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

Yield:618446-06-3 46%

Reaction Conditions:

Stage #1: 3-Methyl-but-3-enoic acid (6-amino-pyridin-2-yl)-amidewith methanesulfonic acid in dichloromethane at 20; for 0.25 h;
Stage #2: with aluminum (III) chloride in dichloromethane at 20;
Stage #3: with potassium hydroxide;water pH=8 - 10;

Steps:

4

EXAMPLE 47-Amino-4,4-dimethyl-3,4-dihydro-lH-[l,8]naphthyridin-2-one; 7-Amino-4,4-dimethyl-3,4-dihydro-lH-[l,8]naphthyridin-2-one, was produced as follows: 3-Methyl-but-3-enoic acid (6-amino-pyridin-2-yl)-amide (49.2 g, 0.26 mol) was dissolved in 500 mL CH₂Cl₂ in a 1000 mL 3-neck flask equipped with mechanical stirring, a 125 mL addition funnel and a thermal couple. While stirring, MeSO₃H (50 mL, 0.78 mol) was added to the flask dropwise. The exotherm upon addition was controlled to maintain a temperature <20 ⁰C by an ice/water bath. The mixture was allowed to stir for 15 minutes. AlCl₃ (274 g, 2.08 mol) was suspended in 1500 mL CH₂Cl₂ in a 5 L 4-neck flask equipped with mechanical stirring, 1000 mL addition funnel, N₂ line and a thermal couple. To this suspension, the amide solution was added dropwise. The exotherm from the addition was again controlled to maintain a temperature <20⁰C with an ice/water bath. The reaction was allowed to warm to room temperature and stir overnight. The reaction had consumed all the beta gamma unsaturated isomer and was deemed complete. The reaction mixture was slowly added to ice as an inverse quench. The quenched mixture was brought to pH 8-10 with 2 N KOH. The salts precipitated out of solution and saturated the aqueous phase. The suspension was transferred to a separatory funnel and extracted twice with 100:8:1 CH₂C^EtORNH₄OH. The organic layers were combined, dried over Na₂SO₄, filtered and concentrated to a crude solid. The solid was triturated with EtOAc and filtered. The resulting solid was 7-Amino-4,4-dimethyl-3,4-dihydro-lH-[l,8]naphthyridin-2-one (22.4 g, 0.117 mol, 46%). MS: APCI: M+l: 192.2 (Exact Mass: 191.11). EPO

References:

WO2006/90272,2006,A1 Location in patent:Page/Page column 32