Process of enantiomeric resolution of D,L-(+_)-threo-methylphenidate
AssigneeArchimica GmbH
InventorsAlexei Kalinin, Guofang Qiu, Thomas J. Marren, James E. Aldred, Yu Ji
Life of this patent
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Abstract
A process for preparing the d-threo isomer of methylphenidate hydrochloride which includes (i) resolving a racemic mixture of racemic threo-methylphenidate hydrochloride with a less than stoichiometric amount of tertiary amine base to obtain a methylphenidate-chiral acid salt, (ii) basifying the methylphenidate-chiral acid salt to obtain methylphenidate free base, and (iii) converting the methylphenidate free base into d-threo-methylphenidate hydrochloride.
Claims26
A process for isolating either d- or l-threo isomer of methylphenidate hydrochloride comprising the steps of:
- (i) resolving a mixture comprising
- racemic threo-methylphenidate hydrochloride;
- less than or equal to about 1.0 equivalent (based on the amount of racemic threo-methylphenidate hydrochloride) of chiral acid selected from one or more di-O—O′-aroyl tartaric acids,
- less than 1.0 equivalent (based on the amount of racemic threo-methylphenidate hydrochloride) of one or more tertiary amine bases, and
- a solvent mixture comprising one or more lower alkanols and water, thereby forming a chiral acid-isomeric methylphenidate salt
- (ii) basifying the chiral acid-isomeric methylphenidate salt to obtain isomeric methylphenidate free base and
- (iii) converting the isomeric methylphenidate free base into isomeric methylphenidate hydrochloride having an enantiomeric excess of greater than about 90% and a yield of greater than about 35% based on racemic threo-methylphenidate hydrochloride.
A process for isolating either d- or l-threo-isomer of methylphenidate hydrochloride comprising the steps of:
- (i) resolving a mixture comprising
- racemic threo-methylphenidate hydrochloride;
- less than or equal to about 1.0 equivalent (based on the amount of racemic threo-methylphenidate) of chiral acid selected from one or more of di-0,0′-p-toluoyl-tartaric acid, di-0,0′-m-toluoyl-tartaric acid, and di-0,0′-benzoyl-tartaric acid,
- less than about 1.0 equivalent (based on the amount of racemic threo-methylphenidate) sodium acetate base, and
- a solvent mixture comprising one or more lower alkanols and water, thereby forming a chiral acid-isomeric methylphenidate salt
- (ii) basifying the chiral acid-isomeric methylphenidate salt to obtain isomeric methyl phenidate free base and
- (iii) converting the isomeric methylphenidate free base into isomeric methylphenidate hydrochloride having an enantiomeric excess of greater than about 90%, and a yield of greater than about 30% or more, bormp.
A process for resolving racemic threo-methylphenidate hydrochloride, said process comprising
- (a) providing a resolution mixture comprising
- racemic threo-methylphenidate hydrochloride;
- less than or equal to about 1.0 equivalent (based on the amount of racemic threo-methylphenidate) of one or more di-0-0′-aroyltartaric acids;
- less than about 1.0 equivalent (based on the amount of racemic threo-methylphenidate) of one or more tertiary amine bases, and
- a solvent mixture comprising one or more lower alkanols and water, wherein said resolution results in chiral acid-isomeric methylphenidate salt having an enantiomeric excess of greater than or equal to about 90%.
Dependencies are inferred from the claim text.