Method for producing 1,3,4-oxadiazole-2-amine compound

Abstract

The problem of the present invention is to provide a new method for producing a 1,3,4-oxadiazole-2-amine compound useful as a precursor of a heterocyclic amide compound useful as a herbicide. The solution is a production method, which is a production method of a 1,3,4-oxadiazole-2-amine compound, after obtaining a crude product containing the compound, adjusting the pH of the system containing the crude product to a specific range, and then performing a crystallization operation to obtain the 1,3,4-oxadiazole-2-amine compound as a target substance with high purity.

Description

Technical Field

[0001] The present invention relates to 1,3,4- A novel method for producing oxadiazole-2-amine compounds. Background Art

[0002] For example, Patent Document 1 discloses a heterocyclic amide compound useful as an active ingredient of a herbicide and 1,3,4- Oxadiazole-2-amine compounds. In addition, 1,3,4- Methods for producing oxadiazole-2-amine compounds are disclosed in, for example, Patent Document 2 and Non-Patent Documents 1 and 2.

[0003] Prior art literature

[0004] Patent Literature

[0005] Patent Document 1: International Publication No. 2014 / 192936

[0006] Patent Document 2: Japanese Patent Application Publication No. 2017-25054

[0007] Non-patent literature

[0008] Non-patent document 1: Journal of Surfactants and Detergents, 2014, Volume 17, Page 509

[0009] Non-patent document 2: Journal of Surfactants and Detergents (Journal of Surfactants and Detergents), 2016, Volume 19, Page 325 Summary of the invention

[0010] Problems to be solved by the invention

[0011] The present invention aims to provide a 1,3,4- A novel method for producing an oxadiazole-2-amine compound, in particular, a method for producing a target compound at a high purity.

[0012] Means for solving problems

[0013] The present inventors have conducted intensive studies to solve the above-mentioned problems and have found that the target 1,3,4-dihydro-1-nitropropene can be obtained with a high purity of more than 90% by performing a specific purification operation after obtaining a crude product by the reaction of a semicarbazide compound with a carboxylic acid compound or by the reaction of acetic hydrazide with a cyanogen halide compound. Specifically, when obtaining the target substance from a system containing the crude product by a crystallization operation, the pH of the system is adjusted to a specific range, for example, pH 9.0 to 10.0 or pH 8.0 to 10.0. The present invention was completed by obtaining oxadiazole-2-amine compounds.

[0014] That is, the present invention relates to the following [1] to [8].

[0015] [1]

[0016] A manufacturing method is a 1,3,4- A method for producing a 2-oxadiazole-2-amine compound,

[0017]

[0018] It includes the following steps:

[0019] The semicarbazide compound represented by formula (2) is reacted with 0.1 to 10 equivalents of at least one selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and phosphorus pentoxide, and a carboxylic acid compound represented by formula (3) relative to 1 equivalent of the semicarbazide compound represented by formula (2) to produce a 1,3,4- The process of producing a 2-oxadiazole-2-amine compound; and

[0020] After the above-mentioned generation step, a step of purifying the reaction product is performed.

[0021]

[0022] The purification step comprises the following steps: putting the mixture containing the reaction product into water to obtain a liquid containing the mixture; adjusting the pH of the obtained liquid containing the mixture to 9.0 to 10.0; and removing the 1,3,4- The stage of crystallization of the oxadiazole-2-amine compound.

[0023] [2]

[0024] The production method according to [1], wherein in the purification step, the pH is adjusted to 9.0 to 10.0 using an inorganic base.

[0025] 〔3〕

[0026] According to the production method described in [2], the above-mentioned inorganic base is selected from sodium hydroxide and potassium hydroxide.

[0027] [4]

[0028] According to the production method described in [3], the above-mentioned inorganic base is potassium hydroxide.

[0029] 〔5〕

[0030] According to any one of the manufacturing methods [1] to [4], the above 1, 3, 4- The process of the oxadiazole-2-amine compound is

[0031] A step of reacting 0.1 to 10 equivalents of phosphorus oxychloride and a carboxylic acid compound represented by the above formula (3) with respect to 1 equivalent of the semicarbazide compound represented by the above formula (2).

[0032] [6]

[0033] The method according to any one of [1] to [5], wherein the 1,3,4- The process of preparing oxadiazole-2-amine compounds.

[0034] 〔7〕

[0035] The production method according to [6], wherein the solvent is 1,2-dimethoxyethane.

[0036] [8]

[0037] The production method according to any one of [6] to [7], wherein the purification step includes the step of distilling off the solvent after the pH adjustment step.

[0038] In addition, the present invention relates to the following [9] to

[16] .

[0039] 〔9〕

[0040] A manufacturing method is a 1,3,4- A method for producing a 2-oxadiazole-2-amine compound,

[0041]

[0042] It includes the following steps:

[0043] The acetic acid hydrazide compound represented by formula (6) is reacted with the cyanogen halide compound represented by formula (7) to cyclize the acetic acid hydrazide compound represented by formula (6) to generate the 1,3,4- The process of producing a 2-oxadiazole-2-amine compound; and

[0044] After the above-mentioned generation step, a step of purifying the reaction product is performed.

[0045]

[0046] Hal-CN (7)

[0047] (In the formula, Hal represents a halogen atom.)

[0048] The purification step includes the following steps: adjusting the pH of the reaction product-containing liquid containing the reaction product to 8.0 to 10.0; and removing the 1,3,4- The stage of crystallization of the oxadiazole-2-amine compound.

[0049] 〔10〕

[0050] The production method according to [9], wherein in the purification step, the pH is adjusted to 8.0 to 10.0 using an inorganic base.

[0051]

[11]

[0052] According to the production method described in

[10] , the above-mentioned inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate.

[0053]

[12]

[0054] According to the production method described in

[11] , the above-mentioned inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

[0055] 〔13〕

[0056] The production method according to any one of [9] to

[12] , wherein in the cyanogen halide compound represented by formula (7), Hal represents a bromine atom.

[0057]

[14]

[0058] The production method according to any one of [9] to

[13] , wherein in the step of adjusting the pH to 8.0 to 10.0 in the purification step, insoluble matter is removed by filtration from the liquid containing the reaction product before the pH is adjusted.

[0059] 〔15〕

[0060] The method according to any one of [9] to

[14] , wherein the 1,3,4- The process of preparing oxadiazole-2-amine compounds.

[0061]

[16]

[0062] According to the production method described in

[15] , the above solvent is methanol.

[0063] Effects of the Invention

[0064] According to the present invention, it is possible to provide 1,3,4- A novel method for producing oxadiazole-2-amine compounds. DETAILED DESCRIPTION

[0065] 〔1,3,4- Method for producing oxadiazole-2-amine compound

[0066] The present invention uses a 1,3,4- The present invention relates to a method for producing a oxadiazole-2-amine compound.

[0067] The following details are given.

[0068] [Manufacturing method (1)]

[0069] The production method of the present invention is characterized in that a semicarbazide compound represented by formula (2) is reacted with a specific amount of a dehydrating agent and a carboxylic acid compound represented by formula (3) to generate a 1,3,4- The oxadiazole-2-amine compound is then subjected to a purification step of the reaction product.

[0070]

[0071] The reaction of the semicarbazide compound represented by formula (2) and the carboxylic acid compound represented by formula (3) can be carried out even without a solvent, but a solvent (also referred to as a reaction solvent) can be used. The above-mentioned solvent is not particularly limited as long as it is inactive to the reaction, and examples thereof include acetonitrile, 1,2-dimethoxyethane, 1,4-dimethoxyethane, Alkane, diethylene glycol dimethyl ether, methoxycyclopentane, tert-butyl methyl ether, toluene, 1,2-dichloroethane, n-heptane, etc., among which 1,2-dimethoxyethane and diethylene glycol dimethyl ether are preferred, and 1,2-dimethoxyethane is particularly suitable. These solvents can be used alone or in combination of two or more thereof. The amount of the solvent used (the total amount of the solvents when two or more solvents are mixed) can be 0.01 to 100 parts by mass relative to the semicarbazide compound shown in formula (2), preferably 0.1 to 50 parts by mass, more preferably 0.5 to 10 parts by mass, and further preferably 0.8 to 3 parts by mass.

[0072] In addition, the above-mentioned dehydrating agent can be at least one selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and phosphorus pentoxide, among which phosphorus oxychloride is suitable. In the present invention, the above-mentioned dehydrating agent is not used in a large excess amount such as a solvent amount (for example, more than 20 equivalents relative to the substrate), but is used in an amount of 0.1 to 10 equivalents relative to 1 equivalent of the semicarbazide compound represented by formula (2), preferably 0.5 equivalents to 5.0 equivalents, more preferably 1.0 equivalents to 3.0 equivalents, for example, it is suitable to use it in the range of 1.8 equivalents to 2.2 equivalents.

[0073] The reaction temperature can be set to any temperature from 0°C to the reflux temperature of the reaction mixture.

[0074] The reaction time also varies depending on the concentration of the reaction substrate and the reaction temperature, but can generally be set arbitrarily within the range of 5 minutes to 100 hours, specifically 5 minutes to 100 hours, preferably 10 minutes to 48 hours, more preferably 5 hours to 36 hours, and for example, can be within the range of 15 hours to 24 hours.

[0075] In the 1,3,4- After the formation of the oxadiazole-2-amine compound, a purification step of the reaction product is performed. This step is characterized by a structure that has not been previously described, including the following steps: a step of adding the mixture containing the reaction product obtained in the above step to water to obtain a liquid containing the mixture; a step of adjusting the pH of the obtained liquid containing the mixture to 9.0 to 10.0; a step of removing the 1,3,4- Crystallization of the oxadiazole-2-amine compound In this step, after adjusting the pH of the liquid containing the mixture including the reaction product to 9.0 to 10.0, a crystallization operation is performed to obtain the target substance with a high purity of even more than 90%.

[0076] In addition, compared with the case where the pH is adjusted to a slightly higher pH than 9.0 to 10.0 and crystallized, the 1,3,4- Oxadiazole-2-amine compounds.

[0077] More specifically, after the above reaction, the mixture containing the reaction product is first put into water to stop the reaction. The substance (i.e., mixture) obtained by the reaction of the oxadiazole-2-amine compound can be directly put into water, that is, in the above mixture, in addition to the reaction product: 1,3,4- In addition to the oxadiazole-2-amine compound, it also contains water generated by dehydration, possible residual raw material compounds (semicarbazide compound represented by formula (2), carboxylic acid compound represented by formula (3), dehydrating agent), and reaction solvent used when a solvent is used during the reaction, etc. By this operation, a liquid containing a mixture is obtained.

[0078] Furthermore, the mixture containing the reaction product may be added to water at a temperature of about room temperature to 50° C. after the generation step. The amount of water is not particularly limited as long as it is an amount sufficient to stop the reaction.

[0079] Furthermore, the pH of the liquid containing the mixture obtained by putting it into water is adjusted to 9.0-10.0. In addition, if the pH adjustment at this time is within the range of pH 9.0-10.0, the lower limit can be adjusted to pH 9.1 or more, pH 9.2 or more, pH 9.3 or more, pH 9.4 or more, or pH 9.5 or more. In addition, as an upper limit, it can be adjusted to pH 9.9 or less, pH 9.8 or less, pH 9.7 or less, or pH 9.6 or less, and the lower limit and the upper limit can be arbitrarily combined.

[0080] The liquid containing the mixture is a liquid showing acidity caused by the dehydrating agent, so the pH can be adjusted by, for example, adding an alkali or alkaline aqueous solution. As the alkali or alkaline aqueous solution, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, or an aqueous solution of the inorganic base can be used. In addition, depending on the circumstances, an organic base such as tert-butoxy potassium can also be used. Preferably, an aqueous solution of sodium hydroxide or potassium hydroxide can be mentioned, and more preferably, an aqueous solution of potassium hydroxide can be mentioned.

[0081] The amount of the alkali or alkaline aqueous solution to be added is not particularly limited as long as it is an amount that can adjust the pH to the target value.

[0082] Furthermore, from the liquid containing the mixture whose pH has been adjusted, the 1,3,4- The oxadiazole-2-amine compound is crystallized. The crystallization temperature is not particularly limited, but may be in the range of -10°C to 40°C, preferably in the range of -5°C to 20°C, for example, in the range of -5°C to 10°C.

[0083] In the case of cooling, the cooling rate is not particularly limited, but is usually 0.1°C / hour to 80°C / hour, preferably 1°C / hour to 60°C / hour, for example 10°C / hour to 30°C / hour, and can be changed to any cooling rate within the above range at any time.

[0084] The crystallization time is not particularly limited, but can be arbitrarily set within the range of 10 minutes to 24 hours, and is preferably 30 minutes to 12 hours, more preferably 30 minutes to 2 hours.

[0085] Examples of the method for precipitating crystals include a method of allowing the crystals to stand still and a method of causing the crystals to precipitate under stirring. Preferably, the method is carried out under stirring.

[0086] When a reaction solvent is used in the reaction of the semicarbazide compound represented by the formula (2) and the carboxylic acid compound represented by the formula (3), the reaction solvent may be removed before crystallization.

[0087] Specifically, after the above reaction, the mixture containing the reaction product is put into water to stop the reaction, and the pH of the liquid containing the mixture that exhibits acidity caused by the dehydrating agent is adjusted. The pH adjustment at this time can be implemented by adding an alkali or the alkaline aqueous solution as described above. In addition, the pH adjustment at this time is as long as it is about pH8-11, but in order to obtain the final target substance with good purity, it is expected to be adjusted to pH9-10. In addition, if the pH adjustment at this time is within the range of pH9.0-10.0, as a lower limit, it can be adjusted to pH9.1 or more, pH9.2 or more, pH9.3 or more, pH9.4 or more, or pH9.5 or more. In addition, as an upper limit, it can be adjusted to pH9.9 or less, pH9.8 or less, pH9.7 or less, or pH9.6 or less, and the lower limit and the upper limit can be arbitrarily combined. In addition, as the amount of the alkali or the alkaline aqueous solution added, as long as it is an amount that can be adjusted to the target pH, there is no particular limitation.

[0088] Thereafter, the reaction solvent is distilled off, but the water introduced to stop the reaction and the water derived from the alkaline aqueous solution may be distilled off together.

[0089] After the reaction solvent is distilled off, water is appropriately added to prepare a liquid containing the mixture (after the reaction solvent is distilled off), the pH of the liquid is adjusted to 9.0 to 10.0, and the subsequent crystallization operation is performed.

[0090] In order to improve the solubility of the residue after distillation in water and to improve the subsequent crystallization efficiency, each operation of adding water after distillation of the reaction solvent and adjusting the pH can be carried out at a temperature of about room temperature to 50°C.

[0091] The amount of water added after the reaction solvent is distilled off is not particularly limited, but 0.01 to 100 parts by mass can be used, preferably 0.1 to 50 parts by mass, more preferably 5 to 10 parts by mass, and even more preferably 9 to 11 parts by mass can be used, relative to the semicarbazide compound represented by formula (2).

[0092] In addition to the above purification step, the target compound can be isolated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, preparative liquid chromatography, etc.

[0093] [Manufacturing method (2)]

[0094] The production method of the present invention is also the following method, characterized in that an acetic acid hydrazide compound represented by the following formula (6) (hereinafter also described as acetic acid hydrazide) is reacted with a cyanogen halide compound represented by the following formula (7) to cyclize the 1,3,4- The oxadiazole-2-amine compound is then subjected to a purification step of the reaction product.

[0095]

[0096] In the above formula (7), Hal represents a halogen atom, for example, a chlorine atom, a bromine atom, or an iodine atom.

[0097] First, the acetic acid hydrazide compound represented by the above formula (6) is reacted with the cyanogen halide compound represented by the above formula (7) to cyclize the 1,3,4- Oxadiazole-2-amine compounds.

[0098] The reaction of the acetic acid hydrazide compound represented by formula (6) and the cyanogen halide compound represented by formula (7) can be carried out even without a solvent, but a solvent (also referred to as a reaction solvent) can be used. The above-mentioned solvent is not particularly limited as long as it is inactive to the reaction, and examples thereof include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, methanol, ethanol, 1-propanol, 2-propanol, ethylene glycol, propylene glycol, 1,2-dimethoxyethane, tert-butyl methyl ether, methoxycyclopentane, diethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dimethoxyethane, tert-butyl methyl ether, cyclopentane, diethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dimethoxyethane, tert-butyl methyl ether, cyclopentane, diethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dimethoxyethane, tert-butyl methyl ether, cyclopentane, diethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dimethylformamide ... Alkane, anisole, ethyl acetate, dichloromethane, 1,2-dichloroethane, n-hexane, n-heptane, toluene, xylene, water, etc. Preferably, tetrahydrofuran, acetonitrile, methanol, ethanol, 1-propanol, 2-propanol, water can be cited, among which methanol, ethanol, 1-propanol, 2-propanol are more preferred, and methanol is particularly suitable. These solvents can be used alone or in combination of two or more thereof. The amount of the solvent used (the total amount of the solvents when two or more solvents are used in combination) can be 0.01 to 100 parts by mass relative to the acetic acid hydrazide compound shown in formula (6), preferably 0.1 to 50 parts by mass, and more preferably 5 to 15 parts by mass.

[0099] The reaction temperature can be set to any temperature from -60°C to the reflux temperature of the reaction mixture, preferably -60°C to 30°C, and more preferably at 0°C or lower.

[0100] The reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but can generally be set arbitrarily within the range of 5 minutes to 100 hours, specifically 5 minutes to 100 hours, preferably 10 minutes to 48 hours, more preferably 1 hour to 36 hours, and even more preferably 3 hours to 24 hours.

[0101] The reaction of the acetic acid hydrazide compound represented by formula (6) with the cyanogen halide compound represented by formula (7) can be carried out by adding a base as needed. For example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, etc. can be used, among which sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate is preferred, and sodium hydroxide, sodium carbonate or potassium carbonate is particularly suitable.

[0102] In the 1,3,4- After the formation of the oxadiazole-2-amine compound, a purification step of the reaction product is performed.

[0103] This process is characterized by including the following steps, which are not conventionally used, including: a step of adjusting the pH of the reaction product-containing liquid obtained in the above step to 8.0 to 10.0; and removing the 1,3,4- Stage of crystallization of the oxadiazole-2-amine compound In this step, by adjusting the pH of the liquid containing the reaction product to 8.0 to 10.0 and then performing a crystallization operation, the target substance can be obtained at a high purity of even more than 90%.

[0104] In addition, compared with the case where the pH was adjusted to a slightly higher pH than 8.0 to 10.0 and crystallized, the 1,3,4- Oxadiazole-2-amine compounds.

[0105] More specifically, after the above reaction, the pH of the liquid containing the reaction product (liquid containing the reaction product) is adjusted.

[0106] When a reaction solvent is used in the reaction of the acetic acid hydrazide compound represented by the above formula (6) and the cyanogen halide compound represented by the above formula (7), the liquid after the reaction can be used as a liquid containing a reaction product for pH adjustment.

[0107] When the reaction of the acetic acid hydrazide compound represented by the above formula (6) and the cyanogen halide compound represented by the formula (7) is carried out in the absence of a solvent, water may be appropriately added to the obtained reaction product to prepare a liquid containing the reaction product for pH adjustment.

[0108] In addition, when the liquid after the reaction of the acetic acid hydrazide compound represented by the above formula (6) and the cyanogen halide compound represented by the above formula (7) is used directly as the liquid containing the reaction product, it is preferred to filter out the insoluble matter (solid) from the liquid containing the reaction product before subjecting it to pH adjustment. That is, it is preferred to carry out the process of generating the 1,3,4- The material obtained by the reaction of the oxadiazole-2-amine compound is filtered to remove the insoluble matter. The temperature during filtration (the temperature of the liquid containing the reaction product) is not particularly limited, and can be set to any temperature of -10°C to 50°C. The liquid containing the reaction product after the insoluble matter (solid) is removed by filtration can be used for pH adjustment described below.

[0109] Furthermore, when a reaction solvent is used in the reaction of the acetic acid hydrazide compound represented by the above formula (6) and the cyanogen halide compound represented by the formula (7), the reaction solvent can be removed before pH adjustment. Specifically, the reaction solvent can be removed from the liquid containing the reaction product, preferably from the liquid containing the reaction product by filtering and removing the insoluble matter (solid) using the above steps, and then distilling the reaction solvent from the liquid containing the reaction product.

[0110] After the reaction solvent is distilled off, water may be appropriately added to prepare a liquid containing the reaction product (after the reaction solvent is distilled off), and the liquid may be subjected to the subsequent pH adjustment.

[0111] The amount of water added after the reaction solvent is distilled off is not particularly limited, but 0.01 to 100 parts by mass can be used, preferably 0.1 to 50 parts by mass, more preferably 1 to 10 parts by mass, and even more preferably 2 to 3 parts by mass can be used, based on the acetic acid hydrazide compound represented by the above formula (6).

[0112] In addition, when the reaction of the acetic acid hydrazide compound represented by the above formula (6) and the cyanogen halide compound represented by the formula (7) is carried out under solvent-free conditions, the above reaction solvent is added to the reaction product obtained after the above reaction, the insoluble matter is filtered out from the liquid, and the reaction solvent is further distilled off from the liquid from which the insoluble matter has been filtered out, and then water is appropriately added thereto to prepare a liquid containing the reaction product for pH adjustment.

[0113] The amount of water added after the reaction solvent is distilled off is not particularly limited, but 0.01 to 100 parts by mass, preferably 0.1 to 50 parts by mass, more preferably 1 to 10 parts by mass, and even more preferably 2 to 3 parts by mass can be used relative to the acetic acid hydrazide compound represented by the above formula (6).

[0114] When the pH of the liquid containing the reaction product is adjusted to 8.0-10.0, it is sufficient to add, for example, an alkali or alkaline aqueous solution. Inorganic alkalis such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, or aqueous solutions of the inorganic alkali can be used, wherein an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate is preferred, and an aqueous solution of sodium hydroxide, sodium carbonate, or potassium carbonate is particularly suitable. In addition, as the amount of the alkali or alkaline aqueous solution added, as long as it is an amount that can be adjusted to the target pH, there is no particular limitation. In addition, in the pH adjustment, if it is within the range of pH 8.0-10.0, as the lower limit, it can be adjusted to pH 8.1 or more, pH 8.2 or more, pH 8.3 or more, pH 8.4 or more, pH 8.5 or more, pH 8.6 or more, pH 8.7 or more, pH 8.8 or more, pH 8.9 or more, or 9.0 or more. The upper limit may be adjusted to pH 9.9 or less, pH 9.8 or less, pH 9.7 or less, pH 9.6 or less, pH 9.5 or less, pH 9.4 or less, pH 9.3 or less, pH 9.2 or less, or pH 9.1 or less, and the lower limit and the upper limit may be arbitrarily combined.

[0115] In order to improve the solubility of the residue after distillation in water and to improve the subsequent crystallization efficiency, the addition of water after distillation of the reaction solvent and the pH adjustment of the liquid containing the reaction product can be carried out at a temperature of about room temperature to 50°C.

[0116] Furthermore, the 1,3,4- The oxadiazole-2-amine compound is crystallized. The crystallization temperature is not particularly limited, and may be in the range of -10°C to 40°C, preferably in the range of -5°C to 20°C, for example, in the range of -5°C to 10°C.

[0117] In the case of cooling, the cooling rate is not particularly limited, and is usually 0.1°C / hour to 80°C / hour, preferably 1°C / hour to 60°C / hour, and more preferably 10°C / hour to 30°C / hour. The cooling rate can be changed to any cooling rate within the above range at any time.

[0118] The crystallization time is not particularly limited, but is usually within the scope of 10 minutes to 24 hours, preferably within the scope of 1 hour to 20 hours, and can be set arbitrarily within the above range at any time. As the method for crystallization, the method for carrying out by standing, the method for carrying out under agitation, etc. can be enumerated, preferably carrying out under agitation.

[0119] In addition to the above purification step, the target compound can be isolated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, preparative liquid chromatography, etc.

[0120] <Reference manufacturing method>

[0121] The production method of the present invention is targeted at 1,3,4- The oxadiazole-2-amine compound can also be produced by the production method shown below (hereinafter referred to as a reference production method).

[0122] The reference production method is a method in which a thiosemicarbazide compound represented by the following formula (4) is reacted with a dialkylsulfuric acid compound represented by the following formula (5), and then treated with an alkali to cyclize the compound to produce a 1,3,4- The oxadiazole-2-amine compound is then subjected to a purification step of the reaction product.

[0123]

[0124] In the above formula (5), R 1 The alkyl group has 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl, and isopropyl.

[0125] The reaction of the thiosemicarbazide compound represented by formula (4) and the dialkylsulfuric acid compound represented by formula (5) can be carried out even without a solvent, but a solvent can be used. The above-mentioned solvent is not particularly limited as long as it is inactive to the reaction, and examples thereof include N,N-dimethylformamide, acetonitrile, acetone, methanol, ethanol, ethyl acetate, 1,2-dichloroethane, etc. These solvents can be used alone or in combination of two or more thereof.

[0126] The reaction temperature can be set to any temperature from -60°C to the reflux temperature of the reaction mixture.

[0127] The reaction time mentioned above varies depending on the concentration of the reaction substrate and the reaction temperature, but can usually be arbitrarily set within the range of 5 minutes to 100 hours.

[0128] After the thiosemicarbazide compound represented by the formula (4) is reacted with the dialkylsulfuric acid compound represented by the formula (5), a cyclization reaction is carried out by treating with an alkali to generate a 1,3,4- Oxadiazole-2-amine compounds.

[0129] The alkali treatment can be carried out by adding a base to the reaction mixture after the reaction. Examples of the alkali include sodium hydroxide, potassium hydroxide, sodium methoxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, 4-(dimethylamino)pyridine, etc., but are not limited thereto. These alkalis can be added to the system as, for example, alkaline aqueous solutions. In addition, the amount of the alkali used is not particularly limited, but can be, for example, 0.001 to 50 equivalents relative to 1 equivalent of the thiosemicarbazide compound represented by formula (4).

[0130] The temperature of the alkali treatment can be set to any temperature from -60°C to the reflux temperature of the reaction mixture.

[0131] The time of the alkali treatment varies depending on the concentration of the reaction substrate and the temperature of the alkali treatment, but can usually be arbitrarily set within the range of 5 minutes to 100 hours.

[0132] In the 1,3,4- After the formation of the oxadiazole-2-amine compound, a purification step of the reaction product is performed. This step is to filter out insoluble matter from the reaction mixture containing the reaction product obtained in the above step, then concentrate the obtained filtrate, and then separate the 1,3,4- A step of crystallizing the oxadiazole-2-amine compound.

[0133] More specifically, after the above reaction, the reaction mixture is first filtered to remove insoluble matter. The temperature during filtration (temperature of the reaction mixture) is not particularly limited, and can be set to any temperature between -10°C and 50°C.

[0134] Next, the obtained filtrate is concentrated to remove the solvent contained in the obtained filtrate. The concentration is preferably carried out under reduced pressure.

[0135] Then, the 1,3,4- The oxadiazole-2-amine compound is crystallized. The crystallization temperature is not particularly limited, but can be in the range of -10°C to 40°C, preferably in the range of -5°C to 20°C, for example, in the range of -5°C to 10°C. The crystallization time is not particularly limited, but can be arbitrarily set in the range of 10 minutes to 24 hours. As a method for crystallizing, a method by standing, a method under stirring, etc. can be cited, but it is preferably carried out under stirring.

[0136] In addition to the above purification steps, the target compound can be isolated and purified by any purification method such as recrystallization, column chromatography, thin layer chromatography, preparative liquid chromatography, etc.

[0137] The thiosemicarbazide compound represented by the above formula (4) is obtained by reacting thiosemicarbazide with a carboxylic acid compound represented by the formula (3).

[0138]

[0139] The present reaction can be carried out without a solvent, but a solvent may be used. The solvent is not particularly limited as long as it is inactive to the reaction, and examples thereof include water, acetonitrile, methanol, ethanol, acetone, tetrahydrofuran, 1,4-dihydrofuran, Alkanes, etc., may be used alone or in combination of two or more thereof.

[0140] The reaction temperature can be set to any temperature between -60°C and the reflux temperature of the reaction mixture, and the reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, but can usually be set to any temperature within the range of 5 minutes to 100 hours.

[0141] Example

[0142] Hereinafter, the present invention will be described in further detail with reference to Examples, but the present invention is not limited to these Examples.

[0143] [Example 1] 5-methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0144] To a mixed solution of 20.00 g (179.32 mmol) of semicarbazide hydrochloride, 11.85 g (197.34 mmol) of acetic acid and 30.0 g of 1,2-dimethoxyethane, 55.00 g (358.66 mmol) of phosphorus oxychloride was added at 50°C over 40 minutes. After the addition was completed, the reaction mixture was stirred at 50°C for 22 hours. After the stirring was completed, the reaction mixture was added to 100.00 g of water. After the addition was completed, 126.00 g of a 50% by mass aqueous solution of potassium hydroxide was added to the reaction mixture under ice cooling to adjust the pH to 9.2. After the addition was completed, 110.00 g of the solvent (1,2-dimethoxyethane and water) in the reaction mixture was distilled off at 40°C under reduced pressure. After the distillation was completed, 210.00 g of water was added to the obtained slurry at 40°C to prepare a uniform solution (hereinafter referred to as solution A1). The pH of solution A1 was 8.4.

[0145] 25.00 g of solution A1 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 710 mg of the target substance as a white solid (quantitative purity 77.4%).

[0146] [Example 2]

[0147] Solution A1 was obtained by the same procedure as in Example 1, and 610 mg of a 50 mass % aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 8.7 (hereinafter referred to as solution A2).

[0148] 25.00 g of solution A2 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 700 mg of the target substance as a white solid (quantitative purity 72.9%).

[0149] [Example 3]

[0150] Solution A2 was obtained by the same procedure as in Example 2, and 1.02 g of a 50 mass % aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 9.0 (hereinafter referred to as solution A3).

[0151] 25.00 g of solution A3 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 685 mg of the target substance as a white solid (quantitative purity 91.8%).

[0152] [Example 4]

[0153] Solution A3 was obtained by the same procedure as in Example 3, and 1.99 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 9.4 (hereinafter referred to as solution A4).

[0154] 25.00 g of solution A4 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 600 mg of the target substance as a white solid (quantitative purity 98.8%).

[0155] [Example 5]

[0156] Solution A4 was obtained by the same procedure as in Example 4, and 5.23 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 10.0 (hereinafter referred to as solution A5).

[0157] 25.00 g of solution A5 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 620 mg of the target substance as a white solid (quantitative purity 97.2%).

[0158] [Example 6]

[0159] Solution A5 was obtained by the same procedure as in Example 5, and 1.30 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 10.2 (hereinafter referred to as solution A6).

[0160] 25.00 g of solution A6 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 680 mg of the target substance as a white solid (quantitative purity 81.3%).

[0161] [Example 7]

[0162] Solution A6 was obtained by the same procedure as in Example 6, and 2.11 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 10.5 (hereinafter referred to as solution A7).

[0163] 25.00 g of solution A7 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 690 mg of the target substance as a white solid (quantitative purity 78.0%).

[0164] In addition, the quantitative analysis conditions using HPLC for the target substances obtained in [Example 1] to [Example 7], and the later-described [Example 8] to [Example 14], [Example 15] to [Example 20], [Example 21] to [Example 26], [Example 27] to [Example 33], [Example 34] to [Example 41], [Example 42] to [Example 49], [Example 50] to [Example 56], [Example 57] to [Example 62], and [Example 63] to [Example 69] are as follows.

[0165] Column: Inertsil Amide 5 μm, 4.6 mm × 250 mm, manufactured by Seiko Co., Ltd.

[0166] Eluent: acetonitrile / 0.1 volume % formic acid aqueous solution = 9 / 1 (volume ratio)

[0167] Flow rate: 1ml / min

[0168] Column temperature: 40°C

[0169] Detection wavelength: 210nm

[0170] Internal standard substance:

[0171] Examples 1-20: 2-Chlorotoluene

[0172] Examples 21 to 69: 4-tertbutyl biphenyl (4-tertbutyl biphenyl)

[0173] [Table 1]

[0174] Table 1

[0175]

[0176] [Example 8] 5-methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0177] To a mixed solution of 20.00 g (179.32 mmol) of semicarbazide hydrochloride, 11.85 g (197.34 mmol) of acetic acid and 30.0 g of 1,2-dimethoxyethane, 49.50 g (322.79 mmol) of phosphorus oxychloride was added at 50°C over 45 minutes. After the addition was completed, the reaction mixture was stirred at 50°C for 23 hours. After the stirring was completed, the reaction mixture was added to 100.00 g of water. After the addition was completed, 112.60 g of a 50% by mass aqueous solution of potassium hydroxide was added to the reaction mixture under ice cooling to adjust the pH to 9.5. After the addition was completed, 84.86 g of the solvent (1,2-dimethoxyethane and water) in the reaction mixture was distilled off under reduced pressure at 40°C. After the distillation was completed, 184.50 g of water and 434 mg of a 50% by mass aqueous solution of potassium hydroxide were added to the obtained slurry at 40°C to prepare a uniform solution (hereinafter referred to as solution B1). The pH of solution B1 was 8.4.

[0178] 25.00 g of solution B1 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 595 mg of the target substance as a white solid (quantitative purity 84.3%).

[0179] [Example 9]

[0180] Solution B1 was obtained by the same procedure as in Example 8, and 275 mg of a 50 mass % aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 8.6 (hereinafter referred to as solution B2).

[0181] 25.00 g of solution B2 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 590 mg of the target substance as a white solid (quantitative purity 83.2%).

[0182] [Example 10]

[0183] Solution B2 was obtained by the same procedure as in Example 9, and 931 mg of a 50 mass % aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 9.0 (hereinafter referred to as solution B3).

[0184] 25.00 g of solution B3 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 590 mg of the target substance as a white solid (quantitative purity 91.1%).

[0185] [Example 11]

[0186] Solution B3 was obtained by the same procedure as in Example 10, and 1.37 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 9.4 (hereinafter referred to as solution B4).

[0187] 25.00 g of solution B4 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 580 mg of the target substance as a white solid (quantitative purity 98.5%).

[0188] [Example 12]

[0189] Solution B4 was obtained by the same procedure as in Example 11, and 3.35 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 10.0 (hereinafter referred to as solution B5).

[0190] 25.00 g of solution B5 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 625 mg of the target substance as a white solid (quantitative purity 92.9%).

[0191] [Example 13]

[0192] Solution B5 was obtained by the same procedure as in Example 12, and 1.70 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 10.2 (hereinafter referred to as solution B6).

[0193] 25.00 g of solution B6 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 650 mg of the target substance as a white solid (quantitative purity 80.8%).

[0194] [Example 14]

[0195] Solution B6 was obtained by the same procedure as in Example 13, and 1.15 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 10.5 (hereinafter referred to as solution B7).

[0196] 25.00 g of solution B7 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 613 mg of the target substance as a white solid (quantitative purity 83.9%).

[0197] [Table 2]

[0198] Table 2

[0199]

[0200] [Example 15] 5-methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0201] To a mixed solution of 20.00 g (179.32 mmol) of semicarbazide hydrochloride, 11.85 g (197.34 mmol) of acetic acid and 30.0 g of 1,2-dimethoxyethane, 60.50 g (394.52 mmol) of phosphorus oxychloride was added at 50°C over 45 minutes. After the addition was completed, the reaction mixture was stirred at 50°C for 23 hours. After the stirring was completed, the reaction mixture was added to 100.00 g of water. After the addition was completed, 185.00 g of a 50% by mass aqueous solution of potassium hydroxide was added to the reaction mixture under ice cooling to adjust the pH to 9.9. After the addition was completed, 80.25 g of the solvent (1,2-dimethoxyethane and water) in the reaction mixture was distilled off at 40°C under reduced pressure. After the distillation was completed, 180.25 g of water was added to the obtained slurry at 40°C to prepare a uniform solution (hereinafter referred to as solution C1). The pH of solution C1 was 8.6.

[0202] After stirring 125.00 g of solution C at 50°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 443 mg of the target substance as a white solid (quantitative purity 84.6%).

[0203] [Example 16]

[0204] Solution C1 was obtained by the same procedure as in Example 15, and 370 mg of a 50 mass % aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 9.0 (hereinafter referred to as solution C2).

[0205] 25.00 g of solution C2 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 532 mg of the target substance as a white solid (quantitative purity 92.6%).

[0206] [Example 17]

[0207] Solution C2 was obtained by the same procedure as in Example 16, and 4.37 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 9.5 (hereinafter referred to as solution C3).

[0208] 25.00 g of solution C3 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 512 mg of the target substance as a white solid (quantitative purity 92.6%).

[0209] [Example 18]

[0210] Solution C3 was obtained by the same procedure as in Example 17, and 7.50 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 10.0 (hereinafter referred to as solution C4).

[0211] 25.00 g of solution C4 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 443 mg of the target substance as a white solid (quantitative purity 98.1%).

[0212] [Example 19]

[0213] Solution C4 was obtained by the same procedure as in Example 18, and 3.66 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 10.2 (hereinafter referred to as solution C5).

[0214] 25.00 g of solution C5 was stirred at 50°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 577 mg of the target substance as a white solid (quantitative purity 79.0%).

[0215] [Example 20]

[0216] Solution C5 was obtained by the same procedure as in Example 19, and 4.53 g of a 50% by mass aqueous solution of potassium hydroxide was added thereto at 40° C. to prepare a uniform solution having a pH of 10.6 (hereinafter referred to as solution C6).

[0217] After stirring 625.00 g of solution C at 50°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 583 mg of the target substance as a white solid (quantitative purity 81.0%).

[0218] [Table 3]

[0219] Table 3

[0220]

[0221] The examples shown in Tables 1 to 3 are obtained by reacting a dehydrating agent with a carboxylic acid compound represented by formula (3) and a semicarbazide compound represented by formula (2) to produce a 1,3,4- After adding the oxadiazole-2-amine compound, the pH of the system was adjusted to perform a crystallization operation.

[0222] As shown in Table 1 (2 equivalents of phosphorus oxychloride as a dehydrating agent relative to 1 equivalent of the semicarbazide compound), by adjusting the pH of the reaction mixture to 9.0 to 10.0 and performing subsequent crystallization operations (Examples 3 to 5), the target substance can be obtained with a quantitative purity exceeding 90%.

[0223] On the other hand, when the pH of the reaction mixture was set to less than 9.0 or exceeded 10.0 and then a crystallization operation was performed (Examples 1 and 2, and Examples 6 and 7), the quantitative purity of the target substance was limited to approximately 70 to 80%.

[0224] In addition, as shown in Table 2 (phosphorus oxychloride as a dehydrating agent was changed to 1.8 equivalents relative to 1 equivalent of the semicarbazide compound) and Table 3 (phosphorus oxychloride as a dehydrating agent was changed to 2.2 equivalents relative to 1 equivalent of the semicarbazide compound), even when the production conditions of the target substance (the amount of the dehydrating agent used, etc.) were changed, it was confirmed that the target substance was obtained with a quantitative purity exceeding 90% by adjusting the pH of the reaction mixture to 9.0 to 10.0 and then performing the subsequent crystallization operation (Examples 10 to 12, Examples 16 to 18). Similarly, when the pH of the reaction mixture was lower than 9 (Examples 8 to 9, Example 15) or the pH was higher than 10 (Examples 13 to 14, Examples 19 to 20) and then performing the subsequent crystallization operation, the quantitative purity of the target substance was limited to less than 85% at most.

[0225] Thus, the semicarbazide compound is reacted with a dehydrating agent and a carboxylic acid compound to produce a 1,3,4- After the oxadiazole-2-amine compound was added, the resulting reaction mixture was poured into water, and then the pH of the reaction mixture was adjusted to 9.0 to 10.0 and crystallized. It was confirmed that the 1,3,4-oxadiazole represented by formula (1) was obtained with a quantitative purity that can be said to be specific, compared with the case where the pH was adjusted to slightly exceed the above-defined range and crystallization was carried out. Oxadiazole-2-amine compounds.

[0226] [Example 21] 5-methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0227] To a solution of 15.00 g (202.48 mmol) of acetic hydrazide in 83.14 g of methanol, a solution of 22.30 g (210.58 mmol) of cyanogen bromide in 52.98 g of methanol was added at -10°C over 17 minutes. After the addition was completed, the reaction mixture was stirred at room temperature (25°C) for 1 hour, and after the reaction mixture was cooled to 0°C, 14.55 g of potassium carbonate was added. After the addition was completed, the reaction mixture was heated to room temperature and stirred for 200 minutes. After the stirring was completed, the reaction mixture was filtered under reduced pressure, and the filtrate was removed by reduced pressure distillation at 40°C and dried and solidified. After adding 45.00 g of water to the residue, 13.61 g of a 50% by mass aqueous solution of potassium carbonate was added to prepare a uniform solution of pH 7.0 (hereinafter referred to as solution D1).

[0228] Solution D1 (10.07 g) was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.05 g of the target substance as a yellow solid (quantitative purity 82.2%).

[0229] [Example 22]

[0230] Solution D1 was obtained by the same procedure as in Example 21, and 1.3 g of a 50 mass % aqueous solution of potassium carbonate was added thereto at 60° C. to prepare a uniform solution having a pH of 7.6 (hereinafter referred to as solution D2).

[0231] Solution D2 (8.61 g) was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 888 mg of the target substance as a light yellow solid (quantitative purity 82.3%).

[0232] [Example 23]

[0233] Solution D2 was obtained by the same procedure as in Example 22, to which 0.5 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 8.0 (hereinafter referred to as solution D3).

[0234] 9.76 g of solution D3 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.01 g of the target substance as a white solid (quantitative purity 92.0%).

[0235] [Example 24]

[0236] Solution D3 was obtained by the same procedure as in Example 23, and 1.0 g of a 50% by mass aqueous solution of potassium carbonate was added thereto at 60° C. to prepare a uniform solution having a pH of 9.4 (hereinafter referred to as solution D4).

[0237] Solution D4 (10.50 g) was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.08 g of the target substance as a white solid (quantitative purity 93.8%).

[0238] [Example 25]

[0239] Solution D4 was obtained by the same procedure as in Example 24, and 1.1 g of a 50% by mass aqueous solution of potassium carbonate was added thereto at 60° C. to prepare a uniform solution having a pH of 9.8 (hereinafter referred to as solution D5).

[0240] 8.28 g of solution D5 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 896 mg of the target substance as a white solid (quantitative purity 93.4%).

[0241] [Example 26]

[0242] Solution D5 was obtained by the same procedure as in Example 25, and 2.60 g of a 50% by mass aqueous solution of potassium carbonate was added thereto at 60° C. to prepare a uniform solution having a pH of 10.2 (hereinafter referred to as solution D6).

[0243] Solution D68.53 g was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 859 mg of the target substance as a light yellow solid (quantitative purity 75.6%).

[0244] [Table 4]

[0245] Table 4

[0246]

[0247] [Example 27] 5-methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0248] To a solution of 15.00 g (202.48 mmol) of acetic hydrazide in 83.14 g of methanol, a solution of 22.30 g (210.58 mmol) of cyanogen bromide in 52.98 g of methanol was added at -9.6°C over 18 minutes. After the addition was completed, the reaction mixture was stirred at room temperature (25°C) for 1 hour, and after the reaction mixture was cooled to 0°C, 8.4 g of sodium hydroxide was added. After the addition was completed, the reaction mixture was heated to room temperature and stirred for 3 hours. After the stirring was completed, the reaction mixture was filtered under reduced pressure, and the filtrate was removed by reduced pressure distillation at 40°C and dried and solidified. After adding 45.00 g of water to the residue, 1.0 g of a 48% by mass aqueous solution of sodium hydroxide was added to prepare a uniform solution of pH 7.4 (hereinafter referred to as solution E1).

[0249] After stirring 18.00 g of solution E at 60°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.09 g of the target substance as a light yellow solid (quantitative purity 76.9%).

[0250] [Example 28]

[0251] Solution E1 was obtained by the same procedure as in Example 27, and 0.15 g of a 48% by mass aqueous solution of sodium hydroxide was added thereto at 60° C. to prepare a uniform solution having a pH of 7.7 (hereinafter referred to as solution E2).

[0252] 6.40 g of solution E2 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 862 mg of the target substance as a white solid (quantitative purity 80.3%).

[0253] [Example 29]

[0254] Solution E2 was obtained by the same procedure as in Example 28, to which 0.26 g of a 48 mass % aqueous solution of sodium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 8.4 (hereinafter referred to as solution E3).

[0255] 7.00 g of solution E3 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 710 mg of the target substance as a white solid (quantitative purity 94.5%).

[0256] [Example 30]

[0257] Solution E3 was obtained by the same procedure as in Example 29, to which 0.26 g of a 48% by mass aqueous solution of sodium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 9.0 (hereinafter referred to as solution E4).

[0258] 6.75 g of solution E4 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 718 mg of the target substance as a white solid (quantitative purity 94.1%).

[0259] [Example 31]

[0260] Solution E4 was obtained by the same procedure as in Example 30, to which 0.30 g of a 48% by mass aqueous solution of sodium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 9.5 (hereinafter referred to as solution E5).

[0261] 9.00 g of solution E5 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 989 mg of the target substance as a white solid (quantitative purity 97.4%).

[0262] [Example 32]

[0263] Solution E5 was obtained by the same procedure as in Example 31, to which 0.25 g of a 48% by mass aqueous solution of sodium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 9.7 (hereinafter referred to as solution E6).

[0264] 11.2 g of solution E6 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.34 g of the target substance as a white solid (quantitative purity 94.3%).

[0265] [Example 33]

[0266] Solution E6 was obtained by the same procedure as in Example 32, to which 0.30 g of a 48% by mass aqueous solution of sodium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 10.3 (hereinafter referred to as solution E7).

[0267] Solution E7 (11.6 g) was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.90 g of the target substance as an orange solid (quantitative purity 62.7%).

[0268] [Table 5]

[0269] Table 5

[0270]

[0271] [Example 34] 5-methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0272] To a solution of 15.00 g (202.48 mmol) of acetic hydrazide in 83.14 g of methanol, a solution of 22.30 g (210.58 mmol) of cyanogen bromide in 52.98 g of methanol was added at -17°C over 10 minutes. After the addition was completed, the reaction mixture was stirred at room temperature (20°C) for 1 hour, and after the reaction mixture was cooled to 0°C, 14.55 g of potassium carbonate was added. After the addition was completed, the reaction mixture was heated to room temperature and stirred for 3 hours. After the stirring was completed, the reaction mixture was filtered under reduced pressure, and the filtrate was removed by reduced pressure distillation at 40°C and dried and solidified. After 30.00 g of water was added to the residue, 0.6 g of a 50% by mass aqueous solution of potassium carbonate was added to prepare a uniform solution of pH 7.4 (hereinafter referred to as solution F1).

[0273] After stirring 16.98 g of solution F at 60°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.11 g of the target substance as a yellow solid (quantitative purity 83.0%).

[0274] [Example 35]

[0275] Solution F1 was obtained by the same procedure as in Example 34, to which 0.11 g of a 50 mass % aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 7.6 (hereinafter referred to as solution F2).

[0276] Solution F28.61 g was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 992 mg of the target substance as a light yellow solid (quantitative purity 81.6%).

[0277] [Example 36]

[0278] Solution F2 was obtained by the same procedure as in Example 35, to which 0.4 g of a 50 mass % aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 8.3 (hereinafter referred to as solution F3).

[0279] 8.12 g of solution F3 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.24 g of the target substance as a white solid (quantitative purity 96.2%).

[0280] [Example 37]

[0281] Solution F3 was obtained by the same procedure as in Example 36, to which 0.33 g of a 50 mass % aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 8.8 (hereinafter referred to as solution F4).

[0282] 7.94 g of solution F4 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.11 g of the target substance as a light yellow solid (quantitative purity 94.1%).

[0283] [Example 38]

[0284] Solution F4 was obtained by the same procedure as in Example 37, to which 0.34 g of a 50 mass % aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 9.2 (hereinafter referred to as solution F5).

[0285] 8.68 g of solution F5 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.42 g of the target substance as a light yellow solid (quantitative purity 94.4%).

[0286] [Example 39]

[0287] Solution F5 was obtained by the same procedure as in Example 38, to which 0.33 g of a 50 mass % aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 9.5 (hereinafter referred to as solution F6).

[0288] 8.04 g of solution F6 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.24 g of the target substance as a light yellow solid (quantitative purity 94.8%).

[0289] [Example 40]

[0290] Solution F6 was obtained by the same procedure as in Example 39, to which 0.85 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 10.1 (hereinafter referred to as solution F7).

[0291] Solution F77.94 g was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.08 g of the target substance as an orange solid (quantitative purity 86.7%).

[0292] [Example 41]

[0293] Solution F7 was obtained by the same procedure as in Example 40, to which 0.60 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 10.3 (hereinafter referred to as solution F8).

[0294] Solution F89.48 g was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.61 g of the target substance as a yellow solid (quantitative purity 82.8%).

[0295] [Table 6]

[0296] Table 6

[0297]

[0298] [Example 42] 5-methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0299] To a solution of 15.00 g (202.48 mmol) of acetic hydrazide in 83.14 g of methanol, a solution of 22.30 g (210.58 mmol) of cyanogen bromide in 52.98 g of methanol was added at -15°C over 10 minutes. After the addition was completed, the reaction mixture was stirred at room temperature (30°C) for 1 hour, and after the reaction mixture was cooled to 0°C, 14.55 g of potassium carbonate was added. After the addition was completed, the reaction mixture was heated to room temperature and stirred for 200 minutes. After the stirring was completed, the reaction mixture was filtered under reduced pressure, and the filtrate was removed by reduced pressure distillation at 40°C and dried and solidified. After adding 45.00 g of water to the residue, 1.1 g of a 50% by mass aqueous solution of potassium carbonate was added to prepare a uniform solution of pH 7.2 (hereinafter referred to as solution G1).

[0300] 7.78 g of solution G1 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 19 hours and then filtered. The obtained solid was dried under reduced pressure to obtain 1.01 g of the target substance as a yellow solid (quantitative purity 78.7%).

[0301] [Example 43]

[0302] Solution G1 was obtained by the same procedure as in Example 42, to which 0.30 g of a 50 mass % aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 7.9 (hereinafter referred to as solution G2).

[0303] 6.31 g of solution G2 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 19 hours and then filtered. The obtained solid was dried under reduced pressure to obtain 632 mg of the target substance as a light yellow solid (quantitative purity 83.0%).

[0304] [Example 44]

[0305] Solution G2 was obtained by the same procedure as in Example 43, to which 0.20 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 8.1 (hereinafter referred to as solution G3).

[0306] 6.70 g of solution G3 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 19 hours and then filtered. The obtained solid was dried under reduced pressure to obtain 726 mg of the target substance as a white solid (quantitative purity 97.7%).

[0307] [Example 45]

[0308] Solution G3 was obtained by the same procedure as in Example 44, to which 0.62 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 8.7 (hereinafter referred to as solution G4).

[0309] 8.95 g of solution G4 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 19 hours and then filtered. The obtained solid was dried under reduced pressure to obtain 1.01 g of the target substance as a white solid (quantitative purity 97.9%).

[0310] [Example 46]

[0311] Solution G4 was obtained by the same procedure as in Example 45, to which 0.32 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 9.0 (hereinafter referred to as solution G5).

[0312] 8.46 g of solution G5 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 19 hours and then filtered. The obtained solid was dried under reduced pressure to obtain 937 mg of the target substance as a white solid (quantitative purity 97.9%).

[0313] [Example 47]

[0314] Solution G5 was obtained by the same procedure as in Example 46, to which 0.86 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 9.6 (hereinafter referred to as solution G6).

[0315] 8.12 g of solution G6 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 19 hours and then filtered. The obtained solid was dried under reduced pressure to obtain 912 mg of the target substance as a white solid (quantitative purity 97.5%).

[0316] [Example 48]

[0317] Solution G6 was obtained by the same procedure as in Example 47, to which 1.42 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 9.9 (hereinafter referred to as solution G7).

[0318] 7.65 g of solution G7 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 19 hours and then filtered. The obtained solid was dried under reduced pressure to obtain 795 mg of the target substance as a white solid (quantitative purity 96.8%).

[0319] [Example 49]

[0320] Solution G7 was obtained by the same procedure as in Example 48, to which 0.90 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 10.2 (hereinafter referred to as solution G8).

[0321] Solution G88.50 g was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 19 hours and then filtered. The obtained solid was dried under reduced pressure to obtain 1.01 g of the target substance as an orange solid (quantitative purity 87.1%).

[0322] [Table 7]

[0323] Table 7

[0324]

[0325] [Example 50] 5-methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0326] To a solution of 15.00 g (202.48 mmol) of acetic hydrazide in 83.14 g of methanol, a solution of 22.30 g (210.58 mmol) of cyanogen bromide in 52.98 g of methanol was added at -14°C over 10 minutes. After the addition was completed, the reaction mixture was stirred at room temperature (25°C) for 1 hour, and after the reaction mixture was cooled to 0°C, 14.55 g of potassium carbonate was added. After the addition was completed, the reaction mixture was heated to room temperature and stirred for 3 hours. After the stirring was completed, the reaction mixture was filtered under reduced pressure, and the filtrate was removed by reduced pressure distillation at 40°C and dried and solidified. After adding 45.00 g of water to the residue, 3.48 g of a 50% by mass aqueous solution of potassium carbonate was added to prepare a uniform solution of pH 7.0 (hereinafter referred to as solution H1).

[0327] After stirring 16.36 g of solution H at 60°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 12°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 903 mg of the target substance as a yellow solid (quantitative purity 61.2%).

[0328] [Example 51]

[0329] Solution H1 was obtained by the same procedure as in Example 50, to which 0.32 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 7.6 (hereinafter referred to as solution H2).

[0330] 7.01 g of solution H2 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 12°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 906 mg of the target substance as a yellow solid (quantitative purity 77.9%).

[0331] [Example 52]

[0332] Solution H2 was obtained by the same procedure as in Example 51, to which 0.6 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 8.0 (hereinafter referred to as solution H3).

[0333] 7.07 g of solution H3 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 12°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 606 mg of the target substance as a white solid (quantitative purity 99.2%).

[0334] [Example 53]

[0335] Solution H3 was obtained by the same procedure as in Example 52, to which 0.93 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 8.6 (hereinafter referred to as solution H4).

[0336] 8.86 g of solution H4 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 12°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 879 mg of the target substance as a white solid (quantitative purity 96.2%).

[0337] [Example 54]

[0338] Solution H4 was obtained by the same procedure as in Example 53, to which 1.30 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 9.1 (hereinafter referred to as solution H5).

[0339] 8.94 g of solution H5 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 12°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 915 mg of the target substance as a light yellow solid (quantitative purity 98.5%).

[0340] [Example 55]

[0341] Solution H5 was obtained by the same procedure as in Example 54, to which 1.40 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 9.7 (hereinafter referred to as solution H6).

[0342] After stirring 68.33 g of solution H at 60°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 12°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 924 mg of the target substance as a light yellow solid (quantitative purity 99.6%).

[0343] [Example 56]

[0344] Solution H6 was obtained by the same procedure as in Example 55, to which 1.50 g of a 50% by mass aqueous solution of potassium carbonate was added at 60° C. to prepare a uniform solution having a pH of 10.3 (hereinafter referred to as solution H7).

[0345] After stirring 710.7 g of solution H at 60°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 12°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.31 g of the target substance as an orange solid (quantitative purity 78.8%).

[0346] [Table 8]

[0347] Table 8

[0348]

[0349] [Example 57]

[0350] To a solution of 15.00 g (202.48 mmol) of acetic hydrazide in 83.14 g of methanol, a solution of 22.30 g (210.58 mmol) of cyanogen bromide in 52.98 g of methanol was added at -14°C over 18 minutes. After the addition was completed, the reaction mixture was stirred at room temperature (25°C) for 1 hour, and after the reaction mixture was cooled to 0°C, 11.2 g of sodium carbonate was added. After the addition was completed, the reaction mixture was heated to room temperature and stirred for 3 hours. After the stirring was completed, the reaction mixture was filtered under reduced pressure, and the filtrate was removed by reduced pressure distillation at 40°C and dried and solidified. After adding 45.00 g of water to the residue, 1.83 g of a 17% by mass aqueous solution of sodium carbonate was added at 60°C to prepare a uniform solution of pH 7.7 (hereinafter referred to as solution I1).

[0351] 9.90 g of solution I1 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.34 g of the target substance as a white solid (quantitative purity 76.6%).

[0352] [Example 58]

[0353] Solution I1 was obtained by the same procedure as in Example 57, to which 0.50 g of a 17 mass % aqueous solution of sodium carbonate was added at 60° C. to prepare a uniform solution having a pH of 8.1 (hereinafter referred to as solution I2).

[0354] 9.30 g of solution I2 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.177 g of the target substance as a white solid (quantitative purity 91.9%).

[0355] [Example 59]

[0356] Solution I2 was obtained by the same procedure as in Example 58, to which 0.50 g of a 17 mass % aqueous solution of sodium carbonate was added at 60° C. to prepare a uniform solution having a pH of 8.5 (hereinafter referred to as solution I3).

[0357] 9.49 g of solution I3 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.165 g of the target substance as a white solid (quantitative purity 90.2%).

[0358] [Example 60]

[0359] Solution I3 was obtained by the same procedure as in Example 59, to which 0.80 g of a 17 mass % aqueous solution of sodium carbonate was added at 60° C. to prepare a uniform solution having a pH of 9.0 (hereinafter referred to as solution I4).

[0360] After stirring 411.96 g of solution I at 60°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.54 g of the target substance as a white solid (quantitative purity 90.5%).

[0361] [Example 61]

[0362] Solution I4 was obtained by the same procedure as in Example 60, to which 1.8 g of a 17 mass % aqueous solution of sodium carbonate was added at 60° C. to prepare a uniform solution having a pH of 9.6 (hereinafter referred to as solution I5).

[0363] After stirring 511.22 g of solution I at 60°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and filtered. The obtained solid was dried under reduced pressure to obtain 1.29 g of the target substance as a white solid (quantitative purity 94.2%).

[0364] [Example 62]

[0365] Solution I5 was obtained by the same procedure as in Example 61, to which 8.3 g of a 17 mass % aqueous solution of sodium carbonate was added at 60° C. to prepare a uniform solution having a pH of 10.2 (hereinafter referred to as solution I6).

[0366] After stirring 610.2 g of solution I at 60°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.40 g of the target substance as an orange solid (quantitative purity 71.5%).

[0367] [Table 9]

[0368] Table 9

[0369]

[0370] [Example 63] 5-methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0371] To a solution of 15.00 g (202.48 mmol) of acetic hydrazide in 83.14 g of methanol, a solution of 22.30 g (210.58 mmol) of cyanogen bromide in 52.98 g of methanol was added at -5.6°C over 18 minutes. After the addition was completed, the reaction mixture was stirred at room temperature (25°C) for 1 hour, and after the reaction mixture was cooled to 0°C, 13.9 g of potassium hydroxide was added. After the addition was completed, the reaction mixture was heated to room temperature and stirred for 3 hours. After the stirring was completed, the reaction mixture was filtered under reduced pressure, and the filtrate was removed by reduced pressure distillation at 32°C and dried and solidified. After adding 45.00 g of water to the residue, 1.5 g of a 50% by mass aqueous solution of potassium hydroxide was added to prepare a uniform solution of pH 7.4 (hereinafter referred to as solution J1).

[0372] Solution J1 (10.60 g) was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.34 g of the target substance as a light yellow solid (quantitative purity 86.3%).

[0373] [Example 64]

[0374] Solution J1 was obtained by the same procedure as in Example 63, to which 0.050 g of a 50 mass % aqueous solution of potassium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 7.8 (hereinafter referred to as solution J2).

[0375] Solution J2 (8.61 g) was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 791 mg of the target substance as a light yellow solid (quantitative purity 89.8%).

[0376] [Example 65]

[0377] Solution J2 was obtained by the same procedure as in Example 64, to which 0.135 g of a 50 mass % aqueous solution of potassium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 8.2 (hereinafter referred to as solution J3).

[0378] 7.56 g of solution J3 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 873 mg of the target substance as a white solid (quantitative purity 96.6%).

[0379] [Example 66]

[0380] Solution J3 was obtained by the same procedure as in Example 65, to which 0.15 g of a 50 mass % aqueous solution of potassium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 8.5 (hereinafter referred to as solution J4).

[0381] Solution J4 (6.52 g) was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 698 mg of the target substance as a white solid (quantitative purity 98.5%).

[0382] [Example 67]

[0383] Solution J4 was obtained by the same procedure as in Example 66, to which 0.25 g of a 50 mass % aqueous solution of potassium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 9.1 (hereinafter referred to as solution J5).

[0384] 7.25 g of solution J5 was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 857 mg of the target substance as a white solid (quantitative purity 96.6%).

[0385] [Example 68]

[0386] Solution J5 was obtained by the same procedure as in Example 67, to which 0.24 g of a 50 mass % aqueous solution of potassium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 9.8 (hereinafter referred to as solution J6).

[0387] Solution J6 (9.58 g) was stirred at 60°C for 30 minutes and then cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.22 g of the target substance as a light yellow solid (quantitative purity 98.8%).

[0388] [Example 69]

[0389] Solution J6 was obtained by the same procedure as in Example 68, to which 0.35 g of a 50% by mass aqueous solution of potassium hydroxide was added at 60° C. to prepare a uniform solution having a pH of 10.3 (hereinafter referred to as solution J7).

[0390] After stirring 711.1 g of solution J at 60°C for 30 minutes, the solution was cooled to 0°C at a cooling rate of 30°C per hour. The obtained slurry was stirred at 0°C for 1 hour and then filtered. The obtained solid was dried under reduced pressure to obtain 1.37 g of the target substance as a light yellow solid (quantitative purity 88.2%).

[0391] [Table 10]

[0392] Table 10

[0393]

[0394] The examples shown in Tables 4 to 10 are obtained by reacting an acetic acid hydrazide compound represented by formula (6) with a cyanogen halide compound represented by formula (7) to form a 1,3,4- After adding the oxadiazole-2-amine compound, the pH of the system was adjusted to perform a crystallization operation.

[0395] As shown in Table 4, by adjusting the pH of the reaction mixture to 8.0 to 10.0 and then performing the subsequent crystallization operation (Examples 23 to 25), the target substance can be obtained with a quantitative purity exceeding 90%.

[0396] On the other hand, when the pH of the reaction mixture was set to less than 8.0 or more than 10.0 and then a crystallization operation was performed (Examples 21 to 22, and 26), the quantitative purity of the target substance was limited to less than 83%.

[0397] In addition, as shown in Tables 5, 9 and 10 (changing the type of inorganic base), Table 6 (changing the amount of water added before crystallization to 2 parts by mass relative to 1 part by mass of the acetylhydrazine compound), Table 7 (changing the crystallization time) and Table 8 (changing the cooling rate during crystallization), even when the production conditions of the target substance were changed, it was confirmed that the target substance could be obtained with a quantitative purity exceeding 90% by adjusting the pH of the reaction mixture to 8.0 to 10.0 and then performing the subsequent crystallization operation (Examples 29 to 32, Examples 36 to 39, etc.). Similarly, when the pH of the reaction mixture was adjusted to less than 8 (Examples 27 to 28, Examples 34 to 35, etc.) or the pH was adjusted to more than 10 (Examples 33, Examples 40 to 41, etc.) and then performing the subsequent crystallization operation, the quantitative purity of the target substance was less than 90% at most.

[0398] Thus, by reacting / cyclizing an acetic acid hydrazide compound with a cyanogen halide compound, a 1,3,4- After the oxadiazole-2-amine compound was prepared, the insoluble matter was removed by filtration, and the pH of the system was adjusted to 8.0 to 10.0 and crystallized. It was confirmed that the 1,3,4-oxadiazole represented by formula (1) was obtained with a specific quantitative purity, as compared with the case where the pH was adjusted to slightly exceed the above-specified range and crystallization was carried out. Oxadiazole-2-amine compounds.

[0399] [Reference Production Method 1] 5-Methyl-1,3,4- Synthesis of 2-oxadiazole-2-amine

[0400] In a mixed solution of 2.00 g (15.0 mmol) of 1-acetyl-3-thiosemicarbazide and 12.0 g of acetone, 1.89 g (15.0 mmol) of dimethylsulfate was added at room temperature. After the addition was completed, the reaction mixture was stirred at room temperature for 24 hours. After the stirring was completed, 3.31 g of a 51% aqueous solution of potassium hydroxide was added to the reaction mixture under ice cooling. After the addition was completed, the reaction mixture was stirred at room temperature for 24 hours. After the stirring was completed, 3.0 g of water was added at room temperature, and the insoluble matter in the reaction mixture was filtered out at 60°C. 9.06 g of the solvent contained in the obtained filtrate was distilled off under reduced pressure. After the obtained residue was stirred at 60°C for 30 minutes, it was cooled to 0°C and stirred for 1 hour. After the stirring was completed, the precipitated solid was filtered out, thereby obtaining 682 mg of the target substance as a white solid.

[0401] Melting point: 184~186℃

[0402] Furthermore, the filtrate obtained after the filtration was cooled to 0° C. and stirred for 1 hour. After the stirring was completed, the precipitated solid was filtered out to obtain 146 mg of the target substance as a white solid.

[0403] Melting point: 181~183℃

[0404] [Reference Example] Synthesis of 1-acetyl-3-thiosemicarbazide

[0405] To 3.00 g (33.0 mmol) of thiosemicarbazide, 4.35 g (72.5 mmol) of acetic acid was added at room temperature. After the addition was completed, the reaction mixture was stirred for 4 hours under heating reflux. After the stirring was completed, the reaction mixture was cooled to 60° C., 4.50 g of water was added, and then stirred for 1 hour under ice cooling. After the stirring was completed, the precipitated solid was filtered to obtain 3.66 g of the target substance as a white solid.

[0406] Melting point: 158~160℃.

Claims

1. A method for producing a 1,3,4- A method for producing a 2-oxadiazole-2-amine compound, It includes the following steps: The semicarbazide compound represented by formula (2) is reacted with 0.1 to 10 equivalents of at least one selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and phosphorus pentoxide, and a carboxylic acid compound represented by formula (3) relative to 1 equivalent of the semicarbazide compound represented by formula (2) to produce a 1,3,4- The process of producing a 2-oxadiazole-2-amine compound; and After the generation step, a step of purifying the reaction product is performed. The purification step includes the following steps: putting the mixture containing the reaction product into water at a temperature of room temperature to 50° C. to obtain a liquid containing the mixture; adjusting the pH of the obtained liquid containing the mixture to 9.0 to 10.0; and removing the 1,3,4- The oxadiazole-2-amine compound is crystallized at a temperature of -10 to 40°C. In the purification step, the pH is adjusted to 9.0 to 10.0 using an inorganic base.

2. The production method according to claim 1, wherein the inorganic base is selected from sodium hydroxide and potassium hydroxide. The production method according to claim 2 , wherein the inorganic base is potassium hydroxide.

4. The method according to any one of claims 1 to 3, wherein the 1, 3, 4- The process of the oxadiazole-2-amine compound is A step of reacting 0.1 to 10 equivalents of phosphorus oxychloride and the carboxylic acid compound represented by the formula (3) with respect to 1 equivalent of the semicarbazide compound represented by the formula (2).

5. A method for producing a 1,3,4- A method for producing a 2-oxadiazole-2-amine compound, It includes the following steps: The acetic acid hydrazide compound represented by formula (6) is reacted with the cyanogen halide compound represented by formula (7) to cyclize the acetic acid hydrazide compound represented by formula (6) to generate the 1,3,4- The process of producing a 2-oxadiazole-2-amine compound; and After the generation step, a step of purifying the reaction product is performed. Hal-CN (7) In the formula, Hal represents a halogen atom, The purification step includes the following steps: adjusting the pH of the reaction product-containing liquid containing the reaction product to 8.0 to 10.0; and removing the 1,3,4- The oxadiazole-2-amine compound is crystallized at a temperature of -10 to 40°C. In the purification step, the pH is adjusted to 8.0 to 10.0 using an inorganic base.

6. The production method according to claim 5, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate.

7. The production method according to claim 6, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. 8 . The production method according to claim 5 , wherein in the step of adjusting the pH to 8.0 to 10.0 in the purification step, insoluble matter is removed by filtration from the liquid containing the reaction product before the pH is adjusted.

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