Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-12
2003-02-04
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S155000, C546S156000, C546S157000, C546S159000, C546S162000, C546S178000
Reexamination Certificate
active
06515127
ABSTRACT:
The present invention relates to a process for preparing quinoline-5,8-diones which find an application as intermediate products, especially in the pharmaceutical industry.
Bracher (Heterocycles, 29, 2093, 1989) has already mentioned a process for preparing quinoline-5,8-dione from 5-amino-8-hydroxyquinoline by oxidation with dichromate. This process requires a double functionalization of the quinoline nucleus, and thus involves starting materials that are expensive and not readily available. S. Ghosh (J. Fluorine Chem., 1994; 67: 53-56) describes quinoline-5,8-dione derivatives obtained by cycloaddition between p-benzoquinone and a substituted diene. 4-Chloroquinoline-5,8-dione is described as a synthetic intermediate of more complex tricyclic or tetracyclic compounds (M. Croisy-Delsey et al., J. Heterocyclic Chem. 1993; 30: 55-60), whereas 2-methoxyquinoline-5,8-dione is presented as a by-product of the N-alkylation of 2,5,8(1H)-quinolinetrione (C. Avendano et al. Synthesis 1991; 727-730). 4-Hydroxy-5,8-quinolinequinone may be synthesized from 2,5-dimethoxyaniline and from the ester of methylacrylic acid (P. Withopf et al. Tetrahedron, 1987; 43(20):4549-4554). Quinoline-5,8-dione and 2-chloro-4-methylquinoline-5,8-dione are starting materials used in the synthesis of azaanthraquinone derivatives (K. T. Potts et al., J. Org. Chem., 1986:2011-2021). Antimalaria agents derived from 6-amino-5,8-dimethoxyquinolines are prepared from 2-trifluoro-4-methyl or from 2,4-dimethyl quinoline-5,8-dione (C. Temple et al., J. Med. Chem., 1974; 17(6):615-619). Finally, EP 0 433 679 describes quinoline-5,8-dione derivatives as inhibitors of the Maillard reaction in the body, this reaction being responsible (by denaturing proteins via sugars) for several consequences of diabetes (neuropathy, retinopathy, etc.).
Methods also exist for preparing quinones by photo-oxidation of phenols (for example Chem. Comm., 2173, 1996), but it has never been envisaged to apply such methods to heterocyclic compounds and in particular to quinoline derivatives.
The reason for this is that it was not obvious that such methods would not be hampered by the presence of the electron-withdrawing pyridine nucleus. Reactions between the quinones and the nitrogen of the pyridine nucleus, leading to colored polymers, could also have been feared. This is what was observed with 5-hydroxyisoquinoline.
It has now been found that a particular group of 8-hydroxyquinolines gives, by photo-oxidation, in the presence of a sensitizer and decomposition of the intermediate hydroxyperoxide, quinoline-5,8-diones in high yields.
One subject of the present invention is a process for preparing quinoline-5,8-diones of formula:
in which:
R
1
, R
2
and R
3
are chosen from hydrogen, a halogen atom, a C
1
-C
6
alkyl group, —CHO, —OH, —OR, —COOH, —CN, —CO
2
R, —CONHR, —CONRR′—, —NH
2
, —NHCOR,
morpholino and SO
3
H, R and R′ being chosen from C
1
-C
6
alkyl groups and Ar being a C
6
-C
14
aryl group,
in which an 8-hydroxyquinoline of formula:
in which R
1
, R
2
and R
3
have the meaning given above, is oxidized with oxygen under the action of actinic radiation in solution in an organic solvent and in the presence of a catalytic amount of a sensitizer, and the hydroperoxide formed, of formula:
is then decomposed to a compound of formula I.
The oxidation reaction with oxygen is carried out in an organic solvent in which the starting 8-hydroxyquinoline of formula II is soluble. The solvent is advantageously chosen such that the sensitizer is also soluble therein.
The sensitizer may especially be tetraphenylporphine (or TPP), in which case the solvent may especially be dichloromethane.
Other suitable sensitizers and solvents may also be used, and in particular:
rose bengal in CH
3
CN, MeOH, EtOH, CHCl
3
or water;
methylene blue in CH
3
CN, MeOH, EtOH, CHCl
3
or water;
tetra(4-pyridyl)porphine in CH
2
Cl
2
or CHCl
3
;
dicyanonaphthalene (DCN), dicyanoanthracene (DCA) or dicyanobenzene (DCB);
N,N′-dimethyl-2,7-diazapyrenium (DAP
2+
) bis(tetrafluoroborate).
The reaction is advantageously carried out in the region of room temperature (15 to 25° C.) under irradiation, with visible light while sparging with oxygen, for a period which may be from 2 to 8 hours.
The hydroperoxide formed, of formula III, spontaneously decomposes with stirring, especially in the presence of Na
2
SO
4
.
A subject of the present invention is also the quinoline-5,8-diones of formula:
in which:
R
1
, R
2
and R
3
are chosen from hydrogen, a halogen atom, a C
1
-C
6
alkyl group, —CHO, —OH, —OR, —COOH, —CN, —CO
2
R, —CONHR, —CONRR′—, —NH
2
, —NHCOR,
morpholino and SO
3
H, R and R′ being chosen from C
1
-C
6
alkyl groups and Ar being a C
6
-C
14
aryl group,
with the exception of the compounds in which:
R
1
=H, R
2
=H and R
3
is chosen from H, CH
3
, CN and CHO,
R
1
=H or CH
3
, R
2
=F and R
3
=H p
1
R
1
=Cl, R
2
=H and R
3
=H
R
1
=OH, R
2
=H and R
3
=COOH, COOCH
3
or CH
3
R
1
=OH, R
2
=COOH or COOC
2
H
5
and R
3
=H
R
1
=H, R
2
=H and R
3
=OCH
3
R
1
=OH, R
2
=H and R
3
=H
R
1
=OCH
3
, R
2
=H and R
3
=H
R
1
=CH
3
, R
2
=H and R
3
=Cl
R
1
=CH
3
, R
2
=H and R
3
=CH
3
REFERENCES:
patent: 4692449 (1987-09-01), Medwid
patent: 4742059 (1988-05-01), Medwid
patent: 2029421 (1991-05-01), None
patent: 0 433 679 (1991-06-01), None
patent: 2000055160 (2000-09-01), None
Babu, CA 69:10339, abstract of Symp Syn Heterocycl, Compounds Physiol Interest, Hyderabad, India, 1966.*
Babu, CA 71:3232, abstract, 1968.*
Pascual-Alfonso, CA 133:43466, 2000.*
By P. Withopf et al., “Synthese Von 8-Azajuglon (4-Hy-droxy-5, 8-Chinolinchinon)”, Tetrahedron, vol. 43, No. 20, 1997, pp. 4549-4554.
By K.T. Potts et al., “Cycloaddition Routes to Azaanthraquinone Derivatives. Use of Azadienophiles”, Journal of Organic Chemistry, vol. 51, No. 11, 1986, pp. 2011-2021.
By C. Temple, Jr. et al., “Synthesis of Potential Antima-larial Agents. Preparation of Some 6-Amino-5,8-dimethoxyquinolines and the Corresponding 6-Amino-5, 8-quinolinediones”, Journal of Medicinal Chemistry, vol. 17, No. 6, 1974, pp. 615-619.
Chemical Abstracts and Database Chemical Abstracts, Nos. XP-002139244 and XP-002139245, vol. 69, No. 3, Jul. 15. 1968.
By G. Matsuo et al., “Two-step synthesis of C-glycosyl juglones from unprotected sugars: a novel approach to angucycline antibiotics”, Chemical Communications, 1996, pp. 2173-2174.
By S. Ghosh et al., “[4+2]-Cycloaddition reactions employing 2-fluoro-2-alkenal N,N-dimethylhydrazones: synthesis of 3-fluoropyridines and dihydro or tetrahydro derivatives thereof”, Journal of Fluorine Chemistry, vol. 67, No. 1, 1994, pp. 53-56.
By M. Croisy-Delcey et al., “Synthesis of 4-amino-substituted-6-hydroxy and 11-hydroxy-naphtho (2,3-g)quinoline-5,12-diones . . . ”, Journal of Heterocyclic Chemsitry, vol. 30, No. 1, 1993, pp. 55-60.
By C. Avendano et al., “A Comparative Study of Synthetic Approaches to 1-Methyl-2,5,8 (1H)-quinolinetrione and 4-Methyl-2,5,8 (1H)-quinolinetrione”, Synthesis, 1991, pp. 727-730.
Belotti Damien
Cossy Janine
Laboratoire L. Lafon
Seaman D. Margaret
Young & Thompson
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