Method for preparing remimazolam and its salts

Abstract

Disclosed herein is an improved method for the preparation of remimazolam and its salts. The present invention improves upon the use of expensive reagents and the cumbersome steps of methods used in the art, thereby making the method of the present invention cost-effective and industrially feasible.

Description

Technical Field

[0001] The present invention relates to an improved method for the preparation of remimazolam and its salts.

Background Art

[0002] Remimazolam (CNS7056) having the IUPAC name methyl 3-{(4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl} propanoate has the following chemical structure;

Chemical formula

[0003] Remimazolam is a short-acting central nervous system depressant. Remimazolam exhibits anxiolytic, amnestic, sedative, muscle relaxant, and anticonvulsant properties. Due to these properties, remimazolam is suitable for use, for example, as a component for inducing and maintaining general anesthesia before and / or together with the administration of other anesthetics, and in intensive care sedation, in anesthetic practice and intensive care, such as preoperative sedation, anxiolytic effects, amnestic use in perioperative cases, conscious sedation during short diagnostic, surgical, or endoscopic procedures. Remimazolam is preferably administered by the intravenous route.

[0004] Patent Document 1 relates to benzodiazepine derivatives containing remimazolam, and Examples 1c to 8 disclose its preparation.

[0005] Patent Document 2 discloses remimazolam and a method for its preparation. This method is described in Scheme 1.

Chemical formula

Prior Art Documents

[0006] [Patent Document 1] European Patent No. 1183243 [Patent Document 2] U.S. Patent No. 7485635 [Overview of the project] [Problems that the invention aims to solve]

[0007] Methods described in the present art are cumbersome and require expensive reagents and extensive post-processing procedures. Therefore, there remains a need in the art to provide an industrially and economically viable method for the preparation of remimazolam and its salts. This remains an object of the present invention. [Means for solving the problem]

[0008] Accordingly, the present invention provides an improved method for the preparation of remimazolam and its salts, i. A step to obtain (S)-benzyl 5-((4-bromo-2-picolinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (3) by condensing 2-amino-5-bromobenzoylpyridine (1) and (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (2) in the presence of a condensing agent at a temperature range of -5 to 0°C; ii. A step of cyclizing the intermediate compound (3) to obtain (S)-benzyl 4-amino-5-((4-bromo-2-picolinoylphenyl)-amino)-5-oxopentanoate hydrochloride (4); iii. A step in which compound (4) is reacted with bismorpholinophosphine chloride in the presence of a base, followed by the addition of 1-amino2-propanol to obtain benzyl 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridine-2-yl)-3H-benzo[e][1,4]diazepine-3-yl)propanoate (5); iv. A step of oxidizing compound (5) with a suitable oxidizing agent to obtain (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate (6); v. A step of converting compound (6) to (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoatebenzenesulfonate (7); vi. A step of treating compound (7) with a base to obtain (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate (6); vii. A step of obtaining remimazolam by transesterification of compound (6) in step (vi) using appropriate reagents, and converting it to an appropriate acid addition salt; and viii. Purification of the crude remimazolamic acid addition salt to obtain the desired product. This provides a method that includes [something].

[0009] In one embodiment, compound (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid (2) is i. A step of reacting benzyl alcohol with L-glutamic acid in the presence of an acid to obtain (S)-2-amino-5-(benzyloxy)-5-oxopentanoic acid (i.e., benzyl L-glutamate); and ii. In step (i), (S)-2-amino-5-(benzyloxy)-5-oxopentanoic acid is reacted with a protecting agent at 0 to 5 °C in the presence of a base to obtain (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid. It is prepared by a method comprising.

Embodiments for Carrying Out the Invention

[0010] Detailed Description of the Invention In one embodiment, the present invention is an improved and cost-effective method for the preparation of remimazolam and its salts, i. A step of condensing 2-amino-5-bromobenzoylpyridine (1) and (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid (2) in the presence of a condensing agent at a temperature range of -5 to 0 °C to obtain (S)-benzyl 5-((4-bromo-2-picolinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (3);

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0011] According to step (i) of the method, a condensing agent selected from dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), etc., dissolved in a solvent at the aforementioned temperature is added dropwise to a solution mixture of 2-amino-5-bromobenzoylpyridine (1) and (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid (2) (i.e., N-Boc L-glutamic acid-γ-benzyl ester). The reaction mixture is stirred at 0°C for approximately 24 hours. The addition of N-Boc L-glutamic acid-γ-benzyl ester and the condensing agent is added intermittently to the mixture at 0°C while stirring, and the reaction is monitored by HPLC. After the reaction is complete, the reaction mass is filtered and washed with a suitable solvent, and the filtrate is distilled under vacuum to obtain (S)-benzyl 5-((4-bromo-2-picolinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (3).

[0012] Step (ii) of the method of the present invention involves dissolving the compound (S)-benzyl 5-((4-bromo-2-picolinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (3) obtained in step (i), cooling to a temperature of 5-10°C, and then slowly adding 1,4-dioxane HCl to the cooled mixture and stirring for about 1-3 hours. After the completion of the reaction, the reaction mixture is slowly poured into a mixture of base and solvent at 5-10°C, the temperature is raised to 10-15°C and stirred until the completion of the reaction. The reaction mixture is then filtered, washed, and the solvent is removed under vacuum, and the crude compound is further purified to obtain (S)-benzyl 4-amino-5-((4-bromo-2-picolinoylphenyl)-amino)-5-oxopentanoate hydrochloride (4).

[0013] According to step (iii) of this method, a base selected from lithium diisopropylamide (LDA) or sodium hydride was added to a solution of compound (4) and dry THF at a low temperature of -20 to -15°C. The reaction mixture was stirred at 0°C for about 1.5 to 3 hours, followed by the addition of bismorpholinophosphine chloride (BMPC) at the same temperature, and the mixture was stirred for a further 2 to 3 hours. 1-amino-2-propanol was added to the reaction mixture at 0°C, and the reaction was stirred overnight at room temperature. The solvent was removed under vacuum, followed by the addition of a suitable solvent and washing. The solvent was removed from the organic layer under vacuum to obtain the crude compound, which was further purified to obtain benzyl 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridine-2-yl)-3H-benzo[e][1,4]diazepine-3-yl)propanoate (5).

[0014] Step (iv) of the method of the present invention comprises adding a suitable mild oxidizing agent selected from desmartin periodinane or pyridinium dichromate to a solution of compound (5) and THF cooled to 15-25°C, and stirring the reaction mixture for about 2-3 hours. After the completion of the reaction, the reaction mixture was filtered and washed. The filtrate was collected, the THF was completely removed by distillation, washed with a solvent, and the solvent was removed by distillation to obtain (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate (6).

[0015] Step (v) of the method includes dissolving compound (6) in a suitable solvent, followed by adding an organic acid selected from methanesulfonic acid, ethanesulfonic acid, and the like to the solvent. The reaction mixture is stirred at room temperature for about 2 hours, filtered, washed with a suitable solvent, and dried to obtain a suitable salt of compound (7).

[0016] According to step (vi), a suitable acid acid compound (7) was added to a mixture of water and an organic solvent. The pH was adjusted to 10-12 using a base selected from alkali metal or alkaline earth metal carbonates or bicarbonates. The layers were separated, the organic layer was washed, and the solvent was removed under vacuum to obtain compound (6) as a free base.

[0017] Step (vii) involves preparing (S)-methyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate (remimazolam) by transesterification. Thus, compound (6) was added to the solvent and cooled to 5-10°C. Furthermore, 15-20% methanolic HCl was added dropwise to the reaction mixture at 5-10°C, and the reaction mixture was stirred at room temperature. After the completion of the reaction, the reaction mixture was cooled to 0-5°C, and water was slowly added to the mixture at the same temperature. The pH was adjusted to 7.0-8.0 using alkali metal or alkaline earth metal carbonates or bicarbonates. Methanol was removed from the reaction mixture under vacuum at 35-40°C. A suitable solvent was added to the mixture, stirred, the layers were separated, and further washed. The solvent was removed under vacuum, and the desired product was obtained.

[0018] In one embodiment, remimazolam obtained by the method of the present invention was further converted to salts such as mesylates and besylates using a suitable acid.

[0019] In yet another embodiment, the remimazolam salt was purified by adding the remimazolam salt to an organic solvent and boiling it to reflux temperature. The mixture was cooled to room temperature and stirred. The product was filtered, washed with a solvent, and dried under vacuum to obtain the pure remimazolam salt.

[0020] In another embodiment, the solvent for the method of the present invention is selected from polar or nonpolar, protic or aprotic solvents, which include, but are not limited to, alcohols selected from lower aliphatic C1-C5 alcohols, aromatic alcohols such as benzyl alcohol, ethers such as DMF, THF, dimethyl ether, and 1,4-dioxane; hydrocarbons selected from aliphatic or aromatic hydrocarbons, halogenated hydrocarbons such as methylene chloride (MDC), ethylene chloride, chloroform, and carbon tetrachloride; ketones, esters, nitriles, etc., either alone or in combination.

[0021] In one embodiment, the method is characterized by a benzyl ester impurity - A, benzyl 3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propanoate; an acid impurity - B3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propanoic acid; and an ethyl ester impurity - C, ethyl 3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propanoate.

[0022] In yet another embodiment, the present invention relates to the preparation of (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid (2), i. A step of reacting benzyl alcohol with L-glutamic acid in the presence of an acid to obtain (S)-2-amino-5-(benzyloxy)-5-oxopentanoic acid (i.e., benzyl L-glutamate); and ii. A step in which (S)-2-amino-5-(benzyloxy)-5-oxopentanoic acid from step (i) is reacted with a protective agent in the presence of a base at 0-5°C to obtain (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid; It is prepared by a method that includes [a specific method].

[0023] Therefore, an acid selected from methanesulfonic acid, ethanesulfonic acid, or benzylsulfonic acid was added dropwise to a mixture of benzyl alcohol and L-glutamic acid at a temperature range of 40-50°C. The reaction mixture was maintained at the aforementioned temperature for about 2 hours, followed by cooling to 25-30°C. Water was added to the reaction mixture, and the layers were separated. A suitable solvent was added to the aqueous layer, and the pH was adjusted with a suitable base. The solid was filtered, washed, and dried under vacuum to obtain (S)-2-amino-5-(benzyloxy)-5-oxopentanoic acid (i.e., benzyl ester of L-glutamate).

[0024] The L-glutamic acid-γ-benzyl ester thus obtained was added to a mixture of water and solvent and cooled to 0-5°C. A suitable protective agent was selected from boc anhydride, Fmoc chloride, phthalic anhydride, or tert-butoxycarbonyl in the presence of a base selected from organic bases such as ethylamine, triethylamine, and pyridine; preferably, triethylamine was added to the L-glutamic acid-γ-benzyl ester mix at the aforementioned temperature. The reaction mixture was stirred overnight at room temperature, the solvent was evaporated, washed, and dried to obtain (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid (2).

[0025] The solvent for the method of preparing the compound (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid (2) in the present invention was selected from water, aliphatic hydrocarbons or aromatic hydrocarbons, ethers, etc., either alone or in combination thereof.

[0026] Herein, the present invention will be described in the following specific examples, but it should be understood that the details shown are merely illustrative of preferred embodiments of the present invention. [Examples]

[0027] Example 1: Preparation of (S)-2-amino-5-(benzyloxy)-5-oxopentanoic acid (i.e., benzyl L-glutamate)

[0028] Benzyl alcohol (55 g) was added to L-glutamic acid (50 g suspended in toluene). Methanesulfonic acid (39.2 g) was added dropwise to the reaction mixture at 45°C. The reaction mixture was maintained for 2 hours, cooled to 25-30°C, and stirred for 3 hours. Water (100 ml) was added to the reaction mixture, and the layers were separated. Ethanol (50 ml) was added to the aqueous layer, and the pH was adjusted to 6.0 using ammonia solution. The solid was filtered and washed with an ethanol:water mixture (1:1). The solid was dried under vacuum at 45°C to obtain the title product (44 g).

[0029] Example 2: Preparation of (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid

[0030] L-glutamic acid-γ-benzyl ester (44 g) was added to a mixture of water (440 ml) and DMF (440 ml). The reaction mixture was cooled to 0-5°C, and Boc anhydride (41 g) and triethylamine (19.2 g) were added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was slowly raised to room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was removed from the reaction mixture under vacuum. 300 ml of ethyl acetate and 100 ml of water were added to the degassed mixture. The reaction mixture was stirred and cooled to 0-5°C. The pH was adjusted to 1.5-2.5 using 1N HCl. The mixture was stirred for 10 minutes, and the layers were separated. The aqueous layer was re-extracted with 250 ml of ethyl acetate. Both organic layers were combined and washed with water and sodium chloride solution. The solvent was removed under vacuum. The residue was stirred in heptane. The product was filtered and dried in a vacuum oven at 40°C. Yield = 50g

[0031] Example 3: Preparation of (S)-benzyl 5-((4-bromo-2-picolinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate.

[0032] 800 ml of methylene chloride, 100 g of 2-amino-5-bromobenzoylpyridine, and 146 g of N-Boc L-glutamic acid-γ-benzyl ester obtained from Example 2) were added to clean, dry RBF, and the reaction mixture was cooled to -5 to 0°C. 89.3 g of dicyclohexylcarbodiimide dissolved in 100 ml of methylene chloride was added dropwise to the reaction mixture at -5 to 0°C. The reaction mixture was stirred at 0°C for 24 hours. 60 g of N-Boc L-glutamic acid-γ-benzyl ester and 37.2 g of dicyclohexylcarbodiimide were added to the reaction mixture at 0°C. The reaction mixture was stirred for 24 hours. 30.4 g of N-Boc L-glutamic acid-γ-benzyl ester and 18.6 g of dicyclohexylcarbodiimide were added to the reaction mixture at 0°C. The reaction mixture was stirred for a further 24 hours. The reaction was monitored by HPLC. The reaction mixture was filtered, and the solid was washed with methylene chloride. The filtrate (ML) was removed under vacuum. Yield = 300 g

[0033] Example 4: (S)-benzyl 4-amino-5-((4-bromo-2-picolinoylphenyl)-amino)-5-oxopentanoate hydrochloride.

[0034] The compound obtained in Example 3 (300 g) was dissolved in methylene chloride (450 ml). The mixture was cooled to 5-10°C, and 1,4-dioxane HCl (470 ml) was slowly added. The reaction mixture was stirred for 1-3 hours. After the reaction was complete, the reaction mixture was slowly poured into acetonitrile (1000 ml) containing sodium bicarbonate (600 g) at 5-10°C. The reaction mixture was maintained at 10-15°C with stirring for 3 hours. After the reaction was complete, the reaction mixture was filtered, and the solid was washed with acetonitrile. The solvent was removed under vacuum at 35-40°C. The crude material was purified by column chromatography to obtain the title compound (150 g).

[0035] Example 5: Benzyl 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridine-2-yl)-3H-benzo[e][1,4]diazepine-3-yl)propanoate.

[0036] A solution of the compound obtained from Example 4 (250 g) and dried THF (1000 ml) was added to lithium diisopropylamide (LDA) (1.05 mol) at -20 to -15°C. The reaction mixture was stirred at 0°C for 1.5 to 2 hours. The added bismorpholinophosphoryl chloride (BMPC-306 g) was added to the reaction mixture at 0°C and stirred for 2 to 3 hours. 1-amino-2-propanol (80 g) was added to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature overnight. 1-amino-2-propanol (27.5 g) from the second batch was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 24 hours. THF was removed by distillation at 35 to 40°C under vacuum. MDC (1250 ml) was added and washed with a saturated solution of sodium bicarbonate (1000 ml). The layers were separated, and the MDC layer was washed with 500 ml of saturated ammonium chloride solution. The MDC was removed by distillation under vacuum at 35-40°C to obtain the title compound (335 g).

[0037] Example 6: (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate

[0038] The compound obtained in Example 5 (330 g) and a solution of THF (2.5 L) were cooled to 15-25°C. Desmartin periodinane (275 g) was added, and the reaction mixture was stirred for 1 hour. After the reaction was complete, the reaction mixture was filtered and washed with THF. The filtrate was collected, and the THF was completely removed by distillation. Ethyl acetate (3.0 L) was added, and the mixture was washed with a saturated solution of sodium bicarbonate (660 ml). The layers were stirred, allowed to settle, and separated. Ethyl acetate was washed with a saturated solution of ammonium chloride. The product was extracted in a 1N HCl solution. Ethyl acetate was added to the HCl solution, and the product was extracted into the ethyl acetate at a basic pH using sodium hydroxide. The layers were separated, and the ethyl acetate was removed by distillation at 30-40°C under vacuum to obtain the title compound (180 g).

[0039] Example 6a: Oxidation using pyridinium dichromate

[0040] The compound obtained in Example 5 (1.0 g) was dissolved in MDC (20 ml). 2.5 g of pyridinium dichromate (2.5 g) was added, and the reaction mixture was stirred for 24 hours. After the reaction was complete, MTBE (40 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes. The solid was filtered, and the filtrate was washed twice with water (10 ml). The layers were separated, and MTBE was removed by distillation under vacuum at a temperature below 40°C to obtain the title compound (0.8 g).

[0041] Example 7: (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate benzenesulfonate

[0042] The compound from Example 6 (175 g) was dissolved in ethyl acetate (1000 ml). A solution of benzenesulfonic acid was slowly added (53.7 g dissolved in 150 ml of ethyl acetate). The reaction mixture was stirred at room temperature for 2 hours. The product was filtered and washed with ethyl acetate (175 ml). The product was dried at 40-45°C to obtain the title compound (180 g).

[0043] Example 8: (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate

[0044] The compound obtained in Example 8 (180 g) was added to ethyl acetate (900 ml) and water (900 ml). The pH was adjusted to 10-12 using an aqueous potassium carbonate solution. The layers were separated, and the organic layer was washed with water (360 ml) and a 20% sodium chloride solution (360 ml). The organic layer was removed by distillation under vacuum to obtain the title compound (135 g).

[0045] Example 9: Preparation of (S)-methyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate (remimazolam)

[0046] The compound obtained in Example 6 (13 g) was added to methanol (130 ml). The reaction mixture was cooled to 5-10°C. 15-20% methanolic HCl (13 ml) was added dropwise to the reaction mixture at 5-10°C. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, methanol was removed under vacuum at 35-40°C. Methylene chloride (130 ml) was added to the residue and washed with a saturated sodium bicarbonate solution (130 ml). The aqueous layer was extracted with methylene dichloride (65 ml). The organic layers were combined and washed with water, followed by a 20% sodium chloride solution. Methylene chloride was removed under vacuum at 35-40°C. Yield = 6.5 g

[0047] Example 10: Preparation of remimazolam besylate (crude)

[0048] Remimazolam (100g) was dissolved in ethyl acetate (400ml) and cooled to 15-20°C. A solution of benzenesulfonic acid (33.1g) was added to ethanol (250ml). The reaction mixture was stirred at room temperature for 1-2 hours. The product was filtered and washed with ethyl acetate. The product was dried under vacuum at 40-45°C to obtain remimazolam besylate (110g). HPLC purity=99.23%,

[0049] Example 11: Purification of crude remimazolam besylate

[0050] 100 g of remimazolam besilate was added to 1000 ml of aqueous acetone. The reaction mixture was heated to reflux and maintained for 30 minutes. It was cooled to room temperature and stirred for 1 hour. The product was filtered and washed with 100 ml of acetone. The product was dried under vacuum at 40-45°C to obtain pure remimazolam besilate (90 g). HPLC purity=99.72%,

[0051] [Table 1]

[0052] Although the present invention has been described in detail above for illustrative purposes, it should be understood that such details are for that purpose only and that those skilled in the art can modify them without departing from the spirit and scope of the invention, except as may be limited by the claims.

Claims

1. An improved and cost-effective method for the preparation of remimazolam and its salts; i. A step of condensing 2-amino-5-bromobenzoylpyridine (1) and (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid (2) in the presence of a condensing agent at a temperature range of -5 to 0°C to obtain (S)-benzyl 5-((4-bromo-2-picolinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (3); 【Chemistry 1】 ii. A step of cyclizing intermediate compound (3) to obtain (S)-benzyl 4-amino-5-((4-bromo-2-picolinoylphenyl)-amino)-5-oxopentanoate hydrochloride (4); 【Chemistry 2】 iii. A step of reacting compound (4) with bismorpholinophosphine chloride in the presence of a base, followed by the addition of 1-amino-2-propanol to obtain benzyl 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridine-2-yl)-3H-benzo[e][1,4]diazepine-3-yl)propanoate (5); 【Transformation 3】 iv. A step of oxidizing the compound (5) with a suitable oxidizing agent to obtain (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate (6); 【Chemistry 4】 v. A step of converting the compound (6) to (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoatebenzenesulfonate (7) using a suitable reagent; 【Transformation 5】 vi. A step of treating compound (7) with a base to obtain (S)-benzyl 3-(8-bromo-1-methyl-6-(pyridine-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine-4-yl)propanoate (6); 【Transformation 6】 vii. A step of obtaining remimazolam by transesterification of compound (6) using appropriate reagents and converting it to an appropriate acid addition salt; and 【Transformation 7】 viiii. The process of purifying the crude remimazolamic acid addition salt to obtain the desired product. This provides a method that includes [something].

2. The method according to claim 1, wherein the condensing agent in step (i) is selected from dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and the like.

3. The method according to claim 1, wherein the oxidizing agent in step (iv) is selected from desmartin periodinane or pyridinium dichromate.

4. The method according to claim 1, wherein the solvent for the method comprises water, an alcohol selected from lower aliphatic C1-C5 alcohols and aromatic alcohols such as benzyl alcohol; an ether selected from DMF, THF, methyl tert-butyl ether, 1,4-dioxane, etc.; a hydrocarbon selected from aliphatic hydrocarbons or aromatic hydrocarbons; a halogenated hydrocarbon selected from methylene chloride (MDC), ethylene chloride, chloroform, carbon tetrachloride, etc.; ketones, esters, nitriles, etc., either alone or in combination thereof.

5. The method according to claim 1, wherein the base is selected from alkali metal carbonate or alkali metal bicarbonate, ammonia solution, lithium diisopropylamide (LDA), sodium hydride, alone or in combination thereof.

6. A method for preparing (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid (2), i. A step of reacting benzyl alcohol with L-glutamic acid in the presence of an acid to obtain (S)-2-amino-5-(benzyloxy)-5-oxopentanoic acid (i.e., benzyl L-glutamate ester); and ii. A step in which (S)-2-amino-5-(benzyloxy)-5-oxopentanoic acid from step (i) is reacted with a protective agent in the presence of a base at 0-5°C to obtain (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)-amino)-5-oxopentanoic acid. Methods that include...

7. The method according to claim 6, wherein the acid in step (i) is selected from methanesulfonic acid, ethanesulfonic acid, benzylsulfonic acid, and the like.

8. The method according to claim 6, wherein the protective agent in step (ii) is selected from boc anhydride, Fmoc chloride, phthalic anhydride, or tert butoxycarbonyl.

9. The method according to claim 6, wherein the base in step (ii) is selected from organic bases such as ethylamine, triethylamine, and pyridine.

10. The method according to claim 6, wherein the solvent for the method is selected from water, aliphatic hydrocarbons or aromatic hydrocarbons, ethers, and the like, either alone or in combination thereof.

11. impurities; i. Benzyl 3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propanoate as impurity A in an amount of approximately 0.04%; ii. 3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propanoic acid as impurity B in an amount of approximately 0.07%; and iii. Approximately 0.06% of ethyl 3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propanoate The method according to claim 1, characterized by...

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