Lithium hydroxide, monohydrate → rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid

HRID 909112Notes

Reaction equation

HRID 909112 reaction equation
C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])=[CH:6][C:5]=1[F:42].O[Li].O>C1COCC1.O>[Cl:40][C:36]1[C:35]([F:41])=[C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][N:14]2[C:12]([NH:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([F:42])[CH:6]=2)=[O:13])[CH:39]=[CH:38][CH:37]=1

Participants

5

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 513541704-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-methyl)-2-fluoro-benzoic acid methyl ester

Product 1

HCID 51354171rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-2-fluoro-benzoic acidYield 75.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-methyl)-2-fluoro-benzoic acid methyl ester (53.0 mg, 0.0838 mmol) in THF (6 mL) was added a solution of LiOH.H2O (Aldrich, 26 mg, 0.615 mmol) in water (3 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid (38.9 mg, 75%). HRMS (ES+) m/z Calcd C31H28Cl2F3N3O3+H (M+H): 618.1533; Found: 618.1532

Workup

  1. concentrationThe reaction mixture was partly concentrated
  2. customquenched with 1 N HCl (pH 5)
  3. extractionextracted with EtOAc
  4. washwashed with water, saturated NaCl
  5. customThe organic phase was separated
  6. dry with materialdried over Na2SO4
  7. concentrationThe mixture was then concentrated

Sources & evidence

ORD record
ord-2d7f391b3c724191b197c74e838ae1c8
Source dataset
uspto-grants-2011_09
Patent number
US08017607B2

Reaction notes

Loading…