FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Modafmil and its enantiomer of Formula I.

BACKGROUND OF THE INVENTION

Modafmil is chemically known as 2-[(diphenylmethyl)sulfinyl]acetarnide or 2-[(benzhydryl)sulfinyl]-acetamide. Modafmil is currently marketed by Cephalon, under the brand name Provigil® as a racemic mixture. Provigil® is indicated for the treatment of excessive sleepiness associated with narcolepsy shift work sleep disorder (SWSD) and obstructive sleep apnea/hypopnea syndrome (OSA/HS).

Armodafinil is chemically known as 2-[(R)-(diphenylmethyl)sulfinyl]acetamide or 2-[(R)-(benzhydryl)sulfinyl]-acetamide. Armodafinil is currently marketed by Cephalon, under the brand name Nuvigil®.

Modafinil was first disclosed in US 4,177,290. This patent discloses different methods to prepare modafmil. The processes are as shown below:

Process I:

By following the above methods the over oxidation product viz sulfone of Formula X is obtained, which is an impurity. This impurity cannot be easily removed from the pure modafinil product and obtaining lesser purity of the final product.

Armodafinil is first disclosed in US 4,927,855. This patent discloses a process for the preparation of Armodafinil, which is as shown below.

In the above process the esterification step was carried out in water, which makes the reaction incomplete and therefore the final product yields and purity are less.

Based on the aforementioned drawbacks, the prior art processes may be unsuitable for preparation of Modafinil and its enantiomer in commercial scale operations. A need remains for an improved and commercially viable process for preparing a pure compound Modafinil and its enantiomer substantially free of sulfone and other impurities.

We have now found an improved process for preparing Modafinil and its enantiomer of Formula I, substantially free of sulfone and other impurities, which is useful for commercial scale preparation.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the preparation of Modafinil and its enantiomer with high purity and good yield on commercial scale.

In yet another objective of the present invention is to provide a process for the preparation of Modafinil and its enantiomer, which is simple, industrially applicable and economically viable.

In yet another objective of the present invention is to provide an improved process for the preparation of methyl-2-[(diphenyl)sulfinyl] acetate and its enantiomer with high yield and high purity.

SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Modafinil and its enantiomer of Formula I,

which comprises:
a) reacting 2-[(diphenylmethyl)sulfinyl)]acetic acid (Modafinic acid) of Formula V,

with dimethylsulfate in the presence of base and aqueous organic solvent to give methyl-2-[(diphenylmethyl) sulfinyl)]acetate of Formula VI;

b) optionally, extracting the reaction mass containing methyl-2-[(diphenylmethyl)sulfinyl)]acetate of Formula VI with water and solvent;

c) optionally, crystallizing methyl-2-[(diphenylmethyl)sulfinyl)]acetate of Formula VI;

d) amidating rnethyl-2-[(diphenylmethyl)sulfinyl)]acetate of Formula VI with methanolic ammonia in the presence of a solvent;

e) adding water and solvent to the reaction mass; and

f) isolating the title compound.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Modafinil and its enantiomer, which comprises reacting 2-[(diphenylmethyl)sulfinyl]acetic acid of Formula V with dimethyl sulfate in presence of base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, alkali carbonate and bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate in aqueous organic solvent selected from acetone, ethylmethylketone, methylisobutylketone or a mixture thereof at a temperature of about 0-30°C. After completion of reaction, the reaction mass containing methyl-2-[(diphenylmethyl)sulfinyl]acetate of Formula VI is diluted with water and filtered the product.

The reaction mass containing methyl-2-[(diphenylmethyl)sulfinyl]acetate of Formula VI is optionally extracted into an organic solvent selected from methylene chloride, ethylene chloride, chloroform, ethyl acetate, butyl acetate, methyl acetate, toluene, xylenes or mixtures thereof. The organic layer is washed with water and concentrated at ambient pressure and the concentrated mass is dissolved in a solvent selected from heptane, cyclohexane, toluene, xylenes, diisopropylether, diethylether or tert-butylmethyl ester to precipitate the methyl-2-[(diphenylmethyl)sulfinyl]acetate of Formula VI.

Methyl-2-[(diphenylmethyl)sulfinyl]acetate of Formula VI is reacted with methanolic ammonia in the presence of a solvent selected from methanol, ethanol, toluene, xylenes, alkyl esters such as methyl acetate, ethyl acetate, ethers such as diethyl ether, tetrahydrofuran, hexanes, cyclohexane, methylene chloride, ethylene chloride, chloroform or mixtures thereof, at 5-30°C till complete conversion to Modafinil. The reaction mass containing Modafinil is diluted with water and water immiscible solvent selected from ethyl acetate, butyl acetate, dichloromethane, dichloroethane, heptane, diisopropyl ether, diehthyl ether, toluene, xylenes, cyclohexane, tert-butylmethyl ether or mixtures thereof and agitating the reaction mixture till complete crystallization of Modafinil at a temperature 15-30°C, preferably at 20-30°C.

The obtained Modafinil can be further purified by using alcohols selected from methanol, ethanol, isopropyl alcohol, water or mixtures thereof.

Methyl-2-[(diphenylmethyl)sulfinyl)]acetate of Formula VI obtained by the process described herein, has a chromatographic purity (Measure by HPLC) greater than 99% and the sulfone impurity less than 0.05%.

In another aspect of the present invention, the enantiomer of Modafinil herein described is Armodafinil of Formula II.

In another aspect of the present invention, the process to prepare Armodafinil, which comprises reacting 2-[(R)-(diphenylmethyl)sulfinyl]acetic acid of Formula XI with dimethyl sulfate in the presence of base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, alkali carbonate or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate in aqueous acetone at a temperature 0-30°C. After completion of reaction, the reaction mass containing methyl-2-[(R)-(diphenylmethyl)sulfinyl]acetate of Formula XII is diluted with water and the product is filtered.

The reaction mass containing methyl-2-[(R)-(diphenylmethyl)sulfinyl]acetate of Formula XII is optionally extracted into an organic solvent selected from methylene chloride, ethylene chloride, chloroform, ethyl acetate, butyl acetate, methyl acetate, toluene, xylenes or mixtures thereof. The organic layer is washed with water and concentrated at ambient pressure and the concentrated mass is dissolved in a solvent selected from heptane, cyclohexane, toluene, xylenes, diisopropylether, diethylether or tert-butylmethyl ester to precipitate methyl-2-[(R)-(diphenylmethyl)sulfinyl)]acetate of Formula XII.

Methyl-2-[(R)-(diphenylmethyl)sulfinyl] acetate of Formula XII is reacted with methanolic ammonia in presence of a solvent selected from methanol, ethanol, toluene, xylenes, alkyl esters such as methyl acetate, ethyl acetate, ethers such as diethyl ether, tetrahydrofuran, hexanes, cyclohexane, methylene chloride, ethylene chloride, chloroform or mixtures thereof, at 5-30°C to give Armodafinil. The reaction mass containing Armodafinil is diluted with water and water immiscible solvent selected from ethyl acetate, butyl acetate, dichloromethane, dichloroethane, heptane, diisopropyl ether, diethyl ether, toluene, xylenes, cyclohexane, tert-butylmethyl ether or mixtures thereof and agitating the reaction mixture till complete crystallization of Armodafinil at a temperature 15-30°C, preferably at 20-30°C.

Methyl-2-[(R)-(diphenylmethyl)sulfinyl)]acetate of Formula XII obtained by the process described herein, has a chromatographic purity (Measure by HPLC) greater than 99% and the sulfone impurity less than 0.05%.
The process to prepare modafinic acid of Formula V, which comprises, reacting 2-[(diphenyl)thio]acetic acid with a suitable oxidizing agent, selected from 50% hydrogen peroxide in acetic acid in the presence of a solvent, selected from water, methanol, butanol, ethanol, acetone, isopropyl alcohol, acetonitrile, methylisobutyl ketone, cyclohexane, toluene, xylenes, heptane, diisopropylether, diethylether, tert-butylmethylether, ethyl acetate, methyl acetate, butyl acetate or mixtures thereof, at 30-60°C, preferably at 40-50°C.

The process to prepare armodafinic acid of Formula XI,
which comprises,

i) reacting 2-[(diphenyl)thio]acetic acid of Formula VII with a suitable oxidizing agent, selected from 50% hydrogen peroxide in acetic acid in the presence of a solvent, selected from water, methanol, butanol, ethanol, acetone, isopropyl alcohol, acetonitrile, methylisobutyl ketone, cyclohexane, toluene, xylenes, heptane, diisopropylether, diethylether, tert-butylmethylether, ethyl acetate, methyl acetate, butyl acetate or mixtures thereof, at 30-60°C, preferably at 40-50°C to give modafinic acid of Formula V;
ii) reacting modafinic acid of Formula V with (S)-benzylmethylamine in water to give (S)-benzylmethylammonium(R)-2-[(diphenylmethyl)sulfinyl]acetate; and iii) neutralizing (S)-benzylmethylammonium (R)-2-[(diphenylmethyl)- sulfinyl]acetate with acid in water to give armodafinic acid of Formula XI.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE 1
PROCESS TO PREPARE 2-[(DIPHENYLMETHYL)SULFINYL]ACETIC
ACID

2-[(Diphenylmethyl)thio]acetic acid (lOOg) was dissolved in acetic acid (250 ml) at 25-30°C and water (50 ml) was added. Diluted the 50% Hydrogen peroxide (30.3lg) in water (100 ml) and this mixture was added to the reaction mixture over a period of about lh. Thereafter, the temperature of the reaction mass was raised to 40-45°C and continued stirring at this temperature to complete the conversion of sulfide into corresponding sulfoxide. Thereafter, the reaction mixture was quenched with aqueous solution of sodium metabisulfite. Cyclohexane (300 ml) was added to the resulting slurry and the suspension was stirred for about 30 min. The solid was filtered, washed with water and dried to yield the title compound as white crystalline powder. Yield: 93.3% Chromatographic Purity (by HPLC): 99.63%

EXAMPLE 2
PREPARATION OF METHYL 2-[(DIPHENYLMETHYL)SULFINYL]-ACETATE
2-[(diphenylmethyl)sulfinyl]acetic acid (20g) was added in a mixture of acetone (60 ml) and water (60 ml) and aqueous sodium hydroxide (3.17g dissolved in 10 ml of water) was added at 25-30°C. Thereafter, sodium bicarbonate (13.50g) was added to the reaction mixture followed by dimethylsulfate (20.23g). The reaction mixture was stirred at room temperature till completion of the reaction. Thereafter, cooled the reaction mass to 0-5°C and stirred for lh at this temperature. The solid was filtered and washed with aqueous acetone (20 ml, 2-5°C). The wet material was dissolved in a mixture of methylene chloride (25 ml) and cyclohexane (100 ml) at 55-60°C. The resulting solution was cooled to 25-30°C and stirred at this temperature for lh. Thereafter, cooled the slurry to 0-5°C and stirred for lh. The product was filtered, washed with cyclohexane (20 ml) and dried to afford the title compound as white crystalline powder. Yield: 90% Chromatographic Purity (by HPLC): 99.5%

EXAMPLE 3
PROCESS TO PREPARE 2-[(DIPHENYLMETHYL)SULFINYL]ACETAMIDE (MODAFINIL)
Methyl 2-[(diphenylmethyl)sulfinyl]acetate (100 g) was suspended in a cooled mixture of methanol (200 ml) and methanolic ammonia (335 ml, 18-20%w/w) at 0-5°C. Thereafter, the temperature was raised to 20-25°C and continued stirring at this temperature till completion of the reaction. Thereafter, water (1000 ml) was added followed by cyclohexane (300 ml) and the suspension was stirred for 30 min at 20-2 5 °C. The product was filtered, washed with water and dried to afford Modafinil. Yield: 94% Chromatographic Purity (by HPLC): 99.79%

EXAMPLE 4
PROCESS TO PREPARE 2-[(R)-(DIPHENYLMETHYL)SULFINYL]ACETIC ACID
2-[(Diphenylmethyl)sulfinyl]acetic acid (lOOg) was suspended in water (1200 ml) and (S)-benzylmethylamine (48.58g) was added at 25-30°C. The reaction mixture was heated to 80-85°C and continued stirring for 30 min. Thereafter, the temperature was brought to 55-60°C and stirred at this temperature for 30 min. The resulting precipitate was cooled to 35-40°C and stirred for lh. The precipitated (S)-benzylmethylammonium (R)-2-[(diphenylmethyl)sulfinyl]acetate was filtered and washed with water. Thereafter, the wet (S)-benzylmethylammonium (R)-2-[(diphenylmethyl)sulfinyl]acetate was suspended in water (1000 ml) and heated to dissolve at 80-85°C. The resulting solution was cooled to 55-60°C and stirred at this temperature for 30 min. Further, the resulting precipitate was cooled to 35-40°C and stirred for lh. The precipitated (S)-benzylmethylammonium (R)-2-[(diphenylmethyl)sulfinyl]acetate was filtered and washed with water. This wet material was suspended in water and pH was adjusted to 1.5-2.0 with hydrochloric acid to precipitate 2-[(R)-(Diphenylmethyl)sulfinyl]acetic acid. Yield: 36 gm
Chromatographic Purity (by HPLC): 99.30% Chiral Purity: 99.95

EXAMPLE 5
PREPARATION OF METHYL 2-[(R)-(DIPHENYLMETHYL)SULFINYL]-ACETATE
2-[(R)-(diphenylmethyl)sulfinyl]acetic acid (30g) was suspended in a mixture of acetone (90 ml) and water (90 ml). Aqueous sodium hydroxide (4.75g dissolved in 15 ml of water) was added to dissolve the acid. Thereafter, sodium bicarbonate (20.24g) was added to the reaction mixture followed by dimethylsulfate (30.35g). The reaction mixture was stirred at room temperature till completion of the reaction. Methylene chloride (60 ml) was added to the reaction mixture followed by water (150 ml) and the layers were separated. The organic layer was washed with water. Thereafter, methylene chloride removed partially and cyclohexane was added to the concentrated mass and distillation was continued till the reaction mass temperature reaches 67-71°C. The concentrated mass was cooled to afford methyl 2-[(R)-(diphenylmethyl)sulfinyl]acetate as white crystalline material. Yield: 86% Chromatographic Purity (by HPLC): 99.66%

EXAMPLE 6
PREPARATION OF METHYL 2-[(R)-(DIPHENYLMETHYL)SULFINYL]-ACETATE
2-[(R)-(diphenylmethyl)sulfinyl]acetic acid (30g) was suspended in a mixture of acetone (90 ml) and water (90 ml). Aqueous sodium hydroxide (4.75g dissolved in 15 ml of water) was added to dissolve the acid. Thereafter, sodium bicarbonate (20.24g) was added to the reaction mixture followed by dimethylsulfate (30.35g). The reaction mixture was stirred at room temperature till completion of the reaction. Cyclohexane (60 ml) was added to the reaction mass and stirred for 30 min at 25-30°C. The precipitate product was filtered, washed with water and dried to afford the title compound as white crystalline powder.
Yield: 95%
Chromatographic Purity (by HPLC): 98.76%

EXAMPLE 7
PREPARATION OF METHYL 2-[(R)-(DIPHENYLMETHYL)SULFINYL]-ACETATE
2- [(R)-(diphenylmethyl)sulfinyl] acetic acid (30g) was suspended in a mixture of acetone (90 ml) and water (90 ml). Aqueous sodium hydroxide (4.75g dissolved in 15 ml of water) was added to dissolve the acid. Thereafter, sodium bicarbonate (20.24g) was added to the reaction mixture followed by dimethylsulfate (30.35g).

The reaction mixture was stirred at room temperature till completion of the reaction. The precipitated solid was filtered, washed with water and dried to afford the title compound as white crystalline powder.
Yield: 95%
Chromatographic Purity (by HPLC): 98.23%

EXAMPLE 8
PURIFICATION OF 2-[(R)-(DIPHENYLMETHYL)SULFINYL]ACETATE
Methyl 2-[(R)-(diphenylmethyl)sulfinyl]acetate (20g), was dissolved in methylene chloride (25 ml) at 25-30°C and heated the solution to 40-45°C. Thereafter, cyclohexane (100 ml) was added and heated to 50-55°C. Cooled the contents to 5-10°C and stirred at this temperature for lh to complete the crystallization. Filtered the crystals, washed with cycohexane (25 ml) and dried to obtain the title compound Yield: 90% Chromatographic Purity (by HPLC): 99.8%

EXAMPLE 9
PURIFICATION OF 2-[(R)-(DIPHENYLMETHYL)SULFINYL] ACETATE
Methyl 2-[(R)-(diphenylmethyl)sulfinyl]acetate (20g) was dissolved in methylene chloride (25 ml) at 25-30°C and heated the solution to 40-45°C. Thereafter, cyclohexane (140 ml) was added and heated to distil about 50 ml of the distillate.
Cooled the contents to 5-10°C and continue stirring at this temperature for lh to complete the crystallization. Filtered the crystals, washed with cycohexane (25 ml) and dried to obtain the title compound Yield: 92% Chromatographic Purity (by HPLC): 99.56%

EXAMPLE 10
PROCESS TO PREPARE 2-[(R)-(DIPHENYLMETHYL)SULFINYL] ACETAMIDE [ARMODAFINIL]
Methyl 2-[(R)-(diphenylmethyl)sulfinyl]acetate (25 g) was suspended in a cooled mixture of methanol (50 ml) and methanolic ammonia (84 ml, 18-20%w/w) at 0-5°C. Thereafter, temperature was raised to 20-25°C and stirred at this temperature till completion of the reaction. Thereafter, water (250 ml) was added followed by cyclohexane (75 ml) and stirred the suspension for 30 min at 20-25°C. The solid was filtered, washed with water and dried to afford armodafinil. Yield: 95% Chromatographic Purity (by HPLC): 98.85%

EXAMPLE 11
PROCESS TO PREPARE 2-[(R)-(DIPHENYLMETHYL)SULFINYL] ACETAMIDE [ARMODAFINIL]
Methyl 2-[(R)-(diphenylmethyl)sulfinyl]acetate (5 g) was suspended in a cooled mixture of methanol (10 ml), cyclohexane (10 ml) and methanolic ammonia (16.80 ml, 18-20%w/w) at 0-5°C. Thereafter, temperature was raised to 20-25°C and stirred at this temperature till completion of the reaction. Thereafter, water (50 ml) was added and stirred the suspension for 30 min at 20-25°C. The solid was filtered, washed with water and dried to afford armodafinil. Yield: 87% Chromatographic Purity (by HPLC): 99.66%

EXAMPLE 12
PROCESS TO PREPARE 2-[(R)-(DIPHENYLMETHYL)SULFINYL] ACETAMIDE [ARMODAFINIL]
Methyl 2-[(R)-(diphenylmethyl)sulfinyl]acetate (5 g) was suspended in a cooled mixture of methanol (10 ml), toluene (10 ml) and methanolic ammonia (16.80 ml, 18-20%w/w) at 0-5°C. Thereafter, temperature was raised to 20-25°C and stirred at this temperature till completion of the reaction. Thereafter, water (50 ml) was added and stirred the suspension for 30 min at 20-25°C. The solid was filtered, washed with water and dried to afford armodafinil. Yield: 89% Chromatographic Purity (by HPLC): 99.61%

WE CLAIM

1) An improved process for the preparation of Modafinil and its enantiomer of Formula I,

which comprises:

a) reacting 2-[(diphenylmethyl)sulfinyl)] acetic acid of Formula V,

with dimethylsulfate in the presence of base and aqueous organic solvent to give methyl-2-[(diphenylmethyl)sulfinyl)]acetate of Formula VI;

b) optionally, extracting the reaction mass containing methyl-2-[(diphenylmethyl)sulfinyl)]acetate of Formula VI, with water and solvent;

c) optionally, crystallizing methyl-2-[(diphenylmethyl)sulfinyl)]acetate of Formula VI;

d) amidating methyl-2-[(diphenylmethyl)sulfinyl)]acetate of Formula VI with methanolic ammonia in the presence of a solvent;

e) adding water and solvent to the reaction mass; and

f) isolating the title compound.

2) The process according to claim 1, wherein the base used in step (a) is selected from alkali or alkaline metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, alkoxides such as sodium methoxide, sodium ethoxide, carbonates and bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.

3) The process according to claim 1, wherein the organic solvent used in step (a) is selected from acetone, ethylmethylketone, methylisobutylketone or mixtures thereof.

4) The process according to claim 1, wherein the solvent used in step (b) is selected from methylene chloride, ethylene chloride, chloroform, ethyl acetate, butyl acetate, methyl acetate, toluene, xylenes or mixtures thereof.

5) The process according to claim 1, crystallization of methyl-2-[(diphenylmethyl)sulfinyl)]acetate comprises:

a) washing the organic layer containing methyl-2-[(diphenylmethyl)sulfinyl)] acetate with water and concentrating at ambient temperature; and

b) the residue obtained in step (a) is dissolved in a solvent selected from heptane, cyclohexane, toluene, xylenes, diisopropylether, diethylether, tert-butylmethyl ester, to precipitate the methyl-2-[(diphenylmethyl)sulfinyl)]acetate.

6) The process according to claim 1, wherein the solvent used in step (d) is selected from methanol, ethanol, toluene, xylenes, alkyl esters such as methyl acetate, ethyl acetate; ethers such as diethyl ether, tetrahydrofuran; hexanes,
cyclohexane, methylene chloride, ethylene chloride, chloroform or mixtures thereof.

7) The process according to claim 1, wherein the solvent used in step (e) is selected from ethyl acetate, butyl acetate, dichloromethane, dichloroethane, heptane, diisopropyl ether, diethyl ether, toluene, xylenes, cyclohexane, tert-
butylmethyl ether or mixtures thereof.

8) The process according to claim 1, wherein the enantiomer is Armodafinil of Formula II.

9) An improved process for the preparation of Modafinil and its enantiomer of Formula I as described in claim 1, substantially as herein described with reference to the examples.