生物转化法制备手性醇(R)-[3,5-二(三氟甲基)苯基]乙醇

Preparation of Chiral Alcohol (R-[3,5-Bis(Trifluoromethyl)Phenyl] Ethanol by Biocatalytic

摘要: 手性醇是一类重要的手性模块化合物，广泛应用于医药、化工和农业等领域。(R)-[3,5-二(三氟甲基)苯基]乙醇是合成用于治疗癌症病人化疗时引起恶心和呕吐的NK-1受体拮抗剂(如阿瑞吡坦和福沙吡坦)的重要手性中间体。不对称生物还原[3,5-双(三氟甲基)苯基]乙酮是制备(R)-[3,5-二(三氟甲基)苯基]乙醇的重要方法。本文从土壤中筛选获得一株对[3,5-双(三氟甲基)苯基]乙酮具有高效还原的微生物菌株HNNQ1，该菌株被鉴定为寡养单胞菌属(Stenotrophomonas sp)，命名为寡养单胞菌HNNQ1。对菌株HNNQ1不对称还原制备(R)-[3,5-二(三氟甲基)苯基]乙醇的条件进行了研究，结果表明，菌株HNNQ1的最佳还原条件如下：辅助底物种类为异丙醇，且浓度为15% (v/v)，反应温度为30℃，反应缓冲液pH为7.2，最适的底物浓度为40 mmol/L，菌体浓度为250 g/L，反应时间为15 h。在上述条件下，产物的产率和对映体过量值(enantiomeric excess, ee)分别为98.8%和99.6%。

Abstract: Chiral alcohols are a group of the most important building blocks, and have been widely used in the pharmaceutical, chemical and agriculture industries for production of chiral information into the products. (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol is an important chiral intermediate for the synthesis of a tachykinin NK1 receptor antagonist widely administered to cancer patients without the nausea and vomiting side effects that often happen with chemotherapy, such as Aprepitant (Emend) and Fosaprepitant (Ivemend). The biocatalytic asymmetric reduction of 3,5-bis(trifluoromethyl) acetophenone is an effective approach for the preparation of (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol. In this paper, a novel strain HNNQ1, which had highly efficient reduction for 3,5-bis(trifluoromethyl) acetophenone, was isolated from a soil sample and identified as Stenotrophomonas sp. The reaction conditions for prepared (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol by whole cells of strain HNNQ1 was carried out. The obtained optimized conditions for the bio-reduction are as follows: 2-propanol with a concentration of 15% (v/v) as co-substrate, buffer pH 7.2, 40 mM of 3,5-bis(trifluoromethyl) acetophenone, 250 g/L of resting cells as biocatalyst, reaction for 15 h at 30˚C and 150 rpm. Under above conditions, best yields of 98.8% and 99.6% of product ee were obtained, respectively.