A method for treating diol re-refining mother liquor

Abstract

The present invention provides a method for treating a diol re-refined mother liquor. The method for treating a diol re-refined mother liquor of the present invention comprises the following steps: S1: mixing the diol re-refined mother liquor with water and stirring to increase the temperature, then dripping a sodium hydroxide solution, keeping the temperature, draining, and washing with water to obtain a recovered 17-hydroxyprogesterone crude product; S2: beating the recovered 17-hydroxyprogesterone crude product with ethanol to obtain a beating product; S3: purifying the beating product to obtain a mixture of diols and 17-hydroxyprogesterone; S4: hydroxylating the mixture of diols and 17-hydroxyprogesterone at the 11th position to obtain a diol crude product; S5: refining the diol crude product to obtain a recovered diol. The method for treating a diol re-refined mother liquor of the present invention can recover diols from the diol re-refined mother liquor, reduce the pollution of steroid waste to the environment, and improve the utilization rate of materials.

Description

Technical Field

[0001] The invention relates to the technical field of chemical drug synthesis, in particular to a method for treating a dihydric re-refined mother liquor. Background Art

[0002] The chemical name of the diol is 11,17-dihydroxyprogesterone, which is an important intermediate for the synthesis of glucocorticoids such as prednisolone acetate, hydrocortisone, and prednisolone. Its products are mainly used for various acute and severe bacterial infections, severe allergic diseases, collagen diseases (lupus erythematosus, periarteritis nodosa, etc.), rheumatism, rheumatoid arthritis, nephrotic syndrome, severe bronchial asthma, thrombocytopenic purpura, granulocytopenia, acute lymphocytic leukemia, various adrenal cortical insufficiency, exfoliative dermatitis, pemphigus, neurodermatitis, eczema, etc. The chemical structure is as follows:

[0003]

[0004] The preparation method of diols is usually to use black root mold or Aspergillus ochraceus to ferment 17-hydroxyprogesterone to achieve 11-position hydroxylation, and then refine it with organic solvents for multiple times to obtain diol products. The main components of the mother liquor produced during the refining process are 17-hydroxyprogesterone and diols. The mother liquor is returned for fermentation and hydroxylated again, and then refined to obtain qualified diol products. The mother liquor obtained by refining the mother liquor is called "old mother liquor", that is, diol re-refined mother liquor. The diol re-refined mother liquor contains 15-20% of 17-hydroxyprogesterone, and also contains about 60-75% of diols and some other organic and inorganic impurities. At present, this part of the mother liquor is mainly transferred and subsequently treated as hazardous waste, with high comprehensive cost and not conducive to environmental protection. At the same time, due to the low content of effective ingredients in the mother liquor and the large amount of oily impurities, it is difficult to treat the diol re-refined mother liquor, and it is difficult to recycle the effective ingredients in the mother liquor.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] The object of the present invention is to provide a method for treating diol re-refining mother liquor, which can recover diol from the diol re-refining mother liquor, reduce the pollution of steroid waste to the environment, and improve the utilization rate of materials.

[0007] The present invention provides a method for treating a diol re-refining mother liquor, comprising the following steps:

[0008] S1: Mix the dihydroxy refined mother liquor with water and stir to raise the temperature, then dropwise add sodium hydroxide solution, keep warm, drain and wash with water to obtain the recovered 17-hydroxyprogesterone crude product;

[0009] S2: beating the recovered 17-hydroxyprogesterone crude product with ethanol to obtain a beating material;

[0010] S3: purifying the slurry to obtain a mixture of dihydroxy and 17-hydroxyprogesterone;

[0011] S4: hydroxylating the mixture of the diol and 17-hydroxyprogesterone at the 11-position to obtain a crude diol;

[0012] S5: Purify the crude diol to obtain recovered diol.

[0013] In the present invention, the dihydric acid re-refined mother liquor refers to the mother liquor produced by refining 17-hydroxyprogesterone by microbial fermentation with Rhizopus nigromatus or Aspergillus ochraceus, and the "old mother liquor" formed by refining again. Specifically, the dihydric acid re-refined mother liquor usually contains 15-20% of 17-hydroxyprogesterone, and also contains about 60-75% of dihydric acid and some other organic and inorganic impurities.

[0014] In step S1, the mass concentration of the sodium hydroxide solution is 35-45%; the usage ratio of the diol re-refining mother liquor, water and the sodium hydroxide solution is 1g: 4-6mL: 0.1-0.3mL; stirring and heating to 90-100°C; the heat preservation time is 10-15min. In step S1, the diol re-refining mother liquor is treated with sodium hydroxide solution, the purpose of which is to remove most of the organic impurities in the diol re-refining mother liquor, which is lower in cost than the traditional repeated refining of organic solvents and has a good impurity removal effect.

[0015] Step S2 includes: mixing the recovered 17-hydroxyprogesterone crude product and ethanol and heating and refluxing, cooling and filtering after heating and refluxing to obtain a pulped product; wherein the ratio of the recovered 17-hydroxyprogesterone crude product to ethanol is 1g:4-5mL; controlling the heating and refluxing temperature to be 75-85°C, and the heating and refluxing time to be 20-30min. In step S2, ethanol is used to pulp the recovered 17-hydroxyprogesterone crude product, the purpose of which is to remove inorganic impurities in the re-refined mother liquor, especially the pulping and refluxing does not need to be concentrated, thereby reducing solvent loss and reducing processing costs.

[0016] In step S3, the pulped material is purified by using a mixed solvent of dichloromethane and methanol; the volume ratio of dichloromethane to methanol in the mixed solvent is (4-6): 1; the dosage ratio between the pulped material, dichloromethane and methanol is 1g: 2-3mL: 0.4-0.6mL. Specifically, step S3 includes: mixing and stirring the pulped material, dichloromethane and methanol, heating to 40-55°C, keeping warm for 20-30min, concentrating, cooling to -5°C to 5°C, discharging and drying to obtain a mixture of dihydroxy and 17-hydroxyprogesterone. In step S3, the pulped material is purified by using a mixed solvent of dichloromethane and methanol, which can increase the solubility of the target and improve the extraction rate of the target.

[0017] In step S4, the 11-position hydroxylation includes: fermenting a mixture of diols and 17-hydroxyprogesterone using Rhizopus niger or Aspergillus ochraceus. The fermentation can be carried out in a conventional manner in the art; the fermentation medium composition is, for example, 1.5-2.5% glucose, 1-2% peptone, 0.4-0.6% ammonium sulfate, 0.8-1.2% yeast extract, 0.6-0.7% potassium dihydrogen phosphate, and a natural pH value; the fermentation process includes: first culturing Rhizopus niger or Aspergillus ochraceus at 29-31°C for 20-24h, then adding a mixture of diols and 17-hydroxyprogesterone, the mixture is added in an amount of 1-3%, and then fermenting and converting at 29-31°C for 24-48h. After the fermentation and conversion is completed, filter to obtain a filter cake (i.e., a crude diol product).

[0018] In step S5, during extraction, the mass ratio of acetone to acetone to crude diol is 8-12:1, and the extraction includes: heating and refluxing at 55-60°C for 20-30min, filtering after heating and refluxing, collecting filter cake and filtrate; the above extraction process can be repeated 2-3 times, the filtrate is combined and concentrated after extraction, and after concentration, it is washed with 1-3 times of drinking water and then discharged to obtain a diol extract; during purification, the volume ratio of chloroform to toluene in the mixed solvent is 3-5:1; the purification includes: adding the diol extract to the above mixed solvent, heating and refluxing at 50-60°C for 20-30min, concentrating after heating and refluxing, cooling to 0-5°C, and discharging; the above purification process can be repeated 3-5 times, and the recovered diol is obtained after purification; the HPLC content of the recovered diol obtained by the present invention is ≥98.8%.

[0019] The treatment method of the present invention overcomes the difficulty of treating the diol re-refining mother liquor and recovers about 30-50% of the diol; the treatment method has stable process, simple operation, high recovery rate, and the recovered diol product meets the corresponding quality standards, thereby reducing the pollution of steroid waste to the environment and improving the utilization rate of materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0021] Figure 1 This is the HPLC spectrum of the recovered diol prepared in Example 1. DETAILED DESCRIPTION

[0022] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0023] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form also includes the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this description, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0024] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] Example 1

[0026] The method for treating the diol re-refining mother liquor of this embodiment comprises the following steps:

[0027] S1: Preparation and recovery of crude 17-hydroxyprogesterone

[0028] Add 50g of old mother liquor of dihydroxide and 250mL of drinking water into the reaction bottle, stir and heat to 95°C, add 10mL of 40wt% sodium hydroxide solution, drip it within 1min, keep warm for 10min, discharge, drain, wash with water, and obtain the recovered 17-hydroxyprogesterone crude product with a wet weight of about 48g.

[0029] S2: Beating

[0030] 48 g of the recovered 17-hydroxyprogesterone crude product and 200 mL of ethanol were added to a reaction bottle, the temperature was raised to 80° C. and refluxed for 25 min, then the temperature was lowered to 25° C. and filtered to obtain 40 g of the recovered 17-hydroxyprogesterone slurry.

[0031] S3: Purification

[0032] 35 g of recovered 17-hydroxyprogesterone slurry, 100 mL of dichloromethane and 20 mL of methanol were added to a reaction flask, stirred and heated to 50°C, kept warm for 25 minutes, concentrated, cooled to 0°C, discharged, and dried to obtain a mixture of 35 g of diol and 17-hydroxyprogesterone, wherein the total mass content of diol and 17-hydroxyprogesterone in the mixture was 99.0%.

[0033] S4: Fermentation

[0034] The mixture of diol and 17-hydroxyprogesterone is fermented by using Aspergillus ochraceus, and the fermentation medium comprises (mass content %): 2% glucose, 1.5% peptone, 0.5% ammonium sulfate, 1% yeast extract, 0.65% potassium dihydrogen phosphate, and natural pH value; the fermentation process is as follows: firstly, the Aspergillus ochraceus is cultured at 30°C for 24h, and then the mixture of diol and 17-hydroxyprogesterone in step S3 is added, and the addition amount of the mixture is 2%; after the addition, the mixture is fermented and converted at 30°C for 36h, and after the fermentation and conversion is completed, the mixture is filtered to obtain a filter cake.

[0035] S5: Refined

[0036] The filter cake of step S4 was extracted with acetone, the mass ratio of acetone to filter cake was 10:1, and after heating and refluxing at 60°C for 20 minutes, the mixture was filtered, and the filtrate and filter cake were collected. The filter cake was extracted twice by the above method, the filtrates were combined and concentrated, and the mixture was rinsed with 2 times of drinking water, and the material was discharged to obtain a dihydroxy extract.

[0037] The diol extract was purified by using a mixed solvent of chloroform and toluene, wherein the volume ratio of chloroform to toluene in the mixed solvent was 4:1. The purification process was as follows: the diol extract was put into the mixed solvent, heated and refluxed at 55°C for 25 minutes, concentrated after heating and refluxed, and cooled to 2°C for recrystallization; the purification method was repeated 4 times to obtain 21.8 g of recovered diol; after testing, the HPLC content of the recovered diol was 98.8%, and the HPLC spectrum was shown in FIG. Figure 1 .

[0038] Example 2

[0039] The method for treating the diol re-refining mother liquor of this embodiment comprises the following steps:

[0040] S1: Preparation and recovery of crude 17-hydroxyprogesterone

[0041] Add 50g of old mother liquor of diol and 200mL of drinking water into the reaction bottle, stir and heat to 90°C, add 15mL of 35% sodium hydroxide solution, drip it within 1min, keep warm for 15min, discharge, drain, wash with water, and obtain the recovered 17-hydroxyprogesterone crude product with a wet weight of about 47g.

[0042] S2: Beating

[0043] 47 g of the recovered 17-hydroxyprogesterone crude product and 190 mL of ethanol were added to a reaction bottle, the temperature was raised to 85° C. and refluxed for 20 min, the temperature was lowered to 20° C., and the mixture was filtered to obtain 39 g of the recovered 17-hydroxyprogesterone slurry.

[0044] S3: Purification

[0045] 39 g of recovered 17-hydroxyprogesterone slurry, 80 mL of dichloromethane and 16 mL of methanol were added to a reaction flask, stirred and heated to 55°C, kept warm for 20 min, concentrated, cooled to 5°C, discharged, and dried to obtain a mixture of 35 g of diol and 17-hydroxyprogesterone, the total mass content of diol and 17-hydroxyprogesterone in the mixture being 98.9%.

[0046] S4: Fermentation

[0047] The mixture of diol and 17-hydroxyprogesterone is fermented by using Aspergillus ochraceus, and the fermentation medium comprises (mass content %): 1.5% glucose, 2% peptone, 0.6% ammonium sulfate, 0.8% yeast extract, 0.7% potassium dihydrogen phosphate, and natural pH value; the fermentation process is as follows: firstly, the Aspergillus ochraceus is cultured at 30°C for 20h, and then the mixture of diol and 17-hydroxyprogesterone in step S3 is added, and the addition amount of the mixture is 3%; after adding, the mixture is converted at 30°C for 24h, and after the fermentation conversion is completed, the mixture is filtered to obtain a filter cake.

[0048] S5: Refined

[0049] The filter cake of step S4 was extracted with acetone, the mass ratio of acetone to filter cake was 8:1, and after heating and refluxing at 55°C for 30 minutes, the mixture was filtered, and the filtrate and filter cake were collected. The filter cake was extracted twice by the above method, the filtrates were combined and concentrated, and the mixture was rinsed with 2 times of drinking water, and the diol extract was obtained.

[0050] The diol extract was purified by using a mixed solvent of chloroform and toluene, wherein the volume ratio of chloroform to toluene in the mixed solvent was 3:1; the purification process was as follows: the diol extract was put into the mixed solvent, heated and refluxed at 50°C for 30 minutes, concentrated after heating and reflux, and cooled to 5°C for recrystallization; the purification method was repeated 4 times to obtain 20.6 g of recovered diol; after testing, the HPLC content of the recovered diol was 99.0%.

[0051] Example 3

[0052] The method for treating the diol re-refining mother liquor of this embodiment comprises the following steps:

[0053] S1: Preparation and recovery of crude 17-hydroxyprogesterone

[0054] Add 50g of old mother liquor of dihydroxide and 300mL of drinking water into the reaction bottle, stir and heat to 100°C, add 5mL of 45% sodium hydroxide solution, drip it within 1min, keep warm for 10min, discharge, drain, wash with water, and obtain the recovered 17-hydroxyprogesterone crude product with a wet weight of about 47g.

[0055] S2: Beating

[0056] 47 g of the recovered 17-hydroxyprogesterone crude product and 230 mL of ethanol were added to a reaction bottle, the temperature was raised to 80° C. and refluxed for 30 min, the temperature was lowered to 25° C., and the mixture was filtered to obtain 41 g of the recovered 17-hydroxyprogesterone slurry.

[0057] S3: Purification

[0058] 41 g of recovered 17-hydroxyprogesterone slurry, 120 mL of dichloromethane and 24 mL of methanol were added to a reaction flask, stirred and heated to 40°C, kept warm for 30 min, concentrated, cooled to -5°C, discharged, and dried to obtain a mixture of 34 g of diol and 17-hydroxyprogesterone, the total mass content of diol and 17-hydroxyprogesterone in the mixture being 99.2%.

[0059] S4: Fermentation

[0060] The mixture of diol and 17-hydroxyprogesterone is fermented by using Aspergillus ochraceus, and the fermentation medium comprises (mass content %): 2.5% glucose, 1% peptone, 0.4% ammonium sulfate, 1.2% yeast extract, 0.6% potassium dihydrogen phosphate, and natural pH value; the fermentation process is as follows: firstly, the Aspergillus ochraceus is cultured at 30°C for 24h, and then the mixture of diol and 17-hydroxyprogesterone in step S3 is added, and the addition amount of the mixture is 1%; after adding, the mixture is fermented and converted at 30°C for 48h, and after the fermentation and conversion is completed, the mixture is filtered to obtain a filter cake.

[0061] S5: Refined

[0062] The filter cake of step S4 was extracted with acetone, the mass ratio of acetone to filter cake was 12:1, and after heating and refluxing at 60°C for 25 minutes, the mixture was filtered, and the filtrate and filter cake were collected. The filter cake was extracted twice by the above method, the filtrates were combined and concentrated, and the mixture was rinsed with 2 times of drinking water, and the diol extract was obtained.

[0063] The diol extract was purified by using a mixed solvent of chloroform and toluene, wherein the volume ratio of chloroform to toluene in the mixed solvent was 5:1. The purification process was as follows: the diol extract was put into the mixed solvent, heated and refluxed at 60°C for 20 minutes, concentrated after heating and reflux, and cooled to 0°C for crystallization. The purification method was repeated 4 times to obtain 22.1 g of recovered diol. After testing, the HPLC content of the recovered diol was 99.1%.

[0064] Comparative Example 1

[0065] This control example is basically the same as Example 1 except that step S1 is not performed. After testing, the HPLC content of the recovered diol obtained in this control example is 95.3%.

[0066] Comparative Example 2

[0067] This control example is basically the same as Example 1 except that step S2 is not performed. After testing, the HPLC content of the recovered diol obtained in this control example is 97.7%.

[0068] Comparative Example 3

[0069] This control example is basically the same as Example 1 except that acetone is not used to extract the crude diol in step S5. In this control example, 15.2 g of diol is recovered, and the HPLC content is 98.1%.

[0070] Comparative Example 4

[0071] This comparative example is substantially the same as Example 1 except that a mixed solvent of dichloroethane and acetone (the volume ratio of dichloroethane to acetone in the mixed solvent is 4:1) is used to replace the mixed solvent of Example 1 in step S5; 20.2 g of diol is recovered in this comparative example, and the HPLC content is 97.8%.

[0072] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for treating a diol re-refined mother liquor, characterized in that: The steps include: S1: Mix the dihydroxy refined mother liquor with water and stir to raise the temperature, then dropwise add sodium hydroxide solution, keep warm, drain and wash with water to obtain the recovered 17-hydroxyprogesterone crude product; S2: beating the recovered 17-hydroxyprogesterone crude product with ethanol to obtain a beating material; S3: purifying the slurry to obtain a mixture of dihydroxy and 17-hydroxyprogesterone; S4: hydroxylating the mixture of the diol and 17-hydroxyprogesterone at the 11-position to obtain a crude diol; S5: purifying the crude diol product to obtain a recovered diol; The diol is 11,17-dihydroxyprogesterone; The diol re-refined mother liquor is formed by refining the mother liquor produced by microbial fermentation of 17-hydroxyprogesterone with Rhizopus nigromatus or Aspergillus ochraceus. Step S2 comprises: mixing the recovered 17-hydroxyprogesterone crude product and ethanol and heating and refluxing, cooling and filtering after heating and refluxing to obtain a slurry; wherein the ratio of the recovered 17-hydroxyprogesterone crude product to ethanol is 1 g: 4-5 mL, the heating and refluxing temperature is controlled to be 75-85° C., and the heating and refluxing time is 20-30 min; Step S3 comprises: mixing the slurry, dichloromethane and methanol, stirring and heating to 40-55°C, keeping warm for 20-30 minutes, concentrating, cooling to -5°C to 5°C, discharging and drying to obtain a mixture of diols and 17-hydroxyprogesterone; wherein the dosage ratio of the slurry, dichloromethane and methanol is 1g:2-3mL:0.4-0.6mL.

2. The processing method according to claim 1, characterized in that: In step S1, the mass concentration of the sodium hydroxide solution is 35-45%; the usage ratio of the diol re-refined mother liquor, water and the sodium hydroxide solution is 1g: 4-6mL: 0.1-0.3mL.

3. The processing method according to claim 1, characterized in that: In step S1, the temperature is raised to 90-100° C. with stirring; the heat preservation time is 10-15 minutes.

4. The processing method according to claim 1, characterized in that: In step S4, the 11-position hydroxylation comprises: fermenting a mixture of diols and 17-hydroxyprogesterone using Rhizopus niger or Aspergillus ochraceus.

5. The processing method according to claim 1, characterized in that: In step S5, the refining includes: firstly extracting the crude diol product with acetone, and then purifying it with a mixed solvent of chloroform and toluene; wherein the volume ratio of chloroform to toluene in the mixed solvent is 3-5:1.

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