Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-05-22
1999-12-14
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544349, A01N 4366, C07D24136
Patent
active
060018313
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel process for the preparation of 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetic acid derivatives.
1,2,3,4-Tetrahydro-2,4-dioxoquinazolin-1-ylacetic acid and derivatives thereof are important intermediate products for the preparation of aldose reductase inhibitors (EP 218 999).
J. Am. Chem. Soc. (1933), pages 2113-2116 describes the reaction of N-ethylanthranilic acid with sodium cyanate and acetic acid and subsequent addition of sodium hydroxide to give 1,2,3,4-tetrahydro-1-ethyl-2,4-dioxoquinazoline. However, disadvantages of this process are the low space yield, because of the dilute reaction solution, and the very high excess of sodium hydroxide.
Monatsh. Chem. (1987) 118; pages 71-79 describes the reaction of methyl N-(methoxycarbonylmethyl)anthranilate with potassium cyanate in glacial acetic acid to give methyl 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetate. Although 10 equivalents of potassium cyanate are employed, the yield is only 19%.
There was therefore the need for an efficient process for conversion of anthranilic acid into 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetic acid derivatives.
This object is achieved by a process for the preparation of 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetic acid derivatives of the formula (I) ##STR2## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 independently of one another are hydrogen, halogen, NO.sub.2, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkyl or halogen-substituted (C.sub.1 -C.sub.6)alkyl and phenyl radical can also be substituted by halogen atoms, (II) ##STR3## in which R.sup.1 to R.sup.5 have the abovementioned meaning and R.sup.6 is hydrogen, (C.sub.1 -C.sub.6)alkyl or phenyl, where the alkyl or phenyl radical can also be substituted by halogen atoms, with a metal cyanate and hydrogen chloride in the presence of an inert solvent.
The process is important for the reaction of compounds of the formula (II) in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 are hydrogen, fluorine, chlorine, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkyl, or chlorine- or fluorine-substituted (C.sub.1 -C.sub.4)alkyl and R.sup.5 and R.sup.6 are hydrogen, (C.sub.1 -C.sub.4)alkyl or phenyl.
The reactions of compounds of the formula (II) in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen, fluorine, chlorine, methyl or ethyl,
The process is also particularly important for the preparation of compounds of the formula (I) in which two, and preferably three, of the radicals R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen.
The process is of particular interest for the preparation of 1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetic acid and the methyl and ethyl ester thereof.
In many cases, it has proved appropriate for the reaction to initially introduce the anthranilic acid derivatives of the formula (II) in a solvent. The anthranilic acid can be present here in dissolved form or as a suspension. Solvents which can be used are aprotic solvents or protic organic solvents or mixtures of these solvents. The use of polar aprotic solvents which show no reaction under the reaction conditions, for example sulfolane, dimethyl sulfoxide, dimethyl sulfone, diphenyl sulfone, tetramethylurea or mixtures thereof, is advantageous.
The concentration of anthranilic acid in the solvent is between 1 and 50% by weight, advantageously between 1.5 and 20% by weight, preferably between 3 and 10% by weight.
Metal cyanates which can be employed are alkali metal and alkaline earth metal cyanates, and also mixtures thereof. The use of sodium cyanate or potassium cyanate or mixtures thereof is advantageous.
It has proved favorable to add the metal cyanates in amounts of between 0.8 and 20 equivalents, in particular between 2 and 5 equivalents, based on the anthranilic acid derivatives. The metal cyanates can be initially introduced together with the anthranilic acid or added continuously or in portions. Hydrogen chloride can be added in gaseous form or as a non-aqueous solution, in one portion, in several portions or continuously, a
REFERENCES:
Derwent Abstract--DE 19532054 A1--German Patent issued Mar. 6, 1997.
J. Am. Chem. Soc. (1933), pp. 2113-2116, "Quinazolines," by Lange & Sheibley.
Journal of the Chemical Society:(1948) Synthetic Antimalarials p. 1759-1766.
Susse et. al., Monatsh Chem. (1987), vol. 118, pp. 71-79.
Krause Stefan
Neumann-Grimm Doris
Papenfuhs Theodor
Pfirmann Ralf
Clariant GmbH
Hanf Scott E.
Shah Mukund J.
Truong Tamthom N.
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