FORM 2 THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
[See section 10, rule 13]
1. TITLE OF THE INVENTION
"More Efficient Synthesis of Alkoxybenzazepines"
2. (a) Atul Ltd. (b) having our administrative office at Ashoka Chambers,
Rasala Marg, Mithakhali Cfoss Road, Ahmedabad 380006 and (c) an Indian Company,
The following specification describes the nature of the invention and the manner in which it is to be performed

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Field of Invention
This Invention relates to the preparation of 10-methoxy-5H-dibenz [b.fjazepine (1) which is a key intermediate for preparation of the anticonvulsant oxcarbazepine by two step reaction starting from Iminostilbene carbonyl chloride (2). The reaction involving bromination of 2 followed by methoxylation by sodium methoxide in methanol is as below:

Background of the Invention
The most popular route for the manufacture of the anticonvulsant drug oxcarbazepine has been via the intermediate 1 prepared by the route shown below in Scheme II. The preparation of 1 involves bromination of acetylated iminostilbene followed by introduction of methoxy group with simultaneous dehydrohalogenation by sodium methoxide in methanol (CH 389619, 1960 CA 59, 43759,19237).
Oxcarbazepine synthesis through this route though lengthy, is robust and simple. Novel routes like described in PCT, WO 2002096881 A1 which involves epoxidation of carbamazepine followed by reductive ring opening and oxidation has been developed in recent years. However, these routes involve very intricate reaction controls and selectivity’s. Some times the reagents used are hazardous as in the route developed by Novartis itself which uses LDA and n-BuLi (Tech. Report Vol. 7, No.3, Albany Mol Res. Inc., 6th International Conference on Org. Proc. Res and Dev., Vancouver, July 2002). Yet it is interesting to note that even the new Novartis route goes through the intermediate 1 only. A recent patent PCT WO 9738978 A1 has also used the same strategy to prepare analogs of alkoxycarbamazepines.

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Though many alternatives routes have been described the Scheme II route seems to be most studied. This route has certain lacunae such as:
1. Use highly moisture sensitive acetyl chloride & pyridine for amino gr. acetylation.
2. Low stability of Dibromo 3a.
3. Bromination of acetyl group is a competitive reaction if excess bromine used.
4. Larger number of impurities in bromination and thus in subsequent methoxylation.
5. Purifications needed at each step therefore loss in yield.
Object of invention
It was interesting for us in commercial perspective that if the secondary amino group of iminostilbene (4) is protected by carbonyl chloride group instead of acetyl there were more than a few advantages. Since side reactions will be minimum, less impurities will be produced. Reactivity may also vary due to an electron withdrawing group, especially during methoxylation step. 2 is also commercially available and thus, one synthetic step can be reduced during manufacture.

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Also the robustness of the 5-chlorocarbonyl iminostilbene molecule is evident from a DSM patent WO 2000055138 A1 in which the compound 2 is nitrated at 10-position and given subsequent treatments to obtain oxcarbazepine. The objects of the invention are:
1. Use of 2 as an alternative raw material for the reactions in place of iminostilbene (4).
2. Eliminate one step of acetylation of iminostilbene,
3. Decrease impurities arising due to possible bromination of -COCH3 group by the prior art route.
Statement of invention
The present invention provides an alternative starting material for the manufacture of 1, through the use of 2 after bromination and the subsequent dehydrohalogenation/methoxylation in one step.
Summary of Invention
Thus in accordance with this invention, the process comprises of:
a) Reaction of 2 with bromine in an inert solvent.
b) The dibromo product 3 obtained after evaporation of solvent.
c) Use of 3 as such without any purification for preparation of crude 1 through refluxing in a solution of sodium methoxide in methanol.
d) Purification of 1 by crystallisation.
Detailed description of the invention
2 is charged in a reactor containing a suitable solvent, and having cooling and stirring. Liquid Br2 is gradually charged in the reactor with stirring and cooling. After the reaction is complete the excess Br2 is destroyed. The solvent is evaporated at low pressure to obtain dibromo 3, which is dried in vacuo and analysed by HPLC and M.Pt.
In the subsequent step, the crude 3 is slurried in a solution of sodium methoxide in methanol and refluxed for 16 hrs under stirring. A part of methanol is distilled off and then refluxed for 24 hrs more. The crude 1 is isolated by quenching the reaction in water and filtration. 1 can be purified by crystallization from solvents like toluene, methanol, acetone, ethyl acetate or a combination of thereof.

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Example 1
Bromination of 2:
In a reactor equipped with cooling and stirring, Iminostilbene carbonyl chloride (2) (100g, 0.39 moles) was charged, followed by dichloromethane (600mL). The slurry was stirred to get a clear solution, the solution was then cooled to 0-10°C. Br2 (68.8g, 0.43 moles) was slowly added with vigorous agitation. After the completion of reaction, the excess bromine was destroyed using a 10% sodium bisulfite solution. The off-white product 3 (151g, 92.8% yield theoritical) was isolated by distilling off dichloromethane under reduced pressure. Melting point of crude 3 is 159-161 °C. If necessary dibromo 3 can be purified to >99% purity by washing with methanol. Methoxylation of 3
Dry crude 3 (150g, 0.361 moles) was slurried in a solution of sodium methoxide (166g, 3.07 moles) in methanol (1L) under vigorous stirring. This slurry was refluxed under stirring for about 16 hrs. A part of methanol was recovered till RM temperature reached 95-100°C. The RM was then further refluxed for 24 hrs at 95-100°C. The crude 1 (80g, 99% yield of theory) was isolated by quenching the reaction with 800 ml water and filtration. M.pt. of crude 1 was 118-124°C and was satisfactory for further use. The crude can be further purified by crystallization if needed.
Example 2
By following the prior art procedure the result was as follows: Bromination of 2a:
In a reactor equipped with cooling and mechnical stirring, charged 5-acetyl-5H-dibenz [b.fjazepine (2a) (100g, 0.424 moles). Dichloromethane was charged and stirred till a clear solution was obtained. The solution was the cooled to 0-10°C. Br2 solution in dichloromethane was slowly added with vigorous agitation and cooling. After the reaction was complete, the excess bromine was destroyed using 10% sodium bisulfite aqueous solution. The dark brown product 3a (159g, 94.6% yield theoritical) was isolated by distilling off dichloromethane under reduced pressure. Melting point of crude 3a is 99-110°C (lit. 134-136°C). This bromo adduct 3a was slightly lachrymatory and decomposed within one week to get a sticky brown mass. As

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such it is dark brown in colour and needs purifications to get a dark yellow crystalline
material.
Methoxylation of 3a
Dry crude 3a (100g, 0.253 moles) was slurried in a solution of sodium methoxide (115g, 2.13 moles) in methanol (740 ml) under vigorous stirring. Refluxed this slurry under stirring for about 16 hrs. A part of methanol was recovered till RM temperature reached 95-100°C. The RM was then further refluxed for 24 hrs at 95-100°C. The crude 1 (80g, 98.6% yield of theory) was isolated by quenching the reaction with 800 ml water and filtration. Crude was brown in colour and number of impurities (TLC) were large.
Example 3
The Brominated compound 3 was prepared as in Example 1
Dry crude 3 (104g, O.moles) was slurried in a solution of sodium (46g, 2.0 moles) in methanol (460g) under vigorous stirring in an S.S. autoclave. This solution was heated to 100-120°C for 24h reaction then queched with 800 ml water and filtration. Crude was obtained in 95% yield and 89% purity (by HPLC).
Example 4
The compound 2 was chlorinated by the process described in Example 1. The dry crude was methoxylated as per Example 3 for 36h. Crude 1 was obtained in 97.6 % yield.
Advantages
1. Since it is apparent from prior art that 5-chlorocarbonyl derivative 2 is a precursor of 4, 2 is commercially available thus the step of acetylation of amine function is avoided.
2. Purification of dibromo adduct 3 is not necessary, resulting in better yield.
3. 5-Chlorocarbonyl-10,11-dibromo-5H-dibenzazepine 3 more stable than its acetyl counterpart 3a. Better colour of crude 3 is achieved.
4. Since purifications of intermediates is avoided, better overall yield
compared to the reported route is achieved.

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We claim
Use of:
1. 5H-dibenz[b,f]azepine-5-carbonyl chloride/carbonyl bromide and mixtures thereof instead of iminostilbene as a starting material.
2. Bromination/chlorination of the 5-carbonyl chloride/bromide 2.
3. Reaction temperature from 90°C to 120°C.
4. Alkali & alkaline earth metal alcolholate solution in respective alcohols in 6-8
Molar excess.
Dated this 14th day of September 2006
Applicant


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Abstract of invention
This invention relates to the preparation of 10-methoxy-5H-dibenz [b.f]azepine (1) which is a key intermediate for preparation of the anticonvulsant oxcarbazepine by two step reaction starting from Iminostilbene carbonyl chloride (2) instead of iminostilbene. The reaction involves bromination of 2 followed by metnoxylation by sodium methoxide in methanol Thus avoiding one step of protection of secondary amino group via acetylation.