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

HRID 1034856노트

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HRID 1034856 반응식
[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.C(OC(=O)[NH:24][C@H:25]1[C@H:30]([CH:31]2[CH2:33][CH2:32]2)[CH2:29][CH2:28][NH:27][CH2:26]1)(C)(C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:52]>CCCCO>[ClH:52].[NH2:24][C@H:25]1[C@H:30]([CH:31]2[CH2:33][CH2:32]2)[CH2:29][CH2:28][N:27]([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)[CH2:26]1

참가 물질

7

반응물 5

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 60205321N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramideHCID 86652140Tert-butyl-trans-4-cyclopropylpiperidin-3-ylcarbamate

생성물 1

HCID 67045541N-(4-(trans-3-amino-4-cyclopropylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride수율 52%

시약·촉매·용매 1

HCID 2631-Butanol용매

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온도
146 °C

실험 절차

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-cyclopropylpiperidin-3-ylcarbamate (0.48 g, 2.00 mmol; Example K) and DIEA (0.35 mL, 2.00 mmol) in n-BuOH (2 mL) was stirred at 146° C. (bath) for 20 hours. The solvent was removed. 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+, 20-80% CH3CN/water, 25 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. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected to give N-(4-(trans-3-amino-4-cyclopropylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.17 g, 52%) as a solid. 1H NMR (400 MHz, D2O) δ 8.21 (s, 1H), 7.26 (s, 1H), 3.81 (m, 1H), 3.48 (m, 1H), 3.38 (m, 1H), 3.11 (m, 2H), 2.60 (m, 1H), 1.88 (m, 1H), 1.82 (m, 1H), 1.52 (m, 1H), 1.16 (m, 1H), 1.07 (t, 6H), 0.77 (m, 1H), 0.39 (m, 1H), 0.14 (m, 1H), 0.11 (m, 1H). LCMS (APCI+) m/z 420(M+H)+.

후처리

  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
  10. dissolutionThe residue was dissolved in DCM (1 mL)
  11. addition2N HCl in ether (3 mL) was added
  12. customThe solid formed
  13. customwas collected

출처 및 근거

ORD 기록
ord-3c4ed5ac72784d84b2a5dce53f275f17
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08545897B2

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