Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing a...
Patent
1992-06-18
1995-07-04
Robinson, Douglas W.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing a...
4352531, 435 53, 435 56, 552586, 552599, 552600, 552623, C12P 3300, C12N 120
Patent
active
054299349
DESCRIPTION:
BRIEF SUMMARY
The invention relates to 20-methyl-5,7-pregnadiene-3.beta.,21-diol derivatives of general formula I ##STR2## in which R.sub.1 means a hydrogen atom or a lower alkyl group and pentamethylene group.
The invention further relates to a process for the production of these 20-methyl-5,7-pregnadiene-3.beta.,21-diol derivatives, which is characterized in that an ergosterol derivative of general formula II ##STR3## in which R.sub.1 and R.sub.2 have the meaning mentioned in claim 1, are fermented with a bacterial culture of genus Mycobacterium.
For fermentation, bacterial cultures of species Mycobacterium spec. NRRL B-3683, Mycobacterium spec. NRRL B-3805, Mycobacterium phlei NRRL B-8154 mycobacterium fortuitum NRRL B-8153 are preferably used.
It is very surprising to one skilled in the art that the 20-methyl-5,7-pregnadiene-3.beta.,21-diol derivatives of general formula I are formed under the conditions of the process according to the invention, since it is known that other sterol-3-acetals are catabolized to 17-oxosteroids under these conditions (U.S. Pat. No. 4,179,336).
The process according to the invention is performed under the same fermentation conditions which are also used with these bacterial cultures in the known microbiological conversions of substrates.
Under the culture conditions usually used for these bacterial cultures, submerged cultures are cultivated in a suitable nutrient medium with aeration. Then, the substrate (dissolved in a suitable solvent or in emulsified form) is added to the cultures and fermented until a maximum substrate conversion is achieved.
Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethylformamide or dimethylsulfoxide. The emulsification of the substrate can be brought about, for example, by the latter being sprayed in micronized form or dissolved in a water-miscible solvent (such as methanol, ethanol, acetone, glycol monomethyl ether, dimethylformamide or dimethylsulfoxide) under strong turbulence in (preferably decalcified) water, which contains the usual emulsifying aids. Suitable emulsifying aids are nonionogenic emulsifiers, such as, for example, ethylenoxy adducts or fatty acid esters of polyglycols. As suitable emulsifiers, the commercially available wetting agents Tegin.sup.(R), Tween.sup.(R) and Span.sup.(R) can be mentioned as examples.
The optimum substrate concentration, substrate addition time and fermentation period depend on the type of substrate and microorganism used and fermentation conditions. These values, as is generally necessary in microbiological steroid conversions, have to be determined in the individual case by preliminary tests, as they are familiar to one skilled in the art.
The 20-methyl-5,7-pregnadiene-3.beta.,21-diol derivatives of general formula I produced according to the process of the invention are valuable intermediate products, which preferably can be used for the synthesis of vitamin D.sub.3 and its derivatives. Thus, for example, these compounds can be esterified to the 21-tosylates and the latter can be reacted under the conditions which A. Furst et al. have described (Helv. Chim. Acta 65, 1982, 1499-1521). Thus, compounds of general formula III ##STR4## are obtained whose acetal groups are cleaved. The photochemical rearrangement of the thus obtained 25-hydroxy cholesterol in 25-hydroxy vitamin D.sub.3 can also be performed according to the process, as was described by A. Furst et al.
The initial compounds for the process according to the invention can be produced under the conditions described in U.S. Pat. No. 4,179,336.
The following embodiment is used to explain the process according to the invention in more detail.
EXAMPLE
a) 400 g of ergosterol is dissolved in 6 l of formaldehyde dimethylacetyl, mixed with stirring at room temperature with 400 g of diatomaceous earth and in portions with 200 g of phosphorus pentoxide and stirred for 2 hours at room temperature. It is filtered off from insolubles, washed with formaldehyde dimethylacetal and the solvent is distilled off in a vacuum.
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Chemical Abstracts, vol. 98, 1983 (98:16936u).
Takayama et al., "Facile, Stereoselective Synthesis of (24R)-24,25-Dihydroxyvitamin D", Tetrahedron Letters, vol. 21, pp. 5027-5028 (1980).
Reg File No. 132705-08.9.
Reg File No. 126771-89-9.
Reg File No. 103656-29-7.
Kennekke Mario
Neef Gunter
Weber Alfred
Robinson Douglas W.
Schering Aktiengesellschaft
Sevigny Jeffrey J.
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