Water → HCID 86692621, compound

HRID 1748674Notes

Reaction equation

HRID 1748674 reaction equation
[CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].[C:10]([C:12]1([C:18]2[N:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=4)[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)#[N:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([N:15]1[CH2:14][CH2:13][C:12]([C:10]#[N:11])([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=4)[C:31]=3[CH3:32])=[O:26])=[CH:22][N:23]=2)[CH2:17][CH2:16]1)([CH3:7])[CH3:6])[CH3:2]

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium Carbonate2×HCID 11745Propanoic acid, 2-bromo-2-methyl-, ethyl ester3×HCID 86692605HCID 86692605, compound

Product 1

HCID 86692621HCID 86692621, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

2-Bromo-2-methylpropanoic acid ethyl ester (193 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (455 mg) described in Reference Example 169 and potassium carbonate (276 mg) in N,N-dimethylformamide (3.3 ml) and stirred at 50° C. for 12 hours. Then, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) and potassium carbonate (276 mg) were added and stirred at 50° C. for 5 hours and at 80° C. for 3 hours. Further, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) was added and stirred at 80° C. for 3 hours. Water was added to the reaction solution, the precipitated solid was purified with silica gel chromatography (chloroform/methanol) to give 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) as a white solid. MS (ESI) m/z: 570 (M+H)+. (2) Lithium borohydride (25 mg) was added to a solution of 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) in tetrahydrofuran (3.7 ml) and stirred at room temperature for 1.5 hours. Then, lithium borohydride (25 mg) was added and stirred at 80° C. for 2 hours. To the reaction solution, were added methanol (1.5 ml) and sodium borohydride (85 mg), and stirred at room temperature for an hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (35 mg) as a white solid.

Workup

  1. stirringstirred at 50° C. for 5 hours and at 80° C. for 3 hours
  2. stirringstirred at 80° C. for 3 hours
  3. customthe precipitated solid was purified with silica gel chromatography (chloroform/methanol)

Sources & evidence

ORD record
ord-411bc63613f24f7b9068cdfd603bad3b
Source dataset
uspto-grants-2015_10
Patent number
US09150555B2

Reaction notes

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