Trifluoroacetic acid → 6-((1R,2S)-2-amino-cyclohexylamino)-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amide

HRID 1396355Notes

Reaction equation

HRID 1396355 reaction equation
C([O:5]C(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15]1[N:16]=[N:17][C:18]([C:28](=[O:30])[NH2:29])=[C:19]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[CH:20]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH4+:7].[OH-:5].[NH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15]1[N:16]=[N:17][C:18]([C:28]([NH2:29])=[O:30])=[C:19]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[CH:20]=1

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 86689723{(1S,2R)-2-[6-carbamoyl-5-(1-methyl-1H-pyrazol-3-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester

Product 2

HCID 14923Ammonium HydroxideHCID 716268926-((1R,2S)-2-amino-cyclohexylamino)-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amideYield 38.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

{(1S,2R)-2-[6-carbamoyl-5-(1-methyl-1H-pyrazol-3-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (34 mg, 0.079 mmol) was dissolved in dichloromethane (1 mL) then cooled to 0° C. Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added drop-wise then the reaction mixture was warmed to 25° C. After 4 h, the mixture was cooled in an ice bath and neutralized with sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layers washed with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. Purification by chromatography (silica, 0 to 80% of a 0.1:0.01 solution of methanol:NH4OH in dichloromethane) gave 6-((1R,2S)-2-amino-cyclohexylamino)-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amide (5 mg, 20%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.84-10.89 (m, 1H) 8.23-8.32 (m, 1H) 7.66 (d, J=2.3 Hz, 1H) 7.48-7.59 (m, 1H) 7.10 (s, 1H) 6.73 (d, J=7.9 Hz, 1H) 6.05 (d, J=2.3 Hz, 1H) 3.91-4.05 (m, 1H) 3.01-3.11 (m, 1H) 1.46-1.72 (m, 6H) 1.25-1.36 (m, 2H); LCMS (EI/CI) m/z: 331 [M+H].

Workup

  1. temperaturethe reaction mixture was warmed to 25° C
  2. temperaturethe mixture was cooled in an ice bath
  3. extractionThe mixture was extracted with ethyl acetate
  4. washthe combined organic layers washed with brine
  5. dry with materialdried (sodium sulfate)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customPurification by chromatography (silica, 0 to 80% of a 0.1:0.01 solution of methanol

Sources & evidence

ORD record
ord-20735b72e5df4f55a617e084aee760f0
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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