Novel preparation method of alpha epoxy steroid compound

Abstract

The invention belongs to the technical field of preparation of steroid hormone drugs, and particularly relates to a preparation method of an alpha epoxy steroid compound, which comprises the following steps: by taking a steroid compound I containing a carbon-carbon double bond as a raw material, adding an alkaline reagent, a catalyst and hydrogen peroxide in a solvent clarified state, carrying out epoxy synthesis reaction to obtain an alpha epoxy steroid compound II; wherein the catalyst refers to 3 ', 5'-dichloro-2, 2, 2-trifluoroacetophenone, and the catalyst refers to 3 ', 5'-dichloro-2, 2, 2-trifluoroacetophenone. The invention effectively solves the problems of many isomerization byproducts, low yield, long production period and high comprehensive production cost in the prior art, and provides the preparation method of the alpha epoxy steroid compound with high selectivity and obvious economic benefit, so that the process is more suitable for industrial mass production.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of steroid hormone drugs, and specifically relates to a preparation method of an alpha epoxy steroid compound. Background Art

[0002] The α-epoxy process of the double bond at the 5(10) position of the steroid is a key step in the synthesis of mifepristone, onapristone, angostrin and other analogs. Generally, the epoxidation reaction is carried out by catalysis with hydrogen peroxide under alkaline conditions. Most methods produce a large number of isomer β-epoxy byproducts, low product yields, and isomers are difficult to separate. For example, the method described in Jilin Huagong Xueyuan Xuebao (2001), 18(2), 31-33, compound II is prepared from compound I using 2,2,2-trifluoro-1-phenylethanone as a catalyst and hydrogen peroxide oxidation. The α-epoxy yield is only 59%, and the chemical reaction is as follows:

[0003]

[0004] At the same time, the present invention has also adopted other methods, such as: using hexachloroacetone as a catalyst and hydrogen peroxide as an oxidant alone, and carrying out a heat preservation reaction at a low temperature below -15°C for more than 80 hours, the obtained α-epoxy is only 70%, and the isomer β-epoxy is 24%; changing the oxidant to use meta-chloroperbenzoic acid for epoxidation, although the reaction time can be reduced to 8 hours, it will also produce other epoxy by-products except isomers, among which the proportion of α-epoxy is reduced to 53%.

[0005] Although the α / β isomer ratio of a few methods is high, the reaction conditions also have the disadvantages of too long time, too low temperature, expensive auxiliary materials, high comprehensive cost, and unsuitability for large-scale industrial production; for example, the process described in Chinese invention patent CN106866778 uses 5(10), 9(11)-diene-estrone (I) as the starting material, dichloromethane or chloroform as the solvent, trichloroacetonitrile, hexafluoroacetone and / or hexachloroacetone and α-phenylethylamine, tartaric acid and / or camphoric acid as the catalyst, and then oxidizes with hydrogen peroxide to obtain (II). The chemical reaction formula is as follows:

[0006]

[0007] The yield is 102%, and the HPLC content is 99.55%, which are higher than the general synthesis method. However, the reaction temperature is below -30°C, the reaction time exceeds 84 hours, and the catalyst types used are difficult to post-process, expensive, safe, and highly toxic. Taking all the conditions into consideration, the production cycle is long, the environmental pressure is high, the production operability requirements are high, the occupational health risks are high, and the production cost is too high, which is not conducive to large-scale industrial production. Summary of the invention

[0008] In view of the problems and shortcomings of the above-mentioned prior art, in order to solve the problems existing in the existing process such as a large number of isomeric by-products, low yield, long production cycle and high comprehensive production cost, the purpose of the present invention is to provide a preparation method of α-epoxy steroid compounds with high selectivity and obvious economic benefits, so as to make the process more suitable for the needs of large-scale industrial production.

[0009] In order to achieve the purpose of the present invention, the inventor provides the following technical solution:

[0010] The following are the definitions of exact measurements:

[0011] W: mass ratio to compound Ⅰ;

[0012] V: volume ratio to compound Ⅰ.

[0013] A method for preparing an α-epoxy steroid compound is to use a steroid compound I containing a carbon-carbon double bond as a raw material, add an alkaline reagent in a solvent-dissolved state, add 0.1-0.3V of a catalyst and 1.5-2.0W of hydrogen peroxide based on compound I, and obtain an α-epoxy steroid compound II through an epoxidation synthesis reaction. The reaction formula is as follows:

[0014]

[0015] In the formula, ring A represents the following groups:

[0016] R is methyl or ethyl;

[0017] The catalyst is: 3',5'-dichloro-2,2,2-trifluoroacetophenone.

[0018] Preferably, in the method for preparing an α-epoxy steroid compound described in the present invention, the alkaline reagent of the reaction is selected from pyridine or triethylamine, and based on compound I, the amount of pyridine added is 0.025V~0.03V, and the amount of triethylamine added is 0.025V~0.03V.

[0019] The inventors have found that organic bases such as pyridine and triethylamine can better balance the pH of the system in the reaction system of the present invention than inorganic bases such as sodium bicarbonate and potassium carbonate, so that the acid-base balance is maintained in a state that is conducive to the reaction.

[0020] More preferably, in the method for preparing an α-epoxy steroid compound of the present invention, the alkaline reagent of the reaction is pyridine.

[0021] Preferably, in the method for preparing an α-epoxy steroid compound described in the present invention, the reaction solvent is selected from dichloromethane or chloroform, and based on compound I, the amount of dichloromethane added is 8-10V, and the amount of chloroform added is 9-10V.

[0022] More preferably, in the method for preparing an α-epoxy steroid compound described in the present invention, the reaction solvent is dichloromethane.

[0023] Preferably, in the method for preparing an α-epoxy steroid compound described in the present invention, the reaction temperature is -10 to 24°C.

[0024] More preferably, in the method for preparing an α-epoxy steroid compound described in the present invention, the reaction temperature is -10 to 0°C.

[0025] Preferably, in the method for preparing an α-epoxy steroid compound described in the present invention, the reaction time is 8 to 72 hours.

[0026] More preferably, in the method for preparing an α-epoxy steroid compound described in the present invention, the reaction time is 48 hours.

[0027] Preferably, the preparation method of an α-epoxy steroid compound described in the present invention further includes the following steps: after the epoxy synthesis reaction is completed, standing and stratifying, adding dichloromethane to the aqueous layer for extraction, combining the organic layers and washing them in sequence with sodium thiosulfate solution or sodium sulfite solution, sodium bicarbonate solution, and sodium chloride solution, combining the three washed aqueous layers and then extracting them with dichloromethane, combining the organic layers, adding anhydrous sodium sulfate and neutral alumina, stirring and filtering, concentrating the filtrate, adding an inert solvent for recrystallization, filtering, and drying to obtain the target product described in the present invention-the finished product of α-epoxy steroid compound II.

[0028] The target product of the present invention is detected by high performance liquid chromatography and liquid chromatography comparison with a reference substance is performed to determine that the chemical structure of the compound is the target α-epoxide.

[0029] Compared with the prior art, the advantages of the present invention are:

[0030] 1. The present invention adopts a single catalyst with high selectivity, fast catalytic speed, low price, easy availability and low toxicity. The α-epoxy conversion rate of the raw material reaches more than 84%, reducing the β-isomer impurities and making the raw material utilization more efficient.

[0031] 2. The raw and auxiliary materials used in the present invention are cheap and easily available, and are all commonly used raw and auxiliary materials for drug synthesis.

[0032] 3. The present invention is easy to operate, has mild reaction conditions and high safety, making the production more economical, environmentally friendly and more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Attached Figure 1 It is the HPLC spectrum of the product 1 of comparative example 1 of the present invention.

[0034] Attached Figure 2 It is the HPLC spectrum of the product 2 of Comparative Example 1 of the present invention.

[0035] Attached Figure 3 It is the HPLC spectrum of the product 1 of Comparative Example 2 of the present invention.

[0036] Attached Figure 4 It is the HPLC spectrum of the product 2 of Comparative Example 2 of the present invention.

[0037] Attached Figure 5 It is the HPLC spectrum of the product solution of Example 1 of the present invention.

[0038] Attached Figure 6 It is the HPLC spectrum of Example 1 comparison of the present invention. DETAILED DESCRIPTION

[0039] The following is a more detailed description of the present invention in conjunction with the following embodiments. It should be understood that the implementation of the present invention is not limited to the following embodiments, and any modifications and / or changes made to the present invention will fall within the scope of protection of the present invention.

[0040] In the present invention, unless otherwise specified, all parts and percentages are by weight, and all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments are conventional methods in the art unless otherwise specified.

[0041] Comparative Example 1

[0042] The method used in industrial production is as follows: 10 g of compound I is put into a reaction bottle, 90 ml of dichloromethane solution is added and stirred to dissolve, 0.3 ml of pyridine and 2 ml of hexachloroacetone are added and stirred to cool to below -15°C. 16 g of 30% hydrogen peroxide is added and the reaction is kept at -15°C for 84 hours. After the reaction is completed, an appropriate amount of 8% sulfuric acid and sodium sulfate solution is added to quench, and the water layer is separated to obtain a dichloromethane solution of compound II as product 1; a sample is taken and sent to HPLC to obtain the HPLC spectrum of product 1 (attached Figure 1 ).

[0043] In the HPLC spectrum, there are two peaks with area percentages of 72.725 and 24.37%, which are α-epoxy and β-epoxy, respectively, with a ratio of about 3:1; the above catalyst is replaced with the catalyst 3',5'-dichloro-2,2,2-trifluoroacetophenone of the present invention, and the reaction is carried out for 48 hours under the same other conditions to obtain the HPLC spectrum of product 2 (see Appendix). Figure 2 ); in the figure, α-epoxy 48.12%, epoxy 9.63%, and 37.26% are catalyst peaks; the α / β-epoxy ratio is 5:1, which is significantly improved compared with the 3:1 of the industrial production method.

[0044] The route is as follows:

[0045]

[0046] Comparative Example 2

[0047] The method reported in the patent literature: put 10g of compound I into a reaction bottle, add 100ml of dichloromethane as the reaction solvent, stir to dissolve, add 0.4ml of pyridine, add 1.3ml of trichloroacetonitrile as the catalyst, add 0.1g of L-tartaric acid, stir and cool to below -15°C; add 10g of 30% hydrogen peroxide dropwise, keep warm below -15°C and react for 56 hours. After the reaction is completed, add an appropriate amount of 6% sodium thiosulfate solution to quench, separate the upper water layer, and obtain a dichloromethane solution of compound II as product 1; take the solution and send it to HPLC to obtain the HPLC spectrum of product 1 (attached Figure 3 ).

[0048] The area percentage of α-epoxy in the HPLC spectrum is only 11.49%, and that of β-epoxy is 4.34%. There is still 65.65% of the raw materials unreacted, and the α / β-epoxy ratio is less than 3:1. The above catalyst is replaced with 1.8 ml of the catalyst of the present invention, 3',5'-dichloro-2,2,2-trifluoroacetophenone, and the HPLC spectrum of the product 2 of the reaction 48 is obtained under the same other conditions (see attached). Figure 4 ); 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 literature, the present invention not only has a more complete raw material reaction, but also a higher α / β-epoxy ratio.

[0049] The route is as follows:

[0050]

[0051] Example 1

[0052] A method for preparing an α-epoxy steroid compound:

[0053] Put 10g of steroid compound I into a reaction bottle, add 100ml of dichloromethane as reaction solvent, stir until dissolved, add 0.3ml of pyridine, add 2ml of catalyst 3',5'-dichloro-2,2,2-trifluoroacetophenone, stir and cool to below -10°C. Add 15g of 30% hydrogen peroxide, keep the temperature at about -5°C and react for 42 hours.

[0054] The mixture was stirred for another 3 hours at room temperature (20-24°C), the layers were separated, and the mixture was extracted with dichloromethane. The organic layers were combined and washed with 8% sodium thiosulfate, saturated sodium bicarbonate solution, and saturated sodium chloride solution in sequence. The aqueous layer was extracted with dichloromethane.

[0055] Combine the organic layers, add neutral alumina and anhydrous sodium sulfate, stir and adsorb to dehydrate, and send the organic layer to HPLC; HPLC spectrum (attached Figure 5 ) contains 48.14% α-epoxy and 9.85% β-epoxy, 37.21% of which is the catalyst peak, and the ratio of α / β-epoxy steroid isomers is 5:1. The organic layer is concentrated and dried, and n-hexane and isopropyl ether are added for stirring and recrystallization, and the temperature is lowered and filtered to obtain compound II. The yield is 94.32%, the HPLC of α-epoxy steroid is 88.5%, and the HPLC of isomer β-epoxy steroid is 7.5%.

[0056] The route is as follows:

[0057]

[0058] Structural identification: Take mifepristone epoxy reference substance and perform HPLC detection to obtain the reference substance HPCL spectrum (attached Figure 6 ), α-epoxy peaks at 27 min, β-epoxy peaks at 31 min, β-epoxy RRT = 1.14, and the product solution spectrum (attached Figure 5 ) were consistent, and the product was determined to be compound II mifepristone intermediate α-epoxide.

[0059] Example 2

[0060] A method for preparing an α-epoxy steroid compound:

[0061] Put 20g of steroid compound I into a reaction bottle, add 160ml of dichloromethane as reaction solvent, stir to dissolve, add 0.5ml of triethylamine, add 3.5ml of catalyst 3',5'-dichloro-2,2,2-trifluoroacetophenone, stir and cool to below -10°C. Add 30g of 30% hydrogen peroxide, and react at -10 to -3°C for 40 hours.

[0062] The mixture was stirred for another 3 hours at room temperature, the layers were separated, and the mixture was extracted with dichloromethane. The organic layers were combined and washed with 6% sodium sulfite solution, saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence. The aqueous layer was extracted.

[0063] Combine the organic layers, add neutral alumina and anhydrous sodium sulfate, stir and adsorb to dehydrate, take the organic layer and send to HPLC to obtain the ratio of α / β epoxy steroid compound isomers of 4.6:1. Add petroleum ether and isopropyl ether to the organic layer, stir and recrystallize, cool and filter to obtain compound II. The yield is 96.85%, HPLC of α epoxy steroid compound is 82%, and HPLC of isomer β epoxy steroid compound is 13.5%.

[0064] The route is as follows:

[0065]

[0066] Example 3

[0067] A method for preparing an α-epoxy steroid compound:

[0068] Put 20g of steroid compound I into a reaction bottle, add 180ml of dichloromethane as reaction solvent, stir to dissolve, add 0.5ml of pyridine, add 2ml of catalyst 3',5'-dichloro-2,2,2-trifluoroacetophenone, add 30g of 30% hydrogen peroxide at room temperature (20-24°C), and react for 8 hours.

[0069] The aqueous layer was separated and extracted with dichloromethane. The organic layers were combined and washed with 6% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride in sequence. The aqueous layer was extracted with dichloromethane. The organic layers were combined and neutral alumina and anhydrous sodium sulfate were added for stirring, adsorption and dehydration to obtain a dichloromethane solution of compound II. The liquid was sent to HPLC to obtain an α / β epoxy steroid compound isomer ratio of 4:1.

[0070] Although the ratio of this method is smaller than 5:1 of Example 1, the reaction time of 8 hours in this method is much shorter than the reaction time of dozens of hours in the general method, which can greatly reduce the production cycle, and the reaction temperature of room temperature 20 to 24°C is more energy-efficient and environmentally friendly than the general reaction temperature of -30 to -10°C; in production, the reaction conditions can be comprehensively selected according to actual needs.

[0071] The route is as follows:

[0072]

[0073] Example 4

[0074] A method for preparing an α-epoxy steroid compound:

[0075] Put 20g of steroid compound I into a reaction bottle, add 200ml of chloroform as reaction solvent, stir to dissolve, add 0.6ml of triethylamine, add 5ml of catalyst 3',5'-dichloro-2,2,2-trifluoroacetophenone, freeze and cool to below -10°C; add 30g of 30% hydrogen peroxide, keep warm at -10 to -5°C for 40 hours.

[0076] Stir at room temperature for 3 hours; let stand to separate the water layer, extract the water layer with chloroform; combine the organic layers, and wash the organic layers with 6% sodium sulfite solution, saturated sodium bicarbonate solution, and saturated sodium chloride in sequence, extract the water layer with chloroform, combine the organic layers, add neutral alumina and anhydrous sodium sulfate, stir, adsorb and dehydrate to obtain a chloroform solution of compound II, take the liquid and send it to HPLC to obtain an α / β epoxy steroid compound isomer ratio of 4.5:1.

[0077] This method is the same as Example 2 to determine that the methyl or ethyl group at the 13th position of the steroid will not affect the selectivity and catalytic rate of the catalyst.

[0078] From the analysis of the steroid structure, the catalyst performs an epoxidation reaction on the double bond at the 5(10) position of the specific structure. Therefore, simple substitution or modification (such as: methyl to ethyl, H to methyl or ethyl) under the steroid structure determined by the present invention will not have a significant effect on the selectivity and catalytic rate of the catalyst.

[0079] The route is as follows:

[0080]

[0081] Example 5

[0082] A method for preparing an α-epoxy steroid compound:

[0083] Put 20g of steroid compound I into a reaction bottle, add 200ml of dichloromethane as reaction solvent, stir to dissolve, add 0.5ml of pyridine, add 3ml of catalyst 3',5'-dichloro-2,2,2-trifluoroacetophenone, freeze and cool to below -20℃; add 30g of 30% hydrogen peroxide, keep warm and react below -20℃. Use TLC to observe the remaining raw materials. When the raw material point is kept warm and reacted until there is no spot display under the analyzer, the reaction is complete.

[0084] The reaction was completed after 72 hours of heat preservation; the water layer was separated by standing, and the water layer was extracted with dichloromethane; the organic layers were combined and washed with 6% sodium thiosulfate solution, saturated sodium bicarbonate solution, and saturated sodium chloride in sequence, and the water layer was extracted with dichloromethane, and neutral alumina and anhydrous sodium sulfate were added to the combined organic layers for stirring, adsorption and dehydration to obtain a dichloromethane solution of compound II, and the liquid was sent to HPLC to obtain an α / β epoxy steroid compound isomer ratio of 5.2:1.

[0085] This method shows that the catalyst used in the present invention still has a high catalytic selectivity at a certain low temperature.

[0086] The route is as follows:

[0087]

[0088] Example 6

[0089] A method for preparing an α-epoxy steroid compound:

[0090] Put 20g of steroid compound I into a reaction bottle, add 180ml of chloroform solvent at room temperature, stir to dissolve, add 0.5ml of triethylamine, add 6ml of catalyst 3',5'-dichloro-2,2,2-trifluoroacetophenone; add 30g of 30% hydrogen peroxide, and keep the reaction at below 20℃ for 8 hours.

[0091] The mixture was allowed to stand and the aqueous layer was separated. The aqueous layer was extracted with chloroform. The organic layers were combined and washed with 6% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride in sequence. The aqueous layer was extracted and the organic layers were combined. Neutral alumina and anhydrous sodium sulfate were added and stirred for adsorption and dehydration to obtain a chloroform solution of compound II. The liquid was sent to HPLC to obtain an α / β epoxy steroid compound isomer ratio of 3.9:1.

[0092] This method shows that temperature has a great influence on catalytic selectivity and reaction time. Industrial large-scale production can balance reaction time and selectivity according to actual conditions.

[0093] The route is as follows:

[0094]

Claims

1. A method for preparing an α-epoxy steroid compound, characterized in that: The preparation method comprises taking a steroid compound I containing a carbon-carbon double bond as a raw material, adding an alkaline reagent in a solvent-dissolved state, adding 0.1-0.3V of a catalyst and 1.5-2.0W of hydrogen peroxide based on compound I, and obtaining the α-epoxy steroid compound II through an epoxidation synthesis reaction, and the reaction formula is as follows: In the formula, ring A represents the following groups: R is methyl or ethyl; The catalyst is 3',5'-dichloro-2,2,2-trifluoroacetophenone.

2. The method for preparing an α-epoxy steroid compound according to claim 1, characterized in that: The alkaline reagent of the reaction is selected from pyridine or triethylamine. Based on compound I, the added amount of pyridine is 0.025V~0.03V, and the added amount of triethylamine is 0.025V~0.03V.

3. The method for preparing an α-epoxy steroid compound according to claim 1 or 2, characterized in that: The alkaline reagent of the reaction is pyridine.

4. The method for preparing an α-epoxy steroid compound according to claim 1, characterized in that: The reaction solvent is selected from dichloromethane or chloroform. Based on compound I, the added amount of dichloromethane is 8-10V, and the added amount of chloroform is 9-10V.

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

6. The method for preparing an α-epoxy steroid compound according to claim 1, characterized in that: The reaction temperature is -10 to 24°C.

7. The method for preparing an α-epoxy steroid compound according to claim 1 or 6, characterized in that: The reaction temperature is -10 to 0°C.

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

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

10. The method for preparing an α-epoxy steroid compound according to claim 1, characterized in that: The preparation method further comprises the following steps: After the epoxy synthesis reaction is completed, the layers are allowed to stand for separation, dichloromethane is added to the aqueous layer for extraction, the organic layers are combined and sequentially washed with sodium thiosulfate solution or sodium sulfite solution, sodium bicarbonate solution, and sodium chloride solution, the aqueous layers are combined for three washes and then extracted with dichloromethane, the organic layers are combined, anhydrous sodium sulfate and neutral alumina are added, stirred and filtered, the filtrate is concentrated, an inert solvent is added for recrystallization, filtered, and dried to obtain the target product of the present invention, i.e., the finished product of α-epoxy steroid compound II.

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