Patent GB-1093673-A (GB)
Title: Novel chromone carboxylic acids
Inventor: FITZMAURICE COLIN
IPC: C07C49/84
Filed: 1963-09-27
Abstract: Novel compounds of Formula I <FORM:1093673/C2/1> and salts, esters and amides thereof, i.e. the salts, esters and amides of any carboxylic acid function present, and the esters of any hydroxylic function present, in which R is an alkyl group substituted by one or more hydroxyl groups or a carboxyl group, an alkyl group interrupted by one or more oxygen atoms which group may be substituted by one or more hydroxyl groups, an aralkyl group wherein the alkyl group is interrupted by one or more oxygen atoms and may be substituted by one or more hydroxyl groups, an aryloxyalkyl group wherein the alkyl group may be interrupted by one or more oxygen atoms and/or substituted by one or more hydroxyl groups, a heterocyclic ring containing carbon and oxygen which ring may be substituted by one or more hydroxyl groups or by one or more alkyl groups, or an alkyl group substituted by a heterocyclic ring containing carbon and oxygen which ring may be substituted by one or more alkyl groups; R1, R2 and R3 are the same or different and each is a hydrogen or halogen atom, a C1- 12 alkyl group, an alkoxy group, or a group -OR, or R1 and R2 together with the adjacent carbon atoms form a saturated or unsaturated oxygen containing heterocyclic ring; and R5 is a hydrogen atom or an alkyl group, are prepared (1) by cyclizing by heating an a ,g -diketo ester of Formula II <FORM:1093673/C2/2> in which R' is a lower alkyl group, and R" is a hydrogen atom or lower alkyl group, and, if desired, hydrolysing the ester, if formed, to the free acid, (2) by reacting a substituted acetophenone of Formula III <FORM:1093673/C2/3> (a) with an equimolar amount of an ester of formula R1-O-C(X)2-COOR1, where R1 is a lower alkyl group and X is halogen, in the presence of a finely divided metal catalyst of the platinum group of metals, or (b) with an ester of formula X-CO-COOR1 at an elevated temperature and in the presence of an acid binding agent, (3) by dehydrogenating the corresponding chromanone-2-carboxylic acid, (4) by reacting acetylene dicarboxylic acid with a phenol of Formula IV <FORM:1093673/C2/4> (a) in which M is hydrogen, in the presence of an excess of polyphosphoric acid, or (b) in which M is an alkali metal and cyclizing the product formed, or (5) by reacting a 5-hydroxychromone of Formula I in which R represents a hydrogen atom with a compound of formula RX in which R is as defined above and X is a halogen atom, in an inert solvent in the presence of an acid binding agent, or with a compound of Formula <FORM:1093673/C2/5> in which R4 together with the adjacent carbon atoms and the resultant hydroxy group on the carbon atom adjacent to R4 has one of the meanings defined for R in which R contains one or more hydroxyl groups.  The chromone-2-carboxylic acids may also be prepared by oxidation of the corresponding 2-aldehydo, 2-methyl, 2-halomethyl, 2-hydroxymethyl or 2-styryl chromones or by hydrolysis of the corresponding 2-cyano-chromones.  Sodium 4 - (2 - ethoxyethoxy) - 9 - methoxy - 5 - oxo - 5H - furo - [3,2 - g][l]benzopyran - 7 - carboxylate is obtained by reacting 4-hydroxy-9-methoxy - 7 - methyl - 5 - oxo - 5H - furo-[3,2-g][l]benzopyran with 2-ethoxyethyl bromide, treating the 4-(2-ethoxyethoxy)-9-methoxy - 7 - methyl - 5 - oxo - 5H - furo[3,2-g][l]-benzopyran obtained with potassium carbonate and acetic acid, and reacting the 5-acetyl-4-(2-ethoxyethoxy) - 6 - hydroxy - 7 - methoxybenzo[b]-furan thus formed with diethyl oxalate to give the free acid which may be converted to the ethyl ester and/or the sodium salt.  a ,g -Diketo esters of Formula II are prepared by condensing a dialkyl oxalate with an acetophenone in the presence of a condensation catalyst, or by condensing a pyruvate ester of formula R5CH2-CO-COOR1 with a benzoic acid ester of Formula VI.  <FORM:1093673/C2/6> Acetophenones of Formula III may be prepared by etherification of compounds in which R is hydrogen.  3,5 - Dichloro - 2,6 - dihydroxy - 4-methylacetophenone is made by treating 2,6-dihydroxy - 4 - methylacetophenone with sulphuryl chloride. 2,6-Dihydroxypropiophenone is obtained by esterifying 4-methyl-7-hydroxycoumarin with propionyl chloride, treating the 4-methyl-7-propionoxycoumarin obtained with aluminium chloride, and treating the 4-methyl-7-hydroxy-8-propionylcoumarin with sodium hydroxide. 2 - Acetyl - 3 - hydroxyphenoxyacetic acid is prepared by treating 2,6-dihydroxyacetophenone with chloracetic acid. Therapeutic compositions, which have activity as inhibitors of the antigen-antibody reaction, and which may be administered orally, topically or parenterally, contain as active ingredient a compound of Formula I above.