Sodium Carbonate → (R)-tert-butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate

HRID 524116

Reaction equation

HRID 524116 reaction equation
C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:9]=1[CH2:10][N:11]1[C:16](=[O:17])[C:15]([CH3:18])=[N:14][N:13]=[C:12]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.[CH3:38][N:39]1C(=O)CCC1>CC(O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+2]>[C:38]([C:8]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:9]=1[CH2:10][N:11]1[C:16](=[O:17])[C:15]([CH3:18])=[N:14][N:13]=[C:12]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1)#[N:39]

Participants

9

Reactant 3

HCID 10340Sodium CarbonateHCID 13387N-methyl-2-pyrrolidone2×HCID 58328539(R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate

Product 1

HCID 58328541(R)-tert-butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate

Reagents, catalysts & solvents 5

HCID 962WaterCatalystHCID 3776IsopropanolCatalystHCID 167845palladium(II) acetateCatalystHCID 9605257Potassium FerrocyanideCatalystHCID 962WaterSolvent

Procedure

To a mixture of Na2CO3 (53 mg, 0.50 mmol) and Pd(OAc)2 (3 mg, 0.013 mmol) in NMP (0.5 mL) was added i-PrOH (3 drops) and water (2 drops). The mixture was stirred at RT for 5 min. A solution of (R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (18, 246 mg, 0.496 mmol) in NMP (1.0 mL) was added. The mixture was heated to 140° C. and then K4[Fe(CN)6].3H2O (209 mg, 0.496 mmol) was added. The mixture was heated at 140° C. for 12 h. After cooling to RT, the mixture was diluted with water (10 mL), and extracted with EtOAc (20 mL×2). The combined extracts were washed with brine, dried over MgSO4, and concentrated to give crude product. This was purified by column chromatography on silica gel, and eluted with 20-35% EtOAc in petroleum ether to provide (R)-tert-butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (20). MS: m/z, 418 (20%), 443 (100%, M+1), 465 (95%, M+23).

Workup

  1. temperatureThe mixture was heated to 140° C.
  2. addition3H2O (209 mg, 0.496 mmol) was added
  3. temperatureThe mixture was heated at 140° C. for 12 h
  4. temperatureAfter cooling to RT
  5. extractionextracted with EtOAc (20 mL×2)
  6. washThe combined extracts were washed with brine
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated
  9. customto give crude product
  10. customThis was purified by column chromatography on silica gel
  11. washeluted with 20-35% EtOAc in petroleum ether

Sources & evidence

ORD record
ord-844d70ca6fb44f6d9d1240e380fc24f8
Source dataset
uspto-grants-2016_05
Patent number
US09340523B2

Linked notes

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