Claims:I/We Claims:
1. A process for the preparation of Tiemonium methylsulfate of formula-1 comprising:
a) reacting morpholine or its salt with 2-acetylthiophene in presence of acid
and paraformaldehyde in a polar solvent to provide 3-morpholino-1-(thiophen-2-yl)propan-1-one of formula-2 or its salt

Formula-2,
b) reacting 3-morpholino-1-(thiophen-2-yl)propan-1-one of formula-2 or its
salt with phenylmagnesium halide in ether solvents to provide 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol of formula-3 or its salt

Formula-3,
c) reacting 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol of formula-
with dimethyl sulfate in hydrocarbon solvents to provide Tiemonium methylsulfate of formula-1

Formula-1.

2. The process as claimed in claim 1, wherein step-b) phenylmagnesium halide selected from phenylmagnesium bromide, phenylmagnesium chloride.

3. A process for the preparation of Tiemonium methylsulfate of formula-1 comprising:
a) reacting aqueous solution of morpholine or its salt with 2-acetylthiophene
and paraformaldehyde in presence of conc. hydrochloride in water as solvent to provide 3-morpholino-1-(thiophen-2-yl)propan-1-one of formula-2 or its salt

Formula-2,
b) reacting 3-morpholino-1-(thiophen-2-yl)propan-1-one of formula-2 or its
salt with phenylmagnesium bromide in tetrahydrofuran as single solvent system to provide 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol of formula-3 or its salt

Formula-3,
c) reacting 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol of formula-
3 with dimethyl sulfate in toluene to provide Tiemonium methylsulfate of formula-1.

4. A process for the purification of compound of formula-1, comprising:
a) dissolving compound of formula-1 in a solvent,
b) isolating substantially pure compound of formula-1.

5. The process as claimed in claim 4, solvent used in step-a) selected from
methanol or ethanol or toluene or mixtures thereof.

6. A process for the purification of compound of formula-1, comprising:
a) dissolving compound of formula-1 in methanol,
b) adding toluene to the solution obtained in step-a),
c) cooling the mixture obtained in step-b) to 5-10ºC,
d) filtering the substantially pure compound of formula-1.

7. The process as claimed in claim 6, wherein compound of formula-1 is crystalline in nature and is characterized by its PXRD pattern substantially in accordance with figure-1 and has melting range at 141-144°C.

8. A process for the purification of compound of formula-1, comprising:
a) dissolving compound of formula-1 in ethanol,
b) cooling the solution obtained in step-b) to 5-10ºC,
c) filtering the substantially pure compound of formula-1.

9. The process as claimed in claim 8, wherein compound of formula-1 is crystalline in nature and is characterized by its PXRD pattern substantially in accordance with figure-2 and has melting range at 148-152°C. , Description:Field of the invention:
The present invention relates to an improved process for the preparation of Tiemonium methylsulfate of formula-1.

Formula-1
Background of the invention:
Tiemonium methylsulfate is a quaternary ammonium salt chemically known as 4-[3-Hydroxy-3-phenyl-3-(2-thienyl) propyl]-4-methylmorpholinium methylsulfate. Tiemonium methylsulfate is an Anti-spasmodic drug used to reduce muscle spasms and pain in the gastrointestinal tract, biliary system, urinary tract and in gynaecology.
GB1047919 patent discloses the process for the preparation of Tiemonium methylsulfate by reacting 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol with dimethyl sulphate in dry acetone.
Process described in GB’919 patent is shown in following scheme

DE2609923 patent discloses the process for the preparation of Tiemonium methylsulfate by reacting 3-morpholino-1-phenylpropan-1-one with thiophene-lithium. Further the obtained compound was reacted with dimethyl sulphate in dry acetone.
Process described in DE’923 patent is shown in following scheme

IN201821014000 patent describes the crystalline forms of Tiemonium methylsulfate and their processes for the preparation.
Still there is a need to develop an improved process for the preparation Tiemonium methylsulfate, which is simple, economic and industrially viable process with excellent yields and good quality.
The present inventors have developed an improved industrially viable economic process which does not involve the usage of any toxic and/or costly solvents or reagents. Accordingly, the present invention provides a process for the preparation of Tiemonium methylsulfate, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality.
Summary of the invention
The first embodiment of the present invention provides a process for the preparation of Tiemonium methylsulfate of formula-1.
The second embodiment of the present invention provides a process for the purification of compound of formula-1.
Brief description of the drawings
Figure 1: Illustrates powder X-ray power diffraction (PXRD) pattern of crystalline form-1 of Tiemonium methylsulfate of formula-1.
Figure 2: Illustrates powder X-ray power diffraction (PXRD) pattern of crystalline form-2 of Tiemonium methylsulfate of formula-1.
Detailed description of the invention
The term "solvent" used in the present invention refers to "non polar solvents like “hydrocarbon solvents" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and thereof; "ether solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and thereof; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and thereof; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, Nmethylpyrrolidone and thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride and thereof; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and thereof; "nitrile solvents" selected form acetonitrile, propionitrile, isobutyronitrile and thereof; "alcoholic solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and thereof; "polar solvents" selected from water or mixtures thereof.
The term "acid" used in the present invention selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, salicylic acid, 2-chloromandelate, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and thereof. The term “pharmaceutically acceptable salts” or ”salts” described in hereinbefore are obtained by reacting compound with acid selected from the above description.
As used herein, the term “substantially free” refers to a compound of the present invention having one or more impurities less than about 0.5% or less than about 0.4% or less than about 0.3% or less than about 0.2% or less than about 0.1% or less than about 0.05% or less than about 0.04% or less than about 0.03%. or less than about 0.02%.
"Substantially pure" as used in the present invention herein refers to the purity of the material which is rages from about 99.0% to 99.9% as measured by a liquid chromatography method.
The first embodiment of the present invention provides a process for the preparation of Tiemonium methylsulfate of formula-1 comprising:
a) reacting morpholine or its salt with 2-acetylthiophene to provide 3-morpholino-1-(thiophen-2-yl)propan-1-one of formula-2 or its salt

Formula-2,
b) reacting 3-morpholino-1-(thiophen-2-yl)propan-1-one of formula-2 or its salt with grignard reagent to provide 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol of formula-3 or its salt

Formula-3,
c) reacting 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol of formula-3 with dimethyl sulfate to provide Tiemonium methylsulfate of formula-1.

In first aspect of first embodiment, wherein step-a) is carried out in presence of acid, paraformaldehyde in a polar solvent; the reaction temperature in step-a) range from about from 15-110°C; morpholine or its salt used in step-a) is optionally dissolved in water.
Wherein acid selected from inorganic acid or organic acid, preferably inorganic acid, more preferably hydrochloric acid.

In second aspect of first embodiment, wherein grignard reagent used in step-b) selected from phenylmagnesium halide selected from phenylmagnesium bromide or phenylmagnesium chloride, preferably phenylmagnesium bromide;
In third aspect of first embodiment, wherein step-b) is carried out in presence of a solvent selected from ether solvents, preferably tetrahydrofuran; the reaction temperature in step-b) range from about 15°C to reflux temperature of the solvent used.
In fourth aspect of first embodiment, wherein step-c) is carried out in presence of a solvent selected from hydrocarbon solvent, ketone solvents or polar solvents or mixtures thereof, preferably hydrocarbon solvents, more preferably toluene; the reaction temperature in step-c) range from about 15°C to reflux temperature of the solvent used.
In fifth aspect of first embodiment of the present invention provides a process for the preparation of Tiemonium methylsulfate of formula-1, comprising:
a) reacting aqueous solution of morpholine or its salt with 2-acetylthiophene and paraformaldehyde in presence of conc. hydrochloride to provide 3-morpholino-1-(thiophen-2-yl)propan-1-one of formula-2 or its salt

Formula-2,
b) reacting 3-morpholino-1-(thiophen-2-yl)propan-1-one of formula-2 or its salt with phenylmagnesium bromide in tetrahydrofuran as a single solvent system to provide 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol of formula-3 or its salt

Formula-3,
c) reacting 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol of formula-3 with dimethyl sulfate in toluene to provide Tiemonium methylsulfate of formula-1.
In sixth aspect of first embodiment of the present invention, the above sequential process for the preparation of compound of formula-1can be carried out as a single-pot process. i.e., the above process can be carried out in a sequential manner without isolating any of the process intermediate from the reaction mixture.
The second embodiment of the present invention provides a process for the purification of compound of formula-1, comprising:
a) dissolving compound of formula-1 in a solvent,
b) isolating substantially pure compound of formula-1.
Dissolving compound in step-a) can be done by optionally heating the mixture to a temperature ranging from about 35°C to reflux temperature of the solvent used.
The solvent used in step-a) selected from ketone solvents, alcohol solvents, polar solvents or any of the mixtures thereof; “isolating” in step-b) refers to solvent removal by known techniques which are selected from distillation, decanting, filtration, centrifugation, evaporation, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, by combining with an anti-solvent; wherein anti-solvent is different from the solvent used in step-a) and selected from chloro solvents, ether solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ketone solvents and polar solvents or mixtures thereof or by any other conventional methods known in the art. Dried the obtained solid, Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and thereof, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 50°C, less than about 25°C, less than about 10°C, less than about 5°C, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.
In first aspect of second embodiment of the present invention provides a process for the purification of compound of formula-1, comprising:
a) dissolving compound of formula-1 in methanol,
b) adding toluene to the solution obtained in step-a),
c) cooling the mixture obtained in step-b) to 5-10ºC,
d) filtering the substantially pure compound of formula-1.
Further aspect of present invention the compound of formula-1 obtained by the above purification process is crystalline in nature and is characterized by its PXRD pattern substantially in accordance with figure-1. The said crystalline form is hereinbefore designated as crystalline form-1.
Another aspect of present invention crystalline form-1 of Tiemonium methylsulfate of formula-1 has melting range at 141-144°C.
In second aspect of second embodiment of the present invention provides a process for the purification of compound of formula-1, comprising:
a) dissolving compound of formula-1 in ethanol,
b) cooling the solution obtained in step-b) to 5-10ºC,
c) filtering the substantially pure compound of formula-1.
Further aspect of present invention the compound of formula-1 obtained by the above purification process is crystalline in nature and is characterized by its PXRD pattern substantially in accordance with figure-2. The said crystalline form is hereinbefore designated as crystalline form-2.
Another aspect of present invention crystalline form-2 of Tiemonium methylsulfate of formula-1 has melting range at 148-152°C.
Advantages of the present invention:
• The process described in the present invention is simple, safe, economic, eco-friendly and suitable for the production of Tiemonium methylsulfate of formula-1 on commercial scale with a high reproducibility.
• In stage1-1 reaction water is used as solvent, this is environment-friendly green chemistry reaction is highly recommended in large scale production.
• Use of commercially available and cheaper reagents and solvent provides cost-effective process.
The other embodiment of the present invention provides a method of treating a patients suffering from muscle spasms and pain in the gastrointestinal tract, biliary system, urinary tract and in gynaecology comprising administering to the patients with a therapeutically effective amount of Tiemonium methylsulfate of formula-1 obtained by the process of the present invention.
In another embodiment of the present invention provides pharmaceutical composition/ formulation comprising Tiemonium methylsulfate and pharmaceutically acceptable excipients wherein, the pharmaceutical acceptable excipients include (but are not limited to) binders, diluents, disintegrants, surfactants and lubricants. Suitable binders that can be include (but are not limited to) polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxylpropyl cellulose and carboxymethyl cellulose and their salts, gelatine, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glycerol dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof and the like; suitable diluents that can be include (but are not limited to) anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol starch, calcium lactate or mixtures of diluents; suitable disintegrants that can be include (but are not limited to) magnesium aluminometa silicate (or magnesium aluminum silicate), starch, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, alginic acid, carboxy methyl cellulose sodium, sodium alginate, calcium alginate and chitosan; suitable lubricants that can be include (but are not limited to) magnesium stearate, stearic acid, palmitic acid, talc, and aerosil. Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene-polyoxy-propylene copolymer and sodium lauryl sulphate.
Various modes of administration of the pharmaceutical composition/ formulation of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Starting materials utilized in the present invention are commercially available in the market (or) they can be prepared according to the any of the processes known in the prior art.
Powder X-ray power diffraction (PXRD) method of analysis:
PXRD analysis of the crystalline forms of Tiemonium methylsulfate were carried out by using Bruker D8 advance X-ray powder diffractometer using Cu-Ka radiation of wavelength 1.54060A° and at continuous scan speed of 0.033°/min.
The First embodiment of the present invention is schematically represented as follows:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the scope of the present invention.
Examples:
Example-1: Preparation of 3-morpholino-1-(thiophen-2-yl)propan-1-one
2-acetylthiophene (345 L, 0.942 mole equivalent), paraformaldehyde (150 kg, 1.45 mole equivalent) and conc.HCl (600 L, 1.43 mole equivalent) were added to 30% aqueous solution of morpholine (300 L, 1 mole equivalent) at 25-30°C. Heated the reaction mixture to 75-75°C and stirred at same temperature for 6 hours. Cooled the reaction mixture to 25-30°C. Aqueous NaOH solution was added to the mixture at 25-30°C and stirred at same temperature for 10 minutes. Toluene was added to the mixture. Layers separated. Distilled off the solvent completely from organic layer. n-Heptane was added to the obtained residue at 0-5°C and stirred at same temperature for 10 minutes. Filtered the solid and dried to get the title compound.
Yield: 567 kg (73%).
Example-2: Preparation of 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol hydrochloride
THF (380 L), bromobenzene (510 kg, 1.04 mole equivalent) and iodine crystals (10 kg) were added to magnesium turnings (75 kg, 1.04 mole equivalent) at 75-75°C and stirred at same temperature for 9 hours under nitrogen atmosphere. 3-morpholino-1-(thiophen-2-yl)propan-1-one (567 kg 0.8 mole equivalent) in THF was added to the above reaction mixture at 75-75°C and stirred at same temperature for 8 hours. Reaction mixture was quenched with water. Layers separated. Acidified the organic layer using hydrochloric acid at 0-5°C and stirred at same temperature for 10 minutes. Filtered the precipitated solid and dried to get the title compound.
Yield: 480 kg (56%).
Example-3: Preparation of Tiemonium methylsulfate
3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol hydrochloride was dissolved in water and toluene mixture at 25-30°C. Neutralized the above solution using aqueous ammonia and Distilled off water azotropically from mixture. Dimethyl sulfate was added to above mixture at 35-40°C and stirred for 8 hours at same temperature. Filtered the solid and dried to get the title compound.
Yield: 520 kg (85.6%); HPLC purity: 98.6%
Example-4: Purification of Tiemonium methylsulfate
Dissolved the Tiemonium methylsulfate (100 g) in methanol (100 ml) at 50-60°. Toluene (200 ml) was added to the above solution and cooled to 5-10°C and stirred for 1 hour at same temperature. Filtered the solid and dried to get the pure compound.
Yield: 95.6 g (95.6%); M.R: 141-144°C; HPLC purity: 99.8%
PXRD pattern of the above obtained compound is illustrated in figure-1.
Example-5: Purification of Tiemonium methylsulfate
Dissolved the Tiemonium methylsulfate (100 g) in ethanol (1000 ml) at 75-80°. Distilled off 600 ml of ethanol from the above solution. The obtained solution was cooled to 5-10°C and stirred for 1 hour at same temperature. Filtered the solid and dried to get the pure compound.
Yield: 97 g (97%); M.R: 148-152°C; HPLC purity: 99.6%
PXRD pattern of the above obtained compound is illustrated in figure-2.