CN113512085B - Preparation method of mometasone furoate - Google Patents

Abstract

The invention relates to the technical field of chemical pharmacy, in particular to a preparation method of mometasone furoate. The method comprises the following steps: the compound I is subjected to cyanohydrination reaction to obtain a compound II, the compound II is subjected to alkylation reaction to obtain a compound III, the compound III is subjected to intramolecular substitution reaction to obtain a compound IV, the compound IV is subjected to furoyl reaction to obtain a compound V, and finally the compound V is subjected to chlorohydrination reaction to obtain mometasone furoate. The mometasone furoate is obtained by adopting the compound I through cyanohydrination reaction, alkylation reaction, intramolecular substitution reaction, furoyl reaction and chlorohydrination reaction, and has obvious competitiveness in quality and yield, high quality yield, high purity which reaches more than 99.20 percent and any impurity content which is less than 0.10 percent. The preparation method of mometasone furoate provided by the invention adopts the compound I which is easy to prepare as the raw material, and has the advantages of low cost and environmental protection.

Description

Preparation method of mometasone furoate

Technical Field

The invention relates to the technical field of chemical pharmacy, in particular to a preparation method of mometasone furoate.

Background

Mometasone furoate has the chemical name: 9, 21-dichloro-11 b, 17-dihydroxy-16 a-methyl pregna-1, 4-diene-3, 20-dione 17- (2-furoate), the product is a synthetic glucocorticoid and has anti-inflammatory and antiallergic effects, and is characterized in that the action intensity is increased and the side effects are disproportionately increased, and the product is effective for treating skin diseases such as skin inflammation and skin itch caused by neurodermatitis, eczema, atopic dermatitis, seborrheic dermatitis, psoriasis and the like.

The chemical structural formula is as follows:

the existing preparation method mostly uses 9 beta, 11 beta-epoxy-17 alpha, 21-dihydroxyl-16 alpha-methyl-1, 4-pregna (steroid) diene-3, 2-dione (8 DM) as a starting material, and carries out a series of structural modification to obtain mometasone furoate. Chinese patent CN105481933B relates to a method for synthesizing mometasone furoate, which uses 9β,11β -epoxy-17α, 21-dihydroxy-16α -methyl-1, 4-pregna (steroid) diene-3, 2-dione (8 DM) as a starting material, carries out sulfonylation reaction to obtain a compound 1, then carries out chlorination reaction while esterifying with the compound 1 and furoyl chloride, prepares a compound 3 from the compound 1 through one step, and then carries out ring opening in a hydrochloric acid-glacial acetic acid system to obtain mometasone furoate. The cost of the substrate 8DM is higher, pyridine is used in the reaction process, the production environment is deteriorated, a large amount of high ammonia nitrogen wastewater is generated, and the method does not accord with the ideas of energy conservation, environmental protection and green development.

The method for synthesizing mometasone furoate disclosed in Chinese patent CN105481933B comprises the following process routes:

aiming at the problems, the preparation method of mometasone furoate with low raw material cost and environmental protection needs to be provided.

Disclosure of Invention

The invention aims to provide a preparation method of mometasone furoate, which is low in cost, environment-friendly, high in purity, high in yield and less in impurities.

The invention provides a preparation method of mometasone furoate, which comprises the following steps: obtaining a compound II through cyanohydrination reaction of the compound I, obtaining a compound III through alkylation reaction of the compound II, obtaining a compound IV through intramolecular substitution reaction of the compound III, obtaining a compound V through furoyl reaction of the compound IV, and finally obtaining mometasone furoate through chlorohydrination reaction of the compound V;

the reaction formula is as follows:

preferably, the method comprises the following steps:

(1) Adding the compound I into a solvent, adding a catalyst, stirring uniformly, adding cyanide for reaction, adding water after the reaction is finished, filtering, and drying to obtain a compound II;

(2) Under the protection of nitrogen, adding a compound II into a solvent, adding a catalyst, stirring uniformly, adding chloromethyl dimethyl chlorosilane for reaction, after the reaction is finished, adding alkali liquor into the reaction liquid, standing for layering, concentrating an organic layer under reduced pressure, filtering, and drying to obtain a compound III;

(3) Under the protection of nitrogen, adding the compound III into a solvent, stirring and cooling, adding an alkali metal reagent for reaction, adjusting the pH value of a reaction solution after the reaction is finished, filtering and drying to obtain a compound IV;

(4) Under the protection of nitrogen, adding the compound IV into a solvent, adding a catalyst, then adding furoyl chloride for reaction, adding an acid solution after the reaction is finished, standing for layering, washing an organic layer by water, concentrating, filtering and drying to obtain a compound V;

(5) Adding the compound V into a solvent, adding a catalyst, then adding a chlorinating agent for reaction, adding a quenching agent after the reaction is finished, filtering, and drying to obtain mometasone furoate.

Preferably, the reaction temperature in step (1) is 25-30 ℃; the solvent in the step (1) is one or more of alcohol or ether with carbon number less than 6, more preferably methanol; the catalyst in the step (1) is one of sodium carbonate aqueous solution, potassium carbonate aqueous solution, sodium bicarbonate aqueous solution and potassium bicarbonate aqueous solution; the cyanide in step (1) is acetone cyanohydrin, sodium cyanide or potassium cyanide, more preferably acetone cyanohydrin; the material ratio of the compound I, the catalyst and the cyanide in the step (1) is 1:0.5:0.5-1:3:1.5, wherein the sodium cyanide and the potassium cyanide in the compound I, the cyanide are calculated in g, and the acetone cyanohydrin in the catalyst and the cyanide is calculated in mL.

Preferably, the reaction temperature in step (2) is 5-10 ℃; the solvent in the step (2) is chlorinated alkane, tetrahydrofuran or tetrahydropyran with the carbon number less than 6, and more preferably dichloromethane; the catalyst in the step (2) is imidazole, triethylamine, diethylamine or 4-dimethylaminopyridine, more preferably imidazole; the alkali liquor in the step (2) is one of potassium carbonate aqueous solution, sodium carbonate aqueous solution and sodium bicarbonate aqueous solution, and is more preferably sodium carbonate aqueous solution; in the step (2), the mass ratio of the compound II to the catalyst to the chloromethyl dimethyl chlorosilane is 1:0.1:0.5-1:1:2.

Preferably, the step (3) is: adding a compound III into a solvent under the protection of nitrogen, stirring and cooling to below-50 ℃, adding an alkali metal reagent, reacting at-60 to-50 ℃, after the reaction is finished, adding an acid solution into the reaction solution, adjusting the pH value of the reaction solution to be 1-2, stirring, adding an alkali liquor to adjust the pH value of the reaction solution to be 7-8, filtering, and drying to obtain a compound IV; the solvent in the step (3) is an ether with the carbon number less than 6, more preferably tetrahydrofuran; the alkali metal reagent in the step (3) is lithium diisopropylamide, n-butyllithium or tert-butyllithium, more preferably lithium diisopropylamide; the material ratio of the compound III to the alkali metal reagent in the step (3) is 1:2-1:5, wherein the compound III is calculated in g, and the alkali metal reagent is calculated in mL; the acid solution for adjusting the pH value of the reaction solution in the step (3) is hydrochloric acid, nitric acid or sulfuric acid, preferably hydrochloric acid, and the alkali solution is a potassium hydroxide aqueous solution or a sodium hydroxide aqueous solution, preferably a potassium hydroxide aqueous solution.

Preferably, the step (4) is: under the protection of nitrogen, adding the compound IV into a solvent, cooling to-5-0 ℃, adding a catalyst, adding furoyl chloride at the temperature below 10 ℃, then reacting at 0-10 ℃, adding an acid solution after the reaction is finished, standing for layering, washing an organic layer with water, concentrating, filtering and drying to obtain the compound V.

Preferably, the solvent in the step (4) is a chlorinated alkane with less than 6 carbon atoms, tetrahydrofuran or tetrahydropyran, more preferably dichloromethane; the catalyst in the step (4) is triethylamine, diethylamine or 4-dimethylaminopyridine, more preferably triethylamine; the acid solution in the step (4) is hydrochloric acid solution, nitric acid solution or sulfuric acid solution; in the step (4), the material ratio of the compound IV to the catalyst to the furoyl chloride is 1:0.5:0.2-1:2:2, the compound IV is calculated in g, and the catalyst and the furoyl chloride are calculated in mL.

Preferably, step (5) is: adding the compound V into a solvent, cooling to-5-0 ℃, adding a catalyst, adding a chlorinating agent at-5-0 ℃ for several times, then reacting at-5-0 ℃, adding a quenching agent after the reaction is finished, filtering, drying to obtain a mometasone furoate crude product, and recrystallizing the mometasone furoate crude product to obtain a mometasone furoate refined product.

Preferably, the solvent in step (5) is one or more of a ketone or an ether having less than 6 carbon atoms, more preferably acetone; the catalyst in the step (5) is an organic acid or an inorganic acid, wherein the organic acid is formic acid or acetic acid, and the inorganic acid is one of hydrochloric acid, nitric acid, sulfuric acid and perchloric acid, and perchloric acid is more preferable; the chlorinating agent in the step (5) is N-chlorosuccinimide or dichloro hydantoin, more preferably dichloro hydantoin; the quenching agent in the step (5) is sodium sulfite aqueous solution or sodium bisulfite aqueous solution; the material ratio of the compound V, the chlorinating agent, the catalyst and the quenching agent in the step (5) is 1:0.1:0.02:0.2-1:2:0.2:2, the compound V and the chlorinating agent are calculated in g, and the catalyst and the quenching agent are calculated in mL.

Preferably, the compound I is prepared by taking 11 alpha-hydroxy-androstane-1, 4-diene-3, 17-dione as a substrate and performing elimination reaction and methylation reaction.

Preferably, the preparation of compound I is as follows:

(1) Under the protection of nitrogen, 50-55g of 11 alpha-hydroxy-androstane-1, 4-diene-3, 17-diketone is added into 300-310mL of tetrahydrofuran, stirred and cooled to minus 60 ℃ to minus 50 ℃, 50-55g of phosphorus pentachloride is added in portions, 20-22 minutes are separated each time, 50-55mL of water is added after 3-3.1 hours of the phosphorus pentachloride is added for reaction, 150-155mL of 30% sodium hydroxide aqueous solution is slowly added dropwise, the pH value of the reaction solution is regulated to 6-7, standing and layering are carried out, a tetrahydrofuran layer is concentrated under reduced pressure, the solvent is recovered, the temperature is reduced, filtration and filter cake drying are carried out, and an eliminator is obtained;

(2) Under the protection of nitrogen, adding 45-48g of the eliminator into 150-155mL of dichloromethane, adding 10-11mL of diethyl oxalate, controlling the temperature to be 0-10 ℃, adding 20-22g of sodium methoxide twice, preserving heat for reaction for 1-1.2 hours, then heating to 20-25 ℃ for reaction for 2-2.2 hours, adding 10-11g of potassium carbonate and 40-42mL of methyl iodide, heating to 30-40 ℃ for reaction for 10-11 hours, dripping glacial acetic acid into the reaction liquid after the reaction is finished, adjusting the pH value of the reaction liquid to be 6-7, concentrating the solvent, cooling, filtering, and drying filter cakes to obtain the compound I.

The esterification reaction of the hydroxy group of the furoyl reaction and furoyl chloride; the chlorohydrin reaction refers to an addition reaction.

In summary, the invention has the following advantages:

(1) The mometasone furoate is obtained by adopting the compound I through cyanohydrination reaction, alkylation reaction, intramolecular substitution reaction, furoyl reaction and chlorohydrination reaction, and has obvious competitiveness in quality and yield, high quality yield, high purity which reaches more than 99.20 percent and any impurity content which is less than 0.10 percent.

(2) The preparation method of mometasone furoate provided by the invention adopts the compound I which is easy to prepare as the raw material, and has the advantages of low cost and environmental protection.

Detailed Description

It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular forms also include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.

The technical solutions of the present invention will be clearly and completely described in the following examples, and it is obvious that the described examples are some, but not all, examples of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Example 1

The preparation process of the compound I is as follows:

(1) Under the protection of nitrogen, 50g of 11 alpha-hydroxy-androstane-1, 4-diene-3, 17-dione is added into 300mL of tetrahydrofuran, stirred and cooled to minus 60 ℃ to minus 50 ℃, 50g of phosphorus pentachloride is added for four times, each time interval is 20 minutes, 50mL of water is added after the phosphorus pentachloride is added for 3 hours to react, then 150mL of 30% sodium hydroxide aqueous solution is slowly added dropwise, the pH value of the reaction solution is regulated to 6-7, standing and layering are carried out, a tetrahydrofuran layer is concentrated under reduced pressure, a solvent is recovered, cooled and filtered, a filter cake is dried, 46g of an eliminator is obtained, the mass yield is 92%, and the purity is 98.3%;

(2) Under the protection of nitrogen, adding 45g of the eliminator into 150mL of dichloromethane, adding 10mL of diethyl oxalate, controlling the temperature to be 0-10 ℃, adding 20g of sodium methoxide twice, carrying out heat preservation reaction for 1 hour, then heating to 20-25 ℃ for 2 hours, adding 10g of potassium carbonate and 40mL of methyl iodide, carrying out heating to 30-40 ℃ for 10 hours, dropwise adding glacial acetic acid into the reaction liquid after the reaction is finished, adjusting the pH value of the reaction liquid to be 6-7, concentrating the solvent, cooling and filtering, and drying a filter cake to obtain 41g of the compound I, wherein the mass yield is 91.1%, and the purity is 95.3%.

The method for preparing mometasone furoate by using the compound I prepared by the method as a raw material comprises the following steps of:

(1) Adding 50g of compound I into 150mL of methanol, stirring uniformly, adding 50mL of 10% sodium carbonate aqueous solution by mass fraction, controlling the temperature to be 20-25 ℃, adding 50mL of acetone cyanohydrin, reacting for 10 hours at 25-30 ℃, tracking almost no raw materials by TLC, adding 500mL of water into the reaction solution, filtering, and drying for 10 hours at 60 ℃ to obtain 48g of compound II with the mass yield of 96% and the purity of 98.0%;

(2) Under the protection of nitrogen, 45g of compound II is added into 225mL of dichloromethane, 13.5g of imidazole is added, the temperature is controlled to be 0-5 ℃, 35mL of chloromethyl dimethyl chlorosilane is dropwise added, the dropwise addition is completed within 1-2 hours, the reaction is carried out for 3 hours at 5-10 ℃ after the addition is completed, TLC is carried out, almost no raw materials are tracked, 100mL of sodium carbonate aqueous solution with the mass fraction of 0.5% is added into the reaction solution for washing, standing and layering are carried out, the organic layer is concentrated under reduced pressure, the solvent is recovered, 50mL of methanol is added, filtration is carried out, and filter residues are dried for 10 hours at 60 ℃ to obtain 56.2g of compound III, the mass yield is 124.9%, and the purity is 98.2%;

(3) Under the protection of nitrogen, adding 55g of compound III into 275mL of tetrahydrofuran, stirring and cooling to-60 to-50 ℃, dropwise adding 150mL of lithium diisopropylamide, finishing dropwise adding for 2-3 hours, reacting for 2 hours at-60 to-50 ℃, tracking almost no raw materials by TLC, controlling the temperature below 20 ℃, dropwise adding 150mL of hydrochloric acid into the reaction solution, at the moment, the pH value of the reaction solution is 1.2, stirring for 30 minutes, dropwise adding potassium hydroxide aqueous solution, adjusting the pH value of the reaction solution to 7-8, filtering, drying filter residues at 60 ℃ for 10 hours to obtain 44.2g of compound IV with the mass yield of 80.4% and the purity of 96.3%;

(4) Under the protection of nitrogen, adding 40g of compound IV into 240mL of dichloromethane, cooling to-5-0 ℃, adding 40mL of triethylamine, controlling the temperature to be 0-10 ℃, slowly dropwise adding 28mL of furoyl chloride, keeping the temperature for reaction for 10 hours within 30 minutes, detecting almost no raw materials by TLC, adding 200mL of 2mol/L hydrochloric acid solution into the reaction solution, stirring for 10 minutes, standing for 30 minutes for layering, separating a dichloromethane layer into another reaction bottle, washing a water layer with 100mL of dichloromethane, stirring for 10 minutes, standing for 30 minutes for layering, merging the dichloromethane layer, concentrating under reduced pressure, recovering the solvent, adding 50mL of mixed solvent of methanol and dichloromethane, filtering, drying at 60 ℃ for 10 hours to obtain 46.2g of compound V, wherein the mass yield is 115.5% and the purity is 98.8%;

(5) 45g of compound V is added into 180mL of acetone, stirred and cooled to-5-0 ℃, 2.25mL of perchloric acid is added, 36g of dichlorohydantoin is added at-5-0 ℃ for four times at intervals of 20 minutes, the reaction is carried out for 3 hours at-5-0 ℃ after each time, TLC is tracked to almost have no raw materials, 45mL of 30% sodium sulfite aqueous solution with mass fraction is dripped for quenching reaction, stirred for 30 minutes, acetone is concentrated, filtered, dried for 10 hours at 60 ℃ to obtain 48g of mometasone furoate crude product, the mass yield is 106.6%, and the purity is 97.8%;

45g of mometasone furoate crude product is added into 135mL of dichloromethane and 90mL of methanol, the temperature is raised to 35-40 ℃, 2.25g of active carbon is added for decoloration for 30 minutes after stirring and dissolving, filtering, concentrating the filtrate, centrifugally discharging, and drying at 60 ℃ for 10 hours to obtain 42g of mometasone furoate refined product, wherein the mass yield is 93.3%, the purity is 99.42%, and any impurity content is less than 0.10%.

Example 2

The method for preparing mometasone furoate by using the compound I prepared in example 1 as a raw material is as follows:

(1) 50g of compound I is added into 150mL of methanol, stirred evenly, 50mL of 10% potassium carbonate aqueous solution is added, 50mL of acetone cyanohydrin is added at 20-25 ℃, the reaction is carried out for 10 hours at 25-30 ℃, TLC is carried out, 500mL of water is added into the reaction liquid, filtration is carried out, drying is carried out for 10 hours at 60 ℃, 47.5g of compound II is obtained, the mass yield is 95%, and the purity is 97.4%;

(2) Under the protection of nitrogen, 45g of compound II is added into 225mL of tetrahydrofuran, 15g of 4-dimethylaminopyridine is added, 35mL of chloromethyl dimethyl chlorosilane is dripped at 0-5 ℃ for 1-2 hours, the reaction is carried out for 3 hours at 5-10 ℃ after the dripping, TLC is carried out, almost no raw materials are tracked, 100mL of sodium carbonate aqueous solution with the mass fraction of 0.5% is added into the reaction solution for washing, standing and layering are carried out, the organic layer is concentrated under reduced pressure, the solvent is recovered, 50mL of mixed solvent of methanol and tetrahydrofuran is added, filtering is carried out, filter residues are collected, and the mixture is dried at 60 ℃ for 10 hours, thus 54.8g of compound III with the mass yield of 121.8% and the purity of 98.0% is obtained;

(3) Under the protection of nitrogen, 50g of compound III is added into 275mL of tetrahydrofuran, the temperature is reduced to minus 60 ℃ to minus 50 ℃, 150mL of n-butyllithium is dripped, the dripping is completed for 2 to 3 hours, the reaction is carried out for 2 hours at minus 60 ℃ to minus 50 ℃, TLC is carried out, almost no raw materials are tracked, the temperature is controlled below 20 ℃, 150mL of hydrochloric acid is dripped into the reaction liquid, the stirring is carried out for 30 minutes, potassium hydroxide aqueous solution is dripped into the reaction liquid, the pH value of the reaction liquid is regulated to 7 to 8, the filtration is carried out, the filter residue is dried for 10 hours at 60 ℃, 41.2g of compound IV is obtained, the mass yield is 82.4%, and the purity is 95.1%;

(4) Under the protection of nitrogen, adding 40g of compound IV into 240mL of dichloromethane, cooling to-5-0 ℃, adding 20g of 4-dimethylaminopyridine, slowly dropwise adding 28mL of furoyl chloride at 0-10 ℃, dropwise adding the mixture within 30 minutes, carrying out heat preservation reaction for 10 hours at 0-10 ℃, detecting that almost no raw materials exist by TLC, adding 200mL of 2mol/L hydrochloric acid solution into the reaction solution, wherein the pH value of the reaction solution is 2, stirring for 10 minutes, standing for 30 minutes for layering, separating a dichloromethane layer into another reaction bottle, washing a water layer with 100mL of dichloromethane, stirring for 10 minutes, standing for 30 minutes for layering, merging the dichloromethane layer, concentrating under reduced pressure, recovering a solvent, adding 50mL of methanol, filtering, drying filter residues at 60 ℃ for 10 hours to obtain 45.8g of compound V with the mass yield of 114.5% and the purity of 98.3%;

(5) 45g of compound V is added into 180mL of butanone, stirred and cooled to-5-0 ℃, 5mL of glacial acetic acid is added, 36g of dichlorohydantoin is added at-5-0 ℃ for four times at intervals of 20 minutes, the reaction is carried out for 3 hours at-5-0 ℃ after each time, TLC is carried out, almost no raw materials are tracked, 45mL of 30% sodium sulfite aqueous solution with mass fraction is dripped for quenching reaction, stirred for 30 minutes, butanone is concentrated, filtration is carried out, filter residues are dried for 10 hours at 60 ℃ to obtain 46g of mometasone furoate crude product, the mass yield is 102.2%, and the purity is 97.5%;

45g of mometasone furoate crude product is added into 135mL of dichloromethane and 90mL of methanol, the temperature is raised to 35-40 ℃, 2.25g of active carbon is added for decoloration for 30 minutes after stirring and dissolving, filtering, concentrating the filtrate, centrifugally discharging, and drying at 60 ℃ for 10 hours to obtain 42.2g of mometasone furoate refined product, wherein the mass yield is 93.8%, the purity is 99.23%, and any impurity content is less than 0.10%.

Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (1)

1. The preparation method of mometasone furoate is characterized by comprising the following specific reaction formula:

the preparation process of the compound I is as follows:

(1) Under the protection of nitrogen, 50g of 11 alpha-hydroxy-androstane-1, 4-diene-3, 17-dione is added into 300mL of tetrahydrofuran, stirred and cooled to-60 to-50 ℃, 50g of phosphorus pentachloride is added for four times, 20 minutes are separated each time, 50mL of water is added after the phosphorus pentachloride is added for 3 hours to react, then 150mL of 30% sodium hydroxide aqueous solution is slowly added dropwise, the pH value of the reaction solution is regulated to 6-7, standing and layering are carried out, a tetrahydrofuran layer is concentrated under reduced pressure, a solvent is recovered, cooled and filtered, a filter cake is dried, 46g of an eliminator is obtained, the mass yield is 92%, and the purity is 98.3%;

(2) Under the protection of nitrogen, adding 45g of the eliminator into 150mL of dichloromethane, adding 10mL of diethyl oxalate, controlling the reaction temperature to be 0-10 ℃, adding 20g of sodium methoxide twice, carrying out heat preservation reaction for 1 hour, then heating to 20-25 ℃ for 2 hours, adding 10g of potassium carbonate and 40mL methyl iodide, carrying out reaction for 10 hours after heating to 30-40 ℃, dropwise adding glacial acetic acid into the reaction liquid after the reaction is finished, adjusting the pH value of the reaction liquid to be 6-7, concentrating the solvent, cooling and filtering, and drying a filter cake to obtain 41g of a compound I, wherein the mass yield is 91.1% and the purity is 95.3%;

the process for preparing mometasone furoate from the compound I as a raw material comprises the following steps:

(1) Adding 50g of compound I into 150mL of methanol, stirring uniformly, adding 50mL of 10% sodium carbonate aqueous solution by mass fraction, controlling the temperature to be 20-25 ℃, adding 50mL of acetone cyanohydrin, reacting for 10 hours at 25-30 ℃, tracking almost no raw materials by TLC, adding 500mL of water into the reaction solution, filtering, and drying for 10 hours at 60 ℃ to obtain 48g of compound II with the mass yield of 96% and the purity of 98.0%;

(2) Under the protection of nitrogen, 45g of compound II is added into 225mL of dichloromethane, 13.5g of imidazole is added, the temperature is controlled to be 0-5 ℃, 35mL of chloromethyl dimethyl chlorosilane is dropwise added, the dropwise addition is completed within 1-2 hours, the reaction is carried out for 3 hours at 5-10 ℃, TLC is carried out, almost no raw materials are tracked, 100mL of sodium carbonate aqueous solution with the mass fraction of 0.5% is added into the reaction liquid for washing, standing and layering are carried out, the organic layer is concentrated under reduced pressure, the solvent is recovered, 50mL of methanol is added, filtration is carried out, and the filter residue is dried for 10 hours at 60 ℃ to obtain 56.2g of compound III, the mass yield is 124.9%, and the purity is 98.2%;

(3) Under the protection of nitrogen, adding 55g of compound III into 275mL of tetrahydrofuran, stirring and cooling to-60 to-50 ℃, dropwise adding 150mL of lithium diisopropylamide, finishing dropwise adding for 2-3 hours, reacting for 2 hours at-60 to-50 ℃, tracking almost no raw materials by TLC, controlling the temperature below 20 ℃, dropwise adding 150mL of hydrochloric acid into the reaction solution, at the moment, the pH value of the reaction solution is 1.2, stirring for 30 minutes, dropwise adding potassium hydroxide aqueous solution, adjusting the pH value of the reaction solution to 7-8, filtering, drying filter residues at 60 ℃ for 10 hours to obtain 44.2g of compound IV with the mass yield of 80.4% and the purity of 96.3%;

(4) Under the protection of nitrogen, adding 40g of compound IV into 240mL of dichloromethane, cooling to-5~0 ℃, adding 40mL of triethylamine, controlling the temperature to be 0-10 ℃, slowly dropwise adding 28mL of furoyl chloride, keeping the temperature for reaction for 10 hours within 30 minutes, detecting almost no raw materials by TLC, adding 200mL of 2mol/L hydrochloric acid solution into the reaction solution, stirring for 10 minutes, standing for 30 minutes for layering, separating a dichloromethane layer into another reaction bottle, washing a water layer with 100mL of dichloromethane, stirring for 10 minutes, standing for 30 minutes for layering, merging the dichloromethane layer, concentrating under reduced pressure, recovering the solvent, adding 50mL of mixed solvent of methanol and dichloromethane, filtering, drying at 60 ℃ for 10 hours to obtain 46.2g of compound V, wherein the mass yield is 115.5%, and the purity is 98.8%;

(5) 45g of compound V is added into 180mL of acetone, stirred and cooled to-5-0 ℃, 2.25mL of perchloric acid is added, 36g of dichlorohydantoin is added at-5~0 ℃ for four times at intervals of 20 minutes, the reaction is carried out for 3 hours at-5~0 ℃ after the addition, TLC tracks almost no raw materials, 45mL of 30% sodium sulfite aqueous solution by mass fraction is dripped for quenching reaction, stirring is carried out for 30 minutes, acetone is concentrated, filtering is carried out, drying is carried out for 10 hours at 60 ℃ to obtain 48g of mometasone furoate crude product, the mass yield is 106.6%, and the purity is 97.8%;

45g of mometasone furoate crude product is added into 135mL of dichloromethane and 90mL of methanol, the temperature is raised to 35-40 ℃, 2.25g of active carbon is added for decoloration for 30 minutes after stirring and dissolving, filtering, concentrating the filtrate, centrifugally discharging, and drying at 60 ℃ for 10 hours to obtain 42g of mometasone furoate refined product, wherein the mass yield is 93.3%, the purity is 99.42%, and any impurity content is less than 0.10%.