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AssigneeISP Investments Inc.
InventorsArie Gutman, Igor Zaltsman, Anton Shalimov, Maxim Sotrihin, Gennady Nisnevich
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The present invention provides a process for the preparation of threo-methylphenidate hydrochloride. According to a preferred embodiment, the process comprises the following steps: (a) contacting 1-(phenylglyoxylyl)piperidine arenesulfonylhydrazone of the formula wherein Ar denotes an aryl group, where the aryl group may be substituted by a C1–C6 alkyl, halo or nitro group; with an inorganic base in the presence of a water immiscible organic solvent and a phase transfer catalyst to obtain (R*,R*)-enriched 7-phenyl-1-azabicyclo [4.2.0]octan-8-one of the formula: (b) reacting the (R*,R*)-enriched 7-phenyl-1-azabicyclo[4.2.0]octan-8-one prepared in step (a) with a solution of hydrogen chloride in methanol to obtain threo-enriched methylphenidate hydrochloride; (c) crystallizing the threo-enriched methylphenidate hydrochloride prepared in step (b) to give the desired threo-methylphenidate hydrochloride. Preferably, the threo-methylphenidate hydrochloride produced by the process of the present invention contains no more than 1% of the erythro-isomer.
A process for the preparation of threo-methylphenidate hydrochloride comprising:
Dependencies are inferred from the claim text.
From the US filing history. Foreign family members aren’t listed.
With substituted hydrocarbon radicals attached to ring carbon atoms: with hydrocarbon radicals, substituted by carbon atoms having three bonds to…
Non condensed pyridines; Hydrogenated derivatives thereof: non condensed piperidines, e.g. piperocaine
Heterocyclic compounds
Medicines and medical preparations
Term ended 4 Mar 2024 (estimated)
The present invention relates to a process for the preparation of threo-methylphenidate hydrochloride.
The following references are considered to be pertinent for the purpose of understanding the background of the present invention: J. M. Axten et al., J. Org. Chem., 1998, v.63, 9628–9 (and supporting information disclosed therein); H. M. Deutsch et al., J. Med. Chem., 1996, v.39, 1201–9; L. Panizzon, Helv. Chim. Acta, 1944, v. 27, 1748–56; K. Patric et al., J. Labelled Compd. Radiopharm., 1982, v. 19, 485–90; L. Szporny et al., Biochem. Pharmacol., 1961, v. 8, 263–8; U.S. Pharmacopoeia USP 26 “Methylphenidate Hydrochloride”; U.S. Pat. No. 2,507,631; U.S. Pat. No. 2,838,519; U.S. Pat. No. 2,957,880; U.S. Pat. No. 5,936,091; WO 99/36403; and WO 01/27070.
Racemic threo-methylphenidate or methyl (R*,R*)-α-phenyl-2-piperidineacetate, having the formula: and its salts are CNS (central nervous system) stimulants that are chemically and pharmacologically similar to the amphetamines. threo-Methylphenidate's CNS actions are milder than those of the amphetamines and have more noticeable effects on mental activities than on motor activities.
The process for preparing threo-methylphenidate hydrochloride according to the present invention comprises reacting 1-(phenylglyoxylyl)piperidine arenesulfonylhydrazone in a water-immiscible organic solvent such as dichloromethane or toluene with a deprotonating aqueous solution comprising a base and a phase transfer catalyst, to form (R*,R*)-enriched 7-phenyl-1-azabicyclo[4.2.0]octan-8-one.
The inorganic base used in the process of the present invention is selected from sodium hydroxide, sodium carbonate, potassium carbonate or potassium hydroxide. Preferably the inorganic base is sodium hydroxide. The inorganic base may be in a solid form or in its aqueous solution.
The phase transfer catalyst (PTC) is used to carry the inorganic base from the aqueous phase or the solid phase into the organic phase. The phase transfer catalyst may be a quaternary onium salt, e.g. quaternary ammonium or phosphonium salts, a crown ether or polyglycol.