Hydrochloric Acid → 2-[6-chloro-4-fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide hydrochloride

HRID 246118ノート

反応式

HRID 246118 の反応式
[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=4[F:25])[N:18]([CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN.Cl>ClCCl.CO.ClCCl.O1CCOCC1.C(OCC)(=O)C.O>[ClH:26].[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=4[F:25])[N:18]([CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]

参加物

10

反応物 4

HCID 313Hydrochloric AcidHCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 712803262-[6-Chloro-4-fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide

生成物 1

HCID 712793962-[6-chloro-4-fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide hydrochloride収率 143.1%

試薬・触媒・溶媒 5

HCID 962Water溶媒HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒HCID 312751,4-Dioxane溶媒HCID 21226129Dichloromethane methanol溶媒

実験手順

2-[6-Chloro-4-fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (66 mg, 0.107 mmol) was dissolved in dichloromethane (1.4 ml) and cooled in ice bath. Trifluoroacetic acid (0.7 ml) was slowly added and the reaction was stirred at room temperature for 2 h. The reaction was evaporated and the residue was dissolved in dichloromethane (1 ml). Ethylenediamine (0.43 ml, 6.4 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (methanol/dichloromethane). The product thus isolated was dissolved in methanol/dichloromethane and treated with 2 eq of 4 M HCl in 1,4-dioxane. Evaporation of the solvent provided a solid which was dried under high vacuum to afford 40 mg (72%) of 2-[6-chloro-4-fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide hydrochloride. MS: (M+H)+=486; mp=190-195° C. 1H NMR (300 MHz, DMSO-d6) δ: 12.86-12.98 (m, 1H), 10.92-11.17 (m, 1H), 9.06 (s, 1H), 8.45 (d, J=3.0 Hz, 1H), 8.26 (d, J=7.9 Hz, 1H), 8.05 (s, 1H), 7.35 (d, J=10.6 Hz, 1H), 5.05 (br. s., 2H), 4.14-4.30 (m, 1H), 3.93-4.09 (m, 2H), 3.68-3.85 (m, 4H), 3.54-3.64 (m, 2H), 3.11-3.30 (m, 2H), 1.24 (d, J=6.4 Hz, 6H).

後処理

  1. temperaturecooled in ice bath
  2. customThe reaction was evaporated
  3. dissolutionthe residue was dissolved in dichloromethane (1 ml)
  4. stirringthe mixture was stirred for 18 h
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted three times with ethyl acetate
  7. washThe combined organic layers were washed with sodium chloride solution
  8. dry with materialdried over sodium sulfate
  9. customevaporated
  10. customThe residue was purified by silica gel chromatography (methanol/dichloromethane)
  11. customThe product thus isolated
  12. customEvaporation of the solvent
  13. customprovided a solid which
  14. customwas dried under high vacuum

出典と根拠

ORDレコード
ord-493bf992a1aa4be0adb25746a332a631
出典データセット
uspto-grants-2014_02
特許番号
US08658646B2

反応ノート

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