JP2008222597A - METHOD FOR PRODUCING beta-FLUOROMETHYLCARBONYL DERIVATIVE - Google Patents
METHOD FOR PRODUCING beta-FLUOROMETHYLCARBONYL DERIVATIVE Download PDFInfo
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Abstract
Description
本発明はβー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 a 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ー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（８）に示される光学活性βー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。
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，塩基触媒用いて前記一般式（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（８）に示されるβー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。本手法は，光学活性な相関移動触媒を用いることで光学活性な前記一般式（３）が得られる。さらに，前記一般式（４）もしくは（５）と（２）とのジアステレオ選択的反応によってそれぞれ得られる前記一般式（６），（７）の製造法と，脱スルホニル化後，前記一般式（９），（１０）の製造法も提供する。
The present invention has been made in order to solve the above-mentioned problems. The object of the present invention is to efficiently react the general formulas (1) and (2) in a solvent using a base catalyst in an industrial scale. It is to produce the general formula (3), to easily convert (3), and to provide a method for producing a β-fluoromethylcarbonyl derivative represented by the general formula (8). In this method, the optically active general formula (3) can be obtained by using an optically active phase transfer catalyst. Furthermore, the production method of the general formulas (6) and (7) obtained by the diastereoselective reaction of the general formula (4) or (5) and (2), respectively, and after desulfonylation, the general formula The manufacturing methods of (9) and (10) are also provided.
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，塩基触媒存在下，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，前記一般式（３）に示されるを得ることを見出した。さらに，塩基存在下，光学活性な相間移動触媒条件下，前記一般式（１）と（２）との反応により光学活性な前記一般式（３）が得られる。さらに，前記一般式（４），（５）を用いてそれぞれジアステレオ選択的に反応を行い，光学活性な前記一般式（６），（７）の製造に至った。前記一般式（３），（６），（７）は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（８），（９），（１０）をそれぞれ得ることを見出し，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 general formula (2) of the fluorobissulfonylmethanes are present in a solvent in the presence of a base catalyst. It was found that the reaction represented by the general formula (3) was obtained. Further, the optically active general formula (3) is obtained by the reaction of the general formulas (1) and (2) under the optically active phase transfer catalyst conditions in the presence of a base. Furthermore, reaction was carried out diastereoselectively using the general formulas (4) and (5), respectively, and the optically active general formulas (6) and (7) were produced. The general formulas (3), (6), and (7) were found to obtain the general formulas (8), (9), and (10), respectively, by a simple desulfonylation reaction with a metal, thereby completing the present invention. It came to do.
すなわち，本発明は下記の（１）〜（９）に関するものである。
（１）溶媒中，塩基触媒存在下，一般式（１）
That is, the present invention relates to the following (1) to (9).
(1) General formula (1) in the presence of a base 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フッ素カルボニル誘導体の製造法。β―フルオロ（フェニルスルホニル）メチル付加体（２）前記塩基存在下，光学活性な相間移動触媒を用いると，前記一般式（３）で表せるβ―フルオロ（フェニルスルホニル）メチル付加体が光学活性である請求項２の記載の製造法。
（３）前記一般式（４），（５）
(Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above)
The manufacturing method of the optically active fluorine-containing carbonyl derivative shown by these. β-fluoro (phenylsulfonyl) methyl adduct (2) When an optically active phase transfer catalyst is used in the presence of the base, the β-fluoro (phenylsulfonyl) methyl adduct represented by the general formula (3) is optically active. The production method according to claim 2.
(3) General formula (4), (5)
（式中，Ｒ５，Ｒ６，Ｒ７，Ｒ８，Ｒ９，Ｒ１０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前記一般式（２）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（６） (Wherein R 5 , R 6 , R 7 , R 8 , R 9 and R 10 represent hydrogen, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group or an aryl group). A conjugated carbonyl compound is subjected to a conjugate addition reaction with a fluorobissulfonylmethane represented by the general formula (2).
（式中，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８，Ｒ９，Ｒ１０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。
（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）メチル付加体を溶媒中，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（８）
(Wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are the same as defined above), an optically active β-fluoro (phenylsulfonyl) methyl adduct represented by Manufacturing method.
(4) The β-fluoro (phenylsulfonyl) methyl adduct represented by the general formula (3) is desulfonylated in a solvent in the presence of a metal as a reducing agent in the general formula (8)
（式中，Ｒ１，Ｒ２は前記定義に同じ。）で示される光学活性βーフルオロメチルカルボニル誘導体の製造法。
（５）基質が前記一般式（６）または（７）で表せる含フッ素カルボニル誘導体である一般式（９），（１０）
(Wherein R 1 and R 2 are the same as defined above), a process for producing an optically active β-fluoromethylcarbonyl derivative.
(5) General formula (9), (10) wherein the substrate is a fluorine-containing carbonyl derivative represented by the general formula (6) or (7)
（式中，Ｒ５，Ｒ６，Ｒ７，Ｒ８，Ｒ９，Ｒ１０は前記定義に同じ。）で示される光学活性βーフルオロメチルカルボニル誘導体の請求項４の記載の製造法。
（６）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２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（１１），（１２）
5. The process according to claim 4, wherein an optically active β-fluoromethylcarbonyl derivative represented by the formula (wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are the same as defined above).
(6) The process according to claim 2, wherein the optically active phase transfer catalyst is at least one salt selected from optically active quaternary ammonium salts.
Examples of the optically active phase transfer catalyst include general formulas (11) and (12).
（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またはトリフルオロメチル基を示す。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。）
（７）前記塩基は，一般に市販されているアミン類もしくは無機塩一般式（５）から選ばれる少なくとも１種類の塩基であることを特徴とする請求項１，２，３いずれか１項に記載の製造法。アミンとしては，トリエチルアミン，ジイソプロピルエチルアミン，ジメチルアミノピリジン，キヌクリジン，ＤＢＵ，ＤＡＢＣＯなどを用いることができる。無機塩は一般式（１３）
（Ｘ）ｎＭ （１３）
（式中，Ｍ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，アルミニウムから選ばれた元素，ｎは，Ｍの原子価と同数の整数を表す。Ｘはアルコシド，フルオリド，カルボネートなどのマイナスイオンを表す。）
（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または５のいずれか１項に記載の製造法。
（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４，５いずれか１項に記載の製造法。
(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 or a trifluoromethyl group, m represents an integer of 0 to 2, and X represents a halogen atom. , IO 4 , ClO 4 , OTf or HSO 4 )
(7) The base according to any one of claims 1, 2 and 3, wherein the base is at least one base selected from generally commercially available amines or inorganic salts of the general formula (5). Manufacturing method. As the amine, triethylamine, diisopropylethylamine, dimethylaminopyridine, quinuclidine, DBU, DABCO and the like can be used. The inorganic salt has the general formula (13)
(X) nM (13)
(In the formula, M is an element selected from transition metals including rare earths, lithium, sodium, magnesium and aluminum, n is an integer having the same number as the valence of M. X is a minus such as alkoxide, fluoride, carbonate, etc. Represents an ion.)
(8) The solvent is at least one selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, toluene, tetrahydrofuran, hexane, and benzene. Or the manufacturing method of any one of 5.
(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. , 5 The manufacturing method of any one of 5.
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ー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 for 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 is problematic in that the fluorinating agent is expensive and a substrate that is not available is produced. The optically active substance 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ーフルオロメチルカルボニル誘導体の製造法は，塩基触媒存在下，前記一般式（１）で示される共役アルデヒドと前記一般式（２）との共役付加反応を行えることから基質汎用性が広い。さらに，光学活性な相間移動触媒を用いることで光学活性前記一般式（３）を得ることができる。基質に不斉補助基をもつ一般式（４），（５）を用いることで，ジアステレオ選択的な共役付加反応を行い，光学活性な前記一般式（６），（７）を得ることが可能である。これらβ―フルオロ（フェニルスルホニル）メチル付加体（３），（６），（７）は簡便な脱スルホニル化により前記一般式（８），（９），（１０）に示されるβーフルオロメチルカルボニル化合物へと誘導することが可能であり，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 a conjugate addition of the conjugated aldehyde represented by the general formula (1) and the general formula (2) in the presence of a base catalyst. Since the reaction can be performed, the versatility of the substrate is wide. Furthermore, the optically active general formula (3) can be obtained by using an optically active phase transfer catalyst. By using the general formulas (4) and (5) having an asymmetric auxiliary group on the substrate, a diastereoselective conjugate addition reaction can be performed to obtain the optically active general formulas (6) and (7). Is possible. These β-fluoro (phenylsulfonyl) methyl adducts (3), (6) and (7) can be converted into β-fluoromethyl represented by the general formulas (8), (9) and (10) by simple desulfonylation. It can be derived into a carbonyl compound, and the present invention has high industrial utility value.
以下，本発明を詳細に説明する。本発明は塩基触媒存在下，前記一般式（１），（４），（５）のいずれか１つに対して，前記一般式（２）と反応させて前記一般式（３），（６），（７）をそれぞれ得た後，脱スルホニル化することにより前記一般式（８），（９），（１０）に示されるβーフルオロメチルカルボニル誘導体を得ることを特徴とする製造法である。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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，３−（フルオロビス（フェニルスルホニル）メチル）ブタナール，エチル−３−（フルオロビス（フェニルスルホニル）メチル）ペンタノエート，フルオロ４−フルオロ−４，４−ビス（フェニルスルホニル）ブタナール，４−フルオロ−３−メチル−４，４−ビス（フェニルスルホニル）ブタナール，３−[フルオロビス（フェニルスルホニル）メチル]ペンタナール，３−[フルオロビス（フェニルスルホニル）メチル]ヘプタナール等が挙げられる。
前記一般式（４），（５）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。
前記一般式（４），（５）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。
前記一般式（４），（５）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。
前記一般式（４），（５）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。
前記一般式（６），（７）で示される
３−（３−（フルオロビス（フェニルスルホニル）メチル）ブタノイル）オキサゾリジン−２−オン，３−（３−（フルオロビス（フェニルスルホニル）メチル）ペンタノイル）オキサゾリジン−２−オン，３−（３−（フルオロビス（フェニルスルホニル）メチル）ヘキサノイル）オキサゾリジン−２−オン，（４S）−３−（４−フルオロ−３−メチル−４，４−ビス（フェニルスルホニル）ブタノイル−４−イソプロピルオキサゾキジン−２−オンなどが挙げられる。
前記一般式（８）で示される
４−フルオロ−３−メチルブタナール，３−（フルオロメチル）ペンタナール，３−（フルオロメチル）ヘキサナール，エチル ４−フルオロ−３−メチルブタノエート，エチル ４−フルオロ−３−メチルペンタノエート，エチル ４−フルオロ−３−メチルヘキサノエートなどが挙げられる。
前記一般式（９），（１０）で示される
３−（３−（フルオロメチル）ブタノイル）オキサゾリジン−２−オン，３−（３−（フルオロメチル）ペンタノイル）オキサゾリジン−２−オン，３−（３−（フルオロメチル）ヘキサノイル）オキサゾリジン−２−オンなどが挙げられる。
前記塩基触媒として特に制限するわけではないが，トリエチルアミン，ジイソプロピルエチルアミン，ジメチルアミノピリジン，キヌクリジン，ＤＢＵ，ＤＡＢＣＯなどを用いることができる。なお，前記一般式（５）塩基も，特に制限するわけではないが，水酸化ナトリウム，炭酸ナトリム，水酸化セシウム等が挙げられる。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。
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。
前記一般式（１１），（１２）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。
前記一般式（１１），（１２）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。
前記一般式（１１），（１２）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。
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。
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。
反応後，前記一般式（３），（６），（７）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。
The present invention will be described in detail below. In the present invention, in the presence of a base catalyst, any one of the general formulas (1), (4), and (5) is reacted with the general formula (2) to produce the general formulas (3), (6 ) And (7), respectively, followed by desulfonylation to obtain a β-fluoromethylcarbonyl derivative represented by the general formulas (8), (9) and (10). is there.
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.
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.
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.
Examples of the alkynyl group in the general formula (1) include an ethynyl group, a phenylethynyl group, and a 2-propynyl group.
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.
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.
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.
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.
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.
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.
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.
Examples of the β-fluoro (phenylsulfonyl) methyl adduct represented by the general formula (3) include 3- (fluorobis (phenylsulfonyl) methyl) butanal, ethyl-3- (fluorobis (phenylsulfonyl) methyl) Pentanoate, fluoro-4-fluoro-4,4-bis (phenylsulfonyl) butanal, 4-fluoro-3-methyl-4,4-bis (phenylsulfonyl) butanal, 3- [fluorobis (phenylsulfonyl) methyl] pentanal, And 3- [fluorobis (phenylsulfonyl) methyl] heptanal.
The alkyl groups in the general formulas (4) and (5) may have a substituent, and are linear or branched alkyl groups having 1 to 20 carbon atoms or cycloalkyl having 3 to 20 carbon atoms. Group is preferable, and an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms is more preferable.
Examples of the aralkyl group in the general formulas (4) and (5) include benzyl group, pentafluorobenzyl group, o-methylbenzyl group, m-methylbenzyl group, p-methylbenzyl group, p-nitrobenzyl group, Examples include naphthylmethyl group, furfuryl group, α-phenethyl group and the like.
Examples of the alkynyl group in the general formulas (4) and (5) include an ethynyl group, a phenylethynyl group, and a 2-propynyl group.
The aryl group in the general formulas (4) and (5) 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.
3- (3- (fluorobis (phenylsulfonyl) methyl) butanoyl) oxazolidin-2-one, 3- (3- (fluorobis (phenylsulfonyl) methyl) pentanoyl represented by the general formulas (6) and (7) ) Oxazolidin-2-one, 3- (3- (fluorobis (phenylsulfonyl) methyl) hexanoyl) oxazolidine-2-one, (4S) -3- (4-fluoro-3-methyl-4,4-bis ( Phenylsulfonyl) butanoyl-4-isopropyloxazoxidin-2-one and the like.
4-fluoro-3-methylbutanal represented by the general formula (8), 3- (fluoromethyl) pentanal, 3- (fluoromethyl) hexanal, ethyl 4-fluoro-3-methylbutanoate, ethyl 4- Examples include fluoro-3-methylpentanoate and ethyl 4-fluoro-3-methylhexanoate.
3- (3- (Fluoromethyl) butanoyl) oxazolidine-2-one, 3- (3- (fluoromethyl) pentanoyl) oxazolidine-2-one, 3- (3) represented by the general formulas (9) and (10) 3- (fluoromethyl) hexanoyl) oxazolidine-2-one and the like.
The base catalyst is not particularly limited, but triethylamine, diisopropylethylamine, dimethylaminopyridine, quinuclidine, DBU, DABCO and the like can be used. The base of the general formula (5) is not particularly limited, and examples thereof include sodium hydroxide, sodium carbonate, cesium hydroxide and the like. These can be used alone or in combination of two or more.
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.
The alkyl group in the general formulas (11) and (12) 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.
The aryl group in the general formulas (11) and (12) 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.
The acyl group in the general formulas (11) and (12) 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.
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.
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.
After the reaction, the β-fluoro (phenylsulfonyl) methyl adduct represented by the general formulas (3), (6), and (7) can be isolated and purified from the reaction solution by a general method. After concentrating the liquid, distillation purification, column chromatography using an adsorbent such as silica gel or alumina, salting out, recrystallization, and the like can be mentioned.
前記一般式（８），（９），（１０）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。
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。
The β-fluoromethylcarbonyl derivatives represented by the general formulas (8), (9), and (10) can be isolated and purified from the reaction solution by a general method. For example, after concentrating the reaction solution, Examples include purification by distillation or column chromatography using an adsorbent such as silica gel and alumina, salting out, recrystallization, and the like.
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
α，β−不飽和カルボニル化合物1a(23.3 mg, 0.150 mmol)，フルオロビス（フェニルスルホニル）メタン2(49.5 mg，0.158 mmol)をDMF(0.3 mL)に溶かし，室温で，DBU （4.5 μL, 0.030 mmol）を加えた。５時間撹拌した後，減圧下，溶媒を留去した。残渣をカラムクロマトグラフィーにて精製し，生成物3a（無色結晶）を得た。
General manufacturing method
α, β-Unsaturated carbonyl compound 1a (23.3 mg, 0.150 mmol) and fluorobis (phenylsulfonyl) methane 2 (49.5 mg, 0.158 mmol) are dissolved in DMF (0.3 mL) at room temperature and DBU (4.5 μL, 0.030 mmol) was added. After stirring for 5 hours, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain the product 3a (colorless crystals).
Compound 3a: ３−（３−（フルオロビス（フェニルスルホニル）メチル）ブタノイル）オキサゾリジン−２−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 1.47 (d, J = 5.2 Hz, 3H), 3.36-3.42 (m, 2H), 3.67-3.76 (m, 1H), 3.97 (t, J = 8.2 Hz , 2H), 4.40 (t, J = 8.2 Hz , 2H), 7.49-7.57 (m, 4H), 7.66-7.70 (m, 2H), 7.89-7.92 (m, 4H). 19F NMR (188 MHz, CDCl3)：δ = -133.1 (s, 1F). IR (KBr)：3099, 2912, 1786, 1694, 1397, 1336, 1225, 1173, 1146, 1124, 726, 686, 585, 566, 514 cm-1. MS (EI)： m/z = 469 (M+)
Compound 3a: 3- (3- (Fluorobis (phenylsulfonyl) methyl) butanoyl) oxazolidine-2-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 1.47 (d, J = 5.2 Hz, 3H), 3.36-3.42 (m, 2H), 3.67-3.76 (m, 1H), 3.97 (t, J = 8.2 Hz, 2H), 4.40 (t, J = 8.2 Hz, 2H), 7.49-7.57 (m, 4H), 7.66-7.70 (m, 2H), 7.89-7.92 (m, 4H). 19 F NMR (188 MHz, CDCl 3 ): δ = -133.1 (s, 1F). IR (KBr): 3099, 2912, 1786, 1694, 1397, 1336, 1225, 1173, 1146, 1124, 726, 686, 585, 566 , 514 cm -1 . MS (EI): m / z = 469 (M + )
Compound 3b: ３−（３−（フルオロビス（フェニルスルホニル）メチル）ペンタノイル）オキサゾリジン−２−オン
White solid; 1H NMR (200 MHz, CDCl3)：δ = 0.86 (t, J = 7.4 Hz, 3H), 1.67-1.83 (m, 2H), 2.08-2.21 (m, 1H), 3.15 (dd, J = 2.4, 5.8 Hz, 2H), 3.20-3.35 (m, 2H), 3.94 (t, J= 7.8 Hz, 2H), 3.99 (dd, J = 2.4, 5.8 Hz, 1H), 4.38 (t, J = 7.8 Hz, 2H), 7.49-7.57 (m, 4H), 7.66-7.74 (m, 2H), 7.88-7.95 (m, 4H). 19F NMR (188 MHz, CDCl3)： δ = -133.0 (s, 1F). 13C NMR (50.3 MHz, CDCl3)： δ = 12.8, 22.8, 34.6, 42.5, 62.3, 116.1 (d, J = 265.0 Hz), 129.0, 130.2, 134.2, 135.4. IR (KBr)： 3392, 2918, 1772, 1672, 1389, 1337, 1277, 685, 601, 580, 564, 533, 471, 437 cm-1. MS (EI)： m/z = 342 (M+−SO2Ph)
Compound 3b: 3- (3- (Fluorobis (phenylsulfonyl) methyl) pentanoyl) oxazolidine-2-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 0.86 (t, J = 7.4 Hz, 3H), 1.67-1.83 (m, 2H), 2.08-2.21 (m, 1H), 3.15 (dd, J = 2.4, 5.8 Hz, 2H), 3.20-3.35 (m, 2H), 3.94 (t, J = 7.8 Hz, 2H), 3.99 (dd, J = 2.4, 5.8 Hz, 1H), 4.38 (t, J = 7.8 Hz, 2H), 7.49-7.57 (m, 4H), 7.66-7.74 (m, 2H), 7.88-7.95 (m, 4H). 19 F NMR (188 MHz, CDCl 3 ): δ = -133.0 ( 13 C NMR (50.3 MHz, CDCl 3 ): δ = 12.8, 22.8, 34.6, 42.5, 62.3, 116.1 (d, J = 265.0 Hz), 129.0, 130.2, 134.2, 135.4. IR (KBr) : 3392, 2918, 1772, 1672, 1389, 1337, 1277, 685, 601, 580, 564, 533, 471, 437 cm -1 . MS (EI): m / z = 342 (M + −SO 2 Ph)
Compound 3c: ３−（３−（フルオロビス（フェニルスルホニル）メチル）ヘキサノイル）オキサゾリジン−２−オン
White solid; 1H NMR (200 MHz, CDCl3)： δ = 0.83 (t, J = 7.2 Hz, 3H), 1.02-1.42 (m, 2H), 1.59-1.78 (m, 1H), 2.02-2.22 (m, 1H), 3.21 (dd, J = 4.0, 15 Hz, 1H), 3.30- 3.48 (m, 1H), 3.94 (t, J = 8.0 Hz, 2H), 4.01 (dd, J = 4.0, 15 Hz, 1H), 4.40 (t, J = 8.0 Hz, 2H), 7.49-7.56 (m, 4H), 7.66-7.74 (m, 2H), 7.86-7.92 (m, 4H). 19F NMR (188 MHz, CDCl3)： δ = -132.6 (s, 1F). 13C NMR (50.3 MHz, CDCl3)： δ = 13.8, 21.4, 31.8, 35.4, 37.5, 42.7, 62.1, 77.0, 116.3 (d, J= 265.3 Hz), 128.5, 130.7, 134.9, 152.9, 170.7. IR (KBr)： 2967, 2928, 1782, 1700, 1448, 1392, 1336, 1300, 1224, 1169, 1148, 756, 731, 688, 603, 580, 563, 534 cm-1. MS (EI)： m/z = 356 (M+−SO2Ph)
Compound 3c: 3- (3- (Fluorobis (phenylsulfonyl) methyl) hexanoyl) oxazolidin-2-one
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 0.83 (t, J = 7.2 Hz, 3H), 1.02-1.42 (m, 2H), 1.59-1.78 (m, 1H), 2.02-2.22 ( m, 1H), 3.21 (dd, J = 4.0, 15 Hz, 1H), 3.30- 3.48 (m, 1H), 3.94 (t, J = 8.0 Hz, 2H), 4.01 (dd, J = 4.0, 15 Hz , 1H), 4.40 (t, J = 8.0 Hz, 2H), 7.49-7.56 (m, 4H), 7.66-7.74 (m, 2H), 7.86-7.92 (m, 4H). 19 F NMR (188 MHz, CDCl 3 ): δ = -132.6 (s, 1F). 13 C NMR (50.3 MHz, CDCl 3 ): δ = 13.8, 21.4, 31.8, 35.4, 37.5, 42.7, 62.1, 77.0, 116.3 (d, J = 265.3 Hz), 128.5, 130.7, 134.9, 152.9, 170.7. IR (KBr): 2967, 2928, 1782, 1700, 1448, 1392, 1336, 1300, 1224, 1169, 1148, 756, 731, 688, 603, 580, 563, 534 cm -1 . MS (EI): m / z = 356 (M + −SO 2 Ph)
Compound 3d:３−（フルオロビス（フェニルスルホニル）メチル）ブタナール
White solid; 1H NMR (200 MHz, CDCl3)： δ = 1.38 (d, J = 6.8 Hz, 3H), 3.02 (dd, J = 9.0, 18.8 Hz, 1H), 3.20-3.35 (m, 1H), 3.57 (dd, J = 9.0, 18.8 Hz, 2H), 7.49-7.56 (m, 4H), 7.66-7.74 (m, 2H), 7.79-7.91 (m, 4H), 9.70 (d, J = 2.2 Hz, 1H). 19F NMR (188 MHz, CDCl3)：δ = -133.9 (s, 1F). 13C NMR (50.3 MHz, CDCl3)： δ = 15.1, 31.5, 45.3, 115.9 (d, J = 265.0 Hz), 128.7, 130.6, 135.0. IR (KBr)：2869, 1716, 1581, 1447, 1337, 1312, 1169, 1147, 1076, 754, 683, 625 cm-1. MS (EI)： m/z = 167 (M-+SO2Ph-Ph)
Compound 3d: 3- (Fluorobis (phenylsulfonyl) methyl) butanal
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 1.38 (d, J = 6.8 Hz, 3H), 3.02 (dd, J = 9.0, 18.8 Hz, 1H), 3.20-3.35 (m, 1H) , 3.57 (dd, J = 9.0, 18.8 Hz, 2H), 7.49-7.56 (m, 4H), 7.66-7.74 (m, 2H), 7.79-7.91 (m, 4H), 9.70 (d, J = 2.2 Hz 19 F NMR (188 MHz, CDCl 3 ): δ = -133.9 (s, 1F). 13 C NMR (50.3 MHz, CDCl 3 ): δ = 15.1, 31.5, 45.3, 115.9 (d, J = 265.0 Hz), 128.7, 130.6, 135.0. IR (KBr): 2869, 1716, 1581, 1447, 1337, 1312, 1169, 1147, 1076, 754, 683, 625 cm -1 . MS (EI): m / z = 167 (M- + SO 2 Ph-Ph)
Compound 3e:エチル−３−（フルオロビス（フェニルスルホニル）メチル）ペンタノエート
White solid; 1H NMR (200 MHz, CDCl3)： δ = 0.84 (t, J = 7.4 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H), 1.64-1.87 (m, 1H), 2.15-2.33 (m, 1H), 2.64 (dd, J = 4.0, 17.2 Hz, 1H), 2.89-3.02 (m, 1H), 3.39 (dd, J = 4.0 , 17.2Hz, 1H), 4.08 (dq, J = 2.4, 7.2 Hz, 2H), 7.50-7.58 (m, 4H), 7.65-7.74 (m, 2H), 7.87-7.94 (m,4H). 19F NMR (188 MHz, CDCl3)： δ = 132.9 (s, 1F). IR (KBr)： 2967, 2928, 1782, 1700, 1448, 1392, 1336, 1300, 1224, 1169, 1148, 756, 731, 688, 603, 580, 563, 534 cm-1. MS (EI)： m/z = 167 (M+−SO2Ph−Ph−OEt)
モノフルオロメチル化体の一般的な製造法
：３−（３−（フルオロメチル）ブタノイル）オキサゾリジン−２−オン
フルオロビス（フェニルスルホニル）メチル化体3a（５０ｍｇ， ０．１０６ mmol）をDMF 0.8 mlに溶かし，酢酸 0.3 ml，酢酸ナトリウム（４０３ｍｇ， ４．９３ mmol）を加えた。さらに室温で撹拌しながら，マグネシウム（７７．７ｍｇ， ３．１９ mmol）を加えた。１６時間後，水を加え，ジエチルエーテルで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液と飽和塩化ナトリウム水溶液で洗った。その後，硫酸マグネシウムで乾燥し，溶媒を留去した。残渣をカラムクロマトグラフィーにて精製し，生成物5a（無色液体）を得た。
Compound 3e: ethyl-3- (fluorobis (phenylsulfonyl) methyl) pentanoate
White solid; 1 H NMR (200 MHz, CDCl 3 ): δ = 0.84 (t, J = 7.4 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H), 1.64-1.87 (m, 1H), 2.15 -2.33 (m, 1H), 2.64 (dd, J = 4.0, 17.2 Hz, 1H), 2.89-3.02 (m, 1H), 3.39 (dd, J = 4.0, 17.2Hz, 1H), 4.08 (dq, J = 2.4, 7.2 Hz, 2H), 7.50-7.58 (m, 4H), 7.65-7.74 (m, 2H), 7.87-7.94 (m, 4H). 19 F NMR (188 MHz, CDCl 3 ): δ = 132.9 (s, 1F). IR (KBr): 2967, 2928, 1782, 1700, 1448, 1392, 1336, 1300, 1224, 1169, 1148, 756, 731, 688, 603, 580, 563, 534 cm -1 . MS (EI): m / z = 167 (M + −SO 2 Ph−Ph−OEt)
General production method of monofluoromethylated product: 3- (3- (fluoromethyl) butanoyl) oxazolidine-2-onefluorobis (phenylsulfonyl) methylated product 3a (50 mg, 0.106 mmol) in DMF 0.8 ml And 0.3 ml of acetic acid and sodium acetate (403 mg, 4.93 mmol) were added. Further, magnesium (77.7 mg, 3.19 mmol) was added with stirring at room temperature. After 16 hours, water was added and extracted with diethyl ether. The extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. Then, it dried with magnesium sulfate and the solvent was distilled off. The residue was purified by column chromatography to obtain the product 5a (colorless liquid).
Compound 5a: ３−（３−（フルオロメチル）ブタノイル）オキサゾリジン−２−オン
Colorless oil; 1H NMR (200 MHz, CDCl3)： δ = 1.04 (d, J = 6.8 Hz, 3H), 2.38-2.57 (m, 1H), 2.85 (dd, J = 7.0, 17.0 Hz, 1H), 3.08 (dd, J = 6.8, 17.0 Hz, 1H), 4.02 (t, J= 8.2 Hz, 2H), 4.22 (dd, J = 2.8, 6.0 Hz, 1H), 4.41 (t, J = 8.2 Hz, 2H), 4.46 (dd, J = 2.8, 6.0 Hz, 1H) . 19F NMR (188 MHz, CDCl3)： δ = -221.9 (dt, J = 19.4, 47.0 Hz, 1F). IR (NaCl)： 2967, 2918, 1779, 1697, 1479, 1388, 1222, 1039, 760, 703 cm-1. MS (EI)： m/z = 156 (M+−CH2F)
Compound 5a: 3- (3- (Fluoromethyl) butanoyl) oxazolidin-2-one
Colorless oil; 1 H NMR (200 MHz, CDCl 3 ): δ = 1.04 (d, J = 6.8 Hz, 3H), 2.38-2.57 (m, 1H), 2.85 (dd, J = 7.0, 17.0 Hz, 1H) , 3.08 (dd, J = 6.8, 17.0 Hz, 1H), 4.02 (t, J = 8.2 Hz, 2H), 4.22 (dd, J = 2.8, 6.0 Hz, 1H), 4.41 (t, J = 8.2 Hz, 2H), 4.46 (dd, J = 2.8, 6.0 Hz, 1H). 19 F NMR (188 MHz, CDCl 3 ): δ = -221.9 (dt, J = 19.4, 47.0 Hz, 1F). IR (NaCl): 2967, 2918, 1779, 1697, 1479, 1388, 1222, 1039, 760, 703 cm -1 . MS (EI): m / z = 156 (M + −CH 2 F)
Compound 5b: ３−（３−（フルオロメチル）ペンタノイル）オキサゾリジン−２−オン
Colorless oil; 1H NMR (200 MHz, CDCl3)： δ = 0.96 (t, J= 7.4 Hz, 3H), 1.39-1.52 (m, 2H), 2.09-2.20 (m, 1H), 2.93 (dd, J = 5.8 Hz, 17.0 Hz, 1H), 3.06 (dd, J = 5.8 Hz, 17.0 Hz, 1H), 4.02 (t, J = 7.4 Hz, 2H), 4.31 (dd, J = 2.4, 5.2 Hz, 2H), 4.41 (t, J = 7.4 Hz, 2H), 4.55 (dd, J = 2.4, 5.2 Hz, 1H). 19F NMR (188 MHz, CDCl3)： δ = -225.2 (dt, J = 24.1, 47.0 Hz, 1F). IR (NaCl)： 2962, 2925, 1778, 1697, 1479, 1386, 1224, 1103, 1039, 968, 761, 704 cm-1. MS (EI)： m/z = 170 (M+−CH2F)
Compound 5b: 3- (3- (Fluoromethyl) pentanoyl) oxazolidine-2-one
Colorless oil; 1 H NMR (200 MHz, CDCl 3 ): δ = 0.96 (t, J = 7.4 Hz, 3H), 1.39-1.52 (m, 2H), 2.09-2.20 (m, 1H), 2.93 (dd, J = 5.8 Hz, 17.0 Hz, 1H), 3.06 (dd, J = 5.8 Hz, 17.0 Hz, 1H), 4.02 (t, J = 7.4 Hz, 2H), 4.31 (dd, J = 2.4, 5.2 Hz, 2H ), 4.41 (t, J = 7.4 Hz, 2H), 4.55 (dd, J = 2.4, 5.2 Hz, 1H). 19 F NMR (188 MHz, CDCl 3 ): δ = -225.2 (dt, J = 24.1, 47.0 Hz, 1F). IR (NaCl): 2962, 2925, 1778, 1697, 1479, 1386, 1224, 1103, 1039, 968, 761, 704 cm -1 . MS (EI): m / z = 170 (M + −CH 2 F)
Compound 5c: ３−（３−（フルオロメチル）ヘキサノイル）オキサゾリジン−２−オン
Colorless oil; 1H NMR (200 MHz, CDCl3)： δ = 0.92 (t, J = 7.2 Hz, 3H), 1.30-1.46 (m, 4H), 2.24-2.47 (m, 1H), 2.93 (dd, J = 7.6, 16.8 Hz, 1H), 3.07 (dd, J = 7.6 Hz, 16.8 Hz, 1H), 3.97(dd, J = , 2H), 4.02 (t, J = 7.8 Hz, 2H), 4.30 (dd, J= 0.6, 4.6 Hz, 1H), 4.41 (t, J = 7.8 Hz, 2H), 4.54 (dd, J = 0.6, 4.6 Hz, 1H). 19F NMR (188 MHz, CDCl3)：δ= -224.5 (dt, J = 22.9, 47.0 Hz, 1F). IR (NaCl)： 2960, 2928, 1779, 1697, 1480, 1391, 1225, 1102, 1040, 761, 705 cm-1. MS (EI)： m/z = 184 (M+−CH2F)
ジアステレオ選択的共役付加反応の一般的な製造法
α，β−不飽和カルボニル化合物1a（19.7ｍｇ，0.1mmol），フルオロビス（フェニルスルホニル）メタン2（33.0ｍｇ，0.105mmol）をキシレン(0.2 mL)に溶かし，室温で，DBU (3.0 μL, 0.020 mmol)を加えた。18時間撹拌した後，減圧下，溶媒を留去した。残渣をカラムクロマトグラフィーにて精製し，生成物3a（無色結晶,30mg, 59%, 44% de）を得た。ジアステレオマー比は19F NMRから決定した。
Compound 5c: 3- (3- (Fluoromethyl) hexanoyl) oxazolidine-2-one
Colorless oil; 1 H NMR (200 MHz, CDCl 3 ): δ = 0.92 (t, J = 7.2 Hz, 3H), 1.30-1.46 (m, 4H), 2.24-2.47 (m, 1H), 2.93 (dd, J = 7.6, 16.8 Hz, 1H), 3.07 (dd, J = 7.6 Hz, 16.8 Hz, 1H), 3.97 (dd, J =, 2H), 4.02 (t, J = 7.8 Hz, 2H), 4.30 (dd , J = 0.6, 4.6 Hz, 1H), 4.41 (t, J = 7.8 Hz, 2H), 4.54 (dd, J = 0.6, 4.6 Hz, 1H). 19 F NMR (188 MHz, CDCl 3 ): δ = -224.5 (dt, J = 22.9, 47.0 Hz, 1F). IR (NaCl): 2960, 2928, 1779, 1697, 1480, 1391, 1225, 1102, 1040, 761, 705 cm -1 . MS (EI): m / z = 184 (M + −CH 2 F)
General production method of diastereoselective conjugate addition reaction α, β-unsaturated carbonyl compound 1a (19.7 mg, 0.1 mmol), fluorobis (phenylsulfonyl) methane 2 (33.0 mg, 0.105 mmol) in xylene (0.2 mL) DBU (3.0 μL, 0.020 mmol) was added at room temperature. After stirring for 18 hours, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain the product 3a (colorless crystals, 30 mg, 59%, 44% de). The diastereomeric ratio was determined from 19 F NMR.
Compound 5f: （４S）−３−（４−フルオロ−３−メチル−４，４−ビス（フェニルスルホニル）ブタノイル−４−イソプロピルオキサゾキジン−２−オン
White solid; 1H NMR (200 MHz, CDCl3 ,diasteromer mixture)：δ = 0.81-0.92 (m, 6H), 1.47 (t, J = 6.2 Hz, 3H), 2.15-2.42 (m, 1H), 3.18-3.82 (m, 3H), 4.13-4.48 (m, 3H), 7.52 (t, J = 7.4 Hz, 4H), 7.69 (t, J = 7.6 Hz, 2H), 7.84-7.96 (m, 4H); 19F NMR (188 MHz, CDCl3)：δ = -132.9 (s,
1/3F), 133.2 (s, 2/3F).
エナンチオ選択的共役付加反応の一般的な製造法
フルオロビス（フェニルスルホニル）メタン2（47.0 mg，0.150 mmol），Ｎ−ベンジル キニジニウムクロリド(6.8 mg,0.015 mmol)，炭酸カリウム（207.3mg, 1.50 mmol）をCH2Cl2 ０．３mＬに溶かし，―４０℃で，クロトンアルデヒド(13.0 μL, 0.158 mmol）を加えた。２時間撹拌した後，飽和塩化アンモニウム水溶液を加え，ジエチルエーテルで抽出した。抽出液を飽和食塩水で洗い，硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去した。これをMeOH (0.3 mＬ)に溶かし，水素化ホウ素ナトリウム(6.8 mg, 0.180 mmol)を撹拌しながら加えた。３０分後，飽和塩化アンモニウム水溶液を加え，酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し，溶媒を留去した。残渣をカラムクロマトグラフィーにて精製し，生成物4a’（無色結晶 18 mg, 30%, 22% ee）を得た。光学収率はＨＰＬＣにて決定し。
Compound 5f: (4S) -3- (4-Fluoro-3-methyl-4,4-bis (phenylsulfonyl) butanoyl-4-isopropyloxazoxin-2-one
White solid; 1 H NMR (200 MHz, CDCl 3 , diasteromer mixture): δ = 0.81-0.92 (m, 6H), 1.47 (t, J = 6.2 Hz, 3H), 2.15-2.42 (m, 1H), 3.18 -3.82 (m, 3H), 4.13-4.48 (m, 3H), 7.52 (t, J = 7.4 Hz, 4H), 7.69 (t, J = 7.6 Hz, 2H), 7.84-7.96 (m, 4H); 19 F NMR (188 MHz, CDCl 3 ): δ = -132.9 (s,
1 / 3F), 133.2 (s, 2 / 3F).
General production method of enantioselective conjugate addition reaction Fluorobis (phenylsulfonyl) methane 2 (47.0 mg, 0.150 mmol), N-benzyl quinidinium chloride (6.8 mg, 0.015 mmol), potassium carbonate (207.3 mg, 1.50) mmol) was dissolved in 0.3 mL of CH 2 Cl 2 and crotonaldehyde (13.0 μL, 0.158 mmol) was added at −40 ° C. After stirring for 2 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. This was dissolved in MeOH (0.3 mL) and sodium borohydride (6.8 mg, 0.180 mmol) was added with stirring. After 30 minutes, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography to obtain the product 4a ′ (colorless crystals 18 mg, 30%, 22% ee). The optical yield is determined by HPLC.
３−（フルオロビス（フェニルスルホニル）メチル）ブタン−１−オール
1H NMR (CDCl3, 200MHz) δ 1.39 (d, J = 5.6 Hz, 3H), 1.60-2.03 (m, 2H), 2.40-2.66 (m, 1H), 2.72-2.98 (m, 1H), 3.58 (dt, J = 4.2 Hz, J = 10.2 Hz, 1H), 3.67 (m, 1H), 7.49 (t, J = 6.8 Hz, 4H), 7.66 (t, J = 6.2 Hz, 2H), 7.85 (t, J = 6.8 Hz, 4H); 19F NMR (CDCl3, 188 MHz) δ -131.8 (s, 1F);13C NMR (CDCl3, 50.3 MHz) δ 13.8 (d, J = 8.0 Hz), 33.2, 33.3, 34.6 (d, J = 16.8Hz), 60.0, 117.1 (d, J = 264.6 Hz), 128.5, 128.6, 130.6, 134.7, 135.3, 135.8; IR (KBr), 2960, 2928, 1779, 1697, 1480, 1391, 1225, 1102, 1040, 761, 705 cm-1; The ee of the product was determined by HPLC using an OD-H column (n-hexane/i-PrOH = 70:30, flow rate 0.5 mL/min, λ = 254 nm, τmaj = 18.5 min, τmin = 23.6 min); 22% ee.
3- (Fluorobis (phenylsulfonyl) methyl) butan-1-ol
1 H NMR (CDCl 3 , 200MHz) δ 1.39 (d, J = 5.6 Hz, 3H), 1.60-2.03 (m, 2H), 2.40-2.66 (m, 1H), 2.72-2.98 (m, 1H), 3.58 (dt, J = 4.2 Hz, J = 10.2 Hz, 1H), 3.67 (m, 1H), 7.49 (t, J = 6.8 Hz, 4H), 7.66 (t, J = 6.2 Hz, 2H), 7.85 (t , J = 6.8 Hz, 4H); 19 F NMR (CDCl 3 , 188 MHz) δ -131.8 (s, 1F); 13 C NMR (CDCl 3 , 50.3 MHz) δ 13.8 (d, J = 8.0 Hz), 33.2 , 33.3, 34.6 (d, J = 16.8Hz), 60.0, 117.1 (d, J = 264.6 Hz), 128.5, 128.6, 130.6, 134.7, 135.3, 135.8; IR (KBr), 2960, 2928, 1779, 1697, 1480, 1391, 1225, 1102, 1040, 761, 705 cm -1 ; The ee of the product was determined by HPLC using an OD-H column (n-hexane / i-PrOH = 70:30, flow rate 0.5 mL / min, λ = 254 nm, τ maj = 18.5 min, τ min = 23.6 min); 22% ee.
本発明のβー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)
（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 a base catalyst in a solvent
(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.
(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:
Β-fluoro (phenylsulfonyl) represented by the general formula (3) by an asymmetric reaction between the conjugated carbonyl represented by the general formula (1) and the general formula (2) in the presence of an optically active phase transfer catalyst in a solvent. ) Method for producing methyl adduct.
（式中，Ｒ５，Ｒ６，Ｒ７，Ｒ８，Ｒ９，Ｒ１０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前記一般式（２）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（６）
（式中，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８，Ｒ９，Ｒ１０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 (4), (5)
(Wherein R 5 , R 6 , R 7 , R 8 , R 9 and R 10 represent hydrogen, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group or an aryl group). A conjugated carbonyl compound is subjected to a conjugate addition reaction with a fluorobissulfonylmethane represented by the general formula (2).
(Wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are the same as defined above), an optically active β-fluoro (phenylsulfonyl) methyl adduct represented by Manufacturing method.
（式中，Ｒ１，Ｒ２は前記定義に同じ。）で示される光学活性βーフルオロメチルカルボニル誘導体の製造法。
The β-fluoro (phenylsulfonyl) methane adduct represented by the general formula (3) is desulfonylated in a solvent in the presence of a metal as a reducing agent in the general formula (8)
(Wherein R 1 and R 2 are the same as defined above), a process for producing an optically active β-fluoromethylcarbonyl derivative.
（式中，Ｒ５，Ｒ６，Ｒ７，Ｒ８，Ｒ９，Ｒ１０は前記定義に同じ。）で示される光学活性βーフルオロメチルカルボニル誘導体の請求項４の記載の製造法。
The general formulas (9) and (10), wherein the substrate is a β-fluoro (phenylsulfonyl) methyl adduct represented by the general formula (6) or (7).
5. The process according to claim 4, wherein an optically active β-fluoromethylcarbonyl derivative represented by the formula (wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are the same as defined above).
（Ｘ）ｎＭ （１１）
（式中，Ｍ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，アルミニウムから選ばれた元素，ｎは，Ｍの原子価と同数の整数を表す。Ｘはアルコシド，フルオリド，カルボネートなどのマイナスイオンを表す。）
The method according to any one of claims 1, 2, and 3, wherein the base is at least one base selected from generally available amines or inorganic salts (11). . As the amine, triethylamine, diisopropylethylamine, dimethylaminopyridine, quinuclidine, DBU, DABCO and the like can be used. The inorganic salt has the general formula (11)
(X) nM (11)
(In the formula, M is an element selected from transition metals including rare earths, lithium, sodium, magnesium and aluminum, n is an integer having the same number as the valence of M. X is a minus such as alkoxide, fluoride, carbonate, etc. Represents an ion.)
光学活性な相間移動触媒としては，一般式（１２），（１３）
（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またはトリフルオロメチル基を示す。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。）
The production method according to claim 2, wherein the optically active phase transfer catalyst is at least one salt selected from optically active quaternary ammonium salts.
Examples of the optically active phase transfer catalyst include general formulas (12) and (13).
(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 or a trifluoromethyl group, m represents an integer of 0 to 2, and X represents a halogen atom. , IO 4 , ClO 4 , OTf or HSO 4. )
6. The solvent according to claim 1, 2, 3, 4, 5, wherein the solvent is at least one selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, toluene, tetrahydrofuran, hexane, and benzene. The manufacturing method of any one of Claims.
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| CN106622385A (en) * | 2016-12-19 | 2017-05-10 | 聊城大学 | Double-core magnesium-germanium tungsten oxide cluster catalyst and preparing method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61155361A (en) * | 1984-12-27 | 1986-07-15 | Daikin Ind Ltd | Fluorine-containing sulfonyl compound |
| JPH05286900A (en) * | 1990-02-16 | 1993-11-02 | Prototek Inc | Reagent for stereospecific fluoromethylation and process therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS61155361A (en) * | 1984-12-27 | 1986-07-15 | Daikin Ind Ltd | Fluorine-containing sulfonyl compound |
| JPH05286900A (en) * | 1990-02-16 | 1993-11-02 | Prototek Inc | Reagent for stereospecific fluoromethylation and process therefor |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106622385A (en) * | 2016-12-19 | 2017-05-10 | 聊城大学 | Double-core magnesium-germanium tungsten oxide cluster catalyst and preparing method and application thereof |
| CN106622385B (en) * | 2016-12-19 | 2019-01-29 | 聊城大学 | A kind of double-core magnesium-germanium tungsten oxygen cluster catalyst, preparation method and its usage |
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