Synthesis process of didrogesterone

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis process of didrogesterone. According to the present invention, the CIM-ZIF and HKUST-1 efficient composite catalyst system is used for the synthesis of the didrogesterone, such that the conversion rate and the selectivity of the reaction are significantly improved, and the generation of the by-product is reduced. Experimental results show that when the CIM-ZIF and HKUST-1 composite catalyst is used, the content of the target product 9beta, 10alpha-dehydroprogesterone diethyl diketal reaches 71.1%, and the unconverted raw material content and impurity content are both lower than those of other catalytic systems in the same embodiment and contrast. The data advantage verifies the catalytic performance of CIM-ZIF and HKUST-1 in the synthesis of degestrol, and compared with the single use of ZIF-8 or HKUST-1 catalyst, the composite system has obvious advantages in conversion rate, selectivity and intermittent control, and shows the creation and practical values of the combination.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a synthesis process of dydrogesterone. Background Art

[0002] Dydrogesterone is an important progestogen drug with the chemical name 9β,10α-pregnane-4,6-diene-3,20-dione. It originated from the significant treatment and wide application in the treatment of various diseases caused by endogenous progesterone deficiency (such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular proliferation cycle, etc.) for the preservation of pregnancy and prevention of miscarriage. In clinical practice, dydrogesterone is mainly used in the form of tablets to treat luteal insufficiency or related external diseases. Its mechanism of action and efficacy have been extensively studied and verified, so its demand is increasing worldwide. However, since the synthesis process of drogesterone involves complex chemical reaction steps, the control of reaction conditions and the high precision requirements of the product, its large-scale production still faces fatal challenges.

[0003] The traditional synthesis process of dydrogesterone mainly includes multiple steps such as photochemical ring opening and closing reactions, decyclization reactions and rearrangement reactions. In particular, in the photochemical ring opening and closing reactions, the requirements for reaction conditions are extremely strict. It is necessary to use a light source with a specific wavelength and to carry out the reaction at a lower temperature to ensure the selectivity of the reaction and the generation of the target product. However, this synthesis route has exposed the following defects in actual production: (1) Low reaction rate: Traditional photochemical reaction steps usually require longer light irradiation to ensure the key conversion of the target molecule, resulting in shortened reaction time and low production efficiency; (2) By-product generation: Due to the difficult and uncontrolled conditions, the reaction is prone to generate unreacted intermediates or fully structured derivatives. These by-products can not only reduce the product, but also reduce the cost and fragrance of the separation step; (3) High energy consumption: Strict control of temperature and nozzles during the reaction process and repeated separation and closure steps increase energy consumption, which is not conducive to the green and sustainable development of the process; (4) Limited catalyst selection: The catalyst in the traditional process often uses a single inorganic or organic acid, which is difficult to effectively balance the reaction rate and sensitivity, and it is difficult to meet the requirements of industrial-scale production for high efficiency and environmental protection.

[0004] Therefore, the traditional synthesis route of dydrogesterone has certain defects in reaction efficiency, product purity and efficient energy consumption, and there is an urgent need for a new, stable catalytic system to optimize the synthesis process. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a synthesis process of dydrogesterone.

[0006] A synthesis process of dydrogesterone comprises the following steps:

[0007] (1) Photoreaction: 14-16 kg of 9α,10β-pregnane-4,6-diene-3,20-dione diethylene acetal is dissolved in 1000-1200 L of tetrahydrofuran solvent, and then 1-3 wt% of a composite catalyst is added. Under nitrogen protection and ultraviolet light irradiation, a first-stage ring-opening reaction is carried out to obtain a tetrahydrofuran solution containing a ring-opening reaction intermediate, and then the tetrahydrofuran solution containing the ring-opening reaction intermediate is irradiated with another wavelength of ultraviolet light under nitrogen protection to carry out a second-stage ring-closing reaction. After the ring-opening reaction intermediate is converted, a solution A is obtained. The reaction temperature of the whole process is controlled at -5 to 5°C, the reaction time is 30 to 40 hours, and the reaction progress of the indicator light is detected by HPLC to determine whether the ring-opening and ring-closing reactions are completed;

[0008] (2) Concentration and separation: The solution A obtained in step (1) is transferred into a concentration kettle, and the solvent tetrahydrofuran is removed by distillation under reduced pressure, and then 1400-1800 L of an ethanol-acetonitrile mixed solvent is added, and the volume ratio of ethanol to acetonitrile is (2-4):1, and refluxed at 75-80°C for 20-30 min, and then cooled to -6--4°C and allowed to stand for 20-25 min, and filtered to obtain a filtrate; 30-40% of the volume of the solvent is removed by distillation of the filtrate under reduced pressure, and then allowed to stand at -3-0°C for 20-30 min, and filtered to obtain a crude product of 9β,10α-dehydroprogesterone diethylene ketal, and the crude product is dissolved in isopropanol and recrystallized for purification to obtain relatively pure 9β,10α-dehydroprogesterone diethylene ketal;

[0009] (3) Deprotection reaction: 8-10 kg of the relatively pure 9β,10α-dehydroprogesterone diethylene acetal obtained in step (2) is dissolved in 300-400 L of tetrahydrofuran-water mixed solvent, wherein the volume ratio of tetrahydrofuran to water is (2-4):1, 100-140 L of acetic acid is added, and the mixture is stirred and refluxed at 78-80° C. The completion of the reaction is detected by HPLC. After the reaction is completed, the solvent is removed by vacuum distillation, and the mixture is extracted with dichloromethane, washed with a 10-14 wt % sodium bicarbonate aqueous solution until the pH value is close to neutral, and then dried, and the dichloromethane is removed by vacuum distillation, and then the mixture is refluxed with an acetone-methanol mixed solvent for 5-10 min, cooled for crystallization, and filtered to obtain a deprotected product, wherein the volume ratio of acetone-methanol is 1:(2-4);

[0010] (4) Rearrangement reaction: 800-900 ml of anhydrous ethanol is added to a 200-400 L reactor, and dry hydrogen chloride gas is introduced at 0-10° C. to prepare an anhydrous ethanol-hydrogen chloride solution, wherein the water content of the anhydrous ethanol-hydrogen chloride solution is controlled to be less than 0.2 wt %, and the hydrogen chloride content is 30-35 wt %; 8-9 kg of the deprotected product obtained in step (3) is dissolved in 70-90 L of anhydrous ethanol, and 800-900 mL of a 30-35 wt % hydrogen chloride ethanol solution is added under stirring, and the reaction is stirred at -5-0° C. After the reaction is completed by HPLC tracking detection, the solvent is removed under reduced pressure to obtain crude dydrogesterone; the crude dydrogesterone is dissolved in dichloromethane, washed with a sodium bicarbonate aqueous solution, dried, and recrystallized with an ethyl acetate-n-hexane mixed solvent, wherein the volume ratio of ethyl acetate to n-hexane is 1:(4-6), and finally purified with isopropanol to obtain the product dydrogesterone.

[0011] The wavelength range of the ultraviolet light source for the first stage ring-opening reaction in step (1) is 285-300 nm, and the light source power is 9-12 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0012] The wavelength range of the ultraviolet light source for the second stage closed-loop reaction in step (1) is 305-365 nm, and the light source power is 9-12 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0013] The composite catalyst in step (1) is prepared by mixing a CIM-ZIF catalyst and a HKUST-1 catalyst in a mass ratio of 1:1.

[0014] The preparation method of the CIM-ZIF catalyst comprises the following steps:

[0015] S1: Dissolve zinc nitrate hexahydrate, 2-methylimidazole, and 5-chloroimidazole in methanol respectively to prepare 0.1-0.2 mol / L zinc salt methanol solution, 0.8-1 mol / L 2-methylimidazole methanol solution, and 0.2-0.4 mol / L 5-chloroimidazole methanol solution;

[0016] S2: Mix the 0.1-0.2 mol / L zinc salt methanol solution, 0.8-1 mol / L 2-methylimidazole methanol solution, and 0.2-0.4 mol / L 5-chloroimidazole methanol solution obtained in step S1, and stir at room temperature for 30-40 min to obtain a reaction mixture A; transfer the reaction mixture to a hydrothermal reactor, react at 60° C. to 80° C. for 4-6 h, filter, wash, and dry to obtain the CIM-ZIF catalyst.

[0017] In the reaction mixture A in step S2, the molar ratio of 5-chloroimidazole to 2-methylimidazole is 1:(2-4); the molar ratio of zinc ion to imidazole group is 1:(3-5).

[0018] The preparation method of the HKUST-1 catalyst comprises the following steps:

[0019] N1: Dissolve copper nitrate trihydrate in water to prepare a 0.01-0.1 mol / L copper nitrate aqueous solution; dissolve 1,3,5-benzenetricarboxylic acid in anhydrous ethanol to prepare a 0.01-0.1 mol / L 1,3,5-benzenetricarboxylic acid ethanol solution;

[0020] N2: Mix the copper nitrate aqueous solution and 1,3,5-benzenetricarboxylic acid ethanol solution obtained in step N1, and stir at room temperature for 30 to 40 minutes to obtain a reaction mixture B; transfer the reaction mixture to a hydrothermal reactor, react at 100° C. to 120° C. for 12 to 24 hours, filter, wash, and dry to obtain the HKUST-1 catalyst.

[0021] The molar ratio of copper ions to 1,3,5-benzenetricarboxylic acid in the reaction mixture B in step N2 is 1:(1-2).

[0022] Beneficial effects of the present invention:

[0023] The present invention adopts a CIM-ZIF and HKUST-1 high-efficiency composite catalyst system for the synthesis of dydrogesterone, which significantly improves the conversion rate and selectivity of the reaction and reduces the generation of by-products.

[0024] The 5-chloroimidazole modification in the CIM-ZIF catalyst gives it an acidic site, which effectively promotes the photochemical ring-opening and ring-closing reactions during the synthesis of dydrogesterone. The acidic site can enhance the activity of the reaction and increase the conversion of the raw materials. The HKUST-1 catalyst provides excellent redox activity, especially in the rearrangement reaction stage, which can further accelerate the product conversion process. This redox characteristic makes the reaction process more outstanding and effectively improves the yield of dydrogesterone. The synergistic effect of the two catalysts significantly improves the reaction efficiency, increases the yield of the target product, and reduces the residue of unreacted raw materials and the generation of by-products, thereby significantly improving the overall synthesis efficiency.

[0025] The experimental results show that when the CIM-ZIF and HKUST-1 composite catalyst is used, the content of the target product 9β,10α-dehydroprogesterone diethylene acetal reaches 71.1%. In the same embodiment and comparative example, the content of unconverted raw materials and impurities are lower than those of other catalytic systems. This data advantage verifies the catalytic performance of CIM-ZIF and HKUST-1 in the synthesis of high-efficiency drogestrel. Compared with the use of ZIF-8 or HKUST-1 catalyst alone, the composite system has significant advantages in conversion rate, selectivity and intermittent control, demonstrating the creative and practical value of the combination.

[0026] The CIM-ZIF and HKUST-1 composite catalytic system proposed in the present invention, with the good effects of acidity and redox active sites, and the optimized pore structure design, enables the synthesis of dydrogesterone to have a higher conversion rate and better process selectivity. The results further prove its significant improvement in catalytic efficiency, showing unique technical advantages and innovation, and has practical application value in industrial synthesis. DETAILED DESCRIPTION

[0027] The experimental methods in the following examples are conventional methods unless otherwise specified. The medicinal materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

[0028] 9α,10β-pregnane-4,6-diene-3,20-dione diethylene ketal: CAS number: 1162-56-7.

[0029] 1,3,5-Benzenetricarboxylic acid: CAS number: 554-95-0.

[0030] Example 1

[0031] A synthesis process of dydrogesterone comprises the following steps:

[0032] (1) Photoreaction: 15 kg of 9α,10β-pregnane-4,6-diene-3,20-dione diethylene acetal was dissolved in 1200 L of tetrahydrofuran solvent, and then 2 wt% of the composite catalyst was added. Under nitrogen protection and ultraviolet light irradiation, the first stage of ring-opening reaction was carried out to obtain a tetrahydrofuran solution containing a ring-opening reaction intermediate, and then the tetrahydrofuran solution containing the ring-opening reaction intermediate was irradiated with another wavelength of ultraviolet light under nitrogen protection to carry out a second stage of ring-closing reaction. After the ring-opening reaction intermediate was converted, solution A was obtained. The reaction temperature of the whole process was controlled at 0°C, the reaction time was 35 h, and the reaction progress of the indicator light was detected by HPLC to determine whether the ring-opening and ring-closing reactions were completed.

[0033] (2) Concentration and separation: The solution A obtained in step (1) is transferred into a concentration kettle, and the tetrahydrofuran solvent is removed by vacuum distillation. Then, 1600 L of an ethanol-acetonitrile mixed solvent is added, and the volume ratio of ethanol to acetonitrile is 3:1. The mixture is refluxed at 78°C for 25 min, and then cooled to -5°C and allowed to stand for 20 min. The mixture is filtered and the filtrate is taken. 35% of the volume of the solvent is removed by vacuum distillation of the filtrate, and then allowed to stand at 0°C for 25 min. The crude product of 9β,10α-dehydroprogesterone diethylene ketal is obtained by vacuum filtration. The crude product is dissolved in isopropanol and purified by recrystallization to obtain relatively pure 9β,10α-dehydroprogesterone diethylene ketal.

[0034] (3) Deprotection reaction: 9 kg of the relatively pure 9β,10α-dehydroprogesterone diethylene acetal obtained in step (2) was dissolved in 360 L of a tetrahydrofuran-water mixed solvent, wherein the volume ratio of tetrahydrofuran to water was 3:1, 120 L of acetic acid was added, and the mixture was stirred and refluxed at 79° C. The completion of the reaction was detected by HPLC. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was extracted with dichloromethane. The mixture was washed with a 12 wt % aqueous sodium bicarbonate solution until the pH value was close to neutral, and then dried. The dichloromethane was removed by vacuum distillation, and the mixture was refluxed with an acetone-methanol mixed solvent for 7 min, cooled for crystallization, and filtered to obtain a deprotected product. The volume ratio of acetone to methanol was 1:3.

[0035] (4) Rearrangement reaction: 820 ml of anhydrous ethanol was added to a 300 L reactor, and dry hydrogen chloride gas was introduced at 5° C. to prepare an anhydrous ethanol-hydrogen chloride solution, wherein the water content of the anhydrous ethanol-hydrogen chloride solution was controlled to be less than 0.2 wt %, and the hydrogen chloride content was 32 wt %; 8.6 kg of the deprotected product obtained in step (3) was dissolved in 80 L of anhydrous ethanol, and 820 mL of a 32 wt % hydrogen chloride ethanol solution was added under stirring, and the reaction was stirred at -5° C. After the reaction was completed by HPLC tracking detection, the solvent was removed under reduced pressure to obtain crude dydrogesterone; the crude dydrogesterone was dissolved in dichloromethane, washed with a sodium bicarbonate aqueous solution, dried, and recrystallized with an ethyl acetate-n-hexane mixed solvent, wherein the volume ratio of ethyl acetate to n-hexane was 1:5, and finally purified with isopropanol to obtain the product dydrogesterone.

[0036] The wavelength range of the ultraviolet light source for the first stage ring-opening reaction in step (1) is 285-300 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0037] The wavelength range of the ultraviolet light source for the second stage closed-loop reaction in step (1) is 305-365 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0038] The composite catalyst in step (1) is prepared by mixing a CIM-ZIF catalyst and a HKUST-1 catalyst in a mass ratio of 1:1.

[0039] The preparation method of the CIM-ZIF catalyst comprises the following steps:

[0040] S1: Dissolve zinc nitrate hexahydrate, 2-methylimidazole, and 5-chloroimidazole in methanol respectively to prepare 0.1 mol / L zinc salt methanol solution, 0.9 mol / L 2-methylimidazole methanol solution, and 0.3 mol / L 5-chloroimidazole methanol solution;

[0041] S2: Mix the 0.1 mol / L zinc salt methanol solution, 0.9 mol / L 2-methylimidazole methanol solution, and 0.3 mol / L 5-chloroimidazole methanol solution obtained in step S1, and stir at room temperature for 35 minutes to obtain a reaction mixture A; transfer the reaction mixture to a hydrothermal reactor, react at 70° C. for 5 hours, filter, wash, and dry to obtain the CIM-ZIF catalyst.

[0042] In the reaction mixture A in step S2, the molar ratio of 5-chloroimidazole to 2-methylimidazole is 1:3; the molar ratio of zinc ions to imidazole groups is 1:4.

[0043] The preparation method of the HKUST-1 catalyst comprises the following steps:

[0044] N1: Dissolve copper nitrate trihydrate in water to prepare a 0.05 mol / L copper nitrate aqueous solution; dissolve 1,3,5-benzenetricarboxylic acid in anhydrous ethanol to prepare a 0.05 mol / L 1,3,5-benzenetricarboxylic acid ethanol solution;

[0045] N2: Mix the copper nitrate aqueous solution and the 1,3,5-benzenetricarboxylic acid ethanol solution obtained in step N1, and stir at room temperature for 30-40 minutes to obtain a reaction mixture B; transfer the reaction mixture to a hydrothermal reactor, react at 110° C. for 18 hours, filter, wash, and dry to obtain the HKUST-1 catalyst.

[0046] The molar ratio of copper ions to 1,3,5-benzenetricarboxylic acid in the reaction mixture B in step N2 is 1:1.

[0047] Example 2

[0048] The difference from Example 1 is that the composite catalyst in step (1) is a mixture of ZIF-8 catalyst and HKUST-1 catalyst in a mass ratio of 1:1.

[0049] The preparation method of the ZIF-8 catalyst comprises the following steps:

[0050] S1: Dissolve zinc nitrate hexahydrate and 2-methylimidazole in methanol to prepare 0.1 mol / L zinc salt methanol solution and 0.9 mol / L 2-methylimidazole methanol solution;

[0051] S2: Mix the 0.1 mol / L zinc salt methanol solution and the 0.9 mol / L 2-methylimidazole methanol solution obtained in step S1, stir at room temperature for 35 minutes to obtain a reaction mixture A; transfer the reaction mixture to a hydrothermal reactor, react at 70° C. for 5 hours, filter, wash and dry to obtain the ZIF-8 catalyst.

[0052] The molar ratio of zinc ion to 2-methylimidazole in the reaction mixture A in step S2 is 1:4.

[0053] The preparation method of the HKUST-1 catalyst comprises the following steps:

[0054] N1: Dissolve copper nitrate trihydrate in water to prepare a 0.05 mol / L copper nitrate aqueous solution; dissolve 1,3,5-benzenetricarboxylic acid in anhydrous ethanol to prepare a 0.05 mol / L 1,3,5-benzenetricarboxylic acid ethanol solution;

[0055] N2: Mix the copper nitrate aqueous solution and the 1,3,5-benzenetricarboxylic acid ethanol solution obtained in step N1, and stir at room temperature for 30-40 minutes to obtain a reaction mixture B; transfer the reaction mixture to a hydrothermal reactor, react at 110° C. for 18 hours, filter, wash, and dry to obtain the HKUST-1 catalyst.

[0056] The molar ratio of copper ions to 1,3,5-benzenetricarboxylic acid in the reaction mixture B in step N2 is 1:1.

[0057] Example 3

[0058] The difference from Example 1 is that the preparation method of the CIM-ZIF catalyst comprises the following steps:

[0059] S1: Dissolve zinc nitrate hexahydrate and 5-chloroimidazole in methanol to prepare 0.1 mol / L zinc salt methanol solution and 0.3 mol / L 5-chloroimidazole methanol solution;

[0060] S2: Mix the 0.1 mol / L zinc salt methanol solution and the 0.3 mol / L 5-chloroimidazole methanol solution obtained in step S1, stir at room temperature for 35 minutes to obtain a reaction mixture A; transfer the reaction mixture to a hydrothermal reactor, react at 70° C. for 5 hours, filter, wash and dry to obtain the CIM-ZIF catalyst.

[0061] The molar ratio of zinc ion to 5-chloroimidazole in the reaction mixture A in step S2 is 1:4.

[0062] The preparation method of the HKUST-1 catalyst comprises the following steps:

[0063] N1: Dissolve copper nitrate trihydrate in water to prepare a 0.05 mol / L copper nitrate aqueous solution; dissolve 1,3,5-benzenetricarboxylic acid in anhydrous ethanol to prepare a 0.05 mol / L 1,3,5-benzenetricarboxylic acid ethanol solution;

[0064] N2: Mix the copper nitrate aqueous solution and the 1,3,5-benzenetricarboxylic acid ethanol solution obtained in step N1, and stir at room temperature for 30-40 minutes to obtain a reaction mixture B; transfer the reaction mixture to a hydrothermal reactor, react at 110° C. for 18 hours, filter, wash, and dry to obtain the HKUST-1 catalyst.

[0065] The molar ratio of copper ions to 1,3,5-benzenetricarboxylic acid in the reaction mixture B in step N2 is 1:1.

[0066] Example 4

[0067] A synthesis process of dydrogesterone comprises the following steps:

[0068] (1) Photoreaction: 15 kg of 9α,10β-pregnane-4,6-diene-3,20-dione diethylene acetal was dissolved in 1200 L of tetrahydrofuran solvent, and then 2 wt% of CIM-ZIF catalyst was added. Under nitrogen protection and ultraviolet light irradiation, a first-stage ring-opening reaction was carried out to obtain a tetrahydrofuran solution containing a ring-opening reaction intermediate. Then, the tetrahydrofuran solution containing the ring-opening reaction intermediate was irradiated with another wavelength of ultraviolet light under nitrogen protection to carry out a second-stage ring-closing reaction. After the ring-opening reaction intermediate was converted, solution A was obtained. The reaction temperature was controlled at 0° C. during the whole process, and the reaction time was 35 h. The reaction progress of the indicator light was detected by HPLC to determine whether the ring-opening and ring-closing reactions were completed.

[0069] (2) Concentration and separation: The solution A obtained in step (1) is transferred into a concentration kettle, and the tetrahydrofuran solvent is removed by vacuum distillation. Then, 1600 L of an ethanol-acetonitrile mixed solvent is added, and the volume ratio of ethanol to acetonitrile is 3:1. The mixture is refluxed at 78°C for 25 min, and then cooled to -5°C and allowed to stand for 20 min. The mixture is filtered and the filtrate is taken. 35% of the volume of the solvent is removed by vacuum distillation of the filtrate, and then allowed to stand at 0°C for 25 min. The crude product of 9β,10α-dehydroprogesterone diethylene ketal is obtained by vacuum filtration. The crude product is dissolved in isopropanol and purified by recrystallization to obtain relatively pure 9β,10α-dehydroprogesterone diethylene ketal.

[0070] (3) Deprotection reaction: 9 kg of the relatively pure 9β,10α-dehydroprogesterone diethylene acetal obtained in step (2) was dissolved in 360 L of a tetrahydrofuran-water mixed solvent, wherein the volume ratio of tetrahydrofuran to water was 3:1, 120 L of acetic acid was added, and the mixture was stirred and refluxed at 79° C. The completion of the reaction was detected by HPLC. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was extracted with dichloromethane. The mixture was washed with a 12 wt % aqueous sodium bicarbonate solution until the pH value was close to neutral, and then dried. The dichloromethane was removed by vacuum distillation, and the mixture was refluxed with an acetone-methanol mixed solvent for 7 min, cooled for crystallization, and filtered to obtain a deprotected product. The volume ratio of acetone to methanol was 1:3.

[0071] (4) Rearrangement reaction: 820 ml of anhydrous ethanol was added to a 300 L reactor, and dry hydrogen chloride gas was introduced at 5° C. to prepare an anhydrous ethanol-hydrogen chloride solution, wherein the water content of the anhydrous ethanol-hydrogen chloride solution was controlled to be less than 0.2 wt %, and the hydrogen chloride content was 32 wt %; 8.6 kg of the deprotected product obtained in step (3) was dissolved in 80 L of anhydrous ethanol, and 820 mL of a 32 wt % hydrogen chloride ethanol solution was added under stirring, and the reaction was stirred at -5° C. After the reaction was completed by HPLC tracking detection, the solvent was removed under reduced pressure to obtain crude dydrogesterone; the crude dydrogesterone was dissolved in dichloromethane, washed with a sodium bicarbonate aqueous solution, dried, and recrystallized with an ethyl acetate-n-hexane mixed solvent, wherein the volume ratio of ethyl acetate to n-hexane was 1:5, and finally purified with isopropanol to obtain the product dydrogesterone.

[0072] The wavelength range of the ultraviolet light source for the first stage ring-opening reaction in step (1) is 285-300 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0073] The wavelength range of the ultraviolet light source for the second stage closed-loop reaction in step (1) is 305-365 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0074] The preparation method of the CIM-ZIF catalyst comprises the following steps:

[0075] S1: Dissolve zinc nitrate hexahydrate, 2-methylimidazole, and 5-chloroimidazole in methanol respectively to prepare 0.1 mol / L zinc salt methanol solution, 0.9 mol / L 2-methylimidazole methanol solution, and 0.3 mol / L 5-chloroimidazole methanol solution;

[0076] S2: Mix the 0.1 mol / L zinc salt methanol solution, 0.9 mol / L 2-methylimidazole methanol solution, and 0.3 mol / L 5-chloroimidazole methanol solution obtained in step S1, and stir at room temperature for 35 minutes to obtain a reaction mixture A; transfer the reaction mixture to a hydrothermal reactor, react at 70° C. for 5 hours, filter, wash, and dry to obtain the CIM-ZIF catalyst.

[0077] In the reaction mixture A in step S2, the molar ratio of 5-chloroimidazole to 2-methylimidazole is 1:3; the molar ratio of zinc ions to imidazole groups is 1:4.

[0078] Example 5

[0079] A synthesis process of dydrogesterone comprises the following steps:

[0080] (1) Photoreaction: 15 kg of 9α,10β-pregnane-4,6-diene-3,20-dione diethylene acetal was dissolved in 1200 L of tetrahydrofuran solvent, and 2 wt % of HKUST-1 catalyst was added. Under nitrogen protection and ultraviolet light irradiation, a first-stage ring-opening reaction was carried out to obtain a tetrahydrofuran solution containing a ring-opening reaction intermediate. Then, the tetrahydrofuran solution containing the ring-opening reaction intermediate was irradiated with another wavelength of ultraviolet light under nitrogen protection to carry out a second-stage ring-closing reaction. After the ring-opening reaction intermediate was converted, solution A was obtained. The reaction temperature was controlled at 0° C. during the whole process, and the reaction time was 35 h. The reaction progress of the indicator light was detected by HPLC to determine whether the ring-opening and ring-closing reactions were completed.

[0081] (2) Concentration and separation: The solution A obtained in step (1) is transferred into a concentration kettle, and the tetrahydrofuran solvent is removed by vacuum distillation. Then, 1600 L of an ethanol-acetonitrile mixed solvent is added, and the volume ratio of ethanol to acetonitrile is 3:1. The mixture is refluxed at 78°C for 25 min, and then cooled to -5°C and allowed to stand for 20 min. The mixture is filtered and the filtrate is taken. 35% of the volume of the solvent is removed by vacuum distillation of the filtrate, and then allowed to stand at 0°C for 25 min. The crude product of 9β,10α-dehydroprogesterone diethylene ketal is obtained by vacuum filtration. The crude product is dissolved in isopropanol and purified by recrystallization to obtain relatively pure 9β,10α-dehydroprogesterone diethylene ketal.

[0082] (3) Deprotection reaction: 9 kg of the relatively pure 9β,10α-dehydroprogesterone diethylene acetal obtained in step (2) was dissolved in 360 L of a tetrahydrofuran-water mixed solvent, wherein the volume ratio of tetrahydrofuran to water was 3:1, 120 L of acetic acid was added, and the mixture was stirred and refluxed at 79° C. The completion of the reaction was detected by HPLC. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was extracted with dichloromethane. The mixture was washed with a 12 wt % aqueous sodium bicarbonate solution until the pH value was close to neutral, and then dried. The dichloromethane was removed by vacuum distillation, and the mixture was refluxed with an acetone-methanol mixed solvent for 7 min, cooled for crystallization, and filtered to obtain a deprotected product. The volume ratio of acetone to methanol was 1:3.

[0083] (4) Rearrangement reaction: 820 ml of anhydrous ethanol was added to a 300 L reactor, and dry hydrogen chloride gas was introduced at 5° C. to prepare an anhydrous ethanol-hydrogen chloride solution, wherein the water content of the anhydrous ethanol-hydrogen chloride solution was controlled to be less than 0.2 wt %, and the hydrogen chloride content was 32 wt %; 8.6 kg of the deprotected product obtained in step (3) was dissolved in 80 L of anhydrous ethanol, and 820 mL of a 32 wt % hydrogen chloride ethanol solution was added under stirring, and the reaction was stirred at -5° C. After the reaction was completed by HPLC tracking detection, the solvent was removed under reduced pressure to obtain crude dydrogesterone; the crude dydrogesterone was dissolved in dichloromethane, washed with a sodium bicarbonate aqueous solution, dried, and recrystallized with an ethyl acetate-n-hexane mixed solvent, wherein the volume ratio of ethyl acetate to n-hexane was 1:5, and finally purified with isopropanol to obtain the product dydrogesterone.

[0084] The wavelength range of the ultraviolet light source for the first stage ring-opening reaction in step (1) is 285-300 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0085] The wavelength range of the ultraviolet light source for the second stage closed-loop reaction in step (1) is 305-365 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0086] The preparation method of the HKUST-1 catalyst comprises the following steps:

[0087] N1: Dissolve copper nitrate trihydrate in water to prepare a 0.05 mol / L copper nitrate aqueous solution; dissolve 1,3,5-benzenetricarboxylic acid in anhydrous ethanol to prepare a 0.05 mol / L 1,3,5-benzenetricarboxylic acid ethanol solution;

[0088] N2: Mix the copper nitrate aqueous solution and the 1,3,5-benzenetricarboxylic acid ethanol solution obtained in step N1, and stir at room temperature for 30-40 minutes to obtain a reaction mixture B; transfer the reaction mixture to a hydrothermal reactor, react at 110° C. for 18 hours, filter, wash, and dry to obtain the HKUST-1 catalyst.

[0089] The molar ratio of copper ions to 1,3,5-benzenetricarboxylic acid in the reaction mixture B in step N2 is 1:1.

[0090] Comparative Example 1

[0091] A synthesis process of dydrogesterone comprises the following steps:

[0092] (1) Photoreaction: 15 kg of 9α,10β-pregnane-4,6-diene-3,20-dione diethylene acetal was dissolved in 1200 L of tetrahydrofuran solvent, and then 2 wt% of ZIF-8 catalyst was added. Under nitrogen protection and ultraviolet light irradiation, the first stage of ring-opening reaction was carried out to obtain a tetrahydrofuran solution containing a ring-opening reaction intermediate, and then the tetrahydrofuran solution containing the ring-opening reaction intermediate was irradiated with another wavelength of ultraviolet light under nitrogen protection to carry out a second stage of ring-closing reaction. After the ring-opening reaction intermediate was converted, solution A was obtained. The reaction temperature of the whole process was controlled at 0°C, the reaction time was 35 h, and the reaction progress of the indicator light was detected by HPLC to determine whether the ring-opening and ring-closing reactions were completed.

[0093] (2) Concentration and separation: The solution A obtained in step (1) is transferred into a concentration kettle, and the tetrahydrofuran solvent is removed by vacuum distillation. Then, 1600 L of an ethanol-acetonitrile mixed solvent is added, and the volume ratio of ethanol to acetonitrile is 3:1. The mixture is refluxed at 78°C for 25 min, and then cooled to -5°C and allowed to stand for 20 min. The mixture is filtered and the filtrate is taken. 35% of the volume of the solvent is removed by vacuum distillation of the filtrate, and then allowed to stand at 0°C for 25 min. The crude product of 9β,10α-dehydroprogesterone diethylene ketal is obtained by vacuum filtration. The crude product is dissolved in isopropanol and purified by recrystallization to obtain relatively pure 9β,10α-dehydroprogesterone diethylene ketal.

[0094] (3) Deprotection reaction: 9 kg of the relatively pure 9β,10α-dehydroprogesterone diethylene acetal obtained in step (2) was dissolved in 360 L of a tetrahydrofuran-water mixed solvent, wherein the volume ratio of tetrahydrofuran to water was 3:1, 120 L of acetic acid was added, and the mixture was stirred and refluxed at 79° C. The completion of the reaction was detected by HPLC. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was extracted with dichloromethane. The mixture was washed with a 12 wt % aqueous sodium bicarbonate solution until the pH value was close to neutral, and then dried. The dichloromethane was removed by vacuum distillation, and the mixture was refluxed with an acetone-methanol mixed solvent for 7 min, cooled for crystallization, and filtered to obtain a deprotected product. The volume ratio of acetone to methanol was 1:3.

[0095] (4) Rearrangement reaction: 820 ml of anhydrous ethanol was added to a 300 L reactor, and dry hydrogen chloride gas was introduced at 5° C. to prepare an anhydrous ethanol-hydrogen chloride solution, wherein the water content of the anhydrous ethanol-hydrogen chloride solution was controlled to be less than 0.2 wt %, and the hydrogen chloride content was 32 wt %; 8.6 kg of the deprotected product obtained in step (3) was dissolved in 80 L of anhydrous ethanol, and 820 mL of a 32 wt % hydrogen chloride ethanol solution was added under stirring, and the reaction was stirred at -5° C. After the reaction was completed by HPLC tracking detection, the solvent was removed under reduced pressure to obtain crude dydrogesterone; the crude dydrogesterone was dissolved in dichloromethane, washed with a sodium bicarbonate aqueous solution, dried, and recrystallized with an ethyl acetate-n-hexane mixed solvent, wherein the volume ratio of ethyl acetate to n-hexane was 1:5, and finally purified with isopropanol to obtain the product dydrogesterone.

[0096] The wavelength range of the ultraviolet light source for the first stage ring-opening reaction in step (1) is 285-300 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0097] The wavelength range of the ultraviolet light source for the second stage closed-loop reaction in step (1) is 305-365 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0098] The preparation method of the ZIF-8 catalyst comprises the following steps:

[0099] S1: Dissolve zinc nitrate hexahydrate and 2-methylimidazole in methanol to prepare 0.1 mol / L zinc salt methanol solution and 0.9 mol / L 2-methylimidazole methanol solution;

[0100] S2: Mix the 0.1 mol / L zinc salt methanol solution and the 0.9 mol / L 2-methylimidazole methanol solution obtained in step S1, stir at room temperature for 35 minutes to obtain a reaction mixture A; transfer the reaction mixture to a hydrothermal reactor, react at 70° C. for 5 hours, filter, wash and dry to obtain the ZIF-8 catalyst.

[0101] The molar ratio of zinc ion to 2-methylimidazole in the reaction mixture A in step S2 is 1:4.

[0102] Comparative Example 2

[0103] A synthesis process of dydrogesterone comprises the following steps:

[0104] (1) Photoreaction: 15 kg of 9α,10β-pregnane-4,6-diene-3,20-dione diethylene acetal was dissolved in 1200 L of tetrahydrofuran solvent, and a first-stage ring-opening reaction was carried out under nitrogen protection and ultraviolet light irradiation to obtain a tetrahydrofuran solution containing a ring-opening reaction intermediate, and then the tetrahydrofuran solution containing the ring-opening reaction intermediate was irradiated with another wavelength of ultraviolet light under nitrogen protection to carry out a second-stage ring-closing reaction. After the ring-opening reaction intermediate was converted, solution A was obtained. The reaction temperature was controlled at 0°C for 35 h during the whole process, and the reaction progress was detected by HPLC to determine whether the ring-opening and ring-closing reactions were completed.

[0105] (2) Concentration and separation: The solution A obtained in step (1) is transferred into a concentration kettle, and the tetrahydrofuran solvent is removed by vacuum distillation. Then, 1600 L of an ethanol-acetonitrile mixed solvent is added, and the volume ratio of ethanol to acetonitrile is 3:1. The mixture is refluxed at 78°C for 25 min, and then cooled to -5°C and allowed to stand for 20 min. The mixture is filtered and the filtrate is taken. 35% of the volume of the solvent is removed by vacuum distillation of the filtrate, and then allowed to stand at 0°C for 25 min. The crude product of 9β,10α-dehydroprogesterone diethylene ketal is obtained by vacuum filtration. The crude product is dissolved in isopropanol and purified by recrystallization to obtain relatively pure 9β,10α-dehydroprogesterone diethylene ketal.

[0106] (3) Deprotection reaction: 9 kg of the relatively pure 9β,10α-dehydroprogesterone diethylene acetal obtained in step (2) was dissolved in 360 L of a tetrahydrofuran-water mixed solvent, wherein the volume ratio of tetrahydrofuran to water was 3:1, 120 L of acetic acid was added, and the mixture was stirred and refluxed at 79° C. The completion of the reaction was detected by HPLC. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was extracted with dichloromethane. The mixture was washed with a 12 wt % aqueous sodium bicarbonate solution until the pH value was close to neutral, and then dried. The dichloromethane was removed by vacuum distillation, and the mixture was refluxed with an acetone-methanol mixed solvent for 7 min, cooled for crystallization, and filtered to obtain a deprotected product. The volume ratio of acetone to methanol was 1:3.

[0107] (4) Rearrangement reaction: 820 ml of anhydrous ethanol was added to a 300 L reactor, and dry hydrogen chloride gas was introduced at 5° C. to prepare an anhydrous ethanol-hydrogen chloride solution, wherein the water content of the anhydrous ethanol-hydrogen chloride solution was controlled to be less than 0.2 wt %, and the hydrogen chloride content was 32 wt %; 8.6 kg of the deprotected product obtained in step (3) was dissolved in 80 L of anhydrous ethanol, and 820 mL of a 32 wt % hydrogen chloride ethanol solution was added under stirring, and the reaction was stirred at -5° C. After the reaction was completed by HPLC tracking detection, the solvent was removed under reduced pressure to obtain crude dydrogesterone; the crude dydrogesterone was dissolved in dichloromethane, washed with a sodium bicarbonate aqueous solution, dried, and recrystallized with an ethyl acetate-n-hexane mixed solvent, wherein the volume ratio of ethyl acetate to n-hexane was 1:5, and finally purified with isopropanol to obtain the product dydrogesterone.

[0108] The wavelength range of the ultraviolet light source for the first stage ring-opening reaction in step (1) is 285-300 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0109] The wavelength range of the ultraviolet light source for the second stage closed-loop reaction in step (1) is 305-365 nm, and the light source power is 10 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

[0110] Test Example 1

[0111] The solution A obtained in step (1) of each embodiment and comparative example was filtered to remove the catalyst, and then the solvent was removed by distillation under reduced pressure. The content of the raw material 9α,10β-dehydroprogesterone diethylene ketal, the content of the target product 9β,10α-dehydroprogesterone diethylene ketal and the content of other impurities in the residue were detected by HPLC. The results are shown in Table 1.

[0112] Table 1: HPLC test results

[0113]

[0114] Table 2: Impurity content test results

[0115]

[0116]

[0117] As can be seen from Table 1 and Table 2, Example 1 uses a composite catalyst of CIM-ZIF and HKUST-1, and its target product 9β,10α-dehydroprogesterone diethylene acetal has the highest content and the lowest impurity content, which indicates that the synergistic effect of the composite catalyst of CIM-ZIF and HKUST-1 significantly improves the conversion efficiency, achieving the highest target product content and the lowest raw material content. CIM-ZIF provides acidic sites, which helps the smooth progress of photochemical ring opening and ring closing reactions, while the redox properties of HKUST-1 help accelerate the conversion of the rearrangement reaction. Therefore, Example 1 shows the best catalytic effect, proving the good effects of the two catalysts. The composite catalyst effect of ZIF-8 and HKUST-1 in Example 2 is slightly worse than that of Example 1. Although HKUST-1 provides redox effects, ZIF-8 lacks the acidic modification brought by 5-chloroimidazole, which makes the catalytic activity slightly lower, so the unconverted raw materials increase, and the target product content decreases accordingly. In Example 3, zinc nitrate hexahydrate and 5-chloroimidazole are used to synthesize CIM-ZIF catalysts. ZIF materials are usually formed by the coordination of zinc ions with smaller imidazole ligands (such as 2-methylimidazole). Due to the presence of chlorine substituents, 5-chloroimidazole may affect its coordination ability and the formation of ZIF structure. Although 5-chloroimidazole can be used as a ligand to form coordination with zinc ions, its increased chlorine substituents may make the reconstructed pore structure different from the common ZIF-8, resulting in different pore sizes and catalytic properties. By comparing Example 1 and Example 3, it can be seen that higher chloride ions are not conducive to the catalytic generation of 9β,10α-dehydroprogesterone diethylene ketal. In Example 4, only CIM-ZIF catalyst was used to show higher catalytic activity, but it was slightly lower than the effect of the composite catalyst. CIM-ZIF provides acidic sites, which are suitable for ring-opening and ring-closing reactions, but lacks the redox effect of HKUST-1 to promote subsequent rearrangement reactions, resulting in a decrease in reaction efficiency. Example 5 uses only HKUST-1 catalyst, which mainly has redox properties, but lacks efficient acidic sites, thereby efficiently promoting ring-opening and ring-closing reactions, resulting in low reaction efficiency. The content of unconverted raw materials is relatively high, indicating that the use of HKUST-1 alone cannot fully improve the synthesis efficiency of dydrogesterone. By comparing Comparative Example 1 with Example 1, it can be seen that the single ZIF-8 catalyst lacks acidic modification and redox activity, so the catalytic effect is relatively reduced. The unconverted raw materials are high and the target product reaction content is low, indicating that ZIF-8 is difficult to significantly improve the conversion rate of the product in this reaction. The results of Comparative Example 2 show that in the absence of a catalyst, the reaction efficiency is the lowest, the target product yield is the lowest, and the yield is the highest, showing that the catalyst plays an important role in the transcriptional progesterone synthesis process. The absence of a catalyst results in the most unconverted raw materials and a significant decrease in the conversion rate of the target product.

[0118] In summary, the CIM-ZIF and HKUST-1 composite catalyst combination of Example 1 performed best, indicating that the combination of the acidic sites of CIM-ZIF and the redox effect of HKUST-1 can effectively promote photochemical ring-opening, ring-closing and rearrangement reactions, and significantly improve the conversion rate of the target product.

Claims

1. A synthesis process of dydrogesterone, characterized in that: The following steps are involved: (1) Photoreaction: 14-16 kg of 9α,10β-pregnane-4,6-diene-3,20-dione diethylene acetal is dissolved in 1000-1200 L of tetrahydrofuran solvent, and then 1-3 wt% of a composite catalyst is added. Under nitrogen protection and ultraviolet light irradiation, a first-stage ring-opening reaction is carried out to obtain a tetrahydrofuran solution containing a ring-opening reaction intermediate, and then the tetrahydrofuran solution containing the ring-opening reaction intermediate is irradiated with another wavelength of ultraviolet light under nitrogen protection to carry out a second-stage ring-closing reaction. After the ring-opening reaction intermediate is converted, a solution A is obtained. The reaction temperature of the whole process is controlled at -5 to 5°C, the reaction time is 30 to 40 hours, and the reaction progress of the indicator light is detected by HPLC to determine whether the ring-opening and ring-closing reactions are completed; (2) Concentration and separation: The solution A obtained in step (1) is transferred into a concentration kettle, and the solvent tetrahydrofuran is removed by distillation under reduced pressure, and then 1400-1800 L of an ethanol-acetonitrile mixed solvent is added, and the volume ratio of ethanol to acetonitrile is (2-4):1, and refluxed at 75-80°C for 20-30 min, and then cooled to -6--4°C and allowed to stand for 20-25 min, and filtered to obtain a filtrate; 30-40% of the volume of the solvent is removed by distillation of the filtrate under reduced pressure, and then allowed to stand at -3-0°C for 20-30 min, and filtered to obtain a crude product of 9β,10α-dehydroprogesterone diethylene ketal, and the crude product is dissolved in isopropanol and recrystallized for purification to obtain relatively pure 9β,10α-dehydroprogesterone diethylene ketal; (3) Deprotection reaction: 8-10 kg of the relatively pure 9β,10α-dehydroprogesterone diethylene acetal obtained in step (2) is dissolved in 300-400 L of tetrahydrofuran-water mixed solvent, wherein the volume ratio of tetrahydrofuran to water is (2-4):1, 100-140 L of acetic acid is added, and the mixture is stirred and refluxed at 78-80° C. The completion of the reaction is detected by HPLC. After the reaction is completed, the solvent is removed by vacuum distillation, and the mixture is extracted with dichloromethane, washed with a 10-14 wt % sodium bicarbonate aqueous solution until the pH value is close to neutral, and then dried, and the dichloromethane is removed by vacuum distillation, and then the mixture is refluxed with an acetone-methanol mixed solvent for 5-10 min, cooled for crystallization, and filtered to obtain a deprotected product, wherein the volume ratio of acetone-methanol is 1:(2-4); (4) Rearrangement reaction: 800-900 ml of anhydrous ethanol is added to a 200-400 L reactor, and dry hydrogen chloride gas is introduced at 0-10° C. to prepare an anhydrous ethanol-hydrogen chloride solution, wherein the water content of the anhydrous ethanol-hydrogen chloride solution is controlled to be less than 0.2 wt %, and the hydrogen chloride content is 30-35 wt %; 8-9 kg of the deprotected product obtained in step (3) is dissolved in 70-90 L of anhydrous ethanol, and 800-900 mL of a 30-35 wt % hydrogen chloride ethanol solution is added under stirring, and the reaction is stirred at -5-0° C. After the reaction is completed by HPLC tracking detection, the solvent is removed under reduced pressure to obtain crude dydrogesterone; the crude dydrogesterone is dissolved in dichloromethane, washed with a sodium bicarbonate aqueous solution, dried, and recrystallized with an ethyl acetate-n-hexane mixed solvent, wherein the volume ratio of ethyl acetate to n-hexane is 1:(4-6), and finally purified with isopropanol to obtain the product dydrogesterone.

2. The synthesis process of dydrogesterone according to claim 1, characterized in that: The wavelength range of the ultraviolet light source for the first stage ring-opening reaction in step (1) is 285-300 nm, and the light source power is 9-12 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

3. The synthesis process of dydrogesterone according to claim 1, characterized in that: The wavelength range of the ultraviolet light source for the second stage closed-loop reaction in step (1) is 305-365 nm, and the light source power is 9-12 W / m 2 , the light source device should be evenly distributed around the reaction vessel, and the light angle should be maintained at 90° to ensure uniform lighting.

4. The synthesis process of dydrogesterone according to claim 1, characterized in that: The composite catalyst in step (1) is prepared by mixing a CIM-ZIF catalyst and a HKUST-1 catalyst in a mass ratio of 1:

1.

5. The synthesis process of dydrogesterone as claimed in claim 4, characterized in that: The preparation method of the CIM-ZIF catalyst comprises the following steps: S1: Dissolve zinc nitrate hexahydrate, 2-methylimidazole, and 5-chloroimidazole in methanol respectively to prepare 0.1-0.2 mol / L zinc salt methanol solution, 0.8-1 mol / L 2-methylimidazole methanol solution, and 0.2-0.4 mol / L 5-chloroimidazole methanol solution; S2: Mix the 0.1-0.2 mol / L zinc salt methanol solution, 0.8-1 mol / L 2-methylimidazole methanol solution, and 0.2-0.4 mol / L 5-chloroimidazole methanol solution obtained in step S1, and stir at room temperature for 30-40 min to obtain a reaction mixture A; transfer the reaction mixture to a hydrothermal reactor, react at 60° C. to 80° C. for 4-6 h, filter, wash, and dry to obtain the CIM-ZIF catalyst.

6. The synthesis process of dydrogesterone as claimed in claim 5, characterized in that: In the reaction mixture A in step S2, the molar ratio of 5-chloroimidazole to 2-methylimidazole is 1:(2-4); the molar ratio of zinc ion to imidazole group is 1:(3-5).

7. The synthesis process of dydrogesterone according to claim 4, characterized in that: The preparation method of the HKUST-1 catalyst comprises the following steps: N1: Dissolve copper nitrate trihydrate in water to prepare a 0.01-0.1 mol / L copper nitrate aqueous solution; dissolve 1,3,5-benzenetricarboxylic acid in anhydrous ethanol to prepare a 0.01-0.1 mol / L 1,3,5-benzenetricarboxylic acid ethanol solution; N2: Mix the copper nitrate aqueous solution and 1,3,5-benzenetricarboxylic acid ethanol solution obtained in step N1, and stir at room temperature for 30 to 40 minutes to obtain a reaction mixture B; transfer the reaction mixture to a hydrothermal reactor, react at 100° C. to 120° C. for 12 to 24 hours, filter, wash, and dry to obtain the HKUST-1 catalyst.

8. The synthesis process of dydrogesterone as claimed in claim 7, characterized in that: The molar ratio of copper ions to 1,3,5-benzenetricarboxylic acid in the reaction mixture B in step N2 is 1:(1-2).

Images