Ethyl Acetate → (R)-3-(6-Bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-5-methoxy-3-((S)-2-methyl-propane-2-sulfinylamino)-pentanoic acid ethyl ester

HRID 1752465Notes

Reaction equation

HRID 1752465 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:22]/[S@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])/[CH2:18][CH2:19][O:20][CH3:21])[C:14]([F:29])=[C:13]([Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:12]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.C[Si](C)(C)Cl.[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:29])=[C:13]([Si:30]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:35][CH3:36])[CH:12]=[C:11]([Br:10])[N:16]=1)([NH:22][S@:23]([C:25]([CH3:26])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][O:20][CH3:21])[CH3:7]

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 25517Ammonium ChlorideHCID 69585Ethyl bromodifluoroacetateHCID 141628093(NE,S)-N-[1-(6-bromo-3-fluoro-4-triethylsilyl-2-pyridinyl)-3-methoxypropylidene]-2-methylpropane-2-sulfinamide

Product 1

HCID 89415138(R)-3-(6-Bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-5-methoxy-3-((S)-2-methyl-propane-2-sulfinylamino)-pentanoic acid ethyl esterYield 64.6%

Reagents, catalysts & solvents 4

HCID 6397ChlorotrimethylsilaneCatalystHCID 23994ZincCatalyst2×HCID 62652Cuprous chlorideCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a suspension of zinc (3.07 g, 47 mmol) and copper(I) chloride (233 mg, 2.349 mmol) in dry THF (90 ml) were added 4 drops of trimethylchlorosilane under nitrogen to activate the zinc. After 10 minutes ethyl 2-bromo-2,2-difluoroacetate (9.54 g, 47 mmol) was added slowly by syringe over a period of 20 minutes between 25° and 30° C. adjusted with an external cooling bath (exothermic). The reaction mixture was kept in an ultrasound bath for 30 minutes. This black fine suspension was added drop wise to a solution of (S)-2-methyl-propane-2-sulfinic acid [1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-3-methoxy-prop-(E)-ylidene]-amide (7.51 g, 15.66 mmol) in dry THF (75 ml) at 0° C. under inert atmosphere. After 15 min the reaction mixture was kept at 50° C. for 2 h and was then added to a cold aq. ammonium chloride solution (5%). Ethyl acetate was added and 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 yellowish oil (9.77 g, roughly a 4:1 mixture of diastereoisomers) was chromatographed over silica gel (Redisep column 120 g, cyclohexane/ethyl acetate 85:15) to give the title compound as a yellow oil. 6.11 g yellow oil. (64.6% yield).

Workup

  1. customadjusted with an external cooling bath
  2. waitAfter 15 min the reaction mixture was kept at 50° C. for 2 h
  3. washthe organic phase was washed with aq. citric acid (5% solution), water, sat. sodium bicarbonate solution and brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. additionThe crude yellowish oil (9.77 g, roughly a 4:1 mixture of diastereoisomers)
  8. customwas chromatographed over silica gel (Redisep column 120 g, cyclohexane/ethyl acetate 85:15)

Sources & evidence

ORD record
ord-2a2ffe0287ad46cfa5c31e03a4c2c604
Source dataset
uspto-grants-2015_10
Patent number
US09163011B2

Reaction notes

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