1,2-Dichloroethane → ((R)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

HRID 2196342Notes

Reaction equation

HRID 2196342 reaction equation
[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1)#[N:27].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:34]([C:31]3[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[CH:33][N:32]=3)=[O:35])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 4

HCID 111,2-DichloroethaneHCID 27960291-Hydroxybenzotriazole hydrateHCID 124007345-Cyanopyridine-2-carboxylic acidHCID 66666080[(R)-5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester

Product 1

HCID 66665639((R)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

[(R)-5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (35 g, 97.4 mmol), 5-cyano-pyridine-2-carboxylic acid (15.87 g, 107.14 mmol) and HOBt hydrate (22.35 g, 146.1 mmol) were dissolved in 185 ml DMF and stirred with ice cooling. When the temperature had reached 0-5° C. EDC (22.33 ml, 126.62 mmol) was added dropwise. The mixture was stirred for 2 h. The ice bath was taken away and stirring was continued for 2 h. The mixture was taken up in EtOAc and water. The phases were separated and the organic phase was washed with 5% aqueous NaHCO3 and brine. The organic phase was dried with MgSO4.H2O and evaporated to provide a beige solid. Crystallisation from EtOAc/hexane gave the title compound as colorless crystals. Yield 44.47 g.

Workup

  1. customhad reached 0-5° C
  2. stirringThe mixture was stirred for 2 h
  3. stirringstirring
  4. customThe phases were separated
  5. washthe organic phase was washed with 5% aqueous NaHCO3 and brine
  6. dry with materialThe organic phase was dried with MgSO4.H2O
  7. customevaporated
  8. customto provide a beige solid
  9. customCrystallisation from EtOAc/hexane

Sources & evidence

ORD record
ord-fbe417b1dd9b4bf8b0d76fd6291efc50
Source dataset
uspto-grants-2012_12
Patent number
US08338413B1

Reaction notes

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