Preparation method of diflucolone or diflucolone valerate

Abstract

The invention discloses a preparation method of diflucolone or diflucolone valerate, which comprises the following steps: in an inert protective atmosphere, carrying out reduction reaction on flumethasone and a reducing agent in a solvent to obtain the diflucolone, the preparation method comprises the following steps: in an inert protective atmosphere, carrying out acylation reaction on difluorocolone and an acylation reagent in a solvent in the presence of a base catalyst to obtain the difluorocolone valerate. The specific solvent is adopted in the reduction reaction, the problems that in the prior art, reaction by-products are large, raw material reaction is not thorough, the yield is low, and the production cost is high are solved, the product purity and the overall yield are obviously improved, and the production cost is reduced. According to the method, inorganic alkali and acetone are used as a solvent in the acylation reaction, the solvent can be recycled after post-treatment, the method is environment-friendly, 11-site hydroxyl is prevented from being acylated under the acylation condition, byproducts are effectively controlled, and the purity and yield of the product are improved.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and particularly relates to a method for preparing difluorocolone or difluorocolone valerate. Background Technology

[0002] Diflucolide valerate, also known as diflucolide valerate, possesses strong anti-inflammatory activity. It can inhibit the chemotaxis and activation of inflammatory cells, reduce the release of inflammatory mediators, and thus alleviate inflammatory responses. It can also inhibit the production and release of various cytokines during allergic reactions, reduce capillary permeability, and decrease tissue exudation and edema. It is mainly used to treat subacute or chronic skin diseases such as eczema, contact dermatitis, and neurodermatitis, effectively relieving symptoms such as itching, redness, and exudation. It can also relieve pain, swelling, and bleeding caused by hemorrhoids.

[0003] In known processes, diflumethasone is synthesized using flumethasone as a raw material and acetonitrile as a solvent in the presence of trimethyliodosilane. The applicant repeated this process and found issues such as incomplete reaction of the raw materials, high levels of impurities, and low yield.

[0004] Using difluorocolone as a raw material, it reacts with valeric anhydride under the catalysis of an alkali to produce difluorocolone valerate. The traditional preparation process uses organic bases such as triethylamine and DMF as a solvent. The post-treatment generates a large amount of wastewater containing ammonia nitrogen, which is very environmentally unfriendly. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiencies and defects mentioned in the background art above, and to provide a method for preparing difluorocolone or difluorocolone valerate to improve purity and yield.

[0006] To solve the above-mentioned technical problems, the technical solution proposed by this invention is as follows: A method for preparing difluorocorona, comprising the following steps: Under an inert protective atmosphere, flumethasone is reduced with a reducing agent in a solvent to obtain diflubenzuron; The reducing agent is trimethyliodosilane, or a combination of trimethylchlorosilane and sodium iodide; The solvent is a mixture of dichloromethane and isopropanol, a mixture of trichloromethane and isopropanol, or a mixture of dichloromethane, acetonitrile, and isopropanol; wherein, in the mixture of dichloromethane and isopropanol, the volume ratio of dichloromethane to isopropanol is (20~30):1, in the mixture of trichloromethane and isopropanol, the volume ratio of trichloromethane to isopropanol is (20~30):1, and in the mixture of dichloromethane, acetonitrile, and isopropanol, the volume ratio of the three components is (200~250):(12~18):(10~15).

[0007] As a further improvement, the molar ratio of flumethasone to reducing agent is 1:(1.2~5.5), and the mass-volume ratio of flumethasone to solvent is 1:(15~45) g / ml.

[0008] As a further improvement, the dripping time is controlled at 30~120 minutes, and the temperature is controlled at -50℃~-10℃.

[0009] As a further improvement, the reaction temperature of the reduction reaction is -50~10℃.

[0010] As a further improvement, after the reaction is complete, the reaction solution is poured into an aqueous solution of sodium thiosulfate, stirred to separate the layers or extracted with ethyl acetate, the organic phase is concentrated with water, stirred and filtered to obtain crude diflubenzuron.

[0011] The present invention provides a method for preparing difluorocolone valerate, comprising the aforementioned method for preparing difluorocolone, and further comprising the following steps: Difluorocolone is acylated with an acylation reagent in a solvent under an inert protective atmosphere in the presence of a base catalyst to obtain difluorocolone valerate.

[0012] As a further improvement, the acylation reagent is valeric anhydride or valeroyl chloride, and the molar ratio of diflucolide to the acylation reagent is 1:(1.1~3.5).

[0013] As a further improvement, the alkaline catalyst is one or more of sodium bicarbonate, sodium carbonate, and potassium carbonate, and the molar ratio of difluorocoline to the alkaline catalyst is 1:(2.5~5.5).

[0014] As a further improvement, the solvent is acetone, and the mass ratio of diflubenzuron to the solvent is 1:5.0~15.

[0015] Research has found that the following byproducts are generated during the synthesis of diflubenzuron:

[0016] Compound IV and Compound V In particular, the high concentration of 21-silyl ether impurity (compound V) generated in patent WO2012011106 A1 is the main reason for the low yield.

[0017] Through extensive experimental comparisons, it was found that the reduction reaction involving trimethyliodosilane is significantly affected by different solvents, and the degree of reaction, the size of impurities, and the yield are closely related to the type of solvent.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention uses a specific solvent in the reduction reaction, which solves the problems of excessively large reaction by-products, incomplete reaction of raw materials, low yield, and high production cost in the prior art. It significantly improves product purity and overall yield, and reduces production costs.

[0019] This invention uses an inorganic base and acetone as a solvent in the acylation reaction. The solvent can be recovered after post-treatment, which is environmentally friendly. Furthermore, under these acylation conditions, the acylation of the 11-position hydroxyl group is avoided, effectively controlling by-products and improving product purity and yield. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 This is the NMR spectrum of compound II obtained in Example 1; Figure 2 This is the NMR spectrum of compound III obtained in Example 1; Figure 3 This is the HPLC chromatogram of the crude compound II obtained in Example 1. Detailed Implementation

[0022] To facilitate understanding of the present invention, the present invention will be described more fully and in detail below with reference to the accompanying drawings and preferred embodiments, but the scope of protection of the present invention is not limited to the following specific embodiments.

[0023] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the scope of the invention.

[0024] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be purchased from the market or prepared by existing methods.

[0025] In some embodiments, the method for preparing difluorocornet (compound II) of the present invention includes the following steps:

[0026] Under an inert protective atmosphere, flumethasone (compound I) is reduced with a reducing agent in a solvent to obtain diflubenzuron (compound II).

[0027] Compound I was used as a raw material, which is already fully commercialized and readily available.

[0028] In some embodiments, the reducing agent may be trimethyliodosilane, or a combination of trimethylchlorosilane and sodium iodide, etc. Trimethyliodosilane is preferred. The molar ratio of compound I to reducing agent is 1:(1.2~5.5). The reducing agent is added dropwise to compound I and solvent, with the addition time controlled at 30~120 minutes and the temperature controlled at -50℃~-10℃.

[0029] In some embodiments, the solvent is preferably a mixture of dichloromethane and isopropanol, a mixture of trichloromethane and isopropanol, or a mixture of dichloromethane, acetonitrile, and isopropanol. In the dichloromethane and isopropanol mixture, the volume ratio of dichloromethane to isopropanol is (20-30):1. In the trichloromethane and isopropanol mixture, the volume ratio of trichloromethane to isopropanol is (20-30):1. In the dichloromethane, acetonitrile, and isopropanol mixture, the volume ratio of the three components is (200-250):(12-18):(10-15). The mass-to-volume ratio of compound I to the solvent is 1:(15-45) g / ml.

[0030] In the reduction reaction involving trimethyliodosilane, or trimethylchlorosilane and sodium iodide, extensive experiments were conducted to compare different solvent systems. By employing a specific mixed solvent of haloalkanes and alcohols, the reaction of the raw materials was ensured to be complete while byproducts were well controlled. This reduced the number of purification steps, increased purity to >95%, and achieved an overall yield of >90%. This solution addresses the problems of large byproducts, long reaction routes, complex processes, and low yields in existing technologies.

[0031] In some embodiments, the reaction temperature is -50 to 10°C, and the reaction time is 1.5 to 4 hours.

[0032] In some embodiments, after the reaction is complete, the reaction solution is poured into an aqueous sodium thiosulfate solution, stirred to separate the layers or extracted with ethyl acetate to separate the layers, the organic phase is concentrated with water, stirred and filtered to obtain crude compound II.

[0033] In some embodiments, the method for preparing the difluorocolonolactone ester (compound III) of the present invention includes the following steps:

[0034] Under an inert protective atmosphere, compound II was reacted with an acylation reagent in the presence of a base catalyst in a solvent to give difluorocolon valerate (compound III).

[0035] In some embodiments, the acylation reagent may be valeric anhydride or valeryl chloride, preferably valeric anhydride. The molar ratio of compound II to the acylation reagent is 1:(1.1~3.5). The acylation reagent is added dropwise to compound II and the solvent at -5 to 0°C.

[0036] In some embodiments, the base catalyst is sodium bicarbonate, sodium carbonate, potassium carbonate, etc. The molar ratio of compound II to the base catalyst is 1:(2.5~5.5).

[0037] In some embodiments, the solvent is acetone, and the mass ratio of compound II to solvent is 1:5.0~15.

[0038] In some embodiments, the reaction temperature is 30~57°C.

[0039] In some embodiments, methanol is added to terminate the reaction after it is complete, followed by stirring, concentration with water, stirring again, and filtration to obtain compound III.

[0040] Example 1:

[0041] Step 1: Preparation of Compound II Under nitrogen protection, 800 ml of dichloromethane and 32 ml of isopropanol were added to a three-necked flask, followed by 20 g of compound I. 40 g of trimethyliodosilane was added slowly to the reaction flask over a constant-pressure dropping funnel at a controlled temperature of -40 to -35°C for 90-120 minutes. After addition, the temperature was maintained at -30 to -15°C for 2-4 hours. TLC was used to monitor the reaction until the reactants were confirmed to be completely reacted. The reaction mixture was then slowly poured into 600 ml of sodium thiosulfate aqueous solution, stirred for 30 minutes, and allowed to stand to separate the layers. The aqueous phase was separated, and the aqueous phase was extracted with 100 ml of dichloromethane. The organic phases were combined, and the mixture was concentrated under reduced pressure at 35-40°C to remove the dichloromethane. 200 ml of water was added, and the concentration was continued until no dichloromethane was removed. The concentration was stopped, and the mixture was stirred for 1 hour. The mixture was then filtered. A white solid was obtained, dried at 55°C for 12 hours, yielding 18.8 g of crude compound II, with a yield of 94% by weight and an HPLC purity of 97.5% (HPLC chromatogram shown). Figure 3 Compound IV was 1.24%. The NMR spectrum of compound II is shown below. Figure 1 .

[0042] Step 2: Preparation of Compound III

[0043] Under nitrogen protection, 180 ml of acetone, 17.9 g of compound II, and 18.5 g of sodium bicarbonate were added to a three-necked flask. The mixture was cooled to -5 to 0 °C. 26.6 g of valeric anhydride was weighed into a constant-pressure dropping funnel, and the anhydride was added dropwise. After the addition was complete, the temperature was raised to 50–56 °C, and the reaction was carried out for 3 to 5 hours. TLC analysis showed that the reactants had reacted completely. 10 ml of methanol was added dropwise to terminate the reaction. The mixture was stirred for 10 minutes, and the acetone was concentrated under reduced pressure. 650 ml of water was added, and the mixture was further concentrated until no acetone remained. Concentration was stopped, and the mixture was stirred for 1 hour. The mixture was filtered, washed with water, pressed dry, and dried at 65 °C for 20 hours to obtain 20.6 g of compound III with an HPLC purity of 99.5%, meeting the standards for active pharmaceutical ingredients. The yield was 103% based on compound I. The NMR spectrum of compound III is shown below. Figure 2 .

[0044] Example 2: Step 1: Preparation of Compound II Under nitrogen protection, add 225 ml of dichloromethane, 15 ml of acetonitrile, and 13.5 ml of isopropanol to a three-necked flask. Add 15 g of compound I. Place 15 g of trimethyliodosilane in a constant-pressure dropping funnel and slowly add it to the reaction flask at a controlled temperature of -35 to -15°C over 30 to 60 minutes. After the addition is complete, maintain the temperature at -30 to -15°C and react for 2 hours. Monitor the reaction on TLC until the reactants have completely reacted. Slowly pour the reaction solution into 550 ml of sodium thiosulfate aqueous solution, add 180 ml of ethyl acetate for extraction, allow to stand and separate the layers. Separate the aqueous phase and extract the aqueous phase with 100 ml of ethyl acetate. Combine the organic phases and wash once with 80 ml of saturated brine. Concentrate the organic phase under reduced pressure at 50°C. Add 200 ml of... The solution was further concentrated in 1 ml of water until no ethyl acetate was obtained. The concentration was stopped, and the mixture was stirred for 1 hour. The mixture was then filtered to obtain a white solid. The solid was dried at 55°C for 12 hours to obtain 13.8 g of crude compound II, with a yield of 92% by weight, an HPLC purity of 96.9%, and a content of 1.74% of compound IV.

[0045] Comparative Example 1: Step 1: Preparation of Compound II (The only difference from Example 2 is that acetonitrile is used as the solvent) Under nitrogen protection, 253.5 ml of acetonitrile and 15 g of compound I were added to a three-necked flask. 15 g of trimethyliodosilane was placed in a constant-pressure dropping funnel and slowly added to the reaction flask over a period of 30-60 minutes, maintaining a temperature of -35 to -15°C. After the addition was complete, the temperature was maintained at -30 to -15°C, and the reaction was allowed to proceed for 2 hours. TLC was used to confirm the complete reaction of the reactants. The reaction solution was then slowly poured into 550 ml of sodium thiosulfate aqueous solution, and 180 ml of ethyl acetate was added for extraction. The mixture was allowed to stand and separate into layers. The aqueous phase was separated, and the aqueous phase was extracted with 100 ml of ethyl acetate. The organic phases were combined and washed once with 80 ml of saturated brine. The organic phase was concentrated under reduced pressure at 50°C, and 200 ml of water was added to continue concentration until no ethyl acetate was removed. Concentration was stopped, and the mixture was stirred for 1 hour. Filtration yielded a white solid, which was dried at 55°C for 12 hours to obtain 13.1 g of crude compound II with an HPLC purity of 93.82% and a yield of 87.3% by weight. The content of compound V was 3.49%.

[0046] Comparative Example 2: Step 1: Preparation of Compound II (The only difference from Example 1 is that dichloromethane is used as the solvent) Under nitrogen protection, 832 ml of dichloromethane and 20 g of compound I were added to a three-necked flask. 40 g of trimethyliodosilane was added slowly to the reaction flask over a constant-pressure dropping funnel at -40 to -35°C for 90-120 minutes. After addition, the temperature was controlled at -30 to -15°C, and the reaction was allowed to proceed for 2-4 hours. The reaction was monitored by TLC until the reactants were confirmed to be completely reacted. The reaction solution was then slowly poured into 600 ml of sodium thiosulfate aqueous solution, stirred for 30 minutes, allowed to stand for separation, and the aqueous phase was separated. The aqueous phase was extracted with 100 ml of dichloromethane. The organic phases were combined and concentrated under reduced pressure at 35-40°C to remove the dichloromethane. 200 ml of water was added, and the concentration was continued until no dichloromethane was removed. The concentration was stopped, and the mixture was stirred for 1 hour and filtered. A white solid was obtained and dried at 55°C for 12 hours to obtain 18.1 g of crude compound II (90.5% yield, HPLC purity 94.5%) and 2.82% compound V.

[0047] Comparative Example 3: Step 1: Preparation of Compound II (The only difference from Example 1 is that chloroform is used as the solvent) Under nitrogen protection, 832 ml of chloroform and 20 g of compound I were added to a three-necked flask. 40 g of trimethyliodosilane was added slowly to the reaction flask over a constant-pressure dropping funnel at -40 to -35°C for 90-120 minutes. After addition, the temperature was controlled at -30 to -15°C, and the reaction was allowed to proceed for 2-4 hours. TLC was used to confirm complete reaction of the reactants. The reaction solution was then slowly poured into 600 ml of sodium thiosulfate aqueous solution, stirred for 30 minutes, and allowed to stand to separate the layers. The aqueous phase was separated, and the aqueous phase was extracted with 100 ml of dichloromethane. The organic phases were combined, and the dichloromethane was concentrated under reduced pressure at 35-40°C. 200 ml of water was added, and the concentration was continued until no dichloromethane was removed. Concentration was stopped, and the mixture was stirred for 1 hour and filtered. A white solid was obtained, which was dried at 55°C for 12 hours to obtain 17.9 g of crude compound II with an HPLC purity of 93.0% and compound V with 5.78%.

[0048] Comparative Example 4: Step 1: Preparation of Compound II (The only difference from Example 1 is that isopropanol is used as the solvent) Under nitrogen protection, add 100 ml of isopropanol and 2.5 g of compound I to a three-necked flask. Place 5 g of trimethyliodosilane in a constant pressure dropping funnel and slowly add it to the reaction flask while maintaining the temperature at -40 to -35°C. Maintain the temperature at -30 to -15°C and react for 2 hours. Under TLC monitoring, there is still a large amount of reactant remaining. Extend the reaction time to 4 hours. Under TLC monitoring, there is no further progress in the reaction. Slowly pour the reaction solution into 60 ml of sodium thiosulfate aqueous solution, stir for 30 minutes, allow it to stand and separate the layers, remove the aqueous phase, extract the aqueous phase with 30 ml of dichloromethane, combine the organic phases, and concentrate under reduced pressure at 35–40°C to remove the dichloromethane. Add 30 ml of water and continue to concentrate until no dichloromethane is removed. Stop the concentration, stir for 1 hour, and filter. A yellow solid was obtained. The purity of compound I was 63.901%, compound II was 0.082%, compound IV was 19.203%, and compound V was 11.118%. A large amount of reactants remained, and there was basically no target product. The byproducts were quite obvious (purity of compound IV was 19.203%, and purity of compound V was 11.118%).

[0049] The experimental data for the crude compound II in step one of the above embodiments and comparative examples are listed in the table below:

[0050] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Therefore, any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention should fall within the protection scope of the present invention.

Claims

1. A method for preparing diflubenzuron, characterized in that, Includes the following steps: Under an inert protective atmosphere, flumethasone is reduced with a reducing agent in a solvent to obtain diflubenzuron; The reducing agent is trimethyliodosilane, or a combination of trimethylchlorosilane and sodium iodide; The solvent is a mixture of dichloromethane and isopropanol, a mixture of trichloromethane and isopropanol, or a mixture of dichloromethane, acetonitrile, and isopropanol; wherein, in the mixture of dichloromethane and isopropanol, the volume ratio of dichloromethane to isopropanol is (20~30):1, in the mixture of trichloromethane and isopropanol, the volume ratio of trichloromethane to isopropanol is (20~30):1, and in the mixture of dichloromethane, acetonitrile, and isopropanol, the volume ratio of the three components is (200~250):(12~18):(10~15).

2. The method for preparing bisfluorocorona according to claim 1, characterized in that, The molar ratio of flumethasone to reducing agent is 1:(1.2~5.5), and the mass-volume ratio of flumethasone to solvent is 1:(15~45) g / ml.

3. The method for preparing bisfluorocorona according to claim 1, characterized in that, The reducing agent is added dropwise to flumethasone and solvent, with the addition time controlled at 30~120 minutes and the temperature controlled at -50℃~-10℃.

4. The method for preparing bisfluorocorona according to claim 1, characterized in that, The reduction reaction is carried out at a temperature of -50 to 10°C.

5. The method for preparing bisfluorocorona according to claim 1, characterized in that, After the reaction is complete, the reaction solution is poured into an aqueous solution of sodium thiosulfate, stirred to separate the layers or extracted with ethyl acetate to separate the layers, the organic phase is concentrated with water, stirred and filtered to obtain crude diflubenzuron.

6. A method for preparing difluoroclonal valerate, characterized in that, The method for preparing diflucolide according to any one of claims 1 to 5 further includes the following steps: Difluorocolone is acylated with an acylation reagent in a solvent under an inert protective atmosphere in the presence of a base catalyst to obtain difluorocolone valerate.

7. The method for preparing difluoroclonal valerate according to claim 6, characterized in that, The acylation reagent is valeric anhydride or valeroyl chloride, and the molar ratio of diflucolide to the acylation reagent is 1:(1.1~3.5).

8. The method for preparing difluoroclonal valerate according to claim 6, characterized in that, The alkaline catalyst is one or more of sodium bicarbonate, sodium carbonate, and potassium carbonate, and the molar ratio of diflucolide to the alkaline catalyst is 1:(2.5~5.5).

9. The method for preparing difluoroclonal valerate according to claim 6, characterized in that, The solvent is acetone, and the mass ratio of diflucozone to the solvent is 1:5.0~15.

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