6-Hydroxy-7-methyl-1(2H)-isoquinolinone synthesis

Yield:940890-82-4 55%

Reaction Conditions:

Stage #1: 6-Methoxy-7-methyl-2H-isoquinolin-1-onewith boron tribromide in dichloromethane at 0 - 20; for 24 h;
Stage #2: with ammonia;water in dichloromethane at 0; pH=9;

Steps:

26.2A

26A: 6-Hydroxy-7-methyl-2H-isoquinolin-1-one A mixture of 3-methoxy-4-methylbenzaldehyde (19.3 g, 0.129 mol), carbomethoxy methylene triphenylphosphorane (51 g) in toluene (250 ml) was refluxed for 24 h. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate and concentrated in vacuo to give a residue. The residue was purified by flash chromatography using ethyl acetate-heptane (1:1) to give 3-(3-methoxy4-methyl-phenyl)acrylic acid methyl ester (27 g, 0.126 mol). A mixture of 3-(3-methoxy4-methyl-phenyl)acrylic acid methyl ester (27 g), sodium hydroxide (14 g), water (70 ml), methanol (140 ml) and tetrahydrofuran (70 ml) was refluxed at 50° C. for 1 h. The mixture was concentrated in vacuo and then water added. The mixture was filtered and 5 M HCl was added until precipitation occurred. The mixture was filtered and the solid precipitate washed with water and dried in-vacuo to give 3-(3-methoxy-4-methylphenyl)acrylic acid (23.5 g, 0.122 mol). Toluene (750 ml) and thionyl chloride (11 ml) were subsequently added to 3-(3-methoxy-4-methylphenyl)acrylic acid (20 g, 0.104 mol) at room temperature. The suspension was refluxed for 2 h while vigorously stirring to give a clear slightly yellow solution. The reaction mixture was concentrated in vacuo, then toluene added and the mixture re-concentrated in vacuo to give 3-(3-methoxy-4-methylphenyl)acryloyl chloride for use in the next step. The 3-(3-methoxy-4-methylphenyl)acryloyl chloride was dissolved in acetone (800 ml). The resulting solution was added slowly (15 min) at 0° C. to a mixture of sodium azide (13 g) in water (100 ml) and acetone (100 ml) while vigorously stirring and cooling with an ice-bath. After addition was complete the reaction mixture was stirred at 0° C. for 90 minutes while vigorously stirring. The reaction mixture was then poured out on ice-water (300ml). After stirring for 15 minutes the mixture was filtered and the solid residue washed with excess water. The remaining solid residue was dissolved in dichloromethane (45 ml). The liberated water was removed with a separatory funnel. The dichloromethane layer was dried with Na₂SO₄ and filtered to give a dichloromethane solution of 3-(3-methoxy-4-methylphenyl)acryloyl azide for immediate use in the next step. The dichloromethane azide solution was added in portions (Carefully .) using a dropping funnel to preheated diphenyl ether (50 ml) at 150° C., while gently stirring, in a three-necked roundbottomed flask, equiped with a Dean-Stark trap. During the addition nitrogen gas evolution takes place under formation of the isocyanate. The added dichloromethane is evaporated and collected with the Dean-Stark trap. After the addition was complete (30 min) and no gas evolution observed, the mixture was heated to reflux (250° C.) while stirring (At 200° C. no more dichloromethane is evaporated and the Dean-Stark trap is removed quickly). The reaction mixture is kept at 250° C. for 1 h then cooled to 125° C. and poured out in a mixture of acetone and heptane (1:10). A solid precipitated and this was filtered and dried in vacuo to give 6-methoxy-7-methyl-2H-isoquinolin-1-one (12 g, 63.49 mmol). A 1 M solution of boron tribromide (2.9 ml, 2.91 mmol) was added dropwise to a stirred suspension of 6-methoxy-7-methyl-2H-isoquinolin-1-one (100 mg, 0.53 mmol) in 1 ml of dichloromethane at 0-4° C. (ice bath). After stirring for 1 day at ambient temperature the reaction mixture was poured into ice and the pH was adjusted to 9 by adding concentrated aqueous ammonia. The precipitated material was collected by filtration, washed with water, and dried in vacuo to give 6-Hydroxy-7-methyl-2H-isoquinolin-1-one (51 mg, 55%), El-MS: 176.6 [M+H]⁺

References:

US2007/135479,2007,A1 Location in patent:Page/Page column 14