Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1996-12-24
1998-09-15
Gupta, Yogendra N.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D22318
Patent
active
058080589
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of 10-oxo-10,11-dihydro-5H-dibenz(b,f)aze-pin-5-carboxamide (IV), also known under the non-proprietary name of oxcarbazepine, a substitute for carbamazepine, starting from 10-methoxy-5H-dibenz(b,f)azepine IV by means of direct carbamoylation with isocyanic acid generated in situ from cyanates and acids and subsequent acid hydrolysis of the enol ether, according to scheme A: ##STR1##
Alternatively, according to a further object of the invention, the hydrolysis reaction can be carried out before the carbamoylation, according to scheme B: ##STR2##
The chemical synthesis of oxcarbazepine is not immediate, in fact a number of alternative routes, very different from each other, are known at present. The main ones are summarized in the following schemes.
SCHEME C
Oxidation of the carbamazepine VII to 10,11-oxiran derivative VIII and rearrangement of the latter to oxcarbazepine VI (German Patent 2,246,842 and Swiss Patent 633,271) ##STR3##
The main drawbacks of this process resides in the use, as a reagent, of the carbamazepine which is expensive, being itself a final product; moreover, the epoxidation reaction gives poor yields, due to the substrate sensitivity, when using conventional epoxidizers such as peracetic acid, or it requires remarkable excesses of expensive reagents such as 3-chloroperbenzoic acid. Moreover, dangerous side-products form during the epoxidation process. The rearrangement reaction epoxide - - - > ketone takes place with important amounts of expensive catalysts, is delicate since a variety of side-products are formed, and it yields a crude product which requires thorough purifications giving low yields.
SCHEME D
Nitration of 5-cyano-5H-dibenz(b,f)azepine (IX, N-cyanoiminostilbene) at the position 10 (X), followed by reduction of the nitro group to amino group and simultaneous hydrolysis of the enamine to ketone, to obtain 10-oxo-10,11-dihydro-5-cyano-5H-dibenz(b,f)azepine (IX) which is hydrolyzed to oxcarbazepine VI (EP-A-0 028 028). ##STR4##
The drawbacks of this process consist above all in the starting product IX which can be obtained, according to EP-A-0029409, either from carbamazepine VII which is an expensive product, or from 5H-dibenz-(b,f)azepine (iminostilbene I) by reaction with cyanogen chloride, which is a toxic gas difficult to handle: ##STR5##
Moreover, the nitration gives acceptable yields only if carried out with nitrating agents such as N.sub.2 O.sub.3 or N.sub.2 O.sub.4, which are difficult to use. Finally the hydrolysis of the cyano group requires preferably the use of BF.sub.3 complexes, which are expensive and must be handled carefully since they are very aggressive. The total yield of the process is low.
SCHEME F
Hydrolysis of the 10 chloro-5H-dibenz(b,f)azepin carboxamide with concentrated sulfuric acid, to give directly oxcarbazepine (Swiss Patent 642,950). ##STR6##
Actually, the hydrolysis reaction is very slow and essentially incomplete at the indicated temperature, whereas an even slight raising of the temperature yields a degradation.
Moreover the preparation of XII requires either the reaction of phosgene, a toxic gas, with 10-chloro-5H-dibenz(b,f)azepine (XIII) or the carbamazepine VII according to the Scheme G and G' as the starting reagent: ##STR7##
Whereas scheme G involves a great number of steps, the drawback of scheme G' resides in the high cost of the starting material VII.
SCHEME H
Carbamoylation reaction of 10-methoxyminostilbene IV by treatment with phosgene followed by ammonolysis of the chlorocarbonyl derivative XVI and hydrolysis of the vinyl ether V (German Patent 2,011,087) ##STR8##
The most important problem with this process is the use of phosgene, a toxic gas which is subjected to very severe regulations.
Now it has surprisingly been found that the carbamoylation reaction of 10-methoxyminostilbene IV takes place in very good yields and in a single step from IV to V (scheme A), by means of isocyanic acid generated in situ from metal cyanate
REFERENCES:
Ahmad et al, Heterocycles, vol. 24, No. 12, 1986.
Gupta Yogendra N.
Trifarma S.r.l.
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