Potassium Carbonate → (S)-ethyl-1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate

HRID 42988Notes

Reaction equation

HRID 42988 reaction equation
O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:42])([F:41])[C:31]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][NH:33][N:32]=1>C(Cl)Cl.CN(C)C=O>[CH2:39]([O:38][C:36]([C:35]1[C:31]([C:30]([F:41])([F:42])[F:29])=[N:32][N:33]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[CH:34]=1)=[O:37])[CH3:40]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 24386Thionyl ChlorideHCID 67088215(S)-N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamideHCID 178469923HCID 178469923, compound

Product 1

HCID 67088144(S)-ethyl-1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylateYield 55.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

(S)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.57 mmol, 692 mg) was dissolved in DCM (10 mL), thionyl chloride (5.14 mmol, 0.373 mL, 611 mg) added and the solution stirred at room temperature. After 45 min the mixture was concentrated then azeotroped with dichloromethane (4×10 mL) to give a yellow oil. To this oil was added dimethylformamide (10 mL) and potassium carbonate (7.71 mmol, 1.07 g) followed by ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.57 mmol, 0.54 g). The mixture was heated to 70° C. with stirring for 1 h. The reaction was concentrated to remove DMF before partitioning between EtOAc/water. The phases were mixed and separated and the aqueous phase further washed with EtOAc (×2). Combined organics were dried and concentrated to give a light yellow oil which was purified on silica eluting with 30% EtOAc/heptane. Desired fractions were collected and concentrated to give (S)-ethyl-1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a colourless solid (0.65 g, 55.1%). 1H NMR (400 MHz, CDCl3) δ 1.33 (t, 3H) 1.39 (d, 6H) 2.9 (m, 2H) 3.17 (sept, 1H) 3.30 (m, 2H) 4.30 (m, 4H) 5.29 (s, 2H) 7.12 (m, 2H) 7.24 (d, 1H) 7.89 (s, 1H)

Workup

  1. concentrationAfter 45 min the mixture was concentrated
  2. customthen azeotroped with dichloromethane (4×10 mL)
  3. customto give a yellow oil
  4. temperatureThe mixture was heated to 70° C.
  5. stirringwith stirring for 1 h
  6. concentrationThe reaction was concentrated
  7. customto remove DMF
  8. custombefore partitioning between EtOAc/water
  9. additionThe phases were mixed
  10. customseparated
  11. washthe aqueous phase further washed with EtOAc (×2)
  12. customCombined organics were dried
  13. concentrationconcentrated
  14. customto give a light yellow oil which
  15. customwas purified on silica eluting with 30% EtOAc/heptane
  16. customDesired fractions were collected
  17. concentrationconcentrated

Sources & evidence

ORD record
ord-829a457dda4a44d1bc640a618bb6cbcf
Source dataset
uspto-grants-2013_09
Patent number
US08536214B2

Reaction notes

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