CN104164470B - 一种拆分制备光学纯r-1-萘乙胺的方法 - Google Patents
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 24
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Abstract
本发明涉及一种拆分制备光学纯R‑1‑萘乙胺的方法。以1‑萘乙胺为原料，Novozym 435为拆分催化剂，R‑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‑萘乙胺转化完全得(R)‑(1‑(1‑萘基)乙基)乙酰胺（ee值99%）；酰胺纯化后进行酸解得R‑1‑萘乙胺盐，盐再通过碱化、萃取、干燥、浓缩等操作得R‑1‑萘乙胺，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R‑1‑萘乙胺的生产制备中，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R-1-萘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-羟基萘乙酸（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）。
在现有的方法中，不对称合成法成本高且经常难得到光学纯度高的产物；化学拆分法及酶法动力学拆分存在原料的利用率低的缺点，最多只有50%；而现报道的酶法动态动力学拆分法中，所使用的消旋催化剂通常是一些钌、铑等贵金属的复合物，这些消旋催化剂成本极高，且拆分制备过程中使用这些消旋催化剂时，虽然实现高转化率但是产品难以获得高的光学纯度。
发明内容
本发明要解决的技术问题是找到一种价格低廉的消旋催化剂，同时实现R-1-萘乙胺在拆分制备过种中的高收率以及高光学纯度。
为了解决上述问题，本发明提供了一种光学纯R-1-萘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-萘乙胺和酰基供体R-1-苯乙醇乙酸酯，最后再按原料1-萘乙胺质量分数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-萘乙胺完全转化为(R)-(N-(1-萘基)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(R)-(N-(1-萘基)乙基)乙酰胺，2）将步骤1中制得的(R)-(N-(1-萘基)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，(R)-(N-(1-萘基)乙基)乙酰胺完全水解得R-1-萘乙胺对映体盐；3）将步骤2所得R-1-萘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R-1-萘乙胺，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R-1-萘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，且最终制备得到的光学纯R-1-萘乙胺收率好，光学纯度高。
具体实施方法：
1）拆分制备(R)-(N-(1-萘基)乙基)乙酰胺
1000mL的高压釜中加入500mL甲苯作为溶剂，依次加入85.5g1-萘乙胺、90.2g R-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-萘乙胺消失完全转化为(R)-(N-(1-萘基)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(R)-(N-(1-萘基)乙基)乙酰胺102.3g，收率为96%。
2）酸解获得R-1-萘乙胺盐
将上步中制得的(R)-(N-(1-萘基)乙基)乙酰胺53g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(R)-(N-(1-萘基)乙基)乙酰胺完全水解得R-1-萘乙胺对映体盐。
3）碱化获得R-1-萘乙胺
往步骤2所得反应完全的溶液加入500mL的二氯甲烷，然后缓慢加入氢氧化钠溶液，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R-1-萘乙胺40.4g，收率为94.4%，HPLC检测最终产品的ee值为99.7%。
Claims (3)
1.光学纯R-1-萘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-萘乙胺和酰基供体R-1-苯乙醇乙酸酯，然后按原料1-萘乙胺质量分数1％-10％的比例加入脂肪酶novozym 435，按原料1-萘乙胺质量分数1％-10％的比例加入雷尼镍，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-萘乙胺完全转化为(R)-(N-(1-萘基)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(R)-(N-(1-萘基)乙基)乙酰胺，2)将步骤1)中制得的(R)-(1-(1-萘基)乙基)乙酰胺溶解在10倍体积比的以体积比1:1配制的醇与酸的混合溶液中，然后加热回流反应24小时，(R)-(N-(1-萘基)乙基)乙酰胺完全水解得R-1-萘乙胺对映体盐；3)将步骤2)所得R-1-萘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R-1-萘乙胺，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R-1-萘乙胺的制备方法，其特征在于：步骤1)中的脂肪酶Novozym 435为生物拆分催化剂，雷尼镍为消旋催化剂。
3.根据权利要求1所述光学纯R-1-萘乙胺的制备方法，其特征在于：步骤2)中的醇为甲醇或乙醇；酸为盐酸。
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| Heterogeneous Raney Nickel and Cobalt Catalysts for Racemization and Dynamic Kinetic Resolution of Amines.;Andrei N. Parvulescu et al.;《Adv. Synth. Catal.》;20071220;113-121 * |
| 新型酰基供体用于酶法动力学拆分制备(R)-1-(2-萘基)乙胺的研究;符思敏 等;《有机化学》;20121231;526-531 * |
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