Claims:1. An improved process for the preparation of armodafinil comprising the steps of:
(i) converting diphenylmethane into sulfonyl chloride compound of formula (II)

in presence of sulfuryl chloride and organolithium reagent in inert solvent;
ii) extracting the compound of formula(II) in organic solvent;
iii) converting the compound of formula (II) into (R/S) menthyldiphenylmethanesulfinate of formula (III);

in presence of L-menthol, base, triphenylphosphine and chlorinated solvent;
iv) filtering the reaction mass of formula III, and concentrating the mother liquor to obtain(+/-) menthyldiphenylsulphinate;
v) separating(+/-) menthyldiphenylsulphinate by column chromatography to obtaindesired diastereomer of formula (IV);
vi) converting(-) menthyldiphenylsulphinate is into compound methyl (-) -benzhydrylsulfinyl acetate of formula (V); and

vii) reactingcompound of formula V with ammonical methanol to obtainarmodafinil of formula (I)

2. Theprocess according to claim 1, wherein the purity compound of formula (I) is at least 99%.
3.The process according to claim 1, wherein the inert solvent is diethylether.
4. Theprocess according to claim 1, wherein the organolithium reagent is n-BuLi.
5. Acompound of formula (IV).

6. Aprocess for preparation of compound of formula (IV) comprising,the steps of
(i) convertingdiphenylmethane into sulfonyl chloride compound of formula (II)

in presence of sulfuryl chloride and organolithium reagent in inert solvent;
ii) extracting the compound of formula (II) in organic solvent;
iii) converting the compound of formula (II) into (R/S) menthyl diphenylmethane sulfinate of formula (III)

in presence of L-menthol, base, triphenylphosphine and chlorinated solvent;
iv) filtering the reaction mass of formula (III), and concentrating the mother liquor to obtain(+/-) menthyldiphenylsulphinate; and
v) separating(+/-) menthyldiphenylsulphinate by column chromatography to get desired diastereomer of formula (IV).

7. The process according to claim 6, wherein the inert solvent is tetrahydrofuran.
8. The compound of formula (IV) as claimed in claim 5, is used for the preparation of armodafinil.
, Description:Field of invention
The present invention encompasses improved process for preparing the intermediates of Armodafinil, and the conversion of intermediates into Armodafinil.

Background of invention
Modafinil is currently marketed by Cephalon Inc. under the trade name PROVIGIL® as a racemic mixture of its Rand S enantiomers. PROVIGIL® is indicated for the treatment of excessive sleepiness associated with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hyponea syndrome.
Studies have shown that while both enantiomers of modafinil are pharmacologically active, the S enantiomer is eliminated from the body threetimes faster than the R enantiomer. Prisinzanoet al. Tetrahedron Asymmetry, vol. 15, 1053-1058 (2004). It is therefore, preferable to develop pharmaceutical compositions of the R enantiomer of modafinil, as opposed to its racemicmixture. The R enantiomer of modafinil is known as armodafinil and has the chemicalname 2-[(R)-(diphenylmethyl)-sulfinyl]acetamide, and has the following chemical structure of formula (I):

Armodafinil is currently marketed by Cephalon Inc. under the trade name NUVIGIL®.

Armodafinil and a method of its preparation were first disclosed in the US Patent 4,927,855). The US '855 patent describes a method for synthesis of armodafinil by following the general scheme:

Tetrahedron Asymmetry 15 (2004), 1053-1058 discloses a process for the preparation of armodafinil by reacting (R)-(-)-(diphenylmethanesulfinyl) acetic acid with methyl iodide/potassium carbonate in acetone. The solvent was reduced under pressure followed by addition of water. The aqueous layer was extracted with dichloromethane and the dichloromethane layer was washed and dried. The solvent was then removed under pressure and the crude solid was recrystallized from isopropyl ether. This process described in the publication had low yields and purity.

A synthesis of modafinil has been described in U.S. Pat. No. 4,177,290, where benzhydrol was reacted with chloroacetic acid. A related process for synthesizing the levorotatory isomer of modafinil is disclosed in U.S. Pat. No.4,927,855.
Processes for synthesizing modafinil derivatives are disclosed in U.S. Pat. No.4,066,686; U.S. Pat. No. 4,489,095 and U.S. Pat. No. 5,719,168. Processes describing reaction of benzhydryl halides with 2-mercaptoacetates were described in U.S. Pat. No.5,571,825; 4,964,893; EP Pat. No. 0,528 172.Processes for preparing modafinil have been described in PCT Publication No. WO02/10125.

The present invention provides an efficient process for the preparation of armodafinil, which offers significant commercial advantages on the industrial scale. The current invention prepares Armodafinilusing fewer steps with enhanced yields. Resolution of isomers in the intermediate stage results into better yield and purity of Armodafinil. An additional benefit of the present invention is a reduction in the undesirable waste products. The overall costs and hazards of the manufacturing process are reduced, as simpler machinery can be used, less labor is involved and fewer undesirable waste products are generated, all of which provide distinct commercial advantages for the preparation of armodafinil on a commercial scale.

Object of the invention
The present invention encompasses novel process for preparing the intermediates of Armodafinil, and the conversion of intermediates into Armodafinil.

Summary of the invention
Accordingly, the present invention provides an improved process for the preparation of armodafinil comprising the steps of:
(i) converting diphenyl methane into sulfonyl chloride compound of formula (II)

in presence of sulfuryl chloride and strong nucleophile in inert solvent;
ii) extracting the compound of formula (II) in organic solvent;
iii) converting the compound of formula( II) into (R/S) menthyl diphenylsulphinate of formula (III)

in presence of L-menthol, base, triphenylphosphine and chlorinated solvent;
iv) filtering the reaction mass of formula (III)and concentrating the mother liquor to obtain (+/-) menthyldiphenylsulphinate;
v) separating(+/-) menthyldiphenylsulphinate by column chromatography to get desired diastereomer of formula (IV);

vi) converting(-) menthyldiphenylsulphinate into compound methyl-(-)-benzhydrylsulfinyl acetate of formula (V); and

vii) reactingcompound of formula (V)with ammonicalmethanol to get armodafinil of formula (I).

Detailed description of the invention
Theinventionisdirectedtoaprocessforpreparationofanopticallypurearmodafinil of formula(I).

One of the embodiments of the present invention is to provide novel process for synthesis of armodafinil.

One of the other embodiments of present invention is to providenovel intermediate of (III). In another embodiment of present invention is to provide a process for preparation of compound of formula (III).
Another embodiment of the invention is the use of the novel intermediate compound in the preparation of compound of formula I and its pharmaceutically acceptable salts thereof.The process of present invention is as depicted in scheme -1below.

According to the process of present invention:
(i) converting diphenyl methane into sulfonyl chloride compound of formula (II) in presence of sulfuryl chloride and organolithium reagent in inert solvent, wherein the inert solvent is THF, diethyl ether, DMF,chloroform, carbon tetrachloride, more preferablydiethyl ether and organolithium reagent is n-BuLi;
ii) extracting the compound of formula (II) in organic solvent wherein organic solvent is hexane, ethyl acetate, dichloromethane, chloroform, and toluene, more preferably dichloromethane;
iii) converting the compound of formula (II) into (R/S) menthyl diphenylmethane sulfinate of formula (III) in presence of L-menthol, base, triphenylphosphine and chlorinated solvent, herein chlorinated solvent is dichloromethane;
iv) filtering the reaction mass of formula (III) is filtered, and concentratingmother liquor to get (+/-) menthyldiphenylsulphinate;
v) separating(+/-) menthyldiphenylsulphinate by column chromatography to obtain desired diastereomer of formula (IV);
vi) converting(-) menthyldiphenylsulphinate into compound methyl(-)benzhydrylsulfinyl acetate of formula(V);
vii) further reacting compound of formula (V) with ammonical methanol to obtainarmodafinil of formula (I).

The present invention is novel, simple and cost effective because use of simple and easily available reagents and reactants. As the enantiopurity is achieved at the intermediate stage, the final product is pure and there is no loss in yield at the final stage, hence, the present invention is suitable for the industrial scale.

The present invention is illustrated by means of following examples.

Step 1: Preparation of diphenylmethanesulfonyl chloride of formula (II):
In a round bottom flask, diphenylmethane (25gm) was added to anhydrous diethyl ether (150ml) and reaction mixture was cooled to 0°C.In this cooled solution, n-BuLi (11.3ml)was added in dropwise fashion over the period of 15mins. The above solution was chargedin sulfuryl chloride(15.7ml) at 0°C.After completion of the reaction the solvent and excess sulfuryl chloride was evaporated under vacuum and then dichloromethane (262.5ml) was added.The solution was washed with water (100mlx2)twice. The organic layer was dried and evaporated to get oil of diphenylmethanesulfonyl chloride of formula (II).
Yield – 22.5gm.

Step 2: Preparation of R/S Menthyl diphenylmethane sulfinate of formula (III):
In a round bottom flask, diphenylmethanesulfonyl chloride of formula (II)(21gm), L-menthol (12.29gm) and triethylamine (109ml) were charged in dichloromethane (63ml) at room temperature. This reaction mixture was added dropwise to solution of triphenylphosphine (20.45gm) in dichloromethane (21ml) over the period of 60mins.After completion of reaction, the reaction mass was filtered, the mother liquor was concentrated under vacuum to get oil of (+/-) menthyldiphenylmethanesulfinate.
Yield = 25.1gm.

Step 3: Separation of Diastereomers:
Diastereomers of menthyldiphenylmethanesulfinate of formula (III) were separated by column chromatography to get the desired diastereomer of formula (IV).
Yield =11gm.

Step 4: Preparation of methyl (-) benzhydrylsulfinyl acetate (V):
In a round bottom flask, methyl acetate in tetrahydrofuran (33ml) was added to solution of n–BuLi (22.26gm) in hexane at -78°C. Thenthe (-) menthyl diphenylsulphinate(11gm) dissolved in tetrahydrofuran (22.26ml) and added slowly to above solution at -78°C for the period of 30mins. The reaction mixture was stirred for 2 hrs at -60 to -78°C. The reaction mixture was cooled to room temperature and quenched with aqueous ammonium chloride to give a suspension. Water was added and layer was separated after 15 mins. stirring. Aqueous layer was extracted with ethyl acetate and combined organic layer concentrated under vacuum to get crude solid. This crude solid was purified by column chromatography to get pure methyl (-) benzhydrylsulfinyl acetate (V).
Yield: 5.5gm.
1H NMR: 3.41-345(d, 1H), 3.53-3.57 (d, 1H), .73-3.76(s, 3H), 5.22(s, 1H), 7.27-7.53 (m, 10H).

Step 5: Preparation of armodafinil (I):
In a round bottom flask, slurry of methyl (-) benzhydrylsulfinyl acetate (V) was prepared in 20ml methanol at room temperature. In another round bottom flask,ammonical methanol (15-20%, 50ml) was added.A slurry of methyl (-) benzhydrylsulfinyl acetate (V) was added to ammonical solution in 5-10mins. The reaction mixture was stirred for 180-200mins. at room temperature. After completion of reaction, methanolwas distilled upto 2-3 volume mass left in flask. Then dichloromethane (50ml) was added to make the clear solution and washed the dichloromethane layer with 5% sodium bicarbonate solution (25ml). The aqueous layer was extractedwith dichloromethane, combined the organic layer and washed with water (25ml) and distilled upto 5 volume remains in flask. Diisopropyl ether was added(25ml) and stirred for 210mins.The solid was filtered, washed the wet solid with diisopropyl ether to get crude armodafinil. Dichloromethane (15ml) was charged and crude armodafinil was dissolved into it. Diisopropyl ether (25ml) was added into clear solution and stirred for further 3hrs. Solid was filtered and washed with diisopropyl ether to get purified armodafinil.
Yield: 4.2g.
MP: 155-158°C.
1H NMR: CDCl3: 3.15-3.18(d, 1H), 3.46-3.50(d,1H), 5.22(s, 1H), 5.28(s,3H), 7.28-7.52(m,10H)