Preparation method of key intermediate of trifluorobenzene pyrimidine

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of a key intermediate of trifluorobenzene pyrimidine. The key intermediate is N-(5-pyrimidinylmethyl)-2-aminopyridine, and the preparation method comprises the following steps: mixing 2-fluoropyridine and ammonia water, heating to react, after the reaction is finished, naturally cooling to room temperature, and slowly releasing residual ammonia gas in a reaction container; and adding acetonitrile and 5-bromomethyl pyrimidine, heating, stirring to react, cooling to normal temperature, keeping the temperature to react for 1 hour, cooling to-5 DEG C, stirring for 2 hours, filtering and drying to obtain the N-(5-pyrimidinylmethyl)-2-aminopyridine. The target product is obtained by taking 2-fluoropyridine as a starting raw material through one-pot substitution, and the route has the advantages of easily available raw materials, controllable cost, simple and easy operation, easily available raw materials, low cost, mild conditions, mature process, high yield and purity, and is suitable for industrial mass production.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and specifically to a method for preparing a key intermediate of trifluorophenylpyrimidine. Background Technology

[0002] Trifluoropyrimidine is a novel mesoionic or zwitterionic insecticide developed by DuPont (now DowDuPont), and is also a novel pyrimidinone compound.

[0003] Trifluoropyrimidine acts on nicotinic acetylcholine receptors, but its mechanism of action differs from that of existing neonicotinoid insecticides. The International Resistant Pesticides Committee (IRAC) classifies competitive modulators of the nicotinic acetylcholine receptor (nAChR) into Group 4, which currently contains 11 active ingredients. Based on their mechanisms of action, these products are further divided into five subgroups. Group 4A includes seven neonicotinoid insecticides: acetamiprid, thiamethoxam, dinotefuran, imidacloprid, acetamiprid, thiamethoxam, and thiamethoxam. Group 4B contains only the neonicotinoid insecticide nicotinine. Group 4C includes only the sulfoxide imide insecticide flonicamid. Group 4D also has only one member: the butenolate insecticide flupyrfuranone. Group 4E similarly has only one active ingredient: the metronidazole insecticide trifluoropyrimidine. Among the products classified as Group 4 by IRAC, trifluoperazine is the only compound that inhibits rather than activates nicotinic acetylcholine receptors. Therefore, it exhibits no cross-resistance with other insecticides within or outside the group (including neonicotinoids). This characteristic provides trifluoperazine with significant potential for development in resistance management. Trifluoperazine is broad-spectrum, systemic, highly effective, persistent, and slightly toxic, exhibiting excellent control efficacy against a variety of pests, including Lepidoptera and Homoptera, and can be used on crops such as cotton, rice, corn, and soybeans.

[0004] Trifluorophenylpyrimidine is very difficult to synthesize. It is mainly obtained by refluxing N-2-pyridin-5-pyrimidine methylamine with bis(2,4,6-trichlorophenyl)malonate in toluene solution.

[0005] N-(pyrimidin-5-ylmethyl)pyridine-2-amine is the main synthetic intermediate, and the entire synthesis is very difficult. The synthetic routes disclosed in world patents (WO201209115, WO2013090547) using pyrimidin-5-carboxaldehyde as the starting material, through condensation and reduction, yield the target product, as follows:

[0006] .

[0007] This route offers mild conditions, but the starting material, pyrimidine-5-carboxaldehyde, is not readily available, is extremely chemically unstable, and is very expensive, far exceeding the selling price of the product. Furthermore, its synthesis is very difficult and costly, making it unsuitable for industrial production.

[0008] Patent (WO2023 / 086802) discloses a method for obtaining the target product by rearrangement, substitution, and cyclization using 3-chloropropionyl chloride as a starting material, as follows:

[0009] ;

[0010] Intermediate 1 is highly unstable and unsuitable for industrial production.

[0011] In view of the above-mentioned defects, the inventors of this invention have finally obtained this invention after a long period of research and practice. Summary of the Invention

[0012] The purpose of this invention is to solve the problem that the synthesis of N-2-pyridine-5-pyrimidine methylamine, an intermediate of trifluorophenylpyrimidine, is difficult and unsuitable for industrial production, and to provide a method for preparing a key intermediate of trifluorophenylpyrimidine.

[0013] To achieve the above objectives, this invention discloses a method for preparing a key intermediate of trifluorophenylpyrimidine, wherein the key intermediate is N-(5-pyrimidinylmethyl)-2-aminopyridine, and the preparation method includes the following steps:

[0014] S1, 2-fluoropyridine and ammonia are mixed and heated to react. After the reaction is completed, the mixture is naturally cooled to room temperature and the residual ammonia gas in the reaction vessel is slowly released.

[0015] S2, add acetonitrile and 5-bromomethylpyrimidine to the reaction solution after the reaction in step S1, heat up, stir the reaction, cool down to room temperature, keep the reaction at room temperature for 1 hour, then cool down to -5℃ and stir for 2 hours, filter, and dry to obtain N-(5-pyrimidinylmethyl)-2-aminopyridine.

[0016] In step S1, the amount of 2-fluoropyridine used is 970g, the amount of ammonia water used is 9700mL, and the concentration of ammonia water is 25%~28%.

[0017] In step S1, the reaction temperature is 100℃ and the reaction time is 12h.

[0018] In step S2, the amount of acetonitrile used is 10L, and the amount of 5-bromomethylpyrimidine used is 1720g.

[0019] In step S2, the stirring reaction temperature is 50°C, the reaction time is 15 hours, and the heat preservation reaction time is 1 hour.

[0020] In step S2, the filtered filter cake is washed with n-hexane and dried under reduced pressure at 35°C.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention uses 2-fluoropyridine as the starting material to obtain the target product through a one-pot substitution method. This route has readily available raw materials, controllable costs, simple and easy operation, readily available raw materials, low cost, mild conditions, mature process, and high yield and purity, making it suitable for large-scale industrial production. Attached Figure Description

[0022] Figure 1 This is a process route diagram for the present invention;

[0023] Figure 2 The N-(pyrimidin-5-ylmethyl)pyridine-2-amine obtained in Example 1 1 HNMR spectrum;

[0024] Figure 3 The HPLC spectrum of N-(pyrimidin-5-ylmethyl)pyridine-2-amine obtained in Example 1 is shown. Detailed Implementation

[0025] The above-mentioned and other technical features and advantages of the present invention will be described in more detail below with reference to the accompanying drawings.

[0026] Example 1

[0027] 970 g (1 eq) of 2-fluoropyridine was added sequentially to a 20 L autoclave, with 9700 mL (10 V) of 25%-28% ammonia solution as the solvent. The autoclave was heated to 100 °C and reacted for 12 h. After the reaction was completed, the autoclave was allowed to cool naturally to room temperature, and the residual ammonia gas in the autoclave was slowly released. The autoclave lid was opened, and the reaction solution was transferred to a 50 L autoclave. 10 L of acetonitrile and 1720 g (1 eq) of 5-bromomethylpyrimidine were added. After the addition was complete, the autoclave was heated to 50 °C and stirred for about 15 h. The temperature was then lowered to room temperature and maintained for 1 h. After that, the temperature was lowered to -5 °C and stirred for 2 h. The mixture was filtered, and the filter cake was washed with n-hexane and dried under reduced pressure at 35 °C to obtain 1488 g of the product N-(5-pyrimidinylmethyl)-2-aminopyridine, a brown solid, with a yield of 80%.

[0028] Example 2

[0029] 97g (1 eq) of 2-fluoropyridine was added sequentially to a 2L high-pressure reactor, and 970mL (10V) of ammonia water (25%-28%) was used as a solvent. The reactor was heated to 80℃ and reacted for 12h. TLC plate detection showed that a large amount of 2-fluoropyridine remained, indicating that the optimization scheme of reducing the reaction temperature was not feasible.

[0030] Example 3

[0031] 97g (1 eq) of 2-fluoropyridine was added sequentially to a 2L high-pressure reactor, and 776mL (8V) of ammonia water (25%-28%) was used as a solvent. The reactor was heated to 100℃ and reacted for 12h. TLC plate detection showed that a large amount of 2-fluoropyridine remained, indicating that the optimization scheme of reducing the proportion of ammonia water was not feasible.

[0032] Example 4

[0033] 97 g (1 eq) of 2-fluoropyridine was added sequentially to a 2L autoclave, using 970 mL (10V) of 25%-28% ammonia solution as the solvent. The autoclave was heated to 100℃ and reacted for 12 h. After the reaction of the 2-fluoropyridine was completed by TLC, the autoclave was allowed to cool naturally to room temperature, and the residual ammonia gas in the autoclave was slowly released. The autoclave lid was opened, and the reaction solution was transferred to a 5L autoclave. 1 L of acetonitrile and 137.6 g (0.8 eq) of 5-bromomethylpyrimidine were added. After the addition was complete, the autoclave was heated to 50℃ and stirred for about 15 h. TLC showed that a large amount of the intermediate 2-aminopyridine remained, indicating that the optimized scheme of reducing the proportion of 5-bromomethylpyrimidine was not feasible.

[0034] Example 5

[0035] 97 g (1 eq) of 2-fluoropyridine was added sequentially to a 2L autoclave, using 970 mL (10V) of 25%-28% ammonia solution as the solvent. The autoclave was heated to 100°C and reacted for 12 h. After the reaction of the 2-fluoropyridine was completed by TLC, the autoclave was allowed to cool naturally to room temperature, and the residual ammonia gas in the autoclave was slowly released. The autoclave lid was opened, and the reaction solution was transferred to a 5L autoclave. 1 L of acetonitrile and 172 g (1 eq) of 5-bromomethylpyrimidine were added. After the addition was complete, the temperature was raised to 30°C and the reaction was stirred for about 15 h. TLC showed that a large amount of the intermediate 2-aminopyridine remained, indicating that lowering the reaction temperature to 30°C was not feasible.

[0036] Example 6

[0037] 97g (1 eq) of 2-fluoropyridine, 970mL (10V) of (25%-28%) ammonia water, 1L of acetonitrile, and 172g (1 eq) of 5-bromomethylpyrimidine were added to a 5L high-pressure reactor. The reactor was heated to 100℃ and reacted for 12h. The TLC plate reaction was very disordered, indicating that the one-pot method optimization scheme is not feasible.

[0038] Example 7

[0039] 97 g (1 eq) of 2-fluoropyridine was added sequentially to a 2L autoclave, using 970 mL (10V) of 25%-28% ammonia solution as solvent. The autoclave was heated to 100°C and reacted for 12 h. After the 2-fluoropyridine reacted completely by TLC, the autoclave was allowed to cool naturally to room temperature, and the residual ammonia gas was slowly released. The autoclave lid was opened, and the reaction solution was transferred to a 5L autoclave. 1 L of acetonitrile and 172 g (1 eq) of 5-bromomethylpyrimidine were added. After the addition was complete, the autoclave was heated to 50°C and stirred for about 15 h. After the intermediate 2-aminopyridine reacted completely by TLC, the autoclave was cooled to room temperature and kept at that temperature for 1 h. Then, the temperature was lowered to -5°C and stirred for 2 h. The mixture was filtered, and the filter cake was washed with n-hexane and dried under reduced pressure at 35°C to obtain 148.8 g of the product N-(5-pyrimidinylmethyl)-2-aminopyridine, a brown solid, with a yield of 80%. This method is feasible. Further scale-up according to Example 1 is also feasible.

[0040] The above description is merely a preferred embodiment of the present invention and is illustrative rather than restrictive. Those skilled in the art will understand that many changes, modifications, and even equivalents can be made within the spirit and scope defined by the claims of the present invention, all of which will fall within the protection scope of the present invention.

Claims

1. A method for preparing a key intermediate of trifluorophenylpyrimidine, characterized in that, The key intermediate is N-(5-pyrimidinylmethyl)-2-aminopyridine, and its preparation method includes the following steps: S1, 2-fluoropyridine and ammonia are mixed and heated to react. After the reaction is completed, the mixture is naturally cooled to room temperature and the residual ammonia gas in the reaction vessel is slowly released. S2, add acetonitrile and 5-bromomethylpyrimidine to the reaction solution after the reaction in step S1, heat up, stir the reaction, cool down to room temperature, keep the reaction at room temperature for 1 hour, then cool down to -5℃ and stir for 2 hours, filter, and dry to obtain N-(5-pyrimidinylmethyl)-2-aminopyridine.

2. The method for preparing a key intermediate of trifluorophenylpyrimidine as described in claim 1, characterized in that, In step S1, the amount of 2-fluoropyridine used is 970g, the amount of ammonia water used is 9700mL, and the concentration of ammonia water is 25%~28%.

3. The method for preparing a key intermediate of trifluorophenylpyrimidine as described in claim 1, characterized in that, In step S1, the reaction temperature is 100℃ and the reaction time is 12h.

4. The method for preparing a key intermediate of trifluorophenylpyrimidine as described in claim 1, characterized in that, In step S2, the amount of acetonitrile used is 10L, and the amount of 5-bromomethylpyrimidine used is 1720g.

5. The method for preparing a key intermediate of trifluorophenylpyrimidine as described in claim 1, characterized in that, In step S2, the stirring reaction temperature is 5°C, the reaction time is 15 hours, and the heat preservation reaction time is 1 hour.

6. The method for preparing a key intermediate of trifluorophenylpyrimidine as described in claim 1, characterized in that, In step S2, the filtered filter cake is washed with n-hexane and dried under reduced pressure at 35°C.

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