Process for the preparation of 10-methoxycarbamazepine

Details Process for the preparation of 10-methoxycarbamazepine Process for the preparation of 10-methoxycarbamazepine

2002-10-09

2003-12-30

Kifle, Bruck (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06670472

ABSTRACT:

The present invention relates to an improved process for preparing 10-methoxycarbamazepine (10-methoxy-5H-dibenz(b,f)azepin-5-carboxamide), an important intermediate in the preparation of 10-oxo-10,11-dihydro-5H-dibenz(b,f)azepine-5-carbaxamide (oxcarbazepine) from 10-methoxy-5H-dibenz(b,f)azepine (10-methoxyiminostilbene).
Oxcarbazepine is an anticonvulsant drug (as described in U.S. Pat. No. 3,642,775), and has been proposed for use as an anti-epileptical agent in the treatment of AIDS-related neural disorders (as described in PCT patent specification no. WO 94/20110); and for the treatment of Parkinson's disease and/or Parkinsonian syndromes (as described in U.S. Pat. No. 5,658,900 and European patent specification no. 678 026).
Various processes for preparing oxcarbazepine have been described in the prior art. For example, U.S. Pat. No. 3,642,775 describes the preparation of oxcarbazepine from 10-methoxyiminostilbene (Scheme-1), which is first phosgenated in toluene, followed by amidation (ethanol and ammonia) and hydrolysis in an acidic medium to furnish the desired product. The main drawback of this process is the use of phosgene (COCl
2
), a toxic and hazardous substance.
Canadian patent specification no. 1 112 241 describes an alternative preparation of oxcarbazepine from the catalysed re-arrangement of 10,11-epoxycarbamazepine, which itself may be prepared from carbamazepine by reaction with m-chloroperbenzoic acid (CPBA) (Scheme-2). However, the drawbacks of this process are: use of carbamazepine, an expensive raw material; and converting this into its corresponding epoxide in poor yields and quality.
Another process, disclosed in European patent specification no. 028 028, starts from 5-cyanoiminostilbene through nitration, reduction and hydrolysis stages (Scheme-3). However, the drawback of the process is in the preparation of the 5-cyanoiminostilbene itself, which can be made from iminostilbene and cyanogen chloride. The latter is also toxic, hazardous and difficult to handle.
Another alternative is described in Swiss patent specification no. 642 950 and comprises hydrolysis, using concentrated sulphuric acid, of the corresponding chloride (10-chloro-5H-dibenz[b,f]azepin-5carboxamide) to form the oxcarbazepine.
More recently, a process has been described in PCT patent specification no. WO 96/21649 (Scheme-4), which starts with 10-methoxyiminostilbene and treats it with an alkali or alkaline earth metal cyanate and acid to produce 10-methoxycarbamazepine which, on acid hydrolysis, furnishes oxcarbazepine. Alternatively, 10-methoxyiminostilbene is first hydrolysed to produce 10-oxo-iminodibenzyl (10-keto-iminodibenzyl) which, upon condensation with chlorosulphonyl isocyanate followed by hydrolysis, furnishes oxcarbazepine. Chlorosulphonyl isocyanate is a very costly, highly moisture-sensitive and toxic reagents which is the main drawback of this latter process.
The biggest problem with the former process is that 10-methoxyiminostilbene undergoes two kinds of competitive reactions when an alkali metal cyanate and an acid are added. The enol-ether moiety of the compound undergoes hydrolysis to give the corresponding ketone (“oxo” compound), which does not undergo a carboxamidation reaction with HOCN, whereas the imino function of the intact 10-methoxyiminostilbene does undergo a carboxamidation reaction. Therefore, the end result is that a mixture of oxcarbazepine, oxo-iminodibenzyl and impurities are obtained, after hydrolysis, making the subsequent crystallization process highly tedious and uneconomical.
The acids that are used in this reaction (Scheme-4), according to the Examples of WO 96/21649, include acetic acid, mono-, di- and tri-chloroacetic acids, dry HCl and concentrated sulphuric acid etc. The general description teaches that concentrated mineral acids are to be used, optionally in solution in the organic acids. Nevertheless, all these acids produce substantial quantities of side products, ie oxo-iminodibenzyl and impurities formed therefrom. Due to this, although the conversion is high, the selectivity leading to the carboxamidation reaction is poor.
Furthermore, international patent specification no. WO 01/56992 describes the use of acetic acid in the absence of an additional solvent in this process, which is stated to result in an improved yield. Nothing about the purity of the end-product (oxcarbazepine) is mentioned, however, and the specific example given shows that the yield thereof is less than or equal to 78% after hydrolysis with water and sulphuric acid in the absence of a solvent such as toluene.
All the known methods therefore suffer from disadvantages, in particular, the requirement to use “environmentally unfriendly” reactants, and/or result in poor yields due to side reactions as mentioned above. In particular, the method described in WO 01/56992 precludes the use of a solvent, which imposes unfavourable limitations on the subsequent processing of the intermediate in the preparation of the end-product.
We have surprisingly found that reaction of 10-methoxyiminostilbene with cyanic acid (HOCN) in the presence of a mild acidic reagent, especially an aromatic acid, enables the disadvantages of the prior art preparation of 10-methoxycarbamazepine to be overcome. In particular, it allows for the use of a solvent in the subsequent reaction steps, which has advantages as will be further described hereinbelow
Accordingly, the present invention provides a process for the preparation of 10-methoxycarbamazepine, which process comprises reacting 10-methoxyiminostilbene with HOCN in a solvent therefor in the presence of a mild acidic reagent. It is important that the mild acidic reagent be chosen so that the enol-ether function is not rapidly hydrolysed. Accordingly, this reagent is preferably a weak acid, such as an aromatic acid. Preferred aromatic acids include weak, non-aliphatic organic acids, such as benzoic acid and substituted benzoic acids; suitable substituents being halo, especially chloro eg para-chlorobenzoic acid. Suitably, the acid has a pKa value in the range of from about 10
−4
to 10
−5
.
Furthermore, the mild acidic reagent is preferably relatively insoluble in the solvent, especially at room temperature but also preferably at the temperature of the reaction, compared to other acids, such as acetic acid. Suitably, the mild acidic reagent has a solubility in the solvent of less than 75%, preferably less than 50% and more preferably less than 25% in the solvent. Especially preferred is when the mild acidic reagent has a solubility of less than about 10-12%, even at elevated temperatures, such as at the temperature of the reaction, and particularly preferred is when the mild acidic reagent has a solubility of less than about 1% at room/ambient Temperature. In this context, it is to be understood that ‘room temperature’ is less than 35° C. and more usually about 20-25° C., such as 21-22° C. Of all the aromatic acids, benzoic acid is the most suitable acid in terms of selectivity (by ‘selectivity’ in this context is meant preference for the carboxamidation reaction over the enol-ether hydrolysis).
Excess molar quantity of the weak acid is preferably used in comparison to the 10-methoxyiminostilbene starting material; for example, in the range of from 2 to 10 molar excess, more preferably about 5 to 8 times, eg 6-7 times, benzoic acid is most preferably employed in the reaction. Most of the acidic reagent can be easily recovered and re-used, such as up to 90-95% can be re-cycled. Such acids less readily hydrolyse the enol-ether moiety present in the 10-methoxyiminostilbene, while nevertheless being able readily to catalyse the reaction between the 10-methoxyiminostilbene and the HOCN.
In another aspect, the present invention provides a process for the preparation of 10-methoxycarbamazepine, which process comprises reacting 10-methoxyiminostilbene with HOCN in the absence of a strong acid. In particular, the present invention provides a process for the preparation of 10-methoxycarbamazepine, which process compr

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