阅读说明：本技术 一种5α-雄甾-2-烯-17酮的制备方法 (Preparation method of 5 alpha-androst-2-ene-17 ketone ) 是由 聂光辉 蔡中文 杜林森 宋小莉 于 2021-09-13 设计创作，主要内容包括：本发明公开一种骨骼肌松弛药药物中间体5α-雄甾-2-烯-17酮的制备方法,属于合成技术领域。本发明方法以表雄酮作为原料,在催化剂的作用下与对十二烷基苯磺酰氯反应生成磺酸酯,然后消去生成5α-雄甾-2-烯-17酮。本发明的合成方法可以有效降低目标产物5α-雄甾-2-烯-17酮的双键位置异构体5α-雄甾-3-烯-17酮,极大的提高了产品质量,同时降低了生产成本。(The invention discloses a preparation method of a skeletal muscle relaxant drug intermediate 5 alpha-androst-2-ene-17 ketone, belonging to the technical field of synthesis. The method takes epiandrosterone as a raw material, reacts with p-dodecylbenzene sulfonyl chloride under the action of a catalyst to generate sulfonic ester, and then eliminates to generate 5 alpha-androstane-2-alkene-17 ketone. The synthesis method can effectively reduce the double bond position isomer 5 alpha-androst-3-ene-17 ketone of the target product 5 alpha-androst-2-ene-17 ketone, greatly improve the product quality and reduce the production cost.)

1. A process for the preparation of 5 α -androst-2-ene-17-one of formula I, the reaction equation is as follows:

2. the process for the preparation of formula I according to claim 1, in particular as follows:

a) adding epiandrosterone formula IV, p-dodecylbenzene sulfonyl chloride formula III and a catalyst into an organic solvent I, starting stirring, and heating for reaction;

b) after the reaction is finished, concentrating the solvent to obtain a crude product solid of the p-dodecyl benzene sulfonate formula II;

c) after the solid II is dissolved, cooling, crystallizing, filtering and drying to obtain a refined product shown in the formula II;

d) adding the refined product of the formula II into an organic solvent II, starting stirring, and heating for reaction;

e) after the reaction is finished, concentrating the solvent, adding drinking water and dilute sulfuric acid for crystallization, and filtering to obtain a 5 alpha-androst-2-ene-17 ketone formula I crude product;

f) adding the 5 alpha-androstane-2-alkene-17 ketone crude product into an aqueous ethanol solvent for recrystallization, and finally filtering and drying to obtain a finished product shown in the formula I.

3. The method of claim 2, wherein: the organic solvent I comprises toluene and dichloromethane.

4. The method of claim 2, wherein: the catalyst is selected from Dimethylaminopyridine (DMAP) and Dicyclohexylcarbodiimide (DCC).

5. The method of claim 2, wherein: the organic solvent II is 2-methylpyridine or 2, 6-dimethylpyridine.

Technical Field

The invention belongs to the technical field of medicine and chemical engineering, and particularly relates to a preparation method of a key intermediate 5 alpha-androstane-2-ene-17 ketone of a skeletal muscle relaxant bromide medicine.

Background

The invention relates to a key intermediate formula of a skeletal muscle relaxant, namely bromide ammonium, wherein the chemical name of the key intermediate formula is 5 alpha-androst-2-ene-17 ketone, the CAS number is 963-75-7, and the formula I is as follows:

the compound of the formula I is a key intermediate of skeletal muscle relaxation ammonium bromide medicines such as rocuronium bromide, vecuronium bromide and the like, and is usually obtained by esterifying and eliminating epiandrosterone.

Foreign literature reports that the synthesis method of the compound shown in the formula I mainly comprises the following steps that firstly, androsterone is used as an initial raw material to react at high temperature under the severe condition of boric acid and acetic anhydride to obtain a product, but the method has high operation difficulty, a plurality of impurities in the finished product and lower yield (Helv Chim Acta,1945,28: 618-627); in the second method, epiandrosterone is used as a starting material to react with p-toluenesulfonyl chloride to obtain a 3-hydroxyl p-toluenesulfonylated product of the epiandrosterone, and then the product is eliminated at high temperature to obtain a target product, the route is easy to realize, but the finally obtained product carries more impurities, namely 5 alpha-androst-3-ene-17-one (generally about 20 percent), and the isomer is difficult to separate and has great influence on the subsequent quality control (Chem Pham Bull,1966,14: 174-186); the method comprises the steps of putting the tri-5 alpha-androstane-3, 17-diketone in tetrahydrofuran as a solvent, and reacting with trimethylchlorosilane under the catalysis of zinc powder and the like to finally obtain a target product, wherein raw materials are difficult to react completely, and a final finished product needs to be separated and purified by a column chromatography method, so that the method is not suitable for large-scale production and is difficult to industrially apply (JCS Perkin Transactions 1,1975,809).

Disclosure of Invention

The invention provides a preparation method of a formula I.

The preparation method of the compound of the formula I comprises the following steps:

a) adding a compound shown in formula IV, a compound shown in formula III and a catalyst into an organic solvent I, starting stirring, and heating;

b) after the reaction is finished, concentrating the solvent to obtain a crude product solid of the compound shown in the formula II;

c) after the crude compound solid of the formula II is dissolved, cooling, crystallizing, filtering and drying to obtain a refined compound of the formula II;

d) adding a refined compound of the formula II into an organic solvent II, starting stirring, and heating for reaction;

e) after the reaction is finished, concentrating the solvent, adding drinking water and dilute sulfuric acid for crystallization, and filtering to obtain a crude product of the compound shown in the formula I;

f) and adding the crude product of the compound shown in the formula I into a hydrous ethanol solvent for recrystallization, and finally filtering and drying to obtain a finished product.

In the preparation method, the organic solvent I III comprises toluene and dichloromethane.

In the above preparation method, the catalyst comprises Dimethylaminopyridine (DMAP) and Dicyclohexylcarbodiimide (DCC).

In the preparation method, the organic solvent II comprises 2-methylpyridine and 2, 6-dimethylpyridine.

The starting material, epiandrosterone formula IV, was synthesized by Chem Pham Bull,1966,14: 174-186.

Detailed Description

The technical solutions of the present invention are further described below with specific examples, which may enable those skilled in the art to better understand the present invention, but the scope of the present invention is not limited thereto.

EXAMPLE 1 preparation of p-dodecylbenzenesulfonate formula II

Adding 500g of dichloromethane and 74g of triethylamine into a reaction bottle in sequence, starting stirring, adding 100g of epiandrosterone, and slowly adding 15g of DMAP; cooling to 0-5 ℃, slowly adding the p-dodecyl benzene sulfonyl chloride, wherein the feeding time is 1.5-2 hours, the feeding is slow and fast, and the temperature is controlled to be 0-25 ℃ during feeding. After the feeding is finished, the reaction is carried out for 9 hours at the internal temperature of 34-35 ℃ controlled by a hot water bath; detecting whether the reaction is complete by TLC; after the reaction is completed, the internal temperature is controlled to be 40 +/-2 ℃ to concentrate the dichloromethane, and the stirring is stopped when the dichloromethane is concentrated to be quick-drying.

Adding 350g of prepared 50% ethanol, soaking for 30 minutes, then starting stirring, and stirring for 5 hours. After the stirring time is over, the temperature of the materials is reduced to 0-5 ℃, the materials are crystallized for 30 minutes under the condition of heat preservation, and then the materials are filtered. Washing the filter cake with drinking water until the washing water is colorless (the pH of the washing water is neutral), then washing the filter cake with a small amount of cold 50% ethanol, and finally drying under reduced pressure to obtain the refined p-dodecyl benzene sulfonate product with the yield of 95 percent, wherein the refined p-dodecyl benzene sulfonate product is not less than 98 percent (an area normalization method).

EXAMPLE 2 preparation of p-dodecylbenzenesulfonate formula II

Adding 500g of toluene and 74g of triethylamine into a reaction bottle in sequence, starting stirring, adding 100g of epiandrosterone, and slowly adding 18g of DCC; cooling to 0-5 ℃, slowly adding p-dodecyl benzene sulfonyl chloride, wherein the feeding time is 1.5-2 hours, the feeding is slow and fast, and the temperature is controlled to be 0-25 ℃ during feeding; after the feeding is finished, the reaction is carried out for 9 hours at the internal temperature of 34-35 ℃ controlled by a hot water bath; TLC check whether the reaction is complete. After the reaction is finished, concentrating toluene at the internal temperature of 40 +/-2 ℃; and stopping stirring when the mixture is concentrated to be quick-dried.

Adding 350g of prepared 50% ethanol, soaking for 30 minutes, then starting stirring, and stirring for 5 hours. After the stirring time is over, the temperature of the materials is reduced to 0-5 ℃, the materials are crystallized for 30 minutes under the condition of heat preservation, and then the materials are filtered. Washing the filter cake with drinking water until the washing water is colorless (the pH of the washing water is neutral), then washing the filter cake with a small amount of cold 50% ethanol, and finally drying under reduced pressure to obtain the p-dodecyl benzene sulfonate type II refined product with the yield of 97 percent (an area normalization method) or more.

EXAMPLE 35 preparation of alpha-androst-2-ene-17-one

150g of 2-methylpyridine were added successively to the reaction flask, followed by the addition of the top product of formula II obtained in example 1. Starting temperature-rising reaction, and starting timing reaction when the internal temperature reaches 110-130 ℃. The reaction is carried out for 5.5 hours, the reflux is ensured in the reaction process, and the internal temperature is kept between 110 and 130 ℃. After the reaction is finished, decompression and concentration are started under the condition of ensuring that the materials are not flushed. Until the materials in the bottle are viscous and the concentration is finished. Sequentially adding 200g of drinking water, and then adding dilute sulfuric acid to adjust to be neutral, wherein the specific dosage is determined according to the actual pH value; after the pH value is measured again after 15 minutes and is qualified, the mixture is stirred for 2 hours under the condition of heat preservation, then the temperature is reduced to 0-25 ℃, the mixture is crystallized under the condition of heat preservation for 1 hour, and the crude product of the 5 alpha-androstane-2-alkene-17 ketone is obtained after filtration.

Adding the obtained 5 alpha-androstane-2-ene-17-ketone wet product into a three-mouth reaction bottle filled with 300g of 95% ethanol, starting stirring and heating, heating to 76-80 ℃ (refluxing), and continuously stirring for 5 minutes to ensure complete dissolution; cooling to-2-10 deg.c, maintaining the temperature and stirring for crystallization for 4 hr; then filtering to obtain a refined product of the 5 alpha-androst-2-ene-17 ketone, and finally drying under reduced pressure to obtain a finished product of the 5 alpha-androst-2-ene-17 ketone with the yield of 90 percent and the isomer 5 alpha-androst-3-ene-17 ketone of more than or equal to 90 percent (an area normalization method).

EXAMPLE 45 preparation of alpha-androst-2-ene-17-one

150g of 2, 6-lutidine was added to the reaction flask in sequence, followed by the fine product of formula II obtained in example 2. Starting temperature-rising reaction, and starting timing reaction when the internal temperature reaches 110-130 ℃; reacting for 5.5 hours, wherein reflux is required to be ensured in the reaction process, and the internal temperature is kept at 110-130 ℃; after the reaction is finished, decompression and concentration are started under the condition of ensuring that the materials are not flushed. Until the materials in the bottle are viscous and the concentration is finished; sequentially adding 200g of drinking water, then adding 10% dilute sulfuric acid to adjust to be neutral, determining the specific dosage according to the actual pH value, keeping the temperature and stirring for 2 hours after the pH value is qualified after re-measurement after 15 minutes, then cooling to 0-25 ℃, keeping the temperature and crystallizing for 1 hour, and filtering to obtain a crude product of 5 alpha-androst-2-ene-17 ketone.

Putting the obtained 5 alpha-androstane-2-alkene-17 ketone wet product into a three-mouth reaction bottle filled with 300g of 95% ethanol, starting stirring and heating, heating to 76-80 ℃ (refluxing), and continuing stirring for 5 minutes to ensure complete dissolution; cooling to-2-10 deg.c, maintaining the temperature and stirring for crystallization for 4 hr; then filtering to obtain a refined product of the 5 alpha-androst-2-ene-17 ketone, and finally drying under reduced pressure to obtain a finished product of the 5 alpha-androst-2-ene-17 ketone with the yield of 92 percent and the isomer 5 alpha-androst-3-ene-17 ketone of about 7 percent, wherein the finished product of the 5 alpha-androst-2-ene-17 ketone is more than or equal to 88 percent (an area normalization method).

The invention has been described in detail, including the preferred embodiments thereof; it will be appreciated that those skilled in the art, on consideration of the present disclosure, may make modifications and/or improvements within the spirit and scope of the present invention as defined by the appended claims, which modifications and enhancements are also considered to fall within the scope of the present invention.