Method for producing voriconazole bulk drug

Abstract

The invention belongs to the technical field of bulk drug production, and particularly relates to a voriconazole bulk drug production method which comprises the steps of voriconazole intermediate preparation, crude product preparation and refining. Crystallizing the voriconazole intermediate in an unwinding agent, and separating an isomer with pharmaceutical activity, namely a voriconazole crude product; the unwinding agent comprises an L-camphorsulfonic acid solution prepared from a voriconazole intermediate and L-camphorsulfonic acid which are fed according to a molar ratio of 1: 1.15. The production process provided by the invention is high in controllability and low in impurity content, the quality and yield of the product meet the specified requirements, and meanwhile, the voriconazole production process is reasonable and effective, has good reproducibility and reliability, and can ensure that the produced product meets the quality requirements.

Description

Technical Field

[0001] The invention belongs to the technical field of raw material medicine production, and specifically relates to a method for producing voriconazole raw material medicine. 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). The method for synthesizing voriconazole with (2R, 3S) configuration disclosed in the literature (Wang Xianqiu. Research on the Synthesis Process of Voriconazole; Chemical Engineering and Equipment, 2018; 11: 40-43) studied the synthesis process route of voriconazole at a laboratory preparation scale. This route uses 4-chloro-6-ethyl-5-fluoropyrimidine (SM1) and 2'4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone (SM2) as starting materials. SM1 undergoes bromination reaction with N-bromosuccinimide to obtain the first intermediate; the first intermediate undergoes Reformatsky reaction with SM2 to obtain the second intermediate; the second intermediate undergoes dechlorination under palladium-carbon catalysis to obtain the third intermediate; the third intermediate is then split with (R)-10-camphorsulfonic acid (L-camphorsulfonic acid) to obtain the crude voriconazole, which is then refined with isopropanol to obtain the finished voriconazole. However, large-scale production under factory production conditions may introduce impurities and cause the product to be unqualified. In addition, the document only made a finished product sample and did not verify the stability of its process.

[0003] 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

[0004] In view of the above technical problems, the present invention provides a method for producing voriconazole raw material, comprising the following steps:

[0005] Preparation of voriconazole intermediate step: preparing voriconazole intermediate based on Reformatsky reaction, wherein the voriconazole 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;

[0006] The step of preparing the crude product: the voriconazole intermediate is crystallized in a detangle agent to separate the isomers with pharmaceutical activity as the crude voriconazole product;

[0007] Purification step: the crude voriconazole product is crystallized in isopropanol and dried to obtain the voriconazole raw material;

[0008] The detethering agent comprises a L-camphorsulfonic acid solution prepared by feeding a voriconazole intermediate and L-camphorsulfonic acid in a molar ratio of 1:1.15.

[0009] Furthermore, the voriconazole intermediate is maintained at a temperature of 25-30° C. in the unwinding agent and crystallized for at least 5 hours.

[0010] Furthermore, the step of preparing the crude product specifically includes:

[0011] The voriconazole intermediate is dissolved in acetone, and a methanol solution of L-camphorsulfonic acid is added, and acetone is added in an amount of 20 times the mass of the voriconazole intermediate and methanol is added in an amount of 6.5 times the mass of the voriconazole intermediate;

[0012] The unwinding agent solution of the voriconazole intermediate is heated to reflux and stirred to dissolve. The reaction solution is cooled to 25° C. and stirred for crystallization for 5 hours, then filtered and the filter cake is collected to obtain L-camphorsulfonate.

[0013] Furthermore, the step of preparing the crude product also includes: dissolving L-camphorsulfonate, dichloromethane and purified water, adjusting the pH value to 10-11, standing for stratification, and collecting the organic phase; washing and filtering the collected organic phase, and then recrystallizing the filter cake in isopropanol, washing and drying to obtain the crude voriconazole.

[0014] Furthermore, in the refining step, the crystallization temperature of the crude voriconazole in isopropanol is 0-10° C., and the crystallization time is 3-5 hours.

[0015] Furthermore, in the refining step, the drying temperature is 60-80° C. and the drying time is ≥6 hours.

[0016] Furthermore, the refining step specifically includes the following steps:

[0017] The crude voriconazole was dissolved in isopropanol, heated to reflux, stirred, cooled to 0-10°C, stirred and crystallized for 3-5h, filtered, the filter cake was collected, and dried under reduced pressure at 60-80°C for not less than 6h to obtain the voriconazole bulk drug.

[0018] Furthermore, the step of preparing the voriconazole intermediate specifically comprises the following steps:

[0019] S1: a step of synthesizing a first intermediate: a first starting material is subjected to a bromination reaction to obtain a first intermediate;

[0020] 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;

[0021] S3 step of synthesizing voriconazole intermediate: the second intermediate is dechlorinated under palladium-carbon catalysis to obtain a voriconazole intermediate;

[0022] Wherein, the first starting material is 4-chloro-6-ethyl-5-fluoropyrimidine;

[0023] The second starting material is 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone;

[0024] The first intermediate is 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine;

[0025] 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;

[0026] The voriconazole intermediate is (2R, 3S / 2S, 3R)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidine)-1-(1H-1,2,4-triazole-1-yl)-2-butanol.

[0027] Furthermore, the specific steps of the step of synthesizing the second intermediate are as follows:

[0028] 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;

[0029] 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.

[0030] Furthermore, the steps for synthesizing the voriconazole intermediate are as follows:

[0031] 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;

[0032] 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;

[0033] 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;

[0034] S34: Dry the filter cake under reduced pressure at 60-80°C for not less than 6 hours to obtain a voriconazole intermediate.

[0035] 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 results of various tests prove that the process of the present invention is suitable for large-scale daily production under factory production conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 : Flowchart of steps of some embodiments;

[0037] Figure 2 : Flowchart of steps of some embodiments;

[0038] Figure 3-1 : A production process flow chart of an embodiment;

[0039] Figure 3-2 : A production process flow chart of an embodiment (continued from the above figure);

[0040] Figure 4 : A production process flow chart of an embodiment. DETAILED DESCRIPTION

[0041] 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.

[0042]

[0043] The production scale of the solutions in the above documents is in the range of tens of grams to several dozen grams.

[0044] 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 substance of the present invention, modifications or substitutions made to the method, steps or conditions of the present invention all belong to the scope of the present invention. It should be noted that in the embodiments of the present invention, the large production batch range is: 4-5kg.

[0045] Some embodiments of the present invention include: Figure 1 Steps shown:

[0046] Preparation of voriconazole intermediate step: preparing voriconazole intermediate based on Reformatsky reaction, wherein the voriconazole 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;

[0047] The step of preparing the crude product: the voriconazole intermediate is crystallized in a detangle agent to separate the isomers with pharmaceutical activity as the crude voriconazole product;

[0048] Purification step: the crude voriconazole is crystallized and dried in isopropanol to obtain the voriconazole raw material;

[0049] The detethering agent comprises a L-camphorsulfonic acid solution prepared by feeding a voriconazole intermediate and L-camphorsulfonic acid in a molar ratio of 1:1.15.

[0050] like Figure 1 The voriconazole intermediate is maintained at a temperature of 25-30° C. in the unwinding agent and crystallized for at least 5 hours.

[0051] like Figure 1 The scheme, wherein the step of preparing the crude product specifically comprises:

[0052] The voriconazole intermediate is dissolved in acetone, and a methanol solution of L-camphorsulfonic acid is added, and acetone is added in an amount of 20 times the mass of the voriconazole intermediate and methanol is added in an amount of 6.5 times the mass of the voriconazole intermediate;

[0053] The unwinding agent solution of the voriconazole intermediate is heated to reflux and stirred to dissolve. The reaction solution is cooled to 25° C. and stirred for crystallization for 5 hours, then filtered and the filter cake is collected to obtain L-camphorsulfonate.

[0054] like Figure 1 The method further comprises the steps of: dissolving L-camphorsulfonate, dichloromethane and purified water, adjusting the pH value to 10-11, standing for stratification, and collecting an organic phase; washing and filtering the collected organic phase, and then recrystallizing the filter cake in isopropanol, washing and drying to obtain a crude voriconazole product.

[0055] like Figure 1 In the purification step, the crystallization temperature of the crude voriconazole in isopropanol is 0-10° C., and the crystallization time is 3-5 hours. The drying temperature is 60-80° C., and the drying time is ≥6 hours.

[0056] Based on the above scheme, some more specific schemes, the refining steps specifically include the following steps:

[0057] The crude voriconazole was dissolved in isopropanol, heated to reflux, stirred, cooled to 0-10°C, stirred and crystallized for 3-5h, filtered, the filter cake was collected, and dried under reduced pressure at 60-80°C for not less than 6h to obtain the voriconazole bulk drug.

[0058] Example 1 Preparation of crude voriconazole from voriconazole intermediate

[0059] This implementation example Figure 3-1 , Figure 3-2 , add 14.3kg of voriconazole intermediate and 286L of acetone to a 500L stainless steel reactor, stir evenly, add a methanol solution of L-camphorsulfonic acid (dissolve 10.9kg of L-camphorsulfonic acid in 92.9L of methanol), heat to reflux, stir to dissolve. Cool the reaction solution to 25-30℃, stir and crystallize for 5h, filter, collect the filter cake, and obtain L-camphorsulfonic acid salt.

[0060] Add the above-mentioned L-camphorsulfonate, 43L of dichloromethane and 43L of purified water to a 500L stainless steel reactor, adjust the pH to 10-11 with an appropriate amount of 32% sodium hydroxide solution, let stand to separate the layers, and collect the organic phase. Wash the organic phase with purified water (14L×2), and collect the organic phase.

[0061] The organic phase was filtered, the filtrate was collected, and transferred to a 50L double-layer glass reactor, concentrated to dryness under reduced pressure at 60°C, 9L of isopropanol was added, the temperature was raised to reflux, stirred to dissolve, cooled to 0-10°C, stirred to crystallize for 3-5h, filtered, the filter cake was washed with an appropriate amount of isopropanol, the filter cake was collected, and dried under reduced pressure at 60-80°C for not less than 6h to obtain a crude product. The materials used in this embodiment are as follows:

[0062] Table 1. List of materials used in the preparation of crude voriconazole

[0063]

[0064]

[0065] Yield range: 30-40%.

[0066] Through this embodiment and test example 1, it is found that when the crystallization temperature is too high, the crude product loss rate in the voriconazole intermediate mother liquor increases, resulting in a low yield; when the crystallization temperature is too low, the isomer content is high and the separation effect cannot be achieved. Therefore, the optimized crystallization temperature and time are: 25-30°C, 5h.

[0067] Example 2: Purification steps of crude voriconazole

[0068] like Figure 4 , add 5.2 kg of crude product and 7.9 L of isopropanol to a 50 L double-layer glass reactor, heat to reflux, stir to dissolve, cool to 0-10 ° C, stir to crystallize for 3-5 hours, filter, collect the filter cake, and dry under reduced pressure at 60-80 ° C for not less than 6 hours to obtain voriconazole. The materials used in this example are as follows:

[0069] Table 2. List of materials used for crude product refining

[0070]

[0071] Yield range: 80-90%. Through this embodiment and Test Example 2, it is found that when the crystallization temperature is too high, the crystallization is incomplete, resulting in a low yield of the finished product. The optimized crystallization temperature and time are 0-10°C, 3-5h. When the drying temperature is too low, it is easy to cause incomplete drying and unqualified residual solvents. The drying temperature and time are 60-80°C, ≥6h.

[0072] Example 3 Finished product test

[0073] 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.

[0074] Table 3. Results of 3 batches of trial production of finished products

[0075]

[0076] ① Yield = voriconazole content × finished product yield / crude product feed amount × 100%;

[0077] 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.

[0078] Example 4 Scale-up production

[0079] The process was scaled up for pilot testing and large-scale production. The main process parameters are shown in Table 4-1. The stability of the process was investigated and the results are shown in Table 4-2.

[0080] Table 4-1. Summary of main parameters of production process

[0081]

[0082]

[0083]

[0084] The inspectors conducted a full inspection and stability test on the three batches of finished products (batch numbers: 221101, 221102, and 221103) produced by the process verification, and the results shown in Table 4-2 met the requirements of the proposed quality standards. Therefore, the voriconazole production process of this embodiment is stable, the process has good reproducibility, and can always produce finished products that meet the requirements of the proposed quality standards.

[0085]

[0086]

[0087] Example 5 Synthesis of Voriconazole Intermediates

[0088] The first stage process is as follows Figure 2 , 15kg SM1, 20.0kg NBS, 767g AIBN and 90L dichloromethane were added to a 500L stainless steel reactor, the temperature was raised to reflux (about 45°C) and stirred for 10h, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, washed with 90L 1% sodium pyrosulfite solution and 90L purified water in sequence, the organic phase was collected, and concentrated to dryness under reduced pressure at 60°C to obtain an oily substance, i.e., the first intermediate.

[0089] The second stage process is as follows Figure 2 . 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 addition, heat to 20-40℃, stir and react for 3h. Then cool to 0-20℃, slowly add 21.1kg first intermediate and 19.6kg SM2 tetrahydrofuran solution (dissolve the first intermediate and SM2 in 190L tetrahydrofuran solution), after addition, control the temperature to 0-20℃ and stir and react for 5h, monitor the reaction progress by TLC. After the reaction is completed, filter, collect the filtrate, add 5.3kg glacial acetic acid and 147L purified water to the filtrate to quench the reaction. The filtrate is concentrated under reduced pressure below 60℃ to remove tetrahydrofuran, and 63L ethyl acetate is 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 below 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. Filtered, the filter cake was washed with an appropriate amount of ethyl acetate, the filter cake was collected, and dried under reduced pressure at 60-70°C for not less than 6h to obtain the second intermediate.

[0090] The third stage process is as follows Figure 2 , add 20.0kg of the second intermediate, 200L of dichloromethane and 140L of purified water to a 500L stainless steel reactor, stir evenly, adjust the pH to 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 of 2% disodium edetate solution and 140L of 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 of 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 not 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 for stratification, 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 voriconazole intermediate.

[0091] Experimental Example 1 Comparative test of key parameters for isomer separation

[0092] In parallel, add 5g (14.3mmol, 1.0eq) of voriconazole intermediate and 100ml of acetone to the reaction bottle, stir evenly, then add 3.82g (16.45mmol, 1.15eq) of methanol solution of L-camphorsulfonic acid (dissolve L-camphorsulfonic acid in 33ml of methanol), heat to reflux, and stir to dissolve. Then cool to 0℃, 10℃, 20℃, 25℃, and 30℃ respectively to stir and crystallize. Samples are taken and filtered at 3h and 5h of crystallization, and the mother liquor is separated and sent for inspection. After 5h of crystallization, filter, weigh the filtrate, wash the filter cake with an appropriate amount of acetone, and sample the filter cake for inspection of related substances and isomers.

[0093] Table 5-1. Results of investigation on crystallization temperature and time of splitting process (split filter cake)

[0094]

[0095] Table 5-2. Results of investigation on crystallization temperature and time of splitting process (3h splitting mother liquor)

[0096]

[0097] Table 5-3. Results of investigation on crystallization temperature and time of splitting process (5h splitting mother liquor)

[0098]

[0099] According to the results of the loss rate of voriconazole in the split mother liquor, the lower the split crystallization temperature, the lower the loss rate of voriconazole in the mother liquor, and when the crystallization temperature is 0°C, the loss rate is the lowest; the crystallization time has no obvious effect on the loss rate of voriconazole in the mother liquor, and the loss rates of crystallization 3h and 5h are basically the same; according to the results of splitting the filter cake, the lower the split crystallization temperature, the higher the content of isomers in the filter cake, when the split crystallization temperature is 0°C, 10°C, and 20°C, the splitting effect cannot be achieved, when the crystallization temperature is 25°C and 30°C, the isomer content is about 2%, so the split crystallization time is preferably 25-30°C, in order to ensure that voriconazole camphorsulfonate is fully precipitated, the crystallization time is preferably 5h; according to the above-mentioned split solvent dosage and crystallization temperature and time investigation results, reducing the solvent dosage and lowering the crystallization temperature can increase the yield, but isomers will also precipitate, and the splitting effect cannot be achieved. Therefore, in this test example, the crystallization temperature of the splitting process is determined to be 25-30°C and the crystallization time is 5h, and the splitting effect is obvious.

[0100] Test Example 2: Crystallization Temperature and Time Comparison Test

[0101] Add 80g (229mmol, 1.0eq) of voriconazole intermediate and 1600ml of acetone to the reaction bottle, stir evenly, then add 61.2g (263.4mmol, 1.15eq) of methanol solution of L-camphorsulfonic acid (dissolve L-camphorsulfonic acid in 533ml of methanol), heat to reflux, stir to dissolve. Then cool to 25-30°C, stir to crystallize for 5h, filter, and collect the filter cake.

[0102] Add the above-mentioned L-camphorsulfonate, 240 ml of dichloromethane and 240 ml of purified water to the reaction bottle, adjust the pH to 10-11 with 32% (w / w) sodium hydroxide solution, let stand for stratification, collect the organic phase, wash the organic phase with purified water (80 ml x 2), take samples and send them for inspection of related substances and content. Divide the organic phase into 8 parts (set two tests for each parameter point).

[0103] Each organic phase was concentrated to dryness under reduced pressure at 60°C, 6 ml of isopropanol was added, the temperature was raised to reflux, stirred to dissolve, and the temperature was lowered to 0°C, 10°C, 20°C, and 30°C respectively to stir and crystallize. The crystallization solution was filtered after 3h and 5h of crystallization, and the mother liquor was collected and sent for content inspection; after 5h of crystallization, the solution was filtered, the filtrate was weighed, the filter cake was washed with an appropriate amount of isopropanol, and dried under reduced pressure at 50°C to obtain the crude voriconazole, and samples were taken for inspection of related substances and isomers.

[0104] Table 6-1. Results of investigation on crystallization temperature and time of free process (3h crystallization mother liquor)

[0105]

[0106] Table 6-2. Results of investigation on crystallization temperature and time of free process (5h crystallization mother liquor)

[0107]

[0108] Table 6-3. Results of investigation on crystallization temperature and time of free process (crude product)

[0109]

[0110] According to the test results of the crystallization mother liquor content, when the crystallization temperature is 0°C and 10°C, the loss rate in the crystallization mother liquor is less than 3%, and when the crystallization temperature is 20°C and 30°C, the loss rate in the crystallization mother liquor is about 3.5%; according to the test results of the related substances and isomers of the crude product, within the parameter investigation range, no impurities and no isomers were detected in the crude product, so based on the results of the crystallization mother liquor content, the crystallization temperature is preferably 0-10°C. According to the test results of the crystallization mother liquor content, there is no significant difference in the crude product loss rate in the crystallization mother liquor after crystallization for 3h and 5h, so the crystallization time is determined to be 3-5h.

[0111] Experimental Example 2 Investigation on the stability and repeatability of crude product preparation process

[0112] Three batches of crude products were trial-produced. The operation process is as follows:

[0113] Add 50g (143.1mmol, 1.0eq) of the third intermediate and 1000ml of acetone to a 3L reaction bottle, stir evenly, then add 38.2g (164.6mmol, 1.15eq) of a methanol solution of L-camphorsulfonic acid (dissolve L-camphorsulfonic acid in 325ml of methanol), heat to reflux, stir to dissolve. Then cool to 25-30°C, stir and crystallize for 5h, filter to obtain L-camphorsulfonate.

[0114] To a 3L reaction bottle, add the above-mentioned L-camphorsulfonate, 150ml of dichloromethane and 150ml of purified water, adjust the pH to 10-11 with 32% (w / w) sodium hydroxide solution, let stand to separate the layers, collect the organic phase, wash the organic phase with purified water (50ml×2), and collect the organic phase.

[0115] The organic phase is concentrated to dryness under reduced pressure at 60°C. 30 ml of isopropanol is added to the concentrate, the temperature is raised to reflux, stirred to dissolve, the temperature is lowered to 0-10°C, stirred to crystallize for 3-5 hours, filtered, the filter cake is washed with an appropriate amount of isopropanol, and dried under reduced pressure at 60-80°C for not less than 4 hours to obtain crude voriconazole.

[0116] Table 7. Results of three trials of crude products

[0117]

[0118] Yield = crude product content × crude product weight / feed amount of medium III × 100%; According to the results of 3 batches of trial production of crude products in Table 5, the yield of 3 batches of voriconazole crude products prepared according to the determined experimental parameters was about 31%, the purity was 100%, and no isomers were detected, indicating that the preparation process of voriconazole crude product was stable and repeatable.

[0119] Experimental Example 3 Investigation on the stability and repeatability of crude product refining process

[0120] The operation is as follows: 4 portions are added to the reaction bottle, 5g (14.3mmol, 1.0eq) of crude product and 7.5ml of isopropanol are added, the temperature is raised to reflux, and stirred to dissolve. Then the temperature is lowered to 0℃, 10℃, 20℃, and 30℃ respectively, and stirred to crystallize. Take the crystallization solution and filter it after 3h and 5h of crystallization, collect the mother liquor, and take samples for content inspection; after 5h of crystallization, filter, weigh the filtrate, collect the filter cake, dry under reduced pressure at 60-80℃, and take samples for inspection of related substances and isomers. The results of the investigation are shown in Tables 6-1, 6-2, and 6-3 below.

[0121] Table 8-1. Crystallization temperature and time investigation results (3h crystallization mother liquor)

[0122]

[0123] ① Loss rate = voriconazole content × filtrate weight / crude product feed amount × 100%;

[0124] Table 8-2. Crystallization temperature and time investigation results (5h crystallization mother liquor)

[0125]

[0126]

[0127] ① Loss rate = voriconazole content × filtrate weight / crude product feed amount × 100%;

[0128] Table 8-3. Crystallization temperature and time investigation results (finished product)

[0129]

[0130] The results of this test example: ① According to the test results of the crystallization mother liquor content, the lower the crystallization temperature, the lower the finished product loss rate in the crystallization mother liquor. When the crystallization temperature is 10°C, the loss rate is about 8-9%. There is no significant difference when the crystallization temperature is further reduced to 0°C; ② According to the test results of related substances and isomers of crude products, within the parameter investigation range, no impurities or isomers were detected in the crude products. Therefore, based on the results of the crystallization mother liquor content, the crystallization temperature is preferably 0-10°C. ③ According to the test results of the crystallization mother liquor content, there is no significant difference in the crude product loss rate in the crystallization mother liquor for 3h and 5h, so the crystallization time is determined to be 3-5h. The crystallization temperature is determined to be 0-10°C and the crystallization time is determined to be 3-5h.

[0131] Experimental Example 4 Study on the Process of Voriconazole Intermediate Comparative Experimental Method 1 for Reaction and Post-treatment Parameters (Dissociation of the Second Intermediate):

[0132] Add 5 g (11.90 mmol, 1.0 eq) of the second intermediate, 50 ml of dichloromethane and 35 ml of purified water to the reaction bottle, stir evenly, and adjust the pH to 10-11 with an appropriate amount of 32% (w / w) sodium hydroxide solution. Let stand for stratification, collect the organic phase, wash the organic phase with 35 ml of 2% disodium edetate solution and 35 ml of purified water in turn, and concentrate to dryness under reduced pressure at below 40°C to obtain an oily substance.

[0133] The above oily substance was dissolved in 25 ml (5V) methanol, 1.5 g (17.85 mmol, 1.5 eq) sodium acetate and 0.3 g 10% palladium carbon were added, and the mixture was stirred evenly. The mixture was transferred to an autoclave, and replaced with nitrogen and hydrogen in turn. The hydrogen pressure was controlled to be 0.1-0.5 MPa. The mixture was stirred at room temperature until the hydrogen pressure did not change within 30 min. The reaction was stopped and the reaction progress was monitored by TLC. 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 voriconazole intermediates.

[0134] Method 2 (without dissociation of the second intermediate):

[0135] Add 5 g (11.90 mmol, 1.0 eq) of the second intermediate, 25 ml (5V) of methanol, 2.4 g (29.75 mmol, 2.5 eq) of sodium acetate and 0.3 g of 10% palladium on carbon to the reaction bottle, stir evenly, transfer to an autoclave, replace with nitrogen and hydrogen in turn, control the hydrogen pressure to 0.1-0.5 MPa, stir at room temperature until the hydrogen pressure does not change within 30 min, stop the reaction, monitor the reaction progress by TLC, filter after the reaction is completed, weigh the filtrate, and take samples for inspection of the content of related substances and voriconazole intermediates.

[0136] Table 9-1. Results of investigation on the necessity of dissociation (related substances)

[0137]

[0138]

[0139] Table 9-2. Results of investigation on the necessity of dissociation (conversion rate)

[0140]

[0141] According to the results of related substances in the reaction liquid of voriconazole intermediates, the purity of the obtained voriconazole intermediates is above 90% by using method 1, and the purity of the obtained voriconazole intermediates is below 30% by using method 2; according to the results of the conversion rate of the reaction liquid of voriconazole intermediates, the conversion rate of the voriconazole intermediates is above 90% by using method 1, and the conversion rate of the obtained voriconazole intermediates is about 30% by using method 2, so method 1 is preferred. It is determined that the second intermediate is dissociated with sodium hydroxide and then catalytically hydrogenated.

[0142] Experimental Example 5 Comparative Experiment on Reformatsky Reaction Temperature and Reaction Time for Synthesis of Second Intermediate

[0143] 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.

[0144] Then, the temperature was controlled to -5-0°C, 0-5°C, 5-10°C, 10-15°C, and 15-20°C, and 10g (41.8mmol, 1.0eq) of intermediate I and 10.3g (46.0mmol, 1.1eq) of SM2 in tetrahydrofuran solution (intermediate I and SM2 were dissolved in 60ml of tetrahydrofuran solution) were added dropwise. After the addition was completed, the temperature was maintained and stirred for reaction. After the addition was completed (0h) and the reaction was continued for 1h, samples were taken for inspection of the content of related substances and the second intermediate.

[0145] Table 10-1. Investigation results of reaction temperature and time (0h reaction solution related substances)

[0146]

[0147] 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.

[0148] Table 10-2. Investigation results of reaction temperature and time (1h reaction solution related substances)

[0149]

[0150]

[0151] 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.

[0152] Table 10-3. Results of investigation on reaction temperature and time (conversion rate)

[0153]

[0154] Conversion rate = second intermediate content × filtrate weight / second intermediate theoretical yield × 100%

[0155] 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 intermediate I 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 intermediate I 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.

[0156] Test Example 6 Study on the Stability of Voriconazole API Finished Product

[0157] According to the relevant guidelines such as the "Guidelines for Stability Testing of APIs and Pharmaceutical Preparations" (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 9001), "Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations) (Revised)", and referring to the relevant provisions of the quality standards of voriconazole, the stability of this product was investigated for its properties, melting point, specific rotation, crystallinity, clarity and color of the solution, related substances, right-handed isomers, loss on drying, bacterial endotoxins, microbial limits, and content determination. See the table below for sample information for stability testing.

[0158] Table 11. Test sample information

[0159]

[0160] According to the quality standards of voriconazole, the three batches of validation samples (batch numbers: 221101, 221102, and 221103) were subjected to accelerated (40°C ± 2°C / 75% ± 5% RH) and long-term (30°C ± 2°C / 65% ± 5% RH) stability tests. After 6 months of accelerated and 6 months of long-term stability tests, the test results of each item met the quality standards. According to the stability test conditions and results, and with reference to the quality standards of voriconazole in Part II of the 2020 edition of the Chinese Pharmacopoeia, the storage conditions of this product are set as sealed and stored in a dry place, and the shelf life is tentatively set at 24 months. The conclusion is shown in the table below.

[0161] Table 12: Stability test results

[0162]

[0163] 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 producing voriconazole bulk drug, characterized in that: The following steps are involved: Preparation of voriconazole intermediate step: preparing voriconazole intermediate based on Reformatsky reaction, wherein the voriconazole 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; The step of preparing the crude product: the voriconazole intermediate is crystallized in a detangle agent to separate the isomers with pharmaceutical activity as the crude voriconazole product; Purification step: the crude voriconazole is crystallized and dried in isopropanol to obtain the voriconazole raw material; The detethering agent comprises a L-camphorsulfonic acid solution prepared by feeding a voriconazole intermediate and L-camphorsulfonic acid in a molar ratio of 1:1.

15.

2. The method for producing voriconazole bulk drug according to claim 1, characterized in that: The voriconazole intermediate is maintained at a temperature of 25-30° C. in the unwinding agent and crystallized for at least 5 hours.

3. The method for producing voriconazole bulk drug according to claim 2, characterized in that: The step of preparing the crude product specifically includes: The voriconazole intermediate is dissolved in acetone, and a methanol solution of L-camphorsulfonic acid is added, and acetone is added in an amount of 20 times the mass of the voriconazole intermediate and methanol is added in an amount of 6.5 times the mass of the voriconazole intermediate; The unwinding agent solution of the voriconazole intermediate is heated to reflux and stirred to dissolve. The reaction solution is cooled to 25° C. and stirred for crystallization for 5 hours, then filtered and the filter cake is collected to obtain L-camphorsulfonate.

4. The method for producing voriconazole bulk drug according to claim 3, characterized in that: The step of preparing the crude product also includes: dissolving L-camphorsulfonate, dichloromethane and purified water, adjusting the pH value to 10-11, standing for stratification, and collecting the organic phase; washing and filtering the collected organic phase, and then recrystallizing the filter cake in isopropanol, washing and drying to obtain the voriconazole crude product.

5. The method for producing voriconazole bulk drug according to claim 1, wherein: In the refining step, the crystallization temperature of the crude voriconazole in isopropanol is 0-10° C., and the crystallization time is 3-5 hours.

6. The method for producing voriconazole bulk drug according to claim 1, characterized in that: In the refining step, the drying temperature is 60-80° C. and the drying time is ≥6 hours.

7. The method for producing fuliconazole bulk drug according to claim 5, characterized in that, The refining step specifically comprises the following steps: The crude voriconazole was dissolved in isopropanol, heated to reflux, stirred, cooled to 0-10°C, stirred and crystallized for 3-5h, filtered, the filter cake was collected, and dried under reduced pressure at 60-80°C for not less than 6h to obtain the voriconazole bulk drug.

8. The method for producing voriconazole bulk drug according to claim 1, characterized in that: The step of preparing the voriconazole intermediate specifically comprises the following steps: S1: a step of synthesizing a first intermediate: a first starting material is subjected to a bromination reaction to obtain a first intermediate; 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; S3 step of synthesizing voriconazole intermediate: the second intermediate is dechlorinated under palladium-carbon catalysis to obtain a voriconazole 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 voriconazole intermediate is (2R, 3S / 2S, 3R)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidine)-1-(1H-1,2,4-triazole-1-yl)-2-butanol.

9. The method for producing voriconazole bulk drug according to claim 8, 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.

10. The method for producing voriconazole bulk drug according to claim 7, characterized in that: The steps for synthesizing the voriconazole intermediate are as follows: 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: Dry the filter cake under reduced pressure at 60-80°C for not less than 6 hours to obtain a voriconazole intermediate.

Images