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

HRID 1799772Notes

Reaction equation

HRID 1799772 reaction equation
FC(F)(F)C(O)=O.CO[CH2:10][N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][Si](C)(C)C.C([O:26][C:27](=[O:38])[C:28]#[C:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)C.[OH-].[Na+]>C(Cl)Cl>[CH2:17]([N:11]1[CH2:10][C:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)=[C:28]([C:27]([OH:38])=[O:26])[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acid2×HCID 14798Sodium HydroxideHCID 353442Benzyl(methoxymethyl)((trimethylsilyl)methyl)amine2×HCID 58312680(3,4-Difluoro-phenyl)-propynoic acid ethyl ester

Product 1

HCID 583126871-Benzyl-4-(3,4-difluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

At r.t., trifluoroacetic acid (0.11 ml, 1.34 mmol, 0.1 eq.) followed by N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (4.89 g, 20.2 mmol, 1.5 eq.) were added dropwise to a stirred solution of (3,4-difluoro-phenyl)-propynoic acid ethyl ester (2.83 g, 13.5 mmol) in CH2Cl2 (80 ml). The yellow solution was stirred at r.t. for 18 h. Trifluoroacetic acid (0.034 ml, 0.44 mmol, 0.033 eq.) and N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl) methylamine (1.66 g, 6.73 mmol, 0.5 eq.) were added, and the solution was stirred for 1 h. It was evaporated to dryness, and the residue was dissolved in dioxane (40 ml). An aqueous solution of NaOH (18.7 ml, 37.4 mmol, 2.8 eq.) was added. The resulting emulsion was stirred at r.t. for 18 h, and the low boiling organic solvent was removed under reduced pressure. Water (40 ml) was added, and the aqueous layer separated and washed twice with TBME (50 ml). The organic layers were washed with the same portion of water (15 ml). The combined aqueous layers were acidified by addition of aqueous 3M HCl (12.4 ml). The resulting suspension was stirred for 48 h at r.t. The white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 4.25 g (58%) of IIc as a white solid.

Workup

  1. customAt r.t.
  2. stirringthe solution was stirred for 1 h
  3. customIt was evaporated to dryness
  4. dissolutionthe residue was dissolved in dioxane (40 ml)
  5. stirringThe resulting emulsion was stirred at r.t. for 18 h
  6. customthe low boiling organic solvent was removed under reduced pressure
  7. additionWater (40 ml) was added
  8. customthe aqueous layer separated
  9. washwashed twice with TBME (50 ml)
  10. washThe organic layers were washed with the same portion of water (15 ml)
  11. additionThe combined aqueous layers were acidified by addition of aqueous 3M HCl (12.4 ml)
  12. stirringThe resulting suspension was stirred for 48 h at r.t
  13. filtrationThe white precipitate was filtered off
  14. washwashed with water and ethanol
  15. customdried under high vacuum
  16. customto yield 4.25 g (58%) of IIc as a white solid

Sources & evidence

ORD record
ord-4372b29614fb4809b022cce522882992
Source dataset
uspto-grants-2013_01
Patent number
US08344161B2

Reaction notes

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