FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
AN IMPROVED PROCESS FOR THE PREPARATION OF SUCCINYLCHOLINE CHLORIDE
AMOLI ORGANICS PVT. LTD,
407 Dalamal House, J.B.Road,
Nariman Point, Mumbai-400021,
India.
an Indian company incorporated under the companies Act, 1956
The following specification particularly describes the invention and the manner in
which it is to be performed

AN IMPROVED PROCESS FOR THE PREPARATION OF SUCCINYLCHOLINE CHLORIDE
OBJECT OF THE INVENTION
The principal object of the present invention is to provide novel and industrially economical process for the preparation of bis[2-(dimethylamino)ethyl] succinate from 2-dimethylaminoethyl hemisuccinate and in turn producing succinylcholine chloride or pharmaceutically acceptable hydrates thereof from bis[2-(dimethylamino)ethyl] succinate.
BACKGROUND OF THE INVENTION
Succinylcholine chloride also known as Suxamethonium chloride is a paralytic drug used to induce muscle relaxation and short-term paralysis, usually to facilitate tracheal intubation. Suxamethonium chloride is sold under the trade names Anectine, Quelicin, and Scoline.
Succinylcholine chloride, chemically 2,2'-[( 1,4-dioxo-1,4-
butanediyl)bis(oxy)]bis(N,N,N-trimethylethanaminium)chloride has following structure:

bis(2-(dimethylamino)ethyl) succinate is an important intermediate in the preparation of succinylcholine chloride. Many processes have been reported for the preparation of bis(2-(dimethylamino)ethyl) succinate from succinic anhydride

Patent DK78264 describes the preparation of bis(2-(dimethylamino)ethyl) succinate by reacting succinic anhydride with sodium alcoholate of a disubstituted P-amino ethanol and then treating the product with a disubstituted β-aminoethyl chloride to obtain bis(2-(dimethylamino)ethyl) succinate

Patent RO76047 (A2) describes process to prepare bis(2-(dimethylamino)ethyl) succinate by condensing succinic anhydride with Me2NCH2CH2OH, in presence of dicyclohexylcarbodiimide in chloromethane environment. This process has drawback that dicyclohexylcarbodiimide is not environmentally friendly.

US 2858329 describes a process for the preparation of bis(2-(dimethylamino)ethyl) succinate by heating succinic anhydride and N,N-dimethylaminoethanol at 135-1 45°C in benzene for 12-18 hrs.

The prior art process mentioned above involves purification of bis(2-(dimethylamino)ethyl) succinate using high vacuum distillation at very high temperature. Since the product is very heat sensitive, substantial portion of it gets

decomposed during high vacuum distillation. The process needs special heating facility, which makes it less desired at industrial level. The high vacuum distillation further poses safety risk. The prior art reaction is carried out in benzene which is carcinogenic hence not desired at industrial level. Moreover, the recovery of benzene used from the reaction is cumbersome.
Indian patent application 2938/MUM/2012 claims condensation of succinic anhydride with N,N-diemthylaminoethanol using a catalyst p-toluene sulfonic acid in presence of a solvent toluene to form bis[2-(dimethylamino)ethyl] succinate.This process suffers from drawback that it involve use of p-toluene sulfonic acid as catalyst which is genotoxic.

Journal of the American Chemical Society (1953), 75, 4725-7, Journal of Mass Spectrometry (2007), 42(7), 929-939 and US4321172 A reports preparation of monoester of succinic acid by using succinic anhydride and 2-(dimethylamino)ethanol in presence of acetone;

However, synthesis of bis[2-(dimethylamino)ethyl] succinate from monoester of succinic acid has not been reported.
Thus it is an aim to develop a process which produces 2-dimethylaminoethyl hemisuccinate and from hemi ester synthesize bis[2-(dimethylamino)ethyl] succinate

which is an important intermediate in the synthesis of succinylcholine chloride.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of 2,2'-[(l,4-dioxo-l,4-butanediyl)bis(oxy)]bis(N,N,N-trimethylethanaminium)chloride (succinylcholine chloride) or pharmaceutically acceptable hydrates thereof of formula I

comprising
1) condensing 2-(dimethylamino)ethanol of formula III

with succinic anhydride of formula II

in suitable solvent to form 2-dimethylaminoethyl hemisuccinate of formula IV.


2) isolating the 2-dimethylaminoethyl hemisuccinate of formula IV

3) condensing 2-(dimethylamino)ethanol of formula III

with 2-dimethylaminoethyl hemisuccinate of formula IV

in solvent using an acid catalyst to form bis[2-(dimethylamino)ethyl] succinate of formula V.


4) isolating bis[2-(dimethylamino)ethyl] succinate of formula V.

5) reacting the obtained bis[2-(dimethylamino)ethyl] succinate of formula V with
methyl chloride gas in presence of solvent to obtain 2,2'-[(l,4-dioxo-l,4-
butanediyl)bis(oxy)]bis(N,N,N-trimethylethanaminium)chloride (succinylcholine
chloride) or pharmaceutically acceptable hydrates thereof of formula I.
6) optionally purifying 2,2'-[(1,4-dioxo-l94-butanediyl)bis(oxy)]bis(N,N,N-
trimethylethanaminium)chloride (succinylcholine chloride) or pharmaceutically
acceptable hydrates thereof of formula I
The present invention can be illustrated by the below reaction scheme:


DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a novel method to synthesize 2,2'-[(l,4-dioxo-l,4-butanediyl)bis(oxy)]bis(N,N,N-trimethylethanaminium)chloride (succinylcholine chloride) or pharmaceutically acceptable hydrates thereof of formula I.

comprising the steps of
1) condensing 2-(dimethylamino)ethanol of formula III


with succinic anhydride of formula II

in suitable solvent to form 2-dimethylaminoethyl hemisuccinate of formula IV.

2) isolating the 2-dimethylaminoethyl hemisuccinate of formula IV

3) condensing 2-(dimethylamino)ethanol of formula III


with 2-dimethylaminoethyl hemisuccinate of formula IV in solvent using an acid catalyst to form bis[2-(dimethylamino)ethyl] succinate of formula V.

4) isolating bis[2-(dimethylamino)ethyl] succinate of formula V.

5) reacting obtained bis[2-(dimethylamino)ethyl] succinate of formula V with methyl
chloride gas in presence of solvent to obtain 2,2'-[(1,4-dioxo-1 ?4-
butanediyl)bis(oxy)]bis(N,N,N-trimethylethanaminium)chloride or dihydrate
(succinylcholine chloride) or pharmaceutically acceptable hydrates thereof of formula
I.

6) optionally purifying 2,2'-[(l,4-dioxo-l,4butanediyl)bis(oxy)]bis(N,N,N-trimethylethanaminium)chloride or dihydrate (succinylcholine chloride) or pharmaceutically acceptable hydrates thereof of formula I
In an embodiment of the invention, condensation of 2-(dimethylamino)ethanol of formula III and succinic anhydride of formula II (step 1) may be carried out by using solvent such as acetone, chloroform or pyridine; preferably acetone. In preferred embodiment of the invention, condensation is carried out by heating reaction mixture of succinic anhydride, 2-(dimethylamino)ethanol and acetone to reflux and maintaining for 6-8 hrs. The reaction is preferably carried out at reflux temperature in the range of about 50-70°C, more preferably about 55-60°C. The reaction produces 2-dimethylaminoethyl hemisuccinate of formula IV.
In another embodiment of the invention, isolation of 2-dimethylaminoethyl hemisuccinate of formula IV (step 2) is carried out by conventional procedure of filtration, washing with solvent and drying under vacuum.
In further embodiment of the invention, condensation of 2-(dimethylamino)ethanol of formula III and 2-dimethylaminoethyl hemisuccinate of formula IV (step 3) may be carried out using inert organic solvent and in presence of acid catalyst or using catalytic amount of acid resin. Preferably, inert organic solvent that may be used are toluene, benzene, chlorobenzene, xylene and the like, with toluene being the preferred solvent. In another embodiment of the invention, acid catalyst that may be used are selected from mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; trifluoro acetic acid or p-toluene sulfonic acid (PTSA). The acid resin is preferably an acidic resin viz. amberlites. Most preferably, catalyst used is sulfuric acid. The reaction is preferably carried out at reflux temperature in the range of about 100-120°C., more preferably about 110-115°C. for 36-38 hours. The reaction produces bis[2-(dimethylamino)ethyl] succinate of formula V

In an embodiment of the invention, base used for purification of bis[2-(dimethylamino)ethyl] succinate of formula V (step 4) may be selected from alkali metal carbonate or bicarbonate, such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, or an aliphatic organic base, such as triethylamine and diisopropylamine or an aromatic organic base, such as pyridine, picoline and the like. The preferred base for the purification is sodium bicarbonate.
In still another embodiment of the invention, after purification of bis[2-(dimethylamino)ethyl] succinate of formula V with base (step 4), layers are allowed to separate for 1 hour, aqueous layer is separated and kept aside. Distillation of organic layer is then carried out under vacuum and mass is degassed at temperature not more than 75 °C. Bis[2-(dimethylamino)ethyl] succinate of formula V is obtained as oily mass.
In further embodiment of the invention, reaction of methyl chloride gas with bis[2-(dimethylamino)ethyl] succinate of formula V (step 5) is carried out using a solvent, such as methanol, ethanol, propanol, butanol, isopropanol, acetone and toluene. The preferred solvent is isopropanol. The Reaction mass preferably take place at temperature of about 55-65°C, more preferably 58-62°C. for 16-18 hours to form 2,2'-[( 1,4-dioxo-1,4-butanediyl)bis(oxy)]bis(N,N,N-trimethyl ethanaminium) chloride (succinylcholine chloride) or pharmaceutically acceptable hydrates thereof of formula I.
In another embodiment of the invention, the purification of crude 2,2'-[(l,4-dioxo-1,4-butanediyl)bis(oxy)]bis(N?N?N-trimethylethanaminium) chloride (succinylcholine chloride) or pharmaceutically acceptable hydrates thereof of formula I (step 6) may be accomplished using water and alcohol, such as methanol, ethanol, propanol, butanol, isopropanol and the like. The preferred alcohol is isopropanol. In preferred embodiment of the invention, purification of 2,2'-[(l,4-dioxo-l,4-

butanediyl)bis(oxy)]bis(N,N,N-trimethyl ethanaminium) chloride (succinylcholine chloride) or pharmaceutically acceptable hydrates thereof is carried out by extraction with water and water insoluble organic solvent such as toluene, ethyl acetate, methylene dichloride, preferably toluene; followed by isolation of the aqueous mass which is then subjected to alcohol water purification. Preferably, alcohol such as methanol, ethanol, propanol, butanol, isopropanol and the like may be used. The most preferred alcohol is isopropanol
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
EXAMPLES
Example 1: Preparation of 2-dimethylaminoethyl hemisuccinate.
To a reaction flask charged with succinic anhydride (100 gm) in acetone (600 ml) dimethylaminoethanol (91 gm) was added at 25-35°C and the reaction mixture was heated to reflux and maintained for 6 hours. The reaction mixture was then cooled to room temperature and further to a temperature of 10-15°C and maintained for 2 hours. The reaction mass was filtered at 10-15°C and the solid was washed with acetone (200 ml). The obtained solid was dried under vacuum for 5 hours at 40-45°C. (Yield: 180gm)
Example 2:Preparation of bis(2-(dimethylamino)ethyl) succinate compound.
To a reaction flask charged with 2-dimethylaminoethyl hemisuccinate (100 gm) in toluene (500ml) was added Dimethyl aminoethanol (56.5 gm) and concentrated sulfuric acid (0.5 gm) at room temperature. The reaction mixture was then heated to reflux by using Dean-Stark apparatus and maintained for 36-38 hrs, which was then allowed to cool to room temperature. A solution of 8% sodium bicarbonate solution

(50 ml) was added to the reaction mass, stirred for 60 minutes, and reaction mass was allowed to settle. The aqueous layer was separated and kept aside. 8% sodium bicarbonate solution (50 ml) was charged again and stirred for 60 minutes. Reaction mass was allowed to settle, aqueous layer was separated and kept aside. Organic layer was charged in clean and dry round bottom flask, toluene was distilled under vacuum and mass was degassed at not more than 75°C. The oily mass was unloaded in the container. (Yield: 98 gm).
Example 3 A: Preparation of succinylcholine chloride dihydrate crude
Bis(2-(dimethylamino)ethyl) succinate (100 gm) was taken in a clean autoclave and isopropyl alcohol (1200 ml) was charged at 25-35°C. To this mixture was then added methyl chloride gas under pressure (1.5 to 2.5 kg/cm2 ) at 25-35 C. The reaction mass was then stirred for 15-20 minutes, temperature was raised up to 58-62°C and maintained for 16-18 hrs. The unreacted methyl chloride gas was released in 20% NaOH solution and N2 was flushed to remove methyl chloride gas completely. The reaction mixture was then allowed to cool up to 10-15°C and maintained for 2 hours. The solid thus obtained was filtered and washed with isopropyl alcohol (200 ml). The wet cake was dried and wet cake along with water (130 ml) was charged in four necked round bottom flask, heated up to 50-55°C and activated charcoal was charged at 50-55°C. The reaction mass was stirred, maintained for 60 minutes at 50-55°C and filtered. The filtrate was cooled and charged into round bottom flask along with toluene (200 ml) at 25-35°C. The reaction mass was stirred for 30-40 min and allowed to settle for 30-40 min at 25-35°C.The layers were separated and organic layer was kept aside. To the aqueous layer toluene (200 ml) was charged and reaction mass was stirred for 30-40 minutes at 25-35°C. The reaction mass was allowed to settle for 30-40 min and layers were separated. The aqueous layer along with isopropyl alcohol (1550 ml) was charged into clean round bottom flask, reaction mass was heated to reflux at 82-85°C and maintained for 1 hour. The reaction mass was cooled at 25-35°C, stirred for 8-12 hours and further cooled up to 10-15°C. The

reaction mass was maintained for 2 hours at 10-15°C and filtered. The bed was washed with isopropyl alcohol (200 ml) and suck dried completely. (Yield: 120 gm).
Example 3 B: Preparation of succinylcholine chloride dihydrate crude
Bis-(2-(dimethylamino)ethyl) succinate (100gm) was taken in a clean autoclave and dichloromethane (1200 ml) was charged at 25-35°C. To this mixture was then added methyl chloride gas under pressure (2.5-3.0 kg/cm ) at 25-35 C. The reaction mass was allowed to stir for 15-20 minutes, temperature was raised up to 58-62 C and maintained for 16-18 hrs. The reaction mixture was then allowed to cool up to 25-35°C and water (210 ml) was charged at 25-35°C. The reaction mixture was stirred for 45-60 min, allowed to settle and aqueous layer was separated. The aqueous layer was heated to 50-55°C, activated charcoal was then charged and maintained for an hour at 50-55°C. The reaction mass was then filtered through hyflo bed and washed with D.M water. The filtrate was then allowed to cool up to 25-30°C and charged to isopropyl alcohol (900 ml). The reaction mass was heated to reflux for 1 hour, allowed to cool at room temperature and further to 5-10°C. Reaction mass was then stirred for 2 hrs and filtered. The obtained precipitate was washed with isopropyl alcohol (200 ml) to obtain colorless solid. The solid was dried at 65°C (Yield: 90 gm)
Example 3 C: Preparation of succinylcholine chloride dihydrate crude
Bis-(2-(dimethylamino) ethyl) succinate (100gm) was taken in a clean autoclave and toluene (1200 ml) was charged at 25-35°C. To this mixture was then added methyl chloride gas under pressure (2.5-3.0 kg/cm ) at 25-35 C. The reaction mass was then allowed to stir for 15-20 minutes, temperature was raised up to 60-65 C and maintained for 16-18 hrs. The reaction mixture was then stirred for 45-60 min, allowed to settle and aqueous layer was separated. The aqueous layer was then heated to 50-55°C, activated charcoal was then charged and maintained for an hour at 50-55°C. The reaction mass was then filtered through hyflo bed and washed with D.M water. The filtrate was then allowed to cool up to 25-30°C and charged to isopropyl

alcohol (900 ml). Reaction was then heated to reflux, maintained for 1 hr and again allowed to cool at room temperature and 5-10°C. Reaction was maintained for 2 hours and filtered to obtain solid which was washed once with chilled isopropyl alcohol (200 ml) to obtain colorless solid. The solid was dried at 65°C (Yield: 90 gm)
Example 4: Preparation of succinylcholine chloride dihydrate pure
The succinylcholine chloride crude (100 gm) obtained in example-3 A was added to a round bottom flask followed by demineralized (D.M) water (100 ml) and the reaction mass was stirred to dissolve. Toluene (200 ml) was added and stirred for 30-40 min at 25-35°C. The reaction mass was allowed to settle for 30-40 min and the layers were separated. The aqueous layer was collected and organic layer was kept aside. Toluene (200 ml) was charged into aqueous layer and stirred for 30-40 min at 25-35°C. The reaction mass was allowed to settle for 30-40 min and the layers were separated. Aqueous layer was filtered and bed was washed with water (40 ml). Aqueous filtrate along with isopropyl alcohol was charged in another clean round bottom flask and heated to reflux at 82-85°C and maintained for 1 hour. The reaction mass was cooled to 25-35°C and stirred for 8-12 hours at 25-35°C. The reaction mass was further cooled up to 10-15 C and maintained for 2 hours. The reaction mass was filtered at 10-15°C and bed was washed with isopropyl alcohol (200 ml) and suck dried completely. The wet cake was unloaded and dried under vacuum at 50-550C for 2 hours. (Yield: 90 gm)

We Claim:
1. A process for the preparation of 2,2'-[(l,4-dioxo-l,4-butanediyl)bis(oxy)]bis(N,N,N-trimethylethanaminium)chloride (succinylcholine chloride) or a pharmaceutically acceptable hydrates thereof of formula I

comprising
1) condensing 2-(dimethylamino)ethanol of formula III

with succinic anhydride of formula II

in suitable solvent to form 2-dimethylaminoethyl hemisuccinate of formula IV.


2) isolating the 2-dimethylaminoethyl hemisuccinate of formula IV

3) condensing 2-(dimethylamino)ethanol of formula III

with 2-dimethylaminoethyl hemisuccinate of formula IV in solver catalyst to form bis[2-(dimethylamino)ethyl] succinate of formula V.

4) isolating bis[2-(dimethylamino)ethyl] succinate of formula V.


5) reacting obtained bis[2-(dimethylamino)ethyl] succinate of formula V with methyl
chloride gas in presence of solvent to obtain 2,2'-[(l,4-dioxo-l,4-
butanediyl)bis(oxy)]bis(N,N;N-trimethylethanaminium)chloride (succinylcholine
chloride) or a pharmaceutically acceptable hydrates thereof of formula I.
6) Optionally purifying 2,2'-[(l,4-dioxo-l,4-butanediyl)bis(oxy)]bis(N,N,N-
trimethylethanaminium)chloride (succinylcholine chloride) or pharmaceutically
acceptable hydrates thereof of formula I
2. The process as claimed in claim 1, wherein solvent used for condensation of 2-(dimethylamino)ethanol of formula III with succinic anhydride of formula II (step 1) is selected from acetone, chloroform or pyridine; preferably acetone.
3. The process as claimed in claim 1, wherein solvent used for condensation of 2-(dimethylamino)ethanol of formula III with 2-dimethylaminoethyl hemisuccinate of formula IV (step 3) is selected from toluene, benzene, chlorobenzene, xylene and the like, with toluene being the preferred solvent.
4. The process as claimed in claim 1, acid catalyst that may be used for condensation of 2-(dimethylamino)ethanol of formula III with 2-dimethylaminoethyl hemisuccinate of formula IV (step 3) is selected from mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid trifluoro acetic acid or p-toluene sulfonic acid (PTSA); preferably, sulfuric acid
5. The process as claimed in claim 1, wherein solvent used for reaction of methyl chloride gas with bis[2-(dimethylamino)ethyl] succinate of formula V (step 5) is

selected from methanol, ethanol, propanol, butanol, isopropanol, acetone and toluene; preferably, isopropanol.
6. The process as claimed in claim 1, wherein purification of 2,2'-[(l,4-dioxo-l,4-
butanediyl)bis(oxy)]bis(N,N,N-trimethyl ethanaminium) chloride (succinylcholine
chloride) or pharmaceutically acceptable hydrates thereof of formula I is carried out
by extraction with water and water insoluble organic solvent such as toluene, ethyl
acetate and methylene dichloride, preferably toluene; followed by isolation of the
aqueous mass which is then subjected to alcohol water purification.
7. A process for the preparation of bis[2-(dimethylamino)ethyl] succinate of formula
V comprising the steps of
1) condensing 2-(dimethylamino)ethanol of formula III

with 2-dimethylaminoethyl hemisuccinate of formula IV in solvent using an acid catalyst to form bis[2-(dimethylamino)ethyl] succinate of formula V.

2) isolating bis[2-(dimethylamino)ethyl] succinate of formula V.

8. The process as claimed in claim 6, wherein solvent used for condensation of 2-(dimethylamino)ethanol of formula III with 2-dimethylaminoethyl hemisuccinate of formula IV (step 1) may be selected from toluene, benzene, chlorobenzene, xylene and the like, with toluene being the preferred solvent.
9. The process as claimed in claim 6, acid catalyst that may be used for condensation of 2-(dimethylamino)ethanol of formula III with 2-dimethylaminoethyl hemisuccinate of formula IV (step 1) may be selected from mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid trifluoro acetic acid or p-toluene sulfonic acid (PTSA); preferably, sulfuric acid