Patent GB-1434090-A (GB)
Title: Halo-4-biphenylyl-butyric acid esters and amides and pharma ceutical compositions containing them
IPC: C07C51/377
Filed: 1973-08-16
Abstract: 1434090 Halo-4-biphenylyl-butyric acids, esters and amides DR KARL THOMAE GmbH 16 Aug 1973 [17 Aug 1972 18 Dec 1972 5 Jan 1973 28 Feb 1973 3 May 1973] 38842/73 Headings C2C and C2P The invention comprises compounds of the formula wherein R 1  is halogen and B is OH, alkoxy, aralkoxy or wherein R 3  and R 4  are H, carboxymethyl, C 1 - C 3  alkyl or phenyl optionally substituted by OH or CH 3  and when B is OH, acid addition salts thereof. They may be obtained by any of the following processes:-(1) when B is OH, by reacting compounds of the formula wherein X is OH, halogen or an acyloxy group, with a 1,1-dihaloethylene in acid and subsequently hydrolysing the intermediate with water; (2) by reduction of compounds of the formula wherein A is (3) when B is OH or alkoxy, by reduction of compounds of Formula III above wherein A is (4) when B is OH, by reacting a compound of the formula wherein Hal is a halogen atom with an alkali metal salt or an alkoxy magnesium salt of a malonate and saponifying the malonate obtained of the formula wherein R 5  is a C 1 -C 3  alkyl group, to a free acid which is subsequently decarboxylated; (5) when B is OH, by saponifying a nitrile of the formula by saponifying and decarboxylating a nitrile of the formula or by reduction and simultaneous saponification and decarboxylation of a nitrile of the formula (6) when B is OH, by oxidation of a carbinol of the formula (7) when B is OH, by reacting a Grignard compound of the formula wherein Hal is a halogen atom, with CO 2 ; (8) when B is OH or alkoxy, by solvolysis of compounds of the formula (9) when B is tertiary alkoxy, by reaction of a compound of Formula IIa with a metalated tert-alkyl acetate of the formula wherein Me is Li or Na and tert.alkyl is a C 4 - C 10  tertiary alkyl group; (10) when B is OH, by hydrolysis of ketene thioacetals of the formula wherein R 8  and R 9  are C 1 -C 3  alkyl groups or together they form a 5-7 membered ring which can optionally be interrupted by a further S atom; (11) when B is alkoxy, by desulphurizing a compound of the formula wherein R 6  is an alkyl group; (12) by decomposing a diazoketone of the formula with water to give a free acid, with an alcohol to give an ester, or with a primary or secondary amine of the formula to give an amide; (13) when B is OH, alkoxy or aralkoxy, by reacting a compound of Formula IIa with an alkali metal salt of an alkyl or aralkyl acetoacetate to form a compound of the formula wherein R, is alkyl or aryl, and cleaving this compound with a strong base; (14) when B is OH, alkoxy or aralkoxy by warming a compound of the formula wherein R 7  is alkyl or aralkyl, with a strong base whereby on acidification an acid of Formula I is produced, or with water whereby a compound of Formula I wherein B is alkoxy or aralkoxy is produced; (15) when B is OH, by oxidation of an aldehyde of the formula Pharmaceutical compositions comprise compounds of Formula I above. They have antiphlogistic activity and may be administered orally, parenterally or rectally. Compounds of Formula II above wherein X is OH may be obtained by reduction of the corresponding ketone. Compounds of Formula II above wherein X is halogen or acyloxy may be obtained by treatment of the corresponding compounds wherein X is OH with hydrohalic acids, phosphorus halides or thionyl halide or by acylation. Compounds of Formula III above wherein A is may be obtained by reacting -a ketone of the formula with a Zn compound of a corresponding halogenoacetate to give a compound of Formula III wherein A is followed by dehydration to give the required products. Compounds of Formula Va may be obtained by reduction of compounds of Formula Vd which may themselves be obtained by reacting a ketone of Formula XVIII with cyanoacetic acid or a derivative of the formula wherein Q is CN, CONH 2  or COOH optionally esterified with an aliphatic or araliphatic alcohol or a phenol. Compounds of Formula V may be obtained by decarboxylation of compounds of Formula Va. Compounds of Formula VI may be obtained by conversions of a compound of formula wherein Hal is halogen, to a Grignard compound followed by reaction with paraformaldehyde. Compounds of Formula XX may be obtained by reacting an appropriately substituted biphenyl with oxalic acid monoethyl ester chloride and anhydrous AlCl 3  to obtain the corresponding 2-(4-biphenyl)-glyoxylic acid ester which on reaction with CH 3 MgBr gives the 2-(4- biphenyl)-2-hydroxy-propionic acid which may then be treated with HI in acetic acid to give the 2-(4-biphenylyl)-propionic acid and reduced with LiAlH 4  in ether to give a propanol of the formula which on treatment with a phosphorus trihalide gives a compound of Formula XX. Compounds of Formula XXI may also be obtained by reduction with NaBH 4  of a compound of formula which may itself be obtained by heating in an alcoholic caustic alkali solution a compound of the formula which may itself be obtained by the reaction of 41-phenylacetophenones with chloroacetoacetates in the presence of NaNH 2  in benzene. Compounds of Formula VIII may be obtained by reacting halides of Formula II wherein X is halogen with metalated heterocycles of the formula Compounds of Formula X may be obtained by reaction of an aldehyde of Formula XXII with a lithium thioacetal of the formula to give compounds of the formula which may be dehydrated to give compounds of Formula X. Compounds of Formula XII may be obtained by alkylation of a compound of the formula wherein R 7  is an alkyl group, with a halogen compound of Formula II (X=halogen) in the presence of a metalating agent. Diazoketones of Formula XIII may be obtained by treating with diazonethane an acyl halide of the formula wherein Hal is Cl, Br or I. Compounds of Formula XVI may be obtained by reacting a compound of Formula IIa with a compound of the formula wherein R 7  is an alkyl or aralkyl group. Compounds of Formula XXXII may be obtained by reduction of a nitrile of Formula V.