Diethyl Ether → (R)-1-(3,5-difluorophenyl)-3-hydroxypyrrolidin-2-one

HRID 1797871Notes

Reaction equation

HRID 1797871 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C@H:12]2[O:16]C(C)(C)[O:14][C:13]2=O)[CH:5]=[C:6]([F:8])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>CO>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][C@@H:12]([OH:16])[C:13]2=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1

Participants

5

Reactant 3

HCID 3283Diethyl EtherHCID 521998p-Toluenesulfonic acid monohydrateHCID 59140613(R)-5-(2-(3,5-difluorophenylamino)ethyl)-2,2-dimethyl-1,3-dioxolan-4-one

Product 1

HCID 59593460(R)-1-(3,5-difluorophenyl)-3-hydroxypyrrolidin-2-oneYield 65.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

A stirred solution of (R)-5-(2-(3,5-difluorophenylamino)ethyl)-2,2-dimethyl-1,3-dioxolan-4-one (8.0 g, 29.5 mmol) and p-toluensulfonic acid monohydrate (508 mg, 2.95 mmol) in MeOH (75 mL) under nitrogen was heated to 70° C. for 75 minutes. The reaction mixture was slowly cooled to RT and then continued to stir at RT overnight. The reaction mixture was concentrated under reduced pressure to provide 9.5 g of a brown waxy solid. The solid was dissolved in MeOH (10 mL) and diethyl ether (100 mL) was added. The solution was allowed to stand at RT overnight. The solid was collected, washed with diethyl ether (2×25 mL) and dried under vacuum to provide (R)-1-(3,5-difluorophenyl)-3-hydroxypyrrolidin-2-one as a tan solid (4.09 g, 19.2 mmol, 65%). 1H-NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 2H), 6.68-6.63 (m, 1H), 4.51 (dd, J=8.3, 9.8 Hz, 1H), 3.85-3.71 (m, 2H), 3.08 (s, 1H), 2.69-2.62 (m, 1H) and 2.19-2.07 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=214.1; tR=0.97 min.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customto provide 9.5 g of a brown waxy solid
  3. waitto stand at RT overnight
  4. customThe solid was collected
  5. washwashed with diethyl ether (2×25 mL)
  6. customdried under vacuum

Sources & evidence

ORD record
ord-48ea4d9ddfd548d7bef25f90d8fd56d1
Source dataset
uspto-grants-2013_01
Patent number
US08343763B2

Reaction notes

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