3-Chlorophenol → 5-(3-Chlorophenoxy)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde

HRID 624790Notes

Reaction equation

HRID 624790 reaction equation
Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)C(=O)OC(C)(C)C)[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.CN1C(=O)CCC1>[Cl:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[O:31][C:2]1[CH:7]=[C:6]([NH:8][CH:16]2[CH2:17][CH2:18]2)[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1

Participants

7

Reactant 4

HCID 79333-ChlorophenolHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 58196421Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate

Product 1

HCID 583139015-(3-Chlorophenoxy)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehydeYield 65%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (1.0 eq, 49 mg, 0.145 mmol) was mixed in a vial with NMP (0.2 ml), 3-chlorophenol (5.0 eq, 93 mg, 0.274 mmol) and potassium carbonate (5.0 eq, 100 mg, 0.723 mmol). The reaction mixture was stirred at room temperature for one hour. Water was added and the resulting gummy material was extracted with methylene chloride. The organic phase was dried over Na2SO4 and the volatiles removed in vacuo. The resulting NMP solution was reacted with a HCl 4N solution in dioxane (5 ml) at room temperature for one hour, at which time LCMS monitoring indicated completion of the reaction. The reaction was treated with water and 6N NaOH and stirred overnight at room temperature. The solid was filtered and dried to afford crude 5-(3-chlorophenoxy)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde as a solid (31 mg). The material was heated with hydantoin (30 mg), piperidine (30 uL) in Ethanol (1 ml) in a vial at 90° C. for seven hours. Water was added and the material was filtered, washed with ethanol, ethanol/water and dried. (Z)-5-((5-(3-chlorophenoxy)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione was isolated as solid (43 mg, 38% over 2 steps)). LCMS (ES): >95% pure, m/z 411 [M+H]+.

Workup

  1. extractionthe resulting gummy material was extracted with methylene chloride
  2. dry with materialThe organic phase was dried over Na2SO4
  3. customthe volatiles removed in vacuo
  4. customThe resulting NMP solution was reacted with a HCl 4N solution in dioxane (5 ml) at room temperature for one hour, at which time LCMS
  5. customcompletion of the reaction
  6. stirringstirred overnight at room temperature
  7. filtrationThe solid was filtered
  8. customdried

Sources & evidence

ORD record
ord-e5cbab6fc2da44beb0ec31a569e7f5a1
Source dataset
uspto-grants-2016_04
Patent number
US09303033B2

Reaction notes

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