JP4529419B2 - Optically active fluorine-containing compounds and methods for producing them - Google Patents

Description

  The present invention relates to a novel optically active fluorine-containing compound, a process for producing the same, and a process for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid using the same.

  The optically active fluorine-containing compounds of the present invention are compounds useful as intermediates for pharmaceuticals and abstracts, for example, optically active 2,3-epoxy-α, α, α-trifluoropropionic acid, which is one of the compounds Benzyl ester can be easily derived into optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, which is known as an extremely useful compound as an intermediate for pharmaceuticals and agricultural chemicals.

  As a method for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, for example, racemic 3,3,3-trifluoro-2 using optically active α-phenylethylamine or the like is used. A production method by optical resolution of -hydroxy-2-methylpropionic acid is known (see, for example, Patent Document 1, Non-Patent Document 1, and Non-Patent Document 2).

  Also, optically active 3,3,3-trifluoro-2-hydroxy-2 is obtained by hydrolyzing the racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid ester derivative using lipase. -A method for producing methylpropionic acid is known (for example, see Patent Document 2).

JP-A-5-286915

International Publication No. 97/38124 Pamphlet J. et al. Chem. Soc. , 2329-2332, 1951 J. et al. Med. Chem. , 39, 4592-4601, 1996

  However, in the production method using an optical resolving agent, there is a problem in efficiency because it is necessary to carry out a de-resolving agent treatment after repeating recrystallization several times or more.

  Further, in the method using lipase, it is not possible to racemize an unnecessary enantiomer and use it again as a raw material when producing 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid. This is not an advantageous method.

  Furthermore, a method for efficiently producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid by an asymmetric synthesis method is not known.

  In order to solve the above-mentioned problems, the present inventors diligently studied a method for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, and as a result, optically active 2,3-epoxy- α, α, α-trifluoropropionic acid benzyl ester can be derived into a novel optically active 2,3-epoxy-α, α, α-trifluoropropionic acid by hydrogenation reaction, and the compound is reacted with a metal hydride It was found that the optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid can be produced easily and efficiently. In addition, novel optically active fluorine-containing compounds including optically active 2,3-epoxy-α, α, α-trifluoropropionic acid benzyl ester are used as asymmetric epoxy compounds for specific α, α, α-trifluoromethacrylic acid derivatives. As a result, the present invention was completed.

That is, the present invention
1. The following general formula (1)

［上記一般式（１）中、Ａは酸素原子、イオウ原子、又はＮＨ基を表す。また、Ｒ^１はメチル基、エチル基、炭素数３〜１０の直鎖、分岐若しくは環式のアルキル基、炭素数６〜２０の芳香族基、芳香環上の水素が任意にハロゲン原子で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意にメチル基で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意にエチル基で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキル基で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意にメトキシ基で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意にエトキシで置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキルオキシ基で置換された炭素数６〜２０の芳香族基、炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にハロゲンで置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にメチル基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にエチル基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキル基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にメトキシ基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にエトキシ基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキルオキシ基で置換された炭素数５〜１９のヘテロ芳香族基、ベンジル基、芳香環上の水素が任意にハロゲン原子で置換されたベンジル基、芳香環上の水素が任意にメチル基で置換されたベンジル基、芳香環上の水素が任意にエチル基で置換されたベンジル基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキル基で置換されたベンジル基、２−フェニルエチル基、又は炭素数６〜２０の芳香族基が結合した炭素数３〜１０の直鎖、分岐若しくは環式のアルキル基を表す。］
又は下記一般式（２）

[In said general formula (1), A represents an oxygen atom, a sulfur atom, or NH group. R ¹ is a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, an aromatic group having 6 to 20 carbon atoms, and hydrogen on the aromatic ring is optionally substituted with a halogen atom. The aromatic group having 6 to 20 carbon atoms, the hydrogen on the aromatic ring optionally substituted with a methyl group, and the hydrogen on the aromatic ring optionally substituted with an ethyl group Aromatic group having 6 to 20 carbon atoms, aromatic group having 6 to 20 carbon atoms, wherein hydrogen on the aromatic ring is optionally substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms An aromatic group having 6 to 20 carbon atoms in which the above hydrogen is optionally substituted with a methoxy group, an aromatic group having 6 to 20 carbon atoms in which a hydrogen on the aromatic ring is optionally substituted with ethoxy, and a hydrogen on the aromatic ring Is optionally substituted with a linear, branched or cyclic alkyloxy group having 3 to 6 carbon atoms. A heteroaromatic group having 5 to 19 carbon atoms, a heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with halogen, and optionally hydrogen on the aromatic ring is a methyl group A heteroaromatic group having 5 to 19 carbon atoms substituted with hydrogen, a heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with an ethyl group, and hydrogen on the aromatic ring optionally having carbon atoms Heteroaromatic group having 5 to 19 carbon atoms substituted with 3 to 6 linear, branched or cyclic alkyl group, Heterocarbon group having 5 to 19 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with methoxy group Aromatic groups, heteroaromatic groups having 5 to 19 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with ethoxy groups, hydrogen atoms on the aromatic ring optionally having 3 to 6 carbon atoms, straight chain, branched or cyclic A heteroaromatic group having 5 to 19 carbon atoms substituted with an alkyloxy group of A benzyl group in which the hydrogen on the ring is optionally substituted with a halogen atom, a benzyl group in which the hydrogen on the aromatic ring is optionally substituted with a methyl group, a benzyl group in which the hydrogen on the aromatic ring is optionally substituted with an ethyl group, A benzyl group, a 2-phenylethyl group, or an aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is arbitrarily substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms is bonded. A linear, branched or cyclic alkyl group having 3 to 10 carbon atoms is represented. ]
Or the following general formula (2)

［上記一般式（２）中、Ａ、Ｒ^１は上記と同じ定義である。］
で示される光学活性含フッ素化合物類、
２．下記式（３）又は式（４）で示される光学活性含フッ素化合物類、

[In the general formula (2), A and R ¹ have the same definitions as above. ]
Optically active fluorine-containing compounds represented by
2. Optically active fluorine-containing compounds represented by the following formula (3) or formula (4),

３．下記一般式（５）

3. The following general formula (5)

（上記一般式中、Ａは酸素原子、イオウ原子、又はＮＨ基を表す。また、Ｒ^１はメチル基、エチル基、炭素数３〜１０の直鎖、分岐若しくは環式のアルキル基、炭素数６〜２０の芳香族基、芳香環上の水素が任意にハロゲン原子で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意にメチル基で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意にエチル基で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキル基で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意にメトキシ基で置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意にエトキシで置換された炭素数６〜２０の芳香族基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキルオキシ基で置換された炭素数６〜２０の芳香族基、炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にハロゲンで置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にメチル基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にエチル基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキル基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にメトキシ基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意にエトキシ基で置換された炭素数５〜１９のヘテロ芳香族基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキルオキシ基で置換された炭素数５〜１９のヘテロ芳香族基、ベンジル基、芳香環上の水素が任意にハロゲン原子で置換されたベンジル基、芳香環上の水素が任意にメチル基で置換されたベンジル基、芳香環上の水素が任意にエチル基で置換されたベンジル基、芳香環上の水素が任意に炭素数３〜６の直鎖、分岐若しくは環式のアルキル基で置換されたベンジル基、２−フェニルエチル基、又は炭素数６〜２０の芳香族基が結合した炭素数３〜１０の直鎖、分岐若しくは環式のアルキル基を表す。）
で示されるα，α，α−トリフルオロメタクリル酸誘導体を不斉エポキシ化することを特徴とする上記一般式（１）又は一般式（２）で示される光学活性含フッ素化合物類の製造方法、
４．上記一般式（５）で示されるα，α，α−トリフルオロメタクリル酸誘導体を、（Ａ）希土類金属アルコキシド、（Ｂ）光学活性１，１’−ビ−２−ナフトール、（Ｃ）トリフェニルフォスフィンオキシド、並びに（Ｄ）クメンヒドロパーオキシド又はｔｅｒｔ−ブチルヒドロパーオキシドを含有する触媒の存在下、不斉エポキシ化反応することを特徴とする上記一般式（１）又は一般式（２）で示される光学活性含フッ素化合物類の製造方法、
５．下記式（６）又は式（７）で示される光学活性含フッ素化合物、

(In the above general formula, A represents an oxygen atom, a sulfur atom, or an NH group. Further, R ¹ represents a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, or a carbon number. An aromatic group having 6 to 20 carbon atoms, an aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is arbitrarily substituted with a halogen atom, and 6 to carbon atoms in which hydrogen on the aromatic ring is optionally substituted with a methyl group 20 aromatic group, aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with ethyl group, hydrogen optionally having 3 to 6 carbon atoms in the aromatic ring, straight chain, branched or ring An aromatic group having 6 to 20 carbon atoms substituted with an alkyl group of the formula, an aromatic group having 6 to 20 carbon atoms optionally substituted with hydrogen on the aromatic ring by a methoxy group, and an optional hydrogen on aromatic ring An aromatic group substituted with ethoxy having 6 to 20 carbon atoms, hydrogen on the aromatic ring is optionally a straight chain having 3 to 6 carbon atoms, C6-C20 aromatic group substituted with a branched or cyclic alkyloxy group, C5-C19 heteroaromatic group, C5-C5 optionally substituted with halogen on hydrogen on aromatic ring 19 heteroaromatic groups, 5 to 19 carbon atoms optionally substituted with hydrogen on the aromatic ring, and 5 to 5 carbon atoms optionally substituted with ethyl on the aromatic ring. 19 heteroaromatic groups, 5 to 19 heteroaromatic groups in which hydrogen on the aromatic ring is optionally substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, on the aromatic ring A heteroaromatic group having 5 to 19 carbon atoms in which hydrogen is optionally substituted with a methoxy group, a heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on an aromatic ring is optionally substituted with an ethoxy group, on an aromatic ring Hydrogen is optionally a linear, branched or cyclic alkyloxy having 3 to 6 carbon atoms A heteroaromatic group having 5 to 19 carbon atoms substituted with benzyl, a benzyl group in which hydrogen on the aromatic ring is optionally substituted with a halogen atom, or a benzyl in which hydrogen on the aromatic ring is optionally substituted with a methyl group A benzyl group in which hydrogen on the aromatic ring is optionally substituted with an ethyl group, a benzyl group in which hydrogen on the aromatic ring is optionally substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, A 2-phenylethyl group or a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms to which an aromatic group having 6 to 20 carbon atoms is bonded.
A process for producing optically active fluorine-containing compounds represented by the general formula (1) or the general formula (2), wherein the α, α, α-trifluoromethacrylic acid derivative represented by
4). The α, α, α-trifluoromethacrylic acid derivative represented by the general formula (5) is converted into (A) rare earth metal alkoxide, (B) optically active 1,1′-bi-2-naphthol, (C) triphenyl. Asymmetric epoxidation reaction is carried out in the presence of a phosphine oxide and a catalyst containing (D) cumene hydroperoxide or tert-butyl hydroperoxide. The above general formula (1) or (2) A process for producing optically active fluorine-containing compounds represented by:
5). An optically active fluorine-containing compound represented by the following formula (6) or formula (7):

６．上記一般式（１）で示される光学活性フッ素化合物を加水分解することを特徴とする上記一般式（６）で示される光学活性含フッ素化合物の製造方法、
７．上記一般式（２）で示される光学活性フッ素化合物を加水分解することを特徴とする上記一般式（７）で示される光学活性含フッ素化合物の製造方法、
８．上記式（３）で示される光学活性含フッ素化合物を水素添加反応することを特徴とする上記式（６）で示される光学活性含フッ素化合物の製造方法、
９．上記式（４）で示される光学活性含フッ素化合物を水素添加反応することを特徴とする上記式（７）で示される光学活性含フッ素化合物の製造方法、
１０．上記式（６）で示される光学活性含フッ素化合物と金属水素化物を反応させることを特徴とする（Ｒ）−３，３，３−トリフルオロ−２−ヒドロキシ−２−メチルプロピオン酸の製造方法、並びに
１１．上記式（７）で示される光学活性含フッ素化合物と金属水素化物を反応させることを特徴とする（Ｓ）−３，３，３−トリフルオロ−２−ヒドロキシ−２−メチルプロピオン酸の製造方法、
である。

6). A method for producing the optically active fluorine-containing compound represented by the general formula (6), wherein the optically active fluorine compound represented by the general formula (1) is hydrolyzed;
7). A method for producing the optically active fluorine-containing compound represented by the general formula (7), wherein the optically active fluorine compound represented by the general formula (2) is hydrolyzed;
8). A method for producing an optically active fluorine-containing compound represented by the above formula (6), wherein the optically active fluorine-containing compound represented by the above formula (3) is hydrogenated;
9. A process for producing an optically active fluorine-containing compound represented by the above formula (7), wherein the optically active fluorine-containing compound represented by the above formula (4) is hydrogenated;
10. A method for producing (R) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, comprising reacting an optically active fluorine-containing compound represented by the above formula (6) with a metal hydride And 11. A method for producing (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, comprising reacting an optically active fluorine-containing compound represented by the above formula (7) with a metal hydride ,
It is.

  The present invention is described in detail below.

  The optically active fluorine-containing compounds represented by the general formula (1) or the general formula (2) of the present invention are obtained by converting the α, α, α-trifluoromethacrylic acid derivative represented by the general formula (5) into an asymmetric epoxy. It can manufacture by reacting.

  In the present invention, in the general formula (1), general formula (2), or general formula (5), A represents an oxygen atom, a sulfur atom, or an NH group. Among these, as A, an oxygen atom or an NH group is preferable, and an oxygen atom is particularly preferable.

In the present invention, in the general formula (1), general formula (2), or general formula (5), R ¹ is a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms. Group, an aromatic group having 6 to 20 carbon atoms, a hydrogen atom on the aromatic ring optionally substituted with a halogen atom, and a hydrogen group on the aromatic ring optionally substituted with a methyl group An aromatic group having 6 to 20 carbon atoms, an aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with an ethyl group, and a straight chain in which hydrogen on the aromatic ring is optionally 3 to 6 carbon atoms An aromatic group having 6 to 20 carbon atoms substituted with a branched or cyclic alkyl group, an aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with a methoxy group, on the aromatic ring An aromatic group having 6 to 20 carbon atoms in which hydrogen is optionally substituted with ethoxy, and hydrogen on the aromatic ring is optionally having 3 to 6 carbon atoms A C6-C20 aromatic group substituted with a linear, branched, or cyclic alkyloxy group, a C5-C19 heteroaromatic group, carbon in which hydrogen on the aromatic ring is optionally substituted with halogen Heteroaromatic group having 5 to 19 carbon atoms, hydrogen on the aromatic ring optionally substituted with a methyl group Carbon atom having 5 to 19 carbon atoms optionally substituted with an ethyl group on the aromatic ring Heteroaromatic group having 5 to 19 carbon atoms, heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, aromatic A heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on the ring is optionally substituted with a methoxy group, a heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with an ethoxy group, aromatic The hydrogen on the ring is optionally a linear, branched or cyclic alkyl having 3 to 6 carbon atoms Heteroaromatic group having 5 to 19 carbon atoms substituted with a xy group, benzyl group, benzyl group in which hydrogen on the aromatic ring is arbitrarily substituted with halogen atom, hydrogen on aromatic ring is optionally substituted with methyl group Benzyl group, hydrogen on the aromatic ring optionally substituted with an ethyl group, hydrogen on the aromatic ring optionally substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms Represents a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms to which a group, 2-phenylethyl group, or an aromatic group having 6 to 20 carbon atoms is bonded. Among these, R ¹ is preferably a tert-butyl group, a phenyl group, a phenyl group in which hydrogen on the aromatic ring is substituted with a halogen atom, or a benzyl group, and particularly preferably a benzyl group.

As the general formula (1) or a compound represented by the general formula (2) of the present invention is not particularly limited, specifically, A is an oxygen atom, R ¹ is 1 to 10 carbon atoms Examples of the compound which is an alkyl group of (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid methyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) ) Propionic acid ethyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid isopropyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid n-butyl Ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid n-butyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propiate Acid tert-butyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid cyclohexyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid cyclohexylmethyl Ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid 2-cyclohexylethyl ester, and the like.

Examples of the compound represented by the above general formula (1) or general formula (2) in which A is an oxygen atom and R ¹ is an aromatic group having 6 to 20 carbon atoms include, for example, (R) -2, 3-epoxy-2- (trifluoromethyl) propionic acid phenyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid p-chlorophenyl ester, (R) -2,3-epoxy- 2- (trifluoromethyl) propionic acid m-chlorophenyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid o-chlorophenyl ester, (R) -2,3-epoxy-2- (Trifluoromethyl) propionic acid p-bromophenyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid m-bromophenyl ester Steal, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid o-bromophenyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid p-fluorophenyl Ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid m-fluorophenyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid o-fluorophenyl Ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid p-methoxyphenyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid m-methoxyphenyl Ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid o-methoxyphenyl ester Etc.

Moreover, A is an oxygen atom and R < ¹ > is shown by the said General formula (1) or General formula (2) which is a C1-C10 alkyl group which the C6-C20 aromatic group couple | bonded. Examples of the compound include (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid benzyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid 2-phenyl Ethyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid (p-chlorophenyl) methyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid ( p-bromophenyl) methyl ester, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid (p-fluorophenyl) methyl ester, and the like.

Also, A is an NH group, the compounds represented by the general formula ^{R 1} is an alkyl group having 1 to 10 carbon atoms (1) or general formula (2), for example, (R)-2,3 -Epoxy-2- (trifluoromethyl) propionic acid methylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid ethylamide, (R) -2,3-epoxy-2- (trifluoro) Methyl) propionic acid isopropylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid n-butyramide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid n -Butyramide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid tert-butyramide, (R) -2,3-epoxy-2- (trifluoro) (Romethyl) propionic acid cyclohexylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid cyclohexylmethylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid 2 -Cyclohexylethylamide etc. are mentioned.

Also, A is an NH group, the compounds represented by the general formula ^{R 1} is an aromatic group having 6 to 20 carbon atoms (1) or general formula (2), for example, (R) -2, 3-epoxy-2- (trifluoromethyl) propionic acid anilide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid p-chlorophenylamide, (R) -2,3-epoxy-2 -(Trifluoromethyl) propionic acid m-chlorophenylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid o-chlorophenylamide, (R) -2,3-epoxy-2- ( (Trifluoromethyl) propionic acid p-bromophenylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid m-bromophenylamide, (R) -2, 3-epoxy-2- (trifluoromethyl) propionic acid o-bromophenylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid p-fluorophenylamide, (R) -2, 3-epoxy-2- (trifluoromethyl) propionic acid m-fluorophenylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid o-fluorophenylamide, (R) -2, 3-epoxy-2- (trifluoromethyl) propionic acid p-methoxyphenylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid m-methoxyphenylamide, (R) -2, And 3-epoxy-2- (trifluoromethyl) propionic acid o-methoxyphenylamide.

Also, A is an NH group, ^{R 1} is represented by the general formula is an alkyl group having 1 to 10 carbon atoms which is aromatic group having 6 to 20 carbon atoms bonded (1) or general formula (2) Examples of the compound include (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid benzylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid 2-phenyl Ethylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid (p-chlorophenyl) methylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid (p -Bromophenyl) methylamide, (R) -2,3-epoxy-2- (trifluoromethyl) propionic acid (p-fluorophenyl) methylamide, and the like.

  The compound represented by the general formula (1) or the general formula (2) of the present invention includes not only the above (R) isomers but also the (S) isomers which have a relationship between these and the enantiomers.

  In the present invention, by optically asymmetric epoxidizing the α, α, α-trifluoromethacrylic acid derivative represented by the general formula (5), the optical represented by the general formula (1) or the general formula (2). Active fluorine-containing compounds can be produced.

Examples of the compound represented by the general formula (5) of the present invention is not particularly limited, specifically, A is an oxygen atom, R ¹ is an alkyl group having 1 to 10 carbon atoms wherein Examples of the compound include α, α, α-trifluoromethacrylic acid methyl ester, α, α, α-trifluoromethacrylic acid ethyl ester, α, α, α-trifluoromethacrylic acid isopropyl ester, α, α, α -Trifluoromethacrylic acid n-butyl ester, α, α, α-trifluoromethacrylic acid n-butyl ester, α, α, α-trifluoromethacrylic acid tert-butyl ester, α, α, α-trifluoromethacrylic acid Cyclohexyl ester, α, α, α-trifluoromethacrylic acid Cyclohexylmethyl ester, α, α, α-trifluoromethacrylic acid 2-Si Examples include cyclohexyl ethyl ester.

Examples of the compound represented by the general formula (5) in which A is an oxygen atom and R ¹ is an aromatic group having 6 to 20 carbon atoms include, for example, α, α, α-trifluoromethacrylic acid phenyl ester. , Α, α, α-trifluoromethacrylic acid p-chlorophenyl ester, α, α, α-trifluoromethacrylic acid m-chlorophenyl ester, α, α, α-trifluoromethacrylic acid o-chlorophenyl ester, α, α, α-trifluoromethacrylic acid p-bromophenyl ester, α, α, α-trifluoromethacrylic acid m-bromophenyl ester, α, α, α-trifluoromethacrylic acid o-bromophenyl ester, α, α, α- Trifluoromethacrylic acid p-fluorophenyl ester, m-fluorophenyl ester, α, α, α-trifluoromethacrylic acid Acid o-fluorophenyl ester, α, α, α-trifluoromethacrylic acid p-methoxyphenyl ester, α, α, α-trifluoromethacrylic acid m-methoxyphenyl ester, α, α, α-trifluoromethacrylic acid o -Methoxyphenyl ester etc. are mentioned.

Also, A is an oxygen atom, R ¹ is a compound represented by the general formula is an alkyl group having 1 to 10 carbon atoms which is aromatic group having 6 to 20 carbon atoms bonded (5), for example, α, α, α-trifluoromethacrylic acid benzyl ester, α, α, α-trifluoromethacrylic acid 2-phenylethyl ester, α, α, α-trifluoromethacrylic acid (p-chlorophenyl) methyl ester, α, α , Α-trifluoromethacrylic acid (p-bromophenyl) methyl ester, α, α, α-trifluoromethacrylic acid (p-fluorophenyl) methyl ester, and the like.

Examples of the compound represented by the general formula (5) in which A is an NH group and R ¹ is an alkyl group having 1 to 10 carbon atoms include, for example, α, α, α-trifluoromethacrylic acid methylamide, α , Α, α-trifluoromethacrylic acid ethylamide, α, α, α-trifluoromethacrylic acid isopropylamide, α, α, α-trifluoromethacrylic acid n-butyramide, α, α, α-trifluoromethacrylic acid n- Butyramide, α, α, α-trifluoromethacrylic acid tert-butylamide, α, α, α-trifluoromethacrylic acid cyclohexylamide, α, α, α-trifluoromethacrylic acid cyclohexylmethylamide, α, α, α-tri Examples include fluoromethacrylic acid 2-cyclohexylethylamide and the like.

Examples of the compound represented by the general formula (5) in which A is an NH group and R ¹ is an aromatic group having 6 to 20 carbon atoms include, for example, α, α, α-trifluoromethacrylic acid anilide, α, α, α-trifluoromethacrylic acid p-chlorophenylamide, α, α, α-trifluoromethacrylic acid m-chlorophenylamide, α, α, α-trifluoromethacrylic acid o-chlorophenylamide, α, α, α -Trifluoromethacrylic acid p-bromophenylamide, α, α, α-trifluoromethacrylic acid m-bromophenylamide, α, α, α-trifluoromethacrylic acid o-bromophenylamide, α, α, α-tri Fluoromethacrylic acid p-fluorophenylamide, α, α, α-trifluoromethacrylic acid m-fluorophenylamide, α, α, α-trifluoro Methacrylic acid o-fluorophenylamide, α, α, α-trifluoromethacrylic acid p-methoxyphenylamide, α, α, α-trifluoromethacrylic acid m-methoxyphenylamide, α, α, α-trifluoromethacrylic acid o-methoxyphenylamide and the like can be mentioned.

Also, A is an NH group, R ¹ is a compound represented by the general formula is an alkyl group having 1 to 10 carbon atoms which is aromatic group having 6 to 20 carbon atoms bonded (5), for example, α, α, α-trifluoromethacrylic acid benzylamide, α, α, α-trifluoromethacrylic acid 2-phenylethylamide, α, α, α-trifluoromethacrylic acid (p-chlorophenyl) methylamide, α, α, Examples include α-trifluoromethacrylic acid (p-bromophenyl) methylamide, α, α, α-trifluoromethacrylic acid (p-fluorophenyl) methylamide, and the like.

  In the method of the present invention, the method for preparing the α, α, α-trifluoromethacrylic acid derivative represented by the general formula (5) is not particularly limited, but for example, α, α, α-trifluoromethacrylic acid is used. The acid is treated with thionyl chloride to form α, α, α-trifluoromethacrylic acid chloride, and then an alcohol or phenol represented by R1-AH in a solvent such as ether or dichloromethane in the presence of a base such as triethylamine. As well as by reaction with amines.

  In the method of the present invention, various asymmetric epoxidation reactions can be applied to the preparation of the optically active fluorine-containing compound represented by the general formula (1) or the general formula (2). For example, titanium tetraisopropoxide, a method using a tartaric acid derivative, a method using a quaternary ammonium salt such as a cinchona alkaloid derivative, a method using a polyamino acid, a metal such as zinc, lithium, magnesium or a lanthanoid, an optically active 1,1 Examples include a method using an asymmetric ligand such as a '-bi-2-naphthol derivative, a method using an optically active dioxirane, a method using a salen-manganese complex, etc. In the method of the present invention, (A) a rare earth In the presence of a catalyst containing a metal alkoxide, (B) optically active 1,1′-bi-2-naphthol, (C) triphenylphosphine oxide, and (D) cumene hydroperoxide or tert-butyl hydroperoxide, An asymmetric epoxidation reaction is preferred.

  In the method of the present invention, the (A) rare earth metal alkoxide used in the asymmetric epoxidation reaction is not particularly limited, but specifically, scandium trimethoxide, scandium triethoxide, scandium triisopropoxy is used. , Scandium tri-n-propoxide, yttrium trimethoxide, yttrium triethoxide, yttrium triisopropoxide, yttrium tri-n-propoxide, lanthanum trimethoxide, lanthanum triethoxide, lanthanum triisopropoxide, Lanthanum tri-n-propoxide, cerium trimethoxide, cerium triethoxide, cerium triisopropoxide, cerium tri-n-propoxide, praseodymium trimethoxide, praseodymium triethoxide, praseodi Triisopropoxide, praseodymium tri-n-propoxide, neodymium trimethoxide, neodymium triethoxide, neodymium triisopropoxide, neodymium tri-n-propoxide, samarium trimethoxide, samarium triethoxide, samarium triisopropoxy , Samarium tri-n-propoxide, europium trimethoxide, europium triethoxide, europium triisopropoxide, europium tri-n-propoxide, gadolin trimethoxide, gadolin triethoxide, gadolin triiso Propoxide, gadolinium tri-n-propoxide, terbium trimethoxide, terbium triethoxide, terbium triisopropoxide, terbium tri-n-propoxide, dysprosium Limethoxide, dysprosium triethoxide, dysprosium triisopropoxide, dysprosium tri-n-propoxide, holmium trimethoxide, holmium triethoxide, holmium triisopropoxide, holmium tri-n-propoxide , Erbium trimethoxide, erbium triethoxide, erbium triisopropoxide, erbium tri-n-propoxide, thulium trimethoxide, thulium triethoxide, thulium triisopropoxide, thulium tri-n-propoxide, ytterbium tri Methoxide, ytterbium triethoxide, ytterbium triisopropoxide, ytterbium tri-n-propoxide, ruthenium trimethoxide, ruthenium triethoxide, ruthenium Examples include triisopropoxide, ruthenium tri-n-propoxide and the like.

  In the method of the present invention, (A) lanthanum triisopropoxide, cerium triisopropoxide, praseodymium triisopropoxide, neodymium triisopropoxide, samarium triisopropoxide, europium triisopropoxide is used as the rare earth metal alkoxide. , Gadolinium triisopropoxide, terbium triisopropoxide, dysprosium triisopropoxide, holmium triisopropoxide, erbium triisopropoxide, thulium triisopropoxide, ytterbium triisopropoxide, ruthenium triisopropoxide And lanthanum triisopropoxides such as lanthanum triisopropoxide and lanthanum triisopropoxide and ytterbium triisopropoxide are more preferable. Sopuropokishido is particularly preferred.

  In the method of the present invention, the method for preparing the rare earth metal alkoxide is not particularly limited. Moreover, as the usage-amount of rare earth metal alkoxide, 0.1 mol%-30 mol% are normally used with respect to (alpha), (alpha), (alpha) -trifluoromethacrylic acid benzyl ester used for reaction.

  In the method of the present invention, the amount of optically active 1,1′-bi-2-naphthol used in the asymmetric epoxidation reaction is usually 1 to 2 times the molar amount of the lanthanoid triisopropoxide used in the reaction. However, the molar amount is preferably 1 to 1.2 times.

  In the method of the present invention, the amount of triphenylphosphine oxide used in the asymmetric epoxidation reaction is 1 to 5 times the molar amount relative to the lanthanoid triisopropoxide used in the reaction. Use 1-3 times molar amount.

  In the method of the present invention, the amount of cumene hydroperoxide or tert-butyl hydroperoxide used in the asymmetric epoxidation reaction is usually 1 to 4 times the molar amount of lanthanoid triisopropoxide at the time of catalyst formation, Further, during the reaction, it is usually used in an amount of 1 to 2 times the molar amount of α, α, α-trifluoromethacrylic acid benzyl ester used in the reaction.

  In the method of the present invention, in preparing the optically active fluorine-containing compound represented by the general formula (1), (A) lanthanoid triisopropoxide as the rare earth metal alkoxide, (B) optically active 1,1′-bi As the 2-naphthol, a catalyst containing (R) -1,1′-bi-2-naphthol, (C) triphenylphosphine oxide, and (D) cumene hydroperoxide was used. It is particularly preferred to carry out a homogeneous epoxidation reaction. Similarly, in the preparation of the optically active fluorine-containing compound represented by the general formula (2), (A) lanthanoid triisopropoxide as the rare earth metal alkoxide, (B) optically active 1,1′-bi-2- Asymmetric epoxidation with cumene hydroperoxide using a catalyst containing (S) -1,1′-bi-2-naphthol, (C) triphenylphosphine oxide, and (D) cumene hydroperoxide as naphthol It is particularly preferred to carry out the reaction.

  In the method of the present invention, in the asymmetric epoxidation reaction, (A) a rare earth metal alkoxide, (B) optically active 1,1′-bi-2-naphthol, (C) triphenylphosphine oxide, and (D) A catalyst solution comprising cumene hydroperoxide or tert-butyl hydroperoxide is prepared in advance, and the substrate and cumene hydroperoxide or tert-butyl hydroperoxide are mixed and supplied to the catalyst solution for reaction. Alternatively, the reaction may be carried out by separately supplying the substrate and cumene hydroperoxide or tert-butyl hydroperoxide to the catalyst solution.

  In the method of the present invention, in the asymmetric epoxidation reaction, an appropriate amount of zeolite such as molecular sieves 3A and molecular sieves 4A in powder or molded form may be used as necessary to keep the system anhydrous. .

  In the method of the present invention, the solvent applicable to the asymmetric epoxidation reaction is not particularly limited, and specifically, ethers such as tetrahydrofuran (hereinafter abbreviated as THF), diethyl ether, diisopropyl ether and the like. Aromatic hydrocarbons such as benzene, toluene and ethylbenzene, and the like are preferable, and ethers are preferable, and THF is particularly preferable.

  In the method of the present invention, the reaction temperature of the asymmetric epoxidation reaction can be carried out in the range of −50 ° C. to 50 ° C., and includes the optical activity represented by the general formula (1) or the general formula (2). In order to obtain fluorine compounds with high optical purity, it is desirable to carry out at −30 ° C. to 10 ° C.

  In the method of the present invention, the reaction time of the asymmetric epoxidation reaction varies depending on the substrate concentration, the catalyst amount, the catalyst concentration, and the reaction temperature, and is not particularly limited, but is usually 2 to 24 hours after adding the substrate. The reaction is completed within.

  In the method of the present invention, the post-treatment of the asymmetric epoxidation reaction is not particularly limited, but usually, after adding a saturated aqueous ammonium chloride solution to decompose the catalyst, surplus cumene hydroperoxide is present. Is purified with an aqueous solution of sodium hydrogen sulfite and the like and then purified by silica gel column chromatography or the like to obtain the target optically active fluorine-containing compound represented by the general formula (1) or (2) with an optical purity of 60. ~ 95% ee can be obtained.

  The optically active fluorine-containing compound represented by the above formula (6) of the present invention hydrolyzes the (2R) -2,3-epoxy-2- (trifluoromethyl) propionic acid derivative represented by the above general formula (1). Can be manufactured. Similarly, the optically active fluorine-containing compound represented by the above formula (7) hydrolyzes the (2S) -2,3-epoxy-2- (trifluoromethyl) propionic acid derivative represented by the above general formula (2). Can be manufactured.

  The hydrolysis conditions of the present invention are not particularly limited, but for hydrolysis of esters, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like are used for the reaction. 1.2 to 3 times the molar amount of the optically active-2,3-epoxy-2- (trifluoromethyl) propionic acid derivative to be used, in a water-methanol mixed solvent at a temperature range of 0 to 60 ° C., By reacting for 1 to 12 hours, the compound represented by the above formula (6) or (7) can be obtained. For hydrolysis of amides, the above-mentioned formula (6) or formula (7) of the target product is obtained by reacting in a solvent in the presence of 10 to 100 mol% hydrochloric acid at a temperature range of 0 to 60 ° C. for 1 to 12 hours. The optically active fluorine-containing compound can be obtained.

  The post-treatment conditions after the hydrolysis of the present invention are not particularly limited, but the desired product is obtained by extraction with a solvent such as ethyl acetate under acidic conditions.

  The optically active fluorine-containing compound represented by the above formula (6) of the present invention is obtained by converting (2R) -2,3-epoxy-2- (trifluoromethyl) propionic acid benzyl ester represented by the above formula (3) into a metal It can be produced by a hydrogenation reaction in the presence of a catalyst. Similarly, the optically active fluorine-containing compound represented by the above formula (7) is obtained by converting (2S) -2,3-epoxy-2- (trifluoromethyl) propionic acid benzyl ester represented by the above formula (4) into a metal catalyst. It can be produced by hydrogenation reaction in the presence.

  In the method of the present invention, the metal catalyst used for the hydrogenation reaction is not particularly limited, and specific examples thereof include platinum, platinum oxide, palladium, palladium hydroxide, rhodium, ruthenium, iridium, Raney nickel and the like. In addition, there may be mentioned those supported on carbon, alumina, calcium sulfate, etc., preferably platinum or platinum oxide.

  In the method of the present invention, the amount of the metal catalyst used for the hydrogenation reaction varies depending on the type of the catalyst and is not particularly limited. However, the optical activity 2,3- (3) represented by the above formula (3) or formula (4) is not limited. It is usually used in an amount of 0.1 to 20% by weight in terms of metal weight based on epoxy-2- (trifluoromethyl) propionic acid benzyl ester.

  In the method of the present invention, the solvent applicable to the hydrogenation reaction is not particularly limited as long as it is inert to the reaction. Specifically, water, alcohols such as methanol and ethanol, acetic acid Examples include ethyl, acetic acid, ethers, benzene, hexane, dioxane and the like. Of these, alcohols are preferable, and methanol is particularly preferable.

  In the method of the present invention, the reaction temperature and reaction time of the hydrogenation reaction vary depending on the type of catalyst, but the reaction is usually carried out in the range of −20 ° C. to 30 ° C. under normal pressure or increased pressure for 5 to 24 hours. Complete.

  In the method of the present invention, the post-treatment of the hydrogenation reaction is not particularly limited. Usually, the catalyst is removed by filtration, and then the solvent is distilled off under reduced pressure to obtain the target formula (6). Alternatively, optically active fluorine-containing compounds represented by the formula (7) can be obtained.

  In the method of the present invention, the optically active 2,3-epoxy-2- (trifluoromethyl) propionic acid benzyl ester represented by the above formula (3) or (4) used for the hydrogenation reaction is not necessarily highly pure. For example, after completion of the asymmetric epoxidation reaction of α, α, α-trifluoromethacrylic acid benzyl ester, cumyl alcohol which is a decomposition product of cumene hydroperoxide, optically active 1,1′-bi You may use in the state of the composition containing 2-naphthol, a triphenylphosphine oxide, etc., and hydrogenation reaction advances on the reaction conditions mentioned above. The post-treatment in this case is not particularly limited, but usually, the catalyst is filtered off, the solvent is distilled off under reduced pressure, ethyl acetate, water, sodium hydrogen carbonate is added, stirred, after layering, the aqueous layer Is made acidic with hydrochloric acid or the like and extracted with ethyl acetate to obtain the objective optically active fluorine-containing compounds represented by the above formula (6) or formula (7).

  (R) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid is produced by reducing the optically active fluorine-containing compound represented by the above formula (6) of the present invention with a metal hydride. can do. Similarly, (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid is produced by reducing the optically active fluorine-containing compound represented by the above formula (7) with a metal hydride. can do.

  In the method of the present invention, the metal hydride used for the reduction reaction is not particularly limited. Specifically, sodium borohydride, sodium trimethoxyborohydride, sodium cyanoborohydride, triacetoxyborohydride Sodium, lithium borohydride, lithium tri-s-butylborohydride, lithium triethylborohydride, lithium triciamylborohydride, potassium borohydride, potassium tri-s-butylborohydride, triciamylborohydride Potassium, zinc borohydride, calcium borohydride, lithium aluminum hydride, lithium trimethoxyaluminum hydride, lithium tri-t-butoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, hydrogenated Isobutyl aluminum and the like, and among these preferably diisobutylaluminum hydride.

  In the method of the present invention, the amount of the metal hydride used for the reduction reaction is based on the optically active 2,3-epoxy-2- (trifluoromethyl) propionic acid represented by the above formula (6) or formula (7). In general, 1 to 5 equivalents are used.

  In the method of the present invention, the solvent applicable to the reduction reaction is not particularly limited as long as it varies depending on the type of metal hydride and is inert to the reaction. Specifically, alcohols such as methanol and ethanol, ethers such as THF, diethyl ether and diisopropyl ether, aliphatic hydrocarbons such as hexane and heptane, halogenated hydrocarbons such as dichloromethane and chloroform, benzene and toluene For example, when diisobutylaluminum hydride is used as the metal hydride, toluene, hexane or the like, or a halogenated hydrocarbon mixture such as dichloromethane and the like is preferable.

  In the method of the present invention, the reaction temperature and reaction time in the reduction reaction are not particularly limited, but the reaction is usually completed within 1 to 24 hours in the range of -100 ° C to 20 ° C.

  In the method of the present invention, the post-treatment in the reduction reaction is not particularly limited, but methanol is added dropwise at -80 ° C. or lower to stop the reaction, the reaction solution is acidified with hydrochloric acid or the like, and then sodium chloride. (R) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid or (S) -3,3,3-trifluoro-2-hydroxy by extraction with ether 2-Methylpropionic acid is obtained. The obtained optically active-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid should usually have an optical purity of 99.9% ee or higher by recrystallization with a solvent such as toluene. Can do.

  The present invention provides novel optically active fluorine-containing compounds and is industrially useful.

  Among the derivatives of the present invention, the optically active 2,3-epoxy-2- (trifluoromethyl) propionic acid benzyl ester represented by the above formula (3) or formula (4) uses an optical resolution agent and an enzyme. And the optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid can be produced easily and efficiently, so that the production method of the present invention is simpler and more efficient than the conventional method. This method is suitable for mass synthesis and is extremely useful industrially.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited only to an Example. The compounds were analyzed using the following equipment.

⁽¹ H-NMR and ¹³ C-NMR measurement)
Performed with Varian Gemini-200.

(Infrared absorption measurement)
Performed with 2000 FT-IR manufactured by Perkin Elmer.

(Elemental analysis)
C, H; Performed on Perkin Elmer 2400IICH F; Performed on HPLC. Column: Tosoh TSKgel IC-Anion-PWXLPEEK (4.6 mm ID × 750 mm), eluent: 1.3 mM gluconic acid-borax buffer, detector: conductivity detector.

(Mass spectrometry)
Implemented with Hitachi M-80B.

(Measurement of specific rotation)
Implemented with HORIBA SEPA-300.

Reference Example 1 Preparation of α, α, α-trifluoromethacrylic acid benzyl ester α, α, α-trifluoromethacrylic acid (154.0 g, 1.10 mol) was added to a 500 ml two-necked round flask equipped with a condenser and a stirrer. ) And thionyl chloride (170.1 g, 1.43 mol) were added and refluxed for 5 hours. By distillation, α, α, α-trifluoromethacrylic acid chloride (92.6 g) having a boiling point of 88 to 92 ° C. was obtained (yield 53%). In addition, α, α, α-trifluoromethacrylic anhydride (34.0 g) having a boiling point of 106 ° C./31 mmHg was obtained as a by-product (yield 24%).

  Benzyl alcohol (54.6 g, 0.51 mol) and diethyl ether (600 ml) were added to a 1000 ml three-necked round flask equipped with a dropping funnel and a stir bar, and then the α, α, α-trile obtained above was added. Fluoromethacrylic acid chloride (80.0 g, 0.51 mol) was added dropwise at −40 ° C., and then a mixture of triethylamine (56.2 g, 0.56 mol) and diethyl ether (200 ml) was added dropwise. After stirring at -40 ° C for 1 hour, the mixture was further stirred at 0 ° C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ether and drying over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by a silica gel column (hexane / ethyl acetate = 9/1: vol / vol) to obtain α, α, α-trifluoromethacrylic acid benzyl ester (95.3 g) (yield 82%).

(result of analysis)
¹ H-NMR (200 MHz, CDCl ₃ ) δ 7.37-7.29 (m, 5H), 6.70-6.67 (m, 1H), 6.38-6.37 (m, 1H), 5 .25 (s, 2H).

Example 1 Preparation of (S) -2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester A 2000 ml three-necked round flask equipped with a dropping funnel and a stirrer was purged with nitrogen, and then molecular sieves 4A (46 3 g, pre-dried product at 180 ° C. for 4 hours under reduced pressure), (R) -1,1′-bi-2-naphthol (7.29 g, 25.5 mmol), triphenylphosphine oxide (19.3 g, 69) 0.5 mmol) and THF (250 ml) were added. After dissolving by stirring for 5 minutes, a THF solution (250 ml) of lanthanum triisopropoxide (7.32 g, 23.2 mmol) was added and stirred at room temperature for 1 hour. Cumene hydroperoxide (7.06 g, 46.4 mmol) was added, and the catalyst was prepared by further stirring at room temperature for 2 hours.

  After confirming that the reaction solution was green, the reaction solution was cooled to -20 ° C. After adding cumene hydroperoxide (89.8 g, 0.59 mol), a solution of α, α, α-trifluoromethacrylic acid benzyl ester (106.6 g, 0.46 mol) in THF (500 ml) was added from a dropping funnel. It was added dropwise over time. After stirring at −20 ° C. for 12 hours, disappearance of the raw materials was confirmed by 1H-NMR.

  Saturated aqueous ammonium chloride solution (300 ml) and 5% aqueous sodium hydrogen sulfite solution (200 ml) were added to stop the reaction, and the insoluble material was filtered off through celite, followed by liquid separation. After the organic phase was concentrated, the origin component was removed with a silica gel column (hexane / ethyl acetate = 3/1: vol / vol). Further, (S) -2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester (104.7 g) was obtained by purification with a silica gel column (hexane / ethyl acetate = 9/1: vol / vol). (Yield 92%, optical purity 78ee%). The optical purity was measured under the following conditions.

Column: CHIRALCEL OD-H (4.6 mm ID × 250 mm) manufactured by Daicel
Eluent: hexane / isopropanol = 9/1 (vol / vol)
Flow rate: 1.0 ml / min
Detector: UV = 254 nm
Holding time: 10.3 min (S), 11.2 min (R).

  The (S) -2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester obtained in Example 1 was isolated and purified using an optical resolution column (CHIRALCEL OD-H, manufactured by Daicel) and analyzed. went. The physical property values are shown below.

(result of analysis)
¹ H-NMR (200 MHz, CDCl ₃ ) δ 7.48-7.26 (m, 5H), 5.36-5.22 (m, 2H), 3.27-3.19 (m, 2H)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ 163.40, 134.15, 128.74, 128.70, 128.19, 121.45 (q, J = 276.5 Hz), 68.30, 53.94 (Q, J = 37.6 Hz), 49.02
IR (KBr; ν cm ⁻¹ ) 3037, 2965, 1755, 1499, 1457, 1389, 1331, 1237, 1179, 1148, 1078, 1030, 958, 870, 782, 752, 696
Elemental analysis; C53.67, H3.68, F23.42 (Calc .; C53.64, H3.74, F23.15)
MASS (m / z) 246 (M +)
Specific rotation [α] _D ²⁵ = 9.8 ° (C = 2.0, methanol).

Example 2 Preparation of (R) -2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester (S) -1,1′- in place of (R) -1,1′-bi-2-naphthol (R) -2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester was obtained by carrying out the reaction in the same manner as in Example 1 using bi-2-naphthol (yield 90%, Optical purity 78ee%). ¹ H and ¹³ C-NMR and IR spectral data were identical to those shown in Example 1.

(result of analysis)
Elemental analysis; C53.45, H3.78, F23.09 (Calc .; C53.64, H3.74, F23.15)
Specific rotation [α] _D ²⁵ = −9.8 ° (C = 2.0, methanol).

Example 3 Preparation of (S) -2,3-epoxy-2-trifluoromethylpropionic acid In a 500 ml round three-necked flask equipped with a stirrer, (S) -2,3-epoxy-2-trifluoro Methylpropionic acid benzyl ester (20.9 g, 84.9 mmol, 99ee%) was added, and 180 ml of methanol was added and dissolved. After adding platinum oxide (1.63 g), the reaction system was replaced with hydrogen. After stirring for 4 hours at room temperature, platinum oxide was filtered off. After the solvent was distilled off under reduced pressure, (S) -2,3-epoxy-2-trifluoromethylpropionic acid (11.9 g) was obtained (yield 90%).

(result of analysis)
¹ H-NMR (CDCl ₃ ) δ 9.28 (br, 1H), 3.36-3.25 (m, 2H)
¹³ C-NMR (CDCl ₃ ) δ 168.76, 121.25 (q, J = 275.6 Hz), 53.71 (q, J = 38.5 Hz)
IR (KBr; ν cm ⁻¹ ) 3528, 2928, 1744, 1636, 1388, 1318, 1259, 1179, 1090, 961, 875, 758, 684
Elemental analysis; C30.78, H1.94, F36.38 (Calc .; C30.59, H1.80, F36.52)
MASS (m / z) 157 ([M + H] +)
Specific rotation [α] _D ²⁵ = 10.9 ° (C = 2.0, methanol).

Example 4 Preparation of (R) -2,3-epoxy-2-trifluoromethylpropionic acid (S) -2,3-epoxy-2-trifluoromethylpropionic acid instead of benzyl ester (R) -2, (R) -2,3-epoxy-2-trifluoromethylpropionic acid is obtained by carrying out the reaction under the same conditions as in Example 3 using 3-epoxy-2-trifluoromethylpropionic acid benzyl ester. (93% yield). The ¹ H and ¹³ C-NMR and IR spectrum data of this product were the same as those shown in Example 3.

(result of analysis)
Elemental analysis; C30.67, H1.72, F36.71 (Calc .; C30.59, H1.80, F36.52)
Specific rotation [α] _D ²⁵ = −10.9 ° (C = 2.0, methanol).

Example 5 Preparation of (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid 1.0 M hydrogenation in a 500 ml round three-necked flask equipped with a stir bar under a nitrogen atmosphere Diisobutylaluminum / hexane solution (2400 ml, 2.40 mol) was added. The solution was cooled to -80 ° C. A solution of (S) -2,3-epoxy-2-trifluoromethylpropionic acid (149.82 g, 0.96 mol) in dichloromethane (600 g) was added from a dropping funnel over 2 hours. After stirring at −70 ° C. for 1 hour, the mixture was stirred at −50 ° C. for 6 hours. The reaction solution was cooled to −80 ° C., and a mixed solution of methanol (100 g) and dichloromethane (100 g) was added dropwise over 2 hours to stop the reaction. The reaction solution was added dropwise to 1800 ml of an 18% aqueous HCl solution cooled to 0 ° C. over 2 hours, and 160 g of sodium chloride was added. Extraction was performed twice with 500 ml of diethyl ether, and the solvent was distilled off under reduced pressure to obtain (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (98.6 g) (yield 65). %). By performing this recrystallization operation twice with toluene (400 ml), (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (51. 3) having an optical purity of 99.9 ee%. 6 g) was obtained (yield 34%). Since this shows the same ¹ H and ¹³ C-NMR and IR spectrum data as (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid already reported (S ) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid.

  The optical purity was measured as follows. To the obtained crystals, an ether solution of diazomethane was added to form a methyl ester, and this solution was analyzed by gas chromatography (GC) under the following conditions to calculate the optical purity.

Column: CP-Chiracil-Dex CB (0.25 mm × 25 m) manufactured by Chrome Pack
Column temperature: 70 ° C
Detector: FID.

(result of analysis)
Specific rotation [α] _D ²⁵ = −18.9 ° (C = 4.0, methanol).

Example 6 Preparation of (R) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (S) instead of (S) -2,3-epoxy-2-trifluoromethylpropionic acid The reaction is carried out under the same conditions as in Example 5 using 2,3-epoxy-2-trifluoromethylpropionic acid, and (R) -3,3,3-trifluoro-2-hydroxy- 2-Methylpropionic acid was obtained (yield 36%). Since this product shows the same 1H and 13C-NMR and IR spectrum data as (R) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid already reported, (R)- It was determined to be 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid.

(result of analysis)
Specific rotation [α] _D ²⁵ = 18.9 ° (C = 4.0, methanol)
Reference Example 2 Preparation of α, α, α-trifluoromethacrylic acid phenyl ester α, α, α-trifluoromethacrylic acid chloride (10 g, 63.0 mmol), phenol (6.5 g, 69) 0.0 mmol) and triethylamine (7.66 g, 75.7 mmol) gave α, α, α-trifluoromethacrylic acid phenyl ester (10.3 g, 47.7 mmol, 63% yield).

(result of analysis)
¹ H-NMR (200 MHz, CDCl ₃ ) δ 7.42-7.14 (m, 5H), 6.94-6.92 (m, 1H), 6.61-6.60 (m, 1H).

Example 7 Preparation of (S) -2,3-epoxy-2-trifluoromethylpropionic acid phenyl ester A 500 ml three-necked round bottom flask equipped with a dropping funnel and a stirrer was purged with nitrogen, and then molecular sieves 4A (3 0.7 g, pre-dried product at 180 ° C. for 4 hours under reduced pressure), (R) -1,1′-bi-2-naphthol (529.8 mg, 1.85 mmol), triphenylphosphine oxide (1.54 g, 5 .6 mmol) and THF (90 ml) were added. After dissolving by stirring for 5 minutes, a THF solution (90 ml) of lanthanum triisopropoxide (585 mgg, 1.85 mmol) was added and stirred at room temperature for 1 hour. Cumene hydroperoxide (740 μl, 80% purity product, 3.9 mmol) was added, and the mixture was further stirred at room temperature for 2 hours to prepare a catalyst.

After confirming that the reaction solution was green, the reaction solution was cooled to -20 ° C. After adding cumene hydroperoxide (8.4 g, 80% purity, 44.1 mmol), α, α, α-trifluoromethacrylic acid phenyl ester (8.0 g, 37.0 mmol) in THF (90 ml) Was dropped from the dropping funnel over 1 hour. After stirring at −20 ° C. for 12 hours, disappearance of the raw materials was confirmed by ¹ H-NMR.

  Saturated aqueous ammonium chloride solution (50 ml) and 5% aqueous sodium hydrogen sulfite solution (10 ml) were added to stop the reaction. Insoluble material was filtered off through Celite, followed by liquid separation. After the organic phase was concentrated, the origin component was removed with a silica gel column (hexane / ethyl acetate = 3/1: vol / vol). Further, (S) -2,3-epoxy-2-trifluoromethylpropionic acid phenyl ester (7.2 g, 31.0 mmol) was purified by silica gel column (hexane / ethyl acetate = 9/1: vol / vol). (Yield 84%, optical purity 79ee%) was obtained. The optical purity was measured under the following conditions.

(result of analysis)
¹ H-NMR (200 MHz, CDCl ₃ ) δ 7.46-7.13 (m, 5H), 3.46-3.41 (m, 1H), 3.36 (d, 1H, J = 6.0 Hz)
¹³ C-NMR (50 MHz, CDCl ₃ ) δ162.17, 149.57, 129.35, 125.86, 121.42 (q, J = 275.9 Hz), 120.84, 54.13 (q, J = 37.8 Hz), 49.33
IR (KBr; ν cm ⁻¹ ) 3511, 3068, 1774, 1592, 1493, 1458, 1386, 13361235, 1187, 1081, 1064, 1044, 1004, 959, 924, 877, 833, 747, 700, 687
Elemental analysis; C51.56, H3.18, F24.47 (Calc .; C51.74, H3.04, F24.55)
MASS (m / z) 232 (M +)
Specific rotation [α] _D ²⁵ = 0.9 ° (C = 2.0, methanol).

Example 8 Preparation of (S) -2,3-epoxy-2-trifluoromethylpropionic acid (S)-obtained in Example 7 in a 100 ml three-necked round bottom flask equipped with a dropping funnel and a stirrer 2,3-epoxy-2-trifluoromethylpropionic acid phenyl ester (7.2 g, 31.0 mmol), methanol (20 ml) and water (20 ml) were charged and the mixture was brought to 0 ° C. on an ice bath, and then a dropping funnel. 3N-aqueous sodium hydroxide solution (30 ml, 90 mmol) was added dropwise over 1 hour, and the mixture was further stirred at the same temperature for 1 hour. After completion of the reaction, methanol was distilled off, followed by extraction with diisopropyl ether (30 ml × 2 times), followed by addition of hydrochloric acid to PH = 3, followed by extraction with ethyl acetate (30 ml × 3 times). The resulting organic layer was extracted over magnesium sulfate. (S) -2,3-epoxy-2-trifluoromethylpropionic acid (4.17 g, 26.7 mmol, yield 87%, optical purity 78% ee). Obtained.

Reference Example 3 Preparation of α, α, α-trifluoromethacrylic acid (p-chloroanilide) α, α, α-trifluoromethacrylic acid chloride (10 g, 63.0 mmol), m-chloro Α, α, α-trifluoromethacrylic acid (m-chloroanilide) (14.5 g, 58.0 mmol, yield 92) from aniline (8.9 g, 69.4 mmol) and triethylamine (7.00 g, 69.4 mmol). %).

(result of analysis)
^{1 H-NMR (200MHz, CDCl} 3) δ7.68-7.13 (m, 4H), 6.68-6.65 (m, 1H), 6.38-6.37 (m, 1H).

Example 9 Preparation of (S) -2,3-epoxy-2-trifluoromethylpropionic acid (m-chloroanilide) A 1000 ml three-necked round bottom flask equipped with a dropping funnel and a stirrer was purged with nitrogen and then molecular. Sieves 4A (3.70 g, pre-dried product at 180 ° C. for 4 hours under reduced pressure), (R) -1,1′-bi-2-naphthol (2.11 g, 7.37 mmol), triphenylphosphine oxide (6 .15 g, 22.1 mmol) and THF (100 ml) were added. After dissolving by stirring for 5 minutes, a THF solution (100 ml) of lanthanum triisopropoxide (2.33 g, 7.37 mmol) was added and stirred at room temperature for 1 hour. Cumene hydroperoxide (2.80 g, 80% purity product, 14.7 mmol) was added, and the mixture was further stirred at room temperature for 2 hours to prepare a catalyst.

After confirming that the reaction solution was green, the reaction solution was cooled to -20 ° C. Cumene hydroperoxide (6.31 g, 80% purity, 33.16 mmol) was added followed by α, α, α-trifluoromethacrylic acid (m-chloroanilide) (9.20 g, 36.8 mmol) in THF. The (100 ml) solution was added dropwise from the dropping funnel over 1 hour. After stirring at −20 ° C. for 12 hours, disappearance of the raw materials was confirmed by ¹ H-NMR.

  Saturated aqueous ammonium chloride solution (200 ml) and 5% aqueous sodium hydrogen sulfite solution (150 ml) were added to stop the reaction, and the insoluble material was filtered off through Celite, followed by liquid separation. After the organic phase was concentrated, the origin component was removed with a silica gel column (hexane / ethyl acetate = 3/1: vol / vol). Furthermore, (S) -2,3-epoxy-2-trifluoromethylpropionic acid (m-chloroanilide) (7.54 g, 7.5 g, by purifying with a silica gel column (hexane / ethyl acetate = 9/1: vol / vol)) 28.5 mmol) (yield 77%, optical purity 84 ee%).

(result of analysis)
¹ H-NMR (200 MHz, CDCl ₃ ) δ 7.68-7.10 (m, 4H), 4.12 (d, 1H, J = 4.4 Hz), 3.19 (d, 1H, J = 4. 4Hz)
Elemental analysis; C45.12, H2.87, N5.19, Cl13.19, F21.35 (Calc .; C45.22, H2.66, N5.27, Cl13.35, F21.46)
MASS (m / z) 265 (M +)
Specific rotation [α] _D ²⁵ = 7.3 ° (C = 2.0, methanol).

Example 10 Preparation of (S) -2,3-epoxy-2-trifluoromethylpropionic acid A stirrer was provided. In a 300 ml round bottom flask, (S) -2,3-epoxy-2-trifluoromethylpropionic acid (m-chloroanilide) (7.54 g, 28.5 mmol) obtained in Example 9 and methanol (100 ml) were added. ) And 35% hydrochloric acid (25 ml) were stirred at room temperature for 4 days.

After completion of the reaction, the methanol was distilled off, followed by extraction with ethyl acetate (30 ml × 3 times), and the combined organic layers were washed with 1N hydrochloric acid (20 ml × 2 times), dried over magnesium sulfate, filtered and concentrated. (S) -2,3-epoxy-2-trifluoromethylpropionic acid (2.75 g 17.6 mmol, yield 62%, optical purity 84% ee) was obtained.

Claims (16)

The following general formula (1)

[In said general formula (1), A represents an oxygen atom, a sulfur atom, or NH group. R1 is a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, an aromatic group having 6 to 20 carbon atoms, and hydrogen on the aromatic ring is optionally substituted with a halogen atom. A C6-C20 aromatic group, a hydrogen atom on the aromatic ring optionally substituted with a methyl group, a C6-C20 aromatic group, a carbon atom optionally substituted with an hydrogen in the aromatic ring An aromatic group having 6 to 20 carbon atoms, an aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, on the aromatic ring An aromatic group having 6 to 20 carbon atoms in which hydrogen is optionally substituted with a methoxy group, an aromatic group having 6 to 20 carbon atoms in which hydrogen on an aromatic ring is optionally substituted with ethoxy, and hydrogen on an aromatic ring 6 to 20 carbon atoms optionally substituted with a linear, branched or cyclic alkyloxy group having 3 to 6 carbon atoms An aromatic group, a heteroaromatic group having 5 to 19 carbon atoms, a heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with halogen, and hydrogen on the aromatic ring is optionally a methyl group Substituted heteroaromatic group having 5 to 19 carbon atoms, hydrogen on aromatic ring optionally substituted with ethyl group, heteroaromatic group having 5 to 19 carbon atoms, hydrogen on aromatic ring optionally having 3 carbon atoms A heteroaromatic group having 5 to 19 carbon atoms substituted with a linear, branched or cyclic alkyl group having 6 to 6 carbon atoms, a heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with a methoxy group Group, a heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with an ethoxy group, and hydrogen on the aromatic ring optionally having a straight chain, branched or cyclic structure having 3 to 6 carbon atoms A C5-C19 heteroaromatic group substituted with an alkyloxy group, a benzyl group, A benzyl group in which the hydrogen on the ring is optionally substituted with a halogen atom, a benzyl group in which the hydrogen on the aromatic ring is optionally substituted with a methyl group, a benzyl group in which the hydrogen on the aromatic ring is optionally substituted with an ethyl group, A benzyl group, a 2-phenylethyl group, or an aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is arbitrarily substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms is bonded. A linear, branched or cyclic alkyl group having 3 to 10 carbon atoms is represented. ]
Or the following general formula (2)

[In the general formula (2), A and R1 have the same definitions as above. ]
Optically active fluorine-containing compounds represented by In the general formula (1) or (2), A is an oxygen atom or NH group, and R1 is a tert-butyl group, a phenyl group, a phenyl group in which hydrogen on the aromatic ring is substituted with a halogen atom, or The optically active fluorine-containing compound according to claim 1, which is a benzyl group. Optically active fluorine-containing compounds represented by the following formula (3) or formula (4).

The following general formula (5)

(In the above general formula, A represents an oxygen atom, a sulfur atom, or an NH group. R1 represents a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, and a carbon number of 6). An aromatic group having 20 to 20 carbon atoms, an aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with a halogen atom, and 6 to 20 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with a methyl group An aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with an ethyl group, and hydrogen on the aromatic ring optionally having 3 to 6 carbon atoms, straight chain, branched or cyclic An aromatic group having 6 to 20 carbon atoms substituted with an alkyl group of the above, an aromatic group having 6 to 20 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with a methoxy group, and optionally hydrogen on the aromatic ring is ethoxy An aromatic group having 6 to 20 carbon atoms substituted with, hydrogen on the aromatic ring is optionally a straight chain having 3 to 6 carbon atoms, An aromatic group having 6 to 20 carbon atoms substituted with a branched or cyclic alkyloxy group, a heteroaromatic group having 5 to 19 carbon atoms, or 5 to 5 carbon atoms in which hydrogen on the aromatic ring is optionally substituted with halogen 19 heteroaromatic groups, 5 to 19 carbon atoms optionally substituted with hydrogen on the aromatic ring, and 5 to 5 carbon atoms optionally substituted with ethyl on the aromatic ring. 19 heteroaromatic groups, 5 to 19 heteroaromatic groups in which hydrogen on the aromatic ring is optionally substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, on the aromatic ring A heteroaromatic group having 5 to 19 carbon atoms in which hydrogen is optionally substituted with a methoxy group, a heteroaromatic group having 5 to 19 carbon atoms in which hydrogen on an aromatic ring is optionally substituted with an ethoxy group, on an aromatic ring Hydrogen is optionally a linear, branched or cyclic alkyloxy having 3 to 6 carbon atoms A heteroaromatic group having 5 to 19 carbon atoms substituted with benzyl, a benzyl group in which hydrogen on the aromatic ring is optionally substituted with a halogen atom, or a benzyl in which hydrogen on the aromatic ring is optionally substituted with a methyl group A benzyl group in which hydrogen on the aromatic ring is optionally substituted with an ethyl group, a benzyl group in which hydrogen on the aromatic ring is optionally substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, A 2-phenylethyl group or a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms to which an aromatic group having 6 to 20 carbon atoms is bonded.
The method for producing optically active fluorine-containing compounds according to any one of claims 1 to 3, wherein the α, α, α-trifluoromethacrylic acid derivative represented by formula (1) is asymmetrically epoxidized. In the general formula (5), A is an oxygen atom or NH group, and R1 is a tert-butyl group, a phenyl group, a phenyl group in which hydrogen on the aromatic ring is substituted with a halogen atom, or a benzyl group. The method for producing optically active fluorine-containing compounds according to claim 4, The method for producing optically active fluorine-containing compounds according to claim 4, wherein in the general formula (5), A is an oxygen atom and R1 is a benzyl group. The α, α, α-trifluoromethacrylic acid derivative represented by the general formula (5) is converted into (A) a rare earth metal alkoxide, (B) optically active 1,1′-bi-2-naphthol, (C) triphenylphosphine. 7. The asymmetric epoxidation reaction in the presence of a fin oxide and a catalyst containing (D) cumene hydroperoxide or tert-butyl hydroperoxide. A method for producing optically active fluorine-containing compounds. (A) Rare earth metal alkoxide is a lanthanoid triisopropoxide, The manufacturing method of the optically active fluorine-containing compounds of Claim 7 characterized by the above-mentioned. (A) Rare earth metal alkoxide is lanthanum triisopropoxide, The manufacturing method of the optically active fluorine-containing compounds of Claim 7 characterized by the above-mentioned. An optically active fluorine-containing compound represented by the following formula (6) or formula (7).

The optically active fluorine-containing compound represented by the general formula (1) according to any one of claims 1 to 3, wherein the optically active fluorine-containing compound represented by the general formula (1) is hydrolyzed. A method for producing an active fluorine-containing compound. The optically active fluorine-containing compound represented by the general formula (2) according to any one of claims 1 to 3, wherein the optically active fluorine-containing compound represented by the general formula (2) is hydrolyzed. A method for producing an active fluorine-containing compound. The method for producing an optically active fluorine-containing compound represented by the formula (6) according to claim 10, wherein the optically active fluorine-containing compound represented by the formula (3) according to claim 3 is subjected to a hydrogenation reaction. The method for producing an optically active fluorine-containing compound represented by the formula (7) according to claim 10, wherein the optically active fluorine-containing compound represented by the formula (4) according to claim 3 is subjected to a hydrogenation reaction. A method for producing (R) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, wherein an optically active fluorine-containing compound represented by the formula (6) according to claim 10 is reacted with a metal hydride Wherein the metal hydride is sodium borohydride, sodium trimethoxyborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, lithium tri-s-butylborohydride, triethyl hydride Lithium borohydride, lithium triciamyl borohydride, potassium borohydride, potassium tri-s-butylborohydride, potassium triciamyl borohydride, zinc borohydride, calcium borohydride, lithium aluminum hydride, trihydride hydride Methoxyaluminum lithium, hydrogenated tri-t Manufacturing method comprising butoxy lithium aluminum hydride bis (2-methoxyethoxy) aluminum hydride, and is selected from the group consisting of diisobutylaluminum hydride. A method for producing (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, wherein an optically active fluorine-containing compound represented by the formula (7) according to claim 10 is reacted with a metal hydride Wherein the metal hydride is sodium borohydride, sodium trimethoxyborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, lithium tri-s-butylborohydride, triethyl hydride Lithium borohydride, lithium triciamyl borohydride, potassium borohydride, potassium tri-s-butylborohydride, potassium triciamyl borohydride, zinc borohydride, calcium borohydride, lithium aluminum hydride, trihydride hydride Methoxyaluminum lithium, hydrogenated tri-t Manufacturing method comprising butoxy lithium aluminum hydride bis (2-methoxyethoxy) aluminum hydride, and is selected from the group consisting of diisobutylaluminum hydride.