CN1105104C - 新的制备方法 - Google Patents
新的制备方法 Download PDFInfo
- Publication number
- CN1105104C CN1105104C CN96199573A CN96199573A CN1105104C CN 1105104 C CN1105104 C CN 1105104C CN 96199573 A CN96199573 A CN 96199573A CN 96199573 A CN96199573 A CN 96199573A CN 1105104 C CN1105104 C CN 1105104C
- Authority
- CN
- China
- Prior art keywords
- felodipine
- obtains
- dichlorin benzylidene
- reaction
- methyl acetoacetate
- 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.)
- Expired - Lifetime
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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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/84—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
一种以醇为溶剂，通过二氯亚苄基和3-氨基丁烯酸乙酯反应制备非洛地平(Felodipine)的新方法。
Description
发明领域
本发明涉及一种制备非洛地平(Felodipine)(4-(2，3-二氯苯基)-1，4-二氢-2，6-二甲基-3，5-吡啶二羧酸甲乙酯)的新方法：经过2，3-二氯亚苄基乙酰乙酸甲酯(以下简称为二氯亚苄基)与3-氨基丁烯酸乙酯的反应路线。
现有技术
EP7293披露了一种以二氯亚苄基和3-氨基丁烯酸乙酯为反应起始原料制备非洛地平(Felodipine)的方法。该反应以叔丁醇为反应溶剂，无催化剂，反应时间长，一般需要90分钟或更长时间。
US 5 310 917公开了一种以二氯亚苄基和3-氨基丁烯酸乙酯为反应起始原料制备非洛地平(Felodipine)的方法，该反应以乙醇为反应溶剂。
发明内容
现在发现作为钙离子通道阻断剂的非洛地平(Felodipine)可以通过一种迅速、污染小、高产率的方法来制备。这种新方法的反应原料同上，该反应使用吡啶为催化剂，并与醇相结合作为反应溶剂。
该方法的反应式如下：
二氯亚苄基 3-氨基丁烯酸乙酯 非洛地平(Felodipine)在吡啶存在下，二氯亚苄基与3-氨基丁烯酸乙酯在醇中回流反应，所述醇可以是甲醇、乙醇、丙醇，最好是乙醇。反应后，优选将醇通过减压蒸馏除去，并加入乙酸乙酯或二氯甲烷。用酸性和中性水溶液萃取该溶液使之纯化。溶剂通过蒸馏除去。反应产物可溶于丙酮或异丙醚中，降温使产物结晶析出，过滤、并最后用丙酮或异丙醚洗涤滤饼。
二氯亚苄基与3-氨基丁烯酸乙酯(0.5g～0.9g/g二氯亚苄基，其中以0.58～0.60g/g二氯亚苄基为最佳)反应。将反应物混和于醇溶剂中(每克二氯亚苄基中用2.5～4.8ml乙醇为宜、优选3.2-3.9ml)催化剂吡啶用量为每克二氯亚苄基用0.03-0.2ml，优选0.035-0.045g。反应原料二氯亚苄基的制备
2，3-二氯苯甲醛 乙酰乙酸甲酯 二氯亚苄基在催化量的乙酸和哌啶存在下，在适当溶剂中，2，3-二氯苯甲醛与乙酰乙酸甲酯反应。反应过程中，水以共沸物的形式从体系中分离出去。反应后，通过萃取反应混合物除去催化剂。蒸去溶剂，加入甲醇。降温使产物结晶析出，过滤分离，并用甲醇洗涤。
实施实例
实施例1
二氯亚苄基 3-氨基丁烯酸乙酯 非洛地平(Felodipine)在1.3g吡啶存在下，35.3g二氯亚苄基与20.7g 3-氨基丁烯酸乙酯在91ml乙醇中回流进行反应。反应后，将乙醇通过减压蒸馏除去，并加入乙酸乙酯195ml以溶解残留物。溶液在酸性条件(7.3g HCl溶于30ml水中)萃取纯化，溶剂通过蒸馏除去，加入116ml丙酮，降温至-10℃，使产物结晶析出，过滤分离并用丙酮洗涤滤饼。
产率：约85％。实施例2
二氯亚苄基 3-氨基丁烯酸乙酯 非洛地平(Felodipine)在5.9g吡啶存在下，30.3g二氯亚苄基与17.8g 3-氨基丁烯酸乙酯在94ml乙醇中回流进行反应。反应后，将乙醇通过减压蒸馏除去，并加入二氯甲烷118ml，该溶液在酸性条件(6.3g HCl溶于24ml水中)萃取纯化。在二氯甲烷相中加入3g无水硫酸钠处理除去残留水份，通过蒸馏除去溶剂。加入85ml异丙醚，将溶液降温至0℃，使产物结晶析出，过滤分离、并用异丙醚洗涤滤饼。产率：约85％。
Claims (12)
1.一种制备非洛地平的方法，其特征在于，吡啶催化剂存在下，将2，3-二氯亚苄基乙酰乙酸甲酯与3-氨基丁烯酸乙酯在醇中回流进行反应。
2.根据权利要求1的方法，其中的醇为乙醇。
3.根据权利要求1-2任意一项的方法，其中将获得的非洛地平溶解成溶液。
4.根据权利要求3的方法，其中将获得的非洛地平溶于乙酸乙酯。
5.根据权利要求3的方法，其中将获得的非洛地平溶于二氯甲烷。
6.根据权利要求1-2任意一项的方法，其中将获得的非洛地平通过结晶纯化。
7.根据权利要求6的方法，其中结晶在丙酮中进行。
8.根据权利要求6的方法，其中结晶在异丙醚中进行。
9.根据权利要求1的方法，其中2，3-二氯亚苄基乙酰乙酸甲酯与3-氨基丁烯酸乙酯的比例为1g：0.5-0.9g。
10.根据权利要求2的方法，其中：乙醇的量为每克2，3-二氯亚苄基乙酰乙酸甲酯用2.5-4.8ml乙醇。
11.根据权利要求1的方法，其中，吡啶的量为每克2，3-二氯亚苄基乙酰乙酸甲酯用0.03-0.2ml吡啶。
12.一种制备药物制剂非洛地平的方法，其中非洛地平根据上述任一项权利要求生产并纯化，将获得的纯非洛地平与赋形剂、稀释剂或载体混和，制成药物制剂。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9600086 | 1996-01-10 | ||
| SE9600086-4 | 1996-01-10 | ||
| SE9600086A SE9600086D0 (sv) | 1996-01-10 | 1996-01-10 | New manufacturing process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1207726A CN1207726A (zh) | 1999-02-10 |
| CN1105104C true CN1105104C (zh) | 2003-04-09 |
Family
ID=20400982
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96199573A Expired - Lifetime CN1105104C (zh) | 1996-01-10 | 1996-12-13 | 新的制备方法 |
Country Status (34)
| Country | Link |
|---|---|
| US (1) | US5942624A (zh) |
| EP (1) | EP0874822B1 (zh) |
| JP (1) | JP4587497B2 (zh) |
| KR (1) | KR100488384B1 (zh) |
| CN (1) | CN1105104C (zh) |
| AR (1) | AR005342A1 (zh) |
| AT (1) | ATE249436T1 (zh) |
| AU (1) | AU706989B2 (zh) |
| BR (1) | BR9612457A (zh) |
| CA (1) | CA2240201C (zh) |
| CZ (1) | CZ291063B6 (zh) |
| DE (1) | DE69629942T2 (zh) |
| DK (1) | DK0874822T3 (zh) |
| EE (1) | EE03438B1 (zh) |
| EG (1) | EG24197A (zh) |
| ES (1) | ES2206617T3 (zh) |
| HK (1) | HK1014941A1 (zh) |
| HU (1) | HU227384B1 (zh) |
| IL (1) | IL125194A (zh) |
| IS (1) | IS1826B (zh) |
| MY (1) | MY116842A (zh) |
| NO (1) | NO310233B1 (zh) |
| NZ (1) | NZ325967A (zh) |
| PL (1) | PL188308B1 (zh) |
| PT (1) | PT874822E (zh) |
| RU (1) | RU2171251C2 (zh) |
| SE (1) | SE9600086D0 (zh) |
| SI (1) | SI0874822T1 (zh) |
| SK (1) | SK281989B6 (zh) |
| TR (1) | TR199801283T2 (zh) |
| TW (1) | TW343194B (zh) |
| UA (1) | UA44914C2 (zh) |
| WO (1) | WO1997025313A1 (zh) |
| ZA (1) | ZA9610937B (zh) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6555139B2 (en) | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
| KR101369207B1 (ko) | 2007-04-11 | 2014-03-04 | 한국과학기술원 | (ｓ)-(-)-펠로디핀의 제조방법 |
| WO2010027113A2 (en) * | 2008-09-04 | 2010-03-11 | Ahn-Gook Pharmaceutical Co., Ltd | Process for preparing (s)-(-)-felodipine |
| CN101613280B (zh) * | 2009-05-13 | 2012-10-17 | 合肥立方制药股份有限公司 | 非洛地平合成中间体2,3-二氯亚苄基乙酰乙酸甲酯的制备方法 |
| CN101735042B (zh) * | 2009-12-15 | 2013-10-09 | 浙江大学 | 2-烷基-4,4-二芳基反-2-丁烯酸乙酯的合成方法 |
| WO2012123966A1 (en) | 2011-03-04 | 2012-09-20 | Arch Pharmalabs Limited | Process for the preparation of 4 -substituted -1, 4-dihydropyridines |
| CN102304079B (zh) * | 2011-09-29 | 2013-09-25 | 合肥立方制药股份有限公司 | 一种非洛地平环合反应液直接水析纯化方法 |
| CN103373956B (zh) * | 2012-04-23 | 2015-07-01 | 黑龙江省格润药业有限责任公司 | 一种制备丁酸氯维地平的方法 |
| CN104557679A (zh) * | 2013-10-23 | 2015-04-29 | 丹阳恒安化学科技研究所有限公司 | 一种西尼地平的合成方法 |
| CN108840819B (zh) * | 2018-04-02 | 2021-07-30 | 常州瑞明药业有限公司 | 一种非洛地平的制备方法 |
| CN115201379B (zh) * | 2022-07-26 | 2023-10-20 | 常州瑞明药业有限公司 | 非洛地平中基因毒性杂质的检测方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0007293A1 (en) * | 1978-06-30 | 1980-01-23 | Aktiebolaget Hässle | 2,6-Dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester having hypotensive properties, process for its preparation and pharmaceutical preparations containing it |
| US5310917A (en) * | 1991-09-13 | 1994-05-10 | Merck & Co., Inc. | Process for the preparation of 4-substituted-1,4-dihydropydrines |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2508181A1 (de) * | 1975-02-26 | 1976-09-09 | Bayer Ag | 1,4-dihydropyridincarbonsaeurearal- kylester, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
-
1996
- 1996-01-10 SE SE9600086A patent/SE9600086D0/xx unknown
- 1996-12-13 UA UA98063019A patent/UA44914C2/uk unknown
- 1996-12-13 CZ CZ19982180A patent/CZ291063B6/cs not_active IP Right Cessation
- 1996-12-13 DK DK96944714T patent/DK0874822T3/da active
- 1996-12-13 JP JP52512297A patent/JP4587497B2/ja not_active Expired - Lifetime
- 1996-12-13 ES ES96944714T patent/ES2206617T3/es not_active Expired - Lifetime
- 1996-12-13 NZ NZ325967A patent/NZ325967A/xx not_active IP Right Cessation
- 1996-12-13 PL PL96327946A patent/PL188308B1/pl unknown
- 1996-12-13 CN CN96199573A patent/CN1105104C/zh not_active Expired - Lifetime
- 1996-12-13 US US08/750,933 patent/US5942624A/en not_active Expired - Lifetime
- 1996-12-13 BR BR9612457A patent/BR9612457A/pt not_active Application Discontinuation
- 1996-12-13 RU RU98112386/04A patent/RU2171251C2/ru active
- 1996-12-13 PT PT96944714T patent/PT874822E/pt unknown
- 1996-12-13 SK SK878-98A patent/SK281989B6/sk not_active IP Right Cessation
- 1996-12-13 EP EP96944714A patent/EP0874822B1/en not_active Expired - Lifetime
- 1996-12-13 HU HU9901392A patent/HU227384B1/hu unknown
- 1996-12-13 IL IL12519496A patent/IL125194A/en not_active IP Right Cessation
- 1996-12-13 KR KR1019980705100A patent/KR100488384B1/ko not_active IP Right Cessation
- 1996-12-13 DE DE69629942T patent/DE69629942T2/de not_active Expired - Lifetime
- 1996-12-13 AU AU13230/97A patent/AU706989B2/en not_active Expired
- 1996-12-13 AT AT96944714T patent/ATE249436T1/de active
- 1996-12-13 SI SI9630642T patent/SI0874822T1/xx unknown
- 1996-12-13 TR TR1998/01283T patent/TR199801283T2/xx unknown
- 1996-12-13 EE EE9800201A patent/EE03438B1/xx unknown
- 1996-12-13 WO PCT/SE1996/001649 patent/WO1997025313A1/en active IP Right Grant
- 1996-12-13 CA CA002240201A patent/CA2240201C/en not_active Expired - Lifetime
- 1996-12-30 TW TW085116296A patent/TW343194B/zh not_active IP Right Cessation
- 1996-12-30 ZA ZA9610937A patent/ZA9610937B/xx unknown
-
1997
- 1997-01-02 AR ARP970100008A patent/AR005342A1/es active IP Right Grant
- 1997-01-07 EG EG1797A patent/EG24197A/xx active
- 1997-01-09 MY MYPI97000093A patent/MY116842A/en unknown
-
1998
- 1998-06-19 IS IS4779A patent/IS1826B/is unknown
- 1998-07-09 NO NO19983166A patent/NO310233B1/no not_active IP Right Cessation
-
1999
- 1999-01-04 HK HK99100002A patent/HK1014941A1/xx not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0007293A1 (en) * | 1978-06-30 | 1980-01-23 | Aktiebolaget Hässle | 2,6-Dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester having hypotensive properties, process for its preparation and pharmaceutical preparations containing it |
| US5310917A (en) * | 1991-09-13 | 1994-05-10 | Merck & Co., Inc. | Process for the preparation of 4-substituted-1,4-dihydropydrines |
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