CN105481677B - ɑ-酮酸类化合物的不对称氢化反应 - Google Patents

ɑ-酮酸类化合物的不对称氢化反应 Download PDF

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CN105481677B
CN105481677B CN201410468805.9A CN201410468805A CN105481677B CN 105481677 B CN105481677 B CN 105481677B CN 201410468805 A CN201410468805 A CN 201410468805A CN 105481677 B CN105481677 B CN 105481677B
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butoxide
alkali
phenyl
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CN105481677A (zh
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严普查
车大庆
李原强
章向东
陈康
鄢永亮
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Abstract

本发明涉及有机化学技术领域，具体为ɑ‑酮酸类化合物的不对称氢化反应，该方案如下：其中R1为苯基，取代苯基，萘基，取代萘基，C1‑C6烷基或芳烷基；所述取代基为C1‑C6烷基，C1‑C6烷氧基，卤素；所述取代基的个数为1‑3个。其中M为具有下列结构的手性螺环吡啶胺基膦配体铱络合物：其中R为氢，3‑甲基，4‑tBu或6‑甲基。

Description

ɑ-酮酸类化合物的不对称氢化反应
技术领域
本发明涉及配体化学技术领域，具体涉及ɑ-酮酸类化合物的不对称氢化反应。
背景技术
ɑ-酮酸类化合物的不对称氢化反应在本领域鲜有报道，利用金属配体络合物直接不对称氢化ɑ-酮酸类化合物在该领域的报道也基本处于空白状态。分析原因为：ɑ-酮酸类化合物类的羧基会与金属络合从而毒化催化剂，降低反应收率；又由于ɑ-酮酸类化合物的ɑ羰基与羧酸羰基在空间上基本是共平面，导致手性配体催化剂ɑ酮酸类化合物两面进攻的机会均等，从而导致反应收率或对应选择性低。
具有下列结构的手性螺环吡啶胺基膦配体络合物最早由南开大学研制开发，
该化合物公开发表在公开号为CN102040625的中国专利申请文件中，主要用于芳基酮、烯酮、酮酸酯类化合物的不对称氢化反应中，并且由其实施例11表1编号27记载的结果可知，其对ɑ-酮酸酯催化结果不理想。
鉴于不对称氢化反应在有机合成中的重要地位，有必要研究开发新的工艺，以解决ɑ-酮酸类化合物很难或不能进行不对称氢化反应这个技术问题。
发明内容
为了解决ɑ-酮酸类化合物很难或不能进行不对称氢化反应这个技术问题，本发明提供如下技术方案：
其中R1为苯基，取代苯基，萘基，取代萘基，C1-C6烷基或芳烷基；所述取代基为C1-C6烷基，C1-C6烷氧基，卤素；所述取代基的个数为1-3个。
其中M为具有下列结构的手性螺环吡啶胺基膦配体铱络合物：
其中R为氢，3-甲基，4-tBu或6-甲基。
所述碱选自氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾所述与底物A化合物的摩尔用量比为(1.0～3)：1；优选的摩尔比为(1.001～1.5)：1。
所述溶剂选自甲醇，乙醇，丙醇，异丙醇，四氢呋喃，甲苯，甲基叔丁基醚，二氧六环，DMF等。
优选的R1为苯基，取代苯基，萘基，取代萘基。
优选的本发明采用如下技术方案：在氮气保护下，氢气压力为0.5-10MPa，碱的用量为1.0～3.0摩尔当量，在有机溶剂中，a-酮酸A化合物在0.00001～0.01摩尔当量的手性螺环吡啶胺基膦配体络合物(M)催化下得到B化合物。
更有选的，在氮气保护下，向氢化内管中加入底物A、1.0～3摩尔当量氢氧化钠、氢氧化钾、叔丁醇钠或叔丁醇钾、0.0001～0.01摩尔当量催化剂M和溶剂。将该反应内管装入高压反应釜中，充氢气压力至0.5-10MPa，并使其在10～90℃搅拌反应1-30小时得到产物B。
本发明通过改变反应中所用碱的量，克服底物分子中羧基与中心金属的强配位作用，实现了a-酮酸的直接不对称催化氢化。
附图说明
图1为在实施例12条件下得到的3a化合物的光学纯度HPLC图谱；
图2为在实施例17条件下得到的3c化合物的光学纯度HPLC图谱；
图3为在实施例26条件下得到的3l化合物的光学纯度HPLC图谱。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
HPLC分析仪器及方法：
仪器型号：Agilent1200
色谱柱：ChiracelOD-H,4.6mm×250mm×5μm
流动相A：正己烷
流动相B：异丙醇
流速：1.0mL/min柱温：35℃
波长：210nm
进样量：5μL
实施例1：2-羟基-2-苯基乙酸的制备
在氮气保护下，向200mL氢化内管中加入底物a-酮酸2a(3g,20mmol)、叔丁醇钾(112mg，1mmol)、催化剂M(20mg，0.02mmol，R＝3-甲基)和溶剂(50mL)。将该反应内管装入高压反应釜中。用氢气置换釜内的气体后，充初始氢气压力至15个大气压，并使其在室温搅拌反应24小时。氢化反应完毕，释放氢气，打开高压釜。反应液经快速短硅胶过滤除去催化剂，用核磁分析反应转化率。产品衍生化成甲酯后，测定光学纯度，结果列于表一。
下表一中实施例2-15为按照实施例1的方法同法操作得到的试验结果：
表一：
其中B/S表示碱与底物ɑ-酮酸的比率，conv.表示核磁检测底物转化率。
下表二实施例16-30是以1c为催化剂，按照实施例1的方法同法操作得到的试验结果：
表二：
实施例31：(R)-2-羟基-2-(2-氯苯基)乙酸的制备
按照实施例1的方法同法操作，进行高转化数实验：S/C＝50000
实施例32：(S)-2-羟基-2-苯基乙酸的制备
在氮气保护下，向200mL氢化内管中加入底物a-酮酸2a(3g,20mmol)、氢氧化钾(1.68g，30mmol)、催化剂1c(20mg，0.02mmol)和正丁醇(50mL)。将该反应内管装入高压反应釜中。用氢气置换釜内的气体后，充初始氢气压力至30个大气压，并使其在室温搅拌反应10小时。氢化反应完毕，释放氢气，打开高压釜。反应液经快速短硅胶过滤除去催化剂，用核磁分析反应转化率100％。产品衍生化成甲酯后，测定光学纯度84％ee。
实施例33：(S)-2-羟基-2-(2-萘基)乙酸的制备
在氮气保护下，向200mL氢化内管中加入底物a-酮酸2m(4g,20mmol)、叔丁醇钾(3.36g，30mmol)、催化剂1b(20mg，0.02mmol)和正丁醇(50mL)。将该反应内管装入高压反应釜中。用氢气置换釜内的气体后，充初始氢气压力至15个大气压，并使其在室温搅拌反应12小时。氢化反应完毕，释放氢气，打开高压釜。反应液经快速短硅胶过滤除去催化剂，用核磁分析反应转化率100％。产品衍生化成甲酯后，测定光学纯度95％ee。
实施例34：(R)-2-羟基-3,3-二甲基丁酸的制备
在氮气保护下，向200mL氢化内管中加入底物a-酮酸2o(2.6g,20mmol)、叔丁醇钾(3.36g，30mmol)、催化剂1b(40mg，0.04mmol)和正丁醇(50mL)。将该反应内管装入高压反应釜中。用氢气置换釜内的气体后，充初始氢气压力至15个大气压，并使其在室温搅拌反应24小时。氢化反应完毕，释放氢气，打开高压釜。反应液经快速短硅胶过滤除去催化剂，用核磁分析反应转化率100％。产品衍生化成苄酯后，测定光学纯度85％ee。
尽管已经结合了具体实施方式对本发明进行了充分的描述，应当注意的是对于本领域技术人员来说其各种变化和修改是显而易见的。这样的变化和修改将可以理解为包括在由所附权利要求所定义的本发明的范围内。

Claims (8)

1.一种下列式(B)化合物的制备方法：
其中R1为苯基，取代苯基，萘基，取代萘基，C1-C6烷基或芳烷基；所述取代基为C1-C6烷基，C1-C6烷氧基，卤素；所述取代基的个数为1-3个；
其中M为具有下列结构的手性螺环吡啶胺基膦配体铱络合物：
其中R为氢，3-甲基，4-tBu或6-甲基；
所述碱选自氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾；
所述碱与底物(A)化合物的摩尔用量比为(1.0～3)：1。
2.根据权利要求1所述的制备方法，所述碱与底物(A)化合物的摩尔用量比为(1.001～1.5)：1。
3.根据权利要求1所述的制备方法，其中所述R1为苯基，取代苯基，萘基，取代萘基。
4.根据权利要求1所述的制备方法，所述R为4-tBu。
5.根据权利要求1所述的制备方法，所述碱为叔丁醇钠、叔丁醇钾。
6.根据权利要求1、3-5任一权利要求所述的制备方法，其特征在于，在氮气保护下，氢气压力为0.5-10MPa，碱的用量为1.0～3.0摩尔当量，在有机溶剂中，式(A)化合物在0.00001～0.01摩尔当量的手性螺环吡啶胺基膦配体络合物(M)催化下得到(B)化合物。
7.根据权利要求1、3-5任一权利要求所述的制备方法，其特征在于，在氮气保护下，向氢化内管中加入式(A)化合物、1.0～3摩尔当量氢氧化钠、氢氧化钾、叔丁醇钠或叔丁醇钾、0.0001～0.01摩尔当量催化剂M和溶剂；将该反应内管装入高压反应釜中，充氢气压力至0.5-10MPa，并使其在10～90℃搅拌反应1-30小时得到式(B)化合物。
8.根据权利要求1所述的制备方法，所述溶剂选自甲醇，乙醇，丙醇，异丙醇，四氢呋喃，甲苯，甲基叔丁基醚，二氧六环，N,N-二甲基甲酰胺。
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