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

HRID 1396382노트

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HRID 1396382 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: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]

참가 물질

5

반응물 2

HCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2회HCID 866897206-Chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide

생성물 2

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

시약·촉매·용매 1

HCID 13387N-methyl-2-pyrrolidone용매

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온도
120 °C

실험 절차

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]+.

후처리

  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

출처 및 근거

ORD 기록
ord-e93bb2af60ca47aa84bf11e5f1ede4e6
출처 데이터셋
uspto-grants-2014_12
특허 번호
US08901124B2

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