Preparation of 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester_Kain Industrial Additive

Background and overview^[1]

4-Hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester can be used as a pharmaceutical synthesis intermediate. Phenol is used as raw material to prepare the intermediate 5-phenoxyisobenzofuran-1(3H)-one, which is further reacted to prepare 2-(chloromethyl)-4-phenoxybenzoic acid methyl ester, and N-p 4-Hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester is prepared by reacting tosylglycine methyl ester.

Preparation^[1]

The preparation of 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester is as follows:

Step one: 5-phenoxyisobenzofuran-1(3H)-one

Add phenol (20.4g, 0.22mol) and DMF 50mL into the reaction flask, start stirring, Add 5-bromoisobenzofuran-1(3H)-one (34.0g, 0.16mmol), acetylacetone (3.2g, 0.03mol), copper bromide (3.6g, 0.03mol), potassium carbonate ( 30.8g, 0.22mol), replace with nitrogen three times, heat to 90°C and stir the reaction overnight. Add 1000mL of purified water to the reaction solution and filter with suction. Dissolve the filter cake with 800mL of methylene chloride. Wash the organic phase with 800mL of 1N hydrochloric acid solution and use purified water. Wash with 1000 mL, dry the organic phase, and concentrate to dryness under reduced pressure to obtain a yellow solid. Add 50 mL of methanol and beat at 0°C for 1 hour. Filter with suction to obtain the title compound 5-phenoxyisobenzofuran-1(3H)-one (22.5 g, 63%).

Second step: 2-(chloromethyl)-4-phenoxybenzoic acid methyl ester

Sequentially add 5-phenoxyisobenzofuran-1(3H )-ketone (1.0g, 4.42mmol), 10mL of xylene, benzyltriethylammonium chloride (300mg, 1.32mmol), and boron trifluoride ether (200mg, 1.41mmol) were added to the reaction bottle and heated to 100°C. Add sulfoxide dichloride (5.0g, 42.03mmol) dropwise. After the dripping is completed, heat to 135°C and react for 5 hours. After thin layer chromatography monitors that the reaction is complete, concentrate the filtrate under reduced pressure. Add 3 mL of methanol to the concentrated solution and stir at 55°C for 1 hour. Afterwards, it was concentrated to dryness under reduced pressure, and the residual liquid was dissolved in ethyl acetate. The organic phase was washed with potassium carbonate solution and sodium chloride solution, and concentrated to dryness to obtain the title compound (1.0g, 83.0%), which was directly used in the next reaction. .

The third step: 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester

Place 2-(chloromethyl)-4-phenoxybenzoic acid methyl ester (0.68g, 2.46mmol), N-p-toluene Sulfonylglycine methyl ester (0.7g, 2.88mmol), potassium carbonate (0.68g, 4.923mmol), potassium iodide (0.16g, 0.96mmol), and DMF were added to the reaction bottle, replaced with nitrogen, heated to 50°C, and reacted for 1 hour. , bring it down to room temperature, add 2 mL of sodium methoxide methanol solution, and stir for 30 minutes. After the reaction is completed by thin layer chromatography, add 40 mL of purified water to the reaction solution, add glacial acetic acid dropwise under stirring to adjust the pH = 7, filter with suction, add 4 mL of acetone to the filter cake, and stir for 2 hours. , suction filtration to obtain the title compound 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (525 mg, 72.5%).

References

[1]CN201810038340.1 Isoquinolinone compounds and their applications