State of the art [(diphenylmethyl)-sulfinyl] acetamide of formula (I) and also known with the name of modafinil (11) has a stimulating effect on the central nervous system.

The psychotropic activity of this substance was first described in US patent 4,177, 290.

Two different methods for preparing modafinil are also given in this patent, both methods involving the oxidation reaction of 2 [(diphenylmethyl) thio] acetamide with hydrogen peroxide.

In the first method of synthesis 2 [(diphenylmethyl)thio] acetamide is prepared by reacting 2 [(diphenyimethyl) thio] acetylchloride with ammonia, while in the second one, namely the industrial method, 2 [ (diphenylmethyl) thio] acetamide is prepared by reacting the corresponding 2 [ (diphenylmethyl) thio] acetylmethylester with ammonia.

In the first method discussed in this prior patent significant quantities of the sulfone (A) are formed

This involves considerable problems in that as it is chemically very similar to modafinil, its separation from the desired product is problematic.

Instead, in the process described in example 1a, significant quantities of the by- products (B) and (C) are obtained:

(B) (C) Patent application US 2002/0043207A1 describes a process which aims to avoid the aforesaid drawbacks.

In particular this process also involves the oxidation of 2 [ (diphenylmethyl) thio] acetamide conducted with hydrogen peroxide mixed with a cyclic, branched or linear alcoholic solvent, a strong mineral acid or a phase transfer catalyst possibly in the presence of an inert liquid as diluent to inhibit the further oxidation to sulfone and thus inhibit the formation of by-product (A). The modafinil separated from the reaction mixture by filtration and washing with water has a purity of 98- 99% after drying and contains in general a quantity of sulfone (A) less than 0. 1%.

The modafinil thus obtained can be further purified by crystallisation from a solvent chosen from methanol, ethanol, dimethylcarbonate, acetone and mixtures

thereof. The aforesaid impurities can be further reduced in this way.

According to this prior patent modafinil crystallised with the aforesaid solvents must be further crystallised to polymorphic form (I), i. e. the polymorphic form normally used in pharmaceutical formulations, by crystallising it from specific solvents or solvent anti-solvent mixtures.

This process enables crude modafinil to be obtained with high purity and with fairly high reaction yields, between 75.7% and 85%, calculated on thioacetamide.

These yields fall considerably to values between 49 and 71% during the first crystallisation, calculated once again on thioacetamide, and fall drastically during the crystallisation of modafinil to give the polymorphic form (I) of modafinil.

The need was therefore felt to provide a process which would enable modafinil in polymorphic form (I) to be obtained with high yields and with a low content of the aforesaid impurities.

Summary of the invention The applicant has unexpectedly found that the process of the present invention enables the polymorphic form (I) of modafinii to be obtained with the process of the present invention, having high yields and a low content of the aforesaid impurities, which comprises the following stages: a) reacting diphenylmethylthioacetic acid (II) with a linear or branched C1-C5 alcohol under acid catalysis to obtain the corresponding ester of formula (III),

(111) b) reacting the ester (III) with hydrogen peroxide in the presence of an organic acid in an apolar solvent to obtain the corresponding sulfinyl ester of formula (IV),

(fiv) c) reacting the ester of formula (IV) with ammonia in linear or branched C1-C5 alcoholic solvent, d) treating the reaction mixture derived from the preceding stage, and from which the reaction solvent was previously removed, with water and ethyl acetate in order to precipitate modafinil.

In this respect the applicant has found that with the aforesaid process the polymorphic form (I) of modafinil can be obtained with reaction yields of about 80%, calculated on the diphenylmethylthioacetic acid (II) intermediate, and in which the quantity of sulfone of formula (A) is between 0.2-0. 5%, while the quantity of acid of formula (C) or of formula (II) i. e. the diphenylmethylthioacetic acid and the ester of formula (III) are less than 0.1% by weight for each by-

product.

In particular the applicant has surprisingly found that modafinil derived from stage (d) is already in modafinil form (I).

Furthermore the applicant has surprisingly found that crystallising the polymorphic form (I) of modafinil derived from stage (d) from DMF and acetone, form (I) of modafinil can be obtained with a yield of about 63% again calculated on the acid (II). The crystallised product contains the impurity (A) in a quantity less than 0.05%, the impurity consisting of the acid (II) and the ester (III) in quantities less than 0.02% each.

The applicant has also found that if form (I) of modafinil, derived from the first crystallisation, is crystallised from DMF and water, modafinil granule size can be increased from values such that at least 10% of said granules have a size of more than 200 um on sieving up to values such that at least 50% have a size of more than 250 um on sieving. The increase in granule size of the active principle can be advantageous in preparing certain types of pharmaceutical formulations.

Description of the figures Figure 1 shows the XRD spectrum of form (I) of modafinil derived from stage (d) of the process of the present invention, where the y-axis represents the number of counts/second while the x-axis represents the measurement of angle 28 in °.

Figure 2 shows the XRD spectrum of form (I) of modafinil derived from the crystallisation from DMF and acetone, where the y-axis represents the number of counts/second while the x-axis represents the measurement of angle 20 in °.

Figure 3 shows the XRD spectrum of polymorphic form (I) of modafinil derived from the crystallisation from DMF and water to increase its particle size distribution, where the y-axis represents the number of counts/second while the x- axis represents the measurement of angle 20 in °.

Detailed description of the invention The alcohol used in stage (a) of the process of the present invention is preferably methanol, while the acid used as catalyst is preferably a strong organic acid and even more preferably methanesulfonic acid.

The solvent used in stage (b) is preferably a hydrocarbon of aliphatic,

cycloaliphatic or aromatic type, such as for example hexane, cyclohexane, benzene or toluene ; in accordance with a particularly preferred embodiment the solvent is toluene.

The hydrogen peroxide used in stage (b) has a concentration between 100 and 200 volumes.

The solvent used in stage (c) is preferably methanol, while the organic acid used in the same stage is acetic acid; in accordance with a particularly preferred embodiment the acid is 80% concentrated acetic acid.

In stage (d) in which modafinil is precipitated with water and ethyl acetate, the water used has a pH preferably of between 7 and 10. This pH is preferably obtained by adding sodium carbonate to water to a concentration between 5 and 10% by weight on the total weight of the water used.

In accordance with a particularly preferred embodiment, in the first crystallisation of form (I) of modafinil, weight ratios of acetone to dimethylformamide equal to 3: 1 are used, while in the possible second crystallisation the weight ratio of dimethylformamide : water is equal to 1: 2.

Diphenylmethylthioacetic acid is prepared as described in the following synthesis scheme as already described in part in example 1a of US 4,177, 290. NaBH4 1) HCI HCI dz 2) thiourea Benzophenone diphenylcarbinol diphenylmethylthiouronium chloride l) NaOH \ \ __ ___

The following illustrative but non-limiting examples are given of the process for preparing form (I) of modafinil of the present invention, form (I) of modafinil crystallised from DMF and acetone, and finally the product crystallised from DMF and water such that on sieving at least 50% of granules have values greater than 250 um in accordance with the aforesaid crystallisation processes, these being a further aspect of the present invention.

EXAMPLE 1 Preparation of crystallised form fi) of modafinil 22.3 kg of diphenylmethylthioacetic acid (II), 67 kg of methyl alcohol and 1.12 kg of methanesulfonic acid are fed under nitrogen into a reactor having undergone 2 vacuum nitrogen scavenging treatments. The reaction mixture is then heated under reflux for about 12 hours again under nitrogen. At the end of this operation methanol is distilled off without the temperature exceeding 60°C until a pasty residue is obtained. 56 kg of toluene are added. The entire contents of a 10% aqueous solution of sodium carbonate composed of 11.2 kg of deionised water and 1.12 kg of sodium carbonate are then added to the aforesaid mixture.

The phases are left to separate. The heavier aqueous phase is then removed while 5. 6 kg of 80% acetic acid are added to the toluene phase again under nitrogen and at the end of the addition 9.8 kg of 197 volume hydrogen peroxide are added.

The reaction mass is stirred under nitrogen at 45-50°C for at least 12 hours and 22.3 kg of deionised water are added. The hydrogen peroxide excess is decomposed with 27.9 kg of 20% sodium bisulfite.

The phases are left to separate. The heavier aqueous phase is discharged and removed.

44.6 kg of methyl alcohol are fed under vacuum under a closed cycle nitrogen

stream into the reactor which contains the residue from the oxidation reaction.

Atmospheric pressure is then restored under nitrogen and the mass is cooled to 30-40°C.

22.3 kg of methyl alcohol and 22.3 kg of 30% aqueous ammonia are then fed into a reactor under a closed cycle nitrogen stream and cooled to a temperature between 25 and 35°C and the mixture thus obtained is stirred. The previous organic (methanolic) phase which contains the ester (III) is then added and the reaction mixture is maintained for about 8 hours at 25-35°C. The reactor is then placed slowly under vacuum and excess ammonia is distilled off. Atmospheric pressure is restored in the reactor by means of nitrogen. The mass is cooled to 40-50°C and, while maintaining the same temperature, the entire quantity of a 7. 5 wt% aqueous solution of sodium carbonate, formed from 44.6 kg of deionised water and 3.35 kg of sodium carbonate, is added.

44. 6 kg of ethyl acetate are added to the mixture thus prepared under a closed cycle nitrogen stream.

The mixture is then stirred for about 30 minutes at 40-50°C, cooled to 20-25°C and is then stirred at this temperature for at least 30 minutes.

The suspension is centrifuged, the centrifuged product is washed with 22.3 kg of deionised water under a closed cycle nitrogen and is pressed. The pressed product is then washed with 22.3 kg of ethyl acetate and further pressed.

The wet pressed centrifuged product is fed into a reactor to which 22.3 kg of N, N- dimethylformamide are added. The reaction mass is heated to a temperature between 55 and 60°C while stirring and 67 kg of acetone are added. The mass is cooled to 50-55°C and stirred for about 30 minutes. The product is then cooled to 5-10°C and is stirred for at least 30 minutes. The suspension is centrifuged and the product is washed with 22.3 kg of acetone.

The product is then pressed, the wet product then being fed into a dryer and dried at 65-75°C. The dried product is fed into a reciprocating granulator fitted with a 32 mesh screen and then placed into a mixer to be homogenized for about 45 minutes.

13.9 kg of dry product are obtained with a yield equal to 62. 5% calculated on the

(diphenylmethyl) thioacetic acid and with a granule size such that on sieving at least 10% have a size greater than 200 jm.

EXAMPLE 2 Preparation of crystallised form (I) of modafinil with a granule size such that on sieving at least 50% have a size greater than 250 um.

14.2 kg of form (I) of modafinil obtained as described in the previous example and 21.3 kg of N, N-dimethylformamide are fed into a reactor. The reaction mixture is stirred and heated under nitrogen to a temperature between 65 and 70°C. While maintaining this temperature, 42.6 kg of deionised water are fed over a period of 30 minutes. When only half the water has been added, the product begins to precipitate. The reaction mass is further stirred at 65-70°C for about 30 minutes, is then cooled to 5-10°C for about 30 minutes. The suspension is centrifuged and the centrifuged product is washed with 28.4 kg of deionised water. The pressed product is fed into a dryer at 65-75°C. 13.5 kg of dry product are obtained with a reaction yield of 95% calculated on the initial crystallised form (I) of modafinil, the particle size distribution being such that at least 50% of the granules have a size greater than 250 pm.