Triethylamine → cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide

HRID 2064675Notes

Reaction equation

HRID 2064675 reaction equation
[CH2:1]([O:3][C:4]1[C:24]([CH2:25][CH3:26])=[CH:23][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH2:16])=[CH:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2].C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]1[C:24]([CH2:25][CH3:26])=[CH:23][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])=[CH:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 77637Cyclopropanecarbonyl chlorideHCID 1357506883-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine

Product 1

HCID 135750746cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amideYield 83.9%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A solution of 3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine [0.3 g, Reference Example 49(a)] and triethylamine (0.8 mL, excess) in tetrahydrofuran (20 mL) was treated dropwise with cyclopropanecarbonyl chloride (0.3 g, 2.4 mmol). This mixture was stirred for 48 hours then diluted with aqueous sodium bicarbonate solution (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was dissolved in tetrahydrofuran (50 mL). This solution was treated with a solution of potassium hydroxide (1.1 g) in ethanol (10 mL) and the mixture was stirred for 2 hours, then poured into water (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel eluting with a mixture of heptane and ethyl acetate (1/1, v/v) to give cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide (0.3 g) as an off-white solid. LC-MS (Method E): RT 2.99 minutes, 424 (M+H)+.

Workup

  1. extractionextracted twice with ethyl acetate (100 mL)
  2. customThe combined extracts were evaporated
  3. dissolutionthe residue was dissolved in tetrahydrofuran (50 mL)
  4. additionThis solution was treated with a solution of potassium hydroxide (1.1 g) in ethanol (10 mL)
  5. stirringthe mixture was stirred for 2 hours
  6. additionpoured into water (100 mL)
  7. extractionextracted twice with ethyl acetate (100 mL)
  8. customThe combined extracts were evaporated
  9. customthe residue was chromatographed on silica gel eluting with a mixture of heptane and ethyl acetate (1/1

Sources & evidence

ORD record
ord-956552a1aa704a318f14e7a79d4c1ab9
Source dataset
uspto-grants-2012_10
Patent number
US08288425B2

Reaction notes

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