(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected → HCID 86689799, compound

HRID 1396465Notes

Reaction equation

HRID 1396465 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][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=1)(=[O:9])[NH2:10]

Participants

4

Reactant 2

HCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2×HCID 86689798HCID 86689798, compound

Product 1

HCID 86689799HCID 86689799, compoundYield 47.1%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

A dry 50 mL round bottom flask was charged with 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (241 mg, 783 μmol) dissolved in NMP (2.00 mL) To this solution was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (168 mg, 783 μmol) and the reaction mixture was heated in an oil bath with stirring at 120° C. for 18 h. After that, it was added more tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (168 mg, 783 μmol) in small portions during 7 hours. After last addition, the reaction was continued for 18 h. After cooling to room temperature, the solvent was distilled off under high vacuum, the residue was dissolved in dichloromethane containing few drops of methanol and then purified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to yield tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (179 mg, 47.1% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 11.54 (br. s., 1H), 8.16 (br. s., 1H), 8.04 (s, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 6.53-6.70 (m, 1H), 5.81 (d, J=3.4 Hz, 1H), 5.43 (br. s., 1H), 3.71-4.14 (m, 3H), 1.23-1.90 (m, 23H); LC-MS 486.2 [M+H]+.

Workup

  1. temperaturethe reaction mixture was heated in an oil bath
  2. additionAfter last addition
  3. waitthe reaction was continued for 18 h
  4. temperatureAfter cooling to room temperature
  5. distillationthe solvent was distilled off under high vacuum
  6. dissolutionthe residue was dissolved in dichloromethane containing few drops of methanol
  7. custompurified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco)
  8. washeluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2

Sources & evidence

ORD record
ord-733aa33c38aa47ca8c39bc5e0ad8945c
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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