WO2008012837A1 - Process for producing 10-oxo-l10, 11-dihydr0-5h-dibenz [b, f] azepine-5-carboxamide starting from 5-cyanoiminostilbene - Google Patents

Process for producing 10-oxo-l10, 11-dihydr0-5h-dibenz [b, f] azepine-5-carboxamide starting from 5-cyanoiminostilbene Download PDF

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WO2008012837A1
WO2008012837A1 PCT/IN2007/000307 IN2007000307W WO2008012837A1 WO 2008012837 A1 WO2008012837 A1 WO 2008012837A1 IN 2007000307 W IN2007000307 W IN 2007000307W WO 2008012837 A1 WO2008012837 A1 WO 2008012837A1
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formula
dibenz
azepine
carbonitrile
dihydro
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PCT/IN2007/000307
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French (fr)
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WO2008012837A8 (en
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Harnam Singh
Nitin Gupta
Pramod Kumar
Sushil Kumar Dubey
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Jubilant Organosys Limited
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Publication of WO2008012837A8 publication Critical patent/WO2008012837A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/26—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a double bond between positions 10 and 11
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11

Definitions

  • azepine-5-carboxamide of formula I comprises of hydrolyzing the intermediate 10- alkoxy-5H-dibenz[ ⁇ j]azepine-5-carbonitrile of formula [XX] in presence of an acid or a base to obtain the product 10-oxo-10,l l-dihydro-5H-dibenz[Z ⁇ /]azepine-5- carboxamide of formula I.

Abstract

Disclosed herein is a process for producing 10-oxo-10,11-dihydro-5H-dibenz[bf ] azepine-5-carboxamide of formula I via novel intermediates 11-alkoxy-10-halo-10,11-dihydro-5H-dibenzo [b,f ] azepine-5-carbonitrile [XIX] or 10-alkoxy-5H-dibenz [b,f] azepine -5-carbonitrile [XX]. Further the present invention also provides a process for preparation of said intermediates.

Description

PROCESS FOR PRODUCING 10-OXO-10 , 11-DIHYDR0-5H-DIBENZ
[B, F] AZEPINE-5-CARBOXAMIDE STARTING FROM δ-CYANOIMINOSTILBENE
Field of the Invention
This invention, in general, relates to a process for producing 10-oxo-10,l l-dihydro- 5H-dibenz[&,/Jazepine-5-carboxamide (Oxcarbazepine). More particularly, the present invention provides an improved process for producing 10-oxo~10,ll-dihydro-5H- dibenz[&j]azepine-5-carboxamide via novel intermediates and process for preparing such intermediates.
^Background of the Invention
Oxcarbazepine is structurally related to carbamazepine (also known as 5H-dibenzo [όj]azepine-5-carboxamide of Formula V). Oxcarbazepine share many chemical and pharmacological properties with carbamazepine. Both are highly lipophilic and neutral at most pH values and both are used mainly for the treatment of partial seizures and generalized tonic-clonic seizures. Oxcarbazepine, however, is often used for patients who are intolerant to carbamazepine treatment. Oxcarbazepine is an anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy and bipolar disorders such as psychosomatic diseases and trigeminal neuralgia. It has also been proposed for use( in the treatment of Parkinsonian syndromes as described in U.S. Pat. No. 5,658,900 and AIDS-related neural disorders as described in WO
94/20110.
Figure imgf000002_0001
[I] A number of processes to prepare oxcarbazepine have been reported in the various prior arts. For example, U.S. Pat. No. 3,642,775 discloses the preparation of oxcarbazepine from 10-methoxy iminostilbene [II] by reaction with phosgene in toluene, followed by amidation (ethanol and ammonia) and hydrolysis in acidic medium to obtain desired product (Scheme 1). Reaction of phosgene with 10-methoxy iminostilbene [II] is carried out at relatively high temperature of around 95°C and the hydrochloric acid produced leads to the formation of undesirablei impurities. The process employs phosgene gas, which is toxic and hazardous, requiring extreme precaution and strict regulations, making this process commercially undesirable.
Figure imgf000003_0001
Scheme 1
Canadian Pat. No. 1,112,241 describes an alternate preparation of oxcarbazepine from the catalyzed re-arrangement of 10, 11-epoxycarbamazepine [VI] which itself is prepared from carbamazepine by reaction with m-chloroperbenzoic acid (m-CPBA) (Scheme 2). The disadvantage of this process is the use of carbamazepine as starting material, which is an expensive raw material, moreover the yield and quality of the epoxide formed from the carbamazepine is very low.
Figure imgf000003_0002
[V] [VI] m
Scheme 2
Another process revealed in European Pat. Appl. No. 028028 involves, the nitration of 5- cyanoiminostilbene [VIII] followed by reduction and hydrolysis (Scheme 3). However, the drawback of the said process is the preparation of the 5- cyanoiminostilbene itself, by reacting iminostilbene [VII] and cyanogen chloride. The latter is also toxic, hazardous and difficult to handle on commercial scale.
Figure imgf000004_0001
Hydrolysis
Figure imgf000004_0003
Figure imgf000004_0002
Scheme 3
U.S. Pat. No. 5,808,058 discloses a process for the preparation of carbamoylation of 10-.methoxyiminostilbene [II] to give 10-methoxycarbamazepine [IV] employing an alkali metal cyanate such as sodium cyanate along with relatively strong organic or inorganic acid, preferably acetic acid. The carbamoylation is followed by hydrolysis of the enol-ether group under mildly acidic aqueous conditions to furnish oxcarbazepine (Scheme 4).
Figure imgf000004_0004
[XI]
Scheme 4 Under the above carbamoylation conditions, a concomitant reaction, hydrolysis of the enol-ether group of 10-methoxyiminostilbene [II] to the corresponding ketone of formula [XI], also occurs. Once formed, the compound of formula [XI] will not undergo further conversion to oxcarbazepine in the presence of the alkali metal cyanate and acid. Consequently, a mixture of products and related impurities are produced which requires a tedious and uneconomical purification procedure, which results in low yields (45% to 65%) of final oxcarbazepine. Also, the purity of the final product is not reported.
Swiss Pat. No. 642,950 describes the synthesis of oxcarbazepine starting from a compound of formula [XII] followed by halogenation, treatment with alkali metal alkoxide and acid hydrolysis (Scheme 5).
Figure imgf000005_0001
Scheme 5
The main drawback of said process is the use of bromine/chlorine gas for the bromination/chlorination step, which is hazardous and is difficult to handle on commercial scale. Moreover, the conversion of [XV] to [XVI] requires deadly toxic phosgene gas.
US Pat. Publ. No. 20050282797 describes the synthesis of oxcarbazepine by reacting oximinostilbene [XI] with chlorosulfonyl isocyanate in an inert organic solvent to give the intermediate of formula [XVIII], which on hydrolysis gives oxcarbazepine [I] (Scheme 6).
Figure imgf000006_0001
Scheme 6
The major drawback of this proςess is that preparation of oximinostilbene [XI]5 which requires harsh conditions and involves a tedious work-up procedure. Moreover, chlorosulfonyl isocyanate is an expensive, highly moisture sensitive and toxic reagent and also the reaction with chlorosulfonyl isocyanate and subsequent hydrolysis requires a relatively complicated isolation procedure and thus gives low yield.
The methods described in the prior art literature have several disadvantages such as low yield, poor quality of the final product, use of hazardous and moisture sensitive reactants such as phosgene, chlorosulphonyl isocyanate which makes the process uneconomical and unviable on commercial scale.
Therefore, there is a need for an improved and industrially feasible process for the preparation of oxcarbazepine, which involves minimum number of reaction steps with higher yield, require less time, highly pure, industrially feasible, cost effective and eco-friendly chemicals.
Summary of the Invention
It is a principal object of the present invention to provide economically viable process for producing lO-oxo-IOjll-dihydro-SH-dibenzf&./Jazepine-S-carboxamide of formula [I], employing cost effective and eco-friendly chemicals.
It is another object of the presentdnvention to provide a process for producing 10-oxo- i
10,l l-dihydro-5H-dibenz[δj]azepine-5-carboxamide of formula I, wherein the process involves minimum number of reaction steps, thereby less time consuming process. The above and other objects afe attained in accordance with the present invention wherein there is provided following embodiments, however the described embodiments hereinafter is in accordance with the best mode of practice and the invention is not restricted to the particular embodiments.
In accordance with a principal embodiment of the present invention, there is provided a process to produce 10-oxo-10,l l-dihydro-5H-dibenz[ό,/Jazepine-5-carboxamide of formula I, wherein the process comprises of preparing novel intermediates to produce said lO-oxo-lOjll-dihydro-rSH-dibenzf^/Jazepine-S-carboxamide of formula I, thereby avoiding the drawback associated with the known arts.
In accordance with another embodiment of the present invention, there is provided a process for producing 10-oxo-10,l l-dihydro-5H-dibenz[δ,y]azepine-5-carboxamide of formula I, wherein said product 10-oxo-10,l l-dihydro-5H-dibenz[fr,/]azepme-5- carboxamide of formula I is achieved via novel intermediates l l-alkoxy-10-halo- 10,l l-dihydro-5H-dibenzo[όj/] azepine-5-carbonitrile of formula [XIX] or 10- alkoxy-5H-dibenz[έj] azepine-5-carbonitrile of formula [XX].
In accordance with one other embodiment of the present invention, there is provided a process for producing 10-oxo-10,l l-dihydro-5H-dibenz[έ,/jazepine-5-carboxamide of formula I, wherein said process comprises of dehydrohalogenation of the intermediate l l-alkoxy-10-halo-10,ll-dihydro-5H-dibenzo[δj/] azepine-5-carbonitrile of formula
[XIX] in presence of a base and optionally in presence of an organic solvent to obtain
10-alkoxy-5H-dibenz[έ,,/J azepine-5-carbonitrile [XX] followed by hydrolysis to produce the product lO-oxo-lOjl l-dihydro-SH-dibenzfø/Jazepine-S-carboxamide of formula I.
In accordance with yet another embodiment of the present invention, there is provided a process for producing 10-oxo-10,l l-dihydro-5H-dibenz[ό,/jazepine-5-carboxamide of formula I, wherein the intermediate 11-alkoxy-l 0-halo- 10,11 -dihydro-5H- dibenzo[έj/] azepine-5-carbonitrile intermediate of formula [XIX] is prepared by alkoxyhalogenating the compound 5/f-dibenz[ό,/]azepine-5-carbonitrile of formula [VIII] in presence of suitable halogenating agent. In accordance with yet another embodiment of the present invention, there is provided a process for producing 10-oxo-10,l l-dihydro-5H-dibenz[&,/|azepine-5-carboxamide of formula I, wherein said process comprises of hydrolyzing the intermediate 10- alkoxy-5H-dibenz[δj]azepine-5-carbonitrile of formula [XX] in presence of an acid or a base to obtain the product 10-oxo-10,l l-dihydro-5H-dibenz[Z\/]azepine-5- carboxamide of formula I.
In accordance with yet another embodiment of the present invention, there is provided a process for producing 10-oxo-10,ll-dihydro-5H-dibenz[δ,/]azepine-5-carboxamide of formula I, wherein the intermediate 10-alkoxy-5H-dibenz[έ,/Jazepine-5- carbonitrile of formula [XX] is prepared by dehydrohalogenating the l l-alkoxy-10- halo-10,l l-dihydro-5H-diberizo[&j/] azepine-5-carbonitrile of formula [XIX] in presence of a base.
In accordance with still another embodiment of the present invention, there is provided a process for producing 10-oxo-10,l l-dihydro-5H-dibenz[έ,/Jazepine-5- carboxamide of formula I via novel intermediate 11-alkoxy-l 0-halo- 10,11 -dihydro- 5H-dibenzo[Z>/| azepine-5-carbonitrile of formula [XIX], wherein said intermediate prepared either by cynating 5H-dibenz[δ,/jazepine of formula [VII] with an suitable cyanating agent or by dehydrating carbamazepine of formula [V] to obtain 5H- dibenz[&,/]azepine-5-carbonitrile of formula [VIII], alkoxyhalogenating the resultant 5H-dibenz[έ,/]azepine-5-carbonitrile of formula [VIII] in presence of a halogenating agent, to obtain intermediate compound of the formula [XIX], which is further used to produce 10-oxo-10,l l~dihydro-5Η-dibenz[&,/jazepine-5-carboxamide of formula I.
In accordance with still another embodiment of the present invention, there is provided a process for producing 10-oxo-10,l l-dihydro-5H-dibenz[Z?,/jazepine-5- carboxamide of formula I via novel intermediate 10-alkoxy-5H-dibenz[έ,/jazepine-5- carbonitrile [XX], wherein said intermediate prepared either by cynating 5Η- dibenz[ό,/jazepine of formula [VII] with an suitable cyanating agent or by dehydrating carbamazepine of formula [V] to obtain 5H-dibenz[&/]azepine-5- carbonitrile of formula [VIII], alkoxyhalogenating the resultant 5H- dibenzfόj] azepine-5-carbonitrile of formula [VIII] in presence of a halogenating agent, to obtain intermediate l l-alkoxy~10-halo-10,l l-dihydro-5H-dibenzo[Z>/] azepine-5-carbonitrile of formula [XIX]5 dehydrohalogenating the resulting compound of formula [XIX] to obtain 10-alkoxy-5H-dibeiiz[&j]azepme-5-carbonitrile [XX], followed by hydrolysis to produce 10-oxo- 10,11 -dihydro-5H- dibenz[δ,/Jazepine-5-carboxamide of formula I.
In accordance with still another embodiment of the present invention, there is provided a process for producing 10-oxo-10,l l-dihydro-5H-dibenz[6/]azepine-5- carboxamide of formula I via novel intermediates, wherein the process comprises of cyanating 5H-dibenz[fr,/jazepine compound of formula [VII] with a suitable cyanating agent or dehydrating 5H-dibenz[5,/]azepine-5-carboxamide compound of formula [V] to obtain 5H-dibeiiz[όj]azepine-5-carbonitrile of formula [VIII], alkoxyhalogenating the 5H-dibenz[δ,/]azepine-5- carbonitrile of formula [VIII] to obtain intermediate 11- alkoxy-10-halo-10,l l-dihydro-5H-dibenzo[&5/] azepine-5-carbonitrile of formula [XEX], dehydrohalogenating the intermediate of formula [XIX] to obtain another intermediate 10-methoxy-5Hτdibenz[Z>,/Jazepine-5-carbonitrile of formula [XX], hydrolyzing the resultant intermediate of formula [XX] to get the pure 10-oxo- 10,11- i dihydro-5H-dibenz[έ,/]azepine-5-carboxamide of formula I.
In accordance with further embodiment of the present invention there is provided a novel intermediate l l-alkoxy-10-halo-10,ll-dihydro-5H-dibenzo[ό/] azepine-5- carbonitrile compound of formula [XIX] used in the preparation of 10-oxo- 10,11- dihydro-5H-dibenz[&,/]azepme-5-carboxamide of formula I, wherein said intermediate is prepared by a process comprises of cyanating 5H-dibenz[&,/]azepine compound of formula [VII] with a suitable cyanating agent or dehydrating 5H- dibenz[£,/jazepme-5-carboxamide compound of formula [V] to obtain 5H- dibenz[ό,/]azepine-5-carbonitrile of formula [VIII], alkoxyhalogenating the 5H- dibenz[&,/jazepine-5-carbonitrile of formula [VIII] to obtain ll-alkoxy-10-halo- 10,ll-dihydro-5H-dibenzo[ό/] azepine-5-carbonitrile compound of formula [XIX].
In accordance with still another embodiment of the present invention, there is provided a novel intermediate 10-alkoxy-5H-diberiz[6,/jazepine-5-carbonitrile compound of formula [XX] used in the preparation of 10-oxo- 10,l l-dihydro-5Η- dibenz[Z>,/jazepine-5-carboxamide of formula I, wherein said intermediate is prepared by a process comprises of dehydrohalogenating l l-alkoxy-10-halo- 10,11- dihydro- 5H-dibenzo[&5/] azepine-5-carbonitrile compound of formula [XIX] to obtain 10- alkoxy-5H-dibenz[όJ]azepine-5-carbonitrile of formula [XX].
Detailed Description of the Invention While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The present invention provides a novel, improved and economical process for the industrial production of oxcarbazepine of formula [I] via novel intermediates such as ll-alkoxy-10-halo-105ll-dihydro-5H-dibenzo[&/l azepine-5-carbonitrile of formula [XIX] and 10-alkoxy-5/f-dibenz[ά,/jazepine-5-carbomtrile [XX].
The process described herein the present invention provides a process for producing 10-oxo-10,ll-dihydro-5H-dibenz[δ,/]azepine-5-carboxamide of formula I represented by the formula [I], comprises of cyanating 5H-dibenz[Z?,/jazepine of formula [VII] with an suitable cyanating agent or by dehydrating 5H-dibenz[fr,/jazepine-5- carboxamide of formula [V], alkoxyhalogenating the resulting 5/f-dibenz[^/]azepine- 5-carbonitrile of formula [VIII] in presence of a halogenating agent to obtain 11- alkoxy-10-halo-10,l l-dihydro-5/f-dibenzo[δ/] azepine-5-carbonitrile of formula [XIX], dehydrohalogenating the resulting compound of formula [XIX] to obtain 10- alkoxy-5H-diberiz[ά,/jazepme-5-carbonitrile of formula [XX] and hydrolyzing the resultant [XX] to get the pure 10-oxo-10,ll-dihydro-5H-dibenz[6,/]azepine-5- carboxamide of formula [I] as shown in Scheme 7.
Figure imgf000011_0001
Scheme 7
wherein R is C1-C3 alkyl chain; and X is Cl, Br, I or F
The halogenating agent used in accordance with the present invention is selected from the group comprising 1,3-dihalo dimethylhydantoin, N-halosuccinimide, N- haloacetamide or 1,3-haloisocyanuric acid, preferably dihalodimethyl hydantoin. The halogenating agent used in the said process is in the molar ratio of 1 :1.2 and 1 :0.4, preferably in the range of 1 :0.5.
The solvent used in the alkoxyhalogenation reaction is selected from lower alcohols such as methanol, ethanol. or propanol alone or a mixture thereof, optional admixture of the lower alcohol with an inert organic solvents such as aromatic hydrocarbons for example benzene, toluene or xylene or a mixture thereof at a temperature of about - 1O0C to 30°C, preferably about 2-200C.
In accordance with one preferred embodiment of the present invention, the novel intermediate compound of formula [XX] is obtained by dehydrohalogenation of compound [XIX] in presence of a base employing suitable organic solvent. Wherein, the suitable organic solvent is selected from halogenated solvents, alcohols, ketones, esters, ethers, amides or aromatic hydrocarbons alone or a mixture thereof. However, the preferable organic solvent is selected from a group of dichloromethane, chloroform, l,2-dichloroethaήe,v methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethyl formamide, dimethyl sulfoxide N,N-dimethylacetamide, N- methylpyrrolidone, toluene, xylene alone or a mixture thereof.
In accordance with another embodiment of the present invention, the dehydrohalogenation of compound [XIX] is carried out at a temperature ranging from room temperature to refluxing temperature. Wherein, the term "room temperature" is defined as an indoor temperature of about 20 to 25° C and the term "refluxing temperature" includes the temperature at which the employed reaction solvent boils out.
In accordance with further embodiment of the present invention is executing the dehydrohalogenation reaction in presence of a base, wherein said base is selected from organic or inorganic bases. The organic base is selected from dialkylamine, trialkylamine, pyridine, l,8-diazabicyclo[2.2.2]octane, l,5-diazabicyclo[4.3.0]non-5- ene, l,8-diazabicyclo[5.4.0]undec-7-ene, N-methyl morpholine, N-methylpiperidine tetramethylguanidine or mixture thereof, preferably triethylamine. The inorganic base is selected from the alkoxides, hydroxides, carbonates or bicarbonate of alkali or alkaline-earth metals or mixture thereof. The alkali metal is selected from a group comprising Li, Na, K, Ca or Mg. The base is taken in the molar ratio of 1 : 1.5 to 1 :2.2, preferably in the range of 1 :2.
The hydrolysis of 10-alkoxy-5H-dibenz [δ,/]azepine-5-carbonitrile intermediate of the formula [XX] is carried out in presence of an suitable acid or base in accordance with one preferred embodiment of the present invention, wherein the preferred acid is selected from mineral acids, lower alkane or halogenated lower alkanecarboxylic acids having up to 4 carbon atoms preferably sulfuric acid, polyphosphoric acid, acetic acid or trichloro or trifluoroacetic acid alone or in combination thereof. The preferred base employed in this reaction is selected from alkoxides, hydroxides, carbonates or bicarbonate of alkali or alkaline earth metals alone or in combination thereof. Wherein, the said alkali or alkaline earth metal is preferably selected from Li, Na, K, Ca or Mg. According to the present invention, wherein the hydrolysis of the intermediate of formula [XX] is carried out by optionally employing an aromatic hydrocarbon at a temperature of about -15° to 4O0C, preferably -5° to 3O0C.
The starting material 5H-dibeiiz[όj]azepine-5-carbonitrile of formula [VIII] according to the process of present invention is obtained either by cyanating 5H- dibenz[ό,/]azepine of formula [VII] with a suitable cyanating reagent or by dehydrating the 5H-diberiz[όjf7azepine-5-carboxamide of formula [V] in presence of dehydrating agent selected from P2O5, POCl3 or SOCl2. The starting material of formula [VIII] can also be prepared by dehydration of formula [V] as disclosed in the prior art.
The process may performed by isolation and optional purification of the novel intermediates of compounds 6f formula [XIX] and [XX] in their proceeding reaction steps or employing the crude novel intermediates without purifying, to enable the successive reaction steps in order to obtain pure 10-oxo-10,ll-dihydro-5H- dibenz[ό,/jazepme-5-carboxamide of formula [I].
The invention is further illustrated but not restricted by the description in the following examples. It should be understood that variation and modification in the process are possible within the ambit of the invention broadly disclosed herein.
Example 1
Preparation of 5H-dibenz[Z>,/1azepine-5-carbonitrile (VIID
To a solution of carbamazepine (100 g, 0.423 mole) in dichloromethane and chloroform, benzyltriethylammonium chloride (4.82 g, 0.021 mole) was added. The resulting mixture was heated up to 40-500C. A hot sodium hydroxide solution (80%, 180 ml) was added under stirring for 5-6 h at 45-5O0C. The resulting solution was diluted with water, stirred at 45-5O0C and then cooled to 30-350C. The organic layer was separated, washed with water and concentrated. Methanol (50 ml) was added to the resulting mixture and was heated up to 60-650C. The resulting mixture was cooled to 15-25°C over a period of one hour. The solid was filtered, washed with chilled methanol and dried to yield 5H-dibenz[έ,/]azepine-5-carbonitrile as title compound.
Example 2
Preparation of 5H-dibenz[6,/1azepme-5-carbonitrile (VIID
A mixture of 5Η-dibenz[ό,/]azepine (100 g, 0.5181 moles), cyanogen bromide (60.4 g) and hexamethylphosphoric triamide (18 ml) was taken in 1,2-dichloroethane (400 ml) and was heated up to 40-500C for 7-8 h. The resulting mixture was cooled; water (200 ml) was added and was stirred for one hour. Sodium hydroxide solution (20%) was added to the resulting mixture. The organic layer was separated off and washed with water. The organic layer was dried over sodium sulfate and concentrated. The resulting residue was taken up in isopropanol and was stirred for 2 h. The resulting solid was filtered off, washed with isopropanol to obtain 5i/-dibenz[ό,/Jazepine-5- carbonitrile as title compound.
Example 3
Preparation of 10-bromo-ll-methoxy-10,ll-dihydro-5H-dibenz[6,f] azepine-5- carbonitrile (XIX) 5H-dibenz[^/]azepine-5-carbonitrile (100 g, 0.458 mole) was suspended in methanol and the mixture was cooled to 0-100C. l,3-dibromo-5,5-dimethylhydantoin (68.1 g, 0.238 mole) was added to the resulting mixture under stirring for 5-6 h. The reaction mixture was filtered, washed with chilled methanol and dried to obtain 10-bromo-l l- methoxy-10,l l-dihydro-5H-dibenz[&,/j azepine-5-carbonitrile as title compound. IR (KBr, cm4): 3066, 2987, 2928, 2217, 1734, 1602, 1592, 1578, 1492,1445,1380, 1343, 1292, 1250, 1236, 1212, 1089, 952, 925, 850, 773, 757, 740, 681, 658, 635, 524.
1H NMR (400MHz5 CDCl3, δ, ppm): 3.47 (s, 3H, -OCH3), 4.95 (d, IH, JK7.2 Hz, - CHOMe), 5.23 (d, IH, J= 7.2 Hz, -CHBr), 7.21 (m, IH), 7.35 (m, 2H), 7.42 (m, IH), 7.47 (m, 2H), 7.60 (m, IH).
ES (m/e): 329 and 331 (M+H)+, 351 and 353 (M+ Na)+ Example 4
Preparation of 10-methoxy-5H-dibenz[ft,/]azepine-5-carboriitrile (XK) A mixture of 10-bromo-ll-methoxy-10,ll-dihydro-5H-dibenz[ό,/] azepine-5- carbonitrile (100 g, 0.3037 mole), triethylamine (84.6 ml) and methyl ethyl ketone (500 ml) was taken and heated to reflux for 24-26 h. The reaction mixture was filtered and the solid was washed with methyl ethyl ketone. The filtrate was washed with water and organic layer was concentrated by distillation. Isopropyl alcohol was added to the resulting residue and was heated to 80-850C under stirring for one hour. The resulting solution was cooled' up to 10-150C and the solid was filtered off, washed with chilled isopropyl alcohol and dried to obtain 10-methoxy-5H-dibenz[Z?,/Jazepine- 5-carbonitrile as title compound.
IR (KBr, cm"1): 3461, 3052, 2098, 2825, 2219, 1636, 1600, 1581, 1492,1440,1388, 1303, 1290, 1259, 1250, 1.226, 1206, 1135, 1100, 981, 939, 815, 752, 635, 556. 1H NMR (400MHz, CDCl3, ppm): 3.91 (s, 3H, -OCH3), 6.04 (s, IH, -CHOMe), 7.20- 7.33 (m, 4H), 7.43-7.52 (m, 3H), 7.6(dd, IH, J=8.0, 1.2 Hz). ES (m/e): 249 (M+H)+
Example 5
Preparation of 10-oxo-10,l l-dihγdro-5H"-dibenz("Z>,/1azepine-5-carboxamide [I] 10-memoxy-5H-dibenκ[&,/Jazepme-5-carbomtrile (100 g, 0.4032 mole) was taken in acetic acid (600 ml) at room temperature. To the resulting mixture, sulfuric acid (150 ml) was added within 5-10 minutes under stirring. The resulting reaction mixture was added to the cold water under vigorous stirring. The solid was precipitated, which was filtered, washed with water and dried at 60-65°C for 15-16 h, to obtain crude 10-oxo- 10Jl-dihydro-5H-dibenz[&j]azepine-5-carboxamide. The resulting compound was taken in methanol and the pH of the reaction mixture was maintained in the range of 7-8. The reaction mixture was heated to reflux at 65-70°C for 2 h under stirring and then cooled, filtered, washed. with methanol and dried to give title compound [I]. The resulting semi pure oxcarbaz^pine was further purified by treating the resulting y compound taken in a mixture of methanol and dichloromethanol, and was heated. The reaction mixture was filtered through Hyflo bed, washed with methanol and dichloromethane mixture (1:1). The solvent was distilled off partially and the resulting mixture was cooled to precipitate the solid. The solid was filtered, washed with methanol and dried under vacuum at 50-60°C to give pure title compound.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention, which is limited only by the appended claims.

Claims

We Claim:
1. A process for producing 10-oxo-l 0, 11 -dihydro-5H-dibenz[&,/]azepine-
5-carboxamide of formula [I]5
Figure imgf000017_0001
via novel intermediates of formula [XIX] and [XX];
Figure imgf000017_0002
the process comprising:
(a) alkoxyhalogenating the 5//-dibenz[&,/]azepine-5- carbonitrile of formula [VIII] to obtain l l-alkoxy-10-halo- 10,11 - dihydro-5H-dibenzo[ό/l azepine-5-carbonitrile compound of formula
[XIX],
Figure imgf000017_0003
rviir [XIX]
wherein R is C1-C3 alkyl chain and X is Cl, Br, I or F;
(b) dehydrohalogenating the l l-alkoxy-10-halo-10,l l- dihydro-5/i-dibenzo[δj/] azepine-5-carbonitrile compound of the formula [XIX] to obtain 10-methoxy-5//-dibenz[£,/jazepine-5- carbonitrile of formula [XX],
Figure imgf000018_0001
[XIX] [XX] wherein R is C1-C3 alkyl chain and X is Cl, Br, I or F; and
(c) hydrolyzing the resultant compound [XX] to get the pure 10-oxo-10,ll-dihydro-5H-dibenz[&,/Jazepine-5-carboxamide of formula [I]. ^
2. The process according to claim 1, wherein the alkoxyhalogenation reaction is carried out in presence of halogenating agent.
3. The process according to claim 2, wherein the halogenating agent is selected from the group comprising 1,3-dihalo-dimethylhydantoin, N- halosuccinimide, N-haloacetamide and 1,3-haloisocyanuric acid, alone or in combination thereof.
4. The process according to claim 1, wherein the alkoxyhalogenation reaction is carried out in presence of an organic solvent.
5. The process according to claim 4, wherein the organic solvent is selected from lower alcohols.
6. The process according to claim 5, wherein the lower alcohol is selected from a group comprising methanol, ethanol and propanol, alone or in combination thereof.
7. The process according to claim 1, wherein the dehydrohalogenation reaction is carried out in presence of an organic or inorganic base.
8. The process accofding to claim 7, wherein the organic base is selected from diethylamine, triethylamine, pyridine, 1,8-diazabicyclo [2.2.2] octane, 1,5- diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methyl morpholine, N-methylpiperidine, or tetramethylguanidine alone or a mixture thereof.
9. The process according to claim 7, wherein the inorganic base is selected from alkali or alkaline earth metal alkoxides, hydroxides, carbonates or bicarbonates or mixture thereof.
10. The process according to claim 9, wherein the alkali or alkaline earth metal is selected from lithium, sodium, potassium, calcium or magnesium.
11. The process according to claim 1, wherein the hydrolysis is carried out in presence of acid or base'.
12. A process according to claim I5 wherein 5H~dibenz[Z\/]azepine-5- carbonitrile of formula [VIII] is prepared by a process comprising:
cy anating 5H-dibenz[δ,/J azepine compound of formula [VII] ;
Figure imgf000019_0001
[VII] [VHIl with a suitable cyanating agent.
13. A process according to claim 1, wherein 5H-dibenz[&,/jazepine-5- carbonitrile of formula [VIII] is prepared by a process comprising:
dehydrating 5H-dibenz[Z>,/]azepine-5-carboxamide compound of formula [V];
Figure imgf000019_0002
in presence of any suitable dehydrating agent.
14. A novel intermediate 11-alkoxy-l O-halo- 10,11 -dih.ydro-5.H- dibenzo[δj/] azepine-5-carbonitrile of formula [XIX] used in the preparation of 10- oxo- 10,11 -dihydro-5Η-dibenz[δ,/J azepine-5-carboxamide;
Figure imgf000020_0001
wherein R is C1-C3 alkyl chain; and X is Cl, Br, I or F.
15. A process for preparing a novel intermediate, 11-alkoxy-l 0-halo- 10,l l-dihydro-5.H-dibenzo[&(/] azepine-5-carbonitrile of formula [XIX] used in the preparation of 10-oxo-10,l l-dihydro-5Η-dibenz[&j]azepine-5-carboxamide of formula [I];
Figure imgf000020_0002
wherein R is C1-C3 alkyl chain and X is Cl, Br, I or F; the process comprising;
(a) cyanating 5H-dibenz[Z>,/jazepine compound of formula [VII]
Figure imgf000020_0003
[VII]
with a suitable cyanating agent to obtain 5H-dibenz[ό,/]azepine-5- carbonitrile of formula [VIII]
Figure imgf000021_0001
(b) alkoxyhalogenating the 5H-dibenz[έ,/]azepme-5- carbonitrile of formula [VIII] to obtain ll-alkoxy-10-halo- 10,11- dihydro-5H-dibenzo[δ/J azepine-5-carbonitrile compound of formula [XIX].
16. The process according to claim 15, wherein the alkoxyhalogenation reaction is carried out in presence of halogenating agent.
17. The process according to claim 16, wherein the halogenating agent is selected from the group comprising 1,3-dihalo-dimethylhydantoin, N- halosuccinimide, N-haloacetamide or 1,3-haloisocyanuric acid.
18. The process according to claim 15, wherein the alkoxyhalogenation reaction is carried out in presence of an organic solvent.
19. The process according to claim 18, wherein the organic solvent is selected from lower alcohols.
20. A process .for preparing a novel intermediate, ll-alkoxy-10-halo- 10,ll-dihydro-5H-dibenzo[6/] azepine-5-carbonitrile of formula [XIX] used in the preparation of 10-oxo-10,ll-dihydro-5Η-dibenz[ό,/]azepine-5-carboxamide of formula [I];
Figure imgf000021_0002
[XIX] wherein R is C1-C3 alkyl chain and X is Cl, Br, I or F; the process comprising;
(a) dehydrating 5H-dibenz[&Λ/]azepine-5- carboxamide compound of formula [V]
Figure imgf000022_0001
[V] with a suitable dehydrating agent to obtain 5/i-dibenz[Z>,/]azepine-5- carbonitrile of formula [VIII]
Figure imgf000022_0002
[VHU ; and
(b) , alkoxyhalogenating the 5H-dibenz[δ,/]azepine-5- carbonitrile of formula [VIII] to obtain l l-alkoxy-10-halo-10,l l- dihydro-5H-dibenzo[5/] azepine-5-carbonitrile compound of formula [XIX].
21. The process according to claim 20, wherein said dehydrating agent is selected from group comprising P2O5 or POCl3 or SOCl2 or a mixture thereof.
22. The process according to claim 20, wherein the alkoxyhalogenation reaction is carried out in presence of halogenating agent.
23. The process according to claim 22, wherein said halogenating agent is selected from the group comprising 1,3-dihalo-dimethylhydantoin, N- halosuccinimide, N-haloacetamide or 1,3-haloisocyanuric acid.
24. The process according to claim 20, wherein the alkoxyhalogenation reaction is carried out in presence of an organic solvent.
25. The process according to claim 24, wherein the organic solvent is selected from lower alcohols.
26. A novel intermediate 10-alkoxy-5H-dibenz[&,/jazepine-5-carbonitrile compound of formula [XX] used in the preparation of 10-oxo-10,ll-dihydro-5H- dibenz[£,/j azepine-5-carboxamide;
Figure imgf000023_0001
[XX] wherein, R is C1-C3 alkyl chain
27. A process for preparing a novel intermediate, 10-alkoxy-5H- dibenz[έ,/]azepine-5-carbonitrile compound of formula [XX] used in the preparation of lO-oxo-10,1 l-dihydro-5H-dibeiiz[έj]azepine-5-carboxamide of formula [I];
Figure imgf000023_0002
[XX] wherein, R is C1-C3 alkyl chain; the process comprising; (a) dehydrohalogenating 11-alkoxy-l 0-halo-l 0,11- dihydro-5/f-dibenzo[&/] azepine-5-carbonitrile compound of formula [XIX];
Figure imgf000023_0003
[XIX] wherein, R is C1-C3 alkyl chain and X is Cl, Br5 1 or F.
28. A process for preparing a novel intermediate, 10-alkoxy-5iy~ dibenz[δ,/|azepme-5-carbonitrile compound of formula [XX] used in the preparation of lO-oxo-10,1 l-dihydro-5H-dibenz[&,/]azepine-5-carboxamide of formula [I];
Figure imgf000024_0001
[XX] wherein, R is C1-C3 alkyl chain; the process comprising;
(a) cyanating 5H-dibenz[ό,/jazepine compound of formula [VII]
Figure imgf000024_0002
[VII]
with a suitable cyanating agent to obtain 5H-dibenz[ά,/jazepine-5- carbonitrile of formula [VIII]
Figure imgf000024_0003
[vπi]
(b) alkoxyhalogenating the 5H-dibenz[δ,/]azepme-5- carbonitrile of formula [VIII] to obtain 11-alkoxy- 10-halo-l O5I l- dihydro-5/f-dibenzo[ό,/] azepine-5-carbonitrile compound of formula
[XIX];
Figure imgf000025_0001
wherein, R is C1-C3 alkyl chain and X is Cl, Br, I or F; and
(c) dehydrohalogenating 11 -alkoxy- 10-halo- 10,11- dihydro-5H-dibenzo[ό/j azepine-5-carbonitrile compound of formula [XIX] to obtain the intermediate, 10-alkoxy-5H-dibenz[Z>j]azepine-5- carbonitrile compound of formula [XX].
29. A process for preparing a novel intermediate, 10-alkoxy-5H- dibenz[ό,/]azepine-5-carbonitrile of formula [XX] used in the preparation of 10-oxo- 10,l l-dihydro-5H-dibenz[δ,/]azepine-5-carboxamide of formula [I];
Figure imgf000025_0002
[XX] wherein, R is C1-C3 alkyl chain; the process comprising;
(a) , dehydrating 5H-dϊbenz[ό,/j azepine -5-carboxamide compound of formula [V]
Figure imgf000025_0003
with a suitable dehydrating agent to obtain 5H-dibenz[&,/]azepme-5- carbonitrile of formula [VIII];
Figure imgf000025_0004
[VIII] (b) alkoxyhalogenating the 5H-dibenz[Z>,/]azepme-5- carbonitrile of formula [VIII] to obtain 1 l-alkoxy-10-halo- 10,11- dihydro-5H-dibenzo[Z>j/] azepine-5-carbonitrile compound of formula
[XiX];
Figure imgf000026_0001
[XIX] wherein, R is C1-C3 alkyl chain and X is Cl, Br, I or F; and
(c) dehydrohalogenating 11 -alkoxy- 10-halo- 10,11- dihydro-5/f-dibenzo[&/] azepine-5-carbonitrile compound of formula [XIX] to obtain the intermediate, 10-alkoxy-5H-dibenz[δ,/Jazepine-5- carbonitrile compound of formula [XX].
30. The process according to any of claims 27, 28 or 29, wherein the dehydrohalogenation reaction is carried out in presence of an organic or inorganic base.
31. The process according to claim 30, wherein the organic base is selected from diethylamine, triethylamine, pyridine, l,8-diazabicyclo[2.2.2]octane, 1,5- diazabicyclo[4.3.0]non-5-ene, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, N-methyl morpholine, N-methylpiperidine, tetramethylguanidine alone or a mixture thereof.
32. The process according to claim 30, wherein the inorganic base is selected from alkali or alkaline earth metal alkoxides, hydroxides, carbonates bicarbonates or mixture thereof.
33. The process according to claim 32, wherein the alkali or alkaline earth metal is selected from lithium, sodium, potassium, calcium or magnesium.
34. The process according to any of claims 28 or 29, wherein the alkoxyhalogenation reaction is carried out in presence of halogenating agent.
35. The process according to claim 34, wherein said halogenating agent is selected from the group comprising 1,3-dihalo-dimethylhydantoin, N- halosuccinimide, N-haloacetamide or 1,3-haloisocyanuric acid.
36. The process according to any of claims 28 or 29, wherein the s alkoxyhalogenation reaction is carried out in presence of an organic solvent.
37. The process according to claim 36, wherein the organic solvent is selected from lower alcohols.
38. The process 'according to claim 29, wherein said dehydrating agent is selected from group comprisirig P2O5 or POCl3 or SOCl2 or a mixture thereof.
PCT/IN2007/000307 2006-07-24 2007-07-24 Process for producing 10-oxo-l10, 11-dihydr0-5h-dibenz [b, f] azepine-5-carboxamide starting from 5-cyanoiminostilbene WO2008012837A1 (en)

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WO2010000197A1 (en) 2008-07-04 2010-01-07 浙江工业大学 A method for preparing 5h-cyano-imido stilbene
WO2013008194A2 (en) 2011-07-13 2013-01-17 Ranbaxy Laboratories Limited Process for the preparation and purification of eslicarbazepine acetate and intermediates thereof
CN103342654A (en) * 2013-07-02 2013-10-09 扬州大学 Novel method for hydrolyzing nitrile group to acylamino
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WO2013008194A2 (en) 2011-07-13 2013-01-17 Ranbaxy Laboratories Limited Process for the preparation and purification of eslicarbazepine acetate and intermediates thereof
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CN103342654A (en) * 2013-07-02 2013-10-09 扬州大学 Novel method for hydrolyzing nitrile group to acylamino

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