Hydrochloric Acid → 4-(6-Chloropyrazolo[1,5-a]pyrimidin-3-yl)-2-thiophenecarboxylic acid

HRID 1842599Notes

Reaction equation

HRID 1842599 reaction equation
Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[N:7][C:6]=12.C[O:13][C:14]([C:16]1[S:17][CH:18]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[K+].Cl>C1COCC1.CO.ClCCl.O.CN(C=O)C>[Cl:11][C:9]1[CH:8]=[N:7][C:6]2[N:5]([N:4]=[CH:3][C:2]=2[C:19]2[CH:20]=[C:16]([C:14]([OH:15])=[O:13])[S:17][CH:18]=2)[CH:10]=1

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 14797Potassium HydroxideHCID 52911233Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylateHCID 673469363-Bromo-6-chloropyrazolo[1,5-a]pyrimidine

Product 1

HCID 772310094-(6-Chloropyrazolo[1,5-a]pyrimidin-3-yl)-2-thiophenecarboxylic acidYield 69.3%

Reagents, catalysts & solvents 5

HCID 887MethanolSolvent3×HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a sealed tube containing DMF (3 mL) and water (1 mL) was added 3-bromo-6-chloropyrazolo[1,5-a]pyrimidine (150 mg, 0.645 mmol), methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate (216 mg, 0.807 mmol), Biotage polymer-bound triphenylphosphine-Pd(0), and sodium carbonate (85 mg, 0.807 mmol). The reaction flask was backfilled with nitrogen gas three times and irradiated in the microwave at 110° C. for 1 h. The solution was allowed to cool to room temperature, and a 1:1 solution of dichloromethane: methanol was added. The solution was filtered and the resulting filtrate concentrated under reduced pressure and water was added. The precipitate was filtered and washed with water once to afford crude methyl 4-(6-chloropyrazolo[1,5-a]-pyrimindin-3-yl)-thiophene-2-carboxylate. The crude methyl ester was taken up in THF (3 mL) and MeOH (3 mL) and 1N KOH in MeOH (2 mL, 3.10 mmol) was added. The solution was heated at 60° C. for 3 h. After hydrolysis, the solution was acidified with 1N HCl and the precipitate collected by filtration to afford the title compound (0.125 g, 0.447 mmol). LRMS (APCI) calc'd for (C11H6ClN3O2S) [M+H]+, 280.0; found 280.0.

Workup

  1. customirradiated in the microwave at 110° C. for 1 h
  2. filtrationThe solution was filtered
  3. concentrationthe resulting filtrate concentrated under reduced pressure and water
  4. additionwas added
  5. filtrationThe precipitate was filtered
  6. washwashed with water once
  7. customto afford crude methyl 4-(6-chloropyrazolo[1,5-a]-pyrimindin-3-yl)-thiophene-2-carboxylate
  8. temperatureThe solution was heated at 60° C. for 3 h
  9. customAfter hydrolysis
  10. filtrationthe precipitate collected by filtration

Sources & evidence

ORD record
ord-bfc09526de144554a874cefaf1cf0679
Source dataset
uspto-grants-2015_02
Patent number
US08946237B2

Reaction notes

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