Process for the preparation of flecainide

Details Process for the preparation of flecainide Process for the preparation of flecainide

1999-10-21

2001-11-13

Aulakh, C. S. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C558S311000, C558S399000, C546S337000

Reexamination Certificate

active

06316627

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Flecainide or a precursor thereof, to a novel intermediate used in this process and its preparation.
BACKGROUND OF THE INVENTION
Flecainide [2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzarnide] is an effective antiarrythnic drug that acts on the cell membrane to reduce fast inward depolarization current.
One prior art method for preparing Flecainide [IV], disclosed in British Patent Application No. 2,045,760, starts from 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid [III].
Compound [III] is prepared by a multi-stage process, comprising the conversion of 1,4dibromobenzene or hydroquinone to 1,4-bis(2,2,2-trifluoroethoxy)benzene, which is acetylated to form 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The acetophenone is then oxidized to form the corresponding benzoic acid derivative, which is then converted to its acid chloride and reacted either with 2-(aminomethyl)piperidine to form the Flecainide product in one step or with 2-(aminomethyl)pyridine, followed by catalytic hydrogenation of the pyridine ring, to form Flecainide in two steps.
The one step process has a serious disadvantage in that the acid chloride reacts non-selectively with both nitrogen atoms of the 2-(aminomethyl)piperidine, resulting in a mixture of the two acylated isomers. This is the main reason why the two-step process via the pyridine intermediate is commercially preferred, A further disadvantage is due to the fact that the acid chloride intermediate disclosed in GB 2,045,760A is a liquid which cannot be stored for long periods of time, but must be used immediately after it is prepared.
Trifluoroethoxybenzoic acids of the formula [I] are useful intermediates in the pharmaceutical industry.
These compounds can be obtained by the reaction of hydroxybenzoic acids of the general formula [V] with 2,2,2-trifluoroethyl triflate [VI] according to Scheme 1 (Banift, E. H. etat.,
J Med. Chem.
18:1130 (1975)).
This method requires the use of trifluoroethyl triflate [VI] which is costly and not easily available commercially.
Another method (GB 2045760A) involves the oxidation of the acetyl group of trifiuoroethoxyacetophenones with hypochlorite as shown in Scheme 2. However, partial halogenation of the benzene ring may occur in this process, thus making it difficult for production of the (2,2,2-trifluoroethoxy)benzoic acids [I] as pharmaceutical precursors.
There is only one reported example of copper assisted fluoroalkoxy-de-halogenation of a 2-bromo-1-naphthalenecarboxylic acid derivative (Wrobel J. et al., J. Med. Chem. 34, 2504 (1991)). This example is very specific since it describes the de-halogenation of an active halogen, i.e. bromine, which is also located in a highly activated ortho position to a carboxylic group.
SUMMARY OF THE INVENTION
It is an object of the invention to provide a novel process for the preparation of trifluoroethoxy benzoic acid derivatives, in particular Flecainide, and their pharmaceutically acceptable salts, which is free of the above-mentioned disadvantages, staring with commercially available halobenzoic acids and involving the use of simple reagents and low cost solvents, to afford high overall yield of the product.
The above object is achieved in accordance with the present invention which, in one aspect thereof, provides a process for preparing a compound of formula (A):
wherein
Ar represents a benzene ring;
R is hydrogen or a substituent selected from alkyl, alkoxy, alkylthio, halogen, haloalkyl, haloalkoxy, haloalkylthio, phenyl, phenoxy, benzyloxy, N-substitated or N,N-disubstituted amino groups, nitro, alkoxycarbonyl, cyano, carboxyl and when m>1 the R substituents may be the same or different;
R′ is a 2-piperidyl or 2-pyridyl radical,
n is 1 , 2or3;
m is 0, 1, 2, 3 or 4; where n+m≦5; and
pharmaceutically acceptable salts thereof, which process comprises the steps of:
a) reacting a halobenzoic acid or a salt thereof of the formula [II]
wherein
Ar, R, n and m are as defined above;
M is hydrogen or a metal, ammonium or phosphonium cation; and
X is Cl, Br or I, and when n >1 the X substituents may be the same or different;
with 2,2,2-trifluoroethanol in the presence of a strong base and a copper containing material, if desired followed by acidification to obtain a compound of formula [I]
wherein
Ar, R, m and n are as defined above, and
b) converting the product obtained in step a) above into the compound of formula (A) or a pharmaceutically acceptable salt thereof.
According to a specific embodiment, the present invention provides a process for the preparation of a compound of formula (A′):
wherein
R′ is a 2-piperidyl or 2-pyridyl radical, and pharmaceutically acceptable salts thereof.
Step b) above may be carried out by known procedures, such as those described in GB 2,045,760A or in Chem. Abs. 114:122069. Alternatively, according to a preferred embodiment, the present invention provides a novel process for step b). This novel process comprises:
(i) reacting a compound of formula [I] or a salt thereof, with a haloacetonitrile of the formula XCH
2
CN, where X is Cl, Br or I, if necessary in the presence of an inorganic or organic base, to form the cyanomethyl ester of the formula:
(ii) reacting the cyanomethyl ester with an amine of the formula R′CH
2
NH
2
where R′ is as defined above and, if desired,
(iii) converting the compound of the formula (A) into a pharmaceutically acceptable salt thereof.
Preferably, the halobenzoic acid in step a) is a compound of formula [XVII] or a salt thereof and the product of step a) is (2,2,2-trifluoroethoxy)-benzoic acid [III] or a salt thereof
wherein:
X
3
is Br or I, X
4
is Cl, Br or I, or one of X
3
and X
4
may also be CF
3
CH
2
O—. (2,2,2-Trifluoroethoxy)benzoic acid [III] or a salt thereof may be converted in step b) into a compound of the formula (A') either by known methods or by the novel process of the present invention, which particularly comprises of:
(i) reacting 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid [III] or a salt thereof, with a haloacetonitrile of the formula XCH
2
CN, where X is Cl, Br or I, if necessary in the presence of an inorganic or organic base, to form the cyanomethyl ester of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid of the formula
(ii) reacting the cyanomethyl ester with an amine of the formula R′ CH
2
NH
2
where R′ is as defined above and, if desired,
(iii) converting the resulting product of the formula (A')
 into a pharmaceutically acceptable salt thereof A' represents Flecainide when R′ is 2-piperidyl.
In accordance with another aspect of this invention, there is provided the novel cyanomethyl ester of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid having the formula above. The novel intermediate of the present invention is a stable, solid comapound, obtainable in high yield, which can be easily purified by crystallization and stored for long periods of time.
DETAILED DESCRIPTION OF THE INVENTION
(2,2,2-Trifluoroethoxy)benzoic acids [I] or salts thereof obtained in step a) of the process of the present invention may contain one or more is 2,2,2-trifluoroethoxy groups. Additionally, other substituents R as defined above may be present on the aromatic ring.
As defined herein, the term “halobenzoic acid” includes benzoic acids containing one or more halogen atoms and optionally additional substituents as defined for R above.
According to a preferred embodiment of the present invention, a chloro-, bromo- or iodo-benzoic acid is reacted with a metal trifluoroethoxide in the presence of copper iodide or bromide in an aprotic solvent Such aprotic solvent may be a dipolar aprotic solvent or an N-containing heterocycle or mixtures thereof Examples of dipolar aprotic solvents are N,N-dimnethylformnamide, N-methylpyrolidone, N,N-dimethylacetamide, DMSO a

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