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 high safety and high 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 represents a C1-4 alkyl group) or a salt thereof, which is a novel compound. According to the present invention, it is possible to provide a safe and high-yield method for producing 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide, which is an important synthetic intermediate for non-azonetin, which is useful as a drug for the treatment of sex hormone-dependent diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to a safe and practical novel production method of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide, which is an important synthetic intermediate of fezolinetan, a non-azasetron developed as a selective antagonist of neurokinin (NK)-3 receptor, and is useful as a compound for the treatment of sex hormone-dependent diseases, in particular, for the treatment of moderate to severe vasomotor symptoms associated with menopause, such as flushing / hot flashes, and the like. BACKGROUND

[0002] Frezolinetan (generic name) (VEOZAH (registered trademark)) is developed as a selective antagonist of NK-3 receptor, and is useful as a compound for the treatment and / or prevention of sex hormone-dependent diseases, such as moderate to severe vasomotor symptoms associated with menopause, such as flushing / hot flashes, and the like. Frezolinetan 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, which is described in Patent Literature 1.

[0003]

[0004] Deuterated frezolinetan, (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, which is described in Patent Literature 2, is also developed for the same purpose.

[0005]

[0006] In Patent Literatures 1 and 2, as a synthetic method of frezolinetan and deuterated frezolinetan, a synthetic method via 3-methyl-1,2,4-thiadiazole-5-carbohydrazide or a compound represented by Formula (I) as a deuterated form thereof as an important intermediate is disclosed.

[0007]

[0008] (In the formula, R 1 represents methyl or methyl-d3.)

[0009] A synthetic method of a non-deuterated intermediate, 3-methyl-1,2,4-thiadiazole-5-carbohydrazide (2n), is disclosed in Patent Literature 3.

[0010]

[0011] which is prepared from the corresponding methyl ester (compound shown in the following formula (2.2n)), which is prepared from an acetamide (compound shown in the following formula (2.0n)), chlorosulfonyl chloride (compound shown in the following formula (2.0n')), and methyl cyanformate (compound shown in the following formula (2.0n")) in one step.

[0012]

[0013] However, chlorosulfonyl chloride and methyl cyanformate are dangerous reagents that cause problems in large-scale procurement, and it is difficult to scale up the batch. In addition, this synthesis route causes sulfur impurities that adversely affect the quality of the final drug product. Furthermore, even after optimization, the overall yield of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide is less than 30%. The same drawbacks are present in the synthesis of 3-(methyl-d3)-1,2,4-thiadiazole-5-carbohydrazide, which is a corresponding deuterated intermediate (Patent Literature 2).

[0014] In Patent Literature 4, as a method for synthesizing an intermediate compound shown in the following formula (I-1), a method is disclosed in which alkyloxycarbonylation based on a lithium exchange reaction or alkyloxycarbonylation based on carbon monoxide insertion reaction in the presence of a metal catalyst is performed from a compound shown in the following formula (III-1-a) or a compound shown in the following formula (III-1-b) which are corresponding halogenated intermediates, to thereby obtain a compound shown in the following formula (II-1-b) or a salt thereof which is a corresponding ester body, and synthesis is performed via the same.

[0015]

[0016]

[0017]

[0018]

[0019] However, the yield of the alkyloxycarbonylation reaction based on the lithium exchange reaction is as low as 29%, and in addition, although the alkyloxycarbonylation reaction based on the carbon monoxide insertion reaction in the presence of a metal catalyst can be performed to obtain the compound shown in the formula (II-1-b) with a good yield, it is necessary to use toxic carbon monoxide gas, and there are limitations in terms of scaling up, etc., and thus there are problems in terms of practical use.

[0020] Therefore, there is a need to develop a practical manufacturing method for 3-methyl-1,2,4-thiadiazole-5-carbohydrazide, which is an important synthetic intermediate of nonazatin, that is safe, has a good yield, and can be scaled up.

[0021] Prior Art Documents

[0022] Patent Literature

[0023] Patent Literature 1: International Publication No. 2014 / 154895

[0024] Patent Literature 2: International Publication No. 2019 / 012033

[0025] Patent Literature 3: International Publication No. 2013 / 050424

[0026] Patent Literature 4: International Publication No. 2020 / 128003 SUMMARY

[0027] PROBLEMS TO BE SOLVED BY THE INVENTION

[0028] An object of the present application is to provide a safe and practical production method of a compound represented by the following formula (I) or a salt thereof, which is an important synthetic intermediate of non-zanetan.

[0029]

[0030] SOLUTION TO PROBLEM

[0031] The present inventors and others have conducted intensive studies in order to solve the above problem, and as a result, have found that: a compound represented by the following formula (2) or a salt thereof is obtained via a process of reacting a compound represented by the following formula (1) or a salt thereof with an alkali metal cyanide in the presence of an organic base, and then reacting the same with MOR (in the formula, M represents an alkali metal, and R represents the same meaning as described above) in the presence of an alcohol represented by the following formula, and thereby a compound represented by the following formula (3) or a salt thereof can be produced in a good yield without using carbon monoxide gas, and as a result thereof, a safe and practical production method of a compound represented by the following formula (I) or a salt thereof, which is an important synthetic intermediate of non-zanetan, can be provided, and thus the present application has been accomplished.

[0032]

[0033] (in the formula, X represents a halogen atom.)

[0034]

[0035] (in the formula, R represents C 1-4 alkyl.)

[0036]

[0037] (in the formula, R represents the same meaning as described above.)

[0038]

[0039] (in the formula, R represents C1-4 alkyl.)

[0040]

[0041] That is, the present invention is as follows. [1]

[0043] A method for producing a compound or a salt thereof of formula (2), characterized in that it comprises the following steps: reacting a compound or a salt thereof of formula (1) with an alkali metal cyanide in a solvent containing an aprotic polar solvent in the presence of an organic base, followed by adding an alcohol of the following formula to react it with MOR (where M and R in the formula have the same meaning as described above),

[0044]

[0045] (In the formula, X represents a halogen atom.)

[0046]

[0047] (In the formula, R represents C) 1-4 alkyl.)

[0048]

[0049] (In the formula, R has the same meaning as described above.) [2]

[0051] According to the manufacturing method described above [1], X is a chlorine atom or a bromine atom. [3]

[0053] The manufacturing method described above [1] includes: adding an organic base when adding an alcohol. [4]

[0055] According to the manufacturing method described above [1], 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]

[0057] According to the manufacturing method described above [1], the alkali metal cyanide is potassium cyanide or sodium cyanide. [6]

[0059] According to the manufacturing method described above [1], the alcohol is methanol or ethanol. [7]

[0061] According to the manufacturing method described above [1], the aprotic polar solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide. [8]

[0063] According to the manufacturing method described above [1], the solvent further includes a non-polar solvent. [9]

[0065] According to the manufacturing method described above [8], the non-polar solvent is toluene, n-hexane, cyclohexane or n-heptane.

[10]

[0067] A method for manufacturing a compound of formula (3) or a salt thereof, comprising the following steps: acid hydrolysis of a compound of formula (2) or a salt thereof obtained by any one of the manufacturing methods described in [1] to [9] above,

[0068]

[0069] (R in the formula has the same meaning as described above.)

[11]

[0071] According to the manufacturing method described above

[10] , 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]

[0073] A method for manufacturing a compound of formula (I) or a salt thereof, comprising the following steps: reacting a compound of formula (3) or a salt thereof obtained by the manufacturing method described above

[10] with hydrazine or a hydrate thereof in a solvent.

[0074]

[13]

[0076] A compound of formula (2) or a salt thereof.

[0077]

[0078] (In the formula, R represents C) 1-4 alkyl.)

[0079] The effects of the invention

[0080] According to the present application, by using 3-methyl-1,2,4-thiadiazole-5-carbonimidic acid ester represented by the aforementioned formula (2) as a novel compound, it is possible to produce 3-methyl-1,2,4-thiadiazole-5-carbohydrazide represented by the aforementioned formula (I) or a salt thereof, which is an important synthetic intermediate of fezolanetan, in good yield without using toxic carbon monoxide gas, and thus, it is possible to provide a practical production method of fezolanetan which is safer and also enables mass production, compared with the conventional method. DETAILED DESCRIPTION

[0081] Hereinafter, definitions of terms and the like used in the present specification are described in detail.

[0082] In the present specification, sometimes a compound represented by a formula is indicated by labeling the number of the formula to the "compound". For example, a compound represented by formula (1) is indicated as "compound (1)".

[0083] In the present specification, a numerical range indicated by "~" or "-" means a numerical range in which the numbers before and after the "~" or "-" are taken as lower limit values or upper limit values.

[0084] In the present specification, in the case where a symbol in which the numerical range is labeled to the element symbol "C" before and after the "-" is labeled to the name of an arbitrary group to be indicated, it means an arbitrary group in which the number of carbon atoms is an integer taken as the lower limit value or the upper limit value before and after the "-". For example, sometimes an alkyl group having 1 to 4 carbon atoms is indicated as "C 1-4 alkyl", which respectively means -CH3, -C2H5, -C3H7, -C4H9, and the like.

[0085] In the present specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0086] In the present specification, "C 1-4 alkyl" means a saturated hydrocarbon group having 1 to 4 carbon atoms which is linear or branched, and as C 1-4 alkyl, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group can be mentioned.

[0087] In the present specification, "solvent containing an aprotic polar solvent" means that an aprotic polar solvent can be contained in the solvent. As the "solvent containing an aprotic polar solvent", there is no particular limitation, and for example, a solvent formed of at least one aprotic polar solvent, a mixed solvent of an aprotic polar solvent and a nonpolar solvent, and the like can be mentioned.

[0088] In the present specification, as the "non-protic polar solvent", there is no particular limitation, and, for example, amide-based solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and the like; sulfoxide-based solvents such as dimethyl sulfoxide, and the like; nitrile-based solvents such as acetonitrile, propionitrile, and the like, and the like can be exemplified, of which, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide is preferable.

[0089] In the present specification, as the "non-protic polar solvent", there is no particular limitation, and, for example, amide-based solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and the like; sulfoxide-based solvents such as dimethyl sulfoxide, and the like; nitrile-based solvents such as acetonitrile, propionitrile, and the like, and the like can be exemplified, of which, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide is preferable.

[0090] In the present specification, as the "alkali metal cyanide", lithium cyanide, potassium cyanide, sodium cyanide, cesium cyanide, and the like can be exemplified.

[0091] In the present specification, the "organic base" refers to an organic compound that functions as a base. The organic base is generally a proton acceptor that contains a nitrogen atom capable of being easily protonated, and amine, nitrogen-containing heterocyclic compounds, and the like can be exemplified. As the "organic base", there is no particular limitation, and, for example, 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), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), and the like can be exemplified.

[0092] In the present specification, the "prevention" includes prevention of onset of a disease, delay of onset of a disease, and prevention of development of a condition.

[0093] In the present specification, the "treatment" includes cure of a disease, improvement of a condition (e.g., one or more symptoms) of a disease, and inhibition of aggravation of a disease (of severity).

[0094] In the present specification, the "subject" refers to a subject to which a medicament (pharmaceutical composition) containing an effective ingredient in an effective amount required for prevention and / or treatment of a disease or a condition of a disease is administered. As the "subject", a human or a non-human animal (particularly, a mammal (e.g., mouse, rat, guinea pig, hamster, rabbit, cat, dog, cow, sheep, monkey, and the like)) can be exemplified.

[0095] In the present specification, as "a salt thereof", there is no particular limitation as long as it is a salt formed by reacting the object compound with a base or an acid, but since the present application relates to a method for producing an important synthetic intermediate of nonazatin, which is useful as a drug, a salt that can be used as a drug (pharmaceutically acceptable salt) is preferred. Each compound used in the production method of the present application, when an alkaline salt or an acid salt is formed by reacting with a base or an acid, represents a salt thereof.

[0096] As "an alkaline salt", for example, a sodium salt, a potassium salt, a lithium salt, a magnesium salt, a calcium salt, an aluminum salt, an ammonium salt, a tetramethylammonium salt, an N-methylmorpholine salt, a diethylamine salt, a triethylamine salt, a tributylamine salt, a diisopropylethylamine salt, a dicyclohexylamine salt, an N-methylpiperidine salt, a pyridine salt, a 4-pyrrolidinopyridine salt, a picoline salt, a choline salt, a diethanolamine salt, a meglumine salt, an ethanolamine salt, an tromethamine salt, a 2- (diethylamino) ethanol salt, a 4- (2-hydroxyethyl) morpholine salt, an arginine salt, a glycine salt, a lysine salt, a benzathine penicillin salt, and the like can be exemplified.

[0097] As "an acid salt", for example, a hydrofluoric acid salt, a hydrochloric acid salt, a hydrobromic acid salt, a hydroiodic acid salt, a nitric acid salt, a perchloric acid salt, a sulfuric acid salt, a bisulfuric acid salt, a boric acid salt, a camphorsulfonic acid salt, a cyclamic acid salt, a carbonic acid salt, a bicarbonic acid salt, a phosphoric acid salt, a hexafluorophosphoric acid salt, a formic acid salt, a lactic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a trifluoromethanesulfonic acid salt, an ethanesulfonic acid salt, an ethanedisulfonic acid salt, a benzoic acid salt, a benzenesulfonic acid salt, a toluenesulfonic acid salt, an acetic acid salt, a malic acid salt, a fumaric acid salt, a succinic acid salt, a malonic acid salt, a citric acid salt, an ascorbic acid salt, a tartaric acid salt, an oxalic acid salt, a maleic acid salt, an adipic acid salt, a nicotinic acid salt, an aspartic acid salt, a gluconic acid salt, a glucuronic acid salt, a pyroglutamic acid salt, a stearic acid salt, a palmitic acid salt, a tannic acid salt, a isethionic acid salt, a naphthoic acid salt, a orotic acid salt, a pamoic acid salt, a xinafoic acid salt, a glucoheptonic acid salt, a hippuric acid salt, and the like can be exemplified.

[0098] In the present application, the compound represented by formula (I) (Compound (I)) or a salt thereof also includes a compound in which the methyl group at the 3-position is replaced with deuterium, 3- (methyl-d3) -1, 2, 4-thiadiazole-5-carbohydrazide or a salt thereof.

[0099]

[0100] (Method for producing the present application)

[0101] Hereinafter, the production method of the present application will be described.

[0102] The compound represented by formula (I) (Compound (I)) or a salt thereof can be produced by the following production method, the following examples, or a method based on them, and the like.

[0103]

[0104] Each of the raw material compounds can form a salt, and the same salts as the aforementioned salts can be exemplified as the salt.

[0105] The raw material compounds can be readily obtained commercially and used without describing specific production methods, or can be produced according to publicly known methods or methods based thereon. In addition, the intermediates generated in the following production methods can be isolated and purified by column chromatography, recrystallization, distillation, or the like, or can be used in the next step without isolation.

[0106] In the present specification, the contents of all patent documents, non-patent documents, or references explicitly cited are incorporated herein as a part of the present specification.

[0107] In the present application, the compound (I) or a salt thereof is produced by the following procedures: a procedure (Procedure 1) in which a compound represented by formula (1) (Compound (1)) or a salt thereof is reacted with an alkali metal cyanide in the presence of an organic base in a solvent containing an aprotic polar solvent, and then an alcohol represented by the following formula is added to be reacted with MOR (in the formula, M represents an alkali metal, and R represents the same meaning as described above), to produce a compound represented by formula (2) (Compound (2)) or a salt thereof; a procedure (Procedure 2) in which Compound (2) or a salt thereof is subjected to acid hydrolysis to produce a compound represented by formula (3) (Compound (3)) or a salt thereof; and a procedure (Procedure 3) in which Compound (3) or a salt thereof is reacted with hydrazine or a hydrate thereof.

[0108]

[0109] (in the formula, X represents a halogen atom.)

[0110]

[0111] (in the formula, R represents C 1-4 alkyl.)

[0112]

[0113] (in the formula, R represents the same meaning as described above.)

[0114]

[0115] (in the formula, R represents the same meaning as described above.)

[0116] Hereinafter, each procedure of the production method of the present application is described in detail.

[0117] (Procedure 1)

[0118] This process is a process of producing compound (2) or a salt thereof by adding an alcohol represented by the following formula to a reaction mixture after reacting compound (1) or a salt thereof with an alkali metal cyanide (M'CN) in the presence of an organic base in a solvent containing an aprotic polar solvent (process 1-1) (process 1-2).

[0119]

[0120] (wherein R represents C 1-4 alkyl.)

[0121] The reaction of this process is performed via 5-cyano-3-methyl-1,2,4-thiadiazole without isolating and purifying 5-cyano-3-methyl-1,2,4-thiadiazole, and compound (2) or a salt thereof can be obtained in one pot.

[0122]

[0123] (wherein M' represents an alkali metal, and the other symbols have the same meanings as described above.)

[0124] Compound (1) or a salt thereof can be suitably used a substance synthesized by a method known per se (for example, refer to International Publication No. 2020 / 128003 (Patent Document 4), Chem. Ber., 1957, 90, 182-187, and the like) or a method based thereon. As compound (1) or a salt thereof, 5-chloro-3-methyl-1,2,4-thiadiazole or 5-bromo-3-methyl-1,2,4-thiadiazole is preferred, and 5-chloro-3-methyl-1,2,4-thiadiazole is more preferred.

[0125] As the alkali metal cyanide (M'CN) used, there is no particular limitation, and for example, lithium cyanide, potassium cyanide, sodium cyanide, cesium cyanide, and the like can be exemplified, and potassium cyanide or sodium cyanide is preferred, and sodium cyanide is more preferred.

[0126] The amount of the alkali metal cyanide used is 0.7 to 3 moles, and preferably 0.8 to 1.5 moles, relative to 1 mole of compound (1) or a salt thereof.

[0127] As the organic base used, there is no particular limitation, and examples include triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMO), pyridine, 2,6-lutidine, 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), and the like, with 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) being preferred, and 1,4-diazabicyclo[2.2.2]octane (DABCO) being more preferred.

[0128] As for the amount of the organic base used, 0.05 to 2 moles, preferably 0.05 to 0.2 moles, per 1 mole of the compound (1) or a salt thereof can be used.

[0129] The present reaction can be performed in a solvent containing an aprotic polar solvent.

[0130] As the solvent containing an aprotic polar solvent, the aforementioned solvents can be used, with a solvent formed of a single aprotic polar solvent, or a mixed solvent of an aprotic polar solvent and a nonpolar solvent being preferred, and a mixed solvent of an aprotic polar solvent and a nonpolar solvent being more preferred.

[0131] As the aprotic polar solvent constituting the mixed solvent of an aprotic polar solvent and a nonpolar solvent, there is no particular limitation, and examples include amide-based solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone; sulfoxide-based solvents such as dimethyl sulfoxide; nitrile-based solvents such as acetonitrile and propionitrile; and the like, with N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide being preferred, and N,N-dimethylformamide being more preferred.

[0132] As the nonpolar solvent constituting the mixed solvent of an aprotic polar solvent and a nonpolar solvent, there is no particular limitation, and examples include aromatic hydrocarbon-based solvents such as toluene and xylene; aliphatic hydrocarbon-based solvents such as n-hexane, cyclohexane, and n-heptane; and the like, with toluene, n-hexane, cyclohexane, or n-heptane being preferred, and toluene being more preferred.

[0133] The mixing ratio (v / v) of the mixed solvent of the aprotic polar solvent and the nonpolar solvent is not particularly limited, and is usually in the range of 0.1 to 100, preferably in the range of 0.2 to 5, and more preferably in the range of 0.5 to 3, as the aprotic polar solvent / nonpolar solvent.

[0134] In the process 1-2, as the alkali metal alkoxide (MOR) used, there is no particular limitation as long as it is an alkali metal alkoxide having 1 to 4 carbon atoms, and sodium methoxide, potassium methoxide, sodium ethoxide, or potassium ethoxide is preferred, and sodium methoxide or sodium ethoxide is more preferred. In addition, as for the amount of the alkali metal alkoxide used, 0.05 to 2 moles, preferably 0.08 to 0.2 moles, per 1 mole of the compound (1) or the salt thereof can be used. In addition, the alcohol used in the process 1-2 is an alcohol that can form an alkali metal alkoxide (specifically, for example, sodium ethoxide / ethanol, etc.).

[0135] The process 1-2 can also be performed in the presence of an organic base as needed. As the organic base, the same organic bases as described above can be listed, and triethylamine (TEA) is preferred.

[0136] By adding the organic base, the alkali metal cyanide (M'CN) remaining in the reaction system at the time of post-treatment can be inactivated, the generation of hydrogen cyanide can be suppressed, and thus the process has the advantage that it can be performed safely.

[0137] As for the amount of the organic base used, 0.05 to 2 moles, preferably 0.1 to 0.3 moles, per 1 mole of the compound (1) or the salt thereof can be used.

[0138] The reaction temperature of the process 1-1 is usually 0°C to 120°C, and the reaction time is usually 3 to 24 hours.

[0139] The reaction temperature of the process 1-2 is usually -10°C to 20°C, and the reaction time is usually 0.5 to 4 hours.

[0140] (Process 2)

[0141] The present process is a process for producing a compound (3) or a salt thereof by subjecting the compound (2) or the salt thereof obtained in the aforementioned process 1 to acid hydrolysis.

[0142]

[0143] As the acid used, either a protic acid or a Lewis acid can be used, and as the protic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid is preferred, and sulfuric acid or hydrochloric acid is more preferred, and as the Lewis acid, aluminum chloride (AlCl3), boron trifluoride (BF3), titanium chloride (TiCl3), or zinc chloride (ZnCl2) is preferred. The acid can be used after being diluted with water.

[0144] As for the amount of the acid, 1 to 3 moles, preferably 1.03 to 1.5 moles, can be used per 1 mole of the compound (2) or the salt thereof.

[0145] The reaction temperature is usually from 0°C to 20°C, preferably from 0°C to 10°C, and the reaction time is usually from 0.5 to 4 hours.

[0146] (Step 3)

[0147] This step is a step for producing the compound (I) or the salt thereof by reacting the compound (3) or the salt thereof obtained in the aforementioned Step 2 with hydrazine or a hydrate thereof in a solvent.

[0148]

[0149] As the hydrazine or the hydrate thereof, there is no particular limitation, and hydrazine monohydrate is preferred.

[0150] As for the amount of the hydrazine or the hydrate thereof, 1 to 2 moles, preferably 1 to 1.2 moles, can be used per 1 mole of the compound (3) or the salt thereof.

[0151] The present reaction can be performed in a solvent that does not affect the reaction. As the reaction solvent, there is no particular limitation, and, for example, aromatic hydrocarbons such as toluene, xylene, and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and the like; alcohols such as methanol, ethanol, isopropanol, and the like; nitriles such as acetonitrile, and the like, or a mixture thereof can be exemplified, of which a mixed solvent of an alcohol and an aromatic hydrocarbon is preferred, and a mixed solvent of isopropanol-toluene is more preferred.

[0152] The reaction temperature is usually from -10°C to 30°C, preferably from 0°C to 10°C, and the reaction time is usually from 3 to 24 hours.

[0153] After the completion of the reaction, the compound (I) or the salt thereof can be isolated and / or purified from the reaction mixture by means of separation methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography, and the like, in accordance with a conventional method.

[0154] The compound (I) or the salt thereof obtained in the aforementioned Step 3 can be converted into nonazatinan by a method known per se (for example, refer to International Publication No. 2014 / 154895 (Patent Document 1), International Publication No. 2019 / 012033 (Patent Document 2)) or a method based thereon.

[0155] The production method of the present application does not use carbon monoxide gas, which is industrially used in a limited amount, at all, and thus has an advantage that the compound (I) or the salt thereof can be synthesized in a good yield through a safe and simple operation, as compared with the conventional method.

[0156] (compounds of the invention)

[0157] The production method of the present invention is characterized by not using carbon monoxide, by using a compound represented by formula (2) (compound (2)) or a salt thereof as a synthetic intermediate, thereby enabling the production of compound (I) or a salt thereof, which is an important synthetic intermediate of nonazatinan, more safely and with a good yield compared to the prior art.

[0158]

[0159] (R in the formula represents the same meaning as described above.)

[0160] Compound (2) or a salt thereof is a novel compound, which is useful as a novel intermediate compound in the synthesis of nonazatinan.

[0161] Examples

[0162] Hereinafter, the present invention will be specifically described by referring to Examples and Reference Examples, but the present invention is not limited to these examples.

[0163] In the present specification, mol / mol% is indicated when referring to a yield, and weight is indicated unless otherwise specified when referring to other matters. In addition, room temperature indicates a temperature of 15 to 30°C unless otherwise specified.

[0164] Nuclear magnetic resonance spectroscopy (NMR) was measured using ECZ400S FT-NMR manufactured by JEOL. 1 H-NMR was measured at 400 MHz with tetramethylsilane as a reference. When a deuterated solvent was used as a measurement solvent, the name of the deuterated solvent was noted.

[0165] Infrared absorption spectroscopy (IR) was measured by the ATR method using Nic-plan / Nicolet 6700 manufactured by Thermo Fisher Scientific.

[0166] Liquid chromatography-mass spectrometry (LC-MS) was measured using UltiMate 3000 and Q Exactive manufactured by Thermo Fisher Scientific.

[0167] High-performance liquid chromatography (HPLC) was measured using 1220 Infinity LC manufactured by Agilent Technologies, and the column used was Atlantis T3 (3 μm (particle diameter), 4.6 x 150 mm, manufactured by Waters).

[0168] In addition, the abbreviations used in the following Examples and the like indicate the following meanings.

[0169] s: singlet

[0170] t: triplet

[0171] q: quartet

[0172] br: broad

[0173] J: coupling constant

[0174] CDCl3: deuterated chloroform

[0175] DMSO-d6: deuterated dimethyl sulfoxide

[0176] CH2Cl2: dichloromethane

[0177] NaOH: sodium hydroxide

[0178] NaCN: sodium cyanide

[0179] DABCO: 1,4-diazabicyclo[2.2.2]octane

[0180] DMF: N,N-dimethylformamide

[0181] TEA: triethylamine

[0182] NaOEt: sodium ethoxide

[0183] EtOH: ethanol

[0184] iPrOH: isopropanol

[0185] [Reference Example 1]

[0186] Production of 5-chloro-3-methyl-1,2,4-thiadiazole (1-1)

[0187]

[0188] To ethanimidamide hydrochloride (100 g, 1.06 mol), trichloromethylsulfonyl chloride (196.8 g, 1.06 mol), and 6 M aqueous sodium hydroxide solution (902.7 g, 4.4 eq.) was added dichloromethane (530 mL (5.3 v / w)) under a nitrogen atmosphere (atmospheric pressure) at 0°C, and the reaction mixture was stirred at 25°C for 2 hours. Then, the reaction mixture was separated into layers, and the obtained organic layer was washed with 6 M hydrochloric acid (350 mL (3.5 v / w)) and water (350 g (3.5 v / w)) in this order. By subjecting the obtained organic layer to simple distillation (reduced pressure: 400-15 Torr, internal temperature: 25-60°C), the title compound (1-1) was obtained in a yield of 54% (quantitative value in LC).

[0189] 1H-NMR (400MHz, CDC13) δ 2.64 (s, 3H).

[0190] [Example 1]

[0191] Production of ethyl 3-methyl-1,2,4-thiadiazole-5-carboximide (2-1)

[0192]

[0193] Under a nitrogen atmosphere (atmospheric pressure), at 15°C, the compound (1-1) obtained in Reference Example 1 (4 g, 29.72 mmol), 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, and the reaction mixture was stirred at the same temperature for 4 hours. Then, to the reaction mixture were added toluene (12.16 mL), triethylamine (0.60 g, 5.94 mmol), ethanol (1.36 g, 29.72 mmol), and 20% sodium ethoxide / ethanol solution (0.83 mL, 2.43 mmol) at 15°C, and further stirred at the same temperature for 1 hour. To the reaction mixture was added water, and after two liquid separation operations, the organic layer was washed with 10% sodium chloride aqueous solution, whereby a toluene solution of the title compound (2-1) was obtained in a yield of 67% (quantitative value in LC).

[0194] 1 H-NMR (400MHz, DMSO-d6) δ 0.52 (t, J=7.3 Hz, 3H), 1.85 (s, 3H), 3.54 (q, J=7.3 Hz, 2H), 8.49 (s, 1H);

[0195] IR (cm -1 ) 3286, 2900-3000, 1653, 1450;

[0196] LC-MS m / z 172.0535 ([M+H] + )

[0197] The hydrogen cyanide gas concentration in the gas phase portion of the reaction vessel in this reaction was below the detection limit (≤10 ppm), and it was confirmed that the reaction was safe.

[0198] [Example 2]

[0199] Production of ethyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (3-1)

[0200]

[0201] A toluene solution (concentration: 14%) of the compound (2-1) obtained in Example 1 (2201.3 g, 1.82 mol) was cooled to 5°C under a nitrogen atmosphere, and water and concentrated sulfuric acid (347.2 g (1.9 eq.)) were added dropwise. After stirring at 5°C for 1 hour, the reaction mixture was subjected to liquid separation. To the obtained organic phase, 10% sodium carbonate aqueous solution was added until the pH reached 5 to 6, and subjected to liquid separation. The obtained organic layer was subjected to quantitative analysis, and a toluene solution of the title compound (3-1) was obtained in a yield of 98% (quantitative value in LC).

[0202] 1 H-NMR (400 MHz, DMSO-d6) δ 1.28 (t, J = 8.0 Hz, 3H), 2.59 (s, 3H), 4.35 (q, J = 7.6 Hz, 2H).

[0203] [Example 3]

[0204] Production of 3-methyl-l,2,4-thiadiazole-5-carbohydrazide (I)

[0205]

[0206] Hydrazine monohydrate (93.7 g, 1.85 mol) was added to isopropanol (1519 mL (5 v / w)) under a nitrogen atmosphere, and the mixture was cooled to 0 to 10°C. A toluene solution (concentration: 15%) of the compound (3-1) obtained in Example 2 (2052.6 g, 1.76 mol) was added dropwise to the mixture, and the mixture was stirred at 0 to 10°C for 12 hours. Then, the reaction mixture was filtered under reduced pressure, and the filtrate was washed with isopropanol (400 mL (4 v / w)) and dried under reduced pressure, whereby a toluene solution of the title compound (I) was obtained in a yield of 94% (quantitative value in LC).

[0207] 1 H-NMR (400 MHz, DMSO-d6) δ 2.56 (s, 3H), 4.82 (br, 2H), 10.56 (br, 1H).

[0208] [Example 4]

[0209] Production of methyl 3-methyl-l,2,4-thiadiazole-5-carboximide (2-2)

[0210]

[0211] A mixture of 5-bromo-3-methyl-l,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) was mixed under a nitrogen atmosphere (atmospheric pressure) at 15°C, and the reaction mixture was stirred at the same temperature for 4 hours. Then, to the reaction mixture were added 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) at 15°C, and further stirred at the temperature for 1 hour. To the reaction mixture was added water, and after two liquid separation operations, the organic layer was washed with 10% sodium chloride aqueous solution, whereby a toluene solution of the title compound (2-2) was obtained in a yield of 61% (quantitative value in NMR).

[0212] 1 H-NMR (400 MHz, CDC13) δ 2.36 (s, 3H), 3.47 (s, 3H), 9.36 (s, IH);

[0213] [Example 5]

[0214] Production of methyl 3-methyl-l,2,4-thiadiazole-5-carboxylate (3-2)

[0215]

[0216] After the toluene solution (concentration: 14%) of the compound (2-2) obtained in Example 4 (204.4 g, 0.18 mol) was cooled to 5°C under a nitrogen atmosphere, water and concentrated sulfuric acid (34.7 g (1.9 eq.)) were added dropwise, and stirred at 5°C for 1 hour, after which the reaction mixture was subjected to liquid separation. To the obtained organic phase was added 10% sodium carbonate aqueous solution until the pH reached 5 to 6, and subjected to liquid separation. As a result of quantification of the obtained organic layer, a toluene solution of the title compound (3-2) was obtained in a yield of 96% (quantitative value in NMR).

[0217] 1 H-NMR (400 MHz, CDC13) δ 2.36 (s, 3H), 3.47 (s, 3H), 9.36 (s, IH);

[0218] [Example 6]

[0219] Production of 3-methyl-l,2,4-thiadiazole-5-carbohydrazide (I)

[0220]

[0221] Hydrazine monohydrate (9.37 g, 0.185 mol) was added to isopropanol (152 mL (5 v / w)) under a nitrogen atmosphere, and after cooling to 0-10°C, a toluene solution (concentration 15%) of the compound (3-2) obtained in Example 5 (188.4 g, 0.176 mol) was added dropwise thereto, and stirred at 0-10°C for 12 hours. Then, the reaction mixture was filtered under reduced pressure, and the filtrate was washed with isopropanol (40 mL (4 v / w)), and dried under reduced pressure, whereby the title compound (I) was obtained in a yield of 92% (quantitative value in LC).

[0222] 1 H-NMR (400 MHz, DMSO-d6) δ 2.56 (s, 3H), 4.82 (br, 2H), 10.56 (br, 1H).

[0223] [Example 7]

[0224] Production of tert-butyl 3-methyl-1,2,4-thiadiazine-5-carboxylate (2-3)

[0225]

[0226] The compound (1-1) obtained in Reference Example 1 (4 g, 29.72 mmol), 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. Then, to the reaction mixture were added toluene (12.16 mL), triethylamine (0.60 g, 5.94 mmol), tert-butanol (2.20 g, 29.72 mmol), and sodium tert-butoxide (0.23 g, 2.43 mmol) at 15°C, and further stirred at the temperature for 1 hour. To the reaction mixture was added water, and after 2 liquid separation operations, the organic layer was washed with 10% sodium chloride aqueous solution, whereby a toluene solution of the title compound (2-3) was obtained in a yield of 67% (quantitative value in NMR).

[0227] 1 H-NMR (400 MHz, CDCl3) δ 1.38 (s, 9H), 2.36 (s, 3H), 9.36 (s, 1H);

[0228] [Example 8]

[0229] Production of tert-butyl 3-methyl-1,2,4-thiadiazine-5-carboxylate (2-3)

[0230]

[0231] After the toluene solution (concentration: 14%) (260.3 g, 0.18 mol) of the compound (2-3) obtained in Example 7 was cooled to 5°C under a nitrogen atmosphere, water and 35% hydrochloric acid (36.0 g (1.9 eq.)) were added dropwise, and stirred at 5°C for 1 hour, after which the reaction mixture was subjected to liquid separation. To the obtained organic phase, 10% sodium carbonate aqueous solution was added until the pH reached 5 to 6, and subjected to liquid separation. As a result of quantification of the obtained organic layer, the toluene solution of the title compound (3-3) was obtained in a yield of 90% (quantitative value in NMR).

[0232] 1 H-NMR (400MHz, CDC13) δ 1.42 (s, 9H), 2.36 (s, 3H).

[0233] [Example 9]

[0234] Production of 3-methyl-l,2,4-thiadiazole-5-carbohydrazide (I)

[0235]

[0236] After hydrazine monohydrate (9.37 g, 0.185 mol) was added to isopropyl alcohol (152 mL (5 v / w)) and cooled to 0 to 10°C under a nitrogen atmosphere, the toluene solution (concentration: 15%) (240.0 g, 0.176 mol) of the compound (3-3) obtained in Example 8 was added dropwise, and stirred at 0 to 10°C for 12 hours. Then, the reaction mixture was filtered under reduced pressure, the filtrate was washed with isopropyl alcohol (40 mL (4 v / w)), and subjected to reduced pressure drying, whereby the title compound (I) was obtained in a yield of 93% (quantitative value in LC).

[0237] 1 H-NMR (400MHz, DMSO-d6) δ 2.56 (s, 3H), 4.82 (br, 2H), 10.56 (br, 1H).

[0238] Industrial applicability

[0239] According to the present application, by passing through 3-methyl-l,2,4-thiadiazole-5-carbohydrazide (compound (I)) or a salt thereof, which is an important synthetic intermediate of non-azanilatans, as a novel compound of 3-methyl-l,2,4-thiadiazole-5-carbohydrazide (compound (I)), it is possible to produce 3-methyl-l,2,4-thiadiazole-5-carbohydrazide (compound (I)) or a salt thereof, which is an important synthetic intermediate of non-azanilatans, in a good yield without using toxic carbon monoxide gas, and thus, it is possible to provide a practical production method of non-azanilatans which is safer than the existing method and also enables mass production.

[0240] This application is based on Japanese Patent Application No. 2023-109328 filed in Japan on July 3, 2023, the content of which is incorporated herein by reference in its entirety.

Claims

1. A method for producing a compound of formula (2) or a salt thereof, characterized in that, which comprises the step of adding an alcohol represented by the following formula to a compound represented by the formula (1) or a salt thereof, which has been reacted with an alkali metal cyanide in the presence of an organic base in a solvent containing an aprotic polar solvent, to allow it to react with MOR, In the formula (1), X represents a halogen atom, In the formula ROH, R represents C 1-4 alkyl, R in the formula (2) represents the same meaning as described above, In the formula MOR, M represents an alkali metal, and R represents the same meaning as described above.

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

3. The manufacturing method of claim 1, comprising: The organic base is further added at the time of adding the alcohol.

4. The manufacturing method according to claim 1, wherein, The organic base is triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine, 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 manufacturing method according to claim 1, wherein, The alkali metal cyanide is potassium cyanide or sodium cyanide.

6. The production method according to claim 1, wherein The alcohol is methanol or ethanol.

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

8. The manufacturing method according to claim 1, wherein, The solvent further contains a nonpolar solvent.

9. The manufacturing method according to claim 8, wherein, The nonpolar solvent is toluene, n-hexane, cyclohexane, or n-heptane.

10. A method for producing a compound represented by the formula (3) or a salt thereof, which comprises the step of subjecting a compound represented by the formula (2) or a salt thereof, which is obtained by the production method described in any one of claims 1 to 9, to acid hydrolysis, R in the formula (3) represents the same meaning as described above.

11. The manufacturing method 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 the formula (I) or a salt thereof, which comprises the step of reacting a compound represented by the formula (3) or a salt thereof, which is obtained by the production method described in claim 10, with hydrazine or a hydrate thereof in a solvent, 。 13. A compound represented by the formula (2) or a salt thereof, In formula (2), R represents C 1-4 alkyl.

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