Preparation and purification method of melengestrol acetate

Abstract

The invention belongs to the technical field of organic chemical synthesis or drug synthesis, and is particularly related to a preparation and purification method of melengestrol acetate, wherein the method comprises: 6-methylene melengestrol acetate and a hydrogenation reagent are subjected to a transposition reaction under a palladium catalyst to prepare a crude melengestrol acetate product; after the crude melengestrol acetate product is dissolved, p-toluenesulfonic acid and an alcohol solvent are added, an etherification reaction is carried out, and a purified melengestrol acetate product is obtained by concentrated crystallization and recrystallization. The preparation and purification method has a short production cycle, a high yield, a low production cost, and a good product purity, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis or drug synthesis, and specifically relates to a preparation and purification method of melengestrol acetate. Background Art

[0002] The chemical name of melengestrol acetate is 17α-acetoxy-6-methyl-16-methylene-pregnane-4,6-diene-3,20-dione, and its English name is Melengestrol acetate. Melengestrol acetate is an excellent progestogen with anti-tumor effects. It is used in livestock weight gain and estrus synchronization. As a growth-promoting additive for livestock breeding, it can improve feeding efficiency and thus quickly increase livestock weight. It has broad market prospects.

[0003] The preparation process of melengestrol acetate is to use 6-methylene melengestrol acetate as raw material, and obtain melengestrol acetate through palladium catalyst transposition reaction. At the same time, in the transposition process, side reactions are inevitable to generate hydrogenated impurities. The specific reaction is as follows:

[0004]

[0005] The hydrogenated impurities are very similar in structure to melengestrol acetate and cannot be removed by solvent recrystallization, and conventional refining methods are ineffective. Since the hydrogenated impurities cannot be removed by refining, the melengestrol acetate products produced have low purity, poor quality, low overall yield, and high production costs. Summary of the invention

[0006] Based on this, in order to solve the above technical problems, the present invention provides a preparation and purification method of melengestrol acetate, which is used to remove hydrogenated impurities. The process is simple to operate, and the obtained melengestrol acetate has high purity and high overall yield.

[0007] The embodiment of the present invention provides a method for preparing and purifying melengestrol acetate, and the method for preparing and purifying melengestrol acetate comprises:

[0008] The crude product of melengestrol acetate is prepared by carrying out a transposition reaction between 6-methylene melengestrol acetate and a hydrogenation reagent under the action of a palladium catalyst;

[0009] After the crude melengestrol acetate is dissolved, p-toluenesulfonic acid and an alcohol solvent are added to carry out an etherification reaction, and the etherification reaction product is removed by concentration and crystallization;

[0010] The product after the concentration and crystallization is recrystallized to obtain a purified product of melengestrol acetate.

[0011] In one embodiment, the hydrogenation agent is any one of cyclohexene, formic acid or ammonium formate.

[0012] In one embodiment, the palladium catalyst is any one of palladium-carbon, palladium-calcium carbonate, and palladium-barium carbonate.

[0013] In one embodiment, the temperature of the metathesis reaction is 50° C. to 100° C., and the time is 6 h to 24 h.

[0014] In one embodiment, the first solvent in the preparation process of the crude melengestrol acetate is selected from methanol, ethanol or isopropanol.

[0015] In one embodiment, the mass ratio of the 6-methylene acetate melengestrol to the volume of the first solvent is 1 g: 10-30 mL.

[0016] In one embodiment, the second solvent in which the crude melengestrol acetate is dissolved is selected from dichloromethane, dichloroethane, tetrahydrofuran or toluene.

[0017] In one embodiment, the mass ratio of the crude melengestrol acetate to the volume of the second solvent is 1 g: 2-10 mL.

[0018] In one embodiment, the temperature of the etherification reaction is 10-40° C., and the time is 0.5 h-3 h.

[0019] In one embodiment, the alcohol solvent is methanol or ethanol.

[0020] In one embodiment, the dissolving agent in the recrystallization process is selected from at least one of tetrahydrofuran, acetone, ether, ethanol, ethyl acetate and isopropyl acetate.

[0021] In one embodiment, the concentration and crystallization process comprises:

[0022] The mixed solution after the etherification reaction is subjected to reduced pressure distillation to remove the solvent with a volume of 75-85% of the mixed solution, an alcohol solvent is added, and the mixture is further subjected to reduced pressure distillation to a volume of 15-25% of the mixed solution to obtain a concentrated solution;

[0023] The concentrated solution is cooled to 0-5°C for crystallization for 1.5-3h.

[0024] Compared with the prior art, the preparation and purification method of melengestrol acetate of the present invention has the following beneficial effects:

[0025] The invention uses a palladium catalyst to carry out a transposition reaction with 6-methylene melengestrol acetate under the action of a hydrogenation agent to obtain a crude melengestrol acetate; toluenesulfonic acid is added to carry out an etherification reaction, so that the hydrogenated impurities are converted into an etherified product having greatly different properties from melengestrol acetate, and then the hydrogenated impurities can be removed by simple recrystallization to obtain high-purity melengestrol acetate. The process has a short production cycle, a high yield, a low production cost, and a good product purity, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The HPLC chromatogram of the crude melengestrol acetate provided in Example 1 of the present invention;

[0027] Figure 2 The HPLC chromatogram of the purified melengestrol acetate provided in Example 1 of the present invention;

[0028] Figure 3 The mass spectrum of the purified melengestrol acetate provided in Example 1 of the present invention;

[0029] Figure 4 The H NMR spectrum of melengestrol acetate provided in Example 1 of the present invention;

[0030] Figure 5 This is the nuclear magnetic carbon spectrum of melengestrol acetate provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0031] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below in conjunction with the accompanying drawings. In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed below.

[0032] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present invention, the meaning of "plurality" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0034] The weight of the relevant components mentioned in the description of the embodiments of the present invention may not only refer to the specific content of each component, but also indicate the weight ratio between the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the description of the embodiments of the present invention, it is within the scope disclosed in the description of the embodiments of the present invention. Specifically, the weight described in the description of the embodiments of the present invention may be a mass unit known in the chemical industry such as μg, mg, g, kg, etc.

[0035] The embodiment of the present invention provides a method for preparing and purifying melengestrol acetate, and the method for preparing and purifying melengestrol acetate comprises:

[0036] The crude product of melengestrol acetate is prepared by performing a transposition reaction of 6-methylene melengestrol acetate and a hydrogenation reagent under the action of a palladium catalyst; the reaction formula is as follows:

[0037]

[0038] After the crude melengestrol acetate is dissolved, p-toluenesulfonic acid and an alcohol solvent are added to carry out an etherification reaction, and the etherification reaction product is removed by concentration and crystallization;

[0039] The reaction formula of the etherification reaction is as follows:

[0040]

[0041] The product after the concentration and crystallization is recrystallized to obtain a purified product of melengestrol acetate.

[0042] In a specific example, the hydrogenation agent is any one of cyclohexene, formic acid or ammonium formate. Preferably, the hydrogenation agent is cyclohexene.

[0043] In a specific example, the palladium catalyst is any one of palladium-carbon, palladium-calcium carbonate, and palladium-barium carbonate. Preferably, the palladium catalyst is palladium-carbon and palladium-calcium carbonate.

[0044] In a specific example, the temperature of the metathesis reaction is 50°C to 100°C, and the time is 6h to 24h. Preferably, the temperature of the metathesis reaction is 60°C to 80°C, and the time is 8h to 20h.

[0045] In a specific example, the first solvent in the preparation process of the crude melengestrol acetate is selected from at least one of methanol, ethanol and isopropanol. Preferably, the first solvent is methanol or ethanol.

[0046] In a specific example, the mass ratio of the 6-methylene acetate melengestrol to the volume ratio of the first solvent is 1g:10-30mL. Optionally, the mass ratio of the 6-methylene acetate melengestrol to the volume ratio of the first organic solvent is 1g:(10ml-20ml). Further, the mass ratio of the compound of formula (I) to the volume ratio of the first organic solvent is 1g:20mL.

[0047] In a specific example, the second solvent in which the crude melengestrol acetate is dissolved is selected from at least one of dichloromethane, dichloroethane, tetrahydrofuran and toluene. Preferably, the second organic solvent is selected from at least one of dichloromethane and tetrahydrofuran.

[0048] In a specific example, the mass ratio of the crude melengestrol acetate to the volume of the second solvent is 1g:2-10mL. Optionally, the mass ratio of the crude melengestrol acetate to the volume of the second organic solvent is 1g:(3mL-5mL). Preferably, the mass ratio of the crude melengestrol acetate to the volume of the second organic solvent is 1g:3mL.

[0049] In a specific example, the temperature of the etherification reaction is 10-40° C., and the time is 0.5 h-3 h.

[0050] In a specific example, the alcohol solvent is methanol or ethanol. When the alcohol solvent is methanol, the etherate is a methyl etherate, and its structure is as follows:

[0051]

[0052] When the alcohol solvent is ethanol, the etherate is ethyl etherate, and its structure is as follows:

[0053]

[0054] In a specific example, the concentration and crystallization process includes:

[0055] The mixed solution after the etherification reaction is subjected to reduced pressure distillation to remove 75-85% of the solvent by volume of the mixed solution, an alcohol solvent is added, and then the reduced pressure distillation is performed to a volume of 15-25% of the mixed solution to obtain a concentrated solution; preferably, 80% of the solvent is removed by reduced pressure distillation, the added alcohol solvent is the same as the alcohol solvent added during the etherification reaction, and then the reduced pressure distillation is performed to a volume of 20% of the mixed solution.

[0056] The concentrated solution is cooled to 0-5°C for crystallization for 1.5-3 hours, preferably, the crystallization time is 2 hours.

[0057] In a specific example, the dissolving agent in the recrystallization process is selected from at least one of tetrahydrofuran, acetone, ether, ethanol, ethyl acetate, and isopropyl acetate. Preferably, the dissolving agent is selected from at least one of ethanol, ethyl acetate, and tetrahydrofuran. It should be understood that the recrystallization process can be performed multiple times to improve the purity of the product.

[0058] In the above-mentioned etherification reaction process, melengestrol acetate cannot undergo etherification reaction due to the presence of multiple conjugated double bonds; the 3-keto-4-ene structure of the hydrogenated impurity is easy to undergo etherification reaction to generate etherified products, thereby changing the similarity between the hydrogenated impurity and melengestrol acetate, and the hydrogenated impurity can be simply and efficiently removed, and a high-purity melengestrol acetate product can be prepared with high yield. The production process is greatly simplified, the production cycle is short, the yield is high, the production cost is low, the product purity is good, and it is suitable for large-scale industrial production.

[0059] The following is an example of the synthesis method of melengestrol acetate of the present invention. It should be understood that the synthesis method of melengestrol acetate of the present invention is not limited to the following examples.

[0060] Example 1

[0061] 50g of 6-methylene melengestrol acetate was added with 1000ml of ethanol, stirred for 10 minutes, 4g of palladium-calcium carbonate and 1g of cyclohexene were added, the air was exhausted twice with a nitrogen balloon, the temperature was raised to 75-80°C, the reaction was continued for 8 hours, the filter was filtered while hot, and the filter cake was washed with a small amount of ethanol. The filtrate was distilled under reduced pressure until it was about 100ml, 5000ml of water was added for hydrolysis, filtered, and the solid was dried at 50-60°C with forced air to obtain 45g of crude melengestrol acetate. Its liquid chromatogram is shown as follows: Figure 1 As shown, the peak at 15.909 min is melengestrol acetate, and the peak at 17.707 min is hydrogenated impurity; HPLC purity is 90.0%, and hydrogenated impurity is 0.96%.

[0062] 45g of crude melengestrol acetate was added with 135ml of dichloromethane and 22.5ml of methanol, stirred to dissolve, and evacuated twice with a nitrogen balloon. 1.35g of p-toluenesulfonic acid was added, and the mixture was kept at 20-30℃ for 1 hour, and 2ml of triethylamine was added to quench the reaction. The reaction solution was distilled under reduced pressure until it was about 90ml, 135ml of methanol was added, and the distillation under reduced pressure was continued until it was about 90ml, and it was cooled to 0-5℃ for crystallization for 2 hours, and filtered to obtain a fine product of melengestrol acetate, with a wet weight of 47g.

[0063] Melengestrol acetate, a fine wet product, 47g, was added with 450ml of ethyl acetate, and the temperature was raised to 70-80℃ to dissolve the clear solution, and the filtrate was filtered while hot, and the filtrate was distilled under reduced pressure until the volume was about 90ml, and then cooled to 0-5℃ to crystallize for 2 hours, filtered, and the solid was dried at 50-60℃ to obtain 36.5g of white solid. The total weight yield was 73%. After testing, the liquid chromatogram of the white solid was as follows: Figure 2 As shown, the peak at 15.830min is melengestrol acetate, and the peak at 17.607min is hydrogenated impurity, HPLC purity is 99.6%, and hydrogenated impurity is 0.12%; the mass spectrum is shown in Figure 3 As shown; NMR hydrogen spectrum as Figure 4 As shown; NMR carbon spectrum as Figure 5 As shown, the white solid is melengestrol acetate. Melengestrol acetate M / Z: 396.23. From the high-resolution mass spectrum of the sample, it can be seen that in the positive ion mode, the [M+H]+ value is 397.27, which is consistent with the sample. 1 H NMR (400MHz, CDCl3) δ5.93(s,1H),5.88(s,1H),5.60(s,1H),5.49(s,1H),2.54~2.68(m,2H),2.40~2.48(dd, 1H),2.21~2.29(m,2H),2.15(s,3H),2.05(s,3H),1.85(s,3H),1.33~1.46(m,2H),1.11(s,3H),0.78(s,3H). 13 C NMR (400MHz, CDCl3) δ202.40,199.80,170.13,163.88,144.37,137.60,131.59,121.35,120.23,93.93,5 0.17,48.14,45.82,36.55,36.13,33.99,33.60,32.19,30.70,27.64,21.26,20.24,19.89,16.39,14.34.

[0064] Example 2

[0065] 50g of 6-methylene melengestrol acetate was added with 1500ml of methanol, stirred for 10 minutes, 5g of palladium-calcium carbonate and 1g of cyclohexene were added, and the air was exhausted twice by a nitrogen balloon. The temperature was raised to 65-70°C for reaction for 24 hours, and the mixture was filtered while hot. The filter cake was washed with a small amount of methanol. The filtrate was distilled under reduced pressure until it was about 100ml, 5000ml of water was added for hydrolysis, filtered, and the solid was dried at 50-60°C by forced air to obtain 46.3g of crude melengestrol acetate. The HPLC purity was 91.6%, and the hydrogenated impurity was 0.89%.

[0066] 46.3g of crude melengestrol acetate was added with 140ml of dichloromethane and 23ml of methanol, stirred to dissolve, and evacuated twice with a nitrogen balloon. 1.0g of p-toluenesulfonic acid was added, and the mixture was kept at 20-30℃ for 1 hour, and 2ml of triethylamine was added to quench the reaction. The reaction solution was distilled under reduced pressure until it was about 90ml, 140ml of methanol was added, and the distillation under reduced pressure was continued until it was about 90ml, cooled to 0-5℃ for crystallization for 2 hours, and filtered to obtain a fine product of melengestrol acetate, with a wet weight of 45g.

[0067] Melengestrol acetate, a fine product, 45g, was added with 460ml of ethyl acetate, and the temperature was raised to 70-80℃ to dissolve the clear solution, and the filtrate was distilled under reduced pressure until the volume was about 90ml, and the solution was cooled to 0-5℃ for crystallization for 2 hours, and filtered, and the solid was dried at 50-60℃ with air blast to obtain 32.1g of white solid. HPLC purity was 99.4%, hydrogenated impurities were 0.15%, and the total weight yield was 64.2%.

[0068] Example 3

[0069] 50g of 6-methylene melengestrol acetate was added with 750ml of ethanol, stirred for 10 minutes, 4g of palladium-calcium carbonate and 1g of cyclohexene were added, and the air was exhausted twice with a nitrogen balloon, and the temperature was raised to 75-80°C for reaction for 8 hours, and the mixture was filtered while hot, and the filter cake was washed with a small amount of ethanol. The filtrate was distilled under reduced pressure until it was about 100ml, 5000ml of water was added for hydrolysis, filtered, and the solid was dried at 50-60°C with forced air to obtain 44.7g of crude melengestrol acetate. HPLC purity was 91.6%, and hydrogenated impurities were 0.78%.

[0070] 44.7g of crude melengestrol acetate was added with 135ml of dichloromethane and 20ml of anhydrous ethanol, stirred to dissolve, and evacuated twice with a nitrogen balloon. 1.3g of p-toluenesulfonic acid was added, and the mixture was kept at 20-30℃ for 1 hour, and 2ml of triethylamine was added to quench the reaction. The reaction solution was distilled under reduced pressure until it was about 90ml, 140ml of ethanol was added, and the mixture was distilled under reduced pressure until it was about 90ml, and then cooled to 0-5℃ for crystallization for 2 hours, and filtered to obtain a fine product of melengestrol acetate, with a wet weight of 46g.

[0071] Melengestrol acetate wet product 46g, add ethyl acetate 450ml, heat to 70-80℃ to dissolve, filter while hot, distill the filtrate under reduced pressure to a volume of about 90ml, cool to 0-5℃ to crystallize for 2 hours, filter, and air dry the solid at 50-60℃ to obtain 35.3g of white solid. HPLC purity 99.5%, hydrogenated impurities 0.11%, total weight yield 70.6%.

[0072] Example 4

[0073] 50g of 6-methylene melengestrol acetate was added with 750ml of ethanol, stirred for 10 minutes, 5g of palladium-carbon and 1g of cyclohexene were added, and the air was exhausted twice by a nitrogen balloon. The temperature was raised to 75-80°C for reaction for 12 hours, and the mixture was filtered while hot. The filter cake was washed with a small amount of ethanol. The filtrate was distilled under reduced pressure until it was about 100ml, 5000ml of water was added for hydrolysis, filtered, and the solid was dried by air blast at 50-60°C to obtain 46.9g of crude melengestrol acetate. The HPLC purity was 90.2%, and the hydrogenated impurities were 2.36%.

[0074] 46.9g of crude melengestrol acetate was added with 140ml of dichloromethane and 20ml of anhydrous ethanol, stirred to dissolve, and evacuated twice with a nitrogen balloon. 1.0g of p-toluenesulfonic acid was added, and the mixture was kept at 20-30℃ for 1 hour, and 2ml of triethylamine was added to quench the reaction. The reaction solution was distilled under reduced pressure until it was about 90ml, 140ml of ethanol was added, and the mixture was distilled under reduced pressure until it was about 90ml, and 140ml of ethanol was added. The mixture was cooled to 0-5℃ for crystallization for 2 hours, and filtered to obtain a fine product of melengestrol acetate, with a wet weight of 44g.

[0075] Melengestrol acetate, a fine wet product, 44g, was added with 460ml of ethyl acetate, and the temperature was raised to 70-80℃ to dissolve the clear solution, and the filtrate was filtered while hot, and the filtrate was distilled under reduced pressure to a volume of about 90ml, and then cooled to 0-5℃ for crystallization for 2 hours, filtered, and the solid was dried at 50-60℃ with air blast to obtain 33.8g of white solid. HPLC purity was 98.6%, hydrogenated impurities were 0.43%, and the total weight yield was 67.6%.

[0076] Example 5

[0077] 50g of 6-methylene melengestrol acetate was added with 1000ml of methanol, stirred for 10 minutes, 6g of palladium-carbon and 1g of cyclohexene were added, and the air was exhausted twice by a nitrogen balloon. The temperature was raised to 65-70°C for reaction for 24 hours, and the mixture was filtered while hot. The filter cake was washed with a small amount of methanol. The filtrate was distilled under reduced pressure until it was about 100ml, 5000ml of water was added for hydrolysis, filtered, and the solid was dried by air at 50-60°C to obtain 47.1g of crude melengestrol acetate. The HPLC purity was 89.3%, and the hydrogenated impurities were 2.72%.

[0078] 47.1g crude melengestrol acetate was added with 150ml of dichloromethane and 25ml of methanol, stirred to dissolve, and evacuated twice with a nitrogen balloon. 1.0g of p-toluenesulfonic acid was added, and the mixture was kept at 20-30℃ for 1 hour, and 2ml of triethylamine was added to quench the reaction. The reaction solution was distilled under reduced pressure until it was about 90ml, 150ml of methanol was added, and the distillation under reduced pressure was continued until it was about 90ml, cooled to 0-5℃ for crystallization for 2 hours, and filtered to obtain a fine product of melengestrol acetate, with a wet weight of 45g.

[0079] Melengestrol acetate, a fine product, 45g, was added with 470ml of ethyl acetate, and the temperature was raised to 70-80℃ to dissolve the clear solution, and the filtrate was distilled under reduced pressure until the volume was about 90ml, and the solution was cooled to 0-5℃ for crystallization for 2 hours, and filtered, and the solid was dried at 50-60℃ with air blast to obtain 33.3g of white solid. HPLC purity was 98.2%, hydrogenated impurities were 0.58%, and the total weight yield was 66.6%.

[0080] Example 6

[0081] 50g of 6-methylene melengestrol acetate was added with 1000ml of ethanol, stirred for 10 minutes, 4g of palladium-calcium carbonate and 1g of cyclohexene were added, and the air was exhausted twice by a nitrogen balloon. The temperature was raised to 75-80°C for reaction for 8 hours, and the mixture was filtered while hot. The filter cake was washed with a small amount of ethanol. The filtrate was distilled under reduced pressure until it was about 100ml, 5000ml of water was added for hydrolysis, filtered, and the solid was dried at 50-60°C with forced air to obtain 45.6g of crude melengestrol acetate. The HPLC purity was 93.1%, and the hydrogenated impurity was 0.69%.

[0082] 45.6g of crude melengestrol acetate was added with 100ml of tetrahydrofuran and 20ml of methanol, stirred to dissolve, and evacuated twice with a nitrogen balloon. 1.0g of p-toluenesulfonic acid was added, and the mixture was kept at 20-30℃ for 1 hour, and 2ml of triethylamine was added to quench the reaction. The reaction solution was distilled under reduced pressure until it was about 75ml, 140ml of methanol was added, and the mixture was distilled under reduced pressure until it was about 90ml, cooled to 0-5℃ for crystallization for 2 hours, and filtered to obtain a fine product of melengestrol acetate, with a wet weight of 47g.

[0083] Melengestrol acetate wet product 47g, add ethyl acetate 450ml, heat to 70-80℃ to dissolve, filter while hot, distill the filtrate under reduced pressure to a volume of about 90ml, cool to 0-5℃ to crystallize for 2 hours, filter, and air dry the solid at 50-60℃ to obtain 35.9g of white solid. HPLC purity 99.3%, hydrogenated impurities 0.13%, total weight yield 71.8%.

[0084] Example 7

[0085] 50g of 6-methylene melengestrol acetate was added with 750ml of ethanol, stirred for 10 minutes, 4g of palladium-calcium carbonate and 1g of cyclohexene were added, and the air was exhausted twice with a nitrogen balloon, and the temperature was raised to 75-80°C for reaction for 8 hours, and the mixture was filtered while hot, and the filter cake was washed with a small amount of ethanol. The filtrate was distilled under reduced pressure until it was about 100ml, and 5000ml of water was added for hydrolysis, filtered, and the solid was dried with air at 50-60°C to obtain 46.2g of crude melengestrol acetate. The HPLC purity was 91.9%, and the hydrogenated impurity was 0.74%.

[0086] 46.2g of crude melengestrol acetate was added with 140ml of dichloromethane and 20ml of methanol, stirred to dissolve, and evacuated twice with a nitrogen balloon. 1.0g of p-toluenesulfonic acid was added, and the mixture was kept at 20-30℃ for 1 hour, and 2ml of triethylamine was added to quench the reaction. The reaction solution was distilled under reduced pressure until it was about 90ml, 200ml of isopropyl ether was added, and the mixture was distilled under reduced pressure until it was about 90ml, and 200ml of isopropyl ether was added, and the mixture was continued to be distilled under reduced pressure until it was about 90ml, cooled to 0-5℃ for crystallization for 2 hours, and filtered to obtain a fine product of melengestrol acetate, with a wet weight of 49g.

[0087] Melengestrol acetate, a fine wet product, 49g, was added with 460ml of ethyl acetate, and the temperature was raised to 70-80℃ to dissolve the clear solution, and the filtrate was distilled under reduced pressure until the volume was about 90ml, and the solution was cooled to 0-5℃ for crystallization for 2 hours, filtered, and the solid was dried at 50-60℃ with air blast to obtain 37.3g of white solid. HPLC purity was 99.1%, hydrogenated impurities were 0.19%, and the total weight yield was 74.6%.

[0088] Comparative Example 1

[0089] 50g of 6-methylene melengestrol acetate was added with 1000ml of ethanol, stirred for 10 minutes, 4g of palladium-calcium carbonate and 1g of cyclohexene were added, and the air was exhausted twice by a nitrogen balloon. The temperature was raised to 75-80°C for reaction for 8 hours, and the mixture was filtered while hot. The filter cake was washed with a small amount of ethanol. The filtrate was distilled under reduced pressure until it was about 100ml, 5000ml of water was added for hydrolysis, filtered, and the solid was dried at 50-60°C with forced air to obtain 45.3g of crude melengestrol acetate. The HPLC purity was 91.2%, and the hydrogenated impurities were 0.71%.

[0090] 45.3 g of crude melengestrol acetate was added with 135 ml of dichloromethane and 225 ml of methanol, and the mixture was heated to 40-45°C to dissolve the mixture. The mixture was distilled under reduced pressure until the volume was about 90 ml. The mixture was cooled to 0-5°C for crystallization for 2 hours and filtered to obtain a fine product of melengestrol acetate with a wet weight of 51 g.

[0091] Melengestrol acetate, a fine product, wet product 51g, add ethyl acetate 450ml, heat to 70-80℃ to dissolve, filter while hot, distill the filtrate under reduced pressure to a volume of about 90ml, cool to 0-5℃ to crystallize for 2 hours, filter, and air dry the solid at 50-60℃ to obtain 37.9g ​​of white solid. HPLC purity 97.7%, hydrogenated impurities 0.77%, total weight yield 75.8%.

[0092] Comparative Example 2

[0093] 50g of 6-methylene melengestrol acetate was added with 750ml of ethanol, stirred for 10 minutes, 4g of palladium-calcium carbonate and 1g of cyclohexene were added, and the air was exhausted twice with a nitrogen balloon, and the temperature was raised to 75-80°C for reaction for 8 hours, and the mixture was filtered while hot, and the filter cake was washed with a small amount of ethanol. The filtrate was distilled under reduced pressure until it was about 100ml, and 5000ml of water was added for hydrolysis, filtered, and the solid was dried with air at 50-60°C to obtain 46.1g of crude melengestrol acetate. HPLC purity was 92.5%, and hydrogenated impurities were 0.69%.

[0094] 46.1 g of crude melengestrol acetate was added with 140 ml of dichloromethane and 140 ml of ethanol, and the mixture was heated to 40-45°C to dissolve the mixture. The mixture was distilled under reduced pressure until the volume was about 90 ml. The mixture was cooled to 0-5°C for crystallization for 2 hours and filtered to obtain a fine product of melengestrol acetate with a wet weight of 49 g.

[0095] Melengestrol acetate, a fine product, 49g, was added with 460ml of ethyl acetate, and the temperature was raised to 70-80℃ to dissolve the clear solution, and the filtrate was filtered while hot, and the filtrate was distilled under reduced pressure to a volume of about 90ml, and then cooled to 0-5℃ for crystallization for 2 hours, filtered, and the solid was dried at 50-60℃ with air blast to obtain 35.9g of white solid. HPLC purity was 98.1%, hydrogenated impurities were 0.73%, and the total weight yield was 71.8%.

[0096] Comparative Example 3

[0097] 50g of 6-methylene melengestrol acetate was added with 750ml of ethanol, stirred for 10 minutes, 5g of palladium-carbon and 1g of cyclohexene were added, and the air was exhausted twice with a nitrogen balloon, and the temperature was raised to 75-80°C for reaction for 12 hours, and the mixture was filtered while hot, and the filter cake was washed with a small amount of ethanol. The filtrate was distilled under reduced pressure until about 100ml was obtained, and 5000ml of water was added for hydrolysis, filtered, and the solid was dried at 50-60°C with forced air to obtain 46.4g of crude melengestrol acetate. HPLC purity was 90.4%, and hydrogenated impurities were 2.28%.

[0098] 46.4 g of crude melengestrol acetate was added with 140 ml of dichloromethane and 140 ml of ethanol, and the mixture was heated to 40-45°C to dissolve the mixture. The mixture was distilled under reduced pressure until the volume was about 90 ml. The mixture was cooled to 0-5°C for crystallization for 2 hours and filtered to obtain a fine product of melengestrol acetate with a wet weight of 48 g.

[0099] Melengestrol acetate wet product 48g, add ethyl acetate 460ml, heat to 70-80℃ to dissolve, filter while hot, distill the filtrate under reduced pressure to a volume of about 90ml, cool to 0-5℃ to crystallize for 2 hours, filter, and air dry the solid at 50-60℃ to obtain 35.4g of white solid. HPLC purity 96.0%, hydrogenated impurities 2.39%, total weight yield 70.8%.

[0100] Comparative Example 4

[0101] 50g of 6-methylene melengestrol acetate was added with 750ml of methanol, stirred for 10 minutes, 6g of palladium-carbon and 1g of cyclohexene were added, and the air was exhausted twice with a nitrogen balloon, and the temperature was raised to 65-70°C for reaction for 24 hours, and the mixture was filtered while hot, and the filter cake was washed with a small amount of methanol. The filtrate was distilled under reduced pressure until it was about 100ml, and 5000ml of water was added for hydrolysis, filtered, and the solid was dried with air at 50-60°C to obtain 47.7g of crude melengestrol acetate. HPLC purity was 89.1%, and hydrogenated impurities were 2.65%.

[0102] 47.7 g of crude melengestrol acetate was added with 250 ml of tetrahydrofuran, and the temperature was raised to 60-70°C to dissolve the mixture. The mixture was distilled under reduced pressure until the volume was about 75 ml. The mixture was cooled to 0-5°C for crystallization for 2 hours and filtered to obtain a fine product of melengestrol acetate with a wet weight of 43 g.

[0103] Melengestrol acetate, a fine product, 43g, was added with 470ml of ethyl acetate, and the temperature was raised to 70-80℃ to dissolve the clear solution, and the filtrate was distilled under reduced pressure until the volume was about 90ml, and the solution was cooled to 0-5℃ for crystallization for 2 hours, filtered, and the solid was dried at 50-60℃ with air blast to obtain 34.2g of white solid. HPLC purity was 96.9%, hydrogenated impurities were 2.17%, and the total weight yield was 68.4%.

[0104] The etherification refining scheme, conventional refining scheme, and yield and purity used in each embodiment and comparative example are shown in Table 1.

[0105] Table 1

[0106] Examples Crude hydrogenation impurities Etherification reaction Recrystallization Yield (%) Hydrogenated impurities Example 1 0.96％ p-Toluenesulfonic acid + methanol Ethyl acetate 73％ 0.12％ Example 2 0.89％ p-Toluenesulfonic acid + methanol Ethyl acetate 64.2％ 0.15％ Example 3 0.78％ p-Toluenesulfonic acid + anhydrous ethanol Ethyl acetate 70.6％ 0.11％ Example 4 2.36％ p-Toluenesulfonic acid + anhydrous ethanol Ethyl acetate 67.6％ 0.43％ Example 5 2.72％ p-Toluenesulfonic acid + methanol Ethyl acetate 66.6％ 0.58％ Example 6 0.69％ p-Toluenesulfonic acid + methanol Ethyl acetate 71.8％ 0.13％ Example 7 0.74％ p-Toluenesulfonic acid + methanol Ethyl acetate 74.6％ 0.19％ Examples Crude hydrogenation impurities Conventional refining Recrystallization Yield Hydrogenated impurities Comparative Example 1 0.71％ Dichloromethane and methanol Ethyl acetate 75.8％ 0.77％ Comparative Example 2 0.69％ Dichloromethane and ethanol Ethyl acetate 71.8％ 0.73％ Comparative Example 3 2.28％ Dichloromethane and ethanol Ethyl acetate 70.8％ 2.39％ Comparative Example 4 2.65％ Tetrahydrofuran Ethyl acetate 68.4％ 2.17％

[0107] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0108] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the attached claims, and the description and drawings can be used to interpret the content of the claims.

Claims

1. A method for preparing and purifying melengestrol acetate, characterized in that: The preparation and purification method comprises: The crude product of melengestrol acetate is prepared by carrying out a transposition reaction between 6-methylene melengestrol acetate and a hydrogenation reagent under the action of a palladium catalyst; After the crude melengestrol acetate is dissolved, p-toluenesulfonic acid and an alcohol solvent are added to carry out an etherification reaction, and the etherification reaction product is removed by concentration and crystallization; Recrystallizing the concentrated and crystallized product to obtain a purified melengestrol acetate product; The hydrogenation reagent is cyclohexene, formic acid or ammonium formate; The alcohol solvent is methanol or ethanol.

2. The method for preparing and purifying melengestrol acetate according to claim 1, characterized in that: The palladium catalyst is palladium-carbon, palladium-calcium carbonate or palladium-barium carbonate.

3. The method for preparing and purifying melengestrol acetate according to claim 1, characterized in that: The temperature of the transposition reaction is 50-100° C., and the time is 6 h to 24 h.

4. The method for preparing and purifying melengestrol acetate according to claim 1, characterized in that: The first solvent in the preparation process of the crude melengestrol acetate is selected from at least one of methanol, ethanol and isopropanol; the mass ratio of the 6-methylene melengestrol acetate to the volume ratio of the first solvent is 1g:10-30mL.

5. The method for preparing and purifying melengestrol acetate according to any one of claims 1 to 4, characterized in that: The second solvent for dissolving the crude melengestrol acetate is selected from at least one of dichloromethane, dichloroethane, tetrahydrofuran and toluene; the mass ratio of the crude melengestrol acetate to the volume of the second solvent is 1g:2-10mL.

6. The method for preparing and purifying melengestrol acetate according to any one of claims 1 to 4, characterized in that: The temperature of the etherification reaction is 10-40° C., and the time is 0.5 h-3 h.

7. The method for preparing and purifying melengestrol acetate according to any one of claims 1 to 4, characterized in that: The concentration and crystallization process comprises: The mixed solution after the etherification reaction is subjected to reduced pressure distillation to remove the solvent with a volume of 75-85% of the mixed solution, an alcohol solvent is added, and the mixture is further subjected to reduced pressure distillation to a volume of 15-25% of the mixed solution to obtain a concentrated solution; The concentrated solution is cooled to 0-5°C for crystallization for 1.5-3h.

8. The method for preparing and purifying melengestrol acetate according to any one of claims 1 to 4, characterized in that: The dissolving agent in the recrystallization process is selected from at least one of tetrahydrofuran, acetone, ether, ethanol, ethyl acetate and isopropyl acetate.

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