CN1202075C - 作为抗菌剂喹诺酮药物的有用中间体的3－环丙基氨基－2－[2,4－二溴－3－(二氟甲氧基 )苯甲酰基]－2－丙烯酸烷酯的－锅合成 - Google Patents
作为抗菌剂喹诺酮药物的有用中间体的3－环丙基氨基－2－[2,4－二溴－3－(二氟甲氧基 )苯甲酰基]－2－丙烯酸烷酯的－锅合成 Download PDFInfo
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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Abstract
本发明涉及一种新颖的工业上有利的一锅法，用于制备3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸烷酯，其中R代表甲基或乙基，它们是生产高度活性的抗菌剂喹诺酮药物的有价值中间体。
Description
发明领域
本发明涉及一种新颖的工业上有利的一锅法，用于制备3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸烷酯，其中R代表甲基或乙基，它们是生产高度活性的抗菌剂喹诺酮药物的有价值中间体。
发明背景
转让给Toyama Chemical Company Ltd.的美国专利号5,935,952中报道了一种先前已知的通用方法，用于合成下式的中间体3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸烷酯：
式I
该专利中描述的通用方法包括下式化合物：
式II
与卤化剂，例如亚硫酰氯反应获得下式的酰氯：
式III
它与下式丙二酸酯的金属盐在氯化镁的存在下，在约45℃反应：
Na/KOOCCH2COOR
式IV
其中R如上定义。式IV脱羧基得到下式的化合物：
式V
其中R如上定义。式V的化合物与缩醛，例如N，N-二甲基甲酰胺二甲缩醛、N，N-二甲基甲酰胺二乙缩醛反应获得下式的化合物：
式VI
其中R1是甲基或乙基，它与环丙胺反应获得式I的中间体3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸甲酯/乙酯。
现有技术中描述的上述制备式I的化合物的方法有下列限制，由于下面描述的各种原因不适合商业用途。
方法冗长，涉及6个步骤。
方法产生许多废料，因此对环境不利。
发明简述
本发明的一个目的是解决现有技术的问题，提供一种有效的方法。
根据本发明的一个方面，提供了一种制备式I的3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸烷酯的一锅法。该方法对于经济和商业规模操作的便利提供了明显的益处。
更具体的，本发明涉及一种制备式I的3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸烷酯的方法，其中R是甲基或乙基，包括使式II的2，4-二溴-3-(二氟甲氧基)苯甲酸与卤化剂反应，得到相应的式III的酰氯，它与下式的3，3-二烷基氨基丙烯酸酯在合适的溶剂中，在有机碱的存在下反应：
式VII
其中R1是甲基或乙基，得到式VI的3，3-二烷基氨基-2[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸烷酯，其中R和R1是甲基或乙基。其用环丙胺处理后得到式I的产物，R如上定义。更具体的，式II的化合物根据现有技术中已知的方法与亚硫酰氯反应得到式III的酰氯。然后酰氯与式VI的3，3-二甲基/二乙基氨基丙烯酸甲酯/乙酯(R和R1是甲基或乙基)在合适的溶剂中，在有机碱的存在下，在40-80℃，优选50-70℃的温度范围内，反应一到数小时。合适的溶剂选自芳族溶剂、氯化溶剂、酯溶剂及其混合物。优选溶剂选自苯、甲苯、二甲苯、氯仿、二氯乙烷、二氯甲烷、乙酸甲酯、乙酸丁酯、乙酸乙酯或其混合物。合适的有机碱选自三乙胺、三甲胺、甲基吡啶、吡啶和吡啶衍生物。然后冷却反应混合物，倒入水中。有机层含有式VI的化合物，其中R1是甲基或乙基，与环丙胺在0-30℃，优选5-10℃的所选温度范围内反应0.5-数小时。用常规方法分离所需的化合物式I的3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸甲酯/乙酯。
在下节中描述了一个优选例，用于举例说明本发明的方法，然而它不是为了用任何方式限制本发明的范围。
发明详述
实施例1
3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸乙酯的制备
在2，4-二溴-3-(二氟甲氧基)苯甲酸(10g)和亚硫酰氯(4.38g)的混合物中加入甲苯(15ml)和N，N-二甲基甲酰胺(0.2mL)的混合物。缓慢加热反应混合物至回流，搅拌约2.5小时。然后将反应混合物冷却到35℃，滴加3，3-二甲基氨基丙烯酸乙酯(4.13g)和三乙胺(3.79g)的甲苯(20mL)溶液，同时维持在35-40℃的温度下约1小时。加完后，将反应温度缓慢提高到60-65℃，搅拌反应混合物24小时。冷却反应混合物至30℃，加水(20mL)并搅拌约10分钟。分离有机层，冷却到约5℃，滴加环丙胺(1.82g)，同时将温度维持在8-10℃10分钟。搅拌反应混合物约2小时，真空除去溶剂(约原来量的80％)，将反应混合物冷却到约20℃。过滤分离的固体，并干燥，得到3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸乙酯(10g)。
虽然已用具体实施例描述了本发明，但是本领域技术人员应明白一些修改和等价方法，它们也包括在本发明的范围内。
实施例2
3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸乙酯的制备
在2，4-二溴-3-(二氟甲氧基)苯甲酸(50g)在乙酸乙酯(175mL)的混合物中加入N，N-二甲基甲酰胺(1mL)和亚硫酰氯(18.1g)。反应混合物加热到回流，在回流搅拌1小时。蒸发乙酸乙酯(125mL)后，在室温下加入三乙胺(16.1g)和3，3-二甲基氨基丙烯酸乙酯(20.7g)。该反应混合物加热至回流，回流搅拌3小时。然后将反应混合物冷却至25℃，加入水(100mL)，搅拌混合物约10分钟。分离有机层，在其中加入环丙胺(9.9g)，25℃搅拌反应混合物1小时。用异丙醇(200mL)更换反应混合物的溶剂，温度维持在约68℃。冷却混合物结晶，然后过滤，用异丙醇洗涤并干燥，得到3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸乙酯(58.6g)。
Claims (10)
1.一种制备3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸烷酯的方法，该3-环丙基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸烷酯具有式：
式I
其中R是甲基或乙基，其特征在于，该方法包括使下式的2，4-二溴-3-(二氟甲氧基)苯甲酸：
式II
与卤化剂反应，得到相应的具有下式的酰氯：
式III
其与具有下式的3，3-二烷基氨基丙烯酸的烷酯在合适的溶剂中，在有机碱的存在下反应：
式VII
其中R1是甲基或乙基，得到具有下式的3，3-二烷基氨基-2-[2，4-二溴-3-(二氟甲氧基)苯甲酰基]-2-丙烯酸烷酯：
式VI
其中R和R1是甲基或乙基，用环丙胺处理式VI的化合物得到式I产物。
2.如权利要求1所述的方法，其特征在于，所述卤化剂是亚硫酰氯。
3.如权利要求1所述的方法，其特征在于，所述3，3-二烷基氨基丙烯酸烷酯是3，3-二甲基氨基丙烯酸甲酯。
4.如权利要求1所述的方法，其特征在于，所述3，3-二烷基氨基丙烯酸烷酯是3，3-二乙基氨基丙烯酸乙酯。
5.如权利要求1所述的方法，其特征在于，所述溶剂选自芳族溶剂、氯化溶剂，酯溶剂及其混合物。
6.如权利要求5所述的方法，其特征在于，所述溶剂选自苯、甲苯、二甲苯、氯仿、二氯甲烷、二氯乙烷、乙酸甲酯、乙酸丁酯、乙酸乙酯及其混合物。
7.如权利要求1所述的方法，其特征在于，所述有机碱选自三乙胺、三甲胺、甲基吡啶、吡啶或吡啶衍生物。
8.如权利要求1所述的方法，其特征在于，所述反应温度在40-80℃范围内。
9.如权利要求8所述的方法，其特征在于，所述反应温度在50-70℃范围内。
10.权利要求1所述的方法制备的式I的化合物用于合成喹诺酮药物的用途。
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| CNB018090362A Expired - Lifetime CN1202075C (zh) | 2000-03-07 | 2001-03-07 | 作为抗菌剂喹诺酮药物的有用中间体的3－环丙基氨基－2－[2,4－二溴－3－(二氟甲氧基 )苯甲酰基]－2－丙烯酸烷酯的－锅合成 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US6835848B1 (zh) |
| EP (1) | EP1278717B1 (zh) |
| JP (1) | JP4751557B2 (zh) |
| KR (1) | KR100763077B1 (zh) |
| CN (1) | CN1202075C (zh) |
| AT (1) | ATE364036T1 (zh) |
| AU (1) | AU3590801A (zh) |
| DE (1) | DE60128797D1 (zh) |
| WO (1) | WO2001066512A1 (zh) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1244582C (zh) * | 2004-04-21 | 2006-03-08 | 中国医学科学院医药生物技术研究所 | 喹诺酮羧酸类化合物及其制备方法和医药用途 |
| US7759362B2 (en) * | 2004-04-21 | 2010-07-20 | Institut Of Medicinal Biotechnology Chinese Academy Of Medical Sciences | Quinolonecarboxylic acid compounds, preparation methods and pharmaceutical uses thereof |
| KR200457934Y1 (ko) * | 2010-10-26 | 2012-01-12 | 주식회사 삼진엘앤디 | 등기구 마운팅 구조 |
| WO2013157018A1 (en) | 2012-04-18 | 2013-10-24 | Indian Institute Of Technology Madras | A process for the preparation of the core structure in quinolone and napthyridone class of antibiotics |
| CN105801482B (zh) * | 2016-04-18 | 2018-06-22 | 浙江中欣氟材股份有限公司 | 一种1-环丙基-4-氧代-7-溴-8-二氟甲氧基-1,4-二氢喹啉-3-羧酸乙酯的制备方法 |
| CN105777631B (zh) * | 2016-04-18 | 2018-06-29 | 浙江中欣氟材股份有限公司 | 一种1-环丙基-4-氧代-7-溴-8-二氟甲氧基-1,4-二氢喹啉-3-羧酸乙酯的合成方法 |
| CN114716373B (zh) * | 2022-04-14 | 2023-01-10 | 内蒙古源宏精细化工有限公司 | 一种加替沙星环合酯的制备方法 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0784423B2 (ja) * | 1987-06-18 | 1995-09-13 | 宇部興産株式会社 | ３−アミノ−２−置換ベンゾイルアクリル酸誘導体 |
| JPH05194336A (ja) * | 1992-01-14 | 1993-08-03 | Kyorin Pharmaceut Co Ltd | アミノアクリル酸誘導体 |
| JP2918134B2 (ja) * | 1992-05-15 | 1999-07-12 | 宇部興産株式会社 | ３−ジアルキルアミノ−２−置換ベンゾイルアクリル酸誘導体 |
| JPH0616642A (ja) | 1992-07-02 | 1994-01-25 | Katayama Seiyakushiyo:Kk | キノリンカルボン酸誘導体の製造方法 |
| EP0775702B1 (en) | 1994-08-12 | 2003-07-23 | Toyama Chemical Co., Ltd. | Novel quinolone- or naphthyridonecarboxylic acid derivative or salt thereof |
| CN1296369C (zh) * | 1997-10-27 | 2007-01-24 | 富山化学工业株式会社 | 制备7－二氢异吲哚喹诺酮羧酸衍生物及其中间体的方法 |
| US6531624B1 (en) | 1998-11-18 | 2003-03-11 | Asahi Glass Company Ltd. | Aminoacrylic acid derivatives and process for producing the same |
| WO2000055116A1 (fr) * | 1999-03-17 | 2000-09-21 | Daiichi Pharmaceutical Co., Ltd. | Procede de production de derives d'acide 5-amino-8- alkylquinolo necarboxylique, et produits intermediaires intervenant dans la production |
-
2001
- 2001-03-07 EP EP01908049A patent/EP1278717B1/en not_active Expired - Lifetime
- 2001-03-07 CN CNB018090362A patent/CN1202075C/zh not_active Expired - Lifetime
- 2001-03-07 JP JP2001565332A patent/JP4751557B2/ja not_active Expired - Lifetime
- 2001-03-07 US US10/221,113 patent/US6835848B1/en not_active Expired - Lifetime
- 2001-03-07 AU AU35908/01A patent/AU3590801A/en not_active Abandoned
- 2001-03-07 WO PCT/IB2001/000316 patent/WO2001066512A1/en active IP Right Grant
- 2001-03-07 AT AT01908049T patent/ATE364036T1/de not_active IP Right Cessation
- 2001-03-07 DE DE60128797T patent/DE60128797D1/de not_active Expired - Lifetime
- 2001-03-07 KR KR1020027011757A patent/KR100763077B1/ko active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| JP4751557B2 (ja) | 2011-08-17 |
| EP1278717B1 (en) | 2007-06-06 |
| DE60128797D1 (de) | 2007-07-19 |
| JP2003534243A (ja) | 2003-11-18 |
| CN1427815A (zh) | 2003-07-02 |
| WO2001066512A1 (en) | 2001-09-13 |
| US6835848B1 (en) | 2004-12-28 |
| AU3590801A (en) | 2001-09-17 |
| KR100763077B1 (ko) | 2007-10-04 |
| US20040267019A1 (en) | 2004-12-30 |
| EP1278717A1 (en) | 2003-01-29 |
| EP1278717A4 (en) | 2005-06-08 |
| KR20030017473A (ko) | 2003-03-03 |
| ATE364036T1 (de) | 2007-06-15 |
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