Benzyltriphenylphosphonium bromide → HCID 59164966, compound

Temperature

0 °C

To a suspension of benzyltriphenylphosphonium bromide (1.75 g, 4.97 mmol) in dry THF (10 mL) under argon at 0° C. was added 1.6 M BuLi in THF (2.33 mL, 3.73 mmol) and the deep red solution left stirring without cooling for 10 min. After re-cooling to 0° C., the aldehyde 46 (335 mg, 1.56 mmol) [G. B. Evans, R. H. Fumeaux, A. Lewandowicz, V. L. Schramm, and P. C. Tyler, Second-Generation Transition State Analogues of Human Purine Nucleoside Phosphorylase, J. Med. Chem., 46 (2003) 5271-5276] in THF (5 mL) was added and the mixture stirred at r.t. for 12 h. The reaction was then quenched with water (1 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with sat. aq. NaHCO3 (15 mL) then water (15 mL), dried (MgSO4) and concentrated in vacuo. The residue was subjected to chromatography to afford a ca. 1:3 cis/trans mixture of (3R,4S)-N-tert-butoxycarbonyl-3-hydroxy-4-(2-phenylethenyl)-pyrrolidine (47) as a syrup (290 mg, 64%). 1H NMR (300 MHz, CDCl3): δ ppm: trans: 7.28 (m, 5H), 6.49 (d, J=15.9 Hz, 1H), 6.03 (dd, J=15.9, 8.1 Hz, 1H), 4.11 (m, 1H), 3.67 (m, 2H), 3.32 (m, 2H), 2.83 (m, 1H), 1.46 (s, 9H); cis: 7.27 (m, 5H), 6.58 (d, J=11.6 Hz, 1H), 5.43 (dd, J=11.6 Hz, 10.0 Hz, 1H), 4.11 (m, 1H), 3.65 (m, 2H), 3.21 (m, 2H), 2.88 (m, 1H), 1.44 (s, 9H). To a solution of intermediate 47 (290 mg, 1.00 mmol) in ethanol (20 mL) was added 10% Pd/C (250 mg) and the suspension was stirred under an atmosphere of hydrogen for 12 h. After filtration, the solvent was removed in vacuo to give (3R,4S)-N-tert-butoxycarbonyl-3-hydroxy-4-(2-phenylethyl)pyrrolidine (48) as a syrup, 254 mg (87%). 1H NMR (300 MHz, CDCl3): δ ppm: 7.10 (m, 5H), 4.00 (m, 1H), 3.47 (m, 2H), 3.07 (m, 2H), 2.67 (m, 2H), 2.04 (m, 1H), 1.83 (m, 1H), 1.54 (m, 1H), 1.45 (s, 9H). 13C NMR (300 MHz, CDCl3): δ ppm (note that some peaks are doubled due to slow conversion of rotamers): 155.17, 142.03, 128.83, 128.71, 126.37, 79.88, (74.94, 71.26), (53.17, 52.90), (49.90, 49.34), (46.11, 45.52), 34.41, 33.69, 28.91. To a solution of intermediate 48 (254 mg, 0.87 mmol) in methanol (10 mL) was added 12N (conc.) HCl (4 mL) and the solution stirred at 40° C. for 30 min. After removal of the solvent in vacuo and azeotroping with toluene, the crude title compound (3R,4S)-3-Hydroxy-4-(2-phenylethyl)pyrrolidine hydrochloride 49 was obtained as a solid (202 mg, 0.89 mmol, 102%). 1H NMR (300 MHz, MeOH-d4): δ ppm: 7.14 (m, 5H), 4.22 (m, 1H), 3.52 (dd, J=11.8, 7.4 Hz, 1H), 3.39 (dd, J=12.3, 4.9 Hz, 1H), 3.14 (dd, J=12.3, 2.8 Hz, 1H), 3.02 (dd, J=11.8 Hz, 1H), 2.71 (m, 2H), 2.20 (m, 1H), 1.84 (m, 1H), 1.62 (m, 1H). 13C NMR (300 MHz, MeOH-d4): δ ppm: 142.94, 129.93, 129.89, 127.56, 75.56, 52.90, 48.55, 47.28, 35.18, 34.44.

1. waitthe deep red solution left
2. temperaturewithout cooling for 10 min
3. stirringthe mixture stirred at r.t. for 12 h
4. customThe reaction was then quenched with water (1 mL)
5. extractionextracted with dichloromethane (100 mL)
6. washThe organic phase was washed with sat. aq. NaHCO3 (15 mL)
7. dry with materialwater (15 mL), dried (MgSO4)
8. concentrationconcentrated in vacuo
9. customto afford
10. stirringthe suspension was stirred under an atmosphere of hydrogen for 12 h
11. filtrationAfter filtration
12. customthe solvent was removed in vacuo

ORD record

ord-36ddc1e8995741e5828732f01e4b5087

Source dataset

uspto-grants-2010_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07655795B2