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WO2010122794A1 - Process for production of pyrazinecarboxylic acid derivative, and intermediate for the production - Google Patents

Process for production of pyrazinecarboxylic acid derivative, and intermediate for the production Download PDF

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Publication number
WO2010122794A1
WO2010122794A1 PCT/JP2010/002898 JP2010002898W WO2010122794A1 WO 2010122794 A1 WO2010122794 A1 WO 2010122794A1 JP 2010002898 W JP2010002898 W JP 2010002898W WO 2010122794 A1 WO2010122794 A1 WO 2010122794A1
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Prior art keywords
alkyl group
producing
acid derivative
pyrazinecarboxylic acid
general formula
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French (fr)
Japanese (ja)
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雅次 織田
幸生 森下
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Nihon Nohyaku Co Ltd
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Nihon Nohyaku Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/06—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
    • C07C251/08—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton being acyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a method for producing a 3-haloalkylpyrazine-2-carboxylic acid derivative useful as an intermediate for pharmaceuticals, agricultural chemicals and the like, in particular, as an intermediate for producing agricultural and horticultural acaricides and fungicides, its synthetic intermediate
  • the present invention relates to a method for producing a synthetic intermediate.
  • the 3-haloalkylpyrazine-2-carboxylic acid derivative is used as an intermediate for pharmaceuticals, agricultural chemicals, etc., especially for agricultural and horticultural acaricides (for example, see Patent Document 1) and fungicides (for example, see Patent Document 2). ).
  • a method for producing pyrazine derivatives a method for synthesizing pyrazine derivatives by reacting haloketone derivatives with trifluoromethanesulfonic acid anilide to lead to imino derivatives, then reacting with 1,2-ethylenediamine and further oxidizing is reported.
  • An object of the present invention is to provide a novel and industrially advantageous production method for pyrazinecarboxylic acid derivatives, particularly 3-haloalkylpyrazine-2-carboxylic acid derivatives useful as intermediates for pharmaceuticals and agricultural chemicals.
  • the inventors of the present application reacted a haloester derivative having a specific structure with an alkali metal azide salt, 1,2-ethylenediamine or its acid salt and a dehydrogenating agent.
  • a haloester derivative having a specific structure with an alkali metal azide salt, 1,2-ethylenediamine or its acid salt and a dehydrogenating agent.
  • the imino derivative which is a production intermediate was found to be a novel compound not described in the literature, and the present invention was completed.
  • an objective compound can be produced efficiently and economically on an industrial scale by using an easily available reagent.
  • R 1 is a halo (C 1 -C 6 ) alkyl group, preferably a fluoro (C 1 -C 6 ) alkyl group, particularly preferably fluoro (C 1 -C 3 ).
  • An alkyl group most preferably a trifluoromethyl group and a difluoromethyl group.
  • R 2 is preferably a (C 1 -C 6 ) alkyl group.
  • X is a halogen atom, preferably a bromine atom or a chlorine atom, and most preferably a chlorine atom.
  • M is preferably a lithium atom, a sodium atom or a potassium atom, particularly preferably a sodium atom.
  • halogen atom is fluorine atom, chlorine atom, bromine atom or iodine atom.
  • (C 1 -C 6 ) alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, An alkyl group such as n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc., which may be the same as or different from the “halo (C 1 -C 6 ) alkyl group” 1 represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms substituted with one or more halogen atoms, and “fluoro (C 1 -C 6 ) alkyl group” is one or more fluorine atoms Substituted or straight chain or branched alkyl group having 1 to 6 carbon atoms
  • fluoro (C 1 -C 3 ) alkyl group represents a linear or branche
  • the “alkali metal atom” refers to a lithium atom, a sodium atom, or a potassium atom.
  • the acid in the acid salt include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid. And sulfonic acids.
  • reaction involved in the present invention is illustrated as follows.
  • One preferred embodiment of the present invention is the one-pot reaction described below.
  • a reaction between a haloester derivative represented by the general formula (II) or a hydrate thereof, an alkali metal azide salt represented by the general formula (III), 1,2-ethylenediamine or an acid salt thereof, and a dehydrogenating agent By doing so, a pyrazinecarboxylic acid derivative represented by the general formula (I) can be produced.
  • Acid salts for example, salts with inorganic acids such as hydrochloric acid and sulfuric acid, salts with organic acids such as formic acid, acetic acid and propionic acid, or salts with sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and toluenesulfonic acid
  • a dehydrogenating agent to produce a pyrazinecarboxylic acid derivative represented by the general formula (I).
  • the haloester derivative represented by the general formula (II) may be used as it is, it can also be used favorably in the form of a hydrate.
  • the alkali metal azide salt is preferably lithium azide, sodium azide or potassium azide, more preferably sodium azide.
  • the alkali metal azide salt can be used in a range of 0.1 to 10 times mol, preferably 1 to 5 times mol of the haloester derivative represented by the general formula (II) or a hydrate thereof. The range is more preferably 1.0 to 2.5 times mol.
  • 1,2-ethylenediamine or an acid salt thereof can be used in a range of 0.1 to 10-fold moles relative to the haloester derivative represented by the general formula (II) or a hydrate thereof, preferably 0
  • the range is from 5 to 5 times mol, and more preferably from 0.9 to 1.2 times mol.
  • the dehydrogenating agent is not particularly limited as long as it has a dehydrogenating ability.
  • manganese compounds such as manganese dioxide; chromic acids such as sodium chromate; lead compounds such as lead tetraacetate; mercury compounds such as mercury oxide;
  • Oxidizing agents such as osmium tetroxide, ruthenium tetroxide and selenium dioxide; metal halides such as iron chloride, copper iodide and copper chloride; halogens such as iodine and bromine; N-chlorosuccinimide, N-bromosuccinimide and diiodo Haloimides such as hydantoin; transition metal compounds such as palladium, platinum, iridium, rhodium, ruthenium, selenium, rhenium; quinone-based oxidizing agents such as DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone); Peroxides
  • the metal compound such as palladium, platinum, iridium, rhodium, ruthenium, selenium, rhenium
  • the metal itself can also be used. C., 1997, 62, 1072-1078, TL, 48 (2007) 2729-2732), and palladium and platinum supported on activated carbon are preferable.
  • transition metal compounds 230-243 can also be used.
  • transition metal compounds are zero-valent, formic acid salts such as sodium formate and ammonium formate; hydroquinone, formaldehyde, etc. in order to carry out the reaction while returning the transition metal compound oxidized in the reaction to zero-valent (reduced type)
  • Organic reducing agents such as formic acid, glucose, and ascorbic acid; reducing gases such as carbon monoxide, ethylene, and methane can also be mixed and used.
  • transition metal compounds in an oxidized state can also be used.
  • PdCl 2 , Pd (OH) 2 palladium oxide, palladium sulfide, Pt / O 2 , iridium chloride (III), rhodium chloride (III), ruthenium chloride.
  • inorganic transition metal compounds such as rhenium oxide; palladium (II) acetate, dichlorobis (benzonitrile) palladium (II), dichlorobis (trialkylphosphine) palladium (II), trans- [iodo (phenyl) bis (dimethyl) Phenylphosphine) palladium (II)], trans- [dimethylbis (triphenylphosphine) palladium (II)], (dioxygen) bis (t-butyl isocyanate), Pd 2 Cl 4 (C 2 H 4 ) 2 , Pd 2 Cl 4 (PPh 3 ) 2, Pd ( 2 H 4) (PPh 3) 2, PdCl 2 (C 8 H 12), [PdCl (C 3 H 5)] 2, Pd (C 3 H 5) (C 5 H 5), Pd (C 3 H 5 ) 2 , [Pd (C 5 H 5 ) (C 8 H 12 )] BF 4
  • Two or more transition metal compounds can also be used in combination, for example, a technique such as Wacker oxidation (“Palladium Reagents and Catalysis”, First Edition 2004, Wiley, 29-35; Synthesis 1984, 369-384). Can be used.
  • dehydrogenating agents can be used in the range of 0.001 to 10-fold mol, preferably in the range of 0.01 to 5-fold mol based on the haloester derivative represented by the general formula (II). is there.
  • the inert solvent used is not particularly limited as long as it does not significantly inhibit the progress of this reaction.
  • aliphatic hydrocarbons such as hexane, cyclohexane, and methylcyclohexane
  • aromatics such as benzene, toluene, xylene, and chlorobenzene.
  • Hydrocarbons Halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; Linear or cyclic ethers such as diethyl ether, t-butyl methyl ether, dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; Methanol, ethanol , N-propanol, 2-propanol, n-butanol, s-butanol, t-butanol and other alcohols; esters such as ethyl acetate; amides such as dimethylformamide and dimethylacetamide; nitriles such as acetonitrile Examples of the inert solvent include 1,3-dimethyl-2-imidazolidinone, pyridine, acetic acid, and water. These solvents may be used alone or in admixture of two or more kinds of inert solvents. it can.
  • Examples of the purpose of adjusting the pH in the reaction system include organic bases such as triethylamine, tributylamine, pyrrolidine, piperidine, morpholine, pyridine, 3-picoline, 4-picoline, 4-dimethylaminopyridine; lithium hydroxide, Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal alkoxides such as sodium methoxide and sodium ethoxide; Carbonates such as sodium hydrogen carbonate and potassium carbonate; Potassium monohydrogen phosphate and trisodium phosphate Phosphates such as sodium formate and sodium acetate; inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid; methanesulfonic acid and trifluoromethanesulfonic acid P-Toluenesulfonic acid It is possible to use the sulfonic
  • phase transfer catalyst such as a quaternary ammonium salt such as tetrabutylammonium chloride or a crown ether such as 18-crown-6 can be used, and is represented by the general formula (II).
  • the amount can be appropriately selected within the range of 0.001 to 0.1 moles relative to the haloester derivative.
  • the reaction temperature may be appropriately selected within the range of ⁇ 20 ° C. to the reflux temperature of the inert solvent used, but is preferably selected from the range of 0 ° C. to 120 ° C.
  • the reaction time varies depending on the reaction scale, reaction temperature, and the like, and is not constant but may be appropriately selected within the range of several minutes to 100 hours.
  • the pyrazinecarboxylic acid derivative represented by the general formula (I) may be isolated from the reaction system containing the target product by a conventional method. If necessary, this may be recrystallized, column chromatography, distillation, etc.
  • the desired product can be produced by purifying with
  • Another preferred embodiment of the present invention is the stepwise reaction described below.
  • (a) a haloester derivative represented by the general formula (II) or a hydrate thereof and an alkali metal azide salt represented by the general formula (III) are reacted stepwise in an inert solvent, Derived into an imino form represented by the general formula (IV) or a hydrate thereof, then (b) reacted with 1,2-ethylenediamine or an acid salt thereof, and finally (c) a dehydrogenating agent is allowed to act.
  • a pyrazinecarboxylic acid derivative represented by the general formula (I) can be produced.
  • the reactions (a), (b) and (c) may be performed according to the method described in 1). Even if each reagent is added simultaneously as described in 1) or sequentially as described in 2), the desired product can be obtained satisfactorily.
  • the compound represented by the general formula (II) can be produced by a known method, for example, the method described in Helvetica Chumica Acta (1965), 48 (6), 1423-6, or the like. Further, the 3-haloalkylpyrazine-2-carboxylic acid derivative obtained by the production method of the present invention can be easily produced by, for example, the method shown in Reference Examples, etc. ) And the like can be produced.
  • Example 1 Preparation of ethyl 3-trifluoromethylpyrazine-2-carboxylate To a 4 mL aqueous solution of sodium azide (2.6 g, 40 mmol) and 1,2-ethylenediamine hydrochloride (3.2 g, 24 mmol) in 2-chloro-4,4 , A solution of ethyl 4-trifluoro-3-oxobutanoate (4.4 g, 20 mmol) in ethyl acetate (8 mL) was added dropwise. Thereafter, 5% Pd / C (2 g; 50% wet) and ethyl acetate (2 mL) were added, and the mixture was stirred at room temperature for 1 hour.
  • reaction mixture was then stirred at 35 ° C. for 1 hour and then heated to reflux for 2.5 hours.
  • the reaction was cooled to room temperature.
  • Ethyl acetate (100 mL) and water (60 mL) were added, Pd / C was removed by filtration, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain ethyl 3-trifluoromethylpyrazine-2-carboxylate.
  • Example 2 Preparation of ethyl 3-trifluoromethylpyrazine-2-carboxylate To a mixed solution of sodium azide (2.6 g, 40 mmol) and tetrabutylammonium chloride (0.6 g, 2 mmol) in toluene (6 mL) and water (4 mL) A toluene solution (2 mL) of ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (4.4 g, 20 mmol) was added dropwise.
  • Example 3 Production of ethyl 3-difluoromethylpyrazine-2-carboxylate Sulfuryl chloride (8.5 g, 63 mol) was added to ethyl 4,4-difluoro-3-oxobutanoate (10 g, 60 mol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (100 ml) and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

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  • Organic Chemistry (AREA)
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Abstract

Disclosed is a novel and industrially advantageous process for producing a pyrazinecarboxylic acid derivative, particularly a 3-haloalkylpyrazine-2-carboxylic acid derivative, which is a compound useful as an intermediate for the production of a pharmaceutical agent, an agrichemical agent or the like. Specifically disclosed is a process for producing a pyrazinecarboxylic acid derivative represented by general formula (I), which is characterized by reacting a haloester derivative represented by general formula (II) with an alkali metal azide salt represented by general formula (III), 1,2-ethylenediamine or an acid salt thereof and a dehydrogenating agent.

Description

ピラジンカルボン酸誘導体の製造方法及びその中間体Method for producing pyrazinecarboxylic acid derivative and intermediate thereof

　本発明は、医薬・農薬等の中間体として、特に農園芸用殺ダニ剤、殺菌剤の製造中間体として有用な３－ハロアルキルピラジン－２－カルボン酸誘導体の製造方法、その合成中間体並びに当該合成中間体の製造方法に関するものである。 The present invention relates to a method for producing a 3-haloalkylpyrazine-2-carboxylic acid derivative useful as an intermediate for pharmaceuticals, agricultural chemicals and the like, in particular, as an intermediate for producing agricultural and horticultural acaricides and fungicides, its synthetic intermediate The present invention relates to a method for producing a synthetic intermediate.

　３－ハロアルキルピラジン－２－カルボン酸誘導体は、医薬・農薬等の中間体として、特に農園芸用殺ダニ剤（例えば、特許文献１を参照。）及び殺菌剤（例えば、特許文献２を参照。）の中間体として有用である。
　ピラジン誘導体の製造方法として、ハロケトン誘導体とトリフルオロメタンスルホン酸アニリドとを反応させることにより、イミノ誘導体に導き、次いで１、２－エチレンジアミンと反応させ、更に酸化することによりピラジン誘導体を合成する方法が報告されているが（例えば、非特許文献１を参照）、本発明のピラジンカルボン酸誘導体の製法、特にハロアルキル基を有するピラジンカルボン酸誘導体に関しては、具体的な開示も示唆もされていない。
　一方、ジケトカルボン酸エステル誘導体と１、２－エチレンジアミンを反応させることにより、ジヒドロピラジン誘導体に導き、次いで酸化することによりピラジンカルボン酸誘導体に変換する方法が報告されているが（例えば、非特許文献２を参照）、本発明とは出発原料が異なり、本発明のようなハロアルキル基が導入された化合物に関しては、具体的な開示も示唆もされていない。 The 3-haloalkylpyrazine-2-carboxylic acid derivative is used as an intermediate for pharmaceuticals, agricultural chemicals, etc., especially for agricultural and horticultural acaricides (for example, see Patent Document 1) and fungicides (for example, see Patent Document 2). ).
As a method for producing pyrazine derivatives, a method for synthesizing pyrazine derivatives by reacting haloketone derivatives with trifluoromethanesulfonic acid anilide to lead to imino derivatives, then reacting with 1,2-ethylenediamine and further oxidizing is reported. However, there is no specific disclosure or suggestion regarding the method for producing the pyrazinecarboxylic acid derivative of the present invention, particularly the pyrazinecarboxylic acid derivative having a haloalkyl group.
On the other hand, a method has been reported in which a diketocarboxylic acid ester derivative and 1,2-ethylenediamine are reacted to lead to a dihydropyrazine derivative and then converted to a pyrazinecarboxylic acid derivative by oxidation (for example, Non-Patent Document 2). The starting materials are different from those of the present invention, and there is no specific disclosure or suggestion regarding a compound into which a haloalkyl group is introduced as in the present invention.

特開２００６－００８６７５号公報JP 2006-008675 A 国際公開第２００７／０７２９９９号パンフレットInternational Publication No. 2007/072999 Pamphlet

Ｊｏｕｒａｎａｌ　ｏｆ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ，４５，１６１，１９８０Journalal of Organic Chemistry, 45, 161, 1980 Ｊｏｕｒａｎａｌ　ｏｆ　Ｃｈｅｍｉｃａｌ　Ｓｏｃｉｔｙ.,　Perkin Trans.1,　２０００，２９９－３０２Journal of Chemical Society., Perkin Trans.1, 2000, 299-302.

　前記非特許文献１及び２の報告には、本発明に係る誘導体及びその製造方法について何の開示も示唆も無い。本発明の課題は、医薬・農薬等の中間体として有用なピラジンカルボン酸誘導体、特に３－ハロアルキルピラジン－２－カルボン酸誘導体の新規で工業的に有利な製造方法を提供することである。 In the reports of Non-Patent Documents 1 and 2, there is no disclosure or suggestion about the derivative according to the present invention and its production method. An object of the present invention is to provide a novel and industrially advantageous production method for pyrazinecarboxylic acid derivatives, particularly 3-haloalkylpyrazine-2-carboxylic acid derivatives useful as intermediates for pharmaceuticals and agricultural chemicals.

　前記課題を解決すべく鋭意研究を行った結果、本願発明者等は特定構造を有するハロエステル誘導体とアルカリ金属アジド塩、１、２－エチレンジアミン又はその酸塩及び脱水素化剤とを反応させることにより、上記のピラジンカルボン酸誘導体を効率よく製造することができることを見出した。また製造中間体であるイミノ誘導体は文献未記載の新規化合物であることを見出し、本発明を完成させるに至った。
　即ち、本発明は、
[１]一般式（ＩＩ）

Figure JPOXMLDOC01-appb-C000001
（式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基及びＸはハロゲン原子を示す。）で表されるハロエステル誘導体又はその水和物と一般式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000002
 （式中、Ｍはアルカリ金属原子を示す。）で表されるアルカリ金属アジド塩及び１、２－エチレンジアミン又はその酸塩及び脱水素化剤と反応させることを特徴とする、一般式（Ｉ）
Figure JPOXMLDOC01-appb-C000003
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるピラジンカルボン酸誘導体の製造方法、
[２]一般式（ＩＩ）
Figure JPOXMLDOC01-appb-C000004
 （式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基及びＸはハロゲン原子を示す。）で表されるハロエステル誘導体又はその水和物と一般式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000005
 （式中、Ｍはアルカリ金属原子を示す。）で表されるアルカリ金属アジド塩と反応させ、次いで１、２－エチレンジアミン又はその酸塩と反応させ、次いで脱水素化剤と反応させることを特徴とする、一般式（Ｉ）
Figure JPOXMLDOC01-appb-C000006
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるピラジンカルボン酸誘導体の製造方法、
[３]一般式（ＩＩ）
Figure JPOXMLDOC01-appb-C000007
 （式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基及びＸはハロゲン原子を示す。）で表されるハロエステル誘導体又はその水和物と一般式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000008
 （式中、Ｍはアルカリ金属原子を示す。）で表されるアルカリ金属アジド塩を反応させて、一般式（ＩＶ）
Figure JPOXMLDOC01-appb-C000009
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるイミノ体またはその水和物に誘導し、次いで該イミノ体又は該水和物を単離しまたは単離せずして、１、２－エチレンジアミン又はその酸塩と反応させて、次いで脱水素化剤と反応させることを特徴とする、一般式（Ｉ）
Figure JPOXMLDOC01-appb-C000010
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるピラジンカルボン酸誘導体の製造方法、
[４]Ｒ１がハロ（Ｃ１－Ｃ６）アルキル基である前記[１]に記載のピラジンカルボン酸誘導体の製造方法、
[５]Ｒ１がハロ（Ｃ１－Ｃ６）アルキル基である前記[２]に記載のピラジンカルボン酸誘導体の製造方法、
[６]Ｒ１がハロ（Ｃ１－Ｃ６）アルキル基である前記[３]に記載のピラジンカルボン酸誘導体の製造方法、
[７]Ｒ１がフルオロ（Ｃ１－Ｃ６）アルキル基である前記[１]に記載のピラジンカルボン酸誘導体の製造方法、
[８]Ｒ１がフルオロ（Ｃ１－Ｃ６）アルキル基である前記[２]に記載のピラジンカルボン酸誘導体の製造方法、
[９]Ｒ１がフルオロ（Ｃ１－Ｃ６）アルキル基である前記[３]に記載のピラジンカルボン酸誘導体の製造方法、
[１０]Ｒ１がフルオロ（Ｃ１－Ｃ３）アルキル基である前記[１]に記載のピラジンカルボン酸誘導体の製造方法、
[１１]Ｒ１がフルオロ（Ｃ１－Ｃ３）アルキル基である前記[２]に記載のピラジンカルボン酸誘導体の製造方法、
[１２]Ｒ１がフルオロ（Ｃ１－Ｃ３）アルキル基である前記[３]に記載のピラジンカルボン酸誘導体の製造方法、
[１３]Ｒ１がジフルオロメチル基又はトリフルオロメチル基である前記[１]に記載のピラジンカルボン酸誘導体の製造方法、
[１４]Ｒ１がジフルオロメチル基又はトリフルオロメチル基である前記[２]に記載のピラジンカルボン酸誘導体の製造方法、
[１５]Ｒ１がジフルオロメチル基又はトリフルオロメチル基である前記[３]に記載のピラジンカルボン酸誘導体の製造方法、
[１６]Ｍが、ナトリウムである前記[１]～[１５]のいずれかに記載のピラジンカルボン酸誘導体の製造方法、
[１７]脱水素化剤が、パラジウム又はその担持体である前記[１]～[１６]のいずれかに記載のピラジンカルボン酸誘導体の製造方法、
[１８]一般式（ＩＶ）
Figure JPOXMLDOC01-appb-C000011
 （式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基を示す。）で表されるイミノ体またはその水和物、および
[１９]一般式（ＩＩ）
Figure JPOXMLDOC01-appb-C000012
 （式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基及びＸはハロゲン原子を示す。）で表されるハロエステル誘導体又はその水和物と一般式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000013
 （式中、Ｍはアルカリ金属原子を示す。）で表されるアルカリ金属アジド塩を反応させることを特徴とする、一般式（ＩＶ）
Figure JPOXMLDOC01-appb-C000014
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるイミノ体またはその水和物の製造方法、
に関する。 As a result of diligent research to solve the above problems, the inventors of the present application reacted a haloester derivative having a specific structure with an alkali metal azide salt, 1,2-ethylenediamine or its acid salt and a dehydrogenating agent. Thus, it was found that the above-mentioned pyrazinecarboxylic acid derivative can be produced efficiently. Moreover, the imino derivative which is a production intermediate was found to be a novel compound not described in the literature, and the present invention was completed.
That is, the present invention
[1] General formula (II)
Figure JPOXMLDOC01-appb-C000001
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, R 2 represents a (C 1 -C 6 ) alkyl group, and X represents a halogen atom). Haloester derivative represented by the formula or its hydrate and general formula (III)
Figure JPOXMLDOC01-appb-C000002
 (Wherein M represents an alkali metal atom), which is reacted with an alkali metal azide salt represented by formula (I), 1,2-ethylenediamine or an acid salt thereof, and a dehydrogenating agent.
Figure JPOXMLDOC01-appb-C000003
 (Wherein R 1 and R 2 are the same as above), a method for producing a pyrazinecarboxylic acid derivative represented by:
[2] General formula (II)
Figure JPOXMLDOC01-appb-C000004
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, R 2 represents a (C 1 -C 6 ) alkyl group, and X represents a halogen atom). Haloester derivative represented by the formula or its hydrate and general formula (III)
Figure JPOXMLDOC01-appb-C000005
 (Wherein M represents an alkali metal atom), and then reacted with 1,2-ethylenediamine or an acid salt thereof, and then reacted with a dehydrogenating agent. General formula (I)
Figure JPOXMLDOC01-appb-C000006
 (Wherein R 1 and R 2 are the same as above), a method for producing a pyrazinecarboxylic acid derivative represented by:
[3] General formula (II)
Figure JPOXMLDOC01-appb-C000007
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, R 2 represents a (C 1 -C 6 ) alkyl group, and X represents a halogen atom). Haloester derivative represented by the formula or its hydrate and general formula (III)
Figure JPOXMLDOC01-appb-C000008
 (Wherein M represents an alkali metal atom), and an alkali metal azide salt represented by the general formula (IV) is reacted.
Figure JPOXMLDOC01-appb-C000009
 (Wherein R 1 and R 2 are the same as defined above), and then the imino form or the hydrate thereof is isolated or not isolated. , 2-ethylenediamine or its acid salt, followed by reaction with a dehydrogenating agent
Figure JPOXMLDOC01-appb-C000010
 (Wherein R 1 and R 2 are the same as above), a method for producing a pyrazinecarboxylic acid derivative represented by:
[4] The method for producing a pyrazinecarboxylic acid derivative according to the above [1], wherein R 1 is a halo (C 1 -C 6 ) alkyl group,
[5] The method for producing a pyrazinecarboxylic acid derivative according to the above [2], wherein R 1 is a halo (C 1 -C 6 ) alkyl group,
[6] The method for producing a pyrazinecarboxylic acid derivative according to the above [3], wherein R 1 is a halo (C 1 -C 6 ) alkyl group,
[7] The method for producing a pyrazinecarboxylic acid derivative according to the above [1], wherein R 1 is a fluoro (C 1 -C 6 ) alkyl group,
[8] The method for producing a pyrazinecarboxylic acid derivative according to the above [2], wherein R 1 is a fluoro (C 1 -C 6 ) alkyl group,
[9] The method for producing a pyrazinecarboxylic acid derivative according to the above [3], wherein R 1 is a fluoro (C 1 -C 6 ) alkyl group,
[10] The method for producing a pyrazinecarboxylic acid derivative according to the above [1], wherein R 1 is a fluoro (C 1 -C 3 ) alkyl group,
[11] The method for producing a pyrazinecarboxylic acid derivative according to the above [2], wherein R 1 is a fluoro (C 1 -C 3 ) alkyl group,
[12] The method for producing a pyrazinecarboxylic acid derivative according to the above [3], wherein R 1 is a fluoro (C 1 -C 3 ) alkyl group,
[13] The method for producing a pyrazinecarboxylic acid derivative according to the above [1], wherein R 1 is a difluoromethyl group or a trifluoromethyl group.
[14] The method for producing a pyrazinecarboxylic acid derivative according to the above [2], wherein R 1 is a difluoromethyl group or a trifluoromethyl group,
[15] The method for producing a pyrazinecarboxylic acid derivative according to the above [3], wherein R 1 is a difluoromethyl group or a trifluoromethyl group,
[16] The method for producing a pyrazinecarboxylic acid derivative according to any one of [1] to [15], wherein M is sodium,
[17] The method for producing a pyrazinecarboxylic acid derivative according to any one of [1] to [16], wherein the dehydrogenating agent is palladium or a support thereof,
[18] General formula (IV)
Figure JPOXMLDOC01-appb-C000011
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, and R 2 represents a (C 1 -C 6 ) alkyl group). Or its hydrate, and
[19] General formula (II)
Figure JPOXMLDOC01-appb-C000012
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, R 2 represents a (C 1 -C 6 ) alkyl group, and X represents a halogen atom). Haloester derivative represented by the formula or its hydrate and general formula (III)
Figure JPOXMLDOC01-appb-C000013
 (Wherein, M represents an alkali metal atom), an alkali metal azide salt represented by the general formula (IV)
Figure JPOXMLDOC01-appb-C000014
 (Wherein R 1 and R 2 are the same as above), a method for producing an imino isomer or a hydrate thereof,
About.

　本発明によれば、入手容易な試薬を用い、目的化合物を効率的且つ経済的に工業的規模で製造できる。 According to the present invention, an objective compound can be produced efficiently and economically on an industrial scale by using an easily available reagent.

　本発明の実施態様としては、Ｒ１はハロ（Ｃ１－Ｃ６）アルキル基であり、好ましくはフルオロ（Ｃ１－Ｃ６）アルキル基であり、特に好ましくはフルオロ（Ｃ１－Ｃ３）アルキル基であり、最も好ましくはトリフルオロメチル基及びジフルオロメチル基である。Ｒ２は（Ｃ１－Ｃ６）アルキル基が好ましい。Ｘはハロゲン原子であり、好ましくは臭素原子又は塩素原子であり、最も好ましくは塩素原子である。Ｍはリチウム原子、ナトリウム原子、カリウム原子が好ましく、特に好ましくはナトリウム原子である。 In an embodiment of the invention, R 1 is a halo (C 1 -C 6 ) alkyl group, preferably a fluoro (C 1 -C 6 ) alkyl group, particularly preferably fluoro (C 1 -C 3 ). An alkyl group, most preferably a trifluoromethyl group and a difluoromethyl group. R 2 is preferably a (C 1 -C 6 ) alkyl group. X is a halogen atom, preferably a bromine atom or a chlorine atom, and most preferably a chlorine atom. M is preferably a lithium atom, a sodium atom or a potassium atom, particularly preferably a sodium atom.

　次に本明細書中に記載する各置換基を説明する。本発明の一般式（Ｉ）～（IＶ）で表される化合物の置換基の定義中、『ハロゲン原子』、『ハロゲン』及び『ハロ』とはフッ素原子、塩素原子、臭素原子又はヨウ素原子を示し、『（Ｃ１－Ｃ６）アルキル基』とは、炭素原子数１～６の直鎖状又は分枝状のアルキル基を示し、例えば、メチル、エチル、ｎ－プロピル、ｉ－プロピル、ｎ－ブチル、ｉ－ブチル、ｓ－ブチル、ｔ－ブチル、ｎ－ペンチル、ｎ－ヘキシル等のアルキル基を示し、『ハロ（Ｃ１－Ｃ６）アルキル基』とは同一又は異なっても良く、１以上のハロゲン原子で置換された炭素原子数１～６の直鎖状又は分枝状のアルキル基を示し、『フルオロ（Ｃ１－Ｃ６）アルキル基』とは１以上のフッ素原子で置換された炭素原子数１～６の直鎖状又は分枝状のアルキル基を示し、『フルオロ（Ｃ１－Ｃ３）アルキル基』とは１以上のフッ素原子で置換された炭素原子数１～３の直鎖状又は分枝状のアルキル基を示す。『アルカリ金属原子』とは、リチウム原子、ナトリウム原子、カリウム原子を示す。また、酸塩における酸としては、例えば、塩酸、硫酸、硝酸等の無機酸類、蟻酸、酢酸、トルフルオロ酢酸、プロピオン酸等の有機酸類、メタンスルホン酸、トリフルオロメタンスルホン酸、ｐ－トルエンスルホン酸等のスルホン酸類等を挙げることができる。 Next, each substituent described in this specification is demonstrated. In the definition of substituents of the compounds represented by the general formulas (I) to (IV) of the present invention, “halogen atom”, “halogen” and “halo” are fluorine atom, chlorine atom, bromine atom or iodine atom. “(C 1 -C 6 ) alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, An alkyl group such as n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc., which may be the same as or different from the “halo (C 1 -C 6 ) alkyl group” 1 represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms substituted with one or more halogen atoms, and “fluoro (C 1 -C 6 ) alkyl group” is one or more fluorine atoms Substituted or straight chain or branched alkyl group having 1 to 6 carbon atoms The “fluoro (C 1 -C 3 ) alkyl group” represents a linear or branched alkyl group having 1 to 3 carbon atoms substituted with one or more fluorine atoms. The “alkali metal atom” refers to a lithium atom, a sodium atom, or a potassium atom. Examples of the acid in the acid salt include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid. And sulfonic acids.

　本発明に関与する反応は以下のように図示される。
　本発明の好ましい実施態様の一つは下記するワンポット反応である。

Figure JPOXMLDOC01-appb-C000015
　（式中、Ｒ１、Ｒ２、Ｘ及びＭは前記に同じ。）
　即ち、一般式（ＩＩ）で表されるハロエステル誘導体又はその水和物と一般式（ＩＩＩ）表されるアルカリ金属アジド塩、１、２－エチレンジアミン又はその酸塩及び脱水素化剤とを反応させることにより一般式（Ｉ）で表されるピラジンカルボン酸誘導体を製造することができる。 The reaction involved in the present invention is illustrated as follows.
One preferred embodiment of the present invention is the one-pot reaction described below.
Figure JPOXMLDOC01-appb-C000015
 (In the formula, R 1 , R 2 , X and M are the same as above.)
That is, a reaction between a haloester derivative represented by the general formula (II) or a hydrate thereof, an alkali metal azide salt represented by the general formula (III), 1,2-ethylenediamine or an acid salt thereof, and a dehydrogenating agent. By doing so, a pyrazinecarboxylic acid derivative represented by the general formula (I) can be produced.

１）　一般式（ＩＩ）　→　一般式（Ｉ）
　本反応は、通常は不活性溶媒中、一般式（ＩＩ）で表されるハロエステル誘導体又はその水和物と一般式（ＩＩＩ）で表されるアルカリ金属アジド塩、１、２－エチレンジアミン又はその酸塩（例えば、塩酸、硫酸などの無機酸との塩、ギ酸、酢酸、プロピオン酸などの有機酸との塩、又はメタンスルホン酸、トリフルオロメタンスルホン酸、トルエンスルホン酸などのスルホン酸との塩）及び脱水素化剤とを反応させて、一般式（Ｉ）で表されるピラジンカルボン酸誘導体を製造するものである。一般式（ＩＩ）で表されるハロエステル誘導体はそのまま用いても良いが、水和物の形でも良好に使用できる。アルカリ金属アジド塩は、リチウムアジド、ナトリウムアジド、カリウムアジドが好ましく、更に好ましくはナトリウムアジドである。アルカリ金属アジド塩は、一般式（ＩＩ）で表されるハロエステル誘導体又はその水和物に対し、０．１～１０倍モルの範囲で使用可能であるが、好ましくは１～５倍モルの範囲であり、更に好ましくは１．０～２．５倍モルの範囲である。１、２－エチレンジアミン又はその酸塩は、一般式（ＩＩ）で表されるハロエステル誘導体又はその水和物に対し、０．１～１０倍モルの範囲で使用可能であるが、好ましくは０．５～５倍モルの範囲であり、更に好ましくは０．９～１．２倍モルの範囲である。 1) General formula (II) → General formula (I)
This reaction is usually carried out in an inert solvent in a haloester derivative represented by the general formula (II) or a hydrate thereof and an alkali metal azide salt represented by the general formula (III), 1,2-ethylenediamine or the like. Acid salts (for example, salts with inorganic acids such as hydrochloric acid and sulfuric acid, salts with organic acids such as formic acid, acetic acid and propionic acid, or salts with sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and toluenesulfonic acid) ) And a dehydrogenating agent to produce a pyrazinecarboxylic acid derivative represented by the general formula (I). Although the haloester derivative represented by the general formula (II) may be used as it is, it can also be used favorably in the form of a hydrate. The alkali metal azide salt is preferably lithium azide, sodium azide or potassium azide, more preferably sodium azide. The alkali metal azide salt can be used in a range of 0.1 to 10 times mol, preferably 1 to 5 times mol of the haloester derivative represented by the general formula (II) or a hydrate thereof. The range is more preferably 1.0 to 2.5 times mol. 1,2-ethylenediamine or an acid salt thereof can be used in a range of 0.1 to 10-fold moles relative to the haloester derivative represented by the general formula (II) or a hydrate thereof, preferably 0 The range is from 5 to 5 times mol, and more preferably from 0.9 to 1.2 times mol.

　脱水素化剤としては、脱水素化能がある化合物なら何でも良く、例えば、二酸化マンガンなどのマンガン化合物；クロム酸ナトリウムなどのクロム酸類；四酢酸鉛などの鉛化合物；酸化水銀などの水銀化合物；四酸化オスミウム、四酸化ルテニウム、二酸化セレンなどの酸化剤；塩化鉄、沃化銅、塩化銅等の金属ハロゲン化物、沃素、臭素などのハロゲン類；Ｎ－クロロスクシンイミド、Ｎ－ブロモスクシンイミド、ジヨードヒダントインなどのハロイミド類；パラジウム、白金、イリジウム、ロジウム、ルテニウム、セレン、レニウムなどの遷移金属化合物；ＤＤＱ（２，３－ジクロロ－５，６－ジシアノ－ｐ－ベンゾキノン）などのキノン系酸化剤；過酸化水素水、過安息香酸、ｍ－クロル過安息香酸などの過酸化物；硫黄原子、活性炭や酸素が挙げられ、これら脱水素化剤は単独もしくは２種以上を混合して使用することもできる。 The dehydrogenating agent is not particularly limited as long as it has a dehydrogenating ability. For example, manganese compounds such as manganese dioxide; chromic acids such as sodium chromate; lead compounds such as lead tetraacetate; mercury compounds such as mercury oxide; Oxidizing agents such as osmium tetroxide, ruthenium tetroxide and selenium dioxide; metal halides such as iron chloride, copper iodide and copper chloride; halogens such as iodine and bromine; N-chlorosuccinimide, N-bromosuccinimide and diiodo Haloimides such as hydantoin; transition metal compounds such as palladium, platinum, iridium, rhodium, ruthenium, selenium, rhenium; quinone-based oxidizing agents such as DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone); Peroxides such as aqueous hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid; sulfur atom, activity Or oxygen, and these dehydrogenation agents may be used alone or as a mixture of two or more.

　パラジウム、白金、イリジウム、ロジウム、ルテニウム、セレン、レニウムなどの遷移金属化合物は、金属そのものも使用できるが、例えば、活性炭、シリカゲル、アルミナ、酸化チタン、珪藻土、軽石、硫酸バリウム又はポリアニリン（Ｊ．Ｏ．Ｃ．，１９９７，６２，１０７２－１０７８、Ｔ．Ｌ．，４８（２００７）２７２９－２７３２）に担持させたものも使用でき、好ましくは、活性炭で担持したパラジウム及び白金である。またカルボニルトリス（トリフェニルホスフィン）パラジウム（０）、ビス（イソシアン化ｔ－ブチル）パラジウム（０）、テトラキス（トリフェニルホスフィン）パラジウム（０）、トリス（ジベンジリデンアセトン）二パラジウム（０）［新実験化学講座１２（有機金属化学）ｐ．２３０－２４３］のような０価の錯体も使用できる。これら遷移金属化合物が０価の場合は、当該反応で酸化された遷移金属化合物を０価（還元型）に戻しつつ反応を行うために、蟻酸ナトリウム、蟻酸アンモニウムなどの蟻酸塩；ヒドロキノン、ホルムアルデヒド、蟻酸、ぶどう糖、アスコルビン酸などの有機還元剤；一酸化炭素、エチレン、メタンのような還元性気体を混合して使用することもできる。 As the transition metal compound such as palladium, platinum, iridium, rhodium, ruthenium, selenium, rhenium, the metal itself can also be used. C., 1997, 62, 1072-1078, TL, 48 (2007) 2729-2732), and palladium and platinum supported on activated carbon are preferable. In addition, carbonyltris (triphenylphosphine) palladium (0), bis (t-butyl isocyanate) palladium (0), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) [new Experimental Chemistry Course 12 (Organic Metal Chemistry) p. 230-243] can also be used. When these transition metal compounds are zero-valent, formic acid salts such as sodium formate and ammonium formate; hydroquinone, formaldehyde, etc. in order to carry out the reaction while returning the transition metal compound oxidized in the reaction to zero-valent (reduced type) Organic reducing agents such as formic acid, glucose, and ascorbic acid; reducing gases such as carbon monoxide, ethylene, and methane can also be mixed and used.

　一方、酸化された状態の遷移金属化合物も使用でき、例えば、ＰｄＣｌ２、Ｐｄ（ＯＨ）２、酸化パラジウム、硫化パラジウム、Ｐｔ／Ｏ２、塩化イリジウム（ＩＩＩ）、塩化ロジウム（ＩＩＩ）、塩化ルテニウム（ＩＩＩ）、酸化レニウムなどの無機遷移金属化合物；酢酸パラジウム（ＩＩ）、ジクロロビス（ベンゾニトリル）パラジウム（ＩＩ）、ジクロロビス（トリアルキルホスフィン）パラジウム（ＩＩ）、ｔｒａｎｓ－［ヨード（フェニル）ビス（ジメチルフェニルホスフィン）パラジウム（ＩＩ）］、ｔｒａｎｓ－［ジメチルビス（トリフェニルホスフィン）パラジウム（ＩＩ）］、（二酸素）ビス（イソシアン化ｔ－ブチル）パラジウム、Ｐｄ２Ｃｌ４（Ｃ２Ｈ４）２、Ｐｄ２Ｃｌ４（ＰＰｈ３）２、Ｐｄ（Ｃ２Ｈ４）（ＰＰｈ３）２、ＰｄＣｌ２（Ｃ８Ｈ１２）、［ＰｄＣｌ（Ｃ３Ｈ５）］２、Ｐｄ（Ｃ３Ｈ５）（Ｃ５Ｈ５）、Ｐｄ（Ｃ３Ｈ５）２、［Ｐｄ（Ｃ５Ｈ５）（Ｃ８Ｈ１２）］ＢＦ４、［Ｐｄ（Ｃ３Ｈ５）（Ｃ８Ｈ１２）］ＢＦ４、［Ｐｄ（ａｃａｃ）（Ｃ８Ｈ１２）］ＢＦ４［新実験化学講座１２（有機金属化学）ｐ．２３０－２４３］などの有機遷移金属化合物が挙げられる。 On the other hand, transition metal compounds in an oxidized state can also be used. For example, PdCl 2 , Pd (OH) 2 , palladium oxide, palladium sulfide, Pt / O 2 , iridium chloride (III), rhodium chloride (III), ruthenium chloride. (III), inorganic transition metal compounds such as rhenium oxide; palladium (II) acetate, dichlorobis (benzonitrile) palladium (II), dichlorobis (trialkylphosphine) palladium (II), trans- [iodo (phenyl) bis (dimethyl) Phenylphosphine) palladium (II)], trans- [dimethylbis (triphenylphosphine) palladium (II)], (dioxygen) bis (t-butyl isocyanate), Pd 2 Cl 4 (C 2 H 4 ) 2 , Pd 2 Cl 4 (PPh 3 ) 2, Pd ( 2 H 4) (PPh 3) 2, PdCl 2 (C 8 H 12), [PdCl (C 3 H 5)] 2, Pd (C 3 H 5) (C 5 H 5), Pd (C 3 H 5 ) 2 , [Pd (C 5 H 5 ) (C 8 H 12 )] BF 4 , [Pd (C 3 H 5 ) (C 8 H 12 )] BF 4 , [Pd (acac) (C 8 H 12 ) ] BF 4 [New Experimental Chemistry Course 12 (Organic Metal Chemistry) p. 230-243] and the like.

　また、２種以上の遷移金属化合物を組み合わせて使用することもでき、例えば、Wacker酸化（“Palladium　Reagents and Catalysis”, First Edition ２００４, Wiley, ２９－３５；Synthesis　１９８４，３６９－３８４）などの手法を用いることができる。 Two or more transition metal compounds can also be used in combination, for example, a technique such as Wacker oxidation (“Palladium Reagents and Catalysis”, First Edition 2004, Wiley, 29-35; Synthesis 1984, 369-384). Can be used.

　これら脱水素化剤は、一般式（ＩＩ）で表されるハロエステル誘導体に対し、０．００１～１０倍モルの範囲で使用可能であるが、好ましくは０．０１～５倍モルの範囲である。 These dehydrogenating agents can be used in the range of 0.001 to 10-fold mol, preferably in the range of 0.01 to 5-fold mol based on the haloester derivative represented by the general formula (II). is there.

　使用する不活性溶媒としては、本反応の進行を著しく阻害しないものであれば良く、例えば、ヘキサン、シクロヘキサン、メチルシクロヘキサンなどの脂肪族炭化水素類；ベンゼン、トルエン、キシレン、クロルベンゼンなどの芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素などのハロゲン化炭化水素類；ジエチルエーテル、ｔ－ブチルメチルエーテル、ジオキサン、テトラヒドロフラン、１，２－ジメトキシエタンなどの鎖状または環状エーテル類；メタノール、エタノール、ｎ－プロパノール、２－プロパノール、ｎ－ブタノール、ｓ－ブタノール、ｔ－ブタノールなどのアルコール類；酢酸エチルなどのエステル類；ジメチルホルムアミド、ジメチルアセトアミドなどのアミド類；アセトニトリルなどのニトリル類；１、３－ジメチル－２－イミダゾリジノン、ピリジン、酢酸又は水などの不活性溶媒を例示することができ、これらの溶媒は単独もしくは２種以上の不活性溶媒を混合して使用することができる。 The inert solvent used is not particularly limited as long as it does not significantly inhibit the progress of this reaction. For example, aliphatic hydrocarbons such as hexane, cyclohexane, and methylcyclohexane; aromatics such as benzene, toluene, xylene, and chlorobenzene. Hydrocarbons; Halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; Linear or cyclic ethers such as diethyl ether, t-butyl methyl ether, dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; Methanol, ethanol , N-propanol, 2-propanol, n-butanol, s-butanol, t-butanol and other alcohols; esters such as ethyl acetate; amides such as dimethylformamide and dimethylacetamide; nitriles such as acetonitrile Examples of the inert solvent include 1,3-dimethyl-2-imidazolidinone, pyridine, acetic acid, and water. These solvents may be used alone or in admixture of two or more kinds of inert solvents. it can.

　反応系内のｐＨを調整する目的としては、例えば、トリエチルアミン、トリブチルアミン、ピロリジン、ピペリジン、モルホリン、ピリジン、３－ピコリン、４－ピコリン、４－ジメチルアミノピリジンなどの有機塩基類；水酸化リチウム、水酸化ナトリウム、水酸化カリウムなどの水酸化アルカリ金属類；ナトリウムメトキシド、ナトリウムエトキシドなどのアルカリ金属アルコキシド類；炭酸水素ナトリウム、炭酸カリウムなどの炭酸塩類；リン酸一水素カリウム、リン酸三ナトリウムなどのリン酸塩類；蟻酸ナトリウム、酢酸ナトリウムなどの有機酸塩基類；塩酸、硫酸、硝酸等の無機酸類；蟻酸、酢酸、トルフルオロ酢酸、プロピオン酸等の有機酸類；メタンスルホン酸、トリフルオロメタンスルホン酸、ｐ－トルエンスルホン酸等のスルホン酸類等を使用することができる。これらの塩基類、有機酸塩基類又は酸類は反応系内のｐＨを１～９になるように適宜加えれば良い。 Examples of the purpose of adjusting the pH in the reaction system include organic bases such as triethylamine, tributylamine, pyrrolidine, piperidine, morpholine, pyridine, 3-picoline, 4-picoline, 4-dimethylaminopyridine; lithium hydroxide, Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal alkoxides such as sodium methoxide and sodium ethoxide; Carbonates such as sodium hydrogen carbonate and potassium carbonate; Potassium monohydrogen phosphate and trisodium phosphate Phosphates such as sodium formate and sodium acetate; inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid; methanesulfonic acid and trifluoromethanesulfonic acid P-Toluenesulfonic acid It is possible to use the sulfonic acids and the like. These bases, organic acid bases or acids may be appropriately added so that the pH in the reaction system is 1-9.

　反応を促進することを目的として、テトラブチルアンモニウムクロリドなどの４級アンモニウム塩、１８－クラウン－６などのクラウンエーテル等の相間移動触媒を使用することもでき、一般式（ＩＩ）で表されるハロエステル誘導体に対して０．００１倍～０．１倍モルの範囲で適宜選択することができる。 For the purpose of accelerating the reaction, a phase transfer catalyst such as a quaternary ammonium salt such as tetrabutylammonium chloride or a crown ether such as 18-crown-6 can be used, and is represented by the general formula (II). The amount can be appropriately selected within the range of 0.001 to 0.1 moles relative to the haloester derivative.

　反応温度は－２０℃から使用する不活性溶媒の還流温度の範囲で適宜選択すればよいが、好ましくは０℃～１２０℃までの範囲から選ばれる。反応時間は反応規模、反応温度などにより変化し、一定ではないが数分～１００時間の範囲で適宜選択すればよい。 The reaction temperature may be appropriately selected within the range of −20 ° C. to the reflux temperature of the inert solvent used, but is preferably selected from the range of 0 ° C. to 120 ° C. The reaction time varies depending on the reaction scale, reaction temperature, and the like, and is not constant but may be appropriately selected within the range of several minutes to 100 hours.

　反応終了後、目的物を含む反応系から常法により、一般式（Ｉ）で表されるピラジンカルボン酸誘導体を単離すれば良く、必要に応じてこれを再結晶、カラムクロマトグラフィー、蒸留等で精製することにより目的物を製造することができる。 After completion of the reaction, the pyrazinecarboxylic acid derivative represented by the general formula (I) may be isolated from the reaction system containing the target product by a conventional method. If necessary, this may be recrystallized, column chromatography, distillation, etc. The desired product can be produced by purifying with

　本発明の他の好ましい実施態様の一つは下記するステップワイズ反応である。

Figure JPOXMLDOC01-appb-C000016
　（式中、Ｒ１、Ｒ２、Ｘ及びＭは前記に同じ。）
　２）　一般式（ＩＩ）　→　一般式（ＩＶ）→　一般式（Ｉ）
　本反応は、不活性溶媒中、段階的に（イ）一般式（ＩＩ）で表されるハロエステル誘導体またはその水和物と一般式（ＩＩＩ)で表されるアルカリ金属アジド塩を反応させ、一般式（ＩＶ）で表されるイミノ体またはその水和物に誘導し、次いで（ロ）１、２－エチレンジアミン又はその酸塩と反応させ、最後に（ハ）脱水素化剤を作用させ、一般式（Ｉ）で表されるピラジンカルボン酸誘導体を製造することができる。 Another preferred embodiment of the present invention is the stepwise reaction described below.
Figure JPOXMLDOC01-appb-C000016
 (In the formula, R 1 , R 2 , X and M are the same as above.)
2) General formula (II) → General formula (IV) → General formula (I)
In this reaction, (a) a haloester derivative represented by the general formula (II) or a hydrate thereof and an alkali metal azide salt represented by the general formula (III) are reacted stepwise in an inert solvent, Derived into an imino form represented by the general formula (IV) or a hydrate thereof, then (b) reacted with 1,2-ethylenediamine or an acid salt thereof, and finally (c) a dehydrogenating agent is allowed to act. A pyrazinecarboxylic acid derivative represented by the general formula (I) can be produced.

　（イ）、（ロ）および（ハ）の反応は、１）で述べた方法に準じて行えば良い。それぞれの試薬は１）に記載のように同時に添加しても、また２）に記載のように順次添加しても良好に目的物を得ることができる。 The reactions (a), (b) and (c) may be performed according to the method described in 1). Even if each reagent is added simultaneously as described in 1) or sequentially as described in 2), the desired product can be obtained satisfactorily.

　一般式（ＩＩ）で表される化合物は、公知の方法、例えば、Ｈｅｌｖｅｔｉｃａ　Ｃｈｕｍｉｃａ　Ａｃｔａ(１９６５),４８(６),１４２３－６等に記載の方法により、またはこれに準じて製造できる。また本願発明の製造方法により得られる３－ハロアルキルピラジン－２－カルボン酸誘導体は、例えば参考例に示した方法等により容易に農園芸用殺ダニ剤（特許文献１）及び殺菌剤（特許文献２）などの有用な化合物を製造することができる。 The compound represented by the general formula (II) can be produced by a known method, for example, the method described in Helvetica Chumica Acta (1965), 48 (6), 1423-6, or the like. Further, the 3-haloalkylpyrazine-2-carboxylic acid derivative obtained by the production method of the present invention can be easily produced by, for example, the method shown in Reference Examples, etc. ) And the like can be produced.

　以下に本発明の代表的な実施例を示すが、本発明はこれらに限定されるものではない。 Hereinafter, representative examples of the present invention will be shown, but the present invention is not limited thereto.

実施例１．　３－トリフルオロメチルピラジン－２－カルボン酸エチルの製造
　アジ化ナトリウム（２．６ｇ、４０ｍｍｏｌ）と１，２－エチレンジアミン塩酸塩（３．２ｇ、２４ｍｍｏｌ）の４ｍＬ水溶液に２－クロロ－４，４，４－トリフルオロ－３－オキソブタン酸エチル（４．４ｇ、２０ｍｍｏｌ）の酢酸エチル溶液（８ｍＬ）を滴下した。その後、５％Ｐｄ／Ｃ（２ｇ；５０％ｗｅｔ）と酢酸エチル（２ｍＬ）を添加し室温にて１時間撹拌した。次いで、反応混合物を３５℃で１時間撹拌後、２．５時間加熱還流した。反応液を室温に冷却した。酢酸エチル（１００ｍＬ）及び水（６０ｍＬ）を加え、ろ過にてＰｄ／Ｃを除去した後、酢酸エチルにて抽出した。有機層を水洗、乾燥し、溶媒を留去し残渣をシリカゲルカラムクロマトグラフィーにて精製し３－トリフルオロメチルピラジン－２－カルボン酸エチルを得た。
　収量；２．１ｇ
　収率；４８％
　物性：１Ｈ－ＮＭＲ［ＣＤＣｌ３／ＴＭＳδ値（ｐｐｍ）］
δ：１．４４（ｔ，Ｊ＝８Ｈｚ，３Ｈ），４．５２（ｑ，Ｊ＝８Ｈｚ，２Ｈ），８．８１（ｄ，Ｊ＝４Ｈｚ，１Ｈ），８．８４（ｄ，Ｊ＝４Ｈｚ，１Ｈ）
　１９Ｆ－ＮＭＲ［ＣＤＣｌ３／ＴＭＳδ値（ｐｐｍ）］
δ：－６５．５ Example 1. Preparation of ethyl 3-trifluoromethylpyrazine-2-carboxylate To a 4 mL aqueous solution of sodium azide (2.6 g, 40 mmol) and 1,2-ethylenediamine hydrochloride (3.2 g, 24 mmol) in 2-chloro-4,4 , A solution of ethyl 4-trifluoro-3-oxobutanoate (4.4 g, 20 mmol) in ethyl acetate (8 mL) was added dropwise. Thereafter, 5% Pd / C (2 g; 50% wet) and ethyl acetate (2 mL) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then stirred at 35 ° C. for 1 hour and then heated to reflux for 2.5 hours. The reaction was cooled to room temperature. Ethyl acetate (100 mL) and water (60 mL) were added, Pd / C was removed by filtration, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain ethyl 3-trifluoromethylpyrazine-2-carboxylate.
Yield; 2.1g
Yield; 48%
Physical properties: 1 H-NMR [CDCl 3 / TMSδ value (ppm)]
δ: 1.44 (t, J = 8 Hz, 3H), 4.52 (q, J = 8 Hz, 2H), 8.81 (d, J = 4 Hz, 1H), 8.84 (d, J = 4 Hz) , 1H)
19 F-NMR [CDCl 3 / TMSδ value (ppm)]
δ: -65.5

実施例２．　３－トリフルオロメチルピラジン－２－カルボン酸エチルの製造
　アジ化ナトリウム（２．６ｇ、４０ｍｍｏｌ）とテトラブチルアンモニウムクロリド（０．６ｇ、２ｍｍｏｌ）のトルエン（６ｍＬ）及び水（４ｍＬ）の混合溶液に２－クロロ－４，４，４－トリフルオロ－３－オキソブタン酸エチル（４．４ｇ、２０ｍｍｏｌ）のトルエン溶液（２ｍＬ）を滴下した。室温にて１．５時間撹拌後、エチレンジアミン塩酸塩（３．２ｇ、２４ｍｍｏｌ）、２－プロパノール（７ｍＬ）及びピリジン（４．０ｇ、５０ｍｍｏｌ）を順次加え更に１時間攪拌した。１０％Ｐｄ／Ｃ（３ｇ；５３％ｗｅｔ）とニトロベンゼン（２ｍＬ）を添加し３５℃で２時間撹拌後、２．５時間加熱還流した。反応液を室温に冷却した。酢酸エチル（１００ｍＬ）及び水（６０ｍＬ）を加え、ろ過にてＰｄ／Ｃを除去し、有機層を水洗、乾燥し、溶媒を留去し残渣をシリカゲルカラムクロマトグラフィーにて精製し３－トリフルオロメチルピラジン－２－カルボン酸エチルを得た。
　収量；１．８ｇ
　収率；４１％ Example 2 Preparation of ethyl 3-trifluoromethylpyrazine-2-carboxylate To a mixed solution of sodium azide (2.6 g, 40 mmol) and tetrabutylammonium chloride (0.6 g, 2 mmol) in toluene (6 mL) and water (4 mL) A toluene solution (2 mL) of ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (4.4 g, 20 mmol) was added dropwise. After stirring at room temperature for 1.5 hours, ethylenediamine hydrochloride (3.2 g, 24 mmol), 2-propanol (7 mL) and pyridine (4.0 g, 50 mmol) were sequentially added, and the mixture was further stirred for 1 hour. 10% Pd / C (3 g; 53% wet) and nitrobenzene (2 mL) were added, and the mixture was stirred at 35 ° C. for 2 hours and then heated to reflux for 2.5 hours. The reaction was cooled to room temperature. Ethyl acetate (100 mL) and water (60 mL) were added, Pd / C was removed by filtration, the organic layer was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 3-trifluoro Ethyl methylpyrazine-2-carboxylate was obtained.
Yield; 1.8g
Yield; 41%

実施例３．　３－ジフルオロメチルピラジン－２－カルボン酸エチルの製造
　４，４－ジフルオロ－３－オキソブタン酸エチル（１０ｇ、６０ｍｏｌ）に塩化スルフリル（８．５ｇ、６３ｍｏｌ）を加え室温にて１２時間攪拌した。反応液を氷水（１００ｍｌ）にあけ酢酸エチルで抽出した。有機層は水、飽和食塩水にて順次洗浄した後、無水硫酸ナトリウムで乾燥し減圧下濃縮した残渣を減圧蒸留にて精製（７３～７８℃／１２－１４ｍｍＨｇ）し２－クロロ－４，４－ジフルオロ－３－オキソブタン酸エチルエステル（６．６ｇ、収率；５５％）を得た。
　アジ化ナトリウム（２．１５ｇ、３３ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（６．４ｍＬ）、水（１．６ｍＬ）溶液に５℃にて２－クロロ－４，４－ジフルオロ－３－オキソブタン酸エチルエステル（３ｇ、１５ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１．６ｍＬ）溶液を滴下した。反応溶液を室温にて１．５時間撹拌後、エチレンジアミン塩酸塩（２ｇ、１５ｍｍｏｌ）とエタノール（４．８ｍＬ）、ピリジン（２．６ｇ、３３ｍｍｏｌ）を加え３時間撹拌した。次いで、５％Ｐｄ／Ｃ（５０％ｗｅｔ；２ｇ）と酢酸（３．２ｍＬ）を添加し、２．５時間加熱還流した。反応液を室温へと冷却後、酢酸エチル（１００ｍＬ）及び水（１００ｍＬ）を加え、濾過にてＰｄ／Ｃを除去し濾液を分液した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し減圧下濃縮した残渣をシリカゲルクロマトグラフィーにて精製し３－ジフルオロメチルピラジン－２－カルボン酸エチルを得た。
　収量；１．１ｇ
　収率；３７％
　物性：１Ｈ－ＮＭＲ［ＣＤＣｌ３／ＴＭＳδ値（ｐｐｍ）］
δ：１．４９（ｔ，Ｊ＝８Ｈｚ，３Ｈ），４．５４（ｑ，Ｊ＝８Ｈｚ，２Ｈ），７．４０（ｔ，Ｊ＝５６Ｈｚ，１Ｈ），８．８２（ｄ，Ｊ＝４Ｈｚ，１Ｈ），８．８６（ｄ，Ｊ＝４Ｈｚ，１Ｈ） Example 3 FIG. Production of ethyl 3-difluoromethylpyrazine-2-carboxylate Sulfuryl chloride (8.5 g, 63 mol) was added to ethyl 4,4-difluoro-3-oxobutanoate (10 g, 60 mol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (100 ml) and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure (73 to 78 ° C / 12-14 mmHg) to give 2-chloro-4,4 -Difluoro-3-oxobutanoic acid ethyl ester (6.6 g, yield; 55%) was obtained.
Ethyl 2-chloro-4,4-difluoro-3-oxobutanoate in a solution of sodium azide (2.15 g, 33 mmol) in N, N-dimethylformamide (6.4 mL) and water (1.6 mL) at 5 ° C. A solution of ester (3 g, 15 mmol) in N, N-dimethylformamide (1.6 mL) was added dropwise. After stirring the reaction solution at room temperature for 1.5 hours, ethylenediamine hydrochloride (2 g, 15 mmol), ethanol (4.8 mL) and pyridine (2.6 g, 33 mmol) were added and stirred for 3 hours. Subsequently, 5% Pd / C (50% wet; 2 g) and acetic acid (3.2 mL) were added, and the mixture was heated to reflux for 2.5 hours. After cooling the reaction solution to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, Pd / C was removed by filtration, and the filtrate was separated. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give ethyl 3-difluoromethylpyrazine-2-carboxylate.
Yield; 1.1g
Yield: 37%
Physical properties: 1 H-NMR [CDCl 3 / TMSδ value (ppm)]
δ: 1.49 (t, J = 8 Hz, 3H), 4.54 (q, J = 8 Hz, 2H), 7.40 (t, J = 56 Hz, 1H), 8.82 (d, J = 4 Hz) , 1H), 8.86 (d, J = 4 Hz, 1H)

　中間体の製造方法
実施例４．　２－イミノ－４，４，４－トリフルオロ－３－オキソブタン酸エチルの製造
　アジ化ナトリウム（２．６ｇ、４０ｍｍｏｌ）の１ｍＬ水溶液に２－クロロ－４，４，４－トリフルオロ－３－オキソブタン酸エチル（４．４ｇ、２０ｍｍｏｌ）のアセトニトリル溶液（２ｍＬ）を滴下した。室温にて２時間撹拌後、反応混合物をろ過し濾液を減圧留去し、粗製の目的物を含む油状物を得た。
　収量：２．２ｇ
　収率：５０％
　物性：１Ｈ－ＮＭＲ［ＤＭＳＯ／ＴＭＳδ値（ｐｐｍ）］
δ：１．２１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），４．１６（ｑ．Ｊ＝７．２Ｈｚ，２Ｈ），７．６５（ｓ，０．５Ｈ），７．８５（ｓ，０．５Ｈ）
　物性：１９Ｆ－ＮＭＲ［ＤＭＳＯ－ｄ６／ＴＭＳδ値（ｐｐｍ）］
δ：－８０．８ Intermediate Production Method Example 4 Preparation of ethyl 2-imino-4,4,4-trifluoro-3-oxobutanoate To a 1 mL aqueous solution of sodium azide (2.6 g, 40 mmol) 2-chloro-4,4,4-trifluoro-3-oxobutane A solution of ethyl acid (4.4 g, 20 mmol) in acetonitrile (2 mL) was added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was filtered and the filtrate was distilled off under reduced pressure to obtain an oily substance containing a crude target product.
Yield: 2.2g
Yield: 50%
Physical properties: 1 H-NMR [DMSO / TMSδ value (ppm)]
δ: 1.21 (t, J = 7.2 Hz, 3H), 4.16 (q.J = 7.2 Hz, 2H), 7.65 (s, 0.5H), 7.85 (s, 0 .5H)
Physical properties: 19 F-NMR [DMSO-d6 / TMSδ value (ppm)]
δ: -80.8

参考例１．　Ｎ－（３’，４’－ジフルオロビフェニル－２－イル）－３－トリフルオロメチルピラジン－２－カルボキサミドの製造
　３’，４’－ジフルオロビフェニル－２－イルアミン（１０ｇ、４９ｍｍｏｌ）のジメチルアセトアミド（１１ｍｌ）溶液に２８％ナトリウムメトキシドメタノール溶液（３０ｍｌ、０．１５ｍｏｌ）を加え、次いで３－トリフルオロメチルピラジン－２－カルボン酸エチル（１２．６ｇ、５７ｍｍｏｌ）のジメチルアセトアミド（１ｍｌ）溶液を加え、室温にて５時間攪拌した。冷却した希塩酸（７５ｍｌ）を加え酢酸エチルで抽出し、有機層を水、重曹水及び飽和食塩水で順次洗浄し無水硫酸ナトリウムで乾燥した。減圧下に濃縮した後、残渣を再結晶化（ヘキサン：酢酸エチル＝４：１（Ｖ／Ｖ））で精製して表題化合物を得た。
　収量：１５．７ｇ
　収率：８５％
　物性：融点　１１６～１１７℃ Reference Example 1 Preparation of N- (3 ′, 4′-difluorobiphenyl-2-yl) -3-trifluoromethylpyrazin-2-carboxamide 3 ′, 4′-Difluorobiphenyl-2-ylamine (10 g, 49 mmol) in dimethylacetamide ( 11 ml) solution was added 28% sodium methoxide methanol solution (30 ml, 0.15 mol), followed by a solution of ethyl 3-trifluoromethylpyrazine-2-carboxylate (12.6 g, 57 mmol) in dimethylacetamide (1 ml). And stirred at room temperature for 5 hours. Cooled dilute hydrochloric acid (75 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by recrystallization (hexane: ethyl acetate = 4: 1 (V / V)) to give the title compound.
Yield: 15.7g
Yield: 85%
Physical property: Melting point 116-117 ° C

Claims (19)

　一般式（ＩＩ）
Figure JPOXMLDOC01-appb-C000017
 （式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基及びＸはハロゲン原子を示す。）で表されるハロエステル誘導体と一般式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000018
 （式中、Ｍはアルカリ金属原子を示す。）で表されるアルカリ金属アジド塩及び１、２－エチレンジアミン又はその酸塩及び脱水素化剤と反応させることを特徴とする、一般式（Ｉ）
Figure JPOXMLDOC01-appb-C000019
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるピラジンカルボン酸誘導体の製造方法。 Formula (II)
Figure JPOXMLDOC01-appb-C000017
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, R 2 represents a (C 1 -C 6 ) alkyl group, and X represents a halogen atom). Haloester derivatives represented by general formula (III)
Figure JPOXMLDOC01-appb-C000018
 (Wherein M represents an alkali metal atom), which is reacted with an alkali metal azide salt represented by formula (I), 1,2-ethylenediamine or an acid salt thereof, and a dehydrogenating agent.
Figure JPOXMLDOC01-appb-C000019
 (Wherein R 1 and R 2 are the same as above), a method for producing a pyrazinecarboxylic acid derivative. 　一般式（ＩＩ）
Figure JPOXMLDOC01-appb-C000020
 （式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基及びＸはハロゲン原子を示す。）で表されるハロエステル誘導体と一般式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000021
 （式中、Ｍはアルカリ金属原子を示す。）で表されるアルカリ金属アジド塩と反応させ、次いで１、２－エチレンジアミン又はその酸塩と反応させ、次いで脱水素化剤と反応させることを特徴とする、一般式（Ｉ）
Figure JPOXMLDOC01-appb-C000022
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるピラジンカルボン酸誘導体の製造方法。 Formula (II)
Figure JPOXMLDOC01-appb-C000020
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, R 2 represents a (C 1 -C 6 ) alkyl group, and X represents a halogen atom). Haloester derivatives represented by general formula (III)
Figure JPOXMLDOC01-appb-C000021
 (Wherein M represents an alkali metal atom), and then reacted with 1,2-ethylenediamine or an acid salt thereof, and then reacted with a dehydrogenating agent. General formula (I)
Figure JPOXMLDOC01-appb-C000022
 (Wherein R 1 and R 2 are the same as above), a method for producing a pyrazinecarboxylic acid derivative. 　一般式（ＩＩ）
Figure JPOXMLDOC01-appb-C000023
 （式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基及びＸはハロゲン原子を示す。）で表されるハロエステル誘導体と一般式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000024
 （式中、Ｍはアルカリ金属原子を示す。）で表されるアルカリ金属アジド塩を反応させて、一般式（ＩＶ）
Figure JPOXMLDOC01-appb-C000025
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるイミノ体またはその水和物に誘導し、次いで該イミノ体又は該水和物を単離しまたは単離せずして、１、２－エチレンジアミン又はその酸塩と反応させて、次いで脱水素化剤と反応させることを特徴とする、一般式（Ｉ）
Figure JPOXMLDOC01-appb-C000026
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるピラジンカルボン酸誘導体の製造方法。 Formula (II)
Figure JPOXMLDOC01-appb-C000023
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, R 2 represents a (C 1 -C 6 ) alkyl group, and X represents a halogen atom). Haloester derivatives represented by general formula (III)
Figure JPOXMLDOC01-appb-C000024
 (Wherein M represents an alkali metal atom), and an alkali metal azide salt represented by the general formula (IV) is reacted.
Figure JPOXMLDOC01-appb-C000025
 (Wherein R 1 and R 2 are the same as defined above), and then the imino form or the hydrate thereof is isolated or not isolated. , 2-ethylenediamine or its acid salt, followed by reaction with a dehydrogenating agent
Figure JPOXMLDOC01-appb-C000026
 (Wherein R 1 and R 2 are the same as above), a method for producing a pyrazinecarboxylic acid derivative. 　Ｒ１がハロ（Ｃ１－Ｃ６）アルキル基である請求項１に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 1, wherein R 1 is a halo (C 1 -C 6 ) alkyl group. 　Ｒ１がハロ（Ｃ１－Ｃ６）アルキル基である請求項２に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 2, wherein R 1 is a halo (C 1 -C 6 ) alkyl group. 　Ｒ１がハロ（Ｃ１－Ｃ６）アルキル基である請求項３に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 3, wherein R 1 is a halo (C 1 -C 6 ) alkyl group. 　Ｒ１がフルオロ（Ｃ１－Ｃ６）アルキル基である請求項１に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 1, wherein R 1 is a fluoro (C 1 -C 6 ) alkyl group. 　Ｒ１がフルオロ（Ｃ１－Ｃ６）アルキル基である請求項２に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 2, wherein R 1 is a fluoro (C 1 -C 6 ) alkyl group. 　Ｒ１がフルオロ（Ｃ１－Ｃ６）アルキル基である請求項３に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 3, wherein R 1 is a fluoro (C 1 -C 6 ) alkyl group. 　Ｒ１がフルオロ（Ｃ１－Ｃ３）アルキル基である請求項１に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 1, wherein R 1 is a fluoro (C 1 -C 3 ) alkyl group. 　Ｒ１がフルオロ（Ｃ１－Ｃ３）アルキル基である請求項２に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 2, wherein R 1 is a fluoro (C 1 -C 3 ) alkyl group. 　Ｒ１がフルオロ（Ｃ１－Ｃ３）アルキル基である請求項３に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 3, wherein R 1 is a fluoro (C 1 -C 3 ) alkyl group. 　Ｒ１がジフルオロメチル基又はトリフルオロメチル基である請求項１に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 1, wherein R 1 is a difluoromethyl group or a trifluoromethyl group. 　Ｒ１がジフルオロメチル基又はトリフルオロメチル基である請求項２に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 2, wherein R 1 is a difluoromethyl group or a trifluoromethyl group. 　Ｒ１がジフルオロメチル基又はトリフルオロメチル基である請求項３に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to claim 3, wherein R 1 is a difluoromethyl group or a trifluoromethyl group. 　Ｍが、ナトリウムである請求項１～１５のいずれか１項に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to any one of claims 1 to 15, wherein M is sodium. 　脱水素化剤が、パラジウム又はその担持体である請求項１～１６のいずれか１項に記載のピラジンカルボン酸誘導体の製造方法。 The method for producing a pyrazinecarboxylic acid derivative according to any one of claims 1 to 16, wherein the dehydrogenating agent is palladium or a support thereof. 　一般式（ＩＶ）
Figure JPOXMLDOC01-appb-C000027
 （式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基を示す。）で表されるイミノ体またはその水和物。 Formula (IV)
Figure JPOXMLDOC01-appb-C000027
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, and R 2 represents a (C 1 -C 6 ) alkyl group). Or its hydrates. 　一般式（ＩＩ）
Figure JPOXMLDOC01-appb-C000028
 （式中、Ｒ１は（Ｃ１－Ｃ６）アルキル基またはハロ（Ｃ１－Ｃ６）アルキル基、Ｒ２は（Ｃ１－Ｃ６）アルキル基及びＸはハロゲン原子を示す。）で表されるハロエステル誘導体と一般式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000029
 （式中、Ｍはアルカリ金属原子を示す。）で表されるアルカリ金属アジド塩を反応させることを特徴とする、一般式（ＩＶ）
Figure JPOXMLDOC01-appb-C000030
 （式中、Ｒ１及びＲ２は前記に同じ。）で表されるイミノ体またはその水和物の製造方法。 Formula (II)
Figure JPOXMLDOC01-appb-C000028
 (Wherein R 1 represents a (C 1 -C 6 ) alkyl group or a halo (C 1 -C 6 ) alkyl group, R 2 represents a (C 1 -C 6 ) alkyl group, and X represents a halogen atom). Haloester derivatives represented by general formula (III)
Figure JPOXMLDOC01-appb-C000029
 (Wherein, M represents an alkali metal atom), an alkali metal azide salt represented by the general formula (IV)
Figure JPOXMLDOC01-appb-C000030
 (Wherein R 1 and R 2 are the same as above), and a method for producing an imino form or a hydrate thereof.
PCT/JP2010/002898 2009-04-23 2010-04-22 Process for production of pyrazinecarboxylic acid derivative, and intermediate for the production Ceased WO2010122794A1 (en)

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WO2018041853A1 (en) 2016-09-01 2018-03-08 Lonza Ltd Method for the preparation of 3-(trifluoromethyl)pyrazine-2-carboxylic acid esters
CN108069915A (en) * 2016-11-15 2018-05-25 华中师范大学 A kind of pyrazinamide class compound and its preparation method and application and a kind of fungicide
CN109096209A (en) * 2017-06-20 2018-12-28 华中师范大学 Pyrazinamide class compound and its preparation method and application and fungicide
CN109666003A (en) * 2017-10-13 2019-04-23 华中师范大学 Pyrazinamide class compound containing iodine and its preparation method and application and fungicide
CN109666004A (en) * 2017-10-13 2019-04-23 华中师范大学 Pyrazinamide class compound containing trifluoromethyl and its preparation method and application and fungicide
CN109689631A (en) * 2016-09-01 2019-04-26 隆萨有限公司 Prepare 3-(trifluoromethyl) method of pyrazine -2- formic acid esters

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Publication number Priority date Publication date Assignee Title
WO2018041853A1 (en) 2016-09-01 2018-03-08 Lonza Ltd Method for the preparation of 3-(trifluoromethyl)pyrazine-2-carboxylic acid esters
CN109689631A (en) * 2016-09-01 2019-04-26 隆萨有限公司 Prepare 3-(trifluoromethyl) method of pyrazine -2- formic acid esters
CN108069915A (en) * 2016-11-15 2018-05-25 华中师范大学 A kind of pyrazinamide class compound and its preparation method and application and a kind of fungicide
CN108069915B (en) * 2016-11-15 2020-05-15 华中师范大学 Pyrazinamide compound, preparation method and application thereof, and bactericide
CN109096209A (en) * 2017-06-20 2018-12-28 华中师范大学 Pyrazinamide class compound and its preparation method and application and fungicide
CN109096209B (en) * 2017-06-20 2022-03-01 华中师范大学 Pyrazinamide compound, preparation method and application thereof, and bactericide
CN109666003A (en) * 2017-10-13 2019-04-23 华中师范大学 Pyrazinamide class compound containing iodine and its preparation method and application and fungicide
CN109666004A (en) * 2017-10-13 2019-04-23 华中师范大学 Pyrazinamide class compound containing trifluoromethyl and its preparation method and application and fungicide
CN109666003B (en) * 2017-10-13 2020-08-21 华中师范大学 Iodine-containing pyrazinamide compounds, preparation method and application thereof, and bactericide
CN109666004B (en) * 2017-10-13 2020-08-21 华中师范大学 Pyrazinamide compounds containing trifluoromethyl group, preparation method and application thereof, and bactericide

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