(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected → [(1S,2R)-2-(6-carbamoyl-5-p-tolylamino-pyridazin-3-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester

HRID 1396344Notes

Reaction equation

HRID 1396344 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])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>CN1CCCC1=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:29]([O:28][C:27](=[O:33])[NH:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:3]=1)([CH3:32])([CH3:30])[CH3:31]

Participants

6

Reactant 2

HCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2×HCID 86689715HCID 86689715, compound

Product 1

HCID 86689714[(1S,2R)-2-(6-carbamoyl-5-p-tolylamino-pyridazin-3-ylamino)-cyclohexyl]-carbamic acid tert-butyl esterYield 8%

Reagents, catalysts & solvents 3

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
150 °C

Procedure

6-Chloro-4-p-tolylamino-pyridazine-3-carboxylic acid amide (199 mg, 0.758 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (325 mg, 1.52 mmol) were dissolved in N-methylpyrrolidinone (4.7 mL). The reaction mixture was heated at 150° C. for 16 h, then additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (550 mg, 2.57 mmol total) was added in three portions over 6 d. The reaction mixture was cooled, diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, then dried (sodium sulfate), filtered, and concentrated in vacuo. The residue obtained was purified by chromatography (silica, 0 to 5% methanol in dichloromethane) to give [(1S,2R)-2-(6-carbamoyl-5-p-tolylamino-pyridazin-3-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (26 mg, 8%) as a light brown amorphous residue. LCMS (EI/CI) m/z: 441 [M+H].

Workup

  1. temperatureThe reaction mixture was cooled
  2. extractionextracted with ethyl acetate
  3. washThe combined organic extracts were washed with water and brine
  4. dry with materialdried (sodium sulfate)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue obtained
  8. customwas purified by chromatography (silica, 0 to 5% methanol in dichloromethane)

Sources & evidence

ORD record
ord-9118aa21d3544a6f9e023f7ae045b021
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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