Hydrochloric Acid → 5-Chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-o-tolyl-isoxazol-4-yl)-amide

HRID 474366Notes

Reaction equation

HRID 474366 reaction equation
C(O[C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[N:10][O:11][CH:12]=1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]2[N:38]=[CH:39][C:40](C(Cl)=O)=[C:34]2[N:33]=1>O1CCOCC1.ClCCl>[C:14]1([CH3:19])[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[C:8]([NH:7][C:6]([C:40]2[CH:39]=[N:38][N:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[N:33][C:34]=23)=[O:20])=[CH:12][O:11][N:10]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 580631365-Chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chlorideHCID 58063348(3-o-Tolyl-isoxazol-4-yl)-carbamic acid tert-butyl ester

Product 1

HCID 580631945-Chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-o-tolyl-isoxazol-4-yl)-amideYield 70%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
40 °C

Procedure

A mixture of (3-o-tolyl-isoxazol-4-yl)-carbamic acid tert-butyl ester (500 mg, 1.82 mmol, 1.0 equiv), 4M HCl in dioxane (4 mL) in 1,4-dioxane (5 mL) was stirred at ambient temperature for 22 hours and at 40° C. for 1 hour. The mixture was concentrated under vacuum affording a residue which was dissolved in dichloromethane (15 mL) and treated with diisopropylethylamine (523 mg, 4.05 mmol, 2.2 equiv). The mixture was cooled with an ice-bath and a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (1.82 mmol, 1.0 equiv) in dichloromethane (10 mL) was added dropwise. The reaction mixture was warmed to room temperature after the addition. After 65 hours, the solution was sequentially washed with 1M HCl aqueous solution, saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution. The organic was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated (methanol) to give 444 mg (70%) of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-o-tolyl-isoxazol-4-yl)-amide. LCMS (ESI) m+H=354.2 (mono Cl); 1H NMR (300 MHz, DMSO-d6) δ: 9.47 (s, 1H), 9.36 (d, 1H), 9.11 (s, 1H), 8.72 (s, 1H), 7.53-7.40 (m, 4H), 7.37 (d, 1H), 2.31 (s, 3H).

Workup

  1. concentrationThe mixture was concentrated under vacuum
  2. customaffording a residue which
  3. temperatureThe mixture was cooled with an ice-bath
  4. temperatureThe reaction mixture was warmed to room temperature
  5. additionafter the addition
  6. waitAfter 65 hours
  7. washthe solution was sequentially washed with 1M HCl aqueous solution, saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution
  8. dry with materialThe organic was dried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under vacuum
  11. customThe residue was triturated (methanol)

Sources & evidence

ORD record
ord-993763c5e09d4f04a86e2a78f6612c57
Source dataset
uspto-grants-2014_01
Patent number
US08637526B2

Reaction notes

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