Dichloromethane → (-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid [2-(N-methyl-N-phenylmethylamino)ethyl]ester

HRID 2248150Notes

Reaction equation

HRID 2248150 reaction equation
[CH2:1]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[C:31]2[C:26](=[CH:27][CH:28]=[N:29][C:30]=2[O:43][CH:44]([CH3:46])[CH3:45])[NH:25][C:24]=1[CH3:47])=O)C1C=CC=CC=1.C(O)(=O)/C=C/C(O)=O.ClCCl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:9][N:8]([CH2:10][CH2:11][O:12][C:21]([C:23]1[CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[C:31]2[C:26](=[CH:27][CH:28]=[N:29][C:30]=2[O:43][CH:44]([CH3:45])[CH3:46])[NH:25][C:24]=1[CH3:47])=[O:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 66876N-Benzyl-N-methylethanolamineHCID 444972Fumaric AcidHCID 13923228(+)-1,4-Dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid benzyl ester

Product 1

HCID 10256740(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid [2-(N-methyl-N-phenylmethylamino)ethyl]ester

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 21.05 g 2-(N-benzyl-N-methylamino)-ethanol in 42 mL toluene are added under nitrogen 0.74 g sodium hydride (80%). After stirring for 30 minites a solution of 8.42 g (0.0174 mole) (-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid benzyl ester is added dropwise. The reaction mixture is stirred under nitrogen and the exclusion of moisture for 4 hours by heating to boiling temperature under reflux. The reaction mixture is subsequently extracted with 2×50 mL 2N acetic acid. The reaction mixture is subsequently dried over sodium sulfate and evaporated to dryness. The residue is purified over silica gel with toluene:ethyl acetate (7:3) as elution agent. After distilling off the elution agent there is obtained an oily product. The oil is dissolved with 1.28 g fumaric acid in 180 mL ethyl acetate under heating to reflux temperature. After filtration the reaction mixture is evaporated to about 20 mL. The precipitated product is filtered off with suction, dispersed in 14 mL toluene and stirred with 3 mL 1M aqueous ammonium hydroxide solution. The toluene phase is washed with 2×5 mL of water. The organic phase is after drying over sodium sulfate evaporated to dryness. There is obtained an oily product, yield 0.8 g (8.5% of theory); [α]D =-40.8° (c=1/dichloromethane).

Workup

  1. additionis added dropwise
  2. temperaturethe exclusion of moisture for 4 hours by heating
  3. temperatureunder reflux
  4. extractionThe reaction mixture is subsequently extracted with 2×50 mL 2N acetic acid
  5. dry with materialThe reaction mixture is subsequently dried over sodium sulfate
  6. customevaporated to dryness
  7. customThe residue is purified over silica gel with toluene:ethyl acetate (7:3) as elution agent
  8. distillationAfter distilling off the elution agent
  9. customthere is obtained an oily product
  10. temperatureunder heating
  11. temperatureto reflux temperature
  12. filtrationAfter filtration the reaction mixture
  13. customis evaporated to about 20 mL
  14. filtrationThe precipitated product is filtered off with suction
  15. additiondispersed in 14 mL toluene
  16. stirringstirred with 3 mL 1M aqueous ammonium hydroxide solution
  17. washThe toluene phase is washed with 2×5 mL of water
  18. dry with materialafter drying over sodium sulfate
  19. customevaporated to dryness
  20. customThere is obtained an oily product, yield 0.8 g (8.5% of theory)

Sources & evidence

ORD record
ord-c0732dc9b0c240cda70310daa78409e0
Source dataset
uspto-grants-1991_08
Patent number
US05037987

Reaction notes

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