JP4316686B2 - Cycloheptimidazole derivative - Google Patents

Description

【０００４】
（式中、Ｒ₁は水素又はイソプロピル基、Ｒ₂は低級アルキル基、Ｒ₃はカルボキシル基又はテトラゾール基を表す。Ａ，Ａ₁はそれぞれ４位又は８位に存在する置換基で、Ａが水素原子のときＡ₁は水素原子又は水酸基であり、またＡとＡ₁とでオキソ基又は＝ＣＨＣＯＯＲ₃（Ｒ₃は低級アルキル基）を表すことがある。……線は二つの二重結合又は飽和された一重結合を表す。）
先に提案したシクロヘプトイミダゾール誘導体の製法は、下記の化学式で示すようにシクロヘプトイミダゾールとハロゲノメチルビフェニル化合物とを塩基の存在下で反応させ、次いでＲ₄のニトリル基をカルボキシル基又はテトラゾール基に変換している。
【０００５】
【化６】

【０００６】
（式中、Ｒ₄はニトリル基、Ｘはハロゲン原子を表す。）
この製造方法によると、Ｒ₄のニトリル基をテトラゾールに変換させる場合には目的物を得るまでに二段階の反応を行わなければならなく、しかも反応の際にＳｎＮ₃（アジ化スズ）等の高価で、且つ取扱いの難しい化合物を使用しなければならない場合があるなどの問題点を有する。
【０００７】
【発明が解決しようとする課題】
本発明は上記の事情に鑑みなされたもので、簡単な操作でしかも収率良く安価にシクロヘプトイミダゾール誘導体を合成し得る方法を提供することを目的とする。
【０００８】
【課題を解決するための手段】
本発明者等は、前記のシクロヘプトイミダゾール誘導体の合成方法について鋭意研究を行ってきた結果、触媒等を使用して実に簡単な操作でしかも収率良く安価にシクロヘプトイミダゾール誘導体を合成し得ることを見い出した。
本発明は、次式の一般式（１）
【０００９】
【化７】

【００１０】
（式中、Ｒ₁は水素又はイソプロピル基、Ｒ₂は炭素数１〜４の低級アルキル基を表す。Ａ、Ａ₁はそれぞれ４位又は８位に存在する基で、Ａが水素原子のとき、Ａ₁は水素原子又は水酸基であり、或いはＡとＡ₁とでオキソ基又は＝ＣＨＣＯＯＲ₃（Ｒ₃は炭素数１〜４の低級アルキル基）を形成してもよい。………線は二つの二重結合又は飽和された一重結合を表す。Ｘはハロゲン原子又はトリフルオロメタンスルホネート基である。）
で示される化合物である。また、本発明は一般式（１）の化合物を次式の一般式（２）
【００１１】
【化８】

【００１２】
〔式中、Ｙは−Ｂ（ＯＨ）₂又は−Ｓｎ（Ｒ₅）₃（但し、Ｒ₅は炭素数１〜４の低級アルキル基を表す）、Ｚは保護基である。〕
で示される化合物と反応させて、次式の一般式（３）
【００１３】
【化９】

【００１４】
（式中、Ｒ₁は水素又はイソプロピル基、Ｒ₂は炭素数１〜４の低級アルキル基を表す。Ａ、Ａ₁はそれぞれ４位又は８位に存在する基で、Ａが水素原子のとき、Ａ₁は水素原子又は水酸基であり、或いはＡとＡ₁とでオキソ基又は＝ＣＨＣＯＯＲ₃（Ｒ₃は炭素数１〜４の低級アルキル基）を形成してもよい。………線は二つの二重結合又は飽和された一重結合を表す。Ｚは保護基である。）
で示される化合物となし、次いで該化合物を脱保護基処理することを特徴とする次式の一般式（４）
【００１５】
【化１０】

【００１６】
（式中、Ｒ₁は水素又はイソプロピル基、Ｒ₂は炭素数１〜４の低級アルキル基を表す。Ａ、Ａ₁はそれぞれ４位又は８位に存在する基で、Ａが水素原子のとき、Ａ₁は水素原子又は水酸基であり、或いはＡとＡ₁とでオキソ基又は＝ＣＨＣＯＯＲ₃（Ｒ₃は炭素数１〜４の低級アルキル基）を形成してもよい。……線は二つの二重結合又は飽和された一重結合を表す。）
で示されるシクロヘプトイミダゾール誘導体の製法である。
本発明における保護基Ｚとしては、ターシャリーブチル基、トリチル基〔−Ｃ（Ｐｈ）₃〕、メトキシメチルエーテル基、ベンジルメチルエーテル基、ｐ−ニトロフェニル基等が挙げられる。また、以下、低級アルキル基は炭素数１〜４の低級アルキル基を指す。
【００１７】
本発明の製造方法を更に詳しく説明する。
（イ）一般式（１）で示される化合物の製造。
一般式（１）で示される化合物は次の方法で製造することができる。
（Ｉ）一般式（１）でＡ、Ａ₁はそれぞれ４位又は８位に存在する基で、Ａが水素原子のとき、Ａ₁は水素原子又は水酸基である場合、或いはＡとＡ₁とでオキソ基を形成している場合の化合物は、次の化１１の方法で合成できる。
【００１８】
【化１１】

【００１９】
（式中、Ｒ₁、Ａ、Ａ₁、Ｒ₂、Ｘは前記と同じ意味である。）
すなわち、シクロヘプトイミダゾール（５）とｐ−ハロゲノベンジルハロゲン化合物（６）とを塩基の存在下で反応させて化合物（１）を合成する。塩基としてはソジウムヒドリド、水酸化ナトリウム、炭酸カリ等が用いられる。反応溶媒としてはジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）、テトラヒドロフラン（ＴＨＦ）、アセトン、ジオキサン等が用いられる。この反応は相間移動触媒を用いて行うこともできる。相間移動触媒としてはテトラブチルアンモニウム・サルフェイト等を用い、反応溶媒としては水、ベンゼン等を用いる。
上記のシクロヘプトイミダゾール（５）は特開平５−３２０１３９号公報に記載の既知の方法で製造する。すなわち、
（ｉ）ＡとＡ₁でオキソ基をつくり、二重結合を有するシクロヘプトイミダゾール化合物については化１２で示す合成法で得ることができる。
【００２０】
【化１２】

【００２１】
（式中、Ｒ₁は水素又はイソプロピル基、Ｒ₂は低級アルキル基である。）
すなわち、トシルトロポロン（７）をアミジン（８）とアルカリ存在下で反応させケトイミダゾール（９）を合成する（ケミカル・アブストラト ７４，５３７８５ａ、日本特許第７０３１１７１号）。
（ii）また、ＡとＡ₁が水素で飽和された一重結合を有するシクロヘプトイミダゾール化合物については化１３に示す合成法で得ることができる。
【００２２】
【化１３】

【００２３】
（式中、Ｒ₁、Ｒ₂は上記と同じ意味である。）
すなわち、メチルトロポロン（１０）をアミジン（８）とソジウムエトキサイドの存在下で反応させ化合物（１１）とした後、酸化白金（ＰｔＯ₂）等を触媒用いて水素化を行いイミダゾール化合物（１２）とする。
（iii）ＡとＡ₁でオキソ基をつくり、飽和された一重結合を有するシクロヘプトイミダゾール化合物については化１４で示す合成法で得ることができる。
【００２４】
【化１４】

【００２５】
（式中、Ｒ₁、Ｒ₂は上記と同じ意味である。）
すなわち、オキソイミダゾール（９）体をパラジウム−炭素（Ｐｄ／Ｃ）又は酸化白銀（ＰｔＯ₂）等を触媒に用いて、水素化を行いイミダゾール化合物（１３）を合成する。
（iv）Ａが水素でＡ₁が水酸基であるシクロヘプトイミダゾール化合物については、上記の化合物（１３）をＮａＢＨ₄やＬｉＡｌＨ₄などで還元することにより、オキソ基を水酸基に変換して製造することができる。
（II）一般式（１）で示される化合物でＡとＡ₁とで＝ＣＨＣＯＯＲ₃（Ｒ₃は低級アルキル基）を形成している化合物の場合は、次の化１５により得ることができる。
【００２６】
【化１５】

【００２７】
（式中、Ｒ₁、Ｒ₂、Ｒ₃、Ｘは上記と同じ意味である。）
すなわち、化合物（１３）をＰ−ハロゲノベンジルハロゲン化合物（６）と塩基の存在下、相間移動触媒例えばテトラブチルアンモニウム・サルフェイト等を用いて化合物（１４）を製造し、該化合物（１４）にＬｉＣＨ₂ＣＯＯＲ₃を反応させ化合物（１５）を得る。化合物（１５）をピリジン中、塩化チオニルを加えることにより脱水処理して化合物（１６）を得ることができる。また、化合物（１４）を塩基存在下ジエチルホスホノ酢酸エステルと反応させて化合物（１６）を直接得ることもできる。
【００２８】
（ロ）一般式（２）で示される化合物の製造。
一般式（２）で示される化合物は、次の方法で製造できる。
（Ｉ）一般式（２）でボロン酸化合物の場合は、次の化１６により得ることができる。
【００２９】
【化１６】

【００３０】
（式中、Ｘはハロゲン原子、Ｚは保護基である。）
すなわち、化合物（１７）をｎ−ブチルリチウム又はグリニヤール反応を行い、トリメトキシボロン酸を加え、希硫酸で加水分解を行い、化合物（２ａ）のボロン酸にする（平成４年９月２５日丸善株式会社発行「実験化学講座２４、有機合成 ＶＩ」第８０頁）。
（II）一般式（２）でスズ化合物はの場合は、次の化１７により得ることができる。
【００３１】
【化１７】

【００３２】
（式中、Ｘはハロゲン原子、Ｚは保護基である。Ｒ₅は低級アルキル基を表す。）
すなわち、化合物（１７）をｎ−ブチルリチウムで反応させ、次にトリアルキルスズクロライドと反応させ、化合物（２ｂ）を得る。
【００３３】
（ハ）一般式（３）の化合物の合成。
本発明において、一般式（１）の化合物と一般式（２）の化合物とを反応させて一般式（３）の化合物を合成するには次のようにして行う。
（Ｉ）一般式（２）の化合物のＹ基が、−Ｂ（ＯＨ）₂の場合。
一般式（１）の化合物と一般式（２）とを、塩基性のもとで、触媒の存在下反応させる[Suzuki；Synthetic Communication，11(7)，513(1981)準用]。触媒としてはテトラキストリフェニルホスフィンパラジウム（Ｐｄ(ＰＰｈ₃)₄）、塩化パラジウム(ＰｄＣｌ₂)、又はパラジウム−炭素(Ｐｄ／Ｃ)等を用いる。塩基としては炭酸ナトリウム、炭酸カルシウム、水酸化ナトリウム、水酸化カルシウム等を用いる。反応溶媒としては水、エタノール、メタノール、ベンゼン、トルエン等を用いる。反応は室温又は加熱還流して行う。斯くして一般式（３）の化合物を得ることができる。
【００３４】
（II）一般式（２）の化合物のＹ基が、−Ｓｎ（Ｒ₅）₃（但し、Ｒ₅ｎは低級アルキル基を表すの場合。
一般式（１）の化合物と一般式（２）の化合物を触媒の存在下で反応させる[Shille;Angew．Chem．Int．Ed．Engl，25，508-524(1986)準用]。触媒としてテトラキストリフェニルホスフィンパラジウム（Ｐｄ（ＰＰｈ₃）₄）、塩化パラジウム（ＰｄＣｌ₂）、パラジウム−炭素(Ｐｄ／Ｃ）、ヨウ化銅（ＣｕＩ）、塩化リチウム（ＬｉＣｌ）等を用いる。反応溶媒としてＴＨＦ、ジメトキシエタン（ＤＭＥ）、ジメチルホルムアミド（ＤＭＦ）等を用いる。反応は室温又は還流させて行う。斯くして一般式（３）の化合物を得ることができる。
【００３５】
（ニ）脱保護化処理。
一般式（３）の脱保護化は、一般式（３）の化合物のベンゼン又はトルエン溶液に、ＨＣｌ又はＣＨ₃ＳＯ₃Ｈ等の酸性の液を加え加熱還流することにより行う。一般式（３）の保護基が離脱し、本発明の目的物質である一般式（４）の化合物を得ることができる。
以下に、実施例及び参考例を示す。
【００３６】
【実施例】
実施例１.
５−［２−（４−（２−プロピル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾリル）メチルビフェニリル）］テトラゾールの製造例。
（ａ） １−（４−ヨウドベンジル）−２−プロピル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾールの製造。
反応容器中に、３０％ＮａＯＨ６０ｍｌとトルエン１５０ｍｌを入れ、更に２−プロピル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾール５．０ｇ、４−ヨウドベンジルブロミド９．２ｇ及びテトラブチルアンモニウムハイドロジエンサルフェートを２．０ｇ添加し、室温で８時間攪拌した。反応終了後濾過し、瀘液を酢酸エチルで抽出し、酢酸エチル層を芒硝で脱水後、濃縮した。シリカゲルカラムクロマトグラフィー（ＳｉＯ₂１２０ｇ）で精製を行った。溶出液はｎ−ヘキサン：酢酸エチル（１：１）を用いた。８．６９ｇの淡黄色の結晶の目的物を得た。この目的物の融点は６４〜６５℃であった。
Mass(m/e)：M⁺=408、217(BP)
IR(cm^-1)：2926、1632、1464、1428
¹H-NMR(CDCl₃)：0.95(3H,t,-CH₂CH₂ CH ₃),1.70(2H,m,-CH₂ CH ₂CH₃),1.87(2H,m,Cyclo環）,1.92(2H,m,Cyclo環),2.58(2H,m,Cyclo環),2.65(2H,m,Cyclo環),2.96(2H,t,-CH ₂CH₂CH₃),5.47(2H,s,-CH ₂-C₆H₅),6.71(2H,d,芳香環),7.62(2H,d,芳香環）
【００３７】
（ｂ） ２−ターシャリーブチル−５−［２−（４−（２−プロピル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾリル）メチルビフェニリル）］テトラゾールの製造。
上記（ａ）で得た化合物１５０ｍｇに［２−（２−ターシャリーブチル−２Ｈ−テトラゾール−５−イル）フェニル］−ボロン酸（実施例３参照）９６ｍｇ、テトラキストリフェニルホスフィンパラジウム３５ｍｇ、２Ｍ炭酸ナトリウム０．７ｍｌ、エタノール１ｍｌ及びトルエン１０ｍｌ添加し、３時間加熱還流した。濃縮し、その後クロロホルム３０ｍｌで３回抽出した。クロロホルム層を水洗し、芒硝で脱水した。その後濾過し、濃縮し、シリカゲルカラムで精製した。溶出液は酢酸エチル：ｎ−ヘキサン（１０：１）を用いた。１７５ｍｇの淡黄色で油状の目的物を得た。
IR(cm^-1)：2926、1632、1464、1428
Mass(m/e)：M⁺=482、426、178(BP)
¹H-NMR(CDCl₃)：0.96(3H,t,-CH₂CH₂ CH ₃),1.55(9H,s,-(CH ₃)₃),1.75(2H,m,-CH₂ CH ₂CH₃),1.80〜2.00(4H,m,Cyclo環),2.59(2H,t,Cyclo環),2.68(2H,m,Cyclo環),3.01(2H,q,-CH ₂CH₂CH₃),5.57(2H,s,-CH ₂C₆H₅),6.90(2H,d,芳香環),7.09(2H,d,芳香環),7.35〜7.60(3H,m,芳香環),7.89(2H,d,芳香環）．
【００３８】
（ｃ） ５−［２−（４−（２−プロピル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾリル）メチルビフェニリル）］テトラゾールの製造。
上記（ｂ）で得た化合物１００ｍｇをメタンスルホン酸２００ｍｇ及びトルエン１０ｍｌに加え、３時間加熱還流して保護基のターシャリーブチル基を離脱させた。次いで濃縮し、氷水にあけ１０％ＮａＯＨでｐＨ８にした。白色結晶が析出した。濾過し、エチルアルコール１．５ｍｌで再結晶を行なった。白色結晶の目的物を７７．４ｍｇ得た。融点２１４〜２１６℃であった。
Mass(m/e)：M⁺=426、383、355、178(BP).152
¹H-NMR(CDCl₃)：0.90(3H,t,-CH₂CH₂ CH ₃),1.58(2H,m,-CH₂ CH ₂CH₃),1.68(2H,m,Cyclo環),1.75(2H,m,Cyclo環),2.30(2H,m,Cyclo環),2.47(2H,m,Cyclo環),2.53(2H,t,-CH ₂CH₂CH₃),5.45(2H,s,-CH ₂C₆H₅),6.75(2H,d,芳香環),7.00(2H,d,芳香環),7.42(2H,d,芳香環),7.52(2H,d,芳香環),7.60(2H,d,芳香環),7.85(2H,d,芳香環).
【００３９】
実施例２．
５−［２−（４−（２−プロピル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾリル）メチルビフェニリル）］テトラゾールの製造例。
実施例１と同様にして１−（４−ヨウドベンジル）−２−プロピル−８−オキソ−５、６、７、８−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾールを合成した。
反応容器に、この１−（４−ヨウドベンジル）−２−プロピル−８−オキソ−５、６、７、８−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾール１００ｍｇと２−（２−（２−ターシャリーブチル−２Ｈ−テトラゾール−５−イル）フェニル］トリ−ｎ−ブチルスタナン（実施例４参照）１２０ｍｇと塩化リチウム３１．１５ｍｇとテトラキストリフェニルフォスフィンパラジウム１．４ｍｇとテトラヒドロフラン８ｍｌを入れ、４８時間加熱還流を行う。濾過し、濃縮し酢酸エチル３０ｍｌで抽出した。酢酸エチル層を水洗し、芒硝で脱水した。次いで濾過し、濃縮した。シリカゲルカラムで精製した。溶出液は酢酸エチルとｎ−ヘキサン（１：１）を用いた。淡黄色で油状の２−ターシャリーブチル−５−［２−（４−（２−プロピル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾリル）メチルビフェニリル）］テトラゾール４５ｍｇを得た。その物性、分析結果は次のとおりであった。
Mass(m/e)：M⁺=482、426、369、178(BP)
IR(cm^-1)：2926、1632、1464、1428、1389
¹H-NMR(CDCl₃)：0.96(3H,t,-CH₂CH₂ CH ₃),1.55(9H,s,-(CH₃)₃),1.74(2H,m,-CH₂ CH ₂CH₃),1.80〜2.00(4H,m,Cyclo環),2.59(2H,t,Cyclo環),2.68(2H,m,Cyclo環),3.01(2H,q,-CH ₂CH₂CH₃),5.57(2H,s,-CH ₂C₆H₅),6.90(2H,d,芳香環),7.09(2H,d,芳香環),7.35〜7.60(3H,m,芳香環),7.89(2H,d,芳香環)．
上記の２−ターシャリーブチル−５−［２−（４−（２−プロピル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾリル）メチルビフェニリル）］テトラゾールを実施例１と同様にして、保護基であるターシャリーブチル基を離脱して、目的物質５−［２−（４−（２−プロピル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾリル）メチルビフェニリル）］テトラゾールを得た。
【００４０】
実施例３.
［２−（２−ターシャリーブチル−２Ｈ−テトラゾール−５−イル）フェニル］−ボロン酸の製造。
５−（２−ブロモフェニル）−２−（１．１−ジメチルエチル）−２Ｈ−テトラゾール体３．３ｇをテトラヒドロフラン２０ｍｌに溶解し、−７８℃に冷却した。この溶液に１．６Ｍのｎ−ブチルリチウム／ｎ−ヘキサン７．８ｍｌを添加し、次にトリイソプロピルボロン酸２．３ｇを加え、室温で１時間攪拌した。次いで０．５Ｎ塩酸４０ｍｌを添加し、３０分間攪拌した。反応液を氷水５０ｍｌにあけ、エーテル３０ｍｌで２回抽出した。エーテル層を１ＮのＫＯＨ１０ｍｌで３回抽出した。アルカリ液を２ＮのＨＣｌで酸性にした。白色結晶の目的物を１．８７ｇ得た。融点は１１７〜１２２℃であった。
¹H-NMR(CDCl₃)：1.72(9H,s,-C(CH₃)₃),7.46(2H,m,芳香環),7.90(2H,m,芳香環)
【００４１】
実施例４.
［２−（２−（２−ターシャリーブチル−２Ｈ−テトラゾール−５−イル）フェニル］トリ−ｎ−ブチルスタナンの製造。
５−（２−ブロモフェニル）−２−（１．１−ジメチルエチル）−２Ｈ−テトラゾール体１．２３ｇをテトラヒドロフラン８ｍｌに溶解し、−７８℃に冷却した。この溶液に１．６Ｍのｎ−ブチルリチウム／ｎ−ヘキサン３．２７ｍｌを加え１時間攪拌した。更に、トリ−ｎ−ブチルスズクロライド１．７１ｇを加え、−７８℃で３時間撹拌し、その後室温で１８時間攪拌した。反応液を水２０ｍｌにあけ、エーテル３０ｍｌで２回抽出した。エーテル層を水洗いし、芒硝で脱水した。次いで濾過し、濃縮した。シリカゲルカラムで精製した（溶出液はｎ−ヘキサン）。淡黄色で油状の目的物を１．０ｇ得た。
¹H-NMR(CDCl₃)：0.78(9H,t,-(-CH₃)₃),0.93(6H,t,-(CH₂-)₃),1.21(6H,m,-(CH₂-)₃),1.43(6H,m,-(CH₂-)₃),1.80(9H,s,(CH₃)₃),7.43(1H,d,芳香環),7.45(1H,d,芳香環),7.60(1H,m,芳香環),8.00(1H,m,芳香環)．
【００４２】
実施例５．
２−エチル−８−カルボキシメチリデン−１−〔（２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル）メチル〕−４、５、６、７−テトラヒドロ−シクロヘプトイミダゾールの製造。
（ａ） １−（４−ブロモベンジル）−２−エチル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾールの製造。
反応容器に、３０％ＮａＯＨ３０ｍｌとトルエン５０ｍｌを入れ、その中に２−エチル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾール２．５ｇと４−ブロモベンジルブロミド３．６ｇとテトラブチルアンモニウムハイドロジエンサルフェート０．５ｇを入れ、室温で８時間攪拌した。反応終了後濾過し、濾液を酢酸エチルで抽出し、酢酸エチル層を水洗し、芒硝で脱水後、濃縮した。シリカゲルクロマトグラフィー（ＳｉＯ₂１００ｇ）で精製を行った。溶出液はｎ−ヘキサンと酢酸エチル（１：１）を用いた。淡黄色で油状の目的物４．０ｇを得た。
Mass(m/e)：M⁺=347、319、169(BP)
IR(cm^-1)：2950、1640、1480、1400、1330
¹H-NMR(CDCl₃)：1.27(3H,t,CH₂ CH ₃),1.85〜1.87(2H,m,Cyclo環),1.91〜1.94(2H,m,Cyclo環),2.60〜2.65(4H,m,Cyclo環),3.01(2H,q,CH ₂CH₃),5.48(2H,s,-CH ₂-C₆H₅),6.86(2H,d,芳香環),7.41(2H,d,芳香環).
【００４３】
（ｂ） １−（４−ブロモベンジル）−２−エチル−８−エトキシカルボニル−８−ヒドロ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾールの製造。
テトラヒドロフラン５ｍｌ中にリチウムビス（トリメチルシリル）アミド２．８８ｍｌを加え−７８℃に冷却し、そこへ酢酸エチル０．２５ｍｌを滴下し、１５分間そのまま攪拌し、更にＴＨＦ３ｍｌに溶解した上記（ａ）で得た化合物０．５ｇを滴下した。滴下終了後１時間攪拌した。反応終了後、反応液に６ＮのＨＣｌを加え攪拌し、酢酸エチルで抽出した。酢酸エチル層を水洗し、飽和ＮａＣｌで洗い、芒硝で脱水した。濾過し、濃縮した。次いでシリカゲルカラムで精製した。溶出液はクロロホルムとメタノール（２０：１）を用いた。淡黄色で油状の目的物３８８ｍｇを得た。
Mass(m/e)：M⁺=435、348、169(BP)、90
IR(cm^-1)：3300、2900、1720、1170、1000
¹H-NMR(CDCl₃)：1.28(3H,t,-CH₂ CH ₃),1.33(3H,t,-CH₂ CH ₃),1.80〜2.20(6H,m,Cyclo環),2.71(2H,m,-CH ₂COOEt),2.78(2H,q-CH ₂CH₃),2.97(2H,m,Cyclo環),4.57(2H,q,-CH ₂CH₃),5.81(2H,s,-CH ₂C₆H₅),7.20〜7.40(4H,m,芳香環)．
【００４４】
（ｃ） １−（４−ブロモベンジル）−２−エチル−８−エトキシカルボニルメチリデン−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾールの製造。
（１）上記（ｂ）で得た１−（４−ブロモベンジル）−２−エチル−８−エトキシカルボニル−８−ヒドロキシ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾール０．３８ｇをピリジン２ｍｌに溶解し、この溶液に室温で塩化チオニル０．３２ｇを加え、そのまま１時間攪拌した。この反応液を１０％ＨＣｌ２０ｍｌに注ぎ込み、次いで酢酸エチルで抽出した。酢酸エチル層を水洗し、芒硝で脱水した。濾過し、濃縮した。その後シリカゲルカラムで精製した。溶出液はクロロホルムとメタノール（２０：１）を用いた。淡黄色で油状の目的物２８０ｍｇを得た。
【００４５】
（２）また、水素化カリウム０．０８ｇをテトラヒドロフラン５ｍｌに懸濁させ、この懸濁液にジエチルホスホノ酢酸エステル０．３７ｇを０〜５℃で滴下した。更に、上記（ａ）で得た１−（４−ブロモベンジル）−２−エチル−８−オキソ−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾール０．５ｇのテトラヒドロフラン溶液１ｍｌを加えた。その後４０℃で５時間加温した。反応液を氷水２０ｍｌにあけ、酢酸エチルで抽出した。酢酸エチル層を飽和ＮａＣｌで洗い、芒硝で脱水した。濾過し、濃縮した。次いでシリカゲルカラムで精製した。溶出液はクロロホルムとメタノール（２０：１）を用いた。淡黄色で油状の目的物６０ｍｇを得た。
Mass(m/e)：M⁺+1=418、371、343、171(BP)、90
IR(cm^-1)：2900、1710、1230、1170、1000
¹H-NMR(CDCl₃)：1.26(3H,t,-CH₂ CH ₃),1.26(3H,t,-CH₂ CH ₃),1.85(2H,m,Cyclo環),1.90(2H,m,Cyclo環),2.91(2H,q,CH ₂CH₃),2.92(2H,q,CH ₂CH₃),4.05〜4.20(4H,m,Cyclo環),5.28(2H,s,-CH ₂C₆H₃),5.68(1H,s,=CHCOOC₂H₅),6.80(d,2H,芳香環),7.55(2H,d,芳香環)
【００４６】
（ｄ） ２−ターシャリーブチル−５−［２−（４−（２−エチル−８−エトキシカルボニルメチリデン−４、５、６、７−テトラヒドロ−１（４Ｈ）−シクロヘプトイミダゾリル）メチルビフェニリル）］テトラゾールの製造。
上記（ｃ）で得た化合物２８０ｍｇに［２−（２−ターシャリーブチル−２Ｈ−テトラゾール−５−イル）フェニル）］−ボロン酸１７５．５ｍｇ、２Ｍ炭酸ナトリウム１．６ｍｌ、エタノール０．１ｍｌ、テトラキストリフェニルホスフィンパラジウム２６．８ｍｇ及びトルエン５ｍｌを添加し、４．５時間加熱還流した。反応液を水３０ｍｌに注ぎ込み、トルエン２０ｍｌで３回抽出した。トルエン層を水洗し、芒硝で脱水した。濾過し、濃縮した。その後シリカゲルカラムで精製した。溶出液は酢酸エチルとｎ−ヘキサン（１：１）を用いた。淡黄色で油状の目的物２３０ｍｇを得た。
Mass(m/e)：M⁺+1=539、451、253、178(BP)
IR(cm^-1)：3420、3000、1230、2950、1720
¹H-NMR(CDCl₃)：1.25(3H,s,t-Bu),1.82(2H,m,Cyclo環),2.55(2H,q,-CH ₂CH₃),2.80〜2.83(2H,m,Cyclo環),3.04〜3.07(2H,m,Cyclo環),4.12(2H,q,-CH ₂CH₃),5.17(2H,s,-CH ₂C₆H₅),5.56(1H,s,=CHCOOC₂H₅),6.82(2H,d,芳香環),7.14(2H,d,芳香環),7.39〜7.88(4H,m,芳香環)．
【００４７】
（ｅ） ２−エチル−８−カルボキシメチリデン−１−［（２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル）メチル］−４、５、６、７−テトラヒドロ−シクロヘプトイミダゾールの製造。
上記（ｄ）で得た化合物２００ｍｇをメタンスルホン酸４００ｍｇ及びトルエン２０ｍｌ入れ３時間加熱還流し、保護基のターシャリーブチル基を離脱させた。次いで、濃縮し、氷水にあけ、１０％ＮａＯＨでｐＨ４にした。白色結晶が析出した。ろ過し、ＭｅＯＨ２ｍｌで再結晶を行なって、目的の化合物を白色結晶１２０ｍｇで得た。
融点191〜193℃
Mass(m/e)：M⁺=408(M⁺-COOH)、367、192(BP)、134
IR(cm^-1)：2914、1692、1611、1452、1362、1197
¹H-NMR(CD₃OD)：1.30(3H,t,-CH₂ CH ₃),1.94(4H,bs,Cyclo環),2.65〜3.03(6H,m,-CH ₂CH₃+Cyclo環),5.43(2H,s,-CH₂C₆H₅),5.92(1H,s,=CHCOOH，6.80〜7.70(8H,ｍ,芳香環),7.96(1H,s,-NH)．
【００４８】
【発明の効果】
本発明によると、簡単な操作で、しかも収率良く、安価にシクロヘプトイミダゾール誘導体を合成することが出来る。[0001]
[Industrial application fields]
The present invention relates to a novel method for producing a cycloheptimidazole derivative having an angiotensin II receptor antagonistic activity and useful as a therapeutic agent for hypertension and congestive heart failure.
[0002]
[Prior art]
The present inventors have synthesized a cyclohept derivative and studied its physiological activity. And a novel cycloheptimidazole derivative represented by the general formula of the following formula 5 which has an angiotensin II receptor antagonistic activity and is extremely useful as a therapeutic agent for hypertension and congestive heart failure or an intraocular pressure lowering agent: The manufacturing method was proposed (Japanese Patent Laid-Open No. 5-320139, Japanese Patent Application No. 5-190153).
[0003]
[Chemical formula 5]

[0004]
(In the formula, R ₁ represents hydrogen or isopropyl group, R ₂ represents a lower alkyl group, R ₃ represents a carboxyl group or a tetrazole group. A and A ₁ are substituents present at the 4-position or 8-position, respectively. In the case of a hydrogen atom, A ₁ is a hydrogen atom or a hydroxyl group, and A and A ₁ may represent an oxo group or = CHCOOR ₃ (R ₃ is a lower alkyl group) .... The line is two double bonds Or a saturated single bond.)
As previously shown, the cycloheptimidazole derivative is prepared by reacting cycloheptimidazole with a halogenomethylbiphenyl compound in the presence of a base, as shown by the following chemical formula, and then converting the nitrile group of R ₄ to a carboxyl group or tetrazole. It is converted to the base.
[0005]
[Chemical 6]

[0006]
(In the formula, R ₄ represents a nitrile group, and X represents a halogen atom.)
According to this production method, when the nitrile group of R ₄ is converted to tetrazole, a two-step reaction must be carried out until the desired product is obtained, and SnN ₃ (tin azide) or the like is used in the reaction. There is a problem that an expensive and difficult-to-handle compound may have to be used.
[0007]
[Problems to be solved by the invention]
The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a method capable of synthesizing a cycloheptimidazole derivative with high yield and low cost by a simple operation.
[0008]
[Means for Solving the Problems]
As a result of diligent research on the synthesis method of the above cycloheptimidazole derivative, the present inventors synthesized a cycloheptimidazole derivative at a low yield with a simple operation using a catalyst or the like. Found out to get.
The present invention relates to the following general formula (1)
[0009]
[Chemical 7]

[0010]
(In the formula, R ₁ represents hydrogen or an isopropyl group, R ₂ represents a lower alkyl group having 1 to 4 carbon atoms. A and A ₁ are groups present at the 4-position or 8-position, respectively, and A is a hydrogen atom. , A ₁ is a hydrogen atom or a hydroxyl group, or A and A ₁ may form an oxo group or ═CHCOOR ₃ (R ₃ is a lower alkyl group having 1 to 4 carbon atoms ). Represents two double bonds or a saturated single bond, X is a halogen atom or a trifluoromethanesulfonate group.)
It is a compound shown by these . In addition, the present invention relates to a compound of the general formula (1) represented by the following general formula (2)
[0011]
[Chemical 8]

[0012]
[Wherein, Y is -B (OH) ₂ or -Sn (R ₅ ) ₃ (where R ₅ represents a lower alkyl group having 1 to 4 carbon atoms ), and Z is a protecting group. ]
Is reacted with a compound represented by the general formula (3):
[0013]
[Chemical 9]

[0014]
(In the formula, R ₁ represents hydrogen or an isopropyl group, R ₂ represents a lower alkyl group having 1 to 4 carbon atoms. A and A ₁ are groups present at the 4-position or 8-position, respectively, and A is a hydrogen atom. , A ₁ is a hydrogen atom or a hydroxyl group, or A and A ₁ may form an oxo group or ═CHCOOR ₃ (R ₃ is a lower alkyl group having 1 to 4 carbon atoms ). Represents two double bonds or a saturated single bond, Z is a protecting group.)
The compound represented by the general formula (4) is characterized in that the compound is then treated with a deprotecting group.
[0015]
Embedded image

[0016]
(In the formula, R ₁ represents hydrogen or an isopropyl group, R ₂ represents a lower alkyl group having 1 to 4 carbon atoms. A and A ₁ are groups present at the 4-position or 8-position, respectively, and A is a hydrogen atom. A ₁ is a hydrogen atom or a hydroxyl group, or A and A ₁ may form an oxo group or ═CHCOOR ₃ (R ₃ is a lower alkyl group having 1 to 4 carbon atoms ). Represents one double bond or a saturated single bond.)
It is a manufacturing method of the cycloheptimidazole derivative shown by these.
Examples of the protecting group Z in the present invention include a tertiary butyl group, a trityl group [—C (Ph) ₃ ], a methoxymethyl ether group, a benzylmethyl ether group, and a p-nitrophenyl group. Hereinafter, the lower alkyl group refers to a lower alkyl group having 1 to 4 carbon atoms.
[0017]
The production method of the present invention will be described in more detail.
(A) Production of the compound represented by the general formula (1).
The compound represented by the general formula (1) can be produced by the following method.
(I) In general formula (1), A and A ₁ are groups present at the 4th and 8th positions, respectively, and when A is a hydrogen atom, A ₁ is a hydrogen atom or a hydroxyl group, or A and A ₁ In the case where an oxo group is formed, the compound can be synthesized by the following chemical formula 11.
[0018]
Embedded image

[0019]
(In the formula, R ₁ , A, A ₁ , R ₂ and X have the same meaning as described above.)
That is, compound (1) is synthesized by reacting cycloheptimidazole (5) with p-halogenobenzyl halogen compound (6) in the presence of a base. As the base, sodium hydride, sodium hydroxide, potassium carbonate and the like are used. As the reaction solvent, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetone, dioxane and the like are used. This reaction can also be performed using a phase transfer catalyst. Tetrabutylammonium sulfate or the like is used as the phase transfer catalyst, and water, benzene or the like is used as the reaction solvent.
The above cycloheptimidazole (5) is produced by a known method described in JP-A-5-320139. That is,
(I) A cycloheptimidazole compound having an oxo group formed of A and A ₁ and having a double bond can be obtained by the synthesis method shown in Chemical Formula 12.
[0020]
Embedded image

[0021]
(In the formula, R ₁ is hydrogen or an isopropyl group, and R ₂ is a lower alkyl group.)
That is, tosyltropolone (7) is reacted with amidine (8) in the presence of alkali to synthesize ketoimidazole (9) (Chemical Abstract 74,53785a, Japanese Patent No. 7031171).
(Ii) A cycloheptimidazole compound having a single bond in which A and A ₁ are saturated with hydrogen can be obtained by the synthesis method shown in Chemical formula 13.
[0022]
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[0023]
(In the formula, R ₁ and R ₂ have the same meaning as described above.)
That is, methyl tropolone (10) is reacted in the presence of amidine (8) with sodium ethoxide to give compound (11), and then hydrogenated using platinum oxide (PtO ₂ ) or the like as a catalyst to give an imidazole compound (12 ).
(Iii) A cycloheptimidazole compound having an oxo group formed of A and A ₁ and having a saturated single bond can be obtained by the synthesis method shown in Chemical Formula 14.
[0024]
Embedded image

[0025]
(In the formula, R ₁ and R ₂ have the same meaning as described above.)
That is, the oxoimidazole (9) compound is hydrogenated using palladium-carbon (Pd / C) or white silver oxide (PtO ₂ ) as a catalyst to synthesize the imidazole compound (13).
(Iv) A cycloheptimidazole compound in which A is hydrogen and A ₁ is a hydroxyl group is produced by reducing the above compound (13) with NaBH ₄ or LiAlH ₄ to convert the oxo group to a hydroxyl group. be able to.
(II) In the case of a compound represented by the general formula (1) in which A and A ₁ form ═CHCOOR ₃ (R ₃ is a lower alkyl group), it can be obtained by the following chemical formula (15).
[0026]
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[0027]
(In the formula, R ₁ , R ₂ , R ₃ and X have the same meanings as described above.)
That is, compound (13) is produced from compound (14) using a phase transfer catalyst such as tetrabutylammonium sulfate in the presence of P-halogenobenzyl halogen compound (6) and a base. LiCH ₂ COOR ₃ is reacted to obtain compound (15). Compound (16) can be obtained by dehydrating compound (15) by adding thionyl chloride in pyridine. Alternatively, compound (16) can be directly obtained by reacting compound (14) with diethylphosphonoacetate in the presence of a base.
[0028]
(B) Production of the compound represented by the general formula (2).
The compound represented by the general formula (2) can be produced by the following method.
(I) In the case of a boronic acid compound in the general formula (2), it can be obtained by the following chemical formula (16)
[0029]
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[0030]
(In the formula, X is a halogen atom, and Z is a protecting group.)
That is, the compound (17) is reacted with n-butyllithium or Grignard, added with trimethoxyboronic acid, and hydrolyzed with dilute sulfuric acid to obtain the boronic acid of the compound (2a) (September 25, 1992 Maruzen) Published by "Co-experimental Chemistry Course 24, Organic Synthesis VI", page 80).
(II) In the case of the general formula (2), the tin compound can be obtained by the following chemical formula (17).
[0031]
Embedded image

[0032]
(In the formula, X is a halogen atom, Z is a protecting group, R ₅ represents a lower alkyl group.)
That is, the compound (17) is reacted with n-butyllithium and then reacted with trialkyltin chloride to obtain the compound (2b).
[0033]
(C) Synthesis of the compound of the general formula (3).
In the present invention, the compound of the general formula (3) is synthesized by reacting the compound of the general formula (1) with the compound of the general formula (2) as follows.
(I) The Y group of the compound of the general formula (2) is —B (OH) ₂ .
The compound of general formula (1) and general formula (2) are reacted in the presence of a catalyst under basic conditions (Suzuki; Synthetic Communication, 11 (7), 513 (1981)). As the catalyst, tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), palladium chloride (PdCl ₂ ), palladium-carbon (Pd / C) or the like is used. As the base, sodium carbonate, calcium carbonate, sodium hydroxide, calcium hydroxide or the like is used. As the reaction solvent, water, ethanol, methanol, benzene, toluene or the like is used. The reaction is carried out at room temperature or with heating to reflux. Thus, the compound of the general formula (3) can be obtained.
[0034]
(II) In the case where the Y group of the compound of the general formula (2) is —Sn (R ₅ ) ₃ (where R ₅ n represents a lower alkyl group).
The compound of general formula (1) and the compound of general formula (2) are reacted in the presence of a catalyst [Shille; Angew. Chem. Int. Ed. Engl, 25, 508-524 (1986))]. Tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), palladium chloride (PdCl ₂ ), palladium-carbon (Pd / C), copper iodide (CuI), lithium chloride (LiCl) or the like is used as the catalyst. THF, dimethoxyethane (DME), dimethylformamide (DMF) or the like is used as a reaction solvent. The reaction is carried out at room temperature or at reflux. Thus, the compound of the general formula (3) can be obtained.
[0035]
(D) Deprotection treatment.
Deprotection of the general formula (3) is performed by adding an acidic liquid such as HCl or CH ₃ SO ₃ H to a benzene or toluene solution of the compound of the general formula (3) and heating to reflux. The protecting group of general formula (3) is removed, and the compound of general formula (4), which is the target substance of the present invention, can be obtained.
Examples and reference examples are shown below.
[0036]
【Example】
Example 1.
Production example of 5- [2- (4- (2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazolyl) methylbiphenylyl)] tetrazole.
(A) Preparation of 1- (4-iodobenzyl) -2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole.
In a reaction vessel, 60 ml of 30% NaOH and 150 ml of toluene were added. Further, 5.0 g of 2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole, 4-iodobenzyl 9.2 g of bromide and 2.0 g of tetrabutylammonium hydrogen sulfate were added and stirred at room temperature for 8 hours. After completion of the reaction, the mixture was filtered, and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was dehydrated with sodium sulfate and concentrated. Purification was performed by silica gel column chromatography (SiO ₂ 120 g). The eluent was n-hexane: ethyl acetate (1: 1). 8.69 g of a pale yellow crystalline target product was obtained. The melting point of this target product was 64-65 ° C.
Mass (m / e): M ⁺ = 408, 217 (BP)
IR (cm ^-1 ): 2926, 1632, 1464, 1428
¹ H-NMR (CDCl ₃ ): 0.95 (3H, t, —CH ₂ CH ₂ CH ₃ ), 1.70 (2H, m, —CH ₂ CH ₂ CH ₃ ), 1.87 (2H, m, Cyclo ring), 1.92 (2H, m, Cyclo ring), 2.58 (2H, m, Cyclo ring), 2.65 (2H, m, Cyclo ring), 2.96 (2H, t, -CH ₂ CH ₂ CH ₃ ), 5.47 (2H, s, -CH ₂ -C ₆ H ₅ ), 6.71 (2H, d, aromatic ring), 7.62 (2H, d, aromatic ring)
[0037]
(B) 2-tertiarybutyl-5- [2- (4- (2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazolyl) methylbiphenylyl) ] Production of tetrazole.
To 150 mg of the compound obtained in (a) above, [2- (2-tertiarybutyl-2H-tetrazol-5-yl) phenyl] -boronic acid (see Example 3) 96 mg, tetrakistriphenylphosphine palladium 35 mg, 2M carbonic acid Sodium 0.7 ml, ethanol 1 ml and toluene 10 ml were added, and the mixture was heated to reflux for 3 hours. Concentrated and then extracted three times with 30 ml of chloroform. The chloroform layer was washed with water and dehydrated with sodium sulfate. It was then filtered, concentrated and purified on a silica gel column. The eluent used was ethyl acetate: n-hexane (10: 1). 175 mg of the pale yellow oily target product was obtained.
IR (cm ^-1 ): 2926, 1632, 1464, 1428
Mass (m / e): M ⁺ = 482, 426, 178 (BP)
¹ H-NMR (CDCl ₃ ): 0.96 (3H, t, -CH ₂ CH ₂ CH ₃ ), 1.55 (9H, s,-( CH ₃ ) ₃ ), 1.75 (2H, m, -CH ₂ CH ₂ CH ₃ ), 1.80 to 2.00 (4H, m, Cyclo ring), 2.59 (2H, t, Cyclo ring), 2.68 (2H, m, Cyclo ring), 3.01 (2H, q, -CH ₂ CH ₂ CH ₃ ), 5.57 (2H, s, - CH 2 C 6 H 5), 6.90 (2H, d, aromatic ring), 7.09 (2H, d, aromatic ring), 7.35~7.60 (3H, m, aromatic ring), 7.89 (2H , d, aromatic ring).
[0038]
(C) Preparation of 5- [2- (4- (2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazolyl) methylbiphenylyl)] tetrazole.
100 mg of the compound obtained in the above (b) was added to 200 mg of methanesulfonic acid and 10 ml of toluene, and the mixture was heated under reflux for 3 hours to remove the tertiary butyl group of the protecting group. It was then concentrated, poured into ice water and brought to pH 8 with 10% NaOH. White crystals precipitated. Filter and recrystallize with 1.5 ml of ethyl alcohol. 77.4 mg of the target product as white crystals was obtained. The melting point was 214 to 216 ° C.
Mass (m / e): M ⁺ = 426, 383, 355, 178 (BP) .152
¹ H-NMR (CDCl ₃ ): 0.90 (3H, t, —CH ₂ CH ₂ CH ₃ ), 1.58 (2H, m, —CH ₂ CH ₂ CH ₃ ), 1.68 (2H, m, Cyclo ring), 1.75 (2H, m, Cyclo ring), 2.30 (2H, m, Cyclo ring), 2.47 (2H, m, Cyclo ring), 2.53 (2H, t, -CH ₂ CH ₂ CH ₃ ), 5.45 (2H, s, -CH ₂ C ₆ H ₅ ), 6.75 (2H, d, aromatic ring), 7.00 (2H, d, aromatic ring), 7.42 (2H, d, aromatic ring), 7.52 (2H, d, aromatic ring), 7.60 (2H, d, aromatic ring), 7.85 (2H, d, aromatic ring).
[0039]
Example 2
Production example of 5- [2- (4- (2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazolyl) methylbiphenylyl)] tetrazole.
In the same manner as in Example 1, 1- (4-iodobenzyl) -2-propyl-8-oxo-5,6,7,8-tetrahydro-1 (4H) -cycloheptimidazole was synthesized.
In a reaction vessel, 100 mg of this 1- (4-iodobenzyl) -2-propyl-8-oxo-5,6,7,8-tetrahydro-1 (4H) -cycloheptimidazole and 2- (2- (2 -Tertiary butyl-2H-tetrazol-5-yl) phenyl] tri-n-butylstannane (see Example 4) 120 mg, lithium chloride 31.15 mg, tetrakistriphenylphosphine palladium 1.4 mg and tetrahydrofuran 8 ml were added. The mixture was filtered, concentrated and extracted with 30 ml of ethyl acetate, the ethyl acetate layer was washed with water, dehydrated with sodium sulfate, filtered and concentrated, and purified with a silica gel column. -Hexane (1: 1) was used, pale yellow oily 2-tertiarybutyl-5- [2- (4- (2-pro Le-8-oxo-4,5,6,7-tetrahydro -1 (4H) -. Cycloalkyl f script imidazolylmethyl) methyl biphenylyl)] to give the tetrazole 45mg their physical properties, the analysis results were as follows.
Mass (m / e): M ⁺ = 482, 426, 369, 178 (BP)
IR (cm ^-1 ): 2926, 1632, 1464, 1428, 1389
¹ H-NMR (CDCl ₃ ): 0.96 (3H, t, -CH ₂ CH ₂ CH ₃ ), 1.55 (9H, s,-(CH ₃ ) ₃ ), 1.74 (2H, m, -CH ₂ CH ₂ CH ₃ ), 1.80 to 2.00 (4H, m, Cyclo ring), 2.59 (2H, t, Cyclo ring), 2.68 (2H, m, Cyclo ring), 3.01 (2H, q, -CH ₂ CH ₂ CH ₃ ), 5.57 (2H, s, - CH 2 C 6 H 5), 6.90 (2H, d, aromatic ring), 7.09 (2H, d, aromatic ring), 7.35~7.60 (3H, m, aromatic ring), 7.89 (2H , d, aromatic ring).
2-tertiarybutyl-5- [2- (4- (2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazolyl) methylbiphenylyl)] In the same manner as in Example 1, tetrazole was removed from the tertiary butyl group, which was a protective group, and the target substance 5- [2- (4- (2-propyl-8-oxo-4,5,6,7- Tetrahydro-1 (4H) -cycloheptimidazolyl) methylbiphenylyl)] tetrazole was obtained.
[0040]
Example 3.
Preparation of [2- (2-tertiarybutyl-2H-tetrazol-5-yl) phenyl] -boronic acid.
3.3 g of 5- (2-bromophenyl) -2- (1.1-dimethylethyl) -2H-tetrazole was dissolved in 20 ml of tetrahydrofuran and cooled to -78 ° C. To this solution, 7.8 ml of 1.6 M n-butyllithium / n-hexane was added, and then 2.3 g of triisopropylboronic acid was added and stirred at room temperature for 1 hour. Then, 40 ml of 0.5N hydrochloric acid was added and stirred for 30 minutes. The reaction solution was poured into 50 ml of ice water and extracted twice with 30 ml of ether. The ether layer was extracted 3 times with 10 ml of 1N KOH. The alkaline solution was acidified with 2N HCl. 1.87 g of the desired product as white crystals was obtained. The melting point was 117-122 ° C.
¹ H-NMR (CDCl ₃ ): 1.72 (9H, s, —C (CH ₃ ) ₃ ), 7.46 (2H, m, aromatic ring), 7.90 (2H, m, aromatic ring)
[0041]
Example 4
Preparation of [2- (2- (2-tertiarybutyl-2H-tetrazol-5-yl) phenyl] tri-n-butylstannane.
1.23 g of 5- (2-bromophenyl) -2- (1.1-dimethylethyl) -2H-tetrazole was dissolved in 8 ml of tetrahydrofuran and cooled to -78 ° C. To this solution, 3.27 ml of 1.6 M n-butyllithium / n-hexane was added and stirred for 1 hour. Furthermore, 1.71 g of tri-n-butyltin chloride was added, and the mixture was stirred at -78 ° C for 3 hours, and then stirred at room temperature for 18 hours. The reaction mixture was poured into 20 ml of water and extracted twice with 30 ml of ether. The ether layer was washed with water and dehydrated with sodium sulfate. It was then filtered and concentrated. The product was purified with a silica gel column (eluent was n-hexane). 1.0 g of the pale yellow oily target product was obtained.
¹ H-NMR (CDCl ₃ ): 0.78 (9H, t,-(-CH ₃ ) ₃ ), 0.93 (6H, t,-(CH _2- ) ₃ ), 1.21 (6H, m,-(CH _2- ) ₃ ), 1.43 (6H, m,-(CH _2- ) ₃ ), 1.80 (9H, s, (CH ₃ ) ₃ ), 7.43 (1H, d, aromatic ring), 7.45 (1H, d, aromatic ring) ), 7.60 (1H, m, aromatic ring), 8.00 (1H, m, aromatic ring).
[0042]
Embodiment 5 FIG.
Of 2-ethyl-8-carboxymethylidene-1-[(2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -4,5,6,7-tetrahydro-cycloheptimidazole Manufacturing.
(A) Preparation of 1- (4-bromobenzyl) -2-ethyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole.
A reaction vessel was charged with 30 ml of 30% NaOH and 50 ml of toluene, into which 2.5 g of 2-ethyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole and 4-bromo were added. 3.6 g of benzyl bromide and 0.5 g of tetrabutylammonium hydrogen sulfate were added and stirred at room temperature for 8 hours. After completion of the reaction, the mixture was filtered, and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dehydrated with sodium sulfate and concentrated. Purification was performed by silica gel chromatography (SiO ₂ 100 g). The eluent used was n-hexane and ethyl acetate (1: 1). 4.0 g of the pale yellow oily target product was obtained.
Mass (m / e): M ⁺ = 347, 319, 169 (BP)
IR (cm ^-1 ): 2950, 1640, 1480, 1400, 1330
¹ H-NMR (CDCl ₃ ): 1.27 (3H, t, CH ₂ CH ₃ ), 1.85 to 1.87 (2H, m, Cyclo ring), 1.91 to 1.94 (2H, m, Cyclo ring), 2.60 to 2.65 (4H , m, Cyclo ring), 3.01 (2H, q, CH ₂ CH ₃ ), 5.48 (2H, s, -CH ₂ -C ₆ H ₅ ), 6.86 (2H, d, aromatic ring), 7.41 (2H, d , Aromatic ring).
[0043]
(B) Preparation of 1- (4-bromobenzyl) -2-ethyl-8-ethoxycarbonyl-8-hydro-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole.
2.88 ml of lithium bis (trimethylsilyl) amide was added to 5 ml of tetrahydrofuran, cooled to −78 ° C., 0.25 ml of ethyl acetate was added dropwise thereto, stirred as it was for 15 minutes, and further obtained in the above (a) dissolved in 3 ml of THF. 0.5 g of the compound was added dropwise. After completion of the dropwise addition, the mixture was stirred for 1 hour. After completion of the reaction, 6N HCl was added to the reaction mixture and stirred, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, washed with saturated NaCl, and dehydrated with sodium sulfate. Filter and concentrate. It was then purified on a silica gel column. The eluent used chloroform and methanol (20: 1). 388 mg of the pale yellow oily target product was obtained.
Mass (m / e): M ⁺ = 435, 348, 169 (BP), 90
IR (cm ^-1 ): 3300, 2900, 1720, 1170, 1000
¹ H-NMR (CDCl ₃ ): 1.28 (3H, t, —CH ₂ CH ₃ ), 1.33 (3H, t, —CH ₂ CH ₃ ), 1.80 to 2.20 (6H, m, Cyclo ring), 2.71 (2H , m, -CH ₂ COOEt), 2.78 (2H, q- CH ₂ CH ₃ ), 2.97 (2H, m, Cyclo ring), 4.57 (2H, q, -CH ₂ CH ₃ ), 5.81 (2H, s, _{- CH 2 C 6 H 5)} , 7.20~7.40 (4H, m, aromatic ring).
[0044]
(C) Preparation of 1- (4-bromobenzyl) -2-ethyl-8-ethoxycarbonylmethylidene-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole.
(1) 1- (4-Bromobenzyl) -2-ethyl-8-ethoxycarbonyl-8-hydroxy-4,5,6,7-tetrahydro-1 (4H) -cycloheptop obtained in (b) above 0.38 g of imidazole was dissolved in 2 ml of pyridine, and 0.32 g of thionyl chloride was added to this solution at room temperature, followed by stirring for 1 hour. The reaction was poured into 20 ml of 10% HCl and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dehydrated with sodium sulfate. Filter and concentrate. Then, it was purified with a silica gel column. The eluent used chloroform and methanol (20: 1). 280 mg of the pale yellow oily target product was obtained.
[0045]
(2) Further, 0.08 g of potassium hydride was suspended in 5 ml of tetrahydrofuran, and 0.37 g of diethylphosphonoacetate was added dropwise to this suspension at 0 to 5 ° C. Furthermore, 1- (4-bromobenzyl) -2-ethyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole 0.5 g of tetrahydrofuran obtained in (a) above. 1 ml of solution was added. Thereafter, the mixture was heated at 40 ° C. for 5 hours. The reaction mixture was poured into 20 ml of ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated NaCl and dehydrated with sodium sulfate. Filter and concentrate. It was then purified on a silica gel column. The eluent used chloroform and methanol (20: 1). 60 mg of the pale yellow oily target product was obtained.
Mass (m / e): M ⁺ + 1 = 418, 371, 343, 171 (BP), 90
IR (cm ^-1 ): 2900, 1710, 1230, 1170, 1000
¹ H-NMR (CDCl ₃ ): 1.26 (3H, t, —CH ₂ CH ₃ ), 1.26 (3H, t, —CH ₂ CH ₃ ), 1.85 (2H, m, Cyclo ring), 1.90 (2H, m , Cyclo ring), 2.91 (2H, q, CH ₂ CH ₃ ), 2.92 (2H, q, CH ₂ CH ₃ ), 4.05 to 4.20 (4H, m, Cyclo ring), 5.28 (2H, s, -CH ₂ C ₆ H ₃ ), 5.68 (1H, s, = C H COOC ₂ H ₅ ), 6.80 (d, 2H, aromatic ring), 7.55 (2H, d, aromatic ring)
[0046]
(D) 2-tertiarybutyl-5- [2- (4- (2-ethyl-8-ethoxycarbonylmethylidene-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazolyl) methyl Biphenylyl)] tetrazole.
To 280 mg of the compound obtained in (c) above, [2- (2-tert-butyl-2H-tetrazol-5-yl) phenyl)]-boronic acid 175.5 mg, 2M sodium carbonate 1.6 ml, ethanol 0.1 ml, Tetrakistriphenylphosphine palladium (26.8 mg) and toluene (5 ml) were added, and the mixture was heated to reflux for 4.5 hours. The reaction solution was poured into 30 ml of water and extracted three times with 20 ml of toluene. The toluene layer was washed with water and dehydrated with sodium sulfate. Filter and concentrate. Then, it was purified with a silica gel column. The eluent used was ethyl acetate and n-hexane (1: 1). 230 mg of the pale yellow oily target product was obtained.
Mass (m / e): M ⁺ + 1 = 539, 451, 253, 178 (BP)
IR (cm ^-1 ): 3420, 3000, 1230, 2950, 1720
¹ H-NMR (CDCl ₃ ): 1.25 (3H, s, t-Bu), 1.82 (2H, m, Cyclo ring), 2.55 (2H, q, -CH ₂ CH ₃ ), 2.80 to 2.83 (2H, m , Cyclo ring), 3.04 to 3.07 (2H, m, Cyclo ring), 4.12 (2H, q, -CH ₂ CH ₃ ), 5.17 (2H, s, -CH ₂ C ₆ H ₅ ), 5.56 (1H, s , = C H COOC ₂ H ₅ ), 6.82 (2H, d, aromatic ring), 7.14 (2H, d, aromatic ring), 7.39-7.88 (4H, m, aromatic ring).
[0047]
(E) 2-ethyl-8-carboxymethylidene-1-[(2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -4,5,6,7-tetrahydro-cyclohe Production of putimidazole.
200 mg of the compound obtained in the above (d) was added with 400 mg of methanesulfonic acid and 20 ml of toluene, and heated under reflux for 3 hours to remove the tertiary butyl group of the protecting group. It was then concentrated, poured into ice water and brought to pH 4 with 10% NaOH. White crystals precipitated. Filtration and recrystallization with 2 ml of MeOH gave the desired compound as white crystals (120 mg).
Melting point: 191-193 ° C
Mass (m / e): M ⁺ = 408 (M ⁺ -COOH), 367, 192 (BP), 134
IR (cm ^-1 ): 2914, 1692, 1611, 1452, 1362, 1197
¹ H-NMR (CD ₃ OD): 1.30 (3H, t, -CH ₂ CH ₃ ), 1.94 (4H, bs, Cyclo ring), 2.65 to 3.03 (6H, m, -CH ₂ CH ₃ + Cyclo ring) , 5.43 (2H, s, -CH 2 C 6 H 5), 5.92 (1H, s, = C H COOH, 6.80~7.70 (8H, m, aromatic ring), 7.96 (1H, s, -NH).
[0048]
【The invention's effect】
According to the present invention, a cycloheptimidazole derivative can be synthesized at a low cost with a simple operation and with a good yield.

Claims (2)

The following general formula (1)

(In the formula, R ₁ represents hydrogen or an isopropyl group, R ₂ represents a lower alkyl group having 1 to 4 carbon atoms. A and A ₁ are groups present at the 4-position or 8-position, respectively, and A is a hydrogen atom. , A ₁ is a hydrogen atom or a hydroxyl group, or A and A ₁ may form an oxo group or ═CHCOOR ₃ (R ₃ is a lower alkyl group having 1 to 4 carbon atoms). Represents two double bonds or a saturated single bond, X is a halogen atom or a trifluoromethanesulfonate group.)
In the compound represented. The compound represented by the general formula (1) according to claim 1 is represented by the following general formula (2):

[Wherein, Y is -B (OH) ₂ or -Sn (R ₅ ) ₃ (where R ₅ represents a lower alkyl group having 1 to 4 carbon atoms ), and Z is a protecting group. ]
Is reacted with a compound represented by the general formula (3):

(In the formula, R ₁ represents hydrogen or an isopropyl group, R ₂ represents a lower alkyl group having 1 to 4 carbon atoms. A and A ₁ are groups present at the 4-position or 8-position, respectively, and A is a hydrogen atom. , A ₁ is a hydrogen atom or a hydroxyl group, or A and A ₁ may form an oxo group or ═CHCOOR ₃ (R ₃ is a lower alkyl group having 1 to 4 carbon atoms ). Represents two double bonds or a saturated single bond, Z is a protecting group.)
The compound represented by the general formula (4) is characterized in that the compound is then treated with a deprotecting group.

(In the formula, R ₁ represents hydrogen or isopropyl group, R ₂ represents a lower alkyl group having 1 to 4 carbon atoms. A and A ₁ are groups present at the 4-position or 8-position, respectively, and A represents a hydrogen atom. In some cases, A ₁ is a hydrogen atom or a hydroxyl group, or A and A ₁ may form an oxo group or ═CHCOOR ₃ (R ₃ is a lower alkyl group having 1 to 4 carbon atoms ). Represents two double bonds or a saturated single bond.)
The manufacturing method of the cycloheptimidazole derivative shown by these.