Methylamine → (Rs)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide

HRID 1244576Notes

Reaction equation

HRID 1244576 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([F:17])=[CH:4][C:3]=1[N:18]1[C:22](=[O:23])[CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]1.[C:27](N1C=CN=C1)([N:29]1C=CN=C1)=O.CN>>[CH3:27][NH:29][C:24]([CH:20]1[CH2:21][C:22](=[O:23])[N:18]([C:3]2[CH:4]=[C:5]([F:17])[C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)=[CH:7][C:2]=2[F:1])[CH2:19]1)=[O:26]

Participants

4

Reactant 3

HCID 6329Methylamine2×HCID 682631,1'-CarbonyldiimidazoleHCID 21920043(RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid

Product 1

HCID 10045181(Rs)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide

Conditions

Temperature
50 °C

Procedure

A solution of 365 mg (1.0 mmol) of (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid is treated with 178 mg (1.1 mmol) of 1,1′-carbonyl-diimidazole, and the mixture is heated at 50° C. for 2 hours. Thereafter, the solution is cooled to RT and 47 mg (1.5 mmol) of methylamine (33% solution in ethanol) are added. After 18 hours the reaction is not complete, so that another 47 mg (1.5 mmol) of methylamine (33% solution in ethanol) are added and stirring is continued for 24 hours at 50° C. For the working-up, the reaction mixture is evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 95:5-mixture of dichloromethane and methanol as the eluent. There are obtained, after crystallization from ether, 136 mg (36% of theory) of the (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as an off-white solid. MS: m/e=379 (M+H)+.

Workup

  1. temperatureThereafter, the solution is cooled to RT
  2. waitis continued for 24 hours at 50° C
  3. customthe reaction mixture is evaporated under reduced pressure
  4. customFor purification
  5. customthe material obtained
  6. customis chromatographed on silica gel using a 95
  7. customThere are obtained
  8. customafter crystallization from ether, 136 mg (36% of theory) of the (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as an off-white solid

Sources & evidence

ORD record
ord-bd82d14b6f234a9680df24b1dc368a1c
Source dataset
uspto-grants-2006_10
Patent number
US07122562B2

Reaction notes

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