New preparation method for α epoxy steroid compounds

Abstract

The present invention belongs to the technical field of preparation of steroid hormone drugs, and specifically relates to a preparation method for α epoxy steroid compounds. The method comprises: using a steroid compound I containing a carbon-carbon double bond as a starting material, and adding a basic reagent, a catalyst and hydrogen peroxide into a solvent under the state of complete dissolution of the starting material in the solvent, and carrying out an epoxide synthesis reaction to obtain an α epoxy steroid compound II, wherein the catalyst refers to 3',5'-dichloro-2,2,2-trifluoroacetophenone. The present invention effectively solves the problems in the prior art such as excessive isomeric by-products, low yield, long production period and high overall production costs, and provides the preparation method for the α epoxy steroid compounds with high selectivity and significant economic benefits, so that the process is more suitable for the requirement of industrial mass production.

Description

New preparation method of alpha epoxy steroid compound TECHNICAL FIELD

[0001] The present application belongs to the technical field of preparation of steroid hormone drugs, and particularly relates to a preparation method of an alpha epoxy steroid compound. BACKGROUND

[0002] The alpha epoxy process of the steroid 5(10) double bond is a key synthesis step of mifepristone, onapristone, anorast, and other similar compounds, and generally uses hydrogen peroxide for catalytic epoxidation under alkaline conditions. Most methods have more isomer beta epoxy by-products, low product yield, and difficult separation of isomers. For example, the method described in Jilin Huagong Xueyuan Xuebao (2001), 18(2), 31-33, compound II is prepared by using 2,2,2-trifluoro-1-phenylethanone as a catalyst and hydrogen peroxide as an oxidant. The alpha epoxy yield is only 59%, and the chemical reaction is as follows:

[0003] Meanwhile, the present application also uses other methods, such as: using hexachloroacetone as a catalyst and hydrogen peroxide as an oxidant, and performing a 80-hour incubation reaction at a low temperature of-15℃ or below, the obtained alpha epoxy is only 70%, and the isomer beta epoxy is 24%; changing the oxidant to perform epoxidation using m-chloroperbenzoic acid, although the reaction time can be reduced to 8 hours, but other epoxy by-products besides isomers are also produced, and the proportion of alpha epoxy is reduced to 53%.

[0004] Although the proportion of alpha / beta isomers of a few methods is high, the reaction conditions also have the disadvantages of long reaction time, low temperature, expensive auxiliary materials, high comprehensive cost, and unsuitability for industrial large-scale production; for example, the process described in Chinese invention patent CN106866778 uses 5(10), 9(11)-dien-estrone (I) as a starting material, dichloromethane or trichloromethane as a solvent, trichloroacetonitrile, hexafluoroacetone, and / or hexachloroacetone, and alpha-phenylethylamine, tartaric acid, and / or camphoric acid as a catalyst, and then performs oxidation with hydrogen peroxide to obtain (II). The chemical reaction formula is as follows: 。

[0005] The yield is 102%, and the HPLC content is 99.55%, which is higher than that of general synthesis methods, but the reaction temperature is-30℃ or below, the reaction time is more than 84 hours, the types of catalysts used are difficult to handle, the price is relatively high, the safety is relatively poor, and the toxicity is relatively strong; the production cycle is long, the environmental protection pressure is large, the production operability requirement is high, the occupational health risk is high, and the production cost is too high, which is not conducive to industrial large-scale production. TECHNICAL PROBLEM

[0006] In view of the problems and deficiencies of the prior art, in order to solve the problems such as more isomer by-products, low yield, long production cycle and high comprehensive production cost in the existing process, the purpose of the present application is to provide a preparation method of alpha epoxy steroid compound with high selectivity and obvious economic benefit, so as to make the process more suitable for industrialized mass production. Technical solutions

[0007] In order to achieve the purpose of the present application, the inventors provide the following technical solutions:

[0008] The accurate measurement in the following text is defined as follows:

[0009] W: mass ratio to compound I;

[0010] V: volume ratio to compound I.

[0011] A preparation method of alpha epoxy steroid compound, which is prepared by using steroid compound I containing carbon-carbon double bond as raw material, adding basic reagent in solvent solution state, adding 0.1-0.3V of catalyst and 1.5-2.0W of hydrogen peroxide based on compound I, and obtaining alpha epoxy steroid compound II through epoxidation reaction, the reaction formula is as follows: , wherein ring A represents the following group: Or , R is methyl or ethyl; the catalyst is 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone.

[0012] As preferred, the preparation method of alpha epoxy steroid compound according to the present application, wherein the basic reagent of the reaction is selected from pyridine or triethylamine, the addition amount of pyridine is 0.025V-0.03V based on compound I, and the addition amount of triethylamine is 0.025V-0.03V.

[0013] The inventors found that, compared with sodium bicarbonate, potassium carbonate and other inorganic bases, pyridine, triethylamine and other organic bases can better balance the PH of the system in the reaction system of the present application, so that the acid-base balance is kept in a state conducive to the reaction.

[0014] As more preferred, the preparation method of alpha epoxy steroid compound according to the present application, wherein the basic reagent of the reaction is pyridine.

[0015] As preferred, the preparation method of alpha epoxy steroid compound according to the present application, wherein the reaction solvent is selected from dichloromethane or trichloromethane, the addition amount of dichloromethane is 8-10V based on compound I, and the addition amount of trichloromethane is 9-10V.

[0016] As more preferably, the preparation method of the alpha epoxy steroid compound according to the present application, wherein the reaction solvent is dichloromethane.

[0017] As preferably, the preparation method of the alpha epoxy steroid compound according to the present application, wherein the reaction temperature is -10~24℃.

[0018] As more preferably, the preparation method of the alpha epoxy steroid compound according to the present application, wherein the reaction temperature is -10~0℃.

[0019] As preferably, the preparation method of the alpha epoxy steroid compound according to the present application, wherein the reaction time is 8~72 hours.

[0020] As more preferably, the preparation method of the alpha epoxy steroid compound according to the present application, wherein the reaction time is 48 hours.

[0021] As preferably, the preparation method of the alpha epoxy steroid compound according to the present application, further comprising the following steps: after the completion of the epoxidation reaction, standing and layering, adding dichloromethane to the water layer for extraction, washing the combined organic layer with sodium thiosulfate solution or sodium sulfite solution, sodium bicarbonate solution and sodium chloride solution in turn, extracting the combined water layer with dichloromethane, combining the organic layers, adding anhydrous sodium sulfate and neutral alumina for stirring and filtration, concentrating the filtrate, adding an inert solvent for recrystallization, filtering, drying, and obtaining the target product, the alpha epoxy steroid compound II product according to the present application.

[0022] The target product according to the present application is detected by high performance liquid chromatography, and compared with the control product by liquid chromatography to determine that the chemical structure of the compound is the target alpha epoxy compound. Advantages

[0023] Compared with the prior art, the advantages of the present application are:

[0024] 1. The present application uses a single catalyst, which is high in selectivity, fast in catalytic speed, cheap and easy to obtain, low in toxicity, the alpha epoxy conversion rate of the raw material reaches more than 84%, reduces the beta isomer impurities, and makes the raw material utilization more efficient.

[0025] 2. The raw and auxiliary materials used in the present application are cheap and easy to obtain, and are common pharmaceutical synthesis raw and auxiliary materials.

[0026] 3. The present application is simple in operation, mild in reaction conditions, and high in safety, which makes the production more economical and environmentally friendly, and is more suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 is the HPLC spectrum of the product 1 of the comparative example 1 of the present application.

[0028] Figure 2 is the HPLC profile of product 2 of Comparative Example 1 of the present application.

[0029] Figure 3 is the HPLC profile of product 1 of Comparative Example 2 of the present application.

[0030] Figure 4 is the HPLC profile of product 2 of Comparative Example 2 of the present application.

[0031] Figure 5 is the HPLC profile of product solution of Example 1 of the present application.

[0032] Figure 6 is the HPLC profile of control of Example 1 of the present application. DETAILED DESCRIPTION

[0033] The present application will be described in more detail by way of examples. It should be understood that the implementations of the application are not limited to the following examples and any modification and / or change made to the application in form will fall within the scope of the present application.

[0034] In the present application, all parts, percentages are by weight unless otherwise specified, and all the equipment and raw materials are commercially available or commonly used in the industry. The methods used in the following examples are conventional methods in the art unless otherwise specified.

[0035] Comparative Example 1

[0036] The method used in industrial production: 10 g of compound I was put into a reaction bottle, 90 ml of dichloromethane solution was added to stir and dissolve, 0.3 ml of pyridine, 2 ml of hexachloroacetone were added to stir and cool to below -15°C. 16 g of 30% hydrogen peroxide was added, and the reaction was kept at -15°C for 84 hours. After the reaction was completed, an appropriate amount of 8% sulfuric acid sodium sulfate solution was added to quench, and the water layer was separated to obtain a dichloromethane solution of compound II as product 1; the sample was sent to HPLC to obtain the HPLC profile of product 1 (Figure 1).

[0037] In the HPLC profile, there are two peaks with area percentages of 72.725 and 24.37% respectively, which are α-epoxide and β-epoxide, and the ratio is about 3:1; under the same conditions, the above-mentioned catalyst was replaced by the catalyst 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone of the present application, and the reaction was carried out for 48 hours to obtain the HPLC profile of product 2 (Figure 2); in the figure, α-epoxide is 48.12%, epoxide is 9.63%, and 37.26% is the catalyst peak; the ratio of α / β-epoxide is 5:1, which is significantly improved compared with the 3:1 of the industrial production method.

[0038] The route is as follows: .

[0039] Comparative Example 2

[0040] The method reported in the patent document: compound Ⅰ 10g is put into a reaction bottle, 100ml of reaction solvent dichloromethane is added, and the solution is stirred and dissolved. Pyridine 0.4ml is added, and 1.3ml of catalyst trichloroacetonitrile is added. 0.1g of L-tartaric acid is added, and the temperature is reduced to below-15℃ by stirring. 30% hydrogen peroxide 10g is added dropwise, and the reaction is kept at-15℃ for 56 hours. After the reaction is completed, a suitable amount of 6% sodium thiosulfate solution is added to quench, and the upper water layer is separated to obtain a dichloromethane solution of compound Ⅱ as product 1. Take the solution to HPLC to obtain the HPLC spectrum of product 1 (Figure 3).

[0041] The area percentage of the HPLC spectrum is only 11.49% for α-epoxy and 4.34% for β-epoxy, and 65.65% of the raw material is unreacted, and the α / β epoxy ratio is less than 3:1. Replace the above catalyst with the catalyst 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone 1.8ml, and the HPLC spectrum of product 2 of reaction 48 (Figure 4) is obtained under the same conditions. In the figure, α-epoxy is 47.53%, β-epoxy is 9.64%, catalyst peak is 37.62%, raw material is 1%, and the α / β epoxy ratio is about 5:1. Compared with the method reported in the patent document, the raw material is more completely reacted, and the α / β epoxy ratio is also higher.

[0042] The route is as follows: 。 Example

[0043] A method for preparing an α-epoxy steroid compound:

[0044] Steroid compound Ⅰ 10g is put into a reaction bottle, 100ml of reaction solvent dichloromethane is added, and the solution is stirred and dissolved. Pyridine 0.3ml is added, and 2ml of catalyst 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone is added. The temperature is reduced to below-10℃ by stirring. 30% hydrogen peroxide 15g is added, and the reaction is kept at about-5℃ for 42 hours.

[0045] Stir for another 3 hours at room temperature of 20~24℃, separate the layers, extract with dichloromethane, and wash the organic layer with 8% sodium thiosulfate, saturated sodium bicarbonate solution, and saturated sodium chloride solution in turn. The water layer is extracted with dichloromethane.

[0046] The combined organic layer is added with neutral alumina and anhydrous sodium sulfate and stirred to adsorb and dehydrate, and the organic layer is taken to HPLC; the HPLC spectrum (Figure 5) shows that the α-epoxide is 48.14%, the β-epoxide is 9.85%, and 37.21% is the catalyst peak, and the isomer ratio of the α / β-epoxide steroid compound is 5:1. The organic layer is concentrated and dried, and then n-hexane and isopropyl ether are added and stirred to recrystallize, and then the compound II is obtained by cooling and filtration. The yield is 94.32%, the HPLC of the α-epoxide steroid compound is 88.5%, and the HPLC of the isomer β-epoxide steroid compound is 7.5%.

[0047] The route is as follows: 。

[0048] Structure identification: The mifepristone epoxide reference substance is detected by high performance liquid chromatography to obtain the reference substance HPLC spectrum (Figure 6), the α-epoxide is 27min, and the β-epoxide is 31min, and the β-epoxide RRT=1.14, which is consistent with the product solution spectrum (Figure 5), and it is determined that the product is the compound II mifepristone intermediate α-epoxide. Example

[0049] A preparation method of an α-epoxide steroid compound:

[0050] The steroid compound I 20g is put into a reaction bottle, 160ml of dichloromethane is added as a reaction solvent, stirred to dissolve, 0.5ml of triethylamine is added, 3.5ml of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone is added as a catalyst, and the temperature is reduced to below-10℃ by stirring. 30g of 30% hydrogen peroxide is added, and the reaction is carried out at-10~-3℃ for 40 hours.

[0051] After stirring at room temperature for another 3 hours, the layers are separated, dichloromethane is extracted, the organic layer is combined, and then the organic layer is washed with 6% sodium sulfite solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution in sequence, and the water layer is extracted.

[0052] The combined organic layer is added with neutral alumina and anhydrous sodium sulfate and stirred to adsorb and dehydrate, and the organic layer is taken to HPLC to obtain the isomer ratio of the α / β-epoxide steroid compound, which is 4.6:1. The organic layer is concentrated and added with petroleum ether and isopropyl ether and stirred to recrystallize, and then the compound II is obtained by cooling and filtration. The yield is 96.85%, the HPLC of the α-epoxide steroid compound is 82%, and the HPLC of the isomer β-epoxide steroid compound is 13.5%.

[0053] The route is as follows:

[0054] 。 Example

[0055] A preparation method of an α-epoxide steroid compound:

[0056] The steroid compound 20g is put into a reaction bottle, reaction solvent dichloromethane 180ml is added, stirred to dissolve, pyridine 0.5ml is added, catalyst 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone 2ml is added, 30% hydrogen peroxide 30g is added at room temperature 20~24℃, and reaction is carried out for 8 hours.

[0057] The water layer is separated, dichloromethane is extracted, the organic layers are combined, and the organic layer is washed with 6% sodium thiosulfate solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution in sequence, the water layer is extracted with dichloromethane, the organic layers are combined, neutral alumina and anhydrous sodium sulfate are added, stirring, adsorption and dehydration are carried out, a dichloromethane solution of the compound II is obtained, and the liquid is sent to HPLC to obtain an α / β epoxy steroid isomer ratio of 4:1.

[0058] Although the ratio of this method is less than 5:1 of example 1, the reaction time of 8 hours is much less than the reaction time of dozens of hours of the general method, which can greatly reduce the production cycle, and the reaction temperature at room temperature 20~24℃ is also more energy-saving and environmentally friendly than the general reaction of-30~-10℃; production can be selected according to actual needs.

[0059] The route is as follows:

[0060] 。 Example

[0061] A preparation method of an α epoxy steroid compound:

[0062] The steroid compound 20g is put into a reaction bottle, reaction solvent dichloromethane 180ml is added, stirred to dissolve, pyridine 0.5ml is added, catalyst 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone 2ml is added, 30% hydrogen peroxide 30g is added at room temperature 20~24℃, and reaction is carried out for 8 hours.

[0063] The water layer is separated, dichloromethane is extracted, the organic layers are combined, and the organic layer is washed with 6% sodium thiosulfate solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution in sequence, the water layer is extracted with dichloromethane, the organic layers are combined, neutral alumina and anhydrous sodium sulfate are added, stirring, adsorption and dehydration are carried out, a dichloromethane solution of the compound II is obtained, and the liquid is sent to HPLC to obtain an α / β epoxy steroid isomer ratio of 4:1.

[0064] This method determines that the methyl or ethyl group at position 13 of the steroid does not affect the selectivity and catalytic rate of the catalyst, which is the same as example 2.

[0065] From the analysis of the steroid structure, the catalyst is used for the epoxidation of the double bond at position 5(10) of the specific structure, and therefore simple substitution or modification (such as: methyl to ethyl, H to methyl or ethyl) does not have a significant effect on the selectivity and catalytic rate of the catalyst under the specific steroid structure of the application.

[0066] The route is as follows: 。 Embodiment

[0067] A preparation method of an alpha epoxide steroid compound:

[0068] The steroid compound I 20 g is put into a reaction bottle, 200 ml of dichloromethane is added as a reaction solvent, and the solution is stirred and dissolved, 0.5 ml of pyridine is added, 3 ml of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone is added as a catalyst, and the temperature is reduced to below -20°C by refrigeration; 30 g of 30% hydrogen peroxide is added, and the reaction is incubated at -20°C. TLC is used to observe the remaining raw materials, and when the incubation reaction is complete and the raw material point is not shown on the analyzer, the reaction is complete.

[0069] 72 hours of incubation reaction is completed; the water layer is separated and the dichloromethane layer is extracted; the organic layer is combined and washed with 6% sodium thiosulfate solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution in sequence, and the water layer is extracted with dichloromethane, and the combined organic layer is added with neutral alumina and anhydrous sodium sulfate, stirred and adsorbed, and dehydrated to obtain a dichloromethane solution of the compound II, and the liquid is sent to HPLC to obtain an alpha / beta epoxide steroid compound isomer ratio of 5.2:1.

[0070] The method shows that the catalyst used in the application still has high catalytic selectivity at a certain low temperature.

[0071] The route is as follows: 。 Embodiment

[0072] A preparation method of an alpha epoxide steroid compound:

[0073] The steroid compound I 20 g is put into a reaction bottle, 180 ml of trichloromethane is added as a solvent at room temperature, the solution is stirred and dissolved, 0.5 ml of triethylamine is added, and 6 ml of 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone is added as a catalyst; 30 g of 30% hydrogen peroxide is added, and the reaction is incubated at 20°C for 8 hours.

[0074] The water layer is separated, and the water layer is extracted with chloroform; the organic layers are combined, and the organic layer is washed with 6% sodium thiosulfate solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution in sequence, and the water layer is extracted. The organic layers are combined, neutral alumina and anhydrous sodium sulfate are added, and stirring adsorption dehydration is performed to obtain a chloroform solution of the compound II. The liquid is subjected to HPLC to obtain an α / β epoxy steroid isomer ratio of 3.9:1.

[0075] The method shows that temperature has a great influence on catalytic selectivity and reaction time, and industrial large-scale production can balance the reaction time and selectivity according to actual conditions.

[0076] The route is as follows: ​

Claims

1. A process for the preparation of an alpha epoxy steroid compound, characterized by, The preparation method comprises the following steps: taking a steroid compound I containing a carbon-carbon double bond as raw material, adding a basic reagent in a solvent-dissolved state, adding 0.1-0.3V of a catalyst and 1.5-2.0W of hydrogen peroxide based on the compound I, and performing an epoxidation reaction to obtain the alpha-epoxy steroid compound II, and the reaction formula is as follows: , wherein A ring represents the following group: Or R is methyl or ethyl; and the catalyst is 3', 5'-dichloro-2, 2, 2-trifluoroacetophenone.

2. The method for preparing an α-epoxysteroid compound according to claim 1, characterized in that, The basic reagent of the reaction is selected from pyridine or triethylamine, and the addition amount of pyridine is 0.025V~0.03V, and the addition amount of triethylamine is 0.025V~0.03V, based on compound I.

3. A method for preparing an α-epoxysteroid compound according to claim 1 or 2, characterized in that, The basic reagent of the reaction is pyridine.

4. The method for preparing an α-epoxysteroid compound according to claim 1, characterized in that, The reaction solvent is selected from dichloromethane or trichloromethane, and the addition amount of dichloromethane is 8~10V, and the addition amount of trichloromethane is 9~10V, based on compound I.

5. A method for preparing an α-epoxysteroid compound according to claim 1 or 4, characterized in that, The reaction solvent is dichloromethane.

6. The method for preparing an α-epoxysteroid compound according to claim 1, characterized in that, The temperature of the reaction is-10~24℃.

7. A method for preparing an α-epoxysteroid compound according to claim 1 or 6, characterized in that, The temperature of the reaction is-10~0℃.

8. The method for preparing an α-epoxysteroid compound according to claim 1, characterized in that, The reaction time is 8~72 hours.

9. A method for preparing an α-epoxysteroid compound according to claim 1 or 8, characterized in that, The reaction time is 48 hours.

10. The method for preparing an α-epoxysteroid compound according to claim 1, characterized in that, The preparation method further comprises the following steps: After the epoxy synthesis reaction is completed, the water layer is extracted with dichloromethane, the combined organic layer is washed with sodium thiosulfate solution or sodium sulfite solution, sodium bicarbonate solution and sodium chloride solution three times, and then extracted with dichloromethane, the combined organic layer is added with anhydrous sodium sulfate and neutral aluminum oxide, stirred and filtered, the filtrate is concentrated, added with an inert solvent for recrystallization, filtered, dried, and the target product, the alpha epoxy steroid compound II product, is obtained.

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