DESC:Related Patent Application
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141038566 filed on August 25, 2021; the disclosure 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 (R)-tetrahydropapaverine or its salts or an intermediate useful for the preparation of cisatracurium and atracurium besylate.
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 structural formula I as follows:

Cisatracurium besylate is one of the 10 isomers of atracurium besylate (i.e. 1R-cis,1'R-cis isomer of atracurium besylate).
Cisatracurium besylate is indicated 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 slowly loses potency with time at a rate of approximately 5% per year under refrigeration (at a temperature of 5°C). Therefore, it should be stored under refrigeration (at a temperature between 2°C to 8°C) and protected from light to preserve potency.
The U.S. patent application 4,179,507 discloses a process for the preparation of atracurium besylate which is useful as neuromuscular blocking agents. The U.S. patent application 5,453,510 discloses a process for the preparation of Cisatracurium besylate and 1R-cis,1'R-cis isomer of Atracurium besylate salts thereof, and its advantageous neuromuscular blocking potency.
The process for the preparation of cisatracurium besylate as disclosed in the patent US5,453,510 involves the steps of: preparing 1,5-pentanediol diacrylate from the reaction of pentane-1,5-diol and 3-bromopropanoic acid; preparing 1R, 1’R-atracurium besylate from the reaction 1,5-pentanediol diacrylate with (R)-tetrahydropapaverine hydrochloride; and separating the cisatracurium besylate from 1R, 1’R-atracurium besylate by column chromatography.

The chromatographic purification, stability issues, and formation of undesired impurities during the process for the preparation of Cisatracurium besylate make the process challenging at every step. The resolution of racemic tetrahydropapaverine hydrochloride by using N-acetyl leucine is also disclosed.
The U.S. patent application 4,442,108 discloses a process for the preparation of tetrahydropapaverine hydrochloride and its intermediate used for the preparation of Cisatracurium besylate. The process involving the steps of: reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid to form an intermediate; cyclizing the formed intermediate in the phosphorous oxychloride to obtain dihydropapaverine hydrochloride; and reducing the dihydropapaverine hydrochloride with sodium borohydride in methanol to form tetrahydropapaverine hydrochloride as mentioned below.

The Publication Jingxi Huagong Zhongjianti, volume: 37, issue-3, pages 49-50 discloses the reduction of dihydropapaverine hydrochloride with sodium borohydride in a mixture of water and methanol to form tetrahydropapaverine hydrochloride.
Besides different processes exists for the preparation of tetrahydropapaverine or its salts, an intermediate used for the preparation of atracurium and cisatracurium besylate, there remains a need to develop a process for the preparation of tetrahydropapaverine or its salts that is commercially significant at large scale.
Summary of the Invention
In one aspect, the present invention provides a process for the preparation of (R)-tetrahydropapaverine or its salts, useful for the preparation of cisatracurium besylate thereof, wherein the process comprises the steps of:
(i) reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid or its ester in an aromatic hydrocarbon solvent to form a compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide;

(ii) cyclizing the compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide obtained in step (i) in the presence of phosphorous oxychloride in an aromatic hydrocarbon solvent to obtain dihydropapaverine or its salts thereof;

(iii) reducing the dihydropapaverine or its salts thereof in the presence of sodium borohydride or potassium borohydride in a solvent to obtain tetrahydropapaverine or its salts thereof;

(iv) providing an ethyl acetate solution of tetrahydropapaverine or its salts thereof obtained in step (iii);
(v) adding (S)-ibuprofen to the ethyl acetate solution of tetrahydropapaverine or its salts thereof provided in step (iv);
(vi) maintaining the mixture obtained in step (v) at a temperature between 25? to 80? until (R)-tetrahydropapaverine (S)-ibuprofen salt is formed;
(vii) isolating the (R)-tetrahydropapaverine (S)-ibuprofen salt as a solid from the mixture maintained in step (vi);
(viii) obtaining (R)-tetrahydropapaverine free base from the (R)-tetrahydropapaverine (S)-ibuprofen salt isolated in step (vii); and
(ix) optionally converting the (R)-tetrahydropapaverine free base obtained in step (viii) to salts thereof.
In one embodiment of the present invention, the 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid is reacted in the aromatic hydrocarbon solvent in the presence of a catalyst at a temperature between 90? to 200?.
In one embodiment of the present invention, the solvent is selected from the group comprising alcohols such as methanol and ethanol, water, and mixtures thereof.
In another aspect, the present invention provides a process for the preparation of tetrahydropapaverine or its salts thereof, useful for the preparation of cisatracurium besylate and atracurium besylate thereof, wherein the process comprises the steps of:
(i) reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid in an aromatic hydrocarbon solvent to form a compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide;

(ii) cyclizing the compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide obtained in step (i) in the presence of phosphorous oxychloride in an aromatic hydrocarbon solvent to obtain dihydropapaverine or its salts thereof; and

(iii) reducing the dihydropapaverine or its salts thereof in the presence of sodium borohydride or potassium borohydride in a solvent to obtain tetrahydropapaverine or its salts thereof.

In yet another aspect, the present invention provides a process for the preparation of (R)-tetrahydropapaverine or its salts, useful for the preparation of cisatracurium besylate thereof, wherein the process comprises the steps of:
(i) providing an ethyl acetate solution of tetrahydropapaverine or its salts thereof;
(ii) adding (S)-ibuprofen to the ethyl acetate solution of tetrahydropapaverine or its salts thereof provided in step (i);
(iii) maintaining the mixture obtained in step (ii) at a temperature between 25? to 80? until (R)-tetrahydropapaverine (S)-ibuprofen salt is formed;
(iv) isolating the (R)-tetrahydropapaverine (S)-ibuprofen salt as a solid from the mixture maintained in step (iii);
(v) obtaining (R)-tetrahydropapaverine free base from the (R)-tetrahydropapaverine (S)-ibuprofen salt isolated in step (iv); and
(vi) optionally converting the (R)-tetrahydropapaverine free base obtained in step (v) to salts thereof.
Detailed description of the Invention
In the first embodiment, the present invention provides a process for the preparation of (R)-tetrahydropapaverine or its salts, useful for the preparation of cisatracurium besylate thereof, wherein the process comprises the steps of:
(i) reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid or its ester in an aromatic hydrocarbon solvent to form a compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide;

(ii) cyclizing the compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide obtained in step (i) in the presence of phosphorous oxychloride in an aromatic hydrocarbon solvent to obtain dihydropapaverine or its salts thereof;

(iii) reducing the dihydropapaverine or its salts thereof in the presence of sodium borohydride or potassium borohydride in a suitable solvent to obtain tetrahydropapaverine or its salts thereof;

(iv) providing an ethyl acetate solution of tetrahydropapaverine or its salts thereof obtained in step (iii);
(v) adding (S)-ibuprofen to the ethyl acetate solution of tetrahydropapaverine or its salts thereof provided in step (iv);
(vi) maintaining the mixture obtained in step (v) until (R)-tetrahydropapaverine (S)-ibuprofen salt is formed;
(vii) isolating the (R)-tetrahydropapaverine (S)-ibuprofen salt as a solid from the mixture maintained in step (vi);
(viii) obtaining (R)-tetrahydropapaverine free base from the (R)-tetrahydropapaverine (S)-ibuprofen salt isolated in step (vii); and
(ix) optionally converting the (R)-tetrahydropapaverine free base obtained in step (viii) to its salts thereof.
The step of reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid or its ester according to step (i) of the present invention is carried out at a temperature between 90? to 200?, preferably at the temperature of 110?.
The step of reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid or its ester according to step (i) of the present invention may be carried out in the presence of suitable catalyst, preferably the catalyst is boric acid.
The step of cyclizing the compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide according to step (ii) of the present invention, is carried out at a temperature between 80? to 200?, preferably at 90?.
The step of reducing the dihydropapaverine or its salts thereof in the presence of sodium borohydride or potassium borohydride according to step (ii) of the present invention is carried out in a suitable solvent selected from a group consisting of alcohols such as methanol, ethanol; water and its mixtures thereof, preferably water.
The step of reducing the dihydropapaverine or its salts thereof in the presence of sodium borohydride or potassium borohydride according to step (ii) of the present invention is carried out at a temperature between 0? to 50?.
The step of maintaining the mixture till the formation of (R)-tetrahydropapaverine (S)-ibuprofen salt according to step (vi) of the present invention is maintained at temperatures suitable for the formation of (R)-tetrahydropapaverine (S)-ibuprofen salt, preferably the temperatures between 25? to 80?.
The step of isolating (R)-tetrahydropapaverine (S)-ibuprofen salt as a solid according to step (vii) of the present invention is done by techniques known in the state of art, preferably filtration.
The step of obtaining (R)-tetrahydropapaverine free base from the (R)-tetrahydropapaverine (S)-ibuprofen salt according to step (viii) of the present invention may be done by the steps of dissolving (R)-tetrahydropapaverine (S)-ibuprofen salt in water; adjusting the pH greater than 7 by the addition of bases; and extracting the (R)-tetrahydropapaverine free base with organic solvents.
The step of converting the (R)-tetrahydropapaverine free base to its salts thereof according to step (ix) of the present invention may be done by techniques known in the state of art.
Prior art processes for the tetrahydropapaverine or its salts employs different solvents for the formation of an intermediate by reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid and cyclization of the formed intermediate.
Surprisingly the inventors of the present invention found aromatic hydrocarbon solvents are suitable for the formation of an intermediate by reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid and cyclization of the formed intermediate, and also has the following advantages than the other solvents:
(A) The intermediate formed in the aromatic hydrocarbon solvent after the reaction of 2-(3,4-dimethoxyphenyl)ethylamine with 3,4-dimethoxyphenyl acetic acid could be taken to the cyclization stage without the isolation of intermediate as a solid.
(B) Water formed during the reaction of 2-(3,4-dimethoxyphenyl)ethylamine with 3,4-dimethoxyphenyl acetic acid in the aromatic hydrocarbon solvent could be removed azeotropically during the reaction.
(C) quenching of phosphorous oxychloride after the cyclization of the intermediate could be avoided, since the excess of phosphorous oxychloride with toluene could be removed by easily distillation with toluene.
Surprisingly the inventors of the present invention found that ethyl acetate used for resolution of tetrahydropapaverine by (S)-ibuprofen results in (R)-tetrahydropapaverine or its salts having isomeric purity more than 99.7%.
Table-1:
Solvents used for the preparation of (S)-Ibuprofen (R)-tetrahydropapaverine salt for the preparation of (R)-tetrahydropapaverine or its salts thereof.
SNo. Equivalents of (S)-Ibuprofen for one equivalent of tetrahydropapaverine Solvent used for the preparation of (S)-Ibuprofen (R)-tetrahydropapaverine salt Isomeric purity
1 1 Acetonitrile 60.08
2 1 IPA 92.43
3 0.65 n-Butanol 94.37
4 0.65 MIBK 72.03
5 0.65 t-Butanol 59.50
6 0.65 Amyl alcohol 61.32
7 0.65 EtOH +5% Water 94.83
8 0.6 Methanol 87.00
9 0.6 Acetone 96.81
10 0.6 Toluene 81.42
11 0.6 Ethanol 96.89
12 0.6 Ethyl acetate 99.91
In the second embodiment, the present invention provides a process for the preparation of tetrahydropapaverine or its salts thereof, useful for the preparation of cisatracurium besylate and atracurium besylate thereof, wherein the process comprises the steps of:
(i) reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid in an aromatic hydrocarbon solvent to form a compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide;

(ii) cyclizing the compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide obtained in step (i) in the presence of phosphorous oxychloride in an aromatic hydrocarbon solvent to obtain dihydropapaverine or its salts thereof; and

(iii) reducing the dihydropapaverine or its salt thereof in the presence of sodium borohydride or potassium borohydride in a suitable solvent to obtain tetrahydropapaverine or its salts thereof.

In the third embodiment, the present invention provides a process for the preparation of (R)-tetrahydropapaverine or its salts, useful for the preparation of cisatracurium besylate thereof, wherein the process comprises the steps of:
(i) providing an ethyl acetate solution of tetrahydropapaverine or its salts thereof;
(ii) adding (S)-ibuprofen to the ethyl acetate solution of tetrahydropapaverine or its salts thereof provided in step (i);
(iii) maintaining the mixture obtained in step (ii) at a temperature between 25? to 80? until (R)-tetrahydropapaverine (S)-ibuprofen salt is formed;
(iv) isolating the (R)-tetrahydropapaverine (S)-ibuprofen salt as a solid from the mixture maintained in step (iii);
(v) obtaining (R)-tetrahydropapaverine free base from the (R)-tetrahydropapaverine (S)-ibuprofen salt isolated in step (iv); and
(vi) optionally converting the (R)-tetrahydropapaverine free base obtained in step (v) to salts thereof.
The (R)-tetrahydropapaverine or its salts is used as intermediate for the preparation of cis-atracurium besylate.
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 of Dihydropapaverine hydrochloride
A mixture of Homoveratric acid (100 g), Homoveratrylamine (92 g), boric acid (1.0 g) and toluene (500 mL) was heated for 24 hours at a temperature of 110°C in an azeotropic condition to remove water. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to a temperature of 90°C. Phosphorous oxychloride (234 g) was slowly added to the reaction mass at a temperature of 90°C; then heated to a temperature of 100°C and maintained at the same temperature for 2 hours. The reaction was monitored by HPLC. After completion of this reaction, toluene was added to the reaction mass and distilled out excess Phosphorous oxychloride with toluene. To the reaction mass, isopropyl alcohol (300 mL) was added and stirred for 2 hours at a temperature of 75±5.0°C. The resultant solid was filtered, washed with isopropyl alcohol (100 mL). To the wet solid, isopropyl alcohol (300 mL) was added and stirred for 1 hour. The obtained solid was filtered, washed with isopropyl alcohol (100mL) and dried. Yield: 172 g.
Example -2: Preparation of Tetrahydropapaverine hydrochloride
To a mixture of Dihydropapaverine hydrochloride obtained in example-1 (70 g) and water (1050 mL) at a temperature of 15±10°C, aqueous sodium borohydride solution (21.07 g of sodium borohydride in 75 mL of water) was slowly added and stirred for 2 hours at a temperature of 10±5.0°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the pH of the reaction mass the pH 3-4 by the addition of concentrated hydrochloric acid solution, then adjusting pH to greater than 9 by addition of 50% aqueous sodium hydroxide solution. The product in the reaction mass was then extracted with dichloromethane (350 mL). The dichloromethane extracts were concentrated under vacuum to obtain a residue. The obtained residue is dissolved in isopropanol (350 mL) followed by the addition of concentrated hydrochloric acid solution (70 mL). The contents were then stirred for 5 hours at a temperature between 25°C-30°C. The resulted solid was filtered, washed with isopropanol (100 mL) and dried. Yield: 46.6 g.
Example-3: Preparation of (R)-Tetrahydropapaverine hydrochloride
Step (a): Preparation of R-Tetrahydropapaverine S-Ibuprofen salt: A biphasic mixture of water (2000 mL) and ethyl acetate (4000 mL) containing (RS)-Tetrahydropapaverine hydrochloride (200 g) was prepared and then adjusted to a pH greater than 7.0 by the addition of aqueous ammonia solution and stirred for 30 minutes. Ethyl acetate layer was separated from the biphasic mixture, washed with water (1000 mL) and then with brine (1000 mL) and then concentrated under vacuum to remove 800 mL of ethyl acetate. To the concentrated ethyl acetate layer containing (RS)-Tetrahydropapaverine free base, S-ibuprofen (65 g) was added and stirred for 15-20 minutes. The contents were heated to at a temperature between 50-60°C and maintained at the temperature between 50°C-60°C for 1.0 hour; then heating was stopped and cooled slowly at a temperature of 25°C. The cooled contents were stirred for 2.0 hours at a temperature of 25°C and then stirred at a temperature between 18-22°C for 4-6 hours. The resultant solid was filtered, washed with ethyl acetate (100 mL) and dried. Yield: 90 g: Chiral purity was greater than 99.5% by HPLC.
Step (b): Preparation of R-Tetrahydropapaverine hydrochloride: The R-Tetrahydropapaverine S-Ibuprofen salt (88 g) obtained in step (a) was dissolved in water (440 mL) and then the pH of the solution was adjusted to greater than 11 by the addition of aqueous 25% sodium hydroxide solution. The pH adjusted solution was then extracted with dichloromethane (440 mL). Dichloromethane extracts were combined and concentrated under vacuum to obtain a residue. The residue was dissolved in isopropanol (440 mL), followed by the addition of concentrated hydrochloric acid solution (44 mL). The contents were then stirred for 5-6 hours at a temperature between 25°C-30°C. The resultant solid was filtered, washed with isopropanol (88 mL) and dried. Yield: 40.0g; Chiral purity: 99.97% by HPLC.
Example-4: Preparation of 5-Prop-2-enoyloxypentyl prop-2-enoate.
A mixture of 1,5-pentanediol (50 g), 3-bromopropionic acid (155 g), sulfuric acid (4 g) and toluene (1 L) was heated for 6±1 hours at a temperature between 90°C-110°C using Dean-Stark apparatus for the removal of water azeotropically. The progress of the reaction was monitored by GC. After completion of the reaction, the reaction mass was cooled to room temperature. To the cooled reaction mass, water (500 mL) was added and stirred for 30 minutes to form a biphasic mixture. The toluene layer was separated from the biphasic mixture. To the separated toluene layer, triethylamine (117 g) was added; then heated to at a temperature between 70-80°C and maintained for 5.0±1 hours at the same temperature. The progress of the reaction was monitored by GC. After completion of the reaction, the reaction mass was cooled; quenched with water (500 mL) and stirred for 15 minutes resulting in a biphasic mixture. The toluene layer was separated from the biphasic mixture and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography in silica gel (100-200) using ethyl acetate and hexanes. Yield: 85 gm
Example-5: Preparation of 1R,1R’Atracurium dioxalate
A mixture of acetonitrile (16.0 mL), water (5.0 mL), (R)-Tetrahydropapaverine hydrochloride obtained in example-3 (8.4 g), 5-Prop-2-enoyloxypentyl prop-2-enoate (2.0 g) and sodium bicarbonate (2.8 g) was stirred for 26 ± 2 hours at 40±3°C. The progress of the reaction was monitored by TLC. After completion of the reaction, Boc anhydride (1.2 g) was added to the reaction mass and stirred for 2.5±0.5 hours at at a temperature between 25°C -30°C to remove excess tetrahydropapaverine. The reaction mass was then filtered through hyflo. The organic layer was separated from the biphasic reaction mixture. The separated organic layer was washed with 20% brine solution; and diluted with acetone (150 mL) and ethyl acetate (20 mL). To the diluted organic layer, oxalic acid (2.68 g) was added and stirred for 2±0.5 hours at a temperature of 27±3°C. The resultant solid was filtered and washed with ethyl acetate (5.0 mL). To the washed solid, acetone (100 mL) and ethyl acetate (20 mL) were added; stirred for 2±0.5 hours at 27±3°C. The resulted solid was filtered and washed with ethyl acetate (5.0 mL), dried at a temperature of 25±5°C under vacuum. Yield: 8.0 g; HPLC Purity: 98.90%.
Example-6: Preparation of 1R,1R’Atracurium besylate
To 1R,1R’Atracurium dioxalate obtained in example-5 (15.0 g), a mixture of water (150mL) and toluene (75 mL) was added to form a biphasic mixture. The pH of the biphasic mixture was adjusted to 7-7.5 by the addition of 10% aqueous sodium bicarbonate solution and stirred for 30 minutes. The toluene layer was separated from the biphasic mixture and concentrated under vacuum to obtain a residue. The obtained residue was dissolved in acetonitrile (22.5 mL), followed by the addition of methyl benzene sulphonate (12.0 g), sodium bicarbonate (0.3 g) and benzyl alcohol (0.3 mL). The contents were then stirred for 48±2 hours at a temperature between 20°C-25°C followed by the addition of water (50 mL) at a temperature of 7±3°C. The resulted solution was washed with methyl tert-butyl ether (4 x 25 mL); and then extracted with dichloromethane (25 mL). All the dichloromethane extracts were combined and concentrated under vacuum to obtain a residue. The residue was dissolved in dichloromethane (10 ml) followed by the addition of methyl tert-butyl ether (100 mL) and then stirred for 3.0 hours at a temperature of 27±3°C. The resultant solid was filtered and dried under vacuum at a temperature of 27±3°C. Yield: 9.8 g
Example-7: Separation of Cisatracurium besylate from a mixture of 1R,1R’Atracurium besylate by flash chromatography
A solution of 1R,1R’Atracurium besylate (1.5 g) in dichloromethane (3.0 mL) was pumped onto irregular 40-63-micron flash chromatography silica column, wherein the column was eluted with a mixture of dichloromethane, methanol and benzene sulphonic acid (10000: 1000: 0.60). The fractions of column eluate were collected and the fractions containing the required 1R-cis, 'R-cis isomer were combined. The combined fractions were washed with cold water (50 mL); and with cold 10% brine solution (25 mL). The washed fractions were concentrated under vacuum to obtain a residue. The obtained residue was then dissolved in a mixture of acetonitrile and isopropanol (1:1, 1.5 mL); followed by the addition of ethyl acetate (30 mL) resulting in a gummy mass. The resultant gummy mass was separated by decanting the solvent. The gummy mass was then dissolved in dichloromethane (1.5 mL) followed by the addition of methyl tert-butyl ether (30 mL) and stirred for 3.0 hrs. The resultant solid was filtered and dried under vacuum at a temperature of 27±3°C. Yield: 0.55g.
Example-8: Separation of Cisatracurium besylate from a mixture of 1R,1R’Atracurium besylate by flash chromatography
A solution of 1R,1R’Atracurium besylate (1.5 g) in dichloromethane (3.0 mL) was pumped onto irregular 25-40-micron flash chromatography silica column, wherein the column was eluted with a mixture of dichloromethane, methanol and benzene sulphonic acid (10000: 1000: 0.60). The fractions of column eluate were collected and the fractions containing the required 1R-cis, 'R-cis isomer were combined. The combined fractions were washed with cold water (50 mL); and with cold 10% brine solution (25 mL). The washed fractions were concentrated under vacuum to obtain a residue. The obtained residue was then dissolved in a mixture of acetonitrile and isopropanol (1:1, 1.5 mL); followed by the addition of ethyl acetate (30 mL) resulting in a gummy mass. The resultant gummy mass was separated by decanting the solvent. The gummy mass was then dissolved in dichloromethane (1.5 mL) followed by the addition of methyl tert-butyl ether (30 mL) and stirred for 3.0 hrs. The resultant solid was filtered and dried under vacuum at a temperature of 27±3°C. Yield: 0.45g.
Example-9: Separation of Cisatracurium besylate from a mixture of 1R,1R’Atracurium besylate by flash chromatography
A solution of 1R,1R’Atracurium besylate (1.5 g) in dichloromethane (3.0 mL) was pumped onto
spherical 20-40-micron flash chromatography silica column, wherein the column was eluted with a mixture of dichloromethane, methanol and benzene sulphonic acid (10000: 1000: 0.60). The fractions of column eluate were collected and the fractions containing the required 1R-cis, 'R-cis isomer were combined. The combined fractions were washed with cold water (50 mL); and with cold 10% brine solution (25 mL). The washed fractions were concentrated under vacuum to obtain a residue. The obtained residue was then dissolved in a mixture of acetonitrile and isopropanol (1:1, 1.5 mL); followed by the addition of ethyl acetate (30 mL) resulting in a gummy mass. The resultant gummy mass was separated by decanting the solvent. The gummy mass was then dissolved in dichloromethane (1.5 mL) followed by the addition of methyl tert-butyl ether (30 mL) and stirred for 3.0 hrs. The resultant solid was filtered and dried under vacuum at a temperature of 27±3°C. Yield: 0.48g.
Example-10: Separation of Cisatracurium besylate from a mixture of 1R,1R’Atracurium besylate by flash chromatography
A solution of 1R,1R’Atracurium besylate (1.5 g) in dichloromethane (3.0 mL) was pumped onto irregular 16-24-micron flash chromatography silica column, wherein the column was eluted with a mixture of dichloromethane, methanol and benzene sulphonic acid (10000: 1000: 0.60). The fractions of column eluate were collected and the fractions containing the required 1R-cis, 'R-cis isomer were combined. The combined fractions were washed with cold water (50 mL); and with cold 10% brine solution (25 mL). The washed fractions were concentrated under vacuum to obtain a residue. The obtained residue was then dissolved in a mixture of acetonitrile and isopropanol (1:1, 1.5 mL); followed by the addition of ethyl acetate (30 mL) resulting in a gummy mass. The resultant gummy mass was separated by decanting the solvent. The gummy mass was then dissolved in dichloromethane (1.5 mL) followed by the addition of methyl tert-butyl ether (30 mL) and stirred for 3.0 hrs. The resultant solid was filtered and dried under vacuum at a temperature of 27±3°C. Yield: 0.40g.
Example-11: Separation of Cisatracurium besylate from a mixture of 1R,1R’Atracurium besylate by Preparative HPLC
A solution of 1R,1R’Atracurium besylate (1.5 g) in dichloromethane (3.0 mL) was purified using preparative HPLC column (10-micron silica column) with a mixture of dichloromethane, methanol and benzenesulphonic acid 4000:1000:0.25. The fractions of column eluate were collected and the fractions containing the required 1R-cis, 'R-cis isomer were combined. The combined fractions were washed with cold water (50 mL); and with cold 10% brine solution (25 mL). The washed fractions were concentrated under vacuum to obtain a residue. The obtained residue was then dissolved in a mixture of acetonitrile and isopropanol (1:1, 1.5 mL); followed by the addition of ethyl acetate (30 mL) resulting in a gummy mass. The resultant gummy mass was separated by decanting the solvent. The gummy mass was then dissolved in dichloromethane (1.5mL) followed by the addition of methyl tert-butyl ether (30 mL) and stirred for 3.0 hrs. The resultant solid was filtered and dried under vacuum at a temperature of 27±3°C. Yield: 0.30g.
Example-12: Separation of Cisatracurium besylate from a mixture of 1R,1R’Atracurium besylate by Preparative HPLC
A solution of 1R,1R’Atracurium besylate (1.5 g) in dichloromethane (3.0 mL) was purified using preparative HPLC column (5-micron silica column) with a mixture of dichloromethane, methanol and benzenesulphonic acid 4000:1000:0.25. The fractions of column eluate were collected and the fractions containing the required 1R-cis, 'R-cis isomer were combined. The combined fractions were washed with cold water (50 mL); and with cold 10% brine solution (25 mL). The washed fractions were concentrated under vacuum to obtain a residue. The obtained residue was then dissolved in a mixture of acetonitrile and isopropanol (1:1, 1.5 mL); followed by the addition of ethyl acetate (30 mL) resulting in a gummy mass. The resultant gummy mass was separated by decanting the solvent. The gummy mass was then dissolved in dichloromethane (1.5mL) followed by the addition of methyl tert-butyl ether (30 mL) and stirred for 3.0 hrs. The resultant solid was filtered and dried under vacuum at a temperature of 27±3°C. Yield: 0.25g.
Example-13: Purification of Cisatracurium besylate
Cisatracurium besylate (3.0 g) was dissolved in water (90 mL) at a temperature of 2±3°C to obtain a solution. The pH of the solution was adjusted to 3.5- 4.0 using 0.1% of aqueous solution of benzene sulfonic acid; and then washed with n-heptane (9.0 ml) at a temperature of 22±3°C. Nitrogen gas was purged into the washed aqueous solution for 30 ±10 minutes at a temperature of 25±5°C followed by application of vacuum for 30±10 minutes at 25±5°C. Nitrogen purging, and vacuum was repeated two more times. The pH of the resultant solution was maintained at 3.5-4.0 using 0.1% of aqueous solution of benzene sulfonic acid and filtered by semipermeable membrane. The obtained filtrate was freeze dried under vacuum to obtain Cisatracurium besylate. % Yield: 80.0%.
,CLAIMS:1. A process for the preparation of (R)-tetrahydropapaverine or its salts, useful for the preparation of cisatracurium besylate thereof, wherein the process comprises the steps of:
(i) reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid or its ester in an aromatic hydrocarbon solvent to form a compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide;

(ii) cyclizing the compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide obtained in step (i) in the presence of phosphorous oxychloride in an aromatic hydrocarbon solvent to obtain dihydropapaverine or its salts thereof;

(iii) reducing the dihydropapaverine or its salts thereof in the presence of sodium borohydride or potassium borohydride in a solvent to obtain tetrahydropapaverine or its salts thereof;

(iv) providing an ethyl acetate solution of tetrahydropapaverine or its salts thereof obtained in step (iii);
(v) adding (S)-ibuprofen to the ethyl acetate solution of tetrahydropapaverine or its salts thereof provided in step (iv);
(vi) maintaining the mixture obtained in step (v) at a temperature between 25? to 80? until (R)-tetrahydropapaverine (S)-ibuprofen salt is formed;
(vii) isolating the (R)-tetrahydropapaverine (S)-ibuprofen salt as a solid from the mixture maintained in step (vi);
(viii) obtaining (R)-tetrahydropapaverine free base from the (R)-tetrahydropapaverine (S)-ibuprofen salt isolated in step (vii); and
(ix) optionally converting the (R)-tetrahydropapaverine free base obtained in step (viii) to salts thereof.
2. The process as claimed in Claim 1, wherein the 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid or its ester is reacted in the aromatic hydrocarbon solvent in the presence of a catalyst at a temperature between 90? to 200?.
3. The process as claimed in Claim 1, wherein the solvent is selected from the group comprising alcohols such as methanol and ethanol, water, and mixtures thereof.
4. A process for the preparation of tetrahydropapaverine or its salts thereof, useful for the preparation of cisatracurium besylate and atracurium besylate thereof, wherein the process comprises the steps of:
(i) reacting 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid in an aromatic hydrocarbon solvent to form a compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide;

(ii) cyclizing the compound N-[2-(dimethoxyphenyl)ethyl]-3.4-dimethoxyphenyl-acetamide obtained in step (i) in the presence of phosphorous oxychloride in an aromatic hydrocarbon solvent to obtain dihydropapaverine or its salts thereof; and

(iii) reducing the dihydropapaverine or its salts thereof in the presence of sodium borohydride or potassium borohydride in a solvent to obtain tetrahydropapaverine or its salts thereof.

5. The process as claimed in Claim 4, wherein the 2-(3,4-dimethoxyphenyl)ethylamine and 3,4-dimethoxyphenyl acetic acid is reacted in the aromatic hydrocarbon solvent in the presence of a catalyst at a temperature between 90? to 200?.
6. The process as claimed in Claim 4, wherein the solvent is selected from the group comprising alcohols such as methanol and ethanol, water, and mixtures thereof.
7. A process for the preparation of (R)-tetrahydropapaverine or its salts, useful for the preparation of cisatracurium besylate thereof, wherein the process comprises the steps of:
(i) providing an ethyl acetate solution of tetrahydropapaverine or its salts thereof;
(ii) adding (S)-ibuprofen to the ethyl acetate solution of tetrahydropapaverine or its salts thereof provided in step (i);
(iii) maintaining the mixture obtained in step (ii) at a temperature between 25? to 80? until (R)-tetrahydropapaverine (S)-ibuprofen salt is formed;
(iv) isolating (R)-tetrahydropapaverine (S)-ibuprofen salt as a solid from the mixture maintained in step (iii);
(v) obtaining (R)-tetrahydropapaverine free base from the (R)-tetrahydropapaverine (S)-ibuprofen salt isolated in step (iv); and
(vi) optionally converting the (R)-tetrahydropapaverine free base obtained in step (v) to its salts thereof.