Process for producing quinolone derivatives

Details Process for producing quinolone derivatives Process for producing quinolone derivatives

1999-10-18

2001-02-13

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S153000, C546S262000

Reexamination Certificate

active

06187926

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel process for producing quinolone derivatives, and, more particularly, to a novel process for producing 2,3-unsubstituted 4-quinolone derivatives. The derivatives produced by the process of the present invention can be used as important intermediates in the production of final products to be used as pharmaceuticals, agricultural chemicals, or the like.
BACKGROUND ART
The following are common processes for producing 2,3-unsubstituted 4-quinolone derivatives. For example, there have been known, as processes for producing 7-chloroquinolone or 5,6,7,8-polysubstituted quinolones, a process comprising allowing an aniline derivative to react with an alkoxymethylene malonic ester in a solvent under high temperature conditions (
Organic Synthesis
, Vol. 3, pp. 272-275 (1955);
Acta Chim. Hung
., Vol. 112, pp. 241-247 (1983)), a process comprising allowing an aniline derivative to react with a propiolic ester in a solvent under high temperature conditions (
Tetrahedron
, Vol. 41, pp. 3033-3036 (1985)), and a process that is conducted in a gaseous phase under high temperature conditions (
J. Chem. Soc. Chem. Commun
., pp. 957-958 (1983)). These conventional processes are summarized in the following Table.
TABLE
Conventional Processes for Producing
2,3-Unsubstituted 4-Quinolone Derivatives
Starting
Number
Reaction
Literature
Compound
of Steps
Conditions
Product
Yield
1
Organic Synthesis
m-chloroaniline
4
heating to 250° C. in
7-chloro-4-
unknown
Vol. 3 pp. 272-275 (1955)
2 steps
quinolone
2
Acta Chim. Hung
3,4-
4
heating to 120° C. in
6,7-methylene-
Sum total
Vol. 112, pp. 241-247 (1983)
methylenedioxy-
one step
dioxy-4-
18%
aniline
heating in diphyl*
quinolone
under reflux in one
step
3
Tetrahedoron
2,3-dimethoxy-
1
heating in diphenyl
7,8-dimethoxy-
72%
Vol. 41, pp. 3033-3036 (1985)
aniline
ether (b.p. 259° C.)
4-quinolone
under reflux
4
J. Chem. Soc. Chem. Commun.
sec-amine
1
in a gaseous phase
4-quinolone
90%
pp. 957-958 (1983)
derivative
at 600° C.
*“diphyl” is a solvent mixture of biphenyl (b.p. 255° C.) and diphenyl ether (b.p. 259° C.), and the boiling point of “diphyl” is also assumed to be approximately 250° C.
Characteristic features of the above conventional processes:
1) All of the processes of Litertures 1 to 4 require heating to high temperature.
2) The processes of Literatures 1 and 2 require multiple steps.
3) The reaction product of Literature 2 is identical with that of Example 3 of the instant invention; and the reaction product of Literature 4 is the same as that of Example 2 of the present invention.
The above-described conventional processes have such disadvantages that they require many steps to be carried out at high temperatures or require high temperature reactions using diphenyl ether as solvent under reflux. They are therefore unsuitable as processes for commercially mass-producing 2,3-unsubstituted 4-quinolone derivatives. It is the present situation that there is a demand for a simpler process free from the foregoing problems.
An object of the present invention is therefore to provide a novel process for producing 2,3-unsubstituted quinolone derivatives by overcoming the aforementioned problems encountered in the conventional processes.
DISCLOSURE OF THE INVENTION
We earnestly made studies in order to attain the above object. As a result, it was found that a 2,3-unsubstituted 4-quinolone derivative can be produced under mild conditions by allowing an o-aminoacetophenone derivative to react with a formic ester in an aprotic solvent in the presence of a suitable base, and adding a protic solvent to the reaction mixture. The present invention was accomplished on the basis of this finding.
The present invention provides a process for producing a quinolone derivative represented by general formula (I):
in which A to D are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxyl, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylthio, lower alkylamino, di-lower alkylamino, halogen, trifluoromethyl and nitro, comprising allowing an o-amino-acetophenone derivative represented by general formula (II):
in which A to D are as defined above, to react with a formic ester in an aprotic solvent in the presence of a base, and adding a protic solvent to the reaction mixture.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention provides, as mentioned hereinbefore, a process for producing a quinolone derivative represented by the above general formula (I), comprising allowing a compound represented by the above general formula (II) to react with a formic ester in an aprotic solvent in the presence of a base, and adding a protic solvent to the reaction mixture.
All of the lower alkyl, lower alkoxyl, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylthio, lower alkylamino, and di-lower alkylamino in the definition of A to D in the above general formulas (I) and (II) have a linear or branched lower alkyl moiety of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl. The halogen in the definition denotes fluorine, chlorine, bromine or iodine.
The formic ester that is used in the present invention can include methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, isobutyl formate, sec-butyl formate, tert-butyl formate, and phenyl formate. Methyl or ethyl formate is preferred. These formic esters may be either commercially available or can be obtained by conventional methods.
The formic ester is used in an amount of 3 to 100 equivalents, preferably 5 to 10 equivalents relative to the derivative represented by general formula (II). The formic ester can often be used also in a large amount in excess of the above range. However, it is wasteful, from an economical point of view, to use the formic ester in such a large amount.
The base that is used in the present invention can include carbonates (e.g., potassium carbonate, sodium carbonate, cesium carbonate, etc.), metallic hydrides (e.g., lithium hydride, sodium hydride, potassium hydride, etc., sodium hydride being preferred), and metallic alkoxides (e.g., lithium methoxide, lithium ethoxide, lithium isopropoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium isobutoxide, sodium sec-butoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium butoxide, potassium isobutoxide, potassium sec-butoxide, potassium tert-butoxide, etc., sodium methoxide and sodium ethoxide being preferred).
The base is used in an amount of 1 to 20 equivalents, preferably 2 to 6 equivalents relative to the derivative represented by general formula (II). The base can often be used also in a large amount exceeding the above-described range. However, the reaction rate is not improved substantially even if such a large amount of the base is used, so that this is wasteful from an economical point of view.
The aprotic solvent for use in the present invention can include aromatic hydrocarbons (e.g., benzene, toluene, chlorobenzene, etc.), ether solvents (e.g., dimethoxyethane, tetrahydrofuran, dioxane, etc.), acetonitrile, and dimethylformamide. Dimethoxyethane, tetrahydrofuran and dioxane are preferred. A solvent mixture of any of these solvents may also be used.
The reaction temperature may vary depending upon the solvent and base used; however, it is generally in the range of −70 to 150° C., preferably in the range of 0 to 100° C. The reaction time may also vary depending upon the other reaction conditions; and it is generally from 10 minutes to 20 hours.
At the end of the above-described period of reaction time, a protic solvent is added to the reaction mixture in an amount of 0.01 to 2 times, preferably 0.02 to 1 time the volume of the aprotic solvent used, thereby terminating the reaction. Examples of the protic solvent include water, methanol, ethanol, propanol, 2-propanol and acetic acid. Water is preferred. The reaction product may be

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