Patent GB-698191-A (GB)
Title: New diphenylmethane derivatives and method of making the same
IPC: C07C65/105
Filed: 1950-12-05
Abstract: Diphenylmethane derivatives are manufactured by condensing formaldehyde with any of the following benzene derivatives: (1) derivatives of 2-hydroxybenzoic acid having 1-3 substituents, one of type R1 and the remainder (if any) of type R2; (2) derivatives of 4-hydroxybenzoic acid having 1-3 substituents, one of type R5 and the remainder (if any) of type R6; (3) derivatives of 3-hydroxybenzoic acid having 1-3 substituents of type R6; (4) 2 : 3-, 2 : 5-, 2 : 6-, 3 : 4- and 3 : 5-dihydroxybenzoic acids, and derivatives thereof having one or two substituents of type R4; (5) derivatives of 2 : 4-dihydroxybenzoic acid having one substituent of type R3 with or without a second substituent of type R4; (6) 2 : 3 : 4- and 2 : 4 : 6-trihydroxybenzoic acid, and derivatives thereof having one substituent of type R4; (7) derivatives of 3 : 4 : 5-trihydroxybenzoic acid having one substituent of type R3; (8) 2 : 4 : 5 : 6-tetrahydroxybenzoic acid; or (9) compounds as in (4)-(8) having SO3H in place of COOH; in the foregoing R1 represents halogen, alkylamino, dialkylamino, alkoxy, ethyl or higher alkyl, or acyloxy, R2 alkylamino, dialkylamino, alkoxy, amino, ethyl or higher alkyl, or acyloxy, R3 a carboxylic or sulphonic acid group, halogen, alkylamino, dialkylamino, alkoxy, amino, alkyl or acyloxy, R4 a carboxylic or sulphonic acid group, alkylamino, dialkylamino, alkoxy, amino, alkyl or acyloxy, R5 halogen, alkylamino, dialkylamino, alkoxy, amino, alkyl or acyloxy, and R6 alkylamino, dialkylamino, alkoxy, amino or acyloxy.  The condensation may be effected by dissolving or suspending the benzene derivative in an inert solvent, adding formaldehyde solution all at once or gradually, and, if necessary, also adding a condensing agent (e.g. a mineral acid or an alkali).  In modifications of the process, some of the substituents may be introduced after the condensation, or substituents originally present or introduced after the condensation may be converted into other substituents.  The products are useful as inhibitors of the action of hyaluronidase.  Examples describe the condensation of formaldehyde with two molecular proportions of: (1) gentisinic acid; (2) 3 : 4-dihydroxybenzoic acid; (3) 2 : 5-dihydroxybenzenesulphonic acid; (4) 2 - hydroxy - 5 - ethylbenzoic acid; (5) 2 : 3-dihydroxybenzoic acid; (6) 2 : 6-dihydroxybenzoic acid; (7) 2 : 4 : 6-trihydroxybenzenesulphonic acid; (8) 2-dimethylamino-4-hydroxybenzoic acid; (9) 2 : 4 : 6-trihydroxy-3-methylbenzoic acid; (10) 2 : 6-dihydroxy-4-methylbenzoic acid; (11) 2 : 4-dihydroxy-5-carboxybenzoic acid; (12) 3 : 5-dihydroxybenzoic acid; (13) 2 : 4 : 5 : 6-tetrahydroxybenzoic acid; (14) 2 : 3 : 4-trihydroxybenzoic acid; (19) 2 : 5-dihydroxy-4-methylbenzoic acid; (20) 2 : 4-dihydroxy - 3 : 6-dimethylbenzoic acid; (23) 2 - hydroxy - 4 - acetoxybenzoic acid; (23) 3 : 4 - dihydroxy - 5 - acetoxybenzoic acid; (24) 2 : 5-dihydroxy-4-sulphobenzoic acid; (25) 3 : 4 : 5-trihydroxy - 5 - sulphobenzoic acid; (26) 2 : 4 - dihydroxy - 5 - sulphobenzoic acid.  In further examples: (15) formaldehyde is condensed with two molecular proportions of 4-hydroxybenzoic acid and the product is warmed with antimony pentachloride to produce 2 : 21-dihydroxy-3 : 31-dichloro - 5 : 5 - dicarboxydiphenylmethane; (16) formaldehyde is condensed with two molecular proportions of 3 : 4 : 5-trihydroxybenzoic acid and the product is stirred with bromine in chloroform to give 2 : 21 : 3 : 31 : 4 : 41-hexahydroxy - 5 : 51 - dibromo - 6 : 61 - dicarboxydiphenylmethane; (17) formaldehyde is condensed with two molecular proportions of phloroglucinol and the product is heated with sodium bicarbonate solution in an atmosphere of carbon dioxide, yielding 2 : 21 : 4 : 41 : 6 : 61-hexahydroxy - 3 : 31 - dicarboxydiphenylmethane; (18) formaldehyde is condensed with two molecular proportions of 3-aminophenol and the product is heated with ammonium carbonate under pressure, to form 2 : 21-dihydroxy-4 : 41-diamino - 5 : 51 - dicarboxydiphenylmethane; (21) 5 : 51 - dicarboxy - 2 : 21 - dihydroxydiphenylmethane is nitrated and the product reduced to 5 : 51-dicarboxy-2 : 21-dihydroxy - 3 : 31-diaminodiphenylmethane.  The isolation and purification of some of the products is described.