JP4453247B2 - Method for purifying 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride - Google Patents
Method for purifying 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride Download PDFInfo
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Description
【０００１】
【発明の属する技術分野】
本発明は、医薬、農薬等の中間体として有用な３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物（以下、酸無水物と略する。）の精製方法に関する。
【０００２】
【従来の技術】
従来、酸無水物を反応で得られた未精製物から精製する方法として例えば、１−メチル−２−ピロリジノンを反応溶媒として用いた場合には減圧下（１ｍｍＨｇ）に回転バンド塔を用いて１−メチル−２−ピロリジノンを精留により留去させる方法（特許文献１参照。）、また未精製物に水と活性炭を加えて１００℃以上で加熱処理した後、不溶物をろ過し、水を減圧下に除去した後再度無水物化する方法（特許文献２、非特許文献１参照。）等が知られている。
【０００３】
【特許文献１】
特開昭５７−１２０５４８号公報
【特許文献２】
特開昭６１−１７１４５３号公報
【非特許文献１】
Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，(２１)，１８７４（１９７８）
【０００４】
【発明が解決しようとする課題】
上記従来法において、前者の反応溶媒である１−メチル−２−ピロリジノンを精留により除去する方法は、目的物である酸無水物と１−メチル−２−ピロリジノンの沸点が近く回転バンド塔などの特殊な分離装置が必要であり、かつ精留残渣に目的物を残すため必ずしも精製が充分なものとはいい難い方法である。さらに、反応後の粗生成物は酸性状態であるため酸無水物が熱的に不安定であり酸無水物自体の蒸留精製が困難な方法である。
また、後者の活性炭処理を行う方法ではタール化、高分子量化した成分などは除去可能であるが、１−メチル−２−ピロリジノンなどの高沸点、親水性溶媒を分離することはできないといった問題点があり、いずれも酸無水物の精製方法としては必ずしも充分に満足できるものではなかった。
【０００５】
【課題を解決するための手段】
本発明者は、下記式（１）で示される３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物の工業的有利な精製方法について鋭意検討したところ、反応で得られた式（１）で示される３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物を含む未精製物を加水分解して、一般式（２）で示されるジカルボン酸の塩に変換し、これを水に溶解させ水に不溶の有機溶媒を用いて洗浄することにより不要な成分を除去し、次いで酸で処理することにより得られる式（３）で示されるジカルボン酸をアシル化剤で処理することにより、式（１）で示される３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物に再度変換することで高純度な酸無水物が得られることを見出した。
この精製操作により酸無水物の熱的な安定性が向上し、さらに精製するために蒸留等の操作を行う際に歩留りよく高純度な酸無水物が得られるものである。
すなわち本発明は、式（１）
で示されるジカルボン酸の塩とし、ついで、水に不溶の有機溶媒で洗浄・分液して得られる水層を酸性とし、式（３）
【０００６】
【発明の実施の形態】
本発明の出発物質となる式（１）で示される３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物（以下、無水物（１）と略記する。）の未精製物は例えば特許文献１に記載の方法または製造例１に記載の方法等により得ることができるが、これらに限定されるものではない。これら未精製物中には例えば塩酸、硫酸、酢酸などの酸、１−メチル−２−ピロリジノンなどの高沸点の親水性溶媒、またはタール化した成分などが不純物として含まれる。
【０００７】
未精製の無水物（１）は水を用いた加水分解により式（３）で示される３，３−ジメチルシクロプロパン−１，２−ジカルボン酸（以下、ジカルボン酸（３）と略記する。）に変換した後、無機塩基により一般式（２）で示されるジカルボン酸の塩（以下、ジカルボン酸塩類（２）と略記する。）に誘導する。または直接無機塩基の水溶液を用いた加水分解によりジカルボン酸塩類（２）に誘導することもできる。
【０００８】
かかる加水分解に用いる水の量は無水物（１）に対して通常０．２〜５０重量倍、好ましくは０．５〜１０重量倍である。
【０００９】
無機塩基としては例えば水酸化リチウム、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、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム等のアルカリ金属およびアルカリ土類金属の炭酸塩、炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属の炭酸水素塩などが挙げられ、好ましくはアルカリ金属水酸化物が用いられる。
かかる塩基の使用量は未精製物中に含まれる無水物（１）を除いた酸を中和せしめる量に加えて、無水物（１）に対し通常１モル倍以上、好ましくは１〜２モル倍程度の範囲である。無水物（１）を加水分解すると、ジカルボン酸となり、塩基はモノカルボン酸を中和する量以上が必要である。未精製物中の酸の量が不明な場合には反応溶液のｐＨで無機塩基の使用量を決定することもできる。かかるｐＨとしては通常７以上、好ましくは７〜９の範囲である。
かかる塩基は通常、水溶液として用いられるが反応溶液中に水が存在する場合には固体を用いることもできる。
【００１０】
加水分解の反応温度は通常０〜１００℃、好ましくは２０〜８０℃である。
反応時間は原料である無水物（１）が消失すればよく、特に限定されるものではないが、通常０．５時間以上である。
【００１１】
得られたジカルボン酸塩類（２）の水溶液にこの溶液と分液可能な有機溶媒を加えて混合、洗浄し、分液により中性成分である１−メチル−２−ピロリジノンなどの高沸点の親水性溶媒などを有機層に除去することができる。洗浄、分液操作は除去可能な成分の水層中の残存量が所望の量まで減少するまで複数回行なわれてもよい。
【００１２】
かかる有機溶媒としては、例えば酢酸メチル、酢酸エチル等のエステル系溶媒、トルエン、キシレン、クロロベンゼン等の芳香族炭化水素系溶媒、ペンタン、ヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素系溶媒、ジクロロメタン、ジクロロエタン、四塩化炭素等のハロゲン化脂肪族炭化水素系溶媒、ジエチルエーテル、ジイソプロピルエーテル、ｔ−ブチルメチルエーテル、テトラヒドロフランなどのエーテル系溶媒、アセトン、メチルエチルケトン、メチルイソブチルケトン等のケトン系溶媒、アセトニトリル、プロピオニトリル等のニトリル系溶媒等が挙げられる。これらは単独または２種以上を混合して用いることができ、好ましく酢酸エチルとアセトンの混合溶媒、メチルイソブチルケトン、テトラヒドロフラン等が用いられる。
【００１３】
かかる有機溶媒の使用量は洗浄操作１回当たり無水物（１）に対して通常０．５〜５０重量倍、好ましくは１〜２０重量倍である。
【００１４】
洗浄、分液操作の際に不溶成分の析出等により分液が困難となる場合には、濾過により不溶成分を除去することで分液を容易にすることができる。またその際に濾過助剤を用いることもできる。さらにかかる濾過操作はジカルボン酸塩類（２）を得るために使用される無機塩基を加える前、使用量の全量を加える途中段階、加え終わった後のいずれの段階でも行なうことができる。
【００１５】
かくして得られるジカルボン酸塩類（２）としては例えば、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸モノナトリウム塩、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸ジナトリウム塩、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸モノカリウム塩、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸ジカリウム塩、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸モノリチウム塩、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸ジリチウム塩、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸カルシウム塩等が挙げられる。
【００１６】
有機溶媒による洗浄操作の後、得られたジカルボン酸塩類（２）を含む溶液に塩酸、硫酸、りん酸等の無機酸を加えて塩分解し、ジカルボン酸（３）へ誘導し、水層と分液可能な有機溶媒を用いて有機層へジカルボン酸（３）を抽出することで、出発原料である未精製の無水物（１）中に含まれる酸成分を除去することができる。
【００１７】
かかる塩分解の際に使用される無機酸の量は溶液のｐＨにより決定され、かかるｐＨとしては通常０〜６、好ましくは１〜３の範囲である。
【００１８】
ジカルボン酸（３）の抽出に用いられる有機溶媒としては、例えば酢酸メチル、酢酸エチル等のエステル系溶媒、トルエン、キシレン、クロロベンゼン等の芳香族炭化水素系溶媒、ジクロロメタン、ジクロロエタン、四塩化炭素等のハロゲン化脂肪族炭化水素系溶媒、ジエチルエーテル、ジイソプロピルエーテル、ｔ−ブチルメチルエーテル等のエーテル系溶媒、メチルエチルケトン、メチルイソブチルケトン等のケトン系溶媒等が挙げられる。これらは単独または２種以上を混合して用いることができ、好ましく酢酸エチルが用いられる。
【００１９】
かかる有機溶媒の使用量は洗浄操作１回当たり無水物（１）に対して通常０．５〜５０重量倍、好ましくは１〜２０重量倍である。
【００２０】
分液操作の際に不溶成分の析出等により分液が困難となる場合には、濾過により不溶成分を除去することで分液を容易にすることができる。またその際に濾過助剤を用いることもできる。
【００２１】
得られたジカルボン酸（３）を含む有機層は続いて以降の反応に用いてよいし、濃縮して一旦ジカルボン酸（３）を取り出してもよい。また再結晶、シリカゲルカラムクロマト等によりさらに精製してもよい。再結晶の方法としては例えば、抽出に用いた溶媒等に加熱溶解させたのち冷却により結晶化させる方法、また抽出に用いた溶媒等に溶解させたのち貧溶媒を加えることにより析出させる方法等が挙げられる。かかる貧溶媒としては例えばヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素系溶媒等が挙げられる。
【００２２】
得られたジカルボン酸（３）は例えば無水酢酸、塩化アセチル等のアシル化剤を加え、加熱することで容易に無水物（１）へ誘導することができ、反応終了後反応試剤であるアセチル化剤および反応で生じる酢酸、塩酸などの酸を濃縮等により除去するだけで目的とする高純度の無水物（１）を得ることができる。
【００２３】
アシル化剤の使用量としてはジカルボン酸（３）に対して通常１〜１０モル倍、好ましくは２〜５モル倍である。
【００２４】
反応温度は通常２０〜１５０℃、好ましくは５０〜１２０℃である。
反応時間は原料であるジカルボン酸（３）が所望の量まで減少すればよく、特に制限されるものではないが、通常０．５時間以上である。
【００２５】
かくして得られた無水物（１）はさらに蒸留、再結晶等の操作を行いさらに精製することもできる。
【００２６】
蒸留は常圧下または減圧下で加熱し、単蒸留により、容易にさらに高純度な無水物（３）を得ることができる。
【００２７】
再結晶の方法としては例えば、ジカルボン酸（３）の抽出に用いた溶媒等に加熱溶解させたのち冷却により結晶化させる方法、また抽出に用いた溶媒等に溶解させたのち貧溶媒を加えることにより析出させる方法等が挙げられる。かかる貧溶媒としては例えばヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素系溶媒等が挙げられる。
【００２８】
【発明の効果】
本発明の方法によれば、医薬、農薬等の中間体として有用な３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物を工業的に有利に精製することが可能である。
【００２９】
【実施例】
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれら実施例に限定されるものではない。
【００３０】
製造例１
３，３−ジメチルシクロプロパン−１，２−ジカルボン酸（Ｔｒａｎｓ／ｃｉｓ比＝６４／３６）５８５．６重量部を含む酢酸エチル溶液８６０重量部に１−メチル−２−ピロリジノン２９３重量部、無水酢酸１１３４重量部、硫酸７２．６重量部を加え、内温を１７０℃まで８．３時間かけて昇温した。１７０〜１７４℃の範囲で４時間保温し３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物４７９．３重量部を含む溶液９７７重量部を得た。この溶液中には３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物以外に１−メチル−２−ピロリジノン２４１．６重量部、硫酸７２．６重量部、無水酢酸３２．０重量部、酢酸１３１．３重量部が含まれていた。
【００３１】
実施例１
製造例１で得られた３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物４７９．３重量部を含む溶液９７７重量部を水６８５重量部に内温４３〜５２℃で０．５時間かけて滴下し、同温で２時間保温した。この溶液に４０％水酸化ナトリウム水溶液８５．０重量部を加えてｐＨを２．０に調整した。酢酸エチル３４０５重量部とラジオライト（珪藻土）１１７重量部を加え、２０〜３４℃で１時間攪拌した後、ろ過により不溶物を除去した。ろ過残渣はアセトン５８６重量部続いて酢酸エチル１０５４重量部で洗浄した。ろ液に３０℃で４０％水酸化ナトリウム水溶液７０２．０重量部を加えｐＨを７．７に調整した後、上層を分液により除去した。下層は酢酸エチル４０９９重量部、アセトン５８６重量部を用いて２回洗浄を行なった後、酢酸エチル４３９２重量部、水２３４重量部を加えた後、３５％塩酸を加えｐＨを２．４に調整した。ラジオライト（珪藻土）６０重量部を加え、３０℃で１時間攪拌した後、ろ過により不溶物を除去した。ろ過残渣は酢酸エチル２７４重量部で洗浄した。ろ液を分液し３，３−ジメチルシクロプロパン−１，２−ジカルボン酸を含む有機層を得た。水層から酢酸エチル２３４２重量部を用いてさらに２回抽出を行い、得られた３つの有機層を合計すると３，３−ジメチルシクロプロパン−１，２−ジカルボン酸５３４．０重量部を含む溶液１０８７０重量部が得られた。（収率９８．７％） この溶液中には３，３−ジメチルシクロプロパン−１，２−ジカルボン酸以外に１−メチル−２−ピロリジノン２４．５重量部、酢酸１８２．９重量部が含まれていた。
この溶液を減圧条件下（２１〜３９ＫＰａ）に溶媒を留去した後、無水酢酸１０３４重量部を加え、１００℃まで２時間かけて昇温した。同温で１時間保温した後、減圧条件下（３〜１９ＫＰａ）、内温３６〜１２０℃で無水酢酸および酢酸を留去し、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物４７０.４重量部（純分４４７．１重量部）を得た。（含量９５．０％、収率９４．５％） この溶液中には３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物以外に１−メチル−２−ピロリジノン２１．５重量部、無水酢酸２．０重量部、酢酸１．２重量部が含まれていた。
【００３２】
実施例２
実施例１で得られた３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物４４９．５重量部（純分４２７．３重量部）を減圧条件下（１〜３ＫＰａ）、内温１２９〜１４４℃で単蒸留し、留出液温度１００〜１４０℃の３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物である留分４１４．２重量部（純分３９５．９重量部）を取得した。（含量９５．６％、蒸留収率９２．７％） この留分には３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物以外に１−メチル−２−ピロリジノン１５．９重量部、無水酢酸１．９重量部、酢酸０．７重量部が含まれていた。
【００３３】
実施例３
実施例２の蒸留で得られた３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物３９７．８重量部（純分３８０．２重量部）をｔｅｒｔ−ブチルメチルエーテル３９１重量部に混合させた溶液にｎ−ヘキサン７６重量部を内温２４〜２７℃で１時間かけて滴下し、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物の種晶０．３重量部を加えて１時間攪拌した。さらにｎ−ヘキサン２９６４重量部を１時間かけて同温で滴下した後、０℃まで５時間かけて冷却した。同温１時間保温した後、結晶をろ過した。得られた結晶はｔｅｒｔ−ブチルメチルエーテル７６重量部、ｎ−ヘキサン６０８重量部からなる溶液で洗浄した後、ろ過器上で窒素を通気させ溶媒を乾燥させ、３，３−ジメチルシクロプロパン−１，２−ジカルボン酸無水物３５１．３重量部（純分３５０．５重量部）を得た。（含量９９．８％、再結晶収率９２．２％）[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for purifying 3,3-dimethylcyclopropane-1,2-dicarboxylic acid anhydride (hereinafter abbreviated as acid anhydride) useful as an intermediate for pharmaceuticals, agricultural chemicals and the like.
[0002]
[Prior art]
Conventionally, as a method of purifying an acid anhydride from an unpurified product obtained by the reaction, for example, when 1-methyl-2-pyrrolidinone is used as a reaction solvent, a 1 is obtained using a rotating band tower under reduced pressure (1 mmHg). -A method of distilling off methyl-2-pyrrolidinone by rectification (see Patent Document 1), adding water and activated carbon to an unpurified product and heat-treating it at 100 ° C or higher, filtering insoluble matter, A method of removing the product under reduced pressure and then making it anhydrous again (see Patent Document 2 and Non-Patent Document 1) is known.
[0003]
[Patent Document 1]
Japanese Patent Laid-Open No. 57-120548 [Patent Document 2]
JP 61-171453 [Non-patent Document 1]
Tetrahedron Lett. , (21), 1874 (1978)
[0004]
[Problems to be solved by the invention]
In the above-mentioned conventional method, the former method of removing 1-methyl-2-pyrrolidinone, which is a reaction solvent, by rectification is a method in which the boiling points of the target acid anhydride and 1-methyl-2-pyrrolidinone are close to each other. This is a method that requires a special separation apparatus and is not necessarily sufficiently purified because the target product remains in the rectification residue. Furthermore, since the crude product after the reaction is in an acidic state, the acid anhydride is thermally unstable, and it is difficult to distill and purify the acid anhydride itself.
In addition, although the latter activated carbon treatment can remove tarized and high molecular weight components, it has a problem that it cannot separate high-boiling and hydrophilic solvents such as 1-methyl-2-pyrrolidinone. None of these methods were sufficiently satisfactory as a method for purifying acid anhydrides.
[0005]
[Means for Solving the Problems]
When this inventor earnestly examined the industrially advantageous refinement | purification method of the 3, 3- dimethylcyclo propane- 1, 2- dicarboxylic acid anhydride shown by following formula (1), formula (1) obtained by reaction was obtained. The unpurified product containing 3,3-dimethylcyclopropane-1,2-dicarboxylic acid anhydride represented by formula (2) is hydrolyzed and converted into a salt of dicarboxylic acid represented by formula (2), which is converted into water. By treating with an acylating agent the dicarboxylic acid represented by the formula (3) obtained by removing the unnecessary components by dissolving in water and washing with an organic solvent insoluble in water and then treating with an acid. The present inventors have found that a high-purity acid anhydride can be obtained by converting again to 3,3-dimethylcyclopropane-1,2-dicarboxylic acid anhydride represented by the formula (1).
This purification operation improves the thermal stability of the acid anhydride, and yields a high-purity acid anhydride with a high yield when performing operations such as distillation for further purification.
That is, the present invention provides the formula (1)
And then the aqueous layer obtained by washing and separating with an organic solvent insoluble in water is acidified, and the formula (3)
[0006]
DETAILED DESCRIPTION OF THE INVENTION
An unpurified product of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid anhydride (hereinafter abbreviated as anhydride (1)) represented by the formula (1) which is a starting material of the present invention is disclosed in, for example, a patent. Although it can obtain by the method of literature 1, the method of the manufacture example 1, etc., it is not limited to these. These unpurified products contain, for example, acids such as hydrochloric acid, sulfuric acid and acetic acid, hydrophilic solvents having a high boiling point such as 1-methyl-2-pyrrolidinone, or tarred components as impurities.
[0007]
The crude anhydride (1) is 3,3-dimethylcyclopropane-1,2-dicarboxylic acid represented by the formula (3) by hydrolysis with water (hereinafter abbreviated as dicarboxylic acid (3)). Is converted into a salt of a dicarboxylic acid represented by the general formula (2) (hereinafter abbreviated as dicarboxylic acid salts (2)) with an inorganic base. Alternatively, the dicarboxylic acid salts (2) can be derived directly by hydrolysis using an aqueous solution of an inorganic base.
[0008]
The amount of water used for the hydrolysis is usually 0.2 to 50 times by weight, preferably 0.5 to 10 times by weight with respect to the anhydride (1).
[0009]
Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal and alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and calcium carbonate, hydrogen carbonate Examples thereof include alkali metal hydrogen carbonates such as sodium and potassium hydrogen carbonate, and alkali metal hydroxides are preferably used.
The amount of the base used is usually 1 mole or more, preferably 1 to 2 moles relative to the anhydride (1), in addition to the amount for neutralizing the acid excluding the anhydride (1) contained in the crude product. The range is about double. When the anhydride (1) is hydrolyzed, it becomes a dicarboxylic acid, and the base needs to be more than the amount that neutralizes the monocarboxylic acid. When the amount of acid in the unpurified product is unknown, the amount of inorganic base used can be determined by the pH of the reaction solution. Such pH is usually 7 or more, preferably in the range of 7-9.
Such a base is usually used as an aqueous solution, but if water is present in the reaction solution, a solid can also be used.
[0010]
The reaction temperature for the hydrolysis is usually 0 to 100 ° C, preferably 20 to 80 ° C.
The reaction time is not particularly limited as long as the anhydride (1) as a raw material disappears, but it is usually 0.5 hours or longer.
[0011]
An organic solvent that can be separated from this solution is added to the aqueous solution of the obtained dicarboxylate (2), mixed, washed, and separated into high-boiling hydrophilic substances such as 1-methyl-2-pyrrolidinone, which is a neutral component. An organic solvent or the like can be removed from the organic layer. The washing and liquid separation operations may be performed a plurality of times until the remaining amount of the removable component in the aqueous layer is reduced to a desired amount.
[0012]
Examples of the organic solvent include ester solvents such as methyl acetate and ethyl acetate, aromatic hydrocarbon solvents such as toluene, xylene, and chlorobenzene, aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and cyclohexane, dichloromethane, Halogenated aliphatic hydrocarbon solvents such as dichloroethane and carbon tetrachloride, ether solvents such as diethyl ether, diisopropyl ether, t-butyl methyl ether and tetrahydrofuran, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, acetonitrile, Examples thereof include nitrile solvents such as propionitrile. These can be used alone or in admixture of two or more. Preferably, a mixed solvent of ethyl acetate and acetone, methyl isobutyl ketone, tetrahydrofuran or the like is used.
[0013]
The amount of the organic solvent used is usually 0.5 to 50 times by weight, preferably 1 to 20 times by weight, relative to the anhydride (1) per washing operation.
[0014]
In the case where separation becomes difficult due to precipitation of insoluble components during washing and liquid separation operations, separation can be facilitated by removing the insoluble components by filtration. In this case, a filter aid can also be used. Further, such a filtration operation can be carried out at any stage before adding the inorganic base used to obtain the dicarboxylic acid salts (2), during the process of adding the total amount of use, or after the addition.
[0015]
Examples of the dicarboxylic acid salts (2) thus obtained include 3,3-dimethylcyclopropane-1,2-dicarboxylic acid monosodium salt, 3,3-dimethylcyclopropane-1,2-dicarboxylic acid disodium salt, 3 , 3-Dimethylcyclopropane-1,2-dicarboxylic acid monopotassium salt, 3,3-dimethylcyclopropane-1,2-dicarboxylic acid dipotassium salt, 3,3-dimethylcyclopropane-1,2-dicarboxylic acid monolithium Salt, 3,3-dimethylcyclopropane-1,2-dicarboxylic acid dilithium salt, 3,3-dimethylcyclopropane-1,2-dicarboxylic acid calcium salt, and the like.
[0016]
After washing with an organic solvent, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or the like is added to the resulting solution containing the dicarboxylic acid salts (2) for salt decomposition, leading to dicarboxylic acid (3), By extracting the dicarboxylic acid (3) into the organic layer using a liquid-separable organic solvent, the acid component contained in the unpurified anhydride (1) as a starting material can be removed.
[0017]
The amount of the inorganic acid used in the salt decomposition is determined by the pH of the solution, and the pH is usually 0 to 6, preferably 1 to 3.
[0018]
Examples of the organic solvent used for extraction of the dicarboxylic acid (3) include ester solvents such as methyl acetate and ethyl acetate, aromatic hydrocarbon solvents such as toluene, xylene and chlorobenzene, dichloromethane, dichloroethane, carbon tetrachloride and the like. Examples thereof include halogenated aliphatic hydrocarbon solvents, ether solvents such as diethyl ether, diisopropyl ether and t-butyl methyl ether, and ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone. These can be used alone or in combination of two or more, and ethyl acetate is preferably used.
[0019]
The amount of the organic solvent used is usually 0.5 to 50 times by weight, preferably 1 to 20 times by weight, relative to the anhydride (1) per washing operation.
[0020]
When separation becomes difficult due to precipitation of insoluble components during the separation operation, separation can be facilitated by removing the insoluble components by filtration. In this case, a filter aid can also be used.
[0021]
The obtained organic layer containing the dicarboxylic acid (3) may be used for subsequent reactions, or may be concentrated to take out the dicarboxylic acid (3) once. Further, it may be further purified by recrystallization, silica gel column chromatography or the like. Examples of the recrystallization method include a method of heating and dissolving in a solvent used for extraction, followed by crystallization by cooling, a method of dissolving in a solvent used for extraction and the like, and precipitating by adding a poor solvent. Can be mentioned. Examples of such a poor solvent include aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane.
[0022]
The obtained dicarboxylic acid (3) can be easily derived into the anhydride (1) by adding an acylating agent such as acetic anhydride or acetyl chloride and heating, and acetylation as a reaction reagent after completion of the reaction. The desired high-purity anhydride (1) can be obtained simply by removing the agent and acids such as acetic acid and hydrochloric acid produced by the reaction by concentration or the like.
[0023]
The amount of the acylating agent used is usually 1 to 10 mol times, preferably 2 to 5 mol times based on the dicarboxylic acid (3).
[0024]
The reaction temperature is usually 20 to 150 ° C, preferably 50 to 120 ° C.
The reaction time is not particularly limited as long as the dicarboxylic acid (3) as a raw material is reduced to a desired amount, but it is usually 0.5 hours or longer.
[0025]
The anhydride (1) thus obtained can be further purified by further operations such as distillation and recrystallization.
[0026]
Distillation can be carried out under normal pressure or reduced pressure, and simpler distillation can easily obtain a higher purity anhydride (3).
[0027]
Examples of the recrystallization method include a method of heating and dissolving in the solvent used for extraction of the dicarboxylic acid (3) and then crystallizing by cooling, or a method of adding a poor solvent after dissolving in the solvent used for extraction. And the like. Examples of such a poor solvent include aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane.
[0028]
【The invention's effect】
According to the method of the present invention, 3,3-dimethylcyclopropane-1,2-dicarboxylic acid anhydride useful as an intermediate for pharmaceuticals, agricultural chemicals and the like can be industrially advantageously purified.
[0029]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.
[0030]
Production Example 1
293 parts by weight of 1-methyl-2-pyrrolidinone and 860 parts by weight of an ethyl acetate solution containing 585.6 parts by weight of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid (Trans / cis ratio = 64/36) 1134 parts by weight of acetic acid and 72.6 parts by weight of sulfuric acid were added, and the internal temperature was raised to 170 ° C. over 8.3 hours. The solution was kept at 170 to 174 ° C. for 4 hours to obtain 977 parts by weight of a solution containing 479.3 parts by weight of 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride. In this solution, in addition to 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride, 241.6 parts by weight of 1-methyl-2-pyrrolidinone, 72.6 parts by weight of sulfuric acid, 32.0 parts by weight of acetic anhydride And 131.3 parts by weight of acetic acid.
[0031]
Example 1
977 parts by weight of a solution containing 479.3 parts by weight of 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride obtained in Production Example 1 was added to 685 parts by weight of water at an internal temperature of 43 to 52 ° C. The solution was added dropwise over time, and kept at the same temperature for 2 hours. To this solution, 85.0 parts by weight of 40% aqueous sodium hydroxide solution was added to adjust the pH to 2.0. After adding 3405 parts by weight of ethyl acetate and 117 parts by weight of radiolite (diatomaceous earth), the mixture was stirred at 20 to 34 ° C. for 1 hour, and then insoluble matters were removed by filtration. The filtration residue was washed with 586 parts by weight of acetone and then 1054 parts by weight of ethyl acetate. After adding 702.0 parts by weight of a 40% aqueous sodium hydroxide solution to the filtrate at 30 ° C. to adjust the pH to 7.7, the upper layer was removed by liquid separation. The lower layer was washed twice with 4099 parts by weight of ethyl acetate and 586 parts by weight of acetone, then 4392 parts by weight of ethyl acetate and 234 parts by weight of water were added, and 35% hydrochloric acid was added to adjust the pH to 2.4. did. After adding 60 parts by weight of radiolite (diatomaceous earth) and stirring at 30 ° C. for 1 hour, insoluble matters were removed by filtration. The filtration residue was washed with 274 parts by weight of ethyl acetate. The filtrate was separated to obtain an organic layer containing 3,3-dimethylcyclopropane-1,2-dicarboxylic acid. Extraction was further performed twice using 2342 parts by weight of ethyl acetate from the aqueous layer, and the total of the three organic layers obtained was a solution containing 534.0 parts by weight of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid 10870 parts by weight were obtained. (Yield 98.7%) In addition to 3,3-dimethylcyclopropane-1,2-dicarboxylic acid, this solution contains 24.5 parts by weight of 1-methyl-2-pyrrolidinone and 182.9 parts by weight of acetic acid. It was.
The solvent was distilled off from this solution under reduced pressure (21-39 KPa), 1034 parts by weight of acetic anhydride was added, and the temperature was raised to 100 ° C. over 2 hours. After keeping at the same temperature for 1 hour, acetic anhydride and acetic acid were distilled off under reduced pressure conditions (3 to 19 KPa) and an internal temperature of 36 to 120 ° C. to obtain 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride. 470.4 parts by weight (447.1 parts by weight) was obtained. (Content: 95.0%, Yield: 94.5%) In this solution, 21.5 parts by weight of 1-methyl-2-pyrrolidinone in addition to 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride, It contained 2.0 parts by weight of acetic anhydride and 1.2 parts by weight of acetic acid.
[0032]
Example 2
449.5 parts by weight (pure content 427.3 parts by weight) of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid anhydride obtained in Example 1 was subjected to reduced pressure (1 to 3 KPa) under an internal temperature of 129. 414.2 parts by weight of a fraction which is 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride having a distillate temperature of 100 to 140 ° C. (pure 395.9 parts by weight) ). (Content 95.6%, distillation yield 92.7%) In addition to 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride, 15.9 parts by weight of 1-methyl-2-pyrrolidinone was added to this fraction. 1.9 parts by weight of acetic anhydride and 0.7 parts by weight of acetic acid were contained.
[0033]
Example 3
397.8 parts by weight of 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride (380.2 parts by weight pure) obtained by distillation in Example 2 was mixed with 391 parts by weight of tert-butyl methyl ether. 76 parts by weight of n-hexane was added dropwise to the resulting solution at an internal temperature of 24 to 27 ° C. over 1 hour, and 0.3 parts by weight of 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride seed crystals were added. The mixture was further stirred for 1 hour. Further, 2964 parts by weight of n-hexane was added dropwise at the same temperature over 1 hour, and then cooled to 0 ° C. over 5 hours. After keeping the same temperature for 1 hour, the crystals were filtered. The obtained crystals were washed with a solution consisting of 76 parts by weight of tert-butyl methyl ether and 608 parts by weight of n-hexane, and then the solvent was dried by bubbling nitrogen through a filter to obtain 3,3-dimethylcyclopropane-1 , 2-dicarboxylic anhydride 351.3 parts by weight (pure content 350.5 parts by weight) was obtained. (Content 99.8%, recrystallization yield 92.2%)
Claims (5)
で示されるジカルボン酸の塩とし、ついで、酢酸エチルとアセトンとの混合溶媒、メチルイソブチルケトンおよびテトラヒドロフランからなる群から選ばれる有機溶媒で洗浄・分液し、ついで、得られる水層を酸性とし、式（３）
And then washing and separating with a mixed solvent of ethyl acetate and acetone, an organic solvent selected from the group consisting of methyl isobutyl ketone and tetrahydrofuran , and then acidifying the aqueous layer obtained, Formula (3)
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