Method for preparing voriconazole intermediate

Abstract

The invention particularly relates to a method for preparing a voriconazole intermediate. The method comprises the following steps: carrying out bromination reaction on a first initiator to obtain a first intermediate; the synthesis method comprises the following steps: activating zinc powder to obtain an organic zinc reagent intermediate state, and carrying out Reformatsky reaction on a tetrahydrofuran solution containing the organic zinc reagent intermediate state, a first intermediate and a second initiator; the Reformatsky reaction product is sequentially subjected to concentration, quenching, tetrahydrofuran removal and extraction, and an organic phase obtained after extraction is washed, concentrated under reduced pressure and stirred for crystallization; finally, washing and drying the separated crystal to obtain a second intermediate; dechlorinating the second intermediate under a palladium-carbon catalysis condition to obtain a third intermediate; the quality and the yield of the voriconazole bulk drug produced by the method meet the specified requirements, the production process is reasonable and effective, good reproducibility and reliability are achieved, and it can be ensured that the produced product meets the quality requirements. The process disclosed by the invention is suitable for large-scale daily production under factory production conditions.

Description

Technical Field

[0001] The invention belongs to the technical field of raw material drug production, and specifically relates to a method for preparing a voriconazole intermediate. Background Art

[0002] Voriconazole is a second-generation triazole antifungal drug with broad-spectrum antifungal activity. It is currently the first-line drug for the treatment of invasive aspergillosis. It can also be used to treat severe invasive infections of fluconazole-resistant Candida albicans, and severe infections of Actinomycetes and Fusarium. Voriconazole is a chiral drug with two chiral centers in the molecule. The active ingredient currently used in clinical practice is a single isomer with an absolute configuration of (2R, 3S).

[0003] Chinese patent CN106117186B discloses a method for preparing a voriconazole intermediate, which uses voriconazole isomers as raw materials, reacts under alkaline conditions and post-treats to obtain 6-ethyl-5-fluoropyrimidine and 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone, and the reactants are used as voriconazole intermediates. The reaction formula is as follows:

[0004]

[0005] The method for preparing the intermediate has a short synthesis route, high yield, low cost, and is easier to scale up industrial production. The prepared voriconazole intermediate can be used to prepare a (2R, 3S) single isomer with higher biological activity as a voriconazole raw material.

[0006] On the basis of existing technologies, how to further control the reaction process, reduce costs while improving production efficiency, ensure that the production volume is enlarged in factory-scale production while the quality and yield of the product meet the specified requirements, and have good reproducibility and reliability, is a technical problem that needs to be solved at present. Summary of the invention

[0007] In view of the above technical problems, the present invention provides a method for preparing a voriconazole intermediate, comprising the following steps of a chemical reaction equation such as Formula 1:

[0008] The first intermediate synthesis step: the first starting material is subjected to a bromination reaction to obtain a first intermediate;

[0009] The second intermediate synthesis step comprises: activating zinc powder to obtain an organic zinc reagent intermediate, and then subjecting a tetrahydrofuran solution including the organic zinc reagent intermediate, the first intermediate and the second starting material to a Reformatsky reaction; sequentially concentrating, quenching, removing tetrahydrofuran, and extracting the Reformatsky reaction product, and then washing the organic phase obtained after the extraction, concentrating under reduced pressure, and stirring to crystallize; and finally washing and drying the precipitated crystals to obtain the second intermediate;

[0010] Step of synthesizing the third intermediate: dechlorinating the second intermediate under palladium-carbon catalysis to obtain the third intermediate;

[0011] Wherein, the first starting material is 4-chloro-6-ethyl-5-fluoropyrimidine;

[0012] The second starting material is 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone;

[0013] The first intermediate is 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine;

[0014] The second intermediate is 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride;

[0015] The third intermediate is (2R, 3S / 2S, 3R)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.

[0016] Furthermore, the step of synthesizing the first intermediate specifically includes: using dichloromethane as solvent and AIBN as catalyst, refluxing the first starting material with NBS at 45±5°C for 24 hours, extracting and washing with purified water, collecting the organic phase, and concentrating to dryness under reduced pressure to obtain the first intermediate.

[0017] Furthermore, the Reformatsky reaction temperature in the step of synthesizing the second intermediate is 0-20°C.

[0018] Furthermore, the Reformatsky reaction time of the step of synthesizing the second intermediate is ≥5h.

[0019] Furthermore, the drying temperature of the step of synthesizing the second intermediate is 60-70° C., and the drying time is ≥6 hours.

[0020] Furthermore, in the step of synthesizing the second intermediate, trimethylchlorosilane is used to activate the zinc powder, and the activation temperature of the zinc powder is 20-40°C.

[0021] Furthermore, in the step of synthesizing the second intermediate, the molar ratio of the first intermediate to the second starting material is 1:1.

[0022] Furthermore, the water content of the first intermediate is controlled below 2% by mass, and the water content of tetrahydrofuran is controlled below 0.1% by mass.

[0023] Furthermore, the step of synthesizing the third intermediate specifically comprises:

[0024] S31: The second intermediate, dichloromethane and purified water are added in a molar ratio of , stirred evenly, adjusted to pH = 10-11, and then the organic phase is collected, washed, and concentrated under reduced pressure at below 60° C. to obtain an oily substance;

[0025] S32: Dissolve the oil in methanol, add 9.7 kg of sodium acetate trihydrate and 0.8 kg of 10% palladium carbon, stir evenly, transfer to a 500 L high pressure reactor, replace with nitrogen and hydrogen in turn, control the pressure to 0.1-1.0 MPa, the temperature to 20-40° C., and react for at least 8 hours under continuous stirring;

[0026] After the reaction of S33 is completed, filter and collect the filtrate, concentrate the filtrate to dryness under reduced pressure below 60°C, add dichloromethane and purified water, stir to dissolve, adjust pH=10-11, stand and separate, collect the organic phase, wash the organic phase, concentrate to dryness under reduced pressure at 60°C, add isopropanol, heat to reflux, stir to dissolve, cool to 0-10°C, stir to crystallize for 3-4h, filter, and collect the filter cake;

[0027] S34 The filter cake is dried under reduced pressure at 60-80°C for not less than 6 hours to obtain a third intermediate.

[0028] Furthermore, the specific steps of the step of synthesizing the second intermediate are as follows:

[0029] S21 Under nitrogen protection, add 105L tetrahydrofuran and 23.0kg zinc powder to a 500L stainless steel reactor, add 11.5kg trimethylsilyl chloride while stirring, after the addition, heat to 20-40℃, stir and react for 3h;

[0030] S22: The reactant obtained in S21 is cooled to 0-20°C, and a tetrahydrofuran solution containing 21.1 kg of the first intermediate and 19.6 kg of the second starting material is slowly added. After the addition is completed, the temperature is controlled to 0-20°C and stirred for reaction for 5 hours.

[0031] The quality and yield of the voriconazole raw material produced by the present invention meet the specified requirements, the production process is reasonable and effective, has good reproducibility and reliability, and can ensure that the produced products meet the quality requirements. The process of the present invention is suitable for large-scale daily production under factory production conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 : A flowchart of steps of an embodiment;

[0033] Figure 2 : A flow chart of the steps of synthesizing the first intermediate of an embodiment;

[0034] Figure 3-1 : A flow chart of the steps of synthesizing the second intermediate of an embodiment;

[0035] Figure 3-2 : A flow chart of the steps of synthesizing the second intermediate of an embodiment;

[0036] Figure 4-1 : A flow chart of the steps of synthesizing the third intermediate in one embodiment;

[0037] Figure 4-2 : A flow chart of the steps of synthesizing the third intermediate of an embodiment. DETAILED DESCRIPTION

[0038] The method for synthesizing (2R, 3S)-configured voriconazole disclosed in the existing literature (Wang Xianqiu. Research on the Synthesis Process of Voriconazole; Chemical Engineering and Equipment, 2018, 11: 40-43) uses m-difluorobenzene and chloroacetyl chloride as starting materials on a laboratory scale to obtain voriconazole through alkylation, chlorination, and condensation. The total yield of the finished product is 67.94%, and the optical purity is 99.9% after detection. The synthetic process route of voriconazole established in the literature is as follows.

[0039]

[0040] The production scale of the solutions in the above documents is in the range of tens of grams to several dozen grams.

[0041] Some embodiments of the present invention include: Figure 1 The process shown includes the following steps:

[0042] S1: a step of synthesizing a first intermediate: a first starting material is subjected to a bromination reaction to obtain a first intermediate;

[0043] S2 step of synthesizing the second intermediate: activating zinc powder to obtain an organic zinc reagent intermediate, and then subjecting a tetrahydrofuran solution including the organic zinc reagent intermediate, the first intermediate and the second starting material to a Reformatsky reaction; sequentially concentrating, quenching, removing tetrahydrofuran, and extracting the Reformatsky reaction product, and then washing the organic phase obtained after the extraction, concentrating under reduced pressure, and stirring to crystallize; finally, washing and drying the precipitated crystals to obtain the second intermediate;

[0044] S3 step of synthesizing the third intermediate: the second intermediate is dechlorinated under palladium-carbon catalysis to obtain the third intermediate;

[0045] Wherein, the first starting material is 4-chloro-6-ethyl-5-fluoropyrimidine;

[0046] The second starting material is 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone;

[0047] The first intermediate is 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine;

[0048] The second intermediate is 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride;

[0049] The third intermediate is (2R, 3S / 2S, 3R)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.

[0050] The following examples further illustrate the content of the present invention, but should not be construed as limiting the present invention. Without departing from the spirit and essence of the present invention, modifications or substitutions made to the methods, steps or conditions of the present invention are within the scope of the present invention. The conversion rate calculation formula in the examples is: Conversion rate = second intermediate content × filtrate weight / second intermediate theoretical yield × 100%

[0051] Example 1 Synthesis of the First Intermediate

[0052] The process flow of this embodiment is as follows Figure 2 The materials and ratios are shown in Table 1. The reaction mechanism of this embodiment is that 4-chloro-6-ethyl-5-fluoropyrimidine (SM1) reacts with N-bromosuccinimide (NBS) under the catalysis of azobisisobutyronitrile (AIBN) to generate a first intermediate.

[0053] like Figure 2 , add 15kg SM1, 20.0kg NBS, 767g AIBN and 90L dichloromethane to a 500L stainless steel reactor, heat to reflux (about 45°C) and stir for 10h. After the reaction is completed, the reaction solution is cooled to room temperature, washed with 90L 1% sodium pyrosulfite solution and 90L purified water in sequence, collect the organic phase, and concentrate to dryness under reduced pressure at 60°C to obtain an oily substance, i.e., the first intermediate. Yield range: 85-95%.

[0054] Table 1-1. List of materials used in the synthesis of the first intermediate

[0055]

[0056] Based on the above steps, three batches of trial production were carried out, and the operation was as follows: 100g (622.7mmol, 1.0eq) SM1, 20.4g (124.2mmol, 0.2eq) AIBN, 133g (747.2mmol, 1.2eq) NBS and 600ml dichloromethane were added to the reaction bottle, and the temperature was raised to reflux (about 45°C) and stirred for reaction for 24h, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, washed with purified water (600ml×2), the organic phase was collected, and concentrated to dryness under reduced pressure at 60°C to obtain an oily substance, namely the first intermediate. The results of the investigation of the first intermediate are shown in Table 1-2.

[0057] Table 1-2. Results of the trial production of three batches of the first intermediate

[0058]

[0059] The three batches of voriconazole first intermediate prepared according to the parameters determined in this example had yields between 90.9% and 92.5%, and purities of no less than 96.0%, indicating that the preparation process of the voriconazole first intermediate was stable and had good repeatability.

[0060] Example 2 Synthesis of the Second Intermediate

[0061] The process flow of this embodiment is shown in Figure 3, and the feeding and ratio are shown in Table 2. Under nitrogen protection, 105L tetrahydrofuran and 23.0kg zinc powder were added to a 500L stainless steel reactor, and 11.5kg trimethylsilyl chloride was added under stirring. After addition, the temperature was raised to 20-40°C and stirred for reaction for 3h. Then the temperature was lowered to 0-20°C, and a tetrahydrofuran solution of 21.1kg of the first intermediate and 19.6kg of SM2 (the first intermediate and SM2 were dissolved in 190L tetrahydrofuran solution) was slowly added. After addition, the temperature was controlled to 0-20°C and stirred for reaction for 5h, and the reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, and 5.3kg glacial acetic acid and 147L purified water were added to the filtrate to quench the reaction. The filtrate was concentrated under reduced pressure below 60°C to remove tetrahydrofuran, and 63L ethyl acetate was added to concentrate and remove the remaining tetrahydrofuran. The residue was extracted with ethyl acetate (147L×1, 64L×1), the organic phases were combined, the organic phases were washed with 2% sodium hydroxide solution (147L×1), filtered, and the organic phases were collected, and washed with 2% disodium edetate solution (147L×1) and saturated sodium chloride solution (74L×1) in sequence, and the organic phases were collected. The organic phase was concentrated to about 40L under reduced pressure at 60°C, cooled to 0-10°C, and 17.8kg hydrochloric acid was added. After the addition was completed, the temperature was controlled to 0-10°C and stirred for crystallization for 6h. Filter, wash the filter cake with an appropriate amount of ethyl acetate, collect the filter cake, and dry it under reduced pressure at 60-70°C for not less than 6h to obtain the second intermediate. The yield range is 50-60%.

[0062] Table 2. List of materials used in the synthesis of the second intermediate

[0063]

[0064] Example 3 Synthesis of the Third Intermediate

[0065] The process flow of this embodiment is shown in Figure 4, and the feeding and ratio are shown in Table 3. Add 20.0kg of the second intermediate, 200L of dichloromethane and 140L of purified water to a 500L stainless steel reactor, stir evenly, adjust pH=10-11 with an appropriate amount of 32% sodium hydroxide solution, let stand for stratification, collect the organic phase, wash the organic phase with 140L 2% disodium edetate solution and 140L purified water in turn, and concentrate to dryness under reduced pressure below 60°C to obtain an oily substance. The oily substance obtained in the previous step is dissolved in 100L methanol, 9.7kg of sodium acetate trihydrate and 0.8kg of 10% palladium carbon are added, stirred evenly, and transferred to a 500L high-pressure reactor. After replacing with nitrogen and hydrogen in turn, the pressure is controlled to be 0.1-1.0MPa, the temperature is 20-40°C, and the reaction is stirred for no less than 8h. Hydrogen is added in time during the reaction until the hydrogen pressure does not change within 30min, the reaction is stopped, and the reaction progress is monitored by TLC. After the reaction is completed, filter, collect the filtrate, transfer to a 500L stainless steel reactor, concentrate to dryness under reduced pressure at 60°C or below, add 120L dichloromethane and 120L purified water, stir to dissolve, adjust pH to 10-11 with 32% sodium hydroxide solution, stand to separate, collect the organic phase, and wash the organic phase with 40L purified water. The organic phase is concentrated to dryness under reduced pressure at 60°C, add 40L isopropanol, heat to reflux, stir to dissolve, cool to 0-10°C, stir to crystallize for 3-4h, filter, collect the filter cake, and dry under reduced pressure at 60-80°C for not less than 6h to obtain the third intermediate.

[0066] Table 3. List of materials used in the synthesis of the third intermediate

[0067]

[0068] The reaction temperature and reaction time of the second step have a great influence on the reaction. When the temperature is too low or the reaction time is too short, it may lead to incomplete reaction of the first intermediate and reduced yield. When the crystallization temperature is too high, the yield is reduced. Therefore, it needs to be defined as a key process step.

[0069] Example 4 Preparation of voriconazole finished product

[0070] In this embodiment, three batches of the finished product were trial-produced, and the operation process was as follows: 10 g (28.6 mmol, 1.0 eq) of the crude product and 15 ml of isopropanol were added to a reaction bottle, the temperature was raised to reflux, and the mixture was stirred to dissolve. The temperature was then lowered to 0-10° C., stirred to crystallize for 3-5 hours, filtered, the filter cake was collected, and dried under reduced pressure at 60-80° C. for not less than 4 hours to obtain the voriconazole finished product.

[0071] Table 4. Results of 3 batches of trial production of finished products

[0072]

[0073] The three batches of voriconazole finished products prepared according to the determined experimental parameters had a yield of about 88%, a purity of 100%, and no isomers were detected, indicating that the preparation process of voriconazole finished products is stable and reproducible.

[0074] Experimental Example 1: NBS dosage control test in the synthesis of the first intermediate step

[0075] In parallel, 20g (124.5mmol, 1.0eq) SM1, 10.2g (62.3mmol, 0.5eq) AIBN and 160ml dichloromethane were added to the reaction bottle, and then 24.4g (137.0mmol, 1.10eq), 25.5g (143.2mmol, 1.15eq), 26.6g (149.4mmol, 1.20eq), 27.7g (155.6mmol, 1.25eq), 28.8g (161.9mmol, 1.30eq) NBS were added respectively. After the addition was completed, the temperature was raised to reflux (about 45°C) and stirred for reaction for 24h. After the reaction was completed, the reaction solution was cooled to room temperature and samples were taken for inspection of related substances.

[0076] Table 5. Results of NBS dosage investigation (reaction solution)

[0077]

[0078] When the NBS dosage is 1.10eq and 1.15eq, the reaction is continued for 24h, and the residual SM1 in the reaction liquid is relatively large (>5%), indicating an incomplete reaction; when the dosage is increased to 1.20eq and the reaction is continued for 24h, the residual SM1 in the reaction liquid is relatively small (<2.5%), indicating that the reaction is basically complete, and when the dosage is further increased to 1.25eq and 1.30eq, the residual SM1 in the reaction liquid does not change, so the preferred NBS dosage is 1.2eq.

[0079] Test Example 2 AIBN dosage control test in the synthesis of the first intermediate step

[0080] In parallel, add 20g (124.5mmol, 1.0eq) SM1, 26.6g (149.4mmol, 1.2eq) NBS and 160ml dichloromethane to the reaction bottle, and then add 2.1g (12.5mmol, 0.1eq), 4.1g (24.9mmol, 0.2eq), 6.1g (37.4mmol, 0.3eq), 8.2g (49.8mmol, 0.4eq), 10.2g (62.3mmol, 0.5eq) AIBN respectively. After the addition, heat to reflux (about 45°C), stir and react for 24h. After the reaction is completed, cool the reaction solution to room temperature and take samples for inspection of related substances.

[0081] Table 6-1. Results of AIBN dosage investigation (reaction solution)

[0082]

[0083] According to the table above, when the amount of AIBN is 0.1-0.5eq, SM1 can react completely, and there is no obvious difference in the related substances of the reaction solution. In order to ensure the full reaction of SM1, the amount of AIBN is tentatively set to 0.2eq. After the above parameters are investigated, three batches of the first intermediate are trial-produced according to the determined experimental parameters. The trial production results are as follows:

[0084] Table 6-2. Results of the pilot test of the first intermediate

[0085]

[0086] According to the trial production results, it was found that the content of the first intermediate was significantly low, and a large amount of white solid precipitated from the first intermediate during storage. After filtering and washing to obtain the white solid, and sending it for structural confirmation, it was found that it was a degradation impurity of the catalyst AIBN. The generation mechanism is as follows:

[0087]

[0088] Since the first intermediate is an oily substance and there is no crystallization process, the impurity will still remain in the organic phase after extraction and washing and cannot be effectively removed. Therefore, it is proposed to reduce the amount of AIBN to reduce the generation of the impurity. Referring to the above-mentioned AIBN dosage investigation experiment, when the AIBN dosage is 0.1eq, SM1 can react completely, so the AIBN dosage is reset to 0.02eq and 0.05eq to investigate the reaction and content change of the first intermediate. In parallel, 10g (62.3mmol, 1.0eq) SM1, 13.3g (74.8mmol, 1.2eq) NBS and 60ml dichloromethane are added to the reaction bottle, and then 0.2g (1.25mmol, 0.02eq) and 0.5g (3.12mmol, 0.05eq) AIBN are added respectively. After the addition is completed, the temperature is raised to reflux (about 45°C) and stirred for 24h. The reaction progress is monitored by TLC. After the reaction is completed, the reaction solution is cooled to room temperature and samples are taken for testing of related substances.

[0089] Table 6-3. Results of AIBN dosage investigation (reaction solution)

[0090]

[0091] Table 6-4. Results of AIBN dosage investigation (first intermediate oil)

[0092]

[0093] According to the results of the related substances in the reaction solution, when the amount of AIBN was 0.02eq, after 40h of reaction, there was still about 1% of SM1 remaining. When the amount of AIBN was 0.05eq, after 24h of reaction, the reaction of SM1 was basically completed. Since the reaction time was too long when the amount of AIBN was 0.02eq, the amount of AIBN was preferably 0.05eq. According to the results of the content of the first intermediate oily substance, when the amount of AIBN was reduced to 0.05eq, the content of the first intermediate was significantly improved, which was basically consistent with the purity results. Therefore, the amount of AIBN was determined to be 0.05eq.

[0094] Test Example 3 Bromination Reaction Temperature Control Test

[0095] Add 20g (124.5mmol, 1.0eq) SM1, 26.6g (149.4mmol, 1.2eq) NBS, 4.1g (24.9mmol, 0.2eq) AIBN and 120ml dichloromethane to the reaction bottle, and heat to 40°C for stirring. After the reaction is completed, cool the reaction solution to room temperature and take samples for testing of related substances.

[0096] Table 7. Investigation results of reaction temperature (reaction solution)

[0097]

[0098] According to Table 7, when the reaction temperature is 40°C and the reaction is stirred for 40 hours, a large amount of starting material I still remains, so the reaction temperature is determined to be about 45°C under reflux.

[0099] Test Example 4 Metal Activation Step Control Test

[0100] Test 4-1 Lead powder + iodine

[0101] Under nitrogen protection, 100 ml of tetrahydrofuran, 14.6 g (224.0 mmol, 4.3 eq) of zinc powder, and 0.7 g (3.6 mmol, 0.07 eq) of lead powder were added to the reaction bottle, and the mixture was heated to reflux (about 66°C) with stirring. After stirring for 3 h, the mixture was cooled to 25°C, stirred for 16 h, and then heated to 45°C. 11.4 g (44.8 mmol, 0.87 eq) of iodine in tetrahydrofuran solution (iodine was dissolved in 40 ml of tetrahydrofuran solution) was added dropwise. After the addition was completed, the mixture was cooled to -5 to 0°C. 12.3 g (51.5 mmol, 1.0 eq) of the first intermediate and 10.0 g (44.8 mmol, 0.87 eq) of SM2 in tetrahydrofuran solution (the first intermediate and SM2 were dissolved in 60 ml of tetrahydrofuran solution) were added dropwise. After the addition was completed, the mixture was heated to 25°C and stirred for 1 h. After the reaction is completed, filter, weigh the filtrate, and take samples for testing of the content of related substances and the second intermediate.

[0102] Test 4-2 Zinc Chloride

[0103] Under nitrogen protection, add 17.5g (268.8mmol, 5.2eq) zinc powder, 18.3g (134.4mmol, 2.6eq) zinc chloride and 100ml tetrahydrofuran to the reaction bottle, heat to reflux (about 66°C) and stir for 3h, then cool to -5-0°C, drop 12.3g (51.5mmol, 1.0eq) first intermediate and 10.0g (44.8mmol, 0.87eq) SM2 tetrahydrofuran solution (dissolve the first intermediate and SM2 in 60ml tetrahydrofuran solution), add dropwise, heat to 25°C, stir for 1h. After the reaction is complete, filter, weigh the filtrate, and take samples for testing of the content of related substances and the second intermediate.

[0104] Test 4-3 Trimethylchlorosilane

[0105] Under nitrogen protection, add 100ml tetrahydrofuran and 13.7g (209mmol, 5.0eq) zinc powder to the reaction bottle, add 11.4g (104.5mmol, 2.5eq) trimethylsilyl chloride under stirring, after adding, heat to reflux (about 66°C) and stir for 3h, cool to -5~0°C, add 10g (41.8mmol, 1.0eq) first intermediate and 8.4g (37.6mmol, 0.9eq) SM2 tetrahydrofuran solution (dissolve the first intermediate and SM2 in 60ml tetrahydrofuran solution), after dropping, heat to 25°C and stir for 1h. After the reaction is completed, filter, weigh the filtrate, and take samples for inspection of the content of related substances and the second intermediate.

[0106] Table 8-1. Results of investigation on zinc powder activation methods (related substances)

[0107]

[0108] Table 8-2. Results of investigation on zinc powder activation methods (conversion rate)

[0109]

[0110] According to the results of the related substances of the second intermediate reaction liquid, when the method one (lead powder + iodine) and the method two (zinc chloride) are used, the purity is relatively low, below 66%. When the method three (trimethylchlorosilane) is used, the purity is the highest, above 75%. According to the results of the content of the second intermediate reaction liquid, when the method one (lead powder + iodine) and the method two (zinc chloride) are used, the conversion rate of the second intermediate is relatively low, below 66%. When the method three (trimethylchlorosilane) is used, the conversion rate is the highest, about 80%, so the preferred method of zinc powder activation is method three (trimethylchlorosilane). In summary, trimethylchlorosilane is used to activate zinc powder.

[0111] Test Example 5 Comparative Test on the Amount of Zinc Powder Used in the Metal Activation Step

[0112] In parallel, under nitrogen protection, add 100 ml of tetrahydrofuran to the reaction bottle, and add 5.5 g (83.6 mmol, 2.0 eq), 8.2 g (125.4 mmol, 3.0 eq), 10.9 g (167.2 mmol, 4.0 eq), 13.7 g (209 mmol, 5.0 eq) and 16.4 g (250.8 mmol, 6.0 eq) of zinc powder respectively. Under stirring, add 4.5 g (41.8 mmol, 1.0 eq), 6.8 g (62.7 mmol, 1.5 eq), 9.1 g (83.6 mmol, 2.0 eq), 11.4 g (104.5 mmol, 2.5 eq) and 13.6 g (125.4 mmol, 3.0 eq) of trimethylsilyl chloride respectively. After the addition is completed, heat to reflux (about 66°C) and stir for 3 hours. Then the temperature was lowered to -5-0°C, and a tetrahydrofuran solution of 10 g (41.8 mmol, 1.0 eq) of the first intermediate and 8.4 g (37.6 mmol, 0.9 eq) of SM2 (the first intermediate and SM2 were dissolved in 60 ml of tetrahydrofuran solution) was added dropwise. After the addition was completed, the temperature was raised to 25°C and stirred for reaction for 0.5 h. After the reaction was completed, the mixture was filtered, the filtrate was weighed, and samples were taken for inspection of the content of related substances and the second intermediate.

[0113] Table 9-1. Results of investigation on zinc powder dosage (related substances)

[0114] Note: The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3.

[0115] Table 9-2. Results of zinc powder dosage investigation (conversion rate)

[0116]

[0117]

[0118] According to the results of the related substances in the reaction solution, when the amount of zinc powder is 2.0eq and 3.0eq, the first intermediate is not completely reacted, more than 10% remains, and the purity of the reaction solution is less than 67%; when the amount of zinc powder is 4.0eq, the first intermediate is completely reacted, and the purity is more than 73%; when the amount of zinc powder is further increased to 5.0eq and 6.0eq, the purity does not change. According to the results of the content of the reaction solution, when the amount of zinc powder is 2.0eq and 3.0eq, the conversion rate of the second intermediate is less than 66%, and when the amount of zinc powder is 4.0eq, the conversion rate of the second intermediate is about 79%; when the amount of zinc powder is further increased to 5.0eq and 6.0eq, the conversion rate does not change, so the amount of zinc powder is preferably 4.0eq.

[0119] Test Example 6: Comparative Test on Dosage of Trimethylchlorosilane

[0120] In parallel, under nitrogen protection, add 100 ml of tetrahydrofuran and 10.9 g (167.2 mmol, 4.0 eq) of zinc powder to the reaction bottle. Under stirring, add 2.3 g (20.9 mmol, 0.5 eq), 4.5 g (41.8 mmol, 1.0 eq), 6.8 g (62.7 mmol, 1.5 eq), 9.1 g (83.6 mmol, 2.0 eq) and 11.4 g (104.5 mmol, 2.5 eq) of trimethylsilyl chloride respectively. After the addition, raise the temperature to reflux (about 66°C) and stir the reaction for 3 h. Then the temperature was lowered to -5-0°C, and a tetrahydrofuran solution of 10 g (41.8 mmol, 1.0 eq) of the first intermediate and 8.4 g (37.6 mmol, 0.9 eq) of SM2 (the first intermediate and SM2 were dissolved in 60 ml of tetrahydrofuran solution) was added dropwise. After the addition was completed, the temperature was raised to 25°C and stirred for reaction for 0.5 h. After the reaction was completed, the mixture was filtered, the filtrate was weighed, and samples were taken for inspection of the content of related substances and the second intermediate.

[0121] Table 10-1. Results of investigation on trimethylchlorosilane dosage (related substances)

[0122]

[0123] The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3.

[0124] Table 10-2. Results of investigation on trimethylchlorosilane dosage (conversion rate)

[0125]

[0126]

[0127] According to the results of the related substances of the reaction liquid, when the amount of trimethylchlorosilane is 0.5eq, no second intermediate is generated; when it is 1.0eq, the purity of the second intermediate is less than 10%; when the amount of trimethylchlorosilane is 1.5eq, the purity of the second intermediate is about 75% to 77%; when the amount is further increased to 2.0eq and 2.5eq, the purity of the second intermediate is not significantly improved. According to the results of the reaction liquid content, when the amount of trimethylchlorosilane is 0.5eq and 1.0eq, the conversion rate of the second intermediate is less than 12%, and when the amount of trimethylchlorosilane is 1.5eq, the conversion rate of the second intermediate is about 80%; when the amount is further increased to 2.0eq and 2.5eq, the conversion rate of the second intermediate is not significantly improved, so the amount of trimethylchlorosilane is preferably 1.5eq.

[0128] Test Example 7: Control Test of Dosage of Second Starting Material SM2

[0129] In parallel, 100 ml of tetrahydrofuran and 10.9 g (167.2 mmol, 4.0 eq) of zinc powder were added to the reaction bottle under nitrogen protection. 6.8 g (62.7 mmol, 1.5 eq) of trimethylsilyl chloride was added under stirring. After the addition was completed, the temperature was raised to reflux (about 66°C) and stirred for reaction for 3 h. Then the temperature was lowered to -5 to 0°C, and 10g (41.8mmol, 1.0eq) of the first intermediate and 8.4g (37.6mmol, 0.9eq), 9.3g (41.8mmol, 1.0eq), 9.8g (43.9mmol, 1.05eq), 10.3g (46.0mmol, 1.1eq), 11.2g (50.16mmol, 1.2eq) of SM2 in tetrahydrofuran solution were added dropwise (the first intermediate and SM2 were dissolved in 60ml of tetrahydrofuran solution), and the temperature was raised to 25°C and stirred for 0.5h. After the reaction was completed, the mixture was filtered, the filtrate was weighed, and samples were taken for testing of the content of related substances and the second intermediate.

[0130] Table 11-1. Results of investigation on the dosage of the second starting material (SM2) (related substances)

[0131]

[0132] The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3.

[0133] Table 11-2 Results of the investigation on the dosage of the second starting material (SM2) (conversion rate)

[0134]

[0135] According to the results of the purity and conversion rate of the reaction liquid, when the dosage of SM2 is low, at 0.9eq, the purity and conversion rate of the reaction liquid are low; when the dosage of SM2 is 1.0eq, 1.05eq, 1.1eq, and 1.2eq, the first intermediate reacts completely, and there is no obvious difference in the purity and conversion rate of the reaction liquid; since SM2 is cheap, in order to ensure that the first intermediate reacts completely and is fully converted into the second intermediate, the SM2 feed amount is appropriately increased, temporarily set at 1.1eq; considering that when the dosage of SM2 is 1.1eq, the remaining amount of SM2 in the reaction liquid is higher than when the dosage is 1.0eq, the dosage of SM2 will be determined based on the results of the crystallization parameter investigation. If SM2 is easily removed by crystallization, it will be determined to be 1.1eq; if SM2 is difficult to remove by crystallization, it will be determined to be 1.0eq.

[0136] Test Example 8 Reformatsky reaction temperature and reaction time comparison test

[0137] In parallel, under nitrogen protection, add 100 ml of tetrahydrofuran, 10.9 g (167.2 mmol, 4.0 eq) of zinc powder, and 6.8 g (62.7 mmol, 1.5 eq) of trimethylsilyl chloride to the reaction bottle. After the addition is complete, raise the temperature to reflux (about 66°C) and stir for 3 h.

[0138] Then, the temperature was controlled to -5-0°C, 0-5°C, 5-10°C, 10-15°C, and 15-20°C, and 10 g (41.8 mmol, 1.0 eq) of the first intermediate and 10.3 g (46.0 mmol, 1.1 eq) of SM2 in tetrahydrofuran solution (the first intermediate and SM2 were dissolved in 60 ml of tetrahydrofuran solution) were added dropwise. After the addition was completed, the temperature was maintained and stirred for reaction. After the addition was completed (0 h) and the reaction was continued for 1 h, samples were taken for inspection of the content of related substances and the second intermediate.

[0139] Table 12-1. Investigation results of reaction temperature and time (0h reaction solution related substances)

[0140]

[0141]

[0142] The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3.

[0143] Table 12-2. Results of investigation on reaction temperature and time (1h reaction solution related substances)

[0144]

[0145] The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3.

[0146] Table 12-3. Results of investigation on reaction temperature and time (conversion rate)

[0147]

[0148]

[0149] According to the results of the purity and conversion rate of the reaction liquid, when the reaction temperature is low, at -5 to 0°C, after reacting for 1 hour, about 45% of the first intermediate is still not completely reacted; when the reaction temperature is 0 to 5°C, 5 to 10°C, 10 to 15°C, and 15 to 20°C, the first intermediate can react completely, and there is no obvious difference in the purity and conversion rate of the reaction liquid, so the reaction temperature is preferably 0 to 20°C.

[0150] Test Example 9 Zinc powder activation temperature

[0151] In parallel, 10.9 g (167.2 mmol, 4.0 eq) zinc powder, 6.8 g (62.7 mmol, 1.5 eq) trimethylsilyl chloride and 50 ml tetrahydrofuran were added to the reaction bottle under nitrogen protection, and the temperature was controlled to 20 ° C, 30 ° C, 40 ° C, 60 ° C, reflux (about 66 ° C) and stirred for 3 h. Then the temperature was controlled to 0-20 ° C, and 10 g (41.8 mmol, 1.0 eq) of the first intermediate and 10.3 g (46.0 mmol, 1.1 eq) of SM2 in tetrahydrofuran solution (the first intermediate and SM2 were dissolved in 90 ml of tetrahydrofuran solution) were added dropwise. After the addition was completed, the temperature was maintained and stirred for 1 h. After the reaction was completed, the filtrate was filtered, the filtrate was weighed, and the content of the related substances and the second intermediate was sampled and sent for inspection.

[0152] Table 13-1. Results of investigation on activation temperature of zinc powder (related substances)

[0153]

[0154] The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3.

[0155] Table 13-2. Results of investigation on zinc powder activation temperature (conversion rate)

[0156]

[0157] According to the results of the purity and conversion rate of the reaction solution, within the range of process parameters, the zinc powder activation temperature has no obvious effect on the reaction, and the conversion rate of the obtained second intermediate is between 75-80%, so the zinc powder activation temperature is preferably 20-40°C.

[0158] Test Example 10. Comparative test of moisture content in reaction system

[0159] The following three experiments were designed to investigate the effects of water in the first intermediate and the reaction solvent (tetrahydrofuran) on the reaction.

[0160] Test 10-1: A first intermediate having a water content of 2% was reacted with anhydrous tetrahydrofuran (water content ≤ 50 ppm);

[0161] Test 10-2: The first intermediate having a water content of 0.03% was reacted with tetrahydrofuran having a water content of 0.1%;

[0162] Experiment 10-3: The first intermediate having a water content of 2% was reacted with tetrahydrofuran having a water content of 0.1%.

[0163] After the reaction is completed, filter, weigh the filtrate, and take samples for testing of the content of related substances and the second intermediate.

[0164] Table 14-1. Investigation results of water content (related substances)

[0165]

[0166] The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3

[0167] Table 14-2. Water content (conversion rate)

[0168]

[0169] Conversion rate = second intermediate content × filtrate weight / second intermediate theoretical yield × 100%

[0170] According to the results of the purity and conversion rate of the reaction solution, within the scope of the process parameter investigation, the water content of the reaction system has no significant effect on the reaction. When the water content of the first intermediate is below 2% and the water content of tetrahydrofuran is below 0.1%, both can react well and the conversion rate is 75-85%. Therefore, the water content of the first intermediate is controlled to be below 2% and the water content of tetrahydrofuran is controlled to be below 0.1%.

[0171] Test Example 11 Comparative Test of Crystallization Temperature and Crystallization Time

[0172] Under nitrogen protection, 87 g (1.34 mol, 4.0 eq) of zinc powder, 54 g (0.50 mol, 1.5 eq) of trimethylsilyl chloride and 400 ml of tetrahydrofuran were added to the reaction bottle, and the temperature was controlled to 20-40° C. and stirred for reaction for 3 h.

[0173] Then the temperature was lowered to 0-20°C, and 80 g (0.33 mol, 1.0 eq) of the first intermediate and 82 g (0.37 mol, 1.1 eq) of SM2 in tetrahydrofuran solution (the first intermediate and SM2 were dissolved in 720 ml of tetrahydrofuran solution) were added dropwise respectively. After the addition was completed, the temperature was maintained and the reaction was stirred for 1 h. The reaction progress was monitored by TLC.

[0174] After the reaction is completed, filter, add 20g (0.33mol, 1.0eq) glacial acetic acid and 560ml purified water to the filtrate to quench the reaction. Concentrate under reduced pressure below 60°C to remove tetrahydrofuran, add 240ml ethyl acetate and continue to concentrate under reduced pressure to remove the remaining tetrahydrofuran, extract the residue with ethyl acetate (560ml×2), combine the organic phases, and wash with 2% disodium edetate aqueous solution (560ml×1) and saturated sodium chloride aqueous solution (280ml×1) in turn. Collect the organic phase. Weigh, take samples and send for inspection of the content of related substances and the second intermediate.

[0175] The organic phase was divided into 8 parts (two tests were set for each parameter point), concentrated to dryness under reduced pressure below 60°C, added with 20ml of ethyl acetate, and stirred to dissolve. The temperature was lowered to -5°C, 0°C, 5°C, and 10°C respectively, 4.2g (0.04mol, 1.0eq) of hydrochloric acid was added, the temperature was maintained and stirred for crystallization for 4h, filtered, and the filter cake and filtrate were collected respectively. The filtrate was weighed, and samples were taken for inspection of the content of related substances and the second intermediate; the filter cake was dried under reduced pressure at 50°C, and samples were taken for inspection of the content of related substances and the second intermediate.

[0176] Table 15-1. Investigation results of crystallization temperature (crystallization mother liquor)

[0177]

[0178] Table 15-2. Investigation results of crystallization temperature (solid)

[0179]

[0180]

[0181] The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3

[0182] According to the results of the loss rate of the second intermediate in the crystallization mother liquor, within the scope of the process parameter investigation, the loss rate at different crystallization temperatures is basically the same; according to the results of the related substances of the crystallization solid, within the scope of the process parameter investigation, the related substances and purity of the second intermediate obtained at different crystallization temperatures are basically the same. In summary, the crystallization temperature is determined to be 0-10°C.

[0183] Under nitrogen protection, 109g (1.67mol, 4.0eq) zinc powder, 68g (0.63mol, 1.5eq) trimethylsilyl chloride and 500ml tetrahydrofuran were added to the reaction bottle, and the temperature was controlled to 20-40°C and stirred for 3h. Then the temperature was lowered to 0-20°C, and 100g (0.42mol, 1.0eq) of the first intermediate and 102.5g (0.46mol, 1.1eq) of SM2 in tetrahydrofuran solution (the first intermediate and SM2 were dissolved in 900ml of tetrahydrofuran solution) were added dropwise, and the temperature was maintained and stirred for 1h. After the reaction was completed, the reaction was filtered, and 25.1g (0.42mol, 1.0eq) of glacial acetic acid and 700ml of purified water were added to the filtrate to quench the reaction. Concentrate under reduced pressure below 60°C to remove tetrahydrofuran, add 300ml of ethyl acetate and continue to concentrate under reduced pressure to remove the remaining tetrahydrofuran, extract the residue with ethyl acetate (700ml×1, 350ml×1), combine the organic phases, wash with 2% disodium edetate aqueous solution (700ml×1) and saturated sodium chloride aqueous solution (350ml×1) in sequence. Collect the organic phase. Divide the organic phase into 2 equal parts (repeat the test twice), concentrate to dryness under reduced pressure below 60°C, add 80ml of ethyl acetate, and stir to dissolve. Cool to 0-10°C, add 21g (0.21mol, 1.0eq) of hydrochloric acid, maintain the temperature and stir to crystallize, take the crystallization solution and filter it after 4h, 6h, and 20h, collect the filtrate, and take samples for inspection of the content of related substances and the second intermediate.

[0184] Table 15-3. Investigation results of crystallization time (crystallization mother liquor)

[0185]

[0186] According to the results of the loss rate of the second intermediate in the crystallization mother liquor, after 4 hours of crystallization, the content of the second intermediate in the mother liquor was high and the loss rate was high. After 6 hours of crystallization, the second intermediate was basically precipitated and the loss rate was about 10-11%. The crystallization time was further extended to 20 hours, and the content of the second intermediate in the mother liquor remained unchanged. Therefore, the preferred crystallization time is 6 hours.

[0187] Test Example 12 Investigation of drying temperature and time

[0188] Under nitrogen protection, 109g (1.67mol, 4.0eq) zinc powder, 54.4g (0.50mol, 1.2eq) trimethylsilyl chloride and 500ml tetrahydrofuran were added to the reaction bottle, and the temperature was controlled to 20-40°C and stirred for 3h. Then the temperature was lowered to 0-20°C, and 100g (0.42mol, 1.0eq) of the first intermediate and 93.2g (0.42mol, 1.0eq) of SM2 in tetrahydrofuran solution (the first intermediate and SM2 were dissolved in 900ml of tetrahydrofuran solution) were added dropwise. After the addition was completed, the temperature was maintained and stirred for 1h. After the reaction was completed, the filtrate was filtered and collected. 25.1g (0.42mol, 1.0eq) of glacial acetic acid and 700ml of purified water were added to the filtrate to quench the reaction. Concentrate under reduced pressure below 60°C to remove tetrahydrofuran, add 300ml of ethyl acetate and continue to concentrate under reduced pressure to remove the remaining tetrahydrofuran, extract the residue with ethyl acetate (700ml×1, 3500ml×1), combine the organic phases, wash with 2% disodium edetate aqueous solution (700ml×1) and saturated sodium chloride aqueous solution (350ml×1) in sequence, and collect the organic phase. Concentrate the organic phase under reduced pressure below 60°C to about 200ml. Cool to 0-10°C, add 84g (0.84mol, 2.0eq) hydrochloric acid, maintain the temperature and stir for crystallization for 6h, filter, collect the filter cake, and take samples for inspection of related substances.

[0189] Table 16-1. Investigation results of drying temperature

[0190]

[0191] The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3.

[0192] Divide the filter cake into 10 portions (set 2 tests for each parameter point), dry under reduced pressure at 50℃, 60℃, 70℃, 80℃, and 90℃ to constant weight, and take samples for testing of related substances and content. Take the sample at the highest point in the determined temperature range, extend the drying time to 24h, and take samples for testing of related substances at 8h, 16h, and 24h.

[0193] Table 16-2. Investigation results of drying time

[0194]

[0195] The relative retention time of impurity L is about 1.7; the relative retention time of the diastereomer is about 0.7; impurity N is a double peak in the HPLC spectrum, and the relative retention time is about 1.3

[0196] According to the test results of related substances under drying temperature, when the drying temperature is 50-90℃, there is no difference in related substances before and after drying, and there is no significant difference in drying time, but the color of the sample will deepen when drying at 80-90℃, so the drying temperature is preferably 60-70℃; when the drying temperature is 70℃, the drying time is extended to 24h, and there is no change in related substances in the crude product. The drying temperature is determined to be 60-70℃. The drying time is not less than 4h.

[0197] Test Example 13: Detection of related substances in small test of finished product

[0198] According to the technical scheme of Example 4, three batches of the finished product were trial-produced, 10 g (28.6 mmol, 1.0 eq) of the crude product and 15 ml of isopropanol were added to the reaction bottle, the temperature was raised to reflux, and the mixture was stirred and dissolved. The temperature was then lowered to 0-10° C., stirred and crystallized for 3-5 h, filtered, the filter cake was collected, and dried under reduced pressure at 60-80° C. for not less than 4 h to obtain the voriconazole finished product.

[0199] Table 17. Results of 3 batches of trial production of finished products

[0200]

[0201]

[0202] The three batches of voriconazole finished products prepared according to the determined experimental parameters had a yield of about 88%, a purity of 100%, and no isomers were detected, indicating that the preparation process of voriconazole finished products is stable and reproducible.

[0203] Test Example 14 Verification of process stability and repeatability of voriconazole API

[0204] According to the technical solution of Example 4, the stability of the process was investigated by scaling up the production scale for pilot and large-scale production. The main changes from the laboratory to the pilot are the amount of feed, site, production equipment, etc., as shown in the following table:

[0205] Table 18. Summary of voriconazole process validation data

[0206]

[0207]

[0208] Although the present invention has been described in detail above by general description, specific implementation methods and experiments, it is obvious to those skilled in the art that some modifications or improvements can be made to the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all belong to the scope of protection claimed by the present invention.

Claims

1. A method for preparing a voriconazole intermediate, characterized in that: The following steps are involved: The first intermediate synthesis step: the first starting material is subjected to a bromination reaction to obtain a first intermediate; The second intermediate synthesis step comprises: activating zinc powder to obtain an organic zinc reagent intermediate, and then subjecting a tetrahydrofuran solution including the organic zinc reagent intermediate, the first intermediate and the second starting material to a Reformatsky reaction; sequentially concentrating, quenching, removing tetrahydrofuran, and extracting the Reformatsky reaction product, and then washing the organic phase obtained after the extraction, concentrating under reduced pressure, and stirring to crystallize; and finally washing and drying the precipitated crystals to obtain the second intermediate; Step of synthesizing the third intermediate: dechlorinating the second intermediate under palladium-carbon catalysis to obtain the third intermediate; Wherein, the first starting material is 4-chloro-6-ethyl-5-fluoropyrimidine; The second starting material is 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone; The first intermediate is 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine; The second intermediate is 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride; The third intermediate is (2R, 3S / 2S, 3R)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.

2. The method for preparing a voriconazole intermediate according to claim 1, characterized in that: The step of synthesizing the first intermediate specifically includes: using dichloromethane as solvent and AIBN as catalyst, reacting the first starting material with NBS at 45±5°C for 24 hours, extracting and washing with purified water, collecting the organic phase, and concentrating to dryness under reduced pressure to obtain the first intermediate.

3. The method for preparing a voriconazole intermediate according to claim 1, characterized in that: The Reformatsky reaction temperature of the step of synthesizing the second intermediate is 0-20°C.

4. The method for preparing a voriconazole intermediate according to claim 1, characterized in that: The Reformatsky reaction time of the step of synthesizing the second intermediate is ≥5h.

5. The method for preparing a voriconazole intermediate according to claim 1, characterized in that: The drying temperature of the step of synthesizing the second intermediate is 60-70° C., and the drying time is ≥6 hours.

6. The method for preparing a voriconazole intermediate according to claim 1, characterized in that: In the step of synthesizing the second intermediate, trimethylchlorosilane is used to activate zinc powder, and the activation temperature of the zinc powder is 20-40°C.

7. The method for preparing a voriconazole intermediate according to claim 1, characterized in that: In the step of synthesizing the second intermediate, the molar ratio of the first intermediate to the second starting material is 1:

1.

8. The method for preparing a voriconazole intermediate according to claim 1, characterized in that: In the step of synthesizing the second intermediate, the water content of the first intermediate is controlled to be below 2% by mass, and the water content of tetrahydrofuran is controlled to be below 0.1% by mass.

9. The method for preparing a voriconazole intermediate according to claim 1, characterized in that: The step of synthesizing the third intermediate specifically comprises: S31: The second intermediate, dichloromethane and purified water are added in a molar ratio of , stirred evenly, adjusted to pH = 10-11, and then the organic phase is collected, washed, and concentrated under reduced pressure at below 60° C. to obtain an oily substance; S32: Dissolve the oil in methanol, add 9.7 kg of sodium acetate trihydrate and 0.8 kg of 10% palladium carbon, stir evenly, transfer to a 500 L high pressure reactor, replace with nitrogen and hydrogen in turn, control the pressure to 0.1-1.0 MPa, the temperature to 20-40° C., and react for at least 8 hours under continuous stirring; After the reaction of S33 is completed, filter and collect the filtrate, concentrate the filtrate to dryness under reduced pressure below 60°C, add dichloromethane and purified water, stir to dissolve, adjust pH=10-11, stand and separate, collect the organic phase, wash the organic phase, concentrate to dryness under reduced pressure at 60°C, add isopropanol, heat to reflux, stir to dissolve, cool to 0-10°C, stir to crystallize for 3-4h, filter, and collect the filter cake; S34 The filter cake is dried under reduced pressure at 60-80°C for not less than 6 hours to obtain a third intermediate.

10. The method for preparing a voriconazole intermediate according to claim 1, characterized in that: The specific steps of the step of synthesizing the second intermediate are as follows: S21 Under nitrogen protection, add 105L tetrahydrofuran and 23.0kg zinc powder to a 500L stainless steel reactor, add 11.5kg trimethylsilyl chloride while stirring, after the addition, heat to 20-40℃, stir and react for 3h; S22: The reactant obtained in S21 is cooled to 0-20°C, and a tetrahydrofuran solution containing 21.1 kg of the first intermediate and 19.6 kg of the second starting material is slowly added. After the addition is completed, the temperature is controlled to 0-20°C and stirred for reaction for 5 hours.

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