JP4030289B2 - Process for producing β-ketonitriles - Google Patents

Process for producing β-ketonitriles Download PDF

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Publication number
JP4030289B2
JP4030289B2 JP2001322935A JP2001322935A JP4030289B2 JP 4030289 B2 JP4030289 B2 JP 4030289B2 JP 2001322935 A JP2001322935 A JP 2001322935A JP 2001322935 A JP2001322935 A JP 2001322935A JP 4030289 B2 JP4030289 B2 JP 4030289B2
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reaction
added
ketonitrile
layer
ketonitriles
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JP2002249477A (en
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勝正 原田
繁栄 西野
健二 弘津
明 中村
崇司 原田
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Ube Corp
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Ube Industries Ltd
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Description

【0001】
【発明の属する技術分野】
本発明は、脂肪族カルボン酸エステル類からβ-ケトニトリル類を製造する方法に関する。β-ケトニトリル類は、医薬・農薬等の合成原料として有用な化合物である。
【0002】
【従来の技術】
従来、金属アルコキシドの存在下、脂肪族カルボン酸エステル類とアセトニトリルを反応させてβ-ケトニトリル類を製造する方法としては、例えば、ナトリウムエトキシド存在下、イソ酪酸エチルとアセトニトリルを反応させる方法(J.Am.Chem.Soc.,56,1171(1934))やアルカリアルコラート存在下、酢酸エステルとアセトニトリルを反応させる方法(特開平6-312966号公報)が開示されている。しかしながら、これらの方法では、反応中に副生する3-オキソブチロニトリル、ピリミジン類等を混入させず、高純度で収率良くβ-ケトニトリル類を得る方法については何ら記載されていなかった。
【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、簡便な方法にて、入手が容易な脂肪族カルボン酸エステル類から、高純度で収率良くβ-ケトニトリル類を得る、工業的に好適なβ-ケトニトリル類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、
(A)金属アルコキシドの存在下、一般式(1)
【0005】
【化4】
【0006】
(式中、R1は、脂肪族基を示し、R2は、反応に関与しない基を示す。)
で示される脂肪族カルボン酸エステル類とアセトニトリルを反応させて、一般式(2)
【0007】
【化5】
【0008】
(式中、R1は、前記と同義であり、Xは金属原子を示す。)
で示されるβ-ケトニトリルの金属塩を合成する反応操作工程、
(B)その後、反応液に有機溶媒と水を添加・混合して、有機層と水層に層分離させて、β-ケトニトリルの金属塩を含む水層(水溶液)を得る層分離工程、
(C)次いで、層分離によって得られたβ-ケトニトリルの金属塩を含む水溶液に酸を加えて中和し、有機溶媒で抽出して遊離のβ-ケトニトリルを取得する中和・抽出工程、
を含むことからなる、一般式(3)
【0009】
【化6】
【0010】
(式中、R1は、前記と同義である。)
で示されるβ-ケトニトリル類の製法によって解決される。
【0011】
【発明の実施の形態】
本発明は、
(A)金属アルコキシドの存在下、一般式(1)で示される脂肪族カルボン酸エステルとアセトニトリルを反応させて、一般式(2)で示されるβ-ケトニトリルの金属塩を合成する反応操作工程、
(B)その後、反応液に有機溶媒と水を添加・混合して、有機層と水層に層分離させて、β-ケトニトリルの金属塩を含む水層(水溶液)を得る層分離工程、
(C)次いで、層分離によって得られたβ-ケトニトリルの金属塩を含む水溶液に酸を加えて中和し、有機溶媒で抽出して遊離のβ-ケトニトリルを取得する中和・抽出工程、
を含むことからなる三つの工程によってβ-ケトニトリルを反応生成物として得るものである。
【0012】
引き続き、前記の三つの工程を順次説明する。
(A)反応操作工程
本発明の反応操作工程は、金属アルコキシドの存在下、一般式(1)で示される脂肪族カルボン酸エステルとアセトニトリルを反応させて、一般式(2)で示されるβ-ケトニトリルの金属塩を合成する工程である。
【0013】
本発明の反応操作工程において使用する脂肪族カルボン酸エステル類は、前記の一般式(1)で示される。その一般式(1)において、R1は、脂肪族基であり、具体的には、例えば、アルキル基、シクロアルキル基又はアラルキル基を示す。
【0014】
前記アルキル基としては、特に炭素数1〜10のアルキル基が好ましく、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等が挙げられる。これらの基は、各種異性体を含む。
【0015】
前記シクロアルキル基としては、特に炭素数3〜7のシクロアルキル基が好ましく、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基等が挙げられる。これらの基は、各種異性体を含む。
【0016】
前記アラルキル基としては、特に炭素数7〜10のアラルキル基が好ましく、例えば、ベンジル基、フェネチル基、フェニルプロピル基、フェニルブチル基等が挙げられる。これらの基は、各種異性体を含む。
【0017】
又、一般式(1)において、R2は、反応に関与しない基、具体的には、炭化水素基であり、例えば、アルキル基、シクロアルキル基、アラルキル基又はアリール基を示す。
【0018】
前記アルキル基としては、特に炭素数1〜10のアルキル基が好ましく、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等が挙げられる。これらの基は、各種異性体を含む。
【0019】
前記シクロアルキル基としては、特に炭素数3〜7のシクロアルキル基が好ましく、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基等が挙げられる。これらの基は、各種異性体を含む。
【0020】
前記アラルキル基としては、特に炭素数7〜10のアラルキル基が好ましく、例えば、ベンジル基、フェネチル基、フェニルプロピル基、フェニルブチル基等が挙げられる。これらの基は、各種異性体を含む。
【0021】
前記アリール基としては、特に炭素数6〜14のアリール基が好ましく、例えば、フェニル基、トリル基、ナフチル基、アントラニル基等が挙げられる。これらの基は、各種異性体を含む。
【0022】
本発明の反応操作工程において使用する金属アルコキシドの金属原子としては、例えば、理化学辞典第4版(岩波書店出版)に記載されている、リチウム原子、ナトリウム原子、カリウム原子等の1A族原子、マグネシウム原子、カルシウム原子等の2A族原子、アルミニウム等の3B族原子が挙げられる。
【0023】
前記金属アルコキシドの具体例としては、例えば、リチウムメトキシド、ナトリウムメトキシド、カリウムメトキシド、ナトリウムエトキシド、カリウムエトキシド、カリウムt-ブトキシド等の1A族金属アルコキシド;マグネシウムメトキシド、カルシウムメトキシド等の2A族金属アルコキシド;アルミニウムイソプロポキシド等の3B族金属アルコキシドが挙げられるが、好ましくはナトリウムアルコキシド、更に好ましくはナトリウムメトキシドが使用される。
【0024】
前記金属アルコキシドの使用量は、脂肪族カルボン酸エステル類に対して、好ましくは1.0〜2.5倍モル、更に好ましくは1.1〜2.0倍モルである。これらの金属アルコキシドは、単独又は二種以上を混合して使用しても良い。
【0025】
本発明の反応操作工程において使用するアセトニトリルの量は、脂肪族カルボン酸エステル類に対して、好ましくは1.1〜2.5倍モル、更に好ましくは1.2〜2.0倍モルである。
【0026】
本発明の反応操作工程は、例えば、不活性ガス雰囲気にて、金属アルコキシド、脂肪族カルボン酸エステル類及びアセトニトリルを混合し、好ましくは50〜110℃、更に好ましくは60〜100℃に加熱して反応させる等の方法によって行われる。その際の反応圧力は、特に限定されない。
【0027】
(B)層分離工程
本発明の層分離工程は、反応操作工程で得られたβ-ケトニトリルの金属塩を含む反応液に、有機溶媒と水を添加・混合して、有機層と水層に分離させて、β-ケトニトリルの金属塩が溶解している水層(水溶液)を得る工程である。
【0028】
本発明の層分離工程において添加される有機溶媒としては、水層と有機層が層分離出来る有機溶媒ならば特に限定はされないが、例えば、ジエチルエーテル、ジイソプロピルエーテル等のエーテル類;ベンゼン、トルエ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;酢酸エチル、酢酸ブチル等のエステル類が挙げられるが、好ましくはエーテル類、芳香族炭化水素類、更に好ましくは芳香族炭化水素類が使用される。これら有機溶媒は、単独又は二種以上を混合して使用しても良く、又、攪拌性を高めるために、低級アルコール類を層の分離を損なわない程度で加えても良い。
【0029】
前記有機溶媒の添加量は、有機層と水層とが分離するような量であれば特に制限がないが、脂肪族カルボン酸エステル類に対して、好ましくは0.5〜30容量倍、更に好ましくは1〜10容量倍である。
【0030】
前記水の添加量は、反応操作工程で得られたβ-ケトニトリルの金属塩を完全に溶解させるような量であれば特に制限されないが、脂肪族カルボン酸エステル類に対して、好ましくは1〜50容量倍、更に好ましくは2〜30容量倍である。
【0031】
なお、本発明の層分離工程では、冷却に伴って反応液が固化するのを防ぐために、反応液に先に有機溶媒を加えて流動性を高め、次いで攪拌下で水を添加・混合するのが好ましい。その際の反応液の温度は、好ましくは10〜50℃、更に好ましくは20〜40℃である。
【0032】
(C)中和・抽出工程
本発明の中和・抽出工程は、層分離工程によって得られたβ-ケトニトリルの金属塩を含む水溶液に酸を加えて中和し、更に有機溶媒で抽出して、遊離のβ-ケトニトリルを取得する工程である。
【0033】
本発明の中和・抽出工程によって使用する酸としては、例えば、塩酸、硫酸、硝酸、リン酸、メタンスルホン酸、酢酸、塩化アンモニウム(又はその水溶液)等が挙げられるが、好ましくは塩酸、硫酸、塩化アンモニウム(又はその水溶液)が使用される。
【0034】
前記酸の使用量は、水溶液のpH値を好ましくは6〜10にするような量であれば特に制限はない。なお、酸の添加は、水溶液の温度が、0〜50℃になるような範囲で行うのが好ましい。
【0035】
本発明の中和・抽出工程において使用する有機溶媒としては、水溶液中(水層中)に含まれる遊離のβ-ケトニトリルを抽出出来る有機溶媒ならば特に限定はされないが、例えば、ベンゼン、トルエン等の芳香族炭化水素類;酢酸エチル、酢酸ブチル等のエステル類;ジクロロメタン、ジクロロエタン等のハロゲン化脂肪族炭化水素類が挙げられるが、好ましくは芳香族炭化水素類、酢酸エステル、更に好ましくは芳香族炭化水素類が使用される。
【0036】
前記有機溶媒の使用量としては、前記の中和で得られた水溶液中(水層中)の遊離のβ-ケトニトリルを抽出出来るような量であれば特に制限されない。
【0037】
本発明の中和・抽出工程によって、遊離のβ-ケトニトリルが有機溶媒溶液として高純度で得られるが、これは、例えば、濃縮、蒸留、晶析、再結晶、カラムクロマトグラフィー等による一般的な方法によって更に分離・精製することが出来る。なお、β-ケトニトリルは熱に対して不安定であるため、蒸留で分離・精製する際には、薄膜式蒸留装置や流下膜式蒸留装置を用いるのが望ましい。
【0038】
【実施例】
次ぎに、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。
【0039】
実施例1(3-シクロプロピル-3-オキソプロピオニトリルの合成)
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1000mlのガラス製フラスコに、窒素雰囲気下、ナトリウムメトキシド81.0g(1.5mol)、シクロプロパンカルボン酸メチル100.0g(1.0mol)及びアセトニトリル61.5g(1.5mol)を加え、還流下(82℃)で6時間反応させた。
反応終了後、トルエン400mlを加えて室温まで冷却し、液温を30℃以下に保ちながら、攪拌下で水200mlをゆるやかに滴下し、得られた水層を分液した。
次いで、水層を氷浴中で冷却しながら、12mol/l塩酸135ml(1.6mol)を加えて水溶液のpHを7.0にした後、トルエン200mlで3回抽出し、得られたトルエン層を飽和炭酸水素ナトリウム水溶液50mlで洗浄した後、硫酸マグネシウムで乾燥した。濾過後、トルエン層を高速液体クロマトグラフィーにより分析(絶対定量法)したところ、目的とする3-シクロプロピル-3-オキソプロピオニトリルが81.1g(反応収率74%)、副生成物である3-オキソブチロニトリルが0.45g(目的物に対して0.55質量%)、ピリミジン類が0.15g(目的物に対して0.18質量%)生成していた。その後、減圧下で濃縮し、帯黄色液体として純度98.2%(高速液体クロマトグラフィーによる分析値)の3-シクロプロピル-3-オキソプロピオニトリル80.2gが得られた(単離収率72%)。
3-シクロプロピル-3-オキソプロピオニトリルの物性値は、以下の通りであった。
【0040】
EI-MS(m/e);69(M-CH2CN)、CI-MS(m/e);110(M+1)
IR(液膜法、cm-1);3200〜2900、2261、1713、1389、1073、953
1H-NMR(CDCl3、δ(ppm));1.05〜1.15(2H,m)、1.18〜1.25(2H,m)、2.06〜2.15(1H,m)、3.64(2H,s)
【0041】
比較例1(3-シクロプロピル-3-オキソプロピオニトリルの合成:層分離工程なし)
実施例1と同様な装置に、窒素雰囲気下、ナトリウムメトキシド81.0g(1.5mol)、シクロプロパンカルボン酸メチル100.0g(1.0mol)及びアセトニトリル61.5g(1.5mol)を加え、還流下(82℃)で6時間反応させた。
反応終了後、トルエン400mlを加えて室温まで冷却し、液温を30℃以下に保ちながら、6mol/l塩酸280ml(1.6mol)及び水100mlを加えて水溶液のpHを2.0にした後、トルエン200mlで3回抽出し、得られたトルエン層を飽和炭酸水素ナトリウム水溶液50mlで洗浄した後、硫酸マグネシウムで乾燥した。濾過後、トルエン層を高速液体クロマトグラフィーにより分析(絶対定量法)したところ、目的とする3-シクロプロピル-3-オキソプロピオニトリルが72.3g(反応収率66%)、副生成物である3-オキソブチロニトリルが0.60g(目的物に対して0.83質量%)、ピリミジン類が1.33g(目的物に対して1.8質量%)生成していた。その後、減圧下で濃縮し、帯黄色液体として純度93.6%(高速液体クロマトグラフィーによる分析値)の3-シクロプロピル-3-オキソプロピオニトリル77.2gが得られた(単離収率66%)。
【0042】
実施例2(4-メチル-3-オキソペンタンニトリルの合成)
実施例1と同様な装置に、窒素雰囲気下、ナトリウムメトキシド81.0g(1.5mol)、イソ酪酸メチル102.1g(1.0mol)及びアセトニトリル61.5g(1.5mol)を加え、還流下(82℃)で6時間反応させた。
反応終了後、トルエン400mlを加えて室温まで冷却し、液温を35℃以下に保ちながら、攪拌下で水200mlをゆるやかに滴下し、得られた水層を分液した。
次いで、水層を氷浴中で冷却しながら、12mol/l塩酸95ml(1.1mol)を加えて水溶液のpHを7.7にした後、トルエン300mlで3回抽出し、得られたトルエン層を飽和炭酸水素ナトリウム水溶液50mlで洗浄した後、硫酸マグネシウムで乾燥した。濾過後、減圧下で濃縮し、薄黄色液体として純度98.5%(ガスクロマトグラフィーによる面積百分率)の4-メチル-3-オキソペンタンニトリル78.9gが得られた(単離収率70%)。
4-メチル-3-オキソペンタンニトリルの物性値は、以下の通りであった。
【0043】
EI-MS(m/e);71(M-CH2CN)、CI-MS(m/e);112(M+1)
IR(液膜法、cm-1);3700〜3100、3100〜2800、2263、1725、1468、1389、1306、1048、939
1H-NMR(CDCl3、δ(ppm));1.18(6H,d,J=6.8Hz)、2.84(1H,m)、3.94(2H,s)
【0044】
実施例3(4,4-ジメチル-3-オキソペンタンニトリルの合成)
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のガラス製フラスコに、窒素雰囲気下、ナトリウムメトキシド8.10g(0.15mol)、ピバリン酸メチル11.62g(1.0mol)及びアセトニトリル6.15g(0.15mol)を加え、還流下(82℃)で6時間反応させた。
反応終了後、トルエン40mlを加えて室温まで冷却し、液温を35℃以下に保ちながら、攪拌下で水45mlをゆるやかに滴下し、得られた水層を分液した。
次いで、水層を氷浴中で冷却しながら、12mol/l塩酸9.5ml(0.11mol)を加えて水溶液のpHを7.7にした後、トルエン30mlで3回抽出し、得られたトルエン層を飽和炭酸水素ナトリウム水溶液50mlで洗浄した後、硫酸マグネシウムで乾燥した。濾過後、トルエン層を高速液体クロマトグラフィーにより分析(絶対定量法)したところ、目的とする4,4-ジメチル-3-オキソペンタンニトリルが7.25g(反応収率58%)、副生成物である3-オキソブチロニトリルが0.01g(目的物に対して0.20質量%)、ピリミジン類が0.01g(目的物に対して0.14質量%)生成していた。その後、減圧下で濃縮し、薄黄色固体として純度98.4%(高速液体クロマトグラフィーによる面積百分率)の4,4-ジメチル-3-オキソペンタンニトリル7.21gが得られた(単離収率58%)。
4,4-ジメチル-3-オキソペンタンニトリルの物性値は、以下の通りであった。
【0045】
EI-MS(m/e);57(M-COCH2CN)、CI-MS(m/e);126(M+1)
IR(液膜法、cm-1);3000〜2800、2266、1721、1485、1391、1325、1067、9351H-NMR(CDCl3、δ(ppm));1.21(9H,s)、3.70(2H,s)
融点;67.8〜68.7℃
【0046】
比較例2(4,4-ジメチル-3-オキソペンタンニトリルの合成:層分離工程なし)実施例3と同様な装置に、窒素雰囲気下、ナトリウムメトキシド8.10g(0.15mol)、ピバリン酸メチル11.62g(0.10mol)及びアセトニトリル6.15g(0.15mol)を加え、還流下(82℃)で6時間反応させた。
反応終了後、トルエン40mlを加えて室温まで冷却し、液温を30℃以下に保ちながら、6mol/l塩酸28ml(0.16mol)及び水10mlを加えて水溶液のpHを2.0にした後、トルエン20mlで3回抽出し、得られたトルエン層を飽和炭酸水素ナトリウム水溶液50mlで洗浄した後、硫酸マグネシウムで乾燥した。濾過後、トルエン層を高速液体クロマトグラフィーにより分析(絶対定量法)したところ、目的とする4,4-ジメチル-3-オキソペンタンニトリルが7.22g(反応収率58%)、副生成物である3-オキソブチロニトリルが0.04g(目的物に対して0.55質量%)、ピリミジン類が0.13g(目的物に対して1.8質量%)生成していた。その後、減圧下で濃縮し、薄黄色液体として純度94.6%(高速液体クロマトグラフィーによる面積百分率)の4,4-ジメチル-3-オキソペンタンニトリル7.63gが得られた(単離収率58%)。
【0047】
【発明の効果】
本発明により、簡便な方法にて、入手が容易な脂肪族カルボン酸エステル類から、高純度で収率良くβ-ケトニトリル類を得る、工業的に好適なβ-ケトニトリル類の製法を提供することが出来る。
[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing β-ketonitriles from aliphatic carboxylic acid esters. β-Ketonitriles are useful compounds as synthetic raw materials for pharmaceuticals and agricultural chemicals.
[0002]
[Prior art]
Conventionally, as a method for producing β-ketonitrile by reacting an aliphatic carboxylic acid ester with acetonitrile in the presence of a metal alkoxide, for example, a method of reacting ethyl isobutyrate with acetonitrile in the presence of sodium ethoxide (J Am. Chem. Soc., 56 , 1171 (1934)) and a method of reacting acetate with acetonitrile in the presence of an alkali alcoholate (JP-A-6-312966). However, these methods did not describe any method for obtaining β-ketonitriles with high purity and high yield without mixing 3-oxobutyronitrile, pyrimidines and the like by-produced during the reaction.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to solve the above-mentioned problems, and to obtain β-ketonitriles with high purity and high yield from easily available aliphatic carboxylic acid esters by a simple method, which is industrially suitable. A method for producing such β-ketonitriles is provided.
[0004]
[Means for Solving the Problems]
The subject of the present invention is
(A) General formula (1) in the presence of a metal alkoxide
[0005]
[Formula 4]
[0006]
(In the formula, R 1 represents an aliphatic group, and R 2 represents a group not involved in the reaction.)
By reacting an aliphatic carboxylic acid ester represented by general formula (2) with acetonitrile.
[0007]
[Chemical formula 5]
[0008]
(In the formula, R 1 has the same meaning as described above, and X represents a metal atom.)
A reaction operation step for synthesizing a metal salt of β-ketonitrile represented by
(B) Then, an organic solvent and water are added to and mixed in the reaction solution, and the organic layer and the aqueous layer are separated into layers, thereby obtaining a water layer (aqueous solution) containing a metal salt of β-ketonitrile,
(C) Next, a neutralization / extraction step in which an acid is added to the aqueous solution containing the metal salt of β-ketonitrile obtained by layer separation to neutralize, and extraction with an organic solvent obtains free β-ketonitrile.
General formula (3) consisting of
[0009]
[Chemical 6]
[0010]
(In the formula, R 1 has the same meaning as described above.)
It is solved by the production method of β-ketonitriles represented by
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The present invention
(A) a reaction operation step of synthesizing a metal salt of β-ketonitrile represented by the general formula (2) by reacting an aliphatic carboxylic acid ester represented by the general formula (1) with acetonitrile in the presence of a metal alkoxide;
(B) Then, an organic solvent and water are added to and mixed in the reaction solution, and the organic layer and the aqueous layer are separated into layers, thereby obtaining a water layer (aqueous solution) containing a metal salt of β-ketonitrile,
(C) Next, a neutralization / extraction step in which an acid is added to the aqueous solution containing the metal salt of β-ketonitrile obtained by layer separation to neutralize, and extraction with an organic solvent obtains free β-ketonitrile.
Β-ketonitrile is obtained as a reaction product by three steps comprising the steps of:
[0012]
Subsequently, the above three steps will be described sequentially.
(A) Reaction operation step The reaction operation step of the present invention comprises reacting an aliphatic carboxylic acid ester represented by the general formula (1) with acetonitrile in the presence of a metal alkoxide to produce a β-- represented by the general formula (2). This is a step of synthesizing a metal salt of ketonitrile.
[0013]
The aliphatic carboxylic acid ester used in the reaction operation step of the present invention is represented by the general formula (1). In the general formula (1), R 1 is an aliphatic group, and specifically represents, for example, an alkyl group, a cycloalkyl group, or an aralkyl group.
[0014]
As the alkyl group, an alkyl group having 1 to 10 carbon atoms is particularly preferable, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. Is mentioned. These groups include various isomers.
[0015]
The cycloalkyl group is particularly preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. These groups include various isomers.
[0016]
As the aralkyl group, an aralkyl group having 7 to 10 carbon atoms is particularly preferable, and examples thereof include a benzyl group, a phenethyl group, a phenylpropyl group, and a phenylbutyl group. These groups include various isomers.
[0017]
In the general formula (1), R 2 is a group not involved in the reaction, specifically a hydrocarbon group, and represents, for example, an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group.
[0018]
As the alkyl group, an alkyl group having 1 to 10 carbon atoms is particularly preferable, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. Is mentioned. These groups include various isomers.
[0019]
The cycloalkyl group is particularly preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. These groups include various isomers.
[0020]
As the aralkyl group, an aralkyl group having 7 to 10 carbon atoms is particularly preferable, and examples thereof include a benzyl group, a phenethyl group, a phenylpropyl group, and a phenylbutyl group. These groups include various isomers.
[0021]
As the aryl group, an aryl group having 6 to 14 carbon atoms is particularly preferable, and examples thereof include a phenyl group, a tolyl group, a naphthyl group, and an anthranyl group. These groups include various isomers.
[0022]
Examples of the metal atom of the metal alkoxide used in the reaction operation process of the present invention include, for example, a group 1A atom such as lithium atom, sodium atom, potassium atom, etc., described in Physics and Chemistry Dictionary 4th edition (Iwanami Shoten), magnesium 2A group atoms, such as an atom and a calcium atom, and 3B group atoms, such as aluminum, are mentioned.
[0023]
Specific examples of the metal alkoxide include, for example, a group 1A metal alkoxide such as lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide; magnesium methoxide, calcium methoxide and the like. 2A group metal alkoxides of the following: Group 3B metal alkoxides such as aluminum isopropoxide are mentioned, preferably sodium alkoxide, more preferably sodium methoxide.
[0024]
The amount of the metal alkoxide to be used is preferably 1.0 to 2.5 times mol, more preferably 1.1 to 2.0 times mol for the aliphatic carboxylic acid esters. These metal alkoxides may be used alone or in combination of two or more.
[0025]
The amount of acetonitrile used in the reaction operation step of the present invention is preferably 1.1 to 2.5 times mol, more preferably 1.2 to 2.0 times mol, based on the aliphatic carboxylic acid esters.
[0026]
In the reaction operation step of the present invention, for example, a metal alkoxide, an aliphatic carboxylic acid ester and acetonitrile are mixed in an inert gas atmosphere, and preferably heated to 50 to 110 ° C., more preferably 60 to 100 ° C. It is carried out by a method such as reacting. The reaction pressure at that time is not particularly limited.
[0027]
(B) Layer Separation Step The layer separation step of the present invention is carried out by adding and mixing an organic solvent and water to the reaction solution containing the metal salt of β-ketonitrile obtained in the reaction operation step. In this step, an aqueous layer (aqueous solution) in which the metal salt of β-ketonitrile is dissolved is obtained.
[0028]
The organic solvent added in the layer separation step of the present invention is not particularly limited as long as the organic solvent can separate the aqueous layer and the organic layer. For example, ethers such as diethyl ether and diisopropyl ether; benzene, toluene and the like Aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; esters such as ethyl acetate and butyl acetate are preferable, but ethers, aromatic hydrocarbons, and more preferably aromatics Group hydrocarbons are used. These organic solvents may be used alone or in admixture of two or more kinds, and lower alcohols may be added to the extent that the separation of the layers is not impaired in order to enhance the stirring ability.
[0029]
The amount of the organic solvent added is not particularly limited as long as the organic layer and the aqueous layer are separated from each other, but is preferably 0.5 to 30 times by volume, more preferably the aliphatic carboxylic acid esters. 1 to 10 times the capacity.
[0030]
The amount of water added is not particularly limited as long as it is an amount that completely dissolves the metal salt of β-ketonitrile obtained in the reaction operation step, but is preferably 1 to 50 times the volume, more preferably 2 to 30 times the volume.
[0031]
In the layer separation step of the present invention, in order to prevent the reaction solution from solidifying with cooling, an organic solvent is first added to the reaction solution to improve fluidity, and then water is added and mixed under stirring. Is preferred. The temperature of the reaction solution at that time is preferably 10 to 50 ° C, more preferably 20 to 40 ° C.
[0032]
(C) Neutralization / extraction process The neutralization / extraction process of the present invention is performed by adding an acid to an aqueous solution containing a metal salt of β-ketonitrile obtained by the layer separation process, followed by extraction with an organic solvent. In this step, free β-ketonitrile is obtained.
[0033]
Examples of the acid used in the neutralization / extraction step of the present invention include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, acetic acid, ammonium chloride (or an aqueous solution thereof), and preferably hydrochloric acid, sulfuric acid , Ammonium chloride (or an aqueous solution thereof) is used.
[0034]
The amount of the acid used is not particularly limited as long as the pH value of the aqueous solution is preferably 6 to 10. In addition, it is preferable to perform addition of an acid in the range which the temperature of aqueous solution becomes 0-50 degreeC.
[0035]
The organic solvent used in the neutralization / extraction step of the present invention is not particularly limited as long as it is an organic solvent capable of extracting free β-ketonitrile contained in an aqueous solution (in the aqueous layer). For example, benzene, toluene, etc. Aromatic hydrocarbons such as ethyl acetate and butyl acetate; halogenated aliphatic hydrocarbons such as dichloromethane and dichloroethane are preferable, but aromatic hydrocarbons and acetates are more preferable, and aromatics are more preferable. Hydrocarbons are used.
[0036]
The amount of the organic solvent used is not particularly limited as long as free β-ketonitrile in the aqueous solution (in the aqueous layer) obtained by the neutralization can be extracted.
[0037]
By the neutralization / extraction step of the present invention, free β-ketonitrile is obtained in high purity as an organic solvent solution. This can be obtained by a general method such as concentration, distillation, crystallization, recrystallization, column chromatography and the like. It can be further separated and purified by the method. Since β-ketonitrile is unstable to heat, it is desirable to use a thin film distillation apparatus or a falling film distillation apparatus when separating and purifying by distillation.
[0038]
【Example】
Next, although an Example is given and this invention is demonstrated concretely, the scope of the present invention is not limited to these.
[0039]
Example 1 (Synthesis of 3-cyclopropyl-3-oxopropionitrile)
To a glass flask with an internal volume of 1000 ml equipped with a stirrer, thermometer, dropping funnel and reflux condenser, in a nitrogen atmosphere, sodium methoxide 81.0 g (1.5 mol), methyl cyclopropanecarboxylate 100.0 g (1.0 mol) and Acetonitrile 61.5 g (1.5 mol) was added, and the mixture was reacted at reflux (82 ° C.) for 6 hours.
After completion of the reaction, 400 ml of toluene was added and cooled to room temperature. While maintaining the liquid temperature at 30 ° C. or lower, 200 ml of water was slowly added dropwise with stirring, and the obtained aqueous layer was separated.
Next, while cooling the aqueous layer in an ice bath, 135 ml (1.6 mol) of 12 mol / l hydrochloric acid was added to adjust the pH of the aqueous solution to 7.0, followed by extraction three times with 200 ml of toluene, and the resulting toluene layer was saturated with carbonate. After washing with 50 ml of aqueous sodium hydrogen solution, it was dried over magnesium sulfate. After filtration, the toluene layer was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 81.1 g (reaction yield: 74%) of the desired 3-cyclopropyl-3-oxopropionitrile was a by-product. 0.45 g (0.55% by mass with respect to the target product) of 3-oxobutyronitrile and 0.15 g (0.18% by mass with respect to the target product) of pyrimidines were produced. Thereafter, the mixture was concentrated under reduced pressure to obtain 80.2 g of 3-cyclopropyl-3-oxopropionitrile having a purity of 98.2% (analyzed by high performance liquid chromatography) as a yellowish liquid (isolation yield: 72%) .
The physical properties of 3-cyclopropyl-3-oxopropionitrile were as follows.
[0040]
EI-MS (m / e); 69 (M-CH 2 CN), CI-MS (m / e); 110 (M + 1)
IR (liquid film method, cm −1 ); 3200 to 2900, 2261, 1713, 1389, 1073, 953
1 H-NMR (CDCl 3 , δ (ppm)); 1.05 to 1.15 (2H, m), 1.18 to 1.25 (2H, m), 2.06 to 2.15 (1H, m), 3.64 (2H, s)
[0041]
Comparative Example 1 (Synthesis of 3-cyclopropyl-3-oxopropionitrile: no layer separation step)
In a nitrogen atmosphere, 81.0 g (1.5 mol) of sodium methoxide, 100.0 g (1.0 mol) of methyl cyclopropanecarboxylate and 61.5 g (1.5 mol) of acetonitrile were added to the same apparatus as in Example 1 and refluxed (82 ° C. ) For 6 hours.
After completion of the reaction, 400 ml of toluene was added and cooled to room temperature. While maintaining the liquid temperature at 30 ° C. or lower, 280 ml (1.6 mol) of 6 mol / l hydrochloric acid and 100 ml of water were added to adjust the pH of the aqueous solution to 2.0, and then 200 ml of toluene. The obtained toluene layer was washed with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After filtration, the toluene layer was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 72.3 g (reaction yield: 66%) of the desired 3-cyclopropyl-3-oxopropionitrile was a by-product. 0.60 g (0.83 mass% with respect to the target product) of 3-oxobutyronitrile and 1.33 g (1.8 mass% with respect to the target product) of pyrimidines were produced. Thereafter, the mixture was concentrated under reduced pressure to obtain 77.2 g of 3-cyclopropyl-3-oxopropionitrile having a purity of 93.6% (analyzed by high performance liquid chromatography) as a yellowish liquid (isolation yield: 66%) .
[0042]
Example 2 (Synthesis of 4-methyl-3-oxopentanenitrile)
In a nitrogen atmosphere, 81.0 g (1.5 mol) of sodium methoxide, 102.1 g (1.0 mol) of methyl isobutyrate and 61.5 g (1.5 mol) of acetonitrile were added to the same apparatus as in Example 1, and the mixture was refluxed (82 ° C.). The reaction was performed for 6 hours.
After completion of the reaction, 400 ml of toluene was added and the mixture was cooled to room temperature. While maintaining the liquid temperature at 35 ° C. or lower, 200 ml of water was slowly added dropwise with stirring, and the obtained aqueous layer was separated.
Next, while cooling the aqueous layer in an ice bath, 95 ml (1.1 mol) of 12 mol / l hydrochloric acid was added to adjust the pH of the aqueous solution to 7.7, followed by extraction three times with 300 ml of toluene, and the resulting toluene layer was saturated with carbonate. After washing with 50 ml of aqueous sodium hydrogen solution, it was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 78.9 g of 4-methyl-3-oxopentanenitrile having a purity of 98.5% (area percentage by gas chromatography) as a pale yellow liquid (isolation yield 70%).
The physical properties of 4-methyl-3-oxopentanenitrile were as follows.
[0043]
EI-MS (m / e); 71 (M-CH 2 CN), CI-MS (m / e); 112 (M + 1)
IR (liquid film method, cm −1 ); 3700-3100, 3100-2800, 2263, 1725, 1468, 1389, 1306, 1048, 939
1 H-NMR (CDCl 3 , δ (ppm)); 1.18 (6H, d, J = 6.8 Hz), 2.84 (1H, m), 3.94 (2H, s)
[0044]
Example 3 (Synthesis of 4,4-dimethyl-3-oxopentanenitrile)
In a 100 mL glass flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser, in a nitrogen atmosphere, sodium methoxide 8.10 g (0.15 mol), methyl pivalate 11.62 g (1.0 mol) and acetonitrile 6.15 g (0.15 mol) was added, and the mixture was reacted at reflux (82 ° C.) for 6 hours.
After completion of the reaction, 40 ml of toluene was added and cooled to room temperature. While maintaining the liquid temperature at 35 ° C. or lower, 45 ml of water was slowly added dropwise with stirring, and the resulting aqueous layer was separated.
Next, while cooling the aqueous layer in an ice bath, 9.5 ml (0.11 mol) of 12 mol / l hydrochloric acid was added to adjust the pH of the aqueous solution to 7.7, followed by extraction three times with 30 ml of toluene, and the resulting toluene layer was saturated. After washing with 50 ml of an aqueous sodium hydrogen carbonate solution, it was dried over magnesium sulfate. After filtration, the toluene layer was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 7.25 g (reaction yield: 58%) of the desired 4,4-dimethyl-3-oxopentanenitrile was a by-product. 0.01 g (0.20% by mass with respect to the target product) of 3-oxobutyronitrile and 0.01g (0.14% by mass with respect to the target product) of pyrimidines were formed. Thereafter, the reaction mixture was concentrated under reduced pressure to obtain 7.21 g of 4,4-dimethyl-3-oxopentanenitrile having a purity of 98.4% (area percentage by high performance liquid chromatography) as a pale yellow solid (isolation yield: 58%). .
The physical properties of 4,4-dimethyl-3-oxopentanenitrile were as follows.
[0045]
EI-MS (m / e); 57 (M-COCH 2 CN), CI-MS (m / e); 126 (M + 1)
IR (liquid film method, cm −1 ); 3000-2800, 2266, 1721, 1485, 1391, 1325, 1067, 935 1 H-NMR (CDCl 3 , δ (ppm)); 1.21 (9H, s), 3.70 (2H, s)
Melting point: 67.8-68.7 ° C
[0046]
Comparative Example 2 (Synthesis of 4,4-dimethyl-3-oxopentanenitrile: no layer separation step) In the same apparatus as in Example 3, in a nitrogen atmosphere, 8.10 g (0.15 mol) of sodium methoxide, 11.62 methyl pivalate g (0.10 mol) and 6.15 g (0.15 mol) of acetonitrile were added and reacted under reflux (82 ° C.) for 6 hours.
After completion of the reaction, 40 ml of toluene was added and cooled to room temperature. While maintaining the liquid temperature at 30 ° C. or lower, 28 ml of 6 mol / l hydrochloric acid (0.16 mol) and 10 ml of water were added to adjust the pH of the aqueous solution to 2.0, and then 20 ml of toluene. The obtained toluene layer was washed with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After filtration, the toluene layer was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 7.22 g (reaction yield: 58%) of the desired 4,4-dimethyl-3-oxopentanenitrile was a by-product. 0.04 g (0.55% by mass with respect to the target product) of 3-oxobutyronitrile and 0.13 g (1.8% by mass with respect to the target product) of pyrimidines were produced. Then, it was concentrated under reduced pressure to obtain 7.63 g of 4,4-dimethyl-3-oxopentanenitrile having a purity of 94.6% (area percentage by high performance liquid chromatography) as a pale yellow liquid (isolation yield 58%) .
[0047]
【The invention's effect】
According to the present invention, there is provided an industrially suitable method for producing β-ketonitriles, which obtains β-ketonitriles with high purity and high yield from easily available aliphatic carboxylic acid esters by a simple method. I can do it.

Claims (5)

(A)金属アルコキシドの存在下、一般式(1)
(式中、R1は、脂肪族基を示し、R2は、反応に関与しない基を示す。)
で示される脂肪族カルボン酸エステル類とアセトニトリルを反応させて、一般式(2)
(式中、R1は、前記と同義であり、Xは金属原子を示す。)
で示されるβ-ケトニトリルの金属塩を合成する反応操作工程、
(B)その後、反応液に有機溶媒と水を添加・混合して、有機層と水層に層分離させて、β-ケトニトリルの金属塩を含む水層(水溶液)を得る層分離工程、
(C)次いで、層分離によって得られたβ-ケトニトリルの金属塩を含む水溶液に酸を加えて水溶液の pH 6 10 とし、有機溶媒で抽出して遊離のβ-ケトニトリルを取得する中和・抽出工程、
を含むことからなる、一般式(3)
(式中、R1は、前記と同義である。)
で示されるβ-ケトニトリル類の製法。
(A) General formula (1) in the presence of a metal alkoxide
(In the formula, R 1 represents an aliphatic group, and R 2 represents a group not involved in the reaction.)
By reacting an aliphatic carboxylic acid ester represented by general formula (2) with acetonitrile.
(In the formula, R 1 has the same meaning as described above, and X represents a metal atom.)
A reaction operation step for synthesizing a metal salt of β-ketonitrile represented by
(B) Then, an organic solvent and water are added to and mixed in the reaction solution, and the organic layer and the aqueous layer are separated into layers, thereby obtaining a water layer (aqueous solution) containing a metal salt of β-ketonitrile,
(C) Then, an acid is added to the aqueous solution containing the metal salt of β-ketonitrile obtained by layer separation to adjust the pH of the aqueous solution to 6 to 10, and extraction with an organic solvent is performed to obtain free β-ketonitrile.・ Extraction process,
General formula (3) consisting of
(In the formula, R 1 has the same meaning as described above.)
A process for producing β-ketonitriles represented by the formula:
反応操作工程において、アセトニトリルの使用量が、脂肪族カルボン酸エステル類に対して1.1〜2.5倍モルである請求項1記載のβ-ケトニトリル類の製法。  The process for producing β-ketonitriles according to claim 1, wherein in the reaction operation step, the amount of acetonitrile used is 1.1 to 2.5 times mol of the aliphatic carboxylic acid esters. 反応操作工程において、反応温度が50〜110℃である請求項1記載のβ-ケトニトリル類の製法。  The process for producing β-ketonitriles according to claim 1, wherein the reaction temperature is 50 to 110 ° C in the reaction operation step. 層分離工程において、先に有機溶媒を加えた後、攪拌しながら水を添加・混合する請求項1記載のβ-ケトニトリル類の製法。  The method for producing β-ketonitriles according to claim 1, wherein, in the layer separation step, the organic solvent is added first, and then water is added and mixed with stirring. 中和・抽出工程において、酸を加えて水溶液のpHを6〜10にする請求項1記載のβ-ケトニトリル類の製法。  The process for producing β-ketonitriles according to claim 1, wherein an acid is added to adjust the pH of the aqueous solution to 6 to 10 in the neutralization / extraction step.
JP2001322935A 2000-12-22 2001-10-22 Process for producing β-ketonitriles Expired - Lifetime JP4030289B2 (en)

Priority Applications (3)

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