JPH06345682A - Carboxylic acid derivative - Google Patents
Carboxylic acid derivativeInfo
- Publication number
- JPH06345682A JPH06345682A JP16635493A JP16635493A JPH06345682A JP H06345682 A JPH06345682 A JP H06345682A JP 16635493 A JP16635493 A JP 16635493A JP 16635493 A JP16635493 A JP 16635493A JP H06345682 A JPH06345682 A JP H06345682A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- acid derivative
- compound
- carboxylic acid
- 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.)
- Pending
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- 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、ロイコトリエン拮抗作
用を有するフェノキシアルキルカルボン酸誘導体の合成
中間体として有用である新規なカルボン酸誘導体に関す
る。FIELD OF THE INVENTION The present invention relates to a novel carboxylic acid derivative useful as a synthetic intermediate for a phenoxyalkylcarboxylic acid derivative having a leukotriene antagonistic activity.
【０００２】[0002]
【従来の技術】本発明のカルボン酸誘導体は、文献未記
載の新規化合物である。2. Description of the Related Art The carboxylic acid derivative of the present invention is a novel compound not described in the literature.
【０００３】[0003]
【発明が解決しようとする課題】本発明の目的は、前記
フェノキシアルキルカルボン酸誘導体を工業的に製造す
るために有用な合成中間体である新規カルボン酸誘導体
を提供することである。An object of the present invention is to provide a novel carboxylic acid derivative which is a synthetic intermediate useful for industrially producing the phenoxyalkylcarboxylic acid derivative.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、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（１）で表される新規カ
ルボン酸誘導体が有用な合成中間体であることを見出
し、本発明を完成した。 ［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。］Means for Solving the Problems As a result of intensive studies on the industrial production method of the phenoxyalkylcarboxylic acid derivative, the present inventors have found that the novel carboxylic acid derivative represented by the general formula (1) is useful for synthesis. The inventors have found that it is an intermediate and completed the present invention. [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. ]
【０００５】本発明に係る一般式（１）の化合物は一般
式（２）の化合物 ［式中、ｍ、ｎ、Ｘ及びＹは前述の通りであり、Ｒはメ
チル基又はエチル基を表す。］を常法に従い加水分解を
行うことにより合成することができる。The compound of the general formula (1) according to the present invention is a compound of the general formula (2) [In the formula, m, n, X and Y are as described above, and R represents a methyl group or an ethyl group. ] Can be synthesized by hydrolysis according to a conventional method.
【０００６】一般式（１）で表される本化合物を特開平
2-1459号公報記載のロイコトリエン拮抗作用を有するフ
ェノキシアルキルカルボン酸誘導体（一般式（３）） ［式中、ｍ及びｎは前述の通りであり、Ｘ1 及びＸは同
一又は相異なって酸素原子、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 とＸは同時に酸素原
子ではない。］とするには、一般式（１）の化合物と一
般式（４）の化合物 ［式中、Ｘ3 は酸素原子又は硫黄原子を表すが、Ｘが酸
素原子の時はＸ3 は酸素原子ではない。］とを反応する
ことにより導くことができる。The present compound represented by the general formula (1) is disclosed in
Phenoxyalkylcarboxylic acid derivatives having a leukotriene antagonistic effect described in JP-A-2-1459 (general formula (3)) [In the formula, m and n are as described above, and X 1 and X are the same or different and represent an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group, but X 1 and X are not oxygen atoms at the same time. ], The compound of the general formula (1) and the compound of the general formula (4) [In the formula, X 3 represents an oxygen atom or a sulfur atom, but when X is an oxygen atom, X 3 is not an oxygen atom. ] It can be derived by reacting with.
【０００７】一般式（２）で表される化合物は特開平2-
1459号公報記載の方法に準拠して、また一般式（４）で
表される化合物は特開昭55-36489号公報記載の方法に準
拠して合成することができる。The compound represented by the general formula (2) is disclosed in JP-A-2-
The compound represented by formula (4) can be synthesized according to the method described in 1459, and according to the method described in JP-A-55-36489.
【０００８】[0008]
【実施例】以下に実施例を示して、本発明をさらに詳細
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 described in more detail with reference to the following examples, but the present invention is not limited to these examples.
【０００９】（実施例１）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］
酪酸エチル38.5ｇをエタノール57.8mlに溶解し、この溶
液に、水 100mlに水酸化ナトリウム10ｇを溶解した水溶
液を水冷下攪拌しながら18〜28℃で滴下した。滴下終了
後、さらに室温下２時間攪拌した。反応液を水 578mlに
投入し、酢酸エチルで洗浄(200ml×２）した。酢酸エチ
ル層を水(200ml）で逆抽出し、水層と合一した。水層を
濃塩酸にて酸性（ｐＨ＝４〜５）とし、酢酸エチルで抽
出(200ml×３）した。酢酸エチル層は、飽和食塩水で洗
浄(200ml×２）したのち無水硫酸ナトリウムにて乾燥し
た。溶媒を減圧留去した後、残渣をイソプロピルエーテ
ルで結晶化し、淡黄白色粉末状の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32.4ｇ（91％）を得た。融点60.5〜62℃(Example 1) 4- [6-acetyl-3-
(3-Chloropropoxy) -2-propylphenoxy]
Ethyl butyrate (38.5 g) was dissolved in ethanol (57.8 ml), and an aqueous solution prepared by dissolving 10 g of sodium hydroxide in 100 ml of water was added dropwise to the solution at 18 to 28 ° C with stirring while cooling with water. After completion of dropping, the mixture was further stirred at room temperature for 2 hours. The reaction solution was poured into 578 ml of water and washed with ethyl acetate (200 ml × 2). The ethyl acetate layer was back-extracted with water (200 ml) and combined with the aqueous layer. The aqueous layer was acidified (pH = 4-5) with concentrated hydrochloric acid and extracted with ethyl acetate (200 ml × 3). The ethyl acetate layer was washed with saturated saline (200 ml × 2) and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was crystallized with isopropyl ether to give 4- [6-acetyl-
32.4 g (91%) of 3- (3-chloropropoxy) -2-propylphenoxy] butyric acid were obtained. Melting point 60.5-62 ℃
【００１０】（参考例１）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21.4ｇと２−ヒドロキシ−４−メルカプト−３−プ
ロピルアセトフェノン15.1ｇをジメチルホルムアミド
（ＤＭＦ） 107mlに溶解し、氷水冷却下に攪拌しながら
無水炭酸カリウム16.6ｇを室温下に投入した。投入終了
後、さらに３時間室温下で攪拌した。反応液を水1070ml
に投入し、酢酸エチルで洗浄（200ml, 100ml）した。水
層を濃塩酸にて酸性（ｐＨ＝４〜５）とし、酢酸エチル
で抽出(200ml×３）した。有機層を飽和食塩水で洗浄(2
00ml×２）した後、無水硫酸ナトリウムにて乾燥した。
溶媒を減圧留去して、得られた油状物をエタノールに加
熱溶解し、活性炭処理した。得られた濾液に水を加えて
結晶化させた。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
24.4ｇを得た。Reference Example 1 4- [6-acetyl-3-
(3-Chloropropoxy) -2-propylphenoxy]
Butyric acid (21.4 g) and 2-hydroxy-4-mercapto-3-propylacetophenone (15.1 g) were dissolved in dimethylformamide (DMF) (107 ml), and anhydrous potassium carbonate (16.6 g) was added at room temperature with stirring under ice-water cooling. After the addition was completed, the mixture was further stirred at room temperature for 3 hours. The reaction solution is 1070 ml of water
And washed with ethyl acetate (200 ml, 100 ml). The aqueous layer was acidified (pH = 4-5) with concentrated hydrochloric acid and extracted with ethyl acetate (200 ml × 3). Wash the organic layer with saturated saline (2
It was dried with anhydrous sodium sulfate after 00 ml × 2).
The solvent was distilled off under reduced pressure, the obtained oily substance was dissolved in ethanol by heating, and treated with activated carbon. Water was added to the obtained filtrate for crystallization. The obtained crystals were recrystallized from ethanol-water to give 4- [6-acetyl-3- [3-] as white powder.
(4-Acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propylphenoxy] butyric acid
24.4 g was obtained.
【００１１】（参考例２）２，４−ジヒドロキシ−３−
プロピルアセトフェノン97.2ｇ、無水炭酸カリウム69.1
ｇ及び１−ブロモ−３−クロロプロパン 115.0ｇをアセ
トン 780mlに投入して還流下７時間攪拌した後、無水炭
酸カリウム34.6ｇを追加してさらに７時間反応した。無
機物を濾去した後、溶媒を留去して４−（３−クロロプ
ロポキシ）−２−ヒドロキシ−３−プロピルアセトフェ
ノン 142.8ｇを得た。このものをＤＭＦ1350mlに溶解
し、γ−ブロモ酪酸エチル 487.7ｇ及び無水炭酸カリウ
ム 138.2ｇを加えて室温下攪拌した。途中、無水炭酸カ
リウム69.1ｇを追加して室温下24時間攪拌した。反応液
を水6.75リットルに注加し、酢酸エチルで抽出（1.35リ
ットル×２）した。抽出液を飽和食塩水で洗浄（1.35リ
ットル×２）した後、無水硫酸ナトリウムにて乾燥し
た。溶媒及びγ−ブロモ酪酸エチルを減圧留去して赤褐
色油状の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］酪酸エチル 210.6ｇ
を得た。Reference Example 2 2,4-dihydroxy-3-
Propylacetophenone 97.2g, anhydrous potassium carbonate 69.1
g and 15.0 g of 1-bromo-3-chloropropane were added to 780 ml of acetone and stirred under reflux for 7 hours, then 34.6 g of anhydrous potassium carbonate was added and the reaction was continued for another 7 hours. After the inorganic substance was filtered off, the solvent was distilled off to obtain 142.8 g of 4- (3-chloropropoxy) -2-hydroxy-3-propylacetophenone. This was dissolved in 1350 ml of DMF, 487.7 g of ethyl γ-bromobutyrate and 138.2 g of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature. On the way, 69.1 g of anhydrous potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into 6.75 liters of water and extracted with ethyl acetate (1.35 liters × 2). The extract was washed with saturated saline (1.35 liter x 2) and then dried over anhydrous sodium sulfate. The solvent and ethyl γ-bromobutyrate were distilled off under reduced pressure to give red-brown oily ethyl 4- [6-acetyl-3- (3-chloropropoxy) -2-propylphenoxy] butyrate 210.6 g.
Got
【００１２】[0012]
【発明の効果】本発明により提供されるカルボン酸誘導
体は、抗アレルギー剤として有用なフェノキシアルキル
カルボン酸誘導体に変換できる。INDUSTRIAL APPLICABILITY The carboxylic acid derivative provided by the present invention can be converted into a phenoxyalkylcarboxylic acid derivative useful as an antiallergic agent.
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。］で表されるカルボ
ン酸誘導体。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 carboxylic acid derivative represented by these.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16635493A JPH06345682A (en) | 1993-06-11 | 1993-06-11 | Carboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16635493A JPH06345682A (en) | 1993-06-11 | 1993-06-11 | Carboxylic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06345682A true JPH06345682A (en) | 1994-12-20 |
Family
ID=15829833
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16635493A Pending JPH06345682A (en) | 1993-06-11 | 1993-06-11 | Carboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06345682A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
-
1993
- 1993-06-11 JP JP16635493A patent/JPH06345682A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
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