Claims:I/We Claims:
1. One pot synthesis for the preparation of Pitofenone hydrochloride of formula
1a, comprising: reacting 2-(4'-hydroxybenzoyl) benzoic acid of formula-2 with thionyl chloride and methanol followed by reaction with 1-(2-chloroethyl) piperidine or its salt in-presence of inorganic base to provide Pitofenone of formula-1 further treating Pitofenone of formula-1 with hydrochloric acid source to provide Pitofenone hydrochloride of formula-1a

2. The process as claimed in claim 1, inorganic base is selected from metal carbonates or metal bicarbonates; hydrochloric acid source is selected from hydrochloric acid (HCl), aqueous HCl, dry HCl, ethyl acetate-HCl, isopropyl acetate-HCl, isopropanol-HCl (IPA-HCl), ethanol-HCl, methanol-HCl or dioxane HCl.

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

4. The process as claimed in claim 3, solvent used in step-a) is selected from methanol or isopropnol. , Description:Field of the invention:
The present invention relates to an improved one pot synthesis for the preparation of Pitofenone of formula-1 or its pharmaceutically acceptable salts.

Formula-1

Background of the invention:
Pitofenone is a benzophenone derivative, chemically known as methyl 2-[4-(2-piperidin-1-yl ethoxy)benzoyl]benzoate.
Pitofenone is an antispasmodic drug approved as Pitofenone hydrochloride used to relieve pain and spasms of smooth muscles of the stomach, intestine, urinary tract, biliary tract and uterus.

US2681340A patent discloses the process for the preparation of Pitofenone hydrochloride by reacting methyl 2-(4'-hydroxybenzoyl) benzoate with 1-(2-chloroethyl) piperidine in-presence of potassium carbonate in methyl ethyl ketone to give Pitofenone which is further converted to its hydrochloride salt by reacting with alcoholic hydrochloric acid.
Process described in US’340 patent is shown in the following scheme

BG107390 patent discloses the process for the preparation of Pitofenone hydrochloride by reacting isobenzofuran-1,3-dione with 1-(2-chloroethoxy) benzene followed by reaction with piperidine subsequently esterification with methanol in-presence of sulfuric acid to give Pitofenone which is further converted to its hydrochloride salt by reacting with alcoholic hydrochloric acid.
Process described in the above is shown in the following scheme.

Organic Letters, 2013, 15 (12), 2930-2933 discloses the process for the preparation of Pitofenone by reacting benzoic acid with 2-(4-fluorophenyl)-2-oxoacetic acid in-presence of Pd(TFA)2 and Ag2CO3 in DME followed by reaction with 1-(2-chloroethyl) piperidine in-presence of NaH in THF subsequently esterification with methanol in-presence of SOCl2 to give Pitofenone, which was further purified by flash chromatography using 1% Et3N and 50% EtOAc in Hexanes as eluents.
Process described in the above is shown in the following scheme.

The above said process has some disadvantages i.e. usage of costly reagents like Pd(TFA)2, longer reaction time and also product was purifying in flash chromatography. Flash chromatography purifications result in the consumption of excess solvents which increases the production cost. And also above process includes the usage of NaH which is a pyrophoric chemical, handling in large scale is very difficult. By considering all the above demerits, this process is not viable in commercial scale.
Thus, there remains a need to develop an improved process for the preparation of Pitofenone or its salts, which is simple, economic and industrially viable process with excellent yields and good quality.
The present inventors have developed an improved industrially viable process which does not involve the usage of any costly reagents and critical workup procedures. Accordingly, the present invention provides an improved process for the preparation of Pitofenone hydrochloride which is one pot, 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 one pot synthesis for the preparation of Pitofenone hydrochloride of formula-1a.
The second embodiment of the present invention provides a process for the purification of Pitofenone hydrochloride of formula-1a.
Brief description of the drawings
Figure 1: Illustrates powder X-ray diffraction (PXRD) pattern of crystalline form of Pitofenone hydrochloride obtained according to Example-5.
Detailed description of the invention
The term "solvent" used in the present invention refers to "non polar solvents like "hydrocarbon solvent" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene or mixtures thereof; "ether solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane or mixtures thereof; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or mixtures thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; "nitrile solvents" selected from acetonitrile, propionitrile, isobutyronitrile or mixtures thereof; "alcoholic solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term “pharmaceutically acceptable salts” or ”salts” described in hereinbefore are obtained by reacting organic compound with acid 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 " inorganic base " used in the present invention selected from but not limited to "metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate or calcium carbonate mixtures and the like ; "metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate or mixtures and the like;
The term "room temperature" as used in the present invention herein refers to the temperature in the range from about 25-35°C.
"Substantially pure" as used in the present invention herein refers to the compound of formula-1a is substantially free from the impurities and having purity ranges from about 99.0% to 99.9% as measured by a liquid chromatography method.

The first embodiment of the present invention provides one pot synthesis for the preparation of Pitofenone hydrochloride of formula-1a, comprising: reacting 2-(4'-hydroxybenzoyl) benzoic acid of formula-2 with thionyl chloride and methanol followed by reaction with 1-(2-chloroethyl) piperidine or its salts in-presence of inorganic base to provide Pitofenone of formula-1 further treating Pitofenone of formula-1 with hydrochloric acid source to provide Pitofenone hydrochloride of formula-1a.

and optionally purifying the compound to provide substantially pure compound of Pitofenone hydrochloride of formula-1a.
In first aspect of first embodiment, inorganic base is selected from metal carbonates or metal bicarbonates; hydrochloric acid source is selected from hydrochloric acid (HCl), aqueous HCl, dry HCl, ethyl acetate-HCl, isopropyl acetate-HCl, isopropanol-HCl (IPA-HCl), ethanol-HCl, methanol-HCl or dioxane HCl, preferably IPA-HCl.
Wherein inorganic base can be used in present invention is in the form of solid or solution obtained by dissolving the inorganic base in aqueous medium.
In second aspect of first embodiment of the present invention provides one pot synthesis for the preparation of Pitofenone hydrochloride of formula-1a, comprising: reacting 2-(4'-hydroxybenzoyl) benzoic acid of formula-2 with thionyl chloride and methanol followed by reaction with 1-(2-chloroethyl) piperidine or its salt in-presence of potassium carbonate to provide Pitofenone of formula-1 further treating Pitofenone of formula-1 with isopropanol-HCl to provide Pitofenone hydrochloride of formula-1a.
In third aspect of first embodiment of the present invention provides one pot synthesis for the preparation of Pitofenone hydrochloride of formula-1a, comprising: reacting 2-(4'-hydroxybenzoyl) benzoic acid of formula-2 with thionyl chloride and methanol followed by reaction with 1-(2-chloroethyl) piperidine or its salt in-presence of sodium carbonate to provide Pitofenone of formula-1 further treating Pitofenone of formula-1 with isopropanol-HCl to provide Pitofenone hydrochloride of formula-1a.

The second embodiment of the present invention provides a process for the purification of Pitofenone hydrochloride of formula-1a, comprising:
a) dissolving compound of formula-1a in a solvent,
b) isolating substantially pure compound of formula-1a.

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 alcohol solvent 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) selected from but not limited to ketone solvents, 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 like thereof, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperature less than about 70°C or less than about 50°C or less than about 25°C or less than about 10°C or less than about 5°C or any other suitable temperature, 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 Pitofenone hydrochloride of formula-1a, comprising:
a) dissolving compound of formula-1a in methanol,
b) adding acetone to the solution obtained in step-a),
c) filtering the substantially pure compound of formula-1a.

Further aspect of present invention the compound of formula-1a obtained by the above purification process is crystalline in nature and is characterized by its PXRD pattern substantially in accordance with figure-1.

In second aspect of third embodiment of the present invention provides a process for the purification of Pitofenone hydrochloride of formula-1a, comprising:
a) dissolving compound of formula-1a in isopropanol,
b) cooling the solution obtained in step-a),
c) filtering the substantially pure compound of formula-1a.

Advantages of the present invention:
• The process described in the present invention is simple, safe, economic, eco-friendly and suitable for the production of Pitofenone hydrochloride of formula-1a on commercial scale with a high reproducibility.
• One pot synthesis for the preparation of Pitofenone hydrochloride of formula-1a provides environment friendly and cost-effective process which avoids the usage of excess solvent and avoids the additional workup process, filtration and drying procedures. This makes the process suitable on commercial scale.
• Usage of commercially available reagents and solvent provides cost-effective process.
• Solvent(s) used in the present invention are recycled and reused in the process.
• Usage of low cost reactants provides cost-effective process.

The other embodiment of the present invention provides a method of treating patients suffering from pain and spasms of smooth muscles of the stomach, intestine, urinary tract, biliary tract and uterus comprising administering to the patients with a therapeutically effective amount of Pitofenone hydrochloride obtained by the process of the present invention.
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 form of Pitofenone hydrochloride is 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 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 Pitofenone hydrochloride of formula-1a
Thionyl chloride (50 g, 1 mole equivalent) was added to the mixture of 2-(4'-hydroxybenzoyl) benzoic acid of formula-2 (100 g, 1 mole equivalent) and methanol (500 ml) at 0-5°C and stirred for 6 hours at same temperature. Methanol was completely distilled off from the reaction mixture. Water (50 ml) and ethyl acetate (500 ml) were added to the above residue at room temperature and stirred for 10 minutes at same temperature. Layers separated. 1-(2-chloroethyl) piperidine hydrochloride (70 g, 0.92 mole equivalent) and 10% aqueous potassium carbonate solution (115 g of potassium carbonate in 1150 ml of water) were added to the above organic layer at room temperature and stirred for 10 minutes at same temperature. Heated the reaction mixture to 60-65°C and stirred for 1 hour at same temperature. Water was added to the above reaction mixture. Layers separated and organic layer was acidified with isopropanol-HCl and stirred for 1 hour. Filtered the solid and dried to get the title compound.
Yield: 154.54 g (92.68%); HPLC purity: 92.1%.
Example-2: Preparation of Pitofenone hydrochloride of formula-1a
Thionyl chloride (50 g, 1 mole equivalent) was added to the mixture of 2-(4'-hydroxybenzoyl) benzoic acid of formula-2 (100 g, 1 mole equivalent) and methanol (500 ml) at 0-5°C and stirred for 6 hours at same temperature. Methanol was completely distilled off from the reaction mixture. Water (50 ml) and ethyl acetate (500 ml) were added to the above residue at room temperature and stirred for 10 minutes at same temperature. Layers separated. 1-(2-chloroethyl) piperidine hydrochloride (70 g, 0.92 mole equivalent) and 10% aqueous sodium carbonate solution (88 g of sodium carbonate in 880 ml of water) were added to the above organic layer at room temperature and stirred for 10 minutes at same temperature. Heated the reaction mixture to 60-65°C and stirred for 1 hour at same temperature. Water was added to the above reaction mixture. Layers separated and organic layer was acidified with isopropanol-HCl and stirred for 1 hour. Filtered the solid and dried to get the title compound.
Yield: 157.70 g (94.57%); HPLC purity: 93.5%.
Example-3: Preparation of Methyl 2-(4'-hydroxybenzoyl) benzoate
Thionyl chloride (50 g, 1 mole equivalent) was added to the mixture of 2-(4'-hydroxybenzoyl) benzoic acid of formula-2 (100 g, 1 mole equivalent) and methanol (500 ml) at 0-5°C and stirred for 6 hours at same temperature. Reaction mixture was concentrated. Water was added to above mixture at room temperature and stirred for 6 hours at same temperature. Filtered the solid and dried to get the title compound.
Yield: 88.74 g (83.89%)
Example-4: Preparation of Pitofenone hydrochloride of formula-1a
1-(2-chloroethyl) piperidine hydrochloride (72 g, 1 mole equivalent) and 10% aqueous sodium carbonate solution (88 g of sodium carbonate in 880 ml of water) were added to the mixture of methyl 2-(4'-hydroxybenzoyl) benzoate (100 g) and ethyl acetate (500 ml) at room temperature and stirred for 10 minutes at same temperature. Heated the reaction mixture to 60-65°C and stirred for 4 hours at same temperature. Water was added to the above reaction mixture. Layers separated and organic layer was acidified with isopropanol-HCl and stirred for 1 hour. Filtered the solid and dried to get the title compound.
Yield: 146.57 g (92.98%), HPLC purity: 90.2%.
Example-5: Purification of Pitofenone hydrochloride of formula-1a
Pitofenone hydrochloride (100 g) was dissolved in methanol (200 ml) at 35-40°C and stirred for 10 minutes at the same temperature and decolorized by using activated carbon. Acetone (500 ml) was added to the above obtained clear filtrate and stirred for 2 hours at 0-5°C temperature. Filtered the solid and dried to get the pure compound.
Yield: 95.58 g (95.58%); HPLC purity: 99.9%.
Example-6: Purification of Pitofenone hydrochloride of formula-1a
Pitofenone hydrochloride (100 g) was dissolved in isopropanol (500 ml) at 35-40°C and stirred for 10 minutes at the same temperature and decolorized by using activated carbon. Cooled the above obtained clear filtrate and to 0-5°C stirred for 2 hours at same temperature. Filtered the solid and dried to get the pure compound.
Yield: 90.62 g (90.62%); HPLC purity: 99.5%.