阅读说明：本技术 一种去氢表雄酮中间体母液回收利用方法 (Method for recycling dehydroepiandrosterone intermediate mother liquor ) 是由 侯海波 杨艳青 郑建雄 张阳洋 赵静 刘林 李廿 罗宇 肖康 狄飞飞 蔡啸 于 2019-10-05 设计创作，主要内容包括：本发明公开了一种去氢表雄酮中间体母液回收利用方法,该方法通过对以4-AD为原料,经过转位、酶催化合成DHEA过程中的5-AD中间体母液进行碱处理、脱色、纯化回收得到4-AD,从而实现5-AD中间体母液的回收利用；本发明方法通过5-AD进行回收利用,提高了物料的利用率,得到的4-AD纯度≥99%,可重新用于合成甾体药物,减少了浪费,节约了成本,同时减少了对环境带来的污染。(The invention discloses a method for recycling dehydroepiandrosterone intermediate mother liquor, which is characterized in that 4-AD is used as a raw material, and the 5-AD intermediate mother liquor in the DHEA synthesis process through transposition and enzyme catalysis is subjected to alkali treatment, decoloration, purification and recycling to obtain 4-AD, so that the 5-AD intermediate mother liquor is recycled; the method improves the utilization rate of materials by recycling the 5-AD, obtains the 4-AD with the purity of more than or equal to 99 percent, can be reused for synthesizing steroid drugs, reduces waste, saves cost and reduces pollution to the environment.)

1. A method for recycling dehydroepiandrosterone intermediate mother liquor is characterized by comprising the following steps: the recycling method comprises the following steps:

step A: taking 5-AD mother liquor generated in the process of synthesizing DHEA by taking androstenedione as a raw material, adding alkali into a reaction bottle, performing temperature-controlled reaction, and monitoring by HPLC;

and B: after the conversion in the step A, concentrating under negative pressure until no methanol solvent exists in a reaction bottle, adding water into the reaction bottle for elutriation, stirring uniformly, carrying out suction filtration, washing the filter cake with water for multiple times until the filtrate is neutral, draining, discharging, and drying to obtain a 4-AD crude product;

and C: and D, adding ethyl acetate, the 4-AD crude product obtained in the step B and activated carbon into a reaction bottle, uniformly stirring, heating for refluxing, carrying out suction filtration, concentrating the filtrate until a small volume of ethyl acetate remains, cooling for crystallization, carrying out vacuum filtration, carrying out suction drying for discharging, and drying to obtain the 4-AD.

2. The method for recycling dehydroepiandrosterone intermediate mother liquor according to claim 1, wherein the base used in step A is potassium hydroxide, the ratio of the mass of the potassium hydroxide to the volume of the 5-AD mother liquor is 0.02 ~ 0.04.04: 1 (g/mL), the reaction temperature is 30 ~ 40 ℃, and the reaction time is 2 ~ 3 hours.

3. The method for recycling dehydroepiandrosterone intermediate mother liquor according to claim 1 or 2, wherein the concentration temperature in step B is 45 ~ 50 ℃, the volume ratio of water for elutriation to 5-AD mother liquor is 1 ~ 1.5.5: 1, the volume ratio of filter cake washing water to 5-AD mother liquor is 0.2 ~ 0.3.3: 1, the washing times are 3 ~ 4 times, and the temperature of the baking material is controlled at 60 ~ 65 ℃.

4. The method for recycling dehydroepiandrosterone intermediate mother liquor according to claim 3, wherein the mass ratio of the ethyl acetate volume to the 4-AD crude product in the step C is 8 ~ 10:1 (ml/g), the mass ratio of the activated carbon to the 4-AD crude product is 0.03 ~ 0.05.05: 1, the reflux time is 30-40min, the ethyl acetate is concentrated until the mass ratio of the remaining small volume to the 4-AD crude product is 1 ~ 1.2.2: 1 (ml/g), the crystallization temperature is 0 ~ 5 ℃, the crystallization time is 2 ~ 4h, and the baking temperature is controlled at 60 ~ 65 ℃.

Technical Field

The invention relates to a method for treating steroid drug mother liquor in the field of organic synthesis, in particular to a method for recycling dehydroepiandrosterone intermediate mother liquor.

Background

Dehydroepiandrosterone, english name: dehydropiandrosterone, chemical name: 3 beta-hydroxy-5-androsten-17-one of formula C₁₉H₂₈O₂. Dehydroepiandrosterone is an important intermediate and raw material for preparing steroid medicaments, and has the effects of delaying aging and keeping youthful vigor; enhancing physical ability, improving emotion and sleep, improving memory, regulating immune system function, and enhancing immunity.

Domestic dehydroepiandrosterone manufacturers generally use androstenedione (4-AD) which is a phytosterol fermentation product as a raw material to synthesize Dehydroepiandrosterone (DHEA) through esterification, ketal reduction and hydrolysis, and the synthesis route is as follows:

in recent years, with the rapid development of biotechnology, more and more scholars adopt androstenedione (4-AD) as a raw material to synthesize dehydroepiandrosterone through two steps of translocation and enzyme reduction, and the route is as follows:

in the process of implementing the invention, the inventor finds that at least the following problems exist in the prior art: the first step of the route is realized by the reaction of converting 4-AD into 5-AD under the action of potassium tert-butoxide, but about 4-8% of the 4-AD raw material does not react completely, and for preparing high-purity DHEA, methanol refining is needed to be carried out on 5-AD so as to obtain high-purity 5-AD, and the 5-AD is reduced by enzyme to obtain a high-purity DHEA product; the 5-AD intermediate mother liquor contains main components such as 4-AD (10% -20%), 5-AD (70% -80%) and the like, and the recycling of the partial materials is particularly important.

Disclosure of Invention

In order to obtain a 5-AD mother liquor recovery technology which is simple and reliable, good in product quality and high in utilization rate, the invention provides a method for recycling dehydroepiandrosterone intermediate mother liquor.

Therefore, the technical scheme adopted by the invention is as follows: a method for recycling dehydroepiandrosterone intermediate mother liquor is characterized by comprising the following steps: the recycling method comprises the following steps:

step A: taking 5-AD mother liquor generated in the process of synthesizing DHEA by taking androstenedione as a raw material, adding alkali into a reaction bottle, performing temperature-controlled reaction, and monitoring by HPLC;

and B: after the conversion in the step A, concentrating under negative pressure until no methanol solvent exists in a reaction bottle, adding water into the reaction bottle for elutriation, stirring uniformly, carrying out suction filtration, washing the filter cake with water for multiple times until the filtrate is neutral, draining, discharging, and drying to obtain a 4-AD crude product;

and C: and D, adding ethyl acetate, the 4-AD crude product obtained in the step B and activated carbon into a reaction bottle, uniformly stirring, heating for refluxing, filtering, concentrating the filtrate until a small volume of ethyl acetate remains, cooling for crystallization, performing suction filtration, draining, discharging and drying to obtain the 4-AD.

Preferably, the alkali in the step A is potassium hydroxide, the ratio of the mass of the potassium hydroxide to the volume of the 5-AD mother liquor is 0.02 ~ 0.04:1 (g/mL), the reaction temperature is 30 ~ 40 ℃, and the reaction time is 2 ~ 3 h.

Preferably, the concentration temperature in the step B is 45 ~ 50 ℃, the volume ratio of water for elutriation to 5-AD mother liquor is 1 ~ 1.5.5: 1, the volume ratio of filter cake washing water to 5-AD mother liquor is 0.2 ~ 0.3.3: 1, the washing times are 3 ~ 4 times, and the temperature of a baking material is controlled to be 60 ~ 65 ℃.

Preferably, the mass ratio of the volume of the ethyl acetate to the 4-AD crude product in the step C is 8 ~ 10:1 (ml/g), the mass ratio of the activated carbon to the 4-AD crude product is 0.03 ~ 0.05.05: 1, the reflux time is 30-40min, the ethyl acetate is concentrated until the mass ratio of the remaining small volume to the 4-AD crude product is 1 ~ 1.2.2: 1 (ml/g), the crystallization temperature is 0 ~ 5 ℃, the crystallization time is 2 ~ 4h, and the baking temperature is controlled at 60 ~ 65 ℃.

Has the advantages that:

the invention can realize the recycling of the dehydroepiandrosterone intermediate mother liquor, and the method has the advantages that:

1) the purity of the recovered 4-AD is equal to or greater than 99%, the recovered 4-AD can be reused as an intermediate, waste is reduced through recovery and utilization, and cost is reduced;

2) the pollution of hormone waste to the environment is reduced.

Detailed Description

The technical solution of the present invention is clearly and completely described below by the following specific examples, but the examples should not be construed as limiting the present invention.