Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-01-18
2001-09-11
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S405000, C568S626000
Reexamination Certificate
active
06288271
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of (2,2,2-trifluoroethoxy)benzoic acids of the general formula [I] or salts thereof
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-substituted or N,N-disubstituted amino groups, nitro, alkoxycarbonyl, cyano, carboxyl and when m>1 the R substituents may be the same or different;
n is 1,2 or 3; and
m is 0, 1, 2, 3 or 4, where n+m≦5.
BACKGROUND OF THE INVENTION
Trifluoroethoxybenzoic acids of the formula [I] above are useful as intermediates in the pharmaceutical industry. For example, 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid [III] is the key intermediate for the synthesis of the antiarrhythmic drug Flecainide [IV] and pharmaceutically acceptable salts thereof
(Banitt, E. H. et al.,
J. Med. Chem.
18:1130 (1975) and 20:821 (1977); Leir, C. M. GB 2 045 760A, (1980) and The Merck Index, 12
th
Edition, 4136).
It is known that (2,2,2-trifluoroethoxy)benzoic acids [VII] 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 (Banitt, E. H. et al.,
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 involves the oxidation of the acetyl group of trifluoroethoxyacetophenones with hypochlorite as shown in Scheme 2 (Lair, C. M., GB 2045 760A). 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.
THE OBJECT OF THE INVENTION
It is the object of the present invention to overcome the above disadvantages of the known processes and to provide a comparatively simple, one-step process for preparing (2,2,2-trifluoroethoxy)benzoic acids [I] in good yields, employing commercially available and relatively inexpensive compounds.
DETAILED DESCRIPTION OF THE INVENTION
The above object is attained by the present invention which provides a process for the preparation of (2,2,2-trifluoroethoxy)benzoic acids of the formula [I] or salts thereof
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-substituted or N,N-disubstituted amino groups, nitro, alkoxycarbonyl, cyano, carboxyl and when m>1 the R substituents may be the same or different;
n is 1, 2, or 3; and
m is 0, 1, 2, 3 or 4, where n+m≦5,
which process comprises reacting a halobenzoic acid or a salt thereof of the formula [II]
wherein
R, m and n are as defined above, and
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.
(2,2,2-Trifluoroethoxy)benzoic acids [I] or salts thereof obtained in accordance with the process of the present invention may contain one or more 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-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, DMSO and hexamethylphosphoramide. N-containing heterocyclic solvents used in the present invention are pyridine, picolines, lutidines, collidines, methylethylpyridine (MEP), other substituted pyridines, quinoline and substituted quinolines.
The reaction is preferable carried out at a temperature in the range of from ambient temperature to 170° C.
In the process of the invention, preferably at least one mole of 2,2,2-trifluoroethanol is used per each halogen atom of the halobenzoic acid [II] which is desired to be replaced by a trifluoroethoxy group. However, a large molar excess of 2,2,2-trifluoroethanol can be used in which cases this reactant may also serve as a solvent. At least one mole of 2,2,2-trifluoroethanol per mole of the strong base should be used and the mole ratio of the copper containing compound to the halobenzoic acid [II] can be in the range of 0.01 to 2.1.
Suitable copper containing materials are for example: copper salts, copper oxides, metallic copper, copper alloys, etc.
The present invention will be described in more detail with the aid of the following examples, which are merely representative and should not serve to limit the scope of the invention.
REFERENCES:
patent: 0455545 (1991-11-01), None
patent: 2045760 (1980-11-01), None
Banitt et al., “Antiarrhythmics. N-(Aminoalkylene)trifluoroethoxybenamides and N-(Aminoalkylene)trifluoroethoxynaphthamides”,Journal of Medicinal Chemistry,vol. 18, No. 11, (1975), 1130-1134.
Banitt et al., “Antiarrhythmics. 2. Synthesis and Antiarrhythmic Activity of N-(Piperidylalkyl) trifluoroethoxybenzamides”,Journal of Medicinal Chemistry,vol. 20, No. 6, (1977), pp. 821-826.
Wrobel et al., “Syntheses of Tolrestat Analogues Containing Additional Substituents in the Ring and Their Evaluation as Aldose Reductase Inhibitors. Indentification of Potent, Orally Active 2-Fluoro Derivatives”J. Med. Chem.,vol. 34, pp. 2504-2520, (1991).
Merck Index, 12thEd. Entry 4136, “Flecainide” 1996, p. 694.
Derwent Abstract of JP 053924 (Japanese Patent Application published Feb. 19, 1993), Abstract AN-096747[12].
Hawley s Condensed Chemical Dictionary, 13thEd., pp. 118, 123-124, 126, & 862, Van Nostrand Reinhold, New York, 1997.
Lindley,J., “Copper Assisted Nucleophillic Substitiion of Aryl Halogen,” Tetrahedron, vol. 40, pp. 1433-1456, 1984.
March, J., “Advanced Organic Chemistry, Fourth Ed.”, pp. 563-565, 648-665, Wiley Interscience, New York 1992.
Gutman Arie L.
Nisnevich Genady
Shkolnik Eleonora
Zaltzman Igor
FineTech, LTD
Needle & Rosenberg P.C.
Seaman D. Margaret
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