Patent GB-1368244-A (GB)
Title: Intermediates for pharmaceutically acitve monochromone-2-carbo xylic acids
IPC: C07C45/67
Filed: 1971-08-02
Abstract: 1368244 Intermediates for making substituted chromone - 2 - carboxylic acids FISONS Ltd 2 Aug 1971 [25 Aug 1970 15 Sept 1970 11 Dec 1970 3 June 1971] 03735/74 03736/74 03737/74 and 03738/74 Divided out of 1368243 Heading C2C The invention comprises compounds of Formula I in which R 5  represents hydrogen, hydroxy or, -OR<SP>1</SP> 5  in which R<SP>1</SP> 5  is a straight or branched saturated, or ethylenically unsatured, hydrocarbon group which group is optionally substituted by an -OH or by a 5 or 6 membered oxygen-containing heterocyclic ring, R<SP>1</SP> 5  together with any substituents thereon containing from 3 to 8 carbon atoms inclusive; R 6  represents hydrogen, alkyl containing from 1 to 6 carbon atoms inclusive, alkenyl containing from 2 to 6 carbon atoms inclusive, or phenyl; R 7  represents hydrogen or lower alkoxy-lower alkoxy; R 8  represents hydrogen, alkyl containing from 1 to 6 carbon atoms inclusive, or alkenyl containing from 2 to 6 carbon atoms inclusive, provided that (i) R 8  does not represent propyl when R 5  represents hydroxypropoxy; (ii) R 8  does not represent ethyl when R 5  is but-3-enoxy; (iii) two or three of R 5 , R 6 , R 7  and R 8  are other than hydrogen, save that: (a) when R<SP>1</SP> 5  represents a straight chain C 5-7  alkyl or alkenyl group or a branched chain C 6-8  alkyl or alkenyl group, then 0, 1, or 2 of R 6 , R 7 , R 8  are other than H; or (b) when R 6  represents Ph, then 0, 1 or 2 of R 7 , R 8  are other than H; (iv) R 6  and R 8  are both ethyl or are both sec. butyl only when R 5  is not hydrogen; (v) R 6  is alkyl containing from 4 to 6 carbon atoms when R 7  is lower alkoxy-lower alkoxy; and (vi) both of R 6  and R 8  contain 2 or more carbon atoms when R 5  is hydrogen or hydroxy, and A<SP>1</SP> and A<SP>2</SP> represent the pairs of groups (i) -COCH 2 - COCOR<SP>11</SP> and -OM; (ii) -H and or (iii) -COCH 3  and -OM, in which R<SP>11</SP> represents -OM, or a group which is hydrolysable thereto; and M represents hydrogen or an alkali metal, or A<SP>1</SP> and A<SP>2</SP> together form a chain -OCH(COOH)CH 2 CO-, or an ester, e.g. a lower alkyl ester, thereof. The term "lower" means up to C 6 . The compounds of Formula I in which A<SP>1</SP> and A<SP>2</SP> represent the pair of groups and -OM may be made by reacting a compound of Formula VII in which R 5 , R 6 , R 7 , R 8 , M and the provisos are as defined above, with a compound of Formula VIII in which R<SP>11</SP> is as defined above; R<SP>1</SP> is a group reactive with a hydrogen in the -COCH 3  group of the compound of Formula VII, e.g. an alkoxy, halo, amino, alkylamino, substituted amino (e.g. an arylsulphonylamino group) or substituted alkylamino group, each Z is a carbonyl oxygen atom, or one Z may represent two halogen atoms and the other a carbonyl oxygen atom, and if necessary hydrolysing the resulting compound to a compound of Formula I. The preferred compounds of Formula VIII are dialkyl oxalates, e.g. diethyl oxalate. The compounds of Formula I in which A<SP>1</SP> and A<SP>2</SP> represent the pair of groups -H and -O-C(COOM) = CH-COOM may be made by reacting a compound of Formula IX in which R 5 , R 6 , R 7 , R 8  and the provisos are as defined above, with a dialkyl acetylene dicarboxylate, in conventional manner, followed if necessary by hydrolysis of the diester first formed. The compounds of Formula I in which A<SP>1</SP> and A<SP>2</SP> together form a chain -OCH(COOH)CH 2 CO- may be made by cyclizing a compound of Formula XI in which R 5 , R 6 , R 7 , R 8 , M and the provisos are as defined above, by treating the compound of Formula XI with a base in a solvent which is inert under the reaction conditions. The compounds of Formula XI may be made by reacting a compound of Formula VII with glyoxalic acid or an ester thereof. Alternatively the compounds of Formula XI may be made by reacting a compound of Formula XI with maleic anhydride in a solvent in the presence of a Lewis acid, e.g. AlCl 3 , and decomposition of the resulting complex with dilute acid. The compounds of Formula I in which A<SP>1</SP> and A<SP>2</SP> together form a chain -OCH(COOH)CH 2 CO- may also be made by selective hydrogenation of a corresponding 2,3-dehydro compound, or by cyclization of a corresponding phenoxysuccinic acid. The compounds of Formulµ VII, VIII and IX may be made from known starting materials using conventional techniques.