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

HRID 909046Notes

Reaction equation

HRID 909046 reaction equation
[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[F:23])([C:14]#[N:15])[CH:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][NH:10]1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45][CH:44]=1>C(Cl)Cl>[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH:50][C:29]([N:10]2[CH2:11][C@@H:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[O:30])=[CH:45][CH:44]=1

Participants

6

Reactant 4

HCID 6371PhosgeneHCID 8471TriethylamineHCID 571728Methyl 4-(aminomethyl)benzoateHCID 67095461rac-(2S,3S,4S)-2-(2,3-dichloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile

Product 1

HCID 67095189rac-4-({[(2S,3S,4S)-2-(2,3-dichloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl esterYield 99.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(2,3-dichloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (88.0 mg, 0.20 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.23 mL, 0.23 mmol), in the presence of triethylamine (TEA, 272.7 mg, 2.7 mmol) in CH2Cl2 (3 mL) followed by reacting with 4-aminomethyl-benzoic acid methyl ester (AK-Scientific, 60.5 mg, 0.30 mmol) at rt for 2 hrs to give rac-4-({[(2S,3S,4S)-2-(2,3-dichloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (126.0 mg, 43.8%) as a white amorphous solid which was used in the next step without further purification.

Sources & evidence

ORD record
ord-a4e1af57faa7446baba559374891bd4c
Source dataset
uspto-grants-2011_09
Patent number
US08017607B2

Reaction notes

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