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                     Synthesis of Adrafinil & Modafinil
                        US Pat 4,066,686 & 4,177,290                      
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            Benzhydrylsulphinyl-acetohydroxamic Acid (Adrafinil)

                             Ph     O     O
                               \   //    //
                                CH-S-CH2-C
                               /          \
                             Ph            NHOH

                            Code No. CRL 40,028

    15.2 g (0.2 mol) of thiourea and 150 ml of demineralized water are
introduced into a 500 ml three-neck flask equipped with a central
mechanical stirrer, and with a dropping funnel and a condenser on the
(respective) side-necks.The temperature of the reaction mixture is brought
to 50øand 49.4g (0.2 mol) of bromodiphenylmethane are added all at once
whilst continuing the heating. After refluxing for about 5 minutes, the
solution,  which has become limpid, is cooled to 20øC and 200 ml of 2.5 N
NaOH are then added dropwise whilst maintaining the said temperature. The
temperature is then again kept at the reflex for 30 minutes after which,
when the mixture has returned toordinary temperature (15-25øC), the aqueous
solution is acidified with 45 ml of concentrated hydrochloric acid. The
supernatant oil is extracted with 250 ml of diethyl ether and the organic
phase is washed with 4x80 ml of water and then dried over magnesium
sulphate. 39 g of crude diphenylmethane-thiol are thus obtained. Yield
97.5%

Benzhydryl-thioacetic acid

    10 g (0.05 mol) of diphenylmethane-thiol and 2g (0.05 mol) of NaOH
dissolved in 60 ml of demineralised water are introduced successively into
a 250 ml flask equipped with a magnetic stirrer and a reflux condenser. The
reactants are left in contact for 10 minutes whilst stirring, and a
solution consisting of 7g (0.075 mol) of chloroacetic acid, 3g (0.075 mol)
of NaOH pellets and 60 ml of demineralized water is then added all at once.
The aqueous solution is gently warmed to about 50øC for 15 minutes, washed
with 50 ml of ether, decanted and acidified with concentrated hydrochloric
acid. after filtration, 10.2g of benzhydryl-thioacetic acid are thus
obtained. Melting point 129-130øC. Yield 79%.

Ethyl benzhydryl-thioacetate

    The following reaction mixture is heated under reflux for 7 hours: 10.2
g (0.0395 mol) of benzhydryl-thioacetic acid, 100 ml of anhydrous ethanol
and 2 ml of sulphuric acid. When heating has been completed, the ethanol is
evaporated in vacuo; the oily residue is taken up in 100 ml of ethyl ether
and the organic solution is then washed with water, with an aqueous sodium
carbonate solution and then with water until the wash waters have a neutral
pH. After drying over sodium sulphate, the solvent is evaporated. 10.5g of
ethyl benzhydryl-thioacetate are thus obtained. Yield 93%.

Benzhydryl-thioacetohydroxamic acid

    The following three solutions are prepared:

    1: Ethyl Benzhydryl-thioacetate 10.8 g (0.0378 mol)
       Methanol                     40 ml
    2: Hydroxylamine hydrochloride  5.25 g (0.0756 mol)
       Methanol                     40 ml
    3: Potassium Hydroxide pellets  7.3 g (0.0134 mol)
       Methanol                     40 ml

    The solutions are heated, if necessary, until they become limpid, and
when the temperatures have again fallen to below 40øC, the solution of
potassium hydroxide in methanol is poured into the solution of
hydroxylamine hydrochloride in alcohol. Finally, at a temperature of about
5ø to 10øC, the solution of ethyl benzhydryl-thioacetate is added in its
turn. After leaving the reactants in contact for 10 minutes, the sodium
chloride is filtered off the limpid solution obtained is kept for about 15
hours at ordinary temperature. The methanol is then evaporated under
reduced pressure, the residual oil is taken up in 100 ml of water and the
aqueous solution is acidified with 3 N hydrochloric acid. The hydroxamic
acid which has crystallized is filtered off, washed with water and then
dried. 9.1 g of product are obtained. Yield = 87.5%. Melting point
118-120øC.

Benzhydrylsulfinyl-acetohydroxamic Acid (CRL 40,028)

    10.4g (0.038 mol) of benzhydryl-thioacetohydroxamic acid are oxidized
at 40øC, over the course of 2 hours, by means of 3.8 ml (0.038 mol) of
hydrogen peroxide of 110 volumes strength (33%), in 100 ml of acetic acid.

    When the oxidation has ended, the acetic acid is evaporated under
reduced pressure and the residual oil is taken up in 60 ml of ethyl
acetate. The product which has crystallized is filtered off and then
purified by recrystallisation from a 3:2 (by volume) mixture of ethyl
acetate and isopropyl alcohol.

    8 g of CRL 40,028 are thus obtained. Melting point 159-160øC. Yield
73%. Solubility in water <1 g/litre.

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                  Benzhydrylsulphinylacetamide (Modafinil)

                             Ph     O     O
                               \   //    //
                                CHÄSÄCH2ÄC
                               /          \
                             Ph            NH2

                            Code No.: CRL 40,476

Benzhydrylthioacetyl chloride

    19.5g (0.076 mol) of benzhydrylthioacetic acid (see Modafinil synthesis
above for preparation) in 114 ml of benzene are placed in a three-necked
flask provided with a condenser and a dropping funnel. The mixture is
heated and 19 ml of thionyl chloride are added drop by drop. Once the
addition is complete, the reflux is continued for about I hour, cooling and
filtering are carried out and the benzene and the excess thionyl chloride
and then evaporated. In this way, a clear orange oil is obtained.

Benzhydrylthioacetamide

    35 ml of ammonia in 40 ml of water are introduced into a three-necked
flask provided with a condenser and a dropping funnel and the
benzhydrylthioacetyl chloride dissolved in about 100 ml of methylene
chloride is added drop by drop. Once the addition is complete, the organic
phase is washed with a dilute solution of soda and dried over Na2SO4, the
solvent is evaporated and the residue is taken up in diisopropyl ether; in
this way, the benzhydrylthioacetamide is crystallized. 16.8 g of product
(yield 86%) are obtained. M.p. 110øC.

CRL 40,476

    14.39 g (0.056) of benzhydrylthioacetamide are placed in a balloon
flask and 60 ml of acetic acid and 5.6 ml of H2O2 (about 110 volumes, 33%)
are added. The mixture is left in contact for one night at 40øC. and about
200 ml of water are then added; the CRL 40476 crystallizes. By
recrystallization from methanol, 11.2 g of benzhydrylsulphinylacetamide are
obtained. Yield: 73%. M.p. 164-66øC.

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