CN102268017B - 广谱长效青霉素类抗生素替卡西林钠的制备方法 - Google Patents

广谱长效青霉素类抗生素替卡西林钠的制备方法 Download PDF

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CN102268017B
CN102268017B CN 201110175843 CN201110175843A CN102268017B CN 102268017 B CN102268017 B CN 102268017B CN 201110175843 CN201110175843 CN 201110175843 CN 201110175843 A CN201110175843 A CN 201110175843A CN 102268017 B CN102268017 B CN 102268017B
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sodium
ticarcillin
preparation
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midbody
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CN102268017A (zh
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隋巍峰
郭顺
刘志
陆祖昆
朱炜
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Shandong Erye Pharmaceutical Co ltd
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Suzhou Erye Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/04—Preparation
    • C07D499/14—Preparation of salts
    • C07D499/16—Preparation of salts of alkali or alkaline earth metals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/72—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by carbon atoms having three bonds to hetero atoms

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

本发明提供一种反应条件温和、副反应少、步骤少、可控性强的替卡西林钠的制备方法：（1）3-噻吩丙二酸在有机溶剂中，在DCC、DMAP的催化下，与N-羟基琥珀酰亚胺反应得到中间体1，经柱层析分离纯化；（2）将中间体1溶于二氯甲烷中，加入6-APA以及碱反应得到替卡西林；（3）替卡西林与成盐剂反应得替卡西林钠。

Description

广谱长效青霉素类抗生素替卡西林钠的制备方法
技术领域
本发明涉及光谱长效青霉素类抗生素替卡西林钠的制备方法，属于药物技术领域。
背景技术
青霉素是从青霉菌培养液中提炼得到，共有7种，其中青霉素G（Penicillin G）的作用最强，产量最高，有临床应用价值。青霉素G在临床上已应用半个多世纪，其特点是抗菌作用强，用于各种球菌和革兰氏阳性菌，但也存在较大缺点，主要是不耐酸、不能口服、不耐酶而引起耐药性和抗菌谱窄。
Figure 737661DEST_PATH_IMAGE001
Penicillin G
Figure 569088DEST_PATH_IMAGE002
6-APA
为解决青霉素存在的缺陷，利用从青霉素发酵液中得到的6-氨基青霉烷酸（6-Aminopenicillanic acid，6-APA）为原料发展了许多半合成青霉素，其中包括光谱长效青霉素类抗生素替卡西林钠（Ticarcillin Disodium，化学名：(2S,5R,6R)-3,3-二甲基-6-[2-羧基-2-(2-噻吩基)乙酰氨基]-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-羧酸二钠盐），结构式为：
Figure 321144DEST_PATH_IMAGE003
替卡西林钠
目前通过6-APA接侧链得到替卡西林钠的合成工艺路线有多种，概括来说多为对6-APA或3-噻吩丙二酸进行羧基或氨基保护后进行缩合反应，然后对反应产物水解、成盐得到最终产品，通常以三甲基氯硅烷保护6-APA的氨基和羧基后，与3-噻吩基丙二酰氯化物缩合，得中间体N-三甲基甲硅烷-6-[α-氯碳酰基-2-(3-噻吩基)-乙酰胺]-青霉酸三甲基甲硅脂，水解后，与2-乙基己酸钠成盐，用乙酸乙酯精制后得最终产品，此种方法需要先进行基团保护然后将反应产物再水解，步骤繁琐，水解反应不易进行且难于控制。
发明内容
本发明的目的是提供一种反应条件温和、副反应少、步骤少、可控性强的替卡西林钠的制备方法。
针对现有技术中对6-APA或3-噻吩丙二酸先进行羧基或氨基保护，然后进行后续反应的技术偏见，本发明提供一种新的合成方法：
（1）3-噻吩丙二酸在有机溶剂中，在DCC、DMAP的催化下，与N-羟基琥珀酰亚胺反应得到中间体1，经柱层析分离纯化；所述有机溶剂优选醇类溶剂，优选乙醇；
（2）将中间体1溶于二氯甲烷中，加入6-APA以及碱反应得到替卡西林；所说的碱是氢氧化钠、氢氧化钾、碳酸氢钠、三乙胺、二乙胺中的一种，优选三乙胺；
（3）替卡西林与成盐剂反应得替卡西林钠，成盐剂为乙酸钠、乙醇钠、异辛酸钠、异己酸钠、碳酸氢钠或氢氧化钠、氢氧化钾，优选碳酸氢钠。
相对于现有的方法，该合成路线有如下优点：
将3-噻吩丙二酸的一个羧基活化后，直接与6-APA的氨基反应，无需水解去除保护基。反应条件温和、副反应少、步骤少、可控性强。
具体实施方式
现通过以下实施例来进一步描述本发明的有益效果，应理解为这些实施例仅用于例证的目的，不限制本发明的范围，同时本领域技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明的范围内。
实施例1：
将3-噻吩丙二酸（0.74g，4.0mmol）溶于10ml乙醇中，加入DMAP（730mg，6mmol）和DCC（1.2g，6.0mmol）室温搅拌半小时后，加入N-羟基琥珀酰亚胺（0.47g，4mmol），室温搅拌半小时后，加入饱和NH4Cl溶液搅拌后，乙酸乙酯萃取，分出乙酸乙酯层，有机相经饱和食盐水洗，无水硫酸钠干燥，蒸除溶剂，柱层析（乙酸乙酯/甲醇=10：1）洗脱，得到中间体1 1.05g，收率93%。
将中间体1（1.05g，3.7mmol）溶于20ml二氯甲烷中，加入6-APA（0.8g，3.7mmol）和三乙胺10ml室温搅拌反应8小时后，用1mol/l的盐酸溶液调酸性（PH=2.0），并在-5℃下反应2h。二氯甲烷萃取，活性炭脱色，干燥后浓缩得替卡西林1.35g，收率95%。
MS(m/z):385(M+H)+。
将替卡西林（1.35g，3.5mmol）溶于10ml乙酸乙酯中，滴入溶有5g碳酸氢钠的乙酸乙酯20ml，25℃搅拌析晶，30℃减压烘干的白色晶体1.45g，收率97%，熔点201℃，HPLC检测纯度为98.89%，MS(m/z):429(M+H)+。

Claims (5)

1.替卡西林钠的制备方法，包括以下步骤：
（1）3-噻吩丙二酸在醇类溶剂中，在DCC、DMAP的催化下，与N-羟基琥珀酰亚胺反应得到中间体1，经柱层析分离纯化；
（2）将中间体1溶于二氯甲烷中，加入6-APA以及碱反应得到替卡西林，所述的碱是氢氧化钠、氢氧化钾、碳酸氢钠、三乙胺、二乙胺中的一种； 
（3）替卡西林与成盐剂反应得替卡西林钠；
所述中间体1结构为：
。
2.根据权利要求1所述的方法，其特征在于，步骤（1）所述的醇类溶剂优选乙醇。
3.根据权利要求1所述的方法，其特征在于，步骤（2）所述的碱优选三乙胺。
4.根据权利要求1所述的方法，其特征在于，步骤（3）所述的成盐剂为乙酸钠、乙醇钠、异辛酸钠、异己酸钠、碳酸氢钠或氢氧化钠。
5.根据权利要求1所述的方法，其特征在于，步骤（3）所述的成盐剂优选碳酸氢钠。
CN 201110175843 2011-06-28 2011-06-28 广谱长效青霉素类抗生素替卡西林钠的制备方法 Active CN102268017B (zh)

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CN 201110175843 CN102268017B (zh) 2011-06-28 2011-06-28 广谱长效青霉素类抗生素替卡西林钠的制备方法
DE112012000225.3T DE112012000225B4 (de) 2011-06-28 2012-06-27 Verfahren zum Herstellen von lang wirkendem Penicillin-Breitbandantibiotikum Ticarcillin-Dinatrium
BR112013008592A BR112013008592A2 (pt) 2011-06-28 2012-06-27 método para preparar um antibiótico de ticarcilina dissódica de penicilina de ação prolongada de amplo espectro
PCT/CN2012/000876 WO2013000277A1 (zh) 2011-06-28 2012-06-27 广谱长效青霉素类抗生素替卡西林钠的制备方法

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101735244A (zh) * 2008-11-05 2010-06-16 鲁南制药集团股份有限公司 青霉素类抗生素替卡西林钠的制备方法
CN101875659A (zh) * 2009-04-29 2010-11-03 瑞阳制药有限公司 替卡西林钠的制备工艺

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1538051A (en) * 1975-01-17 1979-01-10 Beecham Group Ltd 6-methoxy-6-(alpha-carboxyacetamido)-penicillins
GB1579362A (en) * 1977-03-16 1980-11-19 Beecham Group Ltd 6-(a-heterocyclylcarbonyl amino-acetamido)-penicillins and compositions containing them
DE2921422C2 (de) * 1978-12-18 1985-04-18 Bristol-Myers Co., New York, N.Y. Zwischenprodukte zur Herstellung von Penicillinen und deren Verwendung, Verfahren zur Herstellung derselben

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101735244A (zh) * 2008-11-05 2010-06-16 鲁南制药集团股份有限公司 青霉素类抗生素替卡西林钠的制备方法
CN101875659A (zh) * 2009-04-29 2010-11-03 瑞阳制药有限公司 替卡西林钠的制备工艺

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"替卡西林钠的合成工艺改进";王迷娟等;《中国药物化学杂志》;20060630;第16卷(第3期);178页图1，179页第1栏最后一段至第2栏。 *
王迷娟等."替卡西林钠的合成工艺改进".《中国药物化学杂志》.2006,第16卷(第3期),178页图1，179页第1栏最后一段至第2栏。.

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BR112013008592A2 (pt) 2017-10-31
DE112012000225T5 (de) 2013-08-22
DE112012000225B4 (de) 2014-07-10
WO2013000277A1 (zh) 2013-01-03

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