Preparation method of fenticonazole or nitrate thereof

Abstract

The invention relates to a preparation method of fenticonazole or nitrate thereof, and belongs to the technical field of medicine synthesis. In order to solve the problems of difficulty in impurity control and low yield in the existing route, the invention provides the preparation method of fenticonazole or nitrate thereof, the method comprises the following steps: under the action of alkali, reacting a compound in a formula II with a hydroxyl protective agent to obtain a compound in a formula III; in the presence of a condensing agent and an auxiliary catalyst, carrying out imidazole substitution reaction on the compound shown in the formula III and imidazole in an organic solvent to obtain a compound shown in a formula IV; carrying out substitution reaction on the compound in the formula IV and a compound in a formula V to obtain a product fenticonazole; when fenticonazole nitrate is synthesized, fenticonazole reacts with nitric acid to obtain the fenticonazole nitrate. The method can effectively avoid the generation of epoxy compound isomer impurities, reduces the generation of isomers, improves the yield and quality of the intermediate product and the final product, the yield reaches 90% or above, and the purity reaches 97% or above.

Description

Technical Field

[0001] The invention relates to a preparation method of fenticonazole or its nitrate, belonging to the technical field of drug synthesis. Background Art

[0002] Fenticonazole nitrate (C 24 H21Cl 2 N 2 OS·HNO 3 , also known as fenticonazole nitrate) is a broad-spectrum antifungal drug, mainly used to treat infections caused by a variety of fungi. It has been marketed in many countries and regions and is used to treat dermatophytes, tinea corporis and other infections caused by dermatophytes, yeasts and other fungi. Its research and development and application have been widely recognized. The mechanism of action of the drug is to exert its antibacterial effect by interfering with the synthesis of fungal cell walls, especially inhibiting the biosynthesis of ergosterol, the main component of fungal cell walls, thereby destroying the fungal cell structure and achieving the purpose of killing or inhibiting fungi.

[0003] At present, fenticonazole nitrate has a wide range of uses in the pharmaceutical field. The current overall route is basically similar, using different starting materials to synthesize intermediates 4-phenylthiobenzyl chloride and intermediate 1-(2,4-dichlorophenyl)-2-imidazoleethanol in multiple steps, and then condensing under different conditions to obtain fenticonazole, and finally using nitric acid to form salts. There are many patents reporting the synthesis of fenticonazole nitrate at home and abroad, such as the Chinese patent application (publication number: CN107652238A) mainly involving the following synthetic routes:

[0004] Method 1: Diphenyl sulfide and formaldehyde are used as raw materials to react under HCl conditions to generate 4-phenylmercaptobenzyl chloride; m-dichlorobenzene and chloroacetyl chloride are condensed to obtain 2-chloro-1-(2,4-dichlorophenyl)ethanone, which is then reduced with sodium borohydride and condensed with imidazole to obtain the intermediate 1-(2,4-dichlorophenyl)-2-imidazoleethanol, and then the above-obtained 4-phenylmercaptobenzyl chloride and 1-(2,4-dichlorophenyl)-2-imidazoleethanol are reacted under anhydrous and oxygen-free conditions with sodium hydride as a condensation agent in hexamethylphosphoric triamide or dimethyl sulfoxide to obtain fenticonazole. The synthetic route of this method is as follows:

[0005]

[0006] This route uses sodium borohydride as a reducing agent in the preparation of the intermediate 1-(2,4-dichlorophenyl)-2-imidazoleethanol. The reaction conditions are relatively harsh, the reagents are expensive, the cost is high, and it is difficult to control.

[0007] Another method is to use benzenesulfonyl chloride as a raw material, reduce it with zinc powder to obtain thiophenol, then condense thiophenol with p-chlorobenzoic acid under the action of cuprous oxide to obtain 4-phenylmercaptobenzoic acid, then reduce it with sodium borohydride to obtain 4-phenylmercaptobenzyl alcohol, and chlorinate it with hydrochloric acid to obtain 4-phenylmercaptobenzyl chloride; use 2-chloro-1-(2,4-dichlorophenyl)ethanone as a raw material, reduce it with sodium borohydride, and condense it with imidazole to obtain 1-(2,4-dichlorophenyl)-2-imidazoleethanol; then, under anhydrous and oxygen-free conditions, use sodium hydride as a condensing agent, and react 4-phenylmercaptobenzyl chloride and 1-(2,4-dichlorophenyl)-2-imidazoleethanol in dimethyl sulfoxide to obtain fenticonazole. The synthetic route is as follows:

[0008]

[0009] Similarly, the above method uses relatively expensive sodium borohydride in the preparation of 2-chloro-1-(2,4-dichlorophenyl) ethanol, and the reagent cost is high, and the post-processing process is cumbersome. Meanwhile, the method reported in the above two existing documents has experienced the preparation of intermediate 1-(2,4-dichlorophenyl)-2-imidazole ethanol, and the imidazole ethanol obtained by the two methods is all generated by the reaction of 2-chloro-1-(2,4-dichlorophenyl) ethanol and imidazoles under alkaline conditions. Due to the internal molecular potential energy effect of 2-chloro-1-(2,4-dichlorophenyl) ethanol, it is very easy to cause hydroxyl nucleophilic substitution of adjacent chlorine in the presence of alkali, lose a molecule of hydrogen chloride, and obtain intramolecular epoxy compound. The epoxy compound can carry out ring-opening reaction with imidazoles, and then obtain two kinds of compounds, one is the main product 1-(2,4-dichlorophenyl)-2-imidazole ethanol, and the other is the isomer 1-(2,4-dichlorophenyl)-1-imidazole ethanol, and its reaction mechanism is as follows:

[0010]

[0011] In the study, we found that whether screening the reaction solvent, or using organic base or inorganic base, isomers are generated in the above reaction, and in most reaction systems, 10% of the content can be generated. However, due to the similar polarity of the isomer and the main product, it is difficult to purify the target product in post-processing, and the use of the highly polar solvent DMSO will result in a loss in yield; at the same time, the presence of the isomer will also react with 4-phenylthiobenzyl chloride in the last step to obtain another isomer corresponding to the target compound, which increases the difficulty of subsequent purification and also causes a decrease in the yield of the product. Therefore, this isomer will not only reduce the product yield of the reaction, but also have a greater impact on the post-processing of the reaction and the subsequent reaction. Summary of the invention

[0012] The present invention aims at the defects existing in the above prior art and provides a method for preparing fenticonazole or its nitrate, which solves the problem of how to reduce the generation of impurities and improve the yield and purity quality of the final product.

[0013] The object of the present invention is to achieve a method for preparing fenticonazole or its nitrate by the following technical scheme, the method comprising the following steps:

[0014] A. reacting the compound of formula II with a hydroxyl protecting agent under the action of a base to obtain a compound of formula III;

[0015]

[0016] Wherein, in the compound of formula III, R is selected from acyl, alkyl or trimethylsilyl;

[0017] B. In the presence of a condensing agent and an auxiliary catalyst, the compound of formula III is subjected to an imidazole substitution reaction with imidazole in an organic solvent to obtain a compound of formula IV;

[0018]

[0019] C. Substituting the compound of formula IV with the compound of formula V to obtain the product compound of formula VI, fenticonazole;

[0020] When synthesizing fenticonazole nitrate, the obtained compound of formula VI, fenticonazole, is reacted with nitric acid to obtain the compound of formula VI, fenticonazole nitrate;

[0021]

[0022] The present invention first reacts the hydroxyl group of the compound of formula II, 2-chloro-l-(2,4-dichlorophenyl)ethanol, with a hydroxyl protecting agent in the presence of a base, which is equivalent to converting the hydroxyl group of the compound of formula II into an OR group, and then undergoes an imidazole substitution reaction with subsequent imidazole. In this way, by converting the -OH group into an -OR group, the exposed hydroxyl group in the compound of formula II is prevented from undergoing an intramolecular cyclization reaction under the action of a base, thereby effectively avoiding the generation of the following epoxy compound impurity isomer impurities:

[0023]

[0024] The generation of isomer impurities of 1-(2,4-dichlorophenyl)-1-imidazoleethanol in subsequent reactions is further effectively avoided, the generation of isomers is reduced, and the yield quality of intermediate products and final products is improved. The single-step yield in step A reaches more than 97%, and the purity reaches more than 99%. At the same time, since the intermediate compound of formula III after the hydroxyl group is protected in the subsequent reaction process also has the characteristic of being easy to remove in the reaction of step B, the advantage of being able to achieve the deprotection of the protected R group in one step in the process of reacting with imidazole, without the need for additional deprotection treatment, is also conducive to improving the operability of the reaction, and also has the advantage of high yield of the intermediate product, the single-step yield of step B can also reach more than 92%, and the purity reaches more than 96%; and then the reaction of step C can effectively avoid the influence of the yield and purity quality of the final product due to the introduction of isomer impurities in the previous step, and has high yield and high purity quality, the yield reaches more than 92%, and the purity reaches more than 99%. When fenticonazole nitrate (fenticonazole nitrate) needs to be prepared, the fenticonazole obtained in step C can be directly further reacted with nitric acid to obtain fenticonazole nitrate, which has the advantages of high overall yield and good product purity quality.

[0025] In the above-mentioned preparation method of fenticonazole or its nitrate, the hydroxyl protecting agent can be selected according to the introduced group, such as acyl chloride, benzoyl chloride, etc., that is, the corresponding acyl group can be acetyl, formyl, propionyl, benzoyl, etc., and for the alkyl group, it can be a protecting agent introduced by MOM (methoxymethyl), THP group, or a silane protecting group, etc. Preferably, the hydroxyl protecting agent in step A is selected from acetic anhydride, acetyl chloride, benzoyl chloride or trimethylsilyl chloride. The OR group protected by acyl, trimethylsilyl, etc. is obtained by the above-mentioned hydroxyl protecting agent. In the reaction process with imidazole in the later step, it is easier to remove the protecting group here, better achieve the effect of one-step reaction, and the reaction efficiency is high; at the same time, the use of the above-mentioned hydroxyl protecting agent has the advantages of low cost and simple post-processing. In addition, the amount of each raw material used in the reaction process can be reacted according to the molar equivalent of the raw material in the chemical reaction. As a better preference, the molar ratio of the compound of formula II to the hydroxyl protecting agent in step A is 1:1.05-1.3. As a further preference, the molar ratio of the compound of formula II to the hydroxyl protecting agent is preferably 1:1.05-1.2.

[0026] In the above-mentioned method for preparing fenticonazole or its nitrate, the addition of a base to the reaction in step A is intended to activate the hydroxyl groups in the raw materials, increase the reaction rate, and promote the reaction to proceed more effectively in the positive direction. Preferably, the base in step A is selected from an organic base; the organic base is selected from one or more of piperidine, pyridine, pyrrole, triethylamine, diethylamine, 4-dimethylaminopyridine and DBU. As a further preference, the organic base in step A is selected from 4-dimethylaminopyridine, triethylamine, etc. In order to better control the amount and cost of the raw materials, it is best to make the molar ratio of the compound of formula II to the base in step A be 1:0.05-1.5. More specifically, when the protective agent adopts an acyl group, it is best to make the molar ratio of the compound of formula II to the base be 1:0.05-0.2. When the hydroxyl protective agent adopts trimethylsilyl (TMS), it is best to use triethylamine as the base, and the molar ratio of the compound of formula II to the base is 1:1.1-1.3.

[0027] In the above-mentioned method for preparing fenticonazole or its nitrate, preferably, the reaction temperature in step A is 0°C to 30°C. The reaction conditions are mild, the reaction can be carried out better, and it is also more conducive to ensuring the yield and purity of the intermediate product. It is best to control the temperature at 10°C to 20°C. The reaction time can also be controlled according to the needs of the reaction, and it is best to control the reaction time at 4 to 10 hours.

[0028] In the above-mentioned method for preparing fenticonazole or its nitrate, the reaction in step A is carried out in an organic solvent, which can be an ether solvent, an aromatic solvent, a halogenated alkane solvent, and a nitrile solvent. The above-mentioned solvents can make the reaction proceed effectively and the reaction is mild. For the above-mentioned ether solvents, alkyl ethers, furans and other ether solvents; aromatic solvents can be solvents such as toluene; halogenated alkanes can be chlorinated, brominated, etc.; nitrile solvents can be acetonitrile, propionitrile, etc. As a preference, the reaction in step A is carried out in an ether solvent or a halogenated alkane solvent, the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ether and ethylene glycol dimethyl ether; the halogenated alkane is selected from one or more of dichloromethane, chloroform and dichloroethane. It is more conducive to the mild and effective reaction and also conducive to operation. The amount of organic solvent used in this step can be adjusted as needed. It is best to make the amount of the organic solvent 5 to 10 of the mass of the raw material compound of formula I.

[0029] In the above-mentioned method for preparing fenticonazole or its nitrate, as a preference, the condensing agent in step B is selected from an inorganic base; the auxiliary catalyst is selected from one or more of sodium iodide, potassium iodide, DMAP and tetra-n-butylammonium bromide. By using an inorganic base as the condensing agent and cooperating with an auxiliary catalyst, the purpose of activating the reaction can be achieved, the reaction is better accelerated, and it is also beneficial to the reaction and the utilization rate of atoms. The amount of the condensing agent and the auxiliary catalyst may be added in a catalytic amount. In order to better control the amount of each raw material and catalyst, as a further preference, it is best to make the molar ratio of the compound of formula III described in step C: imidazole: condensing agent: auxiliary catalyst be 1: 1.2-3.0: 1.1-3.0: 0.01-0.05. As a further preference, the inorganic base is selected from one or more of alkali metal hydroxides, sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide and potassium carbonate.

[0030] In the above-mentioned preparation method of fenticonazole or its nitrate, the substitution reaction in step B is reacted in an organic solvent, which is conducive to the mild reaction. The amount of the solvent can be based on the general amount of the synthetic reaction in the chemical field. Preferably, the organic solvent in step B is selected from ether solvents, amide solvents or sulfoxide solvents, and the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ether and ethylene glycol dimethyl ether; the amide solvent is selected from one or more of dimethylformamide, dimethylacetamide, N-methylpyrrolidone and dimethylpropionamide; the sulfoxide solvent is such as dimethyl sulfoxide, dithionyl chloride, etc. Not only can the reaction be carried out mildly, but it is also conducive to better control of solvent costs and better realization of industrial production. For the amount of organic solvent, it is best to make the amount of the organic solvent 3 to 10 times the mass of the intermediate compound of formula III.

[0031] In the above-mentioned method for preparing fenticonazole or its nitrate, preferably, step B is specifically:

[0032] First, the condensing agent and imidazole are reacted and the temperature is controlled at 0°C to 20°C to form the corresponding imidazole salt, and then the intermediate compound of formula III and the co-catalyst are added and the temperature is controlled at 45°C to 75°C to perform the imidazole substitution reaction to generate the compound of formula IV. The reaction can be better realized and is easy to operate. It is equivalent to the reaction in step B being carried out in two stages, the first stage is the reaction of the inorganic base and imidazole to form the corresponding imidazole salt, and the intermediate compound of formula III and the corresponding co-catalyst added in the second stage are further reacted to obtain the intermediate product of this step. Therefore, as a further preference, for step B, the condensing agent and imidazole can be specifically added to the organic solvent to react to generate the corresponding imidazole salt, such as sodium imidazole and other salts; then the intermediate compound of formula III and the corresponding co-catalyst are added to the reaction solution to perform the substitution reaction to obtain the intermediate compound of formula IV. Further, it is best to control the reaction temperature of the first stage at 0°C to 20°C, and the reaction time at 0.5 to 2h; the reaction temperature of the second stage is controlled at 45°C to 75°C, which can better ensure the reaction.

[0033] After the substitution reaction in step B is completed, a post-treatment may be further included, wherein the post-treatment is specifically:

[0034] After the reaction is completed, the reaction solution is cooled to 10°C-20°C for low-temperature quenching, and the pH value is adjusted to 7-8. The mixture is allowed to stand for stratification, the organic phase is collected, concentrated, and the residue is recrystallized to obtain the corresponding intermediate product.

[0035] In the above-mentioned method for preparing fenticonazole or its nitrate, preferably, the compound of formula II in step A is synthesized by the following method:

[0036] Under an aluminum isopropoxide and isopropanol reduction system, reducing the compound of formula I to a compound of formula II;

[0037]

[0038] By adopting aluminum isopropoxide and isopropanol system for reduction, compared with the sodium borohydride system, the aluminum isopropoxide used in the present invention has milder reaction activity and higher safety, and is more conducive to improving the yield and purity quality of the intermediate product in this step.

[0039] In the above-mentioned method for preparing fenticonazole or its nitrate, preferably, the compound of formula V in step C is synthesized by the following method:

[0040] Compound VII, 4-phenylmercaptobenzyl alcohol, and SOCl 2 Reaction is performed to form an intermediate compound of formula V;

[0041]

[0042] In the above-mentioned method for preparing fenticonazole or its nitrate, the obtained fenticonazole can be further reacted with nitric acid to obtain fenticonazole nitrate.

[0043] In the above-mentioned method for preparing fenticonazole or its nitrate, the reaction in step C can be specifically synthesized by the route of the corresponding step reported in the existing literature. In order to better apply the synthesis route of the present invention, as a further preference, it is best to make step C specifically synthesized by the following method:

[0044] Under the combined action of an alkali metal hydroxide and an ammonium salt, the compound of formula IV and the compound of formula V are subjected to a substitution reaction in a halogenated alkane solvent to obtain the product compound of formula VI, fenticonazole; the reaction temperature is preferably 25°C to 30°C. This allows the reaction to proceed more efficiently. As a further preferred step, it is best to further include post-treatment after the reaction is completed, and the post-treatment is specifically as follows:

[0045] After the reaction is completed, water is added to the reaction solution for stirring, and the mixture is allowed to stand for stratification. The organic phase is collected and washed, and the obtained organic phase is distilled to remove the solvent. The obtained residue is recrystallized to obtain the corresponding refined product. The above-mentioned halogenated alkane can be a solvent such as dichloromethane and chloroform; the alkali metal hydroxide can be sodium hydroxide, potassium hydroxide or potassium hydroxide; the ammonium salt can be tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, etc.

[0046] When fenticonazole needs to be further prepared into the corresponding fenticonazole nitrate (or fenticonazole nitrate), after the reaction in step C is completed, fenticonazole is reacted with nitric acid to obtain the corresponding fenticonazole nitrate. The salt-forming reaction can directly adopt the salt-forming synthesis method reported in the existing literature.

[0047] The chemical reaction equation of the preparation method of fenticonazole or its nitrate of the present invention is as follows:

[0048]

[0049] In summary, compared with the prior art, the present invention has the following advantages:

[0050] 1. The hydroxyl group of the compound of formula II, 2-chloro-l-(2,4-dichlorophenyl)ethanol, is first reacted with a hydroxyl protecting agent to convert the hydroxyl group into an OR group, and then the imidazole is substituted with imidazole to avoid the intramolecular cyclization reaction of the exposed hydroxyl group in the compound of formula II under the action of a base, thereby effectively avoiding the generation of the following epoxy compound impurities, thereby reducing the generation of isomers, and improving the yield quality of the intermediate product and the final product, the yield reaches more than 90%, and the purity reaches more than 97%.

[0051] 2. The reaction of the present invention not only realizes the effective replacement of chlorine by imidazole, but also, due to the characteristic that the hydroxyl protection is easy to be removed in the subsequent substitution reaction with imidazole of the present invention, the reaction also obtains the intermediate compound with the protective agent removed in one step, without the need for the next step of deprotection reaction, which is also beneficial to improving the operability of the reaction and has the advantage of high yield of the intermediate product. Then, the reaction of step C can effectively avoid the influence of the yield and purity quality of the final product due to the introduction of isomer impurities in the previous step, and has the effect of high yield and high purity quality.

[0052] 3. Use aluminum isopropoxide instead of sodium borohydride. Aluminum isopropoxide has milder reaction activity, better safety, and lower price. It also has higher reaction yield and simpler post-processing. DETAILED DESCRIPTION

[0053] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.

[0054] Example 1

[0055] Synthesis of Formula II Compound 2-Chloro-l-(2,4-dichlorophenyl)ethanol

[0056]

[0057] Weigh 4.2g (0.02mol) of aluminum isopropoxide and 60g of isopropanol into a clean three-necked flask, replace it with nitrogen three times, then heat it to 30°C, weigh 30g (0.14mol) of 2-chloro-l-(2,4-dichlorophenyl)ethanone, and control the internal temperature not to be higher than 30°C, add 2-chloro-l-(2,4-dichlorophenyl)ethanone to the reaction flask in batches, after the addition is completed, heat it to 60°C and control the temperature to react for 7h, HPLC detection reaction is complete, after the reaction is completed, cool to room temperature, concentrate under reduced pressure to dry the solvent, and then weigh 2.0g of concentrated hydrochloric acid to dissolve. The mixture was dissolved in 100 g of water and added to the reaction solution. The mixture was heated to 60 ° C and stirred for 1 h. After the mixture was cooled to room temperature, 50 g of dichloromethane was added to the reaction solution and stirred for 20 min. The mixture was allowed to stand for stratification and the organic phase was collected. The organic phase was distilled under reduced pressure to remove the solvent to obtain a light yellow liquid. 60 g of n-heptane was added to the remaining light yellow liquid. The mixture was heated to 50 ° C and then slowly cooled to -10 ° C for crystallization for 3 h. The solid was fully precipitated. The filter cake was collected by filtration and dried to obtain 30 g of a solid product with an HPLC purity of 99.1% and a yield of 99.1%.

[0058] Example 2

[0059] Synthesis of Formula III Compound 2-Chloro-l-(2,4-dichlorophenyl)acetate

[0060]

[0061] When R in the compound of formula III is acetyl.

[0062] 18 g (0.08 mol) of the compound of formula II 2-chloro-l-(2,4-dichlorophenyl)ethanol, 100 g of dichloromethane and 11.22 g (0.11 mol) of acetic anhydride were added to a clean reaction bottle, the internal temperature was controlled at 20°C-30°C, 0.98 g (0.008 mol) of 4-dimethylaminopyridine was added under stirring, after the addition, the temperature was controlled to react under stirring at room temperature for 5 hours, HPLC sampling was used to detect the completion of the reaction, after the reaction was completed, the organic phase was distilled and dried, and 30 g of methyl tert-butyl ether was added to the residue, and washed with a saturated sodium bicarbonate aqueous solution with a mass fraction of 8% to a pH of 7-8, and then washed with 15 g of water, allowed to stand for stratification, and the organic phase was collected, and the collected organic phase was distilled and dried to remove the solvent to obtain 21 g of a light yellow liquid with an HPLC purity of 99.3% and a yield of 98.3%.

[0063] Example 3

[0064] Synthesis of the compound of formula III [2-chloro-1-(2,4-dichlorophenyl)ethoxy]-trimethylsilane

[0065]

[0066] That is, when R in the compound of formula III is trimethylsilyl.

[0067] Add 5g (0.022mol) of the compound of formula II, 50g of tetrahydrofuran and 4.45g (0.044mol) of triethylamine to a clean reaction bottle, then slowly drop 4.78g (0.044mol) of trimethylsilyl chloride, and control the internal temperature of the reaction at 20-30°C. After the addition, control the temperature and stir the reaction at room temperature for 5h. HPLC (neutral system) sampling is used to detect that the reaction is complete. Filter the reaction liquid, add n-heptane (40g) to wash the filter cake, concentrate the filtrate, add n-heptane (40g) to the residue, stir for 0.5h, filter the reaction liquid, concentrate the filtrate, and obtain 6.4g of colorless liquid by column chromatography, with HPLC purity of 99.7% and yield of 97.0%.

[0068] Example 4

[0069] Synthesis of the intermediate compound of formula IV 1-(2,4-dichlorophenyl)-2-imidazoleethanol

[0070]

[0071] Add 39.3 g (0.58 mol) of imidazole and 195 g of dimethylformamide to a clean three-necked flask, replace with nitrogen three times, stir to dissolve, and control the internal temperature at 0-5 °C. Then add 23.2 g (0.58 mol) of sodium hydroxide to the reaction flask in batches. After the addition is completed, continue to stir for 30 minutes while controlling the internal temperature not to exceed 20 °C. Then add 1 g (0.006 mol) of potassium iodide to the reaction flask, and then drop 50 g of 2-chloro-l-(2,4-dichlorophenyl) acetate. g (0.19 mol), after the addition, the temperature was raised to reflux and stirred for reaction for 6 hours. HPLC sampling was used to detect whether the reaction was complete. After the reaction was completed, it began to cool to below 30°C, and 1M hydrochloric acid was used to adjust the pH of the system to 7-8. Then 150 g of water was added to the reaction to precipitate solids, and then the temperature was slowly lowered to -10°C and kept warm for 3 hours to fully precipitate solids. The filter cake was collected by filtration, and the filter cake was washed with 50 g of water and dried to obtain 45.2 g of solid product with HPLC purity of 96.4% and a yield of 92.9%.

[0072] Example 5

[0073] Synthesis of the intermediate compound of formula IV 1-(2,4-dichlorophenyl)-2-imidazoleethanol

[0074]

[0075] Add 39.3 g (0.58 mol) of imidazole and 195 g of tetrahydrofuran (THF) to a clean three-necked flask, replace with nitrogen three times, stir to dissolve, and control the internal temperature to 0-5 ° C. Then add 23.2 g (0.58 mol) of sodium hydroxide to the reaction flask in batches. After the addition is completed, continue to stir for 30 minutes while controlling the internal temperature not to exceed 20 ° C. Then add 1 g (0.006 mol) of potassium iodide to the reaction flask, and then drop [2-chloro-1-(2,4-dichlorophenyl)ethoxy]-trimethylsilane 56.2g (0.19mol), after the addition, the temperature was raised to reflux and stirred for reaction for 6h. HPLC sampling was used to detect the completion of the reaction. After the reaction was completed, it was cooled to control the internal temperature not to exceed 30°C, and the pH of the system was adjusted to 7-8 with 1M hydrochloric acid. Then 150g of water was added to the reaction to precipitate solids, and then the temperature was slowly lowered to -10°C and kept warm for 3h to fully precipitate solids. The filter cake was collected by filtration, and the filter cake was washed with 50g of water and dried to obtain 44.4g of solid product with HPLC purity of 97.4% and a yield of 91.4%.

[0076] Example 6

[0077] Synthesis of the intermediate compound of formula V 4-phenylmercaptobenzyl chloride

[0078]

[0079] Weigh 30g (0.14mol) of 4-phenylmercaptophenethanol and 90g of dichloromethane and add them to a three-necked flask, replace with nitrogen three times, control the internal temperature at 0-5°C, add 18.2g (0.23mol) of thionyl chloride dropwise to the reaction flask, control the temperature at about 0°C and stir to react for 5h, HPLC sampling and detection reaction is complete, after the reaction is completed, weigh 40g of water, add it dropwise to the reaction solution to quench the reaction, let stand for stratification, collect the organic phase, wash the organic phase with 50g of 5% sodium bicarbonate aqueous solution and saturated brine by mass percentage, respectively, and then distill the collected organic phase under reduced pressure to dry the solvent to obtain 31g of light yellow liquid with HPLC purity of 99.3% and a yield of 95.3%.

[0080] Example 7

[0081] Synthesis of the target product formula VI compound fenticonazole or its nitrate

[0082]

[0083] Take 6g (0.023) of the above-obtained 1-(2,4-dichlorophenyl)-2-imidazoleethanol and 30g of toluene and add them to a three-necked flask, add a sodium hydroxide aqueous solution (weigh 3g (0.075mol) of sodium hydroxide and dissolve it in 3g of water), then add 1g (0.003mol) of tetra-n-butylammonium bromide and 5g (0.021mol) of the intermediate 4-phenylmercaptobenzyl chloride obtained by the method of Example 6 to the reaction flask, control the temperature of the reaction system at 25°C to 30°C for stirring reaction During the reaction, HPLC sampling was used to detect that the reaction was complete. After the reaction was completed, 20 g of water was added to the reaction, stirred for 10 min, and allowed to stand for stratification. The organic phase was collected and washed once with 20 g of saturated brine and then washed twice with 20 g of water. The collected organic phase was subjected to reduced pressure distillation and spin-dried to remove the solvent to obtain a light yellow liquid; 15 g of toluene and 15 g of ethyl acetate were weighed and added to dissolve the light yellow liquid fenticonazole obtained above. If fenticonazole is directly prepared, it can be further recrystallized to obtain solid fenticonazole.

[0084] If fenticonazole nitrate is to be further prepared, a 20% nitric acid EA solution can be directly added dropwise to the above-mentioned light yellow liquid fenticonazole, the pH is adjusted to 1-2, 30 g of water is added for washing once, the organic solvent is removed by vacuum distillation and spin-drying, 30 g of methyl tert-butyl ether is added to the residue, stirred, solid is fully precipitated, and yellow solid fenticonazole nitrate is obtained by filtration; further recrystallization is performed with 20 g of ethanol and 10 g of water, the temperature is raised to 60° C., the temperature is slowly lowered to 25° C., stirred to fully precipitate solid, kept warm for 3 h, and 8.8 g of light yellow solid is obtained by filtration, with HPLC purity of 99.4% and a yield of 92.6%.

[0085] Example 8

[0086] Synthesis of Formula III Compound 2-Chloro-l-(2,4-dichlorophenyl)acetate

[0087]

[0088] When R in the compound of formula III is acetyl.

[0089] 18 g (0.08 mol) of the compound of formula II 2-chloro-l-(2,4-dichlorophenyl)ethanol, 100 g of dichloromethane and 8.64 g (0.11 mol) of acetyl chloride were added to a clean reaction bottle, the internal temperature was controlled at 20°C-25°C, 0.98 g (0.008 mol) of 4-dimethylaminopyridine was added under stirring, after the addition, the temperature was controlled to react under stirring at room temperature for 5 hours, HPLC sampling was used to detect the completion of the reaction, after the reaction was completed, the organic phase was distilled and dried, and 30 g of methyl tert-butyl ether was added to the residue, and washed with a saturated sodium bicarbonate aqueous solution with a mass fraction of 8% to a pH of 7-8, and then washed with 15 g of water, allowed to stand for stratification, and the organic phase was collected, and the collected organic phase was distilled and dried to remove the solvent to obtain 20.8 g of a light yellow liquid with an HPLC purity of 99.4% and a yield of 97.4%.

[0090] Example 9

[0091] Synthesis of the intermediate compound of formula IV 1-(2,4-dichlorophenyl)-2-imidazoleethanol In a clean three-necked flask, add 25.8 g (0.38 mol) of imidazole and 200 g of 1,4-dioxane, replace with nitrogen three times, stir to dissolve, control the internal temperature at 0-5°C, add 96 g (0.6 mol) of a 25% by mass sodium hydroxide aqueous solution to the reaction flask in batches, and continue to stir for 60 min while controlling the internal temperature not to exceed 15°C, then add 0.6 g (0.004 mol) of sodium iodide to the reaction flask, and then dropwise add Example 8 to obtain The intermediate product 2-chloro-l-(2,4-dichlorophenyl) acetate 50g (0.19mol) was added, and the temperature was raised to reflux with stirring for 6h. HPLC sampling was used to detect the completion of the reaction. After the reaction was completed, it began to cool to below 30°C, and the pH of the system was adjusted to 7-8 with 1M hydrochloric acid. Then 150g of water was added to the reaction to precipitate a solid, and then the temperature was slowly lowered to -10°C and kept warm for 3h to fully precipitate the solid. The filter cake was collected by filtration, and the filter cake was washed with 50g of water and dried to obtain 45.6g of a solid product with an HPLC purity of 97.2% and a yield of 93.8%.

[0092] Example 10

[0093] Synthesis of the target product formula VI compound fenticonazole or its nitrate

[0094] Take 6 g (0.023) of 1-(2,4-dichlorophenyl)-2-imidazoleethanol obtained in Example 9 and 30 g of toluene, add potassium hydroxide aqueous solution (4.5 g (0.08 mol) of potassium hydroxide is weighed and dissolved in 3 g of water), and then add 1 g (0.003 mol) of tetra-n-butylammonium bromide and 6.1 g (0.026 mol) of the intermediate 4-phenylmercaptobenzyl chloride obtained by the method of Example 6 to the reaction flask, and control the temperature of the reaction system at 25°C to 30°C. The reaction was stirred, and HPLC sampling was used to detect that the reaction was complete during the reaction. After the reaction was completed, 20 g of water was added to the reaction, stirred for 10 minutes, and allowed to stand for stratification. The organic phase was collected, washed once with 20 g of saturated brine, and then washed twice with 20 g of water. The collected organic phase was subjected to reduced pressure distillation and spin-dried to remove the solvent to obtain a light yellow liquid; 15 g of toluene and 15 g of ethyl acetate were weighed and added to dissolve the light yellow liquid obtained above; if fenticonazole is directly prepared, it can be further recrystallized to obtain solid fenticonazole.

[0095] If fenticonazole nitrate is to be further prepared, a 20% by mass nitric acid EA solution can be directly added to the above-mentioned light yellow liquid fenticonazole, the pH is adjusted to 1-2, 30 g of water is added for washing once, the organic solvent is removed by vacuum distillation and spin-drying, 30 g of methyl tert-butyl ether is added to the residue, stirred, solid is fully precipitated, and yellow solid fenticonazole nitrate is obtained by filtration; further recrystallization is performed with 20 g of ethanol and 10 g of water, the temperature is raised to 60° C., the temperature is slowly lowered to 25° C., stirred to fully precipitate solid, kept warm for 3 h, and 9.1 g of light yellow solid is obtained by filtration, with HPLC purity of 99.6% and a yield of 95.7%.

[0096] Embodiment 11

[0097] Synthesis of 2-chloro-l-(2,4-dichlorophenyl)acetate of Formula III (when R in Formula III is acetyl)

[0098] Add 18g (0.08mol) of the compound of formula II 2-chloro-l-(2,4-dichlorophenyl)ethanol, 110g of 2-methyltetrahydrofuran and 11.22g (0.11mol) of acetic anhydride into a clean reaction bottle, control the internal temperature at 25°C-30°C, add 0.98g (0.008mol) of 4-dimethylaminopyridine under stirring, and after the addition, control the temperature to react at room temperature for 5h with stirring. Take HPLC samples to detect whether the reaction is complete. After the reaction is completed, distill and spin-dry the organic phase, add 30g of methyl tert-butyl ether to the residue, and wash with 8% saturated sodium bicarbonate aqueous solution to pH 7-8, then wash with 15g of water, let stand for stratification, collect the organic phase, distill and spin-dry the collected organic phase to remove the solvent, and obtain 20.9g of light yellow liquid with HPLC purity of 99.2% and yield of 97.9%.

[0099] Example 12

[0100] Synthesis of the intermediate compound of formula IV 1-(2,4-dichlorophenyl)-2-imidazoleethanol

[0101] Add 39.3 g (0.58 mol) of imidazole and 200 g of dimethyl sulfoxide to a clean three-necked flask, replace the atmosphere with nitrogen three times, stir to dissolve, and control the internal temperature at 0-5 °C. Then, add 23.2 g (0.58 mol) of sodium hydride with a mass fraction of 60% to the reaction flask in batches. After the addition is completed, continue to stir for 30 min while controlling the internal temperature not to exceed 20 °C. Then, add 1 g (0.008 mol) of 4-dimethylaminopyridine (DMAP) to the reaction flask, and then drop 2-chloro-l-(2,4-dichlorobenzene) After the addition, the temperature was raised to reflux with stirring for 5 hours. The reaction was completed by HPLC sampling. After the reaction was completed, the temperature of the reaction system was controlled below 30°C, and the pH of the system was adjusted to 7-8 with 1M hydrochloric acid. Then 150g of water was added to the reaction to precipitate a solid. The temperature was slowly lowered to -10°C and kept warm for 3 hours to fully precipitate the solid. The filter cake was collected by filtration, and the filter cake was washed with 50g of water and dried to obtain 5.5g of a solid product with an HPLC purity of 96.9% and a yield of 93.4%.

[0102] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.

[0103] Although the present invention has been described in detail and some specific embodiments have been cited, it is obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

1. A method for preparing fenticonazole or its nitrate, It is characterized in that The method comprises the following steps: A. reacting the compound of formula II with a hydroxyl protecting agent under the action of a base to obtain a compound of formula III; Wherein, in the compound of formula III, R is selected from acyl, alkyl or trimethylsilyl; B. In the presence of a condensing agent and a co-catalyst, the compound of formula III is subjected to an imidazole substitution reaction with imidazole in an organic solvent to obtain a compound of formula IV; C. Substituting the compound of formula IV with the compound of formula V to obtain the product compound of formula VI, fenticonazole; When synthesizing fenticonazole nitrate, the obtained compound of formula VI, fenticonazole, is reacted with nitric acid to obtain the compound of formula VI, fenticonazole nitrate; 2. The method for preparing fenticonazole or its nitrate according to claim 1, It is characterized in that The hydroxyl protecting agent in step A is selected from acetic anhydride, acetyl chloride, benzoyl chloride or trimethylsilyl chloride.

3. The method for preparing fenticonazole or its nitrate according to claim 1, It is characterized in that The base in step A is selected from an organic base; the organic base is selected from one or more of piperidine, pyridine, pyrrole, triethylamine, diethylamine, 4-dimethylaminopyridine and DBU.

4. The method for preparing fenticonazole or its nitrate according to claim 1, 2 or 3, It is characterized in that The reaction temperature in step A is 0°C to 30°C.

5. The method for preparing fenticonazole or its nitrate according to claim 1, 2 or 3, It is characterized in that The reaction in step A is carried out in an ether solvent or a halogenated alkane solvent, wherein the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diethyl ether and ethylene glycol dimethyl ether; and the halogenated alkane is selected from one or more of dichloromethane, chloroform and dichloroethane.

6. The method for preparing fenticonazole or its nitrate according to claim 1, 2 or 3, It is characterized in that In step B, the condensing agent is selected from an inorganic base; and the co-catalyst is selected from one or more of sodium iodide, potassium iodide, DMAP and tetra-n-butylammonium bromide.

7. The method for preparing fenticonazole or its nitrate according to claim 6, It is characterized in that The inorganic base is selected from one or more of alkali metal hydroxides, sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide and potassium carbonate.

8. The method for preparing fenticonazole or its nitrate according to claim 1, 2 or 3, It is characterized in that The organic solvent in step B is selected from ether solvents, sulfoxide solvents or amide solvents, the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ether and ethylene glycol dimethyl ether; the amide solvent is selected from one or more of dimethylformamide, dimethylacetamide, N-methylpyrrolidone and dimethylpropionamide; the sulfoxide solvent is selected from dimethyl sulfoxide and / or dichlorothionyl.

9. The method for preparing fenticonazole or its nitrate according to claim 8, It is characterized in that Step B is specifically as follows: First, the condensing agent is reacted with imidazole and the temperature is controlled at 0°C to 20°C to form the corresponding imidazole salt, and then the intermediate compound of formula III and the co-catalyst are added and the temperature is controlled at 45°C to 75°C to carry out the imidazole substitution reaction to generate the compound of formula IV.

10. The method for preparing fenticonazole or its nitrate according to claim 1, 2 or 3, It is characterized in that The compound of formula II described in step A is synthesized by the following method: Under an aluminum isopropoxide and isopropanol reduction system, reducing the compound of formula I to a compound of formula II;

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