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

HRID 1396348ノート

反応式

HRID 1396348 の反応式
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

参加物

9

反応物 5

HCID 6422Trifluoroacetic acidHCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2 回HCID 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

生成物 2

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

試薬・触媒・溶媒 2

HCID 6344Dichloromethane溶媒HCID 13387N-methyl-2-pyrrolidone溶媒

反応条件

温度
150 °C

実験手順

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].

後処理

  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

出典と根拠

ORDレコード
ord-fdf30e5f435c4f2fb1f7349c01e3406b
出典データセット
uspto-grants-2014_12
特許番号
US08901124B2

反応ノート

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