JPS6191163A - Preparation of anthranylic acid derivative - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as a medicine, easily, in high yield and purity, by reacting a reactive derivative of 3,4-dimethoxycinnamic acid with isatin, and hydrolyzing the resultant novel compound in the presence of an oxidizing agent without separating from the reaction mixture. CONSTITUTION:The objective N-(3,4-dimethoxycinnamoyl)anthranylic acid of formula IV and its salt can be prepared by reacting a reactive derivative of 3,4-dimethoxycinnamic acid of formula I with isatin of formula II, and hydrolyzing the resultant novel N-(3,4-dimethoxycinnamoyl)isatin of formula III in the presence of an oxidizing agent (e.g. hydrogen peroxide). As an alternative method, the compound of formula IV is obtained by hydrolyzing the compound of formula III without using an oxidizing agent, and oxidizing the resultant novel compound of formula V.

Description

【発明の詳細な説明】 本発明は医薬として有用なアントラニル酸誘導体の改良
された製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for producing anthranilic acid derivatives useful as pharmaceuticals.

従来技術と問題点： 近年、Ｎ−（３，４−ジメトキシシンナモイル）アント
ラニル酸が勝れた抗アレルギー作用を有することが確認
された（Ｂｒ、　Ｊ、　Ｐｈａｒｍａｃｏｌ、、　１９
７ｆｉ、胆、４８３）。この化合物の製造方法としては
、（１）３゜４−ジメトキシ桂皮酸又はその反応性誘導
体とアントラニル酸又はそのエステルとを反応させる方
法、（２）３．４−ジメトキシベンズアルデヒドとマロ
ンアントラニル酸とを反応させる方法、（３）２−（３
，４−ジメトキシスチリル）−３，１−ベンゾキサジン
−４−オンを加水分解する方法なとが知られている。し
かしながら、（１）の方法は収率が悪く副反応のために
製品の純度ｌ低下する点に問題があり、（２）は製品の
純度の点は改善されているが、原料のマロンアントラニ
ル酸が熱に不安定でその取り扱いに特別の注意を必要と
するという難点かあり、また、（３）は原料の３，１−
ベンゾキサジン−４−オン誘導体を製造するのに多くの
工程を必要とするなど、これら従来の方法は工業的製造
方法として必ずしも満足できるものでない。Prior art and problems: Recently, it has been confirmed that N-(3,4-dimethoxycinnamoyl)anthranilic acid has excellent antiallergic effects (Br, J. Pharmacol, 19
7fi, bile, 483). Methods for producing this compound include (1) a method in which 3.4-dimethoxycinnamic acid or its reactive derivative is reacted with anthranilic acid or an ester thereof, and (2) a method in which 3.4-dimethoxybenzaldehyde and malonic anthranilic acid are reacted. Reaction method, (3) 2-(3
, 4-dimethoxystyryl)-3,1-benzoxazin-4-one is known. However, method (1) has a problem in that the yield is poor and the purity of the product decreases due to side reactions, and method (2) improves the purity of the product, but the raw material malonic anthranilic acid (3) has the disadvantage that it is unstable under heat and requires special care in its handling.
These conventional methods are not necessarily satisfactory as industrial production methods, as many steps are required to produce benzoxazin-4-one derivatives.

解決手段： 本発明者らは、上記の問題点を解決すへ＜ＬＲ々検討を
重ねた結果本発明を完成した。すなわち、本発明に従え
ば、式（Ｉ）、 で表される３、４−ジメトキシ桂皮酸の反応性誘導体と
、式（ＩＩ） で表されるイサチンとを反応させ、式（ＩＩＩ）Ｊす て表されるＮ−（３，４−ジメトキシシンナモイル）イ
サチンを生成させたのち、これを酸化剤の存在下加水分
解することにより高収率且つ高純度で目的化合物を得る
ことが出来た。Solution: The present inventors have completed the present invention as a result of repeated studies on LR in order to solve the above problems. That is, according to the present invention, a reactive derivative of 3,4-dimethoxycinnamic acid represented by formula (I) and isatin represented by formula (II) are reacted to form a compound of formula (III) After producing N-(3,4-dimethoxycinnamoyl)isatin represented by , the target compound was able to be obtained in high yield and purity by hydrolyzing this in the presence of an oxidizing agent.

そして、式（ＩＩＩ）の化合物を一旦加水分解して式（
■） で示されるＮ−（３＋　　４−ジメトキシシンナモイル
）イサチン酸とし、これを酸化することによっても目的
化合物を得ることが出来た。Then, the compound of formula (III) is once hydrolyzed and the compound of formula (III) is
The target compound could also be obtained by oxidizing N-(3+4-dimethoxycinnamoyl)isacic acid represented by (2).

本発明方法で用いられる３、４−ジメトキシ桂皮酸はそ
れを酸ハロゲン化物、酸無水物、混合酸無水物などの反
応性誘導体として反応に使用する。酸ハロゲン化物は式
（Ｉ）の化合物を無溶媒又は不活性有機溶媒中酸ハロゲ
ン化剤、たとえば塩化千オニルと３０分〜２時間加温す
ることにより得ることかできる。また、酸無水物は式（
Ｉ）の化合物を！！１（木酢／［はＰ−）ルエンスルホ
ン酸クロリドなどと反応させることにより得られる。反
応は両者を不活性有機溶媒、たとえばトルエン、キンレ
ン、テトラヒドロフラン、クロロホルム等中において必
要に応し酸結合剤の存在下、反応させることにより好収
率で式（ＩＩＩ）の化合物を得ることか出来る。酸結合
剤として、たとえばトリエチルアミン、ピリジン、水素
化ナトリウム等を使用することにより、その反応を促進
することができる。かくして、得られた式（ＩＩＩ）の
化合物は文献未載の新規化合物である。本発明の方法で
はその反応生成物を特に＊ｍ精製することなしに、その
まま次の工程の反応に使用することか出来る。The 3,4-dimethoxycinnamic acid used in the method of the present invention is used in the reaction as a reactive derivative such as an acid halide, an acid anhydride, or a mixed acid anhydride. The acid halide can be obtained by heating the compound of formula (I) with an acid halide agent, such as 1,000 onyl chloride, without a solvent or in an inert organic solvent for 30 minutes to 2 hours. In addition, the acid anhydride has the formula (
I) compound! ! 1 (wood vinegar/[is P-)] It can be obtained by reacting with luenesulfonic acid chloride or the like. The reaction can be carried out to obtain a compound of formula (III) in a good yield by reacting both in an inert organic solvent such as toluene, quinolene, tetrahydrofuran, chloroform, etc., if necessary in the presence of an acid binder. . The reaction can be accelerated by using, for example, triethylamine, pyridine, sodium hydride, etc. as an acid binder. The thus obtained compound of formula (III) is a novel compound that has not been described in any literature. In the method of the present invention, the reaction product can be used as it is in the next reaction step without being particularly purified.

加水分解反応は式（ＤＩ）の化合物を適量の水と共に必
要ならばアルカリ、たとえば水酸化ナトリウム、水酸化
カリウム、炭酸カリウム等を加え、酸化剤、たとえば過
酸化水素存在下、加温して実施する。こうして、容易に
目的化合物を高収率で得ることが出来る。この場合、酸
化剤を用いないで加水分解を行うと式（ＩＶ）の化合物
が得られる。。この化合物も文献未載の新規化合物であ
る。その際、本発明方法では、特に単離精製することな
く、上記酸化剤で酸化し容易に目的化合物に導くことが
出来る。The hydrolysis reaction is carried out by heating the compound of formula (DI) in the presence of an oxidizing agent, such as hydrogen peroxide, with an appropriate amount of water, an alkali such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc., if necessary. do. In this way, the target compound can be easily obtained in high yield. In this case, hydrolysis without using an oxidizing agent yields the compound of formula (IV). . This compound is also a new compound that has not been described in any literature. In this case, in the method of the present invention, it is possible to easily lead to the target compound by oxidizing it with the above-mentioned oxidizing agent without any particular isolation and purification.

以下、実施例により、本発明を更に詳しく説明すか本発
明はそれらに限定されるものでない。Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

天井Ｊ１− イサチン７．３５ｇ　（０，０５モル）をクロロホルム
５００ｍ１に加え、更にトリエチルアミン１６０ｍ１を
加えた溶液に、３，４−ジメトキ／桂皮酸クロリド１１
．３３ｇ　（０，０５モル）のクロロホルム１００ｍ１
溶液を、冷却−ドで滴下し、滴下終了後５時間還流した
。反応終了後、溶媒を留去し７υられた粗製Ｎ−（３，
４−ジメトキシシンナモイル）イサチンを０．２規定の
水酸化すトリウム水溶液５００Ｉ１１１に加え加熱溶解
し、これに３５％過酸化水素水７゜５ｍｌを加え１０分
間還流した。反応後室温にもどし、１規定塩酸で弱酸性
とし得られた結晶をろ取、アセトニトリルより再結晶し
てＮ−（３，４−ジメトキシシンナモイル）アントラニ
ル酸１３．４　ｇ　（収率：８３．８％）を得た。Ceiling J1 - 3,4-dimethoxy/cinnamic acid chloride 11 was added to a solution of 7.35 g (0.05 mol) of isatin in 500 ml of chloroform and 160 ml of triethylamine.
．． 33 g (0.05 mol) of chloroform in 100 ml
The solution was added dropwise in a cold door, and after the addition was completed, it was refluxed for 5 hours. After the reaction, the solvent was distilled off and the crude N-(3,
Isatin (4-dimethoxycinnamoyl) was added to a 0.2N aqueous solution of thorium hydroxide (500I111) and dissolved by heating. To this was added 7.5 ml of 35% hydrogen peroxide and refluxed for 10 minutes. After the reaction, the temperature was returned to room temperature, the crystals were made weakly acidic with 1N hydrochloric acid, and the resulting crystals were collected by filtration and recrystallized from acetonitrile to yield 13.4 g of N-(3,4-dimethoxycinnamoyl)anthranilic acid (yield: 83. 8%).

融点　：１８１．５〜１８２°Ｃ ＭＳ　　：Ｍ”＝３２７ 上記の値及びＩＲスペクトルは、標品のそれと一致した
。Melting point: 181.5-182°C MS: M”=327 The above values and IR spectrum matched those of the standard product.

災患伝２ ３．４−ジメトキシ桂皮酸無水物５．９７ｇ　（０゜０
１５モル）とイサチン１．４７ｇ　（０，０１モル）と
を乾燥キシレン１５ｍｌ中で８時間還流した。反応後冷
却し、析出した結晶を分取し、これを氷酢酸３０Ｉｌｌ
に加えて更に数分間還流した。反応後冷却し析出したＮ
−（３，４−ジメトキシシンナモイル）イサチンの粗結
晶を０．２Ｎ−水酸化ナトリウム水溶液１００ｍｌに加
えＪＯ〜６０’Ｃで溶解したのち、３５％過酸化水素水
１．７ｎ＋ｌを加え更に１時間撹拌した。こうして得ら
れた系をＩＮ−［酸で弱酸性とし析出した結晶をろ取、
目的化合物２．５５ｇ（収率ニア８％）を得た。Disaster Den 2 3.4-dimethoxycinnamic anhydride 5.97g (0゜0
15 mol) and 1.47 g (0.01 mol) of isatin were refluxed in 15 ml of dry xylene for 8 hours. After the reaction was cooled, the precipitated crystals were collected and added to 30 Ill of glacial acetic acid.
The mixture was further refluxed for several minutes. N precipitated by cooling after the reaction
-(3,4-dimethoxycinnamoyl)crude crystals of isatin were added to 100 ml of 0.2N aqueous sodium hydroxide solution and dissolved at JO ~ 60'C, then 1.7 n+l of 35% hydrogen peroxide was added for another 1 hour. Stirred. The system thus obtained was made weakly acidic with IN-[acid, and the precipitated crystals were collected by filtration.
2.55 g (yield near 8%) of the target compound was obtained.

実犯例旦 Ｎ−（３，４−ジメトキシシンナモイルｙイサチン３．
３７ｇ−０，０ｆモル）をＩＮ−水酸化ナトリウム２０
ｍ１．水８０＋ｎｌに懸濁し加熱溶解した。この時点で
この系をＩＮ−塩酸で弱酸性にするとＮ−（３，４−ジ
メトキシシンナモイル）イサチン酸の結晶が析出するが
、そうすることなしに、３５％過酸化水素水１．５ｍｌ
を加えて１０分還流し、前者と同様に目的物２．９８ｇ
（収率：９１．１％）を得た。Actual crime example: N-(3,4-dimethoxycinnamoyl y isatin 3.
37 g - 0,0 f mol) IN - sodium hydroxide 20
m1. It was suspended in 80+nl of water and dissolved by heating. At this point, if this system is made weakly acidic with IN-hydrochloric acid, crystals of N-(3,4-dimethoxycinnamoyl)isacic acid will precipitate, but without doing so, 1.5 ml of 35% hydrogen peroxide solution
was added and refluxed for 10 minutes, and 2.98g of the target material was added in the same manner as the former.
(Yield: 91.1%).

実施桝止 Ｎ−（３，４−ジメトキシシンナモイル）イサチン酸３
．５５ｇ　（０，０１モル）を０．２Ｎ−水酸化ナトリ
ウム水溶液５０ｍ１に溶解したのち、３５％過酸化水素
水２＋１を加え８０〜９０”Ｃで３０分撹拌した。こう
して、同様、目的物３．０４（収率：９３％）を得た。Implementation block N-(3,4-dimethoxycinnamoyl)isacic acid 3
．． After dissolving 55 g (0.01 mol) in 50 ml of 0.2N aqueous sodium hydroxide solution, 35% hydrogen peroxide solution 2+1 was added and stirred at 80 to 90"C for 30 minutes. In this way, the desired product 3. 04 (yield: 93%) was obtained.

Claims (1)

【特許請求の範囲】 １）式 ▲数式、化学式、表等があります▼ で表される３，４−ジメトキシ桂皮酸の反応性誘導体と
、式 ▲数式、化学式、表等があります▼ で表されるイサチンとを反応させて、式 ▲数式、化学式、表等があります▼ で表されるＮ−（３，４−ジメトキシシンナモイル）イ
サチンを形成させ、次いでこれを酸化剤存在下で加水分
解することを特徴とする、式 ▲数式、化学式、表等があります▼ で表されるＮ−（３，４−ジメトキシシンナモイル）ア
ントラニル酸又はその塩の製造方法。 ２）式 ▲数式、化学式、表等があります▼ で表されるＮ−（３，４−ジメトキシシンナモイル）イ
サチンを加水分解して、式 ▲数式、化学式、表等があります▼ で表されるＮ−（３，４−ジメトキシシンナモイル）イ
サチン酸を形成させ、次いでこれを酸化することを特徴
とするＮ−（３，４−ジメトキシシンナモイル）アント
ラニル酸又はその塩の製造方法。 ３）式 ▲数式、化学式、表等があります▼ で表されるＮ−（３，４−ジメトキシシンナモイル）イ
サチン酸を溶媒中酸化分解することを特徴とするＮ−（
３，４−ジメトキシシンナモイル）アントラニル酸又は
その塩の製造方法。[Claims] 1) A reactive derivative of 3,4-dimethoxycinnamic acid represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and a reactive derivative of 3,4-dimethoxycinnamic acid represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ isatin to form N-(3,4-dimethoxycinnamoyl)isatin represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, which is then hydrolyzed in the presence of an oxidizing agent. A method for producing N-(3,4-dimethoxycinnamoyl)anthranilic acid or a salt thereof represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼. 2) By hydrolyzing N-(3,4-dimethoxycinnamoyl)isatin, which is represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, it is expressed by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A method for producing N-(3,4-dimethoxycinnamoyl)anthranilic acid or a salt thereof, which comprises forming N-(3,4-dimethoxycinnamoyl)isatinic acid and then oxidizing the same. 3) N-( characterized by oxidative decomposition of N-(3,4-dimethoxycinnamoyl)isacic acid represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc.) in a solvent.
A method for producing 3,4-dimethoxycinnamoyl)anthranilic acid or a salt thereof.