(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected → Ammonium Hydroxide

HRID 1396382Notes

Reaction equation

HRID 1396382 reaction equation
Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN1C(=O)CCC1>[NH4+:6].[OH-:9].[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[N:13]=1)(=[O:9])[NH2:10]

Participants

5

Reactant 2

HCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2×HCID 866897206-Chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide

Product 2

HCID 14923Ammonium HydroxideHCID 86689741tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5,6-dimethylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

6-Chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (841 mg, 3.03 mmol) was dissolved in NMP (2 mL) and to this solution was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (649 mg, 3.03 mmol) and the reaction mixture heated in an oil bath with stirring at 120° C. for 24 h. A second equivalent of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (649 mg, 3.03 mmol) was added and reaction continued for 72 h. The mixture was cooled, then the NMP solvent was distilled off under high vacuum. The residue was dissolved in dichloromethane containing few drops of methanol and passed through a silica plug eluting with 5% of a 9:1 MeOH:NH4OH solution in CH2Cl2 to yield tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5,6-dimethylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate mixed with 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide. The mixture was suspended in CH2Cl2 (3 mL) then TFA (1.48 g, 13.0 mmol) was added and mixture stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the residue obtained was purified by chromatography (spherical silica 20-45 uM, 50 g, Versaflash Supelco, 0 to 10% of a 9:1 MeOH:NH4OH solution in CH2Cl2, 20 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (550 mg, 49% yield over two steps) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.48 (s, 1H), 8.36 (br. s., 1H), 8.05 (s, 1H), 7.60 (br. s., 1H), 7.47 (d, J=8.1 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 3.87 (br. s., 1H), 3.15 (br. s., 1H), 2.45 (s, 3H), 2.20 (s, 3H), 1.44-1.79 (m, 8H), 1.32 (br. s., 2H); LC-MS 356.1 [M+H]+.

Workup

  1. temperaturethe reaction mixture heated in an oil bath
  2. customreaction
  3. waitcontinued for 72 h
  4. temperatureThe mixture was cooled
  5. distillationthe NMP solvent was distilled off under high vacuum
  6. dissolutionThe residue was dissolved in dichloromethane containing few drops of methanol
  7. washeluting with 5% of a 9:1 MeOH

Sources & evidence

ORD record
ord-e93bb2af60ca47aa84bf11e5f1ede4e6
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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