【発明の詳細な説明】[Detailed description of the invention]
本発明は次の一般式〔〕で表わされる文献未
載の新規物質である4′，５―ジ置換―３―ビフエ
ニリル酢酸エステルに関する。
ただし、R1は水素、低級アルコキシ又はハロ
ゲンを表わし、R2は水素、ハロゲン又はアミノ
基を表わし、R3は低級アルキルを表わす。
本発明化合物はこれをたとえばカセイアルカリ
と反応させることにより、容易に4′，５―ジ置換
―３―ビフエニリル酢酸に導くことができる。ま
た本発明化合物はたとえば相間移動触媒の存在下
にメチル化剤と反応させることにより２―（4′，
５―ジ置換―３―ビフエニリル）プロピオン酸エ
ステルに導くことができ、これをたとえばカセイ
カリと反応させることにより容易に２―（4′，５
―ジ置換―３―ビフエニリル）プロピオン酸に導
くことができる。このようにして得られる物質は
優れた抗炎症作用、鎮痛作用を有している。よつ
て本発明化合物は医薬品合成中間体として有用で
ある。なお本発明化合物から導かれる4′，５―ジ
置換―３―ビフエニリル酢酸の示す優れた薬理作
用を表１及び表２に示す。
The present invention relates to 4',5-disubstituted-3-biphenylylacetic acid ester, which is a new substance represented by the following general formula [] and which has not been described in any literature. However, R 1 represents hydrogen, lower alkoxy or halogen, R 2 represents hydrogen, halogen or an amino group, and R 3 represents lower alkyl. The compound of the present invention can be easily converted into 4',5-disubstituted-3-biphenylylacetic acid by reacting it with, for example, caustic alkali. Furthermore, the compounds of the present invention can be prepared by reacting with a methylating agent in the presence of a phase transfer catalyst, for example, to produce 2-(4',
2-(4',5
-disubstituted-3-biphenylyl)propionic acid. The substance thus obtained has excellent anti-inflammatory and analgesic effects. Therefore, the compounds of the present invention are useful as pharmaceutical synthesis intermediates. Tables 1 and 2 show the excellent pharmacological effects of 4',5-disubstituted-3-biphenylylacetic acid derived from the compounds of the present invention.
【表】【table】
【表】
本発明化合物は種々の方法によつて得ることが
できるが、たとえば次のような方法がある。
以下に本発明化合物の製造実施例を掲げ本発明
を一層明らかにする。
参考例
３―オキソ―５―（４―クロロフエニル）―
１―シクロヘキセン―１―イル酢酸メチルオキ
シムの製法
３―オキソ―５―（４―クロロフエニル）―１
―シクロヘキセン―１―イル酢酸メチル57.1ｇを
メタノール500mlに溶解し、ヒドロオキシルアミ
ン塩酸塩15.6ｇ及び酢酸ナトリウム16.99ｇを加
えて３時間加熱還流した。溶媒を留去し残渣をク
ロロホルムに溶かし、水、飽和水酸水素ナトリウ
ム、水の順に洗浄し、硫酸マグネシウムで乾燥し
た。溶媒を留去して粘ちような油として標題の化
合物60ｇを得た。
５―アセチルアミノ―4′―クロロ―３―ビフ
エニリル酢酸メチルの製法
上記で得られた化合物60ｇを無水酢酸42ｇ及
びピリジン16.3ｇの混合物に加え、80℃で30分間
撹拌した。冷却後アセチルクロリド32.3ｇを加え
90〜95℃で１時間加熱した。反応混合物を氷水に
あけ遊離した油を酢酸エチルで抽出した。抽出液
を水、飽和炭酸水素ナトリウム、水の順で洗浄
し、硫酸マグネシウムで乾燥した。酢酸エチルを
留去し赤褐色油状物を得る。これに少量の酢酸エ
チルを加え放置すると標題の化合物45ｇが結晶と
して得られた。
実施例 １
５―アセチルアミノ―4′―クロロ―３―ビフエ
ニリル酢酸メチル1.15ｇを濃塩酸30ml、メタノー
ル10mlの混合物に懸濁し、４時間加熱還流させた
後、冷却放置すると針状晶が析出する。これを
取し18％塩酸：メタノール＝９：１から再結晶
し、５―アミノ―4′―クロロ―３―ビフエニリル
酢酸メチル・塩酸塩、0.65ｇ、収率60％、融点
201〜202℃を白色結晶として得た。
元素分析値 C15H15NO2Cl2
計算値 Ｃ： 57.70 Ｈ：4.84 Ｎ：4.48 Cl：22.71
実験値 Ｃ： 57.29 Ｈ：4.79 Ｎ：4.46 Cl：22.97
同様の方法で以下の化合物を製造した。[Table] The compounds of the present invention can be obtained by various methods, including the following methods. The present invention will be further clarified with reference to production examples of the compounds of the present invention below. Reference example 3-oxo-5-(4-chlorophenyl)-
Method for producing methyloxime 1-cyclohexen-1-yl acetate 3-oxo-5-(4-chlorophenyl)-1
57.1 g of methyl -cyclohexen-1-yl acetate was dissolved in 500 ml of methanol, 15.6 g of hydroxylamine hydrochloride and 16.99 g of sodium acetate were added, and the mixture was heated under reflux for 3 hours. The solvent was distilled off, and the residue was dissolved in chloroform, washed successively with water, saturated sodium hydrogen hydroxide, and water, and dried over magnesium sulfate. Evaporation of the solvent gave 60 g of the title compound as a sticky oil. Method for producing methyl 5-acetylamino-4'-chloro-3-biphenylylacetate 60 g of the compound obtained above was added to a mixture of 42 g of acetic anhydride and 16.3 g of pyridine, and the mixture was stirred at 80° C. for 30 minutes. After cooling, add 32.3g of acetyl chloride.
Heated at 90-95°C for 1 hour. The reaction mixture was poured into ice water, and the liberated oil was extracted with ethyl acetate. The extract was washed with water, saturated sodium bicarbonate, and water in this order, and dried over magnesium sulfate. Ethyl acetate was distilled off to obtain a reddish brown oil. A small amount of ethyl acetate was added to this and the mixture was left to stand, yielding 45 g of the title compound as crystals. Example 1 1.15 g of methyl 5-acetylamino-4'-chloro-3-biphenylylacetate was suspended in a mixture of 30 ml of concentrated hydrochloric acid and 10 ml of methanol, heated to reflux for 4 hours, and then left to cool to precipitate needle-shaped crystals. . This was recrystallized from 18% hydrochloric acid: methanol = 9:1 to obtain methyl 5-amino-4'-chloro-3-biphenylylacetate hydrochloride, 0.65 g, yield 60%, melting point.
Obtained at 201-202°C as white crystals. Elemental analysis value C 15 H 15 NO 2 Cl 2 Calculated value C: 57.70 H: 4.84 N: 4.48 Cl: 22.71 Experimental value C: 57.29 H: 4.79 N: 4.46 Cl: 22.97 The following compounds were produced in a similar manner.
【表】
実施例 ２
５―アミノ―３―ビフエニリル酢酸メチル・塩
酸塩8.4ｇをジメチルホルムアミド90mlと濃塩酸
16mlの混合物に溶かし、これに亜硝酸ナトリウム
2.19ｇを水８mlに溶かしたものを０゜〜２℃で滴
下し３時間撹拌する。これにH3PO2 45mlを同温
で滴下し56時間０゜〜５℃で放置する。水70mlを
加え酢酸エチルで抽出し、水洗、硫酸マグネシウ
ムで乾燥する。溶媒を溜去し、得られた赤褐色油
を無水の18％メタノール性塩酸100mlと１時間加
熱した。メタノールを溜去し残渣を酢酸エチルに
溶かし、水洗、飽和炭酸水素ナトリウム水で洗
滌、再び水洗した後硫酸マグネシウムで乾燥す
る。酢酸エチルを溜去し赤褐色油6.0ｇを得る。
これをシリカゲルカラムクロマトグラフイーに付
し、ベンゼンで溶出し粗３―ビフエニリル酢酸メ
チル4.85ｇを得る。これを蒸溜して３―ビフエニ
リル酢酸メチル4.5ｇ、収率66％、沸点146〜
147.5℃（１mm）を無色油として得る。
元素分析値 C15H14O2
計算値 Ｃ：79.62 Ｈ：6.24
実験値 Ｃ：79.68 Ｈ：6.16
同様の方法で以下の化合物を製造した。[Table] Example 2 8.4 g of methyl 5-amino-3-biphenylylacetate hydrochloride was mixed with 90 ml of dimethylformamide and concentrated hydrochloric acid.
Sodium nitrite dissolved in 16ml of the mixture
A solution of 2.19 g dissolved in 8 ml of water was added dropwise at 0° to 2°C and stirred for 3 hours. 45 ml of H 3 PO 2 was added dropwise to this at the same temperature and left at 0° to 5° C. for 56 hours. Add 70 ml of water, extract with ethyl acetate, wash with water, and dry with magnesium sulfate. The solvent was distilled off and the resulting reddish-brown oil was heated with 100 ml of anhydrous 18% methanolic hydrochloric acid for 1 hour. Methanol is distilled off, and the residue is dissolved in ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, washed again with water, and dried over magnesium sulfate. Ethyl acetate was distilled off to obtain 6.0 g of reddish brown oil.
This was subjected to silica gel column chromatography and eluted with benzene to obtain 4.85 g of crude methyl 3-biphenylylacetate. This was distilled to yield 4.5 g of methyl 3-biphenylylacetate, yield 66%, boiling point 146~
Obtained at 147.5°C (1 mm) as a colorless oil. Elemental analysis value C 15 H 14 O 2 Calculated value C: 79.62 H: 6.24 Experimental value C: 79.68 H: 6.16 The following compounds were produced in a similar manner.
【表】
実施例 ３
濃塩酸46ml、塩化第２銅7.6ｇ、銅3.6ｇ及び水
17mlの混合物を90゜〜100℃で２時間加熱撹拌し
暗緑色溶液を得た。冷却後塩化カリウム12.9ｇを
水22mlに溶かして加えると淡緑色の溶液となり白
色の沈でんを生じる。別に５―アミノ―３―ビフ
エニリル酢酸メチル塩酸塩12ｇをアセトン85mlと
濃塩酸85mlに懸濁し０゜―５℃で亜硝酸ナトリウ
ム3.3ｇを水10mlに溶かしてこれに加えてジアゾ
化する。前者の溶液に後者のジアゾニウム塩の溶
液を室温で加え２時間撹拌後30分加熱、撹拌し
た。冷後クロロホルムで生成物を抽出し、水洗し
硫酸マグネシウムで乾燥した。クロロホルムを溜
去し暗褐色油8.0ｇを得る。これを無水の18％塩
酸―メタノール200mlに溶かし２時間、還流後メ
タノールを溜去し、残渣を酢酸エチルに溶かし、
水洗飽和炭酸水素ナトリウム水溶液で洗滌し再び
水洗し、硫酸マグネシウムで乾燥する。酢酸エチ
ルを溜去し赤色油7.4ｇを得る。これをシリカゲ
ルカラムクロマトグラフイーに付しｎ―ヘキサ
ン：ベンゼン＝１：１で溶出し、無色油として粗
製の５―クロロ―３―ビフエニリル酢酸メチル
5.7ｇを得る。これを蒸溜して５―クロロ―３―
ビフエニリル酢酸メチル5.4ｇ、収率48％、沸点
172〜175℃（２mm）を得る。
元素分析値 C15H13O2Cl
計算値 Ｃ：69.10 Ｈ：5.03 Cl：13.60
実験値 Ｃ：69.07 Ｈ：4.93 Cl：13.64
同様の方法で以下の化合物を製造した。[Table] Example 3 46 ml of concentrated hydrochloric acid, 7.6 g of cupric chloride, 3.6 g of copper, and water
17ml of the mixture was heated and stirred at 90° to 100°C for 2 hours to obtain a dark green solution. After cooling, add 12.9 g of potassium chloride dissolved in 22 ml of water to form a pale green solution and a white precipitate. Separately, 12 g of methyl 5-amino-3-biphenylylacetate hydrochloride was suspended in 85 ml of acetone and 85 ml of concentrated hydrochloric acid, and diazotized by adding 3.3 g of sodium nitrite dissolved in 10 ml of water at 0°-5°C. The latter diazonium salt solution was added to the former solution at room temperature, stirred for 2 hours, and then heated and stirred for 30 minutes. After cooling, the product was extracted with chloroform, washed with water, and dried over magnesium sulfate. The chloroform was distilled off to obtain 8.0 g of a dark brown oil. This was dissolved in 200 ml of anhydrous 18% hydrochloric acid-methanol and refluxed for 2 hours, then the methanol was distilled off, and the residue was dissolved in ethyl acetate.
Wash with water, wash with saturated aqueous sodium bicarbonate solution, wash again with water, and dry with magnesium sulfate. Ethyl acetate was distilled off to obtain 7.4 g of red oil. This was subjected to silica gel column chromatography, eluted with n-hexane:benzene = 1:1, and crude methyl 5-chloro-3-biphenylylacetate was obtained as a colorless oil.
Obtain 5.7g. Distill this to give 5-chloro-3-
Methyl biphenylylacetate 5.4g, yield 48%, boiling point
Obtain 172-175°C (2 mm). Elemental analysis value C 15 H 13 O 2 Cl Calculated value C: 69.10 H: 5.03 Cl: 13.60 Experimental value C: 69.07 H: 4.93 Cl: 13.64 The following compounds were produced in a similar manner.
【表】
実施例 ４
５―アミノ―３―ビフエニリル酢酸メチル・塩
酸塩13ｇに43％ホウフツ化水素酸水溶液91mlを加
え０゜〜５℃で10分間撹拌後、亜硝酸ナトリウム
4.8ｇを水19mlに溶かして約５分間で滴下後、同
温で20分間撹拌した。析出晶を取し氷水で洗滌
後、減圧下に五酸リンを乾燥剤として２日間乾燥
し淡茶色結晶13.5ｇを得る。これを油浴上30分間
80℃〜140℃で加熱分解し黒色溶液を得る。生成
物をクロロホルムで抽出し水洗、硫酸マグネシウ
ムで乾燥する。クロロホルムを溜去し黒色油8.2
ｇを得る。これをシリカゲルカラムクロマトグラ
フイーに付しベンゼンで溶出し粗５―フルオロ―
３―ビフエニリル酢酸メチル5.7ｇを得る。これ
を蒸溜して５―フルオロ―３―ビフエニリル酢酸
メチル4.55ｇ、収率39％、沸点156〜158℃（３
mm）を無色油として得る。
元素分析値 C15H13O2F
計算値 Ｃ：73.76 Ｈ：5.36 Ｆ：7.78
実験値 Ｃ：73.85 Ｈ：5.57 Ｆ：7.62
同様の方法で次の化合物を製造した。[Table] Example 4 91 ml of 43% hydroborofluoric acid aqueous solution was added to 13 g of methyl 5-amino-3-biphenylylacetate hydrochloride, and after stirring at 0° to 5°C for 10 minutes, sodium nitrite was added.
4.8 g was dissolved in 19 ml of water and added dropwise over about 5 minutes, followed by stirring at the same temperature for 20 minutes. The precipitated crystals were collected, washed with ice water, and dried for 2 days under reduced pressure using phosphorus pentate as a drying agent to obtain 13.5 g of pale brown crystals. Leave this on an oil bath for 30 minutes.
Thermal decomposition is performed at 80°C to 140°C to obtain a black solution. The product was extracted with chloroform, washed with water, and dried over magnesium sulfate. Distilled chloroform to produce black oil 8.2
get g. This was subjected to silica gel column chromatography, eluted with benzene, and the crude 5-fluoro-
5.7 g of methyl 3-biphenylylacetate is obtained. This was distilled to obtain 4.55 g of methyl 5-fluoro-3-biphenylylacetate, yield 39%, boiling point 156-158℃ (3
mm) as a colorless oil. Elemental analysis values C 15 H 13 O 2 F Calculated values C: 73.76 H: 5.36 F: 7.78 Experimental values C: 73.85 H: 5.57 F: 7.62 The following compounds were produced in a similar manner.
【表】【table】