Method for preparing 2-aryl or 2-heterocyclyl chiral...

Electrolysis: processes – compositions used therein – and methods – Electrolytic synthesis – Preparing organic compound

Reexamination Certificate

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C205S423000, C205S424000, C205S425000, C205S426000, C205S427000, C205S431000, C205S435000, C205S436000, C205S440000, C205S441000, C205S443000, C205S444000, C205S445000, C205S455000, C205S459000, C205S460000

Reexamination Certificate

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06294069

ABSTRACT:

This invention relates to a method for preparing very highly enantiomerically pure chiral 2-aryl or 2-heterocyclyl propionic acids (R or S) and their esters.
2-Aryl and 2-heterocyclyl propionic acids and their esters are useful as antiinflammatory drugs (for example ketoprofen, ibuprofen, naproxen, tiaprofen, fenoprofen, flurbiprofen, indoprofen, pirprofen, suprofen, cicloprofen, carprofen, benoxaprofen, hexaprofen, pranaprofen) and also as intermediates for the preparation of drugs (for example EP514442, EP516729, EP518961, EP518960, EP520016, EP593639, EP527069, EP607355, EP538099, EP678098, EP679161, EP678088, EP678089, EP766695, EP766696).
The 2-aryl and 2-heterocyclyl propionic acids and their esters are used either in their racemic form or in the form of an enantiomer (R or S), In general, the biological activity of these compounds is associated with a single enantiomer and it is thus necessary to obtain these enantiomers by a simple, inexpensive and non-polluting industrial method.
Many methods of preparation of these compounds have been developed but they generally lead to racemic compounds and the enantiomers must then be separated by chemical resolution or microbial conversion.
The 2-aryl and 2-heterocyclyl propionic acids and their esters are preferably represented by the formula:
in which R
1
represents an optionally substituted aryl or heterocyclic group and R
2
represents a hydrogen atom or an alkyl or phenylalkyl radical.
More particularly, R
1
is (a) a phenyl radical, (b) a phenyl radical substituted by one or more substituents selected from chlorine, bromine. fluorine, alkyl, alkoxy, alkenyl, hydroxy, hydroxyalkyl, acyl, benzoyl, amino, phenyl, chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, —CH(NH
2
)—COOH, saturated or unsaturated heterocycle with 5 to 14 members and containing a heteroatom selected from nitrogen, oxygen or sulfur optionally substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl, (c) a naphthyl radical, (d) a naphthyl radical substituted by one or more substituents selected from chlorine, bromine, fluorine, alkyl, alkoxy, alkenyl, hydroxy, hydroxyalkyl, acyl, benzoyl, amino, phenyl, chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, saturated or unsaturated heterocycle with 5 to 14 members and containing one or more heteroatoms selected from nitrogen, oxygen or sulfur optionally substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl. (e) a 9H-fluorenyl radical, (f) an anthracenyl radical, (g) a phenanthrenyl radical, (h) a saturated or unsaturated heterocycle with 5 to 14 members and containing one or more heteroatoms selected from nitrogen, oxygen or sulfur, (i) a saturated or unsaturated heterocycle with 5 to 14 members and containing one or more heteroatoms selected from nitrogen, oxygen or sulfur and substituted by one or more substituents selected from chlorine, bromine, fluorine, alkyl, alkoxy, acyl, benzoyl, amino, phenyl, chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, saturated or unsaturated heterocycle with 5 to 14 members and containing one or more heteroatoms selected from nitrogen, oxygen or sulfur optionally substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl.
The 5 to 14-membered heterocycles may include carbazole, indan, thiophene, furan, 1-isoindolinone, pyrrole, 2,5-dihydropyrrole, benzoxazole, 5H[1]benzopyrano[2,3-b]pyridine, pyridine, imidazole, oxazole, quinoline, isoquinoline, pyrimidine, phenothiazine, phenoxazine, piperazine.
More particularly, R
1
represents a 3 benzoylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 4-isobutylphenyl, 6-methoxy-2-naphthyl, 5-benzoyl-2-thienyl, 3-phenoxyphenyl, 2-fluoro-4-biphenyl, 3-fluoro-4-biphenyl, 1-oxo-2-isoindolinyl, 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl, 4-(2-thienylcarbonyl)phenyl, 9H-fluoren-2-yl, 6-chloro-9H-carbazol-3-yl, 2-(4-chlorophenyl)benzoxazol-5-yl, 4-cyclohexylphenyl, pyridin-2-yl, 5H[1]benzopyrano[2,3-b]pyridin-7-yl, 3-trifluoromethoxyphenyl, 3-acetylphenyl radical.
More particularly, R
2
represents a hydrogen atom or a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or benzyl radical.
Except where stated otherwise, in the definitions given above or below, the alkyl, alkoxy and alkenyl radicals contain 1 to 6 carbon atoms in straight or branched chains, the acyl radicals contain 2 to 6 carbon atoms and the halogen atoms are chlorine, bromine, iodine and fluorine atoms.
It is known that the electrochemical reduction of a mixture of the methyl ester of chiral 2-chloropropionic acid and iodobenzene, in the presence of nickel catalyst, does not load to the desired chiral product but to the racemic ester (M. DURANDETTI et al., J. Org. Chem., 61, 1748-1755 (1996)).
It has now been unexpectedly found that it is possible to prepare the chiral 2-aryl or 2-heterocyclyl propionic acids and their esters with a very good enantiomeric excess by electrochemical reduction of a mixture of a propionic acid derivative with formula
in which R
3
represents a radical of formula:
and Hal represents a halogen atom, preferably a chlorine atom, or R
3
is an aromatic or heterocyclic halogen derivative in which the halogen is preferably an iodine, bromine or chlorine atom, in the presence of a nickel complex as catalyst and a supporting electrolyte in an electrolysis cell provided with electrodes in organic solvent medium, then either by hydrolysis to obtain the chiral 2-aryl or 2-heterocyclyl propionic acid or by transesterification to obtain the corresponding ester.
The derivatives of formula (II) for which R
3
represents an A or C residue load to 2-aryl or 2-heterocyclyl propionic acids (R) and the derivatives of formula (II) for which R
3
represents a B residue lead to 2-aryl or 2-heterocyclyl propionic acids (S).
The aromatic or heterocyclic halogen derivatives are preferably of formula:
R
1
-Hal  (III)
in which R
1
has the same values as in formula (I) and Hal represents an iodine, chlorine or bromine atom.
The derivatives (II) and the aromatic or heterocyclic halogen derivatives are reacted together in stoichiometric amounts. It is preferable to add the derivative (II) progressively during the electrolysis.
The nickel complex is preferably a complex with a nitrogen-containing ligand and more particularly a NiBr
2
bipyridine or nickel-orthophenanthroline complex. It may be prepared either extemporaneously or in situ before the start of the electrolysis.
The quantity of the nickel complex is generally between 0.01 mole and 0.2 mole for 1 mole of the aromatic or heterocyclic halogen derivative and preferably 0.1 mole for 1 mole of the aromatic or heterocyclic halogen derivative.
The electrolyte is generally a quaternary ammonium salt such as tetrabutylammonium tetrafluoroborate or tetrabutylammonium bromide or an inorganic salt such as sodium bromide. Its concentration is generally between 5×10
−3
M and 2×10
−3
M and preferably 1.5×10
−2
M.
The solvent is generally an aprotic solvent such as dimethlylformamide, N-methylpyrrolidone (preferably dimethylformamide) or a mixture of aprotic and protic solvents, preferably a dimethylformamide-ethanol mixture (80-20% to 20-80%).
The anode is a consumable anode of aluminium or an aluminium alloy such as Duralumin or a zinc, iron or magnesium anode. It is preferable to use an aluminium anode.
The nature of the cathode is not critical for this type of reaction. It may be composed of another conducting material resistant to the conditions of the experiment, such as stainless steel (especially in sintered form), copper, nickel or a carbon fibre fabric. It is preferably composed of a nickel foam grid with a high specific surface area. According to a preferred embodiment of the method, the cathode has a hollow cylindrical shape

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