5-Chloropyrazinoic acid → (R)-N-(3-(2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloropyrazine-2-carboxamide

HRID 1520242Notes

Reaction equation

HRID 1520242 reaction equation
[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:47])=[C:35]([C@:37]2([CH3:46])[C:42]([F:44])([F:43])[CH2:41][O:40][C:39]([NH2:45])=[N:38]2)[CH:36]=1.C([O-])(O)=O.[Na+]>CO>[NH2:45][C:39]1[O:40][CH2:41][C:42]([F:43])([F:44])[C@:37]([C:35]2[CH:36]=[C:31]([NH:30][C:8]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:32]=[CH:33][C:34]=2[F:47])([CH3:46])[N:38]=1

Participants

6

Reactant 4

HCID 4654725-Chloropyrazinoic acidHCID 516892Sodium BicarbonateHCID 231494114-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrateHCID 58304207(R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine2×

Product 1

HCID 53240912(R)-N-(3-(2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloropyrazine-2-carboxamide

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Conditions

Temperature
0 °C

Procedure

5-Chloropyrazine-2-carboxylic acid (367 mg, 2.31 mmol) was combined with MeOH (25 ml) to give a colorless solution. 4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 705 mg, 2.55 mmol) was added at 0° C. and the solution was stirred at 0° C. for 30 min. A solution of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A 8.1, 600 mg, 2.31 mmol) in MeOH (10 ml) was added dropwise and the reaction mixture was stirred overnight at 0° C. Sat. aq. NaHCO3 was added and the product was extracted with three portions of AcOEt. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by flash chromatography (SiO2, 50 g, 50 to 100% EtOAc in heptane). White solid (540 mg, 58%). MS (ISP): m/z=400.1 [M+H]+.

Workup

  1. customto give a colorless solution
  2. stirringthe reaction mixture was stirred overnight at 0° C
  3. extractionthe product was extracted with three portions of AcOEt
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. concentrationconcentrated under vacuum
  6. customThe crude material was purified by flash chromatography (SiO2, 50 g, 50 to 100% EtOAc in heptane)

Sources & evidence

ORD record
ord-c0bfb9703343427291d655376635bf02
Source dataset
uspto-grants-2015_07
Patent number
US09073909B2

Reaction notes

Loading…