FIELD OF THE INVENTION
The present invention relates to a process for the preparation of (±)-Ritalinic acid hydrochloride with cost effective and industrial applicable by employing a novel step.
BACKGROUND OF THE INVENTION
Ritalinic acid is an inactive major metabolite and key intermediate of the psycho stimulant drugs like methylphenidate and ethylphenidate. When administered orally, methylphenidate is extensively metabolized in the liver by hydrolysis of the ester group yielding Ritalinic acid. Methylphenidate was first licensed by the FDA in 1955 for treating attention deficient hyperactivity disorder (ADHD). It is available worldwide with different brand names like Concerta®, Daytrana®, Metadate CD®,
Ritalinic acid hydrochloride is chemically known as (±)-2-phenyl-2-(piperidin-2-yl) acetic acid hydrochloride, represented by the following structure of formula (I).
Ritalinic acid hydrochloride of formula (I) process is disclosed in US 2,957,880 prepared by hydrolysis of a-phenyl-a-piperidyl-2-acetamide of formula (II) in presence of trimethylbenzyl ammonium hydroxide / HC1, ethylene chloride and sulfuric acid to obtained (±)-Ritalinic acid hydrochloride of formula (I), which is depicted in scheme-I given below:

WO 2006064052 discloses a process for the preparation of Ritalinic acid, which comprises a-phenyl-a-pyridyl-2-acetamide of formula (III) on undergoes reduction in 5 presence Rh/C / acetic acid and potassium hydroxide to get a-phenyl-a-piperidyl-2-acetamide of formula (II), which is hydrolyzed in presence of 98% sulfuric acid and 30% NaOH to obtain Ritalinic acid, which is depicted in scheme-II given below:
WO 01/27070 discloses a process for the preparation of Ritalinic acid intermediate, where in benzyl cyanide reacted with 2-chloropyridine in presence of sodium amide and toluene to get a compound of formula (IV), which is further converts into compound of formula (III) and followed by acidification / esterification with methanol in presence of hydrochloric acid to give methyl 2-phenyl-2-(pyridine-2-yl) acetate (V). which is depicted in scheme-Ill given below:

The present invention has disclosed a process for the preparation of Ritalinic acid hydrochloride (I) in such a way that there is no need of further purification and methylphenidate is converted directly into Ritalinic acid hydrochloride with a very good yield and higher purity that overcomes the drawbacks of the processes disclosed as cited above. The disclosed invention is eco-friendly and suits for commercial production.
Thus, present invention fulfills the need of the art and provides an efficient and industrially applicable process for preparation of high purity Ritalinic acid in high yield.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved, simple and cost-effective process for the preparation of (±)-Ritalinic acid hydrochloride of formula (I).
In one aspect of the present invention provides an improved process for the preparation of (±)-Ritalinic acid hydrochloride of formula (I), which comprises:
a) esterification of 2-phenylaceticacidin presence of methanol and catalyst to give methyl 2-phenylacetate (VII),
b) the product of step a) is reacted with 2-chloropyridine in presence of strong base and solvent to give methyl 2-phenyl-2-(pyridine-2-yl) acetate (V),
c) the product of step b) is converts into methylphenidate (VTII) in presence of reducing agent,
d) the product of step c) is hydrolyzed in presence of alkaline base and solvent, and
e) isolated (±)-Ritalinic acid hydrochloride (I).
The above synthetic process is illustrated by the following Scheme

In another aspect of the present invention provides an improved process for the preparation of methyl 2-phenyl-2-(pyridine-2-yl) acetate (V) comprising methyl 2-phenylacetate (VII) is reacted with 2-chloropyridine in presence of strong base and solvent to obtained a compound of formula (V).
) DETAILED DESCRD?TION OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Ritalinic acid hydrochloride and its intermediates.
In one embodiment of the present invention provides an improved process for the preparation of Ritalinic acid hydrochloride of formula (I), which comprises:
a) esterification of 2-phenylaceticacidin presence of methanol and catalyst to give
methyl 2-phenylacetate (VII),
) b) the product of step a) is reacted with 2-chloropyridine in presence of strong
base and solvent to give methyl 2-phenyl-2-(pyridine-2-yl) acetate (V),

c) the product of step b) is converts into methylphenidate (VIII) in presence of reducing agent,
d) the product of step c) is hydrolyzed in presence of alkaline base and solvent, and
e) isolated (±)-Ritalinic acid hydrochloride (I).
According to an embodiment of the present invention, which comprises the 2-phenylaceticacid (VI) is esterified in presence of methanol and catalyst at reflux condition for 2-5 hours to give methyl 2-phenylacetate (VII), further it is reacted with 2-chloropyridine in presence of strong base and solvent at ambient temperature, allow to stir for 20 to 30 hours (hrs.) and adjust pH to 1.0-2.0 to obtain compound of formula (V). The resultant compound of formula (V) is reduced in presence of reducing agent and solvent at suitable temperature to give methylphenidate (VIII), which is hydrolyzed with alkaline base in presence of solvent at 40-60°C for 4 -7 hrs and allow to cool at 25-30°C , adjust pH to 6.0-7.0 with an acid to isolate Ritalinic acid base
Ritalinic base is treated with hydrochloric acid in presence of solvent and heat it to 40-60°C for 1-3 hrs. The resultant solvent is distilled out completely, followed by ketone solvent, stir for 30 to 60 minutes (min) at 30-50°C. Out growth solid was filtered, washed and dried to afford pure Ritalinic acid hydrochloride salt.
In another embodiment of the present invention provides an improved process for the preparation of methyl 2-phenyl-2-(pyridine-2-yl) acetate (V) comprising methyl 2-phenylacetate (VII) is reacted with 2-chloropyridine in presence of strong base and solvent to get a compound of formula (V).
According to an embodiment of the present invention, reducing agent is selected from palladium on carbon (Pd/C), sodiumborohydride, raney. nickel, lithium aluminum hydride, stannic chloride, iron powder, diisobutylaluminum hydride and diborane sodium amalgam. Most preferably Pd/C in presence of acetic acid as a solvent at 50-
70°C.

According to an embodiment of the present invention, catalyst is selected from, thionyl chloride, para toluenesulphonic acid (PTSA), hydrochloric acid and sulfuric acid.
According to embodiments of the present invention, the suitable base is selected from strong bases such as potassium tert.butoxide, sodium tert.butoxide, sodium amide, n-butyl lithium, most preferably potassium tert.butoxide or sodium amide.
Alkaline base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide and barium hydroxide. Most preferably lithium hydroxide.
According to an embodiments of the present invention, the suitable solvents are selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like or mixture thereof; acids such as hydrochloric acid, formic acid and acetic acid; ketones such as acetone, 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 hexane, heptane, toluene, xylene, cyclohexane and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; amides such as N,N-dimethyl formamide, N,N-dimethylacetamide and the like or dimethylsulfoxide or mixture of solvents thereof.
Advantages of the present invention:
1. The present invention is a simple, operation friendly and industrially applicable process.
2. The process is commercially viable and provides the compounds in high yield, which makes the process cost effective.
3. The present invention provides the compound of formula (I) with high purity and very 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.
Experimental procedure:
Example: 1
Process for the preparation of methyl-2-phenylacetate:
To a mixture of phenyl acetic acid (50 gm, 1 mole), methanol (100 ml) were added into the R.B flask and allow to cool at 5-10°C, followed by slowly addition of thionylchloride (52.5 gm., 1.2 mole) into the mixture at below 20°C. The reaction mixture temperature was raised to reflux temperature and maintain for 2-3 hrs. The solvent in the reaction mixture was distilled out completely under reduced pressure and extract the product with dichloromethane (250 ml). The resultant dichloromethane layer was washed with 5% sodium bi carbonate solution (100 ml) / purified water (100 ml), dried with sodium sulphate and distilled out dichloromethane completely under reduced pressure to isolate the residual product of title compound. Weight of the product: 48 gm
Example: 2
Process for the preparation of Ethyl-2-phenylacetate:
To a mixture of phenyl acetic acid (50 gm, 1 mole) and ethanol (100 ml) added into the R.B flask and allow to cool at 5-10°C, followed by slowly addition of thionyl chloride (52.5 gm., 1.2 mole) into the mixture at below 20°C. The reaction mixture temperature was raised to reflux temperature and maintain for 2-3 hrs. The solvent in the reaction mixture was distilled out completely under reduced pressure and extract the product with dichloromethane (250 ml). The resultant dichloromethane layer was washed with 5% sodium bi carbonate solution (100 ml) / purified water (100

ml), dried with sodium sulphate and distilled out dichloromethane completely under reduced pressure to isolate the residual product of title compound. Weight of the product: 50 gm
Example; 3
Process for the preparation of methyl-2-phenvl-2(pyridine-2-vD acetate;
To a mixture of methyl-2-phenylacetate (100 gm) and toluene (500 ml) were added into the R.B. flask, followed by addition of 2-chloropyrine (90 gm) and potassium tertiary butoxide (90.0 gm) at 25-30°C. The reaction mixture was stir for 70-75 hrs at 25-30°C till complies the reaction, quench the mixture into ice water, separate two layers. The obtain toluene layer was washed with purified water (300 ml), dried with sodium sulphate (10 gm) and distilled out toluene completely under reduced pressure to get a residual product. The resultant residue was cool to 25-30°C, added acetone (500 ml) and adjusted reaction mixture pH to 1.0-2.0 with isopropanol hydrochloride solution (50 ml), stir for 30 min at 25-30°C. Obtain solid was filtered, washed with acetone (50 ml) and dried at 50-60°C to afford the title compound. Weight of the product: 100 gm.
Example; 4
Process for the preparation of Ethyl-2-phenvl-2(pyridine-2-vD acetate;
To a mixture of ethyl-2-phenyl acetate (50 gm) and toluene (250 ml) into the R.B. flask, followed by addition of 2-chloropyrine (45 gm) and potassium tertiary but oxide (45 gm) at 25-30°C. The reaction mixture was stir for 30-35 hrs at 25-30°C till complies the reaction, quench the mixture into ice water, separate two layers. The obtain toluene layer was washed with purified water (100 ml), dried with sodium sulphate (5 gm) and distilled out toluene completely under reduced pressure to get a residual product. The resultant residue was cool to 25-30°C, added acetone (250 ml) and adjusted reaction mixture pH to 1.0-2.0 with isopropanol hydrochloride solution (50 ml), stir for 30 min at 25-30°C. Obtain solid was filtered, washed with acetone (25 ml) and dried at 50-60°C to afford the title compound.

Weight of the product: 90 gm
Example; 5
Process for the preparation of methyl-2-phenvl-2(pyridine-2-vD acetate;
To a mixture of methyl-2-phenyl acetate (100 gm) and toluene (500 ml) into the R.B. flask, followed by addition of 2-chloropyrine (90 gm) and sodamide (90 gm) at 25-30°C. The reaction mixture was stir for 30-35 hrs at 25-30°C, till it complies the reaction, quench the mixture into ice water, to separate two layers. The obtain toluene layer was washed with purified water (200 ml), dried with sodium sulphate (10 gm) and distilled out toluene completely under reduced pressure to get a residual product. The resultant residue was cool to 25-30°C, added acetone (500 ml) and adjusted reaction mixture pH to 1.0-2.0 with isopropanol hydrochloride solution (50 ml), stir for 30 min at 25-30°C. Obtain solid was filtered, washed with acetone (50 ml) and dried at 50-60°C to afford the title compound. Weight of the product: 85 gm
Example; 6
Process for the preparation of methyl-2-phenvl-2(pyridine-2-vD acetate;
To a mixture of methyl-2-phenyl acetate (100 gm) and hexanes (500 ml) into the R.B. flask, followed by addition of n-butyl lithium solution (100 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stir for 1-2 hrs at 0-5°C and added 2-chloropyrine (90 gm) and then raise the temperature to 25-30°C. The reaction mixture was stir for 10-12 hrs at 25-30°C, till it complies. The reaction mixture was quenched with ice water to separate layers. The obtain toluene layer was washed with purified water (200 ml), dried with sodiumsulphate and distilled out toluene completely under reduced pressure to get a residual product.
The resultant residue was cool to 25-30°C, added acetone (500 ml) and adjusted reaction mixture pH to 1.0-2.0 with isopropanol hydrochloride solution (50 ml), stir for 30 min at 25-30°C. Obtain solid was filtered, washed with acetone (50 ml) and dried at 50-60°C to afford the title compound.

Example; 7
Process for the preparation of methyl-2-phenyl-2(piperdine-2-vD acetate;
To a mixture of methyl-2-phenyl-2(pyridine-2-yl) acetate (100 gm) and acetic acid (500 ml) were taken into an autoclave, followed by addition of 10% Pd/C (20 gm) under nitrogen atmosphere at 25-30°C and feed hydrogen gas 0.5 kg/cm completely. The reaction mixture was raised to 60-65°C and allow to feed hydrogen gas for 5.0-6.0 kg/cm , stir for 10-15 hrs at same temperature, till it complies the reaction. The resultant mixture was cooled to 25-30°C, filter through hyflobed, and wash the hyflobed with purified water (100 ml).The obtain filtrate was cooled to 0-5°C, adjust the pH 9-10 with 50% sodium hydroxide solution at 0-10°C and stir for 40-60 min at 0-10°C. Out growth solid was filtered, wash with purified water (50 ml) and dried at 45-55°C for 10-12 hrs to afford a title compound. Weight of the compound: 70 gm
Example; 8
Process for the preparation of methyl-2-phenyl-2(piperdine-2-vD acetate;
To a mixture of methyl-2-phenyl-2(pyridine-2-yl) acetate (50 gm), acetic acid (250 ml) and methanol were taken into an autoclave, followed by addition of 10% palladium on carbon (10 gm) under nitrogen atmosphere at 25-30°C and feed hydrogen gas 0.5 kg/cm completely. The reaction mixture was raised to 60-65°C and allow to feed hydrogen gas for 5.0-6.0 kg/cm , stir for 10-15 hrs at same temperature, till it complies the reaction. The resultant mixture was cooled to 25-30°C, filter through hyflobed and wash the hyflobed with purified water (50 ml). The obtain filtrate was cooled to 0-5°C, adjust the pH 9.0-10.0 with 50% sodium hydroxide solution at 0-10°C and stir for 40-60 min at 0-10°C. Obtain solid was filtered, wash with purified water and dried at 45-55°C for 10-12 hrs to afford a title compound. Weight of the compound: 37 gm

Example; 9
Process for the preparation of 2-phenyl-2 (piperdine-2-yl) acetic acid
hydrochloride salt (Y±)-Ritalinic acid hydrochloride);
To a mixture of methyl-2-phenyl-2(piperidine-2-yl) acetate (100 gm) and methanol (500 ml) were taken into the RB.flask at 25-30°C, followed by addition of 50%w/w sodium hydroxide solution (100 gm) at below 40°C, allow to raise the temperature at 50 -60°C and maintain the same temperature for 4-6 hrs, till it complies the reaction. The resultant mixture was cooled to 25-30°C, adjust the pH to 6.0-7.0 with acetic acid (50 ml) at below 30°C. The obtain solid was filtered and washed with purified water (50 ml) to get a wet solid of Ritalinic acid base.
Ritalinic acid base is treated with hydrochloric acid (50 ml) in presence of toluene (500 ml) and heat it to 50-60°C for 1-2 hrs. The solvent in reaction mixture was distilled out completely under reduced pressure, followed by addition of acetone (500 ml) and stir for 30 min at 35-45°C. The resultant solid was filtered, washed with acetone (100 ml) and dried at 50-60°C for 10-12 hrs to afford a pure Ritalinic acid hydrochloride salt. Weight of the compound: 90 gm
Example; 10
Process for the preparation of 2-phenyl-2 (piperdine-2-yl) acetic acid
hydrochloride salt (Y±)-Ritalinic acid hydrochloride);
To a mixture of methyl-2-phenyl-2(piperidine-2-yl)acetate (200 gm) and purified water (600 ml) taken into the R.B. flask at 25-30°C, followed by addition of 50%w/w potassium hydroxide solution (150 ml) at below 40°C, allow to raise the mixture temperature at 50-60°C and maintain the same temperature for 4-6 hrs, till it complies the reaction. The resultant mixture was cooled to 25-30°C, adjust the pH to 6.0-7.0 with acetic acid (100 ml) at below 30°C. The obtain solid was filtered and washed with purified water (100 ml) to get a wet solid of Ritalinic acid base.

Ritalinic acid base is treated with hydrochloric acid (80 ml) in presence of isopropanol (450 ml) and heat it to 50-60°C for 30 min. The solvent in reaction mixture was distilled out completely under reduced pressure, followed by addition of isopropanol (400 ml) and stir for 30 min at 25-30°C. The resultant solid was filtered, washed with isopropanol (100 ml) and dried at 50-60°C for 10-12 hrs to afford a pure Ritalinic acid hydrochloride salt. Weight of the product: 180 gm.

1. An improved process for the preparation of (±)-Ritalinic acid hydrochloride of formula (I), which comprises
a) esterification of 2-phenylaceticacidin presence of methanol and catalyst to give methyl 2-phenylacetate (VII),
b) the product of step a) is reacted with 2-chloropyridine in presence of strong base and solvent to give methyl 2-phenyl-2-(pyridine-2-yl) acetate (V),
c) the product of step b) is converts into methylphenidate (VIII) in presence of reducing agent,
d) the product of step c) is hydrolyzed in presence of alkaline base and solvent, and
e) isolated (±)-Ritalinic acid hydrochloride (I).
2. An improved process for the preparation of methyl 2-phenyl-2-(pyridine-2-yl) acetate (V) comprising methyl 2-phenylacetate (VII) is reacted with 2-chloropyridine in presence of strong base and solvent to obtained a compound of formula (V).
3. The process as claimed in claim 1, wherein the catalyst is selected from, thionyl chloride, para toluenesulphonic acid (PTSA), hydrochloric acid and sulfuric acid.

4. The process as claimed in claim 1 and 2, wherein the suitable base is selected from strong bases such as potassium tert.butoxide, sodium tert.butoxide, sodium amide, n-butyl lithium; Alkaline base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide and barium hydroxide. Most preferably lithium hydroxide.
5. The process as claimed in claim 1 , wherein the reducing agent is selected from palladium carbon (Pd/C), sodiumborohydride, raney. nickel, lithium aluminum hydride, stannic chloride, iron powder, diisobutylaluminum hydride and diborane sodium amalgam. Most preferably Pd/C in presence of acetic acid as a solvent at 50-70°C.
6. The process as claimed in claim 1 and 2, wherein the solvent is selected from methanol, ethanol, hexane, isopropyl alcohol, acetone, toluene and acetic acid,