Hydrochloric Acid → 7-Cyclohexyl-6-(4-methylsulfanylphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

HRID 460703Notes

Reaction equation

HRID 460703 reaction equation
[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]2[C:33]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:32](Br)[CH:31]=[N:30][C:29]=12)=[O:24])C.[Li+].[OH-].Cl>[Pd].O1CCOCC1.O1CCCC1.C(OCC)(=O)C>[CH:34]1([C:33]2[N:28]3[N:27]=[CH:26][C:25]([C:23]([OH:24])=[O:22])=[C:29]3[N:30]=[CH:31][C:32]=2[C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 27339594-(Methylthio)phenylboronic acidHCID 58825033Ethyl 6-bromo-7-cyclohexylpyrazolo[1,5-a]pyrimidine-3-carboxylate

Product 1

HCID 159581417-Cyclohexyl-6-(4-methylsulfanylphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidYield 56%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 14 mg (0.085 mmol) of 4-methylsulfanyl-phenylboronic acid, 2 mg (0.0028 mmol) of Pd catalyst, and 45 mg (0.213 mmol) of potassium phosphate was placed into a 4 mL vial. To this mixture 25 mg (0.077 mmol) of 6-bromo-7-cyclohexyl-pyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester in 1.5 mL of 1,4-dioxane was added, the resulting mixture was flushed with argon and stirred at 80° C. (oil bath) overnight. The reaction mixture was then diluted with ethyl acetate, filtered through a small pad of Celite, and evaporated (savant) to give a residue (crude coupling product). This residue was dissolved in 1 mL of tetrahydrofuran (THF) and treated with 0.5 mL (0.5 mmol) of 1 M LiOH solution, and the resulting mixture was stirred at rt overnight. Since analysis by thin layer chromatography (TLC) revealed that the reaction was not complete, the mixture was then shaken at 55° C. (sand bath) for 15 h. The reaction mixture was diluted with ethyl acetate, and acidified with 1 M HCl solution to pH=2. The organic layer was separated and concentrated (savant) to give a residue which was purified via reverse-phase chromatography (using Gilson) to afford (after lyophilization) 14 mg (56% overall yield) of 7-cyclohexyl-6-(4-methylsulfanyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (472) as a solid as indicated by 1H NMR; LC-MS—calcd for C20H21N3O2S [M++H]+: 368.14, found: 368.2.

Workup

  1. customthe resulting mixture was flushed with argon
  2. additionThe reaction mixture was then diluted with ethyl acetate
  3. filtrationfiltered through a small pad of Celite
  4. customevaporated (savant)
  5. customto give a residue (crude coupling product)
  6. stirringthe resulting mixture was stirred at rt overnight
  7. stirringthe mixture was then shaken at 55° C. (sand bath) for 15 h
  8. customThe organic layer was separated
  9. concentrationconcentrated (savant)
  10. customto give a residue which
  11. customwas purified via reverse-phase chromatography (using Gilson)

Sources & evidence

ORD record
ord-04295eb7c22e4b93bff8c3ea308c01d5
Source dataset
uspto-grants-2007_03
Patent number
US07196111B2

Reaction notes

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