TWI662032B - Method of producing thiamethoxam - Google Patents

Abstract

This article provides a method for preparing thiamethoxam: This method includes 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine: With 2-chloro-5-chloromethylthiazole:

The reaction is performed in the presence of a solvent system containing dimethylformamide (DMF), a phase transfer catalyst, and a base.

Description

Method for preparing thiamethoxam

The present invention relates to a method for preparing 3- (2-chloro-1,3-thiazol-5-ylmethyl) -5-methyl-1,3,5-oxadiazine-4- Method) (thiamethoxam):

Solovay reported a nitromethylene heterocyclic compound with insecticidal activity in 1978 ("Study on the Synthesis of Thiamethoxam", Tao, Xian-jian; Huang, Chao-qun; Luo, Liang-ming, Hunan Chemistry Industrial Research Institute, Changsha, China, Modern Pesticides (2006), 5 (1), pp. 11-13).

In recent years, many researchers have focused on derivatives of nitromethylene heterocyclic compounds by studying functional group changes. In the mid-1980s, Bayer successfully developed the first commercial-scale neonicotinoid insecticide, ( E ) -1- (6-chloro-3-pyridylmethyl) -N- Nitroimidazolidin-2-ylamine (imidacloprid). Because of its new mode of action, selectivity, efficiency, and broad-spectrum environmental compatibility, imidacloprid has attracted great attention in the field, leading to extensive research on neonicotinoids and their synthesis. As a result of this research and development, more than 12 products have been commercialized, of which thiamethoxam is the most prominent.

P. Maienfisch, "Synthesis and Properties of Thiamethoxam and Related Compounds", Z. Naturforsch. 61b , (2006), pages 353-359 describe the development and commercialization of thiamethoxam Into.

Thiamethoxam is the first commercially available neonicotinoid insecticide developed from the thianicotine subclass. It was discovered during the study of neonicotinoids starting in 1985. New changes were made to the nitroimino-heterocycle of imidacloprid and 4-nitroimino-1,3,5-oxadiazine was found to have high insecticidal activity. Among these compounds, thiamethoxam was identified as the best compound and thiamethoxam was selected for worldwide research.

Thiamethoxam works by binding to the nicotine acetamidine receptor. It exhibits outstanding systemic characteristics and is important to a wide range of commercially important pests such as aphids, leafhoppers, whitefly, herbivores, rice planthoppers, Colorado potato beetle, beetle and root-cutting insects, and some Lepidopteran species provide good control. In addition, thiamethoxam has been shown to have a strong preventive effect on the transfer of some viruses. Thiamethoxam was developed for both leaf / soil applications and as seed treatment in most crops worldwide. Low utilization, flexible application methods, good efficiency, long-lasting residual activity and favorable safety distribution make thiamethoxam particularly suitable for modern integrated pest control projects in many crop systems.

There are many different pathways for the synthesis of thiamethoxam. The most straightforward and common method is to prepare thiacloprid from 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine and 2-chloro-5-chloromethylthiazole according to the following reaction sequence Azine:

However, the key intermediate, 2-chloro-5-chloromethylthiazole, is extremely unstable and easily decomposes. Therefore, its stability is very important for the final yield of thiamethoxam. 2-Chloro-5-chloromethylthiazole is also a strong irritant, and its incomplete conversion of thiamethoxam is highly undesirable.

WO 01/00623 relates to a method for preparing nitroguanidine- and nitroenamine derivatives. The method is disclosed as being suitable for the formation of thiamethoxam in which the starting materials are 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine and 2-chloro-5-chloromethyl Thiazole, as described above. The method includes reacting a starting material with a phase transfer catalyst and a base. WO 01/00623 lists a long list for Possible solvents for this method are, for example, carbonates, in particular dimethyl carbonate, dimethylformamide, acetonitrile, dimethylsulfinium, acetone, methyl ethyl ketone, ethyl acetate. WO 01/00623 particularly shows the formation of thiamethoxam by the method described above in the presence of a quaternary ammonium salt, potassium carbonate and dimethyl carbonate as a solvent. The reported final yield of thiamethoxam was only 74%. This yield is not suitable for the large-scale production of thiamethoxam on a commercial scale.

As mentioned above, P. Maienfisch, "Synthesis and Properties of Thiamethoxam and Related Compounds", Z. Naturforsch. 61b , (2006), pages 353-359, disclose Thiamethoxam was prepared from 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine and 2-chloro-5-chloromethylthiazole. This reaction is performed in the presence of potassium carbonate and dimethylformamide (DMF) as a solvent. The yield of the thiamethoxam was 71%. Also, such a low yield makes this method unsuitable for commercial scale.

Therefore, there is a need for an improved method for preparing thiamethoxam. It would be advantageous if the improved method could increase the yield of thiamethoxam. In addition, it is also advantageous if the reaction conditions are favorable for the stability of 2-chloro-5-chloromethylthiazole.

Improved methods of preparing thiamethoxam have now been discovered. Specifically, it was found that 3-methyl-N-nitro-1,3,5-oxadiazine-4 was present in the presence of a base, a phase transfer catalyst, and a solvent system including dimethylformamide (DMF). -The reaction of imine with 2-chloro-5-chloromethylthiazole can produce thiamethoxam in extremely high yields. In particular, this method was found to produce thiamethoxam in high yields while obtaining a minimal amount of undesirable by-products. It appears that the above reaction conditions are favorable for the stability of 2-chloro-5-chloromethylthiazole, while still allowing the reaction to proceed in high yields to convert to thiamethoxam.

Accordingly, the present invention provides a method for preparing thiamethoxam: The method includes converting 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine With 2-chloro-5-chloromethylthiazole

The reaction is performed in the presence of a solvent system containing dimethylformamide (DMF), a phase transfer catalyst, and a base.

It was surprisingly found that when reacting with 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine to form thiamethoxam in the presence of a phase transfer catalyst and a base, a key intermediate 2-Chloro-5-chloromethylthiazole is highly stable in solvent systems containing DMF. It is particularly surprising that the final product is produced with extremely high purity and very high yields. Specifically, the method of the present invention enables the preparation of thiamethoxam with a purity of up to 98% and a yield of more than 90%. This makes the method of the invention particularly advantageous when applied on a commercial scale.

The method of the present invention uses a solvent system containing dimethylformamide (DMF). DMF can be used in combination with one or more other solvents, such as organic solvents. More preferably, the solvent system used in the method of the invention consists essentially of DMF.

The method also uses a phase transfer catalyst. Suitable phase transfer catalysts are known in the art. Examples of suitable phase transfer catalysts are described in WO 01/00623, including polymer phase transfer catalysts, quaternary ammonium salts, quaternary phosphonium salts, crown ethers, chelating agents, DABCO (1,4-diazabicyclo [2.2. 2] octane) and DBU (1,5-diazabicyclo [4.3.0] non-5-ene) and their quaternary ammonium salts.

Preferably, the phase transfer catalyst is a quaternary ammonium salt. A suitable quaternary ammonium salt is listed in the paper "Phase Transfer Catalyst" by Fluka, Buchs, Switzerland, 1986 edition, pages 7-25.

Particularly preferred quaternary ammonium salts are, for example, trimethylbenzylammonium chloride, triethylbenzylammonium chloride, tributylbenzylammonium chloride, triethylbenzylammonium bromide, trimethylbenzylmethanol Ammonium, trimethyl benzyl ammonium hydroxide (triton B), glycidyl trimethyl ammonium chloride, cetyl-trimethyl ammonium chloride, cetyl-trimethyl ammonium bromide, ten Hexyl-pyridinium bromide, cetyl-pyridinium chloride, 2-hydroxyethyl-trimethylammonium chloride, 2-hydroxyethyl-trimethylammonium hydroxide, phenyltrimethyl Ammonium chloride, phenyltrimethylammonium hydroxide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydroxide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium nitrate, tetradecyl Ammonium chloride, tetra (dodecyl) -ammonium acetate, tetraethylammonium chloride, tetraethylammonium hydroxide, tetra (dodecyl) ammonium nitrate, tetra (dodecyl) toluenesulfonic acid Ammonium, tetrahexylammonium chloride, tetrahexylammonium bromide, tetramethylammonium chloride, tetramethyl-ammonium bromide, tetramethylammonium hydroxide, tetramethylammonium iodide, tetramethylammonium toluenesulfonate , Tetraoctyl ammonium chloride, tetrapropyl ammonium chloride, tetrapropyl ammonium bromide, tributyl Methylmethylammonium chloride, tributylheptylammonium bromide, and quaternary ammonium hydroxide, specifically tetramethylammonium hydroxide in a pentahydrate form. A preferred quaternary ammonium salt is triethyl benzyl ammonium chloride (TEBA).

The method of the present invention is also performed in the presence of a base. Suitable bases are known in the art and are commercially available. The base is preferably a metal carbonate, more preferably an alkali or alkaline earth metal carbonate. Preferably, the base is selected from the group consisting of calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and mixtures thereof. Potassium carbonate is a particularly preferred base for use in the process of the invention.

In the method of the present invention, 2-chloro-5-chloromethylthiazole is reacted with 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine. The reaction is preferably carried out at an elevated temperature, specifically, in a range of 50-75 ° C, more preferably 55-70 ° C, and more preferably 60-70 ° C.

In this method, 2-chloro-5-chloromethylthiazole and 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine are reacted in a stoichiometric ratio of 1: 1. . However, it is preferred that 2-chloro-5-chloromethylthiazole is slightly excessive relative to 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine, preferably an excess of 1-10%, more preferably It is preferably about 5%.

The base is present in the reaction mixture in any suitable amount. Preferably, the weight ratio of the base to 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine is from 1.1: 1 to 2: 1, more preferably from 1.4: 1 to 1.8 : 1. In many embodiments, a ratio of about 1.7: 1 is suitable.

The phase transfer catalyst is present in the reaction mixture in any suitable amount. Preferably, the weight ratio of the phase transfer catalyst to 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine is about 0.1: 1 to 0.3: 1, more preferably about 0.2: 1.

2-Chloro-5-chloromethylthiazole and 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine are compounds known in the art and both are commercially available Alternatively, it can be prepared using techniques known in the art.

In another aspect, the present invention provides thiamethoxam prepared by the aforementioned method.

Embodiments of the method of the present invention are described by the following specific examples.

Examples Example 1 Preparation of 3,6-dihydro-3-methyl-N-nitro-2H-1,3,5-oxadiazine-4-amine

The following reaction scheme was used to prepare 3,6-dihydro-3-methyl-N-nitro-2H-1,3,5-oxadiazine-4-amine:

100 kg of N-methyl-nitroguanidine and 64 kg of paraformaldehyde were charged into a 1000 L reactor. After 350 kg of acetic acid was added, the resulting mixture was heated to 70 ° C and maintained at this temperature for 6 hours. After that, the solvent (acetic acid) was distilled off under vacuum. 175 kg of a 10% aqueous NaOH solution was added with stirring, after which the resulting mixture was cooled and stirred for 30 minutes. The resulting mixture was discharged into a centrifuge for separation. The obtained filter cake was dried using a Biconical dryer to obtain 98 kg of 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine as a white powder (97% purity, 71.5% yield) .

Example 2 Preparation of 2-chloro-5-chloromethylthiazole 2.1 Preparation of 2-chloro-allyl thioisonitrile

The following reaction scheme was used to prepare 2-chloro-allyl thioisocyanide:

In a 500 L reactor, 60.5 kg of 2,3-dichloropropene were mixed with 135 kg of toluene, 0.5 kg of TEBA (triethylbenzyl ammonium chloride as a catalyst), and 44.1 kg of sodium thiocyanate. The resulting mixture was heated under reflux conditions (about 100-105 ° C) for 1.5 hours and then cooled to room temperature. 50 kg of water was added and stirred for 15 minutes, after which the mixture was allowed to stand and phase separation occurred. The toluene was removed from the organic phase under vacuum, and the residue was distilled under high vacuum using a Roots vacuum pump. 65 kg of 2-chloro-allyl thioisocyanide was recovered as a yellow oily liquid (yield 80%, purity 90%).

2.2 Preparation of 2-chloro-5- (chloromethyl) thiazole

The following reaction scheme was used to prepare 2-chloro-5- (chloromethyl) thiazole:

65 kg of 2-chloro-allyl thioisocyanide and 140 kg of carbon tetrachloride were mixed in a 500 L glazed reactor. 35 kg of chlorine gas was bubbled into the mixture within 1 hour, and the resulting mixture was heated to reflux (77 ° C) for 3 hours and then cooled to room temperature. Carbon tetrachloride was removed by distillation. 59 kg of dichloromethane was added and stirred until the residue was dissolved, after which the solution was washed with 86 kg of saturated NaHCO ₃ solution and 40 kg of water. The mixture obtained was dried over anhydrous MgSO _4, after the methylene chloride was removed under vacuum distillation. Finally, the reaction product was separated by distillation under high vacuum using a Roots vacuum pump to obtain 61 kg of 2-chloro-5- (chloromethyl) thiazole as a yellow liquid (yield 84%, purity 96%).

Example 3 3.1 Preparation of thiamethoxam

Thiamethoxam is prepared by the following reaction scheme:

47.5 kg of 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine and 50 kg of 2-chloro-5- (chloromethyl) thiazole were fed to 350 kg of dimethylformamidine Amine (DMF) in a 1000 L glazed reactor. The resulting mixture was heated to maintain the temperature at about 65 ° C. Thereafter, 82 kg of potassium carbonate and 1 kg of triethylbenzyl ammonium chloride (TEBA, as a catalyst) were added to the reactor within 20-40 minutes. The resulting mixture was reacted for 4-5 hours, after which the mixture was cooled to room temperature. 280 kg of water was added to the reactor, the mixture was stirred for 15 minutes, and the pH was adjusted to 6-7 with 32% hydrochloric acid. The resulting mixture was stirred vigorously and heated to 65 ° C. The resulting mixture was allowed to stand for 30 minutes, and then the aqueous phase was discharged, and extracted three times with dichloromethane (DCM) (100 kg × 3). The organic phases were combined and the DCM was removed from the mixture by distillation under vacuum. The mixture was dried at 40 ° C using a Biconical dryer to obtain crude thiamethoxam.

3.2 Purification of thiamethoxam

20 g of crude thiamethoxam was heated in 100 g of methanol until completely dissolved. The resulting solution was refluxed for 30-60 minutes and then cooled to room temperature. The resulting mixture was filtered to separate solids. The obtained solid was washed several times with methanol and dried under high vacuum to obtain technical grade pure thiamethoxam crystals (yield 90.5%, purity 98%).

Examples 4-9

Example 3 is repeated in Examples 4-9, but using dimethyl carbonate, carbon tetrachloride, ethyl acetate, 1,2-dichloroethylene (DCE), acetonitrile, and methyl ethyl ketone as solvents instead DMF. The yield and purity data of thiamethoxam obtained in each of Examples 4-9 and Table 3 are shown in Table 1 below.

It can be seen from Table 1 that the use of DMF as a solvent in the reaction scheme compared with the comparison solvent, the yield of thiamethoxam by DMF is significantly higher, and the purity is significantly higher.

Example 10

The following procedure was used to determine the stability of 2-chloro-5- (chloromethyl) thiazole in a series of different solvents: 20 g of 2-chloro-5- (chloromethyl) thiazole was dissolved alone in 100 ml of solvent and stirred for 2 hours . The solvents used were DMF, dimethyl carbonate, carbon tetrachloride, ethyl acetate, 1,2-dichloroethylene (DCE), acetonitrile, and methyl ethyl ketone. In each case, the solvent was subsequently removed under vacuum and the dried precipitate was collected. The amount of 2-chloro-5- (chloromethyl) thiazole and 2-chloroallyl isothiocyanate was determined in each case. The results are shown in Table 2 below. A smaller amount of 2-chloroallyl isothiocyanate indicates that 2-chloro-5- (chloromethyl) thiazole has higher stability and less decomposition rate.

Referring to Table 2, it can be seen that 2-chloro-5-chloromethylthiazole is highly stable in DMF, and the decomposition rate is less than 6% in the presence of DMF. By comparison, the decomposition rate of 2-chloro-5-chloromethylthiazole in other solvents is significantly higher.

Claims (13)

A method for preparing thiamethoxam: This method includes 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine: With 2-chloro-5-chloromethylthiazole: The reaction is performed in the presence of dimethylformamide (DMF), a phase transfer catalyst, and a base. The method according to item 1 of the scope of patent application, wherein the phase transfer catalyst comprises a polymer phase transfer catalyst, a quaternary ammonium salt, a quaternary phosphonium salt, a crown ether, a chelating agent, DABCO (1,4-diazabicyclo [ 2.2.2] octane) and DBU (1,5-diazabicyclo [4.3.0] non-5-ene) or their quaternary ammonium salts. The method according to item 2 of the patent application scope, wherein the phase transfer catalyst comprises a quaternary ammonium salt. The method of claim 3, wherein the quaternary ammonium salt is selected from the group consisting of trimethylbenzyl ammonium chloride, triethylbenzyl ammonium chloride, tributylbenzyl ammonium chloride, and triethylbenzyl Ammonium bromide, trimethyl benzyl ammonium hydroxide, trimethyl benzyl ammonium hydroxide (triton B), glycidyl trimethyl ammonium chloride, cetyl-trimethyl ammonium chloride, cetyl Alkyl-trimethylammonium bromide, cetyl-pyridinium bromide, cetyl-pyridinium chloride, 2-hydroxyethyl-trimethylammonium chloride, 2-hydroxyethyl-trimethyl Methyl ammonium hydroxide, phenyltrimethylammonium chloride, phenyltrimethylammonium hydroxide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydroxide, tetrabutyltetrafluoro Ammonium borate, tetrabutylammonium nitrate, tetradecylammonium chloride, tetra (dodecyl) -ammonium acetate, tetraethylammonium chloride, tetraethylammonium hydroxide, tetra (dodecyl) ammonium nitrate , Tetrakis (dodecyl) toluenesulfonate, Tetrahexylammonium chloride, Tetrahexylammonium bromide, Tetramethylammonium chloride, Tetramethyl-ammonium bromide, Tetramethylammonium hydroxide, Tetramethyl Ammonium iodide, tetramethyltoluenesulfonate, tetraoctylammonium chloride, tetrapropyl Ammonium, tetrapropyl ammonium bromide, methyl tributyl ammonium chloride, heptyl tributyl ammonium bromide, and quaternary ammonium hydroxides. The method according to item 4 of the scope of patent application, wherein the quaternary ammonium salt is triethylbenzyl ammonium chloride (TEBA). The method according to item 1 of the aforementioned patent application scope, wherein the base is a metal carbonate. The method according to item 6 of the patent application scope, wherein the base is an alkali metal carbonate or an alkaline earth metal carbonate, or a mixture thereof. The method according to item 7 of the application, wherein the base is selected from the group consisting of calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and mixtures thereof. The method according to item 8 of the scope of patent application, wherein the base is potassium carbonate. The method according to item 1 of the aforementioned patent application range, wherein the reaction is performed at a temperature range of 50-75 ° C. The method according to item 1 of the aforementioned patent application range, wherein 2-chloro-5-chloromethylthiazole is relative to 3-methyl-N-nitro-1,3,5-oxadiazine-4-yl The amine is present in the reaction mixture in a slight excess of 1 to 10%. The method according to item 1 of the aforementioned patent application range, wherein the weight ratio of the base to 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine is 1.1: 1 to 2 :1. The method according to item 1 of the aforementioned patent application range, wherein the weight ratio of the phase transfer catalyst to 3-methyl-N-nitro-1,3,5-oxadiazine-4-imine is 0.1: 1 To 0.3: 1.