A process for the preparation of a key intermediate of benazepril hydrochloride

Abstract

The application discloses a method for synthesizing a key intermediate (compound I) of benazepril hydrochloride from L-homophenylalanine, which comprises the following steps: (1) dispersing L-homophenylalanine (compound VI) in a solvent, adding a silicon reagent, and reacting and dissolving the solution by heating; (2) adding a base and compound III into the reaction system, and continuing to heat and react for 40-60 hours; and (3) adding an acid into the reaction system for quenching treatment, and cooling and filtering to obtain the compound I.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to the preparation of key intermediates for the antihypertensive drug benazepril hydrochloride. Background Technology

[0002] Angiotensin-converting enzyme (ACE) inhibitors work by inhibiting ACE, preventing the conversion of angiotensin I into active angiotensin II. This allows blood vessels to relax and dilate, reducing resistance to the heart's pumping action, thereby lowering blood pressure and reducing the burden on the heart. They are widely used clinically. (1'S,3S)-3-[(1'-carboxylic acid-3'-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzozazane (Compound I) is a key intermediate in the synthesis of the ACE inhibitor benazepril hydrochloride, and its chemical structure is as follows:

[0003]

[0004] Compound I

[0005] This compound contains two chiral centers (S,S), making its synthesis somewhat challenging. The main synthetic methods reported so far are as follows:

[0006] Patent CN1537103A discloses the synthesis process of compound I, using L-homophenylalanine ethyl ester hydrochloride (compound II) and 3-bromo-2,3,4,5-tetrahydro-1H-1-benzozazon-2-one (compound III) as starting materials, and obtaining compound I through substitution, hydrolysis, and epimerization. The chemical reaction formula is as follows:

[0007]

[0008] This method introduces a chiral center with a chiral raw material (II), and then cleverly uses high-temperature epimerization and dynamic crystallization separation to construct another chiral center. However, it needs to be carried out at a pressure of 1.5 atm and a temperature of 150-155℃. The reaction temperature is high and the equipment requirements are high, which is not conducive to industrial production.

[0009] Similarly, patent CN101830850B reports a method for converting the (1'S,3R) diastereomer of compound I into compound I, with the following reaction formula:

[0010]

[0011] This method purifies and separates the (1'S,3R) diastereomer of compound I in the form of sodium salt, and then performs epimerization in a buffer system with a pH of 5-6, which can significantly reduce the reaction temperature to 110°C. o C, but with the addition of a purification and separation step.

[0012] In summary, existing methods for synthesizing compound I have problems such as demanding conditions, numerous steps, and cumbersome operations, which are not conducive to industrial-scale production. Summary of the Invention

[0013] This invention provides a novel method for synthesizing compound I. This method is simple to operate, has few steps, reduces the generation of waste, and is suitable for large-scale industrial production.

[0014] After extensive experimental research, the inventors made a surprising discovery: L-homophenylalanine (compound VI), in the presence of a silicon reagent, can undergo a substitution reaction with compound III while simultaneously achieving epimerization, directly generating compound I. This significantly improves the synthesis efficiency of compound I. The reaction formula is as follows:

[0015]

[0016] The silicon protecting agent is selected from one of BSA, BSTFA, MTBSTFA, TMSPi, and HMDS, and has the following structural formula:

[0017] ;

[0018] The alkali is selected from one or more of sodium bicarbonate, potassium bicarbonate, dipotassium hydrogen phosphate, and disodium hydrogen phosphate;

[0019] The acid is acetic acid or citric acid;

[0020] The reaction temperature is 80-110°C. o C.

[0021] The method includes the following steps:

[0022] (1) L-Hyperphenylalanine (compound VI) was dispersed in a solvent, a silicon reagent was added, and the mixture was heated to react and dissolve.

[0023] (2) Add alkali and compound III to the reaction system and continue the reaction at a constant temperature for 40-60 h;

[0024] (3) Add acid to the reaction system for quenching, cool and filter to obtain compound I;

[0025] The obtained compound I was then subjected to ethyl esterification, condensation, and detert-butyl ester protection to obtain benazepril hydrochloride, as shown in the following reaction formula:

[0026] Attached Figure Description

[0027] Figure 1 Compound I 1 HNMR image

[0028] Figure 2 HPLC chromatograms of compound I (1'S, 3S) and its diastereomers (1'S, 3R) Detailed Implementation

[0029] The present invention can be understood more specifically through the following examples, but they are illustrative and not intended to limit the scope of the invention.

[0030] Example 1:

[0031] A method for preparing compound I, the synthetic route is as follows:

[0032]

[0033] A three-necked flask equipped with a magnetic stirrer was used. 9.4 g of L-homophenylalanine, 21.3 g of N,O-bis(trimethylsilyl)acetamide (BSA), and 50 mL of toluene were added. The mixture was heated and stirred at 60°C for 1 hour until the reaction was complete. Then, 12.0 g of α-bromobenzocaprolactam (compound III) and 4.6 g of sodium bicarbonate were added. The mixture was heated to 110°C and stirred for 60 hours until the reaction was complete. The temperature was lowered to 25°C, and 50 mL of water and 7.5 g of acetic acid were added to quench the reaction. The mixture was filtered to obtain a white solid. After drying, compound I was obtained, a white solid weighing 11.80 g (60.78% yield).

[0034] Compound (I) was detected by high performance liquid chromatography (HPLC) as a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 99.38:0.62. LCMS analysis was performed at (ESI+) m / z ([M+H]). + ): 339.2.

[0035] Example 2:

[0036] A method for preparing compound I, the synthetic route is as follows:

[0037]

[0038] Take a three-necked flask equipped with a magnetic stirrer, add 9.4 g of L-homophenylalanine, 25.3 g of N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA), and 50 mL of toluene. Heat and stir at 60 °C for 1 h to complete the reaction. Then add 12.0 g of α-bromobenzocaprolactam (compound III) and 4.6 g of sodium bicarbonate. Heat to 110 °C and stir for 60 h to complete the reaction. Cool to 25 °C, add 50 mL of water and 7.5 g of acetic acid to quench the reaction, filter to obtain an off-white solid, dry to obtain compound I, 11.90 g of off-white solid, yield 61.30%.

[0039] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 97.69:2.31.

[0040] Example 3:

[0041] A method for preparing compound I, the synthetic route is as follows:

[0042]

[0043] Take a three-necked flask equipped with a magnetic stirrer, add 9.4 g of L-homophenylalanine, 16.9 g of hexamethyldisilazane (HMDS), and 50 mL of toluene. Heat and stir at 60 °C for 1 h to complete the reaction. Then add 12.0 g of α-bromobenzocaprolactam (compound III) and 4.6 g of sodium bicarbonate. Heat to 110 °C and stir for 60 h to complete the reaction. Cool to 25 °C, add 50 mL of water and 7.5 g of acetic acid to quench the reaction, filter to obtain an off-white solid, dry to obtain compound I, 12.00 g of off-white solid, yield 61.82%.

[0044] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 98.79:1.21.

[0045] Example 4:

[0046] A method for preparing compound I, the synthetic route is as follows:

[0047]

[0048] Take a three-necked flask equipped with a magnetic stirrer, add 9.4 g of L-homophenylalanine, 27.0 g of N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), and 50 mL of toluene. Heat and stir at 60 °C for 1 h to complete the reaction. Then add 12.0 g of α-bromobenzocaprolactam (compound III) and 4.6 g of sodium bicarbonate. Heat to 110 °C and stir for 60 h to complete the reaction. Cool to 25 °C, add 50 mL of water and 7.5 g of acetic acid to quench the reaction, filter to obtain an off-white solid, dry to obtain compound I, 11.60 g of off-white solid, yield 59.75%.

[0049] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 98.98:1.02.

[0050] Example 5:

[0051] A method for preparing compound I, the synthetic route is as follows:

[0052]

[0053] Take a three-necked flask equipped with a magnetic stirrer, add 9.4 g of L-homophenylalanine, 31.3 g of tris(trimethylsilyl)phosphite (TMSPi), and 50 mL of toluene. Heat and stir at 60 °C for 1 h to complete the reaction. Then add 12.0 g of α-bromobenzocaprolactam (compound III) and 4.6 g of sodium bicarbonate. Heat to 110 °C and stir for 60 h to complete the reaction. Cool to 25 °C, add 50 mL of water and 7.5 g of acetic acid to quench the reaction, filter to obtain an off-white solid, dry to obtain compound I, 11.65 g of off-white solid, yield 60.01%.

[0054] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 98.28:1.72.

[0055] Example 6:

[0056] A method for preparing compound I, the synthetic route is as follows:

[0057]

[0058] A three-necked flask equipped with a magnetic stirrer was used. 9.4 g of L-homophenylalanine, 21.3 g of N,O-bis(trimethylsilyl)acetamide (BSA), and 50 mL of acetonitrile were added. The mixture was heated and stirred at 60°C for 1 hour until the reaction was complete. Then, 12.0 g of α-bromobenzocaprolactam (compound III) and 4.6 g of sodium bicarbonate were added. The mixture was heated to 80°C and stirred for 60 hours until the reaction was complete. The temperature was lowered to 25°C, and 50 mL of water and 7.5 g of acetic acid were added to quench the reaction. The mixture was filtered to obtain a white solid. After drying, compound I was obtained, a white solid weighing 11.85 g, with a yield of 61.04%.

[0059] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 99.03:0.97.

[0060] Example 7:

[0061] A method for preparing compound I, the synthetic route is as follows:

[0062]

[0063] A three-necked flask equipped with a magnetic stirrer was used. 9.4 g of L-homophenylalanine, 21.3 g of N,O-bis(trimethylsilyl)acetamide (BSA), and 50 mL of acetonitrile were added. The mixture was heated and stirred at 60°C for 1 hour until the reaction was complete. Then, 12.0 g of α-bromobenzocaprolactam (compound III) and 9.58 g of dipotassium hydrogen phosphate were added. The mixture was heated to 80°C and stirred for 60 hours until the reaction was complete. The temperature was lowered to 25°C, and 50 mL of water and 7.5 g of acetic acid were added to quench the reaction. The mixture was filtered to obtain a white solid. After drying, compound I was obtained, a white solid weighing 12.05 g, with a yield of 62.08%.

[0064] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 98.62:1.38.

[0065] Example 8:

[0066] A method for preparing compound I, the synthetic route is as follows:

[0067]

[0068] A three-necked flask equipped with a magnetic stirrer was used. 9.4 g of L-homophenylalanine, 21.3 g of N,O-bis(trimethylsilyl)acetamide (BSA), and 50 mL of toluene were added. The mixture was heated and stirred at 60°C for 1 hour until the reaction was complete. Then, 12.0 g of α-bromobenzocaprolactam (compound III) and 9.58 g of dipotassium hydrogen phosphate were added. The mixture was heated to 110°C and stirred for 60 hours until the reaction was complete. The temperature was then lowered to 25°C, and 50 mL of water and 7.5 g of acetic acid were added to quench the reaction. The mixture was filtered to obtain a white solid. After drying, compound I was obtained, a white solid weighing 12.11 g (62.38% yield).

[0069] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 98.71:1.29.

[0070] Example 9:

[0071] A method for preparing compound I, the synthetic route is as follows:

[0072]

[0073] A three-necked flask equipped with a magnetic stirrer was used. 9.4 g of L-homophenylalanine, 21.3 g of N,O-bis(trimethylsilyl)acetamide (BSA), and 50 mL of toluene were added. The mixture was heated and stirred at 60°C for 1 hour until the reaction was complete. Then, 12.0 g of α-bromobenzocaprolactam (compound III) and 5.48 g of potassium bicarbonate were added. The mixture was heated to 110°C and stirred for 60 hours until the reaction was complete. The temperature was then lowered to 25°C, and 50 mL of water and 7.5 g of acetic acid were added to quench the reaction. The mixture was filtered to obtain a white solid. After drying, compound I was obtained, a white solid weighing 11.13 g (yield 57.33%).

[0074] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 99.12:0.88.

[0075] Example 10:

[0076] A method for preparing compound I, the synthetic route is as follows:

[0077]

[0078] A three-necked flask equipped with a magnetic stirrer was used. 9.4 g of L-homophenylalanine, 21.3 g of N,O-bis(trimethylsilyl)acetamide (BSA), and 50 mL of acetonitrile were added. The mixture was heated and stirred at 60°C for 1 hour until the reaction was complete. Then, 12.0 g of α-bromobenzocaprolactam (compound III) and 5.48 g of potassium bicarbonate were added. The mixture was heated to 80°C and stirred for 60 hours until the reaction was complete. The temperature was lowered to 25°C, and 50 mL of water and 7.5 g of acetic acid were added to quench the reaction. The mixture was filtered to obtain an off-white solid. After drying, compound I was obtained, yielding 11.15 g of an off-white solid (57.44% yield).

[0079] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 99.23:0.77.

[0080] Example 11:

[0081] A method for preparing compound I, the synthetic route is as follows:

[0082]

[0083] A three-necked flask equipped with a magnetic stirrer was used. 9.4 g of L-homophenylalanine, 21.3 g of N,O-bis(trimethylsilyl)acetamide (BSA), and 50 mL of acetonitrile were added. The mixture was heated and stirred at 60°C for 1 hour until the reaction was complete. Then, 12.0 g of α-bromobenzocaprolactam (compound III) and 7.81 g of disodium hydrogen phosphate were added. The mixture was heated to 80°C and stirred for 60 hours until the reaction was complete. The temperature was then lowered to 25°C, and 50 mL of water and 7.5 g of acetic acid were added to quench the reaction. The mixture was filtered to obtain a white solid. After drying, compound I was obtained, a white solid weighing 11.05 g, with a yield of 56.92%.

[0084] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 99.13:0.87.

[0085] Example 12:

[0086] A method for preparing compound I, the synthetic route is as follows:

[0087]

[0088] A three-necked flask equipped with a magnetic stirrer was used. 9.4 g of L-homophenylalanine, 21.3 g of N,O-bis(trimethylsilyl)acetamide (BSA), and 50 mL of toluene were added. The mixture was heated and stirred at 60 °C for 1 h until the reaction was complete. Then, 12.0 g of α-bromobenzocaprolactam (compound III) and 7.81 g of disodium hydrogen phosphate were added. The mixture was heated to 110 °C and stirred for 60 h until the reaction was complete. The temperature was lowered to 25 °C, and 50 mL of water and 7.5 g of acetic acid were added to quench the reaction. The mixture was filtered to obtain a white solid. After drying, compound I was obtained, a white solid weighing 11.16 g (yield 57.49%).

[0089] Compound (I) was determined by high performance liquid chromatography (HPLC) to be a mixture of diastereomers (1'S,3S):(1'S,3R) in a ratio of 99.25:0.75.

[0090] Diastereomer testing methods

[0091] The liquid chromatography conditions are as follows:

[0092] Column: Octadecyl bonded silica gel as packing material (Shimadzu GL Sciences, 250 mm x 4.6 mm, 5 μm or equivalent column).

[0093] Mobile phase A: Acetonitrile;

[0094] Mobile phase B: Phosphate buffer (1.36 g / L potassium dihydrogen phosphate aqueous solution, adjusted to pH 4.0 with phosphoric acid);

[0095] Mobile phase A : Mobile phase B = 25 : 75

[0096] Flow rate: 1.0 mL / min

[0097] Column temperature: 30℃

[0098] Detection wavelength: 239 nm

[0099] Runtime: 35 min

[0100] Injection volume: 10µL

[0101] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a key intermediate of benazepril hydrochloride, the specific reaction formula of which is as follows: ； Its features Includes the following steps: (1) L-Hyperphenylalanine (compound VI) was dispersed in a solvent, a silicon reagent was added, and the mixture was heated to react and dissolve. (2) Add alkali and compound III to the reaction system and continue the reaction at a constant temperature for 40-60 h; (3) Add acid to the reaction system for quenching, cool and filter to obtain compound I.

2. The method according to claim 1, wherein the silicon protecting agent used in step (1) is selected from one or more of hexamethyldisilazane (HMDS), N,O-bis(trimethylsilyl)acetamide (BSA), N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA), N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), and tri(trimethylsilyl)phosphite (TMSPi).

3. The method according to claim 1, wherein the solvent used in step (1) is selected from one or more mixtures of DMAc, acetonitrile, toluene, and DMF.

4. The method according to claim 1, wherein the base used in step (2) is selected from one or more of sodium bicarbonate, potassium bicarbonate, dipotassium hydrogen phosphate, and disodium hydrogen phosphate.

5. The method according to claim 1, wherein the acid in step (3) is acetic acid or citric acid.

6. The method according to claim 1, wherein the reaction temperature in step (1) is room temperature to 80°C, and the reaction temperature in step (2) is 80°C to 110°C.

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