Preparation method of 2-hydroxymethylene ethyl sterone

Abstract

The invention discloses a preparation method of 2-hydroxymethylene ethyl sterone, and belongs to the technical field of medicine synthesis, and the compound is also one of intermediates for producing danazol. According to the invention, ethisterone is used as a starting raw material, and N, N-dimethylformamide is used as a solvent to react under an alkaline condition to obtain the 2-hydroxymethylethylsterone. The method is simple and convenient to operate, mild in reaction condition, low in cost, high in yield and suitable for large-scale industrial production, and has great significance in production of danazol raw material medicine.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and more specifically relates to a method for preparing 2-hydroxymethylene acetosterone, which is one of the important intermediates in the production of danazol. Background Technology

[0002] Danazol is a synthetic steroidal heterocyclic compound, a derivative of the androgen 17α-ethynyltestosterone. It is a weak androgen with anti-gonadotropic and mild androgenic effects. It can promote the regression of ectopic endometrium and improve symptoms, and may also enable some infertile patients to conceive. It is used to treat endometriosis, and can also be used to treat fibrocystic breast disease, spontaneous thrombocytopenic purpura, hereditary angioedema, systemic lupus erythematosus, male gynecomastia, and precocious puberty.

[0003] CN109517027A discloses a method for preparing danazol, which includes a method for preparing 2-hydroxymethylene acetosterone. The methoxylation reagents used in this method are ethyl formate or methyl formate, and methanol and tetrahydrofuran are also used. The above method has the following drawbacks: 1. The methoxylation requires ethyl formate and methyl formate, increasing production costs; 2. The use of two solvents increases the difficulty of waste solvent disposal.

[0004] In view of this, there is an urgent need to develop a new method for preparing 2-hydroxymethylene acetosterone in order to reduce the treatment of waste solvents and lower production costs. Summary of the Invention

[0005] To address the aforementioned problems in existing technologies, this invention provides a method for preparing 2-hydroxymethyleneacetate. This method uses only N,N-dimethylformamide as a solvent and also as a methylhydroxylating agent, and 2-hydroxymethyleneacetate can be prepared under alkaline conditions. After the reaction, most of the N,N-dimethylformamide is distilled off for reuse, reducing waste solvent disposal and lowering costs. This method is simple to operate, has mild reaction conditions, low cost, and high yield, making it suitable for large-scale industrial production.

[0006] The technical solution adopted in this invention is as follows:

[0007] A method for preparing 2-hydroxymethyleneacetosterone, using ethinylprogesterone as a starting material, reacts under alkaline conditions with N,N-dimethylformamide as a solvent to obtain 2-hydroxymethyleneacetosterone, the structural formula of which is shown below. Figure 1 As shown.

[0008] In a preferred embodiment, the alkali is selected from any one of potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, cesium carbonate, and cesium hydroxide, and more preferably sodium methoxide, sodium ethoxide, or potassium tert-butoxide.

[0009] In a preferred embodiment, the solvent is N,N-dimethylformamide.

[0010] In a preferred embodiment, the reaction temperature is 5–15°C and the reaction time is 5–8 h.

[0011] In a preferred embodiment, the weight ratio of ethinylprogesterone and N,N-dimethylformamide is 1:10-15.

[0012] In a preferred embodiment, the molar ratio of the ethinylprogesterone and the base is 1:6 to 10.

[0013] As a preferred embodiment, the method further includes the following steps: after the reaction is completed, 80% of the volume of N,N-dimethylformamide is removed by vacuum distillation, the remaining volume of reaction solution is added to water, acidified with hydrochloric acid to pH=3-4, stirred, filtered, the filter cake is rinsed with water until neutral, and then dried under vacuum to obtain 2-hydroxymethylene acetosterone.

[0014] As a preferred embodiment, the specific steps are as follows: add ethinylprogesterone to N,N-dimethylformamide, stir until dissolved, control the temperature at 5-15°C, add alkali, and keep the reaction at this temperature for 5-8 hours; after the reaction is completed, remove 80% of the volume of N,N-dimethylformamide by vacuum distillation, add the remaining volume of reaction solution to water, acidify with hydrochloric acid to pH=3-4, stir for 30 minutes, filter, rinse the filter cake with water until neutral, and vacuum dry to obtain 2-hydroxymethylene acetosterone.

[0015] Compared with the prior art, the present invention has the following beneficial effects:

[0016] 1) The preparation method of the present invention is simple to operate, safe, mild in reaction conditions, high in yield, and low in pollution, making it suitable for large-scale industrial production and of great significance to the production of danazol raw materials.

[0017] 2) This invention overcomes the problems of high cost and large amount of waste solvent in the prior art, and provides a new technical solution that is more suitable for industrial production. Attached Figure Description

[0018] Figure 1 The structural diagram of 2-hydroxymethylene acetosterone of the present invention is shown below;

[0019] Figure 2 This is the reaction formula for the preparation method of the present invention. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described below with reference to specific embodiments. Unless otherwise specified, the technical means used in the following embodiments are all conventional means well known to those skilled in the art.

[0021] Example 1

[0022] This embodiment provides a method for preparing 2-hydroxymethylene acetosterone, the reaction process is as follows: Figure 2 As shown, it includes the following steps:

[0023] 0.1 mol of solid ethinylprogesterone was added to 330 mL of N,N-dimethylformamide and stirred at room temperature until dissolved. The solution was then cooled to 10 °C, and 56 g of solid potassium hydroxide was added. The temperature was maintained at 5–15 °C for 5 h. After the reaction was complete, 260 mL of N,N-dimethylformamide was removed by vacuum distillation. The remaining reaction solution was added to 800 mL of water, and the pH was adjusted to 3–4 with 3N hydrochloric acid. The mixture was stirred for 30 min, filtered, and the filter cake was washed with water until neutral. The solution was then dried under vacuum to obtain 30.6 g of 2-hydroxymethylene acetosterone, with a yield of 90% and a purity of 95.2%.

[0024] Example 2

[0025] This embodiment provides a method for preparing 2-hydroxymethylene acetosterone, comprising the following steps:

[0026] 0.2 mol of solid ethinylprogesterone was added to 800 mL of N,N-dimethylformamide and stirred at room temperature until dissolved. The solution was then cooled to 5 °C, and 65 g of solid sodium methoxide was added. The temperature was maintained at 5–15 °C for 7 h. After the reaction was complete, 640 mL of N,N-dimethylformamide was removed by vacuum distillation. The remaining reaction solution was added to 1500 mL of water, and the pH was adjusted to 3–4 with 3N hydrochloric acid. The mixture was stirred for 30 min, filtered, and the filter cake was washed with water until neutral. The solution was then dried under vacuum to obtain 62.5 g of 2-hydroxymethyleneacetate, with a yield of 92% and a purity of 95.6%.

[0027] Example 3

[0028] This embodiment provides a method for preparing 2-hydroxymethylene acetosterone, comprising the following steps:

[0029] 0.1 mol of solid ethinylprogesterone was added to 500 mL of N,N-dimethylformamide and stirred at room temperature until dissolved. The solution was then cooled to 15 °C, and 89 g of solid potassium tert-butoxide was added. The temperature was maintained at 10–15 °C for 8 h. After the reaction was complete, 400 mL of N,N-dimethylformamide was removed by vacuum distillation. The remaining reaction solution was added to 600 mL of water, and the pH was adjusted to 3–4 with 3N hydrochloric acid. The mixture was stirred for 30 min, filtered, and the filter cake was washed with water until neutral. The solution was then dried under vacuum to obtain 32 g of 2-hydroxymethylene acetosterone, with a yield of 93% and a purity of 95.1%.

[0030] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the described embodiments. The embodiments and features in the embodiments of this application can be arbitrarily combined with each other without conflict. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention should be considered equivalent substitutions and are included within the protection scope of the present invention. Furthermore, technical details not described in detail in this specification are well-known to those skilled in the art, and therefore will not be repeated here.

Claims

1. A method for preparing 2-hydroxymethylene acetosterone, characterized in that, 2-Hydroxymethylene ethinylestradiol was obtained by reacting ethinylestradiol as a starting material under alkaline conditions with N,N-dimethylformamide as a solvent.

2. The method according to claim 1, characterized in that, The alkali is selected from any one of potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, cesium carbonate, and cesium hydroxide.

3. The method according to claim 2, characterized in that, The alkali is selected from any one of sodium methoxide, sodium ethoxide, and potassium tert-butoxide.

4. The method according to claim 1, characterized in that, The solvent is N,N-dimethylformamide.

5. The method according to claim 1, characterized in that, The reaction temperature is 5–15°C, and the reaction time is 5–8 hours.

6. The method according to claim 1, characterized in that... The weight ratio of ethinylprogesterone and N,N-dimethylformamide is 1:10-15.

7. The method according to claim 1, characterized in that, The molar ratio of the ethinylprogesterone and the base is 1:6 to 10.

8. The method according to claim 1, characterized in that, The process also includes the following steps: After the reaction is complete, 80% of the volume of N,N-dimethylformamide is removed by vacuum distillation. The remaining volume of the reaction solution is added to water, acidified with hydrochloric acid to pH 3-4, stirred, filtered, and the filter cake is washed with water until neutral. After vacuum drying, 2-hydroxymethylene acetosterone is obtained.

9. The method according to any one of claims 1-8, characterized in that, The specific steps are as follows: Add ethinylprogesterone to N,N-dimethylformamide, stir until dissolved, control the temperature at 5-15℃, add alkali, and keep the reaction at this temperature for 5-8 hours; after the reaction is completed, remove 80% of the volume of N,N-dimethylformamide by vacuum distillation, add the remaining volume of reaction solution to water, acidify with hydrochloric acid to pH=3-4, stir for 30 minutes, filter, rinse the filter cake with water until neutral, and vacuum dry to obtain 2-hydroxymethylene acetosterone.

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