Preparation method of high-purity metiram active compound

Abstract

The invention relates to the technical field of drug synthesis, and provides a preparation method of a high-purity metiram active compound, which comprises the following steps: S1, adding ethylenediamine and an alkaline mixed solution into water, uniformly mixing, adding a carbon disulfide solution, reacting, and filtering to obtain an intermediate sodium thioneb solution; s2, adding an oxidant solution into the intermediate sodium dithane solution, preserving heat for the first time, adding a zinc salt solution, and preserving heat for the second time to obtain a mixed solution; s3, crystallizing the mixed solution, filtering, leaching, adding a stabilizer, uniformly mixing, and drying, so as to obtain a metiram active compound; in the step S1, the alkaline mixed solution comprises a sodium hydroxide solution and sodium zeolite in a weight ratio of (3-9): 1. By means of the technical scheme, the problem that in the related technology, the purity of the metiram raw medicine is low is solved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and specifically, to a preparation method of high-purity metiram technical material. Background Art

[0002] Metiram is an organosulfur protective fungicide and belongs to ethylene bisdithiocarbamate. It is in the form of white to light yellow powder, has low toxicity, and has a wide range of bactericidal effects. It has good control effects on a variety of fungal diseases, can control multiple diseases simultaneously, and reduce the types and frequencies of pesticide use. At the same time, metiram can form a protective film on the plant surface, effectively preventing the invasion and spread of pathogens, and the prevention effect is remarkable.

[0003] Currently, the preparation of metiram mainly uses amine as the raw material, reacts with carbon disulfide, manganese sulfate, zinc sulfate, etc. under alkaline conditions. However, in the actual production process, due to differences in the selection of reaction parameters, impurities are easily generated in the reaction. The appearance of impurities reduces the purity of metiram and has a negative impact on its bactericidal effect and stability, indicating that there is still great room for optimization in the existing preparation methods.

[0004] Therefore, researching and developing a preparation method that can improve the purity of metiram technical material not only can improve the product quality but also has important practical significance for expanding the application range of metiram. Summary of the Invention

[0005] The present invention provides a preparation method of high-purity metiram technical material, which solves the problem of low purity of metiram technical material in the related art.

[0006] The technical solution of the present invention is as follows: The present invention provides a preparation method of high-purity metiram technical material, including the following steps: S1. Add ethylenediamine and an alkaline mixture into water. After mixing evenly, add a carbon disulfide solution, react, and filter to obtain an intermediate sodium metiram solution; S2. After adding an oxidizing agent solution to the intermediate sodium metiram solution, perform the first heat preservation, add a zinc salt solution, and perform the second heat preservation to obtain a mixed solution; S3. After subjecting the mixed solution to crystallization treatment, filter, wash, add a stabilizer, mix evenly, and dry to obtain metiram technical material; In step S1, the components of the alkaline mixture include a sodium hydroxide solution and sodium zeolite with a weight ratio of 3-9:1.

[0007] As a further technical solution, the molar ratio of sodium hydroxide in the sodium hydroxide solution, carbon disulfide in the carbon disulfide solution, and ethylenediamine is 1-2:2-3:1; The mass fraction of the sodium hydroxide solution is 25% - 35%, for example, it can be 25%, 28%, 30%, 32%, 35%, preferably 25%, 30%, 35%, and more preferably 30%; The mass fraction of the carbon disulfide solution is 20% - 30%, for example, it can be 20%, 22%, 24%, 25%, 26%, 28%, 29%, 30%, preferably 20%, 25%, 30%, and more preferably 25%.

[0008] As a further technical solution, the addition amount of water is 5 - 6 times the mass of the ethylenediamine.

[0009] As a further technical solution, in step S1, when adding the carbon disulfide solution, it is added dropwise, and the dropping time is 35 - 50 min.

[0010] As a further technical solution, in step S1, the reaction temperature is 20 - 25 °C and the time is 3 - 4 h.

[0011] As a further technical solution, the oxidant solution includes one or more of sodium hypochlorite solution, potassium hypochlorite solution, and calcium hypochlorite solution; The mass fraction of the oxidant solution is 8% - 10%, for example, it can be 8%, 8.3%, 8.5%, 9%, 9.2%, 9.5%, 9.8%, 10%, preferably 8%, 9%, 10%, and more preferably 9%; The zinc salt solution includes one or two of zinc chloride solution and zinc sulfate solution; The mass fraction of the zinc salt solution is 45% - 55%, for example, it can be 45%, 46%, 48%, 50%, 51%, 52%, 54%, 55%, preferably 45%, 50%, 55%, and more preferably 50%.

[0012] As a further technical solution, the molar ratio of the oxidant in the oxidant solution, the zinc salt in the zinc salt solution, and the ethylenediamine is 0.08 - 0.24:1 - 1.1:1, and it can be 0.08:1 - 1.1:1, 0.1:1:1, 0.1:1.05:1, 0.15:1.05:1, 0.2:1.05:1, 0.24:1.1:1.

[0013] As a further technical solution, in step S2, when performing the first heat preservation, the temperature is 26 - 28 °C and the time is 80 - 100 min; When performing the second heat preservation, the temperature is 26 - 28 °C and the time is 40 - 70 min.

[0014] As a further technical solution, in step S2, when adding the oxidant solution, it is added drop by drop, and the dropping time is 15 to 25 minutes; When adding the zinc salt solution, it is added drop by drop, and the dropping time is 5 to 10 minutes.

[0015] In the present invention, the oxidant solution is added drop by drop, enabling the oxidant to continuously and uniformly contact with the intermediate sodium thiram in the reaction system, which can avoid the problem of uneven reaction caused by the overly violent local reaction due to the one-time addition of a large amount of oxidant; The zinc salt solution is added drop by drop, which can better combine with the intermediate, improve the reaction efficiency of the zinc salt, and reduce the generation of side reaction products, thereby enhancing the purity of the original drug of metiram.

[0016] As a further technical solution, in step S3, the crystallization treatment is divided into the first-step crystallization and the second-step crystallization; During the first-step crystallization, it is cooled at a cooling rate of 2 to 4 °C / min to 12 to 16 °C and then kept warm for 15 to 20 minutes; During the second-step crystallization, it is cooled at a cooling rate of 0.5 to 1 °C / min to 3 to 5 °C and then kept warm for 5 to 8 minutes.

[0017] In the present invention, the crystallization treatment is divided into two steps. First, it is cooled at a relatively fast cooling rate (2 to 4 °C / min), which can reduce the solution temperature in a relatively short time, can reduce the adsorption of impurities by the generated precipitate to a certain extent, thereby effectively reducing the mixing of impurities. Then, the cooling rate is reduced to 0.5 to 1 °C / min to slowly cool the solution, which can improve the stability of the generated precipitate. The precise control of the two-step cooling rate can further improve the purity of the original drug of metiram.

[0018] In the present invention, during the preparation of the original drug of metiram, a stabilizer is added. The addition of the stabilizer helps to keep the original drug of metiram stable, thereby improving the consistency of the original drug of metiram and keeping the original drug of metiram at a high purity. The stabilizer can be one or more of hexamethylenetetramine, ammonium ferrous sulfate, paraformaldehyde, ammonium ferrous sulfate, sodium sulfite, preferably hexamethylenetetramine and ammonium ferrous sulfate. When the stabilizer is hexamethylenetetramine and ammonium ferrous sulfate, the weight ratio is 1 to 4:1, for example, it can be 1:1, 1.5:1, 2:1, 3:1, 4:1, preferably 1:1, 3:1, 4:1, and more preferably 3:1.

[0019] As a further technical solution, the addition amount of the stabilizer is 1% to 1.5% of the mass of the zinc salt solution.

[0020] The working principle and beneficial effects of the present invention are as follows: 1. In the present invention, ethylenediamine is used as a raw material, and under the action of an alkaline mixture, it reacts with carbon disulfide to obtain an intermediate sodium thiram solution. Then, by adding an oxidant solution, the intermediate sodium thiram is appropriately oxidized first. While removing some impurities in the reaction system, it is beneficial to the subsequent efficient reaction with the zinc salt solution, thereby realizing the process of oxidation and precipitation simultaneously. After crystallization treatment and the addition of a stabilizer, a high-purity and high-yield thiram-ethyl original drug can be finally obtained.

[0021] 2. In the present invention, the components of the alkaline mixture include sodium hydroxide solution and sodium-type zeolite. While providing an alkaline environment for the reaction of ethylenediamine and carbon disulfide, the addition of sodium-type zeolite can maintain the stability of the alkaline environment of the sodium hydroxide solution to a certain extent, ensure that the reaction proceeds in a suitable alkaline environment, improve the yield of the intermediate sodium thiram solution, and lay a foundation for the improvement of the purity and yield of subsequent thiram-ethyl. Specific embodiments

[0022] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the present invention.

[0023] In the following examples and comparative examples, the effective ingredient content of ethylenediamine is 99%; the effective ingredient content of hexamine is 99%; the effective ingredient content of ammonium ferrous sulfate is 99%; the specific surface area of sodium-type zeolite is 700m 2 / g, and the average particle size is 4.5μm; the average particle size of clinoptilolite powder is 45μm, the porosity is 52%, and the density is 1.8g / cm 3 .

[0024] Example 1 A preparation method of a high-purity thiram-ethyl original drug includes the following steps: S1. Add 120.2g of ethylenediamine (2mol) and an alkaline mixture to water. After mixing evenly, dropwise add a carbon disulfide solution (mass fraction 20%), and finish dropping within 35 minutes. React at 20°C for 4 hours, and filter to obtain an intermediate sodium thiram solution. Among them, the addition amount of water is 5 times the mass of ethylenediamine, and the molar ratio of sodium hydroxide in the sodium hydroxide solution, carbon disulfide in the carbon disulfide solution, and ethylenediamine is 1:2:1. The components of the alkaline mixture include a sodium hydroxide solution (mass fraction 25%) and sodium-type zeolite with a weight ratio of 3:1. S2. Add sodium hypochlorite solution (mass fraction 8%) dropwise to the intermediate sodium thiram solution, complete the addition within 15 min, keep warm at 26 °C for 100 min, add zinc chloride solution (mass fraction 45%), and keep warm at 26 °C for 70 min to obtain a mixed solution; wherein, the molar ratio of sodium hypochlorite in the sodium hypochlorite solution, zinc chloride in the zinc chloride solution and ethylenediamine is 0.08:1:1; S3. Cool the mixed solution to 3 °C at a cooling rate of 1.5 °C / min, keep warm for 20 min to complete the crystallization process, after filtration and rinsing, add a stabilizer, mix evenly, and dry to obtain the original drug of metiram; wherein, the stabilizer includes hexamine and ammonium ferrous sulfate with a weight ratio of 1:1, and the addition amount of the stabilizer is 1% of the mass of the zinc chloride solution; The yield of the original drug of metiram is 99.2%, and the purity is 93.5%.

[0025] Example 2 A preparation method of high-purity original drug of metiram, comprising the following steps: S1. Add 120.2 g of ethylenediamine (2 mol) and an alkaline mixed solution to water, mix evenly, then add carbon disulfide solution (mass fraction 25%) dropwise, complete the addition within 45 min, react at 25 °C for 3 h, and filter to obtain the intermediate sodium thiram solution; wherein, the addition amount of water is 6 times the mass of ethylenediamine, the molar ratio of sodium hydroxide in the sodium hydroxide solution, carbon disulfide in the carbon disulfide solution and ethylenediamine is 1.5:2.5:1, and the components of the alkaline mixed solution include sodium hydroxide solution (mass fraction 30%) and sodium zeolite with a weight ratio of 4:1; S2. Add sodium hypochlorite solution (mass fraction 9%) dropwise to the intermediate sodium thiram solution, complete the addition within 20 min, keep warm at 28 °C for 80 min, add zinc chloride solution (mass fraction 50%), and keep warm at 28 °C for 40 min to obtain a mixed solution; wherein, the molar ratio of sodium hypochlorite in the sodium hypochlorite solution, zinc chloride in the zinc chloride solution and ethylenediamine is 0.15:1.05:1; S3. Cool the mixed solution to 3 °C at a cooling rate of 1.5 °C / min, keep warm for 20 min to complete the crystallization process, after filtration and rinsing, add a stabilizer, mix evenly, and dry to obtain the original drug of metiram; wherein, the stabilizer includes hexamine and ammonium ferrous sulfate with a weight ratio of 3:1, and the addition amount of the stabilizer is 1.5% of the mass of the zinc chloride solution; The yield of the original drug of metiram is 99.4%, and the purity is 94.4%.

[0026] Example 3 A preparation method of high-purity original drug of metiram, comprising the following steps: S1. Add 120.2 g of ethylenediamine (2 mol) and an alkaline mixture into water. After mixing evenly, dropwise add a carbon disulfide solution (mass fraction 30%). Finish the dropwise addition within 50 min and react at 25 °C for 3 h. Then filter to obtain the intermediate sodium thiram solution. Among them, the addition amount of water is 6 times the mass of ethylenediamine. The molar ratio of sodium hydroxide in the sodium hydroxide solution, carbon disulfide in the carbon disulfide solution, and ethylenediamine is 2:3:1. The components of the alkaline mixture include a sodium hydroxide solution (mass fraction 35%) and sodium zeolite with a weight ratio of 9:1. S2. Dropwise add a sodium hypochlorite solution (mass fraction 10%) into the intermediate sodium thiram solution. Finish the dropwise addition within 25 min and keep warm at 28 °C for 80 min. Then add a zinc chloride solution (mass fraction 55%) and keep warm at 28 °C for 40 min to obtain a mixed solution. Among them, the molar ratio of sodium hypochlorite in the sodium hypochlorite solution, zinc chloride in the zinc chloride solution, and ethylenediamine is 0.24:1.1:1. S3. Cool the mixed solution to 3 °C at a cooling rate of 1.5 °C / min and keep warm for 20 min to complete the crystallization process. After filtration and rinsing, add a stabilizer. After mixing evenly, dry to obtain the original drug of metiram. Among them, the stabilizer includes hexamine and ammonium ferrous sulfate with a weight ratio of 4:1, and the addition amount of the stabilizer is 1.5% of the mass of the zinc chloride solution. The yield of the original drug of metiram is 99.1% and the purity is 93.9%.

[0027] Example 4 The difference between this example and Example 2 is only that in this example, the alkaline mixture includes a sodium hydroxide solution (mass fraction 30%) and sodium zeolite with a weight ratio of 3:1. The yield of the original drug of metiram is 99.2% and the purity is 94.1%.

[0028] Example 5 The difference between this example and Example 2 is only that in this example, the alkaline mixture includes a sodium hydroxide solution (mass fraction 30%) and sodium zeolite with a weight ratio of 9:1. The yield of the original drug of metiram is 99.3% and the purity is 94.3%.

[0029] Example 6 The difference between this example and Example 2 is only that in this example, step S3 is different. Specifically: S3. After cooling the mixture at a cooling rate of 1.5 °C / min to 12 °C, holding for 15 min, then cooling at a cooling rate of 0.1 °C / min to 3 °C, and holding for 5 min to complete the crystallization process. After filtration and rinsing, a stabilizer is added, and after mixing evenly, it is dried to obtain the original drug of metiram; wherein, the stabilizer includes hexamethylenetetramine and ammonium ferrous sulfate with a weight ratio of 3:1, and the addition amount of the stabilizer is 1.5% of the mass of the zinc chloride solution; The yield of the original drug of metiram is 99.2%, and the purity is 95.2%.

[0030] Example 7 The difference between this example and Example 6 is only that step S3 in this example is different, specifically: S3. After cooling the mixture at a cooling rate of 5 °C / min to 12 °C, holding for 15 min, then cooling at a cooling rate of 1.5 °C / min to 3 °C, and holding for 5 min to complete the crystallization process. After filtration and rinsing, a stabilizer is added, and after mixing evenly, it is dried to obtain the original drug of metiram; wherein, the stabilizer includes hexamethylenetetramine and ammonium ferrous sulfate with a weight ratio of 3:1, and the addition amount of the stabilizer is 1.5% of the mass of the zinc chloride solution; The yield of the original drug of metiram is 99.0%, and the purity is 95.3%.

[0031] Example 8 The difference between this example and Example 6 is only that step S3 in this example is different, specifically: S3. After cooling the mixture at a cooling rate of 2 °C / min to 12 °C, holding for 15 min, then cooling at a cooling rate of 0.5 °C / min to 3 °C, and holding for 5 min to complete the crystallization process. After filtration and rinsing, a stabilizer is added, and after mixing evenly, it is dried to obtain the original drug of metiram; wherein, the stabilizer includes hexamethylenetetramine and ammonium ferrous sulfate with a weight ratio of 3:1, and the addition amount of the stabilizer is 1.5% of the mass of the zinc chloride solution; The yield of the original drug of metiram is 99.3%, and the purity is 96.0%.

[0032] Example 9 The difference between this example and Example 6 is only that step S3 in this example is different, specifically: S3. After cooling the mixture at a cooling rate of 3 °C / min to 12 °C, holding for 15 min, then cooling at a cooling rate of 0.8 °C / min to 3 °C, and holding for 5 min to complete the crystallization process. After filtration and rinsing, a stabilizer is added, and after mixing evenly, it is dried to obtain the original drug of metiram; wherein, the stabilizer includes hexamethylenetetramine and ammonium ferrous sulfate with a weight ratio of 3:1, and the addition amount of the stabilizer is 1.5% of the mass of the zinc chloride solution; The yield of the original drug of metiram is 99.5%, and the purity is 96.4%.

[0033] Example 10 The difference between this example and Example 6 is only that step S3 in this example is different. Specifically: S3. After cooling the mixed solution to 12°C at a cooling rate of 4°C / min, keeping it warm for 15 min, then cooling it to 3°C at a cooling rate of 1°C / min, and keeping it warm for 5 min to complete the crystallization process. After filtration and rinsing, a stabilizer is added. After mixing evenly, it is dried to obtain the original drug of metiram; among them, the stabilizer includes hexamine and ammonium ferrous sulfate with a weight ratio of 3:1, and the addition amount of the stabilizer is 1.5% of the mass of the zinc chloride solution; The yield of the original drug of metiram is 99.3%, and the purity is 96.1%.

[0034] Example 11 The difference between this example and Example 6 is only that step S3 in this example is different. Specifically: S3. After cooling the mixed solution to 16°C at a cooling rate of 4°C / min, keeping it warm for 20 min, then cooling it to 5°C at a cooling rate of 1°C / min, and keeping it warm for 8 min to complete the crystallization process. After filtration and rinsing, a stabilizer is added. After mixing evenly, it is dried to obtain the original drug of metiram; among them, the stabilizer includes hexamine and ammonium ferrous sulfate with a weight ratio of 3:1, and the addition amount of the stabilizer is 1.5% of the mass of the zinc chloride solution; The yield of the original drug of metiram is 99.4%, and the purity is 96.2%.

[0035] Comparative Example 1 The difference between this comparative example and Example 1 is only that in this comparative example, the sodium-type zeolite is replaced with an equal amount of sodium hydroxide solution (mass fraction 25%); The yield of the original drug of metiram is 97.9%, and the purity is 85.7%.

[0036] Comparative Example 2 The difference between this comparative example and Example 1 is only that in this comparative example, the sodium-type zeolite is replaced with an equal amount of ammonia water solution (mass fraction 25%); The yield of the original drug of metiram is 96.4%, and the purity is 83.6%.

[0037] Comparative Example 3 The difference between this comparative example and Example 1 is only that in this comparative example, the sodium-type zeolite is replaced with an equal amount of clinoptilolite powder; The yield of the original drug of metiram is 98.1%, and the purity is 85.9%.

[0038] Compared with Comparative Examples 1 to 3, the purity of the metiram technical prepared in Examples 1 to 5 is improved, indicating that when the alkaline mixture includes sodium hydroxide solution and sodium zeolite, the combined use of the two helps the formation of sodium thiram in a stable alkaline environment, and finally improves the purity of the metiram technical.

[0039] In addition, compared with Examples 5 to 7, the purity of the metiram technical prepared in Examples 8 to 11 is improved, indicating that during the crystallization process, in the first crystallization, it is cooled to 12 - 16 °C at a cooling rate of 2 - 4 °C / min, and in the second crystallization, it is cooled to 3 - 5 °C at a cooling rate of 0.5 - 1 °C / min, which can further improve the purity of the metiram technical.

[0040] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A preparation method of high-purity metiram technical, characterized in that, It includes the following steps: S1. Add ethylenediamine and an alkaline mixture into water. After mixing evenly, add a carbon disulfide solution, react, filter, and obtain an intermediate sodium thiram solution; S2. After adding an oxidant solution to the intermediate sodium thiram solution, conduct the first heat preservation, add a zinc salt solution, and conduct the second heat preservation to obtain a mixture; S3. After subjecting the mixture to crystallization treatment, filter, wash, add a stabilizer, mix evenly, and dry to obtain the original drug of metiram; In step S1, the components of the alkaline mixture include a sodium hydroxide solution and sodium-type zeolite with a weight ratio of 3 - 9:

1.

2. The preparation method of a high-purity metiram technical material according to claim 1, characterized in that, The molar ratio of sodium hydroxide in the sodium hydroxide solution, carbon disulfide in the carbon disulfide solution, and ethylenediamine is 1 - 2:2 - 3:1; The mass fraction of the sodium hydroxide solution is 25% - 35%; The mass fraction of the carbon disulfide solution is 20% - 30%.

3. The preparation method of a high-purity metiram technical material according to claim 1, characterized in that, The oxidant solution includes one or more of sodium hypochlorite solution, potassium hypochlorite solution, and calcium hypochlorite solution; The mass fraction of the oxidant solution is 8% - 10%; The zinc salt solution includes one or two of zinc chloride solution and zinc sulfate solution; The mass fraction of the zinc salt solution is 45% - 55%.

4. The preparation method of a high-purity metiram technical material according to claim 1, characterized in that, The molar ratio of the oxidant in the oxidant solution, the zinc salt in the zinc salt solution, and ethylenediamine is 0.08 - 0.24:1 - 1.1:

1.

5. The preparation method of a high-purity metiram technical material according to claim 1, characterized in that, In step S2, during the first heat preservation, the temperature is 26 - 28°C and the time is 80 - 100 min; During the second heat preservation, the temperature is 26 - 28°C and the time is 40 - 70 min.

6. The preparation method of a high-purity metiram technical material according to claim 1, wherein In step S2, when adding the oxidant solution, it is added dropwise, and the dropping time is 15 - 25 min; When adding the zinc salt solution, it is added dropwise, and the dropping time is 5 - 10 min.

7. A method for preparing a high-purity metiram technical, as claimed in claim 1, wherein In step S3, the crystallization treatment is divided into the first-step crystallization and the second-step crystallization; During the first-step crystallization, cool at a cooling rate of 2 - 4°C / min to 12 - 16°C, and then keep warm for 15 - 20 min; During the second-step crystallization, cool at a cooling rate of 0.5 - 1°C / min to 3 - 5°C, and then keep warm for 5 - 8 min.

8. The preparation method of a high-purity metiram technical material according to claim 1, characterized in that, The stabilizer includes hexamine and ammonium ferrous sulfate with a weight ratio of 1 - 4:

1.

9. The preparation method of a high-purity metiram technical material according to claim 1, characterized in that, The addition amount of the stabilizer is 1% - 1.5% of the mass of the zinc salt solution.

10. The preparation method of a high-purity metiram technical material according to claim 1, wherein, In step S1, the temperature of the reaction is 20 - 25°C and the time is 3 - 4 h.