Formaldehyde → N6-(1-Methyl-4-piperidylmethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

HRID 388012Notes

Reaction equation

HRID 388012 reaction equation
FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:42]=[CH:43][C:44]=1[NH:45][C:46]([NH:48][CH:49]1[CH2:51][CH2:50]1)=[O:47])[O:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:40][CH3:41])=[C:20]([C:23]([NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33](OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[O:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].C=O.C([BH3-])#N.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH3:33][N:30]1[CH2:29][CH2:28][CH:27]([CH2:26][NH:25][C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][C:19]=2[O:40][CH3:41])[N:16]=[CH:15][CH:14]=[C:13]3[O:12][C:11]2[CH:42]=[CH:43][C:44]([NH:45][C:46]([NH:48][CH:49]3[CH2:51][CH2:50]3)=[O:47])=[C:9]([Cl:8])[CH:10]=2)=[O:24])[CH2:32][CH2:31]1

Participants

8

Reactant 5

HCID 712FormaldehydeHCID 6422Trifluoroacetic acidHCID 516892Sodium Bicarbonate2×HCID 5003444Sodium cyanoborohydrideHCID 22936930tert-Butyl 4-((((4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolyl)carbonyl)amino)methyl)-1-piperidinecarboxylate

Product 1

HCID 58931341N6-(1-Methyl-4-piperidylmethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamideYield 58.4%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent

Procedure

After adding trifluoroacetic acid (1 ml) to tert-butyl 4-((((4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolyl)carbonyl)amino)methyl)-1-piperidinecarboxylate (249 mg, 0.40 mmol) at room temperature, the mixture was stirred for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate for neutralization and extracted 3 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was dissolved in tetrahydrofuran (5 ml)-methanol (5 ml), and then 37% aqueous formaldehyde (0.5 ml), acetic acid (0.05 ml) and sodium cyanoborohydride (50 mg, 0.8 mmol) were added in that order at room temperature and the mixture was stirred for 1 hour. The reaction solution was distributed between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous sodium sulfate. After distilling off the solvent, ethyl acetate was used for crystallization and the crystals were filtered out and blow-dried to obtain the title compound (125.6 mg, 0.233 mmol, 58.4%) as white crystals.

Workup

  1. extractionextracted 3 times with ethyl acetate
  2. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  3. distillationAfter distilling off the solvent
  4. dissolutionthe residue was dissolved in tetrahydrofuran (5 ml)-methanol (5 ml)
  5. stirringthe mixture was stirred for 1 hour
  6. washthe organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline
  7. dry with materialdried over anhydrous sodium sulfate
  8. distillationAfter distilling off the solvent, ethyl acetate
  9. customwas used for crystallization
  10. filtrationthe crystals were filtered out and
  11. customblow-dried

Sources & evidence

ORD record
ord-caa6edbec392488883f08b423de84ee6
Source dataset
uspto-grants-2013_02
Patent number
US08372981B2

Reaction notes

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