JP4124509B2 - Optically active 4,5-diphenyl-1,3-dialkyl-2- (2-hydroxyethyl) iminoimidazolidine derivatives - Google Patents

Description

【００１１】
〔式中、Ｒ¹ 及びＲ² は同一又は異なってアルキル基を示し、Ｒ³ はアルキル基、アリール基又はアラルキル基を示し、Ｒ⁴ は水素原子又はアリール基を示し、＊は不斉炭素の位置を示す〕
で表わされる光学活性な４，５−ジフェニル−１，３−ジアルキル−２−（２−ヒドロキシエチル）イミノイミダゾリジン誘導体を提供するものである。
【００１２】
【発明の実施の形態】
本発明の４，５−ジフェニル−１，３−ジアルキル−２−（２−ヒドロキシエチル）イミノイミダゾリジン誘導体は前記一般式（１）で表わされるものである。式中、Ｒ¹ 、Ｒ² 及びＲ³ で示されるアルキル基としては、炭素数１〜２４の直鎖又は分岐鎖のアルキル基が好ましく、具体的には、メチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基、ｎ−ブチル基、ｉ−ブチル基、ｓｅｃ−ブチル基、ｔ−ブチル基、ｎ−ペンチル基、ｎ−ヘキシル基、ｉ−ヘキシル基、ｓｅｃ−ヘキシル基、ｔ−ヘキシル基、ｎ−ヘプチル基、ｎ−オクチル基、ｎ−ノニル基、ｎ−デシル基、ｎ−ウンデシル基、ｎ−ドデシル基、ｎ−トリデシル基、ｎ−テトラデシル基、ｎ−ペンタデシル基、ｎ−ヘキサデシル基、ｎ−ヘプタデシル基、ｎ−オクタデシル基、ｎ−ノナデシル基、ｎ−エイコシル基、ｎ−ヘンエイコシル基、ｎ−ドコシル基、ｎ−トリコシル基、ｎ−テトラコシル基等が挙げられる。このうち、炭素数１〜６のものが特に好ましく、炭素数１〜４のものが最も好ましい。
【００１３】
式（１）中、Ｒ³ 及びＲ⁴ で示されるアリール基としては、フェニル基、ナフチル基、アントリル基、フェナントリル基等が好ましく、フェニル基が特に好ましい。
【００１４】
また、Ｒ³ で示されるアラルキル基としては、フェニルアルキル基（アルキル基の炭素数１〜５）、α−ナフチルアルキル基（アルキル基の炭素数１〜５）が好ましく、ベンジル基が特に好ましい。
【００１５】
前記一般式（１）で表わされる４，５−ジフェニル−１，３−ジアルキル−２−（２−ヒドロキシエチル）イミノイミダゾリジン誘導体の３つの不斉炭素原子の立体配置はＳ，Ｒのいずれであってもよいが、イミダゾリジン環の２つの不斉炭素原子は同一であることが好ましい。
【００１６】
本発明化合物（１）は、例えば次の反応式に従って、光学活性な１，２−ジフェニル−１，２−エタンジアミン（２）を出発原料として３工程を経て得られる４，５−ジフェニル−１，３−ジアルキル−２−ハロゲノイミダゾリニウム・ハロゲニド（７）にアミノアルコール類（８）を反応せしめることにより製造することができる。
【００１７】
【化３】

【００１８】
〔式中、Ｒ¹ 、Ｒ² 、Ｒ³ 、Ｒ⁴ 及び＊は前記と同じものを示し、Ｘ、Ｘ¹ 及びＸ² はハロゲン原子を示し、Ｂは塩基を示す〕
以下、上記反応を工程毎に説明する。
【００１９】
（１）工程１
光学活性な１，２−ジフェニル−１，２−エタンジアミン（２）を、尿素（３）及び水を用いて閉環させることにより４，５−ジフェニル−２−イミダゾリジノン（４）が得られる。原料として用いられる光学活性な１，２−ジフェニル−１，２−エタンジアミン（２）としては、（１Ｒ，２Ｒ）−１，２−ジフェニル−１，２−エタンジアミン、（１Ｓ，２Ｓ）−１，２−ジフェニル−１，２−エタンジアミンが挙げられる。この反応は、水を留去しながら加熱することにより行うのが好ましい。
【００２０】
（２）工程２
４，５−ジフェニル−２−イミダゾリジノン（４）にそれぞれ１当量のハロゲン化アルキルＲ¹Ｘ¹（５）及びＲ²Ｘ²（５′）（（５）と（５′）が同一の場合は２当量）を反応させることにより、４，５−ジフェニル−１，３−ジアルキル−２−イミダゾリジノン（６）が得られる。ハロゲン化アルキル（５）及び（５′）の具体例としては、ヨウ化メチル、ヨウ化エチル、臭化エチル、ヨウ化ｎ−プロピル、臭化ｎ−プロピル、塩化ｎ−プロピル、ヨウ化ｉ−プロピル、臭化ｉ−プロピル、ヨウ化ｎ−ブチル、臭化ｎ−ブチル、ヨウ化ｉ−ブチル、臭化ｉ−ブチル、塩化ｔ−ブチル等が挙げられる。この反応は、水素化ナトリウム等の塩基２当量以上の存在下に行うのが好ましい。
【００２１】
（３）工程３
４，５−ジフェニル−１，３−ジアルキル−２−イミダゾリジノン（６）にハロゲン化剤を反応させることにより４，５−ジフェニル−１，３−ジアルキル−２−ハロゲノイミダゾリニウム・ハロゲニド（７）が得られる。ここで使用されるハロゲン化剤としては、オキザリルハロゲニド、三ハロゲン化リン、五ハロゲン化リン、オキシハロゲン化リン、ホスゲン、トリクロロメチルクロロホルメート、トリホスゲン等が挙げられる。反応は４，５−ジフェニル−１，３−ジアルキル−２−イミダゾリジノン（６）とハロゲン化剤をベンゼン等の適当な溶媒に溶解しておき、室温ないし加熱下で数時間〜数十時間反応することによって行うのが好ましい。
【００２２】
（４）工程４
４，５−ジフェニル−１，３−ジアルキル−２−ハロゲノイミダゾリニウム・ハロゲニド（７）とアミノアルコール（８）とを塩基（９）の存在下で反応せしめることにより本発明の４，５−ジフェニル−１，３−ジアルキル−２−（２−ヒドロキシエチル）イミノイミダゾリジン誘導体（１）が得られる。アミノアルコール（８）の具体例としては、アミノエタノール、（Ｓ）−アラニノール、（Ｒ）−アラニノール、（Ｓ）−２−アミノブタノール、（Ｒ）−２−アミノブタノール、（Ｓ）−２−アミノ−ｎ−ペンタノール、（Ｒ）−２−アミノ−ｎ−ペンタノール、（Ｓ）−バリノール、（Ｒ）−バリノール、（Ｓ）−ロイシノール、（Ｒ）−ロイシノール、（Ｓ）−イソロイシノール、（Ｒ）−イソロイシノール、（Ｓ）−フェニルグリシノール、（Ｒ）−フェニルグリシノール、（Ｓ）−フェニルアラニノール、（Ｒ）−フェニルアラニノール、（Ｓ）−２−アミノ−１，１−ジフェニルフェネチルアルコール、（Ｒ）−２−アミノ−１，１−ジフェニルフェネチルアルコール等を挙げることができる。ここで使用される塩基としては、トリエチルアミン、トリブチルアミン、ジメチルアニリン、ピリジン等の有機塩基、炭酸カリウム、炭酸ナトリウム等の無機塩基が挙げられるが、反応に使用されるアミノアルコールを塩基として使用することもできる。反応は４，５−ジフェニル−１，３−ジアルキル−２−ハロゲノイミダゾリニウム・ハロゲニド（７）がアミノアルコール（８）のどちらか一方をベンゼン、アセトニトリル、塩化メチレン等の適当な溶媒に溶解しておき、室温あるいは冷却下で他方をゆっくりと滴下することにより行うのが好ましい。
【００２３】
本発明化合物（１）は、種々の不斉合成反応に不斉合成試薬として用いることができる。例えば、本発明化合物（１）を触媒として用いる不斉マイケル付加反応は次の反応式によって実施することができる。
【００２４】
【化４】

【００２５】
〔式中、Ｒ⁵ 、Ｒ⁶ 、Ｒ⁷ 及びＲ⁸ は有機基を示し、＊は前記と同じ〕
【００２６】
すなわち、エノン（１１）、マロン酸ジエステル（１２）を各１当量と触媒量の本発明化合物（１）をクロロホルム、ジクロロメタン、トルエン、テトラヒドロフラン等の不活性溶媒中に加え、加熱下あるいは室温付近で反応させればマイケル付加反応がエナンチオ選択的に進行し、目的とする光学活性なマイケル付加体（１３）を容易に得ることができる。このマイケル付加体（１３）は、常法に従い、エステルの加水分解、脱炭酸反応を経て医薬品原料として有用な光学活性なケトカルボン酸に導くことができる。なお、上記反応に触媒として用いた本発明化合物（１）は特に精製の操作を必要とせず再使用することができる。
ここで用いられるエノン（１１）は特に限定されるものではなく、Ｒ⁵ 、Ｒ⁶ 、Ｒ⁷ 及びＲ⁸ で示される有機基としては、脂肪族、芳香族のいずれでもよい。
【００２７】
【発明の効果】
本発明化合物を不斉合成試薬として用いれば、光学活性化合物を選択的かつ高収率で製造することができる。
【００２８】
【実施例】
以下、実施例を挙げて本発明を更に詳細に説明するが、本発明はこれらに限定されるものでない。
【００２９】
製造例１ （４Ｓ，５Ｓ）−２−クロロ−４，５−ジフェニル−１，３−ジメチルイミダゾリニウム・クロライドの製造
ベンゼン１００ml中に（４Ｓ，５Ｓ）−４，５−ジフェニル−１，３−ジメチル−２−イミダゾリジノン４．３ｇ（１６mmol）及び塩化オキザリル２．５ｇ（１９mmol）を加え、１２．５時間加熱還流した。放冷後析出晶を濾取し、ベンゼンで洗浄後減圧下に乾燥して標記化合物を２．１ｇ（収率４１％）得た。得られた化合物の物性は以下の通りである。
融点：219.6〜220.4℃（分解）
〔α〕_D ^26.6＝−128.90°(c=1.00, CHCl₃)
UVλ_max ^MeOH nm：246.8(ε 900), 206.8(ε 15200)
IRν_max ^KBrcm^-1：1600, 1275, 755, 700
¹H-NMR(CDCl₃)δ：3.17(6H,s), 5.28(2H,s), 7.08-7.57(10H,m)
【００３０】
実施例１ （４Ｓ，５Ｓ）−４，５−ジフェニル−２−〔（１Ｓ）−１−ベンジル−２−ヒドロキシエチル〕イミノ−１，３−ジメチルイミダゾリジンの製造
アセトニトリル１００ml中にＳ−フェニルアラニノール２．３６ｇ（１５．５８mmol）及びトリエチルアミン１．５８ｇ（１５．５８mmol）を加え、この中に（４Ｓ，５Ｓ）−２−クロロ−４，５−ジフェニル−１，３−ジメチルイミダゾリニウムクロライド５．００ｇ（１５．５８mmol）のアセトニトリル溶液を滴下し、終了後更に室温で３０分間攪拌した。反応液に希塩酸水溶液を加えベンゼンで洗浄し、水層を水酸化ナトリウム水溶液で強アルカリ性とした後塩化メチレンで抽出した。塩化メチレン層は無水硫酸ナトリウムで乾燥後、減圧下に溶媒を留去して５．５８ｇ残渣を得た。この残渣をシリカゲルクロマトグラフィー〔Chromatorex NH（富士シリシア化学（株）製）溶媒クロロホルム／メタノール〕にて精製し標記化合物を５．２５ｇ（収率８５％）得た。
融点：85.5〜87.0℃
〔α〕_D ²⁵＝＋9.12°(c=1.00, CHCl₃)
UVλ_max ^MeOH nm：208.0(ε 45800)
IRν_max ^KBrcm^-1：1630
¹H-NMR(CDCl₃)δ：2.72(6H,bs), 2.97(2H,d,J=7.7Hz), 3.48(2H,bs),
3.89(2H,s), 4.08-4.16(1H,m), 7.13-7.32(15H,m)
¹³C-NMR(CDCl₃)δ：41.27, 57.35, 65.51, 126.13, 127.50, 128.22,
128.32, 128.61, 129.37, 138.32, 139.46, 157.55
【００３１】
実施例２ （４Ｓ，５Ｓ）−４，５−ジフェニル−２−〔（１Ｒ）−１−ベンジル−２−ヒドロキシエチル〕イミノ−１，３−ジメチルイミダゾリジンの製造
塩化メチレン３０ml中に（Ｒ）−フェニルアラニノール１．４１ｇ（９．３５mmol）及びトリエチルアミン１．８９ｇ（１８．６９mmol）を加え、この中に（４Ｓ，５Ｓ）−２−クロロ−４，５−ジフェニル−１，３−ジメチルイミダゾリニウムクロライド３．００ｇ（９．３５mmol）の塩化メチレン３０ml溶液を滴下し、終了後更に室温で３０分間攪拌した。反応液に水酸化ナトリウム水溶液を加え、塩化メチレンで抽出し、抽出液は無水硫酸ナトリウムで乾燥後、減圧下に溶媒を留去して残渣を得た。この残渣をシリカゲルクロマトグラフィー〔Chromatorex NH（富士シリシア化学（株）製）溶媒クロロホルム／メタノール〕にて精製し標記化合物を３．１６ｇ（収率８５％）得た。
融点：111.5-113.5℃
〔α〕_D ²³＝＋76.49°(c=1.00, CHCl₃)
UVλ_max ^MeOH nm：206.8(ε 38600)
IRν_max ^KBrcm^-1：1625
¹H-NMR(CDCl₃)δ：2.70(6H,bs), 2.82(2H,d,J=6.8Hz),
3.60(1H,dd,J=6.0 and 10.1Hz), 3.71(1H,dd,J=4.2 and 10.1Hz),
3.57-3.73(2H,m), 4.25-4.29(1H,m), 7.04-7.36(15H,m)
¹³C-NMR(CDCl₃)δ：40.20, 57.00, 66.22, 125.88, 127.48, 128.09,
128.12, 128.51, 129.73, 138.38, 140.09, 157.87

【００３２】
実施例３ （４Ｓ，５Ｓ）−４，５−ジフェニル−２−〔（１Ｓ）−１−イソプロピル−２−ヒドロキシエチル〕イミノ−１，３−ジメチルイミダゾリジンの製造
塩化メチレン２０ml中に（Ｓ）−バリノール０．８０ｇ（７．７９mmol）及びトリエチルアミン１．５７ｇ（１５．５８mmol）を溶解し、この中に（４Ｓ，５Ｓ）−２−クロロ−４，５−ジフェニル−１，３−ジメチルイミダゾリニウムクロライド２．５０ｇ（７．７９mmol）を加え、終了後更に室温で１時間攪拌した。以下、実施例２と同様の操作を行い標記化合物を２．０３ｇ（収率７４％）得た。
粘稠油状物
〔α〕_D ²⁰＝＋36.28°(c=1.00, CHCl₃)
UVλ_max ^MeOH nm：207.2(ε 35000)
IRν_max ^neatcm^-1：1665
¹H-NMR(CDCl₃)δ：1.03(3H,d,J=6.8Hz), 1.04(3H,d,J=7.0Hz),
1.81-1.95(1H,m),2.70(6H,bs), 3.56-3.67(2H,m), 3.75-3.80(1H,m),
3.89(2H,bs), 7.12-7.15(4H,m), 7.23-7.39(6H,m)
¹³C-NMR(CDCl₃)δ：18.66, 20.29, 32.25, 60.63, 64.07, 127.51,
128.16, 128.32, 128.58, 138.46, 156.68
HRMS(FAB) calcd for C₂₂H₃₀ON₃ 352.2389, found 352.2372
【００３３】
実施例４ （４Ｓ，５Ｓ）−４，５−ジフェニル−２−〔（１Ｒ）−１−イソプロピル−２−ヒドロキシエチル〕イミノ−１，３−ジメチルイミダゾリジンの製造
アセトニトリル１００ml中に（Ｒ）−バリノール１．００ｇ（９．６９mmol）及びトリエチルアミン１．８９ｇ（１８．６９mmol）を溶解し、この中に（４Ｓ，５Ｓ）−２−クロロ−４，５−ジフェニル−１，３−ジメチルイミダゾリニウムクロライド３．００ｇ（９．３５mmol）を加え、終了後更に室温で３０分間攪拌した。以下、実施例１と同様の操作を行い標記化合物を２．７５ｇ（収率８４％）得た。
融点：65.5-68.5℃
〔α〕_D ²³＝＋83.20°(c=1.00, CHCl₃)
UVλ_max ^MeOH nm：207.2(ε 32900)
IRν_max ^neatcm^-1：1655
¹H-NMR(CDCl₃)δ：0.99(6H,s), 1.78-1.89(1H,m), 2.64(3H,bs),
2.82(3H,bs), 3.59-3.65(1H,m), 3.69-3.79(2H,m), 3.85-3.90(2H,m),
6.91-7.35(10H,m)
¹³C-NMR(CDCl₃)δ：19.06, 19.25, 31.75, 33.62, 37.65, 60.81,
64.40, 72.68, 75.09, 127.48, 128.12, 128.58, 138.66, 157.80
【００３４】
実施例５ （４Ｓ，５Ｓ）−４，５−ジフェニル−１，３−ジメチル−２−〔（１Ｓ）−１−フェニル−２−ヒドロキシエチル〕イミノイミダゾリジンの製造
アセトニトリル１００ml中に（Ｓ）−フェニルグリシノール１．２８ｇ（９．３５mmol）及びトリエチルアミン１．８９ｇ（１８．６９mmol）を溶解し、この中に（４Ｓ，５Ｓ）−２−クロロ−１，３−ジメチルイミダゾリニウムクロライド３．００ｇ（９．３５mmol）を加え、終了後更に室温で３０分間攪拌した。以下、実施例１と同様の操作を行い標記化合物を３．２８ｇ（収率９１％）得た。
融点：50.0-52.1℃
〔α〕_D ²⁵＝＋110.26°(c=1.00, CHCl₃)
UVλ_max ^MeOH nm：208.0(ε 47400)
IRν_max ^KBrcm^-1：1650
¹H-NMR(CDCl₃)δ：2.35-2.88(6H,m), 3.51(1H,dd,J=7.9 and 9.5Hz),
3.74(1H,dd,J=4.4 and 9.5Hz), 3.88(2H,s),
4.91(1H,dd,J=4.4 and 7.9Hz), 7.15-7.47(15H,m)
¹³C-NMR(CDCl₃)δ：61.23, 69.42, 126.66, 126.71, 127.49, 128.20,
128.27, 128.60, 138.31, 144.57, 158.71
【００３５】
実施例６ （４Ｓ，５Ｓ）−４，５−ジフェニル−１，３−ジメチル−２−〔（１Ｒ）−１−フェニル−２−ヒドロキシエチル〕イミノイミダゾリジンの製造
アセトニトリル１００ml中に（Ｒ）−フェニルグリシノール１．２８ｇ（９．３５mmol）及びトリエチルアミン１．８９ｇ（１８．６９mmol）を溶解し、この中に（４Ｓ，５Ｓ）−２−クロロ−１，３−ジメチルイミダゾリニウムクロライド３．００ｇ（９．３５mmol）を加え、終了後更に室温で３０分間攪拌した。以下、実施例１と同様の操作を行い標記化合物を３．３８ｇ（収率９４％）得た。
融点：124.0-125.7℃
〔α〕_D ²⁴＝＋26.22 °(c=1.00, CHCl₃)
UVλ_max ^MeOH nm：206.4(ε 39100)
IRν_max ^KBrcm^-1：1645
¹H-NMR(CDCl₃)δ：2.67(6H,bs), 3.49(1H,dd,J=7.9 and 9.5Hz),
3.79(1H,dd,J=3.8 and 9.5Hz), 3.82-3.96(2H,m),
5.05(1H,dd,J=3.8 and 7.9Hz), 6.77-7.38(15H,m)
¹³C-NMR(CDCl₃)δ：60.07, 69.65, 126.07, 126.87, 127.35, 128.09,
128.23, 128.56, 138.46, 143.32, 157.33
【００３６】
実施例７ （４Ｓ，５Ｓ）−４，５−ジフェニル−２−〔（１Ｒ）−１−ベンジル−２，２−ジフェニル−２−ヒドロキシエチル〕イミノ−１，３−ジメチルイミダゾリジンの製造
塩化メチレン１００ml中に（Ｒ）−２−アミノ−１，１，３−トリフェニルプロパノール１．８９ｇ（６．２３mmol）及びトリエチルアミン１．２６ｇ（１２．４６mmol）を溶解し、この中に（４Ｓ，５Ｓ）−２−クロロ−１，３−ジメチルイミダゾリニウムクロライド２．００ｇ（６．２３mmol）を加え、終了後更に室温で１時間攪拌した。以下実施例２と同様の操作を行い標記化合物を２．６８ｇ（収率７８％）得た。
融点：174.2-174.7℃
〔α〕_D ²⁴＝＋30.13°(c=1.00, CHCl₃)
UVλ_max ^MeOH nm：235(ε 64700)
IRν_max ^KBrcm^-1：1665
¹H-NMR(CDCl₃)δ：2.23(3H,s), 2.55(3H,s),
2.65(1H,dd,J=10.1 and 12.9Hz), 2.88(1H,dd,J=2.2 and 12.9Hz),
3.53(1H,d,J=7.5Hz), 3.62(1H,d,J=7.5Hz), 5.15(1H,dd,J=2.2 and 7.5Hz),
6.52(2H,d,J=6.8Hz), 6.83-6.85(2H,m), 7.16-7.41(17H,m),
7.65(2H,d,J=7.3Hz), 7.74(2H,d,J=7.3Hz)
【００３７】
実施例８ （４Ｓ，５Ｓ）−４，５−ジフェニル−２−（２−ヒドロキシエチル）イミノ−１，３−ジメチルイミダゾリジンの製造
塩化メチレン５０ml中に２−アミノエタノール０．９６ｇ（１５．６mmol）を加え、この中に（４Ｓ，５Ｓ）−２−クロロ−１，３−ジメチルイミダゾリニウムクロライド１．００ｇ（３．１２mmol）の塩化メチレン１０ml溶液を滴下し、終了後更に室温で１．５時間攪拌した。以下実施例１と同様の操作を行い標記化合物を０．８９ｇ（収率９４％）得た。
粘稠油状物
〔α〕_D ²³＝＋42.41°(c=1.00, CHCl₃)
IRν_max ^neatcm^-1：1650
¹H-NMR(CDCl₃)δ：2.50-3.00(6H,m), 3.53-3.61(1H,m), 3.66-3.80(3H,m),
3.90(2H,s), 7.13-7.33(10H,m)
【００３８】
参考例 ２−シクロペンテノンとマロン酸ジベンジルエステルとの反応
クロロホルムに２−シクロペンテノン７０mg（８．５４×１０^-4mol）、マロン酸ジベンジルエステル２０２mg（７．１１×１０^-4mol）及び（４Ｓ，５Ｓ）−４，５−ジフェニル−２−〔（１Ｒ）−１−ベンジル−２−ヒドロキシエチル〕イミノ−１，３−ジメチルイミダゾリジン２０１mg（５．０４×１０^-4mol）を加え２１日間加熱還流した。放冷後、反応液をシリカゲルクロマトグラフィーにて精製し、３−オキソシクロペンチルマロン酸ジベンジルエステルを１６７mg（収率６５％）得た。この化合物の光学純度を決定するために、ｐ−トルエンスルホン酸存在下２−エチル−２−メチル−１，３−ジオキソランとの反応により３−オキソシクロペンチルマロン酸ジベンジルエステル・エチレンアセタールに誘導し、ＨＰＬＣ分析（カラム：ＣＨＩＲＡＬＣＥＬ ＯＤ，移動相：ｎ−ヘキサン：イソプロパノール＝４０：１）したところＲ：Ｓの比は７５．５：２４．５であった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a 4,5-diphenyl-1,3-dialkyl-2- (2-hydroxyethyl) iminoimidazolidine derivative useful as an asymmetric synthesis reagent used for selectively producing an optically active compound.
[0002]
[Prior art]
An enantiomer (enantiomer) exists in an organic compound having an asymmetric carbon. When such an organic compound is used as a fragrance or a food additive, it is known that each enantiomer has a different odor and taste. In addition, as shown in the thalidomide example, it is known that pharmaceutical efficacy and toxicity differ greatly depending on both isomers. Furthermore, a compound having a pure chiral molecular structure is required for the ferroelectric liquid crystal, and a decrease in optical purity is considered to cause a significant decrease in function.
[0003]
As described above, in the industrial fields such as pharmaceuticals, agricultural chemicals, fragrances, food additives, and electronics, any enantiomer having high optical purity is required.
[0004]
In order to produce a compound with high optical purity, a method of producing by a normal chemical reaction using an optically active starting material is the easiest and general. Accordingly, optically active raw material compounds are industrially important, and are demanded to be supplied at low cost and in large quantities.
[0005]
[Problems to be solved by the invention]
As a method for producing such an optically active compound, a racemate obtained by a normal reaction is separated using an optically active resolving agent, or only one isomer is obtained using an enzyme or a biological technique. A method of converting into a target object is known.
[0006]
However, in such a method, half of the isomers that cannot be used industrially remain, so that effective use of resources cannot be achieved and it is uneconomical. In addition, the method using an enzyme or a biological technique has a drawback that the application range is limited and the reaction substrate cannot be treated in large quantities because the reaction concentration is low. Therefore, there has been a demand for a method that can produce only the necessary optical isomer without optical resolution without using an enzymatic method or the like.
[0007]
Accordingly, an object of the present invention is to provide an asymmetric synthesis reagent capable of selectively producing a desired optically active compound in high yield.
[0008]
[Means for Solving the Problems]
In view of such circumstances, the present inventors have conducted intensive research, and as a result, if a novel compound represented by the following general formula (1) is used as an asymmetric synthesis reagent, the reaction proceeds with high enantioselectivity and optical activity. The present inventors have found that a compound can be produced selectively and in high yield, and the present invention has been completed.
[0009]
That is, the present invention provides the following general formula (1)
[0010]
[Chemical 2]

[0011]
[Wherein, R ¹ and R ² are the same or different and each represents an alkyl group, R ³ represents an alkyl group, an aryl group or an aralkyl group, R ⁴ represents a hydrogen atom or an aryl group, and * represents an asymmetric carbon. (Indicates position)
An optically active 4,5-diphenyl-1,3-dialkyl-2- (2-hydroxyethyl) iminoimidazolidine derivative represented by the formula:
[0012]
DETAILED DESCRIPTION OF THE INVENTION
The 4,5-diphenyl-1,3-dialkyl-2- (2-hydroxyethyl) iminoimidazolidine derivative of the present invention is represented by the general formula (1). In the formula, the alkyl group represented by R ¹ , R ² and R ³ is preferably a linear or branched alkyl group having 1 to 24 carbon atoms, specifically, methyl group, ethyl group, n-propyl group. Group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n-pentyl group, n-hexyl group, i-hexyl group, sec-hexyl group, t-hexyl Group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group Group, n-heptadecyl group, n-octadecyl group, n-nonadecyl group, n-eicosyl group, n-heneicosyl group, n-docosyl group, n-tricosyl group, n-tetracosyl group and the like. Of these, those having 1 to 6 carbon atoms are particularly preferred, and those having 1 to 4 carbon atoms are most preferred.
[0013]
In the formula (1), the aryl group represented by R ³ and R ⁴ is preferably a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group or the like, and particularly preferably a phenyl group.
[0014]
Moreover, as an aralkyl group shown by R < ³ >, a phenylalkyl group (C1-C5 of an alkyl group) and an alpha-naphthylalkyl group (C1-C5 of an alkyl group) are preferable, and a benzyl group is especially preferable.
[0015]
The configuration of the three asymmetric carbon atoms of the 4,5-diphenyl-1,3-dialkyl-2- (2-hydroxyethyl) iminoimidazolidine derivative represented by the general formula (1) is S or R. Although there may be, it is preferred that the two asymmetric carbon atoms of the imidazolidine ring are the same.
[0016]
The compound (1) of the present invention can be obtained by, for example, 4,5-diphenyl-1 obtained through three steps using optically active 1,2-diphenyl-1,2-ethanediamine (2) as a starting material according to the following reaction formula. , 3-dialkyl-2-halogenoimidazolinium halogenide (7) can be produced by reacting aminoalcohols (8).
[0017]
[Chemical 3]

[0018]
[Wherein R ¹ , R ² , R ³ , R ⁴ and * represent the same as those described above, X, X ¹ and X ² represent a halogen atom, and B represents a base]
Hereafter, the said reaction is demonstrated for every process.
[0019]
(1) Step 1
Ring closure of optically active 1,2-diphenyl-1,2-ethanediamine (2) with urea (3) and water gives 4,5-diphenyl-2-imidazolidinone (4). . Examples of the optically active 1,2-diphenyl-1,2-ethanediamine (2) used as a raw material include (1R, 2R) -1,2-diphenyl-1,2-ethanediamine, (1S, 2S)- 1,2-diphenyl-1,2-ethanediamine may be mentioned. This reaction is preferably carried out by heating while distilling off water.
[0020]
(2) Step 2
4,5-diphenyl-2-imidazolidinone (4) is equivalent to 1 equivalent each of alkyl halide R ¹ X ¹ (5) and R ² X ² (5 ′) ((5) and (5 ′) are identical. In this case, 4,5-diphenyl-1,3-dialkyl-2-imidazolidinone (6) is obtained. Specific examples of the alkyl halides (5) and (5 ′) include methyl iodide, ethyl iodide, ethyl bromide, n-propyl iodide, n-propyl bromide, n-propyl chloride, i-iodide. Examples include propyl, i-propyl bromide, n-butyl iodide, n-butyl bromide, i-butyl iodide, i-butyl bromide, t-butyl chloride and the like. This reaction is preferably carried out in the presence of 2 equivalents or more of a base such as sodium hydride.
[0021]
(3) Process 3
By reacting 4,5-diphenyl-1,3-dialkyl-2-imidazolidinone (6) with a halogenating agent, 4,5-diphenyl-1,3-dialkyl-2-halogenimidazolinium halogenide ( 7) is obtained. Examples of the halogenating agent used here include oxalyl halogenide, phosphorus trihalide, phosphorus pentahalide, phosphorus oxyhalide, phosgene, trichloromethyl chloroformate, and triphosgene. The reaction is carried out by dissolving 4,5-diphenyl-1,3-dialkyl-2-imidazolidinone (6) and a halogenating agent in a suitable solvent such as benzene, and at room temperature or under heating for several hours to several tens of hours. It is preferable to carry out the reaction.
[0022]
(4) Step 4
4,5-Diphenyl-1,3-dialkyl-2-halogenazolinium-halogenide (7) and amino alcohol (8) are reacted in the presence of base (9) to produce 4,5- A diphenyl-1,3-dialkyl-2- (2-hydroxyethyl) iminoimidazolidine derivative (1) is obtained. Specific examples of amino alcohol (8) include aminoethanol, (S) -alaninol, (R) -alaninol, (S) -2-aminobutanol, (R) -2-aminobutanol, (S) -2- Amino-n-pentanol, (R) -2-amino-n-pentanol, (S) -valinol, (R) -valinol, (S) -leucinol, (R) -leucinol, (S) -isoleucinol, (R) -Isoleucinol, (S) -Phenylglycinol, (R) -Phenylglycinol, (S) -Phenylalaninol, (R) -Phenylalaninol, (S) -2-Amino-1,1- Examples thereof include diphenylphenethyl alcohol and (R) -2-amino-1,1-diphenylphenethyl alcohol. Examples of the base used here include organic bases such as triethylamine, tributylamine, dimethylaniline, and pyridine, and inorganic bases such as potassium carbonate and sodium carbonate. The amino alcohol used in the reaction should be used as the base. You can also. In the reaction, 4,5-diphenyl-1,3-dialkyl-2-halogenazolinium-halogenide (7) is dissolved in one of amino alcohols (8) in a suitable solvent such as benzene, acetonitrile, methylene chloride or the like. It is preferable to carry out by slowly dropping the other at room temperature or under cooling.
[0023]
The compound (1) of the present invention can be used as an asymmetric synthesis reagent in various asymmetric synthesis reactions. For example, the asymmetric Michael addition reaction using the compound (1) of the present invention as a catalyst can be carried out according to the following reaction formula.
[0024]
[Formula 4]

[0025]
[Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ represent organic groups, and * is the same as above]
[0026]
That is, 1 equivalent each of enone (11) and malonic acid diester (12) and a catalytic amount of the compound (1) of the present invention are added to an inert solvent such as chloroform, dichloromethane, toluene, tetrahydrofuran, etc., and heated or near room temperature. When reacted, the Michael addition reaction proceeds enantioselectively, and the desired optically active Michael adduct (13) can be easily obtained. This Michael adduct (13) can be converted into an optically active ketocarboxylic acid useful as a pharmaceutical raw material through ester hydrolysis and decarboxylation according to a conventional method. The compound (1) of the present invention used as a catalyst in the above reaction can be reused without requiring any purification operation.
The enone (11) used here is not particularly limited, and the organic group represented by R ⁵ , R ⁶ , R ⁷ and R ⁸ may be either aliphatic or aromatic.
[0027]
【The invention's effect】
If the compound of the present invention is used as an asymmetric synthesis reagent, an optically active compound can be produced selectively and in high yield.
[0028]
【Example】
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these.
[0029]
Production Example 1 Production of (4S, 5S) -2-chloro-4,5-diphenyl-1,3-dimethylimidazolinium chloride (4S, 5S) -4,5-diphenyl-1,3 in 100 ml of benzene -4.3 g (16 mmol) of dimethyl-2-imidazolidinone and 2.5 g (19 mmol) of oxalyl chloride were added and heated to reflux for 12.5 hours. After cooling, the precipitated crystals were collected by filtration, washed with benzene and dried under reduced pressure to obtain 2.1 g (yield 41%) of the title compound. The physical properties of the obtained compound are as follows.
Melting point: 219.6-220.4 ° C (decomposition)
[Α] _D ^26.6 = -128.90 ° (c = 1.00, CHCl ₃ )
UVλ _max ^MeOH nm: 246.8 (ε 900), 206.8 (ε 15200)
IRν _max ^KBr cm ^-1 : 1600, 1275, 755, 700
¹ H-NMR (CDCl ₃ ) δ: 3.17 (6H, s), 5.28 (2H, s), 7.08-7.57 (10H, m)
[0030]
Example 1 Preparation of (4S, 5S) -4,5-diphenyl-2-[(1S) -1-benzyl-2-hydroxyethyl] imino-1,3-dimethylimidazolidine S-phenylalani in 100 ml of acetonitrile 2.36 g (15.58 mmol) of diol and 1.58 g (15.58 mmol) of triethylamine are added, into which (4S, 5S) -2-chloro-4,5-diphenyl-1,3-dimethylimidazolinium chloride. 5.00 g (15.58 mmol) of acetonitrile solution was added dropwise, and after completion, the mixture was further stirred at room temperature for 30 minutes. A dilute hydrochloric acid aqueous solution was added to the reaction solution, which was washed with benzene. The aqueous layer was made strongly alkaline with an aqueous sodium hydroxide solution and then extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.58 g residue. This residue was purified by silica gel chromatography [Chromatorex NH (manufactured by Fuji Silysia Chemical Ltd.) solvent chloroform / methanol] to obtain 5.25 g (yield 85%) of the title compound.
Melting point: 85.5-87.0 ° C
[Α] _D ²⁵ = + 9.12 ° (c = 1.00, CHCl ₃ )
UVλ _max ^MeOH nm: 208.0 (ε 45800)
IRν _max ^KBr cm ^-1 : 1630
¹ H-NMR (CDCl ₃ ) δ: 2.72 (6H, bs), 2.97 (2H, d, J = 7.7 Hz), 3.48 (2H, bs),
3.89 (2H, s), 4.08-4.16 (1H, m), 7.13-7.32 (15H, m)
¹³ C-NMR (CDCl ₃ ) δ: 41.27, 57.35, 65.51, 126.13, 127.50, 128.22,
128.32, 128.61, 129.37, 138.32, 139.46, 157.55
[0031]
Example 2 Preparation of (4S, 5S) -4,5-diphenyl-2-[(1R) -1-benzyl-2-hydroxyethyl] imino-1,3-dimethylimidazolidine (R) in 30 ml of methylene chloride -1.41 g (9.35 mmol) of phenylalaninol and 1.89 g (18.69 mmol) of triethylamine are added, in which (4S, 5S) -2-chloro-4,5-diphenyl-1,3-dimethylimidazo A solution of 3.00 g (9.35 mmol) of linium chloride in 30 ml of methylene chloride was added dropwise, and after completion, the mixture was further stirred at room temperature for 30 minutes. A sodium hydroxide aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography [Chromatorex NH (manufactured by Fuji Silysia Chemical Ltd.) solvent chloroform / methanol] to obtain 3.16 g (yield 85%) of the title compound.
Melting point: 111.5-113.5 ℃
[Α] _D ²³ = + 76.49 ° (c = 1.00, CHCl ₃ )
UVλ _max ^MeOH nm: 206.8 (ε 38600)
IRν _max ^KBr cm ^-1 : 1625
¹ H-NMR (CDCl ₃ ) δ: 2.70 (6H, bs), 2.82 (2H, d, J = 6.8 Hz),
3.60 (1H, dd, J = 6.0 and 10.1Hz), 3.71 (1H, dd, J = 4.2 and 10.1Hz),
3.57-3.73 (2H, m), 4.25-4.29 (1H, m), 7.04-7.36 (15H, m)
¹³ C-NMR (CDCl ₃ ) δ: 40.20, 57.00, 66.22, 125.88, 127.48, 128.09,
128.12, 128.51, 129.73, 138.38, 140.09, 157.87

[0032]
Example 3 Preparation of (4S, 5S) -4,5-diphenyl-2-[(1S) -1-isopropyl-2-hydroxyethyl] imino-1,3-dimethylimidazolidine in 20 ml of methylene chloride (S) -0.80 g (7.79 mmol) of valinol and 1.57 g (15.58 mmol) of triethylamine are dissolved, in which (4S, 5S) -2-chloro-4,5-diphenyl-1,3-dimethylimidazoli 2.50 g (7.79 mmol) of nium chloride was added, and after completion, the mixture was further stirred at room temperature for 1 hour. Thereafter, the same operation as in Example 2 was performed to obtain 2.03 g (yield 74%) of the title compound.
Viscous oil [α] _D ²⁰ = + 36.28 ° (c = 1.00, CHCl ₃ )
UVλ _max ^MeOH nm: 207.2 (ε 35000)
IRν _max ^neat cm ^-1 : 1665
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, d, J = 6.8 Hz), 1.04 (3H, d, J = 7.0 Hz),
1.81-1.95 (1H, m), 2.70 (6H, bs), 3.56-3.67 (2H, m), 3.75-3.80 (1H, m),
3.89 (2H, bs), 7.12-7.15 (4H, m), 7.23-7.39 (6H, m)
¹³ C-NMR (CDCl ₃ ) δ: 18.66, 20.29, 32.25, 60.63, 64.07, 127.51,
128.16, 128.32, 128.58, 138.46, 156.68
HRMS (FAB) calcd for C ₂₂ H ₃₀ ON ₃ 352.2389, found 352.2372
[0033]
Example 4 Preparation of (4S, 5S) -4,5-diphenyl-2-[(1R) -1-isopropyl-2-hydroxyethyl] imino-1,3-dimethylimidazolidine (R)-in 100 ml of acetonitrile Dissolve 1.00 g (9.69 mmol) of valinol and 1.89 g (18.69 mmol) of triethylamine, in which (4S, 5S) -2-chloro-4,5-diphenyl-1,3-dimethylimidazolinium is dissolved. After adding 3.00 g (9.35 mmol) of chloride, the mixture was further stirred at room temperature for 30 minutes. Thereafter, the same operation as in Example 1 was performed to obtain 2.75 g (yield 84%) of the title compound.
Melting point: 65.5-68.5 ℃
[Α] _D ²³ = + 83.20 ° (c = 1.00, CHCl ₃ )
UVλ _max ^MeOH nm: 207.2 (ε 32900)
IRν _max ^neat cm ^-1 : 1655
¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, s), 1.78-1.89 (1H, m), 2.64 (3H, bs),
2.82 (3H, bs), 3.59-3.65 (1H, m), 3.69-3.79 (2H, m), 3.85-3.90 (2H, m),
6.91-7.35 (10H, m)
¹³ C-NMR (CDCl ₃ ) δ: 19.06, 19.25, 31.75, 33.62, 37.65, 60.81,
64.40, 72.68, 75.09, 127.48, 128.12, 128.58, 138.66, 157.80
[0034]
Example 5 Preparation of (4S, 5S) -4,5-diphenyl-1,3-dimethyl-2-[(1S) -1-phenyl-2-hydroxyethyl] iminoimidazolidine (S)-in 100 ml of acetonitrile 1.28 g (9.35 mmol) of phenylglycinol and 1.89 g (18.69 mmol) of triethylamine were dissolved therein, and 3.00 g of (4S, 5S) -2-chloro-1,3-dimethylimidazolinium chloride was dissolved therein. (9.35 mmol) was added, and after completion, the mixture was further stirred at room temperature for 30 minutes. Thereafter, the same operation as in Example 1 was performed to obtain 3.28 g (yield 91%) of the title compound.
Melting point: 50.0-52.1 ℃
[Α] _D ²⁵ = + 110.26 ° (c = 1.00, CHCl ₃ )
UVλ _max ^MeOH nm: 208.0 (ε 47400)
IRν _max ^KBr cm ^-1 : 1650
¹ H-NMR (CDCl ₃ ) δ: 2.35-2.88 (6H, m), 3.51 (1H, dd, J = 7.9 and 9.5Hz),
3.74 (1H, dd, J = 4.4 and 9.5Hz), 3.88 (2H, s),
4.91 (1H, dd, J = 4.4 and 7.9Hz), 7.15-7.47 (15H, m)
¹³ C-NMR (CDCl ₃ ) δ: 61.23, 69.42, 126.66, 126.71, 127.49, 128.20,
128.27, 128.60, 138.31, 144.57, 158.71
[0035]
Example 6 Preparation of (4S, 5S) -4,5-diphenyl-1,3-dimethyl-2-[(1R) -1-phenyl-2-hydroxyethyl] iminoimidazolidine (R)-in 100 ml of acetonitrile 1.28 g (9.35 mmol) of phenylglycinol and 1.89 g (18.69 mmol) of triethylamine were dissolved therein, and 3.00 g of (4S, 5S) -2-chloro-1,3-dimethylimidazolinium chloride was dissolved therein. (9.35 mmol) was added, and after completion, the mixture was further stirred at room temperature for 30 minutes. Thereafter, the same operation as in Example 1 was performed to obtain 3.38 g (yield 94%) of the title compound.
Melting point: 124.0-125.7 ℃
[Α] _D ²⁴ = +26.22 ° (c = 1.00, CHCl ₃ )
UVλ _max ^MeOH nm: 206.4 (ε 39100)
IRν _max ^KBr cm ^-1 : 1645
¹ H-NMR (CDCl ₃ ) δ: 2.67 (6H, bs), 3.49 (1H, dd, J = 7.9 and 9.5 Hz),
3.79 (1H, dd, J = 3.8 and 9.5Hz), 3.82-3.96 (2H, m),
5.05 (1H, dd, J = 3.8 and 7.9Hz), 6.77-7.38 (15H, m)
¹³ C-NMR (CDCl ₃ ) δ: 60.07, 69.65, 126.07, 126.87, 127.35, 128.09,
128.23, 128.56, 138.46, 143.32, 157.33
[0036]
Example 7 Preparation of (4S, 5S) -4,5-diphenyl-2-[(1R) -1-benzyl-2,2-diphenyl-2-hydroxyethyl] imino-1,3-dimethylimidazolidine Methylene chloride Dissolve 1.89 g (6.23 mmol) of (R) -2-amino-1,1,3-triphenylpropanol and 1.26 g (12.46 mmol) of triethylamine in 100 ml, in which (4S, 5S) 2-Chloro-1,3-dimethylimidazolinium chloride (2.00 g, 6.23 mmol) was added, and after completion, the mixture was further stirred at room temperature for 1 hour. Then, the same operation as in Example 2 was performed to obtain 2.68 g (yield 78%) of the title compound.
Melting point: 174.2-174.7 ℃
[Α] _D ²⁴ = + 30.13 ° (c = 1.00, CHCl ₃ )
UVλ _max ^MeOH nm: 235 (ε 64700)
IRν _max ^KBr cm ^-1 : 1665
¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.55 (3H, s),
2.65 (1H, dd, J = 10.1 and 12.9Hz), 2.88 (1H, dd, J = 2.2 and 12.9Hz),
3.53 (1H, d, J = 7.5Hz), 3.62 (1H, d, J = 7.5Hz), 5.15 (1H, dd, J = 2.2 and 7.5Hz),
6.52 (2H, d, J = 6.8Hz), 6.83-6.85 (2H, m), 7.16-7.41 (17H, m),
7.65 (2H, d, J = 7.3Hz), 7.74 (2H, d, J = 7.3Hz)
[0037]
Example 8 Preparation of (4S, 5S) -4,5-diphenyl-2- (2-hydroxyethyl) imino-1,3-dimethylimidazolidine 0.96 g (15.6 mmol) of 2-aminoethanol in 50 ml of methylene chloride ) Was added dropwise thereto, and a solution of 1.00 g (3.12 mmol) of (4S, 5S) -2-chloro-1,3-dimethylimidazolinium chloride in 10 ml of methylene chloride was added dropwise. Stir for 5 hours. Then, the same operation as in Example 1 was performed to obtain 0.89 g (yield 94%) of the title compound.
Viscous oil [α] _D ²³ = + 42.41 ° (c = 1.00, CHCl ₃ )
IRν _max ^neat cm ^-1 : 1650
¹ H-NMR (CDCl ₃ ) δ: 2.50-3.00 (6H, m), 3.53-3.61 (1H, m), 3.66-3.80 (3H, m),
3.90 (2H, s), 7.13-7.33 (10H, m)
[0038]
Reference Example Reaction of 2-cyclopentenone with malonic acid dibenzyl ester 70 mg (8.54 × 10 ⁻⁴ mol) of 2-cyclopentenone and 202 mg (7.11 × 10 ⁻⁴ mol) of malonic acid dibenzyl ester in chloroform ) And (4S, 5S) -4,5-diphenyl-2-[(1R) -1-benzyl-2-hydroxyethyl] imino-1,3-dimethylimidazolidine (201 mg, 5.04 × 10 ⁻⁴ mol) And heated to reflux for 21 days. After cooling, the reaction solution was purified by silica gel chromatography to obtain 167 mg (yield 65%) of 3-oxocyclopentylmalonic acid dibenzyl ester. In order to determine the optical purity of this compound, it was converted to 3-oxocyclopentylmalonic acid dibenzyl ester / ethylene acetal by reaction with 2-ethyl-2-methyl-1,3-dioxolane in the presence of p-toluenesulfonic acid. , HPLC analysis (column: CHIRALCEL OD, mobile phase: n-hexane: isopropanol = 40: 1), the R: S ratio was 75.5: 24.5.

Claims (1)

The following general formula (1)

[Wherein, R ¹ and R ² are the same or different and each represents an alkyl group, R ³ represents an alkyl group, an aryl group or an aralkyl group, R ⁴ represents a hydrogen atom or an aryl group, and * represents an asymmetric carbon. (Indicates position)
An optically active 4,5-diphenyl-1,3-dialkyl-2- (2-hydroxyethyl) iminoimidazolidine derivative represented by the formula: