Water → HCID 178480634, compound

HRID 2274431Notes

Reaction equation

HRID 2274431 reaction equation
FC(F)(F)C(O)=O.O.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:23]=[C:22]([C:24]4[C:28]([NH:29][C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[O:31])=[CH:27][N:26](C5CCCCO5)[N:25]=4)[NH:21][C:20]=3[CH:44]=2)[CH2:12][CH2:11]1>ClCCl>[CH3:9][N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:23]=[C:22]([C:24]4[C:28]([NH:29][C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[O:31])=[CH:27][NH:26][N:25]=4)[NH:21][C:20]=3[CH:44]=2)[CH2:14][CH2:15]1

Participants

5

Reactant 3

HCID 962WaterHCID 6422Trifluoroacetic acidHCID 136388008HCID 136388008, compound

Product 1

HCID 178480634HCID 178480634, compoundYield 16.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
22 °C

Procedure

1 mL of trifluoroacetic acid and 100 μL of water are added to a solution of 290 mg of N-[3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]piperidine-1-carboxamide in solution in 3 mL of dichloromethane. The reaction medium is stirred at 22° C. for 24 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. 0.5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid and 100 μL of water are added. The reaction medium is stirred at 22° C. for 4 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in dichloromethane containing 15% of methanol. 40 mg of N-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are isolated. 123 mg of N-[3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]piperidine-1-carboxamide are isolated and reacted again with 2.8 mL of TFA and 700 μL of water. The reaction medium is stirred at 22° C. for 72 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in dichloromethane containing 15% of methanol. 37 mg of N-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are isolated. That is to say, 77 mg of N-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are isolated in total. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.43 to 1.63 (m, 6H); 2.90 (s, 3H); 3.05 (m, 2H); 3.22 (m, 2H); 3.43 (m, 4H); 3.58 (m, 2H); 3.89 (m, 2H); 7.17 (broad s, 1H); 7.31 (broad d, J=9.0 Hz, 1H); 7.65 (d, J=9.0 Hz, 1H); 8.02 (s, 1H).

Workup

  1. concentrationThe reaction medium is concentrated under vacuum in a rotary evaporator
  2. addition0.5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid and 100 μL of water are added
  3. stirringThe reaction medium is stirred at 22° C. for 4 hours
  4. customAfter evaporation
  5. customthe reaction crude
  6. customis purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge
  7. washThe elution

Sources & evidence

ORD record
ord-e5c681b4133e45629c24b5456c67a370
Source dataset
uspto-grants-2015_09
Patent number
US09126969B2

Reaction notes

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