JP2004002307A - Method for producing intermediate of retinol derivative - Google Patents

Method for producing intermediate of retinol derivative Download PDF

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Publication number
JP2004002307A
JP2004002307A JP2003033322A JP2003033322A JP2004002307A JP 2004002307 A JP2004002307 A JP 2004002307A JP 2003033322 A JP2003033322 A JP 2003033322A JP 2003033322 A JP2003033322 A JP 2003033322A JP 2004002307 A JP2004002307 A JP 2004002307A
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chloride
formula
general formula
group
alkali metal
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JP4250970B2 (en
JP2004002307A5 (en
Inventor
Naoto Konya
紺矢 直人
Toshiya Takahashi
高橋 寿也
Shinzo Seko
世古 信三
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing e.g. a vitamin A as an intermediate of pharmaceuticals, feed additives or food additives, for example, an intermediate of retinol derivatives. <P>SOLUTION: The method for producing the intermediate, a sulfone compound of general formula(3)( wherein, R<SP>1</SP>is H or an OH-protecting group; and Ar and the wavy line mean as described below respectively ) and/or a triene compound of general formula(4), comprises carrying out a reaction between an arylsulfone derivative of general formula(1)[ wherein, Ar is a (substituted) aryl ] and an allyl halide derivative of general formula(2)( wherein, X is a halogen atom; R is an OH-protecting group; and the wavy line indicates that the allyl halide derivative represents one or both of E/Z geometric isomers ) in the presence of an alkali metal hydroxide. <P>COPYRIGHT: (C)2004,JPO

Description

【0001】
【発明の属する技術分野】
本発明は、医薬、飼料添加物、食品添加物の中間体、例えばレチノール誘導体の中間体として有用な化合物の製造方法に関する。
【0002】
【従来の技術および発明が解決しようとする課題】
従来、塩基の存在下、スルホン誘導体とアルデヒド、アリルハライドなどの求電子剤との反応により新規な炭素炭素結合を生成させる反応は、ジュリアカップリングとして幅広く利用されてきた。しかし、ジュリアカップリングではn−ブチルリチウムやカリウムt−ブトキシドなどの高価かつ工業的に取り扱いの難しい強塩基が必要な場合が多く安価なアルカリ金属水酸化物を用いた例は少ない。特に、本発明の下記アリールスルホン誘導体(1)とアリルハライド誘導体(2)との反応では、知られていなかった。
【0003】
【課題を解決するための手段】
このような状況下、本発明者らは、上記課題を解決するために鋭意検討した結果、下記アリールスルホン誘導体(1)とアリルハライド誘導体(2)とをアルカリ金属水酸化物の存在下、反応させることにより、新規な炭素炭素結合を生成させることができることを見出し、本発明に至った。
【0004】
すなわち、本発明は、一般式(1)

Figure 2004002307
(式中、Arは置換基を有していてもよいアリール基を示す。)
で示されるアリールスルホン誘導体と一般式(2)
Figure 2004002307
(式中、Xはハロゲン原子、Rは水酸基の保護基を示し、波線はE/Z幾何異性体のいずれか一方もしくはそれらの混合物であることを示す。)
で示されるアリルハライド誘導体とをアルカリ金属水酸化物の存在下に反応させることを特徴とする一般式(3)
Figure 2004002307
(式中、Rは水素原子または水酸基の保護基を示し、Arおよび波線は前記と同じ意味を表す。)
で示されるスルホン化合物および/または、一般式(4)
Figure 2004002307
(式中、Rおよび波線は前記と同じ意味を表す。)
で示されるトリエン化合物の製造方法を提供するものである。
【0005】
【発明の実施の形態】
以下、本発明について詳細に説明する。
一般式(2)で示されるアリルハライド誘導体におけるRは水酸基の保護基を示し、一般式(3)および(4)で示される化合物におけるRは、水素原子または水酸基の保護基を示す。かかる水酸基の保護基としては、例えばホルミル、アセチル、エトキシアセチル、フルオロアセチル、ジフルオロアセチル、トリフルオロアセチル、クロロアセチル、ジクロロアセチル、トリクロロアセチル、ブロモアセチル、ジブロモアセチル、トリブロモアセチル、プロピオニル、2−クロロプロピオニル、3−クロロプロピオニル、ブチリル、2−クロロブチリル、3−クロロブチリル、4−クロロブチリル、2−メチルブチリル、2−エチルブチリル、バレリル、2−メチルバレリル、4−メチルバレリル、ヘキサノイル、イソブチリル、イソバレリル、ピバロイル、ベンゾイル、o−クロロベンゾイル、m−クロロベンゾイル、p−クロロベンゾイル、o−ヒドロキシベンゾイル、m−ヒドロキシベンゾイル、p−ヒドロキシベンゾイル、o−アセトキシベンゾイル、o−メトキシベンゾイル、m−メトキシベンゾイル、p−メトキシベンゾイル、p−ニトロベンゾイル等のアシル基、トリメチルシリル、トリエチルシリル、t−ブチルジメチルシリル、t−ブチルジフェニルシリルなどのシリル基、テトラヒドロピラニル、メトキシメチル、メトキシエトキシメチル、1−エトキシエチルなどのアルコキシメチル基、ベンジル基、p−メトキシベンジル基、t−ブチル基、トリチル基、2,2,2−トリクロロエトキシカルボニル基、アリルオキシカルボニル基等が挙げられ、アシル基が好ましく、特にアセチル基が好ましく用いられる。
【0006】
一般式(1)および(3)で示される化合物におけるArは、置換基を有してもよいアリール基を示し、アリール基としてはフェニル基、ナフチル基等が挙げられ、置換基としては、C1からC5の直鎖または分枝状のアルキル基、C1からC5の直鎖または分枝状のアルコキシ基、ハロゲン原子、ニトロ基等が挙げられる。
置換基Arの具体例としては、フェニル、ナフチル、o−トリル、m−トリル、p−トリル、o−メトキシフェニル、m−メトキシフェニル、p−メトキシフェニル、o−クロロフェニル、m−クロロフェニル、p−クロロフェニル、o−ブロモフェニル、m−ブロモフェニル、p−ブロモフェニル、o−ヨードフェニル、m−ヨードフェニル、p−ヨードフェニル、o−フルオロフェニル、m−フルオロフェニル、p−フルオロフェニル、o−ニトロフェニル、m−ニトロフェニル、p−ニトロフェニル等が挙げられる。
【0007】
一般式(2)で示されるアリルハライド誘導体におけるXはハロゲン原子を示し、具体的には塩素原子、臭素原子、沃素原子等が挙げられる。
【0008】
本発明の原料化合物であるアリールスルホン誘導体(1)はChem.Lett. 479(1975)に記載された方法により、またアリルハライド誘導体(2)は、米国特許US4175204(1979)に記載された方法により容易に製造することができる。
【0009】
上記反応に用いられるアルカリ金属水酸化物としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化セシウムが挙げられ、好ましくは、水酸化カリウムが用いられる。それらを有機溶媒中で不均一系にて使用することにより、反応を効率よく進行させることができる。かかるアルカリ金属水酸化物は通常、乾式粉砕により粉末状にすることにより、反応を有効に促進することができる。使用するアルカリ金属水酸化物の粒子径は通常、1000μm以下程度、好ましくは500μm以下程度、より好ましくは250μm程度、さらに好ましくは100μm以下程度である。下限値は特に限定されないが20μm程度である。
その使用量はアリールスルホン誘導体(1)に対して通常、1〜50モル倍程度、好ましくは5〜20モル倍程度である。かかるアルカリ金属水酸化物の純度は好ましくは90%以上であり、より好ましくは95%以上である。
使用するアルカリ金属の水酸化物の活性化のために、溶媒等の条件にも依存するが、水を共存させる方が好ましい場合もある。水の添加量はアリールスルホン誘導体(1)に対して通常0.01〜1モル倍程度であり、好ましくは0.05〜0.5モル倍である。
【0010】
上記反応には相間移動触媒を用いることができ、例えば、第4級アンモニウム塩、第4級ホスホニウム塩、スルホニウム塩等が挙げられ、好ましくは、第4級アンモニウム塩が挙げられる。
第4級アンモニウム塩としては、例えば、塩化テトラメチルアンモニウム、塩化テトラエチルアンモニウム、塩化テトラプロピルアンモニウム、塩化テトラブチルアンモニウム、塩化テトラペンチルアンモニウム、塩化テトラヘキシルアンモニウム、塩化テトラヘプチルアンモニウム、塩化テトラオクチルアンモニウム、塩化トリオクチルメチルアンモニウム、塩化テトラデシルアンモニウム、塩化トリデシルメチルアンモニウム、塩化ジデシルジメチルアンモニウム、塩化テトラドデシルアンモニウム、塩化トリドデシルメチルアンモニウム、塩化ジドデシルジメチルアンモニウム、塩化ドデシルトリメチルアンモニウム、塩化ドデシルトリエチルアンモニウム、塩化テトラヘキサデシルアンモニウム、塩化ヘキサデシルトリメチルアンモニウム、塩化ヘキサデシルジメチルエチルアンモニウム、塩化テトラオクタデシルアンモニウム、塩化オクタデシルトリメチルアンモニウム、塩化オクタデシルトリエチルアンモニウム、塩化ベンジルトリメチルアンモニウム、塩化ベンジルトリエチルアンモニウム、塩化ベンジルトリブチルアンモニウム、塩化1−メチルピリジニウム、塩化1−ヘキサデシルピリジニウム、塩化1,4−ジメチルピリジニウム、塩化トリメチルシクロプロピルアンモニウム、あるいはこれら塩化物塩が、それぞれ対応する臭化物塩、沃化物塩、硫酸水素塩となった化合物等が挙げられる。
【0011】
第4級ホスホニウム塩としては、例えば、塩化トリブチルメチルホスホニウム、塩化トリエチルメチルホスホニウム、塩化メチルトリフェノキシホスホニウム、塩化ブチルトリフェニルホスホニウム、塩化テトラブチルホスホニウム、塩化ベンジルトリフェニルホスホニウム、塩化テトラオクチルホスホニウム、塩化ヘキサデシルトリメチルホスホニウム、塩化ヘキサデシルトリブチルホスホニウム、塩化ヘキサデシルジメチルエチルホスホニウム、塩化テトラフェニルホスホニウム、あるいはこれら塩化物塩が、それぞれ対応する臭化物塩、沃化物塩となった化合物等が挙げられる。
【0012】
スルホニウム塩としては、例えば、塩化ベンジルメチルエチルスルホニウム、塩化ベンジルジメチルスルホニウム、塩化ベンジルジエチルスルホニウム、塩化ジブチルメチルスルホニウム、塩化トリメチルスルホニウム、塩化トリエチルスルホニウム、塩化トリブチルスルホニウム、あるいはこれら塩化物塩が、それぞれ対応する臭化物塩、沃化物塩となった化合物等が挙げられる。
【0013】
特に第4級アンモニウム塩が好ましく、特に炭化水素系溶媒を用いる場合は、炭素数10〜20の第4級アンモニウム塩がより好ましい。
【0014】
かかる相間移動触媒の使用量は、アリールスルホン誘導体(1)に対して通常0.01〜0.2モル倍程度であり、好ましくは0.02〜0.1モル倍程度である。
【0015】
上記反応は、通常、有機溶媒中で実施され、アルカリ金属水酸化物が完溶せず、不均一に存在できる溶媒が好ましい。使用される溶媒としてはジエチルエーテル、テトラヒドロフラン、1,4−ジオキサン、アニソール、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテル、トリエチレングリコールジメチルエーテル等のエーテル系溶媒、n−ヘキサン、シクロヘキサン、n−ペンタン、ベンゼン、トルエン、キシレン等の炭化水素系溶媒などが挙げられる。これらは単一であっても2種以上の混合溶媒で使用してもよい。
【0016】
反応温度は通常、−78℃から溶媒の沸点までの範囲内で任意に選択できるが、好ましくは−25〜55℃程度の範囲である。また、反応時間は、用いる塩基の種類ならびに反応温度によって異なるが、通常0.5時間から24時間程度の範囲である。
反応後、通常の後処理、例えば水洗浄、抽出、晶析、各種クロマトグラフィーなどの操作をすることによりスルホン化合物(3)および/またはトリエン化合物(4)を製造することができる。
【0017】
【発明の効果】
本発明によれば、安価で取り扱い容易なアルカリ金属水酸化物を用いて、アリールスルホン誘導体(1)とアリルハライド誘導体(2)とのカップリング生成物を製造することができ、工業的観点から優れている。
本発明により得られるスルホン化合物(3)および/またはトリエン化合物(4)は、下記スキームに従って、ビタミンA(レチノール)へ誘導することができる。すなわち、スルホン化合物(3)および/またはトリエン化合物(4)をアルカリ金属のアリールスルフィン酸塩を使用してスルホン化反応に供し、スルホン誘導体(5)を得、該誘導体にアリルハライド誘導体(2)を反応させ得られるスルホン誘導体(6)を塩基と反応させることによりビタミンAが得られる(EP1199303A1など参照)。
Figure 2004002307
(式中、●印は結合部位を表す)
【0018】
【実施例】
以下、実施例により、本発明をさらに詳細に説明するが、本発明はこれらにより限定されるものではない。
【0019】
(実施例1)
窒素置換した遮光容器に、乾式粉砕により調製した粒子径500μm以下の粉末状の水酸化カリウム 940.0mg(純度95.5%、16mmol)および硫酸水素テトラ−n−ブチルアンモニウム 36.0mg(0.11mmol)を加え、再度窒素置換をおこなった。脱水テトラヒドロフラン 2mlを加え、0℃に冷却した。このスラリーに、アリールスルホン(I) 300.8mg(純度 99.5%、1.0mmol)およびアリルブロマイド(II)500.0mg(純度86.7%、2.1mmol、cis/trans=2/98)を脱水テトラヒドロフラン 2mlに溶解させた溶液を滴下し、0℃のまま3時間攪拌した。反応混合物を、冷却した塩化アンモニウム水溶液と塩化ナトリウム水溶液の混合溶液に加え反応のクエンチをおこない、トルエンで抽出をおこなった。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過の後、エバポレーターで濃縮をおこない黄橙色油状の粗生成物554.6mgを得た。粗生成物を液体クロマトグラフィーにて定量したところ、アリールスルホン(IV)および(V)の収率はそれぞれ77%(cis/trans=1/99)および3%(cis/trans=10/90)であり、目的化合物の合計収率は80%であった。
【0020】
(実施例2)
窒素置換した遮光容器に、乾式粉砕により調製した粒子径500μm以下の粉末状の水酸化カリウム 1175mg(純度95.5%、20mmol)および臭化テトラn−ブチルアンモニウム 32.2mg(0.1mmol)を加え、再度窒素置換をおこなった。アリールスルホン(I) 300.8mg(純度 99.5%、1.0mmol)およびアリルブロマイド(II)500.0mg(純度86.7%、2.1mmol、cis/trans=2/98)を脱水テトラヒドロフラン 2.5mlに溶解させた溶液を20℃で滴下し、20℃のまま0.5時間攪拌した。反応混合物を、冷却した塩化アンモニウム水溶液と塩化ナトリウム水溶液の混合溶液に加え反応のクエンチをおこない、酢酸エチルで抽出をおこなった。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過の後、エバポレーターで濃縮をおこない黄橙色油状の粗生成物554.6mgを得た。粗生成物を液体クロマトグラフィーにて定量したところ、アリールスルホン(IV)および(V)の収率はそれぞれ68%(cis/trans=1/99)および3%(cis/trans=10/90)であり、目的化合物の合計収率は71%であった。
【0021】
(実施例3)
窒素置換した遮光容器に、アリールスルホン(I) 300.8mg(純度 99.5%、1.0mmol)および塩化トリエチルベンジルアンモニウム 11.5mg(0.05mmol)を加え、再度窒素置換をおこなった。水分量500ppmに調製したエチレングリコールジメチルエーテル2mlを加え、−20℃に冷却した。このスラリーに、アリルクロライド(III)209.6mg(純度93.1%、1.2mmol、cis/trans=9/91)を水分量500ppmに調製したエチレングリコールジメチルエーテル2mlに溶解させた溶液を滴下し、続いて乾式粉砕により調製した粒子径90μm以下の粉末状の水酸化カリウム587.4mg(純度95.5%、10mmol)を一気に加え、−20℃のまま2.5時間攪拌した。反応混合物を、冷却した塩化アンモニウム水溶液と塩化ナトリウム水溶液の混合溶液に加え反応のクエンチをおこない、トルエンで抽出をおこなった。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過の後、粗生成物を液体クロマトグラフィーにて定量したところ、アリールスルホン(IV)およびトリエン(VI)の収率はそれぞれ67%(cis/trans=16/84)および0.7%(cis/trans=0/100)の収率であり、目的化合物の合計収率は68%であった。
【0022】
(実施例4)
窒素置換した遮光容器に、アリールスルホン(I) 300.8mg(純度 99.5%、1.0mmol)および硫酸水素テトラ−n−ブチルアンモニウム 34.6mg(0.1mmol)を加え、再度窒素置換をおこなった。水分量3000ppmに調製したテトラヒドロフラン2mlを加え、0℃に冷却した。このスラリーに、アリルクロライド(III)209.6mg(純度93.1%、1.2mmol、cis/trans=9/91)を水分量3000ppmに調製したテトラヒドロフラン2mlに溶解させた溶液を滴下し、続いて乾式粉砕により調製した粒子径90μm以下の粉末状の水酸化カリウム956.3mg(純度95.5%、15mmol)を一気に加え、0℃のまま4時間攪拌した。反応混合物を、冷却した塩化アンモニウム水溶液と塩化ナトリウム水溶液の混合溶液に加え反応のクエンチをおこない、トルエンで抽出をおこなった。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過の後、粗生成物を液体クロマトグラフィーにて定量したところ、アリールスルホン(V)、(IV)およびトリエン(V)、(VII)の収率はそれぞれ41%(cis/trans=16/84)、0.2%および0.7%、0.3%(cis/trans=0/100)の収率であり、目的化合物の合計収率は42%であった。
【0023】
(実施例5)
窒素置換した反応容器に、アリルクロライド(III)0.22g(純度91.8%、1.2mmol)、臭化テトラ−n−ブチルアンモニウム31.4mg(0.1mmol)およびアリールスルホン(I)298.9mg(純度99.45%、1.0mmol)を加えた。水分量1200ppmに調製したエチレングリコールジメチルエーテル4mlを加え、0℃に冷却した。ここに乾式粉砕により調製した粒子径90μm以下の粉末状の水酸化カリウム0.90g(純度95.5%、15mmol)を一気に加え、0℃のまま2時間攪拌した。実施例1と同様の後処理により、粗生成物0.31gを得た。粗生成物を液体クロマトグラフィーにて定量したところ、トリエン(VI)および(VII)の収率は3%および44%であり、目的化合物の合計収率は47%であった。
【0024】
(実施例6)
窒素置換した反応容器に、アリルクロライド(III)0.42g(純度93.1%、2.4mmol)、臭化テトラ−n−ブチルアンモニウム23.2mg(0.1mmol)およびアリールスルホン(I)0.29mg(純度99.5%、1.0mmol)を加えた。水分量500ppmに調製したエチレングリコールジメチルエーテル4mlを加え、−20℃に冷却した。ここに乾式粉砕により調製した粒子径90μm以下の粉末状の水酸化カリウム1.18g(純度95.5%、20mmol)を一気に加え、−20℃のまま3.5時間攪拌した。実施例1と同様の後処理により、粗生成物0.71gを得た。粗生成物を液体クロマトグラフィーにて定量したところ、アリールスルホン(IV)およびトリエン(VI)の収率はそれぞれ90%(cis/trans=18/82)および1.9%(cis/trans=30/70)であり、目的化合物の合計収率は92%であった。
【0025】
(実施例7)
窒素置換した反応容器に、アリルクロライド(III)0.21g(純度93.1%、1.2mmol)、臭化ミリスチルトリメチルアンモニウム34.0mg(0.1mmol)およびアリールスルホン(I)0.29g(純度99.5%、1.0mmol)を加えた。水分量1000ppmに調製したトルエン4mlを加え、ここに乾式粉砕により調製した粒子径90μm以下の粉末状の水酸化カリウム1.18g(純度95.5%、20mmol)を一気に加え、50℃に昇温し、6時間攪拌した。実施例1と同様の後処理により、粗生成物0.69gを得た。粗生成物を液体クロマトグラフィーにて定量したところ、アリールスルホン(IV)およびトリエン(VI)の収率はそれぞれ60%(cis/trans=12/88)および5%(cis/trans=4/96)であり、目的化合物の合計収率は65%であった。
【0026】
以下に実施例および参考例の化合物の構造式を記す。
但し、Tsは、p−トリルスルホニル基を示し、Acはアセチル基を示す。
Figure 2004002307
[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing a compound useful as an intermediate of a pharmaceutical, feed additive, or food additive, for example, an intermediate of a retinol derivative.
[0002]
2. Description of the Related Art
Conventionally, a reaction for generating a novel carbon-carbon bond by reacting a sulfone derivative with an electrophile such as an aldehyde or an allyl halide in the presence of a base has been widely used as Julia coupling. However, Julia coupling often requires a strong base that is expensive and difficult to handle industrially, such as n-butyllithium and potassium t-butoxide, and there are few examples using inexpensive alkali metal hydroxides. In particular, the reaction of the following aryl sulfone derivative (1) of the present invention with an allyl halide derivative (2) has not been known.
[0003]
[Means for Solving the Problems]
Under these circumstances, the present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, the following arylsulfone derivative (1) and allyl halide derivative (2) were reacted in the presence of an alkali metal hydroxide. By doing so, it was found that a new carbon-carbon bond can be generated, and the present invention has been accomplished.
[0004]
That is, the present invention relates to the general formula (1)
Figure 2004002307
(In the formula, Ar represents an aryl group which may have a substituent.)
And a general formula (2)
Figure 2004002307
(In the formula, X represents a halogen atom, R represents a protecting group for a hydroxyl group, and a wavy line represents any one of E / Z geometric isomers or a mixture thereof.)
Reacting with an allyl halide derivative represented by the formula (3) in the presence of an alkali metal hydroxide:
Figure 2004002307
(In the formula, R 1 represents a hydrogen atom or a hydroxyl-protecting group, and Ar and wavy lines represent the same meaning as described above.)
And / or a general formula (4)
Figure 2004002307
(In the formula, R 1 and a wavy line represent the same meaning as described above.)
And a method for producing a triene compound represented by the formula:
[0005]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail.
R in the allyl halide derivative represented by the general formula (2) represents a protecting group for a hydroxyl group, and R 1 in the compounds represented by the general formulas (3) and (4) represents a hydrogen atom or a protecting group for a hydroxyl group. Examples of such a hydroxyl-protecting group include formyl, acetyl, ethoxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl, tribromoacetyl, propionyl, 2-chloro Propionyl, 3-chloropropionyl, butyryl, 2-chlorobutyryl, 3-chlorobutyryl, 4-chlorobutyryl, 2-methylbutyryl, 2-ethylbutyryl, valeryl, 2-methylvaleryl, 4-methylvaleryl, hexanoyl, isobutyryl, isovaleryl, pivaloyl, benzoyl, o -Chlorobenzoyl, m-chlorobenzoyl, p-chlorobenzoyl, o-hydroxybenzoyl, m-hydroxybenzoyl, p-hydroxyben Acyl groups such as yl, o-acetoxybenzoyl, o-methoxybenzoyl, m-methoxybenzoyl, p-methoxybenzoyl and p-nitrobenzoyl; silyls such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl Group, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl, 1-ethoxyethyl, etc., alkoxymethyl group, benzyl group, p-methoxybenzyl group, t-butyl group, trityl group, 2,2,2-trichloroethoxycarbonyl group And an allyloxycarbonyl group. An acyl group is preferred, and an acetyl group is particularly preferred.
[0006]
Ar in the compounds represented by the general formulas (1) and (3) represents an aryl group which may have a substituent. Examples of the aryl group include a phenyl group and a naphthyl group. To C5 linear or branched alkyl groups, C1 to C5 linear or branched alkoxy groups, halogen atoms, nitro groups, and the like.
Specific examples of the substituent Ar include phenyl, naphthyl, o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m-chlorophenyl, p-toluene Chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, p-iodophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitro Phenyl, m-nitrophenyl, p-nitrophenyl and the like.
[0007]
X in the allyl halide derivative represented by the general formula (2) represents a halogen atom, and specific examples include a chlorine atom, a bromine atom, and an iodine atom.
[0008]
The arylsulfone derivative (1) as the starting compound of the present invention is described in Chem. Lett. 479 (1975), and the allyl halide derivative (2) can be easily produced by the method described in US Pat. No. 4,175,204 (1979).
[0009]
Examples of the alkali metal hydroxide used in the above reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, and preferably, potassium hydroxide is used. By using them in an organic solvent in a heterogeneous system, the reaction can proceed efficiently. The reaction can be effectively promoted by making the alkali metal hydroxide into a powder by dry pulverization. The particle diameter of the alkali metal hydroxide used is usually about 1000 μm or less, preferably about 500 μm or less, more preferably about 250 μm, and further preferably about 100 μm or less. The lower limit is not particularly limited, but is about 20 μm.
The amount of use is usually about 1 to 50 mol times, preferably about 5 to 20 mol times with respect to the aryl sulfone derivative (1). The purity of such an alkali metal hydroxide is preferably at least 90%, more preferably at least 95%.
The activation of the alkali metal hydroxide to be used depends on the conditions of the solvent and the like, but it is sometimes preferable to coexist with water. The amount of water to be added is generally about 0.01 to 1 mol, preferably 0.05 to 0.5 mol, per mol of the aryl sulfone derivative (1).
[0010]
A phase transfer catalyst can be used in the above reaction, and examples thereof include quaternary ammonium salts, quaternary phosphonium salts, and sulfonium salts, and preferably, quaternary ammonium salts.
Examples of the quaternary ammonium salt include tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetrapentylammonium chloride, tetrahexylammonium chloride, tetraheptylammonium chloride, tetraoctylammonium chloride, and tetraoctylammonium chloride. Trioctylmethylammonium, tetradecylammonium chloride, tridecylmethylammonium chloride, didecyldimethylammonium chloride, tetradodecylammonium chloride, tridodecylmethylammonium chloride, didodecyldimethylammonium chloride, dodecyltrimethylammonium chloride, dodecyltriethylammonium chloride, chloride Tetrahexadecyl ammonium, hexadecyltrimethylammonium chloride Ium, hexadecyldimethylethylammonium chloride, tetraoctadecylammonium chloride, octadecyltrimethylammonium chloride, octadecyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, 1-methylpyridinium chloride, 1-hexadecyl chloride Examples include pyridinium, 1,4-dimethylpyridinium chloride, trimethylcyclopropylammonium chloride, and compounds in which these chloride salts have been converted to the corresponding bromide, iodide, and hydrogen sulfate salts.
[0011]
As the quaternary phosphonium salt, for example, tributylmethylphosphonium chloride, triethylmethylphosphonium chloride, methyltriphenoxyphosphonium chloride, butyltriphenylphosphonium chloride, tetrabutylphosphonium chloride, benzyltriphenylphosphonium chloride, tetraoctylphosphonium chloride, hexahexyl chloride Examples include decyltrimethylphosphonium, hexadecyltributylphosphonium chloride, hexadecyldimethylethylphosphonium chloride, tetraphenylphosphonium chloride, and compounds obtained by converting these chloride salts into the corresponding bromide salts and iodide salts.
[0012]
Examples of the sulfonium salt include, for example, benzylmethylethylsulfonium chloride, benzyldimethylsulfonium chloride, benzyldiethylsulfonium chloride, dibutylmethylsulfonium chloride, trimethylsulfonium chloride, triethylsulfonium chloride, tributylsulfonium chloride, and chloride salts thereof, respectively. Compounds converted into bromide salts and iodide salts are exemplified.
[0013]
Particularly, a quaternary ammonium salt is preferable, and particularly when a hydrocarbon solvent is used, a quaternary ammonium salt having 10 to 20 carbon atoms is more preferable.
[0014]
The amount of the phase transfer catalyst to be used is generally about 0.01 to 0.2 mol times, preferably about 0.02 to 0.1 mol times, relative to the arylsulfone derivative (1).
[0015]
The above reaction is usually carried out in an organic solvent, and a solvent in which the alkali metal hydroxide is not completely dissolved and which can exist unevenly is preferable. As the solvent used, diethyl ether, tetrahydrofuran, 1,4-dioxane, anisole, ether solvents such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, n-hexane, cyclohexane, n-pentane, benzene, toluene, Examples include hydrocarbon solvents such as xylene. These may be used alone or in a mixture of two or more.
[0016]
The reaction temperature can be arbitrarily selected within the range of -78 ° C to the boiling point of the solvent, but is preferably in the range of about -25 to 55 ° C. The reaction time varies depending on the type of base used and the reaction temperature, but is usually in the range of about 0.5 to 24 hours.
After the reaction, the sulfone compound (3) and / or the triene compound (4) can be produced by ordinary post-treatments such as washing with water, extraction, crystallization, and various kinds of chromatography.
[0017]
【The invention's effect】
ADVANTAGE OF THE INVENTION According to this invention, the coupling product of an aryl sulfone derivative (1) and an allyl halide derivative (2) can be manufactured using an alkali metal hydroxide which is inexpensive and easy to handle. Are better.
The sulfone compound (3) and / or the triene compound (4) obtained according to the present invention can be derived into vitamin A (retinol) according to the following scheme. That is, the sulfone compound (3) and / or the triene compound (4) are subjected to a sulfonation reaction using an alkali metal arylsulfinate salt to obtain a sulfone derivative (5), and the derivative is an allyl halide derivative (2). Vitamin A can be obtained by reacting the sulfone derivative (6) obtained by the reaction with a base (see EP1199303A1 and the like).
Figure 2004002307
(In the formula, ● represents a binding site)
[0018]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
[0019]
(Example 1)
In a light-shielded container purged with nitrogen, 940.0 mg (purity: 95.5%, 16 mmol) of powdery potassium hydroxide having a particle diameter of 500 μm or less and 36.0 mg (0.4%) of tetra-n-butylammonium hydrogen sulfate prepared by dry grinding. 11 mmol), and the atmosphere was replaced with nitrogen again. 2 ml of dehydrated tetrahydrofuran was added and cooled to 0 ° C. To this slurry, 300.8 mg (purity 99.5%, 1.0 mmol) of aryl sulfone (I) and 500.0 mg (purity 86.7%, 2.1 mmol, cis / trans = 2/98) of allyl bromide (II) were added. ) In 2 ml of dehydrated tetrahydrofuran was added dropwise, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was added to a cooled mixed solution of an aqueous ammonium chloride solution and an aqueous sodium chloride solution to quench the reaction, followed by extraction with toluene. The organic layer was washed with saturated saline, dried over sodium sulfate, filtered, and then concentrated by an evaporator to obtain 554.6 mg of a crude product as a yellow-orange oil. When the crude product was quantified by liquid chromatography, the yields of the aryl sulfones (IV) and (V) were 77% (cis / trans = 1/99) and 3% (cis / trans = 10/90), respectively. And the total yield of the target compound was 80%.
[0020]
(Example 2)
In a light-shielded container purged with nitrogen, 1175 mg (purity 95.5%, 20 mmol) of powdery potassium hydroxide having a particle diameter of 500 μm or less and 32.2 mg (0.1 mmol) of tetra-n-butylammonium bromide prepared by dry pulverization were prepared. In addition, nitrogen replacement was performed again. 300.8 mg (purity 99.5%, 1.0 mmol) of aryl sulfone (I) and 500.0 mg (purity 86.7%, 2.1 mmol, cis / trans = 2/98) of allyl bromide (II) were dehydrated in dehydrated tetrahydrofuran. A solution dissolved in 2.5 ml was added dropwise at 20 ° C., and the mixture was stirred at 20 ° C. for 0.5 hour. The reaction mixture was added to a cooled mixed solution of an aqueous ammonium chloride solution and an aqueous sodium chloride solution to quench the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, filtered, and then concentrated by an evaporator to obtain 554.6 mg of a crude product as a yellow-orange oil. When the crude product was quantified by liquid chromatography, the yields of the aryl sulfones (IV) and (V) were 68% (cis / trans = 1/99) and 3% (cis / trans = 10/90), respectively. And the total yield of the target compound was 71%.
[0021]
(Example 3)
300.8 mg of arylsulfone (I) (purity 99.5%, 1.0 mmol) and 11.5 mg (0.05 mmol) of triethylbenzylammonium chloride were added to the nitrogen-shielded light-tight container, and the atmosphere was replaced with nitrogen again. 2 ml of ethylene glycol dimethyl ether adjusted to a water content of 500 ppm was added, and the mixture was cooled to -20 ° C. To this slurry, a solution prepared by dissolving 209.6 mg of allyl chloride (III) (purity 93.1%, 1.2 mmol, cis / trans = 9/91) in 2 ml of ethylene glycol dimethyl ether adjusted to a water content of 500 ppm was added dropwise. Subsequently, 587.4 mg (purity: 95.5%, 10 mmol) of powdered potassium hydroxide having a particle diameter of 90 μm or less prepared by dry pulverization was added all at once, and the mixture was stirred at −20 ° C. for 2.5 hours. The reaction mixture was added to a cooled mixed solution of an aqueous ammonium chloride solution and an aqueous sodium chloride solution to quench the reaction, followed by extraction with toluene. The organic layer was washed with saturated saline, dried over sodium sulfate, and filtered, and then the crude product was quantified by liquid chromatography. The yield of arylsulfone (IV) and triene (VI) was 67% ( cis / trans = 16/84) and 0.7% (cis / trans = 0/100), and the total yield of the target compound was 68%.
[0022]
(Example 4)
300.8 mg (purity 99.5%, 1.0 mmol) of arylsulfone (I) and 34.6 mg (0.1 mmol) of tetra-n-butylammonium hydrogen sulfate were added to the light-tight container purged with nitrogen, and the nitrogen purge was performed again. I did it. 2 ml of tetrahydrofuran adjusted to a water content of 3000 ppm was added, and the mixture was cooled to 0 ° C. To this slurry, a solution prepared by dissolving 209.6 mg of allyl chloride (III) (purity 93.1%, 1.2 mmol, cis / trans = 9/91) in 2 ml of tetrahydrofuran adjusted to a water content of 3000 ppm was added dropwise. 956.3 mg (purity: 95.5%, 15 mmol) of powdered potassium hydroxide having a particle diameter of 90 μm or less prepared by dry pulverization was added all at once, and the mixture was stirred at 0 ° C. for 4 hours. The reaction mixture was added to a cooled mixed solution of an aqueous ammonium chloride solution and an aqueous sodium chloride solution to quench the reaction, followed by extraction with toluene. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, and filtered. After quantification of the crude product by liquid chromatography, arylsulfone (V), (IV) and triene (V), (VII) Are the yields of 41% (cis / trans = 16/84), 0.2% and 0.7%, and 0.3% (cis / trans = 0/100), respectively. The yield was 42%.
[0023]
(Example 5)
In a reaction vessel purged with nitrogen, 0.22 g (purity 91.8%, 1.2 mmol) of allyl chloride (III), 31.4 mg (0.1 mmol) of tetra-n-butylammonium bromide and arylsulfone (I) 298 0.9 mg (purity 99.45%, 1.0 mmol) was added. 4 ml of ethylene glycol dimethyl ether adjusted to a water content of 1200 ppm was added, and the mixture was cooled to 0 ° C. 0.90 g (purity: 95.5%, 15 mmol) of powdered potassium hydroxide having a particle diameter of 90 μm or less prepared by dry pulverization was added thereto at once, and the mixture was stirred at 0 ° C. for 2 hours. By the same post-treatment as in Example 1, 0.31 g of a crude product was obtained. When the crude product was quantified by liquid chromatography, the yields of trienes (VI) and (VII) were 3% and 44%, and the total yield of the target compound was 47%.
[0024]
(Example 6)
In a reaction vessel purged with nitrogen, 0.42 g (purity 93.1%, 2.4 mmol) of allyl chloride (III), 23.2 mg (0.1 mmol) of tetra-n-butylammonium bromide and arylsulfone (I) 0 .29 mg (99.5% purity, 1.0 mmol) were added. 4 ml of ethylene glycol dimethyl ether adjusted to a water content of 500 ppm was added, and the mixture was cooled to -20 ° C. To this, 1.18 g (purity: 95.5%, 20 mmol) of powdery potassium hydroxide having a particle size of 90 μm or less prepared by dry pulverization was added all at once, and the mixture was stirred at −20 ° C. for 3.5 hours. By the same post-treatment as in Example 1, 0.71 g of a crude product was obtained. When the crude product was quantified by liquid chromatography, the yields of arylsulfone (IV) and triene (VI) were 90% (cis / trans = 18/82) and 1.9% (cis / trans = 30, respectively). / 70), and the total yield of the target compound was 92%.
[0025]
(Example 7)
In a reaction vessel purged with nitrogen, 0.21 g (purity 93.1%, 1.2 mmol) of allyl chloride (III), 34.0 mg (0.1 mmol) of myristyltrimethylammonium bromide, and 0.29 g of arylsulfone (I) ( Purity 99.5%, 1.0 mmol) was added. 4 ml of toluene adjusted to a water content of 1000 ppm was added, and 1.18 g (purity: 95.5%, 20 mmol) of powdery potassium hydroxide having a particle diameter of 90 μm or less prepared by dry pulverization was added at a stretch, and the temperature was raised to 50 ° C. And stirred for 6 hours. The same post-treatment as in Example 1 yielded 0.69 g of a crude product. When the crude product was quantified by liquid chromatography, the yields of arylsulfone (IV) and triene (VI) were 60% (cis / trans = 12/88) and 5% (cis / trans = 4/96), respectively. ), And the total yield of the target compound was 65%.
[0026]
The structural formulas of the compounds of Examples and Reference Examples are described below.
Here, Ts represents a p-tolylsulfonyl group, and Ac represents an acetyl group.
Figure 2004002307

Claims (11)

一般式(1)
Figure 2004002307
(式中、Arは置換基を有していてもよいアリール基を示す。)
で示されるアリールスルホン誘導体と一般式(2)
Figure 2004002307
(式中、Xはハロゲン原子、Rは水酸基の保護基を示し、波線はE/Z幾何異性体のいずれか一方もしくはそれらの混合物であることを示す。)
で示されるアリルハライド誘導体とをアルカリ金属水酸化物の存在下に反応させ一般式(3)
Figure 2004002307
(式中、Rは水素原子または水酸基の保護基を示し、Arおよび波線は前記と同じ意味を表す。)
で示されるスルホン化合物および/または、一般式(4)
Figure 2004002307
(式中、Rおよび波線は前記と同じ意味を表す。)
で示されるトリエン化合物の製造方法。
General formula (1)
Figure 2004002307
(In the formula, Ar represents an aryl group which may have a substituent.)
And a general formula (2)
Figure 2004002307
(In the formula, X represents a halogen atom, R represents a protecting group for a hydroxyl group, and a wavy line represents any one of E / Z geometric isomers or a mixture thereof.)
With an allyl halide derivative of the formula (3) in the presence of an alkali metal hydroxide.
Figure 2004002307
(In the formula, R 1 represents a hydrogen atom or a hydroxyl-protecting group, and Ar and wavy lines represent the same meaning as described above.)
And / or a general formula (4)
Figure 2004002307
(In the formula, R 1 and a wavy line represent the same meaning as described above.)
A method for producing a triene compound represented by the formula:
有機溶媒中、不均一系にて反応させることを特徴とする請求項1に記載の製造方法。The method according to claim 1, wherein the reaction is carried out in a heterogeneous system in an organic solvent. 粉末状のアルカリ金属水酸化物を用いる請求項1または2に記載の製造方法。3. The method according to claim 1, wherein a powdery alkali metal hydroxide is used. アルカリ金属水酸化物の粒子径が、20〜1000μmである請求項1または2に記載の製造方法。The production method according to claim 1, wherein the particle diameter of the alkali metal hydroxide is 20 to 1000 μm. 相間移動触媒の存在下に反応させる請求項1、2、3または4に記載の製造方法。5. The method according to claim 1, wherein the reaction is carried out in the presence of a phase transfer catalyst. 相間移動触媒が第四級アンモニウム塩、第四級ホスホニウム塩もしくはスルホニウム塩である請求項5に記載の製造方法。The method according to claim 5, wherein the phase transfer catalyst is a quaternary ammonium salt, a quaternary phosphonium salt or a sulfonium salt. アルカリ金属水酸化物が水酸化カリウムである請求項1〜6のいずれかに記載の製造方法。The method according to any one of claims 1 to 6, wherein the alkali metal hydroxide is potassium hydroxide. 水酸化カリウムが90%以上の純度である請求項7に記載の製造方法。The production method according to claim 7, wherein the potassium hydroxide has a purity of 90% or more. 一般式(1)で示されるアリールスルホン誘導体に対し0.01〜1モル倍の水の存在下に実施することを特徴とする請求項1〜8のいずれかに記載の製造方法。The method according to any one of claims 1 to 8, wherein the method is carried out in the presence of water in an amount of 0.01 to 1 mol times the aryl sulfone derivative represented by the general formula (1). 一般式(2)で示されるアリルハライド誘導体のRがアシル基である請求項1〜9のいずれかに記載の製造方法。The method according to any one of claims 1 to 9, wherein R of the allyl halide derivative represented by the general formula (2) is an acyl group. アシル基がアセチル基である請求項10に記載の製造方法。The method according to claim 10, wherein the acyl group is an acetyl group.
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