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

HRID 587342Notes

Reaction equation

HRID 587342 reaction equation
C([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.FC(F)(F)C(O)=O.CO[CH2:24][N:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][Si](C)(C)C.[OH-].[Na+]>ClCCl.O>[CH2:31]([N:25]1[CH2:26][C:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[C:5]([C:4]([OH:3])=[O:14])[CH2:24]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 353442Benzyl(methoxymethyl)((trimethylsilyl)methyl)amine2×HCID 641307Ethyl 3-(4-chlorophenyl)propiolate

Product 1

HCID 593718091-Benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acidYield 79%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent3×

Procedure

To a solution of (4-chloro-phenyl)-propynoic acid ethyl ester (92.65 g, 444.1 mmol) in dichloromethane (425 mL) was added trifluoroacetic acid (3.4, 44.4 mmol). The reaction mixture was cooled with a water bath and a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (164.7 g, 666.1 mmol) in dichloromethane (325 mL) was added dropwise over a period of 1.5 h. It was stirred for 22 h at ambient temperature. Further N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (27.5 g, 111.0 mmol) in dichloromethane (50 mL) was added and stirring was continued for 2 h at ambient temperature. The solvent was distilled off and the residue was taken up in dioxane (950 mL). After addition of water (475 mL) and sodium hydroxide (32%, 114.3 mL, 1.23 mol), it was stirred for 67 h at ambient temperature. After concentration the residue was diluted with water (400 mL) and extracted with tert-butylmethylether (400 mL). The organic layers were washed with water (400 mL). The aqueous layers were combined, cooled to 5° C. and set to pH=1.5 with aqueous HCl (25%, 172). After stirring for 1 h at 5° C., the solid was filtered off and was washed with water (1400 mL) and ethanol (400 mL). Drying (50° C., 25 mbar) afforded the title compound (109.85 g, 79%) as an off-white solid. MS m/e: 312.2/314.1 [M−H]−.

Workup

  1. temperatureThe reaction mixture was cooled with a water bath
  2. stirringstirring
  3. waitwas continued for 2 h at ambient temperature
  4. distillationThe solvent was distilled off
  5. stirringwas stirred for 67 h at ambient temperature
  6. concentrationAfter concentration the residue
  7. additionwas diluted with water (400 mL)
  8. extractionextracted with tert-butylmethylether (400 mL)
  9. washThe organic layers were washed with water (400 mL)
  10. temperaturecooled to 5° C.
  11. stirringAfter stirring for 1 h at 5° C.
  12. filtrationthe solid was filtered off
  13. washwas washed with water (1400 mL) and ethanol (400 mL)
  14. customDrying (50° C., 25 mbar)

Sources & evidence

ORD record
ord-d334c87115144a5bbf9fe2602690993b
Source dataset
uspto-grants-2016_01
Patent number
US09226916B2

Reaction notes

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