A method for synthesizing a flupyradifuram intermediate N-acetyloxymethyl-2-trifluoromethylbenzamide

Abstract

The application relates to a synthesis method of a fluopicolide intermediate N-acetyloxymethyl-2-trifluoromethylbenzamide, and belongs to the technical field of organic synthesis. The method flow comprises the following steps: Step 1, adding 2-trifluoromethylbenzamide, a base and a solvent into a reaction bottle, dropwise adding halomethyl acetate, and keeping reaction after addition; Step 2, after reaction, water is added for phase separation, and N-acetyloxymethyl-2-trifluoromethylbenzamide is obtained by reducing pressure and concentrating an organic phase. The condensation reaction is directly completed in one step, the target intermediate is synthesized in a high yield and high selectivity under mild conditions by using cheap and easily-obtained raw materials, the process is simple, efficient, economical, safe and easy to implement, perfectly meets the core needs of industrial production, and lays a solid foundation for efficient and low-cost production of fluopicolide.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a synthesis method of fluopyram intermediate N-acetyloxymethyl-2-trifluoromethylbenzamide. BACKGROUND

[0002] Fluopyram is a new type of pyridyl ethyl benzamide fungicide and nematocide developed by Bayer CropScience in 2002. The product was first reported by the media in 2009, and was popularized and put on the market in 2012. The product is now produced by Bayer, and many companies such as Bayer and BASF are involved in market development. At present, fluopyram is developed as a nematocide, fungicide, seed treatment agent, and agricultural product storage preservative in the global market. Since its launch, fluopyram has rapidly grown into the hottest SDHI fungicide due to its unique mechanism of action and excellent performance. The chemical structural formula of fluopyram and its intermediates are as follows:

[0003]

[0004] At present, there are many patents and literatures reporting the synthesis method of fluopyram intermediate N-acetyloxymethyl-2-trifluoromethylbenzamide. As described in patent WO2006067103, the intermediate is obtained by amidation, hydroxymethylation and esterification using o-trifluoromethyl benzoyl chloride as the raw material. The synthesis route is as follows:

[0005]

[0006] The synthesis method has a long route and low total yield. Due to the high cost of raw materials, the cost of product raw materials is high.

[0007] Other synthesis routes of fluopyram, such as described in WO2004016088, require high-pressure hydrogenation process and have low yield and high raw material cost, which makes this route unsuitable for industrial production.

[0008] Therefore, it is the focus of research in the field to seek a clean, efficient and low-cost synthesis process of fluopyram intermediate N-acetyloxymethyl-2-trifluoromethylbenzamide suitable for industrial production. SUMMARY

[0009] The present application provides a synthesis method of fluopyram intermediate N-acetyloxymethyl-2-trifluoromethylbenzamide, which solves the problems raised in the above background technology, shortens the method route, improves the yield, makes the raw material cost more low-cost, and the reaction is safe and reliable, the process is simple, and the reaction condition is mild, which has high industrial application value.

[0010] The technical scheme of the present application for solving the above technical problem is as follows: a synthesis method of a fluopicolide intermediate N-acetyloxymethyl-2-trifluoromethylbenzamide, characterized in that the synthesis method comprises the following steps:

[0011] Step 1, adding 2-trifluoromethylbenzamide and a base and a solvent into a reaction bottle, dropping halomethyl acetate, and reacting after the dropping is completed, wherein the base is triethylamine, the solvent is dichloromethane or dichloroethane, the halomethyl acetate is chloromethyl acetate or bromomethyl acetate, the temperature of the reaction is 0-10 DEG C, and the reaction time is 1-2 hours;

[0012] Step 2, after the reaction is completed, adding water to separate the phases, and concentrating the organic phase under reduced pressure to obtain N-acetyloxymethyl-2-trifluoromethylbenzamide, and the synthesis process route is as follows,

[0013]

[0014] On the basis of the above technical scheme, the present application can also be improved as follows.

[0015] Further, the molar ratio of the 2-trifluoromethylbenzamide and the halomethyl acetate is 1:1.0-1.2.

[0016] Further, the triethylamine can be replaced by triethylamine sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, and pyridine.

[0017] Further, the dichloromethane or dichloroethane can be replaced by a mixed solvent composed of one or more solvents of toluene, dichloromethane, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, DMF, and NMP.

[0018] The present application has the following advantages: the present application provides a synthesis method of a fluopicolide intermediate N-acetyloxymethyl-2-trifluoromethylbenzamide, which has the following advantages:

[0019] The route is significantly shortened, the N-acetyloxymethyl-2-trifluoromethylbenzamide is directly obtained by condensation of 2-trifluoromethylbenzamide with halomethyl acetate under the action of a base, the multi-step complex route of preparing o-trifluoromethylbenzoyl chloride first, then acylating to obtain an amide, then hydroxymethylating, and finally esterifying is avoided, the harsh steps such as high-pressure hydrogenation possibly involved in other routes are also avoided, the process flow is greatly simplified, the operation units and equipment requirements are reduced, the production cycle is shortened, and the cumulative yield loss caused by multi-step reactions is reduced.

[0020] The raw material cost is low, the starting material 2-trifluoromethylbenzamide is more easily available and less expensive than its acyl chloride or special material for a high-pressure hydrogenation route, and the raw material cost can be effectively controlled while ensuring a high yield;

[0021] The reaction condition is mild, the reaction is carried out at a low temperature of 0-10°C, high-pressure equipment is not required, the insulation reaction time is only 1-2 hours, the mild condition reduces the requirement for equipment (such as pressure resistance and high-temperature resistance), the operation is safer, the energy consumption is lower, the scale-up and production control are easier to realize, and the industrial production is suitable;

[0022] The overall process is simple, safe and reliable, the main steps are feeding, temperature control dropping, insulation reaction, liquid separation and concentration, which are all conventional chemical unit operations, only water needs to be added for phase separation after the reaction is completed, and the product can be obtained by reducing pressure concentration of the organic phase, without complex purification steps, the simple operation reduces the risk of human error, and is easy for worker training and operation; simple post-treatment improves production efficiency and equipment utilization; the diversity of solvents and bases facilitates process optimization and adaptation to different situations, and improves the feasibility, safety and reliability of industrial implementation;

[0023] The target intermediate is synthesized in a high yield and high selectivity under mild conditions by designing a one-step direct condensation reaction with cheap and easily available raw materials, and the process is simple, efficient, economical, safe and easy to implement, which perfectly meets the core needs of industrial production, and lays a solid foundation for efficient and low-cost production of fluopyram.

[0024] The above description is only a summary of the technical scheme of the present application, in order to more clearly understand the technical means of the present application and can be implemented according to the content of the description, the following will be described in detail with the preferred embodiments of the present application. The specific embodiments of the present application are described in detail by the following examples. DETAILED DESCRIPTION

[0025] The principles and features of the present application are described below, and the examples are only used to explain the present application and not to limit the scope of the present application. In the following paragraphs, the present application is described in more detail by way of example. The advantages and features of the present application will be more apparent according to the following description.

[0026] Example 1: Step 1, 18.9 g (0.1 mol) of 2-trifluoromethylbenzamide and 11.2 g of triethylamine and 60.0 g of solvent dichloroethane were added to a reaction bottle, 11.9 g of chloromethyl acetate was added dropwise, the temperature was controlled at 0-10°C, and the reaction was kept for 1-2 hours after the addition was completed;

[0027] Step 2, after the reaction was completed, water was added for phase separation, and 24.7 g of N-acetyloxy methyl-2-trifluoromethylbenzamide was obtained by reducing pressure concentration of the organic phase, with a yield of 94.6%.

[0028] NMR of hydrogen: 1 H-NMR (CDC13, 400MHz) 7.5-7.7 (m, 4H), 7.0 (s, 1H), 5.4 (d, 2H), 2.1 (s, 3H).

[0029] Example 2: Step 1, add 18.9g (0.1mol) 2-trifluoromethylbenzamide and 11.2g triethylamine and solvent dichloromethane 60.0g to the reaction bottle, drop 11.9g chloromethyl acetate, control the temperature at 0-10℃, after adding, incubate for 1-2h;

[0030] Step 2, after the reaction is completed, add water to separate the phases, and the organic phase is concentrated under reduced pressure to obtain N-acetyloxymethyl-2-trifluoromethylbenzamide 24.5g, with a yield of 93.8%.

[0031] NMR of hydrogen: 1 H-NMR (CDC13, 400MHz) 7.5-7.7 (m, 4H), 7.0 (s, 1H), 5.4 (d, 2H), 2.1 (s, 3H).

[0032] Example 3: Step 1, add 18.9g (0.1mol) 2-trifluoromethylbenzamide and 12.1g triethylamine and solvent dichloroethane 60.0g to the reaction bottle, drop 13.0g chloromethyl acetate, control the temperature at 0-10℃, after adding, incubate for 1-2h;

[0033] Step 2, after the reaction is completed, add water to separate the phases, and the organic phase is concentrated under reduced pressure to obtain N-acetyloxymethyl-2-trifluoromethylbenzamide 24.6g, with a yield of 94.2%.

[0034] NMR of hydrogen: 1 H-NMR (CDC13, 400MHz) 7.5-7.7 (m, 4H), 7.0 (s, 1H), 5.4 (d, 2H), 2.1 (s, 3H). 3, 400MHz) 7.5-7.7 (m, 4H), 7.0 (s, 1H), 5.4 (d, 2H), 2.1 (s, 3H).

[0035] It should be noted that the NMR of hydrogen of the above examples 1-3 is used to verify the structure of the target compound N-acetyloxymethyl-2-trifluoromethylbenzamide:

[0036] 7.5-7.7 (m, 4H): four hydrogen atoms on the benzene ring.

[0037] 7.0 (s, 1H): nitrogen hydrogen atom (-NH-) on the amide group.

[0038] 5.4 (d, 2H): methylene bridge between the amide nitrogen and the acetoxy group (-NH-CH2-OC(O)-), the doublet splitting is caused by coupling to the N-H.

[0039] 2.1 (s, 3H): methyl on the acetyl group (-OC(O)CH3).

[0040] The chemical shifts, peak shapes, and integrations (number of hydrogen atoms) of each signal in the spectrum were highly consistent with the expected structure, confirming that the compound N-acetyloxymethyl-2-trifluoromethylbenzamide was successfully synthesized.

[0041] The above description is only a preferred embodiment of the present application, and does not limit the present application in any form; those skilled in the art can easily implement the present application according to the above description; however, those skilled in the art can make some changes, modifications, and equivalent changes to the above-mentioned technical content without departing from the scope of the technical solutions of the present application; at the same time, any equivalent changes, modifications, and evolutions made to the above embodiments according to the essential technology of the present application are still within the protection scope of the technical solutions of the present application.

Claims

1. A process for the synthesis of the fluopyram intermediate N-acetyloxymethyl-2- trifluoromethylbenzamide, characterized in that, The synthesis method comprises the following steps: Step 1, adding 2-trifluoromethyl benzamide and a base and a solvent into a reaction bottle, dropwise adding halomethyl acetate, and reacting after the dropwise addition is completed, wherein the base is triethylamine, the solvent is dichloromethane or dichloroethane, the halomethyl acetate is chloromethyl acetate or bromomethyl acetate, the temperature of the reaction is 0-10 DEG C, and the reaction time is 1-2 hours; Step 2, after the reaction is completed, adding water to separate the phases, and concentrating the organic phase under reduced pressure to obtain N-acetyloxy methyl-2-trifluoromethyl benzamide, and the synthesis process route is as shown in the following figure, ； The synthesis method of the intermediate N-acetyloxy methyl-2-trifluoromethyl benzamide of the fluazinam comprises the following steps:

2. The process for synthesis of flupyradifuram intermediate N-acetyloxymethyl-2- trifluoromethylbenzamide as claimed in claim 1 wherein, The molar ratio of the 2-trifluoromethyl benzamide and the halomethyl acetate is 1:1.0-1.

2. The dichloromethane or dichloroethane can be replaced by a mixed solvent composed of one or more solvents of toluene, dichloromethane, dichloroethane, tetrahydrofuran, 2-methyl tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, DMF and NMP. ​

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