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Title:
PROCESS FOR THE PREPARATION OF MODAFINIL ENANTIOMERS
Document Type and Number:
WIPO Patent Application WO/2009/024863
Kind Code:
A2
Abstract:
Disclosed herein is a convenient, commercially viable and environmentally friendly process for the preparation of Armodafinil. The present invention also provides an improved, commercially viable and industrially advantageous process for the preparation of pure 2-[(diphenylmethyl) sulfinyl] acetic acid (also known as modafinic acid) substantially free of sulfone impurity i.e., 2-[(diphenylmethyl)sulfonyl] acetic acid. The intermediate is useful for preparing Modafmil and its enantiomers, or a pharmaceutically acceptable salt thereof, in high yield and purity.

Inventors:
GIRISH, Dixit (E-1 Buildafina Vista, Arvabhom NagarBehind HSB, Bannergatta Road ., Bangalore-560048, IN)
KHILE, Anil, Shahaji (A-207 Nagarrjune Gardens, F-Block60 Feet Roa, Sahakaranagar ., Bangalore-560092, IN)
PRADHAN, Nitin, Sharadchandra (C-602, Runwal Estate Ghoad Bunder Road,Opposite Lawkim Company,Manpada, Thane, Maharashtra 1, 40060, IN)
VALGEIRSSON, Jon (Actavis Pharma Development Center Private Limited, No.15 80 Feet Road, S.T. Bed,Near Maharaja Restaurant,Koramangala, Bangalore 5, Karnataka, 56009, IN)
Application Number:
IB2008/002634
Publication Date:
February 26, 2009
Filing Date:
June 26, 2008
Export Citation:
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Assignee:
ACTAVIS GROUP PTC EHF (Reykjavikurvegi 76-78, 220 Hafnarfjordur, IS)
GIRISH, Dixit (E-1 Buildafina Vista, Arvabhom NagarBehind HSB, Bannergatta Road ., Bangalore-560048, IN)
KHILE, Anil, Shahaji (A-207 Nagarrjune Gardens, F-Block60 Feet Roa, Sahakaranagar ., Bangalore-560092, IN)
PRADHAN, Nitin, Sharadchandra (C-602, Runwal Estate Ghoad Bunder Road,Opposite Lawkim Company,Manpada, Thane, Maharashtra 1, 40060, IN)
VALGEIRSSON, Jon (Actavis Pharma Development Center Private Limited, No.15 80 Feet Road, S.T. Bed,Near Maharaja Restaurant,Koramangala, Bangalore 5, Karnataka, 56009, IN)
International Classes:
C07C315/02; C07C315/04; C07C317/44
Domestic Patent References:
WO2005046854A22005-05-26
WO2008152462A12008-12-18
Foreign References:
FR2849029A12004-06-25
EP1516869A12005-03-23
EP1466897A12004-10-13
Other References:
CARCELLER E ET AL: "SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF 1-ACYL-4-((2-METHYL-3-PYRIDYL)CYANOMETHYL) PIPERAZINES AS PAF ANTAGONISTS" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 36, no. 20, 1 January 1993 (1993-01-01), pages 2984-2997, XP002946792 ISSN: 0022-2623
OLIVO ET AL: "Microbial oxidation/amidation of benzhydrylsulfanyl acetic acid. Synthesis of (+)-modafinil" TETRAHEDRON ASYMMETRY, PERGAMON PRESS LTD, OXFORD, GB, vol. 16, no. 21, 31 October 2005 (2005-10-31), pages 3507-3511, XP005175791 ISSN: 0957-4166
PRISINZANO T ET AL: "Synthesis and determination of the absolute configuration of the enantiomers of modafinil" TETRAHEDRON ASYMMETRY, PERGAMON PRESS LTD, OXFORD, GB, vol. 15, no. 6, 22 March 2004 (2004-03-22), pages 1053-1058, XP004494506 ISSN: 0957-4166
TERNOIS, GUILLEN, PLAQUEVENT, COQUEREL: "Asymmetric synthesis of modafinil and its derivatives by enantioselective oxidation of thioethers: comparison of various methods including synthesis in ionic liquids." TETRAHEDRON:ASYMMETRY, vol. 18, 10 December 2007 (2007-12-10), pages 2959-2964, XP002530475
Attorney, Agent or Firm:
COLE, William, Gwyn (HLBBshaw, Merlin House Falconry Court,Baker's Lane,Essex, Epping CM16 5DQ, GB)
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Claims:
We claim:

1. A process for the preparation of pure armodafinil of formula 1(R):

or a pharmaceutically acceptable salt thereof; which comprises: a) reacting (-)-2-(R)-[(diphenylmethyl)sulfinyl] acetic acid of formula H(R):

with a chloroformate compound of formula V:

wherein R 1 is an alkyl, aryl or aralkyl group; optionally in the presence of a suitable base in a suitable solvent to produce a mixed anhydride compound of formula VI:

wherein R 1 is as defined in formula V; and

b) amidating the mixed anhydride compound of formula VI obtained in step-(a) with ammonia in a suitable solvent to produce pure armodafinil of formula I(R) and optionally converting the armodafinil formed into a pharmaceutically acceptable salt thereof. 2. The process of claim 1, wherein the chloroformate compound of formula V is selected from the group consisting of methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, sec-butyl chloroformate and phenyl chloroformate.

3. The process of claim 2, wherein the chloroformate compound is ethyl chloroformate or isobutyl chloroformate.

4. The process of claim 1, wherein the solvents used in step-(a) or step-(b) each independently selected from the group comprising alcohols, ketones, cyclic ethers, aliphatic ethers, hydrocarbons, chlorinated hydrocarbons, nitriles, esters, and mixtures thereof. 5. The process of claim 4, wherein the solvent used for step-(a) is selected from the group consisting of methylene chloride, toluene, xylene, n-pentane, n-hexane, n- heptane, cyclohexane, and mixtures thereof; and the solvent used for step-(b) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, and mixtures thereof. 6. The process of claim 1, wherein the reaction in step-(a) is carried out at a temperature of about -2O 0 C to about 100°C for at least 30 minutes.

7. The process of claim 6, wherein the reaction is carried out at a temperature of about -1O 0 C to about 80 0 C from about 30 minutes to about 10 hours.

8. The process of claim 1, wherein the amidation reaction in step-(b) is carried out at a temperature of -10 0 C to about 100 0 C for at least 30 minutes.

9. The process of claim 8, wherein the amidation reaction is carried out at a temperature of about -5 0 C to about 80 0 C from about 30 minutes to about 10 hours.

10. The process of claim 1, wherein the ammonia used in step-(b) is in the form of aqueous ammonia or in the form of ammonia gas dissolved in an organic solvent

selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone.

11. The process of claim 1, wherein the armodafinil of formula 1(R) obtained has a total purity of greater than about 99% as measured by HPLC.

12. The process of claim 11, wherein the armodafinil has a total purity of greater than about 99.9% as measured by HPLC.

13. A process for the preparation of modafinic acid or 2-[(diphenylmethyl)sulfinyl] acetic acid of formula II:

substantially free of sulfone impurity, which comprises: a) reacting 2-[(diphenylmethyl)thio] acetic acid of formula III:

with a suitable oxidizing agent in a first solvent optionally in the presence of a suitable base to produce a reaction mass; b) combining the reaction mass obtained in step-(a) with a second solvent; c) optionally, acidifying the reaction mass with a suitable acid; and d) isolating pure 2-[(diphenylmethyl)sulfinyl] acetic acid substantially tree of sulfone impurity from the reaction mass.

14. The process of claim 13, wherein the oxidizing agent used in step (a) is selected from the group comprising 50% hydrogen peroxide, ammonium molybdate/sodium percarbonate, sodium tungstate, sodium per borate, N-halosuccinimide such as N-

chlorosuccinimide, vanadium acetylacetonate/tert-butylhydroperoxide, sodium perborate/acetic anhydride, m-chloroperbenzoic acid, chlorite, chlorate, perchlorate, and other analogous halogen compounds, sodium hypochlorite/(-)-(α)- methylbenzylamine, salts of peπnanganate, ammonium cerium(IV) nitrate and probably related cerium(IV) compounds, hexavalent chromium compounds such as chromic and dichromic acids and chromium trioxide, pyridiniumchlorochromate (PCC), and chrornate/dichromate compounds, Tollen's Reagent, persulfuric acid, osmium tetra oxide (OsO 4 ), selenium dioxide, nitronium hexafluorophosphate, thalium(III) nitrate, nitrogen tetroxide, idosobenzene, iodobenzene diacetate, iodobenzene dichloride, sodium metaperiodate, tert-butylhypochlorite, 1- halobenzotriazoles, sulfurylchloride, 2,4,4,6-tetrabromocyclohexa-dienone, lead tetra acetate, and combinations comprising one or more of the foregoing oxidizing agents.

15. The process of claim 14, wherein the oxidizing agent is selected from the group consisting of 50% hydrogen peroxide, N-chlorosuccinimide, sodium hypochlorite/(-)- (α)-methylbenzylamine, ammonium molybdate/sodium percarbonate, vanadium acetylacetonate/teit-butylhydroperoxide, sodium perborate/acetic anhydride, and combinations comprising one or more of the foregoing oxidizing agents.

16. The process of claim 13, wherein the first solvent used in step-(a) is selected from the group comprising of water, alcohols, ketones, cyclic ethers, aliphatic ethers, hydrocarbons, chlorinated hydrocarbons, nitriles, esters and the like, and mixtures thereof; and the second solvent used in step-(b) is selected from the group comprising water, alcohols, hydrocarbons, and mixtures thereof.

17. The process of claim 16, wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, toluene, xylene, n-pentane, n-hexane, n- heptane, cyclohexane, and mixtures thereof.

18. The process of claim 13, wherein the reaction in step-(a) is carried out at a temperature of -25°C to the reflux temperature of the solvent used for at least 30 minutes.

19. The process of claim 13, wherein the oxidizing agent is employed in a molar ratio of 0.5 to 3.0 equivalents per one equivalent of 2-[(diphenylmethyl)thio] acetic acid of formula III.

20. The process of claim 19, wherein the oxidizing agent is employed in a molar ratio of 1.5 to 2.0 equivalents per one equivalent of 2-[(diphenylmethyl)thio] acetic acid of formula III.

21. The process of claim 16, wherein the solvent used for step-(b) is selected from the group consisting of water, methanol, toluene, and mixtures thereof.

22. The process of claim 13, wherein the acid used in step (c) is selected from the group consisting of acetic acid, sulfuric acid, hydrochloric acid, aliphatic sulfonic acid, arylsulfonic acid, hydrobromic acid, phosphoric acid or mixtures thereof.

23. The process of claim 13, wherein the 2-[(diphenylmethyl)sulfinyl] acetic acid of formula II obtained contains sulfone impurity in an amount of less than about 0.1% by weight. 24. The process of claim 23, wherein the 2-[(diphenylmethyl)sulfinyl] acetic acid of formula II contains sulfone impurity in an amount of less than about 0.05% by weight. 25. A mixed anhydride compound of formula VI:

wherein R 1 is an alkyl, aryl or aralkyl group.

26. The compound of claim 25, wherein the alkyl group is a straight or branched chain having 1 to 12 carbon atoms selected from the group comprising methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, t-butyl and n-pentyl.

27. The compound of claim 25, wherein the aralkyl group is selected from the group comprising benzyl, 2-phenethyl and naphthalenemethyl.

28. The compound of claim 25, wherein the aryl group is an aromatic monocyclic or multicyclic ring system of 6 to 10 carbon atoms selected from the group comprising phenyl and naphthyl.

29. Use of the mixed anhydride compound of formula VI of claim 25 in the process for manufacture of armodafmil and a pharmaceutically acceptable salt thereof.

30. Use of the mixed anhydride compound of formula VI, produced according to the process of any of claims 1 to 13, in the process for manufacture of armodafmil or a pharmaceutically acceptable salt thereof.

31. Use of the modafinic acid or 2-[(diphenylmethyl)sulfinyl] acetic acid of formula II, produced according to the process of any of claims 13 to 24, in the process for manufacture of armodafinil or a pharmaceutically acceptable salt thereof.

32. Armodafinil or a pharmaceutically acceptable salt prepared by a process as claimed in any of claims 1 to 12.

33. Armodafinil or a pharmaceutically acceptable salt prepared from modafinic acid or 2- [(diphenylmethyl)sulfinyl] acetic acid of formula (II) produced according to a process of any of claims 13 to 24.

Description:

PROCESS FOR THE PREPARATION OF MODAFINIL ENANTIOMER

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from Indian Provisional Application No. 1363/CHE/2007 filed on June 26, 2007, which is hereby incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

Disclosed herein is a convenient, commercially viable and environmentally friendly process for the preparation of Armodafmil. The present invention also provides an improved, commercially viable and industrially advantageous process for the preparation of pure 2-[(diphenylmethyl) sulfinyl] acetic acid (also known as modafmic acid) substantially free of sulfone impurity i.e., 2-[(diphenylmethyl)sulfonyl] acetic acid. The intermediate is useful for preparing Modafmil and its enantiomers, or a pharmaceutically acceptable salt thereof, in high yield and purity.

BACKGROUND OF THE INVENTION

Modafmil, also known as 2-(benzhydrylsulfinyl) acetamide or 2- [(diphenylmethyl) sulfinyl] acetamide and represented by the following structural formula I:

Modafmil is an αj-adrenergic agonist having psycho-stimulant activity, used for the treatment of idiopathic narcolepsy. Modafmil has a stereogenic center at the sulphur atom and thus exists as two optical isomers, i.e., enantiomers.

Modafmil in its racemic form has been approved by the United States Food and Drug Administration for use in the treatment of excessive daytime sleepiness associated with narcolepsy.

In the preparation of modafinil and its enantiomers, 2-[(diphenylmethyl) sulfinyl] acetic acid (modafinic acid) of formula II:

is a key intermediate.

Synthetic preparations of modafinil and similar compound were first disclosed by Lafon in U.S. Patent No. 4,177, 290 (herein after referred to as the '290 patent). The process includes reaction of benzhydrol with thiourea to form an intermediate which is then hydrolyzed to produce 2-[(diphenylmethyl)thio]acetic acid. The acid is then oxidized in situ with hydrogen peroxide in a mixture containing chloroacetic acid and water to produce 2-[(diphenylmethyl) sulfinyl] acetic acid of formula II. The resulting sulfoxide is then treated with dimethyl sulfate to methylate the carboxylic acid group followed by treatment with ammonia to produce modafinil.

The process for the preparation of compound of formula II described in the '290 patent suffers from a problem of over-oxidation of the sulfide to produce sulfone of formula IV:

After looking at the above chemical structures it will be readily appreciated that separation of the sulfone once formed from modafinil is a difficult task. Therefore, the development of selective oxidation methods is required in order to obtain 2-

[(diphenylmethyl)sulfinyl]acetic acid of formula III substantially free of sulfone impurity.

US Patent No. 4,927,855 describes the two optical enantiomers of modafinil. More particularly it describes the levorotatory enantiomer also called as R-Modafmil or

Armodafϊnil, chemically designated as (-)-2-(R)-(benzhydrylsulfinyl) acetamide or (-)-2- (R)-[(diphenylmethyl)sulfinyl] acetamide and its use as an antidepressant or stimulant agent in the treatment of hypersomnia and disorders associated with Alzheimer's disease. It can also be represented by following structural formula 1(R):

Armodafinil is R-enantiomer of modafinil, so it is expected to act in a similar manner, with similar effects. However, it acts for a longer duration of time than modafinil.

Lafon also disclosed the use of an intermediate, a racemic mixture of 2- [(diphenylmethyl)sulfinyl] acetic acid of formula II to prepare an isomer of modafinil in

US Patent No. 4,927,855, referring to French patent 2,326,181 B. The process for the preparation of the two optical enantiomers of modafinil described in US Patent No.

4,927,855 comprises carrying out the resolution of optical enantiomers of (±)-2-

[(diphenylmethyl) sulfmyl] acetic acid in a first stage by forming diastereomers with the optically active agent (-)-[α]-methylbenzylamine. The (-)-[α]-methylbenzylamine-(-)-2-

[(diphenylmethyl)sulfmyl]acetate is then converted to (-)-2-[(diphenylmethyl) sulfmyl] acetic acid by acid hydrolysis. The latter is esterifϊed in the presence of dimethyl sulphate and then converted to an amide in the presence of ammonia (gas).

The term "enantiomer" refers to stereoisomer molecules which are non-super imposable mirror images of each other. Enantiomers are typically designated using either (+) and (-) or (d) and (1), which indicates optical rotating power in the chiral centre.

Stereoisomerism may also be denoted by either (D) or (L) or by (R) and (S), these being descriptive of the absolute configuration.

The 2-[(diphenylmethyl)sulfmyl] acetic acid of formula II obtained by the processes described in the above mentioned prior art does not have satisfactory purity.

Unacceptable amounts of impurities are formed during the oxidation of 2- [(diphenylmethyl)thio] acetic acid, thus resulting in a poor product yield. The processes described in the prior art suffer from drawbacks since the overoxidation of the sulfide atom to sulfone occurs relatively consistently and strongly, particularly near the end of the reaction. Moreover, the sulfone impurity of formula IV is not easily removed from the final product, resulting in elevated levels of impurities and reduced overall yield. hi addition to overoxidation, the use of corrosive glacial acetic acid during the oxidation process is undesirable due to associated material handling issues. For example, the waste handling of glacial acetic acid following oxidation requires relatively large amounts of base and relatively long periods of time to neutralize safely.

Based on the aforementioned drawbacks, the prior art processes may be unsuitable for preparation of Modaflnil and its enantiomers (R or S) in commercial scale operations.

A need remains for an improved and commercially viable process of preparing a pure compound of formula II substantially free of sulfone impurity, which avoids the use of corrosive acetic acid and other hazardous or toxic reagents, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large- scale preparation. Desirable process properties include less hazardous, environmentally friendly and easy to handle reagents, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of Modaflnil and its enantiomers (R or S) or a pharmaceutically acceptable salt thereof in high purity and hi high yield. However, a need still remains for an improved and commercially viable process of preparing pure Armodafmil or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION hi one aspect, provided herein is an efficient, convenient, commercially viable and environment friendly process for the preparation of armodafmil of formula I(R).

The present inventors have surprisingly found that the modafϊnic acid or 2-

[(diphenylmethyl)sulfmyrj acetic acid of formula II substantially free of sulfone impurity can be prepared in high purity and with high yield by oxidizing 2-[(diphenylmethyl)thio]

acetic acid with suitable oxidizing agents herein after disclosed optionally in the presence of a suitable base in a suitable solvent under suitable conditions.

In another aspect, provided also herein is an efficient, convenient, commercially viable and environment friendly process for the preparation of modafinic acid or 2- [(diphenylmethyl)sulfinyl] acetic acid of formula II with up to 95% overall yield.

Advantageously, the reagents used for present invention are less hazardous and easy to handle at commercial scale and also involves less expensive reagents.

The term "modafinic acid or 2-[(diphenylmethyl)sulfinyl] acetic acid of formula

II substantially free of sulfone impurity" refers to the 2-[(diphenylmethyl)sulfinyl] acetic acid having the content of sulfone impurity in less than about 0.1 % by weight, specifically less than about 0.05% by weight and still more specifically having no traces of the sulfone impurity.

DETAILED DESCRIPTION OF THE INVENTION Provided herein is an improved process for the preparation of the modafinic acid or 2-[(diphenylmethyl)sulfinyl] acetic acid of formula II:

substantially free of sulfone impurity, which comprises: a) reacting 2-[(diphenylmethyl)thio] acetic acid of formula III:

with a suitable oxidizing agent in a first solvent optionally in the presence of a suitable base to produce a reaction mass; b) combining the reaction mass obtained in step-(a) with a second solvent; c) optionally, acidifying the reaction mass with a suitable acid; and d) isolating pure 2~[(diphenylmethyl)sulfinyl] acetic acid substantially free of sulfone impurity from the reaction mass.

Suitable oxidizing agent used in step (a) is selected from the group comprising 50% hydrogen peroxide, ammonium molybdate/sodium percarbonate, sodium tungstate, sodium per borate, N-halosuccinimide such as N-chlorosuccinimide, vanadium acetylacetonate/tert-butylhydroperoxide, sodium perborate/acetic anhydride, m- chloroperbenzoic acid, chlorite, chlorate, perchlorate, and other analogous halogen compounds, sodium hypochlorite/(-)-(α)-methylbenzylamine, salts of permanganate, ammonium cerium(IV) nitrate and probably related cerium(IV) compounds, hexavalent chromium compounds such as chromic and dichromic acids and chromium trioxide, pyridiniumchlorochromate (PCC), and chromate/dichromate compounds, Tollen's Reagent, persulfuric acid, osmium tetra oxide (OsO 4 ), selenium dioxide, nitronium hexafluorophosphate, thalium(III) nitrate, nitrogen tetroxide, idosobenzene, iodobenzene diacetate, iodobenzene dichloride, sodium metaperiodate, tert-butylhypochlorite, 1- halobenzotriazoles, sulfurylchloride, 2,4,4,6-tetrabromocyclohexa-dienone, lead tetra acetate, and combinations comprising one or more of the foregoing oxidizing agents.

Specific oxidizing agent is selected from the group consisting of 50% hydrogen peroxide, N-chlorosuccinimide, sodium hypochlorite/(-)-(α)-methylbenzylamine, ammonium molybdate/sodium percarbonate, vanadium acetylacetonate/tert- butylhydroperoxide, sodium perborate/acetic anhydride, and combinations comprising one or more of the foregoing oxidizing agents.

The first solvent used in step-(a) include, but are not limited to, water, alcohols, ketones, cyclic ethers, aliphatic ethers, hydrocarbons, chlorinated hydrocarbons, nitriles, esters and the like, and mixtures thereof. Specific solvents are water, hydrocarbons, alcohols, and mixtures thereof.

Exemplary alcohol solvents include, but are not limited to, C 1 to C 8 straight or branched chain alcohol solvents such as methanol, ethanol, propanol, butanol, amyl alcohol, hexanol, and mixtures thereof. Specific alcohol solvents are methanol, ethanol, isopropyl alcohol, and mixtures thereof, and most specific alcohol solvent is methanol. Exemplary ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, and the like, and mixtures thereof. Exemplary cyclic ether solvents include, but are not limited to, tetrahydrofuran, dioxane, and the like, and mixtures thereof. Exemplary nitrile solvents include, but are not limited to, acetonitrile and the like, and mixtures thereof. Exemplary ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and the like and mixtures thereof. Exemplary hydrocarbon solvents include, but are not limited to, n-pentane, n-hexane and n-heptane and isomers or mixtures thereof, cyclohexane, toluene and xylene. Specific hydrocarbon solvent is toluene. Exemplary chlorinated hydrocarbon solvents include, but are not limited to, methylene chloride, ethyl dichloride, chloroform and carbon tetrachloride or mixtures thereof. Specific chlorinated hydrocarbon solvent is methylene chloride.

Most specific solvent for step-(a) is selected from the group consisting of water, methanol, ethanol, isopropanol, toluene, xylene, n-pentane, n-hexane, n-heptane, cyclohexane, and mixtures thereof.

The base used in step-(a) can be an organic or inorganic base. Specific organic bases are organic amine bases of formula NRiR 2 R 3 wherein R 1 , R 2 and R 3 are each independently hydrogen, Ci -6 straight or branched chain alkyl, aryl alkyl, C 3- io single or fused ring optionally substituted, alkylcycloalkyls or independently R 1 , R 2 and R 3 combine with each other to form C 3-7 membered cycloalkyl ring or heterocyclic system containing one or more heteroatom. Preferable base is an inorganic base. Exemplary inorganic bases include, but are not limited to, hydroxides, carbonates, alkoxides and bicarbonates of alkali or alkaline earth metals. Specific alkali metals are lithium, sodium and potassium, and more specifically sodium and potassium. Specific alkaline earth metals are calcium and magnesium, and more specifically magnesium.

Specific inorganic bases are sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium

carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide, and more specifically sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

The reaction in step-(a) is carried out at a temperature of -25°C to the reflux temperature of the solvent used for at least 30 minutes, specifically at a temperature of about -2O 0 C to about 80 0 C from about 30 minutes to about 30 hours, and more specifically at about -15 0 C to about 6O 0 C from about 1 hour to about 25 hours.

As used herein, "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure. In one embodiment, usually 0.5 to 3.0 equivalents, specifically 0.95 to 1.5 equivalents, of the oxidizing agent per one equivalent of 2-[(diphenylmethyl)thio] acetic acid of formula III are employed.

In another embodiment, usually 1.0 to 2.5 equivalents, specifically 1.5 to 2.0 equivalents, of base per one equivalent of 2-[(diphenylmethyl)thio] acetic acid of formula III are employed.

The second solvent used in step-(b) is selected from the group comprising water, alcohols, hydrocarbons, and mixtures thereof. Exemplary alcohol solvents include, but are not limited to, Ci to C 8 straight or branched chain alcohol solvents such as methanol, ethanol, propanol, butanol, amyl alcohol, hexanol, and mixtures thereof. Specific alcohol solvents are methanol, ethanol, isopropyl alcohol, and mixtures thereof, and most specific alcohol solvent is methanol. Exemplary hydrocarbon solvents include, but are not limited to, n-pentane, n-hexane and n-heptane and isomers or mixtures thereof, cyclohexane, toluene and xylene. Specific hydrocarbon solvent is toluene. Most preferable solvents are water, methanol, toluene, and mixtures thereof. The combining in step-(b) may be done in any order, for example, the second solvent may be added to the reaction mass, or alternatively, the reaction mass may be added to the second solvent. The addition may be carried out drop wise or in one portion or in more than one portion. The addition is preferably carried out drop wise at a temperature of below 50°C for at least 10 minutes, and more preferably at a temperature of about 15 0 C to about 35 0 C from about 30 minutes to about 2 hours.

Preferably the pH of the reaction mixture in step-(c) is adjusted to below about 2.5 and more preferably to about 1.5 - 2.5.

Suitable acids in step (c) includes, but are not limited to, acetic acid, sulfuric acid, hydrochloric acid, aliphatic sulfonic acid, arylsulfonic acid, hydrobromic acid, phosphoric acid or mixtures thereof. More preferable acid is hydrochloric acid.

In one embodiment, the compound of formula II obtained is isolated as solid from a suitable organic solvent by methods usually known in the art such as cooling, partial removal of the solvent from the solution, addition of precipitating solvent, or a combination thereof. The separated pure compound of formula II substantially free of sulfone impurity is collected by filtration or centrifugation. The compound of formula II obtained is then optionally subjected to drying using conventional drying techniques like vacuum oven drying.

The compound of formula II obtained by the process disclosed herein, has a purity (measured by High Performance Liquid Chromatography, hereinafter referred to as 'HPLC) greater than about 97%, specifically greater than about 98%, and more specifically greater than about 99%.

The use of suitable oxidizing agents or combinations of suitable oxidizing agents under suitable conditions in the oxidation reaction allows the product to be easily isolated and purified, thereby producing a product with 75-95% overall yield.

The use of less hazardous, readily available and easy to handle reagents allows the process disclosed herein to be suitable for preparation of Modafmil and its enantiomers at lab scale and in commercial scale operations.

The term "modafinic acid or 2-[(diphenylmethyl)sulfinyl] acetic acid of formula II substantially free of sulfone impurity" refers to the 2-[(diρhenylmethyl)sulfinyl] acetic acid having the content of sulfone impurity in less than about 0.1% by weight, specifically less than about 0.05% by weight and still more specifically having no traces of the sulfone impurity.

Modafmil and its enantiomers (R or S) or a pharmaceutically acceptable acid thereof can be prepared in high purity by using the pure compound of formula II

substantially free of sulfone impurity obtained by the method disclosed herein, by known methods, for example as described in U.S. Patent Nos. 4,177,290 and 4,927,855.

Armodafinil or a pharmaceutically acceptable acid thereof can be prepared in high purity by using the pure compound of formula II substantially free of sulfone impurity obtained according to the present invention, by the method disclosed hereinafter.

According to another aspect of the present invention, there is provided a process for preparing pure armodafinil of formula 1(R):

or a pharmaceutically acceptable salt thereof; which comprises: a) reacting (-)-2-(R)-[(diphenylmethyl)sulfinylJ acetic acid of formula II(R):

with a chloroformate compound of formula V: wherein R is an alkyl, aryl or aralkyl group; optionally in the presence of a suitable base in a suitable solvent to produce a mixed anhydride compound of formula VI:

wherein R 1 is as defined in formula V; and b) amidating the mixed anhydride compound of formula VI obtained in step-(a) with ammonia in a suitable solvent to produce pure armodafinil of formula 1(R) and optionally converting the armodafinil formed into a pharmaceutically acceptable salt thereof.

The term "alkyl", as used herein, denotes an aliphatic hydrocarbon group which may be straight or branched having 1 to 12 carbon atoms in the chain. Preferred alkyl groups have 1 to 6 carbon atoms in the chain. The alkyl may be substituted with one or more "cycloalkyl group". Exemplary alkyl groups include methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, cyclopentylmethyl.

The term "cycloalkyl", as used herein, denotes a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term "Aralkyl", as used herein, denotes an aryl-alkyl group wherein the aryl and alkyl are as herein described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl.

The term "Aryl", as used herein, denotes an aromatic monocyclic or multicyclic ring system of 6 to 10 carbon atoms. The aryl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Exemplary aryl groups include phenyl or naphthyl.

Preferable chloroformate compound of formula V is selected from the group consisting of methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, sec-butyl chloroformate, phenyl chloroformate and the like; and more preferably ethyl chloroformate and isobutyl chloroformate.

The base used in step-(a) is preferably non-nucleophilic base selected from organic and inorganic bases such as linear and cyclic amines selected from Ci -4 lower alkyl tertiary amines e.g. trimethylamine and triethylamine, pyridine, substituted

pyridine, dimethylamino pyridine, lutidine and the like; and carbonates or bicarbonates of alkali or alkaline earth metals such as sodium, potassium, lithium, calcium, barium and the like. Most preferable base is triethylamine.

Exemplary solvents used in step-(a) or step-(b) include, but are not limited to, alcohols, ketones, cyclic ethers, aliphatic ethers, hydrocarbons, chlorinated hydrocarbons, nitriles, esters and the like, and mixtures thereof. Specific solvents are alcohols, hydrocarbons, chlorinated hydrocarbons, and mixtures thereof.

Exemplary alcohol solvents include, but are not limited to, C 1 to C 8 straight or branched chain alcohol solvents such as methanol, ethanol, propanol, butanol, amyl alcohol, hexanol, and mixtures thereof. Specific alcohol solvents are methanol, ethanol, isopropyl alcohol, and mixtures thereof, and most specific alcohol solvent is methanol. Exemplary ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, and the like, and mixtures thereof. Exemplary cyclic ether solvents include, but are not limited to, tetrahydrofuran, dioxane, and the like, and mixtures thereof. Exemplary nitrile solvents include, but are not limited to, acetonitrile and the like, and mixtures thereof. Exemplary ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and the like and mixtures thereof. Exemplary hydrocarbon solvents include, but are not limited to, n-pentane, n-hexane and n-heptane and isomers or mixtures thereof, cyclohexane, toluene and xylene. Specific hydrocarbon solvent is toluene. Exemplary chlorinated hydrocarbon solvents include, but are not limited to, methylene chloride, ethyl dichloride, chloroform and carbon tetrachloride or mixtures thereof. Specific chlorinated hydrocarbon solvent is methylene chloride.

Most preferable solvent used in step-(a) is selected from the group consisting of methylene chloride, toluene, xylene, n-pentane, n-hexane, n-heptane, cyclohexane, and mixtures thereof.

The reaction in step-(a) is carried out at a temperature of about -2O 0 C to about 100°C for at least 30 minutes, specifically at a temperature of about -1O 0 C to about 8O 0 C from about 30 minutes to about 10 hours, and more specifically at about -1O 0 C to about 5O 0 C from about 1 hour to about 5 hours.

The compounds of formula VI formed may be used directly in the next step or the compounds of formula VI may be isolated from the reaction medium and then used in the next step.

The compounds of formula VI are novel and constitute another aspect of the present invention.

The amidation reaction in step-(b) is carried out at a temperature of -10 0 C to about 100 0 C for at least 30 minutes, specifically at a temperature of about -5 0 C to about 8O 0 C from about 30 minutes to about 10 hours, and more specifically at about O 0 C to about 5O 0 C from about 1 hour to about 7 hours. Most preferable solvent used in step-(b) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, and mixtures thereof.

Ammonia used in step-(b) may be in the form of aqueous ammonia or in the form of ammonia gas dissolved in an organic solvent. The organic solvent used for dissolving ammonia gas is selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone.

In one embodiment, the armodafϊnil of formula I(R) obtained in step-(b) is isolated as solid from a suitable organic solvent by methods usually known in the art such as cooling, partial removal of the solvent from the solution, addition of precipitating solvent, or a combination thereof. The substantially pure armodafmil obtained by the above processes may be further dried in, for example, Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor, to further lower residual solvents.

The armodafinil of formula I(R) obtained by the process disclosed herein has a total purity (measured by HPLC) of greater than about 98%, specifically greater than about 99%, more specifically greater than about 99.9%, and still more specifically greater than about 99.95%. Experimental:

The HPLC purity was measured by high performance liquid chromatography by using Waters, alliance 2695 HPLC system having dual wavelength UV detector under the following conditions:

Column : Inertsil 0DS-3V (250 x 4.6 mm), 5. Oμm, Make: GL Science,

Column oven temperature: 40°C

Detection : UV at 220 nm

Flow rate : 1.5 mL/minute Injection volume : 20 μL

Run time : 55 minutes

Diluent : Water: acetonitrile (50:50)

Chiral Purity by HPLC: The chiral purity was measured by high performance liquid chromatography by using Waters, alliance 2695 HPLC system having dual wavelength UV detector under the following conditions:

Column Chiral Pack-AD-H (250 x 4.6 mm), 5.0μm, Make: Diacel,

Column oven temperature 28°C Detection UV at 227 nm Flow rate 0.7 mL/minute

Injection volume 20 μL Run time 25 minutes Diluent Ethanol:n-hexane (50:50) The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES

Example 1

Preparation of 2-[(Diphenylmethyl)sulfinyl] acetic acid

2-[(Diphenylmethyl)thio] acetic acid (416 g, 1.61 mol) was suspended in purified water

(4160 ml) at 25 to 30 0 C. This was followed by the addition of 30% sodium hydroxide solution [prepared by dissolving of 70.90 g (1.77 mol) of sodium hydroxide flakes/pellets in 235 ml of purified water] over a period of 15 minutes at 25 to 3O 0 C. Next, 50% of hydrogen peroxide (142.5 g, 2.095 mol) was added in 5 to 6 hours maintaining

temperature 25 to 35°C under agitation. The reaction mixture was further stirred for 15 to 20 hours at 25 to 35 0 C. After completion of the reaction (starting material should be less than 0.5% by area) toluene (1664 ml) was added and the reaction mixture was stirred for 10 minutes. The resulting biphasic mixture was acidified with concentrated hydrochloric acid (250 ml) under stirring while maintaining the temperature between 25 to 3O 0 C. The resulted mass further stirred at 25 to 3O 0 C for 1 hour. The precipitated product was collected by filtration, washed with water (3 x 832 ml) followed by toluene (416 ml) and dried to produce 416 g of 2-[(diphenylmethyl)sulfmyl] acetic acid as a white crystalline powder (Yield: 94.17%; HPLC Purity: 99.3% by area).

Example 2

Preparation of 2-[(Diphenylmethyl)sulfinyl] acetic acid

2-[(Diphenylmethyl) thio] acetic acid (25 g) was suspended in purified water (100 ml) at 25 to 30 0 C. This was followed by the addition of 30% sodium hydroxide solution (prepared by dissolving of 16.0 g of sodium hydroxide flakes/pellets in 50.0 ml purified water) over a period of 15 minutes at 25 to 3O 0 C. The reaction mass was heated to 40 to 45 0 C. Further N-chlorosuccinimide (20.0 g) was added in 1 to 1.5 hours maintaining temperature 40 to 45°C under agitation. The reaction mixture was further stirred for 10 to 12 hours at 40 to 45 0 C. The reaction mass was cooled to 25 to 3O 0 C after the completion of reaction followed by the addition of toluene (100 ml) and reaction mixture further stirred for 10 minutes. The resulting biphasic mixture was acidified with 50% aqueous sulfuric acid under stirring maintaining temperature at 25 to 30 0 C. The resulted mass was further stirred at 25 to 3O 0 C for 1 hour. The precipitated product was collected by filtration, washed with water (3 x 100 ml) followed by toluene (100 ml) and dried to give the 2-[(diphenylmethyl) sulfinyl] acetic acid as a white crystalline powder (Yield: 60.28%; HPLC Purity: 98.50% by area).

Example 3 Preparation of 2-[(Diphenylmethyl)sulfmyl] acetic acid 2-[(Diphenylmethyl) thio] acetic acid (5 g) was suspended in purified water (50 ml) at 25 to 3O 0 C. This was followed by the addition of (-)-(α)-methyl benzyl amine

(2.345 g) and stirred the reaction mass for 15 minutes at 25 to 3O 0 C. The reaction mixture was further heated at 40 to 45°C followed by addition of sodium hypochlorite (5.28%, 33 ml) over period of 30 minutes. The reaction mixture was further stirred for 2 to 2.5 hours at 40 to 45 0 C. The reaction mass was cooled to 25 to 3O 0 C which is then followed by the addition of toluene (20 ml) and stirred the reaction mixture for 10 minutes. The resulting biphasic mixture was acidified with cone, hydrochloric acid under stirring at 25 to 30 0 C. The resulted mass further stirred at 25 to 3O 0 C for 1.5 hour. The precipitated product was collected by filtration, washed with water (3 x 50 ml) followed by toluene (50 nύ) and dried to give the 2-[(diphenylmethyi) sulfmyl] acetic acid as a crystalline powder (Yield: 78.58%; HPLC Purity: 99.4% by area).

Example 4 Preparation of 2-[(DiphenylmethyI)sulfinyl] acetic acid

2-[(Diphenylmethyl) thio] acetic acid (10 g) was dissolved in methanol (50 ml) at 25 to 3O 0 C. This was followed by the addition of ammonium molybdate (0.40 g) and stirring the reaction mass for 15 minutes at 25 to 30 0 C. The reaction mixture was cooled at 10 to 15 0 C followed by the addition of sodium per carbonate (5.0 g) at 10 to 15 0 C under stirring. The reaction mixture was further stirred for 12 to 14 hours at 20 to 25°C.

This was followed by the addition of purified water (200 ml) and toluene (50 ml) under stirring for 10 minutes. The resulting biphasic mixture was acidified with cone. hydrochloric acid at pH less than 2 under stirring maintaining temperature at 25 to 30 0 C.

The resulted mass further stirred at 25 to 3O 0 C for 1 hour. The precipitated product was collected by filtration, washed with water (3 x 100 ml) followed by toluene (100 ml) and dried to give the 2-[(diphenylmethyl) sulfinyl] acetic acid as crystalline powder (Yield: 87.15%; HPLC Purity: 95.70% by area).

Example 5 Preparation of 2-[(DiphenyImethyI)sulfinyl] acetic acid

2-[(Diphenylmethyl) thio] acetic acid (5 g) was dissolved in toluene: methanol (10:1, 55 ml) at 25 to 30 0 C and the resulting mass was cooled at 0 to 5 0 C. This was followed by the addition of vanadium acetyl acetonoate (0.04 g) and stirred the reaction

mass for 15 minutes at 0 to 5 0 C. The tert-butylhydroperoxide (70% solution, 3.54 g) was added at 0 to 5 0 C under stirring over period of 20 to 30 minutes. The reaction mixture was further stirred for 6 to 7 hours at 0 to 5°C. Next, water (100 ml) was added to the reaction mixture and stirring continued for 1 hour at 10 to 15°C. The precipitated product was collected by filtration, washed with water (3 x 100 ml) followed by toluene (50 ml) and dried to give the 2-[(diphenylmethyl) sulfinyl] acetic acid as a crystalline powder (Yield = 88.15%; HPLC Purity: 98.16% by area).

Example 6 Preparation of 2-[(Diphenylmethyl)sulfinyl] acetic acid

Sodium perborate (15.30 g) was suspended in purified water (23 ml) at 25 to 30 0 C. The resulting mass was cooled to 10 to 15°C. This was followed by addition of acetic anhydride: methanol solution (1:1, 10.2 g dissolved in 10.2 g of methanol) at 10 to 15 0 C and continued stirring for 15 minutes at 10 to 15 0 C. The reaction mass was further cooled to -20 to -25 0 C followed by the addition of 2-[(diphenylmethyl) thio] acetic acid solution (20 gm dissolved in 220 ml toluene: methanol, 10:1) at -10 to -15 0 C under stirring over period of 2.5 hours. The reaction mixture was further stirred for 2 hours at -10 to -15°C. The reaction temperature was increased to 0 to 5°C followed by stirring for 2 hours. Then reaction mass was added to purified water (600 ml) and acidified with cone, hydrochloric acid to below 2.0 pH. The resulting precipitate was stirred for 15 minutes. The precipitated product was collected by filtration and washed with water (3 x 100 ml) and toluene (100 ml) and dried to give the 2-[(diphenylmethyl) sulfinyl] acetic acid as a crystalline powder (Yield = 51.81%, HPLC Purity: 97.0% by area).

Example 7 Preparation of pure armodafinil

Dichloromethane (165.0 gm) was added to (-)-2-(R)-[(diphenylmethyl)sulfinyl] acetic acid (22.00 gm) at 25-3O 0 C and the resulting slurry was cooled at 5-15 0 C followed by addition of triethyl amine (11.352 gm) at 5-15 0 C for 30 minutes. The reaction flask was rinsed with dichloromethane (11.0 gm) and transferred to the reaction assembly. To

the resulting mass was added isobutyl chloroformate (14.30 gm) over period of 60 minutes maintaining temperature between 0-10 0 C followed rinsing of charging system with dichloromethane (11.0 gm) and transferring to the reaction assembly. The resulting mass was further stirred for 15 minutes at 5 to 1O 0 C. The mass temperature was increased to 10 to 15°C followed by stirring for further 60 minutes at 10 to 15°C.Further reaction mass was brought to 20 to 25 0 C and stirred 1 hour at same temperature. The reaction was monitored by HPLC. Purified water (66.0 gm) was added to the resulting mass followed by stirring for 10 minutes at 20 to 25°C. The resulting layers were separated and aqueous layer was further extracted with dichloromethane (55.0 gm). The organic layers were combined and aqueous layer was discarded. The organic layer was further washed with aqueous sodium carbonate solution (5.0% w/w, 66.0 gm) followed by washing with purified water (66.0 gm).The dichloromethane was distilled under reduced pressure at 20- 4O 0 C and degassed further under reduced pressure at 40 to 45 0 C. This was followed by the addition of 23% w/w methanolic ammonia solution (Methanolic ammonia is prepared by purging of ammonia gas in to 87.12 gm of methanol till to get more than 23.0% ammonia concentration) at 15 to 25 0 C and increased temperature to 25 to 3O 0 C. The resulting mass was further stirred for 6 hours at 25 to 3O 0 C. The reaction was monitored by HPLC. This was followed by the addition of purified water (110.0 gm) over a period of 30 to 40 minutes at 25 to 30 0 C followed by 15 minutes stirring at same temperature. Further mass was cooled to 5 to 1O 0 C followed by stirring for 2.0 hours at same temperature. The precipitated product was collected by filtration and spins dried for 60 minutes for complete removal of mother liquor. Further wet cake was washed twice with purified water (44.0 gm each time) and dried under reduced pressure at 35 to 5O 0 C to give the title compound as a white solid.

Weight of Dried material : 18.25 gm

Yield : 83.50 % (w/w)

HPLC Purity (% area) : 99.66 %