Thionyl Chloride → N-[4-(2-Pyrimidinylsulfonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoromethyl propionamide

HRID 2259707Notes

Reaction equation

HRID 2259707 reaction equation
[F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:27][CH:26]=1)(=[O:23])=[O:24]

Participants

7

Reactant 4

HCID 24386Thionyl ChlorideHCID 516892Sodium BicarbonateHCID 218172744-(2-Pyrimidylsulfonyl)anilineHCID 222874542,2-Bis-difluoromethyl-2-hydroxyacetic acid

Product 1

HCID 21480149N-[4-(2-Pyrimidinylsulfonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoromethyl propionamideYield 34%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
-10 °C

Procedure

To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmoles) in dimethyl acetamide (10 ml) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution was stirred at -10° C. for approximately 30 mins. 4-(2pyrimidylsulfonyl)aniline (0.59 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and sodium bicarbonate solution was added to give a pH of 7-7.5. A dark colored precipitate was formed that was filtered, washed with water and dried. The crude material was preabsorbed onto silica gel and chromatographed on silica gel eluting with 70-80% ethyl/acetate/hexane. Evaporation of product-containing fractions and crystallization from methylene chloride/methanol/hexane gave the title compound (0.33 g, 34%) as a white solid; mp 209°-210° C. 1H-NMR (300 MHz, d6 -DMSO):6.46(t, J=54.06 Hz, 2H, HCF2), 7.78 (t, J=4.8 Hz, 1H, ArH), 7.95-7.98(m, 3H, ArH, OH), 8.02-8.06(m, 2H, ArH), 9.01 (d, J=5.01 Hz, 2H, ArH), 10.58 (s, 1H, NH). MS(CI):394(M+1, 100%). Analysis for C14H11F4N3O4S: Calculated: C, 42.75; H, 2.82; N, 10.68 Found: C, 42.55; H, 2.80; N, 10.57

Workup

  1. stirringthe reaction mixture was stirred overnight at room temperature
  2. additionwas added
  3. customto give a pH of 7-7.5
  4. customA dark colored precipitate was formed
  5. filtrationthat was filtered
  6. washwashed with water
  7. customdried
  8. customThe crude material was preabsorbed onto silica gel
  9. customchromatographed on silica gel eluting with 70-80% ethyl/acetate/hexane
  10. customEvaporation of product-containing fractions and crystallization from methylene chloride/methanol/hexane

Sources & evidence

ORD record
ord-bd0f4360609c40aab548abcf24c2fba6
Source dataset
uspto-grants-1995_12
Patent number
US05474999

Reaction notes

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