Prothioconazole derivative containing epoxy group and synthesis and detection method thereof

Abstract

The invention relates to the technical field of fine chemical engineering, in particular to a prothioconazole derivative containing an epoxy group and a synthesis and detection method of the prothioconazole derivative. A high-purity product is obtained by optimizing a preparation process, and a specific detection method is subsequently matched, so that the preparation method has important significance in subsequent application of the compound and quality control in synthesis of a prothioconazole product.

Description

Technical Field

[0001] This invention relates to the field of fine chemical technology, specifically to a prothioconazole derivative containing an epoxy group and its synthesis and detection method. Background Technology

[0002] Prothioconazole, a broad-spectrum triazole thione fungicide, is widely used in global agriculture for the control of fungal diseases in crops such as wheat and rice due to its high efficiency and low toxicity. Its chemical structure (as shown in Formula I) exhibits significant fungicidal activity by inhibiting the biosynthesis of ergosterol in fungi. However, during industrial production, the purity of raw materials, reaction conditions (such as temperature and catalyst residue), and post-processing can affect the synthesis of various new compounds. The presence of these compounds may affect the chemical stability of the active pharmaceutical ingredient and the homogeneity of the formulation, and may also introduce potential toxicity risks, threatening environmental and pesticide safety. Some compounds may have positive effects or be applied in other fields. Chinese patent application (publication number CN113788797A) discloses a desulfurized prothioconazole impurity, its synthesis method and application. The impurity is prepared by heating a triazole with formula (II) or formula (III) as raw material in the presence of an acid-binding agent. The impurity is then recrystallized with a solvent to provide a standard for detection and process optimization. However, it cannot accurately detect new prothioconazole derivatives containing epoxy groups. Summary of the Invention

[0003] To address the aforementioned issues, this invention provides an epoxy-containing prothioconazole derivative and its synthesis and detection method. By optimizing the preparation process, a high-purity product is obtained, followed by matching it with a specific detection method. This is of great significance for the subsequent application of the compound and for quality control in the synthesis of prothioconazole products.

[0004] This invention provides a prothioconazole derivative containing an epoxy group, the chemical structure of which is shown in Formula I: , Formula I.

[0005] The prothioconazole derivative structure containing epoxy groups provided by this invention has a unique spirocyclic structure, which gives it different physicochemical properties and biological activities from known impurities, and can be extended to other fields in the future.

[0006] Another aspect of the present invention provides a method for synthesizing a prothioconazole derivative containing an epoxy group, comprising at least the following steps: reacting prothioconazole with an alkali in water, cooling after the reaction is completed, adding hydrochloric acid to precipitate a solid, filtering to obtain a crude product, recrystallizing the crude product, and drying.

[0007] In one embodiment, the molar ratio of prothioconazole to alkali is (0.02-0.03):(0.075-0.105).

[0008] In one embodiment, the base is a hydroxide or carbonate from a Group 1 or Group 2 main group.

[0009] In one embodiment, the alkali is at least one of lithium, sodium, and potassium hydroxides.

[0010] In one embodiment, the molar ratio of prothioconazole to hydrochloric acid is (0.02-0.03):(0.050-0.055).

[0011] In one embodiment, the mass ratio of prothioconazole to water is (8-10):80.

[0012] In one embodiment, the reaction temperature is 50-80°C and the reaction time is 6-10 hours.

[0013] In one embodiment, the reaction temperature is 70-75°C and the reaction time is 7-8 hours.

[0014] In one embodiment, the recrystallization includes the following steps: adding the crude product to a solvent, heating to 65-70°C to dissolve the crude product, cooling to 0-5°C to precipitate the solid, filtering, and rinsing with water.

[0015] In one embodiment, the solvent is an aqueous methanol solution.

[0016] In one embodiment, the mass concentration of the methanol aqueous solution is 30-80%.

[0017] In one embodiment, the mass concentration of the methanol aqueous solution is 50-60%.

[0018] In one embodiment, the mass ratio of the crude product to the methanol aqueous solution is (5-10):100.

[0019] In one embodiment, the cooling rate is 0.3-1.0 °C / min.

[0020] In one embodiment, the drying is vacuum drying, and the vacuum drying temperature is 70-75°C.

[0021] This invention optimizes the synthesis process, especially by controlling the molar ratio of each raw material, reaction conditions, and recrystallization conditions, to prepare high-purity, high-yield prothioconazole derivatives containing epoxy groups, providing technical support for the subsequent application of the product and the quality monitoring of prothioconazole products.

[0022] The third aspect of this invention provides a method for detecting prothioconazole derivatives containing epoxy groups, comprising at least the following steps: dissolving the prothioconazole derivatives containing epoxy groups in acetonitrile; using a 0.1-0.2% (v / v) phosphoric acid aqueous solution as mobile phase A and acetonitrile as mobile phase B; employing a C18 packed column and an ultraviolet or diode array detector; injecting a volume of 20-22 μL; controlling the column temperature and flow rate for gradient elution; performing reversed-phase high-performance liquid chromatography separation of the prothioconazole derivatives containing epoxy groups at a wavelength of 254 nm; and quantitative detection using the external standard method.

[0023] In one embodiment, the gradient elution procedure is shown in Table 1.

[0024] Table 1

[0025] The detection method provided by this invention has a minimum detection limit of 10 μg / L, a recovery rate between 90.0% and 97.8%, accurate detection results, and high detection sensitivity.

[0026] Based on the structural characteristics of prothioconazole impurity compounds containing epoxy structures, this invention provides a sensitive and efficient detection method that can quickly and efficiently monitor the generation of this substance during the production and storage of prothioconazole, providing better technical support for the refined control of the prothioconazole production process, with good results.

[0027] Beneficial effects 1. This invention provides an epoxy-containing prothioconazole derivative and its synthesis and detection method. By optimizing the preparation process, a high-purity product can be obtained, and a specific detection method can be matched subsequently. This is of great significance for the subsequent application of this compound and the quality control in the synthesis of prothioconazole products.

[0028] 2. The prothioconazole derivative structure containing epoxy groups provided by this invention contains a unique spiroepoxide structure, which gives it physicochemical properties and biological activities that are different from those of known impurities, and can be extended to other fields in the future.

[0029] 3. This invention optimizes the synthesis process, especially by controlling the molar ratio of each raw material, reaction conditions, and recrystallization conditions, to prepare high-purity, high-yield prothioconazole derivatives containing epoxy groups, providing technical support for the subsequent application of the product and the quality monitoring of prothioconazole products.

[0030] 4. The detection method provided by this invention has a minimum detection limit of 10 μg / L, a recovery rate between 90.0% and 97.8%, accurate detection results, and high detection sensitivity.

[0031] 5. Based on the structural characteristics of prothioconazole impurity compounds containing epoxy structures, this invention provides a sensitive and efficient detection method that can quickly and efficiently monitor the generation of this substance during the production and storage of prothioconazole, providing better technical support for the refined control of the prothioconazole production process, with good results. Attached Figure Description

[0032] Figure 1 Example 1: HPLC chromatogram of a prothioconazole derivative containing an epoxy group (purity 99.3%).

[0033] Figure 2 Example 1: Ultraviolet absorption spectrum of a prothioconazole derivative containing an epoxy group.

[0034] Figure 3 Example 1: ¹H NMR spectrum of a prothioconazole derivative containing an epoxy group.

[0035] Figure 4 Example 1 provides a prothioconazole derivative containing an epoxy group. 13 C10 NMR spectrum.

[0036] Figure 5 Infrared image of the epoxy-containing prothioconazole derivative provided in Example 1.

[0037] Figure 6 Example 1: DSC diagram of a prothioconazole derivative containing an epoxy group.

[0038] Figure 7 EI-MS image of the epoxy-containing prothioconazole derivative provided in Example 1. Detailed Implementation

[0039] Example 1 Example 1 of the present invention provides a prothioconazole derivative containing an epoxy group. The chemical structure of the prothioconazole derivative containing an epoxy group is shown in Formula I: Formula I (2-[2-(2-chlorobenzyl)-1-oxaspiro[2.2]pent-2-ylmethyl]-2,4-dihydro-1,2,4-triazol-3-thione).

[0040] Example 1 of the present invention provides a method for synthesizing a prothioconazole derivative containing an epoxy group, comprising the following steps: adding prothioconazole (98wt%, 8.78g) and water to a reaction vessel, adding alkali to react, cooling after the reaction is completed, adding hydrochloric acid to precipitate a solid, filtering to obtain a crude product (7.5g), recrystallizing and drying the crude product to obtain 6.27g of white crystals (99.3%), with a molar yield of 81%.

[0041] The molar ratio of prothioconazole to alkali is 0.025:0.075.

[0042] The alkali is a 30 wt% aqueous solution of sodium hydroxide.

[0043] The molar ratio of prothioconazole to hydrochloric acid is 0.025:0.051, and the hydrochloric acid is an aqueous solution with a mass concentration of 37%.

[0044] The mass ratio of prothioconazole to water is 8.78:80.

[0045] The reaction was carried out at a temperature of 70°C for 8 hours.

[0046] The recrystallization includes the following steps: adding the crude product to a solvent, heating to 68°C to dissolve the crude product, cooling to 2°C to precipitate the solid, filtering, and rinsing with water.

[0047] The solvent is an aqueous methanol solution with a mass concentration of 50%.

[0048] The mass ratio of the crude product to the methanol aqueous solution is 7.5:100.

[0049] The cooling rate is 0.5℃ / minute.

[0050] The drying process is vacuum drying, and the vacuum drying temperature is 70°C.

[0051] The third aspect of this invention provides a method for detecting prothioconazole derivatives containing epoxy groups, comprising the following steps: dissolving the prothioconazole derivative containing epoxy groups in acetonitrile, using a 0.1 wt% phosphoric acid aqueous solution as mobile phase A and acetonitrile as mobile phase B, employing a C18 packed column and a diode array detector, with an injection volume of 20 μL, controlling column temperature and flow rate for gradient elution, separating the prothioconazole derivative containing epoxy groups by reversed-phase high-performance liquid chromatography at a wavelength of 254 nm, and quantitatively detecting it using the external standard method (linear regression equation: Y = 57.69X - 0.42; Y is the chromatographic peak area; X is the mass concentration of the prothioconazole derivative containing epoxy groups, mg / L; correlation coefficient: 0.9998).

[0052] The gradient elution procedure is shown in Table 1.

[0053] Table 1

[0054] The retention time of prothioconazole was approximately 13.5 min; the retention time of prothioconazole derivatives containing epoxide groups was approximately 11 min. See the results below. Figure 1The purity of the epoxide-containing prothioconazole derivative is 99.3%, and the resolution between the epoxide-containing prothioconazole derivative and the prothioconazole spectral peak is ≥2.0.

[0055] See the UV absorption spectrum of the epoxy-containing prothioconazole derivative. Figure 2 ,analyze Figure 2 It is known that the epoxy-containing prothioconazole derivative has characteristic absorption peaks at 194 nm and 256 nm.

[0056] The prothioconazole derivative containing an epoxy group 1 The H NMR characterization results are shown in [reference]. Figure 3 ,analyze Figure 3 It can be known that: 1 HNMR (400 MHz, CDCl3) δ 12.63 (brs, 1H), 7.87 (s, 1H), 7.38 (dd, J 1 = 8.0 Hz J 2=3.2Hz, 2H), 7.30 – 7.19 (m, 2H), 4.62 (d, J = 14.4 Hz, 1H), 4.39 (d, J = 14.4Hz, 1H), 3.28 (d, J = 14.0Hz, 1H), 3.19 (d, J = 14.0Hz,1H), 2.95 (m, 1H),2.61 (m,1H),2.21(m, 1H),2.01 (m, 1H). The prothioconazole derivative containing an epoxy group 13 The C NMR characterization results are shown in [reference]. Figure 4 ,analyze Figure 4 It can be known that: 13 CNMR (101 MHz, CDCl3) δ 210.90 (s), 165.97 (s), 137.81 (s), 134.98 (s), 134.20 (s), 132.03 (s), 129.81 (s), 128.49 (s), 127.06 (s), 68.64 (s), 50.75 (s), 44.43 (s), 35.34 (s), 19.09 (s). The infrared characterization results of the epoxy-containing prothioconazole derivative are shown in [reference needed]. Figure 5 See Table 2 for spectral information.

[0057] Table 2

[0058] The differential scanning calorimetry (DSC) analysis results of the epoxy-containing prothioconazole derivatives are shown below. Figure 6 Its melting point is 150.6℃.

[0059] The mass spectrometry (EI-SI) characterization results of the epoxy-containing prothioconazole derivatives are shown in [reference needed]. Figure 7 (MS): EI-MSm / z: 307.05 (100.0%), 308.06 (15.8%), 309.05 (36.6%), consistent with theory.

[0060] Example 2 Example 2 of the present invention provides a prothioconazole derivative containing an epoxy group and its synthesis and detection method. The specific implementation method is the same as that in Example 1, except that the synthesis method of the prothioconazole derivative containing an epoxy group includes the following steps: adding prothioconazole (98wt%, 8.78g) and water to a reaction vessel, adding alkali to react, cooling after the reaction is completed, adding hydrochloric acid to precipitate a solid, filtering to obtain a crude product (7.8g), recrystallizing and drying the crude product to obtain 6.50g of white crystals (99.0%), with a molar yield of 84%; the molar ratio of prothioconazole to hydrochloric acid is 0.025:0.053; the reaction temperature is 75℃ and the reaction time is 7h.

[0061] Example 3 Example 3 of the present invention provides a prothioconazole derivative containing an epoxy group and its synthesis and detection method. The specific implementation method is the same as that of Example 1, except that the synthesis method of the prothioconazole derivative containing an epoxy group includes the following steps: adding prothioconazole (98wt%, 8.78g) and water to a reaction vessel, adding alkali to react, cooling after the reaction is completed, adding hydrochloric acid to precipitate a solid, filtering to obtain a crude product (8.2g), recrystallizing and drying the crude product to obtain 5.80g of white crystals (95.6%), with a molar yield of 72%; the alkali is potassium carbonate solid (98wt%), and the molar ratio of prothioconazole to hydrochloric acid is 0.025:0.050; the reaction temperature is 75℃, and the reaction time is 7h.

[0062] Example 4 Example 4 of the present invention provides an epoxy-containing prothioconazole derivative and its synthesis and detection method. The specific implementation method is the same as in Example 1, except that the detection method for the epoxy-containing prothioconazole derivative is replaced by the method using the 5.5% prothioconazole mass fraction method in GB / T 43175-2023 prothioconazole technical grade, with V... 乙腈 V 0.02wt%磷酸水溶液The mobile phase was 75:25, with a retention time of approximately 6 minutes for prothioconazole; the retention time for prothioconazole derivatives containing epoxide groups was approximately 5 minutes, and the resolution between the peaks of prothioconazole derivatives containing epoxide groups and prothioconazole was <2.0.

Claims

1. A prothioconazole derivative containing an epoxy group, characterized in that, Its chemical structure is shown in Formula I: , Formula I.

2. A method for synthesizing a prothioconazole derivative containing an epoxy group according to claim 1, characterized in that, At least the following steps are included: Prothioconazole reacts with alkali in water. After the reaction is complete, the temperature is lowered, hydrochloric acid is added, and a solid precipitates out. The solid is then filtered to obtain a crude product, which is recrystallized and dried.

3. The method for synthesizing the epoxy-containing prothioconazole derivative according to claim 2, characterized in that, The molar ratio of prothioconazole to alkali is (0.02-0.03):(0.075-0.105).

4. The method for synthesizing the prothioconazole derivative containing an epoxy group according to claim 2, characterized in that, The base is a hydroxide or carbonate from Group I or Group II.

5. The method for synthesizing the prothioconazole derivative containing an epoxy group according to claim 2, characterized in that, The molar ratio of prothioconazole to hydrochloric acid is (0.02-0.03):(0.050-0.055).

6. The method for synthesizing the epoxy-containing prothioconazole derivative according to claim 2, characterized in that, The mass ratio of prothioconazole to water is (8-10):

80.

7. The method for synthesizing the epoxy-containing prothioconazole derivative according to claim 2, characterized in that, The reaction temperature is 50-80℃, and the reaction time is 6-10h.

8. The method for synthesizing the epoxy-containing prothioconazole derivative according to claim 2, characterized in that, The recrystallization includes the following steps: adding the crude product to a solvent, heating to 65-70℃ to dissolve the crude product, cooling to 0-5℃ to precipitate the solid, filtering, and rinsing with water.

9. The method for synthesizing the epoxy-containing prothioconazole derivative according to claim 8, characterized in that, The cooling rate is 0.3-1.0℃ / minute.

10. A method for detecting prothioconazole derivatives containing epoxy groups according to claim 1, characterized in that, At least the following steps are included: The epoxylated prothioconazole derivatives were dissolved in acetonitrile. A 0.1-0.2% aqueous phosphoric acid solution was used as mobile phase A, and acetonitrile as mobile phase B. A C18 packed column and a UV or diode array detector were employed. The injection volume was 20-22 μL. Gradient elution was performed with controlled column temperature and flow rate. The epoxylated prothioconazole derivatives were separated by reversed-phase high-performance liquid chromatography at a wavelength of 254 nm, and quantified using the external standard method.

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