JP2004277349A - Method for catalytic synthesis of optically active phosphorus compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for synthesizing an optically active compound under the control of the steric factor, in terms of phosphorus atom, of a phosphorus compound such as a triphosphite or phosphoric triester. <P>SOLUTION: The method comprises obtaining an optically active phosphite(e.g. 2-benzyloxy-4,4-dimethyl-1,3-dioxaphosphinane) in the presence of a catalytic amount of an optically active promoter[e.g. 3,6-bis(9'-O-quinidyl)pyridazine]. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

【００１２】
（式中、Ｒ１およびＲ２は各々独立して炭素数１から４のアルキル基あるいはアルケニル基を表し、Ｒ３は置換してもよいベンゾイル基あるいは置換してもよいアリール基を表す。）あるいは一般式〔２〕［化６］
【００１３】
【化６】

【００１４】
（式中、Ｒ１およびＲ２は前述と同義であり、Ｑは置換してもよいアリール基を表す。）で表される光学活性な促進剤の存在下に反応を行うことを特徴とする光学活性なフォスファイトの合成方法であり、
［３］Ｒ１はメチル基で、Ｒ２はエチル基またはエテニル基である［２］に記載の合成方法であり、
［４］［１］から［３］の何れか一項で得たフォスファイトを酸化することを特徴とする光学活性なリン酸トリエステルの合成方法であり、
［５］［１］から［３］の何れか一項で得たフォスファイトを硫化することを特徴とする光学活性なチオリン酸トリエステルの合成方法であり、
［６］［１］から［３］の何れか一項で得たフォスファイトをセレン化することを特徴とする光学活性なセレノリン酸トリエステルの合成方法であり、
［７］一般式〔１〕［化７］
【００１５】
【化７】

【００１６】
（式中、Ｒ１およびＲ２は各々独立して炭素数１から４のアルキル基あるいはアルケニル基を表し、Ｒ３は置換してもよいベンゾイル基あるいは置換してもよいアリール基を表す。）で表される光学活性な促進剤であり、
［８］一般式〔２〕［化８］
【００１７】
【化８】

【００１８】
（式中、Ｒ１およびＲ２は各々独立して炭素数１から４のアルキル基あるいはアルケニル基を表し、Ｑは置換してもよいアリール基を表す。）で表される光学活性な促進剤である。
【００１９】
【発明実施の形態】
以下、本発明を詳細に説明する。
本発明でいう促進剤とは、光学活性なフォスファイトあるいはリン酸トリエステルを合成する際、ラセミ混合物であるリン化合物を出発原料とした場合でも、動的速度論分割により、リン原子上の不斉を誘起して一方の光学異性体に偏らせる反応を進行させるような化合物を表す。
【００２０】
本発明で言う光学活性な３級アミンとは、一般式〔１〕で表される促進剤を含み、不斉原子と３級アミンを構造中に有していて光学活性である限り特に限定はされないが、例えば（Ｓ，Ｓ）あるいは（Ｒ，Ｒ）−Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチル−１，２−ジフェニルエチレンジアミン、（Ｓ）あるいは（Ｒ）−２−（１−ｔｅｒｔ−ブチルジメチルシリルオキシエチル）ベンヅイミダゾール、（−）−スパルテイン、１，４−ビス（９’−Ｏ−ジヒドロキニジル）フタラジン、１，４−ビス（９’−Ｏ−キニジル）フタラジン、３，６−ビス（９’−Ｏ−ジヒドロキニジル）ピリダジン、３，６−ビス（９’−Ｏ−キニジル）ピリダジン、１，４−ビス（９’−Ｏ−ジヒドロキニル）フタラジン、１，４−ビス（９’−Ｏ−キニル）フタラジン、３，６−ビス（９’−Ｏ−ジヒドロキニル）ピリダジン、３，６−ビス（９’−Ｏ−キニル）ピリダジン等が挙げられる。
【００２１】
一般式〔１〕で表される促進剤において、Ｒ１およびＲ２における炭素数１から４のアルキル基とは、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、シクロプロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、シクロブチル基等が挙げられる。炭素数１から４のアルケニル基とは、ビニル基、プロペニル基、アリル基、ブテニル基等が挙げられる。
【００２２】
Ｒ３における置換してもよいベンゾイル基とは、ハロゲン原子、炭素数１から４のアルキル基、ハロゲン原子で置換された炭素数１から４のアルキル基等で置換されたベンゾイル基を表し、たとえば２−フルオロベンゾイル基、３−フルオロベンゾイル基、４−フルオロベンゾイル基、２−クロロベンゾイル基、３−クロロベンゾイル基、４−クロロベンゾイル基、２−メチルベンゾイル基、３−メチルベンゾイル基、４−メチルベンゾイル基、２−エチルベンゾイル基、３−エチルベンゾイル基、４−エチルベンゾイル基、２−イソプロピルベンゾイル基、３−イソプロピルベンゾイル基、４−イソプロピルベンゾイル基、２−トリフルオロメチルベンゾイル基、３−トリフルオロメチルベンゾイル基、４−トリフルオロメチルベンゾイル基等が挙げられる。またＲ３における置換されてもよいアリール基とは、炭素数１から４のアルキル基、ハロゲン原子、フェニル基あるいはハロゲン原子で置換された炭素数１から４のアルキル基等で置換された、あるいは無置換のフェニル基、ピリジル基、ピラジニル基、ピリミジニル基、フラニル基、イミダゾリル基、チアゾリル基、ベンゾフラニル基、キノリル基、フタラジニル基、フェナンスリル基、アントラセニル基、アンスラキノニル基等の芳香環、縮合した芳香環あるいは複素環基を表し、例えば、フェニル基、２−ピリジル基、２−ピリミジン基、２−メチルフェニル基、３−メチルフェニル基、４−メチルフェニル基、２−クロロフェニル基、３−クロロフェニル基、４−クロロフェニル基、２−フルオロフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、６−フェニルピリジン−２−イル基、４，６−ジメチルピリミジン−２−イル基、４−メチルキノリン−２−イル基、９−フェナンスリル基等が挙げられる。
【００２３】
一般式〔２〕で表される促進剤において、Ｑにおける置換してもよいアリール基とは、炭素数１から４のアルキル基、ハロゲン原子、フェニル基あるいはハロゲン原子で置換された炭素数１から４のアルキル基等で置換された、あるいは無置換のフェニル基、ピリジル基、ピラジニル基、ピリミジニル基、フラニル基、イミダゾリル基、チアゾリル基、ベンゾフラニル基、キノリル基、フタラジニル基、フェナンスリル基、アントラセニル基、アンスラキノニル基等の芳香環、縮合した芳香環あるいは複素環基を表し、例えば、ピリジン−２，６−ジイル基、ピラジン−３，６−ジイル基、２−フェニルピリミジン−４，６−ジイル基、２−ジフェニルピリミジン−４，６−ジイル基、アントラキノン−１，４−ジイル基等が挙げられる。
【００２４】
光学活性なフォスファイトを得るための出発原料としては、リン上の置換基のひとつが脱離基であり、他の２つの置換基が異なる非対称な３価のリン化合物を用いることができる。好ましくは脱離基がハロゲン原子であり、他の２つの置換基が水酸基を持つ化合物である。さらに好ましくは脱離基が塩素であるようなフォスフォロクロリダイトである。ラセミ混合物であることが好ましいが、光学純度を向上する目的で、低い光学純度の化合物を原料として用いることもできる。たとえば炭素数１から４のアルキル基、炭素数１から４のアルケニル基、置換してもよいアリール基等で置換された２−クロロ−１，３−ジオキサ−２−フォスフィナン化合物、２−クロロ−１，３−ジオキサ−２−フォスフォラン化合物、２−ブロモ−１，３−ジオキサ−２−フォスフィナン化合物、２−ブロモ−１，３−ジオキサ−２−フォスフォラン化合物、２−ヨード−１，３−ジオキサ−２−フォスフィナン化合物、２−ヨード−１，３−ジオキサ−２−フォスフォラン化合物、２−（メタンスルフォニルオキシ）−１，３−ジオキサ−２−フォスフィナン化合物あるいは２−（メタンスルフォニルオキシ）−１，３−ジオキサ−２−フォスフォラン化合物、炭素数１から４のアルキル基、炭素数１から４のアルケニル基、置換してもよいアリール基等で酸素原子が置換された亜リン酸クロリド、亜リン酸ブロミドあるいは亜リン酸ヨード等が挙げられる。具体的には２−クロロ−４，４−ジメチル−１，３−ジオキサ−２−フォスフィナン、２−クロロ−４，４−ジエチル−１，３−ジオキサ−２−フォスフィナン、２−クロロ−４，４−ジプロピル−１，３−ジオキサ−２−フォスフィナン、２−クロロ−４，４−ジブチル−１，３−ジオキサ−２−フォスフィナン、２−クロロ−４−エチル−４−メチル−１，３−ジオキサ−２−フォスフィナン、２−クロロ−４ブチル−４−エチル−１，３−ジオキサ−２−フォスフィナン、２−クロロ−４，４−ジメチル−１，３−ジオキサ−２−フォスフォラン、２−クロロ−４，４−ジエチル−１，３−ジオキサ−２−フォスフォラン、２−クロロ−４，４−ジプロピル−１，３−ジオキサ−２−フォスフォラン、２−クロロ−４，４−ジブチル−１，３−ジオキサ−２−フォスフォラン、２−クロロ−４−エチル−４−メチル−１，３−ジオキサ−２−フォスフォラン、２−クロロ−４ブチル−４−エチル−１，３−ジオキサ−２−フォスフォラン、２−ブロモ−４，４−ジメチル−１，３−ジオキサ−２−フォスフィナン、２−ブロモ−４，４−ジエチル−１，３−ジオキサ−２−フォスフィナン、２−ブロモ−４，４−ジプロピル−１，３−ジオキサ−２−フォスフィナン、２−ブロモ−４，４−ジブチル−１，３−ジオキサ−２−フォスフィナン、２−ブロモ−４−エチル−４−メチル−１，３−ジオキサ−２−フォスフィナン、２−ブロモ−４ブチル−４−エチル−１，３−ジオキサ−２−フォスフィナン、２−ブロモ−４，４−ジメチル−１，３−ジオキサ−２−フォスフォラン、２−ブロモ−４，４−ジエチル−１，３−ジオキサ−２−フォスフォラン、２−ブロモ−４，４−ジプロピル−１，３−ジオキサ−２−フォスフォラン、２−ブロモ−４，４−ジブチル−１，３−ジオキサ−２−フォスフォラン、２−ブロモ−４−エチル−４−メチル−１，３−ジオキサ−２−フォスフォラン、２−ブロモ−４ブチル−４−エチル−１，３−ジオキサ−２−フォスフォラン等が挙げられる。
【００２５】
このようなフォスフォロハロダイト類を一般式〔１〕あるいは〔２〕で表される促進剤の存在下に水酸基を有する化合物と反応し、光学活性なフォスファイトを得る。水酸基を有する化号物としては、特に限定されないが、メタノール、エタノール、プロパノ−ル、ブタノ−ル、イソプロパノ−ル、ｔｅｒｔ−ブタノ−ル、シクロヘキサノール、シクロペタノ−ル、ベンジルアルコール、フェノール等である。
【００２６】
このようにして得たフォスファイトを、所望により酸化、硫化あるいはセレン化して光学活性なリン酸トリエステル、チオリン酸トリエステルあるいはセレノリン酸トリエステルへとそれぞれ変換することもできる。酸化、硫化あるいはセレン化する反応条件は、一般的に用いられる方法が使用でき、特に限定されない。たとえば過酸化水素水、ｔｅｒｔ−ブチルハイドロパーオキサイドあるいは過酸化ベンゾイル、過酢酸等の過酸化物、硫黄、３Ｈ−１，２――ベンゾジチオール−３−オン １，１−オキシド、３−エトキシ−１，２，４−ジチオゾリン−５−オン、１，２，４−ジチオゾリン−３，５−ジオン、３−メチル−エトキシ−１，２，４−ジチオゾリンー５−オン、フェニルアセチル ジスルフィドあるいはテトラエチルチウラム ジスルフィド等の硫化剤、セレン等のセレノ化剤が挙げられる。
【００２７】
【実施例】
以下に実施例を挙げて本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。
参考例１
式〔５〕で表される２−クロロ−４，４−ジメチル−１，３−ジオキサ−２−フォスフィナン［化９］の合成
【００２８】
【化９】

【００２９】
三塩化リン２１ｇ（１５０ｍｍｌ）のＴＨＦ６００ｍＬ溶液に３−メチル−１，３−ブタンジオール１５ｇ（１５０ｍｍｏｌ）とトリエチルアミン３０ｇ（３００ｍｍｏｌ）を−７８℃で２時間かけて滴下し、１２時間攪拌した。反応液をセライト５４５でろ過した後、ろ液を濃縮した。残さを減圧蒸留して表題化合物９．３ｇを得た。収率３７％。
沸点 ３５３７ ｏＣ （０．５６ｍｍＨｇ）； ^１Ｈ ＮＭＲ（４００ＭＨｚ） １．３８ （ｓ， ３Ｈ）， １．６２ （ｓ， ３Ｈ）， １．９５２．００ （ｍ， １Ｈ）， ２．１６２．２４ （ｍ， １Ｈ）， ４．０４４．１２ （ｍ， １Ｈ）， ４．６１４．６８ （ｍ， １Ｈ）； ^１３Ｃ ＮＭＲ ２７．９２， ２７．９４， ３１．７８， ３１．８１， ３８．０１， ３８．０９， ５９．０５， ５９．０８， ７８．８９， ７８．９６； ^３１Ｐ ＮＭＲ １５０．１６； ＨＲＭＳ （ＥＳＩ^＋） ｃａｌｃｄ ｆｏｒ Ｃ_５Ｈ_１０ＣｌＯ_２Ｐ ｍ／ｚ １６５．０３５３， ｆｏｕｎｄ ｍ／ｚ １６５．９８７６．
【００３０】
参考例２
式〔６〕で表される２−クロロ−４，４−ジエチル−１，３−ジオキサ−２−フォスフォラン［化１０］の合成
【００３１】
【化１０】

【００３２】
三塩化リン５．５ｇ（４０ｍｍｌ）のＴＨＦ２００ｍＬ溶液に２−エチル−１，２−ブタンジオール４．７ｇ（４０ｍｍｏｌ）とトリエチルアミン８．１ｇ（８０ｍｍｏｌ）を−７８℃で２時間かけて滴下し、１２時間攪拌した。反応液をセライト５４５でろ過した後、ろ液を濃縮した。残さを減圧蒸留して表題化合物３．３ｇを得た。収率４５％。
沸点５１５３ ｏＣ （２．２ｍｍＨｇ）； ^１Ｈ ＮＭＲ（４００ＭＨｚ） ０．８８ （ｔ， ３Ｈ， Ｊ ＝ ７．２ Ｈｚ）， １．０３ （ｔ， ３Ｈ， Ｊ ＝ ７．２ Ｈｚ）， １．５４１．６７ （ｍ， ２Ｈ）， １．８３２．０４ （ｍ， ２Ｈ）， ４．１２４．１９ （ｍ， ２Ｈ）； ^１３Ｃ ＮＭＲ ７．８１，３０．０８， ３１．００， ３０．４９， ７２．８５， ７２．９２， ９１．００， ９１．０９； ^３１Ｐ ＮＭＲ １７３．６３．
【００３３】
実施例１
式〔７〕で表される２−ベンジロキシ−４，４−ジメチル−１，３−ジオキサフォスフィナンおよび式〔８〕で表される２−ベンジロキシ−４，４−ジメチル−１，３−ジオキサフォスフィナン ２−オキシド［化１１］の合成
【００３４】
【化１１】

【００３５】
式〔９〕で表される光学活性な促進剤７８ｍｇ（０．１ｍｍｏｌ）のＴＨＦ１０ｍＬ溶液に式〔５〕で表されるフォスフォロクロリダイト１６８ｍｇ（１ｍｍｏｌ）を−７８℃で添加した。１０分後、ベンジルアルコール１０８ｍｇ（１ｍｍｏｌ）とジイソプロピルアミン１２９ｍｇ（１ｍｍｏｌ）を−７８℃で加え、２５℃で１２時間攪拌し、式〔７〕で表される表題化合物の溶液を得た。さらに３Ｍ ｔｅｒｔ−ブチルハイドロパーオキシドのトルエン溶液０．５ｍＬ（１．５ｍｍｏｌ）を加え、３０分間攪拌した。反応液に酢酸エチル２０ｍＬを加えて飽和重曹水２０ｍＬおよび飽和食塩水２０ｍＬで洗浄した。有機層を硫酸ナトリウムで乾燥し、濃縮した。残さをシリカゲルクロマトグラフィーで精製し、酢酸エチル−ヘキサン流分から式〔８〕で表される表題化合物を無色油状物として得た。収率８０％、７６％ｅｅ。
式〔８〕で表される化合物の分析データ：^１Ｈ ＮＭＲ （４００ＭＨｚ） １．４２ （ｓ， ３Ｈ）， １．４７ （ｓ， ３Ｈ）， １．７７１．８１ （ｍ， １Ｈ）， ２．０３２．０８ （ｍ， １Ｈ）， ４．２８４．３４ （ｍ， ２Ｈ）， ５．０５５．１０ （ｍ， ２Ｈ）， ７．３１７．３９ （ｍ， ５Ｈ）； ^１３Ｃ ＮＭＲ ２６．６７， ２６．６８， ３０．０３， ３０．１０， ３６．５４， ３６．６１， ６４．６５， ６４．７２， ８３．６０， ８３．６７， １２７．８３， １２８．３６， １２８．４５， １３６．０１， １３６．０８； ^３１Ｐ ＮＭＲ ７．３２； ＨＲＭＳ （ＥＳＩ^＋） ｃａｌｃｄ ｆｏｒ Ｃ_１２Ｈ_１７Ｏ_４Ｐ （［Ｍ＋Ｈ］^＋） ｍ／ｚ ２５７．０９３７， ｆｏｕｎｄ ｍ／ｚ ２５７．０９２６．
式〔９〕で表される促進剤［化１２］
【００３６】
【化１２】

【００３７】
実施例２
式〔１０〕で表される２−ベンジロキシ−４，４−ジエチル−１，３−ジオキサフォスフォランおよび式〔１１〕で表される２−ベンジロキシ−４，４−ジエチル−１，３−ジオキサフォスフォラン ２−オキシド［化１３］の合成
【００３８】
【化１３】

【００３９】
式〔９〕で表される光学活性な促進剤７８ｍｇ（０．１ｍｍｏｌ）のＴＨＦ１０ｍＬ溶液に式〔６〕で表されるフォスフォロクロリダイト１６８ｍｇ（１ｍｍｏｌ）を−７８℃で添加した。１０分後、ベンジルアルコール１０８ｍｇ（１ｍｍｏｌ）とジイソプロピルアミン１２９ｍｇ（１ｍｍｏｌ）を−７８℃で加え、２５℃で１２時間攪拌し、式〔１０〕で表される表題化合物の溶液を得た。さらに３Ｍ ｔｅｒｔ−ブチルハイドロパーオキシドのトルエン溶液０．５ｍＬ（１．５ｍｍｏｌ）を加え、３０分間攪拌した。反応液に酢酸エチル２０ｍＬを加えて飽和重曹水２０ｍＬおよび飽和食塩水２０ｍＬで洗浄した。有機層を硫酸ナトリウムで乾燥し、濃縮した。残さをシリカゲルクロマトグラフィーで精製し、酢酸エチル−ヘキサン流分から式〔１１〕で表される表題化合物を無色油状物として得た。収率７１％、２８％ｅｅ。
式〔１１〕で表される化合物の分析データ：^１Ｈ ＮＭＲ （４００ＭＨｚ） ０．８８ （ｔ， ３Ｈ， Ｊ ＝ ７．２ Ｈｚ）， １．４６１．８０ （ｍ， ４Ｈ）， ３．９８４．１３ （ｍ， ２Ｈ）， ５．１４ （ｄ， ２Ｈ， Ｊ ＝ ９．６ Ｈｚ）， ７．３０７．３８ （ｍ， ５Ｈ）； ^１３Ｃ ＮＭＲ ７．４０， ７．４９， ２３．４９， ２４．７０， ２９．３８， ２９．４２， ２９．６７， ３６．６６， ６９．９９， ７０．０５， ７２．９１， ７２．９３， ８８．４３， １２７．８１， １２８．４９， １２８．５８， １３５．９６， １３６．０３； ^３１Ｐ ＮＭＲ １７．３９； ＨＲＭＳ （ＥＳＩ^＋） ｃａｌｃｄ ｆｏｒ Ｃ_１３Ｈ_１９Ｏ_４Ｐ （［Ｍ＋Ｈ］^＋） ｍ／ｚ ２７１．１０９４， ｆｏｕｎｄ ｍ／ｚ ２７１．１０６５．
【００４０】
【発明の効果】
本発明により、ラセミ化合物を出発原料として光学活性なトリフォスファイトおよびリン酸トリエステルが合成できる。トリフォスファイトおよびリン酸トリエステルは、農薬等の有機リン化合物やアンチセンスＤＮＡ等の化合物に利用されているため、工業的に有用な方法を提供できる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for synthesizing an optically active phosphorus compound. More specifically, the present invention relates to a process for synthesizing an optically active phosphorus compound having an optically active chiral center on phosphorus using a racemic compound as a raw material. The present invention relates to a synthetic method developed to obtain a yield.
[0002]
As for optically active phosphorus compounds, development of practical synthetic methods is expected, as represented by organic phosphorus compounds such as pesticides and useful compounds such as antisense DNA which has been recently developed.
[0003]
[Prior art]
In recent years, attempts to stereocontrol the asymmetric center on the phosphorus atom have become very interesting both biologically and chemically. It has been reported that the properties of many phosphorus compounds are affected by asymmetry on the phosphorus atom. (Prestic. Biochem. Physiol. 1978, 8, 146; J. Agric. Food. Chem. 1982, 30, 546; Prestic. Biochem. Physiol. 1979, 10, 121). Attempts to stereocontrol the chiral center have also been reported. (Drug Discovery and Design. 1996, 4, 17)
[0004]
However, it has been difficult to synthesize an optically active phosphorus compound by a conventional method. Generally, a method of crystallizing and separating a racemic phosphoric acid compound using an optically active base, or derivatizing phosphoric acid chloride with an optically active amine or alcohol to form a diastereomer and then separating and purifying the compound is known. Has been taken. (Chem. Rev. 1994, 94, 1375; Tetrahedron Asymmetry 1998, 9, 1279) On the other hand, a synthesis example by dynamic kinetic division has also been reported. Synlett. In the method described in 1998, 73, an alkylphosphonyl dichloride is reacted with p-nitrophenol and then reacted with methanol in the presence of an equimolar amount of ethyl L-prolinate to obtain an optically active methyl p-nitrophenyl alkyl phosphate. Synthesizes fate. J. Am. Chem. Soc. In the method described in 1998, 120, 5116, tert-butyl phenylphosphine-borane is reacted with butyllithium and an alkyl halide in the presence of an equimolar amount of (-)-sparteine to obtain an optically active alkyl tert-butyl. Phenylphosphine-borane has been synthesized. Also, J.I. Chem. Soc. Chem. Commun. In the method described in 1975, 382, an optically active phosphinic acid ester is synthesized by reacting phosphinyl chloride with an alcohol in the presence of an equimolar amount of (-)-N, N-dimethylphenethylamine.
[0005]
The synthesis by dynamic kinetic resolution is excellent in that a racemic form is used as a starting material, but until now, it has been necessary to coexist an equimolar amount of an optically active compound, so that improvement has been required. Also, no examples of synthesizing optically active triphosphite or phosphoric acid triester using a catalytic amount of an asymmetric source have been reported so far.
[0006]
It has been reported that dihydroquinine and derivatives of dihydroquinidine are used in asymmetric dihydroxylation (J. Org. Chem. 1993, 58, 844; US4871855; US5260461; WO93 / 07142) and asymmetric ring-opening reaction (WO02 / 10096). Have been. However, there is no example used for asymmetric control on a phosphorus atom.
[0007]
[Patent Document 1] US4871855
[Patent Document 2] US5260461
[Patent Document 3] WO93 / 07142
[Patent Document 4] WO 02/10096
[Non-Patent Document 1] Prestic. Biochem. Physiol. 1978, 8, 146
[Non-Patent Document 2] Agric. Food. Chem. 1982, 30, 546
[Non-Patent Document 3] Prestic. Biochem. Physiol. 1979, 10, 121
[Non-Patent Document 4] Drug Discovery and Design. 1996, 4, 17
[Non-Patent Document 5] Chem. Rev .. 1994, 94, 1375
[Non-Patent Document 6] Tetrahedron Asymmetry 1998, 9, 1279
[Non-Patent Document 7] Org. Chem. 1993, 58, 844
[0008]
[Problems to be solved by the invention]
In view of the conventional problems, it is an object of the present invention to provide an optically active phosphorus compound having an asymmetric center on phosphorus by using a racemic form as a starting material and only having a catalytic amount of the optically active compound, To provide an efficient synthesis method.
[0009]
[Means for Solving the Problems]
Means for Solving the Problems As a result of intensive studies on the above problems, the present inventors have found a method for synthesizing optically active triphosphite or phosphoric triester using a catalytic amount of an asymmetric source, and have completed the present invention.
[0010]
That is, the present invention
[1] A method for synthesizing an optically active phosphite, which comprises performing a reaction using an optically active tertiary amine as a reaction accelerator,
[2] General formula [1] [Chemical formula 5]
[0011]
Embedded image

[0012]
(Wherein, R1 and R2 each independently represent an alkyl group or alkenyl group having 1 to 4 carbon atoms, and R3 represents an optionally substituted benzoyl group or an optionally substituted aryl group) or a general formula. [2] [Chemical formula 6]
[0013]
Embedded image

[0014]
(Wherein, R1 and R2 have the same meanings as described above, and Q represents an aryl group which may be substituted.) The reaction is carried out in the presence of an optically active accelerator represented by the formula: Phosphite synthesis method,
[3] The synthesis method according to [2], wherein R1 is a methyl group, and R2 is an ethyl group or an ethenyl group,
[4] A method for synthesizing an optically active phosphoric triester, which comprises oxidizing the phosphite obtained in any one of [1] to [3],
[5] A method for synthesizing an optically active thiophosphoric acid triester, wherein the phosphite obtained in any one of [1] to [3] is sulfurized.
[6] A method for synthesizing an optically active selenophosphate triester, comprising selenizing the phosphite obtained in any one of [1] to [3],
[7] General formula [1] [Chemical formula 7]
[0015]
Embedded image

[0016]
(Wherein, R1 and R2 each independently represent an alkyl group or alkenyl group having 1 to 4 carbon atoms, and R3 represents an optionally substituted benzoyl group or an optionally substituted aryl group). Optically active accelerator,
[8] General formula [2]
[0017]
Embedded image

[0018]
(Wherein, R1 and R2 each independently represent an alkyl group or alkenyl group having 1 to 4 carbon atoms, and Q represents an aryl group which may be substituted). .
[0019]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
The term "promoting agent" as used in the present invention refers to a promoter on a phosphorus atom due to dynamic kinetic resolution even when a racemic mixture of a phosphorus compound is used as a starting material when synthesizing an optically active phosphite or phosphoric acid triester. A compound which induces a chirality to cause a reaction to be biased toward one optical isomer.
[0020]
The optically active tertiary amine referred to in the present invention includes a promoter represented by the general formula [1], and is not particularly limited as long as it has an asymmetric atom and a tertiary amine in the structure and is optically active. However, for example, (S, S) or (R, R) -N, N, N ', N'-tetramethyl-1,2-diphenylethylenediamine, (S) or (R) -2- (1-tert) -Butyldimethylsilyloxyethyl) benzimidazole, (-)-sparteine, 1,4-bis (9'-O-dihydroquinidyl) phthalazine, 1,4-bis (9'-O-quinidyl) phthalazine, 3, 6-bis (9′-O-dihydroquinidyl) pyridazine, 3,6-bis (9′-O-quinidyl) pyridazine, 1,4-bis (9′-O-dihydroquinyl) phthalazine, 1,4-bis (9 '-O-quinyl) phthalazine, 3 3,6-Bis (9'-O-Jihidorokiniru) pyridazine, 3,6-bis (9'-O-Kiniru) pyridazine and the like.
[0021]
In the accelerator represented by the general formula [1], the alkyl group having 1 to 4 carbon atoms in R1 and R2 includes, for example, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group Group, sec-butyl group, isobutyl group, tert-butyl group, cyclobutyl group and the like. Examples of the alkenyl group having 1 to 4 carbon atoms include a vinyl group, a propenyl group, an allyl group, and a butenyl group.
[0022]
The optionally substituted benzoyl group in R3 represents a halogen atom, an alkyl group having 1 to 4 carbon atoms, or a benzoyl group substituted with an alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. -Fluorobenzoyl group, 3-fluorobenzoyl group, 4-fluorobenzoyl group, 2-chlorobenzoyl group, 3-chlorobenzoyl group, 4-chlorobenzoyl group, 2-methylbenzoyl group, 3-methylbenzoyl group, 4-methyl Benzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 2-isopropylbenzoyl, 3-isopropylbenzoyl, 4-isopropylbenzoyl, 2-trifluoromethylbenzoyl, 3-triethyl Fluoromethylbenzoyl group, 4-trifluoromethylbenzoyl Etc. The. The aryl group which may be substituted in R3 refers to an alkyl group having 1 to 4 carbon atoms, a halogen atom, a phenyl group, or a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. Aromatic rings such as substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, imidazolyl, thiazolyl, benzofuranyl, quinolyl, phthalazinyl, phenanthryl, anthracenyl, and anthraquinonyl groups; Represents a ring or a heterocyclic group, for example, a phenyl group, a 2-pyridyl group, a 2-pyrimidine group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group , 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl , 4-fluorophenyl group, 6-phenyl-pyridin-2-yl group, 4,6-dimethyl-pyrimidin-2-yl group, 4-methyl-2-yl group, 9-phenanthryl group and the like.
[0023]
In the accelerator represented by the general formula [2], the optionally substituted aryl group for Q is an alkyl group having 1 to 4 carbon atoms, a halogen atom, a phenyl group or a 1 to 4 carbon atoms substituted with a halogen atom. Or an unsubstituted phenyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, furanyl group, imidazolyl group, thiazolyl group, benzofuranyl group, quinolyl group, phthalazinyl group, phenanthryl group, anthracenyl group, etc. Represents an aromatic ring such as an anthraquinonyl group, a condensed aromatic ring or a heterocyclic group, for example, a pyridine-2,6-diyl group, a pyrazine-3,6-diyl group, a 2-phenylpyrimidine-4,6-diyl Groups, 2-diphenylpyrimidine-4,6-diyl group, anthraquinone-1,4-diyl group and the like.
[0024]
As a starting material for obtaining an optically active phosphite, an asymmetric trivalent phosphorus compound in which one of the substituents on phosphorus is a leaving group and the other two substituents are different. Preferably, the leaving group is a halogen atom and the other two substituents have a hydroxyl group. More preferred is phosphorochloridite in which the leaving group is chlorine. It is preferably a racemic mixture, but a compound with low optical purity can be used as a raw material for the purpose of improving optical purity. For example, a 2-chloro-1,3-dioxa-2-phosphinane compound substituted with an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 1 to 4 carbon atoms, an aryl group which may be substituted, or the like, 2-chloro -1,3-dioxa-2-phosphorane compound, 2-bromo-1,3-dioxa-2-phosphinane compound, 2-bromo-1,3-dioxa-2-phosphorane compound, 2-iodo-1 , 3-dioxa-2-phosphinane compound, 2-iodo-1,3-dioxa-2-phosphorane compound, 2- (methanesulfonyloxy) -1,3-dioxa-2-phosphinane compound or 2- ( (Methanesulfonyloxy) -1,3-dioxa-2-phosphorane compound, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 1 to 4 carbon atoms, Also an aryl group phosphite chlorides oxygen atom is substituted with the like, phosphorous acid bromide or phosphorous iodine, and the like. Specifically, 2-chloro-4,4-dimethyl-1,3-dioxa-2-phosphinane, 2-chloro-4,4-diethyl-1,3-dioxa-2-phosphinan, 2-chloro- 4,4-dipropyl-1,3-dioxa-2-phosphinane, 2-chloro-4,4-dibutyl-1,3-dioxa-2-phosphinan, 2-chloro-4-ethyl-4-methyl- 1,3-dioxa-2-phosphinane, 2-chloro-4butyl-4-ethyl-1,3-dioxa-2-phosphinan, 2-chloro-4,4-dimethyl-1,3-dioxa-2 -Phospholane, 2-chloro-4,4-diethyl-1,3-dioxa-2-phospholane, 2-chloro-4,4-dipropyl-1,3-dioxa-2-phospholane, 2-chloro- 4,4-dibutyl- , 3-Dioxa-2-phospholane, 2-chloro-4-ethyl-4-methyl-1,3-dioxa-2-phospholane, 2-chloro-4butyl-4-ethyl-1,3-dioxa- 2-phospholane, 2-bromo-4,4-dimethyl-1,3-dioxa-2-phosphinane, 2-bromo-4,4-diethyl-1,3-dioxa-2-phosphinan, 2-bromo -4,4-dipropyl-1,3-dioxa-2-phosphinane, 2-bromo-4,4-dibutyl-1,3-dioxa-2-phosphinan, 2-bromo-4-ethyl-4-methyl -1,3-dioxa-2-phosphinane, 2-bromo-4butyl-4-ethyl-1,3-dioxa-2-phosphinane, 2-bromo-4,4-dimethyl-1,3-dioxa- 2-phospho 2-bromo-4,4-diethyl-1,3-dioxa-2-phospholane, 2-bromo-4,4-dipropyl-1,3-dioxa-2-phospholane, 2-bromo-4, 4-dibutyl-1,3-dioxa-2-phospholane, 2-bromo-4-ethyl-4-methyl-1,3-dioxa-2-phospholane, 2-bromo-4butyl-4-ethyl-1 , 3-dioxa-2-phosphorane and the like.
[0025]
Such phosphorohalodites are reacted with a compound having a hydroxyl group in the presence of an accelerator represented by the general formula [1] or [2] to obtain an optically active phosphite. The compound having a hydroxyl group is not particularly limited, but includes methanol, ethanol, propanol, butanol, isopropanol, tert-butanol, cyclohexanol, cyclopetanol, benzyl alcohol, phenol and the like. .
[0026]
The phosphite thus obtained can be oxidized, sulfurized or selenized, if desired, to be converted into optically active phosphoric acid triester, thiophosphate or selenophosphate. The reaction conditions for oxidation, sulfidation, or selenization may be generally used methods, and are not particularly limited. For example, aqueous hydrogen peroxide, tert-butyl hydroperoxide or peroxides such as benzoyl peroxide, peracetic acid, sulfur, 3H-1,2-benzodithiol-3-one 1,1-oxide, 3-ethoxy- 1,2,4-dithiozolin-5-one, 1,2,4-dithiozolin-3,5-dione, 3-methyl-ethoxy-1,2,4-dithiozolin-5-one, phenylacetyl disulfide or tetraethylthiuram disulfide And a selenizing agent such as selenium.
[0027]
【Example】
Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
Reference Example 1
Synthesis of 2-chloro-4,4-dimethyl-1,3-dioxa-2-phosphinan [formula 9] represented by the formula [5]
Embedded image

[0029]
15 g (150 mmol) of 3-methyl-1,3-butanediol and 30 g (300 mmol) of triethylamine were added dropwise to a solution of 21 g (150 mmol) of phosphorus trichloride in 600 mL of THF at -78 ° C over 2 hours, followed by stirring for 12 hours. After the reaction solution was filtered through Celite 545, the filtrate was concentrated. The residue was distilled under reduced pressure to obtain 9.3 g of the title compound. Yield 37%.
Boiling point 3537 ° C (0.56 mmHg); ¹ H NMR (400 MHz) 1.38 (s, 3H), 1.62 (s, 3H), 1.952.00 (m, 1H), 2.162.24 ( m, 1H), 4.044.12 (m, 1H), 4.614.68 (m, 1H); ¹³ C NMR 27.92, 27.94, 31.78, 31.81, 38.01, 38.09, 59.05, 59.08, 78.89, 78.96; ³¹ P NMR 150.16; HRMS (ESI ⁺ ) calcd for C ₅ H ₁₀ ClO ₂ P m / z 165.0353, found m / Z 165.9876.
[0030]
Reference Example 2
Synthesis of 2-chloro-4,4-diethyl-1,3-dioxa-2-phospholane [Formula 10] represented by the formula [6]
Embedded image

[0032]
To a 200 mL solution of 5.5 g (40 mmol) of phosphorus trichloride in THF, 4.7 g (40 mmol) of 2-ethyl-1,2-butanediol and 8.1 g (80 mmol) of triethylamine were added dropwise at -78 ° C over 2 hours. Stirred for hours. After the reaction solution was filtered through Celite 545, the filtrate was concentrated. The residue was distilled under reduced pressure to obtain 3.3 g of the title compound. Yield 45%.
Boiling point 5153 oC (2.2 mmHg); ¹ H NMR (400 MHz) 0.88 (t, 3H, J = 7.2 Hz), 1.03 (t, 3H, J = 7.2 Hz), 1.541 .67 (m, 2H), 1.832.04 (m, 2H), 4.12.419 (m, 2H); ¹³ C NMR 7.81, 30.08, 31.00, 30.49, 72 .85, 72.92, 91.00, 91.09; ³¹ P NMR 173.63.
[0033]
Example 1
2-benzyloxy-4,4-dimethyl-1,3-dioxaphosphinan represented by the formula [7] and 2-benzyloxy-4,4-dimethyl-1,3-di- represented by the formula [8] Synthesis of oxaphosphinane 2-oxide [formula 11]
Embedded image

[0035]
To a solution of 78 mg (0.1 mmol) of the optically active promoter represented by the formula [9] in 10 mL of THF was added 168 mg (1 mmol) of phosphorochloridite represented by the formula [5] at -78 ° C. After 10 minutes, 108 mg (1 mmol) of benzyl alcohol and 129 mg (1 mmol) of diisopropylamine were added at -78 ° C, and the mixture was stirred at 25 ° C for 12 hours to obtain a solution of the title compound represented by the formula [7]. Furthermore, 0.5 mL (1.5 mmol) of a toluene solution of 3M tert-butyl hydroperoxide was added, and the mixture was stirred for 30 minutes. 20 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with 20 mL of saturated aqueous sodium hydrogen carbonate and 20 mL of saturated saline. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography to give the title compound represented by the formula [8] as a colorless oil from a stream of ethyl acetate-hexane. Yield 80%, 76% ee.
Analytical data of the compound represented by the formula ^{(8): 1 H NMR (400MHz) 1.42} (s, 3H), 1.47 (s, 3H), 1.771.81 (m, 1H), 2. 032.08 (m, 1H), 4.284.34 (m, 2H), 5.055.10 (m, 2H), 7.317.39 (m, 5H); ¹³ C NMR 26.67, 26 .68, 30.03, 30.10, 36.54, 36.61, 64.65, 64.72, 83.60, 83.67, 127.83, 128.36, 128.45, 136.01. , 136.08; ³¹ P NMR 7.32; HRMS (ESI ⁺ ) calcd for C ₁₂ H ₁₇ O ₄ P ([M + H] ⁺ ) m / z 257.0937, found m / z 257.0926.
The accelerator represented by the formula [9] [Formula 12]
[0036]
Embedded image

[0037]
Example 2
2-benzyloxy-4,4-diethyl-1,3-dioxaphospholane represented by the formula [10] and 2-benzyloxy-4,4-diethyl-1,3-di- represented by the formula [11] Synthesis of Oxaphospholane 2-oxide [Formula 13]
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[0039]
To a solution of 78 mg (0.1 mmol) of the optically active accelerator represented by the formula [9] in 10 mL of THF was added 168 mg (1 mmol) of phosphorochloridite represented by the formula [6] at -78 ° C. After 10 minutes, 108 mg (1 mmol) of benzyl alcohol and 129 mg (1 mmol) of diisopropylamine were added at -78 ° C, and the mixture was stirred at 25 ° C for 12 hours to obtain a solution of the title compound represented by the formula [10]. Furthermore, 0.5 mL (1.5 mmol) of a toluene solution of 3M tert-butyl hydroperoxide was added, and the mixture was stirred for 30 minutes. 20 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with 20 mL of saturated aqueous sodium hydrogen carbonate and 20 mL of saturated saline. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, and the title compound represented by the formula [11] was obtained as a colorless oil from a stream of ethyl acetate-hexane. Yield 71%, 28% ee.
Analytical data of the compound represented by the formula [11]: ¹ H NMR (400 MHz) 0.88 (t, 3H, J = 7.2 Hz), 1.461.80 (m, 4H), 3.984. 13 (m, 2H), 5.14 (d, 2H, J = 9.6 Hz), 7.307.38 (m, 5H); ¹³ C NMR 7.40, 7.49, 23.49, 24 .70, 29.38, 29.42, 29.67, 36.66, 69.99, 70.05, 72.91, 72.93, 88.43, 127.81, 128.49, 128.58. , 135.96, 136.03; ³¹ P NMR 17.39; HRMS (ESI ⁺ ) calcd for C ₁₃ H ₁₉ O ₄ P ([M + H] ⁺ ) m / z 271.1094, found m / z 271.1065 .
[0040]
【The invention's effect】
According to the present invention, optically active triphosphite and phosphoric acid triester can be synthesized using a racemic compound as a starting material. Since triphosphite and phosphate triester are used for organic phosphorus compounds such as pesticides and compounds such as antisense DNA, industrially useful methods can be provided.

Claims (8)

A method for synthesizing an optically active phosphite, wherein the reaction is performed using an optically active tertiary amine as a reaction accelerator. General formula [1] [Formula 1]

(Wherein, R 1 and R 2 each independently represent an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 1 to 4 carbon atoms, and R 3 represents an optionally substituted benzoyl group or an optionally substituted aryl group. Or the general formula [2]

(Wherein, R1 and R2 have the same meanings as described above, and Q represents an aryl group which may be substituted.) The reaction is carried out in the presence of an optically active accelerator represented by the formula: Phosphite synthesis method. The method according to claim 2, wherein R1 is a methyl group, and R2 is an ethyl group or a vinyl group. A method for synthesizing an optically active phosphoric triester, comprising oxidizing the phosphite obtained in any one of claims 1 to 3. A method for synthesizing an optically active thiophosphoric acid triester, wherein the phosphite obtained in any one of claims 1 to 3 is sulfurized. A method for synthesizing an optically active selenophosphate triester, comprising selenizing the phosphite obtained in any one of claims 1 to 3. General formula [1] [Chemical formula 3]

(Wherein, R 1 and R 2 each independently represent an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 1 to 4 carbon atoms, and R 3 represents an optionally substituted benzoyl group or an optionally substituted aryl group. Represents an optically active accelerator represented by: General formula [2] [Formula 4]

(Wherein, R1 and R2 each independently represent an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 1 to 4 carbon atoms, and Q represents an aryl group which may be substituted). Active accelerator.