(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 1396354노트

반응식

HRID 1396354 반응식
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]

참가 물질

6

반응물 2

HCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2회HCID 866897226-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amide

생성물 1

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

시약·촉매·용매 3

HCID 962Water용매HCID 8857Ethyl Acetate용매HCID 13387N-methyl-2-pyrrolidone용매

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온도
150 °C

실험 절차

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].

후처리

  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)

출처 및 근거

ORD 기록
ord-8366044f47cb484d863ceb11e1c358ea
출처 데이터셋
uspto-grants-2014_12
특허 번호
US08901124B2

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