Field of Invention

The present invention relates to process for the preparation of Armodafinil comprising recycling unwanted (S)-(+)-isomer of 2-(benzhydrylsulfinyl) acetic acid.

Background of the invention

Armodafinil is chemically known as 2-[(R)-(diphenylmethyl) sulfinyl] acetamide, having molecular formula C15H15NO2S and molecular weight 273.35. The current pharmaceutical product containing this drug is being sold by Cephalon using Nuvigil® as tablets.

Armodafinil is a psychotropic agent, used in the treatment of idiopathic narcolepsy. Another nomenclature for armodafinil is (-) modafinil.

U.S. Pat. No. 4,927,855 discloses preparation comprises: a) oxidation of benzhydrylthioacetic acid to give (±) benzhydrylsulfinyl acetic acid; b) reaction of this with (-)--methylbenzyl amine to give (-)--methylbenzyl amine (-) benzhydrylsulfinyl acetate; c) conversion of this to (-) benzhydrylsulfinyl acetic acid; and finally d) amidation to obtain (-) benzhydrylsulfinyl acetamide. However this process gives low yield with deprived enantiomeric excess as this process does not involves recycling of unwanted isomer.

U.S. Pat. No. 20080214862 discloses a process for preparing racemic 2-[(diphenyl methyl) sulfinyl] acetamide comprising combining 2-[(R)-(diphenylmethyl) sulfinyl]acetamide or 2-[(S)-(diphenylmethyl)sulfinyl]acetamide, at least one organic solvent having a boiling point of above 60 0C.; heating to a temperature of above 600C.; and cooling.

Therefore, there is a need for an alternative synthesis of Armodafinil, which can be used industrial scale, provides higher yields and devoid of the drawbacks of prior art.

Object of the invention

It is therefore an object of the present invention is to provide a process for the preparation of Armodafinil.

Another object of the present invention is to provide a process for the preparation of Armodafinil comprising steps of:
i) esterifying S (+) Benzhydrylsulfinyl acetic acid to obtain S (+) Methyl 2-(benzhydrylsulfinyl) acetate
ii) reducing S (+) Methyl 2-(benzhydrylsulfinyl) acetate to obtain Methyl 2-(benzhydrylthio) acetate
iii) hydrolyzing Methyl 2-(benzhydrylthio) acetate to obtain Benzhydryl thioacetic acid
iv) oxidizing Benzhydryl thioacetic acid to obtain Benzhydrylsulfinyl acetic acid
v) converting Benzhydrylsulfinyl acetic acid to Armodafinil

A further object of the present invention is to provide a process for the preparation of Armodafinil via recycling unwanted (S) (+)-isomer of 2-(benzhydrylsulfinyl) acetic acid comprising steps of:
i) esterifying S (+) Benzhydrylsulfinyl acetic acid to obtain S (+) Methyl 2-(benzhydrylsulfinyl) acetate
ii) reducing S (+) Methyl 2-(benzhydrylsulfinyl) acetate in the presence of chlorinating agent and base in suitable solvent to obtain Methyl 2-(benzhydrylthio) acetate
iii) hydrolyzing Methyl 2-(benzhydrylthio) acetate to obtain Benzhydryl thioacetic acid
iv) oxidizing Benzhydryl thioacetic acid to obtain Benzhydrylsulfinyl acetic acid
v) converting Benzhydrylsulfinyl acetic acid to Armodafinil

Another object of the present invention is to provide the process for the preparation of Armodafinil which is operationally simple, easy to handle and applicable at an industrial scale.

Summary of the invention

In one aspect of the present invention, it provides a process for the preparation of Armodafinil comprising steps of:
i) esterifying S (+) Benzhydrylsulfinyl acetic acid to obtain S (+) Methyl 2-(benzhydrylsulfinyl) acetate
ii) reducing S (+) Methyl 2-(benzhydrylsulfinyl) acetate to obtain Methyl 2-(benzhydrylthio) acetate
iii) hydrolyzing Methyl 2-(benzhydrylthio) acetate to obtain Benzhydryl thioacetic acid
iv) oxidizing Benzhydryl thioacetic acid to obtain Benzhydrylsulfinyl acetic acid
v) converting Benzhydrylsulfinyl acetic acid to Armodafinil

In another aspect of the present invention, it provides a process for the preparation of Armodafinil via recycling unwanted (S) (+)-isomer of 2-(benzhydrylsulfinyl) acetic acid comprising steps of:
i) esterifying S (+) Benzhydrylsulfinyl acetic acid to obtain S (+) Methyl 2-(benzhydrylsulfinyl) acetate
ii) reducing S (+) Methyl 2-(benzhydrylsulfinyl) acetate in the presence of chlorinating agent and base in suitable solvent to obtain Methyl 2-(benzhydrylthio) acetate
iii) hydrolyzing Methyl 2-(benzhydrylthio) acetate to obtain Benzhydryl thioacetic acid
iv) oxidizing Benzhydryl thioacetic acid to obtain Benzhydrylsulfinyl acetic acid
v) converting Benzhydrylsulfinyl acetic acid to Armodafinil

Detailed description of the invention

Schematic depiction of the present invention is as follows:-

For the purpose of this specification, the meaning of the term “esterifying/ esterification” as used hereinabove that includes but not limited to adding, suspending, mixing and treating substrate with known esterifying agent according to methods reported in the literature and prior art. In the present invention, esterification of substrate involves i) preparation of base addition salt of substrate by using alkali hydroxide in Dimethylformamide; and ii) esterification of base addition salt of substrate by using dimethyl sulfate in methanol followed by pH adjustment. The esterification may carried out at temperature range between 20 0C to 50 0C. The preferred one is 25 0C.

For the purpose of this specification, the meaning of the term “reducing/reduction” as used hereinabove to reducing S (+) Methyl 2-(benzhydrylsulfinyl) acetate in the presence of that includes but not limited to reducing agent known in the literature and prior art.

In preferred embodiment, reduction of S (+) Methyl 2-(benzhydrylsulfinyl) acetate is carried out in the presence of chlorinating agent and base in suitable solvent.

It has been serendipitously found that this sulfoxide reduction can be carried out very selectively with regard to reduce the sulfoxide and not the carbonyl group.

The reduction may carried out at temperature range between -20 0C to 30 0C. The preferred one is -10 0C.

For the purpose of this specification, the meaning of term “chlorinating agent” as used herein above that includes PCl3, PCl5, COCl2, SO2Cl2 and SOCl2 and the like or mixture thereof.

For the purpose of this specification, the meaning of term “base” as used herein above that includes base inert to the chlorinating agent, can be employed organic bases, such as tertiary amines, both aromatic and aliphatic, i.e. triethylamine, diisopropylethylamine, pyridine, picolines, lutidines, N-methylmorpholine, quinoline, quinolidine, N-methyl pyrrolidine; olefins, i.e. amylene, hexene, cyclooctene, undecene and epoxy compounds, i.e. ethylene oxide and propylene oxide and the like or mixture thereof. The preferred one is beta-picoline.

For the purpose of this specification, the meaning of term “suitable solvent” as used herein above that includes solvents inert to the chlorinating agent are suitable the halogenated solvents, such as methylene chloride, dichloromethane, carbon tetrachloride, chloroform, freon, dichloroethane; ethers, such as ethyl ether, isopropyl ether, tetrahydrofuran; esters, such as ethyl acetate, butyl acetate, dimethyl carbonate, aromatic hydrocarbons, such as benzene, toluene, nitrobenzene, and linear or branched, saturated or partially unsaturated, C5 -C10 aliphatic hydrocarbons and the like or mixture thereof. The preferred one is methylene chloride.

For the purpose of this specification, the meaning of the term “hydrolysis” as used hereinabove that includes but not limited to adding, suspending, mixing and treating substrate with known hydrolysing agent according to methods reported in the literature and prior art. In the present invention, hydrolysis of substrate involves hydrolysis of substrate by using alkali hydroxide in DM water followed by pH adjustment. The hydrolysis may carried out at temperature range between 30 0C to and 90 0C. The preferred one is 70 0C.

For the purpose of this specification, the meaning of the term “oxidizing/ oxidation” as used hereinabove that includes adding, suspending, mixing and treating substrate with known oxidizing agent according to methods reported in the literature and prior art. In present invention, oxidation of substrate involves i) preparation of base addition salt of substrate by using aqueous alkali hydroxide in DM water; and ii) oxidation of base addition salt of substrate by using sodium hypochlorite and aqueous alkali hydroxide in DM water followed by pH adjustment. The oxidation may carried out at temperature range between 20 0C to and 50 0C. The preferred one is 40 0C.

For the purpose of this specification, the meaning of the term “resolution” as used hereinabove that includes but not limited to adding, suspending, mixing and treating substrate with known resolving agent according to methods reported in the literature and prior art.

For the purpose of this specification, the meaning of the term “ammonolysis” as used hereinabove that includes but not limited to adding, suspending, mixing and treating substrate with known ammonolysing agent according to methods reported in the literature and prior art.

For the purpose of this specification, the meaning of the term “converting” as used hereinabove that includes but not limited to converting Benzhydrylsulfinyl acetic acid to Armodafinil according to methods reported in the literature and prior art. It may involve resolution, ammonolysis, esterification etc.

In the examples, purity of obtained compounds was analyzed by HPLC with column C-18, 5µ Endcapped, at 225 nm.

The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.

Example 1

Recovery of S-(+)-2-(Benzhydrylsulfinyl) acetic acid

S (+) -2-(benzhydrylsulfinyl) acetic acid. S (-) alpha methyl benzyl amine salt mother liquor (1000 ml) was stirred at 30-40°C and acidified with conc. HCl at 30-40°C till pH 1.5-2. The reaction mass was stirred at 30-40°C for 15 minutes and at 25-30°C for 1 hour. The obtained solid was filtered, and washed with DM water. The wet cake was dried at 50-55°C to get 94 – 96 gm of the S (+) -2-(benzhydrylsulfinyl) acetic acid.
HPLC purity  98-99.5 %,
SOR  +290 (C=1 in methanol at 200C)
Chiral purity  85-90 % of S-isomer

Example 2

Preparation of S (+) Methyl 2-(Benzhydrylsulfinyl) acetate

NaOH powder (10 g) was charged to a stirred mixture of DMF (70 ml) and S-(+)-2-(Benzhydrylsulfinyl) acetic acid (70 g). The reaction mass was stirred at RT till solid (salt) precipitated out. Methanol (420 ml) was charged and stirred to dissolve the solid (salt) completely. To the clear solution, Dimethyl sulphate was added with in 30 minutes at RT. The reaction mass was stirred at RT for 3 hours. The pH of reaction mass was adjusted to 8.0-9.0 using ammonia solution and stirred for 15 minutes. Solvent was distilled out completely below 55°C under vacuum. The residue (liquid) was dissolved in dichloromethane (350 ml) and washed this dichloromethane layer with DM water. A solvent was distilled out completely at 55°C to get 65-70 gm of S (+) Methyl 2-(Benzhydrylsulfinyl) acetate.
HPLC purity  97-99 %
% Yield  90 -95 %

Example 3

Preparation of Methyl 2-(Benzhydrylthio) acetate

The mixture of dichloromethane (750 ml) and S (+) Methyl 2-(benzhydrylsulfinyl) acetate (50 g) was cooled to -10°C. Beta-Picoline (35 ml) was charged in the reaction mass at -10°C. Phosphorous trichloride (30 ml) was added in the reaction mass at -10°C. The reaction mass was stirred -10°C for 1 hour. DM Water (250 ml) was added in the reaction mass at -10°C and stirred for 10 minutes. A dichloromethane layer was separated out and washed with DM water. A solvent was distilled out the completely at 50°C to get 40 - 45 gm of Methyl 2-(Benzhydrylthio) acetate.
HPLC purity  60-65 %
% Yield  90-95 %

Example 4

Preparation of Benzhydrylthio acetic acid

Methyl 2-(benzhydrylthio) acetate (40g) was charged to a solution of NaOH (15 g) dissolved in DM water (400 ml). The reaction mass was heated to 70°C for 2 hours and then cooled to 25-30°C. Dichloromethane (80 ml) was charged in the reaction mass. A reaction mass was acidified using 50% HCl at 25-30°C till pH 1.5-2.0. A dichloromethane layer was separated out and washed with DM water. A solvent was distilled out completely below 50°C to get 20-25 gm of Benzhydrylthio acetic acid.
HPLC purity  85-90 %
% Yield  60-65 %

Example 5

Preparation of 2-(Benzhydrylsulfinyl) acetic acid

Benzhydryl thioacetic acid (20 g) was charged to stirred mixture of DM water (160 ml) and NaOH (3.4 g). Sodium hypochlorite (13%w/v) (250 ml) was added within 1 hour at 30-35°C. The reaction mass was stirred for 1 hour at 40°C and cooled the reaction mass to 20-25°C and washed it with toluene (40 ml). The aqueous layer was acidified with conc. HCl at 20-30°C till pH 1.5-2.0 and stirred for 1 hour. The solid was filtered, and washed with DM water. The wet cake was dried at 50-55°C to get 15-20 gm of 2-(Benzhydrylsulfinyl) acetic acid.
HPLC purity  96-98 %
% Yield  70-75 %

Example 6

Resolution of 2-(Benzhydrylsulfinyl) acetic acid

S-(-)-α-Methyl benzylamine (5 g) was added to a stirred mixture of DM water (100 ml) and 2-(Benzhydrylsulfinyl) acetic acid (15 g) at 40°C. The reaction mass was heated to 40°C for 10 minutes. The solid (salt 1) was filtered at 40°C. The mixture of DM water (100 ml) and Wet cake was heated to 80-85°C for 10 minutes to dissolve the solid. The reaction mass was filtered and the filtrate was heated to 80-85°C for 10 minutes. The reaction mass was cooled to 25-30°C within 3 hours. The solid (salt 2) was filtered and washed with DM water (3×25 ml). The wet cake was charged in DM water (70 ml) and stirred. The reaction mass was acidified using conc. HCl at 30-40°C till pH 1.5-2.0 and stirred for 1 hour at 25-30°C. The solid was filtered and washed with DM water (3×25 ml). The wet cake was dried at 50-55°C to get 3-5 gm of the product [R (-) isomer] of 2-(Benzhydrylsulfinyl) acetic acid.
HPLC purity  99- 99.5 %,
SOR  + 39.3 0 (C=1 in methanol at 200C)
Chiral HPLC purity  99-99.9 % of R-isomer
% Yield  60-65 %