JP3561148B2 - Method for separating quinaldine isomers - Google Patents

Description

【００１１】
本発明における３位に置換基を有するアニリンとクロトンアルデヒドとの反応は、濃塩酸存在下に加熱、撹拌しつつ、冷却・還流させながら実施する。反応は、７５〜１１０℃で行う。
【００１２】
上記反応における３位置換アニリンに対するクロトンアルデヒドの添加量は、等モル以上、例えば、１．１倍モル〜１．３倍モルとやや余分に用いる。３位置換アニリンに対する濃塩酸の量は、３位置換アニリン１モルに対し、塩酸換算で１．０倍〜１０倍モル、好ましくは１．５倍〜５倍モル用いる。
【００１３】
上記反応により生成するキナルジン異性体は、化２に示す７位に置換基を有するキナルジン、化３に示す５位に置換基を有するキナルジンで、Ｒ_１の置換基が、メチル、エチル、プロピル、ブチル等のアルキル基、メトキシ、エトキシ、プロポキシ、ブトキシ等のアルコキシル基、フッ素、臭素、塩素、ヨウ素のハロゲン基、フェニル、トリル、キシリル、ヒドロキシフェニル等のアリール基であり、Ｒ_２が、水素、メチル、エチル、プロピル、ブチル等のアメキル基、メトキシ、エトキシ、プロポキシ、ブトキシ等のアルコキシル基、フッ素、臭素、塩素、ヨウ素のハロゲン基、フェニル、トリル、キシリル、ヒドロキシフェニル等のアリール基のものである。
【００１４】
【化２】

【００１５】
【化３】

【００１６】
上記反応後の反応液からのキナルジン異性体の分離には、塩化亜鉛（ＺｎＣｌ_２）と脂肪族ケトン類を添加し、キナルジン異性体を塩酸・塩化亜鉛錯体として濾別回収する。反応液に添加する塩化亜鉛量は、出発物質である３位置換アニリンに対して０．０１〜２０倍モル、好ましくは０．１〜５倍モルである。処理温度は、０℃〜１５０℃、好ましくは１０℃〜溶媒の沸点未満である。
【００１７】
本発明の錯体分離溶媒である脂肪族ケトン類は、上記塩化亜鉛とともに添加する。脂肪族ケトン類の添加量は、前記反応液重量に対して１０〜２００重量％、好ましくは、３０〜１００重量％である。
【００１８】
反応液に塩化亜鉛、脂肪族ケトン類を添加して所定時間、例えば０．５〜１時間撹拌すると、キナルジン異性体が塩酸・塩化亜鉛錯体として析出する。このキナルジン異性体の塩酸・塩化亜鉛錯体を濾過すれば、７位置換キナルジンを高純度で含む塩酸・塩化亜鉛錯体を得ることができる。
【００１９】
７位置換キナルジンを高純度で含む塩酸・塩化亜鉛錯体は、アンモニア水で分解すれば、高純度の７位置換キナルジンを高収率で得ることができる。
【００２０】
【実施例】
実施例１
撹拌機、還流コンデンサー付きの容量２ｌの三方フラスコに３−クロロアニリン１２７．６ｇ（１ｍｏｌ）、市販の塩酸濃度３７．２％の濃塩酸３００ｇを仕込み、１００℃に加熱した。容量２５０ｍｌの添加用漏斗を、このフラスコに取付け、クロトンアルデヒド８０ｇ（１．１４ｍｏｌ）で満たした。フラスコ中の混合物を撹拌・加熱し、還流しつつ、クロトンアルデヒドを６０分間に亘って撹拌しながら滴下し反応させた。反応物から試料を採取し、内部標準物質としてビフェニルまたはナフタレン（ピークがビフェニルと重なったとき）を用いたガスクロマトグラフィー（ＧＣ／ＩＳ）により分析したところ、７−クロロキナルジンの反応収率は２５％（クロロキナルジンの反応収率３８％）で、反応液中の７−クロロキナルジン濃度は８．８重量％、５−クロロキナルジン濃度は４．５重量％であった。
【００２１】
反応終了後、反応液に塩化亜鉛１３５ｇ、アセトン２００ｇを添加し、３０℃で０．５時間撹拌した。この液を濾過して得られた粗結晶をアンモニアで分解し、ガスクロマトグラフィーを用いて分析した。その結果、５−クロロキナルジン２．８％、７−クロロキナルジン９７．２％の割合で含有する塩酸・塩化亜鉛錯体を得た。この塩酸・塩化亜鉛錯体をシクロヘキサンと濃度２５％のアンモニア水を用いて分解抽出したのち、有機層より得られた結晶を濾別し、純度９９．３％の７−クロロキナルジン３６ｇを得た。その結果を表１に示す。なお、表１中の選択率は、単離したクロロキナルジン錯体中の７−クロロキナルジン含有率、回収率は、反応液からの７−クロロキナルジン収率である。単位はモル％である。
【００２２】
実施例２〜４
溶媒種をアセトンからシクロヘキサノン、メチルイソブチルケトン、メチルエチルケトンに代えた以外は、実施例１と同一条件で実施した。その結果を実施例１とともに表１に示す。
【００２３】
【表１】

【００２４】
表１に示すとおり、実施例１〜４においては、いずれも選択率が９３％以上、回収率が８８％以上と、高選択率、高回収率を示している。
【００２５】
実施例５〜８
実施例１〜４で原料として用いた３−クロロアニリンに代えて、３−ブロモアニリン、３−フルオロアニリン、３−クロロ−４−フルオロアニリン、３−メトキシアニリンを用いた以外は、実施例１と同一条件で実施した。その結果を表２に示す。
【００２６】
【表２】

【００２７】
表２に示すとおり、実施例５〜８においては、いずれも選択率が９０％以上、回収率が８７％以上と、高選択率、高回収率を示している。
【００２８】
比較例１〜６
溶媒種をアセトンから酢酸エチル、酢酸ブチル、メタノール、イソプロピルアルコール、テトラヒドロフランに代えて使用した場合および溶媒を使用しない以外は、実施例１と同一条件で実施した。その結果を表３に示す。
【００２９】
【表３】

【００３０】
表３に示すとおり、比較例１〜５の溶媒を使用すると、いずれも選択率が９２％以上と高い値を示しているが、回収率が５２〜７７％と本発明に比較して低い値を示している。
【００３１】
【発明の効果】
本発明のキナルジン異性体の分離方法は、キナルジン異性体を塩酸・塩化亜鉛錯体としたのち、脂肪族ケトン類を添加して析出した結晶を濾別することによって、７位置換キナルジンを高純度、高収率で得ることができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for separating a 7-substituted quinaldine having a substituent at the 7-position among quinaldine isomers obtained by the Doebner-Miller method using an aniline having a substituent at the 3-position as a starting material.
[0002]
[Prior art]
The quinaldine isomers have been used for more than 100 years by a production method based on the Doebner-Miller reaction (Doebner et al., Ber., 14 , 2816 (1881)). However, quinaldines obtained by a Doebner-Miller reaction starting from aniline having a substituent at the 3-position generate isomers having substituents at the 5- and 7-positions. Among them, the 7-substituted quinaldine having a substituent at the 7-position is useful as an intermediate of a drug, but when isolated, has a problem in purity as well as low yield.
[0003]
As a method for separating quinaldine isomers, for example, A.I. M. Spivey, et. al. , J. et al. Chem. Soc. , 2656 (1949). P. Utermohlen et. J. Org. Chem. , 8 , 544 (1943). Another method is described in Leir, J. et al. Org. Chem. , 42 , 911 (1971), a method of isolating a quinaldine isomer as a hydrochloric acid / zinc chloride complex; Song et. al. J, Heterocyclic Chem. , 30 , 17 (1993), a method for isolating a 7-substituted quinaldine by converting a quinaldine isomer into a zinc chloride complex using zinc chloride and then using tetrahydrofuran (THF) as a separation solvent, Germany There is a method disclosed in the specification of Japanese Patent No. 3932136 for isolating 7-chloroquinaldine using tartaric acid as an acid.
[0004]
[Problems to be solved by the invention]
In the above-mentioned method for conversion to picrate and distillation method, since the physical properties of the quinaldine isomers at the 5-position and the 7-position are similar, the purity of the quinaldine at the 7-position is low even when the quinaldine at the 7-position is isolated. Not only that, but also the yield is low. In the method of isolating the quinaldine isomer as a hydrochloric acid / zinc chloride complex, the isolation is difficult because a large amount of a polymer is produced. The method of using tetrahydrofuran as a separation solvent after forming a zinc chloride complex is that tetrahydrofuran is an ether-based solvent, is difficult to handle, and is expensive. According to the experiments of the present inventors, the dissolution of quinaldine isomer in tetrahydrofuran It was found that the amount increased and the isolation yield decreased.
[0005]
An object of the present invention is to solve the above-mentioned drawbacks of the prior art, and, among the quinaldine isomers, a 7-substituted quinaldine having a substituent at the 7-position can be isolated with high purity and high yield. It is to provide a separation method.
[0006]
[Means for Solving the Problems]
The method for separating quinaldine isomers of the present invention isolates a 7-substituted quinaldine among quinaldine isomers obtained by a Doebner-Miller reaction starting from a 3-substituted aniline having a substituent at the 3-position. Then, zinc chloride is added to the reaction solution containing the quinaldine isomer to cause a stirring reaction, the quinaldine isomer is converted into a hydrochloric acid / zinc chloride complex, and then the aliphatic ketones are added and the precipitated crystals are separated by filtration.
[0007]
As described above, the quinaldine isomer is converted into a hydrochloric acid / zinc chloride complex, and the crystals precipitated by adding an aliphatic ketone are separated by filtration to obtain a 7-substituted quinaldine with high purity and high yield. Can be released.
[0008]
Examples of the aliphatic ketones used in the present invention include acetone, cyclohexanone, methyl isobutyl ketone and methyl ethyl ketone.
[0009]
BEST MODE FOR CARRYING OUT THE INVENTION
As the starting material, the aniline having a substituent at the 3-position, the substituent of R ₁ shown in the following chemical formula 1 is an alkyl group such as methyl, ethyl, propyl, butyl or the like, or an alkoxyl such as methoxy, ethoxy, propoxy or butoxy. Group, a halogen group of fluorine, bromine, chlorine, iodine, an aryl group such as phenyl, tolyl, xylyl, and hydroxyphenyl, wherein R ₂ shown in Chemical formula 1 is hydrogen, an alkyl group such as methyl, ethyl, propyl, and butyl; And alkoxy groups such as ethoxy, propoxy and butoxy; halogen groups such as fluorine, bromine, chlorine and iodine; and aryl groups such as phenyl, tolyl, xylyl and hydroxyphenyl.
[0010]
Embedded image

[0011]
The reaction between aniline having a substituent at the 3-position and crotonaldehyde in the present invention is carried out in the presence of concentrated hydrochloric acid while heating, stirring, cooling and refluxing. The reaction is performed at 75-110 ° C.
[0012]
The amount of crotonaldehyde to be added to the 3-substituted aniline in the above reaction is equimolar or more, for example, 1.1 to 1.3 times mol, which is slightly extra. Concentrated hydrochloric acid is used in an amount of 1.0 to 10 moles, preferably 1.5 to 5 moles in terms of hydrochloric acid, per 1 mole of the 3-position substituted aniline, based on 1 mole of the 3-position substituted aniline.
[0013]
The quinaldine isomers formed by the above reaction are quinaldine having a substituent at the 7-position shown in Chemical formula 2, and quinaldine having a substituent at the 5-position shown in Chemical formula 3, wherein the substituent of R ₁ is methyl, ethyl, propyl, An alkyl group such as butyl, an alkoxyl group such as methoxy, ethoxy, propoxy and butoxy; a halogen group such as fluorine, bromine, chlorine and iodine; an aryl group such as phenyl, tolyl, xylyl and hydroxyphenyl; and R ₂ is hydrogen, Amalkyl groups such as methyl, ethyl, propyl and butyl, alkoxyl groups such as methoxy, ethoxy, propoxy and butoxy, halogen groups such as fluorine, bromine, chlorine and iodine, and aryl groups such as phenyl, tolyl, xylyl and hydroxyphenyl is there.
[0014]
Embedded image

[0015]
Embedded image

[0016]
To separate the quinaldine isomer from the reaction solution after the above reaction, zinc chloride (ZnCl ₂ ) and an aliphatic ketone are added, and the quinaldine isomer is separated and recovered as a hydrochloric acid / zinc chloride complex. The amount of zinc chloride to be added to the reaction solution is 0.01 to 20 times mol, preferably 0.1 to 5 times mol, of the starting 3-substituted aniline. The processing temperature is 0 ° C to 150 ° C, preferably 10 ° C to less than the boiling point of the solvent.
[0017]
Aliphatic ketones, which are the complex separation solvents of the present invention, are added together with the zinc chloride. The amount of the aliphatic ketone to be added is 10 to 200% by weight, preferably 30 to 100% by weight, based on the weight of the reaction solution.
[0018]
When zinc chloride and aliphatic ketones are added to the reaction solution and stirred for a predetermined time, for example, 0.5 to 1 hour, the quinaldine isomer precipitates as a hydrochloric acid / zinc chloride complex. By filtering the hydrochloric acid / zinc chloride complex of this quinaldine isomer, a hydrochloric acid / zinc chloride complex containing the 7-substituted quinaldine with high purity can be obtained.
[0019]
When the hydrochloric acid / zinc chloride complex containing the 7-substituted quinaldine with high purity is decomposed with aqueous ammonia, high-purity 7-substituted quinaldine can be obtained in high yield.
[0020]
【Example】
Example 1
127.6 g (1 mol) of 3-chloroaniline and 300 g of commercially available concentrated hydrochloric acid having a hydrochloric acid concentration of 37.2% were charged into a 2-liter three-way flask equipped with a stirrer and a reflux condenser, and heated to 100 ° C. A 250 ml addition funnel was attached to the flask and filled with 80 g (1.14 mol) of crotonaldehyde. The mixture in the flask was stirred and heated, and while refluxing, crotonaldehyde was added dropwise with stirring for 60 minutes to cause a reaction. A sample was collected from the reaction product and analyzed by gas chromatography (GC / IS) using biphenyl or naphthalene (when the peak overlapped with biphenyl) as an internal standard substance. The reaction yield of 7-chloroquinaldine was found to be: The reaction solution had a concentration of 7-chloroquinaldine of 8.8% by weight and a concentration of 5-chloroquinaldine of 4.5% by weight at 25% (reaction yield of chloroquinaldine 38%).
[0021]
After completion of the reaction, 135 g of zinc chloride and 200 g of acetone were added to the reaction solution, and the mixture was stirred at 30 ° C. for 0.5 hour. The crude crystals obtained by filtering this liquid were decomposed with ammonia, and analyzed using gas chromatography. As a result, a hydrochloric acid / zinc chloride complex containing 2.8% of 5-chloroquinaldine and 97.2% of 7-chloroquinaldine was obtained. The hydrochloric acid / zinc chloride complex was decomposed and extracted using cyclohexane and 25% ammonia water, and the crystals obtained from the organic layer were separated by filtration to obtain 36 g of 99.3% pure 7-chloroquinaldine. . Table 1 shows the results. The selectivity in Table 1 is the content of 7-chloroquinaldine in the isolated chloroquinaldine complex, and the recovery is the yield of 7-chloroquinaldine from the reaction solution. The unit is mol%.
[0022]
Examples 2 to 4
The procedure was performed under the same conditions as in Example 1 except that the solvent was changed from acetone to cyclohexanone, methyl isobutyl ketone, and methyl ethyl ketone. The results are shown in Table 1 together with Example 1.
[0023]
[Table 1]

[0024]
As shown in Table 1, in Examples 1 to 4, the selectivity was 93% or more and the recovery rate was 88% or more, indicating high selectivity and high recovery rate.
[0025]
Examples 5 to 8
Example 1 was repeated except that 3-bromoaniline, 3-fluoroaniline, 3-chloro-4-fluoroaniline, and 3-methoxyaniline were used instead of 3-chloroaniline used as a raw material in Examples 1 to 4. The test was performed under the same conditions as described above. Table 2 shows the results.
[0026]
[Table 2]

[0027]
As shown in Table 2, in Examples 5 to 8, the selectivity was 90% or more and the recovery rate was 87% or more, indicating high selectivity and high recovery rate.
[0028]
Comparative Examples 1 to 6
Example 1 was carried out under the same conditions as in Example 1 except that the solvent was changed from acetone to ethyl acetate, butyl acetate, methanol, isopropyl alcohol, and tetrahydrofuran, and that no solvent was used. Table 3 shows the results.
[0029]
[Table 3]

[0030]
As shown in Table 3, when the solvents of Comparative Examples 1 to 5 were used, the selectivity was as high as 92% or more, but the recovery was 52 to 77%, which was lower than that of the present invention. Is shown.
[0031]
【The invention's effect】
The method for separating quinaldine isomers of the present invention comprises converting the quinaldine isomer into a hydrochloric acid / zinc chloride complex, adding an aliphatic ketone, and filtering the precipitated crystal to obtain a 7-substituted quinaldine with high purity. It can be obtained in high yield.

Claims (2)

Among the quinaldine isomers obtained by the Doebner-Miller reaction starting from aniline having a substituent at the 3-position, quinaldine having a substituent at the 7-position is isolated. A method for separating quinaldine isomers, comprising adding zinc to convert the quinaldine isomer into a hydrochloric acid / zinc chloride complex, adding an aliphatic ketone, and filtering out precipitated crystals. 2. The method for separating quinaldine isomers according to claim 1, wherein the aliphatic ketone is acetone, cyclohexanone, methyl isobutyl ketone or methyl ethyl ketone.