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EP-4741382-A1 - NOVEL METHOD FOR PRODUCING 3-METHYL-1,2,4-THIADIAZOLE-5-CARBOHYDRAZIDE

EP4741382A1EP 4741382 A1EP4741382 A1EP 4741382A1EP-4741382-A1

Abstract

The present invention aims to provide a method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide safely and in high yield. The present invention relates to a method for producing 3-methyl-1,2,4-thiadiazole-5-carboxamide or a salt thereof without using toxic carbon monoxide gas. According to the present invention, a safe and high-yielding production method of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide, which is an important synthetic intermediate for fezolinetant useful as a medicament for the treatment of sex hormone-dependent diseases, can be provided.

Inventors

  • SUZUKI, HIDEO
  • YAMAZAKI, YUSUKE
  • KODERA, Ikumi
  • SHIMIZU, YUKIYO

Assignees

  • AGC Inc.

Dates

Publication Date
20260513
Application Date
20240628

Claims (8)

  1. A method for producing a compound represented by the formula (2): or a salt thereof, comprising a step of reacting a compound represented by the formula (1): wherein X is a halogen atom, or a salt thereof with an alkali metal cyanide in a mixed solvent of acetonitrile and water in the presence of an organic base.
  2. The production method according to claim 1, wherein X is a chlorine atom or a bromine atom.
  3. The production method 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]non-5-ene.
  4. The production method according to claim 1, wherein the alkali metal cyanide is potassium cyanide or sodium cyanide.
  5. The production method according to claim 1, wherein the mixed solvent of acetonitrile and water has a mixing ratio (v/v) in the range of 1 to 10 as water/acetonitrile.
  6. A method for producing a compound represented by the formula (3): wherein R is a C 1-4 alkyl group, or a salt thereof, comprising a step of reacting a compound represented by the formula (2) which is obtained by the production method according to any one of claims 1 to 5, or a salt thereof with thionyl chloride in the presence of alcohol represented by the following formula: [Chem. 36] ROH wherein R is as defined above.
  7. The production method according to claim 6, wherein the alcohol is methanol or ethanol.
  8. A method for producing a compound represented by the formula (I): or a salt thereof, comprising a step of reacting the compound represented by the formula (3) which is obtained by the production method according to claim 6 or a salt thereof with hydrazine or a hydrate thereof in a solvent.

Description

[Technical Field] The present invention relates to a novel, safe, and practical method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide which is an important synthetic intermediate for fezolinetant which was developed as a selective antagonist of the neurokinin (NK)-3 receptor, and is particularly useful as a compound for the treatment of sex hormone-dependent diseases. [Background Art] Fezolinetant (generic name) (VEOZAH (registered trademark)) was developed as a selective antagonist of NK-3 receptor, and is particularly useful as a compound for the treatment and/or prophylaxis of sex hormone-dependent diseases (e.g., moderate to severe vasomotor symptoms associated with menopause, such as facial flushing, hot flashes, and the like). 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 described in Patent Literature 1. Deuterated fezolinetant, (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 Patent Literature 2. Patent Literatures 1 and 2 disclose, as a synthesis method of fezolinetant and deuterated fezolinetant, a synthesis method going through 3-methyl-1,2,4-thiadiazole-5-carbohydrazide or a deuterated form thereof, which is a compound represented by the formula (I): wherein R1 is methyl or methyl-d3, as an important intermediate. Patent Literature 3 discloses a synthesis method of a non-deuterated intermediate, 3-methyl-1,2,4-thiadiazole-5-carbohydrazide (2n): and in the synthesis method, it is prepared from the corresponding methyl ester (a compound represented by the following formula (2.2n)), which in turn is prepared in a single step from acetamide (a compound represented by the following formula (2.0n)), chlorocarbonylsulfenyl chloride (a compound represented by the following formula (2.0n')), and methyl cyanoformate (a compound represented by the following formula (2.0n")). However, chlorocarbonylsulfenyl chloride and methyl cyanoformate are hazardous reagents that pose problems in large-scale procurement and are difficult to scale up. This synthetic route also results in sulfur impurities that adversely affect the quality of the final pharmaceutical product. Even after optimization, the overall yield of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide remains below 30%. The synthesis of the corresponding deuterated intermediate, 3-(methyl-d3)-1,2,4-thiadiazole-5-carbohydrazide, also has similar drawbacks (Patent Literature 2). Patent Literature 4 discloses, as a synthesis method of an intermediate compound represented by the following formula (I-1): a synthesis method including alkoxycarbonylation by lithium exchange reaction or by carbon monoxide insertion reaction in the presence of a metal catalyst of the corresponding halogenated intermediate, or a compound represented by the following formula (III-1-a): or a compound represented by the following formula (III-1-b): to obtain the corresponding ester form, a compound represented by the following formula (II-1-b): or a salt thereof, a synthesis method via which is disclosed. However, the yield of the alkoxycarbonylation reaction by lithium exchange is as low as 29%. Furthermore, although the alkoxycarbonylation reaction via carbon monoxide insertion in the presence of a metal catalyst affords a compound represented by formula (II-1-b) in good yield, it requires the use of toxic carbon monoxide gas and is limited in terms of scale-up, thus leaving issues for practical application. Therefore, the development of a safe, high-yielding, scalable, and practical method for producing 3-methyl-1,2,4-thiadiazole-5-carbohydrazide which is an important synthetic intermediate for fezolinetant is desired. [Citation List] [Patent Literature] [Patent Literature 1] WO 2014/154895[Patent Literature 2] WO 2019/012033[Patent Literature 3] WO 2013/050424[Patent Literature 4] WO 2020/128003 [Summary of Invention] [Technical Problem] An object of the present invention is to provide a safe, high-yielding, and practical method for producing a compound represented by the following formula (I): or a salt thereof which is an important synthetic intermediate for fezolinetant. [Solution to Problem] The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problem and found that a compound represented by the formula (3): wherein R is a C1-4 alkyl group,or a salt thereof can be produced in a high yield without using carbon monoxide gas, by using a compound represented by the formula (2): or a salt thereof which is obtained by a step of reacting a compound represented by the formula (1): wherein X is a halogen atom,or a salt thereof with an alkali metal cyanide,and that, as a result, a safe and practical production method of a compound represented by the formula (I): or a salt thereof, which is