Process for the isolation and purification of mevinolin

Details Process for the isolation and purification of mevinolin Process for the isolation and purification of mevinolin

2000-04-19

2004-11-02

Marx, Irene (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing heterocyclic carbon compound having only o, n, s,...

C435S117000, C435S118000, C435S170000, C435S244000, C435S115000, C549S292000

Reexamination Certificate

active

06812007

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for the isolation and purification of mevinolin from fermentation liquor.
Mevinolin, also known as lovastatin, Mevacor, monacolin K, and MK 803 is a known antihypercholesteremic agent, which can be produced by fermentation using either a microorganism of the species
Aspergillus terreus
or different microorganism species of the Monascus genus, obtained either as an open chain hydroxy acid or as lactone. The compound has the formula
BACKGROUND OF THE INVENTION
The isolation of the active ingredient is suitably carried out either by directly extracting the fermentation liquor with a solvent, or by extracting the filtered liquor and the biomass and subsequently purifying the crude product such as by chromatography.
Ethyl acetate, chloroform or benzene can be used for the extraction. The fermentation liquor contains partly the open-chain hydroxy acid of mevinolin, 3,5-dihydroxy-7-[1,2,6,7,8,8a-hexahydro-2,6-dimethyl-8-(2-methylbutyryloxy)-naphthalene-1-yl]-heptanoic acid. This compound is heated in toluene to be lactonized to mevinolin. The purification of the mevinolin containing crude product completely in the lactone form can be carried out by chromatography and subsequent recrystallization in accordance with the process disclosed in U.S. Pat. No. 4,319,039.
In addition to extraction an XAD
2
adsorption resin can also be used for the isolation of mevinolin as disclosed in U.S. Pat. Nos. 4,231,938 and 4,319,039.
The main disadvantage of the extraction method is that together with the active ingredient the solvent also dissolves many other contaminants, and thus makes the further purification more complicated and expensive. Purification can be efficiently carried out by multistage column chromatography and subsequent recrystallization.
Experiments have been carried out to compare the extraction method described in Hungarian patent No. 187,296 to the method according to the present invention for the isolation of mevinolin from fermentation liquor obtained by cultivation of an
Aspergillus obscurus
MV-1 holotype strain (deposit No. NCAIM (P)F 001189 at the Hungarian National Collection) and other bacterial strains, such as
Aspergillus terreus
) accessible under ATCC 20542). The results, as shown in Example 1, demonstrate that the product obtained from the fermentation liquor by extraction cannot be properly purified by recrystallization. The preparation by this route of a product is not suitable for pharmaceutical purposes, therefore requires further purification by column chromatography.


REFERENCES:
patent: 5403728 (1995-04-01), Jekkel
patent: 3006216 (1980-04-01), None
patent: 302828 (1981-02-01), None
Nakamura et al., J. Antibiotics, vol. 43, No. 12, pp. 1597-1600, 1990.

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