7-aMino-4,4-diMethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one

846035-54-9

618446-06-3

Example 4: 7-Amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one was synthesized as follows: 1. 3-Methyl-but-3-enoic acid (6-amino-pyridin-2-yl)amide (49.2 g, 0.26 mol) was dissolved in 500 mL of dichloromethane (CH2Cl2) in a 1000 mL three-necked flask equipped with a mechanical stirrer, a 125 mL dosing funnel and a thermocouple. 2. Methanesulfonic acid (MeSO3H, 50 mL, 0.78 mol) was slowly added dropwise to the flask under stirring conditions. The temperature of the reaction was controlled by an ice/water bath to ensure that the temperature was below 20°C. After dropwise addition, continue stirring for 15 minutes. 3. Aluminum trichloride (AlCl3, 274 g, 2.08 mol) was suspended in 1500 mL of dichloromethane in another 5 L four-necked flask equipped with a mechanical stirrer, 1000 mL dosing funnel, N2 inlet, and thermocouple. 4. The amide solution prepared in step 2 was slowly added dropwise to the aluminum trichloride suspension. The temperature of the reaction was controlled by an ice/water bath, keeping the temperature below 20°C. After the dropwise addition was completed, the reaction mixture was allowed to gradually warm up to room temperature and stirred overnight. Upon completion of the reaction, complete consumption of the β,γ-unsaturated isomer was confirmed by TLC. 5. The reaction mixture was slowly poured into ice water for reverse quenching. The pH of the quenched mixture was adjusted to 8-10 with 2 N potassium hydroxide (KOH) solution.At this point, the salts precipitated out of solution and the aqueous phase was saturated. 6. The suspension was transferred to a partition funnel and extracted twice with a solvent mixture of dichloromethane/ethanol/ammonia (100:8:1, v/v/v). The organic layers were combined, dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated to give the crude product. 7. The crude product was ground with ethyl acetate (EtOAc) and filtered to afford 7-amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (22.4 g, 0.117 mol, 46% yield). Mass spectrometry analysis (APCI): m/z 192.2 (M+1, calculated exact mass: 191.11).