Borowiecki Paweł, Paprocki Daniel, Dudzik Agnieszka, Plenkiewicz Jan
Warsaw University of Technology , Faculty of Chemistry, Institute of Biotechnology, Koszykowa St. 3, 00-664 Warsaw, Poland.
Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences , Niezapominajek St. 8, 30-239 Cracow, Poland.
J Org Chem. 2016 Jan 15;81(2):380-95. doi: 10.1021/acs.joc.5b01840. Epub 2016 Jan 6.
A novel synthetic route for preparation of proxyphylline enantiomers using a kinetic resolution (KR) procedure as the key step is presented. The reactions were catalyzed by immobilized Candida antarctica lipase B in acetonitrile. Three types of reactions were examined: (i) enantioselective transesterification of racemic proxyphylline with vinyl acetate as well as (ii) hydrolysis and (iii) methanolysis of its esters. The influence of reaction conditions on the substrate conversion and enantiomeric purity of the products were investigated. Studies on analytical scale reactions revealed that the titled API enantiomers could be successfully obtained with excellent enantiomeric excess (up to >99% ee). The process was easily conducted on a 5 g scale at 100 g/L. In a preparative-scale reaction, unreacted (S)-(+)-butanoate (97% ee) and (R)-(-)-alcohol (96% ee) were obtained after 2 days in yields of 45% and 46%, respectively. When the reaction time was extended to 6 days, (S)-(+)-butanoate was isolated in >99% ee and acceptable high enantioselectivity (E = 90). Importantly, the KR's products could be conveniently isolated by exploiting varying solubility of the ester/alcohol in acetonitrile at room temperature. In addition, a chiral preference of the CAL-B active site for the R-enantiomer was rationalized by in sillico docking studies.
本文介绍了一种新颖的合成路线，该路线以动力学拆分（KR）过程为关键步骤来制备丙羟茶碱对映体。反应在乙腈中由固定化的南极假丝酵母脂肪酶B催化。研究了三种类型的反应：（i）外消旋丙羟茶碱与乙酸乙烯酯的对映选择性酯交换反应，以及（ii）其酯的水解反应和（iii）醇解反应。考察了反应条件对底物转化率和产物对映体纯度的影响。分析规模反应的研究表明，可成功获得具有优异对映体过量（高达>99%ee）的标题活性药物成分对映体。该过程在100 g/L的规模下于5 g规模上易于进行。在制备规模的反应中，2天后分别以45%和46%的产率得到未反应的（S）-（+）-丁酸酯（97%ee）和（R）-（-）-醇（96%ee）。当反应时间延长至6天时，分离得到的（S）-（+）-丁酸酯的对映体过量>99%，对映选择性良好（E = 90）。重要的是，通过利用酯/醇在室温下在乙腈中的不同溶解度，可以方便地分离KR产物。此外，通过计算机对接研究阐明了南极假丝酵母脂肪酶B活性位点对R-对映体的手性偏好。
