Diisopropylethylamine → 7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-4-(((R)-1-(pyridin-2-yl)ethyl)amino)quinoline-3-carboxamide

HRID 1042993

Reaction equation

HRID 1042993 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:30]([NH2:32])[CH3:31].CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C.C(Cl)Cl>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH3:31])=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 1084918(R)-1-Pyridin-2-yl-ethylamineHCID 574655814-Chloro-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinoline-3-carboxamide

Product 1

HCID 574655857-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-4-(((R)-1-(pyridin-2-yl)ethyl)amino)quinoline-3-carboxamide

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 50 g, 151 mmol,) and [(1R)-1-(2-pyridinyl)ethyl]amine (35.3 g, 181 mmol, NetChem) were dissolved in N-methyl-2-pyrrolidone (NMP, 250 ml). DIPEA (79 ml, 452 mmol) was added, the solution was heated at 120° C. overnight, cooled and diluted with ethyl acetate (1 l). The solution was washed with water (2×1 l), brine (500 ml), dried (sodium sulphate) and the solvent evaporated to give a dark brown gum. The aqueous washings were extracted with DCM (2×600 ml). The combined extracts were washed with a mixture of saturated brine (300 ml) and water (1 l) giving a dense emulsion which took around 2 h to separate. The organic layer was dried (sodium sulphate) and evaporated to leave a brown liquid. This liquid was dissolved in ethyl acetate (200 ml), washed with water (2×200 ml), dried (sodium sulphate) and evaporated to give a brown gum. This material was combined with the previous brown gum, dissolved in DCM (150 ml) and loaded onto a silica column (750 g), which was eluted with a 2M ammonia in methanol/DCM gradient (0-12%) to give, after evaporation of the solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-{[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide as beige foam (45.1 g). Used in the subsequent step (Example 36) without further purification.

Workup

  1. temperaturecooled
  2. washThe solution was washed with water (2×1 l), brine (500 ml)
  3. dry with materialdried (sodium sulphate)
  4. customthe solvent evaporated
  5. customto give a dark brown gum
  6. extractionThe aqueous washings were extracted with DCM (2×600 ml)
  7. washThe combined extracts were washed with a mixture of saturated brine (300 ml) and water (1 l)
  8. customgiving a dense emulsion which
  9. customto separate
  10. dry with materialThe organic layer was dried (sodium sulphate)
  11. customevaporated
  12. customto leave a brown liquid
  13. washwashed with water (2×200 ml)
  14. dry with materialdried (sodium sulphate)
  15. customevaporated
  16. customto give a brown gum
  17. washwas eluted with a 2M ammonia in methanol/DCM gradient (0-12%)
  18. customto give
  19. customafter evaporation of the solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-{[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide as beige foam (45.1 g)
  20. customUsed in the subsequent step (Example 36) without further purification

Sources & evidence

ORD record
ord-caa7b928b42b42dead05dd4acbf97e7d
Source dataset
uspto-grants-2013_10
Patent number
US08557984B2

Linked notes

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