Triethylamine → 5-(4-Chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine

HRID 268994Notes

Reaction equation

HRID 268994 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C[Si]([C:25]#[CH:26])(C)C.CCN(CC)CC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:25]#[CH:26])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 66111TrimethylsilylacetyleneHCID 670008755-(4-Chloro-phenyl)-7-cyclopropyl-3-iodo-pyrazolo[1,5-a]pyrimidine

Product 1

HCID 866079965-(4-Chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidineYield 40%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

A mixture of 5-(4-chloro-phenyl)-7-cyclopropyl-3-iodo-pyrazolo[1,5-a]pyrimidine (example C.5, step 4) (1.58 g, 4.0 mmol), trimethylsilylacetylene (0.78 mL, 6.0 mmol), and Et3N (12.0 mL, 45 mmol) in N,N-dimethylformamide (12 mL) was stirred for 10 min at 20° C. while being purged with Argon. Then, PdCl2(PPh3)2 (56 mg, 2 mol %), PPh3 (42 mg, 4 mol %) and CuI (15 mg, 4 mol %) were added and stirring was continued at 75° C. for 15 h in an atmosphere of argon. The mixture was cooled to 20° C. and partitioned between EtOAc and water. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue (2.2 g) was dissolved in a mixture of THF (8 mL) and MeOH (20 mL), potassium carbonate (0.11 g, 0.8 mmol) was added, and the solution was stirred for 2 h at 0° C. followed by 1 h at 20° C. The mixture was partitioned between EtOAc and 10% sodium chloride solution. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel using EtOAc/cyclohexane (1:5 v/v) as eluent and crystallization from EtOAc/cyclohexane gave 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (0.47 g, 40%) as a yellow solid; mp 181-182° C.

Workup

  1. customwhile being purged with Argon
  2. additionThen, PdCl2(PPh3)2 (56 mg, 2 mol %), PPh3 (42 mg, 4 mol %) and CuI (15 mg, 4 mol %) were added
  3. stirringstirring
  4. waitwas continued at 75° C. for 15 h in an atmosphere of argon
  5. temperatureThe mixture was cooled to 20° C.
  6. custompartitioned between EtOAc and water
  7. dry with materialThe organic layer was dried (Na2SO4)
  8. customevaporated in vacuo
  9. additionwas added
  10. stirringthe solution was stirred for 2 h at 0° C.
  11. waitfollowed by 1 h at 20° C
  12. customThe mixture was partitioned between EtOAc and 10% sodium chloride solution
  13. dry with materialThe organic layer was dried (Na2SO4)
  14. customevaporated in vacuo
  15. customThe residue was chromatographed on silica gel
  16. customcrystallization from EtOAc/cyclohexane

Sources & evidence

ORD record
ord-b8dfecc5f52e4379bd7301e0a0b6e42b
Source dataset
uspto-grants-2008_11
Patent number
US07446113B2

Reaction notes

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