CN112209987B - Preparation method of dienogest - Google Patents
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Abstract
The invention relates to a preparation method of dienogest, which comprises the following steps: providing a compound having a structure represented by formula (II); carrying out acidolysis deprotection reaction on the compound shown in the formula (II) in a fluoroboric acid aqueous solution to obtain a compound with a structure shown in the formula (I);
the preparation method of dienogest fundamentally solves the problems of low purity and dark color of the crude product in the acidolysis deprotection process, greatly simplifies the production process and reduces the production cost of enterprises.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of dienogest.
Background
Dienogest (Dienogest) is a progestogenic drug with the chemical name 17 α -cyanomethyl-17 β -hydroxy-13 β -methylstane-4, 9-dien-3-one, which was marketed in germany as a contraceptive in 1995 (2mg +0.03mg) and in australia in 2007 under the name Valette. In 2001, a compound preparation of dienogest and estradiol valerate (containing 2mg of dienogest and 1 or 2mg of estradiol valerate) is marketed by mr. Ling company in Germany for hormone replacement therapy for women with estrogen deficiency for more than one year at menopause. It was marketed in 2002 in European countries such as Denmark, France, Belgium, etc. under the trade name Climodie. Dienogest tablets (1mg) were marketed in japan in 2007 for the treatment of endometriosis.
The traditional dienogest synthesis process comprises the following steps: androstane-4, 9-diene-3, 17-diketone is taken as an initial raw material, protected by a 3-keto group, reacted by acetonitrile and n-butyllithium at low temperature to form 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstane diene-3, 17-diketone-3, 3-ethylidene ketal, and finally subjected to acidolysis and deprotection to obtain a compound 17 alpha-cyanomethyl-17 beta-hydroxy-4, 9-diene-3 ketone. The final step of acid hydrolysis and deprotection is a key step, strong acids such as perchloric acid and sulfuric acid are generally adopted for acidolysis in the traditional method, but certain destructiveness is generated on a substrate when strong acids such as perchloric acid and sulfuric acid are adopted for acidolysis, the color of a generated crude product is dark yellow, and an obtained refined product is still yellow through a common refining method such as a decolorizing agent. Some companies adopt concentrated hydrochloric acid for acidolysis and deprotection to obtain crude products, the purity of the crude products is more than or equal to 98 percent after twice recrystallization by acetone, the yield is only 43.5 percent, and the yield is very low. In addition, the obtained crude product has the purity of 70 percent only by adopting acidolysis deprotection of p-toluenesulfonic acid, hydrochloric acid, acetic acid and the like, and the raw material medicament meeting the medicinal standard can be obtained only by 3-5 times of recrystallization. In addition, the company protects the 3-carbonyl group by using mercaptan, and the last step uses iodine to remove the 3-protecting group in an alkaline environment, but on one hand, the mercaptan has great taste, and the sulfur-containing wastewater generated in the later stage is not environment-friendly; on the other hand, deprotection in an alkaline environment causes unstable cyanomethyl at the 17-position, and the cyanomethyl is easily hydrolyzed into carboxylic acid, thereby reducing the yield of the target product.
Disclosure of Invention
Therefore, the preparation method of the dienogest fundamentally solves the problems of low purity and dark color of the crude product of the acidolysis deprotection process, greatly simplifies the production process and reduces the production cost of enterprises.
A preparation method of dienogest comprises the following steps:
carrying out acidolysis deprotection reaction on the compound shown in the formula (II) in a fluoroboric acid aqueous solution to obtain a compound with a structure shown in the formula (I);
in one embodiment, the concentration of the fluoroboric acid aqueous solution is 30-80%.
In one embodiment, the concentration of the fluoroboric acid aqueous solution is 40-50%.
In one embodiment, the step of performing acidolysis deprotection reaction on the compound with the structure shown in the formula (II) in the fluoroboric acid aqueous solution comprises the following steps:
dissolving a compound with a structure shown in a formula (II) in an organic solvent, adding the fluoroboric acid aqueous solution, reacting for 3-6 h at the temperature of 20-45 ℃, and adjusting the pH to 6.8-7.5 after the reaction is finished to obtain a reaction solution;
mixing the reaction solution with water, separating out solid, solid-liquid separating, collecting solid and drying.
In one embodiment, the volume ratio of the organic solvent to the fluoroboric acid aqueous solution is 10: 1-20: 1; the volume ratio of the reaction liquid to the water is (0.4-1): 1.
In one embodiment, the organic solvent is selected from: at least one of methanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, acetone, and 4-methyl-tetrahydropyran.
In one embodiment, the step of acid hydrolysis deprotection further comprises a refining step, and the refining step comprises the following steps:
dissolving the crude product obtained by the acidolysis deprotection reaction in an organic solvent, treating by adopting medicinal activated carbon, carrying out solid-liquid separation, and collecting filtrate;
and (3) recrystallizing the filtrate, collecting precipitated crystals, and drying to obtain the refined compound with the structure shown in the formula (I).
In one embodiment, the organic solvent is 4-methyltetrahydropyran, and 8 mL-15 mL of 4-methyltetrahydropyran is added to 1g of the crude product of the compound with the structure shown in the formula (I); 0.01-0.1 g of medicinal activated carbon is added into 1g of crude product of the compound with the structure shown in the formula (I).
In one embodiment, the recrystallization step comprises the following steps:
concentrating the filtrate to obtain a residual liquid, wherein the volume of the residual liquid is 1/5-1/2 of the filtrate;
cooling the residual liquid to 0-5 ℃, standing, separating out crystals, carrying out solid-liquid separation, collecting the crystals, washing and drying.
In one embodiment, the method further comprises a preparation step of the compound shown in the formula (II):
and (3) reacting the compound shown in the formula (III) with cyanomethyl lithium to obtain the compound shown in the formula (II).
In one embodiment, the step of reacting the compound of formula (III) with cyanomethyl lithium comprises the steps of:
mixing a butyl lithium reagent and tetrahydrofuran at the temperature of between 50 ℃ below zero and 90 ℃ below zero, adding acetonitrile tetrahydrofuran mixed solution, and reacting for 4 to 15 minutes;
and adding a tetrahydrofuran solution of the compound shown in the formula (III) for reaction, quenching the reaction after the reaction is completed, and performing post-treatment to obtain the compound shown in the formula (II).
In one embodiment, after the reaction is completed, the reaction is quenched, an organic solvent is added for extraction, an organic phase is collected, and an oily substance is obtained by concentration;
and (2) replacing the residual solvent in the oily substance with the organic solvent used in the acidolysis deprotection step by adopting a solvent replacement method to obtain a solution containing the compound with the structure shown in the formula (II), and directly carrying out the subsequent acidolysis deprotection step on the solution containing the compound with the structure shown in the formula (II).
Through a great deal of research, technicians of the invention find that the color of a crude product obtained after acidolysis deprotection in the traditional method is dark yellow, and the crude product still appears yellow even after refining, which is probably caused by the fact that the strength of acid is too strong in acidolysis deprotection; in the acidolysis deprotection process, a byproduct 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone is generated, and the content of the byproduct is closely related to the type of the adopted acid; the technical personnel of the invention find that the content of 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone can be effectively reduced by adopting fluoboric acid, the purity of the target product is improved, the reaction yield can also reach more than 80 percent, the obtained crude product is basically pure white solid, the difficulty of subsequent refining treatment is reduced, the purity can reach more than 99.5 percent only by one-time refining, the single impurity is less than 0.10 percent, the quality standard of pharmacopoeia is met, and the production difficulty is effectively reduced.
In addition, the raw materials in the method are cheap and easy to obtain, the compound with the structure shown in the formula (II) can be obtained only by carrying out nucleophilic addition reaction on corresponding raw materials containing ketone groups and cyanomethyl lithium, the acidolysis deprotection reaction has low requirement on the purity of a substrate, and the subsequent reaction can be directly carried out without column separation after the reaction, so that the target product can be prepared by a real one-pot method, and the production cost is greatly reduced.
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FIG. 1 is a mass spectrum of a target product in example 1 of the present invention;
figure 2 is a product photograph of a portion of the product of the present invention.
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.
One embodiment of the invention provides a preparation method of dienogest, which comprises the following steps:
s101: providing a compound having a structure represented by formula (II);
the compound of formula (II) can be prepared by conventional methods, and is not particularly limited herein, and it is understood that the compound of formula (II) is preferably prepared by the following method:
s1011: providing a compound shown as a formula (III);
the compounds of formula (III) may be prepared by conventional methods, and are not particularly limited herein and are understood to be within the scope of the present invention.
S1012: reacting a compound shown in a formula (III) with cyanomethyl lithium to obtain a compound with a structure shown in a formula (II);
further, step S1012 includes the steps of:
s1012a, mixing the butyl lithium reagent and tetrahydrofuran at the temperature of between 50 ℃ below zero and 90 ℃ below zero, adding acetonitrile tetrahydrofuran mixed solution, and reacting for 4 to 15 minutes;
it can be understood that, in step S1012a, the butyl lithium reagent may be a n-butyl lithium reagent, or may be a tert-butyl lithium reagent, and is preferably a n-butyl lithium reagent;
further, in step S1012a, the concentration of the butyl lithium reagent is 2mol/L to 3 mol/L; further, in step S1012a, the concentration of the butyl lithium reagent is 2.4mol/L to 2.6 mol/L; furthermore, 2 mL-4 mL tetrahydrofuran is added into each 1g acetonitrile tetrahydrofuran solution;
s1012 b: adding tetrahydrofuran solution of the compound shown in the formula (III) for reaction, quenching the reaction after the reaction is completed, and performing post-treatment to obtain the compound shown in the formula (II);
further, in step S1012b, 2mL to 4mL of tetrahydrofuran is added per 1g of the compound represented by the formula (III);
further, in step S1012b, the volume ratio of the acetonitrile tetrahydrofuran solution to the tetrahydrofuran solution of the compound represented by formula (III) is 1:3 to 1: 8; furthermore, the volume ratio of the acetonitrile tetrahydrofuran solution to the tetrahydrofuran solution of the compound shown in the formula (III) is 1: 4-1: 6;
because the method has lower requirement on the purity of the substrate, the crude product obtained in the step can be directly put into the subsequent step of acid hydrolysis deprotection without purification, thereby greatly reducing the difficulty of separation and purification and lowering the production cost.
Specifically, in step S1012b, after the reaction is completed, quenching the reaction, adding an organic solvent for extraction, collecting an organic phase, and concentrating to obtain an oily substance; and (3) replacing the solvent in the oily substance by using an organic solvent (such as acetonitrile) used in the acidolysis deprotection step by using a solvent replacement method to obtain a solution containing the compound with the structure shown in the formula (II), wherein the solution containing the compound with the structure shown in the formula (II) is directly used in the subsequent acidolysis deprotection step.
S102: carrying out acidolysis deprotection on the compound with the structure shown in the formula (II) in a fluoroboric acid aqueous solution to prepare a compound with the structure shown in the formula (I);
it is understood that "acid hydrolysis deprotection" in the present invention refers to a reaction of removing a protecting group by an acid hydrolysis reaction.
Through a great deal of research, technicians of the invention find that the color of a crude product obtained after acidolysis deprotection in the traditional method is dark yellow, and the crude product still appears yellow even after refining, which is probably caused by the fact that the strength of acid is too strong in acidolysis deprotection; in the acidolysis deprotection process, a byproduct 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone is generated, and the content of the byproduct is closely related to the type of the adopted acid; the technical personnel of the invention find that the content of 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone can be effectively reduced by adopting fluoboric acid, the purity of the target product is improved, the reaction yield can also reach more than 80 percent, the obtained crude product is basically pure white solid, the difficulty of subsequent refining treatment is reduced, the purity can reach more than 99.5 percent only by one-time refining, the single impurity is less than 0.10 percent, the quality standard of pharmacopoeia is met, and the production difficulty is effectively reduced.
In addition, the raw materials in the method are cheap and easy to obtain, the compound with the structure shown in the formula (II) can be obtained only by carrying out nucleophilic addition reaction on corresponding raw materials containing ketone groups and cyanomethyl lithium, the acidolysis deprotection reaction has low requirement on the purity of a substrate, and the subsequent reaction can be directly carried out without column separation after the reaction, so that the target product can be prepared by a real one-pot method, and the production cost is greatly reduced.
Further, step S102 includes the steps of: dissolving a compound with a structure shown in a formula (II) in an organic solvent, adding a fluoroboric acid aqueous solution, reacting for 3-6 h at the temperature of 20-45 ℃, and adjusting the pH to 6.8-7.5 after the reaction is finished to obtain a reaction solution; mixing the reaction solution with water, separating out solid, solid-liquid separating, collecting solid, and drying.
Further, the reaction solution is preferably poured slowly into water, so as to be beneficial to obtaining a product with higher purity;
further, the concentration of the fluoboric acid aqueous solution is 30-80 percent; furthermore, the concentration of the fluoboric acid aqueous solution is 40 to 70 percent; furthermore, the concentration of the fluoboric acid aqueous solution is 45 to 65 percent; furthermore, the concentration of the fluoroboric acid aqueous solution is 47-53 percent; further, the concentration of the aqueous fluoroboric acid solution was 50%.
Furthermore, the volume ratio of the organic solvent to the fluoroboric acid aqueous solution is 10: 1-20: 1; furthermore, the volume ratio of the organic solvent to the fluoroboric acid aqueous solution is 12: 1-18: 1; further, the volume ratio of the organic solvent to the fluoroboric acid aqueous solution is 13: 1-16: 1; furthermore, the volume ratio of the organic solvent to the fluoroboric acid aqueous solution is 14: 1-15: 1;
further, the volume ratio of the reaction liquid to water is 0.4: 1-1: 1; furthermore, the volume ratio of the reaction liquid to water is 0.5: 1-0.8: 1; further, the volume ratio of the reaction liquid to water is 0.6: 1-0.7: 1.
Further, the organic solvent is selected from: one or more of methanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, acetone, and 4-methyl-tetrahydropyran; still further, the organic solvent is acetonitrile.
S103: refining;
further, step S103 includes the steps of:
s1031: dissolving the crude product obtained by the acidolysis deprotection reaction in an organic solvent, treating by adopting medicinal activated carbon, carrying out solid-liquid separation, and collecting filtrate;
further, the organic solvent in step S1031 is one or more of dichloromethane, methanol, ethanol, isopropanol, tetrahydrofuran, 4-methyl-tetrahydropyran, acetone, toluene, ethyl acetate and acetonitrile; further, the organic solvent is 4-methyl-tetrahydropyran;
further, 5-15 mL of organic solvent is added into each 1g of the crude product of the structural compound shown in the formula (I); furthermore, 8-15 mL of organic solvent is added into 1g of the crude product of the structural compound shown in the formula (I); further, adding 9-12 mL of organic solvent into 1g of crude product of the structural compound shown in the formula (I);
further, 0.01-0.1 g of medicinal activated carbon is added into each 1g of the crude product of the compound with the structure shown in the formula (I); furthermore, 0.03-0.06 g of medicinal activated carbon is added into 1g of the crude product of the structural compound shown in the formula (I); adding 0.045-0.055 g of medicinal activated carbon into 1g of the crude product of the structural compound shown in the formula (I);
s1032: and (4) recrystallizing the filtrate, collecting precipitated crystals, and drying to obtain the refined compound with the structure shown in the formula (I).
It can be understood that, in step S1032, the existing method can be adopted for recrystallization, and because the acidolysis deprotection method of the present invention has low impurity content and high purity, the recrystallization is relatively simple, and the existing recrystallization method can basically realize refining and purification; the following method is preferably adopted for recrystallization, so as to further improve the purity of the final product, and the operation is simple and convenient:
s1032 a: concentrating the filtrate to obtain a residual liquid, wherein the volume of the residual liquid is 1/5-1/2 of the filtrate;
s1032 b: cooling the residual liquid to 0-5 deg.c, letting stand to separate out crystal, solid-liquid separation, collecting crystal, washing and drying.
Further, in the washing in step S1032b, the washing may be performed with a good solvent or with a mixed solution of a good solvent and a poor solvent, and the washing solvent may be the same as or different from the organic solvent used in the purification process, and is not to be construed as a limitation of the present invention, and the washing with 4-methyl-tetrahydropyran is preferable.
Further, the drying temperature in step S1032b may be adjusted according to the selected organic solvent, and is not to be construed as limiting the present invention, and in one embodiment, the drying temperature is 65 ℃ to 85 ℃; further, the drying temperature is 75 ℃ to 82 ℃.
The present invention will be described below with reference to specific examples.
Example 1
(1) Preparation of a compound of formula (II), namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal
Adding 120ml of 2.5mol/L n-butyllithium into a reaction bottle, cooling to below-50 ℃, adding 240ml of tetrahydrofuran, continuously cooling to below-50 ℃, beginning to dropwise add a mixed solution (8.0g/20ml) of acetonitrile and tetrahydrofuran, stirring for 5 minutes after dropwise addition, dropwise adding a 17 beta-hydroxy-5, 9-androstadiene-3, 7-dione-3, 3-ethylidene ketal (source: New Biomedicine Limited in Hunan, purity is more than or equal to 99.30%, single impurity is less than 0.10%) tetrahydrofuran solution (30g/100ml), controlling the temperature to be between-50 ℃ and-90 ℃ after dropwise addition, reacting for 30 minutes, completely reacting, dropwise adding dilute hydrochloric acid to stop the reaction, layering, concentrating organic phase by pressure to obtain a light yellow oily substance, weighing 32g, yield 106%, and purity 98.5%.
(2) Preparation of 17 alpha-cyanomethyl-17 beta-hydroxy-4, 9-androstadiene-3-one (crude dienogest)
Adding 320ml of acetonitrile into the reaction bottle in the step (1), stirring for dissolving, adding 22.4ml of 50% fluoroboric acid aqueous solution, controlling the temperature to be between 20 and 45 ℃, reacting for 4 hours, completely reacting, adding 20% sodium carbonate aqueous solution, adjusting the pH value to be neutral, slowly pouring the reaction solution into 480ml of water, stirring for elutriation, filtering, drying the filter cake at the temperature of between 50 and 60 ℃ for 20 hours to obtain 26.4g of white-like solid, wherein the yield is 88.0% (calculated by the compound shown in the formula (I), the purity is 98.6%, and the maximum single impurity is the compound 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone (0.88%).
(3) Refining dienogest:
adding 26g of crude dienogest product into a reaction bottle, adding 310ml of 4-methyl-tetrahydropyran, adding 1.3g of medicinal activated carbon, heating to reflux and dissolve, carrying out hot filtration, collecting filtrate, concentrating the filtrate at 45 ℃ under reduced pressure to a small volume, cooling to 0-5 ℃ for crystallization for 2 hours, filtering, leaching a filter cake once with cold 4-methyl-tetrahydropyran, drying the solid at 80 ℃ for 20 hours to obtain 22.8g of white crystalline particles, grinding or crushing the white crystalline particles into white powdery solid with the yield of 87.7 percent, calculating the total yield of the compound shown in the formula (I) to be 76 percent, the purity of the white crystalline particles to be 99.6 percent and the single impurity content of the white crystalline particles to be less than 0.10 percent, wherein the mass spectrum of the compound is shown in figure 1 (Agilent 1260, 6120-LCMS, the conditions A/0.05 percent formic acid, B/acetonitrile, the column temperature of 30 ℃ and the flow rate of 1 ml/min);
nuclear magnetic data1H NMR(400MHz,DMSO-d6)δ5.01(s,1H),2.92–2.75(m,2H),2.69(d,J＝16.4Hz,1H),2.59–2.50(m,2H),2.50–2.39(m,1H),2.39–2.28(m,4H),2.26(s,1H),2.09(dq,J＝15.5,5.1Hz,1H),1.90–1.77(m,3H),1.60(tdd,J＝11.4,7.4,3.5Hz,2H),1.42–1.29(m,2H),1.20(td,J＝13.1,4.3Hz,2H),0.93(s,3H).
Comparative examples 1 to 9
The method is substantially the same as example 1, except that the acid used in the step of acid hydrolysis deprotection is different as follows:
comparative example 1: in the reaction bottle in the step (1), namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal (15.8g, purity of 97.6 percent), 160ml of acetonitrile is added, stirred and dissolved out, 11.8ml of concentrated hydrochloric acid is added, the temperature is controlled between 20 ℃ and 45 ℃, reaction is carried out for 4 hours, after the reaction is completed, 20 percent sodium carbonate aqueous solution is added to adjust the pH value to be neutral, the reaction solution is slowly poured into 180ml water, stirred for elutriation, filtered, the filter cake is dried for 20 hours at 50 to 60 ℃, 11.5g of white-like solid is obtained, the yield is 77.0 percent (based on the compound shown in the formula (I)), the purity is 95.6 percent, and the maximum single hetero is the compound 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone (3.28 percent).
Comparative example 2: adding 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal (31.8g, purity of 97.9%) into 320ml of acetonitrile in a reaction bottle in the step (1), stirring to dissolve clear, adding 23ml of perchloric acid, enabling the reaction system to immediately turn black, dissolving clear, controlling the temperature to be 20-45 ℃, reacting for 1 hour, enabling the system not to separate out solids, completely reacting, adding 20% sodium carbonate aqueous solution to adjust the pH value to be neutral, slowly pouring the reaction liquid into 480ml of water, stirring to separate out water, filtering, drying filter cakes for 20 hours at the temperature of 50-60 ℃ to obtain 25.8g of dark yellow solid, wherein the yield is 86.0% (based on the compound shown in the formula (I), the purity is 97.6%, and the maximum single impurity is 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one (0.85%)
Comparative example 3: in the reaction bottle of the step (1), namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal (10.6g, purity 98.1%), adding 110 acetonitrile, stirring to dissolve, adding 10ml of acetic acid, controlling the temperature to be 20-45 ℃, reacting for 1 hour, controlling the reaction in TLC, prolonging the reaction time to 3 hours, reacting TLC raw materials to be 10-20%, adding 20% sodium carbonate aqueous solution to adjust the pH to be neutral, slowly pouring the reaction liquid into 480ml of water, stirring for elutriation, filtering, drying a filter cake at 50-60 ℃ for 20 hours to obtain 8.3g of yellow solid, the yield is 83% (calculated by the compound shown in the formula (I), 13%, the raw material residue is 78.8%, and the maximum single impurity is 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one (3.94%)
Comparative example 4: in the reaction bottle in the step (1), namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal (21.8g, purity 97.9 percent), 220ml of acetonitrile is added, the mixture is stirred and dissolved, 16ml of propionic acid is added, the reaction is carried out for 3 hours at 20-45 ℃, adding 20% sodium carbonate aqueous solution to adjust pH to neutral, slowly pouring the reaction solution into 350ml water, stirring, precipitating with water, filtering, drying the filter cake at 50-60 deg.C for 20 hr, 16.8g of light yellow solid is obtained, the yield is 84.0 percent (based on the compound shown in the formula (I)), the purity is 82.3 percent, the raw material is remained for 3 percent, and the maximum single hetero is the compound 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone (11.6 percent).
Comparative example 5: in the reaction bottle in the step (1), namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal (11.3g, purity 97.5 percent), adding 120ml of acetonitrile, stirring for dissolving, adding 5.5g of p-toluenesulfonic acid dihydrate, reacting for 3 hours at 20-45 ℃, adding 20% sodium carbonate aqueous solution to adjust pH to neutral, slowly pouring the reaction solution into 150ml water, stirring, precipitating with water, filtering, drying the filter cake at 50-60 deg.C for 20 hr, 7.6g of light yellow solid is obtained, the yield is 76% (based on the compound shown in the formula (I)), the purity is 85.3%, the raw material is remained for 2.3%, and the maximum single impurity is the compound 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone (11.6%).
Comparative example 6: in the reaction bottle in the step (1), namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal (10.5g, purity of 97 percent), 110ml of acetonitrile is added, stirred and dissolved, 7ml of formic acid is added, the reaction is carried out for 3 hours at 20 to 45 ℃, adding 20% sodium carbonate aqueous solution to adjust pH to neutral, slowly pouring the reaction solution into 150ml water, stirring for elutriation, filtering, drying the filter cake at 50-60 deg.C for 20 hr, 6.9g of light yellow solid is obtained, the yield is 69 percent (based on the compound shown in the formula (I)), the purity is 87.5 percent, the raw material is remained for 1.06 percent, and the maximum single hetero is the compound 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone (8.6 percent).
Comparative example 7: in the reaction bottle in the step (1), namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal (10.6g, purity 98.4%), adding 110ml of acetonitrile, stirring to dissolve clear, adding 7ml of hydrobromic acid, reacting for 3 hours at 20-45 ℃, adding 20% sodium carbonate aqueous solution to adjust pH to neutral, slowly pouring the reaction solution into 150ml water, stirring for elutriation, filtering, drying the filter cake at 50-60 deg.C for 20 hr, 8.6g of a grayish green solid is obtained, the yield is 86 percent (based on the compound shown in the formula (I)), the purity is 77.3 percent, the raw material is remained 0.8 percent, and the maximum single impurity is the compound 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one (16.4 percent).
Comparative example 8: in the reaction bottle in the step (1), namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal (11g, purity 98.2 percent), adding 120ml of acetonitrile, stirring to dissolve clear, adding 8ml of phosphoric acid, reacting for 3 hours at 20-45 ℃, adding 20% sodium carbonate aqueous solution to adjust pH to neutral, slowly pouring the reaction solution into 150ml water, stirring for elutriation, filtering, drying the filter cake at 50-60 deg.C for 20 hr, 7.9g of yellow solid is obtained, the yield is 79 percent (based on the compound shown in the formula (I)), the purity is 91 percent, the raw material is remained 2 percent, and the maximum single hetero is the compound 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-ketone (3.3 percent).
Comparative example 9: in the reaction bottle in the step (1), namely 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3, 17-dione-3, 3-ethylidene ketal (10.8g, purity 98.2%), 110ml of acetonitrile is added, stirring is carried out to dissolve the mixture, 8g of oxalic acid is added, 10ml of water is added, the temperature is 20-45 ℃, the reaction is carried out for 3 hours, the reaction is completed, 20% of sodium carbonate aqueous solution is added to adjust the pH value to be neutral, the reaction solution is slowly poured into 150ml of water, stirring is carried out for elutriation, filtering is carried out, a filter cake is dried for 20 hours at 50-60 ℃, 5.8g of yellow solid is obtained, the yield is 58% (based on the compound shown in the formula (I), the target product 17 alpha-cyanomethyl-17 beta-hydroxy-4, 9-androstadiene-3-one has the purity of only 7.5%, and the product is basically 17 alpha-cyanomethyl-17 beta-hydroxy-5, 9-androstadiene-3-one with a purity of 89.6%.
The purity, yield and product appearance of example 1 and comparative examples 1-9 are shown in table 1 below, and some of the product photographs are shown in fig. 2;
TABLE 1
As can be seen from Table 1, the use of the fluoroboric acid aqueous solution can greatly improve the concentration of the final product, and the purity can reach more than 99.5% only by one-time refining, the single impurity is less than 0.10%, the product meets the quality standard of pharmacopoeia, and the production difficulty is effectively reduced.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A preparation method of dienogest is characterized by comprising the following steps:
carrying out acidolysis deprotection reaction on the compound shown in the formula (II) in a fluoroboric acid aqueous solution to obtain a compound with a structure shown in the formula (I);
2. the method for preparing dienogest according to claim 1, wherein the mass concentration of the aqueous solution of fluoroboric acid is 40% to 50%.
3. The method for preparing dienogest according to claim 2, wherein the step of subjecting the compound represented by formula (II) to acidolysis deprotection reaction in an aqueous fluoroboric acid solution comprises the steps of:
dissolving a compound shown as a formula (II) in an organic solvent, adding the fluoroboric acid aqueous solution, reacting for 3-6 h at the temperature of 20-45 ℃, and adjusting the pH value to 6.8-7.5 after the reaction is finished to obtain a reaction solution;
mixing the reaction solution with water, separating out solid, solid-liquid separating, collecting solid and drying.
4. The method for preparing dienogest according to claim 3, wherein the volume ratio of the organic solvent to the aqueous solution of fluoroboric acid is 10:1 to 20: 1; the volume ratio of the mixed reaction liquid and the water is (0.4-1): 1.
5. The method for producing dienogest as claimed in claim 3, wherein the organic solvent is at least one selected from the group consisting of methanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, acetone and 4-methyl-tetrahydropyran.
6. The method for producing dienogest as claimed in any one of claims 1 to 5, further comprising a refining step after the step of acid hydrolysis deprotection reaction, the refining step comprising the steps of:
dissolving the crude product obtained by the acidolysis deprotection reaction in an organic solvent, treating by adopting medicinal activated carbon, carrying out solid-liquid separation, and collecting filtrate;
and (3) recrystallizing the filtrate, collecting precipitated crystals, and drying to obtain the refined compound shown in the formula (I).
7. The process according to claim 6, wherein the organic solvent is 4-methyltetrahydropyran, and 8 to 15mL of the 4-methyltetrahydropyran is added per 1g of the crude compound represented by the formula (I); 0.01g to 0.1g of the medicinal activated carbon is added into each 1g of the crude product of the compound shown in the formula (I).
8. The method of claim 7, wherein the step of recrystallizing comprises the steps of:
concentrating the filtrate to obtain a residual liquid, wherein the volume of the residual liquid is 1/5-1/2 of the filtrate;
cooling the residual liquid to 0-5 ℃, standing, separating out crystals, carrying out solid-liquid separation, collecting the crystals, washing and drying.
9. The method according to any one of claims 1 to 5, further comprising a step of preparing the compound represented by the formula (II):
and (3) reacting the compound shown in the formula (III) with cyanomethyl lithium to obtain the compound shown in the formula (II).
10. The method according to claim 9, wherein the step of reacting the compound represented by the formula (III) with cyanomethyl lithium comprises the steps of:
mixing a butyl lithium reagent and tetrahydrofuran at the temperature of between 50 ℃ below zero and 90 ℃ below zero, adding acetonitrile tetrahydrofuran mixed solution, and reacting for 4 to 15 minutes;
adding tetrahydrofuran solution of the compound shown in the formula (III) for reaction, quenching the reaction after the reaction is completed, and carrying out post-treatment to obtain the compound shown in the formula (II).
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