Patent GB-1104995-A (GB)
Title: Cinnamic acid derivatives
IPC: C07D295/185
Filed: 1965-03-30
Abstract: 1,104,995. Cinnamic acid derivatives; trimethoxybenzenes. ELI LILLY & CO. 30 March, 1965 [6 April, 1964], No. 13495/65. Heading C2C. The invention comprises novel compounds of Formula I wherein R is methyl or ethyl; Z is -OH or -NR<SP>1</SP>R<SP>2</SP>; R<SP>1</SP> is hydrogen or C 1-3  alkyl; R<SP>2</SP> is C 1-3  alkyl, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2  OCH 3 , cyclopropyl, or methylcyclopropyl, or R<SP>1</SP> and R<SP>2</SP> taken together with the nitrogen atom to which they are attached form a pyrrolidino or morpholino radical. The acids of the invention (Z is -OH) may be prepared (1) by mixing with stirring a solution of ethyl acetate in ether and a suspension of lithium amide in anhydrous liquid ammonia, adding 3,4,5 - trimethoxy - acetophenone or - propiophenone with stirring and continuing the stirring until reaction is complete, neutralizing the stirred reaction mixture with solid ammonium chloride and replacing gradually the ammonia with ether, adding cold water, separating the resulting water and ether layers, washing the ether layer, evaporating the washed ether solution to dryness under vacuum, and dehydrating and hydrolysing the ethyl #- hydrozy - # - (methyl or ethyl) - 3,4,5 - trimethoxyhydrocinnamate thus obtained; (2) by bringing a mixture of activated zinc in anhydrous tetrahydrofuran to reflux, adding to the refluxing mixture a solution of ethyl bromoacetate and 3,4,5-trimethoxy-acetophenone or -propiophenone in a mixture of equal volumes of dry benzene and tetrahydrofuran at such a rate as to maintain good reflux, continuing the refluxing until reaction is complete, cooling the reaction mixture and adding thereto excess saturated aqueous ammonium chloride, extracting the reaction mixture with ether, washing the ether extract, evaporating the extract to dryness under vacuum, and dehydrating and hydrolysing the ester thus obtained; and (3) by stirring a mixture of a trialkyl phosphonoacetate and sodium hydride in an inert solvent the molecules of which possess no reactive and replaceable hydrogen atoms, at room temperature until evolution of hydrogen ceases, adding a solution of 3,4,5-trimethoxy-acetophenone or -propiophenone, preferably in the same solvent, stirring the mixture until reaction is complete, and hydrolysing the ethyl #-(methyl or ethyl)- 3,4,5-trimethoxycinnamate thus obtained. The acids thus prepared may be converted to the acid chloride by reacting the acid, suspended in dry benzene, with oxalyl chloride, removing benzene and unreacted oxalyl chloride by evaporation under vacuum, and repeatedly dissolving the crude acid chloride in benzene and removing the benzene under vacuum until the odour of oxalyl chloride is no longer detected. The amides of this invention (Z is -NR<SP>1</SP>R<SP>2</SP>) are prepared by reacting an acid as obtained above, or an acid derivative thereof, with an amine of formula HNR<SP>1</SP>R<SP>2</SP>. 3,4,5 - Trimethoxyacetophenone is prepared by methylating gallic acid, converting the trimethylgallic acid thus obtained to its acid chloride, reacting trimethylgalloyl chloride with diethyl malonate and hydrolysing and decarboxylating the diethyl 3,4,5-trimethoxybenz oylmolonate obtained. 3,4,5-Trimethoxypropio. phenone is made by adding a solution of trimethylgalloyl chloride to a benzene solution of diethylcadmium reagent (prepared by treating ethyl magnesium bromide in anhydrous ether with anhydrous cadmium chloride and replacing the ether with benzene). Therapeutic compositions, which have tranquillizing properties and which also inhibit the growth of certain protozoa, contain as active ingredient compounds of Formula I above.