JP2831808B2 - Optical resolution of racemic β-lactams - Google Patents
Optical resolution of racemic β-lactamsInfo
- Publication number
- JP2831808B2 JP2831808B2 JP2154460A JP15446090A JP2831808B2 JP 2831808 B2 JP2831808 B2 JP 2831808B2 JP 2154460 A JP2154460 A JP 2154460A JP 15446090 A JP15446090 A JP 15446090A JP 2831808 B2 JP2831808 B2 JP 2831808B2
- Authority
- JP
- Japan
- Prior art keywords
- lactams
- racemic
- polysaccharide
- represented
- formula
- 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.)
- Expired - Fee Related
Links
- 150000003952 β-lactams Chemical class 0.000 title claims description 10
- 230000003287 optical effect Effects 0.000 title description 2
- 150000004676 glycans Chemical class 0.000 claims description 25
- 229920001282 polysaccharide Polymers 0.000 claims description 25
- 239000005017 polysaccharide Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 229920000856 Amylose Polymers 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 6
- 229920002678 cellulose Polymers 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000000926 separation method Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- AKZWRTCWNXHHFR-PDIZUQLASA-N [(3S)-oxolan-3-yl] N-[(2S,3S)-4-[(5S)-5-benzyl-3-[(2R)-2-carbamoyloxy-2,3-dihydro-1H-inden-1-yl]-4-oxo-3H-pyrrol-5-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound NC(=O)O[C@@H]1Cc2ccccc2C1C1C=N[C@](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)(Cc2ccccc2)C1=O AKZWRTCWNXHHFR-PDIZUQLASA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000000053 physical method Methods 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004381 surface treatment Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- GRFUMPFWJKGLQC-ZETCQYMHSA-N [(1s)-1-phenylethyl]carbamic acid Chemical compound OC(=O)N[C@@H](C)C1=CC=CC=C1 GRFUMPFWJKGLQC-ZETCQYMHSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 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
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000004132 cross linking Methods 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
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 150000002243 furanoses Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 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
- 238000012856 packing Methods 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 150000003215 pyranoses Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- -1 silane compound Chemical class 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 150000003606 tin compounds Chemical class 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明はβ−ラクタム類の立体異性体（特にラセミ
体）の光学分割法に関するものである。The present invention relates to an optical resolution method for stereoisomers of β-lactams (particularly, racemates).
β−ラクタム類は抗生物質をはじめとする医薬品や、
その他の医薬品原料として重要な物質である。医薬品の
生体に対する作用は、例えばサリドマイドのように各立
体異性体で異なることが多い（G.Blaschke,Angew,Chem.
Int.Ed.Engl.,19,13（1980））ので、その分離は極めて
重要である。β-lactams are used for drugs such as antibiotics,
It is an important substance for other pharmaceutical ingredients. The action of drugs on living organisms often differs for each stereoisomer, for example, thalidomide (G. Blaschke, Angew, Chem.
Int. Ed. Engl., 19 , 13 (1980)), its separation is extremely important.
従来、β−ラクタム類の立体異性体入手方法として
は、不斉合成法、ラセミ体のジアステレオマー誘導体分
離法、ラセミ体のクロマトグラフィー分離法等が知られ
ている。この中で、クロマトグラフィー分離法による立
体異性体の分離法は、純度の高い立体異性体が得られる
点で優れており、ソーベックスの手法を用いれば連続操
作も可能であるなどの利点を有しているが、これまでβ
−ラクタム類のラセミ体の分離並びに立体異性体の分離
に用いられてきた分離カラムの能力は充分ではなく、分
離不能なβ−ラクタム類も少なくなかった。Conventionally, as a method for obtaining a stereoisomer of a β-lactam, an asymmetric synthesis method, a separation method of a racemic diastereomer derivative, a chromatography separation method of a racemate, and the like are known. Among them, the method of separating stereoisomers by the chromatographic separation method is excellent in that stereoisomers with high purity can be obtained, and has the advantage that continuous operation is also possible using the Sobex method. But so far β
-Separation columns used for the separation of racemic lactams as well as for the separation of stereoisomers were not sufficiently effective, and there were not many non-separable β-lactams.
本発明者らは上記課題を解決すべく鋭意研究の結果、
特定の多糖誘導体を主成分とする分離剤を用いるとβ−
ラクタム類の立体異性体（特にラセミ体）が効率良く分
離できることを見出し本発明を完成するに至った。The present inventors have conducted intensive studies to solve the above problems,
When a separating agent containing a specific polysaccharide derivative as a main component is used, β-
The inventors have found that stereoisomers of lactams (especially racemates) can be efficiently separated, and have completed the present invention.
即ち、本発明は、セルロース又はアミロースの有する
水酸基上の水素原子の一部又は全部を下記の式（１）又
は（２） 〔式中、Ｒは （ｔ−Buはtert−ブチル基）を示す。〕 で示される原子団で置換してなる多糖誘導体を主成分と
する分離剤を用いて、下記一般式（３）〜（５）で示さ
れるラセミβ−ラクタム類を光学分割することを特徴と
するラセミβ−ラクタム類の光学分割法を提供するもの
である。That is, in the present invention, a part or all of the hydrogen atoms on the hydroxyl group of cellulose or amylose is represented by the following formula (1) or (2). [Where R is (T-Bu is a tert-butyl group). Wherein the racemic β-lactams represented by the following general formulas (3) to (5) are optically resolved using a separating agent mainly composed of a polysaccharide derivative substituted with an atomic group represented by the following formula: To provide a method for resolving racemic β-lactams.
（式中R1,R2,R3,R4は水素原子、 −OCH2OCH2CH2OCH3を示し、R1とR2、又はR3とR4の少な
くともいずれか１つの組合せが異る置換基である。 (Wherein R 1 , R 2 , R 3 and R 4 are hydrogen atoms, —OCH 2 OCH 2 CH 2 OCH 3 is a substituent in which at least one combination of R 1 and R 2 or R 3 and R 4 is different.
またR5は を示す。） （式中R1,R2は前記の意味を示す。） （式中R1,R2,R3,R4,R5は前記の意味を示す。） 以上のごときβ−ラクタム類は、セルロース又はアミ
ロースの有する水酸基上の水素原子の一部又は全部を前
記の式（１）又は（２）で示される原子団で置換してな
る多糖誘導体を主成分とする分離剤によって、その立体
異性体（特にラセミ体）が効率良く光学分割される。Also R 5 Is shown. ) (In the formula, R 1 and R 2 have the same meanings as described above.) (In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 have the same meanings as described above.) As described above, β-lactams are obtained by replacing a part or all of the hydrogen atoms on the hydroxyl group of cellulose or amylose. The stereoisomer (especially racemic) is efficiently optically resolved by the separating agent mainly composed of the polysaccharide derivative substituted by the atomic group represented by the above formula (1) or (2).
本発明における多糖はセルロース又はアミロースであ
る。The polysaccharide in the present invention is cellulose or amylose.
これら多糖の数平均重合度（１分子中に含まれるピラ
ノース或いはフラノース環の平均数）は５以上、好まし
くは10以上であり、上限は2000、好ましくは500以下で
あることが取り扱いの容易さにおいて好ましい。The number average degree of polymerization of these polysaccharides (the average number of pyranose or furanose rings contained in one molecule) is 5 or more, preferably 10 or more, and the upper limit is 2000 or less, preferably 500 or less in terms of ease of handling. preferable.
導入される原子団としては、多糖の水酸基と反応して
上記（１）又は（２）式で示される、エステル結合又は
ウレタン（カルバメート）結合を形成する化合物であ
る。The introduced atomic group is a compound which reacts with the hydroxyl group of the polysaccharide to form an ester bond or a urethane (carbamate) bond represented by the above formula (1) or (2).
前記多糖誘導体は、例えば以下の様な方法で合成され
る。The polysaccharide derivative is synthesized, for example, by the following method.
１） エステル結合 本発明の多糖のエステル誘導体をなすカルボニル基は
前述の一般式（１）で示され、対応する多糖が有する全
水酸基のうち30％乃至100％、好ましくは50％以上、更
に好ましくは85％以上が該カルボニル基とエステル結合
を形成しているものである。1) Ester bond The carbonyl group forming the ester derivative of the polysaccharide of the present invention is represented by the above-mentioned general formula (1), and accounts for 30% to 100%, preferably 50% or more, more preferably, of all the hydroxyl groups of the corresponding polysaccharide. Is a compound in which 85% or more forms an ester bond with the carbonyl group.
本発明に係るエステル誘導体の合成は、対応するカル
ボン酸を塩化チオニル、オキサリルクロリドなどを用い
て酸クロリドとした後、ピリジン溶媒中、対応する多糖
と反応させることにより、容易に得られる。The synthesis of the ester derivative according to the present invention can be easily obtained by converting the corresponding carboxylic acid into an acid chloride using thionyl chloride, oxalyl chloride or the like, and then reacting the corresponding carboxylic acid with the corresponding polysaccharide in a pyridine solvent.
２） カルバメート結合 本発明の多糖のカルバメート誘導体をなすカルバモイ
ル基は前述の一般式（２）で示され、対応する多糖が有
する全水酸基のうち30％乃至100％、好ましくは50％以
上、更に好ましくは85％以上が該カルバモイル基とウレ
タン結合を形成しているものである。2) Carbamate bond The carbamoyl group forming the carbamate derivative of the polysaccharide of the present invention is represented by the above-mentioned general formula (2), and accounts for 30% to 100%, preferably 50% or more, of the total hydroxyl groups of the corresponding polysaccharide. Are those in which at least 85% form a urethane bond with the carbamoyl group.
本発明に係るカルバメート誘導体の合成には通常のア
ルコールとイソシアナートからウレタンを生ずる反応を
そのまま適用できる。例えば、適当な溶媒中で三級アミ
ン等のルイス塩基、又は錫化合物等のルイス酸を触媒と
して、対応するイソシアナートと多糖を反応させること
により得ることができる。また、イソシアナートの合成
は、例えば、対応するアニリン誘導体のアミノ基にホス
ゲンを作用させることにより容易に得ることができる。In the synthesis of the carbamate derivative according to the present invention, the usual reaction for producing urethane from alcohol and isocyanate can be applied as it is. For example, it can be obtained by reacting a corresponding isocyanate with a polysaccharide in a suitable solvent using a Lewis base such as a tertiary amine or a Lewis acid such as a tin compound as a catalyst. In addition, the synthesis of isocyanate can be easily obtained, for example, by causing phosgene to act on the amino group of the corresponding aniline derivative.
前記多糖誘導体を分離剤として液体クロマトグラフィ
ー法に応用するには、その粉体としてカラムに充填する
方法が簡便である。多糖誘導体を粉砕するかビーズ状に
することが好ましく、粒子は多孔質であることがより好
ましい。更に分離剤の耐圧能力の向上、溶媒置換による
膨潤、収縮の防止、理論段数の向上のために多糖誘導体
を担体に担持させることも好ましい。In order to apply the polysaccharide derivative as a separating agent to a liquid chromatography method, it is convenient to pack the polysaccharide derivative as a powder into a column. The polysaccharide derivative is preferably ground or beaded, and the particles are more preferably porous. Further, it is preferable to support a polysaccharide derivative on a carrier in order to improve the pressure resistance of the separating agent, prevent swelling and shrinkage due to solvent substitution, and improve the number of theoretical plates.
粉体として用いる場合の粒子の大きさおよび担体の大
きさは使用するカラムの大きさによって異なるが、１μ
ｍ〜1mmであり、好ましくは１μｍ〜300μｍである。担
体は多孔質であることが好ましく、その平均孔径は10Å
〜100μｍであり、好ましくは、50Å〜50000Åである。
担体に担持させる多糖誘導体の量は担体に対して１〜10
0重量％、好ましくは５〜50重量％である。When used as a powder, the size of the particles and the size of the carrier vary depending on the size of the column to be used.
m to 1 mm, preferably 1 μm to 300 μm. The carrier is preferably porous and has an average pore size of 10 mm.
100100 μm, preferably 50Å to 50,000Å.
The amount of the polysaccharide derivative supported on the carrier is 1 to 10 with respect to the carrier.
0% by weight, preferably 5 to 50% by weight.
多糖誘導体を担体に担持させる方法は化学的方法でも
物理的方法でもよい。物理的方法としては、多糖誘導体
を可溶性の溶剤に溶解させ、担体と良く混合し、減圧ま
たは加温下、気流により溶剤を留去させる方法や、多糖
誘導体を可溶性の溶剤に溶解させ、担体と良く混合した
後、多糖誘導体に対し不溶性の溶剤に分離させることに
よって可溶性溶剤を拡散させてしまう方法もある。この
様にして得られた分離剤は、加熱、溶媒の添加、洗浄な
どの適当な処理を行うことによって、その分離能を改善
することも可能である。The method for supporting the polysaccharide derivative on the carrier may be a chemical method or a physical method. As a physical method, the polysaccharide derivative is dissolved in a soluble solvent, mixed well with the carrier, under reduced pressure or heating, a method of distilling off the solvent by air flow, or dissolving the polysaccharide derivative in the soluble solvent, There is also a method of diffusing a soluble solvent by mixing well and then separating it into a solvent insoluble in the polysaccharide derivative. The separating agent thus obtained can be improved in its separating ability by performing an appropriate treatment such as heating, addition of a solvent, and washing.
用いる担体としては多孔質有機担体または多孔質無機
担体があり、好ましくは多孔質無機担体である。多孔質
有機担体として適当なものは、ポリスチレン、ポリアク
リルアミド、ポリアクリレート等からなる高分子物質が
挙げられる。多孔質無機担体として適当なものは、シリ
カ、アルミナ、マグネシア、ガラス、カオリン、酸化チ
タン、ケイ酸塩などであり、これらの表面に、カルバメ
ート誘導体との親和性を良くしたり、担体自身の表面の
特性を改質するために処理を施したものを用いても良
い。表面処理の方法としては有機シラン化合物によるシ
ラン化処理やプラズマ重合による表面処理方法等があ
る。The carrier to be used includes a porous organic carrier or a porous inorganic carrier, and is preferably a porous inorganic carrier. Suitable examples of the porous organic carrier include a polymer substance composed of polystyrene, polyacrylamide, polyacrylate, and the like. Suitable examples of the porous inorganic carrier include silica, alumina, magnesia, glass, kaolin, titanium oxide, silicate, etc., which have an improved affinity with a carbamate derivative or a surface of the carrier itself. May be used in order to improve the characteristics of the above. Examples of the surface treatment method include a silanization treatment with an organic silane compound and a surface treatment method with plasma polymerization.
液体クロマトグラフィーを行う場合の展開溶媒として
は多糖誘導体を溶解またはこれと反応するものを除いて
特に制約はない。多糖誘導体を化学的方法で担体に結合
したり、架橋により不溶化した場合にはこれと反応する
ものを除いて特に制約はない。There are no particular restrictions on the developing solvent used in liquid chromatography, except for those that dissolve or react with the polysaccharide derivative. When the polysaccharide derivative is bound to the carrier by a chemical method or insolubilized by cross-linking, there is no particular limitation except for those reacting therewith.
以下、本発明を実施例と比較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。Hereinafter, the present invention will be described in detail by examples and comparative examples,
The present invention is not limited to these examples.
実施例１〜５ 表１に示す分離剤を用い、以下に示す分離対象物（ラ
セミ体混合物）の分離を行った。その結果を表１に示
す。Examples 1 to 5 Using the separating agents shown in Table 1, the following separation target substances (racemic mixture) were separated. Table 1 shows the results.
（上記式においては、Acはアセチル基、Meはメチル基、
ｉ−Prはイソプロピル基、＋はｔ−ブチル基を示す。） 尚、実施例１に使用した分離カラムは、アミロース
（Ｓ）−α−メチルベンジルカルバメートをテトラヒド
ロフランに溶解し、ジフェニルシラン処理したシリカゲ
ル（Merck社製:Lichrospher Si−1000）と混和した後テ
トラヒドロフランを減圧留去して得られた充填剤を、メ
タノールを用いたスラリー法により内径0.46cm、長さ25
cmのステンレス製カラムに充填して調製した。また実施
例2,3,4,5に使用した分離カラムは、セルロース3,5−ジ
メチルフェニルカルバメート、セルロースｐ−メチルベ
ンゾエート、アミロース3,5−ジメチルフェニルカルバ
メート及びアミロースｐ−ｔ−ブチルフェニルカルバメ
ートをそれぞれ同様の方法で調製した。 (In the above formula, Ac is an acetyl group, Me is a methyl group,
i-Pr represents an isopropyl group, and + represents a t-butyl group. The separation column used in Example 1 was prepared by dissolving amylose (S) -α-methylbenzylcarbamate in tetrahydrofuran, mixing with diphenylsilane-treated silica gel (Lichrospher Si-1000, manufactured by Merck), and then adding tetrahydrofuran. Filler obtained by distillation under reduced pressure, the inner diameter 0.46 cm, length 25 by a slurry method using methanol
It was prepared by packing in a cm stainless steel column. The separation columns used in Examples 2, 3, 4, and 5 were cellulose 3,5-dimethylphenylcarbamate, cellulose p-methylbenzoate, amylose 3,5-dimethylphenylcarbamate, and amylose pt-butylphenylcarbamate. Each was prepared in the same manner.
測定には、日本分光製TRI ROTAR−Ｖ型高圧ポンプ、
同社製UV−100−Ｖ紫外検出器を用いた。For the measurement, JASCO's TRI ROTAR-V type high pressure pump,
The company's UV-100-V UV detector was used.
表中の容量比（k1′）、分離係数（α）及び分離度
（Rs）は、それぞれ下式により定義される。The capacity ratio (k 1 ′), separation factor (α) and degree of separation (Rs) in the table are defined by the following equations, respectively.
（分離度が１以上であればほぼ完全分離であることを示
す） (If the degree of separation is 1 or more, it indicates almost complete separation)
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ // Ｃ０７Ｂ 57/00 ３７０ Ｃ０８Ｂ 33/02 Ｃ０７Ｆ 7/18 Ｃ０７Ｄ 205/08 Ｐ Ｃ０８Ｂ 3/00 499/00 Ａ 33/02 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 Identification symbol FI // C07B 57/00 370 C08B 33/02 C07F 7/18 C07D 205/08 P C08B 3/00 499/00 A 33/02
Claims (1)
上の水素原子の一部又は全部を下記の式（１）又は
（２） 〔式中、Ｒは （ｔ−Buはtert−ブチル基）を示す。〕 で示される原子団で置換してなる多糖誘導体を主成分と
する分離剤を用いて、下記一般式（３）〜（５）で示さ
れるラセミβ−ラクタム類を光学分割することを特徴と
するラセミβ−ラクタム類の光学分割法。 （式中R1,R2,R3,R4は水素原子、 −OCH2OCH2CH2OCH3を示し、R1とR2、又はR3とR4の少な
くともいずれか１つの組合せが異る置換基である。 を示す。） （式中R1,R2は前記の意味を示す。） （式中R1,R2,R3,R4,R5は前記の意味を示す。）1. A method according to claim 1, wherein part or all of the hydrogen atoms on the hydroxyl groups of cellulose or amylose are represented by the following formula (1) or (2): [Where R is (T-Bu is a tert-butyl group). Wherein the racemic β-lactams represented by the following general formulas (3) to (5) are optically resolved using a separating agent mainly composed of a polysaccharide derivative substituted with an atomic group represented by the following formula: Resolution of racemic β-lactams. (Wherein R 1 , R 2 , R 3 and R 4 are hydrogen atoms, —OCH 2 OCH 2 CH 2 OCH 3 is a substituent in which at least one combination of R 1 and R 2 or R 3 and R 4 is different. Is shown. ) (In the formula, R 1 and R 2 have the same meanings as described above.) (In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 have the same meanings as described above.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2154460A JP2831808B2 (en) | 1990-06-12 | 1990-06-12 | Optical resolution of racemic β-lactams |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2154460A JP2831808B2 (en) | 1990-06-12 | 1990-06-12 | Optical resolution of racemic β-lactams |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0446154A JPH0446154A (en) | 1992-02-17 |
| JP2831808B2 true JP2831808B2 (en) | 1998-12-02 |
Family
ID=15584725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2154460A Expired - Fee Related JP2831808B2 (en) | 1990-06-12 | 1990-06-12 | Optical resolution of racemic β-lactams |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2831808B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW521226B (en) | 2000-03-27 | 2003-02-21 | Semiconductor Energy Lab | Electro-optical device |
-
1990
- 1990-06-12 JP JP2154460A patent/JP2831808B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0446154A (en) | 1992-02-17 |
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