CN106397117B - 环己基苯基甲酮的还原醇化及拆分方法 - Google Patents

环己基苯基甲酮的还原醇化及拆分方法 Download PDF

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CN106397117B
CN106397117B CN201610800964.3A CN201610800964A CN106397117B CN 106397117 B CN106397117 B CN 106397117B CN 201610800964 A CN201610800964 A CN 201610800964A CN 106397117 B CN106397117 B CN 106397117B
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褚晓晨
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Abstract

本发明公开了一种环己基苯基甲酮的还原醇化及拆分方法。以环己基苯基甲酮为原料，加氢还原得外消旋醇，外消旋的醇再经动态动学拆分即可得光学纯度的R‑环己基(苯基)甲醇。本方法具备操作简单，产品收率高、光学纯度好等特点，在R‑环己基(苯基)甲醇的生产制备过程中具有极大的指导和应用价值。

Description

环己基苯基甲酮的还原醇化及拆分方法
技术领域
本发明涉及一种光学纯手性羟基化合的制备方法，尤其是环己基苯基甲酮还原醇化制备环己基(苯基)甲醇及动态动力学拆分制备 R-环己基(苯基)甲醇的方法。
背景技术
目前已有的研究中，有关于环己基(苯基)甲醇制备方法的相关报道，它主要可以分为以下几类，一是以环己基苯基甲酮为原料，经硼氢化钠还原得到（The AsymmetricPiers Hydrosilylation, Journal of the American Chemical Society, 138(22),6940-6943; 2016）；二是苯甲醛与卤代环己烷加成反应得到（Grignard Reactions inCyclopentyl Methyl Ether，Asian Journal of Organic Chemistry, 5(5), 636-645;2016）三是以Ru金属配合物与异丙醇钠协同作用催化环己基苯基甲酮氢化得环己基(苯基)甲醇（Preparation of Pincer 4-Functionalized 2-Aminomethylbenzo[h]quinolineRuthenium Catalysts for Ketone Reduction，Organometallics, 35(2), 277-287;2016）。在已报道的这几种方法中，硼氢化钠还原环己基苯基甲酮的方法存在后处理复杂，污水多的问题，苯甲醛与卤代环己烷加成反应，存在反应条件苛刻，产品收率不高的问题，而Ru金属配合物与异丙醇钠协同作用催化环己基苯基甲酮氢化得环己基(苯基)甲醇则存在催化剂昂贵的缺点。
关于手性化合物R-环己基(苯基)甲醇的制备方法，则是多以金属配合物催化环己基苯基甲酮不对称氢化还原得到（Highly Enantioselective Transfer Hydrogenationof Polar Double Bonds by Macrocyclic Iron(II)/(NH)2P2 Catalysts，OrganicProcess Research & Development, 20(2), 253-261; 2016；Modular hydroxyamide andthioamide pyranoside-based ligand library from the sugar pool: New class ofligands for asymmetric transfer hydrogenation of ketones，Advanced Synthesis &Catalysis, 356(10), 2293-2302; 2014）；这些方法普遍存在催化剂昂贵，产品收率不高，以及最终产品光学纯度低的缺点。
发明内容
为了解决上述问题，本发明的提供简单易操作，原料及催化剂来源较为普遍的一种环己基苯基甲酮还原醇化制备环己基(苯基)甲醇并进一步进行拆分得到R-环己基(苯基)甲醇的方法，本发明还具备最终所得产品收率好、产品光学纯度高的特点。
环己基苯基甲酮的还原醇化及拆分具体实现过程如下：
1）在高压釜内，加入一定量的醇作为溶剂，加入原料环己基苯基甲酮，按原料环己基(苯基)甲醇质量的5%~20%的比例加入加氢催化剂，然后密封反应釜，排除空气，通入氢气再升至合适温度进行反应，得环己基(苯基)甲醇；
2）在有机溶剂甲苯中，以步骤1)所得环己基(苯基)甲醇为原料，按原料环己基(苯基)甲醇摩尔量的1.0~1.5倍的比例加入酰基供体、按原料环己基(苯基)甲醇质量的1%~5%的比例加入脂肪酶、按原料环己基苯基甲酮质量的5%~15%加入消旋催化剂，在一定的温度下进行动态动力学拆分反应，得R-环己基(苯基)甲醇的酰基化合物，过柱纯化得R-环己基(苯基)甲醇的酰基化合物纯品；
3）将步骤2）所得R-环己基(苯基)甲醇的酰基化合物加入到按一定比例配制的四氢呋喃与氢氧化锂的混合溶液中，室温搅拌过夜反应，TLC检测反应进度，反应结束后，过柱纯化可得纯品R-环己基(苯基)甲醇，最终产品的光学纯度可以达99%以上，产品收率也有90%左右；步骤1）中所述的加氢催化剂为上海迅凯所产镍型催化剂AMG-1200；步骤2）中所述的酰基供体为对氯苯酚乙酸酯；步骤2）中所述的脂肪酶为猪胰脂肪酶；步骤2）中所述的消旋催化剂为酸性树脂D006。
本发明以环己基苯基甲酮为原料经加氢还原、动态动力学拆分得R-环己基(苯基)甲醇酰基化合物，再进行水解最终得R-环己基(苯基)甲醇。本方法具备操作简单，所用消旋催化剂廉价易得、可重复使用，产品收率高、光学纯度好等特点，在环己基苯基甲酮的进一步醇化及拆分研究中具有极大的指导和应用价值。
具体实施方式
实施例1
1）在高压釜内，加入150ml甲醇作为溶剂，再加入 18.8g环己基苯基甲酮、3g加氢催化剂镍型催化剂AMG-1200；加入完毕，密封反应釜，氮气置换出釜内空气，通入H2至压力4.0MPa，开启搅拌，升温至95℃进行反应，反应9小时后，点板检测环己基苯基甲酮消失，转化为环己基(苯基)甲醇；停止反应，冷却、过滤、浓缩得环己基(苯基)甲醇粗品，再经层析柱纯化后得纯品环己基(苯基)甲醇17.2g，收率为90.7%。
2）在100ml蓝盖瓶中加入60ml甲苯作为溶剂，再依次加入步骤1)所得环己基(苯基)甲醇9.5g、11g对氯苯酚乙酸酯、0.3g猪胰脂肪酶PPL、1.2g酸性树脂D006；原料加入完毕，放入45℃振荡摇床内进行反应，反应12小时后，检测原料环己基(苯基)甲醇消失，转化为R-环己基(苯基)甲醇乙酰化合物；将反应后的溶液冷却、过滤、浓缩，得粗产品，再过柱得R-环己基(苯基)甲醇乙酰化合物11.3g，收率97.2%。
3）将步骤2）中所得R-环己基(苯基)甲醇乙酰化合物11.3g加入到60ml四氢呋喃与6gLiOH配制而成的混合溶液中，室温搅拌过夜反应，点板检测R-环己基(苯基)甲醇乙酰化合物消失。将反应液进行浓缩，蒸去四氢呋喃，再用二氯甲烷对剩余溶液进行萃取、分液、干燥、浓缩得含有R-环己基(苯基)甲醇的粗品。
4）将步骤3）所得含有R-环己基(苯基)甲醇的纯品用体积比为10:1的石油醚与乙酸乙酯的混合溶液进行硅胶柱层析。最终可得R-环己基(苯基)甲醇8.8g，收率92.2%，经检测，最终产品R-环己基(苯基)甲醇的ee值为99.4%。
实施例2
1）在1000ml高压釜内，加入700ml甲醇作为溶剂，再加入 188g环己基苯基甲酮、18g加氢催化剂镍型催化剂AMG-1200；加入完毕，密封反应釜，氮气置换出釜内空气，通入H2至压力4.0MPa，开启搅拌，升温至90℃进行反应，反应9小时后，点板检测环己基苯基甲酮消失，转化为环己基(苯基)甲醇；停止反应，冷却、过滤、浓缩得环己基(苯基)甲醇粗品，再进行过柱纯化得环己基(苯基)甲醇纯品173.3g，收率为91.2%
2）在1000ml蓝盖瓶中加入700ml甲苯作为溶剂，再依次加入步骤1)所得环己基(苯基)甲醇纯品95g、102g对氯苯酚乙酸酯、猪胰脂肪酶PPL4g、11g酸性树脂D006；原料加入完毕，放入40℃振荡摇床内进行反应，反应12小时后，检测原料环己基(苯基)甲醇消失，转化为R-环己基(苯基)甲醇乙酰化合物；将反应后的溶液冷却、过滤、浓缩，得粗产品待下步使用。
3）将步骤2）中所得粗产品加入加入到600ml四氢呋喃与60gLiOH配制而成的混合溶液中，室温搅拌过夜反应，点板检测R-环己基(苯基)甲醇乙酰化合物消失。将反应液进行浓缩，蒸去四氢呋喃，再用二氯甲烷对剩余溶液进行萃取、分液、干燥、浓缩得含有R-环己基(苯基)甲醇的粗品。
4）将步骤3）所得含有R-环己基(苯基)甲醇的粗品用体积比为10:1的石油醚与乙酸乙酯的混合溶液进行硅胶柱层析。最终可得R-环己基(苯基)甲醇87.7g，收率92.3%，经检测，最终产品R-环己基(苯基)甲醇的ee值为99.5%。

Claims (3)

1.一种环己基苯基甲酮的还原醇化及拆分方法，其特征在于由以下步骤组成：
1)在高压釜内，加入醇作为溶剂，加入原料环己基苯基甲酮，按原料环己基(苯基)甲醇质量的5％～20％的比例加入加氢催化剂，然后密封反应釜，排除空气，通入氢气至压力为4.0MPa，再升至95℃进行反应，得环己基(苯基)甲醇；
2)在有机溶剂甲苯中，以步骤1)所得环己基(苯基)甲醇为原料，按原料环己基(苯基)甲醇摩尔量的1.0～1.5倍的比例加入酰基供体、按原料环己基(苯基)甲醇质量的1％～5％的比例加入脂肪酶、按原料环己基苯基甲酮质量的5％～15％加入消旋催化剂，在45℃下进行动态动力学拆分反应，得R-环己基(苯基)甲醇的酰基化合物，过柱纯化得R-环己基(苯基)甲醇的酰基化合物纯品；
3)将步骤2)所得R-环己基(苯基)甲醇的酰基化合物加入到按10mL：1g配制的四氢呋喃与氢氧化锂的混合溶液中，室温搅拌过夜反应，TLC检测反应进度，反应结束后，过柱纯化得到纯品R-环己基(苯基)甲醇，最终产品的光学纯度达99％以上，产品收率也有90％以上；根据以上步骤所述，方程式如下：
Figure FDA0002837688980000011
步骤1)中所述的加氢催化剂为上海迅凯所产镍型催化剂AMG-1200；
步骤2)中所述的酰基供体为对氯苯酚乙酸酯。
2.根据权利要求1所述一种环己基苯基甲酮的还原醇化及拆分方法，其特征在于：步骤2)中所述的脂肪酶为猪胰脂肪酶。
3.根据权利要求1所述一种环己基苯基甲酮的还原醇化及拆分方法，其特征在于：步骤2)中所述的消旋催化剂为酸性树脂D006。
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