WO2015180585A1

WO2015180585A1 - Method of producing thiamethoxam

Info

Publication number: WO2015180585A1
Application number: PCT/CN2015/079440
Authority: WO
Inventors: James Timothy Bristow
Original assignee: Rotam Agrochem International Co Ltd
Current assignee: Rotam Agrochem International Co Ltd
Priority date: 2014-05-28
Filing date: 2015-05-21
Publication date: 2015-12-03
Anticipated expiration: 2016-11-28
Also published as: TWI662032B; TW201613913A; BR112016027652A2; CN106029658A; CN106029658B; BR112016027652B1; GB2511010A; GB201409422D0; WO2015180585A9; AR100267A1; GB2511010B

Abstract

A process for the preparation of thiamethoxam: is provided, which process comprises reacting 3-methyl-N-nitro- 1,3,5,oxadiazinan-4-imine: with 2-chloro-5-chloromethyl thiazole: in the presence of a solvent system comprising dimethylformamide (DMF), a phase transfer catalyst and a base.

Description

METHOD OF PRODUCING THIAMETHOXAM

The present invention relates to a method of producing 3- (2-chloro-1, 3-thiazol-5-ylmethyl) -5-methyl-1, 3, 5-oxadiazinan-4-yledene (nitro) amine (thiamethoxam) having the following structure:

Solovay reported nitromethylene heterocyclic compounds exhibiting insecticidal activity in 1978 ( ‘Research on Synthesis Method of Thiamethoxam’ , Tao, Xian-jian； Huang, Chao-qun； Luo, Liang-ming； Hunan Research Institute of Chemical Industry, Changsha, Peop. Rep. China.； Xiandai Nongyao (2006) , 5 (1) , pages 11 to 13) .

More recently, many researchers focused on the derivatives of nitromethylene heterocyclic compounds by investigating changes in the functional groups. In the mid-1980s, Bayer successfully developed on a commercial scale the first neonicotinoid insecticide, (E) -1- (6-chloro-3-pyridylmethyl) -N-nitroimidazolidin-2-ylideneamine (imidacloprid) . As a result of its novel mode of action, selectivity, efficiency, and environmental compatibility of a broad spectrum of good features, imidacloprid aroused significant attention in the art, resulting in extensive research into the neonicotinoid analogues and their synthesis. To date, more than a dozen products have been commercialized as a result of this research and development, with thiamethoxam perhaps being the most outstanding.

The development and commercialization of thiamethoxam is described by P. Maienfisch ‘Synthesis and Properties of Thiamethoxam and Related Compounds’ , Z. Naturforsch. 61b, (2006) pages 353 to 359.

Thiamethoxam is the first commercial neonicotinoid insecticide developed from the thianicotinyl subclass and was discovered in the course of research conducted into the neonicotinoids started in 1985. Novel variations of the nitroimino-heterocycle of imidacloprid led to the discovery of 4-nitroimino-1, 3, 5-oxadiazinanes exhibiting high insecticidal activity. Among these, thiamethoxam was identified as the best compound and selected for worldwide development.

Thiamethoxam acts by binding to nicotinic acetylcholine receptors. It exhibits exceptional systemic characteristics and provides excellent control of a broad range of commercially important pests, such as aphids, jassids, whiteflies, thrips, rice hoppers, Colorado potato beetle, flea beetles and wireworms, as well as some lepidopteran species. In addition, a strong preventative effect on some virus transmissions has been demonstrated for thiamethoxam. Thiamethoxam has been developed both for foliar/soil applications and as a seed treatment for use in most agricultural crops all over the world. Low use rates, flexible application methods, excellent efficacy, long-lasting residual activity and favourable safety profile make thiamethoxam well-suited for modern integrated pest management programmes in many cropping systems.

There are many different routes to synthesize thiamethoxam. The most straight forward and common way is to prepare thiamethoxam from 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine and 2-chloro-5-chloromethyl thiazole according to the following reaction sequence:

However, the key intermediate, 2-chloro-5-chloromethyl thiazole, is highly unstable and is easily decomposed. As a consequence, its stability is highly significant to the ultimate yield of thiamethoxam. 2-chloro-5- chloromethyl thiazole is also a strong irritant and its incomplete conversion to thiamethoxam is highly undesirable.

WO 01/00623 concerns a method of producing nitroguanidine-and nitroenamine derivatives. The method is disclosed as being suitable for forming thiamethoxam, in which case the starting materials are 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine and 2-chloro-5-chloromethyl thiazole, as indicated above. The method involves reacting the starting materials with a phase transfer catalyst and a base. WO 01/00623 suggests a long list of possible solvents for use in the method, such as esters of carbonic acid, especially dimethyl carbonate, dimethylformamide, acetonitrile , dimethyl sulphoxide； acetone, methyl ethyl ketone, ethyl acetate. WO 01/00623 specifically exemplifies the formation of thiamethoxam by the above method in the presence of a quaternary ammonium salt, potassium carbonate and dimethyl carbonate as a solvent. The final yield of thiamethoxam is reported to be only 74％. Such a yield is not suitable for the mass production of thiamethoxam on a commercial scale.

P. Maienfisch ‘Synthesis and Properties of Thiamethoxam and Related Compounds’ , Z. Naturforsch. 61b, (2006) pages 353 to 359, referred to above, discloses the preparation of thiamethoxam from 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine and 2-chloro-5-chloromethyl thiazole. The reaction is conducted in the presence of potassium carbonate and dimethylformamide (DMF) as a solvent. The indicated yield of thiamethoxam is 71％. Again, such a low yield renders this process unsuitable for use on a commercial scale.

Accordingly, there is a need for an improved method for the preparation of thiamethoxam. It would be advantageous if the improved method could provide an increased yield of thiamethoxam. In addition, it would be advantageous if the reaction conditions could be favourable to the stability of 2-chloro-5-chloromethyl thiazole.

An improved method for the preparation of thiamethoxam has now been found. In particular, it has been found that thiamethoxam can be prepared in very high yields by reacting 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine and 2-chloro-5-chloromethyl thiazole in the presence of a base, a phase transfer catalyst and a solvent system comprising dimethylformamide (DMF) . In particular, it has been found that this method produces thiamethoxam in high yields, with minimal amounts of undesired by-products. It appears that the aforementioned reaction conditions are favourable to the stability of 2-chloro-5-chloromethyl thiazole, while still allowing the reaction to proceed in high yield to thiamethoxam.

Accordingly, the present invention provides a process for the preparation of thiamethoxam:

which process comprises reacting 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine:

with 2-chloro-5-chloromethyl thiazole:

in the presence of a solvent system comprising dimethylformamide (DMF) , a phase transfer catalyst and a base.

It is surprising to find that the key intermediate 2-chloro-5-chloromethyl thiazole is highly stable in a solvent system comprising DMF when reacting with 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine in the presence of a phase transfer catalyst and a base to form thiamethoxam. It is particularly surprising that the final product is produced in a very high purity and a very high yield. In particular, the method of the present invention can produce thiamethoxam in a purity of as high as 98％and a yield of over 90％. This renders the method of the present invention particularly advantageous when applied on a commercial scale.

The process of the present invention employs a solvent system comprising dimethylformamide (DMF) . DMF may be present in combination with one or more other solvents, such as organic solvents. Most preferably, the solvent system employed in the process of the present invention consists essentially of DMF.

The process further employs a phase transfer catalyst. Suitable phase transfer catalysts are known in the art. Examples of suitable phase transfer catalysts are as indicated in WO 01/00623 and include polymeric phase transfer catalysts, quaternary ammonium salts, quaternary phosphonium salts, crown ethers, chelating agents, DABCO 1, 4-diazabycyclo [2. 2. 2] octane and DBU (1, 5-diazabicyclo [4. 3. 0] non-5-ene and quaternary ammonium salts thereof.

Preferably, the phase transfer catalyst is a quaternary ammonium salt. Suitable quaternary ammonium salts are listed in the paper "Phase Transfer Catalysts" , by the company Fluka, Buchs, Switzerland, 1986 edition, pages 7 to 25.

Especially preferred quaternary ammonium salts are, for example, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, benzyltributyl ammonium chloride, benzyltriethyl ammonium bromide, benzyltrimethyl ammonium methoxide, benzyltrimethyl ammonium hydroxide (triton B) , glycidyl trimethyl ammonium chloride, hexadecyl-trimethyl ammonium chloride, hexadecyl-trimethyl ammonium bromide, hexadecyl-pyridinium bromide, hexadecyl-pyridinium chloride, 2-hydroxyethyl-trimethylammonium chloride, 2-hydroxyethyl-trimethylammonium hydroxide, phenyltrimethylammonium chloride, phenyltrimethyl ammonium hydroxide, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydroxide, tetrabutyl ammonium tetrafluoroborate, tetrabutyl ammonium nitrate, tetradecyl ammonium chloride, tetradodecyl-ammonium acetate, tetraethyl ammonium chloride, tetraethyl ammonium hydroxide, tetradodecylammonium nitrate, tetradodecyl ammonium toluene sulphonate, tetrahexyl ammonium chloride, tetrahexylammonium bromide, tetramethyl ammonium chloride, tetramethyl-ammonium bromide, tetramethyl ammonium hydroxide, tetramethyl ammonium iodide, tetramethyl ammonium toluene sulphonate, tetraoctyl ammonium chloride, tetrapropyl ammonium chloride, tetrapropyl ammonium bromide, tributylmethyl ammonium chloride, tributylheptyl ammonium bromide, and quaternary ammonium hydroxides, particularly tetramethyl ammonium hydroxide in the form of the pentahydrate. A preferred quaternary ammonium salt is triethyl benzyl ammonium chloride (TEBA) .

The process of the present invention is also carried out 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 a carbonate of an alkali or alkaline earth metal. Preferably, the base is selected from calcium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, and mixtures thereof. Potassium carbonate is preferred a particularly preferred base for use in the process of this invention

In the process of the present invention, 2-chloro-5-chloromethyl thiazole is reacted with 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine. The reaction is preferably conducted at elevated temperature, in particular a temperature in the range of from 50 to 75℃, more preferably from 55 to 70℃, still more preferably from 60 to 70℃.

In the process, 2-chloro-5-chloromethyl and thiazole 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine react in a stiochimetric ratio of 1:1. However, it is preferred that 2-chloro-5-chloromethyl is present in a slight excess amount, preferably from 1 to 10％, more preferably about 5％, relative to thiazole 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine.

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

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

2-chloro-5-chloromethyl and thiazole 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine are compounds known in the art and are either commercially available or may be prepared using techniques known in the art.

In a further aspect, the present invention provides thiamethoxam prepared by a process as hereinbefore described.

Embodiments of the process of the present invention are illustrated by way of the following specific examples.

EXAMPLES

Example 1

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

3, 6-dihydro-3-methyl-N-nitro-2H-1, 3, 5, oxadiazin-4-amine was prepared using following reaction scheme:

100 kg of N-methyl-nitroguanidine and 64 kg of Paraformaldehyde were charged to a 1000L reactor. 350 kg of acetic acid were added, after which the resulting mixture was heated to 70℃and held at this temperature for 6 hours. Thereafter, the solvent (acetic acid) was removed by distillation under vacuum. 175 kg of 10％NaOH aqueous 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 resulting cake was dried using a Biconical dryer, yielding 98 kg of 3-methyl-N-nitro-1, 3, 5, oxadia zinan-4-imine as white powder (purity 97％, yield 71.5％) .

Example 2

Preparation of 2-chloro-5-chloromethyl thiazole

2.1 Preparation of 2-chloro-allyl thioisocyanide

2-chloro-allyl thioisocyanide was prepared using the following reaction scheme:

In a 500L reactor, 60.5 kg of 2, 3-dichloropropene was mixed with 135 kg of toluene, 0.5kg of TEBA (Triethyl benzyl ammonium chloride, as catalyst) and 44.1 kg of sodium thiocyanate. The resulting mixture was heated under reflux (about 100 to 105℃) for 1.5 hours and then cooled to room temperature. 50 kg of water was added with stirring for 15min, after which the mixture was allowed to stand and the phases stratify. Toluene from the organic phase was removed under vacuum and the residue was distilled under high vacuum using a Roots Vacuum Pump. 65 kg of distillate, 2-chloro-allyl thioisocyanid, were recovered as a yellow oil liquid (yield 80％, purity 90％) .

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

2-chloro-5- (chloromethyl) thiazole was prepared using the following reaction procedure:

65 kg of 2-chloro-allyl thioisocyanide was mixed with 140 kg of carbon tetrachloride in a 500L enamel reactor. 35 kg chlorine was bubbled into the mixture over a period of one hour, the resulting mixture heated to reflux (77℃) 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 NaHCO₃ solution and 40 kg of water. The resulting mixture was dried with anhydrous MgSO₄, after which dichloromethane was removed by distillation under vacuum. Finally, the reaction product was isolated by distillation under high vacuum using a Roots vacuum pump, to yield 61 kg of 2-chloro-5- (chloromethyl) thiazole as a yellow liquid (yield 84％, purity 96％) .

Example 3

3.1 Preparation of Thiamethoxam

Thiamethoxam was prepared by the following reaction scheme:

47.5 kg of 3-methyl-N-nitro-1, 3, 5-oxadiazinan-4-imine and 50 kg of 2-chloro-5- (chloromethyl) thiazole were fed to a 1000L enamel reactor containing 350 kg of dimethyl formamide (DMF) . The resulting mixture was heated and the temperature held at about 65℃. Thereafter, 82 kg of potassium carbonate and 1 kg of Triethyl benzyl ammonium chloride (TEBA, as catalyst) were added to the reactor over a period of from 20 to 40 minutes. The resulting mixture was allowed to react for from 4 to 5 hours, after which the mixture was allowed to cool to room temperature. 280 kg of water was added to the reactor, the mixture stirred for 15 minutes and the pH adjusted to between 6 and 7 with 32％hydrochloric acid. The resulting mixture was stirred severely and heated to 65℃. The resulting mixture was allowed to stand for 30 minutes, after which the water phase was discharged and extracted 3 times with dichloromethane (DCM) (100 kg × 3) . The organic phases were combined and DCM removed from the mixture by distillation under vacuum. The mixture was dried using a Biconical dryer at 40℃, to yield crude Thiamethoxam.

3.2 Purification of Thiamethoxam

20 g of crude Thiamethoxam was heated in 100 g of methanol until complete dissolution. The resulting solution was refluxed for 30 to 60 minutes, then cooled to room temperature. The resulting mixture was filtered to isolate a solid. The resulting solid was washed with methanol several times and dried under high vacuum to give crystals of pure thiamethoxam technical (Yield 90.5％, Purity 98％) .

Examples 4 to 9

Example 3 was repeated with DMF replaced by dimethyl carbonate, carbon tetrachloride, ethyl acetate, 1, 2-Dichloroethylene (DCE) , acetonitrile, and methyl ethyl ketone as solvents in Examples 4 to 9 respectively. Data relating to the yield and purity of thiamethoxam obtained in each of Examples 4 to 9 in comparison with Example 3 is set out in Table 1 below.

Table 1: Comparison of the yield and purity of Thiamethoxam in different solvents (Example 3 to

As can be seen from Table 1, the use of DMF as a solvent in the reaction scheme produces thiamethoxam in significantly higher yields and at significantly higher purity than the comparison solvents.

Example 10

The stability of 2-chloro-5- (chloromethyl) thiazole in a range of different solvents was determined using the following procedure:

20 g of 2-chloro-5- (chloromethyl) thiazole was individually dissolved in 100 ml of solvent and stirred for 2 hours. The solvents employed were DMF, dimethyl carbonate, carbon tetrachloride, ethyl acetate, 1, 2-dichloroethylene (DCE) , acetonitrile, and methyl ethyl ketone. In each case, the solvent was then removed under vacuum and the dry precipitate collected. The amount of 2-chloro-5- (chloromethyl) thiazole and 2-chloroallyl isothiocyanate was determined in each case. The results are set out in Table 2 below. A lower amount of 2-chloroallyl isothiocyanate indicates greater stability and less decomposition of 2-chloro-5- (chloromethyl) thiazole.

Table 2: Stability comparison of 2-chloro-5- (chloromethyl) thiazole in different solvents

Referring to Table 2, it can be seen that 2-chloro-5-chloromethyl thiazole is highly stable in DMF, with less than 6％decomposed in the presence of DMF. In comparison, decomposition of 2-chloro-5-chloromethyl thiazole in the other solvents tested was significantly greater.

Claims

A process for the preparation of thiamethoxam:

which process comprises reacting 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine:

with 2-chloro-5-chloromethyl thiazole:

in the presence of a solvent system comprising dimethylformamide (DMF) , a phase transfer catalyst and a base.
The process according to claim 1, wherein the solvent system consists essentially of dimethylformamide.
The process according to either of claims 1 or 2, wherein the phase transfer catalyst comprises a polymeric phase transfer catalyst, a quaternary ammonium salt, a quaternary phosphonium salt, a crown ether, a chelating agent, DABCO 1, 4-diazabycyclo [2.2.2] octane and DBU (1, 5-diazabicyclo [4.3.0] non-5-ene or a quaternary ammonium salt thereof.
The process according to claim 3, wherein the phase transfer catalyst comprises a quaternary ammonium salt.
The process according to claim 4, wherein the quaternary ammonium salt is selected from benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, benzyltributyl ammonium chloride, benzyltriethyl ammonium bromide, benzyltrimethyl ammonium methoxide, benzyltrimethyl ammonium hydroxide (triton B) , glycidyl trimethyl ammonium chloride, hexadecyl-trimethyl ammonium chloride, hexadecyl-trimethyl ammonium bromide, hexadecyl-pyridinium bromide, hexadecyl-pyridinium chloride, 2-hydroxyethyl-trimethylammonium chloride, 2-hydroxyethyl-trimethylammonium hydroxide, phenyltrimethylammonium chloride, phenyltrimethyl ammonium hydroxide, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydroxide, tetrabutyl ammonium tetrafluoroborate, tetrabutyl ammonium nitrate, tetradecyl ammonium chloride, tetradodecyl-ammonium acetate, tetraethyl ammonium chloride, tetraethyl ammonium hydroxide, tetradodecylammonium nitrate, tetradodecyl ammonium toluene sulphonate, tetrahexyl ammonium chloride, tetrahexylammonium bromide, tetramethyl ammonium chloride, tetramethyl-ammonium bromide, tetramethyl ammonium hydroxide, tetramethyl ammonium iodide, tetramethyl ammonium toluene sulphonate, tetraoctyl ammonium chloride, tetrapropyl ammonium chloride, tetrapropyl ammonium bromide, tributylmethyl ammonium chloride, tributylheptyl ammonium bromide, a quaternary ammonium hydroxide.
The process according to claim 5, wherein the quaternary ammonium salt is triethyl benzyl ammonium chloride (TEBA) .
The process according to any preceding claim, wherein the base is a metal carbonate.
The process according to claim 7, wherein the base is a carbonate of an alkali or alkaline earth metal, or a mixture thereof.
The process according to claim 8, wherein the base is selected from calcium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, and mixtures thereof.
The process according to claim 9, wherein the base is potassium carbonate.
The process according to any preceding claim, wherein the reaction is conducted at an elevated temperature.
The process according to claim 11, wherein the reaction is conducted at a temperature in the range of from 50 to 75℃.
The process according to any preceding claim, wherein 2-chloro-5-chloromethyl is present in the reaction mixture in a slight excess amount relative to thiazole 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine.
The process according to claim 13, wherein the slight excess amount is from 1 to 10％relative to thiazole 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine.
The process according to any preceding claim, wherein the base is present in a weight ratio to thiazole 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine of from 1.1: 1 to 2: 1.
The process according to any preceding claim, wherein the phase transfer catalyst is present in a weight ratio to thiazole 3-methyl-N-nitro-1, 3, 5, oxadiazinan-4-imine of from 0.1: 1 to 0.3: 1.
Thiamethoxam prepared by a process according to any preceding claim.
A process for the preparation of thiamethoxam substantially as hereinbefore described.