CN112574270A - Preparation method of key intermediate of glucocorticoid - Google Patents

Abstract

The present invention provides a process for the preparation of a compound of formula III, comprising: in an organic solvent, in the presence of a phase conversion catalyst and an organic acid, controlling the pH value of a reaction system to be 2-6, and oxidizing the compound with the structural formula II by potassium permanganate to obtain the compound with the structural formula III. The invention also provides application of the preparation method in preparation of budesonide.

Description

Preparation method of key intermediate of glucocorticoid

Technical Field

The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of a key intermediate of glucocorticoid.

Background

Budesonide, the structural formula of which is shown in I, is a glucocorticoid with high-efficiency local anti-inflammatory effect.

Budesonide can enhance the stability of endothelial cells, smooth muscle cells and lysosome membranes, inhibit immune reaction and reduce antibody synthesis, thereby reducing the release and activity of allergic active media such as histamine and the like; and can alleviate the enzymatic process triggered by antigen-antibody binding, inhibit the synthesis and release of bronchoconstrictor, and alleviate the contractile reaction of smooth muscle. The anti-inflammatory activity of the compound is stronger than that of other glucocorticoids and is 1000 times of that of hydrocortisone. At the same time, budesonide has long action time and seldom produces systemic side effects of adrenocortical hormone drugs. Among the similar medicines, budesonide is more suitable for local administration because of higher local/systemic action ratio, has the characteristics of small dosage, high curative effect and small side effect, and is particularly suitable for children.

The synthetic route of budesonide has been reported at home and abroad. Wherein the compound of the structural formula III is a key intermediate needed in the preparation process of the budesonide,

for the preparation method of the intermediate compound of the structural formula III, the compound of the structural formula III is generally obtained by using the compound of the structural formula II as a raw material and oxidizing the raw material with an oxidant in the prior art.

For example, chinese patent application CN101279997 (published 2008/10/8) discloses that 80% hydrogen peroxide is used as an oxidant, and the reaction is carried out to obtain an oily substance with a yield of 80%. But epoxide impurities with the content of more than 2 percent are generated in the reaction process, and the volume weight ratio of the solvent acetone to the raw materials reaches 60ml:1g, so that the material charging amount of the reaction kettle is greatly reduced, the batch size of industrial production is small, the cost is high, and the environmental pollution is great.

Chinese patent application CN109384827 (published 2019, 2-26) discloses that an oxidation system of potassium permanganate/formic acid is used to obtain a white solid intermediate of structural formula III after the reaction, and the yield of the wet product (not dried) is 92%. However, the volume weight ratio of the solvent (acetone/water) to the raw material reaches 52.6ml:1g, and the problem of small industrial production batch still exists.

Chinese patent application CN11560047A (published 2020, 8, 21) discloses the use of aqueous potassium permanganate as an oxidant in the presence of glacial acetic acid. In this reaction, the volume weight ratio of acetone to starting material was about 30ml:1 g.

The methods already disclosed above have mostly the following disadvantages: the solvent consumption of a reaction system, large industrial production batch, low conversion rate, low yield, poor control of impurities such as over-oxidation, double bond transfer and the like, so that the yield and the purity of a final product (such as budesonide) are too low.

Disclosure of Invention

Aiming at the technical problem, the invention provides a preparation method of a budesonide key intermediate. The method has the advantages of less organic solvent, reduced discharge of three wastes, high product yield and purity, and suitability for industrial production.

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

a process for preparing a compound of structural formula III comprising: in an organic solvent, in the presence of a phase conversion catalyst and an organic acid, controlling the pH value of a reaction system to be 2-6, oxidizing a compound with a structural formula II by potassium permanganate to obtain a compound with a structural formula III,

preferably, the volume weight ratio of the organic solvent to the compound of the structural formula II is 10-20 ml:1 g;

preferably, the organic solvent is selected from one or more of acetone, diethyl ether, tetrahydrofuran or tert-butyl alcohol; more preferably acetone.

Preferably, the mass ratio of the phase transfer catalyst to the compound II is 0.008-0.020: 1.

More preferably, the mass ratio of the phase transfer catalyst to the compound II is 0.008-0.012: 1.

Preferably, the phase transfer catalyst is selected from cyclic crown ethers.

More preferably, the cyclic crown ether is selected from benzo-12-crown-4-ether, benzo-15-crown-5-ether or benzo-18-crown-6-ether.

Further preferably, the cyclic crown ether is benzo-12-crown-4-ether.

Preferably, the pH of the reaction system is 3-4.5.

Also preferably, the pH of the reaction system is controlled with a buffer salt.

More preferably, the buffer salt is selected from potassium dihydrogen phosphate-dipotassium hydrogen phosphate or sodium dihydrogen phosphate-disodium hydrogen phosphate.

Preferably, the molar ratio of the potassium permanganate to the compound II is 1-1.5: 1.

More preferably, the molar ratio of the potassium permanganate to the compound II is 1-1.2: 1.

Preferably, the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid.

More preferably, the organic acid is formic acid.

Preferably, the molar ratio of the organic acid to the compound of formula II is 1-5: 1.

More preferably, the molar ratio of the organic acid to the compound of formula II is 2-4: 1.

Preferably, the reaction temperature is from-20 ℃ to 10 ℃.

More preferably, the reaction temperature is from-15 ℃ to 0 ℃.

Also preferably, the reaction also comprises the steps of post-treatment purification after completion, including neutralization, filtration and crystallization.

The invention also aims to provide the application of the preparation method in preparing the budesonide.

Specifically, the application comprises the steps of taking a compound with a structural formula II as a raw material, preparing the compound with the structural formula III by the preparation method, and then obtaining the budesonide through hydrolysis and condensation reactions.

The synthetic route for preparing budesonide by using the structural formula II as a raw material is as follows:

compared with the prior art, the invention has the advantages that:

directly feeding solid potassium permanganate for reaction; the used organic solvent is less, the volume-weight ratio of the solvent to the substrate is only 10ml:1g at least, the discharge of three wastes is reduced, and the feeding amount is increased. The compound of the structural formula III prepared by the method has high yield, and the yield after drying is more than 91%; the product has good purity, the purity detected by HPLC is more than 97%, and the impurities are few, especially the epoxidation impurities, over-oxidation impurities and the like.

Drawings

The invention will be further explained with reference to the drawings.

FIG. 1 HPLC chromatogram of the objective product prepared in example 1, wherein the absorption peak with retention time of 5.8min is the chromatogram peak of the objective product.

FIG. 2 NMR spectra of the target product prepared in example 1.

FIG. 3 Mass Spectrometry of the target product prepared in example 1.

FIG. 4 HPLC chromatogram of example 2, with the absorption peak at retention time 5.777min being the chromatogram peak of the target product.

FIG. 5 HPLC chromatogram of example 3, with the absorption peak at retention time 5.767min being the chromatogram peak of the target product.

FIG. 6 HPLC chromatogram of example 4, with the absorption peak at retention time 5.770min being the chromatogram peak of the target product.

FIG. 7 HPLC chromatogram of example 5, with the absorption peak at retention time 5.763min being the chromatogram peak of the target product.

FIG. 8 HPLC chromatogram of example 6, with the absorption peak at retention time 5.767min being the chromatogram peak of the target product.

FIG. 9 HPLC chromatogram of example 7, with the absorption peak at retention time 5.770min being the chromatogram peak of the target product.

FIG. 10 is an HPLC chromatogram of comparative example 1, having an absorption peak with a retention time of 5.763min which is the chromatographic peak of the compound of formula III.

FIG. 11 is an HPLC chromatogram of comparative example 2, having an absorption peak with a retention time of 5.793min which is the chromatographic peak of the compound of formula III.

FIG. 12 is an HPLC chromatogram of comparative example 3, having an absorption peak with a retention time of 5.763min which is the chromatographic peak for the compound of formula III.

FIG. 13 shows the HPLC chromatogram of comparative example 4, and the absorption peak at retention time of 5.787min is the chromatographic peak of the compound of formula III.

Detailed Description

The invention provides a preparation method of a compound of a structural formula III, which comprises the following steps: in an organic solvent, in the presence of a phase conversion catalyst and an organic acid, controlling the pH value of a reaction system to be 2-6, oxidizing a compound with a structural formula II by potassium permanganate to obtain a compound with a structural formula III,

the invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagent materials used in the following examples are all commercially available products unless otherwise specified.

Example 1Preparation of Compounds of formula III

1kg (1.57mol) of a compound shown in a structural formula II, 15L of acetone, 20.0g (0.089mol) of benzo-12-crown 4-ether, 298g (1.88mol) of potassium permanganate and 102.0g of monopotassium phosphate-dipotassium phosphate buffer solution are added into a reaction kettle, the pH value is controlled to be 3.5, the temperature of a reaction system is controlled to be less than or equal to 0 ℃, 72.0g (1.57mol) of formic acid is slowly dripped, and the reaction is carried out for 1 hour at the temperature of-10 ℃ after dripping.

After the reaction is finished, adding 200.5g of sodium bisulfite solid for quenching, stirring at low temperature for 30min, adding 2L of ethanol, heating to 55 ℃ for dissolving, filtering while hot, and concentrating an organic phase to be dry; adding 1L of methanol and 6L of dichloromethane, refluxing for dissolution, cooling to room temperature, dropwise adding 12L of n-hexane, cooling to-10 ℃, and crystallizing for 4 h; filtering, drying the filter cake at 60 ℃ and-0.09 MPa to obtain 1.03kg of white solid, namely the target product, wherein the yield is 95.0%, the purity is 99.31%, the melting point is 211-.

TABLE 1 HPLC chromatogram Peak Main parameters

Example 2Preparation of Compounds of formula III

1kg (1.57mol) of a compound shown in a structural formula II, 15L of acetone, 10.0g (0.044mol) of benzo-12-crown 4-ether, 298g (1.88mol) of potassium permanganate and 102.0g of monopotassium phosphate-dipotassium phosphate buffer solution are added into a reaction kettle, the pH value is controlled to be 3.5, the temperature of a reaction system is controlled to be less than or equal to 0 ℃, 72.0g (1.57mol) of formic acid is slowly dripped, and the reaction is carried out for 1 hour at the temperature of-10 ℃ after dripping.

After the reaction is finished, adding 200.5g of sodium bisulfite solid for quenching, stirring at low temperature for 30min, adding 2L of ethanol, heating to 55 ℃ for dissolving, filtering while hot, and concentrating an organic phase to be dry; adding 1L of methanol and 6L of dichloromethane, refluxing for dissolution, cooling to room temperature, dropwise adding 12L of n-hexane, after finishing dripping, cooling to-10 ℃, crystallizing for 4h, performing suction filtration, and drying a filter cake at 60 ℃ and under-0.09 MPa to obtain 1.05kg of white solid, namely a target product, wherein the yield is 97.2%, the purity is 99.34%, the melting point, the mass spectrum and the nuclear magnetic resonance hydrogen spectrum of the compound III are basically the same as those of the example 1, and the HPLC spectrum is shown in figure 4.

TABLE 2 HPLC chromatogram Main parameters

Example 3Preparation of Compounds of formula III

100g (0.157mol) of the compound with the structural formula II, 1000ml of acetone, 1.0g (0.0044mol) of benzo-12-crown-4-ether, 24.81g (0.157mol) of potassium permanganate and 15.0g of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution are added into a 2L three-necked bottle, the pH value is controlled to be 4.5, the temperature of a reaction system is controlled to be less than or equal to 0 ℃, 7.2g (0.157mol) of formic acid is slowly dripped, and the reaction is carried out for 1h at 0 ℃ after dripping.

After the reaction is finished, adding 20.0g of sodium bisulfite solid for quenching, stirring at low temperature for 30min, adding 200ml of ethanol, heating to 55 ℃ for dissolving, filtering while hot, and concentrating an organic phase to be dry; adding 100ml of methanol and 600ml of dichloromethane, refluxing for dissolution, cooling to room temperature, dropwise adding 1200ml of n-hexane, after finishing dropwise adding, cooling to-10 ℃, crystallizing for 4 hours, performing suction filtration, and drying a filter cake at 60 ℃ and under-0.09 MPa to obtain 105g of a white solid, namely a target product, wherein the yield is 96.49%, the purity is 99.33%, the melting point, the mass spectrum and the nuclear magnetic resonance hydrogen spectrum of the compound III are basically the same as those of the example 1, and the HPLC spectrum is shown in figure 5.

TABLE 3 HPLC chromatogram Main parameters

Example 4Preparation of Compounds of formula III

10g (0.0157mol) of the compound with the structural formula II, 200ml of acetone, 0.08g (0.00036mol) of benzo-12-crown-4-ether, 3.7g (0.023mol) of potassium permanganate and 1.1g of monopotassium phosphate-dipotassium phosphate buffer solution are added into a single-mouth bottle, the pH value is controlled to be 3.5, the temperature of a reaction system is controlled to be less than or equal to 0 ℃, 0.72g (0.0157mol) of formic acid is slowly dripped, and the reaction is carried out for 1h at the temperature of-20 ℃ after dripping.

After the reaction is finished, 2.0g of sodium bisulfite solid is added for quenching, the mixture is stirred at low temperature for 30min, 20ml of ethanol is added, the mixture is heated and dissolved at 55 ℃, the mixture is filtered while hot, an organic phase is concentrated to be dry, 10ml of methanol and 60ml of dichloromethane are added, the mixture is refluxed and dissolved, cooled to room temperature, 120ml of n-hexane is added dropwise, the temperature is reduced to-10 ℃, crystallization is carried out for 4h, suction filtration is carried out, a filter cake is dried at 60 ℃ and-0.09 MPa, 10.16g of white solid is obtained, the target product is obtained, the yield is 93.50%, the purity is 99.37%, the melting point, the mass spectrum and the nuclear magnetic resonance hydrogen spectrum of the compound III are basically the.

TABLE 4 HPLC Profile Main parameters

Example 5Preparation of Compounds of formula III

5.0g (0.00785mol) of the compound with the structural formula II, 75ml of acetone, 0.05g (0.000223mol) of benzo-12-crown 4-ether, 1.26g (0.00785mol) of potassium permanganate and 0.51g of monopotassium phosphate-dipotassium phosphate buffer solution are added into a single-mouth bottle, the pH value is controlled to be 3.5, the temperature of a reaction system is controlled to be less than or equal to 0 ℃, 1.81g (0.03932mol) of formic acid is slowly dripped, and the reaction is carried out for 1h at the temperature of minus 10 ℃.

After the reaction is finished, 1.0g of sodium bisulfite solid is added for quenching, the mixture is stirred at low temperature for 30min, 10ml of ethanol is added, the mixture is heated and dissolved at 55 ℃, the mixture is filtered while hot, an organic phase is concentrated to be dry, 5ml of methanol and 30ml of dichloromethane are added, the mixture is refluxed and dissolved, the mixture is cooled to room temperature, 60ml of n-hexane is dripped, the temperature is reduced to-10 ℃, crystallization is carried out for 4h, suction filtration is carried out, a filter cake is dried at 60 ℃ and-0.09 MPa, 5.05g of white solid is obtained, the target product is obtained, the yield is 92.92%, the purity is 98.94%, the melting point, the mass spectrum and the nuclear magnetism of the compound III.

TABLE 5 HPLC Profile Main parameters

Example 6Preparation of Compounds of formula III

50.0g (0.0785mol) of the compound of the structural formula II, 750ml of acetone, 0.5g (0.00223mol) of benzo-12-crown 4-ether, 12.6g (0.0785mol) of potassium permanganate and 5.0g of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution are added into a 2L three-necked flask, the pH value is controlled to be 3.5, the temperature of a reaction system is controlled to be less than or equal to 0 ℃, 0.86g (0.0188mol) of formic acid is slowly dripped, and the reaction is carried out for 1h at-10 ℃ after dripping.

After the reaction is finished, adding 10.2g of sodium bisulfite solid for quenching, stirring at low temperature for 30min, adding 100ml of ethanol, heating and dissolving at 55 ℃, filtering while hot, concentrating an organic phase to be dry, adding 50ml of methanol and 300ml of dichloromethane, refluxing and dissolving, cooling to room temperature, dropwise adding 600ml of n-hexane, cooling to-10 ℃, crystallizing for 4h, performing suction filtration, and drying a filter cake at 60 ℃ and-0.09 MPa to obtain 53.42g of white solid, namely a target product, wherein the yield is 98.31%, the purity is 99.46%, the melting point, mass spectrum and nuclear magnetic resonance hydrogen spectrum of a compound III are basically the same as those of example 1, and the HPLC spectrum is shown in figure 8.

TABLE 6 HPLC chromatogram Main parameters

Example 7Preparation of Compounds of formula III

50.0g (0.0785mol) of the compound with the structural formula II, 500ml of acetone, 0.5g (0.00186mol) of benzo-15-crown-5-ether, 12.6g (0.0785mol) of potassium permanganate and 5.0g of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution are added into a 2L three-necked flask, the pH value is controlled to be 4.5, the temperature of a reaction system is controlled to be less than or equal to 0 ℃, 3.61g (0.0785mol) of formic acid is slowly dripped, and the reaction is carried out for 1h at-10 ℃ after dripping.

After the reaction is finished, adding 10.2g of sodium bisulfite solid for quenching, stirring at low temperature for 30min, adding 100ml of ethanol, heating and dissolving at 55 ℃, filtering while hot, concentrating an organic phase to be dry, adding 50ml of methanol and 300ml of dichloromethane, refluxing and dissolving, cooling to room temperature, dropwise adding 600ml of n-hexane, cooling to-10 ℃, crystallizing for 4h, performing suction filtration, and drying a filter cake at 60 ℃ and-0.09 MPa to obtain 49.62g of white solid, namely a target product, wherein the yield is 91.31%, the purity is 99.37%, the melting point, mass spectrum and nuclear magnetic resonance hydrogen spectrum of a compound III are basically the same as those of example 1, and the HPLC spectrum is shown in figure 9.

TABLE 7 HPLC chromatogram Main parameters

Comparative example 1The compound of formula III was prepared according to the method disclosed in example 2 of the Chinese patent application CN101279997A

Weighing 100g (0.27mol) of the compound II, adding the compound II into a 10L reaction kettle, adding 6L of acetone, then mechanically stirring and starting, controlling the temperature in the reaction system to be 10 ℃ below zero, stirring, dropwise adding 200ml of 80% hydrogen peroxide, continuously stirring and reacting for 10 hours at 10 ℃ below zero, and concentrating until the mixture is dry to obtain 79g of oily matter with the yield of 72.53%.

HPLC detection shows that the epoxy impurity content is 1.17%, the over-oxidation impurity content is 2.68%, the double bond transfer impurity content is 3.91%, and the purity of the compound of the structural formula III is only 89.58%. The HPLC chromatogram is shown in FIG. 10.

TABLE 8 HPLC chromatogram Main parameters

The impurity structures are respectively as follows:

comparative example 2Preparation of Compounds of formula III

1kg (1.57mol) of a compound shown in a structural formula II, 15L of acetone, 23.0g (0.102mol) of benzo-12-crown 4-ether, 298g (1.88mol) of potassium permanganate and 102.0g of monopotassium phosphate-dipotassium phosphate buffer solution are added into a reaction kettle, the pH value is controlled to be 3.5, the temperature of a reaction system is controlled to be less than or equal to 0 ℃, 72.0g (1.57mol) of formic acid is slowly dripped, and the reaction is carried out for 1h at the temperature of-10 ℃ after dripping.

After the reaction is finished, 200.5g of sodium bisulfite solid is added for quenching, the mixture is stirred at low temperature for 30min, 2L of ethanol is added, the mixture is heated and dissolved at 55 ℃, the mixture is filtered while hot, the organic phase is concentrated to be dry, 1L of methanol and 6L of dichloromethane are added, the mixture is refluxed and dissolved, the mixture is cooled to room temperature, 12L of n-hexane is added dropwise, the temperature is reduced to-10 ℃, crystallization is carried out for 4h, suction filtration is carried out, the filter cake is dried at 60 ℃ and-0.09 MPa, 926g of dry solid is obtained, the yield is 85.0%, and the purity is 95.. The HPLC chromatogram is shown in FIG. 11.

TABLE 9 HPLC chromatogram Main parameters

Comparative example 3Preparation of Compounds of formula III

Adding 1kg (1.57mol) of a compound shown in a structural formula II, 15L of acetone, 298g (1.88mol) of potassium permanganate and 102.0g of monopotassium phosphate-dipotassium phosphate buffer solution into a reaction kettle, controlling the pH value to be 3.5, controlling the temperature of a reaction system to be less than or equal to 0 ℃, slowly dropwise adding 72.0g (1.57mol) of formic acid, and reacting for 1h at-10 ℃ after dropwise adding.

After the reaction is finished, 200.5g of sodium bisulfite solid is added for quenching, the mixture is stirred at low temperature for 30min, 2L of ethanol is added, the mixture is heated and dissolved at 55 ℃, the mixture is filtered while hot, the organic phase is concentrated to be dry, 1L of methanol and 6L of dichloromethane are added, the mixture is refluxed and dissolved, the mixture is cooled to room temperature, 12L of n-hexane is added dropwise, the temperature is reduced to-10 ℃, crystallization is carried out for 4h, suction filtration is carried out, and the filter cake is dried at 60 ℃ and-0.09 MPa, so that 871g of dry solid is obtained, and the yield is.

HPLC detection shows that the content of epoxy impurities is 1.18%, the content of double-bond transfer impurities is 3.73%, the purity of the compound of the structural formula III is only 91.33%, and an HPLC spectrogram is shown in figure 12 in detail.

TABLE 10 HPLC profile Main parameters

Comparative example 4A Compound of formula III was prepared according to CN109384827A example 1

Adding 10g of the compound shown in the structural formula II, acetone (50mL) and purified water (2.6mL) into a reaction bottle, and stirring at room temperature to dissolve; formic acid (0.4mL) and potassium permanganate (1.2g, 7.59mmol) were added sequentially and the reaction stirred at room temperature for 1 h. Adding saturated sodium bisulfite solution (10mL) to quench reaction, filtering to remove manganese dioxide and some solid impurities, evaporating the filtrate under reduced pressure to remove acetone, separating out white solid, filtering, washing the filter cake with water to obtain the target product with the yield of 78.53%.

HPLC detection shows that the double bond transfer impurity (retention time 5.157min) content is 6.74%, and the purity of the compound of formula III is only 89.11%. The HPLC chromatogram is shown in FIG. 13.

TABLE 11 HPLC profile Main parameters

In a word, the invention provides a preparation method of a budesonide key intermediate, namely the compound with the structural formula III.

Claims (10)

1. A process for preparing a compound of structural formula III comprising: in an organic solvent, in the presence of a phase conversion catalyst and an organic acid, controlling the pH value of a reaction system to be 2-6, oxidizing a compound with a structural formula II by potassium permanganate to obtain a compound with a structural formula III,

2. the preparation method of claim 1, wherein the volume-to-weight ratio of the organic solvent to the compound of formula II is 10-20 ml:1 g.

3. The method according to claim 1 or 2, wherein the organic solvent is one or more selected from acetone, diethyl ether, tetrahydrofuran, and tert-butanol; more preferably acetone.

4. The preparation method according to claim 1, wherein the mass ratio of the phase transfer catalyst to the compound II is 0.008 to 0.020: 1;

preferably, the mass ratio of the phase transfer catalyst to the compound II is 0.008-0.012: 1;

also preferably, the phase transfer catalyst is selected from cyclic crown ethers;

more preferably, the cyclic crown ether is selected from benzo-12-crown-4-ether, benzo-15-crown-5-ether or benzo-18-crown-6-ether;

further preferably, the cyclic crown ether is benzo-12-crown-4-ether.

5. The preparation method according to claim 1, wherein the reaction system has a pH of 3 to 4.5;

also preferably, the pH of the reaction system is controlled with a buffer salt;

more preferably, the buffer salt is selected from potassium dihydrogen phosphate-dipotassium hydrogen phosphate or sodium dihydrogen phosphate-disodium hydrogen phosphate.

6. The preparation method according to claim 1, wherein the molar ratio of the potassium permanganate to the compound II is 1-1.5: 1;

preferably, the molar ratio of the potassium permanganate to the compound II is 1-1.2: 1.

7. The method according to claim 1, wherein the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid;

preferably, the organic acid is formic acid;

also preferably, the molar ratio of the organic acid to the compound of formula II is 1-5: 1;

more preferably, the molar ratio of the organic acid to the compound of formula II is 2-4: 1.

8. The method according to claim 1, wherein the reaction temperature is-20 ℃ to 10 ℃;

preferably, the reaction temperature is from-15 ℃ to 0 ℃.

9. The method according to any one of claims 1 to 8, further comprising a post-treatment purification step after completion of the reaction, including neutralization, filtration and crystallization.

10. Use of the preparation process according to any one of claims 1 to 9 for the preparation of budesonide;

specifically, the application comprises the steps of taking a compound with a structural formula II as a raw material, preparing the compound with the structural formula III by the preparation method, and then obtaining the budesonide through hydrolysis and condensation reactions.

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