阅读说明：本技术 一种倍他米松磷酸钠的制备分离方法 (Preparation and separation method of betamethasone sodium phosphate ) 是由 赵思太 马新成 王长斌 张宁 张宗磊 邓玉晓 孔祥雨 刘文涛 冯光玲 龚艳艳 樊 于 2021-09-13 设计创作，主要内容包括：本发明涉及一种倍他米松磷酸钠的制备分离方法,具体包括,倍他米松磷酸酯在醇类溶剂中与氢氧化钠成盐,蒸除醇类溶剂,再加入酯类溶剂,打浆析晶分离得到倍他米松磷酸钠。(The invention relates to a preparation and separation method of betamethasone sodium phosphate, which specifically comprises the steps of salifying betamethasone phosphate with sodium hydroxide in an alcohol solvent, evaporating to remove the alcohol solvent, adding an ester solvent, pulping, crystallizing and separating to obtain the betamethasone sodium phosphate.)

1. A preparation and separation method of betamethasone sodium phosphate is characterized in that betamethasone phosphate reacts with sodium hydroxide in an alcohol solvent to form salt, the alcohol solvent is removed by evaporation, an ester solvent is added, and the betamethasone sodium phosphate is obtained by pulping, crystallizing and separating.

2. The preparation and separation method of betamethasone sodium phosphate according to claim 1, characterized in that: the ester solvent used includes ethyl acetate, isopropyl acetate, etc.

3. The preparation and separation method of betamethasone sodium phosphate according to claim 1, characterized in that: the ratio of betamethasone phosphate to the ester solvent used is 1: 3-1: 20.

4. the preparation and separation method of betamethasone sodium phosphate according to claim 1, characterized in that: the temperature for crystallization and pulping by using an ester solvent is 0-50 ℃.

Technical Field

The invention belongs to the technical field of raw material medicine synthesis, and particularly relates to a synthetic process method of betamethasone sodium phosphate.

Background

Betamethasone Sodium Phosphate (Betamethasone Sodium Phosphate), the chemical name of which is 16 beta-methyl-11 beta, 17 alpha, 21-trihydroxy-9 alpha-fluoropregna-1, 4-diene-3, 20-diketone-21-disodium Phosphate, is a water-soluble derivative of glucocorticoid Betamethasone and is a 16-position epimer of dexamethasone Sodium Phosphate. Betamethasone sodium phosphate is a long-acting hormone medicine, is mainly used for anti-inflammatory treatment, immune disease treatment, antivirus and shock treatment in clinic, has wider action, and has the characteristics of small dosage, long half-life period, obvious action and the like compared with other glucocorticoid medicines. In recent years, the global new coronary pneumonia has exploded, and the market demand of global steroid medicines has increased greatly compared with the current year.

The synthesis process of betamethasone sodium phosphate is characterized in that betamethasone phosphate reacts with alkali to obtain betamethasone sodium phosphate, the reaction solvent is mostly alcohol, and the alkali is sodium hydroxide. The post-treatment is generally to evaporate the alcohol solvent, add acetone for pulping and crystallization, and obtain the final product by centrifugal separation. However, the product obtained by crystallization separation from acetone has a fine particle size and high water content, is easy to absorb moisture in the separation process, and is not easy to dry, so that a good method for preparing and separating betamethasone sodium phosphate is urgently needed.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a better betamethasone sodium phosphate preparation and separation method, and the obtained final product has the advantages of good appearance, large particle size, high quality, less impurities, easiness in drying and good stability.

The technical scheme of the invention is as follows:

a preparation and separation method of betamethasone sodium phosphate comprises the steps of reacting betamethasone phosphate with sodium hydroxide in an alcohol solvent to form a salt, evaporating to remove the alcohol solvent, adding an ester solvent, pulping, crystallizing and separating to obtain the betamethasone sodium phosphate.

In the preparation and separation method of betamethasone sodium phosphate, the alcohol solvent can be selected from low-boiling-point solvents such as methanol, ethanol and the like, and preferably methanol; the mass ratio of the betamethasone phosphate to the alcohol solvent is 1: 2-1: 10, preferably 1: 4-1: 6; the molar ratio of the betamethasone phosphate to the sodium hydroxide is 1: 0.95-1: 1.1, preferably 1: 1; the reaction temperature is 0-40 ℃, preferably 10-20 ℃. The ester solvent can be selected from ethyl acetate, isopropyl acetate, etc., preferably ethyl acetate; the mass ratio of the betamethasone phosphate to the ester solvent is 1: 3-1: 20, preferably 1: 5-1: 10; the pulping and crystallization temperature is 0-50 ℃, and preferably 20-30 ℃.

According to the technical scheme, the ester solvent is used for pulping and crystallizing, the properties of betamethasone sodium phosphate are greatly improved, the product quality is improved, the product is easy to dry and good in stability, the solvent is easy to recycle, and the environment-friendly concept is met.

Detailed Description

The present invention will be described in further detail with reference to specific examples, but the scope of the present invention is not limited thereto, and any technique realized based on the above-described contents of the present invention falls within the scope of the present invention.

Example 1

Adding 20g of betamethasone phosphate and 60ml of methanol into a reaction bottle, stirring for dissolving, dripping a sodium hydroxide solution (containing 3.38g of sodium hydroxide) at the temperature of 0-10 ℃, stirring for 10min, adding 0.4g of active carbon, performing suction filtration, performing reduced pressure evaporation on filtrate, adding 100ml of ethyl acetate, stirring and pulping at the temperature of 20-30 ℃, performing suction filtration, leaching ethyl acetate, and performing vacuum drying at the temperature of 60 ℃ to obtain about 21.75g of betamethasone sodium phosphate, wherein the yield is 99.5%, and the HPLC purity is 99.4%.

Example 2

Adding 20g of betamethasone phosphate and 100ml of methanol into a reaction bottle, stirring for dissolving, dripping a sodium hydroxide solution (containing 3.38g of sodium hydroxide) at 0-10 ℃, stirring for 10min, adding 0.4g of activated carbon, performing suction filtration, performing reduced pressure evaporation on filtrate, adding 100ml of isopropyl acetate, stirring and pulping at 20-30 ℃, performing suction filtration, leaching isopropyl acetate, and performing vacuum drying at 60 ℃ to obtain about 21.70g of betamethasone sodium phosphate, wherein the yield is 99.3%, and the HPLC purity is 99.5%.

Example 3

Adding 20g of betamethasone phosphate and 80ml of methanol into a reaction bottle, stirring for dissolving, dripping a sodium hydroxide solution (containing 3.38g of sodium hydroxide) at the temperature of 0-10 ℃, stirring for 10min, adding 0.4g of active carbon, performing suction filtration, performing reduced pressure evaporation on filtrate, adding 200ml of ethyl acetate, stirring and pulping at the temperature of 20-30 ℃, performing suction filtration, leaching ethyl acetate, and performing vacuum drying at the temperature of 60 ℃ to obtain about 21.72g of betamethasone sodium phosphate, wherein the yield is 99.4%, and the HPLC purity is 99.6%.

Example 4

Adding 20g of betamethasone phosphate and 100ml of methanol into a reaction bottle, stirring for dissolving, dripping sodium hydroxide solution (containing 3.38g of sodium hydroxide) at 0-10 ℃, stirring for 10min, adding 0.4g of active carbon, performing suction filtration, performing reduced pressure evaporation on filtrate, adding 400ml of ethyl acetate, stirring and pulping at 20-30 ℃, performing suction filtration, leaching ethyl acetate, and performing vacuum drying at 60 ℃ to obtain about 21.65g of betamethasone sodium phosphate, wherein the yield is 99.0% and the HPLC purity is 99.7%.