Ethyl orthoformate → 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbonitrile

HRID 1951425Notes

Reaction equation

HRID 1951425 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[C:14]([CH3:20])[C:13]=3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:28][CH3:29]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:20])[CH:15]=[N:16][C:17]=3[O:19][CH2:28][CH3:29])[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]

Participants

4

Reactant 2

HCID 31214Ethyl orthoformateHCID 674158664-(4-Cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile

Product 1

HCID 674168744-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbonitrile

Reagents, catalysts & solvents 1

HCID 1118Sulfuric AcidCatalyst

Conditions

Temperature
140 °C

Procedure

3620 mg (10.83 mmol) of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile are suspended in 150 ml (901 mmol) of anhydrous triethyl orthoformate. The reaction mixture is heated to 140° C. Then 10 drops of concentrated sulfuric acid are added each hour. After complete reaction has been detected (analytical HPLC; reaction time about 36 h), the reaction mixture is cooled to room temperature and the precipitated product is filtered off. The precipitate is washed with ethyl acetate and diethyl ether and then purified by flash chromatography (silica gel; mobile phase: initially dichloromethane, then isohexane/ethyl acetate 1:1). The product fractions are combined and concentrated in a rotary evaporator, and the residue is then crystallized from ethyl acetate. Drying under high vacuum results in 1160 mg (30% of theory) of the title compound in the form of yellowish crystals.

Workup

  1. customAfter complete reaction
  2. custom(analytical HPLC; reaction time about 36 h)
  3. temperaturethe reaction mixture is cooled to room temperature
  4. filtrationthe precipitated product is filtered off
  5. washThe precipitate is washed with ethyl acetate and diethyl ether
  6. custompurified by flash chromatography (silica gel
  7. concentrationconcentrated in a rotary evaporator
  8. customthe residue is then crystallized from ethyl acetate
  9. customDrying under high vacuum

Sources & evidence

ORD record
ord-eb9935e747fe4617b866356baff37fde
Source dataset
uspto-grants-2013_03
Patent number
US08404709B2

Reaction notes

Loading…