Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-09-26
1998-12-08
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5483031, C07D49504
Patent
active
058471529
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/00593 Feb. 18, 1995.
The present invention relates to an improved process for the preparation of heterocyclic compounds which are suitable as intermediates for the preparation of D-(+)-biotin, and to a process for the preparation of D-(+)-biotin itself.
D-(+)-biotin is a substance which has been known for a long time, and accordingly there are also already a number of processes known for its preparation. Common to the processes of industrial interest is the necessity at some particular stage of attaching the carboxybutyl side chain to the ring system. Various solutions for this have been disclosed, such as, for example, the synthesis of the side chain according to the linkage scheme C.sub.4 +C.sub.1 .fwdarw.C.sub.5 or alternatively C.sub.3 +(C.sub.3 -C.sub.1 =C.sub.2).fwdarw.C.sub.5 (e.g. CH Patent Specification 556 867).
It is also known to link the side chain to the ring system in one step by means of a Wittig reaction (e.g. EP Offenlegungsschrift 0 084 337). All these processes, however, have the disadvantage that they either proceed via a comparatively large number of reaction steps or else require a relatively large outlay for the isolation of the desired final product.
Furthermore, EP Offenlegungsschrift 0 154 225 discloses the introduction of the side chain by reaction of the thiolactone of the formula I with 4-(2,4,10-tri-oxaadamantyl)butylmagnesium bromide.
In addition, the introduction of the carboxybutyl side chain via a "bis-Grignard reaction" using a 1,4-di-halomagnesium butane and subsequent carboxylation with carbon dioxide has been known for a long time. According to JP-B-003,580/71 and DE Offenlegungsschrift 20 58 234, the reaction is carried out in a solvent mixture of diethyl ether and toluene.
On the other hand, JP-A-280,037/84 and EP-A-0 273 270 propose carrying out the reaction in tetrahydrofuran in the presence of tetramethylethylenediamine (TMEDA).
In all these cases, the addition product of the formula III ##STR1## is first isolated, at least as a crude extract, and then dehydrated.
These processes, however, have various disadvantages, which can appear to make them unsuitable for industrial implementation.
Only according to the process described in JP-A-280,037/84 can the D-(+)-biotin intermediate of the formula I be prepared in very good yield.
However, this requires the use of the cosolvent TMEDA, which is classified as irritant, as a result of which the working up of the reaction mixture becomes particularly laborious, as this cosolvent must not pass into the effluent.
In addition, the process described there is carried out at high dilution, and the carrying-out of the carboxylation at temperatures between -40.degree. and -45.degree. C. can only be realized with difficulty on the industrial scale.
Furthermore, the dehydration of the Grignard adduct of the formula III is carried out in a solvent mixture of toluene/tetrahydrofuran, which, after working up, must be separated for recycling in a complicated process.
The object of the present invention was then to indicate a process in which the D-(+)-biotin intermediate of the formula I can be prepared in THF as solvent without the use of the cosolvent TMEDA in an improved space-time yield.
There was thus a need for an industrially simple process according to which the side chain can be attached to the ring system in good yield, and, as far as possible, in a "one-pot process". This is now possible by means of the process according to the invention.
The invention thus relates to an improved process for the preparation of a D-(+)-biotin intermediate of the formula I ##STR2## in which R is H or C.sub.1-6 -alkyl, ##STR3## in which R has the meaning. indicated, with 1,4-di-magnesiumchlorobutane and carbon dioxide in an inert solvent and subsequent elimination of water using a mineral acid, characterized in that the following steps are carried out successively: of catalytic amounts of 1,2-dibromoethane in tetrahydrofuran as a solvent, at temperatures between -25.degree. and -15.degree. C., and, if appr
REFERENCES:
patent: 5235065 (1993-08-01), Schwarz et al.
Chem. Abst., Ichiro et al. vol. 70, 1969; p. 1990, 19984 r.
Casutt Michael
Eckstein Jurgen
Koppe Thomas
Schwarz Michael
Merck Patent Gesellschaft mit beschrankter Haftung
Shah Mukund J.
Sripada Pavanaram K.
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