CN104151169A - 一种拆分制备光学纯s-1-苯乙胺的方法 - Google Patents
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Abstract
本发明涉及一种动态动力学拆分制备S-1-苯乙胺的方法。以1-苯乙胺为原料，Novozym435为拆分催化剂，S-1-苯乙醇乙酸酯为酰基供体，雷尼镍为消旋催化剂，在高压釜中通入氢气进行反应，1-苯乙胺转化完全得(S)-(1-苯基乙基)乙酰胺（ee值99%）；酰胺纯化后进行酸解得S-1-苯乙胺盐，盐再通过碱化、萃取、干燥、浓缩等操作得S-1-苯乙胺，各步骤产品收率可达90%以上，ee值均大于99%。本发明具备消旋催化剂廉价易得、原料利用完全、产品收率好、光学纯度高等特点。在S-1-苯乙胺的生产制备中，具有极大的指导和应用价值。
Description
技术领域
本发明涉及一种光学纯手性胺的拆分制备方法，尤其涉及光学纯S-1-苯乙胺的拆分及制备方法。
背景技术
光学纯的手性胺是一种非常重要的药物中间体。目前获得光学纯的手性胺主要通过以下几种方法：酶拆分(Indian J. Chem. Sect. B 2005, 44, 1312-1316; J. Org. Chem. 1997, 62, 3488-3495)；化学拆分：用手性α-羟基苯乙酸（US6342636; Tetrahedron: asymmetry, 1998, 9, 2219-2212）或保护的手性甘油醇衍生物拆分（Tetrahedron: asymmetry, 1996, 7, 1117-1122; Tetrahedron: asymmetry, 2002, 13, 2277-2282）；通过相应的醛经不对称合成得到（WO2004/110976; J. Org. Chem. 1992, 57, 1237-1241）。
在现有的报道中，获得S型手性胺大多通过化学拆分或化学不对称合成。但是这两种方法分别存在着原料利率低及产品光学纯度不高等问题。已有的研究中，也极少有利用脂肪酶实现高选择性催化合成S胺。这些都是S型手性胺合成与应用中存在的重要问题。本发明使用特殊的手性酯作为酰基供体，成功的利用脂肪酶Novozym 435催化外消旋胺拆分制备得到S型胺，且最终产品收率好，纯度高。
发明内容
本发明要解决的技术问题是如何利用脂肪酶Novozym 435高收率、高选择性的拆分制备S-1-苯乙胺。
为了解决上述问题，本发明提供了一种光学纯S-1-苯乙胺的拆分制备方法：1）在高压釜中，以甲苯为溶剂，按摩尔比1:1.0~2.0的比例加入原料1-苯乙胺和酰基供体S-1-苯乙醇乙酸酯，最后再按原料1-苯乙胺质量分数1%-10%的比例加入脂肪酶Novozym 435和雷尼镍，高压釜密封进行氮气置换后，通入氢气至压力0.1-1.0MPa并升温至40-70℃反应20小时，即可将1-苯乙胺完全转化为(S)-(1-苯基乙基)乙酰胺，且产物ee值可达99%；反应结束后，将溶液进行浓缩，柱层析，得纯(S)-(1-苯基乙基)乙酰胺，2）将步骤1中制得的(S)-(1-苯基乙基)乙酰胺溶解在10倍体积比的醇与酸液（v/v=1:1）的混合溶液中，然后加热回流反应24小时，(S)-(1-苯基乙基)乙酰胺完全水解得S-1-苯乙胺对映体盐；3）将步骤2所得S-1-苯乙胺盐进行碱化处理，然后通过有机溶剂萃取、干燥、浓缩即可得到光学纯的S-1-苯乙胺，最终整个步骤产品收率可达90%以上，且产品纯度为99%。
本发明在制备光学纯S-1-苯乙胺过程中使用的消旋催化剂为雷尼镍具有低廉易得的特点，使用S-1-苯乙醇乙酸酯作为酰基供体，成功的利用脂肪酶Novozym 435拆分制备得到S型胺，且最终产品收率好，光学纯度高。
具体实施方法：
1）拆分制备S-1-苯乙胺乙酰胺
1000mL的高压釜中加入500mL甲苯作为溶剂，依次加入依次加入60.5g1-苯乙胺、90.2g S-1-苯乙醇乙酸酯，5g脂肪酶novozym 435和8g雷尼镍，加入完毕后，密封高压釜后用氮气将釜内空气进行置换，然后往高压釜内通入氢气至压力1.0MP，开启搅拌，并升温至60℃进行反应；20小时后，取样检测，1-苯乙胺消失完全转化为(S)-(1-苯基乙基)乙酰胺，且产物ee值达99%；反应结束后，将溶液进行浓缩，然后用体积比为10:1的正已烷与乙醇混合溶剂进行柱层析，得纯(S)-(1-苯基乙基)乙酰胺102.3g，收率为96%。
2）酸解获得S-1-苯乙胺盐
将上步中制得的(S)-(1-苯基乙基)乙酰胺40g加入到500ml的乙醇和浓盐酸以体积比1:1混合的溶液中，然后加热回流，反应24小时后，点板检测(S)-(1-苯基乙基)乙酰胺完全水解得S-1-苯乙胺对映体盐。
3）碱化获得S-1-苯乙胺
往步骤2所得反应完全的溶液加入500mL的二氯甲烷，然后缓慢滴加氢氧化钠溶液，并进行搅拌，检测溶液PH值至13，停止添加氢氧化钠溶液，分液，上层水液再次用200mL的二氯甲烷萃取3次，将几次萃取得到的二氯甲烷溶液用无水硫酸钠进行干燥、浓缩得S-1-苯乙胺29.2g，收率为97.4%，HPLC检测最终产品的ee值为99.5%。
Claims (4)
1.光学纯S-1-苯乙胺的拆分制备方法其特征在于：1）在高压反应釜中，以甲苯为溶剂，按摩尔比1:1.0-2.0的比例加入原料1-苯乙胺和酰基供体S-1-苯乙醇乙酸酯，然后按原料1-苯乙胺质量分数1%-10%的比例加入脂肪酶Novozym 435和雷尼镍，高压釜密封进行氮气置换后，通入氢气至压力0.1-1.0MPa并升温至40-70℃反应20小时，即可将1-苯乙胺完全转化为(S)-(1-苯基乙基)乙酰胺，且产物ee值达99%；反应结束后，将溶液进行浓缩，柱层析，得纯(S)-(1-苯基乙基)乙酰胺，2）将步骤1中制得的(S)-(1-苯基乙基)乙酰胺溶解在10倍体积比的醇与酸液（v/v=1:1）的混合溶液中，加热回流反应24小时，S-1-苯乙胺乙酰胺完全水解得S-1-苯乙胺盐；3）将步骤2所得S-1-苯乙胺盐进行碱化处理，然后通过有机溶剂萃取、干燥、浓缩即可得到光学纯的S-1-苯乙胺，最终整个步骤产品收率可达93%以上，且产品纯度为99%；根据所述，其反应方程式如下： 。
2.根据权利要求1所述，光学纯S-1-苯乙胺的制备方法其特征在于步骤1)中的酰基供体为S-1-苯乙醇乙酸酯，脂肪酶为Novozym 435，消旋催化剂为雷尼镍。
3.根据权利要求1所述，光学纯S-1-苯乙胺的制备方法其特征在于步骤2)中的醇为甲醇或乙醇；酸为盐酸或硫酸。
4.根据权利要求1所述，光学纯S-1-苯乙胺的制备方法其特征在于步骤3)中的碱化处理所用的碱为氢氧化钠、氢氧化钾或氨水；萃取所用的有机溶剂为甲苯、二氯甲烷，1,2-二氯乙烷，乙醚等。
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