Chromone 3-carboxylic acid

The discovery of the utility of the bis-chromone carboxylic acid derivative cromolyn sodium in the treatment of asthma and related allergies has led to an intensive, and thus far not very fruitful, effort to discover analogues which would show oral activity in contrast to the lead which must be administered by inhalation. Preparation of a typical analogue, proxicromil (63), starts with the O-allylated phenol 57. Claisen rearrangement leads to the corresponding C-allylated product 58. 

In addition to the chromone carboxylic acids mentioned in Section 2.23.8.1, a number of other chromones ha,ve shown promising activity as antiallergic compounds, for example 3-hydroxymethyl-8-methoxychromone (76MI22300), chromone-3-carboxylic acid (74CPB2959) and V-tetrazolyl chromonecarboxamides (78JMC1120). 

The major part of this review concerns chromones which possess a carboxyl or related group at C-2 but a few derivatives of the 3-carboxylic acids are known and discussed. Compounds in which the heterocyclic oxygen or the pyrone carbonyl oxygen is replaced by sulphur are also mentioned. The chemistry of chromones has been reviewed up to 1948 [1] and a survey (without references) of the synthesis of coumarins and chromones of therapeutic interest appeared in 1970 [2], Naturally-occurring chromones are covered in a chapter of a book by Dean [3]. The chromone-2- and -3-carboxylic acids have not been reviewed previously, although an early review of chromones [4] contains a short section on chromone carboxylic acids. 

Chromone-2-carbaldehyde, 3-methyl-synthesis, 3, 709 Chromonecarbaldehydes Knoevenagel condensation, 3, 711 Chromone-3-carbaldehydes mass spectra, 3, 615 oxidation, 3, 709 reactions, 3, 712 Schiff bases, 3, 712 synthesis, 3, 821 Chromone-2-carbonyl chloride Grignard reaction, 3, 711 Chromonecarboxamide, N-tetrazolyl-antiallergic activity, 3, 707 Chromone-2-carboxylic acid, 3-chloro-ethyl ester... 

Chromone-2-carboxylic acid, 8-cyano-6-methyl-ethyl ester... 

Grignard reaction, 3, 711 Chromone-2-carboxylic acid, 7-phenyl-ethyl ester reduction, 3, 704... 

Chromone-5-carboxylic acid, 7-hydroxy-2-methyl-decarboxylation, 3, 711 Chromonecarboxylic acids decarboxylation, 3, 710 Chromone-2-carboxylic acids esters... 

Nitration of hydroxypropiophenone (7-1) followed by conversion of the phenol to its methyl ether by means of methyl iodide provides the intermediate (7-2) the nitro group is then reduced to the corresponding amine (7-3) by catalytic reduction. The newly introduced amine is then replaced by a nitrile group by successive conversion to the diazonium salt by means of nitrous acid followed by treatment with cuprous cyanide (7-4). Reaction with aluminum chloride removes the methyl ether to afford the ortho acylphenol (7-5). This is converted to the chromone (7-6) as above by reaction with benzoyl chloride and sodium benzoate. The nitrile is next hydrolyzed to the carboxylic acid (7-7) by means of sulfuric acid. The acid is then converted to its acid chloride by means of thionyl chloride and that treated with 2-(A -piperidyl)ethanol (7-8). There is thus obtained flavoxate (7-9) [8], a muscle relaxant whose name reflects its flavone nucleus. 

The dibenzopyranone ring system may be viewed as a chromone with an additional fused benzene ring and thus generally related to the antiasthmatic mediator release inhibitor cromolyn (see Chapter 11). Two dibenzopyranones have in fact been investigated for this indication in the clinic. Friedel-Crafts cyclization of the substituted cresyloxybenzoic acid (2-1) in sulfuric acid leads to the dibenzopyranone (2-2). The methyl group is then oxidized to a carboxylic acid by means of chromic acid. The acid is then converted to its sodium salt, xanoxate sodium (2-3) [2]. 

Conversion of an aldehyde into a carboxyl group is effected with chromium trioxide-sulfuric acid in moderate yield. This is a synthetically valuable conversion because of the availability of chromone-3-carboxaldehydes (477). Photooxidation of the aldehyde (477 R = H, Me, Cl, OMe or OAc) in the presence of NBS gives high yields of 3-carboxylic acids (80SC889). 

An unusual oxidative breakdown of a p-tolyl group to a carboxylic acid (688) is accomplished in moderate yield without degrading the chroman system (51JCS76) and the stability of this system to oxidation (cf. chromone, Section 2.23.9.3) is further illustrated by the conversion of an ethyl to a carboxyl group in the formation of 2,4,4-trimethylchroman-2,7-dicarboxylic acid (689) (57JCS3060). 

The reaction of chromone-2-carboxylic acid with thionyl chloride or phosphorus halides gives the trihalide (400). This compound readily loses one of its geminal chlorine atoms and with water, for example, affords 4-chlorocoumarin through the simultaneous loss of carbon monoxide (Scheme 131) (63JGU1806). 

The reaction between a phenol and an unsaturated carboxylic ester has been widely used for the synthesis of chromone-2-carboxylic acids (00JCS1119,1179). There is little restriction on the substituents which may be present in the phenol and the necessary basic conditions have been achieved in various ways. 

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