DESC:FIELD OF THE INVENTION
The present invention discloses a commercially viable, cost effective and energy efficient process for the preparation of carbamazepine, oxcarbazepine or imipramine and intermediates thereof. Specifically, the present invention provides a process for preparation of acetyl iminostilbene and/or iminostilbene via application of continuous flow technology in high purity and yield.

BACKGROUND OF THE INVENTION
Iminostilbene (I), chemically 5H-dibenzo [b,f] azepine, is an intermediate in synthesis of antiepileptic drugs Carbamazepine (II), Oxcarbazepine (III) and Imipramine (IV). Iminostilbene is also an important synthetic material for genetically engineering and materialogy. It can be used as the synthetic raw material for porphyrins.

The prior arts disclose different conventional chemical processes for producing 5H-dibenzo [b,f] azepine (Iminostilbene). One of the processes is a multistep process for producing iminostilbene from iminodibenzyl by acylation, bromination, dehydrobromination and dealkylation. Also, this process is laborious and involves formation of byproducts, which adversely affects the production capacity.
One other route for the synthesis of 5H-dibenzo [b,f] azepine starts from ortho nitro toluene as starting material and involves seven steps reaction such as condensation, reduction and cyclization. This route is not only complicated, tediously long, costly, pollute heavily but its productive rate is also low. Therefore, a synthetic route for its synthesis in easy steps which is cost effective and show high productivity is required.
United States Patent No. US3531466 discloses catalytic dehydrogenation of Iminodibenzyl, chemically 10,11-dihydro-5H-dibenzo [b,f] azepine in presence of non-noble metals from iron, nickel, chromium or alloy skeleton at temperature range between 300-700°C in vapor phase to obtain Iminostilbene in good yields ranging from 60-80%. The reaction conversion is disclosed by gas chromatography and pure Iminostilbene is obtained either by distillation of product or recrystallization. This procedure requires very high temperature and difficult operations like distillation and recrystallization to obtain pure Iminostilbene. Also, metal catalysts chosen from non-noble metals increase potential environmental hazards for the environment. Reaction time disclosed for complete conversion also ranges from 1.5 hours to 12 hours. The process disclosed is not feasible for industrial production as the reaction time is too long and reaction temperature required is too high, which results in a lot of energy consumption and further the process fails in providing Iminostilbene directly without purification to remove related impurities.
United States Patent No. US3074931 and J. Org. Chem, 26, 136-138 discloses catalytic dehydrogenation of iminodibenzyl in presence of noble metals like sulfur and selenium in elemental form and palladium-carbon. According to one of the examples disclosed in process, the catalytic hydrogenation is carried out in Pd/C at 160-170°C and only 20-30% Iminodibenzyl is converted. Reaction mass is collected into three different fractions. First fraction contains pure Iminostilbene. Iminostilbene can be isolated from second fraction after crystallization from ethanol. Third fraction which contains major unreacted Iminodibenzyl again undergone dehydrogenation which yields in 50% conversion and 50% loss of material. Further, as per the given process iminodibenzyl is passed through the column (ID-0.5 mm) by heating until sublimation occurs on the top portion of the column and the yellow sublimate is removed by scratching. The catalyst used in this process is very costly and this sublimation technology is unattractive for commercial exploitation.
United States Patent No. US5895815 to Eichberger et al., discloses production of iminostilbene from iminodibenzyl in liquid phase using o-nitrotoluene as reaction solvent and Pd/C as catalyst. Catalysts used in these processes are very costly and solvents used are highly toxic and hazardous. Thus, iminostilbene obtained by this process consists of a large number of impurities mainly acridine and methylacridine and toluidine, which are difficult to remove economically and thus adversely affect the purity of carbamazepine produced thereafter.
Japanese Patent No. 55-017330 to Hidemitsu, discloses the production of iminostilbene from iminodibenzyl through single step catalytic dehydrogenation in vapor phase using a catalyst comprising an oxide of Ce, Mn, Sn or Mg and the reaction is carried out at a temperature of 350-650°C.
European Patent No. EP 0570336 to Milos et al., discloses the production of iminostilbene by high temperature dehydration of iminodibenzyl, using catalyst containing Fe2O3, K2O and Cr2O3.
United States Patent No. US3449324 to Basel, et al., discloses a catalyst containing Fe2O3, CaO, K2O and Cr2O3 for the production of iminostilbene.
British Patent No. GB 1077648, assigned to Degussa, discloses a catalyst containing nickel loaded on kieselguhr for the production of iminostilbene in vapor phase. The reported yield is approximately 45% at 600°C. The high reaction temperature may be the cause for low yield of iminostilbene. Moreover, high reaction temperature in this reference is fairly unattractive for commercial exploitation.
The processes disclosed in the above-mentioned prior arts consist of various disadvantages, like multi step and laborious processes and high demand on production capacity. For minimizing process steps, catalysts are used, which are very costly, and the major drawback of the processes is the formation of undesired byproducts, which decreases the yield and selectivity of Iminostilbene.
Thus, there exists a need in the art of development of an industrially feasible, cost effective, economic and simple process capable of controlling the impurities, for producing iminostilbene with high purity and high yield.
Accordingly, as an alternative to the prior art methods, in the present invention improved conditions have been optimized for the synthesis of iminostilbene by application of continuous flow reactor technology. The process has distinct advantages in regard to cycle time, energy consumption, and product purity over traditional methods known in art.
OBJECTS OF THE INVENTION
The principal object of the present invention is to provide an improved and efficient process for the preparation of iminostilbene which is simple, economic and alleviates one or more problems of the prior art disclosed processes.
An another object of the present invention is to provide an improved process for the preparation of acetyl iminostilbene and/or iminostilbene.
Yet another object of the present invention is to overcome or alleviate at least one of the deficiencies of prior art and provides useful alternative for the preparation of N-protected iminostilbene and/or iminostilbene.
It is yet another object of the present invention to overcome or alleviate at least one of the deficiencies of prior art and provide a useful alternative for the preparation of carbamazepine, oxcarbazepine and/or imipramine involving use of N-protected iminostilbene and/or iminostilbene, prepared according to the process of current invention.
An another object of the present invention is to provide a process for preparation of iminostilbene, which involves dehydrogenation reaction of a solution of acetyliminodibenzyl and sulfur flakes in a continuous flow reactor.
It is yet another object of the present invention to provide a process for preparation of iminostilbene, which involves dehydrogenation reaction of a solution of acetyliminodibenzyl and sulfur flakes in therminol solvent in a continuous flow reactor.
It is another object of the present invention to provide a process for preparation of iminostilbene, which involves one pot process for the preparation of iminostilbene starting from iminodibenzyl to iminostilbene wherein dehydrogenation of acetyliminodibenzyl is carried out using sulfur flakes in a continuous flow reactor.
It is yet another object of the present invention to provide a cost effective and industrially feasible process for producing iminostilbene, wherein the process provides high yield and high purity of the desired product by reducing the formation of impurity, in consistent and reproducible manner.
In yet another object the present invention provides process for the preparation of iminostilbene in high yield and purity, which devoid of dimer impurities of formula V and formula VI.

SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided an efficient and cost effective process for the preparation of acetyl iminostilbene and/or iminostilbene, which involves dehydrogenation reaction of a solution of acetyliminodibenzyl and sulfur flakes in a continuous flow reactor.
In an embodiment, the present invention relates to a process for the preparation of iminostilbene (I) comprising the steps of:
(i) providing a solution of N-protected iminodibenzyl (VIII) and sulfur flakes;
(ii) dehydrogenation of the solution of step (i) in a continuous flow reactor to obtain N-protected iminostilbene (IX); and
(iii) deprotection of N-protected acetyliminostilbene (IX) to obtain iminostilbene (I).
In an embodiment, the present invention relates to a process for the preparation of iminostilbene comprising the steps of:
(i) providing a solution of acetyliminodibenzyl and sulfur flakes;
(ii) dehydrogenation of the solution of step (i) in a continuous flow reactor to obtain acetyliminostilbene; and
(iii) deprotection of acetyl group of acetyliminostilbene to obtain iminostilbene.

In an another embodiment, the present invention relates to a process for the preparation of iminostilbene comprising the steps of:
(i) acetylation of Iminodibenzyl to obtain acetyliminodibenzyl;
(ii) providing a solution of acetyliminodibenzyl and sulfur flakes;
(iii) dehydrogenation of the solution of step (ii) in a continuous flow reactor to obtain acetyliminostilbene;
(iv) deprotection of acetyl group of acetyliminostilbene to obtain iminostilbene; and
(v) optionally, crystallization of crude iminostilbene to obtain pure iminostilbene.

In an embodiment, the present invention relates to a process for the preparation of iminostilbene comprising the steps of:
(i) acetylation of Iminodibenzyl by refluxing in acetic anhydride and then distillation of solvent to obtain acetyliminodibenzyl;
(ii) providing a solution of acetyliminodibenzyl and sulfur flakes in therminol solvent at 100°C;
(iii) dehydrogenation reaction by feeding solution of step (ii) to a continuous flow reactor to obtain acetyliminostilbene;
(iv) deprotection of acetyl group by hydrolysis of acetyliminostilbene to obtain crude iminostilbene; and
(v) optionally, crystallization of crude iminostilbene to obtain pure iminostilbene.

It is another object of the present invention to provide a process for preparation of iminostilbene, which involves one pot process for the preparation of iminostilbene starting from iminodibenzyl to iminostilbene wherein dehydrogenation of acetyliminodibenzyl is carried out using sulfur flakes in a continuous flow reactor.
In an embodiment, the present invention provides process of preparation of iminostilbene in high yield and purity, which devoid of below mentioned impurities of formula V and formula VI

wherein content of each impurity is less than 0.05%.

In yet another embodiment, the present invention provides for the preparation of carbamazepine, oxcarbazepine and/or imipramine involving use of acetyl iminostilbene and/or iminostilbene, prepared according to the process of current invention.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for producing 5H-Dibenzo-(b,f)-azepine (iminostilbene) employing the use of acetyliminodibenzyl and sulfur flakes in a continuous flow reactor, which prevents the formation of byproducts and provides good yield and selectivity for iminostilbene.
Chemical reactors are vessels, wherein chemical reactions are carried out and their performance determines the reliability and suitability of a process, its environment safety, consumption of energy and the raw materials. A continuous reactor is a reactor, where there are no moving parts other than pumps that deliver the reactants. To achieve efficient mixing of reactants the addition of static mixing elements such as glass beads inside the reactor is done that provides ideal conditions of radial mixing and continuous flow necessary to perform reactions. One such example is plug flow reactor. In a plug flow reactor, the flow of reactants pumped in the reactor is laminar and the properties of the reaction medium i.e. pressure, temperature, reactant and product concentrations are the same throughout the entire cross section flow. Further, all the elemental volumes of the reaction medium remain in the reactor for the same period of time, and the change in concentration, temperature and pressure with the time are identical for each elemental volume. Plug flow reactors usually operate in adiabatic and non-isothermal conditions. Consequently, from the standpoint of kinetic parameters of a chemical reaction under isothermal conditions, plug flow reactors are more efficient than stirred tank reactors.
The present invention provides an improved method for the preparation of iminostilbene using a continuous reactor. The process has distinct advantages in regard to cycle time, energy consumption, yield and product purity over traditional methods. The process employs application of continuous reactor technology for the preparation of desired product in high yield and high purity with enhanced in-process control on impurities with shorter reaction time.
In an embodiment, the present invention relates to a process for the preparation of iminostilbene comprising the steps of:
(i) providing a solution of N-protected iminodibenzyl (VIII) and sulfur flakes;
(ii) dehydrogenation of the solution of step (i) in a continuous flow reactor to obtain N-protected iminostilbene (IX); and
(iii) deprotection of N-protected acetyliminostilbene (IX) to obtain iminostilbene (I).
Wherein R in compound formula VIII and IX is any alkyl group from C1-C6 carbon atoms.

In yet another embodiment, the present invention relates to a process for the preparation of iminostilbene comprising the steps of:
(i) providing a solution of acetyliminodibenzyl (VIIIa) and sulfur flakes;
(ii) dehydrogenation of the solution of step (i) in a continuous flow reactor to obtain acetyliminostilbene (IXa); and
(iii) deprotection of acetyl group of acetyliminostilbene (IXa) to obtain iminostilbene (I).
In an another embodiment, the present invention relates to a process for the preparation of iminostilbene (I) comprising the steps of:
(i) acetylation of Iminodibenzyl (VII) to obtain acetyliminodibenzyl (VIIIa);
(ii) providing a solution of acetyliminodibenzyl (VIIIa) and sulfur flakes;
(iii) dehydrogenation of the solution of step (ii) in a continuous flow reactor to obtain acetyliminostilbene (IXa);
(iv) deprotection of acetyl group of acetyliminostilbene to obtain iminostilbene (I); and
(v) optionally, crystallization of crude iminostilbene to obtain pure iminostilbene.
In an embodiment, the present invention relates to a process for the preparation of iminostilbene (I) comprising the steps of:
(i) acetylation of Iminodibenzyl (VII) by refluxing in acetic anhydride and then distillation of solvent to obtain acetyliminodibenzyl (VIIIa);
(ii) providing a solution of acetyliminodibenzyl (VIIIa) and sulfur flakes in therminol solvent at 100°C;
(iii) dehydrogenation reaction by feeding solution of step (ii) to a continuous flow reactor to obtain acetyliminostilbene (IXa);
(iv) deprotection of acetyl group by hydrolysis of acetyliminostilbene to obtain crude iminostilbene (I); and
(v) optionally, crystallization of crude iminostilbene to obtain pure iminostilbene.
It is another object of the present invention to provide a process for preparation of iminostilbene, which involves one pot process for the preparation of iminostilbene starting from iminodibenzyl to iminostilbene wherein dehydrogenation of N-protected iminodibenzyl (VIIIa) is carried out using sulfur flakes in a continuous flow reactor.

Scheme 1
In yet another embodiment, the present invention provides for the preparation of carbamazepine, oxcarbazepine and/or imipramine involving use of acetyl iminostilbene and/or iminostilbene, prepared according to the process of current invention.
According to the present invention, the acetylation of iminodibenzyl is performed using acetic anhydride both as solvent and acetylation reagent. The reaction is carried out at reflux temperature of 140°C for about 5-10 hours. The acetic anhydride used in process is about 1.1 to about 1.5 equivalents for complete acetylation. Mixture of acetic acid and acetic anhydride was distilled under vacuum at temperature below 120°C to obtain acetyliminodibenzyl with more than 99% conversion and almost about 100% yield. Residue obtained on distillation is oily which becomes solid on cooling to room temperature. Purity of the residue acetyliminodibenzyl is more than 99%.
According to the present invention, a solution of acetylaminodibenzyl, sulphur flakes was prepared in therminol at 100°C in a reactor. The dehydrogenation reaction is carried out by feeding the solution prepared above at the flow rate of about 10-18 mL/min at temperature of about 320-330°C to a continuous flow reactor. The self-generated internal pressure is recorded 15-25 Kg/cm2. The continuous flow reactor used is selected from the group comprising of plug flow reactor and the like. In order to obtain a temperature of 320-330°C, coil reactor tube was kept inside a muffle furnace. The heating capacity of muffle furnace is controlled by electronic thermal controller and the system is thermally isolated by glass wool jacket. The reaction is optionally carried out under inert atmosphere or under an inert gas stream at 320-330°C for enhanced safety of the reactor system. Examples of the inert gas include nitrogen, helium, neon, argon and the like.
The residence time necessary in the method according to the invention, depends on various parameters such as, the temperature and reactivity of the starting materials. The term “residence time” refers to the interval volume of the reaction zone within the continuous reactor occupied by the reactant fluid flowing through the space, at the temperature and pressure being used. The residence time is from about 1 minute to about 20 minutes.
After the reaction is complete, the solvent is cooled to 150°C and solvent was removed by distillation under vacuum. The remaining residue acetyliminostilbene is hydrolysed in KOH flakes and n-Butanol solvent at reflux temperature of 115°C for about 7 hours to obtain more than 90% conversion of acetyliminostilbene to imninostilbene. After the hydrolysis reaction is complete the reaction mass cooled to 5-10°C and stirred for few hours preferably 2 hours to precipitate out solid product. Crude iminostilbene thus formed is obtained by filtration of the reaction mass at 5-10°C.
According to present invention, crude iminostilbene is purified in a suitable recrystallization solvent. The recrystallization solvent is selected from the group comprising of organic solvent, water or mixture thereof; preferably protic non polar solvents like toluene, cyclohexane, xylene etc. in a more preferred embodiment crude iminostilbene is recrystallized by refluxing in toluene, then cooling to 5-10°C, filtration and drying at temperatures 40-80°C, preferably at 50-60°C under vacuum.
According to present invention, the iminostilbene obtained is having purity not less than 99.7% and any individual impurity not more than 0.1%. The iminostilbene obtained is substantially pure and can be used as an intermediate for synthesis of drugs carbamazepine, oxcarbazepine and/or imipramine.
According to present invention, dehydrogenation of acetyliminodibenzyl to acetyliminostilbene is carried out in continuous flow reactor at about 320-330°C for about 10-30 minutes to obtain more than 90% conversion. This reaction when carried out in batch reactor with same reaction parameters at 240-257°C shown conversion of about 73 to 84% in 2-3 hours. Reaction conversion in batch reactor does not increase on increasing temperature or reaction time.
The major disadvantage of dehydrogenation of acetyliminodibenzyl to acetyliminostilbene in presence of sulphur when carried out in a batch reactor is formation of dimer impurity (V) which results in lower reaction conversion of acetyliminostilbene and consecutively lowers the purity of crude iminostilbene. Finally, pure iminostilbene is obtained in lower yield due to less purity of crude iminostilbene having dimer impurity (VI) about 12-24%. Due to very less residence time when reaction performed in coil reactor, dimer impurity (V) formed is lesser (<3.0%) and results in formation of lesser dimer impurity (VI) in crude iminostilbene, hence increase in yield of pure iminostilbene after purification in toluene.

wherein content of each impurity is less than 0.05%.
The major advantages realized in the present invention as compared to batch process are:
(i) Better reaction conversion profile around 92% due to very less residence time in
continuous flow compared to batch process reaction conversion around 73%.
(ii) Controlled dimer impurity formation less than 3.0% in reaction mass compared to batch process 12-24%.
(iii) Absence or low formation of impurities.
(iv) High yield and high purity of isolated product.
These distinctively identified advantages of the reactions in continuous flow reactor results from minimized residence time and continuous flow nature of the reaction, which thereby reduces the contact time between desired product and unreacted starting materials.
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 detailed description of the invention and study of the included examples.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of iminostilbene. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES
Example 1: Preparation of Iminostilbene:
Charged iminodibenzyl (180.0g) into a glass reactor at room temperature. Charged acetic anhydride (175.2g) and heated the stirred mixture to reflux temperature140°C. Stirred the reaction mass at reflux for 7 hours. After completion of reaction cooled to 120°C and distilled off mixture of acetic acid and acetic anhydride under vacuum at temperature not more than 120°C till oily residue obtained. Cooled to 100°C and charged therminol (324mL) and sulphur flakes (41.42g). Stirred the mixture at 100°C for 30 minutes to obtain a clear solution. The temperature of coil reactor muffle furnace set to 320-330°C. Feed the above solution into the coil reactor at rate of 14 mL/min maintaining the coil temperature at 320-330°C throughout the reaction. The pressure generated during reaction recorded to be 15-25 Kg/cm2.Flushed the coil reactor with therminol with sufficient quantity and collected the output reaction mass in a separate glass reactor. Cooled the reaction mass to 150°C and distilled of therminol under vacuum at temperature not more than 150°C to obtain an oily residue of acetyliminostilbene. Cooled to temperature 110-115°C. Charged n-butanol (720 mL) and potassium hydroxide flakes (108.0g). Stirred for 7 hours at reflux temperature 110-115°C. After completion of reaction mass cooled to 5-10°C and stirred for 2 hours. Filtered the solid and washed with chilled n-butanol (180 mL). suck dried for 30 minutes and washed with plenty of water till a clear mother liquor comes out. Charged crude iminostilbene wet cake into a glass reactor and charged toluene (600 mL). Reflux at 110°C to remove water azeotropically. Cooled the reaction mass to 70-80°C and charged toluene (606 mL) then again reflux at 110°C for 30-45 minutes. Cooled to 5-10°C and stirred for 2 hours. Filtered the solid and washed with toluene (120 mL) and suck dried wet cake for 30-45 minutes. Unloaded wet cake and dried under vacuum for 4h at 50-60°C.
Yield: 134 g (75%); Purity: 100%

CLAIMS:

We claim:
1. A process for the preparation of iminostilbene comprising the steps of:
(i) providing a solution of N-protected iminodibenzyl (VIII) and sulfur flakes;

(ii) dehydrogenation of the solution of step (i) in a continuous flow reactor to obtain N-protected iminostilbene (IX); and

(iii) deprotection of N-protected acetyliminostilbene (IX) to obtain iminostilbene (I).
wherein R is any alkyl group from C1-C6 carbon atoms.
2. The process as claimed in claim 1, for the preparation of iminostilbene, comprising the steps of:
(i) providing a solution of acetyliminodibenzyl (VIIIa) and sulfur flakes;
(ii) dehydrogenation of the solution of step (i) in a continuous flow reactor to obtain acetyliminostilbene (IXa); and
(iii) deprotection of acetyl group of acetyliminostilbene (IXa) to obtain iminostilbene (I).

3. The process as claimed in claim 1, for the preparation of iminostilbene, comprising the steps of:
(i) acetylation of Iminodibenzyl (VII) to obtain acetyliminodibenzyl (VIIIa);

(ii) providing a solution of acetyliminodibenzyl (VIIIa) and sulfur flakes;
(iii) dehydrogenation of the solution of step (ii) in a continuous flow reactor to obtain acetyliminostilbene (IXa);

(iv) deprotection of acetyl group of acetyliminostilbene to obtain iminostilbene (I); and
(v) optionally, crystallization of crude iminostilbene to obtain pure iminostilbene.

4. The process as claimed in claim 1, for the preparation of iminostilbene comprising the steps of:
(i) acetylation of Iminodibenzyl (VII) by refluxing in acetic anhydride and then distillation of solvent to obtain acetyliminodibenzyl (VIIIa);
(ii) providing a solution of acetyliminodibenzyl (VIIIa) and sulfur flakes in therminol solvent at 100°C;
(iii) dehydrogenation reaction by feeding solution of step (ii) to a continuous flow reactor to obtain acetyliminostilbene (IXa);
(iv) deprotection of acetyl group by hydrolysis of acetyliminostilbene (IXa) to obtain crude iminostilbene (I); and
(v) optionally, crystallization of crude iminostilbene to obtain pure iminostilbene.

5. The process as claimed in claim 3, wherein acetylation is done in presence of acetic anhydride at temperature ranges between 80°C to 140°C.

6. The process as claimed in claim 1, wherein reactor is a continuous flow reactor fitted in a muffle furnace.

7. The process as claimed in claim 1, wherein the temperature in continuous flow reactor fitted in a muffle furnace is 250°C -350°C.

8. The process as claimed in claim 1, wherein iminostilbene comprising any individual impurity less than 0.10%.

9. The process as claimed in claim 1, wherein iminostilbene is converted to compound selected from carbamazepine, oxcarbazepine and imipramine.

10. The process as claimed in claim 1, wherein iminostilbene comprising one or more impurities selected from the group comprising of below mentioned impurities

wherein content of each impurity is less than 0.05%.