PROCESS FOR THE PREPARATION OF METHYLPHENIDATE AND PHARMACEUTICAL SALTS THEREOF

1 . A process for the recrystallization of di-threo-methylphenidate hydrochloride;

wherein the recrystallized di-threo-methylphenidate hydrochloride comprises a total of less than about 0.1 area % of an impurity compound selected from the group consisting of

an impurity compound of formula (IMP-5)

an impurity compound of formula (IMP-6)

an impurity compound of formula (IMP-15)

an impurity compound of formula (IMP-16)

and mixtures thereof; comprising the steps of

(a) dissolving di-threo-methylphenidate hydrochloride in a mixture of an organic solvent and water; wherein the organic solvent is selected from the group consisting of ethanol and isopropanol; and wherein the water is present in an amount in the range of from about 0.1 wt/wt equiv. to about 0.6 wt/wt equiv.;

(b) heating the mixture to about reflux temperature;

(c) optionally distilling off between about 20% and about 65% by volume of the mixture of an organic solvent and water;

(c) cooling the mixture to a temperature less than about room temperature; and

(d) isolating the di-threo-methylphenidate as a solid.

2 . A process as in claim 1 , wherein the organic solvent is ethanol; and wherein the water is present in an amount of about 0.12 wt/wt equiv.

3 . A process as in claim 1 , wherein the recrystallized di-threo-methylphenidate hydrochloride comprises a total of less than about 0.05 area % of the impurity compound selected from the group consisting of the impurity compound of formula (IMP-5), the impurity compound of formula (IMP-6), the impurity compound of formula (IMP-15), the impurity compound of formula (IMP-16), and mixtures thereof.

4 . A process for removing or reducing the amount of one or more of an impurity compound of formula (IMP-A)

or a salt thereof, an impurity compound of formula (IMP-B)

or a salt thereof, an impurity compound of formula (IMP-C)

or a salt thereof, or an impurity compound of formula (IMP-D)

or a salt thereof,

from a pharmaceutically acceptable salt of di-threo-methylphenidate;

comprising the steps of

I. providing a mixture of

i. di-threo-methylphenidate sulfate;

ii. an impurity compound selected from the group consisting of a sulfate salt of the impurity compound of formula (IMP-A), a sulfate salt of the impurity compound of formula (IMP-B), a sulfate salt of the impurity compound of formula (IMP-C), a sulfate salt of the impurity compound of formula (IMP-D), and mixtures thereof;

II. adding an organic solvent to the mixture of Step 1 to yield a second mixture; and

III. reacting the second mixture of Step 2 with an acid; in the presence of water; wherein the water is present in an amount in the range of from about 0.05 wt/wt equiv. to about 1.0 wt/wt equiv.;

to yield a product comprising a corresponding pharmaceutically acceptable salt of di-threo-methylphenidate in a mixture with a corresponding impurity compound selected from the group consisting of a corresponding pharmaceutically acceptable salt of the impurity compound of formula (IMP-A), a corresponding pharmaceutically acceptable salt of the impurity compound of formula (IMP-B), a corresponding pharmaceutically acceptable salt of the impurity compound of formula (IMP-C), a corresponding pharmaceutically acceptable salt of the impurity compound of formula (IMP-D), and mixtures thereof;

wherein the mixture of Step 1, is prepared according to a process comprising the steps of:

A. providing a composition comprising

i. di-threo-ritalinic acid or pharmaceutically acceptable salt thereof; and

ii. one or more of an impurity precursor selected from the group consisting of an impurity compound of formula (IMP-1)

or a salt thereof, an impurity compound of formula (IMP-2)

or a salt thereof, an impurity compound of formula (IMP-11)

or a salt thereof, and an impurity compound of formula (IMP-12)

or a salt thereof;

B. reacting the composition of Step A with dimethylcarbonate, wherein the dimethylcarbonate is present in an amount in the range of from about 2.5 to about 8.0 molar equivalents;

in the presence of methanol, wherein the methanol is present in an amount in the range of from about 0.75 to about 5.0 molar equivalents, wherein said methanol is added as a separate components, wherein the methanol is added in one or more portions or aliquots, and wherein the amount of methanol is independent of any methanol which may be later introduced into the reaction mixture;

in the presence of sulfuric acid, wherein the sulfuric acid is present in an amount in the range of from about 1.05 to about 2.5 molar equivalents;

at a temperature in the range of from about room temperature to about 90° C.; to yield a mixture comprising:

i. di-threo-methylphenidate sulfate; and

ii. the impurity compound selected from the group consisting of the sulfate salt of the impurity compound of formula (IMP-A), the sulfate salt of the impurity compound of formula (IMP-B), the sulfate salt of the impurity compound of formula (IMP-C), the sulfate salt of the impurity compound of formula (IMP-D), and mixtures thereof.

5 . A process as in claim 4 , wherein the acid of Step 3 is hydrochloric acid.

6 . A process as in claim 4 , wherein the amount of the impurity selected from the group consisting of the pharmaceutically acceptable salt of the impurity compound of formula (IMP-A), the pharmaceutically acceptable salt of the impurity compound of formula (IMP-B), the pharmaceutically acceptable salt of the impurity compound of formula (IMP-C), the pharmaceutically acceptable salt of the impurity compound of formula (IMP-D), and mixtures thereof; is present in an amount less than about 0.05 area %.

7 . A process for removing or reducing the amount of one or more of an impurity compound of formula (IMP-A)

or a salt thereof, an impurity compound of formula (IMP-B)

or a salt thereof, an impurity compound of formula (IMP-C)

or a salt thereof, or an impurity compound of formula (IMP-D)

or a salt thereof; from di-threo-methylphenidate or a pharmaceutically acceptable salt of di-threo-methylphenidate;

comprising the steps of

I providing a mixture of

i. di-threo-methylphenidate sulfate;

ii. an impurity compound selected from the group consisting a freebase impurity compound of formula (IMP-A), a freebase impurity compound of formula (IMP-B), a freebase impurity compound of formula (IMP-C), a freebase impurity compound of formula (IMP-D), and mixtures thereof;

iii an organic phase comprising an organic solvent2

II reacting the mixture of Step 1 with an acid; in the presence of water; wherein the water is present in an amount in the range of from about 0.05 wt/wt equiv. to about 1.0 wt/wt equiv.;

to yield a product comprising a corresponding pharmaceutically acceptable salt of di-threo-methylphenidate in a mixture with a corresponding impurity compound selected from the group consisting of a corresponding pharmaceutically acceptable salt of the impurity compound of formula (IMP-A), a corresponding pharmaceutically acceptable salt of the impurity compound of formula (IMP-B), a corresponding pharmaceutically acceptable salt of the impurity compound of formula (IMP-C), a corresponding pharmaceutically acceptable salt of the impurity compound of formula (IMP-D), and mixtures thereof;

wherein the mixture of Step 1, is prepared according to a process comprising the steps of:

A. providing a composition comprising

a. di-threo-ritalinic acid or pharmaceutically acceptable salt thereof; and

b. an impurity precursor selected from the group consisting of an impurity compound of formula (IMP-1)

or a salt thereof, an impurity compound of formula (IMP-2)

or a salt thereof, an impurity compound of formula (IMP-11)

or a salt thereof, an impurity compound of formula (IMP-12)

or a salt thereof, and mixtures thereof;

B. reacting the composition of Step A with dimethylcarbonate, wherein the dimethylcarbonate is present in an amount in the range of from about 2.5 to about 8.0 molar equivalents;

the presence of methanol, wherein the methanol is present in an amount in the range of from about 0.75 to about 5.0 molar equivalents, wherein said methanol is added as a separate components, wherein the methanol is added in one or more portions or aliquots, and wherein the amount of methanol is independent of any methanol which may be later introduced into the reaction mixture;

in the presence of sulfuric acid, wherein the sulfuric acid is present in an amount in the range of from about 1.05 to about 2.5 molar equivalents;

at a temperature in the range of from about room temperature to about 90° C.; to yield a mixture comprising

a. di-threo-methylphenidate sulfate; and

b. an impurity compound selected from the group consisting of a sulfate salt of the impurity compound of formula (IMP-A), a sulfate salt of the impurity compound of formula (IMP-B), a sulfate salt of the impurity compound of formula (IMP-C), a sulfate salt of the impurity compound of formula (IMP-D), and mixtures thereof;

C. reacting the mixture prepared in Step B with a base; and adding an organic solvent; to yield a mixture of di-threo-methylphenidate free base and the impurity compound selected from the group consisting of the freebase impurity compound of formula (IMP-A), the freebase impurity compound of formula (IMP-B), the freebase impurity compound of formula (IMP-C), the freebase impurity compound of formula (IMP-D), and mixtures thereof; in a biphasic mixture comprising an aqueous phase and an organic phase;

D. separating the phases of the biphasic mixture one from the other; wherein the di-threo-methylphenidate free base, and the impurity compound selected from the group consisting of the freebase impurity compound of formula (IMP-A), the freebase impurity compound of formula (IMP-B), the freebase impurity compound of formula (IMP-C), the freebase impurity compound of formula (IMP-D), and mixtures thereof, are present in the organic phase.

8 . A process as in claim 7 , wherein the acid of Step 3 is hydrochloric acid.

9 . A process as in claim 7 , wherein the amount of the impurity selected from the group consisting of the pharmaceutically acceptable salt of the impurity compound of formula (IMP-A), the pharmaceutically acceptable salt of the impurity compound of formula (IMP-B) the pharmaceutically acceptable salt of the impurity compound of formula (IMP-C), the pharmaceutically acceptable salt of the impurity compound of formula (IMP-D), and mixtures thereof; is present in an amount less than about 0.05 area %.

10 . A process for removing or reducing the amount of an impurity compound of formulas (IMP-A)

or a salt thereof, an impurity compound of formula (IMP-B)

or a salt thereof, an impurity compound of formula (IMP-C)

or a salt thereof, an impurity compound of formula (IMP-D)

or a salt thereof, or mixtures thereof, from a process of preparing a compound of formula (I)

or a stereoisomer, mixture of stereoisomers or pharmaceutically acceptable salt thereof, comprising the steps of:

a. providing a composition comprising:

i. a compound of formula (I-A)

or stereoisomer, mixture of stereoisomers or pharmaceutically acceptable salt thereof; and

ii. an impurity compound selected from the group consisting of an impurity compound of formula (IMP-1)

an impurity compound of formula (IMP-2)

an impurity compound of formula (IMP-11)

an impurity compound of formula (IMP-12)

or mixtures thereof.

b. reacting the composition of Step a. with dimethylcarbonate to form a reaction mixture; wherein the dimethylcarbonate is present in an amount in the range of from about 2.5 to about 8.0 molar equivalents;

c. adding methanol to the reaction mixture; wherein the methanol is present in an amount in the range of from about 0.75 to about 5.0 molar equivalents; wherein said methanol is added as a separate component; and wherein the amount of methanol added, in one or more portions or aliquots, is independent of any methanol which may be later introduced into the reaction mixture;

d. adding sulfuric acid to the reaction mixture; wherein the sulfuric acid is present in an amount in the range of from about 1.05 to about 2.5 molar equivalents;

wherein the reaction mixture is at a temperature in the range of from about room temperature to about 90° C.; to yield the corresponding compound of formula (I-S);

in a mixture with a corresponding sulfate salt of the impurity compound of formula (IMP-A), a corresponding sulfate salt of the impurity compound of formula (IMP-B), a corresponding sulfate salt of the impurity compound of formula (IMP-C), a corresponding sulfate salt of the impurity compound of formula (IMP-D), or mixtures thereof;

e. reacting the mixture of Step d. with a base; and then adding an organic solvent; to yield the corresponding compound of formula (I) as a free base, in a mixture with a freebase impurity compound of formula (IMP-A), a freebase impurity compound of formula (IMP-B), a freebase impurity compound of formula (IMP-C), a freebase impurity compound of formula (IMP-D), and mixtures thereof, in a biphasic mixture comprising an aqueous phase and an organic phase;

f. separating the phases of the biphasic mixture one from the other; wherein: i. the compound of formula (I) and ii. the freebase impurity compound of formula (IMP-A), the freebase impurity compound of formula (IMP-B), the freebase impurity compound of formula (IMP-C), the freebase impurity compound of formula (IMP-D), and mixtures thereof, are present in the organic phase;

g. reacting an acid with the organic layer comprising: i. the compound of formula (I) and ii. the impurity compound of formula (IMP-A), the impurity compound of formula (IMP-B), the impurity compound of formula (IMP-C), the impurity compound of formula (IMP-D), and mixtures thereof; in the presence of water; wherein the water is present in an amount in the range of from about 0.05 wt/wt equiv. to about 1.0 wt/wt equiv.; to yield a corresponding acid addition salt of the compound of formula (I) in a mixture with a corresponding acid addition salt of the impurity compound of formula (IMP-A), a corresponding acid addition salt of the impurity compound of formula (IMP-B), a corresponding acid addition salt of the impurity compound of formula (IMP-C), a corresponding acid addition salt of the impurity compound of formula (IMP-D), and mixtures thereof wherein the corresponding acid addition salt of the impurity compound of formula (IMP-A), the corresponding acid addition salt of the impurity compound of formula (IMP-B), the corresponding acid addition salt of the impurity compound of formula (IMP-C), the corresponding acid addition salt of the impurity compound of formula (IMP-D), and mixtures thereof are extracted into the water; and

h. separating the water comprising the corresponding acid addition salt of the impurity compound of formula (IMP-A), the corresponding acid addition salt of the impurity compound of formula (IMP-B), the corresponding acid addition salt of the impurity compound of formula (IMP-C), the corresponding acid addition salt of the impurity compound of formula (IMP-D), and mixtures thereof from the corresponding acid addition salt of compound of formula (I) from the mixture of Step g.

11 . A process for removing or reducing the amount of a impurity compound of formula (IMP-A)

or a salt thereof, an impurity compound of formula (IMP-B)

or a salt thereof, an impurity compound of formula (IMP-C)

or a salt thereof, an impurity compound of formula (IMP-D)

or a salt thereof, or mixtures thereof, from a process of preparing a compound of formula (I)

or a stereoisomer, mixture of stereoisomers or pharmaceutically acceptable salt thereof, comprising the steps of:

a. providing a composition comprising:

i. compound of formula (I-A)

or stereoisomer, mixture of stereoisomers or pharmaceutically acceptable salt thereof; and

ii. an impurity compound selected from the group consisting of an impurity compound of formula (IMP-1),

an impurity compound of formula (IMP-2),

an impurity compound of formula (IMP-11)

an impurity compound of formula (IMP-12)

or mixtures thereof.

b. reacting the composition of Step a. with dimethylcarbonate to form a reaction mixture; wherein the dimethylcarbonate is present in an amount in the range of from about 2.5 to about 8.0 molar equivalents;

c. adding methanol to the reaction mixture; wherein the methanol is present in an amount in the range of from about 0.75 to about 5.0 molar equivalents; wherein said methanol is added as a separate component; and wherein the amount of methanol added, in one or more portions or aliquots, is independent of any methanol which may be later introduced into the reaction mixture;

d. adding sulfuric acid to the reaction mixture; wherein the sulfuric acid is present in an amount in the range of from about 1.05 to about 2.5 molar equivalents;

wherein the reaction mixture is at a temperature in the range of from about room temperature to about 90° C.; to yield the corresponding compound of formula (I-S);

in a mixture with a corresponding sulfate salt of the impurity compound of formula (IMP-A), a corresponding sulfate salt of the impurity compound of formula (IMP-B), a corresponding sulfate salt of the impurity compound of formula (IMP-C), a corresponding sulfate salt of the impurity compound of formula (IMP-D), and mixtures thereof;

e. adding an organic solvent the mixture of Step d. to form a second mixture;

f. reacting the second mixture of Step e. with an acid; in the presence of water; wherein the water is present in an amount in the range of from about 0.05 wt/wt equiv. to about 1.0 wt/wt equiv.; to yield a corresponding acid addition salt of the compound of formula (I) in a mixture with a corresponding acid addition salt of the compound of formula (IMP-1), a corresponding acid addition salt of the compound of formula (IMP-2), a corresponding acid addition salt of the compound of formula (IMP-11), a corresponding acid addition salt of the compound of formula (IMP-12), and mixtures thereof wherein the corresponding acid addition salt of the impurity compound of formula (IMP-A), the corresponding acid addition salt of the impurity compound of formula (IMP-B), the corresponding acid addition salt of the impurity compound of formula (IMP-C), the corresponding acid addition salt of the impurity compound of formula (IMP-D), and mixtures thereof are extracted into the water; and

g. separating the water comprising a corresponding acid addition salt of the impurity compound of formula (IMP-1), a corresponding acid addition salt of the impurity compound of formula (IMP-2), a corresponding acid addition salt of the impurity compound of formula (IMP-11), a corresponding acid addition salt of the impurity compound of formula (IMP-12), and mixtures thereof from the corresponding acid addition salt of compound of formula (I) from the mixture of Step f.