JP3903213B2 - Method for producing 4-biphenylylacetic acid - Google Patents

Description

【０００７】
で表される４−ビフェニル−α−ヒドロキシ酢酸を還元することを特徴とする次式（Ｉ）：
【０００８】
【化１２】

【０００９】
で表される４−ビフェニリル酢酸の製造方法の提供にある。
この場合に、式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸は、例えば、次式（ＩＩＩ）：
【００１０】
【化１３】

【００１１】
（式中、Ｘはハロゲン原子を表し、ｎは１または２の整数を表す。）
で表される４−ハロゲン化アセチルビフェニルを、金属水酸化物による加水分解に付し得ることができる。更に別法としては、次式（ＩＶ）：
【００１２】
【化１４】

【００１３】
の４−ビフェニルアルデヒドを、相間移動触媒の存在下に、クロロホルムと金属水酸化物を反応させ、製造することもできる。
したがって、本発明の具体的態様としては、
▲１▼：式（ＩＩＩ）で表される４−ハロゲン化アセチルビフェニルを、金属水酸化物による加水分解に付し、式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸とし、次いでこれを還元することによる４−ビフェニリル酢酸の製造方法の提供；
▲２▼：式（ＩＶ）の４−ビフェニルアルデヒドを、相間移動触媒の存在下に、クロロホルムおよび金属水酸化物と反応させ、式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸とし、次いでこれを還元することによる４−ビフェニリル酢酸の製造方法の提供；
▲３▼：式（ＩＩＩ）で表される４−ハロゲン化アセチルビフェニルを、金属水酸化物による加水分解に付すことによる、式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸の製造方法の提供；
にある。
【００１４】
これらの本発明の方法を化学式で示せば以下の反応式に記載したようにまとめられる。（なお、反応式中、カッコ内の数字は工程ナンバーを表す。）
【００１５】
【化１５】

【００１６】
【発明の実施の形態】
以下に本発明を上記反応式の各工程を説明することにより詳細に説明する。
工程（１）は、式（ＩＩＩ）で表される４−ハロゲン化アセチルビフェニルを、金属水酸化物による加水分解に付し、式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸を製造する工程である。
この場合、式（ＩＩＩ）で表される４−ハロゲン化アセチルビフェニル中の定義Ｘとしては、塩素、臭素、フッ素、沃素等のハロゲン原子であり、特に塩素が好ましい。またｎは１または２の整数を表すが、通常ｎは１よりも２のほうが好ましい。本工程において好ましく使用されるそのような４−ハロゲン化アセチルビフェニルとしては、例えば、４−ジクロロアセチルビフェニル、４−クロロアセチルビフェニル、４−ジブロモアセチルビフェニル、４−ブロモアセチルビフェニル、４−ジフルオロアセチルビフェニル、４−フルオロアセチルビフェニル等を挙げることができる。
【００１７】
本反応は好ましくは適当な溶媒中、式（ＩＩＩ）の化合物を金属水酸化物と反応させることにより行われるが、そのような溶媒としては、かかる反応に直接の影響を与えないものであれば任意に選択することができ、具体的には、トルエン、ベンゼン等の芳香族炭化水素系溶媒、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、あるいは水が好ましく使用できる。
式（ＩＩＩ）の化合物と反応させる金属水酸化物としては、アルカリ金属水酸化物（例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等）またはアルカリ土類金属水酸化物（例えば、水酸化マグネシウム、水酸化カルシウム、水酸化バリウム等）を挙げることができるが、なかでも本工程においては水酸化リチウムを使用することで好結果を与える。
【００１８】
なお、本加水分解の工程においては金属水酸化物に代わる他の各種アルカリ加水分解も理論上可能であるが、例えば炭酸カリウム、テトラブチルアンモニウムハイドロキサイド等のアルカリを用いた加水分解では反応が進行しにくいことが判明した（後記実施例２〜５参照）。
本反応は、通常０℃〜用いる溶媒の沸点付近の温度、好ましくは２０℃〜７０℃の温度で行われ、反応時間は２〜４８時間、通常は８〜２４時間程度で完結する。なお、２０℃以下の反応温度では反応速度が遅く、また７０℃以上の反応温度では副反応が生じ易い。
本加水分解反応により、目的とする式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸は、自体公知の方法により反応溶液より結晶として単離することができる。
【００１９】
工程（２）は、式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸の別の製造工程であり、式（ＩＶ）の４−ビフェニルアルデヒドを、相間移動触媒の存在下に、クロロホルムと金属水酸化物を反応させ、式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸を製造する工程である。
反応に使用する相間移動触媒としては、テトラｎ−ブチルアンモニウムブロマイド、ベンジルトリエチルアンモニウムクロライドなどの四級アンモニウム塩、テトラｎ−ブチルホスホニウムブロマイドなどのホスホニウム塩が好ましく用いられる。かかる触媒の使用量は、４−ビフェニルアルデヒドに対して１〜２０重量％、好ましくは２〜１０重量％を添加するのが良く、１重量％より少ないと反応が遅く、また２０重量％を越えることは経済的でない。
クロロホルムと共に使用される金属水酸化物としては、例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等のアルカリ金属水酸化物または、水酸化マグネシウム、水酸化カルシウム、水酸化バリウム等のアルカリ土類金属水酸化物を挙げることができる。その使用量としては、４−ビフェニルアルデヒド１モルに対して４倍モル以上を必要とし、好ましくは５〜８倍モル用いるのが良い。
反応は、通常反応試薬となるクロロホルムを反応溶媒とし、これに水を加えた混合溶媒中行われるが、希釈溶媒として反応に直接の影響を与えないベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル系溶媒等の不活性溶媒を一緒に用いることもできる。
反応温度は、好ましくは５０℃〜使用溶媒の沸点付近の温度であり、温度が低いと反応速度が遅くなる傾向にある。
本反応においても、目的とする式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸は、自体公知の方法により反応溶液より結晶として単離することができる。
【００２０】
工程（３）は、各工程（１）または（２）により製造された式（ＩＩ）で表される４−ビフェニル−α−ヒドロキシ酢酸を還元し本発明の目的化合物である式（Ｉ）で表される４−ビフェニリル酢酸を製造する工程である。
本還元反応は、触媒を用いる接触還元、亜鉛、錫あるいはアルミニウム−ニッケル合金（ラネーニッケル）などの金属試薬を用いる還元で好ましく行うことができる。
接触還元の場合に使用する触媒としては、パラジウム−カーボン、パラジウム黒、白金黒等を挙げることができ、その使用量は４−ビフェニル−α−ヒドロキシ酢酸に対する重量比で１〜５０重量％、好ましくは３〜２０重量％の範囲である。なお、あまり触媒を多くするのは経済的ではなく、また触媒量が少ないと反応の完結までに時間がかかる。
反応温度は、一概に限定し得ないが、０℃〜１５０℃、好ましくは２０℃〜１２０℃であり、反応温度を高くすると、ビフェニル環までも還元されたビシクロヘキシル環を生成するので好ましいものではない。
【００２１】
本接触還元における反応圧は、常圧〜１００ｋｇ／ｃｍ² 、好ましくは常圧〜１０ｋｇ／ｃｍ² の範囲内である。あまり反応圧を高くするのは特別な反応設備を必要とし実用的ではなく、しかもビフェニル環までも還元されたビシクロヘキシル環を生成するので好ましいものではない。
反応時間は用いる触媒、その触媒量、反応圧力および反応温度により一概に限定し得ないが、通常は２〜２４時間で十分である。
本接触還元は溶媒を使用することなく行うこともできるが、反応を円滑に行うためには反応に直接の影響を与えない適切な溶媒中で行うのが好ましい。このような溶媒としては、メタノール、エタノール、イソプロパノール等のアルコール類、ジエチルエーテル、ジオキサン、テトラヒドロフラン等のエーテル類、蟻酸、酢酸などの有機酸を挙げることができる。
【００２２】
一方、金属試薬の中でも亜鉛、錫などの金属試薬を用いる還元により本工程を実施する場合には、４−ビフェニル−α−ヒドロキシ酢酸を適切な溶媒中に溶解させ、鉱酸、好ましくは塩酸の存在下に金属試薬を添加することにより行うことができる。この場合の金属試薬の使用量は、４−ビフェニル−α−ヒドロキシ酢酸１モルに対して１〜１０倍モル、好ましくは２〜５倍モル程度用いるのが良い。なお、反応溶液中に存在させる塩酸等の鉱酸の添加量としては、４−ビフェニル−α−ヒドロキシ酢酸１モルに対して１〜１００倍モル、好ましくは２〜１０倍モル程度の範囲内であるのが良い。
反応に用いられる溶媒としては、４−ビフェニル−α−ヒドロキシ酢酸を溶解させる溶媒が好ましく、そのような溶媒としては蟻酸、酢酸などの有機酸類が好ましく使用され、特に蟻酸が好ましい。しかしながら、懸濁状態であっても反応と共に生成される４−ビフェニリル酢酸を徐々に溶解していく溶媒であれば使用し得ることはいうまでもない。反応温度は室温〜反応混合物の還流温度付近で行われるのが良く、好ましくは８０℃〜１２０℃の範囲内で、より好ましくは使用する反応溶媒の沸点付近で行うのが良い。
【００２３】
また金属試薬として、アルミニウム−ニッケル合金（ラネーニッケル）の金属試薬を用いる還元の場合には、水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物の水溶液、好ましくは水酸化カリウム水溶液に還元すべき４−ビフェニル−α−ヒドロキシ酢酸を溶解させ、この溶解液中にラネーニッケルを少量ずつ添加していくのが良い。この場合のラネーニッケルの使用量は、４−ビフェニル−α−ヒドロキシ酢酸１モルに対して、５００〜１，５００ｇ程度用いるのが良い。反応温度は一概に限定し得ないが、反応溶液の還流温度付近で行うのが好ましい。
【００２４】
以上の反応により生成した４−ビフェニリル酢酸の単離は、反応溶液を濾過して触媒を除去した後、通常の抽出操作、濃縮操作、さらには必要により再結晶等の自体公知の操作により行われ、４−ビフェニリル酢酸を結晶として得ることができる。
【００２５】
なお、上記の工程において原料となる式（ＩＩＩ）で表される４−ハロゲン化アセチルビフェニルは、例えば塩化アルミニウム、塩化第二錫、四塩化チタン等のルイス酸、好ましくは塩化アルミニウムの存在下、ビフェニルとハロゲン化アセチルハライドとを反応させるフリーデル・クラフツ反応により得ることができるほか、４−アセチルビフェニルを塩素、臭素等でハロゲン化することにより得ることができる（後記製造例を参照）。
【００２６】
以下に本発明を製造例ならびに実施例によって更に詳細に説明するが、本発明はこれによってなんら限定されるものではない。
【製造例】
製造例１：４−ジクロロアセチルビフェニルの製造：
塩化アルミニウム８０．８ｇを塩化メチレン２００ｍｌ中に懸濁、撹拌させ、この懸濁液中にビフェニル７７．１ｇおよびジクロロアセチルクロライド８８．５ｇの塩化メチレン２００ｍｌ溶液を−１０℃で滴下した。同温度にて３時間反応させた後、水１０００ｍｌ中に反応溶液を注入し、撹拌した。塩化メチレン層を分取し、飽和炭酸水素ナトリウム水溶液で洗浄後、溶媒を減圧乾固した。残留物をイソプロパノールから再結晶し、４−ジクロロアセチルビフェニルを淡褐色結晶として１１２．５ｇ（収率：８４．９％）得た。融点：９０〜９１℃
ＩＲ（ＫＢｒ，ｃｍ^-1）：３０１２，１６９２，１６０３，１２３７，７９８
ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ₃ ），δ：６．７０（１Ｈ，ｓ，−ＣＨ−），７．３９−８．１７（９Ｈ，ｍ，芳香環水素）
【００２７】
製造例２：４−クロロアセチルビフェニルの製造：
製造例１において、ジクロロアセチルクロライドの代わりにクロロアセチルクロライドを用い、それ以外は製造例１と同様にして反応、処理し、４−クロロアセチルビフェニルを淡黄色結晶として１００．１ｇ（収率：８６．８％）得た。
融点：１２８〜１２９℃
ＩＲ（ＫＢｒ，ｃｍ^-1）：２９４５，１６９１，１６０４，１２１５，７６３
ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ₃ ），δ：４．７２（２Ｈ，ｓ，−ＣＨ₂ −），７．３７−８．０４（９Ｈ，ｍ，芳香環水素）
【００２８】
製造例３：４−ジブロモアセチルビフェニルの製造：
４−アセチルビフェニル [Loren M.Long, Henry R.Henze:J.Amer.Chem.Soc.,:63,1939(1940) の方法にい従い製造した］９８．１ｇを塩化メチレン５００ｍｌ中に溶解し、この溶液に臭素１５９．８ｇを０℃〜２０℃にて滴下した。同温度にて２時間反応を行った後、有機層を飽和炭酸水素ナトリウム水溶液で洗浄後、減圧濃縮乾固した。残留物をイソプロパノール−トルエン混合溶媒から再結晶し、４−ジブロモアセチルビフェニルを淡褐色結晶として１４７．６ｇ（収率：８３．４％）得た。融点：１１８〜１２０℃
ＩＲ（ＫＢｒ，ｃｍ^-1）：３０２０，１６８６，１６０１，１２０５，６９５
ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ₃ ），δ：６．７３（１Ｈ，ｓ，−ＣＨ−），７．３９−８．１９（９Ｈ，ｍ，芳香環水素）
【００２９】
【実施例】
実施例１：４−ビフェニル−α−ヒドロキシ酢酸の製造：
製造例１で得た４−ジクロロアセチルビフェニル７．９５ｇをトルエン４０ｍｌに溶解し、水酸化リチウム一水和物９．４４ｇの水４０ｍｌ溶液を加え、６０℃にて２４時間反応させた。反応終了後、析出した４−ビフェニル−α−ヒドロキシ酢酸のリチウム塩を濾取し、塩酸にて遊離酸とした後メチルエチルケトンで抽出した。抽出液を減圧濃縮乾固し、メチルエチルケトン−ｎ−ヘキサンから再結晶して、４−ビフェニル−α−ヒドロキシ酢酸を白色結晶として５．２８ｇ（収率：７７．１％）得た。融点：１９６〜１９８℃
ＩＲ（ＫＢｒ，ｃｍ^-1）：３４１５，１７０６，１０６２
ＮＭＲ（２７０ＭＨｚ，ＤＭＳＯ−ｄ₆ ），δ：５．０８（１Ｈ，ｓ，−ＣＨ−），５．８９（１Ｈ，ｓ，−ＯＨ），７．３３−７．７３（９Ｈ，ｍ，芳香環水素），１２．６６（１Ｈ，ｂｒ，−ＣＯＯＨ）
【００３０】
実施例２〜５：４−ビフェニル−α−ヒドロキシ酢酸の製造：
実施例１において、水酸化リチウム一水和物に代えて下記の各種アルカリを用い、実施例１と同様に反応処理し、４−ビフェニル−α−ヒドロキシ酢酸の白色結晶を得た。
それらの結果を以下にまとめる。

【００３１】
実施例６：４−ビフェニル−α−ヒドロキシ酢酸の製造：
実施例１において、４−ジクロロアセチルビフェニルの代わりに、４−クロロアセチルビフェニル６．９２ｇを用い、それ以外は実施例１と全く同様に反応処理を行い、４−ビフェニル−α−ヒドロキシ酢酸の白色結晶を３．３０ｇ（収率：４８．２％）得た。
このものの物性値は、実施例１で得たものと完全に一致した。
【００３２】
実施例７：４−ビフェニル−α−ヒドロキシ酢酸の製造：
実施例１において、４−ジクロロアセチルビフェニルの代わりに、４−ジブロモアセチルビフェニル１０．６２ｇを用い、それ以外は実施例１と全く同様に反応処理を行い、４−ビフェニル−α−ヒドロキシ酢酸の白色結晶を３．６６ｇ（収率：５３．５％）得た。
このものの物性値は、実施例１で得たものと完全に一致した。
【００３３】
実施例８：４−ビフェニル−α−ヒドロキシ酢酸の製造：
４−ビフェニルアルデヒド９１．１ｇをクロロホルム５００ｍｌ中に溶解させ、さらにテトラｎ−ブチルアンモニウムブロマイド１６ｇを加え、この溶液中に５０％水酸化ナトリウム水溶液２０ｇを５６℃で滴下した。同温度にて４時間反応させた後、濃塩酸３０ｍｌを注入して酸性とし、メチルエチルケトン５００ｍｌで抽出した。抽出液を減圧濃縮乾固し、メチルエチルケトン−ｎ−ヘキサンから再結晶して、４−ビフェニル−α−ヒドロキシ酢酸を白色結晶として８３．３ｇ（収率：７３．０％）得た。
このものの物性値は、実施例１で得たものと完全に一致した。
【００３４】
実施例９：４−ビフェニリル酢酸の製造：
５００ｍｌのオートクレーブに、４−ビフェニル−α−ヒドロキシ酢酸２２．８ｇ、イソプロパノール２００ｍｌおよび５％パラジウム−カーボン１．０ｇを仕込み、水素圧０．３ｋｇ／ｃｍ² とし、８０℃にて８時間還元反応を行った。反応終了後、触媒を濾過して除き、濾液を濃縮乾固した後、残留物をメチルエチルケトンから再結晶し、４−ビフェニリル酢酸を白色結晶として１４．１ｇ（収率：６６．４％）得た。融点：１６３〜１６４℃
ＩＲ（ＫＢｒ，ｃｍ^-1）：３４２６，１６９０，１２５９，９２９
ＮＭＲ（２７０ＭＨｚ，ＤＭＳＯ−ｄ₆ ），δ：３．６１（２Ｈ，ｓ，−ＣＨ₂ −），７．３１−７．６６（９Ｈ，ｍ，芳香環水素），１２．２９（１Ｈ，ｂｒ，−ＣＯＯＨ）
【００３５】
実施例１０：４−ビフェニリル酢酸の製造：
４−ビフェニル−α−ヒドロキシ酢酸２２．８ｇを蟻酸４００ｍｌに溶解させ、亜鉛末３２．６ｇを加え、この溶液に濃塩酸２００ｍｌを１００℃にて２時間かけて滴下した。滴下終了後、同温度にて２時間反応させ、メチルエチルケトン５００ｍｌを注入して不溶物を濾過した。有機層を水洗した後減圧乾固し、残留物をメチルエチルケトンから再結晶し、４−ビフェニリル酢酸を白色結晶として１６．７ｇ（収率：７８．７％）得た。
このものの物性値は、実施例９で得たものと完全に一致した。
【００３６】
実施例１１：４−ビフェニリル酢酸の製造：
４−ビフェニル−α−ヒドロキシ酢酸２２．８ｇを水酸化カリウム５６１ｇの水６００ｍｌ溶液に溶解させ、この溶液にラネーニッケル１００ｇを９０℃にて徐々に添加した。発泡が収まった後、１００℃にて２時間反応を行った。反応終了後、不溶物を濾過して除き、濾液に濃塩酸１２０ｍｌを注入し、析出した結晶を濾取し、４−ビフェニリル酢酸を白色結晶として１８．０ｇ（収率：８４．８％）得た。
このものの物性値は、実施例９で得たものと完全に一致した。
【００３７】
【発明の効果】
以上詳述したように、本発明は優れた消炎・鎮痛作用を有する４−ビフェニリル酢酸を容易に、かつ収率良く、工業的に製造し得る方法を提供するものであり、４−ビフェニリル酢酸の価格低減に大きく寄与する点で有用性が高く、産業上の利用価値は多大なものである。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing 4-biphenylylacetic acid useful as an anti-inflammatory / analgesic agent.
[0002]
[Prior art]
4-Biphenylylacetic acid is a compound widely used clinically as a compound having a strong anti-inflammatory / analgesic action. As a method for producing this 4-biphenylylacetic acid, the following methods have been proposed conventionally.
(A): A method of producing 4-biphenylylacetic acid by using 4-biphenylaldehyde as a raw material and subjecting it to each step of reduction / halogenation / cyanation / hydrolysis [German Patent No. 658114 (1936)].
(B): A method of producing 4-biphenylylacetic acid by Wilgerott reaction after biphenyl is used as a raw material to make 4-acetylbiphenyl by Friedel-Crafts reaction with acetic anhydride and aluminum chloride [E.Schwenk & D.Papa: J .Org.Chem., 11 , 798 (1946)].
(C): A method in which biphenyl is reacted with chloroacetic acid in the presence of ferric oxide and potassium bromide to produce 4-biphenylylacetic acid [Y. Ogata et al.,: J. Org. Chem., 16 , 239 (1951)].
(D): a method of hydrolyzing a reaction intermediate between an oxazine compound and a Grignard reagent of biphenyl to produce 4-biphenylylacetic acid [G.Ray Malone et al.,: J. Org. Chem., 39 , 618 ( 1974)].
(E): A method for producing 4-biphenylylacetic acid by subjecting an azlactone obtained by reacting 4-biphenylaldehyde with N-acylglycine in the presence of a base to a hydrolysis / decarboxylation step (special No. 62-45554).
[0003]
However, each of the above manufacturing methods has the following problems.
The method (A) is not preferable as an industrial production method of pharmaceuticals in that it uses a cyan compound which has a large number of steps and does not necessarily have a high reaction yield and is extremely toxic.
In the method (B), there are many by-products in the reaction step, and therefore it is difficult to obtain a high-purity product, and the reaction yield is inevitably poor. Furthermore, since a sulfur compound is used in the Wilgerott reaction, there is a problem of malodor.
The method (C) is an attractive method in that the desired 4-biphenylylacetic acid is obtained in a short process, but there are many reaction byproducts, the reaction yield is extremely low, and the reaction conditions are severe. Therefore, it is not suitable as an industrial production method.
The method (D) has a problem in the industrial use of the Grignard reagent and also has the problem that the raw material is expensive.
In the method (E), there are many by-products in the reaction process, and therefore a complicated operation must be required to obtain a highly pure product.
Therefore, the present condition is that establishment of the manufacturing method of 4-biphenylyl acetic acid which can manufacture on an industrial scale by which these problems were solved is requested | required.
[0004]
[Problems to be solved by the invention]
In view of the above situation, an object of the present invention is to provide a method capable of producing 4-biphenylylacetic acid on an industrial scale with good workability and high yield.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have found a method for producing 4-biphenylylacetic acid from an inexpensive raw material in good yield, and have completed the present invention.
That is, the present invention provides the following formula (II):
[0006]
Embedded image

[0007]
4-biphenyl-α-hydroxyacetic acid represented by the following formula (I):
[0008]
Embedded image

[0009]
It provides the manufacturing method of 4-biphenylyl acetic acid represented by these.
In this case, 4-biphenyl-α-hydroxyacetic acid represented by the formula (II) is, for example, the following formula (III):
[0010]
Embedded image

[0011]
(In the formula, X represents a halogen atom, and n represents an integer of 1 or 2.)
Can be subjected to hydrolysis with a metal hydroxide. Yet another alternative is the following formula (IV):
[0012]
Embedded image

[0013]
4-biphenylaldehyde can also be produced by reacting chloroform with a metal hydroxide in the presence of a phase transfer catalyst.
Therefore, as a specific aspect of the present invention,
{Circle around (1)} 4-halogenated acetylbiphenyl represented by the formula (III) is subjected to hydrolysis with a metal hydroxide to give 4-biphenyl-α-hydroxyacetic acid represented by the formula (II); Providing a method for producing 4-biphenylylacetic acid by reducing this;
{Circle around (2)} 4-biphenylaldehyde of formula (IV) is reacted with chloroform and a metal hydroxide in the presence of a phase transfer catalyst to give 4-biphenyl-α-hydroxyacetic acid represented by formula (II). And then providing a method for producing 4-biphenylylacetic acid by reducing it;
(3): Production of 4-biphenyl-α-hydroxyacetic acid represented by formula (II) by subjecting 4-halogenated acetylbiphenyl represented by formula (III) to hydrolysis with a metal hydroxide. Providing a method;
It is in.
[0014]
These methods of the present invention can be summarized by the chemical formula as described in the following reaction formula. (In the reaction formula, the number in parenthesis represents the process number.)
[0015]
Embedded image

[0016]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail by explaining each step of the above reaction formula.
In the step (1), 4-halogenated acetylbiphenyl represented by the formula (III) is subjected to hydrolysis with a metal hydroxide, and 4-biphenyl-α-hydroxyacetic acid represented by the formula (II) is converted. It is a manufacturing process.
In this case, the definition X in the 4-halogenated acetylbiphenyl represented by the formula (III) is a halogen atom such as chlorine, bromine, fluorine or iodine, and chlorine is particularly preferable. N represents an integer of 1 or 2, and usually n is preferably 2 rather than 1. Examples of such 4-halogenated acetylbiphenyl preferably used in this step include 4-dichloroacetylbiphenyl, 4-chloroacetylbiphenyl, 4-dibromoacetylbiphenyl, 4-bromoacetylbiphenyl, 4-difluoroacetylbiphenyl. , 4-fluoroacetylbiphenyl and the like.
[0017]
This reaction is preferably carried out by reacting the compound of formula (III) with a metal hydroxide in a suitable solvent, and as such a solvent, any solvent that does not directly affect the reaction can be used. Specifically, an aromatic hydrocarbon solvent such as toluene and benzene, an ether solvent such as diethyl ether, tetrahydrofuran and dioxane, or water can be preferably used.
As the metal hydroxide to be reacted with the compound of the formula (III), alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) or alkaline earth metal hydroxide (for example, hydroxide) Magnesium, calcium hydroxide, barium hydroxide, etc.) can be mentioned, and among these, good results are obtained by using lithium hydroxide in this step.
[0018]
In addition, in this hydrolysis process, various other alkali hydrolysiss in place of metal hydroxides are theoretically possible, but for example, hydrolysis using an alkali such as potassium carbonate or tetrabutylammonium hydroxide does not react. It was found that it was difficult to proceed (see Examples 2 to 5 below).
This reaction is usually carried out at a temperature of 0 ° C. to around the boiling point of the solvent used, preferably 20 ° C. to 70 ° C., and the reaction time is 2 to 48 hours, usually about 8 to 24 hours. It should be noted that the reaction rate is slow at a reaction temperature of 20 ° C. or lower, and a side reaction tends to occur at a reaction temperature of 70 ° C. or higher.
By this hydrolysis reaction, the desired 4-biphenyl-α-hydroxyacetic acid represented by the formula (II) can be isolated as crystals from the reaction solution by a method known per se.
[0019]
Step (2) is another production step of 4-biphenyl-α-hydroxyacetic acid represented by formula (II), and 4-biphenylaldehyde of formula (IV) is converted into chloroform in the presence of a phase transfer catalyst. And a metal hydroxide are reacted to produce 4-biphenyl-α-hydroxyacetic acid represented by the formula (II).
As the phase transfer catalyst used in the reaction, quaternary ammonium salts such as tetra n-butylammonium bromide and benzyltriethylammonium chloride, and phosphonium salts such as tetra n-butylphosphonium bromide are preferably used. The catalyst is used in an amount of 1 to 20% by weight, preferably 2 to 10% by weight, based on 4-biphenylaldehyde. If the amount is less than 1% by weight, the reaction is slow and exceeds 20% by weight. That is not economical.
Examples of the metal hydroxide used with chloroform include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, or alkaline earth metals such as magnesium hydroxide, calcium hydroxide and barium hydroxide. Mention may be made of metal hydroxides. As the amount of use, 4 times mol or more is required with respect to 1 mol of 4-biphenylaldehyde, and preferably 5 to 8 times mol is used.
The reaction is usually carried out in a mixed solvent in which chloroform as a reaction reagent is used as a reaction solvent and water is added to the reaction solvent, but as a diluent solvent, an aromatic hydrocarbon solvent such as benzene, toluene, xylene or the like that does not directly affect the reaction. Inert solvents such as ether solvents such as diethyl ether, tetrahydrofuran and dioxane can also be used together.
The reaction temperature is preferably 50 ° C. to around the boiling point of the solvent used, and the reaction rate tends to be slow when the temperature is low.
Also in this reaction, the target 4-biphenyl-α-hydroxyacetic acid represented by the formula (II) can be isolated as crystals from the reaction solution by a method known per se.
[0020]
In step (3), 4-biphenyl-α-hydroxyacetic acid represented by formula (II) produced by each step (1) or (2) is reduced, and the target compound of the present invention is formula (I). It is the process of manufacturing 4-biphenylyl acetic acid represented.
This reduction reaction can be preferably carried out by catalytic reduction using a catalyst or reduction using a metal reagent such as zinc, tin or an aluminum-nickel alloy (Raney nickel).
Examples of the catalyst used in the catalytic reduction include palladium-carbon, palladium black, platinum black and the like. The amount used is 1 to 50% by weight, preferably 1 to 50% by weight with respect to 4-biphenyl-α-hydroxyacetic acid. Is in the range of 3-20% by weight. It is not economical to add too much catalyst, and if the amount of catalyst is small, it takes time to complete the reaction.
Although the reaction temperature cannot be generally limited, it is 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C. If the reaction temperature is increased, a bicyclohexyl ring reduced to the biphenyl ring is preferably formed. is not.
[0021]
The reaction pressure in this catalytic reduction is from normal pressure to 100 kg / cm ² , preferably from normal pressure to 10 kg / cm ² . It is not preferable to increase the reaction pressure too much because it requires a special reaction facility and is impractical and produces a bicyclohexyl ring in which a biphenyl ring is reduced.
The reaction time cannot be generally limited by the catalyst used, the amount of the catalyst, the reaction pressure and the reaction temperature, but usually 2 to 24 hours is sufficient.
Although this catalytic reduction can be carried out without using a solvent, it is preferably carried out in an appropriate solvent that does not directly affect the reaction in order to carry out the reaction smoothly. Examples of such a solvent include alcohols such as methanol, ethanol and isopropanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, and organic acids such as formic acid and acetic acid.
[0022]
On the other hand, when this step is carried out by reduction using a metal reagent such as zinc or tin among metal reagents, 4-biphenyl-α-hydroxyacetic acid is dissolved in a suitable solvent, and a mineral acid, preferably hydrochloric acid, is dissolved. This can be done by adding a metal reagent in the presence. In this case, the metal reagent is used in an amount of 1 to 10 moles, preferably about 2 to 5 moles per mole of 4-biphenyl-α-hydroxyacetic acid. The amount of mineral acid such as hydrochloric acid to be present in the reaction solution is 1 to 100 times mol, preferably about 2 to 10 times mol per mol of 4-biphenyl-α-hydroxyacetic acid. There should be.
As a solvent used in the reaction, a solvent capable of dissolving 4-biphenyl-α-hydroxyacetic acid is preferable. As such a solvent, organic acids such as formic acid and acetic acid are preferably used, and formic acid is particularly preferable. However, it is needless to say that any solvent that gradually dissolves 4-biphenylylacetic acid produced along with the reaction can be used even in a suspended state. The reaction temperature is preferably from room temperature to the reflux temperature of the reaction mixture, preferably in the range of 80 ° C to 120 ° C, more preferably in the vicinity of the boiling point of the reaction solvent used.
[0023]
In the case of reduction using a metal reagent of an aluminum-nickel alloy (Raney nickel) as the metal reagent, it should be reduced to an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, preferably an aqueous potassium hydroxide solution. It is preferable to dissolve 4-biphenyl-α-hydroxyacetic acid and add Raney nickel to the solution little by little. The amount of Raney nickel used in this case is preferably about 500 to 1,500 g with respect to 1 mol of 4-biphenyl-α-hydroxyacetic acid. Although the reaction temperature cannot be generally limited, it is preferably carried out near the reflux temperature of the reaction solution.
[0024]
Isolation of 4-biphenylylacetic acid produced by the above reaction is carried out by a known operation such as normal extraction operation, concentration operation, and if necessary recrystallization after filtering the reaction solution to remove the catalyst. 4-biphenylylacetic acid can be obtained as crystals.
[0025]
The 4-halogenated acetylbiphenyl represented by the formula (III) as a raw material in the above step is, for example, a Lewis acid such as aluminum chloride, stannic chloride or titanium tetrachloride, preferably in the presence of aluminum chloride. In addition to the Friedel-Crafts reaction in which biphenyl is reacted with a halogenated acetyl halide, it can also be obtained by halogenating 4-acetylbiphenyl with chlorine, bromine or the like (see the production examples described later).
[0026]
Hereinafter, the present invention will be described in more detail with reference to production examples and examples, but the present invention is not limited thereto.
[Production example]
Production Example 1 Production of 4-dichloroacetylbiphenyl:
80.8 g of aluminum chloride was suspended in 200 ml of methylene chloride and stirred, and a solution of 77.1 g of biphenyl and 88.5 g of dichloroacetyl chloride in 200 ml of methylene chloride was added dropwise at -10 ° C. After reacting at the same temperature for 3 hours, the reaction solution was poured into 1000 ml of water and stirred. The methylene chloride layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated to dryness. The residue was recrystallized from isopropanol to obtain 112.5 g (yield: 84.9%) of 4-dichloroacetylbiphenyl as light brown crystals. Melting point: 90-91 ° C
IR (KBr, cm ⁻¹ ): 3012, 1692, 1603, 1237, 798
NMR (270 MHz, CDCl ₃ ), δ: 6.70 (1H, s, —CH—), 7.39-8.17 (9H, m, aromatic ring hydrogen)
[0027]
Production Example 2 : Production of 4-chloroacetylbiphenyl:
In Production Example 1, chloroacetyl chloride was used in place of dichloroacetyl chloride, and the others were reacted and treated in the same manner as in Production Example 1 to give 4-chloroacetylbiphenyl as pale yellow crystals (100.1 g, yield: 86). 8%).
Melting point: 128-129 ° C
IR (KBr, cm ⁻¹ ): 2945, 1691, 1604, 1215, 763
NMR (270 MHz, CDCl ₃ ), δ: 4.72 (2H, s, —CH ₂ —), 7.37-8.04 (9H, m, aromatic ring hydrogen)
[0028]
Production Example 3 Production of 4-dibromoacetylbiphenyl:
4-Acetylbiphenyl [Produced according to the method of Loren M. Long, Henry R. Henze: J. Amer. Chem. Soc., 63 , 1939 (1940)] 98.1 g was dissolved in 500 ml of methylene chloride. To this solution, 159.8 g of bromine was added dropwise at 0 ° C. to 20 ° C. After reacting at the same temperature for 2 hours, the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and concentrated to dryness under reduced pressure. The residue was recrystallized from an isopropanol-toluene mixed solvent to obtain 147.6 g (yield: 83.4%) of 4-dibromoacetylbiphenyl as light brown crystals. Melting point: 118-120 ° C
IR (KBr, cm ⁻¹ ): 3020, 1686, 1601, 1205, 695
NMR (270 MHz, CDCl ₃ ), δ: 6.73 (1H, s, —CH—), 7.39-8.19 (9H, m, aromatic ring hydrogen)
[0029]
【Example】
Example 1 Production of 4-biphenyl-α-hydroxyacetic acid:
7.95 g of 4-dichloroacetylbiphenyl obtained in Production Example 1 was dissolved in 40 ml of toluene, and a solution of 9.44 g of lithium hydroxide monohydrate in 40 ml of water was added and reacted at 60 ° C. for 24 hours. After completion of the reaction, the precipitated lithium salt of 4-biphenyl-α-hydroxyacetic acid was collected by filtration, converted into a free acid with hydrochloric acid, and extracted with methyl ethyl ketone. The extract was concentrated to dryness under reduced pressure and recrystallized from methyl ethyl ketone-n-hexane to obtain 5.28 g (yield: 77.1%) of 4-biphenyl-α-hydroxyacetic acid as white crystals. Melting point: 196-198 ° C
IR (KBr, cm ⁻¹ ): 3415, 1706, 1062
NMR (270 MHz, DMSO-d ₆ ), δ: 5.08 (1H, s, —CH—), 5.89 (1H, s, —OH), 7.33-7.73 (9H, m, aroma Ring hydrogen), 12.66 (1H, br, -COOH)
[0030]
Examples 2 to 5 : Preparation of 4-biphenyl-α-hydroxyacetic acid:
In Example 1, the following various alkalis were used instead of lithium hydroxide monohydrate, and the reaction treatment was performed in the same manner as in Example 1 to obtain 4-biphenyl-α-hydroxyacetic acid white crystals.
The results are summarized below.

[0031]
Example 6 : Preparation of 4-biphenyl-α-hydroxyacetic acid:
In Example 1, instead of 4-dichloroacetylbiphenyl, 6.92 g of 4-chloroacetylbiphenyl was used, and other than that, the reaction treatment was performed in the same manner as in Example 1, except that 4-biphenyl-α-hydroxyacetic acid was white. 3.30 g (yield: 48.2%) of crystals were obtained.
The physical property values of this product completely coincided with those obtained in Example 1.
[0032]
Example 7 : Preparation of 4-biphenyl-α-hydroxyacetic acid:
In Example 1, instead of 4-dichloroacetylbiphenyl, 10.62 g of 4-dibromoacetylbiphenyl was used, and other than that, the reaction treatment was performed in the same manner as in Example 1, and the white color of 4-biphenyl-α-hydroxyacetic acid was obtained. 3.66 g (yield: 53.5%) of crystals were obtained.
The physical property values of this product completely coincided with those obtained in Example 1.
[0033]
Example 8 : Preparation of 4-biphenyl-α-hydroxyacetic acid:
91.1 g of 4-biphenylaldehyde was dissolved in 500 ml of chloroform, 16 g of tetra n-butylammonium bromide was further added, and 20 g of 50% aqueous sodium hydroxide solution was added dropwise at 56 ° C. to this solution. After reacting at the same temperature for 4 hours, 30 ml of concentrated hydrochloric acid was poured to make it acidic, and extracted with 500 ml of methyl ethyl ketone. The extract was concentrated to dryness under reduced pressure and recrystallized from methyl ethyl ketone-n-hexane to obtain 83.3 g (yield: 73.0%) of 4-biphenyl-α-hydroxyacetic acid as white crystals.
The physical property values of this product completely coincided with those obtained in Example 1.
[0034]
Example 9 : Preparation of 4-biphenylyl acetic acid:
A 500 ml autoclave was charged with 22.8 g of 4-biphenyl-α-hydroxyacetic acid, 200 ml of isopropanol and 1.0 g of 5% palladium-carbon, and the reduction reaction was carried out at 80 ° C. for 8 hours at a hydrogen pressure of 0.3 kg / cm ^2. went. After completion of the reaction, the catalyst was removed by filtration, the filtrate was concentrated to dryness, and the residue was recrystallized from methyl ethyl ketone to obtain 14.1 g (yield: 66.4%) of 4-biphenylylacetic acid as white crystals. . Melting point: 163-164 ° C
IR (KBr, cm ⁻¹ ): 3426, 1690, 1259, 929
NMR (270 MHz, DMSO-d ₆ ), δ: 3.61 (2H, s, —CH ₂ —), 7.31-7.66 (9H, m, aromatic ring hydrogen), 12.29 (1H, br , -COOH)
[0035]
Example 10 : Preparation of 4-biphenylyl acetic acid:
4-Biphenyl-α-hydroxyacetic acid (22.8 g) was dissolved in formic acid (400 ml), zinc powder (32.6 g) was added, and concentrated hydrochloric acid (200 ml) was added dropwise at 100 ° C. over 2 hours. After completion of the dropwise addition, the mixture was reacted at the same temperature for 2 hours, 500 ml of methyl ethyl ketone was injected, and insoluble matters were filtered off. The organic layer was washed with water and evaporated to dryness under reduced pressure, and the residue was recrystallized from methyl ethyl ketone to obtain 16.7 g (yield: 78.7%) of 4-biphenylylacetic acid as white crystals.
The physical property values of this product completely coincided with those obtained in Example 9.
[0036]
Example 11 : Preparation of 4-biphenylyl acetic acid:
4-biphenyl-α-hydroxyacetic acid (22.8 g) was dissolved in a solution of potassium hydroxide (561 g) in water (600 ml), and Raney nickel (100 g) was gradually added to the solution at 90 ° C. After foaming subsided, the reaction was performed at 100 ° C. for 2 hours. After completion of the reaction, insoluble matters were removed by filtration, 120 ml of concentrated hydrochloric acid was poured into the filtrate, and the precipitated crystals were collected by filtration to obtain 18.0 g (yield: 84.8%) of 4-biphenylylacetic acid as white crystals. It was.
The physical property values of this product completely coincided with those obtained in Example 9.
[0037]
【The invention's effect】
As described above in detail, the present invention provides a method capable of industrially producing 4-biphenylylacetic acid having excellent anti-inflammatory / analgesic activity easily and in good yield. It is highly useful in that it greatly contributes to price reduction, and its industrial utility value is enormous.

Claims (2)

Formula (III):

(Wherein X represents a halogen atom and n represents an integer of 1 or 2) 4-halogenated acetylbiphenyl represented by the following formula (II), which is hydrolyzed with lithium hydroxide : :

The manufacturing method of 4-biphenylyl-alpha-hydroxyacetic acid represented by these. Formula (III):

(. Wherein, X represents a halogen atom, n represents an integer of 1 or 2) 4-acetyl halide biphenyl represented by, subjected to hydrolysis with lithium hydroxide, the following formula (II):

4-biphenylyl-α-hydroxyacetic acid represented by the following formula (I):

The manufacturing method of 4-biphenylyl acetic acid represented by these.