DESC:RELATED PATENT APPLICATION:

This application claims the priority to and benefit of Indian Patent Application No. 202341032174 filed on May 05, 2023; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION:

The present invention relates to a process for the preparation of cisatracurium besylate and its intermediates thereof. Particularly, the present invention relates to a process for the preparation of cisatracurium besylate that is commercially significant.

BACKGROUND OF THE INVENTION:

Cisatracurium besylate is [1R-[1a,2a(1'R*,2'R*)]]-2,2'-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate and is represented by the formula I.

Cisatracurium besylate is approved as an adjunct to general anaesthesia to facilitate tracheal intubation in adults and in paediatric patients 1 month to 12 years of age, to provide skeletal muscle relaxation in adults during surgical procedures or during mechanical ventilation in the ICU and to provide skeletal muscle relaxation during surgical procedures via infusion in paediatric patients 2 years and older.

Cisatracurium besylate injection should be stored under refrigeration (2 to 8 °C) and protected from light, since the product cisatracurium besylate is heat and light sensitive.

Cisatracurium besylate, the 1R-cis, 1'R-cis isomer of Atracurium besylate is advantageous than atracurium besylate in neuromuscular blocking activity as disclosed in the Patent US 5,453,510. The preparation of atracurium besylate is described in the Patent US 4,179,507.

Cisatracurium besylate is one of the 10 isomers of atracurium besylate (i.e. 1R-cis, 1'R-cis isomer of atracurium besylate). The earliest process for the preparation of cisatracurium besylate is disclosed in the Patent US 5,453,510 involving the reaction 1,5-pentanediol diacrylate with (R)-tetrahydropapaverine hydrochloride to form cisatracurium oxalate; and converting the cisatracurium oxalate to cisatracurium besylate and finally separating by column chromatography as mentioned below.

The reactant 1,5-pentanediol diacrylate is light sensitive and undergoes polymerization. This nature of the reactant 1,5-pentanediol diacrylate makes it undesirable for handling at large scale preparations. Further the chromatographic purification at the final step of the preparation is challenging and difficult.

The Patent application IN410209 discloses the process for the preparation of atracurium besylate from the reaction of tetrahydropapaverine with pentane-1,5-diyl bis(3-chloropropanoate) as mentioned below.

The Patent application EP0219616 discloses the process for the preparation of atracurium besylate from the esterification of N-(2-carboxyethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinnoline with 1,5-pentane diol in the presence of toluene sulfonic acid in toluene, wherein N-(2-carboxyethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinnoline is prepared tetrahydropapaverine with beta-propiolactone as mentioned below.

The Indian Patent application IN 2725/MUM/2008 discloses the process for the preparation of atracurium from the reaction of N-(2-carboxyethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinnoline with dihalopentane in the presence of organic base as mentioned below.

The PCT Publication WO2009007946 discloses the preparation of cisatracurium besylate from (R)-tetrahydropapaverine as mentioned below.

In the aforementioned process, the chiral purity was controlled by purification in the intermediate stages. The purification processes of the intermediates of the process were cumbersome. Particularly, the purification of the intermediate compound (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tert-butoxycarbonylethyl-isoquinoline was achieved through salt formation using oxalic acid.

The Patent application CN113372271 discloses the purification of the intermediate compound (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tertbutoxy-carbonylethyl-isoquinoline from crystallization of one or more of halogenated hydrocarbon solvent, ether solvent, ester solvent, aromatic hydrocarbon solvent and mixtures thereof.

Besides different processes exist for the preparation of cisatracurium besylate, there remains a need to develop a process for the preparation of cisatracurium besylate that is commercially significant at large scale.

OBJECTS OF THE INVENTION:

The primary object of the present invention is to provide a novel and improved process for the preparation of cisatracurium besylate.

Another object of the present invention is to offer a scalable and efficient process for the synthesis of cisatracurium besylate, suitable for large-scale production while maintaining high purity and yield.

Yet another object of the present invention is to utilize acetonitrile as a solvent, facilitating the direct isolation of compound formula-V in an alcoholic solvent without the formation of organic acid salts.

SUMMARY OF THE INVENTION:
Accordingly, the present invention discloses a process for preparation of cisatracurium besylate of formula-I

comprising the steps of:
(i). reacting (R)-tetrahydropapaverine or its salts of formula-VI

with tert-butyl-acrylate of the formula-VII in acetonitrile

to obtain a compound of formula-V;

(ii). isolating the compound of formula-V by employing alcohols or its mixtures thereof;
(iii). reacting the compound of formula-V isolated in step (ii) with organic reagent to obtain a compound of formula-IV;

(iv). hydrolyzing the compound of formula-IV obtained in step (iii) to form a compound of formula-III; and

(v). reacting the compound of formula-III obtained in step (iv) with 1,5-pentanediol of formula-II in the presence of benzene sulfonic acid

to obtain cisatracurium besylate of formula-I.

In step (i) of the said process, temperatures ranging from 20-70 °C are maintained for a duration between from 2 to 48 hrs.
In step (ii) of the said process, the alcoholic solvent is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, butanol and mixtures thereof. Preferably, the alcoholic solvent is isopropanol.
In step (ii) of the said process, the isolated compound of formula-V is solid.
In step (iii) of the said process, the suitable organic reagent is selected from the group comprising Grignard reagent, diethyl ether, lithium aluminium hydride, methyl-benzene sulfonate and N-bromosuccinimide.
In step (iii) of the said process, the organic reagent is methyl-benzene sulfonate.
In step (iii) of the said process, the suitable solvent selected from the group comprising chlorinated solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as toluene and xylene; ester solvents such as ethyl acetate; nitriles such as acetonitrile; dimethylsulfoxide; and mixtures thereof. Preferably, the suitable solvent is dichloromethane.
In step (iv) of the said process, the hydrolysis is conducted using an acid selected from the group comprising hydrochloric acid, hydrobromic acid, hydroiodic acid, tetrafluoroboric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methane sulfonic acid, benzene sulfonic acid, and p-toluene sulfonic acid or the hydrolysis is carried out by hydrogenolysis in acidic ion exchange resin in presence of hydrogen; or by reacting with silylating agent.
Further, in step (iv) of said process, the preferred hydrolysis is performed by acidic ion exchange resin in a mixture of water and tetrahydrofuran.
In step (v) of said process, the suitable solvent is selected from the group comprising chlorinated solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as toluene and xylene; ester solvent such as ethyl acetate; nitriles such as acetonitrile; aliphatic hydrocarbons such as cyclohexane; and its mixtures thereof. Preferably, the suitable solvent is dichloromethane.
According to the present invention, the process for the preparation of compound of formula-V,

Comprising the step of:
reacting (R)-tetrahydropapaverine or its salts of formula-VI

with tert-butyl-acrylate of the formula-VII in acetonitrile

to obtain a compound of formula-V.

Further, in the said process, the temperature range of 20-70 °C is maintained for a duration between from 2 to 48 hrs.
According to the present invention, the process for the preparation of compound of formula-V,

Comprising the steps of:
(i). reacting (R)-tetrahydropapaverine or its salts of formula-VI

with tert-butyl-acrylate of the formula-VII in a solvent

to obtain a compound of formula-V; and

(ii). isolating the compound of formula-V as a solid by employing alcohols or its mixtures thereof.
In step (i) of said process, temperatures ranging from 20-70 °C are maintained for a duration ranging from 2 to 48 hrs.
Further, in step (i) of said process, solvent is selected from the group comprising chlorinated solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as toluene and xylene; ester solvent such as ethyl acetate; nitriles such as acetonitrile; aliphatic hydrocarbons such as cyclohexane; and its mixtures thereof.
Furthermore, in step (ii) of said process, the alcoholic solvent is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, butanol and mixtures thereof. Preferably, the alcoholic solvent is isopropanol.

BRIEF DESCRIPTION OF THE DRAWINGS:

FIG. 1: High-Performance Liquid Chromatography (HPLC) Chromatogram of the compound of formula-V resulting from the reaction of (R)-tetrahydropapaverine or its salts of formula-VI with tert-butyl-acrylate of the formula-VII in toluene.

FIG. 2: High-Performance Liquid Chromatography (HPLC) Chromatogram of the compound of formula-V resulting from the reaction of (R)-tetrahydropapaverine or its salts of formula-VI with tert-butyl-acrylate of the formula-VII in acetonitrile.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a novel process for the preparation of cisatracurium besylate, a neuromuscular blocking agent widely used in anesthesia. The process involves the reaction of (R)-tetrahydropapaverine or its salts of formula-VI with tert-butyl-acrylate of the formula-VII in the presence of a suitable solvent. The reaction results in the formation of cisatracurium besylate, a compound known for its pharmaceutical utility in surgical procedures requiring muscle relaxation. The invention encompasses various aspects of the process, including reaction conditions, solvent selection, purification methods, and the characterization of the obtained product. Additionally, the invention provides improved yields, purity, and scalability compared to existing methods, making it advantageous for commercial production.

Accordingly, the present invention provides a process for the preparation of cisatracurium besylate comprising the steps of:
(i) reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII in acetonitrile to obtain a compound of formula-V as mentioned below;

(ii) isolating the compound of formula-V as a solid by employing alcohols or its mixtures thereof;
(iii) reacting the compound of formula-V isolated in step (ii) with methyl-benzene sulfonate to obtain a compound of formula-IV as mentioned below;

(iv) hydrolysis the compound of formula-IV to obtain a compound of formula-III as mentioned below; and

(v) reacting the compound of formula-III with 1,5-pentanediol of formula-II in the presence of benzene sulfonic acid to obtain cisatracurium besylate of formula-I as mentioned below.

The step (i) of reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII to obtain a compound of formula-V according to the process of the present invention is carried out in temperatures ranging from 20 to 70 ºC.

The step (i) of reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII to obtain a compound of formula-V according to the process of the present invention is carried out in about 2 hours to 48 hours.

The step (ii) isolating the compound of formula-V as a solid according to the process of the present invention is carried out by either by dissolving or mixing the compound of formula-V obtained in step (i) in alcoholic solvent or its mixtures; and precipitating or crystallizing at certain temperature either directly or after concentrating the solution.

The alcoholic solvent according to step (ii) according to the present invention is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, butanol and mixtures thereof. Preferably isopropanol was used in the present invention.
The step (iii) of reacting the compound of formula-V or its salts with methyl-benzenesulfonate to obtain a compound of formula-IV according to the process of the present invention is carried out in suitable solvent selected from the group including chlorinated solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as toluene and xylene; ester solvent such as ethyl acetate; nitriles such as acetonitrile; dimethylsulfoxide; and its mixtures thereof. Preferably dichloromethane was used in the present invention.

The step (iv) of hydrolysis the compound of formula-IV to obtain a compound of formula-III according to the process of the present invention is done by reacting the compound of formula-IV with an acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, tetrafluoroboric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methane sulfonic acid, benzene sulfonic acid, and p-toluene sulfonic acid; or by hydrogenolysis is acidic ion exchange resin such as Amberlyst® hydrogen, Amberlite® IR120 hydrogen and Amberjet®1200 hydrogen; or by reacting with silylating agent. Preferably the hydrolysis is carried out with Amberlyst®15 hydrogen in a mixture of water and water miscible solvent such as tetrahydrofuran.

The step (v) of reacting the compound of formula-III with 1,5-pentanediol of formula-II to obtain cisatracurium besylate of formula-I according to the process of the present invention is carried out in suitable solvent selected from the group including chlorinated solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as toluene and xylene; ester solvent such as ethyl acetate; nitriles such as acetonitrile; aliphatic hydrocarbons such as cyclohexane; and its mixtures thereof. Preferably dichloromethane was used in the present invention.

Another aspect of the present invention provides a process for the preparation of compound of formula-V, that is used for the preparation of cisatracurium besylate of formula-I comprising the steps of: reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII in acetonitrile to obtain a compound of formula-V as mentioned below.

The step reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII to obtain a compound of formula-V according to the process of the present invention is carried out in temperatures ranging from 20 to 70 ºC.

The step reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII to obtain a compound of formula-V according to the process of the present invention is carried out in about 2 hours to 48 hours.

Another aspect of the present invention is to provide a process for the preparation of compound of formula-V, used for the preparation of cisatracurium besylate of formula-I comprising the steps of:

(i) reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII in a suitable solvent to obtain a compound of formula-V as mentioned below; and

(ii) isolating the compound of formula-V as a solid by employing alcohols or its mixtures thereof.
The step (i) of reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII to obtain a compound of formula-V according to the process of the present invention is carried out in temperatures ranging from 20 to 70ºC.

The step (i) of reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII to obtain a compound of formula-V according to the process of the present invention is carried out in about 2 hours to 48 hours.

The step (ii) isolating the compound of formula-V as a solid according to the process of the present invention is carried out by either by dissolving or mixing the compound of formula-V obtained in step (i) in alcoholic solvent or its mixtures; and precipitating or crystallizing at certain temperature either directly or after concentrating the solution.

The alcoholic solvent according to step (ii) in the present invention is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, butanol and mixtures thereof. Preferably isopropanol was used in the present invention.

The compound of formula-V prepared by the process of the present invention could be employed in preparation of cisatracurium besylate in the known processes in the state of the art.

Surprisingly the step of reacting (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII in acetonitrile to obtain a compound of formula-V or its salts is efficient than the reaction of (R)-tetrahydropapaverine of formula-VI with tert-butyl-acrylate of the formula-VII in solvents other than acetonitrile to obtain a compound of formula-V or its salts.

Table 1: Results on the step of reacting (R)-tetrahydropapaverine of formula-VI free base with tert-butyl-acrylate of the formula-VII to obtain a compound of formula-V in different solvents.
Sr. No. Solvent for the reaction % Yield of the compound of formula-V % Purity of the compound of formula-V by HPLC % Impurity appeared at 0.27 RRT in HPLC Chromatogram of the compound of formula-V % Impurity appeared at 0.66 RRT in HPLC Chromatogram of the compound of formula-V % Impurity appeared at 0.43 RRT in HPLC Chromatogram of the compound of formula-V
1 No Solvent 36% 82.51% 4.99% Not Detected Not Detected
2 Toluene 56% 97.50% Not Detected 1.02% Not Detected
3 Isopropyl alcohol Solid did not form Not Applicable Not Applicable Not Applicable Not Applicable
4 Acetonitrile 79% 99.84 Not Detected Not Detected 0.11%

The use of acetonitrile in the reaction of (R)-tetrahydropapaverine of formula-VI free base with tert-butyl-acrylate of the formula-VII increases the yield and purity of the compound of formula-V, than other solvents, thereby increases the final output of cisatracurium besylate.

The impurities formed during the preparation of compound of formula-V in neat reaction and aromatic solvents such as toluene are not formed in acetonitrile solvent.

The removal of the unreacted (R)-tetrahydropapaverine of formula-VI and other undesired process impurities during the formation of compound of formula-V are achieved by the purification of the compound of formula-V.

Unexpectedly, the inventors of the present inventors purified the compound of formula-V directly by isolating it in alcoholic solvent without the formation of organic acid salts as disclosed in the prior arts. The purification of the compound of formula-V by isolating in alcoholic solvent avoids the formation of an organic acid salt of the compound of formula-V, for further processing.

Further, the compound of formula-V is obtained by isolating in alcoholic solvent is pure than the compound of formula-V obtained through the formation of an organic acid salt of the compound of formula-V. Thus making the process economically significant.

Table 2: Results on the step of reacting (R)-tetrahydropapaverine of formula-VI free base with tert-butyl-acrylate of the formula-VII to obtain a compound of formula-V with or without oxalate salt formation.

Sr. No. Solvent for the reaction Method of Isolation of the compound of formula-V % Yield of the compound of formula-V % Purity of the compound of formula-V by HPLC
1 Toluene Isolation as oxalate salt 73% 85.22%
2 Toluene Isolation as
free base 56% 97.50%
3 Acetonitrile
Isolation as oxalate salt 86% 93.28%
4 Acetonitrile
Isolation as
free base 79% 99.84

Certain specific aspects and embodiments of the present invention will be better understood in connection with the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES:

EXAMPLE 1:

Preparation and purification of (1R)-1-[(3, 4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tert-butoxycarbonylethyl-isoquinoline [Compound of formula V]

Step A: Preparation of (R)-tetrahydropapaverine free base of formula-VI:
To a sodium hydroxide solution (8.7 gm of sodium hydroxide in 400 ml of water), (R)-Tetrahydropapaverine-(S)-Ibuprofen salt (100 gm) was added to 30 ± 5? and stirred for 10-15 minutes at the same temperature. Dichloromethane (400 ml) was added to the reaction mixture at 30 ± 5? and stirred for 1 hour at the same temperature to obtain a biphasic mixture. The pH of the biphasic mixture was adjusted more than 11 by the addition of sodium hydroxide pellets. After adjusting the pH of the biphasic mixture, the organic layer was separated, washed with water (400 ml) and concentrated under vacuum to obtain a residue containing (R)-tetrahydropapaverine free base. Yield: 60.5 gm.

Step B: Preparation of (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tert-butoxycarbonylethyl-isoquinoline [Compound of formula V]:
To the residue containing (R)-tetrahydropapaverine free base obtained in Step-A, acetonitrile (100 ml) was added at 40±5?, followed by the addition of tert-butylacrylate (32.6 gm) and acetic acid (5.5 gm). The reaction mixture was heated to 70±3? and maintained for 6 hours at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 30±5? and ethyl acetate (500 ml) was added to the reaction mass. The reaction mass was then washed with sodium chloride solution (6 gm of sodium chloride in 300 ml of water). To the washed reaction mass, sodium bicarbonate solution (15 gm of sodium bicarbonate in 300 ml of water) was added at 30 ± 5? to form a biphasic mixture. The biphasic mixture was stirred for 15±5 minutes at 30 ± 5?. The organic layer was separated from the biphasic mixture and concentrated under vacuum to obtain a residue. Yield: 70 gm.

Step C: Purification of (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tert-butoxycarbonylethyl-isoquinoline [Compound of formula V]:
The residue was mixed with isopropyl alcohol (300 ml) at 50± 5? and stirred for 10± 5 minutes at the same temperature. The contents were then cooled 30± 5? and stirred for 1 hours ± 10 minutes at the same temperature. The stirred contents were further cooled to 12.5± 2.5? and stirred for 2 hours ± 10 minutes at the same temperature. The resultant solid was filtered; washed with prechilled isopropyl alcohol (50 ml); dried under vacuum for 2 hours ± 10 minutes at 30± 5?. The solid was further dried under vacuum for 8 hours ± 10 minutes at 47.5± 2.5?. Yield: 64.3 gm; Purity: 99.46% w/w by HPLC.

EXAMPLE 2:

Preparation of (R)-Tetrahydropapaverine-(S)-Ibuprofen salt from racemic-tetrahydropapaverine hydrochloride:

A mixture of racemic-tetrahydropapaverine hydrochloride (500 gm), sodium carbonate (223.2 gm), water (2500 ml) and ethylacetate (3500 ml) was stirred for about 1 hour at 30±5ºC to and allowed to settle for 30 minutes to form a biphasic mixture. The organic layer was separated. Separated organic layer was washed with sodium chloride solution (150 gm of sodium chloride in 1500 ml of water). To the washed organic layer, ethylacetate (6500 ml) was added at 30±5ºC and heated to 40±5ºC. S(+)-Ibuprofen (271.5 gm) was added to the heated mixture at 40±5ºC and stirred for 2 hours at the same temperature. The reaction mixture was cooled to 35±2ºC and stirred for 2 hours at the same temperature, then the reaction mixture was further cooled to 30±2ºC and stirred for 4 hours at the same temperature. The resultant solid was filtered, washed with prechilled ethylacetate (250 ml) and dried. % Yield: 42 %.

EXAMPLE 3:

Preparation of (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tert-butoxycarbonylethyl-isoquinoline of formula V:

Step A: Preparation of (R)-tetrahydropapaverine free base of formula VI:
To a sodium hydroxide solution (8.7 gm of sodium hydroxide in 400 ml of water), (R)-Tetrahydropapaverine-(S)-Ibuprofen salt (100 gm) was added to 30 ± 5? and stirred for 10-15 minutes at the same temperature. Dichloromethane (400 ml) was added to the reaction mixture at 30 ± 5? and stirred for 1 hour at the same temperature to obtain a biphasic mixture. The pH of the biphasic mixture was adjusted to 11 by the addition of sodium hydroxide pellets. After adjusting the pH of the biphasic mixture, the organic layer was separated, washed with water (400 ml) and concentrated under vacuum to obtain a residue containing (R)-tetrahydropapaverine free base.

Step B: Preparation of (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tert-butoxycarbonylethyl-isoquinoline of Compound of formula V:
To the residue containing (R)-tetrahydropapaverine free base obtained in Step-A, acetonitrile (100 ml) was added at 40±5?, followed by the addition of tert-butylacrylate of formula-VII (32.6 gm). The reaction mixture was heated to 70±3? and maintained for 6 hours at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 30±5? and ethyl acetate (500 ml) was added to the reaction mass. The reaction mass was then washed with sodium chloride solution (6 gm of sodium chloride in 300 ml of water); and with sodium bicarbonate solution (15 gm of sodium bicarbonate in 300 ml of water). The washed organic layer was separated concentrated under vacuum to obtain a residue. To the obtained residue, isopropyl alcohol (300 ml) was added at 50±5? and cooled to 30±5?. The cooled contents were stirred for 1 hour at 30±5?. The stirred contents were further cooled to 3±3? and stirred for 2 hours at the same temperature. The resultant solid was filtered, washed with prechilled isopropyl alcohol (50 ml) and dried. Yield: 75%; Purity: 99.84% by HPLC; % of an Impurity at –RRT: -- by HPLC.

EXAMPLE 4:

Preparation of (lR-cis)-l-[(3,4-dimethoxyphenyl)methyl]-l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-tert-butoxycarbonylethyl-isoquinolinium besylate of formula-IV

To a mixture of the compound (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tert-butoxycarbonylethyl-isoquinoline of formula V (100 gm), sodium bicarbonate (10 gm) and dichloromethane (150 ml), methyl benzene sulfonate (110 gm) was added at 30±2?, followed by the addition of dichloromethane (50 ml) at the same temperature. The reaction mixture of stirred for about 24 hours at 30±2?. The progress of the reaction was monitored by HPLC. After completion of the reaction, dichloromethane (100 ml) was added to the reaction mass at 30±2?, followed by ethylacetate (6000 ml) at 30±2?. The reaction mass was then cooled to 3±3? and stirred for 2 hours at the same temperature. The resultant solid was filtered and washed with ethylacetate (100 ml). The wet solid was then recrystallized with ethylacetate (600 ml) and dried. % Yield: 36%; Purity: 98.87% by HPLC.

EXAMPLE 5:

Preparation of (lR-cis)-l-[(3,4-dimethoxyphenyl)methyl]-l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-carboxyethyl-isoquinolinium besylate of formula-III

To a stirred mixture of the compound of (lR-cis)-l-[(3,4-dimethoxyphenyl)methyl]-l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-tert-butoxycarbonylethyl-isoquinolinium besylate of formula-IV (50 gm), tetrahydrofuran (150 ml) and water (25 ml), Amberlyst resin 15 H (12.5 gm) was added at 30±5?. The reaction mixture was then heated to 47.5±2.5? and stirred for about 12 hours at the same temperature. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 30±5?, then the resin used during the reaction was removed from the reaction mass by filtration. The cooled reaction mass was heated to 40±2? and concentrated at the same temperature in vacuum to obtain a residue. Acetone (250 ml) was added to the obtained residue at 40±2? and the contents were cooled 27.5±2.5?, then stirred for 3 hours at 27.5±2.5?. The cooled contents were further cooled to 12.5±2.5?. The resultant solid was filtered, washed with chilled acetone (50 ml) and dried. % Yield: 67%; Purity: 99.53% by HPLC.

EXAMPLE 6:

Preparation of cisatracurium besylate of formula-I

To a mixture of the (lR-cis)-l-[(3,4-dimethoxyphenyl)methyl]-l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-carboxyethyl-isoquinolinium besylate of formula-III (60 gm), dichloromethane (1800 ml) and benzene sulfonic acid (16.15 gm), 1,5-pentane diol of formula-II (12.5 gm) was added at 30±5? and stirred for 10 minutes at the same temperature. The reaction mixture was then heated to 42±2? and stirred for about 10 hours at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was washed with six times with benzene sulfonic acid solution (10.8 gm of benzene sulfonic acid in 10800 ml of water) at 22.5 ±2.5?. The washed reaction mass was heated to 42±2? and concentrated at the same temperature under vacuum to obtain a residue. To the obtained residue, acetonitrile (60 ml) at 42±2? and cooled to 22.5±2.5?. To the cooled contents, isopropyl alcohol (60 ml) was added at 22.5±2.5? and stirred for 10 minutes at the same temperature. To the stirred contents, ethylacetate (1200 ml) was added at 22.5±2.5? and stirred for 10 minutes at the same temperature. The stirred contents were allowed to settle for 2 hours at 22.5±2.5? and decant the supernatant solution at the same temperature. To the settled thick gummy mass, dichloromethane (60 ml) and acetone (90 ml) was added at 22.5±2.5? and stirred for 10 minutes at the same temperature. The contents were then added to diethylether (660 ml) at 3±3? and stirred for 1 hour at the same temperature. The resultant solid was filtered under nitrogen; washed with pre-chilled diethylether (120 ml); dried under vacuum for 2 hours at 30±5?; and further dried under vacuum for 8 hours at 30±5?.Yield: 30%; Purity: 99.01% by HPLC.
,CLAIMS:

1. A process for preparation of cisatracurium besylate of formula-I

comprising the steps of:
(i). reacting (R)-tetrahydropapaverine or its salts of formula-VI

with tert-butyl-acrylate of the formula-VII in acetonitrile

to obtain a compound of formula-V;

(ii). isolating the compound of formula-V by employing alcohols;
(iii). reacting the compound of formula-V isolated in step (ii) with an organic reagent to obtain a compound of formula-IV;

(iv). hydrolyzing the compound of formula-IV obtained in step (iii) to form a compound of formula-III; and

(v). reacting the compound of formula-III obtained in step (iv) with 1,5-pentanediol of formula-II in the presence of benzene sulfonic acid

to obtain cisatracurium besylate of formula-I.

2. The process as claimed in claim 1, wherein step (i) is conducted at temperatures ranging from 20-70 °C for a duration between 2 to 48 hrs.

3. The process as claimed in claim 1, wherein the alcoholic solvent in step (ii) is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, butanol and mixtures thereof.

4. The process as claimed in claim 3, wherein the alcoholic solvent is isopropanol.

5. The process as claimed in claim 1, wherein the isolated compound of formula-V in step (ii) is solid.

6. The process as claimed in claim 1, wherein the organic reagent in step (iii) is selected from the group comprising Grignard reagent, diethyl ether, lithium aluminium hydride, methyl-benzene sulfonate and N-bromosuccinimide.

7. The process as claimed in claim 6, wherein the organic reagent is methyl-benzene sulfonate.

8. The process as claimed in claim 1, wherein the organic solvent in step (iii) is selected from the group comprising chlorinated solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as toluene and xylene; ester solvents such as ethyl acetate; nitriles such as acetonitrile; dimethylsulfoxide; and mixtures thereof.

9. The process as claimed in claim 8, wherein the solvent is dichloromethane.

10. The process as claimed in claim 1, wherein the hydrolyzing agent in step (iv) is selected from a group comprising hydrochloric acid, hydrobromic acid, hydroiodic acid, tetrafluoroboric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methane sulfonic acid, benzene sulfonic acid, and p-toluene sulfonic acid.

11. The process as claimed in claim 1, wherein hydrolysis in step (iv) is carried out by hydrogenolysis in acidic ion exchange resin in presence of hydrogen.

12. The process as claimed in claim 1, wherein hydrolysis in step (iv) is carried out by reacting with silylating agent.

13. The process as claimed in claim 1, wherein hydrolysis in step (iv) is performed by acidic ion exchange resin in a mixture of water and tetrahydrofuran.

14. The process as claimed in claim 1, wherein the solvent in step (v) is selected from the group comprising chlorinated solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as toluene and xylene; ester solvent such as ethyl acetate; nitriles such as acetonitrile; aliphatic hydrocarbons such as cyclohexane; and its mixtures thereof.

15. The process as claimed in claim 14, wherein the solvent is dichloromethane.

16. A process for preparation of compound of formula-V

comprising the step of:
reacting (R)-tetrahydropapaverine or its salts of formula-VI

with tert-butyl-acrylate of the formula-VII in acetonitrile

to obtain a compound of formula-V.

17. The process as claimed in claim 16, wherein the process is conducted within a temperature range of 20-70 °C for a duration between 2 to 48 hrs.

18. A process for preparation of compound of formula-V,

comprising the steps of:
(i). reacting (R)-tetrahydropapaverine or its salts of formula-VI

with tert-butyl-acrylate of the formula-VII in a solvent

to obtain a compound of formula-V; and

(ii). isolating the compound of formula-V as a solid by employing alcohols or its mixtures thereof.

19. The process as claimed in claim 18, wherein step (i) is conducted at temperatures ranging from 20-70 °C for a duration between 2 to 48 hrs.

20. The process as claimed in claim 18, wherein the solvent in step (i) is selected from the group comprising chlorinated solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as toluene and xylene; ester solvent such as ethyl acetate; nitriles such as acetonitrile; aliphatic hydrocarbons such as cyclohexane; and its mixtures thereof.

21. The process as claimed in claim 18, wherein the alcoholic solvent in step (ii) is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, butanol and mixtures thereof.

22. The process as claimed in claim 21, wherein the alcoholic solvent is isopropanol.