Ethanol → HCID 71009060, compound

HRID 1626100Notes

Reaction equation

HRID 1626100 reaction equation
[CH3:1][O:2][C:3](=[O:8])[C:4](Br)([F:6])[F:5].[Br:9][C:10]1[CH:11]=[C:12]([N:16]2[CH:20]=[C:19](/[C:21](=[N:23]/[S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])/[CH3:22])[CH:18]=[N:17]2)[CH:13]=[CH:14][CH:15]=1.[CH2:30](O)C>O1CCCC1.[Zn].Cl[Cu]>[CH2:1]([O:2][C:3](=[O:8])[C:4]([F:6])([F:5])[C@@:21]([C:19]1[CH:18]=[N:17][N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[CH:11]=2)[CH:20]=1)([NH:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH3:22])[CH3:30]

Participants

7

Reactant 3

HCID 702EthanolHCID 2783339Methyl BromodifluoroacetateHCID 89183665HCID 89183665, compound

Product 1

HCID 71009060HCID 71009060, compoundYield 45%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 62652Cuprous chlorideCatalystHCID 8028TetrahydrofuranSolvent3×

Procedure

A suspension of activated zinc (1.7 g, 26.6 mmol) and CuCl (269 mg, 2.72 mmol) in dry tetrahydrofuran (15 ml) was refluxed for 30 minutes under vigorous stirring. A solution of bromo-difluoroacetic acid methylester (0.87 ml, 6.79 mmol) in tetrahydrofuran (5 ml) was added dropwise at 25° C. and the mixture was stirred for 30 minutes. Thereafter, a solution of (R)-2-methyl-propane-2-sulfinic acid [1-[1-(3-bromo-phenyl)-1H pyrazol-4-yl]-eth-(E)-ylidene]-amide (1.0 g, 2.72 mmol) in tetrahydrofuran (5 ml) was added dropwise at 25° C., and stirring continued for 30 minutes. For the workup, ethanol (0.3 ml, 4.89 mmol) was added to the reaction mixture at 25° C., and the resultant mixture was filtered over a layer of Celite®. The filtrate was diluted with water (20 ml), and extracted with ethyl acetate (5×30 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulphate, and evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a gradient of hexane/ethyl acetate=60:40 to 50:50 as the eluent to give the (R)-3-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (600 mg, 45% yield) as a yellow solid. MS (ISP): m/z=490.0 [M+H]+.

Workup

  1. temperaturewas refluxed for 30 minutes under vigorous stirring
  2. stirringstirring
  3. waitcontinued for 30 minutes
  4. filtrationthe resultant mixture was filtered over a layer of Celite®
  5. additionThe filtrate was diluted with water (20 ml)
  6. extractionextracted with ethyl acetate (5×30 ml)
  7. washThe combined organic layers were washed with brine (50 ml)
  8. dry with materialdried over sodium sulphate
  9. customevaporated at reduced pressure
  10. customThe crude material thus obtained
  11. customwas purified by column chromatography on silica gel using a gradient of hexane/ethyl acetate=60:40 to 50:50 as the eluent

Sources & evidence

ORD record
ord-9eda6421a90f43a2826979a55d125a5a
Source dataset
uspto-grants-2014_07
Patent number
US08785436B2

Reaction notes

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