Diisopropylethylamine → tert-Butyl-(2S,5R)-2-[4-({4-[2-(3,3-difluoropyrrolidin-1-yl)-1-methyl-2-oxoethyl]piperazin-1-yl}carbonyl)benzyl-]-5-[(R)-hydroxyl(phenyl)methyl]pyrrolidine-1-carboxylate

HRID 1804652Notes

Reaction equation

HRID 1804652 reaction equation
[F:1][C:2]1([F:17])[CH2:6][CH2:5][N:4]([C:7](=[O:16])[CH:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])[CH2:3]1.[C:18]([O:22][C:23]([N:25]1[C@@H:29]([C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][C@H:26]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:18]([O:22][C:23]([N:25]1[C@@H:29]([C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][C@H:26]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([N:13]2[CH2:12][CH2:11][N:10]([CH:8]([CH3:9])[C:7]([N:4]3[CH2:5][CH2:6][C:2]([F:1])([F:17])[CH2:3]3)=[O:16])[CH2:15][CH2:14]2)=[O:44])=[CH:41][CH:40]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 670587074-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acidHCID 679727294-(2-(3,3-Difluoropyrrolidin-1-yl)-1-methyl-2-oxoethyl)piperazine

Product 1

HCID 67972027tert-Butyl-(2S,5R)-2-[4-({4-[2-(3,3-difluoropyrrolidin-1-yl)-1-methyl-2-oxoethyl]piperazin-1-yl}carbonyl)benzyl-]-5-[(R)-hydroxyl(phenyl)methyl]pyrrolidine-1-carboxylateYield 73.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 12 mg (0.049 mmol) of 4-(2-(3,3-Difluoropyrrolidin-1-yl)-1-methyl-2-oxoethyl)piperazine (TEA salt), and 20 mg (0.049 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 1 mL anhydrous N,N-dimethylformamide under nitrogen atmosphere was added 0.042 mL (0.24 mmol) of N,N-diisopropylethylamine and 37 mg (0.097 mmol) of 2-(1H-7-azabezotriazole-1-yl)-1,1,3,3,-tetramethyl uranium hexafluoro phosphate methanium. The resulting reaction mixture was stirred at ambient temperature overnight. The reaction was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to give 23 mg of the title compound. LC/MS: (M+1)=641.2.

Workup

  1. customThe resulting reaction mixture
  2. customThe reaction was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient)

Sources & evidence

ORD record
ord-62ffaff97867480fb22aafc6cc34a358
Source dataset
uspto-grants-2013_01
Patent number
US08354403B2

Reaction notes

Loading…