Patent GB-821332-A (GB)
Title: Heterocyclic compounds and the manufacture thereof
Inventor: OSBOND JOHN MERVYN
IPC: C07D455/08
Filed: 1956-06-13
Abstract: <FORM:0821332/IV (a)/1> dl-Emetine and its stereoisomers and salts thereof are prepared by cyclising b -(3,4-dimethoxy-phenyl) ethyl amide of [1-(31,41-dimethoxy-phenylethyl) - 2 - keto - 5 - ethyl - piperidyl-(4)]-acetic acid (I on the flow sheet-see Figure above) with a polyphosphoric acid or with phosphorus pentoxide in an inert solvent, reducing the resulting 1-[[11-(311,411 -dimethoxy-phenylethyl) - 51 - ethyl - 21 - keto - piperidyl-(41)] - methyl] - 6,7 - dimethoxy - 3,4 - dihydroisoquinoline (II on the flow sheet) or a salt thereof, with lithium aluminium hydride or an alkali metal borohydride or by means of catalytic hydrogenation to form 1-[[11-(311,411-dimethoxy - phenylethyl) - 51 - ethyl - 21 - keto-piperidyl - (41)] - methyl] - 6,7 - dimethoxy-1,2,3,4 - tetrahydro - isoquinoline (III on the flow sheet); cyclising this compound or a salt, e.g. the iodide hydroiodide or chloride hydrochloride, thereof with phosphorus oxychloride or pentachloride in an inert solvent to form a dehydroenetinium salt (IV on the flow sheet), reducing this salt, e.g. a hydrohalide salt, by catalytic hydrogenation or by treatment with lithium aluminium hydride or an alkali metal borohydride to form a salt of dl-emetine (V on the flow sheet) or a stereoisomer thereof and, if desired, converting the salt into a free base or a further salt, said process optionally including at any stage the step or steps of separating any mixtures of racemates and, if desired, the resolution of the racemates so obtained into their optically active components. Suitable alkali metal borohydrides are lithium and sodium borohydride.  Methanol may be used as the solvent for each of the reduction steps.  A hydroiodide salt of the compound II may be formed for the next step in the process by treating an aqueous solution thereof with potassium iodide.  It is preferred to separate racemates formed during the process at the earliest possible stage in order to obtain a particular stereoisomer since the number of racemates present increases rapidly at each stage of the process.  Thus it is preferred to use one or other of the racemates of compound I as the initial starting compound.  The separation of the racemates may be carried out by fractional crystallization.  The resolution of racemates into their optically active components may be carried out in the usual way using an optically active acid and fractionally crystallizing the resulting salts before treatment with alkali to obtain the required optically-active base.  In an example, the above synthesis is carried out to form the following compounds: 2 racemate hydroiodides of compound II having melting points of 190-192 DEG  C., and 195.5-197.5 DEG  C.; 4 racemate hydroiodides of compound III having melting points of 214-216 DEG  C., 207-208.5 DEG  C., 241-243 DEG  C., and 204-207 DEG  C.; 4 racemate iodide hydroiodides of compound IV having melting points of 193-198 DEG  C., 195-196 DEG  C., 190-197 DEG  C., and 237-242 DEG  C.; and 7 racemates of compound V having melting points of 250-270 DEG  C. (dihydrochloride), 249-256 DEG  C., 252-257 DEG  C. (dihydroxhloride), 235-240 DEG  C. (dihydrochloride), 261-267 DEG  C. (dihydrochloride), 215-220 DEG  C. (dihydrochloride) and 259-266 DEG  C. (dihydrochloride) and an amorphous hydrochloride. The racemate dihydrochloride of compound V having a melting point of 252-257 DEG  C., dl-emetine dihydrochloride, is converted into the corresponding free base and is then treated with dibenzoyl (+)-tartaric acid and resolution by fractional crystallization of the resulting tartrate yields a bis-(dibenzoyl tartrate) salt having a melting point of 180-181 DEG  C. which is identical with that obtainable from natural emetine.  A piperidone-acetic acid of the formula in the Figure is prepared by hydrogenating [1-(31,41-dimethoxy - phenylethyl) - 2 - keto - 5 - ethyl - ethyl - piperidyl - (4) - acetic acid in methanol in the presence of Adams' catalyst.  Two racemates are formed of melting point 154-156 DEG  C. and 152-153 DEG  C. Specification 808,046 is referred to.