Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-03
2003-03-25
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S399000, C562S474000, C560S065000
Reexamination Certificate
active
06538138
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel process for the preparation of Flecainide and 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)benzamide is an effective antiarrythmic drug that acts on the cell membrane to reduce fast inward depolarization current.
One prior art method for preparing Flecainide, disclosed inter alia, in British Patent Application No. 2,045,760 A, starts from 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. This starting material is prepared by a multi-stage process, comprising the conversion of 1,4-dibromobenzene 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 the Flecainide product 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 can not be stored for long periods of time but must be used immediately after it is prepared.
OBJECTS OF THE INVENTION
It is an object of this invention to provide a novel process for the preparation of Flecainide and its pharmaceutically acceptable salts, which is free of the above-mentioned disadvantages, starting with commercially available halobenzoic acids and involving the use of simple reagents and low cost solvents, to afford high overall yield of the Flecainide product.
It is a further object of this invention to provide a novel reactive intermediate, i.e. the cyanomethyl ester of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid, which is capable of reacting selectively with the primary amino group of 2-(aminomethyl)piperidine, so as to form the Flecainide product in high yield and free of the above mentioned isomeric by-product.
SUMMARY OF THE INVENTION
The above objects are achieved in accordance with the present invention which, in one aspect thereof, provides a process for preparing a compound of formula (A):
wherein R is a 2-piperidyl or 2-pyridyl radical, and pharmaceutically acceptable salts thereof, which process comprises the steps of:
a) reacting 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid 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):
b) reacting the ester of the formula (II) with an amine of the formula RCH
2
NH
2
, where R is as defined above and, if desired,
c) converting the compound of the formula (A) to a pharmaceutically acceptable salt thereof.
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 (II) above. As contrasted to the liquid acid chloride intermediate disclosed in GB 2,045,760A, the novel intermediate of the present invention is a stable, solid compound, obtainable in high yield, which can be easily purified by cristallisation and stored for long periods of time.
DETAILED DESCRIPTION OF THE INVENTION
It was shown by Schwizer et al. (Helvetica Chimica Acta, 1955, V.38,69;80;83) that cyanomethyl esters of aliphatic amino acids react selectively with primary amino groups, R. Buyle (Helvetic Chimica Acta, 1964, V. 47, 2444) showed, that benzylamine reacts with cyanomethyl benzoate considerably slower than with cyanomethyl acectate. The present invention is based on the unexpected finding that 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid activated by conversion to its cyanomethyl ester may react selectively and with high yield with primary amino groups of amines of the formula RCH2NH2, wherein R is as defined above.
Accordingly, the cyanomethyl ester (II) is prepared in high yield, starting with 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid which is reacted with a haloacetonitrile of the formula XCH
2
CN wherein X is Cl, Br or I, preferably Cl, in the presence of an inorganic or organic base. Alternatively, the ester (II) can be prepared by reacting a salt of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid with a haloacetonitrile.
Suitable organic bases for use in the above process are primarily tertiary amines, e.g. triethylamine, diisopropylethylamine, ethylpiperidine and the like, preferably triethylamine. Inorganic bases which may also be used are, e.g., alkali metal or alkaline earth metal carbonates or bicarbonates.
In the second step of the process, the cyanomethyl ester (II) is reacted with an amine of the formula RCH
2
NH
2
, where R is as defined above, optionally in a suitable, inert solvent. Thus, the reaction may be carried out by mixing together 2-(aminomethyl)piperidine with the ester (II) in a solvent such as 1,2-dimethoxyethane or ethyl acetate, or yield Flecainide (I) in a high yield.
The optional conversion of Flecainide into a pharmaceutically acceptable salt such as the acetate salt, is carried out by conventional methods.
The starting material 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is preferably prepared by the process described in co-pending Israel Application No. 120715. Accordingly, this benzoic acid derivative is prepared by contacting a halobenzoic acid of the formula (III):
or a salt thereof, wherein X
1
is selected from Br or I, and X
2
is selected from Cl, Br or I, or one of X
1
and X
2
may also be CF
3
CH
2
O—, with 2,2,2-trifluoroethanol in the presence of a strong base and copper iodide and/or copper bromide, in an aprotic solvent. Suitable solvents are dipolar aprotic solvents or N-containing heterocycles or their mixtures, such as N,N-dimethylformamide, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, DMSO, pyridine, picolines, lutidines, collidines, methylethylpyridine (MEP), quinoline and substituted quinolines. As the strong base there may be used Na, NaH, NaNH
2
, Na— and K-alcoholates, NaOH, KOH and the like, most preferably NaH. For example, 5-bromo-2-chlorobenzoic acid is reacted while heating, with 2,2,2-trifluoroethanol and a strong base, e.g. sodium hydride in a dipolar aprotic solvent, e.g. N,N-dimethylformamide, in the presence of copper iodide.
The present invention will be described in more detail with the aid of the following non-limiting examples.
REFERENCES:
patent: 3900481 (1975-08-01), Banitt et al.
patent: 2 007 802 (1989-07-01), None
patent: 2045760 (1980-11-01), None
Shuichi Takayama et al, “Enzymatic resolutin of Amines and amino Alcohols Using Pent-4-enoyl Derivatives”, Tet. Lett., vol. 37 (1996), pp. 6287-6290.*
Jefferson W. Tilley et al, “N-(Heterocyclic alkyl)pyrido[2,1-b]quinazoline-8carboxamides as Orally Acive antiallergy Agents”, J. Med. Chem., vol. 30 (1987), pp. 185-193.*
Hitomi Suzuki et al, “Copper(I)-Assisted Synthesis of Aryl 2,3,4-Trifluoroethyl Ethers”, Synthesis, (1985), pp. 499-500.*
Jay Wrobel et al, “Syntheses of Tolrestat Analogues Containing Additional Substituents in the Ring and Their Evaluation as Aldose Reductase Inhibitors.Identification of Potent, Orally Active 2-Fluoro Derivatives”, J. Med. Chem., vol. 34(1991), pp. 2504-2520.*
Wrobel et al, “Syntheses of Tolrestat Analogues Containing Additional Substituents in the Ring and Their Evaluation as Aldose Reductase Inhibitors. Identification of Potent, Orally Active 2-Fluoro Derivatives”,J Med Chem34:2504-2520 (1991).
“Flecainide”,Merck Index, 12thEdition, 4136, p. 694.
R. Buyle, “Sur les esters actives I. Aminolyse des derives acyles des oximes et amidoximes”He
Gutman Arie L.
Nisnevich Genady
Shkolnik Eleonora
Zaltzman Igor
FineTech Ltd.
Killos Paul J.
Needle & Rosenberg P.C.
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