Silyl Compounds and their use

Details Silyl Compounds and their use Silyl Compounds and their use

1996-11-25

1998-03-17

Grumbling, Matthew V.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

552505, C07J 7100

Patent

active

057288267

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The invention relates to novel silyl compounds and their use in the synthesis of active compounds which are used in the pharmaceutical industry for the preparation of drugs.


KNOWN TECHNICAL BACKGROUND

U.S. Pat. No. 3,513,163 discloses 21-trialkylsiloxypregnane derivatives, which are said to have anti-inflammatory and gluconeogenic properties. DE-OS 41 29 535 discloses pregna-1,4-diene-3,20-dione 16,17-acetal-21-esters, which bear a butyl, isopropyl, sec-butyl, cyclohexyl or phenyl radical on the cyclic acetal ring, and whose C-21hydroxyl group is acylated by an acetyl or isobutyryl radical.


SUMMARY OF THE INVENTION

In the case of chiral active compounds, one enantiomer or one epimer is frequently more active or linked with fewer side effects than the other. Obtaining the desired enantiomer or epimer as selectively as possible and as pure as possible is therefore of great importance in the case of chiral active compounds.
According to the invention, a novel process is now provided by which the epimers of certain pregna-1,4-diene-3,20-dione derivatives may be separated particularly effectively.


BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 present structural formulae I and II, respectively.


DETAILS

The invention relates to a process for enriching the R-epimer in an R/S epimer mixture of compounds of the formula I (see FIG. 1), in which R1 denotes 1-7C-alkyl or 3-8C-cycloalkyl, which is characterized in that the R/S epimer mixture of the compounds of the formula I is silylated with compounds X-Si(R2) (R3)R4, in which R2, R3 and R4 are identical or different and each signifies a 1-7C-alkyl radical or phenyl radical and X signifies a suitable leaving group, the resulting R/S mixture of the silyl derivative of the formula II (see FIG. 2), in which R1, R2, R3 and R4 have the meanings given above, is fractionally crystallized, and the R-epimer-enriched R/S-epimer mixture of compounds of the formula I is released by acid hydrolysis from the crystal fractions obtained first.
1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Those which may be mentioned by way of example are the heptyl, hexyl, neopentyl, isopentyl, pentyl, butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.
A preferred 1-7C-alkyl radical R1 is the propyl radical.
A preferred 1-7C-alkyl radical R2 is the methyl radical.
A preferred 1-7C-alkyl radical R3 is the methyl radical.
A preferred 1-7C-alkyl radical R4 is the 1,1,2-trimethylpropyl radical (thexyl radical).
3-8C-cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl radical. A preferred 3-8C-cycloalkyl radical is the cyclohexyl radical.
The reaction of the compounds of the formula I with the silyl compounds X-Si(R2) (R3)R4 is performed in a manner known to those skilled in the art in inert solvents, as, for example, in dimethylformamide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran or pyridine at temperatures between 20.degree. C. and 80.degree. C., in particular between 40.degree. C. and 60.degree. C. Suitable leaving groups X which may be mentioned are preferably halogen atoms, in particular chlorine.
The reaction is preferably performed in the presence of an auxiliary base, for example in the presence of an inorganic carbonate, such as potassium carbonate, or in the presence of a suitable organic amine, such as triethylamine, diisopropylethylamine, pyridine or imidazole.
The fractional crystallization is performed in a manner known to those skilled in the art, for example by gradual concentration of the solution in whose solvent the R-epimer is less soluble than the S-epimer, and separating off the precipitating crystals, or by gradual addition of a solvent to a solution in which the R-epimer is less soluble than the S-epimer, and separating off the precipitating crystals. Solvents in which the R-epimer of the compounds of the formula II is less soluble than the S-epimer which may be mentioned by way of example a

REFERENCES:
patent: 3513163 (1970-05-01), Brown
patent: 5482934 (1996-01-01), Calatayud et al.

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