Sodium Carbonate → (+/-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid 2-(N-benzyl-N-methylamino)-ethylamide dihydrochloride

HRID 580011

Reaction equation

HRID 580011 reaction equation
C(Cl)(=O)C([Cl:4])=O.[CH:7]([O:10][C:11]1[N:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])[C:14]([C:22]([OH:24])=O)=[C:15]([CH3:21])[NH:16]2)([CH3:9])[CH3:8].[CH2:35]([N:42]([CH3:46])[CH2:43][CH2:44][NH2:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCCCCC.C(OCC)C.CN(C)C=O>[ClH:4].[ClH:4].[CH2:35]([N:42]([CH2:43][CH2:44][NH:45][C:22]([C:14]1[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[C:12]2[C:17](=[CH:18][CH:19]=[N:20][C:11]=2[O:10][CH:7]([CH3:9])[CH3:8])[NH:16][C:15]=1[CH3:21])=[O:24])[CH3:46])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 65578Oxalyl chlorideHCID 3014812(2-Aminoethyl)(benzyl)methylamineHCID 13670941(+)-1,4-Dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid

Product 1

HCID 67906784(+/-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid 2-(N-benzyl-N-methylamino)-ethylamide dihydrochloride

Reagents, catalysts & solvents 4

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 8058HexaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
20 °C

Procedure

17 ml dry dimethylformamide in 40 ml dry dioxan are cooled to 0° C. and 1.0 g (7.9 mMole) oxalyl chloride added dropwise thereto under an atmosphere of nitrogen. After 20 minutes, 2.7 g (6.9 mMole) (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid (European Patent Application 173 933) are added portionwise thereto at 0° C. and the reaction mixture is warmed to 20° C. After 30 minutes at 20° C., this solution is added dropwise to a solution, cooled to 0° C., of 2.6 g (15.8 mMole) N-benzyl-N-methylethylene-diamine in 20 ml n-hexane. After warming to 20° C., the reaction mixture is stirred for 30 minutes then, with renewed ice cooling, 2 N aqueous sodium carbonate solution is added dropwise thereto and the reaction mixture is extracted twice with dichloromethane. The dichloromethane solutions are washed with water and dried over anhydrous sodium sulphate. The solvent is removed in a vacuum and the residue is chromatographed on silica gel with dichloromethane/methanol (9:1 v/v). The fraction with the Rf of 0.5 is isolated, dissolved in diethyl ether and the dihydrochloride precipitated out with hydrogen chloride in diethyl ether. This is recrystallized twice from acetonitrile. There is obtained (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid 2-(N-benzyl-N-methylamino)-ethylamide dihydrochloride in the form of colorless crystals; mp 178°-180° C.

Workup

  1. waitAfter 30 minutes at 20° C.
  2. additionthis solution is added dropwise to a solution
  3. temperatureAfter warming to 20° C.
  4. extractionthe reaction mixture is extracted twice with dichloromethane
  5. washThe dichloromethane solutions are washed with water
  6. dry with materialdried over anhydrous sodium sulphate
  7. customThe solvent is removed in a vacuum
  8. customthe residue is chromatographed on silica gel with dichloromethane/methanol (9:1 v/v)
  9. customThe fraction with the Rf of 0.5 is isolated
  10. customthe dihydrochloride precipitated out with hydrogen chloride in diethyl ether
  11. customThis is recrystallized twice from acetonitrile

Sources & evidence

ORD record
ord-23f359d8d0164f9d96bf0d5021a6a8f6
Source dataset
uspto-grants-1988_06
Patent number
US04751228

Linked notes

Loading…