Efficient preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine via a recycle process of resolution

Xunlei Lv; Liang Chen; Jing Pan; Xue Meng; Siju Bi; Weiyuan Liu; Ting Zhou; Kuaile Lin; Deyong Ye; Weicheng Zhou

doi:10.1002/chir.23366

Efficient preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine via a recycle process of resolution

Chirality. 2021 Dec;33(12):931-937. doi: 10.1002/chir.23366. Epub 2021 Oct 15.

Authors

Xunlei Lv^{1

2}, Liang Chen², Jing Pan^{1

2}, Xue Meng², Siju Bi², Weiyuan Liu², Ting Zhou², Kuaile Lin², Deyong Ye¹, Weicheng Zhou²

Affiliations

¹ School of Pharmacy, Fudan University, Shanghai, China.
² State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Key Laboratory of Anti-infectives, State Institute of Pharmaceutical Industry, Shanghai, China.

PMID: 34651347
DOI: 10.1002/chir.23366

Abstract

An efficient preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine ((R)-1) from the racemate based on a recycle process of resolution/racemization was described. In the process, the desired (R)-1 was obtained by resolution with D-malic acid in 95% EtOH. Meanwhile, the undesired (S)-1 could be racemized in the presence of potassium hydroxide in DMSO. After three times of recycle process, the desired freebase (R)-1 was obtained in a yield of 61.7% with excellent ee (98.4%).

Keywords: (R)-2-(2,5-difluorophenyl)pyrrolidine; Larotrectinib; racemization.