FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for the preparation of Succinylcholine chloride
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400601, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

Field of Invention
The present invention relates to a novel process for the preparation of Succinylcholine Chloride, a pharmaceutically active compound used as skeletal muscle relaxant.
Background of the Invention
A Muscle Relaxant is a drug that causes skeletal muscle contraction to cease. Muscle relaxants are used to facilitate surgery, to enable tracheal intubations and to facilitate mechanical ventilation. Muscles relaxants typically work by blocking the effect of acetylcholine (ACh) at the neuromuscular junction.
Substances that compete with ACh, for the receptors on a muscle cell can be either depolarizing, or non-depolarizing. Depolarizing muscle relaxants activate the muscle briefly, before blocking it e.g. Succinyl choline or Suxamethonium Nondepolarizing relaxants block the ACh receptors without activating them whereas Curare, Curare-based molecules like Tubocurarine, Pancuronium bromide, Mivacurium, Atracurium and Cisatracurium, Vecuronium, Rocuronium Skeletal muscle relaxants are drugs that relax striated muscles (those that control the skeleton).
The prolonged stimulation of the acetylcholine receptor results first in disorganized muscle contractions, then in profound relaxation. Its medical uses are limited to short-term muscle relaxation in anesthesia and intensive care, usually for facilitation of tracheal intubations. Despite its many undesired effects on the circulatory system and skeletal muscles (including malignant hyperthermia, a rare but life-threatening disease), it is still much used because it arguably has the fastest onset of action of all muscle relaxants.
Succinylcholine chloride is sold under the trade names Anectine, Quelicin, and Scoline. The chemical name of succinylcholine chloride is 2,2'-[(l,4-dioxobutane-l,4-diyl)bis(oxy)]bis (N,N,N-trimethylethanaminium) chloride represented by formula I,


There are few process reported for the preparation of this compound. US patent 2858329 describes a process for the preparation of bis-dimethylaminoethylsuccinate by heating succinic anhydride and N.N-dimethylaminoethanol at 135-145°C in benzene for 12-18hr. The obtained succinylcholine was further purified by high vacuum distillation at very high temperature. The obtained succinylcholine was purged with molar equivalent of methylchloride in 1PA+Water at 40-50°C to obtain succinylcholine chloride.
US Patent No. 5206420 describes a process for the preparation of succinyl choline halide. According to this patent, dialkyl succinate was reacted with large excess of dimethyl amino ethanol, in presence of alkali metal alcoholate or amide as catalyst. The bis (2-dimethylaminoethyl) succinate obtained was reacted with methyl halide in an inert solvent to yield succinyl choline halide.
The prior art process involves purification of bis-dimethylaminoethyl 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 Jess 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 IPA used from the reaction is cumbersome.
Thus it is highly desirable to develop a process which overcomes most of the drawbacks of the prior art. The present inventors have developed a very cost effective and environment friendly process, which overcomes most of the above stated drawbacks.

Summary of the invention
The principal aspect of the present invention is to provide a process for the
preparation of 2,2'-[(l,4-dioxobutane-l,4-diyl)bis(oxy)]bis (N,N,N-
trimethylethanaminium) chloride represented by formula I which comprises:
a) condensing succinic anhydride of formula III with N.N-dimethylaminoethanol of formula IV using a catalyst in presence of a solvent to form bis[2-(dimethylamino)ethyl] succinate of formula II;
b) insitu purifying the bis[2-(dimethylamino)ethyl] succinate of formula II using a base;
c) reacting the obtained bis[2-(dimethylamino)ethyl] succinate of formula II with methyl chloride gas in a solvent to obtain 2,2'-[(l,4-dioxobutane-l,4-diyl)bis(oxy)]bis (N,N.N-trimethylethanaminium) of formula 1; and
d) purifying the obtained crude 2,2'-[(l,4-dioxobutane-l,4-diyl)bis(oxy)]bis (N,N,N-trimethylethanaminium) of formula I using water and alcohol.
The present invention can be illustrated by the below reaction scheme:


Detail Description of the Invention
Accordingly in an embodiment of the invention, the condensation of succinic anhydride of formula ill with N,N-Diemthylaminoethanol of formula IV is carried out using a catalyst selected from the group consisting of mineral acids, trifluoro acetic acid, p-toluene sulfonic acid (PTSA) and acidic resins viz. amberlites. The mineral acid is selected from sulphuric acid, phosphoric acid, hydrochloric acid. Most preferably the catalyst used is p-toluene sulfonic acid. The solvent for the reaction is an inert organic solvent selected from toluene, benzene, xylene and the like, preferably toluene. The reaction is carried out at reflux temperature in the range of about 100-130°C, preferably at 110-120 °C.
In another embodiment of the invention, the base for the purification of bis[2-(dimethylamino)ethyl] succinate is an alkali metal carbonate or bicarbonate selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, or an aliphatic organic bases selected from the group consisting of Triethylamine, diisopropylamine or an aromatic organic bases like pyridine, picoline etc. The base for the purification is preferably potassium carbonate.
In another embodiment of the invention, the reaction of bis[2-(dimethylamino)ethyl] succinate with methyl chloride gas in step (c) is carried out using a solvent selected from methanol, ethanol, propanol, butanol, isopropanol, acetone and toluene, preferably isopropanol at a temperature about 55-65 °C, preferably 60-62 °C.
In another embodiment of the invention, the purification of crude 2,2'-[(l,4-dioxobutane-l,4-diyl)bis(oxy)]bis (N,N,N-trimethylethanaminium) is done using water and alcohol selected from methanol, ethanol, propanol, butanol, isopropanol and the like, preferably isopropanol.
In another embodiment, some of the key advantages of the present invention are
as below:

1. In the process of the present invention purification of bis-dimethylaminoethylsuccinate is done by a simple base avoiding high vacuum distillation which leads to decomposition of the product.
2. The process of the present invention doesn't require special heating facility to obtain pure bis-dimethylaminoethylsuccinate of purity more than 99%.
3. The process of the present invention is carried out in presence of catalyst p-toluene sulfonic acid, which reduces the reaction time significantly.
4. The reaction of bis-dimethylaminoethylsuccinate with methyl chloride gas is carried out in presence of IPA instead fPA+water mixture, which makes the recovery of IPA very easy.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of 2,2'-[(l,4-dioxobutane-l,4-diyI)bis(oxy)]bis (N,N,IV-trimethylethanaminium):
(a) Procedure for the preparation of Bisdimethylaminoethyl succinate
Succinic anhydride (0.756 kg), N,N-DiemthylaminoethanoI (1.483 kg), nd toluene (3.78 L) and p-toluene sulfonic acid (0.0189 kg) were charged into a flask at 30±2°C. and heated to reflux (~I20°C) for 2 hours with stirring, maintained for 30 - 35 hours. The water were removed by azeotropic distillation. After completion of the reaction, the reaction mass was cooled to 30±2°C. Potassium carbonate solution (0.378 kg of potassium carbonate in 0.378 L of DM water) was charged to the above reaction mass, stirred for 30 minutes and allowed to settle for lhour. The layers were separated. Toluene was distilled out completely under vacuum below 75°C and material was unloaded.
Yield: 80% Purity: 99.5%

(b) Procedure for the preparation of succinylcholine chloride
IPA (12.48 L) and bis-dimethylaminoethylsuccinate (1.04 kg) was charged into autoclave at 30±2°C. Methyl chloride gas was purged to the reaction mass at 30±2°C with stirring under 1.5 to 2.5 kg/cm2 pressure, stirred for 15 minutes, heated to 60±2°C for 16 hours and cooled to 30±2°C. After completion of the reaction, it was cooled to 7±2°C and stirred for 1 hour. Reaction mass was washed with IPA (2.08 L) and suck dried.
Yield: 92 % Purity: 97 to 98%
(c) Procedure for the purification of crude sucinylcholine chloride
Crude succinylcholine chloride (1.29 kg) was dissolved in DM water (1.29L) by heating to 50±2°C. Activated charcoal (0.0645 kg) was charged and stirred at 50±2°C for 1 hour under stirring. The reaction mass was filtered through hyflo supercell bed, washed with hot DM water and the filtrate was cooled to 28±2°C. The filtrate was charged into the IPA (11.61 L), stirred and heated to 80±2°C. The reaction mass was cooled under stirring to get crystalline solid and maintained for 2 hours at 7±2°C.The solid was filtered, washed with chilled IPA, suck dried for 2 hours and dried under vacuum.
Yield: 90 % Purity: 99.5%

We claim:
1. A process for the preparation of 2,2'-[(l,4-dioxobutane-l,4-diyl)bis(oxy)]bis (N,N.N-trimethylethanaminium) chloride of formula 1, which comprises:

a) condensation of succinic anhydride of formula III with N,N-diemthylaminoethanol of formula IV using a catalyst in presence of a solvent to form bis[2-(dimethylamino)ethyl] succinate of formula II;

b) insitu purification of bis[2-(dimethylamino)ethyl] succinate of formula II using a base:

c) reaction of obtained bis[2-(dimethylamino)ethyl] succinate of formula II with methyl chloride gas using a solvent to obtain 2,2'-[( 1,4-dioxobutane-1,4-diyl)bis(oxy)]bis (N,N,N-trimethylethanaminium) of formula I; and

d) purification of obtained crude 2,2'-[( 1,4-dioxobutane-1,4-diyI)bis(oxy)]bis (N,N.N-trimethylethanaminium) of formula I using water and alcohol.
2. A process according to claim 1, wherein the catalyst in step a) is selected from the group consisting of mineral acids, trifluoro acetic acid, p-toluene sulfonic acid (PTSA) and acidic resins viz, amberlites..
3. A process according to claim 1, wherein the catalyst in step a) is p- toluene sulfonic acid.
4. A process according to claim 1, wherein solvent in step a) is an inert organic solvent selected from toluene, benzene, xylene.
5. A process according to claim 1, wherein the solvent in step a) is toluene.
6. A process according to claim 1. wherein the condensation in step a) is carried out at 110-120 °C.
7. A process according to claim 1. wherein the base used in step b) is an alkali metal carbonate or alkali metal bicarbonate or an organic base.
8. A process according to claim 1, wherein the base used in step b) is potassium carbonate.
9. A process according to claim 1, wherein the purging in step b) is preferably done at about 55-65 °C
10. A process according to claim 1, wherein the solvent in step c) and alcohol in step d) is isopropanol.