“PREPARATION OF PHENYRAMIDOL HYDROCHLORIDE”
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Phenyramidol hydrochloride of Formula (I) with commercially viable and industrial applicable process.

BACKGROUND OF THE INVENTION:
Phenyramidol hydrochloride (also known as Fenyramidol or IN 511 or MJ 5050) is a drug chemically known as 2-(β-hydroxyphenethylamino) pyridine hydrochloride of formula (I) with a molecular formula C13H14N2O.HCl, attributed for its analgesic and muscle relaxant property.

Preparation of Phenyramidol hydrochloride (I) was first described in Journal of American Chemical Society 81, 4347-4351,1959 and its process for the preparation of Phenyramidol hydrochloride (I) comprises by reacting 2-amino pyridine with sodamide in presence of liquid ammonia, followed by reacted with styrene oxide in presence of ethylene glycol dimethyl ether to get Phenyramidol base and further it is treated with hydrochloric acid to obtain Phenyramidol hydrochloride of formula(I).


US 3,165,527 discloses a process for the preparation of Phenyramidol hydrochloride (I) by reacting 2-amino pyridine is reacted with (dl)-mandelic acid to get 2-mandelamidopyridine, which is converted into Phenyramidol by using Lithium aluminium hydride and ethylene glycol dimethyl ether as a solvent. The resultant Phenyramidol base is treated with hydrochloric acid and recrystallize from a mixture of ethanol and ether solvents to get Phenyramidol hydrochloride.

New Journal of Chemistry, 36(3), 603-612; 2012 discloses a process for the preparation of Phenyramidol, which comprises α-(aminomethyl)benzenemethanol reacted with 2-bromo pyridine in presence of disodium carbonate and dichloro methane to get Phenyramidol.


The major disadvantage with the above prior art process is the usage of caustic and hazardous ammonia and sodamidemay cause for many inconvenient reactions such as fire or explosion, irritation or toxic fumes and the use of too manyreagents caused for unwanted impurities and that leads to lower yield. Hence, the use of ammonia and sodamide may not be suitable for industrial applicable process.
The present invention has many advantages over the prior art processes, which are industrially friendly such as the condensation reaction of 2-amino pyridine and styrene oxide carried out by using potassium tertiary butoxide at ambient temperature and gives high purity of the product without purification. Similarly, the present invention involves simple steps which are commonly adopted in industrial scale.
The present invention involves the use of commercially available and less expensive base such as potassium tertiary butoxide compare to prior art bases in the preparation of Phenyramidol.
The inventors have achieved a simple, mild, facile, short time span and economic cost effective synthesis of Phenyramidol hydrochloride by using key starting raw materials 2-amino pyridine and styrene oxide.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of
Phenyramidol hydrochloride in terms of good yield and purity.
In an aspect of the present invention relates to an improved process for the preparation of Phenyramidol hydrochloride of formula (I), which comprises reacting a 2-amino pyridine with styrene oxide in presence of strong base and organic solvent followed

by reacted with hydrochloric acid to obtain Phenyramidol hydrochloride of formula (I).
The above synthetic process is illustrated by the following Scheme:

DETAILEDDESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Phenyramidol hydrochloride.The present invention is also relates to commercially viable and industrially advantageous process.
An embodiment of the present invention provides an improved process for the preparation of Phenyramidol hydrochloride of formula (I), which comprises reacting a 2-amino pyridine with styrene oxide in presence of strong base and organic solvent followed by reacted with hydrochloric acid to obtain Phenyramidol hydrochloride of formula (I).
According to an embodiment of the present invention, the reaction between the 2-amino pyridine with styrene oxide is carried out in the presence of a strong base and organic solvent at a suitable temperature, allow to stir and then raise the temperature at 20-50°C for 8-14 hours, preferably 25 to 30°C for 10-12hours to obtain Phenyramidol free base, followed by reacted with isopropanolic hydrochloride and

then adjust pH 1.0 to 2.0 and further it is recrystallize with methanol to get Phenyramidol hydrochloride (I).
In an embodiment, the reaction is carried using strong base and in the presence of anorganic solvent at a temperature in the range of 25° to 30°C. The reaction is carried out for a period of 10 to 12 hours to get a desired compound.
According to an embodiments of the present invention, the suitable strong bases are selected from potassium tert butoxide, lithium tert butoxide, sodium tert butoxide, sodium methoxide, lithium methoxide, potassium methoxide and sodium hydride etc. preferably potassium tert butoxide.
According to an embodimentsof the present invention, the suitable organic solvents are selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like or mixture thereof; ketones such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene, cyclohexane and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; and amides such as N,N- dimethylformamide, Ν,Ν-dimethylacetamide and the like or mixture of solvents thereof.
Advantages of the present invention:
1. The present invention is a simple, mild, facile, operation friendly, commercially viable and industrially applicable process.
2. The reaction sequence of the present invention is carried out in a shorter timespan with high purity and less impurity profile.
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 construed to limit the scope of the invention.

Example: 1
Process for the preparation of Phenyramidol hydrochloride :
To the mixture of 2-aminopyridine (50 gm, 0.53 moles) and toluene (150 ml) are taken into R.B.flask and allow to cool at 10-15°C, followed by slow additionof potassium tertiary but oxide (50 gm, 0.44 moles) over a period of 10-15 min. The reaction mixture was stir for 20-30 min at 10-15°C and then slowly added styrene oxide (65 gm, 0.54 moles) at the same temperature, the reaction mixture was allow to raise at 25-30°C for 10-12 hrs. The reaction completion is confirmed by thin layer chromatography (TLC), added purified water (200 ml) to the mixture, stir for 10 min and settle for 20 min to separate the layers. The obtain toluene layer was distilled out under reduced pressure at below 60°C to get a residue and added isopropanol (100 ml) at 25-30°C by adjusting pH 1.0-2.0 by using Isopropanolic hydrochloride solution. The resultant solid was filtered and isolated wet solid was recrystallized with methanol (100 ml ) to afford a title compound.
Dry wt: - 55gm.
Example: 2
Process for the preparation of Phenyramidol hydrochloride :
To the mixture of 2-aminopyridine (100 gm, 1.06 moles) and tetrahydrofuran (150 ml) are taken into R.B.flask and allow to cool at 10-15°C, followed by slow addition of potassium tertiary but oxide (100 gm, 0.88 moles) over a period of 10-15 min. The reaction mixture was stir for 20-30 min at 10-15°C and then slowly added styrene oxide (130 gm, 1.08moles) at the same temperature, the reaction mixture was allow to raise at 25-30°C for 10-12 hrs. The reaction completion is confirmed by thin layer chromatography (TLC), added purified water (400 ml) and ethyl acetate (500 ml) to the mixture, stir for 10 min and settle for 20 min to separate the layers. The obtain ethyl acetate layer was distilled out under reduced pressure at below 60°C to get a residue and added isopropanol (200 ml), at 25-30°C by adjusting pH 1.0-2.0 by using Isopropanolic hydrochloride solution. The resultant solid was filtered and isolated wet

solid was recrystallized with methanol (50 ml) and isopropanol (300 ml) mixture to afford a title compound.
Dry wt:- 120gm.
Example:3
Process for the preparation of Phenyramidol hydrochloride :
To the mixture of 2-aminopyridine (100 gm, 1.06 moles) and N,N-dimethyl formamide(150 ml) are taken into R.B.flask and allow to cool at 10-15°C, followed by slow addition of potassium tertiary but oxide (100 gm, 0.88 moles) over a period of 10-15 min. The reaction mixture was stir for 20-30 min at 10-15°C and then slowly added styrene oxide (130 gm, 1.08 moles) at the same temperature, the reaction mixture was allow to raise at 25-30°C for 10-12 hrs. The reaction completion is confirmed by thin layer chromatography (TLC), added purified water (400 ml) and ethyl acetate (500 ml) to the mixture, stir for 10 min and settle for 20 min to separate the layers. The obtain ethyl acetate layer was distilled out under reduced pressure at below 60°C to get a residue and added isopropanol (200 ml), at 25-30°C by adjusting pH 1.0-2.0 by using Isopropanolic hydrochloride solution. The resultant solid was filtered and isolated wet solid was recrystallized with methanol (50 ml) and isopropanol (300 ml) mixture to afford a title compound.
Dry wt: - 120gm.
Example:4
Process for the preparation of Phenyramidol hydrochloride :
To the mixture of 2-aminopyridine (50 gm, 0.53 moles) and tetrahydrofuran (150 ml) are taken into R.B.flask and allow to cool at 10-15°C, followed by slow addition of lithium tertiary but oxide (50 gm, 0.625 moles) over a period of 10-15 min. The reaction mixture was stir for 20-30 min at 10-15°C and then slowly added styrene oxide (65 gm, 0.54 moles) at the same temperature, the reaction mixture was allow to raise at 25-30°C for 10-12 hrs. The reaction completion is confirmed by thin layer chromatography (TLC), added purified water (200 ml) and ethyl acetate (250 ml) to

the mixture, stir for 10 min and settle for 20 min to separate the layers. The obtain ethyl acetate layer was distilled out under reduced pressure at below 60°C to get a residue and added isopropanol (100 ml), at 25-30°C by adjusting pH 1.0-2.0 by using Isopropanolic hydrochloride solution. The resultant solid was filtered and isolated wet solid was recrystallized with methanol (25 ml) and isopropanol (150 ml) mixture to afford a title compound.
Dry wt:- 60gm.
Example:5
Process for the preparation of Phenyramidol hydrochloride :
To the mixture of 2-aminopyridine (25.0 gm, 0.265 moles) and N,N-dimethyl formamide (75 ml) are taken into R.B.flask and allow to cool at 10-15°C, followed by slow addition of sodium methoxide (20 gm, 0.37 moles) over a period of 10-15 min. The reaction mixture was stir for 20-30 min at 10-15°C and then slowly added styrene oxide (32 gm, 0.27 moles) at the same temperature, the reaction mixture was allow to raise at 25-30°C for 10-12 hrs. The reaction completion is confirmed by thin layer chromatography (TLC), added purified water (100 ml) and ethyl acetate (125 ml) to the mixture, stir for 10 min and settle for 20 min to separate the layers. The obtain ethyl acetate layer was distilled out under reduced pressure at below 60°C to get a residue and added isopropanol (50 ml), at 25-30°C by adjusting pH 1.0-2.0 by using Isopropanolic hydrochloride solution. The resultant solid was filtered and isolated wet solid was recrystallized with methanol (10 ml) and isopropanol (75 ml) mixture to afford a title compound.
Dry wt:- 30gm.
Example:6
Process for the preparation of Phenyramidol hydrochloride :
To the mixture of 2-aminopyridine (50 gm, 0.53 moles) and N,N-dimethylformamide (150 ml) are taken into R.B.flask and allow to cool at 10-15°C, followed by slow addition of sodium hydride (25.0 gm, 1.04 moles) over a period of 10-15 min. The

reaction mixture was stir for 20-30 min at 10-15°C and then slowly added styrene oxide (65 gm, 0.54 moles) at the same temperature, the reaction mixture was allow to raise at 25-30°C for 10-12 hrs. The reaction completion is confirmed by thin layer chromatography (TLC), added purified water (200 ml) and ethyl acetate (250 ml) to the mixture, stir for 10 min and settle for 20 min to separate the layers. The obtain ethyl acetate layer was distilled out under reduced pressure at below 60°C to get a residue and added isopropanol (100 ml), at 25-30°C by adjusting pH 1.0-2.0 by using Isopropanolic hydrochloride solution. The resultant solid was filtered and isolated wet solid was recrystallized with methanol (25 ml) and isopropanol (150 ml) mixture to afford a title compound.
Dry wt:- 50gm.
Example:7
Process for the preparation of Phenyramidol hydrochloride:
Phenyramidol base (50 gm) was dissolved in ethyl acetate and stirred for few minutes, followed by adjusting pH 1.0-2.0 using (200 ml) ethyl acetate + HCl solution at 25-30°C. The resultant solid was filtered and isolated wet solid was recrystallized with methanol (100 ml) to afford a title compound.

We Claims:
1. An improved process for the preparation of Phenyramidol hydrochloride of
formula (I), which comprises reacting a 2-amino pyridine with styrene oxide
in presence of strong base and organic solvent followed by reacted with
hydrochloric acid to obtain Phenyramidol hydrochloride of formula (I).

2. The process as claimed in claim 1, the suitable strong bases are selected from potassium tert butoxide, lithium tert butoxide, sodium tert butoxide, sodium methoxide, lithium methoxide, potassium methoxide and sodium hydride etc. preferably potassium tert butoxide.
3. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of toluene,ethyl acetate, dimethyl formamide, methanol, ethanol, isopropyl alcohol and dichloromethane.