Formaldehyde → 4-(4-Bromo-2-fluoro-phenyl)-1-methyl-pyrrolidine-3-carboxylic acid (4-chloro-phenyl)-amide

HRID 1011653Notes

Reaction equation

HRID 1011653 reaction equation
[CH2:1]=O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:13])=[C:6]([F:22])[CH:5]=1.[NH:23]([CH2:25]C(O)=O)[CH3:24].O>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]([CH:11]2[CH:10]([C:7]3[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][C:6]=3[F:22])[CH2:1][N:23]([CH3:25])[CH2:24]2)=[O:13])=[CH:20][CH:19]=1

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 962WaterHCID 1088SarcosineHCID 673138123-(4-Bromo-2-fluoro-phenyl)-N-(4-chloro-phenyl)-acrylamide

Product 1

HCID 594541604-(4-Bromo-2-fluoro-phenyl)-1-methyl-pyrrolidine-3-carboxylic acid (4-chloro-phenyl)-amideYield 40%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A mixture of paraformaldehyde (15.3 g, 0.51 mol) and 3-(4-bromo-2-fluoro-phenyl)-N-(4-chloro-phenyl)-acrylamide (15 g, 42.5 mmol) was heated under reflux in toluene (150 mL), and sarcosine (15.2 g, 170 mmol, 4.0 equiv) was added in 4 portions over 4 hrs, the H2O formed was removed with the aid of a Dean-Stark trap. After 4 hours, the cooled mixture was filtered. The filtrate was concentrated, and the residue was purified by chromatography on silica gel eluted with dichloromethane-methanol to give 7.0 g of 4-(4-bromo-2-fluoro-phenyl)-1-methyl-pyrrolidine-3-carboxylic acid (4-chloro-phenyl)-amide. Yield was 40%. MS: calc'd 411 (MH+), exp 411 (MH+). 1H NMR (CDCl3, 400 MHz), 9.71 (s, 1H), 7.57 (d, 2H, J=8.8 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.24 (t, 4H, J=8.8 Hz), 4.30 (q, 1H, J=8.8 Hz), 3.76-3.94 (m, 2H), 3.40-3.62 (m, 3H), 2.92 (s, 3H).

Workup

  1. temperaturewas heated
  2. customwas removed with the aid of a Dean-Stark trap
  3. filtrationthe cooled mixture was filtered
  4. concentrationThe filtrate was concentrated
  5. customthe residue was purified by chromatography on silica gel
  6. washeluted with dichloromethane-methanol

Sources & evidence

ORD record
ord-d486ca5d518a447cb6e79ac04046c5fc
Source dataset
uspto-grants-2011_07
Patent number
US07977372B2

Reaction notes

Loading…