JP2004075643A - Method for producing coumarin compound - Google Patents
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、医薬・農薬等の合成原料や合成中間体として有用な、クマリン化合物の新規な製法に関する。クマリン化合物の中でも、特に、６，７−ジヒドロキシクマリン誘導体は、例えば、ホスホリパーゼ活性阻害作用を有し、リウマチ性関節炎、変形性関節症等の炎症性疾患治療薬の合成原料として利用される化合物である（例えば、特表平８−５１２０５７号公報）。又、ヒト腫瘍細胞への殺傷作用を示す化合物の出発原料としても有用である（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ，４１，９５９６（２０００））。
【０００２】
【従来の技術】
従来、フェノール誘導体とアルコキシメチレンマロン酸ジエステルとを反応させてクマリン化合物を製造する方法としては、１，３，５−トリヒドロキシベンゼンや１，２，４−トリヒドロキシベンゼンとエトキシメチレンマロン酸ジエチルとを無溶媒条件下で反応させて、相当するクマリン化合物を収率３０％以下で得る方法が開示されている（Ｃ．Ｒ．Ｈｅｂｄ．Ｓｅａｎｃｅｓ Ａｃａｄ．Ｓｃｉ．，２４６，１７０１（１９５８））。しかしながら、この方法では、収率が極めて低く、工業的な製法としては満足するものではなかった。
【０００３】
【発明が解決しようとする課題】
本発明の課題は、即ち、上記問題点を解決し、入手が容易な原料から、簡便な方法によって高収率でクマリン化合物を得る、工業的に好適なクマリン化合物の製法を提供するものである。
【０００４】
【課題を解決するための手段】
本発明の課題は、酸の存在下、一般式（１）
【０００５】
【化４】
（式中、Ｒ１、Ｒ２及びＲ３は、同一又は異なっていても良く、水素原子、ヒドロキシル基又は炭素数１〜４のアルコキシ基を示す。なお、Ｒ１、Ｒ２及びＲ３は、互いに結合して環を形成していても良い。）
で示されるフェノール誘導体と、一般式（２）
【０００７】
【化５】
（式中、Ｒ４及びＲ５は、炭素数１〜４のアルキル基を示す。）
で示されるアルコキシメチレンマロン酸ジエステルとを反応させることを特徴とする、一般式（３）
【０００９】
【化６】
（式中、Ｒ１、Ｒ２及びＲ３は、前記と同義である。）
で示される、クマリン化合物の製法によって解決される。
【００１１】
【発明の実施の形態】
本発明の反応において使用されるフェノール誘導体は、前記の一般式（１）で示される。その一般式（１）において、Ｒ１、Ｒ２及びＲ３は、同一又は異なっていても良く、水素原子、ヒドロキシル基又は炭素数１〜４のアルコキシ基を示す。炭素数１〜４のアルコキシ基としては、例えば、メトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、ｓｅｃ−ブトキシ基、ｔ−ブトキシ基、メチレンジオキシ基、エチレンジオキシ基、トリメチレンジオキシ基、テトラメチレンジオキシ基が挙げられるが、好ましい態様は、Ｒ１及びＲ２がヒドロキシル基、Ｒ３が水素原子である。なお、Ｒ１、Ｒ２及びＲ３は、互いに結合して環を形成していても良い。
【００１２】
前記フェノール誘導体の使用量は、アルコキシメチレンマロン酸ジエステル１ｍｏｌに対して、好ましくは０．８〜２．０ｍｏｌ、更に好ましくは１．０〜１．４ｍｏｌである。
【００１３】
本発明の反応において使用されるアルコキシメチレンマロン酸ジエステルは、前記の一般式（２）で示される。その一般式（２）において、Ｒ４及びＲ５は、炭素数１〜４のアルキル基を示す。炭素数１〜４のアルキル基としては、例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、ｔ−ブチル基が挙げられる。
【００１４】
本発明の反応において使用される酸としては、メタンスルホン酸、エタンスルホン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、ｐ−ブロモベンゼンスルホン酸等の有機スルホン酸類（水和物も含む）；硫酸、塩酸、硝酸等の無機酸類が挙げられるが、好ましくは有機スルホン酸類、更に好ましくはｐ−トルエンスルホン酸が使用される。なお、これらの酸は、単独又は二種以上を混合して使用しても良い。
【００１５】
前記酸の使用量は、アルコキシメチレンマロン酸ジエステル１ｍｏｌに対して、好ましくは０．０１〜０．３０ｍｏｌ、更に好ましくは０．０２〜０．２５ｍｏｌ、特に好ましくは０．０３〜０．２０ｍｏｌである。
【００１６】
本発明の反応は、溶媒中で行うのが好ましい。使用される溶媒としては、反応を阻害しないものならば特に限定されず、例えば、ギ酸、酢酸、プロピオン酸等のカルボン酸類；メタノール、エタノール、イソプロピルアルコール、ｎ−ブチルアルコール、ｓｅｃ−ブチルアルコール、ｔ−ブチルアルコール等のアルコール類；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、１，３−ジメチル−２−イミダゾリジノン等のアミド類；ジエチルエーテル、ジイソプロピルエーテル、ジブチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類；クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類；ヘキサン、ヘプタン等の脂肪族炭化水素類；塩化メチレン、１，２−ジクロロエタン等のハロゲン化脂肪族炭化水素類；酢酸メチル、酢酸エチル、酢酸ブチル等のカルボン酸エステル類が挙げられるが、好ましくはカルボン酸類が使用される。なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【００１７】
前記酸の使用量は、反応液の均一性や攪拌性により適宜調節するが、アルコキシメチレンマロン酸ジエステル１ｇに対して、好ましくは１〜２００ｍｌである。
【００１８】
本発明の反応は、例えば、不活性ガス雰囲気にて、フェノール誘導体、アルコキシメチレンマロン酸ジエステル、酸及び溶媒を混合して、攪拌しながら反応させる等の方法によって行われる。その際の反応温度は、好ましくは１０〜２００℃、更に好ましくは８０〜１３０℃であり、反応圧力は特に制限されない。
【００１９】
本発明の反応によって得られるクマリン化合物は、反応終了後、例えば、中和、抽出、濃縮、濾過等の処理を行った後、再結晶、蒸留、カラムクロマトグラフィー等の一般的な方法によって単離・精製される。
【００２０】
【実施例】
次に、実施例を挙げて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。
【００２１】
実施例１（６，７−ジヒドロキシクマリンの合成）
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積５０ｍｌのガラス製四つ口フラスコに、酢酸２５ｍｌを加えた後、窒素雰囲気にて、１，２，４−トリヒドロキシベンゼン５．８５ｇ（４６．４ｍｍｏｌ）を加えた。次いで、液温を１００℃まで昇温し、エトキシメチレンマロン酸ジエチル４．２８ｇ（１９．８ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物０．３４ｇ（１．８ｍｍｏｌ）の順でゆるやかに添加し、攪拌しながら１００℃にて２時間反応させた。その後、エトキシメチレンマロン酸ジエチル１．７１ｇ（７．９ｍｍｏｌ）を添加して同温度にて１時間、再びエトキシメチレンマロン酸ジエチル０．８６ｇ（４．０ｍｍｏｌ）を添加して同温度にて１時間、更にエトキシメチレンマロン酸ジエチル０．８６ｇ（４．０ｍｍｏｌ）を添加して同温度にて５時間、攪拌しながら反応させた。反応終了後、反応液を室温まで冷却した後、析出した結晶を濾過して酢酸エチルで洗浄した。得られた結晶を減圧下で乾燥させ、黄土色結晶として、純度９７．３％（高速液体クロマトグラフィーによる定量値（内部標準法））の６，７−ジヒドロキシクマリン４．８７ｇを得た（単離収率：７５％）。
なお、６，７−ジヒドロキシクマリンの物性値は、以下の通りであった。
【００２２】
ＣＩ−ＭＳ（ｍ／ｅ）；１７９（Ｍ＋１）
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；６．２０（１Ｈ，ｄ，Ｊ＝９．４Ｈｚ）、６．７９（１Ｈ，ｓ）、７．０２（１Ｈ，ｓ）、７．８９（１Ｈ，ｄ，Ｊ＝９．４Ｈｚ）、９．４８（１Ｈ，ｂｒｓ）、１０．１７（１Ｈ，ｂｒｓ）
１３Ｃ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；１０２．６、１１０．７、１１１．５、１１２．３、１４２．８、１４４．３、１４８．５、１５０．３、１６０．８
【００２３】
実施例２（６，７−ジヒドロキシクマリンの合成）
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積１００ｍｌのガラス製四つ口フラスコに、酢酸５０ｍｌを加えた後、窒素雰囲気にて、１，２，４−トリヒドロキシベンゼン４．９５ｇ（３９．３ｍｍｏｌ）を加えた。次いで、液温を１１０℃まで昇温し、エトキシメチレンマロン酸ジエチル４．２８ｇ（１９．８ｍｍｏｌ）をゆるやかに加えて２時間攪拌後、ｐ−トルエンスルホン酸一水和物０．３４ｇ（１．８ｍｍｏｌ）をゆるやかに添加し、攪拌しながら１１０℃にて２時間反応させた。その後、エトキシメチレンマロン酸ジエチル１．７１ｇ（７．９ｍｍｏｌ）を添加して１００℃にて１時間、再びエトキシメチレンマロン酸ジエチル０．８６ｇ（４．０ｍｍｏｌ）を添加して同温度にて１時間、更にエトキシメチレンマロン酸ジエチル０．８６ｇ（４．０ｍｍｏｌ）を添加して同温度にて２時間、攪拌しながら反応させた。反応終了後、反応液を室温まで冷却した後、析出した結晶を濾過して酢酸エチルで洗浄した。得られた結晶を減圧下で乾燥させ、黄土色結晶として、純度９７．８％（高速液体クロマトグラフィーによる定量値（内部標準法））の６，７−ジヒドロキシクマリン４．５０ｇを得た（単離収率：６９％）。
【００２４】
実施例３（６，７−ジヒドロキシクマリンの合成）
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積５０ｍｌのガラス製四つ口フラスコに、酢酸２５ｍｌを加えた後、窒素雰囲気にて、１，２，４−トリヒドロキシベンゼン５．８５ｇ（４６．４ｍｍｏｌ）を加えた。次いで、液温を１１０℃まで昇温し、エトキシメチレンマロン酸ジエチル４．２８ｇ（１９．８ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物０．３４ｇ（１．８ｍｍｏｌ）の順でゆるやかに添加し、攪拌しながら１１０℃にて２時間反応させた。その後、エトキシメチレンマロン酸ジエチル３．４２ｇ（１５．８ｍｍｏｌ）を添加して１００℃にて６時間、攪拌しながら反応させた。反応終了後、反応液を室温まで冷却した後、析出した結晶を濾過して酢酸エチルで洗浄した。得られた結晶を減圧下で乾燥させ、黄土色結晶として、純度９６．３％（高速液体クロマトグラフィーによる定量値（内部標準法））の６，７−ジヒドロキシクマリン４．２９ｇを得た（単離収率：６５％）。
【００２５】
実施例４（６−ヒドロキシ−７−メトキシクマリンの合成）
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積５０ｍｌのガラス製四つ口フラスコに、酢酸２５ｍｌを加えた後、窒素雰囲気にて、２，５−ジヒドロキシアニソール３．３２ｇ（２３．７ｍｍｏｌ）を加えた。次いで、液温を１１０℃まで昇温し、エトキシメチレンマロン酸ジエチル２．３４ｇ（１０．８ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物０．１７ｇ（０．９ｍｍｏｌ）の順でゆるやかに添加し、攪拌しながら１１０℃にて２時間反応させた。その後、エトキシメチレンマロン酸ジエチル０．７８ｇ（３．６ｍｍｏｌ）を添加して１０９℃にて１時間、再びエトキシメチレンマロン酸ジエチル０．３９ｇ（１．８ｍｍｏｌ）を添加して同温度にて１時間、更にエトキシメチレンマロン酸ジエチル０．３９ｇ（１．８ｍｍｏｌ）を添加して１０７℃にて１７時間、攪拌しながら反応させた。反応終了後、反応液を室温まで冷却した後、酢酸エチル１２ｍｌを加えて、２℃で３時間攪拌した。析出した結晶を濾過して酢酸エチルで洗浄した。得られた結晶を減圧下で乾燥させ、緑褐色結晶として、純度９９．４％（高速液体クロマトグラフィーによる面積百分率）の６−ヒドロキシ−７−メトキシクマリン１．５４ｇを得た（単離収率：４５％）。
なお、６−ヒドロキシ−７−メトキシクマリンの物性値は、以下の通りであった。
【００２６】
ＣＩ−ＭＳ（ｍ／ｅ）；１９３（Ｍ＋１）
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；３．８５（３Ｈ，ｓ）、６．２２（１Ｈ，ｄ，Ｊ＝９．８Ｈｚ）、６．９８（１Ｈ，ｓ）、６．９９（１Ｈ，ｓ）、７．８７（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ）、９．３５（１Ｈ，ｂｒｓ）
１３Ｃ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；５６．１、１００．０、１１１．５、１１１．９、１１２．５、１４３．６、１４４．２、１４８．４、１５１．８、１６０．７
【００２７】
実施例５（７−ヒドロキシクマリンの合成）
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積５０ｍｌのガラス製四つ口フラスコに、酢酸２５ｍｌを加えた後、窒素雰囲気にて、１，３−ジヒドロキシベンゼン２．６１ｇ（２３．７ｍｍｏｌ）を加えた。次いで、液温を１００℃まで昇温し、エトキシメチレンマロン酸ジエチル２．３４ｇ（１０．８ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物０．１７ｇ（０．９ｍｍｏｌ）の順でゆるやかに添加し、攪拌しながら１００℃にて２時間反応させた。その後、エトキシメチレンマロン酸ジエチル０．７８ｇ（３．６ｍｍｏｌ）を添加して１０６℃にて１時間、再びエトキシメチレンマロン酸ジエチル０．３９ｇ（１．８ｍｍｏｌ）を添加して１０４℃にて１時間、更にエトキシメチレンマロン酸ジエチル０．３９ｇ（１．８ｍｍｏｌ）を添加して１０３℃にて１２時間、攪拌しながら反応させた。反応終了後、反応液を室温まで冷却した後、酢酸エチル１２ｍｌを加えて、２℃で２時間攪拌した。析出した結晶を濾過して酢酸エチルで洗浄した。得られた結晶を減圧下で乾燥させ、淡黄色結晶として、純度９７．１％（高速液体クロマトグラフィーによる面積百分率）の７−ヒドロキシクマリン０．４２ｇを得た（単離収率：１４％）。
なお、７−ヒドロキシクマリンの物性値は、以下の通りであった。
【００２８】
ＣＩ−ＭＳ（ｍ／ｅ）；１６３（Ｍ＋１）
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；６．１７（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ）、６．６９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）、６．７６（１Ｈ，ｄｄ，Ｊ＝８．３，２．４Ｈｚ）、７．４８（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ）、７．８９（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ）、１０．５３（１Ｈ，ｂｒｓ）
１３Ｃ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；１０２．２、１１１．３、１１１．４、１１３．１、１２９．７、１４４．５、１５５．５、１６０．４、１６１．３
【００２９】
実施例６（７，８−ジヒドロキシクマリンの合成）
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積５０ｍｌのガラス製四つ口フラスコに、酢酸２５ｍｌを加えた後、窒素雰囲気にて、１，２，３−トリヒドロキシベンゼン５．８５ｇ（４６．４ｍｍｏｌ）を加えた。次いで、液温を１０４℃まで昇温し、エトキシメチレンマロン酸ジエチル４．２８ｇ（１９．８ｍｍｏｌ）、メタンスルホン酸０．３４ｇ（３．５ｍｍｏｌ）の順でゆるやかに添加し、攪拌しながら１０４℃にて２時間反応させた。その後、エトキシメチレンマロン酸ジエチル１．７１ｇ（７．９ｍｍｏｌ）を添加して９６℃にて１時間、再びエトキシメチレンマロン酸ジエチル０．８６ｇ（４．０ｍｍｏｌ）を添加して９４℃にて１時間、更にエトキシメチレンマロン酸ジエチル０．８６ｇ（４．０ｍｍｏｌ）を添加して９３℃にて３時間、次いでメタンスルホン酸０．１７ｇ（１．８ｍｍｏｌ）を添加して９３℃にて３時間、攪拌しながら反応させた。反応終了後、反応液を室温まで冷却した後、２℃まで冷却して１時間攪拌した。析出した結晶を濾過して酢酸エチルで洗浄した。得られた結晶を減圧下で乾燥させ、茶色結晶として、純度９３．０％（高速液体クロマトグラフィーによる面積百分率）の７，８−ジヒドロキシクマリン１．２５ｇを得た（単離収率：２０％）。
なお、７，８−ジヒドロキシクマリンの物性値は、以下の通りであった。
【００３０】
ＣＩ−ＭＳ（ｍ／ｅ）；１７９（Ｍ＋１）
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；６．２０（１Ｈ，ｄ，Ｊ＝９．８Ｈｚ）、６．８２（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ）、７．０３（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ）、７．９０（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ）
１３Ｃ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；１１１．２、１１２．０、１１２．４、１１８．８、１３２．１、１４３．７、１４５．０、１４９．６、１６０．３
【００３１】
実施例７（６，７−ジメトキシクマリンの合成）
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積５０ｍｌのガラス製四つ口フラスコに、酢酸２５ｍｌを加えた後、窒素雰囲気にて、３，４−ジメトキシフェノール３．６９ｇ（２３．９ｍｍｏｌ）を加えた。次いで、液温を１００℃まで昇温し、エトキシメチレンマロン酸ジエチル２．３４ｇ（１０．８ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物０．１７ｇ（０．９ｍｍｏｌ）の順でゆるやかに添加し、攪拌しながら１００℃にて２時間反応させた。その後、エトキシメチレンマロン酸ジエチル０．７８ｇ（３．６ｍｍｏｌ）を添加して１１０℃にて１時間、再びエトキシメチレンマロン酸ジエチル０．３９ｇ（１．８ｍｍｏｌ）を添加して１０８℃にて１時間、更にエトキシメチレンマロン酸ジエチル０．３９ｇ（１．８ｍｍｏｌ）を添加して１０７℃にて１４時間、攪拌しながら反応させた。反応終了後、反応液を室温まで冷却した後、反応液を減圧濃縮した。濃縮液を高速液体クロマトグラフィーにより分析（内部標準法）したところ、６，７−ジメトキシクマリンが２．２０ｇ生成していた（反応収率：６０％）。濃縮液の一部を薄層クロマトグラフィー（シリカゲル、展開溶媒；塩化メチレン／メタノール＝９５／５）により精製し、灰色結晶として、６，７−ジメトキシクマリン７０ｍｇを得た。
なお、６，７−ジメトキシクマリンの物性値は、以下の通りであった。
【００３２】
ＣＩ−ＭＳ（ｍ／ｅ）；２０７（Ｍ＋１）
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；３．９２（１Ｈ，ｓ）、３．９５（１Ｈ，ｓ）、６．２９（１Ｈ，ｄ，Ｊ＝９．５Ｈｚ）、６．８４（１Ｈ，ｓ）、６．８６（１Ｈ，ｓ）、７．６５（１Ｈ，ｄ，Ｊ＝９．５Ｈｚ）
【００３３】
【発明の効果】
本発明により、入手が容易な原料から、簡便な方法によって高収率でクマリン化合物を得る、工業的に好適なクマリン化合物の製法を提供することが出来る。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel method for producing a coumarin compound, which is useful as a raw material or an intermediate for synthesis of pharmaceuticals, agricultural chemicals and the like. Among the coumarin compounds, in particular, 6,7-dihydroxycoumarin derivatives are compounds which have, for example, a phospholipase activity inhibitory activity and are used as raw materials for the synthesis of drugs for treating inflammatory diseases such as rheumatoid arthritis and osteoarthritis. (For example, Japanese Patent Publication No. Hei 8-512057). It is also useful as a starting material for a compound that has a killing effect on human tumor cells (Tetrahedron Letters, 41 , 9596 (2000)).
[0002]
[Prior art]
Conventionally, as a method for producing a coumarin compound by reacting a phenol derivative with an alkoxymethylene malonate diester, 1,3,5-trihydroxybenzene or 1,2,4-trihydroxybenzene and diethyl ethoxymethylenemalonate are used. Are reacted under solvent-free conditions to obtain the corresponding coumarin compound in a yield of 30% or less (CR Hebd. Sequences Acad. Sci., 246 , 1701 (1958)). However, this method has a very low yield and is not satisfactory as an industrial production method.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to solve the above-mentioned problems, and to provide an industrially suitable method for producing a coumarin compound which is easily available and obtains a coumarin compound in a high yield by a simple method. .
[0004]
[Means for Solving the Problems]
An object of the present invention is to provide a compound represented by the general formula (1):
[0005]
Embedded image
(Wherein, R 1 , R 2 and R 3 may be the same or different and represent a hydrogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms. Note that R 1 , R 2 and R 3 are And may combine with each other to form a ring.)
A phenol derivative represented by the general formula (2)
[0007]
Embedded image
(In the formula, R 4 and R 5 represent an alkyl group having 1 to 4 carbon atoms.)
Characterized by reacting with an alkoxymethylene malonic acid diester represented by the general formula (3):
[0009]
Embedded image
(In the formula, R 1 , R 2 and R 3 are as defined above.)
And is solved by the method for producing a coumarin compound.
[0011]
BEST MODE FOR CARRYING OUT THE INVENTION
The phenol derivative used in the reaction of the present invention is represented by the above general formula (1). In the general formula (1), R 1 , R 2 and R 3 may be the same or different and represent a hydrogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms. Examples of the alkoxy group having 1 to 4 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, methylenedioxy, and ethylenedioxy. Examples thereof include an oxy group, a trimethylenedioxy group, and a tetramethylenedioxy group. In a preferred embodiment, R 1 and R 2 are a hydroxyl group, and R 3 is a hydrogen atom. R 1 , R 2 and R 3 may be bonded to each other to form a ring.
[0012]
The amount of the phenol derivative to be used is preferably 0.8 to 2.0 mol, more preferably 1.0 to 1.4 mol, per 1 mol of the alkoxymethylene malonic acid diester.
[0013]
The alkoxymethylene malonic acid diester used in the reaction of the present invention is represented by the general formula (2). In the general formula (2), R 4 and R 5 represent an alkyl group having 1 to 4 carbon atoms. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and a t-butyl group.
[0014]
Examples of the acid used in the reaction of the present invention include organic sulfonic acids (hydrates) such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and p-bromobenzenesulfonic acid. Inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid and the like, preferably organic sulfonic acids, more preferably p-toluenesulfonic acid. In addition, you may use these acids individually or in mixture of 2 or more types.
[0015]
The amount of the acid to be used is preferably 0.01 to 0.30 mol, more preferably 0.02 to 0.25 mol, and particularly preferably 0.03 to 0.20 mol, based on 1 mol of the alkoxymethylene malonic acid diester. .
[0016]
The reaction of the present invention is preferably performed in a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include carboxylic acids such as formic acid, acetic acid, and propionic acid; methanol, ethanol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, and t-butyl alcohol. Alcohols such as -butyl alcohol; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane Ethers such as benzene, toluene and xylene; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; aliphatic hydrocarbons such as hexane and heptane; methylene chloride; Halo such as dichloroethane Emissions aliphatic hydrocarbons; methyl acetate, ethyl acetate, and carboxylic acid esters such as butyl acetate, is preferably used carboxylic acids. These solvents may be used alone or in combination of two or more.
[0017]
The amount of the acid to be used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 1 to 200 ml per 1 g of the alkoxymethylene malonic acid diester.
[0018]
The reaction of the present invention is carried out by, for example, a method of mixing a phenol derivative, an alkoxymethylenemalonic acid diester, an acid and a solvent in an inert gas atmosphere and reacting the mixture with stirring. The reaction temperature at that time is preferably 10 to 200 ° C, more preferably 80 to 130 ° C, and the reaction pressure is not particularly limited.
[0019]
The coumarin compound obtained by the reaction of the present invention is isolated by a general method such as recrystallization, distillation, and column chromatography after completion of the reaction, for example, after performing treatments such as neutralization, extraction, concentration, and filtration.・ It is purified.
[0020]
【Example】
Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited thereto.
[0021]
Example 1 (Synthesis of 6,7-dihydroxycoumarin)
25 ml of acetic acid was added to a 50 ml glass four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and then 1,2,4-trihydroxybenzene was added under a nitrogen atmosphere. 85 g (46.4 mmol) were added. Then, the temperature of the solution was raised to 100 ° C., and 4.28 g (19.8 mmol) of diethyl ethoxymethylenemalonate and 0.34 g (1.8 mmol) of p-toluenesulfonic acid monohydrate were gradually added in this order. The reaction was carried out at 100 ° C. for 2 hours with stirring. Thereafter, 1.71 g (7.9 mmol) of diethyl ethoxymethylenemalonate was added thereto for 1 hour at the same temperature, and 0.86 g (4.0 mmol) of diethyl ethoxymethylenemalonate was added again for 1 hour at the same temperature. Then, 0.86 g (4.0 mmol) of diethyl ethoxymethylenemalonate was added, and the mixture was reacted at the same temperature for 5 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, and the precipitated crystals were filtered and washed with ethyl acetate. The obtained crystals were dried under reduced pressure to obtain 4.87 g of 6,7-dihydroxycoumarin having a purity of 97.3% (quantitative value by high performance liquid chromatography (internal standard method)) as ocher crystals (simple). (Isolation yield: 75%).
The physical properties of 6,7-dihydroxycoumarin were as follows.
[0022]
CI-MS (m / e); 179 (M + 1)
1 H-NMR (DMSO-d 6, δ (ppm)); 6.20 (1H, d, J = 9.4Hz), 6.79 (1H, s), 7.02 (1H, s), 7 .89 (1H, d, J = 9.4 Hz), 9.48 (1H, brs), 10.17 (1H, brs)
13 C-NMR (DMSO-d 6 , δ (ppm)); 102.6, 110.7, 111.5, 112.3, 142.8, 144.3, 148.5, 150.3, 160. 8
[0023]
Example 2 (Synthesis of 6,7-dihydroxycoumarin)
50 ml of acetic acid was added to a 100 ml glass four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and then 1,2,4-trihydroxybenzene was added in a nitrogen atmosphere. 95 g (39.3 mmol) were added. Next, the temperature of the solution was raised to 110 ° C., 4.28 g (19.8 mmol) of diethyl ethoxymethylenemalonate was slowly added, and the mixture was stirred for 2 hours. Then, 0.34 g of p-toluenesulfonic acid monohydrate (1. 8 mmol) was slowly added, and the mixture was reacted at 110 ° C. for 2 hours with stirring. Thereafter, 1.71 g (7.9 mmol) of diethyl ethoxymethylenemalonate was added thereto for 1 hour at 100 ° C., and 0.86 g (4.0 mmol) of diethyl ethoxymethylenemalonate was added again for 1 hour at the same temperature. Then, 0.86 g (4.0 mmol) of diethyl ethoxymethylenemalonate was added, and the mixture was reacted at the same temperature for 2 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, and the precipitated crystals were filtered and washed with ethyl acetate. The obtained crystals were dried under reduced pressure to obtain 4.50 g of 6,7-dihydroxycoumarin having a purity of 97.8% (quantitative value by high performance liquid chromatography (internal standard method)) as ocher crystals (simple). Isolation yield: 69%).
[0024]
Example 3 (Synthesis of 6,7-dihydroxycoumarin)
25 ml of acetic acid was added to a 50 ml glass four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and then 1,2,4-trihydroxybenzene was added under a nitrogen atmosphere. 85 g (46.4 mmol) were added. Next, the liquid temperature was raised to 110 ° C., and 4.28 g (19.8 mmol) of diethyl ethoxymethylenemalonate and 0.34 g (1.8 mmol) of p-toluenesulfonic acid monohydrate were slowly added in this order. The reaction was carried out at 110 ° C. for 2 hours with stirring. Thereafter, 3.42 g (15.8 mmol) of diethyl ethoxymethylenemalonate was added and reacted at 100 ° C. for 6 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, and the precipitated crystals were filtered and washed with ethyl acetate. The obtained crystals were dried under reduced pressure to obtain 4.29 g of 6,7-dihydroxycoumarin having a purity of 96.3% (quantitative value by high performance liquid chromatography (internal standard method)) as ocher crystals (simple). (Isolation yield: 65%).
[0025]
Example 4 (Synthesis of 6-hydroxy-7-methoxycoumarin)
25 ml of acetic acid was added to a 50 ml glass four-necked flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser, and then 3.32 g of 2,5-dihydroxyanisole (23) in a nitrogen atmosphere. .7 mmol). Next, the temperature of the solution was raised to 110 ° C., and 2.34 g (10.8 mmol) of diethyl ethoxymethylenemalonate and 0.17 g (0.9 mmol) of p-toluenesulfonic acid monohydrate were slowly added in this order. The reaction was carried out at 110 ° C. for 2 hours with stirring. Thereafter, 0.78 g (3.6 mmol) of diethyl ethoxymethylenemalonate was added thereto for 1 hour at 109 ° C., and 0.39 g (1.8 mmol) of diethyl ethoxymethylenemalonate was added again for 1 hour at the same temperature. Then, 0.39 g (1.8 mmol) of diethyl ethoxymethylenemalonate was added, and the mixture was reacted at 107 ° C. for 17 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, 12 ml of ethyl acetate was added, and the mixture was stirred at 2 ° C. for 3 hours. The precipitated crystals were filtered and washed with ethyl acetate. The obtained crystals were dried under reduced pressure to obtain 1.54 g of 6-hydroxy-7-methoxycoumarin having a purity of 99.4% (area percentage by high performance liquid chromatography) as green-brown crystals (isolation yield). : 45%).
The physical properties of 6-hydroxy-7-methoxycoumarin were as follows.
[0026]
CI-MS (m / e); 193 (M + 1)
1 H-NMR (DMSO-d 6, δ (ppm)); 3.85 (3H, s), 6.22 (1H, d, J = 9.8Hz), 6.98 (1H, s), 6 .99 (1H, s), 7.87 (1H, d, J = 9.3 Hz), 9.35 (1H, brs)
13 C-NMR (DMSO-d 6 , δ (ppm)); 56.1, 100.0, 111.5, 111.9, 112.5, 143.6, 144.2, 148.4, 151. 8, 160.7
[0027]
Example 5 (Synthesis of 7-hydroxycoumarin)
25 ml of acetic acid was added to a 50 ml glass four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and then 2.61 g (23) of 1,3-dihydroxybenzene was added in a nitrogen atmosphere. .7 mmol). Next, the temperature of the solution was raised to 100 ° C., and 2.34 g (10.8 mmol) of diethyl ethoxymethylenemalonate and 0.17 g (0.9 mmol) of p-toluenesulfonic acid monohydrate were slowly added in this order. The reaction was carried out at 100 ° C. for 2 hours with stirring. Thereafter, 0.78 g (3.6 mmol) of diethyl ethoxymethylenemalonate was added thereto for 1 hour at 106 ° C, and 0.39 g (1.8 mmol) of diethyl ethoxymethylenemalonate was added again for 1 hour at 104 ° C. Further, 0.39 g (1.8 mmol) of diethyl ethoxymethylenemalonate was added, and the mixture was reacted at 103 ° C. for 12 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, 12 ml of ethyl acetate was added, and the mixture was stirred at 2 ° C for 2 hours. The precipitated crystals were filtered and washed with ethyl acetate. The obtained crystals were dried under reduced pressure to obtain 0.42 g of 7-hydroxycoumarin having a purity of 97.1% (area percentage by high performance liquid chromatography) as pale yellow crystals (isolation yield: 14%). .
The physical properties of 7-hydroxycoumarin were as follows.
[0028]
CI-MS (m / e); 163 (M + 1)
1 H-NMR (DMSO-d 6, δ (ppm)); 6.17 (1H, d, J = 9.3Hz), 6.69 (1H, d, J = 2.0Hz), 6.76 ( 1H, dd, J = 8.3, 2.4 Hz), 7.48 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 9.3 Hz), 10.53 (1H , Brs)
13 C-NMR (DMSO-d 6 , δ (ppm)); 102.2, 111.3, 111.4, 113.1, 129.7, 144.5, 155.5, 160.4, 161. 3
[0029]
Example 6 (Synthesis of 7,8-dihydroxycoumarin)
25 ml of acetic acid was added to a 50 ml glass four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and then 1,2,3-trihydroxybenzene was added under a nitrogen atmosphere. 85 g (46.4 mmol) were added. Then, the temperature of the solution was raised to 104 ° C., and 4.28 g (19.8 mmol) of diethyl ethoxymethylenemalonate and 0.34 g (3.5 mmol) of methanesulfonic acid were slowly added in this order. For 2 hours. Thereafter, 1.71 g (7.9 mmol) of diethyl ethoxymethylenemalonate was added thereto for 1 hour at 96 ° C, and 0.86 g (4.0 mmol) of diethyl ethoxymethylenemalonate was added again for 1 hour at 94 ° C. Then, 0.86 g (4.0 mmol) of diethyl ethoxymethylenemalonate was added thereto, and the mixture was stirred at 93 ° C. for 3 hours, and then 0.17 g (1.8 mmol) of methanesulfonic acid was added, followed by stirring at 93 ° C. for 3 hours. While reacting. After completion of the reaction, the reaction solution was cooled to room temperature, then cooled to 2 ° C., and stirred for 1 hour. The precipitated crystals were filtered and washed with ethyl acetate. The obtained crystals were dried under reduced pressure to obtain 1.25 g of 7,8-dihydroxycoumarin having a purity of 93.0% (area percentage by high performance liquid chromatography) as brown crystals (isolation yield: 20%). ).
The physical properties of 7,8-dihydroxycoumarin were as follows.
[0030]
CI-MS (m / e); 179 (M + 1)
1 H-NMR (DMSO-d 6, δ (ppm)); 6.20 (1H, d, J = 9.8Hz), 6.82 (1H, d, J = 8.3Hz), 7.03 ( 1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 9.3 Hz)
13 C-NMR (DMSO-d 6 , δ (ppm)); 111.2, 112.0, 112.4, 118.8, 132.1, 143.7, 145.0, 149.6, 160. 3
[0031]
Example 7 (Synthesis of 6,7-dimethoxycoumarin)
25 ml of acetic acid was added to a 50 ml glass four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and then, in a nitrogen atmosphere, 3.69 g (23) of 3,4-dimethoxyphenol was added. .9 mmol). Next, the temperature of the solution was raised to 100 ° C., and 2.34 g (10.8 mmol) of diethyl ethoxymethylenemalonate and 0.17 g (0.9 mmol) of p-toluenesulfonic acid monohydrate were slowly added in this order. The reaction was carried out at 100 ° C. for 2 hours while stirring. Thereafter, 0.78 g (3.6 mmol) of diethyl ethoxymethylenemalonate was added thereto at 110 ° C. for 1 hour, and 0.39 g (1.8 mmol) of diethyl ethoxymethylenemalonate was added again at 108 ° C. for 1 hour. Then, 0.39 g (1.8 mmol) of diethyl ethoxymethylenemalonate was added, and the mixture was reacted at 107 ° C. for 14 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, and then concentrated under reduced pressure. Analysis of the concentrated solution by high performance liquid chromatography (internal standard method) revealed that 2.20 g of 6,7-dimethoxycoumarin was produced (reaction yield: 60%). A part of the concentrated solution was purified by thin-layer chromatography (silica gel, developing solvent; methylene chloride / methanol = 95/5) to obtain 70 mg of 6,7-dimethoxycoumarin as gray crystals.
The physical properties of 6,7-dimethoxycoumarin were as follows.
[0032]
CI-MS (m / e); 207 (M + 1)
1 H-NMR (DMSO-d 6, δ (ppm)); 3.92 (1H, s), 3.95 (1H, s), 6.29 (1H, d, J = 9.5Hz), 6 .84 (1H, s), 6.86 (1H, s), 7.65 (1H, d, J = 9.5 Hz)
[0033]
【The invention's effect】
According to the present invention, it is possible to provide an industrially suitable method for producing a coumarin compound, which can obtain a coumarin compound in a high yield from a readily available raw material by a simple method.
Claims (5)
で示されるフェノール誘導体と、一般式（２）
で示されるアルコキシメチレンマロン酸ジエステルとを反応させることを特徴とする、一般式（３）
で示される、クマリン化合物の製法。Formula (1) in the presence of an acid
A phenol derivative represented by the general formula (2)
Characterized by reacting with an alkoxymethylene malonic acid diester represented by the general formula (3):
A method for producing a coumarin compound represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002241508A JP4192526B2 (en) | 2002-08-22 | 2002-08-22 | Production of coumarin compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002241508A JP4192526B2 (en) | 2002-08-22 | 2002-08-22 | Production of coumarin compounds |
Publications (2)
| Publication Number | Publication Date |
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| JP2004075643A true JP2004075643A (en) | 2004-03-11 |
| JP4192526B2 JP4192526B2 (en) | 2008-12-10 |
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| JP2002241508A Expired - Fee Related JP4192526B2 (en) | 2002-08-22 | 2002-08-22 | Production of coumarin compounds |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107915704A (en) * | 2016-10-10 | 2018-04-17 | 北京工商大学 | A kind of synthetic method of simple coumarin kind compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107915704A (en) * | 2016-10-10 | 2018-04-17 | 北京工商大学 | A kind of synthetic method of simple coumarin kind compound |
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| JP4192526B2 (en) | 2008-12-10 |
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