This application claims priority to Indian patent application numbered 2356/CHE/2011 Filed on Jul 11, 2011, the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to the isolated substances of benzazepine derivatives and process for preparation thereof.

BACKGROUND OF THE INVENTION:

The benzazepine derivative Tolvaptan , chemically known as (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-o tolu-m-toluidide (OPC-41061), is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). The trade name of Tolvaptan is Samsca and is structurally represented as shown below.

Formula I.

U.S patent 5258510 discloses the benzazepines compounds, derivatives and process for the preparation thereof. The process for the preparation of Tolvaptanaccording to the prior art process has certain drawbacks especially when a C5-substituent is required or an electron with -drawing groups are present in the aromatic ring. The preparation of Tolvaptan involves 11 steps, few of them are done under very critical conditions that limit the generality of this approach. The process is defined in the Scheme -A below;

U.S application No US20090306369 discloses a process for the preparation of Tolvaptan and its derivatives thereof by using a benzazepine compound of formula 2 and compound of formula X;

Formula 2 Formula X

It is well known that for human administration, safety considerations are required to be established as prescribed by national and international regulatory authorities for identified, but toxicologically uncharacterized impurities / related substances, before an active pharmaceutical ingredient (API) product is commercialized. Typically, these limits are less than about 0.15 percent by weight of each related substance. Limits for unidentified and / or uncharacterized related substances are obviously lower, typically, less than 0.1 percent by weight. Therefore, in the manufacture of APIs, the purity of the products is very important. It is also known that related substances in an API may arise from degradation of the API itself, which is relating to the stability of the pure API during storage, during manufacturing process including the chemical synthesis. Process related substances include unreacted starting materials, chemical derivatives of related substances contained in starting materials, synthetic by-products, and degradation products.

In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization.

Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.

As is known by those skilled in the art, the management of process related substances is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of related substances in the final product.

Like any synthetic compound, benzazepine derivatives contain extraneous compounds or related substances that can come from many sources. They can be unreacted starting materials, by products of the reaction, products of side reactions, or degradation products.

The present invention specifically relates isolated related substances of benzazepine derivatives and process for their preparation thereof. As is known by those skilled in the art, the management of process related substances is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of related substances in the final product.

OBJECT AND SUMMARY OF THE INVENTION:

The main Object of the present invention relates to isolated substances of benzazepine derivatives, shown in the table below:

Table A

Another object of the present invention relates to a process for the preparation of isolated substances of benzazepine derivatives.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to isolated substances of benzazepine derivatives.

In one embodiment, the present invention provides isolated substances of benzazepine derivatives and process for their preparation thereof.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance A', structurally represented as shown below

Yet another embodiment, the present invention provides a process for the preparation of a benzazepine related substance A as depicted in the scheme below:

According to the present invention 7-Chloro-1, 2,3,4-tetrahydro-benzo[b]azepin-5-one of formula 1 is treated with o-toluoyl chloride of formula 2 in the presence of an organic base such as triethyl amine and an organic solvent selected from methanol, ethanol or chlorinated solvent such as dichloromethane or a mixture thereof. The resulting mixture is treated with HCI. Separating the organic layer and removing the solvent by using conventional techniques such as evaporation, distillation, vacuum distillation and filtration affords benzazepine related substance A.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance B', structurally represented as shown below: related substance B

Yet another embodiment, the present invention provides isolated benzazepine derivative related substance B as depicted in the scheme below:

According to the present invention, dissolving isolated benzazepine derivative related substance A is in an organic solvent selected from methanol, ethanol and isopropyl alcohol. Adding sodium borohydride portion wise to the reaction mass, removing the solvent, adding a second solvent selected from methylene chloride, ethylene chloride to the residue, adding water and hydrochloric acid and separating the layers, evaporating the organic solvent by using vacuum distillation to afford benzazepine derivative related substance B.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance C\ structurally represented as shown below

Yet another embodiment, the present invention provides isolated benzazepine derivative related substance C as depicted in the scheme below:

According to the present invention, dissolving 2-methyl 4- amino benzoic acid in an organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, adding a base such as triethyl amine. Adding o-toluoyl chloride to the reaction mass, stirring the reaction mass, adding water and dilute HCI. separating the layers, evaporating the organic solvent by using vacuum distillation; obtains oil which is crystallized in ethyl acetate to afford benzazepine derivative related substance C.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance D', structurally represented as shown below

Yet another embodiment, the present invention provides isolated benzazepine derivative related substance D as depicted in the scheme below:

According to the present invention, dissolving compound of formula C in an organic solvent selected from methanol, ethanol and isopropyl alcohol. Adding sodium borohydride portion wise to the reaction mass, stirring the reaction mass. Removing the solvent by using conventional techniques such as distillation. Adding second solvent selected from methylene chloride, ethylene chloride to the residue, adding water and hydrochloric acid, separating the layers, removing the organic solvent by using conventional techniques such as vacuum distillation, thus obtaining benzazepine derivative related substance D.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance E', structurally represented as shown below

Yet another embodiment, the present invention provides isolated benzazepine derivative related substance E as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance D1 in an organic solvent selected from methylene chloride, ethylene chloride, adding o-toluoyl chloride, stirring the reaction mass, removing the solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related E, which is optionally purified by using column chromatography (Hexane:EtOAc).

Yet another embodiment, the present invention provides isolated substance of benzazepine derivatives designated as 'related substance P, structurally represented as shown below

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance F as depicted in the scheme below:

According to the present invention, dissolving 4-nitrobenzoic acid in an organic solvent selected from toluene, xylene, n-hexane, n-heptane, cyclohexane, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, sulfolane and dioxane or a mixture of thereof, adding thionyl chloride drop wise, heating the reaction mass, removing the solvent under reduced pressure affords corresponding acid chloride. In a separate flask dissolving 7-Chloro-1,2,3,4-tetrahydro-benzo[b]azepin-5-one in an organic solvent selected from methylene chloride, ethylene chloride, adding a base such as triethyl amine, stirring the reaction mass. Adding the above isolated acid chloride of 4- nitro benzoic acid to the reaction mixture, stirring the reaction mass for 2-3 hrs, adding DM water and dilute HCI, separating the layers and removing the solvent by using conventional techniques such as distillation, vacuum distillation to afford benzazepine derivatives related substance F.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance G', structurally represented as shown below

Yet another embodiment, the present invention provides an isolated benzazepine derivatives related substance G as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance F in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-prapanol, n-butanol, tertiary-butyl alcohol, cyclohexanol. Adding Tin(ll) chloride to the reaction mass, cooling the reaction mass to 0°C, adding HCI to the reaction mass, adjusting pH of the solution by using sodium hydroxide solution, extracting the compound into an organic solvent such as ethyl acetate, separating the layers. Removing the solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance G.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance H\ structurally represented as shown below.

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance H as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance G in an organic solvent selected from a chlorinated solvent such as dichloromethane, chloroform, carbon tetrachloride. Adding base such as triethyl amine, adding o-toluoyl chloride to the reaction mass and removing the solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance H.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance I', structurally represented as shown below

Yet another embodiment, the present invention provides an isolated benzazepine derivatives related substance I as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance H in a organic solvent selected form methanol, ethanol, isopropyl alcohol. Adding sodium borohydride to the reaction mass, stirring the reaction mass, removing the solvent, adding a second solvent such as methylene dichloride, adding DM water and dilute HCI, separating the layers and removing the solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance I.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance J', structurally represented as shown below related substance J

Yet another embodiment, the present invention provides isolated benzazepine derivative related substance J as depicted in the scheme below:

According to the present invention, dissolving 4- methyl benzoic acid in an organic solvent selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide or a mixture thereof. Cooling the reaction mass, adding thionyl chloride drop wise, heating the reaction mass, removing the solvent by distillation under reduced pressure to afford the corresponding acid chloride. In another flask dissolving compound of formula J in an organic solvent selected from dichloromethane, chloroform, carbon tetrachloride, adding a base such as triethyl amine. Adding the above isolated acid chloride of 4- methyl benzoic acid to the reaction mixture, stirring the reaction mass, adding DM water and dilute HCI to the reaction mass, separating the layers and removing the solvent by using conventional techniques such as distillation affords benzazepine derivatives related substance J.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance K', structurally represented as shown below

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance K as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance J in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, cyclohexanol, cooling the reaction mass, adding sodium borohydride portion wise, stirring the reaction mass, removing the solvent by using conventional techniques such as distillation. Adding a second solvent such as methylenedichloride, adding water and dil. HCI, separating the layers, removing the organic solvent by using conventional technique such as distillation, vacuum distillation affords benzazepine derivatives related substance K.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance L', structurally represented as shown below; related substance L

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance L as depicted in the scheme below:

According to the present invention, dissolving 3- methyl benzoic acid in an organic solvent selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane, polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide and there mixture thereof. Cooling the reaction mass, adding thionyl chloride drop wise to the reaction mass. Heating the reaction mass, removing the solvent to isolate acid chloride, In a separate flask dissolving compound of formula J in an organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, adding a base such as triethyl amine. Stirring the reaction mass, adding the above isolated acid chloride of 3- methyl benzoic acid to the reaction mass, stirring the reaction mass, adding DM water and dilute HCI, separating the layers, removing the solvent by using conventional techniques such as distillation, vacuum distillation affords crude benzazepine derivatives related substance L which is optionally purified using flash column chromatography.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance M', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance M as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance L in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, cyclohexanol. Adding sodium borohydride portion wise, removing the solvent to obtain a residue, adding a second organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride to the residue, stirring the reaction mass, adding dil HCI and water, separating the layers, removing organic solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance M.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance N', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance N as depicted in the scheme below:

According to the present invention, dissolving 3, 4- dimethyl benzoic acid in an organic solvent selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane, polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide or a mixture thereof. Cooling the reaction mass, adding thionyl chloride drop wise to the reaction mass, heating the reaction mass, removing the solvent obtains acid chloride. In a separate flask dissolving compound of formula J in an organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, adding a base such as triethyl amine. Stirring the reaction mass, adding the above isolated acid chloride of 3,4- dimethyl benzoic acid to the reaction mass, stirring the reaction mass, adding water and dilute HCI, separating the layers, removing the solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance N which is optionally using flash column chromatography.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance O', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance O as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance N in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, cyclohexanol; adding sodium borohydride portion wise, removing the solvent. Adding a second solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride to the residue, stirring the reaction mass, adding dil HCI and water, separating the layers, removing the organic solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance O.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance P', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance P as depicted in the scheme below:

According to the present invention, dissolving 2, 4- dimethyl benzoic acid in an organic solvent selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane, polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide or a mixture thereof. Cooling the reaction mass, adding thionyl chloride drop wise to the reaction mass, raising the temperature, removing the solvent affords corresponding acid chloride. In a separate flask dissolving compound of formula J in an organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride. Adding a base such as triethyl amine, stirring the reaction mass. Adding the above isolated acid chloride of 2,4- dimethyl benzoic acid to the reaction mass, stirring the reaction mass, adding DM water and dilute HCI, separating the layers, removing the solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance P which is optionally purified using flash column chromatography.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance Q', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance Q as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance P in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, cyclohexanol. Adding sodium borohydride portion wise, removing the solvent, adding a second solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride to the residue, stirring the reaction mass, adding dil HCI and water, separating the layers, removing the organic solvent by using conventional techniques such as distillation, vacuum distillation affords Tolvaptan / benzazepine derivatives impurity / related substance Q.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance R', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance R as depicted in the scheme below:

According to the present invention, dissolving 2, methyl 4- nitro benzoic acid in an organic solvent selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane, polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide or a mixture thereof. Cooling the reaction mass, adding thionyl chloride drop wise to the reaction mass, raising the temperature, removing the solvent affords corresponding acid chloride. In a separate flask dissolving 7-Chloro-1,2,3,4-tetrahydro-benzo[b]azepin-5-one in an organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride. Adding a base such as triethyl amine, stirring the reaction mass. Adding the above isolated acid chloride of 2-methyl-4- nitro benzoic acid to the reaction mass, stirring the reaction mass, adding DM water and dilute HCI, separating the layers, removing the organic solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance R.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance S', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance S as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance R in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, cyclohexanol. Adding Tin(ll) chloride to the reaction mass, cooling the reaction mass to 0°C, adding HCI to the reaction mass. Pouring the reaction mass on crushed ice, adjusting pH of the solution by using sodium hydroxide solution, adding second solvent selected from esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl-tert-butyl ether, separate the layers. Removing the solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance S.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance T, structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance T as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance S in an organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride. Adding o-toluoyl chloride to the reaction mass, adding base such as triethyl amine, stirring the reaction mass, removing the solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance T.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance IT, structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance U as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance T in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, cyclohexanol. Adding sodium borohydride portion wise, removing the solvent, adding a second organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride to the residue, stirring the reaction mass, adding dil HCI and water, separating the layers, removing the organic solvent by using conventional techniques such as distillation, vacuum distillation affords related substance U.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance V, structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance V as depicted in the scheme below:

According to the present invention, dissolving benzoic acid in an organic solvent selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane, polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide or a mixture thereof, cooling the reaction mass, adding thionyl chloride drop wise to the reaction mass, raising the temperature, removing the solvent affords corresponding acid chloride. In a separate flask dissolving compound of formula J in an organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride. Adding base such as triethyl amine. Stirring the reaction mass. Adding the above isolated acid chloride of benzoic acid to the reaction mass. Stirring the reaction mass, adding DM water and dilute HCI. Separating the layers, removing the solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance V; which is optionally purified using flash column chromatography.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance W, structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance W as depicted in the scheme below:

According to the present invention, dissolving benzazepine derivatives related substance V in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, cyclohexanol. Cooling the reaction mass, adding sodium borohydride portion wise. Removing the solvent, adding a second organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride to the residue, stirring the reaction mass, adding dil HCI and water, separating the layers, removing the organic solvent by using conventional techniques such as distillation, vacuum distillation affords benzazepine derivatives related substance W which is optionally purified using flash column chromatography.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance X', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance X as depicted in the scheme below:

According to the present invention, dissolving 2-Methyl-4-nitro benzoic acid in an organic solvent selected from toluene, xylene, n-hexane, n-heptane, cyclohexane, adding thionyl chloride, heating the reaction mass to reflux, removing the solvent affords the corresponding acid chloride. In a separate flask dissolving 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepin-5-one in an organic solvent such as dichloromethane, stirring the reaction mass, adding a base such triethylamine. Adjusting the pH using 10 % sodium chloride under stirring, separating the layers, washing the organic layer with 1 N HCI and 5 % sodium bicarbonate, removing the solvent by using conventional techniques such as distillation, vacuum distillation affords 2-methyl-4-nitro-benzoic acid7-chloro-1-(2-methyl-4-nitro-benzoyl)-2,3-dihydro-1W-benzo[b]azeoin-5-yl-ester.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance Y', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivatives related substance Y as depicted in the scheme below:

According to the present invention, dissolving 2-methyl-4-nitro-benzoic acid 7-chloro-1-(2-methyl-4-nitro-benzoyl)-2,3-dihydro-1AV-benzo[b]azeoin-5-yl-ester in an organic solvent selected from alcohols such as methanol, ethanol, isopropyl alcohol, butanoyl mixed with Con HCI, stirring the reaction mass, adding Tin II chloride dehydrate. Diluting the reaction mass by adding a second solvent such as dichloromethane and water, adjusting the pH by using 40 % sodium hydroxide solution, separating the layers, removing the solvent by using conventional techniques such as filtration, distillation, and vacuum distillation affords crude product. The resultant crude is purified by washing with solvent such as ethyl acetate. Optionally the crude product is purified by using column chromatography.

Yet another embodiment, the present invention provides an isolated substance of benzazepine derivatives designated as 'related substance Z', structurally represented as shown below;

Yet another embodiment, the present invention provides isolated benzazepine derivative related substance Z as depicted in the scheme below:

According to the present invention, dissolving 4-Amino-2-methyl-benzoic acid 1-(4-amino-2-methyl-benzoyl)- 7-chloro-2,3-dihydro-1H-benzo[b]azepin-5-yl-ester in an organic solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride. Adding a base such as triethylamine, adding O-toluoyl chloride, cooling the reaction mass, separating the reaction mass. Adding water and sodium bicarbonate, separating the layers, removing the organic solvent by using conventional techniques such as filtration, distillation, vacuum distillation obtains the crude product which is recrystallized using an ethereal solvent such as isopropyl ether to give 2-Methyl-4-(2-methyl-benzoylamino)-benzoic acid 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3-dihydro-1H-benzo[b]azepin-5-yl-ester.

The invention is further illustrated by the following non-limiting examples.

Examples 1: Process for the preparation of isolated benzazepine derivative related substance A

To a solution of 7-Chloro-1, 2,3,4-tetrahydro-benzo[b]azepin-5-one (5g, 0.0303 mol) at 0° C in 40 ml MDC was added triethyl amine drop wise (10.1 ml, 0.0727 mol). Reaction mixture stirred at room temperature for 15 minutes, o-toluoyl chloride (4.174 ml, 0.0302 mol) was charged and the resulting reaction mixture was stirred for 2h. Reaction mixture was washed with DM water (40 ml) and then with dilute HCI (40 ml, 10 %). Organic layer was separated and dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (5.5 g, Yield = 58 %). HPLC purity = 95.33 %

Example 2: Process for the preparation of isolated benzazepine derivative related substance B

To a solution of A (3g, 0.00958 mol)at 0 C in 30 ml methanol was added sodium borohydride portion wise (0.181 g, 0.004 mol). Reaction mixture was stirred for half an hour at the same temperature. Solvent of the reaction mixture distilled under vacuum. 40 ml MDC was added to the residue. It was then washed with water (40 ml) and with dil. HCI (40 ml, 10 %). Organic layer was separated and dried over sodium sulfate and distilled under vacuum to get product as white solid (2.5g, % Yield = 83 %). HPLC purity = 96.87 %

Example 3: Process for the preparation of isolated benzazepine derivative related substance C

To a solution of 2-methyl 4- amino benzoic acid (5g, 0.0331 mol) in MDC (40 ml) at 0° C was added triethyl amine drop wise (10.1 ml, 0.0727 mol). Reaction mixture was stirred at room temperature for 15 minutes, o-toluoyl chloride (4.320 ml, 0.0330 mol) was added to the reaction mixture. Reaction mixture stirred for 2 hours. RM was washed with DM water ( 40 ml) and with dilute HCI (40 ml, 10 %). Organic layer was separated and dried over sodium sulfate. Methanol was also added to dissolve the undissolved particles. Solvent distilled under vacuum to get crude as light yellow solid product which is then washed with ethyl acetate(30 ml) to get product as white solid.( 4 g , % Yield = 45 %) HPLC purity = 95.71 %

Example 4: Process for the preparation of isolated benzazepine derivative related substance D

To a solution of C (3g, 0.0091 mol) in methanol (40 ml) at to 0° C was added sodium borohydride portion wise (0.3 g, 0.000126 mol). The reaction mixture was stirred at the same temperature for 0.5 h. Solvent of the reaction mixture distilled under vacuum. MDC was added to the residue (40 ml). The RM was washed with water (40 ml) and with dil. HCI (40 ml, 10 %). Organic layer was separated and dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (2.5 g , % Yield = 83 %) HPLC purity = 91.66 %

Example 5: Process for the preparation of isolated benzazepine derivative related substance E

To a solution of Tolvaptan/benzazepine derivatives pharma (2g, 0.00447 mol) in MDC (40 ml) was added o-toluoyl chloride (2.4 ml, 0.0200 mol). Reaction mixture stirred for 24 hours. Solvent distilled under vacuum to get crude as light yellow solid Product purified by column chromatography (Hexane : EtOAc). (800 mg , % Yield = 32 %) HPLC purity = 91 % Example 6: Process for the preparation of isolated benzazepine derivative related substance F

To a solution of 4- nitro benzoic acid (11g, 0.0658 mol) in toluene (100 ml) and DMF (3 ml) at 0 C was added thionyl chloride drop wise (7.2 ml, 0.0949 mol). Reaction mixture heated 60 C for 45 minutes. Solvent and excess thionyl chloride was distilled under reduced pressure. To a solution of 7-Chloro-1,2,3,4-tetrahydro-benzo[b]azepin-5-one (9.78 g, 0.0592 mol) in MDC ( 100 ml) was added triethyl amine ( 27 ml, 0.197 mol) and stirred for 15 minutes. The isolated acid chloride of 4- nitro benzoic acid to the reaction mixture and stirred for 2 h. RM washed with DM water (100 ml) and with dilute HCI (100 ml, 10 %). Organic layer was separated , dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (Yield = 15 g, % Yield = 66.2 %). HPLC purity = 91.34%

Example 7: Process for the preparation of isolated benzazepine derivative related substance G

To a solution of F (7g, 0.0203 mol) in ethanol (50 ml) was added SnCI2 (13.7 g, 0.0610 mol)). Reaction mixture cooled to 0 C and cone. HCI (23 ml) was added drop wise. RM was stirred at room temperature for 16 hours. Reaction mixture was poured into crushed ice(100 ml). pH of the solution was adjusted to 9 using NaOH solution. Ethyl acetate (100 ml) was added to it and stirred for 30 minutes. Organic layer was separated, dried over sodium sulfate and concentrated under vacuum to get product as light yellow solid (6.1g , % Yield = 95%).HPLC purity = 90.9 % Example 8: Process for the preparation of isolated benzazepine derivative related substance H

To a solution of G (5g, 0.00318 mol) in MDC ( 40 ml)at 0° C was added triethyl amine drop wise (6.6 ml, 0.0473 mol). Reaction mixture stirred at room temperature for 45 minutes, o-toluoyl chloride (2.5 ml, 0.0191 mol) was added to the reaction mixture and stirred for 1 h. RM was washed with DM water ( 40 ml) and with dilute HCI (40 ml, 10 %). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (6g , %

Yield = 87.3%). HPLC purity = 92.94 %

Example 9: Process for the preparation of isolated benzazepine derivative related substance I

To a solution of H (4g, 0.009 mol )in methanol (40 ml) at 0 C was added sodium borohydride portion wise (0.175 g, 0.00462). The reaction mixture was stirred at same temperature for 0.5 h. Solvent of the reaction mixture was distilled under vacuum. 40 m MDC was to the residue. It was the washed with water (40 ml) and with dil. HCI (40 ml). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as white solid (2.5 g , % Yield = 62.5 %).HPLC purity = 94.37%

Example 10: Process for the preparation of isolated benzazepine derivative related substance J

To a solution of 4- methyl benzoic acid (3g, 0.0220 mol) in toluene ( 20 ml) and DMF (0.2 ml) at 0 C was added thionyl chloride drop wise (2.5 ml, 0.0210 mol). Reaction mixture was heated 60 C for 30 minutes. Solvent and excess thionyl chloride was distilled under reduced pressure. In another reaction, to a solution of compound of formula J(5g, 0.0152 mol) MDC ( 20 ml) was added triethyl amine (6 ml, ). Isolated acid chloride of 4- methyl benzoic acid was added to the reaction mixture. Reaction mixture stirred for 45 minutes. RM washed with DM water ( 30 ml) and with dilute HCI (30 ml, 10 %). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (6g, % Yield = 61 %). HPLC purity = 81.66 %, which is further purified by flash column chromatography.

Example 11: Process for the preparation of isolated benzazepine derivative related substance K

To a solution of J (1.5g, 0.0033 mol) in methanol (20 ml) at 0 C was added sodium borohydride (0.38 g, 0.0100 mol) portion wise. Reaction mixture was stirred at the same temperature for 0.5 h. Solvent of the reaction mixture was distilled under vacuum. MDC was added to the residue (30 ml) and then washed with water (30 ml) and with dil. HCI(30 ml). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as white solid (900 mg, %

Yield = 59.7 %). HPLC purity = 84.61 %

Example 12: Process for the preparation of isolated benzazepine derivative related substance L

To a solution of 3- methyl benzoic acid (2g, 0.0146 mol)in toluene ( 20 ml) and DMF (0.2 ml) at 0 C was added thionyl chloride drop wise (1.7 ml, 0.0142 mol). Reaction mixture was heated 60 C for 30 minutes. Solvent and excess thionyl chloride was distilled under reduced pressure. In another reaction, to solution of compound of formula J ( 5g, 0.0152 mol) in MDC ( 20 ml) was added triethyl amine ( 5 ml, ) and stirred for 15 minutes. Isolated acid chloride of 3- methyl benzoic acid was added to the reaction mixture and stirred for 45 minutes. RM was washed with DM water (30 ml) and with dilute HCI (30 ml, 10 %). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (4g, % yield = 61.06 %). HPLC purity = 79.2 % which is further purified by flash column chromatography

Example 13: Process for the preparation of isolated benzazepine derivative related substance M

To a solution of L (15g, 0.0033 mol) in methanol (20 ml) at 0° C was added sodium borohydride (0.38 g, 0.0102 mol) portion wise. Solvent of the reaction mixture was distilled under vacuum. MDC (40 ml) was added to the residue and washed with water (40 ml) and with dil. HCI(40 ml). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (1.0 g , % Yield = 66 %)

Example 14: Process for the preparation of isolated benzazepine derivative related substance N

To a solution of 3, 4- dimethyl benzoic acid (3.5 g, 0.0233 mol) in toluene (30 ml) and DMF (1 ml) at 0 C was added thionyl chloride drop wise (4.1 ml, 0.0344 mol). Reaction mixture heated 60 C for 45 minutes. Solvent and excess thionyl chloride was distilled under reduced pressure. In another reaction, to a solution of compound of formula J (5g, 0.0152 mol) in MDC ( 30 ml) was added triethyl amine (6 ml, 0.0810 mol ). The reaction mixture was stirred for 15 minutes. The isolated acid chloride of 3, 4 - dimethyl benzoic acid was added to the reaction mixture. Reaction mixture stirred for 45 minutes at room temperature. RM was washed with DM water (30 ml) and with dilute HCI (30 ml, 10%) Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as yellow solid (7g, % Yield = 65.4 %). HPLC purity = 71.5 %, which is further purified by flash column chromatography

Example 15: Process for the preparation of isolated benzazepine derivative related substance

To a solution of N (1.5g, 0.0033 mol) in methanol (20 ml) at 0 C was added sodium borohydride (0.38 g, 0.00978 mol) portion wise. Solvent of the reaction mixture was distilled under vacuum. MDC was added to the residue (30 ml) and washed with water (30 ml) and with dil. HCI (30 ml). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (800 mg, % Yield = 53 %)

Example 16: Process for the preparation of isolated benzazepine derivative related substance P

To a solution of 2, 4- dimethyl benzoic acid (3.0 g, 0.0199 mol) in toluene (30 ml) and DMF (1 ml) at 0 C was added thionyl chloride drop wise (3.2 ml, 0.0294 mol). Reaction mixture heated 60 C for 45 minutes. Solvent and excess thionyl chloride was distilled under reduced pressure. In another reaction, to a solution of compound of formula J (4g, 0.0121 mol) in MDC (30 ml) was added triethyl amine (6 ml, 0.0810 mol). Isolated acid chloride of 2, 4 - dimethyl benzoic acid was added to the reaction mixture and stirred for 45 minutes. RM washed with DM water ( 30 ml) and with dilute HCI (30 ml, 10 %). Organic layer separated, dried over sodium sulfate and distilled under vacuum to get product as yellow solid (= 5 g, %Yield = 54.3 %). HPLC purity = 78.3 % which is further purified by flash column chromatography

Example 17: Process for the preparation of isolated benzazepine derivative related substance Q

To a solution of P (2.2g, 0.00478 mol) in methanol (30 ml) at 0° C was added sodium borohydride (0.542 g, 0.01432 mol) portion wise. Reaction mixture was stirred for 0.5 h. Solvent of the reaction mixture distilled under vacuum. MDC was added to the residue (20 ml) and washed with water (20 ml) and with dil. HCI(20 ml). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (1.2g , % Yield = 54.5 %). HPLC purity = 88.77 %.

Example 18: Process for the preparation of isolated benzazepine derivative related substance R

To a solution of 2, methyl 4- nitro benzoic acid (10g, 0.0552 mol) in toluene (100 ml) and DMF (3 ml) at 0 C was added thionyl chloride drop wise (8.9 ml, 0.0828 mol). Reaction mixture heated 60 C for 45 minutes. Solvent and excess thionyl chloride distilled under reduced pressure. In another reaction, to a solution of 7-Chloro-1,2,3,4-tetrahydro-benzo[b]azepin-5-one (6.79g, 0.052) in MDC (100 ml) was added triethyl amine (27 ml). Isolated acid chloride of 4- nitro benzoic acid was added to the reaction mixture and stirred for 2 h. RM washed with DM water ( 100 ml) and with , dilute HCI (100 ml, 10 %). Organic layer separated and dried over sodium sulfate. Solvent was distilled under vacuum to get product as light yellow solid (10g , % Yield= 55 %). HPLC purity = 86.41 %

Example 19: Process for the preparation of isolated benzazepine derivative related substance S

To a solution of R (8g, 0.0246 mol) in ethanol (80 ml) was added SnCI2 (32g, 0.142 mol). Reaction mixture was cooled to 0 C and cone. HCI (36 ml) was added drop wise. RM stirred at room temperature for 16 hours. Reaction mixture was poured into crushed ice. pH of the solution was adjusted to 9 using NaOH solution. Ethyl acetate and stirred for 30 minutes. Organic layer was separated , dried over sodium sulfate and concentrated under vacuum to get product as light yellow solid (4g , % Yield = 83%). HPLC purity = 94.13 %

Example 20: Process for the preparation of isolated benzazepine derivative related substance T

To a solution of S (4g, 0.0136 mol) in MDC (60 ml) at 0° C triethyl amine drop wise (5.6 ml, 0.0408 mol). Reaction mixture was stirred at room temperature for 45 minutes, o-toluoyl chloride (1.95 ml, 0.0149 mol) was added to the reaction mixture and stirred for 1 h. RM washed with DM water ( 40 ml) and with dilute HCI (40 ml, 10 %). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (4.5 g, % Yield = 80.3%). HPLC purity = 92.16%

Example 21: Process for the preparation of isolated benzazepine derivative related substance U

To a solution of T (3.5g, 0.00849 mol) in methanol (45 ml) at 0°C was added sodium borohydride (0.157g, 0.00424 mol) portion wise. Solvent of the reaction mixture distilled under vacuum MDC was added to the residue (40 ml) and washed with water (40 ml) and with dil. HCI(40 ml). Organic layer was separated and dried over sodium sulfate. Solvent was distilled under vacuum to get product as light yellow solid (3g , % Yield = 85.7 %). HPLC purity = 95.18 % Example 22: Process for the preparation of isolated benzazepine derivative related substance V

To a solution of benzoic acid (3.0 g, 0.0245 mol) in toluene (30 ml) and DMF (0.1 ml) at 0 C was added thionyl chloride drop wise (2.7 ml, 0.0367 mol). Reaction mixture was heated 60 C for 45 minutes. Solvent and excess thionyl chloride was distilled under reduced pressure. In another reaction, to a solution of compound of formula J (8g, 0.0243 mol) in MDC (80 ml) was added triethyl amine (10 ml, 0.0732 mol). Reaction mixture was stirred for 15 minutes. Isolated acid chloride of benzoic acid was added to the reaction mixture and stirred for 45 minutes. RM was washed with DM water (60ml) and with dilute HCI (60 ml, 10 %). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as yellow solid (7.5 g, % Yield= 70.7 )HPLC purity = 77.7 % which is further purified by flash column chromatography

Example 23: Alternate Process for the preparation of isolated benzazepine derivative related substance

To a solution of V (3.5g, 0.00810 mol) in methanol (40 ml) at 0 C was added sodium borohydride (0.5 g, 0.0121 mol) portion wise. Reaction mixture was stirred at same temperature for 0.5 h. Solvent of the reaction mixture was distilled under vacuum. MDC was added to the residue (40 ml) and washed with water (40 ml) and with dil. HCI (40 ml). Organic layer was separated, dried over sodium sulfate and distilled under vacuum to get product as light yellow solid (2.5 g , % Yield = 71.4 %). HPLC purity = 77.27 % which is further purified by flash column chromatography Example 23A: Process for the preparation of isolated benzazepine derivative related substance N-[4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[6]azepin-1-carbonyl)-3-methyl-pheyl]-2-benzamide 5 g was dissolved in methanol (100 ml) and added sodium borohydride (0.5 g) dissolved in 10 ml 5 % NaOH aqueous solution with stirring for a period of one hour. During which reaction mixture was stirred at same cooling temperature for two to three hours. After confirming the disappearance of starting material, there was added 50 ml water and continued the stirring for one hour. Thus isolated solid was filtered and washed with water, to give N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepin-1-carbonyl)-3-methyl-pheyl]-2-benzamide , (4.6 g , % Yield = 90.5 %). HPLC purity = 94.8 %.

1H NMR (DMSO) 6 2.2 (2H), 2.3 (2H), 2.6 (2 H), 5.6 (1H), 6.3 (2 H), 7.0 (2H) 7.4 (2H) 7.5 (5H), 10.2 (1H)

Example 24: Process for the preparation of isolated benzazepine derivative related substance X

Preparation of 2-methyl-4-nitro-benzoic acid 7-chloro-1-(2-methyl-4-nitro-benzoyl)-2,3-dihydro-1H-benzo[b]azepin-5-yl-ester (mass no- 522)

2-Methyl-4-nitro benzoic acid (20 g, 0.1101 mol) is stirred with Toluene (200 ml), and was added thionyl chloride (20 g 0.168 ) with stirring at room temperature about one hour. During which reaction mixture was heated to reflux for two hours. After confirming the absence starting material solvent were removed by atmospheric distillation. The obtained crude was diluted with dichloromethane , The reaction mass was slowly added to stirred mixture of 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepin-5-one (8.64 g 0.044 mol) in dichloromethane and triethylamine ( 55 g 0.5520 mol). Reaction mixture stirred at room temperature for 6 hours to complete reaction. The resulted reaction mixture slowly added to a vessel containing 100 ml of 10 % sodium chloride under stirring. The organic layer is separated and washed twice with 1 N HCI ( 100 ml) and 5 % sodium bicarbonate ( 100 ml) solution and dried over sodium sulphate, Sodium sulfate was removed by filtration ,the filtrate was concentrated under reduced pressure to give 2-methyl-4-nitro-benzoic acid 7-chloro-1 -(2-methyl-4-nitro-benzoyl)-2,3-dihydro-1 H-benzo[b]azeoin-5-yl-ester (Yield 82 %) HPLC purity - 99.0 %.

Example 25: Process for the preparation of isolated benzazepine derivative related substance Y

Process for the preparation of 4-Amino-2-methyl-benzoic acid 1-(4-amino-2-methyl-benzoyl)-7-chloro-2,3-dihydro-1H-benzo[b]azepin-5-yl-ester

To a stirred mixture of methanol (240 ml) and Cone. Hcl ( 84 ml) was added 2-methyl-4-nitro-benzoic acid 7-chloro-1-(2-methyl-4-nitro-benzoyl)-2,3-dihydro-1/-/-benzo[b]azeoin-5-yl-ester ( 12 g 0.023 mol) and added SnCI2.2H20 (42 g 0.186 mol) with stirring at room temperature . The reaction mass was maintained at reflux temperature for 2 hours. After confirming the disappearance of starting material, the crude obtained was diluted with dichloromethane and added water. The biphase obtained was adjusted the pH of reaction mass 12-14 using 40 % NaOH solution. Layer was washed with water (2 x 100 ml) and sodium bicarbonate (2 x 100 ml) and dried over sodium sulfate, after filtering off sodium sulfate; the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was with ethyl acetate to give 4-Amino-2-methyl-benzoic acid 1-(4-amino-2-methyl-benzoyl) - 7-chloro-2,3-dihydro-1H-benzo[b]azepin-5-yl-ester,

The crude product purified in column chromatography using 60-120 mesh silica gel and product was eluted in 30% ethyl acetate in Hexane. (Yield-56 %) (HPLC-92.0%)

Example 26: Process for the preparation of isolated benzazepine derivative related substance Z

Process for the preparation of 2-Methyl-4-(2-methyl-benzoylamino)-benzoic acid 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3 -dihydro-1H-benzo[b]azepin-5-yl-ester 4-Amino-2-methyl-benzoic acid 1-(4-amino-2-methyl-benzoyl)- 7-chloro-2,3-dihydro-1H-benzo[b]azepin-5-yl-ester (5 g 0.0108 mol) was dissolved in dichloromethane (50 ml) and Triethylamine ( 7.5 ml 0.054 mol) and added O-toluoyl chloride(4.17 g 0.027 mol) with stirring under ice cooling over a period of 30 minutes. After confirming the disappearance of starting material, dichloromethane layer was washed with water (2X50 ml) and 5 % sodium bicarbonate (2X50 ml) and dried over sodium sulfate, after filtering off sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude product. The resultant crude was recrystalised in isopropyl ether to give 2-Methyl-4-(2-methyl-benzoylamino)-benzoic acid 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino) benzoyl]-2,3 -dihydro-1H-benzo[b]azepin-5-yl-ester (Yield-65 %) (HPLC-98.0 %).

We Claim:

1) An Isolated Benzazepine derivative selected from


2. A process for the preparation of Isolated Benzazepine derivatives substantially as herein described with reference to the examples.