Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1996-05-28
1999-05-04
Marx, Irene
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
549510, 549511, 4241951, C12P 1702, A61K 3578
Patent
active
059003677
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for mass production of taxol from Taxus genus plant, more specifically, to a rapid and simple method for mass production of taxol with a high purity and recovery, which comprises the steps of solvent extraction of biomass from Taxus genus plant employing methanol, dichloromethane and hexane, adsorbent treatment, precipitation in hexane, fractional precipitation and high performance liquid chromatography.
2. Description of the Prior Art
Taxanes are diterpene compounds containing the taxane skeleton. For example, taxol is famous as the first identified compound with a taxane ring which is effective for the treatment of leukemia and cancer. Recently, it has been reported that taxol Xs capable of curing approximately 30%, 50% and 20% of ovarian, breast and lung cancer patients, respectively. Also, taxane compounds include baccatin III, 10-deacetylbaccatin III, 10-deacetyltaxol, cephalomannine and deacetylcephalomannine, which are employed in the semi-synthesis of taxol.
Taxane compounds are represented as general formula (I) and (II) as followings: ##STR1## wherein, if R.sub.1 =AC, the compound is baccatin III; and, if R.sub.1 =OH, the compound is 10-deacetylbaccatin III. ##STR2## wherein, if R.sub.2 =AC, R.sub.3 =C.sub.6 H.sub.5, the compound is taxol; if R.sub.2 =OH, R.sub.3 =C.sub.6 H.sub.5, the compound is 10-deacetyltaxol; cephalomannine; and, 10-deacetylcephalomannine.
On the other hand, total synthesis, semi-synthesis and extraction methods have been employed to prepare taxol.
The total synthesis method, however, has not been practically applied in the art, since it requires very expensive chemical reagents and the yield is not so high, which can be expected from the complicated chemical structure of taxol.
The semi-synthesis method employing precursors such as 10-deacetylbaccatin III, has revealed some drawbacks since it essentially entails complicated and multiple steps of isolating and purifying taxol precursors from Taxus genus plant and transforming the taxol precursors to taxol, which, in turn, has been an obstacle to the universal use of the method.
Accordingly, extraction methods by which taxol can be isolated from Taxus genus plants in a direct manner, have prevailed in the art, since they have the advantage of economy, and a variety of approaches have been described in the art:
WO 94/12268 discloses a method of isolating taxol by employing a semi-permeable membrane and reverse osmosis apparatus. However, said method has revealed a serious problem that it essentially requires the expensive semi-permeable membrane and reverse osmosis apparatus accompanied by complicated techniques for operating them.
EP 553,780 A teaches a method of isolating taxol and precursor thereofs which comprises the steps of vacuum drying a methanol extract of Taxus genus plant, solvent extraction employing cyclohexane and methylenechloride to give crude taxol followed by silica gel column HPLC.
WO 92/18492 describes a method of purifying taxol which comprises the steps of methanol extraction of Taxus genus plant, partitional fractionation employing methylenechloride or ethylacetate to obtain crude taxol and normal-phase liquid chromatography.
WO 92/07842 illustrates a method isolating taxol which comprises the steps of a series of solvent extractions employing ethanol, chloroform and methanol to give crude taxol followed by reverse-phase HPLC.
WO 94/13827 suggests a method of purifying taxol which comprises the steps of organic solvent extraction using ethanol, methanol and acetone, adsorbent treatment of activated carbon or charcoal to give crude taxol followed by normal-phase liquid chromatography.
JP 6-157329 A offers a method of obtaining crude taxol of low-purity which comprises a series of solvent extractions employing ethylacetate, ether, acetonitrile and acetone.
However, all of the prior art purification methods, which primarily aim to obtain crude taxol of low-purity by employing solvent extraction and chromatograp
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D. R. Wu et al., Preparative Separation of Taxol in Normal and Reversed-Phase Operations, Journal of Chromatoraphy A, 702:233-241(1995).
S.D. Harvey et al, Separation of Taxol from Related Taxanes in Taxus brevifolia Extracts by Isocratic Elution Reversed-Phase Microcolumn High-Performance Liquid Chromatograph, Journal of Chromatography, 587:300-305(1991).
K.V. Roa, Taxol and Related Taxanes. I.Taxanes of Taxus brevifolia Bark, Pharamceutical Research, 10(4):521-524 (1993).
J.H. Cardellina II, HPLC Separation of Taxol and Cephalomannine, Journal of Chromatograph, 14(4):659-665 (1991).
K.V. Rao et al., A new Large-Scale Process for Taxol and Related Taxanes from Taxus brevifolia, Pharmaceutical Research, 12(7):1003-1010(1994).
G.P. Guanawaruana et al., Isolation of 9-dihydro-13-acetylbaccatin III from Taxus canadensis, Journal of Natural Product, 55(11):1686-1689(1992).
The Merck Index, Tenth Edition, 1983, p. 4164.
Hong Seung-Suh
Kang In-Seon
Kim Jin-Hyun
Kim Kwang-Wook
Lee Hyun-Soo
Marx Irene
Samyang Genex Co., Ltd.
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