JP2009215198A - METHOD FOR PRODUCING OPTICALLY ACTIVE beta-FLUOROMETHYLCARBONYL DERIVATIVE - Google Patents

METHOD FOR PRODUCING OPTICALLY ACTIVE beta-FLUOROMETHYLCARBONYL DERIVATIVE Download PDF

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JP2009215198A
JP2009215198A JP2008059160A JP2008059160A JP2009215198A JP 2009215198 A JP2009215198 A JP 2009215198A JP 2008059160 A JP2008059160 A JP 2008059160A JP 2008059160 A JP2008059160 A JP 2008059160A JP 2009215198 A JP2009215198 A JP 2009215198A
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optically active
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phenylsulfonyl
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Tetsuo Shibata
哲男 柴田
Tatsuya Furukawa
達也 古川
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Nagoya Institute of Technology NUC
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an optically active β-fluoromethylcarbonyl derivative. <P>SOLUTION: A compound of formula (1) is reacted with a compound of formula (2) in a solvent in the presence of an optically active phase-transfer catalyst to obtain a compound of formula (3). The carbonyl group of the compound (3) is reduced to obtain a compound of formula (4), or the carbonyl group of the compound (3) is reacted with a nucleophilic agent to obtain a compound of formula (5). The compound of formula (4) or the compound of formula (5) is desulfonylated to obtain a β-fluoromethyl alcohol represented by formula (6). The resultant compound of formula (6) is oxidized to obtain a β-fluoromethylcarbonyl derivative represented by formula (7). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

本発明は光学活性β−フルオロメチルカルボニル誘導体の製造法に関する。   The present invention relates to a method for producing an optically active β-fluoromethylcarbonyl derivative.

β-フルオロメチルアミン誘導体は医農薬産業において重要な合成中間体である。   β-fluoromethylamine derivatives are important synthetic intermediates in the medical and agrochemical industry.

一般的な製造法として，（１）γ−ブロモブチル酸エチルエステルをAgFで加熱条件下，置換反応する方法（非特許文献１）（２）γ−ブロモブチル酸エチルエステルをKFとヘキサデシルトリブチルホスホニウムブロミドの存在下，ブロミドをフッ素に置換する方法（非特許文献２）（３）ヒドロキシシクロブタノン類とDAST（ジエチルアミノサルファ−トリフルオリド）との反応によるヒドロキシ基をフッ素に置換する反応（非特許文献３）（４）４−フルオロ−フェニルクロトン酸エステル類をPd/C存在下，水素添加する方法（特許文献４）が挙げられる。光学活性体においては，（５）（Ｒ）-カンファ−グリシンエステルイミン類とフルオロアルキル類とのジアステレオ選択的アルキル化反応する方法（非特許文献５）（６）リパーゼを用いたフルオロメチルグルタリック酸無水物の不斉開環反応により，光学活性なβ−フルオロメチルδ−バレロラクタム類を得る方法（非特許文献６）が挙げられる。しかしながら，前記（５）の方法では化学量論量の光学活性不斉補助基が必要でありジアステレオ選択性は低い。さらに，前記（６）の方法は，高いエナンチオ選択的で得られるが基質適用範囲が狭い。従来法は，選択性および適用範囲において工業的に光学活性β−フルオロメチルカルボニル誘導体を供給するのに問題がある。従って，工業的スケールで効率良く製造し得る一般式（７）に示される光学活性β−フルオロメチルカルボニル誘導体の製造法が望まれていた。
J. Chem. Soc., 2745(1949) J. Fluorine Chem.,99(1999) J. Fluorine Chem.,126(2005) 特開平18-6328009 Leibigs Analen/Reucil,6,1201(1997) Agric. Biol. Chem.,54,3269(1990) As a general production method, (1) a substitution reaction of γ-bromobutyric acid ethyl ester with AgF under heating conditions (Non-patent Document 1) (2) γ-bromobutyric acid ethyl ester with KF and hexadecyltributylphosphonium bromide Of Substituting Bromide with Fluorine in the Presence of Water (Non-patent Document 2) (3) Reaction of Replacing Hydroxy Group with Fluorine by Reaction of Hydroxycyclobutanones with DAST (Diethylaminosulfur-Trifluoride) (Non-patent Document 3) (4) A method of hydrogenating 4-fluoro-phenylcrotonic acid esters in the presence of Pd / C (Patent Document 4) can be mentioned. In the optically active form, (5) a method of diastereoselective alkylation reaction between (R) -camphor-glycine ester imines and fluoroalkyls (Non-patent Document 5) (6) Fluoromethylglutamate using lipase Examples include a method of obtaining optically active β-fluoromethyl δ-valerolactams by asymmetric ring-opening reaction of ric anhydride (Non-patent Document 6). However, the method (5) requires a stoichiometric amount of an optically active asymmetric auxiliary group and has low diastereoselectivity. Furthermore, the method (6) can be obtained with high enantioselectivity, but the substrate application range is narrow. The conventional method has a problem in supplying an optically active β-fluoromethylcarbonyl derivative industrially in selectivity and application range. Therefore, a method for producing an optically active β-fluoromethylcarbonyl derivative represented by the general formula (7) that can be efficiently produced on an industrial scale has been desired.
J. Chem. Soc., 2745 (1949) J. Fluorine Chem., 99 (1999) J. Fluorine Chem., 126 (2005) JP-A-18-6328009 Leibigs Analen / Reucil, 6,1201 (1997) Agric. Biol. Chem., 54, 3269 (1990)

本発明は，上記課題を解決するためになされたものであり，その目的は，溶媒中，光学活性な相間移動触媒を用いて前記一般式（１）と（２）とを反応させて，工業的スケールで効率良く前記一般式（３）を製造し，（３）を簡便に変換し，前記一般式（６）に示されるβ−フルオロメチルアルコール誘導体および前記一般式（７）に示される光学活性なβ−フルオロメチルカルボニル誘導体の製造法を提供することである。

The present invention has been made in order to solve the above-mentioned problems. The object of the present invention is to react the above general formulas (1) and (2) with an optically active phase transfer catalyst in a solvent to produce an industrial product. The general formula (3) is efficiently produced on a general scale, and (3) is simply converted to produce a β-fluoromethyl alcohol derivative represented by the general formula (6) and an optical represented by the general formula (7). It is to provide a method for producing an active β-fluoromethylcarbonyl derivative.

本発明者らは，上記課題を解決するため鋭意研究を行った結果，溶媒中，光学活性な相間移動触媒存在下，前記一般式（１）の共役カルボニル類と前記一般式（２）フルオロビススルホニルメタン類を反応させて，光学活性な前記一般式（３）に示されるβ−フルオロ（フェニルスルホニル）メチル付加体を得ることを見出した。前記一般式（３）はカルボニル基を還元し，前記一般式（４）また，求核反応により前記一般式（５）を得る。さらに続く金属による簡便な脱スルホニル化反応により，前記一般式（６）を得ることを見出した。また続く酸化反応により，前記一般式（７）を得ることを見出し，本発明を完成するに至った。   As a result of intensive studies to solve the above problems, the present inventors have found that the conjugated carbonyls of the above general formula (1) and the above-mentioned general formula (2) fluorobis are in the presence of an optically active phase transfer catalyst in a solvent. It was found that an optically active β-fluoro (phenylsulfonyl) methyl adduct represented by the general formula (3) was obtained by reacting sulfonylmethanes. In the general formula (3), the carbonyl group is reduced to obtain the general formula (4) or the general formula (5) by nucleophilic reaction. Furthermore, it has been found that the general formula (6) can be obtained by a subsequent simple desulfonylation reaction with a metal. Further, the inventors have found that the general formula (7) is obtained by the subsequent oxidation reaction, and have completed the present invention.


すなわち，本発明は下記の（１）〜（９）に関するものである。
That is, the present invention relates to the following (1) to (9).


（１）溶媒中，光学活性な相間移動触媒存在下，一般式（１）
(1) General formula (1) in the presence of an optically active phase transfer catalyst in a solvent

（式中，Ｒ１は，水素，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基，アルコキシ基またはアミノ基を示す。Ｒ２は，水素，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基またはアリール基を示す。）で表せる共役カルボニル化合物を一般式（２） (Wherein R 1 represents hydrogen, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group, an alkoxy group, or an amino group. R 2 represents hydrogen, a substituted or unsubstituted alkyl group, A conjugated carbonyl compound represented by the general formula (2): an alkenyl group, an aralkyl group, an alkynyl group or an aryl group.

（式中，Ｒ３，Ｒ４はそれぞれ独立に，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基またはアリール基を示す。さらに，Ｒ３およびＲ４が一体となって，環状構造の一部を形成してもよい。）で示されるフルオロビススルホニルメタン類との共役付加反応させることを特徴とする一般式（３） (Wherein R 3 and R 4 each independently represents a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group, alkynyl group or aryl group. Furthermore, R 3 and R 4 are combined to form a cyclic group. A part of the structure may be formed.) A conjugate addition reaction with fluorobissulfonylmethanes represented by the general formula (3)

（式中，Ｒ１，Ｒ２，Ｒ３，Ｒ４は前記定義に同じ。）
で示される光学活性含β−フルオロ（フェニルスルホニル）メチル付加体の製造法。 (Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above)
A process for producing an optically active β-fluoro (phenylsulfonyl) methyl adduct represented by the formula:


（３）前記一般式（３）で示される光学活性含β−フルオロ（フェニルスルホニル）メチル付加体を溶媒中，カルボニル基を還元させることを特徴とする一般式（４）
(3) The general formula (4), wherein the optically active β-fluoro (phenylsulfonyl) methyl adduct represented by the general formula (3) is reduced in a solvent with a carbonyl group.

（式中，Ｒ１，Ｒ２，Ｒ３，Ｒ４は前記定義に同じ。）で示される光学活性β−フルオロ（フェニルスルホニル）メチルアルコール誘導体の製造法。 (Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above), a method for producing an optically active β-fluoro (phenylsulfonyl) methyl alcohol derivative.


（４）前記一般式（３）で表せるβ−フルオロ（フェニルスルホニル）メタン付加体を溶媒中，求核剤存在下，カルボニル基を還元させることを特徴とする一般式（５）
(4) The β-fluoro (phenylsulfonyl) methane adduct represented by the general formula (3) is reduced in the presence of a nucleophile in a solvent in the general formula (5)

（式中，Ｒ１，Ｒ２，Ｒ３，Ｒ４は前記定義に同じ。Ｒ５は，水素，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基またはトリフルオロメチル基を示す。）で示される光学活性β―フルオロ（フェニルスルホニル）メチルアルコール誘導体の製造法。 (Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. R 5 represents hydrogen, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group or trifluoromethyl. A method for producing an optically active β-fluoro (phenylsulfonyl) methyl alcohol derivative represented by:


（５）前記一般式（４），（５）で表せるβ−フルオロ（フェニルスルホニル）メチルアルコール誘導体を溶媒中，還元剤として金属の存在下，脱スルホニル化させることを特徴とする一般式（６）
(5) The β-fluoro (phenylsulfonyl) methyl alcohol derivative represented by the general formulas (4) and (5) is desulfonylated in a solvent in the presence of a metal as a reducing agent. )

（式中，Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５は，前記定義に同じ。）で示される光学活性β―フルオロメチルアルコール誘導体の製造法。 (Wherein R 1 , R 2 , R 3 , R 4 , R 5 are the same as defined above), a method for producing an optically active β-fluoromethyl alcohol derivative.

（６）前記一般式（５）（式中，Ｒ１，Ｒ２は前記定義に同じ。Ｒ５は水素を示す。）で表せるβ−フルオロメチルアルコール誘導体を溶媒中，酸化させることを特徴とする一般式（６） (6) A β-fluoromethyl alcohol derivative represented by the general formula (5) (wherein R 1 and R 2 are the same as defined above; R 5 represents hydrogen) is oxidized in a solvent. General formula (6)

（式中，Ｒ１，Ｒ２は前記定義に同じ。）で示される光学活性β−フルオロメチルカルボニル誘導体の製造法。
（７）前記光学活性な相間移動触媒は，光学活性４級アンモニウム塩類から選ばれる少なくとも１種類の塩であることを特徴とする請求項１に記載の製造法。
光学活性な相間移動触媒としては，一般式（８），（９） (Wherein R 1 and R 2 are the same as defined above).
(7) The method according to claim 1, wherein the optically active phase transfer catalyst is at least one salt selected from optically active quaternary ammonium salts.
As optically active phase transfer catalysts, general formulas (8), (9)

（式中，Ｒ６は水素，置換もしくは未置換のアルキル基もしくはアルコキシ基を示す。もしくはＯＲ１０で表せるＲ１０はアルキル基を示す。Ｒ７は，エチル基もしくはビニル基を示す。Ｒ８は，水素，アルキル基，アリール基またはアシル基を示す。Ｒ９は，水素，置換もしくは未置換のアルキル基，トリフルオロメチル基または3,5−ビストリフルオロメチルフェニル基を示す。ｍは０〜２の整数を表す。Ｘは，ハロゲン原子，IO４，ClO４，OTfまたはHSO４を示す。） (In the formula, R 6 represents hydrogen, a substituted or unsubstituted alkyl group or an alkoxy group, or R 10 represented by OR 10 represents an alkyl group. R 7 represents an ethyl group or a vinyl group. R 8 represents , Hydrogen, an alkyl group, an aryl group, or an acyl group, R 9 represents hydrogen, a substituted or unsubstituted alkyl group, a trifluoromethyl group, or a 3,5-bistrifluoromethylphenyl group, m is 0 to 2; X represents a halogen atom, IO 4 , ClO 4 , OTf or HSO 4. )

（８）前記溶媒が，Ｎ，Ｎ−ジメチルホルムアミド，ジメチルスルホキシド，クロロホルム，ジクロロメタン，ジクロロエタン，トルエン，テトラヒドロフラン，ヘキサン，ベンゼン，メタノール，アセトニトリルからなる群より選ばれる少なくとも1種である請求項１，２，３，４，５のいずれか１項に記載の製造法。 (8) The solvent is at least one selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, toluene, tetrahydrofuran, hexane, benzene, methanol, and acetonitrile. , 3, 4 or 5.

（９）前記還元剤としての金属は，希土類を含む遷移金属リチウム，ナトリウム，マグネシウム，アルミニウム，亜鉛，スズ，インジウム，サマリウムなどから選ばれる少なくとも１種類の元素であることを特徴とする請求項４に記載の製造法。
(9) The metal as the reducing agent is at least one element selected from transition metal lithium containing rare earth, sodium, magnesium, aluminum, zinc, tin, indium, samarium, and the like. The production method described in 1.

従来，前記一般式（８）で示されるβ−フルオロメチルカルボニル誘導体の製造法は，一般的に，γ−ハロブタン酸エステル類のフッ化金属を用いたフッ素の置換反応の方法であるため，大量の廃棄物が生成する点が問題であった。また，γ−ヒドロキシブタン酸エステル類の求電子的フッ素化剤による置換反応は，フッ素化剤が高価であることや入手用意でない基質を製造する点も問題であった。光学活性体の製造法は，（Ｒ）-カンファ−グリシンエステルイミン類とフルオロアルキル類とのジアステレオ選択的アルキル化反応する方法と，リパーゼを用いたフルオロメチルグルタリック酸無水物の不斉開環反応により，光学活性なβ−フルオロメチルδ−バレロラクタム類を得る方法などが報告されている。しかしながら，前者は，化学量論量の光学活性不斉補助基が必要でありジアステレオ選択性は低い。後者は，高いエナンチオ選択的で得られるが基質適用範囲が狭い。従来法は，選択性および適用範囲において工業的に光学活性β−フルオロメチルカルボニル化合物を供給するのに問題がある。   Conventionally, the method for producing a β-fluoromethylcarbonyl derivative represented by the general formula (8) is generally a method of substitution reaction of fluorine using a metal fluoride of γ-halobutanoic acid ester. The problem was that a lot of waste was generated. Further, the substitution reaction of γ-hydroxybutanoic acid esters with an electrophilic fluorinating agent has been problematic in that the fluorinating agent is expensive and a substrate that is not available is produced. The optically active product is produced by a diastereoselective alkylation reaction between (R) -camphor-glycine ester imine and fluoroalkyl, or asymmetric cleavage of fluoromethylglutaric anhydride using lipase. A method for obtaining optically active β-fluoromethyl δ-valerolactams by a ring reaction has been reported. However, the former requires a stoichiometric amount of an optically active asymmetric auxiliary group and has low diastereoselectivity. The latter can be obtained with high enantioselectivity but a narrow substrate application range. The conventional method has a problem in supplying an optically active β-fluoromethylcarbonyl compound industrially in selectivity and application range.

従来法と比較して，本発明における光学活性β−フルオロメチルカルボニル誘導体の製造法は，光学活性な相間移動触媒存在下，前記一般式（１）で示される共役カルボニル化合物と前記一般式（２）との共役付加反応を行うことで光学活性前記一般式（３）を得ることができる。これらβ−フルオロ（フェニルスルホニル）メチル付加体（３）はカルボニル基を還元し前記一般式（４）を得る。また，求核剤と反応させることで前記一般式（５）を得る。さらに続く脱スルホニル化により前記一般式（６）に示されるβ−フルオロメチルアルコールへと誘導することが可能であり，更に酸化することで前記一般式（７）に示されるβ−フルオロメチルカルボニル化合物に変換することができる。本発明は工業的に利用価値が高い。   Compared with the conventional method, the production method of the optically active β-fluoromethylcarbonyl derivative in the present invention is the presence of the optically active phase transfer catalyst and the conjugated carbonyl compound represented by the general formula (1) and the general formula (2). The optically active general formula (3) can be obtained by carrying out a conjugate addition reaction with These β-fluoro (phenylsulfonyl) methyl adducts (3) reduce the carbonyl group to obtain the general formula (4). Moreover, the said General formula (5) is obtained by making it react with a nucleophile. Further, it is possible to derive β-fluoromethyl alcohol represented by the general formula (6) by subsequent desulfonylation, and β-fluoromethylcarbonyl compound represented by the general formula (7) by further oxidation. Can be converted to The present invention has high industrial utility value.

以下，本発明を詳細に説明する。本発明は光学活性な相間移動触媒存在下，前記一般式（１）に対して，前記一般式（２）と反応させて前記一般式（３）を得た後，カルボニル基を還元し，前記一般式（４）を得る。また求核剤と反応させることにより前記一般式（５）を得る。さらに続く脱スルホニル化することにより前記一般式（６）に示されるβ−フルオロメチルアルコール誘導体を得る。またさらに酸化することにより一般式（７）を得ることを特徴とする製造法である。   The present invention will be described in detail below. In the present invention, the general formula (1) is reacted with the general formula (2) in the presence of an optically active phase transfer catalyst to obtain the general formula (3), and then the carbonyl group is reduced. General formula (4) is obtained. Moreover, the said General formula (5) is obtained by making it react with a nucleophile. Furthermore, the β-fluoromethyl alcohol derivative represented by the general formula (6) is obtained by desulfonylation. Further, the production method is characterized by obtaining the general formula (7) by further oxidation.


前記一般式（１）中のアルキル基は，前記一般式（１）中のアルキル基は炭素数が１〜２０の枝分かれがあっても良いアルキル基または炭素数が３〜２０のシクロアルキル基が好ましく，炭素数が１〜１０のアルキル基または炭素数が３〜１０のシクロアルキル基がさらに好ましい。アルキル基はハロゲン原子，シアノ基，ニトロ基，アリール基，アシル基，アルコキシ基，アリールオキシ基，アシルオキシ基などの置換基で置換されていてもよい。
The alkyl group in the general formula (1) is an alkyl group in the general formula (1) that may be branched having 1 to 20 carbon atoms or a cycloalkyl group having 3 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms is more preferable. The alkyl group may be substituted with a substituent such as a halogen atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, or an acyloxy group.


前記一般式（１）中のアルケニル基は炭素数が１〜２０の枝分かれがあっても良いアルケニル基または炭素数が３〜２０のシクロアルケニル基が好ましく，炭素数が１〜１０のアルケニル基または炭素数が３〜１０のシクロアルケニル基がさらに好ましい。アルケニル基の例としては，ビニル基，１−プロペニル基，１−ブテニル基，１−ヘキセニル基，シクロヘキセニル基，アリル基などが挙げられる。アルケニル基はハロゲン原子，シアノ基，ニトロ基，アリール基，アシル基，アルコキシ基，アリールオキシ基，アシルオキシ基などの置換基で置換されていてもよい。
The alkenyl group in the general formula (1) is preferably an alkenyl group having 1 to 20 carbon atoms which may be branched, or a cycloalkenyl group having 3 to 20 carbon atoms, and an alkenyl group having 1 to 10 carbon atoms or More preferred is a cycloalkenyl group having 3 to 10 carbon atoms. Examples of alkenyl groups include vinyl, 1-propenyl, 1-butenyl, 1-hexenyl, cyclohexenyl, allyl and the like. The alkenyl group may be substituted with a substituent such as a halogen atom, cyano group, nitro group, aryl group, acyl group, alkoxy group, aryloxy group, acyloxy group.


前記一般式（１）中のアラルキル基は，例としてベンジル基，ペンタフルオロベンジル基，ｏ−メチルベンジル基，ｍ−メチルベンジル基，ｐ−メチルベンジル基，ｐ−ニトロベンジル基，ナフチルメチル基，フルフリル基，α−フェネチル基等が挙げられる。
Examples of the aralkyl group in the general formula (1) include benzyl group, pentafluorobenzyl group, o-methylbenzyl group, m-methylbenzyl group, p-methylbenzyl group, p-nitrobenzyl group, naphthylmethyl group, Examples include a furfuryl group and an α-phenethyl group.


前記一般式（１）中のアルキニル基は，例としてエチニル基，フェニルエチニル基，２−プロピニル基等が挙げられる。
Examples of the alkynyl group in the general formula (1) include an ethynyl group, a phenylethynyl group, and a 2-propynyl group.


前記一般式（１）中のアリール基は炭素数が６〜２０のアリール基が好ましく，炭素数が６〜１０のアリール基がさらに好ましい。アリール基はアルキル基，ハロゲン原子，シアノ基，ニトロ基，アシル基，アルコキシ基，アシルオキシ基などの置換基で置換されていてもよい。
The aryl group in the general formula (1) is preferably an aryl group having 6 to 20 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms. The aryl group may be substituted with a substituent such as an alkyl group, a halogen atom, a cyano group, a nitro group, an acyl group, an alkoxy group, or an acyloxy group.


前記一般式（１）中のアルコキシ基は炭素数が１〜２０のアルコキシ基が好ましく，炭素数が１〜１０のアルコキシ基がさらに好ましい。アルコキシ基の場合も上記のアルキル基の場合と同様の置換基により置換されていてもよい。
The alkoxy group in the general formula (1) is preferably an alkoxy group having 1 to 20 carbon atoms, and more preferably an alkoxy group having 1 to 10 carbon atoms. In the case of an alkoxy group, it may be substituted with the same substituent as in the case of the above alkyl group.


前記一般式（１）中のアミノ基は，Ｎ上に水素，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基の置換基が１つか２つ置換しているものが挙げられる。置換基はそれぞれ独立しており，同一である必要はない。
（アルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基は前記定義に同じ。）前記一般式（１）中のアミノ基は，置換基を組み合わせて形成されうる環状構造を形成することができる。特に３員環から２０員環でなる単環，双環，またはそれ以上の多環の構造を示すことができる。また，ヘテロ原子の介在もしくは非介在で環状構造の一部を形成してもよい。
The amino group in the general formula (1) is one in which one or two substituents of hydrogen, substituted or unsubstituted alkyl group, alkenyl group, aralkyl group, alkynyl group, and aryl group are substituted on N. Can be mentioned. The substituents are independent of each other and need not be the same.
(The alkyl group, alkenyl group, aralkyl group, alkynyl group, and aryl group are the same as defined above.) The amino group in the general formula (1) can form a cyclic structure that can be formed by combining substituents. . In particular, a monocyclic, bicyclic or higher polycyclic structure composed of 3 to 20 members can be shown. Further, a part of the cyclic structure may be formed with or without hetero atoms.


前記一般式（２）中のアルキル基は，置換基を有していても良く，直鎖または分岐した炭素数が１〜２０のアルキル基または炭素数が３〜２０のシクロアルキル基が好ましく，炭素数が１〜１０のアルキル基または炭素数が３〜１０のシクロアルキル基がさらに好ましい。
The alkyl group in the general formula (2) may have a substituent, and is preferably a linear or branched alkyl group having 1 to 20 carbon atoms or a cycloalkyl group having 3 to 20 carbon atoms, An alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms is more preferable.


前記一般式（２）中のアリール基は炭素数が６〜２０の置換または無置換のアリール基が好ましく，炭素数が６〜１０のアリール基がさらに好ましい。
The aryl group in the general formula (2) is preferably a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms.


前記一般式（２）中のＲ４およびＲ５を組み合わせて形成されうる前記環状構造の例としては，３員環から２０員環でなる単環，双環，またはそれ以上の多環の構造を示すことができる。
Examples of the cyclic structure that can be formed by combining R 4 and R 5 in the general formula (2) include a monocyclic, bicyclic or higher polycyclic structure consisting of 3 to 20 members. Can be shown.


前記求核剤は，特に制限するわけではないが，グリニヤール試薬などのアルキルマグネシウム，またはアルキルリチウムなどの有機金属反応剤，またはトリフルオロメチルトリメチルシランなどから選ばれる少なくとも１種類の反応剤が挙げられる。これらは単独で使用し得るのみならず，２種類以上を混合して用いることも可能である。
The nucleophile is not particularly limited, and examples thereof include at least one kind of reactant selected from alkylmagnesium such as Grignard reagent, organometallic reagents such as alkyllithium, or trifluoromethyltrimethylsilane. . These can be used alone or in combination of two or more.


前記金属は，特に制限するわけではないが，希土類を含む遷移金属リチウム，ナトリウム，マグネシウム，アルミニウム，亜鉛，スズ，インジウム，サマリウムなどから選ばれる少なくとも１種類の元素が挙げられる。これらは単独で使用し得るのみならず，２種類以上を混合して用いることも可能である。
The metal is not particularly limited, and examples thereof include at least one element selected from transition metal lithium including rare earth, sodium, magnesium, aluminum, zinc, tin, indium, samarium and the like. These can be used alone or in combination of two or more.


前記一般式（３）で示されるβ―フルオロ（フェニルスルホニル）メチル付加体としては，例えば，４−フルオロ−１，３−ジフェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン，３−（４−クロロフェニル）−４−フルオロ−１−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン，３−（４−ブロモフェニル）−４−フルオロ−１−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン，３−（３−クロロフェニル）−４−フルオロ−１−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン，３−（２−クロロフェニル）−４−フルオロ−１−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン，３−（フルオロビス（フェニルスルホニル）メチル）−１−フェニルブタン−１−オン等が挙げられる。
Examples of the β-fluoro (phenylsulfonyl) methyl adduct represented by the general formula (3) include 4-fluoro-1,3-diphenyl-4,4-bis (phenylsulfonyl) butan-1-one, 3 -(4-Chlorophenyl) -4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-one, 3- (4-bromophenyl) -4-fluoro-1-phenyl-4,4 -Bis (phenylsulfonyl) butan-1-one, 3- (3-chlorophenyl) -4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-one, 3- (2-chlorophenyl) -4-Fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-one, 3- (fluorobis (phenylsulfonyl) methyl) -1-fe Butane-1-one, and the like.


前記一般式（４）で示されるβ―フルオロ（フェニルスルホニル）メチルアルコールとしては，例えば，４−フルオロ−１，３−ジフェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オール，３−（４−クロロフェニル）−４−フルオロ−１−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オール，３−（３−クロロフェニル）−４−フルオロ−１−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オール，３−（２−クロロフェニル）−４−フルオロ−１−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オール等が上げられる。
Examples of the β-fluoro (phenylsulfonyl) methyl alcohol represented by the general formula (4) include 4-fluoro-1,3-diphenyl-4,4-bis (phenylsulfonyl) butan-1-ol, 3- (4-Chlorophenyl) -4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-ol, 3- (3-chlorophenyl) -4-fluoro-1-phenyl-4,4-bis (Phenylsulfonyl) butan-1-ol, 3- (2-chlorophenyl) -4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-ol, and the like.


前記一般式（５）で示されるβ―フルオロ（フェニルスルホニル）メチルアルコールとしては，例えば，５−フルオロ−２，４−ジフェニル−５，５−ビス（フェニルスルホニル）ペンタン−２−オール，６−フルオロ−２−メチル−３，５−ジフェニル−６，６−ビス（フェニルスルホニル）ヘキサン−３−オール，６−フルオロ−３，５−ジフェニル−６，６ビス（フェニルスルホニル）−１−ヘキセン−３−オール，４−フルオロ−１，３−ジフェニル−４，４−ビス（フェニルスルホニル）−１−p―トリルブタン−１−オールなどが挙げられる。
Examples of β-fluoro (phenylsulfonyl) methyl alcohol represented by the general formula (5) include 5-fluoro-2,4-diphenyl-5,5-bis (phenylsulfonyl) pentan-2-ol, 6- Fluoro-2-methyl-3,5-diphenyl-6,6-bis (phenylsulfonyl) hexane-3-ol, 6-fluoro-3,5-diphenyl-6,6bis (phenylsulfonyl) -1-hexene And 3-ol, 4-fluoro-1,3-diphenyl-4,4-bis (phenylsulfonyl) -1-p-tolylbutan-1-ol.


前記一般式（６）で示されるβ―フルオロ（フェニルスルホニル）メチルアルコールとしては，例えば，４−フルオロ−１，３−ジフェニルブタン−１−オール，５−フルオロ−２，４−ジフェニルペンタン−２−オール，６−フルオロ−２−メチル−３，５−ジフェニルヘキサン−３−オール，６−フルオロ−３，５−ジフェニル−１−ヘキセン−３−オール，４−フルオロ−１，３−ジフェニル−１−p―トリルブタン−１−オールなどが挙げられる。
Examples of the β-fluoro (phenylsulfonyl) methyl alcohol represented by the general formula (6) include 4-fluoro-1,3-diphenylbutan-1-ol, 5-fluoro-2,4-diphenylpentane-2. -Ol, 6-fluoro-2-methyl-3,5-diphenylhexane-3-ol, 6-fluoro-3,5-diphenyl-1-hexen-3-ol, 4-fluoro-1,3-diphenyl- 1-p-tolylbutan-1-ol and the like can be mentioned.


前記一般式（７）で示されるβ―フルオロ（フェニルスルホニル）メチルカルボニル誘導体としては，例えば，４−フルオロ−１，３−ジフェニルブタン−１−オン，３−（４−クロロフェニル）−４−フルオロ−１−フェニルブタン−１−オン，３−（３−クロロフェニル）−４−フルオロ−１−フェニルブタン−１−オン，３−（２−クロロフェニル）−４−フルオロ−１−フェニルブタン−１−オン，４−フルオロ−３―メチル−１−フェニルブタン−１−オンなどが挙げられる。
Examples of the β-fluoro (phenylsulfonyl) methylcarbonyl derivative represented by the general formula (7) include 4-fluoro-1,3-diphenylbutan-1-one and 3- (4-chlorophenyl) -4-fluoro. -1-phenylbutan-1-one, 3- (3-chlorophenyl) -4-fluoro-1-phenylbutan-1-one, 3- (2-chlorophenyl) -4-fluoro-1-phenylbutane-1- On, 4-fluoro-3-methyl-1-phenylbutan-1-one and the like.


前記光学活性な相間移動触媒として，特に制限するわけではないが，光学活性４級アンモニウム塩，光学活性チオニウム塩，光学活性オキソニオウム塩，光学活性ホスホニウム塩などが挙げられる。好ましくは，キナアルカロイドの４級アンモニウム塩が挙げられる。これらは単独で使用し得るのみならず，２種類以上を混合して用いることも可能である。
Examples of the optically active phase transfer catalyst include, but are not limited to, optically active quaternary ammonium salts, optically active thionium salts, optically active oxonium salts, and optically active phosphonium salts. Preferably, the quaternary ammonium salt of quina alkaloid is mentioned. These can be used alone or in combination of two or more.


前記一般式（８），（９）中のアルキル基は炭素数が１〜２０の枝分かれがあっても良いアルキル基が好ましく，炭素数が１〜８の枝分かれがあっても良いアルキル基がさらに好ましい。
The alkyl group in the general formulas (8) and (9) is preferably an alkyl group having 1 to 20 carbon atoms which may be branched, and further having an alkyl group having 1 to 8 carbon atoms which may be branched. preferable.


前記一般式（８），（９）中のアリール基は炭素数が６〜２０の置換または無置換のアリール基が好ましく，炭素数が６〜１０のアリール基がさらに好ましい。
The aryl group in the general formulas (8) and (9) is preferably a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms.


前記一般式（８），（９）中のアシル基は炭素数が１〜２０のアシル基が好ましく，炭素数が１〜１０のアシル基がさらに好ましい。特に制限するわけではないが，例としてホルミル基，アセチル基，マロニル基，ベンゾイル基，シンナモイル基等が挙げられる。
The acyl group in the general formulas (8) and (9) is preferably an acyl group having 1 to 20 carbon atoms, and more preferably an acyl group having 1 to 10 carbon atoms. Although not particularly limited, examples include formyl group, acetyl group, malonyl group, benzoyl group, cinnamoyl group and the like.


本発明の反応は，溶媒として低極性有機溶媒としては，ヘプタン，ヘキサン，キシレン，トルエン，クロロホルム，ジクロロメタン，ジイソプロピルエーテルが好ましく，クロロホルム，ジクロロメタン，トルエン，ベンゼンが好ましい。非プロトン性溶媒としては，Ｎ，Ｎ−ジメチルホルムアミド，ジメチルスルホキシド，テトラヒドロフラン，ジメトキシエタン，ジエチレングリコールジメチルエーテル，ヘキサメチルリン酸トリアミドが好ましく，Ｎ，Ｎ−ジメチルホルムアミド，Ｎ−メチル−２−ピロリドン，１，３−ジメチル−２−イミダゾリジノン，ジメチルスルホキシド，テトラヒドロフランがさらに好ましい。これらは単独で使用し得るのみならず，２種類以上を混合して用いることも可能である。
In the reaction of the present invention, heptane, hexane, xylene, toluene, chloroform, dichloromethane and diisopropyl ether are preferred as the low polar organic solvent, and chloroform, dichloromethane, toluene and benzene are preferred. As the aprotic solvent, N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether, and hexamethylphosphoric triamide are preferable. N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1, More preferred are 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, and tetrahydrofuran. These can be used alone or in combination of two or more.


反応温度は特に限定されるものではないが，通常−８０℃〜１２０℃であり，より好ましくは室温付近である。反応器は大気開放型の反応器，またはオートクレーブ等の密閉型の反応器のいずれも可能である。反応圧力は大気圧下，または加圧下のいずれも可能である。反応時間は特に限定されるものではないが，通常1日〜7日で反応は完結する。
Although reaction temperature is not specifically limited, Usually, it is -80 degreeC-120 degreeC, More preferably, it is room temperature vicinity. The reactor can be either an open-air reactor or a closed reactor such as an autoclave. The reaction pressure can be either atmospheric pressure or pressurized. The reaction time is not particularly limited, but the reaction is usually completed in 1 to 7 days.


反応後，前記一般式（３）で示されるβ―フルオロ（フェニルスルホニル）メチル付加体は一般的な手法によって反応液から単離および精製することができ，例えば反応液を濃縮した後，蒸留精製またはシリカゲル，アルミナ等の吸着剤を用いたカラムクロマトグラフ法での精製，塩析，再結晶等が挙げられる。
After the reaction, the β-fluoro (phenylsulfonyl) methyl adduct represented by the general formula (3) can be isolated and purified from the reaction solution by a general method. For example, the reaction solution is concentrated and purified by distillation. Alternatively, purification by column chromatography using an adsorbent such as silica gel and alumina, salting out, recrystallization and the like can be mentioned.


前記一般式（４）で示されるβ−フルオロ（フェニルスルホニル）メチルアルコール誘導体は，一般的な手法によって反応液から単離および精製することができ，例えば反応液を濃縮した後，蒸留精製またはシリカゲル，アルミナ等の吸着剤を用いたカラムクロマトグラフ法での精製，塩析，再結晶等が挙げられる。
The β-fluoro (phenylsulfonyl) methyl alcohol derivative represented by the general formula (4) can be isolated and purified from the reaction solution by a general method. For example, the reaction solution is concentrated and then purified by distillation or silica gel. And purification by column chromatography using an adsorbent such as alumina, salting out, recrystallization and the like.


前記一般式（５）で示されるβ−フルオロ（フェニルスルホニル）メチルアルコール誘導体は，一般的な手法によって反応液から単離および精製することができ，例えば反応液を濃縮した後，蒸留精製またはシリカゲル，アルミナ等の吸着剤を用いたカラムクロマトグラフ法での精製，塩析，再結晶等が挙げられる。
The β-fluoro (phenylsulfonyl) methyl alcohol derivative represented by the general formula (5) can be isolated and purified from the reaction solution by a general method. For example, the reaction solution is concentrated and then purified by distillation or silica gel. And purification by column chromatography using an adsorbent such as alumina, salting out, recrystallization and the like.


前記一般式（６）で示されるβ−フルオロメチルアルコール誘導体は，一般的な手法によって反応液から単離および精製することができ，例えば反応液を濃縮した後，蒸留精製またはシリカゲル，アルミナ等の吸着剤を用いたカラムクロマトグラフ法での精製，塩析，再結晶等が挙げられる。
The β-fluoromethyl alcohol derivative represented by the general formula (6) can be isolated and purified from the reaction solution by a general method. For example, after concentrating the reaction solution, distillation purification or silica gel, alumina, etc. Examples include purification by column chromatography using an adsorbent, salting out, and recrystallization.


前記一般式（７）で示されるβ−フルオロメチルカルボニル誘導体は，一般的な手法によって反応液から単離および精製することができ，例えば反応液を濃縮した後，蒸留精製またはシリカゲル，アルミナ等の吸着剤を用いたカラムクロマトグラフ法での精製，塩析，再結晶等が挙げられる。
The β-fluoromethylcarbonyl derivative represented by the general formula (7) can be isolated and purified from the reaction solution by a general method. For example, after concentrating the reaction solution, distillation purification or silica gel, alumina, etc. Examples include purification by column chromatography using an adsorbent, salting out, and recrystallization.


以下，実施例により本発明をさらに具体的に説明するが，本発明の範囲は下記の実施例に限定されるものではない。
EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example.

一般的な製造法
炭酸セシウム(342.1 mg, 1.05 mmol)，フルオロビス（フェニルスルホニル）メタン2(110.0 mg，0.350 mmol)，N-3,5-ビス（３，５−ビス（トリフルオロメチル）フェニル）ベンジルキニジニウムブロミド(0.018 mmol, 16.1mg)をジクロロメタン(0.7 mL)に溶かした。−４０℃に冷却後，共役カルボニル化合物1a(80.2 mg, 0.385 mmol)を加え，２０時間撹拌した。反応後，飽和塩化アンモニウム水溶液を加え，ジクロロメタンで抽出した。有機層は硫酸ナトリウムで乾燥し，濃縮した。残渣はカラムクロマトグラフィーにて精製し，生成物3aを得た。 General manufacturing method
Cesium carbonate (342.1 mg, 1.05 mmol), fluorobis (phenylsulfonyl) methane 2 (110.0 mg, 0.350 mmol), N-3,5-bis (3,5-bis (trifluoromethyl) phenyl) benzylquinidinium Bromide (0.018 mmol, 16.1 mg) was dissolved in dichloromethane (0.7 mL). After cooling to −40 ° C., conjugated carbonyl compound 1a (80.2 mg, 0.385 mmol) was added and stirred for 20 hours. After the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to obtain product 3a.

Compound 3a: ４−フルオロ−１，３−ジフェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 4.37 (d, J = 18.0 Hz, 1H), 4.56 (dd, 10.2, 18.0 Hz, 1H), 4.80 (d, J= 11.4 Hz, 1H), 7.08 (d, J = 6.6 Hz , 2H), 7.12-7.16 (m, 3H), 7.45-7.49 (m, 4H), 7.59-7.66 (m, 4H), 7.77 (t, J = 7.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz), 8.03 (d, J = 7.2 Hz, 2H), 19F NMR (188 MHz, CDCl3)：δ = -127.9 (s, 1F). IR (KBr)：2926, 1684, 1582, 1549, 1449, 1343, 1313, 1224, 1163, 1077, 999, 750, 682, 638, 610 cm-1. MS (ESI, m/z) = 523.2 (M＋H+). The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.5 mL/min, λ = 254 nm, τmaj = 35.4 min, τmin= 38.7 min); 97% ee. Compound 3a: 4-Fluoro-1,3-diphenyl-4,4-bis (phenylsulfonyl) butan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 4.37 (d, J = 18.0 Hz, 1H), 4.56 (dd, 10.2, 18.0 Hz, 1H), 4.80 (d, J = 11.4 Hz, 1H ), 7.08 (d, J = 6.6 Hz, 2H), 7.12-7.16 (m, 3H), 7.45-7.49 (m, 4H), 7.59-7.66 (m, 4H), 7.77 (t, J = 7.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz), 8.03 (d, J = 7.2 Hz, 2H), 19 F NMR (188 MHz, CDCl 3 ): δ = -127.9 (s, 1F). IR (KBr): 2926, 1684, 1582, 1549, 1449, 1343, 1313, 1224, 1163, 1077, 999, 750, 682, 638, 610 cm -1 . MS (ESI, m / z) = 523.2 (M + H + ) .The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 70:30, flow rate 0.5 mL / min, λ = 254 nm , τ maj = 35.4 min, τ min = 38.7 min); 97% ee.

Compound 3b: ３−（４−クロロフェニル）−４−フルオロ−1−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 4.36 (dd, J = 2.0, 18.4 Hz, 1H), 4.52 (dd, J = 9.4, 18.2 Hz, 1H), 4.76 (td, 3.0, 9.8 Hz, 1H), 6.99-7.14 (m, 4H), 7.43-7.52 (m, 4H), 7.56-7.69 (m, 4H), 7.78 (t, J = 8.2 Hz, 3H), 7.91 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 6.8 Hz, 2H), 19F NMR (188 MHz, CDCl3)：δ = -128.3 (s, 1F). IR (KBr)： 2922, 1691, 1581, 1493, 1447, 1341, 1223, 1163, 1078, 829, 747, 723, 683 cm-1. MS (ESI, m/z) = 557.1 (M＋H+). The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.6 mL/min, λ = 254 nm, τmaj = 30.4 min, τmin = 38.0 min); 97% ee.
Compound 3b: 3- (4-Chlorophenyl) -4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 4.36 (dd, J = 2.0, 18.4 Hz, 1H), 4.52 (dd, J = 9.4, 18.2 Hz, 1H), 4.76 (td, 3.0, 9.8 Hz, 1H), 6.99-7.14 (m, 4H), 7.43-7.52 (m, 4H), 7.56-7.69 (m, 4H), 7.78 (t, J = 8.2 Hz, 3H), 7.91 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 6.8 Hz, 2H), 19 F NMR (188 MHz, CDCl 3 ): δ = -128.3 (s, 1F). IR (KBr): 2922, 1691, 1581 , 1493, 1447, 1341, 1223, 1163, 1078, 829, 747, 723, 683 cm -1 .MS (ESI, m / z) = 557.1 (M + H + ). The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 70:30, flow rate 0.6 mL / min, λ = 254 nm, τ maj = 30.4 min, τ min = 38.0 min); 97% ee.

Compound 3c: ３−（３−クロロフェニル）−４−フルオロ−1−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 4.35 (d, J = 15.8 Hz, 1H), 4.51 (dd, J = 10.2, 18.2 Hz, 1H), 4.75 (d, J = 10.4 Hz, 1H), 7.05 (dd, J = 8.6, 21.0 Hz, 4H), 7.47 (t, J = 7.6 Hz, 4H), 7.56-7.67 (m, 4H), 7.78 (t, J = 8.0 Hz, 3H), 7.90 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 7.6 Hz, 2H), 19F NMR (188 MHz, CDCl3)： δ = -128.3 (s, 1F). IR (KBr)：1686, 1580, 1448, 1337, 1312, 1222, 1078, 753, 718, 683, 620 cm-1. MS (ESI, m/z) = 557.1 (M＋H+). The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.6 mL/min, λ = 254 nm, τmaj = 33.0 min, τmin = 35.4 min); 98% ee.
Compound 3c: 3- (3-Chlorophenyl) -4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 4.35 (d, J = 15.8 Hz, 1H), 4.51 (dd, J = 10.2, 18.2 Hz, 1H), 4.75 (d, J = 10.4 Hz , 1H), 7.05 (dd, J = 8.6, 21.0 Hz, 4H), 7.47 (t, J = 7.6 Hz, 4H), 7.56-7.67 (m, 4H), 7.78 (t, J = 8.0 Hz, 3H) , 7.90 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 7.6 Hz, 2H), 19 F NMR (188 MHz, CDCl 3 ): δ = -128.3 (s, 1F). IR (KBr) : 1686, 1580, 1448, 1337, 1312, 1222, 1078, 753, 718, 683, 620 cm -1 . MS (ESI, m / z) = 557.1 (M + H + ). The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 70:30, flow rate 0.6 mL / min, λ = 254 nm, τ maj = 33.0 min, τ min = 35.4 min); 98% ee.

Compound 3d: ３−（３−クロロフェニル）−４−フルオロ−1−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 4.58 (dd, J = 2.4, 5.2 Hz, 1H), 5.20 (dd, J = 4.8, 8.0 Hz, 1H), 5.29 (s, 1H), 7.13-7.18 (m, 3H), 7.25-7.73 (m, 9H), 7.83-7.95 (m, 5H), 8.04 (d, J = 6.8 Hz, 2H). 19F NMR (188 MHz, CDCl3)：δ = -132.2 (s, 1F). IR (KBr)：2923, 1685, 1581, 1340, 1314, 1166, 1148, 753, 721, 687, 614 cm-1. MS (ESI, m/z) = 557.1 (M＋H+).The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.6 mL/min, λ = 254 nm, τmaj = 32.2 min, τmin= 40.9 min); 73% ee.
Compound 3d: 3- (3-chlorophenyl) -4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 4.58 (dd, J = 2.4, 5.2 Hz, 1H), 5.20 (dd, J = 4.8, 8.0 Hz, 1H), 5.29 (s, 1H) , 7.13-7.18 (m, 3H), 7.25-7.73 (m, 9H), 7.83-7.95 (m, 5H), 8.04 (d, J = 6.8 Hz, 2H). 19 F NMR (188 MHz, CDCl 3 ) : Δ = -132.2 (s, 1F). IR (KBr): 2923, 1685, 1581, 1340, 1314, 1166, 1148, 753, 721, 687, 614 cm -1 . MS (ESI, m / z) = 557.1 (M + H + ) .The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 70:30, flow rate 0.6 mL / min, λ = 254 nm, τ maj = 32.2 min, τ min = 40.9 min); 73% ee.


Compound 3e: ３−（３−ブロモフェニル）−４−フルオロ−1−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 4.35 (d, J = 18.4 Hz, 1H), 4.50 (dd, J = 10.2, 17.8 Hz, 1H), 4.73 (td, J = 3.0, 9.6 Hz,1H), 6.93 (d, J = 8.0 Hz, 2H), 7.23-7.27 (m, 2H), 7.43-7.67 (m, 8H), 7.80 (d, J = 8.2 Hz, 3H), 7.90 (d, J =8.6 Hz, 2H), 8.01 (d, J = 7.0 Hz, 2H). 19F NMR (188 MHz, CDCl3)：δ = 128.3 (s, 1F). IR (KBr)： 1691, 1581, 1490, 1447, 1340, 1313, 1222, 1163, 1076, 1013, 825, 748, 720, 684, 646 cm-1. MS (ESI, m/z) = 601.0 (M＋H+) .The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.6 mL/min, λ = 254 nm, τmaj = 36.8 min, τmin= 47.2 min); 97% ee.
Compound 3e: 3- (3-bromophenyl) -4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 4.35 (d, J = 18.4 Hz, 1H), 4.50 (dd, J = 10.2, 17.8 Hz, 1H), 4.73 (td, J = 3.0, 9.6 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 7.23-7.27 (m, 2H), 7.43-7.67 (m, 8H), 7.80 (d, J = 8.2 Hz, 3H), 7.90 ( d, J = 8.6 Hz, 2H), 8.01 (d, J = 7.0 Hz, 2H). 19 F NMR (188 MHz, CDCl 3 ): δ = 128.3 (s, 1F). IR (KBr): 1691, 1581 , 1490, 1447, 1340, 1313, 1222, 1163, 1076, 1013, 825, 748, 720, 684, 646 cm -1 .MS (ESI, m / z) = 601.0 (M + H + ) .The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 70:30, flow rate 0.6 mL / min, λ = 254 nm, τ maj = 36.8 min, τ min = 47.2 min); 97% ee.


Compound 3f: ４−フルオロ−１−フェニル−４，４−ビス（フェニルスルホニル）−３−p−トリルブタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 2.22 (s, 3H), 4.32 (d, J = 18.0 Hz, 1H), 4.53 (dd, J = 10.4, 18.0 Hz, 1H), 4.74 (td, J = 2.4, 10.4 Hz, 1H), 6.93 (s, 3H), 7.25-7.50 (m, 3H), 7.54-7.64 (m, 3H), 7.72-7.83 (m, 3H), 7.91 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 7.0 Hz, 2H). 19F NMR (188 MHz, CDCl3)：δ = 128.0 (s, 1F). IR (KBr)： 2924, 1687, 1581, 1515, 1448, 1340, 1224, 1165, 1078, 730, 685, 634 cm-1. MS (ESI, m/z) = 537.2 (M＋H+) The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.6 mL/min, λ = 254 nm, τmaj= 33.5 min, τmin = 45.7 min); 95% ee.
Compound 3f: 4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) -3-p-tolylbutan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 2.22 (s, 3H), 4.32 (d, J = 18.0 Hz, 1H), 4.53 (dd, J = 10.4, 18.0 Hz, 1H), 4.74 (td, J = 2.4, 10.4 Hz, 1H), 6.93 (s, 3H), 7.25-7.50 (m, 3H), 7.54-7.64 (m, 3H), 7.72-7.83 (m, 3H), 7.91 (d , J = 8.0 Hz, 2H), 8.02 (d, J = 7.0 Hz, 2H). 19 F NMR (188 MHz, CDCl 3 ): δ = 128.0 (s, 1F). IR (KBr): 2924, 1687, 1581, 1515, 1448, 1340, 1224, 1165, 1078, 730, 685, 634 cm -1 .MS (ESI, m / z) = 537.2 (M + H + ) The ee of the product was determined by HPLC using an AD- H column (n-hexane / i-PrOH = 70:30, flow rate 0.6 mL / min, λ = 254 nm, τ maj = 33.5 min, τ min = 45.7 min); 95% ee.


Compound 3g: ４−フルオロ−３−（ナフタレン−３−イル）−１−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 4.43 (d, J = 18.8 Hz, 1H), 4.68 (dd, J = 10.4, 18.2 Hz, 1H), 4.98 (d, J = 10.8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.31 (m, 9H), 7.72-7.77 (m, 6H), 7.93-8.04 (m, 6H). 19F NMR (188 MHz, CDCl3)：δ = 127.9 (s, 1F). IR (KBr)： 2924, 1687, 1582, 1448, 1340, 1166, 1077, 753, 728, 684 cm-1. MS (ESI, m/z) = 573.0 (M＋H+) The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.6 mL/min, λ = 254 nm, τmaj = 42.3 min, τmin = 45.7 min); 78% ee.
Compound 3g: 4-Fluoro-3- (naphthalen-3-yl) -1-phenyl-4,4-bis (phenylsulfonyl) butan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 4.43 (d, J = 18.8 Hz, 1H), 4.68 (dd, J = 10.4, 18.2 Hz, 1H), 4.98 (d, J = 10.8 Hz , 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.31 (m, 9H), 7.72-7.77 (m, 6H), 7.93-8.04 (m, 6H). 19 F NMR (188 MHz, CDCl 3 ): Δ = 127.9 (s, 1F). IR (KBr): 2924, 1687, 1582, 1448, 1340, 1166, 1077, 753, 728, 684 cm -1 . MS (ESI, m / z) = 573.0 ( M + H + ) The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 70:30, flow rate 0.6 mL / min, λ = 254 nm, τ maj = 42.3 min, τ min = 45.7 min); 78% ee.


Compound 3h: ３−（フルオロビス（フェニルスルホニル）メチル）−１−フェニルブタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 1.40 (dd, J = 2.0, 6.6 Hz, 3H), 3.78-3.46 (m, 1H), 3.56 (dd, J = 9.4, 17.8 Hz, 1H), 4.00 (d, J = 17.4 Hz, 1H), 7.47-7.62 (m, 6H), 7.66-7.84 (m, 4H), 7.86 (d, J = 8.4 Hz, 2H), 7.95-8.01 (m, 3H). 19F NMR (188 MHz, CDCl3)： δ = 134.2 (s, 1F). The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.6 mL/min, λ = 254 nm, τmaj = 18.2 min, τmin = 26.9 min); 85% ee. Compound 3h: 3- (fluorobis (phenylsulfonyl) methyl) -1-phenylbutan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 1.40 (dd, J = 2.0, 6.6 Hz, 3H), 3.78-3.46 (m, 1H), 3.56 (dd, J = 9.4, 17.8 Hz, 1H), 4.00 (d, J = 17.4 Hz, 1H), 7.47-7.62 (m, 6H), 7.66-7.84 (m, 4H), 7.86 (d, J = 8.4 Hz, 2H), 7.95-8.01 (m 19 F NMR (188 MHz, CDCl 3 ): δ = 134.2 (s, 1F). The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 70: 30, flow rate 0.6 mL / min, λ = 254 nm, τ maj = 18.2 min, τ min = 26.9 min); 85% ee.

Compound 3i: ３−（フルオロビス（フェニルスルホニル）メチル）−１−フェニルペンタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 0.76 (t, J = 7.4 Hz, 3H), 1.68-1.83 (m, 1H), 2.17-2.26 (m, 1H), 3.30-3.44 (m, 2H), 4.14 (dd, J = 5.2, 21.0 Hz, 1H), 7.39-7.78 (m, 9H), 7.88-8.01 (m, 6H). 19F NMR (188 MHz, CDCl3)：δ = 133.8 (s, 1F). The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.6 mL/min, λ = 254 nm, τmaj= 19.3 min, τmin = 23.2 min); 90% ee. Compound 3i: 3- (fluorobis (phenylsulfonyl) methyl) -1-phenylpentan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 0.76 (t, J = 7.4 Hz, 3H), 1.68-1.83 (m, 1H), 2.17-2.26 (m, 1H), 3.30-3.44 ( m, 2H), 4.14 (dd, J = 5.2, 21.0 Hz, 1H), 7.39-7.78 (m, 9H), 7.88-8.01 (m, 6H). 19 F NMR (188 MHz, CDCl 3 ): δ = 133.8 (s, 1F) .The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 70:30, flow rate 0.6 mL / min, λ = 254 nm, τ maj = 19.3 min, τ min = 23.2 min); 90% ee.

Compound 3j: １−（４−ブロモフェニル）−４−フルオロ−３−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 4.32 (d, J = 17.2 Hz, 1H), 4.50 (dd, J = 10.0, 18.4 Hz, 1H), 4.76 (d, J = 10.0 Hz, 1H), 7.07-7.15 (m, 6H), 7.44 (t, J = 7.4 Hz, 2H), 7.56-7.68 (m, 5H), 7.77 (t J = 7.4 Hz, 3H), 7.90 (t, J = 6.2 Hz, 3H). 19F NMR (188 MHz, CDCl3)：δ = 128.0 (s, 1F). The ee of the product was determined by HPLC using an AD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.6 mL/min, λ = 254 nm, τmaj = 51.7 min, τmin = 77.7 min); 95% ee.
Compound 3j: 1- (4-Bromophenyl) -4-fluoro-3-phenyl-4,4-bis (phenylsulfonyl) butan-1-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 4.32 (d, J = 17.2 Hz, 1H), 4.50 (dd, J = 10.0, 18.4 Hz, 1H), 4.76 (d, J = 10.0 Hz , 1H), 7.07-7.15 (m, 6H), 7.44 (t, J = 7.4 Hz, 2H), 7.56-7.68 (m, 5H), 7.77 (t J = 7.4 Hz, 3H), 7.90 (t, J 19 F NMR (188 MHz, CDCl 3 ): δ = 128.0 (s, 1F). The ee of the product was determined by HPLC using an AD-H column (n-hexane / i-PrOH = 70:30, flow rate 0.6 mL / min, λ = 254 nm, τ maj = 51.7 min, τ min = 77.7 min); 95% ee.

アルコール体の一般的な製造法
フルオロビス（フェニルスルホニル）メチル化体3a（127.2 mg, 0.276 mmol）をテトラヒドロフラン (1.2 ml)，メタノール (0.1 ml)に溶かし，水素化ホウ素ナトリウム(12.5 mg, 0.331 mmol)を加えた。１時間後，飽和塩化アンモニウム水溶液を加え，ジクロロメタンで抽出した。有機層は硫酸ナトリウムで乾燥し，濃縮した。残渣をカラムクロマトグラフィーにて精製し，生成物5aを得た。
General production method of alcohol compound Fluorobis (phenylsulfonyl) methylated compound 3a (127.2 mg, 0.276 mmol) is dissolved in tetrahydrofuran (1.2 ml) and methanol (0.1 ml), and sodium borohydride (12.5 mg, 0.331 mmol) is dissolved. ) Was added. After 1 hour, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give product 5a.


Compound 4a: ４−フルオロ−１，３−ジフェニル−４，４−ビス（フェニルスルホニル）ブタン−1−オール
White solid; 1H NMR (200 MHz, CDCl3, diastereomer mixture)： δ = 1.96 (s, 1H), 2.44 (d, J = 3.0 Hz, 1H), 3.22-3.32 (m, 4H), 4.05-4.38 (m, 4H), 7.07-7.15 (m, 10H), 7.41-7.93 (m, 30H) . 19F NMR (188 MHz, CDCl3)： δ = -126.6 (s, 1F) , -127.5 (s, 1F).
Compound 4a: 4-Fluoro-1,3-diphenyl-4,4-bis (phenylsulfonyl) butan-1-ol
White solid; 1 H NMR (200 MHz, CDCl 3 , diastereomer mixture): δ = 1.96 (s, 1H), 2.44 (d, J = 3.0 Hz, 1H), 3.22-3.32 (m, 4H), 4.05-4.38 (m, 4H), 7.07-7.15 (m, 10H), 7.41-7.93 (m, 30H). 19 F NMR (188 MHz, CDCl 3 ): δ = -126.6 (s, 1F), -127.5 (s, 1F).


Compound 4b: ３−（４−クロロフェニル）−４−フルオロ−１−フェニル−４，４−ビス（フェニルスルホニル）ブタン−１−オール
White solid; 1H NMR (200 MHz, CDCl3, diastereomer mixture)： δ = 2.06 (s, 1H), 2.82-3.35 (m, 5H), 4.21-4.42 (m, 3H), 7.07-7.87 (m, 19H). 19F NMR (188 MHz, CDCl3)： δ = -127.0 (s, 1F), -127.6 (s, 1F).
Compound 4b: 3- (4-Chlorophenyl) -4-fluoro-1-phenyl-4,4-bis (phenylsulfonyl) butan-1-ol
White solid; 1 H NMR (200 MHz, CDCl 3, diastereomer mixture): δ = 2.06 (s, 1H), 2.82-3.35 (m, 5H), 4.21-4.42 (m, 3H), 7.07-7.87 (m, 19 H). 19 F NMR (188 MHz, CDCl 3 ): δ = -127.0 (s, 1F), -127.6 (s, 1F).


Compound 5a: ５−フルオロ−２，４−ジフェニル−５，５−ビス（フェニルスルホニル）ペンタン−２−オール
White solid; 1H NMR (200 MHz, CDCl3, diastereomer mixture)： δ = 1.79 (s, 1H), 2.46 (s, 1H), 3.14-3.35 (m, 4H), 3.81 (dd, J = 4.0, 9.0 Hz, 1H), 3.95 (d, J = 8.8 Hz, 1H), 6.40-6.61 (m, 2H), 6.82-7.24 (m, 12H), 7.29-7.57 (m, 12H), 7.59-7.86 (m, 14H). 19F NMR (188 MHz, CDCl3)：δ= -124.0 (s, 1F), -125.8 (s, 1F).
モノフルオロメチルアルコールの一般的な製造法
マグネシウム(189.2 mg, 7.78 mmol)を加熱乾燥し，室温に冷却した。メタノール (2.0 ml)を加え，０℃に冷却後，b―フルオロビス（フェニルスルホニル）メチルアルコール4a（136.1 mg，0.259 mmol）のテトラヒドロフラン(0.1 ml)溶液を加えた。３時間撹拌後，１N 塩酸を加え，ジクロロメタンで抽出した。有機層は硫酸ナトリウムで乾燥後，濃縮した。残渣をカラムクロマトグラフィーにて精製し，生成物6aを得た。 Compound 5a: 5-Fluoro-2,4-diphenyl-5,5-bis (phenylsulfonyl) pentan-2-ol
White solid; 1 H NMR (200 MHz, CDCl 3 , diastereomer mixture): δ = 1.79 (s, 1H), 2.46 (s, 1H), 3.14-3.35 (m, 4H), 3.81 (dd, J = 4.0, 9.0 Hz, 1H), 3.95 (d, J = 8.8 Hz, 1H), 6.40-6.61 (m, 2H), 6.82-7.24 (m, 12H), 7.29-7.57 (m, 12H), 7.59-7.86 (m , 14H). 19 F NMR (188 MHz, CDCl 3 ): δ = -124.0 (s, 1F), -125.8 (s, 1F).
General production method of monofluoromethyl alcohol Magnesium (189.2 mg, 7.78 mmol) was dried by heating and cooled to room temperature. Methanol (2.0 ml) was added, and after cooling to 0 ° C., a solution of b-fluorobis (phenylsulfonyl) methyl alcohol 4a (136.1 mg, 0.259 mmol) in tetrahydrofuran (0.1 ml) was added. After stirring for 3 hours, 1N hydrochloric acid was added, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give product 6a.

Compound 6a: ４−フルオロ−１，３−ジフェニルブタン−１−オール
Colorless oil; 1H NMR (200 MHz, CDCl3 ,diasteromer mixture)：δ = 1.79 (s, 1H), 1.87 (s, 1H), 2.01 (ddd, J = 3.6, 10.6, 14.0 Hz, 1H), 2.22 (ddd, J = 4.6, 10.0, 14.2 Hz, 1H), 2.23 (t, J = 7.6 Hz, 2H), 2.78-3.02 (m, 1H), 3.24-3.48 (m, 1H), 4.30-4.49 (m, 3H), 4.54-4.68 (m, 3H), 7.17-7.39 (m, 20H); 19F NMR (188 MHz, CDCl3)：δ = -217.3 (dt. J = 20.7, 47.0 Hz, 1F), -217.6 (dt, J = 19.6, 47.0 Hz, 1F). Compound 6a: 4-Fluoro-1,3-diphenylbutan-1-ol
Colorless oil; 1 H NMR (200 MHz, CDCl 3 , diasteromer mixture): δ = 1.79 (s, 1H), 1.87 (s, 1H), 2.01 (ddd, J = 3.6, 10.6, 14.0 Hz, 1H), 2.22 (ddd, J = 4.6, 10.0, 14.2 Hz, 1H), 2.23 (t, J = 7.6 Hz, 2H), 2.78-3.02 (m, 1H), 3.24-3.48 (m, 1H), 4.30-4.49 (m , 3H), 4.54-4.68 (m, 3H), 7.17-7.39 (m, 20H); 19 F NMR (188 MHz, CDCl 3 ): δ = -217.3 (dt. J = 20.7, 47.0 Hz, 1F), -217.6 (dt, J = 19.6, 47.0 Hz, 1F).


Compound 6b: ３−（４−クロロフェニル）−４−フルオロ−１−フェニルブタン−１−オール
Colorless oil; 1H NMR (200 MHz, CDCl3 ,diasteromer mixture)：δ = 1.87-2.01 (m, 3H), 2.11-2.25 (m, 3H), 2.83-2.93 (m, 1H), 3.27-3.41 (m, 1H), 4.31-4.44 (m, 3H), 4.54-4.64 (m, 3H), 7.10-7.39 (m, 18H); 19F NMR (188 MHz, CDCl3)：δ = -218.2 (dt, J = 21.8, 47.0 Hz, 1F), -218.6 (dt, J = 20.5, 47.0 Hz, 1F).
モノフルオロメチルケトンの一般的な製造法 Compound 6b: 3- (4-Chlorophenyl) -4-fluoro-1-phenylbutan-1-ol
Colorless oil; 1 H NMR (200 MHz, CDCl 3 , diasteromer mixture): δ = 1.87-2.01 (m, 3H), 2.11-2.25 (m, 3H), 2.83-2.93 (m, 1H), 3.27-3.41 ( m, 1H), 4.31-4.44 (m, 3H), 4.54-4.64 (m, 3H), 7.10-7.39 (m, 18H); 19 F NMR (188 MHz, CDCl 3 ): δ = -218.2 (dt, J = 21.8, 47.0 Hz, 1F), -218.6 (dt, J = 20.5, 47.0 Hz, 1F).
General production method of monofluoromethyl ketone

オルト過ヨウ素酸(24.0 mg, 0.105 mmol)をアセトニトリル(0.8 ml)に溶かし，室温にて１５分撹拌した。０℃に冷却後，モノフルオロメチルアルコール5a(25.0 mg, 0.102 mmol)，ピリジニウムクロロクロメート(0.4 mg, 0.002 mmol)を加え，１時間撹拌した。飽和亜硫酸ナトリウムを加え，濃縮後，酢酸エチルにて抽出した。有機層は硫酸ナトリウムで乾燥後，濃縮した。残渣をカラムクロマトグラフィーにて精製し，目的の生成物6aを得た。

Orthoperiodic acid (24.0 mg, 0.105 mmol) was dissolved in acetonitrile (0.8 ml) and stirred at room temperature for 15 minutes. After cooling to 0 ° C., monofluoromethyl alcohol 5a (25.0 mg, 0.102 mmol) and pyridinium chlorochromate (0.4 mg, 0.002 mmol) were added and stirred for 1 hour. Saturated sodium sulfite was added, concentrated, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to obtain the desired product 6a.


Compound 7a:４−フルオロ−１，３−ジフェニルブタン−１−オン
White solid; 1H NMR (CDCl3, 200MHz) δ 3.37 (dd, J = 7.0, 17.2 1H), 3.56 (dd, J = 6.6, 17.2 Hz 1H), 3.78 (td, J = 5.8, 22.2 Hz, 1H), 4.51 (ddt, J = 5.6, 6.6, 9.0 Hz, 1H), 4.75 (ddt, J = 5.4, 6.6, 9.0 Hz, 1H), 7.22-7.31 (m, 5H), 7.39-7.58 (m, 3H), 7.93 (d, J = 7.2 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -219.6 (dt, J = 22.9, 47.0 Hz, 1F); The ee of the product was determined by HPLC using an OD-H column (n-hexane/i-PrOH = 90:10, flow rate 0.3 mL/min, λ = 254 nm, τmaj = 27.5 min, τmin= 30.5 min); 97% ee. Compound 7a: 4-Fluoro-1,3-diphenylbutan-1-one
White solid; 1 H NMR (CDCl 3 , 200MHz) δ 3.37 (dd, J = 7.0, 17.2 1H), 3.56 (dd, J = 6.6, 17.2 Hz 1H), 3.78 (td, J = 5.8, 22.2 Hz, 1H ), 4.51 (ddt, J = 5.6, 6.6, 9.0 Hz, 1H), 4.75 (ddt, J = 5.4, 6.6, 9.0 Hz, 1H), 7.22-7.31 (m, 5H), 7.39-7.58 (m, 3H ), 7.93 (d, J = 7.2 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -219.6 (dt, J = 22.9, 47.0 Hz, 1F); The ee of the product was determined by HPLC using an OD-H column (n-hexane / i-PrOH = 90:10, flow rate 0.3 mL / min, λ = 254 nm, τ maj = 27.5 min, τ min = 30.5 min); 97% ee.

Compound 7b:３−（４−クロロフェニル）−４−フルオロ−１―フェニルブタン−１−オン
White solid; 1H NMR (CDCl3, 200MHz) δ 3.34 (dd, J = 7.6, 17.6 1H), 3.54 (dd, J = 6.2, 17.2 Hz 1H), 3.65-3.84 (m, 1H), 4.49 (ddt, J = 4.8, 7.4, 9.0 Hz, 1H), 4.73 (ddt, J = 4.8, 7.2, 8.8 Hz, 1H), 7.25-7.267 (m, 5H), 7.41-7.56 (m, 3H), 7.92 (dd, J = 1.4, 7.0 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -220.4 (dt, J = 22.9, 47.0 Hz, 1F); The ee of the product was determined by HPLC using an OD-H column (n-hexane/i-PrOH = 90:10, flow rate 0.3 mL/min, λ = 254 nm, τmaj = 26.4 min, τmin= 29.6 min); 97% ee.
Compound 7b: 3- (4-chlorophenyl) -4-fluoro-1-phenylbutan-1-one
White solid; 1 H NMR (CDCl 3 , 200MHz) δ 3.34 (dd, J = 7.6, 17.6 1H), 3.54 (dd, J = 6.2, 17.2 Hz 1H), 3.65-3.84 (m, 1H), 4.49 (ddt , J = 4.8, 7.4, 9.0 Hz, 1H), 4.73 (ddt, J = 4.8, 7.2, 8.8 Hz, 1H), 7.25-7.267 (m, 5H), 7.41-7.56 (m, 3H), 7.92 (dd , J = 1.4, 7.0 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -220.4 (dt, J = 22.9, 47.0 Hz, 1F); The ee of the product was determined by HPLC using an OD- H column (n-hexane / i-PrOH = 90:10, flow rate 0.3 mL / min, λ = 254 nm, τ maj = 26.4 min, τ min = 29.6 min); 97% ee.


Compound 6h:４―フルオロ−３−メチル−１―フェニルブタン−１−オン
White solid; 1H NMR (CDCl3, 200MHz) δ 1.06 (dd, J = 0.8, 7.0 Hz, 3H), 2.47-2.68 (m, 1H), 2.84 (dd, J = 7.4, 17.0 1H), 3.17 (dd, J = 5.8, 16.8 Hz 1H), 4.26 (ddt, J = 4.8, 7.0, 8.8 Hz, 1H), 4.49 (ddt, J = 4.8, 6.4, 8.8 Hz, 1H), 7.35-7.38 (m, 1H), 7.45-7.56 (m, 2H), 7.95 (dd, J = 0.8, 7.8 Hz, 2H); 19F NMR (CDCl3, 188 MHz) δ -223.1 (dt, J = 21.8, 47.0 Hz, 1F);
Compound 6h: 4-fluoro-3-methyl-1-phenylbutan-1-one
White solid; 1 H NMR (CDCl 3 , 200MHz) δ 1.06 (dd, J = 0.8, 7.0 Hz, 3H), 2.47-2.68 (m, 1H), 2.84 (dd, J = 7.4, 17.0 1H), 3.17 ( dd, J = 5.8, 16.8 Hz 1H), 4.26 (ddt, J = 4.8, 7.0, 8.8 Hz, 1H), 4.49 (ddt, J = 4.8, 6.4, 8.8 Hz, 1H), 7.35-7.38 (m, 1H ), 7.45-7.56 (m, 2H), 7.95 (dd, J = 0.8, 7.8 Hz, 2H); 19 F NMR (CDCl 3 , 188 MHz) δ -223.1 (dt, J = 21.8, 47.0 Hz, 1F) ;

本発明のβ−フルオロメチルカルボニル誘導体の製造法は医農薬産業に利用可能である。   The production method of the β-fluoromethylcarbonyl derivative of the present invention can be used in the medical and agrochemical industry.

Claims (9)

溶媒中，光学活性な相間移動触媒の存在下，一般式（１）

（式中，Ｒ１は，水素，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基，アルコキシ基またはアミノ基を示す。Ｒ２は，水素，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基またはアリール基を示す。）で表せる共役カルボニル化合物を一般式（２）

（式中，Ｒ３，Ｒ４はそれぞれ独立に，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基またはアリール基を示す。さらに，Ｒ３およびＲ４が一体となって，環状構造の一部を形成してもよい。）で示されるフルオロビススルホニルメタン類との共役付加反応させることを特徴とする一般式（３）

式中，Ｒ１，Ｒ２，Ｒ３，Ｒ４は前記定義に同じ。）
で示される光学活性β―フルオロ（フェニルスルホニル）メチル付加体の製造法。
General formula (1) in the presence of an optically active phase transfer catalyst in a solvent

(In the formula, R 1 represents hydrogen, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group, an alkoxy group or an amino group. R 2 represents hydrogen, a substituted or unsubstituted alkyl group. A conjugated carbonyl compound represented by the general formula (2): an alkenyl group, an aralkyl group, an alkynyl group or an aryl group.

(Wherein R 3 and R 4 each independently represents a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group, alkynyl group or aryl group. Furthermore, R 3 and R 4 are combined to form a cyclic group. A part of the structure may be formed.) A conjugate addition reaction with fluorobissulfonylmethanes represented by the general formula (3)

In the formula, R 1 , R 2 , R 3 and R 4 are the same as defined above. )
A process for producing an optically active β-fluoro (phenylsulfonyl) methyl adduct represented by the formula:
前記一般式（３）で表せるβ−フルオロ（フェニルスルホニル）メタン付加体を溶媒中，還元剤存在下，カルボニル基を還元させることを特徴とする一般式（４）

（式中，Ｒ１，Ｒ２，Ｒ３，Ｒ４は前記定義に同じ。）で示される光学活性β−フルオロ（フェニルスルホニル）メチルアルコール誘導体の製造法。
The β-fluoro (phenylsulfonyl) methane adduct represented by the general formula (3) is reduced in a solvent in the presence of a reducing agent in the general formula (4)

(Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above), a method for producing an optically active β-fluoro (phenylsulfonyl) methyl alcohol derivative.
前記一般式（３）で表せるβ−フルオロ（フェニルスルホニル）メタン付加体を溶媒中，求核剤存在下，カルボニル基を還元させることを特徴とする一般式（５）

（式中，Ｒ１，Ｒ２，Ｒ３，Ｒ４は前記定義に同じ。Ｒ５は，水素，置換もしくは未置換のアルキル基，アルケニル基，アラルキル基，アルキニル基，アリール基またはトリフルオロメチル基を示す。）で示される光学活性β−フルオロ（フェニルスルホニル）メチルアルコール誘導体の製造法。
The β-fluoro (phenylsulfonyl) methane adduct represented by the general formula (3) is reduced in the presence of a nucleophile in a solvent in the general formula (5)

(Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. R 5 represents hydrogen, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group or trifluoromethyl. A method for producing an optically active β-fluoro (phenylsulfonyl) methyl alcohol derivative represented by:
前記一般式（４），（５）で表せるβ−フルオロ（フェニルスルホニル）メチルアルコール誘導体を溶媒中，還元剤として金属の存在下，脱スルホニル化させることを特徴とする一般式（６）

（式中，Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５は前記定義に同じ。）で表せる光学活性β−フルオロメチルアルコール誘導体の製造法。
General formula (6), wherein the β-fluoro (phenylsulfonyl) methyl alcohol derivative represented by the general formulas (4) and (5) is desulfonylated in a solvent in the presence of a metal as a reducing agent.

(Wherein R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above), a method for producing an optically active β-fluoromethyl alcohol derivative represented by
前記一般式（６）（式中，Ｒ１，Ｒ２は前記定義に同じ。Ｒ５は水素を示す。）で表せるβ−フルオロメチルアルコール誘導体を溶媒中，酸化剤存在下，カルボニル基を酸化させることを特徴とする一般式（７）

（式中，Ｒ１，Ｒ２は前記定義に同じ。）で示される光学活性β−フルオロメチルカルボニル誘導体の製造法。
A β-fluoromethyl alcohol derivative represented by the general formula (6) (wherein R 1 and R 2 are the same as defined above, R 5 represents hydrogen) is oxidized in the presence of an oxidizing agent in a solvent. General formula (7) characterized by

(Wherein R 1 and R 2 are the same as defined above).
前記記載の光学活性な相間移動触媒は，光学活性４級アンモニウム塩類から選ばれる少なくとも１種類の塩であることを特徴とする請求項１に記載の製造法。
光学活性な相間移動触媒としては，一般式（８），（９）


（式中，Ｒ６は水素，置換もしくは未置換のアルキル基もしくはアルコキシ基を示す。もしくはＯＲ１０で表せるＲ１０はアルキル基を示す。Ｒ７は，エチル基もしくはビニル基を示す。Ｒ８は，水素，アルキル基，アリール基またはアシル基を示す。Ｒ９は，水素，置換もしくは未置換のアルキル基，トリフルオロメチル基または3，5−ビス（トリフルオロメチル）フェニル基を示す。ｍは０〜２の整数を表す。Ｘは，ハロゲン原子，ＩＯ４，ＣｌＯ４，ＯＴｆまたはＨＳＯ４を示す。）
2. The process according to claim 1, wherein the optically active phase transfer catalyst is at least one salt selected from optically active quaternary ammonium salts.
As optically active phase transfer catalysts, general formulas (8), (9)


(In the formula, R 6 represents hydrogen, a substituted or unsubstituted alkyl group or an alkoxy group, or R 10 represented by OR 10 represents an alkyl group. R 7 represents an ethyl group or a vinyl group. R 8 represents , Hydrogen, an alkyl group, an aryl group, or an acyl group, R 9 represents hydrogen, a substituted or unsubstituted alkyl group, a trifluoromethyl group, or a 3,5-bis (trifluoromethyl) phenyl group, where m is Represents an integer of 0 to 2. X represents a halogen atom, IO 4 , ClO 4 , OTf or HSO 4. )
前記溶媒が，Ｎ，Ｎ−ジメチルホルムアミド，ジメチルスルホキシド，クロロホルム，ジクロロメタン，ジクロロエタン，トルエン，テトラヒドロフラン，ヘキサン，ベンゼン，メタノール，アセトニトリルからなる群より選ばれる少なくとも1種である請求項１，２，３，４，５のいずれか１項に記載の製造法。
The solvent is at least one selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, toluene, tetrahydrofuran, hexane, benzene, methanol, and acetonitrile. 4. The production method according to any one of 4 and 5.
前記金属は，希土類を含む遷移金属リチウム，ナトリウム，マグネシウム，アルミニウム，亜鉛，スズ，インジウム，サマリウムなどから選ばれる少なくとも１種類の元素であることを特徴とする請求項４に記載の製造法。
5. The method according to claim 4, wherein the metal is at least one element selected from lithium, sodium, magnesium, aluminum, zinc, tin, indium, samarium, and the like, including rare earths.
前記酸化剤は，ピリジニウムクロロクロメートであることを特徴とする請求項５に記載の製造法。 The manufacturing method according to claim 5, wherein the oxidizing agent is pyridinium chlorochromate.
JP2008059160A 2008-03-10 2008-03-10 METHOD FOR PRODUCING OPTICALLY ACTIVE beta-FLUOROMETHYLCARBONYL DERIVATIVE Pending JP2009215198A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111548298A (en) * 2020-06-18 2020-08-18 成都大学 Chiral trifluoromethyl substituted maleimide derivative and preparation method thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111548298A (en) * 2020-06-18 2020-08-18 成都大学 Chiral trifluoromethyl substituted maleimide derivative and preparation method thereof
CN111548298B (en) * 2020-06-18 2023-03-21 成都大学 Chiral trifluoromethyl substituted maleimide derivative and preparation method thereof

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