Description:FIELD OF INVENTION

The present invention relates to a process for the preparation of Tiemonium Methyl Sulfate (I).

Formula I
BACKGROUND OF THE INVENTION

Tiemonium Methyl sulfate (I) is chemically known as N-Methyl-N-[3-Hydroxy-3-phenyl-3-(α-thienyl)propyl]morpholine methyl sulfate.
Tiemonium methyl sulfate (I) is an antispasmodic drug. It reduces muscle spasms of the intestine, biliary system, uterus & urinary bladder. It is indicated for the pain in gastrointestinal and biliary disease in the urology and gynecology such as gastroenteritis, diarrhea, dysentery, biliary colic, enterocolitis, cholecystytis, colonopathyes, mild cystitis, and spasmodic dysmenorrhoea. Tiemonium methyl sulfate (I) strengthens calcium bonding with phospholipids and proteins thus stabilizing the cell membrane of the Gl tract.

Tiemonium methyl sulfate (I) is disclosed in GB 1047919.

GB 1047919 discloses a process for the preparation of Tiemonium methyl sulfate, wherein alpha-phenyl-beta-thienyl-morpolinoethyl-carbinol is reacted with dimethyl sulphate in the presence of dry acetone, which is further subjected to recrystallization using 95% ethanol to give Tiemonium methyl sulfate.

The process is as shown in scheme-I below:

DE 2609923 discloses a process for the preparation of Tiemonium methyl sulfate, wherein, 1-phenyl-3-morpholino-propanone-1 is reacted with thiophene, in the presence of butyllithium, dioxane, formic acid and base to give N-[1-Thienyl-(2)-1-phenyl-1-hydroxypropyl-(3)]morpholine, which is further reacted with dimethyl sulfate in dry acetone to give Tiemonium methyl sulfate.

The process is as shown in scheme-II below:

The main disadvantages of the above process are, 1,4-Dioxane is a selective carcinogen and a peroxide former. 1,4-dioxane combines with atmospheric oxygen on standing to form explosive peroxides. Hence, industrial use of this is risk for human health and exposure to large amounts of 1,4-dioxane can cause kidney and liver damage to human.
Formic acid is more easily ionized, which can form easily sulfoxides and sulfone impurities in the intermediate N-[1-thienyl-(2)-1-phenyl-1-hydroxypropyl-(3)-]morpholine of Tiemonium methylsulfate.
Moreover, the process disclosed in DE2609923 is expensive process as it utilizes high volumes of 1,4-dioxane as a solvent in reaction and further, it utilizes high quantities of anhydrous formic acid and anhydrous soda (base) for isolation.
Therefore, there is a need to develop a simple and in-expensive method for the synthesis of Tiemonium methyl sulfate which overcomes the drawbacks associated with aforesaid process with high product yield and good purity with commercially available.

IN 201821014000 discloses the crystalline forms of Tiemonium methyl sulfate and their processes for the preparation.

IN 482214 discloses a process for the preparation of Tiemonium methyl sulfate, wherein, 2-acetylthiophene is reacted with morpholine in the presence of paraformaldehyde and conc.HCl to give 3-morpholino-1-(thiophen-2-yl)propan-1-one (VII), which is further reacted with phenylmagnesium halide in presence of THF to give 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol (VI), which is further subjected to alkylation with dimethyl sulfate in toluene to give Tiemonium methyl sulfate. The obtained Tiemonium methyl sulfate is purified using methanol and Toluene.

The process is as shown in scheme-III below:

The main disadvantages of the above process are, Grignard reactions comprise considerable hazard potentials due to the spontaneous heat release during the initiation of the exothermic reactions and the high reactivity of the Grignard compounds. Due to the exothermicity of Grignard formation, as well overall reactivity of Grignard reagents, synthesizing them could be hazardous.
In the above process, the reaction forms a Grignard complex, which depends on its strength and it's not stable; hence it forms multiple impurities and also it has taken more time to complete the reaction at hot condition; Hence, it is difficult to isolate the intermediate of Tiemonium methylsulfate after Grignard reaction and in-consistency in yields and less purity. Moreover, it results in low yield and less purity in the preparation of Tiemonium methyl sulfate.
The aforementioned prior-art processes are not suitable for commercial scale as they are high in cost, operational difficulties and not environment friendly for the preparation of Tiemonium methyl sulfate (I).

However, there is always a need for an alternate process, which for example, involves use of reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product with higher purity.

The present invention involves use of less expensive reagents, less toxic, easier to handle, results in high yield and purity of the product, thus the process is economical and industrially viable.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple, industrially feasible and cost effective process for the preparation of Tiemonium methyl sulfate (I) with high purity and good yield on commercial scale.
SUMMARY OF THE INVENTION

The main embodiment of the present invention is to provide a process for the preparation of Tiemonium methyl sulfate (I).

Formula I

Which comprises,

i. condensation of Benzene (II) ;

Formula II

with 3-halopropanoyl halide (III)

Formula III
wherein, X is F, Cl, Br, I,

in presence of suitable catalyst and suitable solvent to obtain 3-halo-1-phenylpropan-1-one (IV)

Formula IV

ii. condensation of compound (IV) with morpholine in presence of suitable base to obtain 3-morpholino-1-phenylpropan-1-one (V);

Formula V

iii. compound (V) is reacted with thiophene in the presence of n-Butyllithium and suitable solvent to obtain 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol (VI);

Formula VI

iv. compound (VI) is reacted with Dimethyl sulfate in presence of suitable solvent to obtain Tiemonium methyl sulfate (I).

Formula I

Formula VIII

DETAILED DESCRIPTION OF THE INVENTION

The present invention is an improved industrially viable economic process, which is simple, efficient, in-expensive, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality. Use of commercially available and cheaper reagents and solvent provides cost-effective process.
The present invention is related to a process for the preparation of Tiemonium methyl sulfate (I).
The process comprises, Benzene (II) is reacted with 3-halopropanoyl halide (III) in the presence of suitable catalyst to obtain 3-halo-1-phenylpropan-1-one (IV).
The compound III used in the above reaction is selected from 3-chloropropanoyl chloride, 3-bromopropanoyl bromide, 3-fluoropropanoyl fluoride, 3-iodopropanoyl iodide.
Catalysts used in above reaction comprises Ferric chloride, aluminum chloride, zinc chloride and/or magnesium chloride.

The above reaction is carried out in the presence/absence of a solvent or mixture of solvents thereof. The solvent comprises dichloromethane, chloroform, tetrachloromethane, ethylene dichloride (EDC), benzene, toluene, o-xylene, m-xylene, p-xylene, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, acetone, acetonitrile, ethyl acetate, dimethylformamide, dimethyl sulfoxide, water and/or mixture thereof.
The reaction is typically carried out at a temperature in the range of from about -5° C to about 35°C. Preferably, the reaction is carried out at a temperature in the range of from about 0°C to about 30°C.

The reaction is carried out for about 4 hours to about 8 hours, preferably for about 5 hours to about 7 hours.

The reaction may carried out under inert atmosphere, such as nitrogen or argon.

3-halo-1-phenylpropan-1-one (IV) is isolated as solid or as such used in next step. Optionally, 3-halo-1-phenylpropan-1-one (IV) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.
3-halo-1-phenylpropan-1-one (IV) is reacted with morpholine in presence of suitable base to obtain 3-morpholino-1-phenylpropan-1-one (V).
The above reaction is carried out in presence/absence of a solvent or mixture of solvents thereof. The base used in above reaction comprises an organic base selected from triethylamine, pyridine, methyl amine, diisopropyl ethyl amine, DBU, DABCO and 2,6-Lutidine or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

The reaction is typically carried out at a temperature in the range of from about -20° C to about 45°C. Preferably, the reaction is carried out at a temperature in the range of from about -15°C to about 40°C.

The reaction is carried out for about 2 hours to about 6 hours, preferably for about 3 hours to about 5 hours.

The reaction may carried out under inert atmosphere, such as nitrogen or argon.

3-morpholino-1-phenylpropan-1-one (V) is isolated as solid or as such used in next step. Optionally, 3-morpholino-1-phenylpropan-1-one (V) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.

3-morpholino-1-phenylpropan-1-one (V) is reacted with thiophene in the presence of n-Butyllithium to obtain 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol (VI).
The above reaction is carried out in the presence of a solvent or mixture of solvents thereof. The solvent comprises tetrahydrofuran, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, dioxane, dimethylformamide, dimethyl sulfoxide, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

The reaction is typically carried out at a temperature in the range of from about -75° C to about 55°C. Preferably, the reaction is carried out at a temperature in the range of from about -70°C to about 50°C.

The reaction is carried out for about 7 hours to about 14 hours, preferably for about 8 hours to about 13 hours.

The reaction may carried out under inert atmosphere, such as nitrogen or argon.
3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol (VI) is isolated as solid or as such used in next step. Optionally, 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol (VI) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.
3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol (VI) is reacted with dimethyl sulfate to obtain Tiemonium methyl sulfate (I).
The above reaction is carried out in presence/absence of a solvent or mixture of solvents thereof. The solvent comprises acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, water, toluene, benzene, o-xylene, m-xylene, p-xylene, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

The reaction is typically carried out at a temperature in the range of from about -5° C to about 70°C. Preferably, the reaction is carried out at a temperature in the range of from about 0°C to about 65°C.

The reaction is carried out for about 13 hours to about 34 hours, preferably for about 14 hours to about 32 hours.

The reaction may carried out under inert atmosphere, such as nitrogen or argon.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be constructed to limit the scope of the invention.

Examples:

Example-1: Preparation of 3-Morpholino-1-phenyl propan-1-one

Taken dichloromethane (150 L) and aluminium chloride (99 kg, 0.97 mole equivalent) at 25-30°C under N2 atmosphere into a reactor. Cooled to 0-5°C. 3-Chloropropionyl chloride (97.2 kg, 1.0 mole equivalent) was added over a period of 60-120 min at 0-5°C and stirred at same temperature for 30 min under N2 atmosphere at 0-5°C. Benzene (60 kg, 1.0 mole equivalent) was added at 0-5°C and maintained at same temperature for 90-120 min under N2 atmosphere. Charged ice cold water (540 L, 9 times), process water (60 L, 1time) and conc. Hydrochloric acid (75.6 L) into another reactor at below 5°C. Quenched the above reaction mixture into ice water at 5-10°C and maintained at same temperature for 30 min. Layers were separated. Extracted the aqueous layer with dichloromethane (60 L). Combined Organic layers and washed with water (60 L). layers were separated. Organic layer washed with satd.sodium bicarbonate solution (2*60 L) followed by 10% sodium chloride solution; organic layer dried with sodium sulphate.

Taken above prepared 3-Chloro-1-phenylpropan-1-one organic layer into reactor and cooled to 0-5°C. Triethylamine (73.8 kg) was added to reaction mixture at 0-5°C and stirred at same temperature for 15 min. Morpholine (79.02 kg, 1.18 mole equivalents) was added to mixture at 0-5°C and stirred at same temperature for 30 min. Raised the reaction mass temperature to 25-30°C and stirred at same temperature for 2 hours. Reaction mixture was quenched with water (360 L) at 5-20°C. Stirred for 15-20 min at 25-30°C. Layers were separated. Taken aqueous layer and extracted with Dichloromethane (45 L). Combined both organic layers and washed with process water (2*360 L). Organic layer dried with sodium sulphate. Charged activated carbon (6 kg) and stirred for 30 min at 25-30°C and filtered through hyflow bed and washed with MDC (45 L). Distilled off the solvent completely at below 40°C to get the title compound (yellow to brown color liquid).
Yield: 130 kg (76.8% on theory)

Example-2: Preparation of 3-Morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol
Taken tetrahydrofuran (100 L), Toluene (100 L) and thiophene (28.8 kg, 1.50 mole equivalent) into a reactor and stirred for 20 min at 25-30°C under N2 atmosphere. Cooled to -60 to -70°C. Slowly added 100 L 2.5M n-Butyl lithium at -60 to -70°C and stirred at same temperature for 45 min under N2 atmosphere. Added 3-Morpholino-1-phenylpropane-1-one (50 kg) dissolved in toluene (25 L) into reaction mass and stirred for 1 hour at -60 to -70°C under N2 atmosphere. Raised the reaction mixture temperature to 0-5°C. Quenched the above reaction mass with ammonium chloride solution (Ammonium chloride -5 kg, Process water-100 L) at below 20°C. Stirred at same temperature for 20 min at 25-30°C and layers were separated. Organic layer dried with sodium sulphate. Distilled off the solvent completely from organic layer and stripped out with n-Heptane (25 L) under vacuum at below 50°C. Cooled to 25-35 °C and charged n-Heptane (100 L) at 25-35 °C and stirred at same temperature for 2 hours. Filtered the solid and washed with chilled n-Heptane (25 L) and dried the material under vacuum for 4.0-6.0 hours at 40-45°C to get the title compound.
Yield: 59.8 kg (86.7% on theory)

Example-3: Preparation of Tiemonium Methyl sulfate

Taken acetone (177 L), 3-Morpholino-1-phenyl-1-(thiophen-2-yl) propan-1-ol (59 kg, 1.0 mole equivalent) into reactor at 25-35°C under N2 atmosphere. Heated the reaction mixture to 35-45°C and stirred for 60 min under N2 atmosphere. NSPL Carbon was added to reaction mixture and stirred for 30 min at 35-45°C under N2 atmosphere. Filtered the reaction mixture through hyflow bed and washed with acetone (44.25 L) under N2 atmosphere. Taken filtrate into another reactor. Dimethyl sulfate (29.5 kg, 1.20 mole equivalent) was added to the above reaction mass at 35-45°C under N2 atmosphere. Cooled to 25-35°C and stirred at same temperature for 12 hours at 25-35 °C under nitrogen atmosphere. Filtered the solid and washed with Acetone (59 L) under N2 atmosphere and dried the material for 8-10 hours at 50-55°C to get title compound.
Yield: 68.4 g (82% on theory); HPLC purity: 99.7%

Example-4: Purification of Tiemonium Methyl sulfate

Taken Methanol (75 mL) and Tiemonium methyl sulfate (50 g) into clean and dry RBF at 25-35 °C. Stirred the reaction mixture for 15 min. Heated the reaction mixture to 35-40°C and charged NSPL carbon (10 g) at 35-40°C; stirred for 15 minutes at 35-40°C. Filtered the reaction mixture on celite and washed with methanol (25 mL). Distilled off the solvent under vacuum at below 45oC and charged Isopropyl alcohol (75 mL) at 40-45oC. Cooled to 25-35°C. Again cooled to 0-5°C and stirred at same temperature for 2-3 hours. Filtered the solid and washed with chilled Isopropyl alcohol (25 mL) and dried the material for 8-10 hours at 50-55 °C.
Yield: 42 g

Example-5: Purification of Tiemonium Methyl sulfate

Taken Methanol (75 mL) and Tiemonium methyl sulfate (50 g) into clean and dry RBF at 25-35 °C. Stirred the reaction mixture for 15 min. Heated the reaction mixture to 35-40°C and charged NSPL carbon (10 g) at 35-40°C; stirred for 15 minutes at 35-40°C. Filtered the reaction mixture on celite and washed with methanol (25 mL). Distilled off the solvent under vacuum at below 45oC and charged acetone (200 mL) at 40-45oC. Cooled to 25-35°C. Again cooled to 0-5°C and stirred at same temperature for 2-3 hours. Filtered the solid and washed with chilled acetone (25 mL) and dried the material for 8-10 hours at 50-55°C.
Yield: 39 g
, Claims:We Claim:

1. A process for the preparation of Tiemonium methyl sulfate (I).

Formula I

Which comprises,

i. condensation of Benzene (II);

Formula II

with 3-halopropanoyl halide (III);

Formula III
wherein, X is F, Cl, Br, I,

in presence of suitable catalyst and suitable solvent to obtain 3-halo-1-phenylpropan-1-one (IV);

Formula IV

ii. condensation of compound (IV) with morpholine in presence of suitable base and suitable solvent to obtain 3-morpholino-1-phenylpropan-1-one (V);

Formula V

iii. compound (V) is reacted with thiophene in the presence of n-Butyllithium and suitable solvent to obtain 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol (VI);

Formula VI

iv. compound (VI) is reacted with Dimethyl sulfate in presence of suitable solvent to obtain Tiemonium methyl sulfate (I).

2. The process as claimed in claim 1, wherein suitable catalyst used in step-i comprises Ferric chloride, aluminum chloride, zinc chloride or magnesium chloride.

3. The process as claimed in claim 1, wherein suitable solvent used in step-i comprises dichloromethane, chloroform, tetrachloromethane, ethylene dichloride (EDC), benzene, toluene, o-xylene, m-xylene, p-xylene, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, acetone, acetonitrile, ethyl acetate, dimethylformamide, dimethyl sulfoxide, water and/or mixture thereof.

4. The process as claimed in claim 1, wherein suitable base used in step-ii comprises an organic base selected from triethylamine, pyridine, methyl amine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof.

5. The process as claimed in claim 1, wherein suitable solvent used in step-ii comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

6. The process as claimed in claim 1, wherein suitable solvent used in step-iii comprises tetrahydrofuran, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, dioxane, dimethylformamide, dimethyl sulfoxide, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

7. The process as claimed in claim 1, wherein suitable solvent used in step-iv comprises acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, water, toluene, benzene, o-xylene, m-xylene, p-xylene, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

8. A process for the preparation of 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol (VI);

Formula VI

Which comprises;
3-morpholino-1-phenylpropan-1-one (V) is reacted with thiophene in the presence of n-Butyllithium and tetrahydrofuran to obtain 3-morpholino-1-phenyl-1-(thiophen-2-yl)propan-1-ol (VI).