JP4336913B2 - Method for producing amide derivative - Google Patents
Method for producing amide derivative Download PDFInfo
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- JP4336913B2 JP4336913B2 JP03372599A JP3372599A JP4336913B2 JP 4336913 B2 JP4336913 B2 JP 4336913B2 JP 03372599 A JP03372599 A JP 03372599A JP 3372599 A JP3372599 A JP 3372599A JP 4336913 B2 JP4336913 B2 JP 4336913B2
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- Y—GENERAL 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
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Description
【０００１】
【発明の属する技術分野】
本発明は、アミド誘導体の製造方法に関する。
【０００２】
【従来の技術】
一般式
【０００３】
【化３】
〔式中、Ｒ1及びＲ2は、同一又は異なって、水素原子又は低級アルコキシ基を示す。またこのＲ1及びＲ2は互いに結合して低級アルキレンジオキシ基を形成してもよい。Ｘは硫黄原子又は酸素原子を示す。〕
で表されるアミド誘導体は、例えば特開平５−５１３１８号公報に記載の活性酸素抑制剤を製造するための中間体として有用な化合物である。
【０００５】
従来、上記アミド誘導体は、例えば上記特許公報、Ｉｎｄｉａｎ．Ｊ．Ｃｈｅｍ．Ｓｅｅｔ（Ｂ），１８Ｂ（５），ｐ４５５，１９７９ 及びＪ．Ｏｒｇ．Ｃｈｅｍ．，４１（１），ｐ１４８，１９７６等に記載の方法で製造されている。
【０００６】
【発明が解決しようとする課題】
しかしながら、これらの方法は、アミド基の導入される位置（立体配向性）、目的物の収率、操作性等の点で問題点を有している。
【０００７】
【課題を解決するための手段】
本発明者は、上記一般式（１）のアミド誘導体の製造方法につき鋭意研究を重ねた結果、スルホン酸の存在下、下記一般式（２）のベンゼン誘導体にシアン化合物を反応させた場合に、簡便な操作で、位置選択的に（立体配向性よく）、従って高純度且つ高収率で、所望のアミド誘導体が製造されることを見い出した。本発明は、斯かる知見に基づき完成されたものである。
【０００８】
即ち、本発明は、一般式
【０００９】
【化４】
〔式中、Ｒ1及びＲ2は前記に同じ。〕
で表されるベンゼン誘導体をスルホン酸の存在下に一般式
ＭＸＣＮ （３）
〔式中、Ｍはアルカリ金属原子を示す。Ｘは前記に同じ。〕
で表されるシアン化合物と反応させて、一般式（１）で表されるアミド誘導体を得ることを特徴とするアミド誘導体の製造方法に係る。
【００１１】
【発明の実施の形態】
本明細書において示される各基は、より具体的には次の通りである。
【００１２】
低級アルコキシ基としては、例えばメトキシ、エトキシ、ｎ−プロポキシ、イソプロポキシ、ｎ−ブトキシ、ｎ−ペンチルオキシ、ｎ−ヘキシルオキシ基等の炭素数１〜６の直鎖又は分枝鎖状アルコキシ基が挙げられる。
【００１３】
低級アルキレンジオキシ基としては、例えばメチレンジオキシ、エチレンジオキシ、プロピレンジオキシ等の炭素数１〜３のアルキレンジオキシ基が挙げられる。
【００１４】
アルカリ金属原子としては、例えばカリウム、ナトリウム等が挙げられる。
【００１５】
本発明において、出発原料として用いられる一般式（２）のベンゼン誘導体及び一般式（３）のシアン化合物は、いずれも入手容易な公知の化合物である。
【００１６】
本発明によれば、一般式（２）のベンゼン誘導体と一般式（３）のシアン化合物との反応は、スルホン酸の存在下に行われる。スルホン酸としては、従来公知のものを広く使用でき、例えばメタンスルホン酸、エタンスルホン酸等のアルカンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸等のアレンスルホン酸等を挙げることができる。本発明では、これらスルホン酸は、１種単独で又は２種以上混合して使用できる。スルホン酸の使用量としては、特に限定されるものではないが、通常一般式（２）のベンゼン誘導体に対して等モル〜３０倍モル量、好ましくは３〜２５倍モル量とするのがよい。
【００１７】
本発明では、一般式（２）のベンゼン誘導体と一般式（３）のシアン化合物との反応は、適当な溶媒の存在下又は不存在下にて、好ましくは溶媒の不存在下にて行われる。用いられる溶媒としては、例えばジクロロメタン、ジクロロエタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類、クロロベンゼン、ジクロロベンゼン等の芳香族ハロゲン化炭化水素類、酢酸メチル、酢酸エチル、酢酸ブチル等のエステル類、ジエチルエーテル、ジオキサン、テトラヒドロフラン、エチレングリコールジメチルエーテル等のエーテル類、ニトロメタン等の非プロトン性極性溶媒、又はこれらの混合溶媒等が挙げられる。
【００１８】
一般式（２）のベンゼン誘導体と一般式（３）のシアン化合物との反応において、両者の使用割合としては、特に制限されるものではなく、広い範囲内から適宜選択され得るが、通常前者に対して後者を少なくとも等モル量、好ましくは等モル〜３倍モル量使用するのがよい。
【００１９】
本発明の反応は、冷却下、室温下及び加温下のいずれでも進行するが、通常０〜１００℃程度、好ましくは０〜５０℃程度で反応を行うのがよく、一般に１〜２４時間程度で該反応は完結する。
【００２０】
【発明の効果】
本発明の方法によれば、簡便な操作で、位置選択的に（立体配向性よく）、従って高純度且つ高収率で、一般式（１）のアミド誘導体が製造され得る。本発明で製造される一般式（１）のアミド誘導体は、後記参考例に示す方法に従って活性酸素抑制剤として重要な２−（３，４−ジエトキシフェニル）−４−（２−カルボキシ−６−ピリジル）チアゾール等の２−（置換フェニル）−４−（２−カルボキシ−６−ピリジル）チアゾールに誘導され得る。
【００２１】
【実施例】
以下に実施例及び参考例を掲げて、本発明をより一層明らかにする。
【００２２】
実施例１
４−メトキシベンズチオアミドの製造
アニソール７．６０ｇに氷冷下メタンスルホン酸８７ｍｌ、次いでロダンカリ（チオシアン酸カリウム）７．８５ｇを加えた。氷浴を外し、室温で５時間攪拌した。氷水３００ｍｌを注入し、析出晶を濾取した。６０℃で終夜乾燥し、酢酸エチル／ｎ−ヘキサンにより再結晶して７．６３ｇの４−メトキシベンズチオアミドを得た。再結晶母液と濾取時の水層からの残渣をシリカゲルカラムクロマトグラフィーにより精製し、４−メトキシベンズチオアミド０．８２ｇを得、トータルとして８．４５ｇの４−メトキシベンズチオアミドを黄色針状結晶として得た。
【００２３】
融点：１５１．５−１５２．０℃
1Ｈ−ＮＭＲ（２００ＭＨｚ，ＣＤＣｌ3）δｐｐｍ；３．８６（３Ｈ，ｓ），６．８９（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．０５−７．３０（１Ｈ，ｂｒ．ｓ），７．５５−７．８０（１Ｈ，ｂｒ．ｓ），７．９０（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）。
【００２４】
実施例２
３，４−ジエトキシベンズチオアミドの製造
ｏ−ジエトキシベンゼン５０．００ｇに氷冷下メタンスルホン酸３７１ｍｌ、次いでロダンカリ（チオシアン酸カリウム）３３．６０ｇを加えた。氷浴を外し、室温で４時間２０分攪拌した。氷水１リットルを注入し、析出晶を濾取した。６０℃で終夜乾燥し、酢酸エチル／ｎ−ヘキサンにより再結晶して５７．５３ｇの３，４−ジエトキシベンズチオアミドを得た。再結晶母液と濾取時の水層からの残渣をシリカゲルカラムクロマトグラフィーにより精製し、３，４−ジエトキシベンズチオアミド５．３９ｇを得、トータルとして６２．９２ｇ（収率９２．８％）の３，４−ジエトキシベンズチオアミドを黄色針状結晶として得た。
【００２５】
融点：１５１．５−１５３．０℃
1Ｈ−ＮＭＲ（２００ＭＨｚ，ＣＤＣｌ3）δｐｐｍ；１．４６（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．４７（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．１４（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．１５（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），６．８２（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．１０−７．４０（１Ｈ，ｂｒ．ｓ），７．３８（１Ｈ，ｄｄ，Ｊ＝２．４Ｈｚ，８．６Ｈｚ），７．５５−７．８０（１Ｈ，ｂｒ．ｓ），７．６０（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）。
【００２６】
実施例３
３，４−ジメトキシベンズチオアミドの製造
ベラトロール（１，２−ジメトキシベンゼン）５．００ｇを用い、実施例１と同様にして黄色顆粒状の３，４−ジメトキシベンズチオアミド５．９２ｇを得た。
【００２７】
1Ｈ−ＮＭＲ（２００ＭＨｚ，ＤＭＳＯ−ｄ6）δｐｐｍ；３．８０（３Ｈ，ｓ），３．８１（３Ｈ，ｓ），６．９８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５９（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ），７．６１（１Ｈ，ｄｄ，Ｊ＝２．２Ｈｚ，８．０Ｈｚ），９．３３（１Ｈ，ｂｒ．ｓ），９．６５（１Ｈ，ｂｒ．ｓ）。
【００２８】
実施例４
４−メトキシベンズアミドの製造
アニソール５．００ｇに氷冷下メタンスルホン酸５７ｍｌ、次いでシアン酸カリウム４．３１ｇを加えた。室温で４時間３０分攪拌した。更にシアン酸カリウム４．３１ｇを追加し、室温で更に１９時間攪拌した。氷水２００ｍｌを注入し、析出晶を濾取した。６０℃で終夜乾燥し、３．６７ｇの４−メトキシベンズアミドを得た。濾取時の水層は塩化メチレンで抽出し、硫酸マグネシウムで乾燥後、減圧濃縮して、２位及び４位の混合物としてメトキシベンズアミド（２位：４位＝１：２）を２．０６ｇを得、トータルとして５．７３ｇの２位及び４位の混合物（２位：４位＝１：７）を酢酸エチルで再結晶して３．９９ｇの無色柱状の４−メトキシベンズアミドを得た。
【００２９】
融点：１６６．５−１６７．０℃
1Ｈ−ＮＭＲ（２００ＭＨｚ，ＣＤＣｌ3）δｐｐｍ；３．８６（３Ｈ，ｓ），５．８０−６．１５（２Ｈ，ｂｒ．ｓ），６．９３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）。
【００３０】
参考例１
６−カルボキシ−２−メトキシカルボニルピリジン１８０ｇをジクロロメタンに懸濁させた。この懸濁液に室温でＮ，Ｎ−ジメチルホルムアミド（０．３等量）、次いで塩化チオニル（１．０等量）を加えた。４時間加熱還流後、室温に冷却して６−メトキシカルボニル−２−ピリジンカルボニルクロライドの塩化メチレン溶液を得た。
【００３１】
マロン酸モノエチルエステルカリウム塩（１．４等量）をアセトニトリルに懸濁させた。この懸濁液に氷冷下トリエチルアミン（３．０等量）、次いで塩化マグネシウム（３．０等量）を加えた。３０℃前後で３時間３０分攪拌後、氷冷下、この反応液に、上記で得られた６−メトキシカルボニル−２−ピリジンカルボニルクロライドの塩化メチレン溶液を加えた。室温で１時間攪拌後、氷冷下希塩酸を加えクエンチした。常法に従い抽出及び洗浄処理し、エチル ３−オキソ−３−（６−メトキシカルボニル−２−ピリジル）プロピオネート２１０ｇを得た。
【００３２】
上記で得られたエチル ３−オキソ−３−（６−メトキシカルボニル−２−ピリジル）プロピオネートをジクロロメタンに溶解し、氷冷下に塩化スルフリル（１．０５等量）のジクロロメタン溶液を滴下した。２０分攪拌後、氷水（３．６倍容量）及び濃塩酸（４．２等量）を反応液に加えた。加熱してジクロロメタンを除去した後、更に９０℃で３時間３０分間攪拌した。室温でエチレングリコールジメチルエーテル及び上記実施例２で得られた３，４−ジエトキシベンズチオアミド（１．０等量）を加えた後、２時間還流した。氷冷し、析出した結晶を濾取して、２−（３，４−ジエトキシフェニル）−４−（２−カルボキシ−６−ピリジル）チアゾールの粗結晶を得た。これを精製し、６０℃で乾燥して、２−（３，４−ジエトキシフェニル）−４−（２−カルボキシ−６−ピリジル）チアゾール１７４ｇを得た。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing an amide derivative.
[0002]
[Prior art]
General formula
[Chemical 3]
[Wherein, R 1 and R 2 are the same or different and each represents a hydrogen atom or a lower alkoxy group. R 1 and R 2 may be bonded to each other to form a lower alkylenedioxy group. X represents a sulfur atom or an oxygen atom. ]
Is a compound useful as an intermediate for producing an active oxygen inhibitor described in, for example, JP-A No. 5-51318.
[0005]
Conventionally, the amide derivatives are described in, for example, the above-mentioned patent publication, Indian. J. et al. Chem. Seee (B), 18B (5), p455, 1979 and J.A. Org. Chem. 41 (1), p148, 1976 and the like.
[0006]
[Problems to be solved by the invention]
However, these methods have problems in terms of the position where the amide group is introduced (steric orientation), the yield of the target product, operability, and the like.
[0007]
[Means for Solving the Problems]
As a result of intensive studies on the method for producing the amide derivative of the above general formula (1), the present inventor, when a cyanide compound is reacted with a benzene derivative of the following general formula (2) in the presence of sulfonic acid, It has been found that the desired amide derivative can be produced regioselectively (with a good stereo-orientation) and thus with a high purity and a high yield by a simple operation. The present invention has been completed based on such findings.
[0008]
That is, the present invention has the general formula
[Formula 4]
[Wherein, R 1 and R 2 are the same as defined above. ]
A benzene derivative represented by the general formula MXCN (3) in the presence of sulfonic acid
[Wherein, M represents an alkali metal atom. X is the same as above. ]
The amide derivative represented by the general formula (1) is obtained by reacting with a cyanide compound represented by general formula (1).
[0011]
DETAILED DESCRIPTION OF THE INVENTION
More specifically, each group shown in the present specification is as follows.
[0012]
Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentyloxy, and n-hexyloxy groups. Can be mentioned.
[0013]
Examples of the lower alkylenedioxy group include C1-C3 alkylenedioxy groups such as methylenedioxy, ethylenedioxy, propylenedioxy and the like.
[0014]
Examples of the alkali metal atom include potassium and sodium.
[0015]
In the present invention, the benzene derivative of the general formula (2) and the cyan compound of the general formula (3) used as starting materials are both known compounds that are easily available.
[0016]
According to the present invention, the reaction of the benzene derivative of the general formula (2) and the cyanide compound of the general formula (3) is performed in the presence of sulfonic acid. As the sulfonic acid, conventionally known ones can be widely used, and examples thereof include alkanesulfonic acids such as methanesulfonic acid and ethanesulfonic acid, and allenesulfonic acids such as benzenesulfonic acid and toluenesulfonic acid. In this invention, these sulfonic acids can be used individually by 1 type or in mixture of 2 or more types. The amount of sulfonic acid used is not particularly limited, but is usually equimolar to 30-fold molar amount, preferably 3 to 25-fold molar amount relative to the benzene derivative of the general formula (2). .
[0017]
In the present invention, the reaction of the benzene derivative of the general formula (2) and the cyanide compound of the general formula (3) is performed in the presence or absence of a suitable solvent, preferably in the absence of a solvent. . Examples of the solvent used include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, aromatic halogenated hydrocarbons such as chlorobenzene and dichlorobenzene, and esters such as methyl acetate, ethyl acetate and butyl acetate. , Diethyl ether, dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether, aprotic polar solvents such as nitromethane, or mixed solvents thereof.
[0018]
In the reaction of the benzene derivative of the general formula (2) and the cyan compound of the general formula (3), the usage ratio of both is not particularly limited and can be appropriately selected from a wide range. On the other hand, the latter should be used in at least equimolar amount, preferably equimolar to 3-fold molar amount.
[0019]
The reaction of the present invention proceeds under cooling, at room temperature, or under heating, but is usually carried out at about 0 to 100 ° C., preferably about 0 to 50 ° C., and generally about 1 to 24 hours. The reaction is complete.
[0020]
【The invention's effect】
According to the method of the present invention, the amide derivative of the general formula (1) can be produced by a simple operation in a regioselective manner (with good stereo orientation), and thus with high purity and high yield. The amide derivative of the general formula (1) produced according to the present invention is 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6) which is important as an active oxygen inhibitor according to the method shown in Reference Examples below. Can be derived to 2- (substituted phenyl) -4- (2-carboxy-6-pyridyl) thiazole such as -pyridyl) thiazole.
[0021]
【Example】
The present invention will be further clarified by the following examples and reference examples.
[0022]
Example 1
Preparation of 4-methoxybenzthioamide To 7.60 g of anisole, 87 ml of methanesulfonic acid and then 7.85 g of rhodankari (potassium thiocyanate) were added under ice cooling. The ice bath was removed and the mixture was stirred at room temperature for 5 hours. 300 ml of ice water was poured, and the precipitated crystals were collected by filtration. The mixture was dried at 60 ° C. overnight and recrystallized from ethyl acetate / n-hexane to obtain 7.63 g of 4-methoxybenzthioamide. The residue from the recrystallized mother liquor and the aqueous layer upon filtration was purified by silica gel column chromatography to obtain 0.82 g of 4-methoxybenzthioamide, totaling 8.45 g of 4-methoxybenzthioamide as yellow needle crystals Obtained.
[0023]
Melting point: 151.5-152.0 ° C
1 H-NMR (200 MHz, CDCl 3 ) δ ppm; 3.86 (3H, s), 6.89 (2H, d, J = 9.0 Hz), 7.05-7.30 (1H, br. S) 7.55-7.80 (1H, br.s), 7.90 (2H, d, J = 9.0 Hz).
[0024]
Example 2
Production of 3,4-diethoxybenzthioamide To 50.00 g of o-diethoxybenzene, 371 ml of methanesulfonic acid and then 33.60 g of rhodankari (potassium thiocyanate) were added under ice cooling. The ice bath was removed and the mixture was stirred at room temperature for 4 hours and 20 minutes. 1 liter of ice water was poured, and the precipitated crystals were collected by filtration. It was dried at 60 ° C. overnight and recrystallized from ethyl acetate / n-hexane to obtain 57.53 g of 3,4-diethoxybenzthioamide. The residue from the recrystallized mother liquor and the aqueous layer at the time of filtration was purified by silica gel column chromatography to obtain 5.39 g of 3,4-diethoxybenzthioamide, totaling 62.92 g (yield 92.8%). 3,4-diethoxybenzthioamide was obtained as yellow needle crystals.
[0025]
Melting point: 151.5-153.0 ° C
1 H-NMR (200 MHz, CDCl 3 ) δ ppm; 1.46 (3H, t, J = 7.0 Hz), 1.47 (3H, t, J = 7.0 Hz), 4.14 (2H, q, J = 7.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 6.82 (1H, d, J = 8.6 Hz), 7.10-7.40 (1H, br.s) ), 7.38 (1H, dd, J = 2.4 Hz, 8.6 Hz), 7.55-7.80 (1H, br.s), 7.60 (1H, d, J = 2.4 Hz) .
[0026]
Example 3
Production of 3,4-dimethoxybenzthioamide Using 5.00 g of veratrol (1,2-dimethoxybenzene), 5.92 g of yellow granular 3,4-dimethoxybenzthioamide was obtained in the same manner as in Example 1.
[0027]
1 H-NMR (200 MHz, DMSO-d 6 ) δ ppm; 3.80 (3H, s), 3.81 (3H, s), 6.98 (1H, d, J = 8.0 Hz), 7.59 (1H, d, J = 2.2 Hz), 7.61 (1H, dd, J = 2.2 Hz, 8.0 Hz), 9.33 (1H, br.s), 9.65 (1H, br. s).
[0028]
Example 4
Preparation of 4-methoxybenzamide 57 ml of methanesulfonic acid and then 4.31 g of potassium cyanate were added to 5.00 g of anisole under ice cooling. The mixture was stirred at room temperature for 4 hours and 30 minutes. Further, 4.31 g of potassium cyanate was added, and the mixture was further stirred at room temperature for 19 hours. 200 ml of ice water was poured, and the precipitated crystals were collected by filtration. After drying at 60 ° C. overnight, 3.67 g of 4-methoxybenzamide was obtained. The aqueous layer at the time of filtration was extracted with methylene chloride, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 2.06 g of methoxybenzamide (2nd position: 4th position = 1: 2) as a mixture of the 2nd and 4th positions. In total, 5.73 g of the mixture of the 2nd and 4th positions (2nd position: 4th position = 1: 7) was recrystallized from ethyl acetate to obtain 3.99 g of colorless columnar 4-methoxybenzamide.
[0029]
Melting point: 166.5-167.0 ° C
1 H-NMR (200 MHz, CDCl 3 ) δ ppm; 3.86 (3H, s), 5.80-6.15 (2H, br. S), 6.93 (2H, d, J = 9.0 Hz) , 7.79 (2H, d, J = 9.0 Hz).
[0030]
Reference example 1
180 g of 6-carboxy-2-methoxycarbonylpyridine was suspended in dichloromethane. To this suspension was added N, N-dimethylformamide (0.3 eq) followed by thionyl chloride (1.0 eq) at room temperature. After heating under reflux for 4 hours, the mixture was cooled to room temperature to obtain a methylene chloride solution of 6-methoxycarbonyl-2-pyridinecarbonyl chloride.
[0031]
Malonic acid monoethyl ester potassium salt (1.4 equivalents) was suspended in acetonitrile. Triethylamine (3.0 equivalents) and then magnesium chloride (3.0 equivalents) were added to the suspension under ice cooling. After stirring for 3 hours and 30 minutes at around 30 ° C., the methylene chloride solution of 6-methoxycarbonyl-2-pyridinecarbonyl chloride obtained above was added to the reaction solution under ice cooling. After stirring at room temperature for 1 hour, the reaction mixture was quenched by adding dilute hydrochloric acid under ice cooling. Extraction and washing were performed according to a conventional method to obtain 210 g of ethyl 3-oxo-3- (6-methoxycarbonyl-2-pyridyl) propionate.
[0032]
The ethyl 3-oxo-3- (6-methoxycarbonyl-2-pyridyl) propionate obtained above was dissolved in dichloromethane, and a solution of sulfuryl chloride (1.05 equivalents) in dichloromethane was added dropwise under ice cooling. After stirring for 20 minutes, ice water (3.6 times volume) and concentrated hydrochloric acid (4.2 equivalents) were added to the reaction solution. After heating to remove dichloromethane, the mixture was further stirred at 90 ° C. for 3 hours and 30 minutes. Ethylene glycol dimethyl ether and 3,4-diethoxybenzthioamide (1.0 equivalent) obtained in Example 2 were added at room temperature, and the mixture was refluxed for 2 hours. The mixture was cooled with ice, and the precipitated crystals were collected by filtration to obtain 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole crude crystals. This was purified and dried at 60 ° C. to obtain 174 g of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole.
Claims (8)
で表されるベンゼン誘導体をスルホン酸の存在下に一般式
ＭＸＣＮ
〔式中、Ｍはアルカリ金属原子、Ｘは硫黄原子又は酸素原子を示す。〕
で表されるシアン化合物と反応させて、一般式
で表されるアミド誘導体を得ることを特徴とするアミド誘導体の製造方法。General formula
A benzene derivative represented by the general formula MXCN in the presence of sulfonic acid
[Wherein, M represents an alkali metal atom, and X represents a sulfur atom or an oxygen atom. ]
Is reacted with a cyanide represented by the general formula
A process for producing an amide derivative, characterized in that an amide derivative represented by the formula:
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| NL7505904A (en) * | 1974-05-25 | 1975-11-27 | Hoechst Ag | PROCESS FOR PREPARING AROMATIC THIOCARBON ACID AMIDES. |
| DE69132006T2 (en) * | 1990-11-30 | 2000-08-03 | Otsuka Pharma Co Ltd | THIAZOLE DERIVATIVES AS INHIBITORS OF ACTIVE OXYGEN |
| IE71647B1 (en) * | 1991-01-28 | 1997-02-26 | Rhone Poulenc Rorer Ltd | Benzamide derivatives |
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