Improved process for synthesis of benazepril intermediates

Abstract

The present invention relates to an improved process for the stereospecific preparation of a benazepril (Benazepril) intermediate (3S)-3-[[(1S)-1-phenylethyl] amino]-1, 3, 4, 5-tetrahydro-1-benzoazepine-2-one of formula (IS), in particular to a process for the stereospecific preparation of a benazepril intermediate (3S)-3-[[(1S)-1-phenylethyl] amino]-1, 3, 4, 5-tetrahydro-1-benzoazepine-2-one of formula (IS). The method comprises the following steps: heating the compound (3RS)-[[(1S)-1-phenylethyl] amino]-1, 3, 4, 5-tetrahydro-1-benzoazepine-2-one of formula (I) in a predetermined solvent at a predetermined temperature, followed by the separation of the undissolved desired isomer of formula (IS) from the reaction mixture of step (i); recovering the R-isomer of formula (IR) from the filtrate, followed by distillation of the filtrate to separate the R-isomer compound of formula (IR); the R-isomer of formula (IR) is racemized to form a racemic mixture of formula (I), and the racemic compound obtained in step (iv) is recovered by distilling the solvent of the previous step under vacuum, and the racemic compound is added to step (i) for recycling.

Description

Technical Field

[0001] The present invention relates to a method for preparing a benazepril intermediate, and more particularly to an improved method for preparing the benazepril intermediate (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one. Background Art

[0002] Benazepril (A) and its pharmaceutically active salts are an ACE inhibitor and are sold as Lotensin. They are used for hypertension, heart failure and diabetic nephropathy and are chemically named 2-[(3S)-3-[((1S)-1-ethoxycarbonyl-3-phenyl-propyl)amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid.

[0003]

[0004] (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 shown in the following formula (I):

[0005]

[0006] Various methods for preparing such intermediates are known in the literature. Shieh et al. reported the synthesis of (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one in a research article entitled "Asymmetric Synthesis of N-Substituted r-Aminobenzlactam via Crystallization-Induced Asymmetric Transformation of Covalent Diastereomer". The method involves suspending the diastereomers in a non-polar solvent and heating to 140-160°C. The reaction mixture is diluted with cyclohexane and the mixture is cooled to room temperature. The desired (S,S) product is collected by filtration. The literature reports a diastereoisomer ratio of (99:1) with a yield of 93% when the reaction is carried out in mineral oil at 140°C for 16 hours.

[0007] CN102250004B reports a solvent-free reaction method to obtain higher conversions. Racemic (3RS)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one obtained from the previous stage is heated to 130-160°C and the undesired isomer is converted to the desired isomer in the molten state, and the reported yield is 70-80%.

[0008] The benazepril intermediate discussed above is the most critical for preparation because it has two chiral centers and both have S configuration. There are some practical obstacles in the method of Shieh et al. When the method of Shiel et al. was replicated by a person skilled in the art, it was observed that the reaction mass became hard after the addition of cyclohexane. (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one was neither soluble in mineral oil nor in cyclohexane and became a very viscous slurry. It was observed that after cooling, it adhered to the walls of the reactor. In addition, it did not produce the required diastereoisomer ratio. Therefore, due to the inconvenience of operation, the method is not feasible and cannot be mass-produced.

[0009] In the process reported in CN102250004B for racemizing the undesired isomer (IR) to (I), racemization was achieved. However, since the process is solvent-free, decomposition of the compound was observed at higher temperatures (e.g., 160° C.). Due to the decomposition, a loss in yield was observed.

[0010] Due to the above technical difficulties of the methods cited in the prior art, it is necessary to develop a method that can be used for larger-scale production. In addition, a method that is environmentally friendly and easy to operate is needed.

[0011] Purpose of the Invention

[0012] The object of the present invention is to provide an improved method for synthesizing the benazepril intermediate (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one, which is industrially feasible and applicable.

[0013] Another object of the present invention is to racemize the undesired isomer (3R)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one and reuse it in the reaction, thereby increasing the yield and making the process cost-effective. Summary of the invention

[0014] A method for stereospecifically synthesizing [(3S)-3-[((1S)-1-ethoxycarbonyl-3-phenyl-propyl)amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid of formula (I), the method comprising the following steps: heating the compound (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one of formula (I) at a predetermined temperature in a predetermined solvent; separating the undissolved The method comprises the steps of: recovering the desired isomer of formula (IS) from the filtrate, recovering the R-isomer of formula (IR) from the filtrate, and then distilling the filtrate to separate the R-isomer compound of formula (IR); racemizing the isomer by heating the R-isomer of formula (IR) in a predetermined solvent at a predetermined temperature to form a racemic mixture of formula (I); and recovering the racemic compound obtained in step (iv) by distilling the solvent of the previous step under vacuum, and recycling by adding the racemic compound to step (i). The predetermined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, ethyl tert-butyl acetate and methyl acetate. The predetermined temperature in step (i) is 50-90°C, preferably 55-80°C and more preferably 60-70°C. The (IR) isomer is a mixture of (R) and (S) isomers in a ratio ranging from 70:30 to 90:10. The predetermined solvent in step (iv) is selected from o-xylene, toluene, dimethylformamide and dimethylacetamide. The predetermined temperature in step (iv) is 120-160°C, preferably 130-150°C and more preferably 135-145°C. DETAILED DESCRIPTION

[0015] The present invention relates to an improved process for stereospecifically preparing the benazepril intermediate (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one of formula (IS).

[0016]

[0017] The foregoing objects of the present invention are achieved and the problems and disadvantages associated with the prior art, processes and methods are overcome by the present invention as described in the preferred embodiments below.

[0018] All materials used herein were either commercially available as described herein or prepared from commercially available materials as described herein.

[0019] Although specific terms are used in the following description for the sake of clarity, these terms are intended only to refer to specific structures of the present invention selected for illustration in the drawings and are not intended to define or limit the scope of the present invention.

[0020] References in the specification to "preferred embodiments" mean that a particular feature, structure, characteristic, or function is described in detail, whereas well-known constructions and functions are omitted for the purpose of clearly describing the present invention.

[0021] In one embodiment of the present invention, an improved process for preparing the compound of formula (IS) is disclosed.

[0022]

[0023] The method for preparing the benazepril intermediate compound of formula (IS) comprises the following steps:

[0024] i) heating a compound of formula (I) (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one at a predetermined temperature in a predetermined solvent;

[0025]

[0026] ii) separating the undissolved desired isomer of formula (IS) from the reaction mixture of step (i) by filtration;

[0027] iii) recovering the R-isomer of formula (IR) from the filtrate, and then distilling the filtrate to separate the R-isomer compound of formula (IR);

[0028]

[0029] iv) racemizing the R-isomer of formula (IR) by heating the isomer in a predetermined solvent at a predetermined temperature to form a racemic mixture of formula (I); and

[0030]

[0031] v) recovering the racemic compound obtained in step (iv) by distilling the solvent of the previous step under vacuum and recycling it by adding it to step (i).

[0032] According to this embodiment, in step (i), the predetermined temperature is 50-90°C, preferably 55-80°C; in particular 60-70°C. The predetermined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, ethyl tert-butyl acetate and methyl acetate. The (IR) isomer of step (iii) is a mixture of (IR): (IS) isomers in a ratio of 70:30-90:10. The predetermined temperature in step (iv) is 120-160°C, preferably 130-150°C, in particular 135-145°C. The heating in step (iv) is carried out to obtain a 50:50 mixture of compounds of formula (IR) and (IS). The predetermined solvent in step (iv) is selected from o-xylene, toluene, dimethylformamide and dimethylacetamide.

[0033] A schematic diagram of the method of the present invention is shown below.

[0034]

[0035] Examples

[0036] Only a few examples and embodiments are disclosed herein. Variations, modifications and enhancements to the described examples and embodiments and other embodiments may be made based on what is disclosed.

[0037] Examples are set forth below and illustrate different amounts and types of reactants and reaction conditions that can be used to practice the present disclosure. However, it will be apparent that the present disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices can have a variety of properties and uses according to the present disclosure noted above and below.

[0038] Example 1

[0039] Preparation of compounds of formula (IS)

[0040] The compound of formula (I) is charged into ethyl acetate and the mixture is heated to 60-70° C. for at least 1-2 hours. The undesirable (IR) isomer is dissolved in the solvent, while the desired (IS) isomer is separated by filtration. The amount of the undesirable isomer (IR) content in the desired isomer (IS) is analyzed. If the (IR) content is greater than 0.1%, the residue is again charged into fresh ethyl acetate and heated to 60-70° C. for at least 1-2 hours.

[0041] The filtrate was completely distilled off under vacuum at 80-85°C and the undesired isomer (IR) was separated. The undesired isomer (IR) was obtained as a mixture of (IR) and (1S) isomers. The ratio of (IR): (1S) was 70:30 to 90:10.

[0042] o-Xylene is charged to the obtained material and heated at 135-145° C. until a racemic compound (I) with a (S):(R) ratio of 50:50 is obtained. The obtained racemic isomer (I) is separated by complete distillation of o-Xylene under vacuum at less than 80° C. The racemic isomer is recycled in step (I).

[0043] Example 2

[0044] Preparation of (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (I)

[0045] 3-Bromo-1,3,4,5-tetrahydro-1-benzazepin-2-one (100 gm) was charged into propylene glycol (100 ml) and stirred for 10-15 minutes at 30-35° C. (S)-(-)α-methylbenzylamine (55.36 gm) was charged and the temperature was raised to 105° C.-110° C. and the mixture was stirred for about 4 hours.

[0046] The mass was gradually cooled to 75-80°C and isopropanol (50 ml) was gradually added over 60-70 minutes. Water (125 ml) was gradually charged to the mass at 40-45°C over 2-3 hours. The mixture was stirred for 15-20 minutes. The mass was cooled to 30-35°C and stirred for 1-1.5 hours. The mass was filtered and the solid was washed with water (2×100 mL). The solid was sucked dry under vacuum at room temperature and (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (105 gm) was formed.

[0047] Example 3

[0048] Preparation of (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (IS)

[0049] (3RS)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (100 gm) was charged in ethyl acetate (200 ml) at 30-35°C. The mixture was heated to 60-70°C and stirred for 1 hour. The material was cooled to 25-30°C and further cooled to 5-10°C. The material was stirred at 5-10°C for about 1 hour. The material was filtered and the precipitate was washed with ethyl acetate (100 ml). The solid obtained was sucked dry under vacuum and the solid was charged in ethyl acetate (500 ml) at 25-30°C. The temperature of the mixture was raised to 60-65°C and stirred for about 1 hour. The material was gradually cooled to 25-30°C and further cooled to 5-10°C. The suspension was filtered and the wet solid was washed with cooled ethyl acetate (100 ml). The obtained solid was sucked dry and further dried under vacuum at 50-55° C. for 6-7 hours to obtain compound (IS) (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (41 g). The filtrate was kept aside to recover the undesired isomer.

[0050] Chiral HLPC: (IS) isomer: 99.73% and (IR) isomer: 0.27%

[0051] Example 4

[0052] Enrichment of (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (IS)

[0053] Ethyl acetate (500 ml) was charged into the (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 cooled to 5-10°C. The suspension was filtered and washed with cooled ethyl acetate (100 ml). The obtained solid was suction dried and further dried under vacuum at 50-55°C for 6-7 hours to obtain compound (IS) (3S)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one. The filtrate was kept aside to recover the undesired isomer.

[0054] Chiral HPLC: (IS) isomer: 99.94% and (IR): 0.06%

[0055] Example 5

[0056] Recovery of (3R)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one

[0057] The filtrates containing ethyl acetate obtained in Examples 3 and 4 were completely distilled under vacuum to separate (3R)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one.

[0058] Chiral HPLC: (IR) isomer: 70% and (IS): 30%

[0059] Example 6

[0060] By reacting (3R)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (IR) racemization to prepare (I)

[0061] To the (3R)-3-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one recovered in Example 5 was added o-xylene (200 ml). The temperature was raised to 135-145°C and the material was stirred for 6-8 hours. A sample was submitted for in-process analysis. The results of the analysis were as follows:

[0062] Chiral HPLC: (IR) isomer: 60% and (IS): 40%

[0063] The reaction mass was heated at 135-145°C until the limit of the (R)-isomer (NMT 50) was reached. The mass was cooled to 75-80°C. O-Xylene was distilled under vacuum. The isolated (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one (I) was recycled as explained in Example 3.

[0064] In the context of the present invention, the method of the present invention is economically feasible due to the racemization and recycling of undesirable isomers. The method avoids the use of solvents and therefore avoids the generation and decomposition of salts, which reduces the time cycle of the reaction. Due to the simplicity of the processing operation, the method is suitable for large-scale production.

[0065] The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. The embodiments are not intended to be exhaustive or to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teachings.

[0066] The embodiments were chosen and described in order to best explain the principles of the invention and its practical application, to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated.

[0067] It is to be understood that various omissions and substitutions of equivalents are contemplated as circumstances may indicate or render advantageous, but such omissions and substitutions are intended to cover applications or embodiments without departing from the spirit or scope of the invention.

Claims

1. A method for stereospecifically synthesizing [(3S)-3-[((1S)-1-ethoxycarbonyl-3-phenyl-propyl)amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid of formula (I), The method comprises: i) heating a compound of formula (I) (3RS)-[[(1S)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one at a predetermined temperature in a predetermined solvent; ii) separating the 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, and then distilling the filtrate to separate the R-isomer compound of formula (IR); iv) racemizing the R-isomer of formula (IR) by heating the isomer in a predetermined solvent at a predetermined temperature to form a racemic mixture of formula (I); and v) recovering the racemic compound obtained in step (iv) by distilling the solvent of the previous step under vacuum and recycling it by adding it to step (i).

2. The method according to claim 1, wherein the predetermined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, ethyl tert-butyl acetate and methyl acetate.

3. The method according to claim 1, wherein the acetate solvent is ethyl acetate.

4. The method according to claim 1, wherein the predetermined temperature in step (i) is 50-90°C, preferably 55-80°C and more preferably 60-70°C.

5. The method according to claim 1, wherein the (IR) isomer is a mixture of (R) and (S) isomers in a ratio ranging from 70:30 to 90:

10.

6. The method according to claim 1, wherein the predetermined solvent in step (iv) is selected from o-xylene, toluene, dimethylformamide and dimethylacetamide.

7. The method according to claim 1, wherein the predetermined temperature in step (iv) is 120-160°C, preferably 130-150°C and more preferably 135-145°C.

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