Ammonium Chloride → (R)-3-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester

HRID 1752456Notes

Reaction equation

HRID 1752456 reaction equation
Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10][C:11]1[N:16]=[C:15](/[C:17](=[N:19]/[S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[CH3:18])[C:14]([F:26])=[C:13]([Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:12]=1.[Cl-].[NH4+]>C1COCC1.C[Si](C)(C)Cl.C(OCC)(=O)C.[Zn].[Cu]Cl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[C@@:17]([C:15]1[C:14]([F:26])=[C:13]([Si:27]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:32][CH3:33])[CH:12]=[C:11]([Br:10])[N:16]=1)([NH:19][S@@:20]([C:22]([CH3:23])([CH3:24])[CH3:25])=[O:21])[CH3:18])[CH3:7]

Participants

9

Reactant 3

HCID 25517Ammonium ChlorideHCID 69585Ethyl bromodifluoroacetateHCID 89415106(NE,R)-N-[1-(6-bromo-3-fluoro-4-triethylsilyl-2-pyridinyl)ethylidene]-2-methylpropane-2-sulfinamide

Product 1

HCID 86689143(R)-3-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl esterYield 77%

Reagents, catalysts & solvents 5

HCID 6397ChlorotrimethylsilaneCatalystHCID 23994ZincCatalyst2×HCID 62652Cuprous chlorideCatalystHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a suspension of zinc (466 mg, 7.12 mmol) and copper(I) chloride (34 mg, 0.344 mmol) in dry THF (20 ml) were added 3 drops of trimethylchlorosilane under nitrogen to activate the zinc. After 10 minutes ethyl 2-bromo-2,2-difluoroacetate (1.398 g, 6.89 mmol) was added slowly by syringe over a period of 10 minutes at 25° C. (slightly exothermic). The reaction mixture was kept in an ultrasound bath for 45 minutes. This black fine suspension was added dropwise to a solution of (R)-2-methyl-propane-2-sulfinic acid [1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-eth-(E)-ylidene]-amide) (1 g, 2.296 mmol) in dry THF (10 ml) at it under inert atmosphere. After 4 h at it the reaction mixture was added to a cold aq. ammonium chloride solution (5%) and was diluted with ethyl acetate. The organic phase was washed with aq. citric acid (5% solution), water, sat. sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The crude brownish oil (1.5 g) was chromatographed over silica gel (cyclohexane/ethyl acetate 83:17) to give the title compound as a light yellow oil. 984 mg (77% yield).

Workup

  1. washThe organic phase was washed with aq. citric acid (5% solution), water, sat. sodium bicarbonate solution and brine
  2. dry with materialdried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude brownish oil (1.5 g) was chromatographed over silica gel (cyclohexane/ethyl acetate 83:17)

Sources & evidence

ORD record
ord-6de3b259cf004013b8fb25f07fff9a97
Source dataset
uspto-grants-2015_10
Patent number
US09163011B2

Reaction notes

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