1-Boc-3,3-difluoro-4-hydroxypyrrolidine synthesis

Yield:-

Reaction Conditions:

with palladium hydroxide 10 wt. % on activated carbon;hydrogen in methanol at 15 - 25; for 15 h;

Steps:

4B.3; 4B.4
A suspension of rac-tert-butyl 4-(benzyloxy)-3 ,3 -difluoropyrrolidine- 1- carboxylate (50 mg, 0.16 mmol) and 10% Pd(OH)2/C (10 mg) in MeOH (10 mL) and stirredunder an atmosphere of H2 for 15 h at RT. The mixture was filtered and concentrated to give rac-tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate. MS (El) Calc’d for C9H,6F2N03 [M+H], 224; found, 224.A mixture of Intermediate IV (37 mg, 0.13 mmol), rac-tert-butyl 3,3-difluoro-4- hydroxypyrrolidine-1-carboxylate (30 mg, 0.13 rnrnol) in THF (3 mL) was treated with a 60%suspension of NaH in mineral oil (11 mg, 0.27 mmol) and stirred at RT for 15 h. Water (0.5 mL) was added and mixture concentrated to dryness. The residue was purified by chromatography on Si02 (MeOH / DCM 1:10) to give 1-47. ‘H NMR (400 MHz, CD3OD) 9.03 (s, 2 H), 8.52 (s, 1 H), 6.05-5.90 (m, 1 H), 4.39-4.34 (m, 2 H), 3.87-3.66 (m, 4 H), 2.72 (s, 3 H), 1.38-1.30 (m, 12H). MS (El) Calc’d for C21H26F2N703 [M--H], 462; found, 462.

References:

MERCK SHARP & DOHME CORP.;ACHAB, Abdelghani Abe;ALTMAN, Michael D.;DENG, Yongqi;GUZI, Timothy;KATTAR, Solomon;KATZ, Jason D.;METHOT, Joey L.;ZHOU, Hua;MCGOWAN, Meredeth;CHRISTOPHER, Matthew P.;GARCIA, Yudith;ANTHONY, Neville John;FRADERA LLINAS, Francesc Xavier;MU, Changwei;ZHANG, Sixing;ZHANG, Rong;FONG, Kin Chiu;LENG, Xiansheng WO2014/75392, 2014, A1 Location in patent:Page/Page column 72; 73