贝托司汀手性中间体(S)-CPMA整细胞催化合成工艺研究  

Study on Whole Cell Catalytical Synthesis Process of Bepotastine Chiral Intermediate(S)-CPMA

作　　者：古永红[1] 王德林 饶振辉 龚大春 肖玲玲[1] GU Yonghong;WANG Deling;RAO Zhenhui;GONG Dachun;XIAO Lingling(Hubei Three Gorges Polytechnic,Yichang 443000,China;College of College of Biological and Pharmaceutical,China Three Gorges University,Yichang 443002,China;Yichang Humanwell Pharmaceutical Co.,Ltd.,Yichang 443003,China)

机构地区：[1]湖北三峡职业技术学院,湖北宜昌443000 [2]三峡大学生物与制药学院,湖北宜昌443002 [3]宜昌人福药业责任有限公司,湖北宜昌443003

出　　处：《三峡大学学报（自然科学版）》2024年第5期105-112,共8页Journal of China Three Gorges University：Natural Sciences

基　　金：国家自然科学基金面上项目(21776162)。

摘　　要：针对不同条件对贝托司汀手性中间体(S)-CPMA的整细胞催化合成影响,进行单因素实验和正交设计优化研究.首先从耐热克鲁维酵母突变株SXBP-02预处理方式、不同催化反应介质、pH、底物质量浓度、温度、时间、催化剂用量、补料次数等8个方面进行考察,揭示其中pH、底物质量浓度、补料次数和催化剂用量4个因素对(S)-CPMA催化效率的影响较大;进一步对其进行正交优化,得出最佳工艺条件:在pH8的PEG4000双水相体系中,底物质量浓度为6g/L、补料次数为4次、催化剂用量为3g/L,温度为40℃条件下反应36h,可得到(S)-CPMA产率为88.1%,对映选择性在98.5%以上,4个因素对(S)-CPMA收率的影响主次顺序依次为补料次数>pH>催化剂用量>底物质量浓度,其中补料次数、pH为显著性影响因素,与优化前相比,底物质量浓度提高3倍,产率提高了6%.The effects of different conditions on the whole cell catalytic synthesis of the chiral intermediate(S)-CPMA were studied by single factor experiment and orthogonal design optimization.Firstly,eight aspects of Kluyveromyces Thermotolerans SXBP-02 pretreatment methods,catalytic reaction medium,pH,substrate concentration,reaction temperature,reaction time,catalyst dosage,and feeding methods were investigated.It was found that pH,substrate concentration,feeding methods and catalyst dosage had a greater influence on the catalytical efficiency of(S)-CPMA.Then,through orthogonal optimization,the optimal process conditions were obtained:PEG4000 two-phase aqueous system of pH 8,substrate concentration of 6g/L,feeding times of 4 times,catalyst dosage of 3 g/L,and reaction temperature of 40℃for 36 h,the yield of(S)-CPMA reached 88.1%,and the enantioselectivity was above 98.5%.The four factors affecting the yield of(S)-CPMA were in the order of feeding method>pH>catalyst dosage>substrate concentration,among which substrate feeding method and pH were significant factors.Compared with before optimization,the substrate concentration was increased by 3 times and yield increased by 6%.

关 键 词：整细胞催化 (S)-CPMA 工艺 优化 

分 类 号：TQ460.6[化学工程—制药化工]