Triethylamine → rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester

HRID 1806933Notes

Reaction equation

HRID 1806933 reaction equation
[C:1]([O:5][C:6](=[O:23])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[C:26]([F:43])=[C:27](/[CH:31]=[C:32](/[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[F:42])\[C:33]#[N:34])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=2[F:43])[C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[F:42])([C:33]#[N:34])[CH:9]([CH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:8]1)=[O:23])([CH3:3])([CH3:2])[CH3:4]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 59249629(Z)-3-(3-Chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrileHCID 178446421HCID 178446421, compound

Product 1

HCID 66666380rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl esterYield 61.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 6386tert-ButanolSolvent

Procedure

In a manner similar to the method described in Example 100b, [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 105a (1.25 g, 3.64 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (0.93 g, 3 mmol) prepared in Example 52a, AgF (0.57 g, 4.5 mmol), and triethylamine (1.05 mL, 7.5 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (3.6 ml) in tert-butanol (15 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (1.2 g, 61%).

Sources & evidence

ORD record
ord-ee7a16e3a9c44ed690c5cfead2497d4b
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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