Process for preparing N-carboxymethylene-4-chloro-anthranilic ac

Details Process for preparing N-carboxymethylene-4-chloro-anthranilic ac Process for preparing N-carboxymethylene-4-chloro-anthranilic ac

1998-04-14

1999-08-31

Shaver, Paul F.

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

Organic compounds

Carboxylic acid esters

560 43, 562456, C07C22940

Patent

active

059455560

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a process for preparing N-carboxymethylene-4-chloroanthranilic acid, and its dialkyl esters.
These compounds are important starting materials for synthesizing aldose reductase inhibitors.
N-Carboxymethylene-4-chloroanthranilic acid can be prepared according to J. Med. Chem. 1991, 34, 1283 by reacting 4-chloroanthranilic acid with chloroacetic acid. The disadvantage in this case is the use of toxic chloroacetic acid in the substitution reaction. J. Prakt. Chem. 1929, 120, 64 describes the reaction of 4-chloroanthranilic acid with KCN and formaldehyde and subsequent reaction of the intermediate with aqueous KOH.
Methyl N-carbomethoxymethylene-4-chloroanthranilate is obtainable by esterifying N-carboxymethylene-4-chloroanthranilic acid with methanol/sulfuric acid (J. Heterocyc. Chem. 1987, 24,811, J. Med. Chem. 1991, 34, 1283) or with methanol/HCl (J. Prakt. Chem. 1929, 120, 64). An extremely high excess of sulfuric acid and very long reaction times are needed for the esterification.
EP 71 935 describes the following reaction sequences ##STR1##
Thus the overall yield of the diester after this 4-stage synthesis (based on 3-bromo-6-chlorobenzoic acid) is only 19.3%.
There has thus been a need for a process which avoids the described disadvantages and makes N-carboxymethylene-4-chloroanthranilic acid and its dialkyl esters available in high yield and purity.
This object is achieved by a process for preparing N-carboxymethylene-4-chloroanthranilic acid and its dialkyl esters, which comprises reacting 2,4-dichlorobenzoic acid in the presence of a base, of a solvent and of a catalyst with glycine to give N-carboxymethylene-4-chloroanthranilic acid and, where appropriate, reacting the latter in the presence of a base and of a solvent with a dialkyl sulfate, dialkyl carbonate or alkyl halide to give the dialkyl ester.
It has proven suitable to prepare N-carboxymethylene-4-chloroanthranilic acid by employing 0.5 to 10 mol, advantageously 1 to 5 mol, preferably 1 to 2 mol, of glycine per mole of dichlorobenzoic acid. Solvents which can be used are dipolar aprotic solvents, for example N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dimethyl sulfone, diphenyl sulfone, sulfolane, tetramethylurea, tetra-n-butylurea, 1,3-dimethyl-2-indazolidinone, water or protic organic solvents such as primary or secondary alcohols, especially high-boiling alcohols, such as ethylene glycol or glycerol, aliphatic amines or mixtures of the stated solvents. Dimethylacetamide, N-methylpyrrolidone or water have proven beneficial. Copper or copper compounds may have a catalytic effect, for example Cu or basic copper carbonate, copper iodide or mixtures thereof. 0.1 to 20 mol % of the catalyst are employed, advantageously 0.2 to 10 mol %, preferably 0.5 to 5 mol %.
It is possible to employ as base alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxides, basic oxides, phosphates, hydrogen phosphates or dihydrogen phosphates, and mixtures thereof. It is advantageous to use potassium carbonate, where appropriate also in combination with an alkali metal hydroxide, preferably NaOH or KOH. The amount of base is 1 to 10 mol per mole of dichlorobenzoic acid, advantageously 1.2 to 6, preferably 1.5 to 4, mol per mole of dichlorobenzoic acid.
The reaction temperatures are kept at between 40 and 200.degree. C., advantageously between 50 and 160.degree. C., preferably 60 to 150.degree. C.
The reaction times are between 30 min and 20 h, advantageously between 3 and 10 h, preferably 2 to 8 h.
The concentration of 2,4-dichlorobenzoic acid in the solvent is kept between 1 and 90% by weight, advantageously between 3 and 80% by weight, preferably between 5 and 70% by weight.
It has been found that the esterification of the two carboxyl groups can be carried out by the process according to the invention in considerably shorter times and with better yields than in the process disclosed in the literature. N-Carboxymethylene-4-chloroanthranilic acid is reacted und

REFERENCES:
patent: 3692818 (1972-09-01), Boltze et al.
patent: 5821385 (1998-10-01), Krause
J. Med. Chem. 1991, 34, 1283.
J. Prakt. Chem. 1929, 120, 64.
J. Heterocyc. Chem. 1987, 24, 811, J. Med. Chem. 1991, 34, 1283.
Dialkysulfate 102 Band 10 (no English translation).
2021863 Check for correct paragraph.
Derwent Patent Family Report and /or abstract.

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