KR20020020440A - Crown Ether Chiral Stationary Phase and Chiral Column for the Liquid Chromatographic Resolution of Biologically Active Racemic Primary Amino Compounds - Google Patents
Crown Ether Chiral Stationary Phase and Chiral Column for the Liquid Chromatographic Resolution of Biologically Active Racemic Primary Amino Compounds Download PDFInfo
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본 발명은 라세미 의약품들 중 아미노산, 아미노 알코올, 아민 등과 같이 일차 아미노기를 가지고 있는 라세미 생리활성 물질 (라세미 의약품 포함)을 구성하는 두 개의 광학 이성질체를 분리하는데 아주 유용한 것으로 알려져 있는 새로운 크라운 에테르 키랄고정상을 개발하고 이것을 충진한 키랄 칼럼의 제조에 관한 것이다.The present invention is a new crown ether known to be very useful for separating two optical isomers that constitute racemic bioactive substances (including racemic drugs) having primary amino groups, such as amino acids, amino alcohols, amines, etc. It relates to the development of a chiral stationary phase and the preparation of a chiral column packed with it.
라세미 의약품을 구성하는 서로 거울상의 관계에 있는 한 쌍의 광학 이성질체는 물리적 성질과 화학적 성질이 동일하여 구별이 불가능하다. 그러나 본질적으로 키랄성인 인체내에서 서로 거울상의 관계에 있는 두 개의 광학 이성질체 의약품은 각각 서로 다른 생리 활성을 나타내는 경우가 많이 알려져 있다.A pair of optical isomers, which are mirror images of racemic drugs, are indistinguishable due to the same physical and chemical properties. However, it is known that two optical isomeric drugs, which are mirror images of each other in an essentially chiral body, exhibit different physiological activities.
따라서 라세미 의약품을 구성하는 서로 거울상 관계인 두 개의 광학 이성질체를 분리하고 광학활성 의약품의 광학순도를 정확히 측정하는 기술은 아주 중요하다. 이를 수행할 수 있는 여러 가지 기술 중 LC 용 키랄고정상을 이용한 라세미 의약품의 광학분할 기술은 두 개의 광학 이성질체를 획득할 수 있는 기술을 제공할 뿐만 아니라 동시에 광학활성 의약품의 광학순도를 정확하게 측정할 수 있는 기술을 제공한다는 관점에서 아주 중요한 기술이다.Therefore, it is very important to separate two optical isomers which are mirror images of racemic medicines and to accurately measure the optical purity of optically active medicines. Among the various technologies that can accomplish this, the optical splitting technology of racemic drugs using chiral stationary phase for LC not only provides the technology to acquire two optical isomers, but also can accurately measure the optical purity of optically active drugs. It is a very important skill in terms of providing the technology that is present.
라세미 의약품을 구성하는 두 개의 광학 이성질체중 하나의 광학 이성질체는 인체 내에서 원하는 약리 작용을 나타내나 이것의 거울상인 광학 이성질체는 독성 등의 부작용을 나타낸다. 따라서 라세미 의약품의 광학분할을 효율적으로 수행할 수 있는 LC 용 키랄고정상 및 이들로 충진된 키랄 칼럼은 유용성이 지대하다.One of the two optical isomers constituting the racemic medicine exhibits the desired pharmacological action in the human body, but the optical isomer of its mirror image has side effects such as toxicity. Therefore, the chiral stationary phase and LC-filled chiral column for LC, which can efficiently perform optical division of racemic medicines, have great utility.
특히 일차 아미노기를 가지고 있는 라세미 의약품의 광학분할을 위한 키랄고정상으로는 키랄 크라운 에테르를 기저로 하는 키랄고정상이 아주 유용하게 쓰일 수 있음이 알려져 있으며 몇 가지의 LC 용 크라운 에테르 키랄고정상 및 키랄 칼럼이 알려져 있다. 그중 disubstituted alpha,alpha'-binaphthyl-20-crown-6 를 옥타데실 실리카 젤에 소수성 결합으로 코팅시킨 키랄고정상(혹은 키랄 칼럼)이 유용하게 쓰인 바 있다.In particular, it is known that chiral stationary phases based on chiral crown ethers can be very useful as chiral stationary phases for optical division of racemic medicines having primary amino groups. Several LC crown ether chiral stationary phases and chiral columns are known. have. Among them, chiral stationary phases (or chiral columns) coated with disubstituted alpha, alpha'-binaphthyl-20-crown-6 with hydrophobic bonds on octadecyl silica gel have been useful.
(참고문헌 : 1 . T. Shinbo, T. Yamaguchi, K. Nishimura, M. Sugiura, J. Chromatogr.,405(1987) 145. 2. T. Shinbo, T. Yamaguchi, H. Yanagishita, D. Kitamoto, K. Sakaki, M. Sugiura, J. Chromatogr.,625(1992) 101.)(Reference: 1. T. Shinbo, T. Yamaguchi, K. Nishimura, M. Sugiura, J. Chromatogr., 405 (1987) 145. 2.T. Shinbo, T. Yamaguchi, H. Yanagishita, D. Kitamoto , K. Sakaki, M. Sugiura, J. Chromatogr., 625 (1992) 101.)
그러나 이 키랄고정상 (혹은 키랄 칼럼)의 문제점은 다양한 이동상을 사용할 수 없다는 사실이다.However, a problem with this chiral stationary phase (or chiral column) is the fact that various mobile phases cannot be used.
예를 들면 메탄올을 40% 이상 함유한 수용액 이동상을 사용할 경우 키랄 선택자인 disubstituted alpha,alpha'-binaphthyl-20-crown-6 이 옥타데실 실리카 젤에서 유리되어 키랄 칼럼이 손상되기 때문이다.For example, when an aqueous mobile phase containing 40% or more of methanol is used, the chiral selector disubstituted alpha, alpha'-binaphthyl-20-crown-6 is released from the octadecyl silica gel and the chiral column is damaged.
이에 본 발명은 diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1)를 적절한 방법으로 실리카 젤에 공유 결합시켜 어떠한 비율의 유기용매를 포함한 이동상을 사용하더라도 키랄 칼럼에 전혀 손상을 주지 않은 채 일차 아미노기를 가지고 있는 라세미 의약품의 광학분할에 장기간 사용할 수 있는 키랄고정상을 제조하고 제조된 키랄고정상을 LC 용 공 칼럼에 충진시켜 LC 용 키랄칼럼을 제조하고자 한다.Therefore, the present invention does not damage the chiral column at all even when using a mobile phase containing any proportion of organic solvent by covalently bonding diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 ) to silica gel in an appropriate manner. To prepare a chiral column for the long-term use in the optical separation of racemic drugs having a primary amino group, and to prepare a chiral column for LC by filling the prepared chiral stationary phase in the LC column.
도 1은 본 발명인 CSP2의 화학적 구조도 1 is a chemical structural diagram of the present invention CSP 2
도 2는 키랄고정상의 제조방법과 관련된 화합물1의 구조 및 키랄고정상(CSP2)의 합성 흐름도FIG. 2 is a flow chart of the structure of Compound 1 and the synthesis of chiral stationary phase (CSP 2 ) related to the preparation method of chiral stationary phase
도 3은 HPLC 크로마토그램의 예 (상: Methionine, 하: Glutamic acid, 분리조건은 표 1과 동일)Figure 3 is an example of HPLC chromatogram (upper: Methionine, lower: Glutamic acid, separation conditions are the same as in Table 1)
본 발명은 라세미 의약품들 중 아미노산, 아미노 알코올, 아민 등과 같이 일차 아미노기를 가지고 있는 라세미 생리활성 물질 (라세미 의약품 포함)을 구성하는 두 개의 광학 이성질체를 분리하는데 아주 유용한 것으로 알려져 있는 새로운 크라운 에테르 키랄고정상을 개발하고 이것을 충진한 키랄 칼럼을 제공하고자 하는 것으로서, 이하 제조방법 등에 관한 것을 상세히 설명하기로 한다.The present invention is a new crown ether known to be very useful for separating two optical isomers that constitute racemic bioactive substances (including racemic drugs) having primary amino groups, such as amino acids, amino alcohols, amines, etc. To develop a chiral stationary phase and to provide a chiral column packed therein, the following will be described in detail with respect to the production method.
1. 키랄고정상 및 키랄 칼럼의 제조 방법1. Method for preparing chiral stationary phase and chiral column
LC 용 키랄고정상은 광학활성인 diphenyl substituted alpha,alpha'-binaphthyl- 20-crown-6 (1)을 실리카 젤에 공유결합시켜 제조되었으며 구체적인 방법은 다음과 같다.The chiral stationary phase for LC was prepared by covalently bonding optically active diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 ) to silica gel.
(1) diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1)의 실릴 에테르 화합물 합성(1) Synthesis of silyl ether compounds of diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 )
250 ㎖의 이구 둥근바닥플라스크에 50 ㎖의 정제된 THF를 가하고 여기에 1.1g의 광학활성 diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1)을 용해시킨다. 아르곤 기류하에서 50 ㎖의 이구 둥근바닥 플라스크에 0.22g의 NaH과 10 ㎖의 THF를 가하고 30분 동안 저어준 후 생긴 뿌연 상태의 용액을 캐뉼라를 이용하여 diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1) 용액이 들어 있는 250 ㎖의 이구 둥근 바닥플라스크로 천천히 저어주면서 적가하고, 최종 용액을 30분 정도 환류한다.50 ml of purified THF is added to a 250 ml two-necked round bottom flask and 1.1 g of optically active diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 ) is dissolved therein. Diphenyl substituted alpha, alpha'-binaphthyl-20-crown was added to a 50 ml two-necked round bottom flask under argon by adding 0.22 g of NaH and 10 ml of THF and stirring for 30 minutes. Slowly stir with a 250 ml two-necked round bottom flask containing -6 ( 1 ) solution and reflux the final solution for 30 minutes.
여기에 2.5 당량에 해당하는, 알킬기의 끝에 이중 결합이 있는 브롬화 알킬 (예 : allyl bromide)을 가하고 4시간 정도 계속 환류한다.Add 2.5 equivalents of brominated alkyl bromide (eg allyl bromide) with a double bond to the end of the alkyl group and continue refluxing for about 4 hours.
상기 반응 후 용매를 제거하고 나머지를 100 ㎖의 ethyl acetate에 용해하고 이 용액을 100 ㎖의 0.1 N HCl 수용액으로 씻어준다.After the reaction, the solvent was removed and the rest was dissolved in 100 ml of ethyl acetate, and the solution was washed with 100 ml of 0.1 N HCl aqueous solution.
최종적으로 ethyl acetate 용액을 무수 황산 마그네슘으로 건조시킨 후 용매를 제거하고 나머지를 실리카 젤 관 크로마토그라피로 정제하여 에테르 화합물을 얻는다.Finally, the ethyl acetate solution is dried over anhydrous magnesium sulfate, the solvent is removed, and the remainder is purified by silica gel column chromatography to obtain an ether compound.
상기 합성된 에테르 화합물을 아르곤 기류하에서 250 ㎖의 이구 둥근 바닥플라스크에 가하여 50 ㎖의 정제된 CH2Cl2에 용해시키고 여기에 5 ㎎ 정도의 H2PtCl6·6H2O과 10 ㎖의 dimethylchlorosilane을 가하고 40℃에서 5시간정도 가열한다.The synthesized ether compound was added to a 250 ml two-necked round bottom flask under argon stream and dissolved in 50 ml of purified CH 2 Cl 2 , and about 5 mg of H 2 PtCl 6 .6H 2 O and 10 ml of dimethylchlorosilane were added thereto. And heat at 40 ° C. for about 5 hours.
상기에서와 같이 5시간 가열 후 농축기를 이용하여 반응 용매 및 과량의 dimethylchlorosilane을 제거한다. 나머지를 30 ㎖의 CH2Cl2에 용해시키고 이 용액에 10㎖의 triethylamine/ethanol(1:1, v/v) 혼합용매를 얼음 중탕에서 천천히 가하고 실온에서 2시간 정도 저어 준다. 농축기를 이용하여 용매를 제거하고 나머지를 실리카 젤 관 크로마토그래피로 정제하여 최종적으로 diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1)의 실릴 에테르 화합물의 합성을 종료한다.After 5 hours of heating as described above using a concentrator to remove the reaction solvent and excess dimethylchlorosilane. Dissolve the rest in 30 ml of CH 2 Cl 2 and slowly add 10 ml of triethylamine / ethanol (1: 1, v / v) solvent in an ice bath and stir for 2 hours at room temperature. The solvent is removed using a concentrator and the remainder is purified by silica gel column chromatography to finally terminate the synthesis of the silyl ether compound of diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 ).
(2)diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1)의 실릴 에스테르 화합물 합성(2) Synyl ester compound synthesis of diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 )
250 ㎖의 이구 둥근 바닥플라스크에 50 ㎖의 정제된 CH2Cl2를 가하고 여기에 1.1g의 광학활성 diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1)을 용해시킨다. 여기에 알킬기의 끝에 이중 결합을 가지고 있는 2.5 당량의 산 염화물 (예 : undecenoyl chloride) 및 3 당량 정도의 triethylamine을 가하고 실온에서 3시간 정도 저어준다.50 ml of purified CH 2 Cl 2 is added to a 250 ml two-necked round bottom flask and 1.1 g of optically active diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 ) is dissolved therein. Add 2.5 equivalents of acid chloride (eg undecenoyl chloride) and 3 equivalents of triethylamine to the end of the alkyl group and stir at room temperature for 3 hours.
상기 반응 혼합물을 0.1 N의 HCl 수용액, 0.1 N의 NaOH 수용액 및 포화 소금물로 차례로 씻어준 후 무수 황한 마그네슘으로 건조한다. 농축기를 사용하여 용매를 제거한 후 나머지를 실리카 젤 관 크로마토그라피로 정제하여 에스테르 화합물을 얻는다.The reaction mixture was washed sequentially with 0.1 N HCl aqueous solution, 0.1 N NaOH aqueous solution and saturated brine, and dried over anhydrous sulfuric acid. The solvent is removed using a concentrator and the remainder is purified by silica gel column chromatography to obtain an ester compound.
상기와 같이 얻어진 에스테르 화합물을 아르곤 기류하에서 250 ㎖의 이구 둥근 바닥플라스크에 가하여 50 ㎖의 정제된 CH2Cl2에 용해시키고 여기에 5㎎ 정도의 H2PtCl6·6H2O과 10 ㎖의 dimethylchlorosilane을 가하고 40℃에서 5시간정도 가열한다.The ester compound obtained as described above was added to a 250 ml two-necked round bottom flask under argon stream, dissolved in 50 ml of purified CH 2 Cl 2 , and added to about 5 mg of H 2 PtCl 6 .6H 2 O and 10 ml of dimethylchlorosilane. Is added and heated at 40 ° C. for about 5 hours.
이상과 같이 5시간 가열 후 농축기를 이용하여 반응 용매 및 과량의 dimethylchlorosilane을 제거한다. 나머지를 30 ㎖의 CH2Cl2에 용해시키고 이 용액에 10㎖의 triethylamine/ethanol (1:1, v/v) 혼합용매를 얼음 중탕에서 천천히 가하고 실온에서 2시간 정도 저어 준 다음 농축기를 이용하여 용매를 제거하고 나머지를 실리카 젤 관 크로마토그래피로 정제하여 최종적으로 diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1)의 실릴 에스테르 화합물의 합성을 종료한다.After heating for 5 hours as above, the reaction solvent and excess dimethylchlorosilane are removed using a concentrator. The rest was dissolved in 30 ml of CH 2 Cl 2 , and 10 ml of triethylamine / ethanol (1: 1, v / v) mixed solvent was slowly added to the solution in an ice bath, stirred at room temperature for 2 hours, and then using a concentrator. The solvent is removed and the remainder is purified by silica gel column chromatography to finally terminate the synthesis of the silyl ester compound of diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 ).
(3) diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1)의 실릴 카르밤산 에스테르 합성(3) Synthesis of silyl carbamic acid esters of diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 )
250 ㎖의 이구 둥근바닥플라스크에 50 ㎖의 정제된 CH2Cl2를 가하고 여기에 1.1g의 광학활성 diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6 (1)을 용해시킨다.50 ml of purified CH 2 Cl 2 is added to a 250 ml two-necked round bottom flask and 1.1 g of optically active diphenyl substituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 ) is dissolved therein.
여기에 2.5 당량의 isocyanatoalkyltriethoxysilane (예: 3-isocyanatopropyltriethoxysilane)과 3 당량의 triethylamine을 가하고 실온에서 3시간 정도 저어 준 다음 농축기를 이용하여 용매를 제거한 후 나마지를 실리카 젤 관 크로마토그라피로 정제하여 최종적으로 diphenyl substituted alpha,alpha'- binaphthyl-20-crown-6 (1)의 실릴 카르밤산 에스테르의 합성을 종료한다.2.5 equivalents of isocyanatoalkyltriethoxysilane (e.g. 3-isocyanatopropyltriethoxysilane) and 3 equivalents of triethylamine were added and stirred at room temperature for 3 hours, then the solvent was removed using a concentrator. The synthesis of the silyl carbamic acid ester of alpha, alpha'-binaphthyl-20-crown-6 ( 1 ) is terminated.
(4) 키랄고정상의 제조(4) Production of chiral stationary phase
4.5g의 실리카 젤을 Dean-Stark trap 이 장치된 250 ㎖의 이구 둥근 바닥플라스크에 가하고 여기에 정제된 150 ㎖의 톨루엔을 가하여 환류하고 물을 제거함으로서 실리카 젤에 흡착되어 있는 수분을 완전히 제거한다.4.5 g of silica gel is added to a 250 ml two-necked round bottom flask equipped with Dean-Stark trap, and 150 ml of toluene purified thereto is added to reflux to remove water to completely remove the water adsorbed on the silica gel.
여기에 10 ㎖의 톨루엔에 용해되어 있는 위 (1)의 과정에서 합성한 diphenylsubstituted alpha,alpha'-binaphthyl-20-crown-6(1)의 실릴 에테르 화합물 혹은 (2)의 과정에서 합성한 diphenyl substituted alpha,alpha'-binaphthyl-20-crown-6(1)의 실릴 에스테르 화합물 혹은 (3)의 과정에서 합성한 diphenyl substituted alpha,alpha'- binaphthyl-20-crown-6(1)의 실릴 카르밤산 에스테르 화합물을 가하고 환류한 다음 72시간 후 온도를 실온으로 식힌 후 유리 여과기를 이용하여 실리카 젤을 거르고 이것을 톨루엔, ethyl acetate, CH2Cl2, methanol, acetone, hexane의 순으로 씻어주고 감압하에 건조하여 키랄고정상 (CSP2)를 제조한다.Here, diphenylsubstituted alpha, alpha'-binaphthyl-20-crown-6 ( 1 ) silyl ether compound synthesized in the above process (1) dissolved in 10 ml of toluene or diphenyl substituted in the process of (2) alpha, silyl esters of carbamic acid alpha'-binaphthyl-20-crown- 6 (1) or silyl ester compound (3) diphenyl substituted alpha, alpha'- binaphthyl-20-crown-6 (1) synthesized in the course of the After adding the compound and refluxing, after 72 hours, the temperature was cooled to room temperature, and the silica gel was filtered using a glass filter, washed with toluene, ethyl acetate, CH 2 Cl 2 , methanol, acetone, and hexane, and dried under reduced pressure. Prepare stationary phase (CSP 2 ).
(5) 키랄 칼럼의 제조(5) Preparation of chiral column
상기에서 합성한 키랄고정상 (CSP2)를 메탄올에 부유시킨 후 슬러리 충진기를 이용하여 HPLC 용 스텐레스강 공 칼럼에 충진하여 키랄 칼럼을 제조한다.The chiral stationary phase (CSP 2 ) synthesized above was suspended in methanol, and then filled in a stainless steel empty column for HPLC using a slurry filler to prepare a chiral column.
상기 키랄고정상 (CSP2)의 제조방법과 관련된 화합물1의 구조 및 키랄고정상 (CSP2)의 합성 흐름도를 나타낸 화학식은 도 2와 같다.Formula showing a composite flow chart of the architecture and the chiral stationary phase (CSP 2) of Compound 1 related to the manufacturing method of the chiral stationary phase (CSP 2) is shown in Figure 2;
2. 광학분할 실시 예2. Optical Splitting Example
본 발명에서 그 제조 방법이 알려진 키랄고정상 (CSP2)가 충진된 키랄 칼럼을 라세미 아미노산 및 라세미 아민 화합물과 퀴놀론 계 항생제의 광학분할에 응용한 실시 예는 다음 표 1과 같으며 대표적인 HPLC 크로마토그램은 도 3에 도시된 바와 같다.Example of applying a chiral column filled with a chiral stationary phase (CSP 2 ), which is known in the present invention, to an optical fractionation of racemic amino acids, racemic amine compounds, and quinolone antibiotics is shown in Table 1 below. The gram is as shown in FIG. 3.
k1및 k2는 각각 첫 번째 피크와 두 번째 피크에 대한 capacity factor, alpha는 separation factor, RS는 resolution factor임. 이동상 A: 50 % CH3OH inH2O + HClO4(10 mM) + CH3COONH4(1 mM). 이동상 B: 80 % CH3CN in H2O + HClO4(10 mM) + CH3COONH4(1 mM). 이동상 C: 100 % CH3OH + HClO4(10 mM) + CH3COONH4(1 mM). 유속 : 0.5 ml/min. 온도 : 20oC. Detection, 225 nm UV.k 1 and k 2 are the capacity factors for the first and second peaks, alpha is the separation factor and R S is the resolution factor. Mobile phase A: 50% CH 3 OH inH 2 O + HClO 4 (10 mM) + CH 3 COONH 4 (1 mM). Mobile phase B: 80% CH 3 CN in H 2 O + HClO 4 (10 mM) + CH 3 COONH 4 (1 mM). Mobile phase C: 100% CH 3 OH + HClO 4 (10 mM) + CH 3 COONH 4 (1 mM). Flow rate: 0.5 ml / min. Temperature: 20 o C. Detection, 225 nm UV.
이상과 같은 본 발명은 전술한 광학분할의 실시예에서 살펴본 바와 같이 본 발명에서 제조된 LC 용 키랄고정상으로 충진된 키랄칼람들은 일차 아미노기를 가지고 있는 생리활성 라세미 화합물들을 구성하는 두 개의 광학이성질체를 아주 효과적으로 광학분할할 수 있음을 알 수 있는 것으로서, 본 발명에서 제시된 키랄고정상 및 이들로 충진된 키랄칼럼들을 사용함으로써 일차 아미노기를 가지고 있는 라세미 의약품의 광학분할을 가장 효과적으로 할 수 있기 때문에 본 발명은 키랄의약품을 개발하고 생산하는 과정에서 반드시 필요한 광학순도 측정 기술을 제공하는 효과가 있는 매우 우수한 발명이다.As described above, the present invention, as described in the above-described embodiment of the optical split, chiral column-filled chiral column for LC prepared in the present invention comprises two optical isomers constituting physiologically active racemic compounds having a primary amino group As it can be seen that the optical splitting can be performed very effectively, the present invention provides the most effective optical splitting of racemic medicines having a primary amino group by using the chiral stationary phases and chiral columns filled with the present invention. It is an excellent invention that has the effect of providing optical purity measurement technology which is essential in the development and production of chiral drugs.
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| KR100454712B1 (en) * | 2001-08-03 | 2004-11-05 | 한국과학기술연구원 | Chiral stationary phases, chiral columns with the chiral stationary phases and process for producing the chiral stationary phases |
| EP2629091A4 (en) * | 2010-10-13 | 2014-04-02 | Daicel Corp | Separating agent for chromatography |
| CN110652975A (en) * | 2019-11-18 | 2020-01-07 | 昆明医科大学 | (S) -BIONL derivative CSP filler and preparation method and application thereof |
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| EP2629091A4 (en) * | 2010-10-13 | 2014-04-02 | Daicel Corp | Separating agent for chromatography |
| US9145430B2 (en) | 2010-10-13 | 2015-09-29 | Daicel Corporation | Separating agent for chromatography |
| CN110652975A (en) * | 2019-11-18 | 2020-01-07 | 昆明医科大学 | (S) -BIONL derivative CSP filler and preparation method and application thereof |
| CN110652975B (en) * | 2019-11-18 | 2021-10-26 | 昆明医科大学 | (S) -BINOL derivative CSP filler and preparation method and application thereof |
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