阅读说明：本技术 一种罗沙司他的制备方法 (Preparation method of Rosxastat ) 是由 杨志坤 彭磊 何伟 王珑霖 张燕 于 2020-06-08 设计创作，主要内容包括：一种罗沙司他的制备方法,以4-羟基-7-苯氧基异喹啉-3-甲酸甲酯、四甲基甲烷二胺为原料,于冰醋酸中,至反应完毕,得到1-((二甲氨基)甲基)-4-羟基-7-苯氧异喹啉基-3-羧酸甲酯,得到的1-((二甲氨基)甲基)-4-羟基-7-苯氧异喹啉基-3-羧酸甲酯溶于冰醋酸中,加入锌,再加入稀盐酸,至反应完毕,得到4-羟基-1-甲基-7-苯氧基异喹啉-3-羧酸甲酯；得到的4-羟基-1-甲基-7-苯氧基异喹啉-3-羧酸甲酯与甘氨酸混合,溶于甲醇中,加入甲醇钠,至反应完毕,得到目标产物罗沙司他。本发明反应条件温和、操作简单可控,制备成本较低,适用于大规模工业化生产,得到的目标产物纯度高,满足企业生产要求。(A preparation method of Rosesastat comprises the steps of taking 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate and tetramethylmethanediamine as raw materials, putting the raw materials into glacial acetic acid, obtaining 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester after the reaction is finished, dissolving the obtained 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester into the glacial acetic acid, adding zinc, adding diluted hydrochloric acid, and obtaining 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester after the reaction is finished; and mixing the obtained 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester with glycine, dissolving in methanol, and adding sodium methoxide until the reaction is finished to obtain the target product of the rosixostat. The method has the advantages of mild reaction conditions, simple and controllable operation, low preparation cost, suitability for large-scale industrial production, high purity of the obtained target product and capability of meeting the production requirements of enterprises.)

1. A preparation method of a roxarsone is characterized by comprising the following steps:

1) dissolving 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate and tetramethylmethanediamine as raw materials in glacial acetic acid until the reaction is finished to obtain 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-methyl carboxylate;

2) dissolving the 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester obtained in the step 1) in glacial acetic acid, adding zinc, and then adding hydrochloric acid until the reaction is finished to obtain 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester;

3) mixing the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester obtained in the step 2) with glycine, dissolving in methanol, and adding sodium methoxide until the reaction is finished to obtain the target product of the rosixostat.

2. The process for the preparation of Rosesastat according to claim 1 wherein the molar ratio of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate, tetramethylmethanediamine in step 1) is 1: 1-1.5.

3. The process for the preparation of Rosesastat according to claim 1 or 2 characterized in that the molar ratio of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate, tetramethylmethanediamine in step 1) is 1: 1.2.

4. process for the preparation of rasagiline according to claim 1 characterized in that the temperature of the reaction of step 1) is 55-60 ℃.

5. The process for the preparation of Rosesastat according to claim 1 wherein the molar ratio of the solutes of methyl 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolinyl-3-carboxylate, zinc, hydrochloric acid in step 2) is 1: 2-5: 0.1-0.2.

6. The process for the preparation of Rosesastat according to claim 1 or 5, wherein the molar ratio of the solute of 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolinyl-3-carboxylic acid methyl ester, zinc, hydrochloric acid in step 2) is 1: 2.5: 0.15.

7. the process for the preparation of rasagiline according to claim 1 wherein after the reaction in step 2) is completed, filtration is carried out to remove zinc, a mixture of dichloromethane and water is added, layers are separated by shaking, the organic phase is taken, the aqueous phase is extracted with dichloromethane, combined with the organic phase and the organic phase is evaporated to dryness to obtain methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate.

8. The preparation method of the rasagiline of claim 1, wherein after the reaction in step 3), the temperature is reduced, the filtering is performed, the filter cake is dried and then placed into a mixed solution of water and ethyl acetate to be stirred, the layering is performed, the water phase is taken, glacial acetic acid is dripped, the temperature is reduced, the crystallization is performed, the filtering is performed, and the filter cake is refined by acetone to obtain the target product of the rasagiline.

9. Process for the preparation of rasagiline according to claim 1 characterized in that the zinc is in powder and/or granular and/or flake form.

Technical Field

The invention relates to the field of medicines, and in particular relates to a preparation method of a roxarsone.

Background

The roxasistat is a novel Hypoxia Inducible Factor (HIF) -Prolyl Hydroxylase (PH) enzyme inhibitor, and can inhibit the degradation of HIF, activate the transcription of related genes, generate corresponding physiological response, moderately increase the concentration of erythropoietin, improve the sensitivity of an Erythropoietin (EPO) receptor, coordinate the generation of red blood cells, reduce the level of hepcidin, increase the content and activity of a transferrin receptor, promote the absorption and utilization of iron and have good tolerance. The chemical structural formula of the roxasistat is shown as the following formula:

the invention patent WO2014/14834 discloses a synthesis method of the compound, and the reaction process is shown as the following route:

in the route, the reaction time for preparing A2 from A1 is long, about 30 hours is needed, the conversion rate is low, about 60-70 percent, and the production requirements of enterprises cannot be effectively met. A3 is prepared by palladium-carbon hydrogenation reduction and has certain operation difficulty and risk.

Disclosure of Invention

The invention aims to provide a preparation method of the roxasistat, aiming at the defects of the prior art, the preparation method is mild in reaction conditions, simple and controllable in operation, low in preparation cost, suitable for large-scale industrial production, high in purity of the obtained target product and capable of meeting the production requirements of enterprises.

The technical scheme of the invention is as follows: a preparation method of the roxburgh comprises the following steps:

1) dissolving 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate and tetramethylmethanediamine as raw materials in glacial acetic acid until the reaction is finished to obtain 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-methyl carboxylate;

2) dissolving the 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester obtained in the step 1) in glacial acetic acid, adding zinc, and then adding hydrochloric acid until the reaction is finished to obtain 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester;

3) mixing the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester obtained in the step 2) with glycine, dissolving in methanol, and adding sodium methoxide until the reaction is finished to obtain the target product of the rosixostat.

The synthetic route of the invention is as follows:

further, the mol ratio of the 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate to the tetramethylmethanediamine in the step 1) is 1: 1-1.5.

Preferably, the molar ratio of 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester to tetramethylmethanediamine in step 1) is 1: 1.2.

further, the temperature of the reaction in the step 1) is 55-60 ℃.

Further, in the step 2), the molar ratio of the solute of the methyl 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylate, zinc and hydrochloric acid is 1: 2-5: 0.1-0.2.

Preferably, the molar ratio of the solute of 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester, zinc and hydrochloric acid in the step 2) is 1: 2.5: 0.15.

further, after the reaction in the step 2) is finished, filtering, removing zinc, adding a mixture of dichloromethane and water, oscillating and layering, taking an organic phase, extracting a water phase with dichloromethane, combining with the organic phase, and evaporating the organic phase to obtain the 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester.

Further, after the reaction in the step 3) is finished, cooling, filtering, drying a filter cake, then putting the filter cake into a mixed solution of water and ethyl acetate, stirring, layering, taking a water phase, dropwise adding glacial acetic acid, cooling, crystallizing, filtering, and refining the filter cake with acetone to obtain the target product of the rosixostat.

Further, the zinc is in a powder shape and/or a granular shape and/or a flake shape.

Adopt above-mentioned technical scheme to have following beneficial effect:

1. the invention utilizes 1- ((dimethylamino) methyl) -4-hydroxy-7-phenoxyisoquinolyl-3-carboxylic acid methyl ester to react (reduce) with zinc in glacial acetic acid, and hydrochloric acid is added to provide hydrogen ions and enhance the reducibility of zinc, thereby playing a role in catalyzing reaction. The 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-methyl carboxylate obtained by synthesis has the advantages of quick reaction, short reaction time, reaction completion only within about 6 hours, single solvent used in the synthesis process, glacial acetic acid only, and reduced use amount of auxiliary materials, thereby effectively reducing production and management costs of enterprises, avoiding operation risks caused by hydrogenation reaction of palladium and carbon in the traditional synthesis method, reducing reaction procedures, and effectively reducing material cost and production period.

2. After the intermediate of the formula 3 is synthesized, water and dichloromethane are used for extraction treatment, metal salt inorganic impurities in the intermediate of the formula 3 can be efficiently removed, the purity of the intermediate of the formula 3 is improved, the subsequent synthesis of the target product is facilitated, and the yield of the target product is improved.

3. The reaction time for preparing the formula 3 from the formula 2 is only about 6 hours, so that the synthesis efficiency is greatly improved compared with the traditional synthesis route; the yield of the prepared roxasistat is 85-90%, the utilization rate of raw materials is high, the purity of the roxasistat is more than 95%, and the production requirements of enterprises are met.

The following description will be further described with reference to specific embodiments.

Drawings

FIG. 1 is a liquid chromatogram of the objective product of example 5;

FIG. 2 is a nuclear magnetic diagram of the target product of example 5;

FIG. 3 is a mass spectrum of the target product of example 5.

Detailed Description

In the invention, the used 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate is purchased from Moxi pharmaceutical technology company of Tianjin method, and the purity is more than or equal to 99.0 percent; tetramethylmethanediamine, available from Molekay pharmaceutical science and technology, Inc., Changzhou, with a purity of greater than or equal to 98.0%; glycine, a western reagent, more than or equal to 98.0 percent, and sodium methoxide, wherein the content is 5 mol/L.