JP2008120819A - Manufacturing method of substituted aromatic compound, and intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an efficient manufacturing method of various aromatic compounds which are useful as intermediates of medicines, agrichemicals, and commodity chemicals, by dissolving problems regarding to Smiles rearrangement reaction and applying the resultant Smiles reaction. <P>SOLUTION: The compound is represented by formula (I) (wherein ring A represents an aromatic isocyclic or heterocyclic ring and it may have a substituent. X represents -O- or the like and Y represents -NR<SP>1</SP>- or the like, and B represents an aromatic isocyclic or heterocyclic ring and it may have a substituent, or an ethylene group which may be substituted). The method for manufacturing the above compound or its salt wherein the compound or its salt is subjected to Smiles rearrangement reaction, characterized in that the Smiles rearrangement reaction is carried out in an amide solvent in the presence of a basic hydroxide. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing a substituted aromatic compound utilizing a Smiles rearrangement reaction and a production intermediate. More specifically, the present invention provides a simple method for producing a substituted aromatic compound as a production intermediate for pharmaceuticals, agricultural chemicals, or many general-purpose chemicals, which can carry out a Smiles rearrangement reaction under mild and safe conditions, The present invention relates to a production intermediate useful for such a production method.

The Smiles rearrangement reaction is a reaction in which an atom bonded to an aromatic ring is substituted with another atom by a nucleophilic substitution reaction in the molecule. As atoms involved in the rearrangement, hetero atoms such as carbon, nitrogen, oxygen, sulfur, phosphorus, and iodine are generally known. The direction of rearrangement is generally from sulfur to carbon, nitrogen, oxygen, oxygen to carbon, nitrogen, oxygen, sulfur, phosphorus to carbon, and iodine to oxygen.
The rearrangement is generally carried out in a solvent in the presence of a base. As a combination of a base and a solvent necessary for rearrangement, several cases have been known so far (Non-patent Document 1). For example, an aqueous solution of sodium hydroxide or potassium hydroxide, a methanol solution, an ethanol solution, an acetone solution, a methanol solution of sodium methoxide, or an ethanol solution of sodium ethoxide is generally used. However, in these cases, the activity of the reaction is low and generally a high temperature reaction is required, and the reaction may not proceed depending on the substrate. As an alternative method, a strong base such as an ether solution of butyl lithium or a dimethylformamide solution of sodium hydride is used.

On the other hand, there are many aromatic compounds that are useful as intermediates for the production of pharmaceuticals, agricultural chemicals, or many general-purpose chemicals, and various methods including the Smiles rearrangement reaction are known as their production methods. .
For example, aniline derivatives are important compounds that can be used as chemicals and pharmaceuticals, and are often important production intermediates. As a method for producing an aniline derivative, a few methods for converting from a phenol derivative are known, but all have drawbacks such as danger and toxicity. For example, when a phenol derivative is activated with 4-chloro-2-phenylquinazoline, a high temperature of about 300 ° C. and basic conditions are required for the rearrangement reaction. When a phenol derivative is activated with diethyl phosphate, toxic diethyl chlorophosphate or potassium metal in liquid ammonia is used. The Bucherer reaction is limited to a heterocyclic ring such as naphthalene and hydroxyquinoline, and is a heating reaction under pressure with ammonium sulfite (Non-patent Document 2). In addition, as an example of conversion from a phenol derivative to an aniline derivative using a Smiles rearrangement reaction, Non-Patent Document 3 discloses that a 2-aryloxyacetamide derivative is isolated from a phenol derivative and 2-hydroxy-N-arylamine A three-step method for obtaining an aniline derivative after isolating the cetamide derivative has been proposed. Non-patent document 2 and Patent document 1 describe from phenol derivatives to 2-hydroxy-N-arylacetamide derivatives. There is a report on a synthesis method in which these two steps are made into one pot. However, the step of converting the 2-hydroxy-N-aryl acetamide derivative to the aniline derivative is not a one-pot, and complicated operation is required for purification and isolation of the 2-hydroxy-N-aryl acetamide derivative. Therefore, it is not an industrially simple synthesis method. In addition, there is a problem that a high temperature is required to increase the reactivity in the Smiles rearrangement reaction step. Furthermore, an expensive additive such as cesium carbonate is used to increase the reactivity in the step of the alkylation reaction in which the phenol derivative is converted into the 2-hydroxy-N-arylacetamide derivative. Furthermore, sodium hydride, which is dangerous to handle, is used as a base.
Further, among aniline derivatives, 6-amino-1-tetralone derivatives are useful as skeletons for chemicals and pharmaceuticals, and two methods are known as production methods thereof. That is, according to Non-Patent Document 4 and Non-Patent Document 5, nitration of benzoylpropionic acid leads to the meta-nitro form, leads to the corresponding amino form by catalytic reduction, and subsequently acetylates the amine obtained with acetic anhydride. The carbonyl group is reduced by catalytic reduction. In addition, it is led to an acid chloride form with phosphorus pentachloride, and a Friedel-Crafts reaction is performed with aluminum chloride to construct a tetralone skeleton. Finally, a method for synthesizing the target 6-amino-1-tetralone derivative by hydrolysis with hydrochloric acid is proposed. Further, according to Non-Patent Document 6; Non-Patent Document 4; Non-Patent Document 7 and Non-Patent Document 8, tetralin is converted to 6-acetyltetralin by acetyl chloride and aluminum chloride, converted to an oxime, and then converted into oxime by a Beckmann rearrangement reaction. Next, the 1-position of tetralin is carbonylated with chromic acid, acetic anhydride and acetic acid. Finally, a method for synthesizing the target 6-amino-1-tetralone derivative by hydrolysis with hydrochloric acid is proposed. However, neither of the two known methods is long and simple, and cannot be said to be simple. In addition, it has drawbacks such as dangers of nitrating agents and catalytic reduction reactions, and toxicity such as phosphorus pentachloride and chromic acid.
In addition, 6-aminoquinaldine derivatives are useful as skeletons for chemicals and pharmaceuticals, and a method for reducing the 6-nitroquinaldine derivatives is common (Patent Document 2). In Non-Patent Document 9, the target 6-nitroquinaldine is synthesized by refluxing para-nitroaniline and crotonaldehyde in concentrated hydrochloric acid. However, the yield is low and not satisfactory.
US Pat. No. 5,817,874 JP-A-63-201167 Organic Reacts, Vol. 18, p. 99, 1970 Tetrahedron, 53, 6303, 1997 Journal of the Chemical Society Perkin Transactions I (J. Chem. Soc. Perkin Trans., I), p. 767, 1990 Journal of Organic Chemistry (J. Org. Chem.), 27, 70, 1962 Organic Synthetics Collective Volume II (Org. Syntheses, Coll. Vol. II), p. 81, 1943 Journal of Medicinal Chemistry (Vol. 19, 472, 1976) Journal of the Chemical Society (J. Chem. Soc.), P. 2399, 1949 Journal of the American Chemical Society (J. Am. Chem. Soc.), 65, 1097, 1943 Polymer Bulletin, 42, 175, 1999

As described above, the problem of the Smiles rearrangement reaction is low reactivity. In order to increase the reactivity, when the reaction is performed at a high temperature, it cannot be applied to a thermally unstable compound. This means that the advantages of the Smiles rearrangement reaction, in which atoms bonded to the aromatic ring can be easily exchanged, cannot be used effectively. In addition, when a strong base such as butyl lithium or sodium hydride is used as a base to increase reactivity, it is necessary to be careful in handling due to dangers such as ignition, and it is industrially safe. It is difficult to say that it is suitable as a manufacturing method.
An object of the present invention is to solve these problems in the Smiles rearrangement reaction, and to use various smiley compounds useful as production intermediates for pharmaceuticals, agricultural chemicals, or many general-purpose chemicals using the Smiles rearrangement reaction. It is to manufacture efficiently.
That is, one object of the present invention is to enable the Smiles rearrangement reaction to be performed using a safe reagent under mild conditions.
Another object of the present invention is to provide a production method for easily converting a phenol derivative to an aniline derivative using a mildly rearranged reaction using a generally available phenol derivative as a raw material. Is to provide.
A further object of the present invention is to provide a production method for converting a 6-hydroxy-1-tetralone derivative into a 6-amino-1-tetralone derivative using a Smiles rearrangement reaction as a raw material and a production intermediate thereof. is there.
Furthermore, another object of the present invention is to use a 6-hydroxyquinaldine derivative, which is readily available, as a raw material, by utilizing the Smiles rearrangement reaction and simultaneously carrying out N-oxidation, thereby producing 6-amino It is to provide a production method for easily converting into a quinaldine N-oxide derivative and a production intermediate thereof.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have achieved a mild and safe condition for the first problem by a novel combination of a basic hydroxide and an amide solvent. We found the conditions under which the Smiles rearrangement reaction proceeds.
In addition, in the case of 2-arylacetamide having an electron withdrawing group, it has been found that a Smiles rearrangement reaction can be carried out under mild temperature conditions without using dangerous sodium hydride. Based on this knowledge, for the second problem, the three steps from the phenol derivative to the aniline derivative were carried out in one pot, and it was simple and industrially superior using an inexpensive, safe and non-toxic reagent. It has been found that aniline derivatives can be produced by this method.
Furthermore, for the third problem, using the Smiles rearrangement reaction, the 6-hydroxy-1-tetralone derivative is used as a raw material in two steps through two new production intermediates. The present inventors have found that 6-amino-1-tetralone derivatives can be easily produced by a simple and industrially excellent method using a cheap, safe and non-toxic reagent.
Furthermore, for the fourth problem, by inducing a 6-hydroxyquinaldine derivative into an N-oxide form, the activity of the Smiles rearrangement reaction is increased, leading to the 6-aminoquinaldine N-oxide derivative. It has been found that it can be produced by a simple and industrially superior method using three steps in one pot, and using an inexpensive, safe and non-toxic reagent.
As a result of further investigation based on such knowledge, the present invention has been completed.

［式中、Ａ環は置換基を有していてもよい芳香族同素または複素環を示す。Ｘは−Ｏ−；−Ｓ−；−Ｓ（Ｏ）−；−Ｓ（Ｏ）₂−；−Ｐ⁺Ｒ^1xＲ^2x− （Ｒ^1xおよびＲ^2xはそれぞれ水素原子または置換基を示す）；−I⁺−または−ＮＲ¹− （Ｒ¹は水素原子または置換基を示す）を、Ｙは−Ｏ−；−Ｓ−；−Ｓ（Ｏ）−；−Ｓ（Ｏ）₂−；−Ｐ⁺Ｒ^1xxＲ^2xx−（Ｒ^1xxおよびＲ^2xxはそれぞれ水素原子または置換基を示す）；−I⁺−；−ＮＲ^1a−（Ｒ^1aは水素原子または置換基を示す）または−ＣＲ^1''Ｒ^2''− （Ｒ^1''およびＲ^2''はそれぞれ水素原子または置換基を示す）を示す。Ｂは置換基を有していてもよい芳香族同素または複素環、あるいは置換されていてもよいエチレン基を示す。］で表される化合物またはその塩をスマイルス転位反応に付す式（II）

［式中、各記号は上記と同意義である。］で表される置換芳香族化合物またはその塩の製造法であって、塩基性の水酸化物の存在下、アミド系溶媒中でスマイルス転位反応を行うことを特徴とする式（II）で表される置換芳香族化合物またはその塩の製造法；
（２）Ａ環が置換基を有していてもよい芳香族同素環である上記（１）記載の製造法；
（３）Ｘが−Ｏ−；−Ｓ−；−Ｓ（Ｏ）−または−Ｓ（Ｏ）₂−である上記（１）記載の製造法；
（４）Ｙが−ＮＲ¹−〔Ｒ¹は水素原子または置換基を示す〕である上記（１）記載の製造法；
（５）Ｂが置換されていてもよいエチレン基である上記（１）記載の製造法；
（６）式（I）で表される化合物またはその塩が、式(III）

［式中、Ａ環は置換基を有していてもよい芳香族同素または複素環を示す。Ｚは置換されていてもよいメチレン基を示し、Ｗは酸素原子あるいは硫黄原子を示し、Ｒ¹は水素原子または置換基を示す。］で表される化合物またはその塩であり、式（II）で表される化合物またはその塩が、式（IV）

［式中、各記号は上記と同意義である。］で表される化合物またはその塩である上記（１）記載の製造法；
（７）Ａ環が電子吸引基を有し、さらに置換基を有していてもよい芳香族同素または複素環である上記（６）記載の製造法；
（８）Ａ環が電子吸引基を有し、さらに置換基を有していてもよい芳香族同素環である上記（７）記載の製造法；
（９）Ｚが２個のＣ_1-4アルキル基で置換されたメチレン基である上記（６）記載の製造法；
（１０）Ｒ¹が水素原子である上記（６）記載の製造法；
（１１）電子吸引基がアシル基である上記（７）記載の製造法；
（１２）式（III）で表される化合物またはその塩が、式(VII)

［式中、Ａ環は置換基を有していてもよい芳香族同素または複素環を、Ｗは酸素原子あるいは硫黄原子を示す。］で表される化合物またはその塩を式(VIII)

［式中、Ｑは脱離基を示し、Ｚは置換されていてもよいメチレン基を示し、Ｒ¹は水素原子または置換基を示す。］で表されるアルキル化剤またはその塩と反応させて得られた化合物またはその塩である上記（６）記載の製造法；
（１３）Ｑがハロゲン原子である上記（１２）記載の製造法；
（１４）塩基性の水酸化物の存在下に、式（VII）で表わされる化合物またはその塩を式(VIII)で表されるアルキル化剤またはその塩と反応させることを特徴とする上記（１２）記載の製造法；
（１５）アミド系溶媒の存在下に、式（VII）で表わされる化合物またはその塩を式(VIII)で表されるアルキル化剤またはその塩と反応させることを特徴とする上記（１２）記載の製造法；
（１６）塩基性の水酸化物およびアミド系溶媒の存在下に、式（VII）で表わされる化合物またはその塩を式(VIII)で表されるアルキル化剤またはその塩と反応させることを特徴とする上記（１２）記載の製造法；
（１７）生成する式（III）で表される化合物またはその塩を単離しないことを特徴とする上記（１２）記載の製造法；
（１８）上記（６）記載の製造法で得られた式（IV）で表される化合物またはその塩を加水分解反応に付すことを特徴とする、式(IＸ)

［式中、Ａ環は置換基を有していてもよい芳香族同素または複素環を示す。Ｒ¹は水素原子または置換基を示す。］で表されるアニリン誘導体またはその塩の製造法；
（１９）塩基性の水酸化物の存在下に加水分解反応を行うことを特徴とする上記（１８）記載の製造法；
（２０）アミド系溶媒の存在下に加水分解反応を行うことを特徴とする上記（１８）記載の製造法；
（２１）塩基性の水酸化物およびアミド系溶媒の存在下に加水分解反応を行うことを特徴とする上記（１８）記載の製造法；
（２２）生成する式（IV）で表される化合物またはその塩を単離しないことを特徴とする上記（１８）記載の製造法；
（２３）上記（１２）記載の製造法で得られた式（IV）で表される化合物またはその塩を加水分解反応に付すことを特徴とする、式(IＸ)

［式中、Ａ環は置換基を有していてもよい芳香族同素または複素環を示す。Ｒ¹は水素原子または置換基を示す。］で表されるアニリン誘導体またはその塩の製造法；
（２４）塩基性の水酸化物の存在下に加水分解反応を行うことを特徴とする上記（２３）記載の製造法；
（２５）アミド系溶媒の存在下に加水分解反応を行うことを特徴とする上記（２３）記載の製造法；
（２６）塩基性の水酸化物およびアミド系溶媒の存在下に加水分解反応を行うことを特徴とする上記（２３）記載の製造法；
（２７）生成する式（III）で表される化合物またはその塩を単離しないことを特徴とする上記（２３）記載の製造法；
（２８）生成する式（IV）で表される化合物またはその塩を単離しないことを特徴とする上記（２３）記載の製造法；
（２９）生成する式（IV）で表される化合物またはその塩を単離しないことを特徴とする上記（２７）記載の製造法；
（３０）塩基性の水酸化物がアルカリ金属の水酸化物である上記（１）、（１４）、（１６）、（１９）、（２１）、（２４）または（２６）記載の製造法；
（３１）塩基性の水酸化物が水酸化ナトリウムまたは水酸化カリウムである上記（１）、（１４）、（１６）、（１９）、（２１）、（２４）または（２６）記載の製造法；
（３２）アミド系溶媒が鎖状アミド系溶媒である上記（１）、（１５）、（１６）、（２０）、（２１）、（２５）または（２６）記載の製造法；
（３３）アミド系溶媒がＮ，Ｎ−ジメチルホルムアミドまたはＮ，Ｎ−ジメチルアセタミドである上記（１）、（１５）、（１６）、（２０）、（２１）、（２５）または（２６）記載の製造法；
（３４）式（Ｘ）

［式中、Ｚは置換されていてもよいメチレン基を示し、Ｃ…Ｃ…Ｃは置換基を有してもよい炭素鎖を示し、 Ｒ¹、Ｒ²、Ｒ^2aおよびＲ^2bは、同一または異なって、各々、水素原子または置換基を示す。Ｃ…Ｃ…Ｃの炭素鎖の結合は、単結合もしくはどちらかが二重結合であってもよい。］で表される２−アリールオキシアセタミド誘導体またはその塩；
（３５）式（ＸI）

［式中、Ｚは置換されていてもよいメチレン基を示し、Ｃ…Ｃ…Ｃは置換基を有してもよい炭素鎖を示し、 Ｒ¹、Ｒ²、Ｒ^2aおよびＲ^2bは、同一または異なって、各々、水素原子または置換基を示す。Ｃ…Ｃ…Ｃの炭素鎖の結合は、単結合もしくはどちらかが二重結合であってもよい。］で表される２−ヒドロキシ−Ｎ−アリールアセタミド誘導体またはその塩；
（３６）式（ＸII）

［式中、Ｃ…Ｃ…Ｃは置換基を有してもよい炭素鎖を示し、 Ｒ²、Ｒ^2aおよびＲ^2bは同一または異なって、各々、水素原子または置換基を示す。Ｃ…Ｃ…Ｃの炭素鎖の結合は、単結合もしくはどちらかが二重結合であってもよい。］で表される化合物またはその塩を、式（VIII）

［式中、Ｑは脱離基を示し、Ｚは置換されていてもよいメチレン基を示し、Ｒ¹は、水素原子または置換基を示す。］で表されるアルキル化剤またはその塩と反応させることを特徴とする上記（３４）記載の２−アリールオキシアセタミド誘導体またはその塩の製造法；
（３７）上記（３６）記載の製造法で得られた２−アリールオキシアセタミド誘導体またはその塩をスマイルス転位反応に付すことを特徴とする上記（３５）記載の２−ヒドロキシ−Ｎ−アリールアセタミド誘導体またはその塩の製造法；
（３８）上記（３７）記載の製造法で得られた２−ヒドロキシ−Ｎ−アリールアセタミド誘導体またはその塩を加水分解反応に付すことを特徴とする式（ＸIV）

［式中、Ｃ…Ｃ…Ｃは置換基を有してもよい炭素鎖を示し、Ｒ¹、Ｒ²、Ｒ^2aおよびＲ^2bは同一または異なって、各々、水素原子または置換基を示す。Ｃ…Ｃ…Ｃの炭素鎖の結合は、単結合もしくはどちらかが二重結合であってもよい。］で表される化合物またはその塩の製造法；
（３９）式

で示される基が式

［式中、Ｒ²、Ｒ^2ａ、Ｒ^2ｂ、Ｒ^2ｃおよびＲ^2ｄは、同一または異なって、水素原子または置換基を、Ｒ³はC₁₋₆アルキル基を示す］で示される基である上記（６）記載の製造法；
（４０）式（XV）

［式中、Ｚは置換されていてもよいメチレン基を、Ｒ¹、Ｒ²、Ｒ^2ａ、Ｒ^2ｂ、Ｒ^2ｃおよびＲ^2ｄは、同一または異なって、水素原子または置換基を、Ｒ³はC₁₋₆アルキル基を示す］で表される化合物またはその塩；
（４１）式（XVI）

［式中、Ｚは置換されていてもよいメチレン基を、Ｒ¹、Ｒ²、Ｒ^2ａ、Ｒ^2ｂ、Ｒ^2ｃおよびＲ^2ｄは、同一または異なって、水素原子または置換基を、Ｒ³はC₁₋₆アルキル基を示す］で表される化合物またはその塩；
（４２）式（XVII）

［式中、Ｒ²、Ｒ^2ａ、Ｒ^2ｂ、Ｒ^2ｃおよびＲ^2ｄは、同一または異なって、水素原子または置換基を、Ｒ³はC₁₋₆アルキル基を示す］で表される化合物またはその塩；
（４３）式（XIX）

［式中、Ｚは置換されていてもよいメチレン基を、Ｒ¹、Ｒ²、Ｒ^2ａ、Ｒ^2ｂ、Ｒ^2ｃおよびＲ^2ｄは、同一または異なって、水素原子または置換基を、Ｒ³はC₁₋₆アルキル基を示す］で表される化合物またはその塩；
（４４）式（XX）

［式中、Ｚは置換されていてもよいメチレン基を、Ｒ¹、Ｒ²、Ｒ^2ａ、Ｒ^2ｂ、Ｒ^2ｃおよびＲ^2ｄは、同一または異なって、水素原子または置換基を、Ｒ³はC₁₋₆アルキル基を示す］で表される化合物またはその塩；
（４５）上記（４１）記載の化合物またはその塩をスマイルス転位反応に付すことを特徴とする上記（４０）記載の化合物またはその塩の製造法；
（４６）上記（４２）記載の化合物またはその塩と式（VIII）

［式中、Ｑは脱離基を、Ｚは置換されていてもよいメチレン基を、Ｒ¹は水素原子または置換基を示す。］で表されるアルキル化剤またはその塩とを反応させることを特徴とする、上記（４１）記載の化合物またはその塩の製造法；
（４７）上記（４３）記載の化合物またはその塩をＮ−オキシド反応に付すことを特徴とする上記（４１）記載の化合物またはその塩の製造法；
（４８）式（XVIII）

［式中、Ｒ²、Ｒ^2ａ、Ｒ^2ｂ、Ｒ^2ｃおよびＲ^2ｄは、同一または異なって、水素原子または置換基を、Ｒ³はC₁₋₆アルキル基を示す］で表される化合物またはその塩をＮ−オキシド反応に付すことを特徴とする上記（４２）記載の化合物またはその塩の製造法；
（４９）式（XVIII）

［式中、Ｒ²、Ｒ^2ａ、Ｒ^2ｂ、Ｒ^2ｃおよびＲ^2ｄは、同一または異なって、水素原子または置換基を、Ｒ³はC₁₋₆アルキル基を示す］で表される化合物またはその塩をＮ−オキシド反応に付して、上記（４２）記載の化合物またはその塩を得、該化合物またはその塩を式（VIII）

［式中、Ｑは脱離基を、Ｚは置換されていてもよいメチレン基を、Ｒ¹は水素原子または置換基を示す。］で表されるアルキル化剤またはその塩と反応させて、上記（４１）記載の化合物またはその塩を得、該化合物またはその塩をスマイルス転位反応に付すことを特徴とする上記（４０）記載の化合物またはその塩の製造法；
（５０）上記（４２）記載の化合物またはその塩を単離しないことを特徴とする上記（４９）記載の製造法；
（５１）上記（４１）記載の化合物またはその塩を単離しないことを特徴とする上記（４９）記載の製造法；
（５２）上記（４２）記載の化合物またはその塩および上記（４１）記載の化合物またはその塩を単離しないことを特徴とする上記（４９）記載の製造法；
（５３）上記（４３）記載の化合物またはその塩をＮ−オキシド反応に付して、上記（４１）記載の化合物またはその塩を得、該化合物またはその塩をスマイルス転位反応に付すことを特徴とする上記（４０）記載の化合物またはその塩の製造法；
（５４）上記（４１）記載の化合物またはその塩を単離しないことを特徴とする上記（５３）記載の製造法；
（５５）式（XVIII）

［式中、Ｒ²、Ｒ^2ａ、Ｒ^2ｂ、Ｒ^2ｃおよびＲ^2ｄは、同一または異なって、水素原子または置換基を、Ｒ³はC₁₋₆アルキル基を示す］で表される化合物またはその塩と式（VIII）

［式中、Ｑは脱離基を、Ｚは置換されていてもよいメチレン基を、Ｒ¹は水素原子または置換基を示す。］で表されるアルキル化剤またはその塩とを反応させることを特徴とする上記（４３）記載の化合物またはその塩の製造法；
（５６）上記（４３）記載の化合物またはその塩をスマイルス転位反応に付すことを特徴とする上記（４４）記載の化合物またはその塩の製造法；など
を提供するものである。 That is, the present invention
(1) Formula (I)

[In the formula, A ring represents an aromatic allotrope or hetero ring which may have a substituent. X is —O—; —S—; —S (O) —; —S (O) ₂ —; —P ⁺ R ^1x R ^2x — (R ^1x and R ^2x are each a hydrogen atom or a substituent); —I ⁺ — or —NR ¹ — (R ¹ represents a hydrogen atom or a substituent), Y represents —O—; —S—; —S (O) —; —S (O) ₂ —; ⁺ R ^1xx R ^2xx- (R ^1xx and R ^2xx each represent a hydrogen atom or a substituent); -I ⁺ -; -NR ^1a- (R ^1a represents a hydrogen atom or a substituent) or -CR ^{1 ''} R ^{2 ″} − (R ^{1 ″} and R ^{2 ″} each represent a hydrogen atom or a substituent). B represents an aromatic allotrope or heterocyclic ring which may have a substituent, or an ethylene group which may be substituted. Or the salt thereof is subjected to a Smiles rearrangement reaction (II)

[Wherein each symbol is as defined above. Wherein the Smiles rearrangement reaction is carried out in an amide solvent in the presence of a basic hydroxide. A process for producing a substituted aromatic compound or a salt thereof;
(2) The production method according to the above (1), wherein the ring A is an aromatic homocyclic ring which may have a substituent;
(3) The production method according to the above (1), wherein X is -O-; -S-; -S (O)-or -S (O) _2- .
(4) The production method according to the above (1), wherein Y is —NR ¹ — [R ¹ represents a hydrogen atom or a substituent];
(5) The production method according to the above (1), wherein B is an optionally substituted ethylene group;
(6) The compound represented by the formula (I) or a salt thereof is represented by the formula (III)

[In the formula, A ring represents an aromatic allotrope or hetero ring which may have a substituent. Z represents an optionally substituted methylene group, W represents an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a substituent. Or a salt thereof, wherein the compound represented by the formula (II) or a salt thereof is represented by the formula (IV):

[Wherein each symbol is as defined above. ] The manufacturing method of the said (1) description which is a compound represented by these, or its salt;
(7) The production method according to the above (6), wherein the A ring has an electron withdrawing group and may further have a substituent, an aromatic allotrope or heterocycle;
(8) The production method according to the above (7), wherein the ring A has an electron withdrawing group and is an aromatic homocyclic ring which may further have a substituent;
(9) The production method according to the above (6), wherein Z is a methylene group substituted with two C _1-4 alkyl groups;
(10) The production method of the above (6), wherein R ¹ is a hydrogen atom;
(11) The production method according to the above (7), wherein the electron withdrawing group is an acyl group;
(12) The compound represented by the formula (III) or a salt thereof is represented by the formula (VII)

[Wherein, A ring represents an aromatic allotrope or heterocyclic ring which may have a substituent, and W represents an oxygen atom or a sulfur atom. Or a salt thereof is represented by the formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. ] The manufacturing method of the said (6) description which is the compound or its salt obtained by making it react with the alkylating agent represented by this, or its salt;
(13) The process according to the above (12), wherein Q is a halogen atom;
(14) In the presence of a basic hydroxide, the compound represented by the formula (VII) or a salt thereof is reacted with an alkylating agent represented by the formula (VIII) or a salt thereof 12) the production method as described;
(15) The above (12), wherein the compound represented by the formula (VII) or a salt thereof is reacted with the alkylating agent represented by the formula (VIII) or a salt thereof in the presence of an amide solvent. Manufacturing method of
(16) A reaction of a compound represented by the formula (VII) or a salt thereof with an alkylating agent represented by the formula (VIII) or a salt thereof in the presence of a basic hydroxide and an amide solvent. And the production method according to the above (12);
(17) The production method according to the above (12), wherein the compound represented by formula (III) or a salt thereof is not isolated;
(18) A compound represented by the formula (IV) obtained by the production method described in the above (6) or a salt thereof is subjected to a hydrolysis reaction, wherein the formula (IX)

[In the formula, A ring represents an aromatic allotrope or hetero ring which may have a substituent. R ¹ represents a hydrogen atom or a substituent. A method for producing an aniline derivative represented by the formula:
(19) The production method according to the above (18), wherein the hydrolysis reaction is carried out in the presence of a basic hydroxide;
(20) The process according to the above (18), wherein the hydrolysis reaction is carried out in the presence of an amide solvent;
(21) The process according to (18) above, wherein the hydrolysis reaction is carried out in the presence of a basic hydroxide and an amide solvent;
(22) The production method according to the above (18), wherein the compound represented by formula (IV) or a salt thereof is not isolated;
(23) A compound represented by the formula (IV) obtained by the production method described in the above (12) or a salt thereof is subjected to a hydrolysis reaction, wherein the formula (IX)

[In the formula, A ring represents an aromatic allotrope or hetero ring which may have a substituent. R ¹ represents a hydrogen atom or a substituent. A method for producing an aniline derivative represented by the formula:
(24) The production method according to the above (23), wherein the hydrolysis reaction is performed in the presence of a basic hydroxide;
(25) The production method according to the above (23), wherein the hydrolysis reaction is carried out in the presence of an amide solvent;
(26) The production method according to the above (23), wherein the hydrolysis reaction is carried out in the presence of a basic hydroxide and an amide solvent;
(27) The production method according to the above (23), wherein the compound represented by the formula (III) or a salt thereof is not isolated;
(28) The production method according to the above (23), wherein the compound represented by the formula (IV) or a salt thereof is not isolated;
(29) The production method according to the above (27), wherein the compound represented by the formula (IV) or a salt thereof is not isolated;
(30) The production method according to (1), (14), (16), (19), (21), (24) or (26), wherein the basic hydroxide is an alkali metal hydroxide. ;
(31) The production according to (1), (14), (16), (19), (21), (24) or (26), wherein the basic hydroxide is sodium hydroxide or potassium hydroxide. Law;
(32) The production method according to the above (1), (15), (16), (20), (21), (25) or (26), wherein the amide solvent is a chain amide solvent;
(33) The above (1), (15), (16), (20), (21), (25) or (25) wherein the amide solvent is N, N-dimethylformamide or N, N-dimethylacetamide 26) the production method described above;
(34) Formula (X)

[In the formula, Z represents an optionally substituted methylene group, C ... C ... C represents an optionally substituted carbon chain, and R ¹ , R ² , R ^2a and R ^2b are the same. Or differently, each represents a hydrogen atom or a substituent. The carbon chain bond of C ... C ... C may be a single bond or one of them may be a double bond. A 2-aryloxyacetamide derivative represented by the formula:
(35) Formula (XI)

[In the formula, Z represents an optionally substituted methylene group, C ... C ... C represents an optionally substituted carbon chain, and R ¹ , R ² , R ^2a and R ^2b are the same. Or differently, each represents a hydrogen atom or a substituent. The carbon chain bond of C ... C ... C may be a single bond or one of them may be a double bond. A 2-hydroxy-N-arylacetamide derivative represented by the formula:
(36) Formula (XII)

[Wherein C ... C ... C represents a carbon chain which may have a substituent, and R ² , R ^2a and R ^2b are the same or different and each represents a hydrogen atom or a substituent. The carbon chain bond of C ... C ... C may be a single bond or one of them may be a double bond. Or a salt thereof is represented by the formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. A method for producing a 2-aryloxyacetamide derivative or a salt thereof according to the above (34), which is reacted with an alkylating agent represented by the formula:
(37) The 2-aryloxyacetamide derivative obtained by the production method described in (36) or a salt thereof is subjected to a Smiles rearrangement reaction, and 2-hydroxy-N- described in (35) above A process for producing an arylacetamide derivative or a salt thereof;
(38) A 2-hydroxy-N-arylacetamide derivative or a salt thereof obtained by the production method described in (37) above is subjected to a hydrolysis reaction (XIV)

[Wherein C ... C ... C represents an optionally substituted carbon chain, and R ¹ , R ² , R ^2a and R ^2b are the same or different and each represents a hydrogen atom or a substituent. The carbon chain bond of C ... C ... C may be a single bond or one of them may be a double bond. Or a salt thereof;
(39) Formula

Is a group represented by the formula

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group. The production method according to (6) above;
(40) Formula (XV)

[Wherein Z represents an optionally substituted methylene group, R ¹ , R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and represent a hydrogen atom or a substituent, and R ³ represents A C _1-6 alkyl group] or a salt thereof;
(41) Formula (XVI)

[Wherein Z represents an optionally substituted methylene group, R ¹ , R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and represent a hydrogen atom or a substituent, and R ³ represents A C _1-6 alkyl group] or a salt thereof;
(42) Formula (XVII)

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group, or Its salt;
(43) Formula (XIX)

[Wherein Z represents an optionally substituted methylene group, R ¹ , R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and represent a hydrogen atom or a substituent, and R ³ represents A C _1-6 alkyl group] or a salt thereof;
(44) Formula (XX)

[Wherein Z represents an optionally substituted methylene group, R ¹ , R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and represent a hydrogen atom or a substituent, and R ³ represents A C _1-6 alkyl group] or a salt thereof;
(45) The process for producing a compound or a salt thereof according to (40), wherein the compound or a salt thereof according to (41) is subjected to a Smiles rearrangement reaction;
(46) The compound of the above (42) or a salt thereof and the formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. A process for producing a compound or a salt thereof according to the above (41), characterized by reacting with an alkylating agent represented by the formula:
(47) The process for producing a compound or a salt thereof according to (41), wherein the compound or a salt thereof according to (43) is subjected to an N-oxide reaction;
(48) Formula (XVIII)

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group, or A process for producing the compound or a salt thereof according to the above (42), wherein the salt is subjected to an N-oxide reaction;
(49) Formula (XVIII)

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group, or The salt is subjected to an N-oxide reaction to obtain the compound of the above (42) or a salt thereof, and the compound or the salt thereof is represented by the formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. Wherein the compound or salt thereof is obtained, and the compound or salt thereof is subjected to a Smiles rearrangement reaction (40) A process for producing the described compound or a salt thereof;
(50) The process according to (49) above, wherein the compound or salt thereof according to (42) above is not isolated;
(51) The process according to (49) above, wherein the compound or salt thereof according to (41) above is not isolated;
(52) The production method according to (49) above, wherein the compound or salt thereof described in (42) and the compound or salt thereof described in (41) are not isolated;
(53) The compound or salt thereof described in (43) above is subjected to an N-oxide reaction to obtain the compound or salt thereof described in (41), and the compound or salt thereof is subjected to a Smiles rearrangement reaction. A process for producing a compound or a salt thereof according to the above (40),
(54) The process according to (53) above, wherein the compound or salt thereof according to (41) above is not isolated;
(55) Formula (XVIII)

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group, or Its salt and formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. And a salt thereof, or a salt thereof;
(56) A method for producing a compound or a salt thereof according to (44), wherein the compound or a salt thereof according to (43) is subjected to a Smiles rearrangement reaction.

As described above, according to the present invention, since the Smiles rearrangement reaction is carried out under mild conditions, even in a thermally unstable compound, an atom bonded to an aromatic ring can be easily obtained using a safe reagent. Can be replaced.
Furthermore, according to the present invention, a highly pure aniline derivative can be produced in a high yield in a single pot using an inexpensive, safe and non-toxic reagent from a phenol derivative that is generally easily available.
Furthermore, according to the present invention, a 6-amino-1-tetralone derivative can be easily synthesized by using a 6-hydroxy-1-tetralone derivative as a raw material and passing through two novel production intermediates. .
Furthermore, according to the present invention, a 6-hydroxyquinaldine derivative is used as a raw material, and a 6-aminoquinaldine N-oxide derivative is easily synthesized by performing three steps in one pot via a novel production intermediate. be able to.

  Examples of the “basic hydroxide” used in the reaction of the present invention include alkali metal or alkaline earth metal hydroxides. Examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, and potassium hydroxide; examples of the alkaline earth metal hydroxide include magnesium hydroxide and calcium hydroxide. The “basic hydroxide” used in the reaction of the present invention is preferably an alkali metal hydroxide, particularly preferably sodium hydroxide or potassium hydroxide, and more preferably sodium hydroxide.

  Examples of the “amide solvent” used in the reaction of the present invention include a chain or cyclic amide solvent. Examples of the “chain amide solvent” include N, N-dimethylformamide, N, N-dimethylacetamide and the like; examples of the “cyclic amide solvent” include 1-methyl-2-pyrrolidone, 1,3- Examples thereof include dimethyl-2-imidazolidinone. As the “amide solvent” used in the reaction of the present invention, “chain amide solvent” is preferable, and N, N-dimethylformamide and N, N-dimethylacetamide are particularly preferable, and N, N— Dimethylacetamide is more preferred.

[式中、I、Ｊ、Ｋ、Ｌ環は、四環性の縮合炭化水素の環を構成し、さらには、I、Ｊ、Ｋ環のうち１個ないしは３個が芳香族環である。芳香族環でない環については、環を形成する結合に二重結合を含んでもよい。]で示される。
上記式（I）、（II）、（III）、（IV）、（VII）および（IX）中、Ａ環で示される「置換基を有していてもよい芳香族同素または複素環」における「芳香族複素環」としては、芳香族単環式複素環（例、フラン、チオフェン、ピロール、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、イミダゾール、ピラゾール、１,２,３−オキサジアゾール、１,２,４−オキサジアゾール、１,３,４−オキサジアゾール、フラザン、１,２,３−チアジアゾール、１,２,４−チアジアゾール、１,３,４−チアジアゾール、１,２,３−トリアゾール、１,２,４−トリアゾール、テトラゾール、ピリジン、ピリミジン、ピリダジン、ピラジン、トリアジンなど）、および芳香族縮合複素環（例、ベンゾフラン、イソベンゾフラン、ベンゾ[b]チオフェン、インドール、イソインドール、１Ｈ−インダゾール、ベンゾイミダゾール、ベンゾオキサゾール、１,２−ベンゾイソチアゾール、１Ｈ−ベンゾトリアゾール、キノリン、イソキノリン、シンノリン、キナゾリン、キノキサリン、フタラジン、ナフチリジン、プリン、プテリジン、カルバゾール、α−カルボリン、β−カルボリン、γ−カルボリン、アクリジン、フェノキサジン、フェノチアジン、フェナジン、フェノキサチイン、チアントレン、フェナントレジン、フェナントロリン、インドリジン、ピロロ[１,２−b]ピリダジン、ピラゾロ[１,５−a]ピリジン、イミダゾ[１,２−a]ピリジン、イミダゾ[１,５−a]ピリジン、イミダゾ[１,２−b]ピリダジン、イミダゾ[１,２−a]ピリジン、イミダゾ[１,５−a]ピリジン、イミダゾ[１,２−b]ピリダジン、イミダゾ[１,２−a]ピリミジン、１,２,４−トリアゾロ[４,３−a]ピリジン、１,２,４−トリアゾロ[４,３−b]ピリダジン等）などが挙げられる。
Ａ環で示される「置換基を有していてもよい芳香族同素または複素環」は、好ましくは「置換基を有していてもよい芳香族同素環」である。
Ａ環で示される「置換基を有していてもよい芳香族同素または複素環」における「芳香族同素または複素環」は上記の通り「縮合環」であってもよい。 In the above formulas (I), (II), (III), (IV), (VII) and (IX), “aromatic allotropes or heterocycles optionally having substituents” represented by A ring Examples of the “aromatic homocyclic ring” in benzene, naphthalene, anthracene, phenanthrene, pyrene, naphthacene, chrysene, triphenylene, indene, indane, tetrahydronaphthalene, 1,2-dihydronaphthalene, 1,4-dihydronaphthalene, Examples thereof include aromatic rings having 6 to 18 carbon atoms such as steroid skeletons (including non-aromatic hydrocarbon rings condensed with phenyl groups).
The steroid skeleton has the formula:

[Wherein, the I, J, K, and L rings constitute a tetracyclic condensed hydrocarbon ring, and one or three of the I, J, and K rings are aromatic rings. For a ring that is not an aromatic ring, the bond forming the ring may include a double bond. ] Is shown.
In the above formulas (I), (II), (III), (IV), (VII) and (IX), “aromatic allotropes or heterocycles optionally having substituents” represented by A ring As the “aromatic heterocycle”, an aromatic monocyclic heterocycle (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2, 3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, etc.), and aromatic condensed heterocycles (eg, benzofuran, isobenzofuran, benzo [b] thiophene, Indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, α- Carboline, β-carboline, γ-carboline, acridine, phenoxazine, phenothiazine, phenazine, phenoxathiin, thianthrene, phenanthresin, phenanthroline, indolizine, pyrrolo [1,2-b] pyridazine, pyrazolo [1,5- a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,5-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyridine, imidazo [1,5- a] pyridine, imidazo [1,2-b] pyridazine, a Midazo [1,2-a] pyrimidine, 1,2,4-triazolo [4,3-a] pyridine, 1,2,4-triazolo [4,3-b] pyridazine, etc.).
The “aromatic allocyclic or heterocyclic ring optionally having substituent (s)” represented by ring A is preferably “the aromatic allocyclic ring optionally having substituent (s)”.
The “aromatic allotrope or heterocycle” in the “aromatic allotrope or heterocycle optionally having a substituent” represented by the A ring may be a “fused ring” as described above.

［式中、Ｃ…Ｃ…Ｃは置換基を有してもよい炭素鎖を示し、Ｃ…Ｃ…Ｃの炭素鎖の結合は、単結合もしくはどちらかが二重結合であってもよい。Ａ’環は芳香族同素または複素環を示す。］で示される６員環を形成していてもよい。
ここで、Ａ’環で示される「芳香族同素または複素環」は、上記Ａ環で示される「置換基を有していてもよい芳香族同素または複素環」における「芳香族同素または複素環」と同意義を示す。 Examples of the “substituent” in the “aromatic allotrope or heterocycle optionally having a substituent” represented by A ring include a lower (C _1-6 ) alkyl group (eg, methyl, ethyl, propyl). , Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C _2-6 ) alkenyl groups [eg, vinyl, allyl, 1-propenyl, 2- Methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.], lower (C _2-6) alkynyl group (eg, ethynyl, 1-flop Pinyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc.), C _3-7 cycloalkyl group (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), C _6-10 aryl group (eg phenyl, α-naphthyl, β-naphthyl etc.) An aromatic heterocyclic group [eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl Flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1, 3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, Naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thi Anthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [ 1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, etc. (I) an aromatic 5- or 6-membered heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, (ii) a heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom Aromatic 5-membered or 6-membered heterocyclic ring having 1 to 3 atoms and benzene ring or aromatic 5-membered or 6-membered member having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom A condensed bicyclic heterocyclic group formed by condensation with an elemental ring, (iii) (1) an aromatic 5- or 6-membered hetero group having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms Condensation 3 formed by condensation of a ring, (2) a benzene ring and (3) an aromatic 5- or 6-membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, or a benzene ring Cyclic heterocyclic group], non-aromatic heterocyclic group (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like, oxygen atom, sulfur such as a non-aromatic heterocyclic group 4-7 membered 1-3 have a hetero atom selected from the atoms), C _{7 - 14} aralkyl group (e.g., benzyl, off Nechiru, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, alpha-naphthylmethyl, alpha-naphthylethyl, beta-naphthylmethyl, C _6-10 aryl -C such beta-naphthylethyl _1-4 alkyl group), amino group, N-monosubstituted amino group [eg, N- (C _1-6 alkyl) amino group such as methylamino, ethylamino, allylamino, cyclohexylamino, phenylamino, etc. N- (C _2-6 alkenyl) amino group, N- (C _3-7 cycloalkyl) amino group, N- (C _6-10 aryl) amino group, etc.], N, N-disubstituted amino group [Example , dimethylamino, diethylamino, dibutylamino, diallyl (allyl) amino, such as N- methyl -N- phenylamino, C _1-6 alkyl groups, C _2-6 alkenyl groups, C _3-7 cycloalkyl And like C _6-10 2 amino group substituted with a substituent selected from aryl groups, amidino group, an acyl group (eg formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, C _2-8 alkanoyl group such as heptanoyl, octanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonoyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, C _3-8 alkenoyl group, C _3-7 cycloalkyl 5- or 6-membered aromatic having 1 to 3 heteroatoms selected from a carbonyl group, a C _3-7 cycloalkenyl-carbonyl group, a C _6-10 aryl-carbonyl group, a nitrogen atom, an oxygen atom, and a sulfur atom Or non-aromatic heterocycle Heterocyclic carbonyl group formed by bonding - carbonyl group), a carbamoyl group, N- monosubstituted carbamoyl group [e.g., methylcarbamoyl, ethylcarbamoyl, cyclohexylcarbamoyl, etc. phenylcarbamoyl of N-(C _1-6 alkyl) Carbamoyl group, N- (C _2-6 alkenyl) carbamoyl group, N- (C _3-7 cycloalkyl) carbamoyl group, N- (C _6-10 aryl) carbamoyl group, etc.], N, N-disubstituted carbamoyl group [Examples: C _1-6 alkyl group, C _2-6 alkenyl group, C _3-7 cycloalkyl group such as dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, diallyl (allyl) carbamoyl, N-methyl-N-phenylcarbamoyl, etc. and C _6-10, such as 2 substituents carbamoyl substituted by groups selected from aryl group, Rufamoiru group, N- monosubstituted sulfamoyl group [e.g., methylsulfamoyl, ethylsulfamoyl, cyclohexyl sulfamoyl, such as phenyl sulfamoyl N-(C _1-6 alkyl) sulfamoyl group, N- (C _{2 -6} alkenyl) sulfamoyl group, N- (C _3-7 cycloalkyl) sulfamoyl group, N- (C _6-10 aryl) sulfamoyl group], N, N-disubstituted sulfamoyl group [eg, dimethylsulfamoyl, C _1-6 alkyl group, C _2-6 alkenyl group, C _3-7 cycloalkyl group such as diethyl sulfamoyl, dibutyl sulfamoyl, diallyl (allyl) sulfamoyl, N-methyl-N-phenylsulfamoyl And a sulfamoyl group substituted with two substituents selected from a C _6-10 aryl group], a carboxyl group, a lower group (C _{1- 6} ) Alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), oxo , Hydroxyl group, lower (C _1-6 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.), lower (C _2-6 ) alkenyloxy group [e.g., allyl (allyl) oxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy, etc.], C _3-7 cycloalkyl group (e.g., cyclopropyloxy, Shikurobuchi Oxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), C _6-10 aryloxy group (e.g., phenoxy, naphthyloxy), C _{7 - 14} aralkyloxy group (e.g., phenyl -C _1-4 alkyloxy, C _6-10 aryl-C _1-4 alkyloxy group such as naphthyl-C _1-4 alkyloxy), mercapto group, lower (C _1-6 ) alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, Butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, etc.), C _7-14 aralkylthio groups (eg, phenyl-C _1-4 alkylthio, naphthyl-C _{1- 4,} such as C _6-10 aryl -C _1-4 alkylthio group such as alkylthio), C _6-10 aryl O groups (e.g., phenylthio, naphthylthio, etc.), lower (C _1-6) alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, propyl sulfinyl, isopropyl sulfinyl, butylsulfinyl, isobutyl-sulfinyl, sec- butylsulfinyl, tert- butyl sulfinyl, pentylsulfamoyl nyl, iso pentylsulfamoyl alkylsulfinyl, neo pentylsulfamoyl alkylsulfinyl, hexyl sulfinyl, etc.), C _{7 - 14} aralkyl sulfinyl group (e.g., phenyl -C _1-4 alkyl sulfinyl, such as naphthyl -C _1-4 alkylsulfinyl C _{6- 10} an aryl -C _1-4 alkylsulfinyl group), C _6-10 arylsulfinyl group (e.g., phenylsulfinyl, etc. naphthylsulfinyl), lower (C _1-6) alkylsulfonyl group (e.g., methylcarbamoyl Sulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, iso-butylsulfonyl, sec- butylsulfonyl, tert- butylsulfonyl, pentylsulfonyl, isopentyl sulfonyl, neopentyl sulfonyl, hexyl sulfonyl), C _{7 - 14} aralkyl sulfonyl group (Eg, C _6-10 aryl-C _1-4 alkylsulfonyl group such as phenyl-C _1-4 alkylsulfonyl, naphthyl-C _1-4 alkylsulfonyl, etc.), C _6-10 arylsulfonyl group (eg, phenylsulfonyl) , Naphthylsulfonyl, etc.), sulfo group, cyano group, azide group, halogen atom (eg, fluorine, chlorine, bromine, iodine etc.), nitro group, nitroso group, phosphono group which may be esterified [eg, phosphono group , Ethoxyphosphori (C _1-6 alkoxy) phosphoryl groups such as di, di (C _1-6 alkoxy) phosphoryl groups such as diethoxyphosphoryl, etc.], lower (C _1-6 substituted with an optionally esterified phosphono group) ) Alkyl groups (eg, phosphono-C _1-6 alkyl groups, C _1-6 alkoxyphosphoryl-C _1-6 alkyl groups, di (C _1-6 alkoxy) phosphoryl-C _1-6 alkyls such as diethoxyphosphorylmethyl) Group, etc.). The substituent may be substituted at a substitutable position of “aromatic allotrope or heterocycle”, and the number of the substituent is, for example, 1 to 3.
Among the above substituents, when a hydroxyl group and a lower (C _1-6 ) alkoxy group are adjacent as substituents on the “aromatic allotrope or heterocycle”, methylenedioxy, ethylenedioxy, etc. C _1-6 alkylenedioxy may be formed.
Furthermore, the acyl group may form a 5- to 7-membered ring together with a part of the “aromatic allotrope or heterocycle”.

[Wherein, C ... C ... C represents a carbon chain which may have a substituent, and the carbon chain bond of C ... C ... C may be a single bond or one of them may be a double bond. Ring A ′ represents an aromatic allotrope or heterocycle. ] May be formed.
Here, the “aromatic allotrope or heterocycle” represented by the A ′ ring is the “aromatic allotrope or heterocycle which may have a substituent” represented by the above A ring. Or a heterocyclic ring.

［式中の記号は上記と同意義を示す。］で示される６員環を形成していてもよい。
また、式

で示される基の好適な例としては、式

［式中の記号は上記と同意義を示す］で示される基なども挙げられる。ここで、式

［式中の記号は上記と同意義を示す］で示される環は、「電子吸引基を有し、置換基を有していてもよい複素環」である。 The ring A is preferably “an aromatic allotrope or heterocycle having an electron-withdrawing group and optionally further substituted”. Examples of the electron withdrawing group include an acyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonoyl. , 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc., C _2-8 alkanoyl group, C _3-8 alkenoyl group, C _3-7 cycloalkyl-carbonyl group, C _3-7 cycloalkenyl-carbonyl group, C _6-10 Aryl-carbonyl group; a heterocycle formed by combining a 5- or 6-membered aromatic or non-aromatic heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom with a carbonyl group (Carbonyl group etc.) Carbamoyl group; N-monosubstituted carbamoyl group [eg, N- (C _1-6 alkyl) carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, N- (C _2-6 alkenyl) carbamoyl group, N -(C _3-7 cycloalkyl) carbamoyl group, N- (C _6-10 aryl) carbamoyl group, etc.]; N, N-disubstituted carbamoyl group [eg, dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, diallyl (allyl) Two substituents selected from a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _3-7 cycloalkyl group and a C _6-10 aryl group, such as carbamoyl and N-methyl-N-phenylcarbamoyl; Substituted carbamoyl groups, etc.] sulfamoyl groups; N-monosubstituted sulfamoyl groups [eg, methyls Famoiru, ethylsulfamoyl, cyclohexyl sulfamoyl, N-(C _1-6 alkyl) sulfamoyl groups such as phenyl sulfamoyl, N-(C _2-6 alkenyl) sulfamoyl group, N-(C _3-7 cycloalkyl Alkyl) sulfamoyl group, N- (C _6-10 aryl) sulfamoyl group, etc.]; N, N-disubstituted sulfamoyl group [eg, dimethylsulfamoyl, diethylsulfamoyl, dibutylsulfamoyl, diallyl (allyl) sulfamoyl 2 substituents selected from a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _3-7 cycloalkyl group and a C _6-10 aryl group, such as N-methyl-N-phenylsulfamoyl A sulfamoyl group substituted with, etc.]; a carboxyl group; a lower (C _1-6 ) alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxy) Sicarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); nitro group and the like.
The electron withdrawing group is preferably an acyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonoyl. C _2-8 alkanoyl group such as 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, C _3-8 alkenoyl group, C _3-7 cycloalkyl-carbonyl group, C _3-7 cycloalkenyl-carbonyl group, C _6-10 aryl -Heterocycle-carbonyl formed by bonding a 5- or 6-membered aromatic or non-aromatic heterocycle having 1 to 3 heteroatoms selected from a carbonyl group, a nitrogen atom, an oxygen atom and a sulfur atom and a carbonyl group Group) The The acyl group may form a 5- to 7-membered ring with ring A, for example, the formula:

[The symbols in the formula are as defined above. ] May be formed.
Also the formula

As preferable examples of the group represented by the formula,

Examples include a group represented by [wherein the symbols have the same significance as described above]. Where the formula

The ring represented by [the symbols in the formula are as defined above] is “a heterocycle having an electron-withdrawing group and optionally having a substituent”.

In the above formulas (I) and (II), X represents —O—; —S—; —S (O) —; —S (O) ₂ —; —P ⁺ R ^1x R ^2x − (R ^1x and R ^2x represents a hydrogen atom or a substituent, respectively; -I ⁺ -or -NR ^1- (R ¹ represents a hydrogen atom or a substituent). Of these, -O-; -S-; -S (O)-; -S (O) _2- is preferred, and -O- is particularly preferred.
In the above formulas (I) and (II), Y represents —O—; —S—; —S (O) —; —S (O) ₂ —; —P ⁺ R ^1xx R ^2xx — (R ^1xx and R ^2xx represents a hydrogen atom or a substituent, respectively; -I ⁺ -; -NR ^1a- (R ^1a represents a hydrogen atom or a substituent) or -CR ^{1 ''} R ^{2 ''} -(R ^{1 ''} , R ^{2 ″} represents a hydrogen atom or a substituent. Of these, —NR ¹ — (R ¹ represents a hydrogen atom or a substituent) is preferred.
In particular, in formula (I), X is —O—; —S—; —S (O) — or —S (O) ₂ — (especially —O—), and Y is —NR ¹ — (R ¹ is It is preferably a hydrogen atom or a substituent.
Examples of the “substituent” represented by R ¹ , R ^1x , R ^2x , R ^1xx , R ^2xx , R ^1a , R ^{1 ″} and R ² ″ include, for example, methyl, ethyl, allyl, cyclohexyl A C _1-6 alkyl group such as phenyl, a C _2-6 alkenyl group, a C _3-7 cycloalkyl group, a C _6-10 aryl group; an acyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, C _2-8 alkanoyl group such as isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonoyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, C _3-8 alkenoyl group, C _3-7 cycloalkyl - carbonyl group, C _3-7 cycloalkenyl - carbonitrile Le group, C _6-10 aryl - carbonyl group, a nitrogen atom, an oxygen atom, an aromatic or non-aromatic heterocycle and a carbonyl group 5- or 6-membered to chromatic 1-3 heteroatoms selected from sulfur atom bonded A heterocyclic-carbonyl group formed by R ¹ , R ^1x , R ^2x , R ^1xx , R ^2xx , R ^1a , R ^{1 ″} and R ^{2 ″} are preferably a hydrogen atom or a C _1-6 alkyl group.

In the above formulas (I) and (II), when B is an “aromatic allotrope or heterocycle optionally having a substituent”, X and Y are the aromatic allotrope or heterocycle It shall be bonded to each of the adjacent ring atoms above.
In the above formulas (I) and (II), when B is an “optionally substituted ethylene group”, X and Y are bonded to different carbon atoms of the ethylene group, respectively.
In the formulas (I) and (II), when X is -P ⁺ R ^1x R ^2x- (the symbols are as defined above) or -I ⁺ -, and / or Y is -P ⁺ R ^{In the case of 1xx} R ^2xx − (the symbols are as defined above) or —I ⁺ —, the compounds (I) and (II) have a counter ion in the molecule, or are an organic acid or an inorganic acid. It is assumed that a salt is formed.

In the above formulas (I) and (II), examples of the “aromatic allotrope or heterocycle optionally having a substituent” represented by B include those exemplified as the A ring. Examples of the “substituent” in the “optionally substituted ethylene group” represented by B include, for example, the substitution in the “aromatic allotrope or heterocycle optionally having a substituent” represented by the A ring. What was illustrated as a group is mentioned. The substituent is preferably a C _1-4 alkyl group, a hydroxyl group, oxo and the like.
B is preferably an optionally substituted ethylene group, particularly preferably an ethylene group having two C _1-4 alkyl groups and oxo.
In the above formulas (III), (IV) and (VII), W represents an oxygen atom or a sulfur atom. Of these, an oxygen atom is preferable.
In the above formulas (III), (IV), (VIII), (X), (XI), (XV), (XVI), (XIX) and (XX), “optionally substituted” Examples of the substituent in the “methylene group” include those exemplified as the substituents in the “aromatic allotrope or heterocycle optionally having a substituent” group represented by the A ring. The substituent is preferably a C _1-4 alkyl group, and more preferably a methyl group. Z is particularly preferably a methylene group substituted by two methyl groups.
In the above formulas (III), (IV), (VIII), (IX), (X), (XI), (XIV), (XV), (XVI), (XIX) and (XX), R ¹ Examples of the “substituent” shown include C _1-6 alkyl groups such as methyl, ethyl, allyl, cyclohexyl, phenyl, C _2-6 alkenyl groups, C _3-7 cycloalkyl groups, C _{6- 10} aryl group; acyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonoyl, 2-cyclohexene carbonyl, benzoyl, C _2-8 alkanoyl group such as nicotinoyl, C _3-8 alkenoyl group, C _3-7 cycloalkyl - Ca Boniru group, C _3-7 cycloalkenyl - carbonyl group, C _6-10 aryl - carbonyl group; a nitrogen atom, an oxygen atom, an aromatic 5- or 6-membered to 1-3 have a hetero atom selected from sulfur atom or A non-aromatic heterocycle and a carbonyl group formed by a heterocycle-carbonyl group). R ¹ is particularly preferably a hydrogen atom.
The compound represented by the formula (III) and the formula (IV) or a salt thereof is a compound represented by the formula (I) or the formula (II) or a salt thereof, wherein B is an optionally substituted ethylene group. It corresponds to.
The bond of B that was bonded to X in formula (I) was also bonded to X in formula (II) after the Smiles rearrangement reaction, and the bond of B that was bonded to Y in formula (I). Binds to Y in formula (II) after the Smiles rearrangement reaction.
In the above formula (VIII), examples of the leaving group represented by Q include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), a reactive residue of sulfonic acid (eg, methanesulfonyloxy, benzene). Sulfonyloxy, toluenesulfonyloxy and the like), among which a halogen atom is preferable, and a bromine atom is more preferable.

［式中の記号は上記と同意義を示す。］で示される６員環中、Ｃ…Ｃ…Ｃは置換基を有していてもよい炭素鎖を示す。該置換基としては、Ａ環で示される「置換基を有していてもよい芳香族同素または複素環」における置換基と同様の置換基などが挙げられる。Ｃ…Ｃ…Ｃの炭素鎖の結合は、単結合もしくはどちらかが２重結合であってもよい。
上記式（Ｘ）、（ＸI）、（ＸII）および（ＸIＶ）中、Ｒ²、Ｒ^2aおよびＲ^2bは、同一または異なって、水素原子または置換基を示す。該置換基としては、例えば、Ａ環で示される「置換基を有していてもよい芳香族同素または複素環」における置換基と同様の置換基などが挙げられる。
Ｒ²、Ｒ^2aおよびＲ^2bは、好ましくは水素原子である。
上記式（XV）、（XVI）、（XVII）、（XVIII）、（XIX）および（XX）中、Ｒ²、Ｒ^2a、Ｒ^2b、Ｒ^2cおよびＲ^2dは、同一または異なって、水素原子または置換基を示す。該置換基としては、例えば、Ａ環で示される「置換基を有していてもよい芳香族同素または複素環」における置換基と同様の置換基などが挙げられる。
Ｒ²、Ｒ^2a、Ｒ^2b、Ｒ^2cおよびＲ^2dは、好ましくは水素原子である。
上記式（XV）、（XVI）、（XVII）、（XVIII）、（XIX）および（XX）中、Ｒ³で示されるC₁₋₆アルキル基としては、例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシルなどが挙げられる。なかでもメチルが好ましい。 In the above formulas (X), (XI), (XII) and (XIV), the above formula:

[The symbols in the formula are as defined above. In the 6-membered ring represented by C ... C ... C represents a carbon chain which may have a substituent. Examples of the substituent include the same substituents as those in the “aromatic allotrope or heterocycle optionally having substituents” represented by the A ring. The carbon chain bond of C ... C ... C may be a single bond or one of which may be a double bond.
In the above formulas (X), (XI), (XII) and (XIV), R ² , R ^2a and R ^2b are the same or different and represent a hydrogen atom or a substituent. Examples of the substituent include the same substituents as those in the “aromatic allotrope or heterocycle optionally having substituents” represented by the A ring.
R ² , R ^2a and R ^2b are preferably hydrogen atoms.
In the above formulas (XV), (XVI), (XVII), (XVIII), (XIX) and (XX), R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and represent a hydrogen atom Or a substituent is shown. Examples of the substituent include the same substituents as those in the “aromatic allotrope or heterocycle optionally having substituents” represented by the A ring.
R ² , R ^2a , R ^2b , R ^2c and R ^2d are preferably hydrogen atoms.
In the above formulas (XV), (XVI), (XVII), (XVIII), (XIX) and (XX), examples of the C _1-6 alkyl group represented by R ³ include methyl, ethyl, propyl, isopropyl, Examples include butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like. Of these, methyl is preferred.

  The salt of the compound used in the present invention is not particularly limited, but a pharmaceutically acceptable salt is preferable. For example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, an organic acid and And salts with basic or acidic amino acids. Preferable examples of the salt with inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.

In the production method of the present invention, a substituted fragrance represented by formula (II) is obtained by subjecting a compound represented by formula (I) or a salt thereof (hereinafter abbreviated as compound (I)) to a Smiles rearrangement reaction. Group compounds or salts thereof (hereinafter abbreviated as compound (II)) can be produced. The Smiles rearrangement reaction is performed, for example, by adding a basic hydroxide to a solution obtained by dissolving the compound (I) in an amide solvent and stirring the reaction solution.
The usage-amount of the basic hydroxide in this Smiles rearrangement reaction is 1-50 mol normally with respect to 1 mol of compounds (I), Preferably it is 2-25 mol. The reaction temperature in the smile reaction is usually from -20 to 150 ° C, preferably from 0 to 75 ° C, particularly preferably from 15 to 50 ° C. The reaction time in the smile reaction is usually 0.5 to 5 hours.
Compound (II) can be isolated and purified according to a method known per se.
The method for isolating compound (II) differs depending on whether the compound (II) is amorphous or the compound (II) is crystalline.
When compound (II) is amorphous, compound (II) can be isolated by separating the reaction solution containing compound (II) with water and an organic solvent and concentrating the organic phase. Moreover, you may implement refinement | purification operations, such as distillation, as needed.
When compound (II) is a crystal, compound (II) can be isolated by adding water to the reaction solution containing compound (II) and collecting the precipitated crystal by filtration. The compound (II) can also be isolated by the same operation as when the compound (II) is amorphous. Moreover, you may implement refinement | purification operations, such as recrystallization, as needed.
Moreover, you may use the reaction solution containing compound (II) for next reaction as it is, without isolating compound (II).

Among the compounds (I) described above, the compound represented by formula (III) or a salt thereof (hereinafter abbreviated as compound (III)) is, for example, a compound represented by formula (VII) or a salt thereof (hereinafter referred to as “compound”) Compound (VII)) and an alkylating agent represented by formula (VIII) or a salt thereof (hereinafter abbreviated as compound (VIII)) can be produced.
The solvent used in this reaction may be any solvent as long as it does not participate in the reaction with the reaction raw material. For example, halogenated hydrocarbons (eg, chloroform, dichloromethane, 1,2-dichloroethane, tetrachloride hydrocarbon, etc.) , Ethers (eg, diisopropyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), nitriles (eg, acetonitrile, propionitrile, etc.), aromatic hydrocarbons (toluene, Benzene, chlorobenzene, etc.), alcohols (eg, methanol, ethanol, isopropanol, tert-butanol, etc.), the above “amide solvents” and the like. These solvents may be used alone, in a mixture, or as an aqueous solution. The solvent is preferably the above amide solvent.
This reaction is preferably performed in the presence of a base. Examples of the base include metal hydrides (eg, sodium hydride), metal alkoxides (eg, sodium methoxide), organic bases (eg, triethylamine, Diazabicycloundecene, etc.), alkali metal carbonates (eg, sodium carbonate, etc.), the above “basic hydroxides” and the like. These bases may be used alone or as a mixture. The base is preferably the above “basic hydroxide”.
This reaction is particularly preferably carried out in the “amide solvent” in the presence of the “basic hydroxide”.
The amount of the base (preferably basic hydroxide) used in this reaction is usually 1 to 6 mol, preferably 1.5 to 4 mol, more preferably 2 to 3 mol, per 1 mol of compound (VII). The amount of compound (VIII) to be used is generally 1 to 6 mol, preferably 1.5 to 4 mol, more preferably 2 to 3 mol, per 1 mol of compound (VII). The reaction temperature in this reaction is usually -20 to 150 ° C, preferably 0 to 50 ° C, particularly preferably 15 to 30 ° C. The reaction time in this reaction varies depending on the raw materials used, but is usually 1 to 24 hours.
The compound (III) thus obtained can be isolated and purified according to a method known per se, as in the case of the compound (II) described above.
Alternatively, the reaction solution containing compound (III) may be directly subjected to the next Smiles rearrangement reaction without isolating compound (III).
The above-mentioned compound (VII) and compound (VIII) can be produced according to a method known per se.

The compound represented by the formula (IV) contained in the compound (II) or a salt thereof (hereinafter abbreviated as the compound (IV)) is subjected to a hydrolysis reaction, thereby being represented by the formula (IX). An aniline derivative or a salt thereof (hereinafter abbreviated as compound (IX)) can be produced. The hydrolysis reaction is performed, for example, by adding water to the solution of compound (IV) and then heating. If necessary, the hydrolysis reaction may be performed in the presence of the basic hydroxide. As the solution of the compound (IV) (similar to the reaction solution containing the compound (II) described above), the reaction solution containing the compound (IV) may be used as it is, or the isolated compound (IV) may be used as the “amide”. A solution obtained by dissolving in a “system solvent” may be used.
The reaction temperature in the hydrolysis reaction is usually 100 to 150 ° C. The reaction time in the hydrolysis reaction is usually 0.5 to 5 hours.
The compound (IX) thus obtained can be isolated and purified according to a method known per se in the same manner as in the case of the compound (II) described above.
Further, the compound (IX) thus obtained has a high purity. Further, “Production of Compound (III) by Reaction of Compound (VII) with Compound (VIII)”, “Production of Compound (IV) by Subjecting Compound (III) to Smiles Rearrangement Reaction” and “Compound (IV Compound (IX) can be obtained consistently from compound (VII) in a high yield by continuously carrying out the step of “Production of compound (IX) by subjecting to a hydrolysis reaction”).

The compound represented by the formula (XII) or a salt thereof (hereinafter abbreviated as “compound (XII)”) can be easily obtained as a commercially available product. Ind.), 158, 1970, or J. Am. Chem. Soc., 99, 5810, 1977 or Tetrahedron Letters (Tetrahedron Lett.), 28, 4163, 1987.
By reacting compound (XII) with compound (VIII), a 2-aryloxyacetamide derivative represented by formula (X) which is a novel production intermediate or a salt thereof (hereinafter abbreviated as compound (X)). Can be manufactured). This reaction is performed in the same manner as in the reaction of compound (VII) and compound (VIII) described above. Specifically, this reaction is carried out in an amide solvent such as dimethylacetamide in the presence of a basic hydroxide such as sodium hydroxide.
Compound (X) can be used in the next reaction as the reaction mixture or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily obtained by ordinary separation means such as recrystallization. It can also be purified.
Next, by subjecting compound (X) to a Smiles rearrangement reaction, a 2-hydroxy-N-arylacetamide derivative represented by formula (XI) which is a novel production intermediate or a salt thereof (hereinafter referred to as compound) (Abbreviated as (XI)).
This reaction is performed in the same manner as the Smiles rearrangement reaction of the compound (I) described above. Specifically, this reaction is performed by adding a basic hydroxide such as sodium hydroxide to the reaction mixture containing the compound (X).
Compound (XI) can be used in the next reaction as a reaction mixture or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily obtained by ordinary separation means such as recrystallization. It can also be purified.
Furthermore, by subjecting compound (XI) to a hydrolysis reaction, a compound represented by formula (XIV) or a salt thereof (hereinafter abbreviated as compound (XIV)) can be produced. This reaction is performed in the same manner as the hydrolysis reaction of the compound (IV) described above. Specifically, this reaction is performed by adding water to the reaction mixture containing compound (XI) and then heating. In this hydrolysis reaction, if necessary, a basic hydroxide such as sodium hydroxide may be added.
Thus, “Production of Compound (X) by Reaction of Compound (XII) with Compound (VIII)”, “Production of Compound (XI) by Subjecting Compound (X) to Smiles Rearrangement Reaction” and “Compound By continuously carrying out the process of “Production of compound (XIV) by subjecting (XI) to a hydrolysis reaction”, compound (XIV) can be easily obtained from compound (XII) with a high yield.

According to the present invention, a compound represented by formula (XV) or a salt thereof (hereinafter abbreviated as compound (XV)) which is a novel production intermediate can be provided.
Compound (XV) can be produced, for example, by subjecting a compound represented by formula (XVI) or a salt thereof (hereinafter abbreviated as compound (XVI)) to a Smiles rearrangement reaction.
This reaction is performed in the same manner as the Smiles rearrangement reaction of the compound (I) described above.
The compound (XV) thus obtained can be isolated and purified according to a method known per se.
The compound (XVI) can be produced, for example, by reacting the compound represented by the formula (XVII) or a salt thereof (hereinafter abbreviated as compound (XVII)) with the compound (VIII).
This reaction is performed in the same manner as in the reaction of compound (VII) and compound (VIII) described above.
The compound (XVI) thus obtained may be used in the next reaction as a reaction mixture or as a crude product, or may be isolated and purified according to a method known per se.
The compound (XVII) can be produced, for example, by subjecting a compound represented by the formula (XVIII) or a salt thereof (hereinafter abbreviated as compound (XVIII)) to an N-oxide reaction. This reaction can be carried out according to an oxidation reaction known per se.
The compound (XVII) thus obtained may be used in the next reaction as a reaction mixture or as a crude product, or may be isolated and purified according to a method known per se.
Compound (XVIII) can be produced according to a method known per se.

Compound (XVI) can also be produced, for example, by subjecting a compound represented by formula (XIX) or a salt thereof (hereinafter abbreviated as compound (XIX)) to an N-oxidation reaction. This reaction can be carried out according to an oxidation reaction known per se.
The compound (XVI) thus obtained may be used in the next reaction as a reaction mixture or as a crude product, or may be isolated and purified according to a method known per se.
The compound (XIX) can be produced, for example, by reacting the compound represented by the formula (XVIII) or a salt thereof (hereinafter abbreviated as compound (XVIII)) with the compound (VIII).
This reaction is performed in the same manner as in the reaction of compound (VII) and compound (VIII) described above.
The compound (XIX) thus obtained may be used in the next reaction as a reaction mixture or as a crude product, or may be isolated and purified according to a method known per se.
Compound (XV) can also be produced, for example, by subjecting a compound represented by formula (XX) or a salt thereof (hereinafter abbreviated as compound (XX)) to an N-oxidation reaction. This reaction can be carried out according to an oxidation reaction known per se.
Compound (XX) can be produced by subjecting compound (XIX) to a Smiles rearrangement reaction.
This reaction is performed in the same manner as the Smiles rearrangement reaction of the compound (I) described above.
The compound (XX) thus obtained can be isolated and purified according to a method known per se.
Thus, 1) “Production of Compound (XVII) by Subjecting Compound (XVIII) to N-Oxidation Reaction”, “Production of Compound (XVI) by Reaction of Compound (XVII) with Compound (VIII)” And “Production of Compound (XV) by Subjecting Compound (XVI) to Smiles Rearrangement Reaction”, or 2) “Production of Compound (XIX) by Reaction of Compound (XVIII) with Compound (VIII)”, Steps of “Production of Compound (XVI) by Subjecting Compound (XIX) to N-Oxidation Reaction” and “Production of Compound (XV) by Subjecting Compound (XVI) to Smiles Rearrangement Reaction”, or 3) “Production of Compound (XIX) by Reaction of Compound (XVIII) with Compound (VIII)”, “Production of Compound (XX) by Subjecting Compound (XIX) to Smiles Rearrangement Reaction” and “Compound (XX) By subjecting to N-oxidation reaction By continuously carrying out the process of “Production of Compound (XV)”, Compound (XV) can be easily obtained from Compound (XVIII) with a good yield. In particular, the method 1) is more preferable.

The compound obtained by the production method of the present invention or a salt thereof (eg, compound (IX), compound (XIV), compound (XV), etc.) is produced by, for example, producing a compound or a salt thereof used for the treatment or prevention of metabolic diseases. Useful as a raw material.
The compound (XIV) obtained by the production method of the present invention is also useful as a raw material for, for example, the melanin-concentrating hormone antagonist described in WO01 / 21577.
Among the compounds (XV) obtained by the production method of the present invention, a compound in which R ³ is methyl is obtained by, for example, adding a desired substituent to the methyl according to the method described in JP-A-63-201167 or a method analogous thereto. After being introduced and subjected to the same hydrolysis reaction as that of the compound (IV), it can be used as a raw material for antiarrhythmic agents described in JP-A-63-201167.

Hereinafter, the present invention will be described in more detail with reference to test examples, examples and reference examples, but the present invention is not limited thereto.
In the present specification, room temperature means a temperature of 1 ° C. to 30 ° C.

Test example 1
Using 2-methyl-2-[(5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl) oxy] propanamide (247 mg) as a substrate, the reaction rate at room temperature for 2 hours was measured by HPLC (ODS column, mobile phase: phosphate buffer / acetonitrile = 8/2, flow rate: 1 ml / min, detection: UV 254 nm).
Conversion in a system of sodium hydroxide (3 equivalents) -dimethylacetamide (2.5 mL): 100%
Conversion rate in the system of sodium hydroxide (3 equivalents) -methanol (2.5 mL): 0.3%
Conversion rate in the system of sodium methoxide (3 equivalents) -methanol (2.5 mL): 0.1%
Conversion in a system of sodium carbonate (3 equivalents) -dimethylacetamide (2.5 mL): 0.01%

Reference example 1
Synthesis of 6-hydroxy-1-tetralone 30% of 47% hydrobromic acid was added to 8.81 g (50 mmol) of 6-methoxy-1-tetralone and refluxed for 6 hours. 20 mL of water and seed crystals were added to the reaction solution, and the mixture was gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 20 mL of water. Drying under reduced pressure gave 7.68 g of amber crystal 6-hydroxy-1-tetralone.

Example 1 811 mg (5 mmol) of 6-hydroxy-1-tetralone was dissolved in 8 mL of dimethylacetamide. Sodium hydroxide (600 mg, 15 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 2.490 g (15 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 3 hours. To the reaction solution, 16 mL of water and seed crystals were added and gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 8 mL of water. Drying under reduced pressure gave 576 mg of 2-methyl-2-[(5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl) oxy] propanamide as white crystals.
Elemental analysis value: C ₁₄ H ₁₇ NO ₃
Found C, 67.71 H, 6.76 N, 5.71
Calculated value C, 68.00 H, 6.93 N, 5.66
¹ H-NMR (300 MHz, in CDCl ₃ ): δ 1.61 (s, 6H), 2.12 (quint, 2H), 2.61 (t, 2H), 2.91 (t, 2H), 5 .65 (brs, 1H), 6.41 (brs, 1H), 6.75 (d, 1H), 6.84 (dd, 1H), 7.98 (d, 1H).

Example 2
247 mg (1 mmol) of 2-methyl-2-[(5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl) oxy] propanamide was dissolved in 2.5 mL of dimethylacetamide. Sodium hydroxide (120 mg, 3 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. To the reaction solution, 5 mL of water and seed crystals were added and gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 2.5 mL of water. Drying under reduced pressure gave 200 mg of 2-hydroxy-2-methyl-N- (5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl) propanamide as white crystals.
Elemental analysis value: C ₁₄ H ₁₇ NO ₃
Found C, 68.19 H, 7.06 N, 5.64
Calculated value C, 68.00 H, 6.93 N, 5.66
¹ H-NMR (300 MHz, in CDCl ₃ ): δ 1.58 (s, 6H), 2.14 (quint, 2H), 2.65 (t, 2H), 2.73 (s, 1H), 2 .96 (t, 2H), 7.31 (dd, 1H), 7.78 (d, 1H), 8.01 (d, 1H), 8.90 (brs, 1H).

Example 3
6.87 g (30 mmol) of 6-hydroxy-1-tetralone was dissolved in 45 mL of dimethylacetamide. 3.60 g (90 mmol) of sodium hydroxide was added and stirred at room temperature for 1 hour. 14.94 g (90 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 6 hours. 3.60 g (90 mmol) of sodium hydroxide was added and stirred at 50 ° C. for 3 hours. To the reaction solution, 90 mL of water and seed crystals were added and gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 45 mL of water. Drying under reduced pressure gave 5.60 g of 2-hydroxy-2-methyl-N- (5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl) propanamide as white crystals.

Example 4
487 mg (3 mmol) of 6-hydroxy-1-tetralone was dissolved in 4.5 mL of dimethylformamide. 594 mg (9 mmol) of potassium hydroxide was added and stirred at room temperature for 1 hour. 1.494 g (9 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 2 hours. 594 mg (9 mmol) of potassium hydroxide was added, and the mixture was stirred at 50 ° C. for 2.5 hours. Further, 396 mg (6 mmol) of potassium hydroxide was added and stirred at 50 ° C. for 2 hours. To the reaction solution, 9 mL of water and seed crystals were added and gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 4.5 mL of water. Drying under reduced pressure gave 567 mg of 2-hydroxy-2-methyl-N- (5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl) propanamide as light brown crystals.

Example 5
487 mg (3 mmol) of 6-hydroxy-1-tetralone was dissolved in 4.5 mL of dimethylacetamide. 360 mg (9 mmol) of sodium hydroxide was added and stirred at room temperature for 1 hour. 1.494 g (9 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 5 hours. Sodium hydroxide 1.080g (27mmol) was added, and it stirred at 50 degreeC for 1 hour. 4.5 mL of water was added and refluxed for 1 hour. To the reaction solution, 9 mL of water and seed crystals were added and gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 4.5 mL of water. Drying under reduced pressure gave 287 mg of 6-amino-1-tetralone as white crystals.

Example 6
811 mg (5 mmol) of 6-hydroxy-1-tetralone was dissolved in 8 mL of dimethylacetamide. 400 mg (10 mmol) of sodium hydroxide was added and stirred at room temperature for 1 hour. 690 mg (5 mmol) of 2-bromoacetamide was added and stirred for 1.5 hours. Sodium hydroxide (400 mg, 10 mmol) was added, and the mixture was stirred at 100 ° C. for 3.5 hours. To the reaction solution, 24 mL of water, seed crystals and 3.200 g (80 mmol) of sodium hydroxide were added and gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 8 mL of water. Drying under reduced pressure gave 262 mg of 6-amino-1-tetralone as white crystals.

Example 7
451 mg (3 mmol) of p-hydroxypropiophenone was dissolved in 4.5 mL of dimethylacetamide. 360 mg (9 mmol) of sodium hydroxide was added and stirred at room temperature for 1 hour. 2.494 g (9 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 3 hours. 1.800 g (45 mmol) of sodium hydroxide was added and stirred at 50 ° C. for 4 hours. 4.5 mL of water was added and refluxed for 1 hour. To the reaction solution, 9 mL of water was added and gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 4.5 mL of water. Drying under reduced pressure gave 387 mg of p-aminopropiophenone as white crystals.

Example 8
417 mg (3 mmol) of p-nitrophenol was dissolved in 4.5 mL of dimethylacetamide. 360 mg (9 mmol) of sodium hydroxide was added and stirred at room temperature for 1 hour. 1.494 g (9 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 3 days. 1.440 g (36 mmol) of sodium hydroxide was added and stirred at 100 ° C. for 4 hours. 4.5 mL of water was added and refluxed for 1 hour. To the reaction solution, 9 mL of water was added and gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 4.5 mL of water. Drying under reduced pressure gave 156 mg of p-nitroaniline as tan crystals.

Example 9
595 mg (3 mmol) of 2-hydroxybenzophenone was dissolved in 6 mL of dimethylacetamide. 360 mg (9 mmol) of sodium hydroxide was added and stirred at room temperature for 1 hour. 1.494 g (9 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 1 day. Sodium hydroxide 1.080g (27mmol) was added, and it stirred at 50 degreeC for 5 hours. 4.5 mL of water was added and refluxed for 1.5 hours. Further, 1.440 g (36 mmol) of sodium hydroxide was added and refluxed for 1 hour. To the reaction solution, 12 mL of water was added and gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed 3 times with 6 mL of water. Drying under reduced pressure gave 453 mg of 2-aminobenzophenone as yellow crystals.

Example 10
219 mg (1 mmol) of 2- (2,3-dihydro-1H-inden-5-yloxy) -2-methylpropanamide was dissolved in 2 mL of dimethylacetamide. Sodium hydroxide (120 mg, 3 mmol) was added, and the mixture was stirred at 150 ° C. for 3 hours. 6 mL of water was added to the reaction solution, the precipitated crystals were removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. 2 mL of water and seed crystals were added to the concentrated residue. The precipitated crystals were collected by filtration and washed 3 times with 1 mL of water. It was dried under reduced pressure to obtain 70 mg of N- (2,3-dihydro-1H-inden-5-yl) -2-hydroxy-2-methylpropanamide as orange crystals.

Example 11
240 mg (1 mmol) of 2-methyl-2-[(4-nitrophenyl) sulfanyl] propanamide was dissolved in 2.5 mL of dimethylacetamide. To the obtained solution, 120 mg (3 mmol) of sodium hydroxide was added, and the mixture was stirred at 50 ° C. for 1 hour. Sodium hydroxide (600 mg, 15 mmol) and water (2.5 mL) were added to the resulting reaction solution, and the mixture was refluxed at 150 ° C. for 1 hour. After cooling the reaction solution, 5 mL of water and seed crystals were added. The precipitated crystals were collected by filtration, washed 3 times with 2.5 mL of water, and dried under reduced pressure to give 105 mg (yield 76.1%) of 4-nitroaniline as yellow crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 4.39 (brs, 2H), 6.62 (d, 2H), 8.07 (d, 2H).
Example 12
776 mg (5 mmol) of 4-nitrothiophenol was dissolved in 5 mL of dimethylacetamide. To the resulting solution, 600 mg (15 mmol) of sodium hydroxide was added and stirred at room temperature for 1 hour. To the resulting reaction solution, 2.490 g (15 mmol) of 2-bromo-2-methylpropanamide was added, and the mixture was stirred at room temperature for 30 minutes and at an external bath of 100 ° C. for 1 hour. To the resulting reaction solution, 600 mg (15 mmol) of sodium hydroxide was added, and the mixture was stirred at 100 ° C. for 1 hour. Sodium hydroxide (2.4 g, 60 mmol) and water (5 mL) were added to the resulting reaction solution, and the mixture was refluxed at 150 ° C. for 1 hour. After cooling the reaction solution, 10 mL of water and seed crystals were added. The precipitated crystals were collected by filtration, washed 3 times with 5 mL of water, and dried under reduced pressure to give 338 mg (yield 48.9%) of 4-nitroaniline as yellow crystals.

Reference example 2
10 g (57.7 mmol) of 6-methoxy-2-methylquinoline was suspended in 35 mL of 48% hydrobromic acid. The resulting suspension was refluxed at 150 ° C. for 17 hours. Water (10 mL) and seed crystals were added to the reaction solution, and the mixture was gradually cooled to room temperature. The precipitated crystals were collected by filtration, washed twice with 10 mL of water, and dried under reduced pressure to obtain 13.65 g (yield 98.5%) of 2-methyl-6-quinolinol hydrobromide as pale green crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 2.88 (s, 3H), 7.48 (d, 1H), 7.66 (dd, 1H), 7.85 (d, 1H), 8.11 (d, 1H), 8.86 (d, 1H), 10.80 (brs, 1H).

Example 13
2-Methyl-6-quinolinol hydrobromide 2.40 g (10 mmol) was dissolved in 20 mL of dimethylacetamide. To the resulting solution, 2.40 g (60 mmol) of sodium hydroxide was added and stirred at room temperature for 30 minutes. To the resulting reaction solution, 6.64 g (40 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 10 hours. 60 mL of water was added to the reaction mixture, and the mixture was extracted 3 times with 60 mL of ethyl acetate. The organic layer was washed twice with 40 mL of water and then concentrated under reduced pressure to obtain a white crystalline residue. 10 mL of water was added to the residue, and the crystals were collected by filtration. The obtained crystals were washed 3 times with 10 mL of water and dried under reduced pressure to obtain 1.65 g (yield 67.6%) of 2-methyl-2-[(2-methyl-6-quinolinyl) oxy] propanamide as white crystals. It was.
Elemental analysis value: C ₁₄ H ₁₆ N ₂ O ₂
Actual value C, 68.72 H, 6.62 N, 11.67
Calculated C, 68.83 H, 6.60 N, 11.47
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.62 (s, 6H), 2.72 (s, 3H), 5.67 (brs, 1H), 6.67 (brs, 1H), 7.21 (d, J = 2.8Hz, 1H ), 7.27 (d, J = 8.4Hz, 1H), 7.34 (dd, J = 9.1Hz, 2.7Hz, 1H), 7.93 (s, 1H), 7.96 (s, 1H).
Example 14
2-methyl-6-quinolinol hydrobromide 159 mg (0.7 mmol) was dissolved in dimethylacetamide 1.5 mL. To the resulting solution, 120 mg (4 mmol) of sodium hydroxide was added and stirred at room temperature for 30 minutes. To the resulting reaction solution, 498 mg (3 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 1.5 hours. To the resulting reaction solution, 360 mg (9 mmol) of sodium hydroxide and 1.5 mL of dimethylacetamide were added and stirred at 100 ° C. for 8.5 hours. 6 mL of water was added to the reaction mixture, and the mixture was extracted 3 times with 6 mL of ethyl acetate. The organic layer was washed twice with 6 mL of water and then concentrated under reduced pressure to obtain a residue. To the residue was added 1 mL of chloroform, and the crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain 24 mg (yield 14.8%) of 2-hydroxy-2-methyl-N- (2-methyl-6-quinolinyl) propanamide as light green crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 1.38 (s, 6H), 2.61 (s, 3H), 5.79 (s, 1H), 7.35 (d, 1H), 7.82 (d, 1H), 7.94 (dd, 1H), 8.12 (d, 1H), 8.41 (d, 1H), 9.82 (s, 1H).

Example 15
244 mg (1 mmol) of 2-methyl-2-[(2-methyl-6-quinolinyl) oxy] propanamide was dissolved in 2 mL of dimethylacetamide. To the resulting solution, 616 mg (2.5 mmol) of metachloroperbenzoic acid (70%) was added and stirred at 50 ° C. for 3.5 hours. To the resulting reaction solution, 6 mL of 1N sodium hydroxide was added under ice cooling. The precipitated crystals were collected by filtration, washed 3 times with 2 mL of water, and dried under reduced pressure to give 194 mg of 2-methyl-2-[(2-methyl-1-oxide-6-quinolinyl) oxy] propanamide (yield 74.6 %) Was obtained as white crystals.
Elemental analysis value: C ₁₄ H ₁₆ N ₂ O ₃
Measured value C, 64.39 H, 6.12 N, 10.88
Calculated C, 64.60 H, 6.20 N, 10.76
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 1.53 (s, 6H), 2.52 (s, 3H), 7.33 (s, 2H), 7.40 (d, 1H), 7.50 (d, 1H), 7.65 (s, 1H), 7.71 (d, 1H), 8.46 (d, 1H).
Example 16
244 mg (1 mmol) of 2-methyl-2-[(2-methyl-6-quinolinyl) oxy] propanamide was dissolved in 2 mL of dimethylacetamide. To the resulting solution, 296 mg (1.2 mmol) of metachloroperbenzoic acid (70%) was added and stirred at 50 ° C. for 2 hours. To the resulting reaction solution, 240 mg (6 mmol) of sodium hydroxide was added and stirred at 50 ° C. for 3 hours. 6 mL of water was added to the reaction solution, and 4 mL of ethyl acetate was added. The precipitated crystals were collected by filtration, washed 3 times with 2 mL of water, dried under reduced pressure, and 144 mg of 2-hydroxy-2-methyl-N- (2-methyl-1-oxide-6-quinolinyl) propanamide (yield) 55.4%) was obtained as pale yellow crystals.
Elemental analysis: C ₁₄ H ₁₆ N ₂ O ₃・ 1H ₂ O
Measured value C, 60.27 H, 6.45 N, 10.19
Calculated C, 60.42 H, 6.52 N, 10.07
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 1.40 (s, 6H), 2.54 (s, 3H), 5.83 (brs, 1H), 7.52 (d, 1H), 7.75 (d, 1H), 8.04 (dd, 1H), 8.46 (d, 1H), 8.54 (d, 1H), 10.01 (brs, 1H).

Example 17
159 mg (1 mmol) of 2-methyl-6-quinolinol was dissolved in 2 mL of dimethylacetamide. Under ice-cooling, 296 mg (1.2 mmol) of metachloroperbenzoic acid (70%) was added to the resulting solution, and the mixture was stirred at room temperature for 3 hours. To the resulting reaction solution, 168 mg (4.2 mmol) of sodium hydroxide was added and stirred at room temperature for 30 minutes. To the resulting reaction solution, 498 mg (3 mmol) of 2-bromo-2-methylpropanamide was added and stirred for 2 hours. To the resulting reaction solution, 240 mg (6 mmol) of sodium hydroxide was added and stirred at 50 ° C. for 5 hours. After cooling, 6 mL of saturated brine and seed crystals were added to the reaction solution. The precipitated crystals were collected by filtration, washed with 2 mL of water three times, and dried under reduced pressure to give 113 mg (yield of 2-hydroxy-2-methyl-N- (2-methyl-1-oxide-6-quinolinyl) propanamide. 43.5%) was obtained as white crystals.
Elemental analysis: C ₁₄ H ₁₆ N ₂ O ₃・ 1H ₂ O
Measured value C, 60.27 H, 6.45 N, 10.19
Calculated C, 60.42 H, 6.52 N, 10.07
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 1.40 (s, 6H), 2.54 (s, 3H), 5.83 (brs, 1H), 7.52 (d, 1H), 7.75 (d, 1H), 8.04 (dd, 1H), 8.46 (d, 1H), 8.54 (d, 1H), 10.01 (brs, 1H)

As described above, according to the present invention, since the Smiles rearrangement reaction is carried out under mild conditions, even in a thermally unstable compound, an atom bonded to an aromatic ring can be easily obtained using a safe reagent. Can be replaced.
Furthermore, according to the present invention, a highly pure aniline derivative can be produced in a high yield in a single pot using an inexpensive, safe and non-toxic reagent from a phenol derivative that is generally easily available.
Furthermore, according to the present invention, a 6-amino-1-tetralone derivative can be easily synthesized by using a 6-hydroxy-1-tetralone derivative as a raw material and passing through two novel production intermediates. .
Furthermore, according to the present invention, a 6-hydroxyquinaldine derivative is used as a raw material, and a 6-aminoquinaldine N-oxide derivative is easily synthesized by performing three steps in one pot via a novel production intermediate. be able to.

Claims (56)

Formula (I)

[In the formula, A ring represents an aromatic allotrope or hetero ring which may have a substituent. X is —O—; —S—; —S (O) —; —S (O) ₂ —; —P ⁺ R ^1x R ^2x — (R ^1x and R ^2x are each a hydrogen atom or a substituent); —I ⁺ — or —NR ¹ — (R ¹ represents a hydrogen atom or a substituent), Y represents —O—; —S—; —S (O) —; —S (O) ₂ —; ⁺ R ^1xx R ^2xx − (R ^1xx and R ^2xx each represent a hydrogen atom or a substituent); —I ⁺ —; —NR ^1a — (R ^1a represents a hydrogen atom or a substituent) or —CR ^{1 ″} R ^{2 ″} − (R ^{1 ″} and R ^{2 ″} each represent a hydrogen atom or a substituent). B represents an aromatic allotrope or heterocyclic ring which may have a substituent, or an ethylene group which may be substituted. Or the salt thereof is subjected to a Smiles rearrangement reaction (II)

[Wherein each symbol is as defined above. Wherein the Smiles rearrangement reaction is carried out in an amide solvent in the presence of a basic hydroxide. A process for producing a substituted aromatic compound or a salt thereof.   The production method according to claim 1, wherein the ring A is an aromatic homocyclic ring which may have a substituent. The process according to claim 1, wherein X is -O-; -S-; -S (O)-or -S (O) _2- . The production method according to claim 1, wherein Y is -NR ^1- [R ¹ represents a hydrogen atom or a substituent].   The process according to claim 1, wherein B is an optionally substituted ethylene group. The compound represented by the formula (I) or a salt thereof is represented by the formula (III)

[In the formula, A ring represents an aromatic allotrope or hetero ring which may have a substituent. Z represents an optionally substituted methylene group, W represents an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a substituent. Or a salt thereof, wherein the compound represented by the formula (II) or a salt thereof is represented by the formula (IV):

[Wherein each symbol is as defined above. The production method according to claim 1, which is a compound represented by the formula:   The production method according to claim 6, wherein the A ring has an electron withdrawing group and is an aromatic allotrope or heterocyclic ring which may further have a substituent.   The production method according to claim 7, wherein the ring A is an aromatic allocyclic ring having an electron-withdrawing group and further having a substituent. The process according to claim 6, wherein Z is a methylene group substituted with two C _1-4 alkyl groups. The process according to claim 6, wherein R ¹ is a hydrogen atom.   The process according to claim 7, wherein the electron withdrawing group is an acyl group. The compound represented by the formula (III) or a salt thereof is represented by the formula (VII)

[Wherein, A ring represents an aromatic allotrope or heterocyclic ring which may have a substituent, and W represents an oxygen atom or a sulfur atom. Or a salt thereof is represented by the formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. The method according to claim 6, wherein the compound is a compound obtained by reacting with an alkylating agent represented by the formula:   The method according to claim 12, wherein Q is a halogen atom.   13. The compound represented by formula (VII) or a salt thereof is reacted with an alkylating agent represented by formula (VIII) or a salt thereof in the presence of a basic hydroxide. Manufacturing method.   13. The process according to claim 12, wherein the compound represented by the formula (VII) or a salt thereof is reacted with the alkylating agent represented by the formula (VIII) or a salt thereof in the presence of an amide solvent.   A compound represented by formula (VII) or a salt thereof is reacted with an alkylating agent represented by formula (VIII) or a salt thereof in the presence of a basic hydroxide and an amide solvent. Item 13. The production method according to Item 12.   13. The process according to claim 12, wherein the compound represented by formula (III) or a salt thereof is not isolated. A compound represented by the formula (IV) obtained by the production method according to claim 6 or a salt thereof is subjected to a hydrolysis reaction.

[In the formula, A ring represents an aromatic allotrope or hetero ring which may have a substituent. R ¹ represents a hydrogen atom or a substituent. ] The manufacturing method of the aniline derivative represented by this, or its salt.   The process according to claim 18, wherein the hydrolysis reaction is carried out in the presence of a basic hydroxide.   The method according to claim 18, wherein the hydrolysis reaction is carried out in the presence of an amide solvent.   19. The process according to claim 18, wherein the hydrolysis reaction is carried out in the presence of a basic hydroxide and an amide solvent.   The production method according to claim 18, wherein the compound represented by the formula (IV) or a salt thereof is not isolated. A compound represented by the formula (IV) obtained by the production method according to claim 12 or a salt thereof is subjected to a hydrolysis reaction.

[In the formula, A ring represents an aromatic allotrope or hetero ring which may have a substituent. R ¹ represents a hydrogen atom or a substituent. ] The manufacturing method of the aniline derivative represented by this, or its salt.   The production method according to claim 23, wherein the hydrolysis reaction is carried out in the presence of a basic hydroxide.   The production method according to claim 23, wherein the hydrolysis reaction is carried out in the presence of an amide solvent.   The production method according to claim 23, wherein the hydrolysis reaction is carried out in the presence of a basic hydroxide and an amide solvent.   The production method according to claim 23, wherein the compound represented by formula (III) or a salt thereof is not isolated.   The production method according to claim 23, wherein the compound represented by formula (IV) or a salt thereof is not isolated.   28. The process according to claim 27, wherein the compound represented by formula (IV) or a salt thereof is not isolated.   27. The process according to claim 1, 14, 16, 19, 21, 24 or 26, wherein the basic hydroxide is an alkali metal hydroxide.   27. The process according to claim 1, 14, 16, 19, 21, 24 or 26, wherein the basic hydroxide is sodium hydroxide or potassium hydroxide.   27. The production method according to claim 1, 15, 16, 20, 21, 25 or 26, wherein the amide solvent is a chain amide solvent.   27. The process according to claim 1, 15, 16, 20, 21, 25, or 26, wherein the amide solvent is N, N-dimethylformamide or N, N-dimethylacetamide. Formula (X)

[In the formula, Z represents an optionally substituted methylene group, C ... C ... C represents an optionally substituted carbon chain, and R ¹ , R ² , R ^2a and R ^2b are the same. Or differently, each represents a hydrogen atom or a substituent. The carbon chain bond of C ... C ... C may be a single bond or one of them may be a double bond. ] The 2-aryloxyacetamide derivative represented by these, or its salt. Formula (XI)

[In the formula, Z represents an optionally substituted methylene group, C ... C ... C represents an optionally substituted carbon chain, and R ¹ , R ² , R ^2a and R ^2b are the same. Or differently, each represents a hydrogen atom or a substituent. The carbon chain bond of C ... C ... C may be a single bond or one of them may be a double bond. ] The 2-hydroxy-N-aryl acetamide derivative represented by these, or its salt. Formula (XII)

[Wherein C ... C ... C represents a carbon chain which may have a substituent, and R ² , R ^2a and R ^2b are the same or different and each represents a hydrogen atom or a substituent. The carbon chain bond of C ... C ... C may be a single bond or one of them may be a double bond. Or a salt thereof is represented by the formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. A method for producing a 2-aryloxyacetamide derivative or a salt thereof according to claim 34, wherein the alkylating agent or a salt thereof is reacted.   36. The 2-hydroxy-N-arylacetamide derivative according to claim 35, wherein the 2-aryloxyacetamide derivative or a salt thereof obtained by the production method according to claim 36 is subjected to a Smiles rearrangement reaction. Or the manufacturing method of the salt. A 2-hydroxy-N-arylacetamide derivative obtained by the production method according to claim 37 or a salt thereof is subjected to a hydrolysis reaction (XIV)

[Wherein C ... C ... C represents an optionally substituted carbon chain, and R ¹ , R ² , R ^2a and R ^2b are the same or different and each represents a hydrogen atom or a substituent. The carbon chain bond of C ... C ... C may be a single bond or one of them may be a double bond. Or a salt thereof. formula

Is a group represented by the formula

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group. The manufacturing method of Claim 6. Formula (XV)

[Wherein Z represents an optionally substituted methylene group, R ¹ , R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and represent a hydrogen atom or a substituent, and R ³ represents A C _1-6 alkyl group] or a salt thereof. Formula (XVI)

[Wherein Z represents an optionally substituted methylene group, R ¹ , R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and represent a hydrogen atom or a substituent, and R ³ represents A C _1-6 alkyl group] or a salt thereof. Formula (XVII)

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group, or Its salt. Formula (XIX)

[Wherein Z represents an optionally substituted methylene group, R ¹ , R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and represent a hydrogen atom or a substituent, and R ³ represents A C _1-6 alkyl group] or a salt thereof. Formula (XX)

[Wherein Z represents an optionally substituted methylene group, R ¹ , R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and represent a hydrogen atom or a substituent, and R ³ represents A C _1-6 alkyl group] or a salt thereof.   The process for producing a compound or a salt thereof according to claim 40, wherein the compound or a salt thereof according to claim 41 is subjected to a Smiles rearrangement reaction. 43. A compound according to claim 42 or a salt thereof and formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. 42. The method for producing a compound or a salt thereof according to claim 41, wherein the alkylating agent represented by the formula:   44. A process for producing a compound or salt thereof according to claim 41, wherein the compound or salt thereof according to claim 43 is subjected to an N-oxide reaction. Formula (XVIII)

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group, or The method for producing a compound or a salt thereof according to claim 42, wherein the salt is subjected to an N-oxide reaction. Formula (XVIII)

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group, or 45. A salt thereof is subjected to an N-oxide reaction to obtain a compound according to claim 42 or a salt thereof, wherein the compound or salt thereof is represented by formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. The compound or its salt of Claim 41 is obtained by making it react with the alkylating agent represented by this, or its salt, The said compound or its salt is attached | subjected to a Smiles rearrangement reaction, It is characterized by the above-mentioned. A method for producing a compound or a salt thereof.   50. The method according to claim 49, wherein the compound or salt thereof according to claim 42 is not isolated.   The process according to claim 49, wherein the compound or salt thereof according to claim 41 is not isolated.   The method according to claim 49, wherein the compound or salt thereof according to claim 42 and the compound or salt thereof according to claim 41 are not isolated.   43. A compound according to claim 43 or a salt thereof is subjected to an N-oxide reaction to obtain a compound according to claim 41 or a salt thereof, and the compound or a salt thereof is subjected to a Smiles rearrangement reaction. 40. A process for producing a compound according to 40 or a salt thereof.   54. The process according to claim 53, wherein the compound or salt thereof according to claim 41 is not isolated. Formula (XVIII)

Wherein R ² , R ^2a , R ^2b , R ^2c and R ^2d are the same or different and each represents a hydrogen atom or a substituent, and R ³ represents a C _1-6 alkyl group, or Its salt and formula (VIII)

[Wherein, Q represents a leaving group, Z represents an optionally substituted methylene group, and R ¹ represents a hydrogen atom or a substituent. 44. The method for producing a compound or a salt thereof according to claim 43, wherein the alkylating agent represented by the formula:   45. A process for producing a compound or a salt thereof according to claim 44, wherein the compound or a salt thereof according to claim 43 is subjected to a Smiles rearrangement reaction.