JP6400492B2 - Method for producing 4,5-dihydroisoxazole - Google Patents

Description

  The present invention relates to a method for producing 4,5-dihydroisoxazole which is useful as an intermediate for pharmaceuticals and agricultural chemicals.

  4,5-Dihydroisoxazole derivatives are important intermediates of compounds useful in various fine chemicals including physiologically active substances such as pharmaceuticals and agricultural chemicals. For example, Non-Patent Document 1 describes a compound having a 4,5-dihydroisoxazoline ring that exhibits an effective pharmacological action against Chagas disease caused by Trypanosoma cruzi protozoa. Non-Patent Document 2 describes a compound having a 4,5-dihydroisoxazoline ring that is expected to have an effect of improving cognitive impairment. US Pat. No. 6,057,056 describes dihydroisoxazole compounds useful for controlling parasites in both animals and agriculture.

  In the production of 4,5-dihydroisoxazole derivatives, formation of a 4,5-dihydroisoxazoline ring is an important step. Various methods are known for forming 4,5-dihydroisoxazoline rings. For example, Patent Document 2 is represented by the formula (2), characterized by reacting a 1-alkene compound represented by the formula (1) with iron (III) nitrate in the presence of acetone or acetophenone. A method for producing a dihydroisoxazole derivative is described.

  Patent Document 3 discloses 3-bromo-5,5 represented by formula (2), wherein 2-bromopropene is reacted with dibromoform oxime represented by formula (1) in the presence of a base. A process for producing dimethyl-4,5-dihydroisoxazole is described.

  Patent Document 4 discloses a reaction of reacting an oxime represented by the formula (AII) with a carbonyl compound represented by the formula (AIII) in the presence of an acid catalyst or an acid-base catalyst, and optionally in the presence of an organic solvent. A method for producing 3-unsubstituted 4,5-dihydroisoxazole represented by (II) will be described.

  Non-Patent Document 3 describes the synthesis of dihydroisoxazole by [3 + 2] -cycloaddition reaction of nitrone and alkene obtained by oxidizing hydroxyimine.

  Non-Patent Documents 4 and 5 describe a method for constructing a 4,5-dihydroisoxazoline ring using a β, γ-unsaturated oxime using oxygen molecules.

Special Table 2014-515347 JP 2006-328042 A JP 2008-1597 Special Table 2013-512201

Rodrigues, G.C., et al., J. Med. Chem., 2014, Vol. 57, p. 298-308 Patel, N.C., et al., J. Med. Chem., 2013, 56, 9180-9191 Pellissier, H., Tetrahedron, 2007, Vol. 63, p. 3235-3285 Zhu, M.K., et al., J. Am. Chem. Soc., 2010, 132, p. 6284-6285 Yu, W. et al., Tetrahedron, 2013, 69, p. 3274-3280

  As described above, a method for producing a 4,5-dihydroisoxazole derivative including a step of forming a 4,5-dihydroisoxazoline ring is known. However, these methods have some problems. For example, in the case of the methods described in Non-Patent Documents 3 to 5, not only a large amount of an expensive catalyst such as a cobalt complex needs to be used, but also low or high temperature reaction conditions are required. In addition, in the case of the method described in Non-Patent Document 5, it is necessary to use pure oxygen as a reactant. For this reason, when manufacturing a 4, 5- dihydroisoxazole derivative using these well-known methods, there existed a possibility that a manufacturing cost might become high.

  Therefore, an object of the present invention is to provide a means for producing a 4,5-dihydroisoxazole derivative under low production cost and mild reaction conditions.

  The present inventors have studied various means for solving the above problems. The present inventors have incorporated oxygen in the air into the ring by reacting β, γ-unsaturated oxime or α, β-unsaturated oxime with oxygen in the air in the presence of a catalyst containing manganese. It has been found that 4,5-dihydroisoxazole derivatives can be obtained. Based on the above findings, the present inventors have completed the present invention.

［式中、
R¹は、置換若しくは非置換のC₁〜C₂₀アルキル、置換若しくは非置換のC₂〜C₂₀アルケニル、置換若しくは非置換のC₂〜C₂₀アルキニル、置換若しくは非置換のC₃〜C₂₀シクロアルキル、置換若しくは非置換のC₄〜C₂₀シクロアルケニル、置換若しくは非置換のC₄〜C₂₀シクロアルキニル、置換若しくは非置換の3〜6員のヘテロシクロアルキル、置換若しくは非置換のC₇〜C₂₀シクロアルキルアルキル、置換若しくは非置換の3〜6員のヘテロシクロアルキル-C₁〜C₂₀アルキル、置換若しくは非置換のC₄〜C₂₀アリール、置換若しくは非置換のC₅〜C₂₀アリールアルキル、置換若しくは非置換の5〜15員のヘテロアリール、置換若しくは非置換の5〜15員のヘテロアリール-C₁〜C₂₀アルキル、カルボキシル、置換若しくは非置換のアミド又は置換若しくは非置換のエステルであり、
R²は、水素、ヒドロキシル、置換若しくは非置換のC₁〜C₂₀アルキル、置換若しくは非置換のC₂〜C₂₀アルケニル、置換若しくは非置換のC₂〜C₂₀アルキニル、置換若しくは非置換のC₃〜C₂₀シクロアルキル、置換若しくは非置換のC₄〜C₂₀シクロアルケニル、置換若しくは非置換のC₄〜C₂₀シクロアルキニル、置換若しくは非置換の3〜6員のヘテロシクロアルキル、置換若しくは非置換のC₇〜C₂₀シクロアルキルアルキル、置換若しくは非置換の3〜6員のヘテロシクロアルキル-C₁〜C₂₀アルキル、置換若しくは非置換のC₄〜C₂₀アリール、置換若しくは非置換のC₅〜C₂₀アリールアルキル、置換若しくは非置換の5〜15員のヘテロアリール、置換若しくは非置換の5〜15員のヘテロアリール-C₁〜C₂₀アルキル、置換若しくは非置換のC₁〜C₆アルコキシ、置換若しくは非置換のC₃〜C₆シクロアルコキシ、置換若しくは非置換の3〜6員のヘテロシクロアルコキシ、置換若しくは非置換のC₁〜C₆アルコキシカルボニル、置換若しくは非置換のC₃〜C₆シクロアルコキシカルボニル、置換若しくは非置換の3〜6員のヘテロシクロアルコキシカルボニル、又は置換若しくは非置換のC₁〜C₆アシルオキシであり、
R³及びR⁴は、互いに独立して、水素、置換若しくは非置換のC₁〜C₂₀アルキル、置換若しくは非置換のC₂〜C₂₀アルケニル、置換若しくは非置換のC₂〜C₂₀アルキニル、置換若しくは非置換のC₃〜C₂₀シクロアルキル、置換若しくは非置換のC₄〜C₂₀シクロアルケニル、置換若しくは非置換のC₄〜C₂₀シクロアルキニル、置換若しくは非置換の3〜6員のヘテロシクロアルキル、置換若しくは非置換のC₇〜C₂₀シクロアルキルアルキル、置換若しくは非置換の3〜6員のヘテロシクロアルキル-C₁〜C₂₀アルキル、置換若しくは非置換のC₄〜C₂₀アリール、置換若しくは非置換のC₅〜C₂₀アリールアルキル、置換若しくは非置換の5〜15員のヘテロアリール、又は置換若しくは非置換の5〜15員のヘテロアリール-C₁〜C₂₀アルキルであるか、或いは
R²及びR³又はR³及びR⁴は、それらが結合する炭素原子と一緒になって、置換若しくは非置換のC₅〜C₆シクロアルキル、置換若しくは非置換のC₅〜C₆シクロアルケニル、置換若しくは非置換のC₅〜C₆シクロアルキニル、又は置換若しくは非置換の5〜6員のヘテロシクロアルキルを形成する。］
で表される化合物の製造方法であって、以下：
式（III）又は式（IV）：

［式中、R¹、R²、R³及びR⁴は、定義と同義である。］
で表される化合物を、マンガンを含む触媒存在下で、空気中の酸素と反応させて環化生成物を得る、環化工程；
を含む、前記方法。
（2）前記マンガンを含む触媒が、マンガン錯体を含む触媒である、前記（1）に記載の方法。
（3）前記マンガン錯体を含む触媒が、配位子としてβ−ジケトナート、カルボキシラート、アルコキシラート、ハロゲン化物イオン、硝酸イオン、硫酸イオン又はリン酸イオンを有するマンガン錯体、又は1種以上のそれらの混合物を含む、前記（2）に記載の方法。
（4）前記マンガン錯体を含む触媒が、マンガン（III）アセチルアセトナート、マンガン（III）アセタート、マンガン（II）アセチルアセトナート又はマンガン（II）アセタートを含む、前記（3）に記載の方法。
（5）前記環化工程が、メタノール、エタノール、n-プロパノール、イソプロパノール、2-ブタノール、エチレングリコール、2,2,2-トリフルオロエタノール、1,1,1,3,3,3-ヘキサフルオロ-2-プロパノール、並びに1種以上のそれらの組み合わせからなる群より選択されるアルコール系溶媒の存在下で実施される、前記（1）〜（4）のいずれかに記載の方法。
（6）前記環化工程が、室温で実施される、前記（1）〜（5）のいずれかに記載の方法。
（7）前記環化工程で得られる環化生成物と還元剤とを反応させて、式（I）又は（II）で表される化合物を得る、還元工程をさらに含む、前記（1）〜（6）のいずれかに記載の方法。
（8）前記還元剤が、チオ硫酸ナトリウム、亜硫酸ナトリウム、亜ジチオン酸ナトリウム、ジメチルスルフィド及びトリフェニルホスフィン、並びに1種以上のそれらの組み合わせからなる群より選択される、前記（7）に記載の方法。
（9）R¹が、置換若しくは非置換のC₁〜C₂₀アルキル、置換若しくは非置換のC₂〜C₂₀アルケニル、置換若しくは非置換のC₂〜C₂₀アルキニル、置換若しくは非置換のC₃〜C₂₀シクロアルキル、置換若しくは非置換のC₄〜C₂₀シクロアルケニル、置換若しくは非置換のC₄〜C₂₀シクロアルキニル、置換若しくは非置換のC₇〜C₂₀シクロアルキルアルキル、置換若しくは非置換のC₄〜C₂₀アリール、置換若しくは非置換のC₅〜C₂₀アリールアルキル、置換若しくは非置換の5〜15員のヘテロアリール、又は置換若しくは非置換の5〜15員のヘテロアリール-C₁〜C₂₀アルキルであり、
R²が、水素、ヒドロキシル、置換若しくは非置換のC₁〜C₂₀アルキル、置換若しくは非置換のC₂〜C₂₀アルケニル、置換若しくは非置換のC₂〜C₂₀アルキニル、置換若しくは非置換のC₃〜C₂₀シクロアルキル、置換若しくは非置換のC₄〜C₂₀シクロアルケニル、置換若しくは非置換のC₄〜C₂₀シクロアルキニル、置換若しくは非置換のC₇〜C₂₀シクロアルキルアルキル、置換若しくは非置換のC₄〜C₂₀アリール、置換若しくは非置換のC₅〜C₂₀アリールアルキル、置換若しくは非置換のC₁〜C₆アルコキシ、置換若しくは非置換のC₃〜C₆シクロアルコキシ、置換若しくは非置換のC₁〜C₆アルコキシカルボニル、置換若しくは非置換のC₃〜C₆シクロアルコキシカルボニル、又は置換若しくは非置換のC₁〜C₆アシルオキシであり、
R³及びR⁴が、互いに独立して、水素、置換若しくは非置換のC₁〜C₂₀アルキル、置換若しくは非置換のC₂〜C₂₀アルケニル、置換若しくは非置換のC₂〜C₂₀アルキニル、置換若しくは非置換のC₃〜C₂₀シクロアルキル、置換若しくは非置換のC₄〜C₂₀シクロアルケニル、置換若しくは非置換のC₄〜C₂₀シクロアルキニル、置換若しくは非置換のC₇〜C₂₀シクロアルキルアルキル、置換若しくは非置換のC₄〜C₂₀アリール、又は置換若しくは非置換のC₅〜C₂₀アリールアルキルであり、
R¹、R²、R³及びR⁴において、前記基が置換されている場合、該置換基は、それぞれ独立して、ハロゲン、シアノ、ニトロ、アミノ、ヒドロキシル、C₁〜C₆アルキル、C₂〜C₆アルケニル、C₂〜C₆アルキニル、C₃〜C₆シクロアルキル、C₃〜C₆シクロアルケニル、C₃〜C₆シクロアルキニル、C₁〜C₆アルコキシ、C₆〜C₁₅アリールオキシ、C₇〜C₂₀アリールアルキルオキシ、5〜15員のヘテロアリールオキシ、5〜15員のヘテロアリール-C₁〜C₉アルキルオキシ、C₁〜C₆アルコキシカルボニル、C₃〜C₆シクロアルコキシカルボニル、及びC₁〜C₆アシルオキシからなる群より選択される1個以上の1価基である、
前記（1）〜（8）のいずれかに記載の方法。 That is, the gist of the present invention is as follows.
(1) Formula (I) or (II):

[Where:
R ¹ is substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₂₀ alkyl, carboxyl, substituted or unsubstituted amido or substituted or unsubstituted A substituted ester,
R ² is hydrogen, hydroxyl, a substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or C ₄ -C ₂₀ cycloalkynyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl substituted, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy Substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, heterocycloalkoxy 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₆ acyloxy,
R ³ and R ⁴ are independently of each other hydrogen, substituted or unsubstituted C _{1 to} C ₂₀ alkyl, substituted or unsubstituted C _{2 to} C ₂₀ alkenyl, substituted or unsubstituted C _{2 to} C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, the hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or heteroaryl -C ₁ -C ₂₀ alkyl substituted or unsubstituted 5-15 membered, Or
R ² and R ³ or R ³ and R ⁴ together with the carbon atom to which they are attached are substituted or unsubstituted C _{5 to} C ₆ cycloalkyl, substituted or unsubstituted C _{5 to} C ₆ cycloalkenyl. , substituted or unsubstituted C ₅ -C ₆ cycloalkenyl, or form a substituted or unsubstituted 5-6 membered heterocycloalkyl. ]
A method for producing a compound represented by the following:
Formula (III) or Formula (IV):

[Wherein, R ¹ , R ² , R ³ and R ⁴ have the same definitions. ]
A cyclization step in which a compound represented by the following formula is reacted with oxygen in the air in the presence of a catalyst containing manganese to obtain a cyclization product;
Said method.
(2) The method according to (1) above, wherein the manganese-containing catalyst is a catalyst containing a manganese complex.
(3) The catalyst containing the manganese complex is a manganese complex having β-diketonate, carboxylate, alkoxylate, halide ion, nitrate ion, sulfate ion or phosphate ion as a ligand, or one or more of them The method according to (2) above, comprising a mixture.
(4) The method according to (3) above, wherein the catalyst containing the manganese complex contains manganese (III) acetylacetonate, manganese (III) acetate, manganese (II) acetylacetonate or manganese (II) acetate.
(5) The cyclization step includes methanol, ethanol, n-propanol, isopropanol, 2-butanol, ethylene glycol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro. The method according to any one of (1) to (4), which is performed in the presence of -2-propanol and an alcohol solvent selected from the group consisting of one or more combinations thereof.
(6) The method according to any one of (1) to (5), wherein the cyclization step is performed at room temperature.
(7) The cyclization product obtained in the cyclization step and a reducing agent are reacted to obtain a compound represented by the formula (I) or (II), further including the reduction step (1) to The method according to any one of (6).
(8) The reducing agent according to (7), wherein the reducing agent is selected from the group consisting of sodium thiosulfate, sodium sulfite, sodium dithionite, dimethyl sulfide and triphenylphosphine, and one or more combinations thereof. Method.
(9) R ¹ is substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~C is ₂₀ alkyl,
R ² is hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or C ₄ -C ₂₀ cycloalkynyl unsubstituted, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl substituted, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl substituent, a substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₆ acyloxy,
R ³ and R ^4, independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, C ₄ -C ₂₀ cycloalkynyl substituted or unsubstituted, substituted or unsubstituted C ₇ -C ₂₀ cycloalkyl alkyl alkyl, C ₄ -C ₂₀ aryl, or substituted or unsubstituted C ₅ -C ₂₀ arylalkyl substituted or unsubstituted,
In R ¹ , R ² , R ³ and R ⁴ , when the group is substituted, the substituents are each independently halogen, cyano, nitro, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₆ cycloalkenyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₅ aryl Oxy, C ₇ -C ₂₀ arylalkyloxy, 5-15 membered heteroaryloxy, 5-15 membered heteroaryl-C ₁ -C ₉ alkyloxy, C ₁ -C ₆ alkoxycarbonyl, C ₃ -C ₆ cyclo alkoxycarbonyl, and one or more monovalent group selected from the group consisting of C ₁ -C ₆ acyloxy,
The method according to any one of (1) to (8).

According to the present invention, it is possible to provide a means for producing a 4,5-dihydroisoxazole derivative under mild reaction conditions at a low production cost.
Problems, configurations, and effects other than those described above will be clarified by the following description of embodiments.

  Hereinafter, preferred embodiments of the present invention will be described in detail.

<1. Definition of compounds>
In this specification, the prefix “n” used for a group in a chemical formula is normal, “i” or “iso” is iso, “s” or “sec” is secondary, “t” or “tert” "Means tertiary," c "means cyclo," o "means ortho," m "means meta, and" p "means para.

As used herein, “alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing the specified number of carbon atoms. For example, “C ₁ -C ₆ alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing at least 1 and at most 6 carbon atoms. Suitable alkyls include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 1-methyl-n-butyl, 2 -Methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-n-propyl, 1,2-dimethyl-n-propyl, 2,2-dimethyl-n-propyl, 1-ethyl-n -Propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 3-methyl-n-pentyl, 4-methyl-n-pentyl, 1,1-dimethyl-n-butyl, 1 , 2-Dimethyl-n-butyl, 1,3-dimethyl-n-butyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, 3,3-dimethyl-n-butyl, 1 -Ethyl-n-butyl, 2-ethyl-n-butyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 1-ethyl-1-methyl-n-propyl and C ₁ -C ₆ a linear or branched such as 1-ethyl-2-methyl -n- propyl Mention may be made of the kill. Also, suitable alkyl include, but are not limited to, for example, in addition to the groups encompassed by C ₁ -C ₆ alkyl, 1-methyl-1-ethyl -n- pentyl, 1-heptyl, 2- Heptyl, 1-ethyl-1,2-dimethyl-n-propyl, 1-ethyl-2,2-dimethyl-n-propyl, 1-octyl, 3-octyl, 4-methyl-3-n-heptyl, 6- Methyl-2-n-heptyl, 2-propyl-1-n-heptyl, 2,4,4-trimethyl-1-n-pentyl, 1-nonyl, 2-nonyl, 2,6-dimethyl-4-n- Heptyl, 3-ethyl-2,2-dimethyl-3-n-pentyl, 3,5,5-trimethyl-1-n-hexyl, 1-decyl, 2-decyl, 4-decyl, 3,7-dimethyl- 1-n-octyl, 3,7-dimethyl 3-n-octyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n - C ₁ nonadecyl and n- linear or branched eicosyl It can be mentioned C ₂₀ alkyl.

In the present specification, “alkenyl” means a group in which one or more CC single bonds of the alkyl are substituted with double bonds. Suitable alkenyls include, but are not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 Mention may be made of linear or branched C ₂ -C ₆ alkenyls such as -methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-pentenyl and hexenyl. Suitable alkenyls include, but are not limited to, for example, heptenyl, octenyl, nonenyl, decenyl, n-undecenyl, n-dodecenyl, n-, in addition to the groups encompassed by C ₂ -C ₆ alkenyl. tridecenyl, n- tetradecenyl, n- pentadecenyl, n- hexadecenyl, n- heptadecenyl, n- octadecenyl, mention may be made of C ₂ -C ₂₀ alkenyl, straight or branched chain, such as n- nonadecenyl and n- eicosenyl.

In the present specification, “alkynyl” means a group in which one or more CC single bonds of the alkyl are substituted with triple bonds. Suitable alkynyls include, but are not limited to, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl and hexynyl Mention may be made of straight-chain or branched C ₂ -C ₆ alkynyl. Suitable alkynyls also include, but are not limited to, for example, in addition to the groups included in C ₂ -C ₆ alkynyl, heptynyl, octynyl and noninyl, decynyl, n-undecynyl, n-dodecynyl, n- tridecynyl, n- tetradecynyl, n- pentadecynyl, n- hexadecynyl, n- Heputadeshiniru, n- octadecynyl, mention may be made of C ₂ -C ₂₀ alkynyl, straight or branched chain, such as n- Nonadeshiniru and n- Eikoshiniru.

As used herein, “cycloalkyl” means an alicyclic alkyl containing the specified number of carbon atoms. For example, “C ₃ -C ₆ cycloalkyl” means a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms. Suitable cycloalkyls include, but are not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 1,2-dimethylcyclopropyl, 2,3 -Dimethylcyclopropyl, 1-ethylcyclopropyl, 2-ethylcyclopropyl, cyclohexyl, 1-methylcyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 1-ethylcyclobutyl, 2-ethylcyclobutyl, 3-ethylcyclo Butyl, 1,2-dimethylcyclobutyl, 1,3-dimethylcyclobutyl, 2,2-dimethylcyclobutyl, 2,3-dimethylcyclobutyl, 2,4-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, 1-n-propylcyclopropyl, 2-n-propylcyclopropyl, 1-isopropylcyclopropyl, 2-isopropylcyclopropyl Pill, 1,2,2-trimethylcyclopropyl, 1,2,3-trimethylcyclopropyl, 2,2,3-trimethylcyclopropyl, 1-ethyl-2-methylcyclopropyl, 2-ethyl-1-methylcyclo Mention may be made of C _{3 to} C ₆ cycloalkyl such as propyl, 2-ethyl 2-methylcyclopropyl and 2-ethyl-3-methylcyclopropyl. Suitable cycloalkyls include, but are not limited to, linear or branched C ₃ -C ₂₀ such as, for example, cyclooctyl, in addition to the groups included in C ₃ -C ₆ cycloalkyl. Mention may be made of cycloalkyl.

In the present specification, “cycloalkenyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with double bonds. Suitable cycloalkenyl includes, but is not limited to, C ₄ -C ₆ cycloalkenyl such as cyclobutenyl, cyclopentenyl, and cyclohexenyl. Suitable cycloalkenyls include, but are not limited to, for example, in addition to the above groups included in C ₄ -C ₆ cycloalkenyl, straight or branched C ₄ -C ₂₀ cyclo, such as cyclooctenyl. Mention may be made of alkenyl.

In the present specification, “cycloalkynyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with triple bonds. Suitable cycloalkynyl includes, but is not limited to, C ₄ -C ₆ cycloalkynyl such as cyclobutynyl, cyclopentynyl and cyclohexynyl. Suitable cycloalkynyls also include, but are not limited to, for example, straight or branched C ₄ -C ₂₀ cyclo, such as cyclooctynyl, in addition to the groups included in C ₄ -C ₆ cycloalkynyl. Mention may be made of alkynyl.

  In the present specification, “heterocycloalkyl” means that one or more carbon atoms of the cycloalkyl, cycloalkenyl or cycloalkynyl are each independently selected from nitrogen (N), sulfur (S) and oxygen (O). Means a group substituted with one or more heteroatoms. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heterocycloalkyl include, but are not limited to, eg, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Mention may be made of ˜6-membered heterocycloalkyl.

In the present specification, “cycloalkylalkyl” means a group in which one of the hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkylalkyl, but are not limited to, may be, for example, a C ₇ -C ₁₁ cycloalkylalkyl such as cyclohexylmethyl and cyclohexenyl methyl. Suitable cycloalkylalkyls include, but are not limited to, for example, straight or branched C ₇ such as cyclooctylmethyl, in addition to the groups included in C ₇ -C ₁₁ cycloalkylalkyl. ˜C ₂₀ cycloalkylalkyl may be mentioned.

As used herein, “heterocycloalkylalkyl” means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms has been replaced with the heterocycloalkyl. Suitable heterocycloalkylalkyl include, but are not limited to, can be exemplified heterocycloalkyl -C ₁ -C ₂₀ alkyl, for example 3- to 6-membered.

In the present specification, “alkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the alkyl, alkenyl or alkynyl. Suitable alkoxy includes, but is not limited to, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, 1-methyl-n-butoxy, 2-methyl-n-butoxy, 3-methyl-n-butoxy, 1,1-dimethyl-n-propoxy, 1,2-dimethyl-n-propoxy, 2,2-dimethyl-n-propoxy, 1-ethyl- n-propoxy, n-hexyloxy, 1-methyl-n-pentyloxy, 2-methyl-n-pentyloxy, 3-methyl-n-pentyloxy, 4-methyl-n-pentyloxy, 1,1-dimethyl -n-butoxy, 1,2-dimethyl-n-butoxy, 1,3-dimethyl-n-butoxy, 2,2-dimethyl-n-butoxy, 2,3-dimethyl-n-butoxy, 3,3-dimethyl -n-butoxy, 1-ethyl-n-butoxy, 2-ethyl-n-butoxy, 1,1,2-trimethyl-n-propoxy, 1,2,2-trimethyl-n-propoxy, Mention may be made of C ₁ -C ₆ alkoxy such as 1-ethyl-1-methyl-n-propoxy and 1-ethyl-2-methyl-n-propoxy.

In the present specification, “cycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the above cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkoxy includes, but is not limited to, for example, cyclopropoxy, cyclobutoxy, 1-methyl-cyclopropoxy, 2-methyl-cyclopropoxy, cyclopentyloxy, 1-methyl-cyclobutoxy, 2-methyl-cyclobutoxy , 3-methyl-cyclobutoxy, 1,2-dimethyl-cyclopropoxy, 2,3-dimethyl-cyclopropoxy, 1-ethyl-cyclopropoxy, 2-ethyl-cyclopropoxy, cyclohexyloxy, 1-methyl-cyclopentyloxy, 2-methyl-cyclopentyloxy, 3-methyl-cyclopentyloxy, 1-ethyl-cyclobutoxy, 2-ethyl-cyclobutoxy, 3-ethyl-cyclobutoxy, 1,2-dimethyl-cyclobutoxy, 1,3-dimethyl- Cyclobutoxy, 2,2-dimethyl-cyclobutoxy, 2,3-dimethyl-cyclobutoxy, 2,4-dimethyl-cyclobutoxy 3,3-dimethyl-cyclobutoxy, 1-n-propyl-cyclopropoxy, 2-n-propyl-cyclopropoxy, 1-isopropyl-cyclopropoxy, 2-isopropyl-cyclopropoxy, 1,2,2-trimethyl-cyclo Propoxy, 1,2,3-trimethyl-cyclopropoxy, 2,2,3-trimethyl-cyclopropoxy, 1-ethyl-2-methyl-cyclopropoxy, 2-ethyl 1-methyl-cyclopropoxy, 2-ethyl-2 Mention may be made of C ₃ -C ₆ cycloalkoxy, such as -methyl-cyclopropoxy and 2-ethyl-3-methyl-cyclopropoxy.

  In the present specification, “heterocycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heterocycloalkyl. Suitable cycloalkoxy includes, but is not limited to, for example, 3-6 membered heterocycloalkoxy.

In the present specification, “aryl” means an aromatic ring group. Suitable aryls include, but are not limited to, C ₄ -C ₂₀ aryls such as phenyl, o-biphenyl, m-biphenyl, p-biphenyl, terphenyl, α-naphthyl, β-naphthyl and anthracenyl. Can do.

In the present specification, “arylalkyl” means a group in which one of hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the aryl. Preferred arylalkyl include, but are not limited to, for example, benzyl, 1-phenethyl, 2-phenethyl, biphenylmethyl, can be exemplified terphenyl methyl and C ₇ -C ₂₀ arylalkyl styryl like.

  In the present specification, “heteroaryl” means a group in which one or more carbon atoms of the aryl are each independently substituted with one or more heteroatoms selected from N, S and O. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heteroaryl include, but are not limited to, furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, Mention may be made of 5- to 15-membered heteroaryl such as pyrimidinyl, quinolinyl, isoquinolinyl and indolyl.

In the present specification, “heteroarylalkyl” means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms is substituted with the heteroaryl. Suitable heteroarylalkyl includes, but is not limited to, 5- to 15-membered heteroaryl-C ₁ -C ₉ alkyl such as pyridylmethyl.

In the present specification, “aryloxy” means a group in which a hydroxyl hydrogen atom is substituted with the aryl. Suitable aryloxy include, but are not limited to, e.g., phenoxy, biphenyloxy, mention may be made of C ₆ -C ₁₅ aryloxy such as naphthyloxy or anthryloxy (anthracenyloxy).

In the present specification, “arylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the arylalkyl. Preferred arylalkyloxy include, without limitation, may include, for example, benzyloxy, 1-phenethyloxy, a C ₇ -C ₂₀ arylalkyloxy and 2-phenethyloxy and styryloxy.

  In the present specification, “heteroaryloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroaryl. Suitable heteroaryloxy include, but are not limited to, furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, iso 5-15 such as oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy and indolyloxy Mention may be made of member heteroaryloxy.

In the present specification, “heteroarylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroarylalkyl. Preferred heteroarylalkyloxy include, without limitation, mention may be made of heteroaryl -C ₁ -C ₉ alkyl oxy example 5-15 membered.

In the present specification, “acyl” means a group in which a monovalent group selected from the groups described above and carbonyl are linked. Suitable acyls include, but are not limited to, C ₁ -C ₆ aliphatic acyls such as formyl, acetyl, and propionyl, and C ₄ -C ₂₀ aromatic acyls such as benzoyl.

  In the present specification, “ester” means a group having a structure in which an alcohol having a monovalent group selected from the groups described above and carboxyl form an ester bond (that is, alkoxycarbonyl, aryloxycarbonyl, arylalkyloxy). Carbonyl, heteroaryloxycarbonyl or heteroarylalkyloxycarbonyl).

  The groups described above are each independently unsubstituted or can be further substituted with one or more monovalent groups described above.

  In the present specification, “halogen” or “halo” means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

で表される化合物の製造方法に関する。式（I）及び（II）で表される化合物は、4,5-ジヒドロイソオキサゾリン環を有する。本明細書において、式（I）及び（II）で表される化合物のように4,5-ジヒドロイソオキサゾリン環を有する化合物を、「4,5-ジヒドロイソオキサゾール誘導体」と記載する場合がある。4,5-ジヒドロイソオキサゾール誘導体は、医薬品及び農薬等の種々の有用な化合物の重要な中間体である。4,5-ジヒドロイソオキサゾール誘導体の製造方法の重要な工程である4,5-ジヒドロイソオキサゾリン環を形成する手段としては、すでに様々な反応が知られている。本発明者らは、従来技術の4,5-ジヒドロイソオキサゾリン環の形成反応と比較して、より安価な触媒及び基質化合物を使用し、且つより温和な反応条件下で4,5-ジヒドロイソオキサゾリン環を形成できることを見出した。それ故、本発明の方法により、低製造コスト且つ温和な反応条件下で4,5-ジヒドロイソオキサゾール誘導体を製造することができる。 The present invention relates to formula (I) or (II):

It relates to the manufacturing method of the compound represented by these. The compounds represented by the formulas (I) and (II) have a 4,5-dihydroisoxazoline ring. In the present specification, a compound having a 4,5-dihydroisoxazoline ring, such as the compounds represented by formulas (I) and (II), may be referred to as a “4,5-dihydroisoxazole derivative”. . 4,5-Dihydroisoxazole derivatives are important intermediates for various useful compounds such as pharmaceuticals and agricultural chemicals. Various reactions are already known as means for forming a 4,5-dihydroisoxazoline ring, which is an important step in the method for producing 4,5-dihydroisoxazole derivatives. The inventors have used a less expensive catalyst and substrate compound, and under milder reaction conditions, compared to the prior art 4,5-dihydroisoxazoline ring formation reaction. It has been found that an oxazoline ring can be formed. Therefore, according to the method of the present invention, a 4,5-dihydroisoxazole derivative can be produced under low reaction cost and mild reaction conditions.

In one embodiment of the invention, R ¹ in formula (I) or (II) is substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, 3-6 membered substituted or unsubstituted heterocycloalkyl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ ~ C ₂₀ alkyl, potassium Ruboxyl, substituted or unsubstituted amide or substituted or unsubstituted ester. R ¹ is substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₂₀ preferably an alkyl, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₄ ~C ₂₀ ants Le, a substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, or more preferably a substituted or unsubstituted 5-15 membered heteroaryl, tert- butyl, hydroxymethyl, 2-phenylethyl, phenyl, 4 More preferred is -methoxyphenyl, 4-cyanophenyl, 4-benzyloxyphenyl, thiophen-2-yl, or furan-2-yl.

In the definition of R ¹ , when the group is substituted, the substituents are each independently halogen, cyano, nitro, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₆ cycloalkenyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₅ aryloxy, C ₇ -C ₂₀ arylalkyloxy, 5-15 membered heteroaryloxy, 5-15 membered heteroaryl -C ₁ -C ₉ alkyloxy, C ₁ -C ₆ alkoxycarbonyl, C ₃ -C ₆ cycloalkoxy carbonyl, and C ₁ ~ One or more monovalent groups selected from the group consisting of C ₆ acyloxy are preferable, and cyano, hydroxyl, methoxy, benzyloxy or phenyl is more preferable.

In one embodiment of the invention, R ² in formula (I) or (II) is hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, and a substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl - C ₁ C ₂₀ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, heterocycloalkoxy 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy carbonyl, heterocycloalkyl alkoxycarbonyl 3-6 membered substituted or unsubstituted, or a substituted or unsubstituted C ₁ -C ₆ acyloxy. R ² is hydrogen, hydroxyl, a substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or C ₄ -C ₂₀ cycloalkynyl unsubstituted, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl substituted, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl substituent is preferably a substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₆ acyloxy, hydrogen And more preferably is hydroxyl.

In the definition of R ² , when the group is substituted, the substituents are each independently halogen, cyano, nitro, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₆ cycloalkenyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₅ aryloxy, C ₇ -C ₂₀ arylalkyloxy, 5-15 membered heteroaryloxy, 5-15 membered heteroaryl -C ₁ -C ₉ alkyloxy, C ₁ -C ₆ alkoxycarbonyl, C ₃ -C ₆ cycloalkoxy carbonyl, and C ₁ ~ It is preferably one or more monovalent groups selected from the group consisting of C ₆ acyloxy.

In one embodiment of the invention, R ³ and R ⁴ in formula (I) or (II) are independently of one another hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C _2. -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, 3-6 membered substituted or unsubstituted heterocycloalkyl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5 ~ 15 member hetero Aryl -C ₁ -C ₂₀ alkyl. R ³ and R ⁴ are independently of each other hydrogen, substituted or unsubstituted C _{1 to} C ₂₀ alkyl, substituted or unsubstituted C _{2 to} C ₂₀ alkenyl, substituted or unsubstituted C _{2 to} C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, C ₄ -C ₂₀ cycloalkynyl substituted or unsubstituted, substituted or unsubstituted C ₇ -C ₂₀ cycloalkyl cycloalkylalkyl, substituted or preferably unsubstituted C ₄ -C ₂₀ aryl, or a substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or It is more preferably unsubstituted C ₂ -C ₂₀ alkenyl, or substituted or unsubstituted C ₂ -C ₂₀ alkynyl, more preferably hydrogen or methyl.

In the definition of R ³ and R ⁴ , when the group is substituted, the substituent is independently halogen, cyano, nitro, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C _6. alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₆ cycloalkenyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₅ aryloxy, C ₇ -C ₂₀ arylalkyloxy, 5-15 membered heteroaryloxy, 5-15 membered heteroaryl -C ₁ -C ₉ alkyloxy, C ₁ -C ₆ alkoxycarbonyl, C ₃ -C ₆ cycloalkoxy carbonyl and, One or more monovalent groups selected from the group consisting of C _{1 to} C ₆ acyloxy are preferable.

In another embodiment of the invention, R ² and R ³ or R ³ and R ⁴ in formula (I) or (II), together with the carbon atom to which they are attached, are substituted or unsubstituted C ₅ -C ₆ cycloalkyl, substituted or unsubstituted C ₅ -C ₆ cycloalkenyl, substituted or unsubstituted C ₅ -C ₆ cycloalkenyl, or form a substituted or unsubstituted 5-6 membered heterocycloalkyl. R ² and R ³ or R ³ and R ⁴ together with the carbon atom to which they are attached are substituted or unsubstituted C _{5 to} C ₆ cycloalkyl, substituted or unsubstituted C _{5 to} C ₆ cycloalkenyl. , substituted or unsubstituted C ₅ -C ₆ cycloalkenyl, or substituted or unsubstituted preferable to form a 5- or 6-membered heterocycloalkyl, together with the carbon atoms to which they are attached, cyclopentyl, More preferably it forms pentenyl, cyclohexyl or cyclohexenyl.

Particularly preferred compounds represented by formula (I) or (II) are:
R ¹ is a substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₂₀ Alkyl,
R ² is hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or C ₄ -C ₂₀ cycloalkynyl unsubstituted, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl substituted, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl substituent, a substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₆ acyloxy,
R ³ and R ^4, independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, C ₄ -C ₂₀ cycloalkynyl substituted or unsubstituted, substituted or unsubstituted C ₇ -C ₂₀ cycloalkyl alkyl alkyl, C ₄ -C ₂₀ aryl, or substituted or unsubstituted C ₅ -C ₂₀ arylalkyl substituted or unsubstituted,
In R ¹ , R ² , R ³ and R ⁴ , when the group is substituted, the substituents are each independently halogen, cyano, nitro, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₆ cycloalkenyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₅ aryl Oxy, C ₇ -C ₂₀ arylalkyloxy, 5-15 membered heteroaryloxy, 5-15 membered heteroaryl-C ₁ -C ₉ alkyloxy, C ₁ -C ₆ alkoxycarbonyl, C ₃ -C ₆ cyclo One or more monovalent groups selected from the group consisting of alkoxycarbonyl and C ₁ -C ₆ acyloxy.

Particularly preferred compounds of the formula (I) or (II) are:
R ¹ is phenyl, R ² is hydrogen, R ³ is hydrogen or methyl, and R ⁴ is hydrogen;
R ¹ is 4-methoxyphenyl, R ² is hydrogen, R ³ is hydrogen or methyl, and R ⁴ is hydrogen;
R ¹ is 4-cyanophenyl, R ² is hydrogen, R ³ is hydrogen or methyl, and R ⁴ is hydrogen;
R ¹ is tert-butyl, R ² is hydrogen, R ³ is hydrogen or methyl, and R ⁴ is hydrogen;
R ¹ is 2-phenylethyl, R ² is hydrogen, R ³ is methyl, and R ⁴ is hydrogen;
R ¹ is thiophen-2-yl, R ² is hydrogen, R ³ is hydrogen or methyl, and R ⁴ is hydrogen;
R ¹ is furan-2-yl, R ² is hydrogen, R ³ is hydrogen or methyl, and R ⁴ is hydrogen;
R ¹ is hydroxymethyl, R ² is hydroxyl, R ³ and R ⁴ are hydrogen (the hydroxyls of R ¹ and R ² may be in a protected form with a cyclic acetal protecting group introduced) Or
R ¹ is 4-benzyloxyphenyl, R ² is hydrogen, R ³ and R ⁴ are hydrogen;
It is.

  In the present invention, the compounds represented by the formulas (I) and (II) and the compounds represented by the formulas (III), (IV), (V) and (VI) described below are only the compounds themselves. As well as its salts. Examples of the salt of the compound represented by each formula of the present invention include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid, or formic acid and acetic acid. , Maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, With organic acid anions such as itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Salts are preferred. Even when the compounds represented by the formula (I) and the formula (II) and the compounds represented by the formulas (III), (IV), (V) and (VI) are in the form of the salts described above, It can be applied to the method of the present invention.

  The compounds represented by the formula (I) and the formula (II) and the compounds represented by the formulas (III), (IV), (V) and (VI) described below are only the compounds described above or below. In addition, a solvate of the compound or a salt thereof is also included. Solvents that can form solvates with the compound or salt thereof include, but are not limited to, for example, lower alcohols (eg, 1-6 carbons such as methanol, ethanol or 2-propanol (isopropyl alcohol)). Alcohols with the number of atoms), higher alcohols (for example, alcohols with 7 or more carbon atoms such as 1-heptanol or 1-octanol), organics such as dimethyl sulfoxide (DMSO), acetic acid, ethanolamine or ethyl acetate A solvent or water is preferred. A compound represented by formula (I) and formula (II), a compound represented by formula (III), (IV), (V) and (VI) or a salt thereof is a solvate of the above solvent. Even if it is a form, it can be applied to the method of the present invention.

  The compounds represented by the formula (I) and the formula (II) and the compounds represented by the formulas (III), (IV), (V) and (VI) described below are only the compounds described above or below. It also includes its protected form. In the present specification, the “protected form” means a form in which a protective group is introduced into one or more functional groups (for example, a hydroxyl group or a carboxylic acid group). In this specification, the protected form of the compound represented by each formula may be referred to as a protected derivative of the compound represented by each formula. In the present specification, a “protecting group” is a group introduced into a specific functional group in order to prevent an undesirable reaction from progressing, and is quantitatively removed under specific reaction conditions. In other reaction conditions, it means a group that is substantially stable, that is, reaction-inactive. The protecting group capable of forming a protected form of the compound is not limited. For example, in the case of a protecting group for a hydroxyl group, silyl (for example, t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) Or tert-butyldiphenylsilyl (TBDPS)), alkoxy (eg, methoxymethoxy (MOM) or methoxy (Me)) or cyclic acetal (eg, benzylidene acetal or dimethylacetal) is a protective group for a carboxylic acid group, alkyl Preference is given to esters (eg methyl, ethyl or isopropyl esters), arylalkyl esters (eg benzyl esters) or amides, respectively. Protection and deprotection by the protecting group can be appropriately performed by those skilled in the art based on known reaction conditions. This is a case where the compounds represented by the formula (I) and the formula (II) and the compounds represented by the formulas (III), (IV), (V) and (VI) are in a protected form by the protecting group. However, it can be applied to the method of the present invention.

  One or more tautomers of the compounds represented by formula (I) and formula (II) and the compounds represented by formulas (III), (IV), (V) and (VI) described below The compound also includes the individual tautomeric forms of the compound.

  In addition, the compounds represented by the formula (I) and the formula (II) and the compounds represented by the formulas (III), (IV), (V) and (VI) described below are one or more stereocenters. When having (chiral centers), the compounds also include the individual enantiomers and diastereomers of the compounds, as well as mixtures thereof, such as racemates.

<2. Method for producing 4,5-dihydroisoxazole derivative>
The present invention relates to a method for producing a 4,5-dihydroisoxazole derivative represented by the formula (I) or (II). The method of the present invention needs to include a cyclization step. The method of the present invention can also optionally include a reduction step, a protecting group introduction step and a deprotection step. Hereinafter, each step will be described in detail.

で表される化合物を、マンガンを含む触媒存在下で、空気中の酸素と反応させて環化生成物を得る、環化工程を含むことが必要である。
前記式（III）及び（IV）において、R¹、R²、R³及びR⁴は、前記と同義である。 [2-1. Cyclization process]
The method of the present invention comprises a compound of formula (III) or (IV):

It is necessary to include a cyclization step in which a compound represented by the following formula is reacted with oxygen in the air in the presence of a catalyst containing manganese to obtain a cyclized product.
In the formulas (III) and (IV), R ¹ , R ² , R ³ and R ⁴ are as defined above.

  The inventors of the present invention have developed a β, γ-unsaturated oxime compound represented by the formula (III) or an α, β-unsaturated oxime compound represented by the formula (IV) in air in the presence of a catalyst containing manganese. It was found that by contacting with oxygen, a cyclized product having a 4,5-dihydroisoxazoline ring was formed by taking in oxygen in the air. The oxygen in the air used as a substrate in the method of the present invention is specified as a purchased or oxygen generating device, such as pure oxygen used in a prior art method (for example, the method described in Non-Patent Document 5). It is not necessary to prepare by preparing using the means. Therefore, 4,5-dihydroisoxazole derivatives can be produced at a low production cost by the method of the present invention.

で表される化合物である。前記式（V）及び（VI）において、R¹、R²、R³及びR⁴は、前記と同義である。 The cyclized product formed in this step is represented by formula (V) or (VI):

It is a compound represented by these. In the formulas (V) and (VI), R ¹ , R ² , R ³ and R ⁴ are as defined above.

  In this step, the peroxide represented by the formula (V) is formed by the reaction of the compound represented by the formula (III) with oxygen in the air. Moreover, the peroxide represented by the formula (VI) is formed by the reaction of the compound represented by the formula (IV) with oxygen in the air.

  Examples of the catalyst containing manganese used in this step include a heterogeneous catalyst such as a catalyst containing manganese dioxide, and a homogeneous catalyst such as a catalyst containing a manganese complex. The catalyst containing manganese used in this step is preferably a catalyst containing a manganese complex. The catalyst containing a manganese complex includes a β-diketonate, a carboxylate, an alkoxylate, a manganese complex having a halide ion, a nitrate ion, a sulfate ion or a phosphate ion as a ligand, or one or more mixtures thereof. More preferably, it contains a manganese complex having β-diketonate or carboxylate as a ligand, or one or more mixtures thereof, and includes manganese (III) acetylacetonate, manganese (III) acetate, manganese (II ) Acetylacetonate, manganese (II) acetate, or manganese (II) hexafluoroacetate, or one or more mixtures thereof, more preferably manganese (III) acetylacetonate, manganese (III) acetate, Manganese (II) acetylacetona Particularly preferably contains the object or manganese (II) acetate, it is particularly preferably made of manganese (III) acetylacetonate. The catalyst containing manganese can catalyze a reaction that takes in oxygen in the air and cyclizes the compound represented by formula (III) or formula (IV) to form a cyclized product. In particular, a catalyst including a manganese complex catalyzes a reaction that takes in oxygen in the air and cyclizes a compound represented by formula (III) or formula (IV) to form a cyclized product with high efficiency. be able to. Further, a catalyst containing manganese is compared with a catalyst containing a rare metal complex or a noble metal complex such as a cobalt complex or a palladium complex used in a cyclization reaction to form a 4,5-dihydroisoxazoline ring in the prior art. Inexpensive. Furthermore, the manganese complex having the ligand is chemically stable and easy to handle. Therefore, by carrying out this step in the presence of a catalyst containing manganese, particularly a catalyst containing a manganese complex having the above characteristics, the cyclization reaction can be carried out under low production cost and mild reaction conditions.

  In the conventional cyclization reaction for forming a 4,5-dihydroisoxazoline ring, a catalyst containing 1 to several tens of molar equivalents of a palladium complex or a cobalt complex with respect to the total amount of the substrate compound is usually used. The On the other hand, the catalyst used in this step is usually 0.0001 to 0.01 molar equivalent (that is, 0.01 to 1 mol%) with respect to the total amount of the compound represented by formula (III) or (IV). Typically in the range of 0.0005 to 0.005 molar equivalents (ie 0.05 to 0.5 mol%), for example in the range of 0.001 to 0.005 molar equivalents (ie 0.1 to 0.5 mol%). Therefore, by using a catalyst containing manganese in this step, the amount of the catalyst used can be reduced to a range of 1/1000 to 1/100. Thereby, the manufacturing cost of the 4,5-dihydroisoxazole derivative can be significantly reduced. Further, since the cyclization reaction proceeds by adding a very small amount of catalyst, the formation of by-products can be substantially suppressed. Thereby, not only can the yield of the reaction be improved, but also post-treatment of the reaction and purification of the target product can be easily performed.

  The cyclization reaction for forming a 4,5-dihydroisoxazoline ring in the prior art is usually carried out in the presence of an additive that improves the catalytic activity in addition to the catalyst and / or the substrate compound. For example, in the case of the method described in Non-Patent Document 5, it is necessary to add acetic acid and t-butyl hydroperoxide as additives to the reaction system in addition to the catalyst containing the cobalt complex. On the other hand, the cyclization reaction in this step can proceed substantially only with a catalyst containing manganese, and therefore, in the presence or absence of any additive that improves the catalytic activity of the catalyst. Even under these conditions, it can be carried out. The cyclization reaction in this step is preferably performed in the absence of an additive. By carrying out this step in the absence of an additive, the formation of by-products can be substantially suppressed. Thereby, not only can the yield of the reaction be improved, but also post-treatment of the reaction and purification of the target product can be easily performed.

  In this step, the compound represented by formula (III) or (IV) is cyclized with oxygen in the air. For this reason, the pressure of oxygen applied to the reaction in this step may be an oxygen partial pressure in the atmosphere, and is usually in the range of 0.2 to 0.25 atom. Further, this step can be performed in an open system in the presence of air. Therefore, the method of the present invention can be carried out by a simple operation using an open reaction system without using a sealed reaction system provided with oxygen pressurizing means. In general, since an open reaction system is inexpensive, the implementation cost of the method of the present invention can be reduced by using an open reaction system.

  This step is usually performed in the presence of a solvent. The solvent used in this step is not particularly limited as long as it is a solvent that does not substantially participate in the reaction. Examples of the solvent used in this step include methanol, ethanol, n-propanol, isopropanol, 2-butanol, ethylene glycol, 2,2,2-trifluoroethanol, and 1,1,1,3,3,3. -Alcohol solvents such as hexafluoro-2-propanol, alkylamide solvents such as N, N, -dimethylformamide (DMF) and N, N-dimethylacetamide, nitrile solvents such as acetonitrile, diethyl ether, diisopropyl ether and Ether solvents such as tetrahydrofuran, halogen solvents such as 1,1-dichloroethane, 1,2-dichloroethane, methylene chloride, chloroform, chlorobenzene and 1,2-dichlorobenzene, aromatic solvents such as benzene and toluene, and 1 Mention may be made of combinations of more than one species. The solvent used in this step is a solvent selected from the group consisting of the alcohol solvent, alkylamide solvent, nitrile solvent, ether solvent, and one or more combinations thereof exemplified above. Preferably, methanol, ethanol, n-propanol, isopropanol, 2-butanol, ethylene glycol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and 1 More preferably, it is an alcoholic solvent selected from the group consisting of one or more species, more preferably methanol, ethanol, n-propanol, isopropanol or 2-butanol, or one or more combinations thereof. Preferably, it is methanol. Alcohol solvents, alkylamide solvents, nitrile solvents, and ether solvents, particularly alcohol solvents, are organic solvents that have relatively low toxicity. Therefore, by carrying out this step using the solvent exemplified above, undesirable effects on the human body and / or the environment can be substantially reduced. Moreover, since the process of the solvent used can be simplified, the implementation cost of the method of the present invention can be reduced.

  When this step is carried out in the presence of a solvent, the concentration of the compound represented by formula (III) or (IV) in the reaction solution is preferably 5 M or less, and is in the range of 0.1 to 5 M. More preferably, it is in the range of 0.4 to 5 M, more preferably in the range of 0.5 to 4 M. As described above, the amount of the solvent used can be reduced by advancing the reaction in this step in the reaction solution containing the compound represented by the high concentration formula (III) or (IV).

  In the case of the conventional method for producing 4,5-dihydroisoxazole derivatives, it is usually necessary to heat or cool the reaction system. For example, in the case of the method described in Non-Patent Document 3, since the nitrile oxide serving as a reaction intermediate is unstable, it is necessary to carry out the reaction under low temperature conditions. On the other hand, in the case of the method described in Non-Patent Document 5, it is necessary to carry out the reaction under heating conditions in order to advance the reaction. On the other hand, the reaction temperature in this step is not particularly limited, and can be carried out at any temperature within the range of 0 ° C. to the boiling point of the solvent used. Since the cyclization reaction in this step proceeds without heating, it is preferably carried out at room temperature. In this step, the room temperature is usually in the range of 10 to 30 ° C, and typically in the range of 10 to 25 ° C. When the cyclization reaction in this step is performed at room temperature, this step can be performed in an inexpensive reaction system that does not include heating or cooling means. Thereby, the implementation cost of the method of the present invention can be significantly reduced. Moreover, since the cyclization reaction in this step proceeds without heating, the formation of by-products can be substantially suppressed. Thereby, not only can the yield of the reaction be improved, but also post-treatment of the reaction and purification of the target product can be easily performed.

  In this step, the reaction mixture obtained by cyclization of the compound represented by formula (III) or (IV) may be filtered (for example, celite filtration or filter filtration), centrifuged, solvent extraction, distillation, chromatography, if desired. It can be worked up and / or purified by means commonly used in the art such as (eg silica gel column chromatography) or recrystallization. However, in the cyclization reaction in this step, the formation of by-products is substantially suppressed and proceeds with a high reaction yield. For this reason, it is preferable to use the reaction mixture of this process for the reduction | restoration process demonstrated below as it is, without post-processing or refine | purifying. By using the reaction mixture of this step as it is for the reduction step, the method of the present invention can be carried out by a simple operation. Moreover, the implementation cost of the method of the present invention can be reduced.

[2-2. Reduction process]
The method of the present invention optionally further includes a reduction step of reacting the cyclization product obtained in the cyclization step with a reducing agent to obtain a compound represented by the formula (I) or (II). It is preferable. The cyclized product used in this step is a compound represented by the formula (V) or (VI) described above.

  The reducing agent used in this step is preferably selected from the group consisting of sodium thiosulfate, sodium sulfite, sodium dithionite, dimethyl sulfide and triphenylphosphine, and one or more combinations thereof. More preferably, it is sodium. When sodium thiosulfate, sodium sulfite or sodium dithionite is used as the reducing agent, it is preferably used in the form of a saturated aqueous solution. By using the reducing agent, the cyclized product obtained in the cyclization step can be reduced to obtain a compound represented by the formula (I) or (II).

  This step is usually performed in the presence of a solvent. The solvent used in this step is not particularly limited as long as it is a solvent that does not substantially participate in the reduction reaction of the cyclized product and the reducing agent. Examples of the solvent used in this step include water, a solvent that can be used in the cyclization step exemplified above, and one or more combinations thereof. For example, in the case of using the reaction mixture of the cyclization step as it is in the reduction step, this step includes only the solvent used in the cyclization step, or the solvent and the solvent used in the cyclization step. It is preferable to carry out in the presence of a mixed solvent. In this embodiment, for example, when sodium thiosulfate, sodium sulfite or sodium dithionite is used as the reducing agent, the solvent used in this step is a mixed solvent of the solvent used in the cyclization step and water. It is preferable that By carrying out this step in the presence of the solvent, the cyclized product obtained in the cyclization step can be reduced to obtain a compound represented by the formula (I) or (II).

  In this step, the conditions for the reduction reaction of the cyclized product and the reducing agent can be appropriately set by those skilled in the art based on the reducing agent used. The temperature of the reduction reaction is usually in the range of 0-100 ° C., typically room temperature. In this step, the room temperature is usually in the range of 10 to 30 ° C, and typically in the range of 10 to 25 ° C. The reduction reaction time is usually 0.1 hour or longer, typically 0.1 to 5 hours, for example 0.5 to 5 hours.

  In this step, the reaction mixture obtained by reducing the cyclized product and the reducing agent is subjected to filtration (for example, Celite filtration or), centrifugation, solvent extraction, distillation, chromatography (for example, silica gel column chromatography), or, as desired. It is preferable to work up and / or purify by means usually used in the art such as recrystallization. By subjecting the reaction mixture in this step to post-treatment and / or purification by the above means, the compound represented by the formula (I) or (II) can be obtained with high purity.

[2-3. Protecting group introduction step and deprotection step]
Each step included in the method of the present invention uses a protected derivative of a compound represented by formula (I), (II), (III), (IV), (V) and / or (VI), if desired. May be implemented. In that case, each said process is a protective group introduction | transduction process which introduce | transduces a protective group into the specific functional group of the compound represented by said each formula, and obtains the protected derivative of this compound, and the compound represented by said each formula It is preferable to further include a deprotecting step of deprotecting a specific protecting group of the protected derivative. The protecting group applied to the compound represented by the formula (I), (II), (III), (IV), (V) and / or (VI) is a functional group to be protected, as well as other functional groups. And a person skilled in the art can select as appropriate based on the kind of the protecting group. Further, protection by the protecting group in the protecting group introduction step and deprotection of the protecting group in the deprotecting step can be appropriately performed by those skilled in the art based on known reaction conditions.

  As described above, the method of the present invention can be carried out under mild reaction conditions using oxygen in the air as a reaction substrate in the presence of a very small amount of catalyst as compared with the prior art method. Therefore, the compound of the formula (I) or (II) having various functional groups can be produced with a low production cost and a high reaction yield by the method of the present invention.

の化合物の合成中間体として極めて有用である。本化合物は、トリパノソーマ・クルージ原虫により引き起こされるシャーガス病に対して有効な薬理作用を示すことから、抗トリパノソーマ薬の有効成分として使用し得る（Rodrigues, G.C.ら, J. Med. Chem., 2014年, 第57巻, p. 298-308）。それ故、本発明はまた、式（I）又は（II）で表される化合物から種々の4,5-ジヒドロイソオキサゾール誘導体を得る工程をさらに含む、4,5-ジヒドロイソオキサゾール誘導体を製造する方法に関する。本発明の方法により、医薬品及び農薬等の有効成分である種々の4,5-ジヒドロイソオキサゾール誘導体を大規模に合成することができる。 In addition, the compound represented by the formula (I) or (II) can be used as an intermediate of various 4,5-dihydroisoxazole derivatives. For example, the compound represented by formula (I) is:

It is extremely useful as an intermediate for the synthesis of this compound. Since this compound exhibits an effective pharmacological action against Chagas disease caused by Trypanosoma cruzi protozoa, it can be used as an active ingredient of antitrypanosoma drugs (Rodrigues, GC et al., J. Med. Chem., 2014) 57, p. 298-308). Therefore, the present invention also produces 4,5-dihydroisoxazole derivatives further comprising the step of obtaining various 4,5-dihydroisoxazole derivatives from the compound represented by formula (I) or (II) Regarding the method. By the method of the present invention, various 4,5-dihydroisoxazole derivatives which are active ingredients such as pharmaceuticals and agricultural chemicals can be synthesized on a large scale.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

<Experiment 1: Production of 4,5-dihydroisoxazole derivative using manganese (III) acetylacetonate catalyst that takes in oxygen molecules in the air (1)>

A 2.0 mL methanol solution in which manganese (III) acetylacetonate (Mn (acac) ₃ ) (6 mg, 0.0314 mmol) was dissolved was prepared. beta, .gamma.-unsaturated oxime 1b (157.7 mg, 0.900 mmol) in methanol (0.35 mL) was added to this to the prepared with Mn (acac) ₃ in methanol _{0.1 mL (Mn (acac) 3} , 0.000852 mmol, 0.1 mol%) was added. The reaction mixture was stirred for 24 hours under air at room temperature. A saturated aqueous sodium thiosulfate solution (1 mL) was added to the reaction mixture, and the mixture was stirred for 0.5 hr. The reaction solution was filtered through Celite. The filtrate was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain 4,5-dihydroisoxazole 2b (149.7 mg, 0.783 mmol, 87%) as a colorless liquid. .

¹ H-NMR (400 MHz, CDC1 ₃ ) δ; 7.67-7.64 (2H, m), 7.41-7.39 (3H, m), 3.76 (1H, d, J = 12.0 Hz), 3.59 (1H, d, J = 12.0 Hz), 3.50 (1H, d, J = 16.8 Hz), 3.02 (1H, d, J = 16.6 Hz) 1.43 (3H, s); LRMS (ESI) m / z Calculated from the following formula: C _{11 H 13 NO 2 [M + Na} ] + 214.09; found: 214.09.

<Experiment 2: Production of 4,5-dihydroisoxazole derivative using manganese (III) acetylacetonate catalyst that takes in oxygen molecules in the air (2)>

In the procedure of Experiment 1, the reaction was carried out using the same materials and method as in Experiment 1, except that the amount of Mn (acac) ₃ used was changed to 0.05 mol% with respect to β, γ-unsaturated oxime 1b. The reaction solution was filtered through Celite. The filtrate was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. ¹ H-NMR was measured using the obtained residue as a composition organism. In the ¹ H-NMR spectrum of the constituent organism, the conversion yield of this reaction was determined to be 66% based on the area ratio between the target product 2b and the raw material 1b. The remaining 34% was raw material 1b. Formation of other by-products was not confirmed.

<Experiment 3: Production of 1,4-dihydroisoxazole derivatives using catalysts containing other manganese complexes>

In the procedure of Experiment 1, Mn (acac) ₃ which is a catalyst containing a manganese complex is converted into manganese (III) acetate (Mn (OAc) ₃ ), manganese (II) acetylacetonate (Mn (acac) ₂ ) or manganese ( II) Change to acetate (Mn (OAc) ₂ ), the amount of catalyst used is 1 mol% with respect to β, γ-unsaturated oxime 1, and the reaction time of the cyclization reaction The reaction was performed using the same materials and methods as in Experiment 1, except that the changes were made. The reaction solution was worked up and purified in the same manner as in Experiment 1 to obtain 4,5-dihydroisoxazole 2b in the following yield.

<Experiment 4: Production of 4,5-dihydroisoxazole derivatives using various substrates>

In the procedure of Experiment 1, the amount of Mn (acac) ₃ used was 0.2 mol% with respect to β, γ-unsaturated oxime 1, and the amount of methanol used as the solvent was changed to that of β, γ-unsaturated oxime 1. The reaction was carried out using the same materials and methods as in Experiment 1, except that the final concentration was 0.5 M and the reaction time of the cyclization reaction was changed to the predetermined time. The reaction solution was worked up and purified in the same manner as in Experiment 1 to obtain 4,5-dihydroisoxazole 2a-2m in the above yield.

<Experiment 5: Comparison of Production Method of 4,5-Dihydroisoxazole Derivative of the Present Invention with Conventional Method>

Using the same substrate, the synthesis yield by the method of the present invention and the synthesis yield by the method described in Non-Patent Document 5 (Yu, W. et al., Tetrahedron, 2013, Vol. 69, p. 3274-3280) And compared. In an example according to the method of the present invention, in the procedure of Experiment 1, the amount of Mn (acac) ₃ used is 0.2 mol% with respect to β, γ-unsaturated oxime 1, and the amount of methanol used as a solvent is The reaction was carried out using the same materials and methods as in Experiment 1, except that the final concentration of β, γ-unsaturated oxime 1 was changed to 0.2 M and the reaction time of the cyclization reaction was changed to the following predetermined times, respectively. It was. The reaction solution was worked up and purified in the same manner as in Experiment 1 to obtain 4,5-dihydroisoxazole. In the comparative example, the reaction was performed under the above conditions based on the method described in Non-Patent Document 5. The reaction solution was worked up and purified in the same manner as in Experiment 1 to obtain 4,5-dihydroisoxazole. Table 2 shows the results of Examples and Comparative Examples.

As shown in Table 2, the reaction of the example showed a higher yield compared to the reaction of the comparative example when any substrate was used. In the case of the method described in Non-Patent Document 5, which is a comparative example, an expensive cobalt complex was used as the catalyst for the cyclization reaction, and 1 atm pure oxygen was used as the oxygen supply source. In contrast, in the examples according to the method of the present invention, a catalyst containing a chemically stable manganese complex (Mn (acac) ₃ ) is used as a catalyst for the cyclization reaction, and oxygen in the air (0.21) is used as the oxygen supply source. A high yield was achieved using each of the oxygen partial pressures of atoms). Therefore, according to the method of the present invention, 4,5-dihydroisoxazole derivatives can be produced under low reaction cost and mild reaction conditions.

  In addition, this invention is not limited to an above-described Example, Various modifications are included. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the configurations described. Moreover, it is possible to add, delete, and / or replace another configuration with respect to a part of the configuration of each embodiment.

Claims (12)

Formula (I) or (II):

[Where:
R ¹ is substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₂₀ alkyl, carboxyl, substituted or unsubstituted amido or substituted or unsubstituted A substituted ester,
R ² is hydrogen, hydroxyl, a substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or C ₄ -C ₂₀ cycloalkynyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl substituted, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy Substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, heterocycloalkoxy 3-6 membered substituted or unsubstituted, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxycarbonyl, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₆ acyloxy,
R ³ and R ⁴ are independently of each other hydrogen, substituted or unsubstituted C _{1 to} C ₂₀ alkyl, substituted or unsubstituted C _{2 to} C ₂₀ alkenyl, substituted or unsubstituted C _{2 to} C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, the hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or heteroaryl -C ₁ -C ₂₀ alkyl substituted or unsubstituted 5-15 membered, Or
R ² and R ³ or R ³ and R ⁴ together with the carbon atom to which they are attached are substituted or unsubstituted C _{5 to} C ₆ cycloalkyl, substituted or unsubstituted C _{5 to} C ₆ cycloalkenyl. , substituted or unsubstituted C ₅ -C ₆ cycloalkenyl, or form a substituted or unsubstituted 5-6 membered heterocycloalkyl. ]
A method for producing a compound represented by the following:
Formula (III) or Formula (IV):

[Wherein, R ¹ , R ² , R ³ and R ⁴ have the same definitions. ]
In the presence of a catalyst containing manganese in an amount ranging from 0.0001 to 0.01 molar equivalents relative to the total amount of the compound represented by formula (III) or (IV). Reacting to obtain a cyclized product, a cyclization step;
Said method.   2. The method according to claim 1, wherein the catalyst containing manganese is a catalyst containing a manganese complex.   The catalyst including the manganese complex includes a β-diketonate, a carboxylate, an alkoxylate, a halide complex, a manganese complex having a nitrate ion, a sulfate ion, or a phosphate ion as a ligand, or a mixture of one or more thereof. The method according to claim 2.   4. The method of claim 3, wherein the catalyst comprising a manganese complex comprises manganese (III) acetylacetonate, manganese (III) acetate, manganese (II) acetylacetonate or manganese (II) acetate. 5. The method of claim 4, wherein the manganese complex-containing catalyst comprises manganese (III) acetylacetonate or manganese (III) acetate. 6. The method of claim 5, wherein the catalyst comprising a manganese complex comprises manganese (III) acetylacetonate. The cyclization step includes methanol, ethanol, n-propanol, isopropanol, 2-butanol, ethylene glycol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2- The process according to any one of claims 1 to 6 , which is carried out in the presence of propanol and an alcohol-based solvent selected from the group consisting of one or more combinations thereof. The method according to any one of claims 1 to 7 , wherein the cyclization step is performed at room temperature. The cyclization product obtained by the said cyclization process and a reducing agent are made to react, and the reduction process of obtaining the compound represented by Formula (I) or (II) is further included in any one of Claims 1-8 The method according to item 1. 10. The method of claim 9 , wherein the reducing agent is selected from the group consisting of sodium thiosulfate, sodium sulfite, sodium dithionite, dimethyl sulfide and triphenylphosphine, and one or more combinations thereof. R ¹ is a substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkynyl, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₂₀ Alkyl,
R ² is hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, substituted or C ₄ -C ₂₀ cycloalkynyl unsubstituted, substituted or unsubstituted C ₇ -C ₂₀ cycloalkylalkyl, substituted or unsubstituted C ₄ -C ₂₀ aryl substituted, substituted or unsubstituted C ₅ -C ₂₀ arylalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl substituent, a substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₆ acyloxy,
R ³ and R ^4, independently of one another, hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₂ -C ₂₀ alkenyl, substituted or unsubstituted C ₂ -C ₂₀ alkynyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₂₀ cycloalkenyl, C ₄ -C ₂₀ cycloalkynyl substituted or unsubstituted, substituted or unsubstituted C ₇ -C ₂₀ cycloalkyl alkyl alkyl, C ₄ -C ₂₀ aryl, or substituted or unsubstituted C ₅ -C ₂₀ arylalkyl substituted or unsubstituted,
In R ¹ , R ² , R ³ and R ⁴ , when the group is substituted, the substituents are each independently halogen, cyano, nitro, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₆ cycloalkenyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₅ aryl Oxy, C ₇ -C ₂₀ arylalkyloxy, 5-15 membered heteroaryloxy, 5-15 membered heteroaryl-C ₁ -C ₉ alkyloxy, C ₁ -C ₆ alkoxycarbonyl, C ₃ -C ₆ cyclo alkoxycarbonyl, and one or more monovalent group selected from the group consisting of C ₁ -C ₆ acyloxy,
The method according to any one of claims 1 to 10 . 12. In the cyclization step, the reaction is carried out in an open system in the presence of air, and the pressure of oxygen applied to the reaction is in the range of 0.2 to 0.25 atm. Method.