Claims:1. One pot synthesis for the preparation of Phenyramidol hydrochloride of
formula-1a comprising: reacting 2-aminopyridine of formula-2 with Styrene oxide in presence of a metal hydroxide and a catalyst in a solvent to provide Phenyramidol of formula-1 which is on in-situ reaction with hydrochloric acid source to provide Phenyramidol hydrochloride of formula-1a.

2. The process as claimed in claim 1, metal hydroxide is selected from alkali
metal hydroxide or alkaline earth hydroxides; catalyst is selected from ammonia or organic amine; solvent is selected from hydrocarbon solvent; 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. One pot synthesis for the preparation of Phenyramidol hydrochloride of
formula-1a, comprising: reacting 2-aminopyridine of formula-2 with Styrene oxide in presence of potassium hydroxide and ammonia in toluene to provide Phenyramidol of formula-1 which is on in-situ reaction with hydrochloric acid source to provide Phenyramidol hydrochloride of formula-1a.

4. The process as claimed in claim 3, 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.

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

6. The process as claimed in claim 5, solvent used in step-a) is selected from methanol.
, Description:Field of the invention:
The present invention relates to an improved one pot synthesis for the preparation of Phenyramidol hydrochloride of formula-1a.

Formula-1a
Background of the invention:
Phenyramidol hydrochloride is a aminopyridine derivative, chemically known as 2-(ß-hydroxyphenethylamino) pyridine hydrochloride.
Phenyramidol also known as Fenyramidol used as analgesic and muscle relaxant indicated in the symptomatic treatment of lumbago, integumental pain, and musculoskeletal pain.
US3165527 patent discloses the process for the preparation of Phenyramidol hydrochloride by reacting 2-aminopyridine with dl-mandelic acid in xylene to produce 2-mandelamidopyridine which is further reduced with Lithium aluminum hydride (LAH) in dry ethylene glycol dimethyl ether. The obtained Phenyramidol base was then reacted with hydrochloric acid (HCl) in ether to give Phenyramidol hydrochloride.
Process described in US’527 patent is shown in the following scheme

The above said process has some disadvantages includes the usage of pyrophoric chemical Lithium aluminum hydride is the process. Lithium aluminum hydride is highly flammable and moisture sensitive compound handling in the large scale is unsafe. Further process for the preparation of 2-mandelamidopyridine involves the usage of dl-mandelic acid which is a costly raw material and also requires high temperature (165-170°C) and longer reaction time (20 hours) for the completion of reaction. In this manufacturing process, benzene is involved in the workup procedure. Benzene is a carcinogenic solvent. By considering all the above demerits, this process is not viable in commercial scale.
IN270303 patent describes the process for the preparation of (S)-Phenyramidol by reacting 2-aminopyridine with alkali metal amide (LiNH2) in dimethyl formamide (DMF) followed by reaction with (S)-styrene oxide further the obtained compound is converted to its acid addition salt.
Process described in the above patent is shown in the following scheme.

The above said process has some disadvantages i.e. LiNH2 is a costly reagent. Moreover LiNH2 is a highly explosive and reactive chemical. Using such hazardous chemical in large scale is very difficult.
IN201741009880 patent discloses the process for the preparation of Phenyramidol hydrochloride by reacting 2-aminopyridine with styrene oxide in presence of strong inorganic base (Potassium tert butoxide) in toluene followed by treating with hydrochloric acid in isopropanol.
Process described in the above patent is shown in the following scheme.

The above said process has some disadvantages i.e. Potassium tert butoxide is a costly reagent and its usage results in low yield. Moreover Potassium tert butoxide is highly hygroscopic compound and it is hydrolyzes in water to form tert-butanol and potassium hydroxide. By considering the above demerits, the above said process is not viable on commercial scale.

The prior art processes have some disadvantages includes, usage of hazardous, toxic, expensive solvents and reagents like LiNH2, dl-mandelic acid, Potassium tert butoxide and benzene in the reaction, multiple step processes and produces huge quantity of effluent and inorganic waste in the process. These disadvantages make the processes not suitable in large scale production.
Thus, there remains a need to develop an improved process for the preparation of Phenyramidol hydrochloride, 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 toxic and/or costly solvents or reagents and critical workup procedures. Accordingly, the present invention provides an improved process for the preparation of Phenyramidol 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 Phenyramidol hydrochloride of formula-1a.
The second embodiment of the present invention provides a process for the purification of Phenyramidol hydrochloride of formula-1a.

Brief description of the drawings
Figure 1: Illustrates powder X-ray diffraction (PXRD) pattern of line form of Phenyramidol hydrochloride of formula-1a obtained according to Example-2.

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 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, dimethylsulfoxide, 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 and 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 "acid" used in the present invention selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, methane sulfonic acid, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic 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.
The term "base" used in the present invention selected from but not limited to inorganic acids selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tertiary butyl amine, benzyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide mixtures thereof.
The term "hydrochloric acid source" used in the present invention is selected from but not limited to hydrochloric acid (HCl), aqueous HCl, dry HCl, ethyl acetate-HCl, isopropyl acetate-HCl, isopropanol-HCl (IPA-HCl), ethanol-HCl, methanol-HCl or dioxane-HCl 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-1 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 Phenyramidol hydrochloride of formula-1a, comprising: reacting 2-aminopyridine of formula-2 with Styrene oxide in presence of a metal hydroxide and a catalyst in a solvent to provide Phenyramidol of formula-1 which is on in-situ reaction with hydrochloric acid source to provide Phenyramidol hydrochloride of formula-1a.

and optionally purifying the compound to provide substantially pure compound of Phenyramidol hydrochloride of formula-1a.

In first aspect of first embodiment, metal hydroxide is selected from alkali metal hydroxide or alkaline earth hydroxides, preferably alkali metal hydroxide, more preferably potassium hydroxide; catalyst is selected from ammonia or organic amine selected from but not limited to dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tertiary butyl amine, benzyl amine , preferably ammonia; solvent is selected from but not limited to hydrocarbon solvent, preferably toluene; 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; the reaction temperature ranges from about 0-50°C.
In second aspect of first embodiment, the amount of metal hydroxide used in range from 1.5 to 3.0 mole equivalent with respect to compound of formula-2; Styrene oxide used in range from 0.8 to 1.5 mole equivalent with respect to compound of formula-2; the amount of catalyst used in range from 0.2 to 0.7 mole equivalent with respect to compound of formula-2;
In third aspect of first embodiment of the present invention provides one pot synthesis for the preparation of Phenyramidol hydrochloride of formula-1a, comprising: reacting 2-aminopyridine of formula-2 with Styrene oxide in presence of potassium hydroxide and ammonia in toluene to provide Phenyramidol of formula-1 which is on in-situ reaction with hydrochloric acid source to provide Phenyramidol hydrochloride of formula-1a and optionally purifying the compound to provide substantially pure compound of Phenyramidol hydrochloride of formula-1a.
Wherein, hydrochloric acid source used in third aspect 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.
The second embodiment of the present invention provides a process for the purification of Phenyramidol 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 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), 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 temperature less than about 50°C, less than about 25°C, less than about 10°C, 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 Phenyramidol hydrochloride of formula-1a, comprising:
a) dissolving compound of formula-1a in methanol,
b) adding Isopropyl alcohol to 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 line in nature and is characterized by its PXRD pattern substantially in accordance with figure-1.

Advantages of the present invention:
• The process described in the present invention is simple, safe, economic, eco-friendly and suitable for the production of Phenyramidol hydrochloride of formula-1a on commercial scale with a high reproducibility.
• One pot synthesis for the preparation of Phenyramidol hydrochloride provide environment friendly and cost-effective process which avoids the usage of excess solvent, and also avoids the extra filtration and drying process. This makes the process suitable on commercial scale.
• Usage of commercially available reagents and solvent provides cost-effective process.
• Solvents used in the present invention are recycled and reused in the process.

The other embodiment of the present invention provides a method of treating a patients suffering from lumbago, integumental pain, and musculoskeletal pain comprising administering to the patients with a therapeutically effective amount of Phenyramidol 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 line form of Phenyramidol 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.

High Performance Liquid Chromatography (HPLC) analysis method:
Phenyramidol hydrochloride and its related substances of present invention were analysed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatographic system is equipped with variable wavelength UV detector; Column: octadecylsilyl silica; 5µm (or) equivalent; Wavelength: 306 nm; Flow rate: 1.0 mL/min; Injection volume: 20 µL; Elution: Gradient; Mobile phase: mixture of 900 volumes of water, 1 volume of orthophosphoric acid and 100 volumes of acetonitrile. Test solution: dissolve 0.1 g of the substance under examination in the mobile phase and dilute to 100 ml with the mobile phase. Reference solution: A 0.001 percent w/v solution of Phenyramidol hydrochloride RS in the mobile phase.

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 Phenyramidol hydrochloride of formula-1a
Potassium hydroxide (150 g, 2.5 mole equivalent) and styrene oxide (130 g, 1 mole equivalent) were added to the mixture of 2-aminopyridine (100 g, 1 mole equivalent) in toluene (400 ml) at room temperature. Purged the ammonia gas (5 g) to the reaction mixture at 5-10°C and stirred for 8 hours at same temperature. Water was added to the reaction mixture and layers were separated. Organic layer decolorized by using activated carbon. Isopropanol-HCl (120 g) was added to the organic layer at room temperature and stirred for 12 hours at same temperature. Filtered the precipitated solid washed with isopropanol and dried to get the title compound.
Yield: 205.14 g (77%); HPLC purity: 99.1%.
Example-2: Purification of Phenyramidol hydrochloride of formula-1a
Phenyramidol hydrochloride (100 g) was dissolved in methanol (300 ml) at 50-55°C. Activated carbon was added to above solution at 50-55°C and stirred for 10 minutes at the same temperature. Filtered the mixture through 0.2 micron filter. Isopropyl alcohol was added to the above obtained clear filtrate and stirred for 4 hours at room temperature. Filtered the solid and dried to get the pure compound.
Yield: 95.97 g (95.97%); HPLC purity: 99.9%.
PXRD pattern of the above compound is illustrated in figure-1.
Example-3: Preparation of Phenyramidol hydrochloride of formula-1a
Sodium hydroxide (128 g, 3 mole equivalent) and styrene oxide (130 g, 1 mole equivalent) were added to the mixture of 2-aminopyridine (100 g, 1 mole equivalent) in toluene (400 ml) at room temperature. Purged the ammonia gas (15 g) to the reaction mixture at 5-10°C and stirred for 8 hours at same temperature. Water was added to the reaction mixture and layers were separated. Organic layer decolorized by using activated carbon. Isopropanol-HCl (100 g) was added to the organic layer at room temperature and stirred for 12 hours at same temperature. Filtered the precipitated solid washed with isopropanol and dried to get the title compound.
Yield: 171 g (64.18%).
Example-4: Preparation of Phenyramidol hydrochloride of formula-1a
Potassium hydroxide (150 g, 2.5 mole equivalent) and styrene oxide (130 g, 1 mole equivalent) were added to the mixture of 2-aminopyridine (100 g, 1 mole equivalent) in toluene (400 ml) at room temperature. Triethylamine (30 g) was added to the reaction mixture at 5-10°C and stirred for 8 hours at same temperature. Water was added to the reaction mixture and layers were separated. Organic layer decolorized by using activated carbon. Isopropanol-HCl (200 g) was added to the organic layer at room temperature and stirred for 12 hours at same temperature. Filtered the precipitated solid washed with isopropanol and dried to get the title compound.
Yield: 182.5 g (68.5%).

Example-5: Preparation of Phenyramidol hydrochloride of formula-1a
Potassium hydroxide (150 g, 2.5 mole equivalent) and styrene oxide (130 g, 1 mole equivalent) were added to the mixture of 2-aminopyridine (100 g, 1 mole equivalent) in toluene (400 ml) at room temperature. Pyridine (47 g) was added to the reaction mixture at 5-10°C and stirred for 8 hours at same temperature. Water was added to the reaction mixture and layers were separated. Organic layer decolorized by using activated carbon. Isopropanol-HCl (110 g) was added to the organic layer at room temperature and stirred for 12 hours at same temperature. Filtered the precipitated solid washed with isopropanol and dried to get the title compound.
Yield: 176.37 g (66.2%).