阅读说明：本技术 倍他米松或***合成母液料的回收利用方法 (Method for recycling betamethasone or dexamethasone synthetic mother liquor material ) 是由 唐杰 曾春玲 邹元 于 2019-11-25 设计创作，主要内容包括：本发明涉及一种倍他米松或地塞米松合成母液料的回收利用方法,包括步骤：从母料液提取式1所示化合物；将式1所示化合物进行20位羟基基团的保护反应,得到式2所示化合物；将式2所示化合物进行21位醛基的还原反应,得到式3所示化合物,继续进行氧化反应和水解反应,得到式4所示化合物,所述式4所示化合物即为倍他米松或地塞米松；<Image he="144" wi="700" file="DDA0002287294270000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>上述回收利用方法可将倍他米松或地塞米松母液料转化成药用价值和经济效益高的倍他米松或地塞米松,具有巨大的经济效益。(The invention relates to a method for recycling betamethasone or dexamethasone synthetic mother liquor, which comprises the following steps: extracting the compound shown in the formula 1 from the master batch liquid; carrying out a protection reaction on a 20-position hydroxyl group of the compound shown in the formula 1 to obtain a compound shown in a formula 2; carrying out a reduction reaction of 21-bit aldehyde group on the compound shown in the formula 2 to obtain a compound shown in a formula 3, and continuously carrying out an oxidation reaction and a hydrolysis reaction to obtain a compound shown in a formula 4, wherein the compound shown in the formula 4 is betamethasone or dexamethasone; the recovery and utilization method can convert the betamethasone or dexamethasone mother liquor into betamethasone or dexamethasone with high medicinal value and economic benefit, and has great economic benefit.)

1. A method for recycling betamethasone or dexamethasone synthetic mother liquor, which is characterized in that,

the master batch liquid is prepared from betamethasone and/or dexamethasone by the following synthesis steps:

the recycling method comprises the following steps:

extracting the compound shown in the formula 1 from the master batch liquid;

carrying out a protection reaction on a 20-position hydroxyl group of the compound shown in the formula 1 to obtain a compound shown in a formula 2;

carrying out a reduction reaction of 21-bit aldehyde group on the compound shown in the formula 2 to obtain a compound shown in a formula 3, and continuing carrying out an oxidation reaction and a hydrolysis reaction to obtain a compound shown in a formula 4, wherein the compound shown in the formula 4 is betamethasone or dexamethasone;

wherein R is a hydroxyl protecting group.

2. The recycling method of claim 1, wherein the reducing agent used in the reduction reaction is borohydride, and the mass ratio of the reducing agent to the compound represented by the formula 2 is (0.25-1.0): 1.

3. The recycling method according to claim 1, wherein the temperature of the reduction reaction is 0 ℃ to 10 ℃.

4. The recycling method according to claim 1, wherein the oxidizing agent used in the oxidation reaction is a peroxide.

5. The recycling method according to claim 1, wherein the reaction temperature of the oxidation reaction is-10 ℃ to 50 ℃.

6. The recycling method according to claim 1, wherein the hydrolysis reaction is carried out under acidic conditions, and the temperature of the hydrolysis reaction is 30 ℃ to 35 ℃.

7. The recycling method according to claim 1, further comprising a step of crude purification of the compound represented by the formula 4 after the hydrolysis reaction: adjusting pH value to neutral, evaporating solvent of system, separating out solid, adding water, mixing, and filtering to obtain crude product.

8. The recycling method of claim 7, further comprising the step of refining the crude product: dissolving the crude product in a mixed solvent of methanol and dichloromethane, adding activated carbon for refluxing, filtering while the solution is hot after the refluxing is finished, concentrating the filtrate, adding a methanol replacement solvent, cooling and crystallizing, and filtering to obtain a solid.

9. The recycling method according to claim 1, wherein R is methyl, ethyl, acetyl or trimethylsilyl.

10. The recycling method according to any one of claims 1 to 9, wherein the step of extracting the compound represented by formula 1 from the master batch liquid is specifically: dissolving the master batch liquid in an organic solvent, adsorbing and removing oil through silica gel, filtering, and then crystallizing and enriching, wherein the crystallization mode is that ethyl acetate is used as solvent for crystallization.

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a method for recycling betamethasone or dexamethasone synthetic mother liquor.

Background

The last step in the synthesis process of betamethasone and dexamethasone is the fluorination reaction, which is carried out in hydrofluoric acid. Taking the synthesis process of betamethasone as an example, the reaction formula is shown as follows.

As the reaction is carried out in high-concentration hydrofluoric acid, a plurality of byproducts are inevitably generated in the reaction process, the molar yield of dexamethasone and betamethasone is only about 80-85% after refining and purification, and a large amount of impurities enter a mother liquor material for synthesizing the dexamethasone and the betamethasone. In the existing production process, the mother liquor is basically unrecoverable due to large impurity content and more tar, and is treated as solid waste after concentration, so that pollution and great waste of materials are caused.

Disclosure of Invention

Based on the above, a method for recycling betamethasone or dexamethasone synthetic mother liquor with high medicinal value and economic benefit is needed.

A method for recycling betamethasone or dexamethasone synthetic mother liquor material,

the master batch liquid is prepared from betamethasone and/or dexamethasone by the following synthesis steps:

the recycling method comprises the following steps:

extracting the compound shown in the formula 1 from the master batch liquid;

carrying out a protection reaction on a 20-position hydroxyl group of the compound shown in the formula 1 to obtain a compound shown in a formula 2;

carrying out a reduction reaction of 21-bit aldehyde group on the compound shown in the formula 2 to obtain a compound shown in a formula 3, and continuing carrying out an oxidation reaction and a hydrolysis reaction to obtain a compound shown in a formula 4, wherein the compound shown in the formula 4 is betamethasone or dexamethasone;

wherein R is a hydroxyl protecting group.

The method for recycling the betamethasone or dexamethasone synthetic mother liquor takes the mother liquor treated as solid waste as a raw material, extracts the compound shown in the formula 1 from the mother liquor, and can prepare the betamethasone or dexamethasone with high medicinal value and economic benefit through hydroxyl protection, 21-aldehyde group reduction, oxidation and hydrolysis reaction. The invention provides a new method for recycling betamethasone or dexamethasone mother liquor, avoids the problems of pollution and waste caused by the fact that the existing mother liquor cannot be basically recycled and concentrated as solid waste, is beneficial to improving the total yield of betamethasone or dexamethasone, reduces the cost and the pollutant emission, meets the requirement of environmental protection, and has great economic benefit.

In some embodiments, the reducing agent used in the reduction reaction is borohydride, and the mass ratio of the reducing agent to the compound represented by formula 2 is (0.25-1.0): 1.

In some of these embodiments, the temperature of the reduction reaction is between 0 ℃ and 10 ℃.

In some of these embodiments, the oxidizing agent used in the oxidation reaction is a peroxide.

In some of these embodiments, the oxidation reaction is carried out at a reaction temperature of-10 ℃ to 50 ℃.

In some of these embodiments, the hydrolysis reaction is carried out under acidic conditions, and the temperature of the hydrolysis reaction is from 30 ℃ to 35 ℃.

In some embodiments, the method further comprises a step of crude purification of the compound represented by formula 4 after the hydrolysis reaction: adjusting pH value to neutral, evaporating solvent of system, separating out solid, adding water, mixing, and filtering to obtain crude product.

In some embodiments, the method further comprises the step of refining the crude product: dissolving the crude product in a mixed solvent of methanol and dichloromethane, adding activated carbon for refluxing, filtering while the solution is hot after the refluxing is finished, concentrating the filtrate, adding a methanol replacement solvent, cooling and crystallizing, and filtering to obtain a solid.

In some of these embodiments, R is methyl, ethyl, acetyl, or trimethylsilyl.

In some embodiments, the step of extracting the compound represented by formula 1 from the masterbatch liquid is specifically: dissolving the master batch liquid in an organic solvent, adsorbing and removing oil through silica gel, filtering, and then crystallizing and enriching, wherein the crystallization mode is to adopt ethyl acetate as a solvent for recrystallization.

Detailed Description

In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

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 terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

An embodiment of the invention provides a method for recycling a betamethasone or dexamethasone synthetic mother liquor material, which comprises the following steps S1-S3.

Wherein, the master batch liquid is prepared from betamethasone and/or dexamethasone by the following synthesis steps:

the present inventors have analyzed the above mother liquor and found that the main impurity component is a compound represented by formula 1. Thus, the mother liquor can be recycled through the synthesis steps, and further converted into betamethasone or dexamethasone with high medicinal value and economic benefit.

Step S1: and extracting the compound shown in the formula 1 from the master batch liquid.

Step S2: and (3) carrying out a protection reaction on the 20-position hydroxyl group of the compound shown in the formula 1 to obtain the compound shown in the formula 2.

And S3, performing a reduction reaction on the 21-bit aldehyde group of the compound shown in the formula 2 to obtain a compound shown in the formula 3, and continuing to perform an oxidation reaction and a hydrolysis reaction to obtain a compound shown in the formula 4, wherein the compound shown in the formula 4 is betamethasone or dexamethasone, when the 16-bit in the compound shown in the formula 4 is β methyl, the compound shown in the formula 4 is betamethasone, and when the 16-bit in the compound shown in the formula 4 is α methyl, the compound shown in the formula 4 is dexamethasone.

The synthetic route of the method for recycling the betamethasone or dexamethasone synthetic mother liquor material is as follows:

wherein R is a hydroxyl protecting group.

It is understood that the reagent used for protecting the reaction in step S2 may be a conventional hydroxyl protecting reagent, and in some examples, R is methyl, ethyl, acetyl, trimethylsilyl, or the like.

In some embodiments, step S1 is specifically: dissolving the master batch liquid in an organic solvent, adsorbing and removing oil by silica gel, filtering, and then crystallizing and enriching, wherein the crystallization mode is to adopt ethyl acetate as a solvent for recrystallization; the raw material with the compound shown in the formula 1 of 55-75 wt% can be obtained.

In a specific example, step S1 is specifically: dissolving the master batch liquid in dichloromethane, adsorbing and removing oil through silica gel, filtering, and then crystallizing and enriching, wherein the crystallization mode is to concentrate and remove the dichloromethane and add ethyl acetate for recrystallization.

In some embodiments, step S2 further comprises a step of purifying the compound of formula 2: after the protection reaction is finished, adding water, layering, taking the organic phase, washing, concentrating, adding acetone to replace the solvent, cooling, and crystallizing in acetone to obtain the catalyst.

In some embodiments, the reducing agent used in the reduction reaction in step S3 is a borohydride, such as sodium borohydride, potassium borohydride, calcium borohydride, sodium triacetoxyborohydride, or the like, preferably potassium borohydride.

Further, the mass ratio of the borohydride to the compound represented by formula 2 is (0.25-1.0): 1, preferably 0.3: 1.

Further, the temperature of the reduction reaction is 0 ℃ to 10 ℃.

In some embodiments, the oxidizing agent employed in the oxidation reaction is a peroxide; at least one of hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid (m-CBPA), tert-butyl hydroperoxide, peroxyphthalic acid and Magnesium Monoperoxyphthalate (MMPP). The oxidizing agent is preferably peroxyphthalic acid.

In some embodiments, the reaction solvent for the oxidation reaction is selected from one or more of dichloromethane, methanol, ethanol, ethyl acetate, acetone, dioxane, and DMF (N, N-dimethylformamide), and a mixed solvent of dichloromethane and ethyl acetate is preferred.

Further, the reaction temperature of the oxidation reaction is-10 ℃ to 50 ℃, preferably 10 ℃.

In some embodiments, the hydrolysis reaction is carried out under acidic conditions, and the temperature of hydrolysis is from 30 ℃ to 35 ℃.

In some embodiments, the method further comprises a step of crude purification of the compound represented by formula 4 after the hydrolysis reaction: adjusting pH value to neutral, evaporating solvent of system, separating out solid, adding water, mixing, and filtering to obtain crude product. Further, the reagent used for adjusting the pH is a hydroxide, preferably NaOH solution.

In some embodiments, further comprising the step of refining the crude product: dissolving the crude product in a mixed solvent of methanol and dichloromethane, adding activated carbon for refluxing, filtering while the reflux is hot, concentrating the filtrate, adding a methanol replacement solvent, cooling, crystallizing, and filtering to obtain a solid.

The method for recycling the betamethasone or dexamethasone synthetic mother liquor takes the mother liquor treated as solid waste as a raw material, extracts the compound shown in the formula 1 from the mother liquor, and can prepare the betamethasone or dexamethasone with high medicinal value and economic benefit through hydroxyl protection, 21-aldehyde group reduction, oxidation and hydrolysis reaction. The invention provides a new method for recycling betamethasone or dexamethasone mother liquor, avoids the problems of pollution and waste caused by the fact that the existing mother liquor cannot be basically recycled and concentrated as solid waste, is beneficial to improving the total yield of betamethasone or dexamethasone, reduces the cost and the pollutant emission, meets the requirement of environmental protection, and has great economic benefit.

The following are specific examples.