Dichloromethane → N-(4-(3-amino-3-methylpiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride

HRID 408325노트

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HRID 408325 반응식
F[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[C:3]=12.[CH3:21][C:22]1([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:53]>CCCCO>[ClH:53].[NH2:28][C:22]1([CH3:21])[CH2:27][CH2:26][CH2:25][N:24]([C:2]2[C:7]([F:8])=[CH:6][N:5]=[C:4]3[NH:9][CH:10]=[C:11]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[C:3]=23)[CH2:23]1

참가 물질

7

반응물 5

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 19691473Tert-butyl (3-methylpiperidin-3-yl)carbamateHCID 60205314HCID 60205314, 화합물

생성물 1

HCID 60205512N-(4-(3-amino-3-methylpiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride수율 56%

시약·촉매·용매 1

HCID 2631-Butanol용매

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온도
150 °C

실험 절차

A mixture of N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (50 mg, 0.18 mmol; Example 13, Step D), tert-butyl 3-methylpiperidin-3-ylcarbamate (78 mg, 0.37 mmol, Example C) and DIEA (0.032 mL, 0.182 mmol) in n-BuOH (1 mL) was stirred at 150° C. (bath) for 24 hours in a sealed tube. The solvent was removed, and the resulting 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 obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-80% CH3CN/water gradient; 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. The residue was dissolved in MeOH (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give N-(4-(3-amino-3-methylpiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.050 g, 56%) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (s, 1H), 11.03 (s, 1H), 9.49 (s, 1H), 8.95 (m, 2H), 8.27 (s, 2H), 8.18 (d, 1H), 7.93 (m, 1H), 7.53 (d, 1H), 3.43 (m, 1H), 3.36 (m, 2H), 3.04 (m, 1H), 1.71 (m, 1H), 1.51 (m, 2H), 1.31 (m, 1H), 1.22 (s, 3H). LCMS (APCI+) m/z 369 (M+H)+.

후처리

  1. customThe solvent was removed
  2. dissolutionthe resulting 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 obtained
  7. customwas purified by C-18 reverse phase flash chromatography (Biotage SP4 unit
  8. customThe product isolated
  9. stirringThe mixture was stirred at room temperature for 1 hour
  10. customThe solvent was removed
  11. dissolutionThe residue was dissolved in MeOH (1 mL)
  12. addition2N HCl in ether (3 mL) was added
  13. customThe solid formed
  14. filtrationwas collected by filtration

출처 및 근거

ORD 기록
ord-222b729ca96f43df84d5a280d2a0d3d4
출처 데이터셋
uspto-grants-2014_06
특허 번호
US08758830B2

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