JP3913329B2 - Optical resolution method of (±) -chromancarboxylic acid - Google Patents
Optical resolution method of (±) -chromancarboxylic acid Download PDFInfo
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Description
【０００１】
【発明の属する技術分野】
本発明は、（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の光学分割法に関する。本発明により製造される光学活性な６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸は、光学活性なビタミンＥ誘導体の合成中間体として有用である［例えば、Ｈｅｌｖｅｔｉｃａ Ｃｈｉｍｉｃａ Ａｃｔａ、６４巻、１１５８ペ−ジ（１９８１年）参照］。
【０００２】
【従来の技術】
従来、光学活性な６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の合成方法としては、▲１▼（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸エステルを酵素を用いて不斉加水分解する方法（米国特許第５３４８９７３号明細書参照）、▲２▼光学活性なアシルプロリン誘導体をハロラクトン化する方法［Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ、４６５ページ（１９８９年参照］、▲３▼有機チタン化合物と光学活性なピルビン酸エステルを反応させる方法（特開昭６１−６０６２８号公報参照）が知られている。
【０００３】
【発明が解決しようとする課題】
しかしながら、上記▲１▼の方法は、不斉加水分解後の目的物の単離・精製操作および酵素の分離除去操作が煩雑であるという問題点を有しており、また、上記▲２▼および▲３▼の方法では、使用する出発物質を容易に入手もしくは合成することが困難である。したがって、いずれの方法も、光学活性な６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の工業的に有利な製造方法とは言い難い。一方、（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を光学分割する方法として、光学活性なα−フェニルエチルアミンを使用する例が知られている（特公昭６０−２６９７５号公報参照）。しかしながら、後述の比較例から明らかなように、光学活性なα−フェニルエチルアミンを使用した場合の分割効率は低く、さらに再結晶が複数回必要となるという問題点を有している。
しかして、本発明の目的は、（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を効率よく分割し、光学活性な６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を得る方法を提供することにある。
【０００４】
【課題を解決するための手段】
上記の目的は、（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸（以下、単に（±）−クロマンカルボン酸という）に、光学活性なＮ−ベンジル−α−フェニルエチルアミンを作用させることを特徴とする（±）−クロマンカルボン酸の光学分割法を提供することによって達成される。
【０００５】
【発明の実施の形態】
本発明の光学分割法においては、分割剤として光学活性なＮ−ベンジル−α−フェニルエチルアミンが使用される。光学活性なＮ−ベンジル−α−フェニルエチルアミンの使用量は、特に限定されないが、（±）−クロマンカルボン酸に対して０．５〜１．０当量の範囲で使用するのが、効率よく、かつ高純度で分割するために好ましい。
【０００６】
本発明の反応は、一般に溶媒の存在下で行われる。使用される溶媒としては、例えば、水；メタノール、エタノール、イソプロパノールなどのアルコール；ジメトキシエタン、ジイソプロピルエーテル、第３級ブチルメチルエーテルなどのエーテル；酢酸エチル、酢酸メチルなどのエステル；アセトン、メチルエチルケトンなどのケトン；ベンゼン、トルエン、キシレンなどの炭化水素などが挙げられる。これらは必要に応じて２種以上の混合物として用いることもできる。中でも、水、メタノール、エタノール、イソプロパノール、酢酸エチル、第３級ブチルメチルエーテル、またはこれらの混合溶媒が、高純度の光学活性な６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を得ることができるので好ましい。
【０００７】
溶媒の使用量は、溶媒の種類、溶解度、晶析温度などによっても異なるが、通常、（±）−クロマンカルボン酸に対して１〜１００重量倍、好ましくは２〜５０重量倍の範囲で用いられる。
【０００８】
本発明は、例えば次のような方法で実施される。（±）−クロマンカルボン酸、光学活性なＮ−ベンジル−α−フェニルエチルアミンおよび溶媒を混合し、加熱溶解したのち冷却してジアステレオマー塩を過飽和となし、好ましくは（＋）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（−）−Ｎ−ベンジル−α−フェニルエチルアミン塩または（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（＋）−Ｎ−ベンジル−α−フェニルエチルアミン塩を少量接種して、同種の難溶性のジアステレオマー塩を析出させ、これを分離する。ジアステレオマー塩の分離方法としては、濾過、遠心分離などの方法が用いられる。
【０００９】
晶析温度は、溶媒の使用量、溶媒の種類、溶解温度などによって適宜選択することができるが、経済的見地からは−１０〜５０℃の範囲が好ましい。
【００１０】
得られたジアステレオマー塩は、水酸化ナトリウム、水酸化カリウム、ナトリウムメトシキドなどの塩基で処理して（＋）−Ｎ−ベンジル−α−フェニルエチルアミンまたは（−）−Ｎ−ベンジル−α−フェニルエチルアミンを回収し、さらに、塩酸、硫酸、リン酸、ｐ−トルエンスルホン酸などの酸を作用させて、（＋）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸または（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を得る。なお、かかる操作は酸処理、次いで任意的な塩基処理の順に行ってもよい。
【００１１】
原料として使用する（±）−クロマンカルボン酸は、例えば特開平７−９７３８０号公報に記載された方法により、容易にかつ安価に合成できる。
【００１２】
【実施例】
以下、実施例により本発明を具体的に説明するが、本発明はこれらの実施例により何ら限定されるものではない。
【００１３】
実施例１
（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸５０６ｍｇ（２．０２ｍｍｏｌ）を酢酸エチル３．０ｍＬに懸濁させ、その懸濁液に（＋）−Ｎ−ベンジル−α−フェニルエチルアミン４２７ｍｇ（２．０２ｍｍｏｌ）の第３級ブチルメチルエーテル４．０ｍＬ溶液を加え、加熱溶解させた。室温まで冷却後、（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（＋）−Ｎ−ベンジル−α−フェニルエチルアミン塩を少量接種し、室温で一夜放置した。析出した結晶を濾過することにより、４７６ｍｇ（１．０３ｍｍｏｌ）の（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（＋）−Ｎ−ベンジル−α−フェニルエチルアミン塩を得た。この（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（＋）−Ｎ−ベンジル−α−フェニルエチルアミン塩のうち３２０ｍｇに１規定水酸化ナトリウム水溶液を加え、エーテルで抽出を行った。次に、水相に１規定塩酸を加え、析出した結晶を濾過することにより、（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸１２１ｍｇ（０．４８４ｍｍｏｌ）を得た。［α］D ＝−５６．７゜（ｃ１．２、エタノール）。仕込み（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸中の（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸に対する収率は７１％であった。また、得られた（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の光学純度は、旋光度分析で８７％ｅｅ、液体クロマトグラフ分析では８８％ｅｅであった。
【００１４】
実施例２
（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸５３．４ｋｇ（水９ｋｇを含む、純分換算１７７ｍｏｌ）、（＋）−Ｎ−ベンジル−α−フェニルエチルアミン３７．５ｋｇ（１７７ｍｏｌ）、エタノール１６６ｋｇ、イソプロパノール２６ｋｇを混合し、７０℃まで加熱し、溶解させた。次に、７０℃で水１１４ｋｇを加え、５０℃まで冷却後、（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（＋）−Ｎ−ベンジル−α−フェニルエチルアミン塩を少量接種した。４０℃で３時間撹拌した後、徐々に冷却しながら一夜放置した。析出した結晶を濾過することにより、湿重量４３．０ｋｇ（純分換算６３ｍｏｌ）の（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（＋）−Ｎ−ベンジル−α−フェニルエチルアミン塩を得た。この（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（＋）−Ｎ−ベンジル−α−フェニルエチルアミン塩に１規定水酸化ナトリウム水溶液１００ｋｇを加え、第３級ブチルメチルエーテル６０Ｌで２回抽出を行った。水相に濃塩酸１１．５ｋｇを加え、酢酸エチル３０Ｌで３回抽出を行った。溶媒を留去し、エタノール３６Ｌ、水７０Ｌから再結晶を行い、析出した結晶を濾過・乾燥することにより、（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸１１．９ｋｇ（４８ｍｏｌ）を得た。仕込み（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸中の（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸に対する収率は５４％であった。また、得られた（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の光学純度は９９％ｅｅであった（液体クロマトグラフ分析による）。
【００１５】
比較例
（±）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸５００ｍｇ（２．００ｍｏｌ）、（−）−α−フェニルエチルアミン２４２ｍｇ（２．００ｍｍｏｌ）、酢酸エチル１０ｍＬを混合し加熱溶解させた。室温まで冷却後、一夜放置した。析出した結晶を濾過することにより、２７８ｍｇ（０．７５ｍｏｌ）の（＋）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（−）−α−フェニルエチルアミン塩を得た。この（＋）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸・（−）−α−フェニルエチルアミン塩に１規定水酸化ナトリウム水溶液を加え、エーテルで抽出を行った。次に、水相に１規定塩酸を加え、析出した結晶を濾過することにより、（＋）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を得た。［α］D ＝＋０．３３゜（ｃ１．２、エタノール）。得られた（＋）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸の光学純度は０．５％ｅｅであった（旋光度分析による）。
【００１６】
【発明の効果】
本発明によれば、（±）−クロマンカルボン酸を効率よく光学分割して、光学純度の高い（＋）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸または（−）−６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸を得ることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an optical resolution method for (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The optically active 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid produced by the present invention is useful as an intermediate for the synthesis of optically active vitamin E derivatives [for example, Helvetica Chimica Acta, 64, 1158 (1981)].
[0002]
[Prior art]
Conventionally, methods for synthesizing optically active 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid include: (1) (±) -6-hydroxy-2,5,7,8- A method of asymmetric hydrolysis of tetramethylchroman-2-carboxylic acid ester using an enzyme (see US Pat. No. 5,348,973), (2) a method of halolactonizing an optically active acylproline derivative [Chemistry Letters, 465 Page (see 1989), (3) a method of reacting an organotitanium compound with an optically active pyruvate (see JP-A-61-60628) is known.
[0003]
[Problems to be solved by the invention]
However, the method {circle around (1)} has a problem that the operation of isolating / purifying the target product after asymmetric hydrolysis and the operation of separating and removing the enzyme are complicated, and the methods {circle around (2)} and In the method (3), it is difficult to easily obtain or synthesize the starting material to be used. Therefore, none of the methods is an industrially advantageous method for producing optically active 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. On the other hand, as a method for optical resolution of (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, an example using optically active α-phenylethylamine is known ( (See Japanese Patent Publication No. 60-26975). However, as will be apparent from the comparative examples described later, the resolution efficiency is low when optically active α-phenylethylamine is used, and there are problems that recrystallization is required a plurality of times.
Therefore, the object of the present invention is to efficiently resolve (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid to produce optically active 6-hydroxy-2,5, It is to provide a method for obtaining 7,8-tetramethylchroman-2-carboxylic acid.
[0004]
[Means for Solving the Problems]
The above object is to produce (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter simply referred to as (±) -chromancarboxylic acid) with optically active N-benzyl. It is achieved by providing an optical resolution method of (±) -chromancarboxylic acid, characterized by acting α-phenylethylamine.
[0005]
DETAILED DESCRIPTION OF THE INVENTION
In the optical resolution method of the present invention, optically active N-benzyl-α-phenylethylamine is used as a resolving agent. The amount of the optically active N-benzyl-α-phenylethylamine is not particularly limited, but it is efficient to use it in the range of 0.5 to 1.0 equivalent to (±) -chromancarboxylic acid, In addition, it is preferable for dividing with high purity.
[0006]
The reaction of the present invention is generally performed in the presence of a solvent. Examples of the solvent used include water; alcohols such as methanol, ethanol and isopropanol; ethers such as dimethoxyethane, diisopropyl ether and tertiary butyl methyl ether; esters such as ethyl acetate and methyl acetate; acetone and methyl ethyl ketone Ketone; hydrocarbons such as benzene, toluene, xylene and the like. These can also be used as a mixture of two or more as required. Among them, water, methanol, ethanol, isopropanol, ethyl acetate, tertiary butyl methyl ether, or a mixed solvent thereof is a highly pure optically active 6-hydroxy-2,5,7,8-tetramethylchroman-2. -It is preferable because a carboxylic acid can be obtained.
[0007]
The amount of solvent used varies depending on the type of solvent, solubility, crystallization temperature, etc., but is usually used in the range of 1 to 100 times by weight, preferably 2 to 50 times by weight with respect to (±) -chromancarboxylic acid. It is done.
[0008]
The present invention is implemented, for example, by the following method. (±) -chromancarboxylic acid, optically active N-benzyl-α-phenylethylamine and solvent are mixed, dissolved by heating and then cooled to make the diastereomeric salt supersaturated, preferably (+)- 6-hydroxy -2,5,7,8-tetramethylchroman-2-carboxylic acid (-)-N-benzyl-α-phenylethylamine salt or (-)- 6-hydroxy-2,5,7,8-tetramethyl A small amount of chroman-2-carboxylic acid / (+)-N-benzyl-α-phenylethylamine salt is inoculated to precipitate the same kind of hardly soluble diastereomeric salt, which is separated. As a method for separating the diastereomeric salt, methods such as filtration and centrifugation are used.
[0009]
The crystallization temperature can be appropriately selected depending on the amount of solvent used, the type of solvent, the dissolution temperature, and the like, but is preferably in the range of −10 to 50 ° C. from an economic standpoint.
[0010]
The obtained diastereomeric salt is treated with a base such as sodium hydroxide, potassium hydroxide or sodium methoxide to give (+)-N-benzyl-α-phenylethylamine or (−)-N-benzyl-α- Phenylethylamine is recovered and further reacted with an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, and (+)- 6-hydroxy-2,5,7,8-tetramethylchroman-2- Carboxylic acid or (−)- 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid is obtained. Such an operation may be performed in the order of acid treatment and then optional base treatment.
[0011]
The (±) -chromancarboxylic acid used as a raw material can be easily and inexpensively synthesized by, for example, the method described in JP-A-7-97380.
[0012]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited at all by these Examples.
[0013]
Example 1
506 mg (2.02 mmol) of (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid was suspended in 3.0 mL of ethyl acetate, and (+)- A solution of 427 mg (2.02 mmol) of N-benzyl-α-phenylethylamine in 4.0 mL of tertiary butyl methyl ether was added and dissolved by heating. After cooling to room temperature, a small amount of (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid / (+)-N-benzyl-α-phenylethylamine salt is inoculated, and at room temperature. Left overnight. By filtering the precipitated crystals, 476 mg (1.03 mmol) of (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (+)-N-benzyl-α -Phenylethylamine salt was obtained. Of this (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid · (+)-N-benzyl-α-phenylethylamine salt, 320 mg of 1N aqueous sodium hydroxide solution was added. In addition, extraction was performed with ether. Next, 1N hydrochloric acid was added to the aqueous phase, and the precipitated crystals were filtered to give 121 mg (0.484 mmol) of (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. ) [Α] D = −56.7 ° (c1.2, ethanol). Preparation (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid in (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid The yield based on the acid was 71%. The optical purity of the obtained (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid was 87% ee by optical rotation analysis and 88% ee by liquid chromatography analysis. Met.
[0014]
Example 2
(±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid 53.4 kg (including 9 kg of water, 177 mol in terms of pure content), (+)-N-benzyl-α-phenyl 37.5 kg (177 mol) of ethylamine, 166 kg of ethanol, and 26 kg of isopropanol were mixed, heated to 70 ° C. and dissolved. Next, 114 kg of water was added at 70 ° C., and after cooling to 50 ° C., (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid · (+)-N-benzyl- A small amount of α-phenylethylamine salt was inoculated. After stirring at 40 ° C. for 3 hours, the mixture was allowed to stand overnight while gradually cooling. By filtering the precipitated crystals, a wet weight of 43.0 kg (63 mol in terms of pure content) (-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid / (+)- N-benzyl-α-phenylethylamine salt was obtained. To this (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid / (+)-N-benzyl-α-phenylethylamine salt, 100 kg of 1N aqueous sodium hydroxide solution was added, Extraction was performed twice with 60 L of tertiary butyl methyl ether. 11.5 kg of concentrated hydrochloric acid was added to the aqueous phase, and extraction was performed 3 times with 30 L of ethyl acetate. The solvent was distilled off, recrystallization was performed from 36 L of ethanol and 70 L of water, and the precipitated crystals were filtered and dried to give (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2- 11.9 kg (48 mol) of carboxylic acid was obtained. Preparation (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid in (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid The yield based on the acid was 54%. The obtained (−)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid had an optical purity of 99% ee (by liquid chromatographic analysis).
[0015]
Comparative Example (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid 500 mg (2.00 mol), (−)-α-phenylethylamine 242 mg (2.00 mmol), ethyl acetate 10 mL was mixed and dissolved by heating. After cooling to room temperature, it was left overnight. By filtering the precipitated crystals, 278 mg (0.75 mol) of (+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid / (−)-α-phenylethylamine salt Got. To this (+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid / (−)-α-phenylethylamine salt was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ether. It was. Next, 1N hydrochloric acid was added to the aqueous phase, and the precipitated crystals were filtered to obtain (+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. [Α] D = + 0.33 ° (c1.2, ethanol). The optical purity of the obtained (+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid was 0.5% ee (by optical rotation analysis).
[0016]
【The invention's effect】
According to the present invention, (±) -chromancarboxylic acid is efficiently optically resolved, and (+)- 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid having high optical purity or (-)- 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid can be obtained.
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| DE10028443C1 (en) * | 2000-06-14 | 2002-05-29 | Sanol Arznei Schwarz Gmbh | Production of optically active 3,3-diaryl-propylamine derivatives comprises six step process from 4-hydroxybenzoic acid or alkyl 4-hydroxybenzoate and cinnamic acid |
| JP2004002206A (en) * | 2000-07-26 | 2004-01-08 | Chugai Pharmaceut Co Ltd | Method for producing optically active thiazolidinone derivative |
| JP2002167381A (en) * | 2000-08-03 | 2002-06-11 | Kuraray Co Ltd | Optical resolution method of (±)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid |
| WO2002012221A1 (en) * | 2000-08-03 | 2002-02-14 | Kuraray Co., Ltd. | Method for optical resolution of (±)-6-hydroxy-2,5,7,8-tetramethylcoumarone-2-carboxylic acid |
| JPWO2004108944A1 (en) * | 2003-06-04 | 2006-07-20 | 三菱瓦斯化学株式会社 | Method for producing optically active chromancarboxylic acid ester |
| JP4826132B2 (en) * | 2005-04-28 | 2011-11-30 | 三菱瓦斯化学株式会社 | 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and process for producing the same |
| JP4826133B2 (en) * | 2005-04-28 | 2011-11-30 | 三菱瓦斯化学株式会社 | S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and process for producing the same |
| US8080676B2 (en) | 2006-10-26 | 2011-12-20 | Mitsubishi Gas Chemical Company, Inc. | Method of producing S-(−)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid and product obtained by the method |
| CA2704473C (en) | 2007-11-06 | 2016-10-04 | Edison Pharmaceuticals, Inc. | 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases |
| ES2912585T3 (en) | 2014-12-16 | 2022-05-26 | Ptc Therapeutics Inc | Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide |
| EP3233819A1 (en) * | 2014-12-16 | 2017-10-25 | Bioelectron Technology Corporation | Methods for chiral resolution of trolox |
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