A dydrogesterone intermediate and a process for its preparation

Abstract

This invention belongs to the field of organic synthesis, specifically relating to a synthetic intermediate for dydrogesterone and its preparation method, comprising the following steps: (1) hydrolyzing compound 3 in the presence of an organic solvent and an inorganic base to obtain compound 4; (2) reducing compound 4 to obtain compound 5. This invention also provides a method for obtaining dydrogesterone from readily available and inexpensive progesterone through multiple steps; it has advantages such as a short synthetic route, low cost, simple purification, high yield, and avoidance of the use of toxic reagents; and it is easy to achieve large-scale industrial production.

Description

Technical Field

[0001] This invention relates to a dydrogesterone intermediate and its preparation method, belonging to the fields of pharmaceutical and chemical technology. Background Technology

[0002] Dydrogesterone (CAS: 152-62-5), chemically named 9β,10α-pregn-4,6-diene-3,20-dione, also known as dehydroprogesterone, is manufactured by Abbott Laboratories in the Netherlands. It is used to maintain pregnancy and prevent miscarriage, as well as to treat various conditions caused by insufficient endogenous progesterone, such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycles, dysfunctional uterine bleeding, premenstrual syndrome, threatened or recurrent miscarriage due to progesterone deficiency, and infertility due to luteal insufficiency. Currently, two products are sold in multiple countries and regions: Duphaston (dydrogesterone tablets) and Femoston (estradiol / estradiol-dydrogesterone combination pack). Compared to natural progestins (such as progesterone), due to the presence of olefins at positions 6 and 7 and the opposite configuration at positions 9 and 10, it is stable during digestion, absorption, and metabolism, less easily destroyed, can be taken orally, and does not have the common side effects of hormones. The molecular structure of dydrogesterone is as follows:

[0003]

[0004] Patent CN110198949B reports a total synthetic method for preparing dydrogesterone. However, this method requires multiple synthetic steps of starting materials and uses the highly toxic reagent acrylonitrile. The overall route is inefficient and not suitable for industrial scale-up. The reaction formula is as follows:

[0005]

[0006] Patent WO2018109622 reports a nine-step synthesis of dydrogesterone using progesterone as a raw material. The process involves multiple redox reactions and precious metal catalysts, resulting in a total yield of less than 5%, which is not suitable for industrial production.

[0007]

[0008] Patent CN110818760B reports a method for obtaining dydrogesterone from progesterone as a starting material through steps including carbonyl protection, bromination, elimination, photo-induced ring opening, photo-induced ring closing, deprotection, and isomerization. The key steps in this route are two photo-induced reactions, but the yield of these two photo-induced reactions is only about 30%, and the required equipment is complex, making it unsuitable for industrial production.

[0009]

[0010] The literature *Recueil des Travaux Chimiques des Pays-Bas* (1971), 90:27-32, reports a route for obtaining dydrogesterone from progesterone via ethylene glycol protection of diketones, bromination, debromination, and rearrangement under high-pressure mercury lamp irradiation. This route has a relatively low yield for ethylene glycol protection (32-67%, *The Journal of Organic Chemistry*, 1952, vol. 17, pp. 1369, 1373), and the bromination and debromination processes also involve numerous isomers, resulting in low yields in both steps (49%). Even in the crucial light irradiation step, the yield is only 22%, which is unfavorable for industrial production.

[0011]

[0012] Patent CN114957369B reports the following route for preparing dydrogesterone, which involves six steps: photochemical reaction, bio-fermentation, double bond transfer, oxidation, enamidation, and oxidation to obtain the final product. The photochemical and bio-fermentation steps only yield 7%, resulting in a low overall yield and hindering industrial scale-up. The reaction formula is as follows:

[0013]

[0014] Patent CN114957372B reports the following route for preparing dydrogesterone, which involves seven steps: photochemical reaction, oxidation, double bond transfer, hydrolysis, oxidation, enamidation, and oxidation to obtain the final product. In this route, the photochemical yield is only 24.5% with the addition of a filter, and only 9% without the filter. The low yield is not conducive to industrial scale-up. The reaction formula is as follows:

[0015]

[0016] Currently, there are two main approaches to the synthesis of dydrogesterone: 1) using pregnane compounds with the same 9,10-position configuration as dydrogesterone as substrates to construct a carbonyl group at the 20-position. The problem is that the steps are long and the operation is complex, resulting in a low final yield; 2) constructing the 9,10-position configuration through photoreaction. The difficulty lies in the double bond shift to construct 5,7-diene and the photoreaction process. The problem is that 5,7-diene is not easy to achieve or has poor atom economy, and the photoreaction yield is not high.

[0017] Therefore, there is an urgent need to develop a new method for preparing dydrogesterone. Summary of the Invention

[0018] To address the technical problems mentioned above, this invention provides a novel method for synthesizing dydrogesterone, as well as a novel dydrogesterone intermediate and its preparation method.

[0019] To overcome the shortcomings of existing technologies and meet the requirements of commercial scale-up production, the present invention adopts the following preferred technical solution:

[0020] The first aspect of this invention provides a method for preparing a compound of formula 5, wherein the reaction formula is shown below:

[0021]

[0022] Includes the following steps:

[0023] (1) The compound of formula 3 was hydrolyzed in the presence of an organic solvent and an inorganic base to obtain the compound of formula 4.

[0024] (2) The compound of formula 4 was reduced to obtain the compound of formula 5;

[0025] As a further improvement of the present invention, the inorganic base in step (1) is selected from one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, cesium carbonate, etc.

[0026] As a further improvement of the present invention, the molar ratio of the compound of formula 3 to the inorganic base in step (1) is 1:(1-5), preferably 1:(1.5-3);

[0027] As a further improvement of the present invention, the organic solvent in step (1) is selected from one or more of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, and acetonitrile;

[0028] As a further improvement of the present invention, the volume (mL) of the organic solvent used in step (1) is 2 to 10 times the mass (g) of the compound of formula 3, preferably 4 to 6 times;

[0029] As a further improvement of the present invention, the temperature of the hydrolysis reaction in step (1) is 15-45°C;

[0030] As a further improvement of the present invention, the reaction time of the hydrolysis reaction in step (1) is 1 to 5 hours;

[0031] As a further improvement of the present invention, after the hydrolysis reaction in step (1) is complete, the inorganic base (e.g., potassium carbonate) is filtered out, the filtrate is concentrated under reduced pressure, the residue is dissolved in water, the pH is adjusted to 5-6 with dilute hydrochloric acid, extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4.

[0032] As a further improvement of the present invention, the reduction reaction in step (2) includes the compound of formula 4, which reacts in the presence of a reducing agent in a mixed solvent of ether solvent or nitrile solvent and alcohol solvent;

[0033] As a further improvement of the present invention, the reducing agent in step (2) is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, aluminum borohydride, borane, etc.

[0034] As a further improvement of the present invention, the molar ratio of the compound of formula 4 to the reducing agent in step (2) is 1:(1-5), preferably 1:(1.1-2);

[0035] As a further improvement of the present invention, the ether in step (2) is selected from tetrahydrofuran, diethyl ether or a combination thereof;

[0036] As a further improvement of the present invention, the nitrile solvent in step (2) is selected from acetonitrile;

[0037] As a further improvement of the present invention, the alcohol solvent in step (2) is selected from one or a combination of methanol, ethanol, and isopropanol;

[0038] As a further improvement of the present invention, the volume (mL) of the ether solvent or nitrile solvent in step (2) is 1 to 10 times the mass (g) of the compound of formula 4, preferably 3 to 5 times;

[0039] As a further improvement of the present invention, the volume (mL) of the ether solvent or nitrile solvent in step (2) is 1 to 10 times that of the volume (mL) of the alcohol solvent, preferably 1 to 3 times.

[0040] As a further improvement of the present invention, the reaction temperature of the reduction reaction in step (2) is -20 to 10°C, preferably -15 to 0°C;

[0041] As a further improvement of the present invention, the reaction time of the reduction reaction in step (2) is 5 to 18 hours, preferably 10 to 15 hours;

[0042] As a further improvement of the present invention, after the reaction in step (2) is complete, the reaction solution is slowly poured into ice water, followed by the slow addition of glacial acetic acid. After the solid precipitates, it is filtered and the filter cake is washed with water. The filter cake can be selectively dissolved in dichloromethane, washed with water and saturated brine, the organic phase is concentrated under reduced pressure, the residue is dissolved in methanol, and distilled under reduced pressure. When the volume of the remaining mixture is reduced to 1 / 6 to 1 / 3, it is placed at 0 to 5°C to crystallize, filtered, and selectively washed with cold methanol. The filter cake is dried by blowing air at 55-60°C to obtain compound 5.

[0043] A second aspect of this invention provides a method for preparing a compound of formula 6, wherein the reaction formula is shown below:

[0044]

[0045] Includes the following steps:

[0046] (1) The compound of formula 3 was hydrolyzed in the presence of an organic solvent and an inorganic base to obtain the compound of formula 4.

[0047] (2) The compound of formula 4 was reduced to obtain the compound of formula 5;

[0048] (3) The compound of formula 5 was subjected to a photochemical reaction to obtain the compound of formula 6.

[0049] Including the following methods:

[0050] The preparation methods in steps (1) and (2) refer to all the technical solutions in the first aspect above.

[0051] As a further improvement of the present invention, the photochemical reaction in step (3) includes the compound of formula 5, which undergoes a photochemical reaction in the presence of an alkali under the irradiation of an LED lamp and a high-pressure mercury lamp in an organic solvent, causing the methyl group at the C-10 position to change from the β configuration to the α configuration.

[0052] As a further improvement of the present invention, the photochemical reaction in step (3) is carried out in two stages. The first stage is an open-loop reaction under LED lamp irradiation in the wavelength range of 200-300nm, and the second stage is a closed-loop reaction under high-pressure mercury lamp in the wavelength range of 300-400nm. Preferably, the main wavelength for the open-loop reaction under LED lamp irradiation in the first stage is 254nm, and the main wavelength for the closed-loop reaction under high-pressure mercury lamp in the second stage is 365nm.

[0053] As a further improvement of the present invention, the reaction time of the first or second stage of the photochemical reaction in step (3) is 5 to 15 hours, preferably 8 to 12 hours.

[0054] As a further improvement of the present invention, the organic solvent in step (3) is selected from one or more of toluene, methanol, ethanol, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, ethyl formate, dioxane, and acetonitrile.

[0055] As a further improvement of the present invention, the temperature of the photochemical reaction in step (3) is 0 to 40°C, preferably 5 to 25°C;

[0056] As a further improvement of the present invention, the base in step (3) is selected from one or more of triethylamine, diisopropylethylamine, triisopropylamine, pyridine, trimethylpyridine, etc.

[0057] As a further improvement of the present invention, the volume (mL) of the alkali used in step (3) is 2 to 10 times the volume (L) of the organic solvent, preferably 4 to 6 times;

[0058] As a further improvement of the present invention, the volume (L) of the organic solvent used in step (3) is 0.1 to 0.5 times the mass (g) of the compound of formula 6, preferably 0.2 to 0.3 times;

[0059] As a further improvement of the present invention, after the photochemical reaction in step (3) is completed, the solvent in the reaction solution is evaporated under reduced pressure, and then ethanol is added to prepare a suspension with a mass concentration of 2.3% to 3%. After filtration, the clear solution obtained is placed in a solution below 5°C for 6 hours to crystallize. After filtration, solid compound 6 is obtained.

[0060] A third aspect of this invention provides a method for preparing a compound of formula 3, wherein the reaction formula is shown below:

[0061]

[0062] Compound of Formula 2 was subjected to a double bond transfer reaction in the presence of acetyl chloride and acetic anhydride to give compound of Formula 3;

[0063] As a further improvement of the present invention, the molar mass ratio of the compound of double bond transfer reaction formula 2 to acetyl chloride is 1:(1-10), preferably 1:(1.1-5), for example 1:4.4;

[0064] As a further improvement of the present invention, the volume (mL) of acetic anhydride used in the double bond transfer reaction is 3 to 10 times the mass (g) of the compound of formula 2, preferably 4 to 8 times;

[0065] As a further improvement of the present invention, the reaction temperature of the double bond transfer reaction is 30-80°C, preferably 40-60°C;

[0066] As a further improvement of the present invention, the reaction time of the double bond transfer reaction is 5 to 20 hours, preferably 6 to 15 hours, and even more preferably 8 to 12 hours;

[0067] As a further improvement of the present invention, after the double bond transfer reaction is completed, the reaction solution is cooled to room temperature, concentrated under reduced pressure at about 75°C, placed at room temperature, methanol is added dropwise, then acetone is added, the solvent is removed under reduced pressure, the residue is dissolved in acetone again, concentrated under reduced pressure to 1 / 3 to 1 / 2 of the volume of the mixture, placed at 0 to 5°C to crystallize, filtered after 2 hours, washed, and the filter cake is dried at 55-60°C to obtain compound 3.

[0068] A fourth aspect of this invention provides a novel key intermediate compound of formula 3, with the following structure:

[0069]

[0070] The fifth aspect of this invention provides the use of the compound of formula 3 in the preparation of dydrogesterone or its intermediate, specifically a method for preparing dydrogesterone, comprising the following steps:

[0071]

[0072] Includes the following steps:

[0073] (1) Compound of Formula 2 was subjected to a double bond transfer reaction in the presence of acetyl chloride and acetic anhydride to obtain compound of Formula 3;

[0074] (2) The compound of formula 3 was hydrolyzed in the presence of an organic solvent and an inorganic base to obtain the compound of formula 4.

[0075] (3) The compound of formula 4 was reduced to obtain the compound of formula 5;

[0076] (4) The compound of formula 5 was subjected to a photochemical reaction to obtain the compound of formula 6;

[0077] (5) Compound 6 was oxidized in an organic solvent under the conditions of tetramethylpiperidine oxide (TEMPO), potassium bromide and sodium hypochlorite to obtain compound 7.

[0078] (6) The compound of formula 7 was subjected to a double bond transfer reaction in an organic solvent, tert-butylhydroquinone, and ethanol hydrochloride to obtain dydrogesterone.

[0079] Including the following methods:

[0080] The preparation methods in steps (1) to (4) refer to all the technical solutions in the first, second and third aspects mentioned above.

[0081] As a further improvement of the present invention, step (5) oxidation reaction includes the following steps: dissolving compound 7 in dichloromethane, adding tetramethylpiperidine oxide (TEMPO) and potassium bromide, stirring at 0-5°C, adding 7.5% sodium hypochlorite aqueous solution dropwise at this temperature, and stirring for 30 minutes after the addition is complete.

[0082] As a further improvement of the present invention, after the oxidation reaction in step (5) is completed, a saturated sodium thiosulfate solution is added to quench the reaction. The organic phase is washed once with saturated sodium thiosulfate and once with 3% dilute hydrochloric acid water. The organic phase is dried with anhydrous sodium sulfate, filtered, concentrated, and the crude product is dissolved in a mixed solvent of n-heptane and methyl tert-butyl ether (volume ratio 3:1). Crystallization is carried out at 0-5°C for 1 hour. The product is then filtered, the filter cake is washed with n-heptane, and the filter cake is dried by forced air at 55-60°C to obtain compound of formula 7.

[0083] As a further improvement of the present invention, the double bond transfer reaction in step (6) includes the following steps: dissolving compound 8 in dichloromethane, adding tert-butylhydroquinone, stirring, and under nitrogen protection, adding a 35% hydrochloric acid ethanol solution by mass dropwise at 0-10°C. After the addition is complete, the reaction is maintained at 0-10°C for 2 hours.

[0084] As a further improvement of the present invention, after the double bond transfer reaction in step (6) is completed, deionized water is added to quench the reaction. The organic phase is washed with a saturated sodium bicarbonate solution until neutral. The organic phase is concentrated and then dissolved in ethanol. The concentration is repeated 1 to 3 times. The mixture is then concentrated to about 1 / 3 to 1 / 2 of its volume. The mixture is placed at -20°C to crystallize and frozen for 2 hours. The mixture is filtered, the filter cake is washed with cold ethanol, and then suspended in n-heptane and slurried for 2 hours. The mixture is filtered, washed with n-heptane, and the filter cake is dried in a forced-air dryer at 55-60°C to obtain dydrogesterone.

[0085] Compared with the prior art, the present invention has the following beneficial effects:

[0086] This application uses inexpensive and readily available progesterone as the starting material, and obtains dydrogesterone through oxidation, double bond shifting, ester hydrolysis, reduction, configuration conversion, oxidation, and double bond shifting; it has the advantages of a short synthetic route, low cost, simple purification, high yield, and avoidance of the use of toxic reagents; and it is easy to realize large-scale industrial production.

[0087] The two-step molar yield of compounds 4 and 5 prepared in this application is 70%, while the yield of simultaneous reduction of two carbonyl groups in the prior art is only 60%, and the highest yield of hydrolysis of different substrates such as potassium carbonate is only 85%. This application has a significant technical advantage over the prior art.

[0088] This application replicates the conditions of anhydrous calcium chloride, pyridine + sodium borohydride in the example of Hunan Kerui Biopharmaceutical CN112608361B, but the yield is only 53.8%. This is because the conditions are not applicable to the substrate of this application, and it is difficult to obtain a technical advantage.

[0089] In the photoreaction of compound 7, existing technologies, without the addition of antioxidants, photoreaction promoters, microreactors, filters, etc., yield less than 30% of the photoreaction. This application achieves a yield of 39%, representing a 9% increase in yield. Detailed Implementation

[0090] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0091] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0092] Example 1

[0093] Synthesis of compound 2:

[0094]

[0095] Progesterone (100g, 0.318mol) was dissolved in 1L of toluene, and then 2L of acetic acid was added. After stirring until homogeneous, DDQ (108.3g, 0.477mol) was added in batches under nitrogen protection. After the addition was complete, the mixture was stirred until homogeneous, and then refluxed at 110℃ for 5 hours. The reaction was stopped when the starting material disappeared as detected by TLC. The reaction solution was cooled to room temperature, and the insoluble matter was removed by filtration. Toluene and acetic acid were evaporated under vacuum (and recycled). The residue was dissolved in 300mL of acetone, and 1L of 5% NaOH aqueous solution was added. The product precipitated, was filtered, and the filter cake was dried to obtain compound 2 (89g, yield 89.6%).

[0096] 1 H-NMR (400MHz, CDCl3) δ7.05 (d, J=10.0Hz, 1H), 6.24 (dd, J=10.0, 2.0Hz, 1H), 6.08 (s,1H),2.56-2.43(m,2H),2.40-2.33(m,1H),2.12(s,3H),2.10-2.04(m,1H),1.9 6(dt,J=8.0,6.0Hz,1H),1.67(ddd,J=16.0,8.8,3.6Hz,5H),1.50-1.38(m,2H),1. 32-1.24(m,1H),1.23(s,3H),1.16-1.01(m,3H),0.70(s,3H).LC-MS: 313.13[M+1] + .

[0097] Example 2

[0098] Synthesis of compound 3:

[0099]

[0100] Compound 2 (100 g, 0.320 mol) was dissolved in 500 mL of acetic anhydride, and 100 mL of acetyl chloride was added. After stirring at room temperature, the mixture was stirred at 50 °C for 8-12 hours. The reaction was stopped when the starting material disappeared, as detected by TLC. The reaction solution was cooled to room temperature and concentrated under reduced pressure at around 75 °C. After being placed at room temperature, 50 mL of methanol was added dropwise, followed by 100 mL of acetone. The solvent was removed by evaporation under reduced pressure, and the residue was dissolved again in 100 mL of acetone. The solution was concentrated under reduced pressure until 50 mL of acetone remained. Crystallization was carried out at 0 °C. After 2 hours, the solution was filtered and washed with cold acetone. The filtrate was repeated until no product was found. The filter cake was dried at 55-60 °C to obtain compound 3 (103 g, yield 90.8%).

[0101] 1 H-NMR (400MHz, CDCl3) δ6.99(d,J=8.0Hz,1H),6.71(d,J=8.0Hz,1H),5.30(s,1H),2.70-2.52(m,3H),2.31(t,J=9.2Hz,1H),2.27(s,3H),2.1 9(s,3H),2.09(dd,J=9.2,2.8Hz,1H),1.92-1.67(m,5H),1.42-1.37(m,2H),1.31(s,3H),1.30-1.15(m,3H),0.82(s,3H).LC-MS: 355.29[M+1] + .

[0102] Example 3

[0103] Synthesis of compound 4:

[0104]

[0105] Compound 3 (100 g, 0.282 mol) was dissolved in 500 mL of methanol, and potassium carbonate (78 g, 0.564 mol) was added. The mixture was stirred at room temperature for 2 hours. The starting material disappeared as detected by TLC. The potassium carbonate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water, and the pH was adjusted to 5-6 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was dried by pumping to obtain 86.4 g of compound 4.

[0106] Example 4

[0107] Synthesis of compound 5:

[0108]

[0109] Compound 4 (100 g, 0.320 mol) was dissolved in 400 mL of tetrahydrofuran, and 200 mL of methanol was added. The mixture was cooled to -10 to -15 °C, and sodium borohydride (14.53 g, 0.384 mol) was added in portions at this temperature. After the addition was complete, the reaction was maintained at -10 to -5 °C. After about 12 hours, the reaction was detected by TLC to be complete. The reaction solution was then slowly poured into ice water while stirring. Then, 20 mL of glacial acetic acid was slowly added dropwise. The precipitated solid was filtered, and the filter cake was washed with water. The filter cake was then dissolved in 300 mL of dichloromethane and washed with water and saturated brine. The organic phase was concentrated under reduced pressure, and the residue was dissolved in methanol. The dichloromethane was removed by vacuum distillation, and about 50 mL of the remaining mixture was obtained. The mixture was placed at 0 °C to crystallize, filtered, and washed with cold methanol. The filter cake was dried at 55-60 °C by forced air drying to obtain compound 5 (71 g, yield 70.1%).

[0110] Example 5

[0111] Synthesis of compound 6:

[0112]

[0113] Add compound 5 (10g, 31.6 mmol), 2.5L MTBE, and 12.5mL triethylamine to a 5L four-necked round-bottom flask, and stir until clear. Purge the solution three times with nitrogen to remove oxygen, and cool to 10-20°C in an ice-salt bath. Turn on the peristaltic pump to circulate the reaction mixture. Irradiate with a 254nm, 75W lamp for 10 hours; the intermediate conversion rate is 98.11%. Pump 1.2L of the above ring-opening reaction solution into the outer layer of a 2L jacketed bottle using a water pump, and purge nitrogen into it using a nitrogen cylinder. Irradiate with a high-pressure mercury lamp (365nm, 1000W) for 10 hours; the yield of compound 6 is approximately 43%. The reaction solution was transferred to a distillable storage tank, the solvent was evaporated under reduced pressure, and then 435 g of ethanol was added to prepare a suspension with a mass concentration of 2.3%. The suspension was filtered, and the resulting clear solution was placed in a refrigerator at 5°C for 6 hours. The product precipitated, and the product was filtered to obtain a white solid compound 6 (3.9 g, yield 39%).

[0114] 1 H NMR (400MHz, CDCl3) δ5.58(t,J=2.0Hz,1H),5.40(t,J=2.0Hz,1H),3.91-3.80(m,1H),3.53 -3.37(m,1H),2.25-2.14(m,2H),2.09-1.91(m,1H),1.90-1.75(m,3H),1.74-1.58(m,2H), 1.57-1.50(m,4H),1.50-1.43(m,2H),1.37(s,1H),1.36-1.30(m,1H),1.30-1.26(m,1H),1 .25(s,1H),1.24-1.15(m,2H),1.14(s,2H),1.12(s,3H),0.94(s,3H).LC-MS: 317.36[M+1] + .

[0115] Example 6

[0116] Synthesis of compound 7:

[0117]

[0118] Compound 6 (100 g, 0.316 mol) was dissolved in 200 mL of dichloromethane. Tetramethylpiperidine oxide (TEMPO) (1.23 g, 7.9 mmol) and potassium bromide (1.88 g, 15.80 mmol) were added, and the mixture was stirred at 0-5 °C. At this temperature, 660 mL of sodium hypochlorite aqueous solution (7.5%, 0.664 mol) was added dropwise. After the addition was complete, the mixture was stirred for 30 minutes. The starting material disappeared as detected by TLC. 100 mL of saturated sodium thiosulfate solution was added to quench the reaction. The organic phase was washed once with saturated sodium thiosulfate and once with 100 mL of 3% dilute hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was dissolved in a mixed solvent of n-heptane and methyl tert-butyl ether (volume ratio 3:1) and crystallized at 0-5 °C for 1 hour. The crystals were filtered, and the filter cake was washed with n-heptane and dried by forced air at 55-60 °C to obtain compound 7 (86 g, yield 87.1%).

[0119] Example 7

[0120] Synthesis of dydrogesterone:

[0121]

[0122] Compound 7 (100 g, 0.32 mol) was dissolved in 1 L of dichloromethane, and tert-butylhydroquinone (1 g, 6.02 mmol) was added and stirred until homogeneous. Under nitrogen protection, 1.2 L of hydrochloric acid-ethanol solution (35% by mass) was added dropwise at 0-10 °C. After the addition was complete, the mixture was kept at 0-10 °C for 2 hours. When the substrate was almost completely eliminated by TLC, the reaction was quenched with deionized water. The reaction mixture was separated into layers using a separatory funnel. The organic phase was washed with saturated sodium bicarbonate solution until neutral. The organic phase was concentrated and then dissolved in 200 mL of ethanol. The concentration was repeated 1-3 times, and then concentrated to about 100 mL of ethanol. The mixture was placed at -20 °C to crystallize and frozen for 2 hours. After filtration, the filter cake was washed with cold ethanol and then suspended in n-heptane and stirred for 2 hours. After filtration and washing with n-heptane, the filter cake was dried in a forced-air oven at 55-60 °C to obtain a white solid dydrogesterone (70 g, yield 70%).

[0123] 1 H NMR (400MHz, CDCl3) δ6.13-6.19(m,2H),5.66(s,1H),2.41-2.56(m,4H),2.19-2.29(m,2H),2.12(s,3H) ,1.98-1.94(m,2H),1.62-1.87(m,7H),1.31-1.55(m,1H),1.29(s,3H),0.69(s,3H).LC-MS: 313.15[M+1] + .

[0124] Comparative Example 1

[0125] Synthesis of compound 5:

[0126]

[0127] Take a 2L reaction flask and add anhydrous CaCl2 (6.9g, 0.062mol), pyridine (40.1g, 0.508mol), 400mL methanol and 400mL tetrahydrofuran. Stir and dissolve at room temperature. After dissolution, cool to about -12℃ and add sodium borohydride (12.8g, 0.338mol) in portions, followed by compound 3 (100g, 0.282mol). After the addition is complete, maintain the system temperature at about -8℃ and react for 12 hours. TLC monitoring shows that almost no starting material remains. Slowly pour the reaction solution into 1L ice water while stirring. After the solid has precipitated, stir for 20 minutes. Slowly add 20mL glacial acetic acid to the system, filter, and rinse with water. The solid was dissolved in 300 mL of dichloromethane, the aqueous layer was separated, and the organic phase was concentrated under reduced pressure to remove most of the solvent. Methanol was added and the concentration was continued until the dichloromethane was almost removed. About 50 mL of methanol was retained, and the mixture was cooled to 0 °C to crystallize for 1 hour. The mixture was filtered, washed with cold methanol, and the filter cake was dried in a forced-air oven at 55-60 °C to obtain compound 5 (48 g, yield 53.8%).

[0128] 1H NMR (400MHz, CDCl3) δ5.62(t,J=2.0Hz,1H),5.61(t,J=2.0Hz,1H),4.18-4.08(m,1H),3.58-3.44(m,1H),2.49-2 .31(m,1H),2.24-2.10(m,2H),2.04-1.86(m,2H),1.68-1.47(m,6H),1.47(s,1H),1.46-1.39(m,1H),1.38-1.37 (m,1H),1.37(s,1H),1.36-1.34(m,1H),1.32(ddd,J=7.2,3.2,1.2Hz,1H),1.29-1.25(m,1H),1.23(q,J=3.6Hz, 1H),1.21(dd,J=3.6,2.0Hz,1H),1.19-1.15(m,1H),1.14(s,1H),1.12(s,3H),0.94(s,3H).LC-MS: 317.34[M+1] + .

Claims

1. A method for preparing a compound of formula 5, wherein the reaction formula is shown below: Includes the following steps: (1) The compound of formula 3 was hydrolyzed in the presence of an organic solvent and an inorganic base to obtain the compound of formula 4. (2) The compound of formula 4 was reduced to obtain the compound of formula 5; The reducing agent in the reduction reaction is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, aluminum borohydride, and borane.

2. A method for preparing a compound of formula 6, wherein the reaction formula is shown below: Includes the following steps: (1) The compound of formula 3 was hydrolyzed in the presence of an organic solvent and an inorganic base to obtain the compound of formula 4. (2) The compound of formula 4 was reduced to obtain the compound of formula 5; (3) The compound of formula 5 was subjected to a photochemical reaction to obtain the compound of formula 6; The reducing agent in the reduction reaction is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, aluminum borohydride, and borane. The photochemical reaction, comprising compound of formula 5, is carried out in an organic solvent under the irradiation of LED lamps and high-pressure mercury lamps in the presence of a base, causing the methyl group at the C-10 position to change from the β configuration to the α configuration. The photochemical reaction proceeds in two stages: the first stage involves ring opening under LED light irradiation in the wavelength range of 200-300 nm, and the second stage involves ring closing under high-pressure mercury lamp irradiation in the wavelength range of 300-400 nm. The organic solvent used in the photochemical reaction is selected from one or more of toluene, methanol, ethanol, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, ethyl formate, dioxane, and acetonitrile. The base for the photochemical reaction is selected from one or more of triethylamine, diisopropylethylamine, triisopropylamine, pyridine, and trimethylpyridine.

3. A method for preparing dydrogesterone, comprising the following steps: Includes the following steps: (1) The compound of formula 3 was hydrolyzed in the presence of an organic solvent and an inorganic base to obtain the compound of formula 4. (2) The compound of formula 4 was reduced to obtain the compound of formula 5; (3) The compound of formula 5 was subjected to a photochemical reaction to obtain the compound of formula 6; (4) Compound 6 was oxidized in an organic solvent under the conditions of tetramethylpiperidine oxide, potassium bromide and sodium hypochlorite to obtain compound 7. (5) The compound of formula 7 was subjected to a double bond transfer reaction in an organic solvent, tert-butylhydroquinone, and ethanol hydrochloride to obtain dydrogesterone. The reducing agent in the reduction reaction is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, aluminum borohydride, and borane. The photochemical reaction, comprising compound of formula 5, is carried out in an organic solvent under the irradiation of LED lamps and high-pressure mercury lamps in the presence of a base, causing the methyl group at the C-10 position to change from the β configuration to the α configuration. The photochemical reaction proceeds in two stages: the first stage involves ring opening under LED light irradiation in the wavelength range of 200-300 nm, and the second stage involves ring closing under high-pressure mercury lamp irradiation in the wavelength range of 300-400 nm. The organic solvent used in the photochemical reaction is selected from one or more of toluene, methanol, ethanol, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, ethyl formate, dioxane, and acetonitrile. The base for the photochemical reaction is selected from one or more of triethylamine, diisopropylethylamine, triisopropylamine, pyridine, and trimethylpyridine.

4. The production method according to claim 1 or 2 or 3, characterized by, The preparation method of the compound of formula 3 includes the following steps: Compound of Formula 2 was subjected to a double bond transfer reaction in the presence of acetyl chloride and acetic anhydride to give compound of Formula 3.

5. The preparation method according to claim 4, characterized in that, The double bond transfer reaction also satisfies one or more of the following conditions: 1) The molar mass ratio of compound 2 in the double bond transfer reaction formula to acetyl chloride is 1:(1~10). 2) The volume (mL) of acetic anhydride used in the double bond transfer reaction is 3 to 10 times the mass (g) of the compound in Formula 2; 3) The reaction temperature of the double bond transfer reaction is 30~80℃; 4) The reaction time for the double bond transfer reaction is 5 to 20 hours.

6. The preparation method according to claim 5, characterized in that, The double bond transfer reaction also satisfies one or more of the following conditions: 1) The molar mass ratio of compound 2 in the double bond transfer reaction formula to acetyl chloride is 1:(1.1~5). 2) The volume (mL) of acetic anhydride used in the double bond transfer reaction is 4 to 8 times the mass (g) of the compound in Formula 2; 3) The reaction temperature of the double bond transfer reaction is 40~60℃; 4) The reaction time for the double bond transfer reaction is 6 to 15 hours.

7. The preparation method according to claim 6, characterized in that, The reaction time for the double bond transfer reaction is 8 to 12 hours.

8. The preparation method according to claim 1, 2, or 3, characterized in that, The hydrolysis reaction in step (1) of claim 1, step (1) of claim 2, or step (1) of claim 3 further satisfies one or more of the following conditions: 1) The inorganic base in the hydrolysis reaction is selected from one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, and cesium carbonate; 2) The molar ratio of compound 3 to inorganic base in the hydrolysis reaction is 1: (1~5); 3) The organic solvent used in the hydrolysis reaction is selected from one or more of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, and acetonitrile; 4) The volume of organic solvent used in the hydrolysis reaction (mL) is 2 to 10 times the mass (g) of the compound in Formula 3; 5) The hydrolysis reaction is carried out at a temperature of 15~45℃; 6) The reaction time of the hydrolysis reaction is 1~5 h.

9. The preparation method according to claim 8, characterized in that, In step 2), the molar ratio of compound 3 to inorganic base is 1:(1.5~3).

10. The preparation method according to claim 8, characterized in that, In step 4), the volume of the organic solvent used (mL) is 4 to 6 times the mass of the compound in formula 3 (g).

11. The preparation method according to claim 1, 2, or 3, characterized in that, The reduction reaction in step (2) of claim 1, or step (2) of claim 2, or step (2) of claim 3, further satisfies one or more of the following conditions: a) The reduction reaction comprises a compound of formula 4, reacting in the presence of a reducing agent in a mixed solvent of an ether solvent or a nitrile solvent and an alcohol solvent; b) In the reduction reaction, the molar ratio of compound 4 to the reducing agent is 1: (1~5); c) The reaction temperature of the reduction reaction is -20~10℃; d) The reaction time of the reduction reaction is 5~18 h.

12. The preparation method according to claim 11, characterized in that, In step a), the volume (mL) of the ether solvent or nitrile solvent used is 1 to 10 times the mass (g) of the compound in Formula 4.

13. The preparation method according to claim 11, characterized in that, In step a), the volume (mL) of ether or nitrile solvent is 1 to 10 times that of alcohol solvent.

14. The preparation method according to claim 11, characterized in that, In step b), the molar ratio of compound 4 to reducing agent is 1:(1.1~2).

15. The preparation method according to claim 11, characterized in that, The reaction temperature in step c) is -15~0℃.

16. The preparation method according to claim 11, characterized in that, The reaction time in step c) is 10-15 h.

17. The preparation method according to claim 11, characterized in that, In step a), the ether solvent is selected from tetrahydrofuran or diethyl ether, or a combination thereof; the nitrile solvent is acetonitrile; and the alcohol solvent is selected from methanol, ethanol, or isopropanol, or a combination thereof.

18. The preparation method according to claim 12, characterized in that, In step a), the volume (mL) of the ether solvent or nitrile solvent used is 3 to 5 times the mass (g) of the compound in Formula 4.

19. The preparation method according to claim 13, characterized in that, In step a), the volume (mL) of ether or nitrile solvent is 1 to 3 times that of alcohol solvent.

20. The preparation method according to claim 2 or 3, characterized in that, The photochemical reaction in step (3) of claim 2 or step (3) of claim 3 also satisfies one or more of the following conditions: 1) The reaction time for the first or second stage of the photochemical reaction is 5-15 hours; 2) The temperature of the photochemical reaction is 0~40℃; 3) The volume of alkali used in the photochemical reaction (mL) is 2 to 10 times the volume of organic solvent (L); 4) The volume L of the organic solvent used in the photochemical reaction is 0.1 to 0.5 times the mass g of the compound in Formula 6.

21. The preparation method according to claim 2 or 3, characterized in that, The photochemical reaction in step (3) of claim 2 or step (3) of claim 3 also satisfies one or more of the following conditions: 1) The photochemical reaction is carried out in two stages. In the first stage, the main wavelength of the open-loop reaction occurs under LED lamp irradiation at 254nm, and in the second stage, the main wavelength of the closed-loop reaction occurs under high-pressure mercury lamp irradiation at 365nm. 2) The reaction time for the first or second stage of the photochemical reaction is 8-12 hours; 3) The temperature of the photochemical reaction is 5~25℃; 4) The volume of alkali used in the photochemical reaction (mL) is 4 to 6 times the volume of organic solvent (L); 5) The volume L of the organic solvent used in the photochemical reaction is 0.2 to 0.3 times the mass g of the compound in Formula 6.

22. An intermediate compound of formula 3, with the following structure: 。 23. The preparation method according to claim 3, characterized in that, The oxidation reaction in step (4) includes the following steps: dissolving compound 6 in dichloromethane, adding tetramethylpiperidine oxide and potassium bromide, stirring at 0~5℃, adding 7.5% sodium hypochlorite aqueous solution dropwise at this temperature, and stirring for 30 minutes after the addition is complete.

24. The preparation method according to claim 3 or 23, characterized in that, After the oxidation reaction in step (4) is completed, a saturated sodium thiosulfate solution is added to quench the reaction. The organic phase is washed once with saturated sodium thiosulfate and once with 3% dilute hydrochloric acid. The organic phase is dried with anhydrous sodium sulfate, filtered, concentrated, and the crude product is dissolved in a mixed solvent of n-heptane and methyl tert-butyl ether. Crystallization is carried out at 0-5°C for 1 hour. The product is filtered, the filter cake is washed with n-heptane, and the filter cake is dried by blowing air at 55-60°C to obtain compound of formula 7.

25. The preparation method according to claim 3, characterized in that, The double bond transfer reaction in step (5) includes the following steps: dissolving compound 7 in dichloromethane, adding tert-butylhydroquinone, stirring, and under nitrogen protection, adding a 35% hydrochloric acid ethanol solution dropwise at 0~10℃. After the addition is complete, the reaction is maintained at 0~10℃ for 2 hours.

26. The preparation method according to claim 3 or 25, characterized in that, After the double bond transfer reaction in step (5) is completed, deionized water is added to quench the reaction. The organic phase is washed with a saturated sodium bicarbonate solution until neutral. The organic phase is concentrated and then dissolved in ethanol. The concentration is repeated 1 to 3 times. The mixture is then concentrated to 1 / 3 to 1 / 2 of its volume. The mixture is placed at -20°C to crystallize and frozen for 2 hours. The mixture is filtered, and the filter cake is washed with cold ethanol. The filter cake is then suspended in n-heptane and slurried for 2 hours. The mixture is filtered, washed with n-heptane, and the filter cake is dried in a forced-air dryer at 55-60°C to obtain dydrogesterone.

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