Patent GB-1326745-A (GB)
Title: Chromone-2-carboxylic acid derivatives
IPC: C07C59/90
Filed: 1970-04-25
Abstract: 1326745 Chromone-2-carboxylic acid derivatives FISONS Ltd 19 April 1971 [25 April 1970] 20002/70 Heading C2C Novel compounds of the Formula I in which P, Q, T, P<SP>1</SP>, Q<SP>1</SP> and T<SP>1</SP> may be the same or different and may be H or substituents other than H, R<SP>1</SP> is H or substituted or unsubstituted C 1-10  alkyl or alkoxy groups or a substituted or unsubstituted aryl group, R<SP>12</SP> is H, -COCH 2 R<SP>1</SP>, alkyl or an allyl-alkyl group of up to 6C, X is a carbon-carbon bond or a single atom which may carry substituents not forming part of the linkage between the two benzene nuclei, and W is H or -COCH 2 R<SP>1</SP>, and salts, esters or amides thereof may be obtained by (a) reacting a compound of Formula II with a compound of Formula III in which L<SP>1</SP> is a good leaving group or a group -X<SP>1</SP>Y, Y being H or alkali metal, R is H or, together with the OOC group, forms an ester, L<SP>2</SP> is a good leaving group when L<SP>1</SP> is -X<SP>1</SP>Y, and a group -X<SP>1</SP>Y when L<SP>1</SP> is a good leaving group, and X<SP>1</SP> denotes -S- or -O-, (b) by cyclization of groups A<SP>1</SP> and A<SP>2</SP> in a compound of Formula VI where A<SP>1</SP> and A<SP>2</SP> represent pairs of groups (i) -COOHR<SP>1</SP>COCOR<SP>6</SP> and -OM, or (ii) -H- and -OC(COOM)=CR<SP>1</SP>-COOM, in which R<SP>6</SP> is an -OM group or a group convertible thereto, M is H or an alkali metal; (c) (i) subjecting to a Fries rearrangement a compound of Formula Id or (ii) opening the pyrone ring of a single chromone nucleus in a corresponding compound of Formula VIII under alkaline conditions; (d) by hydrolysing or oxidizing a compound of Formula I in which -COOH is replaced by D where D denotes a group which is hydrolysable or oxidizable to -COOH; (e) dehydrogenating a compound of Formula X (f) selectively hydrogenating a compound of I in which at least one of groups P to T<SP>1</SP> represents an alkenyl group; (g) subjecting to an elevated temperature a compound of Formula I in which R<SP>12</SP> is alkyl or allyl-alkyl and at least one of P<SP>1</SP> to T<SP>1</SP> is H; (h) by reacting an R ester of a compound of Formula I in which R<SP>12</SP> is H with a compound of formula R<SP>1</SP>CH 2 COOH or an anhydride or acid halide thereof; or (i) reacting a compound as used in (h) with R<SP>11</SP>Hal in which R<SP>11</SP> is an alkyl or allyl-alkyl group, and where desired or necessary converting the compound of Formula I into a pharmaceutically acceptable derivative thereof, or vice versa. The preparation of the following intermediates is also described: p-iodophenol reacts with acetylenedicarboxylic acid dimethyl ester to form 4-iodophenoxyfumaric acid dimethyl ester which is converted to the free acid which on heating with H 2 SO 4  yields 2-carboxy-6-iodochromone, the latter being esterified to the ethyl ester; 2-amino-2-hydroxyacetophenone is diazotized and reacted with potassium xanthate forming 2-hydroxy-5-mercaptoacetophenone; 4- acetyl-3-hydroxyaniline is diazotized and reacted with SO 2  forming 4-acetyl-3-hydroxybenzenesulphonyl chloride which is reduced to 4-acetyl-3- hydroxythiophenol and an Na salt is formed; 2-hydroxy-4-methoxy-acetophenone and chlorosulphonic acid yield 5-acetyl-4-hydroxy-2-methoxybenzenesulphonic acid, the K salt of which is reacted with POCl 3  to give the corresponding sulphonyl chloride which is then reduced to 5- acetyl - 4 - hydroxy - 2 - methoxy - thiophenol; 4 - (4 - hydroxyphenoxy)phenylacetate reacts with chlorobenzene forming 2-hydroxy-5-(4- hydroxyphenoxy)acetophenone which is reacted with dimethyl acetylene dicarboxylate to form 60% of 4-(3-acetyl-4-hydroxyphenoxy)phenoxy fumaric acid and 40% of the corresponding substituted maleic acid; 4,41-dihydroxydiphenylmethane reacts with acetic anhydride forming 4-acetoxy-4<SP>1</SP>-dihydroxydiphenyl methane (and also the diacetoxy compound) which rearranges in the presence of TiCl 4  to 3-acetyl-4,41-dihydroxydiphenylmethane. Pharmaceutical compositions useful in the treatment of disorders in which the slowreacting substance of anaphylaxis (SRS-A) is a factor, e.g. skin afflictions, hay fever, or asthma, comprise compounds of the Formula I with a pharmaceutically acceptable diluent or carrier in forms suitable for administration parenterally, orally, by inhalation or topically.