摘要
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.
出处
《高校化学工程学报》
EI
CAS
CSCD
北大核心
2008年第5期860-865,共6页
Journal of Chemical Engineering of Chinese Universities