Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-04-10
1993-10-05
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548110, 5483181, C07D23302, C07D23304, C07D23320, C07D23350, C07D23348, C07D23352
Patent
active
052506991
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for the preparation of D-(+)-biotin from a cysteine hydantoin of the formula I ##STR2## in which R.sup.1 is H, or a group R.sup.3 R.sup.4 CH-- or SiR.sup.5 R.sup.6 R.sup.7, in which unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or heteroaryl or, taken together, are unsubstituted or substituted alkylene or heteroalkylene, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or heteroaryl, alkoxycarbonyl group or a dialkylamino group.
The invention was based on the object of providing a novel process for the preparation of optically active D-(+)-biotin, which avoids carrying out a racemate cleavage and thus discarding or feeding back the undesired enantiomer.
Processes for the stereospecific synthesis of D-(+)-biotin from sugars of suitable configuration are known. Thus, in Tetrahedron Letters No. 32, pp. 2765-2766 (1975), D-mannose is used as a starting material, in Agric. Biol. Chem. No. 42, p. 465 (1978), D-glucose is used as a starting material and in DE-OS 3,122,562 and DE-OS 3,320,140, D-arabinose is used as a chiral starting material.
However, all these processes are characterized by a high number of synthesis steps with a consequently low total yield. The intermediates, usually uncrystallizable owing to their sugar nature, are often only obtained in unsatisfactory purity and require, owing to their polyfunctionality and the chemical lability associated therewith, the maintenance of comparatively narrow reaction parameters. A number of sugars are also inaccessible from natural sources, which results in a high price.
The use of L-cysteine, as known from U.S. Pat. Nos. 4,009,172, 4,130,713, 4,337,345 and Journal of the American Chemical Society No. 99, p. 7020 (1977), does avoid the handling of labile intermediates, but leads over a total of 18 reaction steps and with separation of undesired isomers to optically active D-(+)-biotin only in an unsatisfactory yield.
A very elegant synthesis of D-(+)-biotin from cysteine or cystine via an optically active bicyclic hydantoin derivative as an intermediate was described by E. Poetsch and M. Casutt (Chimia, 41, 148 (1987) and EP-A2-0,242,686/EP-A2-0,243,734).
The only disadvantage of this tolan synthesis is that a cyano group has to be introduced into an intermediate and the reaction thus has to be carried out using highly toxic alkali metal cyanide or trimethylsilyl cyanide.
The total synthesis of D-(+)-biotin from the hydantoin of L-cystine described by Corey et al. (Tetrahedron Letters 29, 57 (1988)) gives only a 12% yield of D-(+)-biotin over many synthesis steps and is thus unsuitable for carrying out industrially.
In a further process, substituted 3H,5H-imidazo[1,5-c]tetrahydrothiazoles are described in Journal of the American Chemical Society No. 105, p. 5946 (1983) and in EP-OS 0,094,776, from which optionally active biotin is obtained after racemate cleavage.
As the comparatively high number of steps (lacuna) associated with moderate yields in some cases and the necessity of an optical separation, even these starting materials can appear as not very suitable for the preparation of D-(+)-biotin, and there was furthermore a need for a suitable process for the simple, economic and stereospecific preparation of D-(+)-biotin.
It has now surprisingly been found that D-(+)-biotin is obtainable without additional racemate cleavage from chiral (4R/S, 5R)-5-mercaptomethylimidazolidin-4-ol of the formula II. This can be prepared from the naturally occurring amino acids L-cystine or L-cystine via a cysteine hydantoin of the formula I.
The invention therefore relates to a process for the preparation of D-(+)-biotin, characterized in that a cysteine hydantoin of the formula I ##STR3## in which R.sup.1 is H, or a group R.sup.3 R.sup.3 CH-- or SiR.sup.5 R.sup.6 R.sup.7, in which unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or heteroaryl or, taken together, are unsubstituted or substituted alkylene or heteroalkylene, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or heteroaryl,
REFERENCES:
patent: 4713390 (1987-12-01), Dumont et al.
Corey et al, Tetrahedron Letters, vol. 29(1), pp. 57-60 (1988).
Kazarinoff et al, J. of Biological Chem., vol. 247(1), pp. 75-83 (1972).
Casutt Michael
Poetsch Eike
Speckamp Willem N.
Higel Floyd D.
Merck Patent Gesellschaft mit beschrankter Haftung
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