FIELD OF INVENTION:
This invention relates to a process the production of Succinyl Choline Halide, which are pharmaceutical^ active compounds used as skeletal muscle relaxants. Succinyl Choline Halide also referred as suxamethonium halide and is chemically known as 2,2'-[(l,4,-dioxo-l,4-butanediyl)bis(oxy)]bis[N,N,N-trimethyl ethanaminium) dihalide.
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
Non-depolarizing relaxants block the ACh receptors without activating them e.g. 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). They are a separate class of drugs from the muscle relaxant drugs used during intubations and surgery to reduce the need for anesthesia and facilitate intubations. Skeletal muscle relaxants are used to relax certain muscles in your body and relieve the stiffness, pain, and discomfort caused by strains, sprains, or other injury to your muscles.
Skeletal muscle relaxants may also be used for relief of spasticity in neuromuscular diseases, such as multiple sclerosis, as well as for spinal cord injury and stroke. They may also be used for pain relief in minor strain injuries and control of the muscle symptoms of tetanus. Skeletal muscle relaxants act in the central nervous system (CNS) to produce their muscle relaxant

effects. Their actions in the CNS may also produce some of their side effects.
Although the muscle relaxants may be divided into only two groups, centrally acting and peripherally acting, the centrally acting group, which appears to act on the central nervous system, contains 10 drugs which are chemically different, while only dantrolene has a direct action at the level of the nerve-muscle connection.
Suxamethonium chloride (also known as succinyl choline or scoline) is a white crystalline substance; it is odorless and highly soluble in water. The compound consists of two acetylcholine molecules that are linked by their acetyl groups.
Suxamethonium acts as a depolarizing muscle relaxant. It imitates the action of acetylcholine at the neuromuscular junction, but it is not degraded by acetylcholinesterase but by pseudocholinesterase, a plasma cholinesterase. This hydrolysis by pseudocholinesterase is much slower than that of acetylcholine by acetylcholinesterase. 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.
A single intravenous dose of 0.6 to 1.0 milligram per kilogram of body weight will cause flaccid paralysis within a minute of injection. For intramuscular injection higher doses are used and the effects last somewhat longer. Suxamethonium is quickly degraded by plasma cholinesterase and the duration of effect is usually in the range of a few minutes. When plasma levels of cholinesterase are greatly diminished or an atypical form of cholinesterase is present (an otherwise harmless inherited disorder), paralysis may last much longer

PRIOR ART:
Relevant Prior Art references are summarized below:
U.S Patents No.5, 206,420 describes drawbacks of earlier processes and an improved 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 process involved recovery of excess dimethyl amino ethanol by distillation, which is a tedious operation. Further it involves use of methyl chloride gas, which is difficult to handle in industrial scale.
A review of synthetic methods for preparation of succinyl choline halides was published in 'The Bulletin of Institute of Chemistry', Academia Sinica, pages 47-54, Volume 26 (1979). A modified method for producing succinyl choline chloride was described in Organic Preparations and Procedures Int. 11(2) 93-101(1979) by reacting succinic anhydride with choline chloride in presence of catalytic quantity of dry hydrogen chloride gas and azeotropic removal of water using benzene as a solvent. The disadvantage of this process is the use of choline chloride in the process, which is hygroscopic, use of dry hydrogen chloride gas which is difficult to handle, added to this further disadvantage of this process is the use of benzene as a solvent in the process, which is well known carcinogenic.
Slightly modified process for producing succinyl choline chloride was described in Farmatsiya(Sofia) 11, no.6, 29-32(1961) by heating bis-(2-chloroethyl) succinate with trimethyl amine in the presence of absolute alcohol. Yield and the purity the product were not reported in this paper.
Much latter in 'The Bulletin of Institute of Chemistry', Academia Sinica, pages 47-54, Volume 26 (1979) in method III-2, it was reported that this method failed to work. Only choline chloride was obtained as product instead of succinyl choline chloride, which is in disagreement with Farmatsiya (Sofia) 11, no.6, 29-32(1961)

However, Acad. Rep. populare Romine Inst. Biochimie, Studii ceetari biochimie, 1, 167-70, (1958), Chem.Abstr 53, 11208h, (1959) describe that if benzene is used as a solvent in above reaction , succinyl choline chloride was obtained in 46% The disadvantage of this process is the use of benzene as a solvent in the process, which is well known carcinogenic added to that cumbersome method of purification in involved in the process.
On going through the above cited literature for preparation of succinyl choline halides, need is always been felt by us to provide a simple improved process, which will be amenable to large scale production.
During our investigation, it was discovered that by using CI, C3, C4 & C5 alkanol as solvent in reaction of bis (2-chloroethyl) succinate with trimethyl amine, all tedious work up procedures, recoveries of extra reactants, use of difficult reagents to handle etc. were eliminated and succinyl choline halides (I) was isolated by simple filtration process.
OBJECT OF THE INVENTION:
The object of the present invention is to provide a process for the production of Succinyl Choline Halide, which are pharmaceutical^ active compounds used as skeletal muscle relaxants..
Further object of the present invention is to provide for a method of preparation of succinyl choline halide (I) by condensation of bis -(2-chloroethyl) succinate with trimethyl amine in presence of alcoholic solvent.
Yet another object of the present invention is to make succinyl choline halide (I) free from choline halide. Accordingly, the present invention provides a process for preparing succinyl choline halide (II) comprising the step of reaction of bis -(2-halo ethyl) succinate (III) with the trimethyl amine in C-l to C-5 alcoholic solvent.
SUMMARY OF THE INVENTION:
A process for the manufacture of succinyl choline halide (I) otherwise known as suxamethonium halide and is chemically known as 2,2'-[(l,4-di-oxo-l,4-butanediyl)bis(oxy)]bis[N,N,N-

trimethyl ethanaminium) dihalide comprising the reaction of the bis (2-halo ethyl) succinate (III), with trimethyl amine in the presence of alcohol from group comprising CI, C3, C4 & C5 alkanols
In an embodiment of the present invention succinyl choline halide (I) characterized as its salts as Chloride, Bromide and Iodide.
In an embodiment of the present invention bis-(2- halo ethyl) succinate (III), halo is characterized as Chloro, Bromo and Iodo
In an embodiment of the present invention the CI, C3, C4 & C5 alkanols consists of methanol, propanol, 2-propanol, butanol, 2-butanol, t-butanol and pentanol
In an embodiment of the present invention, the most preferred alcohol is 2-propanol
In an embodiment of the present invention the volume of 2-propanol used is 0.2 to 1 volume of bis (2 -halo ethyl) succinate
In an embodiment of the present invention the most preferred volume of 2- propanol is 0.5 on the basis of volume of bis -(2-halo ethyl) succinate
In an embodiment of the present invention the preferred temperature range for formation of the invention is 80°-140° Celsius.
In an embodiment of the present invention the most preferred temperature is 90-95° Celsius for the formation of the product.
DETAILED DESCRIPTION OF THE INVENTION:
Accordingly to the present invention succinyl choline halide (I) is prepared from bis- (2-chloro ethyl) succinate (III) by single step process as per Fig 1:
Bis-(2-halo ethyl) succinate(III) used in the process is prepared according to known route by the reaction of succinic acid with 2-halo ethanol in the presence of sulfuric acid as catalyst in toluene as solvent with continuous removal of water from the system by the azotropic remval as

per reference ' The Bulletin of the Institute of Chemistry, Academia Sinica, 26 (1979), 47-54'. The bis-(2 halo ethyl) succinate (III) thus prepared was further reacted with trimethylamine in the presence of alkanol to give succinyl choline halide (I). In this reaction, bis-(2-halo ethyl) succinate (III) is diluted with alcohol, preferably 0.1 vol to 1.0 vol. The alcohol is selected from the group consisting methyl, propyl, iso propyl and n/iso/tertiary butyl (CI, C3, C4 & C5 alkanol). The most preferred alcohol for the reaction is 2-propanol. Tri methylamine gas is introduced into the cooled suspension of bis-(2-halo ethyl) succinate (III) in alkanol. Tri methylamine used is 2.0 to 4 mol of trimethyl amine per mol of ester. After closing the system, mixture is then heated to 80° to 140 °Celsius under autogeneous pressure. The most preferred temperature for reaction is 90-95 ° Celsius. The reaction duration is 6-15 hours. The reaction mixture is cooled and the crude precipitated succinyl choline halide (I) is isolated by filtration. The yield obtained at 55° Celsius is 16%, at 90° Celsius is 77.3%; at 100° Celsius is 69%, The yield obtained at the end of 6hrs at 90° Celsius is 30% and at 12hrs is 77.3% at 15 hrs. 78%
The pure succinyl choline halide (I) thus obtained is recrystallised using an isopropyl alcohol/ water mixture.
The present invention is illustrated in the following examples, which are not intended to limit the scope of the invention, but are provided by way of illustration only. The preparation for succinyl choline chloride (II) and the purification succinyl choline chloride (II) dihydrate is given below.
Example 1:
Preparation of Succinyl Choline Chloride (II): In this illustration bis-(2-chloro ethyl) succinate (III) 100 gm, (88ml, 0.411 mol) was dissolved in 50 ml of 2-propanol and cooled to 5-12 ° Celsius. Trimethyl amine 60 gm (1.017 mol) was introduced to the above solution at 5-12 ° Celsius. After closing the vent values, the system was heated to 90-95 ° Celsius and the temperature was maintained at 90-95 ° Celsius for 12 hours. Then the reaction mixture was cooled to room temperature and 2-propanol (400 ml) was added to the reaction mass and stirred for 2 hours. The precipitated succinyl choline chloride (II) was then filtered to give 115gm. Yield: 77.4%

Purification of succinyl choline chloride (II) dihydrate: To the crude succinyl chloride (II) 100 gm, 720 ml of 2-propanol was added and was heated to 80 ° Celsius. Water 180 ml was added drop wise to the above solution till the complete dissolution at 80 ° Celsius. The solution was treated with 10 gm of charcoal, filtered and cooled to 15-20 ° Celsius. The crystallized succinyl choline chloride (II) dehydrate was then filtered dried at 60-65 ° Celsius till moisture content reaches 8-10%
Yield: 76.6 gm (69.7%), white crystalline powder, assay 100% by trimetry. Melting point: 160-161 ° Celsius.

WE CLAIM:
1. A process for the preparation of succinyl choline halide characterized in that bis (2-halo
ethyl) succinate is reacted with trimethyl amine in the presence of alcohol solvent.
2. Process according to Claim 1 where succinyl choline halide (I) characterized as its salts
as chloride, bromide and iodide.
3. Process according to Claim 1, in bis (2 halo ethyl) succinate (III), halo is characterized as
chloro, bromo and iodo.
4. Process according to Claim 1. alcohol is characterized as from a group of CI, C3, C4 &
C5 alkanols that consist of methanol, propanol, 2-propanol, butanol, 2-butanol, and t-
butanol and pentanol.
5. Process according to Claim 1 & 4, the most preferred alcohol is 2 - propanol.
6. Process according to Claim 5, the volume of 2 - propanol used is 0.2 to 1 volume of bis
(2 -halo ethyl) succinate.
7. The most preferred volume, according to Claim 5 & 6 is 0.5 on the basis of volume of
bis- (2-halo ethyl) succinate used.
8. Process according to Claim 1 characterized in that the preferred temperature is 80-140 °
Celsius.
9. Process according to the Claim 1 & 8, the most preferred temperature is 90-95 ° Celsius