Potassium Carbonate → Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-1H-pyrazol-4-yl}-amide hydrochloride

HRID 529769Notes

Reaction equation

HRID 529769 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[CH3:29][N:30]([CH3:46])[CH:31]1[CH2:36][CH2:35][N:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42](I)=[CH:41][CH:40]=2)=[O:38])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([C:42]3[CH:43]=[CH:44][C:39]([C:37]([N:34]4[CH2:33][CH2:32][CH:31]([N:30]([CH3:46])[CH3:29])[CH2:36][CH2:35]4)=[O:38])=[CH:40][CH:41]=3)[N:9]=2)[CH:7]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 60763941(4-Dimethylamino-piperidin-1-yl)-(4-iodo-phenyl)-methanoneHCID 178522413HCID 178522413, compound

Product 1

HCID 131735626Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-1H-pyrazol-4-yl}-amide hydrochlorideYield 79.8%

Reagents, catalysts & solvents 1

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst

Conditions

Temperature
110 °C

Procedure

A microwave vial was charged with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide (100 mg, 0.25 mmol), (4-dimethylamino-piperidin-1-yl)-(4-iodo-phenyl)-methanone (107 mg, 0.30 mmol), copper (I) iodide (15 mg, 0.08 mmol), potassium carbonate (73 mg, 0.53 mmol), trans-N,N′-dimethyl-1,2-cyclohexane diamine (24 μL, 0.15 mmol). The vessel was sealed and purged with argon before the addition of toluene (1.0 mL). The reaction mixture was stirred at 110° C. for 18 hours. The reaction was cooled to room temperature, diluted with water and the resultant precipitate was collected by filtration, washed with ethyl acetate and dried under reduced pressure. The resultant solid was purified by MDAP (Method 1), the solid was taken up into a mixture of MeOH/DCM and loaded onto an Isolute® SCX-2 cartridge which had been conditioned with MeOH. The cartridge was washed with MeOH then eluted with 2M NH3/MeOH. The basic fractions were combined, evaporated and the resultant solid suspended in MeOH before being treated with 1.25M HCl in MeOH. The suspension was allowed to evaporate and the solid was triturated with ethyl acetate, dried under reduced pressure giving the title compound as a yellow solid (67 mg, 40%). LCMS (Method 5) [M+H]+=635.2, RT=3.27 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.88 (s, 1H), 9.38 (dd, 1H, J=7.1, 1.8 Hz), 9.04 (s, 1H), 8.71 (s, 1H), 8.70 (dd, 1H, J=4.3, 1.7 Hz), 8.04-7.99 (m, 2H), 7.79 (d, 1H, J=2.7 Hz), 7.72 (dd, 1H, J=8.8, 2.6 Hz), 7.63-7.57 (m, 2H), 7.53 (d, 1H, J=8.8 Hz), 7.33 (dd, 1H, J=7.0, 4.3 Hz), 7.31 (t, 1H, J=73.1 Hz), 4.65 (brs, 1H), 2.98 (s, 2H), 2.67 (s, 6H), 2.14-1.82 (m, 2H), 1.69-1.54 (m, 2H).

Workup

  1. customThe vessel was sealed
  2. custompurged with argon before the addition of toluene (1.0 mL)
  3. temperatureThe reaction was cooled to room temperature
  4. additiondiluted with water
  5. filtrationthe resultant precipitate was collected by filtration
  6. washwashed with ethyl acetate
  7. customdried under reduced pressure
  8. customThe resultant solid was purified by MDAP (Method 1)
  9. additionthe solid was taken up into a mixture of MeOH/DCM
  10. washThe cartridge was washed with MeOH
  11. washthen eluted with 2M NH3/MeOH
  12. customevaporated
  13. additionbefore being treated with 1.25M HCl in MeOH
  14. customto evaporate
  15. customthe solid was triturated with ethyl acetate
  16. customdried under reduced pressure

Sources & evidence

ORD record
ord-d9a2a079052b4cd0a3b9b8cc4f137311
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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