2-(Trifluoromethyl)benzylamine → rac rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide

HRID 1807112Notes

Reaction equation

HRID 1807112 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH:35][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[NH:10]1)=[O:28]

Participants

6

Reactant 4

HCID 764472-(Trifluoromethyl)benzylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67296837rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid

Product 1

HCID 68619151rac rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamideYield 32.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-trifluoromethyl-benzyl amine (52.55 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide (38 mg, 32.3%) as an off-white powder. HRMS (ES+) m/z Calcd for C31H30Cl2F3N3O+H [(M+H)+]: 588.1791. found: 588.1795.

Workup

  1. washwashed with water, brine
  2. customThe organic phase was separated
  3. filtrationfiltered
  4. dry with materialdried over Na2SO4
  5. concentrationThe mixture was then concentrated
  6. custompurified by reverse phase chromatography (20-95% of ACN/water)

Sources & evidence

ORD record
ord-46b8809a7b5943cba40cc99605e29d4b
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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