이트라코나졸 항진균제의 효과적인 합성법 개발

백두종; Du-Jong Baek

Journal of the Korean Industrial and Engineering Chemistry, Vol.17, No.6, 633-637, December, 2006

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이트라코나졸 항진균제의 효과적인 합성법 개발

Development of the Efficient Synthetic Route for Itraconazole Antifungal Agent

백두종^†

상명대학교 자연과학대학 화학과

Du-Jong Baek^†

Department of Chemistry, College of Natural Sciences, Sangmyung University, Seoul 110-743, Korea

E-mail:

초록

본 연구에서는 triazole계 항진균제인 이트라코나졸의 대량합성을 위한 효과적인 합성법을 제시하였다. Janssen Pharmaceutica에 의해 발표된 기존의 의약화학적 합성경로는 2,4-dichloroacetophenone을 출발물질로 하는 직렬(linear) 합성의 14 단계로서 전체수율이 1.4%에 불과하였고 대량합성에 부적합한 위험물질로서 methanesulfonyl chloride (CH3SO2Cl)와 수소기체 및 sodium hydride (NaH)를 사용하고 있다. 또한 고가의 1-acetyl-4-(4-hydroxyphenyl)piperazine 및 팔라듐을 사용함으로써 생산 단가가 높은 문제점이 있었다. 이를 개선하기 위해서 병렬(convergent) 합성 전략을 수립하였는데, 이트라코나졸의 대략 반에 해당하는 중간체 Ⅱ와 Ⅲ을 각각 합성한 다음 두 부분을 결합시키는 12단계의 합성공정을 개발하였고 전체 수율은 12.0%로서 합성효율이 크게 개선되었다. 이 과정에서 공정을 간략화하고 위험물질 및 고가의 반응물의 사용을 배제함으로써 생산 원가를 크게 절감시킬 수 있었다.

In this study, the efficient large-scale synthetic route for itraconazole, triazole antifungal agent, was developed. The original synthetic route for medicinal chemistry reported by Janssen Pharmaceutica was linear (14 linear steps) starting from 2,4-dichloroacetophenone with the total yield of 1.4%, and potential hazardous materials such as methanesulfonyl chloride (CH3SO2Cl), hydrogen gas, and sodium hydride (NaH) were used. Furthermore, the expensive 1-acetyl-4-(4-hydroxyphenyl) piperazine and palladium were used in this medicinal chemistry route, thus the manufacturing cost would be practically high. In order to improve the commercial route, we developed the process of 12 step convergent synthesis combining two intermediates which are roughly halves of itraconazole with the total yield of 12.0%, and hazardous materials and expensive reagents were excluded in this process, thus the manufacturing cost could be cut down to a great extent.

Keywords:Itraconazole;Antifungal agent;Synthesis;Process development

[References]

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Bailey EM, Krakovsky DJ, Rybak MJ, Pharmacotherapy, 10, 146 (1990)
Haria M, Bryson HM, Goa KL, Drugs, 51, 586 (1996)
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Koltin Y, Hitchcock CA, Curr. Opin. Chem. Biol., 1, 176 (1997)
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Willis C, Wills M, Organic Synthesis, Oxford Chemistry Primers, Vol. 31, pp. 34-35, Oxford University Press Inc., New York, U.S.A. (1995)

[1] FDA Approval based on NDA No. 020083, Sporanox,TM Janssen Pharma, September 11 (1992)

[2] Bailey EM, Krakovsky DJ, Rybak MJ, Pharmacotherapy, 10, 146 (1990)

[3] Haria M, Bryson HM, Goa KL, Drugs, 51, 586 (1996)

[4] Sheehan DJ, Hitchcock CA, Sibley CM, Clinical Microbiol. Rev., 12, 40 (1999)

[5] Koltin Y, Hitchcock CA, Curr. Opin. Chem. Biol., 1, 176 (1997)

[6] 건강보험심사평가원, EDI 청구액 추이 (2005)

[7] Heeres J, Backx LJJ, (Janssen Pharmaceutica N. V.), Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloymethyl-1, 3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles, U. S. Patent 4,267,179 (1979)

[8] Heeres J, Backx LJJ, Mostmans JH, Van Cutsem J, J. Med. Chem., 22, 1003 (1979)

[9] Heeres J, Hendrickx R, Van Cutsem J, J. Med. Chem., 26, 611 (1983)

[10] Heeres J, Backx LJJ, Van Cutsem J, J. Med. Chem., 27, 894 (1984)

[11] Willis C, Wills M, Organic Synthesis, Oxford Chemistry Primers, Vol. 31, pp. 34-35, Oxford University Press Inc., New York, U.S.A. (1995)