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

HRID 327215
Notes
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Reaction equation

HRID 327215 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]=[CH:18][C:17]=1[C:22]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)=[O:23].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:26][CH:25]=1)=[O:23]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 24386Thionyl ChlorideHCID 516892Sodium BicarbonateHCID 10726619(4-Aminophenyl)-2-pyridinylmethanoneHCID 222874542,2-Bis-difluoromethyl-2-hydroxyacetic acid

Product 1

HCID 21480101N-[4-(2-Pyridylcarbonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoromethyl propionamideYield 39.3%

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 dimethylacetamide (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-(2-Pyridylcarbonyl)aniline (0.58 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water, sodium bicarbonate solution added to give a pH of 7 and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water, brine, dried (Na2SO4), decolorized (charcoal), and evaporated. The crude solid was dissolved in ether, clarified by filtration, and evaporated to give a yellow orange gum. Crystallization from methylene chloride/hexane gave the title compound (0.35 g, 35%) as a tan solid; mp 158°-161° C. 1H--NMR (300 MHz, d6 --DMSO); 6.48(t, J=54.12 Hz, 2H, HCF2), 7.67(t, J=6.18 Hz, 1H, ArH), 7.91-8.10 (m, 7H, ArH, OH), 8.73 (d, J=7.35 Hz, 1H, ArH), 10.40 (s, 1H, NH). MS(CI),CH4 : 357(M+H, 100%).

Workup

  1. stirringthe reaction mixture was stirred overnight at room temperature
  2. additionadded
  3. customto give a pH of 7
  4. extractionextracted with ethyl acetate
  5. washwashed with water, brine
  6. dry with materialdried (Na2SO4)
  7. customevaporated
  8. dissolutionThe crude solid was dissolved in ether
  9. filtrationclarified by filtration
  10. customevaporated
  11. customto give a yellow orange gum
  12. customCrystallization from methylene chloride/hexane

Sources & evidence

ORD record
ord-31bfabcf52bc4650af4e8bc0352ade93
Source dataset
uspto-grants-1993_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05272163

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes