JP3440196B2 - Method for producing thiobenzamide derivative - Google Patents
Method for producing thiobenzamide derivativeInfo
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- JP3440196B2 JP3440196B2 JP21851797A JP21851797A JP3440196B2 JP 3440196 B2 JP3440196 B2 JP 3440196B2 JP 21851797 A JP21851797 A JP 21851797A JP 21851797 A JP21851797 A JP 21851797A JP 3440196 B2 JP3440196 B2 JP 3440196B2
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、医薬品として有用
な２−（３−シアノフェニル）チアゾール誘導体の製造
中間体となるチオベンズアミド誘導体およびベンゾチア
ゾール誘導体の製造法に関する。さらに詳しくは、本発
明は、例えば痛風、高尿酸血症治療剤等のキサンチンオ
キシダーゼ（以下「ＸＯＤ」という）阻害剤として有用
な２−（３−シアノフェニル）チアゾール誘導体の製造
中間体となるチオベンズアミド誘導体および２−フェニ
ルチアゾール誘導体の製造法に関する。TECHNICAL FIELD The present invention relates to a process for producing a thiobenzamide derivative and a benzothiazole derivative which are intermediates for producing a 2- (3-cyanophenyl) thiazole derivative useful as a medicine. More specifically, the present invention provides a thiol which is a production intermediate of a 2- (3-cyanophenyl) thiazole derivative useful as a xanthine oxidase (hereinafter referred to as “XOD”) inhibitor such as a therapeutic agent for gout and hyperuricemia. The present invention relates to a method for producing a benzamide derivative and a 2-phenylthiazole derivative.
【０００２】[0002]
【従来の技術】痛風は高尿酸血症を基礎疾患とし、発作
の寛解後は高尿酸血症の改善療法が行われる。高尿酸血
症の治療薬は、大別して尿酸***剤と尿酸合成酵素阻害
剤（ＸＯＤ阻害剤）に分けられ、疾患の態様や程度に応
じて適宜選択される。ＸＯＤ阻害剤としては、２−（３
−シアノフェニル）チアゾール誘導体が知られている
（国際公開ＷＯ９２／０９２７９号パンフレット参
照）。2. Description of the Related Art Gout is a basic disease of hyperuricemia, and after remission of an attack, improvement therapy for hyperuricemia is performed. The therapeutic agents for hyperuricemia are roughly classified into uric acid excretion agents and uric acid synthase inhibitors (XOD inhibitors), and are appropriately selected according to the mode and degree of the disease. As the XOD inhibitor, 2- (3
-Cyanophenyl) thiazole derivatives are known (see International Publication WO92 / 09279 pamphlet).
【０００３】通常、２−（３−シアノフェニル）チアゾ
ール誘導体の基本骨格となる１，３−チアゾールの構築
方法に関しては、α−ハロケトン類とチオアミドを反応
させる方法が用いられる（新実験化学講座１４有機合成
と反応［IV］ｐ２１９２参照）。実際、２−（３−シア
ノフェニル）チアゾール誘導体の合成においても、４−
ヒドロキシベンゾニトリルをチオベンズアミド誘導体と
して単離後、３−クロロアセト酢酸エチルと反応させ、
２−フェニルチアゾール誘導体としている（特開平６−
３２９６４７号公報参照）。Usually, as a method of constructing 1,3-thiazole, which is a basic skeleton of a 2- (3-cyanophenyl) thiazole derivative, a method of reacting α-haloketones with thioamide is used (New Experimental Chemistry Course 14). Organic synthesis and reaction [IV] p2192). In fact, even in the synthesis of 2- (3-cyanophenyl) thiazole derivative,
After isolating hydroxybenzonitrile as a thiobenzamide derivative, it was reacted with ethyl 3-chloroacetoacetate,
A 2-phenylthiazole derivative is used (JP-A-6-
329647).
【０００４】そこで、２−フェニルチアゾール誘導体製
造のためには、その合成前駆体となるチオベンズアミド
誘導体の製造方法が重要となる。一般に知られているチ
オアミド類を合成する反応では、硫黄源として硫化水
素、五硫化リンを用いていたり（新実験化学講座１４有
機合成と反応［III］ｐ１８２８−１８２９参照）反応
試薬、溶媒に６Ｎ−塩酸ジメチルホルムアミド溶液を用
いている（J. Med. Chem., ２９，６，１０６５−１０
８０（１９８６）参照）。６Ｎ−塩酸ジメチルホルムア
ミド溶液には腐食性があり、この調製には有毒な塩酸ガ
スを用いること、操作時にも塩酸ガスが発生する等の問
題があ。また、硫化水素、五硫化リンは毒物であり、工
業的製造において大量に使用するには問題がある。Therefore, in order to produce a 2-phenylthiazole derivative, a method for producing a thiobenzamide derivative which is a synthetic precursor thereof is important. In the generally known reaction for synthesizing thioamides, hydrogen sulfide and phosphorus pentasulfide are used as a sulfur source (see New Experimental Chemistry Course 14 Organic Synthesis and Reaction [III] p1828-1829). -Using a dimethylformamide hydrochloride solution (J. Med. Chem., 29, 6, 1065-10
80 (1986)). The 6N-dimethylformamide hydrochloride solution is corrosive, and there are problems that a toxic hydrochloric acid gas is used for this preparation and that hydrochloric acid gas is generated during operation. Further, hydrogen sulfide and phosphorus pentasulfide are poisonous substances, and there is a problem in using them in large quantities in industrial production.
【０００５】ところで、ポリリン酸中でベンゾニトリル
誘導体を加熱反応させると高収率でベンツアミド誘導体
に変換できることが知られている（J. Am. Chem. Soc.,
７６，３０３９（１９５４））。しかし、ポリリン酸
中、硫黄源としてチオアセトアミドをいれてベンゾニト
リル誘導体を反応させ、チオベンズアミド誘導体へと変
換した例はない。By the way, it is known that a benzonitrile derivative can be converted into a benzamide derivative at a high yield by heating a benzonitrile derivative in polyphosphoric acid (J. Am. Chem. Soc.,
76, 3039 (1954)). However, there is no example in which thioacetamide was added as a sulfur source in polyphosphoric acid to react with a benzonitrile derivative to convert it into a thiobenzamide derivative.
【０００６】[0006]
【発明が解決しようとする課題】本発明者らは、上述し
た従来技術に鑑み、ＸＯＤ阻害剤として有用な２−（３
−シアノフェニル）チアゾール誘導体の製造中間体とし
て有用な、チオベンズアミド誘導体および２−フェニル
チアゾール誘導体の製造法の開発を指向して、チオアミ
ド化反応、チアゾール化反応を鋭意研究した結果、本発
明に到達したものである。DISCLOSURE OF THE INVENTION In view of the above-mentioned prior art, the present inventors have found that 2- (3) useful as an XOD inhibitor.
As a result of earnest research on thioamidation reaction and thiazolization reaction aiming at development of a production method of a thiobenzamide derivative and a 2-phenylthiazole derivative useful as a production intermediate of a -cyanophenyl) thiazole derivative, the present invention has been achieved. It was done.
【０００７】[0007]
【課題を解決するための手段】すなわち、本発明は第一
に、下記式（１）That is, the first aspect of the present invention is to provide the following formula (1):
【０００８】[0008]
【化５】 [Chemical 5]
【０００９】［式中、Ｒ1は芳香環上の置換基で、水素
原子、ハロゲン原子、水酸基、無置換もしくは置換され
たＣ1〜Ｃ5のアルキル基、または、無置換もしくは置換
されたＣ1〜Ｃ5のアルコキシル基を表す。］で表される
ベンゾニトリル誘導体を、ポリリン酸中、チオアセトア
ミドと反応させることを特徴とする、下記式（２）[Wherein R 1 is a substituent on the aromatic ring, and is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C 1 -C 5 alkyl group, or an unsubstituted or substituted C 1 an alkoxyl group having 1 -C 5. ] The benzonitrile derivative represented by the following formula (2) characterized by reacting with thioacetamide in polyphosphoric acid
【００１０】[0010]
【化６】 [Chemical 6]
【００１１】［式中、Ｒ1の定義は前記式（１）におけ
るものと同じ。］で表されるチオベンズアミド誘導体の
製造法である。[In the formula, the definition of R 1 is the same as in the above formula (1). ] It is a manufacturing method of the thiobenzamide derivative represented by this.
【００１２】さらに、本発明は第二に、前記式（１）で
表されるベンゾニトリル誘導体を、ポリリン酸中チオア
セトアミドと反応後、単離することなく、下記式（３）Furthermore, the present invention secondly provides the benzonitrile derivative represented by the above formula (1) after the reaction with thioacetamide in polyphosphoric acid without isolation, and the following formula (3)
【００１３】[0013]
【化７】 [Chemical 7]
【００１４】［式中、Ｒ2は水素原子またはＣ1〜Ｃ4の
アルキル基を表し、Ｒ3は水素原子、Ｃ1〜Ｃ4のアルキ
ル基、Ｃ1〜Ｃ4のアルキルカルボニル基、Ｃ1〜Ｃ4のア
ルキル（モノもしくはジ置換）アミノカルボニル基、カ
ルバモイル基、Ｃ1〜Ｃ4のアルコキシカルボニル基、ま
たはカルボキシル基を表し、Ｘは塩素原子、臭素原子、
またはヨウ素原子を表す。］で表されるα−ハロケトン
類を反応させることを特徴とする、下記式（４）[Wherein R 2 represents a hydrogen atom or a C 1 -C 4 alkyl group, R 3 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkylcarbonyl group, C 1 to C 4 alkyl (mono or disubstituted) aminocarbonyl group, carbamoyl group, C 1 to C 4 alkoxycarbonyl group, or carboxyl group, X is a chlorine atom, a bromine atom,
Or represents an iodine atom. ] The following formula (4) characterized by reacting α-haloketones represented by
【００１５】[0015]
【化８】 [Chemical 8]
【００１６】［式中、Ｒ1の定義は前記式（１）におけ
るものと同じであり、Ｒ2およびＲ3の定義は前記式
（３）におけるものに同じである。］で表される２−フ
ェニルチアゾール誘導体の製造法である。[In the formula, the definition of R 1 is the same as that in the above formula (1), and the definitions of R 2 and R 3 are the same as those in the above formula (3). ] It is a manufacturing method of the 2-phenyl thiazole derivative represented by these.
【００１７】[0017]
【発明の実施の形態】前記式（１）、（２）、および
（４）で表される化合物において、Ｒ1は芳香環上の置
換基で、水素原子、ハロゲン原子、水酸基、無置換もし
くは置換されたＣ1〜Ｃ5のアルキル基、または、無置換
もしくは置換されたＣ1〜Ｃ5のアルコキシル基を表す。
かかるハロゲン原子としては、例えばフッ素原子、塩素
原子、臭素原子、またはヨウ素原子を表すが、これらの
中でも臭素原子が好ましいものとして挙げられる。無置
換もしくは置換されたＣ1〜Ｃ5のアルキル基としては、
メチル基、エチル基、プロピル基、イソプロピル基、ブ
チル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−
ブチル基、ペンチル基、３−ペンチル基、ｎｅｏ−ペン
チル基、シクロペンチル基などが挙げられる。無置換も
しくは置換されたＣ1〜Ｃ5のアルコキシル基としては、
メトキシ基、エトキシ基、プロポキシ基、イソプロピル
オキシ基、ブトキシ基、イソブチルオキシ基、ｓｅｃ−
ブチルオキシ基、ｔｅｒｔ−ブチルオキシ基、ペンチル
オキシ基、３−ペンチルオキシ基、ｎｅｏ−ペンチルオ
キシ基、シクロペンチルオキシ基などか挙げられる。BEST MODE FOR CARRYING OUT THE INVENTION In the compounds represented by the above formulas (1), (2), and (4), R 1 is a substituent on the aromatic ring, which is a hydrogen atom, a halogen atom, a hydroxyl group, unsubstituted or It represents a substituted C 1 -C 5 alkyl group or an unsubstituted or substituted C 1 -C 5 alkoxyl group.
Examples of such a halogen atom include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and of these, a bromine atom is preferable. As an unsubstituted or substituted C 1 -C 5 alkyl group,
Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-
Examples thereof include a butyl group, a pentyl group, a 3-pentyl group, a neo-pentyl group and a cyclopentyl group. As an unsubstituted or substituted C 1 -C 5 alkoxyl group,
Methoxy group, ethoxy group, propoxy group, isopropyloxy group, butoxy group, isobutyloxy group, sec-
Examples thereof include a butyloxy group, a tert-butyloxy group, a pentyloxy group, a 3-pentyloxy group, a neo-pentyloxy group and a cyclopentyloxy group.
【００１８】前記式（３）および（４）で表される化合
物において、Ｒ2は水素原子またはＣ1〜Ｃ4のアルキル
基を表す。かかるＣ1〜Ｃ4のアルキル基としては、メチ
ル基、エチル基、プロピル基、イソプロピル基、ブチル
基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチ
ル基などが挙げられる。なかでも好ましくはメチル基、
エチル基、プロピル基が挙げられ、より好ましくはメチ
ル基が挙げられる。前記式（３）および（４）で表され
る化合物において、Ｒ3は水素原子、Ｃ1〜Ｃ4のアルキ
ル基、Ｃ1〜Ｃ4のアルキルカルボニル基、Ｃ1〜Ｃ4のア
ルキル（モノもしくはジ置換）アミノカルボニル基、カ
ルバモイル基、Ｃ1〜Ｃ4のアルコキシカルボニル基、ま
たはカルボキシル基を表す。Ｃ1〜Ｃ4のアルキル基とし
ては、メチル基、エチル基、プロピル基、イソプロピル
基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅ
ｒｔ−ブチル基などが挙げられる。Ｃ1〜Ｃ4のアルキル
カルボニル基としては、メチルカルボニル基、エチルカ
ルボニル基、プロピルカルボニル基、ブチルカルボニル
基などが挙げられる。Ｃ1〜Ｃ4のアルキル（モノもしく
はジ置換）アミノカルボニル基としては、メチルアミノ
カルボニル基、ジメチルアミノカルボニル基、エチルア
ミノカルボニル基、ジエチルアミノカルボニル基、ブチ
ルアミノカルボニル基、ジブチルアミノカルボニル基な
どが挙げられ、Ｃ1〜Ｃ4のアルコキシカルボニル基とし
ては、メトキシカルボニル基、エトキシカルボニル基、
ｔｅｒｔ−ブトキシカルボニル基などが挙げられ、好ま
しくはメトキシカルボニル基、エトキシカルボニル基が
挙げられる。In the compounds represented by the above formulas (3) and (4), R 2 represents a hydrogen atom or a C 1 -C 4 alkyl group. Examples of the C 1 to C 4 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Among them, preferably a methyl group,
An ethyl group and a propyl group are mentioned, and a methyl group is more preferable. In the compounds represented by the above formulas (3) and (4), R 3 is a hydrogen atom, a C 1 to C 4 alkyl group, a C 1 to C 4 alkylcarbonyl group, a C 1 to C 4 alkyl (mono Or (di-substituted) aminocarbonyl group, carbamoyl group, C 1 -C 4 alkoxycarbonyl group, or carboxyl group. The alkyl group of C 1 -C 4, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, te
Examples thereof include an rt-butyl group. Examples of the C 1 -C 4 alkylcarbonyl group include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group and a butylcarbonyl group. Examples of the C 1 -C 4 alkyl (mono or di-substituted) aminocarbonyl group include a methylaminocarbonyl group, a dimethylaminocarbonyl group, an ethylaminocarbonyl group, a diethylaminocarbonyl group, a butylaminocarbonyl group, a dibutylaminocarbonyl group and the like. Examples of the C 1 to C 4 alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group,
Examples thereof include a tert-butoxycarbonyl group, and preferably a methoxycarbonyl group and an ethoxycarbonyl group.
【００１９】前記式（３）および（４）で表される化合
物において、Ｒ2、Ｒ3、およびＸの最も好ましい組み合
わせとして、Ｒ2はメチル基、Ｒ3はエトキシカルボニル
基、Ｘは塩素原子の組み合わせが挙げられる。In the compounds represented by the above formulas (3) and (4), the most preferred combination of R 2 , R 3 and X is R 2 is a methyl group, R 3 is an ethoxycarbonyl group and X is a chlorine atom. The combination of
【００２０】本発明の製造法のうち、化合物（１）から
化合物（２）への反応（チオアミド化反応）に用いるポ
リリン酸の量は、反応を円滑に進行させるのに十分な量
があればよいが、通常、原料の３〜１５倍重量、好まし
くは５〜１０倍重量用いられる。また、かかるチオアミ
ド化反応に用いるチオアセトアミドの量は、反応を円滑
に進行させるのに十分な量があればよいが、通常、原料
の１〜５倍モル、好ましくは１．５〜２倍モル用いられ
る。さらに、かかるチオアミド化反応を行う反応温度
は、通常、２５〜１５０℃の範囲であり、好ましくは７
０〜１００℃である。反応時間は反応温度に依存して異
なるが、通常、３０分から１日程度で反応は完結する。In the production method of the present invention, the amount of polyphosphoric acid used in the reaction from compound (1) to compound (2) (thioamidation reaction) is sufficient if the reaction proceeds smoothly. Although it is good, it is usually used in an amount of 3 to 15 times, preferably 5 to 10 times the weight of the raw material. The amount of thioacetamide used in the thioamidation reaction may be an amount sufficient to allow the reaction to proceed smoothly, but is usually 1 to 5 times mol of the raw material, preferably 1.5 to 2 times mol. Used. Further, the reaction temperature for carrying out the thioamidation reaction is usually in the range of 25 to 150 ° C., preferably 7
It is 0 to 100 ° C. Although the reaction time varies depending on the reaction temperature, the reaction is usually completed in about 30 minutes to 1 day.
【００２１】反応後、得られた生成物は通常の手段によ
り反応液から分離精製される。例えば、抽出、洗浄、ク
ロマトグラフィー、再結晶、あるいはこれらの組み合わ
せにより行われる。After the reaction, the obtained product is separated and purified from the reaction solution by a conventional means. For example, extraction, washing, chromatography, recrystallization, or a combination thereof is performed.
【００２２】さらに、化合物（１）から化合物（４）へ
の反応を連続して１ポット（チオアミド化〜チアゾール
化反応）で実施することもでき、そのときの実施形態
は、チオアミド化反応までは、上記の条件に従う。チオ
アミド化反応が終わったところで用いる上記式（３）で
表されるα−ハロケトン類の量は、反応を円滑に進行さ
せるのに十分な量があればよいが、通常、原料の１〜５
倍モル、好ましくは、２〜３倍モル用いられる。チアゾ
ール化反応を行う反応温度は、通常、２５〜１５０℃の
範囲であり、好ましくは７０〜１００℃である。反応時
間は反応温度に依存して異なるが、通常、３０分〜１日
程度で反応は完結する。Further, the reaction from the compound (1) to the compound (4) can be continuously carried out in one pot (thioamidation-thiazolization reaction), and the embodiment at that time is up to the thioamidation reaction. , Subject to the above conditions. The amount of the α-haloketones represented by the above formula (3) used at the end of the thioamidation reaction may be an amount sufficient for the reaction to proceed smoothly.
It is used in an amount of 2 times, preferably 2 to 3 times. The reaction temperature for carrying out the thiazole-forming reaction is usually in the range of 25 to 150 ° C, preferably 70 to 100 ° C. Although the reaction time varies depending on the reaction temperature, the reaction is usually completed in about 30 minutes to 1 day.
【００２３】反応後、得られた生成物は通常の手段によ
り反応液から分離精製される。例えば、抽出、洗浄、ク
ロマトグラフィー、再結晶、あるいはこれらの組み合わ
せにより行われる。After the reaction, the obtained product is separated and purified from the reaction solution by a conventional means. For example, extraction, washing, chromatography, recrystallization, or a combination thereof is performed.
【００２４】[0024]
［実施例１］４−ヒドロキシチオベンズアミドの合成 Example 1 Synthesis of 4-hydroxythiobenzamide
【００２５】[0025]
【化９】 [Chemical 9]
【００２６】１００ｍＬ三ツ口フラスコに、チオアセト
アミド７．５１ｇ、ポリリン酸４０ｇを入れ、８５℃で
加熱攪拌した。ここに、４−ヒドロキシベンゾニトリル
５．９６ｇを加え、４時間、８５℃で加熱攪拌を行っ
た。放冷後、内温が６０℃となったところで酢酸エチル
８ｍＬと水８ｍＬを加え、室温まで攪拌放冷した。反応
液を５００ｍＬビーカーに移し、酢酸エチル２４０ｍＬ
と水１８０ｍＬを加え、３０分間攪拌した。この液の不
溶物を濾別後、分液ロートに移し、分液した。水層より
酢酸エチル１２０ｍＬで抽出した。各有機層を水１１０
ｍＬで２回、１０％食塩水１１０ｍＬで洗浄後、合わ
せ、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、
濾液を濃縮し、粗体８．４ｇを得た。これをシリカゲル
カラムクロマトグラフィー（シリカ２５０ｇ、ヘキサン
／酢酸エチル＝２／１〜１／２）で精製し、目的物７．
８５ｇ（収率quant）を得た。1
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δ：6.75(d, J=8.8H
z, 2H), 7.86(d, J=8.8Hz, 2H), 9.2(br, 1H), 9.5(br,
1H), 10.11(s, 1H)To a 100 mL three-necked flask, 7.51 g of thioacetamide and 40 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. To this, 5.96 g of 4-hydroxybenzonitrile was added and heated and stirred at 85 ° C. for 4 hours. After cooling, 8 mL of ethyl acetate and 8 mL of water were added when the internal temperature reached 60 ° C., and the mixture was allowed to cool to room temperature with stirring. Transfer the reaction mixture to a 500mL beaker and add 240mL of ethyl acetate.
And 180 mL of water were added, and the mixture was stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. The aqueous layer was extracted with 120 mL of ethyl acetate. Water each organic layer 110
After washing twice with 10 mL of 10% brine 110 mL, combining, drying over anhydrous magnesium sulfate, and filtering off the desiccant,
The filtrate was concentrated to obtain 8.4 g of a crude product. This was purified by silica gel column chromatography (silica 250 g, hexane / ethyl acetate = 2/1 to 1/2) to obtain the desired product 7.
85 g (yield quant) was obtained. 1 H-NMR (DMSO-d6) δ: 6.75 (d, J = 8.8H
z, 2H), 7.86 (d, J = 8.8Hz, 2H), 9.2 (br, 1H), 9.5 (br,
1H), 10.11 (s, 1H)
【００２７】［実施例２］４−メチルチオベンズアミドの合成 Example 2 Synthesis of 4-methylthiobenzamide
【００２８】[0028]
【化１０】 [Chemical 10]
【００２９】５０ｍＬ三ツ口フラスコに、チオアセトア
ミド３．７６ｇ、ポリリン酸２０ｇを入れ、８５℃で加
熱攪拌した。ここに、４−メチルベンゾニトリル２．９
３ｇを加え、３時間４０分、８５℃で加熱攪拌した。放
冷後、内温が６０℃となったところで酢酸エチル４ｍＬ
と水４ｍＬを加え、室温まで攪拌放冷した。反応液を３
００ｍＬビーカーに移し、酢酸エチル１２０ｍＬと水９
０ｍＬを加え、３０分間攪拌した。この液の不溶物を濾
別後、分液ロートに移し、分液した。水層より酢酸エチ
ル７０ｍＬで抽出した。各有機層を水６０ｍＬで２回、
１０％食塩水６０ｍＬで洗浄後、合わせ、無水硫酸マグ
ネシウムで乾燥後、乾燥剤を濾別し、濾液を濃縮し、粗
体５．１７ｇを得た。これをシリカゲルカラムクロマト
グラフィー（シリカ１５０ｇ、ヘキサン／酢酸エチル＝
４／１〜２／１）で精製し、目的物３．９３ｇ（収率qu
ant）を得た。1
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δ：2.33(s, 3H), 7.
21(d, J=8.3Hz, 2H), 7.82(d, J=8.3Hz, 2H), 9.41(br,
1H), 9.76(br, 1H)To a 50 mL three-necked flask, 3.76 g of thioacetamide and 20 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. Here, 4-methylbenzonitrile 2.9
3 g was added, and the mixture was heated with stirring at 85 ° C. for 3 hours and 40 minutes. After standing to cool, when the internal temperature reached 60 ° C, 4 mL of ethyl acetate
And 4 mL of water were added, and the mixture was allowed to cool to room temperature with stirring. 3 reaction liquids
Transfer to a 00 mL beaker, 120 mL of ethyl acetate and water 9
0 mL was added and stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. The aqueous layer was extracted with 70 mL of ethyl acetate. Each organic layer twice with 60 mL of water,
After washing with 60 mL of 10% saline, they were combined, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated to obtain 5.17 g of a crude product. This was subjected to silica gel column chromatography (silica 150 g, hexane / ethyl acetate =
4/1 to 2/1) and then 3.93 g of the desired product (yield qu
ant). 1 H-NMR (DMSO-d6) δ: 2.33 (s, 3H), 7.
21 (d, J = 8.3Hz, 2H), 7.82 (d, J = 8.3Hz, 2H), 9.41 (br,
1H), 9.76 (br, 1H)
【００３０】［実施例３］チオベンズアミドの合成 Example 3 Synthesis of thiobenzamide
【００３１】[0031]
【化１１】 [Chemical 11]
【００３２】５０ｍＬ三ツ口フラスコに、チオアセトア
ミド３．７６ｇ、ポリリン酸２０ｇを入れ、８５℃で加
熱攪拌した。ここに、ベンゾニトリル２．５８ｇを加
え、４時間１５分、８５℃で加熱攪拌した。放冷後、内
温が６０℃となったところで酢酸エチル４ｍＬと水４ｍ
Ｌを加え、室温まで攪拌放冷した。反応液を３００ｍＬ
ビーカーに移し、酢酸エチル１２０ｍＬと水９０ｍＬを
加え、３０分間攪拌した。この液の不溶物を濾別後、分
液ロートに移し、分液した。水層より酢酸エチル７０ｍ
Ｌで抽出した。各有機層を水６０ｍＬで２回、１０％食
塩水６０ｍＬで洗浄後、合わせ、無水硫酸マグネシウム
で乾燥後、乾燥剤を濾別し、濾液を濃縮し、粗体４．６
６ｇを得た。これをシリカゲルカラムクロマトグラフィ
ー（シリカ１５０ｇ、ヘキサン／酢酸エチル＝４／１）
で精製し、目的物２．４１ｇ（収率７０％）を得た。1
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δ：7.3〜7.7(m, 3
H), 7.8〜8.0(m, 2H), 9.51(br, 1H), 9.89(br, 1H)To a 50 mL three-necked flask, 3.76 g of thioacetamide and 20 g of polyphosphoric acid were placed, and the mixture was heated and stirred at 85 ° C. To this, 2.58 g of benzonitrile was added, and the mixture was heated and stirred at 85 ° C. for 4 hours and 15 minutes. After allowing to cool, when the internal temperature reached 60 ° C, 4 mL of ethyl acetate and 4 m of water
L was added and the mixture was allowed to cool to room temperature with stirring. 300 mL of reaction solution
The mixture was transferred to a beaker, 120 mL of ethyl acetate and 90 mL of water were added, and the mixture was stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. 70m ethyl acetate from the water layer
Extracted with L. Each organic layer was washed twice with 60 mL of water, 60 mL of 10% brine, combined, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated to give a crude product 4.6.
6 g was obtained. This was subjected to silica gel column chromatography (silica 150 g, hexane / ethyl acetate = 4/1).
And purified to obtain 2.41 g of the desired product (yield 70%). 1 H-NMR (DMSO-d6) δ: 7.3 to 7.7 (m, 3
H), 7.8 ~ 8.0 (m, 2H), 9.51 (br, 1H), 9.89 (br, 1H)
【００３３】［実施例４］４−ブロモチオベンズアミドの合成 Example 4 Synthesis of 4-bromothiobenzamide
【００３４】[0034]
【化１２】 [Chemical 12]
【００３５】５０ｍＬ三ツ口フラスコに、チオアセトア
ミド３．７６ｇ、ポリリン酸２０ｇを入れ、８５℃で加
熱攪拌した。ここに、４−ブロモベンゾニトリル４．５
５ｇを加え、４時間１５分、８５℃で加熱攪拌した。放
冷後、内温が６０℃となったところで酢酸エチル４ｍＬ
と水４ｍＬを加え、室温まで攪拌放冷した。反応液を３
００ｍＬビーカーに移し、酢酸エチル１２０ｍＬと水９
０ｍＬを加え、３０分間攪拌した。この液の不溶物を濾
別後、分液ロートに移し、分液した。水層より酢酸エチ
ル７０ｍＬで抽出した。各有機層を水６０ｍＬで２回、
１０％食塩水６０ｍＬで洗浄後、合わせ、無水硫酸マグ
ネシウムで乾燥後、乾燥剤を濾別し、濾液を濃縮した。
これをシリカゲルカラムクロマトグラフィー（シリカ１
５０ｇ、ヘキサン／酢酸エチル＝４／１）で精製し、目
的物２．７８ｇ（収率５１％）を得た。1
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δ：7.62(d, J=8.6H
z, 2H), 7.82(d, J=8.6Hz, 2H), 9.58(br, 1H), 9.97(b
r, 1H)To a 50 mL three-necked flask, 3.76 g of thioacetamide and 20 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. Here, 4-bromobenzonitrile 4.5
5 g was added, and the mixture was heated with stirring at 85 ° C. for 4 hours and 15 minutes. After standing to cool, when the internal temperature reached 60 ° C, 4 mL of ethyl acetate
And 4 mL of water were added, and the mixture was allowed to cool to room temperature with stirring. 3 reaction liquids
Transfer to a 00 mL beaker, 120 mL of ethyl acetate and water 9
0 mL was added and stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. The aqueous layer was extracted with 70 mL of ethyl acetate. Each organic layer twice with 60 mL of water,
After washing with 60 mL of 10% saline, they were combined, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated.
This is subjected to silica gel column chromatography (silica 1
The product was purified with 50 g and hexane / ethyl acetate = 4/1) to obtain 2.78 g of the desired product (yield 51%). 1 H-NMR (DMSO-d6) δ: 7.62 (d, J = 8.6H
z, 2H), 7.82 (d, J = 8.6Hz, 2H), 9.58 (br, 1H), 9.97 (b
r, 1H)
【００３６】［実施例５］４−イソブチルオキシチオベンズアミドの合成 Example 5 Synthesis of 4-isobutyloxythiobenzamide
【００３７】[0037]
【化１３】 [Chemical 13]
【００３８】５０ｍＬ三ツ口フラスコに、チオアセトア
ミド３．７６ｇ、ポリリン酸２０ｇを入れ、８５℃で加
熱攪拌した。ここに、４−イソブチルオキシベンゾニト
リル５．３５４ｇを加え、４時間４０分、８５℃で加熱
攪拌した。放冷後、内温が６０℃となったところで酢酸
エチル４ｍＬと水４ｍＬを加え、室温まで攪拌放冷し
た。反応液を３００ｍＬビーカーに移し、酢酸エチル１
２０ｍＬと水９０ｍＬを加え、３０分間攪拌した。この
液の不溶物を濾別後、分液ロートに移し、分液した。水
層より酢酸エチル７０ｍＬで抽出した。各有機層を水６
０ｍＬで２回、１０％食塩水６０ｍＬで洗浄後、合わ
せ、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別し、
濾液を濃縮した。これをシリカゲルカラムクロマトグラ
フィー（シリカ３００ｇ、ヘキサン／酢酸エチル＝４／
１）で精製し、目的物４．６２ｇ（収率８９％）を得
た。1
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δ：6.94(d, J=9Hz,
3H), 7.94(d, J=9Hz, 3H), 9.32(br, 1H), 9.63(br, 1
H)In a 50 mL three-necked flask, 3.76 g of thioacetamide and 20 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. 5.354 g of 4-isobutyloxy benzonitrile was added here, and it heat-stirred at 85 degreeC for 4 hours and 40 minutes. After cooling, 4 mL of ethyl acetate and 4 mL of water were added when the internal temperature reached 60 ° C., and the mixture was cooled to room temperature with stirring. Transfer the reaction mixture to a 300 mL beaker, and add ethyl acetate 1
20 mL and 90 mL of water were added and stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. The aqueous layer was extracted with 70 mL of ethyl acetate. Water each organic layer 6
After washing twice with 0 mL and 60 mL of 10% saline, they were combined, dried over anhydrous magnesium sulfate, and the desiccant was filtered off.
The filtrate was concentrated. This was subjected to silica gel column chromatography (silica 300 g, hexane / ethyl acetate = 4 /
The product was purified in 1) to obtain 4.62 g of the desired product (yield 89%). 1 H-NMR (DMSO-d6) δ: 6.94 (d, J = 9Hz,
3H), 7.94 (d, J = 9Hz, 3H), 9.32 (br, 1H), 9.63 (br, 1
H)
【００３９】［実施例６］２−（４−ヒドロキシフェニル）−４−メチル−５−チ
アゾールカルボン酸エチルの合成 Example 6 2- (4-hydroxyphenyl) -4-methyl-5-thio
Synthesis of ethyl azolecarboxylate
【００４０】[0040]
【化１４】 [Chemical 14]
【００４１】２００ｍＬ三ツ口フラスコに、チオアセト
アミド７．６ｇ、ポリリン酸４０ｇを入れ、８５℃で加
熱攪拌した。ここに、４−ヒドロキシベンゾニトリル
８．０ｇを加え、３時間、８５℃で加熱攪拌した。ここ
に、３−クロロアセト酢酸エチル１８．３１ｇを滴下
し、その後１時間、８５℃で加熱攪拌した。放冷後、内
温が６０℃となったところで水８ｍＬを加え、室温まで
攪拌放冷した。反応液に水８０ｍＬを加え、再度６０℃
で加熱攪拌を１５分間行い、放冷し、析出物を濾取し
た。得られた固体をエタノール４０ｍＬで２回洗浄後、
乾燥し、目的物８．１２ｇ（収率４６％）を得た。1
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δ：1.29(t, J=7.3H
z, 3H), 2.66(s, 3H), 3.9(br, 1H), 4.28(q, J=7.2H
z), 6.87(d, J=8.6Hz, 2H), 7.84(d, J=8.6Hz, 2H)In a 200 mL three-necked flask, 7.6 g of thioacetamide and 40 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. To this, 8.0 g of 4-hydroxybenzonitrile was added, and the mixture was heated with stirring at 85 ° C. for 3 hours. 18.31 g of ethyl 3-chloroacetoacetate was added dropwise thereto, and then heated and stirred at 85 ° C. for 1 hour. After cooling, 8 mL of water was added when the internal temperature reached 60 ° C., and the mixture was cooled to room temperature with stirring. 80 mL of water was added to the reaction solution, and the temperature was again 60 ° C.
The mixture was heated and stirred for 15 minutes, allowed to cool, and the precipitate was collected by filtration. After washing the obtained solid twice with 40 mL of ethanol,
It was dried to obtain 8.12 g of the desired product (yield 46%). 1 H-NMR (DMSO-d6) δ: 1.29 (t, J = 7.3H
z, 3H), 2.66 (s, 3H), 3.9 (br, 1H), 4.28 (q, J = 7.2H
z), 6.87 (d, J = 8.6Hz, 2H), 7.84 (d, J = 8.6Hz, 2H)
【００４２】[0042]
【発明の効果】本発明によれば、安全な試薬を使って、
チオベンズアミド誘導体および２−フェニルチアゾール
誘導体を容易かつ安価に得ることができる。According to the present invention, using a safe reagent,
A thiobenzamide derivative and a 2-phenylthiazole derivative can be obtained easily and inexpensively.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 平６−345724（ＪＰ，Ａ) 特開 平６−65222（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) C07C 327/48 C07D 277/22 C07D 277/32 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-6-345724 (JP, A) JP-A-6-65222 (JP, A) (58) Fields investigated (Int.Cl. 7 , DB name) C07C 327/48 C07D 277/22 C07D 277/32
Claims (6)
ン原子、水酸基、無置換もしくは置換されたＣ1〜Ｃ5の
アルキル基、または、無置換もしくは置換されたＣ1〜
Ｃ5のアルコキシル基を表す。］で表されるベンゾニト
リル誘導体を、ポリリン酸中、チオアセトアミドと反応
させることを特徴とする、下記式（２） 【化２】 ［式中、Ｒ1の定義は前記式（１）におけるものと同
じ。］で表されるチオベンズアミド誘導体の製造方法。1. The following formula (1): [Wherein, R 1 is a substituent on the aromatic ring, and is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C 1 to C 5 alkyl group, or an unsubstituted or substituted C 1 to
Represents a C 5 alkoxyl group. ] The benzonitrile derivative represented by the formula is reacted with thioacetamide in polyphosphoric acid, and is represented by the following formula (2): [In the formula, the definition of R 1 is the same as in the above formula (1). ] The manufacturing method of the thiobenzamide derivative represented by these.
求項１記載のチオベンズアミド誘導体の製造方法。2. The method for producing a thiobenzamide derivative according to claim 1, wherein R 1 is a substituent at the 4-position on the aromatic ring.
チル基、またはイソブチルオキシ基である、請求項２記
載のチオベンズアミド誘導体の製造方法。3. The method for producing a thiobenzamide derivative according to claim 2, wherein R 1 is a hydrogen atom, a bromine atom, a hydroxyl group, a methyl group, or an isobutyloxy group.
誘導体を、ポリリン酸中チオアセトアミドと反応後、単
離することなく、下記式（３） 【化３】 ［式中、Ｒ2は水素原子またはＣ1〜Ｃ4のアルキル基を
表し、Ｒ3は水素原子、Ｃ1〜Ｃ4のアルキル基、Ｃ1〜Ｃ
4のアルキルカルボニル基、Ｃ1〜Ｃ4のアルキル（モノ
もしくはジ置換）アミノカルボニル基、カルバモイル
基、Ｃ1〜Ｃ4のアルコキシカルボニル基、またはカルボ
キシル基を表し、Ｘは塩素原子、臭素原子、またはヨウ
素原子を表す。］で表されるα−ハロケトン類を反応さ
せることを特徴とする、下記式（４） 【化４】 ［式中、Ｒ1の定義は前記式（１）におけるものと同じ
であり、Ｒ2およびＲ3の定義は前記式（３）におけるも
のに同じである。］で表される２−フェニルチアゾール
誘導体の製造方法。4. A benzonitrile derivative represented by the above formula (1) is reacted with thioacetamide in polyphosphoric acid and then isolated without being isolated from the following formula (3): [In the formula, R 2 represents a hydrogen atom or a C 1 to C 4 alkyl group, R 3 represents a hydrogen atom, a C 1 to C 4 alkyl group, and a C 1 to C 4
4 alkylcarbonyl group, C 1 -C 4 alkyl (mono- or di-substituted) aminocarbonyl group, carbamoyl group, C 1 -C 4 alkoxycarbonyl group, or carboxyl group, X is a chlorine atom, a bromine atom, Or represents an iodine atom. ] An α-haloketone represented by the formula: [In the formula, the definition of R 1 is the same as that in the above formula (1), and the definitions of R 2 and R 3 are the same as those in the above formula (3). ] The manufacturing method of the 2-phenyl thiazole derivative represented by these.
求項４記載の２−フェニルチアゾール誘導体の製造方
法。5. The method for producing a 2-phenylthiazole derivative according to claim 4, wherein R 1 is a substituent at the 4-position on the aromatic ring.
−フェニルチアゾール誘導体の製造方法。6. The method according to claim 5, wherein R 1 is a hydroxyl group.
-A method for producing a phenylthiazole derivative.
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|---|---|---|---|
| JP21851797A JP3440196B2 (en) | 1997-08-13 | 1997-08-13 | Method for producing thiobenzamide derivative |
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|---|---|---|---|
| JP21851797A JP3440196B2 (en) | 1997-08-13 | 1997-08-13 | Method for producing thiobenzamide derivative |
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|---|---|---|---|---|
| JP4711494B2 (en) * | 2000-08-10 | 2011-06-29 | 住友精化株式会社 | Method for producing thiobenzamides |
| US20050027128A1 (en) * | 2003-07-30 | 2005-02-03 | Robbins Timothy A. | Substituted thiazoles |
| CA2752485C (en) | 2009-02-27 | 2017-01-03 | Teijin Pharma Limited | Process for producing phenyl-substituted heterocyclic derivative through coupling using transition metal catalyst |
| BRPI1011014A2 (en) * | 2009-06-09 | 2019-09-24 | Teijin Pharma Ltd | production method. |
| CN102086169B (en) * | 2009-12-04 | 2014-01-15 | 重庆医药工业研究院有限责任公司 | Preparation method of intermediates of Febuxostat |
| AU2011294204B2 (en) | 2010-08-27 | 2015-07-23 | Teijin Limited | Method for producing phenyl-substituted heterocyclic derivative by means of coupling method using a palladium compound |
-
1997
- 1997-08-13 JP JP21851797A patent/JP3440196B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH1160552A (en) | 1999-03-02 |
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