Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-07
2001-10-23
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06307050
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to a novel synthetic process for the manufacture of flosequinan, 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone, starting with 4-fluoroanthranilic acid.
BACKGROUND OF THE INVENTION
Flosequinan is one of a class of quinoline compounds having therapeautic potential as antihypertensive agents or in the treatment of heart failure. Recently, flosequinan has been found potentially useful in the treatment of erectile dysfunction, as disclosed in commonly owned U.S. Pat. No. 6,110,489 and patent application Ser. No. 09/166,703, the contents of which are incorporated by reference herein.
The synthesis of flosequinan has been discussed in the literature and has been the subject of several patents. In Birch et al.,
Synthesis of Flosequinan: A Novel
4-
Quinolone shown to be useful in Congestive Heart Failure,
J. Chem. Soc. Perkins Trans. 1994, 387-392, the authors describe two approaches to the synthesis of flosequinan and its metabolite, flosequinoxan. The first approach was used in part by the inventors in developing the novel pathway disclosed herein. However, there are several significant differences and improvements in the novel pathway disclosed by the inventors herein, which result in high yields and purity as compared to the prior art.
Some of the authors of the above literature reference are named as inventors on several patents, including U.S. Pat. Nos. 5,011,931 and 5,079,264 and European Patent No. 0135367. These three patents include various synthetic steps that have been used historically in the synthesis of flosequinan. These patents do not, however, disclose or suggest the inventive pathway described by the inventors herein.
Other literature references relating to the synthesis and characterization of flosequinan include Kashiyama et. al.,
Stereoselective S
-
Oxidation of Flosequinan Sulfide By Rat Hepatic Flavin
-
Containing Monooxygenase
1
A
1
Expressed in Yeast,
Biochemical Pharmacology, Vol. 47, No. 8, 1357-1363 (1994); Russell et. al.,
The Synthesis of
2,3-
Ring
-
Fused Analognues of
7-
Flouro
-1-
methyl
-3-(
methylsulfinyl
)-4(1
H
)-
quinoline,
Synthesis, 753-755 (August 1992), and Morita et. al.,
Synthesis and Absolute Configuration of the Enantiomers of
7-
Flouro
-1-
methyl
-3-(
methylsulfinyl
)-4(1
H
)-
quinoline
(
Flosequinan
), Chem. Pharm. Bull. 42(10), 2157-2160 (1994). The last of these references addresses synthesis of optically active flosequinan via diastereomeric separation of certain (R)-methylbenzylamine derivatives and the determination of their absolute configuration by X-ray crystallographic analysis.
SUMMARY OF THE INVENTION
The inventive process is a 4-step pathway for the high-yield synthesis of flosequinan starting from 4-fluoroanthranilic acid. In the inventive process, the starting material (formula I):
is cyclized by reaction with phosgene to form intermediate-A, 4-fluoro-anthranilic acid isatoic anhydride (formula II):
which is then methylated using a source of methyl groups such as dimethyl sulfate to form intermediate-B, N-methyl-4-fluro-anthranilic acid isatoic anhydride (formula III):
which is then reacted with dimsyl sodium to produce intermediate-C, 1-(4-fluoro-2-methylaminophenyl)-2-methylsulfinylethanone (formula IV):
which is then treated with triethyl orthoformate in the presence of piperidine and acetic acid to produce flosequinan, 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone (formula V):
REFERENCES:
patent: 4302460 (1981-11-01), Davies et al.
Eisenberg Rodney
Kwiatkowski Stephan
Lawrence Lowell Jeffry
Mobley Steven G.
Mukhopadhyay Sudarsan
Milbank Tweed Hadley & McCloy LLP
Morris Patricia L.
R. T. Alamo Venture I LLC
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