Novel method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide

Abstract

The present invention addresses the problem of providing a method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide safely at a good yield. The present invention relates to a method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide or a salt thereof via 3-methyl-1,2,4-thiadiazole-5-carboxamide or a salt thereof without using toxic carbon monoxide. The present invention makes it possible to provide a method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide, which is an important synthesis intermediate of fezolinetant which is useful as a drug for the treatment of sex hormone-dependent diseases, safely and at a good yield.

Description

Novel method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide

[0001] The present invention relates to a novel, safe and practical method for preparing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide, an important synthetic intermediate for fezolinethant, which has been developed as a selective antagonist of neurokinin (NK)-3 receptors and is particularly useful as a compound for treating sex hormone-dependent diseases.

[0002] Fezolinetant (generic name) (VEOZAH®) has been developed as a selective NK-3 receptor antagonist and is particularly useful as a compound for the treatment and / or prevention of sex hormone-dependent diseases (e.g., moderate to severe vasomotor symptoms associated with menopause, such as hot flashes and flushing). Fezolinetant is (R)-(4-fluorophenyl)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone, and is described in Patent Document 1.

[0003]

[0004] Deuterated fezolinetanant, (R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone, was also developed for the same purpose and is described in US Pat. No. 5,623,999.

[0005]

[0006] Patent Documents 1 and 2 disclose a method for synthesizing fesorinetanant and deuterated fesorinetanant, in which 3-methyl-1,2,4-thiadiazole-5-carbohydrazide or its deuterated form, represented by the formula (I):

[0007]

[0008] (In the formula, R １represents methyl or methyl-d3.) A synthesis method via a compound represented by the following formula is disclosed.

[0009] Patent Document 3 describes a non-deuterated intermediate, 3-methyl-1,2,4-thiadiazole-5-carbohydrazide (2n):

[0010]

[0011] is disclosed, which is prepared from the corresponding methyl ester (compound represented by the following formula (2.2n)), which in turn is prepared in one step from acetamide (compound represented by the following formula (2.0n)), chlorocarbonylsulfenyl chloride (compound represented by the following formula (2.0n')), and methyl cyanoformate (compound represented by the following formula (2.0n'')).

[0012]

[0013] However, chlorocarbonylsulfenyl chloride and methyl cyanoformate are hazardous reagents that pose large-scale procurement challenges and are difficult to scale up. This synthetic route also introduces sulfur impurities that adversely affect the quality of the final pharmaceutical product. Furthermore, even after optimization, the overall yield of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide is still less than 30%. The corresponding deuterated intermediate, 3-(methyl-d ３ The synthesis of 4-(2,4-dichloro-1,2,4-thiadiazole-5-carbohydrazide also has the same drawbacks (Patent Document 2).

[0014] Patent Document 4 describes the following formula (I-1):

[0015]

[0016] As a method for synthesizing an intermediate compound represented by the following formula (III-1-a):

[0017]

[0018] or a compound represented by the following formula (III-1-b):

[0019]

[0020] The compound represented by the following formula (II-1-b):

[0021]

[0022] However, the yield of the alkoxycarbonylation reaction by lithium exchange reaction is low at 29%, and while the alkoxycarbonylation reaction by carbon monoxide insertion reaction in the presence of a metal catalyst can produce the compound represented by formula (II-1-b) in good yield, it requires the use of toxic carbon monoxide gas, and there are limitations on scale-up, etc., so there remain issues in practical application.

[0023] Therefore, there is a need for the development of a practical method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide, an important synthetic intermediate for fezolinethant, which is safe, has a good yield, and is scalable.

[0024] International Publication No. WO 2014 / 154895 International Publication No. WO 2019 / 012033 International Publication No. WO 2013 / 050424 International Publication No. WO 2020 / 128003

[0025] The object of the present invention is to provide a compound of formula (I) below, which is an important synthetic intermediate for fezolinethant:

[0026]

[0027] The present invention aims to provide a practical method for producing a compound represented by the following formula (I):

[0028] As a result of extensive investigations aimed at solving the above problems, the present inventors have found that it is possible to obtain a compound represented by the formula (1):

[0029]

[0030] (wherein X represents a halogen atom) or a salt thereof with an alkali metal cyanide,

[0031]

[0032] or a salt thereof,

[0033]

[0034] (Wherein R is C １－４ The compound represented by the formula (I):

[0035]

[0036] The present invention has been completed based on the discovery that this method can provide a safe and practical method for producing a compound represented by the formula (I) or a salt thereof.

[0037] That is, the present invention is as follows: [1] A method for producing a compound represented by the formula (1):

[0038]

[0039] (wherein X represents a halogen atom) or a salt thereof with an alkali metal cyanide,

[0040]

[0041] or a salt thereof. [2] The production method according to the above [1], wherein X is a chlorine atom or a bromine atom. [3] The production method according to the above [1], wherein the organic base is triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-dimethylpyridine, N,N-dimethyl-4-aminopyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, or 1,5-diazabicyclo[4.3.0]-5-nonene. [4] The production method according to the above [1], wherein the alkali metal cyanide is potassium cyanide or sodium cyanide. [5] The production method according to the above [1], wherein the mixing ratio (v / v) of the acetonitrile-water mixed solvent is within the range of 1 to 10, as water / acetonitrile. [6] The compound represented by formula (2) or a salt thereof obtained by the production method according to any one of the above [1] to [5] is reacted with a compound represented by the following formula:

[0042]

[0043] (Wherein R is C １－４ (representing an alkyl group),

[0044]

[0045] (wherein R has the same meaning as defined above) or a salt thereof. [7] The production method according to the above-mentioned [6], wherein the alcohol is methanol or ethanol. [8] A method for producing a compound represented by formula (I):

[0046]

[0047] A method for producing a compound represented by the formula:

[0048] According to the present invention, 3-methyl-1,2,4-thiadiazole-5-carbohydrazide represented by the formula (I) or a salt thereof, which is an important synthetic intermediate for fezorinetanant, can be produced in a good yield without using toxic carbon monoxide gas, and therefore a practical method for producing fezorinetanant can be provided which is safer than conventional methods and can be scaled up.

[0049] The definitions of terms used in this specification will be explained in detail below.

[0050] In this specification, a compound represented by a formula may be referred to by adding the formula number to the "compound." For example, a compound represented by formula (1) is referred to as "compound (1)."

[0051] In this specification, a numerical range expressed by "to" or "-" means a numerical range in which the numbers before and after "to" or "-" are the lower or upper limit.

[0052] In this specification, when the element symbol "C" is used with a numerical range indicated by numbers before and after "-" attached to the name of an arbitrary group, it indicates an arbitrary group having an integer number of carbon atoms, with the numbers before and after "-" being the lower or upper limit. For example, an alkyl group having 1 to 4 carbon atoms is referred to as "C １－４ The alkyl group is sometimes referred to as an alkyl group. ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ etc. are shown.

[0053] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0054] In this specification, "C １－４ "Alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms, １－４ Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0055] In this specification, the term "alkali metal cyanide" includes lithium cyanide, potassium cyanide, sodium cyanide, cesium cyanide, and the like.

[0056] As used herein, the term "organic base" refers to an organic compound that functions as a base. Organic bases are typically proton acceptors that contain a nitrogen atom that can be easily protonated, and examples of such bases include amines and nitrogen-containing heterocyclic compounds. The term "organic base" is not particularly limited, but examples thereof include triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMO), N,N-dimethyl-4-aminopyridine (DMAP), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,5-diazabicyclo[4.3.0]-5-nonene (DBN).

[0057] As used herein, "prevention" includes preventing the onset of a disease, delaying the onset of a disease, and preventing the development of a pathology in a subject.

[0058] As used herein, "treatment" includes curing a disease, ameliorating the pathology of a disease (e.g., one or more symptoms), and inhibiting the progression (of the severity) of a disease in a subject.

[0059] As used herein, the term "subject" refers to a subject to which a pharmaceutical composition containing an effective amount of an active ingredient is administered to prevent and / or treat a disease or a pathological condition of a disease. The "subject" may be a human or a non-human animal, particularly a mammal (e.g., a mouse, a rat, a guinea pig, a hamster, a rabbit, a cat, a dog, a cow, a sheep, a monkey, etc.).

[0060] In the present specification, the term "salt thereof" is not particularly limited as long as it is a salt formed by reacting the target compound with a base or an acid, but since the present invention relates to a method for producing an important synthetic intermediate of fezolinethant, which is useful as a pharmaceutical, a salt that can be used as a pharmaceutical (a pharmaceutically acceptable salt) is preferred. When each compound used in the production method of the present invention forms a basic salt or an acid salt by reacting with a base or an acid, the term refers to that salt.

[0061] Examples of the "basic salt" include sodium salt, potassium salt, lithium salt, magnesium salt, calcium salt, aluminum salt, ammonium salt, tetramethylammonium salt, N-methylmorpholine salt, diethylamine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt, choline salt, diolamine salt, mecurumine salt, olamine salt, tromethamine salt, 2-(diethylamino)ethanol salt, 4-(2-hydroxyethyl)morpholine salt, arginine salt, glycine salt, lysine salt, benzathine salt and the like.

[0062] Examples of "acid salts" include hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, bisulfate, borate, camsylate, cyclamate, carbonate, bicarbonate, phosphate, hexafluorophosphate, formate, lactate, trifluoroacetate, mesylate, trifluoromethanesulfonate, esylate, edisylate, benzoate, besylate, tosylate, acetate, malate, fumarate, succinate, malonate, citrate, ascorbate, tartrate, oxalate, maleate, adipate, nicotinate, aspartate, gluconate, glucuronate, pyroglutamate, stearate, palmitate, tannate, isethionate, naphthoate, orotate, pamoate, xinafoate, gluceptate, and hybenzate.

[0063] In the present invention, the compound of formula (I):

[0064]

[0065] The compound (compound (I)) or a salt thereof is a compound in which the 3-position methyl group is deuterated, 3-(methyl-d ３ )-1,2,4-thiadiazole-5-carbohydrazide or a salt thereof.

[0066] (Production Method of the Present Invention) The production method of the present invention will be described below.

[0067]

[0068] The compound represented by the following formula (compound (I)) or a salt thereof can be produced by the production method described below, the Examples described later, or a method similar thereto.

[0069] Each raw material compound may form a salt as long as it does not inhibit the reaction, and examples of such salts include the same as those described above. Unless a specific production method is described, the raw material compounds can be easily obtained commercially and used, or can be produced according to a method known per se or a method similar thereto. In addition, intermediates produced in the following production methods may be isolated and purified by methods such as column chromatography, recrystallization, distillation, etc., or may be used in the next step without isolation.

[0070] The contents of all patent, non-patent, or literature references explicitly cited in this specification are hereby incorporated by reference in their entirety.

[0071] In the present invention, compound (I) or a salt thereof is reacted with a compound represented by the formula (1):

[0072]

[0073] (wherein X represents a halogen atom), or a salt thereof is reacted with an alkali metal cyanide (MCN) (Step 1), thereby obtaining a compound represented by the formula (2):

[0074]

[0075] or a salt thereof, and then reacting the compound represented by formula (3):

[0076]

[0077] (Wherein R is C １－４ The compound (3) is produced by converting the compound (3) represented by the formula (2) into a compound represented by the formula (2) or a salt thereof (Step 2), followed by reacting the compound (3) with hydrazine or a hydrate thereof (Step 3).

[0078] Each step of the production method of the present invention will be described in detail below.

[0079] (Step 1) This step is a step of producing compound (2) or a salt thereof by reacting compound (1) or a salt thereof with alkali metal cyanide (MCN) in the presence of an organic base in a mixed solvent of acetonitrile and water.

[0080]

[0081] (In the formula, X represents a halogen atom, and M represents an alkali metal.)

[0082] Compound (1) or a salt thereof can be suitably synthesized by a method known per se (see, for example, WO 2020 / 128003 (Patent Document 4), Chem. Ber., 1957, 90, 182-187, etc.) or a method equivalent thereto. Compound (1) or a salt thereof is preferably 5-chloro-3-methyl-1,2,4-thiadiazole or 5-bromo-3-methyl-1,2,4-thiadiazole, more preferably 5-chloro-3-methyl-1,2,4-thiadiazole.

[0083] The alkali metal cyanide (MCN) is not particularly limited, but examples thereof include lithium cyanide, potassium cyanide, sodium cyanide, and cesium cyanide, and is preferably potassium cyanide or sodium cyanide, and more preferably sodium cyanide. The amount of the alkali metal cyanide used is 1 to 3 mol, preferably 1.1 to 1.5 mol, per mol of compound (1) or a salt thereof.

[0084] The organic base is not particularly limited, but examples thereof include triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMO), pyridine, 2,6-dimethylpyridine, N,N-dimethyl-4-aminopyridine (DMAP), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diaminopyridine (1,5-dimethyl-2,6-diaminopyridine ... Examples of the organic base include azabicyclo[4.3.0]-5-nonene (DBN), and preferably N,N-diisopropylethylamine (DIPEA), N,N-dimethyl-4-aminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,4-diazabicyclo[2.2.2]octane (DABCO), and more preferably 1,4-diazabicyclo[2.2.2]octane (DABCO). The amount of the organic base used is usually 0.01 to 2 moles, and preferably 0.05 to 0.2 moles, per mole of compound (1) or a salt thereof.

[0085] This reaction can be carried out in an acetonitrile-water mixed solvent, where the mixing ratio (v / v) of the acetonitrile-water mixed solvent is usually within the range of 0.1 to 20, preferably within the range of 1 to 10, and more preferably within the range of 2 to 8, in terms of water / acetonitrile.

[0086] The reaction temperature is usually 0° C. to 80° C., preferably 5° C. to 40° C., and the reaction time is usually 1 to 12 hours.

[0087] (Step 2) In this step, the compound (2) or a salt thereof obtained in the above step 1 is reacted with a compound of the following formula:

[0088]

[0089] (Wherein R is C １－４ This is a process for producing compound (3) or a salt thereof by reacting the compound (3) with thionyl chloride in the presence of an alcohol represented by the formula (I) (representing an alkyl group).

[0090]

[0091] (In the formula, R has the same meaning as above.)

[0092] The alcohol is not particularly limited as long as it has 1 to 4 carbon atoms, but is preferably methanol or ethanol. The amount of alcohol used is not particularly limited, and the amount of the solvent can be used.

[0093] The amount of thionyl chloride used is usually 1 to 3 moles, preferably 1.1 to 1.5 moles, per mole of compound (2) or a salt thereof.

[0094] The reaction temperature is usually 20° C. to 80° C., preferably 40° C. to 70° C. (heating reflux temperature), and the reaction time is usually 4 to 12 hours.

[0095] (Step 3) This step is a step of producing compound (I) or a salt thereof by reacting compound (3) or a salt thereof obtained in the above step 2 with hydrazine or a hydrate thereof in a solvent.

[0096]

[0097] The hydrazine or its hydrate is not particularly limited, but is preferably hydrazine monohydrate. The amount of hydrazine or its hydrate used is usually 1 to 2 moles, preferably 1 to 1.2 moles, per mole of compound (3) or a salt thereof.

[0098] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, but examples thereof include aromatic hydrocarbons such as toluene and xylene; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; alcohols such as methanol, ethanol, and isopropanol; nitriles such as acetonitrile; and mixtures thereof. Among these, a mixed solvent of an alcohol and an aromatic hydrocarbon is preferred, and a mixed solvent of isopropanol and toluene is more preferred.

[0099] The reaction temperature is usually −10° C. to 30° C., preferably 0° C. to 10° C., and the reaction time is usually 3 to 24 hours.

[0100] After completion of the reaction, compound (I) or a salt thereof can be isolated and / or purified from the reaction mixture by a conventional separation method such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc.

[0101] Compound (I) or a salt thereof obtained in Step 3 can be converted to fezolinethant by a method known per se (see, for example, WO 2014 / 154895 (Patent Document 1) and WO 2019 / 012033 (Patent Document 2)) or a method equivalent thereto.

[0102] The production method of the present invention does not use any carbon monoxide gas, the use of which is restricted on an industrial scale, and therefore has the advantage of being able to synthesize compound (I) or a salt thereof in good yield by a safe and simple operation compared to conventional methods.

[0103] The present invention will be specifically explained below with reference to Reference Examples and Examples, but the present invention is not limited to these examples.

[0104] In this specification, % indicates mol / mol% for yield, and % by weight for other values ​​unless otherwise specified. Furthermore, room temperature indicates a temperature of 15 to 30°C unless otherwise specified.

[0105] Nuclear magnetic resonance spectroscopy (NMR) was measured using an ECZ400S FT-NMR manufactured by JEOL Ltd. １ H-NMR was measured at 400 MHz using tetramethylsilane as the standard. When a deuterated solvent was used as the measurement solvent, the name of the deuterated solvent is listed. The high-performance liquid chromatograph (HPLC) used was an Agilent Technologies 1220 Infinity LC, and the column used was an Atlantis T3 (3 μm (particle size), 4.6 × 150 mm, Waters). The abbreviations used in the following examples have the following meanings.

[0106] s: Singlet br: Broad CDCl3: Deuterated chloroform DMSO-d6: Deuterated dimethyl sulfoxide CH2Cl2: Dichloromethane NaOH: Sodium hydroxide NaCN: Sodium cyanide DABCO: 1,4-diazabicyclo[2.2.2]octane MeCN: Acetonitrile MeOH: Methanol iPrOH: Isopropanol

[0107] Reference Example 1: Preparation of 5-chloro-3-methyl-1,2,4-thiadiazole (1-1)

[0108]

[0109] Dichloromethane (530 mL (5.3 v / w)) was added to acetamidine hydrochloride (100 g, 1.06 mol), trichloromethanesulfenyl chloride (196.8 g, 1.06 mol), and 6 M aqueous sodium hydroxide solution (902.7 g, 4.4 eq.) under a nitrogen atmosphere (atmospheric pressure) at 0°C, and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was then separated, and the resulting organic layer was washed sequentially with 6 M hydrochloric acid (350 mL (3.5 v / w)) and water (350 g (3.5 v / w)). The resulting organic layer was subjected to simple distillation (vacuum pressure: 400-15 Torr, internal temperature: 25-60°C) to obtain the title compound (1-1) in a 54% yield (quantitative value by LC). １ H-NMR (400MHz, CDCl ３ ) δ 2.64 (s, 3H).

[0110] Example 1: Preparation of 3-methyl-1,2,4-thiadiazole-5-carboxamide (2)

[0111]

[0112] Compound (1-1) (150 g, 1.10 mol) obtained in Reference Example 1, acetonitrile (150 mL (1.0 v / w)), water (562.5 mL (3.75 v / w)), DABCO (12.1 g, 0.11 mol), and sodium cyanide (68.9 g, 1.41 mol) were mixed under a nitrogen atmosphere (normal pressure) at 25°C, and the reaction mixture was stirred at 25 to 40°C for 2 hours. Thereafter, the reaction mixture was cooled to 5°C and filtered under reduced pressure, and the residue was washed three times with water (300 g (2 v / w)). The residue was dried under reduced pressure to obtain the title compound (2) in a 67% yield (quantitative value by LC). １ H-NMR (400MHz, CDCl ３ ) δ 2.72 (s, 3H), 7.01 (s, 2H).

[0113] Example 2: Preparation of methyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (3-1)

[0114]

[0115] Compound (2) (30.0 g, 0.21 mol) obtained in Example 1 and methanol (120 mL (4 v / w)) were mixed under a nitrogen atmosphere (atmospheric pressure) at 25°C, and the mixture was heated to 40-50°C. A solution of thionyl chloride (29.5 g, 0.25 mol) in methanol (60 mL (2 v / w)), which had been separately prepared at 0-20°C, was added dropwise thereto, and the mixture was stirred at 64°C for 6 hours. The methanol in the reaction mixture was distilled off under reduced pressure, and the solvent was replaced with toluene. Impurities were then removed by filtration under reduced pressure, and a 10% aqueous sodium chloride solution (6 v / w) was added to the filtrate, followed by phase separation. The resulting organic layer was concentrated under reduced pressure to 5 v / w, yielding a toluene solution of the title compound (3-1) in 82% yield (quantitative value by LC). １ H-NMR (400MHz, CDCl ３ ) δ 2.79 (s, 3H), 4.05 (s, 3H).

[0116] Example 3: Preparation of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide (I)

[0117]

[0118] Under a nitrogen atmosphere, hydrazine monohydrate (33.2 g, 0.66 mol) was added to isopropanol (1000 mL (10 v / w)) and cooled to 0 to 10° C., and then a toluene solution of compound (3-1) (0.63 mol) obtained in Example 2 was added dropwise thereto, followed by stirring at 0 to 10° C. for 12 hours. Thereafter, the reaction mixture was filtered under reduced pressure, and the residue was washed with isopropanol (400 mL (4 v / w)) and dried under reduced pressure to obtain the title compound (I) in a 95% yield (quantitative value by LC). １ H-NMR (400MHz, DMSO-d ６ ) δ 2.56 (s, 3H), 4.82 (br, 2H), 10.56 (br, 1H).

[0119] According to the present invention, 3-methyl-1,2,4-thiadiazole-5-carbohydrazide (compound (I)) or a salt thereof, which is an important synthetic intermediate for fezorinetanant, can be produced in a good yield without using toxic carbon monoxide gas. Therefore, a practical method for producing fezorinetanant can be provided which is safer than conventional methods and can be scaled up.

[0120] This application is based on Japanese Patent Application No. 2023-109329 filed on July 3, 2023 in Japan, the contents of which are incorporated in their entirety herein.

Claims

1. In a mixed solvent of acetonitrile and water, in the presence of an organic base, a compound represented by the formula (1): (wherein X represents a halogen atom) or a salt thereof with an alkali metal cyanide, A method for producing a compound represented by the formula:

2. The method according to claim 1, wherein X is a chlorine atom or a bromine atom.

3. The process according to claim 1, wherein the organic base is triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-dimethylpyridine, N,N-dimethyl-4-aminopyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, or 1,5-diazabicyclo[4.3.0]-5-nonene.

4. The process according to claim 1, wherein the alkali metal cyanide is potassium cyanide or sodium cyanide.

5. The method according to claim 1, wherein the mixing ratio (v / v) of the acetonitrile-water mixed solvent is within the range of 1 to 10 in terms of water / acetonitrile.

6. A compound represented by formula (2) or a salt thereof obtained by the method according to any one of claims 1 to 5, comprising the compound represented by formula (2) or a salt thereof represented by the following formula: (Wherein, R is C １－４ (representing an alkyl group), in the presence of an alcohol represented by formula (3): (wherein R has the same meaning as defined above) or a salt thereof.

7. The process according to claim 6, wherein the alcohol is methanol or ethanol.

8. A method for producing a compound represented by formula (I): comprising the step of reacting the compound represented by formula (3) or a salt thereof obtained by the method according to claim 6 with hydrazine or a hydrate thereof in a solvent. A method for producing a compound represented by the formula: