JP3773064B2 - Process for producing phenoxyalkylcarboxylic acid derivatives - Google Patents
Process for producing phenoxyalkylcarboxylic acid derivatives Download PDFInfo
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- JP3773064B2 JP3773064B2 JP24463694A JP24463694A JP3773064B2 JP 3773064 B2 JP3773064 B2 JP 3773064B2 JP 24463694 A JP24463694 A JP 24463694A JP 24463694 A JP24463694 A JP 24463694A JP 3773064 B2 JP3773064 B2 JP 3773064B2
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- general formula
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- 0 CC(C(**)CC=C1*)=C1O Chemical compound CC(C(**)CC=C1*)=C1O 0.000 description 2
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【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。
【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。
【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。
【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。
【０００５】
即ち本発明は、一般式（１）
で表される化合物と、
一般式（２）
で表される化合物を加水分解して生成する一般式（３）
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）
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。
【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。
【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。
【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。
【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。
【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。
【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。[0001]
[Industrial application fields]
The present invention relates to a method for producing a phenoxyalkylcarboxylic acid derivative having a potent leukotriene antagonistic action and useful for the prevention and treatment of allergic diseases such as asthma.
[0002]
[Prior art]
The phenoxyalkylcarboxylic acid derivative can be derived by reacting the compounds represented by the following general formulas (1) and (3), but in the general formula (3), compounds in which X 1 is a sulfur atom are not suitable. It is a stable substance, and when this compound is isolated and used in a reaction, it easily forms a dimer, resulting in a decrease in the yield and quality of the target compound represented by the following general formula (4). It was.
[0003]
[Problems to be solved by the invention]
The object of the present invention is to suppress dimerization of a compound in which X 1 is a sulfur atom in the general formula (3), and to industrially produce the compound of the general formula (4) simply and with high quality and high purity. It is to provide an advantageous synthesis method.
[0004]
[Means for Solving the Problems]
As a result of extensive research on the industrial production method of the phenoxyalkylcarboxylic acid derivative, the compound of the general formula (1) was added without isolating the compound of the general formula (3), and the general formula (4) It was found that the above compound can be easily obtained with high purity and high yield, and the present invention has been completed.
[0005]
That is, the present invention relates to the general formula (1)
A compound represented by
General formula (2)
General formula (3) produced by hydrolysis of a compound represented by
The compound represented by the general formula (4) is reacted at 1 pot without isolation.
Is a process for producing a phenoxyalkylcarboxylic acid derivative represented by the formula:
[0006]
Typically, the compound represented by the general formula (2) is treated with an appropriate base, preferably sodium hydroxide or potassium hydroxide, in an appropriate solvent such as water or hydrous alcohol at room temperature to the boiling point of the solvent. Thus, 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 and reacted at 1 pot without isolating the compound. The compound represented by (4) can be easily obtained with high purity and high yield.
In addition, the compound represented by the general formula (1) can be added to the reaction system in advance.
[0007]
The compound represented by the general formula (1) can be synthesized by the method described in Japanese Patent Application No. 5-166354, and the compound represented by the general formula (3) can be synthesized by the method described in JP-A-2-14659.
[0008]
【Example】
EXAMPLES The present invention will be further described below with reference to examples. However, the present invention is not limited to these examples.
[0009]
(Example 1)
N, N-dimethylthiocarbamic acid S- (4-acetyl-3-hydroxy-2-propylphenyl) ester (10 g), potassium hydroxide (10 g) and water (55 ml) were mixed and stirred at 95 ° C. for 1.5 hours under a nitrogen stream. At 35 to 40 ° C., 12.7 g of 4- [6-acetyl-3- (3-chloropropoxy) -2-propylphenoxy] butyric acid was added to the reaction solution, and stirred at the same temperature for 21 hours under a nitrogen stream. Under water cooling, the solution was acidified with 68% acetic acid (pH 4-5) and extracted with ethyl acetate (45 ml × 2). The ethyl acetate layer was washed with saturated brine (45 ml × 2), and then the solvent was distilled off under reduced pressure. The residue was dissolved in 190 ml of methanol, treated with activated carbon, crystallized by adding 95 ml of water, and crude brown 4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenyl) 25 g (wet weight) of (thio) 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 in the form of white powder. Phenoxy] butyric acid (15.2 g) was obtained.
[0010]
(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 3.57 g Then, 3.37 g of potassium hydroxide was added to 34.0 ml of 10% ethanol and stirred for 2.5 hours under reflux. After cooling with water, 10 ml of water was added to the reaction solution and washed with ethyl acetate (15 ml × 2). The aqueous layer was adjusted to pH 4-5 with concentrated hydrochloric acid and extracted with ethyl acetate (15 ml × 2). The extract was washed with saturated brine (15 ml × 2), and 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 crystallized by adding 27 ml of water. Precipitated crystals were collected by filtration and dried to give a slightly brown crude crystal 4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propylphenoxy] butyric acid. 3.92 g was obtained.
[0011]
【The invention's effect】
Phenoxyalkylcarboxylic acid derivatives useful as antiallergic agents can be easily obtained in high purity and high yield by 1pot reaction in which the compound of general formula (1) is added without isolating the compound of general formula (3) .
Claims (1)
で表される化合物と、
一般式（２）
で表される化合物を加水分解して生成する一般式（３）
で表される化合物を、単離することなく１pot で上記の加水分解に続いて反応させるか、加水分解と同時に反応させることを特徴とする、一般式（４）
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。General formula (1)
A compound represented by
General formula (2)
General formula (3) produced by hydrolysis of a compound represented by
The compound represented by either reacted following the above hydrolysis in 1pot without isolation, is characterized by simultaneously reacting with the hydrolysis, the general formula (4)
The manufacturing method of the phenoxyalkyl carboxylic acid derivative represented by these.
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 JPH0881412A (en) | 1996-03-26 |
| JP3773064B2 true 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) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7060854B2 (en) * | 2003-06-24 | 2006-06-13 | Medicinova, Inc. | Process for making polymorphic form A of 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid |
| US7064146B2 (en) * | 2003-06-24 | 2006-06-20 | 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 |
-
1994
- 1994-09-13 JP JP24463694A patent/JP3773064B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0881412A (en) | 1996-03-26 |
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