Patent GB-927694-A (GB)
Title: New tetracycline compounds and the preparation thereof
IPC: C07C233/00
Filed: 1960-01-18
Abstract: The invention relates to octahydronaphthacene derivatives (1) of the formula <FORM:0927694/IV(a)/1> where R is hydrogen, halogen, hydroxy, alkyl, alkoxy, aralkoxy or acyloxy, R2 is hydrogen, cyano; carboxamide which may be substituted or unsubstituted, or a group -COOR1, where R1 is an alkyl group of 1-6 carbon atoms or a mononuclear aryl or aralkyl group, and R3 is hydrogen or an alkyl group of 1-6 carbon atoms, or (2) of the formula <FORM:0927694/IV(a)/2> where R and R3 are as above, R1 is an alkyl, aralkyl or acyl group and R5 is a group -COOR1, where R1 is as above, or (3) of the formula <FORM:0927694/IV(a)/3> where R2 and R3 are as above, R6 is hydrogen or halogen and R7 is hydrogen, an alkyl group of 1-6 carbon atoms, an acyl or a mononuclear aralkyl radical.  The products of the first formula are prepared by subjecting an appropriately substituted anthracene derivative to ring closure with a malonic acid derivative of the formula R2CH2Y, where R2 is as above and Y is a nitrile or an ester group, in the presence of a Claisen-type condensing agent, e.g. an alkali metal or an hydride, amide, hydroxide or alkoxide thereof.  The products of the second and third formulae are prepared by subjecting to ring closure an anthracene derivative of the formula <FORM:0927694/IV(a)/4> An example is given in which 5-benzyloxy-10-methoxy - 8 - chloro - 1,2,3,4-tetrahydro-4-oxo-2-anthracene acetic acid is subjected to ringclosure by treatment with ethyl malonate in the presence of sodium hydride to yield ethyl 10 - benzyloxy - 7 - chloro-11-methoxy-1,3,12-trioxo - 1,2,3,4,4A,5,12,12A - octahydronaph - thacene-2-carboxylate.  The products are useful as complexing agents for polyvalent metal ions.  A description is given, as follows, of the preparation of certain intermediates for use in the process.  8-Chloro-5-methoxy- 4-oxo-1,2,3,4-tetrahydronaphthalene-2-acetic acid is prepared from 2 - chloro - 5 - methoxytoluene by successive operations of bromination, treatment with diethyl malonate, reduction, conversion of the resulting propanediol into a bis-methane sulphonate conversion of this to a dinitrile, hydrolysis of the benzyl glutaric acid derivative and conversion of this to the corresponding naphthaleneacetic acid by treatment with polyphosphoric acid. 8-Chloro-5-methoxy- 4-oxo-1,2,3,4-tetrahydronaphthaleneacetyl chloride is prepared from the corresponding acid (see above) and oxalyl chloride.  2,21-Dicyano-3-(8-chloro- 1,2,3,4-tetrahydro-5-methoxy-4 -oxo-2- naphthylmethyl)-glutarimide is prepared from cyanoacetamide and 8 - chloro-1,2,3,4-tetrahydro-5-methoxy-4-oxo-2 naphthaleneacetaldehyde, which is itself obtained by reduction of the corresponding acetyl chloride (see above).  3-(8-Chloro-1,2,3,4- tetrahydro-5-hydroxy-4-oxo-2-naphthylmethyl) -glutaric acid is prepared from the corresponding 5-methoxy compound (see above) by treatment with hyd rochloric and glacial acetic acids. 3-(8-Chloro-1,2,3,4-tetrahydro-5-benzyloxy-4-oxo-2-naphthylmethyl) -glutaric acid is prepared from the corresponding 5-hydroxy compound (see above) and benzyl chloride.  Dimethyl 3-(8-chloro- 1,2,3,4-tetrahydro-4-oxo-5-benzyloxy-2-naphthylmethyl) -glutarate is prepared by esterification of the corresponding acid (see above). Methyl 8-chloro-1,2,3,4, 4A, 9,9A,10-octahydro-5-benzyloxy-4,10-dioxo- 2-anthracene acetate is prepared by subjecting the glutaric ester specified above to ring-closure in the presence of sodium hydride.  Methyl 8-chloro-1,2,3,4-tetrahydro-5-benzyl -oxo-4-oxo-10-hydroxy-2-anthracene acetate is prepared by brominating the octahydro compound specified above and treating the product with collidine.  Methyl 8-chloro-1,2,3,4-tetrahydro-5-benzyl -oxy-4-oxo-10-methoxy-2-anthracene acetate is prepared from the 10-hydroxy acid specified above and dimethyl sulphate. 8-Chloro-1,2,3,4- tetrahydro-5-benzyloxy-4 -oxo-10-methoxyanthraceneacetic acid is prepared by saponifying the corresponding methyl ester (see above).