JP2007210938A - Method for production of isothiazolopyridine compound - Google Patents

Method for production of isothiazolopyridine compound Download PDF

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JP2007210938A
JP2007210938A JP2006032147A JP2006032147A JP2007210938A JP 2007210938 A JP2007210938 A JP 2007210938A JP 2006032147 A JP2006032147 A JP 2006032147A JP 2006032147 A JP2006032147 A JP 2006032147A JP 2007210938 A JP2007210938 A JP 2007210938A
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isothiazolopyridine
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JP4729742B2 (en
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Masao Shimizu
政男 清水
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National Institute of Advanced Industrial Science and Technology AIST
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a new method for producing isothiazolopyridine compound. <P>SOLUTION: The method for producing the isothiazolopyridine compound represented by general formula (A) comprises treatment of a 2-sulfenamoyl nicotinate compound represented by general formula (B), in the presence of a base. In the formula, substituent R<SP>1</SP>is a 1-8C chain alkyl or a 3-8C cyclic alkyl, etc. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

本発明は、イソチアゾロピリジン化合物の新規な製造方法に関するものである。   The present invention relates to a novel method for producing an isothiazolopyridine compound.

イソチアゾロピリジン化合物の誘導体には種々の生理活性があることが報告されている。例えば、窒素に結合している置換基を有する化合物の誘導体は、抗菌作用（特許文献１、非特許文献１、非特許文献２）、血小板凝集阻害作用（特許文献２）、抗座瘡作用（特許文献３、特許文献４、特許文献５）等を有していることが知られている。これらの化合物の出発原料となるイソチアゾロピリジン化合物の必要性が注目されており、そのための製造方法の研究が期待されている。   It has been reported that derivatives of isothiazolopyridine compounds have various physiological activities. For example, a derivative of a compound having a substituent bonded to nitrogen has antibacterial action (Patent Document 1, Non-Patent Document 1, Non-Patent Document 2), platelet aggregation inhibitory action (Patent Document 2), anti-acne action ( It is known to have Patent Literature 3, Patent Literature 4, Patent Literature 5) and the like. The need for isothiazolopyridine compounds as starting materials for these compounds has attracted attention, and research on production methods therefor is expected.

従来から知られているイソチアゾロピリジン化合物を製造する方法には、塩化２−クロロチオニコチニル化合物とアミン類を反応させる方法（非特許文献３）、２−メルカプトニコチンアミド化合物をヨウ素やフェロシアン化カリウムにより酸化する方法（非特許文献２、非特許文献４）、Ｎ，Ｎ−ジメチル−２−メルカプトニコチンアミド化合物とオキサジリジン化合物を反応させる方法（非特許文献５）、２−メルカプトニコチノニトリルと硫酸を反応させる方法（非特許文献６），２−メルカプトニコチン酸とアジド化合物を反応させる方法（非特許文献７）等が一般的に知られている。
これらのうち塩化２−クロロチオニコチニル化合物を用いる方法では、原料の塩化２−クロロチオニコチニル化合物を合成する際に塩素ガスを用いなければならず、その製造工程では塩素ガスは使用するために、取り扱いに困難さを有しており、できれば使用したしたくない反応とされる。又、酸化反応を利用する反応の場合には、硫黄原子など部位が酸化される可能性がある。又、オキサジリジン化合物を用いる反応においては、原料化合物であるオキサジリジンを製造することができないので、工業的な方法として確立することはできない。２−メルカプトニコチノニトリルと硫酸を反応させる方法では、濃硫酸中で１００℃に加熱するという過酷な反応条件を克服する必要がある。２−メルカプトニコチン酸とアゾ化合物を反応させる方法では、アジド化合物は爆発性を有するため、反応に際して危険を伴うことが指摘されている。 Conventionally known methods for producing isothiazolopyridine compounds include a method of reacting a 2-chlorothionicotinyl chloride compound with an amine (Non-patent Document 3), a 2-mercaptonicotinamide compound containing iodine or potassium ferrocyanide. (Non-patent document 2, Non-patent document 4), N, N-dimethyl-2-mercaptonicotinamide compound and oxaziridine compound (non-patent document 5), 2-mercaptonicotinonitrile and sulfuric acid In general, there are known a method of reacting a non-patent document 6 and a method of reacting 2-mercaptonicotinic acid and an azide compound (non-patent document 7).
Among these, in the method using a 2-chlorothionicotinyl chloride compound, chlorine gas must be used when synthesizing the raw material 2-chlorothionicotinyl chloride compound, and chlorine gas is used in the production process. In addition, the reaction is difficult to handle, and if possible, the reaction is not desired. In the case of a reaction utilizing an oxidation reaction, a site such as a sulfur atom may be oxidized. Moreover, in the reaction using an oxaziridine compound, oxaziridine which is a raw material compound cannot be produced, and therefore cannot be established as an industrial method. In the method of reacting 2-mercaptonicotinonitrile and sulfuric acid, it is necessary to overcome the severe reaction condition of heating to 100 ° C. in concentrated sulfuric acid. In the method of reacting 2-mercaptonicotinic acid and an azo compound, it has been pointed out that the azide compound is explosive and therefore dangerous.

このようなことから、安全で、確実な方法によるイソチアゾロピリジン化合物を製造する方法が望まれている。

アメリカ国特許３９６５１０７号。 ドイツ国特許２７１８７０７号。 ドイツ国特許３３１３７７８号。 ドイツ国特許３３４２５３８号。 フランス国特許２５５５４５０号。 W. Malinka等，Farmaco, 53, 504-512 (1998). M. Pregnolato等, Pharmaco,55, 669-679 (2000). V. Martinez-Merino等, Heterocycles,38, 333 (1994). W. Schaper, Synthesis, 1985, 861-867. S. Andreae, J. Prakt. Chem., 339, 152-158 (1997). T. Zawisza andW. Malinka, Farmaco Ed. Sc., 40, 124-132 (1985). T. Chiyoda等, Synlett,2000, 1427-1428. Therefore, a method for producing an isothiazolopyridine compound by a safe and reliable method is desired.

US patent 3965107. German patent No. 2718707. German patent 33133778. German patent 3342538. French patent No. 2555450. W. Malinka et al., Farmaco, 53, 504-512 (1998). M. Pregnolato et al., Pharmaco, 55, 669-679 (2000). V. Martinez-Merino et al., Heterocycles, 38, 333 (1994). W. Schaper, Synthesis, 1985, 861-867. S. Andreae, J. Prakt. Chem., 339, 152-158 (1997). T. Zawisza and W. Malinka, Farmaco Ed. Sc., 40, 124-132 (1985). T. Chiyoda et al., Synlett, 2000, 1427-1428.

本発明の課題は、イソチアゾロピリジン化合物の新規な製造方法を提供することである。   An object of the present invention is to provide a novel method for producing an isothiazolopyridine compound.

本発明者らは、イソチアゾロピリジン化合物の製造方法について鋭意研究を重ねた結果、２−スルフェナモイルニコチン酸エステル化合物を塩基の存在下に処理すると、Ｓ原子に結合しているアミノ基によるアミド結合が形成されて環化反応が進行し、イソチアゾロピリジン化合物を製造することができることを見いだして、本発明を完成させたものである。   As a result of intensive studies on a method for producing an isothiazolopyridine compound, the present inventors have found that when a 2-sulfenamoylnicotinic acid ester compound is treated in the presence of a base, an amide derived from an amino group bonded to an S atom is obtained. The present invention has been completed by finding that a bond is formed and a cyclization reaction proceeds to produce an isothiazolopyridine compound.

本発明によれば、以下の発明が提供される。
（１）下記一般式（Ａ）で表されるイソチアゾロピリジン化合物を製造する方法において、下記一般式（Ｂ）で表される２−スルフェナモイルニコチン酸エステル化合物を塩基の存在下に処理することを特徴とするイソチアゾロピリジン化合物の製造方法。

Figure 2007210938
（式中、置換基Ｒ１は、炭素数１〜８の鎖状又は炭素数３〜８の環状アルキル基、炭素数１〜８の鎖状又は炭素数3〜８の環状アルコキシル基、炭素数２〜１２の鎖状又は炭素数４から９の環状アルコキシカルボニル基、フェニル基、及びハロゲン原子から選ばれる基又は原子を表す。Ｒ１が複数ある場合は、各Ｒ１は互いに同一であっても異なっていてもよい。ｎは、０又は１〜３の整数である。）
Figure 2007210938
 （式中、置換基Ｒ１は、炭素数１〜８の鎖状又は炭素数３〜８の環状アルキル基、炭素数１〜８の鎖状又は炭素数3〜８の環状アルコキシル基、炭素数２〜１２の鎖状又は炭素数４から９の環状アルコキシカルボニル基、フェニル基、及びハロゲン原子から選ばれる基又は原子を表す。Ｒ１が複数ある場合は、各Ｒ１は互いに同一であっても異なっていてもよい。ｎは、０又は１〜３の整数である。Ｒ２は、炭素数１〜６のアルキル基を示す。）
（２）前記塩基が水酸化カリウムであることを特徴とするイソチアゾロピリジン化合物の製造方法。 According to the present invention, the following inventions are provided.
(1) In the method for producing an isothiazolopyridine compound represented by the following general formula (A), the 2-sulfenamoylnicotinic acid ester compound represented by the following general formula (B) is treated in the presence of a base. A process for producing an isothiazolopyridine compound, characterized in that
Figure 2007210938
 (In the formula, the substituent R 1 is a chain having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, a chain having 1 to 8 carbon atoms, or a cyclic alkoxyl group having 3 to 8 carbon atoms, carbon number. 2-12 linear or cyclic alkoxycarbonyl group having a carbon number of 4-9, phenyl group, and if .R 1 represents a group or atom selected from a halogen atom is more, each R 1 is the same as each other And n is an integer of 0 or 1 to 3).
Figure 2007210938
 (In the formula, the substituent R 1 is a chain having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, a chain having 1 to 8 carbon atoms, or a cyclic alkoxyl group having 3 to 8 carbon atoms, carbon number. 2-12 linear or cyclic alkoxycarbonyl group having a carbon number of 4-9, phenyl group, and if .R 1 represents a group or atom selected from a halogen atom is more, each R 1 is the same as each other (N is an integer of 0 or 1 to 3. R 2 represents an alkyl group having 1 to 6 carbon atoms.)
(2) The method for producing an isothiazolopyridine compound, wherein the base is potassium hydroxide.

本発明の方法によれば、２−スルフェナモイルニコチン酸エステル化合物を塩基存在下に処理することにより、イソチアゾロピリジン化合物を得ることができる。従来法である塩素ガスを用いる塩化スルフェニル化合物を経由する製造方法に比べ、塩素を直接使用しないので製造工程には、塩素を使用することに伴う危険性はない。又、他の製造方法に比較して目的物質の選択性もよく、製造方法として良好なものである。   According to the method of the present invention, an isothiazolopyridine compound can be obtained by treating a 2-sulfenamoylnicotinic acid ester compound in the presence of a base. Compared to the conventional production method using a chlorinated sulfenyl compound using chlorine gas, chlorine is not used directly, so there is no danger associated with the use of chlorine in the production process. In addition, the selectivity of the target substance is good compared to other production methods, which is a good production method.

本発明の方法は、下記一般式（Ｂ）で表されるスルフェンアミド化合物を塩基の存在下に処理して下記一般式（A）で表されるイソチアゾロピリジン化合物を製造する方法である。

Figure 2007210938
Figure 2007210938
 （上記二つの式中、置換基Ｒ１は、炭素数１〜８の鎖状又は炭素数３〜８の環状アルキル基、炭素数１〜８の鎖状又は炭素数3〜８の環状アルコキシル基、炭素数２〜１２の鎖状又は炭素数４から９の環状アルコキシカルボニル基、フェニル基、及びハロゲン原子から選ばれる基又は原子を表す。Ｒ１が複数ある場合は、各Ｒ１は互いに同一であっても異なっていてもよい。ｎは、０又は１〜３の整数である。Ｒ２は、炭素数１〜６のアルキル基を示す。） The method of the present invention is a method for producing an isothiazolopyridine compound represented by the following general formula (A) by treating a sulfenamide compound represented by the following general formula (B) in the presence of a base.
Figure 2007210938
Figure 2007210938
 (In the above two formulas, the substituent R 1 is a chain having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, a chain having 1 to 8 carbon atoms, or a cyclic alkoxyl group having 3 to 8 carbon atoms. , cyclic alkoxycarbonyl group having a chain-like or a C 4 having 2 to 12 carbon atoms 9, a phenyl group, and if .R 1 represents a group or atom selected from a halogen atom is more, each R 1 is each independently And n is an integer of 0 or 1 to 3. R 2 represents an alkyl group having 1 to 6 carbon atoms.

前記式中のＲ１の鎖状アルキル基は炭素数１から８であり、具体的には、メチル、エチル、プロピル、イソプロピル、ｎ−ブチル、t−ブチル、イソブチル、ｎ−ペンチル、イソペンチル、ｔ−ペンチル、ｎ−ヘキシル、イソヘキシル、ｔ−ヘキシル、ｎ−ヘプチル、イソヘプチル、ｔ−ヘプチル、ｎ−オクチル、イソオクチル、ｔ−オクチル基等が挙げられる。
同じく、Ｒ１の環状のアルキル基は炭素数３〜８であり、具体的には、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、メチルシクロヘキシル、シクロヘプチル、シクロオクチル基を挙げることができる。
前記式中、Ｒ１の鎖状アルコキシ基は炭素数１〜８であり、具体的には、メトキシ、エトキシ、プロポキシ、イソプロポキシ、シクロプロポキシ、ブトキシ、イソブトキシ、t−ブトキシ、ペンチロキシ基を挙げることができる。
同じく、Ｒ１の環状アルコキシ基は炭素数３〜８であり、シクロプロピロキシ、シクロブトキシ、シクロペンチロキシ、シクロヘキシル、メチルシクロヘキシル、シクロヘプチル、シクロオクチル基を挙げることができる。
前記式中、Ｒ１の鎖状アルコキシカルボニル基は炭素数２〜１２であり、具体的には、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、t−ブトキシカルボニル、ペンチロキシカルボニル、ヘキシロキシカルボニル基を挙げることができる。
同じく、Ｒ１の環状アルキロキシカルボニル基は炭素数４〜９であり、具体的には、シクロプロポキシカルボニル、シクロブチロキシカルボニル、シクロペンチロキシカルボニル、シクロヘキシロキシカリボニル、メチルシクロヘキシロキシカルボニル、シクロヘプチロキシ、シクロオクチロキシ基を挙げることができる。 The chain alkyl group of R 1 in the above formula has 1 to 8 carbon atoms, and specifically includes methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-pentyl, isopentyl, t -Pentyl, n-hexyl, isohexyl, t-hexyl, n-heptyl, isoheptyl, t-heptyl, n-octyl, isooctyl, t-octyl group and the like.
Similarly, the cyclic alkyl group of R 1 has 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl groups.
In the above formula, the chain alkoxy group of R 1 has 1 to 8 carbon atoms, and specific examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, t-butoxy, and pentyloxy groups. Can do.
Similarly, the cyclic alkoxy group of R 1 has 3 to 8 carbon atoms, and examples thereof include cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl groups.
In the above formula, the linear alkoxycarbonyl group of R 1 has 2 to 12 carbon atoms, specifically, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl , Pentyloxycarbonyl, and hexyloxycarbonyl groups.
Similarly, the cyclic alkyloxycarbonyl group of R 1 has 4 to 9 carbon atoms, and specifically includes cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, methylcyclohexyloxycarbonyl, cyclohexyl Mention may be made of propyloxy and cyclooctyloxy groups.

前記式中、Ｒ２の鎖状アルキル基は炭素数１〜６であり、具体的には、メチル、エチル、プロピル、イソプロピル、ｎ−ブチル、イソブチル、t−ブチル、ｎ−ペンチル、イソペンチル、ｔ−ペンチル、ｎ−ヘキシル、イソヘキシル、ｔ−ヘキシル基を挙げることができる。 In the above formula, the chain alkyl group of R 2 has 1 to 6 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, t -Pentyl, n-hexyl, isohexyl, t-hexyl groups can be mentioned.

上記処理に際して用いられる原料物質である一般式（Ｂ）で表される２−スルフェナモイルニコチン酸エステル化合物は公知物質である。
（Ｂ）の製法の一例を挙げれば、２−メルカプトニコチン酸エステル化合物のヒドロキシルアミン−Ｏ−スルホン酸によるＳ−アミノ化反応による製造方法を挙げることができる。 The 2-sulfenamoyl nicotinic acid ester compound represented by the general formula (B), which is a raw material used in the above treatment, is a known substance.
If an example of the manufacturing method of (B) is given, the manufacturing method by S-amination reaction by the hydroxylamine-O-sulfonic acid of 2-mercaptonicotinic acid ester compound can be mentioned.

前記処理に際して用いられる反応条件は以下のとおりである。
反応温度は、０℃〜１５０℃の範囲の温度で行うことができる。この温度範囲以下の低温の場合には反応時間が遅くなり、この範囲を超えて高すぎる場合には、異常な分解反応や副反応が多い結果となる。このようなことから、前記温度範囲は、１０℃〜１００℃の範囲であることが好ましい。 The reaction conditions used for the treatment are as follows.
The reaction temperature can be carried out at a temperature in the range of 0 ° C to 150 ° C. When the temperature is lower than this temperature range, the reaction time is delayed, and when it is too high beyond this range, there are many abnormal decomposition reactions and side reactions. Therefore, the temperature range is preferably in the range of 10 ° C to 100 ° C.

この反応は、反応溶媒中行われる。溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ｔ−ブタノール、クロロホルム、ベンゼン、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、アニソール、アセトニトリル、テトラヒドロフラン、1,4−ジオキサン等の有機溶媒が挙げられ、これらの混合溶媒の形で使用してもかまわない。   This reaction is performed in a reaction solvent. Examples of the solvent include organic solvents such as methanol, ethanol, propanol, isopropanol, t-butanol, chloroform, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, anisole, acetonitrile, tetrahydrofuran, and 1,4-dioxane. It may be used in the form of a mixed solvent.

反応時間は、採用される反応温度、及び存在させる前記溶媒の種類により左右され、一概に定めることはできないが、通常は５〜２０時間である。   The reaction time depends on the reaction temperature employed and the kind of the solvent to be present, and cannot be generally defined, but is usually 5 to 20 hours.

この反応に用いる塩基は、水酸化ナトリウム、水酸化カリウム、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム ｔ−ブトキシド、カリウム、ｔ−ブトキシドから選ばれる塩基物質である。   The base used in this reaction is a basic substance selected from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium and t-butoxide.

本発明の方法では、溶媒を減圧下留去させ反応混合物に水を加え生成物を塩化メチレンなどの有機溶媒で抽出することにより分離され、生成物として得ることができる。反応生成物は原料物質に対して高収率で得られる。   In the method of the present invention, the solvent is distilled off under reduced pressure, water is added to the reaction mixture, and the product is extracted with an organic solvent such as methylene chloride to obtain a product as a product. The reaction product is obtained in a high yield relative to the raw material.

本発明で得られる一般式Ａで表されるイソチアゾロピリジン化合物は、除草剤、殺菌剤の原料として用いられる。
イソチアゾロピリジン化合物の具体例について例示すると以下の化学式（１）〜（２）で示される化合物である。しかしながら、これらの化合物に限定されるものではない。

Figure 2007210938
The isothiazolopyridine compound represented by the general formula A obtained in the present invention is used as a raw material for herbicides and fungicides.
Specific examples of the isothiazolopyridine compound are compounds represented by the following chemical formulas (1) to (2). However, it is not limited to these compounds.
Figure 2007210938

次に、本発明を実施例により詳細に説明する。
以下に述べる実施例は本発明の理解を容易にするために代表的な化合物の一例をあげたものであり、本発明はこれに限定されるものではない。また、製造された化合物（１）〜（２）は、前記で示した化合物（１）〜（２）に対応するものである。 Next, the present invention will be described in detail with reference to examples.
Examples described below are examples of typical compounds for facilitating the understanding of the present invention, and the present invention is not limited thereto. Further, the produced compounds (1) to (2) correspond to the compounds (1) to (2) shown above.

内容積２００ｍｌのガラス製容器中に２−スルフェナモイルニコチン酸メチル（１００ｍｇ，０．５４ｍｍｏｌ）をエタノール（１０ｍｌ）に溶解させ、水酸化カリウム（１００ｍｇ）を加えて、室温で４５分間攪拌した。反応終了後、溶媒を減圧下留去させ反応混合物に水を加え生成物を塩化メチレンで抽出し生成物を得た。粗生成物をシリカゲルクロマトグラフィー（溶媒塩化メチレン：アセトン：メタノール＝１００：１０：２）で精製した後、目的生成物である化合物（１）のイソチアゾロピリジンを得た（収率：８２％）。さらにメタノールを溶媒として再結晶でさらに精製することができた。融点２２２．０−２２３．５℃（文献値：２２２−２２４℃）。   In a glass container with an internal volume of 200 ml, methyl 2-sulfenamoylnicotinate (100 mg, 0.54 mmol) was dissolved in ethanol (10 ml), potassium hydroxide (100 mg) was added, and the mixture was stirred at room temperature for 45 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the reaction mixture, and the product was extracted with methylene chloride to obtain the product. After the crude product was purified by silica gel chromatography (solvent methylene chloride: acetone: methanol = 100: 10: 2), the desired product compound (1), isothiazolopyridine, was obtained (yield: 82%). . Further purification was possible by recrystallization using methanol as a solvent. Melting point 222.0-223.5 ° C. (literature value: 222-224 ° C.).

内容積２００ｍｌのガラス製容器中に２−スルフェナモイルニコチン酸エチル（１００ｍｇ，０．５０ｍｍｏｌ）をエタノール（１０ｍｌ）に溶解させ、水酸化カリウム（１００ｍｇ）を加えて、室温で４５分間攪拌した。反応終了後、溶媒を減圧下留去させ反応混合物に水を加え生成物を塩化メチレンで抽出し生成物を得た。粗生成物をシリカゲルクロマトグラフィー（溶媒塩化メチレン：アセトン：メタノール＝１００：１０：２）で精製した後、目的生成物である化合物（１）のイソチアゾロピリジンを得た（収率：９２％）。   In a glass container having an internal volume of 200 ml, ethyl 2-sulfenamoylnicotinate (100 mg, 0.50 mmol) was dissolved in ethanol (10 ml), potassium hydroxide (100 mg) was added, and the mixture was stirred at room temperature for 45 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the reaction mixture, and the product was extracted with methylene chloride to obtain the product. After the crude product was purified by silica gel chromatography (solvent methylene chloride: acetone: methanol = 100: 10: 2), the desired product compound (1), isothiazolopyridine, was obtained (yield: 92%). .

内容積２００ｍｌのガラス製容器中に６−メチル−２−スルフェナモイルニコチン酸エチル（１００ｍｇ，０．４７ｍｍｏｌ）をエタノール（１０ｍｌ）に溶解させ、水酸化カリウム（１００ｍｇ）を加えて、室温で４５分間攪拌した。反応終了後、溶媒を減圧下留去させ反応混合物に水を加え生成物を塩化メチレンで抽出し生成物を得た。粗生成物をシリカゲルクロマトグラフィー（溶媒塩化メチレン：アセトン：メタノール＝１００：１０：２）で精製した後、目的生成物である化合物（２）のイソチアゾロピリジンを得た（収率：６９％）。
In a glass container having an internal volume of 200 ml, ethyl 6-methyl-2-sulfenamoylnicotinate (100 mg, 0.47 mmol) was dissolved in ethanol (10 ml), and potassium hydroxide (100 mg) was added. Stir for minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the reaction mixture, and the product was extracted with methylene chloride to obtain the product. After the crude product was purified by silica gel chromatography (solvent methylene chloride: acetone: methanol = 100: 10: 2), the desired product compound (2), isothiazolopyridine, was obtained (yield: 69%). .

Claims (2)

下記一般式（Ａ）で表されるイソチアゾロピリジン化合物を製造する方法において、下記一般式（Ｂ）で表されるスルフェンアミド化合物を塩基存在下に処理することを特徴とするイソチアゾロピリジン化合物の製造方法。
Figure 2007210938
 （式中、置換基Ｒ１は、炭素数１〜８の鎖状又は炭素数３〜８の環状アルキル基、炭素数１〜８の鎖状又は炭素数3〜８の環状アルコキシル基、炭素数２〜１２の鎖状又は炭素数４から９の環状アルコキシカルボニル基、フェニル基、及びハロゲン原子から選ばれる基又は原子を表す。Ｒ１が複数ある場合は、各Ｒ１は互いに同一であっても異なっていてもよい。ｎは、０又は１〜３の整数である。）
Figure 2007210938
 （式中、置換基Ｒ１は、炭素数１〜８の鎖状又は炭素数３〜８の環状アルキル基、炭素数１〜８の鎖状又は炭素数3〜８の環状アルコキシル基、炭素数２〜１２の鎖状又は炭素数４から９の環状アルコキシカルボニル基、フェニル基、及びハロゲン原子から選ばれる基又は原子を表す。Ｒ１が複数ある場合は、各Ｒ１は互いに同一であっても異なっていてもよい。ｎは、０又は１〜３の整数である。Ｒ２は、炭素数１〜６のアルキル基を示す。） A method for producing an isothiazolopyridine compound represented by the following general formula (A), wherein the sulfenamide compound represented by the following general formula (B) is treated in the presence of a base: Manufacturing method.
Figure 2007210938
 (In the formula, the substituent R 1 is a chain having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, a chain having 1 to 8 carbon atoms, or a cyclic alkoxyl group having 3 to 8 carbon atoms, carbon number. 2-12 linear or cyclic alkoxycarbonyl group having a carbon number of 4-9, phenyl group, and if .R 1 represents a group or atom selected from a halogen atom is more, each R 1 is the same as each other And n is an integer of 0 or 1 to 3).
Figure 2007210938
 (In the formula, the substituent R 1 is a chain having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, a chain having 1 to 8 carbon atoms, or a cyclic alkoxyl group having 3 to 8 carbon atoms, carbon number. 2-12 linear or cyclic alkoxycarbonyl group having a carbon number of 4-9, phenyl group, and if .R 1 represents a group or atom selected from a halogen atom is more, each R 1 is the same as each other (N is an integer of 0 or 1 to 3. R 2 represents an alkyl group having 1 to 6 carbon atoms.) 前記塩基が水酸化カリウムであることを特徴とするイソチアゾロピリジン化合物の製造方法。
The method for producing an isothiazolopyridine compound, wherein the base is potassium hydroxide.
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WO2012072019A1 (en) * 2010-11-29 2012-06-07 Zee-Fen Chang Targeting human thymidylate kinase induces dna repair toxicity in malignant tumor cells
US9662328B2 (en) 2010-11-29 2017-05-30 National Yang-Ming University Targeting human thymidylate kinase induces DNA repair toxicity in malignant tumor cells

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Publication number Priority date Publication date Assignee Title
WO2012072019A1 (en) * 2010-11-29 2012-06-07 Zee-Fen Chang Targeting human thymidylate kinase induces dna repair toxicity in malignant tumor cells
US9278982B2 (en) 2010-11-29 2016-03-08 National Yang-Ming University Targeting human thymidylate kinase induces DNA repair toxicity in malignant tumor cells
US9662328B2 (en) 2010-11-29 2017-05-30 National Yang-Ming University Targeting human thymidylate kinase induces DNA repair toxicity in malignant tumor cells

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