JPH07224058A - Production of 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1h-azepin-4-yl)-1(2h)-phthalazinone or its salt - Google Patents

Abstract

PURPOSE:To obtain azelastine useful as an anti-allergic agent under mild condi tion by reacting chlorocyanobenzylphthalazinone with methylazoniabicycloheptane chloride and subjecting the reaction product to hydrolysis and decarbonation. CONSTITUTION:This azelastine of formula IV can be produced by the hydrolysis and decarbonation of a compound of formula III obtained by reacting (A) 4-(p- chloro-1-cyanobenzyl)-1(2H)-phthalazinone of formula I which is a new compound obtained by reacting 1,4-dichlorophthalazine with 4-chlorobenzyl cyanide and hydrolyzing the resultant 1-chloro-4-(p-chloro-1-cyanobenzyl)-phthalazine with (B) 1-methyl-1-azoniabicyclo[3,2,0]-heptane chloride of formula II obtained by heating 2-(2-chloroethyl)-N-methyl-pyrrolidine hydrochloride in the presence of an alkali.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【産業上の利用分野】本発明は、抗アレルギー剤として
有用な４−（ｐ−クロロベンジル）−２−（ヘキサハイ
ドロ−１−メチル−１Ｈ−アゼピン−４−イル）−１
（２Ｈ）−フタラジノン（一般名アゼラスチン）又はそ
の塩の製造方法に関する。The present invention relates to 4- (p-chlorobenzyl) -2- (hexahydro-1-methyl-1H-azepin-4-yl) -1 which is useful as an antiallergic agent.
It relates to a method for producing (2H) -phthalazinone (generic name azelastine) or a salt thereof.

【０００２】[0002]

【従来の技術及び発明が解決しようとする課題】従来、
アゼラスチンの製造方法としては、下記方法（１）〜
（３）が知られている（特公昭５５−３１１５４号公
報）。2. Description of the Related Art Conventionally, the problems to be solved by the invention
As a method for producing azelastine, the following method (1)-
(3) is known (Japanese Patent Publication No. 55-31154).

【０００３】[0003]

【化１】 [Chemical 1]

【０００４】しかしながら、上記（１）〜（３）の方法
における原料である２−（ｐ−クロロフェナセチル）−
ベンゾイックアシッドの製造には、高温（２５０℃）を
必要とする工程があり、工業的製造には問題があった。However, 2- (p-chlorophenacetyl)-which is a raw material in the above methods (1) to (3).
The production of benzoic acid involves a step requiring a high temperature (250 ° C.), which is a problem in industrial production.

【０００５】[0005]

【課題を解決するための手段及び作用】本発明者は、ア
ゼラスチン又はその塩をより有利に得ることができる新
規製造方法につき鋭意検討を行った。その結果、下記式
（Ｖ）で示される１，４−ジクロロフタラジンと下記式
（ＶＩ）で示される４−クロロベンジルシアナイドとを
反応させて下記式（ＶＩＩ）で示される１−クロロ−４
−（ｐ−クロロ−１−シアノベンジル）−フタラジンを
合成した後、これを加水分解することにより、下記式
（ＩＩ）で示される新規化合物４−（ｐ−クロロ−１−
シアノベンジル）−１（２Ｈ）−フタラジノンが得られ
ることを見い出すと共に、この式（ＩＩ）の４−（ｐ−
クロロ−１−シアノベンジル）−１（２Ｈ）−フタラジ
ノンを出発原料とし、これに下記式（ＩＩＩ）で示され
る２−（２−クロロエチル）−Ｎ−メチル−ピロリジン
塩酸塩をアルカリ存在下に加熱して得られる下記式（Ｉ
ＩＩ’）の１−メチル−１−アゾニアビシクロ〔３．
２．０〕−ヘプタンクロライドを反応させることによ
り、下記式（ＩＶ）で示される４−（ｐ−クロロ−１−
シアノベンジル）−２−（ヘキサハイドロ−１−メチル
−１Ｈ−アゼピン−４−イル）−１（２Ｈ）−フタラジ
ノンを得ることができ、更にこれを加水分解、脱炭酸す
ることにより、式（Ｉ）の目的物質アゼラスチンが得ら
れること、そして、この方法は全工程を通して温和な条
件下で反応を行うことができるため、工業的に有利であ
ることを知見し、本発明をなすに至ったものである。Means and Actions for Solving the Problems The present inventor has conducted earnest studies on a novel production method by which azelastine or a salt thereof can be obtained more advantageously. As a result, 1,4-dichlorophthalazine represented by the following formula (V) is reacted with 4-chlorobenzylcyanide represented by the following formula (VI) to produce 1-chloro-represented by the following formula (VII). Four
After synthesizing-(p-chloro-1-cyanobenzyl) -phthalazine, it is hydrolyzed to give a novel compound 4- (p-chloro-1-) represented by the following formula (II).
It was found that cyanobenzyl) -1 (2H) -phthalazinone is obtained, and 4- (p- of the formula (II) is obtained.
Chloro-1-cyanobenzyl) -1 (2H) -phthalazinone was used as a starting material, and 2- (2-chloroethyl) -N-methyl-pyrrolidine hydrochloride represented by the following formula (III) was heated in the presence of an alkali. The following formula (I
II ′) of 1-methyl-1-azoniabicyclo [3.
2.0] -Heptane chloride is reacted to give 4- (p-chloro-1-) represented by the following formula (IV).
(Cyanobenzyl) -2- (hexahydro-1-methyl-1H-azepin-4-yl) -1 (2H) -phthalazinone can be obtained, which is further hydrolyzed and decarboxylated to give a compound of formula (I ) That the target substance azelastine is obtained, and that this method is industrially advantageous because the reaction can be carried out under mild conditions throughout all steps, and the present invention has been accomplished. Is.

【０００６】[0006]

【化２】 [Chemical 2]

【０００７】従って、本発明は、４−（ｐ−クロロ−１
−シアノベンジル）−１（２Ｈ）−フタラジノン〔Ｉ
Ｉ〕と１−メチル−１−アゾニアビシクロ〔３．２．
０〕−ヘプタンクロライド〔ＩＩＩ’〕とを反応させて
４−（ｐ−クロロ−１−シアノベンジル）−２−（ヘキ
サハイドロ−１−メチル−１Ｈ−アゼピン−４−イル）
−１（２Ｈ）−フタラジノン〔ＩＶ〕を得た後、加水分
解、脱炭酸することを特徴とする４−（ｐ−クロロベン
ジル）−２−（ヘキサハイドロ−１−メチル−１Ｈ−ア
ゼピン−４−イル）−１（２Ｈ）−フタラジノン〔Ｉ〕
又はその塩の製造方法を提供する。Therefore, the present invention provides 4- (p-chloro-1)
-Cyanobenzyl) -1 (2H) -phthalazinone [I
I] and 1-methyl-1-azoniabicyclo [3.2.
0] -Heptane chloride [III ′] to give 4- (p-chloro-1-cyanobenzyl) -2- (hexahydro-1-methyl-1H-azepin-4-yl)
After obtaining -1 (2H) -phthalazinone [IV], 4- (p-chlorobenzyl) -2- (hexahydro-1-methyl-1H-azepine-4 is characterized in that it is hydrolyzed and decarboxylated. -Yl) -1 (2H) -phthalazinone [I]
Alternatively, a method for producing a salt thereof is provided.

【０００８】以下、本発明につき更に詳しく説明する。
まず、本発明は、４−（ｐ−クロロ−１−シアノベンジ
ル）−１（２Ｈ）−フタラジノンを出発原料とするが、
これは新規物質であり、この新規物質４−（ｐ−クロロ
−１−シアノベンジル）−１（２Ｈ）−フタラジノン
は、下記式（Ｖ）の１，４−ジクロロフタラジンと下記
式（ＶＩ）の４−クロロベンジルシアナイドとを反応さ
せて下記式（ＶＩＩ）で示される１−クロロ−４−（ｐ
−クロロ−１−シアノベンジル）−フタラジンを合成し
た後、これを加水分解することにより製造することがで
きる。The present invention will be described in more detail below.
First, the present invention uses 4- (p-chloro-1-cyanobenzyl) -1 (2H) -phthalazinone as a starting material,
This is a novel substance, and this novel substance 4- (p-chloro-1-cyanobenzyl) -1 (2H) -phthalazinone is represented by the following formula (V): 1,4-dichlorophthalazine and the following formula (VI): 1-chloro-4- (p represented by the following formula (VII)
It can be produced by synthesizing -chloro-1-cyanobenzyl) -phthalazine and then hydrolyzing it.

【０００９】[0009]

【化３】 [Chemical 3]

【００１０】上記反応の条件は別に限定されないが、ア
ルゴン等の不活性ガスで置換した容器内でジメチルスル
ホキシド等の有機溶媒を使用し、１０〜６０℃で１〜４
時間反応させることが好ましい。Although the conditions of the above reaction are not particularly limited, an organic solvent such as dimethylsulfoxide is used in a container which is replaced with an inert gas such as argon and the temperature is 1 to 4 at 10 to 60 ° C.
It is preferable to react for a time.

【００１１】このように式（Ｖ）の化合物と式（ＶＩ）
の化合物とを反応させると上記式（ＶＩＩ）の１−クロ
ロ−４−（ｐ−クロロ−１−シアノベンジル）−フタラ
ジンが得られ、次いでこの式（ＶＩＩ）の化合物を単
離、乾燥後、通常の方法で加水分解することにより、上
記式（ＩＩ）の４−（ｐ−クロロ−１−シアノベンジ
ル）−１（２Ｈ）−フタラジノンを得ることができる。Thus, the compound of formula (V) and the compound of formula (VI)
When the compound of formula (VII) is reacted with 1-chloro-4- (p-chloro-1-cyanobenzyl) -phthalazine, the compound of formula (VII) is isolated and dried, 4- (p-chloro-1-cyanobenzyl) -1 (2H) -phthalazinone of the above formula (II) can be obtained by hydrolysis by a usual method.

【００１２】一方、もう一つの出発原料である１−メチ
ル−１−アゾニアビシクロ〔３．２．０〕−ヘプタンク
ロライド〔ＩＩＩ’〕は２−（２−クロロエチル）−Ｎ
−メチル−ピロリジン塩酸塩〔ＩＩＩ〕を水に懸濁し、
水酸化ナトリウム又は水酸化カリウムを加え、６０〜９
０℃で１〜２時間加熱撹拌することにより得ることがで
きる。On the other hand, another starting material, 1-methyl-1-azoniabicyclo [3.2.0] -heptane chloride [III '], is 2- (2-chloroethyl) -N.
-Methyl-pyrrolidine hydrochloride [III] was suspended in water,
Add sodium hydroxide or potassium hydroxide, 60-9
It can be obtained by heating and stirring at 0 ° C. for 1 to 2 hours.

【００１３】本発明の製造方法を具体的に実施する場合
は、下記式に示すように、化合物〔ＩＩＩ〕を水に懸濁
し、水酸化カリウム又は水酸化ナトリウムを加え、６０
〜９０℃で１〜２時間加熱撹拌し、式〔ＩＩＩ’〕の１
−メチル−１−アゾニアビシクロ〔３．２．０〕−ヘプ
タンクロライドとした後、化合物〔ＩＩ〕を加え、６０
〜９０℃で水酸化カリウム水溶液又は水酸化ナトリウム
水溶液を加え、９０〜１００℃で１〜４時間加熱撹拌す
る。反応液を５０〜６０℃に冷却後、水酸化カリウム又
は水酸化ナトリウムを加え、内容物を溶解後、ピリジン
を加え、９０〜１００℃で２〜１２時間加熱撹拌する。
反応液を濃縮後、アゼラスチン・塩酸塩を得る場合は、
これを塩酸水溶液中に注入し、クロロホルムで抽出す
る。クロロホルム層を濃縮し、得られた油状残渣にアセ
トンを加え、５〜２５℃で１〜４時間撹拌し、晶出物を
濾取し、アセトン洗浄後、乾燥し、粗結晶〔Ｉ〕・塩酸
塩を得るものである。When the production method of the present invention is specifically carried out, as shown in the following formula, the compound [III] is suspended in water, potassium hydroxide or sodium hydroxide is added, and 60
The mixture is heated and stirred at ˜90 ° C. for 1 to 2 hours to give 1 of the formula [III ′].
-Methyl-1-azoniabicyclo [3.2.0] -heptan chloride, then compound [II] was added, and 60
A potassium hydroxide aqueous solution or a sodium hydroxide aqueous solution is added at ˜90 ° C., and the mixture is heated with stirring at 90 to 100 ° C. for 1 to 4 hours. The reaction solution is cooled to 50 to 60 ° C., potassium hydroxide or sodium hydroxide is added, the contents are dissolved, pyridine is added, and the mixture is heated and stirred at 90 to 100 ° C. for 2 to 12 hours.
When azelastine / hydrochloride is obtained after concentrating the reaction solution,
It is poured into a hydrochloric acid aqueous solution and extracted with chloroform. The chloroform layer was concentrated, acetone was added to the obtained oily residue, the mixture was stirred at 5 to 25 ° C. for 1 to 4 hours, the crystallized product was collected by filtration, washed with acetone, and dried to give crude crystals [I] hydrochloric acid. To get the salt.

【００１４】これを精製する方法としては、粗結晶にア
セトン、水、水酸化カリウム又は水酸化ナトリウムを加
え、０〜１５℃で１〜１０時間撹拌後、析出物を濾取
し、析出物をクロロホルムに溶解後、塩酸水溶液を加え
て５〜２５℃で３０分撹拌し、次いでクロロホルム層を
濃縮し、濃縮残渣にアセトンを加えて濾過し、得られた
結晶をエタノールから再結晶後、減圧下１０５℃、４時
間乾燥して、精製した塩酸アゼラスチンを得ることがで
きる。As a method for purifying this, acetone, water, potassium hydroxide or sodium hydroxide is added to the crude crystals, the mixture is stirred at 0 to 15 ° C. for 1 to 10 hours, and the precipitate is collected by filtration. After dissolving in chloroform, an aqueous hydrochloric acid solution was added and the mixture was stirred at 5 to 25 ° C for 30 minutes, then the chloroform layer was concentrated, acetone was added to the concentrated residue and filtered, and the obtained crystals were recrystallized from ethanol and then under reduced pressure. The purified azelastine hydrochloride can be obtained by drying at 105 ° C. for 4 hours.

【００１５】[0015]

【化４】 [Chemical 4]

【００１６】[0016]

【発明の効果】本発明によれば、アゼラスチン又はその
塩を温和な条件下で工業的有利に製造できる。INDUSTRIAL APPLICABILITY According to the present invention, azelastine or its salt can be industrially advantageously produced under mild conditions.

【００１７】[0017]

【実施例】以下、実施例を示し、本発明を具体的に示す
が、本発明は下記の実施例に制限されるものではない。EXAMPLES The present invention will now be specifically described with reference to examples, but the present invention is not limited to the following examples.

【００１８】〔実施例〕２−（２−クロロエチル）−Ｎ
−メチル−ピロリジン塩酸塩３．０ｇに水１０ｍｌ、水
酸化カリウム１．１ｇを加え８０〜８５℃にて１時間加
熱撹拌し、１−メチル−１−アゾニアビシクロ〔３．
２．０〕−ヘプタンクロライドとした後、これに化合物
（ＩＩ）４．８ｇを加え、９０℃にて水酸化カリウム
１．３２ｇを水５ｍｌに溶かした溶液を加え、９０〜９
５℃で２時間加熱撹拌した。反応後、５０℃まで冷却
し、水酸化カリウム３．３ｇを加え、内容物を溶解さ
せ、ピリジン４５ｍｌを加えて９５〜９８℃にて６時間
加熱撹拌した。反応後、反応液を濃縮し、濃縮残渣を６
Ｎ−塩酸水溶液６０ｍｌ中に注ぎ、クロロホルムで抽出
した。クロロホルム層を濃縮し、得られた油状物にアセ
トン７０ｍｌを加えて溶解後、１０〜１５℃で２時間撹
拌した。結晶を濾取し、アセトン洗浄後、乾燥し、アゼ
ラスチン塩酸塩の粗結晶を得た。[Example] 2- (2-chloroethyl) -N
To 3.0 g of -methyl-pyrrolidine hydrochloride, 10 ml of water and 1.1 g of potassium hydroxide were added, and the mixture was heated with stirring at 80 to 85 ° C for 1 hour, and 1-methyl-1-azoniabicyclo [3.
2.0] -Heptane chloride, 4.8 g of compound (II) was added thereto, and a solution prepared by dissolving 1.32 g of potassium hydroxide in 5 ml of water was added at 90 ° C. to give 90-9.
The mixture was heated and stirred at 5 ° C for 2 hours. After the reaction, the mixture was cooled to 50 ° C., 3.3 g of potassium hydroxide was added to dissolve the contents, 45 ml of pyridine was added, and the mixture was heated with stirring at 95 to 98 ° C. for 6 hours. After the reaction, the reaction solution was concentrated, and the concentrated residue was mixed with 6
It was poured into 60 ml of an aqueous N-hydrochloric acid solution and extracted with chloroform. The chloroform layer was concentrated, 70 ml of acetone was added to the obtained oily substance to dissolve it, and the mixture was stirred at 10 to 15 ° C. for 2 hours. The crystals were collected by filtration, washed with acetone and then dried to obtain crude crystals of azelastine hydrochloride.

【００１９】これに粗結晶に対して１５倍容量のアセト
ン、水、０．１６倍量の水酸化カリウムを加え、０〜５
℃で５時間撹拌後、結晶を濾取し、クロロホルムに溶解
した。結晶に対して５倍容量の６Ｎ−塩酸を加えて室温
下３０分撹拌した。クロロホルム層を濃縮し、得られた
残渣に１０倍容量のアセトンを加えて濾過し、得られた
結晶をエタノールより再結晶後、減圧下１０５℃で４時
間乾燥し、アゼラスチン塩酸塩〔融点２２５℃（分
解）〕１．０ｇを得た。Acetone, water, and potassium hydroxide in an amount of 0.16 times the volume of the crude crystals were added to this, and the mixture was added to 0-5.
After stirring at ℃ for 5 hours, the crystals were collected by filtration and dissolved in chloroform. 5 times volume of 6N-hydrochloric acid was added to the crystals, and the mixture was stirred at room temperature for 30 minutes. The chloroform layer was concentrated, 10 times volume of acetone was added to the obtained residue, and the obtained crystals were recrystallized from ethanol and dried under reduced pressure at 105 ° C. for 4 hours to give azelastine hydrochloride [melting point 225 ° C. (Decomposition)] 1.0 g was obtained.

【００２０】なお、化合物（ＩＩ）の合成例を参考例と
して下記に示す。 〔参考例〕アルゴン置換した容器に水素化ナトリウム
１．５２ｇを入れ、ジメチルスルホキシド３５ｍｌを加
えた。そこへジメチルスルホキシド５ｍｌに溶解させた
４−クロロベンジルシアナイド（ＶＩ）６ｇを撹拌下３
０℃以下で２０分かけて滴下した。滴下後２０〜２５℃
で３０分撹拌し、次に１，４−ジクロロフタラジン
（Ｖ）５ｇを少量ずつ加え、その後室温にて２時間撹拌
した。反応液を水８０ｍｌ中にあけ、１０〜１５℃で１
時間撹拌した後、室温にて一夜放置した。析出した結晶
を濾取し、水、イソプロパノールで洗浄後、乾燥して１
−クロロ−４−（ｐ−クロロ−１−シアノベンジル）−
フタラジン（ＶＩ）７．２ｇを得た。これにアセトン４
５ｍｌ、水３０ｍｌ、６Ｎ−ＨＣｌ １５ｍｌを加え、
４時間加熱還流させた。反応終了後、１０〜１５℃で３
時間撹拌し、析出した結晶を濾取、５０％アセトン水で
洗浄後乾燥したところ、４−（ｐ−クロロ−１−シアノ
ベンジル）−１（２Ｈ）−フタラジノン（ＩＩ）６．１
ｇが得られた（収率８２．２％）。A synthetic example of compound (II) is shown below as a reference example. [Reference Example] Sodium hydride (1.52 g) was placed in a container replaced with argon, and dimethyl sulfoxide (35 ml) was added. 6 g of 4-chlorobenzyl cyanide (VI) dissolved in 5 ml of dimethylsulfoxide was stirred therein 3
It was added dropwise at 0 ° C or lower over 20 minutes. 20-25 ° C after dropping
After stirring for 30 minutes at room temperature, 5 g of 1,4-dichlorophthalazine (V) was added little by little and then stirred at room temperature for 2 hours. Pour the reaction mixture into 80 ml of water and stir at 10-15 ° C for 1
After stirring for an hour, the mixture was left at room temperature overnight. The precipitated crystals were collected by filtration, washed with water and isopropanol, and dried to 1
-Chloro-4- (p-chloro-1-cyanobenzyl)-
7.2 g of phthalazine (VI) was obtained. Acetone 4
5 ml, 30 ml of water, 15 ml of 6N-HCl were added,
The mixture was heated under reflux for 4 hours. After the reaction is completed, 3 at 10 to 15 ° C
After stirring for an hour, the precipitated crystals were collected by filtration, washed with 50% acetone water, and dried to give 4- (p-chloro-1-cyanobenzyl) -1 (2H) -phthalazinone (II) 6.1.
g was obtained (yield 82.2%).

【００２１】得られた４−（ｐ−クロロ−１−シアノベ
ンジル）−１（２Ｈ）−フタラジノン（ＩＩ）の融点及
び赤外吸収スペクトルの測定結果は以下の通りであっ
た。 融点１８３〜１８４℃ 赤外吸収スペクトルν^Nujol _maxｃｍ^-1：３１７５（Ｎ
Ｈ），２２４０（ＣＮ），１６７０（Ｃ＝Ｏ）The melting point and infrared absorption spectrum of the obtained 4- (p-chloro-1-cyanobenzyl) -1 (2H) -phthalazinone (II) were measured as follows. Melting point 183 to 184 ° C Infrared absorption spectrum ν ^Nujol _max cm ^-1 : 3175 (N
H), 2240 (CN), 1670 (C = O)

Claims (1)

【特許請求の範囲】[Claims] 【請求項１】 ４−（ｐ−クロロ−１−シアノベンジ
ル）−１（２Ｈ）−フタラジノンと１−メチル−１−ア
ゾニアビシクロ〔３．２．０〕−ヘプタンクロライドと
を反応させて４−（ｐ−クロロ−１−シアノベンジル）
−２−（ヘキサハイドロ−１−メチル−１Ｈ−アゼピン
−４−イル）−１（２Ｈ）−フタラジノンを得た後、加
水分解、脱炭酸することを特徴とする４−（ｐ−クロロ
ベンジル）−２−（ヘキサハイドロ−１−メチル−１Ｈ
−アゼピン−４−イル）−１（２Ｈ）−フタラジノン又
はその塩の製造方法。1. 4- (p-Chloro-1-cyanobenzyl) -1 (2H) -phthalazinone is reacted with 1-methyl-1-azoniabicyclo [3.2.0] -heptane chloride to give 4- ( p-chloro-1-cyanobenzyl)
2- (Hexahydro-1-methyl-1H-azepin-4-yl) -1 (2H) -phthalazinone is obtained, and then hydrolyzed and decarboxylated 4- (p-chlorobenzyl) -2- (Hexahydro-1-methyl-1H
-Azepin-4-yl) -1 (2H) -phthalazinone or a salt thereof.