Voriconazole synthesis method

Abstract

The invention provides a synthesis method of voriconazole, and belongs to the field of medicine synthesis. The method comprises the following steps: taking an intermediate A as a raw material, and carrying out continuous flow on the intermediate A and hydrogen under the catalysis of palladium-carbon to obtain the voriconazole raceme. According to the synthesis method, hydrogen is used as a hydrogen source, palladium-carbon is used as a catalyst, chlorine atoms on a pyrimidine ring of an intermediate A are removed, and the raceme of voriconazole is obtained. The synthesis method has the advantages of few by-products, high product quality, mild reaction conditions, low cost and high process safety, and is suitable for industrial mass production.

Description

Technical Field

[0001] The present invention relates to, in particular to, a method for synthesizing voriconazole. Background Art

[0002] Voriconazole is a new type of broad-spectrum triazole antifungal drug synthesized by Pfizer Inc. based on the structure of fluconazole. It has the advantages of good pharmacokinetic characteristics and a broad antibacterial spectrum. It has become the first-line treatment for invasive aspergillosis. 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, and its structural formula is as follows:

[0003]

[0004] At present, in the prior art, during the hydrogenation process of synthesizing voriconazole, the amount of palladium carbon used is high, which greatly increases the cost, and the high-pressure reaction makes it difficult to ensure safety during the scale-up process. Summary of the invention

[0005] In view of the above defects and problems, the present invention provides a method for preparing voriconazole, and the technical problem to be solved is that the preparation method can synthesize voriconazole racemate safely, efficiently and at low cost.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] A method for preparing voriconazole comprises the following steps:

[0008] Step A, adding voriconazole intermediate A to 70% ethanol, adding sodium acetate to dissolve while stirring, heating to 70° C. to obtain a clear solution, and adding 3% palladium on carbon;

[0009] Step B: Debug the continuous flow equipment to fill the continuous flow equipment with hydrogen, and maintain the equipment pressure at 0.5 MPa and the temperature at 80°C.

[0010] Step C: Pump the reaction solution in step A into a continuous flow device to obtain a crude voriconazole hydrogenation reaction solution in a receiving tank.

[0011] Step D: Filter, concentrate and wash with water to obtain a crude voriconazole mixture.

[0012] The method adopts a continuous flow hydrogenation method to synthesize the voriconazole racemic body. The method is simple to operate and has a high yield. It improves the safety of the voriconazole hydrogenation production process, greatly reduces the use of palladium carbon, reduces costs, and is convenient for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The HPLC spectrum of voriconazole in Example 2; DETAILED DESCRIPTION

[0014] Intermediate A is an intermediate product produced in the process of synthesizing voriconazole. The last step reaction in multiple synthetic routes of voriconazole is the reaction of obtaining voriconazole from intermediate A, and this reaction is also the rate-limiting step in the synthesis process of voriconazole. That is, the key to obtaining high-quality voriconazole lies in whether intermediate A can be smoothly converted into voriconazole.

[0015] The synthesis method uses hydrogen as a hydrogen source and palladium carbon as a catalyst to remove the chlorine atom on the pyrimidine ring of the intermediate A through a continuous flow device to obtain the racemic form of voriconazole, and the reaction formula is:

[0016]

[0017] Compared with reactions using autoclaves, the pressure and palladium carbon of the continuous flow are greatly reduced, and the amount of hydrogen in the continuous flow is extremely small, which greatly improves the safety of the reaction in industrial production and the production cost.

[0018] In the prior art, ammonium formate is often used as a hydrogen source. During the reaction, ammonium formate decomposes into carbon dioxide gas and volatile free ammonia. These two substances will undergo a chemical reaction in the condenser to regenerate solids and adhere to the condenser, causing condenser blockage and posing a greater safety risk. In contrast, the hydrogen reaction has fewer side reactions, uses less catalyst, and reacts quickly.

[0019] In a preferred embodiment of the present invention, the mass fraction of palladium in the palladium carbon is 3%. 3% palladium carbon can be directly purchased on the market. In this reaction, palladium carbon is used as a catalyst to facilitate the generation of voriconazole. The mass ratio of intermediate A to palladium carbon in the catalytic reaction is 10:0.3. With this mass ratio, the catalytic efficiency of palladium carbon is the highest.

[0020] In order to make the reaction proceed more completely, in a preferred embodiment of the present invention, the reaction solvent of the catalytic reaction is ethanol, methanol or ethyl acetate, and the reaction solvent is preferably ethanol.

[0021] In a preferred embodiment of the present invention, the reaction temperature of the catalytic reaction is 50-80°C, preferably 80°C; the reaction pressure is 0.5Mpa-1.0Mpa, preferably 0.5Mpa. Under this condition, the impurity content in the obtained crude voriconazole is low, and it is easy to purify to obtain high-purity voriconazole.

[0022] Usually in the synthesis route of voriconazole, the intermediate A obtained exists in the form of an organic salt or an inorganic salt, and the inorganic salt of intermediate A, such as the hydrochloride of intermediate A, can also be directly purchased on the market. In order to improve the solubility of the salt of intermediate A, in a preferred embodiment of the present invention, the above-mentioned organic solution is a 70% ethanol solution, and the pH value is adjusted by sodium acetate to make intermediate A more soluble. The characteristics and performance of the present invention are further described in detail in conjunction with the embodiments below:

[0023] Example 1

[0024] This embodiment provides a method for synthesizing voriconazole, which comprises the following steps:

[0025] 10 g of intermediate A hydrochloride was dissolved in 70 g of 70% ethanol and 3 g of sodium acetate, 0.2 g of 3% palladium carbon was added, and the reaction solution was passed through a continuous flow device to control the pressure of the continuous flow device to 0.5 MPa and the temperature to 80° C. After the reaction was detected to be complete by HPLC, the palladium carbon catalyst in the reaction solution was removed by suction filtration, and an off-white powder was obtained after concentrating and removing the solvent, which was the crude voriconazole. After washing with water, 7.5 g of voriconazole was obtained, with a yield of 90.2% and a purity of 98.2%.

[0026] Example 2

[0027] This embodiment provides a method for synthesizing voriconazole, which comprises the following steps:

[0028] 10 g of intermediate A hydrochloride was dissolved in 70 g of 70% ethanol and 3 g of sodium acetate, 0.3 g of 3% palladium carbon was added, and the reaction solution was passed through a continuous flow device to control the pressure of the continuous flow device to 0.5 MPa and the temperature to 80° C. After the reaction was detected to be complete by HPLC, the palladium carbon catalyst in the reaction solution was removed by suction filtration, and an off-white powder was obtained after concentrating and removing the solvent, which was the crude voriconazole. After washing with water, 8.0 g of voriconazole was obtained, with a yield of 96.2% and a purity of 99.7%.

[0029] Example 3

[0030] This embodiment provides a method for synthesizing voriconazole, which comprises the following steps:

[0031] 10 g of intermediate A hydrochloride was dissolved in 70 g of 70% ethanol and 3 g of sodium acetate, 0.4 g of 3% palladium carbon was added, and the reaction solution was passed through a continuous flow device to control the pressure of the continuous flow device to 0.5 MPa and the temperature to 80° C. After the reaction was detected to be complete by HPLC, the palladium carbon catalyst in the reaction solution was removed by suction filtration, and an off-white powder was obtained after concentrating and removing the solvent, which was the crude voriconazole. After washing with water, 7.9 g of voriconazole was obtained, with a yield of 95.0% and a purity of 98.9%.

[0032] It can be seen from Examples 1-3 that the optimal usage of palladium carbon is 3%.

[0033] Embodiment 4-6

[0034] The synthesis method of voriconazole provided in Example 4-6 is different from the method and feed ratio of Example 2 in that in Example 4-6, the reaction temperatures of 50±5°C, 60±5°C, and 70±5°C are respectively selected as shown in Table 1:

[0035] Table 1 Reaction results of Examples 4-6

[0036] Examples Reaction temperature purity Yield Example 4 50±5℃ 90.5％ 89.2％ Example 5 60±5℃ 92.4％ 91.2％ Example 6 70±5℃ 97.9％ 93.2％

[0037] As shown in Table 1, the higher the temperature, the better the reaction, 80±5°C. The yield is 96.2% and the purity is 99.1%.

[0038] Embodiment 7-9

[0039] The method for synthesizing voriconazole provided in Example 7-9 is different from the method and feed ratio of Example 2 in that, in Examples 7-9, the continuous flow equipment pressures of 0.25 MPa, 0.75 MPa, and 1.0 MPa were screened, respectively.

[0040] As shown in Table 2:

[0041] Table 2 Example 7-9 reaction results

[0042] Examples Reaction pressure purity Yield Example 7 0.25Mpa 85.5％ 80.2％ Example 8 0.75Mpa 99.0％ 96.2％ Example 9 1.0Mpa 99.2％ 96.0％

[0043] As shown in Table 2, the higher the hydrogen pressure of the continuous flow equipment, the better the reaction. For safety reasons, Example 2, 0.5Mpa, has a yield of 96.2% and a purity of 99.7%.

[0044] In summary, the method for synthesizing voriconazole from intermediate A provided by the present invention uses hydrogen as a hydrogen source and palladium carbon as a catalyst, and removes the chlorine atom on the pyrimidine ring of intermediate A through a continuous flow device to obtain a racemic form of voriconazole. This synthesis method has few by-products, high product quality, mild reaction conditions, low cost, and high process safety.

[0045] Although the present invention has been illustrated and described with specific embodiments, it will be appreciated that many other changes and modifications may be made without departing from the spirit and scope of the present invention. Therefore, it is intended to include all such changes and modifications within the scope of the present invention in the appended claims.

Claims

1. A method for preparing voriconazole, characterized in that: The steps include: A method for preparing voriconazole comprises the following steps: Step A, adding voriconazole intermediate A to 70% ethanol, adding sodium acetate to dissolve while stirring, heating to 70° C. to obtain a clear solution, and adding 3% palladium on carbon; Step B: Debug the continuous flow equipment to fill the continuous flow equipment with hydrogen, and maintain the equipment pressure at 0.5 MPa and the temperature at 80°C. Step C: Pump the reaction solution in step A into a continuous flow device to obtain a crude voriconazole hydrogenation reaction solution in a receiving tank. Step D: Filter, concentrate and wash with water to obtain a crude voriconazole mixture.

2. The method for preparing voriconazole according to claim 1, characterized in that: In the step A, the solvent is 70% ethanol, and the amount of 3% palladium on carbon used is 3% of the voriconazole intermediate A.

3. The method for preparing voriconazole according to claim 1, characterized in that: In step C, the pressure in the continuous flow silicon carbide plate is 0.5 MPa and the temperature is 80° C.

Images