 2020-08-29 2020-08-29 盐酸多奈哌齐杂质及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010890593.9A CN114105862A (zh) 2020-08-29 2020-08-29 盐酸多奈哌齐杂质及其制备方法

Publications (1)

Publication Number Publication Date
CN114105862A true CN114105862A (zh) 2022-03-01

Family

ID=80359854

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010890593.9A Pending CN114105862A (zh) 2020-08-29 2020-08-29 盐酸多奈哌齐杂质及其制备方法

Country Status (1)

Country Link
CN (1) CN114105862A (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040192919A1 (en) * 2002-08-14 2004-09-30 Finetech Laboratories, Ltd. Process for production of highly pure donepezil hydrochloride
CN101343248A (zh) * 2008-08-24 2009-01-14 浙江华海药业股份有限公司 一种盐酸多奈哌齐关键中间体的精制方法
CN101628889A (zh) * 2008-07-20 2010-01-20 浙江华海药业股份有限公司 一种改进的盐酸多奈哌齐关键中间体的制备方法
CN108047131A (zh) * 2017-12-08 2018-05-18 重庆植恩药业有限公司 盐酸多奈哌齐杂质及其制备方法和用途
CN109354580A (zh) * 2018-11-21 2019-02-19 山东罗欣药业集团股份有限公司 一种盐酸多奈哌齐的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040192919A1 (en) * 2002-08-14 2004-09-30 Finetech Laboratories, Ltd. Process for production of highly pure donepezil hydrochloride
CN101628889A (zh) * 2008-07-20 2010-01-20 浙江华海药业股份有限公司 一种改进的盐酸多奈哌齐关键中间体的制备方法
CN101343248A (zh) * 2008-08-24 2009-01-14 浙江华海药业股份有限公司 一种盐酸多奈哌齐关键中间体的精制方法
CN108047131A (zh) * 2017-12-08 2018-05-18 重庆植恩药业有限公司 盐酸多奈哌齐杂质及其制备方法和用途
CN109354580A (zh) * 2018-11-21 2019-02-19 山东罗欣药业集团股份有限公司 一种盐酸多奈哌齐的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
曹嘉;冉兰;陈霞;: "HPLC法检测盐酸多奈哌齐片中有关物质含量", 中国药房, no. 13, 7 April 2010 (2010-04-07) *
王伟;邵庆峰;顾国庆;齐洪侠;: "盐酸多奈哌齐杂质的合成", 广东化工, no. 17, 15 September 2015 (2015-09-15) *

Similar Documents

Publication Publication Date Title
JP7398436B2 (ja) メチル６－（２，４－ジクロロフェニル）－５－［４－［（３ｓ）－１－（３－フルオロプロピル）ピロリジン－３－イル］オキシフェニル］－８，９－ジヒドロ－７ｈ－ベンゾ［７］アンヌレン－２－カルボキシレートの塩およびその製造方法
EP2155684B1 (en) Process for producing cisatracurium compounds and associated intermediates
EP2142510A1 (en) Novel isoquinolinium compounds useful in the preparation of cisatracurium and associated intermediates
CN101863948A (zh) 高纯度(2β,3α,5α,16β,17β)-2-(4-吗啉基)-16-(1-吡咯烷基)-雄甾烷-3,17-二醇或其组合物及其制备方法
JP2009502750A (ja) ネビボロールの製造方法
CN114105862A (zh) 盐酸多奈哌齐杂质及其制备方法
Carreño et al. Stereoselective reactions of AlMe3 with chiral acyclic β-ketosulfoxides.
JP2001521498A (ja) Ｏ−（３−アミノ−２−ヒドロキシ−プロピル）−ヒドロキシミック酸ハロゲン化物の製造方法
CN110317170B (zh) 一种3-菲啶基甲酸丙酯类化合物的绿色合成方法
EP0089037B1 (en) Process for preparing optically active (s)-2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran and salts thereof
CN110885315A (zh) 左西孟旦药重要中间体的制备方法
CN111777554A (zh) 一种合成苯磺顺阿曲库铵的方法
DE19853558A1 (de) Verfahren zur Herstellung von 2,3-Dihydroindolen (Indolinen), neuartige 2,3-Dihydroindole sowie deren Verwendung
JP4057088B2 (ja) ピロリジン誘導体の製造方法
JP2605538B2 (ja) キラル誘導体化試薬およびそれを用いた分離分析法
KR100911720B1 (ko) 결정형 염산 사포그릴레이트의 제조방법
CN111995569B (zh) 一种细胞周期蛋白依赖性激酶抑制剂中间体的制备方法
EP2051963B1 (en) Process for resolving chiral piperidine alcohol and process for synthesis of pyrazolo [1,5-a]pyrimidine derivatives using same
KR100390777B1 (ko) 피리돈 유도체의 제조방법
JP2680683B2 (ja) ソラネシルアミン誘導体の製造方法
DE60308170T2 (de) Verfahren zur herstellung von chinolinderivaten
KR900007314B1 (ko) N-(메톡시아세틸)-n-(2,6-디메틸페닐)-3-아미노-옥사조리딘-2-온의 제조방법
KR20170123132A (ko) 트레프로스티닐의 제조방법
CN119504695A (zh) 一种药物中间体氮杂螺[4.5]癸烷衍生物的制备方法
KR20050062944A (ko) 디이소프로필((1-((2-아미노-6-클로로-9ｈ-퓨린-9-일)메틸)사이클로프로필)옥시)-메틸포스포네이트의 새로운 제조방법

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination