JP2004091403A - Method for producing quinazoline derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing quinazolines by which green chemistry can be achieved by using nontoxic nonflammable carbon dioxide instead of an organic solvent having toxicity and flammability and releasing the carbon dioxide by incineration after use. <P>SOLUTION: The method for producing the quinazoline derivative comprises using the carbon dioxide in a high-density gas state or a supercritical state as a solvent and a raw material, adding the carbon dioxide to 2-aminobenzonitriles in the presence of an organic base catalyst, or an inorganic base catalyst used with an onium salt. <P>COPYRIGHT: (C)2004,JPO

Description

【００１１】
（式中、Ｒ^１およびＲ^２は、水素原子、ハロゲン原子、アルキル基、シクロアルキル基、アルコキシ基、アリール基、アルケニル基、アルコキシカルボニル基、アミノカルボニル基、カルボニルアミノ基、シアノ基、スルホ基、又はニトロ基を表し、これらは置換基を有していてもよい。Ｒ^１およびＲ^２は同一でも異なっていてもよく、またＲ^１およびＲ^２は連結して環を形成していてもよい。さらにＲ^１とＲ^２のいずれか一方は水素原子でもよい。）
且つ、キナゾリン誘導体が、下記一般式（ＩＩ）　で示されるキナゾリン誘導体であることを特徴とする請求項１に記載のキナゾリン誘導体の製造方法。
【００１２】
一般式（ＩＩ）
【化４】

【００１３】
（式中、Ｒ^１およびＲ^２は上記と同じである。）
【００１４】
（請求項３）塩基触媒が、第３級アミンあるいは、アルカリ金属またはアルカリ土類金属の炭酸塩またはリン酸塩であることを特徴とする請求項１又は２に記載のキナゾリン誘導体の製造方法。
【００１５】
（請求項４）塩基触媒にアルカリ金属またはアルカリ土類金属の炭酸塩またはリン酸塩を用いる場合、オニウム塩を併用することを特徴とする請求項１、２又は３に記載のキナゾリン誘導体の製造方法。
【００１６】
（請求項５）オニウム塩が、Ｒ^３Ｒ^４Ｒ^５Ｒ^６Ｎ^＋Ｘ⁻またはＲ^３Ｒ^４Ｒ^５Ｒ^６Ｐ^＋Ｘ⁻（但し、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は各々置換または無置換のアルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アリール基、アラルキル基、アラルケニル基、アルケナリール基、またはアルカリール基を表す。Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は同一でも異なっていてもよく、またそのうちの１個ないし３個が水素原子でもよい。Ｘはハロゲン原子、水酸基、硫酸水素基、リン酸水素基、亜リン酸水素基または次亜リン酸基を表す。）で表される化合物であることを特徴とする請求項４に記載のキナゾリン誘導体の製造方法。
【００１７】
【発明の実施の形態】
以下、本発明の実施の形態を説明する。
【００１８】
本発明において、原料として使用される２−アミノベンゾニトリル類は、前記の一般式（Ｉ）で示される。その一般式（Ｉ）において、Ｒ^１およびＲ^２は、水素原子、ハロゲン原子、アルキル基、シクロアルキル基、アルコキシ基、アリール基、アルケニル基、アルコキシカルボニル基、アミノカルボニル基、カルボニルアミノ基、シアノ基、スルホ基、又はニトロ基を表し、それらは置換基を有していてもよい。Ｒ^１およびＲ^２は同一でも異なっていてもよく、またＲ^１およびＲ^２は連結して環を形成していてもよい。さらにＲ^１とＲ^２のいずれか一方は水素原子でもよい。
【００１９】
ハロゲン原子としては、フッ素、塩素、臭素、ヨウ素が挙げられる。
【００２０】
アルキル基としては、メチル基、エチル基、ｎ−プロピル基、ｉｓｏ−プロピル基、ｎ−ブチル基、ｉｓｏ−ブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ｎ−ペンチル基、ｉｓｏ−ペンチル基、ｎ−ヘキシル基、ｎ−オクチル基等が挙げられる。
【００２１】
シクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基等が挙げられる。
【００２２】
アルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、ヘキシルオキシ基、オクチルオキシ基等が挙げられる。
【００２３】
アリール基としては、フェニル基、ナフチル基、トリル基等が挙げられる。
【００２４】
アルケニル基としては、ビニル基、アリル基、イソプロペニル基、２−ブテニル基等が挙げられる。
【００２５】
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、プロポキシカルボニル基、イソプロポキシカルボニル基、ブトキシカルボニル基、ヘキシルオキシカルボニル基、オクチルオキシカルボニル基等が挙げられる。
【００２６】
アミノカルボニル基としては、カルバモイル基、Ｎ−メチルカルバモイル基、Ｎ−エチルカルバモイル基、Ｎ，Ｎ−ジメチルカルバモイル基、Ｎ，Ｎ−ジエチルカルバモイル基等が挙げられる。
【００２７】
カルボニルアミノ基としては、アセトアミド基、ベンズアミド基、スクシンイミド基等が挙げられる。
【００２８】
Ｒ^１とＲ^２で表される上記の各基は、置換されていてもよく、かかる置換基としては、アミノ基、水酸基、ニトロ基、カルボキシル基、アルコキシカルボニル基、アシル基、エーテル基、ハロゲン原子等が挙げられる。
【００２９】
またＲ^１とＲ^２で５員環又は６員環を形成していてもよく、Ｒ^１とＲ^２で形成される５員環としては、ピロリジン、ピロール、イミダゾール等があげられ、６員環としては、ピペリジン、モルホリン、ピリジン等が挙げられる。
【００３０】
本発明において、反応速度を向上させるために、有機塩基触媒及び又は無機塩基触媒が用いられる。
【００３１】
有機塩基触媒としては、ＤＢＵ（１，８−ジアザビシクロ［５．４．０］ウンデック−７−エン）、ＤＢＮ（１，５−ジアザビシクロ［４．３．０］ノン−５−エン）、ＤＡＢＣＯ（１，４−ジアザビシクロ［２．２．２］オクタン）、トリエチルアミン、ジイソプロピルメチルアミン、ＴＭＥＤＡ（テトラメチルエチレンジアミン）等が挙げられる。
【００３２】
無機塩基触媒としては、炭酸カリウム、炭酸セシウム、リン酸カリウム等が挙げられる。無機塩基触媒を用いるときには、触媒量のオニウム塩を添加すると反応速度が上がる。オニウム塩が、Ｒ^３Ｒ^４Ｒ^５Ｒ^６Ｎ^＋Ｘ⁻またはＲ^３Ｒ^４Ｒ^５Ｒ^６Ｐ^＋Ｘ⁻（但し、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は各々置換または無置換のアルキル基、シクロアルキル基、アルケニル基、シクロアルケニル基、アリール基、アラルキル基、アラルケニル基、アルケナリール基、またはアルカリール基を表す。Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は同一でも異なっていてもよく、またそのうちの１個ないし３個が水素原子でも良い。Ｘはハロゲン原子、水酸基、硫酸水素基、リン酸水素基、亜リン酸水素基または次亜リン酸基を表す。）で表される化合物から選ばれる少なくとも１種であることが好ましい。
【００３３】
オニウム塩の具体例としては、テトラブチルアンモニウムブロマイド、テトラブチルアンモニウム硫酸水素塩、テトラオクチルアンモニウムブロマイド、テトラフェニルホスホニウムブロマイド等が挙げられる。
【００３４】
オニウム塩の使用量は触媒量である。ここに触媒量とは、主原料である２−アミノベンゾニトリル類のモル数以下の量で、かつ目的の生成物のモル数以下の量であることを意味する。
【００３５】
本発明では、１〜２０　ＭＰａの二酸化炭素を、原料及び溶媒の両方の目的で使用するところに大きな特徴がある。即ち、高密度の気体状または超臨界状態の二酸化炭素を溶媒かつ原料として使用することにより、有機溶媒を使用する必要がなくなり、環境負荷の低減になる。
【００３６】
高密度の気体状または超臨界状態の二酸化炭素をキナゾリン誘導体の製造に用いると、ＤＭＦ等の有機溶媒中で有効な塩基触媒は、高価な強塩基であるＤＢＵとＤＢＮに限られるのに対して、工業的に汎用されるトリエチルアミンや炭酸カリウムでも有効である。
【００３７】
上記のように、高密度の気体状または超臨界状態の二酸化炭素を有機溶媒の代りに用いると、効率の良い反応になるが、高密度の気体状または超臨界状態の二酸化炭素をキナゾリン誘導体の製造に用いるとき、強極性試薬を原料の０．２〜３．０当量添加し、原料と会合（クラスタリング）させると、反応効率がさらに向上する。
【００３８】
【実施例】
以下、本発明の実施例について説明するが、かかる実施例によって本発明が限定されるものではない。
【００３９】
実施例１
＜有機塩基触媒の検討＞
５０　ｍｌのステンレス製オートクレーブ（耐圧容器）に２−アミノベンゾニトリル（０．１１８　ｇ，　１．００　ｍｍｏｌ）と有機塩基（２．０　ｍｍｏｌ）を加え、二酸化炭素でオートクレーブ内を２回置換した後、常温で液化二酸化炭素を１４．１　ｇ導入し、８０　℃に加熱すると８　ＭＰａとなり、１時間撹拌反応した。反応後、反応容器を氷冷し常圧に戻し、クロロホルムを用いてオートクレーブから取りだし、ろ過することでテトラヒドロキナゾリン−２，４−ジオンが得られた。生成物はＩＲ、ＮＭＲにより、構造及び純度を確認した。この結果を表１に示す。
【００４０】
【表１】

【００４１】
表１より超臨界二酸化炭素中の反応では、塩基触媒がＤＢＵやＤＢＮのような強塩基に限定されず、トリエチルアミンのような工業的に汎用される塩基でも、触媒として使用可能であることがわかった。
【００４２】
実施例２
＜ＤＢＵの量検討＞
５０　ｍｌのステンレス製オートクレーブ（耐圧容器）に２−アミノベンゾニトリル（０．１１８　ｇ，　１．００　ｍｍｏｌ）とＤＢＵを加え、二酸化炭素でオートクレーブ内を２回置換した後、常温で液化二酸化炭素を１８．０　ｇ導入し、６０　℃に加熱すると８　ＭＰａとなり、１時間撹拌反応した。反応後、反応容器を氷冷し常圧に戻し、クロロホルムを用いてオートクレーブから取りだし、ろ過することでテトラヒドロキナゾリン−２，４−ジオンが得られた。生成物はＩＲ、ＮＭＲにより、構造及び純度を確認した。この結果を図１に示す。
【００４３】
図１より、塩基は触媒量でも有効であることがわかった。
【００４４】
実施例３
＜二酸化炭素圧力の検討＞
５０　ｍｌのステンレス製オートクレーブ（耐圧容器）に２−アミノベンゾニトリル（０．１１８　ｇ，　１．００　ｍｍｏｌ）とＤＢＵ（０．０５　ｇ，　０．３　ｍｍｏｌ）を加え、二酸化炭素でオートクレーブ内を２回置換した後、常温で液化二酸化炭素を導入し、６０　℃に加熱、１時間撹拌反応した。反応後、反応容器を氷冷し常圧に戻し、クロロホルムを用いてオートクレーブから取りだし、ろ過することでテトラヒドロキナゾリン−２，４−ジオンが得られた。生成物はＩＲ、ＮＭＲにより、構造及び純度を確認した。この結果を図２に示す。
【００４５】
図２より、二酸化炭素は８　ＭＰａの反応圧力で示される密度の時、効率良く反応し、圧力が高すぎても低すぎても反応効率は低下することがわかった。
【００４６】
実施例４
【００４７】
【化５】

【００４８】
５０　ｍｌのステンレス製オートクレーブ（耐圧容器）に２−アミノベンゾニトリルあるいはその誘導体（１．００　ｍｍｏｌ）とＤＢＵあるいはトリエチルアミンを加え、二酸化炭素でオートクレーブ内を２回置換した後、常温で液化二酸化炭素を導入し、所定の反応温度に加熱すると８　ＭＰａとなり、撹拌反応した。反応後、反応容器を氷冷し常圧に戻し、クロロホルムを用いてオートクレーブから取りだし、ろ過することでテトラヒドロキナゾリン−２，４−ジオンあるいはその誘導体が得られた。生成物はＩＲ、ＮＭＲにより、構造及び純度を確認した。この結果を表２に示す。
【００４９】
【表２】

【００５０】
表２より、置換基がかわっても触媒量、反応温度、反応時間を適当に選べば、高収率でテトラヒドロキナゾリン−２，４−ジオン類が得られることが明らかになった。
【００５１】
実施例６
＜無機塩基触媒の効果＞
５０　ｍｌのステンレス製オートクレーブ（耐圧容器）に２−アミノベンゾニトリル　（０．１１８　ｇ，　１．００　ｍｍｏｌ）と無機塩基とテトラブチルアンモニウムブロマイド（０．０３２　ｇ，　０．１　ｍｍｏｌ）を加え、二酸化炭素でオートクレーブ内を２回置換した後、常温で液化二酸化炭素を１３．５　ｇ導入し、１００℃に加熱すると８　ＭＰａとなり、１時間撹拌反応した。反応後、反応容器を氷冷し常圧に戻し、クロロホルムと水を用いてオートクレーブから取りだし、ろ過することでテトラヒドロキナゾリン−２，４−ジオンが得られた。生成物はＩＲ、ＮＭＲにより、構造及び純度を確認した。この結果を表３に示す。
【００５２】
【表３】

【００５３】
表３より、無機塩基は炭酸塩でもリン酸塩でも有効であることが明らかになった。
【００５４】
実施例６
＜オニウム塩の効果＞
５０　ｍｌのステンレス製オートクレーブ（耐圧容器）に２−アミノベンゾニトリル　（０．１１８　ｇ，　１．００　ｍｍｏｌ）と炭酸カリウム（０．１３８　ｇ，　１．０　ｍｍｏｌ）とオニウム塩（０．１　ｍｍｏｌ）を加え、二酸化炭素でオートクレーブ内を２回置換した後、常温で液化二酸化炭素を１３．５　ｇ導入し、１００℃に加熱すると８　ＭＰａとなり、１時間撹拌反応した。反応後、反応容器を氷冷し常圧に戻し、クロロホルムと水を用いてオートクレーブから取りだし、ろ過することでテトラヒドロキナゾリン−２，４−ジオンが得られた。生成物はＩＲ、ＮＭＲにより、構造及び純度を確認した。この結果を表４に示す。
【００５５】
【表４】

【００５６】
表４の結果より、アンモニウム塩ばかりでなくホスホニウム塩も有効であることがわかった。さらに、オニウム塩を添加しないとこの反応条件では、反応は全く進行しなかった。
【００５７】
実施例７
５０　ｍｌのステンレス製オートクレーブ（耐圧容器）に２−アミノベンゾニトリルあるいはその誘導体（１．００　ｍｍｏｌ）と炭酸カリウム（０．１３８　ｇ，　１．０　ｍｍｏｌ）とテトラブチルアンモニウムブロマイドを加え、二酸化炭素でオートクレーブ内を２回置換した後、常温で液化二酸化炭素を導入し、所定の温度に加熱すると８　ＭＰａとなり、撹拌反応した。反応後、反応容器を氷冷し常圧に戻し、クロロホルムと水を用いてオートクレーブから取りだし、ろ過することでテトラヒドロキナゾリン−２，４−ジオンが得られた。生成物はＩＲ、ＮＭＲにより、構造及び純度を確認した。この結果を表５に示す。
【００５８】
【化６】

【００５９】
【表５】

【００６０】
表５より、置換基がかわっても触媒量、反応温度、反応時間を適当に選べば、高収率でテトラヒドロキナゾリン−２，４−ジオン類が得られることが明らかになった。さらに、ＤＭＦのような強極性試薬を原料の２．０当量添加し、原料と会合（クラスタリング）させると、反応効率がさらに向上することがわかった。
【００６１】
【発明の効果】
本発明によれば、特に毒性の高い試薬を必要とせず、またこれまでの製造方法が塩などの副生成物が発生するのに対して、用いた原料に対して二酸化炭素が付加するだけで、副生成物が発生しない原子効率の良い製造方法であるとともに、環境に負荷をかける有機溶媒を用いずに、高密度の気体状または超臨界状態の二酸化炭素を溶媒かつ原料として用いた、グリーンケミストリーを実現するキナゾリン類の製造方法を提供できる。
【図面の簡単な説明】
【図１】テトラヒドロキナゾリン−２，４−ジオン合成反応におけるＤＢＵ量の効果を示すグラフ
【図２】テトラヒドロキナゾリン−２，４−ジオン合成反応における二酸化炭素圧力の効果を示すグラフ[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing a quinazoline derivative, and more particularly to a method for producing a quinazoline derivative that can realize green chemistry and provides an environmentally friendly production process.
[0002]
[Prior art]
In the past, “chemistry” has been making large quantities of convenient products at low cost and contributing to humankind, but has been making things without giving much consideration to the synthesis and disposal of products. As a result, it put a great burden on the environment, and had to make new investments as a countermeasure against pollution.
[0003]
Green chemistry called "environmentally friendly chemical synthesis", "new synthesis method to prevent pollution", and "environmentally friendly design of molecules and reactions" has attracted attention as chemistry in the 21st century. There is a need for the creation of new manufacturing processes, such as low environmental impact, high-efficiency material conversion, safe processes, and the use of carbon dioxide.
[0004]
Quinazoline derivatives are often applied to pharmaceuticals due to their strong physiological activity, but are also known as intermediate materials for fine chemical products such as agricultural chemicals and electronic materials. The method of synthesizing a quinazoline ring is generally a method of obtaining a quinazoline derivative using anthranilic acid, anthranilamide, or a derivative thereof as a raw material, but it is highly toxic, such as phosgene, isocyanate, carbon monoxide, or cyanate. A reagent is required (Heteroatom Chem., 2, 473 (1991), JP-A-9-291080, JP-A-10-251237, JP-A-11-152275, JP-A-2002-145868 and the like). In contrast to these production methods, Tetrahedron, 58, 3155 (2002) uses 2-aminobenzonitrile or a derivative thereof as a raw material and reacts carbon dioxide to obtain tetrahydroquinazoline-2,4-diones. A method has been disclosed. This reaction does not require highly toxic reagents, and the conventional production method produces by-products such as salts. This is a production method with high atomic efficiency (the sum of the molecular weight of the target substance / the molecular weight of the raw material and the reaction reagent) in which no product is generated.
[0005]
[Problems to be solved by the invention]
However, the above-mentioned production method uses a toxic and flammable organic solvent, and the use of the organic solvent not only causes deterioration of the working environment, but also causes incineration after use. Emissions put a burden on the environment. Therefore, it is necessary to develop a method for producing a quinazoline derivative which does not use an organic solvent and realizes green chemistry.
[0006]
Therefore, an object of the present invention is to provide a method for producing a quinazoline derivative which can realize green chemistry and is an environment-friendly production process.
[0007]
[Means for Solving the Problems]
The present inventor has conducted intensive studies to solve the above problems, and as a result, compared to a conventional production method using an organic solvent, toxic, non-flammable carbon dioxide was pressurized instead of the organic solvent, and By using it as a raw material, an environmentally friendly method for producing a quinazoline derivative from 2-aminobenzonitrile or a derivative thereof has been found, and the present invention described below has been completed.
[0008]
(Claim 1) A method for producing a quinazoline derivative, comprising using, as a solvent and a raw material, high-density gaseous or supercritical carbon dioxide with respect to 2-aminobenzonitrile under a base catalyst.
[0009]
(Claim 2) The 2-aminobenzonitrile is an aminobenzonitrile represented by the following general formula (I):
[0010]
General formula (I)
Embedded image

[0011]
(Wherein R ¹ and R ² represent a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, an aryl group, an alkenyl group, an alkoxycarbonyl group, an aminocarbonyl group, a carbonylamino group, a cyano group, a sulfo group Or a nitro group, which may have a substituent, R ¹ and R ² may be the same or different, and R ¹ and R ² may be linked to form a ring. (Either R ¹ or R ² may be a hydrogen atom.)
The method for producing a quinazoline derivative according to claim 1, wherein the quinazoline derivative is a quinazoline derivative represented by the following general formula (II).
[0012]
General formula (II)
Embedded image

[0013]
(In the formula, R ¹ and R ² are the same as described above.)
[0014]
(3) The method for producing a quinazoline derivative according to (1) or (2), wherein the base catalyst is a tertiary amine or an alkali metal or alkaline earth metal carbonate or phosphate.
[0015]
(4) The production of a quinazoline derivative according to any one of (1) to (3), wherein an onium salt is used in combination when an alkali metal or alkaline earth metal carbonate or phosphate is used as the base catalyst. Method.
[0016]
(Claim 5) When the onium salt is R ³ R ⁴ R ⁵ R ⁶ N ⁺ X ⁻ or R ³ R ⁴ R ⁵ R ⁶ P ⁺ X ⁻ (where R ³ , R ⁴ , R ⁵ and R ⁶ are each R ³ , R ⁴ , R ⁵ and R ⁶ represent a substituted or unsubstituted alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, aralkyl group, aralkenyl group, alkenaryl group, or alkaryl group. X may be the same or different, and one to three of them may be a hydrogen atom, and X represents a halogen atom, a hydroxyl group, a hydrogen sulfate group, a hydrogen phosphate group, a hydrogen phosphite group or a hypophosphite group. The method for producing a quinazoline derivative according to claim 4, wherein the compound is represented by the following formula:
[0017]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, embodiments of the present invention will be described.
[0018]
In the present invention, 2-aminobenzonitrile used as a raw material is represented by the general formula (I). In the general formula (I), R ¹ and R ² represent a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, an aryl group, an alkenyl group, an alkoxycarbonyl group, an aminocarbonyl group, a carbonylamino group, a cyano group. Represents a group, a sulfo group, or a nitro group, which may have a substituent. R ¹ and R ² may be the same or different, and R ¹ and R ² may be linked to form a ring. Further, ^one of R ¹ and R ² may be a hydrogen atom.
[0019]
Examples of the halogen atom include fluorine, chlorine, bromine, and iodine.
[0020]
Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and an iso-pentyl group. , N-hexyl group, n-octyl group and the like.
[0021]
Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and the like.
[0022]
Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a hexyloxy group, and an octyloxy group.
[0023]
Examples of the aryl group include a phenyl group, a naphthyl group, and a tolyl group.
[0024]
Examples of the alkenyl group include a vinyl group, an allyl group, an isopropenyl group, and a 2-butenyl group.
[0025]
Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, a hexyloxycarbonyl group, an octyloxycarbonyl group, and the like.
[0026]
Examples of the aminocarbonyl group include a carbamoyl group, an N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N, N-dimethylcarbamoyl group, and an N, N-diethylcarbamoyl group.
[0027]
Examples of the carbonylamino group include an acetamido group, a benzamide group, and a succinimide group.
[0028]
Each of the above groups represented by R ¹ and R ² may be substituted, and examples of such a substituent include an amino group, a hydroxyl group, a nitro group, a carboxy group, an alkoxycarbonyl group, an acyl group, an ether group, and a halogen atom. Atoms and the like.
[0029]
R ¹ and R ² may form a 5-membered or 6-membered ring. Examples of the 5-membered ring formed by R ¹ and R ² include pyrrolidine, pyrrole, imidazole and the like. Examples thereof include piperidine, morpholine, pyridine and the like.
[0030]
In the present invention, an organic base catalyst and / or an inorganic base catalyst are used to improve the reaction rate.
[0031]
Examples of the organic base catalyst include DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene), DABCO ( 1,4-diazabicyclo [2.2.2] octane), triethylamine, diisopropylmethylamine, TMEDA (tetramethylethylenediamine) and the like.
[0032]
Examples of the inorganic base catalyst include potassium carbonate, cesium carbonate, potassium phosphate and the like. When using an inorganic base catalyst, adding a catalytic amount of an onium salt increases the reaction rate. When the onium salt is R ³ R ⁴ R ⁵ R ⁶ N ⁺ X ⁻ or R ³ R ⁴ R ⁵ R ⁶ P ⁺ X ⁻ (where R ³ , R ⁴ , R ⁵ and R ⁶ are each substituted or unsubstituted) Represents an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an aryl group, an aralkyl group, an aralkenyl group, an alkenaryl group, or an alkaryl group, wherein R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different. And one to three of them may be a hydrogen atom. X represents a halogen atom, a hydroxyl group, a hydrogen sulfate group, a hydrogen phosphate group, a hydrogen phosphite group or a hypophosphite group.) It is preferable that the compound is at least one selected from the compounds described above.
[0033]
Specific examples of the onium salt include tetrabutylammonium bromide, tetrabutylammonium hydrogensulfate, tetraoctylammonium bromide, tetraphenylphosphonium bromide and the like.
[0034]
The amount of onium salt used is a catalytic amount. Here, the term "catalyst amount" means that the amount is not more than the number of moles of the main raw material 2-aminobenzonitrile and not more than the number of moles of the target product.
[0035]
In the present invention, there is a great feature in that carbon dioxide of 1 to 20 MPa is used for both purposes of a raw material and a solvent. That is, by using high-density gaseous or supercritical carbon dioxide as a solvent and a raw material, it is not necessary to use an organic solvent, and the environmental load is reduced.
[0036]
When high-density gaseous or supercritical carbon dioxide is used for producing quinazoline derivatives, effective base catalysts in organic solvents such as DMF are limited to expensive strong bases DBU and DBN. Also, triethylamine and potassium carbonate which are widely used in industry are effective.
[0037]
As described above, when high-density gaseous or supercritical carbon dioxide is used in place of an organic solvent, an efficient reaction occurs, but high-density gaseous or supercritical carbon dioxide is converted into a quinazoline derivative. When used in the production, if the strongly polar reagent is added in an amount of 0.2 to 3.0 equivalents of the raw material and is associated with the raw material (clustering), the reaction efficiency is further improved.
[0038]
【Example】
Hereinafter, examples of the present invention will be described, but the present invention is not limited to the examples.
[0039]
Example 1
<Examination of organic base catalyst>
2-aminobenzonitrile (0.118 g, 1.00 mmol) and an organic base (2.0 mmol) were added to a 50 ml stainless steel autoclave (pressure-resistant vessel), and the inside of the autoclave was replaced twice with carbon dioxide. After introducing 14.1 g of liquefied carbon dioxide at room temperature and heating to 80 ° C., the pressure became 8 MPa, and the mixture was stirred and reacted for 1 hour. After the reaction, the reaction vessel was cooled on ice and returned to normal pressure, taken out of the autoclave using chloroform, and filtered to obtain tetrahydroquinazoline-2,4-dione. The structure and purity of the product were confirmed by IR and NMR. Table 1 shows the results.
[0040]
[Table 1]

[0041]
From Table 1, it can be seen that in the reaction in supercritical carbon dioxide, the base catalyst is not limited to a strong base such as DBU or DBN, and a base widely used in industry such as triethylamine can be used as a catalyst. Was.
[0042]
Example 2
<Examination of DBU quantity>
2-Aminobenzonitrile (0.118 g, 1.00 mmol) and DBU were added to a 50 ml stainless steel autoclave (pressure vessel), and the inside of the autoclave was replaced twice with carbon dioxide. When 18.0 g was introduced and heated to 60 ° C., the pressure became 8 MPa, and the mixture was stirred and reacted for 1 hour. After the reaction, the reaction vessel was cooled on ice and returned to normal pressure, taken out of the autoclave using chloroform, and filtered to obtain tetrahydroquinazoline-2,4-dione. The structure and purity of the product were confirmed by IR and NMR. The result is shown in FIG.
[0043]
From FIG. 1, it was found that the base was effective even with a catalytic amount.
[0044]
Example 3
<Examination of carbon dioxide pressure>
2-Aminobenzonitrile (0.118 g, 1.00 mmol) and DBU (0.05 g, 0.3 mmol) were added to a 50 ml stainless steel autoclave (pressure vessel), and the inside of the autoclave was added with carbon dioxide. After substitution twice, liquefied carbon dioxide was introduced at room temperature, and the mixture was heated to 60 ° C. and reacted with stirring for 1 hour. After the reaction, the reaction vessel was cooled on ice and returned to normal pressure, taken out of the autoclave using chloroform, and filtered to obtain tetrahydroquinazoline-2,4-dione. The structure and purity of the product were confirmed by IR and NMR. The result is shown in FIG.
[0045]
From FIG. 2, it was found that the carbon dioxide reacted efficiently at the density indicated by the reaction pressure of 8 MPa, and the reaction efficiency decreased when the pressure was too high or too low.
[0046]
Example 4
[0047]
Embedded image

[0048]
2-aminobenzonitrile or its derivative (1.00 mmol) and DBU or triethylamine were added to a 50 ml stainless steel autoclave (pressure vessel), and the inside of the autoclave was replaced twice with carbon dioxide. When introduced and heated to a predetermined reaction temperature, the pressure became 8 MPa, and a stirring reaction was performed. After the reaction, the reaction vessel was cooled on ice and returned to normal pressure, taken out of the autoclave using chloroform, and filtered to obtain tetrahydroquinazoline-2,4-dione or a derivative thereof. The structure and purity of the product were confirmed by IR and NMR. Table 2 shows the results.
[0049]
[Table 2]

[0050]
From Table 2, it is clear that tetrahydroquinazoline-2,4-diones can be obtained in high yield by appropriately selecting the amount of catalyst, the reaction temperature, and the reaction time even when the substituent is changed.
[0051]
Example 6
<Effect of inorganic base catalyst>
2-Aminobenzonitrile (0.118 g, 1.00 mmol), an inorganic base and tetrabutylammonium bromide (0.032 g, 0.1 mmol) were added to a 50 ml stainless steel autoclave (pressure-resistant vessel), and After replacing the inside of the autoclave twice with carbon, 13.5 g of liquefied carbon dioxide was introduced at room temperature, and when heated to 100 ° C., the pressure became 8 MPa, and the mixture was stirred and reacted for 1 hour. After the reaction, the reaction vessel was cooled on ice and returned to normal pressure, taken out of the autoclave using chloroform and water, and filtered to obtain tetrahydroquinazoline-2,4-dione. The structure and purity of the product were confirmed by IR and NMR. Table 3 shows the results.
[0052]
[Table 3]

[0053]
Table 3 shows that the inorganic base is effective for both carbonates and phosphates.
[0054]
Example 6
<Effect of onium salt>
In a 50 ml stainless steel autoclave (pressure vessel), 2-aminobenzonitrile (0.118 g, 1.00 mmol), potassium carbonate (0.138 g, 1.0 mmol) and onium salt (0.1 mmol) Was added, and the inside of the autoclave was replaced twice with carbon dioxide. Then, 13.5 g of liquefied carbon dioxide was introduced at room temperature, and when heated to 100 ° C., the pressure became 8 MPa, and the mixture was stirred and reacted for 1 hour. After the reaction, the reaction vessel was cooled on ice and returned to normal pressure, taken out of the autoclave using chloroform and water, and filtered to obtain tetrahydroquinazoline-2,4-dione. The structure and purity of the product were confirmed by IR and NMR. Table 4 shows the results.
[0055]
[Table 4]

[0056]
From the results in Table 4, it was found that not only ammonium salts but also phosphonium salts were effective. Furthermore, the reaction did not proceed at all under these reaction conditions unless the onium salt was added.
[0057]
Example 7
2-Aminobenzonitrile or its derivative (1.00 mmol), potassium carbonate (0.138 g, 1.0 mmol) and tetrabutylammonium bromide were added to a 50 ml stainless steel autoclave (pressure-resistant vessel), and carbon dioxide was added. After the inside of the autoclave was replaced twice, liquefied carbon dioxide was introduced at room temperature, and when heated to a predetermined temperature, the pressure became 8 MPa, and a stirring reaction was performed. After the reaction, the reaction vessel was cooled on ice and returned to normal pressure, taken out of the autoclave using chloroform and water, and filtered to obtain tetrahydroquinazoline-2,4-dione. The structure and purity of the product were confirmed by IR and NMR. Table 5 shows the results.
[0058]
Embedded image

[0059]
[Table 5]

[0060]
From Table 5, it has been clarified that tetrahydroquinazoline-2,4-diones can be obtained in high yield by appropriately selecting the amount of catalyst, the reaction temperature and the reaction time even when the substituent is changed. Furthermore, it was found that when 2.0 equivalents of a raw material was added to a strong polar reagent such as DMF and the raw material was associated (clustered), the reaction efficiency was further improved.
[0061]
【The invention's effect】
According to the present invention, a particularly highly toxic reagent is not required, and the conventional production methods generate by-products such as salts, whereas carbon dioxide is simply added to the raw materials used. A green method that uses high-density gaseous or supercritical carbon dioxide as a solvent and raw material without using an organic solvent that places a burden on the environment, as well as an atomically efficient production method that does not generate by-products. A method for producing quinazolines that can realize chemistry can be provided.
[Brief description of the drawings]
FIG. 1 is a graph showing the effect of the amount of DBU on the synthesis reaction of tetrahydroquinazoline-2,4-dione. FIG. 2 is a graph showing the effect of carbon dioxide pressure on the synthesis reaction of tetrahydroquinazoline-2,4-dione.

Claims (5)

A method for producing a quinazoline derivative, comprising using gaseous or supercritical carbon dioxide at a high density as a solvent and a raw material for 2-aminobenzonitrile under a base catalyst. 2-aminobenzonitrile is an aminobenzonitrile represented by the following general formula (I),
General formula (I)

(Wherein R ¹ and R ² represent a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, an aryl group, an alkenyl group, an alkoxycarbonyl group, an aminocarbonyl group, a carbonylamino group, a cyano group, a sulfo group Or a nitro group, which may have a substituent, R ¹ and R ² may be the same or different, and R ¹ and R ² may be linked to form a ring. (Either R ¹ or R ² may be a hydrogen atom.)
The method for producing a quinazoline derivative according to claim 1, wherein the quinazoline derivative is a quinazoline derivative represented by the following general formula (II).
General formula (II)

(In the formula, R ¹ and R ² are the same as described above.) The method for producing a quinazoline derivative according to claim 1 or 2, wherein the base catalyst is a tertiary amine or a carbonate or phosphate of an alkali metal or an alkaline earth metal. 4. The method for producing a quinazoline derivative according to claim 1, wherein an onium salt is used in combination when an alkali metal or alkaline earth metal carbonate or phosphate is used as the base catalyst. When the onium salt is R ³ R ⁴ R ⁵ R ⁶ N ⁺ X ⁻ or R ³ R ⁴ R ⁵ R ⁶ P ⁺ X ⁻ (where R ³ , R ⁴ , R ⁵ and R ⁶ are each substituted or unsubstituted) Represents an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an aryl group, an aralkyl group, an aralkenyl group, an alkenaryl group, or an alkaryl group, wherein R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different. And one to three of them may be a hydrogen atom, and X represents a halogen atom, a hydroxyl group, a hydrogen sulfate group, a hydrogen phosphate group, a hydrogen phosphite group or a hypophosphite group.) The method for producing a quinazoline derivative according to claim 4, which is a compound to be prepared.

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