Process for the preparation of dexmethylphenidate hydrochloride

1. A process for the preparation of dexmethylphenidate hydrochloride having high optical purity wherein said threo-N-Broc-ritalinic acid is prepared by a process comprising:

(1) reacting a solution of threo-N-Boc-ritalinic acid with (S)-1-phenylethylamine, separating precipitated salt of (R,R)-enriched N-Boc-ritalinic acid with (S)-1-phenylethylamine from the reaction mixture and recrystallizing, reslurrying and/or trituring of said salt in crystalline form;

(2) mixing the solid salt of (R,R)-N-Boc-ritalinic acid and (S)-1-phenylethylamine, obtained in step (1) with aqueous acid and separating (R,R)-N-Boc-ritalinic acid from the mixture;

(3) deprotecting and esterifying the (R,R)-N-Boc-ritalinic acid prepared in step (2) to give dexmethylphenidate hydrochloride with optical purity of at least 99% ee;

(4) contacting a solution of 1-(phenylglyoxylyl)piperidine arenesulfonylhydrazone of the formula

wherein Ar is an aryl group, in a water immiscible organic solvent, with an inorganic base, in the presence of phase transfer catalyst to obtain 7-phenyl-1-azabicyclo[4.2.0]octan-8-one;

(5) reacting the 7-phenyl-1-azabicyclo[4.2.0]octan-8-one of the formula:

obtained in step (4) with a solution of hydrogen chloride in methanol to give methylphenidate;

(6) reacting the methylphenidate prepared in step (5) with di-tert-butyl dicarbonate to give N-Boc-methylphenidate;

(7) reacting N-Boc-methylphenidate with sodium hydroxide in an alcohol solution or aqueous alcohol solution and separating precipitated solid sodium salt of threo-N-Boc-ritalinic acid from the reaction mixture;

(8) mixing the salt obtained in step (7) with an aqueous acid and separating threo-N-Boc-ritalinic acid from the obtained mixture.

2. The process of claim 1 , further comprising the following steps after step (7) and before step (8):

(i) acidifying the mother liquor of step (4) (7) and isolating erythro-enriched N-Boc-ritalinic acid from the obtained mixtures;

(ii) esterifying of the erythro-enriched acid obtained in step (i);

(iii) recycling the N-Boc-methylphenidate obtained in step (ii) to act as the starting material for step (7).

3. The process of claim 1 , wherein said alcohol used in step (4) is methanol, ethanol or isopropanol.

4. The process of claim 1 , where said phase transfer catalyst is selected from quaternary ammonium and phosphonium salts, polyglycols, crown ethers and podans.

5. The process of claim 1 , wherein said phase transfer catalyst is methyltrioctylamminium chloride.

6. The process of claim 1 wherein said water-immiscible organic solvent is dichloromethane or toluene.

7. The process of claim 1 wherein said inorganic base is used in solid state or in an aqueous solution.

8. The process of claim 1 wherein said inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

9. The process of claim 1 wherein the aryl group is selected from phenyl, p-tolyl, p-chlorophenyl and p-nitrophenyl.

10. A salt of (R,R)-N-Boc-ritalinic acid with (S)-1-phenylethylamine in a substantially pure solid form of optical purity.

11. Sodium salt of N-Boc-threo-ritalinic acid in a substantially pure solid form of optical purity.