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New synthetic method of ARCA (Alanine Racemise Chiral Analogue) for industrial application

Title
New synthetic method of ARCA (Alanine Racemise Chiral Analogue) for industrial application
Authors
이한영
Issue Date
2009
Department/Major
대학원 화학·나노과학과
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
김관묵
Abstract
본 연구는 자연계에 amino acid의 자연계에 존재하는 L-form을 자연계에 존재하지 않는 D-form으로 전환시켜주는 바이놀유도체, ARCA(Alanine Racemize Chiral Analogue, (S)-[1,1’-Binaphthalene]-2-Hydroxy-2’-phenylurylbenzyl ?3?carboxaldehyde, 화합물 1)를 산업화하기 위한 새로운 합성방법을 개발하고 이를 바탕으로 새로운 ARCA derivative를 합성하여 키랄변환체로서의 효율을 향상시켜 보고자 하였다. 기존의 ARCA 합성 과정은 대량생산시에 몇가지 문제점이 발견되었다. 첫 번째로 starting 물질인 (S)-Binaphthol이 비싸며, 두번째는 합성에 필요한 시약인 n-BuLi은 반응성이 매우 커서 대량으로 사용할 경우 폭발의 위험성이 있다는 것이다. 그러므로 이를 해결하고자 본 연구는 새로운 합성방법을 시도하였다. 본 연구의 시도는 화합물 1의 합성에 methyl-3-hydroxy-naphthoate와 2- naphthol을 oxidative coupling 방법을 이용하여 [1,1’-Binaphthalene]-2,2’-Hydroxy-3-carboxly ester(화합물 6) 를 합성하는 단계를 포함한다. 기존에 사용하던 (S)-Binaphthol 대신에 가격이 싼 starting 물질을 사용하여 경제적인 문제점을 해결하였다. 합성하여 얻은 화합물 6을 cinchonine으로 resolution하여 98%ee로 광학적으로 순수한 (S)-form으로 분리된 것을 확인하였다. 새로운 합성방법의 경우, 기존에 (S)-Binaphthol에 n-BuLi을 사용하여 aldehyde를 도입하였던 것을 화합물 6의 ester를 PDC를 이용하여 aldehyde로 바꾸어서 기존의 n-BuLi 사용 문제점을 해결하였다. 그리고 화합물 1의 재생 효율성을 실험하였다. 화합물 1 20g이 DMSO 200ml에서 T.E.A를 base로 이용하여서 L-Phenylalanine과 반응하였을 때, L-form을 D-form으로 바꾸었다. 그리고 chloroform과 brine으로 추출하여서 유기층에서 화합물 1을 20g을 회수하였으며 물층에서 D-amino acids를 회수하였다. water 층에서 얻은 D-amino acids은 83%ee 였으나, 이를 EtOH로 재결정 하였더니 98%ee값의 순수한 D-amino acid을 얻을 수 있었다. 그리고 이 실험을 3번 반복하였을 때에 화합물 1을 98%를 얻어 높은 재생률을 보였다. 또한 3-hydroxy-7-methoxy-2-naphthoate 와 2-naphthol을 oxidative coupling으로 합성한 후, cinchonidine과 cinchonine을 이용하여 resolution하여 새로운 화합물 (S)-2,2’-dihydroxy-1,1’-binaphthalene-7-methoxy-3-carboxyl ester (화합물2, 97.6%ee)을 합성하였다. 그리고 같은방법으로 3-hydroxy-2-naphthoate와 7-methoxy-2-naphthol을 이용하여 (S)-1,1’-binaphthalene-7’-methoxy-3-carboxyl ester(화합물3, 88.4%ee)을 합성하였고, 3-hydroxy-2-naphthoate와 7-bromo-2-naphthol로 (S)-1,1’-binaphthalene-7’-bromo-3-carboxyl ester(화합물 4, 84.4%ee)를 합성하였다. 이를 ARCA derivatives로 이용할 수 있을 것으로 예상된다.;ARCA (Alanine Rcemize Chiral Analogue, (S)-[1,1’-Binaphthalene]-2-hydroxy-2’-phenylurylbenzyl-3-carboxaldehyde, compound 1) is a binol derivative which can convert naturally existent L-form of amino acid to naturally inexistent D-form of amino acid. This study is for development of new synthetic method in order to industrialization. From this new synthetic method, new ARCA derivatives were synthesized to improve efficiency as chiral transformer. The synthetic process of before had several problem for production on a large scale. First, starting material ((S)-binaphthol) is expensive. Second, n-BuLi used for synthesize, has dangerousness of explosion when it used in large quantity. Thus, new synthetic method was tried to solve these problems. It was tried that synthesis of [1,1’-Binaphthalene]-2,2’-hydroxy-3-carboxly ester (compound 6) through oxidative coupling of methyl-3-hydroxy-naphthoate and 2-naphthol. The economic problem was solved as using of cheap starting material in place of (S)-Binaphthol. Resolution was carried out through treatment compound 6 with cinchonine. It was confirmed that optically pure (S)-form was obtained as 98%ee. The problem on using of n-BuLi was settled by using of PDC for change ester of compound 6 to aldehyde. Recycling efficiency of compound 1 was also experimented. When 20g of compound 1 reacts with L-phenylalnine in 200ml of DMSO under T.E.A as base, L-form was converted to D-form. After extraction with chloroform and brine, 20g of compound 1 was recovered from organic layer and D-amino acids was recovered from aqueous layer. At first D-amino acid from aqueous layer shows 83%ee. But after recrystalization with EtOH, pure D-amino acid was obtained with 98%ee. When repeat 3 times this experiment, 98% of compound 1 was obtained. It means high recycling efficiency. After oxidative coupling of 3-hydroxy-7-methoxy-2-naphthoate and 2-naphthol, (S)-2,2’-dihydroxy-1,1’-binaphthalene-7methoxy-3-carboxyl ester (compound 2, 97.6%ee) was synthesized by resolution with cinchonidine and cinchonine. With the same method, (S)-1,1’-binaphthalene-7-methoxy-3-carboxyl ester (compound 3, 88.4%ee) was synthesized from 3-hydroxy-2-naphthoate and 7-methoxy-2-naphthol. Also (S)-1,1’-binaphthalene-7’-bromo-3-carboxyl ester (compound 4, 84.4%ee) was synthesized from 3-hydroxy-2-naphthoate and 7-methoxy-2-naphthol. It is expected that these can used as ARCA derivatives.
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