Phosgene → rac-4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester

HRID 909042Notes

Reaction equation

HRID 909042 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)=[C:4]([F:28])[CH:3]=1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.Cl.[CH3:41][O:42][C:43](=[O:52])[C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH2:51])=[CH:46][CH:45]=1>C(Cl)Cl>[CH3:41][O:42][C:43](=[O:52])[C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH:51][C:29]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:28])=[O:30])=[CH:46][CH:45]=1

Participants

6

Reactant 4

HCID 6371PhosgeneHCID 8471TriethylamineHCID 2729253Methyl 4-(aminomethyl)benzoate hydrochlorideHCID 67095473rac-(2S,3S,4S)-2,3-bis(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile

Product 1

HCID 67095125rac-4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl esterYield 149.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2,3-bis(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (126.9 mg, 0.30 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 90 mg, 0.90 mmol) in CH2Cl2 (2 mL) followed by reacting with 4-aminomethyl-benzoic acid methyl ester hydrochloride (90.7 mg, 0.45 mmol) at rt for 30 min to give rac-4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (110.5 mg, 60.9%) as a white amorphous solid.

Sources & evidence

ORD record
ord-6baf6390318b4fb8b67227fbb3cce6a2
Source dataset
uspto-grants-2011_09
Patent number
US08017607B2

Reaction notes

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