(R)-和(S)-醋丁洛尔的合成研究

Study on the Synthesis of (R)-and (S)-Acebutolol

介绍了一种不对称合成(R)-和(S)-醋丁洛尔的新方法。首先,用自制的(R,R)-Salen-CoⅢ催化剂催化水解动力学拆分外消旋环氧氯丙烷得到高光学纯的(S)-环氧氯丙烷,然后,以2-乙酰基-4-正丁酰胺基苯酚为原料,经与(S)-环氧氯丙烷缩合、异丙胺化开环得到目标化合物(R)-醋丁洛尔,总收率为47.3%,光学纯度大于98%。对其中的关键步骤——缩合化反应进行了优化,确定了较佳的反应条件:2-乙酰基-4-正丁酰胺基苯酚、(S)-环氧氯丙烷与5%NaOH溶液的摩尔比为1:2.5:1.1,DMSO为溶剂,反应温度为20℃,反应时间为12h。用自制的(S,S)-Salen-CoⅢ催化剂代替(R,R)-Salen-CoⅢ催化剂,以同样的方法得到(S)-醋丁洛尔,总收率为46.7%,光学纯度大于98%。产品结构经1H-NMR、13CNMR及MS表征。该路线原料廉价易得,条件温和,操作简单,目标化合物收率和光学纯度高,有较好的工业化应用前景。

A new asymmetric synthetic route for （R）- and （S）-acebutolol was proposed. In this synthsis, （S）-epichlorohydrin was firstly obtained through the hydrolytic kinetic resolution （HKR） of racemic epichlorohydrin catalyzed by a self-made （R,R）-Salen-Com complex, with 43.6% yield and greater than 99% optical purity. （R）-acebutolol was then prepared from 2-acetyl-4-n-butyramidophenol via condensation with （S）-epichlorohydrin and further reacted with isopropyl amine to give an overall yield of 47.3% and an optical purity of greater than 98%. The condensation reaction was investigated in detail, and the appropriate reaction conditions were given as follows： the molar ratio between 2-acetyl-4-n-butyramidophenol, （S）-epichrolohydrine and 5% aqueous sodium hydroxide is 1：2.5：1.1, and the dimethyl sulfoxide（DMSO） is used as solvent with reaction temperature of 20℃ and reaction time of 12 h. Using （S,S）-Salen-Co^Ⅲ complex instead of （R,R）-Salen-Co^Ⅲ complex, （S）-acebutolol was obtained in the same way with 46.7% yield and greater than 98% optical purity. The structures of the title compounds were confirmed by means of MS, ^1H-NMR and ^13CNMR. This synthetic route has many advantages, such as inexpensive raw materials, high yield and high optical purity. With such advantages, this method should accordingly have good prospects for industrial application.