Claims:WE CLAIM:

1. A process for stereospecific synthesis of [(3S)-3-[((1S)-1-ethoxycarbonyl-3-phenyl-propyl)amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid of formula (I),

comprising:
i) heating the compound of Formula (I) (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one at a predefined temperature in a predefined solvent;
ii) separating undissolved desired isomer of formula (IS) from the reaction mixture of step (i) by filtration;
iii) recovering the R-isomer of formula (IR) from the filtrate followed by distilling the filtrate to isolate the compound of R-isomer of formula (IR);
iv) racemizing R-isomer of formula (IR) by heating the isomer at a predefined temperature in a predefined solvent to form racemic mixture of formula (I); and
v) recovering the racemic compound obtained in step (iv) by distilling the solvent of previous step under vacuum and recycling by adding the racemic compound to step (i).

2. The process as claimed in claim 1, wherein the predefined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, tertbutyl ethyl acetate and methyl acetate.

3. The process as claimed in claim 1, wherein the acetate solvent is ethyl acetate.

4. The process as claimed in claim 1, wherein the predefined temperature in step (i) is 50-90ºC, preferably at 55-80ºC and more preferably at 60-70ºC.

5. The process as claimed in claim 1, wherein (IR) isomer is the mixture of (R) and (S) isomer having ratio in the range of 70:30 - 90:10.

6. The process as claimed in claim 1, wherein the predefined solvent in step (iv) is selected from o-xylene, Toluene, dimethyl formamide and dimethyl acetamide.

7. The process as claimed in claim 1, wherein the predefined temperature in step (iv) is 120-160°C, preferably 130-150ºC and more preferably 135-145ºC.

Dated this 19th day of March 2022
FOR AARTI INDUSTRIES LIMITED

ANAND GOPALKRISHNA MAHURKAR
(IN/PA- 1862)
(Agent for Applicant)

, Description:FIELD OF THE INVENTION
The present invention relates to a process for preparation of intermediates of Benazepril and more to an improved process for preparation of Benazepril intermediate (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one.

BACKGROUND OF THE INVENTION
Benazepril (A) and its pharmaceutically active salt is an ACE inhibitor and is marketed as Lotensin. It is used for high blood pressure, heart failure and diabetic kidney disease and is chemically named as 2-[(3S)-3-[((1S)-1-ethoxycarbonyl-3-phenyl-propyl)amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid.

(3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one of formula (IS) is a key intermediate of Benazepril and is represented as formula (I) below:

Various processes are known in literature for the preparation of this intermediate. The synthesis of (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one is reported in a research article titled “Asymmetric Synthesis of N-Substituted r-Aminobenzlactam via Crystallization-Induced Asymmetric Transformation of Covalent Diastereomer” by Shieh et.al.. The process involves suspending diastereoisomer in a non-polar solvent and heated to 140-160ºC. The reaction mixture was diluted with cyclohexane and the mixture was cooled to room temperature. The desired (S,S) product is collected by filtration. The literature reports diastereomeric ratio (99:1) with 93% yield when the reaction is carried out in mineral oil at 140°C for 16 hours.

CN102250004B reports solventless reaction method for higher conversion rate. The racemic (3RS)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one obtained from previous stage is heated to 130-160ºC and in the molten state the undesired isomer is converted to the desired isomer and the yield reported is 70-80%.

The benazepril intermediate discussed above is most critical to prepare as it has two chiral centres and both having S-configuration. The process by Shieh et.al has some practical impediments. When the processof Shiel et.al was replicated by person skilled in art, it was observed that after the addition of cyclohexane the reaction mass became hard. (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one being insoluble in mineral oil as well as in cyclohexane became very thick slurry. It was observed that after cooling it stuck to the walls of reactor. Also, it does not yield diasteromeric ratio as claimed. Thus the process is not feasible and scalable for large scale production due to lack of operational ease.
In the racemization process of undesired isomer (IR) to (I) as reported in CN102250004B, racemization is achieved. However, as the process is solventless, the decomposition of the compound was observed at higher temperature such as 160°C. Due to decomposition, the yield loss is observed.

Due to the above-mentioned technical difficulties of the processes cited in prior art, there is a need to develop a process that is feasible for higher scale production. Further, there is a need of a process that is environmental friendly and has operational ease.

Objects of the invention
The object of present invention is to provide an improved process for synthesis of Benazepril intermediate, (3S)-3-[[(1S) -1-phenylethyl] amino]-1, 3, 4, 5 -tetrahydro -1-benzazepin- 2-one, which is industrially feasible and applicable.
Another object of the present invention is to provide racemization of undesired isomer (3R)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one and re-use in the reaction, which improves yields and makes the process cost-effective.

SUMMARY OF THE INVENTION
A process for stereospecific synthesis of [(3S)-3-[((1S)-1-ethoxycarbonyl-3-phenyl-propyl)amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid of formula (I),
that includes the steps of heating the compound of Formula (I) (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one at a predefined temperature in a predefined solvent; separating undissolved desired isomer of formula (IS) from the reaction mixture of step (i) by filtration; recovering the R-isomer of formula (IR) from the filtrate followed by distilling the filtrate to isolate the compound of R-isomer of formula (IR); racemizing R-isomer of formula (IR) by heating the isomer at a predefined temperature in a predefined solvent to form racemic mixture of formula (I); and recovering the racemic compound obtained in step (iv) by distilling the solvent of previous step under vacuum and recycling by adding the racemic compound to step (i). The predefined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, tertbutyl ethyl acetate and methyl acetate. The predefined temperature in step (i) is 50-90ºC, preferably at 55-80ºC and more preferably at 60-70ºC. The (IR) isomer is the mixture of (R) and (S) isomer having ratio in the range of 70:30 - 90:10. The predefined solvent in step (iv) is selected from o-xylene, Toluene, dimethyl formamide and dimethyl acetamide. The predefined temperature in step (iv) is 120-160°C, preferably at 130-150ºC and more preferably at 135-145ºC.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the stereo-specific preparation of Benazepril intermediate (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one of formula (IS).

The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.
Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.
References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.
In an embodiment of the present invention, an improved process for the preparation of compound of formula (IS), is disclosed.

The process for preparation of Benazepril intermediate compound of Formula (IS) includes the following steps:
i) heating the compound of Formula (I) (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one at a predefined temperature in a predefined solvent;

ii) separating undissolved desired isomer of formula (IS) from the reaction mixture of step (i) by filtration;
iii) recovering the R-isomer of formula (IR) from the filtrate followed by distilling the filtrate to isolate the compound of R-isomer of formula (IR);

iv) racemizing R-isomer of formula (IR) by heating the isomer at a predefined temperature in a predefined solvent to form racemic mixture of formula (I); and

v) recovering the racemic compound obtained in step (iv) by distilling the solvent of previous step under vacuum and recycling by adding the racemic compound to step (i).

In accordance with this embodiment, in step (i) the predefined temperature is 50-90ºC, preferably at 55-80ºC; particularly at 60-70ºC. The predefined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, tertbutyl ethyl acetate and methyl acetate. The (IR) isomer of step (iii) is a mixture of (IR):(IS) isomer in the ratio of 70:30 - 90:10. The predefined temperature in step (iv) is 120-160ºC, preferably at 130-150ºC, particularly at 135-145ºC. The heating in step (iv) is done to obtain 50:50 mixture of compounds of formulae (IR) and (IS). The predefined solvent in step (iv) is selected from o-xylene, Toluene, dimethyl formamide and dimethyl acetamide.

The schematic representation of the process of the present invention is shown below.

EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of Compound of Formula (IS)
The compound of formula (I) is charged to ethyl acetate and the mixture is heated to 60-70ºC for at least 1-2 hours. The undesired (IR) isomer solubilizes in the solvent and the desired (IS) isomer is separated by filtration. The desired isomer (IS) is analyzed for the amount of undesired isomer (IR) content. If the (IR) content is more than 0.1%, then the residue is again charged to fresh ethyl acetate and heated to 60-70ºC for at least 1-2 hours.
The filtrate is distilled out completely under vacuum at 80-85°C and undesired isomer (IR) is isolated. The undesired isomer (IR) obtained is the mixture of (IR) and (1S) isomer. The ratio of (IR):(1S) is 70:30 to 90:10.
o-xylene was charged to the mass obtained and heated at 135-145°C till the racemic compound (I) with 50:50 ratio of (S):(R) is obtained. The racemic isomer (I) obtained is isolated by complete distillation of o-xylene under vacuum below 80°C. The racemic isomer is recycled in the step (I).

Example 2
Preparation of (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (I)
3-bromo-1,3,4,5-tetrahydro-1-benzazepin-2-one (100 gm) was charged to propylene glycol (100 ml) and stirred for 10-15 minutes at 30-35ºC. (S)-(-)alpha-methylbenzylamine (55.36 gm) was charged and the temperature was raised to 105-110ºC and the mixture was stirred for about 4 hours.
The mass was gradually cooled to 75-80ºC and isopropyl alcohol (50 ml) was added gradually over 60-70 minutes. Water (125 ml) was charged gradually to the mass at 40-45ºC over 2-3 hours. The mixture was stirred for 15-20 minutes. The mass was cooled to 30-35ºC and stirred for 1-1.5 hours. The mass was filtered and the solid was washed with water (2x100 ml). The solid was suck dried under vacuum at room temperature and (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (105 gm) was formed.

Example 3
Preparation of (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (IS)
(3RS)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (100 gm) was charged to ethyl acetate (200 ml) at 30-35ºC. The mixture was heated to 60-70ºC and stirred for 1 hour. The mass was cooled to 25-30ºC and further cooled to 5-10ºC. The mass was stirred for about 1 hour at 5-10ºC. The mass was filtered and the precipitate was washed with ethyl acetate (100 ml). The solid obtained was suck dried well under vacuum and the solid was charged to ethyl acetate (500 ml) at 25-30ºC. The temperature of the mixture was raised to 60-65ºC and stirred for about 1 hour. The mass was gradually cooled to 25-30ºC and further to 5-10ºC. The suspension was filtered and the wet solid was washed with chilled ethyl acetate (100 ml). The solid obtained was suck dried and further dried under vacuum at 50-55ºC for 6-7 hours to obtain the compound (IS) (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (41 g). The filtrate was kept aside for recovery of undesired isomer.
Chiral HLPC: (IS) isomer: 99.73% and (IR) isomer: 0.27%

Example 4
Enrichment of (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (IS)
Ethyl acetate (500 ml) was charged to (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one isolated in example 2 at 25-30°C. The mixture was stirred for 15-20 minutes. The mixture was heated to 60-65°C and then stirred for 1-2 hours. The mixture was gradually cooled to 25-30°C and further to 5-10°C. The suspension was filtered and washed with chilled ethyl acetate (100 ml). The solid obtained was suck dried and further dried under vacuum at 50-55ºC for 6-7 hours to obtain the compound (IS) (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one. The filtrate was kept aside for recovery of undesired isomer.
Chiral HPLC: (IS) isomer: 99.94% and (IR): 0.06%

Example 5
Recovery of (3R)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one
The filtrate obtained in example 3 and 4 containing ethyl acetate was distilled under vacuum completely to isolate (3R)-3-[[(1S)-1-phenylethyl] amino]-1,3,4,5-tetrahydro -1-benzazepin -2-one.
Chiral HPLC: (IR) isomer: 70% and (IS): 30%

Example 6
Preparation of (I) by racemization of (3R)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (IR)
o-xylene (200 ml) was added to the recovered (3R)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one in example 5. The temperature was raised to 135-145ºC and the mass was stirred for 6-8 hours. The sample was submitted for in process analysis. The result of the analysis was as follows:
Chiral HPLC: (IR) isomer: 60% and (IS): 40%
The heating of the reaction mass at 135-145ºC was continued till the limit of (R)-isomer (NMT 50) is achieved. The mass was cooled to 75-80ºC. o-xylene was distilled under vacuum. The isolated (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (I) was recyled in process as explained in example 3.

In the context of the present invention, the process of the present invention is economically feasible due to the racemization and recycling of the undesired isomer. The process avoids use of resolving agent and hence it avoids salt making and breaking which reduces time cycle of the reaction. Due to ease of handling operations, the process is suitable for large scale production.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.