Ammonia → 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

HRID 2170981Notes

Reaction equation

HRID 2170981 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24](O)=[O:25])=[C:5]([O:27][CH3:28])[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:31]1C=CN=C1)=O.N>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([NH2:31])=[O:25])=[C:5]([O:27][CH3:28])[CH:4]=1)#[N:2]

Participants

5

Reactant 3

HCID 222AmmoniaHCID 682631,1'-CarbonyldiimidazoleHCID 593496564-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid

Product 1

HCID 249930454-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

1.46 g (3.84 mmol) of the compound from Example 30A are introduced into 50 ml of ethyl acetate and, after addition of 777 mg (4.79 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature overnight. A TLC check (silica gel; mobile phase: ethyl acetate) shows complete conversion. The volatile components are removed in a rotary evaporator, and the residue is taken up in 20 ml of DMF. Then 10.74 ml of ammonia (28% by weight solution in water, 76.8 mmol) are added, and the reaction mixture is heated at 100° C. for 30 min. The solvent is distilled out under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). The residue after concentration of the product fractions is dissolved in 40 ml of dichloromethane/methanol (1:1 v/v) and mixed with 100 ml of ethyl acetate. The solvent is concentrated to a volume of about 20 ml, whereupon the product crystallizes. The precipitate is filtered off and washed with a little diethyl ether. Drying at 40° C. in a vacuum drying oven results in 1.40 g (96% of theory) of the title compound.

Workup

  1. customThe volatile components are removed in a rotary evaporator
  2. temperaturethe reaction mixture is heated at 100° C. for 30 min
  3. distillationThe solvent is distilled out under reduced pressure
  4. customthe residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5)
  5. dissolutionThe residue after concentration of the product fractions is dissolved in 40 ml of dichloromethane/methanol (1:1 v/v)
  6. additionmixed with 100 ml of ethyl acetate
  7. concentrationThe solvent is concentrated to a volume of about 20 ml, whereupon the product
  8. customcrystallizes
  9. filtrationThe precipitate is filtered off
  10. washwashed with a little diethyl ether
  11. customDrying at 40° C. in a vacuum
  12. customdrying oven

Sources & evidence

ORD record
ord-fc1024e198414084acb092b375217ea5
Source dataset
uspto-grants-2015_06
Patent number
US09051316B2

Reaction notes

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