Hydrochloric Acid → 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-4-yl)piperidine-4-carboxamide

HRID 336890노트

반응식

HRID 336890 반응식
[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:36])[CH2:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([C:28]([O:30]C)=O)[CH2:24][CH2:23]5)=[C:18]([C:32]([F:35])([F:34])[F:33])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1.O.[OH-].[Li+].Cl.[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1.O.C(Cl)Cl.O.CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:36])[CH2:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:23][CH2:24][CH:25]([C:28]([NH:48][CH:45]6[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]6)=[O:30])[CH2:26][CH2:27]5)=[C:18]([C:32]([F:33])([F:34])[F:35])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1

참가 물질

11

반응물 6

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrateHCID 27375314-Amino-1-methylpiperidineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67008030HCID 67008030, 화합물

생성물 1

HCID 585250731-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-4-yl)piperidine-4-carboxamide수율 71.3%

시약·촉매·용매 4

HCID 962Water용매HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 21881883Oxolane--water (1/1)용매

실험 절차

To a solution of compound 8.4 methyl 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (55 mg, 0.10 mmol, 1 equiv.) in THF/H2O (1.0 mL/1.5 mL) was added lithium hydroxide monohydrate (13 mg, 0.30 mmol, 1 equiv.). The resulting mixture was stirred overnight at room temperature. Upon completion, the reaction was diluted with CH2Cl2 (5 mL) and water (5 mL). The aqueous layer was adjusted with 1 N HCl to about pH3 and extracted with CH2Cl2 (5 mL×3). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was used for the next step without further purification. To a solution of the above acid in DMF (2 mL) was added 1-methylpiperidin-4-amine (25 μL, 0.20 mmol, 2 equiv.), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (95 mg, 0.25 mmol, 2.5 equiv.) and DIEA (52 μL, 0.30 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for overnight. After removal of the solvent, the residue was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4. Removal of solvent under vacuum afforded crude product 8.5 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-4-yl)piperidine-4-carboxamide 46 mg. It was used for next step without further purification. LC-MS (M+H): 645.22

후처리

  1. extractionextracted with CH2Cl2 (5 mL×3)
  2. washThe combined organic layer was washed with brine (20 mL)
  3. dry with materialdried over Na2SO4
  4. customAfter removal of solvent under vacuum
  5. customthe resulting residue was used for the next step without further purification
  6. stirringThe reaction mixture was stirred at room temperature for overnight
  7. customAfter removal of the solvent
  8. additionthe residue was diluted with EtOAc (20 mL)
  9. washwashed with water (20 mL) and brine (20 mL)
  10. dry with materialThe organic phase was dried over Na2SO4
  11. customRemoval of solvent under vacuum

출처 및 근거

ORD 기록
ord-49e613248fd4442585f1448a60ab8f10
출처 데이터셋
uspto-grants-2014_11
특허 번호
US08889706B2

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