WO2023037237A1

WO2023037237A1 - Process for the preparation of remimazolam

Info

Publication number: WO2023037237A1
Application number: PCT/IB2022/058364
Authority: WO
Inventors: Vikram S. JAGADALE; Amol S. PATIL; Arjun R. BODKHE; Ashutosh V. JOSHI
Original assignee: Wavelength Enterprises Ltd
Priority date: 2021-09-09
Filing date: 2022-09-06
Publication date: 2023-03-16

Abstract

A process is described for preparing 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo [ 1,2-a] [ 1,4]benzodiazepine-4-yl]propionic acid methyl ester of formula (B) which comprises reacting methyl 3-((3S)-7-bromo-2-(2-hydroxy-propylamino)-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoate of formula (A) with an oxidizing agent which is pyridine sulfur trioxide, chromic acid or a salt thereof.

Description

PROCESS FOR THE PREPARATION OF REMIMAZOLAM

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Prov. Appl. No. 63/242,185, filed on September 9, 2021 and U.S. Prov. Appl. No. 63/292,176, filed on December 21, 2021, both of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present disclosure relates to a novel process for the preparation of a short acting benzodiazepine, methyl 3-[(4S)-8-bromo-l-methyl-6-(pyridin-2-yl)-4H-imidazo[l,2- a] [l,4]benzodiazepin-4-yl]propanoate, commonly known as remimazolam.

[0003] More specifically, the present invention relates to a novel preparation process starting from the alcohol intermediate, methyl 3-((3S)-7-bromo-2-(2-hydroxy- propylamino)-5-(pyridin-2-yl)-2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)propanoate, using a chromic acid (e.g., such as but not limited to pyridinium dichromate (PDC), pyridinium chlorochromate (PCC) or pyridine sulphur trioxide complex) as oxidizing agents and without isolation of a ketone intermediate.

BACKGROUND OF THE INVENTION

[0004] Remimazolam is a benzodiazepine derivative drug used in induction of anesthesia and conscious sedation for minor invasive procedures. Remimazolam was found to be both faster acting and shorter lasting than midazolam, and human clinical trials showed a faster recovery time and predictable, consistent pharmacokinetics, suggesting some advantages over existing drugs for these applications.

[0005] The chemical name of remimazolam is methyl 3-[(4S)-8-bromo-l-methyl-6- (pyridin-2-yl)-4H-imidazo[l,2-a][l,4]benzodiazepin-4-yl]propanoate. It has a molecular formula of C2iHi9BrN4C>2 and a molecular weight of 439.305 g/mol. Remimazolam has the following structural formula:

Remimazolam

[0006] Remimazolam is recited in U.S. Patent No. 7,485,635 (hereinafter the ‘635 patent) along with pharmaceutical formulations containing it. The synthesis of Remimazolam is recited, e.g., in Example Ic-8 of the '635 patent. The process is described in scheme 1.

[0007] Scheme 1

The process disclosed in ’635 patent involves Swem oxidation, which needs to be carried out in the presence of dimethyl sulfoxide (DMSO) and oxalyl chloride and requires extremely low temperature of about -78° C., therefore this process cannot easily be adopted for industrial scale manufacturing.

[0008] U.S. Patent No. 9,156,842 (hereinafter the ’ 842 patent) describes a process for preparing remimazolam. The synthesis of remimazolam mainly involves six chemical transformations from 2-amino-5 -bromobenzoyl -pyridine as a key starting material. The process comprises inter alia subjecting 3-[(S)-7-bromo-2-((R and/or S)-2-hydroxy- propylamino)-5-pyridin-2-yl-3H-benzo[e] [1,4] diazepin-3-yl] -propionic acid methyl ester of formula (E) to Dess-Martin (Dess-Martin periodinane) oxidation or TEMPO (2, 2,6,6- tetramethylpiperidin-N-oxyl) oxidation. This process is described in Scheme 2.

Scheme 2

[0009] The Dess-Martin oxidation or TEMPO oxidation are well-known processes for converting a secondary alcohol compound into a corresponding ketone compound. Although Dess-Martin oxidation or TEMPO oxidation is capable of oxidizing a secondary alcohol compound under mild conditions, it is not completely suited for industrial level production, because it involves the use of potentially explosive hazardous reagents such as Dess martin reagent, azido and hydroxy azido compounds, TEMPO/NaOCl, etc.

[0010] As reported above, the processes disclosed in the prior art suffer from poor yield and involve hazardous chemicals, extremely tough reaction conditions, and expensive reagents. Additional disadvantages of the synthetic methods described in the prior processes is that they involve extra synthetic step of forming and isolating the ketone compounds as one of the intermediates following by further converting it to remimazolam. [0011] For at least these reasons, there is need to develop a process for the preparation of remimazolam, which provides the final product in high yield and purity, avoids hazardous chemicals and can be utilized in industrial scale.

SUMMARY OF THE INVENTION

[0012] In one aspect, the present invention provides a process for preparing remimazolam and salts thereof, comprising oxidizing the alcohol intermediate, methyl 3- ((3S)-7-bromo-2-(2-hydroxy-propylamino)-5-(pyridin-2-yl)-2,3-dihydro-lH- benzo[e][l,4]diazepin-3-yl)propanoate of formula (A) using a chromic acid as an oxidizing agent (preferably pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) as oxidizing agents), and without isolation of the ketone intermediate. As per the modified process, remimazolam is isolated in a single step without ketone intermediate which reduces one step and makes it more appropriate to commercial feasibility. The scheme of the present invention is illustrated in scheme 3:

MolecularWeight: 459.34 Molecular Weight: 439.31

[0014] As noted above, the synthesis of Remimazolam mainly involves six synthetic steps from 2-amino-5-bromobenzoyl-pyridine as key starting material. The synthesis of compound A or alcohol intermediate is common for both new process as well as other reported processes. However, unlike the reported process, due to the acidic nature of reaction mass, after the oxidation was carried out by using PDC or PCC, the ketone intermediate is immediately converted to remimazolam, and it was not even detected during reaction monitoring. This reaction is at 20-30°C so there is no need of any special requirements. Handling of PDC and PCC does not have any issue as both are solid compounds and can be used safely at commercial scale.

[0015] The complete synthesis of Remimazolam besylate compared to the synthesis of the prior art is illustrated in scheme 4:

[0016] Scheme 4:

[0017] In another aspect, the present invention provides additional improved process for the preparation of remimazolam (compound of Formula B) from alcohol intermediate (BHDP/compound A) using pyridine sulphur trioxide complex as an oxidizing agent followed by cyclization to get remimazolam, without isolation of the ketone intermediate (BODP). As per this modified process, the oxidizing agent is not hazardous and can be used on large scale. Also, the purity of ketone intermediate after oxidation is better than other prior art processes, and advantageously, the ketone intermediate is in situ converted to remimazolam without isolation of ketone. The scheme of the present invention is illustrated in scheme 5 :

[0018] Scheme 5:

DETAILED DESCRIPTION OF THE INVENTION

[0019] In one embodiment, the present disclosure relates to novel processes for preparation of short acting benzodiazepine. More particularly the disclosure relates to process for preparation of methyl 3-[(4S)-8-bromo-l-methyl-6-(pyridin-2-yl)-4H-imidazo [1,2-a] [l,4]benzodiazepin-4-yl]propanoate, commonly known as remimazolam.

[0020] The process of the present disclosure provides the final product, remimazolam, in excellent yield and purity. The new process is carried on at 20-30°C and does not require extremely low temperature of about -78°C, as required by the process of the prior art. In addition, it avoids the use of hazardous reagents, such as DMSO and oxalyl chloride, as well as other hazardous reagents such as Dess martin reagent, azido and hydroxy azido compounds, TEMPO, etc., which are not feasible and create some safety issues on commercial scale. Handling of PDC and PCC, the oxidation reagents of this process, does not have any issue as both are solid compounds and can be used safely at commercial scale. Therefore, this new process is suitable for use in industrial scale.

[0021] The present invention provides a process for the preparation of remimazolam or salts thereof, which comprises: Reacting methyl 3-((3S)-7-bromo-2-(2-hydroxy-propylamino)-5-(pyridin-2-yl)-2,3- dihydro-lH-benzo[e][l,4]diazepin-3-yl)propanoate of formula (A)

with the use of a chromic acid and its salts as an oxidizing agent.

[0022] The oxidizing agent is an agent apt to oxidize a secondary alcohol to a ketone without reacting with the other reactive groups of the compound of formula (A). Due to acidic nature of the reaction mass this ketone intermediate is immediately converted to remimazolam, and it is not even detected during reaction monitoring.

[0023] A preferred chromic acid oxidizing agent is selected from pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC).

[0024] The compound of formula (A) is generally dissolved in a solvent or a solvent mixture at a temperature of 20-30 °C, following by the addition of PDC or PCC as oxidizing agent to the reaction mixture.

[0025] Examples of suitable solvents are dichloromethane, acetone, acetonitrile, DMF, MIBK, toluene, etc.

[0026] Preferred organic solvents are dichloromethane and acetonitrile.

[0027] The compound of formula (B) may be isolated by methods routinely used in the art of synthetic organic chemistry, e.g., which may include evaporating the solvent under vacuum, dissolving the residue in a suitable solvent, filtering, washing with different aqueous solutions and re-extracting the combined aqueous solutions with a suitable solvent. For the purposes of the present invention, it is preferred to obtain the compound of the formula (B) at an optical purity of >95%, preferably >99%, more preferably >99.5%, and most preferably >99.9%.

[0028] That method allows to obtain 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H- imidazofl ,2-a] [l,4]benzodiazepine-4-yl]propionic acid methyl ester of formula (B) or its besylate salt, namely 3-[(4S)-8-Bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo[l,2- a][l,4]benzodiazepine-4-yl]propionic acid methyl ester benzene sulfonate, with very high chemical and chiral purities.

[0029] In another embodiment of the present invention, there is provided a process for the synthesis of remimazolam as shown in scheme 5, comprising the steps of:

(a) Dissolving a compound A (BHDP) in a suitable organic solvents (or a mixture of organic solvents;.

(b) Removing the solvent to obtain a residue, which is redissolved in a suitable organic solvent,

(c) Dissolution of pyridine Sulphur trioxide complex (98.8g, 621 mmol) and dimethyl sulfoxide (300 ml) in dichloromethane in another flask

(d) Cooling the solution of step c (e.g., to about 0-5°C), followed by addition of a suitable base (e.g., triethylamine), and

(e) Addition of compound A (BHDP) solution from step b to the reaction product obtained in step (d) to obtain BODP compound.

(f) Obtained BODP compound is treated with organic acid to obtain remimazolam.

[0030] In step (a) suitable organic solvents include but are not limited to dichloromethane, , toluene and mixtures thereof or combinations thereof, including combinations in various proportions. Preferably, the organic solvents is toluene ..

[0031] In step (b) obtained residue is redissolved in dichloromethane .

[0032] In step (c) Dissolution of pyridine sulphur trioxide complex in suitable organic solvents includes but are not limited to dichloromethane , dimethyl sulfoxide , THF , 2- Methyl THF, Toluene and mixture thereof or combinations thereof, including combinations in various proportions .Preferably the organic solvents are mixture of dichloromethane and DMSO.

[0033] In step (d) suitable cooling temperature ranges from about 0°C to 5°C

[0034] Suitable bases include but are not limited to organic bases such as alkyl amines, preferably triethylamine.

[0035] Step (e) involves oxidation of the compound of formula A (BHDP) using pyridine sulphur trioxide complex. Pyridine sulfur trioxide complex is moisture sensitive so reaction should be done under inert atmosphere. In one embodiment of step (e) the reaction mixture is treated for 3 to 4 hours. Suitable temperature for conducting the reaction ranges from about 0°C to 5°C. In another embodiment of step (e) the progress of the reaction is monitored by HPLC to check unreacted BHDP (Limit NMT 5 %). In further embodiment, after the completion of the reaction, the reaction mixture is treated with dichloromethane and water and obtained as an oily material.

[0036] Any suitable reverse or normal phase HPLC method can be used to determine the percentage of unreacted BHDP (compound of formula A) compared to BODP (the ketone intermediate) provided that the methods afford at least baseline resolution between the BHDP HPLC signal and the BODP HPLC signal. One particularly useful method is as follows: RP-HPLC: HPLC system, equipped with a detector, column oven, quaternary gradient pump, and auto sampler such as an HPLC system form Waters Inc., Milford, Mass, or an equivalent. Detection wavelength set to 240 nm. The RP HPLC column is a USP LI packing, 5 pm, 250 4.6 mm or equivalent (Upchurch Scientific, Innertsil). The run time is 45 minutes with an injection volume of lOpL. The mobile phases include Mobile Phase A: 0.1% Orthophosphoric acid in water and Mobile Phase B: Acetonitrile. The gradient is as follows:

[0037] Step ( f ) is the in-situ conversion of the intermediate BODP to remimazolam by reacting BODP with methanolic hydrochloride. In one embodiment of step (f) the oily BODP is first dissolved in an organic solvent including but not limited to ethanol, ethyl acetate, 2-methyl THF, THF and methanol at a temperature range from about 0°C to about 5°C. In one embodiment the organic acid solution is selected from methanolic hydrochloride, benzene sulphonic acid, para toluene sulphonic acid, preferably, methanolic hydrochloride. In another embodiment the organic acid solution is 10% solution in an organic solvent such as methanol, ethanol, isopropyl alcohol or ethyl acetate. In further embodiment, following the addition of the acid solution the temperature is raised to about 20°C to about 25 °C, and stirred for 8 to 10 hours. In another embodiment of step (d) the progress of the reaction is monitored by HPLC to check unreacted BODP (Limit NMT 1.0 %).

[0038] Any suitable reverse or normal phase HPLC method can be used determine the percentage of unreacted BODP compared to remimazolam provided that the methods afford at least baseline resolution between the BODP HPLC signal and the remimazolam HPLC signal. One particularly useful method is as follows: RP-HPLC: HPLC system, equipped with a detector, column oven, quaternary gradient pump, and auto sampler such as an HPLC system form Waters Inc., Milford, Mass, or an equivalent. Detection wavelength set to 240 nm. The RP HPLC column is a USP LI packing, 5 pm, 250 4.6 mm or equivalent (Upchurch Scientific, Innertsil). The run time is 45 minutes with an injection volume of lOpL. The mobile phases include Mobile Phase A: 0.1% Orthophosphoric acid in water and Mobile Phase B: Acetonitrile. The gradient is as follows:

[0039] In one embodiment of step (d), for the workup the solution is added to an aqueous basic solution. In another embodiment, the aqueous basic solution is about 10% wt. sodium carbonate. In one embodiment, dichloromethane is added to the solution, the solution is cooled to 0°C to 5 °C and stirred for 15-30 minutes. In further embodiment, the phases are separated, and remimazolam is isolated from the organic layer.

[0040] The invention also concerns a process for preparing the besylate salt of remimazolam which comprises:

(a) reacting 3-[(S)-7-bromo-2[(-2-hydroxypropylamino)]-5-pyridin-2-yl-3H- benzo[e][l,4]diazepin-3-yl]-propionic acid methyl ester of formula (A)

with an oxidizing agent selected from PDC or PCC; and (b) treating the reaction product obtained in step (a) with benzene sulfonic acid in an organic solvent or an organic solvent mixture, such as to produce the remimazolam besylate.

[0041] The invention further relates to a process for preparing the besylate salt of remimazolam which comprises:

(a) reacting 3-[(S)-7-bromo-2[(-2-hydroxypropylamino)]-5-pyridin-2-yl-3H- benzo[e] [1,4] diazepin-3-yl] -propionic acid methyl ester of formula (A) with Pyridine sulphur trioxide complex an oxidizing agent in the presence of a base;

(b) In situ cyclization of the obtained intermediate using methanolic hydrochloride; and

(c) treating the reaction product obtained in step (b) with benzene sulfonic acid in an organic solvent or an organic solvent mixture, such as to produce the remimazolam besylate.

[0042] Remimazolam besylate may be isolated by methods routinely used in the art of synthetic organic chemistry, e.g., which may include crystallization of the besylate salt.

[0043] The present invention provides pharmaceutical compositions comprising the remimazolam besylate obtainable by a process depicted in Scheme 3 and at least one pharmaceutically acceptable excipient.

EXAMPLES

[0044] The following examples further illustrate the invention but should not be construed as in any way limiting its scope.

[0045] Example 1- Preparation of 3-[(4S)-8-bromo-l -methyl-6-(2-pyridinyl)-4H- imidazo[ 1,2-a] [ l,4]benzodiazepine-4-yl]propionic acid methyl ester of formula (B) using pyridinium dichromate as oxidizing agent

[0046] The compound of formula (A) (1.0 g, 2 mmol) prepared according to Example A4 of WO2011032692, was dissolved in dichloromethane (10 ml), and stirred at a temperature of 20-30°C for 15-20 minutes. Pyridinium dichromate (PDC) (2.4g, 6 mmol) was added, stirring at 20-30°C was continued for 25-30 hours. HPLC in Acetone and acetonitrile showed a main product remimazolam (-90% ) and -1% of the unreacted compound A. After reaction completion the reaction mass was diluted with 10 ml Methyl tert-butyl ether. The solids were removed by fdtration and washed with methyl tert-butyl ether. (5ml). The combined filtrates of all MTBE layers were washed twice with water (5 ml X 2). The MTBE layer was separated and distilled under reduced pressure below 40°C. Remimazolam base was obtained as oily mass (-1.0 g).

[0047] The remimazolam base was dissolved in ethyl acetate (10 ml) and stirred until a clear solution was obtained. A solution of benzenesulfonic acid (0.23gm, 1.5 mmol) in methanol (1 ml) was added slowly to ethyl acetate reaction mass at 20-30°C, until a clear solution was observed. The resulting reaction mass was stirred at another 30 minutes until crystals were observed. Then the stirring was continued for additional 2-3 hours at 20- 30°C. the solid was isolated by filtration washed with ethyl acetate (1 ml) then dried under vacuum below 50°C for 6-8 hours. Yield was 0.5 g.

[0048] Example 2- Preparation of 3-[(4S)-8-bromo-l -methyl-6-(2-pyridinyl)-4H- imidazo[ 1,2-a] [ l,4]benzodiazepine-4-yl]propionic acid methyl ester of formula (B) using pyridinium chlorochromate as oxidizing agent

[0049] The compound of formula (A) (1.0 g, 2 mmol) prepared according to Example A4 of WO2011032692, was dissolved in dichloromethane (10 ml), and stirred at a temperature of 20-30°C for 15-20 minutes. Pyridinium chlorochromate (PCC) (1.58g, 7.3 mmol) was added, stirring at 20-30°C was continued for 25-30 hours. HPLC in Acetone and acetonitrile showed a main product remimazolam (-90%) and -1% of the unreacted compound A. After reaction completion the reaction mass was diluted with 10 ml Methyl tert-butyl ether. The solids were removed by fdtration and washed with methyl tert-butyl ether. (5ml). The combined filtrates of all MTBE layers were washed twice with water (5 ml X 2). The MTBE layer was separated and distilled under reduced pressure below 40°C. Remimazolam base was obtained as oily mass (-1.0 g).

[0050] The remimazolam base was dissolved in ethyl acetate (10 ml) and stirred until a clear solution was obtained. A solution of benzenesulfonic acid (0.23gm, 1.5 mmol) in methanol (1 ml) was added slowly to ethyl acetate reaction mass at 20-30°C, until a clear solution was observed. The resulting reaction mass was stirred at another 30 minutes until crystals were observed. Then the stirring was continued for additional for 2-3 hours at 20- 30°C. the solid was isolated by filtration washed with ethyl acetate (1 ml) then dried under vacuum below 50°C for 6-8 hours. Yield was 0.5 g

[0051] Example 3- Preparation of (S)-3-(7-bromo-2-((2-oxopropyl)amino)-5- (pyridin-2-yl)-3H-benzo[e] [l,4]diazepin-3-yl)propyl acetate (BODP) using Pyridine sulphur trioxide complex [0052] The compound of formula A (11.4 g, 24.8 mmol) and toluene (50 ml) was charged into a clean and dry round bottom flask followed by heating to 45-50°C, until clear solution was formed. The solvent was distilled completely under vacuum at below 50°C. The obtained residue was redissolved in toluene (50 ml). The solvent was distilled completely under vacuum at below 50°C. The obtained oil residue, dichloromethane (20 ml) and dimethyl sulfoxide (30 ml) were charged in a 500 ml 4 neck round bottom flask under nitrogen atmosphere followed by stirring. Resultant solution was cooled to about 0- 5°C. followed by addition of triethylamine (12.5 g) over about 15 minutes. In parallel Pyridine sulfur trioxide complex (9.5 g, 59.7 mmol) was dissolved in dimethyl sulfoxide under nitrogen atmosphere at 20-30°C. The pyridine sulfur trioxide complex solution was added to the reaction over 45-60 minutes, while maintaining the temperature at 0-5 °C. The reaction mass was further stirred for 3-4 hours at 0-5°C. The reaction progress was monitored by HPLC to check unreacted BHDP (limit is NMT 5%, preferably NMT 1%). After the completion of the reaction the reaction mixture was quenched by the addition of dichloromethane (50 ml) and water (50 ml) at 0-5 °C. The temperature was raised to 20- 30°C and stirred for 10-15 minutes. Organic and aqueous phases were separated, and the organic phase was washed with water (50 ml), followed by distillation under vacuum at 40°C to afford the titled compound. The obtained oil (13.2 g, purity by HPLC > 91%) was used ‘as is’ in the next step.

[0053] Example 4: Preparation of 3-[(4S)-8-bromo-l -methyl-6-(2-pyridinyl)-4H- imidazo[ 1,2-a] [ l,4]benzodiazepine-4-yl]propionic acid methyl ester of formula (B) from BODP

[0054] BODP oil (13.2 g), obtained from example 3, was dissolved in methanol (20 ml) and cooled to 0-5°C. 10% Methanolic hydrochloride (52 ml) was charge followed by heating to 20-25°C for about 8-10 hours. The reaction progress was monitored by HPLC to check unreacted BODP (limit NMT 1%). In parallel, water (100 ml) and sodium carbonate (9.2g) were stirred to get clear solution. Dichloromethane (50 ml) was charged into the sodium carbonate solution at 0-5 °C. After the completion of the reaction, the reaction mixture was slowly added to the pre-cooled sodium carbonate solution. After the addition, the mixture was stirred for 15 minutes, and the aqueous phase was separated and discarded. The organic phase was washed with water (50 ml), followed by distillation under vacuum below 45 °C to afford remimazolam base as oily residue. The obtained oil (11.4 g, purity by HPLC > 90%) was used ‘as is’ in the next step. [0055] Example 5: Preparation of Remimazolam besyalte

[0056] Remimazolam base oil (11.4 g), obtained from example 5, was dissolved in ethyl acetate (100 ml) and cooled to 5-10°C. In parallel, a solution of benzene sulphonic acid was prepared by dissolving benzene sulphonic acid (3.5 g, 22 mmol) with methanol (10 ml) at 20-25 °C. The benzene sulphonic acid solution was added into reaction mass at a temperature of 5-10°C over 50-60 minutes. The temperature was raised to 20-25 °C and maintained for 2-3 hours. After completion of the reaction, the solid was filtered, the wet cake was washed with ethyl acetate (20 ml) and subjected to suction over about 30 minutes. The obtained off white solid was dried in vacuum oven for 8-10 hours to afford the title compound (dry weight: 10g, yield -64%, purity by HPLC: > 98%).

[0057] Example 6: Preparation of methyl (S)-3-(7-bromo-2-((2-oxopropyl) amino)- 5-(pyridin-2-yl)-3H-benzo[e] [l,4]diazepin-3-yl)propanoate (BODP) using Pyridine Sulphur trioxide complex

[0058] The compound of formula A (114 g, 248 mmol) and toluene (500 ml) was charged into a clean and dry round bottom flask followed by heating to 45-50°C, until clear solution was formed. The solvent was distilled out completely under vacuum below 50°C. The obtained residue was redissolved in toluene (500 ml). The solvent was distilled out completely under vacuum below 50°C. The obtained oil residue was dissolved in dichloromethane (300ml).

[0059] In another 2 -lit. 4 neck round bottom flask kept under nitrogen atmosphere, pyridine Sulphur trioxide complex (98.8g, 621 mmol) and dimethyl sulfoxide (300 ml) were charged at 20-25°C and stirred for 30-45 minutes. 200 ml dichloromethane was charged under nitrogen atmosphere. Resultant solution was cooled to about 0-5 °C, followed by addition of triethylamine (125.4 g, 1239.2 mmol) over about 15-30 minutes. Solution of compound formula A prepared above was added into the reaction mass at 0- 5°C. The reaction mass was further stirred for 3-4 hours at 0-5°C. The reaction progress was monitored by HPLC to check unreacted BHDP (limit NMT 2%). After completion of the reaction, the reaction mixture was quenched by the addition of dichloromethane (500 ml) and water (900 ml) at 0-5 °C. The temperature was raised to 20-30°C and stirred for 15- 30 minutes. Organic and aqueous phases were separated, and the organic phase was washed with water (900 ml), followed by distillation under vacuum at 40°C to afford the titled compound. The obtained oil (151 g, purity by HPLC > 85%) was used ‘as is’ in the next step. [0060] Example 7: Preparation of Methyl 3-[(4S)-8-bromo-l-methyl-6-pyridin-2- yl-4H-imidazo[l,2-a] [l,4]benzodiazepin-4-yl] propanoate of formula (B) from BODP [0061] BODP oil (151 g) obtained from example 6 was dissolved in methanol (200 ml) and cooled to 0-5°C. 10% Methanolic HC1 (453ml) was added within 30-45 minutes maintaining temp, between 0-10 °C. Temperature of the reaction mass was raised to 20- 25°C and maintained further for about 8-10 hours under stirring. The reaction progress was monitored by HPLC to check unreacted BODP (limit NMT 1%). In parallel, water (1000 ml) and sodium carbonate (92.2g) were stirred to get a clear solution. Dichloromethane (500 ml) was charged into the sodium carbonate solution at 0-5°C. After the completion of the reaction, the reaction mixture was slowly added to the pre-cooled sodium carbonate solution. After the addition, mixture was stirred for 15 minutes and the aqueous phase was separated and discarded. The organic phase was washed with water (500 ml), followed by distillation under vacuum below 45 °C to afford remimazolam base as an oily residue. The obtained oil (143 g, purity by HPLC > 91%) was used ‘as is’ in the next step.

[0062] Example 8: Preparation of Remimazolam besylate

[0063] Remimazolam base oil (143 g), obtained from example 7 was dissolved in acetone (800 ml) at 20-25°C. In parallel, a solution of benzene sulphonic acid was prepared by dissolving benzene sulphonic acid (35.3 g, 223 mmol) with acetone (200 ml) at 20- 25°C. The benzene sulphonic acid solution was added into reaction mass at a temperature of 20-25°C within 50-60 minutes and maintained for 2-3 hours. After completion of the reaction, the solid was filtered, the wet cake was washed with acetone (200 ml) and subjected to suction for about 30 minutes. The obtained white to off white solid was dried in vacuum oven for 8-10 hours, to afford the title compound (dry weight: ~92g, yield -60% , w.r.t. BBDP input , purity by HPLC: > 99.5%).

[0064] Example 9: Purification of Remimazolam besylate

[0065] Remimazolam besylate (92 g) obtained from example 8, dissolved in aqueous sodium carbonate solution (92 gm sodium carbonate dissolved in 1000 ml water) and dichloromethane (500 ml) mixture and stirred for 15 minutes and separated layers, organic layer washed with water. Distilled out solvent under vacuum below 45°C.

[0066] The obtained remimazolam base dissolved in acetone (800 ml) at 20-25°C. In parallel, a solution of benzene sulphonic acid was prepared by dissolving benzene sulphonic acid (21.6 g) in 200ml acetone at 20-25°C. The benzene sulphonic acid solution was added into remimazolam base solution at 20-25 °C temperature within 50-60 minutes and maintained for 2-3 hours. Solid was fdtered, the wet cake was washed with acetone (200 ml) and subjected to suction for about 30 minutes. The obtained white to off white solid was dried in vacuum oven for 8-10 hours, at 50-55°C. to afford the title compound (dry weight: 75 g, yield -50% w.r.t. BBDP input, purity by HPLC: > 99.9%).

Claims

1. A process for preparing 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo [1,2-a] [l,4]benzodiazepine-4-yl]propionic acid methyl ester of formula (B):

which comprises reacting methyl 3-((3S)-7-bromo-2-(2-hydroxy- propylamino)-5-(pyridin-2-yl)-2,3-dihydro-lH-benzo[e][l,4]diazepin-3- yl)propanoate of formula (A):

with an oxidizing agent which is a chromic acid, or a salt thereof.

2. The process according to claim 1, wherein the chromic acid is pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC).

3. The process according to claim 1, wherein the process is one-pot process.

4. A process for preparing 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo[l,2- a] [l,4]benzodiazepine-4-yl] -propionic acid methyl ester benzene sulfonate which comprises:

(a) reacting methyl 3-((3S)-7-bromo-2-(2-hydroxy-propylamino)-5- (pyridin-2-yl)-2, 3 -dihydro- IH-benzo [e] [ 1 ,4]diazepin-3 - yl)propanoate of formula (A):

with an oxidizing agent which is pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC),

(b) treating the reaction product obtained in step (a) with benzene sulfonic acid in an organic solvent or an organic solvent mixture, to produce the remimazolam besylate, and optionally (c) isolating the compound remimazolam besylate. A process for preparing remimazolam of formula B :

comprising reacting a compound of formula A:

with a pyridine sulphur trioxide complex to provide the ketone intermediate, (S)-3-(7- bromo-2-((2-oxopropyl)amino)-5 -(pyridin-2-yl)-3H-benzo [e] [ 1 ,4] diazepin-3 -yl)propyl acetate (BODP), of the following formula:

followed by cyclization step to obtain remimazolam, without isolation of the ketone intermediate.

6. The process of claim 5, wherein the compound of formula A is dissolved in a suitable organic solvent(s) or a mixture of organic solvents.

7. The process of claim 6, wherein the organic solvents are selected from the group consisting of dichloromethane, dimethyl sulfoxide, THF, 2-methyl THF, toluene and mixtures thereof, or combinations thereof in various proportions.

8. The process of claim 7, wherein the organic solvents are a mixture of dichloromethane and dimethyl sulfoxide.

9. The process of claim 5, wherein the reaction of the compound of formula A with pyridine sulphur trioxide is performed in the presence of a base.

10. The process of claim 9, wherein the base is an amine.

11. The process of claim 9, wherein the amine is an alkylamine, preferably, triethylamine.

12. The process of claim 5, wherein in the cyclization step, BODP reacts with an organic acid solution.

13. The process of claim 12, wherein the organic acid solution is selected from the group consisting of methanolic hydrochloride, benzene sulphonic acid, PTSA and mixtures thereof.

14. The process of claim 5, further comprising the conversion of remimazolam to a salt thereof.

15. The process of claim 14, wherein the salt is remimazolam besylate.