CN101870674B - 改进的瑞巴派特中间体的制备方法 - Google Patents

改进的瑞巴派特中间体的制备方法 Download PDF

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CN101870674B
CN101870674B CN2009100221145A CN200910022114A CN101870674B CN 101870674 B CN101870674 B CN 101870674B CN 2009100221145 A CN2009100221145 A CN 2009100221145A CN 200910022114 A CN200910022114 A CN 200910022114A CN 101870674 B CN101870674 B CN 101870674B
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rebamipide
yield
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CN101870674A (zh
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白振奎
杨刚利
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SHAANXI DASHENG PHARMACEUTICAL TECHNOLOGY CO., LTD.
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Abstract

本发明提供一种改进的瑞巴派特中间体的制备方法，以中间体(2)和中间体(3)在DMF/NaOH中缩合，得到中间体(4)，反应时间5-7小时，收率85-92％，产物纯度大于98.5％，反应条件温和，操作简便，该方法能够显著提高产品收率和工业上的可操作性，有利于工业化生产。

Description

改进的瑞巴派特中间体的制备方法
技术领域
本发明提供了一种治疗胃溃疡药物瑞巴派特中间体的制备方法。
背景技术
胃粘膜保护剂瑞巴派特(1)由日本大冢制药研制，其化学名称为：2-(4-氯苯甲酰胺基)-3-[2(1H)-喹诺酮-4-基]丙酸，1990年在日本上市，目前在欧美等国已普遍使用。
Figure G2009100221145D00011
该药物与H2受体拮抗剂和质子泵抑制剂抗溃疡机理不同，主要是通过增加胃粘膜血流量、前列腺素E2合成和胃粘液分泌、清除氧自由基等环节，促进消化道溃疡的愈合及炎症的改善，减少溃疡复发，并能提高对幽门螺杆菌的根除率。
瑞巴派特(1)的生产中，中间体(4)是必不可少的关键一步，US6680386，US2007249835，JP-A-60-19767等均以中间体(2)和中间体(3)与醇钠在绝对无水的醇中缩合，得到中间体(4)。
Figure G2009100221145D00021
这样的缺点是原料、溶剂必须严格无水处理，反应过程也必须严格禁水带入；由于采用金属钠，非常的危险；而且，反应时间6-18小时，反应收率低30-45％，产物纯度低，需再精制一次。这样，成本相应提高很多。
发明内容
本发明的目的是提供一种改进的瑞巴派特中间体的制备方法，以固体氢氧化钠代替醇钠，以DMF(N，N-二甲基甲酰胺)代替无水乙醇，反应条件温和，操作简便，该方法能够显著提高产品收率和工业上的可操作性，有利于工业化生产。
具体的制备方法如下：
Figure G2009100221145D00031
其中中间体(2)∶中间体(3)∶DMF∶NaOH＝1∶1.05∶5∶0.25(重量比)。
室温下先加入DMF，搅拌下加入NaOH，搅拌一段时间后，降温至15℃，加入中间体(3)，再搅拌一段时间，同温下加入中间体(2)，反应2小时，升温至30℃，反应3小时，冷却至10℃左右，搅拌一小时，析出，过滤，水洗即可得高纯度、高收率的中间体(4)。DMF母液可以回收使用。
本发明以中间体(2)与中间体(3)在DMF/NaOH中缩合，得到中间体(4)，反应时间5-7小时，收率85-92％，产物纯度高(大于98.5％)。本反应条件温和，操作简便，该方法能够显著提高产品收率和工业上的可操作性，有利于工业化生产。
具体实施方式
实施例1
水浴下，250mL三口烧瓶中加入DMF75mL，冷却至20℃，搅拌下缓缓加入NaOH 2.8g，加完继续搅拌30分钟，降温至10-15℃，一次性加入中间体(3)13.5g，加完再搅拌30min，然后加入中间体(2)12.4g，15℃下搅拌2小时。升温至30℃，再反应3小时。
冰水浴冷却至10℃，搅拌1小时，中间大量析出，过滤，滤饼用水洗涤至pH中性，得到白色粉末17.5g，收率90％，纯度98.83％(HPLC)。
实施例2
水浴下，3000mL三口烧瓶中加入DMF1500mL，冷却至20℃，搅拌下缓缓加入NaOH 56.0g，加完继续搅拌45分钟，降温至10-15℃，一次性加入中间体(3)270g，加完再搅拌30min，然后加入中间体(2)248g，15℃下搅拌2小时。升温至30℃，再反应3小时。
冰水浴冷却至10℃，搅拌1小时，中间大量析出，过滤，滤饼用水洗涤至pH中性，得到白色粉末345.7g，收率88.7％，纯度98.64％(HPLC)。

Claims (1)

1.一种瑞巴派特中间体的制备方法，其特征是以中间体(2)和中间体(3)在DMF/NaOH中缩合，得到中间体(4)，反应时间5-7小时，收率85-92％，产物纯度大于98.5％
Figure FSB00000624875200011
其中中间体(2)、中间体(3)、DMF和NaOH重量之间存在如下关系：中间体(2)∶中间体(3)∶DME∶NaOH＝1∶1.05∶5∶0.25。
CN2009100221145A 2009-04-21 2009-04-21 改进的瑞巴派特中间体的制备方法 Expired - Fee Related CN101870674B (zh)

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WO2006059781A1 (en) * 2004-12-01 2006-06-08 Otsuka Pharmaceutical Co., Ltd. Improved process for preparing rebamipide

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US4578381A (en) * 1982-07-05 1986-03-25 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
WO2006059781A1 (en) * 2004-12-01 2006-06-08 Otsuka Pharmaceutical Co., Ltd. Improved process for preparing rebamipide

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Uchida, Minoru et al.Studies on 2(1H)-quinolinone derivatives as gastric antiulcer active gents. 2-(4-Chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid and related compounds.《Chemical & Pharmaceutical Bulletin》.1985,
Uchida, Minoru et al.Studies on 2(1H)-quinolinone derivatives as gastric antiulcer active gents. 2-(4-Chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid and related compounds.《Chemical & Pharmaceutical Bulletin》.1985, *
刘大学 等.3-(2-氧代-1,2-二氢喹啉-4-基)丙氨酸的合成研究.《化学与生物工程》.2005, *
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叶蕴华 等.1,2-二氢-2-氧代喹啉衍生物的合成及其生理活性的研究.《北京大学学报(自然科学版)》.1990, *
叶蕴华等.1 2-二氢-2-氧代喹啉衍生物的合成及其生理活性的研究.《北京大学学报（自然科学版）》.1990

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