JP2004189625A - Method for purifying 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for purifying 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride. <P>SOLUTION: The method for purifying the acid anhydride comprises hydrolyzing unpurified 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride represented by formula (1) to form a dicarboxylate represented by formula (2) (wherein Ms are independently hydrogen atoms, alkali metal atoms, or alkaline earth metal atoms), acidifying an aqueous layer obtained by washing with a water-insoluble organic solvent and separating to obtain a dicarboxylic acid represented by formula (3), and reacting the obtained dicarboxyllic acid represented by formula (3) with an acylating agent to obtain 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride represented by formula (1). <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

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未精製物を加水分解し、一般式（２）

（式中、Ｍは独立して、水素原子、アルカリ金属原子又はアルカリ土類金属原子を表す。）
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）

で示されるジカルボン酸を得、得られた式（３）で示されるジカルボン酸をアシル化剤と反応させ、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得ることを特徴とする酸無水物の精製方法を提供するものである。
【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]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for purifying 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride (hereinafter abbreviated as acid anhydride), which is useful as an intermediate for medicines, agricultural chemicals and the like.
[0002]
[Prior art]
Conventionally, as a method for 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, 1-methyl-2-pyrrolidinone is used under reduced pressure (1 mmHg) using a rotating band tower. A method of distilling off -methyl-2-pyrrolidinone by rectification (see Patent Document 1), adding water and activated carbon to an unpurified substance, subjecting it to heat treatment at 100 ° C or higher, filtering insoluble substances, and removing water. There is known a method of removing the compound under reduced pressure and then converting the product into an anhydride again (see Patent Document 2 and Non-Patent Document 1).
[0003]
[Patent Document 1]
JP-A-57-120548 [Patent Document 2]
JP-A-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 acid anhydride and 1-methyl-2-pyrrolidinone, which are the target substances, are so close to each other that a rotating band column is used. This is a method that requires a special separation device and that 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 purify the acid anhydride by distillation.
Further, in the latter method of performing the activated carbon treatment, the tarified and high molecular weight components can be removed, but a high boiling point and hydrophilic solvent such as 1-methyl-2-pyrrolidinone cannot be separated. However, none of these methods was necessarily satisfactory as a method for purifying an acid anhydride.
[0005]
[Means for Solving the Problems]
The present inventors have conducted intensive studies on an industrially advantageous method for purifying 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride represented by the following formula (1), and found that the formula (1) obtained by the reaction was obtained. ) Is converted to a dicarboxylic acid salt represented by the general formula (2) by hydrolyzing a crude product containing 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride represented by the formula (2), By washing with an organic solvent insoluble in water to remove unnecessary components, and then treating the dicarboxylic acid of the formula (3) obtained by treating with an acid with an acylating agent. And 3,3-dimethylcyclopropane-1,2-dicarboxylic acid anhydride represented by the formula (1), to obtain a high-purity acid anhydride.
By this purification operation, the thermal stability of the acid anhydride is improved, and a high-purity acid anhydride can be obtained with good yield when performing operations such as distillation for further purification.
That is, the present invention relates to the formula (1)

An unpurified 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride represented by the formula is hydrolyzed to obtain a compound represented by the general formula (2):

(In the formula, M independently represents a hydrogen atom, an alkali metal atom or an alkaline earth metal atom.)
And then the aqueous layer obtained by washing and separating with a water-insoluble organic solvent is made acidic to obtain a salt of the formula (3)

And the obtained dicarboxylic acid of the formula (3) is reacted with an acylating agent to give a 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride of the formula (1). And a method for purifying an acid anhydride, characterized by obtaining a product.
[0006]
BEST MODE FOR CARRYING OUT THE INVENTION
Unpurified 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride (hereinafter abbreviated as anhydride (1)) represented by formula (1) as a starting material of the present invention is described in, for example, Patent It can be obtained by the method described in Literature 1 or the method described in Production Example 1, but is not limited thereto. These unpurified substances include, as impurities, acids such as hydrochloric acid, sulfuric acid, and acetic acid, hydrophilic solvents having a high boiling point such as 1-methyl-2-pyrrolidinone, and tarified components.
[0007]
The unpurified anhydride (1) is hydrolyzed with water to give 3,3-dimethylcyclopropane-1,2-dicarboxylic acid of the formula (3) (hereinafter abbreviated as dicarboxylic acid (3)). After that, the salt is derived with an inorganic base into a dicarboxylic acid salt represented by the general formula (2) (hereinafter abbreviated as dicarboxylic acid salts (2)). Alternatively, dicarboxylic acid salts (2) can be directly derived by hydrolysis using an aqueous solution of an inorganic base.
[0008]
The amount of water used for such hydrolysis is usually 0.2 to 50 times by weight, preferably 0.5 to 10 times by weight, relative 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, and hydrogen carbonate. Examples thereof include hydrogen carbonates of alkali metals such as sodium and potassium hydrogen carbonate, and alkali metal hydroxides are preferably used.
The amount of the base to be used is, in addition to the amount for neutralizing the acid excluding the anhydride (1) contained in the unpurified product, usually 1 mol or more, preferably 1 to 2 mol, per 1 mol of the anhydride (1). The range is about double. When the anhydride (1) is hydrolyzed, it becomes a dicarboxylic acid, and the base must be used in an amount that neutralizes the monocarboxylic acid or more. When the amount of the acid in the unpurified product is unknown, the amount of the inorganic base used can be determined by the pH of the reaction solution. The pH is usually 7 or more, preferably 7 to 9.
Such a base is generally used as an aqueous solution, but when water is present in the reaction solution, a solid can also be used.
[0010]
The reaction temperature of 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 is usually 0.5 hour or more.
[0011]
To the obtained aqueous solution of dicarboxylates (2), an organic solvent capable of being separated from this solution is added, mixed, washed, and separated to give a high-boiling hydrophilic compound such as 1-methyl-2-pyrrolidinone as 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 residual amount of the removable component in the aqueous layer decreases to a desired amount.
[0012]
Such organic solvents include, for example, ester solvents such as methyl acetate and ethyl acetate, aromatic hydrocarbon solvents such as toluene, xylene and chlorobenzene, pentane, hexane, heptane, aliphatic hydrocarbon solvents such as cyclohexane, dichloromethane, and the like. Dichloroethane, halogenated aliphatic hydrocarbon solvents such as carbon tetrachloride, diethyl ether, diisopropyl ether, t-butyl methyl ether, ether solvents such as tetrahydrofuran, acetone, methyl ethyl ketone, ketone solvents such as methyl isobutyl ketone, acetonitrile, Examples thereof include nitrile solvents such as propionitrile. These may be used alone or as a mixture of two or more, and preferably a mixed solvent of ethyl acetate and acetone, methyl isobutyl ketone, tetrahydrofuran and the like are used.
[0013]
The amount of the organic solvent used is usually 0.5 to 50 times, preferably 1 to 20 times the weight of the anhydride (1) per washing operation.
[0014]
When liquid separation becomes difficult due to precipitation of insoluble components during washing and liquid separation operations, separation can be facilitated by removing insoluble components by filtration. At that time, a filter aid can be used. Further, such a filtering operation can be performed at any stage before adding the inorganic base used for obtaining the dicarboxylates (2), in the middle of adding the entire amount used, or after finishing adding.
[0015]
The dicarboxylates (2) thus obtained include, for example, monosodium salt of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid, disodium salt of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid, Monopotassium 3,3-dimethylcyclopropane-1,2-dicarboxylate, dipotassium 3,3-dimethylcyclopropane-1,2-dicarboxylate, monolithium 3,3-dimethylcyclopropane-1,2-dicarboxylate Salts, 3,3-dimethylcyclopropane-1,2-dicarboxylic acid dilithium salt, 3,3-dimethylcyclopropane-1,2-dicarboxylic acid calcium salt, and the like.
[0016]
After a washing operation 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 dicarboxylates (2) to cause salt decomposition, and the salt is decomposed into dicarboxylic acids (3), and the aqueous layer is formed. By extracting the dicarboxylic acid (3) into the organic layer using an organic solvent capable of liquid separation, the acid component contained in the crude 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 generally in the range of 0 to 6, preferably 1 to 3.
[0018]
Examples of the organic solvent used for the 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 and carbon tetrachloride. Examples 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, preferably 1 to 20 times the weight of the anhydride (1) per washing operation.
[0020]
When liquid separation becomes difficult due to precipitation of insoluble components during the liquid separation operation, the separation can be facilitated by removing the insoluble components by filtration. At that time, a filter aid can be used.
[0021]
The obtained organic layer containing the dicarboxylic acid (3) may be subsequently used for the subsequent reaction, 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. As a method of recrystallization, for example, a method of heating and dissolving in a solvent or the like used for extraction and then crystallization by cooling, or a method of dissolving in a solvent or the like used for extraction and then adding a poor solvent to precipitate the solution. No. Examples of such poor solvents include aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane.
[0022]
The dicarboxylic acid (3) thus obtained can be easily converted to the anhydride (1) by adding an acylating agent such as acetic anhydride, acetyl chloride and the like, and heating. The desired high-purity anhydride (1) can be obtained only by removing the agent and the acid such as acetic acid and hydrochloric acid generated in the reaction by concentration or the like.
[0023]
The amount of the acylating agent to be used is generally 1 to 10 moles, preferably 2 to 5 moles, relative to the dicarboxylic acid (3).
[0024]
The reaction temperature is usually 20-150 ° C, preferably 50-120 ° C.
The reaction time may be any amount as long as the amount of the raw material dicarboxylic acid (3) is reduced to a desired amount, and is not particularly limited, but is usually 0.5 hour or more.
[0025]
The anhydride (1) thus obtained can be further purified by performing operations such as distillation and recrystallization.
[0026]
The distillation is heated under normal pressure or reduced pressure, and simple distillation can easily obtain a higher purity anhydride (3).
[0027]
As a method of recrystallization, for example, a method of heating and dissolving in a solvent or the like used for extraction of dicarboxylic acid (3) and then crystallization by cooling, or a method of dissolving in a solvent or the like used for extraction and then adding a poor solvent And the like. Examples of such poor solvents include aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane.
[0028]
【The invention's effect】
According to the method of the present invention, it is possible to industrially and advantageously purify 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride, which is useful as an intermediate for medicines, agricultural chemicals and the like.
[0029]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
[0030]
Production Example 1
To 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), 293 parts by weight of 1-methyl-2-pyrrolidinone, anhydrous 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 mixture 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. for 0.5 part. The solution was dropped over a period of time, and kept at the same temperature for 2 hours. To this solution, 85.0 parts by weight of a 40% aqueous sodium hydroxide solution was added to adjust the pH to 2.0. 3405 parts by weight of ethyl acetate and 117 parts by weight of radiolite (diatomaceous earth) were added, and the mixture was stirred at 20 to 34 ° C. for 1 hour, and then insolubles were removed by filtration. The filtration residue was washed with 586 parts by weight of acetone and subsequently with 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 the pH was adjusted to 2.4 by adding 35% hydrochloric acid. did. After adding 60 parts by weight of radiolite (diatomaceous earth) and stirring at 30 ° C. for 1 hour, insoluble materials 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. The aqueous layer was further extracted twice with 2342 parts by weight of ethyl acetate, and the obtained three organic layers were combined to give 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%) This solution contains 24.5 parts by weight of 1-methyl-2-pyrrolidinone and 182.9 parts by weight of acetic acid in addition to 3,3-dimethylcyclopropane-1,2-dicarboxylic acid. Had been.
After distilling off the solvent from this solution under reduced pressure (21 to 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 (3 to 19 KPa) at an internal temperature of 36 to 120 ° C. to obtain 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride. 470.4 parts by weight (pure amount: 447.1 parts by weight) were obtained. (Content 95.0%, Yield 94.5%) In this solution, in addition to 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride, 21.5 parts by weight of 1-methyl-2-pyrrolidinone, 2.0 parts by weight of acetic anhydride and 1.2 parts by weight of acetic acid were contained.
[0032]
Example 2
449.5 parts by weight (pure 427.3 parts by weight) of 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride obtained in Example 1 was subjected to reduced pressure conditions (1 to 3 KPa) at an internal temperature of 129. Simple distillation at 〜144 ° C., and 414.2 parts by weight of a fraction which is 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride having a distillate temperature of 100-140 ° C. ). (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 is contained in this fraction. 1.9 parts by weight of acetic anhydride and 0.7 parts by weight of acetic acid.
[0033]
Example 3
397.8 parts by weight (purity 380.2 parts by weight) of 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride obtained by distillation in Example 2 were mixed with 391 parts by weight of tert-butyl methyl ether. 76 parts by weight of n-hexane was added dropwise to the solution at an internal temperature of 24 to 27 ° C. over 1 hour, and 0.3 parts by weight of seed crystals of 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride was 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 passing nitrogen through a filter to obtain 3,3-dimethylcyclopropane-1. , 2-Dicarboxylic anhydride 351.3 parts by weight (purity 350.5 parts by weight). (Content 99.8%, recrystallization yield 92.2%)

Claims (4)

Equation (1)

An unpurified 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride represented by the formula is hydrolyzed to obtain a compound represented by the general formula (2):

(In the formula, M independently represents a hydrogen atom, an alkali metal atom or an alkaline earth metal atom.)
And then the aqueous layer obtained by washing and separating with a water-insoluble organic solvent is made acidic to obtain a salt of the formula (3)

And the obtained dicarboxylic acid of the formula (3) is reacted with an acylating agent to give a 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride of the formula (1). A method for purifying an acid anhydride, characterized by obtaining a product. A purification method comprising distilling 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride represented by the formula (1) obtained by the method according to claim 1. A purification method comprising recrystallizing the 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride represented by the formula (1) obtained by the method according to claim 1. A purification method comprising distilling 3,3-dimethylcyclopropane-1,2-dicarboxylic anhydride represented by the formula (1) obtained by the method according to claim 1 and recrystallizing the resulting product.