Dimethylformamide → N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-7 a-yl]-4-fluoro-phenyl]-5-chloro-pyrazine-2-carboxamide

HRID 1754857Notes

Reaction equation

HRID 1754857 reaction equation
[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(#N)C.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:43])=[C:30]([C@:32]23[CH2:40][O:39][CH2:38][C@@:37]2([F:41])[CH2:36][O:35][C:34]([NH2:42])=[N:33]3)[CH:31]=1>C(OCC)(=O)C.O.C(O)C>[NH2:42][C:34]1[O:35][CH2:36][C@:37]2([F:41])[CH2:38][O:39][CH2:40][C@:32]2([C:30]2[CH:31]=[C:26]([NH:25][C:8]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:27]=[CH:28][C:29]=2[F:43])[N:33]=1

Participants

9

Reactant 5

HCID 6228DimethylformamideHCID 6342AcetonitrileHCID 65578Oxalyl chlorideHCID 4654725-Chloropyrazinoic acidHCID 117738453(4aR,7aS)-7a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-2-amine

Product 1

HCID 117738587N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-7 a-yl]-4-fluoro-phenyl]-5-chloro-pyrazine-2-carboxamideYield 94%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

Scheme 3, steps M, substep 2 or step N, substep 3 (amidation): A mixture of 5-chloropyrazine-2-carboxylic acid (1.53 g, 9.66 mmol) in acetonitrile (15 mL, 283 mmol) is treated with DMF (115 μL, 1.49 mmol) and oxalyl chloride (970 μL, 11.1 mmol). The mixture is stirred at ambient temperature under nitrogen for 20 minutes. In a separate flask is added (4aR,7aS)-7a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-2-amine (2.00 g, 7.43 mmol), ethanol (7.4 mL), water (7.4 mL) and the mixture is heated at 50° C. The acid chloride is added to the solution prepared above and the reaction mixture is stirred at 50° C. for 20 minutes. The reaction is cooled to room temperature, diluted with ethyl acetate (200 mL), and washed with water (40 mL) and saturated aqueous NaHCO3 (40 mL). The aqueous washes are combined and extracted with ethyl acetate (100 mL). The combined organic layers are dried (Na2SO4) and the solvent removed in vacuo to give the crude product. The crude product is purified by silica gel flash chromatography, eluting with ethyl acetate to give the title product (2.85 g, 94%). ES/MS (m/e): 410 (M+1)

Workup

  1. temperaturethe mixture is heated at 50° C
  2. customprepared above and the reaction mixture
  3. stirringis stirred at 50° C. for 20 minutes
  4. temperatureThe reaction is cooled to room temperature
  5. washwashed with water (40 mL) and saturated aqueous NaHCO3 (40 mL)
  6. extractionextracted with ethyl acetate (100 mL)
  7. dry with materialThe combined organic layers are dried (Na2SO4)
  8. customthe solvent removed in vacuo
  9. customto give the crude product
  10. customThe crude product is purified by silica gel flash chromatography
  11. washeluting with ethyl acetate

Sources & evidence

ORD record
ord-bb208b57192f4db19e55c2485b90749c
Source dataset
uspto-grants-2015_10
Patent number
US09169271B2

Reaction notes

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