Method for producing optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl) alkylamine N-monoalkyl derivative
There is provided a method for producing an optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl derivative, which includes the steps of conducting reductive alkylation of an optically active secondary amine and a formaldehyde (including an equivalent thereof) or lower aldehyde in the presence of a transition metal catalyst under a hydrogen gas atmosphere, thereby converting the secondary amine to an optically active tertiary amine of the formula, and subjecting the tertiary amine to hydrogenolysis. The target optically active compound can be produced efficiently by this production method.
1. A method for producing an optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl compound of the formula [4], comprising:
conducting reductive alkylation of an optically active secondary amine of the formula [1] and a formaldehyde (including an equivalent thereof) or lower aldehyde of the formula [2] in the presence of a transition metal catalyst under a hydrogen gas atmosphere, thereby converting the secondary amine to an optically active tertiary amine of the formula [3]; and
subjecting the tertiary amine to hydrogenolysis
where R represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group; n is an integer of 1 to 5; the substitution position is arbitrary; R 1 represents an alkyl group having a carbon number of 1 to 6; R 2 represents a hydrogen atom or an alkyl group having a carbon number of 1 to 5; Me represents a methyl group; Ar represents a phenyl group or 1- or 2-naphthyl group; and * represents an asymmetric carbon.
2. The method for producing the optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl compound according to claim 1 , wherein the optically active secondary amine of the formula [1] is formed by:
conducting dehydration condensation of a fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl alkyl ketone of the formula [5] and an optically active primary amine of the formula [6], thereby converting the ketone to an optically active imine of the formula [7]; and
conducting asymmetric reduction of the imine in the presence of a transition metal catalyst under a hydrogen gas atmosphere
where R represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group; n is an integer of 1 to 5; the substitution position is arbitrary; R 1 represents an alkyl group having a carbon number of 1 to 6; Me represents a methyl group; Ar represents a phenyl group or 1- or 2-naphthyl group; the wavy line represents E configuration or Z configuration; and * represents an asymmetric carbon.
3. The method for producing the optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl compound according to claim 2 , wherein the optically active tertiary amine of the formula [3] is formed by:
conducting said asymmetric reduction of the optically active imine of the formula [7] in the presence of the transition metal catalyst under the hydrogen gas atmosphere to provide a reaction solution containing the optically active secondary amine of the formula [1];
directly adding the formaldehyde (including its equivalent) or lower aldehyde of the formula [2] to the reaction solution; and
conducting said reductive alkylation of the secondary amine and the formaldehyde or lower aldehyde under the hydrogen gas atmosphere by the reuse of the transition metal catalyst remaining in the reaction solution.
4. The method for producing the optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl compound according to claim 1 , wherein the optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl compound of the formula [4] is produced with high purity by converting the N-monoalkyl compound to an inorganic or organic acid salt and subjecting the salt to recrystallization purification.
5. A method for producing an optically active 1-(trifluoromethyl-substituted phenyl)alkylamine N-monoalkyl compound of the formula [11], comprising:
conducting reductive alkylation of an optically active secondary amine of the formula [8] and a paraformaldehyde of the formula [9] in the presence of a transition metal catalyst under a hydrogen gas atmosphere, thereby converting the secondary amine to an optically active tertiary amine of the formula [10]; and
subjecting the tertiary amine to hydrogenolysis
where Me represents a methyl group; Ph represents a phenyl group; m represents a positive integer; and * represents an asymmetric carbon.
6. The method for producing an optically active 1-(trifluoromethyl-substituted phenyl)alkylamine N-monoalkyl compound according to claim 5 , wherein the optically active secondary amine of the formula [8] is formed by:
conducting dehydration condensation of a trifluoromethyl-substituted phenyl alkyl ketone of the formula [12] and an optically active primary amine of the formula [13], thereby converting the ketone to an optically active imine of the formula [14]; and
conducting asymmetric reduction of the imine in the presence of a transition metal catalyst under a hydrogen gas atmosphere
where Me represents a methyl group; Ph represents a phenyl group; the wavy line represents E configuration or Z configuration; and * represents an asymmetric carbon.
7. The method for producing an optically active 1-(trifluoromethyl-substituted phenyl)alkylamine N-monoalkyl compound according to claim 6 , wherein the optically active tertiary amine of the formula [10] is formed by:
conducting said asymmetric reduction of the optically active imine of the formula [14] in the presence of the transition metal catalyst under the hydrogen gas atmosphere to provide a reaction solution containing the optically active secondary amine of the formula [8];
directly adding the paraformaldehyde of the formula [9] to the reaction solution; and
conducting said reductive alkylation of the secondary amine and the paraformaldehyde under the hydrogen gas atmosphere by the reuse of the transition metal catalyst remaining in the reaction solution.
8. The method for producing an optically active 1-(trifluoromethyl-substituted phenyl)alkylamine N-monoalkyl compound according to claim 5 , wherein the optically active 1-(trifluoromethyl-substituted phenyl)alkylamine N-monoalkyl compound of the formula [11] is produced with high purity by converting the N-monoalkyl compound to an inorganic or organic acid salt and subjecting the salt to recrystallization purification.
9. The method for producing the optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl compound according to claim 3 , wherein the optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl compound of the formula [4] is produced with high purity by converting the N-monoalkyl compound to an inorganic or organic acid salt and subjecting the salt to recrystallization purification.
10. The method for producing the optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl compound according to claim 3 , wherein the optically active 1-(fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl)alkylamine N-monoalkyl compound of the formula [4] is produced with high purity by converting the N-monoalkyl compound to an inorganic or organic acid salt and subjecting the salt to recrystallization purification.
11. The method for producing an optically active 1-(trifluoromethyl-substituted phenyl)alkylamine N-monoalkyl compound according to claim 6 , wherein the optically active 1-(trifluoromethyl-substituted phenyl)alkylamine N-monoalkyl compound of the formula [11] is produced with high purity by converting the N-monoalkyl compound to an inorganic or organic acid salt and subjecting the salt to recrystallization purification.
12. The method for producing an optically active 1-(trifluoromethyl-substituted phenyl)alkylamine N-monoalkyl compound according to claim 8 , wherein the optically active 1-(trifluoromethyl-substituted phenyl)alkylamine N-monoalkyl compound of the formula [11] is produced with high purity by converting the N-monoalkyl compound to an inorganic or organic acid salt and subjecting the salt to recrystallization purification.