JP4029992B2 - Production of tartranic acid - Google Patents
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Description
【０００１】
【発明の属する技術分野】
本発明は、（＋）−タートラニル酸、新規（±）−タートラニル酸、又は新規（−）−タートラニル酸及びその工業的製造法に関する。（＋）−、及び（−）−タートラニル酸はラセミ塩基性有機化合物の光学分割剤として有用である。言うまでもなく、医薬、農薬、化粧品、液晶材料、あるいは不斉有機反応や生物活性物質を対象とする研究などの分野で、光学活性物質を取り扱う機会は益々多くなってきている。光学活性物質を得る手段としての、光学分割剤を用いるジアステレオマー法は古典的ではあるが、現在もなお有効な方法として広く用いられている。（＋）−、及び（−）−タートラニル酸はラセミ塩基性有機化合物の光学分割剤のみならず、アルコールの光学分割や不斉有機反応におけるchiral auxiliaryとして利用することも可能である。
【０００２】
【従来の技術】
ラセミ塩基性有機化合物の光学分割剤として最も多用されるのは天然酒石酸である。天然酒石酸は、極めて水溶性が大で光学分割後の回収再使用には煩雑な操作が必要である。高価な非天然酒石酸では更に経済的な問題が加わる。又、ジベンゾイル酒石酸、ジトルオイル酒石酸は、酒石酸に次いで広く用いられている。これらは回収再使用の問題は少ないと思われるが、比較的アルカリに不安定なエステル結合を有するので、反復使用の際に徐々に加水分解が生じ、分割剤の品質低下は避けられない。その他、天然物由来の光学分割剤、例えばカンファースルホン酸、修飾アミノ酸等も高価な物が多く、それらの対掌体は通常入手困難であり合成上検討すべき問題もあり、現時点に於いては、工業的規模での利用は困難である。
【０００３】
これらの観点から、（＋）−、及び（−）−タートラニル酸は、既存の光学分割剤と比較していくつかの長所をもっている。これらは水には比較的難溶、アルカリ水溶液に易溶な良結晶性の安定な物質で、通常の光学分割条件下ではラセミ化、アミド結合の加水分解等が起こる確率は極めて小さいと考えられる。（＋）−、及び（−）−タートラニル酸は、光学分割で塩基性物質を分離した後の母液を酸性にすることによって容易に結晶として分離回収され回収率も良好である。天然酒石酸由来の（＋）−タートラニル酸の文献記載は古く(Arppe,Ann.,93,352(1855),Bischoff,Nastvogel,Ber.,23 、2047(1890), Polikier,Ber.,24,2959(1891),Tingle,Bates,J.Am.Chem.Soc, 31,1240(1909),Casale,Gazz.Chimm.Ital., 471,272(1917),Pressman,et al,J.Am.Chem.Soc.,70,1352(1948)), また、（＋）−タートラニル（Ｎ−フェニル酒石酸イミド）を用いたアルコールの光学分割の例もあるが(Barrow,Atkinson,J.Chem.Soc., 1939,638),ラセミ塩基性有機化合物の光学分割に用いられた例は少ない（特公昭57-8102 号公報、Montzka,et al,J.Org.Chem.,33,3993(1968),Montzka,U.S.P.3,452,086(1969))。
【０００４】
（±）−、及び（−）−タートラニル酸の合成、応用に関する文献記載は、２’−クロロ−，又は２’−ブロモ−（−）−タートラニル酸を除けば未載であり、従って、それらは新規物質である。（±）−、及び（−）−タートラニル酸の原料となる（±）−、及び（−）−酒石酸は近年工業的規模での生産が行われるようになり、容易に入手可能である。従って（＋）−、及び（−）−タートラニル酸の合成で得られる一組の光学分割剤によって、ラセミ塩基性有機化合物の何れの対掌体も全く同じ操作を行うことで容易に得ることが可能となった。（＋）−、及び（−）−タートラニル酸は（±）−タートラニル酸の光学分割によって得ることも出来るので該酸の合成も又工業的に有意義である。
【０００５】
（＋）−タートラニル酸の製法としては、酒石酸モノアニリドの加熱脱水による方法が知られている。本発明者らはこの方法を追試した結果、反応生成物は複雑であり、高温加熱による着色物の生成が多く、目的物の収率も低く旋光度は文献記載値よりも低かった。上記文献中Pressman等の方法は、（＋）−酒石酸を無水酢酸と触媒量の硫酸の作用によりジアセチル酒石酸無水物に誘導し、この物質にアニリンを反応させて得られるジアセチル酒石酸モノアニリド（ジアセチルタートラニル酸）を加水分解して、（＋）−タートラニル酸を得ると言うものである。上記文献中Montzka 等は、この方法を用いてベンゼン環に置換基を有するタートラニル酸を合成している。
ジアセチル酒石酸無水物の合成法は、N.Rabjohn,Ed., Organic Syntheses,Coll.Vol.IV, John Wiley & Sons,INC.,New York N.Y.,1963,p 242 に記載されている。本法によれば、酒石酸と無水酢酸は触媒量の硫酸存在下に激しく反応し生成した酢酸は沸騰するに至る。反応物を冷却して析出したジアセチル酒石酸無水物は濾過し、ベンゼン、エーテルで漏斗上洗浄すれば、７１〜７７％の収率で得られる。此の物質はやや不安定で長時間の保存には耐えられないので、必要に応じて調製するのが望ましいとされている。
【０００６】
ジアセチル酒石酸無水物とアニリンの反応は、メチレンクロライド、クロロホルムの様な不活性な溶媒に前者を溶解又は懸濁し、この中にアニリンを直接、又は溶媒に希釈して、室温ないし溶媒の沸騰温度で添加することによって行われる。反応完結のために、普通数時間加熱する。
生成したジアセチルタートラニル酸は、３．３モル当量のアルカリ水溶液を用いて抽出し、抽出層は暫時５０℃程度に保ってアセチル基の加水分解を行い、冷却後、酸性にして析出したタートラニル酸を濾過する。
【０００７】
【発明が解決しようとする課題】
タートラニル酸を工業的規模で光学分割剤として利用している例は少ない（特公昭57-8102 号公報,Montzka,U.S.P.3,452,086(1969)) 。しかしながら、本発明者らは（＋）−、又は（−）−タートラニル酸が、安価な原料、少ない工程数、高い収率で得られること、又、これらタートラニル酸が極めて取扱い容易であることを研究の結果知ったので、工業的規模での製造は、これらによって光学分割して得られる光学活性アミン、即ち、医薬、農薬、液晶組成物等、有用物の生産にとって貢献するところ大であると考え、工業生産に適する方法を研究し、本発明を完成した。
（±）−タートラニル酸は、（＋）−、又は（−）−タートラニル酸を得る中間体として重要である。
本発明は光学分割剤として有用なタートラニル酸を工業的有利に製造する方法を提供することを目的とする。
【０００８】
【課題を解決するための手段】
本発明者らは上記課題を解決するため鋭意研究したところ酒石酸と無水酢酸との反応においては、従来必要とされて来た硫酸触媒の代わりに、無触媒或いは有機スルホン酸、ルイス酸等温和な触媒を用いることにより、副生する酢酸、過剰の無水酢酸を直接反応混合物から留去することを可能とし、それにより不安定なジアセチル酒石酸無水物を単離することなく直ちにアニリン類との反応を行うことができることを発見し本発明に到達した。すなわち、本発明は以下の各項に要約することができる。
【０００９】
（１）（＋）−、（−）−又は（±）−酒石酸１モルに対し、３．０〜３．５モル若しくは３．３８モル又は３．７モルの無水酢酸を混合し、触媒量の有機スルホン酸又はルイス酸の存在下で、７０〜１００℃に加熱して反応させた後、直ちに副生した酢酸及び過剰の無水酢酸を溜去することを特徴とする結晶性の（＋）−、（−）−又は（±）−ジアセチル酒石酸無水物の製造方法。
（２）上記（１）に記載の製造方法で得られた結晶性の（＋）−、（−）−又は（±）−ジアセチル酒石酸無水物１モルに対し、１〜１．２モルの下記式１で表されるアニリン類と、不活性溶媒とを混合し、室温乃至前記溶媒の沸点の温度範囲で反応させて、下記式２で表されるジアセチルタートラニル酸類を得て、前記ジアセチルタートラニル酸類を単離することなく、室温乃至冷却下において、３．３〜３．５モル若しくは３．９０モル又は３．９２モルのアルカリ水溶液に転溶し、室温又は加熱下において加水分解させた後、酸性とすることを特徴とする結晶性の下記式３で表される（＋）−、（−）−又は（±）−タートラニル酸類の製造方法。
【化５】
【化６】
【化７】
【００１０】
（３）上記（１）に記載の製造方法で得られた結晶性の（＋）−、（−）−又は（±）−ジアセチル酒石酸無水物１モルに対し、１〜１．２モルの式１で表されるアニリン類と、不活性溶媒とを混合し、室温乃至前記溶媒の沸点の温度範囲で反応させて、式２で表されるジアセチルタートラニル酸類を得て、前記ジアセチルタートラニル酸類を単離することなく、前記不活性溶媒を溜去した後メタノールに置換し、３．３〜３．５モル若しくは３．９０モル又は３．９２モルのＫＯＨのメタノール溶液を加えて加水分解し、結晶状に分離した下記式４で表される（＋）−、（−）−又は（±）−ジアセチルタートラニル酸カリウム水和物類を濾取し、水に溶解後酸性とすることを特徴とする結晶状の式３で表される（＋）−、（−）−又は（±）−タートラニル酸類の製造方法。
【００１２】
（４）結晶性の（＋）−、（−）−又は（±）−ジアセチル酒石酸無水物１モルに対し、１〜１．２モルの式１で表されるアニリン類と、不活性溶媒とを混合し、室温乃至前記溶媒の沸点の温度範囲で反応させて、式２で表されるジアセチルタートラニル酸類を得て、前記ジアセチルタートラニル酸類を単離することなく、前記不活性溶媒を溜去した後メタノールに置換し、３．３〜３．５モル若しくは３．９０モル又は３．９２モルのＫＯＨのメタノール溶液を加えて加水分解し、結晶状に分離した下記式４で表される（＋）−、（−）−又は（±）−ジアセチルタートラニル酸カリウム水和物類を濾取し、水に溶解後酸性とすることを特徴とする結晶状の式３で表される（＋）−、（−）−又は（±）−タートラニル酸類の製造方法。
【化８】
【００１３】
（５）下記一般式で表される（−）−又は（±）−タートラニル酸。
【化９】
【発明の実施の形態】
上記Org.Synth.所載のジアセチル酒石酸無水物の合成法によれば、硫酸の様な強酸性触媒の使用、生じたジアセチル酒石酸無水物の濾過、ベンゼン洗浄、エーテル処理等現代化学工業上好ましくない副原料の使用、不安定な目的物を取り扱うには不適当な工程などが含まれている。本発明者は、この反応を検討した結果、酒石酸と無水酢酸の反応によって生ずる酢酸を留去することを考えた。ところが、硫酸の存在によって、例え低温で濃縮しても、あるいは無水酢酸ナトリウムで中和した後低温で濃縮しても、ジアセチル酒石酸無水物が著しく着色してしまい、その後の反応によって得られたタートラニル酸の収量、品質ともに満足できるものではなかった。そこで硫酸触媒に代わる、（＋）−、（−）−又は（±）−酒石酸と無水酢酸の反応触媒を見出せば課題を解決出来ると考え研究した。
【００１５】
上記文献中Pressmanらは、ジアセチル酒石酸無水物をクロロホルム、メチレンクロライド等の不活性溶媒中アニリンと反応させ、生じたジアセチルタートラニル酸を単離せず、過剰のアルカリ水溶液に抽出しそのままアセチル基を加水分解し、塩酸で酸性にして、析出するタートラニル酸を濾取している。本反応の後処理として、加える塩酸の量はタートラニル酸に対して３．３モル当量以上必要である。その結果、酢酸２モル当量、タートラニル酸１モル当量、塩化アルカリ３．３モル当量が生成する。しかしながら、２モル当量の酢酸の存在は目的物であるタートラニル酸の溶解度を増大させるので、収量が低下し、又、酢酸臭の除去は困難で品質低下の原因となる。更に、副生する塩化アルカリは目的物に付着し、タートラニル酸を分析するとハロゲンの反応が陽性であり、再結晶を繰り返す必要が生じる。
本発明者らはタートラニル酸合成の後処理の段階で、これらの問題を解決出来れば、目的物タートラニル酸の収量、品質向上に役立つと考えた。
【００１６】
本発明者らは、硫酸触媒を加えない場合でも、（＋）−、又は（−）−酒石酸と無水酢酸の反応は約１００℃で容易に進行するが（±）−酒石酸と無水酢酸の反応は１００℃でも極めて遅いことを見出した。前述したように、不安定なジアセチル酒石酸無水物を単離せずに次の工程に用いる為には副生した酢酸、過剰の無水酢酸を溜去すれば良いが、硫酸触媒が存在するのでジアセチル酒石酸無水物が褐変し、更に目的のタートラニル酸の収量、品質も満足できるものではなかった。無触媒でも反応が進行したので、そのまま副生した酢酸、過剰の無水酢酸の留去を試みたところ、ジアセチル酒石酸無水物が無色の結晶状で得られ、収率も定量的であった。
【００１７】
そこで、温和な酸性触媒の有無を更に検討した。その結果、ベンゼンスルホン酸、トルエンスルホン酸、メタンスルホン酸等の有機スルホン酸、塩化亜鉛、塩化錫、塩化アルミニウム、塩化鉄等のいわゆるルイス酸が酸性触媒として、無触媒の場合よりも極めて顕著に触媒効果を示し、７０〜１００℃において３〜１０分で酒石酸が消失し、２０〜３０分の反応後、副生酢酸、過剰の無水酢酸の溜去においても生成ジアセチル酒石酸無水物の着色もなく、無色の結晶として目的物が定量的収率で得られた。反応性の低い（±）−酒石酸と無水酢酸の反応の場合でも１０〜１５分で原料酒石酸が消失し、（＋）−、又は（−）−酒石酸におけると全く同様の結果が得られた。これらの酸性触媒はその後の工程においても全く影響を与えなかった。
上記触媒は一般に酒石酸に対して０〜１．０重量％の範囲で用いるのが好ましい（触媒量）。
【００１８】
（従来の技術）の項で説明した様にタートラニル酸製造工程においては、
１）ジアセチル酒石酸無水物の単離
２）不活性溶媒中でのジアセチル酒石酸無水物とアニリン類の反応
３）生成ジアセチルタートラニル酸の苛性アルカリ水溶液による抽出、加水分解
４）加水分解後、酸性として分離析出したタートラニル酸の単離
５）タートラニル酸の精製
がある。
本発明によれば、ジアセチル酒石酸無水物の単離精製は不要で、副生酢酸の留去後直ちに２）の工程を行い、更に溶媒留去後ＫＯＨメタノール溶液に置換して加水分解し、難溶性のタートラニル酸カリウム塩・水和物を濾過して易溶性の酢酸カリウムと分離、次いで上記４）、５）の工程を行う。この間、ジアセチル酒石酸無水物の製造からジアセチルタートラニル酸の加水分解までの工程を反応容器を変えることなく１ポットで行うことが出来るので極めて合理的である。
【００１９】
すなわち、ジアセチル酒石酸無水物製造工程で、副生酢酸、過剰の無水酢酸を溜去後、反応容器にメチレンクロライド、ジクロロエタン、クロロホルム、トルエン等の不活性溶媒を注入してジアセチル酒石酸無水物の大部分を溶解し、一部懸濁のまま室温乃至４０℃で攪拌しながら、１．０５〜１．１６モル当量のアニリン又はハロゲン置換アニリン誘導体、例えば４−クロロアニリンをそのまま、又は上記溶媒に溶解してゆっくりと注入すると一部懸濁していたジアセチル酒石酸無水物は消失して反応が進行する。この間顕著な発熱は無いが必要に応じて流水で冷却する。添加後２〜４時間４０℃に保ち反応を完結させる。次いで溶媒を留去すると、ジアセチルタートラニル酸が粘稠なオイル状残さとして得られる。ジアセチルタートラニル酸は単離することなく、これにメタノールを加えて溶解し、さらにＫＯＨ３．３〜３．９２モル当量のメタノール溶液を攪拌しながら水冷却下に加える。暫くするとカリウム塩が析出し始める。アルカリ溶液添加後反応温度を６０〜７０℃に保って加水分解する。
【００２０】
この間嵩高な微細結晶が多量析出して来るが時間と共に重質な結晶に変化する。６０〜７０℃で３〜４時間反応させた後十分に冷却し、タートラニル酸カリウム塩を濾過し、冷メタノールで洗浄、乾燥する。収率８０〜９０％。少量を取り、メタノール・水から再結晶するとタートラニル酸カリウム・１．５水和物が得られ、分析一致した。
Ｃ10Ｈ13ＮＯ5 Ｋ・1.5 Ｈ2 Ｏ（分子量２９０．３０７）
理論値：Ｃ；４１．３８％，Ｈ；４．５１％，Ｎ；４．８２％
実験値：Ｃ；４１．４３％，Ｈ；４．７９％，Ｎ；４．６０％
【００２１】
この工程は次のように示される。
【化１０】
即ち、タートラニル酸カリウム塩１モル、酢酸カリウム２モル及び水１モルが生じるが前者はメタノールに難溶であるのに対して後者は極めて易溶である。従って両者は濾過によって容易に分離することが出来、次工程のタートラニル酸単離・精製が容易となる。この工程において、文献に従ってジアセチルタートラニル酸の加水分解をアルカリ水溶液中で行った場合タートラニル酸単離に必要な塩酸は３．３モル等量以上となり、副生する酢酸はタートラニル酸の回収量を低下させ、且つ品質に悪影響を及ぼす。本発明の方法によれば、タートラニル酸カリウム塩は精製することなく４倍量の熱水に溶解し、計算量より若干過剰の濃塩酸を加えるとタートラニル酸が析出してくる。冷後氷水で十分冷却し濾過、冷水少量で洗い乾燥すると約９０％の収率でタートラニル酸が得られる。本品はそのまま光学分割に使用できる純度であるが、必要に応じて４倍量の水から再結晶すれば回収率８０〜９０％で純粋なタートラニル酸が得られる。
【００２３】
（＋）−タートラニル酸
(+)-(2R,3R)-2,3-ジヒドロキシ -4-オキソ -4-フェニルアミノブタン酸
Ｃ10Ｈ11ＮＯ5 （分子量２２５．２０）
理論値：Ｃ；５３．３３％，Ｈ；４．９２％，Ｎ；６．２２％
実験値：Ｃ；５３．２４％，Ｈ；４．９９％，Ｎ；６．１５％
〔α〕D ＋１１４．０°（Ｃ ４．０５，ＭｅＯＨ，２５℃）
ｍ．ｐ．１７９〜１８２℃
【００２４】
（−）−タートラニル酸
(-)-(2S,3S)-2,3-ジヒドロキシ -4-オキソ -4-フェニルアミノブタン酸
Ｃ10Ｈ11ＮＯ5 （分子量２２５．２０）
理論値：Ｃ；５３．３３％，Ｈ；４．９２％，Ｎ；６．２２％
実験値：Ｃ；５３．３７％，Ｈ；５．１２％，Ｎ；６．３８％
〔α〕D −１１４．６°（Ｃ ４．０３，ＭｅＯＨ，２５℃）
ｍ．ｐ．１７９〜１８２℃
【００２５】
（±）−タートラニル酸
(±)-(2RS,3RS)-2,3-ジヒドロキシ -4-オキソ -4-フェニルアミノブタン酸
Ｃ10Ｈ11ＮＯ5 （分子量２２５．２０）
理論値：Ｃ；５３．３３％，Ｈ；４．９２％，Ｎ；６．２２％
実験値：Ｃ；５３．１５％，Ｈ；５．０５％，Ｎ；６．２７％
ｍ．ｐ．１７９〜１８２℃
【００２６】
（＋）−４−クロロ−タートラニル酸
(+)-(2R,3R)-2,3-ジヒドロキシ -4-オキソ -4-(4'-クロロフェニルアミノ）ブタン酸
Ｃ10Ｈ10ＣｌＮＯ5 （分子量２６９．５）
理論値：Ｃ；４６．２６％，Ｈ；３．８３％，Ｎ；５．４０％
実験値：Ｃ；４６．０４％，Ｈ；３．５２％，Ｎ；５．４５％
〔α〕D ＋１１０．５°（Ｃ ４．００，ＭｅＯＨ，２５℃）
ｍ．ｐ．１９２〜１９５℃
【００２７】
（−）−４−クロロ−タートラニル酸
(-)-(2S,3S)-2,3-ジヒドロキシ -4-オキソ -4-(4'-クロロフェニルアミノ）ブタン酸
Ｃ10Ｈ10ＣｌＮＯ5 （分子量２６９．５）
理論値：Ｃ；４６．２６％，Ｈ；３．８３％，Ｎ；５．４０％
実験値：Ｃ；４６．２５％，Ｈ；３．５１％，Ｎ；５．２８％
〔α〕D −１１２．１°（Ｃ ４．０１，ＭｅＯＨ，２５℃）
ｍ．ｐ．１９２〜１９５℃
以上説明したタートラニル酸の製法は（＋）−、（−）−及び（±）−酒石酸のいずれの酸を原料としても適応できる。（−）−及び（±）−タートラニル酸は文献未載の新規化合物であり、（±）−タートラニル酸から光学分割によって（＋）−、及び（−）−タートラニル酸を得ることができる。
反応装置、中間生成物の処理、副原料等に問題のあった従来の方法を工業生産に適するよう触媒の選定、加水分解法等の研究を行った結果、高品質のタートラニル酸を、短時間、好収量で得ることを可能にした。
【００２８】
【実施例】
以下、実施例を上げて本発明を更に詳しく説明するが、勿論下記実施例に限定されるものではない。
（実施例１）
（＋）−酒石酸 ７５ｇ（０．５０ｍｏｌ）、無水酢酸１６０ｍｌ（ｄ＝１．０８，１７２．８ｇ，１．６９ｍｏｌ）を１Ｌナス型フラスコに仕込み、ロータリー・エバポレーターに装着する。沸騰水浴中で攪拌すると約１０分で酒石酸が完全に消失して無色均一溶液となった。そのまま３０分攪拌してから浴温を７０℃に下げ、減圧下に副生した酢酸と過剰の無水酢酸を可及的に留去すると、残留物は固化し結晶塊となった。冷却後メチレンクロライド５００ｍｌを加えて攪拌すると、大部分のジアセチル酒石酸無水物は溶解し一部懸濁状態となった。この懸濁液に、攪拌下アニリン５１ｇ（０．５４８ｍｏｌ）のメチレンクロライド２００ｍｌ溶液を浴温２０〜２５℃で添加した。不溶物は急速に溶解して淡桃色透明溶液になった。次いで浴温を４０℃に上げて更に４時間反応させた。メチレンクロライドを減圧留去するとジアセチルタートラニル酸が淡褐色透明なオイルとして得られた。この物を単離することなく、メタノール４３０ｍｌを加えて溶解し、攪拌しながらＫＯＨ １１０ｇ（１．９６ｍｏｌ）のメタノール４００ｍｌ溶液を水で冷却しながら加えた。この時、中和熱で反応温度が上がり結晶の析出が始まった。添加後浴温を７０℃に上げて４〜６時間加熱攪拌を続けた。この間結晶の量が増加して攪拌効果が低下したが、そのまま攪拌していると結晶の状態は徐々に変化し、重質の結晶となった。反応後冷却し、結晶を吸引濾過した。濾斗上冷メタノールで洗い、乾燥すると無色の（＋）−タートラニル酸カリウム塩１１７ｇ（１水和物として８３．２％）が得られた。
【００２９】
（実施例２）
（＋）−酒石酸 １５０ｇ（１．００ｍｏｌ）、無水酢酸３５０ｍｌ（ｄ＝１．０８，３７８ｇ，３．７０ｍｏｌ）及び無水塩化亜鉛１ｇを２Ｌナス型フラスコに仕込み、ロータリー・エバポレーターに装着する。沸騰水浴中で攪拌すると約３分で酒石酸が完全に消失して無色均一溶液となった。そのまま３０分攪拌してから浴温を７０℃に下げ、減圧下に副生した酢酸と過剰の無水酢酸を可及的に留去すると、残留物は固化し結晶塊となった。冷却後メチレンクロライド１２００ｍｌを加えて攪拌すると、大部分のジアセチル酒石酸無水物は溶解し一部懸濁状態となった。この懸濁液に、攪拌下アニリン１０８ｇ（１．１６ｍｏｌ）のメチレンクロライド４００ｍｌ溶液を浴温２０〜２５℃で添加した。不溶物は急速に溶解して淡桃色透明溶液になった。次いで浴温を４０℃に上げて更に４時間反応させた。メチレンクロライドを減圧留去するとジアセチルタートラニル酸が淡褐色透明なオイルとして得られた。この物を単離することなく、メタノール１０００ｍｌを加えて溶解し、攪拌しながらＫＯＨ ２２０ｇ（３．９２ｍｏｌ）のメタノール５００ｍｌ溶液を水で冷却しながら加えた。この時、中和熱で反応温度が上がり結晶の析出が始まった。添加後浴温を７０℃に上げて４〜６時間加熱攪拌を続けた。この間結晶の量が増加して攪拌効果が低下したが、そのまま攪拌していると結晶の状態は徐々に変化し、重質の結晶となった。反応後冷却し、結晶を吸引濾過した。濾斗上冷メタノールで洗い、乾燥すると無色の（＋）−タートラニル酸カリウム塩２５２ｇ（１水和物として８９．６％）が得られた。
【００３０】
（実施例３）
（−）−酒石酸 １５ｇ（０．１０ｍｏｌ）、無水酢酸３５ｍｌ（ｄ＝１．０８，３７．８ｇ，０．３７ｍｏｌ）及び無水塩化亜鉛０．１ｇを２００ｍｌナス型フラスコに仕込み、ロータリー・エバポレーターに装着する。沸騰水浴中で攪拌すると約３分で酒石酸が完全に消失して無色均一溶液となった。そのまま３０分攪拌してから浴温を７０℃に下げ、減圧下に副生した酢酸と過剰の無水酢酸を可及的に留去すると、残留物は固化し結晶塊となった。冷却後メチレンクロライド１２０ｍｌを加えて攪拌すると、大部分のジアセチル酒石酸無水物は溶解し一部懸濁状態となった。この懸濁液に、攪拌下アニリン１０．８ｇ（０．１１６ｍｏｌ）のメチレンクロライド４０ｍｌ溶液を浴温２０〜２５℃で添加した。不溶物は急速に溶解して淡桃色透明溶液になった。次いで浴温を４０℃に上げて更に４時間反応した。メチレンクロライドを減圧留去するとジアセチルタートラニル酸が淡褐色透明なオイルとして得られた。この物を単離することなく、メタノール１００ｍｌを加えて溶解し、攪拌しながらＫＯＨ２２ｇ（０．３９ｍｏｌ）のメタノール５０ｍｌ溶液を水で冷却しながら加えた。この時、中和熱で反応温度が上がり結晶の析出が始まった。添加後浴温を７０℃に上げて４〜６時間加熱攪拌を続けた。この間結晶の量が増加して攪拌効果が低下したが、そのまま攪拌していると結晶の状態は徐々に変化し、重質の結晶となった。反応後冷却し、結晶を吸引濾過した。濾斗上冷メタノールで洗い、乾燥すると無色の（−）−タートラニル酸カリウム塩２５ｇ（１水和物として８９％）が得られた。
【００３１】
（実施例４）
（＋）−酒石酸１５ｇ（０．１０ｍｏｌ）、無水酢酸３５ｍｌ（ｄ＝１．０８，３７．８ｇ，０．３７ｍｏｌ）及びｐ−トルエンスルホン酸・１水和物０．１ｇを用いて実施例１と同じ反応を行い、得られたジアセチル酒石酸無水物をアニリン１０．８ｇ（０．１１６ｍｏｌ）と反応させた。反応生成物（ジアセチルタートラニル酸）をメタノール中ＫＯＨ２２ｇ（０．３９ｍｏｌ）で加水分解し、（＋）−タートラニル酸カリウム塩２５ｇ（１水和物として８９％）を得た。
【００３２】
（実施例５）
（＋）−酒石酸１５ｇ（０．１０ｍｏｌ）、無水酢酸３５ｍｌ（ｄ＝１．０８，３７．８ｇ，０．３７ｍｏｌ）及びメタンスルホン酸０．１ｇを用いて実施例１と同じ反応を行い、得られたジアセチル酒石酸無水物をアニリン１０．８ｇ（０．１１６ｍｏｌ）と反応させた。反応生成物（ジアセチルタートラニル酸）をメタノール中ＫＯＨ２２ｇ（０．３９ｍｏｌ）で加水分解し、（＋）−タートラニル酸カリウム塩２３ｇ（１水和物として８２％）を得た。
【００３３】
（実施例６）
（±）−酒石酸１５ｇ（０．１０ｍｏｌ）、無水酢酸３５ｍｌ（ｄ＝１．０８，３７．８ｇ，０．３７ｍｏｌ）及び無水塩化亜鉛０．１ｇを用いて実施例１と同じ反応を行い、得られたジアセチル酒石酸無水物をアニリン１０．８ｇ（０．１１６ｍｏｌ）と反応させた。反応生成物（ジアセチルタートラニル酸）をメタノール中ＫＯＨ２２ｇ（０．３９ｍｏｌ）で加水分解し、（±）−タートラニル酸カリウム塩２４ｇ（１水和物として８５％）を得た。
【００３４】
（実施例７）
（＋）−酒石酸１５ｇ（０．１０ｍｏｌ）、無水酢酸３５ｍｌ（ｄ＝１．０８，３７．８ｇ，０．３７ｍｏｌ）及び塩化第二錫０．１ｇを用いて実施例１と同じ反応を行い、得られたジアセチル酒石酸無水物をアニリン１０．８ｇ（０．１１６ｍｏｌ）と反応させた。反応生成物（ジアセチルタートラニル酸）をメタノール中ＫＯＨ２２ｇ（０．３９ｍｏｌ）で加水分解し、（＋）−タートラニル酸カリウム塩２４ｇ（１水和物として８５％）を得た。
【００３５】
（実施例８）
（＋）−酒石酸７５ｇ（０．５０ｍｏｌ）、無水酢酸１６０ｍｌ（ｄ＝１．０８，１７２．８ｇ，１．６９ｍｏｌ）及び無水塩化亜鉛０．５ｇを１Ｌナス型フラスコに仕込み、ロータリー・エバポレーターに装着する。沸騰水浴中で攪拌すると約１０分で酒石酸が完全に消失して無色均一溶液となった。そのまま３０分攪拌してから浴温を７０℃に下げ、減圧下に副生した酢酸と過剰の無水酢酸を可及的に留去すると、残留物は固化し結晶塊となった。冷却後メチレンクロライド５００ｍｌを加えて攪拌すると、大部分のジアセチル酒石酸無水物は溶解し一部懸濁状態となった。この懸濁液に、攪拌下アニリン５１ｇ（０．５４８ｍｏｌ）のメチレンクロライド２００ｍｌ溶液を浴温２０〜２５℃で添加した。不溶物は急速に溶解して淡桃色透明溶液になった。次いで浴温を４０℃に上げて更に４時間反応させた。室温に冷却してＫＯＨ１１０ｇ（１．９６ｍｏｌ）の水６００ｍｌ溶液でジアセチルタートラニル酸を水層に抽出し、そのまま４０℃に２時間保って加水分解した。黄褐色の水溶液に濃塩酸２００ｍｌを加えて酸性とし、氷水中で十分冷却した後、析出したタートラニル酸を吸収濾過した。濾斗上冷水少量で洗い乾燥した。収量８１．７ｇ（７２．６％）。淡褐色で僅かに酢酸臭があり、熱水溶液はハロゲン試験に対して強陽性であった。本品を３００ｍｌの水から再結晶して６８ｇ（回収率８３％）の回収率でハロゲン含有率の低いタートラニル酸を得た。
【００３６】
（実施例９）
実施例１〜７に準じて合成した（＋）−タートラニル酸カリウム塩・１水和物２５２ｇ（０．８９ｍｏｌ）に水１リットルを加えて加熱溶解した。この熱水溶液に濃塩酸１００ｍｌを加えると発熱して反応し、（＋）−タートラニル酸が析出した。氷水中十分冷却し、結晶を吸引濾過、濾斗上冷水少量で洗い乾燥した。１８５ｇ（９２％）。本品は殆ど無色の長薄片状結晶でハロゲン試験に対して微陽性であった。更に水７５０ｍｌから再結晶して１４９ｇ（８０．５％回収率）の純（＋）−タートラニル酸が得られた。
【００３７】
（実施例１０）
実施例９に記載した（＋）−タートラニル酸再結晶母液（約８５０ｍｌ）に２５５．５ｇ（０．９１ｍｏｌ）の（＋）−タートラニル酸カリウム塩・１水和物を加えて加熱溶解し、これに濃塩酸９０ｍｌを加えた。発熱して反応し、（＋）−タートラニル酸が析出した。氷水中十分冷却し、結晶を吸引濾過、濾斗上冷水少量で洗い乾燥した。２１６ｇ（９２％）。本品は殆ど無色の長薄片状結晶でハロゲン試験に対して微陽性であった。更に水８００ｍｌから再結晶して１７２ｇ（７９．５％回収率）の純（＋）−タートラニル酸が得られた。
【００３８】
（実施例１１）
実施例６に準じて、（＋）−酒石酸１５ｇ（０．１ｍｏｌ）、無水酢酸３５ｍｌ及び無水塩化亜鉛０．１ｇを反応させて（＋）−ジアセチル酒石酸無水物を得、４−クロルアニリンと反応させて４’−クロル−ジアセチルタートラニル酸に誘導した。この物質をメタノール中ＫＯＨで加水分解して４’−クロルタートラニル酸カリウム塩水和物２７．８ｇ（８８％）を得た。本品を１５０ｍｌの熱水に溶解し濃塩酸１１ｍｌを加えて酸性とし、定法に従って処理して（＋）−４’−クロルタートラニル酸２３．５ｇ（９０％回収、収率７９．２％）を得た。ｍ．ｐ．１９２〜１９４℃，〔α〕D ＋１１１．０°（Ｃ ２．３，ＥｔＯＨ，２５℃）
【００３９】
（実施例１２）
実施例４に準じて、（−）−酒石酸１５ｇ（０．１ｍｏｌ）、無水酢酸３５ｍｌ及びｐ−トルエンスルホン酸０．１ｇを反応させてジアセチル酒石酸無水物を得、４−クロルアニリンと反応させて４’−クロル−ジアセチルタートラニル酸に誘導した。この物質をメタノール中ＫＯＨで加水分解して４’−クロルタートラニル酸カリウム塩水和物２８．４ｇ（９０％）を得た。本品を１５０ｍｌの熱水に溶解し濃塩酸１１ｍｌを加えて酸性とし、定法に従って処理して（−）−４’−クロルタートラニル酸２３．８ｇ（８８％回収、収率８０．１％）を得た。ｍ．ｐ．１９２〜１９４℃，〔α〕D −１１１．０°（Ｃ ２．２，ＥｔＯＨ，２５℃）。本品を水から再結晶して、ｍ．ｐ．１９２〜１９５℃，〔α〕D −１１２．１°（Ｃ ４．０１，ＥｔＯＨ，２５℃）の純品を得た。
【００４０】
（参考例）
（＋）−酒石酸７５ｇ（０．５ｍｏｌ）を無水酢酸１７０ｍｌに加え、これに濃硫酸４滴を加えて７５℃で攪拌すると約２分で酒石酸が溶解消失した。そのまま３０分反応させ、これに無水酢酸ナトリウム０．３ｇを加えて１０分攪拌した。副生した酢酸及び過剰の無水酢酸を７０〜７５℃で減圧下に留去した。反応物は次第に褐色を帯びてきた。この後実施例１に準じて反応し、茶褐色に着色した（＋）−タートラニル酸カリウム塩・１水和物９６ｇを得た。本品を定法に従って処理し６０ｇ（５３．３％）の不純なタートラニル酸を得た。
【００４１】
【発明の効果】
i）酒石酸と無水酢酸の反応に於いて、従来必要とされて来た硫酸触媒の代わりに、無触媒或いは有機スルホン酸、ルイス酸等緩和な触媒を用いることにより、副生する酢酸、過剰の無水酢酸を直接反応混合物から留去することを可能にした。このことにより不安定なジアセチル酒石酸無水物を単離することなく直ちにアニリン類との反応を行うことができる。
ii）ジアセチルタートラニル酸の加水分解をメタノール中ＫＯＨによって行い、生成したメタノール難溶性のタートラニル酸カリウム塩・１水和物を濾過洗浄するのみで易溶性の酢酸カリウム塩から容易に且つ高純度に分離取得できる。
iii）この結果、タートラニル酸カリウム塩の複分解に要する塩酸の量を１／３に削減でき、同時に酢酸の副生を避けることが出来るので、回収タートラニル酸の収率が向上し、酢酸臭、無機塩の混入が殆ど無い。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to (+)-terthranilic acid, novel (±) -terthranilic acid, or novel (-)-terthranilic acid and its industrial production method. (+)-And (-)-Tartranilic acid are useful as optical resolution agents for racemic basic organic compounds. Needless to say, there are more and more opportunities to handle optically active substances in fields such as pharmaceuticals, agricultural chemicals, cosmetics, liquid crystal materials, or research on asymmetric organic reactions and biologically active substances. The diastereomeric method using an optical resolving agent as a means for obtaining an optically active substance is classic but is still widely used as an effective method at present. (+)-And (-)-Tartranylic acid can be used not only as an optical resolution agent for racemic basic organic compounds but also as a chiral auxiliary in optical resolution of alcohols and asymmetric organic reactions.
[0002]
[Prior art]
Natural tartaric acid is most frequently used as an optical resolution agent for racemic basic organic compounds. Natural tartaric acid is extremely water-soluble and requires complicated operations for recovery and reuse after optical resolution. Expensive non-natural tartaric acid adds further economic problems. Dibenzoyl tartaric acid and ditoluoyl tartaric acid are widely used next to tartaric acid. Although these are considered to have little problem of recovery and reuse, they have a relatively alkali labile ester bond, so that they gradually undergo hydrolysis upon repeated use, and the quality of the resolving agent is inevitably reduced. In addition, there are many optical resolution agents derived from natural products, such as camphorsulfonic acid, modified amino acids, etc., and their enantiomers are usually difficult to obtain and there are problems to be studied in synthesis. It is difficult to use on an industrial scale.
[0003]
From these points of view, (+)-and (-)-terthranilic acid have several advantages over existing optical resolution agents. These are highly crystalline and stable substances that are relatively poorly soluble in water and easily soluble in aqueous alkali solutions. Under normal optical resolution conditions, the probability of racemization, hydrolysis of amide bonds, etc. is considered to be extremely low. . (+)-And (-)-tartranic acid are easily separated and recovered as crystals by acidifying the mother liquor after separating the basic substance by optical resolution, and the recovery rate is also good. The literature description of (+)-tartranic acid derived from natural tartaric acid is old (Arppe, Ann.,93, 352 (1855), Bischoff, Nastvogel, Ber., 23, 2047 (1890), Polikier, Ber.,twenty four, 2959 (1891), Tingle, Bates, J. Am. Chem. Soc,31, 1240 (1909), Casale, Gazz.Chimm.Ital.,471,272 (1917), Pressman, et al, J. Am. Chem. Soc.,701352 (1948)), and there is also an example of optical resolution of alcohol using (+)-tartranyl (N-phenyltartarimide) (Barrow, Atkinson, J. Chem. Soc.,1939, 638), and few examples have been used for optical resolution of racemic basic organic compounds (JP-B-57-8102, Montzka, et al, J. Org. Chem., 33, 3993 (1968), Montzka, USP 3,452,086 (1969)).
[0004]
The literature description regarding the synthesis and application of (±)-and (−)-terthranilic acid is not described except for 2′-chloro- or 2′-bromo-(−)-tartranic acid. Is a new substance. (±)-and (−)-tartaric acid, which are raw materials for (±)-and (−)-tartranic acid, have recently been produced on an industrial scale and are readily available. Therefore, any enantiomer of a racemic basic organic compound can be easily obtained by carrying out the same operation with a set of optical resolution agents obtained by the synthesis of (+)-and (-)-tartranilic acid. It has become possible. Since (+)-and (-)-terthranilic acid can also be obtained by optical resolution of (±) -terthranilic acid, the synthesis of the acid is also industrially significant.
[0005]
As a method for producing (+)-tartranilic acid, a method by heat dehydration of tartaric acid monoanilide is known. As a result of further examination of this method, the present inventors have found that the reaction product is complicated, a large amount of colored product is produced by heating at high temperature, the yield of the target product is low, and the optical rotation is lower than the value described in the literature. In the above-mentioned document, the method of Pressman et al. Describes that diacetyl tartaric acid monoanilide (diacetyl tartar) obtained by reacting (+)-tartaric acid into diacetyl tartaric anhydride by the action of acetic anhydride and a catalytic amount of sulfuric acid and reacting this material with aniline. (Nilic acid) is hydrolyzed to give (+)-terthranilic acid. In this document, Montzka et al. Synthesize tartarnilic acid having a substituent on the benzene ring using this method.
A method for synthesizing diacetyltartaric anhydride is described in N. Rabjohn, Ed., Organic Syntheses, Coll. Vol. IV, John Wiley & Sons, INC., New York N.Y., 1963, p242. According to this method, tartaric acid and acetic anhydride react vigorously in the presence of a catalytic amount of sulfuric acid, and the acetic acid produced results in boiling. The diacetyltartaric anhydride precipitated by cooling the reaction product is filtered and washed on the funnel with benzene and ether to give a yield of 71-77%. Since this material is somewhat unstable and cannot withstand long-term storage, it is desirable to prepare it as needed.
[0006]
The reaction between diacetyltartaric anhydride and aniline is carried out by dissolving or suspending the former in an inert solvent such as methylene chloride or chloroform and diluting the aniline directly or in the solvent at room temperature to the boiling temperature of the solvent. By adding. In order to complete the reaction, it is usually heated for several hours.
The produced diacetyl terthranilic acid is extracted using 3.3 molar equivalents of an alkaline aqueous solution, and the extracted layer is kept at about 50 ° C. for a while to hydrolyze the acetyl group. Filter the acid.
[0007]
[Problems to be solved by the invention]
There are few examples of using tartranilic acid as an optical resolution agent on an industrial scale (Japanese Patent Publication No. 57-8102, Montzka, U.S.P.3,452,086 (1969)). However, the present inventors have found that (+)-or (-)-terthranilic acid can be obtained with an inexpensive raw material, a small number of steps and a high yield, and that these tartranilic acids are extremely easy to handle. As a result of research, we learned that manufacturing on an industrial scale greatly contributes to the production of optically active amines obtained by optical resolution, that is, pharmaceuticals, agricultural chemicals, liquid crystal compositions, etc. The present invention was completed by studying methods suitable for industrial production.
(±) -Tartranylic acid is important as an intermediate to obtain (+)-or (−)-Tartranylic acid.
An object of the present invention is to provide a method for industrially advantageously producing tartranilic acid useful as an optical resolution agent.
[0008]
[Means for Solving the Problems]
The present inventors have intensively studied to solve the above-mentioned problems, and in the reaction between tartaric acid and acetic anhydride, instead of the sulfuric acid catalyst which has been conventionally required, no catalyst or a mild organic sulfonic acid, Lewis acid or the like is used. By using a catalyst, it is possible to distill off by-product acetic acid and excess acetic anhydride directly from the reaction mixture, thereby immediately reacting with anilines without isolating unstable diacetyltartaric anhydride. We have found that we can do it and have arrived at the present invention. That is, the present invention can be summarized in the following items.
[0009]
(1) (+)-, (-)-or (±) -tartaric acid 1 molWhereas3.0 to3.5MoleOr 3.38 moles or 3.7Molar acetic anhydrideMixIn the presence of catalytic amounts of organic sulfonic acids or Lewis acidssoThe crystalline (+) −, (−) − or (±) − is characterized in that after reacting by heating to 70 to 100 ° C., acetic acid and excess acetic anhydride as by-products are distilled off. A method for producing diacetyltartaric anhydride.
(2) As described in (1) aboveManufacturingCrystalline (+)-, (-)-or (±) -diacetyltartaric anhydride obtained by the method1 to 1.2 moles of aniline represented by the following formula 1 and an inert solvent are mixed with respect to 1 mole, and reacted in a temperature range from room temperature to the boiling point of the solvent. Diacetyl terthranilic acid is obtained, and 3.3 to 3.5 mol or 3.90 mol or 3.92 mol of alkali can be obtained at room temperature to under cooling without isolation of the diacetyl terthranilic acid. Crystalline (+)-, (-)-or (±) -tartranyl represented by the following formula 3, which is converted into an aqueous solution, hydrolyzed at room temperature or under heating, and then made acidic Method for producing acids.
[Chemical formula 5]
[Chemical 6]
[Chemical 7]
[0010]
(3) Above (1)InDescribedManufacturingCrystalline (+)-, (-)-or (±) -diacetyltartaric anhydride obtained by the method1 to 1.2 mol of aniline represented by Formula 1 and an inert solvent are mixed with respect to 1 mol, and reacted in a temperature range from room temperature to the boiling point of the solvent. Diacetyl terthranilic acids were obtained, and without isolating the diacetyl terthranilic acids, the inert solvent was distilled off and replaced with methanol, and 3.3 to 3.5 mol or 3.90 mol or (+)-, (−)-Or (±) -diacetylterthranilate potassium hydrate represented by the following formula 4 which was hydrolyzed by adding a methanol solution of 3.92 mol of KOH and separated into crystals. A method for producing (+)-, (-)-or (±) -tertranilic acids represented by the crystalline formula 3, wherein the substances are collected by filtration, dissolved in water and rendered acidic.
[0012]
(4) Crystalline (+)-, (-)-or (±) -diacetyltartaric anhydride1 to 1.2 mol of aniline represented by Formula 1 and an inert solvent are mixed with respect to 1 mol, and reacted in a temperature range from room temperature to the boiling point of the solvent. Diacetyl terthranilic acids were obtained, and without isolating the diacetyl terthranilic acids, the inert solvent was distilled off and replaced with methanol, and 3.3 to 3.5 mol or 3.90 mol or (+)-, (−)-Or (±) -diacetylterthranilate potassium hydrate represented by the following formula 4 which was hydrolyzed by adding a methanol solution of 3.92 mol of KOH and separated into crystals. A method for producing (+)-, (-)-or (±) -tertranilic acids represented by the crystalline formula 3, wherein the substances are collected by filtration, dissolved in water and rendered acidic.
[Chemical 8]
[0013]
(5) (−)-Or (±) -Tartranilic acid represented by the following general formula.
[Chemical 9]
DETAILED DESCRIPTION OF THE INVENTION
According to the synthesis method of diacetyltartaric anhydride described in the above Org.Synth., Use of a strong acid catalyst such as sulfuric acid, filtration of the resulting diacetyltartaric anhydride, benzene washing, ether treatment, etc. are not preferable in modern chemical industry. Use of secondary materials and processes unsuitable for handling unstable objects are included. As a result of examining this reaction, the present inventor considered that acetic acid produced by the reaction between tartaric acid and acetic anhydride was distilled off. However, due to the presence of sulfuric acid, diacetyl tartaric acid anhydride is markedly colored even if it is concentrated at low temperature, or neutralized with anhydrous sodium acetate and then concentrated at low temperature. The acid yield and quality were not satisfactory. Therefore, research was conducted on the idea that the problem could be solved by finding a reaction catalyst of (+)-, (-)-or (±) -tartaric acid and acetic anhydride instead of the sulfuric acid catalyst.
[0015]
In the above document, Pressman et al. Reacted diacetyltartaric anhydride with aniline in an inert solvent such as chloroform and methylene chloride, and did not isolate the resulting diacetylterthranilic acid, but extracted it into an excess of alkaline aqueous solution and left the acetyl group as it was. Hydrolyzed and acidified with hydrochloric acid, and the precipitated tartranylic acid is collected by filtration. As a post-treatment for this reaction, the amount of hydrochloric acid to be added must be 3.3 molar equivalents or more based on tartranilic acid. As a result, 2 molar equivalents of acetic acid, 1 molar equivalent of tartranylic acid, and 3.3 molar equivalents of alkali chloride are formed. However, the presence of 2 molar equivalents of acetic acid increases the solubility of the target product, tartranilic acid, resulting in a decrease in yield, and removal of the acetic acid odor is difficult and causes quality degradation. Further, the alkali chloride produced as a by-product adheres to the target substance, and when tartranilic acid is analyzed, the halogen reaction is positive, and recrystallization must be repeated.
The present inventors thought that if these problems could be solved in the post-treatment stage of tartranilic acid synthesis, it would be useful for improving the yield and quality of the target tartranilic acid.
[0016]
The present inventors show that the reaction between (+)-or (−)-tartaric acid and acetic anhydride proceeds easily at about 100 ° C. even when no sulfuric acid catalyst is added, but the reaction between (±) -tartaric acid and acetic anhydride. Was found to be very slow even at 100 ° C. As described above, acetic acid produced as a by-product and excess acetic anhydride may be distilled off for use in the next step without isolating unstable diacetyltartaric anhydride, but diacetyltartaric acid is present because a sulfuric acid catalyst exists. The anhydride browned, and the yield and quality of the target tartranilic acid were not satisfactory. Since the reaction proceeded even without catalyst, an attempt was made to distill off the acetic acid produced as a by-product and excess acetic anhydride. As a result, diacetyltartaric anhydride was obtained in the form of colorless crystals, and the yield was also quantitative.
[0017]
Therefore, the presence or absence of a mild acidic catalyst was further examined. As a result, organic sulfonic acids such as benzene sulfonic acid, toluene sulfonic acid, methane sulfonic acid, and so-called Lewis acids such as zinc chloride, tin chloride, aluminum chloride, and iron chloride are used as acidic catalysts, much more markedly than when no catalyst is used. Shows catalytic effect, tartaric acid disappears at 70-100 ° C in 3-10 minutes, and after reaction for 20-30 minutes, there is no coloring of diacetyltartaric anhydride produced even by distillation of by-product acetic acid and excess acetic anhydride The desired product was obtained in quantitative yield as colorless crystals. Even in the case of the reaction of (±) -tartaric acid and acetic anhydride having low reactivity, the raw tartaric acid disappeared in 10 to 15 minutes, and the same result as in (+)-or (-)-tartaric acid was obtained. These acidic catalysts had no effect on the subsequent steps.
In general, the catalyst is preferably used in the range of 0 to 1.0% by weight based on tartaric acid (catalytic amount).
[0018]
As described in the section of (Prior Art), in the tartranilic acid production process,
1) Isolation of diacetyltartaric anhydride
2) Reaction of diacetyltartaric anhydride and anilines in an inert solvent
3) Extraction and hydrolysis of the generated diacetylterthranilic acid with aqueous caustic solution
4) Isolation of tartranilic acid separated and precipitated as acidic after hydrolysis
5) Purification of tartranilic acid
There is.
According to the present invention, isolation and purification of diacetyltartaric anhydride is unnecessary, and the step 2) is performed immediately after the by-product acetic acid is distilled off. The soluble potassium tartranylate / hydrate is filtered and separated from the easily soluble potassium acetate, and then the steps 4) and 5) are carried out. In the meantime, the steps from the production of diacetyltartaric anhydride to the hydrolysis of diacetyl tartranylic acid can be carried out in one pot without changing the reaction vessel, which is extremely reasonable.
[0019]
That is, by distilling off by-product acetic acid and excess acetic anhydride in the diacetyl tartaric acid anhydride production process, an inert solvent such as methylene chloride, dichloroethane, chloroform, and toluene was poured into the reaction vessel, and most of the diacetyl tartaric acid anhydride was injected. While stirring at room temperature to 40 ° C. while partially suspended, 1.05 to 1.1 is dissolved.6When a molar equivalent of aniline or a halogen-substituted aniline derivative such as 4-chloroaniline is dissolved as it is or slowly dissolved in the solvent, the diacetyltartaric anhydride partially suspended disappears and the reaction proceeds. During this time, there is no significant heat generation, but cooling with running water is necessary. The reaction is completed by keeping at 40 ° C. for 2 to 4 hours after the addition. Then, when the solvent is distilled off, diacetylterthranilic acid is obtained as a viscous oily residue. Diacetyl terthranilic acid is dissolved without adding methanol, and further, KOH 3.3-3.92A molar equivalent of methanol solution is added with water cooling with stirring. After a while, potassium salt begins to precipitate. After the alkali solution is added, hydrolysis is carried out while maintaining the reaction temperature at 60 to 70 ° C.
[0020]
During this time, a large amount of bulky fine crystals are precipitated, but changes to heavy crystals over time. After reacting at 60 to 70 ° C. for 3 to 4 hours, the mixture is sufficiently cooled, and potassium tartranylate is filtered, washed with cold methanol and dried. Yield 80-90%. When a small amount was taken and recrystallized from methanol / water, potassium tartranylate / 1.5 hydrate was obtained, which was analytically consistent.
CTenH13NOFiveK ・ 1.5 H2O (molecular weight 290.307)
Theoretical value: C; 41.38%, H; 4.51%, N; 4.82%
Experimental value: C; 41.43%, H; 4.79%, N; 4.60%
[0021]
This process is shown as follows.
Embedded image
That is, 1 mol of tartranilic acid potassium salt, 2 mol of potassium acetate and 1 mol of water are formed, while the former is hardly soluble in methanol, whereas the latter is extremely soluble. Therefore, both can be easily separated by filtration, and the isolation and purification of tartranilic acid in the next step is facilitated. In this step, when hydrolysis of diacetylterthranilic acid is carried out in an alkaline aqueous solution according to the literature, the amount of hydrochloric acid required for isolating tartranilic acid is 3.3 molar equivalents or more, and acetic acid produced as a by-product is the recovered amount of tartranilic acid. And adversely affects quality. According to the method of the present invention, tartranilic acid potassium salt is dissolved in 4 times the amount of hot water without purification, and when a slightly excess of concentrated hydrochloric acid is added than the calculated amount, tartranilic acid is precipitated. After cooling, the mixture is sufficiently cooled with ice water, filtered, washed with a small amount of cold water and dried to obtain tartranic acid in a yield of about 90%. This product has a purity that can be used for optical resolution as it is, but if necessary, it can be recrystallized from 4 times the amount of water to obtain pure tartranilic acid with a recovery rate of 80-90%.
[0023]
(+)-Tartranylic acid
(+)-(2R, 3R) -2,3-Dihydroxy-4-oxo-4-phenylaminobutanoic acid
CTenH11NOFive(Molecular weight 225.20)
Theoretical value: C; 53.33%, H; 4.92%, N; 6.22%
Experimental value: C; 53.24%, H; 4.99%, N; 6.15%
[Α]D+ 14.0 ° (C 4.05, MeOH, 25 ° C.)
m. p. 179-182 ° C
[0024]
(-)-Tartranylic acid
(-)-(2S, 3S) -2,3-Dihydroxy-4-oxo-4-phenylaminobutanoic acid
CTenH11NOFive(Molecular weight 225.20)
Theoretical value: C; 53.33%, H; 4.92%, N; 6.22%
Experimental value: C; 53.37%, H; 5.12%, N; 6.38%
[Α]D−114.6 ° (C 4.03, MeOH, 25 ° C.)
m. p. 179-182 ° C
[0025]
(±) -Tartranylic acid
(±)-(2RS, 3RS) -2,3-Dihydroxy-4-oxo-4-phenylaminobutanoic acid
CTenH11NOFive(Molecular weight 225.20)
Theoretical value: C; 53.33%, H; 4.92%, N; 6.22%
Experimental value: C; 53.15%, H; 5.05%, N; 6.27%
m. p. 179-182 ° C
[0026]
(+)-4-Chloro-terthranilic acid
(+)-(2R, 3R) -2,3-Dihydroxy-4-oxo-4- (4'-chlorophenylamino) butanoic acid
CTenHTenClNOFive(Molecular weight 269.5)
Theoretical value: C; 46.26%, H; 3.83%, N; 5.40%
Experimental value: C; 46.04%, H; 3.52%, N; 5.45%
[Α]D+ 110.5 ° (C 4.00, MeOH, 25 ° C.)
m. p. 192-195 ° C
[0027]
(-)-4-Chloro-terthranilic acid
(-)-(2S, 3S) -2,3-Dihydroxy-4-oxo-4- (4'-chlorophenylamino) butanoic acid
CTenHTenClNOFive(Molecular weight 269.5)
Theoretical value: C; 46.26%, H; 3.83%, N; 5.40%
Experimental value: C; 46.25%, H; 3.51%, N; 5.28%
[Α]D-112.1 ° (C 4.01, MeOH, 25 ° C)
m. p. 192-195 ° C
The method for producing tartranilic acid described above can be applied using any of (+)-, (-)-and (±) -tartaric acid as a raw material. (−)-And (±) -Tartranilic acid are novel compounds not yet described in literature, and (+)-and (−)-Tartranilic acid can be obtained from (±) -Tartranylic acid by optical resolution.
As a result of research on selection of catalysts and hydrolysis methods so that conventional methods with problems in reactors, processing of intermediate products, auxiliary materials, etc. are suitable for industrial production, high-quality tartranilic acid can be obtained in a short time. Made it possible to obtain a good yield.
[0028]
【Example】
EXAMPLES Hereinafter, although an Example is raised and this invention is demonstrated in more detail, of course, it is not limited to the following Example.
Example 1
(+)-Tartaric acid 75 g (0.50mol), 160 ml of acetic anhydride (d = 1.08, 172.8 g, 1.6).9mol)Is placed in a 1 L eggplant-shaped flask and mounted on a rotary evaporator. When stirred in a boiling water bath, tartaric acid disappeared completely in about 10 minutes to give a colorless homogeneous solution. After stirring for 30 minutes, the bath temperature was lowered to 70 ° C., and acetic acid by-produced and excess acetic anhydride were distilled off as much as possible under reduced pressure to solidify the residue into a crystal lump. After cooling and adding 500 ml of methylene chloride and stirring, most of the diacetyltartaric anhydride was dissolved and partially suspended. To this suspension, 51 g (0.54 of aniline) was stirred.8mol) in 200 ml of methylene chloride was added at a bath temperature of 20-25 ° C. The insoluble material dissolved rapidly and became a pale pink transparent solution. Subsequently, the bath temperature was raised to 40 ° C., and the reaction was further continued for 4 hours. When methylene chloride was distilled off under reduced pressure, diacetylterthranilic acid was obtained as a light brown transparent oil. Without isolating this product, 430 ml of methanol was added and dissolved, and 110 g of KOH (1.96 mo) was added with stirring.l)Of methanol in 400 ml was added while cooling with water. At this time, the reaction temperature rose due to the heat of neutralization, and crystal precipitation began. After the addition, the bath temperature was raised to 70 ° C. and stirring was continued for 4 to 6 hours. During this time, the amount of crystals increased and the stirring effect decreased, but when stirring as it was, the crystal state gradually changed to become heavy crystals. After the reaction, the reaction mixture was cooled and the crystals were filtered with suction. Washing with cold methanol on the funnel and drying gave 117 g (83.2% as monohydrate) of colorless (+)-terthranilic acid potassium salt.
[0029]
(Example 2)
(+)-Tartaric acid 150 g (1.00mol), 350 ml of acetic anhydride (d = 1.08, 378 g, 3.7)0mol)And 1 g of anhydrous zinc chloride are charged into a 2 L eggplant-shaped flask and mounted on a rotary evaporator. When stirred in a boiling water bath, tartaric acid disappeared completely in about 3 minutes to give a colorless homogeneous solution. After stirring for 30 minutes, the bath temperature was lowered to 70 ° C., and acetic acid by-produced and excess acetic anhydride were distilled off as much as possible under reduced pressure to solidify the residue into a crystal lump. After cooling and adding 1200 ml of methylene chloride and stirring, most of the diacetyltartaric anhydride was dissolved and partially suspended. To this suspension, a solution of 108 g (1.16 mol) of aniline in 400 ml of methylene chloride was added at a bath temperature of 20 to 25 ° C. with stirring. The insoluble material dissolved rapidly and became a pale pink transparent solution. Subsequently, the bath temperature was raised to 40 ° C., and the reaction was further continued for 4 hours. When methylene chloride was distilled off under reduced pressure, diacetylterthranilic acid was obtained as a light brown transparent oil. Without isolating this product, 1000 ml of methanol was added and dissolved, and 220 g of KOH (3.92 mo) was stirred with stirring.l)Of methanol in 500 ml was added while cooling with water. At this time, the reaction temperature rose due to the heat of neutralization, and crystal precipitation began. After the addition, the bath temperature was raised to 70 ° C. and stirring was continued for 4 to 6 hours. During this time, the amount of crystals increased and the stirring effect decreased, but when stirring as it was, the crystal state gradually changed to become heavy crystals. After the reaction, the reaction mixture was cooled and the crystals were filtered with suction. Washing with cold methanol on the funnel and drying gave 252 g (89.6% as monohydrate) of colorless (+)-terthranilic acid potassium salt.
[0030]
(Example 3)
(-)-Tartaric acid 15 g (0.10mol), 35 ml of acetic anhydride (d = 1.08, 37.8 g, 0.37 mo)l)Then, 0.1 g of anhydrous zinc chloride is charged into a 200 ml eggplant-shaped flask and mounted on a rotary evaporator. When stirred in a boiling water bath, tartaric acid disappeared completely in about 3 minutes to give a colorless homogeneous solution. After stirring for 30 minutes, the bath temperature was lowered to 70 ° C., and acetic acid by-produced and excess acetic anhydride were distilled off as much as possible under reduced pressure to solidify the residue into a crystal lump. After cooling, 120 ml of methylene chloride was added and stirred, and most of the diacetyltartaric anhydride was dissolved and partially suspended. To this suspension, 10.8 g (0.1% of aniline) was stirred.16mol) in 40 ml of methylene chloride was added at a bath temperature of 20-25 ° C. The insoluble material dissolved rapidly and became a pale pink transparent solution. Subsequently, the bath temperature was raised to 40 ° C. and the reaction was continued for another 4 hours. When methylene chloride was distilled off under reduced pressure, diacetylterthranilic acid was obtained as a light brown transparent oil. Without isolating this product, 100 ml of methanol was added and dissolved, and 22 g of KOH (0.39 mo) was stirred with stirring.l)Of methanol in 50 ml was added while cooling with water. At this time, the reaction temperature rose due to the heat of neutralization, and crystal precipitation began. After the addition, the bath temperature was raised to 70 ° C. and stirring was continued for 4 to 6 hours. During this time, the amount of crystals increased and the stirring effect decreased, but when stirring as it was, the crystal state gradually changed to become heavy crystals. After the reaction, the reaction mixture was cooled and the crystals were filtered with suction. Washing with cold methanol on the funnel and drying gave 25 g (89% as monohydrate) of colorless (-)-tartranyl acid potassium salt.
[0031]
Example 4
(+)-Tartaric acid 15 g (0.10mol), 35 ml of acetic anhydride (d = 1.08, 37.8 g, 0.37 mo)l)And p-toluenesulfonic acid monohydrate (0.1 g), the same reaction as in Example 1 was carried out, and the resulting diacetyltartaric anhydride was converted to 10.8 g (0.116mol). The reaction product (diacetylterthranilic acid) was added with 22 g (0.39 mo) of KOH in methanol.l)To obtain 25 g of (+)-terthranilic acid potassium salt (89% as a monohydrate).
[0032]
(Example 5)
(+)-Tartaric acid 15 g (0.10mol), 35 ml of acetic anhydride (d = 1.08, 37.8 g, 0.37 mo)l)Then, the same reaction as in Example 1 was performed using 0.1 g of methanesulfonic acid, and 10.8 g (0.1% of aniline) of the obtained diacetyltartaric anhydride was obtained.16mol). The reaction product (diacetylterthranilic acid) was added with 22 g (0.39 mo) of KOH in methanol.l)To obtain 23 g of (+)-tartranyl acid potassium salt (82% as a monohydrate).
[0033]
(Example 6)
(±) -tartaric acid 15 g (0.10mol), 35 ml of acetic anhydride (d = 1.08, 37.8 g, 0.37 mo)l)Then, the same reaction as in Example 1 was performed using 0.1 g of anhydrous zinc chloride, and 10.8 g (0.1% of aniline) of the obtained diacetyltartaric acid anhydride was obtained.16mol). The reaction product (diacetylterthranilic acid) was added with 22 g (0.39 mo) of KOH in methanol.l)To obtain 24 g of (±) -tartranyl acid potassium salt (85% as a monohydrate).
[0034]
(Example 7)
(+)-Tartaric acid 15 g (0.10mol), 35 ml of acetic anhydride (d = 1.08, 37.8 g, 0.37 mo)l)Then, the same reaction as in Example 1 was performed using 0.1 g of stannic chloride, and 10.8 g of aniline (0.116mol). The reaction product (diacetylterthranilic acid) was added with 22 g (0.39 mo) of KOH in methanol.l)To obtain 24 g (85% as a monohydrate) of (+)-terthranilic acid potassium salt.
[0035]
(Example 8)
(+)-Tartaric acid 75 g (0.50mol), 160 ml of acetic anhydride (d = 1.08, 172.8 g, 1.69 mo)l)Then, 0.5 g of anhydrous zinc chloride is charged into a 1 L eggplant-shaped flask and attached to a rotary evaporator. When stirred in a boiling water bath, tartaric acid disappeared completely in about 10 minutes to give a colorless homogeneous solution. After stirring for 30 minutes, the bath temperature was lowered to 70 ° C., and acetic acid by-produced and excess acetic anhydride were distilled off as much as possible under reduced pressure to solidify the residue into a crystal lump. After cooling and adding 500 ml of methylene chloride and stirring, most of the diacetyltartaric anhydride was dissolved and partially suspended. To this suspension, 51 g (0.54 of aniline) was stirred.8mol) in 200 ml of methylene chloride was added at a bath temperature of 20-25 ° C. The insoluble material dissolved rapidly and became a pale pink transparent solution. Subsequently, the bath temperature was raised to 40 ° C., and the reaction was further continued for 4 hours. After cooling to room temperature, 110 g of KOH (1.96 mo)l)Diacetylterthranilic acid was extracted into an aqueous layer with 600 ml of water and hydrolyzed by keeping it at 40 ° C. for 2 hours. 200 mL of concentrated hydrochloric acid was added to the yellowish brown aqueous solution to make it acidic, and after sufficiently cooling in ice water, the precipitated tartranic acid was subjected to absorption filtration. The filter funnel was washed with a small amount of cold water and dried. Yield 81.7 g (72.6%). It was light brown with a slight acetic acid odor, and the hot water solution was strongly positive for the halogen test. This product was recrystallized from 300 ml of water to obtain tartranylic acid having a low halogen content at a recovery rate of 68 g (recovery rate: 83%).
[0036]
Example 9
One liter of water was added to 252 g (0.89 mol) of (+)-terthranilic acid potassium salt monohydrate synthesized according to Examples 1 to 7 and dissolved by heating. When 100 ml of concentrated hydrochloric acid was added to this hot aqueous solution, it reacted exothermically to precipitate (+)-terthranilic acid. The mixture was sufficiently cooled in ice water, and the crystals were filtered by suction, washed with a small amount of cold water on the filter funnel and dried. 185 g (92%). This product was almost colorless long flake crystals and was slightly positive for the halogen test. Further, recrystallization from 750 ml of water gave 149 g (80.5% recovery) of pure (+)-terthranilic acid.
[0037]
(Example 10)
255.5 g (0.91 mol) of (+)-terthranilic acid potassium salt monohydrate was added to the (+)-terthranilic acid recrystallization mother liquor (about 850 ml) described in Example 9 and dissolved by heating. 90 ml of concentrated hydrochloric acid was added. The reaction was exothermic and (+)-tartranic acid was precipitated. The mixture was sufficiently cooled in ice water, and the crystals were filtered by suction, washed with a small amount of cold water on the filter funnel and dried. 216 g (92%). This product was almost colorless long flake crystals and was slightly positive for the halogen test. Further, 172 g (79.5% recovery rate) of pure (+)-terthranilic acid was obtained by recrystallization from 800 ml of water.
[0038]
(Example 11)
According to Example 6, 15 g (0.1 mol) of (+)-tartaric acid, 35 ml of acetic anhydride and 0.1 g of anhydrous zinc chloride were reacted to obtain (+)-diacetyltartaric anhydride, which was reacted with 4-chloroaniline. To 4′-chloro-diacetylterthranilic acid. This material was hydrolyzed with KOH in methanol to give 27.8 g (88%) of 4'-chlorterthranilic acid potassium salt hydrate. This product was dissolved in 150 ml of hot water, acidified with 11 ml of concentrated hydrochloric acid, treated according to a conventional method, and 23.5 g of (+)-4′-chlortarranic acid (90% recovery, yield 79.2%). ) m. p. 192-194 ° C, [α]D+ 111.0 ° (C 2.3, EtOH, 25 ° C)
[0039]
Example 12
According to Example 4, 15 g (0.1 mol) of (-)-tartaric acid, 35 ml of acetic anhydride and 0.1 g of p-toluenesulfonic acid were obtained to obtain diacetyltartaric anhydride, which was reacted with 4-chloroaniline. Derived to 4'-chloro-diacetylterthranilic acid. This material was hydrolyzed with KOH in methanol to give 28.4 g (90%) of 4'-chlorterthranilic acid potassium salt hydrate. This product was dissolved in 150 ml of hot water, acidified with 11 ml of concentrated hydrochloric acid, treated according to a conventional method, and 23.8 g of (−)-4′-chlortarranic acid (88% recovered, yield 80.1%) ) m. p. 192-194 ° C, [α]D-111.0 ° (C 2.2, EtOH, 25 ° C). Recrystallize the product from water, m. p. 192-195 ° C, [α]DA pure product of −112.1 ° (C 4.01, EtOH, 25 ° C.) was obtained.
[0040]
(Reference example)
75 g (0.5 mol) of (+)-tartaric acid was added to 170 ml of acetic anhydride, and 4 drops of concentrated sulfuric acid was added thereto, followed by stirring at 75 ° C., and tartaric acid dissolved and disappeared in about 2 minutes. The reaction was allowed to proceed for 30 minutes, and 0.3 g of anhydrous sodium acetate was added thereto and stirred for 10 minutes. By-product acetic acid and excess acetic anhydride were distilled off under reduced pressure at 70 to 75 ° C. The reaction gradually became brownish. Thereafter, the reaction was carried out according to Example 1 to obtain 96 g of (+)-terthranilic acid potassium salt monohydrate colored brown. This product was treated according to a conventional method to obtain 60 g (53.3%) of impure tartranic acid.
[0041]
【The invention's effect】
i) In the reaction of tartaric acid and acetic anhydride, by using a non-catalytic catalyst or a mild catalyst such as organic sulfonic acid or Lewis acid instead of the sulfuric acid catalyst which has been conventionally required, acetic acid produced as a by-product or excess It was possible to distill off acetic anhydride directly from the reaction mixture. This allows immediate reaction with anilines without isolating unstable diacetyltartaric anhydride.
ii) Diacetylterthranilic acid is hydrolyzed with KOH in methanol, and the resulting methanol-poor tartranyl acid potassium salt monohydrate is easily and highly purified from the easily soluble potassium acetate salt simply by filtering and washing. Can be separated.
iii) As a result, the amount of hydrochloric acid required for metathesis of potassium tartranylate can be reduced to 1/3, and at the same time, the by-product of acetic acid can be avoided. There is almost no salt contamination.
Claims (4)
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| JP2007291096A (en) * | 2006-03-31 | 2007-11-08 | National Institute Of Advanced Industrial & Technology | Selective sequential polyacylation and device therefor |
| JP2007297338A (en) * | 2006-04-28 | 2007-11-15 | National Institute Of Advanced Industrial & Technology | N-acyl compound, and method and device for producing the same |
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