JPS599555B2 - P- Chikanstiril Yudou Taino Seizouhouhou - Google Patents
P- Chikanstiril Yudou Taino SeizouhouhouInfo
- Publication number
- JPS599555B2 JPS599555B2 JP7778174A JP7778174A JPS599555B2 JP S599555 B2 JPS599555 B2 JP S599555B2 JP 7778174 A JP7778174 A JP 7778174A JP 7778174 A JP7778174 A JP 7778174A JP S599555 B2 JPS599555 B2 JP S599555B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- substituted
- yudou
- seizouhouhou
- chikanstiril
- 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.)
- Expired
Links
Description
【発明の詳細な説明】
本発明は、炎症を抑制する作用を有する新規な４−置換
フェニル脂肪酸を製造する際有用な中間原料となる。DETAILED DESCRIPTION OF THE INVENTION The present invention provides a useful intermediate material for producing a novel 4-substituted phenyl fatty acid having an anti-inflammatory effect.
一般式（■） Ｘ−ＣＨ＝ＣＨ０Ｃ０ＣＨ３（■） （但し、Ｘはｕ又はｎ を示す。General formula (■) X-CH=CH0C0CH3 (■) (However, X represents u or n.
）で表わされるｐ−置換スチリル誘導体の製造方法に関
するものである。) The present invention relates to a method for producing a p-substituted styryl derivative represented by:
従来、炎症を抑制する作用を有する一群の化合物として
、下記の一般式ＧＡ０〒Ｈ−Ｃ０ｏＨ
（但し、Ａは酸素原子、イミノ基を示し、Ｂは水素原子
、低級アルキル基を示す。Conventionally, compounds having the following general formula GA0〒H-C0oH (where A represents an oxygen atom or an imino group, and B represents a hydrogen atom or a lower alkyl group) are used as a group of compounds having an effect of suppressing inflammation.
）で表わされる４−置換フェニル脂肪酸類が抗炎症剤と
して知られている。4-substituted phenyl fatty acids represented by ) are known as anti-inflammatory agents.
本発明者等は、抗炎症剤として新規な化学構造を有した
４−置換フェニル脂肪酸類の開発研究を行なつてきたが
、上記一般式に組み込まれている酸素原子、イミノ基等
の代りに、これらの原子と異なり且つ等電子的な置換基
で置換された化合物に着目し、上記一般式中、Ａの置換
基として、ビニール基を基本骨格にした置換ビニール基
を採用し、該化合物中に置換ビニール基を導入する方法
につき、鋭異研究した結果、その有用な中間原料となる
置換ビニール基を有したｐ一置換スチリル誘導体を工業
的に有利に製造する本発明を完成するに至つたのである
。The present inventors have been conducting research on the development of 4-substituted phenyl fatty acids with novel chemical structures as anti-inflammatory agents. , focused on compounds substituted with isoelectronic substituents different from these atoms, and adopted a substituted vinyl group with a vinyl group as the basic skeleton as the substituent for A in the above general formula, and in the compound. As a result of intensive research into methods for introducing substituted vinyl groups into , we have completed the present invention, which enables industrially advantageous production of p-substituted styryl derivatives having substituted vinyl groups, which serve as useful intermediate raw materials. It is.
即ち、本発明は、一般式（１） （但し、Ｘは前記一般式（）と同じ。That is, the present invention provides general formula (1) (However, X is the same as the above general formula ().
）で表わされるβ一置換アクリル酸に、一般式（）（但
し、Ｙは無機酸イオンを示す。) to the β-monosubstituted acrylic acid represented by the general formula ( ) (where Y represents an inorganic acid ion.
）で表わされる４−７置換フエニルジアゾニウム塩を縮
合反応せしめ、一般式（）（但し、Ｘは前記一般式（）
に同じ。) is subjected to a condensation reaction with a 4-7 substituted phenyldiazonium salt represented by the general formula () (where X is the general formula ()).
Same as .
）で表わされるｐ一置換スチリル誘導体を製造すること
を特徴とする。) is characterized in that it produces a p-monosubstituted styryl derivative represented by:
本発明の実施に当つて一般式（１）の化合物と一般式（
）の化合物の反応は、メヤバイン縮合の条件下にて行な
われる。In carrying out the present invention, a compound of general formula (1) and a compound of general formula (
) The reaction of the compound is carried out under Meyabain condensation conditions.
メヤバイン反応は、銅塩、例えば塩化第二銅等を触媒と
してジアゾニウム塩によるオレフイン化合物のアリール
化反応である。本発明の方法に於ては、オレフイン化合
物として、β一置換アクリル酸誘導体が用いられ、又ジ
アゾニウム塩としては、アシル基で置換された芳香族ジ
アゾニウム塩が用いられる。The Meyerbain reaction is an arylation reaction of an olefin compound with a diazonium salt using a copper salt such as cupric chloride as a catalyst. In the method of the present invention, a β-monosubstituted acrylic acid derivative is used as the olefin compound, and an aromatic diazonium salt substituted with an acyl group is used as the diazonium salt.
後者は対応するアミンのジアゾ化により、容易に合成さ
れる。本発明は下記に示すような方法で実施される。対
応する芳香族アミンを２．５〜３．０当量の塩酸或いは
臭化水素水溶液にて溶解し、氷冷下、亜硝酸ナトリウム
を加えてジアゾ化を行なう。場合によつては、過剰の亜
硝酸ナトリウムはスルフアミン酸或いは尿素にて除去す
る。The latter is easily synthesized by diazotization of the corresponding amine. The present invention is carried out in the manner described below. The corresponding aromatic amine is dissolved in 2.5 to 3.0 equivalents of hydrochloric acid or hydrogen bromide aqueous solution, and diazotization is performed by adding sodium nitrite under ice cooling. In some cases, excess sodium nitrite is removed with sulfamic acid or urea.
次いで酢酸ソーダを加えてＰＨ３〜４に調整後、β一置
換アクリル酸誘導体を水或いはアセトンに溶解させた溶
液に加える。ＰＨの調整とβ一置換アクリル酸誘導体の
添加の順序は逆であつてもよい。溶媒として水或いはア
セトンに、原料が難溶性を示す時は、アセトニトリル、
ジメチルスルホキシド、スルホラン等が用いられる。上
記混液に塩化或いは臭化第二銅を原料β一置換アクリル
酸誘導体に対し０．０５〜０．５倍モル加え、必要なら
ば混液を均一にするために更に溶媒が追加される。窒素
ガスが直ちに発生し始めるが、そのまま２５℃以下にて
攪拌を一昼夜続ける。この際強く冷却すると、反応が遅
くなるため注意を要する。窒素ガスの発生が止んだら、
アセトン等の溶媒を減圧留去するか或いは水蒸気蒸留に
て副生成物を除く。生成物は水と混和しない溶剤で抽出
し、生成物の単離は蒸留によるか、蒸留が出来なければ
、アルミナカラムクロマトグラフイ一などの操作によつ
て行なわれる。以上の操作にて得た粗物質は、石油エー
テル、四塩化炭素、ベンゼン等の有機溶剤にて晶出され
る。Next, sodium acetate is added to adjust the pH to 3 to 4, and then added to a solution in which the β-monosubstituted acrylic acid derivative is dissolved in water or acetone. The order of adjusting the pH and adding the β-monosubstituted acrylic acid derivative may be reversed. When the raw material is poorly soluble in water or acetone as a solvent, acetonitrile,
Dimethyl sulfoxide, sulfolane, etc. are used. Cupric chloride or bromide is added to the above mixed solution in an amount of 0.05 to 0.5 times the mole of the starting material β-monosubstituted acrylic acid derivative, and if necessary, a solvent is added to make the mixed solution uniform. Nitrogen gas begins to be generated immediately, but stirring is continued at 25° C. or lower all day and night. Care must be taken at this time, as strong cooling will slow down the reaction. Once the nitrogen gas generation has stopped,
By-products are removed by distilling off the solvent such as acetone under reduced pressure or by steam distillation. The product is extracted with a water-immiscible solvent, and the product is isolated by distillation or, if distillation is not possible, by an operation such as alumina column chromatography. The crude substance obtained by the above operation is crystallized from an organic solvent such as petroleum ether, carbon tetrachloride, or benzene.
本発明によつて得た一般式（）の化合物は例えば、クロ
ル酢酸エステルとを反応しグリシド酸エステルとしこれ
を加水分解し、開環脱炭酸して得た対応するアルデヒド
を酸化することにより、で表わされる４置換フエニルプ
ロピオン酸を得ることができる。The compound of the general formula () obtained by the present invention can be obtained by, for example, reacting with chloroacetic ester to form a glycidic acid ester, hydrolyzing this, and oxidizing the corresponding aldehyde obtained by ring-opening decarboxylation. It is possible to obtain a 4-substituted phenylpropionic acid represented by
この物は優れた抗炎症作用を有する。即ち一例をあげる
と、ラツト後肢足うら（足踏）皮下におけるカラゲニン
誘起浮腫の抑制効果において（）式の化合物は経口投与
で顕著な効果を示した。（Ｅ）−２−〔ｐ−（β−２チ
エニルビニル）フエニル〕プロピオン酸の上記カラゲニ
ン誘起浮腫の抑制のＥＤ，Ｏ値は２３〜／Ｋｇであり、
イブプロフエンと同等ないし２倍の消炎性を示す。従つ
て本発明は一般式（）の化合物製造の中間体の製造方法
を提供する点で有用である。以下実施例にて本発明を説
明する。This product has excellent anti-inflammatory properties. That is, to give one example, the compound of formula () showed a remarkable effect in suppressing carrageenan-induced edema in the subcutaneous hind paw pads (steps) of rats when administered orally. The ED,O value of (E)-2-[p-(β-2thienylvinyl)phenyl]propionic acid for inhibiting the carrageenan-induced edema is 23 ~/Kg,
Shows anti-inflammatory properties equivalent to or twice that of ibuprofen. Therefore, the present invention is useful in that it provides a method for producing an intermediate for producing the compound of general formula (). The present invention will be explained below with reference to Examples.
実施例 １
２−（ｐ−アセチルスチリル）−フランの製造ｐ−アミ
ノアセトフエノン１８．１８７、濃塩酸３６ＣＣ及び水
３６７との混合物に、最小量の水に溶解させた亜硝酸ナ
トリウム９．３ｙを加えて氷冷し、攪拌下ジアゾ化する
。Example 1 Preparation of 2-(p-acetylstyryl)-furan 9.3 y of sodium nitrite dissolved in a minimum amount of water in a mixture of 18.187 cc of p-aminoacetophenone, 36 cc of concentrated hydrochloric acid and 367 cc of water. was added, cooled on ice, and diazotized with stirring.
ジアゾ化溶液へ２０７のβ−２−フリルアクリル酸の１
２７ＣＣのアセトン溶解溶液を加える。ついで酢酸ソー
ダ２５．４ｙを水１０ＣＣに溶かした水溶液及び塩化第
二銅５．６７を加えるとガスを発生し反応が進行する。
冷時一昼夜攪拌後、アセトンを留去し、ベンゼン抽出す
る。ベンゼン層はアルカリ水溶液と振盪後、水洗し、乾
燥（Ｎａ２ＳＯ４）する。乾燥剤を沢過後、溶剤を留去
して得た物質は、展開溶媒にベンゼンを用いてアルミナ
カラムクロマトグラフイ一にて精製する。融 点 １４
６℃（ベンゼン）
ＩＲｖｃｍ−１ ；１６８０（ＣＯ）
ＮＭＲ（ＣＤＣｌ３）δ；２．５６（３Ｈ，．ｓ，．Ｃ
Ｈ３）６．３６〜８．１６（９Ｈ．．ｍ１オレフインフ
エニル一Ｈ）実施例 ２
２−（Ｐ−アセチルスチリル）−チオフエンの製造β−
２−フリルアクリル酸の代りにβ−２−チエニルアクリ
ル酸１０７を用い、実施例１と同様の方法で本化合物は
合成される。1 of 207 β-2-furyl acrylic acid into the diazotization solution
Add 27 CC of acetone dissolution solution. Next, an aqueous solution of 25.4 y of sodium acetate dissolved in 10 cc of water and 5.67 y of cupric chloride are added to generate gas and the reaction proceeds.
After stirring all day and night in the cold, the acetone was distilled off and the mixture was extracted with benzene. The benzene layer is shaken with an alkaline aqueous solution, washed with water, and dried (Na2SO4). After filtering off the desiccant, the solvent is distilled off, and the resulting material is purified by alumina column chromatography using benzene as a developing solvent. Melting point 14
6℃ (benzene) IRvcm-1; 1680 (CO) NMR (CDCl3) δ; 2.56 (3H, .s, .C
H3) 6.36-8.16 (9H..m1 olefin phenyl-H) Example 2 Production of 2-(P-acetylstyryl)-thiophene β-
This compound is synthesized in the same manner as in Example 1, using β-2-thienyl acrylic acid 107 instead of 2-furyl acrylic acid.
融 点 １２８℃（ベンゼン）Melting point 128℃ (benzene)
Claims (1)
数式、化学式、表等があります▼を示す。 で表わされるβ−置換アクリル酸に 一般式（II） ▲数式、化学式、表等があります▼（II）（但し、Ｙは
無機酸イオンを示す。 ）で表わされる４−置換フェニルジアゾニウム塩を縮合
反応させる一般式（III） ▲数式、化学式、表等があります▼（III）（但し、Ｘ
は前記一般式（ I ）に同じ。 ）で表わされるｐ−置換スチリル誘導体の製造方法。[Claims] 1 General formula (I)
There are mathematical formulas, chemical formulas, tables, etc. Showing ▼. β-substituted acrylic acid is condensed with a 4-substituted phenyldiazonium salt represented by the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (where Y represents an inorganic acid ion) General formula for reaction (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (However, X
is the same as the general formula (I) above. ) A method for producing a p-substituted styryl derivative represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7778174A JPS599555B2 (en) | 1974-07-09 | 1974-07-09 | P- Chikanstiril Yudou Taino Seizouhouhou |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7778174A JPS599555B2 (en) | 1974-07-09 | 1974-07-09 | P- Chikanstiril Yudou Taino Seizouhouhou |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS51125049A JPS51125049A (en) | 1976-11-01 |
| JPS599555B2 true JPS599555B2 (en) | 1984-03-03 |
Family
ID=13643497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7778174A Expired JPS599555B2 (en) | 1974-07-09 | 1974-07-09 | P- Chikanstiril Yudou Taino Seizouhouhou |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS599555B2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60181049U (en) * | 1984-05-10 | 1985-12-02 | 九州日本電気株式会社 | Bending mold for semiconductor devices |
| JPS63196067A (en) * | 1987-02-10 | 1988-08-15 | Toshiba Corp | Method and device for molding lead of semiconductor device |
| JPH0368536B2 (en) * | 1985-11-21 | 1991-10-28 | Yamada Seisakusho Kk | |
| JPH0588548B2 (en) * | 1986-06-24 | 1993-12-22 | Nippon Electric Co | |
| CN1332166C (en) * | 2004-06-14 | 2007-08-15 | 三洋电机株式会社 | Refrigeration storage warehouse |
-
1974
- 1974-07-09 JP JP7778174A patent/JPS599555B2/en not_active Expired
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60181049U (en) * | 1984-05-10 | 1985-12-02 | 九州日本電気株式会社 | Bending mold for semiconductor devices |
| JPH0368536B2 (en) * | 1985-11-21 | 1991-10-28 | Yamada Seisakusho Kk | |
| JPH0588548B2 (en) * | 1986-06-24 | 1993-12-22 | Nippon Electric Co | |
| JPS63196067A (en) * | 1987-02-10 | 1988-08-15 | Toshiba Corp | Method and device for molding lead of semiconductor device |
| CN1332166C (en) * | 2004-06-14 | 2007-08-15 | 三洋电机株式会社 | Refrigeration storage warehouse |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS51125049A (en) | 1976-11-01 |
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