Diisopropylethylamine → pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amide

HRID 529739Notes

Reaction equation

HRID 529739 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:25])[F:24])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1.[N:26]1[N:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]2=[C:28]([C:35](Cl)=[O:36])[CH:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:24])[F:25])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[N:11]=[CH:10][C:9]=2[NH:21][C:35]([C:28]2[CH:27]=[N:26][N:30]3[CH:31]=[CH:32][CH:33]=[N:34][C:29]=23)=[O:36])[CH:7]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 19623233Pyrazolo[1,5-a]pyrimidine-3-carbonyl chlorideHCID 1231430925-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine

Product 1

HCID 131735618pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amideYield 73%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine (60.0 g, 154 mmol) in THF (100 mL) was added dropwise over 30 minutes to an ice/water cooled mixture of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (27.8 g, 153 mmol), and DIPEA (49.5 g, 383 mmol) in THF (300 mL). On complete addition the mixture was left to stir at room temperature for 1 hour. The solvent was evaporated and the residue diluted with 0.5 N aqueous HCl and extracted with ethyl acetate. The combined organic extract was passed through Celite® to remove the residual solid and the filtrate washed with 1M aqueous K2CO3, water and brine, dried (Na2SO4) and evaporated to give a red solid. The solid was triturated with 10% diethyl ether in cyclohexane. The solid was collected by filtration, washed with 1:1 diethyl ether in cyclohexane and left to air dry to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amide as an off-white solid (59.2 g, 73%). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.61 (s, 1H), 8.77-8.78 (m, 1H), 8.51 (dd, 1H), 8.36 (s, 1H), 7.65 (d, 1H), 7.52 (dd, 1H), 7.36 (d, 1H), 7.29 (s, 1H), 7.01 (dd, 1H), 6.42 (t, 1H), 5.39-5.41 (m, 2H), 3.60-3.64 (m, 2H), 0.87-0.89 (m, 2H), 0.09 (s, 9H).

Workup

  1. temperaturecooled
  2. additionOn complete addition the mixture
  3. waitwas left
  4. customThe solvent was evaporated
  5. additionthe residue diluted with 0.5 N aqueous HCl
  6. extractionextracted with ethyl acetate
  7. extractionThe combined organic extract
  8. customto remove the residual solid
  9. washthe filtrate washed with 1M aqueous K2CO3, water and brine
  10. dry with materialdried (Na2SO4)
  11. customevaporated
  12. customto give a red solid
  13. customThe solid was triturated with 10% diethyl ether in cyclohexane
  14. filtrationThe solid was collected by filtration
  15. washwashed with 1:1 diethyl ether in cyclohexane
  16. waitleft to air
  17. customdry

Sources & evidence

ORD record
ord-077dcfcc5332491ca92699bf7db90794
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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