JPH07188120A - Racemization of optically active 1(halogenophenyl) ethylamines - Google Patents
Racemization of optically active 1(halogenophenyl) ethylaminesInfo
- Publication number
- JPH07188120A JPH07188120A JP33544693A JP33544693A JPH07188120A JP H07188120 A JPH07188120 A JP H07188120A JP 33544693 A JP33544693 A JP 33544693A JP 33544693 A JP33544693 A JP 33544693A JP H07188120 A JPH07188120 A JP H07188120A
- Authority
- JP
- Japan
- Prior art keywords
- halogenophenyl
- optically active
- ethylamine
- ethylamines
- racemization
- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、光学活性１−（ハロゲ
ノフェニル）エチルアミン類の新規ラセミ化法に関す
る。FIELD OF THE INVENTION The present invention relates to a novel racemization method for optically active 1- (halogenophenyl) ethylamines.
【０００２】光学活性１−（ハロゲノフェニル）エチル
アミン類は、除草剤または殺菌剤のごとき農薬、あるい
は医薬中間原料として、また、塩基性光学分割剤として
有用である。Optically active 1- (halogenophenyl) ethylamines are useful as pesticides such as herbicides or fungicides, or as intermediate raw materials for pharmaceuticals, and as basic optical resolving agents.
【０００３】[0003]
【従来の技術】一般的に、光学活性１−（ハロゲノフェ
ニル）エチルアミン類はラセミ体で製造され、それらの
対掌体に光学分割される。たとえば、(1) （ＲＳ）−１
−（４−ハロゲノフェニル）エチルアミンをＬ−酒石酸
で光学分割する方法（Ｊｏｕｒｎａｌ ｏｆ Ｃｈｅｍ
ｉｃａｌ Ｓｏｃｉｅｔｙ（Ｂ），２４１８，（１９７
１））、(2) 光学活性テトラヒドロフラン−２−カルボ
ン酸で光学分割する方法（特開平１−２１６９６２号公
報）、(3) 光学活性Ｎ−ホルミルフェニルアラニンで光
学分割する方法（特開平２−３０６９４２号公報）、あ
るいは (4)光学活性酒石酸アニリド誘導体などで光学分
割する方法（特開平４−２６０４１８号公報）により、
容易に光学活性１−（ハロゲノフェニル）エチルアミン
類を得ることができる。2. Description of the Related Art Generally, optically active 1- (halogenophenyl) ethylamines are produced in a racemic form and are optically resolved into their antipodes. For example, (1) (RS) -1
Method for optically resolving-(4-halogenophenyl) ethylamine with L-tartaric acid (Journal of Chem)
ical Society (B), 2418, (197)
1)), (2) Optical resolution with optically active tetrahydrofuran-2-carboxylic acid (JP-A 1-216962), (3) Optical resolution with optically active N-formylphenylalanine (JP-A-2-306942) Or (4) a method of optically resolving with an optically active tartaric acid anilide derivative (JP-A-4-260418).
Optically active 1- (halogenophenyl) ethylamines can be easily obtained.
【０００４】さらに、有用な光学対掌体を分離した後、
不用な対掌体をラセミ化し、そのラセミ体を再度光学対
掌体に分割する。これを繰り返すことができれば、工業
的に有利な光学活性体の製造法となる。従って、ラセミ
化は非常に重要な技術となる。Further, after separating the useful optical antipodes,
The undesired enantiomer is racemized and the racemate is again divided into optical antipodes. If this can be repeated, it will be an industrially advantageous method for producing an optically active substance. Therefore, racemization is a very important technique.
【０００５】光学活性１−（ハロゲノフェニル）エチル
アミン類のラセミ化方法としては、例えば、光学活性１
−（４−クロロフェニル）エチルアミンを適宜適当なア
ルコ−ル存在下にジメチルスルホキシド中で、金属アル
コキシド類と反応させる方法（特開平４−２７５２５８
号公報）などが知られている。As a method for racemizing optically active 1- (halogenophenyl) ethylamines, for example, optically active 1
A method of reacting-(4-chlorophenyl) ethylamine with a metal alkoxide in dimethylsulfoxide in the presence of a suitable alcohol (JP-A-4-275258).
No. publication) is known.
【０００６】[0006]
【発明が解決しようとする課題】しかし、上記ラセミ化
法は脱ハロゲン化が起こりやすく収率が十分でないこ
と、また沸点が高く、水と均一になるジメチルスルホキ
シドを溶媒として用いるために１−（ハロゲノフェニ
ル）エチルアミン類との分離が工業的規模での操作上難
しいなどの欠点を有している。However, in the above-mentioned racemization method, dehalogenation is liable to occur, the yield is not sufficient, and dimethyl sulfoxide, which has a high boiling point and becomes uniform with water, is used as a solvent. It has the drawback that separation from halogenophenyl) ethylamines is difficult in terms of operation on an industrial scale.
【０００７】[0007]
【課題を解決するための手段】そこで、本発明者らは、
光学活性１−（ハロゲノフェニル）エチルアミン類の工
業的に有利なラセミ化方法について鋭意検討した結果、
本発明に到達した。Therefore, the present inventors have
As a result of diligent studies on an industrially advantageous racemization method of optically active 1- (halogenophenyl) ethylamines,
The present invention has been reached.
【０００８】すなわち、本発明は、一般式（Ｉ）That is, the present invention has the general formula (I)
【化２】 （式中、Ｘは塩素原子または臭素原子を表す。）で表さ
れる光学活性１−（ハロゲノフェニル）エチルアミン類
と一般式（ＩＩ）[Chemical 2] (In the formula, X represents a chlorine atom or a bromine atom.) And optically active 1- (halogenophenyl) ethylamines represented by the general formula (II)
【化３】 （式中、Ｙは水素原子、塩素原子または臭素原子を表
す。）で表されるアセトフェノン類を脱水、濃縮した液
に、アルカリ金属アルコキシド存在下に加熱し、しかる
後加水分解することを特徴とする光学活性１−（ハロゲ
ノフェニル）エチルアミン類のラセミ化法である。[Chemical 3] (Wherein Y represents a hydrogen atom, a chlorine atom or a bromine atom), a dehydrated and concentrated liquid of acetophenone is heated in the presence of an alkali metal alkoxide, and then hydrolyzed. Is a racemization method for optically active 1- (halogenophenyl) ethylamines.
【０００９】すなわち、光学活性１−（ハロゲノフェニ
ル）エチルアミン類とアセトフェノン類を共沸脱水する
ことにより、式（ＩＩ）に示すようなイミンを作り、そ
の二重結合の移動により異性化させ、光学活性１−（ハ
ロゲノフェニル）エチルアミン類をラセミ化させるもの
である。That is, the optically active 1- (halogenophenyl) ethylamines and acetophenones are azeotropically dehydrated to produce an imine represented by the formula (II), which is isomerized by the transfer of its double bond. It is for racemizing active 1- (halogenophenyl) ethylamines.
【００１０】[0010]
【化４】 二重結合の異性化により、Ａ，Ｂ２種のイミンが生成す
る。式中、ＸとＹが、同じで置換位置も同じであれば、
Ａ，Ｂは同種となり、イミンを加水分解することによ
り、どちらからも目的のラセミ化した１−（ハロゲノフ
ェニル）エチルアミン類とハロゲノアセトフェノン類が
生成する。式中、ＸとＹが異なった場合、ＸとＹが同じ
でもその置換位置が異なった場合はＡ，Ｂは異種のイミ
ンとなる。Ａのイミンを加水分解すると、目的のラセミ
化した１−（ハロゲノフェニル）エチルアミン類とアセ
トフェノン類が、Ｂのイミンを加水分解すれば、Ｙ置換
アセトフェノン類に由来する１−フェニルエチルアミン
類とハロゲノアセトフェノン類が生成する。ここで、副
生した１−フェニルエチルアミンとアセトフェノン、ハ
ロゲノアセトフェノン類は回収してリサイクルが可能で
ある。[Chemical 4] The isomerization of the double bond produces A and B2 imines. In the formula, if X and Y are the same and the substitution positions are also the same,
A and B are of the same type, and the hydrolysis of the imine produces the desired racemized 1- (halogenophenyl) ethylamines and halogenoacetophenones. In the formula, when X and Y are different, or when X and Y are the same but the substitution positions are different, A and B are different imines. When the imine of A is hydrolyzed, the desired racemized 1- (halogenophenyl) ethylamines and acetophenones are hydrolyzed. If the imine of B is hydrolyzed, 1-phenylethylamines and halogenoacetophenone derived from Y-substituted acetophenones are hydrolyzed. Kind is generated. Here, the by-produced 1-phenylethylamine, acetophenone, and halogenoacetophenones can be recovered and recycled.
【００１１】以下、本発明の構成を詳細に説明する。The structure of the present invention will be described in detail below.
【００１２】本発明において適用される光学活性１−
（ハロゲノフェニル）エチルアミン類は１−（２−クロ
ロフェニル）エチルアミン、１−（３−クロロフェニ
ル）エチルアミン、１−（４−クロロフェニル）エチル
アミン、１−（２−ブロモフェニル）エチルアミン、１
−（３−ブロモフェニル）エチルアミン、１−（４−ブ
ロモフェニル）エチルアミンなどが挙げられる。Optical activity applied in the present invention 1-
(Halogenophenyl) ethylamines include 1- (2-chlorophenyl) ethylamine, 1- (3-chlorophenyl) ethylamine, 1- (4-chlorophenyl) ethylamine, 1- (2-bromophenyl) ethylamine, 1
Examples include-(3-bromophenyl) ethylamine and 1- (4-bromophenyl) ethylamine.
【００１３】本発明でラセミ化に使用される光学活性１
−（ハロゲノフェニル）エチルアミン類は、Ｒ体、Ｓ
体、あるいはこれらのうち１つの光学異性体を等量以上
含むものも使用することができる。Optical activity 1 used for racemization in the present invention
-(Halogenophenyl) ethylamines are R-form, S-form
Or a substance containing one or more of these optical isomers in equal amounts or more can be used.
【００１４】アルカリ金属アルコキシドとしては１〜６
の炭素数を有するアルカリ金属アルコキシドが好まし
く、具体的にはカリウムエトキシド、イソプロポキシ
ド、ｓｅｃ−ブトキシド、ｔｅｒｔ−ブトキシド、ｓｅ
ｃ−ペントキシド、ｔｅｒｔ−ペントキシドである。そ
の使用量は、光学活性１−（ハロゲノフェニル）エチル
アミン類１モルに対し、０．０１〜５モル、好ましくは
０．０５〜１．０モルである。1 to 6 as the alkali metal alkoxide
Alkali metal alkoxides having the number of carbon atoms of are specifically, specifically, potassium ethoxide, isopropoxide, sec-butoxide, tert-butoxide, se.
They are c-pentoxide and tert-pentoxide. The amount used is 0.01 to 5 mol, preferably 0.05 to 1.0 mol, per 1 mol of optically active 1- (halogenophenyl) ethylamines.
【００１５】本発明のラセミ化は、光学活性１−（ハロ
ゲノフェニル）エチルアミン類とアセトフェノン類を脱
水してイミンを生成せしめ、この反応液を濃縮した後、
アルカリ金属アルコキシド存在下に加熱し、しかる後加
水分解することによって実施できる。In the racemization of the present invention, optically active 1- (halogenophenyl) ethylamines and acetophenones are dehydrated to form an imine, and the reaction solution is concentrated.
It can be carried out by heating in the presence of an alkali metal alkoxide and then hydrolyzing.
【００１６】光学活性１−（ハロゲノフェニル）エチル
アミン類とアセトフェノン類との脱水は、共沸脱水な
ど、常法によって容易に進行し、イミンが生成する。Dehydration of the optically active 1- (halogenophenyl) ethylamines and acetophenones easily proceeds by a conventional method such as azeotropic dehydration to produce an imine.
【００１７】本発明法におけるラセミ化反応は無溶媒、
溶媒存在下でも実施できるが、イミンの濃度が高い方が
イミンの二重結合の移動、すなわちラセミ化速度が速
い。使用可能な溶媒は光学活性１−（ハロゲノフェニ
ル）エチルアミン類、生成したイミンを変質せしめるこ
となく、かつラセミ化反応を妨害しないものであれば何
でも良く、ベンゼン、トルエンなどの芳香族系、ジオキ
サン、ジエチレングリコ−ルジメチルエ−テル等のエ−
テル系、２−プロパノ−ル、ｔｅｒｔ−ブタノ−ル等の
アルコ−ル系溶媒、あるいは、ヘキサン、シクロヘキサ
ンなどの脂肪族炭化水素系溶媒を用いることができる。The racemization reaction in the method of the present invention is solvent-free,
It can be carried out in the presence of a solvent, but the higher the imine concentration, the faster the imine double bond transfer, that is, the racemization rate. The solvent that can be used is any optically active 1- (halogenophenyl) ethylamine, as long as it does not deteriorate the formed imine and does not interfere with the racemization reaction, and aromatic solvents such as benzene and toluene, dioxane, Diethylene glycol dimethyl ether, etc.
Alcohol solvents such as ter, 2-propanol and tert-butanol, or aliphatic hydrocarbon solvents such as hexane and cyclohexane can be used.
【００１８】アセトフェノン類の使用量は、式（Ｉ）の
光学活性１−（ハロゲノフェニル）エチルアミン類１モ
ルに対して、０．２〜２．０モル、好ましくは０．５〜
１．５モルである。The amount of acetophenones used is 0.2 to 2.0 mol, preferably 0.5 to 2.0 mol, per 1 mol of the optically active 1- (halogenophenyl) ethylamines of the formula (I).
It is 1.5 mol.
【００１９】ラセミ化反応は、通常温度５０〜２００
℃、好ましくは７０〜１５０℃で行われ、通常常圧で実
施されるが、微加圧、微減圧下においても実施可能であ
る。The racemization reaction is usually carried out at a temperature of 50 to 200.
C., preferably 70 to 150.degree. C., usually under normal pressure, but can be carried out under slight pressure or slight pressure reduction.
【００２０】ラセミ化後イミンの加水分解は、常法によ
り容易に進行し、１−（ハロゲノフェニル）エチルアミ
ン類、１−フェニルエチルアミン、ハロゲノアセトフェ
ノン類、アセトフェノンが生成する。After racemization, the imine is easily hydrolyzed by a conventional method to produce 1- (halogenophenyl) ethylamines, 1-phenylethylamine, halogenoacetophenones and acetophenone.
【００２１】本発明方法の好ましい実施態様では、光学
活性１−（ハロゲノフェニル）エチルアミン類をアセト
フェノン類と、微量の塩化亜鉛触媒とともにトルエン溶
媒中デイーン・スタークで共沸脱水した後濃縮し、その
濃縮液にアルカリ金属アルコキシドを添加して通常５０
〜２００℃で加熱処理する。処理後希硫酸などの酸水溶
液を加えて加水分解する。この反応混合物はアセトフェ
ノン、ハロゲノアセトフェノン類をトルエン等の有機溶
媒で抽出した後、水層を苛性ソ−ダなどの塩基の水溶液
でアルカリ性とし、トルエン等の有機溶媒で目的とする
ラセミ化された１−（ハロゲノフェニル）エチルアミン
類、１−フェニルエチルアミンを抽出する。抽出液を濃
縮、必要に応じて蒸留することにより１−（ハロゲノフ
ェニル）エチルアミン類を得ることができ、光学分割工
程にもどすことができる。１−（ハロゲノフェニル）エ
チルアミン類と共沸脱水したアセトフェノン類に由来す
る１−フェニルエチルアミン類は蒸留によって容易に除
去できる。さらに回収したアセトフェノン類は繰り返し
使用が可能である。In a preferred embodiment of the method of the present invention, optically active 1- (halogenophenyl) ethylamines are azeotropically dehydrated with acetophenones together with a trace amount of a zinc chloride catalyst in Dane Stark in a toluene solvent, then concentrated, and then concentrated. Alkali metal alkoxide is added to the solution, usually 50
Heat treatment at ~ 200 ° C. After the treatment, an aqueous acid solution such as dilute sulfuric acid is added to hydrolyze. The reaction mixture was extracted with acetophenone and halogenoacetophenones with an organic solvent such as toluene, and then the aqueous layer was made alkaline with an aqueous solution of a base such as caustic soda, and then racemized with an organic solvent such as toluene. Extract the-(halogenophenyl) ethylamines, 1-phenylethylamine. By concentrating the extract and distilling it if necessary, 1- (halogenophenyl) ethylamines can be obtained, which can be returned to the optical resolution step. 1-Phenylethylamines derived from acetophenones azeotropically dehydrated with 1- (halogenophenyl) ethylamines can be easily removed by distillation. Furthermore, the recovered acetophenones can be used repeatedly.
【００２２】[0022]
【実施例】以下、実施例により、本発明を説明するが、
本発明はこれらの実施例により限定されるものではな
い。EXAMPLES The present invention will be described below with reference to examples.
The invention is not limited by these examples.
【００２３】なお、実施例中の１−（ハロゲノフェニ
ル）エチルアミンのラセミ化に伴う光学純度（％ｅｅ）
の変化は、アミンとジ−ｐ−トルオイル−Ｌ−酒石酸無
水物（Ｌ−ＰＴＡＮ）と反応させた後、高速液体クロマ
トグラフィー（ＨＰＬＣ）により次の条件下で分析を行
った。The optical purity (% ee) accompanying racemization of 1- (halogenophenyl) ethylamine in the examples.
The change of was analyzed by high performance liquid chromatography (HPLC) under the following conditions after reacting the amine with di-p-toluoyl-L-tartaric anhydride (L-PTAN).
【００２４】カラム：ＣＡＰＣＥＬＬ ＰＡＫ ＳＧ１
２０（資生堂）４．６mmφ×１５０mm 溶離液：０．０５％リン酸／メタノール＝３５／６５ 流速：１．０ml／min 検出：ＵＶ ２５４nm 保持時間：（Ｒ）−１−（４−クロロフェニル）エチル
アミンとＬ−ＰＴＡＮとの反応物１５．８分、（Ｓ）−
１−（４−クロロフェニル）エチルアミンとＬ−ＰＴＡ
Ｎとの反応物１９．０分。Column: CAPCELL PAK SG1
20 (Shiseido) 4.6 mmφ × 150 mm Eluent: 0.05% phosphoric acid / methanol = 35/65 Flow rate: 1.0 ml / min Detection: UV 254 nm Retention time: (R) -1- (4-chlorophenyl) ethylamine Reaction product of L-PTAN with 15.8 minutes, (S)-
1- (4-chlorophenyl) ethylamine and L-PTA
Reaction with N 19.0 min.
【００２５】ラセミ化率は次式によった。The racemization rate was calculated by the following equation.
【００２６】[0026]
【数１】 実施例１ 光学純度９６％ｅｅの（Ｒ）−１−（４−クロロフェニ
ル）エチルアミン１９．９ｇ（０．１２８モル）とアセ
トフェノン１５．７ｇ（０．１３０モル）塩化亜鉛０．
３ｇおよびトルエン７０ｍｌを２００ｍｌフラスコに仕
込み、デイーン・スタークを用いて８時間共沸脱水し
た。エバポレーターで濃縮して濃縮液３７．７ｇを得
た。この濃縮液６．２ｇ（２１ミリモル）とカリウムｔ
ｅｒｔ−ブトキシド０．７５ｇ（７ミリモル）を冷却管
をつけた５０ｍｌ２口フラスコに仕込み、アルゴン気流
下１００℃で６時間加熱攪拌した。冷却後、２Ｎ硫酸１
７ｍｌを加えて１時間加熱還流して加水分解し、アセト
フェノン、４−クロロアセトフェノンをジクロロメタン
で抽出により除去した。水層に２Ｎ苛性ソーダ１８ｍｌ
を添加し、ジクロロメタン１５ｍｌで２回抽出、有機層
を水洗、硫酸マグネシウムで乾燥した。ジクロロメタン
を留去して蒸留することにより、沸点１０３℃／１６ｔ
ｏｒｒの１−（４−クロロフェニル）エチルアミン１．
０ｇ（６ミリモル）を得た。光学純度は７％ｅｅであ
り、ラセミ化率は９３％であった。なお、水層を硝酸銀
滴定したところクロル分解率は３．０モル％であった。[Equation 1] Example 1 19.9 g (0.128 mol) of (R) -1- (4-chlorophenyl) ethylamine having an optical purity of 96% ee and 15.7 g (0.130 mol) of acetophenone zinc chloride.
3 g and 70 ml of toluene were charged into a 200 ml flask and subjected to azeotropic dehydration for 8 hours using Dean Stark. It concentrated by the evaporator and obtained 37.7 g of concentrates. 6.2 g (21 mmol) of this concentrated liquid and potassium t
0.75 g (7 mmol) of ert-butoxide was charged into a 50 ml two-necked flask equipped with a cooling tube, and heated and stirred at 100 ° C. for 6 hours under an argon stream. After cooling, 2N sulfuric acid 1
7 ml was added and heated to reflux for 1 hour for hydrolysis, and acetophenone and 4-chloroacetophenone were removed by extraction with dichloromethane. 18 ml of 2N caustic soda in the water layer
Was added and extracted twice with 15 ml of dichloromethane. The organic layer was washed with water and dried over magnesium sulfate. By distilling off dichloromethane and distilling, a boiling point of 103 ° C / 16t
orr 1- (4-chlorophenyl) ethylamine 1.
0 g (6 mmol) was obtained. The optical purity was 7% ee and the racemization rate was 93%. When the aqueous layer was titrated with silver nitrate, the chlor decomposition rate was 3.0 mol%.
【００２７】実施例２ 実施例１の共沸脱水濃縮液５．１ｇ（１８ミリモル）と
カリウムｔｅｒｔ−ブトキシド１．１ｇ（１０ミリモ
ル）およびｔｅｒｔ−ブタノール２．０ｇを冷却管をつ
けた５０ｍｌ２口フラスコに仕込み、アルゴン気流下１
００℃で１０時間加熱攪拌した。冷却後、２Ｎ硫酸１５
ｍｌを加えて１時間加熱還流してＨＰＬＣ分析した結
果、１−（４−クロロフェニル）エチルアミンの光学純
度は１２％ｅｅ，ラセミ化率は８８％であった。硝酸銀
滴定によるクロル分解率は２．８モル％であった。Example 2 5.1 g (18 mmol) of the azeotropic dehydration concentrate of Example 1, 1.1 g (10 mmol) of potassium tert-butoxide and 2.0 g of tert-butanol were added to a 50 ml two-necked flask equipped with a cooling tube. Charged in a stream of argon 1
The mixture was heated and stirred at 00 ° C for 10 hours. After cooling, 2N sulfuric acid 15
As a result of HPLC analysis by adding ml and heating under reflux for 1 hour, 1- (4-chlorophenyl) ethylamine had an optical purity of 12% ee and a racemization rate of 88%. The decomposition rate of chloro by silver nitrate titration was 2.8 mol%.
【００２８】実施例３ 実施例１の共沸脱水濃縮液５．１ｇ（１８ミリモル）と
カリウムｔｅｒｔ−ブトキシド１．１ｇ（１０ミリモ
ル）およびｔｅｒｔ−ブタノ−ル５．１ｇを冷却管をつ
けた５０ｍｌ２口フラスコに仕込み、アルゴン気流下１
００℃で１４時間加熱攪拌した。冷却後、２Ｎ硫酸１６
ｍｌを加えて１時間加熱還流してＨＰＬＣ分析した結
果、１−（４−クロロフェニル）エチルアミンの光学純
度は１２％ｅｅ，ラセミ化率は８８％で，硝酸銀滴定に
よるクロル分解率は２．７モル％であった。Example 3 5.1 g (18 mmol) of the azeotropic dehydration concentrated liquid of Example 1, 1.1 g (10 mmol) of potassium tert-butoxide and 5.1 g of tert-butanol were attached to a 50 ml 2 tube equipped with a cooling tube. Charge into a necked flask and under argon flow 1
The mixture was heated and stirred at 00 ° C for 14 hours. After cooling, 2N sulfuric acid 16
As a result of HPLC analysis by adding 1 ml and heating under reflux for 1 hour, the optical purity of 1- (4-chlorophenyl) ethylamine was 12% ee, the racemization rate was 88%, and the chlorine decomposition rate by silver nitrate titration was 2.7 mol. %Met.
【００２９】実施例４ 実施例１の共沸脱水濃縮液７．０ｇ（２４ミリモル）と
カリウムｔｅｒｔ−ブトキシド１．３ｇ（１２ミリモ
ル）および１，４−ジオキサン７．０ｇを冷却管をつけ
た５０ｍｌ２口フラスコに仕込み、アルゴン気流下１２
０℃で６時間加熱攪拌した。冷却後、２Ｎ硫酸２０ｍｌ
を加えて１時間加熱還流してＨＰＬＣ分析した結果、１
−（４−クロロフェニル）エチルアミンの光学純度は２
３％ｅｅ，ラセミ化率は７６％であった。Example 4 7.0 g (24 mmol) of the azeotropic dehydration concentrate of Example 1, 1.3 g (12 mmol) of potassium tert-butoxide and 7.0 g of 1,4-dioxane were added to a 50 ml 2 tube equipped with a cooling tube. Charge into a necked flask and under an argon stream 12
The mixture was heated and stirred at 0 ° C. for 6 hours. After cooling, 2ml sulfuric acid 20ml
Was added, and the mixture was heated under reflux for 1 hour and analyzed by HPLC.
The optical purity of-(4-chlorophenyl) ethylamine is 2
3% ee, the racemization rate was 76%.
【００３０】[0030]
【発明の効果】本発明によれば、光学分割の際に不用と
なる残りの光学活性１−（ハロゲノフェニル）エチルア
ミン類を工業的に実用化可能な手段でラセミ化でき、さ
らに光学分割を繰り返すことにより、収率よく、有用な
光学活性体に変換できる。INDUSTRIAL APPLICABILITY According to the present invention, the remaining optically active 1- (halogenophenyl) ethylamines, which are unnecessary during the optical resolution, can be racemized by a commercially practical means, and the optical resolution is repeated. As a result, it can be converted into a useful optically active substance with a high yield.
【手続補正書】[Procedure amendment]
【提出日】平成７年２月９日[Submission date] February 9, 1995
【手続補正１】[Procedure Amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】０００９[Correction target item name] 0009
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【０００９】すなわち、光学活性１−（ハロゲノフェニ
ル）エチルアミン類とアセトフェノン類を共沸脱水する
ことにより、式（ＩＩＩ）に示すようなイミンを作り、
その二重結合の移動により異性化させ、光学活性１−
（ハロゲノフェニル）エチルアミン類をラセミ化させる
ものである。That is, the optically active 1- (halogenophenyl) ethylamines and acetophenones are azeotropically dehydrated to prepare an imine represented by the formula (III) ,
It is isomerized by the transfer of the double bond, and the optically active 1-
(Halogenophenyl) ethylamines are racemized.
【手続補正２】[Procedure Amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】００１０[Correction target item name] 0010
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【００１０】[0010]
【化１】 二重結合の異性化により、Ａ，Ｂ２種のイミンが生成す
る。式中、ＸとＹが、同じで置換位置も同じであれば、
Ａ，Ｂは同種となり、イミンを加水分解することによ
り、どちらからも目的のラセミ化した１−（ハロゲノフ
ェニル）エチルアミン類とハロゲノアセトフェノン類が
生成する。式中、ＸとＹが異なった場合、ＸとＹが同じ
でもその置換位置が異なった場合はＡ，Ｂは異種のイミ
ンとなる。Ａのイミンを加水分解すると、目的のラセミ
化した１−（ハロゲノフェニル）エチルアミン類とアセ
トフェノン類が、Ｂのイミンを加水分解すれば、Ｙ置換
アセトフェノン類に由来する１−フェニルエチルアミン
類とハロゲノアセトフェノン類が生成する。ここで、副
生した１−フェニルエチルアミンとアセトフェノン、ハ
ロゲノアセトフェノン類は回収してリサイクルが可能で
ある。[Chemical 1] The isomerization of the double bond produces A and B2 imines. In the formula, if X and Y are the same and the substitution positions are also the same,
A and B are of the same type, and the hydrolysis of the imine produces the desired racemized 1- (halogenophenyl) ethylamines and halogenoacetophenones. In the formula, when X and Y are different, or when X and Y are the same but the substitution positions are different, A and B are different imines. When the imine of A is hydrolyzed, the desired racemized 1- (halogenophenyl) ethylamines and acetophenones are hydrolyzed. If the imine of B is hydrolyzed, 1-phenylethylamines and halogenoacetophenone derived from Y-substituted acetophenones are hydrolyzed. Kind is generated. Here, the by-produced 1-phenylethylamine, acetophenone, and halogenoacetophenones can be recovered and recycled.
【手続補正３】[Procedure 3]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】００２６[Correction target item name] 0026
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【００２６】[0026]
【数１】 実施例１ 光学純度９６％ｅｅの（Ｒ）−１−（４−クロロフェニ
ル）エチルアミン１９．９ｇ（０．１２８モル）とアセ
トフェノン１５．７ｇ（０．１３０モル）、塩化亜鉛
０．３ｇおよびトルエン７０ｍｌを２００ｍｌフラスコ
に仕込み、デイーン・スタークを用いて８時間共沸脱水
した。エバポレーターで濃縮して濃縮液３７．７ｇを得
た。この濃縮液６．２ｇ（２１ミリモル）とカリウムｔ
ｅｒｔ−ブトキシド０．７５ｇ（７ミリモル）を冷却管
をつけた５０ｍｌ２口フラスコに仕込み、アルゴン気流
下１００℃で６時間加熱攪拌した。冷却後、２Ｎ硫酸１
７ｍｌを加えて１時間加熱還流して加水分解し、アセト
フェノン、４−クロロアセトフェノンをジクロロメタン
で抽出により除去した。水層に２Ｎ苛性ソーダ水溶液１
８ｍｌを添加し、ジクロロメタン１５ｍｌで２回抽出、
有機層を水洗、硫酸マグネシウムで乾燥した。ジクロロ
メタンを留去して蒸留することにより、沸点１０３℃／
１６ｔｏｒｒの１−（４−クロロフェニル）エチルアミ
ン１．０ｇ（６ミリモル）を得た。光学純度は７％ｅｅ
であり、ラセミ化率は９３％であった。なお、水層を硝
酸銀滴定したところクロル分解率は３．０モル％であっ
た。[Equation 1] Example 1 19.9 g (0.128 mol) of (R) -1- (4-chlorophenyl) ethylamine having an optical purity of 96% ee and 15.7 g (0.130 mol) of acetophenone , 0.3 g of zinc chloride and 70 ml of toluene. Was charged in a 200 ml flask and azeotropically dehydrated for 8 hours using Dean Stark. It concentrated by the evaporator and obtained 37.7 g of concentrates. 6.2 g (21 mmol) of this concentrated liquid and potassium t
0.75 g (7 mmol) of ert-butoxide was charged into a 50 ml two-necked flask equipped with a cooling tube, and heated and stirred at 100 ° C. for 6 hours under an argon stream. After cooling, 2N sulfuric acid 1
7 ml was added and heated to reflux for 1 hour for hydrolysis, and acetophenone and 4-chloroacetophenone were removed by extraction with dichloromethane. 2N caustic soda solution 1 in the water layer
Add 8 ml and extract twice with 15 ml dichloromethane,
The organic layer was washed with water and dried over magnesium sulfate. By distilling off dichloromethane and distilling, a boiling point of 103 ° C /
1.0 g (6 mmol) of 16 torr of 1- (4-chlorophenyl) ethylamine was obtained. Optical purity is 7% ee
And the racemization rate was 93%. When the aqueous layer was titrated with silver nitrate, the chlor decomposition rate was 3.0 mol%.
Claims (2)
れる光学活性１−（ハロゲノフェニル）エチルアミン類
とアセトフェノン類を脱水、濃縮した後、アルカリ金属
アルコキシド存在下に加熱し、しかる後加水分解するこ
とを特徴とする光学活性１−（ハロゲノフェニル）エチ
ルアミン類のラセミ化法。1. A compound represented by the general formula (I): (In the formula, X represents a chlorine atom or a bromine atom.) Optically active 1- (halogenophenyl) ethylamines and acetophenones are dehydrated and concentrated, and then heated in the presence of an alkali metal alkoxide. A racemization method for optically active 1- (halogenophenyl) ethylamines, which comprises hydrolysis.
ｓｅｃ−ブトキシドまたはカリウムｔｅｒｔ−ブトキシ
ドである光学活性１−（ハロゲノフェニル）エチルアミ
ン類のラセミ化法。2. A racemization method for optically active 1- (halogenophenyl) ethylamines, wherein the alkali metal alkoxide is potassium sec-butoxide or potassium tert-butoxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33544693A JP3252579B2 (en) | 1993-12-28 | 1993-12-28 | Racemization method for optically active 1- (halogenophenyl) ethylamines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33544693A JP3252579B2 (en) | 1993-12-28 | 1993-12-28 | Racemization method for optically active 1- (halogenophenyl) ethylamines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07188120A true JPH07188120A (en) | 1995-07-25 |
| JP3252579B2 JP3252579B2 (en) | 2002-02-04 |
Family
ID=18288655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP33544693A Expired - Fee Related JP3252579B2 (en) | 1993-12-28 | 1993-12-28 | Racemization method for optically active 1- (halogenophenyl) ethylamines |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3252579B2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0778260A1 (en) | 1995-12-07 | 1997-06-11 | Sumitomo Chemical Company, Limited | Process for racemization of optically active 1-phenylethylamine derivatives |
| EP0791569A1 (en) * | 1996-02-20 | 1997-08-27 | Basf Aktiengesellschaft | Process for the razemization of optically active amines |
| WO1998003465A1 (en) * | 1996-07-23 | 1998-01-29 | Bayer Aktiengesellschaft | Process for preparing racemic phenethylamines |
| US5739401A (en) * | 1995-03-30 | 1998-04-14 | Sumitomo Chemical Company, Limited | N-(α-alkylbenzylidene)-α-phenylalkylamine, its use and process for producing the same and process for producing intermediate therefor |
| US5969186A (en) * | 1996-03-28 | 1999-10-19 | Nagase & Company, Ltd. | Process for racemizing of optically active amines |
| WO2000047545A1 (en) * | 1999-02-12 | 2000-08-17 | Basf Aktiengesellschaft | Method for the racemization of optically active amines |
-
1993
- 1993-12-28 JP JP33544693A patent/JP3252579B2/en not_active Expired - Fee Related
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5739401A (en) * | 1995-03-30 | 1998-04-14 | Sumitomo Chemical Company, Limited | N-(α-alkylbenzylidene)-α-phenylalkylamine, its use and process for producing the same and process for producing intermediate therefor |
| US6093851A (en) * | 1995-03-30 | 2000-07-25 | Sumitomo Chemical Company, Ltd. | N-(α-alkylbenzylidene)-α-phenylalkylamine, its use and process for producing the same and process for producing intermediate therefor |
| EP0778260A1 (en) | 1995-12-07 | 1997-06-11 | Sumitomo Chemical Company, Limited | Process for racemization of optically active 1-phenylethylamine derivatives |
| US5723672A (en) * | 1995-12-07 | 1998-03-03 | Sumitomo Chemical Company, Limited | Process for racemization of optically active 1-phenylethylamine derivative |
| CN1119317C (en) * | 1995-12-07 | 2003-08-27 | 住友化学工业株式会社 | Process for racemization of optically active 1-phenylethylamine derivative |
| EP0791569A1 (en) * | 1996-02-20 | 1997-08-27 | Basf Aktiengesellschaft | Process for the razemization of optically active amines |
| US5847215A (en) * | 1996-02-20 | 1998-12-08 | Basf Aktiengesellschaft | Racemization of optically active amines |
| CN1122000C (en) * | 1996-02-20 | 2003-09-24 | 巴斯福股份公司 | Racemization of optically active amines |
| US5969186A (en) * | 1996-03-28 | 1999-10-19 | Nagase & Company, Ltd. | Process for racemizing of optically active amines |
| WO1998003465A1 (en) * | 1996-07-23 | 1998-01-29 | Bayer Aktiengesellschaft | Process for preparing racemic phenethylamines |
| US6046351A (en) * | 1996-07-23 | 2000-04-04 | Bayer Aktiengesellschaft | Process for preparing racemic phenethylamines |
| WO2000047545A1 (en) * | 1999-02-12 | 2000-08-17 | Basf Aktiengesellschaft | Method for the racemization of optically active amines |
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| Publication number | Publication date |
|---|---|
| JP3252579B2 (en) | 2002-02-04 |
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