Preparation method of racemic voriconazole

Abstract

The invention provides a preparation method of racemic voriconazole, and relates to the technical field of organic synthesis. The invention relates to a racemic voriconazole preparation method, which comprises: material dissolving: adding an auxiliary agent and chloro-racemic voriconazole hydrochloride into a solvent, dissolving, and uniformly mixing to obtain a material liquid; hydrogenation reduction reaction: mixing the feed liquid and hydrogen through a mixer, and carrying out hydrogenation dehalogenation reaction in a reactor filled with a catalyst; quenching, concentrating and crystallizing: adding an alkaline aqueous solution into the reaction liquid for quenching, and then concentrating under reduced pressure; filtering: cooling and stirring, filtering, and leaching a filter cake with water; and drying: carrying out vacuum drying on the filter cake to obtain the racemic voriconazole. The preparation method of the racemic voriconazole, provided by the invention, has the advantages of high automation degree in a continuous preparation process, safety, controllability, high conversion efficiency, high purity, small impurities and strong production capacity.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a preparation method of racemic voriconazole. Background Art

[0002] Voriconazole is a broad-spectrum triazole antifungal drug, mainly used to treat invasive aspergillosis, severe invasive infections caused by fluconazole-resistant Candida species, and severe infections caused by Actinomyces and Fusarium species. Its chemical name is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (IV). Due to its wide application and important clinical value, the development of efficient, safe and cost-effective methods for preparing voriconazole has always been a research hotspot in the field of drug synthesis. At present, the industry mainly uses the method of synthesizing the racemate (III) and then chiral resolution to obtain voriconazole. The preparation route is as follows:

[0003] Racemic voriconazole (III) is an important intermediate for the preparation of voriconazole (IV). There are many existing preparation methods, but they all have some shortcomings. For example, in the literature on the optimization of the synthesis process of the new antifungal drug voriconazole, it was reported that the synthesis process of voriconazole involved a method for preparing racemic voriconazole by hydrogenation reduction dehalogenation reaction of chlorinated racemic voriconazole hydrochloride. Chlorinated racemic voriconazole hydrochloride was freed by sodium methoxide, concentrated, hydrogenated and dehalogenated, filtered, extracted, concentrated, crystallized, and filtered to obtain the key intermediate racemic voriconazole with a purity of 96%. This method is cumbersome to operate, prone to impurities, low purity, and introduces new solvents during crystallization, which reduces production efficiency and increases costs, and also pollutes the environment.

[0004] Patent CN114057699 discloses that chlorinated racemic voriconazole uses sodium formate as a chemical hydrogen source and palladium carbon catalyzes the reaction to obtain racemic voriconazole. Specifically, the chlorinated racemic voriconazole is first dissolved, and then a hydrogen source and a catalyst are added to cause a dehalogenation reaction. After the reaction is completed, sodium hydroxide is used to free, crystallize, and dry to obtain racemic voriconazole. The method is slightly cumbersome to operate, is prone to impurities, has a low yield of only about 90%, and has a significantly high cost.

[0005] Based on this, the present invention provides a method for preparing racemic voriconazole. Summary of the invention

[0006] The purpose of the present invention is to provide a method for preparing racemic voriconazole, which has the advantages of high automation, safety and controllability in the continuous preparation process, high conversion efficiency, high purity, low impurities and strong production capacity.

[0007] The present invention provides a method for preparing racemic voriconazole, the steps comprising: (1) Dissolving materials: adding the auxiliary agent and racemic voriconazole to the solvent and dissolving them, and mixing them evenly to obtain a liquid feed; (2) Hydrogenation reduction reaction: The feed liquid and hydrogen are mixed in a mixer, and a hydrogenation dehalogenation reaction occurs in a reactor filled with a catalyst; excess hydrogen is recovered and used in the reaction of this step; (3) Quenching, concentrating and crystallizing: adding alkaline aqueous solution to the reaction solution for quenching and concentrating under reduced pressure; (4) Filtration: Cool down, stir, filter, and rinse the filter cake with water; (5) Drying: The filter cake is dried under vacuum to obtain racemic voriconazole.

[0008] Furthermore, the auxiliary agent in step (1) comprises sodium acetate or triethylamine; the auxiliary agent is 1%-10% by weight of chlororacemic voriconazole hydrochloride; the solvent comprises at least one of ethanol, methanol, isopropanol and water; after the auxiliary agent and the solvent are dissolved, the concentration of chlororacemic voriconazole hydrochloride is 1-15%.

[0009] Furthermore, the hydrogenation reduction dehalogenation reaction in step (2) is carried out in a specific reactor to achieve continuous production; the reactor includes a tubular reactor, a microchannel reactor and a fixed bed reactor.

[0010] Furthermore, a catalyst is added during the preparation process, and the adding method includes directly mixing with the raw materials or placing in a reactor, and the catalyst includes Pd / AC, Pd / Al2O3 or Pt / AC.

[0011] Furthermore, in step (2), the hydrogen flow rate is 180-220 mL / min, and the feed liquid flow rate is 1.5-2.5 mL / min.

[0012] Furthermore, in step (2), the reaction temperature is 45-55° C. and the pressure is 1 MPa.

[0013] Furthermore, the alkaline aqueous solution in step (3) is a sodium bicarbonate aqueous solution with a mass concentration of 1.5-2.5% and an amount of 900-1100 mL.

[0014] Furthermore, the temperature of the reduced pressure concentration crystallization is 45-50°C.

[0015] Furthermore, the filtration temperature in step (4) is 10-30°C.

[0016] Furthermore, the stirring time in step (4) is 1-2h.

[0017] Furthermore, the vacuum drying temperature in step (5) is 75-85°C.

[0018] The beneficial effects of the present invention are: The original hydrogenation reduction process uses a kettle reaction, which has a small heat exchange area, requires a long reaction time, and is relatively difficult to control pressure and reaction conditions. The material residence time is long and impurities are easily generated. Other methods use inventions of different hydrogen sources, which have low conversion rates, low yields, and high costs. In the present invention, a specific auxiliary agent is used to dissolve chloro-racemic voriconazole to a certain concentration to meet the needs of micro-reaction hydrogenation reduction technology. The micro-reaction hydrogenation reduction technology has the characteristics of high conversion efficiency and high-purity small impurities, so that it can be concentrated and removed after the reaction is quenched, while concentrating and crystallizing, and then filtering and drying to obtain a high-yield, high-purity racemic voriconazole product. In addition, the micro-reaction hydrogenation reduction technology has the characteristics of fast heat and mass transfer, controllable process, continuous reaction, short material residence time and easy to amplify. Its continuous preparation process is safe and controllable, with high conversion efficiency, high purity, small impurities, and high production capacity. And the present invention simplifies the operating steps, the catalyst used has a high life, greatly reduces production costs, and has a certain market value. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0020] Figure 1 It is a preparation device of racemic voriconazole of the present invention; Figure 2 The liquid chromatography of the product prepared in Example 1 of the present invention is Figure 1 ; Figure 3 The liquid chromatography of the product prepared in Example 1 of the present invention is Figure 2 ; Figure 4 The liquid chromatography of the product prepared in Example 1 of the present invention is Figure 3 ; Figure 5 This is the liquid phase spectrum of the product at the end of the reaction of Example 1 of the present invention Figure 1 ; Figure 6 This is the liquid phase spectrum of the product at the end of the reaction of Example 1 of the present invention Figure 2 . DETAILED DESCRIPTION

[0021] The technical scheme of the present invention is described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. It should be noted that the raw materials can be obtained commercially.

[0022] Reaction equation of the present invention is:

[0023] Racemic voriconazole is (2R,3S / 2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol; chloro-racemic voriconazole hydrochloride is (2R,3S / 2S,3R)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride.

[0024] The present invention also provides a method for preparing racemic voriconazole, the steps comprising: (1) Dissolving materials: Add an auxiliary agent and chloro-racemic voriconazole to a solvent and dissolve them, and mix them evenly to obtain a liquid; the auxiliary agent is at least one of sodium acetate, ammonium acetate or triethylamine; the auxiliary agent is 1%-10% of the weight of chloro-racemic voriconazole hydrochloride. The solvent includes at least one of ethanol, methanol, isopropanol and water; after the auxiliary agent and the solvent are dissolved, the concentration of chloro-racemic voriconazole hydrochloride is 1-15%.

[0025] (2) Hydrogenation reduction reaction: hydrogen flow rate 180-220 mL / min, feed liquid flow rate 1.5-2.5 mL / min, the feed liquid and hydrogen are mixed in a mixer and reacted in a reactor; the reaction temperature is controlled at 45-55 ° C and the pressure is 1 MPa; The reactor includes a tubular reactor, a microchannel reactor and a fixed bed reactor; A catalyst is also added during the preparation process, and the addition method includes directly mixing with the raw materials or placing in a reactor, and the catalyst includes Pd / AC, Pd / Al2O3 or Pt / AC; (3) Quenching and concentrating the crystals: add 900-1100 mL of a 1.5-2.5% sodium bicarbonate aqueous solution, set the temperature to 45-50°C, and perform vacuum distillation and concentrating the crystals; (4) Filtration: Cool to 20±10℃, stir for 1-2h, filter, and rinse the filter cake with 90-110mL of water; (5) Drying: The filter cake is vacuum dried at a temperature of 75-85°C to obtain racemic voriconazole.

[0026] On this basis, the present invention also provides a device for preparing racemic voriconazole, comprising a dissolving tank, a delivery pump, a mixer, a packed bed, a solvent receiving tank 1, a distillation kettle and a solvent receiving tank 2 which are cyclically connected in sequence; a back pressure valve is also connected between the packed bed and the solvent receiving tank 1; the mixer is also provided with an air inlet, the air inlet is connected to a hydrogen bottle, and the gas flow rate of the hydrogen bottle entering the mixer is controlled by a gas mass flowmeter arranged between the hydrogen bottle and the mixer.

[0027] The present invention will be further explained below with examples: Example 1

[0028] This embodiment provides a method for preparing racemic voriconazole, the steps comprising: (1) Material dissolution: dissolve 100 g of raw material voriconazole chloride, 70 g of sodium acetate, and 2 g of 10% Pd / AC in a mixed solvent of 900 g of methanol and 100 g of water, and mix well; Hydrogenation reduction reaction: Turn on the delivery pump and hydrogen valve, set the hydrogen flow rate to 200 mL / min, the feed liquid flow rate to 2 mL / min, mix the feed liquid and hydrogen through the mixer, and then pass through the fixed bed reactor. The reactor has a diameter of 25 mm and a length of 250 mm. The reaction temperature is controlled at 50 ° C and the pressure is 1 MPa. The receiving tank receives the reaction solution, and the raw materials react completely; Quenching and concentrating the crystals: Add 1000 mL of 2% sodium bicarbonate aqueous solution to the reaction solution, set the temperature to 50°C, and perform vacuum distillation and concentration; (4) Filtration: Cool to 20°C, stir for 2 h, filter, and rinse the filter cake with 100 mL of water; (5) Drying: The filter cake was vacuum dried at 80°C until the moisture content was less than 0.5%, yielding 81.5 g of racemic voriconazole with a yield of 98% and a purity of 99.3%.

[0029] like Figure 2-Figure 4 is a liquid chromatogram of the product prepared in Example 1 of the present invention; Figure 5 and Figure 6 It is the liquid chromatogram of the product at the end of the reaction of Example 1 of the present invention.

[0030] in, Figure 2-Figure 4 The data of the obtained liquid chromatogram are shown in Table 1 below:

[0031] Figure 5 and Figure 6 The data of the obtained liquid chromatogram are shown in Table 2 below:

[0032] Example 2 (1) Material dissolution: dissolve 100 g of raw material racemic voriconazole, 100 g of sodium acetate, and 2 g of 1% Pd / Al2O3 in a mixed solvent of 900 g of methanol and 100 g of water, and mix well; (2) Hydrogenation reduction reaction: Turn on the delivery pump, set the hydrogen flow rate to 200 mL / min, the feed liquid flow rate to 2 mL / min, mix the feed liquid and hydrogen through the mixer, and then pass through the microchannel reactor, the microchannel retention volume is 50 mL, the reaction temperature is controlled at 50 ° C, the pressure is 0.5 MPa, and the receiving tank receives the reaction solution; the raw material reaction is complete; (3) Quenching and concentrating the crystals: Filter the reaction solution, rinse the filter cake with methanol, add 1000 mL of 2% sodium bicarbonate aqueous solution to the filtrate reaction solution, set the temperature to 45°C, and concentrate under reduced pressure; (4) Filtration: Cool to 20°C, stir for 2 hours, filter, and rinse the filter cake with 100 mL of water (5) Drying: The filter cake was vacuum dried at 80°C until the moisture content was less than 0.5%, yielding 81.2 g of racemic voriconazole with a yield of 97.7% and a purity of 99.3%.

[0033] Example 3 (1) Material dissolution: Dissolve 5 g of the raw material racemic voriconazole chloride and 3 g of sodium acetate in a mixed solvent of 66 g of methanol and 3.3 g of water, and mix well.

[0034] (2) Hydrogenation reduction reaction: Turn on the delivery pump, set the hydrogen flow rate to 100 mL / min, the feed liquid flow rate to 2 mL / min, mix the feed liquid and hydrogen through the mixer, and then pass through the fixed bed reactor. The fixed bed reactor has a diameter of 40 mm, a height of 165 mm, a catalyst of 2% Pd / AC 25 mL, and a reaction temperature of 60 ° C and a pressure of 0.4 MPa. The receiving tank receives the reaction solution. The raw materials react completely.

[0035] (3) Quenching and concentrating the crystals: Add 1000 mL of 2% sodium bicarbonate aqueous solution to the reaction solution, set the temperature to 45-50°C, and concentrate under reduced pressure.

[0036] (4) Filtration: Cool to 20°C, stir for 2 hours, filter, and rinse the filter cake with 100 mL of water (5) Drying: The filter cake was vacuum dried at 80°C until the moisture content was less than 0.5%, yielding 81.6 g of racemic voriconazole with a yield of 98.2% and a purity of 99.2%.

[0037] Example 4 (1) Material dissolution: Dissolve 5 g of the raw material voriconazole chloride and 3 g of sodium acetate in a mixed solvent of 80 g of ethanol and 4.0 g of water, and mix well.

[0038] (2) Hydrogenation reduction reaction: Turn on the delivery pump, set the hydrogen flow rate to 100 mL / min, the feed liquid flow rate to 2 mL / min, mix the feed liquid and hydrogen through the mixer, and then pass through the fixed bed reactor with a diameter of 40 mm, a height of 165 mm, a catalyst of 5% Pt / AC25 mL, control the reaction temperature to 30 ° C, the pressure to 0.5 MPa, and the receiving tank receives the reaction solution. The raw material reaction is complete.

[0039] (3) Quenching and concentrating the crystals: Add 1000 mL of 2% sodium bicarbonate aqueous solution to the reaction solution, set the temperature to 50°C, and concentrate under reduced pressure.

[0040] (4) Filtration: Cool to 20°C, stir for 2 h, filter, and rinse the filter cake with 100 mL of water; (5) Drying: The filter cake was vacuum dried at 80°C until the moisture content was less than 0.5%, yielding 81.5 g of racemic voriconazole with a yield of 98.0% and a purity of 99.3%.

[0041] Example 5 (1) Material dissolution: dissolve 5 g of the raw material voriconazole and 3.5 g of triethylamine in a mixed solvent of 80 g of isopropanol and 4 g of water, and mix well; (2) Hydrogenation reduction reaction: Turn on the delivery pump, set the hydrogen flow rate to 100mL / min, the feed liquid flow rate to 2mL / min, mix the feed liquid and hydrogen through the mixer, and then pass through the fixed bed reactor with a diameter of 40mm, a height of 165mm, a catalyst of 5%Pt / AC25mL, control the reaction temperature to 30℃, the pressure to 0.5Mpa, and the receiving tank receives the reaction solution. The raw material reaction is complete; (3) Quenching and concentrating the crystals: Add 1000 mL of 2% sodium bicarbonate aqueous solution to the reaction solution, set the temperature to 45-50°C, and concentrate under reduced pressure; (4) Filtration: Cool to 20±10℃, stir for 1-2h, filter, and rinse the filter cake with 100mL of water; (5) Drying: The filter cake was vacuum dried at a temperature of 75-85°C until the moisture content was less than 0.5%, yielding 80.4 g of racemic voriconazole with a yield of 96.7% and a purity of 99.0%.

[0042] The material dissolution step in the present invention and the dissolution of the raw materials under different conditions have a great impact on the application of the micro-reaction technology, including the blockage of the reactor, the deactivation of the catalyst, the agglomeration of the catalyst, etc. For example, sodium carbonate cannot be dissolved in the solution and may block the reactor, etc., as follows:

[0043] The raw materials have good solubility in ethanol, methanol and isopropanol under the conditions of auxiliary agents sodium acetate, ammonium acetate, ammonia water and triethylamine, meeting the requirements of micro-reaction technology. On the basis of Example 1, when different catalysts, reaction temperature and reaction pressure are selected, these are also the main factors affecting the conversion efficiency of the reaction and the purity of the product. The specific data are as follows:

[0044] Finally, it should be noted that: the present invention illustrates the product and detailed preparation method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned product and detailed preparation method, that is, it does not mean that the present invention must rely on the above-mentioned product and detailed preparation method to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention and addition of auxiliary materials, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0045] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited to the specific details in the above embodiments, and the technical solution of the present invention can be subjected to a variety of simple modifications within the technical concept of the present invention. These simple modifications all belong to the protection scope of the present invention.

[0046] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0047] In addition, various embodiments of the present invention may be arbitrarily combined, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A method for preparing racemic voriconazole, characterized in that the steps include: (1) Dissolving materials: adding the auxiliary agent and racemic voriconazole hydrochloride into a solvent and dissolving them, and mixing them evenly to obtain a liquid feed; (2) Hydrogenation reduction reaction: The feed liquid and hydrogen are mixed in a mixer, and a hydrogenation dehalogenation reaction occurs in a reactor filled with a catalyst; excess hydrogen is recovered and used in the reaction of this step; (3) Quenching, concentrating and crystallizing: adding alkaline aqueous solution to the reaction solution for quenching and concentrating under reduced pressure; (4) Filtration: Cool down, stir, filter, and rinse the filter cake with water; (5) Drying: The filter cake is dried under vacuum to obtain racemic voriconazole.

2. The method for preparing racemic voriconazole according to claim 1, characterized in that: The auxiliary agent in step (1) comprises sodium acetate or triethylamine; the auxiliary agent is 1%-10% by weight of chlororacemic voriconazole hydrochloride; the solvent comprises at least one of ethanol, methanol, isopropanol and water; after the auxiliary agent and the solvent are dissolved, the concentration of chlororacemic voriconazole hydrochloride is 1-15%.

3. The method for preparing racemic voriconazole according to claim 1, characterized in that: The hydrogenation reduction dehalogenation reaction in step (2) is carried out in a specific reactor to achieve continuous production; the reactor includes a tubular reactor, a microchannel reactor and a fixed bed reactor.

4. The method for preparing racemic voriconazole according to claim 3, characterized in that: A catalyst is also added during the preparation process. The addition method includes directly mixing with the raw materials or placing in a reactor. The catalyst includes Pd / AC, Pd / Al2O3 or Pt / AC.

5. The method for preparing racemic voriconazole according to claim 1, characterized in that: In the step (2), the hydrogen flow rate is 180-220 mL / min, and the feed liquid flow rate is 1.5-2.5 mL / min.

6. The method for preparing racemic voriconazole according to claim 1, characterized in that: In step (2), the reaction temperature is 45-55°C and the pressure is 1 MPa.

7. The method for preparing racemic voriconazole according to claim 1, characterized in that: The alkaline aqueous solution in step (3) is a sodium bicarbonate aqueous solution with a mass concentration of 1.5-2.5% and an amount of 900-1100 mL.

8. The method for preparing racemic voriconazole according to claim 1, characterized in that: The temperature of the reduced pressure concentration crystallization is 45-50°C.

9. The method for preparing racemic voriconazole according to claim 1, characterized in that: The filtration temperature in step (4) is 10-30° C. and the stirring time is 1-2 h.

10. The method for preparing racemic voriconazole according to claim 1, characterized in that: The temperature of vacuum drying in step (5) is 75-85°C.

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