Acetic Acid → 4-(1-(3-Fluoroazetidin-1-yl)ethyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-2-amine

HRID 59171Notes

Reaction equation

HRID 59171 reaction equation
Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C[O-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:24][C:25]2[N:30]=[C:29]([C:31](=O)[CH3:32])[CH:28]=[C:27]([CH2:34][O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:26]=2)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+].O.CO>[F:2][CH:3]1[CH2:6][N:5]([CH:31]([C:29]2[CH:28]=[C:27]([CH2:34][O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:26]=[C:25]([NH:24][C:14]3[CH:15]=[CH:16][C:17]([N:18]4[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]4)=[C:12]([O:11][CH3:10])[CH:13]=3)[N:30]=2)[CH3:32])[CH2:4]1

Participants

10

Reactant 5

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 101250543-fluoroazetidine HydrochlorideHCID 10942334Sodium MethoxideHCID 1178240761-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-4-yl)ethanone

Product 1

HCID 863451654-(1-(3-Fluoroazetidin-1-yl)ethyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-2-amine

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

3-Fluoroazetidine hydrochloride (28 mg, 0.25 mmol) was mixed with methanol (5 mL). Sodium methoxide (0.046 mL, 0.25 mmol) was added followed by 1-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)ethanone (90 mg, 0.21 mmol). The mixture was stirred for 2 min. Acetic acid (0.044 mL, 0.76 mmol) was added. The mixture was stirred for 5 min. Sodium cyanoborohydride (18 mg, 0.29 mmol) was added and the mixture was stirred at rt under nitrogen atmosphere for 16 hours. Water was added and the mixture was stirred for 5 min then diluted with DCM and sodium bicarbonate (sat, aq). The phases were separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica eluting with a gradient of MeOH and DCM. The residue was purified by preparative HPLC to give the title compound as a dry film, 33 mg (32%).

Workup

  1. stirringThe mixture was stirred for 5 min
  2. stirringthe mixture was stirred at rt under nitrogen atmosphere for 16 hours
  3. stirringthe mixture was stirred for 5 min
  4. customThe phases were separated
  5. extractionthe aqueous layer was extracted with DCM
  6. dry with materialThe combined organic layer was dried over anhydrous sodium sulfate
  7. concentrationconcentrated
  8. customThe residue was purified by column chromatography on silica eluting with a gradient of MeOH and DCM
  9. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-a19859a1bdf34e9498128c04e417d150
Source dataset
uspto-grants-2016_09
Patent number
US09439904B2

Reaction notes

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