JP3662761B2 - New production method of phenoxyalkyl halide derivatives - Google Patents

Description

（式中、Ｒは低級アルキル基を、Ｙは脱離基を意味する。以下同様）
ハロゲン化物を反応させることを特徴とする下記一般式(I)で示されるフェノキシアルキルハライド誘導体の製造法。（以下、製法１という。）
【化１５】

（式中、Ｘはハロゲン原子を意味する。）
２）下記一般式(III)で示される（アルコキシフェノキシ）エチルアルコールに、
【化１６】

スルフォニルハロゲン化物を反応させ下記一般式(II)で示される（アルコキシフェノキシ）エチルスルフォニル化合物とした後、
【化１７】

ハロゲン化物を反応させることを特徴とする下記一般式(I)で示されるフェノキシアルキルハライド誘導体の製造法。（以下、製法２という。）
【化１８】

３）下記一般式(IV)で示される低級アルコキシフェノールと
【化１９】

炭酸エチレン又は酸化エチレンを反応させ下記一般式(III)で示される（アルコキシフェノキシ）エチルアルコールとし、
【化２０】

更に、アルキルスルフォニルハロゲン化物を反応させ下記一般式(II)で示される（アルコキシフェノキシ）エチルスルフォニル化合物とした後、
【化２１】

ハロゲン化物を反応させることを特徴とする下記一般式(I)で示されるフェノキシアルキルハライド誘導体の製造法。（以下、製法３という。）
【化２２】

４） 下記一般式(II)で示される（アルコキシフェノキシ）エチルスルフォニル化合物に
【化２３】

ハロゲン化アルカリ金属を反応させる下記一般式(I)で示されるフェノキシアルキルハライドとし、
【化２４】

下記一般式で示されるアミン化合物（Ｖ）
【化２５】

（式中、Ｒ₁、Ｒ₃は水素原子又は低級アルキル基を、Ｒ₂は水酸基、低級アルキル基、又は−Ｏ−低級アルキル基を、Ｒ₆は水素原子又はハロゲン原子を意味する。以下同様）
を反応させることを特徴とする下記一般式で示されるスルファモイル置換フェネチルアミン誘導体の製造法（以下、製法４という。）
【化２６】

【０００７】
【発明の実施の形態】
本発明の一般式の基の定義において、低級アルキル基とは炭素数１〜５個の直鎖状又は分枝状のアルキル基を意味する。この例としては、メチル、エチル、プロピル、イソプロピル、ブチル、ペンチル、イソペンチル等であり、好ましくは、メチル、エチル、プロピル等である。また、ハロゲン原子としてはフッ素、塩素、臭素等である。
以下に本発明製法を詳述する。尚、製法１及び製法２は製法３の各工程に含まれるため（製法１は製法３の第３工程、製法２は製法３の第２及び第３工程）、下記製法の説明では、製法３及び製法４について詳述する。
【０００８】
１）製法３
【化２７】

本製法の第１工程は一般式（ＩＶ）で示される低級アルコキシフェノールに塩基存在下又は不存在下、等量乃至過剰量の炭酸エチレン又は酸化エチレンを室温乃至加熱下反応させ一般式（ＩＩＩ）で示される（アルコキシフェノキシ）エチルアルコールを得る工程である。
【０００９】
この反応を円滑に進行させるため塩基を添加しても良い。この場合の塩基としては、有機或いは無機の塩基で有れば、特に限定されないが、好ましくは、無機塩基であり、例えば、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム等の炭酸塩、水酸化ナトリウム、水酸化カリウムなどの水酸化物、水素化ナトリウム、水素化リチウム等の水素化金属、臭化テトラブチルアンモニウムなどの４級アンモニウム塩等である。
【００１０】
また、反応溶媒としては、反応に関与しない溶媒であれば限定されないが、好ましくは反応を促進させるため高温化で行う為、高沸点の溶媒、例えば、ジメチルホルムアミド、ジメチルアセタミド、ジメチルスルフォキシド或いはこれらの混合溶媒等が挙げられる。また、この反応は必要により溶媒不存在下にも行うことができる。反応時間は、数時間乃至２４時間程度である。
【００１１】
このようにして得られた（アルコキシフェノキシ）エチルアルコールは単離され或いは単離せずしてそのまま次工程に付される。
【００１２】
本製法の第２工程は一般式（ＩＩＩ）で示される（アルコキシフェノキシ）エチルアルコールに塩基存在下又は不存在下、等量乃至過剰量のスルフォニルハロゲン化物を冷却下乃至室温下反応させ一般式（ＩＩ）で示される（アルコキシフェノキシ）エチルスルフォニル化合物を得る工程である。
【００１３】
スルフォニルハロゲン化物としては、塩化メタンスルフォニル、塩化エタンスルフォニル、塩化ベンゼンスルフォニル、塩化トルエンスルフォニル或いはこれらのスルフォン酸無水物等のスルフォニル化剤であり、従って、一般式（ＩＩ）で示される化合物中、Ｙの意味する脱離基としては、メチルスルフォニルオキシ基、トルエンスルフォニルオキシ基等である。この反応を円滑に進行させるため塩基を添加しても良い。この場合の塩基としては、有機或いは無機の塩基で有れば、特に限定されないが、好ましくは、有機塩基であり、例えばトリエチルアミン、トリメチルアミン、ピリジン、ピコリン、ルチジン等である。反応溶媒としては、反応に関与しない溶媒、例えば、ジメチルホルムアミド、ジメチルアミド、ジオキサン、テトラヒドロフラン、ジクロロエタン、クロロホルム、四塩化炭素、ジメトキシメタン、ジメトキシエタン、酢酸エチル、ベンゼン、トルエン、アセトニトリル、ジメチルスルホキシド等やこれらの混合溶媒が挙げられる。反応時間は、数分乃至２４時間程度である。
このようにして得られた（アルコキシフェノキシ）エチルスルフォニル化合物は単離され或いは単離せずしてそのまま次工程に付すことができる。
【００１４】
本製法の第３工程は一般式（ＩＩ）で示される（アルコキシフェノキシ）エチルスルフォニル化合物に等量乃至過剰量のハロゲン化物を室温下乃至加熱下反応させ本発明の目的化合物である一般式（Ｉ）で示されるフェノキシアルキルハライドを得る工程である。
【００１５】
ハロゲン化物としては、例えば、臭化リチウム、臭化カリウム、臭化マグネシウム、臭化カルシウム、臭化テトラブチルアンモニウム等である。反応溶媒としては、反応に不活性な溶媒で有れば特に制限はなく、例えば、アセトン、メチルエチルケトン、酢酸エチル、ベンゼン、トルエン、テトラヒドロフラン、ジクロロエタン、クロロホルム、四塩化炭素、アセトニトリル、ジメチルスルホキシド等である。反応時間は、１時間乃至２４時間程度であり、反応温度は、室温下乃至加熱下である。
このようにして得られた目的化合物（Ｉ）は、周知の方法、例えば、抽出、沈殿、クロマトグラフィー、分別結晶化、再結晶等により単離精製することができる。工業的には再結晶による精製が好ましい。
【００１６】
２）製法４
【化２８】

【００１７】
本製法は、一般式（ＩＩ）で示される（アルコキシフェノキシ）エチルスルフォニル化合物を本発明の目的化合物（Ｉ）とした後、一般式（Ｖ）で示されるアミン化合物と反応させ、一般式（ＶＩ）で示されるスルファモイル置換フェネチルアミン誘導体を製造する方法である。
【００１８】
即ち、上記製法３第３工程により得られた本発明化合物（Ｉ）に対して等量乃至過剰量の一般式（Ｖ）で示されるアミン化合物を室温下乃至加温下、或いは加熱還流して反応させることにより行うことができる。反応溶媒としては、ベンゼン、トルエン、キシレン、ジメチルホルムアミド、ジクロロメタン、ジクロロエタン、メタノール、エタノール等の反応に関与しない溶媒で有れば特に制限はない。また反応に際し、ピリジン、ピコリン、Ｎ、Ｎ−ジメチルアニリン、Ｎ−メチルモルホリン、トリエチルアミン、ジメチルアニリン等の有機塩基、炭酸カリウム、炭酸水素ナトリウム、炭酸ナトリウム等を添加すると反応を円滑に進行させる上で有利な場合がある。この製法の具体的態様については後記実施例並びに特公昭６２−５２７４２号参照のこと。
【００１９】
【実施例】
以下に、本発明を更に具体的に開示するために、実施例を記載するが、本発明は実施例に限定されるものではない。
【００２０】
（実施例１）
ｏ−エトキシフェノール ５０ｇ（１.０等量）、炭酸エチレン ３８.２ｇ（１.２等量）、炭酸カリウム ２.５ｇ（０.０５等量）をＤＭＦ ２５０ｍｌに加え、約１１０℃で終夜攪拌して２−（ｏ−エトキシフェノキシ）エタノールを得る。 冷却後、酢酸エチル ５００ｍｌとトリエチルアミン ５４.９ｇ（１.５等量）を加えた後、０℃以下で塩化メタンスルホニル ５８.０ｇ（１.４等量）を滴下する。 滴下後、水 １０００ｍｌとメチルエチルケトン ２００ｍｌの混合液に分散して有機層を取り、更に１０％臭化ナトリウム水溶液 ５００ｍｌで洗浄した後に得た有機層を濃縮し２−（ｏ−エトキシフェノキシ）エチルメタンスルフォネートを得る。 濃縮後、メチルエチルケトン ２５０ｍｌと臭化リチウム・一水和物 ７５.９ｇ（２.０等量）を加えて、約９０℃に３時間程度加温する。 冷却後に、水 ５００ｍｌと酢酸エチル １５０ｍｌに分散し、取り出した有機層を１％炭酸カリウム水溶液 ３００ｍｌ、次いで、水 ３００ｍｌで順次洗浄し、得た有機層を濃縮する。 濃縮残査を８５％メタノール水溶液 ３００ｍｌで再結晶し、真空乾燥すると２−（ｏ−エトキシフェノキシ）エチルブロマイドを７２.４ｇ（融点：４４〜４５℃、純度：９９.１％）得た。
【００２１】
（実施例２）
実施例１と同様にして得られる２−（ｏ−エトキシフェノキシ）エチルメタンスルフォネートにメチルエチルケトンと臭化リチウム・一水和物 を加えて、約９０℃に３時間程度加温する。 冷却後に、水 と酢酸エチルに分散し、取り出した有機層を１％炭酸カリウム水溶液、次いで、水 で順次洗浄し、得た有機層を濃縮する。 濃縮残査を８５％メタノール水溶液で再結晶し、真空乾燥すると２−（ｏ−エトキシフェノキシ）エチルブロマイドを得る。この化合物とＲ（−）−５−［（２−アミノ−２−メチル）エチル］−２−メトキシベンゼンスルフォンアミドをエタノールに溶解し、加熱還流する。反応後溶媒を留去して残留物を１０％水酸化ナトリウム水でアルカリ性にし、析出油状物を酢酸エチルで抽出し、抽出液を飽和塩化ナトリウム水溶液で洗い、無水硫酸マグネシウムで乾燥する。溶液を留去し、常法により精製し、塩酸エタノールで処理して（Ｒ）−５−［２−［［２−（ｏ−エトキシフェノキシ）エチル］アミノ］−２−メチルエチル］−２−メトキシベンゼンスルフォンアミド塩酸塩を得る。
【００２２】
【発明の効果】
本発明製法によれば、α−アドレナリン受容体遮断作用を有する一連のスルファモイル置換フェネチルアミン誘導体、殊に、タムスロシン・塩酸塩の製造中間体として有用な目的化合物（Ｉ）を高純度且つ高収率（一般式（ＩＶ）で示される化合物からの収率は８０％以上に達する）で得ることができる。また、原料としてアルキルジハロゲン化物を使用せず、汎用性の高い原料を使用することができる。そして、そのアルカリ分解物のハロゲン化ビニル（揮発性が高い）が副成しない為、工業生産における環境保全及び安全確保上優れている。更に、不純物として２量体が副成しない為、これを除去する為に不可欠な高温、高真空での特殊蒸留設備を必要とせず一般汎用設備で対応できる為に生産規模の拡大が容易となって生産性やエネルギー効率が向上し経済的に安価となる。また、目的化合物（Ｉ）が蒸留時の高温下にさらされない為、分解等の二次的問題が生じない点でも優れた製法である。
従って、目的化合物（Ｉ）は勿論、最終生成物であるタムスロシン・塩酸塩を工業的に製造する場合の製法としては極めて優れた製法といえる。
また、目的化合物（Ｉ）を経由して最終物質であるタムスロシン・塩酸塩を含む一連のスルファモイル置換フェネチルアミン誘導体へ至る経路は上記製法４となる。[0001]
[Field of the Invention]
The present invention relates to (R) -5- [2-[[2- (o-ethoxyphenoxy) ethyl] amino] -2-methylethyl] -2-methoxybenzenesulfonamide hydrochloride (generic name: tamsulosin hydrochloride) A novel series of phenoxyalkyl halide derivatives useful as industrially superior intermediates for a series of sulfamoyl-substituted phenethylamine derivatives including “)”, in particular 2- (o-ethoxyphenoxy) ethyl halide, and The present invention relates to a novel process for producing the sulfamoyl-substituted phenethylamine derivative via an intermediate.
[0002]
[Prior art]
Conventionally, as a general method for producing a phenoxyalkyl halide, a method in which phenol and an alkylene dihalide are condensed is known. That is, J. et al. Med. Chem. 8 (3) 356-367 (1965) describes reacting o-methoxyphenol with ethylene dihalide in the presence of sodium hydroxide.
However, in order to produce a phenoxyalkyl halide, a method of reacting a lower alkoxyphenol and an alkylene dihalide in the presence of an alkali was investigated by the present inventors. As a result, the alkylene dihalide and two alkoxyphenols were condensed. A large amount of 1,2-bis (alkoxyphenoxy) ethane, which is a dimer, was formed as a by-product, reducing the production rate of the target product, and subsequent distillation purification was indispensable.
In addition, when 2 equivalents of ethylene 1,2-dibromide is used with respect to o-ethoxyphenol according to the experimental examples in the above document, the dimer other than the desired 2- (o-ethoxyphenoxy) ethyl bromide. 1,2-bis (o-ethoxyphenoxy) ethane as a byproduct. In order to suppress this dimer by-product, it is necessary to use a large excess of alkylene dihalide with respect to alkoxyphenol, but the vinyl halide produced as a by-product by decomposition of the alkylene dihalide with alkali is lower. Since it is a substance that easily scatters at its boiling point, it has problems in terms of environmental protection or safety and health.
In addition, high-temperature, high-vacuum distillation purification, which is indispensable for removing a large amount of by-produced dimers, requires special equipment for industrial production, so it is a major negative factor in scale expansion, operability and economic effects. It was said.
[0003]
On the other hand, the phenoxyalkyl halide which is the target compound of the present invention is a useful compound as an important intermediate for reacting with an amino compound such as benzylamine to produce an amine derivative. For example, Japanese Examined Patent Publication No. 62-52742 describes that a sulfamoyl-substituted phenethylamine derivative having an excellent α-adrenergic receptor blocking action and useful as an antihypertensive agent can be obtained by reacting a corresponding amine derivative. Yes. Among these compounds having an α-adrenergic receptor blocking action, tamsulosin / hydrochloride has been developed by the applicant company and has already been marketed as a therapeutic agent for dysuria associated with prostatic hypertrophy. It has been desired to develop a production method for producing a phenoxyalkyl halide derivative and tamsulosin / hydrochloride itself at a low cost and in a high yield.
[0004]
[Problems to be solved by the invention]
An object of the present invention is to provide a novel process for producing a phenoxyalkyl halide derivative represented by the general formula (I). Another object of the present invention is to provide a novel process for producing tamsulosin / hydrochloride using the general formula (I) which is the target compound of the present invention.
[0005]
[Means for Solving the Problems]
The inventors of the present invention have completed the present invention as a result of intensive studies on a novel process for producing a phenoxyalkyl halide derivative and, in particular, a novel process for producing tamsulosin hydrochloride using the general formula (I).
[0006]
[Means for Solving the Problems]
That is, the present invention relates to the following production method.
1) An (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II):

(In the formula, R means a lower alkyl group, Y means a leaving group, and so on)
A process for producing a phenoxyalkyl halide derivative represented by the following general formula (I), characterized by reacting a halide. (Hereafter, it is called manufacturing method 1.)
Embedded image

(In the formula, X means a halogen atom.)
2) To (alkoxyphenoxy) ethyl alcohol represented by the following general formula (III):
Embedded image

After reacting a sulfonyl halide to give an (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II),
Embedded image

A process for producing a phenoxyalkyl halide derivative represented by the following general formula (I), characterized by reacting a halide. (Hereafter, it is called manufacturing method 2.)
Embedded image

3) a lower alkoxyphenol represented by the following general formula (IV):

(Alkoxyphenoxy) ethyl alcohol represented by the following general formula (III) by reacting ethylene carbonate or ethylene oxide,
Embedded image

Furthermore, after reacting an alkylsulfonyl halide to give an (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II),
Embedded image

A process for producing a phenoxyalkyl halide derivative represented by the following general formula (I), characterized by reacting a halide. (Hereinafter referred to as production method 3)
Embedded image

4) (Alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II):

A phenoxyalkyl halide represented by the following general formula (I) to be reacted with an alkali metal halide,
Embedded image

Amine compound (V) represented by the following general formula
Embedded image

(Wherein R ₁ and R ₃ represent a hydrogen atom or a lower alkyl group, R ₂ represents a hydroxyl group, a lower alkyl group, or an —O-lower alkyl group, and R ₆ represents a hydrogen atom or a halogen atom. )
Is a method for producing a sulfamoyl-substituted phenethylamine derivative represented by the following general formula (hereinafter referred to as production method 4).
Embedded image

[0007]
DETAILED DESCRIPTION OF THE INVENTION
In the definition of the group of the general formula of the present invention, the lower alkyl group means a linear or branched alkyl group having 1 to 5 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl and the like, and preferably methyl, ethyl, propyl and the like. The halogen atom is fluorine, chlorine, bromine or the like.
The production method of the present invention will be described in detail below. Since manufacturing method 1 and manufacturing method 2 are included in each step of manufacturing method 3 (manufacturing method 1 is the third step of manufacturing method 3, manufacturing method 2 is the second and third steps of manufacturing method 3), in the description of manufacturing method below, manufacturing method 3 And the manufacturing method 4 is explained in full detail.
[0008]
1) Manufacturing method 3
Embedded image

In the first step of this production method, the lower alkoxyphenol represented by the general formula (IV) is reacted with an equivalent amount or an excess amount of ethylene carbonate or ethylene oxide in the presence or absence of a base at room temperature or under heating, in the general formula (III). (Alkoxyphenoxy) ethyl alcohol represented by the formula:
[0009]
A base may be added to facilitate this reaction. The base in this case is not particularly limited as long as it is an organic or inorganic base, but is preferably an inorganic base, for example, carbonates such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, Examples thereof include hydroxides such as potassium hydroxide, metal hydrides such as sodium hydride and lithium hydride, and quaternary ammonium salts such as tetrabutylammonium bromide.
[0010]
The reaction solvent is not limited as long as it is a solvent that does not participate in the reaction. Preferably, the reaction is carried out at a high temperature in order to promote the reaction. For this reason, a solvent having a high boiling point such as dimethylformamide, dimethylacetamide, dimethylsulfo Examples thereof include xoxide or a mixed solvent thereof. Further, this reaction can be carried out in the absence of a solvent, if necessary. The reaction time is about several hours to 24 hours.
[0011]
The (alkoxyphenoxy) ethyl alcohol thus obtained is isolated or not subjected to the next step without isolation.
[0012]
In the second step of this production method, (alkoxyphenoxy) ethyl alcohol represented by the general formula (III) is reacted in the presence or absence of a base with an equivalent or excess amount of sulfonyl halide under cooling to room temperature. This is a step of obtaining an (alkoxyphenoxy) ethylsulfonyl compound represented by II).
[0013]
The sulfonyl halide is a sulfonylating agent such as methane sulfonyl chloride, ethane sulfonyl chloride, benzene sulfonyl chloride, toluene sulfonyl chloride or sulfonic anhydride thereof, and therefore, in the compound represented by the general formula (II), Y Examples of the leaving group include a methylsulfonyloxy group and a toluenesulfonyloxy group. A base may be added to facilitate this reaction. The base in this case is not particularly limited as long as it is an organic or inorganic base, but is preferably an organic base such as triethylamine, trimethylamine, pyridine, picoline, lutidine and the like. Examples of the reaction solvent include solvents not involved in the reaction, such as dimethylformamide, dimethylamide, dioxane, tetrahydrofuran, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, toluene, acetonitrile, dimethyl sulfoxide, and the like. These mixed solvents are mentioned. The reaction time is about several minutes to 24 hours.
The (alkoxyphenoxy) ethylsulfonyl compound thus obtained can be isolated or not subjected to the next step without isolation.
[0014]
In the third step of this production method, an (alkoxyphenoxy) ethylsulfonyl compound represented by the general formula (II) is reacted with an equal or excess amount of a halide at room temperature or under heating to give a general formula (I Is a step of obtaining a phenoxyalkyl halide represented by
[0015]
Examples of the halide include lithium bromide, potassium bromide, magnesium bromide, calcium bromide, and tetrabutylammonium bromide. The reaction solvent is not particularly limited as long as it is an inert solvent for the reaction, and examples thereof include acetone, methyl ethyl ketone, ethyl acetate, benzene, toluene, tetrahydrofuran, dichloroethane, chloroform, carbon tetrachloride, acetonitrile, dimethyl sulfoxide and the like. . The reaction time is about 1 to 24 hours, and the reaction temperature is from room temperature to heating.
The target compound (I) thus obtained can be isolated and purified by well-known methods such as extraction, precipitation, chromatography, fractional crystallization, recrystallization and the like. Industrially, purification by recrystallization is preferable.
[0016]
2) Manufacturing method 4
Embedded image

[0017]
In this production method, an (alkoxyphenoxy) ethylsulfonyl compound represented by the general formula (II) is used as the target compound (I) of the present invention, and then reacted with an amine compound represented by the general formula (V) to give a general formula (VI Is a method for producing a sulfamoyl-substituted phenethylamine derivative represented by
[0018]
That is, an equivalent amount or an excess amount of the amine compound represented by the general formula (V) with respect to the compound (I) of the present invention obtained in the third step of production method 3 is heated to reflux at room temperature or under heating. It can be performed by reacting. The reaction solvent is not particularly limited as long as it is a solvent that does not participate in the reaction, such as benzene, toluene, xylene, dimethylformamide, dichloromethane, dichloroethane, methanol, and ethanol. In addition, in the reaction, when an organic base such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, triethylamine, dimethylaniline, potassium carbonate, sodium hydrogen carbonate, sodium carbonate or the like is added, the reaction proceeds smoothly. May be advantageous. For specific embodiments of this production method, refer to Examples and JP-B-62-52742 described later.
[0019]
【Example】
EXAMPLES Examples will be described below for more specifically disclosing the present invention, but the present invention is not limited to the examples.
[0020]
(Example 1)
50 g (1.0 equivalent) of o-ethoxyphenol, 38.2 g (1.2 equivalent) of ethylene carbonate, and 2.5 g (0.05 equivalent) of potassium carbonate were added to 250 ml of DMF and stirred at about 110 ° C. overnight. To give 2- (o-ethoxyphenoxy) ethanol. After cooling, 500 ml of ethyl acetate and 54.9 g (1.5 equivalents) of triethylamine are added, and then 58.0 g (1.4 equivalents) of methanesulfonyl chloride is added dropwise at 0 ° C. or lower. After the dropwise addition, the organic layer was taken by dispersing in a mixed solution of 1000 ml of water and 200 ml of methyl ethyl ketone, and further washed with 500 ml of 10% aqueous sodium bromide solution. Get the phonate. After concentration, 250 ml of methyl ethyl ketone and 75.9 g (2.0 equivalents) of lithium bromide monohydrate are added and heated to about 90 ° C. for about 3 hours. After cooling, the mixture is dispersed in 500 ml of water and 150 ml of ethyl acetate, and the extracted organic layer is washed successively with 300 ml of 1% aqueous potassium carbonate solution and then with 300 ml of water, and the obtained organic layer is concentrated. The concentrated residue was recrystallized with 300 ml of 85% aqueous methanol solution and dried under vacuum to obtain 72.4 g (melting point: 44 to 45 ° C., purity: 99.1%) of 2- (o-ethoxyphenoxy) ethyl bromide.
[0021]
(Example 2)
Methyl ethyl ketone and lithium bromide monohydrate are added to 2- (o-ethoxyphenoxy) ethyl methanesulfonate obtained in the same manner as in Example 1, and heated to about 90 ° C. for about 3 hours. After cooling, the mixture is dispersed in water and ethyl acetate, and the extracted organic layer is washed successively with 1% aqueous potassium carbonate solution and then with water, and the obtained organic layer is concentrated. The concentrated residue is recrystallized with 85% aqueous methanol and dried in vacuo to give 2- (o-ethoxyphenoxy) ethyl bromide. This compound and R (−)-5-[(2-amino-2-methyl) ethyl] -2-methoxybenzenesulfonamide are dissolved in ethanol and heated to reflux. After the reaction, the solvent is distilled off, the residue is made alkaline with 10% aqueous sodium hydroxide, the precipitated oil is extracted with ethyl acetate, the extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solution was distilled off, purified by a conventional method, and treated with hydrochloric acid ethanol to give (R) -5- [2-[[2- (o-ethoxyphenoxy) ethyl] amino] -2-methylethyl] -2- Methoxybenzenesulfonamide hydrochloride is obtained.
[0022]
【The invention's effect】
According to the process of the present invention, a series of sulfamoyl-substituted phenethylamine derivatives having an α-adrenergic receptor blocking action, in particular, a target compound (I) useful as an intermediate for producing tamsulosin / hydrochloride is obtained with high purity and high yield ( The yield from the compound represented by the general formula (IV) reaches 80% or more). Moreover, a highly versatile raw material can be used without using an alkyl dihalide as a raw material. And since the vinyl halide (high volatility) of the alkali decomposition product is not by-produced, it is excellent in environmental protection and safety ensuring in industrial production. In addition, since dimers do not form by-products as impurities, the production scale can be easily expanded because they can be handled by general-purpose equipment without the need for special distillation equipment at high temperature and high vacuum, which is indispensable for removing them. This improves productivity and energy efficiency and makes it economically cheap. Further, since the target compound (I) is not exposed to high temperatures during distillation, it is an excellent production method in that secondary problems such as decomposition do not occur.
Therefore, it can be said that it is an extremely excellent production method for industrially producing tamsulosin hydrochloride as the final product as well as the target compound (I).
Further, the route to the series of sulfamoyl-substituted phenethylamine derivatives containing the final substance tamsulosin / hydrochloride via the target compound (I) is the above production method 4.

Claims (2)

Formula (IV)

Formula (III) produced by reacting 2-ethoxyphenol represented by the formula with ethylene carbonate

Without isolating 2- (2-ethoxyphenoxy) ethanol represented by formula (II), by reacting with methanesulfonyl chloride and distilling off the solvent of the reaction solution.

2- (2-ethoxyphenoxy) ethyl methanesulfonate represented by the formula: from the group consisting of lithium bromide, lithium bromide monohydrate, potassium bromide, magnesium bromide, calcium bromide and tetrabutylammonium bromide Comprising the action of a selected halide, of formula (I)

The manufacturing method of 2- (2-ethoxyphenoxy) ethyl bromide shown by these. 2- (2-Ethoxyphenoxy) ethyl bromide produced by the production method according to claim 1 and formula (V)

(R)-(-)-5-[(2-amino-2-methyl) ethyl] -2-methoxybenzenesulfonamide represented by the formula (VI)

(R) -5- (2-{[2- (2-Ethoxyphenoxy) ethyl] amino} -2-methylethyl) -2-methoxybenzenesulfonamide represented by formula (1).