Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-08
2003-07-29
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S229000, C546S236000, C514S331000
Reexamination Certificate
active
06599922
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns a process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide (FLECAINIDE).
PRIOR ART
FLECAINIDE base, in general the pharmaceutically acceptable salts thereof, and in particular in hydrochloride form, is described in the U.S. Pat. No. 3,900,481. FLECAINIDE is a principal active ingredient used in human therapy as an anti-arrhythmic agent, as described in the U.S. Pat. No. 4,005,209.
The processes described in the art for the synthesis of this molecule are many. U.S. Pat. No. 4,024,175 describes the preparation of FLECAINIDE starting from 1,4-dibromobenzene transformed by reaction with trifluoroethoxyls and acetylating agents into 2,5-bis-(2,2,2-trifluoroethoxy)-acetophenone which, by oxidation (treatment with hydrochloric acid and with 2-aminomethyl-piperidine) gives FLECAINIDE.
This process, along with the others described in the art, are complex and laborious synthetic processes and, however, so as to render difficult their exploitation at the industrial size.
The need to develop new synthetic pathways, with reactions characterized by high yield, easily reproducible on an industrial scale, with high purity intermediates through the use of reagents easily commercially available, was then felt.
SUMMARY OF THE INVENTION
A new process for the preparation of FLECAINIDE, overcoming the disadvantage, inherent to the processes known in the art, has been now discovered.
The applicant has unexpectedly and surprisingly found a new process for the preparation of FLECAINIDE, as flecainide base or any one of its pharmaceutically acceptable salts, comprising the synthesis of the intermediate 2′,2′,2′-trifluoroethanol 2,5-bis-(2,2,2-trifluoroethoxy)benzoate by reaction of 2,5-dihydroxybenzoic acid, gentisic acid, with 2,2,2-trifluoroethanol perfluorobutanesulphonate.
The process object of the present invention is characterized by easily industrially applicable steps with high yield, starting from easily commercially available reagents, of limited costs, allowing, as a further benefit, the quantitative recovery of by-products obtained in the formation reaction of the intermediate 2′,2′,2′-trifluoroethanol 2,5-bis-(2,2,2-trifluoroethoxy)benzoate with considerable advantages from the industrial and environmental points of view.
DETAILED DESCRIPTION OF THE INVENTION
It is therefore an object of the present invention a FLECAINIDE preparation process, as flecainide base or any pharmaceutically acceptable salts thereof, comprising the synthesis of the intermediate 2′,2′,2′-trifluoroethanol 2,5-bis-(2,2,2-trifluoroethoxy)benzoate, defined as phase a) by the reaction of 2,5-dihydroxybenzoic acid with 2,2,2-trifluoroethanol perfluorobutanesulphonate in the presence of inorganic bases.
Preferably the 2,2,2-trifluoroethanol perfluorobutanesulphonate is 2,2,2-trifluoroethyl-perfluoro-n-butanesulphonate.
Preferably the molar ratio between 2,5-dihydroxybenzoic acid and 2,2,2-trifluoroethanol perfluorobutanesulphonate is comprised from 1:3 to 1:5, more preferably it is 1:3.
According to the process object of the present invention, the reaction at phase a) is preferably carried out in the presence of inorganic bases selected from the group consisting of carbonates and/or bicarbonates of sodium and/or potassium, or mixtures thereof. More preferably the base is potassium carbonate.
The reaction at phase a) is preferably carried out in oxygenated aliphatic solvents from 2 to 6 carbon atoms. The ketones from three to six carbon atoms are the most preferred. Ketones selected from the group consisting of: acetone, methylethyl-ketone, methylisobutyl-ketone are particularly preferred.
The reaction at phase a) is carried out at a temperature from 30° C. to 140° C.; the range from 50° C. to 80° C. is preferred; and the range from 50° C. to 60° C. is particularly preferred.
The perfluorobutanesulphonate alkaline salts obtained as by-products of the reaction at phase a), are recovered in a quantitative manner through their complete reconversion in 2,2,2-trifluoroethanol perfluorobutanesulphonate, which is recycled in the reaction at phase a).
The perfluorobutanesulphonate alkaline salts obtained as by-products, precipitated in the reaction mixture, are removed by filtration. Said alkaline salts are quantitatively reconverted in the 2,2,2-trifluoroethanol perfluorobutanesulphonate which is recycled in phase a).
The reconversion of the alkaline salts of perfluorobutanesulphonate in the corresponding 2,2,2-trifluoroethanol takes place according to reactions known and described in the literature as in “A new method for recovering waste alkaline perfluoro-n-butanesulphonate”, Journal of fluorine chemistry, 53 (1991) 277-283. Preferably the perfluorobutanesulphonate alkaline salts are treated in lower aliphatic alcohols with gaseous mineral acids to give the corresponding perfluorobutanesulphonic acid which, after treatment with 2,2,2-trifluoroethanol in thionyl chloride, or after halogenation and successive treatment with 2,2,2-trifluoroethanol and ternary amines in aliphatic or halogenated aromatic solvents, is transformed into 2,2,2-trifluoroethanol perfluorobutanesulphonate, which is recycled in the reaction at phase a). More preferably the perfluorobutanesulphonate alkaline salts are solubilised in methanol and treated with gaseous hydrochloric acid to give the corresponding perfluorobutanesulphonic acid which, after treatment with 2,2,2-trifloroethanol in thionyl chloride, is transformed into 2,2,2-trifluoroethanol perfluorobutanesulphonate, which is recycled in the reaction at phase a); or the perfluorobutanesulphonate alkaline salts are solubilised in methanol and treated with gaseous hydrochloric acid to give the corresponding perfluorobutanesulphonic acid which, after treatment with PCl
5
is transformed into the corresponding perfluorobutanesulphonyl chloride, the latter reacts with 2,2,2-trifloroethanol and triethylamine in dichloromethane to give 2,2,2-trifluoroethanol perfluorobutanesulphonate, which is recycled in the reaction at phase a).
The intermediate 2′,2′,2′-trifluoroethanol 2,5-bis-(2,2,2-trifluoroethoxy)benzoate is easily converted into FLECAINIDE, as flecainide base or pharmaceutically acceptable salts thereof, through reactions well known in the art.
Among these reactions, constituting a particularly preferred embodiment form of the FLECAINIDE preparation process, as flecainide base or pharmaceutically acceptable salts thereof, object of the present invention, the reaction of the intermediate obtained in phase a) with 2-aminomethyl-piperidine is described. Therefore, a further object of the present invention is constituted by, as a preferred embodiment of the invention, a process which comprises, following on from phase a) the formation of the intermediate 2′,2′,2′-trifluoroethanol 2,5-bis-(2,2,2-trifluoroethoxy)benzoate, the reaction of said intermediate with 2-aminomethylpiperidine, said phase b), to give FLECAINIDE base.
2-aminomethyl-piperidine is an easily commercially available reagent or easily synthesized in situ, for example by catalytic hydrogenation, starting from easily available precursors, for example 2-aminomethyl-pyridine.
The reaction at phase b) is preferably carried out in aliphatic, cycloaliphatic, or aromatic solvents from one to nine carbon atoms or ethers from two to nine carbon atoms. Solvents selected from the group consisting of: heptane, hexane, cyclohexane, diethyleneglycol dimethyl ether (Diglyme), 1,2-dimethoxyethane (Glyme), toluene, xylene are the most preferred. Toluene is particularly preferred.
The reaction at phase b) is carried out at a temperature from 20° C. to 200° C.; the range of temperatures from 50° C. to 100° C. is preferred; and the range from 75° C. to 85° C. is particularly preferred.
The reaction at phase b) is carried out with a molar excess of amine. Preferably the molar ratio between the intermediate 2′,2′,2′-trifluoroethanol 2,5-bis-(2,2,2-trifluoroeth
Lanfranconi Simona
Molteni Renato
Pizzatti Enrica
Vigano Enrico
A.M.S.A. Anonima Materie Sintetiche e Affini S.p.A.
Coppins Janet
Morgan & Finnegan , LLP
Rotman Alan L.
LandOfFree
Process for the preparation of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3060161