Sodium Bicarbonate → 1-((4S,5R)-5-(4-(6-(3-aminooxetan-3-yl)pyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-3-yl)-2,2-difluoroethanone

HRID 525588Notes

Reaction equation

HRID 525588 reaction equation
C1(C)C=CC=CC=1.C(O)C.[F:11][CH:12]([F:39])[C:13]([N:15]1[C@H:19]([CH2:20][F:21])[C@@H:18]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[O:17][C:16]1([CH3:38])[CH3:37])=[O:14].[Cl-].Br[C:42]1[CH:43]=[CH:44][C:45]([C:48]2([NH3+:52])[CH2:51][O:50][CH2:49]2)=[N:46][CH:47]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:52][C:48]1([C:45]2[N:46]=[CH:47][C:42]([C:25]3[CH:24]=[CH:23][C:22]([C@H:18]4[O:17][C:16]([CH3:38])([CH3:37])[N:15]([C:13](=[O:14])[CH:12]([F:39])[F:11])[C@@H:19]4[CH2:20][F:21])=[CH:27][CH:26]=3)=[CH:43][CH:44]=2)[CH2:51][O:50][CH2:49]1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 21863594Toluene ethanolHCID 866954142,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-3-yl)ethanoneHCID 866954673-(5-Bromopyridin-2-yl)oxetan-3-aminium chloride

Product 1

HCID 866954691-((4S,5R)-5-(4-(6-(3-aminooxetan-3-yl)pyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-3-yl)-2,2-difluoroethanoneYield 70%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a toluene/ethanol (15 ml toluene, 12 ml ethanol) solution of 2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-3-yl)ethanone (594 mg, 1.44 mmol) is added 3-(5-bromopyridin-2-yl)oxetan-3-aminium chloride (434 mg, 1.44 mmols), sodium bicarbonate (3 mL of a 2M solution) and Pd(dppf)2Cl2 (150 mg, 0.2 mmol)). The reaction mixture is heated to 80° C. while stirring under nitrogen for two hours. The reaction is cooled to room temperature and diluted with ethyl acetate (60 ml). The mixture is washed water (2×10 ml). The organic phase is dried over sodium sulfate and concentrated. The residual material is purified on silica gel (mobile phase 6% methanol in methylene chloride) to give the title compound (436 mg, 70%): m/z (Cl) 436 [M+H]+.

Workup

  1. temperatureThe reaction is cooled to room temperature
  2. washThe mixture is washed water (2×10 ml)
  3. dry with materialThe organic phase is dried over sodium sulfate
  4. concentrationconcentrated
  5. customThe residual material is purified on silica gel (mobile phase 6% methanol in methylene chloride)

Sources & evidence

ORD record
ord-83a9c9c7d0744cc0a95a481c7e9dab55
Source dataset
uspto-grants-2016_05
Patent number
US09340564B2

Reaction notes

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