Progesterone preparation intermediate and preparation method thereof

Abstract

The invention relates to the technical field of preparation of progesterone preparation intermediates, in particular to a progesterone preparation intermediate and a preparation method thereof.The progesterone preparation intermediate comprises dinorcitol, the main component of the dinorcitol is anagesterone, the structural formula of the dinorcitol is R1-OH R2-OH, R1 and R2 represent two different organic groups respectively, the molecule of the dinorcitol contains two hydroxyl functional groups, and the molecular weight of the dinorcitol is larger than that of the angesterone. According to the method, two carbon atoms are respectively connected to two different carbon atoms, soil samples are preferentially obtained from soil, wet land and peat land which are not chemically polluted, so that the quality and the stability of raw materials are ensured, and the raw materials are strictly pretreated, such as purification, drying and the like, so that impurities and moisture in the raw materials are removed. According to the present invention, by adjusting the reaction temperature, the reaction pressure and other conditions and optimizing the reaction process, the generation of the side reaction can be easily reduced, the reaction selectivity and the reaction conversion rate can be easily improved, and the purity and the yield of the dinorhydrin can be improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of progesterone preparation intermediates, in particular to a progesterone preparation intermediate and a preparation method thereof. BACKGROUND

[0002] Progesterone preparation intermediates refer to compounds used as raw materials or intermediate products in the synthesis of progesterone or related drugs. These intermediates usually have specific chemical structures and properties and are an indispensable part of progesterone synthesis. Progesterone preparation intermediates can be classified in various ways according to their chemical structures and synthesis paths.

[0003] Bianjiaol (BA), also known as progesterone intermediate, is a plant extract with white to light yellow needle-like crystals or crystalline powder. Bianjiaol is widely used in the medical field as a pharmaceutical intermediate for the production of steroid hormone drugs, such as ursodeoxycholic acid, progesterone, and plant-derived cholesterol.

[0004] Due to the influence of factors such as raw material, reaction conditions, and process control, various by-products and impurities may be produced during the preparation of bianjiaol. The presence of these impurities can seriously affect the purity of bianjiaol and thus affect its subsequent application effect. The yield of bianjiaol is influenced by various factors such as raw material quality, reaction conditions, and catalyst performance. Therefore, in actual production, the yield of bianjiaol often fluctuates greatly and is difficult to maintain stable. SUMMARY

[0005] The present application aims to solve the technical problems raised in the background art by providing a progesterone preparation intermediate and a preparation method thereof. The present application aims to solve the technical problems raised in the background art by providing a progesterone preparation intermediate and a preparation method thereof.

[0006] To achieve the above-mentioned purposes, the present application provides the following technical solutions: A progesterone preparation intermediate includes bianjiaol, the main component of which is anaprostaglandin. The structural formula of bianjiaol is: R1-OH R2-OH, where R1 and R2 represent two different organic groups. Bianjiaol molecules contain two hydroxyl functional groups, which are connected to two different carbon atoms. The main components of anaprostaglandin include ethyl abietate, kainic acid, 2-amino phenyl ether, and docosapentaenoic acid. The preparation ratio of ethyl abietate, kainic acid, 2-amino phenyl ether, and docosapentaenoic acid is 1:1.2:0.8:1.5.

[0007] Preferably, the ethyl abirate is a compound with the molecular formula C22H34O2, a density of 1.019±0.1 g / cm3, a boiling point of 417.9±19.0 ℃ at 760 mmHg, and a flash point of 201.6 ℃.

[0008] Preferably, the oxalic acid has the same molecular formula, C22H34O2, with CAS number 2548-85-8 and molecular weight of 330.50416.

[0009] Preferably, the 2-aminophenethyl ether has the chemical formula C8H11NO, a density of 1.0519±0.1 g / cm³, a boiling point of 230.3±23.0 ℃ at 760 mmHg, and a melting point of -20℃ at 760 mmHg.

[0010] Preferably, the docosapentaenoic acid has the molecular formula C22H34O2, a molecular weight of 330.504, a CAS number of 24880-45-3, a density of 0.9±0.1 g / cm3, and a boiling point of 442.2±24.0 ℃ at 760 mmHg.

[0011] A method for preparing a progesterone preparation intermediate includes the following preparation process; S1: Select an appropriate amount of live mycobacterial bacteria from actinomycetes for multiple mutagenesis to prepare strains with dual deficiencies of C1,2 dehydrogenase and C22 dehydrogenase. S1.1: The live mycobacterial strains in the actinomycetes are obtained from soil samples collected from soil rich in organic matter and free from chemical pollution. The collected soil samples are then ground, sieved, and dried to remove impurities and moisture. The microorganisms in the soil are dispersed onto the culture medium by the streak plating method. After culturing for 1-2 days, colonies suspected to be mycobacteria are selected. The selected colonies are further purified until pure cultured live mycobacterial strains are obtained. S2: The C1,2 dehydrogenase and C22 dehydrogenase dual-deficient strains were placed in the fermentation medium, and the fermentation broth was stirred and heated in a water bath. S2.1: The stirring frequency of the fermentation broth is 30 revolutions per minute, the stirring time is 1 to 2 hours, the water bath heating temperature during stirring is 80 to 100°C, and pressure treatment is carried out during water bath heating. The pressure treatment adopts a closed pressure treatment method, and the pressure of the closed space is 1.1 to 1.3 MPa. S3: Extract an appropriate amount of dilute sulfuric acid, neutralize the dilute sulfuric acid to pH 3-3.5, add perlite filter aid, heat and stir for 1-2 hours, pressurize during heating and stirring, use a closed pressurization method, the pressure of the closed space is 1.2-1.5MPa, set a one-way exhaust valve, and set the safety threshold of the one-way exhaust valve to 1.5MPa; S4: Add polyaluminum chloride and polyacrylamide, stir continuously for 2-3 hours at a stirring frequency of 60 revolutions per minute, stop heating, drain the hot water, and cool to 45-50°C using a cold water bath to obtain the progesterone preparation.

[0012] The beneficial effects of this invention are as follows: 1. Prioritize obtaining soil samples from soils, wetlands, and peatlands that have never been chemically contaminated to ensure the quality and stability of the raw materials. Perform strict pretreatment on the raw materials, such as purification and drying, to remove impurities and moisture, which helps to improve the utilization rate of the raw materials and the conversion rate of the reaction, thereby increasing the yield of diol.

[0013] 2. By adjusting reaction temperature, pressure and other conditions, the reaction process can be optimized, which helps to reduce the occurrence of side reactions, improve the selectivity and conversion rate of the reaction, and thus improve the purity and yield of diol. Detailed Implementation

[0014] The technical solutions in the embodiments of the present invention have been clearly and completely described. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0015] Example 1 An intermediate for progesterone preparation includes anaprogesterone, the main component of which is anaprogesterone. The structural formula of anaprogesterone is R1-OH R2-OH, where R1 and R2 represent two different organic groups. The anaprogesterone molecule contains two hydroxyl (-OH) functional groups attached to two different carbon atoms. The main components of anaprogesterone include ethyl abirate, hainanoxalic acid, 2-aminophenethyl ether, and eicosapentaenoic acid. The preparation ratio of ethyl abirate, hainanoxalic acid, 2-aminophenethyl ether, and eicosapentaenoic acid is 1:1.2:0.8:1.5. Ethyl abirate is a compound with the molecular formula C22H34O2, a density of 1.019±0.1 g / cm3, and a boiling point of 417.9±19.0 ℃ at 760°C. With a molecular weight of 201.6℃ and a flash point of 201.6℃, it is mainly used as a plasticizer in cellulose ester coatings. Oxalic acid also has the molecular formula C22H34O2, its CAS number is 2548-85-8, and its molecular weight is 330.50416. This compound is associated with multiple targets. 2-Aminophene ether has the chemical formula C8H11NO, a density of 1.0519±0.1 g / cm³, a boiling point of 230.3±23.0℃ at 760 mmHg, and a melting point of -20℃ at 760 mmHg. Eicosapentaenoic acid has the molecular formula C22H34O2, a molecular weight of 330.504, a CAS number of 24880-45-3, a density of 0.9±0.1 g / cm³, and a boiling point of 442.2±24.0℃ at 760 mmHg.

[0016] Example 2 A method for preparing a progesterone preparation intermediate includes the following preparation process; S1: Select an appropriate amount of live mycobacterial bacteria from actinomycetes for multiple mutagenesis to prepare strains with dual deficiencies of C1,2 dehydrogenase and C22 dehydrogenase. S1.1: The live mycobacterial strains in the actinomycetes can be obtained from soil samples collected from places rich in organic matter and free from chemical pollution, such as soil, wetlands, and peatlands. The collected soil samples are then processed appropriately, such as grinding, sieving, and drying, to remove impurities and moisture. The microorganisms in the soil are dispersed onto the culture medium by methods such as coating and streaking. After a period of cultivation, colonies suspected to be mycobacteria are selected, and the selected colonies are further purified until pure cultured live mycobacterial strains are obtained. Further purification of suspected mycobacterial colonies involves treating the sample with a digestive solution (such as the N-acetyl-L-cysteine-sodium hydroxide method) to kill other microorganisms, which facilitates the isolation of mycobacteria. The treated sample is then centrifuged to remove the supernatant, and then resuspended in sterile phosphate buffer to prepare a suspension.

[0017] S1.2: The aforementioned multiple mutagenesis of live mycobacterial strains refers to the use of ultraviolet light to irradiate mycobacteria, causing changes in their DNA molecular structure and resulting in gene mutations; S2: The C1,2 dehydrogenase and C22 dehydrogenase dual-deficient strains were placed in the fermentation medium, and the fermentation broth was stirred and heated in a water bath. S2.1: The stirring frequency of the fermentation broth is 30 revolutions per minute, the stirring time is 2 hours, the water bath heating temperature during stirring is 100℃, and pressure treatment is carried out during water bath heating. The pressure treatment adopts a closed pressure treatment method, and the pressure of the closed space is 1.1~1.3MPa. S3: Extract an appropriate amount of dilute sulfuric acid, neutralize the dilute sulfuric acid to pH 3.5, add perlite filter aid, heat and stir for 2 hours, and pressurize during the heating and stirring process. The pressurization process adopts a closed pressurization method with a closed space pressure of 1.5MPa. A one-way exhaust valve is set with a safety threshold of 1.5MPa to avoid excessive reaction pressure and damage to the reaction vessel. The exhaust gas discharged from the one-way exhaust valve is collected to prevent diffuse diffusion and pollution of the reaction environment.

[0018] S3.1: The perlite filter aid is a powdered chemical product with a certain particle size distribution, obtained by selectively expanding small-particle-size mineral sand in a vertical kiln after heating with purified coal gas and grinding and purifying it after expansion. The perlite filter aid itself does not contain organic matter. It achieves sterilization through high-temperature (1100℃) combustion during the production process. It has good chemical stability and no potential pollutants. Its heavy metal ion content is generally less than 0.005%. S4: Add polyaluminum chloride and polyacrylamide, stir continuously for 3 hours at a stirring frequency of 60 revolutions per minute, stop heating, drain the hot water, and cool to 50°C using a cold water bath to obtain the progesterone preparation; S4.1: The polyaluminum chloride is obtained by reacting aluminum raw material with hydrochloric acid, and then adjusting the alkalinity with sodium aluminate to obtain the product PAC; S4.2: The preparation method of the polyacrylamide involves purifying the acrylamide monomer solution through ion exchange to ensure that the reaction medium is deionized water. A redox initiation system composed of persulfate and sulfite is often used to lower the reaction initiation temperature. In addition, chain transfer agents (such as isopropanol) and chelating agents (such as ethylenediaminetetraacetic acid, EDTA) are added to eliminate the influence of possible metal ions. To facilitate temperature control, the monomer concentration is usually below 25%. Due to the high heat of polymerization of acrylamide, the heat of polymerization must be removed promptly. When producing low molecular weight products, intermittent operation or continuous production of several reactors in series can be carried out in a batch reactor, with jacket cooling to maintain the reaction temperature. When producing high molecular weight products, since the product is in a gel-like state and cannot be stirred, the materials in the formula must be mixed evenly and immediately fed into polyethylene bags for cooling and reaction in a water tank. After the reaction is completed, the product needs to undergo post-processing steps such as drying and pulverizing to obtain the final product.

[0019] Example 3 A method for preparing a progesterone preparation intermediate includes the following preparation process; S1: Select an appropriate amount of live mycobacterial bacteria from actinomycetes for multiple mutagenesis to prepare strains with dual deficiencies of C1,2 dehydrogenase and C22 dehydrogenase. S1.1: The live mycobacterial strains in the actinomycetes can be obtained from soil samples collected from places rich in organic matter and free from chemical pollution, such as soil, wetlands, and peatlands. The collected soil samples are then processed appropriately, such as grinding, sieving, and drying, to remove impurities and moisture. The microorganisms in the soil are dispersed onto the culture medium by methods such as coating and streaking. After a period of cultivation, colonies suspected to be mycobacteria are selected, and the selected colonies are further purified until pure cultured live mycobacterial strains are obtained. Further purification of suspected mycobacterial colonies involves treating the sample with a digestive solution (such as the N-acetyl-L-cysteine-sodium hydroxide method) to kill other microorganisms, which facilitates the isolation of mycobacteria. The treated sample is then centrifuged to remove the supernatant, and then resuspended in sterile phosphate buffer to prepare a suspension.

[0020] S1.2: The aforementioned multiple mutagenesis of live mycobacterial strains refers to the use of ultraviolet light to irradiate mycobacteria, causing changes in their DNA molecular structure and resulting in gene mutations; S2: The C1,2 dehydrogenase and C22 dehydrogenase dual-deficient strains were placed in the fermentation medium, and the fermentation broth was stirred and heated in a water bath. S2.1: The stirring frequency of the fermentation broth is 30 revolutions per minute, the stirring time is 1 hour, the water bath heating temperature during stirring is 80℃, and pressure treatment is carried out during water bath heating. The pressure treatment adopts a closed pressure treatment method, and the pressure of the closed space is 1.1MPa. S3: Extract an appropriate amount of dilute sulfuric acid, neutralize the dilute sulfuric acid to pH 3, add perlite filter aid, heat and stir for 1 hour, and pressurize during the heating and stirring process. The pressurization process adopts a closed pressurization method with a closed space pressure of 1.2 MPa. A one-way exhaust valve is set with a safety threshold of 1.5 MPa to avoid excessive reaction pressure and damage to the reaction vessel. The exhaust gas discharged from the one-way exhaust valve is collected to prevent diffuse diffusion and pollution of the reaction environment.

[0021] S3.1: The perlite filter aid is a powdered chemical product with a certain particle size distribution, obtained by selectively expanding small-particle-size mineral sand in a vertical kiln after heating with purified coal gas and grinding and purifying it after expansion. The perlite filter aid itself does not contain organic matter. It achieves sterilization through high-temperature (1100℃) combustion during the production process. It has good chemical stability and no potential pollutants. Its heavy metal ion content is generally less than 0.005%. S4: Add polyaluminum chloride and polyacrylamide, stir continuously for 2 hours at a stirring frequency of 60 revolutions per minute, stop heating, drain the hot water, and cool to 45°C using a cold water bath to obtain the progesterone preparation; S4.1: The polyaluminum chloride is obtained by reacting aluminum raw material with hydrochloric acid, and then adjusting the alkalinity with sodium aluminate to obtain the product PAC; S4.2: The preparation method of the polyacrylamide involves purifying the acrylamide monomer solution through ion exchange to ensure that the reaction medium is deionized water. A redox initiation system composed of persulfate and sulfite is often used to lower the reaction initiation temperature. In addition, chain transfer agents (such as isopropanol) and chelating agents (such as ethylenediaminetetraacetic acid, EDTA) are added to eliminate the influence of possible metal ions. To facilitate temperature control, the monomer concentration is usually below 25%. Due to the high heat of polymerization of acrylamide, the heat of polymerization must be removed promptly. When producing low molecular weight products, intermittent operation or continuous production of several reactors in series can be carried out in a batch reactor, with jacket cooling to maintain the reaction temperature. When producing high molecular weight products, since the product is in a gel-like state and cannot be stirred, the materials in the formula must be mixed evenly and immediately fed into polyethylene bags for cooling and reaction in a water tank. After the reaction is completed, the product needs to undergo post-processing steps such as drying and pulverizing to obtain the final product.

[0022] In summary, the progesterone intermediate prepared in Example 2 can effectively improve the purity and yield of dichlorol during the process, and its effect is superior to the result obtained in Example 3.

[0023] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A progesterone preparation intermediate, characterized in that, This includes dichlorvos, the main component of which is anargorne, and the structural formula of which is: R1-OH R2-OH; R1 and R2 represent two different organic groups. The dichlorol molecule contains two hydroxyl functional groups, which are attached to two different carbon atoms. The main components of the alpha-pregnant ketone include ethyl abirate, hainan oxalic acid, 2-aminophenethyl ether, and eicosapentaenoic acid, and the preparation ratio of ethyl abirate, hainan oxalic acid, 2-aminophenethyl ether, and eicosapentaenoic acid is 1:1.2:0.8:1.

5.

2. The progesterone preparation intermediate according to claim 1, characterized in that: Ethyl abirate is a compound with the molecular formula C22H34O2, a density of 1.019±0.1 g / cm3, a boiling point of 417.9±19.0 ℃ at 760 mmHg, and a flash point of 201.6 ℃.

3. The progesterone preparation intermediate according to claim 1, characterized in that: The oxalic acid mentioned also has the molecular formula C22H34O2, its CAS number is 2548-85-8, and its molecular weight is 330.50416.

4. The progesterone preparation intermediate according to claim 1, characterized in that: The 2-aminophenethyl ether has the chemical formula C8H11NO, a density of 1.0519±0.1 g / cm³, a boiling point of 230.3±23.0 ℃ at 760 mmHg, and a melting point of -20℃ at 760 mmHg.

5. The progesterone preparation intermediate according to claim 1, characterized in that: The molar formula of the docosapentaenoic acid is C22H34O2, the molecular weight is 330.504, the CAS number is 24880-45-3, the density is 0.9±0.1 g / cm3, and the boiling point is 442.2±24.0 ℃ at 760 mmHg.

6. A method for preparing a progesterone formulation intermediate as described in any one of claims 1-5, characterized in that: The following preparation processes are included; S1: Select an appropriate amount of live mycobacterial bacteria from actinomycetes for multiple mutagenesis to prepare strains with dual deficiencies of C1,2 dehydrogenase and C22 dehydrogenase. S1.1: The live mycobacterial strains in the actinomycetes are obtained from soil samples collected from soil rich in organic matter and free from chemical pollution. The collected soil samples are then ground, sieved, and dried to remove impurities and moisture. The microorganisms in the soil are dispersed onto the culture medium by the streak plating method. After culturing for 1-2 days, colonies suspected to be mycobacteria are selected. The selected colonies are further purified until pure cultured live mycobacterial strains are obtained. S2: The C1,2 dehydrogenase and C22 dehydrogenase dual-deficient strains were placed in the fermentation medium, and the fermentation broth was stirred and heated in a water bath. S2.1: The stirring frequency of the fermentation broth is 30 revolutions per minute, the stirring time is 1 to 2 hours, the water bath heating temperature during stirring is 80 to 100°C, and pressure treatment is carried out during water bath heating. The pressure treatment adopts a closed pressure treatment method, and the pressure of the closed space is 1.1 to 1.3 MPa. S3: Extract an appropriate amount of dilute sulfuric acid, neutralize the dilute sulfuric acid to pH 3-3.5, add perlite filter aid, heat and stir for 1-2 hours, pressurize during heating and stirring, use a closed pressurization method, the pressure of the closed space is 1.2-1.5MPa, set a one-way exhaust valve, and set the safety threshold of the one-way exhaust valve to 1.5MPa; S4: Add polyaluminum chloride and polyacrylamide, stir continuously for 2-3 hours at a stirring frequency of 60 revolutions per minute, stop heating, drain the hot water, and cool to 45-50°C using a cold water bath to obtain the progesterone preparation.