Method for producing quinolin-4(1H)-one derivative
[Problem] The present invention provides a method for producing and isolating a target quinolone derivative using general industrial facilities with high purity. [Solving means] The present invention also provides a method for producing a quinolone derivative, the method including reacting a ketone with an anthranilic acid derivative using an aluminum halide and removing the aluminum halide under basic conditions.
1. A method for producing a quinolone derivative represented by formula (7):
wherein R 1 , R 2 , R 6 , and X 2 are as defined below,
the method comprising, in the presence of an aluminum halide represented by formula (1):
AlZ 3 (1)
wherein Z represents a halogen atom,
reacting a ketone represented by formula (2):
wherein
R 1 and R 2 each independently represent:
an optionally substituted linear or branched C 1-4 alkyl group,
an optionally substituted linear or branched C 2-4 alkenyl group,
an optionally substituted linear or branched C 2-4 alkynyl group,
an optionally substituted C 3-8 cyclic aliphatic hydrocarbon group,
an optionally substituted aromatic hydrocarbon group, or
an optionally substituted heterocyclic group,
alternatively, R 1 and R 2 are combined together to represent a group —(CH 2 ) p — (in which p represents 2 to 6),
wherein each of the substituents in the linear or branched C 1-4 alkyl group, the linear or branched C 2-4 alkenyl group and the linear or branched C 2-4 alkynyl group is at least one group selected from the group consisting of a halogen atom and a C 1-4 alkoxy group optionally substituted with a halogen atom,
the substituent in the C 3-8 cyclic aliphatic hydrocarbon group is at least one group selected from the group consisting of a linear or branched C 1-4 alkyl group, a halogen atom, and a C 1-4 alkoxy group optionally substituted with a halogen atom,
the substituent in the aromatic hydrocarbon group is at least one group selected from the group consisting of a halogen atom, a linear or branched C 1-4 alkyl group optionally substituted with a halogen atom, a linear or branched C 1-4 alkoxy group optionally substituted with a halogen atom, and a phenoxy group which is optionally substituted with a linear or branched C 1-4 alkoxy group optionally substituted with a halogen atom, and
the substituent in the heterocyclic group is at least one group selected from the group consisting of a halogen atom, a linear or branched C 1-4 alkyl group optionally substituted with a halogen atom, and a linear or branched C 1-4 alkoxy group optionally substituted with a halogen atom,
with an anthranilic acid derivative represented by formula (6):
wherein
R 5 represents:
an optionally substituted linear or branched C 1-4 alkyl group, or
an optionally substituted C 3-8 cyclic aliphatic hydrocarbon group,
R 6 represents a hydrogen atom, a halogen atom, or —B—R 7 ,
wherein,
B represents:
an oxygen atom, a sulfur atom, N(R 8 ), N(R 8 )—CO, or CO—N(R 8 ),
R 7 and R 8 each independently represent:
a hydrogen atom,
an optionally substituted linear or branched C 1-4 alkyl group,
an optionally substituted linear or branched C 2-4 alkenyl group,
an optionally substituted linear or branched C 2-4 alkynyl group,
an optionally substituted C 3-8 cyclic aliphatic hydrocarbon group,
an optionally substituted aromatic hydrocarbon group, or
an optionally substituted heterocyclic group,
wherein each of the substituents in the linear or branched C 1-4 alkyl group, the linear or branched C 2-4 alkenyl group, and the linear or branched C 2-4 alkynyl group is at least one group selected from the group consisting of a halogen atom and a C 1-4 alkoxy group optionally substituted with a halogen atom,
the substituent in the C 3-8 cyclic aliphatic hydrocarbon group is at least one group selected from the group consisting of a linear or branched C 1-4 alkyl group, a halogen atom, and a C 1-4 alkoxy group optionally substituted with a halogen atom, and
each of the substituents in the aromatic hydrocarbon group and the heterocyclic group is at least one group selected from the group consisting of:
a halogen atom,
a linear or branched C 1-4 alkyl group optionally substituted with a halogen atom,
a linear or branched C 1-4 alkyl group which is optionally substituted with a C 1-4 alkoxy group optionally substituted with a halogen atom,
a linear or branched C 2-4 alkenyl group optionally substituted with a halogen atom,
a linear or branched C 2-4 alkenyl group which is optionally substituted with a C 1-4 alkoxy group optionally substituted with a halogen atom,
a linear or branched C 2-4 alkynyl group optionally substituted with a halogen atom,
a linear or branched C 2-4 alkynyl group which is optionally substituted with a C 1-4 alkoxy group optionally substituted with a halogen atom,
a linear or branched C 1-4 alkoxy group optionally substituted with a halogen atom,
a linear or branched C 1-4 alkoxy group which is optionally substituted with a C 1-4 alkoxy group optionally substituted with a halogen atom,
a linear or branched C 2-4 alkenyloxy group optionally substituted with a halogen atom,
a linear or branched C 2-4 alkenyloxy group which is optionally substituted with a C 1-4 alkoxy group optionally substituted with a halogen atom,
a linear or branched C 2-4 alkynyloxy group optionally substituted with a halogen atom,
a linear or branched C 2-4 alkynyloxy group which is optionally substituted with a C 1-4 alkoxy group optionally substituted with a halogen atom, and
a phenoxy group which is optionally substituted with a linear or branched C 1-4 alkoxy group optionally substituted with a halogen atom, and
X 2 represents:
a hydrogen atom,
a halogen atom,
an optionally substituted linear or branched C 1-4 alkyl group, or
an optionally substituted linear or branched C 1-4 alkoxy group,
in which each of the substituents in the linear or branched C 1-4 alkyl group, and the linear or branched C 1-4 alkoxy group is at least one group selected from the group consisting of a halogen atom and a C 1-4 alkoxy group optionally substituted with a halogen atom;
and removing the aluminum halide under basic conditions.
2. The method according to claim 1 , comprising a step of mixing the aluminum halide represented by formula (1) in advance with the ketone represented by formula (2).
3. The method according to claim 1 , comprising a step of further adding a sulfide represented by formula (4):
R 3 —S(═O) l —R 4 (4)
in which R 3 and R 4 each independently represent an optionally substituted linear or branched C 1-4 alkyl group, or R 3 and R 4 are combined together to represent a group —(CH 2 ) q — (q is 3 to 7), and 1 represents 1 or 2, to a mixture of the aluminum halide represented by formula (1) and the ketone represented by formula (2).
4. The method according to claim 3 , wherein
Z represents a halogen atom,
R 1 and R 2 each independently represent:
an optionally substituted linear or branched C 1-4 alkyl group,
an optionally substituted linear or branched C 2-4 alkenyl group, or
an optionally substituted linear or branched C 2-4 alkynyl group,
in which each of the substituents in the linear or branched C 1-4 alkyl group, the linear or branched C 2-4 alkenyl group, and the linear or branched C 2-4 alkynyl group is at least one group selected from the group consisting of a halogen atom and a C 1-4 alkoxy group optionally substituted with a halogen atom,
R 3 and R 4 are combined together to represent a group —(CH 2 ) q — (q is 3 to 7), and 1 represents 1 or 2,
R 5 represents a linear or branched C 1-4 alkyl group, or a C 3-8 cyclic aliphatic hydrocarbon group,
R 6 represents a hydrogen atom, a halogen atom, or —B—R 7 ,
wherein B represents an oxygen atom, a sulfur atom, N(R 8 ), N(R 8 )—CO, or CO—N(R 8 ),
R 7 and R 8 each independently represent a halogen atom, or an aromatic hydrocarbon group which is optionally substituted with a linear or branched C 1-4 alkoxy group optionally substituted with a halogen atom, and
X 2 represents a hydrogen atom, a halogen atom, a linear or branched C 1-4 alkyl group optionally substituted with a halogen atom, or a linear or branched C 1-4 alkoxy group optionally substituted with a halogen atom.
5. The method according to claim 1 , wherein the aluminum halide represented by formula (1) is aluminum chloride.
6. The method according to claim 1 , wherein the ketone represented by formula (2) is 3-pentanone.
7. The method according to claim 1 , wherein the anthranilic acid derivative represented by formula (6) represents the following formula (8):
wherein R 5 and X 2 are as defined above,
R 9 , R 10 , R 11 , R 12 , and R 13 each independently represent:
a hydrogen atom,
a halogen atom,
an optionally substituted linear or branched C 1-4 alkyl group,
an optionally substituted linear or branched C 2-4 alkenyl group,
an optionally substituted linear or branched C 2-4 alkynyl group,
an optionally substituted linear or branched C 1-4 alkoxy group,
an optionally substituted linear or branched C 2-4 alkenyloxy group, or,
an optionally substituted linear or branched C 2-4 alkynyloxy group,
in which each of the substituents in R 9 , R 10 , R 11 , R 12 , and R 13 is at least one group selected from the group consisting of a halogen atom and a C 1-4 alkoxy group optionally substituted with a halogen atom.
8. The method according to claim 3 , wherein the sulfide represented by formula (4) is tetrahydrothiophene-1,1-dioxide.
9. The method according to claim 1 , wherein the removal of the aluminum halide under basic conditions is performed by filtration under basic conditions using an aqueous caustic solution and an alcohol.
10. The method according to claim 1 , wherein the quinolone derivative represented by formula (7) represents the following formula (9):
wherein R 1 , R 2 , R 9 , R 10 , R 11 , R 12 , R 13 , and X 2 are as defined above.
11. The method according to claim 1 , wherein the quinolone derivative represented by formula (7) is 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one.