Process for the preparation of voriconazole and intermediates thereof

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of voriconazole and an intermediate thereof. The preparation method of the voriconazole intermediate II comprises the following steps: mixing zinc powder, trimethyl halogen silane and an aprotic organic solvent to obtain a suspension and heating to reflux; adding 1,2-dibromoethane into the suspension to perform a reflux reaction to obtain a reaction solution; and then adding a compound shown in formula III and a compound shown in formula IV in sequence to perform a reaction to prepare the voriconazole intermediate II or an acid addition salt thereof. The trimethyl halogen silane is used to remove water from the aprotic solvent and activate the zinc powder, so that the use of the toxic heavy metal lead is avoided. In addition, the 1,2-dibromoethane is used as an organic zinc reagent to prepare an initiator, so that the problems that the aprotic solvent itself has too high water content to be directly used and the lewis acid is easy to absorb moisture to cause the reaction system to have too high water content and thus the reaction is terminated are solved. The method has high safety and is more suitable for industrial application.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing voriconazole and its intermediates. Background Technology

[0002] Voriconazole, developed by Pfizer's Central Research Institute, is a novel triazole antifungal drug. It is structurally similar to fluconazole, with the main difference being the introduction of a methyl group onto the propyl backbone of fluconazole and the replacement of a triazole ring with a fluoropyrimidine ring. In an in vitro comparative study against yeast and Aspergillus, voriconazole showed similar antibacterial activity to itraconazole against most yeast-specific fungi, comparable to amphotericin B, and superior to fluconazole. Furthermore, voriconazole has a broader antibacterial spectrum and better safety profile, particularly effective against invasive Aspergillus infections. Clinically, voriconazole is primarily used to treat candidiasis, deep subcutaneous candidiasis, and candidiasis of the abdomen, kidneys, bladder wall, and wounds. Its "highly effective and low-toxicity" characteristics give voriconazole significant economic value and market potential.

[0003] The chemical name of voriconazole is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, and its structural formula is shown in Formula I.

[0004]

[0005] Voriconazole intermediate II is a key intermediate of voriconazole, with the chemical name (2R,3S / 2S,3R)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride, and its structural formula is shown in Formula II.

[0006]

[0007] Currently, the synthesis of voriconazole intermediate II mainly involves reacting 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl ketone (structure III) with 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine (structure IV) in the presence of zinc, lead, iodine, or Lewis acid and aprotic organic solvents. The reaction mechanism involves zinc powder reacting with the compound shown in formula IV to form an organozinc reagent, which then reacts with the compound shown in formula III. Both the compounds shown in formula III and formula IV can be prepared using commercially available raw materials or methods disclosed in existing technologies.

[0008]

[0009] However, this preparation method has certain drawbacks, such as: 1) Zinc powder is easily oxidized upon contact with air, posing a problem of initiation and activation during the preparation of zinc reagents. In existing methods, the activation of zinc powder often involves lead powder, which is a highly toxic metallic element and is strictly controlled in the preparation of pharmaceutical raw materials. Using lead powder in the process carries the risk of excessive heavy metal content in the finished product, which is detrimental to large-scale industrial production. 2) The aprotic solvents required for the reaction often have excessive moisture content, making them unsuitable for direct use and requiring additional drying. Furthermore, the reaction requires the addition of iodine or Lewis acid as a catalyst, but commonly used Lewis acids often have excessive moisture content in the reaction system due to their hygroscopic nature, leading to reaction termination.

[0010] Therefore, it is necessary to study new methods to overcome the shortcomings of the existing technology and further synthesize high-quality voriconazole intermediate II and voriconazole. Summary of the Invention

[0011] In view of this, one of the objectives of this invention is to provide a method for preparing voriconazole intermediate II or its acid addition salt. This invention uses excess trimethylhalosilane to dehydrate the aprotic solvent, and the resulting hydrogen chloride can simultaneously activate zinc powder, avoiding the use of lead powder and eliminating the danger of highly toxic metal residues in the drug. Simultaneously, 1,2-dibromoethane is used as an organozinc reagent to prepare the initiator, avoiding the use of Lewis acid. This invention provides technical support for the subsequent preparation of high-quality voriconazole.

[0012] To achieve the above objectives, the present invention adopts the following technical solution:

[0013] A method for preparing voriconazole intermediate II or its acid addition salt, using compounds shown in Formula III and Formula IV as raw materials, employing an aprotic organic solvent as the solvent, and reacting zinc powder, trimethylhalosilane, and 1,2-dibromoethane to obtain voriconazole intermediate II or its acid addition salt; wherein the trimethylhalosilane dehydrates the aprotic organic solvent while simultaneously activating the zinc powder; the structural formula of voriconazole intermediate II is shown in Formula II.

[0014]

[0015] Furthermore, the method specifically includes the following steps:

[0016] (1) The zinc powder, the trimethylhalosilane and the aprotic organic solvent are mixed to obtain a suspension and heated to reflux;

[0017] (2) The 1,2-dibromoethane is added dropwise to the suspension prepared in step (1) and refluxed to obtain a reaction solution;

[0018] (3) After mixing the compound shown in Formula III with the aprotic organic solvent, add it to the reaction solution obtained in step (2) and stir at high speed to form a complex.

[0019] (4) The compound shown in Formula IV is mixed with the aprotic organic solvent and then added to the complex obtained in step (3) to react and obtain the voriconazole intermediate II or its acid addition salt.

[0020] Furthermore, the trimethylhalosilane includes any one or more of trimethylchlorosilane, trimethylbromosilane, and trimethyliodosilane.

[0021] Preferably, the trimethylhalosilane is trimethylchlorosilane.

[0022] Furthermore, the aprotic organic solvent includes C2-C 10 It can be any one or more of substituted or unsubstituted ether solvents, alkane solvents, and aromatic solvents.

[0023] Preferably, the aprotic organic solvent is tetrahydrofuran.

[0024] Furthermore, the weight ratio of the trimethylhalosilane to the compound shown in Formula III is 0.02-0.1:1, preferably 0.03-0.05:1; the molar ratio of the zinc powder, the 1,2-dibromoethane, and the compound shown in Formula III is 2.5-5.5:0.4-2.4:1, preferably 3.0-3.5:1.2-1.6:1.

[0025] Further, in step (2), 1,2-dibromoethane and an aprotic organic solvent are mixed at a mass ratio of 50-100:100 to obtain a mixed solution; the mixed solution is then added dropwise to the suspension obtained in step (1) for reflux reaction. Preferably, the mass ratio of 1,2-dibromoethane to the aprotic organic solvent is 60-90:100.

[0026] Furthermore, in step (2), the reflux reaction time is 0.5-2 hours, more preferably 1 hour.

[0027] Furthermore, in step (3), the mass ratio of the compound shown in Formula III to the aprotic organic solvent is 1:4-8, preferably 7:40.

[0028] Furthermore, in step (4), the mass ratio of the compound shown in Formula IV to the aprotic organic solvent is 0.8-1:1, preferably 0.95:1.

[0029] Furthermore, in step (4), the reaction temperature is -20℃ to 50℃, preferably -10℃ to -5℃; the reaction time is 0.4h to 1h, preferably 0.5h.

[0030] Furthermore, in step (4), a 50% aqueous solution of glacial acetic acid is used for quenching reaction.

[0031] Furthermore, the voriconazole intermediate II can be converted into its acid addition salt using any conventional method in the art.

[0032] Furthermore, step (4) is followed by step (5): refining.

[0033] Further, step (5) specifically involves: filtering and concentrating the product under reduced pressure; adding dichloromethane and water to the concentrated residue, and adding ammonia to adjust the pH of the system; separating the liquid and collecting the organic phase; extracting the aqueous phase with dichloromethane; combining the organic phases; concentrating under reduced pressure, dissolving the concentrated residue in acetone, adding hydrochloric acid at a controlled temperature of 40-45℃ to form a salt, cooling to crystallize, filtering, and vacuum drying to obtain the voriconazole intermediate II or its acid addition salt.

[0034] A second objective of this invention is to provide a method for preparing the compound shown in Formula V.

[0035] To achieve the above objectives, the present invention adopts the following technical solution:

[0036] The preparation method of the compound shown in Formula V includes the following steps:

[0037] (1) Prepare voriconazole intermediate II or its acid addition salt using the aforementioned method;

[0038] (2) The voriconazole intermediate II or its acid addition salt is subjected to hydrogenation dechlorination to obtain the compound shown in formula V;

[0039]

[0040] Furthermore, step (2) specifically involves:

[0041] The voriconazole intermediate II or its acid addition salt was added to dichloromethane and water, stirred to dissolve, and sodium hydroxide was added to adjust the pH of the system to 10-11. The mixture was extracted by separation, concentrated under reduced pressure, and then dissolved in 95% ethanol. Anhydrous sodium acetate and wet palladium on carbon were added to a hydrogenation reactor. The reactor was purged with nitrogen three times, pressurized to 0.2 MPa, and held for 30 min. The nitrogen was then purged with hydrogen three times, pressurized to 0.2 MPa, and the reactor temperature was controlled at 30-35°C. The reaction was stirred for 3-4 h until the pressure inside the reactor remained unchanged for 30 min. The product was discharged and purified to obtain the compound shown in Formula V.

[0042] Furthermore, the wet palladium on carbon is 5% wet palladium on carbon.

[0043] Furthermore, the mass ratio of the voriconazole intermediate II or its acid addition salt, dichloromethane and water is 1:3.4-4.5:1.5-2.2, preferably 1:4:2.

[0044] Furthermore, the mass ratio of the voriconazole intermediate II or its acid addition salt, anhydrous sodium acetate, and wet palladium on carbon is 1:0.2-0.3:0.04-0.06, preferably 1:0.25:0.05.

[0045] Furthermore, during the hydrogen replacement process, if the pressure drops to 0.1 MPa, it is repressurized to 0.2 MPa.

[0046] The third objective of this invention is to provide a method for preparing voriconazole.

[0047] To achieve the above objectives, the present invention adopts the following technical solution:

[0048] The preparation method of voriconazole includes the following steps:

[0049] (1) The compound shown in formula V was prepared using the aforementioned method;

[0050] (2) The compound shown in Formula V was resolved by L-camphor sulfonic acid to obtain the compound shown in Formula VI; the compound shown in Formula VI was then recrystallized from the free base to obtain the voriconazole.

[0051]

[0052] Furthermore, the chemical name of the compound shown in Formula VI is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol L-camphor sulfonate.

[0053] Furthermore, the mass ratio of the compound shown in Formula V to the L-camphor sulfonic acid is 1:0.7-1.0, preferably 1:0.77.

[0054] Furthermore, in step (2), the reaction solvents are acetone and methanol.

[0055] Furthermore, the mass ratio of the compound shown in Formula V, acetone, and methanol is 25-35:8-12:1, preferably 30:10:1.

[0056] Furthermore, step (2) is as follows:

[0057] Acetone and methanol were added to the compound shown in Formula V, and after stirring to dissolve, L-camphorsulfonic acid was added. The mixture was heated to reflux for 30 min, cooled to 30°C, and stirred for 1 h. Then, the temperature was slowly lowered to 0-5°C and kept at that temperature for 3 h to crystallize. The mixture was filtered, the filter cake was washed with acetone, and dried under vacuum to obtain the compound shown in Formula VI. The compound shown in Formula VI was dissolved in dichloromethane, the pH was adjusted to 10-11, the liquid was separated, the organic phase was collected, concentrated under reduced pressure, and the concentrated residue was added to isopropanol. The mixture was heated to reflux and stirred for 30 min, then slowly cooled to -5 to 0°C and kept at that temperature to crystallize. The mixture was filtered, and the filter cake was dried under vacuum to obtain voriconazole.

[0058] Furthermore, in step (2), the alkali is preferably a sodium hydroxide solution.

[0059] The fourth objective of this invention is to provide the application of trimethylhalosilane as a dehydrating agent and / or zinc powder activator in the preparation of voriconazole and its intermediates.

[0060] The beneficial effects of this invention are as follows:

[0061] 1. This invention provides a novel method for synthesizing voriconazole and its intermediates. This method uses excess trimethylhalosilane to dehydrate an aprotic organic solvent. The resulting hydrogen chloride can simultaneously activate zinc powder, avoiding the use of lead powder and eliminating the danger of highly toxic metal residues in the drug. This method has extremely high industrial applicability.

[0062] 2. This invention uses 1,2-dibromoethane to initiate the reaction, avoiding the problem that adding additional Lewis acid may lead to excessive water content in the system, thus terminating the reaction.

[0063] 3. The voriconazole and its intermediates prepared by the method of the present invention have high yield and purity, especially the final voriconazole with a liquid phase purity of up to 100%. Attached Figure Description

[0064] Figure 1 This is a synthetic route diagram for voriconazole. Detailed Implementation

[0065] The technical solution of the present invention will be described more clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0066] In this embodiment of the invention, according to Figure 1 The synthetic route shown is used to prepare voriconazole and its intermediates.

[0067] Example 1. Preparation of voriconazole intermediate II

[0068] Under nitrogen protection, 70g of zinc powder, 180g of tetrahydrofuran, and 2.1g of trimethylchlorosilane were added to a clean, dry three-necked flask. The mixture was stirred at high speed to form a suspension, and the temperature was raised to reflux. A 1,2-dibromoethane / tetrahydrofuran solution prepared with 80g of 1,2-dibromoethane and 100g of tetrahydrofuran was slowly added dropwise. Numerous bubbles were generated in the reaction solution. After the reaction was complete, reflux was continued for 1 hour. The system was then cooled to 20°C, and a solution prepared with 70g of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetone and 400g of tetrahydrofuran was added. The mixture was stirred at high speed to form a complex. The reaction temperature was controlled at 15–20°C, and a solution prepared with 95g of 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise. After the addition was complete, the reaction was maintained at 15-20℃ for 0.5 h. 42 g of 50% glacial acetic acid aqueous solution was added to quench the reaction. The mixture was filtered, concentrated under reduced pressure, and the concentrated residue was added to 600 g of dichloromethane and 200 g of water. Ammonia was added to adjust the pH of the system to 10-11. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with 200 g of dichloromethane. The organic phases were combined and concentrated under reduced pressure. The concentrated residue was dissolved in 390 g of acetone, and hydrochloric acid was added at 40-45℃ to form a salt. The mixture was cooled to crystallize, filtered, and vacuum dried to obtain 86.2 g of (2R,3S / 2S,3R)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride, with a yield of 65.3% and a liquid phase purity of 95.6%.

[0069] Example 2. Preparation of voriconazole intermediate II

[0070] Under nitrogen protection, 70g of zinc powder, 180g of tetrahydrofuran, and 2.1g of trimethylchlorosilane were added to a clean, dry three-necked flask. The mixture was stirred at high speed to form a suspension, and the temperature was raised to reflux. A 1,2-dibromoethane / tetrahydrofuran solution prepared with 80g of 1,2-dibromoethane and 100g of tetrahydrofuran was slowly added dropwise. Numerous bubbles were generated in the reaction solution. After the reaction was complete, reflux was continued for 1 hour. The system was then cooled to 20°C, and a solution prepared with 70g of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetone and 400g of tetrahydrofuran was added. The mixture was stirred at high speed to form a complex. The reaction temperature was controlled at -10 to -5°C, and a solution prepared with 95g of 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise. After the addition was complete, the reaction was maintained at -10 to -5℃ for 0.5 h. 42 g of 50% glacial acetic acid aqueous solution was added to quench the reaction. The mixture was filtered, concentrated under reduced pressure, and the concentrated residue was added to 600 g of dichloromethane and 200 g of water. Ammonia was added to adjust the pH of the system to 10-11. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with 200 g of dichloromethane. The organic phases were combined and concentrated under reduced pressure. The concentrated residue was dissolved in 390 g of acetone, and hydrochloric acid was added at 40-45℃ to form a salt. The mixture was cooled to crystallize, filtered, and vacuum dried to obtain 97.2 g of (2R,3S / 2S,3R)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride, with a yield of 73.6% and a liquid phase purity of 97.2%.

[0071] Example 3. Preparation of voriconazole intermediate II

[0072] Under nitrogen protection, 70g of zinc powder, 180g of tetrahydrofuran, and 1.4g of trimethylchlorosilane were added to a clean, dry three-necked flask. The mixture was stirred at high speed to form a suspension, and the temperature was raised to reflux. A 1,2-dibromoethane / tetrahydrofuran solution prepared with 80g of 1,2-dibromoethane and 100g of tetrahydrofuran was slowly added dropwise. Numerous bubbles were generated in the reaction solution. After the reaction was complete, reflux was continued for 1 hour. The system was then cooled to 20°C, and a solution prepared with 70g of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetone and 400g of tetrahydrofuran was added. The mixture was stirred at high speed to form a complex. The reaction temperature was controlled at 15–20°C, and a solution prepared with 95g of 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise. After the addition was complete, the reaction was maintained at 15-20℃ for 0.5 h. 42 g of 50% glacial acetic acid aqueous solution was added to quench the reaction. The mixture was filtered, concentrated under reduced pressure, and the concentrated residue was added to 600 g of dichloromethane and 200 g of water. Ammonia was added to adjust the pH of the system to 10-11. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with 200 g of dichloromethane. The organic phases were combined and concentrated under reduced pressure. The concentrated residue was dissolved in 390 g of acetone, and hydrochloric acid was added at 40-45℃ to form a salt. The mixture was cooled to crystallize, filtered, and vacuum dried to obtain 84.8 g of (2R,3S / 2S,3R)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride, with a yield of 64.2% and a liquid phase purity of 94.6%.

[0073] Example 4. Preparation of voriconazole intermediate II

[0074] Under nitrogen protection, 54g of zinc powder, 180g of tetrahydrofuran, and 1.4g of trimethylchlorosilane were added to a clean, dry three-necked flask. The mixture was stirred at high speed to form a suspension, and the temperature was raised to reflux. A 1,2-dibromoethane / tetrahydrofuran solution prepared with 60g of 1,2-dibromoethane and 100g of tetrahydrofuran was slowly added dropwise. Numerous bubbles were generated in the reaction solution. After the reaction was complete, reflux was continued for 1 hour. The system was then cooled to 20°C, and a solution prepared with 70g of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetone and 400g of tetrahydrofuran was added. The mixture was stirred at high speed to form a complex. The reaction temperature was controlled at 15–20°C, and a solution prepared with 95g of 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise. After the addition was complete, the reaction was maintained at 15-20℃ for 0.5 h. 42 g of 50% glacial acetic acid aqueous solution was added to quench the reaction. The mixture was filtered, concentrated under reduced pressure, and the concentrated residue was added to 600 g of dichloromethane and 200 g of water. Ammonia was added to adjust the pH of the system to 10-11. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with 200 g of dichloromethane. The organic phases were combined and concentrated under reduced pressure. The concentrated residue was dissolved in 390 g of acetone, and hydrochloric acid was added at 40-45℃ to form a salt. The mixture was cooled to crystallize, filtered, and vacuum dried to obtain 70.3 g of (2R,3S / 2S,3R)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride, with a yield of 53.2% and a liquid phase purity of 92.3%.

[0075] Example 5. Preparation of voriconazole intermediate II

[0076] Under nitrogen protection, 80g of zinc powder, 180g of tetrahydrofuran, and 1.4g of trimethylchlorosilane were added to a clean, dry three-necked flask. The mixture was stirred at high speed to form a suspension, and the temperature was raised to reflux. A 1,2-dibromoethane / tetrahydrofuran solution prepared with 90g of 1,2-dibromoethane and 100g of tetrahydrofuran was slowly added dropwise. Numerous bubbles were generated in the reaction solution. After the reaction was complete, reflux was continued for 1 hour. The system was then cooled to 20°C, and a solution prepared with 70g of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetone and 400g of tetrahydrofuran was added. The mixture was stirred at high speed to form a complex. The reaction temperature was controlled at -10 to -5°C, and a solution prepared with 95g of 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise. After the addition was complete, the reaction was maintained at -10 to -5℃ for 0.5 h. 42 g of 50% glacial acetic acid aqueous solution was added to quench the reaction. The mixture was filtered, concentrated under reduced pressure, and the concentrated residue was added to 600 g of dichloromethane and 200 g of water. Ammonia was added to adjust the pH of the system to 10-11. The mixture was separated, and the organic phase was collected. The aqueous phase was extracted with 200 g of dichloromethane. The organic phases were combined and concentrated under reduced pressure. The concentrated residue was dissolved in 390 g of acetone, and hydrochloric acid was added at 40-45℃ to form a salt. The mixture was cooled to crystallize, filtered, and vacuum dried to obtain (2R,3S / 2S,3R)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride (92.7 g, yield 70.2%), with a liquid phase purity of 96.8%.

[0077] Example 6. Preparation of the compound shown in Formula V

[0078] Add 160g of dichloromethane, 80g of water, and 40g of compound II to a three-necked flask, stir to dissolve, add sodium hydroxide to adjust the pH of the system to 10-11, separate the liquid and collect the organic phase, extract the aqueous phase with 120g of dichloromethane, and combine the organic phases. Concentrate under reduced pressure, dissolve the concentrated residue in 120g of 95% ethanol, transfer to a hydrogenation reactor, add 10g of anhydrous sodium acetate and 2g of 5% wet palladium on carbon, purge the reactor with nitrogen three times, pressurize with nitrogen to 0.2MPa and maintain the pressure for 30min. If the pressure does not change, the gas tightness is good. Then purge the nitrogen with hydrogen three times, pressurize with hydrogen to 0.2MPa, control the temperature inside the reactor at 30-35℃, stir the reaction for 3-4h until the pressure inside the reactor does not change for 30min (if the pressure drops to 0.1MPa during the reaction, repressurize to 0.2MPa). The material was discharged, concentrated to dryness under reduced pressure, and then mixed with 140g of water to form a slurry. After filtration, crude product of compound formula V was obtained. 40g of isopropanol was added to the crude product, and the mixture was heated to reflux and stirred for 30min. Then, the temperature was slowly lowered to -5 to 0℃ and kept at this temperature for 2h to allow crystallization. After filtration, the filter cake was dried under vacuum to obtain 29.4g of compound formula V, with a yield of 88.2% and a liquid phase purity of 99.9%.

[0079] Example 7. Preparation of voriconazole

[0080] In a three-necked flask, 600 g of acetone, 200 g of methanol, and 20 g of the compound shown in formula V were added. After stirring until dissolved, 15.4 g of L-camphorsulfonic acid was added, and the mixture was heated to reflux for 30 min. The temperature was then lowered to 30 °C and stirred for 1 h. The temperature was then slowly lowered to 0–5 °C and maintained for 3 h to allow crystals to crystallize. The mixture was filtered, the filter cake was washed with acetone, and dried under vacuum to give 15.9 g of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidin)-1-(1H-1,2,4-triazol-1-yl)-2-butanol L-camphorsulfonate, with a yield of 47.7%. The prepared (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidin)-1-(1H-1,2,4-triazol-1-yl)-2-butanol L-camphor sulfonate was dissolved in 110 g of dichloromethane. Sodium hydroxide solution was added to adjust the pH of the system to 10-11. The mixture was separated, the organic phase was collected, and concentrated under reduced pressure. 20 g of isopropanol was added to the concentrated residue, and the mixture was heated to reflux and stirred for 30 min. Then, the temperature was slowly lowered to -5 to 0 °C and kept at this temperature for 2 h to allow crystals to precipitate. The mixture was filtered, and the filter cake was dried under vacuum to obtain 8.5 g of voriconazole, with a yield of 88.7% and a liquid phase purity of 100.0%.

Claims

1. A method for preparing voriconazole intermediate II or its acid addition salt, characterized in that, Using the compounds shown in Formula III and Formula IV as raw materials, and employing an aprotic organic solvent as a solvent, the voriconazole intermediate II or its acid addition salt was prepared in the presence of zinc powder, trimethylhalosilane and 1,2-dibromoethane. The trimethylhalosilane dehydrates the aprotic organic solvent while simultaneously activating the zinc powder; the structural formula of the voriconazole intermediate II is shown in Formula II.

2. The method according to claim 1, characterized in that, The method specifically includes the following steps: (1) The zinc powder, the trimethylhalosilane and the aprotic organic solvent are mixed to obtain a suspension and heated to reflux; (2) The 1,2-dibromoethane is added dropwise to the suspension prepared in step (1) and refluxed to obtain a reaction solution; (3) After mixing the compound shown in Formula III with the aprotic organic solvent, add it to the reaction solution obtained in step (2) and stir at high speed to form a complex; (4) After mixing the compound shown in Formula IV with the aprotic organic solvent, add it to the complex obtained in step (3) and react to obtain the voriconazole intermediate II or its acid addition salt.

3. The method according to claim 1, characterized in that, The trimethylhalosilane includes any one or more of trimethylchlorosilane, trimethylbromosilane, and trimethyliodosilane.

4. The method according to claim 1, characterized in that, The aprotic organic solvent includes C2-C 10 It can be any one or more of substituted or unsubstituted ether solvents, alkane solvents, and aromatic solvents.

5. The method according to claim 4, characterized in that, The aprotic organic solvent is tetrahydrofuran.

6. The method according to claim 1, characterized in that, The weight ratio of the trimethylhalosilane to the compound shown in Formula III is 0.02-0.1:1; the molar ratio of the zinc powder, the 1,2-dibromoethane, and the compound shown in Formula III is 2.5-5.5:0.4-2.4:

1.

7. The method according to claim 2, characterized in that, In step (4), the reaction temperature is -20℃ to 50℃; the reaction time is 0.4h to 1h.

8. A method for preparing the compound shown in Formula V, characterized in that, Includes the following steps: (1) Voriconazole intermediate II or its acid addition salt prepared by the method of claim 1; (2) The voriconazole intermediate II or its acid addition salt is subjected to hydrogenation dechlorination to obtain the compound shown in formula V; 9. A method for preparing voriconazole, characterized in that, Includes the following steps: (1) The compound of formula V is prepared by the method of claim 8; (2) The compound shown in Formula V was resolved by L-camphor sulfonic acid to obtain the compound shown in Formula VI; the compound shown in Formula VI was then recrystallized from the free base to obtain the voriconazole.

Images