Trifluoroacetic acid → 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide

HRID 1396348노트

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HRID 1396348 반응식
ClC1N=[N:6]C(C(N)=[O:9])=C(NC2C=CC=C(C(C)C)N=2)C=1.N[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C.[C:36]([C:39]1[N:44]=[N:43][C:42]([NH:45][C@@H:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C@@H:47]2[NH:52]C(=O)OC(C)(C)C)=[CH:41][C:40]=1[NH:60][C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]([CH3:69])[CH3:68])[N:62]=1)(=[O:38])[NH2:37].N[C@H]1CCCC[C@H]1NC1N=NC(C(N)=O)=C(NC2C=CC=C(C(C)C)N=2)C=1.C(O)(C(F)(F)F)=O>CN1CCCC1=O.ClCCl>[NH4+:6].[OH-:9].[NH2:52][C@H:47]1[CH2:48][CH2:49][CH2:50][CH2:51][C@H:46]1[NH:45][C:42]1[N:43]=[N:44][C:39]([C:36]([NH2:37])=[O:38])=[C:40]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]([CH3:69])[CH3:68])[N:62]=2)[CH:41]=1

참가 물질

9

반응물 5

HCID 6422Trifluoroacetic acidHCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2회HCID 716268226-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamideHCID 866897176-Chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamideHCID 86689718tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate

생성물 2

HCID 14923Ammonium HydroxideHCID 716268226-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide수율 9%

시약·촉매·용매 2

HCID 6344Dichloromethane용매HCID 13387N-methyl-2-pyrrolidone용매

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온도
150 °C

실험 절차

To a solution of 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (102 mg, 350 μmol) in N-methyl-2-pyrrolidinone (6 ml) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) and the mixture heated to 150° C. for 3 d. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) was added and the reaction heated to 150° C. for an additional 2 d, then cooled, concentrated, and purified by chromatography (silica, 50 μm, 40 g, Analogix, 96:3.8:0.2 to 84:15.2:0.8; dichloromethane:MeOH:NH4OH) to give a mixture of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate and 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (33 mg). This mixture was dissolved in dichloromethane (2 mL) then TFA (370 mg, 250 μL, 3.24 mmol) was added. After 18 h, the mixture was concentrated in vacuo and the residue obtained was purified by chromatography (spherical silica, 20-45 μm, 25 g, Versaflash Supelco, 96:3.8:0.2 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 25 min gradient to afford 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (12 mg, 9%) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.35 (br. s., 1H) 8.33 (s, 1H) 7.96 (br. s., 1H) 7.44 (t, J=7.83 Hz, 1H) 6.70 (d, J=7.58 Hz, 1H) 6.61 (d, J=8.08 Hz, 1H) 5.61 (br. s., 1H) 5.31 (br. s., 1H) 3.75 (br. s., 1H) 3.19 (d, J=3.28 Hz, 1H) 2.89-3.01 (m, 1H) 1.32-1.80 (m, 8H) 1.27 (d, J=6.82 Hz, 6H). LCMS (EI/CI) m/z: 370 [M+H].

후처리

  1. temperaturethe reaction heated to 150° C. for an additional 2 d
  2. temperaturecooled
  3. concentrationconcentrated
  4. custompurified by chromatography (silica, 50 μm, 40 g, Analogix, 96:3.8:0.2 to 84:15.2:0.8; dichloromethane:MeOH:NH4OH)
  5. customto give
  6. concentrationthe mixture was concentrated in vacuo
  7. customthe residue obtained
  8. customwas purified by chromatography (spherical silica, 20-45 μm, 25 g, Versaflash Supelco, 96:3.8:0.2 to 84:15.2:0.8 dichloromethane

출처 및 근거

ORD 기록
ord-fdf30e5f435c4f2fb1f7349c01e3406b
출처 데이터셋
uspto-grants-2014_12
특허 번호
US08901124B2

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