Process for the preparation of dydrogesterone

Abstract

The application provides a preparation method of dydrogesterone, which comprises the following steps: performing a selective epoxidation reaction on a compound I in a first solution containing meta-chloroperoxybenzoic acid and hydrogen peroxide to obtain a compound II; the content of the meta-chloroperoxybenzoic acid in the first solution is more than 1 times of the amount of substance of the compound I; performing a reduction reaction on the compound II under the action of hydrogen and a catalyst to obtain a compound III; performing a hydrolysis reaction on the compound III in a dilute acid solution, and then performing a hydroxyl elimination reaction on the compound III in a second solution to obtain the dydrogesterone; the structural formulae of the compound I, the compound II, the compound III and the dydrogesterone are as follows:; and. The preparation method has less by-products and a higher reaction yield.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly to a method for preparing dydrogesterone. Background Art

[0002] Dydrogesterone, also known as dehydroprogesterone, has a chemical name of 9β,10α-pregn-4,6-diene-3,20-dione, and a CAS number of 152-62-5. The chemical formula of dydrogesterone is shown in the following formula:

[0003] .

[0004] Dydrogesterone is widely used for preventing miscarriage and treating various diseases caused by insufficient endogenous progesterone, such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, infertility caused by luteal insufficiency, etc.

[0005] Currently, the existing synthesis route of dydrogesterone has problems of more by-products and lower reaction yield. Therefore, developing a method for preparing dydrogesterone with fewer by-products and higher reaction yield has become one of the important research directions in this field. Summary of the Invention

[0006] Based on this, it is necessary to provide a method for preparing dydrogesterone with fewer by-products and higher reaction yield. A

[0007] The technical solution provided by the present invention is as follows:

[0008] According to one aspect of the present invention, there is provided a method for preparing dydrogesterone, comprising the following steps:

[0009] Performing a selective epoxidation reaction on compound I in a first solution containing meta-chloroperoxybenzoic acid (m-CPBA) and hydrogen peroxide to obtain compound II; the content of meta-chloroperoxybenzoic acid in the first solution is more than 1 time the amount of substance of compound I;

[0010] Performing a reduction reaction on compound II under the action of hydrogen and a catalyst to obtain compound III; and

[0011] Performing a hydrolysis reaction on compound III in a dilute acid solution, and then performing a hydroxy elimination reaction in a second solution to obtain dydrogesterone;

[0012] Wherein, the structural formulas of compound I, compound II, compound III, and dydrogesterone are as follows:

[0013] ; ; ; .

[0014] In the above preparation method, by using m-chloroperbenzoic acid and hydrogen peroxide together as oxidants in the selective epoxidation reaction and controlling the content of m-chloroperbenzoic acid to be more than 1 times the amount of substance of Compound I, the carbon-carbon double bond on the 5,6-position carbon atoms of the nucleus of Compound I can be epoxidized with high selectivity, while the carbon-carbon double bond on the 7,8-position carbon atoms remains unchanged. By using a dilute acid solution for hydrolysis in the hydrolysis reaction, the racemization of the chiral carbon atom at the 17-position on the nucleus can be reduced, and the reaction yield can be increased. In the hydroxy elimination reaction, a favorable configuration in which the carbonyl group at the 3-position carbon atom forms a conjugated structure with the carbon-carbon double bonds at the 4,5-position carbon atoms and the 6,7-position carbon atoms is preferably generated. The above preparation method of dydrogesterone in the present invention has fewer side reactions and higher reaction yield. [[ID=,10]]

[0015] In any embodiment, the content of m-chloroperbenzoic acid in the first solution is 1.1 to 2 times the amount of substance of Compound I, and the content of hydrogen peroxide in the first solution is 0.5 to 2 times the amount of substance of Compound I. Thus, the selective epoxidation reaction can have a higher yield.

[0016] In any embodiment, the first solution further includes an alkaline substance, and the content of the alkaline substance in the first solution is 1.5 to 4 times the amount of substance of Compound I. Thus, the reaction rate can be further increased, side reactions can be further reduced, and the reaction yield can be increased.

[0017] In any embodiment, the alkaline substance includes one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide.

[0018] In any embodiment, the reaction temperature of the selective epoxidation reaction is 0°C to 40°C. Thus, the epoxidation reaction can proceed well, and the epoxidation reaction can have high selectivity and yield.

[0019] In any embodiment, the reaction temperature of the selective epoxidation reaction is 0°C to 20°C. Thus, side reactions can be further reduced, and the reaction yield can be increased.

[0020] In any embodiment, the reaction temperature of the selective epoxidation reaction is 从0°C to 10°C. Thus, side reactions can be further reduced, and the reaction yield can be further increased.

[0021] In any embodiment, the reaction time of the selective epoxidation reaction is 0.5 h to 4 h. The progress of the reaction can be monitored by TLC (thin layer chromatography).

[0022] In any embodiment, the dilute acid solution includes one or more of hydrochloric acid, acetic acid, and sulfuric acid, and the concentration of the acid in the dilute acid solution is 0.5 mol / L to 4 mol / L. Thus, not only can the ketal group and epoxy bond in Compound III be effectively hydrolyzed, but also the proportion of racemic impurities of the chiral carbon atom at the 17th position on the mother nucleus can be reduced, and the reaction yield can be increased.

[0023] In any embodiment, the second solution includes one or more of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, and an aqueous potassium tert-butoxide solution.

[0024] In any embodiment, the reaction temperature of the reduction reaction is 0°C to 40°C, and the reaction time is 3 h to 8 h. Thus, the reduction reaction can have a high yield.

[0025] In any embodiment, the reaction temperature of the hydrolysis reaction is 0°C to 40°C, and the reaction time is 0.5 h to 4 h. Thus, the hydrolysis reaction can have a high yield. Detailed Embodiments

[0026] To make the above objects, features, and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail. Many specific details are set forth in the following description in order to fully understand 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 departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention. Unless otherwise specifically stated, various raw materials, reagents, instruments, and equipment used in the present invention can be obtained through market purchases or can be prepared by existing methods.

[0028] There are currently two main synthetic routes for dydrogesterone: The first synthetic route starts from ergosterol, undergoes photochemical synthesis to obtain a 19α-configured intermediate, and then undergoes oxidation, double bond rearrangement, ozonolysis, and enamination, and finally oxidation to obtain dydrogesterone. This synthetic route requires the use of ozonolysis, has safety risks, and has many by-products. The reaction equation for synthesizing dydrogesterone from ergosterol is as follows:

[0029]

[0030] The second synthetic route starts from progesterone and obtains the diketene compound with double bonds at the 5,7 positions through ketalization, oxidation, hydrazonation, and de-hydrazonation. Then, it obtains dydrogesterone through a photochemical reaction and a hydrolysis rearrangement reaction. The reaction equation for synthesizing dydrogesterone from progesterone is as follows:

[0031]

[0032] In the above second synthetic route, in the hydrolysis rearrangement reaction step, high-concentration hydrogen chloride ethanol needs to be used. High-concentration hydrogen chloride ethanol is highly corrosive to equipment and will greatly increase the operation risk. In addition, carrying out the hydrolysis reaction under high-concentration acid conditions (high-concentration hydrogen chloride ethanol) will lead to an increase in the proportion of racemic impurities of the chiral carbon atom at the 17th position on the parent nucleus, resulting in a relatively low overall yield. If the hydrolysis reaction is carried out under dilute acid conditions, the double bond rearrangement cannot occur.

[0033] Aiming at the problems that the hydrolysis rearrangement reaction in the above second synthetic route needs to use high-concentration hydrogen chloride ethanol, resulting in high equipment corrosion, high operation risk, high proportion of racemic impurities, and low reaction yield; the present invention improves the above preparation method of dydrogesterone.

[0034] An embodiment of the present invention provides a preparation method of dydrogesterone, and this preparation method includes the following steps:

[0035] Step S100: Perform a selective epoxidation reaction on Compound I in a first solution containing m-chloroperbenzoic acid and hydrogen peroxide to obtain Compound II; wherein, the content of m-chloroperbenzoic acid in the first solution is more than 1 times the amount of substance of Compound I;

[0036] Step S200: Perform a reduction reaction on Compound II under the action of hydrogen and a catalyst to obtain Compound III;

[0037] Step S300: Perform a hydrolysis reaction on Compound III in a dilute acid solution, and then perform a hydroxy elimination reaction in a second solution to obtain dydrogesterone.

[0038] The structural formulas of Compound I, Compound II, Compound III, and dydrogesterone are as follows:

[0039] ; ; ; .

[0040] Among them, the carbon atom numbers on the dydrogesterone parent nucleus are as follows:

[0041]

[0042] In the above preparation method of dydrogesterone of the present invention, firstly, compound I (i.e., the product after the photochemical reaction in the second synthetic route) is subjected to a selective epoxidation reaction in a first solution containing m-chloroperoxybenzoic acid and hydrogen peroxide, and the content of m-chloroperoxybenzoic acid in the first solution is controlled to be more than 1 times the amount of substance of compound I, selectively epoxidizing the carbon-carbon double bond on the 5,6-position carbon atoms of the mother nucleus of compound I, while keeping the carbon-carbon double bond on the 7,8-position carbon atoms unchanged, to obtain compound II.

[0043] Then, compound II is subjected to a hydrogen reduction reaction under the action of hydrogen and a catalyst to reduce the carbon-carbon double bond on the 7,8-position carbon atoms of the mother nucleus of compound II, to obtain compound III.

[0044] Compound III is then subjected to a hydrolysis reaction in a dilute acid solution. Hydrolysis under dilute acid conditions can hydrolyze the two ketal groups in compound III into hydroxyl groups, and at the same time open the epoxy bond to form hydroxyl groups, and can avoid the problem of a large proportion of racemic impurities of the 17-position chiral carbon atom under high-concentration acidic conditions, so as to reduce side reactions and improve the reaction yield; then a hydroxyl elimination reaction is carried out in a second solution. The structure in which the carbonyl group on the 3-position carbon atom is conjugated with the carbon-carbon double bond on the 4,5-position carbon atoms and the carbon-carbon double bond on the 6,7-position carbon atoms in the elimination reaction is a favorable configuration, so as to obtain dydrogesterone in a high yield.

[0045] In the above preparation method, m-chloroperoxybenzoic acid and hydrogen peroxide are used together as oxidants in the selective epoxidation reaction, and the content of m-chloroperoxybenzoic acid is controlled to be more than 1 times the amount of substance of compound I, which can highly selectively epoxidize the carbon-carbon double bond on the 5,6-position carbon atoms of the mother nucleus of compound I, while keeping the carbon-carbon double bond on the 7,8-position carbon atoms unchanged; if m-chloroperoxybenzoic acid is used alone, the reaction will be incomplete and the amount of oxidant used will be large; if hydrogen peroxide is used alone, the selectivity of the reaction will decrease, side reactions will increase, and the reaction yield will decrease. Hydrolysis is carried out with a dilute acid solution in the hydrolysis reaction, which can reduce the racemization of the 17-position chiral carbon atom on the mother nucleus and improve the reaction yield. In the hydroxyl elimination reaction, the favorable configuration in which the carbonyl group on the 3-position carbon atom forms a conjugate structure with the carbon-carbon double bond on the 4,5-position carbon atoms and the carbon-carbon double bond on the 6,7-position carbon atoms is preferably generated. Therefore, the above preparation method of the present invention has fewer side reactions, higher reaction yield, and better safety; it can effectively avoid the problems of large equipment corrosion, high operation risk, large proportion of racemic impurities, and low reaction yield caused by using high-concentration hydrogen chloride ethanol for hydrolysis transposition reaction.

[0046] In some of these embodiments, the content of m-chloroperbenzoic acid in the first solution is 1.1 to 2 times the amount of substance of Compound I, and the content of hydrogen peroxide in the first solution is 0.5 to 2 times the amount of substance of Compound I. Thus, by further controlling the content of m-chloroperbenzoic acid in the first solution to be 1.1 to 2 times the amount of substance of Compound I and the content of hydrogen peroxide in the first solution to be 0.5 to 2 times the amount of substance of Compound I, the selective epoxidation reaction can have a higher yield.

[0047] It can be understood that the content of m-chloroperbenzoic acid in the first solution can be, but is not limited to, 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times the amount of substance of Compound I; the content of hydrogen peroxide in the first solution can be, but is not limited to, 0.5 times, 0.6 times, 0.7 times, 0.8 times, 0.9 times, 1.0 times, 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times the amount of substance of Compound I.

[0048] In one specific example, the content of m-chloroperbenzoic acid in the first solution is 1.1 times the amount of substance of Compound I, and the content of hydrogen peroxide in the first solution is 0.5 times the amount of substance of Compound I.

[0049] In some of these embodiments, the first solution further includes a basic substance, and the content of the basic substance in the first solution is 1.5 to 4 times the amount of substance of Compound I. By adding a basic substance with a content of 1.5 to 4 times the amount of substance of Compound I to the first solution, the reaction rate can be further increased, side reactions can be further reduced, and the reaction yield can be increased. It can be understood that the content of the basic substance in the first solution can be, but is not limited to, 1.5 times, 1.6 times, 1.8 times, 2.0 times, 2.2 times, 2.4 times, 2.5 times, 2.8 times, 3.0 times, 3.2 times, 3.4 times, 3.5 times, 3.8 times, 4 times the amount of substance of Compound I.

[0050] Specifically, the basic substance used in the first solution can include one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide.

[0051] In some of these embodiments, the reaction temperature of the selective epoxidation reaction is 0°C to 40°C. Controlling the temperature of the selective epoxidation reaction within the range of 0°C to 40°C allows the epoxidation reaction to proceed better, resulting in a higher selectivity and yield for the epoxidation reaction. It can be understood that the reaction temperature of the selective epoxidation reaction can be 0°C, 2°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C, 30°C, 32°C, 35°C, 38°C, 40°C, as well as the range values between any two of these point values.

[0052] In some of these embodiments, the reaction temperature of the selective epoxidation reaction is 0°C to 20°C. Further controlling the reaction temperature of the selective epoxidation reaction within the range of 0°C to 20°C can further reduce side reactions and improve the reaction yield.

[0053] In some of these embodiments, the reaction temperature of the selective epoxidation reaction is 0°C to 10°C. Further controlling the reaction temperature of the selective epoxidation reaction within the range of 0°C to 10°C can further reduce side reactions and further improve the reaction yield.

[0054] In some of these embodiments, the reaction time of the selective epoxidation reaction is 0.5 h to 4 h. It can be understood that the reaction time of the selective epoxidation reaction can be 0.5 h, 0.8 h, 1.0 h, 1.2 h, 1.5 h, 1.8 h, 2.0 h, 2.2 h, 2.5 h, 2.8 h, 3.0 h, 3.2 h, 3.5 h, 3.8 h, 4 h, as well as the range values between any two of these point values.

[0055] In some of these embodiments, the solvent used in the first solution can be one or more of dichloromethane, ethyl acetate, tetrahydrofuran, and acetone.

[0056] In some of these embodiments, the catalyst used for the hydrogen reduction reaction of Compound II can be palladium on carbon catalyst (Pd / C) or Raney nickel (Raney Ni). The solvent used can be one or more of dichloromethane, ethyl acetate, tetrahydrofuran, and acetone, or a mixed solvent of dichloromethane and methanol or a mixed solvent of dichloromethane and ethanol. The reaction temperature of the reduction reaction is controlled at 0°C to 40°C, and the reaction time is 3 h to 8 h.

[0057] It can be understood that the reaction temperature of the reduction reaction can be 0°C, 2°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C, 30°C, 32°C, 35°C, 38°C, 40°C, and the range values between any two of these point values. The reaction time of the reduction reaction can be 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, and the range values between any two of these point values.

[0058] In some of these embodiments, the dilute acid solution used for the hydrolysis reaction of Compound III can be one or more of dilute hydrochloric acid, acetic acid, and dilute sulfuric acid, and the concentration of the acid in the dilute acid solution is 0.5 mol / L to 4 mol / L. Using the above dilute acid solution for the hydrolysis reaction of Compound III can not only effectively hydrolyze the ketal group and epoxy bond in Compound III, but also reduce the proportion of racemic impurities of the chiral carbon atom at the 17th position on the mother nucleus and improve the reaction yield. The reaction temperature of the hydrolysis reaction is controlled at 0°C to 40°C, and the reaction time is 0.5 h to 4 h.

[0059] It can be understood that the concentration of the acid in the dilute acid solution can be 0.5 mol / L, 1 mol / L, 1.5 mol / L, 2 mol / L, 2.5 mol / L, 3 mol / L, 3.5 mol / L, 4 mol / L, and the range values between any two of these point values. The reaction temperature of the hydrolysis reaction can be 0°C, 2°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C, 30°C, 32°C, 35°C, 38°C, 40°C, and the range values between any two of these point values. The reaction time of the hydrolysis reaction can be 0.5 h, 0.8 h, 1 h, 1.2 h, 1.5 h, 1.8 h, 2 h, 2.2 h, 2.5 h, 2.8 h, 3 h, 3.2 h, 3.5 h, 3.8 h, 4 h, and the range values between any two of these point values.

[0060] In some of these embodiments, when performing the hydroxy elimination reaction on the product after the hydrolysis reaction in the second solution, the second solution used is one or more of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, and an aqueous potassium tert-butoxide solution. Using the above alkaline solution for the hydroxy elimination reaction dehydrates to form a molecular configuration in which the carbonyl group at the 3rd position on the mother nucleus is conjugated with the carbon-carbon double bonds at the 4th and 5th positions and the carbon-carbon double bonds at the 6th and 7th positions, and dydrogesterone is obtained in high yield. The reaction temperature of the hydroxy elimination reaction is controlled at 0°C to 40°C, and the reaction time is 3 h to 8 h.

[0061] It is understandable that the reaction temperature of the hydroxyl elimination reaction can be 0°C, 2°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C, 30°C, 32°C, 35°C, 38°C, 40°C, and the range values between any two of these point values. The reaction time of the hydroxyl elimination reaction can be 3h, 3.2h, 3.5h, 3.8h, 4h, 4.2h, 4.5h, 4.8h, 5h, 5.2h, 5.5h, 5.8h, 6h, 6.2h, 6.5h, 6.8h, 7h, 7.2h, 7.5h, 7.8h, 8h, and the range values between any two of these point values.

[0062] The present invention will be further described below in conjunction with specific examples and comparative examples, but it should not be construed as a limitation to the protection scope of the present invention.

[0063] Example 1:

[0064] 1) Epoxidation reaction

[0065] Add 600 mL of dichloromethane and 100.0 g (0.250 mol) of Compound I into a 2 L three-necked flask, and stir until the solution is clear; dissolve 39.69 g of sodium bicarbonate (0.472 mol, 1.89 times the equivalent of Compound I) in 300 mL of water, and stir until the solution is clear; add the above sodium bicarbonate aqueous solution to the dichloromethane solution of Compound I, and cool down to 0°C - 5°C; then add 47.4 g (0.275 mol, 1.1 times the amount of substance of Compound I) of m-chloroperbenzoic acid and 14.2 g of hydrogen peroxide (0.125 mol of hydrogen peroxide, 0.5 times the amount of substance of Compound I) in sequence, and react at 0°C - 10°C for 1 h. Monitor the complete reaction of the raw materials by TLC (thin-layer chromatography); separate the liquid, wash the organic phase with sodium bicarbonate aqueous solution until the pH is 7 - 8; then concentrate the organic phase below 50°C, add ethanol for replacement, retain about 200 mL of ethanol, cool down to -10°C - 0°C for crystallization for 2 h, filter, and dry to obtain 92.0 g of off-white solid Compound II. The purity of Compound II is 98.5%, and the molar yield of Compound II is 88%.

[0066] 2) Hydrogenation reaction

[0067] Add 450 mL of dichloromethane, 450 mL of ethanol, and 90.0 g (0.216 mol) of the compound II prepared in the above step 1) into a 2-L three-necked flask, and stir until the solution is clear; add 9.0 g of palladium-carbon catalyst, and displace the gas three times with a hydrogen balloon; react at 20 °C to 25 °C for 4 h, and monitor the reaction of the raw materials completely by TLC; filter, concentrate the organic phase below 50 °C, add ethanol for displacement, retain about 180 mL of ethanol, cool down to -10 °C to 0 °C for crystallization for 2 h, filter, and dry to obtain 86.2 g of a white solid compound III. The purity of compound III is 98.8%, and the molar yield of compound III is 95.3%.

[0068] 3) Hydrolysis reaction and hydroxyl elimination reaction

[0069] Add 400 mL of dichloromethane and 80.0 g (0.191 mol) of the above-prepared compound III into a 1-L three-necked flask, and stir until the solution is clear; add 381 mL of dilute hydrochloric acid (concentration: 2 mol / L, 0.762 mol), and react at 20 °C to 25 °C for 1 h, and monitor the reaction of the raw materials completely by TLC. <00001�7>Cool down to 0 °C to 5 °C, add 38.2 g (0.955 mol) of sodium hydroxide, heat up to 35 °C to 40 °C, and react for 4 h. Monitor the reaction of the raw materials completely by TLC; concentrate the reaction solution below 50 °C, add water for displacement, retain about 400 mL of water, filter, add the wet product to 1000 mL of acetone, heat up to 50 °C until the solution is clear, add 8.0 g of activated carbon, stir for 1 h, filter while it is hot, concentrate the filtrate below 50 °C, and concentrate to about 120 mL of acetone; then cool down to -10 °C to 0 °C for crystallization for 2 h, filter, and dry to obtain a white solid of dydrogesterone 50.2 g. The purity of dydrogesterone is 99.9%, and the molar yield of dydrogesterone is 84.1%. Among them, the purity of dydrogesterone is obtained by high-performance liquid chromatography test; the molar yield of dydrogesterone = the molar amount of dydrogesterone / the molar amount of compound III.

[0071] Perform 1H NMR, 13C NMR, and mass spectrometry tests on the product dydrogesterone. The test data are as follows:

[0072] 1H NMR data: 1H NMR (400 MHz, CDCl3) δ 6.18 – 6.02 (m, 2H), 5.62 (s, 1H), 2.59 – 2.44 (m, 2H), 2.43 – 2.31 (m, 2H), 2.28 – 2.05 (m, 5H), 2.03 – 1.88 (m, 2H), 1.84 – 1.54 (m, 7H), 1.35 – 1.18 (m, 4H), 0.66 (s, 3H).

[0073] Carbon spectrum data: 13C NMR (101 MHz, CDCl3) δ 208.94 (s), 199.36 (s), 163.03(s), 140.53 (s), 127.13 (s), 123.92 (s), 63.42 (s), 49.92 (s), 44.29 (s),39.74 (s), 38.65 (s), 37.78 (s), 37.25 (s), 35.65 (s), 34.02 (s), 31.57 (s),25.23 (s), 22.63 (s), 22.36 (s), 20.62 (s), 12.14 (s).

[0074] Mass spectrometry data: Molecular formula C 21 H 28 O2, molecular weight 313.0.

[0075] Example 2:

[0076] The preparation method of this example is basically the same as that of Example 1, except that: in step 1) the epoxidation reaction, the amount of m-chloroperbenzoic acid is 2 times the amount of substance of Compound I, and the hydrogen peroxide content in hydrogen peroxide is 2 times the amount of substance of Compound I; and no sodium bicarbonate aqueous solution is added; the temperature of the epoxidation reaction is controlled at 20°C - 30°C.

[0077] Example 3:

[0078] The preparation method of this example is basically the same as that of Example ①, except that: in step 1) the epoxidation reaction, the hydrogen peroxide content in hydrogen peroxide is 1.1 times the amount of substance of Compound I; and no sodium bicarbonate aqueous solution is added; the temperature of the epoxidation reaction is controlled at 20°C - 30°C. [[ID=P22]]

[0079] Example 4:

[0080] The preparation method of this example is basically the same as that of Example 1, except that: in step 1) the epoxidation reaction, no sodium bicarbonate aqueous solution is added; the temperature of the epoxidation reaction is controlled at 20°C - 30°C.

[0081] Example 5:

[0082] The preparation method of this example is basically the same as that of Example 1, except that: in step ) the epoxidation reaction, no sodium bicarbonate aqueous solution is added; the temperature of the epoxidation reaction is controlled at 10°C - 20°C.

[0083] Example 6:

[0084] Note: There seems to be a small error in the original text where "Example 3: The preparation method of this example is basically the same as that of Example ①" has "Example ①" which should probably be "Example 1". This has been noted in the translation as well.The preparation method of this example is basically the same as that of Example 1, except that: in step 1) the epoxidation reaction, an aqueous sodium bicarbonate solution is not added; the temperature of the epoxidation reaction is controlled at 0°C to 10°C.

[0085] Example 7:

[0086] The preparation method of this example is basically the same as that of Example 1, except that: in step 1) the epoxidation reaction, an aqueous sodium hydroxide solution with the same volume and the same molar concentration is used to replace the aqueous sodium bicarbonate solution in Example 1.

[0087] Comparative Example 1:

[0088] The preparation method of this comparative example is basically the same as that of Example 1, except that: in step 1) the epoxidation reaction, the amount of m-chloroperbenzoic acid used is 2 times the amount of substance of Compound I, and hydrogen peroxide and an aqueous sodium bicarbonate solution are not added; the temperature of the epoxidation reaction is controlled at 20°C to 30°C.

[0089] Comparative Example 2:

[0090] The preparation method of this comparative example is basically the same as that of Example 1, except that: in step 1) the epoxidation reaction, the content of hydrogen peroxide in hydrogen peroxide is 2 times the amount of substance of Compound I, and m-chloroperbenzoic acid and an aqueous sodium bicarbonate solution are not added; the temperature of the epoxidation reaction is controlled at 20°C to 30°C.

[0091] Comparative Example 3:

[0092] The preparation method of this comparative example is basically the same as that of Example 1, except that: in step 1) the epoxidation reaction, the amount of m-chloroperbenzoic acid used is 0.5 times the amount of substance of Compound I, and the content of hydrogen peroxide in hydrogen peroxide is 0.5 times the amount of substance of Compound I; and an aqueous sodium bicarbonate solution is not added; the temperature of the epoxidation reaction is controlled at 20°C to 30°C.

[0093] The reaction conditions of step 1) and the molar yield data of the obtained Compound II in each of the above examples and comparative examples are shown in Table 1. “eq” in Table 1 represents the equivalent, that is, the multiple of the amount of this raw material relative to the amount of substance of Compound I; “ / ” in the columns of the amount of m-CPBA used, the amount of hydrogen peroxide used, and the base and its amount in Table 1 means non-existence; “N / A” in the column of the molar yield of Compound II in Table 1 means that the yield was not tested due to incomplete reaction or too many by-products.

[0094] Table 1

[0095]

[0096] As can be seen from Table 1, in step 1) of the preparation methods of the embodiments of the present invention, the molar yield of the prepared Compound II is relatively high and the side reactions are few. Correspondingly, the yield of the final product, dienogest, in each embodiment of the present invention is also relatively high.

[0097] It can be seen by comparing Example 2, Example 3 and Example 4 that controlling the amount of hydrogen peroxide to be 0.5 times to 1.1 times the amount of substance of Compound I can further improve the molar yield of Compound II. It can be seen by comparing Example 4, Example 5 and Example 6 that controlling the temperature of the epoxidation reaction to be 10°C to 20°C and further controlling it to be 0°C to 10°C can better improve the molar yield of Compound II. It can be seen by comparing Example 1, Example 6 and Example 7 that adding an appropriate amount of base to the first solution can further improve the molar yield of Compound II.

[0098] It can be seen by comparing Comparative Example 1 with Example 2 that only adding m-chloroperbenzoic acid as an oxidant to the first solution and not adding hydrogen peroxide will result in incomplete reaction. It can be seen by comparing Comparative Example 2 with Example 2 that only adding hydrogen peroxide as an oxidant to the first solution and not adding m-chloroperbenzoic acid will result in poor selectivity of the peroxidation reaction and too many by-products. It can be seen by comparing Comparative Example 3 with Example 4 that too little addition of m-chloroperbenzoic acid to the first solution will also result in incomplete reaction.

[0099] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.

[0100] The above-described embodiments only represent several implementation manners of the present invention. Their descriptions are relatively specific and detailed, but they should not be construed as limitations on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims.

Claims

1. A method for preparing dydrogesterone, characterized in that, Includes the following steps: Compound I was subjected to a selective epoxidation reaction in a first solution containing m-chloroperoxybenzoic acid and hydrogen peroxide to obtain compound II; the content of m-chloroperoxybenzoic acid in the first solution was 1.1 to 2 times the molar amount of compound I; the content of hydrogen peroxide in the first solution was 0.5 to 2 times the molar amount of compound I. Compound II was reduced in the presence of hydrogen and a catalyst to obtain compound III. and The compound III was hydrolyzed in a dilute acid solution, followed by a hydroxyl elimination reaction in a second solution to obtain dydrogesterone. The second solution includes one or more of the following: aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, and aqueous potassium tert-butoxide solution; The structural formulas of compounds I, II, III, and dydrogesterone are as follows: ； ； ； 。 2. The method for preparing dydrogesterone according to claim 1, characterized in that, The first solution also includes an alkaline substance, the content of which is 1.5 to 4 times the amount of compound I.

3. The method for preparing dydrogesterone according to claim 2, characterized in that, The alkaline substance includes one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide.

4. The method for preparing dydrogesterone according to claim 1, characterized in that, The reaction temperature for the selective epoxidation reaction is 0℃~40℃.

5. The method for preparing dydrogesterone according to claim 1, characterized in that, The reaction temperature for the selective epoxidation reaction is 0℃~20℃.

6. The method for preparing dydrogesterone according to claim 1, characterized in that, The reaction temperature for the selective epoxidation reaction is 0℃~10℃.

7. The method for preparing dydrogesterone according to claim 1, characterized in that, The reaction time for the selective epoxidation reaction is 0.5 h to 4 h.

8. The method for preparing dydrogesterone according to any one of claims 1 to 7, characterized in that, The dilute acid solution includes one or more of hydrochloric acid, acetic acid, and sulfuric acid, and the concentration of the acid in the dilute acid solution is 0.5 mol / L to 4 mol / L.

9. The method for preparing dydrogesterone according to any one of claims 1 to 7, characterized in that, The reduction reaction is carried out at a temperature of 0℃ to 40℃ and for a time of 3h to 8h.

10. The method for preparing dydrogesterone according to any one of claims 1 to 7, characterized in that, The hydrolysis reaction is carried out at a temperature of 0℃ to 40℃ and for a time of 0.5h to 4h.

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