技術分野
本発明は、医薬品として有用な新規２，２−ジフェニルブタンアミド誘導体に関するものであり、抗コリン薬としてとりわけ選択的なムスカリン受容体拮抗作用を有する２，２−ジフェニルブタンアミド誘導体及びその製造法に関する。
背景技術
コリン作動性受容体拮抗薬として、新規イミダゾール誘導体が開示されている（特開平７−２１５９４３）。このようなコリン作動性受容体拮抗薬は抗コリン作用、とりわけ消化管、気管、膀胱等の平滑筋のムスカリン受容体に対し、強力な選択的拮抗作用を示し、過敏性腸症候群、憩室疾患、機能性下痢、食道無弛緩症、噴門痙攣等の消化管自動運動性障害治療、胆道、尿道の痙攣、尿失禁等の治療あるいは慢性気道閉塞性疾患の治療に有効であることが知られている（Ｈ．Ｍｉｙａｃｈｉら、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，８〔１９９８〕１８０７−１８１２、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．，７〔１９９９〕１１５１−１１６１、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，９〔１９９９〕３００３−３００８．）。
一般的にムスカリン性アセチルコリン受容体遮断薬の拮抗作用には臓器選択性が乏しいため、副作用の発現が問題となっており、選択性の高い抗コリン薬の開発が望まれている。
本発明は、心臓のムスカリン受容体よりも、平滑筋のムスカリン受容体に対する選択性が高く、強い拮抗作用を有する薬物を提供することにある。
発明の開示
本発明者らは、上記課題を解決するため、２，２−ジフェニルブタンアミド誘導体に着目し、鋭意検討した結果 一般式（１）
［式中、Ｘは水素原子又は水酸基を、Ｒ１は水素原子又は１−デオキシ−Ｄ−グルコピランウロン酸基を、Ｒ２はオキサミド基、オキサミド酸基、アセチルグリシルアミノ基、４，５−ジオキソ−２−メチルイミダゾリジニル基、１−（２−メチル−１−イミダゾリオ）−１−デオキシ−β−Ｄ−ピランウロネート基、１−（２−メチル−１−イミダゾリオ）−１−デオキシ−α−Ｄ−ピランウロネート基、アセトイミドイルアミノ基、２−メチル−５−オキソイミダゾリニル基又は２−メチル−４，５−ジオキソイミダゾリニル基を示す］で表される新規な２，２−ジフェニルブタンアミド誘導体及びその塩並びに水和物に平滑筋のムスカリン受容体に選択的拮抗作用を見出し、発明を完成したものである。
このうち特に主要な化合物として
４−（２−メチル−４，５−ジオキソ−１，３−イミダゾリジン−１−イル）−２、２−ジフェニルブタンアミド（ＲＣ２と略記）、２−アセチルアミノ−Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）アセトアミド（ＲＣ３と略記）、Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド（ＲＣ４と略記）、Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド酸（ＲＣ５と略記）、１−［３−（３−カルバモイル−３，３−ジフェニル）プロピル−２−メチル−１−イミダゾリオ］−１−デオキシ−β−Ｄ−グルコピランウロネート（ＲＣ７と略記）、Ｎ−［３−カルバモイル−３−（４−ヒドロキシフェニル）−３−フェニルプロピル］オキサミド（ＲＣ８と略記）、１−［２，２−ジフェニル−４−（２−メチルイミダゾール−１−イル）ブチリルアミノ］−１−デオキシ−Ｄ−グルコピランウロン酸（ＲＣ９と略記）、１−［３−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチル−１−イミダゾリオ］−１−デオキシ−α−Ｄ−グルコピランウロネート（ＲＣ１０と略記）、４−アセトイミドイルアミノ−２，２−ジフェニルブタンアミド（ＲＣ１１と略記）、４−（２−メチル−５−オキソ−４，５−ジヒドロイミダゾール−１−イル）−２，２−ジフェニルブタンアミド（ＲＣ１２と略記）、４−（２−メチル−４，５−ジオキソ−４，５−ジヒドロイミダゾール−１−イル）−２，２−ジフェニルブタンアミド（ＲＣ１３と略記）である化合物が挙げられる。
本発明によれば、化合物（ＲＣ２）はスキーム１に示す方法で合成することができる。
既知の方法で合成したＮ−（１−アミノエチル）ベンズアミド塩酸塩（８）にクロルアセチル化後、塩基（例えば水素化ナトリウム、ｔ−ブトキシカリウム等）の存在下、不活性溶媒（例えばジメチルホルムアミドなどのアミド類、ジメチルスルホキシド又はテトラヒドロフランなどのエーテル類）中で、−２０℃〜８０℃で１〜８時間反応させて化合物（９）とし、次いでｔ−ブトキシカルボニル（Ｂｏｃ）化して化合物（１０）とした。これを、テトラヒドロフランなどのエーテル類やトルエン等の溶媒中でデービス試薬と−７８〜２０℃で反応させるか、或はＮ−ブロモこはく酸イミド（ＮＢＳ）等と四塩化炭素中で２０〜８０℃で反応させた後、不活性溶媒（例えば塩化メチレン、クロロホルムなどのハロゲン化炭化水素等）中でクロム酸等の酸化剤（例えば、クロロクロム酸ピリジニウム（ＰＣＣ）、二クロム酸ピリジニウム（ＰＤＣ）、或はそれらを含んだ担体等）と２０〜４０℃で１〜２４時間反応させ、化合物（１１）とした。次いでこれを、１級アミン（例えばｎ−ブチルアミン、ベンジルアミン等）と不活性溶媒（好ましくはアセトニリル、塩化メチレン等）中で−４０〜８０℃で１〜２４時間反応させ、化合物（１２）とした。これを適当な塩基（例えば水素化ナトリウム、ｔ−ブトキシカリウム等）の存在下、不活性溶媒（好ましくはジメチルホルムアミドなどのアミド類やテトラヒドロフラン）中で４−ブロモ−２，２−ジフェニルブチロニトリルと２０〜１２０℃で反応させ、続いて、Ｂｏｃ基を除去して化合物（１３）とした。更にこれを水又は不活性溶媒（好ましくはジオキサン、塩化メチレン等）中でＮ，Ｎ−ジエチルヒドロキシルアミンと ２０〜１１０℃で反応させることによりＲＣ２を合成した。
化合物（ＲＣ３）および化合物（ＲＣ５）はスキーム２に示す方法で合成することができる。
市販のジフェニルアセトニトリル（１４）に既知の方法で合成したクロロエチルジベンジルアミンを塩基（例えば水素化ナトリウム、ｔ−ブトキシカリウム等）の存在下で、不活性溶媒（好ましくはジメチルホルムアミド、テトラヒドロフラン等）中で０〜８０℃で１〜２４時間反応させ化合物（１５）とした。次いで無機塩基（例えば水酸化カリウム、水酸化ナトリウム等）あるいは酸（例えば硫酸等）と無溶媒又は適当な溶媒（例えば酢酸、イソプロパノール等）中で２０〜１６０℃で、１〜６０時間反応させ化合物（１６）とし、更にこれを接触水素添加による還元、即ち、不活性溶媒（例えばエタノール、メタノール、ジメチルホルムアミド、酢酸エチル等）中、適当な触媒（例えば、パラジウム炭素、水酸化パラジウム炭素等）の存在下、２０〜８０℃、１０１〜４９０ｋＰａで水素添加することにより、化合物（１７）とした。これをクロログリオキシル酸エステルでアシル化後、炭酸ナトリウム水溶液で加水分解することにより化合物（ＲＣ５）を得た。
一方、化合物（１７）をｔ−ブトキシカルボニルグリシンあるいはベンジルオキシカルボニルグリシンと適当な縮合剤（例えば、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（ＥＤＣ）、シアノホスホン酸ジエチル（ＤＥＰＣ）等）と適当な溶媒（例えばジメチルホルムアミド、塩化メチレン等）中で、有機塩基（例えばトリエチルアミン等）存在下、−５〜５０℃で０．５〜２４時間反応させることにより化合物（１８）とした。更にこれを公知の方法でカルバメート基を脱保護した後、アセチル化することによりＲＣ３を合成した。
化合物（ＲＣ４）と化合物（ＲＣ１１）はスキーム３に示す方法で合成することができる。
このうち化合物（ＲＣ４）は次の二つの方法で合成できる。
公知（特開平７−２１５９４３）の４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブタンアミド（３、Ｘ＝Ｈ）にＮ−ハロゲンこはく酸イミド（例えば、Ｎ−ブロモこはく酸イミド（ＮＢＳ）、Ｎ−クロロこはく酸イミド（ＮＣＳ）等）を含水ジメチルホルムアミド中で、−５℃〜４０℃で１〜８時間反応させて化合物（１９）とし、この化合物をアンモニア水と含水テトラヒドロフラン中で−５〜４０℃で０．５〜２４時間反応させることによりＲＣ４を合成した。また、上述の化合物（１７）にオキサミド酸を適当な縮合剤（例えばＥＤＣ、１，１’−カルボニルジイミダゾール（ＣＤＩ）等）あるいは活性エステル化剤（例えば１−ヒドロキシベンゾトリアゾール（ＨＯＢｔ）との組み合わせ等）と不活性溶媒（好ましくは塩化メチレン、テトラヒドロフラン等）中、０〜４０℃で１〜２４時間反応させてＲＣ４を合成した。
化合物（ＲＣ１１）は化合物（１７）に既知の方法で合成したＳ−ベンジルチオアセトイミデート臭化水素酸塩を適当な溶媒（好ましくはエタノールなどのアルコール類）中で、−５〜４０℃で０．５〜２４時間反応させ、合成した。
化合物（ＲＣ８）はスキーム４に示す方法で合成することができる。
既知の方法で合成できる化合物（２０）にクロロエチルジベンジルアミンを塩基（例えば水素化ナトリウム、ｔ−ブトキシカリウム等）を用いて不活性溶媒（好ましくはジメチルホルムアミド、テトラヒドロフラン等）中で、−２０℃〜８０℃で１〜８時間反応させて化合物（２１）とした。これを、無機塩基（例えば水酸化カリウム、水酸化ナトリウム等）あるいは酸（例えば硫酸等）と無溶媒あるいは適当な溶媒（例えば酢酸、エタノール、イソプロパノール等）中で２０〜１６０℃で、１〜６０時間反応させ化合物（２２）とし、これを接触水素添加による還元、即ち、適当な溶媒（例えばエタノール、メタノール、ジメチルホルムアミド、酢酸エチル等）中、適当な触媒（例えば、パラジウム炭素、水酸化パラジウム炭素等）の存在下、２０〜８０℃、１０１〜４９０３ｋＰａで水素添加することにより、化合物（２３）とした。次いで、これをクロログリオキシル酸エチルと有機塩基（例えばトリエチルアミン、Ｎ−メチルモルホリン等）の存在下で、不活性溶媒（好ましくは塩化メチレン、ジメチルホルムアミド等）中、−７８〜３０℃で反応させ、化合物（２４）とし、これをアンモニア水と不活性溶媒（好ましくはジオキサン、テトラヒドロフランなどのエーテル類）中、−５〜３０℃で０．５〜２時間反応させ化合物（２５）とした。更にこれを三臭化ホウ素と不活性溶媒（好ましくは塩化メチレン、テトラヒドロフラン等）中、−７８〜４０℃で１〜２４時間反応させＲＣ８を合成した。
化合物（ＲＣ７）はスキーム５および６に示す２つの方法で合成することができる。
（方法１）
既知の方法で合成できる化合物（２６）をｐ−メトキシベンジル化し化合物（２７）とした。これを還元剤（例えばジイソブチルアルミニウムヒドリド、リチウムアルミニウムヒドリド等）と不活性溶媒（好ましくはトルエン、塩化メチレン、エーテル等）中で、−７８〜３０℃で０．５〜２４時間反応させて化合物（２８）とした。化合物（２８）をアルコールのカルボン酸へ酸化する方法（好ましくはアセトン中でクロム酸−硫酸、あるいはジメチルホルムアミド中でＰＤＣによる酸化方法）で酸化し、続いて生成するカルボキシル基をエステル化して化合物（２９）とし、次いでｐ−メトキシベンジル基を除去した後、ベンゾイル化して化合物（３１）とした。これに無水酢酸と硫酸を不活性溶媒（好ましくはアセトン、テトラヒドロフラン等）中で、−５〜５０℃で０．５〜２４時間反応させ化合物（３２）とした。化合物（３２）をメタノール、テトラヒドロフランあるいはその混合溶媒等中で、−５〜３０℃でアンモニア水と０．５〜２４時間反応させ化合物（３３）とした。更にこの１位のアルコール基をハロゲンに変換方法（好ましくはトリフェニルホスフィン／四臭化炭素、あるいは三臭化りん塩化メチレン／テトラヒドロフラン等を用い、−５〜５０℃で０．５〜２４時間反応）により化合物（３４）とした。これと化合物（３、Ｘ＝Ｈ）を不活性溶媒（好ましくはトルエン、キシレン、ジオキサン、クロロホルム等）中で、２０〜１５０℃で１〜２４時間反応させ化合物（３５）とした。これに塩化第一鉄を塩化メチレン中、０〜５０℃で０．５〜２４時間反応させた後、続いて、水酸化ナトリウムと不活性溶媒（好ましくは水、メタノール、エタノール或はその混合溶媒）中で、０〜４０℃で０．５〜２４時間反応させ、ＲＣ７を合成した。
（方法２）
既知の方法で合成できる化合物（３６）にメタンスルホン酸と不活性溶媒（好ましくは塩化メチレン、テトラヒドロフラン）中で、０〜５０℃で０．５〜６時間反応させ化合物（３７）とし、これと化合物（３、Ｘ＝Ｈ）を不活性溶媒（好ましくはトルエン、キシレン、ジオキサン、クロロホルム等）中で、１〜２４時間反応させ化合物（３８）とした。これを無機塩基水溶液（例えば水酸化ナトリウム水溶液、炭酸カリウム水溶液、炭酸水素ナトリウム水溶液等）中で、−５０〜４０℃で１〜２４時間反応させ、ＲＣ７を合成した。
化合物（ＲＣ９）はスキーム７に示す方法で合成することができる。
化合物（３、Ｘ＝Ｈ）を塩酸中で２〜２４時間、加熱還流して化合物（３９）とし、このカルボキシル基を酸クロリドに変換後、既知の方法で合成できる化合物（４０）と有機塩基（例えばトリエチルアミン、Ｎ−メチルモルホリン等）存在下、不活性溶媒（好ましくは塩化メチレン、クロロホルム等のハロゲン化炭化水素）中で、０〜５０℃で０．５〜２４時間反応させ化合物（４１）とし、ついでエステル基をアルカリ加水分解、続いてベンジル基を接触水素化により除去して、ＲＣ９を合成した。
化合物（ＲＣ１０）はスキーム８に示す方法で合成することができる。
既知の方法で合成できる化合物（４２）と化合物（３、Ｘ＝Ｈ）を不活性溶媒（好ましくはトルエン、キシレン、ジオキサン等）中で、２０〜１５０℃で１〜２４時間反応させ化合物（４３）とした。これに塩化第一鉄を塩化メチレン中、０〜５０℃で０．５〜２４時間反応させた後、続いて、水酸化ナトリウムと不活性溶媒（好ましくは水、メタノール、エタノール或はその混合溶媒）中で、０〜４０℃で０．５〜２４時間反応させ、ＲＣ１０を合成した。
化合物（ＲＣ１２）はスキーム９に示す方法で合成することができる。
化合物（１６）を接触水素添加による還元、即ち、不活性溶媒（例えばエタノール、メタノール、ジメチルホルムアミド、酢酸エチル等）中、適当な触媒（例えば、パラジウム炭素、水酸化パラジウム炭素等）の存在下、２０〜８０℃、１０１〜４９０ｋＰａで水素添加することにより、化合物（１７）とし、精製することなくこれを適当な溶媒（例えば塩化メチレン、クロロホルム等）中で、有機塩基（例えばトリエチルアミン等）存在下塩化アセチルと−５〜５０℃で１〜４８時間反応させることにより化合物（４４）とした。次にこれを適当な溶媒（例えばベンゼン、トルエン、クロロホルム等）中で、有機塩基（例えばトリエチルアミン等）存在下塩化クロロアセチルと室温〜溶媒の還流温度で１〜１０時間反応させることにより化合物（４５）とした。次にこれを適当な非極性溶媒（例えばジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド等）中でアジ化ナトリウムと−５〜５０℃で１０分〜２時間反応させることにより化合物（４６）とした。さらにこれを適当な溶媒（例えばベンゼン、トルエン、クロロホルム等）中でトリアルキルホスフィンやトリアリールホスフィン（例えばトリ−ｎ−ブチルホスフィン、トリフェニルホスフィン等）と−２０〜５０℃で１〜２４時間反応させることにより化合物（ＲＣ１２）を得た。
化合物（ＲＣ１３）はスキーム１０に示す方法で合成することができる。
公知（特開平７−２１５９４３）の４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブチルアミド（３，Ｘ＝Ｈ）を不活性溶媒（例えばエタノール、メタノール、ジメチルホルムアミド、酢酸エチル等、アセトニトリル、塩化メチレン、クロロホルム）中、テトラフェニルポルフィリンマンガンクロリド（又はテトラフェニルポルフィリン鉄クロリド）およびヨードソベンゼンの存在下、０〜８０℃で６〜４８時間反応させることにより化合物（ＲＣ１３）を得た。
発明を実施するための最良の形態
次に本発明を具体例によって説明するが、これらの例によって本発明が限定されるものではない。
＜実施例１＞
４−（２−メチル−４，５−ジオキソ−１，３−イミダゾリジン−１−イル）−２，２−ジフェニルブタンアミド（ＲＣ２）
〔１〕Ｎ−（１−アミノエチル）ベンズアミド塩酸塩（８）
ビス（トリフルオロアセトキシ）ヨードベンゼン（２０５．１ｇ，４６２ｍｍｏｌ）のアセトニトリル／精製水（１：１）混液（２１００ｍＬ）溶液にＮ−ベンゾイル−ｄｌ−アラニンアミド（８０．７ｇ，４２０ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液にエーテル（２０００ｍＬ）を加え、分離する水層を分取した。有機層を１ｍｏｌ／Ｌ塩酸（４２０ｍＬ×２，２１０ｍＬ）で抽出した後、水層を合わせ減圧濃縮した。残渣をエーテル／エタノール（９：１）混液（１０００ｍＬ）で懸濁洗浄し、５０℃で減圧乾燥後、白色粉末のＮ−（１−アミノエチル）ベンズアミド塩酸塩を４８．８ｇ（５８％）得た。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δ：１．５３（３Ｈ，ｄ，Ｊ＝６．４Ｈｚ），５．１８（１Ｈ，ｂｒ），７．４８−７．６０（３Ｈ，ｍ），７．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．５０（３Ｈ，ｂｒ），９．３４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ）．
ＥＩ−ＭＳ（ｍ／ｚ）：１６４（Ｍ＋），１０５．
〔２〕Ｎ−［（１−クロロアセチルアミノ）エチル］ベンズアミド
Ｎ−（１−アミノエチル）ベンズアミド塩酸塩（４７．２ｇ，２３５ｍｍｏｌ）の無水ジメチルホルムアミド（２３５ｍＬ）懸濁溶液に、氷水冷却下でジイソプロピルエチルアミン（９８．２ｍＬ，５６４ｍｍｏｌ）を加え、１時間撹拌した。混合物に内温５−７℃でクロルアセチルクロリド（２２．４ｍＬ，２８２ｍｍｏｌ）を３０分間で滴下し、同温で２時間撹拌した。反応液を減圧濃縮し、得られた残渣を塩化メチレン（１５００ｍＬ）に溶解した。塩化メチレン溶液を水洗後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をエーテルで懸濁洗浄した後、７０℃で減圧乾燥し、褐色粉末のＮ−［（１−クロロアセチルアミノ）エチル］ベンズアミドを２９．８ｇ（５３％）得た。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δ：１．３７（３Ｈ，ｄ，Ｊ＝６．８Ｈｚ），４．０７（２Ｈ，ｑ，Ｊ＝１３．２Ｈｚ），５．６２−５．７１（１Ｈ，ｍ），７．４４−７．５５（３Ｈ，ｍ），７．８３−７．８５（２Ｈ，ｍ），８．４７（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．７０（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ）．
ＦＡＢ−ＭＳ（ｍ／ｚ）：２４１［Ｍ＋Ｈ］＋．
〔３〕１−ベンゾイル−２−メチル−１，３−イミダゾリジン−４−オン（９） Ｎ−［（１−クロロアセチルアミノ）エチル］ベンズアミド（２８．９ｇ，１２０ｍｍｏｌ）の無水ジメチルホルムアミド（１２００ｍＬ）溶液に、氷水冷却下で水素化ナトリウム（１４．４ｇ，３６０ｍｍｏｌ）を加え、４時間撹拌した。反応液に酢酸（３０ｍＬ）を加え室温に戻し０．５時間撹拌した後、一夜放置した。反応液を減圧濃縮し、得られた残渣を塩化メチレン（３００ｍＬ）と精製水（１００ｍＬ）に溶解した。塩化メチレン層を分取し、水層を塩化メチレン（１００ｍＬ×４）で抽出した。塩化メチレン層を合わせ、飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を減圧濃縮した。残留物にエーテル（３００ｍＬ）を加え、析出した結晶をろ取し、７０℃で減圧乾燥後、褐色粉末の１−ベンゾイル−２−メチル−１，３−イミダゾリジン−４−オンを２０．６ｇ（８４％）得た。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，９０ＭＨｚ）δ：１．３５（３Ｈ，ｂｒ），３．６２−４．２９（２Ｈ，ｍ），５．４４（１Ｈ，ｑ，Ｊ＝５．１Ｈｚ，），７．４４−７．６２（５Ｈ，ｍ），８．７３（１Ｈ，ｂｒ）．
ＥＩ−ＭＳ（ｍ／ｚ）：２０４（Ｍ＋），１０５．
〔４〕１−ベンゾイル−３−ｔ−ブトキシカルボニル−２−メチル−１，３−イミダゾリジン−４−オン（１０）
１−ベンゾイル−２−メチル−１，３−イミダゾリジン−４−オン（１９．８ｇ，９７．０ｍｍｏｌ）とｔ−ブチルジカーボネート（２３．３ｇ，１０６．７ｍｍｏｌ）の無水アセトニトリル（４８５ｍＬ）溶液に、室温で４，４−ジメチルアミノピリジン（５９３ｍｇ，４．８５ｍｍｏｌ）を加え、１時間撹拌した。反応液を減圧濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝２：１で溶出した。溶媒を留去し、得られた残渣を石油エーテル（５０ｍＬ）で懸濁洗浄し、５０℃で減圧乾燥後、白色粉末の１−ベンゾイル−３−ｔ−ブトキシカルボニル−２−メチル−１，３−イミダゾリジン−４−オンを２０．０ｇ（６８％）得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：１．５７−１．６６（１２Ｈ，ｍ），４．０５−４．２８（２Ｈ，ｍ），６．２４（１Ｈ，ｂｒ），７．４４−７．５２（５Ｈ，ｍ）．
ＦＡＢ−ＭＳ（ｍ／ｚ）：３０５［Ｍ＋Ｈ］＋．
〔５〕１−ベンゾイル−３−ｔ−ブトキシカルボニル−２−メチル−１，３−イミダゾリジン−４，５−ジオン（１１）
１−ベンゾイル−３−ｔ−ブトキシカルボニル−２−メチル−１，３−イミダゾリジン−４−オン（１９．２ｇ，６３．０ｍｍｏｌ）とＮ−ブロモこはく酸イミド（１２．３ｇ，６９．３ｍｍｏｌ）の四塩化炭素（３１５ｍＬ）懸濁溶液に、過酸化ベンゾイル（１０．０ｍｇ）を加え、０．５時間加熱還流した。反応液を飽和炭酸水素ナトリウム水溶液（２００ｍＬ）、飽和亜硫酸水素ナトリウム水溶液（２００ｍＬ）、精製水（２００ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物を塩化メチレン（３１５ｍＬ）に溶解し、重クロム酸ピリジニウム（４７．４ｇ，１２６ｍｍｏｌ）を加え室温で２０時間撹拌した。不溶物をセライトパッドを用い除去した後、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝２：１で溶出した。溶媒を濃縮し、得られた残渣をｎ−ペンタン（３０ｍＬ）で懸濁洗浄した後、５０℃で減圧乾燥し、白色粉末の１−ベンゾイル−３−ｔ−ブトキシカルボニル−２−メチル−１，３−イミダゾリジン−４，５−ジオンを１０．１ｇ（５０％）得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：１．６２（９Ｈ，ｓ），１．７８（３Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．０７（１Ｈ，ｑ，Ｊ＝５．９Ｈｚ），７．４６−７．５０（２Ｈ，ｍ），７．６２−７．６６（１Ｈ，ｍ），７．６９−７．７１（２Ｈ，ｍ）．
ＦＡＢ−ＭＳ（ｍ／ｚ）：３１９［Ｍ＋Ｈ］＋．
〔６〕３−ｔ−ブトキシカルボニル−２−メチル−１，３−イミダゾリジン−４，５−ジオン（１２）
１−ベンゾイル−３−ｔ−ブトキシカルボニル−２−メチル−１，３−イミダゾリジン−４，５−ジオン（９．８７ｇ，３１．０ｍｍｏｌ）の無水アセトニトリル（１５５０ｍＬ）溶液に、氷水冷却下でｎ−ブチルアミン（２．２７ｇ，３１．０ｍｍｏｌ）の無水アセトニトリル（１５５ｍＬ）溶液を２時間で滴下した。反応液を減圧濃縮し、得られた残渣をエーテル（３０ｍＬ）で懸濁洗浄した後、３０℃で減圧乾燥し、白色粉末の３−ｔ−ブトキシカルボニル−２−メチル−１，３−イミダゾリジン−４，５−ジオンを６．０７ｇ（９１％）得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：１．５９（９Ｈ，ｓ），１．６６（３Ｈ，ｄ，Ｊ＝５．９Ｈｚ），５．３８（１Ｈ，ｑ，Ｊ＝５．９Ｈｚ，），９．３７（１Ｈ，ｂｒ ｓ）．
ＦＡＢ−ＭＳ（ｍ／ｚ）：２１３［Ｍ−Ｈ］−．
〔７〕４−（２−メチル−４，５−ジオキソ−１，３−イミダゾリジン−１−イル）−２，２−ジフェニルブチロニトリル（１３）
３−ｔ−ブトキシカルボニル−２−メチル−１，３−イミダゾリジン−４，５−ジオン（６．００ｇ，２８．０ｍｍｏｌ）の無水ジメチルホルムアミド（５６０ｍＬ）溶液に、氷水冷却下で水素化ナトリウム（１．３４ｇ，３３．６ｍｍｏｌ）を加え０．５時間で撹拌した後、室温に戻し１時間撹拌した。混合物に４−ブロモ−２，２−ジフェニルブチロニトリル（８４．１ｇ，２８０ｍｍｏｌ）を加え、８０℃で２時間撹拌した。反応液を減圧濃縮し、残留物を酢酸エチル（５００ｍＬ）に溶解した。酢酸エチル層を水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物を塩化メチレン（２８０ｍＬ）に溶解し、氷水冷却下、トリフルオロ酢酸（１００ｍＬ）を加え室温に戻し４時間撹拌した。反応液を減圧濃縮し、得られた残渣を塩化メチレン（５００ｍＬ）に溶解した。塩化メチレン層を飽和炭酸水素ナトリウム水溶液（２００ｍＬ×２）、精製水（１００ｍＬ）で順次洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残渣をエーテル（３００ｍＬ）で懸濁洗浄した後、５０℃で減圧乾燥し、白色粉末の４−（２−メチル−４，５−ジオキソ−１，３−イミダゾリジン−１−イル）−２，２−ジフェニルブチロニトリルを６．５３ｇ（７０％）得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：１．４５（３Ｈ，ｄ，Ｊ＝５．９Ｈｚ），２．６６−２．７４（１Ｈ，ｍ），２．８２−２．９０（１Ｈ，ｍ），３．３８−３．４５（１Ｈ，ｍ），３．７０−３．７７（１Ｈ，ｍ），４．９０（１Ｈ，ｑ，Ｊ＝５．９Ｈｚ），７．３０−７．４５（１０Ｈ，ｍ），９．００（１Ｈ，ｂｒ ｓ）．
ＥＩ−ＭＳ（ｍ／ｚ）：３３３（Ｍ＋），１９２，１６５．
〔８〕４−（２−メチル−４，５−ジオキソ−１，３−イミダゾリジン−１−イル）−２，２−ジフェニルブタンアミド（ＲＣ２）
４−（２−メチル−４，５−ジオキソ−１，３−イミダゾリジン−１−イル）−２，２−ジフェニルブチロニトリル（６．３３ｇ，１９．０ｍｍｏｌ）の無水ジオキサン（３１７ｍＬ）懸濁溶液に、Ｎ，Ｎ−ジエチルヒドロキシルアミン（１００ｍＬ，９５０ｍｍｏｌ）を加え、１００℃で９６時間撹拌した。反応液を減圧濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィーに付し、塩化メチレン：メタノール＝２０：１で溶出した。溶媒を留去し、得られた残留物をクロロホルム（３０ｍＬ）に溶解し、室温で０．５時間撹拌した後、析出した固体をろ取した。固体をクロロホルム−アセトン（４：１）混液（２００ｍＬ）から再結晶し、８０℃〜１００℃で減圧乾燥後、室温で１４時間放置し、白色粉末の目的化合物を３．９０ｇ（５８％）得た。
ｍｐ．２０３〜２０４℃
ＩＲ（ＫＢｒ）ｃｍ−１：３２３６，１７４７，１６６６．
Ａｎａｌ．ｃａｌｃｄ Ｃ２０Ｈ２１Ｎ３Ｏ３・０．３Ｈ２Ｏ：Ｃ，６７．３２；Ｈ，６．１０；Ｎ，１１．７８．
Ｆｏｕｎｄ：Ｃ，６７．１３；Ｈ，５．９９；Ｎ，１１．９６．
ＥＩ−ＭＳ（ｍ／ｚ）：１９３（Ｂａｓｅ ｐｅａｋ），２１１，３５１［Ｍ］＋．
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δ：１．１８（３Ｈ，ｄ，Ｊ＝５．９Ｈｚ），２．３８（１Ｈ，ｄｄｄ，Ｊ＝５．４，１２．７，１７．６Ｈｚ），２．６８（１Ｈ，ｄｄｄ，Ｊ＝３．９，１２．７，１６．９Ｈｚ），２．７８−２．８５（１Ｈ，ｍ），３．２６（１Ｈ，ｄｄｄ，Ｊ＝５．４，１３．２，１７．６Ｈｚ），４．９５（１Ｈ，ｑ，Ｊ＝５．９Ｈｚ），６．８７（１Ｈ，ｂｒ ｓ），７．２４−７．３６（１１Ｈ，ｍ），９．８０（１Ｈ，ｂｒ ｓ）．水分測定（カールフィシャー法）：１．４７％
＜実施例２＞
Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド酸（ＲＣ５）
〔１〕Ｎ−（２−クロロエチル）ジベンジルアミン
Ｎ−（２−クロロエチル）ジベンジルアミン塩酸塩（２３．７ｇ，８０．０ｍｍｏｌ）に１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１２０ｍＬ）を加え、室温で１０分間撹拌した。混合物を酢酸エチル（１００ｍＬ、５０ｍＬ）で抽出し、酢酸エチル層を合わせ飽和食塩水（５０ｍＬ）で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物を真空ポンプで乾燥し、淡黄色油状物のＮ−（２−クロロエチル）ジベンジルアミンを２０．８ｇ（定量的）得た。
１Ｈ−ＮＭＲ（９０ＭＨｚ，ＣＤＣｌ３）δ：２．８３（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．４９（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．６６（４Ｈ，ｓ），７．２３−７．３９（１０Ｈ，ｍ）．
〔２〕４−ジベンジルアミノ−２，２−ジフェニルブチロニトリル（１５）
ジフェニルアセトニトリル（１１．６ｇ，６０．０ｍｍｏｌ）の無水ジメチルホルムアミド６０ｍＬ溶液に、水素化ナトリウム（２．８８ｇ，７２．０ｍｍｏｌ）を加え室温で１時間撹拌した。混合物にＮ−（２−クロロエチル）ジベンジルアミン（２０．８ｇ）を加え、室温で４時間続いて５０℃で４時間撹拌した後、室温に戻し一夜放置した。反応液を減圧濃縮し、得られた残留物を酢酸エチル（１００ｍＬ）と水（５０ｍＬ）に溶解した。酢酸エチル層を分取し、水（５０ｍＬ）で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝１５：１で溶出した。溶媒を留去して、黄色油状物の４−ジベンジルアミノ−２，２−ジフェニルブチロニトリルを２１．１ｇ（８４％）得た。
ＥＩ−ＭＳ（ｍ／ｚ）：９１（Ｂａｓｅ Ｐｅａｋ），２１０，４１６（Ｍ＋）．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．４８−２．５５（２Ｈ，ｍ），２．５７−２．６６（２Ｈ，ｍ），３．５８（４Ｈ，ｓ），７．２０−７．３４（２０Ｈ，ｍ）．
〔３〕４−ジベンジルアミノ−２，２−ジフェニルブタンアミド（１６）
４−ジベンジルアミノ−２，２−ジフェニルブチロニトリル（２０．８ｇ，５０．０ｍｍｏｌ）のイソプロパノール（１０４ｍＬ）溶液に、水酸化カリウム（１９．６ｇ，３５０ｍｍｏｌ）を加え３３時間加熱還流した後、室温に戻し４日放置した。反応液を氷水（２００ｍＬ）に注ぎ、１０分間撹拌した後、混合物を酢酸エチル（３００ｍＬ）で抽出した。酢酸エチル層を水洗（５０ｍＬ）した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝３：１で溶出した。溶媒を留去し、得られた残渣をジイソプロピルエーテル（５０ｍＬ）で懸濁洗浄した後、５０℃で減圧乾燥し白色粉末の４−ジベンジルアミノ−２，２−ジフェニルブタンアミドを１５．６ｇ（７２％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：４３５［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ：２．０５−２．０９（２Ｈ，ｍ），２．５４−２．５８（２Ｈ，ｍ），３．４６（４Ｈ，ｓ），６．９３と７．０８（ｅａｃｈ １Ｈ，ｓ），７．１１−７．２９（２０Ｈ，ｍ）．
〔４〕４−アミノ−２，２−ジフェニルブタンアミド（１７）
中圧還元装置を用い、４−ジベンジルアミノ−２，２−ジフェニルブタンアミド（１４．８ｇ，３４．０ｍｍｏｌ）の酢酸エチル−エタノール（１：１）混液（５９２ｍＬ）溶液に、２０％水酸化パラジウム−炭素（２．９６ｇ）を加え、水素圧（４１２ｋＰａ）下、４０℃で７時間水素添加した。触媒をろ別した後、反応液を減圧濃縮し、得られた残渣を酢酸エチル（２００ｍＬ）に溶解した。酢酸エチル溶液を１ｍｏｌ／Ｌ塩酸（５０ｍＬ×２）で抽出し、抽出した塩酸層に１ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加えｐＨ＝９．０とした後、酢酸エチル（２００ｍＬ×３）で抽出した。酢酸エチル溶液を合わせ、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残渣をｎ−ヘキサン−酢酸エチル（３：１）混液（２００ｍＬ）で懸濁洗浄し、５０℃で減圧乾燥した後、白色粉末の４−アミノ−２，２−ジフェニルブタンアミドを５．６７ｇ（６６％）得た。
ＥＩ−ＭＳ（ｍ／ｚ）：１９３，２３７（ＢＰ），２５４（Ｍ）＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ：１．３７（２Ｈ，ｂｒ），２．１８−２．２２（２Ｈ，ｍ），２．３３−２．３７（２Ｈ，ｍ），７．１１（１Ｈ，ｓ），７．１８−７．３１（１１Ｈ，ｍ）．
〔５〕Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミン酸エチル
４−アミノ−２，２−ジフェニルブタンアミド（６．７７ｇ，２６．６ｍｍｏｌ）を塩化メチレン（２００ｍＬ）に溶かし、氷水冷却下、トリエチルアミン（３．００ｇ，２９．６ｍｍｏｌ）を加えた後、クロログリオキシル酸エチル（４．００ｇ，２９．３ｍｍｏｌ）を滴下した．室温で１０分間撹拌後、反応液に塩化メチレン（２００ｍＬ）を加え、水（２００ｍＬ）、飽和炭酸水素ナトリウム水溶液（２００ｍＬ）で順次洗浄した。水層を順次塩化メチレン（２００ｍＬ）で抽出した。塩化メチレン層を合一し、無水硫酸ナトリウムで乾燥した後、溶媒を減圧留去した。残渣をエタノール（１０ｍＬ）で洗浄し、白色結晶のＮ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミン酸エチルを７．２９ｇ（６７％）得た。
ｍｐ．２０３〜２０６℃
ＦＡＢ−ＭＳ（ｍ／ｚ）：３５５［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：１．３６（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．６９（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．２１（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），４．３１（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），５．７０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２６−７．３８（１０Ｈ，ｍ），７．９６（１Ｈ，ｂｒ ｓ）．
〔６〕Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミン酸（ＲＣ５）
Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミン酸エチル（１０．６ｇ，３０．０ｍｍｏｌ）をエタノール（５００ｍＬ）に懸濁し、１０％炭酸ナトリウム水溶液（１０６ｍＬ）を加え、撹拌しながら４時間加熱還流した。反応液を減圧濃縮し、得られた残渣に精製水（８００ｍＬ）を加え溶解した後、不溶物をろ過し、ろ液を塩化メチレン（４００ｍＬ）、及び酢酸エチル（４００ｍＬ）で順次洗浄した。水層に氷水冷却下２ｍｏｌ／Ｌ塩酸（１２０ｍＬ）を滴下し中和して、析出した結晶をろ取した。この結晶をエタノール（３００ｍＬ）で再結晶し、１００℃で減圧乾燥して白色結晶の目的化合物６．１６ｇ（６３％）を得た。
ｍｐ．１９３〜１９５℃（ｄｅｃ．）
ＩＲ（ＫＢｒ）ｃｍ−１：３４２８，３３１９，３２５１，１７５９，１６５４，１１５９，７０１．
Ａｎａｌ．Ｃａｌｃｄ Ｃ１８Ｈ１８Ｎ２Ｏ４：Ｃ，６６．２５；Ｈ，５．５６；Ｎ，８．５８．
Ｆｏｕｎｄ：Ｃ，６６．０７；Ｈ，５．５８；Ｎ，８．６４．
ＦＡＢ−ＭＳ（ｍ／ｚ）：３２７［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δ：２．４７−２．５１（２Ｈ，ｍ），２．７８−２．８３（２Ｈ，ｍ），６．９５（１Ｈ，ｓ），７．２３−７．３７（１１Ｈ，ｍ），８．８１（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），１３．７７（１Ｈ，ｂｒ ｓ）．
＜実施例３＞
２−アセチルアミノ−Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）アセトアミド（ＲＣ３）
〔１〕２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）アセトアミド
４−アミノ−２，２−ジフェニルブタンアミド（１７）（２．５４ｇ，１０．０ｍｍｏｌ）、ｔｅｒｔ−ブトキシカルボニルグリシン（１．７５ｇ，１０．０ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール・１水和物（１．３５ｇ，１０．０ｍｍｏｌ）の塩化メチレン（５０ｍＬ）溶液に１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（１．９２ｇ，１０．０ｍｍｏｌ）及びトリエチルアミン（２．０２ｇ，２０．０ｍｍｏｌ）を加えて１０分間撹拌した後、室温で１５．５時聞放置した。反応液に酢酸エチル（５００ｍＬ）を加え、０．５ｍｏｌ／Ｌ水酸化ナトリウム水溶液（２００ｍＬ×２）、１ｍｏｌ／Ｌ塩酸（２００ｍＬ）、水（２００ｍＬ）、飽和塩化ナトリウム水溶液（２００ｍＬ）で順次洗浄した。水層を順次酢酸エチル（５００ｍＬ）で抽出した後、酢酸エチル層を合一し、無水硫酸ナトリウムで乾燥した後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーに付し、塩化メチレン→塩化メチレン：メタノール（２０：１）で溶出した。目的の分画を減圧留去し、残留物をエタノール（２０ｍＬ）に溶かし、析出した結晶をろ取し、８０℃で減圧乾燥して白色の結晶の２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）アセトアミドを２．７９ｇ（６８％）得た。
ｍｐ１８７〜１９０℃（ｄｅｃ．）．
Ａｎａｌ．Ｃａｌｃｄ Ｃ２３Ｈ２９Ｎ３Ｏ４：Ｃ，６７．１３；Ｈ，７．１０；Ｎ，１０．２１．
Ｆｏｕｎｄ：Ｃ，６７．０５；Ｈ，７．２０；Ｎ，１０．２９．
ＦＡＢ−ＭＳ（ｍ／ｚ）：４１２［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δ：１．３７（９Ｈ，ｓ），２．４０−２．４４（２Ｈ，ｍ），２．６８−２．７３（２Ｈ，ｍ），３．４５（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．８８（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．０３（１Ｈ，ｂｒ ｓ），７．２２（１Ｈ，ｂｒ ｓ），７．２２−７．３４（１０Ｈ，ｍ），７．７９（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ）．
〔２〕２−アセチルアミノ−Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）アセトアミド（ＲＣ３）
２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）アセトアミド（２．７４ｇ，６．６６ｍｍｏｌ）にトリフルオロ酢酸（７．６０ｇ，６６．７ｍｍｏｌ）を加えて溶解した後、溶媒を減圧留去した。残留物を塩化メチレン（５０ｍＬ）に溶解し、トリエチルアミン（３．０３ｇ，２９．９ｍｍｏｌ）及び無水酢酸（２．０４ｇ，２０．０ｍｍｏｌ）を加えた後、溶媒を減圧留去した。残留物を塩化メチレン（２００ｍＬ）に溶かし、飽和炭酸水素ナトリウム水溶液（２００ｍＬ）で洗浄した。分液中に析出した結晶をろ取し、ろ液の塩化メチレン層を分取した。水層を塩化メチレン（２００ｍＬ）で抽出し、塩化メチレン層を合一し、無水硫酸ナトリウムで乾燥した後、溶媒を減圧留去した。残渣と先にろ取した結晶を合一して塩化メチレン（４００ｍＬ）に加熱溶解し、シリカゲルカラムクロマトグラフィーに付し、塩化メチレン→塩化メチレン：メタノール（２０：１）で溶出した。目的の分画を減圧留去し、得られた粗結晶（２．０８ｇ）をメタノール（５０ｍＬ）に溶解した。析出した結晶をろ取し、８０℃で減圧乾燥してメタノール含有結晶を１．８５ｇ得た。この結晶をメタノール（５０ｍＬ）に加熱溶解し、ろ過した後、ろ液に精製水（３０ｍＬ）を加え、メタノールを減圧留去した後、析出した結晶をろ取し、１００℃で減圧乾燥して白色結晶の目的化合物を１．７３ｇ（９５％）得た。
ｍｐ．２２１〜２２４℃．
ＩＲ（ＫＢｒ）ｃｍ−１：３３３７，１６８３，１６６５，１６３１，１５３８．
Ａｎａｌ．Ｃａｌｃｄ Ｃ２０Ｈ２３Ｎ３Ｏ３：Ｃ，６７．９７；Ｈ，６．５６；Ｎ，１１．８９．
Ｆｏｕｎｄ：Ｃ，６７．８１；Ｈ，６．５４；Ｎ，１１．８４．
ＦＡＢ−ＭＳ（ｍ／ｚ）：３５４［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δ：１．８４（３Ｈ，ｓ），２．４０−２．４４（２Ｈ，ｍ），２．６７−２．７３（２Ｈ，ｍ），３．５８（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０３（１Ｈ，ｂｒ ｓ），７．２２（１Ｈ，ｂｒ ｓ），７．２３−７．３４（１０Ｈ，ｍ），７．８５（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），８．０４（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ）．
＜実施例４＞
２−アセチルアミノ−Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）アセトアミド（ＲＣ３）
４−アミノ−２，２−ジフェニルブタンアミド（１７）（５０９ｍｇ，２．０ｍｍｏｌ）、ベンジルオキシカルボニルグリシン（４１８ｍｇ，２．００ｍｍｏｌ）、ＨＯＢｔ・Ｈ２Ｏ（２７０ｍｇ，２．００ｍｍｍｏｌ）および塩化メチレン（１０ｍＬ）の溶液にＥＤＣ・ＨＣｌ（３８３ｍｇ，２．０ｍｍｏｌ）、トリエチルアミン（５５８μＬ，４．００ｍｍｏｌ）を加え、室温で８時間撹拌した後、一夜放置した。これに酢酸エチルを加え、有機層を１ｍｏｌ／Ｌの水酸化ナトリウム水溶液で２回、１ｍｏｌ／Ｌ塩酸水溶液で１回、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を留去して無色固体（８１０ｍｇ）を得た。これを、７．５％Ｐｄ−Ｃ（１６２ｍｇ）、ＴＨＦ（１６ｍＬ）、無水酢酸（１８９μＬ，２．００ｍｍｏｌ）の懸濁液を常温、常圧で６時間接触還元した。反応液にＤＭＦを加え、不溶物をろ別した後、ろ液を減圧濃縮し、得られた残渣を再びメタノールに溶解した後、セライトでろ過し、ろ液を減圧濃縮した。得られた残渣をエタノールから再結晶し、無色粉末（３６８ｍｇ）を得た。これをアセトニトリル（３６ｍＬ）に熱時懸濁洗浄し、目的化合物３２０ｍｇ（４７％）を得た。
ｍｐ．２１４〜２１５℃．
ＩＲ（ＫＢｒ，ｃｍ−１）；３４３２，１６８２，１６５５，１６３２．
Ａｎａｌ．Ｃａｌｃｄ Ｃ２０Ｈ２３Ｎ３Ｏ３：Ｃ，６７．９７；Ｈ，６．５６；Ｎ，１１．８９
Ｆｏｕｎｄ：Ｃ，６７．９５；Ｈ，６．６５；Ｎ，１１．８８．
ＦＡＢ−ＭＳ（ｍ／ｚ）；３５４（Ｍ＋Ｈ）＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；１．８４（３Ｈ，ｓ），２．４０−２．４４（２Ｈ，ｍ），２．６７−２．７３（２Ｈ，ｍ），３．５８（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．２３−７．３５（１０Ｈ，ｍ）．
１３Ｃ−ＮＭＲ（ＤＭＳＯ−ｄ６，４００ＭＨｚ）δ；２２．５１，３６．１７，３６．７８，４２．０２，５８．７２，１２６．４，１２７．８，１２８．７，１４３．２，１６９．０，１６９．５，１７５．０．
＜実施例５＞
Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド（ＲＣ４）
実施例２に記載した同様の方法により、４−ジベンジルアミノ−２，２−ジフェニルブタンアミド２．７ｇ（６．２１ｍｍｏｌ）から得られた粗製の４−アミノ−２，２−ジフェニルブタンアミド（１７）、オキサミド酸（０．５７ｇ）、１−ヒドロキシベンゾトリアゾール１水和物（１．７０ｇ）、トリエチルアミン（０．６５ｇ）のジメチルホルムアミド（３０ｍＬ）溶液を撹拌下、室温で１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド塩酸塩（１．２１ｇ）を加えた。２．５時間撹拌した後、室温で一夜放置した。反応液に水（１５０ｍＬ）を加え、酢酸エチルで２回抽出し、これを水洗後、無水硫酸ナトリウムで乾燥した。溶媒を留去し、得られた油状物をシリカゲルクロマトグラフィーに付し、酢酸エチルで溶出した。溶媒を留去し、得られたアモルファス状物質を少量のメタノールに溶かし、水を添加することにより再結晶化した。結晶をろ取し、１００℃で減圧乾燥した後、白色粉末の目的化合物０．７１ｇ（３５％）を得た。
ｍｐ．１７７．５〜１８０．０℃．
ＩＲ（ＫＢｒ，ｃｍ−１）；３４２４，３３６０，３３２８，３２７９，３１９１，１７２８，１６５５，１６２０．
Ａｎａｌ．Ｃａｌｃｄ Ｃ１８Ｈ１９Ｎ３Ｏ３：Ｃ，６６．４５；Ｈ，５．８９；Ｎ，１２．９１
Ｆｏｕｎｄ：Ｃ，６６．３４；Ｈ，５．８７；Ｎ，１２．８６．
ＦＡＢ−ＭＳ（ｍ／ｚ）：３２６［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；２．４７−２．５１（２Ｈ，ｍ），２．７８−２．８３（２Ｈ，ｍ），６．９９（１Ｈ，ｓ），７．２２−７．３２（６Ｈ，ｍ），７．７３（１Ｈ，ｓ），８．０２（１Ｈ、ｓ），８．７０（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ）．
１３Ｃ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；３６．２５，３６．３７，５８．６８，１２６．４２，１２７．８１，１２８．７１，１４３．１６，１６０．２４，１６２．０５，１７５．１１．
＜実施例６＞
Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド（ＲＣ４）
〔１〕Ｎ−アセチル−Ｎ’−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド（１９）
Ｎ−ブロモこはく酸イミド（１３．１ｇ，７３．６ｍｍｏｌ）のジメチルホルムアミド（１３０ｍＬ）溶液に精製水（１００ｍＬ）を加え２０分間氷水冷却下で撹拌した後、４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブタンアミド（３、Ｘ＝Ｈ、特開平７−２１５９４３）（７．０５ｇ，２２．１ｍｍｏｌ）を少量ずつ加え、その後、室温で４時間撹拌した。反応液に亜硫酸水素ナトリウム水溶液及び酢酸エチル（４００ｍＬ）を加え、水洗（２００ｍＬ×２回）し、水層を酢酸エチル（４００ｍＬ）で抽出した。酢酸エチル層を合一し、炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた油状物に酢酸エチルを加え結晶化させ析出固体をろ取し、粗生成物のＮ−アセチル−Ｎ’−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド（４．７０ｇ）を得た。これを塩化メチレン−酢酸エチルより再結晶し、無色綿状晶のＮ−アセチル−Ｎ’−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド３．３４ｇ（４１％）を得た。
ＥＩ−ＭＳ（ｍ／ｚ）：３６７（Ｍ＋）．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ；２．４７（３Ｈ，ｓ），２．７０（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．２１（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），５．４７（１Ｈ，ｂｒ），５．８１（１Ｈ，ｂｒ），７．２８−７．３９（１０Ｈ，ｍ），８．５６（１Ｈ，ｂｒ），９．５５（１Ｈ，ｂｒ）．
〔２〕Ｎ−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド（ＲＣ４）
Ｎ−アセチル−Ｎ’−（３−カルバモイル−３，３−ジフェニルプロピル）オキサミド（３．１３ｇ，８．５２ｍｍｏｌ）をジオキサン１００ｍＬに熱時溶解させ、室温放冷後２５％アンモニア水７ｍＬを加え１５時間放置した。反応液を減圧濃縮し、残渣をカラムクロマトグラフィーに付し、塩化メチレン：メタノール（１５：１）で溶出した。溶媒を留去し、得られた油状物にメタノールを加え結晶化させ粗結晶（２．１０ｇ）を得た。これをメタノール−水より再結晶し、１００℃で減圧乾燥して無色プリズム晶の目的化合物を１．４３ｇ（５２％）得た。
ｍｐ１８０−１８１℃．
ＩＲ（ＫＢｒ）ｃｍ−１：３４２４，３３６１，１６８０，１６５５．
Ａｎａｌ．ｃａｌｃｄ Ｃ１８Ｈ１９Ｎ３Ｏ３：Ｃ，６６．４５；Ｈ，５．８９；Ｎ，１２．９１
Ｆｏｕｎｄ：Ｃ，６６．３６；Ｈ，５．８４；Ｎ，１２．８４．
ＥＩ−ＭＳ（ｍ／ｚ）：３２５（Ｍ＋），２８１，２１１，１９３．
ＦＡＢ−ＭＳ（ｍ／ｚ）：３２６［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ；２．６８（２Ｈ，ｄｄ，Ｊ＝５．９，８．３Ｈｚ），３．２１（２Ｈ，ｄｔ，Ｊ＝８．３，５．９Ｈｚ），５．５６−５．６７（３Ｈ，ｂｒ），７．２３（１Ｈ，ｂｒ），７．２８−７．３９（１０Ｈ，ｍ），７．９３（１Ｈ，ｂｒ）．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；２．４７−２．５１（２Ｈ，ｍ），２．７８−２．８３（２Ｈ，ｍ），６．９８（１Ｈ，ｂｒ ｓ），７．２２−７．３４（１１Ｈ，ｍ），７．７３（１Ｈ，ｂｒ ｓ），８．０１（１Ｈ，ｂｒ ｓ），８．６９（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ）．
１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；３６．１，３６．３，５８．６，１２６．３，１２７．７，１２８．６，１４３．１，１６０．１，１６１．９，１７５．０．
＜実施例７＞
Ｎ−［３−カルバモイル−３−（４−ヒドロキシフェニル）−３−フェニルプロピル］オキサミド（ＲＣ８）
〔１〕４−ジベンジルアミノ−２−（４−メトキシフェニル）−２−フェニルブチロニトリル（２１）
塩酸Ｎ−（２−クロロエチル）ジベンジルアミン（６２．７ｇ，２１２ｍｍｏｌ）を精製水（５００ｍＬ）溶液に、水酸化ナトリウム（１７．８ｇ，４２７ｍｍｏｌ）を加えて中和した後、塩化メチレン（２５０ｍＬ）で２回抽出した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧濃縮し、油状物Ｎ−（２−クロロエチル）ジベンジルアミンを５４．０ｇ得た。
次に水素化ナトリウム（６．７７ｇ，１６９ｍｍｏｌ）を脱水エーテル（２０ｍＬ）で３回洗浄し、これに脱水ジメチルホルムアミド（２２１ｍＬ）を加え、水冷撹拌下、α−（４−メトキシフェニル）フェニルアセトニトリル（２０）（３１．５ｇ，１４１ｍｍｏｌ）を加え、３０分間撹拌した後、６０℃で１５分間撹拌した。再び水冷し、ヨウ化カリウム（２３．４ｇ，１４１ｍｍｏｌ）、ヨウ化テトラブチルアンモニウム（５．２１ｇ，１４．１ｍｍｏｌ）とＮ−（２−クロロエチル）ジベンジルアミン（５４．０ｇ）のジメチルホルムアミド（９４ｍＬ）溶液を滴下し、続いて反応液を６０℃で５時間撹拌した。反応液を氷冷し、酢酸（４ｍＬ）を加えた後、氷水３Ｌに注加し、酢酸エチル（１Ｌ、５００ｍＬ×２）で抽出した。有機層を水（１Ｌ）、飽和食塩水（１Ｌ）で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサン：塩化メチレン＝２：１→１：１で溶出した。目的の分画を減圧濃縮し、混合物の分画はを再度シリカゲルカラムクロマトグラフィーに付し、同様に精製した後、橙色油状物の４−ジベンジルアミノ−２−（４−メトキシフェニル）−２−フェニルブチロニトリル５９．３ｇ（９４％）を得た。
ＥＩ−ＭＳ（ｍ／ｚ）：４４６［Ｍ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ；２．４５−２．４９（２Ｈ，ｍ），２．５７−２．６２（２Ｈ，ｍ），３．５８（４Ｈ，ｓ），３．７７（３Ｈ，ｓ），６．７６（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．１１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．１９−７．３２（１５Ｈ，ｍ）．
〔２〕４−ジベンジルアミノ−２−（４−メトキシフェニル）−２−フェニルブタンアミド（２２）
イソプロピルアルコール（４１２ｍＬ）に４−ジベンジルアミノ−２−（４−メトキシフェニル）−２−フェニルブチロニトリル（５８．８ｇ，１３２ｍｍｏｌ）、精製水（４．７ｍＬ）と水酸化カリウム（８５．９ｇ，８６％，１．３２ｍｏｌ）を加え、撹拌しながら１９時間加熱還流した。反応液を減圧濃縮し、得られた残留物に氷水冷却下、精製水（１．２Ｌ）と酢酸（６０ｍＬ）を加えた後、塩化メチレン（６００ｍＬ×２、、３００ｍＬ）で抽出した。有機層を合一し、飽和食塩水（６００ｍＬ）で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサン：酢酸エチル＝４：１→１：１で溶出した。目的の分画を減圧濃縮し、油状物の４−ジベンジルアミノ−２−（４−メトキシフェニル）−２−フェニルブチロニトリル１７．７ｇ（３０％回収）及び黄色油状物の４−ジベンジルアミノ−２−（４−メトキシフェニル）−２−フェニルブタンアミド４１．９ｇ（６９％）を得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：４６５［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；２．０７−２．０８（２Ｈ，ｍ），２．５３−２．５５（２Ｈ，ｍ），３．４７（４Ｈ，ｓ），３．７１（３Ｈ，ｓ，），６．７３（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），６．８８（１Ｈ，ｂｒ ｓ），７．０２−７．０４（３Ｈ，ｍ），７．１１−７．３０（１５Ｈ，ｍ）．
〔３〕３−カルバモイル−３−（４−メトキシフェニル）−３−フェニルプロピルアミン塩酸塩（２３）
４−ジベンジルアミノ−２−（４−メトキシフェニル）−２−フェニルブタンアミド（４１．８ｇ）をエタノール（４００ｍＬ）に溶解させ、７．５％Ｐｄ−Ｃ（ｄｒｙ，２０．０ｇ）と濃塩酸（２０ｍＬ）加え、水素圧（４９０３ｋＰａ）下で、５０℃で８時間水素添加した。触媒をろ別した後、反応液を減圧濃縮し、得られたアモルファス状物の残留物にイソプロピルエーテル（４００ｍＬ）とアセトン（４０ｍＬ）を加えて３０分間撹拌した。析出した固体をろ取し、イソプロピルエーテル（２００ｍＬ）で洗浄後、４０℃で減圧乾燥し、白色固体の３−カルバモイル−３−（４−メトキシフェニル）−３−フェニルプロピルアミン塩酸塩を２２．１ｇ（７７％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：２８５［Ｍ−ＨＣｌ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；２．４１−２．６５（４Ｈ，ｍ），３．７６（３Ｈ，ｓ，０ＣＨ３），６．８１（１Ｈ，ｂｒ ｓ），６．９３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．１９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２３−７．３７（６Ｈ，ｍ），７．９１（３Ｈ，ｂｒ ｓ）．
〔４〕Ｎ−〔３−カルバモイル−３−（４−メトキシフェニル）−３−フェニルプロピル〕オキサミン酸エチル（２４）
３−カルバモイル−３−（４−メトキシフェニル）−３−フェニルプロピルアミン塩酸塩（２２．０ｇ，７０．８ｍｍｏｌ）を塩化メチレン（２２０ｍＬ）に溶解し、トリエチルアミン（１７．９ｇ，１７７ｍｍｏｌ）を加え、ドライアイス−アセトン浴上で冷却下、撹拌しながら、クロログリオキシル酸エチル（１０．２ｇ）の塩化メチレン（１１０ｍＬ）溶液を２０分間で滴下した後、反応液を水冷下で５５分間撹拌した。反応液に水（３００ｍＬ）を加えて有機層を分取し、水層を塩化メチレン（１５０ｍＬ×２）で抽出した。有機層を合一し、減圧濃縮した後、残留物をカラムクロマトグラフィーに付し、ヘキサン：メタノール＝４０：１で溶出した。溶媒を減圧濃縮し、白色固体のＮ−〔３−カルバモイル−３−（４−メトキシフェニル）−３−フェニルプロピル〕オキサミン酸エチルを１８．６ｇ（７１％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：３８５［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ；１．３６（３Ｈ，ｔ，Ｊ＝７．３Ｈ），２．６４−２．６７（２Ｈ，ｍ），３．１９−３．２４（２Ｈ，ｍ），３．８１（３Ｈ，ｓ），４．３１（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），５．６６（１Ｈ，ｂｒ ｓ），６．８８（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２７−７．３７（５Ｈ，ｍ），７．９５（１Ｈ，ｂｒ ｓ）．
〔５〕Ｎ−〔３−カルバモイル−３−（４−メトキシフェニル）−３−フェニルプロピル〕オキサミド（２５）
Ｎ−〔３−カルバモイル−３−（４−メトキシフェニル）−３−フェニルプロピル〕オキサミン酸エチル（１８．５ｇ，４８．１ｍｍｏｌ）をジオキサン（１００ｍＬ）に溶解し、氷水冷却下、撹拌しながら２５％アンモニア水（１００ｍＬ）を加え、２５分間撹拌した。反応液に濃塩酸（１００ｍＬ）を加え酸性とした後、塩化メチレン（５００ｍＬ）と水（５００ｍＬ）を加えて有機層を分取し、水層を塩化メチレン（３００ｍＬ×２）で抽出した。有機層を合一し、減圧濃縮した後、得られた残留物をシリカゲルカラムクロマトグラフィーに付し、酢酸エチル：メタノール＝４０：１で溶出した。溶媒を減圧濃縮し、得られた残渣にイソプロピルエーテル（３３０ｍＬ）、アセトン（３３ｍＬ）を加えて３０分間撹拌した後、析出した結晶をろ取し、イソプロピルエーテル（１５０ｍＬ）で洗浄し後、５０℃で減圧乾燥し、白色固体のＮ−〔３−カルバモイル−３−（４−メトキシフェニル）−３−フェニルプロピル〕オキサミドを１５．２ｇ（８９％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：３５６［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；２．４３−２．４７（２Ｈ，ｍ），２．７７−２．８３（２Ｈ，ｍ），３．７５（３Ｈ，ｓ），６．８７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），６．９３（１Ｈ，ｂｒ ｓ），７．１９（１Ｈ，ｂｒ ｓ），７．２２（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２８−７．３３（５Ｈ，ｍ），７．７３（１Ｈ，ｂｒ ｓ），８．０２（１Ｈ，ｂｒ ｓ），８．６８（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ）．
〔６〕Ｎ−〔３−カルバモイル−３−（４−ヒドロキシフェニル）−３−フェニルプロピル〕オキサミド（ＲＣ８）
Ｎ−〔３−カルバモイル−３−（４−メトキシフェニル）−３−フェニルプロピル〕オキサミド（１５．１ｇ，４２．５ｍｍｏｌ）を脱水塩化メチレン（５４０ｍＬ）に懸濁し、ドライアイス−アセトン浴上で冷却撹拌しながら、三臭化ホウ素（４０ｍＬ，４２３ｍｍｏｌ）を２０分間で滴下した後、反応液を室温で１４時間撹拌した。反応液を氷水冷却し、６ｍｏｌ／Ｌ塩酸（３００ｍＬ）と水（１．５Ｌ）を加え、塩化メチレン（１Ｌ×２）と酢酸エチル（５００ｍＬ×３）で抽出した。有機層を合わせ減圧濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー［▲１▼ジクロロメタン：メタノール＝２０：１，▲２▼酢酸エチル：メタノール＝４０：１］で二回、分取ＴＬＣ［塩化メチレン：メタノール＝１０：１］で一回、シリカゲルカラムクロマトグラフィー［塩化メチレン→塩化メチレン：メタノール＝１０：１］で精製した。得られた残渣にメタノール（１３．６ｍＬ）と精製水（６８ｍＬ）を加え、加熱溶解した後、氷水冷却した。析出した結晶をろ取し、冷水１４０ｍＬで洗浄し後、３０℃〜５０℃で減圧乾燥し、微黄色粉末の目的化合物を２．３４ｇ（１６％）得た。
ｍｐ１１１〜１１３℃．
ＩＲ（ＫＢｒ）ｃｍ−１；３３２８，１６６３，１５１３．
Ａｎａｌ．Ｃａｌｃｄ Ｃ１８Ｈ１９Ｎ３Ｏ４：Ｃ，６３．３３；Ｈ，５．６１；Ｎ，１２．３１．
Ｆｏｕｎｄ：Ｃ，６３．０７；Ｈ，５．６２；Ｎ，１２．２３．
ＦＡＢ−ＭＳ（ｍ／ｚ）：３４２［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；２．３９−２．４３（２Ｈ，ｍ），２．７６−２．８１（２Ｈ，ｍ），６．６８（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．８４（１Ｈ，ｂｒ ｓ），７．０９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．１４（１Ｈ，ｂｒ ｓ），７．１９−７．３１（５Ｈ，ｍ），７．７１（１Ｈ，ｂｒ ｓ），８．００（１Ｈ，ｂｒ ｓ），８．６６（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），９．３３（１Ｈ，ｓ）．
＜実施例８＞
１−［３−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチル−１−イミダゾリオ］−１−デオキシ−β−Ｄ−グコピランウロネート（ＲＣ７）
〔１〕メチル３−Ｏ−ベンジル−４，６−Ｏ−ベンジリデン−２−Ｏ−（４−メトキシベンジル）−α−Ｄ−グルコピラノシド（２７）
３−Ｏ−ベンジル−４，６−Ｏ−ベンジリデン−α−Ｄ−グルコピラノシド（２６）（５６５ｍｇ，２．００ｍｍｏｌ）の無水ジメチルホルムアミド（３０ｍＬ）溶液に、氷水冷却下、水素化ナトリウム（０．９６ｇ，２４．０ｍｍｏｌ）を加え、室温で０．５時間撹拌した。混合物に４−メトキシベンジルクロリド（３．２５ｍＬ，２４．０ｍｍｏｌ）を加え１時間撹拌した。反応液にメタノールを加え、１０分間撹拌した後、減圧乾固した。得られた残渣を酢酸エチルに溶解し、水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝４：１で溶出した。溶媒を留去し、得られた残渣をｎ−ヘキサンで懸濁洗浄後、５０℃で減圧乾燥し、白色粉末のメチル３−Ｏ−ベンジル−４，６−Ｏ−ベンジリデン−２−Ｏ−（４−メトキシベンジル）−α−Ｄ−グルコピラノシドを８．６９ｇ（８８％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：４９３［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．３９（３Ｈ，ｓ），３．５３（１Ｈ，ｄｄ，Ｊ＝３．５Ｈｚ，９．３Ｈｚ），３．５９（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），３．７０（１Ｈ，ｔ，Ｊ＝１０．３Ｈｚ），３．８０（３Ｈ，ｓ），３．７９−３．８５（１Ｈ，ｍ），４．０２（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．２６（１Ｈ，ｄｄ，Ｊ＝４．４Ｈｚ，１０．３Ｈｚ），４．５３（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），４．６３（１Ｈ，ｄ，Ｊ＝１１．７Ｈｚ），４．７９（１Ｈ，ｄ，Ｊ＝１１．７Ｈｚ），４．８３（１Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．９０（１Ｈ，ｄ，Ｊ＝１１．７Ｈｚ），５．５４（１Ｈ，ｓ），６．８４−６．８８（２Ｈ，ｍ），７．２６−７．５０（１３Ｈ，ｍ）．
〔２〕メチル３，４−ジ−Ｏ−ベンジル−２−Ｏ−（４−メトキシベンジル）−α−Ｄ−グルコピラノシド（２８）
３−Ｏ−ベンジル−４，６−Ｏ−ベンジリデン−２−Ｏ−（４−メトキシベンジル）−α−Ｄ−グルコピラノシド（８．８７ｇ，１８．０ｍｍｏｌ）の無水トルエン（１００ｍＬ）溶液に、氷水冷下、水素化ジイソブチルアルミニウム１．０ｍｏｌ／Ｌ ｎ−ヘキサン溶液（４５ｍＬ，４５．０ｍｍｏｌ）を滴下した。反応液を室温に戻し４時間撹拌した後、飽和塩化アンモニウム水溶液を加え、０．５時間撹拌した。不溶物をセライトパッドを用いて除去した後、水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝２：１で溶出した。溶媒を留去し、無色アモルファスのメチル３，４−ジ−Ｏ−ベンジル−２−Ｏ−（４−メトキシベンジル）−α−Ｄ−グルコピラノシドを７．４５ｇ（８５％）得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．３６（３Ｈ，ｓ），３．４５−３．５３（２Ｈ，ｍ），３．６２−３．８３（３Ｈ，ｍ），３．８０（３Ｈ，ｓ），３．９８（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．５１（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），４．５９（１Ｈ，ｄ，Ｊ＝１１．７Ｈｚ），４．６４（１Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．７４（１Ｈ，ｄ，Ｊ＝１１．７Ｈｚ），４．８２（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），４．８８（１Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．９８（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），６．８４−６．８７（２Ｈ，ｍ），７．２７−７．３９（１３Ｈ，ｍ）．
〔３〕メチル１−メチル−３，４−ジ−Ｏ−ベンジル−２−Ｏ−（４−メトキシベンジル）−α−Ｄ−グルコピランウロネート（２９）
メチル３，４−ジ−Ｏ−ベンジル−２−Ｏ−（４−メトキシベンジル）−α−Ｄ−グルコピラノシド（７．４２ｇ，１５．０ｍｍｏｌ）のアセトン（１５０ｍＬ）溶液に、氷水冷却下、撹拌しながらＪｏｎｅｓ’試薬（２．６７ｍｏｌ／Ｌ，１６．９ｍＬ）を０．５時間で滴下し、その後０．５時間撹拌した。反応液を酢酸エチル（１５０ｍＬ）で希釈した後、水洗し、無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮した。残留物を塩化メチレン−メタノール（９：１）混液（１００ｍＬ）に溶解した後、トリメチルシリルジアゾメタンヘキサン溶液（２．０ｍｏｌ／Ｌ，８．０ｍＬ）を加えた。反応液を減圧濃縮後、シリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝４：１で溶出した。溶媒を留去し、無色油状のメチル１−メチル−３，４−ジ−Ｏ−ベンジル−２−Ｏ−（４−メトキシベンジル）−α−Ｄ−グルコピランウロネートを４．２０ｇ（５４％）得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．３９（３Ｈ，ｓ），３．５５（１Ｈ，ｄｄ，Ｊ＝３．４Ｈｚ，９．８Ｈｚ），３．６９−３．７３（１Ｈ，ｍ），３．７０（３Ｈ，ｓ），３．８０（３Ｈ，ｓ），３．９６（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．１８（１Ｈ，ｄ，Ｊ＝１０．３Ｈｚ），４．５３−４．５９（３Ｈ，ｍ），４．７３−４．８２（３Ｈ，ｍ），４．９５（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），６．８３−６．８７（２Ｈ，ｍ），７．２０−７．３４（１３Ｈ，ｍ）．
〔４〕メチル１−メチル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネート（３０）
メチル１−メチル−３，４−ジ−Ｏ−ベンジル−２−Ｏ−（４−メトキシベンジル）−α−Ｄ−グルコピランウロネート（４．１８ｇ，８．００ｍｍｏｌ）のアセトニトリル−水（９：１）混液（４０ｍＬ）溶液に、硝酸アンモニウムセリウム（ＩＶ）（８．８７ｇ，１６．０ｍｍｏｌ）を加え、室温で１．５時間撹拌した。反応液を減圧濃縮し、残留物を酢酸エチル−水に溶解した後、酢酸エチル層を分取した。酢酸エチル層を水洗し、無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝２：１で溶出した。溶媒を留去し、淡黄色油状のメチル１−メチル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネートを２．９０ｇ（８８％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：４０３［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．４７（３Ｈ，ｓ），３．７３（３Ｈ，ｓ），３．７５−３．８１（３Ｈ，ｍ），４．２１−４．２６（１Ｈ，ｍ），４．６０（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），４．７８（１Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．８２−４．８８（３Ｈ，ｍ），７．２５−７．３７（１０Ｈ，ｍ）．
〔５〕メチル１−メチル−２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネート（３１）
メチル１−メチル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネート（２．８２ｇ，７．００ｍｍｏｌ）、ベンゾイルクロリド（１．１８ｇ，８．４０ｍｍｏｌ）とトリエチルアミン（８５０ｍｇ，８．４０ｍｍｏｌ）のベンゼン（３０ｍＬ）溶液を４時間加熱還流した。反応液を水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝４：１で溶出した。溶媒を留去し、淡黄色油状のメチル１−メチル−２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネートを２．７０ｇ（７６％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：５０７［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．４０（３Ｈ，ｓ），３．７５（３Ｈ，ｓ），３．９０（１Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ，９．８Ｈｚ），４．１８（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．２９（１Ｈ，ｔ，Ｊ＝９．８Ｈｚ），４．６３（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），４．８１（２Ｈ，ｓ），４．８１（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），５．０９−５．１５（２Ｈ，ｍ），７．１９−７．３５（１０Ｈ，ｍ），７．４３−７．４６（２Ｈ，ｍ），７．５６−７．６１（１Ｈ，ｍ），８．０３−８．０６（２Ｈ，ｍ）．
〔６〕メチル１−Ｏ−アセチル−２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネート（３２）
メチル１−メチル−２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネート（２．０３ｇ，４．００ｍｍｏｌ）と無水酢酸（４．０８ｇ，４０．０ｍｍｏｌ）の酢酸（４０ｍＬ）溶液に、濃硫酸（２０２ｍｇ，２．００ｍｍｏｌ）を加え、８０℃で１時間撹拌した。反応液を減圧濃縮後、残留物を酢酸エチルに溶解し、飽和炭酸水素ナトリウム水溶液、水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサシ：酢酸エチル＝４：１で溶出した。溶媒を留去し、白色粉末のメチル１−Ｏ−アセチル−２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネートを８２０ｍｇ（３８％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：６４０［Ｍ＋ジエタノールアミン］＋．
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：２．１２（３Ｈ，ｓ），３．７５（３Ｈ，ｓ），３．９８（１Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ，９．３Ｈｚ），４．１６（１Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ，９．８Ｈｚ），４．３９（１Ｈ，ｔ，Ｊ＝９．８Ｈｚ），４．６３（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），４．７７−４．８４（３Ｈ，ｍ），５．３４（１Ｈ，ｄｄ，Ｊ＝３．４Ｈｚ，９．８Ｈｚ），６．４５（１Ｈ，ｄ，Ｊ＝３．４Ｈｚ），７．１２−７．３６（１０Ｈ，ｍ），７．４１−７．４５（２Ｈ，ｍ），７．５６−７．６０（１Ｈ，ｍ），７．９４−７．９７（２Ｈ，ｍ）．
〔７〕メチル２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネート（３３）
メチル１−Ｏ−アセチル−２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネート（８０２ｍｇ，１．５０ｍｍｏｌ）のテトラヒドロフラン−メタノール（５：１）混液（６ｍＬ）に、２５％アンモニア水（４ｍＬ）を加え、室温で１時間撹拌した。反応液を減圧濃縮後、残渣を塩化メチレンに溶解し、水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝４：１で溶出した。溶媒を留去し、得られた粗結晶をｎ−ヘキサン：酢酸エチル（１：１）混液で懸濁洗浄後、５０℃で減圧乾燥し、白色粉末のメチル２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネートを４８８ｍｇ（６６％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：４９３［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：２．９９（１Ｈ，ｄｄ，Ｊ＝１．０Ｈｚ，３．９Ｈｚ），３．７４（３Ｈ，ｓ），３．９３（１Ｈ，ｔ，９．３Ｈｚ），４．２４（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．５８（１Ｈ，ｔ，Ｊ＝９．８Ｈｚ），４．６５（１Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．７７−４．８５（３Ｈ，ｍ），５．１４−５．１７（１Ｈ，ｍ），５．６２（１Ｈ，ｔ，Ｊ＝３．９Ｈｚ），７．１７−７．３５（１０Ｈ，ｍ），７．４１−７．４６（２Ｈ，ｍ），７．５６−７．６０（１Ｈ，ｍ），７．９９−８．０４（２Ｈ，ｍ）．
〔８〕メチル（２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピラノシルブロミド）ウロネート（３４）
メチル２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピランウロネート（４９３ｍｇ，１．００ｍｍｏｌ）の無水塩化メチレン（１０ｍＬ）溶液に、四臭化炭素（６６３ｍｇ，２．００ｍｍｏｌ）とトリフェニルホスフィン（３９３ｍｇ，１．５０ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液を減圧濃縮後、シリカゲルカラムクロマトグラフィーに付し、ｎ−ヘキサン：酢酸エチル＝７：１で溶出した。溶媒を留去して、無色油状のメチル（２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピラノシルブロミド）ウロネートを４５０ｍｇ（８１％）得た。
ＦＡＢ−ＭＳ＋（ｍ／ｚ）：５５５［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．７６（３Ｈ，ｓ），３．９９（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．２７（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．５７（１Ｈ，ｔ，Ｊ＝１０．３Ｈｚ），４．６５（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），４．８０−４．８６（３Ｈ，ｍ），５．１１（１Ｈ，ｄｄ，Ｊ＝３．９Ｈｚ，９．８Ｈｚ），６．７０（１Ｈ，ｔ，Ｊ＝３．９Ｈｚ），７．１９−７．３７（１０Ｈ，ｍ），７．４４−７．４８（２Ｈ，ｍ），７．５８−７．６３（１Ｈ，ｍ），８．０１−８．０３（２Ｈ，ｍ）．
〔９〕メチル［２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−１−デオキシ−β−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムブロミド］］ウロネート（３５）
メチル（２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−α−Ｄ−グルコピラノシルブロミド）ウロネート（４４４ｍｇ，０．８０ｍｍｏｌ）と４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブタンアミド（３、Ｘ＝Ｈ、特開平７−２１５９４３）（２．５６ｇ，８．００ｍｍｏｌ）の無水トルエン（２４ｍＬ）懸濁溶液を、１００℃で１０時間加熱した。反応液を１ｍｏｌ／Ｌ塩酸、精製水で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、塩化メチレン：メタノール＝１９：１で溶出した。溶媒を留去し、無色アモルファスのメチル［２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−１−デオキシ−β−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウム ブロミド］］ウロネートを２２２ｍｇ（３２％）得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：７９４［Ｍ＋Ｈ−Ｂｒ］＋．
１Ｈ−ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：２．２５−２．３３（１Ｈ，ｍ），２．４５（３Ｈ，ｓ），２．７９−２．８６（１Ｈ，ｍ），３．７４（３Ｈ，ｓ），３．７７−３．８４（１Ｈ，ｍ），３．９６−４．０４（１Ｈ，ｍ），４．１３（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．２９（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．５２（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），４．６８（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．８２（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），５．５５（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），６．１１（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．０６−７．１４（７Ｈ，ｍ），７．２６−７．４３（１７Ｈ，ｍ），７．５９−７．６３（１Ｈ，ｍ），７．８０（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．８６−７．８８（２Ｈ，ｍ）．
〔１０〕１−［３−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチル−１−イミダゾリオ］−１−デオキシ−β−Ｄ−グルコピランウロネート（ＲＣ７）
メチル［２−Ｏ−ベンゾイル−３，４−ジ−Ｏ−ベンジル−１−デオキシ−β−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムブロミド］］ウロネート（２０１ｍｇ，０．２３ｍｍｏｌ）の無水塩化メチレン（５ｍＬ）溶液に、塩化鉄（ＩＩＩ）（１４９ｍｇ，０．９２ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液に氷水を加え、不溶物をろ別した後、水層を分取した。水層を１ｍｏｌ／Ｌ水酸化ナトリウム水溶液でｐＨ＝７．０３とし、浮遊物をセライトパッドを用いてろ別した後、減圧乾固した。残渣を１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（３ｍＬ）に溶解し、室温で２時間放置した。反応液を１ｍｏｌ／Ｌ塩酸でｐＨ＝７．０２とした後、減圧乾固した。残渣を逆相シリカゲルカラムクロマトグラフィーに付し、水→３０％メタノール水溶液で溶出した。目的の分画を減圧濃縮し、得られた残渣をメタノール（３０ｍＬ）で熱時懸濁洗浄した。８０℃で減圧乾燥後、室温で放置し、白色結晶の目的化合物を１００ｍｇ（８８％）得た。
ＩＲ（ＫＢｒ）ｃｍ−１：３６６３，１６７８，１６２７，７０４．
ＦＡＢ−ＭＳ（ｍ／ｚ）：４９６［Ｍ＋Ｈ］＋．
Ａｎａｌ．ｃａｌｃｄ Ｃ２６Ｈ２９Ｎ３Ｏ７・１．５Ｈ２Ｏ：Ｃ，５９．７６；Ｈ，６．１７；Ｎ，８．０４．
Ｆｏｕｎｄ：Ｃ，５９．７０；Ｈ，５．９７；Ｎ，８．０８．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ：２．５１（３Ｈ，ｓ），２．７９−２．８４（２Ｈ，ｍ），３．２５（１Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ，１０．３Ｈｚ），３．３４−３．３９（１Ｈ，ｍ），３．４１−３．４７（１Ｈ，ｍ），３．５３（１Ｈ，ｄ，Ｊ＝１０．３Ｈｚ），３．８７−３．９１（２Ｈ，ｍ），５．０１（１Ｈ，ｍ），５．３３（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），５．３５（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），６．６０（１Ｈ，ｂｒ），７．２８−７．３９（１２Ｈ，ｍ），７．６０（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．７１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
＜実施例９＞
１−［３−（３−カルバモイル−３，３−ジフェニル）プロピル−２−メチル−１−イミダゾリオ］−１−デオキシ−β−Ｄ−グルコピランウロネート（ＲＣ７）
〔１〕メチル２，３，４−トリ−Ｏ−ベンゾイル−１−メタンスルホニル−α−Ｄ−グルコピランウロネート（３７）
メチル１，２，３，４−テトラ−Ｏ−ベンゾイル−β−Ｄ−グルコピラノウロネート（３６）（４４．３ｇ，７２．４ｍｍｏｌ）の脱水塩化メチレン（３００ｍＬ）溶液に室温でメタンスルホン酸（５５．８ｇ，５８１ｍｍｏｌ）を加え、４５分間撹拌した。反応液に５％炭酸水素ナトリウム水溶液（１．４Ｌ）を加え、塩化メチレン（５００ｍＬ×２回）で抽出した後、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーに付し、ヘキサン−塩化メチレン−酢酸エチル＝５：１０：１で溶出した。溶媒を留去し、得られた残渣を塩化メチレン−ヘキサンより再結晶し、室温で減圧乾燥後、無色綿状晶のメチル２，３，４−トリ−Ｏ−ベンゾイル−１−メタンスルホニル−α−Ｄ−グルコウロネートを２０．６ｇ（４９％）得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ；３．１１（３Ｈ，ｓ），３．７０（３Ｈ，ｓ），４．７９（１Ｈ，ｄ，Ｊ＝９．８Ｈｚ），５．５４（１Ｈ，ｄｄ，Ｊ＝３．４，９．８Ｈｚ），５．７５（１Ｈ，ｔ，Ｊ＝９．８Ｈｚ），６．１７（１Ｈ，ｔ，Ｊ＝９．８Ｈｚ），６．４１（１Ｈ，ｄ，Ｊ＝３．４Ｈｚ），７．３１−７．５７（９Ｈ，ｍ），７．８８−７．９９（６Ｈ，ｍ）．
〔２〕メチル［２，３，４−トリ−Ｏ−ベンゾイル−１−デオキシ−β−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムクロリド］］ウロネート（３８）
４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブタンアミド（３、Ｘ＝Ｈ、特開平７−２１５９４３）（４５．４ｇ，１４２ｍｍｏｌ）及びメチル２，３，４−トリ−Ｏ−ベンゾイル−１−メタンスルホニル−α−Ｄ−グルコピランウロネート（１０．０ｇ，１６．７ｍｍｏｌ）に脱水クロロホルム（５００ｍＬ）を加えアルゴン雰囲気撹拌下、１３時間加熱還流した。冷後、溶媒を減圧留去し、残渣に塩化メチレン及び希塩酸を加え抽出し、塩化メチレン層を分取した。水層を塩化メチレンで抽出し、塩化メチレン層を合一した後、希塩酸で洗浄し、洗浄した水層を塩化メチレンで抽出した。塩化メチレン層を合一し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーに付し、塩化メチレン→塩化メチレン−メタノール＝１００：３→塩化メチレン−メタノール＝１０：１→塩化メチレン−メタノール＝２０：３で順次溶出した。目的物を含む分画を減圧濃縮し、得られた油状物を塩化メチレン−イソプロピルエーテル混液で結晶化させた。析出した固体をろ取し、５０℃で減圧乾燥後、灰白色粉末のメチル［２，３，４−トリ−Ｏ−ベンゾイル−１−デオキシ−β−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムクロリド］］ウロネートを５．８２ｇ（４１％）得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；２．３８−２．４５（１Ｈ，ｍ），２．５２（３Ｈ，ｓ），２．６９−２．７６（１Ｈ，ｍ），３．５８（３Ｈ，ｓ），３．６８−３．８５（２Ｈ，ｍ），５．１０（１Ｈ，ｄ，Ｊ＝９．８Ｈｚ），５．８７（１Ｈ，ｔ，Ｊ＝９．８Ｈｚ），６．２０（１Ｈ，ｔ，Ｊ＝８．８Ｈｚ），６．２５（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），６．６８（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．７６（１Ｈ，ｂｒ ｓ），７．１５−７．８５（２７Ｈ，ｍ），８．１５（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
〔３〕１−［３−（３−カルバモイル−３，３−ジフェニル）プロピル−２−メチル−１−イミダゾリニオ］−１−デオキシ−β−Ｄ−グルコピランウロネート１．１水和物（ＲＣ７）
メチル［２，３，４−トリ−Ｏ−ベンゾイル−１−デオキシ−β−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムクロリド］］ウロネート（３．０２ｇ，３．５２ｍｍｏｌ）のメタノール（１２０ｍＬ）溶液に、塩−氷冷却下撹拌しながら、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（５０ｍＬ）をゆっくり滴下し、同温で３０分間撹拌した後、室温で３０分間撹拌した。精製水を加え酢酸エチルで洗浄し、水層に希塩酸を加えｐＨ１とし塩化メチレンで２回洗浄した。水層に水酸化ナトリウム水溶液を加えｐＨ７とし酢酸エチルで洗浄後、水層を減圧濃縮した。得られた残渣を合成吸着剤カラムクロマトグラフィー［ＨＰ−２０ＳＳ］に付し、精製水→精製水：メタノール＝２：１で溶出した。目的物を含む分画を合し減圧濃縮し、得られた固体をイソプロピルアルコール−精製水で再結晶し、６０℃で減圧乾燥後、粗結晶（１．４３ｇ）を得た。粗結晶（１．４３ｇ）を分取ＨＰＬＣ［Ｉｎｅｒｔｓｉｌ ＯＤＳ−２（２０ｍｍＩＤ×２５０ｍｍ）；移動相アセトニトリル−精製水＝１：５；流量１０ｍＬ／ｍｉｎ；カラム温度３０℃；検出波長２３０ｎｍ；１ショット３０ｍｇ］に付し、留出液を減圧濃縮し、残渣を精製水−イソプロピルアルコールより再結晶し、６０℃で減圧乾燥後、２日間放置し、無色板状晶の目的化合物を１．００ｇ（５５％）得た。
ｍｐ２０７〜２１５℃（ｄｅｃｏｍｐ．）．
ＩＲ（ＫＢｒ）ｃｍ−１；３４１２，１６６３，１６２６．
［α］Ｄ ２３＝＋６．３°（ｃ＝０．３７，Ｈ２Ｏ）．
Ａｎａｌ．Ｃａｌｃｄ Ｃ２６Ｈ２９Ｎ３Ｏ７・１．１Ｈ２Ｏ：Ｃ，６０．６０；Ｈ，６．１０；Ｎ，８．１５．
Ｆｏｕｎｄ：Ｃ，６０．７０；Ｈ，６．０１；Ｎ，８．２６．
ＦＡＢ−ＭＳ（ｍ／ｚ）：４９６［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，Ｄ２Ｏ）δ；２．４９（３Ｈ，ｓ），２．９２−３．００（２Ｈ，ｍ），３．６６（１Ｈ，ｔ，Ｊ＝８．８Ｈｚ），３．７３（１Ｈ，ｔ，Ｊ＝８．８Ｈｚ），３．７８（１Ｈ，ｔ，Ｊ＝８．８Ｈｚ），４．００（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），４．０６−４．１４（２Ｈ，ｍ），５．５１（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３６−７．４７（１１Ｈ，ｍ），７．６７（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
水分測定（カールフィッシャー法）：３．７１％．
＜実施例１０＞
１−［２，２−ジフェニル−４−（２−メチルイミダゾール−１−イル）ブチリルアミノ］−１−デオキシ−Ｄ−グルコピランウロン酸（ＲＣ９）
〔１〕２，２−ジフェニル−４−（２−メチルイミダゾール−１−イル）ブタン酸（３９）
４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブタンアミド（３、Ｘ＝Ｈ、特開平７−２１５９４３）（３．００ｇ，９．３９ｍｍｏｌ）の塩酸溶液を２１時間加熱還流した。反応液を減圧濃縮し、得られた残留物を２ｍｏｌ／Ｌ水酸化ナトリウム溶液に溶解した。この溶液を酢酸エチルで洗浄した後、塩酸でｐＨ＝７．０に調整し、析出する結晶をろ取し、水洗後、１００℃で減圧乾燥して白色粉末の２，２−ジフェニル−４−（２−メチルイミダゾール−１−イル）ブタン酸を２．２１ｇ（９３％）得た。
ＥＩ−ＭＳ（ｍ／ｚ）：３２０（Ｍ）＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ：２．０７（３Ｈ，ｓ），２．６３−２．６７（２Ｈ，ｍ），３．５７−３．６１（２Ｈ，ｍ），６．７５（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），６．９７（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．２５−７．３６（１０Ｈ，ｍ）．
〔２〕メチル２，３，４−トリ−Ｏ−ベンジル−１−［２，２−ジフェニル−４−（２−メチルイミダゾール−１−イル）ブチリルアミノ］−１−デオキシ−Ｄ−グルコピランウロネート（４１）
２，２−ジフェニル−４−（２−メチルイミダゾール−１−イル）ブタン酸（７６．９ｍｇ，０．２４ｍｍｏｌ）の無水塩化メチレン３ｍＬ懸濁溶液に、オキザリルクロリド（２５．６μＬ，０．３０ｍｍｏｌ）を加え、室温で３０分間撹拌した。反応液を飽和炭酸水素ナトリウム水溶液、水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物を無水クロロホルム５ｍＬに溶解し、文献記載の方法で合成したメチル１−アミノ−２，３，４−トリ−Ｏ−ベンジル−１−デオキシ−Ｄ−グルコピランウロネート（４０）（５７．３ｍｇ，０．２４ｍｍｏｌ）、トリエチルアミン（３３．９μＬ，０．２４ｍｍｏｌ）と４，４−ジメチルアミノピリジン（５ｍｇ）を加え、３日間加熱還流した。反応液を水洗し、無水硫酸ナトリウムで乾燥後、溶媒を留去した。粗生成物を分取ＴＬＣ（ＣＨ２Ｃｌ２：ＣＨ３ＯＨ＝５：１，２０×２０ｃｍ ０．５ｍｍ２枚）で精製し、淡褐色アモルファスのメチル２，３，４−トリ−Ｏ−ベンジル−１−［２，２−ジフェニル−４−（２−メチルイミダゾール−１−イル）ブチリルアミノ］−１−デオキシ−Ｄ−グルコピランウロネートを６５ｍｇ（６９％）得た。
一部、分取ＴＬＣによりα体、β体の分離を行った。
〔α体の機器分析〕
ＦＡＢ−ＭＳ（ｍ／ｚ）：７８０［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．２３（３Ｈ，ｓ），２．５２−２．５９ ａｎｄ ２．８１−２．８７（ｅａｃｈ １Ｈ，ｍ），３．２６（１Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．４８−３．５８（２Ｈ，ｍ），３．７２（３Ｈ，ｓ），３．８０（１Ｈ，ｔ，Ｊ＝６．４Ｈｚ），４．０１−４．０７（１Ｈ，ｍ），４．０１（１Ｈ，ｄ，Ｊ＝６．４Ｈｚ），４．２６ ａｎｄ ４．４４（ｅａｃｈ ２Ｈ，ｓ），４．６１−４．５４（２Ｈ，ｍ），５．９２（１Ｈ，ｄｄ，Ｊ＝４．４Ｈｚ，７．８Ｈｚ），６．３３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．７３ ａｎｄ ６．８５（ｅａｃｈ １Ｈ，ｓ），７．００−７．４１（２５Ｈ，ｍ）．
〔β体の機器分析〕
ＦＡＢ−ＭＳ（ｍ／ｚ）：７８０［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．２７（３Ｈ，ｓ），２．４７−２．５４ ａｎｄ ２．８１−２．８８（ｅａｃｈ １Ｈ，ｍ），３．１０（１Ｈ，ｔ，Ｊ＝８．８Ｈｚ），３．５２−３．５９（２Ｈ，ｍ），３．７１（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），３．７３（３Ｈ，ｓ），３．９４（１Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），３．９７−４．０５（２Ｈ，ｍ），４．０８（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），４．３５（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），４．５２（１Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．７０−４．７９（３Ｈ，ｍ），５．３１（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），５．９０（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），６．７２（１Ｈ，ｓ），６．８８（１Ｈ，ｄ，Ｊ＝１．０Ｈｚ），７．０５−７．４０（２５Ｈ，ｍ）．
〔３〕１−［２，２−ジフェニル−４−（２−メチルイミダゾール−１−イル）ブチリルアミノ］−１−デオキシ−Ｄ−グルコピランウロン酸（ＲＣ９）
メチル２，３，４−トリ−Ｏ−ベンジル−１−［２，２−ジフェニル−４−（２−メチルイミダゾール−１−イル）ブチリルアミノ］−１−デオキシ−Ｄ−グルコピランウロネート（７０．２ｍｇ，０．０９ｍｍｏｌ）のメタノール３ｍＬ溶液に、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１４０μｌ，０．１４ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液を減圧濃縮後、残留物を精製水３ｍＬに溶解し、１ｍｏｌ／Ｌ塩酸でｐＨ＝７．０５とした後、酢酸エチルで７回抽出した。酢酸エチル層を合一し、無水硫酸ナトリウムで乾燥後、溶媒を留去した。得られた無色アモルファスをメタノール５ｍＬに溶解し、ぎ酸アンモニウム（１１４ｍｇ，１．８０ｍｍｏｌ）と１０％Ｐｄ−Ｃ（４６．０ｍｇ）を加え、３時間加熱還流した。触媒をろ過した後、反応液を減圧濃縮した。残留物を精製水３ｍＬに溶解し、１ｍｏｌ／Ｌ塩酸でｐＨ＝７．０とした後、減圧乾固した。残渣を分取ＴＬＣ（ＣＨ２Ｃｌ２：ＣＨ３ＯＨ＝１：２，２０×２０ｃｍ ０．５ｍｍ１枚）に付し、無色アモルファスの目的化合物を６５ｍｇ（６９％）得た。
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ，４００ＭＨｚ）δ：２．１６（３Ｈ，ｓ），２．１７（３Ｈ，ｓ），２．７０−２．９２（４Ｈ，ｍ），２．９６（１Ｈ，ｔ，Ｊ＝８．８Ｈｚ），３．３５−３．４２（４Ｈ，ｍ），３．５９（１Ｈ，ｄｄ，Ｊ＝７．３，５．４Ｈｚ），３．７３−３．９２（４Ｈ，ｍ），５．５６（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），５．５９（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），６．７５（２Ｈ，ｄ，Ｊ＝１．０Ｈｚ），６．９１（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），６．９３（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．２７−７．４５（２０Ｈ，ｍ）．
ＦＡＢ−ＭＳ（ｍ／ｚ）：４９６［Ｍ＋Ｈ］＋
＜実施例１１＞
１−［３−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチル−１−イミダゾリオ］−１−デオキシ−α−Ｄ−グルコピランウロネート（ＲＣ１０）
〔１〕メチル［２，３，４−トリ−Ｏ−ベンゾイル−１−デオキシ−α−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムブロミド］］ウロネート（４４）
メチル（２，３，４−トリ−Ｏ−ベンジル−α−Ｄ−グルコピラノシルブロミド）ウロネート（１０８ｍｇ，０．２０ｍｍｏｌ）と４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブタンアミド（３、Ｘ＝Ｈ、特開平７−２１５９４３）（６３９ｍｇ，２．００ｍｍｏｌ）の無水トルエン（１０ｍＬ）懸濁溶液を、１００℃で１６時間加熱した。反応液を１ｍｏｌ／Ｌ塩酸、精製水で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物を分取 ＴＬＣ（ＣＨ２Ｃｌ２：ＣＨ３ＯＨ＝５：１，２０×２０ｃｍ，厚さ０．５ｍｍ）で精製し、無色アモルファスのメチル［２，３，４−トリ−Ｏ−ベンゾイル−１−デオキシ−α−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムブロミド］］ウロネートを５０ｍｇ（２９％）得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．６４（３Ｈ，ｓ），２．８５−２．９３（１Ｈ，ｍ），３．２５−３．３１（１Ｈ，ｍ），３．６１（３Ｈ，ｓ），３．８２（１Ｈ，ｓ），３．９７（１Ｈ，ｓ），４．００−４．０６（１Ｈ，ｍ），４．１７−４．２７（１Ｈ，ｍ），４．３９−４．７０（８Ｈ，ｍ），５．６３（１Ｈ，ｂｒ），６．５０（１Ｈ，ｂｒ），６．３２（１Ｈ，ｓ），７．１８−７．７１（２６Ｈ，ｍ），７．７２（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＦＡＢ−ＭＳ（ｍ／ｚ）：７８０［Ｍ＋Ｈ］＋
〔２〕１−［３−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチル−１−イミダゾリオ］−１−デオキシ−α−Ｄ−グルコピランウロネート（ＲＣ１０）
メチル［２，３，４−トリ−Ｏ−ベンゾイル−１−デオキシ−α−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムブロミド］］ウロネート（４３．０ｍｇ，０．０５ｍｍｏｌ）の無水塩化メチレン（３ｍＬ）溶液に、氷水冷却下で塩化鉄（ＩＩＩ）（７６．０ｍｇ，０．４５ｍｍｏｌ）を加え、同温で５時間撹拌した。反応液に氷水を加え、不溶物をろ別した後、水層を分取した。水層を１ｍｏｌ／Ｌ水酸化ナトリウム水溶液でｐＨ＝７．０とし、浮遊物をセライトパッドを用いてろ別した後、減圧乾固した。残渣をメタノール（１ｍＬ）に溶解し、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１００μＬ）を加え、室温で５時間撹拌した。反応液を減圧乾固後、残渣を精製水３ｍＬに溶解し、１ｍｏｌ／Ｌ塩酸でｐＨ＝７．０に調整した後、溶媒を減圧乾固した。残渣を分取ＴＬＣ（塩化メチレン：メタノール＝１：２，２０×２０ｃｍ厚さ０．５ｍｍ）で精製し、白色アモルファスの目的化合物を７．５ｍｇ（３０％）得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ：２．５６（３Ｈ，ｓ），２．７１−２．８４（２Ｈ，ｍ），３．６１（１Ｈ，ｂｒ），３．７３−３．７８（３Ｈ，ｍ），３．８２（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），５．６０（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），６．１０（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），６．８２（１Ｈ，ｓ），７．４５（１Ｈ，ｓ），７．２８−７．３９（１０Ｈ，ｍ），７．５４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
ＦＡＢ−ＭＳ（ｍ／ｚ）：４９４［Ｍ−Ｈ］−
＜実施例１２＞
４−アセトイミドイルアミノ−２，２−ジフェニルブタンアミド（ＲＣ１１）
〔１〕４−アセトイミドイルアミノ−２，２−ジフェニルブタンアミド臭化水素酸塩
実施例２に記載した同様の方法により合成した４−アミノ−２，２−ジフェニルブタンアミド（５．０９ｇ，２０．０ｍｍｏｌ）のエタノール（１００ｍＬ）懸濁溶液に氷水冷却下、Ｓ−ベンジルチオアセトイミデート臭化水素酸塩（４．９２ｇ，２０．０ｍｍｏｌ）を加え、同温で２時間撹拌した。反応液を減圧濃縮し、得られた残渣を酢酸エチル（５０ｍＬ）で懸濁洗浄し、粗結晶を得た。得られた粗結晶をエタノール（１００ｍＬ）から再結晶し、９０℃で減圧乾燥後、白色粉末の４−アセトイミドイルアミノ−２，２−ジフェニルブタンアミド臭化水素酸塩を３．８７ｇ（５１％）得た。
ｍｐ２１７−２１８℃．
ＩＲ（ＫＢｒ）ｃｍ−１；３１７３，３０８０，１６８８，１６５８，７０５．Ａｎａｌ．Ｃａｌｃｄ Ｃ１８Ｈ２２ＢｒＮ３Ｏ：Ｃ，５７．４５；Ｈ，５．８９；Ｎ，１１．１７．
Ｆｏｕｎｄ：Ｃ，５７．２８；Ｈ，５．８９；Ｎ，１１．１５．
ＦＡＢ−ＭＳ（ｍ／ｚ）：２９６［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）：２．０６（３Ｈ，ｓ），２．５１−２．６０（２Ｈ，ｍ），２．７５−２．８６（２Ｈ，ｍ），６．９９（１Ｈ，ｓ），７．２７−７．３８（１０Ｈ，ｍ），７．５２（１Ｈ，ｓ），８．５６（１Ｈ，ｓ），９．０４（１Ｈ，ｓ），９．２５（１Ｈ，ｓ）．
〔２〕４−アセトイミドイルアミノ−２，２−ジフェニルブタンアミド（ＲＣ１１）
４−アセトイミドイルアミノ−２，２−ジフェニルブタンアミド臭化水素酸塩（２．６３ｇ，７．００ｍｍｏｌ）の精製水（５３ｍＬ）懸濁溶液に氷水冷却下、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（７．７ｍＬ，７．７０ｍｍｏｌ）を加え、２時間撹拌した。析出した結晶をろ取し、氷水冷却した水（３０ｍＬ）で洗浄し粗結晶を得た。この粗結晶をアセトニトリル（２０ｍＬ）に加熱溶解し、ジイソプロピルエーテル（２０ｍＬ）を加え、室温放冷した。析出した結晶をろ取し、ジイソプロピルエーテル（２０ｍＬ）で洗浄後、５０℃で減圧乾燥し、白色粉末の目的化合物を１．２６ｇ（６１％）得た。
ｍｐ１６６−１６７℃．
ＩＲ（ＫＢｒ）ｃｍ−１；３４１８，１６１９，１３８４，６９５．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ１８Ｈ２１Ｎ３Ｏ：Ｃ，７３．１９；Ｈ，７．１７；Ｎ，１４．２３．
Ｆｏｕｎｄ：Ｃ，７３．０４；Ｈ，７．１８；Ｎ，１４．２０．
ＦＡＢ−ＭＳ（ｍ／ｚ）：２９６［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）：１．７８（３Ｈ，ｓ），２．５２−２．６１（４Ｈ，ｍ），６．２１（２Ｈ，ｂｒ），７．１０（１Ｈ，ｓ），７．１１−７．３０（１０Ｈ，ｍ），８．９４（１Ｈ，ｂｒ）．
＜実施例１３＞ ４−（２−メチル−５−オキソ−４，５−ジヒドロイミダゾール−１−イル）−２，２−ジフェニルブタンアミド（ＲＣ１２）
〔１〕４−Ｎ−アセチルアミノ−２，２−ジフェニルブタンアミド（４４）
５００ｍＬ用耐圧ボトル中に４−Ｎ，Ｎ−ジベンジルアミノ−２，２−ジフェニルブタンアミド（１６）（１３．０ｇ，２９．９ｍｍｏｌ）、水酸化パラジウム３．００ｇ及び酢酸エチルとエタノールの混合溶媒２８０ｍＬを仕込み初期水素圧４７１ｋＰａにて８時間水素添加した。触媒をろ過しエタノールで触媒を洗浄後ろ液を濃縮した。得られた残留物とトリエチルアミン（４．６５ｍＬ，３３．３ｍｍｏｌ）及びクロロホルム２００ｍＬを混合し、氷冷攪拌下塩化アセチル（２．３７ｍＬ，３３．３ｍｍｏｌ）を滴下した。０℃にて１０分、室温にて一晩攪拌後反応液を１０％クエン酸水溶液、０．５ｍｏｌ／Ｌ炭酸水素ナトリウム、飽和食塩水にて順次洗浄後無水硫酸ナトリウムで乾燥し濃縮した。残留物に酢酸エチルと少量のアセトンを加え氷冷下３０分攪拌した。不溶の固体をろ過、乾燥し２．５０ｇ（２８％）の目的物を無色粉末として得た。
〔２〕４−Ｎ−アセチル−Ｎ−クロロアセチルアミノ−２，２−ジフェニルブタンアミド（４５）
１Ｌ用ナス型フラスコ中に４−Ｎ−アセチルアミノ−２，２−ジフェニルブタンアミド（４４）（３．５０ｇ，１１．８ｍｍｏｌ）、トリエチルアミン（１．６４ｍＬ，１１．８ｍｍｏｌ）及びベンゼン４５０ｍＬを仕込み、室温にてアルゴン雰囲気クロロアセチルクロライド（０．９４ｍＬ，１１．８ｍｍｏｌ）を加えた。３．５時間加熱還流後反応液を濃縮し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：エタノール＝６：１ｖ／ｖ）にて精製し、褐色油状の目的物を１．５０ｇ（収率３４％）得た。
〔３〕４−Ｎ−アセチル−Ｎ−アジドアセチルアミノ−２，２−ジフェニルブタンアミド（４６）
５００ｍＬ用ナス型フラスコ中に４−Ｎ−アセチル−Ｎ−クロロアセチルアミノ−２，２−ジフェニルブタンアミド（４５）（１．５０ｇ，４．０２ｍｍｏｌ）及びジメチルスルホキシド３０ｍＬを仕込み、室温にてアジ化ナトリウム（４６０ｍｇ，７．０８ｍｍｏｌ）を加えた。室温にて３０分攪拌し、水を加えエーテル抽出した。抽出液は飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥し濃縮した。残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン：エタノール＝１３：１ｖ／ｖ）にて精製し、微黄色泡状の目的物を４５０ｍｇ（収率２９％）得た。
質量分析値 ＦＡＢ−ＭＳ（ｍ／ｚ）：３８０（Ｍ＋Ｈ）＋
〔４〕４−（２−メチル−５−オキソ−４，５−ジヒドロイミダゾール−１−イル）−２，２−ジフェニルブタンアミド（ＲＣ１２）
５００ｍＬ用ナス型フラスコ中に４−Ｎ−アセチル−Ｎ−アジドアセチルアミノ−２，２−ジフェニルブタンアミド（４６）（４５０ｍｇ，１．１９ｍｍｏｌ）及びトルエン３０ｍＬを仕込み、室温にてトリフェニルホスフィン（３４３ｍｇ，１．３１ｍｍｏｌ）を加えた。室温にて２時間攪拌し、一晩放置した。反応液を濃縮し、残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン：メタノール＝１３：１ｖ／ｖ）にて精製し、泡状の目的物を２６６ｍｇを得た。
質量分析値 ＦＡＢ−ＭＳ（ｍ／ｚ）：３３６（Ｍ＋Ｈ）＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．１４（３Ｈ，ｔ，Ｊ＝２．０Ｈｚ），２．６１−２．６５（２Ｈ，ｍ），３．４４−３．４７（２Ｈ，ｍ），３．９９（２Ｈ，ｄ，Ｊ＝２．０Ｈｚ），５．５１（１Ｈ，ｂｒ ｓ），５．５７（１Ｈ，ｂｒ ｓ），７．３０−７．４０（１０Ｈ，ｍ）．
１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ１５．７１，３７．７７，３８．４１，５８．２３，５８．９２，１２８．４４−１２８．８０，１４２．２６，１６３．５７，１７６．２４，１８１．４２．
＜実施例１４＞ ４−（２−メチル−４，５−ジオキソ−４，５−ジヒドロイミダゾール−１−イル）−２，２−ジフェニルブタンアミド（ＲＣ１３）
４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブタンアミド（３、Ｘ＝Ｈ、特開平７−２１５９４３）（３２０ｍｇ、１．００ｍｍｏｌ）、テトラフェニルポルフィリンマンガンクロライド（７．００ｍｇ，９．９６μｍｏｌ）、ヨードソベンゼン（２２０ｍｇ，１．００ｍｍｏｌ）、塩化メチレン５ｍＬ及びアセトニトリル５ｍＬを混合し室温にて７．５時間攪拌した後一晩放置した。反応溶液を濃縮し、残留物をシリカゲルカラムクロマトグラフィー（溶離液 クロロホルム：メタノール＝５０：３ｖ／ｖ）にて生成し、Ｒｆ値０．２４の分画を集め濃縮し、７０ｍｇ（２１％）の微黄色粉末状の目的物を得た。
ＦＡＢ−ＭＳ（ｍ／ｚ）：３５０（Ｍ＋Ｈ）＋
ＨＲＭＳ Ｃ２０Ｈ２０Ｎ３Ｏ３ ｃａｌｃｄ．３５０．１５０５，ｆｏｕｎｄ ３５０．１５２８．
＜実施例１５＞
１−［３−（３−カルバモイル−３，３−ジフェニル）プロピル−２−メチル−１−イミダゾリオ］−１−デオキシ−β−Ｄ−グルコピランウロネート（ＲＣ７）
〔１〕メチル［２，３，４−トリ−Ｏ−ベンゾイル−１−デオキシ−β−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムクロリド］］ウロネート（３８）
４−（２−メチル−１−イミダゾリル）−２，２−ジフェニルブチルアミド（３、Ｘ＝Ｈ、特開平７−２１５９４３）（２４８ｇ，７７５ｍｍｏｌ）及びメチル２，３，４−トリ−Ｏ−ベンゾイル−１−メタンスルホニル−α−Ｄ−グルコピランウロネート（５４．５ｇ，９１．０ｍｍｏｌ）に脱水クロロホルム（１３５０ｍＬ）を加えアルゴン雰囲気撹拌下、６．５時間加熱還流した（加熱還流開始４時間後からクロロホルム（５５０ｍＬ）を常圧留去した）。冷後、溶媒を減圧留去し、残渣に塩化メチレン（１０００ｍＬ）及び２ｍｏｌ／Ｌ塩酸（５００ｍＬ）を加え溶解し、塩化メチレン層を分取した。水層を塩化メチレン（２５０ｍＬ）で抽出し、塩化メチレン層を合一した後、２ｍｏｌ／Ｌ塩酸（２５０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーに付し、塩化メチレン→塩化メチレン−メタノール＝４０：１→塩化メチレン−メタノール＝３０：１→塩化メチレン−メタノール＝２０：１で順次溶出した。目的物を含む分画を減圧濃縮し、得られた油状物にイソプロピルエーテル（１００ｍＬ）を加え結晶化させた。析出した結晶をろ取し、褐色粉末のメチル［２，３，４−トリ−Ｏ−ベンゾイル−１−デオキシ−β−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムクロリド］］ウロネートを３２．９ｇ（４２％）得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ；２．４０−２．４６（１Ｈ，ｍ），２．５２（３Ｈ，ｓ），２．６９−２．７６（１Ｈ，ｍ），３．５８（３Ｈ，ｓ），３．６８−３．８５（２Ｈ，ｍ），５．０９（１Ｈ，ｄ，Ｊ＝９．８Ｈｚ），５．８８（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），６．２０（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），６．２５（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），６．６５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．７６（１Ｈ，ｓ），７．１５−７．８５（２７Ｈ，ｍ），８．１５（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
〔２〕１−［３−（３−カルバモイル−３，３−ジフェニル）プロピル−２−メチル−１−イミダゾリニオ］−１−デオキシ−β−Ｄ−グルコピランウロネート１．０水和物（ＲＣ７）
メチル［２，３，４−トリ−Ｏ−ベンゾイル−１−デオキシ−β−Ｄ−グルコピラノシル［１−（３−カルバモイル−３，３−ジフェニルプロピル）−２−メチルイミダゾリウムクロリド］］ウロネート（３２．７ｇ，３８．１ｍｍｏｌ）のメタノール（１３１０ｍＬ）溶液に、ドライアイス−アセトン浴上で冷却下撹拌しながら、内温−５２〜−４８℃で１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（５４５ｍＬ）を２０分間で滴下し、同温で３０分間撹拌した後、室温に戻し２時間撹拌した。反応液に活性炭（３．３ｇ）を加え２０分間撹拌した後、セライトパッドを用いて不溶物をろ去し、ろ液に６ｍｏｌ／Ｌ塩酸を加えｐＨ７とした後、減圧濃縮した。得られた残留物を精製水（５００ｍＬ）に溶解し、塩化メチレン（５００ｍＬ×３）で洗浄した後、減圧濃縮し、得られた残渣を合成吸着剤カラムクロマトグラフィー［ＨＰ−２０ＳＳ］に付し、精製水→精製水：メタノール＝２：１で溶出した。目的物を含む分画を合一し、減圧濃縮した後、得られた固体を精製水（２０ｍＬ）に溶解し、イソプロピルアルコール（６００ｍＬ）を徐々に加え、析出した結晶をろ取した後、イソプロピルアルコール（１００ｍＬ）で洗浄し、粗結晶を１７．８ｇ得た。得られた粗結晶をイソプロピルアルコール（１００ｍＬ）に懸濁し、８０℃で精製水（３０ｍＬ）を加え溶解した後、イソプロピルアルコール（５０ｍＬ）を加え、室温で２時間放置した。析出した結晶をろ取し、イソプロピルアルコール（１００ｍＬ）で洗浄した後、減圧下、６０℃で４時間乾燥し、淡褐色結晶の目的化合物を１４．３ｇ（７３％）得た。
ｍｐ２０９〜２１５℃（ｄｅｃｏｍｐ．）．
ＩＲ（ＫＢｒ）ｃｍ−１；３４１２，１６６３，１６２６．
［α］Ｄ ２１＝＋９．６°（ｃ＝０．５０，Ｈ２Ｏ）．
Ａｎａｌ．Ｃａｌｃｄ Ｃ２６Ｈ２９Ｎ３Ｏ７・１．０Ｈ２Ｏ：Ｃ，６０．８１；Ｈ，６．０８；Ｎ，８．１８．
Ｆｏｕｎｄ：Ｃ，６０．６４；Ｈ，６．０２；Ｎ，８．２６．
ＦＡＢ−ＭＳ＋ ｍ／ｚ：４９６［Ｍ＋Ｈ］＋．
１Ｈ−ＮＭＲ（４００ＭＨｚ，Ｄ２Ｏ）δ；２．４９（３Ｈ，ｓ），２．９０−３．０１（２Ｈ，ｍ），３．６６（１Ｈ，ｔ，Ｊ＝９．３Ｈｚ），３．７３（１Ｈ，ｔ，Ｊ＝８．８Ｈｚ），３．７８（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），４．００（１Ｈ，ｄ，Ｊ＝９．８Ｈｚ），４．０４−４．１６（２Ｈ，ｍ），５．５２（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３６−７．４８（１１Ｈ，ｍ），７．６７（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
水分測定（カールフィッシャー法）：３．４６％．
産業上利用可能性
＜摘出モルモット回腸及び心房に対する抗コリン作用＞
ハートレー系雄性モルモットのより心臓及び盲腸直近の回腸部を摘出した。回腸は、長さ約３ｃｍの小片として、マグヌス管内に１ｇの負荷をかけて懸垂し、標本の反応を等張性に記録した。栄養液はタイロード液を用い、Ｏ２：９５％、ＣＯ２：５％の混合ガスを通気し、液温は３２℃とした。アセチルコリンは累積的に投与し、試験化合物は５分間前処理した。試験化合物の親和性（ｐＡ２）はシルド法（Ｂｒｉｔ．Ｊ．Ｐｈａｒｍａｃｏｌ．，１４ ４８−５８（１９５９））により求めた。
分離した心房はマグヌス管内に０．５ｇの負荷をかけて懸垂し、標本の反応を等尺性に記録した。栄養液はタイロード液を用い、Ｏ２：９５％、ＣＯ２：５％の混合ガスを通気し、液温は３２℃とした。アセチルコリンは累積的に投与し、試験化合物は１０分前に処理した。試験化合物の親和性回腸の場合と同様にして求めた。その結果、本発明化合物は回腸のムスカリン受容体に対し有意な拮抗作用を示した。
＜律動性膀胱収縮に対する作用＞
ウィスター系雄性ラットをハロタン麻酔下、背位に固定し、腹部正中切開により露出させた膀胱の頂部からバルーン付カテーテルを挿入し、巾着縫合した。縫合した上部腹部からカテーテルを導出し、三方活栓を連結、一方にはシリンジを、他方には膀胱内圧測定用の圧トランデューサーを連結した。バルーン内には約０．１〜０．３ｍＬの蒸留水を注入し、惹起された律動膀胱収縮が安定した振幅を示すことを確認した後、試験化合物を予め留置したカテーテルを介して十二指腸内に投与した。抑制効果は律動的膀胱収縮の振幅の減少から評価した。その結果、本願化合物は有意な抑制効果を示した。
以上のことから、本発明化合物は過敏性腸症候群、頻尿及び尿失禁の治療等に有用である。Technical field
The present invention relates to a novel 2,2-diphenylbutanamide derivative useful as a pharmaceutical, and particularly to a 2,2-diphenylbutanamide derivative having a muscarinic receptor antagonistic action that is particularly selective as an anticholinergic agent and a method for producing the same. .
Background art
A novel imidazole derivative has been disclosed as a cholinergic receptor antagonist (Japanese Patent Laid-Open No. 7-215943). Such cholinergic receptor antagonists have anti-cholinergic effects, particularly strong selective antagonism to the smooth muscle muscarinic receptors such as the gastrointestinal tract, trachea, and bladder, irritable bowel syndrome, diverticular disease, It is known to be effective in treating gastrointestinal motility disorders such as functional diarrhea, esophageal anorexia, cardia spasm, treatment of biliary tract, urethral spasm, urinary incontinence, etc. (H. Miyachi et al., Bioorg. Med. Chem. Lett., 8 [1998] 1807-1812, Bioorg. Med. Chem., 7 [1999] 1151-1116, Bioorg. Med. Chem. Lett., 9 [1999]. ] 3003-3008.).
In general, the antagonistic action of a muscarinic acetylcholine receptor blocker has poor organ selectivity, and thus the occurrence of side effects is a problem, and the development of a highly selective anticholinergic drug is desired.
It is an object of the present invention to provide a drug having a strong antagonistic action with higher selectivity for smooth muscle muscarinic receptors than cardiac muscarinic receptors.
Disclosure of the invention
In order to solve the above-mentioned problems, the present inventors have focused attention on 2,2-diphenylbutanamide derivatives, and as a result of intensive studies, general formula (1)
Of these, as the main compounds
4- (2-methyl-4,5-dioxo-1,3-imidazolidin-1-yl) -2, 2-diphenylbutanamide (abbreviated as RC2), 2-acetylamino-N- (3-carbamoyl- 3,3-diphenylpropyl) acetamide (abbreviated as RC3), N- (3-carbamoyl-3,3-diphenylpropyl) oxamide (abbreviated as RC4), N- (3-carbamoyl-3,3-diphenylpropyl) oxamide Acid (abbreviated as RC5), 1- [3- (3-carbamoyl-3,3-diphenyl) propyl-2-methyl-1-imidazolio] -1-deoxy-β-D-glucopyranuronate (abbreviated as RC7) ), N- [3-carbamoyl-3- (4-hydroxyphenyl) -3-phenylpropyl] oxamide (abbreviated as RC8), 1- [2,2-dipheny -4- (2-Methylimidazol-1-yl) butyrylamino] -1-deoxy-D-glucopyranuronic acid (abbreviated as RC9), 1- [3- (3-carbamoyl-3,3-diphenylpropyl)- 2-methyl-1-imidazolio] -1-deoxy-α-D-glucopyranuronate (abbreviated as RC10), 4-acetimidoylamino-2,2-diphenylbutanamide (abbreviated as RC11), 4- ( 2-methyl-5-oxo-4,5-dihydroimidazol-1-yl) -2,2-diphenylbutanamide (abbreviated as RC12), 4- (2-methyl-4,5-dioxo-4,5- And a compound that is dihydroimidazol-1-yl) -2,2-diphenylbutanamide (abbreviated as RC13).
According to the present invention, compound (RC2) can be synthesized by the method shown in Scheme 1.
N- (1-aminoethyl) benzamide hydrochloride (8) synthesized by a known method is chloroacetylated and then in the presence of a base (for example, sodium hydride, t-butoxypotassium, etc.) in an inert solvent (for example, dimethylformamide). Amides such as dimethyl sulfoxide or ethers such as tetrahydrofuran) to react at −20 ° C. to 80 ° C. for 1 to 8 hours to give compound (9), and then converted to t-butoxycarbonyl (Boc) to give compound (10 ). This is reacted with a Davis reagent at −78 to 20 ° C. in an ether such as tetrahydrofuran or a solvent such as toluene, or 20 to 80 ° C. in carbon tetrachloride with N-bromosuccinimide (NBS) or the like. And an oxidizing agent such as chromic acid (eg, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), etc. in an inert solvent (eg, halogenated hydrocarbon such as methylene chloride or chloroform), Or a carrier containing them) at 20 to 40 ° C. for 1 to 24 hours to give compound (11). Next, this is reacted with a primary amine (eg, n-butylamine, benzylamine, etc.) in an inert solvent (preferably acetonylyl, methylene chloride, etc.) at −40-80 ° C. for 1-24 hours to obtain compound (12) did. This is treated with 4-bromo-2,2-diphenylbutyronitrile in an inert solvent (preferably amides such as dimethylformamide or tetrahydrofuran) in the presence of a suitable base (for example, sodium hydride, t-butoxypotassium, etc.). And 20 to 120 ° C., followed by removal of the Boc group to obtain a compound (13). Furthermore, RC2 was synthesized by reacting this with N, N-diethylhydroxylamine at 20 to 110 ° C. in water or an inert solvent (preferably dioxane, methylene chloride, etc.).
Compound (RC3) and compound (RC5) can be synthesized by the method shown in Scheme 2.
Chloroethyldibenzylamine synthesized by a known method on commercially available diphenylacetonitrile (14) in the presence of a base (for example, sodium hydride, t-butoxypotassium, etc.) and an inert solvent (preferably dimethylformamide, tetrahydrofuran, etc.) It was made to react at 0-80 degreeC in 1 to 24 hours, and it was set as the compound (15). Next, the compound is reacted with an inorganic base (for example, potassium hydroxide, sodium hydroxide, etc.) or an acid (for example, sulfuric acid) without solvent or in a suitable solvent (for example, acetic acid, isopropanol, etc.) at 20 to 160 ° C. for 1 to 60 hours. (16) and further reduction by catalytic hydrogenation, that is, in an inert solvent (eg, ethanol, methanol, dimethylformamide, ethyl acetate, etc.), an appropriate catalyst (eg, palladium carbon, palladium hydroxide carbon, etc.) Compound (17) was obtained by hydrogenation at 20 to 80 ° C. and 101 to 490 kPa in the presence. This was acylated with chloroglyoxylate, and then hydrolyzed with an aqueous sodium carbonate solution to obtain compound (RC5).
On the other hand, the compound (17) is mixed with t-butoxycarbonylglycine or benzyloxycarbonylglycine and a suitable condensing agent (for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), diethyl cyanophosphonate (DEPC) And the like in a suitable solvent (eg dimethylformamide, methylene chloride, etc.) in the presence of an organic base (eg triethylamine etc.) at −5 to 50 ° C. for 0.5 to 24 hours to give compound (18). . Furthermore, after deprotecting the carbamate group by a known method, RC3 was synthesized by acetylation.
Compound (RC4) and compound (RC11) can be synthesized by the method shown in Scheme 3.
Of these, the compound (RC4) can be synthesized by the following two methods.
N-halogen succinimide (for example, N-bromosuccinic acid, for example) is added to 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide (3, X = H) disclosed in JP-A-7-215943. Imide (NBS), N-chlorosuccinimide (NCS), etc.) is reacted in hydrated dimethylformamide at -5 ° C to 40 ° C for 1 to 8 hours to give compound (19). RC4 was synthesized by reacting in tetrahydrofuran at −5 to 40 ° C. for 0.5 to 24 hours. Further, oxamic acid can be combined with the above compound (17) with a suitable condensing agent (for example, EDC, 1,1′-carbonyldiimidazole (CDI), etc.) or an active esterifying agent (for example, 1-hydroxybenzotriazole (HOBt)). RC4 was synthesized by reacting in an inert solvent (preferably methylene chloride, tetrahydrofuran, etc.) at 0 to 40 ° C. for 1 to 24 hours.
Compound (RC11) is obtained by synthesizing S-benzylthioacetimidate hydrobromide synthesized by a known method for compound (17) in an appropriate solvent (preferably an alcohol such as ethanol) at -5 to 40 ° C. It was reacted for 0.5 to 24 hours and synthesized.
Compound (RC8) can be synthesized by the method shown in Scheme 4.
A compound (20) that can be synthesized by a known method is prepared by using chloroethyldibenzylamine and a base (for example, sodium hydride, t-butoxypotassium, etc.) in an inert solvent (preferably dimethylformamide, tetrahydrofuran, etc.), −20 The compound (21) was obtained by reacting at 80 to 80 ° C. for 1 to 8 hours. This is treated with an inorganic base (for example, potassium hydroxide, sodium hydroxide, etc.) or acid (for example, sulfuric acid, etc.) and no solvent or in a suitable solvent (for example, acetic acid, ethanol, isopropanol, etc.) at 20-160 ° C., 1-60 Compound (22) is allowed to react for a period of time, and this is reduced by catalytic hydrogenation, that is, in an appropriate solvent (eg, ethanol, methanol, dimethylformamide, ethyl acetate, etc.), and an appropriate catalyst (eg, palladium carbon, palladium hydroxide carbon). Etc.) was hydrogenated at 20 to 80 ° C. and 101 to 4903 kPa to obtain Compound (23). Next, this is reacted at -78 to 30 ° C in an inert solvent (preferably methylene chloride, dimethylformamide, etc.) in the presence of ethyl chloroglyoxylate and an organic base (eg triethylamine, N-methylmorpholine, etc.) Compound (24) was obtained, and this was reacted in aqueous ammonia and an inert solvent (preferably ethers such as dioxane and tetrahydrofuran) at −5 to 30 ° C. for 0.5 to 2 hours to obtain compound (25). Further, this was reacted with boron tribromide in an inert solvent (preferably methylene chloride, tetrahydrofuran, etc.) at −78 to 40 ° C. for 1 to 24 hours to synthesize RC8.
Compound (RC7) can be synthesized by two methods shown in Schemes 5 and 6.
(Method 1)
Compound (26), which can be synthesized by a known method, was p-methoxybenzylated to give compound (27). This is reacted in a reducing agent (eg, diisobutylaluminum hydride, lithium aluminum hydride, etc.) and an inert solvent (preferably toluene, methylene chloride, ether, etc.) at −78 to 30 ° C. for 0.5 to 24 hours to give a compound ( 28). The compound (28) is oxidized to a carboxylic acid of an alcohol (preferably chromic acid-sulfuric acid in acetone or an oxidation method by PDC in dimethylformamide), and then the resulting carboxyl group is esterified to give a compound ( 29), and then the p-methoxybenzyl group was removed, followed by benzoylation to give compound (31). This was reacted with acetic anhydride and sulfuric acid in an inert solvent (preferably acetone, tetrahydrofuran, etc.) at −5 to 50 ° C. for 0.5 to 24 hours to obtain a compound (32). Compound (32) was reacted with aqueous ammonia at −5 to 30 ° C. for 0.5 to 24 hours in methanol, tetrahydrofuran or a mixed solvent thereof to obtain Compound (33). Furthermore, the alcohol group at the 1-position is converted to a halogen (preferably using triphenylphosphine / carbon tetrabromide or methylene phosphomethylene chloride / tetrahydrofuran at −5 to 50 ° C. for 0.5 to 24 hours. ) To give compound (34). This was reacted with compound (3, X = H) in an inert solvent (preferably toluene, xylene, dioxane, chloroform, etc.) at 20 to 150 ° C. for 1 to 24 hours to obtain compound (35). This was reacted with ferrous chloride in methylene chloride at 0 to 50 ° C. for 0.5 to 24 hours, followed by sodium hydroxide and an inert solvent (preferably water, methanol, ethanol or a mixed solvent thereof). ) Was reacted at 0 to 40 ° C. for 0.5 to 24 hours to synthesize RC7.
(Method 2)
The compound (36) that can be synthesized by a known method is reacted with methanesulfonic acid and an inert solvent (preferably methylene chloride, tetrahydrofuran) at 0 to 50 ° C. for 0.5 to 6 hours to obtain a compound (37). The compound (3, X═H) was reacted in an inert solvent (preferably toluene, xylene, dioxane, chloroform, etc.) for 1 to 24 hours to obtain a compound (38). This was reacted in an inorganic base aqueous solution (for example, sodium hydroxide aqueous solution, potassium carbonate aqueous solution, sodium hydrogen carbonate aqueous solution, etc.) at −50 to 40 ° C. for 1 to 24 hours to synthesize RC7.
Compound (RC9) can be synthesized by the method shown in Scheme 7.
The compound (3, X = H) is heated to reflux in hydrochloric acid for 2 to 24 hours to obtain a compound (39). After converting this carboxyl group to an acid chloride, the compound (40) which can be synthesized by a known method and an organic base Compound (41) is reacted in an inert solvent (preferably a halogenated hydrocarbon such as methylene chloride or chloroform) in the presence of (for example, triethylamine, N-methylmorpholine, etc.) at 0-50 ° C. for 0.5-24 hours. RC9 was then synthesized by removing the ester group by alkaline hydrolysis followed by catalytic hydrogenation.
Compound (RC10) can be synthesized by the method shown in Scheme 8.
Compound (42), which can be synthesized by a known method, and compound (3, X═H) are reacted in an inert solvent (preferably toluene, xylene, dioxane, etc.) at 20 to 150 ° C. for 1 to 24 hours to give compound (43 ). This was reacted with ferrous chloride in methylene chloride at 0 to 50 ° C. for 0.5 to 24 hours, followed by sodium hydroxide and an inert solvent (preferably water, methanol, ethanol or a mixed solvent thereof). ) Was reacted at 0 to 40 ° C. for 0.5 to 24 hours to synthesize RC10.
Compound (RC12) can be synthesized by the method shown in Scheme 9.
Reduction of compound (16) by catalytic hydrogenation, ie, in an inert solvent (eg, ethanol, methanol, dimethylformamide, ethyl acetate, etc.) in the presence of a suitable catalyst (eg, palladium carbon, palladium hydroxide carbon, etc.) By hydrogenating at 20 to 80 ° C. and 101 to 490 kPa, a compound (17) is obtained, which is purified without purification in an appropriate solvent (for example, methylene chloride, chloroform or the like) in the presence of an organic base (for example, triethylamine or the like). Compound (44) was obtained by reacting with acetyl chloride at −5 to 50 ° C. for 1 to 48 hours. Next, the compound (45) is reacted with chloroacetyl chloride in an appropriate solvent (for example, benzene, toluene, chloroform, etc.) in the presence of an organic base (for example, triethylamine) at room temperature to the solvent reflux temperature for 1 to 10 hours. ). Next, this was reacted with sodium azide in a suitable nonpolar solvent (for example, dimethyl sulfoxide, N, N-dimethylformamide, etc.) at −5 to 50 ° C. for 10 minutes to 2 hours to give compound (46). Further, this is reacted with a trialkylphosphine or a triarylphosphine (eg, tri-n-butylphosphine, triphenylphosphine) at -20 to 50 ° C. for 1 to 24 hours in an appropriate solvent (eg, benzene, toluene, chloroform, etc.). To give compound (RC12).
Compound (RC13) can be synthesized by the method shown in Scheme 10.
4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyramide (3, X = H) of known (JP-A-7-215943) is used as an inert solvent (for example, ethanol, methanol, dimethylformamide, ethyl acetate) In the presence of tetraphenylporphyrin manganese chloride (or tetraphenylporphyrin iron chloride) and iodosobenzene in acetonitrile, methylene chloride, chloroform, etc., the compound (RC13) is reacted at 0-80 ° C. for 6-48 hours. Obtained.
BEST MODE FOR CARRYING OUT THE INVENTION
Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
<Example 1>
4- (2-Methyl-4,5-dioxo-1,3-imidazolidin-1-yl) -2,2-diphenylbutanamide (RC2)
[1] N- (1-aminoethyl) benzamide hydrochloride (8)
N-benzoyl-dl-alaninamide (80.7 g, 420 mmol) was added to a solution of bis (trifluoroacetoxy) iodobenzene (205.1 g, 462 mmol) in acetonitrile / purified water (1: 1) (2100 mL) at room temperature. For 2 hours. Ether (2000 mL) was added to the reaction solution, and the separated aqueous layer was separated. The organic layer was extracted with 1 mol / L hydrochloric acid (420 mL × 2,210 mL), and then the aqueous layers were combined and concentrated under reduced pressure. The residue was suspended and washed with a mixture of ether / ethanol (9: 1) (1000 mL) and dried under reduced pressure at 50 ° C. to obtain 48.8 g (58%) of N- (1-aminoethyl) benzamide hydrochloride as a white powder. It was.
1H-NMR (DMSO-d6, 400 MHz) δ: 1.53 (3H, d, J = 6.4 Hz), 5.18 (1H, br), 7.48-7.60 (3H, m), 7.94 (2H, d, J = 7.8 Hz), 8.50 (3H, br), 9.34 (1H, d, J = 7.3 Hz).
EI-MS (m / z): 164 (M+), 105.
[2] N-[(1-chloroacetylamino) ethyl] benzamide
To a suspension of N- (1-aminoethyl) benzamide hydrochloride (47.2 g, 235 mmol) in anhydrous dimethylformamide (235 mL) was added diisopropylethylamine (98.2 mL, 564 mmol) under ice water cooling, and the mixture was stirred for 1 hour. . Chloracetyl chloride (22.4 mL, 282 mmol) was added dropwise to the mixture at an internal temperature of 5-7 ° C. over 30 minutes, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in methylene chloride (1500 mL). The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended and washed with ether and then dried under reduced pressure at 70 ° C. to obtain 29.8 g (53%) of N-[(1-chloroacetylamino) ethyl] benzamide as a brown powder.
1H-NMR (DMSO-d6, 400 MHz) δ: 1.37 (3H, d, J = 6.8 Hz), 4.07 (2H, q, J = 13.2 Hz), 5.62-5.71 (1H, m), 7. 44-7.55 (3H, m), 7.83-7.85 (2H, m), 8.47 (1H, d, J = 7.3 Hz), 8.70 (1H, d, J = 7) .3 Hz).
FAB-MS (m / z): 241 [M + H]+.
[3] 1-Benzoyl-2-methyl-1,3-imidazolidin-4-one (9) N-[(1-chloroacetylamino) ethyl] benzamide (28.9 g, 120 mmol) in anhydrous dimethylformamide (1200 mL) ) Sodium hydride (14.4 g, 360 mmol) was added to the solution while cooling with ice water, and the mixture was stirred for 4 hours. Acetic acid (30 mL) was added to the reaction solution, the temperature was returned to room temperature, and the mixture was stirred for 0.5 hour, and then left overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in methylene chloride (300 mL) and purified water (100 mL). The methylene chloride layer was separated, and the aqueous layer was extracted with methylene chloride (100 mL × 4). The methylene chloride layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Ether (300 mL) was added to the residue, and the precipitated crystals were collected by filtration, dried under reduced pressure at 70 ° C., and 20.6 g of brown powder 1-benzoyl-2-methyl-1,3-imidazolidin-4-one. (84%) obtained.
1H-NMR (DMSO-d6, 90 MHz) δ: 1.35 (3H, br), 3.62-4.29 (2H, m), 5.44 (1H, q, J = 5.1 Hz), 7.44-7.62 (5H, m), 8.73 (1H, br).
EI-MS (m / z): 204 (M+), 105.
[4] 1-benzoyl-3-t-butoxycarbonyl-2-methyl-1,3-imidazolidin-4-one (10)
To a solution of 1-benzoyl-2-methyl-1,3-imidazolidin-4-one (19.8 g, 97.0 mmol) and t-butyl dicarbonate (23.3 g, 106.7 mmol) in anhydrous acetonitrile (485 mL) Then, 4,4-dimethylaminopyridine (593 mg, 4.85 mmol) was added at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, eluting with n-hexane: ethyl acetate = 2: 1. The solvent was distilled off, and the resulting residue was suspended and washed with petroleum ether (50 mL), dried under reduced pressure at 50 ° C., and then white powder of 1-benzoyl-3-t-butoxycarbonyl-2-methyl-1,3. -20.0 g (68%) of imidazolidin-4-one was obtained.
1H-NMR (CDCl3, 400 MHz) δ: 1.57-1.66 (12H, m), 4.05-4.28 (2H, m), 6.24 (1H, br), 7.44-7.52 (5H, m).
FAB-MS (m / z): 305 [M + H]+.
[5] 1-benzoyl-3-t-butoxycarbonyl-2-methyl-1,3-imidazolidine-4,5-dione (11)
1-benzoyl-3-t-butoxycarbonyl-2-methyl-1,3-imidazolidin-4-one (19.2 g, 63.0 mmol) and N-bromosuccinimide (12.3 g, 69.3 mmol) Benzoyl peroxide (10.0 mg) was added to a suspension of carbon tetrachloride (315 mL), and the mixture was heated to reflux for 0.5 hours. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution (200 mL), saturated aqueous sodium hydrogen sulfite solution (200 mL) and purified water (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methylene chloride (315 mL), pyridinium dichromate (47.4 g, 126 mmol) was added, and the mixture was stirred at room temperature for 20 hr. The insoluble material was removed using a celite pad, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane: ethyl acetate = 2: 1. The solvent was concentrated, and the obtained residue was suspended and washed with n-pentane (30 mL), and then dried under reduced pressure at 50 ° C. to give 1-benzoyl-3-t-butoxycarbonyl-2-methyl-1, white powder. 10.1 g (50%) of 3-imidazolidine-4,5-dione was obtained.
1H-NMR (CDCl3, 400 MHz) δ: 1.62 (9H, s), 1.78 (3H, d, J = 5.9 Hz), 6.07 (1H, q, J = 5.9 Hz), 7.46-7. 50 (2H, m), 7.62-7.66 (1H, m), 7.69-7.71 (2H, m).
FAB-MS (m / z): 319 [M + H]+.
[6] 3-t-Butoxycarbonyl-2-methyl-1,3-imidazolidine-4,5-dione (12)
To a solution of 1-benzoyl-3-t-butoxycarbonyl-2-methyl-1,3-imidazolidine-4,5-dione (9.87 g, 31.0 mmol) in anhydrous acetonitrile (1550 mL) was added n -A solution of butylamine (2.27 g, 31.0 mmol) in anhydrous acetonitrile (155 mL) was added dropwise over 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended and washed with ether (30 mL), and then dried under reduced pressure at 30 ° C. to give 3-t-butoxycarbonyl-2-methyl-1,3-imidazolidine as white powder. 6.07 g (91%) of -4,5-dione was obtained.
1H-NMR (CDCl3, 400 MHz) δ: 1.59 (9H, s), 1.66 (3H, d, J = 5.9 Hz), 5.38 (1H, q, J = 5.9 Hz), 9.37 (1H , Br s).
FAB-MS (m / z): 213 [M-H]−.
[7] 4- (2-Methyl-4,5-dioxo-1,3-imidazolidin-1-yl) -2,2-diphenylbutyronitrile (13)
To a solution of 3-t-butoxycarbonyl-2-methyl-1,3-imidazolidine-4,5-dione (6.00 g, 28.0 mmol) in anhydrous dimethylformamide (560 mL) was added sodium hydride (cooling with ice water). 1.34 g, 33.6 mmol) was added, and the mixture was stirred for 0.5 hour, then returned to room temperature and stirred for 1 hour. 4-Bromo-2,2-diphenylbutyronitrile (84.1 g, 280 mmol) was added to the mixture and stirred at 80 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (500 mL). The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was dissolved in methylene chloride (280 mL), trifluoroacetic acid (100 mL) was added with cooling with ice water, and the mixture was returned to room temperature and stirred for 4 hr. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in methylene chloride (500 mL). The methylene chloride layer was washed successively with a saturated aqueous sodium bicarbonate solution (200 mL × 2) and purified water (100 mL), then dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was suspended and washed with ether (300 mL) and then dried under reduced pressure at 50 ° C. to give 4- (2-methyl-4,5-dioxo-1,3-imidazolidin-1-yl) -2, 6.53 g (70%) of 2-diphenylbutyronitrile was obtained.
1H-NMR (CDCl3, 400 MHz) δ: 1.45 (3H, d, J = 5.9 Hz), 2.66-2.74 (1H, m), 2.82-2.90 (1H, m), 3.38- 3.45 (1H, m), 3.70-3.77 (1H, m), 4.90 (1H, q, J = 5.9 Hz), 7.30-7.45 (10H, m), 9.00 (1H, br s).
EI-MS (m / z): 333 (M+), 192, 165.
[8] 4- (2-Methyl-4,5-dioxo-1,3-imidazolidin-1-yl) -2,2-diphenylbutanamide (RC2)
A suspension of 4- (2-methyl-4,5-dioxo-1,3-imidazolidin-1-yl) -2,2-diphenylbutyronitrile (6.33 g, 19.0 mmol) in anhydrous dioxane (317 mL). N, N-diethylhydroxylamine (100 mL, 950 mmol) was added to the solution and stirred at 100 ° C. for 96 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, eluting with methylene chloride: methanol = 20: 1. The solvent was distilled off, and the resulting residue was dissolved in chloroform (30 mL), stirred at room temperature for 0.5 hour, and the precipitated solid was collected by filtration. The solid was recrystallized from chloroform-acetone (4: 1) mixed solution (200 mL), dried under reduced pressure at 80 ° C. to 100 ° C., and allowed to stand at room temperature for 14 hours to obtain 3.90 g (58%) of the target compound as a white powder. It was.
mp. 203-204 ° C
IR (KBr) cm-1: 3236, 1747, 1666.
Anal. calcd C20H21N3O3・ 0.3H2O: C, 67.32; H, 6.10; N, 11.78.
Found: C, 67.13; H, 5.99; N, 11.96.
EI-MS (m / z): 193 (Base peak), 211, 351 [M]+.
1H-NMR (DMSO-d6, 400 MHz) δ: 1.18 (3H, d, J = 5.9 Hz), 2.38 (1H, ddd, J = 5.4, 12.7, 17.6 Hz), 2.68 (1H, ddd) , J = 3.9, 12.7, 16.9 Hz), 2.78-2.85 (1H, m), 3.26 (1H, ddd, J = 5.4, 13.2, 17.6 Hz) ), 4.95 (1H, q, J = 5.9 Hz), 6.87 (1H, brs), 7.24-7.36 (11H, m), 9.80 (1H, brs). Moisture measurement (Karl Fischer method): 1.47%
<Example 2>
N- (3-carbamoyl-3,3-diphenylpropyl) oxamic acid (RC5)
[1] N- (2-chloroethyl) dibenzylamine
A 1 mol / L aqueous sodium hydroxide solution (120 mL) was added to N- (2-chloroethyl) dibenzylamine hydrochloride (23.7 g, 80.0 mmol), and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate (100 mL, 50 mL), the ethyl acetate layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was dried with a vacuum pump to obtain 20.8 g (quantitative) of pale yellow oily N- (2-chloroethyl) dibenzylamine.
1H-NMR (90 MHz, CDCl3) Δ: 2.83 (2H, t, J = 7.5 Hz), 3.49 (2H, t, J = 7.5 Hz), 3.66 (4H, s), 7.23-7.39 ( 10H, m).
[2] 4-Dibenzylamino-2,2-diphenylbutyronitrile (15)
Sodium hydride (2.88 g, 72.0 mmol) was added to a 60 mL anhydrous dimethylformamide solution of diphenylacetonitrile (11.6 g, 60.0 mmol), and the mixture was stirred at room temperature for 1 hour. N- (2-chloroethyl) dibenzylamine (20.8 g) was added to the mixture, and the mixture was stirred at room temperature for 4 hours, then at 50 ° C. for 4 hours, then returned to room temperature and left overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (100 mL) and water (50 mL). The ethyl acetate layer was separated, washed with water (50 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane: ethyl acetate = 15: 1. The solvent was distilled off to obtain 21.1 g (84%) of 4-dibenzylamino-2,2-diphenylbutyronitrile as a yellow oily substance.
EI-MS (m / z): 91 (Base Peak), 210, 416 (M+).
1H-NMR (400 MHz, CDCl3) Δ: 2.48-2.55 (2H, m), 2.57-2.66 (2H, m), 3.58 (4H, s), 7.20-7.34 (20H, m) .
[3] 4-Dibenzylamino-2,2-diphenylbutanamide (16)
To a solution of 4-dibenzylamino-2,2-diphenylbutyronitrile (20.8 g, 50.0 mmol) in isopropanol (104 mL) was added potassium hydroxide (19.6 g, 350 mmol), and the mixture was heated to reflux for 33 hours. The temperature was returned to room temperature and left for 4 days. The reaction solution was poured into ice water (200 mL) and stirred for 10 minutes, and then the mixture was extracted with ethyl acetate (300 mL). The ethyl acetate layer was washed with water (50 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane: ethyl acetate = 3: 1. The solvent was distilled off, and the resulting residue was suspended and washed with diisopropyl ether (50 mL), and then dried under reduced pressure at 50 ° C. to obtain 15.6 g of white powder of 4-dibenzylamino-2,2-diphenylbutanamide ( 72%).
FAB-MS (m / z): 435 [M + H]+.
11 H-NMR (400 MHz, DMSO-d6) Δ: 2.05 to 2.09 (2H, m), 2.54 to 2.58 (2H, m), 3.46 (4H, s), 6.93 and 7.08 (each 1H, s) ), 7.11-7.29 (20H, m).
[4] 4-Amino-2,2-diphenylbutanamide (17)
Using a medium pressure reduction apparatus, 20% hydroxylation was performed on a solution of 4-dibenzylamino-2,2-diphenylbutanamide (14.8 g, 34.0 mmol) in ethyl acetate-ethanol (1: 1) (592 mL). Palladium-carbon (2.96 g) was added, and hydrogenated at 40 ° C. for 7 hours under hydrogen pressure (412 kPa). After the catalyst was filtered off, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (200 mL). The ethyl acetate solution was extracted with 1 mol / L hydrochloric acid (50 mL × 2), and 1 mol / L sodium hydroxide aqueous solution was added to the extracted hydrochloric acid layer to adjust pH = 9.0, followed by extraction with ethyl acetate (200 mL × 3). . The ethyl acetate solutions were combined, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was suspended and washed with a mixed solution (200 mL) of n-hexane-ethyl acetate (3: 1), dried under reduced pressure at 50 ° C., and 5.67 g of 4-amino-2,2-diphenylbutanamide as a white powder ( 66%).
EI-MS (m / z): 193, 237 (BP), 254 (M)+.
11 H-NMR (400 MHz, DMSO-d6) Δ: 1.37 (2H, br), 2.18-2.22 (2H, m), 2.33-2.37 (2H, m), 7.11 (1H, s), 7.18 -7.31 (11H, m).
[5] Ethyl N- (3-carbamoyl-3,3-diphenylpropyl) oxamate
4-Amino-2,2-diphenylbutanamide (6.77 g, 26.6 mmol) was dissolved in methylene chloride (200 mL), triethylamine (3.00 g, 29.6 mmol) was added with cooling with ice water, and then chloroglyoxyl. Ethyl acid (4.00 g, 29.3 mmol) was added dropwise. After stirring at room temperature for 10 minutes, methylene chloride (200 mL) was added to the reaction mixture, and the mixture was washed successively with water (200 mL) and saturated aqueous sodium hydrogen carbonate solution (200 mL). The aqueous layer was extracted sequentially with methylene chloride (200 mL). The methylene chloride layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was washed with ethanol (10 mL) to obtain 7.29 g (67%) of white crystalline ethyl N- (3-carbamoyl-3,3-diphenylpropyl) oxamate.
mp. 203-206 ° C
FAB-MS (m / z): 355 [M + H]+.
1H-NMR (CDCl3, 400 MHz) δ: 1.36 (3H, t, J = 7.3 Hz), 2.69 (2H, t, J = 6.8 Hz), 3.21 (2H, q, J = 6.4 Hz), 4.31 (2H, q, J = 7.3 Hz), 5.70 (2H, d, J = 7.8 Hz), 7.26-7.38 (10H, m), 7.96 (1H, br) s).
[6] N- (3-carbamoyl-3,3-diphenylpropyl) oxamic acid (RC5)
Ethyl N- (3-carbamoyl-3,3-diphenylpropyl) oxamate (10.6 g, 30.0 mmol) was suspended in ethanol (500 mL), 10% aqueous sodium carbonate solution (106 mL) was added, and the mixture was stirred while stirring. Heated to reflux for hours. The reaction solution was concentrated under reduced pressure, purified water (800 mL) was added to the resulting residue to dissolve it, the insoluble material was filtered, and the filtrate was washed successively with methylene chloride (400 mL) and ethyl acetate (400 mL). 2 mol / L hydrochloric acid (120 mL) was added dropwise to the aqueous layer under ice water cooling to neutralize, and the precipitated crystals were collected by filtration. The crystals were recrystallized from ethanol (300 mL) and dried under reduced pressure at 100 ° C. to obtain 6.16 g (63%) of the target compound as white crystals.
mp. 193-195 ° C. (dec.)
IR (KBr) cm-1: 3428, 3319, 3251, 1759, 1654, 1159, 701.
Anal. Calcd C18H18N2O4: C, 66.25; H, 5.56; N, 8.58.
Found: C, 66.07; H, 5.58; N, 8.64.
FAB-MS (m / z): 327 [M + H]+.
1H-NMR (DMSO-d6, 400 MHz) δ: 2.47-2.51 (2H, m), 2.78-2.83 (2H, m), 6.95 (1H, s), 7.23-7.37 (11H, m), 8.81 (1H, t, J = 5.4 Hz), 13.77 (1H, br s).
<Example 3>
2-acetylamino-N- (3-carbamoyl-3,3-diphenylpropyl) acetamide (RC3)
[1] 2- (tert-Butoxycarbonylamino) -N- (3-carbamoyl-3,3-diphenylpropyl) acetamide
4-amino-2,2-diphenylbutanamide (17) (2.54 g, 10.0 mmol), tert-butoxycarbonylglycine (1.75 g, 10.0 mmol) and 1-hydroxybenzotriazole monohydrate ( 1.35 g (10.0 mmol) in methylene chloride (50 mL) in 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.92 g, 10.0 mmol) and triethylamine (2.02 g, 20. 0 mmol) was added and the mixture was stirred for 10 minutes and then left at room temperature for 15.5 hours. Ethyl acetate (500 mL) was added to the reaction solution, and the mixture was washed successively with 0.5 mol / L aqueous sodium hydroxide solution (200 mL × 2), 1 mol / L hydrochloric acid (200 mL), water (200 mL), and saturated aqueous sodium chloride solution (200 mL). . The aqueous layer was sequentially extracted with ethyl acetate (500 mL), and then the ethyl acetate layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with methylene chloride → methylene chloride: methanol (20: 1). The desired fraction was distilled off under reduced pressure, the residue was dissolved in ethanol (20 mL), and the precipitated crystals were collected by filtration and dried under reduced pressure at 80 ° C. to give white crystals of 2- (tert-butoxycarbonylamino) -N. 2.79 g (68%) of-(3-carbamoyl-3,3-diphenylpropyl) acetamide was obtained.
mp 187-190 ° C (dec.).
Anal. Calcd C23H29N3O4: C, 67.13; H, 7.10; N, 10.21.
Found: C, 67.05; H, 7.20; N, 10.29.
FAB-MS (m / z): 412 [M + H]+.
1H-NMR (DMSO-d6, 400 MHz) δ: 1.37 (9H, s), 2.40-2.44 (2H, m), 2.68-2.73 (2H, m), 3.45 (2H, d, J = 5.9 Hz), 6.88 (1 H, t, J = 5.9 Hz), 7.03 (1 H, br s), 7.22 (1 H, br s), 7.22-7.34 (10 H, m), 7.79 (1H, t, J = 5.4 Hz).
[2] 2-acetylamino-N- (3-carbamoyl-3,3-diphenylpropyl) acetamide (RC3)
To 2- (tert-butoxycarbonylamino) -N- (3-carbamoyl-3,3-diphenylpropyl) acetamide (2.74 g, 6.66 mmol) was added trifluoroacetic acid (7.60 g, 66.7 mmol). After dissolution, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (50 mL), triethylamine (3.03 g, 29.9 mmol) and acetic anhydride (2.04 g, 20.0 mmol) were added, and the solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (200 mL) and washed with saturated aqueous sodium bicarbonate (200 mL). Crystals precipitated in the liquid separation were collected by filtration, and the methylene chloride layer of the filtrate was collected. The aqueous layer was extracted with methylene chloride (200 mL), the methylene chloride layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue and the crystals collected earlier were combined, dissolved in methylene chloride (400 mL) with heating, subjected to silica gel column chromatography, and eluted with methylene chloride → methylene chloride: methanol (20: 1). The objective fraction was distilled off under reduced pressure, and the resulting crude crystals (2.08 g) were dissolved in methanol (50 mL). The precipitated crystals were collected by filtration and dried under reduced pressure at 80 ° C. to obtain 1.85 g of methanol-containing crystals. The crystals were heated and dissolved in methanol (50 mL), filtered, purified water (30 mL) was added to the filtrate, methanol was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and dried at 100 ° C. under reduced pressure. 1.73 g (95%) of the target compound as white crystals was obtained.
mp. 221-224 ° C.
IR (KBr) cm-1: 3337, 1683, 1665, 1631, 1538.
Anal. Calcd C20H23N3O3: C, 67.97; H, 6.56; N, 11.89.
Found: C, 67.81; H, 6.54; N, 11.84.
FAB-MS (m / z): 354 [M + H]+.
1H-NMR (DMSO-d6, 400 MHz) δ: 1.84 (3H, s), 2.40-2.44 (2H, m), 2.67-2.73 (2H, m), 3.58 (2H, d, J = 5.9 Hz), 7.03 (1H, br s), 7.22 (1 H, br s), 7.23-7.34 (10 H, m), 7.85 (1 H, t, J = 5. 4 Hz), 8.04 (1H, t, J = 5.9 Hz).
<Example 4>
2-acetylamino-N- (3-carbamoyl-3,3-diphenylpropyl) acetamide (RC3)
4-amino-2,2-diphenylbutanamide (17) (509 mg, 2.0 mmol), benzyloxycarbonylglycine (418 mg, 2.00 mmol), HOBt · H2EDC.HCl (383 mg, 2.0 mmol) and triethylamine (558 μL, 4.00 mmol) were added to a solution of O (270 mg, 2.00 mmol) and methylene chloride (10 mL), and the mixture was stirred at room temperature for 8 hours and then left overnight. . Ethyl acetate was added thereto, and the organic layer was washed twice with a 1 mol / L aqueous sodium hydroxide solution, once with a 1 mol / L aqueous hydrochloric acid solution, once with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a colorless solid (810 mg). A suspension of 7.5% Pd—C (162 mg), THF (16 mL) and acetic anhydride (189 μL, 2.00 mmol) was catalytically reduced at room temperature and normal pressure for 6 hours. DMF was added to the reaction solution, insolubles were filtered off, the filtrate was concentrated under reduced pressure, the resulting residue was dissolved again in methanol, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to obtain a colorless powder (368 mg). This was suspended and washed in acetonitrile (36 mL) while hot to obtain 320 mg (47%) of the target compound.
mp. 214-215 ° C.
IR (KBr, cm-1; 3432, 1682, 1655, 1632.
Anal. Calcd C20H23N3O3: C, 67.97; H, 6.56; N, 11.89
Found: C, 67.95; H, 6.65; N, 11.88.
FAB-MS (m / z); 354 (M + H)+.
11 H-NMR (400 MHz, DMSO-d6) Δ; 1.84 (3H, s), 2.40-2.44 (2H, m), 2.67-2.73 (2H, m), 3.58 (2H, d, J = 5. 9 Hz), 7.23-7.35 (10 H, m).
13C-NMR (DMSO-d6, 400 MHz) δ; 22.51, 36.17, 36.78, 42.02, 58.72, 126.4, 127.8, 128.7, 143.2, 169.0, 169.5, 175 0.0.
<Example 5>
N- (3-carbamoyl-3,3-diphenylpropyl) oxamide (RC4)
In a similar manner as described in Example 2, crude 4-amino-2,2-diphenylbutanamide (2.7 g (6.21 mmol)) obtained from 2.7 g (6.21 mmol) of 4-dibenzylamino-2,2-diphenylbutanamide ( 17) A solution of oxalic acid (0.57 g), 1-hydroxybenzotriazole monohydrate (1.70 g), triethylamine (0.65 g) in dimethylformamide (30 mL) at room temperature with stirring. (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.21 g) was added. After stirring for 2.5 hours, it was left overnight at room temperature. Water (150 mL) was added to the reaction solution, extracted twice with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting oil was subjected to silica gel chromatography, eluting with ethyl acetate. The solvent was distilled off, and the resulting amorphous material was dissolved in a small amount of methanol and recrystallized by adding water. The crystals were collected by filtration and dried at 100 ° C. under reduced pressure to obtain 0.71 g (35%) of the target compound as a white powder.
mp. 177.5-180.0 ° C.
IR (KBr, cm-13424, 3360, 3328, 3279, 3191, 1728, 1655, 1620.
Anal. Calcd C18H19N3O3: C, 66.45; H, 5.89; N, 12.91.
Found: C, 66.34; H, 5.87; N, 12.86.
FAB-MS (m / z): 326 [M + H]+.
11 H-NMR (400 MHz, DMSO-d6) Δ; 2.47-2.51 (2H, m), 2.78-2.83 (2H, m), 6.99 (1H, s), 7.22-7.32 (6H, m) , 7.73 (1H, s), 8.02 (1H, s), 8.70 (1H, t, J = 5.9 Hz).
13C-NMR (400 MHz, DMSO-d6) Δ; 36.25, 36.37, 58.68, 126.42, 127.81, 128.71, 143.16, 160.24, 162.05, 175.11.
<Example 6>
N- (3-carbamoyl-3,3-diphenylpropyl) oxamide (RC4)
[1] N-acetyl-N ′-(3-carbamoyl-3,3-diphenylpropyl) oxamide (19)
Purified water (100 mL) was added to a solution of N-bromosuccinimide (13.1 g, 73.6 mmol) in dimethylformamide (130 mL), and the mixture was stirred for 20 minutes under cooling with ice water, followed by 4- (2-methyl-1-imidazolyl). ) -2,2-diphenylbutanamide (3, X = H, JP-A-7-215943) (7.05 g, 22.1 mmol) was added little by little, and then the mixture was stirred at room temperature for 4 hours. To the reaction solution were added an aqueous sodium hydrogen sulfite solution and ethyl acetate (400 mL), washed with water (200 mL × 2 times), and the aqueous layer was extracted with ethyl acetate (400 mL). The ethyl acetate layers were combined, washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained oil for crystallization, and the precipitated solid was collected by filtration to give crude product N-acetyl-N ′-(3-carbamoyl-3,3-diphenylpropyl) oxamide (4.70 g). Obtained. This was recrystallized from methylene chloride-ethyl acetate to obtain 3.34 g (41%) of colorless cotton-like N-acetyl-N '-(3-carbamoyl-3,3-diphenylpropyl) oxamide.
EI-MS (m / z): 367 (M+).
1H-NMR (400 MHz, CDCl3) Δ; 2.47 (3H, s), 2.70 (2H, t, J = 6.4 Hz), 3.21 (2H, q, J = 6.4 Hz), 5.47 (1H, br) , 5.81 (1H, br), 7.28-7.39 (10H, m), 8.56 (1H, br), 9.55 (1H, br).
[2] N- (3-carbamoyl-3,3-diphenylpropyl) oxamide (RC4)
N-acetyl-N ′-(3-carbamoyl-3,3-diphenylpropyl) oxamide (3.13 g, 8.52 mmol) was dissolved in 100 mL of dioxane with heating, allowed to cool to room temperature, and then 7 mL of 25% aqueous ammonia was added. Left for hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography, eluting with methylene chloride: methanol (15: 1). The solvent was distilled off, and methanol was added to the obtained oil to crystallize to obtain crude crystals (2.10 g). This was recrystallized from methanol-water and dried under reduced pressure at 100 ° C. to obtain 1.43 g (52%) of the objective compound as colorless prism crystals.
mp 180-181 ° C.
IR (KBr) cm-1: 3424, 3361, 1680, 1655.
Anal. calcd C18H19N3O3: C, 66.45; H, 5.89; N, 12.91.
Found: C, 66.36; H, 5.84; N, 12.84.
EI-MS (m / z): 325 (M+), 281, 211, 193.
FAB-MS (m / z): 326 [M + H]+.
1H-NMR (400 MHz, CDCl3) Δ; 2.68 (2H, dd, J = 5.9, 8.3 Hz), 3.21 (2H, dt, J = 8.3, 5.9 Hz), 5.56-5.67 (3H) , Br), 7.23 (1H, br), 7.28-7.39 (10H, m), 7.93 (1H, br).
11 H-NMR (400 MHz, DMSO-d6) Δ; 2.47-2.51 (2H, m), 2.78-2.83 (2H, m), 6.98 (1H, br s), 7.22-7.34 (11H, m) ), 7.73 (1H, br s), 8.01 (1 H, br s), 8.69 (1 H, t, J = 5.9 Hz).
13C-NMR (100 MHz, DMSO-d6) Δ; 36.1, 36.3, 58.6, 126.3, 127.7, 128.6, 143.1, 160.1, 161.9, 175.0.
<Example 7>
N- [3-carbamoyl-3- (4-hydroxyphenyl) -3-phenylpropyl] oxamide (RC8)
[1] 4-Dibenzylamino-2- (4-methoxyphenyl) -2-phenylbutyronitrile (21)
After neutralizing N- (2-chloroethyl) dibenzylamine hydrochloride (62.7 g, 212 mmol) with purified water (500 mL) by adding sodium hydroxide (17.8 g, 427 mmol), methylene chloride (250 mL) And extracted twice. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure to obtain 54.0 g of oily N- (2-chloroethyl) dibenzylamine.
Next, sodium hydride (6.77 g, 169 mmol) was washed three times with dehydrated ether (20 mL), dehydrated dimethylformamide (221 mL) was added thereto, and α- (4-methoxyphenyl) phenylacetonitrile ( 20) (31.5 g, 141 mmol) was added, and the mixture was stirred for 30 minutes and then stirred at 60 ° C. for 15 minutes. Water-cooled again, potassium iodide (23.4 g, 141 mmol), tetrabutylammonium iodide (5.21 g, 14.1 mmol) and N- (2-chloroethyl) dibenzylamine (54.0 g) in dimethylformamide (94 mL) ) The solution was added dropwise and the reaction was subsequently stirred at 60 ° C. for 5 hours. The reaction mixture was ice-cooled, acetic acid (4 mL) was added, and the mixture was poured into 3 L of ice water and extracted with ethyl acetate (1 L, 500 mL × 2). The organic layer was washed with water (1 L) and saturated brine (1 L), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane: methylene chloride = 2: 1 → 1: 1. The desired fraction was concentrated under reduced pressure, and the fraction of the mixture was subjected to silica gel column chromatography again and purified in the same manner, and then orange oil 4-dibenzylamino-2- (4-methoxyphenyl) -2 was obtained. -59.3 g (94%) of phenylbutyronitrile was obtained.
EI-MS (m / z): 446 [M]+.
1H-NMR (400 MHz, CDCl3) Δ; 2.45-2.49 (2H, m), 2.57-2.62 (2H, m), 3.58 (4H, s), 3.77 (3H, s), 6.76 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.19-7.32 (15H, m).
[2] 4-Dibenzylamino-2- (4-methoxyphenyl) -2-phenylbutanamide (22)
4-Dibenzylamino-2- (4-methoxyphenyl) -2-phenylbutyronitrile (58.8 g, 132 mmol), purified water (4.7 mL) and potassium hydroxide (85.9 g) in isopropyl alcohol (412 mL) , 86%, 1.32 mol) was added, and the mixture was heated to reflux with stirring for 19 hours. The reaction mixture was concentrated under reduced pressure, purified water (1.2 L) and acetic acid (60 mL) were added to the resulting residue under ice water cooling, and the mixture was extracted with methylene chloride (600 mL × 2, 300 mL). The organic layers were combined, washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane: ethyl acetate = 4: 1 → 1: 1. The desired fraction was concentrated under reduced pressure to give 17.7 g (30% recovery) of 4-dibenzylamino-2- (4-methoxyphenyl) -2-phenylbutyronitrile as an oil and 4-dibenzyl as a yellow oil. 41.9 g (69%) of amino-2- (4-methoxyphenyl) -2-phenylbutanamide were obtained.
FAB-MS (m / z): 465 [M + H]+.
11 H-NMR (400 MHz, DMSO-d6) Δ; 2.07-2.08 (2H, m), 2.53-2.55 (2H, m), 3.47 (4H, s), 3.71 (3H, s,), 6. 73 (2H, d, J = 8.8 Hz), 6.88 (1H, brs), 7.02-7.04 (3H, m), 7.11-7.30 (15H, m).
[3] 3-carbamoyl-3- (4-methoxyphenyl) -3-phenylpropylamine hydrochloride (23)
4-Dibenzylamino-2- (4-methoxyphenyl) -2-phenylbutanamide (41.8 g) was dissolved in ethanol (400 mL) and concentrated with 7.5% Pd-C (dry, 20.0 g). Hydrochloric acid (20 mL) was added, and hydrogenated at 50 ° C. for 8 hours under hydrogen pressure (4903 kPa). After the catalyst was filtered off, the reaction solution was concentrated under reduced pressure, and isopropyl ether (400 mL) and acetone (40 mL) were added to the resulting amorphous residue, followed by stirring for 30 minutes. The precipitated solid was collected by filtration, washed with isopropyl ether (200 mL), and dried under reduced pressure at 40 ° C. to give 22.1 g of white solid 3-carbamoyl-3- (4-methoxyphenyl) -3-phenylpropylamine hydrochloride. (77%) obtained.
FAB-MS (m / z): 285 [M-HCl + H]+.
11 H-NMR (400 MHz, DMSO-d6) Δ; 2.41-2.65 (4H, m), 3.76 (3H, s, 0CH)3), 6.81 (1H, brs), 6.93 (2H, d, J = 8.3 Hz), 7.19 (2H, d, J = 8.3 Hz), 7.23-7.37 ( 6H, m), 7.91 (3H, br s).
[4] Ethyl N- [3-carbamoyl-3- (4-methoxyphenyl) -3-phenylpropyl] oxamate (24)
3-carbamoyl-3- (4-methoxyphenyl) -3-phenylpropylamine hydrochloride (22.0 g, 70.8 mmol) was dissolved in methylene chloride (220 mL), triethylamine (17.9 g, 177 mmol) was added, and the solution was dried. While cooling on an ice-acetone bath and stirring, a solution of ethyl chloroglyoxylate (10.2 g) in methylene chloride (110 mL) was added dropwise over 20 minutes, and then the reaction solution was stirred under water cooling for 55 minutes. Water (300 mL) was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with methylene chloride (150 mL × 2). After the organic layers were combined and concentrated under reduced pressure, the residue was subjected to column chromatography and eluted with hexane: methanol = 40: 1. The solvent was concentrated under reduced pressure to obtain 18.6 g (71%) of ethyl N- [3-carbamoyl-3- (4-methoxyphenyl) -3-phenylpropyl] oxamate as a white solid.
FAB-MS (m / z): 385 [M + H]+.
1H-NMR (400 MHz, CDCl3) Δ; 1.36 (3H, t, J = 7.3H), 2.64-2.67 (2H, m), 3.19-3.24 (2H, m), 3.81 (3H, s), 4.31 (2H, q, J = 7.3 Hz), 5.66 (1H, br s), 6.88 (2H, d, J = 9.3 Hz), 7.22 (2H, d) , J = 8.8 Hz), 7.27-7.37 (5H, m), 7.95 (1H, brs).
[5] N- [3-carbamoyl-3- (4-methoxyphenyl) -3-phenylpropyl] oxamide (25)
Ethyl N- [3-carbamoyl-3- (4-methoxyphenyl) -3-phenylpropyl] oxamate (18.5 g, 48.1 mmol) was dissolved in dioxane (100 mL), and the mixture was stirred while cooling with ice water. % Aqueous ammonia (100 mL) was added and stirred for 25 minutes. The reaction solution was acidified with concentrated hydrochloric acid (100 mL), methylene chloride (500 mL) and water (500 mL) were added, the organic layer was separated, and the aqueous layer was extracted with methylene chloride (300 mL × 2). The organic layers were combined and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, eluting with ethyl acetate: methanol = 40: 1. The solvent was concentrated under reduced pressure, isopropyl ether (330 mL) and acetone (33 mL) were added to the resulting residue, and the mixture was stirred for 30 min. And dried under reduced pressure to obtain 15.2 g (89%) of white solid N- [3-carbamoyl-3- (4-methoxyphenyl) -3-phenylpropyl] oxamide.
FAB-MS (m / z): 356 [M + H]+.
11 H-NMR (400 MHz, DMSO-d6) Δ; 2.43-2.47 (2H, m), 2.77-2.83 (2H, m), 3.75 (3H, s), 6.87 (2H, d, J = 8. 8 Hz), 6.93 (1 H, br s), 7.19 (1 H, br s), 7.22 (2 H, d, J = 8.8 Hz), 7.28-7.33 (5 H, m) , 7.73 (1H, br s), 8.02 (1H, br s), 8.68 (1 H, t, J = 5.9 Hz).
[6] N- [3-carbamoyl-3- (4-hydroxyphenyl) -3-phenylpropyl] oxamide (RC8)
N- [3-carbamoyl-3- (4-methoxyphenyl) -3-phenylpropyl] oxamide (15.1 g, 42.5 mmol) was suspended in dehydrated methylene chloride (540 mL) and cooled on a dry ice-acetone bath. While stirring, boron tribromide (40 mL, 423 mmol) was added dropwise over 20 minutes, and then the reaction solution was stirred at room temperature for 14 hours. The reaction mixture was cooled with ice water, 6 mol / L hydrochloric acid (300 mL) and water (1.5 L) were added, and the mixture was extracted with methylene chloride (1 L × 2) and ethyl acetate (500 mL × 3). The organic layers were combined and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [1] dichloromethane: methanol = 20: 1, 2) ethyl acetate: methanol = 40: 1 twice, preparative TLC [ The product was purified once by silica gel column chromatography [methylene chloride → methylene chloride: methanol = 10: 1] once with methylene chloride: methanol = 10: 1]. Methanol (13.6 mL) and purified water (68 mL) were added to the resulting residue, dissolved by heating, and then cooled with ice water. The precipitated crystals were collected by filtration, washed with 140 mL of cold water, and dried under reduced pressure at 30 ° C. to 50 ° C. to obtain 2.34 g (16%) of the target compound as a slightly yellow powder.
mp 111-113 ° C.
IR (KBr) cm-13328, 1663, 1513.
Anal. Calcd C18H19N3O4: C, 63.33; H, 5.61; N, 12.31.
Found: C, 63.07; H, 5.62; N, 12.23.
FAB-MS (m / z): 342 [M + H]+.
11 H-NMR (400 MHz, DMSO-d6) Δ; 2.39-2.43 (2H, m), 2.76-2.81 (2H, m), 6.68 (2H, d, J = 8.3 Hz), 6.84 (1H, br s), 7.09 (2H, d, J = 8.8 Hz), 7.14 (1 H, br s), 7.19-7.31 (5 H, m), 7.71 (1 H, br s) ), 8.00 (1H, br s), 8.66 (1 H, t, J = 5.9 Hz), 9.33 (1 H, s).
<Example 8>
1- [3- (3-carbamoyl-3,3-diphenylpropyl) -2-methyl-1-imidazolio] -1-deoxy-β-D-gucopyranuronate (RC7)
[1] Methyl 3-O-benzyl-4,6-O-benzylidene-2-O- (4-methoxybenzyl) -α-D-glucopyranoside (27)
To a solution of 3-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (26) (565 mg, 2.00 mmol) in anhydrous dimethylformamide (30 mL) was added sodium hydride (0.96 g) with ice water cooling. , 24.0 mmol) was added and stirred at room temperature for 0.5 hour. 4-Methoxybenzyl chloride (3.25 mL, 24.0 mmol) was added to the mixture and stirred for 1 hour. Methanol was added to the reaction solution, and the mixture was stirred for 10 minutes and then dried under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane: ethyl acetate = 4: 1. The solvent was distilled off, and the resulting residue was suspended and washed with n-hexane, dried under reduced pressure at 50 ° C., and white powder of methyl 3-O-benzyl-4,6-O-benzylidene-2-O- ( There were obtained 8.69 g (88%) of 4-methoxybenzyl) -α-D-glucopyranoside.
FAB-MS (m / z): 493 [M + H]+.
1H-NMR (CDCl3, 400 MHz) δ: 3.39 (3H, s), 3.53 (1H, dd, J = 3.5 Hz, 9.3 Hz), 3.59 (1H, t, J = 9.3 Hz), 3. 70 (1H, t, J = 10.3 Hz), 3.80 (3H, s), 3.79-3.85 (1H, m), 4.02 (1H, t, J = 9.3 Hz), 4.26 (1H, dd, J = 4.4 Hz, 10.3 Hz), 4.53 (1H, d, J = 3.9 Hz), 4.63 (1H, d, J = 11.7 Hz), 4 .79 (1H, d, J = 11.7 Hz), 4.83 (1H, d, J = 111.2 Hz), 4.90 (1H, d, J = 11.7 Hz), 5.54 (1H, s), 6.84-6.88 (2H, m), 7.26-7.50 (13H, m).
[2] Methyl 3,4-di-O-benzyl-2-O- (4-methoxybenzyl) -α-D-glucopyranoside (28)
To a solution of 3-O-benzyl-4,6-O-benzylidene-2-O- (4-methoxybenzyl) -α-D-glucopyranoside (8.87 g, 18.0 mmol) in anhydrous toluene (100 mL) was cooled with ice water. Then, 1.0 mol / L n-hexane solution (45 mL, 45.0 mmol) of diisobutylaluminum hydride was added dropwise. The reaction solution was returned to room temperature and stirred for 4 hours, and then a saturated aqueous ammonium chloride solution was added and stirred for 0.5 hour. The insoluble material was removed using a celite pad, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane: ethyl acetate = 2: 1. The solvent was distilled off to obtain 7.45 g (85%) of colorless amorphous methyl 3,4-di-O-benzyl-2-O- (4-methoxybenzyl) -α-D-glucopyranoside.
1H-NMR (CDCl3, 400 MHz) δ: 3.36 (3H, s), 3.45-3.53 (2H, m), 3.62-3.83 (3H, m), 3.80 (3H, s), 3 .98 (1H, t, J = 9.3 Hz), 4.51 (1H, d, J = 3.9 Hz), 4.59 (1H, d, J = 11.7 Hz), 4.64 (1H, d, J = 11.2 Hz), 4.74 (1H, d, J = 11.7 Hz), 4.82 (1H, d, J = 10.8 Hz), 4.88 (1H, d, J = 11) .2 Hz), 4.98 (1 H, d, J = 10.8 Hz), 6.84-6.87 (2 H, m), 7.27-7.39 (13 H, m).
[3] Methyl 1-methyl-3,4-di-O-benzyl-2-O- (4-methoxybenzyl) -α-D-glucopyranuronate (29)
A solution of methyl 3,4-di-O-benzyl-2-O- (4-methoxybenzyl) -α-D-glucopyranoside (7.42 g, 15.0 mmol) in acetone (150 mL) was stirred while cooling with ice water. Then, Jones' reagent (2.67 mol / L, 16.9 mL) was added dropwise over 0.5 hour, followed by stirring for 0.5 hour. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was dissolved in a methylene chloride-methanol (9: 1) mixture (100 mL), and then a trimethylsilyldiazomethanehexane solution (2.0 mol / L, 8.0 mL) was added. The reaction solution was concentrated under reduced pressure, subjected to silica gel column chromatography, and eluted with n-hexane: ethyl acetate = 4: 1. The solvent was distilled off to obtain 4.20 g (54%) of colorless oily methyl 1-methyl-3,4-di-O-benzyl-2-O- (4-methoxybenzyl) -α-D-glucopyranuronate. )Obtained.
1H-NMR (CDCl3, 400 MHz) δ: 3.39 (3H, s), 3.55 (1H, dd, J = 3.4 Hz, 9.8 Hz), 3.69-3.73 (1H, m), 3.70 ( 3H, s), 3.80 (3H, s), 3.96 (1H, t, J = 9.3 Hz), 4.18 (1H, d, J = 10.3 Hz), 4.53-4. 59 (3H, m), 4.73-4.82 (3H, m), 4.95 (1 H, d, J = 10.8 Hz), 6.83-6.87 (2H, m), 7. 20-7.34 (13H, m).
[4] Methyl 1-methyl-3,4-di-O-benzyl-α-D-glucopyranuronate (30)
Methyl 1-methyl-3,4-di-O-benzyl-2-O- (4-methoxybenzyl) -α-D-glucopyranuronate (4.18 g, 8.00 mmol) in acetonitrile-water (9: 1) To the mixed solution (40 mL) solution was added ammonium cerium (IV) nitrate (8.87 g, 16.0 mmol), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-water, and then the ethyl acetate layer was separated. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with n-hexane: ethyl acetate = 2: 1. The solvent was distilled off to obtain 2.90 g (88%) of light yellow oily methyl 1-methyl-3,4-di-O-benzyl-α-D-glucopyranuronate.
FAB-MS (m / z): 403 [M + H]+.
1H-NMR (CDCl3, 400 MHz) δ: 3.47 (3H, s), 3.73 (3H, s), 3.75-3.81 (3H, m), 4.21-4.26 (1H, m), 4 .60 (1H, d, J = 10.8 Hz), 4.78 (1 H, d, J = 11.2 Hz), 4.82-4.88 (3H, m), 7.25-7.37 ( 10H, m).
[5] Methyl 1-methyl-2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranuronate (31)
Methyl 1-methyl-3,4-di-O-benzyl-α-D-glucopyranuronate (2.82 g, 7.00 mmol), benzoyl chloride (1.18 g, 8.40 mmol) and triethylamine (850 mg, 8 .40 mmol) in benzene (30 mL) was heated to reflux for 4 hours. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane: ethyl acetate = 4: 1. The solvent was distilled off to obtain 2.70 g (76%) of methyl 1-methyl-2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranuronate as a pale yellow oil.
FAB-MS (m / z): 507 [M + H]+.
1H-NMR (CDCl3, 400 MHz) δ: 3.40 (3H, s), 3.75 (3H, s), 3.90 (1H, dd, J = 8.8 Hz, 9.8 Hz), 4.18 (1H, t, J = 9.3 Hz), 4.29 (1H, t, J = 9.8 Hz), 4.63 (1H, d, J = 10.8 Hz), 4.81 (2H, s), 4.81 ( 1H, d, J = 10.8 Hz), 5.09-5.15 (2H, m), 7.19-7.35 (10H, m), 7.43-7.46 (2H, m), 7.56-7.61 (1H, m), 8.03-8.06 (2H, m).
[6] Methyl 1-O-acetyl-2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranuronate (32)
Methyl 1-methyl-2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranuronate (2.03 g, 4.00 mmol) and acetic anhydride (4.08 g, 40.0 mmol) Concentrated sulfuric acid (202 mg, 2.00 mmol) was added to an acetic acid (40 mL) solution, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexa: ethyl acetate = 4: 1. The solvent was distilled off to obtain 820 mg (38%) of methyl 1-O-acetyl-2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranuronate as a white powder.
FAB-MS (m / z): 640 [M + diethanolamine]+.
1H-NMR (CDCl3, 400 MHz) δ: 2.12 (3H, s), 3.75 (3H, s), 3.98 (1H, dd, J = 8.8 Hz, 9.3 Hz), 4.16 (1H, dd, J = 8.8 Hz, 9.8 Hz), 4.39 (1H, t, J = 9.8 Hz), 4.63 (1H, d, J = 10.8 Hz), 4.77-4.84 (3H) , M), 5.34 (1H, dd, J = 3.4 Hz, 9.8 Hz), 6.45 (1H, d, J = 3.4 Hz), 7.12-7.36 (10H, m) , 7.41-7.45 (2H, m), 7.56-7.60 (1H, m), 7.94-7.97 (2H, m).
[7] Methyl 2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranuronate (33)
Methyl 1-O-acetyl-2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranuronate (802 mg, 1.50 mmol) in tetrahydrofuran-methanol (5: 1) (6 mL) ) Was added 25% aqueous ammonia (4 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography and eluted with n-hexane: ethyl acetate = 4: 1. The solvent was distilled off, and the resulting crude crystals were suspended and washed with a mixed solution of n-hexane: ethyl acetate (1: 1) and dried under reduced pressure at 50 ° C. 488 mg (66%) of -di-O-benzyl-α-D-glucopyranuronate were obtained.
FAB-MS (m / z): 493 [M + H]+.
1H-NMR (CDCl3, 400 MHz) δ: 2.99 (1H, dd, J = 1.0 Hz, 3.9 Hz), 3.74 (3H, s), 3.93 (1 H, t, 9.3 Hz), 4.24 ( 1H, t, J = 9.3 Hz), 4.58 (1H, t, J = 9.8 Hz), 4.65 (1H, d, J = 11.2 Hz), 4.77-4.85 (3H M), 5.14-5.17 (1H, m), 5.62 (1H, t, J = 3.9 Hz), 7.17-7.35 (10H, m), 7.41-7. .46 (2H, m), 7.56-7.60 (1H, m), 7.9-8.04 (2H, m).
[8] Methyl (2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranosyl bromide) uronate (34)
To a solution of methyl 2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranuronate (493 mg, 1.00 mmol) in anhydrous methylene chloride (10 mL) was added carbon tetrabromide (663 mg, 2 0.000 mmol) and triphenylphosphine (393 mg, 1.50 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, subjected to silica gel column chromatography, and eluted with n-hexane: ethyl acetate = 7: 1. The solvent was distilled off to obtain 450 mg (81%) of colorless oily methyl (2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranosyl bromide) uronate.
FAB-MS+(M / z): 555 [M + H]+.
1H-NMR (CDCl3, 400 MHz) δ: 3.76 (3H, s), 3.99 (1H, t, J = 9.3 Hz), 4.27 (1H, t, J = 9.3 Hz), 4.57 (1H, t, J = 10.3 Hz), 4.65 (1 H, d, J = 10.8 Hz), 4.80-4.86 (3 H, m), 5.11 (1 H, dd, J = 3.9 Hz) 9.8 Hz), 6.70 (1 H, t, J = 3.9 Hz), 7.19-7.37 (10 H, m), 7.44-7.48 (2 H, m), 7.58. -7.63 (1H, m), 8.01-8.03 (2H, m).
[9] Methyl [2-O-benzoyl-3,4-di-O-benzyl-1-deoxy-β-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl) -2-methylimidazo [Rium bromide]] uronate (35)
Methyl (2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranosyl bromide) uronate (444 mg, 0.80 mmol) and 4- (2-methyl-1-imidazolyl) -2 , 2-diphenylbutanamide (3, X = H, JP-A-7-215943) (2.56 g, 8.00 mmol) in anhydrous toluene (24 mL) was heated at 100 ° C. for 10 hours. The reaction solution was washed successively with 1 mol / L hydrochloric acid and purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with methylene chloride: methanol = 19: 1. The solvent was distilled off and colorless amorphous methyl [2-O-benzoyl-3,4-di-O-benzyl-1-deoxy-β-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl) was obtained. ) -2-Methylimidazolium bromide]] uronate was obtained in 222 mg (32%).
FAB-MS (m / z): 794 [M + H-Br]+.
1H-NMR (CDCl3, 400 MHz) δ: 2.25-2.33 (1H, m), 2.45 (3H, s), 2.79-2.86 (1H, m), 3.74 (3H, s), 3 .77-3.84 (1H, m), 3.96-4.04 (1H, m), 4.13 (1H, t, J = 9.3 Hz), 4.29 (1H, t, J = 9.3 Hz), 4.52 (1H, t, J = 9.3 Hz), 4.68 (2H, d, J = 11.2 Hz), 4.82 (2H, d, J = 11.2 Hz), 5.55 (1H, t, J = 9.3 Hz), 6.11 (1H, d, J = 9.3 Hz), 7.06-7.14 (7H, m), 7.26-7.43 (17H, m), 7.59-7.63 (1H, m), 7.80 (1H, d, J = 2.4 Hz), 7.86-7.88 (2H, m).
[10] 1- [3- (3-carbamoyl-3,3-diphenylpropyl) -2-methyl-1-imidazolio] -1-deoxy-β-D-glucopyranuronate (RC7)
Methyl [2-O-benzoyl-3,4-di-O-benzyl-1-deoxy-β-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl) -2-methylimidazolium bromide] To a solution of uronate (201 mg, 0.23 mmol) in anhydrous methylene chloride (5 mL) was added iron (III) chloride (149 mg, 0.92 mmol), and the mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction solution, the insoluble material was filtered off, and the aqueous layer was separated. The aqueous layer was adjusted to pH = 7.03 with a 1 mol / L aqueous sodium hydroxide solution, and the suspended matter was filtered off using a celite pad and then dried under reduced pressure. The residue was dissolved in 1 mol / L aqueous sodium hydroxide solution (3 mL) and allowed to stand at room temperature for 2 hours. The reaction solution was adjusted to pH = 7.02 with 1 mol / L hydrochloric acid and then dried under reduced pressure. The residue was subjected to reverse phase silica gel column chromatography and eluted with water → 30% aqueous methanol. The desired fraction was concentrated under reduced pressure, and the resulting residue was washed with methanol (30 mL) in suspension while hot. After drying under reduced pressure at 80 ° C., the mixture was allowed to stand at room temperature to obtain 100 mg (88%) of the target compound as white crystals.
IR (KBr) cm-1: 3663,1678,1627,704.
FAB-MS (m / z): 496 [M + H]+.
Anal. calcd C26H29N3O7・ 1.5H2O: C, 59.76; H, 6.17; N, 8.04.
Found: C, 59.70; H, 5.97; N, 8.08.
11 H-NMR (400 MHz, DMSO-d6) Δ: 2.51 (3H, s), 2.79-2.84 (2H, m), 3.25 (1H, dd, J = 8.8 Hz, 10.3 Hz), 3.34-3. 39 (1H, m), 3.41-3.47 (1H, m), 3.53 (1H, d, J = 10.3 Hz), 3.87-3.91 (2H, m), 5. 01 (1H, m), 5.33 (1H, d, J = 8.8 Hz), 5.35 (1H, d, J = 5.4 Hz), 6.60 (1H, br), 7.28- 7.39 (12H, m), 7.60 (1H, d, J = 2.4 Hz), 7.71 (1H, d, J = 2.0 Hz).
<Example 9>
1- [3- (3-carbamoyl-3,3-diphenyl) propyl-2-methyl-1-imidazolio] -1-deoxy-β-D-glucopyranuronate (RC7)
[1] Methyl 2,3,4-tri-O-benzoyl-1-methanesulfonyl-α-D-glucopyranuronate (37)
Methanesulfonic acid in a solution of methyl 1,2,3,4-tetra-O-benzoyl-β-D-glucopyranouronate (36) (44.3 g, 72.4 mmol) in dehydrated methylene chloride (300 mL) at room temperature (55.8 g, 581 mmol) was added and stirred for 45 minutes. A 5% aqueous sodium hydrogen carbonate solution (1.4 L) was added to the reaction mixture, and the mixture was extracted with methylene chloride (500 mL × 2 times). The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-methylene chloride-ethyl acetate = 5: 10: 1. The solvent was distilled off, and the resulting residue was recrystallized from methylene chloride-hexane, dried under reduced pressure at room temperature, and then colorless cotton-like methyl 2,3,4-tri-O-benzoyl-1-methanesulfonyl-α. -20.6 g (49%) of D-glucouronate was obtained.
1H-NMR (400 MHz, CDCl3) Δ; 3.11 (3H, s), 3.70 (3H, s), 4.79 (1H, d, J = 9.8 Hz), 5.54 (1H, dd, J = 3.4) 9.8 Hz), 5.75 (1 H, t, J = 9.8 Hz), 6.17 (1 H, t, J = 9.8 Hz), 6.41 (1 H, d, J = 3.4 Hz), 7.31-7.57 (9H, m), 7.88-7.99 (6H, m).
[2] Methyl [2,3,4-tri-O-benzoyl-1-deoxy-β-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl) -2-methylimidazolium chloride]] Uronate (38)
4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutanamide (3, X = H, JP-A-7-215943) (45.4 g, 142 mmol) and methyl 2,3,4-tri-O Dehydrated chloroform (500 mL) was added to -benzoyl-1-methanesulfonyl-α-D-glucopyranuronate (10.0 g, 16.7 mmol), and the mixture was heated to reflux for 13 hours under stirring in an argon atmosphere. After cooling, the solvent was distilled off under reduced pressure, methylene chloride and dilute hydrochloric acid were added to the residue for extraction, and the methylene chloride layer was separated. The aqueous layer was extracted with methylene chloride, the methylene chloride layers were combined, washed with dilute hydrochloric acid, and the washed aqueous layer was extracted with methylene chloride. The methylene chloride layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted sequentially with methylene chloride → methylene chloride-methanol = 100: 3 → methylene chloride-methanol = 10: 1 → methylene chloride-methanol = 20: 3. The fraction containing the desired product was concentrated under reduced pressure, and the resulting oil was crystallized with a methylene chloride-isopropyl ether mixture. The precipitated solid was collected by filtration, dried under reduced pressure at 50 ° C., and then grayish white powder of methyl [2,3,4-tri-O-benzoyl-1-deoxy-β-D-glucopyranosyl [1- (3-carbamoyl-3 , 3-diphenylpropyl) -2-methylimidazolium chloride]] uronate, 5.82 g (41%).
11 H-NMR (400 MHz, DMSO-d6) Δ; 2.38-2.45 (1H, m), 2.52 (3H, s), 2.69-2.76 (1H, m), 3.58 (3H, s), 3.68 −3.85 (2H, m), 5.10 (1H, d, J = 9.8 Hz), 5.87 (1H, t, J = 9.8 Hz), 6.20 (1H, t, J = 8.8 Hz), 6.25 (1 H, t, J = 9.3 Hz), 6.68 (1 H, d, J = 8.3 Hz), 6.76 (1 H, br s), 7.15-7. .85 (27H, m), 8.15 (1H, d, J = 2.4 Hz).
[3] 1- [3- (3-Carbamoyl-3,3-diphenyl) propyl-2-methyl-1-imidazolinio] -1-deoxy-β-D-glucopyranuronate 1.1 hydrate (RC7 )
Methyl [2,3,4-tri-O-benzoyl-1-deoxy-β-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl) -2-methylimidazolium chloride]] uronate (3 0.02 g, 3.52 mmol) in methanol (120 mL), 1 mol / L aqueous sodium hydroxide solution (50 mL) was slowly added dropwise with stirring under salt-ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Stir for 30 minutes. Purified water was added and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH 1 with diluted hydrochloric acid and washed twice with methylene chloride. Aqueous sodium hydroxide was added to the aqueous layer to adjust the pH to 7, and after washing with ethyl acetate, the aqueous layer was concentrated under reduced pressure. The obtained residue was subjected to synthetic adsorbent column chromatography [HP-20SS] and eluted with purified water → purified water: methanol = 2: 1. Fractions containing the desired product were combined and concentrated under reduced pressure. The resulting solid was recrystallized from isopropyl alcohol-purified water and dried under reduced pressure at 60 ° C. to obtain crude crystals (1.43 g). Crude crystals (1.43 g) were collected by preparative HPLC [Inertsil ODS-2 (20 mm ID × 250 mm); mobile phase acetonitrile-purified water = 1: 5; flow rate 10 mL / min; column temperature 30 ° C .; detection wavelength 230 nm; The distillate is concentrated under reduced pressure, the residue is recrystallized from purified water-isopropyl alcohol, dried at 60 ° C. under reduced pressure, and left for 2 days to give 1.00 g (55 of colorless plate-like target compound). %)Obtained.
mp 207-215 ° C (decomp.).
IR (KBr) cm-13412, 1663, 1626.
[Α]D 23= + 6.3 ° (c = 0.37, H2O).
Anal. Calcd C26H29N3O7・ 1.1H2O: C, 60.60; H, 6.10; N, 8.15.
Found: C, 60.70; H, 6.01; N, 8.26.
FAB-MS (m / z): 496 [M + H]+.
1H-NMR (400 MHz, D2O) δ; 2.49 (3H, s), 2.92-3.00 (2H, m), 3.66 (1H, t, J = 8.8 Hz), 3.73 (1H, t, J = 8.8 Hz), 3.78 (1H, t, J = 8.8 Hz), 4.00 (1H, d, J = 9.3 Hz), 4.06-4.14 (2H, m), 5 .51 (1H, d, J = 8.8 Hz), 7.36-7.47 (11H, m), 7.67 (1H, d, J = 2.4 Hz).
Moisture measurement (Karl Fischer method): 3.71%.
<Example 10>
1- [2,2-diphenyl-4- (2-methylimidazol-1-yl) butyrylamino] -1-deoxy-D-glucopyranuronic acid (RC9)
[1] 2,2-Diphenyl-4- (2-methylimidazol-1-yl) butanoic acid (39)
A hydrochloric acid solution of 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide (3, X = H, JP-A-7-215943) (3.00 g, 9.39 mmol) was heated to reflux for 21 hours. . The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 2 mol / L sodium hydroxide solution. This solution was washed with ethyl acetate, adjusted to pH = 7.0 with hydrochloric acid, the precipitated crystals were collected by filtration, washed with water, dried under reduced pressure at 100 ° C., and white powder of 2,2-diphenyl-4- 2.21-g (93%) of (2-methylimidazol-1-yl) butanoic acid was obtained.
EI-MS (m / z): 320 (M)+.
11 H-NMR (400 MHz, DMSO-d6) Δ: 2.07 (3H, s), 2.63-2.67 (2H, m), 3.57-3.61 (2H, m), 6.75 (1H, d, J = 1. 5 Hz), 6.97 (1 H, d, J = 1.5 Hz), 7.25-7.36 (10 H, m).
[2] Methyl 2,3,4-tri-O-benzyl-1- [2,2-diphenyl-4- (2-methylimidazol-1-yl) butyrylamino] -1-deoxy-D-glucopyranuronate (41)
To a suspension of 2,2-diphenyl-4- (2-methylimidazol-1-yl) butanoic acid (76.9 mg, 0.24 mmol) in anhydrous methylene chloride (3 mL) was added oxalyl chloride (25.6 μL, 0.30 mmol). ) And stirred at room temperature for 30 minutes. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was dissolved in 5 mL of anhydrous chloroform, and methyl 1-amino-2,3,4-tri-O-benzyl-1-deoxy-D-glucopyranuronate (40) (57. 3 mg, 0.24 mmol), triethylamine (33.9 μL, 0.24 mmol) and 4,4-dimethylaminopyridine (5 mg) were added, and the mixture was heated to reflux for 3 days. The reaction solution was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The crude product was purified by preparative TLC (CH2Cl2: CH3OH = 5: 1, 20 × 20 cm 0.5 mm × 2) and light brown amorphous methyl 2,3,4-tri-O-benzyl-1- [2,2-diphenyl-4- (2-methyl) 65 mg (69%) of imidazol-1-yl) butyrylamino] -1-deoxy-D-glucopyranuronate were obtained.
In part, α-form and β-form were separated by preparative TLC.
[Analyzer analysis of α body]
FAB-MS (m / z): 780 [M + H]+.
1H-NMR (400 MHz, CDCl3) Δ: 2.23 (3H, s), 2.52-2.59 and 2.81-2.87 (each 1H, m), 3.26 (1H, t, J = 6.4 Hz), 3 .48-3.58 (2H, m), 3.72 (3H, s), 3.80 (1H, t, J = 6.4 Hz), 4.01-4.07 (1H, m), 4 .01 (1H, d, J = 6.4 Hz), 4.26 and 4.44 (each 2H, s), 4.61-4.54 (2H, m), 5.92 (1H, dd, J = 4.4 Hz, 7.8 Hz), 6.33 (1 H, d, J = 7.8 Hz), 6.73 and 6.85 (each 1 H, s), 7.00-7.41 (25 H, m ).
[Instrumental analysis of β-form]
FAB-MS (m / z): 780 [M + H]+.
1H-NMR (400 MHz, CDCl3) Δ: 2.27 (3H, s), 2.47-2.54 and 2.81-2.88 (each 1H, m), 3.10 (1H, t, J = 8.8 Hz), 3 .52-3.59 (2H, m), 3.71 (1H, t, J = 9.3 Hz), 3.73 (3H, s), 3.94 (1H, d, J = 11.2 Hz) 3.97-4.05 (2H, m), 4.08 (1H, d, J = 9.3 Hz), 4.35 (1H, d, J = 10.8 Hz), 4.52 (1H, d, J = 11.2 Hz), 4.70-4.79 (3H, m), 5.31 (1H, t, J = 9.3 Hz), 5.90 (1H, d, J = 9.3 Hz) ), 6.72 (1H, s), 6.88 (1H, d, J = 1.0 Hz), 7.05-7.40 (25H, m).
[3] 1- [2,2-Diphenyl-4- (2-methylimidazol-1-yl) butyrylamino] -1-deoxy-D-glucopyranuronic acid (RC9)
Methyl 2,3,4-tri-O-benzyl-1- [2,2-diphenyl-4- (2-methylimidazol-1-yl) butyrylamino] -1-deoxy-D-glucopyranuronate (70. To a solution of 2 mg, 0.09 mmol) in 3 mL of methanol was added 1 mol / L aqueous sodium hydroxide solution (140 μl, 0.14 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 3 mL of purified water, adjusted to pH = 7.05 with 1 mol / L hydrochloric acid, and extracted seven times with ethyl acetate. The ethyl acetate layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained colorless amorphous was dissolved in 5 mL of methanol, ammonium formate (114 mg, 1.80 mmol) and 10% Pd—C (46.0 mg) were added, and the mixture was heated to reflux for 3 hours. After filtering the catalyst, the reaction solution was concentrated under reduced pressure. The residue was dissolved in 3 mL of purified water, adjusted to pH = 7.0 with 1 mol / L hydrochloric acid, and then dried under reduced pressure. Residue was separated by preparative TLC (CH2Cl2: CH3OH = 1: 2, 20 × 20 cm 0.5 mm (1 sheet) to obtain 65 mg (69%) of a colorless amorphous target compound.
1H-NMR (CD3OD, 400 MHz) δ: 2.16 (3H, s), 2.17 (3H, s), 2.70-2.92 (4H, m), 2.96 (1H, t, J = 8.8 Hz) ), 3.35-3.42 (4H, m), 3.59 (1H, dd, J = 7.3, 5.4 Hz), 3.73-3.92 (4H, m), 5.56. (1H, d, J = 9.3 Hz), 5.59 (1H, d, J = 5.4 Hz), 6.75 (2H, d, J = 1.0 Hz), 6.91 (1H, d, J = 1.5 Hz), 6.93 (1 H, d, J = 1.5 Hz), 7.27-7.45 (20 H, m).
FAB-MS (m / z): 496 [M + H]+
<Example 11>
1- [3- (3-carbamoyl-3,3-diphenylpropyl) -2-methyl-1-imidazolio] -1-deoxy-α-D-glucopyranuronate (RC10)
[1] Methyl [2,3,4-tri-O-benzoyl-1-deoxy-α-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl) -2-methylimidazolium bromide]] Uronate (44)
Methyl (2,3,4-tri-O-benzyl-α-D-glucopyranosyl bromide) uronate (108 mg, 0.20 mmol) and 4- (2-methyl-1-imidazolyl) -2,2-diphenyl An anhydrous toluene (10 mL) suspension of butanamide (3, X = H, JP-A-7-215943) (639 mg, 2.00 mmol) was heated at 100 ° C. for 16 hours. The reaction solution was washed successively with 1 mol / L hydrochloric acid and purified water, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Preparative residue TLC (CH2Cl2: CH3OH = 5: 1, 20 × 20 cm, thickness 0.5 mm) and colorless amorphous methyl [2,3,4-tri-O-benzoyl-1-deoxy-α-D-glucopyranosyl [1- ( 3-carbamoyl-3,3-diphenylpropyl) -2-methylimidazolium bromide]] uronate was obtained, yielding 50 mg (29%).
1H-NMR (400 MHz, CDCl3) Δ: 2.64 (3H, s), 2.85-2.93 (1H, m), 3.25-3.31 (1H, m), 3.61 (3H, s), 3.82 (1H, s), 3.97 (1H, s), 4.00-4.06 (1H, m), 4.17-4.27 (1H, m), 4.39-4.70 (8H) M), 5.63 (1H, br), 6.50 (1H, br), 6.32 (1H, s), 7.18-7.71 (26H, m), 7.72 (1H, d, J = 2.4 Hz).
FAB-MS (m / z): 780 [M + H]+
[2] 1- [3- (3-Carbamoyl-3,3-diphenylpropyl) -2-methyl-1-imidazolio] -1-deoxy-α-D-glucopyranuronate (RC10)
Methyl [2,3,4-tri-O-benzoyl-1-deoxy-α-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl) -2-methylimidazolium bromide]] uronate (43 To an anhydrous methylene chloride (3 mL) solution of 0.0 mg, 0.05 mmol) was added iron (III) chloride (76.0 mg, 0.45 mmol) under ice water cooling, and the mixture was stirred at the same temperature for 5 hours. Ice water was added to the reaction solution, the insoluble material was filtered off, and the aqueous layer was separated. The aqueous layer was adjusted to pH = 7.0 with a 1 mol / L aqueous sodium hydroxide solution, and the suspended matter was filtered off using a celite pad and then dried under reduced pressure. The residue was dissolved in methanol (1 mL), 1 mol / L aqueous sodium hydroxide solution (100 μL) was added, and the mixture was stirred at room temperature for 5 hr. After the reaction liquid was dried under reduced pressure, the residue was dissolved in 3 mL of purified water, adjusted to pH = 7.0 with 1 mol / L hydrochloric acid, and then the solvent was dried under reduced pressure. The residue was purified by preparative TLC (methylene chloride: methanol = 1: 2, 20 × 20 cm thickness 0.5 mm) to obtain 7.5 mg (30%) of the white amorphous target compound.
11 H-NMR (400 MHz, DMSO-d6) Δ: 2.56 (3H, s), 2.61-2.84 (2H, m), 3.61 (1H, br), 3.73-3.78 (3H, m), 3.82 (2H, t, J = 7.8 Hz), 5.60 (2H, t, J = 6.8 Hz), 6.10 (1H, d, J = 1.5 Hz), 6.82 (1H, s) 7.45 (1H, s), 7.28-7.39 (10H, m), 7.54 (1H, d, J = 2.0 Hz), 7.78 (1H, d, J = 2. 0 Hz).
FAB-MS (m / z): 494 [M-H]−
<Example 12>
4-acetimidoylamino-2,2-diphenylbutanamide (RC11)
[1] 4-acetimidoylamino-2,2-diphenylbutanamide hydrobromide
To a suspension of 4-amino-2,2-diphenylbutanamide (5.09 g, 20.0 mmol) synthesized in the same manner as described in Example 2 in ethanol (100 mL) under ice water cooling, S-benzylthioacetate was added. Imidate hydrobromide (4.92 g, 20.0 mmol) was added and stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was suspended and washed with ethyl acetate (50 mL) to obtain crude crystals. The obtained crude crystals were recrystallized from ethanol (100 mL), dried under reduced pressure at 90 ° C., and then white powder of 4-acetimidoylamino-2,2-diphenylbutanamide hydrobromide 3.87 g (51 %)Obtained.
mp 217-218 ° C.
IR (KBr) cm-13173, 3080, 1688, 1658, 705; Anal. Calcd C18H22BrN3O: C, 57.45; H, 5.89; N, 11.17.
Found: C, 57.28; H, 5.89; N, 11.15.
FAB-MS (m / z): 296 [M + H]+.
11 H-NMR (400 MHz, DMSO-d6): 2.06 (3H, s), 2.51-2.60 (2H, m), 2.75-2.86 (2H, m), 6.99 (1H, s), 7.27- 7.38 (10H, m), 7.52 (1H, s), 8.56 (1H, s), 9.04 (1H, s), 9.25 (1H, s).
[2] 4-acetimidoylamino-2,2-diphenylbutanamide (RC11)
To a suspension of purified 4-acetimidoylamino-2,2-diphenylbutanamide hydrobromide (2.63 g, 7.00 mmol) in purified water (53 mL) under cooling with ice water, a 1 mol / L aqueous sodium hydroxide solution ( (7.7 mL, 7.70 mmol) was added and stirred for 2 hours. The precipitated crystals were collected by filtration and washed with ice-cooled water (30 mL) to obtain crude crystals. The crude crystals were dissolved by heating in acetonitrile (20 mL), diisopropyl ether (20 mL) was added, and the mixture was allowed to cool to room temperature. The precipitated crystals were collected by filtration, washed with diisopropyl ether (20 mL), and dried under reduced pressure at 50 ° C. to obtain 1.26 g (61%) of the target compound as a white powder.
mp 166-167 ° C.
IR (KBr) cm-13418, 1619, 1384, 695.
Anal. Calcd for C18H21N3O: C, 73.19; H, 7.17; N, 14.23.
Found: C, 73.04; H, 7.18; N, 14.20.
FAB-MS (m / z): 296 [M + H]+.
11 H-NMR (400 MHz, DMSO-d6): 1.78 (3H, s), 2.52-2.61 (4H, m), 6.21 (2H, br), 7.10 (1H, s), 7.11-7.30 ( 10H, m), 8.94 (1H, br).
Example 13 4- (2-Methyl-5-oxo-4,5-dihydroimidazol-1-yl) -2,2-diphenylbutanamide (RC12)
[1] 4-N-acetylamino-2,2-diphenylbutanamide (44)
4-N, N-dibenzylamino-2,2-diphenylbutanamide (16) (13.0 g, 29.9 mmol), palladium hydroxide 3.00 g and a mixed solvent of ethyl acetate and ethanol in a pressure bottle for 500 mL 280 mL was charged and hydrogenated at an initial hydrogen pressure of 471 kPa for 8 hours. The catalyst was filtered, washed with ethanol, and the back solution was concentrated. The obtained residue, triethylamine (4.65 mL, 33.3 mmol) and 200 mL of chloroform were mixed, and acetyl chloride (2.37 mL, 33.3 mmol) was added dropwise with stirring under ice cooling. After stirring at 0 ° C. for 10 minutes and at room temperature overnight, the reaction mixture was washed successively with 10% aqueous citric acid solution, 0.5 mol / L sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. Ethyl acetate and a small amount of acetone were added to the residue, and the mixture was stirred for 30 minutes under ice cooling. The insoluble solid was filtered and dried to obtain 2.50 g (28%) of the desired product as a colorless powder.
[2] 4-N-acetyl-N-chloroacetylamino-2,2-diphenylbutanamide (45)
4-N-acetylamino-2,2-diphenylbutanamide (44) (3.50 g, 11.8 mmol), triethylamine (1.64 mL, 11.8 mmol) and 450 mL of benzene were charged into a 1 L eggplant-shaped flask, Argon atmosphere chloroacetyl chloride (0.94 mL, 11.8 mmol) was added at room temperature. After heating under reflux for 3.5 hours, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 6: 1 v / v) to give 1.50 g (yield 34) %)Obtained.
[3] 4-N-acetyl-N-azidoacetylamino-2,2-diphenylbutanamide (46)
4-N-acetyl-N-chloroacetylamino-2,2-diphenylbutanamide (45) (1.50 g, 4.02 mmol) and 30 mL of dimethyl sulfoxide were charged into a 500 mL eggplant-shaped flask and azinated at room temperature. Sodium (460 mg, 7.08 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and water was added to extract with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methylene chloride: ethanol = 13: 1 v / v) to obtain 450 mg (yield 29%) of the objective product as a slightly yellow foam.
Mass spectrometry value FAB-MS (m / z): 380 (M + H)+
[4] 4- (2-Methyl-5-oxo-4,5-dihydroimidazol-1-yl) -2,2-diphenylbutanamide (RC12)
In a 500 mL eggplant-shaped flask, 4-N-acetyl-N-azidoacetylamino-2,2-diphenylbutanamide (46) (450 mg, 1.19 mmol) and 30 mL of toluene were charged, and triphenylphosphine (343 mg) was added at room temperature. , 1.31 mmol). Stir at room temperature for 2 hours and let stand overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 13: 1 v / v) to obtain 266 mg of the foamy target product.
Mass spectrometry value FAB-MS (m / z): 336 (M + H)+.
1H-NMR (400 MHz, CDCl3) Δ 2.14 (3H, t, J = 2.0 Hz), 2.61-2.65 (2H, m), 3.44-3.47 (2H, m), 3.99 (2H, d, J = 2.0 Hz), 5.51 (1 H, br s), 5.57 (1 H, br s), 7.30-7.40 (10 H, m).
13C-NMR (100 MHz, CDCl3) 15.71, 37.77, 38.41, 58.23, 58.92, 128.44-128.80, 142.26, 163.57, 176.24, 181.42.
Example 14 4- (2-Methyl-4,5-dioxo-4,5-dihydroimidazol-1-yl) -2,2-diphenylbutanamide (RC13)
4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutanamide (3, X = H, JP-A-7-215943) (320 mg, 1.00 mmol), tetraphenylporphyrin manganese chloride (7.00 mg, 9.96 μmol), iodosobenzene (220 mg, 1.00 mmol), 5 mL of methylene chloride and 5 mL of acetonitrile were mixed and stirred at room temperature for 7.5 hours, and then left overnight. The reaction solution was concentrated, and the residue was produced by silica gel column chromatography (eluent chloroform: methanol = 50: 3 v / v), and fractions having an Rf value of 0.24 were collected and concentrated to give 70 mg (21%) A slightly yellow powdery target product was obtained.
FAB-MS (m / z): 350 (M + H)+
HRMS C20H20N3O3 calcd. 350.1505, found 350.1528.
<Example 15>
1- [3- (3-carbamoyl-3,3-diphenyl) propyl-2-methyl-1-imidazolio] -1-deoxy-β-D-glucopyranuronate (RC7)
[1] Methyl [2,3,4-tri-O-benzoyl-1-deoxy-β-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl) -2-methylimidazolium chloride]] Uronate (38)
4- (2-Methyl-1-imidazolyl) -2,2-diphenylbutyramide (3, X = H, JP-A-7-215943) (248 g, 775 mmol) and methyl 2,3,4-tri-O-benzoyl Dehydrated chloroform (1350 mL) was added to -1-methanesulfonyl-α-D-glucopyranuronate (54.5 g, 91.0 mmol), and the mixture was heated to reflux for 6.5 hours with stirring in an argon atmosphere (4 hours after the start of heating reflux). From the solution, chloroform (550 mL) was distilled off at normal pressure. After cooling, the solvent was distilled off under reduced pressure, and methylene chloride (1000 mL) and 2 mol / L hydrochloric acid (500 mL) were added to the residue for dissolution, and the methylene chloride layer was separated. The aqueous layer was extracted with methylene chloride (250 mL), the methylene chloride layers were combined, washed with 2 mol / L hydrochloric acid (250 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted sequentially with methylene chloride → methylene chloride-methanol = 40: 1 → methylene chloride-methanol = 30: 1 → methylene chloride-methanol = 20: 1. The fraction containing the desired product was concentrated under reduced pressure, and isopropyl ether (100 mL) was added to the obtained oil to crystallize. Precipitated crystals were collected by filtration, and brown powdered methyl [2,3,4-tri-O-benzoyl-1-deoxy-β-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl)- 22.9 g (42%) of 2-methylimidazolium chloride]] uronate.
11 H-NMR (400 MHz, DMSO-d6) Δ; 2.40-2.46 (1H, m), 2.52 (3H, s), 2.69-2.76 (1H, m), 3.58 (3H, s), 3.68 −3.85 (2H, m), 5.09 (1H, d, J = 9.8 Hz), 5.88 (1H, t, J = 9.3 Hz), 6.20 (1H, t, J = 9.3 Hz), 6.25 (1 H, t, J = 9.3 Hz), 6.65 (1 H, d, J = 7.8 Hz), 6.76 (1 H, s), 7.15-7. 85 (27H, m), 8.15 (1H, d, J = 2.0 Hz).
[2] 1- [3- (3-Carbamoyl-3,3-diphenyl) propyl-2-methyl-1-imidazolinio] -1-deoxy-β-D-glucopyranuronate 1.0 hydrate (RC7 )
Methyl [2,3,4-tri-O-benzoyl-1-deoxy-β-D-glucopyranosyl [1- (3-carbamoyl-3,3-diphenylpropyl) -2-methylimidazolium chloride]] uronate (32 0.7 g, 38.1 mmol) in methanol (1310 mL) with 1 mol / L sodium hydroxide aqueous solution (545 mL) at an internal temperature of −52 to −48 ° C. for 20 minutes while stirring on a dry ice-acetone bath while cooling. The mixture was added dropwise and stirred at the same temperature for 30 minutes, then returned to room temperature and stirred for 2 hours. Activated carbon (3.3 g) was added to the reaction solution, and the mixture was stirred for 20 minutes. Insoluble material was filtered off using a celite pad, and the filtrate was adjusted to pH 7 with 6 mol / L hydrochloric acid, and concentrated under reduced pressure. The obtained residue was dissolved in purified water (500 mL), washed with methylene chloride (500 mL × 3), concentrated under reduced pressure, and the obtained residue was subjected to synthetic adsorbent column chromatography [HP-20SS]. Elute with purified water → purified water: methanol = 2: 1. Fractions containing the desired product were combined and concentrated under reduced pressure. The obtained solid was dissolved in purified water (20 mL), isopropyl alcohol (600 mL) was gradually added, and the precipitated crystals were collected by filtration, and then isolated with isopropyl. Washing with alcohol (100 mL) gave 17.8 g of crude crystals. The obtained crude crystals were suspended in isopropyl alcohol (100 mL), purified water (30 mL) was added and dissolved at 80 ° C., isopropyl alcohol (50 mL) was added, and the mixture was allowed to stand at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed with isopropyl alcohol (100 mL), and dried under reduced pressure at 60 ° C. for 4 hours to obtain 14.3 g (73%) of the target compound as light brown crystals.
mp 209-215 [deg.] C. (decomp.).
IR (KBr) cm-13412, 1663, 1626.
[Α]D 21= + 9.6 ° (c = 0.50, H2O).
Anal. Calcd C26H29N3O7・ 1.0H2O: C, 60.81; H, 6.08; N, 8.18.
Found: C, 60.64; H, 6.02; N, 8.26.
FAB-MS+ m / z: 496 [M + H]+.
1H-NMR (400 MHz, D2O) δ; 2.49 (3H, s), 2.90-3.01 (2H, m), 3.66 (1H, t, J = 9.3 Hz), 3.73 (1H, t, J = 8.8 Hz), 3.78 (1H, t, J = 8.3 Hz), 4.00 (1H, d, J = 9.8 Hz), 4.04-4.16 (2H, m), 5 .52 (1H, d, J = 8.8 Hz), 7.36-7.48 (11H, m), 7.67 (1H, d, J = 2.4 Hz).
Moisture measurement (Karl Fischer method): 3.46%.
Industrial applicability
<Anticholinergic action on isolated guinea pig ileum and atria>
From the Hartley male guinea pig, the heart and the ileum near the cecum were removed. The ileum was suspended as a small piece of about 3 cm in length with a load of 1 g in the Magnus tube, and the specimen reaction was recorded isotonic. The nutrient solution uses Tyrode's solution and O2: 95%, CO2: 5% mixed gas was passed through, and the liquid temperature was 32 ° C. Acetylcholine was administered cumulatively and test compounds were pretreated for 5 minutes. Test compound affinity (pA2) Was determined by the Schild method (Brit. J. Pharmacol., 1448-58 (1959)).
The separated atrium was suspended in a Magnus tube with a load of 0.5 g, and the specimen reaction was recorded isometrically. The nutrient solution uses Tyrode's solution and O2: 95%, CO2: A gas mixture of 5% was vented, and the liquid temperature was 32 ° C. Acetylcholine was administered cumulatively and the test compound was treated 10 minutes ago. The test compound was determined in the same manner as in the case of the affinity ileum. As a result, the compound of the present invention showed a significant antagonism against the muscular receptor of the ileum.
<Action on rhythmic bladder contraction>
A Wistar male rat was fixed to the dorsal position under halothane anesthesia, a catheter with a balloon was inserted from the apex of the bladder exposed by a midline abdominal incision, and a purse string suture was performed. A catheter was led out from the sutured upper abdomen, and a three-way stopcock was connected. One was connected to a syringe, and the other was connected to a pressure transducer for measuring intravesical pressure. About 0.1 to 0.3 mL of distilled water is injected into the balloon, and after confirming that the induced rhythmic bladder contraction has a stable amplitude, the test compound is placed in the duodenum via a catheter previously placed. Administered. The inhibitory effect was evaluated from the decrease in amplitude of rhythmic bladder contraction. As a result, the present compound showed a significant inhibitory effect.
From the above, the compounds of the present invention are useful for the treatment of irritable bowel syndrome, frequent urination and urinary incontinence.