JPH0881412A - Production of phenoxyalkylcarboxylic acid derivative - Google Patents
Production of phenoxyalkylcarboxylic acid derivativeInfo
- Publication number
- JPH0881412A JPH0881412A JP24463694A JP24463694A JPH0881412A JP H0881412 A JPH0881412 A JP H0881412A JP 24463694 A JP24463694 A JP 24463694A JP 24463694 A JP24463694 A JP 24463694A JP H0881412 A JPH0881412 A JP H0881412A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- general formula
- integer
- acetyl
- 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
Landscapes
- 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、強力なロイコトリエン
拮抗作用を有し、喘息等のアレルギー疾患の予防及び治
療に有用であるフェノキシアルキルカルボン酸誘導体の
製造方法に関する。TECHNICAL FIELD The present invention relates to a method for producing a phenoxyalkylcarboxylic acid derivative which has a strong leukotriene antagonistic activity and is useful for the prevention and treatment of allergic diseases such as asthma.
【０００２】[0002]
【従来の技術】前記フェノキシアルキルカルボン酸誘導
体は、下記一般式（１）と（３）で表される化合物を反
応させることにより導くことができるが、一般式（３）
においてＸ1 が硫黄原子である化合物は不安定な物質で
あり、この化合物を単離して反応に使用すると、容易に
二量体を形成し、目的とする下記一般式（４）で表され
る化合物の収率及び品質の低下をもたらしていた。The above-mentioned phenoxyalkylcarboxylic acid derivative can be obtained by reacting compounds represented by the following general formulas (1) and (3).
The compound in which X 1 is a sulfur atom is an unstable substance, and when this compound is isolated and used in the reaction, it easily forms a dimer and is represented by the following general formula (4). This resulted in a decrease in the yield and quality of the compound.
【０００３】[0003]
【発明が解決しようとする課題】本発明の目的は一般式
（３）においてＸ1 が硫黄原子である化合物の二量化を
抑制し、高品質、高純度、かつ簡便に一般式（４）の化
合物を製造するための工業的に有利な合成方法を提供す
ることである。The object of the present invention is to suppress the dimerization of a compound of the general formula (3) in which X 1 is a sulfur atom, to obtain a high quality, high purity and simple compound of the general formula (4). An object of the present invention is to provide an industrially advantageous synthetic method for producing a compound.
【０００４】[0004]
【課題を解決するための手段】前記フェノキシアルキル
カルボン酸誘導体の工業的製法に関して鋭意研究を重ね
た結果、一般式（３）の化合物を単離することなく一般
式（１）の化合物を加え、１pot 反応により、一般式
（４）の化合物を容易に高純度、高収率で得ることを見
いだし、本発明を完成するに至った。Means for Solving the Problems As a result of intensive studies on the industrial production method of the phenoxyalkylcarboxylic acid derivative, the compound of the general formula (1) was added without isolation of the compound of the general formula (3), The inventors have found that the compound of general formula (4) can be easily obtained with high purity and high yield by the 1-pot reaction, and have completed the present invention.
【０００５】即ち本発明は、一般式（１） ［式中、ｍは２〜５の整数を、ｎは３〜８の整数を、Ｘ
は酸素原子、硫黄原子、スルフィニル基又はスルフォニ
ル基を、Ｙはハロゲン原子を表す。］で表される化合物
と、一般式（２） ［式中、Ｘ1 は硫黄原子又は酸素原子を表す。］で表さ
れる化合物を加水分解して生成する一般式（３） ［式中、Ｘ1 は硫黄原子又は酸素原子を表す。］で表さ
れる化合物とを、単離することなく１pot で反応させる
ことを特徴とする、一般式（４） ［式中、ｍは２〜５の整数を、ｎは３〜８の整数を、Ｘ
1 は硫黄原子又は酸素原子を、Ｘは酸素原子、硫黄原
子、スルフィニル基又はスルフォニル基を表すが、
Ｘ1 、Ｘは同時に酸素原子ではない。］で表されるフェ
ノキシアルキルカルボン酸誘導体の製造法である。That is, the present invention relates to the general formula (1) [In formula, m is an integer of 2-5, n is an integer of 3-8, X
Represents an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group, and Y represents a halogen atom. ] The compound represented by the general formula (2) [In the formula, X 1 represents a sulfur atom or an oxygen atom. ] The general formula (3) produced by hydrolyzing the compound represented by [In the formula, X 1 represents a sulfur atom or an oxygen atom. ] The compound of the general formula (4) characterized by reacting with a compound represented by [In formula, m is an integer of 2-5, n is an integer of 3-8, X
1 represents a sulfur atom or an oxygen atom, X represents an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group,
X 1 and X are not oxygen atoms at the same time. ] It is a manufacturing method of the phenoxy alkyl carboxylic acid derivative represented by this.
【０００６】典型的には、一般式（２）で表される化合
物を適当な溶媒、例えば水あるいは含水アルコール中で
適当な塩基、好ましくは水酸化ナトリウムや水酸化カリ
ウムを用い、室温〜溶媒の沸点で処理することにより、
一般式（３）で表される化合物を生成せしめ、この化合
物を単離することなく、反応液に一般式（１）で表され
る化合物を加え１pot で反応させることにより一般式
（４）で表される化合物を容易に高純度、高収率で得る
ことができる。また、一般式（１）で表される化合物
を、あらかじめ反応系に加えておくことも可能である。Typically, the compound represented by the general formula (2) is used in a suitable solvent such as water or hydrous alcohol using a suitable base, preferably sodium hydroxide or potassium hydroxide, at room temperature to the solvent temperature. By treating at boiling point,
The compound represented by the general formula (3) is produced, and the compound represented by the general formula (1) is added to the reaction solution without isolation of the compound to react with 1 pot to give the compound represented by the general formula (4). The represented compound can be easily obtained with high purity and high yield. It is also possible to add the compound represented by the general formula (1) to the reaction system in advance.
【０００７】一般式（１）で表される化合物は特願平５
−１６６３５４号公報記載の、一般式（３）で表される
化合物は特開平２−１４５９号公報記載の方法により合
成することができる。The compound represented by the general formula (1) is disclosed in Japanese Patent Application No.
The compound represented by the general formula (3) described in JP-A-166354 can be synthesized by the method described in JP-A No. 2-1459.
【０００８】[0008]
【実施例】以下に実施例を示して、本発明を更に説明す
るが、本発明はこれら実施例によって何らの制限を受け
るものではない。The present invention will be further described with reference to the following examples, but the present invention is not limited to these examples.
【０００９】（実施例１）Ｎ，Ｎ−ジメチルチオカルバ
ミン酸Ｓ−（４−アセチル−３−ヒドロキシ−２−プロ
ピルフェニル）エステル10ｇ、水酸化カリウム10ｇ及び
水55mlを混合し、窒素気流下 1.5時間、95℃で攪拌し
た。35〜40℃で４−［６−アセチル−３−（３−クロロ
プロポキシ）−２−プロピルフェノキシ］酪酸12.7ｇを
この反応液にいれ、窒素気流下21時間同温度で攪拌し
た。水冷下、68％酢酸にて酸性（ｐＨ４〜５）とし、酢
酸エチルで抽出（45ml×２）した。酢酸エチル層は飽和
食塩水で洗浄（45ml×２）した後、溶媒を減圧留去し
た。残渣をメタノール190ml に溶解し、活性炭処理後、
水95mlを加えて結晶化し、微褐色の粗結晶４−［６−ア
セチル−３−［３−（４−アセチル−３−ヒドロキシ−
２−プロピルフェニルチオ）プロポキシ］−２−プロピ
ルフェノキシ］酪酸25ｇ（湿潤重量）を得た。これをメ
タノール水に溶解し、合成吸着剤（ＨＰ−20）処理し
た。得られた結晶をエタノール−水から再結晶して白色
粉末状の４−［６−アセチル−３−［３−（４−アセチ
ル−３−ヒドロキシ−２−プロピルフェニルチオ）プロ
ポキシ］−２−プロピルフェノキシ］酪酸15.2ｇを得
た。(Example 1) 10 g of N, N-dimethylthiocarbamic acid S- (4-acetyl-3-hydroxy-2-propylphenyl) ester, 10 g of potassium hydroxide and 55 ml of water were mixed, and the mixture was mixed under a nitrogen stream of 1.5. Stir at 95 ° C. for hours. 12.7 g of 4- [6-acetyl-3- (3-chloropropoxy) -2-propylphenoxy] butyric acid was added to this reaction solution at 35 to 40 ° C, and the mixture was stirred at the same temperature for 21 hours under a nitrogen stream. The mixture was acidified (pH 4 to 5) with 68% acetic acid under water cooling and extracted with ethyl acetate (45 ml × 2). The ethyl acetate layer was washed with saturated brine (45 ml × 2), and the solvent was evaporated under reduced pressure. Dissolve the residue in 190 ml of methanol and treat with activated carbon.
Crystallization was carried out by adding 95 ml of water, and a pale brown crude crystal 4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-
25 g (wet weight) of 2-propylphenylthio) propoxy] -2-propylphenoxy] butyric acid were obtained. This was dissolved in methanol water and treated with a synthetic adsorbent (HP-20). The obtained crystals were recrystallized from ethanol-water to give 4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propyl as white powder. Phenoxy] butyric acid 15.2 g was obtained.
【００１０】（実施例２）Ｎ，Ｎ−ジメチルチオカルバ
ミン酸Ｓ−（４−アセチル−３−ヒドロキシ−２−プロ
ピルフェニル）エステル3.71ｇ、４−［６−アセチル−
３−（クロロプロポキシ）−２−プロピルフェノキシ］
酢酸3.57ｇ及び水酸化カリウム3.37ｇを10％エタノール
34.0mlに投入して 2.5時間還流下、攪拌した。水冷後、
反応液に水10mlを加えて酢酸エチル洗浄（15ml×２）
し、水層を濃塩酸でｐＨ４〜５として酢酸エチル抽出
（15ml×２）した。抽出液を飽和食塩水洗浄（15ml×
２）し、溶媒を減圧留去した。得た油状物を90％エタノ
ール53mlに溶解し、活性炭処理後、水27mlを加えて結晶
化させた。析出晶をろ取、乾燥し、微褐色の粗結晶４−
［６−アセチル−３−［３−（４−アセチル−３−ヒド
ロキシ−２−プロピルフェニルチオ）プロポキシ］−２
−プロピルフェノキシ］酪酸3.92ｇを得た。Example 2 N, N-Dimethylthiocarbamic acid S- (4-acetyl-3-hydroxy-2-propylphenyl) ester 3.71 g, 4- [6-acetyl-
3- (chloropropoxy) -2-propylphenoxy]
Acetic acid 3.57g and potassium hydroxide 3.37g are added to 10% ethanol.
It was put into 34.0 ml and stirred under reflux for 2.5 hours. After water cooling,
10 ml of water was added to the reaction solution and washed with ethyl acetate (15 ml x 2).
The aqueous layer was adjusted to pH 4-5 with concentrated hydrochloric acid and extracted with ethyl acetate (15 ml × 2). Wash the extract with saturated saline solution (15 ml x
Then, the solvent was distilled off under reduced pressure. The obtained oily substance was dissolved in 53 ml of 90% ethanol, treated with activated carbon, and then added with 27 ml of water for crystallization. Precipitated crystals were collected by filtration and dried to give slightly brown crude crystals 4-
[6-Acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2
3.92 g of -propylphenoxy] butyric acid were obtained.
【００１１】[0011]
【発明の効果】抗アレルギー剤として有用なフェノキシ
アルキルカルボン酸誘導体が一般式（３）の化合物を単
離することなく、一般式（１）の化合物を加える１pot
反応により、容易に高純度、高収率で得られる。INDUSTRIAL APPLICABILITY A phenoxyalkylcarboxylic acid derivative useful as an antiallergic agent is added to a compound of the general formula (1) without isolation of the compound of the general formula (3).
By the reaction, high purity and high yield can be easily obtained.
フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｃ 319/20 323/22 7419−4Ｈ 323/65 7419−4Ｈ Continuation of the front page (51) Int.Cl. 6 Identification code Office reference number FI Technical display area C07C 319/20 323/22 7419-4H 323/65 7419-4H
Claims (1)
は酸素原子、硫黄原子、スルフィニル基又はスルフォニ
ル基を、Ｙはハロゲン原子を表す。］で表される化合物
と、 一般式（２） ［式中、Ｘ1 は硫黄原子又は酸素原子を表す。］で表さ
れる化合物を加水分解して生成する一般式（３） ［式中、Ｘ1 は硫黄原子又は酸素原子を表す。］で表さ
れる化合物とを、単離することなく１pot で反応させる
ことを特徴とする、一般式（４） ［式中、ｍは２〜５の整数を、ｎは３〜８の整数を、Ｘ
1 は硫黄原子又は酸素原子を、Ｘは酸素原子、硫黄原
子、スルフィニル基又はスルフォニル基を表すが、
Ｘ1 、Ｘは同時に酸素原子ではない。］で表されるフェ
ノキシアルキルカルボン酸誘導体の製造法。1. The general formula (1) [In formula, m is an integer of 2-5, n is an integer of 3-8, X
Represents an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group, and Y represents a halogen atom. ] The compound represented by the general formula (2) [In the formula, X 1 represents a sulfur atom or an oxygen atom. ] The general formula (3) produced by hydrolyzing the compound represented by [In the formula, X 1 represents a sulfur atom or an oxygen atom. ] The compound of the general formula (4) characterized by reacting with a compound represented by [In formula, m is an integer of 2-5, n is an integer of 3-8, X
1 represents a sulfur atom or an oxygen atom, X represents an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group,
X 1 and X are not oxygen atoms at the same time. ] The manufacturing method of the phenoxy alkyl carboxylic acid derivative represented by this.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24463694A JP3773064B2 (en) | 1994-09-13 | 1994-09-13 | Process for producing phenoxyalkylcarboxylic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24463694A JP3773064B2 (en) | 1994-09-13 | 1994-09-13 | Process for producing phenoxyalkylcarboxylic acid derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0881412A true JPH0881412A (en) | 1996-03-26 |
| JP3773064B2 JP3773064B2 (en) | 2006-05-10 |
Family
ID=17121707
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP24463694A Expired - Lifetime JP3773064B2 (en) | 1994-09-13 | 1994-09-13 | Process for producing phenoxyalkylcarboxylic acid derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3773064B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1636176A2 (en) * | 2003-06-24 | 2006-03-22 | Medicinova, Inc. | The polymorphic form a of 4- 6-acetyl-3- 3-(4-acetyl-3- hydroxy-2-propylphenylthio)propoxy -2-propylphenoxy butryric acid |
| JP2007526229A (en) * | 2003-06-24 | 2007-09-13 | メディシノバ，インコーポレーテッド | Process for the preparation of polymorph Form A of 4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propylphenoxy] butyric acid |
-
1994
- 1994-09-13 JP JP24463694A patent/JP3773064B2/en not_active Expired - Lifetime
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1636176A2 (en) * | 2003-06-24 | 2006-03-22 | Medicinova, Inc. | The polymorphic form a of 4- 6-acetyl-3- 3-(4-acetyl-3- hydroxy-2-propylphenylthio)propoxy -2-propylphenoxy butryric acid |
| JP2007524624A (en) * | 2003-06-24 | 2007-08-30 | メディシノバ，インコーポレーテッド | Polymorphic form A of 4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propylphenoxy] butyric acid |
| JP2007526229A (en) * | 2003-06-24 | 2007-09-13 | メディシノバ，インコーポレーテッド | Process for the preparation of polymorph Form A of 4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propylphenoxy] butyric acid |
| EP1636176A4 (en) * | 2003-06-24 | 2010-03-31 | Medicinova Inc | The polymorphic form a of 4- 6-acetyl-3- 3-(4-acetyl-3- hydroxy-2-propylphenylthio)propoxy -2-propylphenoxy butryric acid |
| US7728169B2 (en) | 2003-06-24 | 2010-06-01 | Medicinova, Inc. | Pharmaceutical compositions of isolated orthorhombic crystalline 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid and methods of use |
| JP2014097989A (en) * | 2003-06-24 | 2014-05-29 | Medicinova Inc | Polymorphic form a of 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3773064B2 (en) | 2006-05-10 |
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