Process for preparing 2,2-difluoroethylamine derivatives by alkylation with 2,2-difluoroethyl-1-haloethanes
View Patent ↗Process for preparing 2,2-difluorethylamine derivatives of the general formula (III) in which A is an optionally substituted heterocycle as described in the description, by reacting a 2,2-difluoroethyl-1-haloethane compound of the general formula (I) in which Hal is Cl, Br or iodine, with an amine of the general formula (II) in which A is as defined above, optionally in the presence of a base.
1. Process for preparing a 2,2-difluoroethylamine derivative of formula (III)
in which
A is an optionally substituted heterocycle which is selected from the group consisting of pyrid-2-yl, pyrid-4-yl and pyrid-3-yl which is optionally 6-substituted by fluorine, chlorine, bromine, methyl, trifluoromethyl or trifluoromethoxy, and pyridazin-3-yl, which is optionally 6-substituted by chlorine or methyl, and pyrazin-3-yl, 2-chloropyrazin-5-yl and 1,3-thiazol-5-yl which is optionally 2-substituted by chlorine or methyl, and pyrimidinyl, pyrazolyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,4-oxa-diazolyl, isothiazolyl, 1,2,4-triazolyl and 1,2,5-thiadiazolyl, which are optionally substituted by fluorine, chlorine, bromine, cyano, nitro, optionally fluorine- and/or chlorine-substituted C 1 -C 4 -alkyl, optionally fluorine- and/or chlorine-substituted C 1 -C 3 -alkylthio, or optionally fluorine- and/or chlorine-substituted C 1 -C 3 -alkylsulphonyl, and a pyrid-3-yl of the following formula
in which
X is halogen, C 1 -C 12 -alkyl or C 1 -C 12 -haloalkyl and
Y is halogen, C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, C 1 -C 12 -haloalkoxy, azido or cyano, by reacting a 2,2-difluoroethyl-1-haloethane compound of formula (I)
in which Hal is Cl, Br or iodine with an amine of the general formula (II)
optionally in the presence of a base.
2. Process according to claim 1 , wherein the molar ratio of 2,2-difluoro-1-haloethane of formula (I) to the amine of formula (II) used is in the range from 1:1.5 to 20:1.
3. Process according to claim 1 , wherein the base is present and is selected from tertiary nitrogen bases, inorganic aqueous bases, and alkali metal or alkaline earth metal hydroxides, hydrogencarbonates or carbonates.
4. Process according to claim 1 , wherein the base is present and is selected from substituted and unsubstituted pyridines, substituted and unsubstituted quinolines and tertiary amines of formula (IV)
NR 1 R 2 R 3 (IV)
in which
R 1 , R 2 and R 3 are each independently C 1-12 -alkyl, C 6-18 -aryl, C 7-19 -alkylaryl- or C 7-19 -arylalkyl, or in which two of the radicals together are a 5- to 8-membered nitrogen-containing heterocycle, or in which all three radicals together are part of an N-heterobicyclic or N-tricyclic radical having 5 to 9 ring atoms per cycle, where the cycles may contain further heteroatoms, which can optionally be oxygen or sulphur.
5. Process according to claim 1 , wherein the base is present and is selected from triethylamine, trimethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2-, 3-, 4-picoline, 2-methyl-5-ethylpyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridin, quinoline, quinaldine, N,N,N,N-tetramethylethyldiamine, N,N-dimethyl-1,4-diazacyclohexane, N,N-diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane, diazabicyclononane, diazabicycloundecane, methylimidazole and butylimidazole, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate.
6. Process according to claim 1 , wherein the reaction takes place in the presence of a catalyst and optionally in the presence of a base.
7. Process according to claim 6 , wherein the catalyst is selected from alkali metal bromides and iodides, ammonium bromide and ammonium iodide, tetraalkylammonium bromides and iodides, tetraalkyl- or tetraarylphosphonium halides, tetrakis(dimethylamino)phosphonium bromide, tetrakis(diethylamino)phosphonium bromide, tetrakis(dipropylamino)phosphonium chloride and tetrakis(dipropylamino)phosphonium bromide, and bis(dimethylamino)[(1,3-dimethylimidazolidin-2-ylidene)amino]methylium bromide.
8. Process according to claim 6 , wherein the catalyst is selected from potassium bromide, sodium iodide, potassium iodide, tetrabutylammonium bromide and tetraphenylphosphonium bromide.
9. Process according to claim 2 , wherein the base is present and is selected from tertiary nitrogen bases, inorganic aqueous bases, and alkali metal or alkaline earth metal hydroxides, hydrogencarbonates or carbonates.
10. Process according to claim 2 , wherein the reaction takes place in the presence of a catalyst and optionally in the presence of a base.
11. Process according to claim 3 , wherein the reaction takes place in the presence of a catalyst and optionally in the presence of a base.
12. Process according to claim 4 , wherein the reaction takes place in the presence of a catalyst and optionally in the presence of a base.
13. Process according to claim 5 , wherein the reaction takes place in the presence of a catalyst and optionally in the presence of a base.
14. Process according to claim 2 , wherein the base is present and is selected from substituted and unsubstituted pyridines, substituted and unsubstituted quinolines and tertiary amines of formula (IV)
NR 1 R 2 R 3 (IV)
in which
R 1 , R 2 and R 3 are each independently C 1-12 -alkyl, C 6-18 -aryl, C 7-19 -alkylaryl- or C 7-19 -arylalkyl, or in which two of the radicals together are a 5- to 8-membered nitrogen-containing heterocycle, or in which all three radicals together are part of an N-heterobicyclic or N-tricyclic radical
having 5 to 9 ring atoms per cycle, where the cycles may contain further heteroatoms, which can optionally be oxygen or sulphur.
15. Process according to claim 10 , wherein the catalyst is selected from alkali metal bromides and iodides, ammonium bromide and ammonium iodide, tetraalkylammonium bromides and iodides, tetraalkyl- or tetraarylphosphonium halides, tetrakis(dimethylamino)phosphonium bromide, tetrakis(diethylamino)phosphonium bromide, tetrakis(dipropylamino)phosphonium chloride and tetrakis(dipropylamino)phosphonium bromide, and bis(dimethylamino)[(1,3-dimethylimidazolidin-2-ylidene)amino]methylium bromide.
16. Process according to claim 10 , wherein the catalyst is selected from potassium bromide, sodium iodide, potassium iodide, tetrabutylammonium bromide and tetraphenylphosphonium bromide.
17. Process according to claim 11 , wherein the catalyst is selected from alkali metal bromides and iodides, ammonium bromide and ammonium iodide, tetraalkylammonium bromides and iodides, tetraalkyl- or tetraarylphosphonium halides, tetrakis(dimethylamino)phosphonium bromide, tetrakis(diethylamino)phosphonium bromide, tetrakis(dipropylamino)phosphonium chloride and tetrakis(dipropylamino)phosphonium bromide, and bis(dimethylamino)[(1,3-dimethylimidazolidin-2-ylidene)amino]methylium bromide.
18. Process according to claim 11 , wherein the catalyst is selected from potassium bromide, sodium iodide, potassium iodide, tetrabutylammonium bromide and tetraphenylphosphonium bromide.
19. Process according to claim 12 , wherein the catalyst is selected from alkali metal bromides and iodides, ammonium bromide and ammonium iodide, tetraalkylammonium bromides and iodides, tetraalkyl- or tetraarylphosphonium halides, tetrakis(dimethylamino)phosphonium bromide, tetrakis(diethylamino)phosphonium bromide, tetrakis(dipropylamino)phosphonium chloride and tetrakis(dipropylamino)phosphonium bromide, and bis(dimethylamino)[(1,3-dimethylimidazolidin-2-ylidene)amino]methylium bromide.
20. Process according to claim 12 , wherein the catalyst is selected from potassium bromide, sodium iodide, potassium iodide, tetrabutylammonium bromide and tetraphenylphosphonium bromide.