CN112079819B

CN112079819B - Improved voriconazole racemate preparation method

Info

Publication number: CN112079819B
Application number: CN202011016898.3A
Authority: CN
Inventors: 朱学东; 孙建华; 张建强; 杨洪楠; 顾伟伟
Original assignee: Nanjing Easeheal Pharmaceutical Co ltd
Current assignee: Nanjing Easeheal Pharmaceutical Co ltd
Priority date: 2020-09-24
Filing date: 2020-09-24
Publication date: 2022-06-17
Anticipated expiration: 2040-09-24
Also published as: CN112079819A

Abstract

The invention relates to an improved voriconazole racemate preparation method. The method comprises the following steps: (1) reacting 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone with 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine in the presence of zinc powder, lead powder and iodine to prepare R, S/S and R-1; (2) under the conditions of palladium-carbon catalyst and heating, R, S/S, R-1 or salt thereof is taken as a reaction substrate to react with ammonium formate in a reaction solvent to prepare voriconazole racemate reaction liquid; filtering the reaction solution, collecting the filtrate, concentrating, adding water, adjusting the pH of the solution to 7-9, stirring, filtering, collecting a filter cake, and drying to obtain the compound I; (3) voriconazole racemic body is resolved by 1R- (-) -camphorsulfonic acid to prepare voriconazole. The preparation method of the invention avoids alkali degradation and reduces impurities; meanwhile, the preparation method does not need to process R, S/S and R-1 hydrochloride, can directly react, does not need extraction and other operations in the post-treatment, and has the advantages of simple and convenient operation, safety, controllability, good reproducibility, high yield of the obtained product, high purity, low cost, suitability for industrial production and the like.

Description

Improved voriconazole racemate preparation method

Technical Field

The invention relates to the field of drug synthesis, in particular to an improved preparation method of voriconazole racemate.

Background

Voriconazole is a fluconazole derivative, is a second-generation triazole antifungal new drug which is developed by sponish corporation in the united states and first marketed in 2002, is mainly used for treating acute or chronic deep fungal infection clinically, is a first-line drug for treating invasive aspergillosis, and has the advantages of wide antibacterial spectrum, strong antibacterial effect, good safety, high efficiency, low toxicity and the like. With the rapid increase of clinical demand of domestic hospitals and ICUs on antifungal drugs, voriconazole and preparations thereof still have great market potential, and optimization of preparation processes thereof, improvement of drug quality and reduction of production cost have industrial value.

Voriconazole is a chiral drug, the molecule of the voriconazole contains two chiral centers and four optical isomers, wherein the antibacterial activity of the 2R,3S/2S,3R racemate is more than 200 times of that of the 2S,3S/2R,3R racemate. Compared with the 2S,3R configuration, the single optical pure isomer 2R,3S configuration (voriconazole medicinal configuration), has higher inhibition activity on aspergillus and wider antibacterial spectrum. The clinically used active ingredient (API) is the 2R,3S configurational isomer, voriconazole.

The synthetic method of voriconazole uses 2R,3S/2S,3R raceme as key intermediate, uses 1R- (-) -10-camphorsulfonic acid as chiral resolution reagent, and obtains voriconazole by salt resolution. The improvement of the preparation process of voriconazole racemate becomes the key of the improvement of voriconazole.

Document 1(Organic Process Research & development.2001,5: 28-36) discloses a preparation method of voriconazole racemate, which takes R, S/S, R-1 free state as a substrate, palladium carbon as a catalyst and hydrogen as a hydrogen source to remove chlorine atoms to prepare the voriconazole racemate.

The method comprises the steps of taking a compound R, S/SR-1 hydrochloride as a substrate, carrying out dissociation, desalination, extraction and concentration to obtain a free state R, S/SR-1, dissolving the free state R, S/SR-1 in methanol or ethanol, adding a palladium-carbon catalyst and a certain amount of sodium acetate, and introducing hydrogen to react to obtain the voriconazole racemate. The substrate R, S/S, R-1 hydrochloride used in the method is a reaction product of the last step of Reformatsky coupling, the Reformatsky reaction system is very complex, a large number of diastereomers are generated in reaction liquid except residual intermediates, most impurities and diastereomers can be removed by salt formation, and the product R, S/S, R-1 hydrochloride becomes a substrate which must be adopted in a dechlorination process. In order to increase the dissolubility of a substrate and the catalytic activity of a palladium catalyst, before dechlorination, a hydrochloric acid state is made into a free state, and then catalytic hydrogenation is carried out.

WO2012114273A1 discloses a method for preparing voriconazole racemate by taking R, S/S and R-1 hydrochloride as a substrate, neutralizing with strong alkali to prepare a free state, and removing chlorine atoms by taking palladium-carbon as a catalyst and ammonium formate as a hydrogen source without extraction operation. This method has the following drawbacks: firstly, before dechlorination, strong alkali is adopted to neutralize R, S/S and R-1 hydrochloride to prepare free R, S/S and R-1 which are easy to degrade to generate byproducts; secondly, after the free state is prepared, post-treatment operations such as extraction and the like are not carried out, sodium chloride and sodium hydroxide in a reaction system are adsorbed on the surface of the palladium-carbon catalyst, so that the activity of the catalyst is reduced, and the slow reaction and the incomplete reaction are caused; thirdly, the extraction operation after the dechlorination is finished increases the usage amount of the solvent, increases the energy consumption cost, the labor cost and the time cost, and in addition, the salt-forming purification operation is needed, so the period is prolonged, the cost is increased, the reduced pressure concentration is realized, the difficulty in evaporating water is high, the by-products are increased when water, especially acid water, is evaporated for a long time, the time cost is increased, the requirement on equipment is strict, and the production cost is increased; fourthly, the voriconazole racemate hydrochloride prepared by the method has difficult recrystallization in the later step of resolution process, and seed crystal seeding is needed.

In order to avoid using hydrogen and solve the problem that ammonium formate is not reacted or the yield is low, CN106632267A discloses a method for preparing voriconazole racemate by removing chlorine atoms by using free R, S/SR-1 as a substrate, palladium carbon as a catalyst and potassium formate as a hydrogen source. This method avoids the use of hydrogen, but has the following drawbacks: firstly, the free R, S/S and R-1 are still used as substrates, and the R, S/S and R-1 hydrochloride is neutralized by strong alkali before dechlorination to prepare the free state, but the substrates are unstable in alkali and are easy to degrade, and the prepared free state needs extraction operation, so that the energy consumption is increased; secondly, in the dechlorination process, the potassium formate has strong activity, strict requirements on reaction substrates, conditions and the like, and byproducts are easily generated; thirdly, the catalyst palladium carbon is used in a large amount (10%), so that the post-treatment difficulty is increased; fourthly, after the dechlorination reaction is finished, products need to be extracted and separated, the using amount of a solvent and a drying agent is increased, and the energy consumption and the cost are increased; fifthly, the voriconazole racemate prepared by the method is light yellow oily matter and needs to be recrystallized and purified.

Therefore, a preparation method of voriconazole racemate, which is simple and convenient to operate, controllable in process, high in yield and purity and suitable for industrial production, is urgently needed.

Disclosure of Invention

The invention aims to provide a preparation method of voriconazole racemate, which comprises the following steps: 1) under the conditions of palladium-carbon catalyst and heating, R, S/S, R-1 or salt thereof is taken as a reaction substrate to react with ammonium formate in a reaction solvent to prepare voriconazole racemate reaction liquid; 2) Filtering the reaction solution, collecting the filtrate, concentrating, adding water, adjusting the pH of the solution to 7-9, stirring, filtering, collecting the filter cake, and drying to obtain the final product.

In a preferred embodiment of the present invention, the salt is selected from any one of hydrochloride, hydrobromide, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, acetate, oxalate, malonate, valerate, glutamate, oleate, p-toluenesulfonate, methanesulfonate, isethionate, fumarate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanilliate, mandelate, succinate, gluconate, lactobionate, or a combination thereof.

In a preferred technical scheme of the invention, ammonium formate: the molar ratio of the reaction substrates is 1:2-1:6, preferably 1:3-1: 5.

In a preferred technical scheme of the invention, the mass ratio of the palladium to the carbon to the reaction substrate is 1-10%, preferably 4-8%, and more preferably 5-6%.

In the preferred technical scheme of the invention, the mass fraction of the palladium loading in the palladium-carbon is 5% or 10%.

In the preferred technical scheme of the invention, the heating temperature is 40-65 ℃, and is preferably 55-60 ℃.

In a preferred embodiment of the present invention, the reaction solvent is a mixed solvent of alcohol and water, wherein the alcohol is selected from any one of methanol, ethanol, and isopropanol, or a combination thereof.

In a preferred embodiment of the present invention, the alcohol in the reaction solvent: the volume ratio of water is 5:1 to 15:1, preferably 10: 1.

In a preferred technical scheme of the invention, a reaction solvent: the volume mass ratio of the reaction substrates is 8:1-15:1, preferably 10:1-13:1, and more preferably 11: 1.

In the preferred technical scheme of the invention, the pH value of the solution is adjusted to 7-8.

In a preferred technical scheme of the invention, the post-treatment of the reaction liquid prepared in the step 1) comprises the following steps: filtering the reaction solution, collecting filtrate, concentrating the filtrate under reduced pressure to dryness, adding water into the concentrated residue, adjusting the pH of the solution to 7-8, stirring for 0.5-8h, filtering, washing a filter cake with water, and drying at the temperature of 60-70 ℃ to obtain the voriconazole racemate.

In a preferred technical scheme of the invention, the base used for adjusting the pH of the solution is any one or combination of potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate.

In a preferred embodiment of the present invention, the drying is selected from any one of reduced pressure drying and atmospheric pressure drying, or a combination thereof.

In the preferred technical scheme of the invention, the water adding amount in the step 2) is as follows: the volume mass ratio of the reaction substrate is 5:1-30:1, preferably 10:1-20:1, more preferably 10:1-15: 1.

Another object of the present invention is to provide a method for preparing voriconazole, which comprises the following steps:

in the preferable technical scheme of the invention, in the step 1, 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone and 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine react in the presence of zinc powder, lead powder and iodine to prepare R, S/S and R-1.

In the preferable technical scheme of the invention, in the step 1, zinc powder and lead powder react firstly, then react with iodine, and then react with 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone and 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine to prepare R, S/S, R-1.

In a preferred technical scheme of the invention, the step 2 comprises the following steps: 1) under the conditions of palladium-carbon catalyst and heating, R, S/S, R-1 or salt thereof is taken as a reaction substrate to react with ammonium formate in a reaction solvent to prepare voriconazole racemate reaction liquid; 2) filtering the reaction solution, collecting the filtrate, concentrating, adding water, adjusting the pH of the solution to 7-9, stirring, filtering, collecting a filter cake, and drying to obtain the compound.

In the preferable technical scheme of the invention, in the step 3, voriconazole racemic body is resolved by 1R- (-) -camphorsulfonic acid to prepare voriconazole.

Another object of the present invention is to provide the use of voriconazole racemate for the preparation of voriconazole.

Another object of the present invention is to provide a pharmaceutical composition comprising voriconazole or its racemate or a pharmaceutically acceptable salt thereof according to the present invention and a pharmaceutically acceptable excipient.

Another object of the present invention is to provide a pharmaceutical composition comprising a first antibacterial agent voriconazole of the present invention or its racemate or a pharmaceutically acceptable salt thereof, and a second antibacterial agent.

In a preferred technical scheme of the invention, the second antibacterial agent is selected from any one of quinolone drugs, penicillins drugs, cephalosporins drugs, beta-lactams drugs, aminoglycosides, macrolides drugs and lincomycin drugs or a combination thereof.

In a preferred technical scheme of the invention, the quinolone drug is selected from any one or combination of norfloxacin (norfloxacin), enoxacin, ciprofloxacin, ofloxacin, levofloxacin, pefloxacin and sparfloxacin.

In a preferred technical scheme of the invention, the penicillin drug is any one or combination of penicillin G, penicillin V, methicillin (neopenicillin I), ampicillin (ampicillin), amoxicillin (amoxicillin), ticarcillin (carboxythiophenicin), piperacillin (piperacillin).

In a preferred embodiment of the present invention, the cephalosporin drugs are selected from any one or a combination of cefazolin, cephradine, cephalexin, cephradine, cefadroxil, cefuroxime (cefuroxime), cefamandole, cefoxitin, cefmetazole, cefuroxime axetil, cefaclor, cefotaxime, ceftazidime, ceftriaxone, cefoperazone, ceftizoxime, cefodizime, cefixime, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefepime, and cefpirome.

In a preferred technical scheme of the invention, the beta-lactam drugs are selected from any one of imipenem, sitagliptin and meropenem or a combination thereof.

In a preferred technical scheme of the invention, the aminoglycoside drug is any one or the combination of gentamicin, tobramycin, netilmicin, amikacin (amikacin), streptomycin and spectinomycin.

In a preferred embodiment of the present invention, the macrolide is any one or a combination of erythromycin, clarithromycin, roxithromycin, azithromycin, josamycin, midecamycin and spiramycin.

In a preferred technical scheme of the invention, the lincomycin medicines are selected from any one or combination of lincomycin and clindamycin.

Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.

Compared with the prior art, the invention has the following beneficial technical effects:

1. the preparation method takes R, S/S and R-1 salts as reaction substrates, avoids adopting alkali for neutralization, avoids sodium chloride and sodium hydroxide from being adsorbed to reduce the catalytic efficiency and the reaction yield of Pd/C; and complicated free extraction operation is not needed, so that the energy consumption and materials are saved, the target substance loss and the generation of three wastes are reduced, the preparation yield of the voriconazole racemate is remarkably improved, and the technology is applied to the synthesis of voriconazole bulk drugs, and the total yield is remarkably improved.

2. The post-treatment of the preparation method is filtration, and the preparation method has the advantages of simple and convenient operation, no need of using a large amount of organic solvent for extraction, reduction of three wastes, environmental protection, higher cost and the like.

3. The product obtained by the preparation method can be used for preparing the voriconazole bulk drug without further purification, so that the production period is shortened, and the material cost and the time cost are saved; and the obtained crude drug has high purity, and meets the requirements of drug quality standards.

4. The preparation method has the advantages of simple operation, high yield, high process safety, no need of introducing a large amount of auxiliaries and solvents, energy conservation, environmental protection, cost and the like, and is suitable for industrial scale-up production.

Detailed Description

The present invention is illustrated by the following examples, which should be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Other insubstantial modifications and adaptations of the present invention can be made without departing from the scope of the present invention.

EXAMPLE 1 Synthesis and purification of the Compound R, S/SR-1 hydrochloride

0.95kg of zinc powder, 43.2g of lead powder and 5L of THF are added into a three-mouth reaction bottle, heated and refluxed for 3 hours under the protection of nitrogen, and cooled to room temperature. 1.06kg of iodine simple substance is dissolved in 3L of THF, and the solution is dripped into a reaction system, the temperature is controlled not to exceed 45 ℃, and after the dripping is finished, the solution is stirred for 0.5 h.

The system was cooled to 0-5 ℃ and 0.66kg of 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone and 1.00kg of 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine were dissolved in 6L of THF and added dropwise to the reaction system while controlling the system temperature to not more than 5 ℃.

An acetic acid solution (850mL of acetic acid in 7L of water) was added to the reaction system, followed by stirring. Filtering, removing solid, and collecting filtrate.

The filtrate was evaporated at 60 ℃ under reduced pressure to remove THF, 8L of ethyl acetate was added, stirred, and the organic phase was collected. The organic phase was washed three times with 4L each time of 5% disodium EDTA solution. The organic layer was collected, washed once with 3L of saturated sodium chloride solution, and dried by adding 335.6g of anhydrous sodium sulfate.

The mixture was filtered, the filtrate was concentrated to dryness at 40 ℃ under reduced pressure, and 3L of ethyl acetate, 600mL of isopropanol and 240mL of concentrated hydrochloric acid were added to the residue, followed by crystallization with stirring. Filtering, collecting, and drying the filter cake under reduced pressure to obtain 776.0g of white solid, wherein the yield is 61.9 percent, and the purity is 99.0 percent.

Example 2 Synthesis of voriconazole racemate

100.0g R, S/SR-1 hydrochloride, 60.0g ammonium formate, 1L methanol and 100mL water are sequentially added into a three-neck reaction flask, stirred at room temperature and dissolved, 5.0g 10% palladium carbon catalyst is added, the temperature is heated to 60 ℃, and the reaction is carried out for 4 hours until the reaction is complete. The reaction mixture was cooled to 40 ℃ and the methanol was evaporated under reduced pressure, and 1L of purified water was added to the residue, and after adjusting the pH to 7-8 with a saturated sodium carbonate solution, stirring was continued at room temperature for 6 hours. Filtering, washing a filter cake with purified water, collecting the filter cake, and drying the filter cake at 60-70 ℃ under reduced pressure to constant weight to obtain 82.1g of off-white solid, namely voriconazole racemate, wherein the yield is as follows: 98.8 percent and the purity is 98.2 percent.

Examples 3-5 Effect of ammonium formate dosage on voriconazole racemate Synthesis

The effect of the amount of added ammonium formate on the synthesis of voriconazole racemate was investigated with reference to the synthesis of example 2, but without changing other conditions (see table 1).

When the molar ratio of ammonium formate to substrate is 3: when 1 hour, the reaction speed is slow, and after 4 hours of reaction, the residual quantity of R, S/SR-1 hydrochloride in the reaction liquid is 35.12 percent; when the mixture ratio is increased to 4-5: 1 hour, the reaction is obviously accelerated, and the reaction is basically complete within 4 hours. The reaction rate increases with increasing ammonium formate usage.

The residual amounts of R, S/SR-1 and R, S/SR-1 hydrochloride are calculated by high performance liquid chromatography detection and area normalization.

TABLE 1

Examples 6-8 Effect of palladium on carbon amounts on voriconazole racemate Synthesis

Referring to the synthesis method of example 2, palladium on carbon with 10% palladium loading was selected, and the influence of the parameters on the reaction was investigated by changing the amount of palladium on carbon under otherwise unchanged conditions (see table 2).

When the amount of the palladium-carbon is 4%, the reaction speed is slow, and the reaction can not be completed within 7 hours; when the amount of palladium-carbon is increased to 5% to 6%, the reaction is substantially complete within 4 h. The reaction rate increases with increasing palladium on carbon.

The residual amounts of R, S/S, R-1 and R, S/SR-1 hydrochlorides are calculated by liquid phase detection and area normalization.

TABLE 2

Example 9 Synthesis of voriconazole

Dissolving 70.00g of voriconazole racemic mixture in 1200mL of acetone, and filtering; 46.55g of 1R- (-) -camphorsulfonic acid was dissolved in 420mL of methanol and filtered; mixing the two filtrates, heating to reflux, and dissolving; slowly cooling to 0-5 deg.C, stirring and crystallizing for 4-6 h. Filtering, collecting filter cake, and drying under reduced pressure. The resulting solid was dispersed in 300mL ethyl acetate over 5% Na₂CO₃Adjusting the pH value of the solution to 8-9, standing for layering, and collecting an organic layer; washing the organic layer once by 200mL of saturated NaCl solution, layering, and collecting the organic layer; 30.00g of anhydrous sodium sulfate was added and dried for 1 hour.

Filtering, and concentrating the filtrate at 45 deg.C under reduced pressure to dryness. Adding 50mL of isopropanol into the residue, heating to 80 ℃, stirring, dissolving, naturally cooling to about 0 ℃, and stirring for crystallization for 4-6 h. Filtration and drying under reduced pressure gave 28.05g of white solid, yield: 40.1%, purity: 99.9 percent.

Comparative example 1

Example 6 of CN106632267A was reproduced.

10g of the hydrochloride of intermediate A, 100mL of dichloromethane and 20mL of water are mixed, the temperature of the reaction mixture is controlled to below 15 ℃ by means of an ice-water bath, the pH8-9 of the reaction mixture is adjusted by adding sodium hydroxide in a volume fraction of 20% dropwise, the organic phase is separated and washed twice with 50mL of water each time. After the water washing is finished, 1.0g of activated carbon is added, stirring and decoloring are carried out for 30min, filtering is carried out, and a filter cake is washed by a small amount of dichloromethane to obtain a free intermediate A.

Dissolving 10g of the intermediate A in 90mL of ethanol, sequentially adding 1.0g of 10% palladium-carbon and 10mL of 0.24g/mL potassium formate aqueous solution under the protection of nitrogen, and stirring and refluxing at 30 ℃ for reaction for 60 min. And (3) detecting complete reaction by using HPLC, performing suction filtration, removing the palladium-carbon catalyst in the reaction liquid, concentrating, and removing the solvent to obtain a light yellow oily substance, namely the crude voriconazole product.

Dissolving crude voriconazole with ethyl acetate, washing with water for 3 times, and removing ethyl acetate; and then methanol is used for dissolving the crude voriconazole product at 50 ℃, and cooling crystallization is carried out at the temperature lower than 30 ℃ to obtain 7.9g of voriconazole with the purity of 99.9%.

The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined in the appended claims.

Claims

1. A preparation method of voriconazole racemate is characterized by comprising the following steps: adding 100.0g R, S/SR-1 hydrochloride, 60.0g ammonium formate, 1L methanol and 100mL water into a three-neck reaction flask in sequence, stirring at room temperature to dissolve, adding 5.0g 10% palladium-carbon catalyst, heating to 60 ℃, and reacting for 4 hours until the reaction is complete; cooling the reaction liquid to 40 ℃, evaporating methanol under reduced pressure, adding 1L of purified water into the residue, adjusting the pH value to 7-8 by using a saturated sodium carbonate solution, and continuing stirring at room temperature for 6 hours; filtering, washing filter cakes with purified water, collecting the filter cakes, drying the filter cakes at 60-70 ℃ under reduced pressure until the weight of the filter cakes is constant to obtain off-white solid 82.1g, namely voriconazole racemate,

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