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 1944613Notes

Reaction equation

HRID 1944613 reaction equation
[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.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

Participants

10

Reactant 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, compound

Product 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-carboxamideYield 71.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 21881883Oxolane--water (1/1)Solvent

Procedure

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 CH2Cl, (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

Workup

  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

Sources & evidence

ORD record
ord-d1ed691a39d04442be2adf2ea45b5966
Source dataset
uspto-grants-2013_03
Patent number
US08394818B2

Reaction notes

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