DESC:FIELD OF INVENTION
The present invention relates to a novel process for the preparation of Remimazolam intermediate.

BACKGROUND OF THE INVENTION
Remimazolam (CNS 7056) is chemically known as methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate. It is a benzodiazepine drug which is commonly used for the induction and maintenance of procedural sedation in adults for invasive diagnostic and surgical procedures. Both Besylate and Tosylate salt forms have been developed for Remimazolam. The chemical structure of Remimazolam is as given below in the formula (I):

Remimazolam

Remimazolam intermediate which is chemically known as (2-amino-5-bromophenyl) (pyridin-2-yl) methanone (Formula-) commonly used in the preparation of Remimazolam.

Formula-[D]

Remimazolam besylate salt was approved on 2020 by the US FDA under brand name “BYFAVO” and is marketed by Acacia Pharma Inc for medical use in United States. Remimazolam tosylate salt is approved for procedural sedation in China.

Remimazolam and process for its preparation is first disclosed in US patent 7485635 B2. US 9156842 discloses a process for the preparation of Remimazolam by using Dess-Martin periodinane (DMP) as an oxidizing agent. The usage of DMP is not suggestable because of its potential explosive nature.
US 9193730 discloses the process for the preparation of Besylate salt of Remimazolam and its polymorphs.

The processes for the preparation of Remimazolam reported in the prior art literature are suffered from lot of disadvantages like poor yield, usage of hazardous chemicals, expensive reagents and extremely critical reaction conditions.

In view of the above, there is an obvious need to find an efficient and industrially advantageous process for the synthesis of Remimazolam and its intermediates which overcomes the problems associated with the prior art such as prolonged reaction time, use of hazardous reagents, stringent reaction conditions, low yields and tedious purifications.

The processes for the preparation of Remimazolam intermediate reported in the prior art literature is as follows.

Scheme-I

Scheme-II

Process for the preparation of Remimazolam intermediate disclosed in Scheme-I having several disadvantages like formation of ortho and para bromo substituted compounds which leads to laborious purification methods such as column chromatography which is a time consuming and tedious process, especially for large quantities hence it is not suitable for large scale production and further results in low yields of Remimazolam intermediate. Process disclosed in scheme-II involves multiple steps like amino protection, bromination followed by deprotection. The above said drawbacks make the process unviable on commercial scale.

In view of the above, there is an obvious need to find an efficient and industrially advantageous process for the synthesis of above said key intermediate of Remimazolam which overcomes the problems associated with the prior art such as commercially unviable, prolonged reaction time, low yields and tedious purifications. Therefore, it is desirable to develop a novel process for the preparation of Remimazolam intermediate which is industrially feasible and commercially viable.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides cost effective and efficient process for the preparation of Remimazolam or its pharmaceutically acceptable salts with higher yield and purity.

One embodiment of the present invention relates to a novel process for the preparation of Remimazolam intermediate of formula-[D]

[D]
comprising;
a) Bromination of compound of formula-[A]

[A]
With brominating agent to obtain compound of formula-[B];

[B]
b) condensation of compound of formula-[B] with morpholine to obtain compound of formula-[C];

[C]
c) reacting compound of formula-[C] with 2-Bromo pyridine in presence of a reagent and solvent to obtain Remimazolam Intermediate of formula-[D].

Other embodiment of the present invention relates to a process for the preparation of Remimazolam Intermediate of formula-[D] with high purity greater than 99.8% and good yield.

Another embodiment of the present invention relates to an improved process for the preparation of Remimazolam or its pharmaceutically acceptable salts comprising:
a) Bromination of compound of formula-[A]

[A]
With brominating agent to obtain compound of formula-[B];

[B]
b) condensation of compound of formula-[B] with morpholine to obtain compound of formula-[C];

[C]
c) reacting compound of formula-[C] with 2-Bromo pyridine in presence of a reagent and solvent to obtain Remimazolam Intermediate of formula-[D];

[D]
d) chlorination of compound of formula-[E]

[E]
with chlorinating agent in a solvent to obtain compound of formula-[F];

[F]
e) condensation of compound of formula-[F] with compound of formula-[D] obtained in step-(C) in a solvent to obtain compound of formula-[G];

[G]
f) deprotection and cyclization of compound of formula-[G] in presence of a base and solvent to obtain compound of formula-[H];

[H]
g) condensation of compound of formula-[H] with 1-Amino-2-propanol in presence of Dimorpholinophosphonic chloride and LiHMDS to obtain compound of formula-[I];

[I]
h) oxidation of compound of formula-[I] with an oxidizing agent in presence of base and solvent to obtain Remimazolam;

Remimazolam
i) optionally converting Remimazolam to Remimazolam salt by using pharmaceutically acceptable acid.

Another embodiment of the present invention relates to a process for the preparation of Remimazolam or its pharmaceutically acceptable salt with high purity greater than 99.8% and good yield.

DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

As used herein the term solvent refers to alcoholic solvent like methanol, ethanol, isopropyl alcohol, n-propanol, butanol; ester solvents like ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate, ether solvents like tetrahydrofuran, diethylether, methyl tert-butylether, dioxane; hydrocarbon solvents like toluene, xylene, cyclohexane, hexane, heptane, n-pentane; chlorinated solvents like methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform; polar aprotic solvents like dimethylformamide, dimethylacetamide, dimethylsulfoxide; nitrile solvents like acetonitrile; ketone solvents like acetone, methyl isobutyl ketone.

As used herein the term brominating agent refers to liquid bromine, N-bromo succinamide, hydrobromic acid, pyridinium hydrobromide perbromide, phenyltrimethylammonium perbromide. The suitable brominating agent used herein the present invention is liquid bromine.

As used herein the chlorinating agent refers to thionyl chloride, oxalyl chloride, trichloro isocyanuric acid, phosphorous trichloride, phosphorous pentachloride. The suitable chlorinating agent used herein the present invention is thionyl chloride.

As used herein the oxidizing agent refers to pyridinium chlorochromate (PCC), Dess-Martin periodinane, hydrogen peroxide, oxalyl chloride, peroxydisulfuric acid, sodium dichromate, potassium permanganate, chromium trioxide, sodium hypochlorite, 2,2,6,6-tetramethyl piperidine-1-oxide (TEMPO). The suitable oxidizing agent used herein the present invention is oxalyl chloride.

As used herein the term “base” is selected from organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tributyl amine, 4-dimethylaminopyridine, N-methyl morpholine and the like.

The term as used herein “pharmaceutically acceptable acid” means inorganic acids like hydrochloric acid, sulfuric acid; organic acids like benzene sulfonic acid, para toluene sulfonic acid, acetic acid. The suitable acid used herein the present invention is benzene sulfonic acid.
The term as used herein “purity” is based on the "organic" purity of the compound. Purity does not include a measure of any amount of water, solvent, metal, inorganic salt, etc. In one aspect, the purity of desired compound is compared to the purity of the reference standard by comparing the area under the peak.

The term used as herein “improved yield” means a sufficiently good overall weight of the chemical compound or the drug molecule. In another aspect of the present invention it essentially means the overall weight of the chemical compound or the drug molecule is preferably increased by using the said process disclosed in the present invention.
The term used as herein “Lyophilization” means it’s a freeze-drying process that removes solvent from product after it is frozen and placed under a vacuum. Lyophilization process Enhancing the stability of a dry powder as well as the product stability in a dry state and water or solvent is removed without excessive heating of the product. Freezing takes place in stage one of the lyophilization process. Freezing temperatures are around -40°C to -70°C. Freeze-drying works by freezing the liquid material and then reducing the surrounding pressure to allow the frozen water in the material to sublimate directly from the solid phase to the gas phase. This leaves us with a dry powder.

The main embodiment of the present invention provides a novel process for the preparation of Remimazolam intermediate as shown in the scheme-III given below.

Scheme-III

In step-1, bromination of compound of formula-[A] with a brominating agent and solvent to obtain compound of formula-[B].

The brominating agent used in this step is selected from the group consisting of liquid bromine, N-bromo succinamide, hydrobromic acid, pyridinium hydrobromide perbromide, phenyltrimethyl ammonium perbromide. Preferably using liquid bromine.

The reaction temperature may range from 40-70 °C and preferably at a temperature in the range from 45-65 °C. The duration of the reaction may range from 1-3 hours, preferably for a period of 1-2 hours.
Solvent used in the reaction is selected from the group consisting of alcoholic solvents, chlorinated solvents, ester solvents, ketone solvents, nitrile solvents and water. Preferably using water.

In step-2, condensation of compound of formula-[B] with morpholine in presence of solvent to obtain compound of formula-[C]. Solvent used in the reaction is selected from the group consisting of alcoholic solvents such as methanol, ethanol or propanol; chlorinated solvents such as dichloromethane or carbon tetrachloride; nitrile solvent such as acetonitrile or propionitrile; ester solvents such as ethyl acetate or isopropyl acetate; ketone solvents such as acetone or methyl tert-butyl ketone; aromatic organic solvents such as toluene or xylene; polar aprotic solvent such as dimethyl formamide; water or its mixture thereof; preferably using toluene.

The reaction temperature may range from 60-90 °C and preferably at a temperature in the range from 85-90 °C. The duration of the reaction may range from 1-3 hours, preferably for a period of 1-2 hours.

In step-3, compound of formula-[C] is reacted with 2-bromo pyridine in presence of a reagent and solvent to obtain compound of formula-[D].

Reagent used in this step is organo lithium reagents selected from the group consisting of n-butyl lithium, n-hexyl lithium, tert-butyl lithium, phenyl lithium. Preferably using n-butyl lithium.

Solvent used in the reaction is selected from the group consisting of alcoholic solvents such as methanol, ethanol or propanol; chlorinated solvents such as dichloromethane or carbon tetrachloride; nitrile solvent such as acetonitrile or propionitrile; ester solvents such as ethyl acetate or isopropyl acetate; ketone solvents such as acetone or methyl tert-butyl ketone; aromatic organic solvents such as toluene or xylene; polar aprotic solvent such as dimethyl formamide; water or its mixture thereof; preferably using toluene.

The reaction temperature may range from -60 to -90 °C and preferably at a temperature in the range from -60 to -70 °C. The duration of the reaction may range from 1-3 hours, preferably for a period of 1-2 hours.

In yet another embodiment, the present invention provides pure Remimazolam intermediate (compound of formula-[D]) which is isolated as a yellowish solid with HPLC purity of 99.9 %. The present invention provides simple workup procedures to get compound of formula- [D] as a solid which is useful in bulk manufacturing.

The Another main embodiment of the present invention provides an improved process for the preparation of Remimazolam as shown in the scheme-IV given below.

Scheme-IV

In step-1, bromination of compound of formula-[A] with a brominating agent and solvent to obtain compound of formula-[B].

The brominating agent used in this step is selected from the group consisting of liquid bromine, N-bromo succinamide, hydrobromic acid, pyridinium hydrobromide perbromide, phenyltrimethyl ammonium perbromide. Preferably using liquid bromine.

The reaction temperature may range from 40-70 °C and preferably at a temperature in the range from 45-65 °C. The duration of the reaction may range from 1-3 hours, preferably for a period of 1-2 hours.
Solvent used in the reaction is selected from the group consisting of alcoholic solvents, chlorinated solvents, ester solvents, ketone solvents, nitrile solvents and water. Preferably using water.

In step-2, condensation of compound of formula-[B] with morpholine in presence of solvent to obtain compound of formula-[C]. Solvent used in the reaction is selected from the group consisting of alcoholic solvents such as methanol, ethanol or propanol; chlorinated solvents such as dichloromethane or carbon tetrachloride; nitrile solvent such as acetonitrile or propionitrile; ester solvents such as ethyl acetate or isopropyl acetate; ketone solvents such as acetone or methyl tert-butyl ketone; aromatic organic solvents such as toluene or xylene; polar aprotic solvent such as dimethyl formamide; water or its mixture thereof; preferably using toluene.

The reaction temperature may range from 60-90 °C and preferably at a temperature in the range from 85-90 °C. The duration of the reaction may range from 1-3 hours, preferably for a period of 1-2 hours.

In step-3, compound of formula-[C] is reacted with 2-bromo pyridine in presence of a reagent and solvent to obtain compound of formula-[D].

Reagent used in this step is organo lithium reagents selected from the group consisting of n-butyl lithium, n-hexyl lithium, tert-butyl lithium, phenyl lithium. Preferably using n-butyl lithium. Solvent used in the reaction is selected from the group consisting of aprotic solvents like tetrahydrofuran, toluene, benzene, xylene, hexane, heptane, diethyl ether; preferably using toluene.

The reaction temperature may range from -60 to -90 °C and preferably at a temperature in the range from -60 to -70 °C. The duration of the reaction may range from 1-3 hours, preferably for a period of 1-2 hours.

In step-4, chlorination of compound of formula-[E] with a chlorinating agent in a solvent to obtain compound of formula-[F].
Chlorinating agent used in this step is selected from the group consisting of thionyl chloride, oxalyl chloride, trichloro isocyanuric acid, phosphorous trichloride, phosphorous pentachloride; preferably using thionyl chloride. Solvent used in this step is selected from the group consisting of the group consisting of aprotic solvents like dichloromethane, MTBE, DMSO, DMF, tetrahydrofuran, toluene, benzene, xylene, hexane, heptane, diethyl ether; preferably using dichloromethane.
The reaction temperature may range from 10 to 30 °C and preferably at a temperature in the range from 15 to 20 °C. The duration of the reaction may range from 2-4 hours, preferably for a period of 2-3 hours.

In step-5, condensation of compound of formula-[F] with compound of formula-[D] in a solvent to obtain compound of formula-[G]. Solvent used in this step is selected from the group consisting of dichloromethane, MTBE, DMSO, DMF, tetrahydrofuran, toluene, benzene, xylene, hexane, heptane, diethyl ether; preferably using dichloromethane.

The reaction temperature may range from 30 to 50 °C and preferably at a temperature in the range from 40 to 45 °C. The duration of the reaction may range from 2-4 hours, preferably for a period of 2-3 hours.

In step-6, deprotection and cyclization of compound of formula-[G] is carried out in presence of a base and solvent to obtain compound of formula-[H]. base used in this reaction is selected from the group consisting of organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tributyl amine, 4-dimethylaminopyridine, N-methyl morpholine. Preferably using triethylamine.

Solvent used in this step is selected from the group consisting of alcoholic solvents, chlorinated solvents, nitrile solvent, ester solvent, ketone solvent, aromatic organic solvent, polar aprotic solvent such as dimethyl formamide; water or its mixture thereof; preferably using dichloromethane.

The reaction temperature may range from 30 to 50 °C and preferably at a temperature in the range from 35 to 40 °C. The duration of the reaction may range from 12-16 hours, preferably for a period of 14-15 hours.

In step-7, compound of formula-[H] is reacted with Dimorpholinophosphonic chloride in presence of lithium bis(trimethylsilyl)amide followed by reacting with 1-Amino-2-propanol and a solvent to obtain compound of formula-[I].

Solvent used in this step is selected from the group consisting of dichloromethane, MTBE, DMSO, DMF, tetrahydrofuran, toluene, benzene, xylene, hexane, heptane, diethyl ether; preferably using THF.

The reaction temperature may range from -10 to -30 °C and preferably at a temperature in the range from -20 to -30 °C. The duration of the reaction may range from 15-30 hours, preferably for a period of 20-25 hours.

In step-8, compound of formula-[I] is oxidized using an oxidizing agent followed by treatment with a base and solvent to obtain Remimazolam as a brown colored fluffy solid.
Oxidizing agent used in this step is selected from the group consisting of pyridinium chlorochromate (PCC), Dess-Martin periodinane, hydrogen peroxide, oxalyl chloride, peroxydisulfuric acid, sodium dichromate, potassium permanganate, chromium trioxide, sodium hypochlorite, 2,2,6,6-tetramethyl piperidine-1-oxide (TEMPO). Preferably using oxalyl chloride.

Base used in this reaction is selected from the group consisting of organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tributyl amine, 4-dimethylaminopyridine, N-methyl morpholine. Preferably using triethylamine.

Solvent used in this step is selected from the group consisting of chlorinated solvents, nitrile solvent, ester solvent, ketone solvent, polar aprotic solvent such as dimethyl formamide or its mixture thereof; preferably using dichloromethane.

The reaction temperature may range from -60 to -80 °C and preferably at a temperature in the range from -70 to -80 °C. The duration of the reaction may range from 2-5 hours, preferably for a period of 3-4 hours.

Optionally, Remimazolam may be converted to Remimazolam salt by using pharmaceutically acceptable acid in a solvent.
Pharmaceutically acceptable acid used in this reaction is selected from the group consisting of inorganic acids like hydrochloric acid, sulfuric acid; organic acids like benzene sulfonic acid, para toluene sulfonic acid, acetic acid. Preferably using benzene sulfonic acid.

Solvent used in this step is selected from the group consisting of alcoholic solvents, chlorinated solvents, nitrile solvent, ester solvent, ketone solvent, aromatic organic solvent, polar aprotic solvent such as dimethyl formamide; water or its mixture thereof. Preferably using mixture of ethyl acetate and ethanol.
The reaction temperature may range from 20 to 40 °C and preferably at a temperature in the range from 25 to 30 °C. The duration of the reaction may range from 2-5 hours, preferably for a period of 3-4 hours.

Certain specific aspects and embodiments of the invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the invention in any manner.

The invention can be illustrated with the few examples shown below which are no way limit the scope of the present invention.

EXPERIMENTAL SECTION
Example 1: Preparation of 5-Bromo isatoic anhydride of formula-[B]:
Liquid Bromine (1.7 mL) was added to a mixture of Isatoic anhydride and water at room temperature and stirred for 10 minutes at the same temperature. Heated the resulting reaction mixture to 45-50°C and stirred for 60 minutes at the same temperature. After completion of reaction, Flushed the reaction mass with Nitrogen gas under stirring and cooled to 25-30°C. Filtered the reaction mass and washed the solid with water followed by washed with Acetone and dried to get the title compound as a pale pink color fluffy solid.
Yield: 85 %; Purity by HPLC: >95%

Example 2: Preparation of (2-Amino-5-bromophenyl) (pyridine-2-yl) methanone:

5-Bromo isatoic anhydride obtained from example-1 is portion wise added to a mixture of toluene and morpholine (3.5 mL) at 85-90°C and stirred for 60 minutes at the same temperature. After completion of reaction, reaction mixture was cooled to 25-30°C.
2-Bromo pyridine (9 mL) in Toluene was pre-cooled to -60 to -65°C under Nitrogen atmosphere and slowly added to n-BuLi (38 mL) at same temperature. Stirred the reaction mixture at same temperature for 60 minutes.
The above prepared Morpholide solution was added to it slowly at -60 to -65°C. Raised the reaction mixture temperature to 25-30°C within 12 hours. After completion of reaction, the reaction mixture was quenched with cooled HCl solution and adjusted pH to 9-10 with Sodium Hydroxide flakes. Both layers were separated and aqueous layer was extracted twice with MDC. Combine the organic layers and dried over anhydrous sodium sulphate. Distilled off the organic layer under reduced pressure to get the title compound as yellowish solid.
Yield: 55%; Purity by HPLC: >98%

Example 3: Preparation of compound of formula-[G]:
Thionyl chloride (4.7 mL) was added to a mixture of Fmoc-Glu(OMe)-OH and methylene chloride at 25-30°C and stirred for 3 hours at the same temperature. Distilled off the resulting reaction mixture under reduced pressure to get crude compound. It is dissolved in methylene chloride and added (2-Amino-5-bromophenyl) (pyridine-2-yl) methanone obtained in example-2 at 5-10°C. Heated the reaction mixture to 40-45°C and stirred for 2 hours at the same temperature.
After completion of reaction, resulting reaction mixture was cooled to 25-30°C and washed the reaction mixture with aqueous saturated sodium bicarbonate solution. Both layers were separated and solvent removed from organic layer under reduced pressure to get title compound as pale yellow color solid.
Yield: 85%; Purity by HPLC: >98%

Example 4: Preparation of compound of formula-[H]:
Triethyl amine (40 mL) was added to a mixture of compound of formula-[G] obtained from example-3 and methylene chloride at 35-40°C and stirred for 16 hours at the same temperature. After completion of reaction, concentrated the reaction mass under vacuum. The obtained crude compound was dissolved in acetone and Refluxed for 60 minutes. Cooled the reaction mixture to 25-30°C and filtered the reaction mixture. Solvent removed from the obtained filtrate under reduced pressure to obtain crude compound. Toluene was added to the obtained crude and extracted with 1N hydrochloric acid. Aqueous layer was basified using 20% Aqueous NaOH solution and extracted twice with ethyl acetate. Combine the organic layers and solvent removed from the organic layer under reduced pressure to get the title compound.
Yield: 65%; Purity by HPLC: >98%
Example-5: Preparation of compound of formula-[I]
Compound of formula-[H] (1 eq) obtained from example-4 was dissolved in tetrahydrofuran and cooled the reaction mixture to -20 to-30°C. Lithium bis(trimethylsilyl)amide (1.2 eq) in tetrahydrofuran was added to the resulting reaction mixture and stirred for 60 minutes at the same temperature. Dimorpholinophosphonic chloride (15 mg) was added lot wise to the reaction mixture at -20 to -30°C. Stirred the reaction mixture at -5 to 0°C for 4 hours. 1-Amino-2-propanol (6.7 mL) was added to the reaction mixture at the same temperature. Stirred the reaction mixture for 3 hours.
After completion of reaction, reaction mixture was quenched with 1N aqueous HCl solution at 5-10°C. Raised the reaction mixture temperature to 25-30°C within 30 minutes. The reaction mixture pH was adjusted to 7.5 to 8 by addition of aqueous Sodium bicarbonate solution, Both layers were separated and extracted the aqueous layer twice with ethyl acetate. Combine the organic layers and washed with saturated aqueous sodium bicarbonate solution followed by washed with saturated aq-Ammonium chloride solution and water. Distilled off the organic layer under reduced pressure to get the title compound as light yellow colored fluffy solid.
Yield: 80%; Purity by HPLC: >95%
Example-6: Preparation of Remimazolam:
Oxalyl chloride (3 eq) was added to a mixture of methylene chloride and dimethylsulfoxide at -70 to -78°C and stirred for 60 minutes at the same temperature. Compound of formula-[I] (1 eq) obtained from example-5 was dissolved in methylene chloride and slowly added this mixture to reaction mass at -70 to -78°C. Stirred the reaction for 3 hours at the same temperature. Triethyl amine was added slowly to the reaction mixture at -70 to -78°C. Raised the reaction mixture temperature to 25-30°C and stirred for 3 hours at the same temperature. After completion of reaction, reaction mixture was quenched with aqueous sodium bicarbonate solution followed by brine solution. Both the layers were separated and distilled off the organic layer under reduced pressure to get title compound as brown color fluffy solid.
Yield: 75%; Purity by HPLC: >95%

Example-7: Preparation of Remimazolam Besylate:
Remimazolam (1 eq) obtained in example-6 was dissolved in ethyl acetate at 25-30°C and stirred for 10 minutes at the same temperature. Pre-dissolved mixture of benzene sulfonic acid (0.98 eq) in ethanol was added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound as white colored solid.
Yield: 50%; Purity by HPLC: > 99.5%
Example-8: Preparation of Remimazolam Tosylate:
Remimazolam obtained in example-6 was dissolved in ethyl acetate at 25-30°C and stirred for 10 minutes at the same temperature. Pre-dissolved mixture of para toluene sulfonic acid in ethanol was added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound as white colored solid.
Yield: 70%; Purity by HPLC: > 99.5%
Example-9: Lyophilization process for Remimazolam salt:
Remimazolam salt was dissolved in mixture of methanol and water. The reaction mixture was passed through 0.2micron membrane filter to get clear solution. Freezed the clear solution using dry ice acetone mixture at less than -70°C and lyophilized the compound for 24 hours to get solid. Unloaded solid is preserved in dehumidifier under nitrogen atmosphere.
Yield: 90%

,CLAIMS:We Claim:

1. A novel process for the preparation of Remimazolam intermediate of formula-[D]

[D]
comprising;
a) Bromination of compound of formula-[A]

[A]
With brominating agent to obtain compound of formula-[B];

[B]
b) condensation of compound of formula-[B] with morpholine in a solvent to obtain compound of formula-[C];

[C]
c) reacting compound of formula-[C] with 2-halo pyridine in presence of a reagent and solvent to obtain Remimazolam Intermediate of formula-[D].

2. The process as claimed in step-a) of claim 1, wherein said brominating agent is selected from liquid bromine, N-bromo succinamide, hydrobromic acid, pyridinium hydrobromide perbromide, or phenyltrimethyl ammonium perbromide.

3. The process as claimed in step-c) of claim 1, wherein reagent is selected from n-butyl lithium, n-hexyl lithium, tert-butyl lithium or phenyl lithium; wherein 2-halo pyridine is selected from 2-bromo pyridine or 2-chloro pyridine

4. The process as claimed in step-b) and step-c) of claim 1, wherein solvent is selected from Toluene or xylene.

5. An improved process for the preparation of Remimazolam or its pharmaceutically acceptable salts comprising:
a) Bromination of compound of formula-[A]

[A]
With brominating agent to obtain compound of formula-[B];

[B]
b) condensation of compound of formula-[B] with morpholine to obtain compound of formula-[C];

[C]
c) reacting compound of formula-[C] with 2-Bromo pyridine in presence of a reagent and solvent to obtain Remimazolam Intermediate of formula-[D];

[D]

d) chlorination of compound of formula-[E]

[E]
with chlorinating agent in a solvent to obtain compound of formula-[F];

[F]

e) condensation of compound of formula-[F] with compound of formula-[D] obtained in step-(C) in a solvent to obtain compound of formula-[G];

[G]
f) deprotection and cyclization of compound of formula-[G] in presence of a base and solvent to obtain compound of formula-[H];

[H]

g) condensation of compound of formula-[H] with 1-Amino-2-propanol in presence of Dimorpholinophosphonic chloride and LiHMDS to obtain compound of formula-[I];

[I]

h) oxidation of compound of formula-[I] with an oxidizing agent in presence of base and solvent to obtain Remimazolam;

Remimazolam

i) optionally converting Remimazolam to Remimazolam salt by using pharmaceutically acceptable acid.

6. The process as claimed in claim 5, wherein
in step-a), brominating agent is selected from liquid bromine, N-bromo succinamide, hydrobromic acid, pyridinium hydrobromide perbromide, or phenyltrimethyl ammonium perbromide
in step-c), reagent is selected from n-butyl lithium, n-hexyl lithium, tert-butyl lithium or phenyl lithium; solvent is Tetrahydrofuran.
in step-d), chlorinating agent is selected from thionyl chloride, oxalyl chloride, trichloro isocyanuric acid, phosphorous trichloride or phosphorous pentachloride; solvent is selected from dichloromethane, carbon tetrachloride or chloroform.

7. The process as claimed in claim 5, wherein
in step-e), solvent is selected from dichloromethane, carbon tetrachloride or chloroform
in step-f), base is selected from triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, tributyl amine, 4-dimethylaminopyridine or N-methyl morpholine; solvent is selected from dichloromethane, carbon tetrachloride or chloroform.

8. The process as claimed in claim 5, wherein
in step-h), oxidizing agent is selected from pyridinium chlorochromate (PCC), Dess-Martin periodinane, hydrogen peroxide, oxalyl chloride, peroxydisulfuric acid, sodium dichromate, potassium permanganate, chromium trioxide, sodium hypochlorite or 2,2,6,6-tetramethyl piperidine-1-oxide (TEMPO).
in step-i), pharmaceutically acceptable acid selected from benzene sulfonic acid or para toluene sulfonic acid.

9. A pharmaceutical composition comprising Remimazolam salt obtained as claim 1-8 and atleast one pharmaceutically acceptable excipient.

10. Highly pure Remimazolam intermediate of formula-[D] having HPLC purity of 99% used in the preparation of Remimazolam.

[D]

Dated this 9th December, 2023

Signature: ___________________ Name: Dr. C.S VENKATESAN
Senior Vice President-SR&D
Gland Pharma Ltd