FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Armodafinil of Formula I

BACKGROUND OF THE INVENTION

Armodafinil is chemically known as 2-[(R)-(diphenylmethyl)sulfinyl]acetamide or 2-[(R)-(benzhydryl)sulfinyl]acetamide. Armodafinil is currently marketed by Cephalon, under the trade name Nuvigif®. Nuvigil® is indicated for the treatment excessive sleepiness associated with narcolepsy shift work sleep disorder (SWSD) and obstructive sleep apnea/hypopnea syndrome (OSA/HS).

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

In the above process the esterification step was carried out in water, which makes the reaction incomplete and gives low yield as the process does not involve recycling of unwanted isomer, S-modafinic acid.

US 7,057,068 B2 discloses a process for the preparation of modafmil, which comprises reacting the modafinic acid with a condensing agent selected from dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, N, N-carbonyl ditriazole and thereafter with ammonia.

US 2008/0214862 Al discloses a process for preparing racemic 2-[(diphenylmethyl)-sulfmyl|acetic acid, which comprises combining 2-[(R)-(diphenylmethyl)sulfinyl]acetic acid or 2-|(S)-(diphenylmethyl)sulfinyl]acetic acid, at least one organic solvent having a boiling point of above 60°C and heating to a temperature of above 60°C and cooling. The disadvantage of this process is that the quality of the recovered armodafinic acid is not meeting the required quality.

Organic Process Research & Development 2008, 12, 614-617, discloses a process for the raccmization of (S)-modafinic acid, which comprises the reduction of (S)-modafinic acid and then oxidation. The disadvantage of this process is use of costly reagents during reprocessing.

Indian Patent Application IN 943/MUM/2009 A, discloses a process for the preparation of armodafinil. The process is as shown below:

The disadvantage of this process is use of large quantity of solvents and poor yields.

The present inventors have now found an improved process for the preparation of Armodafinil of Formula I, which is very useful in the large scale synthesis, due to high yields.

The present inventors also found a process for the preparation of modafinic acid from recycling unwanted isomer of modafinic acid which also contains armodafinic acid, which is more cost effective than the reported processes.

OBJECTIVE OF THE INVENTION

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

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

In yet another objective of the present invention is to provide a process for the preparation of armodafinil having high purity from recycling unwanted 2-[(S)-(diphenylmethyl)-sulfinyl|acctic acid which also contains armodafinic acid.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Armodafinil of Formula I

which comprises:

a) reacting 2-[(R)-(diphenylmethyl)sulfinyl]acetic acid (armodafinic acid) of Formula
III,

with an activating agent in the presence of a methanol to give methyl ester of 2-|(R)-(diphenylmethyl)sulfinyl]acetate of Formula IV;

b) extracting the methyl ester of 2-[(R)-(diphenylmethyl)sulfinyl]acetate of Formula IV with water immiscible solvent in the presence of base;

c) amidating the methyl ester of 2-[(R)-(diphenylmethyl)sulfinyl]acetate of Formula IV with methanolic ammonia, optionally in the presence of solvent to give Armodafinil of Formula I; and

d) isolating the compound of Formula I.
In another embodiment, the present invention also relates to a process for the preparation of modafinic acid of Formula II,

which comprises:
a) reacting mother liquor of armodafinic acid containing predominantly S-isomer with an acid halide in an organic solvent to give diphenylmethyl halide of Formula IX; and

wherein X represents CI, Br or I

b) converting diphenylmethyl halide of Formula IX into modafinic acid of Formula II.

DEI AILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for preparing Armodafinil, which comprises, reacting armodafmic acid with an activating agent selected from dicyclohcxylcarbodiimide (DCC), N,N'-carbonyldiimidazole (CDI) in the presence of a solvent at a temperature between 0-60°C preferably at 25-40°C. After completion of the reaction the reaction mass is extracted with water immiscible solvent and separated the organic layer, concentrated at ambient pressure and a solvent is added to precipitate methyl ester of armodafmic acid, which is then treated with methanolic ammonia, optionally in the presence of solvent to give armodafinil.

In another embodiment, the present invention relates to a process for the preparation of armodafinil, which comprises reacting armodafmic acid with dicyclohexylcarbodiimide (DCC) in the presence of solvent at 10-40°C. To the reaction mass a polar aprotic solvent selected from M N'-dimcthylformamide, N,N'-dimethylacetamide, N-methylpyrrolidinone or a mixture thereof is added and the byproduct dicyclohexyl urea (DCU) is filtered off. Thereafter, the reaction mass is extracted from the filtrate by the addition of water immiscible solvent and the organic layer is washed with base to remove the unreacted acid. The separated organic layer is concentrated at ambient pressure and a solvent is added to precipitate methyl-2-[(R)-(diphenylmethyl)sulfmyl)]acetate.

In another embodiment, methyl-2-[(R)-(diphenylmethyl)sulfinyl)]acetate is treated with methanolic ammonia, optionally in presence of a solvent at 15-30°C, preferably 20-30°C.

The present invention also relates to a process for the preparation of modafinic acid from the mother liquor containing predominantly (S)-modafininc acid using an acid halide in a

solvent at a temperature 0-100°C, most preferably at 5-25°C to give diphenylmethyl halidc, which is thereupon treated with thiourea and chloroacetic acid to give modafinic acid, which is as shown below in the schematic diagram:

wherein predominantly means containing -75 % (S)-isomer; X is selected from CI, Br, I.

The modafinic acid is converted to armodafinic acid by using the prior-art process as shown below in the schematic diagram:

The water immiscible solvent used for the extraction during the reaction of methyl ester of armodafinic acid is selected from methyl acetate, ethyl acetate, butyl acetate, dichloromethane, dichlorocthane, chloroform, toluene, xylenes and mixture thereof.
1 he base is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, barium hydroxide, calcium hydroxide, triethylamine, diisopropylethylamine, pyridine, dimethylamine or a mixture thereof.

The solvent used to precipitate the methyl ester of armodafinic acid is selected from . hcxancs, heptanes, cyclohexane, diisopropylether, diethylether or tert-butylmethyl ester or a mixture thereof.

The solvent used in the preparation of armodafmil is selected from toluene, xylenes, ethyl acetate, methyl acetate, t-butyl acetate, diisopropyl ether, diethyl ether, t-butylmethyl ether, tctrahydrofuran, hexanes, cyclohexane, methylene chloride, ethylene chloride, chloroform or a mixture thereof; and water immiscible solvent is selected from ethyl acetate, butyl acetate, dichloromethane, dichloroethane, heptane, diisopropyl ether, diethyl ether, toluene, xylenes, cyclohexane, tert-butylmethyl ether or a mixture thereof.

The acid halidc is selected from acetyl chloride, propionyl chloride, butyryl chloride, valcryl chloride, hexanoyl chloride, acetyl bromide, propionyl bromide, butyryl bromide, mcthanesulfonyl chloride, p-toluenesulfonyl chloride or a mixture thereof.

The solvent used for the preparation of modafinic acid is selected from methylene chloride, ethylene chloride, chloroform, chlorobenzene, ethyl acetate, methyl acetate, butyl acetate, toluene, xylenes or a mixture thereof.

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

PREPARATION OF METHYL 2-[(R)-(DIPHENYLMETHYL)

SULFINYL] ACETATE

2-[(R)-(Diphenylmethyl)sulfinyl]acetic acid (15g) was suspended in methanol (75ml) at 10-15°C. Thereafter, a solution of dicyclohexylcarbodiimide (DCC, 11.85g in 15ml of methanol) was added at 10-40°C and stirred at 35-40°C temperature till completion of the reaction. Thereafter, the reaction mixture was diluted with N,N-dimethylacetamide (15ml) and cooled to 10-15°C. Remove the byproduct, DCU by filtration and concentrated the filtrate. The concentrated mass was diluted with methylene chloride and washed with aqueous sodium bicarbonate solution. The organic layer was concentrated at atmospheric pressure till the temperature reaches to 50-55°C. Thereafter, cyclohexane (75ml) was added and the distillation was continued till the reaction mass temperature reached 70-75°C. The resulting precipitate is cooled to 25-30°C. The solid was filtered and dried to afford methyl 2-[(R)-(diphenylmethyl)sulfinyl]acetate as white crystalline powder. Yield: 13.50g (85.65%) Chromatographic Purity (by HPLC): 99.58%

EXAMPLE 2

PREPARATION OF METHYL 2-[(R)-(DIPHENYLMETHYL)SULFINYL]-ACETATE

2-|(R)-(diphenylmethyl)sulfinyl]acetic acid (15g) was suspended in a mixture of acetone (45ml) and water (45ml). Aqueous sodium hydroxide (2.90g dissolved in 10ml of water) was added to dissolve the acid. Thereafter, sodium bicarbonate (10.12g) was added to the reaction mixture followed by dimethyl sulfate (15.18g). The reaction mixture was stirred at room temperature till completion of the reaction. Methylene chloride (30ml) and water (75 ml) were added to the reaction mixture and the layers were separated. The organic layer was washed with water. Thereafter, methylene chloride was removed partially by distillation and cyclohexane was added to the concentrated mass. Distillation was

continued till the reaction mass temperature reaches 67-71 °C. The concentrated mass was
cooled, filtered the solid and dried to afford methyl 2-[(R) -(diphenylmethyl)-
sulfinyl |acetate as white crystalline material.
Yield: 13g(85%)
Chromatographic Purity (by HPLC): 99.5%

EXAMPLE 3

PROCESS TO PREPARE 2-[(R)-(DIPHENYLMETHYL) SULFINYL]
ACETAMIDE [ARMODAFINIL]

Methyl 2-|(R)-(diphenylmethyl)sulfinyl]acetate (lOg) was suspended in a precooled mixture of methanol (20ml) and methanolic ammonia (38ml, 18-20%w/w) at 0-5°C. Thereafter, the temperature was raised to 20-25°C and stirring continued at this temperature till completion of the reaction. Thereafter, water (100ml) and cyclohexane (30ml) were added and stirred the suspension for 30 min at 20-25°C. The product was filtered, washed with water and dried to obtain armodafinil as white crystalline powder. Yield: 9g (94.9%)
Chromatographic Purity (by HPLC): 99.5% Chiral Purity: 99.9%; (S)-isomer: 0.1%

EXAMPLE 4

RECOVERY OF MODAFINIC ACID PREDOMINENTLY CONTAINING S-ISOMER

The mother liquor (10 It) obtained after isolation of 2-[(R)-(diphenylmethyl)-sulfinyl|acetic acid was acidified with hydrochloric acid to adjust the pH between 1.5-2.0 at 30-35°C. The resulting precipitate was stirred at this temperature for 30 min. The precipitate was filtered, washed with water and dried to afford modafinic acid predominantly containing S-isomer as white powder. Yield: 286g (90.40%)
Chromatographic purity (by HPLC): 99.55% Chiral Purity: 77.68% (S-isomer)

EXAMPLE 5

PREPARATION OF 2-[(DIPHENYLMETHYL)THIO]ACETIC ACID
2-|(S)-(diphcnylmcthyl)sulfinyl]acetic acid (30g) was suspended in methylene chloride (45ml) at 25-30°C and cooled to 10-15°C. Thereafter, acetyl chloride (18.70g) was added over a period of 30 min at 10-15°C and stirring was continued at this temperature till completion of the reaction. Thereafter, the resulting solution containing diphenylmethyl chloride was cooled to 0-5 °C and a solution of thiourea (9.70 g) in 20 ml water was added in 10 min at 0-15°C and the reaction mass is subjected to concentration at atmospheric pressure till the reaction mass temperature reaches 58-62°C. Thereafter, stirring was continued till completion of the reaction. The resulting isothiouronium hydrochloride salt was filtered and washed with water. The wet material (~30g) was suspended in water (230ml) and heated to 58-62°C. A solution of sodium hydroxide (16.30g of sodium hydroxide was dissolved in 32 ml of water) was added followed by an aqueous solution of chloroacctic acid (10.15g in 20 ml of water) at below 62°C.

Thereafter, the reaction mixture was stirred at this temperature till completion of the reaction. The reaction mass was cooled to 40-45°C and its pH was adjusted to 1.5-2.0 with hydrochloric acid. The resulting precipitate was filtered and washed with water. The wet material was heated with toluene (50 ml) for 30 min at 65-70°C. Thereafter, the suspension was cooled to 5-10°C and stirred for 30 min. The solid was filtered, washed with toluene and dried to afford 2-|(diphcnylmcthyl)thio|acetic acid as white crystalline powder. Yield: 22.5g (79.8%) Chromatographic purity (by HPLC): 99.90%

EXAMPLE 6

PREPARATION OF 2-[(DIPHENYLMETHYL)SULFINYL]ACETIC ACID

2-[(Diphenylmethyl)thiojacetic acid (60g) was dissolved in acetic acid (150ml) at 25-30°C and water (30ml) was added. A solution of 50% Hydrogen peroxide (18g) in water (30ml) was added to the reaction mixture over a period of 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 3% w/w aqueous solution of sodium metabisUlfite (100 ml).
Cyclohcxane (180ml) 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 afford the racemic
mixture of 2-[(diphenylmethyl)sulfinyl] acetic acid.
Yield: 60g (94%)
Chromatographic purity (by HPLC): 99.5%

EXAMPLE 7

PREPARATION OF 2-[(R)-(DIPHENYLMETHYL) SULFINYLJACETIC ACID
2-|(Diphenylmcthyl)sulfinyl]acetic acid (50g) was suspended in water (600ml) and (S)-a-bcnzylmcthylamine (24.30g) 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 Ih. The precipitated benzylmethyl amine salt of (R)-2-|(diphenylmethyl)sulfinyl]acetic acid was filtered and washed with water. Thereafter, the wet benzylmethyl amine salt of (R)-2-[(diphenylmethyl)sulfinyl]acetic acid was suspended in water (500 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 benzylmethyl amine salt of (R)-2-|(diphenylmethyl)sulfinyl [acetic acid 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: 17g (68%) Chiral Purity: 99.9%; (S)-isomer: 0.1%

EXAMPLE 8

PURIFICATION OF ARMODAFINIL
Armodafinil crude (5g) was suspended in a mixture of ethanol (35ml) and methanolic ammonia (1.25ml, 20% w/w) at 20-25°C and carbon (0.25g) was added and heated the suspension to reflux for 30 min and filtered the carbon, washed the residue with hot

cthanol (10ml). The filtrate was cooled to 25-30°C and continued stirring at this temperature for lh. Thereafter, the precipitate was cooled to 0-5°C and continued stirring at this temperature for 30 min. The precipitated product was filtered and washed with water followed by pre-cooled ethanol to afford armodafinil as white crystalline powder. Yield: 4.5g (90%)
Chromatographic purity (by HPLC): 99.8%

EXAMPLE 9

PURIFICATION OF ARMODAFINIL
Armodafinil crude (5g) and carbon (5g) were suspended in ethanol (50ml) at 20-25°C and heated the suspension to reflux for 30 min and filtered the carbon, washed the residue with hot cthanol (10ml). The filtrate was cooled to 25-30°C and continued stirring at this temperature for lh. Thereafter, the precipitate was cooled to 0-5°C and continued stirring at this temperature for 30 min. The precipitated product was filtered and washed with water followed by prc-cooled ethanol to afford armodafinil as white crystalline powder. Yield: 4.6g (90%) Chromatographic purity (by HPLC): 99.8%

WE CLAIM

1. An improved process for the preparation of Armodafinil of Formula I
which comprises:

a) reacting 2-|(R)-(diphenylmethyl)sulfinyl]acetic acid (armodafinic acid) of Formula III,
with an activating agent in the presence of methanol to give methyl ester of 2-[(R)-(diphenylmethyl)sulfinyl]acetate of Formula IV;

b) extracting the methyl ester of 2-[(R)-(diphenylmethyl)sulfinyl]acetate of Formula IV with water immiscible solvent in the presence of base;

c) amidating the methyl ester of 2-[(R)-(diphenylmethyl)sulfinyl]acetate of Formula IV with methanolic ammonia, optionally in the presence of solvent to give Armodafinil of Formula I; and

d) isolating the compound of Formula I.

2. The process as claimed in claim 1, wherein activating agent is selected from dicyclohexylcarbodiimide (DCC), A^iV-carbonyldiimidazole (CDI).

3. The process as claimed in claim 1, wherein water immiscible solvent used in step (b) lor the extraction is selected from methyl acetate, ethyl acetate, butyl acetate, dichloromcthane, dichloroethane, chloroform, toluene, xylenes and mixture thereof.

4. The process as claimed in claim 1, wherein base in step (b) is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, barium hydroxide, calcium hydroxide, triethylamine, diisopropylethylaminc, pyridine, dimethylamine or a mixture thereof.

5. The .process as claimed in claim 1, wherein the solvent used in step (C) is selected from toluene, xylenes, ethyl acetate, methyl acetate, t-butyl acetate, diisopropyl ether, diethyl ether, t-butylmethyl ether, tetrahydrofuran, hexanes, cyclohexane, methylene chloride, ethylene chloride, chloroform or a mixture thereof; and water immiscible solvent is selected from ethyl acetate, butyl acetate, dichloromethane, dichloroethane, heptane, diisopropyl ether, diethyl ether, toluene, xylenes, cyclohexane, tert-butylmethyl ether or a mixture thereof.

6. A process for the preparation of modafinic acid of Formula II,
which comprises:
a) reacting mother liquor of armodafinic acid containing predominantly S-isomer with
an acid halide in an organic solvent to give diphenylmethyl halide of Formula IX;
and
wherein X represents CI, Br or I b) converting diphenylmethyl halide of Formula IX into modafinic acid of Formula II.

7. The process as claimed in claim 7, wherein the acid halide is selected from acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, hexanoyl chloride, acetyl bromide, propionyl bromide, butyryl bromide, methanesulfonyl chloride, p-tolucncsulfonyl chloride or a mixture thereof.

8. The process as claimed in claim 7, wherein the solvent used for the preparation of modafmic acid is selected from methylene chloride, ethylene chloride, chloroform, chlorobcnzcne, ethyl acetate, methyl acetate, butyl acetate, toluene, xylenes or a mixture thereof.

9. The process as claimed in claim 1, where Armodafinil is prepared using the process as described in the examples.