JP3587473B2 - Purification method of valproic acid - Google Patents
Purification method of valproic acid Download PDFInfo
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- JP3587473B2 JP3587473B2 JP16609794A JP16609794A JP3587473B2 JP 3587473 B2 JP3587473 B2 JP 3587473B2 JP 16609794 A JP16609794 A JP 16609794A JP 16609794 A JP16609794 A JP 16609794A JP 3587473 B2 JP3587473 B2 JP 3587473B2
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Description
【０００１】
【産業上の利用分野】
本発明は、医薬品を始めとして各種の用途に有用なバルプロ酸の精製方法に関するものである。
【０００２】
【従来の技術】
バルプロ酸の製造方法としては、従来、▲１▼４−ヒドロキシヘプタン法、▲２▼シアノ酢酸法、▲３▼マロン酸エステル法等が知られている。又、本出願人も以前に特開昭６０−１５６６３８号公報及び特開昭６３−１２２６４６号公報においてバルプロ酸の製造方法を提案した。即ち、特開昭６０−１５６６３８号公報は（１）アセト酢酸エステルとアリルハライドを反応させて２，２−ジアリルアセト酢酸エステルを得る工程、（２）２，２−ジアリルアセト酢酸エステルをアルコールと反応させて２，２−ジアリル酢酸エステルを得る工程、（３）２，２−ジアリル酢酸エステルを加水分解してジアリル酢酸とした後還元するか、又は（３）′２，２−ジアリル酢酸エステルを還元してバルプロ酸エステルとした後、加水分解する工程の組み合わせからなる製造方法であり、一方、特開昭６３−１２２６４６号公報は（１）アセト酢酸エステルとプロピルハライドを反応させて２，２−ジプロピルアセト酢酸エステルを得る工程、（２）２，２−ジプロピルアセト酢酸エステルをアルコールで脱アセチルしてバルプロ酸エステルを得る工程、（３）バルプロ酸エステルを加水分解する工程よりなる製造方法である。
【０００３】
これらバルプロ酸の製造方法の中でも、上記▲１▼はグリニヤー試薬や青酸ナトリウム等の高価でかつ取り扱いに細心の注意が必要とされる試薬を用いなければならなかったり、▲２▼の方法では反応条件がかなり苛酷であったり、又▲３▼の方法では高価な原料が必要である等の欠点があるため、本出願人の開示方法のほうがはるかに有利であるといえる。
【０００４】
【発明が解決しようとする課題】
しかしながら、本出願人の提案した特開昭６０−１５６６３８号公報開示の方法では、還元工程において未還元の２−アリル吉草酸や２，２−ジアリル酢酸が不純物としてバルプロ酸とともに残ってしまう。又、特開昭６３−１２２６４６号公報開示の方法でも、原料であるプロピルハライド中に不純物として少量混在しているアリルブロミド、アリルクロリド、ジブロモプロパン等がアセト酢酸エステルと反応してしまい、最終的に、前記と同様２−アリル吉草酸や２，２−ジアリル酢酸が不純物として目的物であるバルプロ酸とともに混在してしまう。ここで、不純物として存在しているものには、２−アリル吉草酸や２，２−ジアリル酢酸の他に、２−アリル吉草酸や２，２−ジアリル酢酸の二重結合が異性化した化合物、例えばα−プロピル−β−エチルアクリル酸等も含まれる（以下、断りがなくとも不純物として２−アリル吉草酸や２，２−ジアリル酢酸といった場合には、これらの二重結合が異性化した化合物をも含めることがある。）。
【０００５】
該バルプロ酸の不純物である２−アリル吉草酸や２，２−ジアリル酢酸は、沸点等の物性面においてバルプロ酸と非常に似ており、従来の蒸留、金属塩の再結晶、活性炭吸着等による精製方法ではバルプロ酸との分離は非常に難しく、高度に精製されたバルプロ酸を効率良く得ることはできなかった。
そこで、これらバルプロ酸の製造時において、不純物としてバルプロ酸と混在する２−アリル吉草酸や２，２−ジアリル酢酸、更にはα−プロピル−β−エチルアクリル酸等の２−アリル吉草酸や２，２−ジアリル酢酸の二重結合が異性化した化合物を容易に除去し、高純度のバルプロ酸を得る精製方法の開発が望まれている。
【０００６】
【課題を解決するための手段】
しかるに、本発明者等はかかる課題を解決すべく鋭意研究を重ねた結果、２−アリル吉草酸及び／又は２，２−ジアリル酢酸の金属塩あるいはアンモニウム塩を含有するバルプロ酸塩水溶液を、亜硫酸イオン又は亜硫酸水素イオンの存在下で空気又は酸素と接触させ、２−アリル吉草酸及び／又は２，２−ジアリル酢酸の金属塩あるいはアンモニウム塩を、該塩のスルホン酸塩又はスルホン酸付加物として、系から分離するバルプロ酸の精製方法が、バルプロ酸の不純物である２−アリル吉草酸及び／又は２，２−ジアリル酢酸、更には２−アリル吉草酸や２，２−ジアリル酢酸の二重結合が異性化した化合物を容易に除去できることを見出し、本発明を完成した。
以下、本発明について具体的に説明する。
【０００７】
本発明におけるバルプロ酸は前述した如き▲１▼〜▲３▼の製造方法や特開昭６０−１５６６３８号公報及び特開昭６３−１２２６４６号公報開示の製造方法等、従来公知の方法により製造されるものである。又、２−アリル吉草酸及び／又は２，２−ジアリル酢酸というのは、該バルプロ酸製造時に生じる不純物の化合物のことである。これらの不純物は、反応生成物として得られる２，２−ジアリル酢酸エステル又は２，２−ジアリル酢酸の還元工程で未還元物として生じたり（特開昭６０−１５６６３８号公報）、又、原料となるプロピルハライド中に含まれるアリルブロミド、アリルクロリド、ジブロモプロパン等がアセト酢酸エステルと反応してしまった結果生じたり（特開昭６３−１２２６４６号公報）して、バルプロ酸と混在することになる。
【０００８】
本発明においては、２−アリル吉草酸及び／又は２，２−ジアリル酢酸の金属塩あるいはアンモニウム塩を含有するバルプロ酸塩水溶液に亜硫酸イオン、又は亜硫酸水素イオンを添加し、更に空気又は酸素を反応系中に吹き込むことが最大の特徴であり、このとき亜硫酸イオン、又は亜硫酸水素イオンの反応性を落とさないために水溶液のｐＨを４〜１１、好ましくは７〜１０、更に好ましくは８〜１０に調整することが望ましい。亜硫酸イオン、又は亜硫酸水素イオンとｐＨ調整試薬の添加順序には特に制限はなく、空気又は酸素を吹き込む前であればどちらが先でも差し支えない。
【０００９】
以下、本発明の精製工程を順に説明する。
まず、上記の不純物２−アリル吉草酸及び／又は２，２−ジアリル酢酸を含有したバルプロ酸に、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、アンモニア水等のアルカリ水溶液を加え、バルプロ酸アルカリ塩水溶液を調製し、これに該不純物あたり少なくとも３当量以上の亜硫酸イオン、又は亜硫酸水素イオンを添加し、ｐＨ調整試薬で該水溶液のｐＨを４〜１１、好ましくは７〜１０、更に好ましくは８〜１０となるように調整する。
【００１０】
本発明に用いる亜硫酸イオン、又は亜硫酸水素イオンとしては反応系中で該イオンとして存在すればよく、それにはメタ重亜硫酸ナトリウム、亜硫酸ナトリウム、亜硫酸水素ナトリウム、二酸化イオウ等が挙げられるが、原料入手の容易さの点から特に好ましいのはメタ重亜硫酸ナトリウムであり、又、ｐＨ調整試薬としては、硫酸、塩酸、硝酸等の鉱酸や酢酸、ギ酸等の有機酸、及び水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、アンモニア水等の塩基性物質が挙げられ、特に好ましいのは硫酸及び水酸化ナトリウムであるが、いずれもこれらに限定されるものではない。
【００１１】
その後、該水溶液を０℃以上、好ましくは室温〜８０℃で撹拌しながら、該水溶液中に１０ｍｌ以上／分／ｌ、好ましくは５０〜３００ｍｌ／分／ｌの空気又は酸素を通常１０分間以上吹き込む。かかる処理により、バルプロ酸の不純物のみにスルホン化が起こり、スルホン酸ナトリウム塩付加物が生じるのであって、例えば２−アリル吉草酸のナトリウム塩の場合では、以下の化１に示す如き反応によって二重結合部にスルホン酸ナトリウム塩が付加された反応生成物、即ち２−プロピル吉草酸ナトリウムのスルホン酸ナトリウム塩が生じていると推察される。他の不純物（２，２−ジアリル酢酸、α−プロピル−β−エチルアクリル酸等）についても同様にスルホン酸ナトリウム塩が付加された反応生成物が容易に得られる。
【００１２】
【化１】
上記スルホン化の反応終了後は、該不純物のスルホン酸ナトリウム塩を系から分離するために該反応液の酸性化を行う。かかる酸性化によって、バルプロ酸の金属塩あるいはアンモニウム塩は水に難溶なバルプロ酸となり油層部を形成する。この時、トルエン、酢酸エチル、メチルエチルケトン、塩化メチレン等の有機溶媒により抽出してもよい。水層部と油層部を２層分離させ油層部を分取する。そして、その後、該抽出物は水で洗浄され、抽出溶媒を用いた場合は溶媒除去されて、不純物のない精製されたバルプロ酸が得られるのである。一方、該スルホン酸ナトリウム塩又は該スルホン酸は水層に取り込まれて該水層とともに系外に取り除かれる。
該酸性化に用いられる酸としては、前記と同様、硫酸、塩酸、硝酸等の鉱酸や酢酸、ギ酸等の有機酸が挙げられる。
【００１４】
かくして本発明の精製方法により得られるバルプロ酸は、２−アリル吉草酸や２，２−ジアリル酢酸を不純物として含有することのない高純度のバルプロ酸となる。勿論必要に応じて、更に蒸留等の精製処理を行うこともできる。
【００１５】
【作用】
本発明は、バルプロ酸の製造時に不純物としてバルプロ酸と混在してしまう２−アリル吉草酸及び／又は２，２−ジアリル酢酸を、亜硫酸イオン又は亜硫酸水素イオンの存在下で、空気又は酸素と接触させることにより、２−アリル吉草酸及び／又は２，２−ジアリル酢酸をスルホン化し、スルホン酸塩又はスルホン酸として容易にバルプロ酸と分離することができ、製造面、収率面において非常に有利である。
【００１６】
【実施例】
以下、本発明について実施例を挙げて具体的に説明する。
尚、実施例中、「％」とあるのは特に断りのない限り重量基準である。
実施例１
バルプロ酸の製造
アセト酢酸メチル０．１８モル、アリルクロリド０．５４モル、炭酸カリウム０．３８モル、ジメチルホルムアミド１８０ｍｌにより反応を行い、２，２−ジアリルアセト酢酸メチル３１．２ｇを製造し、次いで、メタノールで処理して２，２−ジアリル酢酸メチル２２．５ｇを製造した。更に該２，２−ジアリル酢酸メチル２２．５ｇを水酸化ナトリウム水溶液で加水分解を行い、２，２−ジアリル酢酸を得、これをパラジウム／活性炭とともにオートクレーブ中で仕込み還元反応を行い、目的物のバルプロ酸を２０．０ｇ得た。
かかるバルプロ酸中には、不純物として２−アリル吉草酸０．０９％、及びα−プロピル−β−エチルアクリル酸１．１％が含まれていた（ガスクロマトグラフィーにより検出された）。
【００１７】
バルプロ酸の精製
上記２−アリル吉草酸０．０９％、及びα−プロピル−β−エチルアクリル酸１．１％を含有したバルプロ酸２０．０ｇに水１１ｍｌ、２５％水酸化ナトリウム水溶液３０．７ｇ、メタ重亜硫酸ナトリウム０．５ｇを混合しｐＨ１４の均一溶液を得た。該溶液に９７％硫酸３．１ｇを加え、ｐＨ８．０に調整した後、２７〜３９℃で撹拌しながら、該溶液中に１００ｍｌ／分の空気を７０分間吹き込んだ。反応終了後、９７％硫酸１７．１ｇを加え、遊離した油層を分液し、該油層を水３０ｍｌで水洗したところ１９．７ｇの油層を得た。ガスクロマトグラフィーによる分析結果から、かかる油層中には不純物である２−アリル吉草酸及びα−プロピル−β−エチルアクリル酸は検出されなかった。
尚、ガスクロマトグラフィーによる分析条件は次の通りである。
カラム：ＤＥＧＳ１５％＋Ｈ３ＰＯ４２％ ｏｎ ｃｈｒｏｍｏｓｏｒｂ ＷＡＷ（ＤＭＣＳ）３ｍｍＩＤ．２ｍ（ガラスカラム）
カラム温度：１４０℃
インジェクション温度：２５０℃
検出器：ＦＩＤ ｒａｎｇｅ１０２（島津７Ａ）
キャリアーガス：ヘリウム ４０ｍｌ／ｍｉｎ
【００１８】
実施例２
バルプロ酸の製造
テトラブチルアンモニウムブロミド０．０３２モル、３５％水酸化ナトリウム水溶液３６．６ｇ、プロピルブロミド０．３２モルを仕込み、撹拌しながらアセト酢酸メチル０．１６モルを反応させ、２，２−ジプロピルアセト酢酸メチルを製造し、次いで、メタノールで処理してバルプロ酸メチルを製造した。更に該バルプロ酸メチルを水酸化ナトリウム水溶液で加水分解を行い、目的物のバルプロ酸を２０．０ｇ得た。
かかるバルプロ酸中には、不純物として２−アリル吉草酸０．０７％、及び２，２−ジアリル酢酸０．０１％が含まれていた（ガスクロマトグラフィーにより検出された）。
【００１９】
バルプロ酸の精製
上記２−アリル吉草酸０．０７％、及び２，２−ジアリル酢酸０．０１％を含有したバルプロ酸２０．０ｇに水１５ｍｌ、２５％水酸化ナトリウム水溶液２７ｇ、亜硫酸水素ナトリウム０．３ｇを混合しｐＨ１３の均一溶液を得た。該溶液に５０％硫酸水溶液を２．５ｇ加え、ｐＨ９．０に調整した後、２７〜３９℃で撹拌しながら、該溶液中に８０ｍｌ／分の空気を７０分間吹き込んだ。反応終了後、５０％硫酸水溶液を２０．１ｇ加え、遊離した油層を分液し、該油層を水３０ｍｌで水洗したところ１９．６ｇの油層を得た。ガスクロマトグラフィーによる分析結果から、かかる油層中には不純物である２−アリル吉草酸及び２，２−ジアリル酢酸は検出されなかった。
【００２０】
【発明の効果】
本発明の精製方法は、バルプロ酸の製造時に不純物としてバルプロ酸と混在してしまう２−アリル吉草酸及び／又は２，２−ジアリル酢酸をスルホン化し、スルホン酸塩又はスルホン酸として容易にバルプロ酸と分離することができ、製造面、収率面において非常に有利である。[0001]
[Industrial applications]
The present invention relates to a method for purifying valproic acid, which is useful for various uses including pharmaceuticals.
[0002]
[Prior art]
As a method for producing valproic acid, conventionally, (1) a 4-hydroxyheptane method, (2) a cyanoacetic acid method, and (3) a malonic ester method are known. The present applicant has also previously proposed a method for producing valproic acid in JP-A-60-15638 and JP-A-63-122646. That is, JP-A-60-156638 discloses (1) a step of reacting acetoacetate with allyl halide to obtain 2,2-diallylacetoacetate, and (2) a step of converting 2,2-diallylacetoacetate with alcohol. Reacting to obtain 2,2-diallylacetic acid ester, (3) hydrolyzing 2,2-diallylacetic acid ester to diallylacetic acid and reducing it, or (3) '2,2-diallylacetic acid ester Is reduced to valproate and then hydrolyzed. On the other hand, JP-A-63-122646 discloses (1) reacting acetoacetate with propyl halide to produce 2,2. Step of obtaining 2-dipropyl acetoacetate, (2) Deacetylation of 2,2-dipropyl acetoacetate with alcohol Obtaining an acid ester, a manufacturing method consisting of (3) valproic acid ester hydrolyzing.
[0003]
Among these methods for producing valproic acid, the above-mentioned (1) requires the use of expensive reagents such as Grignard reagents and sodium hydrocyanate, which require careful handling, and the method (2) requires a reaction. The method disclosed by the present applicant can be said to be much more advantageous because of the drawbacks that the conditions are quite severe and the method (3) requires expensive raw materials.
[0004]
[Problems to be solved by the invention]
However, in the method disclosed in Japanese Patent Application Laid-Open No. 60-156638 proposed by the present applicant, unreduced 2-allylvaleric acid and 2,2-diallylacetic acid remain as impurities along with valproic acid in the reduction step. Further, even in the method disclosed in JP-A-63-122646, allyl bromide, allyl chloride, dibromopropane and the like mixed as impurities in a small amount in the raw material propyl halide react with the acetoacetate ester. Further, as described above, 2-allylvaleric acid and 2,2-diallylacetic acid are mixed as impurities with valproic acid as a target. Here, compounds present as impurities include, in addition to 2-allylvaleric acid and 2,2-diallylacetic acid, compounds in which double bonds of 2-allylvaleric acid and 2,2-diallylacetic acid are isomerized. For example, α-propyl-β-ethylacrylic acid and the like are also included (hereinafter, in the case where 2-allylvaleric acid or 2,2-diallylacetic acid is used as an impurity, unless otherwise specified, these double bonds are isomerized). Compounds may also be included.).
[0005]
2-Allylvaleric acid and 2,2-diallylacetic acid, which are impurities of the valproic acid, are very similar to valproic acid in terms of physical properties such as boiling point, and are obtained by conventional distillation, recrystallization of metal salt, adsorption of activated carbon and the like. In the purification method, separation from valproic acid was extremely difficult, and highly purified valproic acid could not be efficiently obtained.
Therefore, during the production of these valproic acids, 2-allylvaleric acid and 2,2-diallylacetic acid mixed with valproic acid as impurities and 2-allylvaleric acid such as α-propyl-β-ethylacrylic acid and 2 Development of a purification method for easily removing a compound in which the double bond of 2,2-diallylacetic acid is isomerized to obtain valproic acid of high purity is desired.
[0006]
[Means for Solving the Problems]
However, the present inventors have conducted intensive studies in order to solve such problems, and as a result, have found that an aqueous solution of valproate containing a metal salt or an ammonium salt of 2-allylvaleric acid and / or 2,2-diallylacetic acid is converted to a sulfite solution. A metal salt or ammonium salt of 2-allylvaleric acid and / or 2,2-diallylacetic acid as a sulfonate or a sulfonic acid adduct of the salt by contacting with air or oxygen in the presence of an ion or bisulfite ion. The method for purifying valproic acid which is separated from the system is a method for purifying 2-allylvaleric acid and / or 2,2-diallylacetic acid, which is an impurity of valproic acid, and furthermore, the double method of 2-allylvaleric acid and 2,2-diallylacetic acid The present inventors have found that a compound whose bond is isomerized can be easily removed, and completed the present invention.
Hereinafter, the present invention will be described specifically.
[0007]
The valproic acid in the present invention is produced by a conventionally known method such as the production methods (1) to (3) described above and the production methods disclosed in JP-A-60-15638 and JP-A-63-122646. Things. In addition, 2-allylvaleric acid and / or 2,2-diallylacetic acid are impurity compounds generated during the production of valproic acid. These impurities are produced as unreduced substances in the reduction step of 2,2-diallylacetic acid ester or 2,2-diallylacetic acid obtained as a reaction product (Japanese Patent Laid-Open No. 60-156638), Allyl bromide, allyl chloride, dibromopropane, and the like contained in propyl halide may react with acetoacetate (Japanese Patent Application Laid-Open No. 63-122646) or may be mixed with valproic acid. .
[0008]
In the present invention, sulfite ions or hydrogen sulfite ions are added to an aqueous solution of valproate containing a metal salt or ammonium salt of 2-allylvaleric acid and / or 2,2-diallylacetic acid, and further reacted with air or oxygen. The biggest feature is that the solution is blown into the system. At this time, the pH of the aqueous solution is adjusted to 4 to 11, preferably 7 to 10, more preferably 8 to 10 in order not to reduce the reactivity of sulfite ions or hydrogen sulfite ions. It is desirable to adjust. The order of adding the sulfite ion or the hydrogen sulfite ion and the pH-adjusting reagent is not particularly limited, and either one may be used before air or oxygen is blown.
[0009]
Hereinafter, the purification process of the present invention will be described in order.
First, an alkali aqueous solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonia water, etc. is added to valproic acid containing the above-mentioned impurities 2-allylvaleric acid and / or 2,2-diallylacetic acid. An aqueous solution of an acid alkali salt is prepared, and at least 3 equivalents or more of sulfite ion or hydrogen sulfite ion is added per impurity to adjust the pH of the aqueous solution to 4 to 11, preferably 7 to 10, more preferably 7 to 10 with a pH adjusting reagent. Is adjusted to be 8 to 10.
[0010]
The sulfite ion or bisulfite ion used in the present invention may be present as the ion in the reaction system, and examples thereof include sodium metabisulfite, sodium sulfite, sodium bisulfite, and sulfur dioxide. Particularly preferred from the viewpoint of easiness is sodium metabisulfite. Examples of the pH adjusting reagent include mineral acids such as sulfuric acid, hydrochloric acid and nitric acid, organic acids such as acetic acid and formic acid, and sodium hydroxide and potassium hydroxide. , Sodium carbonate, potassium carbonate, aqueous ammonia and the like, and particularly preferred are sulfuric acid and sodium hydroxide, but neither is limited to these.
[0011]
Thereafter, while stirring the aqueous solution at 0 ° C. or more, preferably at room temperature to 80 ° C., air or oxygen of 10 ml or more / min, preferably 50 to 300 ml / min / l is blown into the aqueous solution for usually 10 minutes or more. . By this treatment, sulfonation occurs only in the impurity of valproic acid and a sodium sulfonate adduct is produced. For example, in the case of the sodium salt of 2-allylvaleric acid, the sulfonation is carried out by the reaction shown in the following chemical formula 1. It is presumed that a reaction product in which a sodium sulfonate salt was added to the heavy bond, that is, a sodium sulfonate salt of sodium 2-propylvalerate was produced. Similarly, for other impurities (2,2-diallylacetic acid, α-propyl-β-ethylacrylic acid, etc.), a reaction product to which sodium sulfonate is added can be easily obtained.
[0012]
Embedded image
After the completion of the sulfonation reaction, the reaction solution is acidified to separate the impurity sodium sulfonate from the system. By this acidification, the metal salt or ammonium salt of valproic acid becomes valproic acid which is hardly soluble in water, and forms an oil layer. At this time, extraction may be performed with an organic solvent such as toluene, ethyl acetate, methyl ethyl ketone, or methylene chloride. The water layer and the oil layer are separated into two layers to separate the oil layer. After that, the extract is washed with water and, if an extraction solvent is used, the solvent is removed to obtain purified valproic acid without impurities. On the other hand, the sulfonic acid sodium salt or the sulfonic acid is taken into the aqueous layer and removed out of the system together with the aqueous layer.
Examples of the acid used for the acidification include mineral acids such as sulfuric acid, hydrochloric acid, and nitric acid, and organic acids such as acetic acid and formic acid, as described above.
[0014]
Thus, the valproic acid obtained by the purification method of the present invention is high-purity valproic acid containing no 2-allylvaleric acid or 2,2-diallylacetic acid as an impurity. Of course, if necessary, further purification treatment such as distillation can be performed.
[0015]
[Action]
The present invention relates to contacting 2-allylvaleric acid and / or 2,2-diallylacetic acid, which is mixed with valproic acid as an impurity during production of valproic acid, with air or oxygen in the presence of sulfite ions or bisulfite ions. By doing so, 2-allylvaleric acid and / or 2,2-diallylacetic acid can be sulfonated and easily separated as sulfonic acid salt or sulfonic acid from valproic acid, which is very advantageous in terms of production and yield. It is.
[0016]
【Example】
Hereinafter, the present invention will be described specifically with reference to examples.
In Examples, "%" is based on weight unless otherwise specified.
Example 1
Production of valproic acid Methyl acetoacetate 0.18 mol, allyl chloride 0.54 mol, potassium carbonate 0.38 mol, and reacted with 180 ml of dimethylformamide, 31.2 g of methyl 2,2-diallylacetoacetate was obtained. Prepared and then treated with methanol to produce 22.5 g of methyl 2,2-diallylacetate. Further, 22.5 g of the methyl 2,2-diallylacetate is hydrolyzed with an aqueous sodium hydroxide solution to obtain 2,2-diallylacetic acid, which is charged and reduced in an autoclave together with palladium / activated carbon to obtain the desired product. 20.0 g of valproic acid was obtained.
Such valproic acid contained 0.09% of 2-allylvaleric acid and 1.1% of α-propyl-β-ethylacrylic acid as impurities (detected by gas chromatography).
[0017]
Purification of valproic acid 20.0 g of valproic acid containing 0.09% of 2-allylvaleric acid and 1.1% of α-propyl-β-ethylacrylic acid was added with 11 ml of water and 25% sodium hydroxide. An aqueous solution having a pH of 14 was obtained by mixing 30.7 g of an aqueous solution and 0.5 g of sodium metabisulfite. After adding 3.1 g of 97% sulfuric acid to the solution and adjusting the pH to 8.0, 100 ml / min of air was blown into the solution for 70 minutes while stirring at 27 to 39 ° C. After the reaction was completed, 17.1 g of 97% sulfuric acid was added, the separated oil layer was separated, and the oil layer was washed with 30 ml of water to obtain 19.7 g of an oil layer. According to the result of analysis by gas chromatography, impurities such as 2-allylvaleric acid and α-propyl-β-ethylacrylic acid were not detected in the oil layer.
The analysis conditions by gas chromatography are as follows.
Column: DEGS 15% + H 3 PO 4 2% on chromosorb WAW (DMCS) 3 mm ID. 2m (glass column)
Column temperature: 140 ° C
Injection temperature: 250 ° C
Detector: FID range10 2 (Shimadzu 7A)
Carrier gas: helium 40ml / min
[0018]
Example 2
Production of valproic acid 0.032 mol of tetrabutylammonium bromide, 36.6 g of 35% aqueous sodium hydroxide solution and 0.32 mol of propyl bromide were charged, and 0.16 mol of methyl acetoacetate was reacted with stirring. Methyl 2,2-dipropylacetoacetate was prepared and then treated with methanol to prepare methyl valproate. Further, the methyl valproate was hydrolyzed with an aqueous sodium hydroxide solution to obtain 20.0 g of valproic acid as a target product.
Such valproic acid contained 0.07% of 2-allylvaleric acid and 0.01% of 2,2-diallylacetic acid as impurities (detected by gas chromatography).
[0019]
Purification of valproic acid 15 ml of water, 27 g of 25% aqueous sodium hydroxide solution were added to 20.0 g of valproic acid containing 0.07% of the 2-allylvaleric acid and 0.01% of 2,2-diallylacetic acid, 0.3 g of sodium bisulfite was mixed to obtain a pH 13 homogeneous solution. After adding 2.5 g of a 50% aqueous sulfuric acid solution to the solution and adjusting the pH to 9.0, 80 ml / min of air was blown into the solution for 70 minutes while stirring at 27 to 39 ° C. After the reaction was completed, 20.1 g of a 50% aqueous sulfuric acid solution was added, the separated oil layer was separated, and the oil layer was washed with 30 ml of water to obtain 19.6 g of an oil layer. From the results of gas chromatography analysis, no impurities such as 2-allylvaleric acid and 2,2-diallylacetic acid were detected in the oil layer.
[0020]
【The invention's effect】
In the purification method of the present invention, 2-allylvaleric acid and / or 2,2-diallylacetic acid, which is mixed with valproic acid as an impurity during the production of valproic acid, is sulfonated and easily converted to sulfonic acid or sulfonic acid. And is very advantageous in terms of production and yield.
Claims (2)
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| JP16609794A JP3587473B2 (en) | 1994-06-23 | 1994-06-23 | Purification method of valproic acid |
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| Application Number | Priority Date | Filing Date | Title |
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| JP16609794A JP3587473B2 (en) | 1994-06-23 | 1994-06-23 | Purification method of valproic acid |
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| JP3587473B2 true JP3587473B2 (en) | 2004-11-10 |
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| FR2383907A1 (en) * | 1977-03-15 | 1978-10-13 | Labaz | PROCESS FOR PREPARING DERIVATIVES OF ACETIC ACID AND DERIVATIVES OBTAINED BY THIS PROCESS |
| US4125568A (en) * | 1977-06-29 | 1978-11-14 | Mobil Oil Corporation | Removal of carbonyl impurities |
| DE2844636C2 (en) * | 1978-10-13 | 1986-07-31 | Ruhrchemie Ag, 4200 Oberhausen | Process for the preparation of di-n-propyl acetic acid |
| JPS6072844A (en) * | 1983-09-29 | 1985-04-24 | Mitsubishi Petrochem Co Ltd | Preparation of formylnorbornane containing polar functional group |
| JPS60152438A (en) * | 1984-01-21 | 1985-08-10 | Nippon Shokubai Kagaku Kogyo Co Ltd | Purification of methacrylic acid |
| JPH0662488B2 (en) * | 1984-01-25 | 1994-08-17 | 日本合成化学工業株式会社 | Method for producing valproic acid |
| JPH0662489B2 (en) * | 1985-10-30 | 1994-08-17 | 日本合成化学工業株式会社 | Valproic acid manufacturing method |
| JPH01135740A (en) * | 1987-11-24 | 1989-05-29 | Nippon Mining Co Ltd | 2-alkyl-1-alkanoic acid having optical activity and production thereof |
| GB2215344B (en) * | 1988-02-29 | 1992-02-26 | Shell Int Research | A process for purification of alkenyl aromatic compounds |
| JPH0768161B2 (en) * | 1989-04-18 | 1995-07-26 | 三井東圧化学株式会社 | Method for producing high-purity alkoxymethylbenzaldehyde |
| JPH07278053A (en) * | 1994-04-07 | 1995-10-24 | Mitsubishi Gas Chem Co Inc | Purification of methacrylic acid ester |
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