Lithium Hydroxide → 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)-cyclohexanecarboxylic acid

HRID 909088Notes

Reaction equation

HRID 909088 reaction equation
COC(=O)[C:4]1C=C[C:7]([NH:10][C:11]([N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:6][C:5]=1OC.[Li+].[OH-:45].[CH2:46]1[CH2:50][O:49][CH2:48][CH2:47]1>O>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:17][N:13]2[C:11]([NH:10][CH2:7][CH:6]2[CH2:5][CH2:4][CH:47]([C:48]([OH:45])=[O:49])[CH2:46][CH2:50]2)=[O:12])[CH:38]=[CH:37][CH:36]=1

Participants

5

Reactant 3

HCID 3939Lithium HydroxideHCID 8028Tetrahydrofuran2×HCID 51357251rac-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}-2-methoxy-benzoic acid methyl ester

Product 1

HCID 51357249rac-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)-cyclohexanecarboxylic acidYield 99.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

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}-2-methoxy-benzoic acid methyl ester (26.5 mg, 0.042 mmol, Example 70) in THF (2.4 mL) was added a solution of LiOH (Aldrich, 12.9 mg, 0.307 mmol) in water (1.2 mL) and the reaction mixture was stirred at rt for 16 hrs then more THF (3 mL) and water (1.5 mL) was added and stirred for 5 additional hrs at 50° C. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5-7), 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)-cyclohexanecarboxylic acid (25.7 mg, 99.2%). HRMS (ES+) m/z Calcd for C31H29O2F2N3O4+H [(M+H)+]: 616.1576; Found: 616.1573.

Workup

  1. stirringstirred for 5 additional hrs at 50° C
  2. concentrationThe reaction mixture was partly concentrated
  3. customquenched with 1 N HCl (pH 5-7)
  4. extractionextracted with EtOAc
  5. washwashed with water, saturated NaCl
  6. customThe organic phase was separated
  7. dry with materialdried over Na2SO4
  8. concentrationThe mixture was then concentrated

Sources & evidence

ORD record
ord-c49a7af5ce064758886721e228db3d69
Source dataset
uspto-grants-2011_09
Patent number
US08017607B2

Reaction notes

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