JPH01221331A - Method for separation - Google Patents
Method for separationInfo
- Publication number
- JPH01221331A JPH01221331A JP4652788A JP4652788A JPH01221331A JP H01221331 A JPH01221331 A JP H01221331A JP 4652788 A JP4652788 A JP 4652788A JP 4652788 A JP4652788 A JP 4652788A JP H01221331 A JPH01221331 A JP H01221331A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- normal phase
- carboxyl group
- examples
- phase system
- 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
- 238000000926 separation method Methods 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 238000004811 liquid chromatography Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 17
- 229920001282 polysaccharide Polymers 0.000 abstract description 15
- 239000005017 polysaccharide Substances 0.000 abstract description 15
- 230000003287 optical effect Effects 0.000 abstract description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 abstract description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 abstract description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 5
- 150000001413 amino acids Chemical class 0.000 abstract description 5
- 235000019253 formic acid Nutrition 0.000 abstract description 5
- 238000012856 packing Methods 0.000 abstract description 5
- 239000000741 silica gel Substances 0.000 abstract description 5
- 229910002027 silica gel Inorganic materials 0.000 abstract description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 abstract description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 abstract description 3
- 239000008108 microcrystalline cellulose Substances 0.000 abstract description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 abstract description 3
- 239000002245 particle Substances 0.000 abstract description 3
- 239000004793 Polystyrene Substances 0.000 abstract description 2
- 229920002223 polystyrene Polymers 0.000 abstract description 2
- 150000004676 glycans Chemical class 0.000 abstract 1
- 229920002678 cellulose Polymers 0.000 description 21
- 239000001913 cellulose Substances 0.000 description 21
- 235000010980 cellulose Nutrition 0.000 description 21
- 239000007983 Tris buffer Substances 0.000 description 13
- 239000000945 filler Substances 0.000 description 13
- 150000004804 polysaccharides Chemical class 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229920000856 Amylose Polymers 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- -1 cyclic polysaccharides Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- KPCOLEDDUNYSQA-UHFFFAOYSA-N (3,5-dimethylphenyl)carbamic acid Chemical class CC1=CC(C)=CC(NC(O)=O)=C1 KPCOLEDDUNYSQA-UHFFFAOYSA-N 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000011256 inorganic filler Substances 0.000 description 2
- 229910003475 inorganic filler Inorganic materials 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012766 organic filler Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229920001221 xylan Polymers 0.000 description 2
- DZSGDHNHQAJZCO-UHFFFAOYSA-N 1-isocyanato-3,5-dimethylbenzene Chemical compound CC1=CC(C)=CC(N=C=O)=C1 DZSGDHNHQAJZCO-UHFFFAOYSA-N 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 229920002498 Beta-glucan Polymers 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 229920001202 Inulin Polymers 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-RWOPYEJCSA-N beta-D-mannose Chemical compound OC[C@H]1O[C@@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-RWOPYEJCSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 1
- 229940029339 inulin Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- LPNBBFKOUUSUDB-UHFFFAOYSA-M p-toluate Chemical compound CC1=CC=C(C([O-])=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-M 0.000 description 1
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920005640 poly alpha-1,3-glucan Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000004381 surface treatment Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 150000004823 xylans Chemical class 0.000 description 1
Landscapes
- Indole Compounds (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、アミノ酸などのカルボキシル基を含有する化
合物の混合物を液体クロマトグラフィーにより効率良く
分離する方法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for efficiently separating a mixture of compounds containing carboxyl groups, such as amino acids, by liquid chromatography.
アミノ酸などのカルボキシル基を含有する化合物の混合
物、例えば光学異性体の混合物を液体クロマトグラフィ
ーにより効率よく分離する方法については、これまでに
も種々研究されてきた。Various studies have been conducted on methods for efficiently separating mixtures of compounds containing carboxyl groups such as amino acids, for example, mixtures of optical isomers, by liquid chromatography.
しかしながら、従来提案されたものは何れも分離性能に
於いて満足すべきものではなかった。However, none of the methods proposed so far have been satisfactory in terms of separation performance.
本発明者らは、かかる問題点について鋭意検討した結果
、本発明を完成したものである。The present inventors have completed the present invention as a result of intensive study on such problems.
即ち本発明は、液体クロマトグラフィーにおいて、カル
ボキシル基を含有する化合物の混合物を順相系で分離す
る際に、酸を用いることを特徴とする分離方法に関する
。That is, the present invention relates to a separation method characterized in that an acid is used when separating a mixture of compounds containing carboxyl groups in a normal phase system in liquid chromatography.
本発明において、順相系とは移動相が固定相に比べて極
性の低い場合を順相系と呼び、例えば固定相にシリカゲ
ルを用い移動相にへキサン等を使用する場合などが例示
できる。In the present invention, a normal phase system refers to a case where the mobile phase has lower polarity than the stationary phase, and examples thereof include a case where silica gel is used as the stationary phase and hexane is used as the mobile phase.
本発明においてカルボキシル基を含有する化合物として
は、有機化合物の分子中にカルボキシル基を少なくとも
１個含有する化合物である。In the present invention, the compound containing a carboxyl group is a compound containing at least one carboxyl group in the molecule of an organic compound.
そしてその混合物としては、光学異性体からなる混合物
がある。例示するならば、光学活性なアミノ酸などがあ
る。The mixture includes a mixture of optical isomers. Examples include optically active amino acids.
また、幾何異性体、位置異性体などのその他の異性体か
らなる混合物がある。例示するならば、幾何異性体とし
てはシス−トランス異性体、オルト、パラ、メタ異性体
などがある。位置異性体としては、各種の環状多糖があ
る。その他、カルボキシル基を含有する種々の有機化合
物の混合物がある。There are also mixtures of other isomers such as geometric isomers and positional isomers. For example, geometric isomers include cis-trans isomers, ortho, para, meta isomers, and the like. Positional isomers include various cyclic polysaccharides. In addition, there are mixtures of various organic compounds containing carboxyl groups.
また本発明においては、カルボキシル基を含有する有機
化合物中にカルボキシル基以外の官能基があれば、分離
効率を上げるためそれを化学修飾しても□良い。Furthermore, in the present invention, if the organic compound containing a carboxyl group has a functional group other than a carboxyl group, it may be chemically modified to increase separation efficiency.
この様に本発明の分離方法は、種々の異性体、特に光学
異性体の分離に最適である。As described above, the separation method of the present invention is most suitable for separating various isomers, especially optical isomers.
本発明の分離方法に用いる充填剤としては、種々の溶媒
又はそれらの混合物を液体クロマトグラフィーの展開溶
媒として用いたとき、少なくとも１種の溶媒系で順相系
を示す充填剤を選択することが重要である。As the packing material used in the separation method of the present invention, it is possible to select a packing material that exhibits a normal phase system in at least one solvent system when various solvents or mixtures thereof are used as a developing solvent for liquid chromatography. is important.
かかる充填剤としては、無機充填剤と有機充填剤がある
。無機充填剤としては、シリカゲル、アルミナ、ガラス
などが例示され、有機充填剤としては、ポリスチレン、
ポリアクリルアミド、ポリアクリレートなどのホモポリ
マー、或いは種々の反応性モノマーからなるコポリマー
が例示される。Such fillers include inorganic fillers and organic fillers. Examples of inorganic fillers include silica gel, alumina, and glass, and examples of organic fillers include polystyrene,
Examples include homopolymers such as polyacrylamide and polyacrylate, and copolymers made of various reactive monomers.
特に異性体、例えば光学異性体を分離する充填剤として
は、不斉中心を持つか、分子不斉な化合物を有効成分と
する充填剤がある。不斉中心を持つ、即ち不斉炭素を持
つ化合物を有効成分とする充填剤としては、光学活性な
アミノ酸などを用いたものが例示され得る。具体的なも
のとしては、特開昭５６（３５０や特開昭６０−６６１
６２などに記載されるものがあり、また、高分子タイプ
のものとしては、ポリアミノ酸やセルロース、アガロー
スなどの多糖又はその誘導体などが例示され得る。Particularly, as a filler for separating isomers, for example, optical isomers, there are fillers having an asymmetric center or containing a compound having asymmetric molecular structure as an active ingredient. Examples of fillers containing a compound having an asymmetric center, that is, an asymmetric carbon, as an active ingredient include those using optically active amino acids. Specific examples include JP-A-56 (350) and JP-A-60-661.
Examples of the polymer type include polyamino acids, polysaccharides such as cellulose and agarose, and derivatives thereof.
多糖又はその誘導体を具体的に示すと、ここでいう多糖
とは合成多糖、天然多糖、天然物変成多糖のいずれかを
問わず、光学活性であればいかなるものでも良いが、好
ましくは規則性の高いホモグリカンであり、しかも結合
様式も一定であるものである。更に好ましくは高純度の
多糖を容易に得ることのできるセルロース、アミロース
、β−１，４−キトサン、キチン、β−１，４−マンナ
ン、β−１，４−キシラン、イヌリン、α−１，３−グ
ルカン、β−１，３−グルカン等である。多糖の誘導体
とは、上記多糖の有する水酸基又はアミノ基上の水素原
子の一部或いは全部、即ち、３０％以上、好ましくは５
０％以上、更に好ましくは８５％以上を他の原子団で置
換し１ま
たものである。ここでいう原子団は、−Ｃ−Ｒ”、Ｒ′
は炭素数１〜３よりなる脂肪族基、３〜８よりなる環式
脂肪族基、炭素数６〜２０よりなる芳香族基もしくは炭
素数４〜２０よりなるヘテロ芳香族基であり、原子団と
してはこれらの１種を用いても良いが、２種以上を用い
てもかまわない。これは分離性能の面から選択すること
が好ましい。Specifically referring to the polysaccharide or its derivative, the polysaccharide referred to herein may be any optically active polysaccharide, regardless of whether it is a synthetic polysaccharide, a natural polysaccharide, or a modified natural polysaccharide, but preferably a regular polysaccharide. It is a highly homoglycan and has a fixed binding pattern. More preferably, cellulose, amylose, β-1,4-chitosan, chitin, β-1,4-mannan, β-1,4-xylan, inulin, α-1, 3-glucan, β-1,3-glucan, and the like. A polysaccharide derivative refers to a part or all of the hydrogen atoms on the hydroxyl group or amino group of the polysaccharide, that is, 30% or more, preferably 5
At least 0%, more preferably at least 85% of the atoms are substituted with other atomic groups. The atomic groups mentioned here are -C-R", R'
is an aliphatic group having 1 to 3 carbon atoms, a cycloaliphatic group having 3 to 8 carbon atoms, an aromatic group having 6 to 20 carbon atoms, or a heteroaromatic group having 4 to 20 carbon atoms; One type of these may be used, but two or more types may be used. This is preferably selected from the viewpoint of separation performance.
また、いずれも置換基を有しても良い。ここでいう置換
基としては、メチル基やｔ−ブチル基などのＣ，−Ｃ，
の枝分かれを有しても良いアルキル基、塩素などのハロ
ゲンなどが例示され得るが、それ以外でも分離の性能を
向上させる範囲で種々の置換基を用いることができる。Moreover, all may have a substituent. The substituents mentioned here include C, -C, such as methyl group and t-butyl group.
Examples include an alkyl group that may have a branch, a halogen such as chlorine, and various other substituents can be used as long as they improve the separation performance.
また、置換基の数も分離の性能を向上させる範囲で１又
はそれ以上が選択できる。また置換基の位置も例えば、
フェニル基などの芳香族基を用いた時は、置換基が１種
の場合、オルト、メタ、パラ位など分離の性能を向上さ
せる範囲で選択できる。更に置換基が２種の場合、３．
４位や３゜５位など同様に種々の配置が選択できる。Further, the number of substituents can be selected to be one or more within a range that improves the separation performance. In addition, the position of the substituent may be, for example,
When an aromatic group such as a phenyl group is used, if there is only one type of substituent, the substituent can be selected from the ortho, meta, and para positions within a range that improves the separation performance. Furthermore, when there are two types of substituents, 3.
Similarly, various arrangements can be selected, such as 4th position, 3°5th position, etc.
これらの誘導体は公知の各種の化学反応を用いて容易に
得ることかで幸る。例えば芳香族基を含むセルロース誘
導体を合成の一例として示せば、セルロースの有する水
酸基の水素の一部或いは全部を、芳香族基によって置換
したものである。この置換に右ける結合の様式としては
、例えばエステル結合、エーテル結合、ウレタン結合等
がある。These derivatives can be easily obtained using various known chemical reactions. For example, as an example of synthesis of a cellulose derivative containing an aromatic group, some or all of the hydrogen atoms in the hydroxyl groups of cellulose are replaced with aromatic groups. Examples of the type of bond depending on this substitution include an ester bond, an ether bond, and a urethane bond.
上記の如き多糖又はその誘導体を例示するならば、多糖
としては、微結晶セルロースなどがあり、多糖誘導体と
しては、セルローストリアセテート、セルローストリベ
ンゾエート、セルローストリス（ｐ−メチルベンゾエー
ト）、セルローストリスフェニルカルバメート、七ルロ
ーストリス （ｐ−メチルフェニルカルノくメート）、
セルローストリス（３，５−ジメチルフェニルカルバメ
ート）、セルローストリス（ｐ−タロロフェニル力ルバ
メート）、セルローストリス（ｐ−ｔ−−ｆチルフェニ
ルカルバメート）、セルローストリシンナメートなどが
ある。Examples of the above-mentioned polysaccharides or derivatives thereof include microcrystalline cellulose, and examples of the polysaccharide derivatives include cellulose triacetate, cellulose tribenzoate, cellulose tris(p-methylbenzoate), cellulose tris phenyl carbamate, Seven rulosetris (p-methylphenylcarnocumate),
Examples include cellulose tris (3,5-dimethylphenyl carbamate), cellulose tris (p-talolophenyl rubamate), cellulose tris (p-t--f tylphenyl carbamate), cellulose tricinnamate, and the like.
また、アミロース、キトサン、キシラン、デキストラン
などセルロース以外の多糖の上記例示の如き誘導体を用
いることもできる。Further, derivatives of polysaccharides other than cellulose such as amylose, chitosan, xylan, and dextran as exemplified above can also be used.
また、分子不斉な化合物としては、例えば下式で示され
る重合性単量体を主成分とした光学活性なポリマーがあ
る。Examples of molecularly asymmetric compounds include optically active polymers whose main component is a polymerizable monomer represented by the following formula.
ＣＨ。CH.
ＣＩ□＝Ｃ
□
Ｒ，−ＣＬ
式中、Ｒ，、Ｒ，及びＲ３は同−又は異なっていてＹは
０１〜Ｃ１の枝分かれを有しても良いアルキル基、ハロ
ゲン又はアミノ基であり、Ａ、ｍｌｊ置換基の個数を示
し、■より５までの整数である。CI□=C □ R, -CL In the formula, R,, R, and R3 are the same or different, Y is an alkyl group, halogen, or amino group which may have branching from 01 to C1, and A , mlj indicates the number of substituents, and is an integer from ■ to 5.
また、特開昭６１−１６００５９ 、同６１−１６２７
５０〜１や同５１−８１８９１などに記載されたものが
ある。Also, JP-A No. 61-160059, No. 61-1627
There are those described in 50-1 and 51-81891.
本発明に用いる充填剤は、無機系、有機系ともいずれも
そのまま、１μｍ〜１０闘、好ましくは１μｍ〜３００
μｍの粒径にした担体として用いることができる。好ま
しくは多孔質のものであり、その平均孔径は１０人〜１
００μｍ１好ましくは３０人〜１００００人である。The filler used in the present invention, whether inorganic or organic, has a particle diameter of 1 μm to 10 μm, preferably 1 μm to 300 μm.
It can be used as a carrier with a particle size of μm. It is preferably porous, with an average pore size of 10 to 1
00 μm 1 preferably 30 to 10,000 people.
また、有機系のものについては、担体に１〜１００重量
％、好ましくは５〜５０重量％保持させることが好まし
い。Furthermore, it is preferable that the organic type be retained in the carrier in an amount of 1 to 100% by weight, preferably 5 to 50% by weight.
担体としては有機系のものも用いられるが、シリカゲル
などの無機系のものが好ましく、その性状は前述したも
のである。また、保持させる方法としては、物理的方法
や、化学結合させる方法などがあり、また、担体を有機
シラン化合物を用いてシラン処理などの表面処理をする
ことが好ましい。Although organic carriers can be used, inorganic carriers such as silica gel are preferred, and their properties are as described above. In addition, methods for retaining include physical methods and chemical bonding methods, and it is preferable to subject the carrier to surface treatment such as silane treatment using an organic silane compound.
本発明に用いる順相系の溶媒としては、極性の低い化合
物があり、好ましくはＣ１〜Ｃ２゜の枝分かれを有して
も良い炭化水素である。但し順相系をこわさない範囲で
極性溶媒、例えばＣ１〜Ｃ１のアルコールなどを添加し
ても良く、またその方が分離効率を向上させる場合があ
る。The normal phase solvent used in the present invention includes compounds with low polarity, preferably hydrocarbons which may have C1 to C2 degree branching. However, a polar solvent such as a C1 to C1 alcohol may be added within a range that does not damage the normal phase system, and this may improve the separation efficiency.
また、本発明に用いる酸としては、有機酸、無機酸があ
り、有機酸としては、ギ酸、酢酸、プロピオン酸、ジク
ロロ酢酸、トリクロロ酢酸、トリフルオロ酢酸などが例
示され、無機酸としては、硫酸、リン酸などが例示され
る。In addition, acids used in the present invention include organic acids and inorganic acids. Examples of organic acids include formic acid, acetic acid, propionic acid, dichloroacetic acid, trichloroacetic acid, and trifluoroacetic acid, and examples of inorganic acids include sulfuric acid. , phosphoric acid, etc.
特に好ましくは、分離すべきカルボキシル基を含有する
化合物の酸の強度よりも強い酸を用いることである。Particular preference is given to using an acid stronger than the acid strength of the compound containing the carboxyl group to be separated.
更に好ましくは、酸の強度ｐＫＡが５以下、好ましくは
４以下のものであればよく、例えばギ酸（３，７） 、
トリフルオロ酢酸（０，２３）などが例示できる。More preferably, the acid strength pKA is 5 or less, preferably 4 or less, such as formic acid (3,7),
Examples include trifluoroacetic acid (0,23).
本発明の分離方法に際し、酸を用いる方法は、分離する
前に充填剤を酸で処理する方法、又は分離すべきカルボ
キシル基を含有する化合物に酸を添加する方法などが例
示できるが、作業性等の点から、順相系の展開溶媒に酸
を添加する方法が好ましい。またその使用量は、順相系
展開溶媒全体に対して０．０１〜２０重量％、好ましく
は０．１〜１０重量％含有させることが好ましい。In the separation method of the present invention, examples of methods using acid include a method in which a filler is treated with an acid before separation, or a method in which an acid is added to a compound containing a carboxyl group to be separated. From these points, it is preferable to add an acid to a normal phase developing solvent. The amount used is preferably 0.01 to 20% by weight, preferably 0.1 to 10% by weight, based on the entire normal phase developing solvent.
尚、分離する前に充填剤を酸で処理する方法の具体的態
様としては次の様な方法が例示される。即ち、ヘキサン
−２−ＰｒＯＨの７＝３の割合の混合液中に３％のトリ
フルオロ酢酸と２％の蟻酸を含有する混合溶媒を移動相
として充填剤のカラムに流し、０．５ｍｌ／分で１時間
以上流した後、ヘキサン−２−ＰｒＯＨ（７： ３ ）
混合液を流してカラムを平衡化させてから、分離する方
法がある。又分離すべき試料に酸を添加する方法の具体
的態様としては次の様な方法が例示される。Note that the following method is exemplified as a specific method for treating the filler with acid before separation. That is, a mixed solvent containing 3% trifluoroacetic acid and 2% formic acid in a mixture of hexane-2-PrOH at a ratio of 7=3 was used as a mobile phase to flow through a column of packing material at a rate of 0.5 ml/min. After flowing for more than 1 hour, hexane-2-PrOH (7:3)
There is a method of equilibrating a column by flowing a mixed solution and then performing separation. Further, the following method is exemplified as a specific method of adding acid to the sample to be separated.
即ち、移動相としてヘキサン−２−ＰｒＯＨ（７： ３
）の混合液をカラムに流し、試料は２％の蟻酸を含有す
るヘキサン−２−ＰｒＯＨ（７： ３ ）混合液中に添
加しておく方法がある。That is, hexane-2-PrOH (7:3
) is passed through the column, and the sample is added to a hexane-2-PrOH (7:3) mixture containing 2% formic acid.
以下本発明を合成例及び実施例によって詳述するが、本
発明はこれらの実施例に限定されるものではない。なお
、実施例中に表わされる用語の定義は以下の通りである
。The present invention will be explained in detail below using synthesis examples and examples, but the present invention is not limited to these examples. The definitions of terms used in the examples are as follows.
容量比（ｋ’ ） −
分離係数（α）＝
分離度（Ｒｓ） −
両ピークのバンド幅の合計
合 成 例 １ （充填剤）
セルローストリス（３，５−ジメチルフェニルカルバメ
ート）の合成
微結晶セルロース（メルク社製、重合度１０１００）１
ピリジン５０ｍ１’、３．５−ジメチルフェニルイソシ
アナート６．５ｍｉ！を１００℃で１７時間加熱した後
、反応混合物をメタノール５００ｍ１に注いだ。Capacity ratio (k') - Separation factor (α) = Resolution (Rs) - Synthesis of total band width of both peaks Example 1 (filler) Synthesis of cellulose tris (3,5-dimethylphenylcarbamate) Microcrystalline cellulose (manufactured by Merck & Co., degree of polymerization 10100) 1
50 ml of pyridine, 6.5 mi of 3,5-dimethylphenylisocyanate! After heating at 100° C. for 17 hours, the reaction mixture was poured into 500 ml of methanol.
生じた沈殿を濾別乾燥して３，５−ジメチルフェニルカ
ルバメート誘導体を得た。置換度はほぼ１００％であっ
た。The resulting precipitate was filtered and dried to obtain a 3,5-dimethylphenylcarbamate derivative. The degree of substitution was approximately 100%.
収量 ３．２６ ｇ
収率 ８８％
元素分析
得られたセルローストリス（３，５−ジメチルフェニル
カルバメート） １部を８部のアセトンに溶解し、ジフ
ェニルシラン処理したシリカケル（Ｍｅｒｃｋ社製Ｌｉ
ｃｈｒｏｓｐｈｅｒ ５ｉ−１０００） ４部と混和し
た後、アセトンを減圧留去することにより充填剤を得た
。該充填剤をメタノールを用いたスラリー法により内径
０．４６ｃｍ、長さ２５ｃｍのカラムに充填した。Yield 3.26 g Yield 88% Elemental analysis 1 part of the obtained cellulose tris (3,5-dimethylphenyl carbamate) was dissolved in 8 parts of acetone, and silica gel treated with diphenylsilane (Merck Li
After mixing with 4 parts of Chrospher 5i-1000), acetone was distilled off under reduced pressure to obtain a filler. The packing material was packed into a column having an inner diameter of 0.46 cm and a length of 25 cm by a slurry method using methanol.
実施例１
前記の合成例で得られた充填剤を用いて、種々の光学活
性なカルボン酸を展開溶媒の温度２５℃、流速０．５ｄ
／分で光学分割した結果を表−１に示す。Example 1 Using the filler obtained in the above synthesis example, various optically active carboxylic acids were prepared at a developing solvent temperature of 25°C and a flow rate of 0.5 d.
Table 1 shows the results of optical resolution at /min.
表−ｌ
セルローストリス（３，５−ジメチルフェニルカルバメ
ート）により光学分割されたカルボン酸
（註） ａ ８６Ｍ溶媒：ヘヰ”ｔン２−ＰｒＯＨＮＣ
Ｏ２１（（８（１：２（１： ｌ）ｂ展開溶媒；ヘキサ
：／−２−ＰｒＯＨＨＣＯ２Ｈ（９５： ５ ： １）
Ｃ展開溶媒；ヘキサン−２−Ｐｒｏ）Ｉ−ＨＣＯ，）Ｉ
（９８： ２ ： １）実施例２
合成例１でセルロースの代わりにアミロースで同様の充
填剤を作り、これらのセルロース及びアミロースの３．
５−ジメチルフェニルカルバメート誘導体を用いて種々
分離した結果を表−２に示す。Table-1 Carboxylic acids optically resolved by cellulose tris(3,5-dimethylphenylcarbamate) (Note) a 86M solvent: H-2-PrOHNC
O21((8(1:2(1:l)bDeveloping solvent; Hexa:/-2-PrOHHCO2H(95:5:1)
C developing solvent; hexane-2-Pro)I-HCO,)I
(98: 2: 1) Example 2 A similar filler was made using amylose instead of cellulose in Synthesis Example 1, and 3.
Table 2 shows the results of various separations using 5-dimethylphenyl carbamate derivatives.
表 −２
３，５−ジメチルフェニルカルバメート誘導体によるＰ
ｈｃｌ１２０ｃＯ−ＮＨＯＩ （Ｒ） Ｃ００ＩＩ化
合物の光学分割展開溶媒：ヘキサン−２−１ｒｏｌＩ−
１１（、ｏｏｌｌ （８０： ２０ ： ｌ ）実施
例３
合成例１と同様に種々の充填剤を合成し、分離した結果
を表−３に示す。Table 2 P by 3,5-dimethylphenylcarbamate derivatives
hcl120cO-NHOI (R) Optical resolution developing solvent of C00II compound: hexane-2-1rolI-
11 (, ooll (80: 20: l)) Example 3 Various fillers were synthesized and separated in the same manner as in Synthesis Example 1, and the results are shown in Table 3.
表 −３
種々のトリフェニル力ルノイメート誘導体（こよる二つ
のカルボン酸の光学分、８１１
ｂ）；セルローストリスフエニルカルノくメートＣ〉；
セルローストリス （４−エチルフェニルカルｄ）；セ
ルローストリス （４−メトキンフエニルカルノイメー
ト）ｅ）；セルローストリス（３．５−’；メチルフエ
ニルカルノイメート）ｆ）；アミローストリス（３，５
−”メチルフェニルカル実施例４
合成例１の充填剤を用いた展開溶媒の検討した結果を表
−４、５に示す。Table 3 Various triphenylcarnomate derivatives (optical spectra of two carboxylic acids, 811b); Cellulose trisphenylcarnomate C>;
Cellulose tris (4-ethyl phenyl carnimate) e); cellulose tris (3.5-'; methyl phenyl carnimate) f); amylose tris (3, 5
-"Methylphenylcal Example 4 Tables 4 and 5 show the results of an investigation of the developing solvent using the filler of Synthesis Example 1.
表 − ４
セルローストリス（３， ５−ジメチルフェニルカルバ
メート）によるマンゾリン酸の光学分割への展開溶媒の
影響表 − ５
セルローストリス（３． ５−ジメチルフェニルカルバ
メート）によるＰｈＣＨ２０ＣＯ−ＮＨＣＨ （ＣＯＯ
Ｈ） ＣＨ２［：口Ｎｌ１２の光学分割への展開溶媒の
影響（註）ａ）；温度 ４０℃
１１） ；２，２．２ − ）リフルオ口エタノール〔
発明の効果〕
本発明によれば順相系で酸を用いることにより、液体ク
ロマトグラフィーによるカルボキシル基含有化合物の分
離効率を顕著に向上せしめることが出来る。Table - 4 Effect of developing solvent on the optical resolution of manzolinic acid by cellulose tris (3, 5-dimethylphenyl carbamate) Table - 5 Table of effects of developing solvent on the optical resolution of manzolinic acid by cellulose tris (3, 5-dimethylphenyl carbamate) PhCH20CO-NHCH (COO
H) Effect of developing solvent on the optical resolution of CH2[:Nl12 (Note) a); Temperature 40°C 11) ;2,2.2-)Refluid ethanol [
Effects of the Invention] According to the present invention, by using an acid in a normal phase system, the separation efficiency of carboxyl group-containing compounds by liquid chromatography can be significantly improved.
出願人代理人 古 谷 馨Applicant's agent Kaoru Furutani
Claims (1)
有する化合物の混合物を順相系で分離する際に、酸を用
いることを特徴とする分離方法。In liquid chromatography, a separation method characterized in that an acid is used when separating a mixture of compounds containing carboxyl groups in a normal phase system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63046527A JP2590184B2 (en) | 1988-02-29 | 1988-02-29 | Separation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63046527A JP2590184B2 (en) | 1988-02-29 | 1988-02-29 | Separation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01221331A true JPH01221331A (en) | 1989-09-04 |
| JP2590184B2 JP2590184B2 (en) | 1997-03-12 |
Family
ID=12749755
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63046527A Expired - Lifetime JP2590184B2 (en) | 1988-02-29 | 1988-02-29 | Separation method |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2590184B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104062367A (en) * | 2014-03-21 | 2014-09-24 | 湘潭大学 | Method for directly analyzing content of 1,5-naphthalene diisocyanate by normal-phase high performance liquid chromatography |
| KR20160134741A (en) * | 2014-03-13 | 2016-11-23 | 키노인 기요기스제르 에스 베기에스제티 테르메크에크 기야라 제트알티. | New process for the preparation of high purity prostaglandins |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59190955A (en) * | 1983-04-11 | 1984-10-29 | ユ−オ−ピ−・インコ−ポレイテツド | Resolution of amino acid racemic body |
-
1988
- 1988-02-29 JP JP63046527A patent/JP2590184B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59190955A (en) * | 1983-04-11 | 1984-10-29 | ユ−オ−ピ−・インコ−ポレイテツド | Resolution of amino acid racemic body |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20160134741A (en) * | 2014-03-13 | 2016-11-23 | 키노인 기요기스제르 에스 베기에스제티 테르메크에크 기야라 제트알티. | New process for the preparation of high purity prostaglandins |
| EP3116854A1 (en) * | 2014-03-13 | 2017-01-18 | Chinoin Gyógyszer Es Vegyészeti Termékek Gyára Rt. | New process for the preparation of high purity prostaglandins |
| JP2017513816A (en) * | 2014-03-13 | 2017-06-01 | キノイン・ジヨージセル・エーシユ・ベジエーセテイ・テルメーケク・ジヤーラ・ゼー・エル・テー | New method for producing high-purity prostaglandins |
| EP3116854B1 (en) * | 2014-03-13 | 2022-01-26 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | New process for the preparation of high purity prostaglandins |
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