4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carbaldehyde → (S)-4-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine

HRID 1626105Notes

Reaction equation

HRID 1626105 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:13][CH2:12][O:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.[Cl:17][C:18]1[C:19]([CH:26]=O)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[Cl:17][C:18]1[C:19]([CH2:26][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]3([CH3:15])[CH2:13][CH2:12][O:11][C:10]([NH2:14])=[N:9]3)[CH:7]=2)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1

Participants

5

Reactant 3

HCID 574971684-chloro-1-(difluoromethyl)-1H-pyrazole-3-carbaldehydeHCID 67236054(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamineHCID 178419135HCID 178419135, compound

Product 1

HCID 71008867(S)-4-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamineYield 20.6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
25 °C

Procedure

In a 5 ml-reaction tube a solution of (S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.4) (22 mg, 0.1 mmol) in methanol (0.3 ml) was treated at room temperature at under an inert atmosphere with 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (19.9 mg, 110 μmol). The tube was closed and the reaction mixture was stirred at 25° C. for 60 minutes. Then decaborane (24.4 mg, 200 μmol) was added in one portion, the tube was closed, and the mixture was warmed to 45° C. for 15 hours. For the workup, the reaction solution was quenched with a solution of sodium carbonate (10%). Methanol was removed at reduced pressure, then the residue was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduce pressure. The crude product was purified by basic preparative HPLC and after evaporation triturated with a mixture of ether and heptane. The (S)-4-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (8 mg, 20% yield) was obtained as a colorless oil. MS (ISP): m/z=388.2 [M+H]+.

Workup

  1. customThe tube was closed
  2. customthe tube was closed
  3. temperaturethe mixture was warmed to 45° C. for 15 hours
  4. customFor the workup, the reaction solution was quenched with a solution of sodium carbonate (10%)
  5. customMethanol was removed at reduced pressure
  6. extractionthe residue was extracted three times with ethyl acetate
  7. dry with materialThe combined organic layers were dried over sodium sulphate
  8. customevaporated
  9. customThe crude product was purified by basic preparative HPLC
  10. customafter evaporation
  11. customtriturated with a mixture of ether and heptane

Sources & evidence

ORD record
ord-55a7d1cdd09f4a4e887a9329108d3847
Source dataset
uspto-grants-2014_07
Patent number
US08785436B2

Reaction notes

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