JP4214707B2 - Method for producing pyridine compound - Google Patents
Method for producing pyridine compound Download PDFInfo
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- JP4214707B2 JP4214707B2 JP2002088577A JP2002088577A JP4214707B2 JP 4214707 B2 JP4214707 B2 JP 4214707B2 JP 2002088577 A JP2002088577 A JP 2002088577A JP 2002088577 A JP2002088577 A JP 2002088577A JP 4214707 B2 JP4214707 B2 JP 4214707B2
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- UDEKVJGLGNAUNN-UHFFFAOYSA-N CN(C(C(F)(F)F)=CC(N1c(cc(c(Cl)c2)OC3=CC=CNC3=O)c2F)=O)C1=O Chemical compound CN(C(C(F)(F)F)=CC(N1c(cc(c(Cl)c2)OC3=CC=CNC3=O)c2F)=O)C1=O UDEKVJGLGNAUNN-UHFFFAOYSA-N 0.000 description 1
- MEAZFFPMMJSRGX-UHFFFAOYSA-N CN(C(C(F)(F)F)=CC(N1c(cc(c(Cl)c2)Oc3cccnc3OC)c2F)=O)C1=O Chemical compound CN(C(C(F)(F)F)=CC(N1c(cc(c(Cl)c2)Oc3cccnc3OC)c2F)=O)C1=O MEAZFFPMMJSRGX-UHFFFAOYSA-N 0.000 description 1
- 0 CN(C(C(F)(F)F)=CC(N1c2c(*)cc(*)c(Oc3c(*)nccc3)c2)=O)C1=O Chemical compound CN(C(C(F)(F)F)=CC(N1c2c(*)cc(*)c(Oc3c(*)nccc3)c2)=O)C1=O 0.000 description 1
Description
【0001】
【発明の属する技術分野】
本発明はピリジン化合物の製造法に関する。
【0002】
【従来の技術および発明が解決しようとする課題】
式(3)
【化3】
(式中、R1はハロゲン原子またはニトロ基を表し、R2は水素原子またはハロゲン原子を表し、R3は低級アルコキシ基を表す。)
で示される2−アルコキシピリジン化合物は優れた除草活性を有する化合物(ヨーロッパ特許公開EP1122244A1参照)であり、その有利な製造法の開発が望まれている。
【0003】
【課題を解決するための手段】
本発明者は、式(3)で示されるピリジン化合物の有利な製造法を開発すべく鋭意検討した結果、後記式(1)で示されるピリドン化合物と後記式(2)で示されるジアゾ酢酸エステル化合物とを酸の存在下で反応させることにより位置選択的にO−アルキル化反応が進行し、式(3)で示される化合物が高選択的に得られることを見出し、本発明を完成した。
【0004】
即ち、本発明は式(1)
【化4】
(式中、R1はハロゲン原子またはニトロ基を表し、R2は水素原子またはハロゲン原子を表す。)
で示されるピリドン化合物と、式(2)
N2CHCOR3 (2)
(式中、R3は低級アルコキシ基を表す。)
で示されるジアゾ酢酸エステル化合物とを酸の存在下で反応させることを特徴とする式(3)で示されるピリジン化合物の製造法(以下、本発明製造法と記す。)を提供する。
【0005】
【発明の実施の形態】
本発明において、R1およびR2で示されるハロゲン原子としては例えばフッ素原子、塩素原子および臭素原子があげられ、R3で示される低級アルコキシ基としては例えばC1−C6アルコキシ基、具体的には例えばメトキシ基およびエトキシ基があげられる。
【0006】
本発明製造法は式(1)で示されるピリドン化合物と式(2)で示されるジアゾ酢酸エステル化合物とを酸の存在下で反応させることを特徴とする。
該反応は、通常溶媒中で行われる。反応に用いられる溶媒としては、例えばトルエン、キシレン等の芳香族炭化水素類、1,2−ジクロロエタン、クロロベンゼン等のハロゲン化炭化水素類、ジエチルエーテル、1,4−ジオキサン等のエーテル類、酢酸エチル、酢酸ブチル等のエステル類、アセトニトリル、ブチルニトリル等のニトリル類、メチルイソブチルケトン等のケトン類およびこれらの混合物があげられる。
該反応に用いられる酸としては、非プロトン酸およびプロトン酸があげられ、非プロトン酸としては例えばボロントリフルオリドエーテレート(BF3・O(C2H5)2)および四塩化スズがあげられ、プロトン酸としては例えばトリフルオロメタンスルホン酸等のスルホン酸類があげられる。
反応に用いられる試剤の量は式(1)で示されるピリドン化合物1モルに対して式(2)で示されるジアゾ酢酸エステル化合物が0.5〜5モルの割合、収率の点から好ましくは0.8モル以上、経済性の点から好ましくは2モル以下の割合であり、酸が0.001〜5モルの割合、反応速度の点から好ましくは0.01モル以上、経済性の点から好ましくは1モル以下の割合である。
反応温度は通常−50〜150℃の範囲、反応速度の点から好ましくは−20℃以上であり、反応時間は通常瞬時〜72時間の範囲である。
該反応は例えば以下の方法により行うことができる。
1)式(1)で示されるピリドン化合物、酸および溶媒を混合し、その中に式(2)で示されるジアゾ酢酸エステル化合物を滴下する方法。
2)式(1)で示されるピリドン化合物と溶媒とを混合し、その中に酸と式(2)で示されるジアゾ酢酸エステル化合物とを並行して滴下する方法。
3)式(2)で示されるジアゾ酢酸エステル溶解し、その中に酸と式(1)で示されるピリドン化合物とを滴下する方法。
反応終点は例えば反応混合物の一部をとり、液体クロマトグラフィー、薄層クロマトグラフィー等の分析手段で式(1)で示される化合物の消失を確認することにより決定することができる。
反応終了後は例えば以下の方法による後処理操作を行うことにより、式(3)で示されるピリジン化合物を単離することができる。
1)反応混合物をそのままシリカゲルカラムクロマトグラフィーに付する方法。
2)反応混合物を水に注加し、これを有機溶媒抽出し、得られた有機層を乾燥、濃縮し、得られた残渣を必要に応じてシリカゲルカラムクロマトグラフィー、再結晶等で精製する方法。
3)反応混合物に酸性水(例えば硫酸水)を注加してしばらく攪拌した後、弱塩基性水(例えば炭酸水素ナトリウム水溶液)を加え、これを有機溶媒抽出し、得られた有機層を乾燥、濃縮し、得られた残渣を必要に応じてシリカゲルカラムクロマトグラフィー、再結晶等で精製する方法。
【0007】
本発明製造法に用いられる式(1)で示されるピリドン化合物のうちR1がハロゲン原子である化合物は、例えば下記のスキームで示すルートで製造することができる。
【化5】
(式中、R1-1はハロゲン原子を表し、R2は前記と同じ意味を表す。)
【0008】
式(4)で示される化合物→式(6)で示される化合物
式(6)で示される化合物は式(4)で示される化合物と式(5)で示される化合物とを塩基(例えば炭酸カリウム)の存在下で反応させることにより製造することができる。
【0009】
式(6)で示される化合物→式(7)で示される化合物
式(7)で示される化合物は式(6)で示される化合物を還元反応に付すことにより製造することができる。
該還元反応の方法としては、例えば▲1▼水素化触媒(例えば、パラジウム−炭素)の存在下、水素と反応させる方法、および▲2▼酸性水(例えば酢酸水)中で鉄粉と反応させる方法があげられる。
【0010】
式(7)で示される化合物→式(8)で示される化合物
式(8)で示される化合物は式(7)で示される化合物をジアゾ化し、次いでハロゲン化剤と反応させることにより製造することができる。
ジアゾ化反応は式(7)で示される化合物を必要に応じて酸の存在下でジアゾ化剤(例えば、亜硝酸ナトリウム等の亜硝酸塩および亜硝酸イソアミル等の亜硝酸低級アルキルがあげられる。)とを反応させることにより行われ、ハロゲン化剤との反応は前記反応により得られたジアゾニウム塩とハロゲン化剤(塩化銅、臭化銅、テトラフルオロホウ素ナトリウム等)とを混合することにより行われる。
【0011】
式(8)で示される化合物→式(1)で示される化合物
式(1)で示される化合物は式(8)で示される化合物と三臭化ホウ素とを反応させることにより製造することができる。
【0012】
式(1)で示される化合物のうちR1がニトロ基である化合物は例えば式(6)で示される化合物と三臭化ホウ素とを反応させることにより製造することができる。
【0013】
【実施例】
以下、製造例等により本発明をさらに詳しく説明するが、本発明はこれらの例に
限定されるものではない。
【0014】
製造例
3−[4−クロロ−2−フルオロ−5−(2−オキソ−1,2−ジヒドロピリジン−3−イルオキシ)フェニル]−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオン(下式(A)で示される化合物)
【化6】
とボロントリフルオリドエーテレート42μlとを1,2−ジクロロエタン40mlに溶解し、ここに室温でジアゾ酢酸エチル(純度90%)0.4mlを2時間かけて滴下し、滴下終了後さらに2時間攪拌した。その後、反応混合物をそのままシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル=2/1)に付し、{3−[2−クロロ−4−フルオロ−5−(3−メチル−2,6−ジオキソ−4−(トリフルオロメチル)−3,6−ジヒドロ−2H−ピリミジン−1−イル)フェノキシ]ピリジン−2−イルオキシ}酢酸エチル(下式(B)で示される化合物)
【化7】
1.10gを得た。
1H−NMR(CDCl3/300MHz)δ(ppm):1.25(t,3H,J=7.1Hz),3.50(q,3H,J=1.2Hz),4.16(q,2H,J=7.1Hz),4.88(d,1H,J=15.9Hz),4.96(d,1H,J=15.9Hz),6.29(s,1H),6.9−7.0(m,2H),7.3−7.4(m,2H),7.9−8.0(m,1H)
【0015】
生成物を分析したところ、N−アルキル化された生成物である{3−[2−クロロ−4−フルオロ−5−(3−メチル−2,6−ジオキソ−4−(トリフルオロメチル)−3,6−ジヒドロ−2H−ピリミジン−1−イル)フェノキシ]−2−オキソ−2H−ピリジン−1−イル}酢酸エチルは検出されなかった。
分析条件
高速液体クロマトグラフィー
液体クロマトグラフLC−10AS(島津製作所製)
検出器:UV−Vis検出器 SPD−10A(島津製作所製)
検出波長:254nm
カラム:SUMIPAX ODS A−212(住化分析センター製)
カラム温度:室温
移動層:アセトニトリル/水=1/1
【0016】
次に、上記製造法に用いた原料化合物である3−[4−クロロ−2−フルオロ−5−(2−オキソ−1,2−ジヒドロピリジン−3−イルオキシ)フェニル]−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオンの製造につき、参考製造例として記す。
【0017】
参考製造例
3−(2,5−ジフルオロ−4−ニトロフェニル)−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオン(下式(C)で示される化合物)
【化8】
10gと3−ヒドロキシ−2−メトキシピリジン5.0gとをN,N−ジメチルホルムアミド100mlに溶解し、炭酸カリウム7.8gを加えて室温で6時間攪拌した。その後、反応混合物を水に注加し、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した後、濃縮して、3−[2−フルオロ−5−(2−メトキシピリジン−3−イルオキシ)−4−ニトロフェニル]−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオン(下式(D)で示される化合物)
【化9】
12.8gを得た。
1H−NMR(CDCl3/300MHz)δ(ppm):3.52(q,3H,J=1.2Hz),3.93(s,3H),6.32(s,1H),6.76(d,1H,J=5.8Hz),6.93(dd,1H,J=5.0Hz,7.8Hz),7.40(dd,1H,J=1.4Hz,7.8Hz),7.90(d,1H,J=8.6Hz),8.04(dd,1H,J=1.4Hz,5.0Hz)
【0018】
鉄粉6.3gを酢酸50mlよ水50mlの混合物に懸濁し、ここに80℃で3−[2−フルオロ−5−(2−メトキシピリジン−3−イルオキシ)−4−ニトロフェニル]−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオン12.8gを酢酸エチル60mlに溶解した溶液を滴下した。滴下終了後、同温で15分間攪拌した後、反応混合物を室温まで冷却した。その後、反応混合物を水に注加し、酢酸エチルで抽出した。有機層を水、炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した後、濃縮して3−[4−アミノ−2−フルオロ−5−(2−メトキシピリジン−3−イルオキシ)フェニル]−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオン(下式(E)で示される化合物)
【化10】
12.1gを得た。
1H−NMR(CDCl3/300MHz)δ(ppm):3.51(q,3H,J=1.0Hz),4.00(s,3H),4.20(br,1H),6.30(s,1H),6.62(d,1H,J=10.6Hz),6.63(d,1H,J=7.1Hz),6.82(dd,1H,J=5.0Hz,7.8Hz),7.18(dd,1H,J=1.4Hz,7.8Hz),7.90(dd,1H,J=1.4Hz,5.0Hz)
【0019】
3−[4−アミノ−2−フルオロ−5−(2−メトキシピリジン−3−イルオキシ)フェニル]−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオン12g、塩化第一銅2.8gおよび塩化第二銅5.7gをアセトニトリル100mlに加え、ここに室温で亜硝酸イソアミル4.6gを滴下し、滴下終了後、2時間攪拌し、さらに2日間放置した。その後反応混合物にアンモニア水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した後、濃縮した。残渣をシルカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル=2/1)に付し、3−[4−クロロ−2−フルオロ−5−(2−メトキシピリジン−3−イルオキシ)フェニル]−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオン(下式(F)で示される化合物)
【化11】
8.6gを得た。
融点:179.5℃
【0020】
3−[4−クロロ−2−フルオロ−5−(2−メトキシピリジン−3−イルオキシ)フェニル]−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオン0.5gをクロロホルム10mlに溶解し、ここに三臭化ホウ素0.5gを加え、室温で3時間攪拌した。その後、反応混合物を濃縮した。濃縮残渣を水に注加し、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、濃縮した。残渣をシルカゲルカラムクロマトグラフィー(展開溶媒:酢酸エチル)に付し、3−[4−クロロ−2−フルオロ−5−(2−オキソ−1,2−ジヒドロピリジン−3−イルオキシ)フェニル]−1−メチル−6−(トリフルオロメチル)−1H−ピリミジン−2,4−ジオン0.31gを得た。
融点:180.8℃
【0021】
【発明の効果】
本発明製造法により式(1)で示されるピリドン化合物から式(3)で示されるシピリジン化合物を選択的に製造することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a pyridine compound.
[0002]
[Background Art and Problems to be Solved by the Invention]
Formula (3)
[Chemical 3]
(In the formula, R 1 represents a halogen atom or a nitro group, R 2 represents a hydrogen atom or a halogen atom, and R 3 represents a lower alkoxy group.)
Is a compound having excellent herbicidal activity (see European Patent Publication EP1122244A1), and development of an advantageous production method thereof is desired.
[0003]
[Means for Solving the Problems]
As a result of intensive studies to develop an advantageous method for producing a pyridine compound represented by the formula (3), the present inventor has found that a pyridone compound represented by the following formula (1) and a diazoacetate ester represented by the following formula (2) By reacting the compound with an acid in the presence of an acid, the O-alkylation reaction proceeds regioselectively, and the compound represented by formula (3) was found to be obtained with high selectivity, and the present invention was completed.
[0004]
That is, the present invention provides the formula (1)
[Formula 4]
(In the formula, R 1 represents a halogen atom or a nitro group, and R 2 represents a hydrogen atom or a halogen atom.)
A pyridone compound represented by formula (2)
N 2 CHCOR 3 (2)
(In the formula, R 3 represents a lower alkoxy group.)
A method for producing a pyridine compound represented by the formula (3) (hereinafter referred to as the production method of the present invention) is provided, which comprises reacting the diazoacetate compound represented by formula (2) in the presence of an acid.
[0005]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, examples of the halogen atom represented by R 1 and R 2 include a fluorine atom, a chlorine atom and a bromine atom, and examples of the lower alkoxy group represented by R 3 include a C1-C6 alkoxy group, specifically Examples thereof include a methoxy group and an ethoxy group.
[0006]
The production method of the present invention is characterized in that a pyridone compound represented by the formula (1) and a diazoacetate compound represented by the formula (2) are reacted in the presence of an acid.
The reaction is usually performed in a solvent. Examples of the solvent used in the reaction include aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as 1,2-dichloroethane and chlorobenzene, ethers such as diethyl ether and 1,4-dioxane, and ethyl acetate. And esters such as butyl acetate, nitriles such as acetonitrile and butyl nitrile, ketones such as methyl isobutyl ketone, and mixtures thereof.
Examples of the acid used in the reaction include an aprotic acid and a protonic acid. Examples of the aprotic acid include boron trifluoride etherate (BF 3 .O (C 2 H 5 ) 2 ) and tin tetrachloride. Examples of the protonic acid include sulfonic acids such as trifluoromethanesulfonic acid.
The amount of the reagent used in the reaction is preferably 0.5 to 5 mol of the diazoacetate compound represented by the formula (2) with respect to 1 mol of the pyridone compound represented by the formula (1), preferably from the viewpoint of yield. 0.8 mole or more, preferably 2 moles or less from the viewpoint of economy, a ratio of 0.001 to 5 moles of acid, preferably from 0.01 mole or more, from the viewpoint of economy, from the viewpoint of reaction rate The ratio is preferably 1 mol or less.
The reaction temperature is usually in the range of −50 to 150 ° C., preferably from −20 ° C. or more from the viewpoint of the reaction rate, and the reaction time is usually in the range of instantaneous to 72 hours.
The reaction can be performed, for example, by the following method.
1) A method in which a pyridone compound represented by formula (1), an acid and a solvent are mixed, and a diazoacetic acid ester compound represented by formula (2) is dropped therein.
2) A method in which a pyridone compound represented by the formula (1) and a solvent are mixed, and an acid and a diazoacetic acid ester compound represented by the formula (2) are dropped therein in parallel.
3) A method in which a diazoacetate ester represented by the formula (2) is dissolved, and an acid and a pyridone compound represented by the formula (1) are dropped therein.
The reaction end point can be determined, for example, by taking a part of the reaction mixture and confirming the disappearance of the compound represented by the formula (1) by an analytical means such as liquid chromatography or thin layer chromatography.
After completion of the reaction, for example, a pyridine compound represented by the formula (3) can be isolated by performing a post-treatment operation by the following method.
1) A method in which the reaction mixture is directly subjected to silica gel column chromatography.
2) A method in which the reaction mixture is poured into water, extracted with an organic solvent, the obtained organic layer is dried and concentrated, and the resulting residue is purified by silica gel column chromatography, recrystallization or the like, if necessary. .
3) After adding acidic water (for example, sulfuric acid aqueous solution) to the reaction mixture and stirring for a while, weakly basic water (for example, aqueous sodium hydrogen carbonate solution) is added, this is extracted with an organic solvent, and the resulting organic layer is dried. Concentrate, and purify the resulting residue by silica gel column chromatography, recrystallization, etc. as necessary.
[0007]
Of the pyridone compounds represented by the formula (1) used in the production method of the present invention, the compound in which R 1 is a halogen atom can be produced, for example, by the route shown in the following scheme.
[Chemical formula 5]
(In the formula, R 1-1 represents a halogen atom, and R 2 has the same meaning as described above.)
[0008]
Compound represented by formula (4) → compound represented by formula (6) The compound represented by formula (6) is obtained by converting a compound represented by formula (4) and a compound represented by formula (5) into a base (for example, potassium carbonate). ) In the presence of.
[0009]
Compound represented by Formula (6) → Compound represented by Formula (7) The compound represented by Formula (7) can be produced by subjecting the compound represented by Formula (6) to a reduction reaction.
Examples of the reduction reaction include (1) a method of reacting with hydrogen in the presence of a hydrogenation catalyst (eg, palladium-carbon), and (2) a reaction with iron powder in acidic water (eg, acetic acid water). There are methods.
[0010]
Compound represented by formula (7) → compound represented by formula (8) The compound represented by formula (8) is produced by diazotizing the compound represented by formula (7) and then reacting with a halogenating agent. Can do.
In the diazotization reaction, a compound represented by the formula (7) is optionally diazotized in the presence of an acid (for example, nitrite such as sodium nitrite and lower alkyl nitrite such as isoamyl nitrite). The reaction with the halogenating agent is carried out by mixing the diazonium salt obtained by the above reaction with a halogenating agent (copper chloride, copper bromide, sodium tetrafluoroboron, etc.). .
[0011]
Compound represented by Formula (8) → Compound represented by Formula (1) The compound represented by Formula (1) can be produced by reacting the compound represented by Formula (8) with boron tribromide. .
[0012]
Among the compounds represented by formula (1), a compound in which R 1 is a nitro group can be produced, for example, by reacting a compound represented by formula (6) with boron tribromide.
[0013]
【Example】
Hereinafter, the present invention will be described in more detail with reference to production examples and the like, but the present invention is not limited to these examples.
[0014]
Production Example 3- [4-Chloro-2-fluoro-5- (2-oxo-1,2-dihydropyridin-3-yloxy) phenyl] -1-methyl-6- (trifluoromethyl) -1H-pyrimidine-2 , 4-dione (compound represented by the following formula (A))
[Chemical 6]
And 42 μl of boron trifluoride etherate were dissolved in 40 ml of 1,2-dichloroethane, and 0.4 ml of ethyl diazoacetate (purity 90%) was added dropwise at room temperature over 2 hours, followed by further stirring for 2 hours. . Thereafter, the reaction mixture was directly subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1) to give {3- [2-chloro-4-fluoro-5- (3-methyl-2,6- Dioxo-4- (trifluoromethyl) -3,6-dihydro-2H-pyrimidin-1-yl) phenoxy] pyridin-2-yloxy} acetate (compound represented by the following formula (B))
[Chemical 7]
1.10 g was obtained.
1 H-NMR (CDCl 3 /300MHz)δ(ppm):1.25(t,3H,J=7.1Hz),3.50(q,3H,J=1.2Hz),4.16(q , 2H, J = 7.1 Hz), 4.88 (d, 1H, J = 15.9 Hz), 4.96 (d, 1H, J = 15.9 Hz), 6.29 (s, 1H), 6 .9-7.0 (m, 2H), 7.3-7.4 (m, 2H), 7.9-8.0 (m, 1H)
[0015]
The product was analyzed and found to be N-alkylated product {3- [2-chloro-4-fluoro-5- (3-methyl-2,6-dioxo-4- (trifluoromethyl)- 3,6-Dihydro-2H-pyrimidin-1-yl) phenoxy] -2-oxo-2H-pyridin-1-yl} ethyl acetate was not detected.
Analysis conditions high performance liquid chromatography liquid chromatograph LC-10AS (manufactured by Shimadzu Corporation)
Detector: UV-Vis detector SPD-10A (manufactured by Shimadzu Corporation)
Detection wavelength: 254 nm
Column: SUMPAX ODS A-212 (manufactured by Sumika Chemical Analysis Center)
Column temperature: room temperature Moving bed: acetonitrile / water = 1/1
[0016]
Next, 3- [4-chloro-2-fluoro-5- (2-oxo-1,2-dihydropyridin-3-yloxy) phenyl] -1-methyl-6-, which is a raw material compound used in the above production method. The production of (trifluoromethyl) -1H-pyrimidine-2,4-dione will be described as a reference production example.
[0017]
Reference Production Example 3- (2,5-difluoro-4-nitrophenyl) -1-methyl-6- (trifluoromethyl) -1H-pyrimidine-2,4-dione (compound represented by the following formula (C))
[Chemical 8]
10 g and 5.0 g of 3-hydroxy-2-methoxypyridine were dissolved in 100 ml of N, N-dimethylformamide, 7.8 g of potassium carbonate was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3- [2-fluoro-5- (2-methoxypyridin-3-yloxy) -4- Nitrophenyl] -1-methyl-6- (trifluoromethyl) -1H-pyrimidine-2,4-dione (compound represented by the following formula (D))
[Chemical 9]
12.8 g was obtained.
1 H-NMR (CDCl 3 /300MHz)δ(ppm):3.52(q,3H,J=1.2Hz),3.93(s,3H),6.32(s,1H),6 . 76 (d, 1H, J = 5.8 Hz), 6.93 (dd, 1H, J = 5.0 Hz, 7.8 Hz), 7.40 (dd, 1H, J = 1.4 Hz, 7.8 Hz) 7.90 (d, 1H, J = 8.6 Hz), 8.04 (dd, 1H, J = 1.4 Hz, 5.0 Hz)
[0018]
6.3 g of iron powder was suspended in a mixture of 50 ml of acetic acid and 50 ml of water, and 3- [2-fluoro-5- (2-methoxypyridin-3-yloxy) -4-nitrophenyl] -1- A solution prepared by dissolving 12.8 g of methyl-6- (trifluoromethyl) -1H-pyrimidine-2,4-dione in 60 ml of ethyl acetate was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 15 minutes, and then the reaction mixture was cooled to room temperature. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated to give 3- [4-amino-2-fluoro-5- (2-methoxypyridin-3-yloxy) phenyl] -1- Methyl-6- (trifluoromethyl) -1H-pyrimidine-2,4-dione (compound represented by the following formula (E))
[Chemical Formula 10]
12.1 g was obtained.
1 H-NMR (CDCl 3 /300MHz)δ(ppm):3.51(q,3H,J=1.0Hz),4.00(s,3H),4.20(br,1H),6 . 30 (s, 1H), 6.62 (d, 1H, J = 10.6 Hz), 6.63 (d, 1H, J = 7.1 Hz), 6.82 (dd, 1H, J = 5.0 Hz) , 7.8 Hz), 7.18 (dd, 1 H, J = 1.4 Hz, 7.8 Hz), 7.90 (dd, 1 H, J = 1.4 Hz, 5.0 Hz)
[0019]
3- [4-amino-2-fluoro-5- (2-methoxypyridin-3-yloxy) phenyl] -1-methyl-6- (trifluoromethyl) -1H-pyrimidine-2,4-dione 12 g, chloride 2.8 g of cuprous and 5.7 g of cupric chloride were added to 100 ml of acetonitrile, and 4.6 g of isoamyl nitrite was added dropwise thereto at room temperature. After completion of the dropwise addition, the mixture was stirred for 2 hours and allowed to stand for 2 days. Thereafter, aqueous ammonia was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1) to give 3- [4-chloro-2-fluoro-5- (2-methoxypyridin-3-yloxy) phenyl]- 1-methyl-6- (trifluoromethyl) -1H-pyrimidine-2,4-dione (compound represented by the following formula (F))
Embedded image
8.6 g was obtained.
Melting point: 179.5 ° C
[0020]
3- [4-Chloro-2-fluoro-5- (2-methoxypyridin-3-yloxy) phenyl] -1-methyl-6- (trifluoromethyl) -1H-pyrimidine-2,4-dione 0.5 g Was dissolved in chloroform (10 ml), and boron tribromide (0.5 g) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was then concentrated. The concentrated residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate) to give 3- [4-chloro-2-fluoro-5- (2-oxo-1,2-dihydropyridin-3-yloxy) phenyl] -1 0.31 g of -methyl-6- (trifluoromethyl) -1H-pyrimidine-2,4-dione was obtained.
Melting point: 180.8 ° C
[0021]
【The invention's effect】
The pyridine compound represented by the formula (3) can be selectively produced from the pyridone compound represented by the formula (1) by the production method of the present invention.
Claims (1)
で示されるピリドン化合物と、式(2)
N2CHCOR3 (2)
(式中、R3は低級アルコキシ基を表す。)
で示されるジアゾ酢酸エステル化合物とをボロントリフルオリドエーテレートの存在下で反応させることを特徴とする式(3)
で示されるピリジン化合物の製造法。Formula (1)
A pyridone compound represented by formula (2)
N 2 CHCOR 3 (2)
(In the formula, R 3 represents a lower alkoxy group.)
And a diazoacetate compound represented by the formula (3), wherein the compound is reacted in the presence of boron trifluoride etherate.
The manufacturing method of the pyridine compound shown by these.
Priority Applications (21)
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JP2002088577A JP4214707B2 (en) | 2002-03-27 | 2002-03-27 | Method for producing pyridine compound |
BRPI0211652-9A BR0211652B1 (en) | 2001-08-02 | 2002-07-31 | pyridone compounds and process for producing pyridine compound. |
DE60233664T DE60233664D1 (en) | 2001-08-02 | 2002-07-31 | PROCESS FOR THE PREPARATION OF PYRIDINE COMPOUNDS |
RU2004106028/04A RU2272035C2 (en) | 2001-08-02 | 2002-07-31 | Method for preparing pyridine derivative and intermediate substance |
HU0401486A HUP0401486A3 (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound |
MXPA04001041A MXPA04001041A (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound. |
AU2002318564A AU2002318564B2 (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound |
PL392482A PL215049B1 (en) | 2001-08-02 | 2002-07-31 | Pyridol compound with herbicidal properties, and useful for manufacturing of herbicidal compounds |
KR1020047001550A KR100846649B1 (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound |
EP02746150A EP1422227B1 (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound |
CNB028151550A CN1238352C (en) | 2001-08-02 | 2002-07-31 | Process for producing pylidine compound |
ES02746150T ES2331513T3 (en) | 2001-08-02 | 2002-07-31 | PROCEDURE FOR THE PRODUCTION OF PIRIDINE COMPOUNDS. |
PCT/JP2002/007793 WO2003014109A1 (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound |
AT02746150T ATE442363T1 (en) | 2001-08-02 | 2002-07-31 | METHOD FOR PRODUCING PYRIDINE COMPOUNDS |
CA002456093A CA2456093C (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound |
IL15993102A IL159931A0 (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound |
PL367963A PL209873B1 (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound |
US10/486,037 US7157579B2 (en) | 2001-08-02 | 2002-07-31 | Process for producing pyridine compound |
IL159931A IL159931A (en) | 2001-08-02 | 2004-01-19 | Process for producing pyridine compound and pyridone intermediates thereof |
ZA2004/00844A ZA200400844B (en) | 2001-08-02 | 2004-02-02 | Process for producing pyridine compound |
US11/382,354 US7223862B2 (en) | 2001-08-02 | 2006-05-09 | Pyridone compounds useful for producing pyridine compounds |
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