JPH0641105A - Production of glycide derivative - Google Patents
Production of glycide derivativeInfo
- Publication number
- JPH0641105A JPH0641105A JP5113158A JP11315893A JPH0641105A JP H0641105 A JPH0641105 A JP H0641105A JP 5113158 A JP5113158 A JP 5113158A JP 11315893 A JP11315893 A JP 11315893A JP H0641105 A JPH0641105 A JP H0641105A
- Authority
- JP
- Japan
- Prior art keywords
- derivative
- optically active
- production
- glycid
- glycidyl tosylate
- 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.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は医薬品、特に循環器薬、
制癌効果増強剤等の製造にあたり、重要な中間体である
グリシド誘導体（アリールグリシジルエーテルまたはヘ
テロアリールグリシジルエーテル誘導体）の製造法に関
し、特に、高率的かつ経済的な製造法であって光学活性
体においては高い光学純度でグリシド誘導体を製造する
方法に関する。FIELD OF THE INVENTION The present invention relates to pharmaceuticals, in particular cardiovascular drugs,
Regarding the production of glycid derivatives (aryl glycidyl ether or heteroaryl glycidyl ether derivatives), which are important intermediates in the production of anti-cancer effect enhancers, etc. The present invention relates to a method for producing a glycid derivative with high optical purity in the body.
【０００２】[0002]
【従来の技術】グリシド誘導体は、各種医薬品製造にお
いて重要な中間体である。例えば、循環器薬、特に抗不
整脈剤、抗高血圧薬として多用されている、いわゆるβ
−受容体遮断剤は、基本的にこのグリシド誘導体をその
重要中間体として製造される。β−受容体遮断剤の代表
例として以下に塩酸プロプラノロールの製造法を記す
が、他のβ−受容体遮断剤も、出発原料としてα−ナフ
トールの代りに他のヒドロキシアリールを用いグリシド
誘導体を中間体とした同様な反応で目的の医薬品が製造
されている。BACKGROUND OF THE INVENTION Glycid derivatives are important intermediates in the production of various pharmaceutical products. For example, so-called β, which is often used as a cardiovascular drug, particularly as an antiarrhythmic drug and an antihypertensive drug
-Receptor blockers are basically produced with this glycid derivative as its key intermediate. A method for producing propranolol hydrochloride is described below as a representative example of β-receptor blockers.However, other β-receptor blockers also use other hydroxyaryl instead of α-naphthol as a starting material, and intermediate glycid derivatives. The target drug is manufactured by the same reaction as the body.
【０００３】[0003]
【化２】 また、特開平３−101662号公報等に開示されている制癌
効果増強剤等であるキノリン誘導体はグリシド誘導体を
中間体として以下の方法で製造されている。[Chemical 2] Further, the quinoline derivative, which is an antitumor effect enhancer disclosed in JP-A-3-101662 and the like, is produced by the following method using a glycid derivative as an intermediate.
【０００４】[0004]
【化３】 これらの例からも解る様に、グリシドは医薬品製造にお
いて重要な化合物である。従来、このグリシドの製法
は、先にも示した様に、相当するヒドロキシアリールと
エピクロルヒドリンまたはグリシジルトシレートとをナ
トリウム、カリウム等の金属塩基またはトリエチルアミ
ン、ピリジン等の有機塩基の存在下で反応させる方法が
知られている。しかし、これらの方法では工業的大量製
造の際に操作性、安定性等に問題が多く、さらに効率的
かつ経済的にも課題があった。[Chemical 3] As can be seen from these examples, glycid is an important compound in drug production. Conventionally, this glycid is produced by reacting the corresponding hydroxyaryl with epichlorohydrin or glycidyl tosylate in the presence of a metal base such as sodium or potassium or an organic base such as triethylamine or pyridine, as shown above. It has been known. However, these methods have many problems in operability, stability, etc. during industrial mass production, and also have problems in efficiency and economy.
【０００５】ところで、これら一連の医薬品は不斉炭素
を有し光学活性体であり、近年、光学活性体化合物の医
薬品の開発の際には、それぞれの光学活性体について各
種生理作用の検討がされている。例えば、下記に示され
る硫酸ペンブトロールの様に光学活性体そのものを医薬
品とする場合もある。By the way, these series of pharmaceuticals have asymmetric carbons and are optically active substances. In recent years, when developing pharmaceuticals of optically active compounds, various physiological actions of each optically active substance have been studied. ing. For example, the optically active substance itself may be used as a drug, such as penbutrol sulfate shown below.
【０００６】[0006]
【化４】 すなわちこれら一連の化合物の光学活性体を、容易にか
つ高い光学純度（エナンチオマーエクセス％［％e.
e.］）で製造する方法の確立も重要な課題である。この
課題の解決策として、従来光学活性エピクロルヒドリン
または光学活性グリシジルトシレートを用い、各種塩基
との組み合わせが検討されて来た。これらの例として
は、特開平１−121282号公報，特開平１−279890号公
報、特開平１−279887号公報、ＥＰ（欧州特許）−4543
85号、Chem. Pharm. Bull., 35, 8691(1987)、同38，20
92(1990)さらにJ．Org．Chem., 54 1295(1989)等に報告
されている。しかし、これらの方法のうち、例えば、金
属塩基として水素化ナトリウム、溶媒としてジメチルホ
ルムアミドを用い、５−ヒドロキシキノリンとグリシジ
ルトシレートとを反応させた場合、生成するグリシジル
エーテルの光学純度は80％e.e.以下となり、満足できる
ものでない。すなわち、これら光学活性化合物は、下記
に示す様に反応点を２ヶ所有しており、そのコントロー
ルが困難で、満足できる光学純度での製造法は現在ま
で、確立されていない。[Chemical 4] That is, the optically active isomers of these series of compounds are easily and highly optically purified (enantiomeric excess% [% e.
e.]) Establishment of manufacturing method is also an important issue. As a solution to this problem, conventionally, optically active epichlorohydrin or optically active glycidyl tosylate was used, and combination with various bases has been studied. Examples of these are JP-A 1-121282, JP-A 1-279890, JP-A 1-279887, and EP (European patent) -4543.
No. 85, Chem. Pharm. Bull., 35, 8691 (1987), 38, 20
92 (1990) Furthermore, J. Org. Chem., 54 1295 (1989). However, among these methods, for example, when sodium hydride is used as a metal base and dimethylformamide is used as a solvent and 5-hydroxyquinoline is reacted with glycidyl tosylate, the optical purity of glycidyl ether produced is 80% ee. The following is not satisfied. That is, these optically active compounds possess two reaction points as shown below, and their control is difficult, and a production method with satisfactory optical purity has not been established until now.
【０００７】[0007]
【化５】 [Chemical 5]
【０００８】[0008]
【発明が解決しようとする課題】本発明は、上述従来技
術の実情に鑑み、医薬品製造における重要中間体である
グリシド誘導体を製造するにあたり、一定の出発原料を
用いかつ特定の塩基を用いることにより効率的かつ経済
的にかかるグリシド誘導体を製造することを目的とす
る。本発明はまた、グリシド誘導体の光学活性体を容易
にかつ高い光学純度で製造することを目的とする。In view of the above-mentioned conventional circumstances, the present invention provides a glycid derivative, which is an important intermediate in drug production, by using a certain starting material and a specific base. The purpose is to produce such glycid derivatives efficiently and economically. Another object of the present invention is to easily produce an optically active glycid derivative with high optical purity.
【０００９】[0009]
【課題を解決するための手段】本発明者等は、上記目的
を達成するため鋭意検討した結果、ヒドロキシアリール
若しくはヘテロアリール誘導体とグリシジルトシレート
とを、塩基としてセシウム塩基の存在下、反応させるこ
とにより、効率的かつ経済的にグリシド誘導体が製造さ
れることを見出した。さらに、驚くべきことに、光学活
性グリシジルトシレートを用いた場合、セシウム塩は、
非常に高収率で光学活性体を生成させることができるこ
とを見出し本発明を完成した。このグリシド誘導体には
アリールグリシジルエーテル誘導体およびヘテロアリー
ルグリシジルエーテル誘導体が包含される。Means for Solving the Problems As a result of intensive studies for achieving the above object, the present inventors have found that a hydroxyaryl or heteroaryl derivative is reacted with glycidyl tosylate in the presence of a cesium base as a base. It was found that the glycid derivative can be produced efficiently and economically. Furthermore, surprisingly, when using optically active glycidyl tosylate, the cesium salt is
The present invention has been completed by finding that an optically active substance can be produced in a very high yield. This glycid derivative includes aryl glycidyl ether derivatives and heteroaryl glycidyl ether derivatives.
【００１０】すなわち、本発明は下記一般式（Ｉ）で表
わされるグリシド誘導体を製造するにあたり、Ａ−ＯＨ
で表わされるヒドロキシアリール若しくはヘテロアリー
ルとグリシジルトシレートとを、塩基としてセシウム塩
基の存在下、反応させること特徴とするグリシド誘導体
の製造法である。That is, according to the present invention, when the glycid derivative represented by the following general formula (I) is produced, A-OH is used.
A method for producing a glycid derivative, which comprises reacting hydroxyaryl or heteroaryl represented by and glycidyl tosylate in the presence of a cesium base as a base.
【００１１】[0011]
【化６】 また、グリシジルトシレートとして光学活性グリシジル
トシレートを用い、光学活性な一般式（Ｉ）で表わされ
るグリシド誘導体を製造する上記の製造方法である。[Chemical 6] Further, it is the above-mentioned production method wherein an optically active glycidyl derivative represented by the general formula (I) is produced by using an optically active glycidyl tosylate as the glycidyl tosylate.
【００１２】ここで、セシウム塩とは、水酸化セシウ
ム、炭酸セシウム等のセシウム金属塩基を、アリール基
とは、フェニル基、ナフチル基、インデニル基等の炭素
芳香環を、ヘテロアリール基とは、インドリル基、フリ
ル基、チエニル基、ピリジル基、キノリル基、イソキノ
リル基、ベンゾフリル基、チアジアゾリル基等の複素芳
香環を表わす。ここで、このアリール基又はヘテロアリ
ール基には、アルキル基、シクロアルキル基、ヒドロキ
シ基、アルコキシ基、ハロゲン原子、アシル基、シアノ
基等の置換基が導入されたものを含有するものとする。The cesium salt is a cesium metal base such as cesium hydroxide or cesium carbonate, the aryl group is a carbon aromatic ring such as a phenyl group, a naphthyl group or an indenyl group, and the heteroaryl group is a heteroaryl group. It represents a heteroaromatic ring such as an indolyl group, a furyl group, a thienyl group, a pyridyl group, a quinolyl group, an isoquinolyl group, a benzofuryl group and a thiadiazolyl group. Here, the aryl group or the heteroaryl group includes a group in which a substituent such as an alkyl group, a cycloalkyl group, a hydroxy group, an alkoxy group, a halogen atom, an acyl group or a cyano group is introduced.
【００１３】また、グリシジルトシレートには、グリシ
ジルベンゼンスルホネートおよびグリシジルニトロベン
ゼンスルホネート等も含有されるものとする。これらは
反応させるにあたり、溶媒としては水溶媒及び有機溶媒
またはそれらの混合溶媒が使用される。有機溶媒として
は、メタノール、エタノール等のアルコール溶媒；エチ
ルエーテル、テトラヒドロフラン等のエーテル溶媒；ジ
メチルホルムアミド、ジメチルイミダゾリジノン等のア
ミド溶媒；ヘキサン、ベンゼン、トルエン等の炭化水素
溶媒；さらにはアセトニトリル、ジメチルスルホキシド
等が用いられる。温度としては、０℃から用いられる溶
媒の沸点まで可能であるが、好ましくは室温から70℃の
範囲である。The glycidyl tosylate also contains glycidyl benzene sulfonate, glycidyl nitrobenzene sulfonate and the like. When these are reacted, a water solvent, an organic solvent or a mixed solvent thereof is used as a solvent. Examples of the organic solvent include alcohol solvents such as methanol and ethanol; ether solvents such as ethyl ether and tetrahydrofuran; amide solvents such as dimethylformamide and dimethylimidazolidinone; hydrocarbon solvents such as hexane, benzene, and toluene; and acetonitrile and dimethyl. Sulfoxide or the like is used. The temperature can be from 0 ° C to the boiling point of the solvent used, but is preferably in the range of room temperature to 70 ° C.
【００１４】セシウム塩の使用量は特に制限はないが、
通常Ａ−ＯＨ（ヒドロキシアリール若しくはヘテロアリ
ール）１モル当り０．１〜１０当量であり、好ましくは
１〜３当量程度がよい。The amount of cesium salt used is not particularly limited,
Usually, it is 0.1 to 10 equivalents, preferably about 1 to 3 equivalents per mol of A-OH (hydroxyaryl or heteroaryl).
【００１５】また、ヒドロキシアリール若しくはヘテロ
アリールとグリシジルトシレートの量比は、当モルが好
ましいがいずれが過剰でも例えば一方が他方の10モル倍
でも問題なく反応は進行する。また、光学活性なグリシ
ド誘導体の場合は、光学活性グリシジルトシレートを用
いれば良く、反応条件は前述と同様である。特に、炭酸
セシウムを塩基として用い、溶媒としてはジメチルホル
ムアミドを用いる場合約90％e.e.（エナンチオマーエク
セス）以上の光学純度を得ることが出来る。The amount ratio of hydroxyaryl or heteroaryl and glycidyl tosylate is preferably equimolar, but the reaction proceeds without problems even if either is in excess or, for example, one is 10 times the molar amount of the other. In the case of an optically active glycid derivative, optically active glycidyl tosylate may be used, and the reaction conditions are the same as those described above. In particular, when cesium carbonate is used as a base and dimethylformamide is used as a solvent, an optical purity of about 90% ee (enantiomer excess) or higher can be obtained.
【００１６】[0016]
【実施例】以下に本発明を更に詳しく説明するために、
実施例を示すが、本発明はこれに限定されるものではな
い。EXAMPLES In order to explain the present invention in more detail below,
Examples will be shown, but the present invention is not limited thereto.
【００１７】実施例１ ジメチルホルムアミド600ml に炭酸セシウム297gを添加
し、さらに５−ヒドロキシキノリン83.5g を加え、25〜
30℃で30分間攪拌する。この反応液にグリシジルトシレ
ート109gを徐々に添加し、更に25〜30℃で15時間攪拌す
る。この反応液を氷水３ｌに注ぎ、攪拌後酢酸エチル２
ｌで抽出する。水層はさらに２ｌの酢酸エチルで抽出
し、有機層は合わせてさらに２ｌの水で２回水洗する。
酢酸エチル層は無水ボウ硝で乾燥した後、減圧下溶媒を
留去する。残渣をシリカゲルカラムクロマト（ヘキサ
ン：酢酸エチル＝１：１）で精製し、目的の５−（２，
３−エポキシプロポキシ）キノリン76.8g （収率66％）
を淡黄色粉末として得た。 ＩＲν（ＫＢｒ）cm-1：3054，1590，1270，1098， 91
5 ，856 ，797 ＮＭＲδppm(CDCl3 ）：2.86(m,1H)，2.99(m,1H)， 3.
45〜3.53(m,1H)，4.12(dd,1H) ，4.46(m,1H)，6.89(d,1
H)，7.43(dd,1H) ，7.62(t,1H)，7.76(d,1H)，8.67(d,1
H)，8.92(dd,1H) 実施例２ ５−ヒドロキシキノリン108mg のエタノール溶液 3.7m
l に、室温下炭酸セシウム255mg を加えた。室温で３時
間攪拌後、濃縮し、さらに減圧下５℃にて固化するまで
乾燥した。得られた固体をジメチルホルムアミド3.2ml
に懸濁し、室温でＲ（−）−グリシジルトシレート187m
g （96％e.e.）を加えて12時間攪拌した。反応終了後、
濃縮し、水を加えて水層を酢酸エチル50mlで抽出し、飽
和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。
濃縮し、残渣をシリカゲルカラムクロマト（クロロホル
ム：メタノール＝100 ：１）にて精製することにより、
目的のＲ（−）−５−（２，３−エポキシプロポキシ）
キノリン114mg （収率76％、光学純度94％e.e.）を無色
粉末性結晶として得た。ＩＲ，ＮＭＲの値は実施例１で
得られた値と同じであった。 ［α］D （23℃，ΕｔＯＨ，ｃ＝2.18）＝−35.6° 実施例３ エタノール3.3ml に炭酸セシウム417mg を添加し、さら
にフェノール109mg を加え、25〜30℃で30分間攪拌す
る。この反応液を濃縮乾固した後、ジメチルホルムアミ
ド3.3ml およびＲ（−）−グリシジルトシレート292mg
（98.4％e.e.）を添加し、更に25〜30℃で15時間攪拌す
る。この反応液を濃縮後、残渣をシリカゲルカラムクロ
マト（ヘキサン：イソプロパノール＝50：１）で精製
し、目的のＲ（−）−２，３−エポキシプロポキシベン
ゼン155mg （収率89％、光学純度92％e.e.）を無色油状
物として得た。 ＮＭＲδppm(CDCl3 ）：2.76(m,1H)，2.90(m,1H)， 3.
30〜3.45(m,1H)，3.96(dd,1H) ，4.21(m,1H)，6.85〜7.
09(m,3H)，7.21〜7.41(m,2H) ［α］D （24℃，ＭｅＯＨ，ｃ＝2.86）＝−14.1° 実施例４ ジメチルホルムアミド8.8ml に炭酸セシウム365mg を添
加し、さらに１−ナフトール147mg を加え、減圧下に半
分量の溶媒を留去する。この反応溶液にＲ（−）−グリ
シジルトシレート（98.4％e.e.）256mg を添加し、更に
25〜30℃で15時間攪拌する。この反応液を濃縮後、残渣
をシリカゲルカラムクロマト（ヘキサン：イソプロパノ
ール＝50：１）で精製し、目的のＲ（−）−１−（２，
３−エポキシプロポキシ）ナフタレン198mg （収率97
％、光学純度93％e.e.）を無色油状物として得た。 ＮＭＲδppm(CDCl3 ）：2.85(m,1H)，2.96(m,1H)， 3.
43〜3.51(m,1H)，4.14(dd,1H) ，4.40(m,1H)，6.80(d,1
H)，7.32〜7.52(m,4H)，7.74〜7.83(m,1H)，8.24〜8.34
(m,2H) ［α］D （24℃，ＭｅＯＨ，ｃ＝3.85）＝−36.6° 実施例５ ジメチルホルムアミド9.8ml に炭酸セシウム363mg を添
加し、さらに２−シクロペンチルフェノール167 mgを加
え、減圧下に半分量の溶媒を留去する。この反応溶液に
Ｒ（−）−グリシジルトシレート（98.4％e.e.）254mg
を添加し、更に25〜30℃で15時間攪拌する。この反応液
を濃縮後、残渣をシリカゲルカラムクロマト（ヘキサ
ン：イソプロパノール＝50：１）で精製 し、目的のＲ
（−）−１−（２，３−エポキシプロポキシ）−２−シ
クロペンチルベンゼン194mg （収率86％、光学純度89％
e.e.）を無色油状物として得た。 ＮＭＲδppm(CDCl3 ）：1.46〜2.12(m,9H)，2.77(m, 1
H) ，2.91(m,1H)，3.30〜3.42(m,1H)，3.98(dd,1H) ，
4.23(m,1H)，6.76〜6.95(m,2H)，7.08〜7.28(m,1H) ［α］D （24℃，ＭｅＯＨ，ｃ＝3.49）＝−15.6° 実施例６ ジメチルホルムアミド7.8ml に炭酸セシウム350mg を添
加し、さらに４−ヒドロキシインドール130mg を加え、
減圧下に半分量の溶媒を留去する。この反応溶液にＲ
（−）−グリシジルトシレート（98.4％e.e.）245mg を
添加し、更に25〜30℃で15時間攪拌する。この反応液を
濃縮後、残渣をシリカゲルカラムクロマト（ヘキサン：
イソプロパノール＝20：１）で精製し、目的のＲ（−）
−４−（２，３−エポキシプロポキ シ）インドール13
4mg （収率72％、光学純度90％e.e.）を無色油状物とし
て得た。 ＮＭＲδppm(CDCl3 ）：2.82(m,1H)，2.94(m,1H)， 3.
40〜3.50(m,1H)，4.15(dd,1H) ，4.36(m,1H)，6.80(d,1
H)，6.48〜6.55(m,1H)，6.65〜6.72(m,1H)，7.00〜7.18
(m,3H)，8.02〜8.35(br,1H) ［α］D （24℃，ＭｅＯＨ，ｃ＝2.68）＝−21.0° 参考例１ 実施例２で得られたＲ（−）−５−（２，３−エポキシ
プロポキシ）キノリン1.75g をイソプロパノール11mlに
懸濁し、ジベンゾスベラニルピペラジン3.1gのイソプロ
パノール溶液10mlに加え、加熱攪拌して完全に溶解し、
そのまま室温まで終夜放置した。反応液を濃縮し、残渣
をシリカゲルカラムクロマト（クロロホルム：メタノー
ル＝50：１）で精製し、さらにエーテル・ヘキサン混合
溶媒で再結晶することにより、目的物である、Ｒ（＋）
−５−［３−｛４−（ジベンゾスベラン−５−イル）ピ
ペラジン−１−イル｝−２−ヒドロキシプロポキシ］キ
ノリン3.08g を無色針状晶として得た。Example 1 To 600 ml of dimethylformamide, 297 g of cesium carbonate was added, and further, 83.5 g of 5-hydroxyquinoline was added.
Stir for 30 minutes at 30 ° C. To this reaction solution, 109 g of glycidyl tosylate is gradually added, and the mixture is further stirred at 25 to 30 ° C for 15 hours. The reaction solution was poured into 3 liters of ice water, and after stirring, ethyl acetate 2
Extract with l. The aqueous layer is further extracted with 2 l of ethyl acetate, and the organic layers are combined and washed twice with 2 l of water.
The ethyl acetate layer is dried over anhydrous Glauber's salt, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and the desired 5- (2,2
3-Epoxypropoxy) quinoline 76.8 g (66% yield)
Was obtained as a pale yellow powder. IR ν (KBr) cm -1 : 3054, 1590, 1270, 1098, 91
5, 856, 797 NMR δppm (CDCl 3 ): 2.86 (m, 1H), 2.99 (m, 1H), 3.
45 ~ 3.53 (m, 1H), 4.12 (dd, 1H), 4.46 (m, 1H), 6.89 (d, 1
H), 7.43 (dd, 1H), 7.62 (t, 1H), 7.76 (d, 1H), 8.67 (d, 1)
H), 8.92 (dd, 1H) Example 2 3.7m solution of 108 mg of 5-hydroxyquinoline in ethanol
To the l, 255 mg of cesium carbonate was added at room temperature. The mixture was stirred at room temperature for 3 hours, concentrated, and further dried under reduced pressure at 5 ° C. until solidified. 3.2 ml of the obtained solid was dimethylformamide.
Suspended in water, and at room temperature R (-)-glycidyl tosylate 187 m
g (96% ee) was added and the mixture was stirred for 12 hours. After the reaction,
The mixture was concentrated, water was added, the aqueous layer was extracted with 50 ml of ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate.
By concentrating and purifying the residue by silica gel column chromatography (chloroform: methanol = 100: 1),
Desired R (-)-5- (2,3-epoxypropoxy)
Quinoline (114 mg, yield 76%, optical purity 94% ee) was obtained as colorless powdery crystals. The IR and NMR values were the same as those obtained in Example 1. [Α] D (23 ° C., ETOH, c = 2.18) = − 35.6 ° Example 3 To 3.3 ml of ethanol was added 417 mg of cesium carbonate, 109 mg of phenol was added, and the mixture was stirred at 25 to 30 ° C. for 30 minutes. The reaction mixture was concentrated to dryness, then dimethylformamide (3.3 ml) and R (-)-glycidyltosylate (292 mg) were added.
(98.4% ee) is added, and the mixture is further stirred at 25 to 30 ° C for 15 hours. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (hexane: isopropanol = 50: 1) to obtain the desired R (−)-2,3-epoxypropoxybenzene 155 mg (yield 89%, optical purity 92% ee) was obtained as a colorless oil. NMR δ ppm (CDCl 3 ): 2.76 (m, 1H), 2.90 (m, 1H), 3.
30 to 3.45 (m, 1H), 3.96 (dd, 1H), 4.21 (m, 1H), 6.85 to 7.
09 (m, 3H), 7.21 to 7.41 (m, 2H) [α] D (24 ° C, MeOH, c = 2.86) = -14.1 ° Example 4 To 8.8 ml of dimethylformamide, 365 mg of cesium carbonate was added, and further 1 -Add 147 mg of naphthol and distill off half the solvent under reduced pressure. To this reaction solution, 256 mg of R (-)-glycidyltosylate (98.4% ee) was added, and further,
Stir at 25-30 ° C for 15 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane: isopropanol = 50: 1) to obtain the desired R (-)-1- (2,
3-Epoxypropoxy) naphthalene 198 mg (yield 97
%, Optical purity 93% ee) was obtained as a colorless oil. NMR δ ppm (CDCl 3 ): 2.85 (m, 1H), 2.96 (m, 1H), 3.
43 to 3.51 (m, 1H), 4.14 (dd, 1H), 4.40 (m, 1H), 6.80 (d, 1)
H), 7.32 to 7.52 (m, 4H), 7.74 to 7.83 (m, 1H), 8.24 to 8.34
(m, 2H) [α] D (24 ° C., MeOH, c = 3.85) = − 36.6 ° Example 5 To 9.8 ml of dimethylformamide, 363 mg of cesium carbonate was added, and further 167 mg of 2-cyclopentylphenol was added, and the mixture was concentrated under reduced pressure. Then, half of the solvent is distilled off. 254 mg of R (-)-glycidyltosylate (98.4% ee) was added to this reaction solution.
Is added and the mixture is further stirred at 25 to 30 ° C. for 15 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane: isopropanol = 50: 1) to obtain the desired R
(-)-1- (2,3-Epoxypropoxy) -2-cyclopentylbenzene 194 mg (yield 86%, optical purity 89%
ee) was obtained as a colorless oil. NMR δ ppm (CDCl 3 ): 1.46 to 2.12 (m, 9H), 2.77 (m, 1
H), 2.91 (m, 1H), 3.30 ~ 3.42 (m, 1H), 3.98 (dd, 1H),
4.23 (m, 1H), 6.76 to 6.95 (m, 2H), 7.08 to 7.28 (m, 1H) [α] D (24 ° C, MeOH, c = 3.49) = -15.6 ° Example 6 To 7.8 ml of dimethylformamide. 350 mg of cesium carbonate was added, and further 130 mg of 4-hydroxyindole was added,
Evaporate half the solvent under reduced pressure. R in this reaction solution
245 mg of (−)-glycidyl tosylate (98.4% ee) is added, and the mixture is further stirred at 25 to 30 ° C. for 15 hours. After concentrating the reaction solution, the residue is subjected to silica gel column chromatography (hexane:
Purify with isopropanol = 20: 1) and then obtain the target R (-)
-4- (2,3-epoxypropoxy) indole 13
4 mg (yield 72%, optical purity 90% ee) was obtained as a colorless oil. NMR δ ppm (CDCl 3 ): 2.82 (m, 1H), 2.94 (m, 1H), 3.
40 to 3.50 (m, 1H), 4.15 (dd, 1H), 4.36 (m, 1H), 6.80 (d, 1)
H), 6.48 ~ 6.55 (m, 1H), 6.65 ~ 6.72 (m, 1H), 7.00 ~ 7.18
(m, 3H), 8.02 to 8.35 (br, 1H) [α] D (24 ° C., MeOH, c = 2.68) = − 21.0 ° Reference Example 1 R (−)-5- (obtained in Example 2 2,3-Epoxypropoxy) quinoline (1.75 g) was suspended in isopropanol (11 ml), added to dibenzosuberanylpiperazine (3.1 g) in isopropanol solution (10 ml), and stirred under heating to completely dissolve it.
It was left to stand at room temperature overnight. The reaction solution is concentrated, the residue is purified by silica gel column chromatography (chloroform: methanol = 50: 1), and recrystallized with a mixed solvent of ether and hexane to give the desired product, R (+).
3.08 g of -5- [3- {4- (dibenzosuberan-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline was obtained as colorless needle crystals.
【００１８】光学純度 98.5％e.e. 融 点 112.5 〜114 ℃ 旋光度 ［α］D ＝＋20.8° 参考例２ 実施例２において、Ｒ（−）−グリシジルトシレートを
Ｓ（＋）−グリシジルトシレートにかえ、同様の反応に
より得られたＳ（＋）−５−（２，３−エポキシプロポ
キシ）キノリン1.92g を使用して参考例１と同様に反応
させ、Ｓ（−）−５−［３−｛４−（ジベンゾスベラン
−５−イル）ピペラジン−１−イル｝−２−ヒドロキシ
プロポキシ］キノリン3.3gを無色針状晶として得た。Optical purity 98.5% ee Melting point 112.5 to 114 ° C. Optical rotation [α] D = + 20.8 ° Reference Example 2 In Example 2, R (−)-glycidyltosylate was replaced with S (+)-glycidyltosylate. Instead, S (+)-5- (2,3-epoxypropoxy) quinoline (1.92 g) obtained by a similar reaction was used and reacted in the same manner as in Reference Example 1 to give S (-)-5- [3 3.3 g of-{4- (dibenzosuberan-5-yl) piperazin-1-yl} -2-hydroxypropoxy] quinoline was obtained as colorless needle crystals.
【００１９】光学純度 98.4％e.e. 融 点 112.5 〜114 ℃ 旋光度 ［α］D ＝−21.4° 参考例３ 実施例２で得られたＲ（−）−５−（２，３−エポキシ
プロポキシ）キノリン2.7gをイソプロパノール20mlに懸
濁し、ジフェニルアセチルピペラジン4.8gのイソプロパ
ノール溶液42mlを加える。反応液を加熱攪拌して完全に
溶解させた後、室温で終夜放置した。反応液を濃縮し、
残渣をシリカゲルカラムクロマト（クロロホルム：メタ
ノール＝40：１）で精製し、酢酸エチルより再結晶する
ことによりＲ（＋）−５−［３−｛４−（２，２−ジフ
ェニルアセチル）ピペラジン−１−イル｝−２−ヒドロ
キシプロポキシ］キノリン4.25g を無色針状晶として得
た。Optical purity 98.4% ee Melting point 112.5 to 114 ° C. Optical rotation [α] D = −21.4 ° Reference Example 3 R (−)-5- (2,3-epoxypropoxy) quinoline obtained in Example 2 2.7 g is suspended in 20 ml of isopropanol and 42 ml of a solution of 4.8 g of diphenylacetylpiperazine in isopropanol is added. The reaction solution was heated and stirred to completely dissolve it, and then left overnight at room temperature. The reaction solution is concentrated,
The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) and recrystallized from ethyl acetate to give R (+)-5- [3- {4- (2,2-diphenylacetyl) piperazine-1. 4.25 g of -yl} -2-hydroxypropoxy] quinoline were obtained as colorless needles.
【００２０】光学純度 96.9％e.e. 融 点 137 〜140 ℃ 旋光度 ［α］D ＝＋14.2° 参考例４ 実施例２において、Ｒ（−）−グリシジルトシレートを
Ｓ（＋）−グリシジルトシレートにかえ、同様の反応に
より得られたＳ（＋）−５−（２，３−エポキシプロポ
キシ）キノリン1.3gを用いて、参考例３と同様に反応さ
せ、Ｓ（−）−５−［３−｛４−（２，２−ジフェニル
アセチル）ピペラジン−１−｝−２−ヒドロキシプロポ
キシ］キノリン2.1gを無色針状晶として得た。Optical purity 96.9% ee Melting point 137 to 140 ° C. Optical rotation [α] D = + 14.2 ° Reference Example 4 In Example 2, R (−)-glycidyltosylate was replaced with S (+)-glycidyltosylate. Instead, 1.3 g of S (+)-5- (2,3-epoxypropoxy) quinoline obtained by a similar reaction was used and reacted in the same manner as in Reference Example 3 to give S (-)-5- [3 2.1 g of-{4- (2,2-diphenylacetyl) piperazine-1-}-2-hydroxypropoxy] quinoline was obtained as colorless needle crystals.
【００２１】光学純度 96.5％ee 融 点 137 〜140 ℃ 旋光度 ［α］D ＝−14.8°Optical purity 96.5% ee Melting point 137-140 ° C Optical rotation [α] D = -14.8 °
【００２２】[0022]
【発明の効果】以上説明したように、本発明によれば、
医薬品製造における重要中間体であるグリシド誘導体を
製造するにあたり、一定の出発原料を用いかつ特定の塩
基としてセシウム塩基を用いたことにより、効率的かつ
経済的にかかるグリシド誘導体を製造することができ
た。また、この方法によれば光学活性原料を用いること
により、グリシド誘導体の光学活性体を容易にかつ高い
光学純度で製造することができた。As described above, according to the present invention,
In producing a glycid derivative, which is an important intermediate in pharmaceutical production, it was possible to efficiently and economically produce such a glycid derivative by using a constant starting material and using a cesium base as a specific base. . Further, according to this method, an optically active substance of the glycid derivative could be easily produced with high optical purity by using an optically active raw material.
【００２３】本発明で得られるグリシド誘導体は、先に
本発明者等が報告した（特開平３−101662号公報）毒性
および副作用の低い制癌効果増強剤の製造中間体として
極めて重要な化合物である。さらに光学活性化合物であ
る制癌効果増強剤の製造においても、良好な化学収率お
よび光学純度で、目的の光学活性化合物を製造すること
が出来る。この様に、本発明は、癌化学療法でその有用
性が期待される制癌効果増強剤の製造において極めて有
益な方法を提供するものである。The glycid derivative obtained in the present invention is a very important compound as an intermediate for the production of an antitumor effect enhancer with low toxicity and side effects previously reported by the present inventors (JP-A-3-101662). is there. Furthermore, also in the production of an antitumor effect enhancer which is an optically active compound, the desired optically active compound can be produced with a good chemical yield and optical purity. Thus, the present invention provides a very useful method in the production of an antitumor effect enhancer, which is expected to be useful in cancer chemotherapy.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｄ 417/12 ３０３ 9051−4Ｃ // Ｃ０７Ｂ 61/00 ３００ (72)発明者 小松 弘典 千葉県茂原市東郷1144番地 三井東圧化学 株式会社内 (72)発明者 大塚 健悟 千葉県茂原市東郷1144番地 三井東圧化学 株式会社内 (72)発明者 中島 由紀 千葉県茂原市東郷1144番地 三井東圧化学 株式会社内─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Internal reference number FI Technical display location C07D 417/12 303 9051-4C // C07B 61/00 300 (72) Inventor Hironori Komatsu Shigehara, Chiba Prefecture City Togo 1144 Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Kengo Otsuka 1144 Togo Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Yuki Nakajima 1144 Togo, Mobara City Chiba Prefecture Mitsui Toatsu Chem. Within the corporation
Claims (4)
誘導体を製造するにあたり、Ａ−ＯＨで表わされるヒド
ロキシアリール若しくはヘテロアリールとグリシジルト
シレートとを、塩基としてセシウム塩基の存在下、反応
させること特徴とするグリシド誘導体の製造法。 【化１】 1. In producing a glycid derivative represented by the following general formula (I), a hydroxyaryl or heteroaryl represented by A-OH is reacted with glycidyl tosylate in the presence of a cesium base as a base. A method for producing a characterized glycid derivative. [Chemical 1]
リシジルトシレートを用い、光学活性な一般式（Ｉ）で
表わされるグリシド誘導体を製造する請求項１記載の製
造法。2. The production method according to claim 1, wherein an optically active glycidyl derivative represented by the general formula (I) is produced by using an optically active glycidyl tosylate as the glycidyl tosylate.
項１または２記載の製造法。3. The method according to claim 1, wherein the cesium base is cesium carbonate.
る請求項３記載の製造法。4. The method according to claim 3, wherein A-OH is 5-hydroxyquinoline.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5113158A JP2837606B2 (en) | 1992-05-15 | 1993-05-14 | Method for producing glycid derivative |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12333892 | 1992-05-15 | ||
| JP4-123338 | 1992-05-15 | ||
| JP5113158A JP2837606B2 (en) | 1992-05-15 | 1993-05-14 | Method for producing glycid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0641105A true JPH0641105A (en) | 1994-02-15 |
| JP2837606B2 JP2837606B2 (en) | 1998-12-16 |
Family
ID=26452178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5113158A Expired - Fee Related JP2837606B2 (en) | 1992-05-15 | 1993-05-14 | Method for producing glycid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2837606B2 (en) |
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