Continuous synthesis method of pyrimidone compound

Abstract

The invention relates to the technical field of pesticide chemical industry, in particular to a continuous synthesis method of pyrimidone compounds, which comprises the following steps: mixing anilino acid ester and trifluoroaminocrotonate used as reaction raw materials with alkali in a tubular reactor or a micro-channel reactor for reaction to obtain the pyrimidone compounds. According to the invention, the reaction is carried out in the tubular reactor or the micro-channel reactor and is used for synthesizing the pyrimidone compound, so that the use of a traditional reaction kettle is avoided, the reaction liquid holdup is reduced, and the reaction safety is improved; the reaction time can be shortened, the reaction efficiency is improved, the reaction risk is reduced, and the reaction cost is saved; furthermore, by adjusting reaction parameters, the reaction selectivity is improved, and the loss of raw materials can be reduced.

Description

Technical Field

[0001] The invention relates to the technical field of pesticide chemical industry, and in particular to a continuous synthesis method of pyrimidone compounds. Background Art

[0002] Safensulfuron is an important tool for controlling glyphosate-resistant weeds. It can replace phenoxy herbicides 2,4-D or sulfonylurea herbicides in combination with glyphosate, and has a "synergistic effect" on glyphosate, which can kill weeds very quickly and promote the absorption and conduction of glyphosate by weeds. Weeds will die after 1-3 days of application; it can usually reduce the amount of glyphosate used by 30%-50%. The global application amount of glyphosate is about 800,000 tons per year. The use of safensulfuron with glyphosate is conducive to the promotion and use of safensulfuron among farmers, and the future market prospects are good.

[0003] Pyrimidone compounds are key intermediates in the preparation of saflufenacil. The existing production process of pyrimidone compounds is a traditional kettle reaction, and the separation yield can reach up to 90%. With the increasing competition in the pesticide market, it is increasingly important to find a simple, energy-saving, suitable for industrial production and improved intermediate quality synthesis method. Summary of the invention

[0004] In view of this, the technical problem to be solved by the present invention is to provide a continuous synthesis method of pyrimidone compounds with a higher separation yield.

[0005] The present invention provides a continuous synthesis method of pyrimidone compounds, comprising the following steps:

[0006] The aniline acid ester and trifluoroamino crotonate are used as reaction raw materials, and are mixed with a base in a tubular reactor or a microchannel reactor to react to obtain pyrimidone compounds.

[0007] Optionally, the base is sodium methoxide or sodium ethoxide.

[0008] Optionally, the molar ratio of the anilino acid ester, the trifluoroamino crotonate, and the base is 1:1.0-2.5:2.0-4.5.

[0009] Optionally, the molar ratio of the anilino acid ester, the trifluoroamino crotonate, and the base is 1:1.5:2.5.

[0010] Optionally, the solvent of the reaction is one or more of DMF and DMAC.

[0011] Optionally, the ratio of the mass of the solvent to the total mass of the anilinoic acid ester and the trifluoroamino crotonic acid ester is 5 to 10:1.

[0012] Optionally, the reaction temperature is 100-180°C.

[0013] Optionally, the reaction time is 5 to 40 minutes.

[0014] Compared with the prior art, the present invention provides a continuous synthesis method for pyrimidone compounds, comprising the following steps: using anilinoic acid ester and trifluoroamino crotonate as reaction raw materials and mixing them with a base in a tubular reactor or a microchannel reactor to react to obtain pyrimidone compounds.

[0015] The present invention carries out the reaction in a tubular reactor or a microchannel reactor for synthesizing pyrimidone compounds, thereby avoiding the use of a traditional reactor, reducing the reaction liquid holding volume, and improving the reaction safety; and can reduce the reaction time, improve the reaction efficiency, reduce the reaction risk, and save the reaction cost; further, by adjusting the reaction parameters, the reaction selectivity is improved, and the loss of raw materials can be reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is the central control liquid phase spectrum in Example 3. DETAILED DESCRIPTION

[0017] The present invention provides a continuous synthesis method of pyrimidone compounds, comprising the following steps:

[0018] The aniline acid ester and trifluoroamino crotonate are used as reaction raw materials, and are mixed with a base in a tubular reactor or a microchannel reactor to react to obtain pyrimidone compounds.

[0019] The equation for the above reaction is as follows:

[0020]

[0021] The above reaction may produce the following side reactions to produce impurities 1-3:

[0022] Impurity 1:

[0023]

[0024] Impurity 2:

[0025]

[0026] Impurity 3:

[0027]

[0028] The present invention adopts a tubular reactor or a microchannel reactor as a reaction container, thereby reducing the reaction time and the liquid holding capacity of the reaction container without changing the solvent and the raw materials, while reducing the reaction risk, improving the reaction efficiency and reaction selectivity, and reducing the impurity content in the finished product.

[0029] Preferably, the base is sodium methoxide or sodium ethoxide, more preferably sodium methoxide.

[0030] Preferably, the molar ratio of the anilino acid ester, the trifluoroamino crotonate, and the base is 1:1.0-2.5:2.0-4.5, more preferably 1:1.5:2.5.

[0031] The experimental results show that when using tubular reactors and microchannel reactors for reactions, it is necessary to pay attention to controlling the feed rate. An imbalance in the ratio will lead to a cliff-like drop in the separation yield and an increase in impurities, especially a significant increase in impurities 1 and impurity 3.

[0032] The solvent of the reaction is preferably one or more of DMF and DMAC, more preferably DMF.

[0033] The ratio of the mass of the solvent to the total mass of the anilino ester and the trifluoroamino crotonate is preferably 5 to 10:1, more preferably 5:1.

[0034] The reaction temperature is preferably 100 to 180°C, more preferably 120 to 140°C.

[0035] The reaction time is preferably 5 to 40 minutes.

[0036] In some specific embodiments of the present invention, anilinoic acid ester is dissolved in 5 to 10 times the mass of DMF and DMAC at room temperature and stirred to dissolve. The anilinoic acid ester is set aside after being completely dissolved. 1.0 to 2.5 times the molar amount of trifluoroamino crotonate is dissolved in 5 to 10 times the mass of DMF and DMAC and mixed evenly for use. 2.0 to 4.5 times the molar amount of alkali solution is set aside. The tubular reactor or microchannel reactor is heated to 100° C. to 180° C., and the three raw materials are introduced into the reactor in a certain proportion, and the residence time is 5 min to 40 min.

[0037] After the reaction in the tubular reactor or microchannel reactor is completed, the product does not need to be recrystallized, the raw material content is controlled to be ≤0.5% in HPLC, and the product content is ≥97%. The product yield obtained by post-treatment is >95%.

[0038] In order to further illustrate the present invention, the following is a detailed description in conjunction with the embodiments. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention.

[0039] All raw materials of the present invention have no particular limitation on their sources, and can be purchased from the market or prepared according to conventional methods known to those skilled in the art.

[0040] In the following examples, the tubular reactor / microchannel reactor model and source are:

[0041] Tubular reactor: Hammer MIC tube bundle reactor;

[0042] Microchannel reactor: Corning G1 microchannel reactor;

[0043] Example 1 Tubular Reactor Reaction

[0044] At room temperature, 50g of 97% aniline acid ester was put into the preparation flask, and then 250g of DMF was added and stirred to dissolve completely. 32g of 97% trifluoroamino crotonate was put into the preparation bottle, and then 250g of DMF was added and stirred evenly. 55.6g of 28.3% sodium methoxide methanol solution was taken for standby use. Take a tubular reactor with a liquid holding volume of 20ml and heat it to 140℃. The three raw materials were introduced into the reactor according to the mass flow rate of aniline acid ester: trifluoroamino crotonate: sodium methoxide = 1: 0.94: 0.19 (molar ratio of 1: 1.5: 2.5), and the residence time was 30min. The raw material content was 0.3% and the product content was 97.5% when the HPLC test was carried out of the reactor. The reaction was qualified. The reaction solution was desolventized, acidified, filtered and dried to obtain the product, with a content of 97.1% (no need for recrystallization) and a separation yield of 96.1%.

[0045] In-process control of the reaction liquid (HPLC detection): Impurity 1 accounts for about 2%, impurity 2 accounts for about 0.5%, and impurity 3 accounts for about 0.3%.

[0046] Example 2

[0047] According to the method of Example 1, the reaction was carried out in a tubular reactor using the conditions in Table 1. The reaction data are shown in Table 1.

[0048] Table 1 Reaction parameters of Example 2

[0049]

[0050]

[0051] In Table 1, A represents anilinoic acid ester; B represents crotonic acid ester; and C represents sodium methoxide.

[0052] Example 3 Microchannel Reactor

[0053] At room temperature, 50g of 97% aniline acid ester was put into the preparation flask, and then 250g of DMF was added and stirred to dissolve completely. 32g of 97% trifluoroamino crotonate was put into the preparation bottle, and then 250g of DMF was added and stirred evenly. 55.6g of 28.3% sodium methoxide methanol solution was taken for standby use. A tubular reactor with a liquid holding volume of 20ml was taken and heated to 120°C. The three raw materials were introduced into the microchannel reactor according to the mass flow rate of aniline acid ester: trifluoroamino crotonate: sodium methoxide = 1: 0.94: 0.19 (molar ratio of 1: 1.5: 2.5), and the residence time was 15min. The raw material content was 0.1% and the product content was 97.2% after HPLC detection out of the reactor. The reaction was qualified. The reaction solution was desolventized, acidified, filtered and dried to obtain the product, with a separation yield of 97.25% (the product does not need to be recrystallized).

[0054] In-process control of the reaction liquid (HPLC detection): Impurity 1 accounts for 1.27%, impurity 2 accounts for about 1.12%, and impurity 3 accounts for 0.05%.

[0055] Liquid phase diagram Figure 1 shown.

[0056] The spectrum data are shown in Table 2:

[0057] Table 2 Central control map data

[0058]

[0059]

[0060] Example 4

[0061] According to the method of Example 3, the conditions in Table 3 were adopted to carry out the reaction in a microchannel reactor. The reaction data are shown in Table 3.

[0062] Table 3 Reaction parameters of Example 4

[0063] Reaction temperature / ℃ Residence time / min Material mol ratio A:B:C Product separation yield / % 110 20 1:1.5:2.5 95.0 140 15 1:1.5:2.5 97.3 160 10 1:1.5:2.5 96.8 160 8 1:2:4 96.9 160 8 1:3:5 94.7 180 6 1:2:4 96.1 180 6 1:1.5:2.5 96.7 180 5 1:1.5:2.5 97.1 180 4 1:1.5:2.5 95.5

[0064] In Table 3, A represents anilinoic acid ester; B represents crotonic acid ester; and C represents sodium methoxide.

[0065] The test results show that when the reaction temperature is 180°C, the side reactions increase and the impurity content increases.

[0066] Example 5

[0067] According to the method of Example 3, the solvent was replaced with DMAC, NMP or toluene, the molar ratio of anilino ester: trifluoroamino crotonate: sodium methoxide was 1:1.5:2.5, the reaction temperature was 120°C, and the product separation yield was shown in Table 4.

[0068] Table 4 Solvent screening

[0069] Solvents Separation yield / % DMF 97.3 DMAC 97.2 NMP 92.1 Toluene 60.4

[0070] Example 6

[0071] According to the method of Example 3, the amount of solvent (mass ratio of aniline ester) was adjusted, and the other parameters were the same as Example 3. The product separation yield is shown in Table 5.

[0072] Table 5 Solvent quantity screening

[0073] Solvent amount Separation yield / % 10 97.3 9 97.3 8 97.3 7 97.0 6 96.5 5 96.4

[0074] Example 7

[0075] According to the method of Example 3, the base was replaced by sodium ethoxide, the molar ratio of anilino ester: trifluoroamino crotonate: sodium methoxide was 1:1.5:2.5, the reaction temperature was 120°C, and the product separation yield was shown in Table 6

[0076] Table 6 Screening of alkali

[0077] Types of alkali Separation yield / % Sodium Methanol 97.3 Sodium ethoxide 97.0

[0078] Comparative Example 1 Tank Reaction

[0079] At room temperature, 50g of 97% anilinoic acid ester, 32g of 97% trifluoroamino crotonate, 500g of DMF, and 27.8g of 28.3% sodium methoxide methanol solution were placed in a configuration flask and heated to 120°C (1 hour). Sodium methoxide methanol solution was slowly added according to the pH of the reaction solution, and a total of 32.1g was added (4 hours). The reaction was qualified (5 hours in total). The reaction solution was desolventized, acidified, and filtered to obtain the product, which was then recrystallized with ethyl acetate and dried to obtain a product content of 97.1% (recrystallization was required once), and the separation yield was 83%.

[0080] Reaction solution test results:

[0081] In-process control of the reaction liquid (HPLC detection): Impurity 1 accounts for 4%, impurity 2 accounts for 1.5%, and impurity 3 accounts for 1.1%.

[0082] Comparative Example 2 Tubular / Microchannel Reaction

[0083] Tubular / microchannel reaction according to the feed amount of the kettle reaction

[0084] At room temperature, 50g of 97% aniline acid ester was put into the preparation flask, and then 250g of DMF was added and stirred to dissolve completely. 25.6g of 97% trifluoroamino crotonate was put into the preparation bottle, and then 250g of DMF was added and stirred evenly. 48.9g of 28.3% sodium methoxide methanol solution was taken for standby use. A tubular reactor with a liquid holding volume of 20ml was taken and heated to 120°C. The three raw materials were introduced into the microchannel reactor according to the mass flow rate of aniline acid ester: trifluoroamino crotonate: sodium methoxide = 1: 0.75: 0.17 (molar ratio of 1: 1.2: 2.2), and the residence time was 40min. HPLC detection of the raw material content out of the reactor was 45%, and the product content was 50.2%. The reaction was unqualified. The reaction solution was desolventized, acidified, filtered, and dried to obtain the product with a yield of 49.5%. The content was 70%.

[0085] It can be seen from the above embodiments and comparative examples that a higher separation yield can be obtained by using a tubular reactor and a microchannel reactor, and the reaction yield is only about 50% when moved to a tubular reactor and a microchannel reactor in the manner of a kettle reaction. Therefore, before using a tubular reactor or a microchannel reactor for reaction, it is necessary to correctly understand the reaction and make a lot of adjustments and verifications to the parameters.

[0086] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A continuous synthesis method of pyrimidone compounds, comprising the following steps: The aniline acid ester and trifluoroamino crotonate are used as reaction raw materials, and are mixed with a base in a tubular reactor or a microchannel reactor to react to obtain pyrimidone compounds.

2. The continuous synthesis method according to claim 1, characterized in that The base is sodium methoxide or sodium ethoxide.

3. The continuous synthesis method according to claim 1, characterized in that The molar ratio of the anilino acid ester, the trifluoroamino crotonate and the base is 1:1.0-2.5:2.0-4.

5.

4. The continuous synthesis method according to claim 3, characterized in that: The molar ratio of the anilino acid ester, the trifluoroamino crotonate and the base is 1:1.5:2.

5.

5. The continuous synthesis method according to claim 1, characterized in that: The solvent of the reaction is one or more of DMF and DMAC.

6. The continuous synthesis method according to claim 5, characterized in that: The ratio of the mass of the solvent to the total mass of the anilinoic acid ester and the trifluoroamino crotonic acid ester is 5 to 10:

1.

7. The continuous synthesis method according to claim 1, characterized in that: The reaction temperature is 100-180°C.

8. The continuous synthesis method according to claim 1, characterized in that: The reaction time is 5 to 40 minutes.

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