CN101143849A - 奥硝唑的光学对映体的制备及纯化方法 - Google Patents

奥硝唑的光学对映体的制备及纯化方法 Download PDF

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CN101143849A
CN101143849A CNA2007100188576A CN200710018857A CN101143849A CN 101143849 A CN101143849 A CN 101143849A CN A2007100188576 A CNA2007100188576 A CN A2007100188576A CN 200710018857 A CN200710018857 A CN 200710018857A CN 101143849 A CN101143849 A CN 101143849A
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苏红军
强建华
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XI'AN TIANYI QINKUN PHARMACEUTICAL CO Ltd
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Abstract

本发明提供了奥硝唑光学对映体的制备及纯化方法，将乙酸氯甲酯与2－甲基－5硝基咪唑在适宜的条件下反应得乙酸硝基咪唑甲酯；将手性3－氯－1，2丙二醇与二氯亚砜反应，得到的产物氧化得手性环硫酸酯；最后将乙酸硝基咪唑甲酯与手性环硫酸酯反应，产物水解，得相应的奥硝唑的光学对映体。本发明操作简便，产品纯度高，适用于工业化大生产。

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奥硝唑的光学对映体的制备及纯化方法
技术领域：
本发明涉及奥硝唑光学对映体的制备及纯化方法。
技术背景：
奥硝唑为((+)1-(3-氯-2-羟丙基)-2-甲基-5-硝基咪唑(Ornidazole，CAS16773-42-5)。奥硝唑为硝基咪唑类衍生物，是一种强力抗厌氧菌及抗原虫感染的药物，也是继甲硝唑后新研制制成的疗效更高、疗程更短、耐受性更好、体内分布更广的第三代硝基咪唑类衍生物。奥硝唑的抗微生物作用是通过其分子中的硝基在无氧环境中还原成氨基，或通过自由基的形成与细胞成分相互作用，从而导致微生物的死亡。现有技术有两种制备奥硝唑光学对映体的方法。一种是用酶法进行拆分见中国专利CN1400312A，此方法得奥硝唑光学对映体所需成本较大，并不适用于大生产；另一种方法是中国专利200510127033.3公开的，此反应工艺简单，反应步骤少，缺点是手性环氧乙烷副反应多，得率低。
发明内容：
本发明的目的是提供一种产率高，反应条件温和，纯度高、外观好的且适用于工业化生产的奥硝唑光学对映体的制备及纯化方法。
本发明是通过如下技术来实现的：
Figure A20071001885700031
Figure A20071001885700041
右旋奥硝唑
本发明共采用如下实验获得纯度高的奥硝唑光学对映体，该方法是步骤是：1、将乙酸氯甲酯与2-甲基-5硝基咪唑在适宜的条件下反应得乙酸硝基咪唑甲酯。
2、将手性3-氯-1，2丙二醇与二氯亚砜反应，得到的产物氧化得手性环硫酸酯。
3、将乙酸硝基咪唑甲酯与手性环硫酸酯反应，产物水解得相应的奥硝唑的光学对映体。
更具体的说步骤1的反应溶剂为：乙酸乙酯、甲苯、乙腈、二氯甲烷、丙酮等，优选乙腈、乙酸乙酯。反应温度优选回流温度。傅酸剂为碳酸钠、三乙胺等。
步骤2的反应溶剂为二氯甲烷、乙酸乙酯、乙腈、丙酮等，优选二氯甲烷、乙酸乙酯。反应温度-10-50℃。
步骤3的反应溶剂为甲苯、乙酸乙酯、乙腈等。优选甲苯。反应温度为20-100℃。水解溶剂为：1mol-5mo l/L的硫酸、盐酸或磷酸，优选硫酸。
本发明所述重结晶所用的溶剂为30％-70％的乙醇溶液，优选70％的乙醇溶液。
本发明操作简单，产率高，反应条件温和，纯度可达99.6％以上。
下面结合实施例对本发明作进一步详细说明，但应理解本发明的范围非仅限于这些实施例的范围。
具体实施方式：
实施例1：
a.乙酸硝基咪唑甲酯的制备
500L搪瓷反应釜中将2-甲基-5-硝基咪唑30kg，41kg无水碳酸钠，乙酸乙酯200L及少量相转移催化剂混合搅拌，慢慢加入乙酸氯甲酯40kg，加毕，加热至回流7小时，冷却至室温，过滤，水洗，加入无水硫酸钠干燥，回收乙酸乙酯至干，得乙酸硝基咪唑甲酯56kg。
b.环硫酸酯的制备
1000L搪瓷反应釜中将S-3-氯-1，2丙二醇110kg溶于500L二氯甲烷中，冰盐水冷却下滴加200kg二氯亚砜与100L二氯甲烷的混合溶液，滴加完毕，升高温度至回流，反应1.5小时。冷却至-10℃-0℃，然后慢慢加入30％的双氧水100L，0-10℃保温反应3小时，分液，水洗，无水硫酸钠干燥，回收二氯甲烷至干得S-环硫酸酯180.1kg。
c.左旋奥硝唑的制备。
将22kg乙酸硝基咪唑甲酯与17kg S—环硫酸酯投入到200L搪瓷反应釜中，加入50L甲苯溶液，加热至90℃，反应12小时，然后加入2mol/L的硫酸溶液50L，90℃反应4小时，取下层溶液加入氨水调pH为7-7.5，过滤得S-(-)—奥硝唑粗品，用70％的乙醇重结晶二次，干燥得左旋奥硝唑精制品15.2kg，[a]D 20＝-68.4(C＝1.0，二氯甲烷)，纯度为99.8％。
实施例2：
c.乙酸硝基咪唑甲酯的制备
300L搪瓷反应釜中将2-甲基-5-硝基咪唑25kg，37kg无水碳酸钠，乙腈150L及少量相转移催化剂混合搅拌，慢慢加入乙酸氯甲酯40kg，加毕，加热至回流6小时，过滤，回收乙腈，残留物用乙酸乙酯溶解，水洗，加入无水硫酸钠干燥，回收乙酸乙酯至干，得乙酸硝基咪唑甲酯46.1kg。
d.环硫酸酯的制备
1000L搪瓷反应釜中将R--3-氯-1，2丙二醇110kg溶于500L二氯甲烷中，冰盐水冷却下滴加200kg二氯亚砜与100L二氯甲烷的混合溶液，滴加完毕，升高温度至回流，反应1.5小时。冷却至-10℃-0℃，然后慢慢加入30％的双氧水100L，0-10℃保温反应3小时，分液，水洗，无水硫酸钠干燥，回收二氯甲烷至干得R-环硫酸酯175.6kg。
c.右旋奥硝唑的制备。
将22kg乙酸硝基咪唑甲酯与17kg R—环硫酸酯投入到200L搪瓷反应釜中，加入50L甲苯溶液，加热至90℃，反应12小时，然后加入2mol/L的硫酸溶液50L，90℃反应4小时，取下层溶液加入氨水调pH为7-7.5，过滤得右旋奥硝唑粗品，用70％的乙醇重结晶二次，干燥得左旋奥硝唑精制品16.7kg，[a]D 20＝+69.7(C＝1.0，二氯甲烷)，纯度为99.9％。

Claims (5)

1.奥硝唑光学对映体的制备方法，该方法含有以下步骤：
a.将乙酸氯甲酯与2-甲基-5硝基咪唑在适宜的条件下反应得乙酸硝基咪唑甲酯。
b.将手性3-氯-1，2丙二醇与二氯亚砜反应，得到的产物氧化得手性环硫酸酯。
c.将乙酸硝基咪唑甲酯与手性环硫酸酯反应，产物水解得相应的奥硝唑的光学对映体，如果有必要，再纯化的纯品奥硝唑的光学对映体。
2.根据权利1所述的奥硝唑光学对映体的制备方法，其特征在于反应步骤a的反应溶剂为：乙酸乙酯、甲苯、乙腈、二氯甲烷、丙酮等，优选乙腈、乙酸乙酯；反应温度优选回流温度；傅酸剂为碳酸钠、三乙胺等。
3.根据权利1所述的奥硝唑光学对映体的制备方法，其特征在于反应步骤b的反应溶剂为：二氯甲烷、乙酸乙酯、乙腈、丙酮等，优选二氯甲烷、乙酸乙酯；反应温度-10～50℃。
4.根据权利1所述的奥硝唑光学对映体的制备方法，其特征在于反应步骤c的反应溶剂为：甲苯、乙酸乙酯、乙腈等。优选甲苯；反应温度为20～100℃；水解溶剂为：1mol～5mol/L的硫酸、盐酸或磷酸，优选硫酸。
5.根据权利1所述的奥硝唑光学对映体的制备方法，其特征在于重结晶所用的溶剂为30％～70％的乙醇溶液，优选70％的乙醇溶液。
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102321029A (zh) * 2011-07-15 2012-01-18 海南美兰史克制药有限公司 一种奥硝唑化合物及其新制法
CN103772289A (zh) * 2014-01-03 2014-05-07 湖南迪诺制药有限公司 合成塞克硝唑的方法及塞克硝唑
CN105037272A (zh) * 2015-06-30 2015-11-11 湖南三清药业有限公司 左奥硝唑化合物及其药物组合物
CN105777648A (zh) * 2014-12-22 2016-07-20 山东齐都药业有限公司 左奥硝唑α晶型及其制备方法
CN114195757A (zh) * 2022-01-05 2022-03-18 香河昆仑新能源材料股份有限公司 一种硫酸乙烯酯的合成方法

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102321029A (zh) * 2011-07-15 2012-01-18 海南美兰史克制药有限公司 一种奥硝唑化合物及其新制法
CN102321029B (zh) * 2011-07-15 2013-04-03 海南美兰史克制药有限公司 一种奥硝唑化合物及其新制法
CN103772289A (zh) * 2014-01-03 2014-05-07 湖南迪诺制药有限公司 合成塞克硝唑的方法及塞克硝唑
CN103772289B (zh) * 2014-01-03 2016-02-17 湖南迪诺制药有限公司 合成塞克硝唑的方法及塞克硝唑
CN105777648A (zh) * 2014-12-22 2016-07-20 山东齐都药业有限公司 左奥硝唑α晶型及其制备方法
CN105037272A (zh) * 2015-06-30 2015-11-11 湖南三清药业有限公司 左奥硝唑化合物及其药物组合物
CN105037272B (zh) * 2015-06-30 2017-04-19 湖南三清药业有限公司 左奥硝唑化合物及其药物组合物
CN114195757A (zh) * 2022-01-05 2022-03-18 香河昆仑新能源材料股份有限公司 一种硫酸乙烯酯的合成方法

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