Patent GB-829246-A (GB)
Title: Improvements in or relating to new perfluoroalkyl-phenothiazine derivatives
IPC: C07D279/28
Filed: 1957-10-21
Abstract: The invention comprises compounds of the general formula <FORM:0829246/IV (b)/1> and their non-toxic acid addition salts (wherein Y is a perfluoralkyl radical of 1 to 3 carbon atoms, A is an alkylene chain of from 2 to 6 carbon atoms separating the nitrogen atoms linked thereto by at least two carbon atoms, R1 is a hydrogen atom, R2, R3, R4 and R5 are hydrogen atoms or methyl or ethyl radicals, R6 is cycloalkyl with 5 or 6 carbon atoms, cycloalkylalkyl with 6 to 10 carbon atoms, alkenyl with 2 to 6 carbon atoms, dialkylamino-lower-alkyl with 1 to 6 carbon atoms in each of the alkyl portions and 2 to 6 carbon atoms in the lower-alkyl portion, hydroxy-lower-alkyl with 2 to 6 carbon atoms in the lower alkyl portion, hydroxy-lower-alkyl-oxy-lower-alkyl, the lower-alkyl portions having 2 to 6 carbon atoms, phenyl, cinnamyl, furoyloxybutyl, furoyl, thenyl, monocyclic aralkyl with 2 to 6 carbon atoms in the alkyl portion, aliphatic acyl with 1 to 6 carbon atoms, alicyclic aliphatic acyl with 7 to 10 carbon atoms, monocyclic aryl-aliphatic acyl with 6 to 10 carbon atoms, carbomethoxy, carbethoxy, carbobenzoxy, carbamyl, dialkyl carbamyl with 1 to 6 carbon atoms in the alkyl portions, N-phenyl carbamyl, aliphatic acyloxy-lower-alkyl with 1 to 6 carbon atoms in the acyloxy portion and 2 to 6 carbon atoms in the lower-alkyl portion, or monocyclic aroyloxy-lower-alkyl with 2 to 6 carbon atoms in the lower-alkyl portion).  The compounds of the invention may be made by the following general reactions: (1) condense a 2-perfluoroalkyl phenthiazine with a reactive piperazinyl ester having the desired piperazinyl alkyl group; (2) react a piperazine with a 2-perfluoroalkylphenthiazine which is substituted in the 10-position by an alkyl chain with a reactive terminal group; (3) hydrolyse off R6 (when this is an easily-removable group like acyl) in the 2-perfluorophenthiazine derivative, and react the product so obtained with a reactive ester or ethylene oxide; (4) condense a 10-(o -amino-alkyl)-2-perfluoroalkylphenthiazine with a substituted bis-(b -haloalkyl)-amine.  The general reactions (1) to (3) are illustrated in the examples.  1 - Formyl - 4 - (31 - chloropropyl) - piperazine is made by reacting thionyl chloride with 1-formyl-4-(31-hydroxypropyl)-piperazine, which is made from 1-(31-hydroxypropyl)-piperazine and methyl formate.  10 - (31 - Piperazinylpropyl) - 2 - trifluoromethylphenthiazine is made by treating 10-[31-(N - formylpiperazinyl) - propyl] - 2 - trifluoromethylphenthiazine in ethanol with sodium hydroxide.  2 - Trifluoromethylphenthiazine is reacted with ethylene oxide, and the b -hydroxyethyl compound obtained is reacted with thonyl chloride to give 10-(21-chloroethyl)-2-trifluomethylphenthiazine, treatment of which with piperazine yields 10-(2-piperazinylethyl)-2-trifluoromethylphenthiazine.  N - carbethoxy - N1 - (g  - chloro - b  - methylpropyl)-piperazine is made from N-carbethoxypiperazine and 3-bromo-2-methylpropylchloride. 10 - [3 - (N - carbethoxy - piperazinyl) - 21 - methylpropyl] - 2 - trifluoromethylphenthiazine in ethanol is treated with sodium hydroxide to give 10 - (21 - methyl - 31 - piperazinylpropyl) - 2 - trifluoromethylphenthiazine.  N - diethylcarbamyl - N1 - (g  - chloropropyl) - piperazine is made from N-diethylcarbamylpiperazine and g -chloropropyl bromide.  N - carbobenzoxy - 2,5 - diethylpiperazine is reacted with g -chloropropyl bromide to give 4 - carbobenzoxy - 1 - (o  - chloropropyl) - 2,5 - diethylpiperazine, reaction of which with 2-trifluoromethyl-phenthiazine yields 10-[31-(N-carbobenzoxy - 211,511 - diethylpiperazinyl) - propyl] - 2-trifluorophenthiazine, treatment of which with sodium hydroxide gives 10-[31-(211,511-diethylpiperazinyl) - propyl] - 2 - trifluoromethylphenthiazine.  10 - [31 - (N - hydroxyethylpiperazinyl - propyl] - 2 - trifluoromethylphenthiazine is reacted with dichloroacetyl chloride, chloroacetyl chloride and chloroethyl chloroformate to give respectively 10 - [31 - (N - dichloroacetoxyethylpiperazinyl) - propyl] - 3 - trifluoromethylphenthiazine dihydrochloride, 10-[31-(N-chloroacetoxyethylpiperazinyl) - propyl] - 2 - trifluoromethylphenthiazine dihydrochloride and 10 - [31 - (N - chloroethoxycarbonyloxyethylpiperazinyl)-propyl]-2 - trifluoromethylphenthiazine dihydrochloride. Heptafluoropropylbenzene is nitrated by a mixture of nitric acid and concentrated sulphuric acid to give 1-heptafluoropropyl-3-nitrobenzene, reduction of which by hydrogen in the presence of Raney nickel gives 3-heptafluoropropylaniline, which on reacting with 2-chlorobenzoic acid yields 2 - (3 - heptafluoropropylphenylamino) - benzoic acid, decarboxylation of which gives 3-heptafluoropropyldiphenylamine, which on reacting with sulphur in the presence of iodine yields 2-heptafluoropropylphenthiazine.