JPH1180149A - Optical resolution of (+,-)-chromancarboxylic acid - Google Patents
Optical resolution of (+,-)-chromancarboxylic acidInfo
- Publication number
- JPH1180149A JPH1180149A JP24670197A JP24670197A JPH1180149A JP H1180149 A JPH1180149 A JP H1180149A JP 24670197 A JP24670197 A JP 24670197A JP 24670197 A JP24670197 A JP 24670197A JP H1180149 A JPH1180149 A JP H1180149A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- tetramethylchroman
- hydroxy
- phenylethylamine
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[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］。TECHNICAL FIELD The present invention relates to (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-
The present invention relates to a method for resolving carboxylic acids. The optically active 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid produced according to the present invention is useful as a synthetic intermediate of an optically active vitamin E derivative [for example,
Helvetica Chimica Acta, 64
Vol., Page 1158 (1981)].
【０００２】[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、（±）−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）、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［Ｃｈｅｍｉ
ｓｔｒｙ Ｌｅｔｔｅｒｓ、４６５ページ（１９８９年
参照］、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。2. Description of the Related Art Conventionally, optically active 6-hydroxy-2,
As a method for synthesizing 5,7,8-tetramethylchroman-2-carboxylic acid, (±) -6-hydroxy-2,
Asymmetric hydrolysis of 5,7,8-tetramethylchroman-2-carboxylic acid ester using an enzyme (see U.S. Pat. No. 5,348,973), a method of converting an optically active acylproline derivative into a halolacton [Chemi
A method of reacting an organotitanium compound with an optically active pyruvate (see JP-A-61-60628) is known.
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、上記
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、上記およびの方法では、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。However, the above method has a problem that the operation of isolating and purifying the target substance after the asymmetric hydrolysis and the operation of separating and removing the enzyme are complicated. , Above and the above methods make it difficult to easily obtain or synthesize the starting materials used. Therefore, both methods are optically active 6-hydroxy-2,5,7,8-tetramethylchroman-2-.
This is not an industrially advantageous method for producing carboxylic acids. On the other hand, as a method of optically resolving (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, there is known an example using optically active α-phenylethylamine ( See JP-B-60-26975). However, as is apparent from the comparative examples described later, there is a problem that the separation efficiency when optically active α-phenylethylamine is used is low, and that recrystallization is required a plurality of times. Thus, an object of the present invention is to efficiently separate (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and obtain optically active 6-hydroxy-2,5, It is to provide a method for obtaining 7,8-tetramethylchroman-2-carboxylic acid.
【０００４】[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。The above object is achieved by (±) −
Optically active N-benzyl-α-phenylethylamine is allowed to act on 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter simply referred to as (±) -chromancarboxylic acid). Characterized by (±)
-It is achieved by providing an optical resolution method for chromancarboxylic acid.
【０００５】[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。DESCRIPTION OF THE PREFERRED EMBODIMENTS In the optical resolution method of the present invention,
Optically active N-benzyl-α-phenylethylamine is used as a resolving agent. Optically active N-benzyl-α
The amount of -phenylethylamine to be used is not particularly limited, but is 0.5-1.% With respect to (±) -chromancarboxylic acid.
Use in the range of 0 equivalents is preferred for efficient and high-purity separation.
【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クロマンカルボン酸を
得ることができるので好ましい。[0006] The reaction of the present invention is generally carried out in the presence of a solvent. Examples of the solvent used include water; alcohols such as methanol, ethanol and isopropanol; dimethoxyethane, diisopropyl ether and tertiary alcohol.
Ethers such as tert-butyl methyl ether; ethyl acetate,
Esters such as methyl acetate; ketones such as acetone and methyl ethyl ketone; and hydrocarbons such as benzene, toluene and xylene. These are 2 if necessary
It can also be used as a mixture of more than one species. Among them,
Water, methanol, ethanol, isopropanol, ethyl acetate, tertiary butyl methyl ether, or a mixed solvent thereof is preferable since a high-purity optically active chromancarboxylic acid can be obtained.
【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。The amount of the solvent used varies depending on the type of the solvent, the solubility, the crystallization temperature and the like, but is usually 1 to 100 times by weight, preferably 2 to 100 times (±) -chromancarboxylic acid.
It is used in a range of up to 50 times by weight.
【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（＋）−クロマンカルボン酸・
（−）−Ｎ−ベンジル−α−フェニルエチルアミン塩ま
たは（−）−クロマンカルボン酸・（＋）−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。[0008] The present invention is implemented, for example, by the following method. (±) -Chromancarboxylic acid, optically active N-benzyl-α-phenylethylamine and a solvent are mixed, dissolved by heating, and then cooled to make the diastereomer salt supersaturated, preferably (+)-chromancarboxylic acid.・
A small amount of (-)-N-benzyl-α-phenylethylamine salt or (−)-chromancarboxylic acid · (+)-N-benzyl-α-phenylethylamine salt is inoculated to obtain the same hardly soluble diastereomer salt. And is separated. As a method for separating diastereomeric salts, filtration,
A method such as centrifugation is used.
【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。The crystallization temperature depends on the amount of the solvent used, the type of the solvent,
It can be appropriately selected depending on the dissolution temperature and the like, but is preferably in the range of -10 to 50 ° C from an economic viewpoint.
【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、ナトリウムメトキシドなど
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、
（＋）−クロマンカルボン酸または（−）−クロマンカ
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。The resulting diastereomer 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,
(+)-Chromancarboxylic acid or (-)-chromancarboxylic acid is obtained. Such an operation may be performed in the order of acid treatment and then optional base treatment.
【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。The (±) -chromancarboxylic acid used as a raw material can be easily and inexpensively synthesized, for example, by the method described in JP-A-7-97380.
【００１２】[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。EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.
【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（２．０２ｍｍ
ｏｌ）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４
２７ｍｇ（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（０．４８４ｍｍｏ
ｌ）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。Example 1 506 mg (2.02 mm) of (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
ol) was suspended in 3.0 mL of ethyl acetate, and (+)-N-benzyl-α-phenylethylamine 4
A solution of 27 mg (2.02 mmol) of tert-butyl methyl ether in 4.0 mL was added and dissolved by heating. After cooling to room temperature, (-)-6-hydroxy-2,5,7,8-
Tetramethylchroman-2-carboxylic acid (+)-N-
Inoculate a small amount of benzyl-α-phenylethylamine salt,
Left at room temperature overnight. The precipitated crystals were filtered to obtain 476 mg (1.03 mmol) of (-)-6-hydroxy-2,5,7,8-tetramethylchroman-2.
-Carboxylic acid • (+)-N-benzyl-α-phenylethylamine salt was obtained. This (-)-6-hydroxy-
To 320 mg of 2,5,7,8-tetramethylchroman-2-carboxylic acid · (+)-N-benzyl-α-phenylethylamine salt was added a 1N aqueous sodium hydroxide solution, and the mixture was extracted with ether. 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 121 mg (0.484 mmol
1) was obtained. [Α] D = −56.7 ° (c1.2, ethanol). Preparation (±) -6-hydroxy-2,5
The yield based on (-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid in 7,8-tetramethylchroman-2-carboxylic acid was 71%. In addition, the obtained (-)-6-hydroxy-2,
The optical purity of 5,7,8-tetramethylchroman-2-carboxylic acid was 87% ee by optical rotation analysis and 88% ee by liquid chromatography analysis.
【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（１７７ｍｏ
ｌ）、エタノール１６６ｋｇ、イソプロパノール２６ｋ
ｇを混合し、７０℃まで加熱し、溶解させた。次に、７
０℃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１
１．５ｋｇ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（４８ｍ
ｏｌ）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）。Example 2 53.4 kg of (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (177 kg of water, containing 9 kg of water), (+)-N -Benzyl-α-phenylethylamine 37.5 kg (177 mo
l), 166 kg of ethanol, 26 k of isopropanol
g were mixed and heated to 70 ° C. to dissolve. Next, 7
At 0 ° C, 114 kg of water was added, and after cooling to 50 ° C, (-)
A small amount of -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. (+)-N-benzyl-α-phenylethylamine salt was inoculated. After stirring at 40 ° C. for 3 hours, the mixture was left overnight while gradually cooling. The precipitated crystals were filtered to obtain a wet weight of 43.0 kg (63 mol in terms of pure content) of (-)-6-hydroxy-2,
5,7,8-tetramethylchroman-2-carboxylic acid
(+)-N-benzyl-α-phenylethylamine salt was obtained. This (-)-6-hydroxy-2,5,7,8-
Tetramethylchroman-2-carboxylic acid (+)-N-
100 kg of a 1 N aqueous solution of sodium hydroxide was added to the benzyl-α-phenylethylamine salt, and extracted twice with 60 L of tertiary butyl methyl ether. Concentrated hydrochloric acid 1 in aqueous phase
1.5 kg was added, and extraction was performed three 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 obtain (-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-. Carboxylic acid 11.9 kg (48 m
ol). Preparation (±) -6-hydroxy-2,
The yield based on (-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid in 5,7,8-tetramethylchroman-2-carboxylic acid was 54%. In addition, the obtained (-)-6-hydroxy-2,
The optical purity of 5,7,8-tetramethylchroman-2-carboxylic acid was 99% ee (by liquid chromatography analysis).
【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（２．００ｍｏ
ｌ）、（−）−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（０．７５ｍ
ｏｌ）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）。Comparative Example (±) -6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid 500 mg (2.00 mol)
l) 242 mg of (-)-α-phenylethylamine
(2.00 mmol) and 10 mL of ethyl acetate were mixed and dissolved by heating. After cooling to room temperature, it was left overnight. By filtering the precipitated crystals, 278 mg (0.75 m
ol) of (+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. (-)-α-phenylethylamine salt. To this (+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid / (-)-α-phenylethylamine salt was added a 1N aqueous sodium hydroxide solution, and the mixture was extracted with ether. 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 was obtained. [Α] D = + 0.33 ° (c1.2, ethanol). The resulting (+)-6-hydroxy-2,5,7,
The optical purity of 8-tetramethylchroman-2-carboxylic acid was 0.5% ee (by optical rotation analysis).
【００１６】[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（＋）
−クロマンカルボン酸または（−）−クロマンカルボン
酸を得ることができる。According to the present invention, (±) -chromancarboxylic acid is efficiently optically resolved to obtain (+) having high optical purity.
-Chromancarboxylic acid or (-)-chromancarboxylic acid can be obtained.
Claims (1)
８−テトラメチルクロマン−２−カルボン酸に、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（±）−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。(1) (±) -6-hydroxy-2,5,7,
(±) -6-hydroxy-2, characterized in that optically active N-benzyl-α-phenylethylamine is allowed to act on 8-tetramethylchroman-2-carboxylic acid.
Optical resolution method of 5,7,8-tetramethylchroman-2-carboxylic acid.
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|---|---|---|---|
| JP24670197A JP3913329B2 (en) | 1997-09-11 | 1997-09-11 | Optical resolution method of (±) -chromancarboxylic acid |
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|---|---|---|---|
| JP24670197A JP3913329B2 (en) | 1997-09-11 | 1997-09-11 | Optical resolution method of (±) -chromancarboxylic acid |
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| JP3913329B2 JP3913329B2 (en) | 2007-05-09 |
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