Method for producing 2-amino-5-substituted-1, 3, 4-diazole

Abstract

The present invention is a method for producing a 2-amino-5-substituted-1, 3, 4-# imgabs0 # diazole, said method comprising the following steps (A) to (E), and a process for producing a 2-amino-5-substituted-1, 3, 4-# imgabs0 # diazole. A step (A) for preparing a cyanogen chloride solution from hydrogen cyanide and chlorine. And a step (B) in which the amount of the by-product hydrochloric acid, which is a by-product together with the cyanogen chloride in the step (A), is adjusted to 0.5 equivalents or less with respect to the generated cyanogen chloride. And (C) a step for reacting the carboxylic acid hydrazide with a cyanogen chloride solution to obtain a 2-amino-5-substituted-1, 3, 4-# imgabs 1 # diazole hydrochloride. And a step (D) in which an alkali is added to the solution obtained in step (C) in an amount equal to or greater than the sum of the amount of the by-product hydrochloric acid and the amount of the cyanogen chloride in the cyanogen chloride solution used in step (C). And a step (E) in which the solution containing the hydrochloride of the alkali obtained in step (D) is cooled and the precipitated crystals are separated. # imgabs2 #

Description

Technical Field

[0001] The present invention relates to The production method of oxadiazoles, in particular, relates to 2-amino-5-substituted-1,3,4- A method for producing oxadiazole. Background Art

[0002] 2-amino-5-substituted-1,3,4- Oxadiazoles are used as important intermediates for the manufacture of pharmaceuticals or agricultural and horticultural herbicides. For example, in pharmaceuticals, they are disclosed as metabotropic glutamate receptor antagonists, for the treatment or prevention of acute and chronic neurological disorders, and as antibacterial drugs for bacterial diseases. In pesticides, they are disclosed as intermediates for various herbicides. As useful compounds, oxadiazoles have also attracted attention for their production methods. The following synthesis methods are known as main methods for producing oxadiazoles.

[0003] Preparation method 1): Acylation of semicarbazide with carboxylic anhydride is followed by simultaneous chlorination and cyclization with phosphorus oxychloride to obtain 2-amino-5-substituted-1,3,4- Oxadiazoles (Patent Documents 1, 2);

[0004] Preparation method 2): Using semicarbazide and aldehyde to convert semicarbazide into hydrazone, followed by organic electrolysis reaction, to obtain 2-amino-5-substituted-1,3,4- Oxadiazoles (Non-Patent Document 1);

[0005] Preparation method 3): react carboxylic acid hydrazide with purified cyanogen chloride or cyanogen bromide to obtain 2-amino-5-substituted-1,3,4- Oxadiazoles (Patent Documents 3, 4, Non-Patent Document 2);

[0006] Preparation method 4): react carboxylic acid hydrazide with phenyl cyanate to obtain 2-amino-5-substituted-1,3,4- Oxadiazoles (Non-patent Document 3);

[0007] Production method 5): react carboxylic acid hydrazide with trimethylsilyl isothiocyanate to obtain 2-amino-5-substituted-1,3,4- Oxadiazoles (Non-Patent Document 4)

[0008] Prior art literature

[0009] Patent Literature

[0010] Patent Document 1: Japanese Patent Application Publication No. 2017-25054;

[0011] Patent Document 2: Japanese Patent Application Publication No. 2018-76298;

[0012] Patent Document 3: EP3133063;

[0013] Patent Document 4: Japanese Patent Application No. 2002-542229;

[0014] Non-patent literature

[0015] Non-patent document 1: Russian Journal of Electrochemistry (2010), 46(1), 34-40; Non-patent document 2: Khimiya Geterotsiklicheskikh Soedinenii (1975), (11), 1493-8;

[0016] Non-patent document 3: Buletinul Stiintific si Tehnic al InstitutuluiPolitehnic Traian Vuia Timisoara, Seria Chimie (1981), 26(2), 111-16;

[0017] Non-patent document 4: RSC Advances (2013), 3(21), 7684-7687. Summary of the Invention

[0018] Problems to be solved by the invention

[0019] The above-mentioned production method 1) uses high-priced semicarbazide. In the chlorination and cyclization steps of the intermediate, more than an equivalent amount of phosphorus oxychloride is used, thus generating a large amount of phosphorus waste liquid and resulting in a low yield.

[0020] Production method 2) also uses a high-valent semicarbazide as a starting material. In the cyclization step, the hydrazone obtained by the reaction of semicarbazide with an aldehyde is subjected to an electron cyclization reaction using high-valent lithium perchlorate. Production is performed at a low reaction concentration of 1%.

[0021] By the production method 3) 2-amino-5-substituted-1,3,4- However, cyanogen chloride is purified and requires purification steps such as distillation. Oxadiazole has high solubility in water. Therefore, after using an organic solvent to react carboxylic acid hydrazide with cyanogen chloride, it is necessary to separate the hydrochloride generated during the neutralization by filtration, concentrate the filtrate to dryness, and then add a small amount of water to the residue to crystallize the product. This is a complex operation. Moreover, concentration and drying require special equipment. Here, even if cyanogen bromide is used, 2-amino-5-substituted-1,3,4- However, cyanogen bromide is expensive and requires crystallization to handle highly toxic substances, so safety considerations are necessary.

[0022] In the production method 4), phenyl cyanate is expensive and the yield of the target product is low.

[0023] In the production method 5), trimethylsilyl isothiocyanate is expensive and produces hydrogen sulfide, a highly toxic and malodorous substance, as a by-product of the reaction.

[0024] As mentioned above, the conventionally known 2-amino-5-substituted-1,3,4- The synthesis of oxadiazoles is not a satisfactory economical and efficient manufacturing method.

[0025] The present invention aims to solve the problems associated with the prior art as described above and to provide an industrial production method that can produce 2-amino-5-substituted-1,3,4-diaminobenzene in high yield and high purity from inexpensive and easily prepared starting materials by a method simpler than the prior art. Oxadiazole.

[0026] Means for solving problems

[0027] The present inventors have discovered that, when a cyanogen chloride solution synthesized from hydrogen cyanide and chlorine is reacted with carboxylic acid hydrazide, even without purifying the cyanogen chloride, by controlling the amount of hydrochloric acid produced as a by-product together with the cyanogen chloride (hereinafter also referred to as "by-product hydrochloric acid") to be 0.5 equivalents or less relative to the cyanogen chloride used in the reaction, 2-amino-5-hydroxy-1,3,4-diol can be synthesized without complicated operations. The hydrochloride of oxadiazole; and, in the resulting 2-amino-5-substituted-1,3,4- A base is added to an aqueous solution of hydrochloride of oxadiazole, and the target product is precipitated by the salting-out effect of the hydrochloride of hydrochloric acid produced as a by-product by the addition of the base, and solid-liquid separation is performed. Thus, 2-amino-5-substituted-1,3,4-oxadiazole can be obtained simply and with high purity without removing the produced hydrochloride. The present invention has been completed by obtaining crystals of oxadiazole.

[0028] That is, the present invention is 2-amino-5-substituted-1,3,4- A method for producing oxadiazole comprises the following steps:

[0029] Step (A) of preparing a cyanogen chloride solution from hydrogen cyanide and chlorine;

[0030] Step (B) of adjusting the amount of by-produced hydrochloric acid produced together with cyanogen chloride in step (A) to be 0.5 equivalent or less relative to the generated cyanogen chloride;

[0031] Step (C) is to react the carboxylic acid hydrazide represented by the general formula (1) with a cyanogen chloride solution to obtain a 2-amino-5-substituted-1,3,4- Oxadiazole hydrochloride,

[0032]

[0033] In formula (1), R is a hydrogen atom, a C1-C6 alkyl group, an aryl group, a 5- or 6-membered aromatic heterocyclic group, or an alkoxy group, and these groups may be substituted by a halogen atom or a C1-C4 alkyl group.

[0034]

[0035] In formula (2), R is a hydrogen atom, a C1-C6 alkyl group, an aryl group, a 5- or 6-membered aromatic heterocyclic group, or an alkoxy group, and these groups may be substituted by a halogen atom or a C1-C4 alkyl group;

[0036] Step (D) of adding a base in an amount equivalent to or greater than the sum of the amount of cyanogen chloride in the cyanogen chloride solution used in step (C) and the amount of by-produced hydrochloric acid to the solution obtained in step (C);

[0037] Step (E) is to cool the solution containing the hydrochloride of the base obtained in step (D) and separate the precipitated crystals to obtain 2-amino-5-substituted-1,3,4- oxadiazole,

[0038]

[0039] In formula (3), R is a hydrogen atom, a C1-C6 alkyl group, an aryl group, a 5- or 6-membered aromatic heterocyclic group, or an alkoxy group, and these groups may be substituted by a halogen atom or a C1-C4 alkyl group.

[0040] That is, the present invention also provides 2-amino-5-substituted-1,3,4- A method for producing an oxadiazole, wherein the 2-amino-5-substituted-1,3,4- The amount of by-produced hydrochloric acid in the solution of the hydrochloride of oxadiazole in step (A) is 0.5 equivalents or less relative to the reacted cyanogen chloride.

[0041] Effects of the Invention

[0042] In the present invention, 2-amino-5-substituted-1,3,4- In the method for producing oxadiazoles, a solution of cyanogen chloride and carboxylic acid hydrazide, which are inexpensive and easy to prepare, is used. Without the need for complicated operations such as separation or concentration to dryness of the generated hydrochloride, the target product can be precipitated from a solvent in which the generated hydrochloride is dissolved, thereby obtaining 2-amino-5-substituted-1,3,4-diazoles in high yield and high purity. A simple and industrially feasible method for producing oxadiazoles is provided. DETAILED DESCRIPTION

[0043] The 2-amino-5-substituted-1,3,4- The method for producing oxadiazoles comprises the following steps (A) to (E).

[0044] In step (A), a cyanogen chloride solution is prepared from hydrogen cyanide and chlorine.

[0045] In step (B), the amount of by-produced hydrochloric acid produced together with cyanogen chloride in step (A) is adjusted to be 0.5 equivalent or less relative to the produced cyanogen chloride.

[0046] Step (C) is to react carboxylic acid hydrazide with cyanogen chloride as shown in the following reaction formula A to obtain 2-amino-5-substituted-1,3,4- Oxadiazole hydrochloride.

[0047]

[0048] In step (D), a base is added to the solution obtained in step (C) in an amount equivalent to or greater than the sum of the amount of cyanogen chloride in the cyanogen chloride solution used in step (C) and the amount of by-produced hydrochloric acid.

[0049] Step (E) is to cool the solution containing the hydrochloride of the base obtained in step (D) and separate the precipitated crystals to obtain 2-amino-5-substituted-1,3,4- Oxadiazole.

[0050] Hereinafter, the 2-amino-5-substituted-1,3,4- The method for producing oxadiazole will be described in detail.

[0051] Process (A)

[0052] Step (A) is a step of preparing a cyanogen chloride solution from hydrogen cyanide and chlorine.

[0053] Cyanogen chloride can be synthesized by reacting hydrogen cyanide with chlorine. In the reaction of synthesizing cyanogen chloride from hydrogen cyanide and chlorine, it is preferred that an equivalent amount of hydrochloric acid be produced as a byproduct in an amount equivalent to the amount of cyanogen chloride produced by reacting an equivalent amount or more of hydrogen cyanide with chlorine.

[0054] Hydrogen cyanide can be used as a single gas or liquid, but it is also possible to use a substance obtained in advance by reacting a metal cyanide with an acid. Examples of metal cyanides include potassium cyanide and sodium cyanide. These metal cyanides can be added to a solvent and used as a liquid (not necessarily dissolved) at a concentration of 5 to 20% by mass. For example, by adding dropwise to an acidic solution such as hydrochloric acid at -5 to 15°C, a solution containing hydrogen cyanide can be obtained. The resulting hydrogen cyanide can be directly mixed in a solvent and used for the reaction with chlorine. The solvent is not particularly limited, and water or aliphatic hydrocarbons such as pentane, hexane, and cyclohexane, or halogenated hydrocarbons such as dichloromethane and chloroform can be used. Water, which has a high solubility for metal cyanide, is preferred. These solvents can be used alone or as a mixture of two or more, and the mixing ratio can be any ratio.

[0055] In the present invention, chlorine may be used in the form of gas or liquid, and preferably, chlorine gas is blown into the reaction solution.

[0056] The amount of hydrogen cyanide is 1 equivalent or more, preferably 1.0 to 1.1 equivalents relative to chlorine. If excessive chlorine remains in the cyanogen chloride solution, the chlorine will volatilize due to the heat of neutralization when the by-produced hydrochloric acid is neutralized, and the cyanogen chloride will also be lost due to the volatilization of the chlorine.

[0057] The reaction temperature in the reaction of hydrogen cyanide and chlorine is not particularly limited, but is preferably -10°C to 5°C from the viewpoint of preventing the loss of cyanogen chloride by volatilization.

[0058] The reaction pressure in the reaction of hydrogen cyanide and chlorine may be normal pressure or pressurized. The reaction atmosphere is not particularly limited and may be an inert gas atmosphere such as nitrogen, helium, or argon, as needed.

[0059] The reaction solvent for blowing in chlorine is not particularly limited, and examples thereof include aqueous solutions, aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane, and halogenated hydrocarbons such as dichloromethane and chloroform. These solvents may be used alone or in combination of two or more, and the mixing ratio may be any desired ratio.

[0060] The time for blowing chlorine into the solution containing hydrogen cyanide is not particularly limited, but is preferably 10 minutes to 20 hours, more preferably 30 minutes to 15 hours. Furthermore, stirring is preferably performed while maintaining the reaction temperature for the next 10 minutes to 1 hour.

[0061] Process (B)

[0062] Step (B) is a step of adjusting the amount of by-product hydrochloric acid produced along with cyanogen chloride in step (A) to 0.5 equivalents or less relative to the produced cyanogen chloride. Here, adjusting the amount to 0.5 equivalents or less relative to the produced cyanogen chloride means that the equivalent of the produced cyanogen chloride, i.e., the equivalent of the by-product hydrochloric acid produced as a by-product in the same amount, is regarded as 1.0, and the amount of the by-product hydrochloric acid is adjusted to 0.5 equivalents or less relative to this equivalent, thereby making the equivalent of the by-product hydrochloric acid no more than half the equivalent of the produced cyanogen chloride.

[0063] In the present invention, the amount of by-product hydrochloric acid in the cyanogen chloride solution when reacting carboxylic acid hydrazide with cyanogen chloride solution is important. The amount is preferably 0.5 equivalents or less, more preferably 0.4 equivalents or less relative to the generated cyanogen chloride. When the amount is 0.5 equivalents or more, the reaction rate decreases, and the 2-amino-5-substituted-1,3,4- The yield of oxadiazole hydrochloride is significantly reduced. In contrast, when the amount is 0.5 equivalent or less, a sufficient reaction rate is achieved, and it is not necessary to use purified cyanogen chloride such as distillation.

[0064] In addition, the by-produced hydrochloric acid can be removed in its entirety. However, when the by-produced hydrochloric acid is removed by neutralization, if the neutralization is performed with an alkali in an amount greater than the amount of the by-produced hydrochloric acid, the generated cyanogen chloride is decomposed by the alkali. Therefore, it is not preferred to neutralize with an alkali in an amount greater than the amount of the by-produced hydrochloric acid.

[0065] In order to reduce the amount of by-produced hydrochloric acid in the cyanogen chloride solution used in the subsequent step (C) to 0.5 equivalents or less relative to the generated cyanogen chloride, the following method is exemplified.

[0066] A method in which the cyanogen chloride solution obtained in step (A) is subjected to a simple treatment, such as neutralization or extraction, to reduce the amount of by-produced hydrochloric acid to 0.5 equivalents or less relative to the cyanogen chloride, and the cyanogen chloride solution is used. Alternatively, an untreated cyanogen chloride solution (i.e., a solution containing 0.5 equivalents or more of by-produced hydrochloric acid) is used, and the cyanogen chloride solution, carboxylic acid hydrazide, and a base are simultaneously mixed, or the cyanogen chloride solution and carboxylic acid hydrazide are mixed and then a base is added, and then the cyanogen chloride solution and carboxylic acid hydrazide are reacted.

[0067] Specifically, as a method for reducing the amount of by-produced hydrochloric acid in the cyanogen chloride solution obtained in step (A) to 0.5 equivalents or less relative to cyanogen chloride, there can be mentioned: a method of adding a base in the absence or presence of an organic solvent to convert a portion of the by-produced hydrochloric acid into a hydrochloride (hereinafter also referred to as a "neutralization method"); and a method of adding an organic solvent and extracting cyanogen chloride into the organic solvent to reduce the amount of by-produced hydrochloric acid to 0.5 equivalents or less (hereinafter also referred to as an "extraction method").

[0068] In the case of a neutralization method, a base is added to a cyanogen chloride solution prepared from hydrogen cyanide and chlorine, or a base is added to neutralize a portion of the by-produced hydrochloric acid while or after mixing the carboxylic acid hydrazide and the cyanogen chloride solution to form a by-produced hydrochloride. It should be noted that the salt generated during neutralization is usually removed from the reaction system, but in the present invention, it is preferably not removed and is used directly in the form of a salt containing the by-produced hydrochloric acid.

[0069] The base used to neutralize the hydrochloric acid produced as a by-product in the synthesis of cyanogen chloride is not particularly limited. Examples include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and organic bases such as triethylamine and pyridine. Furthermore, the carboxylic acid hydrazide used as the raw material can be used as the base. The form in which these bases are used is not limited; they can be used as aqueous solutions dissolved in water. Furthermore, one type of base can be used alone or in combination of two or more types.

[0070] The equivalent of the alkali used in the neutralization of the by-product hydrochloric acid (i.e., the generated cyanogen chloride) is in the range of 0.5 to 1.0 equivalents, preferably 0.6 equivalents or more. When the equivalent of the alkali is 0.5 equivalents or less, the amount of hydrochloric acid that does not form a salt after the reaction of step (C), i.e., the amount of by-product hydrochloric acid, is 0.5 equivalents or more relative to the cyanogen chloride used in the reaction, resulting in a delayed reaction and a significant decrease in yield. On the other hand, if an equivalent amount of alkali is added, decomposition of cyanogen chloride occurs. In this case, 2-amino-5-substituted-1,3,4- The yield of oxadiazole hydrochloride was also reduced.

[0071] The solvent used in the neutralization of the above-mentioned by-product hydrochloric acid can be water alone, but it is more preferable to include an organic solvent. There is no particular limitation on the organic solvent, and aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, octane, decane, and halogenated hydrocarbons such as dichloromethane, chloroform, trichloroethylene, and tetrachloroethylene can be used. The amount of organic solvent added is 0.6 to 7.0 times the weight of the hydrogen cyanide used. In addition, the organic solvent can be added again during neutralization, or it can be the organic solvent used since the synthesis of cyanogen chloride in step (A), thereby replacing the addition of the organic solvent during neutralization. The organic solvent used here is used to prevent the loss of cyanogen chloride by volatilization. When no organic solvent is used or when no organic solvent is added during neutralization, the yield of the target product may sometimes be reduced due to the loss caused by the volatilization of cyanogen chloride during neutralization. In this regard, its role / effect is different from the organic solvent used for extraction in the "extraction method" described below.

[0072] The neutralization temperature of the by-produced hydrochloric acid is in the range of -10 to 50°C, preferably in the range of -5 to 20°C.

[0073] The dropwise addition time of the base used for neutralization is in the range of 10 minutes to 20 hours, preferably in the range of 1 hour to 15 hours.

[0074] The cyanogen chloride solution in which the amount of by-produced hydrochloric acid is reduced by adding a base in this manner is directly subjected to a reaction with carboxylic acid hydrazide in the presence of an organic solvent as a two-layer solution.

[0075] Furthermore, when a solution containing 0.5 equivalents or more of by-product hydrochloric acid is used as a cyanogen chloride solution, the cyanogen chloride solution, carboxylic acid hydrazide and a base are mixed together, or the cyanogen chloride solution and carboxylic acid hydrazide are mixed, and then a base is added to reduce the amount of by-product hydrochloric acid to 0.5 equivalents or less, and then the carboxylic acid hydrazide and the cyanogen chloride solution are reacted in a subsequent step to synthesize 2-amino-5-substituted-1,3,4- The hydrochloride salt of oxadiazole.

[0076] On the other hand, when the extraction method is adopted, cyanogen chloride is extracted and separated from a cyanogen chloride prepared solution containing water (including a solution to which water is added after synthesis in an organic solvent) using an organic solvent, thereby reducing the amount of by-produced hydrochloric acid.

[0077] Halogenated hydrocarbons such as dichloromethane and tetrachloroethylene are preferably used as organic solvents for extracting cyanogen chloride from a cyanogen chloride solution synthesized from hydrogen cyanide and chlorine. These organic solvents may be used alone or in combination. Furthermore, the aforementioned extraction solvents may be included in the system during the synthesis of cyanogen chloride. The amount of organic solvent added is not particularly limited, but is 1.0 to 8.0 times, preferably 3.0 to 6.0 times, the weight of the hydrogen cyanide used.

[0078] The extraction temperature is not limited and is usually carried out at -5 to 10° C. Then, the extraction / separation organic solvent is used to react with carboxylic acid hydrazide.

[0079] It should be noted that in the present invention, when adjusting the amount of by-product hydrochloric acid, either the neutralization method or the extraction method described above can be used alone. However, in addition to this, the amount of by-product hydrochloric acid can also be adjusted by using both methods. For example, if the amount of by-product hydrochloric acid in the extract obtained by the extraction method exceeds 0.5 equivalents, the amount of by-product hydrochloric acid can be adjusted by a neutralization method in which a base is added to the extract. Alternatively, the extract can be further extracted to adjust the amount of by-product hydrochloric acid.

[0080] Process (C)

[0081] Step (C) is to react carboxylic acid hydrazide with cyanogen chloride to synthesize 2-amino-5-substituted-1,3,4- The process of preparing the hydrochloride salt of oxadiazole.

[0082] Although 2-amino-5-substituted-1,3,4- oxadiazole and hydrochloric acid, but the hydrochloric acid produced is reacted with 2-amino-5-substituted-1,3,4- The oxadiazole forms a salt, and as a result, 2-amino-5-substituted-1,3,4- Therefore, as the solution after the reaction is completed, the 2-amino-5-substituted-1,3,4- The hydrochloride of oxadiazole and a portion of the by-produced hydrochloric acid in step (A).

[0083] The carboxylic acid hydrazide that reacts with cyanogen chloride is a compound represented by the following general formula (1). Carboxylic acid hydrazide can be used as the compound itself, but from the perspective of temperature control during the dropwise addition operation, an aqueous solution or other organic solvent solution is preferred. Typically, it is often used in the form of an aqueous solution with a concentration of approximately 5 to 80% by mass.

[0084]

[0085] The substituent R in the formula is a hydrogen atom, a C1-C6 alkyl group, an aryl group, a 5- or 6-membered aromatic heterocyclic group, or an alkoxy group, and these groups may be substituted by halogen or a C1-C4 alkyl group.

[0086] The alkyl group having 1 to 6 carbon atoms, that is, C1 to C6, includes both linear and branched alkyl groups, and a methyl group is preferred among these alkyl groups.

[0087] Examples of the aryl group include a phenyl group and a naphthyl group, and a phenyl group is preferred.

[0088] A 5- or 6-membered aromatic heterocyclic group refers to a monocyclic aromatic heterocyclic group having 5 or 6 ring atoms and containing 1 to 5 heteroatoms (the heteroatoms are nitrogen atoms, oxygen atoms, or sulfur atoms) among the ring atoms, and examples thereof include pyridyl, furyl, and thienyl. As these 5- or 6-membered aromatic heterocyclic groups, pyridyl is preferred.

[0089] Furthermore, examples of the alkoxy group include phenoxy and the like in addition to so-called alkoxy groups such as alkoxy, ethoxy, and isopropoxy. Of these alkoxy groups, an alkoxy group is preferred.

[0090] In addition, the above groups may be further substituted with halogen or C1-C4 alkyl. However, as the number of carbon atoms in R increases, the reactivity decreases, so the upper limit of the number of carbon atoms is preferably C18. Examples of such substituents include tolyl groups substituted with a methyl group on a phenyl group, and haloalkyl groups substituted with a halogen (e.g., fluorine, chlorine, bromine, etc.) on an alkyl group.

[0091] The above-mentioned carboxylic acid hydrazide can be simply synthesized by reacting hydrazine with carboxylic acid esters, carboxylic acid chlorides, carboxylic acid anhydrides, carbonates, or carbamates. There is no limitation on the form in which the carboxylic acid hydrazide is used; a carboxylic acid hydrazide synthesis solution, a concentrated solution obtained by concentration, or a crystal of the carboxylic acid hydrazide can be used. Furthermore, the diluent can be diluted with a solvent as needed. The diluent is not particularly limited, and examples thereof include water or alcohols such as methanol, ethanol, and isopropanol; aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; ethers such as diethyl ether and diisopropyl ether; and halogenated hydrocarbons such as dichloromethane and chloroform.

[0092] The product obtained by reacting cyanogen chloride with the carboxylic acid hydrazide of the above formula (1) is a 2-amino-5-substituted-1,3,4- Hydrochloride salts of oxadiazoles.

[0093]

[0094] In the formula, the substituent R is derived from R in the carboxylic acid hydrazide and is the same as R. Specifically, the substituent R is a hydrogen atom, a C1-C6 alkyl group, an aryl group, a 5- or 6-membered aromatic heterocyclic group, or an alkoxy group, and these groups may be substituted with halogen or a C1-C4 alkyl group.

[0095] In the present invention, the reaction solvent for the reaction of cyanogen chloride with carboxylic acid hydrazide is not particularly limited. For example, water, aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; and halogenated hydrocarbons such as dichloromethane and chloroform can be used. These solvents can be used alone or in combination of two or more, and the mixing ratio can be any ratio. In consideration of economic efficiency and environmental impact, aqueous solvents are preferred.

[0096] In the present invention, the greater the amount of cyanogen chloride, the greater the amount of alkali added in step (D) described later. The greater the excess of cyanogen chloride relative to carboxylic acid hydrazide, the greater the amount of water required to dissolve the hydrochloride of the alkali, and the lower the production capacity. Therefore, it is preferable to set the equivalent amount of carboxylic acid hydrazide relative to cyanogen chloride so as to effectively consume cyanogen chloride.

[0097] In the present invention, the equivalent weight of the carboxylic acid hydrazide relative to cyanogen chloride is preferably 0.95 to 1.5 equivalents. If the equivalent weight of the carboxylic acid hydrazide is 0.95 or less, productivity decreases. On the other hand, if the equivalent weight is 1.5 or more, there is no advantage from an economical point of view.

[0098] In the present invention, there is no limitation on the filling method in the reaction of the cyanogen chloride solution and the carboxylic acid hydrazide. However, since the reaction is accompanied by heat generation, the dropwise addition method is preferred. The dropwise addition method can be performed by dropping the carboxylic acid hydrazide solution into the cyanogen chloride solution to reduce the amount of by-product hydrochloric acid to 0.5 equivalent or less, or by dropping the cyanogen chloride solution into the carboxylic acid hydrazide solution.

[0099] On the other hand, when using cyanogen chloride in an amount containing 0.5 equivalents or more of by-produced hydrochloric acid relative to cyanogen chloride in the cyanogen chloride solution, the following method can be adopted: a method in which the cyanogen chloride solution is added dropwise to the carboxylic acid hydrazide solution, and the amount of by-produced hydrochloric acid is first reduced to 0.5 equivalents or less; or a method in which the carboxylic acid hydrazide solution and a base are simultaneously added dropwise to the cyanogen chloride solution; or a method in which a base is added dropwise after the carboxylic acid hydrazide solution is added to the cyanogen chloride solution.

[0100] In the present invention, the temperature when the carboxylic acid hydrazide solution is added dropwise to the cyanogen chloride solution is in the range of -10°C to 15°C, preferably in the range of -7°C to 10°C, and more preferably in the range of -5°C to 5°C. Furthermore, the addition time is set to maintain the above-mentioned temperature and is in the range of 10 minutes to 20 hours, preferably in the range of 30 minutes to 15 hours. It should be noted that these are also the same as when the cyanogen chloride solution is added dropwise to the carboxylic acid hydrazide solution.

[0101] After the completion of the dropwise addition, the temperature is preferably raised to 5°C to 40°C, preferably 10°C to 35°C, more preferably 20°C to 30°C, and stirred while maintaining this temperature for 30 minutes to 3 hours, preferably 1 hour to 2 hours. The heating time after the completion of the dropwise addition is not particularly limited, but is in the range of 10 minutes to 15 hours, preferably 30 minutes to 10 hours, and more preferably 1 hour to 6 hours.

[0102] Process (D)

[0103] Step (D) is to add a base to the reaction solution obtained in step (C) to neutralize the by-produced hydrochloric acid contained in the reaction solution and simultaneously convert 2-amino-5-substituted-1,3,4- Conversion of oxadiazole hydrochloride into 2-amino-5-substituted-1,3,4- Therefore, the amount of base added is equal to the amount of cyanogen chloride in the cyanogen chloride solution used for the reaction in the above step (C) (which is equivalent to 2-amino-5-substituted-1,3,4- The amount of alkali is an amount equivalent to or greater than the sum of the amount of the hydrochloride of oxadiazole (the amount of hydrochloride produced) and the amount of by-product hydrochloric acid remaining in the cyanogen chloride solution.

[0104] In addition, in the present invention, in any of the methods for reducing by-product hydrochloric acid after cyanogen chloride synthesis (treatment by neutralization or treatment by extraction), the organic solvent contained in the reaction solution after the reaction in step (C) is removed by liquid separation, and the product is separated without containing the organic solvent. In addition, if hydrochloride precipitates in the reaction solution, additional water may be added to dissolve the hydrochloride.

[0105] When the by-produced hydrochloric acid is reduced by the neutralization method during the preparation of the cyanogen chloride solution in step (A), since the reaction solution obtained in step (C) contains the organic solvent used for neutralization, the organic layer is separated from the reaction solution obtained in step (C) and the aqueous layer is treated with an alkali to neutralize the residual by-produced hydrochloric acid and convert the 2-amino-5-substituted-1,3,4- Conversion of oxadiazole hydrochloride into 2-amino-5-substituted-1,3,4- Oxadiazole.

[0106] On the other hand, when using a cyanogen chloride solution obtained by an extraction method, after reacting with a carboxylic acid hydrazide solution, water is added to dissolve the crystals to form a two-layer structure of an organic layer and an aqueous layer. The organic layer is then separated and the aqueous layer is treated with an alkali.

[0107] When the organic layer is separated and the aqueous layer is treated with a base, the base may be added dropwise to the aqueous layer, or the treatment may be performed by back titration neutralization such as adding the aqueous layer dropwise to the base.

[0108] The temperature for separating the organic layer and the aqueous layer at this time is not particularly limited, but is preferably in the range of 5°C to 40°C, and more preferably in the range of 10°C to 30°C.

[0109] In the present invention, the base used in step (D) is not particularly limited. Examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and organic bases such as triethylamine and pyridine. The form in which these bases are used is not limited; they can be used as aqueous solutions dissolved in water. Furthermore, one type can be used alone or in combination of two or more types. Furthermore, the treatment with the base can be performed by dripping the base into the reaction solution, or by dripping the reaction solution into the base as described above.

[0110] In the present invention, the treatment temperature during the alkali treatment is in the range of 5° C. to 80° C., preferably 5° C. to 40° C. The neutralization time is in the range of 10 minutes to 20 hours, preferably 20 minutes to 15 hours.

[0111] In the present invention, the cyanogen chloride solution prepared in step (A) contains hydrochloric acid as a by-product. In step (C), 2-amino-5-substituted-1,3,4- The by-product hydrochloric acid contained in the cyanogen chloride solution is removed by a neutralization method or an extraction method. In addition, in the case of the above-mentioned untreated state, it is removed by a method of reacting carboxylic acid hydrazide with a base. Therefore, the equivalent of the base added in step (D) needs to be the by-product hydrochloric acid contained in the cyanogen chloride solution subjected to the above-mentioned optional treatment and the 2-amino-5-substituted-1,3,4- When the amount of the added base is less than the equivalent of the hydrochloric acid of the above sum, 2-amino-5-substituted-1,3,4- Since the oxadiazole keeps the form of hydrochloride unchanged, the yield is greatly reduced. In addition, in order to completely decompose the unreacted cyanogen chloride and operate safely, it is also preferred to add a base of the equivalent of the above sum or more. Moreover, in the case of adding a base of the same equivalent as the hydrochloric acid equivalent of the above sum, there is a tendency to obtain colored crystals. In contrast, if a base of the equivalent of the above sum or more is added, white crystals can be obtained. From these aspects, the amount of alkali added is more preferably set to the range of 1.1 to 3.0 equivalents, and further preferably to the range of 1.2 to 1.5 equivalents, relative to the total amount of by-product hydrochloric acid contained in the cyanogen chloride solution of step (C) and the cyanogen chloride used in step (C). It should be noted that the hydrochloride usually generated is removed from the reaction system, but the hydrochloride generated in the present invention is not removed, but is used in step (E) in a dissolved state to obtain a salting-out effect.

[0112] It should be noted that in the above-mentioned step (D) of adding a base in the present invention, that is, in the step of neutralizing with a base, 2-amino-5-substituted-1,3,4- Conversion of oxadiazole hydrochloride into 2-amino-5-substituted-1,3,4- The oxadiazole and the residual by-product hydrochloric acid are simultaneously neutralized. Therefore, as long as the pH of the solution after the neutralization treatment is the pH value at the end of these neutralization reactions, that is, a pH of about 4.5 or above, the neutralization purpose is achieved. In the solution after the neutralization treatment, 2-amino-5-substituted-1,3,4- 2-amino-5-substituted-1,3,4-diazole can be obtained by crystallization. However, in the present invention, the pH of the solution of the cyanide (e.g., NaCN, etc.) generated during the treatment is as high as 11 to 12. At a pH below 11, it may remain as HCN. Therefore, in order to safely handle the cyanide, the pH of the solution after the neutralization treatment must be 11 or higher. Therefore, the pH of the solution after the neutralization treatment is preferably set to 11 or higher. For this reason, as described above, an equivalent amount or more of the base is also required.

[0113] Process (E)

[0114] Step (E) is to utilize the salting-out effect of the hydrochloride of the base (i.e., the base used for neutralization) produced in step (D) to precipitate the target product, and to obtain the 2-amino-5-substituted-1,3,4- The process of diazole.

[0115]

[0116] In the formula, the substituent R is derived from R in the carboxylic acid hydrazide and is the same as R. Specifically, the substituent R is a hydrogen atom, a C1-C6 alkyl group, an aryl group, a 5- or 6-membered aromatic heterocyclic group, or an alkoxy group, and these groups may be substituted with halogen or a C1-C4 alkyl group.

[0117] In the present invention, although 2-amino-5-substituted-1,3,4- The solubility of oxadiazoles in water is very high, but in aqueous solutions containing salt, the solubility is reduced due to the salting-out effect, and the product can be obtained in high yield. The solubility of oxadiazole in water at 30°C is 13.9% by mass, but in a 10% by mass aqueous solution of NaCl, 2-amino-5-methyl-1,3,4- The solubility of oxadiazole decreased to 7.9% by mass, and the solubility in a 26.4% by mass NaCl aqueous solution decreased to 3.5% by mass. In view of the above, in the solution obtained by step (D), the concentration of the hydrochloride based on the added base is preferably 10% by mass or more, and is preferably below the saturation concentration of the hydrochloride of the base used.

[0118] In the present invention, 2-amino-5-substituted-1,3,4- The solubility of oxadiazoles in aqueous solutions (including hydrochloride of the added base) is highly temperature-dependent, and the lower the separation temperature, the higher the yield. In addition, in aqueous solutions containing hydrochloride of the base, separation is possible even below 0°C due to the freezing point depression. For example, 2-amino-5-methyl-1,3,4- The solubility of oxadiazole in a 26.4% by mass NaCl aqueous solution at 30°C is 3.5% by mass. When the temperature is lowered to -5°C, the solubility decreases to 1.1% by mass. On the other hand, if the separation temperature is too low, impurities may be mixed in. Therefore, the separation temperature range is -7°C to 30°C, preferably -5°C to 10°C. In addition, the cooling time to reach the separation temperature is not particularly limited, but is in the range of 10 minutes to 15 hours, preferably 30 minutes to 10 hours.

[0119] In the present invention, since the crystals separated from the solution containing the hydrochloride of the alkali obtained in the above step (D) contain the hydrochloride of the alkali, it is preferably washed with water or an organic solvent containing water. When washed with water or an organic solvent containing water, the content of the hydrochloride in the crystals is 0.5% by mass or less. In addition, after washing with water, washing with an organic solvent can be performed. In addition, the temperature range of the washing liquid is, if it is water, it is in the range of 0°C to 20°C, preferably in the range of 0°C to 10°C. If it is an organic solvent containing water, it is in the range of -10°C to 20°C, preferably in the range of -5°C to 10°C.

[0120] As described above, the pH of the solution containing the salt of by-produced hydrochloric acid after the neutralization treatment, that is, the solution to be crystallized, is preferably pH 11 or higher.

[0121] In the present invention, the separated crystals are washed and then dried to obtain 2-amino-5-substituted-1,3,4- Thus, a simple production method is provided using inexpensive and easily prepared raw materials. Therefore, this method becomes an excellent production method that can be implemented industrially.

[0122] Example

[0123] Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

[0124] (Example 1)

[0125] Acetylhydrazine synthesis process

[0126] In a four-necked flask, 120.0g (2.517 moles) of 100% hydrazine hydrate was added, and 221.8g of ethyl acetate (1.05 equivalents / hydrazine hydrate) was added dropwise at room temperature. After the addition, the reaction solution was warmed to 77.0°C and reacted under reflux for 7 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 215.5g of acetic acid hydrazide concentrate (yield 93.5%). According to the analysis based on gas chromatography, the acetic acid hydrazide content in the concentrate was 77.0% by mass. In subsequent steps, the scale was adjusted so that the concentrate weight was 64.9g and used.

[0127] ·2-amino-5-methyl-1,3,4- Oxadiazole synthesis process

[0128] In a separable flask, 19.0 g of hydrocyanic acid (0.703 mol) was blown into 130.3 g of water and 28.7 g of hexane, and the mixture was cooled to -5°C. After cooling, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the blowing, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 46.8 g of a 48% aqueous sodium hydroxide solution (0.80 equivalents per cyanogen chloride) was added dropwise at a temperature between -5°C and 0°C over 1 hour to adjust the byproduct hydrochloric acid in the reaction solution to 0.20 equivalents per cyanogen chloride. After neutralizing the byproduct hydrochloric acid, 64.9 g of a 77.0% acetic hydrazide concentrate (0.96 equivalents per hydrocyanic acid) was added dropwise at a temperature between -5°C and 5°C over 40 minutes. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid remaining at the end of the reaction, i.e., the amount of hydrochloric acid produced as a by-product in step (A), was 0.20 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0129] Next, 77.9 g of 48% aqueous sodium hydroxide solution (1.33 equivalents / hydrocyanic acid) was added to a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was cooled and stirred at -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered out and washed with cold water to obtain 48.7 g of 2-amino-5-methyl-1,3,4- The product content was 99.7% by mass and the salt content was 0.2% by mass.

[0130] (Example 2)

[0131] In a separable flask, 19.0 g of hydrocyanic acid (0.703 mol) was blown into 130.3 g of water and 28.7 g of dichloromethane, and the mixture was cooled to -5°C. After cooling, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the blowing, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 46.8 g of 48% sodium hydroxide (0.80 equivalents per cyanogen chloride) was added dropwise at a temperature between -5°C and 0°C over 1 hour to adjust the by-product hydrochloric acid in the reaction solution to 0.20 equivalents per cyanogen chloride. After neutralizing the by-product hydrochloric acid, 64.9 g of a 77.0% acetic hydrazide concentrate (0.96 equivalents per hydrocyanic acid) prepared in the same manner as in Example 1 was added dropwise at a temperature between -5°C and 5°C over 40 minutes. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid produced as a by-product at the end of the reaction was 0.20 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0132] Next, 77.9 g of 48% aqueous sodium hydroxide solution (1.33 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was cooled and stirred at -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered out and washed with cold water to obtain 48.5 g of 2-amino-5-methyl-1,3,4- The product content was 99.6% by mass and the salt content was 0.3% by mass.

[0133] (Example 3)

[0134] In a separable flask, 19.0 g (0.703 mol) of hydrocyanic acid was blown into 130.3 g of water and 28.7 g of hexane, and the mixture was cooled to -5°C. After cooling, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the blowing, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 53.3 g of 48% sodium hydroxide (0.90 equivalents per cyanogen chloride) was added dropwise over 1 hour at a temperature between -5°C and 0°C to adjust the by-product hydrochloric acid in the reaction solution to 0.10 equivalents per cyanogen chloride. After neutralizing the by-product hydrochloric acid, 64.9 g of a 77.0% acetic hydrazide concentrate (0.96 equivalents per hydrocyanic acid) prepared in the same manner as in Example 1 was added dropwise over 40 minutes at a temperature between -5°C and 5°C. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid produced as a by-product at the end of the reaction was 0.10 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0135] Next, 72.0 g of 48% aqueous sodium hydroxide solution (1.23 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was cooled and stirred at -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered out and washed with cold water to obtain 47.2 g of 2-amino-5-methyl-1,3,4- The product content was 99.4% by mass and the salt content was 0.2% by mass.

[0136] (Example 4)

[0137] In a separable flask, 19.0 g (0.703 mol) of hydrocyanic acid was blown into 130.3 g of water and 28.7 g of hexane, and the mixture was cooled to -5°C. After cooling, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the blowing, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 41.0 g of 48% sodium hydroxide (0.70 equivalents per cyanogen chloride) was added dropwise at a temperature between -5°C and 0°C over 1 hour to adjust the by-product hydrochloric acid in the reaction solution to 0.30 equivalents per cyanogen chloride. After neutralizing the by-product hydrochloric acid, 64.9 g of a 77.0% acetic hydrazide concentrate (0.96 equivalents per hydrocyanic acid) prepared in the same manner as in Example 1 was added dropwise at a temperature between -5°C and 5°C over 40 minutes. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid produced as a by-product at the end of the reaction was 0.30 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0138] Next, 83.4 g of 48% aqueous sodium hydroxide solution (1.42 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was cooled and stirred at -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered out and washed with cold water to obtain 48.6 g of 2-amino-5-methyl-1,3,4- The product content was 99.5% by mass and the salt content was 0.2% by mass.

[0139] (Example 5)

[0140] In a separable flask, 19.0 g (0.703 mol) of hydrocyanic acid was blown into 130.3 g of water and 28.7 g of hexane, and the mixture was cooled to -5°C. After cooling, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the blowing, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 32.2 g of 48% sodium hydroxide (0.55 equivalents per cyanogen chloride) was added dropwise at a temperature between -5°C and 0°C over 1 hour to adjust the by-product hydrochloric acid in the reaction solution to 0.45 equivalents per cyanogen chloride. After neutralizing the by-product hydrochloric acid, 64.9 g of a 77.0% acetic hydrazide concentrate (0.96 equivalents per hydrocyanic acid) prepared in the same manner as in Example 1 was added dropwise at a temperature between -5°C and 5°C over 40 minutes. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid produced as a by-product at the end of the reaction was 0.45 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0141] Next, 92.5 g of 48% aqueous sodium hydroxide solution (1.58 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was cooled and stirred at -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered out and washed with cold water to obtain 42.5 g of 2-amino-5-methyl-1,3,4- The product content was 99.2% by mass and the salt content was 0.3% by mass.

[0142] (Example 6)

[0143] A separable flask was charged with 71.2 g (0.703 mol) of concentrated hydrochloric acid, 117.5 g of water, and 28.7 g of hexane and cooled to -5°C. After cooling, 125.7 g of a 27.8% aqueous sodium cyanide solution (0.703 mol) was added dropwise at a temperature between -5.0 and 5°C. Following the addition, 49.1 g of chlorine (0.985 equivalents per sodium cyanide) was blown into the reaction mixture over 3 hours at a temperature between -5 and 0°C. After the addition, the mixture was stirred at a temperature between -5 and 0°C for 40 minutes. Analysis of the reaction mixture by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 46.8 g of 48% sodium hydroxide (0.80 equivalents per cyanogen chloride) was added dropwise at a temperature between -5 and 0°C over 1 hour to adjust the by-produced hydrochloric acid in the reaction mixture to 0.20 equivalents per cyanogen chloride. After neutralizing the by-product hydrochloric acid, 64.9 g of a 77.0% acetic acid hydrazide concentrate (0.96 equivalents / sodium cyanide) prepared in the same manner as in Example 1 was added dropwise at a temperature of -5 to 5°C over 40 minutes. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid produced as a by-product at the end of the reaction was 0.20 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0144] Next, 77 g of 48% aqueous sodium hydroxide solution (1.33 equivalents / sodium cyanide) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was cooled and stirred at -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered out and washed with cold water to obtain 45.9 g of 2-amino-5-methyl-1,3,4- Oxadiazole (yield: 66.1% / sodium cyanide). Product content: 99.5% by mass, NaCl content: 0.3% by mass.

[0145] (Example 7)

[0146] Acetylhydrazine synthesis process

[0147] 120.0g (2.517 moles) of 100% hydrazine hydrate was loaded into a four-necked flask and 221.8g of ethyl acetate (1.05 equivalents / hydrazine hydrate) was added dropwise at room temperature. After the addition, the reaction solution was warmed to 77.0°C and reacted under reflux for 7 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 215.5g of acetohydrazide concentrate (yield was 93.5%). According to gas chromatography analysis, acetohydrazide content was 77.0% by mass. 162.5g of water was added to the obtained acetohydrazide concentrate and the content was modulated to 43.9% by mass. In subsequent steps, the scale was adjusted so that the liquid weight reached 120.6g for use.

[0148] ·2-amino-5-methyl-1,3,4- Oxadiazole synthesis process

[0149] In a separable flask, 20.1 g (0.745 mol) of hydrocyanic acid was blown into 83.6 g of water and 123.5 g of trichloroethylene, and the mixture was cooled to -5°C. After cooling, 51.9 g of chlorine (0.985 equivalents / hydrocyanic acid) was blown in at -5 to 0°C for 3 hours. After blowing, the mixture was stirred at -5 to 0°C for 40 minutes. When the reaction liquid was analyzed by gas chromatography, it was confirmed that 0.718 mol of cyanogen chloride was generated. After the reaction was completed, the organic layer was extracted into a four-necked flask. Next, 62.6 g of trichloroethylene was added to the aqueous layer, stirred for 15 minutes, allowed to stand, and the organic layer was extracted and mixed with the first organic layer. This operation was repeated 5 times. 120.6 g of 43.9% aqueous acetic hydrazide solution (0.96 equivalents / hydrocyanic acid) was added dropwise to the separated organic layer at -5 to 5°C for 40 minutes. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The hydrochloride of oxadiazole. The by-product hydrochloric acid at the end of the reaction was 0.19 equivalents relative to the cyanogen chloride used in the reaction. After the reaction was completed, 50.1 g of water was added, stirred for 15 minutes, allowed to stand for 15 minutes, and the organic layer was extracted and discarded.

[0150] Next, 93.1 g of 48% sodium hydroxide aqueous solution (1.50 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution was added dropwise to the sodium hydroxide aqueous solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The pH after the addition of 48% sodium hydroxide aqueous solution was 13. After neutralization, the mixture was cooled and stirred at a temperature of -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered and washed with cold water to obtain 51.7 g of 2-amino-5-methyl-1,3,4- The product content was 99.5% by mass and the salt content was 0.3% by mass.

[0151] (Example 8)

[0152] In a separable flask, 20.0 g of hydrocyanic acid (0.739 mol) was blown into 84.5 g of water and 125.5 g of dichloromethane, and the mixture was cooled to -5°C. After cooling, 51.6 g of chlorine (0.985 equivalents / hydrocyanic acid) was blown into the mixture over 3 hours at a temperature of -5 to 0°C. After blowing, the mixture was stirred for 40 minutes at a temperature of -5 to 0°C. When the reaction solution was analyzed by gas chromatography, it was confirmed that 0.728 mol of cyanogen chloride was generated. After the reaction was completed, the organic layer was extracted into a four-necked flask. Next, 62.7 g of dichloromethane was added to the aqueous layer, stirred for 15 minutes, allowed to stand, and the organic layer was extracted and mixed with the first organic layer. This operation was repeated twice. 120.6 g of a 43.9% aqueous solution of acetic hydrazide (0.96 equivalents / hydrocyanic acid) prepared in the same manner as in Example 7 was added dropwise to the separated organic layer at a temperature of -5 to 5°C for 40 minutes. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The hydrochloride of oxadiazole. The by-product hydrochloric acid at the end of the reaction was 0.43 equivalents relative to the cyanogen chloride used in the reaction. After the reaction was completed, 32.3 g of water was added, stirred for 15 minutes, allowed to stand for 15 minutes, and the organic layer was extracted and discarded.

[0153] Next, 98.5 g of 48% sodium hydroxide aqueous solution (1.60 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution was added to the sodium hydroxide aqueous solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The pH after the addition of 48% sodium hydroxide aqueous solution was 13. After neutralization, the mixture was cooled and stirred at a temperature of -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered and washed with cold water to obtain 46.1 g of 2-amino-5-methyl-1,3,4- The product content was 99.2% by mass and the salt content was 0.3% by mass.

[0154] (Example 9)

[0155] In a separable flask, 19.0 g (0.703 mol) of hydrocyanic acid was blown into 130.3 g of water and 28.7 g of hexane, and the mixture was cooled to -5°C. After cooling, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the blowing, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 46.8 g of a 48% aqueous sodium hydroxide solution (0.80 equivalents per cyanogen chloride) and 64.9 g of a 77.0% acetic acid hydrazide concentrate (0.96 equivalents per hydrocyanic acid) prepared in the same manner as in Example 1 were simultaneously added dropwise over 1 hour at a temperature between -5°C and 0°C. The by-product hydrochloric acid in the solution after the additions was adjusted to 0.20 equivalents per cyanogen chloride. After the addition was completed, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid remaining at the end of the reaction, i.e., the amount of hydrochloric acid produced as a by-product in step (A), was 0.20 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0156] Next, 77.9 g of 48% aqueous sodium hydroxide solution (1.33 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was cooled and stirred at -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered out and washed with cold water to obtain 48.0 g of 2-amino-5-methyl-1,3,4- The product content was 99.4% by mass and the salt content was 0.2% by mass.

[0157] (Example 10)

[0158] In a separable flask, 19.0 g (0.703 mol) of hydrocyanic acid was blown into 130.3 g of water and 28.7 g of hexane, and the mixture was cooled to -5°C. After cooling, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the blowing, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 64.9 g of a 77.0% acetic acid hydrazide concentrate (0.96 equivalents per hydrocyanic acid) prepared in the same manner as in Example 1 was added dropwise over 40 minutes at a temperature between -5°C and 5°C. Following this addition, 46.8 g of a 48% aqueous sodium hydroxide solution (0.80 equivalents per cyanogen chloride) was added dropwise over 1 hour at a temperature between -5°C and 0°C, and the by-product hydrochloric acid in the solution was adjusted to 0.20 equivalents per cyanogen chloride. After the addition was completed, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid remaining at the end of the reaction, i.e., the amount of hydrochloric acid produced as a by-product in step (A), was 0.20 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0159] Next, 77.9 g of 48% aqueous sodium hydroxide solution (1.33 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was cooled and stirred at -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered out and washed with cold water to obtain 47.1 g of 2-amino-5-methyl-1,3,4- The product content was 99.5% by mass and the salt content was 0.3% by mass.

[0160] (Example 11)

[0161] In a separable flask, 19.0 g (0.703 mol) of hydrocyanic acid was blown into 666.7 g of water and 28.7 g of hexane, and the mixture was cooled to -5°C. After cooling, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the blowing, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 46.8 g of 48% sodium hydroxide (0.80 equivalents per cyanogen chloride) was added dropwise at a temperature between -5°C and 0°C over 1 hour to adjust the by-product hydrochloric acid in the reaction solution to 0.20 equivalents per cyanogen chloride. After neutralizing the by-product hydrochloric acid, 64.9 g of a 77.0% acetic hydrazide concentrate (0.96 equivalents per hydrocyanic acid) prepared in the same manner as in Example 1 was added dropwise at a temperature between -5°C and 5°C over 40 minutes. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid produced as a by-product at the end of the reaction was 0.20 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0162] Next, 77.9 g of 48% aqueous sodium hydroxide solution (1.33 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was cooled and stirred at a temperature of 0 to 1°C for 1 hour. After stirring, the precipitated solid was filtered out and washed with cold water to obtain 38.0 g of 2-amino-5-methyl-1,3,4- Oxadiazole (yield: 54.7%), product content: 99.8% by mass, salt content: 0.1% by mass.

[0163] (Example 12)

[0164] In a separable flask, 19.0 g (0.703 mol) of hydrocyanic acid was blown into 130.3 g of water and 28.7 g of hexane, and the mixture was cooled to -5°C. After the addition, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the addition, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography confirmed the formation of 0.690 mol of cyanogen chloride. After confirming the completion of the reaction, 46.8 g of 48% sodium hydroxide (0.80 equivalents per cyanogen chloride) was added dropwise at a temperature between -5°C and 0°C over 1 hour to adjust the by-product hydrochloric acid in the reaction solution to 0.20 equivalents per cyanogen chloride. After neutralizing the by-product hydrochloric acid, 64.9 g of a 77.0% acetic hydrazide concentrate (0.96 equivalents per hydrocyanic acid) prepared in the same manner as in Example 1 was added dropwise over 40 minutes at a temperature between -5°C and 5°C. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid produced as a by-product at the end of the reaction was 0.20 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0165] Next, 77 g of 48% aqueous sodium hydroxide solution (1.33 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the aqueous sodium hydroxide solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% aqueous sodium hydroxide solution was 13. After neutralization, the mixture was stirred at a temperature of 32 to 35°C for 1 hour, the precipitated solid was filtered out, and washed with cold water to obtain 36.0 g of 2-amino-5-methyl-1,3,4- Oxadiazole (yield: 51.7% / hydrocyanic acid). Product content: 99.3% by mass, NaCl content: 0.2% by mass.

[0166] (Comparative Example 1)

[0167] In a separable flask, 19.0 g (0.703 mol) of hydrocyanic acid was blown into 130.3 g of water and 28.7 g of hexane, and the mixture was cooled to -5°C. After cooling, 49.1 g of chlorine (0.985 equivalents per hydrocyanic acid) was blown into the mixture over 3 hours at a temperature between -5°C and 0°C. After the blowing, the mixture was stirred at a temperature between -5°C and 0°C for 40 minutes. Analysis of the reaction solution by gas chromatography revealed the formation of 0.690 mol of cyanogen chloride. After the reaction was completed, 26.4 g of a 48% aqueous sodium hydroxide solution (0.45 equivalents per cyanogen chloride) was added dropwise over 1 hour at a temperature between -5°C and 0°C to adjust the byproduct hydrochloric acid in the reaction solution to 0.55 equivalents per cyanogen chloride. After neutralization of the byproduct hydrochloric acid, 64.9 g of a 77.0% acetic hydrazide concentrate (0.96 equivalents per hydrocyanic acid) prepared in the same manner as in Example 1 was added dropwise over 40 minutes at a temperature between -5°C and 5°C. After the addition, the reaction solution was heated to 30°C and stirred at 30°C for 2 hours to synthesize 2-amino-5-methyl-1,3,4- The amount of hydrochloric acid produced as a by-product at the end of the reaction was 0.55 equivalents relative to the amount of cyanogen chloride used in the reaction. After the reaction was completed, the mixture was allowed to stand for 15 minutes.

[0168] Next, 98.4 g of 48% sodium hydroxide aqueous solution (1.68 equivalents / hydrocyanic acid) was placed in a four-necked flask and stirred at room temperature. The aqueous layer of the reaction solution in the separable flask was added dropwise to the sodium hydroxide aqueous solution in the four-necked flask at a temperature of 10 to 40°C for neutralization. The remaining organic layer was separated and removed. The pH after the addition of 48% sodium hydroxide aqueous solution was 13. After neutralization, the mixture was cooled and stirred at -3 to 0°C for 1 hour. After stirring, the precipitated solid was filtered and washed with cold water to obtain 34.5 g of 2-amino-5-methyl-1,3,4-#imgpt92#oxadiazole (yield 49.5%) as white crystals. The product content was 99.4% by mass and the salt content was 0.1% by mass.

Claims

1. 2-amino-5-substituted-1,3,4- A method for producing oxadiazole comprises the following steps: Step (A) of preparing a cyanogen chloride solution from hydrogen cyanide and chlorine; Step (B) of adjusting the amount of by-produced hydrochloric acid produced together with cyanogen chloride in step (A) to be 0.5 equivalent or less relative to the generated cyanogen chloride; Step (C) is to react the carboxylic acid hydrazide represented by the general formula (1) with a cyanogen chloride solution to obtain a 2-amino-5-substituted-1,3,4- A solution of diazole hydrochloride, In formula (1), R is a hydrogen atom, a C1-C6 alkyl group, an aryl group, a 5-membered or 6-membered aromatic heterocyclic group, or an alkoxy group, and these groups may be substituted by a halogen atom or a C1-C4 alkyl group. In formula (2), R is a hydrogen atom, a C1-C6 alkyl group, an aryl group, a 5-membered or 6-membered aromatic heterocyclic group, or an alkoxy group, and these groups may be substituted by a halogen atom or a C1-C4 alkyl group; Step (D) of adding a base in an amount equivalent to or greater than the sum of the amount of cyanogen chloride in the cyanogen chloride solution used in step (C) and the amount of by-produced hydrochloric acid to the solution obtained in step (C); as well as Step (E) is to cool the solution containing the hydrochloride of the base obtained in step (D) and separate the precipitated crystals to obtain 2-amino-5-substituted-1,3,4- oxadiazole, In formula (3), R is a hydrogen atom, a C1-C6 alkyl group, an aryl group, a 5-membered or 6-membered aromatic heterocyclic group, or an alkoxy group, and these groups may be substituted by a halogen atom or a C1-C4 alkyl group.

2. The 2-amino-5-substituted-1,3,4- A method for producing oxadiazole, wherein The cyanogen chloride solution in step (A) is synthesized from chlorine and hydrogen cyanide in an equivalent amount or more relative to the chlorine.

3. The 2-amino-5-substituted-1,3,4- A method for producing oxadiazole, wherein Step (B) is a step of adding a base to the cyanogen chloride solution obtained in step (A) to prepare a cyanogen chloride solution in which the amount of by-produced hydrochloric acid is 0.5 equivalent or less relative to the generated cyanogen chloride, and the prepared cyanogen chloride solution is used in step (C).

4. The 2-amino-5-substituted-1,3,4- A method for producing oxadiazole, wherein Step (B) is a step of neutralizing the cyanogen chloride solution obtained in step (A) with a base in an organic solvent to prepare a cyanogen chloride solution in which the amount of by-produced hydrochloric acid is 0.5 equivalents or less relative to the generated cyanogen chloride, and the prepared cyanogen chloride solution is used in step (C).

5. The 2-amino-5-substituted-1,3,4- A method for producing oxadiazole, wherein Step (B) is a step of mixing the cyanogen chloride solution obtained in step (A), carboxylic acid hydrazide, and a base so that the amount of by-product hydrochloric acid present in the cyanogen chloride solution is 0.5 equivalents or less relative to the generated cyanogen chloride, and using the resulting mixed solution to carry out the reaction of step (C).

6. The 2-amino-5-substituted-1,3,4- A method for producing oxadiazole, wherein Step (B) is a step in which the cyanogen chloride solution obtained in step (A) and carboxylic acid hydrazide are mixed and then a base is added so that the amount of by-produced hydrochloric acid present in the cyanogen chloride solution is 0.5 equivalents or less relative to the generated cyanogen chloride. The reaction of step (C) is carried out using the resulting mixed solution.

7. The 2-amino-5-substituted-1,3,4- A method for producing oxadiazole, wherein Step (B) is a step of extracting cyanogen chloride from the cyanogen chloride solution obtained in step (A) using an organic solvent to prepare a cyanogen chloride solution in which the amount of by-produced hydrochloric acid is 0.5 equivalent or less relative to the generated cyanogen chloride. The prepared cyanogen chloride solution is used in step (C).

8. The 2-amino-5-substituted-1,3,4- A method for producing oxadiazole, wherein The concentration of the hydrochloride of the alkali in the solution in step (E) is 10% by mass or more.

9. The 2-amino-5-substituted-1,3,4- A method for producing oxadiazole, wherein In step (E), the temperature of the crystals of the separated target product is set to 30° C. or lower.

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