Trifluoroacetic acid → 1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid

HRID 1799774Notes

Reaction equation

HRID 1799774 reaction equation
CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C([O:19][C:20](=[O:31])[C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=1)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=2)=[C:21]([C:20]([OH:31])=[O:19])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 353442Benzyl(methoxymethyl)((trimethylsilyl)methyl)amineHCID 58312631(4-Chloro-3-fluoro-phenyl)-propynoic acid ethyl ester

Product 1

HCID 583126211-Benzyl-4-(4-chloro-3-fluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (61.3 g, 0.26 mol) in CH2Cl2 (120 ml) was added dropwise over 90 minutes to a stirred solution of (4-chloro-3-fluoro-phenyl)-propynoic acid ethyl ester (39.0 g, 0.17 mol) and trifluoroacetic acid (1.30 ml, 0.02 mol) in CH2Cl2 (170 ml). The reaction mixture was stirred at 25° C. for 72 h and afterward evaporated to dryness. The residue was dissolved in dioxane (390 ml). An aqueous solution of NaOH (45.0 ml, 0.48 mol, 2.8 eq.) was added, and the resulting emulsion was stirred at r.t. for 18 h. The low boiling organic solvent was removed under vacuum. Water (100 ml) was added, the aqueous layer was separated and washed with TBME (2 times 100 ml). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was stirred overnight and the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 42.0 g (75%) of IId as a white solid.

Workup

  1. customafterward evaporated to dryness
  2. dissolutionThe residue was dissolved in dioxane (390 ml)
  3. stirringthe resulting emulsion was stirred at r.t. for 18 h
  4. customThe low boiling organic solvent was removed under vacuum
  5. additionWater (100 ml) was added
  6. customthe aqueous layer was separated
  7. washwashed with TBME (2 times 100 ml)
  8. additionThe aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl
  9. stirringThe resulting suspension was stirred overnight
  10. filtrationthe white precipitate was filtered off
  11. washwashed with water and ethanol
  12. customdried under high vacuum
  13. customto yield 42.0 g (75%) of IId as a white solid

Sources & evidence

ORD record
ord-45004448ab3f4340a798f96748399c59
Source dataset
uspto-grants-2013_01
Patent number
US08344161B2

Reaction notes

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