Synlett 2019; 30(10): 1228-1230
DOI: 10.1055/s-0037-1611553
letter
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of cis-(S,R)-3-Amino-4-fluoro-1-methylpyrrolidine

Zhongbo Fei
a  Chemical and Analytical Development, Suzhou Novartis Pharma Technology Co., Ltd, Changshu, Jiangsu 215537, P. R. of China   Email: jianwei.bian@novartis.com
,
Xin Xiong
a  Chemical and Analytical Development, Suzhou Novartis Pharma Technology Co., Ltd, Changshu, Jiangsu 215537, P. R. of China   Email: jianwei.bian@novartis.com
,
Chiming Cheung
a  Chemical and Analytical Development, Suzhou Novartis Pharma Technology Co., Ltd, Changshu, Jiangsu 215537, P. R. of China   Email: jianwei.bian@novartis.com
,
Weipeng Liu
a  Chemical and Analytical Development, Suzhou Novartis Pharma Technology Co., Ltd, Changshu, Jiangsu 215537, P. R. of China   Email: jianwei.bian@novartis.com
,
Qirong Shen
b  Zhejiang Jiuzhou Pharmaceutical Technology Co., Ltd., Jiangling Road 88, Binjiang, Hangzhou, Zhejiang 310000, P. R. of China
,
Jinzhu Zhang
b  Zhejiang Jiuzhou Pharmaceutical Technology Co., Ltd., Jiangling Road 88, Binjiang, Hangzhou, Zhejiang 310000, P. R. of China
,
Hongjun Gao
b  Zhejiang Jiuzhou Pharmaceutical Technology Co., Ltd., Jiangling Road 88, Binjiang, Hangzhou, Zhejiang 310000, P. R. of China
,
Jianwei Bian*
a  Chemical and Analytical Development, Suzhou Novartis Pharma Technology Co., Ltd, Changshu, Jiangsu 215537, P. R. of China   Email: jianwei.bian@novartis.com
› Author Affiliations
All work described in this paper was funded by Novartis, Inc.
Further Information

Publication History

Received: 14 March 2019

Accepted after revision: 30 April 2019

Publication Date:
20 May 2019 (online)


Abstract

The development of the stereoselective synthesis of cis-(S,R)-3-amino-4-fluoro-1-methylpyrrolidine is described starting from chiral, non-racemic 1-[(3S,4S)-3-azido-4-hydroxypyrrolidin-1-yl]-2,2,2-trifluoroethan-1-one. Two sets of deoxyfluorination conditions are developed for achieving inversion of the chiral center with high or complete stereoselectivity.

Supporting Information

 
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  • 10 Characterization of 1. Yield: 99 mg (94%); white solid; mp 264–266 °C. 1H NMR (400 MHz, D2O): δ = 5.55 (dt, J = 51.7, 3.5 Hz, 1 H), 4.36 (dtd, J = 23.4, 8.9, 3.5 Hz, 1 H), 4.01 (m, 1 H), 3.88 (m, 1 H), 3.82–3.52 (m, 2 H), 3.00 (s, 3 H). 13C NMR (101 MHz, D2O): δ = 90.4 (d, J = 183.82 Hz), 59.6 (d, J = 21.21 Hz), 54.4, 50.3 (d, J = 17.17 Hz), 42.6. 19F NMR (376 MHz, D2O): δ = –196.7. 19F NMR (376 MHz, CD3OD): δ = –198.1. HRMS (ESI): m/z [M + H – 2 HCl]+ calcd for C5H12FN2: 119.0979; found: 119.0978.