JP2007031356A - 3-oxa-7-thiatricyclo[4.2.1.04,8]nonane derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a 3-oxa-7-thiatricyclo[4.2.1.0<SP>4,8</SP>]nonane derivative which is useful as a monomer component or the like for highly functional polymers or the like, capable of improving characteristics such as hydrophilicity, while holding stability such as chemical resistance, when derived into polymers or the like. <P>SOLUTION: The 3-oxa-7-thiatricyclo[4.2.1.0<SP>4,8</SP>]nonane derivative represented by formula (1) [R<SP>a</SP>is H, a 1 to 6C alkyl or the like; R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>are each H, a 1 to 6C alkyl or the like; R<SP>5</SP>, R<SP>6</SP>, R<SP>7</SP>are H, a 1 to 6C alkyl, a substituted oxycarbonyl, cyano or the like; (n) is 1 or 2]. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention is a novel 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative useful as a raw material for paints and functional polymers, a raw material for pharmaceuticals, agricultural chemicals and other fine chemicals. And a production method thereof, and 5-hydroxy-3-oxa-7-thiatricyclo [4.2.4] useful as a raw material for synthesizing the 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative. 1.0 ^4,8 ] nonane derivative and a method for producing the same.

3-oxatricyclo [4.2.1.0 ^4,8 ] nonan-2-one derivative having a polymerizable unsaturated group at the 5-position (= 2-oxatricyclo having a polymerizable unsaturated group at the 9-position [4.2.1.0 ^4,8 ] nonan-3-one derivative) is a hydrophobic, bulky and highly stable alicyclic carbocycle and a lactone ring that is both hydrophilic and hydrolyzable. In addition to having a polymerizable unsaturated group, it is used as a raw material for paints and functional polymers utilizing its structural specificity. Moreover, the simple manufacturing method is also proposed (patent documents 1, 2, etc.). However, depending on the application, there is a problem that the hydrophobicity is too high as a whole and a desired function is not sufficiently exhibited, and various properties such as solvent solubility are inferior.

JP 2002-193961 A JP 2002-212174 A

The object of the present invention is a novel useful as a monomer component such as a high-functional polymer that can improve the properties such as hydrophilicity while maintaining the stability such as chemical resistance when induced to a polymer or the like. It is an object to provide a 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative and an efficient production method thereof.
Another object of the present invention is to provide a novel 5-hydroxy-3-oxa-7-thiatricyclo [ ⁴ ] useful as a raw material for the synthesis of the 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative. 4.2.1.0 ^4,8 ] nonane derivative and its efficient production method.

As a result of intensive studies to achieve the above object, the present inventors have found that when derived into a polymer or the like, a 3-oxatricyclo [4.2.1.0 ^4,8 ] nonan-2-one derivative is preferred. A novel 3-oxa-7-thia-tricyclo [4.2.1.0 ^4,8 ] nonane derivative capable of improving properties such as hydrophilicity and an efficient production method thereof have been found, and the present invention has been completed.

（式中、Ｒ^aは水素原子、ハロゲン原子、又はハロゲン原子を有していてもよい炭素数１〜６のアルキル基を示し、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴は、同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子を有していてもよい炭素数１〜６のアルキル基、又はヒドロキシル基部分が保護基で保護されていてもよく且つハロゲン原子を有していてもよい炭素数１〜６のヒドロキシアルキル基を示し、Ｒ⁵、Ｒ⁶、Ｒ⁷は、同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子を有していてもよい炭素数１〜６のアルキル基、塩を形成していてもよいカルボキシル基、置換オキシカルボニル基、又はシアノ基を示す。ｎは１又は２を示す。Ｒ¹とＣＨ₂＝Ｃ（Ｒ^a）ＣＯＯ−基の立体的な位置は、それぞれ、エンド、エキソの何れであってもよい）
で表される３−オキサ−７−チアトリシクロ［４．２．１．０^4,8］ノナン誘導体を提供する。 That is, the present invention provides the following formula (1):

(In the formula, R ^a represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, and R ¹ , R ² , R ³ and R ⁴ are the same or different. In addition, a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, or a hydroxyl group part may be protected with a protecting group and may have a halogen atom. A C 1-6 hydroxyalkyl group, wherein R ⁵ , R ⁶ , and R ⁷ are the same or different and are a hydrogen atom, a halogen atom, or a C 1-6 alkyl group optionally having a halogen atom; Represents a carboxyl group which may form a salt, a substituted oxycarbonyl group, or a cyano group, n represents 1 or 2. Steric position of R ¹ and CH ₂ ═C (R ^a ) COO— group. Are either end or exo respectively Stomach)
A 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula:

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴は、同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子を有していてもよい炭素数１〜６のアルキル基、又はヒドロキシル基部分が保護基で保護されていてもよく且つハロゲン原子を有していてもよい炭素数１〜６のヒドロキシアルキル基を示し、Ｒ⁵、Ｒ⁶、Ｒ⁷は、同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子を有していてもよい炭素数１〜６のアルキル基、塩を形成していてもよいカルボキシル基、置換オキシカルボニル基、又はシアノ基を示す。ｎは１又は２を示す。Ｒ¹とＯＨの立体的な位置は、それぞれ、エンド、エキソの何れであってもよい）
で表される５−ヒドロキシ−３−オキサ−７−チアトリシクロ［４．２．１．０^4,8］ノナン誘導体と、下記式（３）

（式中、Ｒ^aは水素原子、ハロゲン原子、又はハロゲン原子を有していてもよい炭素数１〜６のアルキル基を示す）
で表される不飽和カルボン酸又はその反応性誘導体を反応させて、下記式（１）

（式中、Ｒ^a、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、ｎは前記に同じ。Ｒ¹とＣＨ₂＝Ｃ（Ｒ^a）ＣＯＯ−基の立体的な位置は、それぞれ、エンド、エキソの何れであってもよい）
で表される３−オキサ−７−チアトリシクロ［４．２．１．０^4,8］ノナン誘導体を得る３−オキサ−７−チアトリシクロ［４．２．１．０^4,8］ノナン誘導体の製造法を提供する。 The present invention also provides the following formula (2):

(In the formula, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a halogen atom, or a hydroxyl group moiety. Represents a hydroxyalkyl group having 1 to 6 carbon atoms which may be protected with a protecting group and may have a halogen atom, and R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, A halogen atom, an alkyl group having 1 to 6 carbon atoms that may have a halogen atom, a carboxyl group that may form a salt, a substituted oxycarbonyl group, or a cyano group, and n is 1 or 2. The three-dimensional positions of R ¹ and OH may be either endo or exo)
A 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by formula (3):

(In the formula, Ra represents ^a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms which may have a halogen atom)
Is reacted with an unsaturated carboxylic acid represented by the following formula (1):

(In the formula, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and n are the same as described above. R ¹ and CH ₂ ═C (R ^a ) COO— (Each position may be either end or exo)
Preparation of 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula: 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative Provide law.

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴は、同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子を有していてもよい炭素数１〜６のアルキル基、又はヒドロキシル基部分が保護基で保護されていてもよく且つハロゲン原子を有していてもよい炭素数１〜６のヒドロキシアルキル基を示し、Ｒ⁵、Ｒ⁶、Ｒ⁷は、同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子を有していてもよい炭素数１〜６のアルキル基、塩を形成していてもよいカルボキシル基、置換オキシカルボニル基、又はシアノ基を示す。ｎは１又は２を示す。Ｒ¹とＯＨの立体的な位置は、それぞれ、エンド、エキソの何れであってもよい）
で表される５−ヒドロキシ−３−オキサ−７−チアトリシクロ［４．２．１．０^4,8］ノナン誘導体を提供する。 The present invention further provides the following formula (2):

(In the formula, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a halogen atom, or a hydroxyl group moiety. Represents a hydroxyalkyl group having 1 to 6 carbon atoms which may be protected with a protecting group and may have a halogen atom, and R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, A halogen atom, an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, a carboxyl group which may form a salt, a substituted oxycarbonyl group, or a cyano group, and n represents 1 or 2. The three-dimensional positions of R ¹ and OH may be either endo or exo)
A 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula:

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴は、同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子を有していてもよい炭素数１〜６のアルキル基、又はヒドロキシル基部分が保護基で保護されていてもよく且つハロゲン原子を有していてもよい炭素数１〜６のヒドロキシアルキル基を示し、Ｒ⁵、Ｒ⁶、Ｒ⁷は、同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子を有していてもよい炭素数１〜６のアルキル基、塩を形成していてもよいカルボキシル基、置換オキシカルボニル基、又はシアノ基を示し、Ｒ^bは水素原子又は有機基を示し、ｎは１又は２を示す）
で表される２，３−エポキシ−７−チアビシクロ［２．２．１］ヘプタン誘導体を環化反応に付して、下記式（２）

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、ｎは前記に同じ。Ｒ¹とＯＨの立体的な位置は、それぞれ、エンド、エキソの何れであってもよい）
で表される５−ヒドロキシ−３−オキサ−７−チアトリシクロ［４．２．１．０^4,8］ノナン誘導体を得る５−ヒドロキシ−３−オキサ−７−チアトリシクロ［４．２．１．０^4,8］ノナン誘導体の製造法を提供する。 The present invention further provides the following formula (4):

(In the formula, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a halogen atom, or a hydroxyl group moiety. Represents a hydroxyalkyl group having 1 to 6 carbon atoms which may be protected with a protecting group and may have a halogen atom, and R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, A halogen atom, an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, a carboxyl group which may form a salt, a substituted oxycarbonyl group or a cyano group, and R ^b is a hydrogen atom or an organic group And n represents 1 or 2)
A 2,3-epoxy-7-thiabicyclo [2.2.1] heptane derivative represented by the following formula (2)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are the same as above. The steric positions of R ¹ and OH are either endo or exo, respectively. May be)
5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula: 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] A method for producing a nonane derivative is provided.

The position numbers in the 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane ring are shown below.

According to the present invention, novel polymers useful as monomer components such as high-functional polymers that can improve properties such as hydrophilicity while maintaining stability such as chemical resistance when induced to polymers and the like. A 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative and an efficient production method thereof are provided. In addition, novel 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1., Useful as a raw material for the synthesis of the 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative. 0 ^4,8 ] nonane derivatives and their efficient production processes are provided.

The 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative of the present invention is represented by the formula (1). In Formula (1), R ^a represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, and R ¹ , R ² , R ³ and R ⁴ are the same. Or, differently, a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, or a hydroxyl group part may be protected with a protecting group and have a halogen atom. 1 to 6 represents a hydroxyalkyl group having 1 to 6 carbon atoms, and R ⁵ , R ⁶ and R ⁷ may be the same or different and each having a hydrogen atom, a halogen atom or a halogen atom and having 1 to 6 carbon atoms An alkyl group, a carboxyl group that may form a salt, a substituted oxycarbonyl group, or a cyano group; n represents 1 or 2;

Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Examples of the alkyl group having 1 to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl groups. Among these, a C _1-3 alkyl group, particularly a methyl group is preferable. Examples of the alkyl group having 1 to 6 carbon atoms having a halogen atom include chloroalkyl groups such as chloromethyl group; fluoroalkyl groups such as trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl groups ( Preferably, a _C1-3 fluoroalkyl group) etc. are mentioned.

  Examples of the hydroxyalkyl group having 1 to 6 carbon atoms include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, and 6-hydroxyhexyl groups. It is done. Examples of the C1-C6 hydroxyhaloalkyl group having a halogen atom include difluorohydroxymethyl, 1,1-difluoro-2-hydroxyethyl, 2,2-difluoro-2-hydroxyethyl, 1,1,2, Examples include 2-tetrafluoro-2-hydroxyethyl group. Among the hydroxyalkyl groups having 1 to 6 carbon atoms which may have a halogen atom, a hydroxyalkyl group or hydroxyhaloalkyl group having 1 or 2 carbon atoms (particularly 1 carbon atom) is preferable. Examples of the protective group for the hydroxyl group of a hydroxyalkyl group having 1 to 6 carbon atoms which may have a halogen atom include a protective group usually used as a protective group for a hydroxyl group in the field of organic synthesis, such as a methyl group, a methoxy group, and the like. Examples include groups that form an ether or acetal bond with an oxygen atom that constitutes a hydroxyl group such as a methyl group; groups that form an ester bond with an oxygen atom that constitutes a hydroxyl group such as an acetyl group or a benzoyl group. Examples of the carboxyl group salt include alkali metal salts, alkaline earth metal salts, and transition metal salts.

Examples of the substituted oxycarbonyl group include alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, propoxycarbonyl group (C _1-4 alkoxy-carbonyl group, etc.); vinyloxycarbonyl, allyloxycarbonyl group, etc. Examples thereof include alkenyloxycarbonyl groups (C _2-4 alkoxy-carbonyl groups and the like); cycloalkyloxycarbonyl groups such as cyclohexyloxycarbonyl groups; aryloxycarbonyl groups such as phenyloxycarbonyl groups and the like. Examples of the substituted oxysulfinyl group and the substituted oxysulfonyl group include a substituted oxysulfinyl group and a substituted oxysulfonyl group corresponding to the above substituted oxycarbonyl group.

R ^a is preferably a hydrogen atom, a C _1-3 alkyl group such as a methyl group, or a C _1-3 haloalkyl group such as a trifluoromethyl group, and particularly preferably a hydrogen atom or a methyl group. R ¹ , R ² , R ³ and R ⁴ are each a hydrogen atom, an alkyl group having 1 to 3 carbon atoms such as a methyl group or a trifluoromethyl group, a haloalkyl group, or a hydroxy moiety protected with a protecting group. Preferred is a hydroxyalkyl group having 1 to 3 carbon atoms or a hydroxyhaloalkyl group (particularly a hydroxymethyl group which may be protected with a protective group such as a hydroxymethyl group or an acetoxymethyl group). R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom, an alkyl group having 1 to 3 carbon atoms such as a methyl group or a trifluoromethyl group or a haloalkyl group (particularly a methyl group or a halomethyl group), a substituted oxycarbonyl group, a cyano group Groups are preferred.

As a typical example of the 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula (1), 5- (meth) acryloyloxy- represented by the following formula 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane-2,7,7-trione compounds (including each stereoisomer), and oxygen at the 7-position sulfur atom of these compounds Corresponding 5- (meth) acryloyloxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane-2,7-dione compound in which one atom is bonded instead of two (each stereo Isomers). In the formula, R represents an acryloyl group or a methacryloyl group, and Ac represents an acetyl group.

The 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula (1) is a 5-hydroxy-3-oxa-7- represented by the formula (2). It can be produced by reacting a thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative with an unsaturated carboxylic acid represented by the formula (3) or a reactive derivative thereof. R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and n in Formula (2) and Formula (3) are the same as described above.

Typical examples of the unsaturated carboxylic acid represented by the formula (3) include acrylic acid, methacrylic acid, α-trifluoromethylacrylic acid and the like. Examples of the reactive derivative of the unsaturated carboxylic acid represented by the formula (3) include acid halides, acid anhydrides and esters. A typical example of the 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula (2) is represented by the formula (1). As a typical example of a 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative, a compound corresponding to the compound mentioned above (a compound in which R is a hydrogen atom) can be given.

More specifically, the 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the above formula (1) is a solvent such as (a) tetrahydrofuran, toluene, methylene chloride or the like. In the compound represented by the formula (2), a (meth) acrylic acid halide such as (meth) acrylic acid chloride or (meta) in the presence of a base such as triethylamine, pyridine or 4-dimethylaminopyridine, if necessary. ) Reacting an active reactive derivative of an unsaturated carboxylic acid such as acrylic anhydride, or (b) an ester such as titanium isopropoxide in a compound represented by formula (2) in the same solvent as described above. In the presence of an exchange catalyst, an unsaturated carboxylic acid ester such as methyl (meth) acrylate is reacted, or (c) a compound represented by the formula (2) is mixed with hydrochloric acid, sulfuric acid, p in a solvent similar to the above. -Torr Can be obtained by reacting in the presence of a strong acid such as Nsuruhon acid and (meth) unsaturated carboxylic acids such as acrylic acid.

  The reaction conditions in these methods are the same as in the usual ester production method. For example, in the method (a), the amount of the active reactive derivative of the unsaturated carboxylic acid used is, for example, about 1 to 1.5 moles per 1 mole of the compound represented by the formula (2). Is used in an amount of, for example, about 1 to 3 mol (may be a large excess) with respect to 1 mol of the active reactive derivative of the unsaturated carboxylic acid, and the reaction temperature is, for example, from −20 ° C. to It is about 50 ° C. In the method (b), the amount of the unsaturated carboxylic acid ester used is, for example, about 1 to 10 mol (a large excess amount may be used) with respect to 1 mol of the compound represented by the formula (2). ), The amount of the transesterification catalyst used is, for example, about 0.0001 to 1 mol, and the reaction temperature is about 0 to 150 ° C., for example, with respect to 1 mol of the compound represented by the formula (2). Furthermore, in the method (c), the amount of the unsaturated carboxylic acid used is, for example, about 1 to 5 mol (may be a large excess amount) with respect to 1 mol of the compound represented by the formula (2). The amount of the strong acid used is, for example, about 0.0001 to 1 mol with respect to 1 mol of the compound represented by the formula (2), and the reaction temperature is about 0 to 150 ° C., for example. In addition, in order to suppress superposition | polymerization in these reactions, polymerization inhibitors, such as hydroquinone monomethyl ether, and oxygen can also be introduce | transduced.

The 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula (1) generated by the reaction is, for example, filtered, concentrated, distilled, extracted, crystallized, recrystallized. Separation and purification can be performed by separation means such as column chromatography, or a combination thereof.

The 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula (2) is a 2,3-epoxy represented by the formula (4). It can be obtained by subjecting a -7-thiabicyclo [2.2.1] heptane derivative to a cyclization reaction. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n in the formula (4) are the same as described above.

The organic group for R ^b may be any group that constitutes a carboxylic acid ester, and examples thereof include alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, and t-butyl groups (particularly, C _1-6 alkyl groups). Alkenyl groups such as vinyl and allyl groups (especially C _1-6 alkenyl groups); cycloalkenyl groups such as cyclohexyl groups; aryl groups such as phenyl groups; heterocyclic groups such as pyridyl groups; R ^b is particularly preferably a hydrogen atom, or a C _1-4 alkyl group such as a methyl or ethyl group.

When R ^b is a hydrogen atom, the cyclization reaction proceeds, for example, only by dissolving the compound represented by formula (4) in a solvent. When R ^b is an organic group, the compound represented by formula (4) is subjected to a conventional hydrolysis reaction (alkali hydrolysis reaction, acid hydrolysis reaction, etc.) to produce a compound in which R ^b is a hydrogen atom. As a result, the cyclization reaction proceeds immediately to produce the compound represented by the formula (2). The 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula (2) generated by the reaction is, for example, filtered, concentrated, distilled, extracted, crystallized. Separation and purification can be performed by separation means such as precipitation, recrystallization, column chromatography, or a combination thereof.

Of the compounds represented by the formula (2), a compound in which one or more fluorine atoms are bonded to the 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane ring is 3 A compound in which at least one hydrogen atom is bonded to the oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane ring is subjected to a conventional fluorination reaction using a fluorinating agent such as fluorine. Can also be manufactured.

The 2,3-epoxy-7-thiabicyclo [2.2.1] heptane derivative represented by the above formula (4) can be produced, for example, according to the following reaction process formula. In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^b and n are the same as described above.

That is, Diels-Alder reaction of a thiophene derivative (thiophene-1-oxide derivative or thiophene-1,1-dioxide derivative) represented by formula (5) with an unsaturated carboxylic acid or ester thereof represented by formula (6) To obtain a 7-thiabicyclo [2.2.1] heptan-2-ene derivative represented by the formula (7), and reacting this with a peracid or peroxide, the formula (4) 2,3-epoxy-7-thiabicyclo [2.2.1] heptane derivative represented by the following formula can be obtained. In the case where R ^b is a hydrogen atom, the compound represented by formula (7) is cyclized immediately after epoxidation by acting a peracid or peroxide on the compound represented by formula (2). May be obtained as the main product.

  As typical examples of the thiophene derivative represented by the formula (5), for example, thiophene-1,1-dioxide, 2-methylthiophene-1,1-dioxide, 3-methylthiophene-1,1-dioxide, 2 , 5-dimethylthiophene-1,1-dioxide, 3,4-dimethylthiophene-1,1-dioxide, 2,3,4,5-tetramethylthiophene-1,1-dioxide, 2-hydroxymethylthiophene-1 , 1-dioxide, 2,5-bis (hydroxymethyl) thiophene-1,1-dioxide, 2-acetoxymethylthiophene-1,1-dioxide, 2,5-bis (acetoxymethyl) thiophene-1,1-dioxide Thiophene-1,1-dioxide derivatives such as thiophene-1-oxide derivatives corresponding to these compounds Etc. are exemplified. As typical examples of the compound represented by the formula (6), for example, acrylic acid, methacrylic acid, crotonic acid, 2-cyanoacrylic acid, 3-cyanoacrylic acid, 2-carboxyacrylic acid, maleic acid, fumaric acid Unsaturated carboxylic acids such as, and esters thereof (methyl esters, ethyl esters, etc.).

  The reaction between the compound represented by formula (5) and the compound represented by formula (6) is performed in the presence or absence of a solvent. Examples of the solvent include esters such as ethyl acetate; organic acids such as acetic acid; alcohols such as t-butyl alcohol; halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane; aromatic hydrocarbons such as benzene. Aliphatic hydrocarbons such as hexane, heptane and octane; alicyclic hydrocarbons such as cyclohexane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; nitriles such as acetonitrile, propionitrile and benzonitrile A linear or cyclic ether such as ethyl ether or tetrahydrofuran; These solvents may be used alone or in combination of two or more.

In order to improve the reaction rate and reaction selectivity (stereoselectivity, etc.), a Lewis acid may be added to the system. Examples of the Lewis acid include, but are not limited to, AlCl ₃ , SnCl ₄ , TiCl ₄ , BF ₃ , ZnI _{2 and the} like. Although reaction temperature can be suitably selected according to the kind etc. of reaction raw material, generally it is about -80 to 300 degreeC, Preferably it is about -70 to 250 degreeC. The reaction is carried out at normal pressure or under pressure. The reaction may be carried out by any method such as batch, semi-batch and continuous methods. The produced 7-thiabicyclo [2.2.1] heptan-2-ene derivative represented by the formula (7) is separated by, for example, filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, etc. Separation and purification can be performed by means or by combining them.

  Among the peracids or peroxides to be reacted with the compound represented by the formula (7), as the peracid, for example, performic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, Organic peracids such as monoperoxyphthalic acid; inorganic peracids such as permanganic acid. Peracids can also be used in the form of salts. The organic peracid may be an equilibrium peracid (eg, equilibrium formic acid, equilibrium peracetic acid, etc.). That is, for example, organic acids such as formic acid and acetic acid may be used in combination with hydrogen peroxide to generate the corresponding organic peracid in the system. When using an equilibrium peracid, a small amount of a strong acid such as sulfuric acid may be added as a catalyst. The amount of peracid to be used is, for example, 0.8 to 2 mol, preferably 0.9 to 1.5 mol, more preferably 0.95 to 1 mol with respect to 1 mol of the compound represented by formula (7). .About 2 moles.

  Examples of the peroxide to be reacted with the compound represented by the formula (7) include hydrogen peroxide, peroxide, hydroperoxide, peroxo acid, and a salt of peroxo acid. As hydrogen peroxide, pure hydrogen peroxide may be used, but from the viewpoint of handling, it is usually used in a form diluted with an appropriate solvent, for example, water (for example, 30% by weight hydrogen peroxide). . The amount of peroxide such as hydrogen peroxide is, for example, about 0.9 to 5 mol, preferably about 0.9 to 3 mol, more preferably about 1 mol of the compound represented by formula (7). It is about 0.95 to 2 mol.

  The hydrogen peroxide is often used together with a metal compound. Examples of the metal compound include oxides containing metal elements such as W, Mo, V, Mn, and Re, oxo acids or salts thereof, sulfides, halides, oxyhalides, borides, carbides, silicides, Examples thereof include nitrides, phosphides, peroxides, complexes (inorganic complexes and organic complexes), and organometallic compounds. These metal compounds can be used alone or in combination of two or more.

Examples of the oxide include tungsten oxide (WO ₂ , WO ₃ etc.), molybdenum oxide (MoO ₂ , MoO ₃ etc.), vanadium oxide (VO, V ₂ O ₃ , VO ₂ , V ₂ O ₅ etc.), Examples include manganese oxide (MnO, Mn ₂ O ₃ , Mn ₃ O ₄ , MnO ₂ , Mn ₂ O _7, etc.), composite oxides containing metal elements such as W, Mo, V, and Mn.

  Oxo acids include tungstic acid, molybdic acid, vanadic acid, manganic acid, and other isopolyacids such as isopolytungstic acid, isopolymolybdic acid, isopolyvanadate; phosphotungstic acid, silicotungstic acid, phosphomolybdenum sun And heteropolyacids composed of the above metal elements such as silicomolybdic acid and phosphovanadmolybdic acid and other metal elements. As the other metal element in the heteropolyacid, phosphorus or silicon, particularly phosphorus is preferable.

  Examples of the salt of oxo acid include alkali metal salts such as sodium salt and potassium salt of oxo acid; alkaline earth metal salts such as magnesium salt, calcium salt and barium salt; ammonium salt; transition metal salt and the like. The salt of an oxo acid (for example, a salt of a heteropoly acid) may be a salt in which a part of the hydrogen atom corresponding to the cation is replaced with another cation.

  Examples of the peroxide containing a metal element include peroxo acids (for example, peroxotungstic acid, peroxomolybdic acid, peroxovanadate, etc.), salts of peroxo acids (alkali metal salts, alkaline earth metal salts of the peroxo acids, Ammonium salts, transition metal salts, etc.), peracids (permanganic acid, etc.), peracid salts (alkali metal salts, alkaline earth metal salts, ammonium salts, transition metal salts, etc. of the peracids).

  The amount of the metal compound used together with the hydrogen peroxide is, for example, about 0.0001 to 2 mol, preferably about 0.0005 to 0.5 mol, with respect to 1 mol of the compound represented by the formula (7). More preferably, it is about 0.001-0.2 mol.

  The reaction between the compound represented by formula (7) and the peracid or peroxide is carried out in the presence or absence of a solvent. Examples of the solvent include alcohols such as t-butyl alcohol; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane; aromatic hydrocarbons such as benzene; and aliphatic hydrocarbons such as hexane, heptane, and octane. Alicyclic hydrocarbons such as cyclohexane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; nitriles such as acetonitrile, propionitrile and benzonitrile; linear or cyclic ethers such as ethyl ether and tetrahydrofuran An ester such as ethyl acetate; an organic acid such as acetic acid; water and the like. These solvents are used alone or in combination of two or more. In the case of performing the reaction in a heterogeneous system, water or a solvent containing water is often used as a solvent.

  The reaction temperature can be appropriately selected in consideration of the reaction rate and reaction selectivity, but is generally about 0 to 100 ° C, preferably about 10 to 80 ° C. The reaction may be carried out by any method such as batch, semi-batch and continuous methods.

By the said reaction, the epoxidation of the double bond of the compound represented by Formula (7) occurs, and the epoxy compound represented by Formula (4) produces | generates. For example, when R ^b is a hydrogen atom, an intramolecular cyclization reaction involving the opening of an epoxy ring proceeds, and a 5-hydroxy-3-oxa compound represented by the formula (2) is obtained. A -7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative can be formed.

  The epoxy compound represented by the formula (4) and the compound represented by the formula (2) produced by the reaction are separated by means of separation such as filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography and the like. Or by combining them, it can be separated and purified.

In the formula (1), a compound in which one or more fluorine atoms are bonded to the 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane ring represented by the formula is represented by the formula (1) A compound in which a hydrogen atom is bonded to the 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane ring represented by the formula in the formula, using a conventional fluorinating agent such as fluorine It can also be produced by subjecting to a reaction.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. In the chemical formula, Me represents a methyl group.

Example 1
5-Methacryloyloxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane-2,7,7-trione was produced according to the following reaction scheme.

11.6 g (0.1 mol) of the compound (5a) and 12.9 g (0.15 mol) of methyl acrylate (6a) were dissolved in 300 ml of dichloromethane, and trifluoroborane / diethyl was dissolved in this solution in an ice bath under a nitrogen atmosphere. 114 g (0.8 mol) of the ether complex was added dropwise, and then the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with an aqueous sodium hydrogen carbonate solution and then concentrated. The concentrate was dissolved in 100 ml of dichloromethane, and 12.9 g (0.075 mol) of m-chloroperbenzoic acid (mCPBA) was added to the solution, followed by stirring at room temperature for 4 hours. To the reaction solution, 10 ml of a 10% by weight aqueous sodium carbonate solution was added and stirred at room temperature for 6 hours. The reaction solution was separated, 200 ml of 35 wt% hydrochloric acid was added to the obtained aqueous layer, and the mixture was stirred at room temperature for 4 hours. When this liquid was extracted twice with 300 ml of dichloromethane and concentrated, an oily substance was obtained. This oily substance was dissolved in 100 ml of dichloromethane, and 10.1 g (0.1 mol) of triethylamine and 10.5 g (0.1 mol) of methacrylic acid chloride were added and stirred at 0 ° C. for 3 hours. The reaction solution is washed with an aqueous sodium hydrogen carbonate solution, concentrated, purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and 5-methacryloyloxy-3-oxa-7 represented by the formula (1a). -3.4 g (0.012 mol) of thiatricyclo [4.2.1.0 ^4,8 ] nonane-2,7,7-trione was obtained.
[Spectral data of 5-methacryloyloxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane-2,7,7-trione represented by the formula (1a)]
¹ H-NMR (CDCl ₃ ) δ: 2.0 (m, 3H), 2.3-2.9 (m, 3H), 3.0-3.5 (m, 2H), 4.2-4.6 (m, 2H), 5.7 (s, 1H) , 6.2 (s, 1H)
MS m / z: 69 (methacrylic acid-OH), 272 (M)

Claims (4)

Following formula (1)

(In the formula, R ^a represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, and R ¹ , R ² , R ³ and R ⁴ are the same or different. In addition, a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, or a hydroxyl group part may be protected with a protecting group and may have a halogen atom. A C 1-6 hydroxyalkyl group, wherein R ⁵ , R ⁶ , and R ⁷ are the same or different and are a hydrogen atom, a halogen atom, or a C 1-6 alkyl group optionally having a halogen atom; Represents a carboxyl group which may form a salt, a substituted oxycarbonyl group, or a cyano group, n represents 1 or 2. Steric position of R ¹ and CH ₂ ═C (R ^a ) COO— group. Are either end or exo respectively There)
A 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by: Following formula (2)

(In the formula, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a halogen atom, or a hydroxyl group moiety. Represents a hydroxyalkyl group having 1 to 6 carbon atoms which may be protected with a protecting group and may have a halogen atom, and R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, A halogen atom, an alkyl group having 1 to 6 carbon atoms that may have a halogen atom, a carboxyl group that may form a salt, a substituted oxycarbonyl group, or a cyano group, and n is 1 or 2. The three-dimensional positions of R ¹ and OH may be either endo or exo)
A 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by formula (3):

(In the formula, Ra represents ^a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms which may have a halogen atom)
Is reacted with an unsaturated carboxylic acid represented by the following formula (1):

(In the formula, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and n are the same as described above. R ¹ and CH ₂ ═C (R ^a ) COO— (Each position may be either end or exo)
Preparation of 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula: 3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative Law. Following formula (2)

(In the formula, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a halogen atom, or a hydroxyl group moiety. Represents a hydroxyalkyl group having 1 to 6 carbon atoms which may be protected with a protecting group and may have a halogen atom, and R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, A halogen atom, an alkyl group having 1 to 6 carbon atoms that may have a halogen atom, a carboxyl group that may form a salt, a substituted oxycarbonyl group, or a cyano group, and n is 1 or 2. The three-dimensional positions of R ¹ and OH may be either endo or exo)
A 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by: Following formula (4)

(Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, or a hydroxyl group moiety. Represents a hydroxyalkyl group having 1 to 6 carbon atoms which may be protected with a protecting group and may have a halogen atom, and R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, A halogen atom, an alkyl group having 1 to 6 carbon atoms which may have a halogen atom, a carboxyl group which may form a salt, a substituted oxycarbonyl group or a cyano group, and R ^b is a hydrogen atom or an organic group And n represents 1 or 2)
A 2,3-epoxy-7-thiabicyclo [2.2.1] heptane derivative represented by the following formula (2)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are the same as above. The steric positions of R ¹ and OH are either endo or exo, respectively. May be)
5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] nonane derivative represented by the formula: 5-hydroxy-3-oxa-7-thiatricyclo [4.2.1.0 ^4,8 ] Method for producing nonane derivative.