Process for the preparation of sameridine

Details Process for the preparation of sameridine Process for the preparation of sameridine

1996-03-07

1998-05-26

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546225, 546228, C07D21156, C07D21130, C07D21132, C07D21160

Patent

active

057567484

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention is directed to a new and improved process for the preparation of sameridine and its hydrochloride salt.


BACKGROUND AND PRIOR ART

In WO 91/09845 the compound sameridine is disclosed, as well as a process for preparing and using the same. The starting material in the process disclosed in WO 91/09845 is norpetidin, while the starting material in the process according to the present invention is cyanophenylpiperidine, thus providing a substantially different synthetic method, even after the first step.
The process according to the present invention for the preparation of sameridine and its hydrochloride salt is commercially more advantageous than the process known from WO91/09845. The process according to the present invention is also more advantageous from a technical point of view than the process according to WO91/09845. Actually, the products produced by the improved process are used for the same purposes and in the same manner as sameridine prepared by the prior art process.


OUTLINE OF THE INVENTION

The present invention is directed to a new and improved process for preparing sameridine, N-ethyl-N-methyl-1-hexyl-4-phenyl-4-piperidinecarboxamide which is the compound of the formula (I) ##STR1## and its hydrochloride salt.
Scheme 1 shows the synthetic route for the preparation of the compound (I) as well as the preparation of the hydrochloride salt of the compound of the formula (I). ##STR2## In the process according to the invention the compound (I) is prepared by liberating the starting material 4-cyano-4-phenylpiperidine.times.HCl from its HCl salt by extraction in an organic solvent with diluted base, whereafter alkylation with 1-bromohexane, 1-iodohexane or 1-chlorohexane takes place in the presence of a base and a catalyst. Optionally the reaction is performed without a catalyst, but results in a more time-consuming reaction.
Examples of bases that can be used in the first reaction step are carbonates such as sodium carbonate and potassium carbonate, or amines, such as triethylamine.
Other possible bases will be appreciated as useful by a person skilled in the art. Preferably, potassium carbonate is used.
The organic solvent can be selected from isobutyl methylketone, acetonitrile, ethanol, butanol and toluene. However, other suitable organic solvents are useful, as would be appreciated by a person skilled in the art.
The optional catalyst employed is an iodide catalyst, preferably sodium iodide.
The reaction is completed by heating to reflux temperature, and the inorganic salts are removed by extraction with water. The product is precipitated as the HCl salt of the formula (III) and thereafter isolated.
The compound of the formula (III) precipitated as its HCl salt is converted by is reaction in HCl (aq) or HBr (aq). After complete conversion the product of the formula (IV) is crystallized by cooling, and is thereafter isolated.
The compound (IV) in an organic solvent or in mixtures of organic solvents, is reacted with oxalyl chloride followed by reaction with ethylmethylamine. The product (I) is washed with water and the solvent is evaporated. The organic solvent includes chlorinated solvents such as methylene chloride or toluene, or mixtures thereof.
The product (I) is thereafter dissolved in an organic solvent and precipitated as a HCl salt, whereafter the product is isolated. Examples of useful organic solvents are ethyl acetate, acetone and methylisobutylketone. The intermediates may be dried or used in moist form.
The purity of the final product of the formula (I) and of its HCl salt respectively, is more than 99% based on GC (gas chromatography) or HPLC (High Performance Liquid Chromatography) analyses.
The NMR spectra of the hydrochloride salt of the product of the formula (I) were obtained from solutions in CDCl.sub.3 at room temperature on a Varian Gemini 300 NMR instrument.


DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail by the following examples.


EXAMPLE 1 A

4-Cyano-4-phenylpiperidine.times.HCl (

REFERENCES:
patent: 5227389 (1993-07-01), Ask et al.
patent: 5360805 (1994-11-01), Ask et al.

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