Hydrochloric Acid → 5-Chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide

HRID 474360Notes

Reaction equation

HRID 474360 reaction equation
C(O[C:6](=[O:23])[NH:7][C:8]1[CH:9]=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][N:38]2[N:41]=[CH:42][C:43](C(Cl)=O)=[C:37]2[N:36]=1>O1CCOCC1.ClCCl>[F:22][C:19]([F:20])([F:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[O:11][N:10]=[CH:9][C:8]=1[NH:7][C:6]([C:43]1[CH:42]=[N:41][N:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[N:36][C:37]=12)=[O:23]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 580631365-Chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chlorideHCID 66677514[5-(2-Trifluoromethyl-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester

Product 1

HCID 866614435-Chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amideYield 86%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
40 °C

Procedure

A mixture of [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (345 mg, 1.05 mmol, 1.0 equiv), 4M HCl in dioxane (2 mL) in 1,4-dioxane (3 mL) was heated to 40° C. for 20 hours. The mixture was concentrated under vacuum affording a residue which was dissolved in dichloromethane (12 mL) and treated with diisopropylethylamine (271 mg, 2.10 mmol, 2.0 equiv). The mixture was cooled with an ice-bath, and a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (1.05 mmol, 1.0 equiv) in dichloromethane (6 mL) was added dropwise. The resultant mixture was stirred at ambient temperature for 18 hours. The solution was washed sequentially with 1M HCl aqueous solution, saturated aqueous sodium bicarbonate solution and water. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated (methanol), and the isolated solid was washed with methanol and diethyl ether before drying under vacuum to give 367 mg (86%) of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide. LCMS (ESI) m+H=408.0 (mono Cl); 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 9.35 (d, 1H), 9.22 (s, 1H), 8.71 (s, 1H), 8.03 (d, 1H), 7.97-7.82 (m, 3H), 7.38 (d, 1H).

Workup

  1. concentrationThe mixture was concentrated under vacuum
  2. customaffording a residue which
  3. temperatureThe mixture was cooled with an ice-bath
  4. washThe solution was washed sequentially with 1M HCl aqueous solution, saturated aqueous sodium bicarbonate solution and water
  5. dry with materialThe collected organic was dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customThe residue was triturated (methanol)
  9. washthe isolated solid was washed with methanol and diethyl ether
  10. custombefore drying under vacuum

Sources & evidence

ORD record
ord-75aefa52218d44f6b4f58aa44d4b4b7f
Source dataset
uspto-grants-2014_01
Patent number
US08637526B2

Reaction notes

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