MX2008010140A - Improved method for producing nitroisourea derivative - Google Patents

Abstract

Disclosed is an improved method for producing a nitroisourea derivative which is necessary for producing a nitroguanidine derivative having an insecticidal activity. Specifically disclosed is a method for producing a nitroisourea derivative represented by the general formula (3) below, which is characterized in that a nitroisourea represented by the general formula (1) below and an amine represented by the general formula (2) below or a salt thereof are reacted in the co-presence of a catalytic amount of a hydrogen carbonate.

Description

IMPROVED PROCESS TO PRODUCE NITROISOUREA DERIVATIVES Field of the Invention The present invention relates to an improved process for producing nitroisourea derivatives which is an important intermediate of the nitroguanidine derivatives having insecticidal activity. Background of the Invention A process for producing nitroguanidine derivatives having insecticidal activity has been described in Japanese Patent No. 2779403, Japanese Patent No. 2546003, Japanese Patent No. 2766848. However, for example, as described in Japanese Patent No. 2766848, the problem occurs in the production method, since the substitution reactions between isothiourea derivatives and amines are used in a way that they release mercaptans in the form of byproducts which have a strong unpleasant odor. As an alternative method, in Japanese Patent Laid-open No. 2000-103776, a process for producing nitroisourea derivatives has been described wherein the nitroisourea derivatives and the amines or a salt thereof, are reacted at a pH of 7.0 to 9.0. However, in a production method according to this method, the desired yields of nitroisourea derivatives are not high enough, and therefore, the method is economically inconvenient in some cases. Patent Document 1 Japanese Patent No. 2779403. Patent Document 2: Japanese Patent No. 2546003. Patent Document 3: Japanese Patent No. 2766848.

Patent Document 4: Japanese Patent Revealed No. 2000-103776. Brief Description of the Invention An object of the present invention is to provide a method for cheaply and simply producing nitroisourea derivatives which are intermediates necessary to produce nitroisourea derivatives having an insecticidal activity, overcoming the aforementioned problems encountered in the prior art, with an easier operation than that used in the prior art. In order to solve the above objects, the inventors of the present invention have carried out an extensive study and as a result, have found that the nitroisourea derivatives represented by the formula (1) and the amines represented by the general formula (2) or a salt thereof, are reacted in the presence of a hydrogen carbonate, thereby increasing the yield and, thus, the present invention is completed. That is, the present invention relates to a process for producing nitroisourea derivatives represented by the following general formula (3), which the nitroisourea derivatives represented by the following general formula (1), and the amines represented by the following general formula (2), or a salt thereof, are reacted in the presence of a catalytic amount of a hydrogen carbonate. wherein, in the formula, Ri represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R2 HN (2) R3 wherein in the formula, R 2 represents an alkyl group having 1 to 4 carbon atoms; and R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R2 * 3 (3) N. * N02 where, in the formula, Ri represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 2 represents an alkyl group having 1 to 4 carbon atoms; and R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Further, in the present invention, the nitroisourea derivatives represented by the general formula (1) may contain nitroisourea derivatives having a double bond between the other nitrogen atom and the carbon atom. The nitroisourea derivatives represented by the general formula (3) are the same. In accordance with the present invention, nitroisourea derivatives of the general formula (3), which are essential intermediates for producing nitroguanidine derivatives having insecticidal activity, can be easily and inexpensively produced. Detailed Description of the Invention The present invention will be illustrated in detail below. The process for producing nitroisourea derivatives of the present invention, is a process for producing nitroisourea derivatives represented by the following general formula (3), wherein the nitroisourea derivatives represented by the following general formula (1) with amines represented by the following general formula (2) or a salt of them, they are reacted in the presence of a quantity catalytic of a hydrogen carbonate, wherein, in the formula, R- represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, wherein in the formula, R 2 represents an alkyl group having 1 to 4 carbon atoms; and R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, wherein, in the formula, R- \ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 2 represents an alkyl group having 1 to 4 carbon atoms; and R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

In the present invention according to a method in which the nitroisourea derivatives represented by the general formula (1) and the amines represented by the general formula (2) or a salt thereof, is reacted in the presence of a catalytic amount of a hydrogen carbonate, it is possible to suppress the generation of by-products, such as nitroguanidine derivatives represented by the following general formula (4), or the like, and it is possible to obtain nitroisourea derivatives represented by the general formula (3 ) with high performance, wherein, in the formula, R 2 represents an alkyl group having 1 to 4 carbon atoms; and R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Examples of the hydrogen carbonate in the present invention include alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; and hydrogen carbonates of alkaline earth metal, such as magnesium hydrogen carbonate, calcium hydrogen carbonate, barium hydrogen carbonate and the like.

Preferably, potassium hydrogen carbonate and sodium hydrogen carbonate can be used. In the present invention, one or more types of these hydrogen carbonates can be used. It is important that the amount of hydrogen carbonate should be a catalytic amount, and specifically from 0.01 to 0.5 moles and preferably from 0.05 to 0.2 moles, based on 1 mole of nitroisourea derivatives above represented by the general formula (1) . The amount of hydrogen carbonate within the above range makes it possible to obtain nitroisourea derivatives represented by the general formula (3), with a higher yield. Examples of the salt of the amines of the general formula (2) include salts of inorganic acids such as hydrochloride, bromate, iodate, sulfate, nitrate, chlorate, perchlorate, phosphate and the like; and salts of organic acids such as acetate, oxalate, benzenesulfonate and the like. Hydrochloride and sulfate are preferably used. The amount of the amines of the general formula (2) or a salt thereof used in the reaction is important because they go through a competition reaction with ammonia generated during the reaction. The amine needs to be used in more than 2 mol equivalents based on the nitroisourea derivatives represented by the general formula (1). From the economic perspectives, the amount is preferably from more than 2 to no more than 3 mol equivalents. The nitroisourea derivatives represented by the general formula (1) are a known compound, and can be produced, for example, by the method described through the Network Publication. Chim. Pays-Bas, Vol. 81, p. 69 (1962) or a method similar to it. Examples of the solvent used for the reaction include water; alcohol solvents such as methanol, ethanol, propanol, butanol and the like; halogenated hydrocarbon solvent such as dichloromethane, chloroform and the like; aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like; ether solvents such as ethyl ether, tetrahydrofuran, dioxane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and ketone solvents such as acetone, isopropyl ketone and the like. Of these solvents, those used particularly preferably are water and alcohols. In addition, the reaction can be carried out with a mixed solvent of water and the organic solvent mentioned above. When the water is selected as a solvent and an aqueous solution containing a neutral inorganic salt is used, it is effective in additionally increase the yield of the nitroisourea derivatives. Said inorganic salt refers to an inorganic salt in addition to hydrogen carbonate, and examples thereof include alkali metal salts such as, lithium chloride, sodium chloride, potassium chloride, lithium iodide, sodium iodide, iodide of potassium, lithium bromide, sodium bromide, potassium bromide, lithium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, sodium chlorate and the like; and salts of metal and alkaline earth such as magnesium chloride, calcium chloride, magnesium bromide, calcium bromide, magnesium iodide, calcium iodide, magnesium sulfate, calcium sulfate, magnesium nitrate, calcium nitrate and the like . As the organic solvent, sodium chloride can be used preferably from the point of view of the above effect. In the present invention, the inorganic salt can be selected from one or more types of these salts and can be used. The amount of the salt is suitably selected within the range of 0.1% concentration for saturation in water to carry out the reaction. In the present invention, by using hydrogen carbonate, it is possible to suppress the generation of by-products such as the aforementioned nitroguanidine derivatives represented by the general formula (4) or the like. In addition, by using an inorganic salt other than hydrogen carbonate, it is possible to suppress the decomposition of a starting material and a product. For this reason, it is possible to obtain nitroisourea derivatives in an additional yield through a more convenient operation than that used in the prior art. In this way, through the use of a hydrogen carbonate of an inorganic salt in addition to hydrogen carbonate, the method can be improved in terms of productivity, environmental sustainability and economic efficiency, and is also useful as an industrial production method. The reaction temperature is usually within the range of -20 to 100 degrees centigrade, and preferably within the range of about 0 to 50 degrees centigrade. The reaction time is usually within the range of about 10 minutes, up to 50 hours and preferably within the range of 1 to 20 hours. The nitroisourea derivatives of the general formula (3) produced in the present invention can be separated by extraction with an appropriately selected organic solvent or the like, or they can be separated by filtration as a crystal as such. In addition, when it is separated by filtration in the form of a crystal, the nitroisourea derivatives can be extracted with an organic solvent such as ethyl acetate or the like, from the filtrate and used for the reaction again. EXAMPLES The present invention is illustrated below with greater detail with reference to the Examples and Comparative Examples.

However, the present invention should not be limited in any way by these Examples and Comparative Examples. Example 1 In a 100-ml 4-neck flask with a stirrer, 1.5 g of O-methyl-N-nitroisourea, 11 g of water, 3 g of sodium chloride and 2 g of methylamine hydrochloride were introduced, and the material The resultant was maintained at a temperature of 20 degrees centigrade. Subsequently, 0.1 g of sodium hydrogen carbonate was added to the mixture and the mixture was stirred at a temperature of 20 degrees centigrade for 16 hours. Subsequently, still stirring the reaction mixture, 0.1 of concentrated hydrochloric acid and 200 ml of water were added to the mixture to provide a homogeneous aqueous solution of β, β-dimethyl-N'-nitroisourea, which was analyzed by HPLC. In the aqueous solution, 1.2 g of?,? - dimethyl-N'-nitroisourea were contained, and the yield of the reaction was 73%. 1 H-RM N (CDCl 3, ppm): 3.02 (3 H, d, J = 4.9 Hz), 3.97 (3 H, s), 9.10 (1 H, s). Example 2 In a 100-ml 4-neck flask equipped with a stirrer, 1.5 g (11.3 mmol) of O-ethyl-N-nitroisourea, 8 g of water, 2 g of sodium chloride and 2 g (29.6 g) were introduced. mmoles) of methylamine hydrochloride, and the resulting material it was maintained at a temperature of 15 degrees centigrade. Subsequently, 0.1 g of sodium hydrogen carbonate was added to the mixture and the mixture was stirred at a temperature of 30 degrees centigrade for 15 hours. Subsequently, still stirring the reaction mixture, 0.1 ml of concentrated hydrochloric acid and 200 ml of water were added to the mixture to provide a homogeneous aqueous solution of O-ethyl-N-methyl-N'-nitroisourea, which was analyzed by HPLC. In the aqueous solution, 1.2 g of O-ethyl-N-methyl-N'-nitroisourea was contained, and the yield of the reaction was 70%. Example 3 In a 2000-ml 4-neck flask equipped with a stirrer, 121 g of O-methyl-N-nitroisourea, 907 g of water, 250 g of sodium chloride and 172 g of methylamine hydrochloride were introduced, and the resulting material was maintained at a temperature of 20 degrees centigrade. Subsequently, 8 g of sodium hydrogen carbonate was added to the mixture and the mixture was stirred at a temperature of 20 degrees centigrade for 16 hours. Subsequently, still stirring the reaction mixture, 3.5 concentrated hydrochloric acid was added to the mixture. Subsequently, the reaction mixture was cooled with ice, the precipitated N, γ-dimethyl-N'-nitroisourea was collected by filtration, washed with cold water and subsequently dried. 91 g of N, γ-dimethyl-N'-nitroisourea crystals with a purity of 99% were obtained. He Isolated yield was 67%. Example 4 In a 2000-ml 4-neck flask equipped with a stirrer, 97 g of O-methyl-N-nitroisourea, 726 g of water, 200 g of sodium chloride and 138 g of methylamine hydrochloride were introduced, and the resulting material was maintained at a temperature of 20 degrees centigrade. Subsequently, 6.4 g of sodium hydrogen carbonate was added to the mixture and the mixture was stirred at a temperature of 20 degrees centigrade for 16 hours. Subsequently, still stirring the reaction mixture, 2.8 concentrated hydrochloric acid were added to the mixture. Subsequently, 200 g of ethyl acetate was added to the mixture and the mixture was separated at a temperature of 50 degrees centigrade. Subsequently, the aqueous layer was extracted with 200 g of ethyl acetate twice at a temperature of 50 degrees centigrade, and the combined organic layers were concentrated under reduced pressure. This concentrated mixture was cooled with ice, and the precipitated?,? -dimethyl-N'-nitroisourea was collected by filtration, washed with cold ethyl acetate and subsequently dried. 66 g of a crystal of,? - dimethyl-N'-nitroisourea with a purity of 99% was obtained. The isolated yield was 61%. Comparative Example 1 To 1.5 g of O-methyl-N-nitroisourea was added 15 ml of water for the suspension. 0.9 g of hydrochloride of methylamine to the aqueous suspension (pH = 3.3). An aqueous sodium hydroxide solution (1%) was gradually added to maintain the pH of the aqueous suspension at 8, at room temperature. The aqueous suspension was stirred at room temperature for 3 hours while maintaining the pH thereof at 8, and subsequently an aqueous solution of hydrochloric acid (4M) was added to the aqueous suspension and subsequently the aqueous suspension was extracted with ethyl acetate. ethyl. In Comparative Example 1, 14 mol% of 1-methyl-2-nitroguanidine was generated as a by-product based on 100 mol% of the starting material. On the other hand, since the reaction proceeded with a high yield and high selectivity through the method described in Example 1, the amount of 1-methyl-2-nitroguanidine of a by-product was 4% moles, reducing this largely forms the amount of the by-product. That is, according to the present invention, it is possible to reduce the strain during the purification of?,? - dimethyl-N'-nitroisourea. Therefore the method is useful as a method of industrial production.

Claims (5)

1. CLAIMS 1. A process for producing nitroisourea derivatives represented by the following general formula (3), wherein the nitroisourea derivatives represented by the following general formula (1), and the amines represented by the following general formula (2), or a salt thereof, are reacted in the presence of a catalytic amount of a hydrogen carbonate. wherein, in the formula, R represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, wherein in the formula, R 2 represents an alkyl group having 1 to 4 carbon atoms; and R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, wherein, in the formula, Ri represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, R 2 represents an alkyl group having 1 to 4 carbon atoms; and R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
2. 2. The process for producing nitroisourea derivatives as described in claim 1, characterized in that an aqueous solution obtained by dissolving an inorganic salt other than hydrogen carbonate is used as a solvent.
3. 3. The process for producing nitroisourea derivatives as described in claim 2, wherein the inorganic salt other than hydrogen carbonate is sodium chloride.
4. 4. The process for producing nitroisourea derivatives as described with any of claims 1 to 3, characterized in that the amines represented by the general formula (2) or a salt thereof are used in more than 2 equivalents with mol, based on the nitroisourea derivatives represented by the general formula (1).
5. 5. The process for producing nitroisourea derivatives as described with any of claims 1 to 4, characterized in that R † and R2 are each a methyl group, and R3 is a hydrogen atom.