JP3740835B2 - Process for producing 6,7-disubstituted-2,4-dioxoquinazoline - Google Patents
Process for producing 6,7-disubstituted-2,4-dioxoquinazoline Download PDFInfo
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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
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Description
【０００１】
【発明の属する技術分野】
本発明は、4,5-ジ置換アントラニルアミドから6,7-ジ置換-2,4-ジオキソキナゾリンを高収率且つ高選択的に製造する方法に関する。6,7-ジ置換-2,4-ジオキソキナゾリンは、医薬・農薬の合成原料として有用な化合物である。
【０００２】
【従来の技術】
従来、4,5-ジ置換アントラニルアミドから6,7-ジ置換-2,4-ジオキソキナゾリンを得る方法としては、J.Chem.Soc.,1948,1759に2-ウレイド-4,5-ジメトキシ安息香酸を水酸化ナトリムで処理して6,7-ジ置換-2,4-ジオキソキナゾリンを合成する方法が開示されているが、この方法では収率が極めて低いという問題があった。また、特開昭59-73558号公報には、ジメトキシアントラニルアミドから誘導された2-ウレイド-4,5-ジメトキシ安息香酸アミドを水酸化ナトリウムで処理して、6,7-ジメトキシ-2,4-ジオキソキナゾリンを得る方法が記載されている。しかしながら、この方法では二段階の反応であって工業的には生産性が悪く不利であるとともに、毒性の強いシアン酸カリウムを用いるため工業的な製造方法としては有効ではなかった。
【０００３】
【発明が解決しようとする課題】
本発明の課題は、即ち、4,5-ジ置換アントラニルアミドから、煩雑な操作を必要とすることなく、6,7-ジ置換-2,4-ジオキソキナゾリンを高収率且つ高選択的に製造することが出来る、工業的に好適な6,7-ジ置換-2,4-ジオキソキナゾリンの製造法を提供するものである。
【０００４】
【課題を解決するための手段】
本発明の目的は、一般式（１）
【０００５】
【化４】
（式中、Ｒ１及びＲ２は、同一或いは異なっていても良く、水素原子、非置換又は置換された、炭素数１〜８のアルキル基、炭素数２〜８のアルケニル基、炭素数６〜２０のアリール基若しくは炭素数２〜２０のアシル基のいずれかを示す。また、Ｒ１とＲ２は連結して環を形成していても良い。）で示される4,5-ジ置換アントラニルアミドを炭酸ジフェニルと反応させる、一般式（２）
【０００８】
【化６】
【０００９】
【発明の実施の形態】
本発明の反応において使用される原料4,5-ジ置換アントラニルアミドは、前記の一般式（１）で示される。その一般式（１）において、Ｒ1及びＲ2は、同一或いは異なっていても良く、水素原子、非置換又は置換された、炭素数１〜８のアルキル基、炭素数２〜８のアルケニル基、炭素数６〜２０のアリール基若しくは炭素数２〜２０のアシル基のいずれかを示す。また、Ｒ1とＲ2は連結して環を形成していても良い。
【００１０】
炭素数１〜８のアルキル基としては、例えば、メチル基、エチル基、n-プロピル基、i-プロピル基、n-ブチル基、s-ブチル基、t-ブチル基、n-ペンチル基、n-へキシル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基等が挙げられる。
【００１１】
炭素数２〜８のアルケニル基としては、例えば、ビニル基、アリル基、i-プロペニル基、シクロプロペニル基、シクロブテニル基、シクロペンテニル基等が挙げられる。
【００１２】
炭素数６〜２０のアリール基としては、例えば、フェニル基、トリル基、キシリル基、ビフェニル基、ナフチル基、アントリル基、フェナントリル基等が挙げられる。
【００１３】
炭素数２〜２０のアシル基としては、例えば、アセチル基、プロピオニル基、ピバロイル基、シクロヘキシルカルボニル基、ベンゾイル基、ナフトイル基、トルオイル基等が挙げられる。
【００１４】
前記の炭素数１〜８のアルキル基、炭素数２〜８のアルケニル基、炭素数６〜２０のアリール基又は炭素数２〜２０のアシル基は、置換基を有していても良い。その置換基としては、ハロゲン原子、炭素原子を介して出来る置換基、酸素原子を介して出来る置換基、窒素原子を介して出来る置換基、硫黄原子を介して出来る置換基の中から選ばれる少なくとも一つが挙げられる。
【００１５】
前記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。
【００１６】
前記炭素原子を介して出来る置換基としては、メチル基、エチル基、n-プロピル基、n-ブチル基、s-ブチル基、t-ブチル基、n-ペンチル基、n-ヘキシル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基等のアルキル基；ビニル基、アリル基、i-プロペニル基、シクロプロペニル基、シクロブテニル基、シクロペンテニル基等のアルケニル基；ピロリジニル基、ピロリル基、フリル基、チエニル基等の複素環式アルケニル基；フェニル基、トリル基、キシリル基、ビフェニル基、ナフチル基、アントリル基、フェナントリル基等のアリール基；ホルミル基、アセチル基、プロピオニル基、ピバロイル基、シクロヘキシルカルボニル基、ベンゾイル基、ナフトイル基、トルオイル基等のアシル基（アセタール化されていても良い）；カルボキシル基；メトキシカルボニル基、エトキシカルボニル基等のアルコキシカルボニル基；フェノキシカルボニル基等のアリールオキシカルボニル基；トリフルオロメチル基等のハロゲン化アルキル基；シアノ基が挙げられる。
【００１７】
前記酸素原子を介して出来る置換基としては、ヒドロキシ基；メトキシ基、エトキシ基、プロポキシ基、i-プロポキシ基、ブトキシ基、i-ブトキシ基、s-ブトキシ基、t-ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、i-ペンチルオキシ基、ベンジルオキシ基等のアルコキシ基；フェノキシ基、p-トルイルオキシ基、2-ナフチルオキシ基等のアリールオキシ基が挙げられる。
【００１８】
前記窒素原子を介して出来る置換基としては、メチルアミノ基、エチルアミノ基、n-ブチルアミノ基、シクロヘキシルアミノ基、フェニルアミノ基、2-ナフチルアミノ基等の第一級アミノ基；ジメチルアミノ基、ジエチルアミノ基、ジn-ブチルアミノ基、メチルエチルアミノ基、メチルn-ブチルアミノ基、ジフェニルアミノ基等の第二級アミノ基；モルホリノ基、ピペリジノ基、ピペラジニル基、ピラゾリジニル基、ピロリジノ基、インドリニル基等の複素環式アミノ基；イミノ基が挙げられる。
【００１９】
前記硫黄原子を介して出来る置換基としては、メルカプト基；チオメトキシ基、チオエトキシ基、チオプロポキシ基等のチオアルコキシ基；チオフェノキシ基、チオ-p-トルイルオキシ基、チオ-2-ナフチルオキシ基等のチオアリールオキシ基が挙げられる。
【００２０】
本発明の反応において使用される4,5-ジ置換アントラニルアミドとしては、例えば、4,5-ジメトキシアントラニルアミド、4,5-ジエトキシアントラニルアミド、5-エトキシ-4-メトキシアントラニルアミド、4,5-メチレンジオキシアントラニルアミド、4-メトキシ-5-(3-モルフィリノプロピオキシ)アントラニルアミド、4,5-ビス(2-メトキシエトキシ)アントラニルアミド等が挙げられる。これらの4,5-ジ置換アントラニルアミドは、特公昭46-10543号公報に準じて、相当する4,5-ジ置換アントラニル酸から合成出来る。
【００２１】
本発明の反応において使用される炭酸ジフェニルの使用量は、原料の4,5-ジ置換アントラニルアミド１モルに対して好ましくは1〜10倍モル、更に好ましくは1〜5倍モルである。
【００２２】
本発明の反応において、反応速度を向上させるために塩基性触媒を反応液中に存在させても良い。前記塩基性触媒としては、無機塩基又は有機塩基が挙げられるが、無機塩基としては、例えば、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等のアルカリ金属炭酸塩；炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素セシウム等のアルカリ金属炭酸水素塩；水素化リチウム、水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物；水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム等のアルカリ金属水酸化物又はアルカリ土類金属水酸化物が挙げられ、有機塩基としては、例えば、ナトリウムメトキシド、ナトリウムエトキシド、カリウムエトキシド、カリウムt-ブトキシド等のアルカリ金属アルコキシドが挙げられる。その中でも特に好ましくは炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等のアルカリ金属炭酸塩；ナトリウムメトキシド、ナトリウムエトキシド、カリウムエトキシド、カリウムt-ブトキシド等のアルカリ金属アルコキシドが使用される。
【００２３】
前記触媒の使用量は、原料の4,5-ジ置換アントラニルアミド1モルに対して、好ましくは1/10000〜1/2モル、更に好ましくは1/10000〜1/5である。これらの触媒は、単独又は二種以上を混合して使用しても良い。
【００２４】
本発明の反応は溶媒中で行われるのが好ましい。使用される溶媒としては、N,N-ジメチルホルムアミド、N,N-ジメチルアセタミド、ジメチルスルホキシド、ジメチルイミダゾリジノン、N-メチルピロリドン等の非プロトン性極性溶媒；n-ブタノール、n-ペンタノール、エチレングリコール、フェノール等のアルコール溶媒；ジグリム等のエーテル溶媒が挙げられるが、好ましくはN,N-ジメチルホルムアミド、N,N-ジメチルアセタミド、ジメチルスルホキシド、ジメチルイミダゾリジノン、N-メチルピロリドン等の非プロトン性極性溶媒である。
【００２５】
前記溶媒の使用量は、原料の4,5-ジ置換アントラニルアミド1gに対して好ましくは1〜100ml、更に好ましくは1〜50mlである。これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【００２６】
本発明の反応は、4,5-ジ置換アントラニルアミドと炭酸エステルとを液相で接触させることが好ましく、例えば、不活性ガス雰囲気にて、4,5-ジ置換アントラニルアミド、炭酸エステル、溶媒及び触媒を混合し、加熱攪拌する等の方法によって、常圧下又は加圧下で行われる。その際の反応温度は、好ましくは50〜250℃、更に好ましくは100〜200℃である。また得られた生成物は、例えば、再結晶等の一般的な方法によって分離精製される。
【００２７】
【実施例】
次に、実施例を挙げて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。
【００２８】
実施例１
内容積300mlのガラス製オートクレーブに、4,5-ジメトキシアントラニルアミド1g(5.10mmol)、炭酸ジフェニル2.19g(10.20mmol)、ジメチルイミダゾリジノン5ml及び炭酸カリウム7mg(0.05mmol)を入れた後、窒素雰囲気下、110℃まで昇温した。引き続き、同温度で2.5時間攪拌した後、反応液を0℃まで冷却した。析出した結晶を濾過し、メタノールで洗浄した後に減圧下で乾燥し、6,7-ジメトキシ-2,4-ジオキソキナゾリン1.08g(収率95%)を得た。
【００２９】
実施例２
実施例１において、炭酸カリウムを存在させず、反応温度を150℃に、反応時間を6時間に変えたこと以外は、実施例１記載と同様な操作を行った。その結果、6,7-ジメトキシ-2,4-ジオキソキナゾリン1.07g(収率94%)を得た。
【００３０】
参考例１
4,5-ジエトキシアントラニルアミドの合成
特公昭46-10543号公報に準じて、相当する4,5-ジ置換アントラニル酸から合成した。物性値は、1H-NMR(CDCl3)；1.381ppm(3H,t,J=6.83Hz)，1.456ppm(3H,t, J=6.84Hz)，3.991ppm(2H,q,J=6.83Hz)，4.055ppm(2H,q,J=6.84Hz)，5.568ppm(4H,brs)，6.162ppm(1H,s)，6.911ppm(1H,s)：MS(M+)；224であった。
【００３１】
参考例２
5-エトキシ-4-メトキシアントラニルアミドの合成
参考例１と同様に相当する4,5-ジ置換アントラニル酸から合成した。物性値は、1H-NMR(CDCl3)；1.403ppm(3H,t,J=6.83Hz)，3.846ppm(3H,s)，3.996ppm(2H,q,J=6.83Hz)，5.574ppm(4H,brs)，6.176ppm(1H,s)，6.899ppm(1H,s)：MS(M+)；210であった。
【００３２】
参考例３
4-メトキシ-5-(3-モルホリノプロピオキシ)アントラニルアミドの合成
参考例１と同様に相当する4,5-ジ置換アントラニル酸から合成した。物性値は、1H-NMR(CDCl3)；1.91〜2.04ppm(2H,m)，2.45〜2.55ppm(6H,m)，3.72ppm(4H,t,J=4.4Hz)，3.83ppm(3H,s)，3.98ppm(2H,t,J=6.6Hz)，4.18ppm(2H,s)，6.23ppm(1H,s)，6.85ppm(1H,s)：MS(M+)；309であった。
【００３３】
参考例４
4,5-ビス(2-メトキシエトキシ)アントラニルアミドの合成
参考例１と同様に相当する4,5-ジ置換アントラニル酸から合成した。物性値は、1H-NMR(CDCl3)；3.437ppm(3H,s)，3.439ppm(3H,s)，3.690ppm(2H,t,J=4.40Hz)，3.770ppm(2H,t,J=4.40Hz)，4.078ppm(2H,t,J=4.40Hz)，4.121ppm(2H,t,J=4.40Hz)，5.633ppm(4H,brs)，6.175ppm(1H,s)，7.029ppm(1H,s)：MS(M+)；284であった。
【００３４】
実施例３〜８
実施例１において、原料の4,5-ジ置換アントラニルアミド、炭酸エステル量、炭酸カリウム量、反応温度及び反応時間を変えたこと以外は、実施例１記載と同様な操作を行った。結果を表１に示す。また、原料化合物５及び６から得られた目的化合物の物性値を以下に示す。
7-メトキシ-6-(3-モルホリノプロピオキシ)-2,4-ジオキソキナゾリン（原料：化合物５）
1H-NMR(DMSO-d6);1.861ppm(2H,tt,J=6.83,6.35Hz),2.342ppm(4H,m),2.396ppm(2H,t,J=6.83Hz),3.559ppm(4H,t,J=4.40Hz),3.814ppm(3H,s),3.995ppm(2H,t,J=6.35Hz),6.662ppm(1H,s), 7.247ppm(1H,s),10.892ppm(1H,brs),11.071ppm(1H,brs)：MS(MH+)；336
6,7-ビス(2-メトキシエトキシ)-2,4-ジオキソキナゾリン（原料：化合物６）
1H-NMR(DMSO-d6);3.302(3H,s),3.318(3H,s),3.644(2H,t,J=4.39Hz),3.694(2H,t,J=4.39Hz),4.088(2H,t,J=4.39Hz),4.124(2H,t,J=4.39Hz),6.674(1H,s),7.278(1H,s),10.888(1H,brs),11.074(1H,brs)：MS(M+)；310
【００３５】
【表１】
【発明の効果】
本発明により、4,5-ジ置換アントラニルアミドから、煩雑な操作を必要とすることなく、6,7-ジ置換-2,4-ジオキソキナゾリンを高収率且つ高選択的に製造することが出来る、工業的に好適な6,7-ジ置換-2,4-ジオキソキナゾリンの製造法を提供することが出来る。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing 6,7-disubstituted-2,4-dioxoquinazoline with high yield and high selectivity from 4,5-disubstituted anthranilamides. 6,7-disubstituted-2,4-dioxoquinazoline is a useful compound as a raw material for the synthesis of pharmaceuticals and agricultural chemicals.
[0002]
[Prior art]
Conventionally, as a method for obtaining 6,7-disubstituted-2,4-dioxoquinazoline from 4,5-disubstituted anthranilamides, J. Chem. Soc., 1948 , 1759 and 2-ureido-4,5- A method of synthesizing 6,7-disubstituted-2,4-dioxoquinazoline by treating dimethoxybenzoic acid with sodium hydroxide has been disclosed, but this method has a problem that the yield is extremely low. JP-A-59-73558 discloses that 2-ureido-4,5-dimethoxybenzoic acid amide derived from dimethoxyanthranilamide is treated with sodium hydroxide to give 6,7-dimethoxy-2,4. A method for obtaining dioxoquinazoline is described. However, this method is a two-step reaction, which is disadvantageous in terms of industrial productivity and disadvantageous, and is not effective as an industrial production method because it uses highly toxic potassium cyanate.
[0003]
[Problems to be solved by the invention]
The object of the present invention is to obtain 6,7-disubstituted-2,4-dioxoquinazoline from a 4,5-disubstituted anthranilamide in a high yield and high selectivity without requiring complicated operation. The present invention provides an industrially suitable method for producing 6,7-disubstituted-2,4-dioxoquinazoline.
[0004]
[Means for Solving the Problems]
The object of the present invention is to formula (1)
[0005]
[Formula 4]
(In the formula, R 1 and R 2 may be the same or different and are a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, and 6 carbon atoms. Any one of ˜20 aryl groups or C 2-20 acyl groups, and R 1 and R 2 may be linked to form a ring. Reaction of anthranilamides with diphenyl carbonate, general formula (2)
[0008]
[Chemical 6]
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The raw material 4,5-disubstituted anthranilamides used in the reaction of the present invention is represented by the general formula (1). In the general formula (1), R 1 and R 2 may be the same or different and are a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms, and an alkenyl group having 2 to 8 carbon atoms. Or an aryl group having 6 to 20 carbon atoms or an acyl group having 2 to 20 carbon atoms. R 1 and R 2 may be linked to form a ring.
[0010]
Examples of the alkyl group having 1 to 8 carbon atoms include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, t-butyl group, n-pentyl group, n -Hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like.
[0011]
Examples of the alkenyl group having 2 to 8 carbon atoms include vinyl group, allyl group, i-propenyl group, cyclopropenyl group, cyclobutenyl group, and cyclopentenyl group.
[0012]
Examples of the aryl group having 6 to 20 carbon atoms include a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.
[0013]
Examples of the acyl group having 2 to 20 carbon atoms include an acetyl group, a propionyl group, a pivaloyl group, a cyclohexylcarbonyl group, a benzoyl group, a naphthoyl group, and a toluoyl group.
[0014]
The alkyl group having 1 to 8 carbon atoms, the alkenyl group having 2 to 8 carbon atoms, the aryl group having 6 to 20 carbon atoms, or the acyl group having 2 to 20 carbon atoms may have a substituent. The substituent is at least selected from a halogen atom, a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, and a substituent formed through a sulfur atom. One is mentioned.
[0015]
Examples of the halogen atom include fluorine, chlorine, bromine and iodine.
[0016]
Examples of the substituent formed through the carbon atom include methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and cyclopropyl. Group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and other alkyl groups; vinyl group, allyl group, i-propenyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group and other alkenyl groups; pyrrolidinyl group, pyrrolyl group Heterocyclic groups such as furyl and thienyl groups; aryl groups such as phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl and phenanthryl; formyl, acetyl, propionyl and pivaloyl , Acyl groups such as cyclohexylcarbonyl group, benzoyl group, naphthoyl group, toluoyl group (a A carboxyl group; an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group; an aryloxycarbonyl group such as a phenoxycarbonyl group; a halogenated alkyl group such as a trifluoromethyl group; a cyano group It is done.
[0017]
Examples of the substituent formed through the oxygen atom include a hydroxy group; a methoxy group, an ethoxy group, a propoxy group, an i-propoxy group, a butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, and a pentyloxy group. And alkoxy groups such as hexyloxy group, i-pentyloxy group and benzyloxy group; aryloxy groups such as phenoxy group, p-toluyloxy group and 2-naphthyloxy group.
[0018]
Examples of the substituent formed through the nitrogen atom include a primary amino group such as a methylamino group, an ethylamino group, an n-butylamino group, a cyclohexylamino group, a phenylamino group, and a 2-naphthylamino group; a dimethylamino group , Diethylamino group, di-n-butylamino group, methylethylamino group, methyln-butylamino group, diphenylamino group and the like secondary amino group; morpholino group, piperidino group, piperazinyl group, pyrazolidinyl group, pyrrolidino group, indolinyl A heterocyclic amino group such as a group; and an imino group.
[0019]
Examples of the substituent formed through the sulfur atom include a mercapto group; a thioalkoxy group such as a thiomethoxy group, a thioethoxy group, and a thiopropoxy group; a thiophenoxy group, a thio-p-toluyloxy group, a thio-2-naphthyloxy group, and the like Thioaryloxy group.
[0020]
Examples of the 4,5-disubstituted anthranilamides used in the reaction of the present invention include 4,5-dimethoxyanthranilamide, 4,5-diethoxyanthranilamide, 5-ethoxy-4-methoxyanthranylamide, Examples include 5-methylenedioxyanthranilamide, 4-methoxy-5- (3-morpholinopropoxy) anthranilamide, 4,5-bis (2-methoxyethoxy) anthranilamide, and the like. These 4,5-disubstituted anthranilamides can be synthesized from the corresponding 4,5-disubstituted anthranilic acid according to Japanese Patent Publication No. 46-10543.
[0021]
The amount of diphenyl carbonate used in the reaction of the present invention is preferably 1 to 10 times mol, more preferably 1 to 5 times mol, based on 1 mol of 4,5-disubstituted anthranilamide as a raw material.
[0022]
In the reaction of the present invention, a basic catalyst may be present in the reaction solution in order to improve the reaction rate. Examples of the basic catalyst include inorganic bases and organic bases. Examples of inorganic bases include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; sodium bicarbonate, potassium bicarbonate, Alkali metal hydrogen carbonates such as cesium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide And organic bases include, for example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide and the like. Among them, particularly preferred are alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide and potassium t-butoxide.
[0023]
The amount of the catalyst to be used is preferably 1/10000 to 1/2 mol, more preferably 1/10000 to 1/5, relative to 1 mol of 4,5-disubstituted anthranilamide as a raw material. These catalysts may be used alone or in admixture of two or more.
[0024]
The reaction of the present invention is preferably carried out in a solvent. Solvents used include aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, dimethylimidazolidinone, N-methylpyrrolidone; n-butanol, n-pen Alcohol solvents such as ethanol, ethylene glycol, phenol, etc .; ether solvents such as diglyme are mentioned, preferably N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, dimethylimidazolidinone, N-methyl An aprotic polar solvent such as pyrrolidone.
[0025]
The amount of the solvent to be used is preferably 1 to 100 ml, more preferably 1 to 50 ml, based on 1 g of 4,5-disubstituted anthranilamide as a raw material. These solvents may be used alone or in combination of two or more.
[0026]
In the reaction of the present invention, 4,5-disubstituted anthranilamide and carbonate ester are preferably brought into contact with each other in a liquid phase. For example, in an inert gas atmosphere, 4,5-disubstituted anthranilamide, carbonate ester, solvent And the catalyst is mixed, heated and stirred, etc., under normal pressure or under pressure. The reaction temperature in that case becomes like this. Preferably it is 50-250 degreeC, More preferably, it is 100-200 degreeC. The obtained product is separated and purified by a general method such as recrystallization.
[0027]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
[0028]
Example 1
A glass autoclave with an internal volume of 300 ml was charged with 1 g (5.10 mmol) of 4,5-dimethoxyanthranilamide, 2.19 g (10.20 mmol) of diphenyl carbonate, 5 ml of dimethylimidazolidinone and 7 mg (0.05 mmol) of potassium carbonate, and then nitrogen. The temperature was raised to 110 ° C. in an atmosphere. Subsequently, after stirring at the same temperature for 2.5 hours, the reaction solution was cooled to 0 ° C. The precipitated crystals were filtered, washed with methanol, and dried under reduced pressure to obtain 1.08 g (yield 95%) of 6,7-dimethoxy-2,4-dioxoquinazoline.
[0029]
Example 2
In Example 1, the same operation as described in Example 1 was performed except that potassium carbonate was not present, the reaction temperature was changed to 150 ° C., and the reaction time was changed to 6 hours. As a result, 1.07 g (yield 94%) of 6,7-dimethoxy-2,4-dioxoquinazoline was obtained.
[0030]
Reference example 1
Synthesis of 4,5-diethoxyanthranilamide was synthesized from the corresponding 4,5-disubstituted anthranilic acid according to Japanese Patent Publication No. 46-10543. Physical property values are 1 H-NMR (CDCl 3 ); 1.381 ppm (3H, t, J = 6.83 Hz), 1.456 ppm (3H, t, J = 6.84 Hz), 3.991 ppm (2H, q, J = 6.83 Hz) ), 4.055 ppm (2H, q, J = 6.84 Hz), 5.568 ppm (4H, brs), 6.162 ppm (1 H, s), 6.911 ppm (1 H, s): MS (M + ); 224.
[0031]
Reference example 2
Synthesis of 5-ethoxy-4-methoxyanthranilamide In the same manner as in Reference Example 1, it was synthesized from the corresponding 4,5-disubstituted anthranilic acid. Physical property values are: 1 H-NMR (CDCl 3 ); 1.403 ppm (3H, t, J = 6.83 Hz), 3.848 ppm (3H, s), 3.996 ppm (2H, q, J = 6.83 Hz), 5.574 ppm ( 4H, brs), 6.176 ppm (1H, s), 6.899 ppm (1H, s): MS (M + ); 210.
[0032]
Reference example 3
Synthesis of 4-methoxy-5- (3-morpholinopropioxy) anthranilamide In the same manner as in Reference Example 1, it was synthesized from the corresponding 4,5-disubstituted anthranilic acid. Physical property values are 1 H-NMR (CDCl 3 ); 1.91 to 2.04 ppm (2H, m), 2.45 to 2.55 ppm (6H, m), 3.72 ppm (4H, t, J = 4.4 Hz), 3.83 ppm (3H , s), 3.98 ppm (2 H, t, J = 6.6 Hz), 4.18 ppm (2 H, s), 6.23 ppm (1 H, s), 6.85 ppm (1 H, s): MS (M + ); 309 It was.
[0033]
Reference example 4
Synthesis of 4,5-bis (2-methoxyethoxy) anthranilamide
The compound was synthesized from the corresponding 4,5-disubstituted anthranilic acid as in Reference Example 1. The physical property values are 1 H-NMR (CDCl 3 ); 3.437 ppm (3H, s), 3.439 ppm (3H, s), 3.690 ppm (2H, t, J = 4.40 Hz), 3.770 ppm (2H, t, J = 4.40Hz), 4.078ppm (2H, t, J = 4.40Hz), 4.121ppm (2H, t, J = 4.40Hz), 5.633ppm (4H, brs), 6.175ppm (1H, s), 7.029ppm ( 1H, s): MS (M + );
[0034]
Examples 3-8
In Example 1, the same operation as described in Example 1 was performed except that the raw material 4,5-disubstituted anthranilamide, the amount of carbonate, the amount of potassium carbonate, the reaction temperature and the reaction time were changed. The results are shown in Table 1. Moreover, the physical property value of the target compound obtained from the raw material compounds 5 and 6 is shown below.
7-methoxy-6- (3-morpholinopropoxy) -2,4-dioxoquinazoline (raw material: Compound 5)
1 H-NMR (DMSO-d6); 1.861ppm (2H, tt, J = 6.83,6.35Hz), 2.342ppm (4H, m), 2.396ppm (2H, t, J = 6.83Hz), 3.559ppm (4H , t, J = 4.40Hz), 3.814ppm (3H, s), 3.995ppm (2H, t, J = 6.35Hz), 6.662ppm (1H, s), 7.247ppm (1H, s), 10.892ppm (1H , brs), 11.071 ppm (1H, brs): MS (MH + ); 336
6,7-bis (2-methoxyethoxy) -2,4-dioxoquinazoline (raw material: compound 6)
1 H-NMR (DMSO-d6); 3.302 (3H, s), 3.318 (3H, s), 3.644 (2H, t, J = 4.39Hz), 3.694 (2H, t, J = 4.39Hz), 4.088 ( 2H, t, J = 4.39Hz), 4.124 (2H, t, J = 4.39Hz), 6.674 (1H, s), 7.278 (1H, s), 10.888 (1H, brs), 11.074 (1H, brs): MS (M + ); 310
[0035]
[Table 1]
【The invention's effect】
According to the present invention, 6,7-disubstituted-2,4-dioxoquinazoline can be produced from 4,5-disubstituted anthranilamides with high yield and high selectivity without requiring complicated operations. Thus, an industrially suitable method for producing 6,7-disubstituted-2,4-dioxoquinazoline can be provided.
Claims (2)
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| JP09149098A JP3740835B2 (en) | 1998-04-03 | 1998-04-03 | Process for producing 6,7-disubstituted-2,4-dioxoquinazoline |
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