A continuous flow synthesis of secnidazole

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a continuous flow synthesis method of secnidazole. The continuous flow synthesis method comprises the following steps: step 1, pumping a mixed solution of 2-methyl-5-nitroimidazole, formic acid and concentrated sulfuric acid with a mass fraction of 98%-100% into a continuous flow mixer 1, pumping a toluene solution of propylene oxide into the continuous flow mixer 1, mixing, and then reacting in a continuous flow reactor 1 to obtain a reaction liquid A; step 2, pumping the reaction liquid A into a continuous flow mixer 2, pumping a toluene solution of propylene oxide into the continuous flow mixer 2, pumping concentrated sulfuric acid with a mass fraction of 98%-100% into the continuous flow mixer 2, mixing, and then reacting in a continuous flow reactor 2, collecting a reaction liquid, and separating to obtain a secnidazole product. The method has the advantages of low cost, simple process, safety and green environmental protection, and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a continuous flow synthesis method for secnidazole. Background Technology

[0002] Secnidazole, chemically named 1-(2-hydroxypropyl)-2-methyl-5-nitroimidazole, is a 5-nitroimidazole antiprotozoal and antianaerobic drug. The synthesis of secnidazole was initially reported by Rhone-poulec SA (French Patent 1427627 and French Patent M3270), with the main reaction formula as follows:

[0003]

[0004] The above synthesis method was carried out in a test reactor, which raises concerns about process safety and contamination. Furthermore, the reaction yield was low, at only 47.94%.

[0005] Continuous flow reactions, compared to traditional batch reactions, offer advantages such as smaller reactor volume, larger specific surface area, better sealing, higher heat exchange efficiency, easier and more precise control of reaction temperature and material ratios, and greater safety and environmental friendliness. Implementing the above synthesis process via continuous flow reactions would significantly improve process safety and reduce leakage, corrosion, and environmental pollution during operation, which would be highly beneficial. However, significant differences exist in the thermodynamics and kinetics of batch reactions and continuous flow reactions. Therefore, how to rationally set reaction conditions to achieve high-yield continuous flow reactions remains a pressing issue to be addressed in the synthesis of secnidazole. Summary of the Invention

[0006] To address the problems of existing technologies, this invention provides a continuous flow synthesis method for secnidazole.

[0007] A continuous flow synthesis method for secnidazole includes the following steps:

[0008] Step 1: A mixture of 2-methyl-5-nitroimidazole, formic acid, and concentrated sulfuric acid with a mass fraction of 98%-100% is pumped into a continuous flow mixer 1. A toluene solution of propylene oxide is also pumped into the continuous flow mixer 1. After mixing, the mixture is reacted in the continuous flow reactor 1 to obtain reaction solution A.

[0009] Step 2: Feed reaction solution A into continuous flow mixer 2, pump the toluene solution of propylene oxide into continuous flow mixer 2, and pump concentrated sulfuric acid with a mass fraction of 98%-100% into continuous flow mixer 2. After mixing, react in continuous flow reactor 2, collect the reaction solution, separate it, and obtain secnidazole product.

[0010] Preferably, in step 1, the flow rate of the mixture is 69.76-71.18 ml / min, and the flow rate of the propylene oxide toluene solution is 28.82-30.24 ml / min.

[0011] Preferably, in step 1, the formic acid is selected from an aqueous formic acid solution with a concentration greater than or equal to 85% by volume; the ratio of formic acid to concentrated sulfuric acid is a mass ratio of (1-20):1.

[0012] Preferably, in step 1, the formic acid is selected from an aqueous formic acid solution with a concentration greater than or equal to 99% by volume; the ratio of formic acid to concentrated sulfuric acid is 5:1 by mass.

[0013] Preferably, in step 2, the flow rate of the toluene solution of propylene oxide is 29.18-31.08 ml / min, and the flow rate of concentrated sulfuric acid with a mass fraction of 98%-100% is 6.13-9.92 ml / min.

[0014] Preferably, in steps 1 and 2, the reaction temperature is 30-90℃.

[0015] Preferably, the reaction temperature in steps 1 and 2 is 90°C.

[0016] Preferably, the total residence time of the reaction in steps 1 and 2 is 10-30 min.

[0017] Preferably, in steps 1 and 2, the concentration of propylene oxide in the toluene solution is 20%-50% by mass.

[0018] Preferably, in steps 1 and 2, the molar ratio of 2-methyl-5-nitroimidazole to propylene oxide is 1:(1.1-2).

[0019] In this invention, "anhydrous formic acid" refers to an aqueous solution of formic acid with a concentration greater than or equal to 99% by volume.

[0020] This invention provides a continuous flow reaction process for the synthesis of secnidazole. In a preferred embodiment, the process parameters for each step are further optimized. This invention achieves a high-yield, high-selectivity, and high-purity continuous flow synthesis of secnidazole, effectively improving the safety of secnidazole production. Therefore, this invention has excellent application prospects.

[0021] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0022] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0023] Figure 1 The continuous flow reaction apparatus used in Examples 1 to 3 of the present invention. Detailed Implementation

[0024] In the following examples and experimental cases, reagents and raw materials not specifically described are commercially available products.

[0025] Example 1: Screening of formic acid concentration in the continuous flow synthesis of secnidazole

[0026] The reaction apparatus used in this embodiment is as follows: Figure 1 As shown, the pipeline for inputting the mixture of 2-methyl-5-nitroimidazole, formic acid solution, and concentrated sulfuric acid (98%-100% by mass) is connected to continuous flow mixer 1 via metering pump 1; the pipeline for inputting the toluene solution of propylene oxide is connected to continuous flow mixer 1 via metering pump 2. A continuous flow reactor 1 is connected to the rear end of continuous flow mixer 1. A continuous flow mixer 2 is connected to the rear end of continuous flow reactor 1; the pipeline for conveying the toluene solution of propylene oxide is connected to continuous flow mixer 2 via metering pump 3; the pipeline for conveying concentrated sulfuric acid (98%-100% by mass) is connected to continuous flow mixer 2 via metering pump 4. A continuous flow reactor 2 is connected to the rear end of continuous flow mixer 2.

[0027] The reaction steps are as follows:

[0028] Step 1: A mixture of 2-methyl-5-nitroimidazole, formic acid solution, and concentrated sulfuric acid with a mass fraction of 98%-100% is pumped into continuous flow mixer 1. A toluene solution of propylene oxide is also pumped into continuous flow mixer 1. After mixing, the mixture is reacted in continuous flow reactor 1 to obtain reaction solution A.

[0029] Step 2: Feed reaction solution A into continuous flow mixer 2, pump the toluene solution of propylene oxide into continuous flow mixer 2, and pump concentrated sulfuric acid with a mass fraction of 98%-100% into continuous flow mixer 2. After mixing, react in continuous flow reactor 2, collect the reaction solution, separate it, and obtain secnidazole product.

[0030] The mass ratio of formic acid to concentrated sulfuric acid was 2:1, the amount of propylene oxide was 1.1 eq, the reaction temperature was 90℃, and the residence time was 10 min. The following four experimental groups investigated the effects of different formic acid concentrations on the yield and selectivity of secnidazole synthesis.

[0031] (1) 85% formic acid (by volume)

[0032] Metering pump 1 is connected to a mixed solution of 2-methyl-4-nitroimidazole (200g, 1.57mol), 85% formic acid (235.3g, 4.34mol), and 98% sulfuric acid (100g, 1.02mol);

[0033] Metering pump 2 was connected to: propylene oxide (54.83 g, 944.13 mmol) and toluene (54.83 g, 595.08 mmol);

[0034] Metering pump 3 inputs: propylene oxide (45.7 g, 786.8 mmol) and toluene (45.7 g, 496 mmol);

[0035] Metering pump 4 is connected to: 98% sulfuric acid (100g, 1.02mol).

[0036] The continuous flow heater circulation temperature was set to 90℃ and stabilized.

[0037] The flow rate of metering pump 1 was set to 71.18 ml / min, the flow rate of metering pump 2 was set to 28.82 ml / min, the flow rate of metering pump 3 was set to 29.18 ml / min, and the flow rate of metering pump 4 was set to 9.58 ml / min.

[0038] Simultaneously turn on metering pumps 1 and 2, and run for 5 minutes. Then turn on metering pumps 3 and 4, and run for 5 minutes. Collect the reaction solution. The HPLC purity is 89.7%. After post-processing, the product is obtained with a yield of 82.7%.

[0039] Product characteristics: 1 HNMR: δ (ppm, 400HZ, CDCl3) 1.329-1.347 (d, 3H), 2.519 (s, 3H), 4.013-4.070 (m, 1H), 4.478-4.520 (m, 1H), 7.920 (s, 1H). m / z: 185.08 (100.0%), 186.08 (6.5%).

[0040] (2) 90% formic acid (volume fraction)

[0041] The flow rate of metering pump 1 was set to 70.67 ml / min, the flow rate of metering pump 2 was set to 29.33 ml / min, the flow rate of metering pump 3 was set to 29.55 ml / min, and the flow rate of metering pump 4 was set to 9.71 ml / min.

[0042] The remaining parameters were exactly the same as those for 85% formic acid. The purity of the product was 91.3% under central HPLC control. After post-processing, the product was obtained with a yield of 85.4%.

[0043] (3) 95% formic acid (volume fraction)

[0044] The flow rate of metering pump 1 was set to 70.2 ml / min, the flow rate of metering pump 2 was set to 29.8 ml / min, the flow rate of metering pump 3 was set to 29.9 ml / min, and the flow rate of metering pump 4 was set to 9.82 ml / min.

[0045] The remaining parameters were exactly the same as those for 85% formic acid. The HPLC purity was 92.0% under central control. The product was obtained after post-processing, with a yield of 87.9%.

[0046] (4) Anhydrous formic acid

[0047] The flow rate of metering pump 1 was set to 69.76 ml / min, the flow rate of metering pump 2 was set to 30.24 ml / min, the flow rate of metering pump 3 was set to 30.2 ml / min, and the flow rate of metering pump 4 was set to 9.92 ml / min.

[0048] The remaining parameters were exactly the same as those for 85% formic acid. The purity of the product was 93.4% under central HPLC control. After post-processing, the product was obtained with a yield of 89.7%.

[0049] Example 2: Screening of the formic acid / sulfuric acid ratio in the continuous flow synthesis of secnidazole

[0050] The continuous flow synthesis apparatus in this embodiment is the same as that in Embodiment 1, and the synthesis conditions not specifically described are also the same as those in Embodiment 1.

[0051] Using anhydrous formic acid and 98% sulfuric acid, the effects of different formic acid / sulfuric acid ratios on the yield and selectivity of secnidazole were investigated in four experimental groups.

[0052] (1) Mass ratio of formic acid: concentrated sulfuric acid = 20:1

[0053] Metering pump 1 is connected to a mixed solution of 2-methyl-4-nitroimidazole (200g, 1.57mol), anhydrous formic acid (200g, 4.35mol), and 98% sulfuric acid (10g, 99.92mol);

[0054] Metering pump 2 was connected to: propylene oxide (54.83 g, 944.13 mmol) and toluene (54.83 g, 595.08 mmol);

[0055] Metering pump 3 inputs: propylene oxide (45.7 g, 786.8 mmol) and toluene (45.7 g, 496 mmol);

[0056] Metering pump 4 is connected to: 98% sulfuric acid (10g, 99.92mol).

[0057] The continuous flow heater circulation temperature was set to 90℃ and stabilized.

[0058] The flow rate of metering pump 1 was set to 69.76 ml / min, the flow rate of metering pump 2 was set to 30.24 ml / min, the flow rate of metering pump 3 was set to 31.08 ml / min, and the flow rate of metering pump 4 was set to 6.13 ml / min.

[0059] Simultaneously turn on metering pumps 1 and 2, and run for 5 minutes. Then turn on metering pumps 3 and 4, and run for 5 minutes. Collect the reaction solution. The HPLC purity is 47%. After post-processing, the product is obtained with a yield of 40.4%.

[0060] (2) Mass ratio of formic acid: concentrated sulfuric acid = 10:1

[0061] The product was obtained with a purity of 90% by HPLC and post-processing, yielding a yield of 84.0%.

[0062] (3) Mass ratio of formic acid: concentrated sulfuric acid = 5:1

[0063] The purity of the product obtained by HPLC was 95.4%, and the yield was 90.2% after post-processing.

[0064] (4) Mass ratio of formic acid to concentrated sulfuric acid = 1:1

[0065] The purity of the product obtained by HPLC was 92.5%, and the yield was 86.6% after post-processing.

[0066] Example 3: Temperature screening in the continuous flow synthesis reaction of secnidazole

[0067] The continuous flow synthesis apparatus in this embodiment is the same as that in Embodiment 1, and the synthesis conditions not specifically described are also the same as those in Embodiment 1.

[0068] Using anhydrous formic acid and 98% concentrated sulfuric acid, the effects of different reaction temperatures on the yield and selectivity of secnidazole synthesis were investigated in four experimental groups.

[0069] (1) Reaction temperature 30℃

[0070] Metering pump 1 is connected to a mixed solution of 2-methyl-4-nitroimidazole (200g, 1.57mol), anhydrous formic acid (200g, 4.34mol), and 98% sulfuric acid (100g, 1.02mol);

[0071] Metering pump 2 was connected to: propylene oxide (54.83 g, 944.13 mmol) and toluene (54.83 g, 595.08 mmol);

[0072] Metering pump 3 inputs: propylene oxide (45.7 g, 786.8 mmol) and toluene (45.7 g, 496 mmol);

[0073] Metering pump 4 is connected to: 98% sulfuric acid (100g, 1.02mol).

[0074] The continuous flow heater circulation temperature was set to 30℃ and stabilized.

[0075] The flow rate of metering pump 1 was set to 69.76 ml / min, the flow rate of metering pump 2 was set to 30.24 ml / min, the flow rate of metering pump 3 was set to 30.20 ml / min, and the flow rate of metering pump 4 was set to 9.92 ml / min.

[0076] Simultaneously turn on metering pumps 1 and 2, and run for 5 minutes. Then turn on metering pumps 3 and 4, and run for 5 minutes. Collect the reaction solution. The HPLC purity is 49.0%. After post-processing, the product is obtained with a yield of 42.3%.

[0077] (2) Reaction temperature 60℃

[0078] The circulating temperature of the continuous flow heater is set to 60℃.

[0079] The purity of the product obtained by HPLC was 83.6%, and the yield was 78.0% after post-processing.

[0080] (3) Reaction temperature 90℃

[0081] Set the continuous flow heater circulation temperature to 90℃;

[0082] The purity of the product obtained by HPLC was 93.4%, and the yield was 89.7% after post-processing.

[0083] The process conditions, product purity, selectivity, and yield of Examples 1 to 3 are summarized in the table below.

[0084]

[0085]

[0086] The above comparison shows that, in the continuous flow synthesis method of secnidazole of the present invention, the preferred ratio of mixed acid is anhydrous formic acid and 98% concentrated sulfuric acid at a mass ratio of (2-5):1; the preferred reaction temperature is 90°C.

[0087] As can be seen from the above embodiments, the present invention achieves continuous flow synthesis of secnidazole, and by optimizing process parameters, obtains optimal product selectivity, yield, and purity. The method of the present invention has the advantages of low cost, simple process, safety, and environmental friendliness, and has excellent application prospects.

Claims

1. A continuous flow process for the synthesis of secnidazole, characterized in that, The method comprises the following steps: Step 1, pumping a mixture of 2-methyl-5-nitroimidazole, anhydrous formic acid and mass fraction 98% concentrated sulfuric acid into a continuous flow mixer 1, pumping a propylene oxide toluene solution into the continuous flow mixer 1, mixing and then reacting in a continuous flow reactor 1 to obtain a reaction liquid A; Step 2, pumping the reaction liquid A into a continuous flow mixer 2, pumping a propylene oxide toluene solution into the continuous flow mixer 2, pumping mass fraction 98%-100% concentrated sulfuric acid into the continuous flow mixer 2, mixing and then reacting in a continuous flow reactor 2, collecting the reaction liquid and separating to obtain the secnidazole product; The anhydrous formic acid is prepared according to a mass ratio (2-5):1 of the anhydrous formic acid to the 98% concentrated sulfuric acid; in steps 1 and 2, the reaction temperature is 90°C; the anhydrous formic acid refers to a formic acid aqueous solution with a concentration greater than or equal to a volume fraction of 99%.

2. The continuous flow synthesis process according to claim 1, characterized in that: In step 1, the flow rate of the mixture is 69.76-71.18 ml / min, and the flow rate of the propylene oxide toluene solution is 28.82-30.24 ml / min.

3. The continuous flow synthesis process according to claim 1, wherein: In step 2, the flow rate of the propylene oxide toluene solution is 29.18-31.08 ml / min, and the flow rate of the mass fraction 98%-100% concentrated sulfuric acid is 6.13-9.92 ml / min.

4. The continuous flow synthesis process according to claim 1, wherein: In steps 1 and 2, the total residence time of the reaction is 10-30 min.

5. The continuous flow synthesis process according to claim 1, wherein: In steps 1 and 2, the concentration of propylene oxide in the propylene oxide toluene solution is mass fraction 20%-50%.

6. The continuous flow synthesis process according to claim 1, wherein: In steps 1 and 2, the amount ratio of 2-methyl-5-nitroimidazole to propylene oxide is a molar ratio of 1:(1.1-2).

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