Method for preparing O-methyl-N-nitroisourea

Abstract

The invention relates to the technical field of synthesis of medicine and pesticide intermediates, and discloses a method for preparing O-methyl-N-nitroisourea. The method comprises the following steps: (1) mixing O-methylisourea salt with a sulfuric acid solution to obtain an O-methylisourea salt solution; (2) introducing the O-methylisourea salt solution and the nitric acid solution into a mixer, and mixing to obtain a reaction solution; (3) reacting the reaction liquid in a tubular reactor at 20-40 DEG C; the molar ratio of the O-methylisourea salt to the sulfuric acid is 1: (2.5-3), and the concentration of the sulfuric acid solution is 98-100wt%; the molar ratio of the O-methylisourea salt to the nitric acid is 1: (1.2-1.8), and the concentration of the nitric acid solution is 95-98wt%; the retention time of the reaction liquid in the tubular reactor is 30-90 minutes. The industrial production of the O-methyl-N-nitroisourea is realized by adopting a conventional tubular reactor continuous flow process, and the production cost is greatly reduced.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical pesticide intermediate synthesis, and in particular to a method for preparing O-methyl-N-nitroisourea. Background Art

[0002] Dinotefuran is the only nicotinoid insecticide that does not contain chlorine atoms and aromatic rings. It belongs to the third generation of nicotinoid insecticides and has the advantages of high efficiency, low toxicity, broad insecticide spectrum and long lasting effect. Dinotefuran is widely used in agriculture to kill insects in crops such as rice, cotton, vegetables, fruit trees, and flowers. It is also highly effective against sanitary pests such as flies, termites, and houseflies. O-Methyl-N-nitroisourea is an important pesticide intermediate for the preparation of guanidine derivatives with insecticidal activity and dinotefuran.

[0003] At present, there are few reports on the preparation method of O-methyl-N-nitroisourea, which is mainly synthesized by nitration of O-methylisourea hydrogen sulfate by mixed acid. For example, in the "Synthesis of O-methyl-N-nitroisourea" published by Zeng Yu et al., O-methylisourea sulfate is precooled to 10°C, and the mixed acid is added dropwise at a temperature of 0-10°C. After the addition is completed, the reaction is stirred for 6 hours to complete, and O-methyl-N-nitroisourea is obtained by post-treatment. This method has a long production duration, a large reaction heat release, and high energy consumption. If the temperature of the production process is out of control, there will be a risk of explosion, endangering the safety of life and property, and is not suitable for industrial production.

[0004] Patent application CN 111362839A discloses a method for preparing O-methyl-N-nitroisourea, wherein O-methylisourea sulfate is dissolved in fuming sulfuric acid to obtain an O-methylisourea sulfate solution, fuming nitric acid is mixed with concentrated sulfuric acid to obtain a mixed acid, and then the O-methylisourea sulfate solution and the mixed acid are mixed and reacted in a microchannel reactor at 30-60° C. to obtain O-methyl-N-nitroisourea. Although this method shortens the reaction time and improves the yield, its microchannel reactor has a small flux, is expensive, and has a huge investment cost, and is not suitable for industrial production. Summary of the invention

[0005] The purpose of the present invention is to overcome the problems of existing preparation methods such as large heat release, easy explosion, high cost, and unsuitability for industrial production, and to provide a method for preparing O-methyl-N-nitroisourea.

[0006] In order to achieve the above object, the present invention provides a method for preparing O-methyl-N-nitroisourea, which comprises the following steps:

[0007] (1) mixing O-methyl isourea salt with a sulfuric acid solution to obtain an O-methyl isourea salt solution;

[0008] (2) introducing the O-methylisourea thioate solution and the nitric acid solution into a mixer and mixing them to obtain a reaction solution;

[0009] (3) reacting the reaction solution in a tubular reactor at 20-40° C.;

[0010] Wherein, the molar ratio of O-methylisourea salt to sulfuric acid is 1:2.5-3, and the concentration of the sulfuric acid solution is 98-100wt%;

[0011] The molar ratio of O-methylisourea sulfate to nitric acid is 1:1.2-1.8, and the concentration of the nitric acid solution is 95-98wt%;

[0012] The residence time of the reaction liquid in the tubular reactor is 30-90 minutes.

[0013] Preferably, in step (2), the flow rate of the O-methylisourea sulfate solution is 2-8 L / min.

[0014] Preferably, in step (2), the flow rate of the nitric acid solution is 0.5-2 L / min.

[0015] Preferably, in step (3), the reaction pressure is 0.01-5 MPa.

[0016] Preferably, the method further comprises: adding the reaction material obtained in step (3) dropwise into ice water at ≤0°C, and then performing solid-liquid separation and drying.

[0017] Preferably, the amount of ice water used is 1.5-2.5 times the weight of the reaction materials.

[0018] Preferably, the solid-liquid separation method is centrifugation;

[0019] Preferably, the centrifugal conditions include: temperature < 0°C, and rotation speed of 1000-3000 rpm.

[0020] Preferably, the residence time of the reaction solution in the tubular reactor is 60 min.

[0021] Preferably, the reaction temperature is 30°C.

[0022] Preferably, the O-methylisourea salt is O-methylisourea hydrogen sulfate and / or O-methylisourea sulfate.

[0023] Compared with the prior art, the beneficial effects of the present invention are:

[0024] 1. The method of the present invention does not have the step of preparing a high-concentration mixed acid solution, thereby reducing the risk brought by the mixed acid preparation process. A specific O-methyl isourea salt solution is prepared, and then mixed with fuming nitric acid to obtain a reaction solution, and the reaction solution is passed into a tubular reactor to react for 30-90 minutes at 20-40° C., and then precipitated in ice water to obtain high-purity O-methyl-N-nitroisourea. By limiting the ratio of O-methyl isourea salt, concentrated sulfuric acid and fuming nitric acid in the raw materials, the reaction solution obtained by mixing can produce O-methyl-N-nitroisourea under mild conditions and in a short time, which has the advantages of mild reaction conditions, low explosion risk and high conversion rate, and is suitable for industrial production.

[0025] 2. In the method described in the present invention, the conventional tubular reactor continuous flow process is used to realize the industrial production of O-methyl-N-nitroisourea, which greatly reduces the production cost.

[0026] 3. Furthermore, in the method described in the present application, the reaction material obtained by the reaction is added dropwise into ice water, and the temperature of the environment and the amount of ice water during the dropwise addition are controlled, which effectively improves the yield and purity of O-methyl-N-nitroisourea. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The product prepared in Example 1 1 HNMR characterization result diagram;

[0028] Figure 2 This is a graph showing the HPLC characterization results of the product prepared in Example 1. DETAILED DESCRIPTION

[0029] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0030] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0031] The present invention provides a method for preparing O-methyl-N-nitroisourea, which comprises the following steps:

[0032] (1) mixing O-methyl isourea salt with a sulfuric acid solution to obtain an O-methyl isourea salt solution;

[0033] (2) introducing the O-methylisourea thioate solution and the nitric acid solution into a mixer and mixing them to obtain a reaction solution;

[0034] (3) reacting the reaction solution in a tubular reactor at 20-40° C.;

[0035] Wherein, the molar ratio of O-methylisourea salt to sulfuric acid is 1:2.5-3, and the concentration of the sulfuric acid solution is 98-100wt%;

[0036] The molar ratio of O-methylisourea sulfate to nitric acid is 1:1.2-1.8, and the concentration of the nitric acid solution is 95-98wt%;

[0037] The residence time of the reaction liquid in the tubular reactor is 30-90 minutes.

[0038] The traditional preparation method of O-methyl-N-nitroisourea usually requires the preparation of a mixed acid solution first. Concentrated sulfuric acid and concentrated nitric acid are both strong acids with strong corrosiveness, and the process of mixing concentrated sulfuric acid and concentrated nitric acid to obtain a mixed acid is an exothermic process. If the operation is improper, there is a risk of explosion. If industrial production is carried out according to the traditional method, the demand for the mixed acid solution is very large, and there will be great safety hazards. Based on this, the present invention provides a preparation method of O-methyl-N-nitroisourea that does not require the pre-preparation of a mixed acid, and the entire preparation process is carried out under mild conditions, which greatly reduces safety hazards and can achieve industrial production.

[0039] According to some specific embodiments of the present invention, in step (1), the molar ratio of O-methylisourea salt to sulfuric acid can be 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9 or 1:3.

[0040] In a preferred embodiment, the O-methylisourea salt is O-methylisourea hydrogen sulfate and / or O-methylisourea sulfate. The O-methylisourea hydrogen sulfate may be a commercially available product with a purity of 90-98 wt %; the O-methylisourea sulfate may be a commercially available product with a purity of 95-98 wt %.

[0041] According to some specific embodiments of the present invention, the molar ratio of O-methylisourea salt to nitric acid can be 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7 or 1:1.8.

[0042] In a preferred embodiment, in step (2), the flow rate of the O-methylisourea sulfate solution can be 2-8 L / min; specifically, it can be 2 L / min, 3 L / min, 4 L / min, 5 L / min, 6 L / min, 7 L / min or 8 L / min. In a preferred case, the flow rate of the nitric acid solution is 0.5-2 L / min; specifically, it can be 0.5 L / min, 1 L / min, 1.5 L / min or 2 L / min. In the present invention, the O-methylisourea solution and the nitric acid solution can be introduced into the mixer at a larger flow rate for reaction, which can achieve large-scale industrial production.

[0043] In the present invention, in step (2), the mixer may be a common mixer in the art, which can achieve mixing of the O-methylisourea thioate solution and the nitric acid solution.

[0044] According to some preferred embodiments of the present invention, in step (3), the reaction liquid is reacted in a tubular reactor at 25-35°C, more preferably 30°C; the residence time of the reaction liquid in the tubular reactor is 50-70min, more preferably 60min. In the present invention, by reasonably controlling the proportion of each component in the raw material and combining the premixing process, the reaction liquid can be reacted in a tubular reactor at a relatively low temperature, and the reaction time is moderate, so that the reaction materials can be kept at a relatively low temperature while ensuring a high conversion rate, reducing the difficulty of post-treatment and improving the purity of the final product.

[0045] According to some preferred embodiments of the present invention, in step (3), the reaction pressure is 0.01-5 MPa, more preferably 0.1-4 MPa.

[0046] In a preferred embodiment, the method further comprises step (4), which mainly comprises post-treating the reaction mass obtained in step (3) to obtain a high-purity O-methyl-N-nitroisourea product. Specifically, the specific process of step (4) is as follows: adding the reaction mass obtained in step (3) dropwise into ice water at a temperature of ≤0°C, and then performing solid-liquid separation and drying. The system temperature is maintained at ≤0°C, and the reaction mass is added dropwise into ice water, so that O-methyl-N-nitroisourea can be precipitated, and then the O-methyl-N-nitroisourea product can be collected by solid-liquid separation.

[0047] In the present invention, the amount of ice water used in step (4) can be reasonably controlled. If the amount of ice water is too much, the amount of product dissolved will increase, resulting in a decrease in the amount of product collected. If the amount of ice water is too little, it will be unfavorable for temperature control and will also affect the amount of product collected. In a preferred case, the amount of ice water used is 1.5-2.5 times the weight of the reaction solution; specifically, it can be 1.5 times, 2 times or 2.5 times. Using the above amount of ice water can not only increase the amount of product collected, but also reduce the volume of the waste acid solution and reduce pollution.

[0048] In a preferred embodiment, the solid-liquid separation method is centrifugation. Centrifugation under relatively low temperature and high speed conditions is beneficial to increase the weight of the collected product. The centrifugation conditions include: temperature <0°C and speed of 1000-3000rpm.

[0049] In the present invention, the drying can be performed using common equipment and conventional conditions in the art.

[0050] The preparation method of the present invention is carried out under mild conditions throughout the whole process, does not require mixed acid preparation, has low equipment cost, small safety hazards, and a small volume of waste acid, is very suitable for industrial production, and has good application prospects.

[0051] The present invention will be described in detail below through examples, but the protection scope of the present invention is not limited thereto.

[0052] The O-methylisourea hydrogen sulfate used in the following examples and comparative examples was provided by Wuhan Qingjiang Chemical Huanggang Co., Ltd., with a purity of 94 wt%.

[0053] Example 1

[0054] (1) mixing O-methylisourea hydrogen sulfate with concentrated sulfuric acid solution to obtain O-methylisourea hydrogen sulfate solution; wherein the amount of O-methylisourea hydrogen sulfate used is 2750 kg, the molar ratio of methylisourea hydrogen sulfate to sulfuric acid is 1:2.7, and the concentration of the sulfuric acid solution is 99 wt %;

[0055] (2) introducing an O-methylisourea hydrogen sulfate solution and a nitric acid solution into a mixer for mixing to obtain a reaction solution; wherein the molar ratio of O-methylisourea hydrogen sulfate to nitric acid is 1:1.5, and the concentration of the nitric acid solution is 97 wt %; the flow rate of the O-methylisourea hydrogen sulfate solution is 4 L / min, and the flow rate of the nitric acid solution is 1 L / min;

[0056] (3) reacting the reaction liquid in a tubular reactor at 28-32° C., the reaction pressure is 0.5-2 MPa, and the residence time of the reaction liquid in the tubular reactor is 60 min;

[0057] (4) adding the reaction mass obtained in step (3) dropwise into ice water at ≤0°C, centrifuging at a centrifugal temperature of less than 0°C and a rotation speed of 3000 rpm, and then drying in a double cone dryer, wherein the amount of ice water used is twice the weight of the reaction mass.

[0058] Example 2

[0059] (1) mixing O-methylisourea hydrogen sulfate with concentrated sulfuric acid solution to obtain an O-methylisourea hydrogen sulfate solution; wherein the amount of O-methylisourea hydrogen sulfate used is 2750 kg, the molar ratio of O-methylisourea hydrogen sulfate to sulfuric acid is 1:2.6, and the concentration of the sulfuric acid solution is 99 wt %;

[0060] (2) introducing an O-methylisourea hydrogen sulfate solution and a nitric acid solution into a mixer for mixing to obtain a reaction solution; wherein the molar ratio of O-methylisourea hydrogen sulfate to nitric acid is 1:1.3, and the concentration of the nitric acid solution is 97 wt %; the flow rate of the O-methylisourea hydrogen sulfate solution is 5 L / min, and the flow rate of the nitric acid solution is 1 L / min;

[0061] (3) reacting the reaction liquid in a tubular reactor at 28-32° C., the reaction pressure is 0.5-3 MPa, and the residence time of the reaction liquid in the tubular reactor is 50 min;

[0062] (4) adding the reaction mass obtained in step (3) dropwise into ice water at ≤0°C, centrifuging at a temperature of less than 0°C and a rotation speed of 2500 rpm, and then drying in a double cone dryer, wherein the amount of ice water is 1.8 times the weight of the reaction mass.

[0063] Example 3

[0064] (1) mixing O-methylisourea hydrogen sulfate with concentrated sulfuric acid solution to obtain an O-methylisourea hydrogen sulfate solution; wherein the amount of O-methylisourea hydrogen sulfate used is 2750 kg, the molar ratio of O-methylisourea hydrogen sulfate to sulfuric acid is 1:2.8, and the concentration of the sulfuric acid solution is 99 wt %;

[0065] (2) introducing an O-methylisourea hydrogen sulfate solution and a nitric acid solution into a mixer for mixing to obtain a reaction solution; wherein the molar ratio of O-methylisourea hydrogen sulfate to nitric acid is 1:1.7, and the concentration of the nitric acid solution is 97 wt %; the flow rate of the O-methylisourea hydrogen sulfate solution is 5 L / min, and the flow rate of the nitric acid solution is 1 L / min;

[0066] (3) reacting the reaction liquid in a tubular reactor at 28-32° C., the reaction pressure is 0.05-2 MPa, and the residence time of the reaction liquid in the tubular reactor is 65 min;

[0067] (4) adding the reaction mass obtained in step (3) dropwise into ice water at ≤0°C, and then centrifuging at a centrifugal temperature of less than 0°C and a rotation speed of 1000 rpm, and then drying in a double cone dryer, wherein the amount of ice water used is 2.5 times the weight of the reaction mass.

[0068] Example 4

[0069] The method described in Example 1 is used, except that in step (4), the amount of ice water used is 1 times the weight of the reaction materials.

[0070] Example 5

[0071] The method described in Example 1 is used, except that in step (4), the amount of ice water used is 3 times the weight of the reaction materials.

[0072] Example 6

[0073] The method described in Example 1 is used for implementation, except that in step (3), the residence time of the reaction solution in the tubular reactor is 40 min.

[0074] Comparative Example 1

[0075] Synthesis of O-methyl-N-nitroisourea by kettle reaction:

[0076] Pump 2000 kg of 98 wt% sulfuric acid solution into the acid preparation kettle, keep stirring and control the temperature at 30°C, add 1500 kg of 97 wrt% nitric acid solution to obtain a mixed acid solution for standby use; add 2000 kg of 98 wt% sulfuric acid solution into the nitration kettle, control the temperature at 10°C, add 2750 kg of O-methylisourea hydrogen sulfate solid, stir for 30 minutes to dissolve and clarify, control the temperature of the reactor at 0-10°C, add the mixed acid solution dropwise for 5-8 hours, continue to keep warm and stir the reaction for 10 hours, add the reaction material obtained in the step dropwise into ice water at ≤0°C, then centrifuge, the centrifugation temperature is ≤0°C, the rotation speed is 1500 rpm, and the product is transferred to a double cone dryer for drying, wherein the amount of ice water used is 20000 kg.

[0077] Comparative Example 2

[0078] The method described in Example 1 is used for implementation, except that in step (3), the residence time of the reaction solution in the tubular reactor is 20 min.

[0079] Comparative Example 3

[0080] The method described in Example 1 was followed, except that the molar ratio of O-methylisourea salt to sulfuric acid was 1:2.

[0081] Comparative Example 4

[0082] The method described in Example 1 was followed, except that the molar ratio of O-methylisourea salt to nitric acid was 1:1.

[0083] Test Example 1

[0084] use 1 The product prepared in Example 1 was characterized by HNMR and HPLC, wherein the 1HNMR diagram is as follows: Figure 1 As shown in the HPLC diagram Figure 2 As shown. Combined Figure 1 and Figure 2 It can be seen that the product prepared in Example 1 is O-methyl-N-nitroisourea, and the purity of O-methyl-N-nitroisourea measured by the area normalization method is 99.77%.

[0085] Test Example 2

[0086] The purity and yield of the products prepared in Examples 1-5 and the comparative example were tested, and the results are shown in Table 1.

[0087] Table 1

[0088] Example No. Yield % purity% Example 1 95.6 99.77 Example 2 94.7 97.62 Example 3 96.1 96.89 Example 4 94.1 95.25 Example 5 92.5 97.72 Example 6 84.4 95.75 Comparative Example 1 76.7 96.12 Comparative Example 2 65.5 94.26 Comparative Example 3 74.3 93.53 Comparative Example 4 77.8 93.68

[0089] It can be seen from the results in Table 1 that the method described in the present invention can realize the industrial preparation of high-purity O-methyl-N-nitroisourea and has the advantage of high conversion rate.

[0090] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing O-methyl-N-nitroisourea, characterized in that: The method comprises the following steps: (1) mixing O-methyl isourea salt with a sulfuric acid solution to obtain an O-methyl isourea salt solution; (2) introducing the O-methylisourea salt solution and the nitric acid solution into a mixer and mixing them to obtain a reaction solution; (3) reacting the reaction solution in a tubular reactor at 20-40° C.; Wherein, the molar ratio of O-methylisourea salt to sulfuric acid is 1:2.5-3, and the concentration of the sulfuric acid solution is 98-100wt%; The molar ratio of O-methylisourea salt to nitric acid is 1:1.2-1.8, and the concentration of the nitric acid solution is 95-98wt%; The residence time of the reaction liquid in the tubular reactor is 30-90 minutes.

2. The method according to claim 1, characterized in that In step (2), the flow rate of the O-methylisourea sulfate solution is 2-8 L / min.

3. The method according to claim 1 or 2, characterized in that: In step (2), the flow rate of the nitric acid solution is 0.5-2 L / min.

4. The method according to claim 1, characterized in that: In step (3), the reaction pressure is 0.01-5 MPa.

5. The method according to claim 1, characterized in that The method further comprises: adding the reaction material obtained in step (3) dropwise into ice water at a temperature of ≤0°C, and then performing solid-liquid separation and drying.

6. The method according to claim 5, characterized in that The amount of ice water used is 1.5-2.5 times the weight of the reaction materials.

7. The method according to claim 5, characterized in that The method of solid-liquid separation is centrifugation; Preferably, the centrifugal conditions include: temperature < 0°C, and rotation speed of 1000-3000 rpm.

8. The method according to claim 1, characterized in that The residence time of the reaction liquid in the tubular reactor is 60 min.

9. The method according to claim 1, characterized in that: The temperature of the reaction was 30°C.

10. The method according to claim 1, characterized in that The O-methylisourea salt is O-methylisourea hydrogen sulfate and / or O-methylisourea sulfate.

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