Process For Stereoselective Synthesis Of5-subtituded Pyrrolidine Derivertives

This thesis deals with development of process for synthesis of5-subtituded pyrrolidine derivertives as intermediates for anti-tumor drugs.In the first part, a synthetic process strating from pyroglutamate followed by reduction and allylation to5-subtituded pyrrolidine derivertives is optimized. For the reduction with DIBAL, the proper reagent equivalent and reaction temperature were developed, which led to less side reaction. And for this step, a scalable workup process was developed. A moderate stereoselectivity (cis/trans=2/1) was obtained in the direct allylation of the reduction product without methylation. A one-pot procedure for the allylation and deprotection was developed and the purity of final product was improved via workup. The overall yield was improved to50%from30%, and the quality of the product was improved by recrystallization of the only one solid intermediate. The process performed well on kilo scale manufacture.Several synthetic routes were explored for improving stereoselectivity of cis isomer of5-subtituded pyrrolidine derivertives. Model reaction indicated high de value could be obtained via catalytic hydrogenation of5-position unsaturated double bond (steric hindrance effect of2-position group). Then ring opening of pyroglutamate with several metal organic reagents and routes of thioamide, Reformatsky and coupling with glutamic acid derivative were explored. A promising route was developed strating from ring opening of N-Boc-pyroglutamate with lithium methyl acetate, followed by de-Boc and dehydration to form enamine, catalytic hydrogenation with Pd/C to give the cis product. This route has several advantages:less steps, cheap reagents, simple operation and very high stereoselectivity (cis/trans=97/3), promising a great potential for scale-up.