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 3-methyl-1, 2, 4-thiadiazole-5-carboxamide or a salt thereof without the use of toxic carbon monoxide, and more particularly, 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. 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] This invention relates to a safe and practical novel method for manufacturing 3-methyl-1,2,4-thiadiazole-5-carbonylhydrazine, which is an important synthetic intermediate of fezonetan, developed as a selective antagonist of neurokinin (NK)-3 receptors and particularly useful as a therapeutic compound for sex hormone-dependent diseases. Background Technology

[0002] Fezolinetant (generic name) (VEOZAH, registered trademark) was 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 disorders, such as moderate to severe vasomotor symptoms associated with amenorrhea, including hot flashes / fever. 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) methyl ketone, as described in Patent Document 1.

[0003]

[0004] For the same purpose, deuterated fezoniltan and (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) methyl ketone have also been developed, as described in Patent Document 2.

[0005]

[0006] In Patent Documents 1 and 2, methods for synthesizing fezonatem and deuterated fezonatem are disclosed, which involve the synthesis of 3-methyl-1,2,4-thiadiazole-5-carbonylhydrazine as an important intermediate or the compound represented by formula (I) as its deuterated form.

[0007]

[0008] (where R) 1 (This indicates methyl or methyl-d3.)

[0009] Patent document 3 discloses a method for synthesizing a non-deuterated intermediate, 3-methyl-1,2,4-thiadiazole-5-carbonylhydrazine (2n).

[0010]

[0011] It is prepared from the corresponding methyl ester (the compound shown in formula (2.2n) below), which is prepared in one step from acetamide (the compound shown in formula (2.0n) below), chlorocarbonyl sulfinyl chloride (the compound shown in formula (2.0n') below) and methyl cyanoformate (the compound shown in formula (2.0n) below).

[0012]

[0013] However, chlorocarbonyl sulfinyl chloride and methyl cyanoformate are hazardous reagents that can cause large-scale procurement problems and are difficult to scale up. Furthermore, this synthetic route introduces sulfur impurities that adversely affect the quality of the final pharmaceutical product. Consequently, even after optimization, the overall yield of 3-methyl-1,2,4-thiadiazole-5-carbonylhydrazide remains less than 30%. The same drawback exists in the synthesis of 3-(methyl-d3)-1,2,4-thiadiazole-5-carbonylhydrazide, which serves as the corresponding deuterated intermediate (Patent Document 2).

[0014] In Patent Document 4, as a method for synthesizing the intermediate compound shown in Formula (I-1), it is disclosed that: by alkoxycarbonylation based on lithium exchange reaction or alkoxycarbonylation based on carbon monoxide insertion reaction in the presence of a metal catalyst, the compound shown in Formula (II-1-b) or its salt as the corresponding ester body is obtained, and a method for synthesis is carried out via the following:

[0015]

[0016]

[0017]

[0018]

[0019] However, the yield of alkoxycarbonylation based on lithium exchange reaction is as low as 29%. In addition, although alkoxycarbonylation based on carbon monoxide insertion reaction in the presence of metal catalyst can yield the compound shown in the above formula (II-1-b) in good yield, it requires the use of toxic carbon monoxide gas, which limits its scale-up and other aspects, thus leaving challenges for practical application.

[0020] Therefore, there is a need to develop a safe, high-yield, and scalable practical manufacturing method for 3-methyl-1,2,4-thiadiazole-5-carbonylhydrazide, an important synthetic intermediate for fezonetane.

[0021] Existing technical documents

[0022] Patent documents

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

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

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

[0026] Patent Document 4: International Publication No. 2020 / 128003 Summary of the Invention

[0027] The problem the invention aims to solve

[0028] The object of the present invention is to provide a safe, well-yielding, and practical method for manufacturing compounds of formula (I) or salts thereof, which are important synthetic intermediates of fezonilant.

[0029]

[0030] Solution for solving the problem

[0031] In order to solve the above-mentioned problems, the inventors conducted in-depth research and found that by reacting the compound or its salt represented by formula (1) with an alkali metal cyanide in the presence of an organic base, the compound or its salt represented by formula (3) can be efficiently manufactured without the use of carbon monoxide gas. As a result, a safe and practical method for manufacturing the compound or its salt represented by formula (I) as an important synthetic intermediate for fezonilant is available, thus completing the present invention.

[0032]

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

[0034]

[0035]

[0036] (In the formula, R represents C) 1-4 alkyl.)

[0037]

[0038] That is, the present invention is as follows. [1]

[0040] 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 mixed solvent of acetonitrile and water, in the presence of an organic base.

[0041]

[0042] (In the formula, X represents a halogen atom.)

[0043] . [2]

[0045] According to the manufacturing method described above [1], X is a chlorine atom or a bromine atom. [3]

[0047] 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. [4]

[0049] According to the manufacturing method described above [1], the alkali metal cyanide is potassium cyanide or sodium cyanide. [5]

[0051] According to the manufacturing method described above [1], the mixing ratio (v / v) of the acetonitrile-water mixed solvent is in the range of 1 to 10, calculated as water / acetonitrile. [6]

[0053] A method for manufacturing a compound of formula (3) or a salt thereof, comprising the following steps: reacting a compound of formula (2) or a salt thereof obtained by any one of the manufacturing methods described in [1] to [5] with thionyl chloride in the presence of an alcohol of the formula shown below.

[0054]

[0055] (In the formula, R represents C) 1-4 alkyl.)

[0056]

[0057] (R in the formula has the same meaning as described above). [7]

[0059] According to the manufacturing method described above [6], the alcohol is methanol or ethanol. [8]

[0061] 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 [6] or [7] with hydrazine or a hydrate thereof in a solvent.

[0062]

[0063] The effects of the invention

[0064] According to the present invention, 3-methyl-1,2,4-thiadiazole-5-carbonylhydrazine or its salt, which is an important synthetic intermediate of fezonatem, can be produced in good yield without the use of toxic carbon monoxide gas. Therefore, a practical method for manufacturing fezonatem, which is safer and can be scaled up in batches, can be provided compared with existing methods. Detailed Implementation

[0065] The following is a detailed description of the definitions of terms used in this specification.

[0066] In this specification, the compound is sometimes designated by the number of the formula to indicate the compound represented by the formula. For example, the compound represented by formula (1) is referred to as "compound (1)".

[0067] In this specification, the numerical range indicated by "~" or "-" refers to the numerical range with the numbers before and after "~" or "-" as the lower or upper limit values.

[0068] In this specification, when the element symbol "C" is indicated by numbers before and after "-" indicating a numerical range, it represents any group name containing an integer number of carbon atoms, with the numbers before and after "-" serving as the lower or upper limit. For example, sometimes an alkyl group with 1 to 4 carbon atoms is represented by "C". 1-4 "alkyl" refers to -CH3, -C2H5, -C3H7, -C4H9, etc.

[0069] In this specification, "halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom.

[0070] In this specification, "C" 1-4 "Alkyl" refers to a saturated hydrocarbon group with 1 to 4 carbon atoms, either straight-chain or branched, and is a C14 group. 1-4 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, can be listed.

[0071] In this specification, lithium cyanide, potassium cyanide, sodium cyanide, cesium cyanide, etc., can be listed as "alkali metal cyanides".

[0072] In this specification, "organic base" refers to an organic compound that functions as a base. Organic bases are generally proton acceptors containing nitrogen atoms that can be readily tetrolated, and examples include amines and nitrogen-containing heterocyclic compounds. There is no particular limitation on the definition of "organic base," and examples 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).

[0073] In this specification, "prevention" includes preventing the onset of disease, delaying the onset of disease, and preventing the development of disease.

[0074] In this specification, "treatment" includes the cure of the subject's disease, the improvement of the condition of the disease (e.g., one or more symptoms), and the suppression of the aggravation of the disease (severity).

[0075] In this specification, "object" means the person to whom a medicament (pharmaceutical composition) is given, which contains an effective amount of an active ingredient required for the prevention and / or treatment of a disease or the condition of a disease. Examples of such "objects" include humans or non-human animals (particularly mammals such as mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, etc.).

[0076] In this specification, the term "its salt" is not particularly limited to any salt formed by reacting the target compound with a base or acid. However, since this invention relates to a method for manufacturing an important synthetic intermediate of fezonalant that is useful as a pharmaceutical, a salt that can be used as a pharmaceutical product (a pharmaceutically acceptable salt) is preferred. The compounds used in the manufacturing method of this invention are referred to as their salts when they form basic or acidic salts by reacting with a base or acid.

[0077] Examples of "basic salts" include sodium salts, potassium salts, lithium salts, magnesium salts, calcium salts, aluminum salts, ammonium salts, tetramethylammonium salts, N-methylmorpholine salts, diethylamine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidine salts, pyridine salts, 4-pyrrolylpyridine salts, methylpyridine salts, choline salts, diethanolamine salts, meglumine salts, ethanolamine salts, tromethamine salts, 2-(diethylamino)ethanol salts, 4-(2-hydroxyethyl)morpholine salts, arginine salts, glycine salts, lysine salts, and benzathine penicillin salts.

[0078] Examples of "acid salts" include hydrofluoric acid salts, hydrochloride salts, hydrobromide salts, hydroiodide salts, nitrates, perchlorate salts, sulfates, hydrogen sulfate salts, borates, camphor sulfonates, cyclohexane salts, carbonates, bicarbonates, phosphates, hexafluorophosphates, formates, lactates, trifluoroacetates, methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, ethanedisulfonates, benzoates, benzenesulfonates, toluenesulfonates, acetates, malates, fumarates, succinates, malonates, citrates, ascorbic acid salts, tartrates, oxalates, maleates, adipates, nicotinates, aspartate salts, gluconates, glucuronates, pyroglutamate, stearates, palmitates, tannates, hydroxyethanesulfonates, naphthates, orotates, pamoates, ximetates, glucoheponicates, and phenacetinates.

[0079] In this invention, the compound represented by formula (I) (compound (I)) or its salt also includes compounds formed by deuteration of the 3-methyl group, 3-(methyl-d3)-1,2,4-thiadiazole-5-carbonylhydrazine or its salt.

[0080]

[0081] (Manufacturing method of the present invention)

[0082] The manufacturing method of the present invention will be described below.

[0083] The compound (compound (I)) shown in formula (I) or its salt can be manufactured by the manufacturing methods described below, the examples described later, or methods based thereon.

[0084]

[0085] Each of the raw material compounds can form a salt as long as it does not hinder the reaction. As such, salts similar to the salts mentioned above can be listed.

[0086] Without describing specific preparation methods, the raw material compounds are readily available commercially available substances and can be used, or they can be manufactured according to methods known in themselves or methods based thereon. Furthermore, intermediates generated in the following manufacturing methods can be separated and purified by methods such as column chromatography, recrystallization, and distillation, or they can be used in the next step without separation.

[0087] All patent documents, non-patent documents or references expressly cited in this specification are incorporated herein by reference as part of this specification.

[0088] In this invention, compound (I) or its salt is manufactured by the following steps: by reacting the compound (1) or its salt of formula (1) with an alkali metal cyanide (MCN) in a mixed solvent of acetonitrile-water in the presence of an organic base (step 1), to manufacture the compound (2) or its salt of formula (2), and then reacting it with hydrazine or its hydrate via a conversion step (step 2) to convert the compound (3) or its salt of formula (3).

[0089]

[0090] (In the formula, X represents a halogen atom.)

[0091]

[0092]

[0093] (In the formula, R represents C) 1-4 alkyl.)

[0094] The following describes in detail each step of the manufacturing method of the present invention.

[0095] (Process 1)

[0096] This process involves reacting compound (1) or its salt with an alkali metal cyanide (MCN) in a mixed solvent of acetonitrile and water in the presence of an organic base to produce compound (2) or its salt.

[0097]

[0098] (In the formula, X represents a halogen atom, and M represents an alkali metal.)

[0099] Compound (1) or a salt thereof may suitably be a substance synthesized by methods known per se (e.g., refer to International Publication No. 2020 / 128003 (Patent Document 4), Chem. Ber., 1957, 90, 182-187, etc.) or according to methods thereof. Preferably, 5-chloro-3-methyl-1,2,4-thiadiazole or 5-bromo-3-methyl-1,2,4-thiadiazole is preferred, and more preferably 5-chloro-3-methyl-1,2,4-thiadiazole is preferred.

[0100] There are no particular limitations on the alkali metal cyanide (MCN), and examples include lithium cyanide, potassium cyanide, sodium cyanide, cesium cyanide, etc. Potassium cyanide or sodium cyanide is preferred, and sodium cyanide is more preferred.

[0101] The amount of alkali metal cyanide used is 1 to 3 moles relative to 1 mole of compound (1) or its salt, preferably 1.1 to 1.5 moles.

[0102] As an organic base, there are no particular limitations; examples 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) and the like, 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), more preferably 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0103] Regarding the amount of organic base used, 0.01 to 2 moles are typically used relative to 1 mole of compound (1) or its salt, preferably 0.05 to 0.2 moles.

[0104] This reaction can be carried out in a mixed solvent of acetonitrile and water.

[0105] The mixing ratio (v / v) of the acetonitrile-water mixed solvent, calculated as water / acetonitrile, is typically in the range of 0.1 to 20, preferably in the range of 1 to 10, and more preferably in the range of 2 to 8.

[0106] The reaction temperature is usually 0℃~80℃, preferably 5℃~40℃, and the reaction time is usually 1~12 hours.

[0107] (Process 2)

[0108] This process involves reacting the compound (2) or its salt obtained in the aforementioned process 1 with thionyl chloride in the presence of an alcohol as shown in the following formula, thereby producing the compound (3) or its salt.

[0109]

[0110] (In the formula, R represents C) 1-4 alkyl.)

[0111]

[0112] (In the formula, R has the same meaning as described above.)

[0113] As an alcohol, there are no particular limitations as long as it has 1 to 4 carbon atoms, but methanol or ethanol are preferred.

[0114] There is no particular limit to the amount of alcohol used; the amount of solvent can be used.

[0115] Regarding the amount of thionyl chloride used, 1 to 3 moles can usually be used relative to 1 mole of compound (2) or its salt, preferably 1.1 to 1.5 moles.

[0116] The reaction temperature is usually 20℃~80℃, preferably 40℃~70℃ (heating reflux temperature), and the reaction time is usually 4~12 hours.

[0117] (Process 3)

[0118] This process involves producing compound (I) or its salt by reacting the compound (3) or its salt obtained in step 2 above with hydrazine or its hydrate in a solvent.

[0119]

[0120] There are no particular limitations on whether it is hydrazine or its hydrate, but hydrazine monohydrate is preferred.

[0121] Regarding the amount of hydrazine or its hydrate used, 1 to 2 moles can usually be used relative to 1 mole of compound (3) or its salt, preferably 1 to 1.2 moles.

[0122] This reaction can be carried out in a solvent that does not affect the reaction. There are no particular limitations on the reaction solvent; examples 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, or mixtures thereof. Preferably, a mixed solvent of alcohols and aromatic hydrocarbons is preferred, and a mixed solvent of isopropanol and toluene is more preferred.

[0123] The reaction temperature is usually -10℃ to 30℃, preferably 0℃ to 10℃, and the reaction time is usually 3 to 24 hours.

[0124] After the reaction is complete, the compound (I) or its salt can be separated and / or purified from the reaction mixture by conventional methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, and chromatography.

[0125] The compound (I) or its salt obtained in step 3 above can be converted into fezonatem by methods known per se (e.g., referring to International Publication No. 2014 / 154895 (Patent Document 1) and International Publication No. 2019 / 012033 (Patent Document 2)) or methods based thereon.

[0126] The manufacturing method of the present invention does not use carbon monoxide gas, which is restricted in industrial-scale use, and therefore has the advantage of being able to synthesize compound (I) or its salt in good yield through safe and simple operation compared with existing methods.

[0127] Example

[0128] The present invention will now be described in detail with reference to examples and embodiments, but the present invention is not limited to these examples.

[0129] In this specification, % means mol / mol% when referring to yield, and % means weight% when referring to other quantities unless otherwise specified. Additionally, unless otherwise specified, room temperature means a temperature of 15–30°C.

[0130] Nuclear magnetic resonance (NMR) spectroscopy was performed using an ECZ400S FT-NMR spectrometer manufactured by JEOL Ltd. 1 ¹H-NMR was performed at 400 MHz using tetramethylsilane as a reference. When a deuterated solvent was used as the determination solvent, the name of the deuterated solvent was recorded.

[0131] 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).

[0132] Furthermore, the abbreviations used in the following embodiments, etc., have the following meanings.

[0133] s: single peak

[0134] br: broad peak

[0135] CDCl3: Deuterated chloroform

[0136] DMSO-d6: Deuterated dimethyl sulfoxide

[0137] CH2Cl2: Dichloromethane

[0138] NaOH: Sodium hydroxide

[0139] NaCN: Sodium cyanide

[0140] DABCO: 1,4-diazabicyclo[2.2.2]octane

[0141] MeCN: Acetonitrile

[0142] MeOH: Methanol

[0143] iPrOH: Isopropanol

[0144] [Reference Example 1]

[0145] Manufacturing of 5-chloro-3-methyl-1,2,4-thiadiazole (1-1)

[0146]

[0147] Under a nitrogen atmosphere (at normal pressure) and at 0 °C, dichloromethane (530 mL (5.3 v / w) was added to acetamidine hydrochloride (100 g, 1.06 mol), trichloromethanesulfonyl chloride (196.8 g, 1.06 mol), and 6 M sodium hydroxide aqueous solution (902.7 g, 4.4 eq.). 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 title compound (1-1) was given in 54% yield (quantitative value in LC) by simple distillation of the resulting organic layer (reduced pressure: 400-15 Torr, internal temperature: 25-60 °C).

[0148] 1 H-NMR (400MHz, CDCl3) δ 2.64 (s, 3H).

[0149] [Example 1]

[0150] Manufacturing of 3-methyl-1,2,4-thiadiazole-5-carboxamide (2)

[0151]

[0152] Under a nitrogen atmosphere (at normal pressure) and at 25°C, compound (1-1) obtained in Reference Example 1 (150 g, 1.10 mol), 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, and the reaction mixture was stirred at 25–40°C for 2 hours. The reaction mixture was then cooled to 5°C, filtered under reduced pressure, and the filtrate was washed three times with water (300 g (2 v / w)). The filtrate was dried under reduced pressure to give the title compound (2) in 67% yield (quantitative value in LC).

[0153] 1 H-NMR (400MHz, CDCl3) δ 2.72 (s, 3H), 7.01 (s, 2H).

[0154] [Example 2]

[0155] Manufacturing of methyl 3-methyl-1,2,4-thiadiazole-5-carboxylic acid ester (3-1)

[0156]

[0157] Under a nitrogen atmosphere (at normal pressure) and at 25°C, compound (2) obtained in Example 1 (30.0 g, 0.21 mol) was mixed with methanol (120 mL (4 v / w)). The mixture was heated to 40–50°C, and a methanol solution (60 mL (2 v / w) of thionyl chloride (29.5 g, 0.25 mol), prepared separately at 0–20°C, was added dropwise. The mixture was stirred at 64°C for 6 hours. The methanol in the reaction mixture was removed by vacuum distillation, and the solvent was replaced with toluene. Then, impurities were removed by vacuum filtration, and the filtrate was separated by adding a 10% sodium chloride aqueous solution (6 v / w). The resulting organic layer was concentrated under vacuum to 5 v / w, thereby giving a toluene solution of the title compound (3-1) in 82% yield (quantitative value in LC).

[0158] 1 H-NMR (400MHz, CDCl3) δ 2.79 (s, 3H), 4.05 (s, 3H).

[0159] [Example 3]

[0160] Production of 3-methyl-1,2,4-thiadiazole-5-carbonylhydrazine (I)

[0161]

[0162] Under a nitrogen atmosphere, hydrazine monohydrate (33.2 g, 0.66 mol) was added to isopropanol (1000 mL (10 v / w)). After cooling to 0–10 °C, a toluene solution of compound (3-1) (0.63 mol) obtained in Example 2 was added dropwise, and the mixture was stirred at 0–10 °C for 12 hours. The reaction mixture was then filtered under reduced pressure, the filtrate was washed with isopropanol (400 mL (4 v / w)) and dried under reduced pressure, thereby giving the title compound (I) in 95% yield (quantitative value in LC).

[0163] 1 H-NMR (400MHz, DMSO-d6) δ 2.56 (s, 3H), 4.82 (br, 2H), 10.56 (br, 1H).

[0164] Industrial availability

[0165] According to the present invention, 3-methyl-1,2,4-thiadiazole-5-carbonylhydrazine (compound (I)) or its salt, which is an important synthetic intermediate for fezonatem, can be produced in good yield without the use of toxic carbon monoxide gas. Therefore, a practical method for the manufacture of fezonatem that is safer and can also be scaled up in batches compared with existing methods can be provided.

[0166] This application is based on Japanese Special Application No. 2023-109329 filed on July 3, 2023, the contents of which are included in this specification.

Claims

1. A method for producing a compound of formula (2) or a salt thereof, characterized in that, which comprises a step of reacting a compound represented by the formula (1) or a salt thereof with an alkali metal cyanide in the presence of an organic base in a mixed solvent of acetonitrile-water, In the formula (1), X represents a halogen atom, 。 2. The manufacturing method according to claim 1, wherein, X is a chlorine atom or a bromine atom.

3. 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.

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

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

6. A production method of a compound represented by the formula (3) or a salt thereof, which comprises a step of reacting a compound represented by the formula (2) or a salt thereof obtained by the production method according to any one of claims 1 to 5 with thionyl chloride in the presence of an alcohol represented by the following formula, wherein R represents C 1-4 alkyl, R in the formula (3) represents the same meaning as described above.

7. The manufacturing method according to claim 6, wherein The alcohol is methanol or ethanol.

8. A production method of a compound represented by the formula (I) or a salt thereof, which comprises a step of reacting a compound represented by the formula (3) or a salt thereof obtained by the production method according to claim 6 with hydrazine or a hydrate thereof in a solvent, 。

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