JPH05140157A - Phenothiazine derivative - Google Patents
Phenothiazine derivativeInfo
- Publication number
- JPH05140157A JPH05140157A JP33405291A JP33405291A JPH05140157A JP H05140157 A JPH05140157 A JP H05140157A JP 33405291 A JP33405291 A JP 33405291A JP 33405291 A JP33405291 A JP 33405291A JP H05140157 A JPH05140157 A JP H05140157A
- Authority
- JP
- Japan
- Prior art keywords
- phenothiazine
- mol
- formula
- azabicyclo
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明はフェノチアジン誘導体に
関する。更に詳しくは、メキタジン〔１０−（１−アザ
ビシクロ〔２．２．２〕オクト−３−イルメチル）フェ
ノチアジン〕およびその誘導体は、抗ヒスタミン、コリ
ン作働抑制、抗アドレナリン、神経鎮静、精神安定、鎮
痙作用などを有する医薬上有用な物質であるが、本発明
は、該メキタジンおよびその誘導体の合成中間体として
有用なフェノチアジン誘導体、その製造方法および該中
間体を用いたメキタジン等の製造方法に関する。This invention relates to phenothiazine derivatives. More specifically, mequitazine [10- (1-azabicyclo [2.2.2] oct-3-ylmethyl) phenothiazine] and its derivatives are antihistamine, cholinergic suppressant, antiadrenergic, nerve sedative, psychostable, antispasmodic. The present invention relates to a phenothiazine derivative useful as a synthetic intermediate for the mequitazine and its derivatives, which is a pharmaceutically useful substance having actions and the like, a method for producing the same, and a method for producing mequitazine and the like using the intermediate.
【０００２】[0002]
【従来の技術】従来より、メキタジンはフェノチアジン
と３−クロロメチルキヌクリジンとを塩基の存在下、脱
塩酸反応させて得ることができることが知られている
（特公昭４７−１６３１１号公報）。このメキタジンの
合成において用いられる３−クロロメチルキヌクリジン
の合成方法は、 HELVETICA CHEIMICA ACTA, 37, 1689〜
1698, 1954に３−キヌクリジノンから６工程を経て３−
クロロメチルキヌクリジンを得る方法が開示されてい
る。また特公平２−３３７１６号公報には、３−キヌク
リジノンから３−メチレンキヌクリジンを経て、水素化
リチウムアルミニウムと塩素から３−クロロメチルキヌ
クリジンを合成する方法と３−メチレンキヌクリジンを
経て、水素化リチウムアルミニウムと過酸化水素から３
−ヒドロキシメチルキヌクリジンを合成する方法が開示
されている。2. Description of the Related Art It has been known that mequitazine can be obtained by subjecting phenothiazine and 3-chloromethylquinuclidine to a dehydrochlorination reaction in the presence of a base (Japanese Patent Publication No. 47-16311). The synthetic method of 3-chloromethylquinuclidine used in the synthesis of this mequitazine is described in HELVETICA CHEIMICA ACTA, 37, 1689 ~
1698, 1954 from 3-quinuclidinone through 6 steps 3-
A method of obtaining chloromethylquinuclidine is disclosed. Further, in Japanese Patent Publication No. 2-33716, a method for synthesizing 3-chloromethylquinuclidine from lithium aluminum hydride and chlorine through 3-methylenequinuclidine from 3-quinuclidinone and 3-methylenequinuclidine are disclosed. Through 3 from lithium aluminum hydride and hydrogen peroxide
-A method of synthesizing hydroxymethylquinuclidine is disclosed.
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、このよ
うな従来法は、工程数が長く、かつ低収率であり、また
シアン化物や水素化リチウムアルミニウムの使用が必要
であるなど、工業的な製造方法としては有利とは言えな
いことが問題点として指摘されていた。そのため、当業
界では３−クロロメチルキヌクリジンを用いず、他の中
間体を用いてのメタキジンおよびその誘導体の製造方法
の開発が期待されているが、未だ満足すべきものは見出
されていないのが実情である。However, such a conventional method has a long number of steps and a low yield, and it requires the use of cyanide or lithium aluminum hydride. It has been pointed out as a problem that the method is not advantageous. Therefore, in the art, it is expected to develop a method for producing metaxidine and its derivatives by using other intermediates without using 3-chloromethylquinuclidine, but no satisfactory method has been found yet. Is the reality.
【０００４】本発明者らは先に１０−（３−ヒドロキシ
−１−アザビシクロ〔２．２．２〕オクト−３−イルメ
チル）フェノチアジンを中間体とするメキタジンの合成
方法を見出し、特許出願をした（特願平２−２９４４３
６号）。この方法では３−メチレンキヌクリジンオキシ
ドを使用することから上記のような問題点は生起しない
が、メキタジンへの反応過程において、後述の一般式
（１ａ）、（１ｂ）または（１ｃ）で表されるフェノチ
アジン誘導体が副生することが判った。この副生物の有
用性について検討するためにさらに研究を進めた結果、
これらの化合物が新規な化合物であり、しかもメキタジ
ンを合成するのに有用な合成中間体であることを見出
し、本発明に至った。The present inventors previously found a method for synthesizing mequitazine using 10- (3-hydroxy-1-azabicyclo [2.2.2] oct-3-ylmethyl) phenothiazine as an intermediate, and filed a patent application. (Japanese Patent Application No. 2-29443)
No. 6). Since this method uses 3-methylenequinuclidine oxide, the above-mentioned problems do not occur, but in the reaction process to mequitazine, it is represented by the general formula (1a), (1b) or (1c) described below. It was found that the phenothiazine derivative produced by-product. As a result of further research to examine the usefulness of this by-product,
The present inventors have found that these compounds are novel compounds, and are useful synthetic intermediates for synthesizing mequitazine, and have completed the present invention.
【０００５】[0005]
【課題を解決するための手段】即ち、本発明の要旨は、 （１）一般式（１ａ）、（１ｂ）または（１ｃ）で表さ
れるフェノチアジン誘導体、That is, the gist of the present invention is (1) a phenothiazine derivative represented by the general formula (1a), (1b) or (1c),
【化４】 （式中、Ｒ1 およびＲ2 は同一または異なって水素原
子、ハロゲン原子、アルキル基、アルコキシ基またはア
ルキルチオ基を示す。） （２）一般式（２）で表されるフェノチアジン誘導体[Chemical 4] (In the formula, R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group.) (2) A phenothiazine derivative represented by the general formula (2).
【化５】 （式中、Ｒ1 およびＲ2 は前記と同意義である。）を塩
基の存在下に脱塩酸することを特徴とする一般式（１
ａ）、（１ｂ）または（１ｃ）で表されるフェノチアジ
ン誘導体の製造方法、および （３）一般式（１ａ）、（１ｂ）または（１ｃ）で表さ
れる化合物を水素添加用触媒の存在下に還元することを
特徴とする一般式（３）[Chemical 5] (Wherein R 1 and R 2 have the same meanings as described above) are dehydrochlorinated in the presence of a base.
a), a method for producing a phenothiazine derivative represented by (1b) or (1c), and (3) a compound represented by the general formula (1a), (1b) or (1c) in the presence of a hydrogenation catalyst. General formula (3) characterized by reduction to
【化６】 （式中、Ｒ1 およびＲ2 は前記と同意義である。）で表
されるフェノチアジン誘導体の製造方法に関する。[Chemical 6] (In the formula, R 1 and R 2 have the same meanings as described above.) The present invention relates to a method for producing a phenothiazine derivative.
【０００６】一般式（１ａ）、（１ｂ）、（１ｃ）、
（２）および（３）において、Ｒ1 およびＲ2 は同一ま
たは異なって水素原子、ハロゲン原子、アルキル基、ア
ルコキシ基、またはアルキルチオ基を示す。ここでハロ
ゲン原子としてはフッ素、塩素、臭素または沃素を表わ
すが、好ましくは塩素原子である。アルキル基としては
通常、炭素数１〜５、好ましくは１〜４の、直鎖状また
は分岐状のいずれでもよく、たとえばメチル、エチル、
プロピル、イソプロピル、ブチル、アミル等が例示され
る。アルコキシ基としては、メトキシ、エトキシ、プロ
ポキシ、イソプロポキシ、ｎ−ブトキシ等の炭素数１〜
５のものが通常用いられ、好ましくは炭素数１〜４のも
のである。アルキルチオ基としては、そのアルキル部分
が前記のアルキル基と同様のものが用いられる。General formulas (1a), (1b), (1c),
In (2) and (3), R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, or an alkylthio group. Here, the halogen atom represents fluorine, chlorine, bromine or iodine, but is preferably a chlorine atom. The alkyl group generally has 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, and may be linear or branched, for example, methyl, ethyl,
Examples include propyl, isopropyl, butyl, amyl and the like. The alkoxy group has 1 to 1 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy and n-butoxy.
Usually, those having 5 carbon atoms are used, and those having 1 to 4 carbon atoms are preferable. As the alkylthio group, those whose alkyl part is the same as the above alkyl group are used.
【０００７】一般式（２）で表されるフェノチアジン誘
導体から一般式（１ａ）、（１ｂ）または（１ｃ）で表
されるフェノチアジン誘導体への脱塩酸反応は、塩基の
存在下、不活性溶媒中で行われるのが好ましい。塩基と
してはアルカリ金属のアルコラート、水酸化物、水素化
物などの強塩基が好ましい。例えば、ナトリウムメチラ
ート、ナトリウムエチラート、ナトリウムｔ−ブトキシ
ド、カリウムｔ−ブトキシド、水酸化ナトリウム、水酸
化カリウム、水素化ナトリウム等が挙げられ、好ましく
はナトリウムメチラート、ナトリウムエチラート、水素
化ナトリウムである。使用する塩基の量は生成する塩酸
を中和する量以上存在すればよく、原料化合物１モルに
対して通常１〜１０倍モル、好ましくは２〜３倍モルで
ある。The dehydrochlorination reaction from the phenothiazine derivative represented by the general formula (2) to the phenothiazine derivative represented by the general formula (1a), (1b) or (1c) is carried out in the presence of a base in an inert solvent. Is preferably carried out. As the base, strong bases such as alkali metal alcoholates, hydroxides and hydrides are preferable. For example, sodium methylate, sodium ethylate, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be mentioned, preferably sodium methylate, sodium ethylate and sodium hydride. is there. It suffices that the amount of the base used is at least an amount that neutralizes the generated hydrochloric acid, and is usually 1 to 10 times mol, preferably 2 to 3 times mol, relative to 1 mol of the starting compound.
【０００８】溶媒としては塩基としてアルコラート、水
酸化物を用いる場合はメタノール、エタノール、ｔ−ブ
タノール、イソプロピルアルコール等のアルコール類
を、また塩基として水素化物を用いる場合はジグライ
ム、テトラヒドロフラン等のエーテル類が用いられる。
反応は通常０〜１５０℃の温度で１〜４０時間、好まし
くは７０〜１３０℃の温度で１〜１０時間で終了する。
得られる一般式（１ａ）、（１ｂ）、（１ｃ）で表され
る化合物は、クロロホルム、ジクロロメタン等のハロゲ
ン化炭化水素や、トルエン、キシレン等の芳香族炭化水
素により抽出され、カラムクロマトグラフィー、再結晶
などの公知の方法により精製することができる。As the solvent, alcohols such as alcoholate as a base, alcohols such as methanol, ethanol, t-butanol and isopropyl alcohol when a hydroxide is used, and ethers such as diglyme and tetrahydrofuran when a hydride is used as a base are used. Used.
The reaction is usually completed at a temperature of 0 to 150 ° C. for 1 to 40 hours, preferably at a temperature of 70 to 130 ° C. for 1 to 10 hours.
The obtained compounds represented by the general formulas (1a), (1b) and (1c) are extracted with halogenated hydrocarbons such as chloroform and dichloromethane and aromatic hydrocarbons such as toluene and xylene, and subjected to column chromatography, It can be purified by a known method such as recrystallization.
【０００９】塩基としてアルコラートを用いる場合の反
応過程において、アルコラートに対応したアルコキシ体In the reaction process when an alcoholate is used as a base, an alkoxy compound corresponding to the alcoholate is used.
【化７】 （式中、Ｒ1 およびＲ2 は前記と同意義である。Ｒ3は
アルコキシ基を示す。）が副生（混合比は液体クロマト
グラフィーによる分析で、アルコキシ体は通常約６５％
である）する。一般式（１ａ）、（１ｂ）、（１ｃ）で
表される化合物は前記のアルコキシ体とはアルコールに
対する溶解度が異なるので容易に分離することができ
る。[Chemical 7] (In the formula, R 1 and R 2 have the same meanings as described above. R 3 represents an alkoxy group.) Is a by-product (mixing ratio is analyzed by liquid chromatography, the alkoxy form is usually about 65%.
To do). The compounds represented by the general formulas (1a), (1b) and (1c) have different solubilities in alcohol from the above-mentioned alkoxy compounds and thus can be easily separated.
【００１０】一般式（２）で表されるフェノチアジン誘
導体は下式The phenothiazine derivative represented by the general formula (2) is represented by the following formula
【化８】 （式中、Ｒ1 およびＲ2 は前記と同意義を示す。）で表
される反応経路を経て合成される。一般式（Ａ）で表わ
される化合物は、それ自体公知の化合物であり、公知の
合成方法により製造することができる。また、３−メチ
レンキヌクリジンオキシドも、それ自体公知の化合物で
あり、３−キヌクリジノンから容易に公知の合成法また
はそれに準ずる方法により合成することができる（USP
3,725,410号公報、USP3,792,053号公報、特開昭61−280
497号公報、特開平２−62883号公報) 。[Chemical 8] (In the formula, R 1 and R 2 have the same meanings as described above.) The compound represented by the general formula (A) is a compound known per se and can be produced by a known synthetic method. 3-Methylenequinuclidine oxide is also a compound known per se, and can be easily synthesized from 3-quinuclidinone by a known synthesis method or a method analogous thereto (USP.
3,725,410, USP 3,792,053, JP 61-280
497, JP-A-2-62883).
【００１１】一般式（Ｂ）で表わされるフェノチアジン
誘導体は、これらの両化合物を縮合剤の存在下、窒素気
流下にトルエン、キシレン、ヘキサン、メタノール、エ
タノール、テトラヒドロフラン、ジオキサン、酢酸エチ
ル、クロルベンゼン、ジクロルベンゼン、ジクロルメタ
ン、ジクロルエタンなどの不活性溶媒中で反応させるこ
とにより、製造することができる。また、縮合剤として
は、通常アルカリ金属誘導体が用いられ、例えばアルカ
リ金属の水酸化物、水素化物、アミドなどが挙げられ
る。具体的には水酸化カリウム、水酸化ナトリウム、水
素化カリウム、水素化ナトリウムおよびナトリウムアミ
ドからなる群から選ばれた少なくとも１種が例示され
る。これらの縮合剤の使用量は、通常１〜１０倍モル、
好ましくは２〜５倍モルである。反応温度は通常室温〜
１５０℃、反応時間は３０分〜２０時間である。反応終
了後は、濃縮、抽出、クロマトグラフィー、再沈殿、再
結晶など常法により単離、精製することができる。The phenothiazine derivative represented by the general formula (B) comprises toluene, xylene, hexane, methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate, chlorobenzene in the presence of a condensing agent in the presence of a condensing agent under a nitrogen stream. It can be produced by reacting in an inert solvent such as dichlorobenzene, dichloromethane or dichloroethane. As the condensing agent, an alkali metal derivative is usually used, and examples thereof include alkali metal hydroxides, hydrides, and amides. Specifically, at least one selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride and sodium amide is exemplified. The amount of these condensing agents used is usually 1 to 10 times mol,
It is preferably 2 to 5 times mol. Reaction temperature is usually room temperature ~
The reaction time is 150 minutes and the reaction time is 30 minutes to 20 hours. After completion of the reaction, it can be isolated and purified by a conventional method such as concentration, extraction, chromatography, reprecipitation, recrystallization and the like.
【００１２】一般式（２）で表されるフェノチアジン誘
導体は、一般式（Ｂ）で表されるフェノチアジン誘導体
とオキシ塩化リン、塩化チオニル、五塩化リン等のクロ
ル化剤とを、モノクロルベンゼン、ジクロルエタン、ジ
クロルメタン等のハロゲン系溶媒中で反応させることに
より製造することができる。ここで用いられるクロル化
剤の使用量は、一般式（Ｂ）で表される化合物に対し
て、通常３〜１０倍モル用いられる。反応温度は通常、
室温〜１５０℃である。反応終了後は、前記の一般式
（Ｂ）で表される化合物の場合と同様の常法により単
離、精製することができる。The phenothiazine derivative represented by the general formula (2) comprises a phenothiazine derivative represented by the general formula (B) and a chlorinating agent such as phosphorus oxychloride, thionyl chloride or phosphorus pentachloride, and monochlorobenzene or dichloroethane. It can be produced by reacting in a halogen-based solvent such as chloromethane or dichloromethane. The amount of the chlorinating agent used here is usually 3 to 10 times the molar amount of the compound represented by the general formula (B). The reaction temperature is usually
Room temperature to 150 ° C. After the completion of the reaction, the compound represented by the general formula (B) can be isolated and purified by the same conventional method.
【００１３】さらに、本発明は、一般式（１ａ）、（１
ｂ）または（１ｃ）で表される化合物を水素添加用触媒
の存在下に還元することを特徴とする一般式（３）で表
されるフェノチアジン誘導体（メキタジンまたはその誘
導体）の製造方法を提供するものである。水素添加用触
媒としては特に限定されることなくいずれであってもよ
い。例えば白金黒、コロイド白金、酸化白金、パラジウ
ム／炭素、パラジウム／炭酸カルシウム、パラジウム／
硫酸バリウム、ニッケル、コバルト、鉄などのラニー触
媒、ニッケル／ケイソウ土、亜クロム酸銅等が例示され
る。Furthermore, the present invention provides the general formulas (1a) and (1
There is provided a method for producing a phenothiazine derivative (mequitazine or a derivative thereof) represented by the general formula (3), which comprises reducing the compound represented by b) or (1c) in the presence of a hydrogenation catalyst. It is a thing. The hydrogenation catalyst is not particularly limited and may be any. For example, platinum black, colloidal platinum, platinum oxide, palladium / carbon, palladium / calcium carbonate, palladium /
Examples thereof include Raney catalysts such as barium sulfate, nickel, cobalt and iron, nickel / diatomaceous earth, and copper chromite.
【００１４】本還元反応はメタノール，エタノール，水
等の不活性溶媒中で行うが、この場合、酢酸，プロピオ
ン酸等のプロトン酸を一般式（１ａ）、（１ｂ）、（１
ｃ）の化合物に対して通常１〜５倍モル添加して行なう
のが好ましい。これらのプロトン酸を添加しなくても反
応は進行するがその反応速度は遅くなる。また、常圧の
水素雰囲気下でも可能であるが、加圧下の方が反応速度
が早いので好ましい。この場合、通常２〜１０ｋｇ／ｃ
ｍ2 程度に加圧される。本還元反応で用いる水素添加用
触媒の使用量は、一般式（１ａ）、（１ｂ）、（１ｃ）
で表される化合物に対して、通常同量である。使用する
水素ガス量は、一般式（１ａ）、（１ｂ）、（１ｃ）で
表される化合物に対して等モル量である。反応終了後の
分離精製は、公知の手段、例えばろ過、再結晶等の手段
を適宜使用することによって一般式（３）で表されるフ
ェノチアジン誘導体を容易に単離することができる。This reduction reaction is carried out in an inert solvent such as methanol, ethanol or water. In this case, a protic acid such as acetic acid or propionic acid is used in the general formulas (1a), (1b) and (1
Usually, it is preferable to carry out by adding 1 to 5 times the molar amount of the compound of c). The reaction proceeds even if these protic acids are not added, but the reaction rate becomes slow. Further, it is possible to perform the reaction under a hydrogen atmosphere at normal pressure, but it is preferable to apply pressure because the reaction rate is faster. In this case, usually 2-10kg / c
Pressurized to about m 2 . The amount of the hydrogenation catalyst used in this reduction reaction is determined by the general formula (1a), (1b), (1c)
It is usually the same amount as the compound represented by. The amount of hydrogen gas used is an equimolar amount with respect to the compounds represented by the general formulas (1a), (1b) and (1c). For the separation and purification after the completion of the reaction, the phenothiazine derivative represented by the general formula (3) can be easily isolated by appropriately using known means such as filtration and recrystallization.
【００１５】[0015]
【実施例】以下、実施例により本発明をさらに詳しく説
明するが、本発明はこれらの実施例に何ら限定されるも
のではない。 参考例１ １０−（３−ヒドロキシ−１−アザビシクロ〔２．２．
２〕オクト−３−イルメチル）フェノチアジンの合成
例：窒素気流下にフェノチアジン５９．８ｇ（０．３モ
ル）、水酸化カリウム（８５％）９７．９ｇ（１．５０
モル）をトルエン５００ｍｌに加え、加熱し、１００℃
で１時間攪拌した。次にＵＳＰ3,725,410 記載の方法で
製造した３−メチレンキヌクリジンオキシド４１．２ｇ
（０．３モル）を加え１１０℃で２時間攪拌した。反応
終了後、室温にまで冷却し、水２００ｍｌを加え、析出
する結晶を濾取し、水１００ｍｌで洗浄した。次いで得
られた結晶を１０％酢酸溶液２００ｇに溶解し、トルエ
ン２００ｍｌを加え攪拌抽出し、水層を分取した。さら
に水層に３０％水酸化ナトリウム溶液５０ｇを滴下し晶
析する白色結晶を濾取して目的化合物４９．８ｇ（０．
１５モル）を得た（収率５０％）。The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Reference Example 1 10- (3-hydroxy-1-azabicyclo [2.2.
2] Synthesis example of oct-3-ylmethyl) phenothiazine: Phenothiazine 59.8 g (0.3 mol) and potassium hydroxide (85%) 97.9 g (1.50) under nitrogen stream.
Mol) to 500 ml of toluene and heated to 100 ° C.
It was stirred for 1 hour. Next, 41.2 g of 3-methylenequinuclidine oxide prepared by the method described in USP 3,725,410
(0.3 mol) was added and the mixture was stirred at 110 ° C. for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, 200 ml of water was added, and the precipitated crystals were collected by filtration and washed with 100 ml of water. Next, the obtained crystals were dissolved in 200 g of a 10% acetic acid solution, 200 ml of toluene was added, the mixture was extracted with stirring, and the aqueous layer was separated. Further, 50 g of 30% sodium hydroxide solution was added dropwise to the aqueous layer, and white crystals that crystallized were collected by filtration to obtain 49.8 g of the target compound (0.
15 mol) was obtained (yield 50%).
【００１６】融点：１２７〜１３０℃ 元素分析： 計算値 Ｃ：70.97 Ｈ：6.55 Ｎ：8.28 実測値 Ｃ：71.09 Ｈ：6.70 Ｎ：8.151 Ｈ−ＮＭＲ（ＣＤＣｌ3 ）δ： 6.60〜7.30（8H, m), 4.00（1H, d,15Hz), 4.25 (1H,
d, 15Hz),2.37〜3.01 (6H, m), 2.25 (1H, s), 0.70〜
2.03 (5H, m) ＭＳ：338(Ｍ+ ), 212, 198, 180, 140, 122Melting point: 127 to 130 ° C. Elemental analysis: Calculated value C: 70.97 H: 6.55 N: 8.28 Actual value C: 71.09 H: 6.70 N: 8.15 1 H-NMR (CDCl 3 ) δ: 6.60 to 7.30 (8H, m), 4.00 (1H, d, 15Hz), 4.25 (1H,
d, 15Hz), 2.37 ~ 3.01 (6H, m), 2.25 (1H, s), 0.70 ~
2.03 (5H, m) MS: 338 (M + ), 212, 198, 180, 140, 122
【００１７】参考例２ １０−（３−クロル−１−アザビシクロ〔２．２．２〕
オクト−３−イルメチル）フェノチアジンの合成：参考
例１で得られた１０−（３−ヒドロキシ−１−アザビシ
クロ〔２．２．２〕オクト−３−イルメチル）フェノチ
アジン１６．９ｇ（０．０５モル）、オキシ塩化リン２
３．０ｇ（０．１５モル）をモノクロルベンゼン５０ｍ
ｌに加え、加熱し１１０〜１２０℃で１３時間攪拌し
た。反応終了後、室温にまで冷却し、水１００ｍｌ中へ
滴下し過剰のオキシ塩化リンを分解し、次にジクロルメ
タン２５０ｍｌ、20％水酸化ナトリウム溶液１５０ｇを
加え水層を強アルカリ性とし、ジクロルメタン層を分取
した。溶媒を減圧下に濃縮し、晶析する結晶にアセトニ
トリル５０ｍｌを加え白色結晶を濾取して目的化合物
７．８ｇ（０．０２２モル）を得た（収率４４％）。Reference Example 2 10- (3-chloro-1-azabicyclo [2.2.2]]
Synthesis of oct-3-ylmethyl) phenothiazine: 16.9 g (0.05 mol) of 10- (3-hydroxy-1-azabicyclo [2.2.2] oct-3-ylmethyl) phenothiazine obtained in Reference Example 1 , Phosphorus oxychloride 2
3.0 g (0.15 mol) of monochlorobenzene 50 m
In addition to 1, the mixture was heated and stirred at 110 to 120 ° C. for 13 hours. After completion of the reaction, the mixture was cooled to room temperature, dropped into 100 ml of water to decompose excess phosphorus oxychloride, and then 250 ml of dichloromethane and 150 g of 20% sodium hydroxide solution were added to make the aqueous layer strongly alkaline, and the dichloromethane layer was separated. I took it. The solvent was concentrated under reduced pressure, 50 ml of acetonitrile was added to the crystal to be crystallized, and white crystals were collected by filtration to obtain 7.8 g (0.022 mol) of the target compound (yield 44%).
【００１８】融点：156 〜160 ℃（分解） 元素分析： 計算値 Ｃ：67.30 Ｈ：5.93 Ｎ：7.85 Ｃｌ：
9.93 実測値 Ｃ：67.43 Ｈ：6.00 Ｎ：7.79 Ｃｌ：
10.051 Ｈ−ＮＭＲ（ＣＤＣｌ3 ）δ： 6.53〜7.52 (8H, m), 4.58 (1H, d, 15Hz), 4.36 (1H,
d, 15Hz),0.92〜3.51 (11H, m) ＭＳ：356(Ｍ+ ), 320, 212, 198, 158, 122Melting point: 156-160 ° C. (decomposition) Elemental analysis: Calculated value C: 67.30 H: 5.93 N: 7.85 Cl:
9.93 Measured value C: 67.43 H: 6.00 N: 7.79 Cl:
10.05 1 H-NMR (CDCl 3 ) δ: 6.53 to 7.52 (8H, m), 4.58 (1H, d, 15Hz), 4.36 (1H,
d, 15Hz), 0.92 to 3.51 (11H, m) MS: 356 (M + ), 320, 212, 198, 158, 122
【００１９】実施例１ １０−（１−アザビシクロ〔２．２．２〕オクト−２−
エン−３−イルメチル）フェノチアジンの合成：参考例
２で得られた１０−（３−クロロ−１−アザビシクロ
〔２．２．２〕オクト−３−イルメチル）フェノチアジ
ン１０．０ｇ（０．０２８モル）と２８％ナトリウムメ
チラート溶液１０．８ｇ（０．０５６モル）をメタノー
ル１００ｍｌに加え、還流下に１０時間攪拌を行った。
反応終了後、減圧下にメタノールを留去し、水５０ｍｌ
とクロロホルム５０ｍｌを加え抽出し、クロロホルム層
を分取した。クロロホルム層を無水硫酸マグネシウムで
脱水後、減圧下にクロロホルムを留去し、１０−（１−
アザビシクロ〔２．２．２〕オクト−２−エン−３−イ
ルメチル）フェノチアジンと１０−（３−メトキシ−１
−アザビシクロ〔２．２．２〕オクト−３−イルメチ
ル）フェノチアジンの混合物の結晶８．２ｇを得た。こ
の結晶をカラムクロマトグラフィーにかけて、１％アン
モニア水／メタノールで溶出し、適当なフラクションを
濃縮して１０−（１−アザビシクロ〔２．２．２〕オク
ト−２−エン−３−イルメチル）フェノチアジンの白色
結晶１．９ｇ（０．００５９モル、収率２１．２％）と
１０−（３−メトキシ−１−アザビシクロ〔２．２．
２〕オクト−３−イルメチル）フェノチアジンの白色結
晶５．４ｇ（０．０１５３モル、収率５４．７％）を得
た。Example 1 10- (1-Azabicyclo [2.2.2] oct-2-
Synthesis of en-3-ylmethyl) phenothiazine: 10- (3-chloro-1-azabicyclo [2.2.2] oct-3-ylmethyl) phenothiazine obtained in Reference Example 2 10.0 g (0.028 mol) And 10.8 g (0.056 mol) of 28% sodium methylate solution were added to 100 ml of methanol, and the mixture was stirred under reflux for 10 hours.
After the reaction was completed, methanol was distilled off under reduced pressure and 50 ml of water was added.
And 50 ml of chloroform were added for extraction, and the chloroform layer was separated. The chloroform layer was dehydrated with anhydrous magnesium sulfate, chloroform was distilled off under reduced pressure, and 10- (1-
Azabicyclo [2.2.2] oct-2-en-3-ylmethyl) phenothiazine and 10- (3-methoxy-1)
8.2 g of crystals of a mixture of -azabicyclo [2.2.2] oct-3-ylmethyl) phenothiazine were obtained. The crystals were subjected to column chromatography, eluted with 1% aqueous ammonia / methanol, and the appropriate fractions were concentrated to give 10- (1-azabicyclo [2.2.2] oct-2-en-3-ylmethyl) phenothiazine. 1.9 g (0.0059 mol, yield 21.2%) of white crystals and 10- (3-methoxy-1-azabicyclo [2.2.
2] 5.4 g (0.0153 mol, yield 54.7%) of white crystals of octo-3-ylmethyl) phenothiazine were obtained.
【００２０】得られた１０−（１−アザビシクロ〔２．
２．２〕オクト−２−エン−３−イルメチル）フェノチ
アジンの物性は以下の通りである。 融点：１５３〜１５４℃ 元素分析：計算値 Ｃ：74.96 ％ Ｈ： 6.29 ％ Ｎ：
8.74 ％ 実測値 Ｃ：75.02 ％ Ｈ： 6.38 ％ Ｎ： 8.76％ 1 Ｈ−ＮＭＲ（CDCl3 ) δ： 6.66〜7.37 (8H, m), 6.45 (1H, s), 4.52 (2H, s),2.0
8〜3.22 (5H,m), 0.88 〜1.92 (4H, m) ＭＳ： 320(M+ ), 198The obtained 10- (1-azabicyclo [2.
2.2] The physical properties of oct-2-en-3-ylmethyl) phenothiazine are as follows. Melting point: 153-154 ° C Elemental analysis: Calculated value C: 74.96% H: 6.29% N:
8.74% Actual value C: 75.02% H: 6.38% N: 8.76% 1 H-NMR (CDCl 3 ) δ: 6.66 to 7.37 (8H, m), 6.45 (1H, s), 4.52 (2H, s), 2.0
8 to 3.22 (5H, m), 0.88 to 1.92 (4H, m) MS: 320 (M + ), 198
【００２１】得られた１０−（３−メトキシ−１−アザ
ビシクロ〔２．２．２〕オクト−３−イルメチル）フェ
ノチアジンの物性は以下の通りである。 1 Ｈ−ＮＭＲ（CDCl3 ) δ： 6.70〜7.37 (8H, m), 4.35 (1H, d, 17Hz), 4.08 (1H,
d, 17Hz),3.03 (3H,s), 0.77〜2.97 (11H, m)The physical properties of the obtained 10- (3-methoxy-1-azabicyclo [2.2.2] oct-3-ylmethyl) phenothiazine are as follows. 1 H-NMR (CDCl 3 ) δ: 6.70 to 7.37 (8H, m), 4.35 (1H, d, 17Hz), 4.08 (1H,
d, 17Hz), 3.03 (3H, s), 0.77 to 2.97 (11H, m)
【００２２】実施例２ １０−（１−アザビシクロ〔２．２．２〕オクト−２−
エン−３−イルメチル）フェノチアジンの合成：参考例
２で得られた１０−（３−クロロ−１−アザビシクロ
〔２．２．２〕オクト−３−イルメチル）フェノチアジ
ン１０．０ｇ（０．０２８モル）と９０％ナトリウムエ
チラート４．２ｇ（０．０５６モル）をエタノール１０
０ｍｌに加え、還流下に７時間攪拌を行った。反応終了
後、５℃に冷却し、析出する結晶を濾取した。減圧下に
乾燥し、１０−（１−アザビシクロ〔２．２．２〕オク
ト−２−エン−３−イルメチル）フェノチアジンの結晶
２．３ｇ（０．００７モル、収率２５．６％）を得た。
得られた化合物の物性から実施例１で得られた化合物と
同一であることが認められた。Example 2 10- (1-Azabicyclo [2.2.2] oct-2-
Synthesis of en-3-ylmethyl) phenothiazine: 10- (3-chloro-1-azabicyclo [2.2.2] oct-3-ylmethyl) phenothiazine obtained in Reference Example 2 10.0 g (0.028 mol) And 90% sodium ethylate 4.2 g (0.056 mol) in ethanol 10
0 ml was added, and the mixture was stirred under reflux for 7 hours. After completion of the reaction, the mixture was cooled to 5 ° C, and the precipitated crystals were collected by filtration. It was dried under reduced pressure to obtain 2.3 g (0.007 mol, yield 25.6%) of 10- (1-azabicyclo [2.2.2] oct-2-en-3-ylmethyl) phenothiazine crystals. It was
From the physical properties of the obtained compound, it was confirmed to be the same as the compound obtained in Example 1.
【００２３】実施例３ メキタジンの合成：実施例１で得られた１０−（１−ア
ザビシクロ〔２．２．２〕オクト−２−エン−３−イル
メチル）フェノチアジン３．２ｇ（０．０１モル）、酢
酸０．９ｇ（０．０１５モル）と１０％パラジウム炭素
３ｇをメタノール１００ｍｌに加えた。反応容器を水素
で置換し、加圧下（５ｋｇ／ｃｍ2）で１０時間攪拌を
行った。水素の吸収が止まるのを確認し、パラジウム炭
素を濾別した。濾液を減圧下に濃縮し、残留物に水５０
ｍｌを加えた。８０℃に加熱し、１０％水酸化ナトリウ
ム溶液１０ｇ（０．０２５モル）を滴下し、結晶を析出
させた。冷却後、結晶を濾取し、水で十分洗浄し減圧下
に乾燥した。メタノールから再結晶し、メキタジンの結
晶２．９ｇ（０．００９モル、収率９０．０％）を得
た。Example 3 Synthesis of mequitazine: 3.2 g (0.01 mol) of 10- (1-azabicyclo [2.2.2] oct-2-en-3-ylmethyl) phenothiazine obtained in Example 1. Acetic acid 0.9 g (0.015 mol) and 10% palladium carbon 3 g were added to methanol 100 ml. The reaction vessel was replaced with hydrogen, and the mixture was stirred under pressure (5 kg / cm 2 ) for 10 hours. After confirming that the absorption of hydrogen stopped, the palladium carbon was filtered off. The filtrate is concentrated under reduced pressure and the residue is treated with water 50
ml was added. The mixture was heated to 80 ° C. and 10 g (0.025 mol) of 10% sodium hydroxide solution was added dropwise to precipitate crystals. After cooling, the crystals were collected by filtration, washed thoroughly with water and dried under reduced pressure. Recrystallization from methanol gave 2.9 g (0.009 mol, yield 90.0%) of mequitazine crystals.
【００２４】実施例４ メキタジンの合成：参考例２で得られた１０−（３−ク
ロロ−１−アザビシクロ〔２．２．２〕オクト−３−イ
ルメチル）フェノチアジン１７．８５ｇ（０．０５モ
ル）と水素化ナトリウム４．０ｇ（０．１モル）をジク
ライム５０ｍｌに加え、１３０℃で１時間攪拌を行っ
た。冷却後、メタノール１０ｍｌを注意して加え、次い
で水１００ｍｌを加えた。析出した結晶を濾取し、減圧
下に乾燥し、１０−（１−アザビシクロ〔２．２．２〕
オクト−２−エン−３−イルメチル）フェノチアジンと
１０−（１−アザビシクロ〔２．２．２〕オクト−３−
イレンメチル）フェノチアジン（異性体の混合比は前者
３：後者１）との混合物の結晶１４．１ｇ（０．０４４
モル）を得た。得られた混合物をそれぞれ単離精製する
ことなく、実施例３と同様に処理し、メキタジンの結晶
１２．１ｇ（０．０３７モル、収率７５．０％）を得
た。Example 4 Synthesis of mequitazine: 17.85 g (0.05 mol) of 10- (3-chloro-1-azabicyclo [2.2.2] oct-3-ylmethyl) phenothiazine obtained in Reference Example 2. And sodium hydride (4.0 g, 0.1 mol) were added to diclime (50 ml), and the mixture was stirred at 130 ° C. for 1 hour. After cooling, 10 ml of methanol was added carefully, followed by 100 ml of water. The precipitated crystals were collected by filtration and dried under reduced pressure to give 10- (1-azabicyclo [2.2.2]].
Oct-2-en-3-ylmethyl) phenothiazine and 10- (1-azabicyclo [2.2.2] oct-3-
14.1 g (0.044 g) of a crystal of a mixture with irenmethyl) phenothiazine (the mixing ratio of isomers is the former 3: the latter 1).
Mol) was obtained. The obtained mixture was treated in the same manner as in Example 3 without isolation and purification, to obtain 12.1 g (0.037 mol, yield 75.0%) of crystals of mequitazine.
【００２５】[0025]
【発明の効果】本発明によって、メキタジン合成のため
の有用な中間体を提供することができ、これを用いるこ
とにより高収率でかつ工程数が少なくかつシアン化物や
水素化リチウムアルミニウムの使用が不要であることか
ら工業的有利にメキタジンを合成することができる。INDUSTRIAL APPLICABILITY According to the present invention, a useful intermediate for the synthesis of mequitazine can be provided. By using this intermediate, it is possible to obtain a high yield and a small number of steps, and to use cyanide or lithium aluminum hydride. Since it is unnecessary, mequitazine can be synthesized industrially advantageously.
Claims (3)
ｃ）で表されるフェノチアジン誘導体。 【化１】 （式中、Ｒ1 およびＲ2 は同一または異なって水素原
子、ハロゲン原子、アルキル基、アルコキシ基またはア
ルキルチオ基を示す。）1. A formula (1a), (1b) or (1)
A phenothiazine derivative represented by c). [Chemical 1] (In the formula, R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group.)
誘導体 【化２】 （式中、Ｒ1 およびＲ2 は前記と同意義である。）を塩
基の存在下に脱塩酸することを特徴とする一般式（１
ａ）、（１ｂ）または（１ｃ）で表されるフェノチアジ
ン誘導体の製造方法。2. A phenothiazine derivative represented by the general formula (2): (Wherein R 1 and R 2 have the same meanings as described above) are dehydrochlorinated in the presence of a base.
A method for producing a phenothiazine derivative represented by a), (1b) or (1c).
ｃ）で表される化合物を水素添加用触媒の存在下に還元
することを特徴とする一般式（３） 【化３】 （式中、Ｒ1 およびＲ2 は前記と同意義である。）で表
されるフェノチアジン誘導体の製造方法。3. General formula (1a), (1b) or (1
a compound represented by the general formula (3): wherein the compound represented by c) is reduced in the presence of a hydrogenation catalyst. (In the formula, R 1 and R 2 have the same meanings as described above.) A method for producing a phenothiazine derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3334052A JP2979358B2 (en) | 1991-11-22 | 1991-11-22 | Phenothiazine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3334052A JP2979358B2 (en) | 1991-11-22 | 1991-11-22 | Phenothiazine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05140157A true JPH05140157A (en) | 1993-06-08 |
| JP2979358B2 JP2979358B2 (en) | 1999-11-15 |
Family
ID=18272976
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3334052A Expired - Fee Related JP2979358B2 (en) | 1991-11-22 | 1991-11-22 | Phenothiazine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2979358B2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999029692A1 (en) * | 1997-12-08 | 1999-06-17 | Pierre Fabre Medicament | Method for preparing mequitazine and novel synthesis intermediate |
| EP1074552A3 (en) * | 1999-07-26 | 2001-03-07 | SUMIKA FINE CHEMICALS Co., Ltd. | Process for the preparation of a highly pure phenothiazine compound |
| JP2001199985A (en) * | 1999-07-26 | 2001-07-24 | Sumika Fine Chemicals Co Ltd | High purity phenothiazine compound and method of production therefor, method of production for intermediate therefor, and hydrate of raw material for the intermediate and new crystal |
| US8158784B2 (en) | 2007-01-18 | 2012-04-17 | Pierre Fabre Medicament | Quinuclidine derivative useful in the preparation of mequitazine |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110204540B (en) * | 2019-05-29 | 2022-06-24 | 宁波斯迈克制药有限公司 | Industrial production method of mequitazine |
-
1991
- 1991-11-22 JP JP3334052A patent/JP2979358B2/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999029692A1 (en) * | 1997-12-08 | 1999-06-17 | Pierre Fabre Medicament | Method for preparing mequitazine and novel synthesis intermediate |
| EP1074552A3 (en) * | 1999-07-26 | 2001-03-07 | SUMIKA FINE CHEMICALS Co., Ltd. | Process for the preparation of a highly pure phenothiazine compound |
| JP2001199985A (en) * | 1999-07-26 | 2001-07-24 | Sumika Fine Chemicals Co Ltd | High purity phenothiazine compound and method of production therefor, method of production for intermediate therefor, and hydrate of raw material for the intermediate and new crystal |
| US6433168B1 (en) | 1999-07-26 | 2002-08-13 | Sumika Fine Chemicals Co., Ltd. | Highly pure phenothiazine compound, production method thereof, production method of intermediate therefor, and hydrate and novel crystal as starting materials for the intermediate |
| US8158784B2 (en) | 2007-01-18 | 2012-04-17 | Pierre Fabre Medicament | Quinuclidine derivative useful in the preparation of mequitazine |
| US8304545B2 (en) | 2007-01-18 | 2012-11-06 | Pierre Fabre Medicament | Quinuclidine derivative useful in the preparation of mequitazine |
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| JP2979358B2 (en) | 1999-11-15 |
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