JPH0884598A - Method for producing optically active chromane compound - Google Patents
Method for producing optically active chromane compoundInfo
- Publication number
- JPH0884598A JPH0884598A JP22142594A JP22142594A JPH0884598A JP H0884598 A JPH0884598 A JP H0884598A JP 22142594 A JP22142594 A JP 22142594A JP 22142594 A JP22142594 A JP 22142594A JP H0884598 A JPH0884598 A JP H0884598A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- compound
- formula
- chromane
- lipase
- 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.)
- Pending
Links
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、光学活性なクロマン化
合物の製造方法に関する。本発明により製造される光学
活性なクロマン化合物は、医薬品、食品、化粧品などに
用いられるクロマン誘導体の光学活性中間体として有用
である。TECHNICAL FIELD The present invention relates to a method for producing an optically active chroman compound. The optically active chroman compound produced by the present invention is useful as an optically active intermediate of a chroman derivative used in pharmaceuticals, foods, cosmetics and the like.
【０００２】[0002]
【従来の技術】従来、酵素を用いた光学活性なクロマン
化合物の合成法としては、６位の水酸基をベンジル基で
保護したクロマン誘導体をアシル化または加水分解する
方法が知られている（特開平４−１９０７９５号公報参
照）。2. Description of the Related Art Conventionally, as a method of synthesizing an optically active chroman compound using an enzyme, a method of acylating or hydrolyzing a chroman derivative in which a hydroxyl group at the 6-position is protected with a benzyl group has been known (Japanese Patent Laid-Open No. Hei 10-1999) See 4-190795).
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、上記の
方法が、６位の水酸基が保護されていないクロマン化合
物について適用できるか否かについては確認されていな
い。また、６位の水酸基が保護されていないクロマン誘
導体をアシル化反応に付すと、６位の水酸基が反応点と
なるため、複雑な生成物が得られることが知られている
［バイオインダストリー、9 巻、12号（1992年）参
照］。そのため、６位に水酸基を有する光学活性なクロ
マン誘導体を得るためには、原料化合物の６位の水酸基
を保護したのち、アシル化反応に付し、次いで保護基を
脱離する必要があった。しかして、本発明の目的は、６
位の水酸基が保護されていないラセミ体のクロマン化合
物から、６位の水酸基を保護する工程および該保護基を
脱離する工程を必要とせず、６位の水酸基が保護されて
いない光学活性なクロマン化合物を高い光学純度で製造
する方法を提供することにある。However, it has not been confirmed whether the above method can be applied to a chroman compound in which the hydroxyl group at the 6-position is not protected. It is also known that when a chroman derivative in which the hydroxyl group at the 6-position is not protected is subjected to an acylation reaction, the hydroxyl group at the 6-position serves as a reaction site, so that a complex product can be obtained [Bioindustry, 9 Vol. 12, No. 12 (1992)]. Therefore, in order to obtain an optically active chroman derivative having a hydroxyl group at the 6-position, it was necessary to protect the hydroxyl group at the 6-position of the raw material compound, followed by an acylation reaction, and then removing the protecting group. Therefore, the object of the present invention is to
An optically active chromane in which the hydroxyl group at the 6-position is not protected, without the need for a step for protecting the hydroxyl group at the 6-position and a step for removing the protective group from a racemic chroman compound in which the hydroxyl group at the 6-position is not protected. It is to provide a method for producing a compound with high optical purity.
【０００４】[0004]
【課題を解決するための手段】本発明によれば、上記の
目的は、下記式（Ｉ）According to the present invention, the above object is achieved by the following formula (I):
【０００５】[0005]
【化３】 [Chemical 3]
【０００６】で示されるクロマン化合物を、不活性溶媒
中、アシル化剤の存在下にシュードモナス属フラジ種に
属する微生物由来のリパーゼで処理することを特徴とす
る下記式（II）The chroman compound represented by the formula (II) is treated with a lipase derived from a microorganism belonging to the genus Pseudomonas frazi in the presence of an acylating agent in an inert solvent.
【０００７】[0007]
【化４】 [Chemical 4]
【０００８】で示される光学活性なクロマン化合物の製
造方法を提供することによって達成される。It is achieved by providing a method for producing an optically active chroman compound represented by:
【０００９】かかる反応に用いられるリパーゼは、シュ
ードモナス属フラジ種（Pseudomonas fragi ）に属する
微生物により生産されるリパーゼであり、シュードモナ
ス属フラジ種２２．３９Ｂ（Pseudomonas fragi 22.39
B ）により生産されるリパーゼが好ましい。該リパーゼ
は、上記微生物から容易に得ることができる［アグリカ
ルチュラル バイオロジカル ケミストリー（Agric. B
iol. Chem.）、41巻、8 号、1353-1358 頁（1977年）お
よび同51巻、1 号、181-186 頁（1987年）参照］。リパ
ーゼは、基質となる式（Ｉ）で示されるクロマン化合物
の重量に対して０．１〜１００重量％の範囲で用いられ
ることが好ましい。The lipase used in such a reaction is a lipase produced by a microorganism belonging to Pseudomonas fragi spp. (Pseudomonas fragi 22.39B).
The lipase produced by B) is preferred. The lipase can be easily obtained from the above microorganisms [Agricultural Biological Chemistry (Agric.
iol. Chem.), Vol. 41, No. 8, pp. 1353-1358 (1977) and Vol. 51, No. 1, pp. 181-186 (1987)]. The lipase is preferably used in the range of 0.1 to 100% by weight based on the weight of the chroman compound represented by the formula (I) which is a substrate.
【００１０】アシル化剤としては、酢酸ビニル、酢酸イ
ソプロペニル、プロピオン酸ビニルなどのビニルエステ
ルなどが挙げられる。アシル化剤の使用量は、式（Ｉ）
で示されるクロマン化合物に対して１〜５０当量である
ことが好ましい。Examples of the acylating agent include vinyl esters such as vinyl acetate, isopropenyl acetate and vinyl propionate. The amount of the acylating agent used is represented by the formula (I)
It is preferably 1 to 50 equivalents relative to the chroman compound represented by.
【００１１】不活性溶媒としては、アセトン、メチルエ
チルケトンなどのケトン系溶媒；イソプロピルエーテ
ル、ｔ−ブチルメチルエーテルなどのエーテル系溶媒な
どの含酸素系溶媒が使用される。また、反応温度は−１
０℃から３０℃の範囲が好ましく、０℃付近がより好ま
しい。As the inert solvent, ketone-based solvents such as acetone and methyl ethyl ketone; and oxygen-containing solvents such as ether-based solvents such as isopropyl ether and t-butyl methyl ether are used. The reaction temperature is -1
The range of 0 ° C to 30 ° C is preferable, and the vicinity of 0 ° C is more preferable.
【００１２】基質となる式（Ｉ）で示されるクロマン化
合物は、反応液に対して１〜２０重量％の範囲で用いら
れることが好ましい。The chroman compound represented by the formula (I) used as a substrate is preferably used in the range of 1 to 20% by weight based on the reaction solution.
【００１３】式（II）で示される光学活性なクロマン化
合物の反応混合物からの分離は、酵素を濾過したのち洗
浄、溶媒抽出、減圧濃縮し、シリカゲルカラムクロマト
グラフィにより、または未反応の式（Ｉ）で示されるク
ロマン化合物を常法によりコハク酸エステルに変換して
重曹水で抽出後加水分解することにより行うことができ
る。Separation of the optically active chroman compound represented by the formula (II) from the reaction mixture is carried out by filtering the enzyme followed by washing, solvent extraction, concentration under reduced pressure, silica gel column chromatography or unreacted formula (I). It can be carried out by converting the chroman compound represented by the above into a succinic acid ester by a conventional method, extracting with a sodium hydrogen carbonate solution and then hydrolyzing.
【００１４】[0014]
【実施例】以下、実施例および参考例により本発明をさ
らに詳しく説明するが、本発明はこれらの実施例等によ
りなんら限定されるものではない。EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.
【００１５】実施例１ ２−（３，４−ジヒドロ−６−ヒドロキシ−２，５，
７，８−トリメチル−２Ｈ−ベンゾ−１−ピラン−２−
イル）エタノール５０ｍｇをアセトン０．８ｍｌに溶解
し、リパーゼＢ５０ｍｇおよび酢酸ビニル１．５ｍｌを
加え、３℃で２４時間撹拌した。得られた反応液を濾過
し、濾液を濃縮したのちシリカゲルクロマトグラフィで
分離精製することにより、光学活性な（Ｓ）−２−
（３，４−ジヒドロ−６−ヒドロキシ−２，５，７，８
−トリメチル−２Ｈ−ベンゾ−１−ピラン−２−イル）
エタノール１８ｍｇを得た（収率３６％、光学純度９９
％e.e.以上）。Example 1 2- (3,4-dihydro-6-hydroxy-2,5
7,8-Trimethyl-2H-benzo-1-pyran-2-
50 mg of acetone) was dissolved in 0.8 ml of acetone, 50 mg of lipase B and 1.5 ml of vinyl acetate were added, and the mixture was stirred at 3 ° C. for 24 hours. The reaction solution obtained is filtered, the filtrate is concentrated and then purified by silica gel chromatography to obtain an optically active (S) -2-
(3,4-dihydro-6-hydroxy-2,5,7,8
-Trimethyl-2H-benzo-1-pyran-2-yl)
18 mg of ethanol was obtained (yield 36%, optical purity 99
% Ee or more).
【００１６】比較例１〜４ ２−（３，４−ジヒドロ−６−ヒドロキシ−２，５，
７，８−トリメチル−２Ｈ−ベンゾ−１−ピラン−２−
イル）エタノール５０ｍｇをアセトン０．８ｍｌに溶解
し、これにリパーゼＡＹ（キャンディダ属由来；天野製
薬株式会社製）、リパーゼＰＬ（アルカリゲネス属由
来；名糖産業株式会社製）、リパーゼＰＳ（シュードモ
ナス属由来；天野製薬株式会社製）、リパーゼＯＦ（キ
ャンディダ属由来；名糖産業株式会社製）各５０ｍｇお
よび酢酸ビニル１．５ｍｌを加え、室温で撹拌した。得
られた反応液を濾過し、濾液を濃縮したのちシリカゲル
クロマトグラフィで分離精製することにより、光学活性
な２−（３，４−ジヒドロ−６−ヒドロキシ−２，５，
７，８−トリメチル−２Ｈ−ベンゾ−１−ピラン−２−
イル）エタノールを得た。その結果を表１に示す。Comparative Examples 1 to 4 2- (3,4-dihydro-6-hydroxy-2,5
7,8-Trimethyl-2H-benzo-1-pyran-2-
50 mg of ethanol are dissolved in 0.8 ml of acetone, and lipase AY (derived from Candida; manufactured by Amano Pharmaceutical Co., Ltd.), lipase PL (derived from Alcaligenes, manufactured by Meito Sangyo Co., Ltd.), lipase PS (Pseudomonas) Origin: manufactured by Amano Pharmaceutical Co., Ltd.), lipase OF (derived from Candida; manufactured by Meito Sangyo Co., Ltd.) (50 mg each) and vinyl acetate (1.5 ml) were added, and the mixture was stirred at room temperature. The obtained reaction liquid is filtered, and the filtrate is concentrated and then purified by silica gel chromatography to give optically active 2- (3,4-dihydro-6-hydroxy-2,5,2).
7,8-Trimethyl-2H-benzo-1-pyran-2-
I got ethanol. The results are shown in Table 1.
【００１７】[0017]
【表１】 [Table 1]
【００１８】[0018]
【発明の効果】本発明によれば、６位の水酸基が保護さ
れていない光学活性なクロマン化合物を、単工程かつ高
い光学純度で製造する方法を提供することができる。According to the present invention, it is possible to provide a method for producing an optically active chroman compound in which the hydroxyl group at the 6-position is not protected, in a single step and with high optical purity.
Claims (1)
剤の存在下にシュードモナス属フラジ種に属する微生物
由来のリパーゼで処理することを特徴とする下記式（I
I） 【化２】 で示される光学活性なクロマン化合物の製造方法。1. The following formula (I): The chroman compound represented by the formula (I) is treated with a lipase derived from a microorganism belonging to the genus Pseudomonas spp. In the presence of an acylating agent in an inert solvent.
I) [Chemical 2] A method for producing an optically active chroman compound represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22142594A JPH0884598A (en) | 1994-09-16 | 1994-09-16 | Method for producing optically active chromane compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22142594A JPH0884598A (en) | 1994-09-16 | 1994-09-16 | Method for producing optically active chromane compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0884598A true JPH0884598A (en) | 1996-04-02 |
Family
ID=16766547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22142594A Pending JPH0884598A (en) | 1994-09-16 | 1994-09-16 | Method for producing optically active chromane compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0884598A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999055898A1 (en) * | 1998-04-28 | 1999-11-04 | Novo Nordisk A/S | Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman |
-
1994
- 1994-09-16 JP JP22142594A patent/JPH0884598A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999055898A1 (en) * | 1998-04-28 | 1999-11-04 | Novo Nordisk A/S | Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman |
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