Hydrochloric Acid → N-(4-(trans-3-amino-4-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride

HRID 1034837ノート

反応式

HRID 1034837 の反応式
[Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][C@@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@H:20]1[NH:25]C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.[ClH:49]>CCCCO.C(Cl)Cl.CO.CCOCC>[ClH:49].[NH2:25][C@H:20]1[C@H:19]([CH3:18])[CH2:24][CH2:23][N:22]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C:4]=23)[CH2:21]1

参加物

10

反応物 5

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 57931128trans-tert-Butyl (4-methylpiperidin-3-yl)carbamateHCID 60205321N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

生成物 1

HCID 67045573N-(4-(trans-3-amino-4-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride収率 4%

試薬・触媒・溶媒 4

HCID 2631-Butanol溶媒HCID 887Methanol溶媒HCID 3283Diethyl Ether溶媒HCID 6344Dichloromethane溶媒

反応条件

温度
146 °C

実験手順

A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.20 g, 0.67 mmol; Example 15, Step A), tert-butyl trans-4-methylpiperidin-3-ylcarbamate (0.43 g, 2.00 mmol; Example I) and DIEA (0.35 mL, 2.00 mmol) in n-BuOH (3 mL) was stirred at 146° C. (bath) for 24 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 10-80% CH3CN/water, 30 CV). The product isolated was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-80% CH3CN/water gradient, 20 CV). The product isolated was dissolved in MeOH (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected to give N-(4-(trans-3-amino-4-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.011 g, 4%) as a solid. 1H NMR (400 MHz, D2O) δ 8.20 (s, 1H), 7.27 (s, 1H), 3.72 (m, 1H), 3.26 (m, 1H), 3.19 (m, 3H), 2.63 (m, 1H), 1.76 (m, 1H), 1.68 (m, 1H), 1.41 (m, 1H), 1.10 (t, 6H), 1.00 (d, 3H). LCMS (APCI+) m/z 394(M+H)+.

後処理

  1. customThe solvent was removed
  2. dissolutionthe residue was dissolved in ethyl acetate (20 mL)
  3. washwashed with water (10 mL), brine (10 mL)
  4. dry with materialdried (sodium sulfate)
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by reverse phase chromatography (Biotage SP4
  7. customThe product isolated
  8. stirringThe mixture was stirred at room temperature for 1 hour
  9. customThe solvent was removed in vacuo
  10. customThe residue was purified by reverse phase chromatography (Biotage SP4
  11. customThe product isolated
  12. customThe solid formed
  13. customwas collected

出典と根拠

ORDレコード
ord-f11642a3adf9466a88c14a125e61724c
出典データセット
uspto-grants-2013_10
特許番号
US08545897B2

反応ノート

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