Preparation method of progesterone
Through 4-AD as the starting material, condensation, epoxidation, carbonylation and hydrolysis reaction methods are used to solve the problems of high raw materials and the use of highly toxic chemicals in the existing progesterone synthesis process, and efficient and safe preparation of progesterone is achieved.
Patent Information
- Application Number
- CN201911407374.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2019-12-31
- Publication Date
- 2025-05-09
- Estimated Expiration
- 2039-12-31
AI Technical Summary
In the existing progesterone synthesis process, the raw material cost is high and highly toxic chemicals are used, resulting in operational hazards and increased production costs.
4-AD is used as the starting material to produce progesterone through condensation, epoxidation, carbonylation and hydrolysis reactions, avoiding the use of highly toxic chemicals, and improving the readiness of raw materials and the safety of the process.
High yield and high purity progesterone preparation is achieved, which reduces production costs and provides a process route suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing progesterone. Background Art
[0002] Progesterone, also known as progesterone hormone and luteinizing hormone, is a natural progesterone secreted by the corpus luteum of the ovary. It has a significant morphological effect on the stimulated endometrium in the body and is necessary to maintain pregnancy. It is clinically used for threatened abortion, habitual abortion, etc. At the same time, progesterone is a key intermediate for steroid drugs such as corticosteroids and androgens.
[0003] At present, the traditional process of industrial production of progesterone is mainly to use dienolone acetate as raw material to produce progesterone through hydrogenation, hydrolysis and oxidation reactions. The reaction route is as follows:
[0004]
[0005] The diosgenin acetate used in this route is extracted from Diosgenin and Turmeric as raw materials, and Diosgenin is obtained through several steps of chemical synthesis. At present, Diosgenin and Turmeric are mainly cultivated artificially, and the labor cost is high, which leads to an upward trend in the price of diosgenin acetate, which greatly increases the cost of progesterone synthesis.
[0006] Patents and literature reports use cheap 4-AD as a raw material to synthesize progesterone. The reaction route is as follows:
[0007]
[0008] This route uses highly toxic acetone cyanohydrin for hydroxycyanation reaction, which can easily poison the operator and has a low yield, making it unsuitable for industrialization.
[0009] In view of this, the present invention is proposed. Summary of the invention
[0010] The main purpose of the present invention is to provide a method for preparing progesterone, in order to at least partially solve at least one of the above technical problems.
[0011] In order to complete the present invention, the technical solution adopted is:
[0012] The present invention provides a method for preparing progesterone, comprising the following steps:
[0013] (a) the carbonyl group at the C3 position of the compound of formula 2 is subjected to a condensation reaction to obtain a compound of formula 3 having a ketal at the C3 position;
[0014] (b) subjecting the carbonyl group at position C17 of the compound of formula 3 to epoxidation to obtain a compound of formula 4 having an epoxy group at position C17;
[0015] (c) The epoxy group at position C17 of the compound of formula 4 is subjected to carbonylation reaction, and the ketal at position C3 is subjected to hydrolysis reaction to obtain the compound of formula 1; the reaction formula is as follows:
[0016]
[0017] The method for preparing progesterone provided by the present invention uses 4-AD (compound of formula 2) as a starting material, and obtains progesterone (compound of formula 1) through condensation, epoxidation, carbonylation and hydrolysis reactions. The starting material is easy to obtain, no highly toxic chemicals are required, the method is environmentally friendly and has a high safety factor; the obtained progesterone has a high yield and high purity, and provides a process route that can be industrialized for production.
[0018] Furthermore, in the step (a), the compound of formula 2 and the lower aliphatic diol undergo condensation reaction under the action of a condensation agent and a catalyst to obtain a compound of formula 3.
[0019] Furthermore, in the step (a), the lower aliphatic diol is selected from ethylene glycol.
[0020] Furthermore, in the step (a), the molar ratio of the compound of formula 2 to the lower aliphatic diol is 1:(1.1-1.5).
[0021] Wherein, in step (a), a typical but non-limiting molar ratio of the compound of formula 2 to the lower aliphatic diol may be, for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5.
[0022] The present invention optimizes the molar ratio of the compound of formula 2 to the lower aliphatic diol in step (a). When the molar ratio of the compound of formula 2 to the lower aliphatic diol is 1:(1.1-1.5), the selectivity of the condensation reaction of the carbonyl group at the C3 position of the compound of formula 2 can be higher, and the condensation reaction of the carbonyl group at the C17 position can be reduced.
[0023] Furthermore, in step (a), the condensing agent is selected from one or a combination of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate or triethyl orthoacetate.
[0024] Furthermore, in the step (a), the condensation agent is selected from triethyl orthoformate.
[0025] Furthermore, in the step (a), the molar ratio of the compound of formula 2 to the condensing agent is 1:(1.6-2.5).
[0026] Wherein, in step (a), a typical but non-limiting molar ratio of the compound of formula 2 to the condensing agent can be, for example, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4 or 1:2.5.
[0027] Furthermore, in step (a), the catalyst is selected from p-toluenesulfonic acid and / or pyridine hydrobromide.
[0028] Furthermore, in the step (a), the temperature of the condensation reaction is 0-60°C.
[0029] Wherein, in step (a), the typical but non-limiting temperature of the condensation reaction can be, for example, 0°C, 2°C, 4°C, 6°C, 8°C, 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, 22°C, 24°C, 26°C, 28°C, 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, 42°C, 44°C, 46°C, 48°C, 50°C, 52°C, 54°C, 56°C, 58°C or 60°C.
[0030] Furthermore, in the step (a), the temperature of the condensation reaction is 15-25°C.
[0031] The present invention optimizes the temperature of the condensation reaction in step (a). When the temperature of the condensation reaction is 0-60° C., and further, when the temperature of the condensation reaction is 15-25° C., the selectivity of the condensation reaction of the carbonyl group at the C3 position of the compound of formula 2 can be higher, and the condensation reaction of the carbonyl group at the C17 position can be reduced.
[0032] Furthermore, in step (a), the solvent used in the condensation reaction is selected from one or a combination of benzene, toluene, dichloromethane or chloroform.
[0033] Furthermore, in the step (b), the compound of formula 3 undergoes epoxidation reaction under the action of sulfonium salt and alkaline reagent to obtain a compound of formula 4.
[0034] In step (b) of the present invention, the sulfonium salt reacts with the alkaline reagent to generate a ylide, which then reacts with the carbonyl group at position C17 of the compound of formula 3 to obtain an epoxide.
[0035] Furthermore, in the step (b), the alkaline reagent is selected from an organic base or an inorganic base.
[0036] Furthermore, in step (b), the alkaline agent is selected from an inorganic base, and the inorganic base is selected from one or a combination of sodium hydroxide, potassium hydroxide or lithium hydroxide.
[0037] Furthermore, in step (b), the sulfonium salt is selected from trimethylsulfonium bromide and / or trimethylsulfonium iodide.
[0038] Furthermore, in the step (b), the solvent used in the epoxidation reaction is selected from a mixture of an organic solvent and water, and the organic solvent is selected from dichloromethane and / or chloroform.
[0039] Furthermore, in the step (b), the solvent used in the epoxidation reaction is selected from a mixture of dichloromethane and water.
[0040] Furthermore, in the step (b), the temperature of the epoxidation reaction is 40-80°C.
[0041] Wherein, in step (b), typical but non-limiting temperatures for the epoxidation reaction may be, for example, 40°C, 42°C, 44°C, 46°C, 48°C, 50°C, 52°C, 54°C, 56°C, 58°C, 60°C, 62°C, 64°C, 66°C, 68°C, 70°C, 72°C, 74°C, 76°C, 78°C or 80°C.
[0042] Furthermore, in the step (c), the compound of formula 4 and methanol undergo carbonylation reaction under the action of boron trifluoride and an alkali reagent, and then undergo hydrolysis reaction with an acid reagent to obtain the compound of formula 1.
[0043] Furthermore, in the step (c), the alkaline reagent is selected from an organic base or an inorganic base.
[0044] Furthermore, in the step (c), the alkaline reagent is selected from an organic base, and the organic base is selected from one or a combination of DBU (diazabicyclopentyl), tert-butylamine, diisopropylethylamine or triethylamine.
[0045] Furthermore, in step (c), the acid reagent is selected from one or a combination of hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
[0046] Furthermore, in the step (c), the temperature of the carbonylation reaction is -10-30°C.
[0047] Wherein, in step (c), typical but non-limiting temperatures for the carbonylation reaction may be, for example, -10°C, -8°C, -6°C, -4°C, -2°C, 0°C, 2°C, 4°C, 6°C, 8°C, 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, 22°C, 24°C, 26°C, 28°C or 30°C.
[0048] Furthermore, in the step (c), the temperature of the hydrolysis reaction is 40-45°C.
[0049] In step (c), a typical but non-limiting temperature for the hydrolysis reaction may be, for example, 40°C, 41°C, 42°C, 43°C, 44°C or 45°C.
[0050] Furthermore, in the step (c), the solvent used in the carbonylation reaction is selected from an ether solvent, and the ether solvent is selected from one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether or methyl tert-butyl ether.
[0051] Compared with the prior art, the present invention has the following beneficial effects:
[0052] The method for preparing progesterone provided by the present invention uses 4-AD (compound of formula 2) as a starting material, and obtains progesterone (compound of formula 1) through condensation, epoxidation, carbonylation and hydrolysis reactions. The starting material is easy to obtain, no highly toxic chemicals are required, the method is environmentally friendly and has a high safety factor; the obtained progesterone has a high yield and high purity, and provides a process route that can be industrialized for production. DETAILED DESCRIPTION
[0053] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, conventional conditions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.
[0054] In order to help to more clearly understand the present invention, the technical scheme of the present invention will be further described below in conjunction with embodiments and comparative examples.
[0055] Example 1 Preparation of the compound of formula 3
[0056]
[0057] Example 1-1
[0058] Under nitrogen protection, 50 mL of dichloromethane, 10 g of 4-AD (compound 2), 2.6 mL of ethylene glycol, 11.7 mL of triethyl orthoformate and 0.01 g of p-toluenesulfonic acid were added to the reaction bottle, and the reaction was carried out at 20°C. TLC monitoring was performed until no compound of formula 2 was obtained. After the reaction was completed, triethylamine was added to quench the reaction, and the reaction was concentrated to 2-3 times the volume under reduced pressure. After cooling to room temperature, the concentrate was diluted into ice water, filtered and dried to obtain 11.3 g of off-white solid compound of formula 3, with a yield of 97.9% and an HPLC content of 97.0%.
[0059] Example 1-2
[0060] Under nitrogen protection, 55 mL of chloroform, 10 g of 4-AD (compound 2), 2.3 mL of ethylene glycol, 6.5 mL of trimethyl orthoformate and 0.01 g of p-toluenesulfonic acid were added to the reaction bottle, and the reaction was carried out at 25°C. TLC monitoring was performed until no compound of formula 2 was obtained. After the reaction was completed, pyridine was added to quench the reaction, and the mixture was concentrated to 2-3 times the volume under reduced pressure. After cooling to room temperature, the concentrate was diluted into ice water, filtered and dried to obtain 11.2 g of off-white solid compound of formula 3, with a yield of 97.1% and an HPLC content of 96.8%.
[0061] Examples 1-3
[0062] Under nitrogen protection, 45 mL of benzene, 10 g of 4-AD (compound 2), 2.7 mL of ethylene glycol, 9.8 mL of ethyl methyl orthoacetate and 0.01 g of p-toluenesulfonic acid were added to the reaction bottle, and the reaction was carried out at 15°C. TLC monitoring showed that no compound of formula 2 was obtained. After the reaction was completed, 10% sodium bicarbonate solution was added to quench the reaction, and the reaction was concentrated to 2-3 times the volume under reduced pressure. After cooling to room temperature, the concentrate was diluted into ice water, filtered and dried to obtain 11.1 g of off-white solid compound of formula 3, with a yield of 96.2% and an HPLC content of 96.6%.
[0063] Examples 1-4
[0064] Under nitrogen protection, 60 mL of toluene, 10 g of 4-AD (compound 2), 2.2 mL of ethylene glycol, 10.7 mL of triethyl orthoacetate and 0.01 g of p-toluenesulfonic acid were added to the reaction bottle, and the reaction was carried out at 0°C. TLC monitoring was performed until no compound of formula 2 was obtained. After the reaction was completed, 10% potassium bicarbonate solution was added to quench the reaction, and the reaction was concentrated to 2-3 times the volume under reduced pressure. After cooling to room temperature, the concentrate was diluted into ice water, filtered and dried to obtain 11 g of off-white solid compound of formula 3, with a yield of 95.3% and an HPLC content of 96.4%.
[0065] Examples 1-5
[0066] Under nitrogen protection, 40 mL of dichloromethane, 10 g of 4-AD (compound 2), 3 mL of ethylene glycol, 14.6 mL of triethyl orthoformate and 0.01 g of p-toluenesulfonic acid were added to the reaction bottle, and the reaction was carried out at 60°C. TLC monitoring was performed until no compound of formula 2 was obtained. After the reaction was completed, 10% sodium carbonate solution was added to quench the reaction, and the reaction was concentrated to 2-3 times the volume under reduced pressure. After cooling to room temperature, the concentrate was diluted into ice water, filtered and dried to obtain 10.9 g of off-white solid compound of formula 3, with a yield of 94.5% and an HPLC content of 96.2%.
[0067] Examples 1-6
[0068] The difference between this example and example 1-1 is that the reaction is carried out at 25° C., and the other conditions are the same, to obtain 11.2 g of an off-white solid compound of formula 3, with a yield of 97.1% and an HPLC content of 97.1%.
[0069] Examples 1-7
[0070] The difference between this example and example 1-1 is that the reaction is carried out at 15° C., and the other conditions are the same, to obtain 11.2 g of an off-white solid compound of formula 3, with a yield of 97.1% and an HPLC content of 97.3%.
[0071] Examples 1-8
[0072] The difference between this example and example 1-1 is that the reaction is carried out at 0°C, and the other conditions are the same, to obtain 10.9 g of an off-white solid compound of formula 3, with a yield of 94.5% and an HPLC content of 96.8%.
[0073] Examples 1-9
[0074] The difference between this example and example 1-1 is that the reaction temperature is 60° C., and the other conditions are the same, to obtain 10.8 g of off-white solid compound of formula 3, with a yield of 93.6% and an HPLC content of 96.5%.
[0075] Examples 1-10
[0076] The difference between this example and example 1-1 is that the reaction is carried out at -5°C, and the other conditions are the same, to obtain 9.2 g of an off-white solid compound of formula 3, with a yield of 79.2% and an HPLC content of 94.6%.
[0077] Examples 1-11
[0078] The difference between this example and example 1-1 is that the reaction temperature is 70° C., and the other conditions are the same, to obtain 9.5 g of off-white solid compound of formula 3, with a yield of 82.3% and an HPLC content of 94.3%.
[0079] Examples 1-12
[0080] The difference between this embodiment and embodiment 1-1 is that 2.3 mL of ethylene glycol is added, and the other conditions are the same, to obtain 11.2 g of off-white solid compound of formula 3, with a yield of 97.1% and an HPLC content of 97.2%.
[0081] Examples 1-13
[0082] The difference between this embodiment and embodiment 1-1 is that 2.7 mL of ethylene glycol is added, and the other conditions are the same, to obtain 11.2 g of off-white solid compound of formula 3, with a yield of 96.2% and an HPLC content of 97.1%.
[0083] Examples 1-14
[0084] The difference between this embodiment and embodiment 1-1 is that 2.2 mL of ethylene glycol is added, and the other conditions are the same, to obtain 11 g of off-white solid compound of formula 3, with a yield of 95.3% and an HPLC content of 96.8%.
[0085] Examples 1-15
[0086] The difference between this embodiment and embodiment 1-1 is that 3 mL of ethylene glycol is added, and the other conditions are the same, to obtain 10.9 g of off-white solid compound of formula 3, with a yield of 94.5% and an HPLC content of 96.5%.
[0087] Examples 1-16
[0088] The difference between this embodiment and embodiment 1-1 is that 1 mL of ethylene glycol is added, and the other conditions are the same, to obtain 9.5 g of off-white solid compound of formula 3, with a yield of 82.3% and an HPLC content of 95.4%.
[0089] Examples 1-17
[0090] The difference between this embodiment and embodiment 1-1 is that 4 mL of ethylene glycol is added, and the other conditions are the same, to obtain 9.8 g of off-white solid compound of formula 3, with a yield of 84.9% and an HPLC content of 89.6%.
[0091] Example 2 Preparation of the compound of formula 4
[0092]
[0093] Example 2-1
[0094] Under nitrogen protection, 50 mL of dichloromethane, 5 mL of drinking water, 6 g of sodium hydroxide and 6.6 g of trimethylsulfonium bromide were added to the reaction bottle, and after the temperature was raised to 60°C, 10 g of the compound of formula 3 was added in batches, and the reaction was carried out at 60°C, and TLC was monitored until there was no compound of formula 3. After the reaction was completed, the pH was adjusted to neutral with 5% acetic acid solution, and the volume was concentrated under reduced pressure to 1.5-2 times, and after cooling to room temperature, it was filtered and dried to obtain 10.2 g of off-white solid compound of formula 4, with a yield of 97.9% and an HPLC content of 98.8%.
[0095] Example 2-2
[0096] Under nitrogen protection, 45 mL of dichloromethane, 5 mL of drinking water, 7.6 g of potassium hydroxide and 6.1 g of trimethylsulfonium bromide were added to the reaction bottle, and after the temperature was raised to 50°C, 10 g of the compound of formula 3 was added in batches, and the reaction was carried out at 50°C, and TLC was monitored until there was no compound of formula 3. After the reaction was completed, the pH was adjusted to neutral with 5% sulfuric acid solution, and the volume was concentrated under reduced pressure to 1.5-2 times, and the temperature was lowered to room temperature, filtered, and dried to obtain 10.1 g of off-white solid compound of formula 4, with a yield of 96.9% and an HPLC content of 98.6%.
[0097] Example 2-3
[0098] Under nitrogen protection, 55 mL of dichloromethane, 5 mL of drinking water, 4 g of lithium hydroxide and 5.7 g of trimethylsulfonium bromide were added to the reaction bottle, and after the temperature was raised to 70°C, 10 g of the compound of formula 3 was added in batches, and the reaction was carried out at 70°C, and TLC was monitored until there was no compound of formula 3. After the reaction was completed, the pH was adjusted to neutral with 5% hydrochloric acid solution, and the volume was concentrated under reduced pressure to 1.5-2 times, and the temperature was lowered to room temperature, filtered, and dried to obtain 10 g of off-white solid compound of formula 4, with a yield of 96.0% and an HPLC content of 98.7%.
[0099] Embodiment 2-4
[0100] Under nitrogen protection, 60 mL of chloroform, 5 mL of drinking water, 8.2 g of sodium ethoxide and 6.7 g of trimethylsulfonium iodide were added to the reaction bottle, and after the temperature was raised to 40°C, 10 g of the compound of formula 3 was added in batches, and the reaction was carried out at 40°C, and TLC was monitored until there was no compound of formula 3. After the reaction was completed, the pH was adjusted to neutral with 5% phosphoric acid solution, and the volume was concentrated under reduced pressure to 1.5-2 times, and the temperature was lowered to room temperature, filtered, and dried to obtain 9.8 g of off-white solid compound of formula 4, with a yield of 94.0% and an HPLC content of 95.6%.
[0101] Embodiment 2-5
[0102] Under nitrogen protection, 40 mL of chloroform, 5 mL of drinking water, 20.2 g of potassium tert-butoxide and 9.2 g of trimethylsulfonium iodide were added to the reaction bottle, and after heating to 80°C, 10 g of compound 3 was added in batches, and reacted at 80°C, and TLC was monitored until there was no compound 3. After the reaction was completed, the pH was adjusted to neutral with 5% nitric acid solution, and the volume was concentrated under reduced pressure to 1.5-2 times, and after cooling to room temperature, filtered and dried to obtain 9.7 g of off-white solid compound 4, with a yield of 93.1% and an HPLC content of 95.4%.
[0103] Embodiment 2-6
[0104] The difference between this example and example 2-1 is that the reaction temperature is 50° C., and the other conditions are the same, to obtain 10.2 g of off-white solid compound of formula 4, with a yield of 97.9% and an HPLC content of 98.7%.
[0105] Embodiment 2-7
[0106] The difference between this example and example 2-1 is that the reaction temperature is 70° C., and the other conditions are the same, to obtain 10.1 g of off-white solid compound of formula 4, with a yield of 96.9% and an HPLC content of 98.6%.
[0107] Embodiment 2-8
[0108] The difference between this example and example 2-1 is that the reaction is carried out at 40° C., and the other conditions are the same, to obtain 9.9 g of off-white solid compound of formula 4, with a yield of 95.0% and an HPLC content of 96.1%.
[0109] Embodiment 2-9
[0110] The difference between this example and example 2-1 is that the reaction temperature is 80° C., and the other conditions are the same, to obtain 9.8 g of off-white solid compound of formula 4, with a yield of 94.0% and an HPLC content of 96.2%.
[0111] Embodiment 2-10
[0112] The difference between this example and example 2-1 is that the reaction is carried out at 20° C., and the other conditions are the same, to obtain 8.3 g of off-white solid compound of formula 4, with a yield of 79.7% and an HPLC content of 92.3%.
[0113] Example 2-11
[0114] The difference between this example and example 2-1 is that the reaction temperature is 90° C., and the other conditions are the same, to obtain 8.5 g of off-white solid compound of formula 4, with a yield of 81.6% and an HPLC content of 93.1%.
[0115] Example 2-12
[0116] The difference between this example and example 2-1 is that drinking water is not added to the reaction medium, and the other conditions are the same, and 7.8 g of off-white solid compound of formula 4 is obtained with a yield of 74.9% and an HPLC content of 91.0%.
[0117] Example 2-13
[0118] The difference between this embodiment and embodiment 2-1 is that the reaction solvent is 50 mL of acetonitrile and 5 mL of drinking water, and the other conditions are the same, and 8.6 g of off-white solid compound of formula 4 is obtained with a yield of 82.5% and an HPLC content of 93.4%.
[0119] Example 3
[0120]
[0121] Example 3-1
[0122] Under nitrogen protection, 40mL tetrahydrofuran and 10g of formula 4 compound were added to the reaction bottle. After cooling to 0°C, 7.5mL of boron trifluoride ether solution was added dropwise to the system, and the reaction was carried out at 0°C. TLC was monitored until there was no formula 4 compound. 2mL of methanol and 2mL of DBU were added dropwise to the system. After the addition was complete, the temperature was raised to 10°C for reaction, and the reaction was monitored by TLC. After the reaction was completed, 40mL of purified water and 10mL of concentrated hydrochloric acid were added dropwise to the system, and the temperature was raised to 42°C for reaction. TLC was monitored until the reaction was completed. After the reaction was completed, the temperature was lowered to room temperature, diluted into ice water, filtered, washed with water, and dried to obtain 8.5g of off-white solid formula 1 compound (progesterone), with a yield of 93.1% and an HPLC content of 93.6%. The obtained formula 1 compound (progesterone) was refined with ethanol to obtain pure progesterone, with an HPLC content of 99.6%.
[0123] Example 3-2
[0124] Under nitrogen protection, 45mL 2-methyltetrahydrofuran and 10g of formula 4 compound were added to the reaction bottle, cooled to 5°C, 7mL boron trifluoride ether solution was added dropwise to the system, reacted at 5°C, TLC monitored until no formula 4 compound was found, 1.8mL methanol and 1.5mL tert-butylamine were added dropwise to the system, and after the addition was complete, the temperature was raised to 20°C for reaction, and the reaction was monitored by TLC. After the reaction was completed, 40mL purified water and 6.5mL concentrated sulfuric acid were added dropwise to the system, the temperature was raised to 43°C for reaction, and TLC monitored until the reaction was completed. After the reaction was completed, the temperature was lowered to room temperature, diluted into ice water, filtered, washed with water, and dried to obtain 8.3g off-white solid formula 1 compound (progesterone), with a yield of 90.9% and an HPLC content of 93.3%. The obtained formula 1 compound (progesterone) was refined with ethanol to obtain pure progesterone, with an HPLC content of 99.5%.
[0125] Example 3-3
[0126] Under nitrogen protection, 35mL of ethylene glycol dimethyl ether and 10g of compound 4 were added to the reaction bottle. After cooling to -10°C, 8mL of boron trifluoride ether solution was added dropwise to the system, and the reaction was carried out at -10°C. TLC was monitored until there was no compound 4. 2.1mL of methanol and 2.2mL of diisopropylethylamine were added dropwise to the system. After the addition was complete, TLC was used to monitor the reaction. After the reaction was completed, 40mL of purified water and 7.3mL of concentrated phosphoric acid were added dropwise to the system, and the temperature was raised to 40°C for reaction. TLC was used to monitor the reaction. After the reaction was completed, the temperature was lowered to room temperature, diluted into ice water, filtered, washed with water, and dried to obtain 8.2g of off-white solid compound 1 (progesterone), with a yield of 89.8% and an HPLC content of 92.3%. The obtained compound 1 (progesterone) was refined with ethanol to obtain pure progesterone, with an HPLC content of 99.3%.
[0127] Embodiment 3-4
[0128] Under nitrogen protection, 50mL of methyl tert-butyl ether and 10g of compound 4 were added to the reaction bottle. After cooling to 10°C, 9mL of boron trifluoride ether solution was added dropwise to the system, and the reaction was carried out at 10°C. TLC was monitored until there was no compound 4. 2.4mL of methanol and 1.8mL of triethylamine were added dropwise to the system. After the addition was complete, TLC was used to monitor the reaction. After the reaction was completed, 40mL of purified water and 10mL of concentrated hydrochloric acid were added dropwise to the system, and the temperature was raised to 45°C for reaction. TLC was used to monitor the reaction. After the reaction was completed, the temperature was lowered to room temperature, diluted into ice water, filtered, washed with water, and dried to obtain 8g of off-white solid compound 1 (progesterone), with a yield of 87.6% and an HPLC content of 93.0%. The obtained compound 1 (progesterone) was refined with ethanol to obtain pure progesterone, with an HPLC content of 99.0%.
[0129] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing progesterone, characterized in that: The steps include: (a) the carbonyl group at the C3 position of the compound of formula 2 is subjected to a condensation reaction to obtain a compound of formula 3 having a ketal at the C3 position; (b) subjecting the carbonyl group at position C17 of the compound of formula 3 to epoxidation to obtain a compound of formula 4 having an epoxy group at position C17; (c) The epoxy group at position C17 of the compound of formula 4 and methanol undergo carbonylation reaction under the action of boron trifluoride ether solution and an alkali reagent, and the ketal at position C3 undergoes hydrolysis reaction with an acid reagent to obtain a compound of formula 1; the reaction formula is as follows: In the step (c), the alkaline reagent is selected from one or a combination of DBU, tert-butylamine, diisopropylethylamine or triethylamine; the acid reagent is selected from one or a combination of hydrochloric acid, sulfuric acid or phosphoric acid.
2. The method for preparing progesterone according to claim 1, characterized in that: In the step (a), the compound of formula 2 and the lower aliphatic diol undergo condensation reaction under the action of a condensing agent and a catalyst to obtain a compound of formula 3.
3. The method for preparing progesterone according to claim 2, characterized in that: In the step (a), the lower aliphatic diol is selected from ethylene glycol; The condensing agent is selected from one or a combination of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate or triethyl orthoacetate; The catalyst is selected from p-toluenesulfonic acid and / or pyridine hydrobromide.
4. The method for preparing progesterone according to claim 1 or 2, characterized in that: In the step (a), the temperature of the condensation reaction is 0-60°C.
5. The method for preparing progesterone according to claim 2, characterized in that: In the step (a), the molar ratio of the compound of formula 2 to the lower aliphatic diol is 1:(1.1-1.5).
6. The method for preparing progesterone according to claim 1, characterized in that: In the step (b), the compound of formula 3 undergoes epoxidation reaction under the action of sulfonium salt and alkaline reagent to obtain a compound of formula 4.
7. The method for preparing progesterone according to claim 6, characterized in that: In the step (b), the alkaline agent is selected from an inorganic base, and the inorganic base is selected from one or a combination of sodium hydroxide, potassium hydroxide or lithium hydroxide; The sulfonium salt is selected from trimethylsulfonium bromide and / or trimethylsulfonium iodide.
8. The method for preparing progesterone according to claim 1, characterized in that: In the step (b), the temperature of the epoxidation reaction is 40-80°C.
Citation Information
Patent Citations
Preparation method of 17 beta-androst-4-ene-3-one-17-carboxylic acid
CN107629101A