2-Propanol, 1-methoxy-2-methyl- → 2-Methoxy-1,1-dimethylethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

HRID 521234Notes

Reaction equation

HRID 521234 reaction equation
[CH3:1][O:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].ClC(Cl)(O[C:12](=[O:18])OC(Cl)(Cl)Cl)Cl.FC(F)(F)C([O-])=O.[C:27]([C:30]1[C:31]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[N:32][N:33]([C:35]2([CH2:41][C:42]#[N:43])[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]2)[CH:34]=1)(=[O:29])[NH2:28]>C1COCC1.C(Cl)Cl>[C:27]([C:30]1[C:31]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=2)=[N:32][N:33]([C:35]2([CH2:41][C:42]#[N:43])[CH2:40][CH2:39][N:38]([C:12]([O:6][C:4]([CH3:7])([CH3:5])[CH2:3][O:2][CH3:1])=[O:18])[CH2:37][CH2:36]2)[CH:34]=1)(=[O:29])[NH2:28]

Participants

6

Reactant 3

HCID 771372-Propanol, 1-methoxy-2-methyl-HCID 94429TriphosgeneHCID 867294014-(4-carbamoyl-3-((4-fluorophenyl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidin-1-ium 2,2,2-trifluoroacetate2×

Product 1

HCID 867294072-Methoxy-1,1-dimethylethyl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 1-methoxy-2-methyl-2-propanol (91 mg, 0.88 mmol) in THF (1.5 mL) and TEA (0.20 mL, 1.4 mmol) was cooled to 0° C. and allowed to stir. Triphosgene (260 mg, 0.876 mmol) was added and the resulting mixture was allowed to warm to ambient temperature and was stirred for 15 minutes. A solution of 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (80 mg, 0.18 mmol) and TEA (0.061 mL, 0.44 mmol) in DCM (1.0 mL) was then added to the reaction mixture dropwise. The resulting mixture was heated to 50° C. and allowed to stir for 16 hours. The solution was cooled to ambient temperature, diluted with DCM, washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #28.

Workup

  1. stirringwas stirred for 15 minutes
  2. temperatureThe resulting mixture was heated to 50° C.
  3. stirringto stir for 16 hours
  4. temperatureThe solution was cooled to ambient temperature
  5. washwashed with water
  6. dry with materialdried over anhydrous MgSO4
  7. concentrationconcentrated in vacuo
  8. customThe resulting residue was purified by MPLC on silica gel (
  9. washa gradient elution of 0-10% MeOH/DCM)

Sources & evidence

ORD record
ord-5c26ebc64f024e9f95d70d7e3c383e21
Source dataset
uspto-grants-2016_05
Patent number
US09328099B2

Reaction notes

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