Process for preparing aryl- and heteroarylacetic acid derivatives
View Patent ↗The present invention relates to a process for preparing α-arylmethylcarbonyl compound of the formula (III), characterized in that aryl- and heteroarylacetic acids and derivatives thereof of the formula (I) are reacted with α-halomethylcarbonyl compounds of the formula (II) in the presence of a palladium catalyst, of a phosphine ligand, of an inorganic base and of a phase transfer catalyst, optionally using an organic solvent.
1. A process for preparing a compound of formula (III)
in which
Ar is the group
Ar is a heteroaromatic radical or
Ar is 1- or 2-naphthyl,
where R 5 , R 6 , R 7 , R 8 and R 9 are the same or different and are each independently hydrogen, halogen, optionally halogen-substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, phenyl, —CO—C 1 -C 3 -alkyl, —COO—C 1 -C 6 -alkyl or —COO—C 6 -C 10 -aryl,
R 3 is hydroxyl, in each case optionally substituted C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, phenyl, aryl, phenoxy or aryloxy, or NR 4 R 4′ ,
where R 4 and R 4′ are the same or different and are each independently hydrogen, C 1 -C 4 -alkyl, phenyl optionally substituted by C 1 -C 3 -alkyl which may be substituted by fluorine or chlorine, or by nitro, cyano or di-C 1 -C 3 -alkylamino, or, together with the nitrogen atom to which they are bonded, are a saturated or unsaturated, substituted or unsubstituted cycle,
comprising, reacting a compound of formula (I)
in which
R 1 is hydrogen or C 1 -C 8 -alkyl,
R 2 is hydrogen or C 1 -C 8 -alkyl, or
R 1 and R 2 together with the atoms to which they are bonded are a saturated or unsaturated, substituted or unsubstituted cycle,
and Ar is as defined above
with a compound of formula (II)
in which
Hal is halogen,
and R 3 is as defined above,
in the presence of a palladium catalyst, a phosphine ligand, an inorganic base, and a phase transfer catalyst, optionally using an organic solvent.
2. The process for preparing the compound of formula (III) according to claim 1 , wherein
R 1 is hydrogen or C 1 -C 4 -alkyl,
R 2 is hydrogen or C 1 -C 4 -alkyl, or
R 1 and R 2 , together with the atoms to which they are bonded, are optionally C 1 -C 4 -alkyl-or aryl-substituted C 2 -C 3 -alkanediyl,
R 3 is hydroxyl, optionally fluorine-substituted C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, in each case optionally substituted phenyl, phenoxy, or NR 4 R 4′ ,
where R 4 and R 4′ are the same or different and are each independently hydrogen, methyl, ethyl, i-propyl, n-propyl, or optionally methyl-, ethyl-, i-propyl-, n-propyl-, CF 3 -, C 2 F 5 -, C 3 F 7 -, nitro-, cyano-, N(methyl) 2 -, N(ethyl) 2 -, N(n-propyl) 2 -, N(i-propyl) 2 -substituted phenyl, or, together with the nitrogen atom to which they are bonded, are a saturated or unsaturated, substituted or unsubstituted, 5- or 6-membered cycle,
Ar is 1- or 2-naphthyl or the group
where
R 5 , R 6 , R 7 , R 8 and R 9 are the same or different and are each independently hydrogen, fluorine, chlorine, optionally fluorine-substituted C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, phenyl, —CO—C 1 -C 3 -alkyl, —COO—C 1 -C 4 -alkyl or —COO—C 6 -C 8 -aryl, and
Hal is fluorine, chlorine, bromine or iodine.
3. The process for preparing the compound of formula (III) according to claim 1 , wherein
R 1 is hydrogen, methyl, ethyl, i-propyl or n-propyl,
R 2 is hydrogen, methyl, ethyl, i-propyl or n-propyl, or
R 1 and R 2 together with the atoms to which they are bonded are optionally mono- to tetra-methyl-substituted C 2 -alkanediyl, optionally mono- to hexa-methyl-substituted C 3 -alkanediyl,
R 3 is methyl, ethyl, i-propyl, n-propyl, CF 3 , C 2 F 5 , C 3 F 7 , methoxy, ethoxy, i-propoxy, n-propoxy or tert-butoxy, in each case optionally substituted phenyl, or NR 4 R 4′ ,
where R 4 and R 4′ are the same or different and are each independently hydrogen, methyl, ethyl, i-propyl, or n-propyl, or, together with the nitrogen atom to which they are bonded, are a saturated, unsubstituted, 5- or 6-membered cycle,
Ar is 1-naphthyl or the group
where
R 5 , R 6 , R 7 , R 8 and R 9 are the same or different and are each independently hydrogen, fluorine, chlorine, methyl, ethyl, i-propyl, n-propyl, CF 3 , C 2 F 5 , C 3 F 7 , methoxy, ethoxy, phenyl, —CO-methyl, —CO-ethyl, —COO-methyl, —COO-ethyl or —COO-phenyl, and
Hal is chlorine, bromine or iodine.
4. The process for preparing the compound of formula (III) according to claim 1 , wherein
R 1 is hydrogen,
R 2 is hydrogen,
R 3 is methoxy, ethoxy, tert-butoxy, phenyl or NR 4 R 4′ ,
where R 4 and R 4′ , together with the nitrogen atom to which they are bonded, are a saturated, unsubstituted 6-membered cycle,
Ar is 1-naphthyl, phenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 4-acetylphenyl, 4-chloro-2,6-dimethylphenyl, 2,6-diethyl-4-methylphenyl, 4-methoxyphenyl, 4-ethoxycarbonylphenyl, and
Hal is bromine.
5. The process for preparing the compound of formula (III) according to claim 1 , wherein the palladium catalyst used is bis(dibenzylideneacetone)palladium, tris(dibenzylidene-acetone)dipalladium, palladium chloride, palladium bromide or palladium acetate.
6. The process for preparing the compound of formula (III) according to claim 1 , wherein the phosphine ligand used is triphenylphosphine, tri(1-naphthyl)phosphine or tri(o-tolyl)phosphine.
7. The process for preparing the compound of formula (III) according to claim 1 , wherein the base used is potassium fluoride, potassium carbonate or potassium phosphate.
8. The process for preparing the compound of formula (III) according to claim 1 , wherein the phase transfer catalyst used is tetrabutylammonium fluoride, chloride, bromide, iodide or acetate, tetraethylammonium iodide, benzyltriethylammonium bromide, dodecyltrimethylammonium bromide or methyltridecylammonium chloride.
9. A process for preparing the compound of formula (III) according to claim 1 , wherein Ar is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl or 3-thienyl.