A method of synthesizing an esconazole sulfate intermediate in a microchannel continuous flow reactor

Abstract

This invention belongs to the field of chemical drug synthesis technology and discloses a method for the efficient synthesis of isaconazole sulfate intermediate. The specific steps are as follows: (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyramide (SM-1) is dissolved in a mixed solvent. The SM-1 solution is pumped into the pre-cooling module of a continuous flow reactor using plunger pump A, and phosphorus oxychloride is pumped into the pre-cooling module using plunger pump B. The two materials are then mixed and reacted in the reaction module, with the temperature controlled. After the reaction, the mixture enters the quenching module. Simultaneously, sodium hydroxide solution is pumped into the quenching module using plunger pump C. The mixture is separated, dried, filtered, and evaporated to dryness to obtain the isaconazole sulfate intermediate. This method features fast reaction speed, high heat and mass transfer efficiency, high reaction safety, high selectivity, high yield and purity, and convenient post-processing.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug synthesis technology, specifically relating to a method for the efficient synthesis of isaconazole sulfate intermediate. Background Technology

[0002] Isaconazole and rivconazole are triazole drugs widely used to treat systemic fungal infections. They also have broad-spectrum antifungal activity. Isaconazole sulfate is a water-soluble prodrug of the triazole issaconazole and is used to treat invasive Aspergillus and Mucor infections in patients over 18 years of age.

[0003] Ester is a prodrug of isaconazole, a triazole antifungal drug. Isaconazole inhibits the synthesis of ergosterol, an important component of fungal cell membranes, by inhibiting 14-α-ergosterol demethylase in the cytochrome P450 enzyme system. This leads to changes in the chemical composition of the fungal cell membrane, membrane dysfunction, increased permeability, and leakage of intracellular fluid, thereby achieving antibacterial and bactericidal effects.

[0004] Currently, the main synthetic route suitable for industrial production is provided by patent US20040176432. This synthetic method can simultaneously form two chiral carbons and generate only one configuration of compound under the conditions of divalent palladium catalysis and the presence of diethylzinc.

[0005]

[0006] However, the synthesis of the intermediate (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyronitrile currently uses phosphorus oxychloride, which is highly hazardous. When heated, phosphorus oxychloride reacts violently with protic solvents such as alcohols and water. The post-reaction process requires quenching with water, generating large amounts of hydrochloric acid gas, which is extremely dangerous. Furthermore, this process is difficult to control in large-scale production, and is highly susceptible to temperature and material spillage.

[0007] Therefore, there is an urgent need in this field to develop a method for preparing intermediates that is mild, easy to control, and suitable for industrial-scale production. Summary of the Invention

[0008] To address the above problems, this invention provides a method for synthesizing isaconazole sulfate intermediate in a microchannel continuous flow reactor. The preparation method is simple, the conditions are mild, the reaction yield is high, the product quality is good, and it is suitable for industrial production.

[0009] The specific technical solution of the present invention is as follows:

[0010]

[0011] (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyramide (SM-1) was dissolved in a mixed solvent. The SM-1 solution was pumped into the pre-cooling module of a continuous flow reactor using plunger pump A, and phosphorus oxychloride was pumped into the pre-cooling module using plunger pump B. The two materials were then introduced into the reaction module for mixing and reaction, with the temperature of the reaction module controlled. After the reaction, the mixture entered the quenching module. Simultaneously, sodium hydroxide solution was pumped into the quenching module using plunger pump C. The reaction solution was separated, dried, filtered, and evaporated to dryness to obtain the isaconazole sulfate intermediate.

[0012] Preferably, the continuous flow reactor includes at least a precooling module, a reaction module, and a quenching module.

[0013] Preferably, the flow rates of pumps A, B, and C are 1–2000 g / min, and more preferably 1–100 g / min.

[0014] Preferably, the flow rate ratio of pump A, pump B and pump C is 1:0.2-0.4:1.8-3.5.

[0015] Preferably, the mixed solvent is a combination of two or more of DMSO, DMF, ethanol, acetone, acetonitrile, and THF.

[0016] Preferably, the concentration of the SM-1 solution is 20–40 wt%.

[0017] Preferably, the temperature of the precooling module is 15–25°C.

[0018] Preferably, the temperature of the reaction module is 15–25°C.

[0019] Preferably, the reaction dwell time of the reaction module is 0.5 to 1.2 min.

[0020] Preferably, the concentration of the sodium hydroxide solution is 25-30 wt%.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. The synthesis of isaconazole sulfate intermediate via a microchannel continuous flow reactor allows for precise control of the phosphorus oxychloride equivalence and reaction time, reducing the amount of phosphorus oxychloride used, reaction temperature, and solvent consumption, thus significantly lowering production costs, improving selectivity, and ultimately increasing product yield and purity. Specifically, according to the examples, the method of this invention achieves a yield of over 96% and a purity of over 99.6% for the synthesis of isaconazole sulfate intermediate.

[0023] 2. The microchannel continuous flow reactor features a low liquid holdup, ensuring reaction safety. The process enables continuous operation of reaction and quenching. Highly hazardous phosphorus oxychloride is introduced into the reactor via a continuous flow metering pump, where it undergoes reaction quenching and is then directly separated and evaporated to obtain the intermediate. This ensures operator safety.

[0024] It should be understood that although there are existing records of using continuous flow reactors in organic synthesis to improve reaction efficiency, these methods are fundamentally different from the method of this invention. Specifically, this invention employs a fully continuous flow technology. However, continuous flow reactors are typically only suitable for about 30% of reactions; that is, only with suitable reaction rates and substrate properties can a continuous flow reaction be achieved. Therefore, successfully applying continuous flow reaction technology to achieve the desired reaction objective requires extensive experimental exploration and parameter tuning. This invention, through parameter tuning, has made it suitable for the synthesis of isaconazole sulfate intermediates, and the entire process reduces production costs while improving reaction safety, yield, and purity. Therefore, existing technologies are not applicable to this invention. Attached Figure Description

[0025] Figure 1 This is a flow chart of the synthesis process in a continuous flow reactor. Detailed Implementation

[0026] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments or drawings of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0027] Example 1

[0028] Weigh 100g of SM-1 and dissolve it in a mixed solvent of 5g DMF and 200g tetrahydrofuran. Use plunger pump A to pump the SM-1 solution into the pre-cooling module of the continuous flow reactor at a flow rate of 20g / min to cool it to 15℃. Use plunger pump B to pump phosphorus oxychloride into the pre-cooling module at a flow rate of 6.79g / min to cool it to 15℃. The two materials then enter the reaction module after passing through the pre-cooling module to mix and react. The temperature of the reaction module is controlled at 15℃, and the residence time is 1.2min. After the reaction, the mixture enters the quenching module. Simultaneously, use plunger pump C to pump a 25% sodium hydroxide solution into the quenching module at a flow rate of 53g / min to mix with the reactants and quench any unreacted phosphorus oxychloride. The residence time is 6s, and the temperature is 25℃. The reaction liquid outlet was connected to a separatory funnel for separation to obtain an organic phase. 20g of anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was then filtered to obtain another organic phase. The organic phase was evaporated under reduced pressure at 50℃ to obtain 91.13g of intermediate, with a yield of 97.04% and a purity of 99.71%.

[0029] Example 2

[0030] Weigh 100g of SM-1 and dissolve it in a mixed solvent of 5g DMF and 200g tetrahydrofuran. Use plunger pump A to pump the SM-1 solution into the pre-cooling module of the continuous flow reactor at a flow rate of 20g / min to cool it to 25℃. Use plunger pump B to pump phosphorus oxychloride into the pre-cooling module at a flow rate of 5.06g / min to cool it to 25℃. The two materials then enter the reaction module after passing through the pre-cooling module to mix and react. The temperature of the reaction module is controlled at 25℃, and the residence time is 1min. After the reaction, the mixture enters the quenching module. Simultaneously, use plunger pump C to pump a 30% sodium hydroxide solution into the quenching module at a flow rate of 36g / min to mix with the reactants and quench any unreacted phosphorus oxychloride. The residence time is 6s, and the temperature is 15℃. The reaction liquid outlet was connected to a separatory funnel for separation to obtain an organic phase. 20g of anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was then filtered to obtain another organic phase. The organic phase was evaporated under reduced pressure at 50℃ to obtain 90.94g of intermediate, with a yield of 96.83% and a purity of 99.66%.

[0031] Example 3

[0032] Weigh 100g of SM-1 and dissolve it in a mixed solvent of 5g DMF and 200g tetrahydrofuran. Use plunger pump A to pump the SM-1 solution into the pre-cooling module of the continuous flow reactor at a flow rate of 20g / min to cool it to 20℃. Use plunger pump B to pump phosphorus oxychloride into the pre-cooling module at a flow rate of 8.44g / min to cool it to 20℃. The two materials then enter the reaction module through the pre-cooling module to mix and react. The temperature of the reaction module is controlled at 20℃, and the residence time is 0.5min. After the reaction, the mixture enters the quenching module. Simultaneously, use plunger pump C to pump a 25% sodium hydroxide solution into the quenching module at a flow rate of 70.44g / min, mixing it with the reactants and quenching any unreacted phosphorus oxychloride. The residence time is 6s, and the temperature is 10℃. The reaction liquid outlet was connected to a separatory funnel for separation to obtain an organic phase. 20g of anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was then filtered to obtain another organic phase. The organic phase was evaporated under reduced pressure at 50℃ to obtain 90.34g of intermediate, with a yield of 96.19% and a purity of 99.68%.

[0033] Example 4

[0034] Weigh 100g of SM-1 and dissolve it in a mixed solvent of 10g DMSO and 390g tetrahydrofuran. Use plunger pump A to pump the SM-1 solution into the pre-cooling module of the continuous flow reactor at a flow rate of 20g / min to cool it to 15℃. Use plunger pump B to pump phosphorus oxychloride into the pre-cooling module at a flow rate of 4.14g / min to cool it to 15℃. The two materials then enter the reaction module after passing through the pre-cooling module to mix and react. The temperature of the reaction module is controlled at 15℃, and the residence time is 1.2min. After the reaction, the mixture enters the quenching module. Simultaneously, use plunger pump C to pump a 25% sodium hydroxide solution into the quenching module at a flow rate of 53g / min to mix with the reactants and quench any unreacted phosphorus oxychloride. The residence time is 6s, and the temperature is 25℃. The reaction liquid outlet was connected to a separatory funnel for separation to obtain an organic phase. 20g of anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was then filtered to obtain another organic phase. The organic phase was evaporated under reduced pressure at 50℃ to obtain 91.12g of intermediate, with a yield of 97.03% and a purity of 99.70%.

[0035] Example 5

[0036] Weigh 100g of SM-1 and dissolve it in a mixed solvent of 5g acetone and 140g tetrahydrofuran. Pump the SM-1 solution into the pre-cooling module of the continuous flow reactor at a flow rate of 20g / min using plunger pump A to cool it to 15℃. Pump phosphorus oxychloride into the pre-cooling module at a flow rate of 8.28g / min using plunger pump B to cool it to 15℃. The two materials then enter the reaction module after passing through the pre-cooling module to mix and react. The temperature of the reaction module is controlled at 15℃, and the residence time is 1.2min. After the reaction, the mixture enters the quenching module. Simultaneously, pump 25% sodium hydroxide solution into the quenching module at a flow rate of 53g / min using plunger pump C to mix with the reactants and quench any unreacted phosphorus oxychloride. The residence time is 6s, and the temperature is 25℃. The reaction liquid outlet was connected to a separatory funnel for separation to obtain an organic phase. 20g of anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was then filtered to obtain another organic phase. The organic phase was evaporated under reduced pressure at 50℃ to obtain 91.06g of intermediate, with a yield of 96.96% and a purity of 99.62%.

[0037] Example 6

[0038] Weigh 100g of SM-1 and dissolve it in a mixed solvent of 5g DMF and 200g tetrahydrofuran. Use plunger pump A to pump the SM-1 solution at a flow rate of 20g / min into the pre-cooling module of the continuous flow reactor to cool it to 15℃. Use plunger pump B to pump phosphorus oxychloride into the pre-cooling module at a flow rate of 13.5g / min to cool it to 15℃. The two materials then enter the reaction module after passing through the pre-cooling module to mix and react. The temperature of the reaction module is controlled at 15℃, and the residence time is 1.2min. After the reaction, the mixture enters the quenching module. Simultaneously, use plunger pump C to pump a 25% sodium hydroxide solution at a flow rate of 53g / min into the quenching module to mix with the reactants and quench any unreacted phosphorus oxychloride. The residence time is 6s, and the temperature is 25℃. The reaction liquid outlet was connected to a separatory funnel for separation to obtain an organic phase. 20g of anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was then filtered to obtain another organic phase. The organic phase was evaporated under reduced pressure at 50℃ to obtain 77.53g of intermediate, with a yield of 82.55% and a purity of 90.32%.

[0039] Example 7

[0040] Weigh 100g of SM-1 and dissolve it in a mixed solvent of 5g DMF and 200g tetrahydrofuran. Use plunger pump A to pump the SM-1 solution at a flow rate of 20g / min into the pre-cooling module of the continuous flow reactor to cool it to 40℃. Use plunger pump B to pump phosphorus oxychloride into the pre-cooling module at a flow rate of 6.79g / min to cool it to 40℃. The two materials then enter the reaction module after passing through the pre-cooling module to mix and react. The temperature of the reaction module is controlled at 40℃, and the residence time is 1.2min. After the reaction, the mixture enters the quenching module. Simultaneously, use plunger pump C to pump a 25% sodium hydroxide solution at a flow rate of 53g / min into the quenching module to mix with the reactants and quench any unreacted phosphorus oxychloride. The residence time is 6s, and the temperature is 25℃. The reaction liquid outlet was connected to a separatory funnel for separation to obtain an organic phase. 20g of anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was then filtered to obtain another organic phase. The organic phase was evaporated under reduced pressure at 50℃ to obtain 83.66g of intermediate, with a yield of 89.08% and a purity of 91.61%.

[0041] Example 8

[0042] Weigh 100g of SM-1 and dissolve it in a mixed solvent of 5g DMF and 200g tetrahydrofuran. Pump the SM-1 solution into the pre-cooling module of the continuous flow reactor at a flow rate of 20g / min using plunger pump A to cool it to 15℃. Pump phosphorus oxychloride into the pre-cooling module at a flow rate of 6.79g / min using plunger pump B to cool it to 15℃. The two materials then enter the reaction module after passing through the pre-cooling module to mix and react. The temperature of the reaction module is controlled at 15℃, and the residence time is 2min. After the reaction, the mixture enters the quenching module. Simultaneously, pump 25% sodium hydroxide solution into the quenching module at a flow rate of 53g / min using plunger pump C to mix with the reactants and quench any unreacted phosphorus oxychloride. The residence time is 6s, and the temperature is 25℃. The reaction liquid outlet was connected to a separatory funnel for separation to obtain an organic phase. 20g of anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was then filtered to obtain another organic phase. The organic phase was evaporated under reduced pressure at 50℃ to obtain 87.87g of intermediate, with a yield of 93.56% and a purity of 94.36%.

[0043] Finally, it should be noted that the above embodiments are only for illustration and not for limiting the technical solutions of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the present invention without departing from the spirit and scope of the present invention. Any modifications or partial substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing isaconazole sulfate intermediate in a microchannel continuous flow reactor, characterized in that, The synthetic route is as follows: Includes the following steps: (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyramide (SM-1) was dissolved in a mixed solvent. The SM-1 solution was pumped into the precooling module of the continuous flow reactor using plunger pump A, and phosphorus oxychloride was pumped into the precooling module using plunger pump B. The two materials were mixed and reacted in the reaction module after passing through the precooling module. The temperature of the reaction module was controlled. After the reaction was completed, the solution was pumped into the quenching module. At the same time, sodium hydroxide solution was pumped into the quenching module using plunger pump C. The reaction solution was separated, dried, filtered, and evaporated to dryness to obtain the isaconazole sulfate intermediate.

2. The method for synthesizing isaconazole sulfate intermediate according to claim 1, characterized in that, The flow rate ratio of pumps A, B, and C is 1:0.2-0.4:1.8-3.

5.

3. The method for synthesizing isaconazole sulfate intermediate according to claim 1, characterized in that, The mixed solvent is a combination of two or more of DMSO, DMF, ethanol, acetone, acetonitrile, and THF.

4. The method for synthesizing isaconazole sulfate intermediate according to claim 1, characterized in that, The concentration of the SM-1 solution in the above step is 20–40 wt%.

5. The method for synthesizing isaconazole sulfate intermediate according to claim 1, characterized in that, The temperature of the precooling module is 15-25℃.

6. The method for synthesizing isaconazole sulfate intermediate according to claim 1, characterized in that, The temperature of the reaction module is 15–25°C.

7. The method for synthesizing isaconazole sulfate intermediate according to claim 1, characterized in that, The reaction time in the reaction module is 0.5 to 1.2 minutes.

8. The method for synthesizing isaconazole sulfate intermediate according to claim 1, characterized in that, The quenching module has a temperature of 15-25℃.

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