A preparation method of estradiol-17β-alkyl ester

Abstract

The application discloses a preparation method of estradiol-17beta-alkyl acid ester and belongs to the technical field of preparation and processing of steroid hormone drugs. The method uses estradiol as raw material, dissolves the raw material in an organic solvent, adds alkyl acid, and then adds a catalyst and a dehydrating agent to generate a mixture of 3, 17beta-dialkyl acid ester and 17beta-alkyl acid ester, and then adds a hydrolysis reagent to generate 17beta-alkyl acid ester. The method uses a new dehydrating agent and a specific catalyst to solve the problems of high temperature, low yield, expensive and toxic reagents in the estradiol 17beta-hydroxyl esterification process of the traditional process, and the process conditions are more moderate, the purity and yield of the prepared product are higher, the reagents are more green and environmentally friendly, and the method is more in line with the industrial development trend of green chemistry.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation and processing of steroid hormone drugs, and in particular to a method for preparing estradiol-17β-alkyl ester. Background Art

[0002] Estradiol-17β-alkyl esters are estrogenic drugs with estrogen-like pharmacological effects. They promote and regulate the normal development of female reproductive organs and secondary sexual characteristics, and participate in the regulation of ovarian axis function. They are clinically used to treat various symptoms caused by ovarian insufficiency or ovarian hormone deficiency, primarily functional uterine bleeding, primary amenorrhea, menopausal syndrome, and prostate cancer. Estradiol valerate and estradiol enanthate are the most representative estradiol-17β-alkyl esters.

[0003] The traditional preparation process of estradiol valerate mainly uses estradiol as the raw material, azeotropically dehydrates it with n-valeric acid to produce 3,17β-divalerate, and then alkaline hydrolyzes it to obtain estradiol valerate. The synthesis route is as follows:

[0004]

[0005] The disadvantage of this method is that the azeotropic dehydration reaction temperature is as high as 170-200°C, resulting in more impurities and lower yield.

[0006] Chinese patent CN 109503690A reports a method for preparing estradiol enanthate. Estradiol is used as a raw material, and an esterification reaction with heptanoyl chloride occurs under the action of pyridine to produce a mixture of 3,17β-diheptanoate and 17β-heptanoate, which is then subjected to alkaline hydrolysis to obtain estradiol enanthate. The synthetic route is as follows:

[0007]

[0008] Pyridine and heptanoyl chloride used in this method are both highly toxic chemical reagents, and heptanoyl chloride is expensive, resulting in high costs and a low yield for the entire route. Summary of the Invention

[0009] In order to solve the problems existing in the prior art, the present invention provides a method for preparing estradiol-17β-alkyl ester with mild reaction, environmental protection and high yield.

[0010] The object of the present invention is achieved in the following manner:

[0011] A method for preparing estradiol-17β-alkyl ester, the synthetic route of the method is as follows:

[0012]

[0013] Wherein, R is a C2-C18 alkyl group;

[0014] The specific steps include:

[0015] 1) Esterification reaction: Compound I, i.e., estradiol, is dissolved in an organic solvent A, and an alkyl acid, a catalyst, and a dehydrating agent are added. The reaction is stirred at 5-35° C. until complete, and then water is added to quench the reaction. A base is then added to adjust the pH to neutral. The layers are separated, and the organic layer is concentrated to dryness to obtain a mixture of Compounds II and III.

[0016] Furthermore, the organic solvent A is at least one of dichloromethane, chloroform or toluene, and its volume is 2 to 20 times the weight of the substrate compound I;

[0017] Furthermore, the alkyl acid is one of C2 to C18 alkyl acids, and its volume or weight amount is 0.2 to 2 times the weight of the substrate compound I;

[0018] Preferably, the alkyl acid is n-pentanoic acid or n-heptanoic acid;

[0019] Furthermore, the catalyst is 4-dimethylaminopyridine, and its weight amount is 0.02 to 0.5 times the weight of the substrate compound I;

[0020] Furthermore, the dehydrating agent is one or more of N,N-diisopropylcarbodiimide (DIC), 1,1'-carbonyldiimidazole (CDI) or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), and its weight amount is 0.4 to 2 times the weight of the substrate compound I;

[0021] Furthermore, the base is one or more of a hydroxide, carbonate or bicarbonate aqueous solution with a mass concentration of 2% to 20%;

[0022] 2) Hydrolysis reaction: The mixture of compounds II and III obtained in step 1 is dissolved in an organic solvent B, a hydrolysis reagent is added, and the reaction is completed under stirring at -10 to 20°C. Acid is added to adjust the pH to 6 to 7, and the mixture is concentrated, precipitated, filtered, dried, and purified to obtain compound III, i.e., estradiol-17β-alkyl ester.

[0023] Furthermore, the organic solvent B is one or more of methanol, ethanol, acetone or dichloromethane, and its volume is 2 to 20 times the weight of the substrate compound I;

[0024] Furthermore, the hydrolysis reagent is one or more of a sulfite, carbonate or bicarbonate aqueous solution with a mass concentration of 2% to 20%, and its volume usage is 1 to 10 times the weight of the substrate compound I;

[0025] Furthermore, the acid is one or more of acetic acid, formic acid, hydrochloric acid or sulfuric acid aqueous solution with a mass concentration of 5% to 100%;

[0026] Preferably, the alcohol is methanol or ethanol.

[0027] The technical features and beneficial effects of the present invention are:

[0028] 1) The present method utilizes a novel dehydrating agent in combination with a specific catalyst, utilizing the principle that the dehydrating agent first reacts with an acid reagent to form an active ester, which then reacts with a substrate to form an ester. This method avoids the use of azeotropic dehydration and reagents such as acyl chloride and pyridine, thereby addressing the problems of high temperature, low yield, expensive reagents, and high toxicity in the esterification process of estradiol 17β-hydroxy in traditional preparation processes.

[0029] 2) The synthesis process of estradiol-17β-alkyl esters described in the present invention can be carried out smoothly at 5-35°C, which is a milder condition. The process is simple and controllable, making it more suitable for industrial production.

[0030] 3) The product prepared by the preparation method of the present invention has a purity of greater than 99%, an estradiol valerate yield of greater than 110%, and an estradiol enanthate yield of greater than 115%, with stable quality;

[0031] 4) The reagents used in the preparation method of the present invention are low-cost, green and environmentally friendly, more in line with the industrial development trend of green chemistry, and have good economic and social benefits. DETAILED DESCRIPTION

[0032] The present invention will be further described below with reference to the examples, which are not intended to limit the present invention.

[0033] If no specific experimental steps or conditions are described in the examples, the experiments can be carried out according to conventional experimental methods described in the open texts in the art. If the manufacturer of the reagents or equipment is not indicated, they are all conventional products that can be purchased commercially.

[0034] Example 1 Preparation method of estradiol valerate

[0035] 1) Compound I, i.e., estradiol 20 g, dichloromethane 200 mL, n-valeric acid 12 mL, 4-dimethylaminopyridine 2 g, and N,N-diisopropylcarbodiimide 15 g were added to a reaction flask. The reaction was stirred at 25° C. until complete. 50 mL of water was added to quench the reaction, and the pH was adjusted to neutral with 10 wt % aqueous sodium carbonate solution. The layers were separated, and the organic layer was concentrated to remove the solvent to obtain a mixture of compounds II and III.

[0036] 2) A mixture of compounds II and III obtained in the previous step was added to a reaction flask, followed by 200 mL of methanol and 100 mL of a 10 wt% aqueous sodium carbonate solution. The reaction was completed with stirring at 20° C. Acetic acid was added to adjust the pH to 6-7, and the mixture was concentrated, precipitated, filtered, dried, and purified with ethanol to obtain 22 g of compound III, i.e., estradiol valerate. The total mass yield was 110%, and the HPLC purity was 99.3%.

[0037] Example 2 Preparation method of estradiol valerate

[0038] 1) Compound II, i.e., estradiol 20 g, toluene 200 mL, n-valeric acid 12 mL, 4-dimethylaminopyridine 2 g, and 1,1'-carbonyldiimidazole 15 g were added to a reaction flask. The reaction was stirred at 10°C until complete. 50 mL of water was added to quench the reaction, and the pH was adjusted to neutral with 10 wt% aqueous potassium bicarbonate solution. The layers were separated, and the organic layer was concentrated to remove the solvent to obtain a mixture of Compounds II and III.

[0039] 2) A mixture of compounds II and III obtained in the previous step was added to a reaction flask, 200 mL of ethanol was added, 100 mL of a 2 wt% aqueous sodium sulfite solution was added, and the reaction was completed under stirring at 0°C. A 10 wt% aqueous hydrochloric acid solution was added to adjust the pH to 6-7, and the mixture was concentrated, precipitated, filtered, dried, and purified with ethanol to obtain 22.2 g of compound III, i.e., estradiol valerate, with a total mass yield of 111% and an HPLC purity of 99.2%.

[0040] Example 3 Preparation method of estradiol enanthate

[0041] 1) Compound I, i.e., estradiol 20 g, chloroform 200 mL, n-heptanoic acid 13 mL, 4-dimethylaminopyridine 2 g, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride 20 g were added to a reaction flask. The reaction was stirred at 25° C. until complete. 50 mL of water was added to quench the reaction, and the pH was adjusted to neutral with 2 wt % aqueous sodium hydroxide solution. The layers were separated, and the organic layer was concentrated to remove the solvent to obtain a mixture of compounds II and III.

[0042] 2) A mixture of compounds II and III obtained in the previous step was added to a reaction flask, 200 mL of methanol was added, 100 mL of a 10 wt% aqueous solution of potassium carbonate was added, and the reaction was completed under stirring at 20°C. A 5 wt% aqueous solution of sulfuric acid was added to adjust the pH to 6-7, and the mixture was concentrated, precipitated, filtered, dried, and purified with methanol to obtain 23.1 g of compound III, i.e., estradiol heptanoate, with a total mass yield of 115.5% and an HPLC purity of 99.4%.

[0043] Example 4 Preparation method of estradiol enanthate

[0044] 1) Compound I, i.e., estradiol 20 g, dichloromethane 200 mL, n-heptanoic acid 13 mL, 4-dimethylaminopyridine 2 g, and N,N-diisopropylcarbodiimide 15 g were added to a reaction flask. The reaction was stirred at 10° C. until complete. 50 mL of water was added to quench the reaction, and the pH was adjusted to neutral with 10 wt % aqueous potassium carbonate solution. The layers were separated, and the organic layer was concentrated to remove the solvent to obtain a mixture of compounds II and III.

[0045] 2) A mixture of compounds II and III obtained in the previous step was added to a reaction flask, 200 mL of acetone was added, 100 mL of a 20 wt% aqueous solution of potassium bicarbonate was added, and the reaction was completed under stirring at 20°C. A 10 wt% aqueous solution of hydrochloric acid was added to adjust the pH to 6-7, and the mixture was concentrated, precipitated, filtered, dried, and purified with methanol to obtain 23.3 g of compound III, i.e., estradiol heptanoate, with a total mass yield of 116.5% and an HPLC purity of 99.2%.

[0046] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by any technician familiar with this technical field within the technical scope disclosed by the present invention should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing estradiol-17β-alkyl ester, characterized in that: The synthetic route of this method is as follows: Wherein, R is a C2-C18 alkyl group; The specific steps include: 1) Esterification reaction: Compound I, i.e., estradiol, is dissolved in an organic solvent A, and an alkyl acid, a catalyst, and a dehydrating agent are added. The reaction is allowed to complete at 5-35°C with stirring, and then water is added to quench the reaction. A base is then added to adjust the pH to neutral, and the layers are separated. The organic layer is concentrated to dryness to obtain a mixture of compounds II and III. 2) Hydrolysis reaction: The mixture of Compounds II and III obtained in step 1 is dissolved in an organic solvent B, a hydrolysis reagent is added, and the reaction is completed by stirring at -10 to 20°C. Acid is added to adjust the pH to 6 to 7, the mixture is concentrated, precipitated, filtered, dried, and purified with an alcohol to obtain Compound III, i.e., estradiol-17β-alkyl ester; In step 1), the catalyst is 4-dimethylaminopyridine, and the dehydrating agent is one or more of N,N-diisopropylcarbodiimide (DIC), 1,1'-carbonyldiimidazole (CDI) or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI).

2. The method for preparing estradiol-17β-alkyl ester according to claim 1, characterized in that: The weight amount of the catalyst is 0.02 to 0.5 times the weight of the substrate compound I; the weight amount of the dehydrating agent is 0.4 to 2 times the weight of the substrate compound I.

3. The method for preparing estradiol-17β-alkyl ester according to claim 1, characterized in that: In step 1), the organic solvent A is at least one of dichloromethane, chloroform or toluene, and its volume is 2 to 20 times the weight of the substrate compound I; the alkyl acid is one of C2 to C18 alkyl acids, and its volume or weight is 0.2 to 2 times the weight of the substrate compound I; the base is one or more of a hydroxide, carbonate or bicarbonate aqueous solution with a mass concentration of 2% to 20%.

4. The method for preparing estradiol-17β-alkyl ester according to claim 1, characterized in that: The alkyl acid in step 1) is n-pentanoic acid or n-heptanoic acid.

5. The method for preparing estradiol-17β-alkyl ester according to claim 1, characterized in that: In step 2), the organic solvent B is one or more of methanol, ethanol, acetone or dichloromethane, and its volume is 2 to 20 times the weight of the substrate compound I; the hydrolysis reagent is one or more of a sulfite, carbonate or bicarbonate aqueous solution with a mass concentration of 2% to 20%, and its volume is 1 to 10 times the weight of the substrate compound I; the acid is one or more of acetic acid, formic acid, hydrochloric acid or sulfuric acid aqueous solution with a mass concentration of 5% to 100%.

6. The method for preparing estradiol-17β-alkyl ester according to claim 1, characterized in that: The alcohol in step 2) is methanol or ethanol.

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