阅读说明：本技术 羟苯磺酸酯类化合物的合成工艺 (Synthetic process of hydroxybenzene sulfonate compound ) 是由 王建 邓斐 冷志 于 2019-12-25 设计创作，主要内容包括：本发明公开了一种羟苯磺酸酯类化合物及合成工艺,其特征在于,以羟苯磺酸为原料,分别与甲醇、无水乙醇、异丙醇等脂肪醇类发生酯化,经浓缩、萃取、柱层析分离得到羟苯磺酸酯类化合物；本发明合成路线、目标化合物结构目前无文献报道,是一种突破性发明,作为一个基因毒性杂质,可以制备成对照品,用于羟苯磺酸钙质量标准研究,提高产品质量。(The invention discloses a hydroxybenzene sulfonate compound and a synthesis process, which are characterized in that hydroxybenzene sulfonic acid is taken as a raw material, and is respectively esterified with fatty alcohols such as methanol, absolute ethyl alcohol, isopropanol and the like, and the hydroxybenzene sulfonate compound is obtained by concentration, extraction and column chromatography separation; the synthetic route and the target compound structure of the invention are not reported in documents at present, and the invention is a breakthrough invention, and can be used as a genotoxic impurity to prepare a reference substance for the quality standard research of calcium dobesilate and improve the product quality.)

1. A synthesis process of a hydroxybenzene sulfonate compound is characterized in that hydroxybenzene sulfonic acid is taken as a raw material and is respectively esterified with methanol, absolute ethyl alcohol and isopropanol to obtain the hydroxybenzene sulfonate compound;

wherein R represents alkyl or aryl, including methyl, ethyl, isopropyl; the catalyst comprises sulfuric acid or sulfonic acid substances.

2. The process for synthesizing the dobesilate compound according to claim 1, characterized by comprising the following steps in sequence:

① reaction, namely putting alcohol, hydroxybenzene sulfonic acid (I) and a catalyst into a reaction bottle, wherein the reaction temperature is 20-200 ℃, and the reaction time is 2-40 hours;

② post-treatment, namely, after the reaction is finished, decompressing and concentrating to remove excessive alcohol solvent, adding conventional organic solvent for extraction, washing and concentrating to obtain crude product of the hydroxybenzene sulfonate compound, and performing column chromatography separation by using developing solvent to obtain refined product of the hydroxybenzene sulfonate compound with higher purity.

3. The process for synthesizing the hydroxybenzene sulfonate compound according to claim 1,

the mass ratio of the I to the alcohol solvent is 1: 1-50;

the molar ratio of the I to the catalyst is 1: 0.001-0.2.

4. The process of claim 1, wherein the organic solvent used for extraction comprises one or a mixture of cyclohexane, toluene, xylene, dichloromethane, chloroform, ethyl acetate, and butyl acetate.

5. The process for synthesizing the hydroxybenzene sulfonate compound according to claim 1, wherein the developing solvent used for column chromatography separation is a conventional organic solvent, and comprises one or a mixture of any two of petroleum ether, n-hexane, n-heptane, cyclohexane, toluene, dichloromethane, chloroform, ethyl acetate, methanol, ethanol, etc.

6. The use of the dobesilate compounds prepared by the synthesis process of dobesilate compounds as claimed in claim 1 in the preparation of compounds or medicaments.

7. The hydroxybenzene sulfonate compound prepared by the synthesis process of the hydroxybenzene sulfonate compound according to claim 1 is used for the quality research and the quality standard formulation of calcium hydroxybenzene sulfonate.

Technical Field

The invention relates to a method for synthesizing an impurity-calcium dobesilate compound possibly generated in the production process of a drug for treating microangiopathy, belonging to the technical field of drug synthesis.

Background

The chemical name of the calcium dobesilate is 2, 5-dihydroxy benzene sulfonate, the calcium dobesilate is firstly marketed in 1971 by France Carroin company, and the calcium dobesilate is clinically used as a microvascular circulation improving agent, can reduce capillary high permeability, blood high viscosity and platelet high activity, so as to reduce retinal exudation and hemorrhage, reduce microangioma and the like, is mainly used for preventing and treating various diseases caused by microvascular circulation disorder, particularly is widely applied to diabetic nephropathy, and indicates that the calcium dobesilate has good application prospect. The european pharmacopoeia was loaded in 1997, the british pharmacopoeia was loaded in 1998, and the drug was marketed in 6 months in 2001.

The inspection of related substances is specified in the two calcium p-dobesilate bulk drugs in the Chinese pharmacopoeia 2015 edition, and the amount of hydroquinone (raw material residue) which is known as an impurity is specified to be not more than 1 per thousand; the unknown impurities are not more than 1 per mill of single impurities and not more than 2 per mill of total impurities compared with the raw materials.

Disclosure of Invention

The invention aims to provide a synthesis process of an impurity-calcium dobesilate compound possibly generated in the production process of a microangiopathy treatment drug calcium dobesilate; the compound of the class of the hydroxybenzene sulfonate is used for the quality research and the quality standard establishment of calcium hydroxybenzene sulfonate.

The technical idea of the invention is as follows: p-hydroxybenzene sulfonic acid is used as a raw material, and is respectively esterified with alcohol solvents such as methanol, absolute ethyl alcohol, isopropanol and the like, and the hydroxybenzene sulfonate compound is obtained through concentration, extraction and column chromatography separation.

The molecular structural formula of the target compound is as follows:

；

wherein R represents an alkyl group or an aryl group such as methyl, ethyl, isopropyl, etc.; the catalyst is sulfuric acid or sulfonic acid.

The invention is realized by adopting the following technical scheme:

a process for synthesizing the dobesilate compound as impurity possibly generated in the production process of calcium dobesilate used as medicine for treating microangiopathy sequentially comprises the following steps:

① reaction, namely putting alcohol, hydroxybenzene sulfonic acid (I) and a catalyst into a reaction bottle, and carrying out heat preservation reaction at a certain temperature;

② post-treatment, namely, after the reaction is finished, decompressing and concentrating to remove excessive alcohol solvent, adding conventional organic solvent for extraction, washing and concentrating to obtain crude product of the hydroxybenzene sulfonate compound, and performing column chromatography separation by using developing solvent according to a certain proportion to obtain refined product (II) of the hydroxybenzene sulfonate compound with higher purity.

。

Further, the mass ratio of the I to the alcohol solvent is 1: 1-50;

further, the alcohol solvent is alkane or aromatic hydrocarbon alcohol and the like;

further, the molar ratio of the I to the catalyst is 1: 0.001-0.2;

further, the catalyst is sulfuric acid or sulfonic acid, etc.;

further, the reaction temperature is 20-200 ℃;

the reaction time is kept at 2-40 hours;

further, one or a mixture of any two of conventional organic solvents such as cyclohexane, toluene, xylene, dichloromethane, chloroform, ethyl acetate, butyl acetate and the like is used for extraction;

the developing agent used for column layer separation is one or a mixture of any two of conventional organic solvents such as petroleum ether, n-hexane, n-heptane, cyclohexane, toluene, dichloromethane, chloroform, ethyl acetate, methanol, ethanol and the like.

The dobesilate compound is a novel compound, can be used for quality research and quality standard establishment of calcium dobesilate, and a synthetic route related to the invention is a breakthrough invention without literature reports at present.

Drawings

FIG. 1 is a H-NMR spectrum of methyl hydroxybenzoate sulfonate;

FIG. 2 is a H-NMR spectrum of ethyl hydroxybenzoate;

FIG. 3 is a H-NMR spectrum of isopropyl dobesilate.

Detailed Description

The technical solution of the present invention will be described in detail with reference to the following embodiments.