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 with good safety and good yield. The present invention relates to a method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide or a salt thereof via a compound represented by formula (2): (In the formula, R denotes an alkyl group having 1-4 carbon atoms) or a salt thereof, which is a novel compound. The present invention is capable of providing a method for producing, with good safety and good yield, 3-methyl-1,2,4-thiadiazole-5-carbohydrazide that is an important synthesis intermediate for fezolinetant which is useful as a drug for treating sex hormone-dependent diseases.

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 １ is methyl or methyl-d ３A synthesis method is disclosed in which a compound represented by the formula:

[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 a compound represented by the formula (1):

[0029]

[0030] (wherein X represents a halogen atom) or a salt thereof is reacted with an alkali metal cyanide, and then a compound represented by the following formula:

[0031]

[0032] (Wherein R is C １－４ (wherein M represents an alkali metal, and R has the same meaning as defined above), in the presence of an alcohol represented by formula (2):

[0033]

[0034] (wherein R has the same meaning as defined above) or a salt thereof, thereby obtaining a compound represented by formula (3):

[0035]

[0036] (Wherein R is C １－４ The compound represented by the formula (I):

[0037]

[0038] 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.

[0039] That is, the present invention is as follows: [1] A method for producing a compound represented by the formula (1): in a solvent containing an aprotic polar solvent, in the presence of an organic base.

[0040]

[0041] (wherein X represents a halogen atom) or a salt thereof is reacted with an alkali metal cyanide, and then a compound represented by the following formula:

[0042]

[0043] (Wherein R is C １－４ and reacting the resulting alcohol with MOR (wherein M and R are as defined above).

[0044]

[0045] (wherein R has the same meaning as defined above) 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 addition of an organic base is further included when adding the alcohol. [4] 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. [5] The production method according to the above [1], wherein the alkali metal cyanide is potassium cyanide or sodium cyanide. [6] The production method according to the above [1], wherein the alcohol is methanol or ethanol. [7] The production method according to the above [1], wherein the aprotic polar solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide. [8] The production method according to the above [1], wherein the solvent further comprises a non-polar solvent. [9] The production method according to the above [8], wherein the non-polar solvent is toluene, n-hexane, cyclohexane, or n-heptane.

[10] A production method according to the above [1], comprising a step of acid hydrolyzing a compound represented by formula (2) or a salt thereof obtained by the production method according to any one of the above [1] to [9], to obtain a compound represented by formula (3):

[0046]

[0047] (wherein R has the same meaning as defined above) or a salt thereof.

[11] The production method according to the above-mentioned

[10] , wherein the acid is sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, aluminum chloride, boron trifluoride, titanium chloride, or zinc chloride.

[12] A method for producing a compound represented by formula (I):

[0048]

[0049]

[13] A method for producing a compound represented by formula (2): or a salt thereof.

[0050]

[0051] (Wherein R is C １－４ 2. A compound represented by the formula (I) or a salt thereof:

[0052] 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 fezolinetant, can be produced in a good yield without using toxic carbon monoxide gas by going through a novel compound, 3-methyl-1,2,4-thiadiazole-5-carboimidate ester represented by the formula (2), thereby providing a practical method for producing fezolinetant that is safer than conventional methods and can be scaled up.

[0053] The definitions of terms used in this specification will be explained in detail below.

[0054] 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)."

[0055] 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.

[0056] 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.

[0057] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0058] 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.

[0059] In this specification, the term "solvent containing an aprotic polar solvent" means that the solvent contains an aprotic polar solvent. The "solvent containing an aprotic polar solvent" is not particularly limited, and examples thereof include a solvent consisting of at least one aprotic polar solvent, a mixed solvent of an aprotic polar solvent and a nonpolar solvent, and the like.

[0060] In the present specification, the "aprotic polar solvent" is not particularly limited, and examples thereof include amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone; sulfoxide solvents such as dimethyl sulfoxide; and nitrile solvents such as acetonitrile and propionitrile; and among these, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide are preferred.

[0061] In the present specification, the "non-polar solvent" is not particularly limited, but examples thereof include aromatic hydrocarbon solvents such as toluene and xylene; and aliphatic hydrocarbon solvents such as n-hexane, cyclohexane, and n-heptane; and among these, toluene, n-hexane, cyclohexane, or n-heptane is preferable.

[0062] In this specification, the term "alkali metal cyanide" includes lithium cyanide, potassium cyanide, sodium cyanide, cesium cyanide, and the like.

[0063] 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).

[0064] 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.

[0065] 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.

[0066] 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.).

[0067] 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.

[0068] 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.

[0069] 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.

[0070] In the present invention, the compound of formula (I):

[0071]

[0072] 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.

[0073] (Production Method of the Present Invention) The production method of the present invention will be described below.

[0074]

[0075] 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.

[0076] 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.

[0077] The contents of all patent, non-patent, or literature references explicitly cited in this specification are hereby incorporated by reference in their entirety.

[0078] In the present invention, compound (I) or a salt thereof is reacted with a compound represented by formula (1):

[0079]

[0080] (wherein X represents a halogen atom), or a salt thereof is reacted with an alkali metal cyanide, and then a compound represented by the following formula:

[0081]

[0082] (Wherein R is C １－４ (wherein M represents an alkali metal, and R has the same meaning as above), to give a compound represented by the formula (2):

[0083]

[0084] (wherein R has the same meaning as defined above) or a salt thereof (Step 1), followed by acid hydrolysis of compound (2) or a salt thereof to obtain a compound represented by formula (3):

[0085]

[0086] (wherein R has the same meaning as defined above) or a salt thereof (Step 2), and reacting Compound (3) or a salt thereof with hydrazine or a hydrate thereof (Step 3).

[0087] Each step of the production method of the present invention will be described in detail below.

[0088] (Step 1) In this step, compound (1) or a salt thereof is reacted with alkali metal cyanide (M′CN) in a solvent containing an aprotic polar solvent in the presence of an organic base (step 1-1), and then a reaction product of the following formula:

[0089]

[0090] (Wherein R is C １－４ represents an alkyl group), and reacting with MOR (wherein M represents an alkali metal (preferably sodium or potassium, more preferably sodium), and R has the same meaning as defined above) (Step 1-2), to produce compound (2) or a salt thereof. The reaction in this step proceeds via 5-cyano-3-methyl-1,2,4-thiadiazole, but it is not necessary to isolate and purify 5-cyano-3-methyl-1,2,4-thiadiazole, and compound (2) or a salt thereof can be obtained in one pot.

[0091]

[0092] (In the formula, M′ represents an alkali metal, and the other symbols are as defined above.)

[0093] 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.

[0094] The alkali metal cyanide (M'CN) used is not particularly limited, but examples thereof include lithium cyanide, potassium cyanide, sodium cyanide, cesium cyanide, etc., and is preferably potassium cyanide or sodium cyanide, more preferably sodium cyanide. The amount of the alkali metal cyanide used is 0.7 to 3 mol, preferably 0.8 to 1.5 mol, per mol of compound (1) or a salt thereof.

[0095] The organic base to be used 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 -diazabicyclo[4.3.0]-5-nonene (DBN), etc., are preferred, including N,N-diisopropylethylamine (DIPEA), N,N-dimethyl-4-aminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and more preferred is 1,4-diazabicyclo[2.2.2]octane (DABCO). The amount of organic base used is usually 0.05 to 2 moles, and preferably 0.05 to 0.2 moles, per mole of compound (1) or a salt thereof.

[0096] This reaction can be carried out in a solvent containing an aprotic polar solvent. Examples of the aprotic polar solvent include the above-mentioned solvents, but preferably a solvent consisting of a single aprotic polar solvent or a mixed solvent of an aprotic polar solvent and a nonpolar solvent, and more preferably a mixed solvent of an aprotic polar solvent and a nonpolar solvent.

[0097] The aprotic polar solvent constituting the mixed solvent of an aprotic polar solvent and a nonpolar solvent is not particularly limited, and examples thereof include amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone; sulfoxide solvents such as dimethyl sulfoxide; and nitrile solvents such as acetonitrile and propionitrile. Among these, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide is preferred, and N,N-dimethylformamide is more preferred.

[0098] The non-polar solvent constituting the mixed solvent of an aprotic polar solvent and a non-polar solvent is not particularly limited, and examples thereof include aromatic hydrocarbon solvents such as toluene and xylene; and aliphatic hydrocarbon solvents such as n-hexane, cyclohexane, and n-heptane; and among these, toluene, n-hexane, cyclohexane, or n-heptane is preferred, and toluene is more preferred.

[0099] The mixing ratio (v / v) of the mixed solvent of the aprotic polar solvent and the nonpolar solvent is not particularly limited, but is usually in the range of 0.1 to 100, preferably 0.2 to 5, and more preferably 0.5 to 3, in terms of aprotic polar solvent / nonpolar solvent.

[0100] The alkali metal alkoxide (MOR) used in step 1-2 is not particularly limited as long as it is an alkali metal alkoxide having 1 to 4 carbon atoms, but is preferably sodium methoxide, potassium methoxide, sodium ethoxide, or potassium ethoxide, and more preferably sodium methoxide or sodium ethoxide. The amount of alkali metal alkoxide used is usually 0.05 to 2 moles, preferably 0.08 to 0.2 moles, per mole of compound (1) or a salt thereof. The alcohol used in step 1-2 is an alcohol capable of forming an alkoxide of the alkali metal alkoxide (specifically, for example, sodium ethoxide / ethanol).

[0101] Step 1-2 can also be carried out in the coexistence of an organic base, if necessary. Examples of the organic base include those mentioned above, but triethylamine (TEA) is preferred. Addition of an organic base inactivates the alkali metal cyanide (M'CN) remaining in the reaction system during post-treatment, thereby suppressing the generation of hydrogen cyanide, thereby providing the advantage of enabling this step to be carried out safely. The amount of organic base used is typically 0.05 to 2 moles, preferably 0.1 to 0.3 moles, per mole of compound (1) or a salt thereof.

[0102] The reaction temperature in step 1-1 is usually 0° C. to 120° C., and the reaction time is usually 3 to 24 hours.

[0103] The reaction temperature in step 1-2 is usually −10° C. to 20° C., and the reaction time is usually 0.5 to 4 hours.

[0104] (Step 2) This step is a step of producing compound (3) or a salt thereof by acid hydrolyzing compound (2) or a salt thereof obtained in the above step 1.

[0105]

[0106] The acid used may be either a protonic acid or a Lewis acid. The protonic acid is preferably sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid, more preferably sulfuric acid or hydrochloric acid. The Lewis acid is preferably aluminum chloride (AlCl ３ ), boron trifluoride (BF ３ ), titanium chloride (TiCl ３ ), or zinc chloride (ZnCl ２ The acid may be diluted with water before use. The amount of the acid used is usually 1 to 3 moles, preferably 1.03 to 1.5 moles, per mole of compound (2) or a salt thereof.

[0107] The reaction temperature is usually 0° C. to 20° C., preferably 0° C. to 10° C., and the reaction time is usually 0.5 to 4 hours.

[0108] (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.

[0109]

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] (Compound of the Present Invention) The production method of the present invention is characterized by not using carbon monoxide, and is a method for producing a compound of formula (2):

[0117]

[0118] (wherein R has the same meaning as defined above) (compound (2)) or a salt thereof can be used as a synthetic intermediate to produce compound (I), an important synthetic intermediate of fezolinethant, more safely and in a higher yield than conventional methods. Compound (2) or a salt thereof is a novel compound and is useful as a novel intermediate compound in the synthesis of fezolinethant.

[0119] 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.

[0120] 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.

[0121] 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. Infrared absorption spectra (IR) were measured by the ATR method using a Nic-plan / Nicolet 6700 manufactured by Thermo Fisher Scientific. Liquid chromatography-mass spectrometry (LC-MS) was measured using an UltiMate 3000 and Q Exactive manufactured by Thermo Fisher Scientific. For high-performance liquid chromatography (HPLC), an Agilent Technologies 1220 Infinity LC was used, and the column used was an Atlantis T3 (3 μm (particle size), 4.6 × 150 mm, manufactured by Waters). In addition, the abbreviations used in the following examples have the following meanings.

[0122] s: Singlet t: Triplet q: Quartet br: Broad J: Coupling constant CDCl3: Deuterated chloroform DMSO-d6: Deuterated dimethyl sulfoxide CH2Cl2: Dichloromethane NaOH: Sodium hydroxide NaCN: Sodium cyanide DABCO: 1,4-diazabicyclo[2.2.2]octane DMF: N,N-dimethylformamide TEA: Triethylamine NaOEt: Sodium ethoxide EtOH: Ethanol iPrOH: Isopropanol

[0123] Reference Example 1: Preparation of 5-chloro-3-methyl-1,2,4-thiadiazole (1-1)

[0124]

[0125] 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).

[0126] Example 1: Preparation of ethyl 3-methyl-1,2,4-thiadiazole-5-carbimidate (2-1)

[0127]

[0128] Compound (1-1) (4 g, 29.72 mmol) obtained in Reference Example 1, DABCO (0.667 g, 5.94 mmol), toluene (3.46 mL), DMF (3.79 mL), and sodium cyanide (1.63 g, 32.7 mmol) were mixed under a nitrogen atmosphere (atmospheric pressure) at 15°C, and the reaction mixture was stirred at the same temperature for 4 hours. Subsequently, toluene (12.16 mL), triethylamine (0.60 g, 5.94 mmol), ethanol (1.36 g, 29.72 mmol), and a 20% sodium ethoxide / ethanol solution (0.83 mL, 2.43 mmol) were added to the reaction mixture at 15°C, and the mixture was stirred at the same temperature for an additional 1 hour. Water was added to the reaction mixture, and the mixture was separated twice. The organic layer was then washed with a 10% aqueous sodium chloride solution to obtain a toluene solution of the title compound (2-1) in 67% yield (quantitative by LC). １ H-NMR (400MHz, DMSO-d ６ ) δ 0.52 (t, J=7.3Hz, 3H), 1.85 (s, 3H), 3.54 (q, J=7.3Hz, 2H), 8.49 (s, 1H); IR (cm －１) 3286,2900-3000,1653,1450; LC-MS m / z 172.0535 ([M+H] ＋ )

[0129] The hydrogen cyanide gas concentration in the gas phase of the reaction vessel during this reaction was below the detection limit (≦10 ppm), confirming that the reaction was safe.

[0130] Example 2: Preparation of ethyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (3-1)

[0131]

[0132] Under a nitrogen atmosphere, a toluene solution (concentration 14%) (2201.3 g, 1.82 mol) of compound (2-1) obtained in Example 1 was cooled to 5°C, and then water and concentrated sulfuric acid (347.2 g (1.9 eq.)) were added dropwise thereto, followed by stirring at 5°C for 1 hour, after which the reaction mixture was separated into layers. A 10% aqueous solution of sodium carbonate was added to the obtained organic phase until the pH reached 5 to 6, and the layers were separated. The obtained organic layer was quantified, and as a result, it was found that a toluene solution of the title compound (3-1) was obtained in 98% yield (quantitative value by LC). １ H-NMR (400MHz, DMSO-d ６ ) δ 1.28 (t, J=8.0Hz, 3H), 2.59 (s, 3H), 4.35 (q, J=7.6Hz, 2H).

[0133] Example 3: Preparation of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide (I)

[0134]

[0135] Under a nitrogen atmosphere, hydrazine monohydrate (93.7 g, 1.85 mol) was added to isopropanol (1519 mL (5 v / w)) and the mixture was cooled to 0 to 10° C., and then a toluene solution (15% concentration) of compound (3-1) obtained in Example 2 (2052.6 g, 1.76 mol) was added dropwise thereto, and the mixture was stirred 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 94% yield (quantitative value by LC). １H-NMR (400MHz, DMSO-d ６ ) δ 2.56 (s, 3H), 4.82 (br, 2H), 10.56 (br, 1H).

[0136] Example 4: Preparation of methyl 3-methyl-1,2,4-thiadiazole-5-carbimidate (2-2)

[0137]

[0138] Under a nitrogen atmosphere (atmospheric pressure) at 15°C, 5-bromo-3-methyl-1,2,4-thiadiazole (compound (1-2)) (5.32 g, 29.72 mmol), N,N-diisopropylethylamine (0.768 g, 5.94 mmol), toluene (3.46 mL), DMF (3.79 mL), and potassium cyanide (2.13 g, 32.7 mmol) were mixed, and the reaction mixture was stirred at the same temperature for 4 hours. Thereafter, toluene (12.16 mL), triethylamine (0.60 g, 5.94 mmol), methanol (1.28 g, 29.72 mmol), and sodium methoxide (0.13 g, 2.43 mmol) were added to the reaction mixture at 15°C, and the mixture was further stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was separated twice. The organic layer was then washed with a 10% aqueous sodium chloride solution to obtain a toluene solution of the title compound (2-2) in a yield of 61% (quantitative value by NMR). １ H-NMR (400MHz, CDCl ３ ) δ 2.36 (s, 3H), 3.47 (s, 3H), 9.36 (s, 1H);

[0139] Example 5: Preparation of methyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (3-2)

[0140]

[0141] Under a nitrogen atmosphere, a toluene solution (concentration 14%) (204.4 g, 0.18 mol) of compound (2-2) obtained in Example 4 was cooled to 5°C, and then water and concentrated sulfuric acid (34.7 g (1.9 eq.)) were added dropwise thereto, followed by stirring at 5°C for 1 hour, after which the reaction mixture was separated into layers. A 10% aqueous solution of sodium carbonate was added to the obtained organic phase until the pH reached 5 to 6, and the layers were separated. The obtained organic layer was quantified, and as a result, it was found that a toluene solution of the title compound (3-2) was obtained in 96% yield (quantitative value by NMR). １ H-NMR (400MHz, CDCl ３ ) δ 2.36 (s, 3H), 3.90 (s, 3H).

[0142] Example 6: Preparation of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide (I)

[0143]

[0144] Under a nitrogen atmosphere, hydrazine monohydrate (9.37 g, 0.185 mol) was added to isopropanol (152 mL (5 v / w)) and cooled to 0 to 10° C., and then a toluene solution (188.4 g, 0.176 mol) of compound (3-2) obtained in Example 5 (concentration: 15%) was added dropwise thereto, and the mixture was stirred at 0 to 10° C. for 12 hours. Thereafter, the reaction mixture was filtered under reduced pressure, and the residue was washed with isopropanol (40 mL (4 v / w)) and dried under reduced pressure to obtain the title compound (I) in a 92% 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).

[0145] Example 7: Preparation of tert-butyl 3-methyl-1,2,4-thiadiazole-5-carbimidate (2-3)

[0146]

[0147] Compound (1-1) (4 g, 29.72 mmol) obtained in Reference Example 1, pyridine (0.470 g, 5.94 mmol), toluene (3.46 mL), DMF (3.79 mL), and potassium cyanide (2.13 g, 32.7 mmol) were mixed under a nitrogen atmosphere (atmospheric pressure) at 15°C, and the reaction mixture was stirred at the same temperature for 4 hours. To the reaction mixture, toluene (12.16 mL), triethylamine (0.60 g, 5.94 mmol), tert-butyl alcohol (2.20 g, 29.72 mmol), and sodium tert-butoxide (0.23 g, 2.43 mmol) were then added at 15°C, and the mixture was stirred at the same temperature for an additional 1 hour. Water was added to the reaction mixture, and the mixture was separated twice. The organic layer was then washed with a 10% aqueous sodium chloride solution to obtain a toluene solution of the title compound (2-3) in 67% yield (quantitative value by NMR). １ H-NMR (400MHz, CDCl ３ ) δ 1.38 (s, 9H), 2.36 (s, 3H), 9.36 (s, 1H);

[0148] Example 8: Preparation of tert-butyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (3-3)

[0149]

[0150] Under a nitrogen atmosphere, a toluene solution (concentration 14%) (260.3 g, 0.18 mol) of compound (2-3) obtained in Example 7 was cooled to 5°C, and then water and 35% hydrochloric acid (36.0 g (1.9 eq.)) were added dropwise thereto, followed by stirring at 5°C for 1 hour. The reaction mixture was then separated into layers. A 10% aqueous solution of sodium carbonate was added to the obtained organic phase until the pH reached 5 to 6, and the layers were separated. The obtained organic layer was quantified, and it was found that a toluene solution of the title compound (3-3) was obtained in 90% yield (quantitative value by NMR). １ H-NMR (400MHz, CDCl ３ ) δ 1.42 (s, 9H), 2.36 (s, 3H).

[0151] Example 9: Preparation of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide (I)

[0152]

[0153] Under a nitrogen atmosphere, hydrazine monohydrate (9.37 g, 0.185 mol) was added to isopropanol (152 mL (5 v / w)) and the mixture was cooled to 0 to 10° C., and then a toluene solution (15% concentration) of compound (3-3) obtained in Example 8 (240.0 g, 0.176 mol) was added dropwise thereto, and the mixture was stirred at 0 to 10° C. for 12 hours. Thereafter, the reaction mixture was filtered under reduced pressure, and the residue was washed with isopropanol (40 mL (4 v / w)) and dried under reduced pressure to obtain the title compound (I) in a 93% 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).

[0154] 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 of fezorinetanant, can be produced in good yield without using toxic carbon monoxide gas by going through a novel compound, 3-methyl-1,2,4-thiadiazole-5-carbimidic acid ester (compound (2)), and therefore a practical method for producing fezorinetanant, which is safer than conventional methods and can be scaled up, can be provided.

[0155] This application is based on Japanese Patent Application No. 2023-109328 filed on July 3, 2023 in Japan, the contents of which are incorporated in their entirety herein.

Claims

1. In a solvent containing an aprotic polar solvent, in the presence of an organic base, a compound represented by the formula (1): (wherein X represents a halogen atom) or a salt thereof is reacted with an alkali metal cyanide, and then a compound represented by the following formula: (Wherein, R is C １－４ (wherein M represents an alkali metal, and R has the same meaning as defined above), (wherein R has the same meaning as defined above) or a salt thereof.

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

3. The process of claim 1, further comprising the addition of an organic base during the addition of the alcohol.

4. 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.

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

6. The process according to claim 1, wherein the alcohol is methanol or ethanol.

7. The method according to claim 1, wherein the aprotic polar solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethylsulfoxide.

8. The method of claim 1, wherein the solvent further comprises a non-polar solvent.

9. The process according to claim 8, wherein the non-polar solvent is toluene, n-hexane, cyclohexane, or n-heptane.

10. A method for producing a compound represented by formula (3): (wherein R has the same meaning as defined above) or a salt thereof.

11. The process according to claim 10, wherein the acid is sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, aluminum chloride, boron trifluoride, titanium chloride, or zinc chloride.

12. 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 10 with hydrazine or a hydrate thereof in a solvent. A method for producing a compound represented by the formula:

13. Formula (2): (Wherein, R is C １－４ 2. A compound represented by the formula:

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