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Novel method for preparing dehydroepiandrosterone

A new type of dehydroepiandrosterone technology, applied in the field of preparation of dehydroepiandrosterone, can solve the impact on the quality and yield of dehydroepiandrosterone, the poor stability of intermediate 5-AD, and the influence of 5-AD purity Larger problems, etc., to achieve the effect of high industrial application value, single organic solvent, and low requirements for reaction conditions

Active Publication Date: 2021-11-09
ZHEJIANG SHENZHOU PHARMA
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  • Abstract
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Problems solved by technology

[0011] The chemically synthesized intermediate 5-AD in this method has poor stability. According to the report in the literature Org.ProcessRes.Dev.2016, 20, 1520-1528, the potassium alkoxide obtained after 4-AD is treated with tert-butanol and potassium tert-butoxide The intermediate state is easy to react with oxygen, so an antioxidant must be added during the water analysis of glacial acetic acid. According to the patent CN105483198A, the yield of 5-AD from 4-AD is only 32%, which is very low. However, it is recorded in CN105339382A and CN106086148A Potassium tert-butoxide was used in the synthesis of 5-AD in the method, and sodium ascorbate was needed to inhibit the oxidation of 5-AD. The operation was complicated and difficult to control, and the purity of 5-AD was the main problem affecting the next reaction, which brought Impurities seriously affect the quality and yield of dehydroepiandrosterone, which brings great difficulties to industrialized production
[0012] According to literature Org.Process Res.Dev.2016,20,1520-1528, CN105483198A report 5-AD method yield and quality are all poor, according to CN105339382A, CN106086148A report 5-AD method, even adding sodium ascorbate to inhibit 5-AD Oxidation of -AD, we found through stability experiments that 5-AD is still easy to transform into other impurities under airtight conditions, which has a greater impact on the purity of 5-AD, thus affecting the next step of the reaction to obtain dehydroepiandrosterone quality and yield

Method used

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Experimental program
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Effect test

Embodiment 1

[0042] The preparation and stability test of embodiment 1 compound II, specifically as follows:

[0043] 1) Under the protection of nitrogen, mix 50g of compound I, 250ml of acetic anhydride and 10g of p-toluenesulfonic acid into the reactor, control the temperature at 20°C and stir the reaction until the reaction of the raw materials is detected by thin layer chromatography, water analysis, filtration, and drying , to obtain 55.6g of compound II, with an HPLC content of 97.3%, such as figure 1 shown.

[0044] After placing the above compound II at 20-30°C for 6 hours in a sealed and light-shielded place, the HPLC content was stable at 97.3%, as shown in figure 2 shown.

Embodiment 2

[0045] Embodiment 2 A kind of preparation method of dehydroepiandrosterone, comprises the steps:

[0046] 1) Under the protection of nitrogen, mix 50g of compound I, 250ml of acetic anhydride and 10g of p-toluenesulfonic acid into the reactor, control the temperature at 20°C and stir the reaction until the reaction of the raw materials is detected by thin layer chromatography, water analysis, filtration, and drying 55.5 g of compound II was obtained, with an HPLC content of 97.5%.

[0047] 2) Dissolve 55.5 g of the above-mentioned compound II in 167 ml of tert-butanol, add 390 ml of 100 mM pH6.5 phosphate enzyme buffer solution, start stirring, then add 555 mg of ketoreductase, 277.5 mg of ester hydrolase, and 220 mg of nicotinamide adenine Dinucleotide, 30g glucose, 220mg glucose dehydrogenase, biological enzyme reaction at 26-28°C, and 10% sodium carbonate aqueous solution to control the pH value of 6.8-7.2. After 5 hours, take a sample and test, the conversion rate is 99.3 %...

Embodiment 3

[0048] Embodiment 3 A kind of preparation method of dehydroepiandrosterone, comprises the steps:

[0049] 1) Under nitrogen protection, mix 50 g of compound I, 100 ml of dichloromethane, 150 ml of acetic anhydride, and 25 g of methanesulfonic acid into the reactor, and stir the reaction at 0°C until the reaction of the raw materials is detected by thin-layer chromatography. Concentrate Remove dichloromethane, analyze with water, filter, and dry to obtain 55.6 g of compound II with an HPLC content of 97.6%.

[0050] 2) Dissolve 55.6g of the above-mentioned compound II in 167ml of tert-butanol, add 390ml of 100mM pH6.5 phosphate buffer solution, start stirring, add 834mg of ketoreductase, 417mg of ester hydrolase, and 220mg of nicotinamide adenine dinuclear Nucleic acid, 30g glucose, 220mg glucose dehydrogenase, under the temperature condition of 28-30 ℃, carry out biological enzyme reaction, and use 10% sodium carbonate aqueous solution to control the pH value of 7.2-7.6. Sampl...

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Abstract

The invention provides a novel method for preparing dehydroepiandrosterone, discloses a preparation method of dehydroepiandrosterone, and belongs to the technical field of preparation and processing of compounds. The method comprises the following steps of: taking 4-androstenedione (I) as a starting raw material, carrying out an acetylation reaction to obtain 3-acetoxyl-delta 3, 5-androstadiene-17-ketone (II), and then carrying out a biological enzyme method reaction on the obtained intermediate compound (II) to obtain the product dehydroepiandrosterone. The compound II in the invention is used as a key intermediate, the property of the compound II is more stable than that of 5-AD, and the purity is high, so that the stability of entering the next step of the biological enzyme method is effectively ensured; the biological enzyme method of the reaction route adopts a composite biological enzyme with a specific ratio, and the composite biological enzyme with the specific ratio acts on the compound II and has a better and more stable conversion effect; and the single-batch yield of the route is larger than 90%, the purity of the product compound III is high, the purity is larger than 99%, and the industrial application value is higher.

Description

technical field [0001] The invention relates to the technical field of preparation and processing of compounds, in particular to a preparation method of dehydroepiandrosterone. Background technique [0002] Dehydroepiandrosterone (DehydroepⅠandrosterone, referred to as DHEA), the chemical name is (3β)-3-hydroxy-5-en-17-sterone, the molecular formula is C19H22O2, the molecular weight is 288.42, and the structural formula is as follows: [0003] [0004] Dehydroepiandrosterone is a precursor of adrenal hormone secreted by the reticular layer of the human adrenal cortex. It has physiological activities such as regulating obesity, preventing diabetes, resisting cancer and viral infection, improving memory, immune response and stress response, and reducing tension. It is an intermediate in the manufacture of steroid hormones and participates in the synthesis of various hormones secreted by the adrenal gland. [0005] CN102603839A discloses a method for preparing dehydroepiand...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/06C07J1/00
CPCC12P33/06C07J1/0011
Inventor 王友富邵振平王荣罗敏王洪福黄橙橙雷灵芝
Owner ZHEJIANG SHENZHOU PHARMA
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