阅读说明：本技术 一种依托咪酯的制备方法 (Etomidate preparation method ) 是由 黄岭 朱墨 吴俊� 于 2020-05-25 设计创作，主要内容包括：本发明属于生物医药技术领域,具体涉及一种依托咪酯的制备方法,该方法为：取依托咪酯粗品,加去离子水,搅拌,加入氨基酸,继续搅拌,加入有机溶剂,冷却至0-10℃后,加热至70-75℃,静置,过滤,有机溶剂层回收有机溶剂至尽,干燥,得到依托咪酯精品原料；所述氨基酸为天冬氨酸,所述有机溶剂为四氯化碳和2-丙醇。本发明提供的依托咪酯的提纯方法,提纯得到的依托咪酯的纯度达到99.8％,可用于进一步制备注射制剂。(The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method of etomidate, which comprises the following steps: adding deionized water into the etomidate crude product, stirring, adding amino acid, continuing stirring, adding an organic solvent, cooling to 0-10 ℃, heating to 70-75 ℃, standing, filtering, recovering the organic solvent from the organic solvent layer to the maximum, and drying to obtain etomidate fine raw material; the amino acid is aspartic acid, and the organic solvent is carbon tetrachloride and 2-propanol. According to the method for purifying etomidate provided by the invention, the purity of etomidate obtained by purification reaches 99.8%, and the etomidate can be further used for preparing injection preparations.)

1. The method for purifying etomidate is characterized by comprising the following steps of:

adding deionized water into the etomidate crude product, stirring, adding amino acid, continuing stirring, adding an organic solvent, cooling to 0-10 ℃, heating to 70-75 ℃, standing, filtering, recovering the organic solvent from the organic solvent layer to the maximum, and drying to obtain etomidate fine raw material; the amino acid is aspartic acid, and the organic solvent is carbon tetrachloride and 2-propanol.

2. The method for purifying etomidate according to claim 1, wherein the mass ratio of carbon tetrachloride to 2-propanol is 1: 3-5.

3. The method for purifying etomidate as claimed in claim 1, wherein the mass ratio of the crude etomidate to the amino acid is 100: 4-6.

4. The method for purifying etomidate as claimed in claim 1, wherein the mass ratio of the crude etomidate to the organic solvent is 1: 2-3.

5. The method for purifying etomidate as claimed in claim 1, wherein the mass ratio of the crude etomidate to the deionized water is 1: 3.3.

6. The method for purifying etomidate according to claim 2, wherein the mass ratio of carbon tetrachloride to 2-propanol is 1: 4.

7. The method for purifying etomidate as claimed in claim 3, wherein the mass ratio of the crude etomidate to the amino acid is 1000: 5.

8. The method for purifying etomidate as claimed in claim 4, wherein the mass ratio of the crude etomidate to the organic solvent is 1: 2.5.

Technical Field

The invention relates to the technical field of biological medicines, and particularly relates to a preparation method of etomidate.

Background

Etomidate is an ultra-short-acting non-barbiturate intravenous general anesthetic, also known as mebendazole, pyrimidinecarbol and etomidate, belongs to imidazole derivatives, is white crystalline powder in appearance, and has similar effect on the central nervous system to barbiturates. Has strong hypnotic effect which is about 12 times of the efficacy of thiopentone sodium, and has no analgesic effect. The anesthetic has quick response, can be generated 20 seconds after intravenous injection, can be maintained for about 5 minutes, can be recovered quickly, and has correspondingly prolonged action duration of increasing the dosage. Compared with thiopentone sodium, the anesthetic strength is higher, and the influence on the respiration and the circulatory system is smaller. Is suitable for inducing anesthesia. During intravenous anesthesia, coronary blood flow can be increased by 19%, and resistance is reduced by 19%. Its outstanding advantages are no negative influence on cardiovascular system, low toxicity, less influence on respiration and circulation system, short-term respiratory inhibition, slightly decreased systolic pressure and slightly increased heart rate, and less influence and no histamine release. Can affect liver and kidney function, reduce oxygen consumption of brain, and reduce cerebral blood flow and intracranial pressure. The clinical dosage is generally 0.1-0.4 mg/kg, and the natural recovery is realized after 7-14 minutes. The distribution half-life was 2.8 minutes and the elimination half-life was 160 minutes. Hydrolyzed in the liver and plasma, and most of the metabolites are excreted by the kidneys. Etomidate has the major disadvantage of inhibiting adrenocortical function, especially after prolonged administration.

Etomidate has two main formulations in clinical application: (1) water aqua: etomidate is dissolved in 35% 2-propanol to prepare injection; (2) fat emulsion: braun import china, "yiduli" for example. Etomidate is dissolved in 20% medium-long chain triglyceride to prepare injection, and the two preparations have different osmotic concentrations, wherein the osmotic concentration of the aqueous preparation is 4640mOsm/L which is far higher than the physiological osmotic concentration, and compared with the aqueous preparation, the fat emulsion can obviously reduce the side effects of injection pain, vascular injury and the like. Etomidate is easily hydrolyzed to produce etomidate as an impurity. The content of etomidate is higher according to the 'Yiduli' import registration standard, the limit is less than 2 percent when the content is measured by an impurity external standard method, the preparation is stored at the temperature of below 25 ℃, the freezing is avoided, and the effective period is 2 years.

Etomidate was successfully developed in 1979 in China and obtained by first synthesizing a racemate and splitting the racemate (Shanghai pharmaceutical industry research institute, trial study of the hypnotic and sedative anesthetic, mebendazole, pharmaceutical industry, 1979,4: 18). However, etomidate prepared by the existing synthetic method has low purity and poor stability, is easy to generate impurities, and cannot meet the requirements of etomidate in actual medical use.

Disclosure of Invention

In order to solve the technical problems, the invention discloses a preparation method of etomidate, which takes a crude etomidate product as a raw material, further purifies the raw material to obtain a refined etomidate product, and the etomidate obtained by purification has high purity and good stability and can be used as a raw material of an injection preparation.

The invention adopts the following technical scheme:

a method for purifying etomidate comprises the following steps:

adding deionized water into the etomidate crude product, stirring, adding amino acid, continuing stirring, adding an organic solvent, cooling to 0-10 ℃, heating to 70-75 ℃, standing, filtering, recovering the organic solvent from the organic solvent layer to the maximum, and drying to obtain etomidate fine raw material;

the amino acid is aspartic acid, and the organic solvent is carbon tetrachloride and 2-propanol.

The mass ratio of the carbon tetrachloride to the 2-propanol is 1: 3-5.

The mass ratio of the etomidate crude product to the amino acid is 100: 4-6.

The mass ratio of the etomidate crude product to the organic solvent is 1: 2-3.

The mass ratio of the etomidate crude product to the deionized water is 1: 3.3.

Preferably, the mass ratio of the carbon tetrachloride to the 2-propanol is 1: 4.

Preferably, the mass ratio of the crude etomidate to the amino acid is 100: 5.

Preferably, the mass ratio of the crude etomidate to the organic solvent is 1: 2.5.

The crude etomidate product is purchased from Longyunyuan Yao (Beijing) scientific and technology Limited company, the purchase date is 2019, 10 months and 11 days, and the content of the etomidate in the crude product is 89.4%.

The aspartic acid is also called aspartic acid, is alpha-amino acid, is purchased from Longyu Yao (Beijing) science and technology Limited company, and is purchased from 2019, 10 months and 11 days.

The organic solvent of the invention: carbon tetrachloride and 2-propanol are purchased from Longyu Yao (Beijing) science and technology Limited and are purchased for 10 months and 11 days in 2019.

The invention has the beneficial effects that:

1. the process is suitable for industrial production, and although the process steps are not complex, the process is discovered by scientific researchers through multiple creative researches for many years.

2. According to the method for purifying etomidate provided by the invention, the purity of etomidate obtained by purification reaches 99.8%, and the etomidate can be further used for preparing injection preparations. The invention unexpectedly discovers that the purity of the etomidate obtained by purification is high, the impurities are less and the stability of the prepared etomidate is good by adopting aspartic acid and selecting carbon tetrachloride and 2-propanol in a certain proportion as organic solvents.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. The experimental methods in the following examples, which are not specified under specific conditions, were generally conducted under conventional conditions. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The crude etomidate adopted in the embodiment is a commercial product, and the purity is 89.4%.