JP2004075643A - Method for producing coumarin compound - Google Patents

Method for producing coumarin compound Download PDF

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JP2004075643A
JP2004075643A JP2002241508A JP2002241508A JP2004075643A JP 2004075643 A JP2004075643 A JP 2004075643A JP 2002241508 A JP2002241508 A JP 2002241508A JP 2002241508 A JP2002241508 A JP 2002241508A JP 2004075643 A JP2004075643 A JP 2004075643A
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added
mmol
acid
coumarin compound
reaction
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JP4192526B2 (en
Inventor
Katsutaka Onzuka
恩塚 克孝
Suzuo Takiguchi
滝口 寿々夫
Kensaku Fuse
布施 建策
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Ube Ind Ltd
宇部興産株式会社
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Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially suitable method for producing a coumarin compound from an easily available raw material with a simple procedure in high yield. <P>SOLUTION: The coumarin compound of general formula (3) (R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are each independently H, hydroxy or a 1-4C alkoxy; R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>may be bonded together to form a ring) is produced by reacting a phenol derivative of general formula (1) (R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are the same as those defined above) with an alkoxymethylene malonic acid diester of general formula (2) (R<SP>4</SP>and R<SP>5</SP>are each a 1-4C alkyl) in the presence of an acid. <P>COPYRIGHT: (C)2004,JPO

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】
【0006】
(式中、R、R及びR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、R、R及びR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】
【0008】
(式中、R及びR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】
【0010】
(式中、R、R及びR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、R、R及びR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、R及びRがヒドロキシル基、Rが水素原子である。なお、R、R及びR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、R及びR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)
H−NMR(DMSO−d,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−d,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)
H−NMR(DMSO−d,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−d,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)
H−NMR(DMSO−d,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−d,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)
H−NMR(DMSO−d,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−d,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)
H−NMR(DMSO−d,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
[0006]
(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
[0008]
(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
[0010]
(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)

  1. 酸の存在下、一般式(1)
    (式中、R、R及びR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、R、R及びR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)
    (式中、R及びR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)
    (式中、R、R及びRは、前記と同義である。)
    で示される、クマリン化合物の製法。
    Formula (1) in the presence of an acid
    (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)
    (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):
    (In the formula, R 1 , R 2 and R 3 are as defined above.)
    A method for producing a coumarin compound represented by
  2. 酸が有機スルホン酸類である請求項1記載のクマリン化合物の製法。The method for producing a coumarin compound according to claim 1, wherein the acid is an organic sulfonic acid.
  3. 反応を溶媒中で行う請求項1記載のクマリン化合物の製法。The method for producing a coumarin compound according to claim 1, wherein the reaction is carried out in a solvent.
  4. 溶媒がカルボン酸類である請求項3記載のクマリン化合物の製法。The method for producing a coumarin compound according to claim 3, wherein the solvent is a carboxylic acid.
  5. 及びRがヒドロキシル基、Rが水素原子である請求項1記載のクマリン化合物の製法。The method for producing a coumarin compound according to claim 1, wherein R 1 and R 2 are hydroxyl groups, and R 3 is a hydrogen atom.
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Cited By (1)

* Cited by examiner, † Cited by third party
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

Cited By (1)

* Cited by examiner, † Cited by third party
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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