JPH01261380A - Separation of optical isomer - Google Patents
Separation of optical isomerInfo
- Publication number
- JPH01261380A JPH01261380A JP63090952A JP9095288A JPH01261380A JP H01261380 A JPH01261380 A JP H01261380A JP 63090952 A JP63090952 A JP 63090952A JP 9095288 A JP9095288 A JP 9095288A JP H01261380 A JPH01261380 A JP H01261380A
- Authority
- JP
- Japan
- Prior art keywords
- silica gel
- optical isomer
- group
- methyl
- difluoro
- 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
- 230000003287 optical effect Effects 0.000 title claims abstract description 21
- 238000000926 separation method Methods 0.000 title description 13
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000741 silica gel Substances 0.000 claims abstract description 10
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 239000001913 cellulose Substances 0.000 claims abstract description 6
- 229920002678 cellulose Polymers 0.000 claims abstract description 6
- 229920000642 polymer Polymers 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 4
- 239000000945 filler Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- -1 pyridonecarboxylic acid compound Chemical class 0.000 abstract description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000011084 recovery Methods 0.000 abstract description 5
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 150000002367 halogens Chemical class 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 238000012856 packing Methods 0.000 abstract 2
- 238000000034 method Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000001212 derivatisation Methods 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XJDDLMJULQGRLU-UHFFFAOYSA-N 1,3-dioxane-4,6-dione Chemical compound O=C1CC(=O)OCO1 XJDDLMJULQGRLU-UHFFFAOYSA-N 0.000 description 3
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011403 purification operation Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical compound C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-UHFFFAOYSA-N 0.000 description 1
- 101100005001 Caenorhabditis elegans cah-5 gene Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明は、不斉炭素を有するピリドンカルボン酸系化合
物の光学異性体の分析及び分取に関す。DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to the analysis and fractionation of optical isomers of pyridonecarboxylic acid compounds having an asymmetric carbon.
ピリドンカルボン酸系化合物は、合成抗菌剤として広く
用いられている。これらのうち不斉炭素を有する化合物
の光学異性体およびそれに対応する光学活性な合成中間
体の分析法及び分取精製法を確立することは極めて重要
である。Pyridonecarboxylic acid compounds are widely used as synthetic antibacterial agents. Among these, it is extremely important to establish analytical methods and preparative purification methods for optical isomers of compounds having asymmetric carbon atoms and optically active synthetic intermediates corresponding thereto.
〈従来の技術〉
光学異性体の分析法として光学純度を評価する方法は、
ｌ）直接法として旋光度を測定する方法、２）間接法と
して適当な誘導体に導き高速液体クロマトグラフィー（
以下ＨＰＬＣと略す）により分離分析する方法（特開昭
６２−８７５７７）などがある。<Prior art> The method for evaluating optical purity as an analytical method for optical isomers is
l) A direct method to measure the optical rotation; 2) An indirect method in which a suitable derivative is derived and high-performance liquid chromatography (
There is a method of separating and analyzing by HPLC (hereinafter abbreviated as HPLC) (Japanese Patent Application Laid-Open No. 62-87577).
しかし、１）の方法では、測定条件による変動が大きく
光学活性体の生成比を高感度、高精度で測定し難く定量
性に乏しい。２）の方法では、誘導体化操作が煩雑であ
り且つ誘導体化試剤は、不安定又は高価であるなどの欠
点を有する。However, method 1) has large fluctuations depending on the measurement conditions, making it difficult to measure the production ratio of optically active substances with high sensitivity and precision, resulting in poor quantitative performance. Method 2) has drawbacks such as the derivatization operation is complicated and the derivatization reagent is unstable or expensive.
光学異性体の精製法は、３）適当なジアステレオマー誘
導体に導き光学分割する方法（特願昭６２−１９４０１
７、特願昭６２−３３３３４０）、４） ＨＰＬＣで移
動相に光学活性な試剤を添加して直接分取する方法（特
願昭５２−１７０３７８）などがある。The method for purifying optical isomers is as follows: 3) A method of optically resolving the derivatives into appropriate diastereomer derivatives (Japanese Patent Application No. 19401/1983)
7, Japanese Patent Application No. 62-333340), 4) Direct fractionation method by adding an optically active reagent to the mobile phase in HPLC (Japanese Patent Application No. 52-170378).
しかし、３）の方法では、２）と同様の欠点を有し４）
の方法では移動相にアミノ酸及び金属イオンなどの添加
物を含むため分取後の精製操作が煩雑となるなどの欠点
を有する。However, method 3) has the same drawbacks as 2) and 4)
This method has the disadvantage that the mobile phase contains additives such as amino acids and metal ions, making the purification operation after fractionation complicated.
〈発明によって解決された問題点〉
本発明者等は、純度の低い合成中間体を原料にしても迅
速に且つ高純度に光学異性体の一方のみを取得可能な）
ＩＰＬＣによる光学分割に着目し、その充填剤と移動相
の条件を鋭意検討した。その結果特定な充填剤を用いる
ことにより、高い回収率で巧めで精度よく光学異性体を
、誘導体化や特定物質の添加などを経る事なく、直接分
離できる工業的に有利な方法を見い出しこの発明を完成
した。<Problems Solved by the Invention> The present inventors are able to rapidly and highly purified obtain only one of the optical isomers even if a synthetic intermediate with low purity is used as a raw material)
Focusing on optical resolution by IPLC, the conditions of the filler and mobile phase were carefully studied. As a result, we discovered an industrially advantageous method that can directly separate optical isomers with a high recovery rate, skillfully, and accurately without derivatization or addition of specific substances by using a specific filler.This invention is the present invention. completed.
〈発明の構成〉
本発明は一般式Ｉ
（式中Ｘａ及びｘｂはそれぞれハロゲン原子を、Ｒ１は
水素又はＣＨ−Ｃ（Ｃ，００低級アルキル）２を、Ｒ２
は低級アルキルを意味する）で表わされる化合物を、置
））基を有するセルロースでコーティングされたシリカ
ゲル、または光学活性ナフチルエチルアミノ基を有する
高分子が結合したシリカゲルを充填剤とした高速液体ク
ロマトグラフィにより分割する光学異性体の分取法であ
る。<Structure of the Invention> The present invention relates to the general formula I (wherein Xa and xb each represent a halogen atom, R1 represents hydrogen or CH-C(C,00 lower alkyl)2, R2
means lower alkyl) by high-performance liquid chromatography using silica gel coated with cellulose having ()) groups or silica gel bound with a polymer having an optically active naphthylethylamino group as a filler. This is a preparative method for separating optical isomers.
式ｌの化合物のハロゲン原子としては、フッ素原子、塩
素原子等が、低級アルキルとしてはメチル、エチル等が
例示される。Examples of the halogen atom of the compound of formula I include fluorine atom, chlorine atom, etc., and examples of lower alkyl include methyl, ethyl, etc.
充填剤に関し、置換基を有す名セルロースとしては例え
ば、シンナモイル（Ｃ６Ｈ６ＣＨ−ＣＨＣＯ−）で置換
されたセルロース、またはフェニルカルバモイル（Ｃａ
ＨｓＮ）ＩＣＯ−）で置換されたセルロースもしくはさ
らにそのフェニル基がモノもしくはジアルキル置換、モ
ノもしくはジハロゲノ（塩素等）置換、モノもしくはジ
アルコキシ置換したもの等を挙げることができる。Regarding fillers, examples of cellulose having substituents include cellulose substituted with cinnamoyl (C6H6CH-CHCO-) or phenylcarbamoyl (Ca
Examples include cellulose substituted with HsN)ICO-) or those in which the phenyl group is mono- or dialkyl-substituted, mono- or dihalogeno (chlorine, etc.) substituted, or mono- or dialkoxy-substituted.
更に具体的に、市販されている以下の様なタイプのキラ
ルセル（ＣＨＩＲＡＬＣＥＬ：ダイセル化学工業■製、
名称と置換基を示す）を挙げることができる。More specifically, the following types of commercially available chiral cells (CHIRALCEL: manufactured by Daicel Chemical Industries, Ltd.),
(showing names and substituents).
Ｃ）ＩＩＲ八しＣＥＬ ＯＤ ： ３，５−ジメチルフ
ェニルカルバモイルＣＨＩＲＡＬＣＥＬ ＱＣ ：フェ
ニルカルバモイル（ＣｓＨｓＮＨＣＯ−）
Ｃ）ＩＩＲＡＬｃＥＬ ＯＦ ： ４−クロロフェニル
カルバモイル（４−ＣＩ−ＣａＨＪＨＣＯ−）
Ｃ）ＩＩＲＡＬＣＥＬ ＯＧ ： ４−メチルフェニル
カルバモイル（４−Ｍｅ−（：６Ｈ４ＮＨＣＱ−）
Ｃ）ＩＩＲＡＬＣＥＬ Ｏに：シンナモイル（ＣａＨ５
Ｃｌｌ−（：Ｈ−Ｃｏ−）
また、光学活性ナフチルエチルアミノ基を有する高分子
が結合したシリカゲルとしては、Ｓ−またはＲ−配位の
１−α−ナフチルエチルアミノ基を有するポリマーが結
合したシリカゲル、ＹＭＣ Ａ−に０３（山村化学研究
新製）等がある。C) IIR Yashi CEL OD: 3,5-dimethylphenylcarbamoyl CHIRALCEL QC: Phenylcarbamoyl (CsHsNHCO-) C) IIRALcEL OF: 4-chlorophenylcarbamoyl (4-CI-CaHJHCO-) C) IIRALCEL OG: 4-methylphenylcarbamoyl Niru Carbamoyl (4-Me-(:6H4NHCQ-) C) IIRALCEL O: Cinnamoyl (CaH5
Cll-(:H-Co-) In addition, as a silica gel to which a polymer having an optically active naphthylethylamino group is bound, a polymer having an S- or R-coordinated 1-α-naphthylethylamino group is bound to the silica gel. Silica gel, YMC A-03 (manufactured by Yamamura Kagaku Kenkyushin), etc. are available.
移動相としては、脂肪族炭化水素、低級アルコールまた
は含ハロゲン炭化水素系溶媒を用いるのが適当である。As the mobile phase, it is appropriate to use an aliphatic hydrocarbon, a lower alcohol, or a halogen-containing hydrocarbon solvent.
脂肪族炭化水素の例としてはｎ−ヘキサン、ｎ−ペンタ
ン、ｎ−へブタン等、低級アルコールの例としては２−
プロパツール、エタノール、メタノニル等、含ハロゲン
炭化水素の例としてはジクロロメタン、クロロホルム、
四塩化炭素、１、２−ジクロロエタン等が挙げられるが
、ｎ−プロパンと２−プロパツールの混液、ｎ−ヘキサ
ンとエタノールの混液、ｎ−へキサンとジクロロメタン
とエタノールの混液等が好ましい。Examples of aliphatic hydrocarbons include n-hexane, n-pentane, n-hebutane, etc., and examples of lower alcohols include 2-
Examples of halogen-containing hydrocarbons include propatool, ethanol, methanonyl, dichloromethane, chloroform,
Examples include carbon tetrachloride and 1,2-dichloroethane, but preferred are a mixture of n-propane and 2-propanol, a mixture of n-hexane and ethanol, a mixture of n-hexane, dichloromethane, and ethanol, and the like.
各々の光学異性体が適当な保持時間の後溶出されるよう
単一溶媒または混合溶媒の種類と組成比を調整すること
ができる。温度は１０〜４０℃の範囲でよく、操作上室
温が好ましい。検出には通常紫外部吸光光度計を用い、
選択的且つ高感度に検出できる。The type and composition ratio of the single solvent or mixed solvent can be adjusted so that each optical isomer is eluted after an appropriate retention time. The temperature may range from 10 to 40°C, with room temperature being preferred for operational reasons. Detection is usually done using an ultraviolet spectrophotometer.
Can be detected selectively and with high sensitivity.
式Ｉの化合物の光学異性体をＨＰＬＣにより分取するに
は、その化合物を適当な溶媒に高濃度に溶解し、ＨＰＬ
Ｃに直接注入し、上記のＨＰＬＣ条件で溶出液を分取後
、溶媒を減圧留去すればよい。To separate the optical isomers of a compound of formula I by HPLC, the compound is dissolved in a suitable solvent at high concentration and subjected to HPLC.
The solvent may be directly injected into C, and the eluate may be fractionated under the above HPLC conditions, and then the solvent may be distilled off under reduced pressure.
〈発明の効果〉
本発明は不斉炭素を有するピリドンカルボン酸系化合物
の合成中間体等を誘導体化操作なしにＨＰＬＣにより容
易に高純度且つ高精度に分離する方法を提供するもので
ある。また、）ＩＰＬＣの移動相がアミノ酸や金属イオ
ンなどの添加物を含まない低沸点で純粋な有機溶媒であ
るため、分取後の精製操作が極めて容易且つ工業的であ
り目的の光学活性体を高回収率、高純度で得ることがで
きる。従って、本発明の分析法及び分取精製法は工業的
にも優れた方法である。<Effects of the Invention> The present invention provides a method for easily separating synthetic intermediates of pyridonecarboxylic acid compounds having an asymmetric carbon with high purity and precision by HPLC without derivatization. In addition, since the mobile phase of IPLC is a pure organic solvent with a low boiling point that does not contain additives such as amino acids or metal ions, the purification operation after fractionation is extremely easy and industrial, and the desired optically active substance can be extracted. It can be obtained with high recovery rate and high purity. Therefore, the analytical method and preparative purification method of the present invention are industrially excellent methods.
次に本発明の構成と効果を実施例により説明するが、本
発明はこの実施例によって限定されるものではない。Next, the configuration and effects of the present invention will be explained using examples, but the present invention is not limited to these examples.
実施例１： （±）−７，８−ジフルオロ−３−メチル
−３，４−ジヒドロ−２８−［１，４］ベンゾオキサジ
ンの分離（±）−７，８−ジフルオロ−３−メチル−３
，４−ジヒドロ−２８−［１，４］ベンゾオキサジンの
０．５ｍｇ／ｍｌメタノール溶液３μρをＨＰＬＣに直
接注入し、下記条件で良好な分離が達成された。分離係
数α−１，３２で得られたクロマトグラムのピークの保
持時間は別途に合成済の標品の保持時間と一致している
。クロマトグラムを第１図に示す。Example 1: Separation of (±)-7,8-difluoro-3-methyl-3,4-dihydro-28-[1,4]benzoxazine (±)-7,8-difluoro-3-methyl-3
, 4-dihydro-28-[1,4]benzoxazine (3 μρ) of 0.5 mg/ml methanol was directly injected into HPLC, and good separation was achieved under the following conditions. The retention time of the peak in the chromatogram obtained with the separation factor α-1, 32 coincides with the retention time of a separately synthesized standard sample. The chromatogram is shown in FIG.
カラム； （：ＨＩＲＡＬＣＥＬ ＯＤ ４．６１．Ｄ
、 Ｘ ２５Ｑｍｍ穆動相：ｎ−ヘキサン・２−プロパ
ツール、 （９６：４）流 速； １．Ｏｍｌ／ｍｉｎ
検出器；紫外部吸光光度計（測定波長２５４ｎｍ）温
度；室温
実施例２：各種カラム、移動相による （±）−７，８
−ジフルオロ−３−メチル−３，４−ジヒドロ−２）１
−［１，４］ベンゾオキサジンの分離
下記に示すカラム及び移動相を用い、実施例１の条件で
分離を実施し、良好な結果を得た。得られた分離係数α
を表１に示す。Column; (:HIRALCEL OD 4.61.D
, X 25Qmm mobile phase: n-hexane/2-propertool, (96:4) flow rate; 1. Oml/min Detector: Ultraviolet absorption photometer (measurement wavelength 254 nm) Temperature
degree; room temperature Example 2: Depending on various columns and mobile phase (±) -7,8
-difluoro-3-methyl-3,4-dihydro-2)1
- Separation of [1,4]benzoxazine Separation was carried out under the conditions of Example 1 using the column and mobile phase shown below, and good results were obtained. The obtained separation factor α
are shown in Table 1.
得られた分離係数αを表１に示す。Table 1 shows the obtained separation coefficient α.
表１
実施例３ ： （−）−７，８−ジフルオロ−３−メ
チル−３，４−ジヒドロ−２１４−［１，４］ベンゾオ
キサジンの分取（±）−７，８−ジフルオロ−３−メチ
ル−３，４−ジヒドロ−２８−［１，４］ベンゾオキサ
ジン０．１８をメタノールに溶解して１ｍｌとし、その
２０μβを実施例１に示した条件でＨＰＬＣに直接注入
しく−）−７，８−ジフルオロ−３−メチル−３，４−
ジヒドロ−２）１− ［１、４］ ベンゾオキサジンを
含む溶出液を分取する。この操作を１０回繰り返した後
溶出液を濃縮し、残留物として９，９ｍｇの結晶を得た
く融点２７．７℃）。回収率９９ 、０！ｌｉでこのも
のはＩＲ，ＮＭＲなどによる分析及び実施例１のＨＰＬ
Ｃによる光学純度定量の結果、５−（−） −７，８−
ジフルオロ−３−メチル−３，４−ジヒドロ−２１（−
［１，４］ベンゾオキサジン（特開昭６２−２５２７９
０）に一致シ、光学純度は９９．８９６ ｅ、ｅ、であ
った。Table 1 Example 3: Preparation of (−)-7,8-difluoro-3-methyl-3,4-dihydro-214-[1,4]benzoxazine (±)-7,8-difluoro-3- Dissolve 0.18 of methyl-3,4-dihydro-28-[1,4]benzoxazine in methanol to make 1 ml, and inject 20 μβ directly into HPLC under the conditions shown in Example 1. 8-difluoro-3-methyl-3,4-
The eluate containing dihydro-2)1-[1,4]benzoxazine is collected. After repeating this operation 10 times, the eluate was concentrated to obtain 9.9 mg of crystals as a residue (melting point: 27.7°C). Recovery rate: 99, 0! This product was analyzed by IR, NMR, etc. and HPL of Example 1.
As a result of optical purity determination using C, 5-(-)-7,8-
Difluoro-3-methyl-3,4-dihydro-21(-
[1,4]Benzoxazine (JP-A-62-25279
0), and the optical purity was 99.896 e,e.
実施例４： （±）−ジエチル・ （７，８−ジフルオ
ロ−３−メチル−３，４−ジヒドロ−２８−（１，４］
ベンゾオキサジン−４−イル）メチレンマロネートの分
離（±）−ジエチル・ （７，８−ジフルオロ−３−メ
チル−３，４−ジヒドロ−２１（−［１，４］ベンゾオ
キサジン−４−イル）メチレンマロネートを実施例１と
同様に操作し、下記の条件で良好な分離が達成された。Example 4: (±)-diethyl (7,8-difluoro-3-methyl-3,4-dihydro-28-(1,4)
Separation of (±)-diethyl (7,8-difluoro-3-methyl-3,4-dihydro-21(-[1,4]benzoxazin-4-yl) Methylene malonate was operated in the same manner as in Example 1, and good separation was achieved under the following conditions.
分離係数α−１，４３で得られたクロマトグラムのピー
クの保持時間は別途に合成済の標品の保持時間と一致し
た。クロマトグラムを第２図に示す。The retention time of the peak in the chromatogram obtained with the separation factor α-1.43 coincided with the retention time of a separately synthesized standard sample. The chromatogram is shown in FIG.
カラム； Ｃ）ＩＩＲＡＬＣＥＬ ００４．６１．Ｄ、
Ｘ ２５０ｍｍ移動相：ｎ−ヘキサン・２−プロパツ
ール（９：１ ）流 速； １．Ｏｍｌ／ｍｉｎ
検出器；紫外部吸光光度計（測定波長２５４ｎｍ）温
度；室温
実施例５：各種カラム、移動相による （±）−ジエチ
ル・ （７，８−ジフルオロ−３−メチル−３，４−ジ
ヒドロ−２８−［１，４］ベンゾオキサジン−４−イル
）メチレンマロネートの分離
下記のカラム及び移動相を用い、実施例４の条件で （
±）−ジエチル・ （７，８−ジフルオロ−３−メチル
−３，４−ジヒドロ−２８−［１，４］ベンゾオキサジ
ン−４−イル）メチレンマロネートの分離を実施し良好
な結果を得た。分離係数αを表２に示す。Column; C) IIRALCEL 004.61. D.
X 250mm Mobile phase: n-hexane/2-propatol (9:1) flow rate; 1. Oml/min Detector: Ultraviolet absorption photometer (measurement wavelength 254 nm) Temperature
temperature; room temperature Example 5: Various columns, mobile phase (±)-Diethyl (7,8-difluoro-3-methyl-3,4-dihydro-28-[1,4]benzoxazin-4-yl) Separation of methylene malonate Using the column and mobile phase shown below, under the conditions of Example 4 (
±)-diethyl (7,8-difluoro-3-methyl-3,4-dihydro-28-[1,4]benzoxazin-4-yl)methylenemalonate was separated with good results. . Table 2 shows the separation coefficient α.
表２
実施例６：（＋）−ジエチル・ （７，８−ジフルオロ
−３−メチル−３，４−ジヒドロ−２８−［１，４］ベ
ンゾオキサジン−４−イル）メチレンマロネートの分取
（±）−ジエチル・ （７，８−ジフルオロ−３−メチ
ル−３，４−ジヒドロ−２８−［１，４］ベンゾオキサ
ジン−４−イル）メチレンマロネートを、実施例４のＨ
ＰＬＣ条件により実施例３と同様に操作し、油状物質を
得た。回収率９９．１９６でこのものはＩＲ，ＮＭＲな
どによる分析及び実施例４のＨＰＬＣによる光学純度定
量の結果、Ｓ−（＋）−ジエチル・（７，８−ジフルオ
ロ−３−メチル−３，４−ジヒドロ−２）１−［１，４
］−ベンゾオキサジン−４−イル）メチレンマロネート
（特願昭６２−３３６４８９）に一致し、光学純度は９
９．Ｈｅ、ｅ、であった。Table 2 Example 6: Preparation of (+)-diethyl (7,8-difluoro-3-methyl-3,4-dihydro-28-[1,4]benzoxazin-4-yl)methylene malonate ( ±)-diethyl (7,8-difluoro-3-methyl-3,4-dihydro-28-[1,4]benzoxazin-4-yl)methylenemalonate in Example 4
The same procedure as in Example 3 was carried out under PLC conditions to obtain an oily substance. The recovery rate was 99.196, and as a result of analysis by IR, NMR, etc. and determination of optical purity by HPLC in Example 4, S-(+)-diethyl (7,8-difluoro-3-methyl-3,4 -dihydro-2)1-[1,4
]-benzoxazin-4-yl) methylene malonate (Japanese Patent Application No. 62-336489), and the optical purity is 9.
9. It was He,e.
第１図および第２図はクロマトグラムである。 ロ ０．（、ψ ロ ２ 窃） Figures 1 and 2 are chromatograms. B 0. (,ψ (b) 2 theft)
Claims (1)
は水素又はＣＨ＝Ｃ（ＣＯＯ低級アルキル）＿２を、Ｒ
＿２は低級アルキルを意味する）で表わされる化合物を
、置換基を有するセルロースでコーティングされたシリ
カゲルまたは光学活性ナフチルエチルアミノ基を有する
高分子が結合したシリカゲルを充填剤とした高速液体ク
ロマトグラフィにより分割することを特徴とする光学異
性体の分取法。[Claims] General formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, Xa and Xb each represent a halogen atom, R_1
is hydrogen or CH=C(COO lower alkyl)_2, R
_2 means lower alkyl) is separated by high performance liquid chromatography using silica gel coated with cellulose having a substituent or silica gel bonded with a polymer having an optically active naphthylethylamino group as a filler. A preparative method for optical isomers characterized by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63090952A JP2653464B2 (en) | 1988-04-13 | 1988-04-13 | Preparative method for optical isomers |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63090952A JP2653464B2 (en) | 1988-04-13 | 1988-04-13 | Preparative method for optical isomers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01261380A true JPH01261380A (en) | 1989-10-18 |
| JP2653464B2 JP2653464B2 (en) | 1997-09-17 |
Family
ID=14012817
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63090952A Expired - Lifetime JP2653464B2 (en) | 1988-04-13 | 1988-04-13 | Preparative method for optical isomers |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2653464B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007141900A1 (en) * | 2006-06-02 | 2007-12-13 | Daiichi Pharmaceutical Co., Ltd. | Separation method |
-
1988
- 1988-04-13 JP JP63090952A patent/JP2653464B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007141900A1 (en) * | 2006-06-02 | 2007-12-13 | Daiichi Pharmaceutical Co., Ltd. | Separation method |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2653464B2 (en) | 1997-09-17 |
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