A method for continuously synthesizing prothioconazole using a tubular reactor

Abstract

The present invention relates to a method for continuously synthesizing prothioconazoles using a tubular reactor, and belongs to the technical field of synthesis of broad-spectrum triazole thione fungicides, and uses 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane as raw material, and in the presence of an oxidant, reacts with a solvent in a tubular reactor to obtain the prothioconazoles. In the reaction, the material enters the pipe reactor through a metering pump, and the length of the residence time of the system in the pipeline can be controlled by controlling the flow rate, and the reaction time is adjusted; the temperature can also be more accurately controlled by heat transfer, so that the material is prevented from affecting the reaction effect because the temperature cannot be adjusted in time during the reaction; after passing through the pipeline, the material is directly subjected to crystallization treatment, and the whole process greatly shortens the reaction time, improves the atomic utilization efficiency, reduces the raw material cost, and has a small amount of three wastes, which is conducive to continuous production.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of broad-spectrum triazole thione fungicides, and particularly relates to a method for continuously synthesizing prothioconazole by utilizing a tubular reactor. Background Art

[0002] Prothioconazole is a broad-spectrum triazolethione fungicide. Its chemical name is (RS)-2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-2,4-dihydro-1,2,4-triazole-3-thione. It is a broad-spectrum fungicide produced and developed by Bayer. It has a unique triazolethione structure. Its mechanism of action is to inhibit the demethylation of lanosterol or 2,4-methylenedihydrolanosterol, the precursor of sterol in fungi, at the 14th position, namely, demethylation inhibitor (DMIS). Prothioconazole not only has systemic activity, but also has excellent protection, treatment and eradication activities, and has obvious yield-increasing effects. Compared with triazole fungicides, prothioconazole has a broader spectrum of fungicidal activity. Prothioconazole has low toxicity, no teratogenicity, no mutagenicity, no toxicity to embryos, and is safe for humans and the environment. It is mainly used to prevent and control many diseases of crops such as cereals, wheat, and beans. It has a good preventive effect on almost all wheat diseases, such as powdery mildew, sheath blight, wilt, leaf spot, rust, sclerotinia, web spot, and moire disease.

[0003] At present, there are few patent documents on the synthesis of prothioconazole original drug in China. The existing industrial production process basically uses α-acetyl-γ-butyrolactone as the starting material, generates 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane through a series of reactions, and then generates the required prothioconazole through oxidation. In the oxidation reaction, the reaction time is long and there are many solid wastes. Patents CN108689952A and CN109232452A use ferric chloride to directly oxidize 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-1,2,4-triazolidine-5-thione-1-yl)-propane or catalyze it through a phase transfer catalyst, and the yield of prothioconazole can reach more than 95%. However, the biggest disadvantage of ferric chloride oxidation is that it produces a large amount of solid waste, which is generally more than twice the mass of the product. Patents CN109912522A, CN111303059A and CN111527071A use oxidants such as nitric acid, hydrogen peroxide and sodium nitrite to oxidize, which can also achieve good yields, but they do not fundamentally improve the problem of three wastes.

[0004] Based on the above content, a method for continuously synthesizing prothioconazole using a tubular reactor is proposed. Summary of the invention

[0005] The object of the present invention is to provide a method for continuously synthesizing prothioconazole using a tubular reactor in order to solve the above problems.

[0006] The present invention achieves the above-mentioned purpose through the following technical solutions:

[0007] The present invention provides a method for continuously synthesizing prothioconazole using a tubular reactor, comprising the following steps:

[0008] (1) using a tubular reactor as a reaction vessel, dissolving 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane in a solvent, and adding an oxidant to the solvent and mixing well;

[0009] (2) The mixture of step (1) and oxygen are simultaneously introduced into a tubular reactor to react. After the reaction process is completed, the reaction liquid discharged from the outlet of the tubular reactor is purified and crystallized to obtain high-purity prothioconazole.

[0010] As a further optimization scheme of the present invention, the oxidant in step (1) is one of ferric chloride, cuprous chloride, cupric chloride, cuprous bromide, cuprous iodide, and lead acetate.

[0011] As a further optimization scheme of the present invention, the solvent of step (1) is one of methanol, toluene, dichloroethane and water.

[0012] As a further optimization scheme of the present invention, the molar ratio of the 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane, the oxidant, and the oxygen is 1:0.01:1.

[0013] As a further optimization scheme of the present invention, the temperature of step (1) is 30-80°C.

[0014] As a further optimization scheme of the present invention, the pressure of oxygen in step (2) is 0.4MPa-1.06MPa.

[0015] As a further optimization scheme of the present invention, the flow rate of the mixed material into the tubular reactor is 0.2-1.0 L / min, and the flow rate of the oxygen into the tubular reactor is 0.1-1.0 L / min.

[0016] As a further optimization scheme of the present invention, the reaction temperature after the mixture and oxygen in step (1) are introduced into the tubular reactor is 10°C-100°C.

[0017] As a further optimization scheme of the present invention, the reaction time after the mixed material and oxygen in step (1) are introduced into the tubular reactor is 1-20 minutes.

[0018] The beneficial effects of the present invention are:

[0019] The present invention achieves the purpose of producing propyl sulfide by passing 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane through a tubular reactor in a corresponding solvent in the presence of oxygen and other oxidants. In the reaction, the material enters the tubular reactor through a metering pump, and the length of the retention time of the system in the pipeline can be controlled by controlling the flow rate to adjust the reaction time; the temperature can also be more accurately controlled by heat transfer to avoid affecting the reaction effect due to the failure to adjust the temperature of the material in time during the reaction process; after passing through the pipeline, the material is directly crystallized, and the entire process greatly shortens the reaction time, improves the atomic utilization efficiency, reduces the raw material cost, reduces the amount of three wastes, and is conducive to continuous production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is the equation for continuously synthesizing prothioconazole using a tubular reactor in the present invention. DETAILED DESCRIPTION

[0021] The present application is described in further detail below. It is necessary to point out that the following specific implementation methods are only used to further illustrate the present application and cannot be understood as limiting the scope of protection of the present application. Technicians in this field can make some non-essential improvements and adjustments to the present application based on the above application content.

[0022] Example 1

[0023] 500g of raw material 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (1.45mol) was dissolved in 800g of methanol, 19.6g of ferric chloride hexahydrate (0.072mol) was added and stirred to dissolve, and then pumped into the tubular reactor at 0.5L / min using a metering pump. Air was simultaneously introduced into the vent at a flow rate of 0.5L / min. The temperature in the pipeline was regulated to 50°C. The timing was started from the time when the raw material entered the pipeline port. After 68s, all the feed liquid in the pipeline was pumped out. The reaction was detected to be complete, and the feed liquid was directly cooled, crystallized, and filtered to obtain 493.2g of product (content: 98.35%) with a yield of 97%.

[0024] Example 2

[0025] 500g of raw material 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (1.45mol) was dissolved in 800g of methanol, 196g of ferric chloride hexahydrate (0.72mol) was added and stirred to dissolve, and then pumped into the tubular reactor at 0.5L / min using a metering pump. Air was simultaneously introduced into the vent at a flow rate of 0.5L / min. The temperature in the pipeline was regulated to 45°C. The timing was started from the time when the raw material entered the pipeline port. After 65s, all the feed liquid in the pipeline was pumped out. The reaction was detected to be complete, and the feed liquid was directly cooled, crystallized, and filtered to obtain 497.2g of product (content: 98.1%) with a yield of 97.5%.

[0026] Example 3

[0027] 500g of raw material 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (1.45mol) was dissolved in 800g of toluene, 19.6g of ferric chloride hexahydrate (0.072mol) was added and stirred to dissolve, and then pumped into the tubular reactor at 0.2L / min using a metering pump. Air was simultaneously introduced into the vent at a flow rate of 0.2L / min. The temperature in the pipeline was regulated to 50°C. The timing was started from the time when the raw material entered the pipeline port. After 165s, all the feed liquid in the pipeline was pumped out. The reaction was detected to be complete, and the feed liquid was directly cooled, crystallized, and filtered to obtain 476.7.2g of product (content: 97.2%) with a yield of 93%.

[0028] Example 4

[0029] 500g of raw material 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (1.45mol) was dissolved in 800g of methanol, 7.18g of cuprous chloride (0.072mol) was added and stirred to dissolve, and then pumped into the tubular reactor at 0.2L / min using a metering pump. Air was simultaneously introduced into the vent at a flow rate of 0.2L / min. The temperature in the pipeline was regulated to 50°C. The timing was started from the time when the raw material entered the pipeline port. After 165s, all the feed liquid in the pipeline was pumped out. The reaction was detected to be complete, and the feed liquid was directly cooled, crystallized, and filtered to obtain 470.2g of product (content: 97.0%) with a yield of 91.2%.

[0030] Example 5

[0031] 500g of raw material 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (1.45mol) was dissolved in 800g of methanol, 19.6g of ferric chloride hexahydrate (0.072mol) was added and stirred to dissolve, and then pumped into the tubular reactor at 0.5L / min using a metering pump. Oxygen was simultaneously introduced into the vent at a flow rate of 0.5L / min. The temperature in the pipeline was regulated to 50°C. The timing was started from the time when the raw material entered the pipeline port. After 66s, all the feed liquid in the pipeline was pumped out. The reaction was detected to be complete, and the feed liquid was directly cooled, crystallized, and filtered to obtain 490g of product (content: 99%) with a yield of 98%.

[0032] Example 6

[0033] 500g of raw material 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (1.45mol) was dissolved in 800g of methanol, 19.6g of ferric chloride hexahydrate (0.072mol) was added and stirred to dissolve, and then pumped into the tubular reactor at 0.2L / min using a metering pump. Oxygen was simultaneously introduced into the vent at a flow rate of 0.2L / min. The temperature in the pipeline was regulated to 50°C. The timing was started from the time when the raw material entered the pipeline port. After 30s, all the feed liquid in the pipeline was pumped out. The reaction was detected to be complete, and the feed liquid was directly cooled, crystallized, and filtered to obtain 485g of product (content: 99%) with a yield of 97%.

[0034] The filtrate was subjected to reduced pressure distillation at 60°C and 0.03 MPa to obtain 790 g of methanol (containing 0.1% water) and 25 g of residual liquid. The residual liquid was mainly composed of ferric chloride hexahydrate, and the residual liquid was further used for catalytic oxidation reaction, and the catalyst TON value could reach more than 500. The entire reaction produced almost no "three wastes".

[0035] Example 7

[0036] 500g of raw material 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (1.45mol) was dissolved in 800g of methanol, 588g of ferric chloride hexahydrate (2.16mol) was added, and then the temperature was raised to 40°C and stirred for 1h. High performance liquid chromatography detected that the raw material reaction was complete, and the feed liquid was directly cooled, crystallized and filtered to obtain 479g of product (content: 98%), with a yield of 95%.

[0037] The filtrate was subjected to vacuum distillation at 60°C and 0.03 MPa to obtain 760 g of methanol (containing 0.2% water) and 610 g of residual liquid. The main components of the residual liquid were a mixture of ferrous chloride and basic ferric chloride. The iron in the residual liquid could only be treated as "three wastes" without treatment and could not be reused.

[0038] The types, amounts and reaction conditions of the oxidants in Examples 1-7 are summarized in the following table:

[0039]

[0040]

[0041] It can be seen from Examples 1 and 2 that Example 1 uses 0.072 mol of ferric chloride hexahydrate as an oxidant, and Example 2 uses 0.72 mol of ferric chloride hexahydrate as an oxidant, and the changes in reaction time, reaction temperature and yield are not obvious;

[0042] It can be seen from Examples 1 and 3 that in Example 1, the mixture of the raw material and the oxidant and the air were introduced at a flow rate of 0.5 L / min, and in Example 3, the mixture of the raw material and the oxidant and the air were introduced at a flow rate of 0.2 L / min, and the reaction time increased from 68 s to 165 s, and the yield decreased;

[0043] It can be seen from Examples 3 and 4 that in Example 4, 0.072 mol of cuprous chloride was used as the oxidant, and the mixture of the raw material and the oxidant and air were introduced at a flow rate of 0.2 L / min, and the reaction time remained unchanged, and the yield was further reduced;

[0044] It can be seen from Example 1 and Example 5 that both Example 1 and Example 5 use 0.072 mol of ferric chloride hexahydrate as the oxidant, but the difference is that Example 5 uses oxygen at a flow rate of 0.5 L / min instead of air, which has a beneficial but not obvious effect on the reaction time and yield;

[0045] It can be seen from Example 6 and Example 5 that the difference between Example 6 and Example 5 is that Example 6 uses a flow rate of 0.2 L / min to pass the mixture of the raw material and the oxidant and oxygen, so that the reaction time is greatly shortened from 66 s to 30 s. The yield is inferior to that of Example 5, but compared with Example 1, it has the effect of shortening the reaction time;

[0046] It can be seen from Example 7 that when the amount of oxidant is increased, oxygen is not introduced during the reaction, and the reaction is not carried out in a tubular reactor, the reaction time is much longer than that of Examples 1-6.

[0047] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for continuously synthesizing prothioconazole using a tubular reactor, characterized in that: The following steps are involved: 500g of the raw material 2-(1-chloro-cyclopropyl-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane was dissolved in 800g of methanol, 19.6g of ferric chloride hexahydrate was added and stirred to dissolve, and then the mixture was pumped into the tubular reactor at a rate of 0.2L / min using a metering pump. Oxygen was introduced into the vent at a flow rate of 0.2L / min, and the temperature in the pipeline was regulated to 50°C. The timing starts from the time of entering the pipe mouth. After 30 seconds, all the feed liquid in the pipe is pumped out, and the reaction is detected to be complete. The feed liquid is directly cooled, crystallized, and filtered to obtain 485g of product with a content of 99% and a yield of 97%. The filtrate is subjected to reduced pressure distillation at 60°C and 0.03MPa to obtain 790g of methanol containing 0.1% water and 25g of residual liquid. The main component of the residual liquid is ferric chloride hexahydrate, and the residual liquid is further used for catalytic oxidation reaction, and the catalyst TON value can reach more than 500.

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