Patent GB-723525-A (GB)
Title: Method of making new triphenylmethane derivatives
IPC: C07C65/105
Filed: 1951-11-08
Abstract: The invention comprises the manufacture of triphenylmethane derivatives by oxidizing in acid solution by means of nitrous acid, in the presence of formaldehyde (or a substance yielding it such as trioxymethylene, methyl alcohol, methylene chloride or formaldehyde acetals), a compound selected from (1) derivatives of 2-hydroxybenzoic acid having 1-3 substituents, one of type R2 and the remainder (if any) of type R3; (2) 3-hydroxybenzoic acid and its derivatives having 1-3 substituents, one of type R3 and the remainder (if any) of type R1; (3) derivatives of 4-hydroxybenzoic acid having 1-3 substituents of type R1; (4) derivatives of 2 : 4- and 2 : 5-dihydroxybenzoic acid having 1-2 substituents of type R3; (5) 2 : 6-dihydroxybenzoic acid and its derivatives having 1-2 substituents of type R3; and (6) derivatives of 3 : 4 : 5-trihydroxybenzoic acid having one substituent of type R3, wherein R1 denotes COOH, SO3H, alky;, dialkylamino, alkoxy, NH2, acyloxy or NO2, R2 denotes COOH, alkoxy or acyloxy, and R3 denotes OH, COOH, halogen, alkyl, dialkylamino, alkoxy, NH2, acyloxy or NO2, or by similarly oxidizing, in the presence of a benzene derivative having 1-5 substituents of type R3 (which in this case may also denote SO3H), a methylene-di-(hydroxybenzoic acid) corresponding to the compounds in (1) to (6) above, or by introducing carboxylic or sulphonic acid groups or halogen into the nuclei after the foregoing condensations, and the products so obtainable, especially compounds of the general formula <FORM:0723525/IV (b)/1> wherein R5 and R6 denote OH,COOH,SO3H, halogen, alkyl or acyloxy, or R5 may also be hydrogen, and R4 denotes 2 : 5-dihydroxy-3-carboxyphenyl, 2 : 4 - dihydroxy - 6 - carboxy - phenyl or 2 : 4 - dihydroxy - 3 - carboxyphenyl. Reference is also made to the conversion of groups present in the nuclei after condensation, e.g. reduction of nitro groups or hydrolysis of acylamino groups to NH2.  The products are useful as inhibitors of the action of hyaluronidase.  In examples: (1)-(3) the following compounds are dissolved in a mixture of concentrated sulphuric acid and methyl alcohol and the mixture warmed and agitated with sodium nitrite: (1) 3-hydroxybenzoic acid; (2) 2 : 5-dihydroxybenzoic acid; (3) 2 : 4 : 6-trihydroxybenzoic acid; (4)-(21) the following pairs of compounds are agitated with sodium nitrite and concentrated sulphuric acid: (4)-(6) methylene - di - (3 - hydroxybenzoic acid) and 3- or 4-hydroxy- or 6-methyl-4-hydroxy-benzoic acid; (7)-(9) methylene-di-(g -resorcylic acid) and 3 - or 4 - hydroxy - or 2 : 5 - dihydroxy - benzoic acid; (10)-(11) methylene-di-(2 : 4 : 5-trihydroxybenzoic acid) and phenol or salicylic acid; (12)-(14) methylene-di-gentisic acid and gentisic acid, salicylic acid or resorcinol; (15)-(16) methylene-di-(g -resorcylic acid) and g -resorcylic acid or gentisic acid; (17) methylene - di - (2 - dimethylamino - 4 - hydroxy - benzoic acid) and gentisic acid; (18)-(20) methylene - di - (phloroglucincarboxylic acid) and gentisic acid, m-sulphobenzoic acid or o-nitrophenol; (21) methylene - di - (4 - sulpho - gentisic acid) and gentisic acid; (22) the nitro group in the product of (20) is reduced to NH2 by means of hydrogen in the presence of palladium in alkaline solution; (23) the product of (18) is tribrominated with a solution of bromine in chloroform; (24) methylene-di-(a -resorcylic acid) and a -resorcylic acid are reacted as in (15); (25) the gentisic acid in (12) is replaced by gallic acid; (26) 2-hydroxy-5-ethoxybenzoic acid is agitated with formaldehyde solution, concentrated sulphuric acid and sodium nitrite; (27) methylene-di-(2-hydroxy-5-propoxybenzoic acid) and 2-hydroxy-5-propoxy-benzoic acid are reacted as in (4); (28) methylene - di - (2 - hydroxy - 4 - acetoxybenzoic acid) and gentisic acid are similarly reacted.  The isolation and purification of some of the products is described.