JP2670302B2 - Microbial optical resolution method - Google Patents
Microbial optical resolution methodInfo
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- JP2670302B2 JP2670302B2 JP17961688A JP17961688A JP2670302B2 JP 2670302 B2 JP2670302 B2 JP 2670302B2 JP 17961688 A JP17961688 A JP 17961688A JP 17961688 A JP17961688 A JP 17961688A JP 2670302 B2 JP2670302 B2 JP 2670302B2
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- Japan
- Prior art keywords
- dihydro
- benzoxazine
- alkyl
- fbo
- strain
- Prior art date
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Description
【発明の詳細な説明】 ＜産業上の利用分野＞ 本発明は、合成抗菌剤であるピリドンカルボン酸化合
物の合成中間体の製法に関する。The present invention relates to a method for producing a synthetic intermediate of a pyridonecarboxylic acid compound which is a synthetic antibacterial agent.
＜従来の技術＞ （±）−３−アルキル−3,4−ジヒドロ−2H−［1,4］−
ベンゾオキサジン （式中X aおよびX bはそれぞれハロゲン原子を、R1はメ
チル基、エチル基等の低級アルキル基を意味する。）お
よびその関連化合物の光学異性体の製造法として、化合
物IIをジアステレオマーに誘導後、分別結晶化による光
学分割法（EP−206283A公報参照）、クロマトグラフィ
による光学分割法、有機化学的な不斉合成法などが知ら
れているが、これらの方法は操作の煩雑さ、低収率、生
成物の光学純度が低いなどの欠点を有している。<Prior Art> (±) -3-Alkyl-3,4-dihydro-2H- [1,4]-
Benzoxazine (In the formula, X a and X b each represent a halogen atom, R 1 represents a lower alkyl group such as a methyl group and an ethyl group.) And its related compound as a method for producing optical isomers. After induction into mer, optical resolution method by fractional crystallization (see EP-206283A), optical resolution method by chromatography, organic chemical asymmetric synthesis method, etc. are known, but these methods are complicated in operation. However, it has drawbacks such as low yield and low optical purity of the product.
＜問題を解決するための手段＞ 本発明者は、４−アシル−３−アルキル−3,4−ジヒ
ドロ−2H−［1,4］−ベンゾオキサジンのラセミ体の
（−）体にのみ作用してアシル基を除去し、（＋）体に
は作用しない能力を有する微生物について探索したとこ
ろ、バチルス属に属する微生物およびデバリオマイセス
属に属する酵母が（−）−３−アルキル−3,4−ジヒド
ロ−2H−［1,4］−ベンゾオキサジン生産能を有するこ
とを見出し、本発明を完成するに至った。<Means for Solving the Problem> The present inventor acts only on the racemic (−) form of 4-acyl-3-alkyl-3,4-dihydro-2H- [1,4] -benzoxazine. When a microorganism having an ability to remove an acyl group and does not act on the (+) form was searched, it was found that a microorganism belonging to the genus Bacillus and a yeast belonging to the genus Debaryomyces showed (-)-3-alkyl-3,4-dihydro- They have found that they have 2H- [1,4] -benzoxazine-producing ability, and have completed the present invention.
＜発明の構成＞ 本発明は、一般式 （式中X aおよびX bはそれぞれフッソ、塩素等のハロゲ
ン原子を、R1はメチル、エチル、プロピル等の低級アル
キル基を意味し、R2はホルミル、アセチル、ハロゲノア
セチル、プロピオニル、ベンゾイル、メトキシベンゾイ
ル等のアシル基を意味する。）で表わされる４−アシル
−３−アルキル−3,4−ジヒドロ−2H−［1,4］−ベンゾ
オキサジンのラセミ体を、バチルス属細菌、デバリオマ
イセス属酵母またはそれらの菌体処理物と接触反応さ
せ、次いで（−）−３−アルキル−3,4−ジヒドロ−2H
−［1,4］−ベンゾオキサジンを分離することを特徴と
する（−）−３−アルキル−3,4−ジヒドロ−2H−［1,
4］−ベンゾオキサジンの製造法に関する。<Structure of Invention> The present invention has the general formula (In the formula, X a and X b each represent a halogen atom such as fluorine, chlorine and the like, R 1 represents a lower alkyl group such as methyl, ethyl and propyl, R 2 represents formyl, acetyl, halogenoacetyl, propionyl, benzoyl, Meaning an acyl group such as methoxybenzoyl etc.), a racemic 4-acyl-3-alkyl-3,4-dihydro-2H- [1,4] -benzoxazine represented by Alternatively, they are contacted with a treated product of the cells, and then (−)-3-alkyl-3,4-dihydro-2H.
(-)-3-alkyl-3,4-dihydro-2H- [1,
4] -benzoxazine production method.
更に詳細には、４−アシル−３−アルキル−3,4−ジ
ヒドロ−2H−［1,4］−ベンゾオキサジンのラセミ体を
含みグルコースなどの発酵性糖類を主炭素源として含む
培地にバチルス（Bacillus）属細菌またはデバリオマイ
セス（Debaryomyces）属酵母を接種し好気的に培養して
培養液中に（−）−３−アルキル−3,4−ジヒドロ−2H
−［1,4］−ベンゾオキサジンを生成蓄積せしめ、これ
を採取することを特徴とする（−）−３−アルキル−3,
4−ジヒドロ−2H−［1,4］−ベンゾオキサジンの製造方
法である。More specifically, a medium containing a racemic 4-acyl-3-alkyl-3,4-dihydro-2H- [1,4] -benzoxazine and a fermentable saccharide such as glucose as a main carbon source in Bacillus ( Bacillus) or yeast of the genus Debaryomyces are inoculated and aerobically cultured to obtain (−)-3-alkyl-3,4-dihydro-2H in the culture solution.
-[1,4] -benzoxazine is produced and accumulated, and this is collected, wherein (-)-3-alkyl-3,
This is a method for producing 4-dihydro-2H- [1,4] -benzoxazine.
バチルス属細菌としては種々のものが使用できるが、
本発明者が土壌より発見した微生物であるバチルス属細
菌は次の様な菌学的性質を有する。Various kinds of Bacillus bacteria can be used,
Bacillus bacteria, which are microorganisms discovered by the present inventors from soil, have the following mycological properties.
Ｂ）各培地における成育状態 １）肉汁寒天斜面培養 生育 良好 良好 良好 光沢 無 無 無 ２）肉汁液体培養 生育 良好 良好 良好 沈査 大 大 大 上記の株のうち、DSC−1010は工業技術院微生物工業
技術研究所に微工研菌寄第10134号（FERM P−10134）と
して保存されている。他にバチルス属細菌の例として、
東京大学応用微生物研究所に保存されているIAM−1623
（Bacillus subtilis sbsp.niger）、IAM−12077（Baci
llus thringiensis）を挙げることができ、また、デバ
リオマイセス属酵母の例として財団法人醗酵研究所に保
存されているIFO−0668（Debaryomyces marama）、広島
大学工学部醗酵研究所に保存されているHUT−7041（Deb
aryomyces sake）を挙げることができるが、これらに限
定されることはなく、通常の知識を有する者が行う通常
の試験によりこれらの属の適当な菌を選ぶことができ
る。 B) Growth condition in each medium 1) Meat broth agar slope culture Good growth Good Good Good Luster No nothing 2) Meat broth liquid culture Good growth Good Good Precipitation Large Large Among the above-mentioned strains, DSC-1010 is preserved in the Institute of Microbial Science and Technology of the Institute of Industrial Science and Technology as Microindustrial Research Institute No. 10134 (FERM P-10134). Other examples of Bacillus bacteria include:
IAM-1623 stored in Institute for Applied Microbiology, University of Tokyo
(Bacillus subtilis sbsp.niger), IAM-12077 (Baci
llus thringiensis), and IFO-0668 (Debaryomyces marama) stored at the Fermentation Research Institute as an example of yeast belonging to the genus Debaryomyces, and HUT-7041 ( Deb
aryomyces sake), but is not limited thereto, and an appropriate bacterium of these genera can be selected by a normal test performed by a person having ordinary knowledge.
これらの微生物の培養は、通常、振盪培養などの好気
的条件下で行なうのが適当である。温度は25〜35℃、pH
は７〜８で１〜２日間培養するのが適当である。培地に
は、使用菌が資化しうる炭素源、窒素源、無機塩類およ
び微量有機栄養分を含ませる。炭素源としては、グルコ
ース、フルクトースなどの炭水化物、窒素源としては、
アンモニア、塩化アンモニウムなどの各種の無機塩類お
よび有機のアンモニウム塩類または肉エキス、酵母エキ
ス、コーンスティープリカーなどの天然有機窒素源も使
用可能である。無機塩としては、マグネシウム、鉄、マ
ンガン、カリウム、ナトリウムなどの塩が適宜用いられ
る。さらに必要に応じて微生物の生育に必要な各種の有
機物、無機物あるいは通常用いられている消泡剤などを
添加することができる。Cultivation of these microorganisms is usually appropriate under aerobic conditions such as shaking culture. Temperature is 25-35 ℃, pH
It is suitable to culture 7 to 8 for 1 to 2 days. The medium contains a carbon source, a nitrogen source, inorganic salts, and trace organic nutrients that can be used by the bacteria used. As a carbon source, carbohydrates such as glucose and fructose, and as a nitrogen source,
Various inorganic salts such as ammonia and ammonium chloride and organic ammonium salts or natural organic nitrogen sources such as meat extract, yeast extract and corn steep liquor can also be used. As the inorganic salt, salts of magnesium, iron, manganese, potassium, sodium and the like are appropriately used. If necessary, various organic and inorganic substances necessary for the growth of microorganisms, or a commonly used antifoaming agent can be added.
反応に使用する基質であるラセミ体化合物Ｉの濃度
は、0.1〜1.0％の範囲で可能であるが、通常0.1〜0.2％
が好ましく、温度は10〜40℃、好ましくは25〜35℃、pH
は４〜９、好ましくは６〜８の範囲で２〜３日間反応さ
せる。なお、培養液中の反応生成物の定量は、薄層クロ
マトグラフィ（TLC）、高速液体クロマトグラフィ（HPL
C）等によって行うことができる。また、光学異性体
は、光学異性体分離カラムを用いることにより判別する
ことができる。反応液からの（−）−３−アルキル−3,
4−ジヒドロ−2H−［1,4］−ベンゾオキサジンの分離は
常法に従い、濾過、遠心分離、溶媒抽出、結晶化などの
操作を適宜組合せて行う。The concentration of the racemic compound I, which is a substrate used in the reaction, can be in the range of 0.1 to 1.0%, but is usually 0.1 to 0.2%.
The temperature is preferably 10 to 40 ° C, preferably 25 to 35 ° C, pH
Is reacted in the range of 4-9, preferably 6-8 for 2-3 days. The reaction products in the culture medium can be quantified by thin layer chromatography (TLC), high performance liquid chromatography (HPL).
C) etc. The optical isomer can be identified by using an optical isomer separation column. (-)-3-alkyl-3,
Separation of 4-dihydro-2H- [1,4] -benzoxazine is carried out according to a conventional method by appropriately combining operations such as filtration, centrifugation, solvent extraction and crystallization.
＜発明の効果＞ 本発明によれば、バチルス属細菌またはデバリオマイ
セス属酵母を使用することにより化合物Ｉのラセミ体か
ら（−）−３−アルキル−3,4−ジヒドロ−2H−［1,4］
−ベンゾオキサジンを高光学純度でしかも収率良く取得
することができる。<Effects of the Invention> According to the present invention, by using a bacterium of the genus Bacillus or a yeast of the genus Debaryomyces, (-)-3-alkyl-3,4-dihydro-2H- [1,4] is obtained from the racemate of compound I.
-Benzoxazine can be obtained with high optical purity and high yield.
次に実施例を示し更に詳細に説明するが、本発明はこ
れによって限定されるものではない。Next, examples will be shown and described in more detail, but the present invention is not limited thereto.
実施例１ 肉エキス0.3％、ペプトン１％、塩化ナトリウム0.5％
を含有する栄養培地（pH7.0）6.5を10容の発酵槽に
入れ、120℃、20分間滅菌した。放冷後これに上記と同
様の培地で一晩培養を行なったバチルス属細菌（DSC−1
012菌株）の種培養液300mlを加えて30℃で30時間培養を
行なった。得られた菌体懸濁液に（±）−４−アセチル
−7,8−ジフルオロ−3,4−ジヒドロ−３−メチル−2H−
［1,4］−ベンゾオキサジン（以下、Ac（±）−FBOと略
する。）6.5gを添加し、さらに30℃で３日間反応を行な
った。反応終了後、二塩化エタン1.0を加え生成物を
抽出し、次いでセライト濾過により菌体を除去した。反
応液の分析は次の条件で行った。Example 1 Meat extract 0.3%, peptone 1%, sodium chloride 0.5%
Was placed in a 10-volume fermenter and sterilized at 120 ° C. for 20 minutes. After allowing it to cool, it was cultured overnight in the same medium as described above.
(012 strain) was added to the culture medium (300 ml), and the mixture was cultured at 30 ° C. for 30 hours. (±) -4-acetyl-7,8-difluoro-3,4-dihydro-3-methyl-2H- was added to the obtained cell suspension.
6.5 g of [1,4] -benzoxazine (hereinafter abbreviated as Ac (±) -FBO) was added, and the mixture was further reacted at 30 ° C. for 3 days. After completion of the reaction, ethane dichloride (1.0) was added to extract the product, and then the cells were removed by filtration through celite. The reaction solution was analyzed under the following conditions.
カラム：キラルセルOD（ダイセル化学工業） 移動層:n−ヘキサン−IPA （96:4） 流速:1.0ml/分 測定波長:254nm 温度:30℃ 反応液組成 Ac（＋）FBO 3.20g （49.2％） Ac（−）FBO 0.13g （ 2.0％） （＋）FBO 0g （ 0％） （−）FBO 2.39g （45.2％） 上記二塩化エタン層を、10％塩酸で抽出し、Ac−FBO
とFBOを分離した。水層を中和後、酢酸エチルで抽出
し、濃塩酸を滴下することにより、2.63gの（−）FBOを
塩酸塩として単離した。この結晶は、NMR、IR、光学異
性体分離カラムなどの測定結果から（−）−7,8−ジフ
ルオロ−3,4−ジヒドロ−３−メチル−2H−［1,4］−ベ
ンゾオキサジンと同定され、その光学純度は99％e.e.以
上であった。なお、DSC−1010、1011菌株についても同
様に反応を行ない、以下の４結果を得た。Column: Chiralcel OD (Daicel Chemical Industries) Mobile phase: n-hexane-IPA (96: 4) Flow rate: 1.0 ml / min Measurement wavelength: 254 nm Temperature: 30 ° C Reaction solution composition Ac (+) FBO 3.20 g (49.2%) Ac (-) FBO 0.13g (2.0%) (+) FBO 0g (0%) (-) FBO 2.39g (45.2%) The ethane dichloride layer was extracted with 10% hydrochloric acid and Ac-FBO
And FBO separated. After neutralizing the aqueous layer, the mixture was extracted with ethyl acetate, and concentrated hydrochloric acid was added dropwise to isolate 2.63 g of (−) FBO as a hydrochloride. This crystal was identified as (−)-7,8-difluoro-3,4-dihydro-3-methyl-2H- [1,4] -benzoxazine from the results of measurements by NMR, IR, optical isomer separation columns, etc. The optical purity was 99% ee or higher. The DSC-1010 and 1011 strains were similarly reacted, and the following 4 results were obtained.
収率 光学純度 DSC−1010菌株 81.5％ 99.0％e.e. DSC−1011菌株 79.2％ 99.4％e.e. DSC−1012菌株 83.4％ 99.2％e.e. 実施例２ 実施例１と同様の栄養培地6.5にバチルス属細菌IAM
−1623菌株の種培養液300mlを加え30℃で培養後、Ac
（±）FBO 6.5gを加え、３日間反応を行なった。Yield Optical purity DSC-1010 strain 81.5% 99.0% ee DSC-1011 strain 79.2% 99.4% ee DSC-1012 strain 83.4% 99.2% ee Example 2 Bacillus bacterium IAM in the same nutrient medium 6.5 as in Example 1.
After adding 300 ml of the seed culture solution of the -1623 strain, culturing at 30 ° C
6.5 g of (±) FBO was added and the reaction was carried out for 3 days.
反応液組成 Ac（＋）FBO 3.22g （49.2％） Ac（−）FBO 1.94g （29.8％） （＋）FBO 0g （ 0％） （−）FBO 0.90g （17.0％） 実施例１と同様の操作を行ない、（−）−7,8−ジフ
ルオロ−3,4−ジヒドロ−３−メチル−2H−［1,4］−ベ
ンゾオキサジン塩酸塩0.82gを単離した。その光学純度
は99％e.e.以上であった。なお、IAM− 12077菌株につ
いても同様に反応を行ない、以下の結果を得た。Reaction solution composition Ac (+) FBO 3.22g (49.2%) Ac (-) FBO 1.94g (29.8%) (+) FBO 0g (0%) (-) FBO 0.90g (17.0%) Same as Example 1. Operation was carried out to isolate 0.82 g of (−)-7,8-difluoro-3,4-dihydro-3-methyl-2H- [1,4] -benzoxazine hydrochloride. Its optical purity was 99% ee or higher. The same results were obtained for the IAM-12077 strain and the following results were obtained.
収率 光学純度 IAM− 1623菌株 26.4％ 99.2％e.e. IAM− 12077菌株 24.9％ 99.0％e.e. 実施例３ グルコース４％、ペプトン１％を含有する栄養培地
（pH6.0）6.5にデバリオマイセス属酵母IFO−0668菌
株の種培養液300mlを加えて30℃で培養後Ac（±）FBO
6.5gを加え、３日間反応を行なった。実施例１と同様の
操作を行ない（−）−7,8−ジフルオロ−3,4−ジヒドロ
−３−メチル−2H−［1,4］−ベンゾオキサジンを塩酸
塩として単離した。Yield Optical purity IAM-1623 strain 26.4% 99.2% ee IAM12077 strain 24.9% 99.0% ee Example 3 Debaryomyces yeast IFO-0668 in a nutrient medium (pH 6.0) 6.5 containing 4% glucose and 1% peptone After adding 300 ml of the seed culture solution of the strain and culturing at 30 ℃, Ac (±) FBO
6.5 g was added and the reaction was carried out for 3 days. The same operation as in Example 1 was performed to isolate (-)-7,8-difluoro-3,4-dihydro-3-methyl-2H- [1,4] -benzoxazine as a hydrochloride salt.
収率 光学純度 IFO−0668菌株 31.7％ 99.0％e.e. HUT−7041菌株 27.9％ 98.3％e.e. 本発明の目的化合物を製造するには、原料化合物Ｉの
４−位のアシル基として各種のものが使用でき、最も普
通には、アセチル、プロピオニル、ブチリル等の脂肪族
アシル基があり、これらにハロゲン、アルコキシ等が置
換したものがある。また、ホルミル基も利用可能であ
る。さらに、ベンゾイルのような芳香族アシル基及びフ
ェニルアセチル基の如きアシル基及びこれらにアルコキ
シ、ハロゲン、アルキル、ニトロ等がｏ−、ｍ−、ｐ−
モノ置換又は、2,4−、3,5−ジ置換あるいはトリ置換し
たアシル基等も挙げることができる。さらに具体的に
は、アセチル、ベンゾイル、ｐ−メトキシベンゾイル、
2,4−ジメトキシベンゾイルを挙げることができ、最も
普通に取扱われるアセチル基が便利である。Yield Optical purity IFO-0668 strain 31.7% 99.0% ee HUT-7041 strain 27.9% 98.3% ee In order to produce the target compound of the present invention, various compounds can be used as the 4-position acyl group of the starting compound I. Most commonly, there are aliphatic acyl groups such as acetyl, propionyl, butyryl and the like, some of which are substituted by halogen, alkoxy and the like. Also, formyl group can be used. Further, aromatic acyl groups such as benzoyl and acyl groups such as phenylacetyl group, and alkoxy, halogen, alkyl, nitro and the like are o-, m-, p-
Mention may also be made of mono-substituted, 2,4-, 3,5-di-substituted or tri-substituted acyl groups and the like. More specifically, acetyl, benzoyl, p-methoxybenzoyl,
2,4-Dimethoxybenzoyl can be mentioned, and the most commonly used acetyl group is convenient.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ１２Ｒ 1:01） ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 Identification code Agency reference number FI Technical indication C12R 1:01)
Claims (1)
級アルキル基を、R2はアシル基を意味する。）で表わさ
れる４−アシル−３−アルキル−3,4−ジヒドロ−2H−
［1,4］−ベンゾオキサジンのラセミ体を、バチルス属
細菌、デバリオマイセス属酵母またはそれらの菌体処理
物と接触反応させ、次いで（−）−３−アルキル−3,4
−ジヒドロ−2H−［1,4］−ベンゾオキサジンを分離す
ることを特徴とする（−）−３−アルキル−3,4−ジヒ
ドロ−2H−［1,4］−ベンゾオキサジンの製造法。(1) Expression (In the formula, X a and X b are each a halogen atom, R 1 is a lower alkyl group, and R 2 is an acyl group.) 4-acyl-3-alkyl-3,4-dihydro-2H −
A racemic form of [1,4] -benzoxazine is reacted with a Bacillus bacterium, a Debaryomyces yeast or a treated product thereof, and then (−)-3-alkyl-3,4
A method for producing (-)-3-alkyl-3,4-dihydro-2H- [1,4] -benzoxazine, which comprises separating -dihydro-2H- [1,4] -benzoxazine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17961688A JP2670302B2 (en) | 1988-07-19 | 1988-07-19 | Microbial optical resolution method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17961688A JP2670302B2 (en) | 1988-07-19 | 1988-07-19 | Microbial optical resolution method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0231695A JPH0231695A (en) | 1990-02-01 |
| JP2670302B2 true JP2670302B2 (en) | 1997-10-29 |
Family
ID=16068869
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17961688A Expired - Fee Related JP2670302B2 (en) | 1988-07-19 | 1988-07-19 | Microbial optical resolution method |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2670302B2 (en) |
-
1988
- 1988-07-19 JP JP17961688A patent/JP2670302B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0231695A (en) | 1990-02-01 |
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