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

HRID 1396354Notes

Reaction equation

HRID 1396354 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:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:3]=1.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN1CCCC1=O.C(OCC)(=O)C.O>[C:28]([O:27][C:26](=[O:32])[NH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:3]=1)([CH3:31])([CH3:29])[CH3:30]

Participants

6

Reactant 2

HCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2×HCID 866897226-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amide

Product 1

HCID 86689723{(1S,2R)-2-[6-carbamoyl-5-(1-methyl-1H-pyrazol-3-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl esterYield 17.6%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
150 °C

Procedure

6-Chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amide (60 mg, 0.237 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (102 mg, 0.475 mmol) were dissolved in N-methylpyrrolidinone (1.5 mL). The reaction mixture was heated at 150° C. for 16 h, then additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (100 mg, 0.47 mmol total) was added in three portions over 6 d. The reaction mixture was cooled, diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, and then dried (sodium sulfate), filtered, and concentrated in vacuo. The residue obtained was purified by chromatography (silica, 0 to 7% methanol in dichloromethane) to give {(1S,2R)-2-[6-carbamoyl-5-(1-methyl-1H-pyrazol-3-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (18 mg, 17%) as a brown amorphous residue. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.68-10.80 (m, 1H) 7.89-8.06 (m, 1H) 7.34-7.37 (m, 1H) 7.25 (d, J=2.3 Hz, 1H) 5.93 (d, J=2.3 Hz, 1H) 5.56-5.64 (m, 1H) 5.02-5.14 (m, 1H) 3.91-4.01 (m, 1H) 3.86 (s, 3H) 1.55 (br. s., 8H) 1.40 (s, 9H); LCMS (EI/CI) m/z: 431 [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 7% methanol in dichloromethane)

Sources & evidence

ORD record
ord-8366044f47cb484d863ceb11e1c358ea
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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