JP2017206453A

JP2017206453A - Manufacturing method of pyrazole derivative and intermediate products thereof

Info

Publication number: JP2017206453A
Application number: JP2016098760A
Authority: JP
Inventors: 周平窪田; Shuhei Kubota
Original assignee: Nihon Nohyaku Co Ltd
Current assignee: Nihon Nohyaku Co Ltd
Priority date: 2016-05-17
Filing date: 2016-05-17
Publication date: 2017-11-24

Abstract

PROBLEM TO BE SOLVED: To provide an improved manufacturing method of a compound expressed by a general formula (2) (in the general formula, R, Ror Ris a (C-C) alkyl group), the compound useful as an intermediate product for a medical drug or an agricultural chemical, the improved manufacturing method desired due to a conventional manufacturing method of the compound (2) not being industrially advantageous in view of economical efficiency, environmental load and operation safety .SOLUTION: In a manufacturing method of a compound (2), a compound expressed by a general formula (5) (in the general formula, Rand Rare the same as in the above and X is a halogen atom) is successively or integrally reacted in a reaction vessel under a presence of bases.SELECTED DRAWING: None

Description

本発明は、医薬又は農薬等の中間体として、特に農園芸用除草剤及び枯凋剤の製造中間体として有用な５‐ヒドロキシ‐３‐フェニルピラゾール誘導体の製造方法に関する。 The present invention relates to a method for producing a 5-hydroxy-3-phenylpyrazole derivative useful as an intermediate for pharmaceuticals, agricultural chemicals, etc., particularly as an intermediate for producing herbicides for agricultural and horticultural use and wiping agents.

本発明の５‐ヒドロキシ‐３‐フェニルピラゾール誘導体は、医薬又は農薬等の中間体として、特に農園芸用除草剤及び枯凋剤（例えば、特許文献１を参照。）の中間体として有用である。その製造方法として、特許文献２において開示されている方法や、置換ベンゼンに対するFriedel-Crafts アシル化反応（例えば、特許文献３を参照。）、それに続くシアノ化反応（例えば、特許文献４を参照。）及び加水分解反応（例えば、特許文献５を参照。）を経由する方法等が報告されている。
しかし、いずれの方法にも本発明のような置換ハロベンゼンとオレフィンとの遷移金属触媒クロスカップリング反応を経由するような方法に関しては、具体的な開示も示唆もされていない。 The 5-hydroxy-3-phenylpyrazole derivative of the present invention is useful as an intermediate for pharmaceuticals or agricultural chemicals, and particularly as an intermediate for agricultural and horticultural herbicides and wiping agents (see, for example, Patent Document 1). As its production method, see the method disclosed in Patent Document 2, Friedel-Crafts acylation reaction for substituted benzene (for example, see Patent Document 3), and subsequent cyanation reaction (for example, see Patent Document 4). ) And a hydrolysis reaction (for example, see Patent Document 5).
However, no specific disclosure or suggestion is made regarding any of the methods via a transition metal catalyzed cross-coupling reaction between a substituted halobenzene and an olefin as in the present invention.

特許第２８１３８９５号Japanese Patent No. 2813895 特許第３２００７３７号Japanese Patent No. 3300247 特許第３６４６２２３号Japanese Patent No. 3646223 特許第３６４６２２４号Patent No. 3646224 特許第３６４６２２５号Japanese Patent No. 3646225

前記特許文献３の方法では、その製造過程において、大量の水酸化アルミニウムを含有する排水が発生するため、経済性、環境負荷の観点から必ずしも工業的に有利な製造方法とは言えない。また前記特許文献４の方法では、その製造過程において有害なシアン化合物を含む廃液が多量に発生すること、またその原料となる化合物が皮膚刺激性および感作性を有する疑いがあることから、こちらも環境負荷、作業上の安全性の観点から工業的に有利な製造方法とは言えない。本発明の課題は、医薬又は農薬等の中間体として有用な５‐ヒドロキシ‐３‐フェニルピラゾール誘導体類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 method of Patent Document 3, wastewater containing a large amount of aluminum hydroxide is generated in the production process, and therefore, it is not necessarily an industrially advantageous production method from the viewpoint of economy and environmental load. Further, in the method of Patent Document 4, a large amount of waste liquid containing a harmful cyanide compound is generated in the production process, and the compound as a raw material is suspected of having skin irritation and sensitization. However, it cannot be said that it is an industrially advantageous production method from the viewpoint of environmental load and work safety. An object of the present invention is to provide a novel and industrially advantageous production method of 5-hydroxy-3-phenylpyrazole derivatives useful as intermediates for pharmaceuticals or agricultural chemicals.

本発明者は前記課題を解決すべく鋭意研究を重ねた結果、置換ハロベンゼンとオレフィンとの遷移金属触媒クロスカップリング反応と、それに続く反応により、前記課題となる製造工程を回避した３‐フェニルピラゾール誘導体のより効率的で安全な製造方法を見出した。さらに一般式（２）、（５）及び（６）で表される化合物は文献未記載の新規化合物であることを見出し、本発明を完成させた。 As a result of intensive studies to solve the above-mentioned problems, the present inventor has obtained 3-phenylpyrazole which avoids the above-mentioned production process by a transition metal-catalyzed cross-coupling reaction between a substituted halobenzene and an olefin and a subsequent reaction. We have found a more efficient and safe method for producing derivatives. Further, the present inventors have found that the compounds represented by the general formulas (2), (5) and (6) are novel compounds not described in any literature, and completed the present invention.

即ち本発明は、
[１]一般式（５）
（式中、Ｒ^１及びＲ^２は（Ｃ_１-Ｃ_６）アルキル基を示し、Ｘはハロゲン原子を示す。）で表される化合物を、塩基の存在下、逐次的又は一反応容器内において一括に反応を行うことを特徴とする一般式（２）
（式中Ｒ^１及びＲ^２は前記に同じくし、Ｒ^３は（Ｃ_１-Ｃ_６）アルキル基を示す。）で表される化合物の製造方法。
[２]一般式（５）
（式中、Ｒ^１、Ｒ^２及びＸは前記に同じ。）で表される化合物を、塩基の存在下、逐次的又は一反応容器内において一括に反応を行うことにより一般式（２）
（式中Ｒ^１、Ｒ^２及びＲ^３は前記に同じ。）で表される化合物を製造し、該化合物（２）の酸加水分解と、それに引き続くメチルヒドラジンとの反応を特徴とする一般式（１）
（式中Ｒ^１は前記に同じ。）で表される化合物の製造方法。
[３]一般式（６）
（式中Ｒ^１及びＲ^２は前記に同じ。）で表される化合物をハロゲン化剤と反応させることにより、一般式（５）
（式中、Ｒ^１、Ｒ^２及びＸは前記に同じ。）で表される化合物を製造し、該化合物（５）を塩基類の存在下、逐次的又は一反応容器内において一括に反応を行うことを特徴とする一般式（２）
（式中Ｒ^１、Ｒ^２及びＲ^３は前記に同じ。）で表される化合物の製造方法。
[４]一般式（７）
（式中、Ｒ^２は前記に同じ。）で表される化合物と、一般式（８）
（式中、Ｒ^１は前記に同じくし、Ｚはハロゲン原子又はトリフラート基を示す。）で表される化合物とを遷移金属触媒存在下、カップリング反応を行うことにより、一般式（６）
（式中Ｒ^１及びＲ^２は前記に同じ。）で表される化合物を製造し、該化合物（６）をハロゲン化剤と反応させることにより、一般式（５）
（式中、Ｒ^１、Ｒ^２及びＸは前記に同じ。）で表される化合物を製造し、該化合物（５）を塩基類の存在下、逐次的又は一反応容器内において一括に反応を行うことを特徴とする一般式（２）
（式中Ｒ^１、Ｒ^２及びＲ^３は前記に同じ。）で表される化合物の製造方法。
[５]一般式（９）
（式中、Ｒ^１は前記に同じくし、Ｙはハロゲン原子、メシルオキシ基、トシルオキシ基及びトリフラート基を示す。）で表される化合物と、一般式（１０）

（式中、Ｚは前記に同じくし、Ｒ^４は（Ｃ_１-Ｃ_６）アルキル基を示す。）で表される化合物とを塩基類の存在下、反応させることにより、一般式（８）
（式中、Ｒ^１及びＺは前記に同じ。）で表される化合物を製造し、該化合物（８）と、一般式（７）
（式中、Ｒ^２は前記に同じ。）で表される化合物とを遷移金属触媒存在下、カップリング反応を行うことにより、一般式（６）
（式中Ｒ^１及びＲ^２は前記に同じ。）で表される化合物を製造し、該化合物（６）をハロゲン化剤と反応させることにより、一般式（５）
（式中、Ｒ^１、Ｒ^２及びＸは前記に同じ。）で表される化合物を製造し、該化合物（５）を塩基類の存在下、逐次的又は一反応容器内において一括に反応を行うことを特徴とする一般式（２）
（式中Ｒ^１、Ｒ^２及びＲ^３は前記に同じ。）で表される化合物の製造方法。
[６]一般式（９）
（式中、Ｒ^１及びＹは前記に同じ。）で表される化合物と、一般式（１０）

（式中、Ｒ^４及びＺは前記に同じ。）で表される化合物とを塩基類の存在下、反応させることにより、一般式（８）
（式中、Ｒ^１及びＺは前記に同じ。）で表される化合物を製造し、該化合物（８）と、一般式（７）
（式中、Ｒ^２は前記に同じ。）で表される化合物とを遷移金属触媒存在下、カップリング反応を行うことにより、一般式（６）
（式中Ｒ^１及びＲ^２は前記に同じ。）で表される化合物を製造し、該化合物（６）をハロゲン化剤と反応させることにより、一般式（５）
（式中、Ｒ^１、Ｒ^２及びＸは前記に同じ。）で表される化合物を製造し、該化合物（５）を塩基類の存在下、逐次的又は一反応容器内において一括に反応を行うことにより、一般式（２）
（式中Ｒ^１、Ｒ^２及びＲ^３は前記に同じ。）で表される化合物を製造し、該化合物（２）の酸加水分解と、それに引き続くメチルヒドラジンとの反応を特徴とする一般式（１）
（式中Ｒ^１は前記に同じ。）で表される化合物の製造方法。
[７]一般式（５）
（式中、Ｒ^１、Ｒ^２、Ｒ^３及びＸは前記と同じ。）で表される化合物を塩基類の存在下、反応させることにより、一般式（４）
（式中、Ｒ^１、Ｒ^２及びＸは前記と同じ。）で表される化合物を製造し、該化合物（４）を一般式（３）
（式中、Ｒ^３は前記と同じく、Ｍはアルカリ金属を示す。）で表されるアルコールアルカリ金属塩と反応させることにより、一般式（２）
（式中Ｒ^１、Ｒ^２及びＲ^３は前記に同じ。）で表される化合物を製造する工程を含む[１]乃至[６]のいずれかに記載の製造方法。
[８]一般式（５）
（式中、Ｒ^１、Ｒ^２、Ｒ^３及びＸは前記と同じ。）で表される化合物を、一般式（３）
（式中、Ｒ^３及びＭは前記と同じ。）で表されるアルコールアルカリ金属塩と反応させることにより、一般式（２）
（式中Ｒ^１、Ｒ^２及びＲ^３は前記に同じ。）で表される化合物を製造する工程を含む[１]乃至[６]のいずれかに記載の製造方法。
[９]Ｒ^１、Ｒ^２及びＲ^３は（Ｃ_１-Ｃ_３）アルキル基を示す、[１]に記載の製造方法。
[１０]Ｒ^１、Ｒ^２及びＲ^３は（Ｃ_１-Ｃ_３）アルキル基を示す、[２]に記載の製造方法。
[１１]Ｒ^１、Ｒ^２及びＲ^３は（Ｃ_１-Ｃ_３）アルキル基を示す、[３]に記載の製造方法。
[１２]Ｒ^１、Ｒ^２及びＲ^３は（Ｃ_１-Ｃ_３）アルキル基を示す、[４]に記載の製造方法。
[１３]Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は（Ｃ_１-Ｃ_３）アルキル基を示し、Ｙはハロゲン原子を示す、[５]に記載の製造方法。
[１４]Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は（Ｃ_１-Ｃ_３）アルキル基を示し、Ｙはハロゲン原子を示す、[６]に記載の製造方法。
[１５]Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は（Ｃ_１-Ｃ_３）アルキル基を示し、Ｙはハロゲン原子を示す[７]に記載の製造方法。
[１６]Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は（Ｃ_１-Ｃ_３）アルキル基を示し、Ｙはハロゲン原子を示す、[８]に記載の製造方法。
[１７]Ｒ^１及びＲ^３はメチル基を示し、Ｒ^２はメチル基又はエチル基を示し、Ｘは臭素原子を示す、[１]又は[９]に記載の製造方法。
[１８]Ｒ^１及びＲ^３はメチル基を示し、Ｒ^２はメチル基又はエチル基を示し、Ｘは臭素原子を示す、[２]又は[１０]に記載の製造方法。
[１９]Ｒ^１及びＲ^３はメチル基を示し、Ｒ^２はメチル基又はエチル基を示し、Ｘは臭素原子を示す、[３]又は[１１]に記載の製造方法。
[２０]Ｒ^１及びＲ^３はメチル基を示し、Ｒ^２はメチル基又はエチル基を示し、Ｘ及びＺは臭素原子を示す、[４]又は[１２]に記載の製造方法。
[２１]Ｒ^１及びＲ^３はメチル基を示し、Ｒ^２はメチル基又はエチル基を示し、Ｘ及びＺは臭素原子を示し、Ｙは塩素原子を示す、[５]又は[１３]に記載の製造方法。
[２２]Ｒ^１及びＲ^３はメチル基を示し、Ｒ^２はメチル基又はエチル基を示し、Ｘ及びＺは臭素原子を示し、Ｙは塩素原子を示す、[６]又は[１４]に記載の製造方法。
[２３]Ｒ^１及びＲ^３はメチル基を示し、Ｒ^２はメチル基又はエチル基を示し、Ｘ及びＺは臭素原子を示し、Ｙは塩素原子を示す、[７]又は[１５]に記載の製造方法。
[２４]Ｒ^１及びＲ^３はメチル基を示し、Ｒ^２はメチル基又はエチル基を示し、Ｘ及びＺは臭素原子を示し、Ｙは塩素原子を示す、[８]又は[１６]に記載の製造方法。
[２５]一般式（２）
（式中、Ｒ^１、Ｒ^２及びＲ^３は（Ｃ_１-Ｃ_６）アルキル基を示す。）で表される化合物。
[２６]Ｒ^１、Ｒ^２及びＲ^３は（Ｃ_１-Ｃ_３）アルキル基を示す、[２５]に記載の化合物。
[２７]Ｒ^１及びＲ^３はメチル基を示し、Ｒ^２はメチル基又はエチル基を示す、[２６]に記載の化合物。
[２８]一般式（５）
（式中、Ｒ^１及びＲ^２は（Ｃ_１-Ｃ_６）アルキル基を示し、Ｘはハロゲン原子を示す。）で表される化合物。
[２９]Ｒ^１、Ｒ^２及びＲ^３は（Ｃ_１-Ｃ_３）アルキル基を示す、[２８]に記載の化合物。
[３０]Ｒ^１、Ｒ^２及びＲ^３はメチル基を示し、Ｘは臭素原子を示す、[２９]に記載の化合物。
[３１]一般式（６）
（式中、Ｒ^１及びＲ^２は（Ｃ_１-Ｃ_６）アルキル基を示す。）で表される化合物。
[３２]Ｒ^１及びＲ^２は（Ｃ_１-Ｃ_３）アルキル基を示す、[３１]に記載の化合物。
[３３]Ｒ^１及びＲ^２はメチル基を示す、[３２]に記載の化合物。
等に関する。 That is, the present invention
[1] General formula (5)
(Wherein R ¹ and R ² represent a (C ₁ -C ₆ ) alkyl group, and X represents a halogen atom), in the presence of a base, sequentially or in one reaction vessel. General formula (2) characterized by performing the reaction in a lump
(Wherein R ¹ and R ² are the same as described above, and R ³ represents a (C ₁ -C ₆ ) alkyl group).
[2] General formula (5)
(In the formula, R ¹ , R ² and X are the same as above.) The compound represented by the general formula (2) is reacted in the presence of a base sequentially or batchwise in one reaction vessel.
(Wherein R ¹ , R ² and R ³ are the same as above), a general formula characterized by acid hydrolysis of the compound (2) and subsequent reaction with methyl hydrazine (1)
(Wherein R ¹ is the same as defined above).
[3] General formula (6)
(In the formula, R ¹ and R ² are the same as above.) By reacting a compound represented by the formula (5)
(Wherein R ¹ , R ² and X are the same as above), and the compound (5) is reacted in the presence of bases sequentially or in a single reaction vessel. General formula (2) characterized by
(Wherein R ¹ , R ² and R ³ are the same as above).
[4] General formula (7)
(Wherein R ² is the same as defined above) and the general formula (8)
(Wherein R ¹ is the same as defined above, Z represents a halogen atom or a triflate group) and a compound represented by the general formula (6)
(Wherein R ¹ and R ² are the same as described above), and the compound (6) is reacted with a halogenating agent to produce a compound represented by the general formula (5)
(Wherein R ¹ , R ² and X are the same as above), and the compound (5) is reacted in the presence of bases sequentially or in a single reaction vessel. General formula (2) characterized by
(Wherein R ¹ , R ² and R ³ are the same as above).
[5] General formula (9)
(Wherein R ¹ is the same as defined above, Y represents a halogen atom, a mesyloxy group, a tosyloxy group and a triflate group), and a general formula (10)

(Wherein Z is the same as defined above, and R ⁴ represents a (C ₁ -C ₆ ) alkyl group). In the presence of a base, the compound represented by formula (8) is reacted.
(Wherein R ¹ and Z are the same as defined above), and the compound (8) and the general formula (7) are produced.
(Wherein R ² is the same as above) and a coupling reaction in the presence of a transition metal catalyst to give a compound represented by the general formula (6)
(Wherein R ¹ and R ² are the same as described above), and the compound (6) is reacted with a halogenating agent to produce a compound represented by the general formula (5)
(Wherein R ¹ , R ² and X are the same as above), and the compound (5) is reacted in the presence of bases sequentially or in a single reaction vessel. General formula (2) characterized by
(Wherein R ¹ , R ² and R ³ are the same as above).
[6] General formula (9)
(Wherein, R ¹ and Y are the same as defined above) and the general formula (10)

(Wherein, R ⁴ and Z are the same as defined above) in the presence of a base to react with the compound represented by the general formula (8)
(Wherein R ¹ and Z are the same as defined above), and the compound (8) and the general formula (7) are produced.
(Wherein R ² is the same as above) and a coupling reaction in the presence of a transition metal catalyst to give a compound represented by the general formula (6)
(Wherein R ¹ and R ² are the same as described above), and the compound (6) is reacted with a halogenating agent to produce a compound represented by the general formula (5)
(Wherein R ¹ , R ² and X are the same as above), and the compound (5) is reacted in the presence of bases sequentially or in a single reaction vessel. By performing the general formula (2)
(Wherein R ¹ , R ² and R ³ are the same as above), a general formula characterized by acid hydrolysis of the compound (2) and subsequent reaction with methyl hydrazine (1)
(Wherein R ¹ is the same as defined above).
[7] General formula (5)
(Wherein R ¹ , R ² , R ³ and X are the same as above), by reacting the compound represented by the general formula (4) in the presence of a base.
(Wherein R ¹ , R ² and X are the same as described above), and the compound (4) is represented by the general formula (3).
(Wherein R ³ is the same as described above, M represents an alkali metal), by reacting with an alcohol alkali metal salt represented by the general formula (2)
(Wherein R ¹ , R ² and R ³ are the same as described above). The production method according to any one of [1] to [6], comprising a step of producing a compound represented by the formula:
[8] General formula (5)
(Wherein R ¹ , R ² , R ³ and X are as defined above), the compound represented by the general formula (3)
(Wherein R ³ and M are the same as above), by reacting with an alcohol alkali metal salt represented by the general formula (2)
(Wherein R ¹ , R ² and R ³ are the same as described above). The production method according to any one of [1] to [6], comprising a step of producing a compound represented by the formula:
[9] The production method according to [1], wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.
[10] The production method according to [2], wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.
[11] The production method according to [3], wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.
[12] The production method according to [4], wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.
[13] The production method according to [5], wherein R ¹ , R ² , R ³ and R ⁴ represent a (C ₁ -C ₃ ) alkyl group, and Y represents a halogen atom.
[14] The production method according to [6], wherein R ¹ , R ² , R ³ and R ⁴ represent a (C ₁ -C ₃ ) alkyl group, and Y represents a halogen atom.
[15] The production method according to [7], wherein R ¹ , R ² , R ³ and R ⁴ represent a (C ₁ -C ₃ ) alkyl group, and Y represents a halogen atom.
[16] The production method according to [8], wherein R ¹ , R ² , R ³ and R ⁴ represent a (C ₁ -C ₃ ) alkyl group, and Y represents a halogen atom.
[17] The production method according to [1] or [9], wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, and X represents a bromine atom.
[18] The production method according to [2] or [10], wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, and X represents a bromine atom.
[19] The production method according to [3] or [11], wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, and X represents a bromine atom.
[20] The production method according to [4] or [12], wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, and X and Z represent a bromine atom.
[21] R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, X and Z represent a bromine atom, and Y represents a chlorine atom, described in [5] or [13] Manufacturing method.
[22] R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, X and Z represent a bromine atom, Y represents a chlorine atom, described in [6] or [14] Manufacturing method.
[23] R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, X and Z represent a bromine atom, and Y represents a chlorine atom, described in [7] or [15] Manufacturing method.
[24] R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, X and Z represent a bromine atom, and Y represents a chlorine atom, described in [8] or [16] Manufacturing method.
[25] General formula (2)
(Wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₆ ) alkyl group).
[26] The compound according to [25], wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.
[27] The compound according to [26], wherein R ¹ and R ³ represent a methyl group, and R ² represents a methyl group or an ethyl group.
[28] General formula (5)
(Wherein R ¹ and R ² represent a (C ₁ -C ₆ ) alkyl group, and X represents a halogen atom).
[29] The compound according to [28], wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.
[30] The compound according to [29], wherein R ¹ , R ² and R ³ represent a methyl group, and X represents a bromine atom.
[31] General formula (6)
(Wherein R ¹ and R ² represent a (C ₁ -C ₆ ) alkyl group).
[32] The compound according to [31], wherein R ¹ and R ² represent a (C ₁ -C ₃ ) alkyl group.
[33] The compound according to [32], wherein R ¹ and R ² represent a methyl group.
Etc.

本発明によれば、従来問題であった、水酸化アルミニウム、有害なシアンガス及びシアン化合物を含む多量の排水を発生することなく、目的化合物を効率的且つ経済的有利に工業的規模で製造できる。また皮膚刺激性及び感作性が危惧される中間体を回避することができ、作業上の安全性の観点からも好ましい製造方法である。 According to the present invention, the target compound can be produced efficiently and economically on an industrial scale without generating a large amount of waste water containing aluminum hydroxide, harmful cyanide gas and cyanide compound, which has been a problem in the past. In addition, intermediates that are likely to cause skin irritation and sensitization can be avoided, and this is a preferable production method from the viewpoint of work safety.

本明細書中に記載する各置換基を説明する。「ハロ」とは「ハロゲン原子」を意味し、塩素原子、臭素原子、ヨウ素原子又はフッ素原子を示す。「メシルオキシ基」、「トシルオキシ基」及び「トリフラート基」とはそれぞれ、メチルスルホニルオキシ基、４‐メチルフェニルスルホニルオキシ基及びトリフルオロメチルスルホニルオキシ基を示す。
「（Ｃ_１−Ｃ_６）アルキル基」とは、例えばメチル基、エチル基、ノルマルプロピル基、イソプロピル基、ノルマルブチル基、イソブチル基、セカンダリーブチル基、ターシャリーブチル基、ノルマルペンチル基、イソペンチル基、ターシャリーペンチル基、ネオペンチル基、２，３−ジメチルプロピル基、１−エチルプロピル基、１−メチルブチル基、２−メチルブチル基、ノルマルヘキシル基、イソヘキシル基、２−ヘキシル基、３−ヘキシル基、２−メチルペンチル基、３−メチルペンチル基、１，１，２−トリメチルプロピル基、３，３−ジメチルブチル基等の直鎖又は分岐鎖状の炭素原子数１〜６個のアルキル基を示し、「（Ｃ_１−Ｃ_３）アルキル基」とは、例えばメチル基、エチル基、ノルマルプロピル基、イソプロピル基を示す。 Each substituent described in this specification will be described. “Halo” means “halogen atom” and represents a chlorine atom, a bromine atom, an iodine atom or a fluorine atom. “Mesyloxy group”, “tosyloxy group” and “triflate group” represent a methylsulfonyloxy group, a 4-methylphenylsulfonyloxy group and a trifluoromethylsulfonyloxy group, respectively.
“(C ₁ -C ₆ ) alkyl group” means, for example, methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, secondary butyl group, tertiary butyl group, normal pentyl group, isopentyl group. Tertiary pentyl group, neopentyl group, 2,3-dimethylpropyl group, 1-ethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, normal hexyl group, isohexyl group, 2-hexyl group, 3-hexyl group, A linear or branched alkyl group having 1 to 6 carbon atoms such as 2-methylpentyl group, 3-methylpentyl group, 1,1,2-trimethylpropyl group and 3,3-dimethylbutyl group is shown. the _"(C 1 -C ₃₎ alkyl group" such as methyl group, ethyl group, normal propyl group, isopropyl It is shown.

「（Ｃ_１−Ｃ_６）」、「（Ｃ_１−Ｃ_３）」等の表現は各種置換基の炭素原子数の範囲を示し、例えば、「（Ｃ_１−Ｃ_６）アルキル基」の場合は直鎖又は分岐鎖状の炭素数１〜６個のアルキル基を示し、「（Ｃ_１−Ｃ_３）アルキル基」の場合は直鎖又は分岐鎖状の炭素数１〜３個のアルキル基を示す。 _"(C 1 -C _6)", _"(C 1 -C _3)" representation of such indicates the range of the number of carbon atoms of the various substituents, e.g., in the case of _"(C 1 -C ₆₎ alkyl group" Represents a linear or branched alkyl group having 1 to 6 carbon atoms, and in the case of “(C ₁ -C ₃ ) alkyl group”, a linear or branched alkyl group having 1 to 3 carbon atoms. Indicates.

本発明の製造方法に含まれる一般式（１）、（２）、（４）、（５）、（６）、（８）、（１０）で表される化合物は、その構造式中に１つ又は複数個の不斉中心を有する場合があり、２種以上の光学異性体及びジアステレオマーが存在する場合もあり、本発明の製造方法は各々の光学異性体及びそれらが任意の割合で含まれる混合物をも全て包含するものである。 The compounds represented by the general formulas (1), (2), (4), (5), (6), (8), and (10) included in the production method of the present invention are 1 in the structural formula. There may be one or a plurality of asymmetric centers, and there may be two or more optical isomers and diastereomers. The production method of the present invention uses each optical isomer and any of them in an arbitrary ratio. All mixtures included are also included.

本明細書において、逐次的な反応とは、複数の工程が必要な化合物の製造において、１つの工程毎に反応を停止させ、場合によっては生成物の単離精製を行った後、得られた生成物を次の工程に用いる方法であり、一反応容器内において一括に反応とは、複数の工程が必要な化合物の製造において、単一の反応容器内において、複数の工程を一括で行うことで目的とする化合物を製造する方法を表すものである。 In the present specification, the sequential reaction is obtained after the reaction is stopped for each step in the production of a compound that requires a plurality of steps, and in some cases, the product is isolated and purified. A method of using a product in the next step. Batch reaction in one reaction vessel refers to performing a plurality of steps in a single reaction vessel in the production of a compound that requires multiple steps. This represents a method for producing a target compound.

本発明の好ましい実施態様を示す。Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は（Ｃ_１-Ｃ_６）アルキル基が良く、好ましくは、（Ｃ_１-Ｃ_３）アルキル基良く、さらに好ましくはメチル基が良い。Ｘはハロゲン原子が良く、さらに好ましくは臭素原子が良い。Ｙは、ハロゲン原子、メシル基、トシル基及びトリフラート基が良く、好ましくはハロゲン原子が良く、さらに好ましくは、塩素原子が良い。Ｚはハロゲン原子又はトリフラート基が良く、好ましくはハロゲン原子が良く、さらに好ましくは臭素原子が良い。 1 shows a preferred embodiment of the present invention. R ¹ , R ² , R ³ and R ⁴ are preferably (C ₁ -C ₆ ) alkyl groups, preferably (C ₁ -C ₃ ) alkyl groups, more preferably methyl groups. X is preferably a halogen atom, more preferably a bromine atom. Y is preferably a halogen atom, mesyl group, tosyl group or triflate group, preferably a halogen atom, more preferably a chlorine atom. Z is preferably a halogen atom or a triflate group, preferably a halogen atom, and more preferably a bromine atom.

本発明に関与する反応は以下のように図示される。 The reaction involved in the present invention is illustrated as follows.

製造方法１
Manufacturing method 1

｛式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｍ、Ｘ、Ｙ及びＺは前記に同じ。｝
即ち、一般式（１０）で表される化合物と、一般式（９）で表される化合物とを反応させ、一般式（８）で表される化合物とし、該化合物（８）と一般式（７）で表される化合物とをカップリング反応することにより、一般式（６）で表される化合物とする。次に、該化合物（６）をハロゲン化することにより、一般式（５）で表される化合物とする。該化合物（５）の脱ハロゲン化反応、及び一般式（３）で表される化合物との反応を一反応容器内において行う、又は逐次的に、該化合物（５）を脱ハロゲン化反応により一般式（４）で表される化合物とし、該化合物（４）と一般式（３）で表される化合物とを反応させることにより、一般式（２）で表される化合物とする。該化合物（２）を酸加水分解し、次いでメチルヒドラジンと環化反応を行うことにより、一般式（１）で表される化合物を製造することができる。 {Wherein R ¹ , R ² , R ³ , R ⁴ , M, X, Y and Z are the same as above. }
That is, the compound represented by the general formula (10) and the compound represented by the general formula (9) are reacted to obtain a compound represented by the general formula (8), and the compound (8) and the general formula ( It is set as the compound represented by General formula (6) by coupling-reacting with the compound represented by 7). Next, the compound (6) is halogenated to obtain a compound represented by the general formula (5). The dehalogenation reaction of the compound (5) and the reaction with the compound represented by the general formula (3) are carried out in one reaction vessel, or the compound (5) is generally dehalogenated by a dehalogenation reaction. The compound represented by the formula (4) is reacted with the compound represented by the formula (3) and the compound represented by the formula (2). The compound represented by the general formula (1) can be produced by acid hydrolysis of the compound (2) and then cyclization with methylhydrazine.

一般式（１０） → 一般式（８）
本反応は一般式（１０）で表される化合物と、一般式（９）で表される化合物とを、塩基及び不活性溶媒存在下反応させることにより、一般式（８）で表される化合物を製造することができる。 General formula (10) → General formula (8)
In this reaction, the compound represented by the general formula (10) and the compound represented by the general formula (9) are reacted in the presence of a base and an inert solvent to thereby obtain a compound represented by the general formula (8). Can be manufactured.

本反応で使用できる塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム等の水酸化物、炭酸リチウム、炭酸水素リチウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸カルシウム、炭酸マグネシウム等の炭酸塩、酢酸リチウム、酢酸ナトリウム、酢酸カリウム等の酢酸塩、ナトリウムメトキサイド、ナトリウムエトキサイド、ナトリウムターシャリーブトキサイド、カリウムターシャリーブトキサイド等のアルコールアルカリ金属塩、水素化ナトリウム、水素化カリウム等の金属ヒドリド、ピリジン、ピコリン、ルチジン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン等の有機塩基等を挙げることができ、それらの使用量は一般式（１０）で表される化合物に対して通常１〜１０倍モルの範囲で使用され、好ましくは１〜２倍モルの範囲で使用される。 Bases that can be used in this reaction include hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium carbonate, lithium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate. Carbonates such as calcium carbonate and magnesium carbonate, acetates such as lithium acetate, sodium acetate and potassium acetate, alcohol alkali metal salts such as sodium methoxide, sodium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, Examples thereof include metal hydrides such as sodium hydride and potassium hydride, organic bases such as pyridine, picoline, lutidine, triethylamine, tributylamine and diisopropylethylamine, and the amount used thereof is represented by the general formula (10). Which is used in the range of generally 1 to 10 mol per mol of compound it is preferably used in the range of 1 to 2 times mole.

本反応で使用できる不活性溶媒としては、本反応を著しく阻害しないものであれば良く、例えば、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン等の鎖状又は環状エーテル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、アセトニトリル等のニトリル類、酢酸エチル等のエステル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、ジメチルスルホキシド、１，３−ジメチル−２−イミダゾリジノン等の極性溶媒、メタノール、エタノール、イソプロパノール等のアルコール類、水等を挙げることができ、これらの不活性溶媒は単独で又は２種以上混合して使用することもできる。 The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this reaction. For example, chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, benzene, toluene, xylene, etc. Aromatic hydrocarbons, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, nitriles such as acetonitrile, esters such as ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, Examples include polar solvents such as 1,3-dimethyl-2-imidazolidinone, alcohols such as methanol, ethanol and isopropanol, water, etc., and these inert solvents are used alone or in combination of two or more. You can also

本反応は等モル反応であるので、各化合物を等モル使用すればよいが、いずれかの化合物を過剰に用いることもできる。反応温度は通常約０℃から使用する溶媒の沸点の範囲で行えば良く、反応時間は反応規模、反応温度等により変化し、一定ではないが、数分〜４８時間の範囲で適宜選択すれば良い。反応終了後、目的物を含む反応系から目的物を常法により単離すれば良く、必要に応じて再結晶、カラムクロマトグラフィー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。 Since this reaction is an equimolar reaction, each compound may be used in an equimolar amount, but any compound can be used in excess. The reaction temperature is usually from about 0 ° C. to the boiling point of the solvent used, and the reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but it can be appropriately selected within the range of several minutes to 48 hours. good. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

一般式（８） → 一般式（６）
前記製造方法によって製造した一般式（８）で表される化合物と、一般式（７）で表される化合物から “ＭｏｄｅｒｎＡｒｙｌａｔｉｏｎＭｅｔｈｏｄｓ”，Ｗｉｌｌｙ−ＶＨＣ，２２１−２７０（Ｍｉｚｏｒｏｋｉ−Ｈｅｃｋ反応）に記載されている反応に従って、一般式（６）で表される化合物を製造することができる。 General formula (8) → General formula (6)
The compound represented by the general formula (8) produced by the above production method and the compound represented by the general formula (7) are described in “Modern Array Methods”, Willy-VHC, 221-270 (Mizoroki-Heck reaction). According to the reaction being carried out, the compound represented by the general formula (6) can be produced.

一般式（６） → 一般式（５）
前記製造方法によって製造した一般式（６）で表される化合物を、不活性溶媒存在下、ハロゲン化剤によりハロゲン化することにより、一般式（５）で表される化合物を製造することができる。 General formula (6) → General formula (5)
A compound represented by the general formula (5) can be produced by halogenating a compound represented by the general formula (6) produced by the above production method with a halogenating agent in the presence of an inert solvent. .

本反応で使用できるハロゲン化剤としては、塩素、臭素、ヨウ素等を挙げることができ、臭素が好ましい。それらの使用量は一般式（６）で表される化合物に対して通常１〜１０倍モルの範囲で使用され、好ましくは１〜２倍モルの範囲で使用され、さらに好ましくは１〜１．３倍モルの範囲で使用される。 Examples of the halogenating agent that can be used in this reaction include chlorine, bromine, iodine and the like, and bromine is preferred. The amount thereof used is usually in the range of 1 to 10 times mol, preferably in the range of 1 to 2 times mol, more preferably 1 to 1. mol, relative to the compound represented by the general formula (6). It is used in the range of 3 times mole.

本反応で使用できる不活性溶媒としては、本反応を著しく阻害しないものであれば良く、例えば、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン等の鎖状又は環状エーテル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、塩化メチレン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類、モノクロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、アセトニトリル等のニトリル類、酢酸エチル等のエステル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、ジメチルスルホキシド、１，３−ジメチル−２−イミダゾリジノン等の極性溶媒、メタノール、エタノール、イソプロパノール等のアルコール類、水等を挙げることができ、これらの不活性溶媒は単独で又は２種以上混合して使用することもできる。 The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this reaction. For example, chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, benzene, toluene, xylene, etc. Aromatic hydrocarbons, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, halogenated aromatic hydrocarbons such as monochlorobenzene and dichlorobenzene, nitriles such as acetonitrile, esters such as ethyl acetate, Examples include polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, alcohols such as methanol, ethanol and isopropanol, and water. These inert solvents are used alone or in combination of two or more. Combined and can also be used.

反応温度は通常約０℃から使用する溶媒の沸点の範囲で行えば良く、好ましくは０℃から６０℃の範囲、さらに好ましくは０℃から４０℃の範囲が良い。反応時間は反応規模、反応温度等により変化し、一定ではないが、数分〜４８時間の範囲で適宜選択すれば良い。反応終了後、目的物を含む有機層を次の反応にそのまま使用することができる。 The reaction temperature is usually from about 0 ° C to the boiling point of the solvent used, preferably from 0 ° C to 60 ° C, more preferably from 0 ° C to 40 ° 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 48 hours. After completion of the reaction, the organic layer containing the target product can be used as it is for the next reaction.

一般式（５）から一般式（２）の製造方法
前記製造方法によって製造した一般式（５）で表される化合物を不活性溶媒存在下、アルコールアルカリ金属塩との反応を行うことにより一般式（２）で表される化合物を製造することができる。 Production method of general formula (2) from general formula (5)
A compound represented by the general formula (2) can be produced by reacting the compound represented by the general formula (5) produced by the production method with an alcohol alkali metal salt in the presence of an inert solvent. .

本反応で使用できるアルコールアルカリ金属塩としては、ナトリウムメトキサイド（ＭｅＯＮａ）、ナトリウムエトキサイド、ナトリウムターシャリーブトキサイド、カリウムターシャリーブトキサイド等が挙げることができ、ナトリウムメトキサイド（ＭｅＯＮａ）が好ましい。それらの使用量は一般式（５）で表される化合物に対して通常２〜１０倍モルの範囲で使用され、好ましくは２〜３倍モルの範囲で使用され、さらに好ましくは２〜２．２倍モルの範囲で使用される。 Examples of the alcohol alkali metal salt that can be used in this reaction include sodium methoxide (MeONa), sodium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, and the like, and sodium methoxide (MeONa) is preferable. The amount of them used is usually in the range of 2 to 10 times mol, preferably in the range of 2 to 3 times mol, and more preferably 2 to 2 times the amount of the compound represented by the general formula (5). Used in the range of 2 moles.

本反応で使用できる不活性溶媒としては、本反応を著しく阻害しないものであれば良く、例えば、メタノール、エタノール、プロパノール、ブタノール、２−プロパノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン等の鎖状又は環状エーテル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、モノクロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、ジメチルスルホキシド、１，３−ジメチル−２−イミダゾリジノン等の極性溶媒を挙げることができ、これらの不活性溶媒は単独で又は２種以上混合して使用することもできる。 The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this reaction. Examples thereof include alcohols such as methanol, ethanol, propanol, butanol, and 2-propanol, diethyl ether, tetrahydrofuran (THF), dioxane, and the like. Linear or cyclic ethers such as, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated aromatic hydrocarbons such as monochlorobenzene and dichlorobenzene, N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone and the like, and these inert solvents can be used alone or in admixture of two or more.

本反応における反応温度は通常約０℃から使用する溶媒の沸点の範囲で行えば良く、反応時間は反応規模、反応温度等により変化し、一定ではないが、数分〜４８時間の範囲で適宜選択すれば良い。反応終了後、目的物を含む反応系から目的物を常法により単離すれば良く、必要に応じて再結晶、カラムクロマトグラフィー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。 The reaction temperature in this reaction may usually be in the range of about 0 ° C. to the boiling point of the solvent used, and the reaction time varies depending on the reaction scale, reaction temperature, etc. Just choose. After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

一般式（５）から一般式（２）の製造方法としては、上記方法のほかに以下のような方法も上げることができる。即ち、前記製造方法によって製造した一般式（５）で表される化合物を不活性溶媒及び塩基類存在下、脱ハロゲン化することにより、一旦一般式（４）で表される化合物を製造し、この化合物（４）とアルコールアルカリ金属塩との反応を行うことによっても、一般式（２）で表される化合物を製造することができる。 In addition to the above method, the following method can be used as a production method of the general formula (5) to the general formula (2). That is, by dehalogenating the compound represented by the general formula (5) produced by the above production method in the presence of an inert solvent and a base, a compound represented by the general formula (4) is once produced. The compound represented by the general formula (2) can also be produced by reacting this compound (4) with an alcohol alkali metal salt.

本反応で使用できる塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム等の水酸化物、炭酸リチウム、炭酸水素リチウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸カルシウム、炭酸マグネシウム等の炭酸塩、酢酸リチウム、酢酸ナトリウム、酢酸カリウム等の酢酸塩、ナトリウムメトキサイド、ナトリウムエトキサイド、ナトリウムターシャリーブトキサイド、カリウムターシャリーブトキサイド等のアルコキサイド等、水素化ナトリウム、水素化カリウム等の金属ヒドリド類、ピリジン、ピコリン、ルチジン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン等の有機塩基等が挙げることができ、それらの使用量は一般式（５）で表される化合物に対して通常１〜１０倍モルの範囲で使用され、好ましくは１〜３倍モルの範囲で使用され、さらに好ましくは１〜１．２倍モルの範囲で使用される。 Bases that can be used in this reaction include hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium carbonate, lithium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate. Hydrogenation, carbonates such as calcium carbonate, magnesium carbonate, acetates such as lithium acetate, sodium acetate, potassium acetate, alkoxides such as sodium methoxide, sodium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, etc. Examples thereof include metal hydrides such as sodium and potassium hydride, organic bases such as pyridine, picoline, lutidine, triethylamine, tributylamine and diisopropylethylamine, and the amount used thereof is represented by the general formula (5). It is used in the range of generally 1 to 10 mol per mol of the object, preferably used in the range of 1 to 3 moles, more preferably in a range of 1 to 1.2 moles.

本反応で使用できるアルコールアルカリ金属塩としては、ナトリウムメトキサイド（ＭｅＯＮａ）、ナトリウムエトキサイド、ナトリウムターシャリーブトキサイド、カリウムターシャリーブトキサイド等が挙げることができ、ナトリウムメトキサイド（ＭｅＯＮａ）が好ましい。それらの使用量は一般式（４）で表される化合物に対して通常１〜１０倍モルの範囲で使用され、好ましくは１〜３倍モルの範囲で使用され、さらに好ましくは１〜１．２倍モルの範囲で使用される。 Examples of the alcohol alkali metal salt that can be used in this reaction include sodium methoxide (MeONa), sodium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, and the like, and sodium methoxide (MeONa) is preferable. The amount of them used is usually in the range of 1 to 10 times mol, preferably in the range of 1 to 3 times mol, more preferably 1 to 1. mol with respect to the compound represented by the general formula (4). Used in the range of 2 moles.

本反応で使用できる不活性溶媒としては、本反応を著しく阻害しないものであれば良く、例えば、メタノール、エタノール、プロパノール、ブタノール、２−プロパノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン等の鎖状又は環状エーテル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、塩化メチレン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類、クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、アセトニトリル等のニトリル類、酢酸エチル等のエステル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、ジメチルスルホキシド、１，３−ジメチル−２−イミダゾリジノン等の極性溶媒を挙げることができ、これらの不活性溶媒は単独で又は２種以上混合して使用することもできる。 The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this reaction. Examples thereof include alcohols such as methanol, ethanol, propanol, butanol, and 2-propanol, diethyl ether, tetrahydrofuran (THF), dioxane, and the like. Linear or cyclic ethers such as benzene, toluene, xylene and other aromatic hydrocarbons, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, and halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene , Nitriles such as acetonitrile, esters such as ethyl acetate, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone These inert solvents are simple In or as a mixture of two or more thereof may be used.

一般式（２） → 一般式（１）
前記製造方法によって製造した一般式（２）で表される化合物を不活性溶媒、水及び酸存在下、加水分解した後、一旦塩基類により中和し、続いて酸存在下メチルヒドラジンと反応させることにより、一般式（１）で表される化合物を製造することができる。 General formula (2) → General formula (1)
The compound represented by the general formula (2) produced by the above production method is hydrolyzed in the presence of an inert solvent, water and acid, then neutralized once with a base, and subsequently reacted with methyl hydrazine in the presence of acid. Thus, the compound represented by the general formula (1) can be produced.

本反応で使用できる酸としては、塩酸、硫酸、硝酸、リン酸、酢酸、メチレンスルホン酸、パラトルエンスルホン酸、トリフルオロメチル酢酸、トリフルオロメチルスルホン酸等を挙げることができ、それらの使用量は一般式（４）で表される化合物に対して通常０．１〜１０倍モルの範囲で使用され、好ましくは０．１〜３倍モルの範囲で使用され、さらに好ましくは０．１〜１倍モルの範囲で使用される。 Examples of acids that can be used in this reaction include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, methylene sulfonic acid, paratoluene sulfonic acid, trifluoromethyl acetic acid, trifluoromethyl sulfonic acid, and the like. Is usually used in the range of 0.1 to 10-fold mol, preferably in the range of 0.1 to 3-fold mol, more preferably 0.1 to 3-fold mol based on the compound represented by the general formula (4). Used in the range of 1 mole.

本反応で使用できる塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム等の水酸化物、炭酸リチウム、炭酸水素リチウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸カルシウム、炭酸マグネシウム等の炭酸塩、酢酸リチウム、酢酸ナトリウム、酢酸カリウム等の酢酸塩、ナトリウムメトキサイド、ナトリウムエトキサイド、ナトリウムターシャリーブトキサイド、カリウムターシャリーブトキサイド等のアルコキサイド等、ピリジン、ピコリン、ルチジン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン等の有機塩基等が挙げることができ、それらの使用量は加水分解に用いた酸と同モル量用いられる。 Bases that can be used in this reaction include hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium carbonate, lithium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate. Carbonates such as calcium carbonate and magnesium carbonate, acetates such as lithium acetate, sodium acetate and potassium acetate, alkoxides such as sodium methoxide, sodium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, pyridine, Examples thereof include organic bases such as picoline, lutidine, triethylamine, tributylamine, diisopropylethylamine and the like, and the amount used is the same molar amount as the acid used for hydrolysis.

本反応で使用できる不活性溶媒としては、本反応を著しく阻害しないものであれば良く、例えば、メタノール、エタノール、プロパノール、ブタノール、２−プロパノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン等の鎖状又は環状エーテル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類等を挙げることができ、これらの不活性溶媒は単独で又は２種以上混合して使用することもできる。 The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this reaction. Examples thereof include alcohols such as methanol, ethanol, propanol, butanol, and 2-propanol, diethyl ether, tetrahydrofuran (THF), dioxane, and the like. And chain ethers such as benzene, toluene, xylene and the like, and halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene. These inert solvents are used alone. Alternatively, two or more kinds can be mixed and used.

以下に本発明の代表的な実施例を例示するが、本発明はこれらに限定されるものではない。 Although the typical example of this invention is illustrated below, this invention is not limited to these.

実施例１．
Ｎ‐メチル‐（５‐ブロモ‐２‐クロロ‐４‐フルオロフェノキシ）酢酸アミド（８ａ）の製造
炭酸（５‐ブロモ‐２‐クロロ‐４‐フルオロフェニル）メチル（１０ａ）（５２．７ｇ、１８６ｍｍｏｌ）、Ｎ‐メチル‐クロロ酢酸アミド（２３．０ｇ、２１４ｍｍｏｌ）のエタノール（１１２ｇ）溶液を撹拌しながら、ここに４０％水酸化ナトリウム水溶液（２２．３ｇ、２２３ｍｍｏｌ）を室温で滴下した。その後、反応溶液を加熱還流させ、１０時間撹拌した後、水を加えて反応を停止させた。反応溶液を冷却後、析出した結晶をろ集し、得られた結晶を水で洗浄し、乾燥させることで表題化合物を白色結晶として得た。
収量；５０．９ｇ
収率；９２．３％
物性；^１ＨＮＭＲ[４００ＭＨｚ、ＤＭＳＯ‐ｄ_６] δ ７．９１（１Ｈ、ｂｒ）、７．６７（１Ｈ、ｄ）、７．４２（１Ｈ、ｄ）、４．６４（２Ｈ、ｓ）、２．６８（３Ｈ、ｄ） Example 1.
Preparation of N-methyl- (5-bromo-2-chloro-4-fluorophenoxy) acetamide (8a)
(5-Bromo-2-chloro-4-fluorophenyl) methyl carbonate (10a) (52.7 g, 186 mmol), N-methyl-chloroacetamide (23.0 g, 214 mmol) in ethanol (112 g ) While stirring the solution, 40% aqueous sodium hydroxide solution (22.3 g, 223 mmol) was added dropwise thereto at room temperature. Thereafter, the reaction solution was heated to reflux and stirred for 10 hours, after which water was added to stop the reaction. After cooling the reaction solution, the precipitated crystals were collected by filtration, and the obtained crystals were washed with water and dried to give the title compound as white crystals.
Yield; 50.9 g
Yield; 92.3%
Physical properties: ¹ H NMR [400 MHz, DMSO-d ₆ ] δ 7.91 (1H, br), 7.67 (1H, d), 7.42 (1H, d), 4.64 (2H, s) 2.68 (3H, d)

実施例２．
３‐｛４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝アクリル酸エチル（６ａ）の製造
Ｎ‐メチル‐（５‐ブロモ‐２‐クロロ‐４‐フルオロフェノキシ）酢酸アミド（８ａ）（５０．９ｇ、１７３ｍｍｏｌ）、アクリル酸エチル（２０．６ｇ、２０７ｍｍｏｌ）、炭酸水素ナトリウム（１５．９ｇ、２０７ｍｍｏｌ）、臭化テトラブチルアンモニウム（８．３０ｇ、２５．９ｍｍｏｌ）、酢酸パラジウム（１９．３ｍｇ、０．０８６３ｍｍｏｌ）のＤＭＦ（６８．６ｇ）溶液をアルゴン雰囲気下、１２０℃で４時間反応させた。反応溶液を冷却した後、水を滴下し、滴下終了後、反応溶液を１０℃以下に冷却し、析出した結晶をろ集、水で洗浄した後、乾燥させることで表題の化合物を灰白色の結晶として得た。
収量；５４．５ｇ
収率；定量的
物性；１ＨＮＭＲ[４００ＭＨｚ、ＤＭＳＯ‐ｄ_６] δ ７．８２（１Ｈ、ｂｒ）、７．６３（１Ｈ、ｓ）、７．５８（１Ｈ、ｄ）、７．５５（１Ｈ、ｓ）、６．７９（１Ｈ、ｄ）、４．６７（２Ｈ、ｓ）、４．２１（２Ｈ、ｑ）、２．６９（３Ｈ、ｄ）、１．２７（３Ｈ、ｔ） Example 2
Preparation of ethyl 3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} acrylate (6a)
N-methyl- (5-bromo-2-chloro-4-fluorophenoxy) acetamide (8a) (50.9 g, 173 mmol), ethyl acrylate (20.6 g, 207 mmol), sodium bicarbonate ( 15.9 g, 207 mmol), tetrabutylammonium bromide (8.30 g, 25.9 mmol), palladium acetate (19.3 mg, 0.0863 mmol) in DMF (68.6 g) The reaction was performed at 120 ° C. for 4 hours in an atmosphere. After cooling the reaction solution, water is added dropwise. After completion of the addition, the reaction solution is cooled to 10 ° C. or lower, and the precipitated crystals are collected by filtration, washed with water, and dried to give the title compound as gray-white crystals. Got as.
Yield; 54.5 g
Yield; Quantitative properties; 1H NMR [400 MHz, DMSO-d ₆ ] δ 7.82 (1H, br), 7.63 (1H, s), 7.58 (1H, d), 7.55 ( 1H, s), 6.79 (1H, d), 4.67 (2H, s), 4.21 (2H, q), 2.69 (3H, d), 1.27 (3H, t)

実施例３．
２，３‐ジブロモ‐３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝プロピオン酸エチル（５ａ）の製造
３‐｛４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝アクリル酸エチル（６ａ）（５０．６ｇ、１６０ｍｍｏｌ）のモノクロロベンゼン（１７６ｇ）溶液に氷冷下、臭素（２９．４ｇ、１８４ｍｍｏｌ）をゆっくりと滴下した。滴下終了後、反応溶液を５０℃で１時間撹拌した後、冷却し、８％チオ硫酸ナトリウム水溶液を加えて反応を停止させた。水層をモノクロロベンゼンで抽出し、有機層を活性炭でろ過することにより、表題化合物を含むろ液（２７０ｇ）を得た。
物性；１ＨＮＭＲ[４００ＭＨｚ、ＣＤＣｌ_３] δ ７．２１（１Ｈ、ｄ）、６．９２（１Ｈ、ｄ）、６．７２（１Ｈ、ｂｒ）、５．５３（１Ｈ、ｄ）、４．８８（１Ｈ、ｄ）、４．５６（２Ｈ、ｓ）、４．３６（２Ｈ、ｑ）、２．９６（３Ｈ、ｄ）、１．３８（３Ｈ、ｔ） Example 3 FIG.
Preparation of ethyl 2,3-dibromo-3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} propionate (5a)
3- {4-Chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} ethyl acrylate (6a) (50.6 g, 160 mmol) in a monochlorobenzene (176 g) solution under ice cooling, Bromine (29.4 g, 184 mmol) was slowly added dropwise. After completion of the dropwise addition, the reaction solution was stirred at 50 ° C. for 1 hour, then cooled, and an 8% aqueous sodium thiosulfate solution was added to stop the reaction. The aqueous layer was extracted with monochlorobenzene, and the organic layer was filtered with activated carbon to obtain a filtrate (270 g) containing the title compound.
Physical properties: 1H NMR [400 MHz, CDCl ₃ ] δ 7.21 (1H, d), 6.92 (1H, d), 6.72 (1H, br), 5.53 (1H, d), 4. 88 (1H, d), 4.56 (2H, s), 4.36 (2H, q), 2.96 (3H, d), 1.38 (3H, t)

実施例４．
３‐メトキシ‐３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝アクリル酸エチル（２ａ）の製造
上記実施例３でろ液として得られた２，３‐ジブロモ‐３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝プロピオン酸エチル（５ａ）のモノクロロベンゼン溶液（１４７ｇ、９０ｍｍｏｌ相当）に４０℃で２８％ＭｅＯＮａメタノール溶液（３６．５ｇ、１８９ｍｍｏｌ）をゆっくりと滴下した。滴下終了後、約４０℃で1時間撹拌した後、反応溶液中のメタノールを留去し、ここに水を加えた後、分液操作を行った。水層をモノクロロベンゼンで再抽出し、先のものと合わせて得られた有機層を濃縮することで、表題の化合物を含有する粗成生物(２６．３ｇ)を得た。
物性；（Ｚ体）１ＨＮＭＲ[４００ＭＨｚ、ＣＤＣｌ_３] δ ７．２４（１Ｈ、ｄ）、６．９７（１Ｈ、ｄ）、６．７４（１Ｈ、ｂｒ）、５．４６（１Ｈ、ｓ）、４．５２（２Ｈ、ｓ）、３．７８（２Ｈ、ｓ）、３．７５（３Ｈ、ｓ）、２．９５（３Ｈ，ｄ）
（Ｅ体）１ＨＮＭＲ[４００ＭＨｚ、ＣＤＣｌ_３] δ ７．１８（１Ｈ、ｄ）、６．８４（１Ｈ、ｄ）、６．７４（１Ｈ、ｂｒ）、５．４１（１Ｈ、ｓ）、４．５１（２Ｈ、ｓ）、３．８２（２Ｈ、ｓ）、３．６１（３Ｈ、ｓ）、２．９４（３Ｈ、ｄ） Example 4
Preparation of ethyl 3-methoxy-3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} acrylate (2a)
Monochlorobenzene solution of ethyl 2,3-dibromo-3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} propionate (5a) obtained as a filtrate in Example 3 above (147 g, corresponding to 90 mmol), a 28% MeONa methanol solution (36.5 g, 189 mmol) was slowly added dropwise at 40 ° C. After completion of the dropwise addition, the mixture was stirred at about 40 ° C. for 1 hour, methanol in the reaction solution was distilled off, water was added thereto, and a liquid separation operation was performed. The aqueous layer was re-extracted with monochlorobenzene, and the organic layer obtained by combining with the previous one was concentrated to obtain a crude product (26.3 g) containing the title compound.
Physical properties: (Z-form) 1H NMR [400 MHz, CDCl ₃ ] δ 7.24 (1H, d), 6.97 (1H, d), 6.74 (1H, br), 5.46 (1H, s ), 4.52 (2H, s), 3.78 (2H, s), 3.75 (3H, s), 2.95 (3H, d)
(E) 1H NMR [400 MHz, CDCl ₃ ] δ 7.18 (1H, d), 6.84 (1H, d), 6.74 (1H, br), 5.41 (1H, s), 4.51 (2H, s), 3.82 (2H, s), 3.61 (3H, s), 2.94 (3H, d)

実施例５．
２‐ブロモ‐３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝アクリル酸エチル（４ａ）の製造
上記実施例３でろ液として得られた２，３‐ジブロモ‐３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝プロピオン酸エチル（５ａ）のモノクロロベンゼン溶液（２７０ｇ、１６０ｍｍｏｌ相当）に４０℃でトリエチルアミン（１７．８ｇ、１７６ｍｍｏｌ）を滴下した。滴下終了後、７０℃に昇温し１．５時間撹拌した後、水を加えて反応を停止させた。有機層を５％食塩水で洗浄した後、濃縮し、これにヘプタンを加えることで析出した結晶をろ集、乾燥させることで表題の化合物を淡黄色の結晶として得た。
収量；５６．９ｇ
収率；８９．２％
物性；（Ｚ体）１ＨＮＭＲ[４００ＭＨｚ、ＣＤＣｌ_３] δ ７．３０（１Ｈ、ｓ）、７．１６（１Ｈ、ｄ）、６．９４（１Ｈ、ｄ）、６．７２（１Ｈ、ｂｒ）、４．４７（２Ｈ、ｓ）、４．２４（２Ｈ、ｑ）、２．９４（３Ｈ、ｄ）、１．２４（３Ｈ、ｔ）
（Ｅ体）１ＨＮＭＲ[４００ＭＨｚ、ＣＤＣｌ_３] δ ８．２７（１Ｈ、ｓ）、７．８１（１Ｈ、ｄ）、７．２３（１Ｈ、ｄ）、６．７２（１Ｈ、ｂｒ）、４．５６（２Ｈ、ｓ）、４．３７（２Ｈ、ｑ）、２．９５（３Ｈ、ｄ）、１．３９（３Ｈ、ｔ） Example 5 FIG.
Preparation of ethyl 2-bromo-3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} acrylate (4a)
Monochlorobenzene solution of ethyl 2,3-dibromo-3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} propionate (5a) obtained as a filtrate in Example 3 above (270 g, corresponding to 160 mmol), triethylamine (17.8 g, 176 mmol) was added dropwise at 40 ° C. After completion of dropping, the temperature was raised to 70 ° C. and stirred for 1.5 hours, and then water was added to stop the reaction. The organic layer was washed with 5% brine, concentrated, and heptane was added thereto, and the precipitated crystals were collected by filtration and dried to give the title compound as pale yellow crystals.
Yield; 56.9 g
Yield; 89.2%
Physical properties; (Z-form) 1H NMR [400 MHz, CDCl ₃ ] δ 7.30 (1H, s), 7.16 (1H, d), 6.94 (1H, d), 6.72 (1H, br ), 4.47 (2H, s), 4.24 (2H, q), 2.94 (3H, d), 1.24 (3H, t)
(E-form) 1H NMR [400 MHz, CDCl ₃ ] δ 8.27 (1H, s), 7.81 (1H, d), 7.23 (1H, d), 6.72 (1H, br), 4.56 (2H, s), 4.37 (2H, q), 2.95 (3H, d), 1.39 (3H, t)

実施例６．
３‐メトキシ‐３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝アクリル酸エチル（２ａ）の製造
２‐ブロモ‐３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝アクリル酸エチル（４ａ）（５６．７ｇ、１４３ｍｍｏｌ）のメタノール溶液に２８％ＭｅＯＮａメタノール溶液（３０．３ｇ、１５７ｍｍｏｌ）をゆっくりと滴下した。滴下終了後、約４０℃で1時間撹拌した後、濃塩酸（２．３８ｇ、２２．９ｍｍｏｌ）を加えて反応溶液を弱酸性（約ｐＨ５）とした。溶媒を留去し、得られた残渣に水を加え、酢酸エチルで抽出を行った。得られた有機層を１０％食塩水で洗浄後、濃縮することにより、表題の化合物を含む反応粗生成物（４６．０ｇ）を得た。 Example 6
Preparation of ethyl 3-methoxy-3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} acrylate (2a)
2-Bromo-3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} ethyl acrylate (4a) (56.7 g, 143 mmol) in methanol with 28% MeONa methanol solution (30.3 g, 157 mmol) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at about 40 ° C. for 1 hour, and concentrated hydrochloric acid (2.38 g, 22.9 mmol) was added to make the reaction solution weakly acidic (about pH 5). The solvent was distilled off, water was added to the resulting residue, and extraction was performed with ethyl acetate. The obtained organic layer was washed with 10% brine and concentrated to give a crude reaction product (46.0 g) containing the title compound.

実施例７．
３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝‐１‐メチルピラゾール‐５‐オン（１ａ）の製造
上記実施例４又は６で得られた３‐メトキシ‐３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝アクリル酸メチル（２ａ）を含有する反応粗成生物（４６．０ｇ、１４０ｍｍｏｌ）をエタノール（５６．０ｇ）に溶解させ、室温で濃塩酸（５．８４ｇ、５６．０ｍｍｏｌ）を加えた後、６０℃に昇温して２時間撹拌した。反応溶液を冷却し、酢酸ナトリウム（４．６０ｇ、５６．０ｍｍｏｌ）、酢酸（６．７０ｇ、１１２ｍｍｏｌ）を加えた後、さらに冷却して３５％メチルヒドラジン水溶液（２２．１ｇ、１６８ｍｍｏｌ）を加えた。６０℃で２時間、８０℃で１時間撹拌した。ここに水を加えた後、反応溶液を冷却し、析出した結晶をろ集し、３０％エタノール水溶液及び水で洗浄し、乾燥させることで表題の化合物を淡黄色結晶として得た。
収量；３７．２ｇ
収率；８４．８％ Example 7
Preparation of 3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} -1-methylpyrazol-5-one (1a)
A reaction crude product containing methyl 3-methoxy-3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} acrylate (2a) obtained in Example 4 or 6 above ( 46.0 g, 140 mmol) was dissolved in ethanol (56.0 g), concentrated hydrochloric acid (5.84 g, 56.0 mmol) was added at room temperature, and the mixture was heated to 60 ° C. and stirred for 2 hours. did. The reaction solution was cooled, sodium acetate (4.60 g, 56.0 mmol) and acetic acid (6.70 g, 112 mmol) were added, and the mixture was further cooled to 35% aqueous methylhydrazine (22.1 g, 168 mmol) was added. The mixture was stirred at 60 ° C. for 2 hours and at 80 ° C. for 1 hour. Water was added thereto, the reaction solution was cooled, and the precipitated crystals were collected by filtration, washed with a 30% aqueous ethanol solution and water, and dried to obtain the title compound as pale yellow crystals.
Yield; 37.2 g
Yield; 84.8%

参考例１．
３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝‐５‐ジフルオロメトキシ‐１‐メチルピラゾールの製造
３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝‐１‐メチルピラゾール‐５‐オン（１ａ）（３６．１ｇ、１１５ｍｍｏｌ）のアセトニトリル溶液（２１０ｇ）に塩化テトラブチルアンモニウム（２．６２ｇ、１１．５ｍｍｏｌ）を加え、ここに室温で１２％水酸化ナトリウム水溶液（７６．７ｇ、２３０ｍｍｏｌ）をゆっくりと滴下した。反応溶液にＣＨＣｌＦ_２ガス（１４．９ｇ、１７３ｍｍｏｌ）を吹き込んだ後、５時間撹拌した。反応終了後、濃縮し、得られた残渣に水及び２‐ブタノールを加えて加熱し、結晶が溶解したことを確認後、冷却することで析出した結晶をろ集した。得られた結晶を水及び２‐ブタノールで洗浄することにより表題の化合物を白色結晶として得た。
収量；２８．１ｇ
収率；６７．８％
参考例２．
３‐{４‐クロロ‐２‐フルオロ‐５‐（エトキシカルボニルメトキシ）フェニル｝‐４‐クロロ‐５‐ジフルオロメトキシ‐１‐メチルピラゾールの製造
３‐{４‐クロロ‐２‐フルオロ‐５‐（Ｎ‐メチルカルバモイルメトキシ）フェニル｝‐５‐ジフルオロメトキシ‐１‐メチルピラゾール（２７．３ｇ、７５．０ｍｍｏｌ）のモノクロロベンゼン（１４６ｇ）溶液に、酢酸（４．５１ｇ、７５．０ｍｍｏｌ）を加え、ここに室温で塩化スルフリル（１１．１ｇ、８２．５ｍｍｏｌ）をゆっくりと滴下した。滴下終了後、４０℃に昇温し１時間撹拌した後、反応溶液を冷却し、エタノール（２０．７ｇ）、濃硫酸（２３．３ｇ）を加えた。反応溶液を１００℃に加熱し、９時間撹拌した後、減圧下溶媒を留去した。得られた残渣にモノクロロベンゼン及び水を加えて溶解させ、分液により得られた有機層を水で洗浄後、濃縮した。得られた粗生成物を、エタノールを用いた再結晶により精製することで表題の化合物を白色結晶として得た。
収量；２６．５ｇ
収率；８５．５％
Reference Example 1
Preparation of 3- {4-Chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} -5-difluoromethoxy-1-methylpyrazole
A solution of 3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} -1-methylpyrazol-5-one (1a) (36.1 g, 115 mmol) in acetonitrile (210 g) Was added tetrabutylammonium chloride (2.62 g, 11.5 mmol), and 12% aqueous sodium hydroxide solution (76.7 g, 230 mmol) was slowly added dropwise thereto at room temperature. CHClF ₂ gas (14.9 g, 173 mmol) was blown into the reaction solution, followed by stirring for 5 hours. After completion of the reaction, the mixture was concentrated, and water and 2-butanol were added to the resulting residue and heated. After confirming that the crystals were dissolved, the crystals that precipitated by cooling were collected by filtration. The obtained crystals were washed with water and 2-butanol to give the title compound as white crystals.
Yield; 28.1 g
Yield; 67.8%
Reference Example 2
Preparation of 3- {4-chloro-2-fluoro-5- (ethoxycarbonylmethoxy) phenyl} -4-chloro-5-difluoromethoxy-1-methylpyrazole
Monochlorobenzene (146 g) of 3- {4-chloro-2-fluoro-5- (N-methylcarbamoylmethoxy) phenyl} -5-difluoromethoxy-1-methylpyrazole (27.3 g, 75.0 mmol) Acetic acid (4.51 g, 75.0 mmol) was added to the solution, and sulfuryl chloride (11.1 g, 82.5 mmol) was slowly added dropwise thereto at room temperature. After completion of the dropwise addition, the mixture was heated to 40 ° C. and stirred for 1 hour, and then the reaction solution was cooled, and ethanol (20.7 g) and concentrated sulfuric acid (23.3 g) were added. The reaction solution was heated to 100 ° C. and stirred for 9 hours, and then the solvent was distilled off under reduced pressure. Monochlorobenzene and water were added to the resulting residue for dissolution, and the organic layer obtained by liquid separation was washed with water and concentrated. The obtained crude product was purified by recrystallization using ethanol to obtain the title compound as white crystals.
Yield; 26.5 g
Yield; 85.5%

Claims

General formula (5)
(Wherein R ¹ and R ² represent a (C ₁ -C ₆ ) alkyl group, and X represents a halogen atom), in the presence of a base, sequentially or in one reaction vessel. General formula (2) characterized by performing the reaction in a lump
(Wherein R ¹ and R ² are the same as described above, and R ³ represents a (C ₁ -C ₆ ) alkyl group).

General formula (5)
(In the formula, R ¹ , R ² and X are the same as above.) The compound represented by the general formula (2) is reacted in the presence of a base sequentially or batchwise in one reaction vessel.
(Wherein R ¹ , R ² and R ³ are the same as above), a general formula characterized by acid hydrolysis of the compound (2) and subsequent reaction with methyl hydrazine (1)
(Wherein R ¹ is the same as defined above).

General formula (6)
(In the formula, R ¹ and R ² are the same as above.) By reacting a compound represented by the formula (5)
(Wherein R ¹ , R ² and X are the same as above), and the compound (5) is reacted in the presence of bases sequentially or in a single reaction vessel. General formula (2) characterized by
(Wherein R ¹ , R ² and R ³ are the same as above).

General formula (7)
(Wherein R ² is the same as defined above) and the general formula (8)
(Wherein R ¹ is the same as defined above, Z represents a halogen atom or a triflate group) and a compound represented by the general formula (6)
(Wherein R ¹ and R ² are the same as described above), and the compound (6) is reacted with a halogenating agent to produce a compound represented by the general formula (5)
(Wherein R ¹ , R ² and X are the same as above), and the compound (5) is reacted in the presence of bases sequentially or in a single reaction vessel. General formula (2) characterized by
(Wherein R ¹ , R ² and R ³ are the same as above).

General formula (9)
(Wherein R ¹ is the same as defined above, Y represents a halogen atom, a mesyloxy group, a tosyloxy group and a triflate group), and a general formula (10)
(Wherein Z is the same as defined above, and R ⁴ represents a (C ₁ -C ₆ ) alkyl group). In the presence of a base, the compound represented by formula (8) is reacted.
(Wherein R ¹ and Z are the same as defined above), and the compound (8) and the general formula (7) are produced.
(Wherein R ² is the same as above) and a coupling reaction in the presence of a transition metal catalyst to give a compound represented by the general formula (6)
(Wherein R ¹ and R ² are the same as described above), and the compound (6) is reacted with a halogenating agent to produce a compound represented by the general formula (5)
(Wherein R ¹ , R ² and X are the same as above), and the compound (5) is reacted in the presence of bases sequentially or in a single reaction vessel. General formula (2) characterized by
(Wherein R ¹ , R ² and R ³ are the same as above).

General formula (9)
(Wherein, R ¹ and Y are the same as defined above) and the general formula (10)
(Wherein, R ⁴ and Z are the same as defined above) in the presence of a base to react with the compound represented by the general formula (8)
(Wherein R ¹ and Z are the same as defined above), and the compound (8) and the general formula (7) are produced.
(Wherein R ² is the same as above) and a coupling reaction in the presence of a transition metal catalyst to give a compound represented by the general formula (6)
(Wherein R ¹ and R ² are the same as described above), and the compound (6) is reacted with a halogenating agent to produce a compound represented by the general formula (5)
(Wherein R ¹ , R ² and X are the same as above), and the compound (5) is reacted in the presence of bases sequentially or in a single reaction vessel. By performing the general formula (2)
(Wherein R ¹ , R ² and R ³ are the same as above), a general formula characterized by acid hydrolysis of the compound (2) and subsequent reaction with methyl hydrazine (1)
(Wherein R ¹ is the same as defined above).

General formula (5)
(Wherein R ¹ , R ² , R ³ and X are the same as above), by reacting the compound represented by the general formula (4) in the presence of a base.
(Wherein R ¹ , R ² and X are the same as described above), and the compound (4) is represented by the general formula (3).
(Wherein R ³ is the same as described above, M represents an alkali metal), by reacting with an alcohol alkali metal salt represented by the general formula (2)
The manufacturing method in any one of the Claims 1 thru | or 6 including the process of manufacturing the compound represented by (In formula, R < ¹ >, R < ² > and R < ³ > are the same as the above.).

General formula (5)
(Wherein R ¹ , R ² , R ³ and X are as defined above), the compound represented by the general formula (3)
(Wherein R ³ and M are the same as above), by reacting with an alcohol alkali metal salt represented by the general formula (2)
The manufacturing method in any one of the Claims 1 thru | or 6 including the process of manufacturing the compound represented by (In formula, R < ¹ >, R < ² > and R < ³ > are the same as the above.).

The production method according to claim ¹ , wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.

The production method according to claim ^2, wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.

The production method according to claim 3, wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.

The production method according to claim 4, wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.

The production method according to claim 5, wherein R ¹ , R ² , R ³ and R ⁴ represent a (C ₁ -C ₃ ) alkyl group, and Y represents a halogen atom.

The production method according to claim 6, wherein R ¹ , R ² , R ³ and R ⁴ represent a (C ₁ -C ₃ ) alkyl group, and Y represents a halogen atom.

The production method according to claim 7, wherein R ¹ , R ² , R ³ and R ⁴ represent a (C ₁ -C ₃ ) alkyl group, and Y represents a halogen atom.

The production method according to claim 8, wherein R ¹ , R ² , R ³ and R ⁴ represent a (C ₁ -C ₃ ) alkyl group, and Y represents a halogen atom.

The production method according to claim 1 or 9, wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, and X represents a bromine atom.

The production method according to claim 2 or 10, wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, and X represents a bromine atom.

The production method according to claim 3 or 11, wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, and X represents a bromine atom.

The production method according to claim 4 or 12, wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, and X and Z represent a bromine atom.

The production method according to claim 5 or 13, wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, X and Z represent a bromine atom, and Y represents a chlorine atom.

The production method according to claim 6 or 14, wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, X and Z represent a bromine atom, and Y represents a chlorine atom.

The production method according to claim 7 or 15, wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, X and Z represent a bromine atom, and Y represents a chlorine atom.

The production method according to claim 8 or 16, wherein R ¹ and R ³ represent a methyl group, R ² represents a methyl group or an ethyl group, X and Z represent a bromine atom, and Y represents a chlorine atom.

General formula (2)
(Wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₆ ) alkyl group).

R ^1, ^{R 2} and ^{R 3} is a _{(C 1} -C ₃₎ alkyl A compound according to claim 25.

The compound according to claim 26, wherein R ¹ and R ³ represent a methyl group, and R ² represents a methyl group or an ethyl group.

General formula (5)
(Wherein R ¹ and R ² represent a (C ₁ -C ₆ ) alkyl group, and X represents a halogen atom).

The compound according to claim 28, wherein R ¹ , R ² and R ³ represent a (C ₁ -C ₃ ) alkyl group.

R ^1, ^{R 2} and ^{R 3} represents a methyl group, X represents a bromine atom, compound of claim 29.

General formula (6)
(Wherein R ¹ and R ² represent a (C ₁ -C ₆ ) alkyl group).

The compound according to claim 31, wherein R ¹ and R ² represent a (C ₁ -C ₃ ) alkyl group.

The compound according to claim 32, wherein R ¹ and R ² represent a methyl group.