Patent GB-831091-A (GB)
Title: Improvements in the production of derivatives of phenothiazine-10-carboxylic acid esters and their decarboxylation products and esters of 3-halogen-phenothiazine-n-carboxylic acids with amino alcohols
IPC: C09B23/10
Filed: 1956-10-10
Abstract: The invention comprises esters of the formula <FORM:0831091/IV (b)/1> (wherein R1 is an alkylene chain of 2 to 4 carbon atoms which may bear an alkyl group or a chlorine atom to form a side group, R2 and R3 are alkyl groups having 1 to 8 carbon atoms or cycloalkyl groups having 5 to 8 ring atoms, or two of the substituents R1, R2 and R3 may be joined to form an alkylene chain thus forming together with the nitrogen atom a saturated heterocyclic ring of 5 to 7 ring atoms which may have nitrogen or oxygen as additional hetero atoms and to which the COO-group is directly connected when R1 forms part of the ring) and hydrochlorides thereof; and the preparation of these compounds and of compounds of the above general formula wherein the substituent in the 3-position may be any halogen atom, the phenothiazine nucleus may be further substituted, e.g. by alkyl or alkoxy groups or halogen atoms, no limitation is placed on the number of carbon atoms in R2 and R3 and the heterocyclic tertiary amino group may bear further substituents, by esterifying the appropriate phenothiazine-10-carboxylic acid chloride with the appropriate tertiary amino alcohol.  This process may be combined with the additional step of heating the so-formed esters to a temperature between about 150 DEG  and about 220 DEG  C. until no more carbon dioxide is split off to form 3-halogeno-phenothiazines bearing an -R1NR2R3 group in the 10-position, isolated as free bases or as their hydrochlorides.  This process may also occur during the esterification reaction or during distillation of the ester, if these are carried out at sufficiently high temperatures.  The invention also particularly comprises esters of the formula <FORM:0831091/IV (b)/2> (wherein Z is an aliphatic hydrocarbon radical of 1 to 8 carbon atoms) and hydrochlorides thereof.  Suitable tertiary amino alcohols for use in the above process include N : N-diethylamino - ethanol, N : N - dimethylamino - ethanol, 1 - (N : N - dimethylamino) - propanol(3), 2-pyrrolidino-, 2-piperidino-, 2-morpholinoand 2-hexamethyleneimino-ethanol, 3-dimethylamino - 2 - chloro - propanol - (1), 2 - methylamino - propanol - (1) or - butanol - (1), N - cyclohexyl - N - methyl - amino - ethanol, N : N - dicyclohexylamino - ethanol, 3 - (N - iso - butyl - N - methyl - amino) - butanol - (1), N - hydroxyethyl - piperazine, N - methyl - N1-hydroxyethyl - piperazine, N : N1 - bis - (hydroxyethyl)-piperazine and N-methyl or N-ethyl - 3 - hydroxy - pyrrolidine or - piperidine. An hydrogen chloride binding agent, such as a molar excess of the amino alcohol or a base such as pyridine, quinoline or dimethylaniline, or sodium acetate or an alkali or alkaline earth metal hydroxide or carbonate or magnesium oxide, may be used in the esterification process, but such agent may be omitted, in which case a hydrochloride of the ester is formed.  The splitting off of carbon dioxide is facilitated by catalysts such as copper powder, and this process may be conducted at reduced pressure. Examples are given.  3-Halogeno-phenothiazine 10-carboxylic acid chlorides are prepared by reacting the 3-halogeno-phenothiazine with phosgene, preferably at elevated temperature and pressure.