Field of the Invention:

The present invention relates to an improved process for the preparation of Armodafinil with high purity and high yield. The present invention also relates to preparation of Armodafinil polymorphic Form-1 with a particle size of above 200|am by direct crystallization.

Background of the Invention:

The R enantiomer of modafinil is known as armodafinil and has the chemical name 2-[(R)-(diphenylmethyl)sulfinyl]acetamide and structurally represented as below.

Armodafinil was first disclosed in US 4927855 patent and marketed under the brand name of NUVIGIL® and it is indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD).

The preparation of armodafinil is also disclosed in the '855 patent, and it is summarized in the following scheme:

The process disclosed in the '855 patent uses (-) alpha-methylbenzylamine in the resolution step. Furthermore, two additional crystallization steps are performed in order to increase the enantiomeric purity of the modafinic acid. As a consequence, the overall yield reported in the US'855 patent is rather unsatisfactory.

U.S. Pat. No. 7,132,570 describes polymorphic Form I of armodafinil, a process for its preparation and a pharmaceutical composition comprising crystalline Form I of armodafinil.

The inventors of the present of invention have developed an alternate improved process for the preparation of Armodafinil with high yield and purity. The present process is feasible in large scale production also.

Summary of the present Invention:

One aspect of the present invention is to provide a process for the preparation of Armodafinil comprising the steps of:

a) reacting benzydrol with thioglycolic acid in dichloromethane or toluene and catalytic amount of methane sulfonic acid to get the (Benzhydrylsulfanyl) acetic acid,

b) oxidizing the (Benzhydrylsulfanyl) acetic acid with hydrogen peroxide/sodium carbonate and catalytical amount of ammonium molybdate in methanol to obtain the (±) - (Diphenylmethanesulfinyl) acetic acid, or

c) oxidizing the (Benzhydrylsulfanyl) acetic acid with urea hydrogen peroxide complex in methanol to obtain the (±) - (Diphenylmethanesulfinyl) acetic acid,

d) reacting (±) - (Diphenylmethanesulfinyl) acetic acid with (S)-(-)-cc-methylbenzylamine in water to obtain the levorotatory or (-) isomer of (R)-(-)- (Diphenylmethanesulfinyl) acetic acid (-)-ct-methylbenzylamine salt crude compound,

e) crude compound was recrystallized from water to obtain the pure compound with free of (+) isomer.

f) (R)-(-) - (Diphenylmethanesulfinyl) acetic acid (-)-ot-methylbenzylamine salt compound was neutralized with hydrochloric acid in water to obtain the ( R )-(-)-(Diphenylmethanesulfinyl) acetic acid crude compound,

g) crude compound was recrystalized from isopropyl alcohol to get pure compound,

h) esterifiying of the (R) - (-) - (Diphenylmethanesulfinyl) acetic acid with methyl iodide in presence of a base in solvent at low temperature to get methyl (R) - (-) - (Diphenylmethanesulfinyl) acetate crude compound, i) crude compound was recrystallized from isopropyl alcohol to get the pure compound, j) amidification of the methyl (R)-(-) - (Diphenylmethanesulfinyl) acetate with aqueous ammonia in presence of catalyst to obtain the Armodafinil and recrystallized from water to obtain the pure compound,

k) crystallization of armodafinil in neat isopropyl alcohol or aqueous isopropyl alcohol and water, to obtain the pure crystalline anhydrous product.

In another aspect of the present invention relates to a process for the preparation of armodafinil polymorphic form I with particle size d90 is less than 200 microns, d50 is less than 60microns and dlO is less than lOmicrons comprising direct recrystallization of armodafinil in neat isopropyl alcohol or aqueous isopropyl alcohol and water.

Yet another aspect of the present invention relates to an armodafinil polymorphic form I with particle size d90 is less than 200 microns, d50 is less than 60microns and dlO is less than lOmicrons. .

The present invention is shown in below scheme.

Detailed description of the Invention:

The present invention relates to an improved process for the preparation of Armodafinil, wherein benzydrol is reacted with thioglycolic acid to get the (Benzhydrylsulfanyl) acetic acid,

oxidizing this compound to get the (±) - (Diphenylmethanesulfinyl) acetic acid, reacting this compound with (S)-(-)-ot-methylbenzylamine to get the corresponding salt and neutralized with hydrochloric acid, recrystallized from isopropyl alcohol, esterifying the resulted compound with methyl iodide to get methyl (R) - (-) - (Diphenylmethanesulfinyl) acetate, amidification of this compound with aqueous ammonia to get armodafinil further it was recrystallized to obtain pure armodafinil.

One embodiment of the present invention is to provide a process for the preparation of Armodafinil comprising the steps of:

a) reacting benzydrol with thioglycolic acid in dichloromethane or toluene and catalytic amount of methane sulfonic acid to get the (Benzhydrylsulfanyl) acetic acid,

b) oxidizing the (Benzhydrylsulfanyl) acetic acid with hydrogen peroxide/sodium carbonate and catalytical amount of ammonium molybdate in methanol to obtain the (±) - (Diphenylmethanesulfinyl) acetic acid, or

c) oxidizing the (Benzhydrylsulfanyl) acetic acid with urea hydrogen peroxide complex in methanol to obtain the (±) - (Diphenylmethanesulfinyl) acetic acid,

d) reacting (±) - (Diphenylmethanesulfinyl) acetic acid with (S)-(-)-a-methylbenzylamine in water to obtain the levorotatory or (-) isomer of (R)-(-)- (Diphenylmethanesulfinyl) acetic acid (-)-ct-methylbenzylamine salt crude compound,

e) crude compound was recrystallized from water to obtain the pure compound with free of (+) isomer.

f) (R)-(-) - (Diphenylmethanesulfinyl) acetic acid (-)-a-methylbenzylamine salt compound was neutralized with hydrochloric acid in water to obtain the ( R )-(-)-(Diphenylmethanesulfinyl) acetic acid crude compound,

g) crude compound was recrystallized from isopropyl alcohol to get pure compound,

h) esterifying of the (R) - (-) - (Diphenylmethanesulfinyl) acetic acid with methyl iodide in presence of a base in solvent at low temperature to get methyl (R) - (-) - (Diphenylmethanesulfinyl) acetate crude compound, i) crude compound was recrystallized from isopropyl alcohol to get the pure compound, j) amidification of the methyl (R)-(-) - (Diphenylmethanesulfinyl) acetate with aqueous.

ammonia in presence of catalyst to obtain the Armodafinil and recrystallized from water to obtain the pure compound,

k) crystallization of armodafinil in neat isopropyl alcohol or aqueous isopropyl alcohol and water, to obtain the crystalline anhydrous product.

According to the present invention, benzhydrol is reacted with thioglycolic acid in dichloromethane or toluene solvent and catalytic amount of methane sulfonic acid to get the (Benzhydrylsulfanyl) acetic acid, further it is reacted with hydrogen peroxide in methanol and with catalytic amount of ammonium molybdate and sodium carbonate to get the (±) -(Diphenylmethanesulfinyl) acetic acid. In other way (Benzhydrylsulfanyl) acetic acid is reacted with urea hydrogen peroxide complex to get the (±) - (Diphenylmethanesulfinyl) acetic acid. (±) - (Diphenylmethanesulfinyl) acetic acid is reacted with (S)-(-)-ot-methylbenzylamine in water to obtain the levorotatory or (-) isomer of (R)-(-)- (Diphenylmethanesulfinyl) acetic acid (-)-a-methylbenzylamine salt crude compound and crude compound was recrystallized from water to obtain the pure compound with free of (+) isomer. The amount of (S)-(-)-ot-methylbenzylamine should be sufficient to obtain the enantiomerically enriched product. Preferably, the amount of (S)-(-)-a-methylbenzylamine is at least about 0.90 equivalents. Preferably, the (S)-(-)-a-methylbenzylamine is present about 0.90 to 1.50 equivalents to the racemic modafinic acid and more preferably, the (S)-(-)-a-methylbenzylamine is present in an amount of about l.lOequivalents. the crystallization is done in the presence of water by following the slow crystallization, mass temperature was cooled to 62.5±2.5°C in 60-90 min, and mass temperature was cooled to 52.5±2.5°C in 150-180 min further mass temperature was cooled to 32.5±2.5°C in 150-180 min maintained the mass temperature at 32.5±2.5°C for 60-90 min.

(R)-(-)- (Diphenylmethanesulfinyl) acetic acid (-)-cx-methylbenzylamine salt is reacted with hydrochloric acid maintaining the reaction mass temperature at 27.5±2.5°C after completion of reaction, mass is washed the with water and crystalized from isopropyl alcohol to get to obtain the (R)-(-)- (Diphenylmethanesulfinyl) acetic acid.

(R)-(-)- (Diphenylmethanesulfinyl) acetic acid is reacted with methyl iodide in presence of a base selected form sodium carbonate, ammonium carbonate, potassium carbonate calcium carbonate, preferably potassium carbonate in solvent selected from acetone, dimethylformamide, methylethyl ketone, preferably the solvent is dimethylformamide at low temperature to get methyl (R) - (-) - (Diphenylmethanesulfinyl) acetate crude compound and recrystallized from solvent, recrystallization solvent selected from methanol, isopropyl alcohol, acetone, acetonitrile, toluene, more preferably, isopropyl alcohol.

methyl (R) - (-) - (Diphenylmethanesulfinyl) acetate is reacted with aqueous ammonia in presence of catalyst selected from ammonium chloride, potassium chloride, calcium chloride. Preferably, the catalyst is ammonium chloride to obtain armodafinil. Armodafinil crude compound recrystallized from solvent selected from methanol, isopropyl alcohol, acetone, acetonitrile, ethyl acetate, and water more preferably, water. Further it was recrystallized from isopropyl alcohol or aqueous isopropyl alcohol and water, to obtain the crystalline armodafinil form I.

Another embodiment of the present invention relates to a process for the preparation of armodafinil polymorphic form I with particle size d90 is less than 200 microns, d50 is less than 60microns and dlO is less than lOmicrons comprising direct recrystallization of armodafinil in neat isopropyl alcohol or aqueous isopropyl alcohol and water.

Yet another embodiment of the present invention relates to an armodafinil polymorphic form I with particle size d90 is less than 200 microns, d50 is less than 60microns and dlO is less than lOmicrons.

Advantages of the present process:

1. Present process provides elimination of usage of expensive reagent/solvent such as trifluoroacetic acid.

2. The present invention also provides a novel method of sulfoxidation of Benzahydrolthioacetic acid using hydrogen peroxide and a percatalyst which enables, completion of the reaction in 2 hours rather than 2-3 days as mentioned in the prior art.

Brief Description of drawings:

• Figure 1: Powder X Ray Diffractogram for crystalline anhydrous polymorphic form -I armodafinil of the present invention recrystallization from isopropyl alcohol.

• Figure 2: Particle size histogram for novel particle size crystalline anhydrous polymorphic form - I armodafinil of the present invention recrystallization from isopropyl alcohol.

• Figure 3: DSC thermogram for crystalline anhydrous polymorphic form -1 armodafinil of the present invention recrystallization from isopropyl alcohol.

• Figure 4: Powder X Ray Diffractogram for crystalline anhydrous polymorphic form -I armodafinil of the present invention recrystallization from water.

• Figure 5: Particle size histogram for novel particle size crystalline anhydrous polymorphic form -1 armodafinil of the present invention recrystallization from water.

• Figure 6: DSC thermogram for crystalline anhydrous polymorphic form -1 armodafinil of the present invention recrystallization from water.

The following examples are provided for illustration purpose only and are not intended to limit the scope of invention.

EXPERIMENTAL SECTION:

Example -1: Preparation of (Benzhydrylsulfanyl) acetic acid

To a stirred solution of 600 g of trifluoroacetic acid and 200 g (1.087 mol) of benzhydrol was added 113 g (0.981 mol) of thioglycolic acid at 25 to 30°C. The solution was further stirred at 25 to 30°C for 3 hours. Solid was filtered and washed with 200 ml of water. To a stirred suspension mass of 3000 ml of water and wet compound and mass pH was adjusted to 13.5 with 130 ml of caustic soda lye solution at 25 to 30°C. Solution was treated with carbon (20 g) at 45 to 50°C. Carbon was filtered and pH was adjusted to 1.5 with 210 ml of concentrated hydrochloric acid at 25 to 30°C. Mass was further stirred for 1 hour. Solid was filtered and washed with 400 ml of water. Compound was dried at 55 to 60°C to give 230-g (yield: 85.22%) with purity by HPLC: 99.9%.

Example: 1A: Preparation of (Benzhydrylsulfanyl) acetic acid

To a stirred solution of 100 ml of methylene chloride and 10 g (0.054 mol) of benzhydrol was added 6.88 g (0.059 mol) of thioglycolic acid and 0.20 g (2.0 mmol) of methane sulfonic acid. Temperature was raised to reflux by azetropically. Separated water collected by distillation of methylene chloride. Reaction was monitored for benzhydrol absence of by TLC. Methylene chloride was completely distilled off under vacuum and mass was cooled to 25 to 30°C. 100 ml of water was added to reaction mass. Solid was filtered and dried at 55 to 60°C to give 13.5 g (yield: 96.4 %). Purity by HPLC: 96.1%. To a suspended mass 150 ml of water and 13 g of crude and mass pH was adjusted to 13.5 with 65 ml of caustic soda lye solution at 30 to 35°C. The solution was further treated with carbon and mass pH was adjusted to 1.5 with 10.5 ml of concentrated hydrochloric acid. Solid was filtered and dried at 55 to 60°C to give 11.8 g (yield: 84.1%) with purity by HPLC: 99.78 %.

Example-IB: Preparation of (Benzhydrylsulfanyl) acetic acid

To a stirred a mass of 100 ml of toluene and 10 g (0.054mol) of benzhydrol was added 6.88 g (0.059 mol) of thioglycolic acid, 0.2 g (2.0 mmol) of methane sulfonic acid. Temperature was raised to reflux by azetropically. Separated water from reaction collected by azeotropically reflux. Reaction was monitored for benzhydrol absence by TLC. The toluene was removed by distilled under vacuum at 90°C. Cooled to 25 to 30°C and 100 ml of water was added and further stirred for 45 min. Solid was filtered and dried at 55 to 60°C to give 13.40g with purity by HPLC: 97.30 %. To a suspended mass in 150 ml of water and 13 g of crude. Mass pH was adjusted to 13.5 with 65 ml of caustic soda lye solution at 30 to 35°C, and solution was treated with carbon. The solution pH was adjusted to 1.5 with 10.5 ml of concentrated hydrochloric acid at 30 to 35°C. Solid was filtered and dried at 55 to 60 °C to give 11.60 g (yield: 84.16%) with purity by HPLC: 99.78 %.

Example-2: Preparation of (±) - (Diphenylmethanesulfinyl) acetic acid

To a stirred solution of 500 ml of methanol and 100 g (0.387 mol) of (benzhydrylsulfanyl) acetic acid was cooled to 10 to 15°C and 1.0 g (0.81mmol) of ammonium molybdate tetrahydrate was dissolved 5.0 ml of water and this solution was added to the reaction mass. 2 g (0.019 mol) of sodium carbonate was added. 28 g (0.387 mol) of hydrogen peroxide (chemical assay: 47.1 % w/w) was added and the solution was further stirred at 10 to 15°C for 2 hours. Reaction was monitored for absence of (benzhydrylsulfanyl) acetic acid by TLC. Sodium thio sulphate solution [2.0 g (8.0 rrimol) of sodium thiosulphate pent hydrate was dissolved in 5.0 ml of water] was added to reaction mass at 10 to 15°C. Reaction mass was added to 5.0 L of water and mass was further stirred for 2 hour. Solid was filtered and was dried at 55 to 60°C to give 98.0 g of crude purity by HPLC is 97.5%. To a suspended mass of 900 ml of ethyl acetate and 98 g of crude mass temperature was raised to reflux and further stirred at reflux for 1 hour. Cooled to 25-30°C and further stirred for 1 hour. Solid was filtered and dried at 50 to 55°C to give 88 g (yield: 83.0 %) with HPLC purity 99.6%.

Example-2A: Preparation of (±) - (Diphenylmethanesulfinyl) acetic acid

To a stirred solution of 50 ml of methanol and 10 g (0.038 mol) of (benzhydrylsulfanyl) acetic acid was added 11.4 g (0.043 mol) of urea-hydrogen peroxide complex (chemical assay: 35.0 % w/w) solution [11.4 g urea-hydrogen peroxide complex was dissolved in 25ml of methanol and 7.5 ml of water mixed solution] at 10 to 15°C. Reaction was monitored for absence of (benzhydrylsulfanyl) acetic acid by TLC. Reaction mass was added to 500 ml of water at 10 to 15°C and the mass was further stirred for 2 hours. Solid was filtered and dried at 55 to 60°C to give 8.80 g crude. To a suspended mass of 90 ml of ethyl acetate and 8.70 g of crude mass was heated to reflux and further stirred for 1 hour. Mass was cooled to 25 to 30°C and further stirred for 1 hour. Solid was filtered and dried at 50 to 55°C to give 6.30 g (yield: 59.3%).

Example: 3: Preparation of (R)-(-) - (Diphenylmethanesulfinyl) acetic acid (-)-<*-methylbenzylamine salt monohydrate

To a suspended mass of 1800 ml of water and 100 g (0.365 mol) of (±) -(diphenylmethanesulfinyl) acetic acid was added 48.8 g (0.403 mol) of (S)-(-)-a-methylbenzylamine at 25-30°C for 30-45 min. Mass was heated to reflux and further stirred at reflux for 1 hour. Cooled to 50-55°C and further stirred for 3 hours. Cooled to 30-35°C and it was further stirred for 3 hour. Solid was filtered and suspended in 1100 ml of water. Raised to reflux and further stirred for 1 hour. The mass was further cooled to 30-35°C and stirred the mass for 1 hour. Solid was filtered and dried at 55-60°C to give 62 g (yield: 82.27%) with purity by HPLC: 99.9%. S (+) enantiomer content is 0.04%.

Example-4: Preparation of (R)-(-) - (Diphenylmethanesulfinyl) acetic acid

To a suspended mass in 2000 ml of water and 100 g of (R)-(-)- (diphenylmethanesulfinyl) acetic acid (-)-a-methylbenzylamine salt monohydrate and mass pH was adjusted to 1.5 with hydrochloric acid at 25-30°C. The mass was further stirred for 2 hours and solid was filtered and washed with 200 ml of water. Wet compound was dried at 50-55°C to give 65 g crude. 65 g of crude mass was suspended in 550 ml of isopropyl alcohol and heated to reflux. The mass was cooled to 25-30°C and stirred for 1 hour. The mass was further cooled to 0-5°C and stirred for 1 hour. Solid was filtered and dried at 50-55°C to give 63 g (yield: 95.0%) with purity by . HPLC: 99.7%.

Example- 5: Preparation of Methyl (R)-(-) - (Diphenylmethanesulfinyl) acetate

To a suspension solution of 240 ml of dimethylformamide and 50 g (0.182 mol) of (R)-(-)-(Diphenylmethanesulfinyl) acetic acid was added 39.0 g (0.274 mol) of methyl iodide at 25-30°C and 28 g (0.202 mol) of potassium carbonate and further stirred for 5 hours. Reaction mass was added to 3600 ml of water at 25-30°C. Cooled to 5-10°C and stirred for 1 hour. Solid was filtered and dried at 50-55°C to give 51 g crude. 51 g of crude was suspended in 250 ml of isopropyl alcohol and heated to reflux. Stirred the mass at reflux for 1 hour. Mass was cooled to 25-30°C and stirred for 1 hour. Mass was further cooled to 0-5°C and stirred for 2 hours.

Solid was filtered and dried at 50 to 55°C to give 49 g (yield: 94 %) with purity by HPLC: 99.8%.

Example: 6: Preparation of (R)-(-) - [2-(Diphenyl) methanesulfinyl) acetamide.

To a suspended mass of 1200 g of ammonia liquid (Chemical assay: 23.0%w/w) and 75 g (0.260 mol) of methyl (R)-(-) - (diphenylmethanesulfinyl) acetate was added 17.0 g (0.318 mol) of ammonium chloride at 27.5±2.5°C and further stirred for 5 hours. Reaction was monitored for absence of methyl (R)-(-) - (diphenylmethanesulfinyl) acetate by HPLC. 1200.0 ml of water was added and stirred the mass for 1 hour. Solid was filtered and washed with 250 ml of water. Wet compound was twice recrystallized form water to give 56 g (yield: 78.87%) with purity by HPLC: 99.87%.

Example- 7: Recrystallization of (R)-(-) - [2-(Diphenyl) methanesulfinyl) acetamide [Armodafinil]

50 g of (R)-(-) - [2-(Diphenyl) methanesulfinyl) acetamide was suspended in 1000 ml of isopropyl alcohol and heated to 70 to 75°C. The Solution was filtered through micro filter and solution was cooled to 50-55°C. Mass temperature was Cooled to 44±2.0°C in 60-75 min. Mass temperature was cooled to 35 ±2.5°C in 60-75 min. Mass temperature was cooled to 20 ±2.5°C in 60-75 min. Maintained the mass temperature at 20±2.5°C for 240-270 min. Solid was filtered and washed with 30 ml of isopropyl alcohol. Wet compound was dried at 50-55°C under vacuum to give 45.0g (yield: 90.0 %) of Armodafinil.

We Claim:

1. A process for the preparation of Armodafinil comprising the steps of:

a) reacting benzydrol with thioglycolic acid in dichloromethane or toluene and catalytic amount of methane sulfonic acid to get the (Benzhydrylsulfanyl) acetic acid,

b) oxidizing the (Benzhydrylsulfanyl) acetic acid with hydrogen peroxide/sodium carbonate and catalytical amount of ammonium molybdate in methanol to obtain the (±) - (Diphenylmethanesulfinyl) acetic acid, or

c) oxidizing the (Benzhydrylsulfanyl) acetic acid with urea hydrogen peroxide complex in methanol to obtain the (±) - (Diphenylmethanesulfinyl) acetic acid,

d) reacting (±) - (Diphenylmethanesulfinyl) acetic acid with (S)-(-)-ct-methylbenzylamine in water to obtain the levorotatory or (-) isomer of (R)-(-)-(Diphenylmethanesulfinyl) acetic acid (-)-ct-methylbenzylamine salt crude compound,
e) crude compound was recrystallized from water to obtain the pure compound with free of (+) isomer.

f) (R)-(-) - (Diphenylmethanesulfinyl) acetic acid (-)-a-methylbenzylamine salt compound was neutralized with hydrochloric acid in water to obtain the (R )-(-)-(Diphenylmethanesulfinyl) acetic acid crude compound,

g) crude compound was recrystallized from isopropyl alcohol to get pure compound,
h) esterifying of the (R) - (-) - (Diphenylmethanesulfinyl) acetic acid with methyl
iodide in presence of a base in solvent at low temperature to get methyl (R) - (-) -
(Diphenylmethanesulfinyl) acetate crude compound, i) crude compound was recrystallized from isopropyl alcohol to get the pure compound, j) amidification of the methyl (R)-(-) - (Diphenylmethanesulfinyl) acetate with aqueous ammonia in presence of catalyst to obtain the Armodafinil and recrystallized from water to obtain the pure compound, k) crystallization of armodafinil in neat isopropyl alcohol or aqueous isopropyl alcohol and water, to obtain the pure crystalline anhydrous product.

2. The process according to claim 1, wherein base used in step h) is selected form sodium carbonate, ammonium carbonate, potassium carbonate calcium carbonate.

3. The process according to claim 1, wherein solvent used in step h) is selected from acetone, dimethylformamide, methylethyl ketone.

4. The process according to claim 1, wherein catalyst used in step j) is selected from ammonium chloride, potassium chloride, calcium chloride.

5. A process for the preparation of armodafinil polymorphic form I with particle size d90 is less than 200 microns, d50 is less than 60microns and dlO is less than lOmicrons comprising direct recrystallization of armodafinil in neat isopropyl alcohol or aqueous isopropyl alcohol and water.
6. Armodafinil polymorphic form I with particle size d90 is less than 200 microns, d50 is less than 60microns and dlO is less than lOmicrons.