JPS6121620B2 - - Google Patents

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Publication number
JPS6121620B2
JPS6121620B2 JP56181951A JP18195181A JPS6121620B2 JP S6121620 B2 JPS6121620 B2 JP S6121620B2 JP 56181951 A JP56181951 A JP 56181951A JP 18195181 A JP18195181 A JP 18195181A JP S6121620 B2 JPS6121620 B2 JP S6121620B2
Authority
JP
Japan
Prior art keywords
group
compound
general formula
reaction
benzyl alcohol
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.)
Expired
Application number
JP56181951A
Other languages
Japanese (ja)
Other versions
JPS5883661A (en
Inventor
Ikuo Iijima
Akio Nakao
Mitsunori Gaino
Atsuo Ooishi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tanabe Seiyaku Co Ltd
Original Assignee
Tanabe Seiyaku Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tanabe Seiyaku Co Ltd filed Critical Tanabe Seiyaku Co Ltd
Priority to JP56181951A priority Critical patent/JPS5883661A/en
Priority to CA000415011A priority patent/CA1196342A/en
Priority to CH6482/82A priority patent/CH650247A5/en
Priority to SE8206352A priority patent/SE454775B/en
Priority to DK502682A priority patent/DK163660C/en
Priority to IT68332/82A priority patent/IT1191227B/en
Priority to ES517297A priority patent/ES8401013A1/en
Priority to AT0409882A priority patent/AT382866B/en
Priority to KR828205098A priority patent/KR870000471B1/en
Priority to HU823632A priority patent/HU189190B/en
Publication of JPS5883661A publication Critical patent/JPS5883661A/en
Publication of JPS6121620B2 publication Critical patent/JPS6121620B2/ja
Granted legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/70—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

【発明の詳細な説明】[Detailed description of the invention]

本発明は一般式 （但し、R1は水素原子又はアラルキル基を表わ
す。） で示されるベンジルアルコール誘導体の新規製法
に関する。 ベンジルアルコール誘導体（）は有用な医薬
化合物であり、例えばα−（３・４−ジメトキシ
フエチチルアミノメチル）−２−ヒドロキシベン
ジルアルコール及びα−（３・４−ジメトキシフ
エネチルアミノメチル）−２−ベンジルオキシベ
ンジルアルコールは血糖降下剤として、またα−
（３・４−ジメトキシフエネチルアミノメチル）−
４−ヒドロキシベンジルアルコールは強心剤とし
て有用な化合物である（特公昭55−16500号及び
同55−32701号）。 本発明者らは上記ベンジルアルコール誘導体
（）の別途合成法について種々研究を重ねた結
果、従来公知の方法とは全く異なる新規な製法を
見い出し本発明を完成するに至つた。 すなわち、本発明によればベンジルアルコール
誘導体（）は (A) 一般式 （但し、R2は水素原子、アルカノイル基又はア
ラルキル基を表わす。） で示されるアセトフエノン誘導体をチオニルハ
ライドと反応させ、得られる反応生成物を３・
４−ジメトキシフエネチルアミンと反応させて
一般式 （但し、R2は前記と同一意味を有する。） で示されるチオアセタミド誘導体とし、 (B‐1)該化合物（）を還元脱硫化反応に付す
か、 (B‐2)化合物（）を一旦アルキル化して一般式 （但し、R3はアルキル基を表わし、R2は前記
と同一意味を有する。） で示されるアセトフエノン誘導体とした後、
該化合物（）を還元脱硫化反応に付すか、
或いは (B‐3)化合物（）を還元して一般式 （但し、R1は前記と同一意味を有する。） で示されるベンジルアルコール誘導体とした
後、該化合物（）をアルキル化して一般式 （但し、R1及びR3は前記と同一意味を有す
る。） で示されるベンジルアルコール誘導体とし、
次いで該化合物（）を還元脱硫化反応に付
すことにより製造することができる。 上記本発明方法において用いられる原料化合物
であるアセトフエノン誘導体（）としては、一
般式（）において記号R2で示される基が例え
ば水素原子；アセチル基、プロピオニル基の如き
アルカノイル基；ベンジル基の如きアラルキル基
である化合物が挙げられる。他方の原料化合物で
あるチオニルハライドとしてはチオニルクロリド
が好適に挙げられる。 以下、本発明方法を詳細に説明する。 アセトフエノン誘導体（）とチオニルハライ
ドとの反応は化合物（）をチオニルハライドに
溶解させ、かく拌することにより実施することが
できる。この際、反応系に触媒量の有機塩基を存
在させておくのが好ましい。有機塩基としては、
例えばピリジン、トリエチルアミン、ジメチルア
ニリンの如き有機アミンを好適に用いることがで
きる。またチオニルハライドはアセトフエノン誘
導体（）１モルに対し３〜10モル程度用いるの
が好ましい。本反応は10〜50℃で実施するのが好
ましい。本反応により一般式 The present invention is based on the general formula (However, R 1 represents a hydrogen atom or an aralkyl group.) This invention relates to a new method for producing a benzyl alcohol derivative represented by the following formula. Benzyl alcohol derivatives () are useful pharmaceutical compounds, such as α-(3,4-dimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol and α-(3,4-dimethoxyphenethylaminomethyl)-2 -Benzyloxybenzyl alcohol is used as a hypoglycemic agent and
(3,4-dimethoxyphenethylaminomethyl)-
4-Hydroxybenzyl alcohol is a compound useful as a cardiotonic agent (Japanese Patent Publication Nos. 16500/1982 and 32701/1982). The present inventors have conducted various studies on separate methods for synthesizing the above-mentioned benzyl alcohol derivative (2), and as a result, they have discovered a new manufacturing method that is completely different from conventionally known methods and have completed the present invention. That is, according to the present invention, the benzyl alcohol derivative () has the general formula (A) (However, R 2 represents a hydrogen atom, an alkanoyl group, or an aralkyl group.) The acetophenone derivative represented by is reacted with thionyl halide, and the resulting reaction product is 3.
By reacting with 4-dimethoxyphenethylamine, the general formula (However, R 2 has the same meaning as above.) (B-1) The compound () is subjected to a reductive desulfurization reaction, or (B-2) The compound () is and general formula (However, R 3 represents an alkyl group, and R 2 has the same meaning as above.) After forming the acetophenone derivative shown by
The compound () is subjected to a reductive desulfurization reaction, or
Or (B-3) Compound () is reduced to give the general formula (However, R 1 has the same meaning as above.) After forming the benzyl alcohol derivative represented by the formula, the compound () is alkylated to form the general formula (However, R 1 and R 3 have the same meanings as above.) A benzyl alcohol derivative represented by
The compound (2) can then be produced by subjecting it to a reductive desulfurization reaction. In the acetophenone derivative () which is the raw material compound used in the above method of the present invention, the group represented by the symbol R 2 in the general formula () is, for example, a hydrogen atom; an alkanoyl group such as an acetyl group or a propionyl group; an aralkyl group such as a benzyl group. Examples include compounds that are groups. As the thionyl halide, which is the other raw material compound, thionyl chloride is preferably mentioned. The method of the present invention will be explained in detail below. The reaction between the acetophenone derivative () and thionyl halide can be carried out by dissolving the compound () in thionyl halide and stirring. At this time, it is preferred that a catalytic amount of an organic base be present in the reaction system. As an organic base,
For example, organic amines such as pyridine, triethylamine, and dimethylaniline can be suitably used. Further, it is preferable to use about 3 to 10 mol of thionyl halide per 1 mol of the acetophenone derivative (). This reaction is preferably carried out at 10-50°C. By this reaction, the general formula

【式】及び （但し、Ｘはハロゲン原子を表わし、R2は前記と
同一意味を有する。） で示される二種の化合物が生成していると推定さ
れるが、これら混合物は単離精製することなく次
の反応に用いるのが好ましい。 上記で得られる反応生成物と３・４−ジメトキ
シフエネチルアミンとの反応は適当な溶媒中脱酸
剤の存在もしくは非存在下に実施することができ
る。脱酸剤としては、例えばピリジン、トリエチ
ルアミン、ジメチルアニリン、Ｎ−メチルピロリ
ジンの如き有機塩基又は炭酸カリウム、炭酸ナト
リウム、炭酸水素ナトリウム、水酸化ナトリウム
の如き無機塩基をいずれも好適に用いることがで
きる。また溶媒としては例えばベンゼン、クロロ
ホルム、メチレンクロリド、酢酸エチル、ジメチ
ルホルムアミド等の有機溶媒又はこれら有機溶媒
と水との混合物を好適に用いることができる。本
反応は０〜30℃で実施するのが好ましい。 かくして得られるチオアセタミド誘導体（）
からベンジルアルコール誘導体（）を製するに
は前記した（Ｂ−１）〜（Ｂ−３）の方法によつ
て実施することができる。 （Ｂ−１）の方法によればチオアセタミド誘導
体（）を還元脱硫化反応に付すことにより一挙
に化合物（）を製することができる。本還元脱
硫化反応は化合物（）を適当な溶媒中無機金属
塩の存在下還元剤で処理することにより実施する
ことができる。無機金属塩としては、例えば塩化
ニツケル、塩化第一鉄、塩化第一スズ、塩化亜
鉛、塩化コバルト等を用いるのが好ましい。また
還元剤としては、例えばソジウムボロヒドリド、
リチウムボロヒドリド等を好適に用いることがで
きる。さらに溶媒としては、例えばメタノール、
エタノール、プロパノールの如きアルカノール；
テトラヒドロフラン、ジオキサン、ジメトキシエ
タン等を用いるのが好ましい。本反応は20〜50℃
で実施するのが好ましい。本反応により、チオア
セタミド誘導体（）の硫黄原子の脱離と２位オ
キソ基の還元が起ると共に化合物（）において
記号R2で示される基がアルカノイル基である場
合には、該アルカノイル基の加水分解も同時に生
起して、ベンジルアルコール誘導体（）が得ら
れる。 また（Ｂ−２）の方法によれば、チオアセタミ
ド誘導体（）を一旦アルキル化した後還元脱硫
化反応に付すことによつても化合物（）を製す
ることができる。 化合物（）のアルキル基は適当な溶媒中脱酸
剤の存在もしくは非存在下アルキル化剤で処理す
ることにより実施することができる。アルキル化
剤としては、例えばヨウ化メチル、臭化エチルの
如きハロゲン化アルキル；トリメチルオキソニウ
ムフロロボラート、トリエチルオキソニウムフロ
ロボラートの如きトリアルキルオキソニウムフロ
ロボラート；ジメチル硫酸、ジエチル硫酸などを
いずれも好適に用いることができる。また脱酸剤
としては、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の如き無機塩基又はピリ
ジン、トリエチルアミン、１・５−ジアザビシク
ロ〔５・４・０〕−５−ウンデセンの如き有機塩
基をいずれも好適に用いることができる。さらに
溶媒としては、例えば塩化メチレン、アセトン、
クロロホルム、メタノール、エタノール、エーテ
ル、ジメチルホルムアミド、テトラヒドロフラン
等を好適に用いることができる。本反応は０〜30
℃で実施するのが好ましい。かくして、アセトフ
エノン誘導体（）が得られるが、該化合物
（）は単離することなく次の反応に用いるのが
好ましい。 アセトフエノン誘導体（）の還元脱硫化反応
は適当な溶媒中還元剤で処理することにより実施
することができる。還元剤としては、例えばソジ
ウムボロヒドリド、リチウムボロヒドリド、リチ
ウムアルミニウムヒドリド等を好適に用いること
ができる。また溶媒としては、例えばメタノー
ル、エタノール、プロパノールの如きアルカノー
ル；テトラヒドロフラン、ジオキサン、ジメトキ
シエタン等を用いるのが好ましい。本反応は０〜
30℃で実施するのが好ましい。本反応により、ア
セトフエノン誘導体（）のアルキルチオ基の脱
離とケトン基の還元が起ると共に化合物（）に
おいてR2で示される基がアルカノイル基である
場合には、該アルカノイル基の加水分解も同時に
生起して、ベンジルアルコール誘導体（）が得
られる。 さらに（Ｂ−３）の方法によれば、チオアセタ
ミド誘導体（）を還元してベンジルアルコール
誘導体（）とした後、該化合物（）をアルキ
ル化し、次いで得られるベンジルアルコール誘導
体（）を還元脱硫化反応に付すことによつて化
合物（）を製することができる。 チオアセタミド誘導体（）の還元は適当な溶
媒中還元剤で処理することにより実施することが
できる。還元剤としては、例えばソジウムボロヒ
ドリド、リチウムボロヒドリド等を好適に用いる
ことができる。また溶媒としては、例えばメタノ
ール、エタノール、プロパノールの如きアルカノ
ール；テトラヒドロフラン、ジオキサン等を用い
るのが好ましい。本反応は０〜30℃で実施するの
が好ましい。本反応により、チオアセタミド誘導
体（）の２位オキソ基の還元と共に化合物
（）においてR2で示される基がアルカノイル基
である場合には、該アルカノイル基の加水分解も
同時に生起して、ベンジルアルコール誘導体
（）が得られる。 ベンジルアルコール誘導体（）のアルキル化
は（Ｂ−２）の方法におけるチオアセタミド誘導
体（）のアルキル化と同様にして実施すること
ができる。 かくして得られるベンジルアルコール誘導体
（）の還元脱硫化反応は（Ｂ−２）の方法にお
けるアセトフエノン誘導体（）の還元脱硫化反
応と同様にして実施することができる。本反応に
より、ベンジルアルコール誘導体（）のアルキ
ルチオ基が脱離して、ベンジルアルコール誘導体
（）が得られる。 上記の如くして得られるベンジルアルコール誘
導体（）は、要すればさらにその薬理的に許容
しうる酸付加塩とすることもできる。 上記の如き本発明方法によれば、副反応が少な
くベンジルアルコール誘導体（）を収率よく得
ることができると共に中間体である化合物（）
は精製容易な安定な化合物であるので精製・単離
操作が非常に容易であるという利点がある。 実施例 １ (1) ４−ベンジルオキシアセトフエノン4.97ｇを
チオニルクロリド15mlに溶解し、該溶液にピリ
ジン0.02mlを加え室温で５時間かく拌する。反
応混合物を減圧下に濃縮して過剰のチオニルク
ロリドを留去する。残査をベンゼン30mlに溶解
する。該溶液を３・４−ジメトキシフエネチル
アミン4.78ｇ、10％炭酸カリウム水溶液90ml及
びベンゼン50mlの混合物に滴下し、室温で４時
間かく拌する。反応混合物からベンゼン液を分
取し、水層を酢酸エチルで抽出する。ベンゼン
液と酢酸エチル液を合わせ、該溶液を水、10％
塩酸、水で順次洗浄する。有機層を乾燥後減圧
下に溶媒を留去する。残査をエタノールから再
結晶することにより、２−（４−ベンジルオキ
シフエニル）−２−オキソ−Ｎ−（３・４−ジメ
トキシフエネチル）チオアセタミド7.67ｇを淡
黄色針状晶として得る。収率80.1％ M.p.132〜133℃ (2) ２−（４−ベンジルオキシフエニル）−２−オ
キソ−Ｎ−（３・４−ジメトキシフエネチル）
チオアセタミド500mg及び塩化ニツケル・６水
和物610mgをメタノール30mlに溶解し、該溶液
にソジウムボロヒドリド700mgを室温で加え、
同温で1.5時間かく拌する。不溶物をろ別し、
ろ液を減圧下に濃縮する。残査をクロロホルム
に溶解し、該溶液を水で洗浄し、乾燥後減圧下
に溶媒を留去する。残査にエタノール性塩酸を
加えて塩酸塩とし、析出晶をろ取することによ
り、α−（３・４−ジメトキシフエネチルアミ
ノメチル）−４−ベンジルオキシベンジルアル
コール・塩酸塩360mgを得る。収率70％ M.p.168〜170℃ 実施例 ２ ２−（４−ベンジルオキシフエニル）−２−オキ
ソ−Ｎ−（３・４−ジメトキシフエネチル）チオ
アセタミド2.0ｇをメチレンクロリド40mlに溶解
し、該溶液にトリエチルオキソニウムフロロボラ
ート1.05ｇを加え室温で1.5時間かく拌する。反
応混合物を減圧下に濃縮する。残査をエタノール
30mlに溶解し、該溶液にソジウムボロヒドリド
2.1ｇを加え室温で１時間かく拌する。反応終了
後、混合物に水を加え、減圧下に溶媒を留去す
る。析出結晶をろ取し水洗後イソプロパノールか
ら再結晶することにより、α−（３・４−ジメト
キシフエネチルアミノメチル）−４−ベンジルオ
キシベンジルアルコール（遊離塩基）1.45ｇを無
色針状晶として得る。収率77.5％ M.p.114.5〜116℃ 実施例 ３ ２−（４−ベンジルオキシフエニル）−２−オキ
ソ−Ｎ−（３・４−ジメトキシフエネチル）チオ
アセタミド2.2ｇをアセトン30mlに溶解し、該溶
液に炭酸カリウム850mg及びヨウ化メチル1.0ｇを
加え室温で一夜かく拌する。不溶物をろ別し、ろ
液を減圧下に濃縮する。残査をエタノール50mlに
溶解し、該溶液にソジウムボロヒドリド300mgを
加え室温で30分間かく拌する。反応終了後、実施
例２と同様に処理することにより、α−（３・４
−ジメトキシフエネチルアミノメチル）−４−ベ
ンジルオキシベンジルアルコール（遊離塩基）
1.65ｇを無色針状晶として得る。収率80％ 本品の物理化学的性質は実施例２で得た標品と
一致した。 実施例 ４ (1) ２−（４−ベンジルオキシフエニル）−２−オ
キソ−Ｎ−（３・４−ジメトキシフエネチル）
チオアセタミド8.0ｇをメタノール150mlに溶解
し、該溶液にソジウムボロヒドリド500mgを加
え室温で１時間かく拌する。反応終了後、反応
混合物を減圧下に濃縮して溶媒を留去する。残
査をクロロホルムに溶解し、該溶液を水洗し、
乾燥後減圧下に溶媒を留去する。残査をイソプ
ロパノールで結晶化させることにより、２−
（４−ベンジルオキシフエニル）−２−ヒドロキ
シ−Ｎ−（３・４−ジメトキシフエネチル）チ
オアセタミド7.5ｇを無色針状晶として得る。
収率93％ M.p.82〜84℃ (2) ２−（４−ベンジルオキシフエニル）−２−ヒ
ドロキシ−Ｎ−（３・４−ジメトキシフエネチ
ル）チオアセタミド1.0ｇをメチレンクロリド
20mlに溶解し、該溶液にトリエチルオキソニウ
ムフロロボラート460mgを加え室温で30分間か
く拌する。反応混合物を減圧下に濃縮する。残
査をメタノール20mlとクロロホルム20mlとの混
液に溶解し、該溶液にソジウムボロヒドリド
440mgを加え室温で１時間かく拌する。反応終
了後、実施例２と同様に処理することにより、
α−（３・４−ジメトキシフエネチルアミノメ
チル）−４−ベンジルオキシベンジルアルコー
ル（遊離塩基）780mgを無色針状晶として得
る。収率84％ 本品の物理化学的性質は実施例２で得た標品と
一致した。 実施例 ５ (1) ４−アセトキシアセトフエノン5.34ｇ、チオ
ニルクロリド20ml、ピリジン0.03ml及び３・４
−ジメトキシフエネチルアミン6.51ｇを用い実
施例１の(1)と同様に処理することにより、２−
（４−アセトキシフエニル）−２−オキソ−Ｎ−
（３・４−ジメトキシフエネチル）チオアセタ
ミド8.5ｇを淡黄色油状物としている。収率73
％ IRνｌｉｑ ｎａｘ（cm-1）：1755、1665 Mass ｍ／ｅ：387（M+） NMR（CDCl3）δ： 2.30（ｓ、3H、ＣＨ 3COO−）、3.00（ｔ、
2H、Ｊ＝7.5Hz、−ＣＨ ２−CH2−）、3.84
（ｓ、6H、−OCＨ ３×２） (2) ２−（４−アセトキシフエニル）−２−オキソ
−Ｎ−（３・４−ジメトキシフエネチル）チオ
アセタミド1.94ｇ、トリエチルオキソニウムフ
ロロボラート1.14ｇ及びソジウムボロヒドリド
1.0ｇを用い実施例２と同様に処理することに
より、α−（３・４−ジメトキシフエネチルア
ミノメチル）−４−ヒドロキシベンジルアルコ
ール1.47ｇを無色プリズム晶として得る。収率
92％ M.p.151〜153℃ 実施例 ６ (1) ４−ヒドロキシアセトフエノン4.08ｇ、チオ
ニルクロリド12ml、ピリジン0.06ml及び３・４
−ジメトキシフエネチルアミン6.51ｇを用い実
施例１の(1)と同様に処理することにより、２−
（４−ヒドロキシフエニル）−２−オキソ−Ｎ−
（３・４−ジメトキシフエネチル）チオアセタ
ミド3.1ｇを淡黄色針状晶として得る。収率30
％ M.p.179〜180℃（エタノールから再結晶） (2) ２−（４−ヒドロキシフエニル）−２−オキソ
−Ｎ−（３・４−ジメトキシフエネチル）チオ
アセタミド1.0ｇ、塩化ニツケル・６水和物
1.37ｇ及びソジウムボロヒドリド1.1ｇを用い
実施例１の(2)と同様に処理することにより、α
−（３・４−ジメトキシフエネチルアミノメチ
ル）−４−ヒドロキシベンジルアルコール230mg
を無色プリズム晶として得る。収率25％ 本品の物理化学的性質は実施例５の(2)で得た標
品と一致した。 実施例 ７ ２−（４−ヒドロキシフエニル）−２−オキソ−
Ｎ−（３・４−ジメトキシフエネチル）チオアセ
タミド1.58ｇ、トリエチルオキソニウムフロロボ
ラート1.13ｇ及びソジウムボロヒドリド870mgを
用い実施例２と同様に処理することにより、α−
（３・４−ジメトキシフエネチルアミノメチル）−
４−ヒドロキシベンジルアルコール940mgを無色
プリズム晶として得る。収率65％ 本品の物理化学的性質は実施例５の(2)で得た標
品と一致した。 実施例 ８ (1) ２−ベンジルオキシアセトフエノン6.78ｇ、
チオニルクロリド21ml、ピリジン0.05ml及び
３・４−ジメトキシフエネチルアミン6.54ｇを
用い実施例１の(1)と同様に処理することによ
り、２−（２−ベンジルオキシフエニル）−２−
オキソ−Ｎ−（３・４−ジメトキシフエネチ
ル）チオアセタミド10.3ｇを淡黄色プリズム晶
として得る。収率79％ M.p.112〜114℃ (2) ２−（２−ベンジルオキシフエニル）−22−オ
キソ−Ｎ−（３・４−ジメトキシフエネチル）
チオアセタミド500mg、塩化ニツケル・６水和
物90.0mg及びソジウムボロヒドリド700mgを用
い実施例１の(2)と同様に処理することにより、
α−（３・４−ジメトキシフエネチルアミノメ
チル）−２−ベンジルオキシベンジルアルコー
ル・塩酸塩165mgを無色針状晶として得る。収
率32％ M.p.159〜160℃ 実施例 ９ ２−（２−ベンジルオキシフエニル）−２−オキ
ソ−Ｎ−（３・４−ジメトキシフエネチル）チオ
アセタミド2.0ｇ、トリエチルオキソニウムクロ
ロボラート1.13ｇ及びソジウムボロヒドリド870
mgを用い実施例２と同様に処理することにより、
α−（３・４−ジメトキシフエネチルアミノメチ
ル）−２−ベンジルオキシベンジルアルコール
（遊離塩基）1.65ｇを無色針状晶として得る。収
率82％ M.p.95〜97℃（イソプロパノールから再結晶） 実施例 10 ２−（２−ベンジルオキシフエニル）−２−オキ
ソ−Ｎ−（３・４−ジメトキシフエネチル）チオ
アセタミド2.2ｇ、炭酸カリウム850mg、ヨウ化メ
チル1.0ｇ及びソジウムボロヒドリド300mgを用い
実施例３と同様に処理することにより、α−
（３・４−ジメトキシフエネチルアミノメチル）−
２−ベンジルオキシベンジルアルコール（遊離塩
基）1.1ｇを無色針状晶として得る。収率53％ 本品の物理化学的性質は実施例９で得た標品と
一致した。 実施例 11 (1) ２−ヒドロキシアセトフエノン2.73ｇ、チオ
ニルクロリド８ml、ピリジン0.03ml及び３・４
−ジメトキシフエネチルアミン2.53ｇを用い実
施例１の(1)と同様に処理することにより、２−
（２−ヒドロキシフエニル）−２−オキソ−Ｎ−
（３・４−ジメトキシフエネチル）チオアセタ
ミド4.0ｇを淡赤褐色針状晶として得る。収率
58％ M.p.166〜168℃（エタノールから再結晶） (2) ２−（２−ヒドロキシフエニル）−２−オキソ
−Ｎ−（３・４−ジメトキシフエネチル）チオ
アセタミド1.58ｇ、トリエチルオキソニウムフ
ロロボラート1.13ｇ及びソジウムボロヒドリド
1.4ｇを用い実施例２と同様に処理することに
より、α−（３・４−ジメトキシフエネチルア
ミノメチル）−２−ヒドロキシベンジルアルコ
ール850mgを無色油状物として得る。収率58％ 本品の修酸塩 M.p.175〜176℃ 実施例 12 (1) ２−アセトキシアセトフエノン1.78ｇ、チオ
ニルクロリド６ml、ピリジン0.02ml及び３・４
−ジメトキシフエネチルアミン1.27ｇを用い実
施例１の(1)と同様に処理することにより、２−
（２−アセトキシフエニル）−２−オキソ−Ｎ−
（３・４−ジメトキシフエネチル）チオアセタ
ミド1.37ｇを淡黄色油状物として得る。収率
35.4％ IRνＣＨＣｌ３ ｎａｘ（cm-1）：1760、1670 Mass ｍ／ｅ：387（M+） NMR（CDCl3）δ： 2.20（ｓ、3H、ＣＨ 3COO−）、2.94（ｔ、
2H、Ｊ＝7.5Hz、−ＣＨ ２−CH2−）、3.85
（ｓ、6H、−OCＨ ３×２） (2) ２−（２−アセトキシフエニル）−２−オキソ
−Ｎ−（３・４−ジメトキシフエネチル）チオ
アセタミド、トリエチルオキソニウムフロロボ
ラート及びソジウムボロヒドリドを用い実施例
２と同様に処理することにより、α−（３・４
−ジメトキシフエネチルアミノメチル）−２−
ヒドロキシベンジルアルコールを得る。 本品の物理化学的性質は実施例11の(2)で得た標
品と一致した。[Formula] and (However, X represents a halogen atom, and R 2 has the same meaning as above.) It is presumed that two types of compounds are produced, but these mixtures can be prepared as follows without isolation and purification. Preferably used in the reaction. The reaction between the reaction product obtained above and 3,4-dimethoxyphenethylamine can be carried out in a suitable solvent in the presence or absence of a deoxidizing agent. As the deoxidizing agent, any of organic bases such as pyridine, triethylamine, dimethylaniline, and N-methylpyrrolidine, or inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium hydroxide can be suitably used. Further, as the solvent, for example, organic solvents such as benzene, chloroform, methylene chloride, ethyl acetate, dimethylformamide, etc., or mixtures of these organic solvents and water can be suitably used. This reaction is preferably carried out at 0 to 30°C. The thus obtained thioacetamide derivative ()
The benzyl alcohol derivative () can be produced by the methods (B-1) to (B-3) described above. According to the method (B-1), the compound () can be produced all at once by subjecting the thioacetamide derivative () to a reductive desulfurization reaction. This reductive desulfurization reaction can be carried out by treating the compound () with a reducing agent in the presence of an inorganic metal salt in an appropriate solvent. As the inorganic metal salt, it is preferable to use, for example, nickel chloride, ferrous chloride, stannous chloride, zinc chloride, cobalt chloride, or the like. Examples of reducing agents include sodium borohydride,
Lithium borohydride and the like can be suitably used. Furthermore, as a solvent, for example, methanol,
Alkanols such as ethanol and propanol;
Preferably, tetrahydrofuran, dioxane, dimethoxyethane, etc. are used. This reaction is 20-50℃
It is preferable to carry out. Through this reaction, the sulfur atom of the thioacetamide derivative () is eliminated and the 2-position oxo group is reduced, and when the group represented by the symbol R 2 in the compound () is an alkanoyl group, the alkanoyl group is hydrated. Decomposition also occurs simultaneously to obtain the benzyl alcohol derivative (). According to the method (B-2), the compound () can also be produced by once alkylating the thioacetamide derivative () and then subjecting it to a reductive desulfurization reaction. The alkyl group of compound () can be treated with an alkylating agent in an appropriate solvent in the presence or absence of a deoxidizing agent. Examples of the alkylating agent include alkyl halides such as methyl iodide and ethyl bromide; trialkyloxonium fluoroborates such as trimethyloxonium fluoroborate and triethyloxonium fluoroborate; dimethyl sulfate and diethyl sulfate. Any of them can be suitably used. Suitable deoxidizing agents include inorganic bases such as potassium carbonate, sodium carbonate, and sodium bicarbonate, and organic bases such as pyridine, triethylamine, and 1,5-diazabicyclo[5.4.0]-5-undecene. It can be used for. Furthermore, as a solvent, for example, methylene chloride, acetone,
Chloroform, methanol, ethanol, ether, dimethylformamide, tetrahydrofuran, etc. can be suitably used. This reaction is 0-30
Preferably, it is carried out at .degree. In this way, an acetophenone derivative () is obtained, but it is preferable to use the compound () in the next reaction without isolation. The reductive desulfurization reaction of the acetophenone derivative () can be carried out by treating it with a reducing agent in an appropriate solvent. As the reducing agent, for example, sodium borohydride, lithium borohydride, lithium aluminum hydride, etc. can be suitably used. As the solvent, it is preferable to use alkanols such as methanol, ethanol, and propanol; tetrahydrofuran, dioxane, dimethoxyethane, and the like. This reaction is 0~
Preferably it is carried out at 30°C. Through this reaction, the alkylthio group of the acetophenone derivative () is eliminated and the ketone group is reduced, and when the group represented by R 2 in the compound () is an alkanoyl group, the alkanoyl group is simultaneously hydrolyzed. Upon reaction, a benzyl alcohol derivative () is obtained. Furthermore, according to method (B-3), the thioacetamide derivative () is reduced to a benzyl alcohol derivative (), the compound () is alkylated, and the resulting benzyl alcohol derivative () is then subjected to a reductive desulfurization reaction. Compound () can be produced by subjecting to. Reduction of the thioacetamide derivative () can be carried out by treatment with a reducing agent in an appropriate solvent. As the reducing agent, for example, sodium borohydride, lithium borohydride, etc. can be suitably used. As the solvent, it is preferable to use, for example, alkanols such as methanol, ethanol, and propanol; tetrahydrofuran, dioxane, and the like. This reaction is preferably carried out at 0 to 30°C. Through this reaction, the oxo group at the 2-position of the thioacetamide derivative () is reduced, and when the group represented by R 2 in the compound () is an alkanoyl group, hydrolysis of the alkanoyl group also occurs simultaneously, resulting in a benzyl alcohol derivative. () is obtained. The alkylation of the benzyl alcohol derivative () can be carried out in the same manner as the alkylation of the thioacetamide derivative () in the method (B-2). The reductive desulfurization reaction of the benzyl alcohol derivative (2) thus obtained can be carried out in the same manner as the reductive desulfurization reaction of the acetophenone derivative (2) in the method (B-2). Through this reaction, the alkylthio group of the benzyl alcohol derivative () is eliminated, and the benzyl alcohol derivative () is obtained. The benzyl alcohol derivative () obtained as described above can be further converted into a pharmacologically acceptable acid addition salt thereof, if necessary. According to the method of the present invention as described above, the benzyl alcohol derivative () can be obtained in high yield with few side reactions, and the intermediate compound () can be obtained in high yield.
Since it is a stable compound that is easy to purify, it has the advantage that purification and isolation operations are very easy. Example 1 (1) 4.97 g of 4-benzyloxyacetophenone was dissolved in 15 ml of thionyl chloride, 0.02 ml of pyridine was added to the solution, and the mixture was stirred at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure to remove excess thionyl chloride. Dissolve the residue in 30 ml of benzene. This solution was added dropwise to a mixture of 4.78 g of 3,4-dimethoxyphenethylamine, 90 ml of 10% aqueous potassium carbonate solution, and 50 ml of benzene, and the mixture was stirred at room temperature for 4 hours. A benzene solution is separated from the reaction mixture, and the aqueous layer is extracted with ethyl acetate. Combine the benzene solution and ethyl acetate solution, and dilute the solution with water and 10%
Wash sequentially with hydrochloric acid and water. After drying the organic layer, the solvent was distilled off under reduced pressure. The residue is recrystallized from ethanol to obtain 7.67 g of 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)thioacetamide as pale yellow needles. Yield 80.1% Mp132-133℃ (2) 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)
500 mg of thioacetamide and 610 mg of nickel chloride hexahydrate were dissolved in 30 ml of methanol, and 700 mg of sodium borohydride was added to the solution at room temperature.
Stir at the same temperature for 1.5 hours. Filter out insoluble matter,
Concentrate the filtrate under reduced pressure. The residue is dissolved in chloroform, the solution is washed with water, and after drying, the solvent is distilled off under reduced pressure. Ethanolic hydrochloric acid is added to the residue to form a hydrochloride, and the precipitated crystals are collected by filtration to obtain 360 mg of α-(3,4-dimethoxyphenethylaminomethyl)-4-benzyloxybenzyl alcohol hydrochloride. Yield 70% Mp168-170℃ Example 2 2.0 g of 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)thioacetamide was dissolved in 40 ml of methylene chloride. Add 1.05 g of triethyloxonium fluoroborate to the solution and stir at room temperature for 1.5 hours. The reaction mixture is concentrated under reduced pressure. Ethanol the residue
Dissolve sodium borohydride in 30 ml and add sodium borohydride to the solution.
Add 2.1g and stir at room temperature for 1 hour. After the reaction is complete, water is added to the mixture and the solvent is distilled off under reduced pressure. The precipitated crystals are collected by filtration, washed with water, and then recrystallized from isopropanol to obtain 1.45 g of α-(3,4-dimethoxyphenethylaminomethyl)-4-benzyloxybenzyl alcohol (free base) as colorless needle-shaped crystals. . Yield 77.5% Mp 114.5-116°C Example 3 2.2 g of 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)thioacetamide was dissolved in 30 ml of acetone. 850 mg of potassium carbonate and 1.0 g of methyl iodide were added to the solution, and the mixture was stirred overnight at room temperature. Insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue was dissolved in 50 ml of ethanol, 300 mg of sodium borohydride was added to the solution, and the mixture was stirred at room temperature for 30 minutes. After the reaction, α-(3・4
-dimethoxyphenethylaminomethyl)-4-benzyloxybenzyl alcohol (free base)
1.65 g are obtained as colorless needles. Yield: 80% The physicochemical properties of this product were consistent with the specimen obtained in Example 2. Example 4 (1) 2-(4-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)
Dissolve 8.0 g of thioacetamide in 150 ml of methanol, add 500 mg of sodium borohydride to the solution, and stir at room temperature for 1 hour. After the reaction is completed, the reaction mixture is concentrated under reduced pressure to remove the solvent. Dissolve the residue in chloroform, wash the solution with water,
After drying, the solvent is distilled off under reduced pressure. By crystallizing the residue with isopropanol, 2-
7.5 g of (4-benzyloxyphenyl)-2-hydroxy-N-(3,4-dimethoxyphenethyl)thioacetamide are obtained as colorless needles.
Yield 93% Mp82-84℃ (2) 1.0 g of 2-(4-benzyloxyphenyl)-2-hydroxy-N-(3,4-dimethoxyphenethyl)thioacetamide was dissolved in methylene chloride.
460 mg of triethyloxonium fluoroborate was added to the solution and stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure. Dissolve the residue in a mixture of 20 ml of methanol and 20 ml of chloroform, and add sodium borohydride to the solution.
Add 440 mg and stir at room temperature for 1 hour. After the reaction was completed, the same procedure as in Example 2 was carried out to obtain
780 mg of α-(3,4-dimethoxyphenethylaminomethyl)-4-benzyloxybenzyl alcohol (free base) are obtained as colorless needles. Yield: 84% The physicochemical properties of this product were consistent with those of the sample obtained in Example 2. Example 5 (1) 5.34 g of 4-acetoxyacetophenone, 20 ml of thionyl chloride, 0.03 ml of pyridine and 3.4
2-
(4-acetoxyphenyl)-2-oxo-N-
8.5 g of (3,4-dimethoxyphenethyl)thioacetamide is a pale yellow oil. Yield 73
% IRν liq nax (cm -1 ): 1755, 1665 Mass m/e: 387 (M + ) NMR (CDCl 3 ) δ: 2.30 (s, 3H, CH 3 COO−), 3.00 (t,
2H, J=7.5Hz, -CH2 - CH2- ), 3.84
(s, 6H, -OC H 3 ×2) (2) 1.94 g of 2-(4-acetoxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)thioacetamide, triethyloxonium fluorocarbon 1.14g Lato and Sodium Borohydride
By using 1.0 g and treating in the same manner as in Example 2, 1.47 g of α-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol was obtained as colorless prism crystals. yield
92% Mp151-153℃ Example 6 (1) 4-hydroxyacetophenone 4.08g, thionyl chloride 12ml, pyridine 0.06ml and 3.4
2-
(4-hydroxyphenyl)-2-oxo-N-
3.1 g of (3,4-dimethoxyphenethyl)thioacetamide are obtained as pale yellow needles. Yield 30
% Mp179-180℃ (recrystallized from ethanol) (2) 2-(4-hydroxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)thioacetamide 1.0g, nickel chloride hexahydrate thing
By treating 1.37 g and 1.1 g of sodium borohydride in the same manner as in Example 1 (2), α
-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol 230mg
obtained as colorless prismatic crystals. Yield: 25% The physicochemical properties of this product were consistent with the specimen obtained in Example 5 (2). Example 7 2-(4-hydroxyphenyl)-2-oxo-
α-
(3,4-dimethoxyphenethylaminomethyl)-
940 mg of 4-hydroxybenzyl alcohol is obtained as colorless prismatic crystals. Yield: 65% The physicochemical properties of this product were consistent with the specimen obtained in Example 5 (2). Example 8 (1) 6.78 g of 2-benzyloxyacetophenone,
2-(2-benzyloxyphenyl)-2-
10.3 g of oxo-N-(3,4-dimethoxyphenethyl)thioacetamide is obtained as pale yellow prismatic crystals. Yield 79% Mp112-114℃ (2) 2-(2-benzyloxyphenyl)-22-oxo-N-(3,4-dimethoxyphenethyl)
By treating in the same manner as in Example 1 (2) using 500 mg of thioacetamide, 90.0 mg of nickel chloride hexahydrate and 700 mg of sodium borohydride,
165 mg of α-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol hydrochloride was obtained as colorless needles. Yield 32% Mp159-160℃ Example 9 2-(2-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)thioacetamide 2.0g, triethyloxonium chloroborate 1.13g and sodium borohydride 870
By treating in the same manner as in Example 2 using mg,
1.65 g of α-(3,4-dimethoxyphenethylaminomethyl)-2-benzyloxybenzyl alcohol (free base) are obtained as colorless needles. Yield 82% Mp95-97°C (recrystallized from isopropanol) Example 10 2-(2-benzyloxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)thioacetamide 2.2 g, potassium carbonate α-
(3,4-dimethoxyphenethylaminomethyl)-
1.1 g of 2-benzyloxybenzyl alcohol (free base) are obtained as colorless needles. Yield: 53% The physicochemical properties of this product were consistent with those of the sample obtained in Example 9. Example 11 (1) 2-hydroxyacetophenone 2.73g, thionyl chloride 8ml, pyridine 0.03ml and 3.4
2-
(2-hydroxyphenyl)-2-oxo-N-
4.0 g of (3,4-dimethoxyphenethyl)thioacetamide is obtained as pale reddish brown needles. yield
58% Mp166-168℃ (recrystallized from ethanol) (2) 2-(2-hydroxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)thioacetamide 1.58g, triethyloxonium fluorocarbon Lato 1.13g and sodium borohydride
By using 1.4 g and treating in the same manner as in Example 2, 850 mg of α-(3,4-dimethoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol was obtained as a colorless oil. Yield 58% Oxalate Mp of this product 175-176℃ Example 12 (1) 1.78 g of 2-acetoxyacetophenone, 6 ml of thionyl chloride, 0.02 ml of pyridine and 3.4
2-
(2-acetoxyphenyl)-2-oxo-N-
1.37 g of (3,4-dimethoxyphenethyl)thioacetamide are obtained as a pale yellow oil. yield
35.4% IRν CHCl3 nax (cm -1 ): 1760, 1670 Mass m/e: 387 (M + ) NMR (CDCl 3 ) δ: 2.20 (s, 3H, CH 3 COO-), 2.94 (t,
2H, J=7.5Hz, -CH2 - CH2- ), 3.85
(s, 6H, -OC H 3 ×2) (2) 2-(2-acetoxyphenyl)-2-oxo-N-(3,4-dimethoxyphenethyl)thioacetamide, triethyloxonium fluoroborate and α-(3・4
-dimethoxyphenethylaminomethyl)-2-
Obtain hydroxybenzyl alcohol. The physicochemical properties of this product were consistent with the specimen obtained in Example 11 (2).

Claims (1)

【特許請求の範囲】 １ (A) 一般式 （但し、R2は水素原子、アルカノイル基又アラ
ルキル基を表わす。） で示されるアセトフエノン誘導体をチオニルハ
ライドと反応させ、得られる反応生成物を３・
４−ジメトキシフエネチルアミンと反応させて
一般式 （但し、R2は前記と同一意味を有する。） で示されるチオアセタミド誘導体とし、次いで (B‐1)該化合物（）を還元脱硫化反応に付す
か、 (B‐2)化合物（）を一旦アルキル化して一般式 （但し、R3はアルキル基を表わし、R2は前記
と同一意味を有する。） で示されるアセトフエノン誘導体とした後、
該化合物（）を還元脱硫化反応に付すか、
或いは (B‐3)化合物（）を還元して一般式 （但し、R1は水素原子又はアラルキル基を表
わす。） で示されるベンジルアルコール誘導体とし、
該化合物（）をアルキル化して一般式 （但し、R1及びR3は前記と同一意味を有す
る。） で示されるベンジルアルコール誘導体とした
後、該化合物（）を還元脱硫化反応に付
し、 (C) 要すれば、上記（Ｂ−１）、（Ｂ−２）又は
（Ｂ−３）で得られた生成物をその薬理的に許
容しうる酸付加塩とすることを特徴とする一般
式 （但し、R1は前記と同一意味を有する。） で示されるベンジルアルコール誘導体もしくは
その薬理的に許容しうる酸付加塩の製法。 ２ 記号R2で示される基が水素原子、アセチル
基又はベンジル基であり、記号R3で示される基
がメチル基又はエチル基である特許請求の範囲第
１項記載の製法。[Claims] 1 (A) General formula (However, R 2 represents a hydrogen atom, an alkanoyl group or an aralkyl group.) The acetophenone derivative represented by is reacted with thionyl halide, and the resulting reaction product is 3.
By reacting with 4-dimethoxyphenethylamine, the general formula (However, R 2 has the same meaning as above.) Then, (B-1) the compound () is subjected to a reductive desulfurization reaction, or (B-2) the compound () is once Alkylated to general formula (However, R 3 represents an alkyl group, and R 2 has the same meaning as above.) After forming the acetophenone derivative shown by
The compound () is subjected to a reductive desulfurization reaction, or
Or (B-3) Compound () is reduced to give the general formula (However, R 1 represents a hydrogen atom or an aralkyl group.) A benzyl alcohol derivative represented by
The compound () is alkylated to give the general formula (However, R 1 and R 3 have the same meanings as above.) After forming the benzyl alcohol derivative represented by General formula characterized by converting the product obtained in -1), (B-2) or (B-3) into a pharmacologically acceptable acid addition salt thereof (However, R 1 has the same meaning as above.) A method for producing a benzyl alcohol derivative or a pharmacologically acceptable acid addition salt thereof. 2. The production method according to claim 1, wherein the group represented by the symbol R 2 is a hydrogen atom, an acetyl group, or a benzyl group, and the group represented by the symbol R 3 is a methyl group or an ethyl group.
JP56181951A 1981-11-12 1981-11-12 Preparation of benzyl alcohol derivative Granted JPS5883661A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
JP56181951A JPS5883661A (en) 1981-11-12 1981-11-12 Preparation of benzyl alcohol derivative
CA000415011A CA1196342A (en) 1981-11-12 1982-11-05 Process for preparing benzylalcohol derivatives
CH6482/82A CH650247A5 (en) 1981-11-12 1982-11-08 Process for preparing benzyl alcohol derivatives
SE8206352A SE454775B (en) 1981-11-12 1982-11-09 SET TO MAKE BENZYL ALCOHOL derivatives
DK502682A DK163660C (en) 1981-11-12 1982-11-11 PROCEDURE FOR PREPARING BENZYLAL ALCOHOL DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS.
IT68332/82A IT1191227B (en) 1981-11-12 1982-11-11 PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF BENZYL ALCOHOL
ES517297A ES8401013A1 (en) 1981-11-12 1982-11-11 Preparation of benzyl alcohol derivative
AT0409882A AT382866B (en) 1981-11-12 1982-11-11 METHOD FOR PRODUCING BENZYL ALCOHOL DERIVATIVES AND THEIR SALTS
KR828205098A KR870000471B1 (en) 1981-11-12 1982-11-11 Process for preparing benzylalcohol derivatives
HU823632A HU189190B (en) 1981-11-12 1982-11-11 Process for preparing benzylalcohole derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP56181951A JPS5883661A (en) 1981-11-12 1981-11-12 Preparation of benzyl alcohol derivative

Publications (2)

Publication Number Publication Date
JPS5883661A JPS5883661A (en) 1983-05-19
JPS6121620B2 true JPS6121620B2 (en) 1986-05-28

Family

ID=16109721

Family Applications (1)

Application Number Title Priority Date Filing Date
JP56181951A Granted JPS5883661A (en) 1981-11-12 1981-11-12 Preparation of benzyl alcohol derivative

Country Status (10)

Country Link
JP (1) JPS5883661A (en)
KR (1) KR870000471B1 (en)
AT (1) AT382866B (en)
CA (1) CA1196342A (en)
CH (1) CH650247A5 (en)
DK (1) DK163660C (en)
ES (1) ES8401013A1 (en)
HU (1) HU189190B (en)
IT (1) IT1191227B (en)
SE (1) SE454775B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0735693U (en) * 1993-12-14 1995-07-04 協和電機化学株式会社 Seal for sealing the butt of glass doors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4579972A (en) * 1983-04-28 1986-04-01 Smithkline Beckman Corporation Intermediates for preparing secondary amines
US7985168B2 (en) 2009-03-25 2011-07-26 Graa Innovations, Llc Power stride apparatus and method of training therefor

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5310974B2 (en) * 1974-06-10 1978-04-18
JPS6241829Y2 (en) * 1980-03-28 1987-10-26

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0735693U (en) * 1993-12-14 1995-07-04 協和電機化学株式会社 Seal for sealing the butt of glass doors

Also Published As

Publication number Publication date
AT382866B (en) 1987-04-27
DK502682A (en) 1983-05-13
SE8206352L (en) 1983-05-13
CH650247A5 (en) 1985-07-15
IT1191227B (en) 1988-02-24
KR840002343A (en) 1984-06-25
ES517297A0 (en) 1983-12-01
SE8206352D0 (en) 1982-11-09
DK163660B (en) 1992-03-23
ATA409882A (en) 1986-09-15
JPS5883661A (en) 1983-05-19
ES8401013A1 (en) 1983-12-01
SE454775B (en) 1988-05-30
KR870000471B1 (en) 1987-03-11
HU189190B (en) 1986-06-30
IT8268332A0 (en) 1982-11-11
DK163660C (en) 1992-08-17
CA1196342A (en) 1985-11-05

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