Patent GB-1003648-A (GB)
Title: Hydroanthracene derivatives and their manufacture
IPC: C11B5/00
Filed: 1962-11-19
Abstract: The invention relates in part to the manufacture of hydroanthracene derivatives of the formula <FORM:1003648/C2/1> in which X is a hydrogen or a halogen atom or an alkoxy or nitro group, R is a hydrogen or a carboxy, lower carbalkoxy or phenyl lower carbalkoxy group, R1 is hydrogen or a methyl or benzyl group, and A is either (a) a group -CH(NO2)Z, in which Z is hydrogen or a lower carbalkoxy or a lower alkanoyl group or (b) a group -C(Y)(Z1)NR1R2, in which R1 is hydrogen or a methyl group, R2 is hydrogen or a methyl or formyl group, Z1 is a cyano, carboxy or lower carbalkoxy group and Y is hydrogen or a cyano or carbalkoxy group.  The compounds in which A is -CH2NO2 may be treated to reduce the nitro group, and the resulting amino group may then be alkylated or formylated. The invention relates also to hydroanthracene derivatives of the formula <FORM:1003648/C2/2> in which X is a hydrogen or a halogen atom or an alkoxy or nitro group, R1 is hydrogen or a lower alkyl or a benzyl group, and Z2 is a hydrogen or a halogen atom or a lower alkoxy, phenyl lower alkoxy, amino or substituted amino group, e.g. a mono- or di-methyl or -ethylamino group or a piperidino, morpholino, pyrrolidino or N-methylpiperizino group.  The term "lower" denotes a group containing up to 6 carbon atoms. Compounds of formula I may be prepared by reacting a 4,10-dioxo-hydroanthracene derivative carrying the substituents X, R and R1 in the position shown with a compound of the formula HA, where A is as defined above, in an inert solvent in the presence of a strongly basic condensing agent, for example by the Michael addition of a nitromethane derivative of the formula CH2(NO2)Z or a glycine derivative of the formula CH(Y)(Z1)NR1R2 to an appropriately substituted 4,10-dioxo-hydroanthracene derivative in a solvent in the presence of sodium hydride, metallic sodium or an alkali-metal alkoxide. The compounds of Formula II are obtainable from appropriately substituted 1,2,3,4 - tetrahydro - 4 - oxo - 2-naphthaleneacetaldehydes by reactions comprising (1) the condensation of the naphthaleneacetaldehyde compound with a malonic ester to form a 2-naphthylethylidene malonate, (2) treatment of the malonate derivative with cyclopentadiene to form the corresponding adduct, (3) treating the adduct with a strongly basic cyclizing agent to form a substituted 1,4,11,11a ,12,12a  - hexahydro - 1.4 - methanonaphthacene - 4a(6H) - carboxylate, (4) saponifying the carboxylate and (5) thermally decomposing it, optionally after converting it into the corresponding acid halide and optionally after reaction of the acid halide with ammonia or a primary or secondary amine.  Examples are given describing (1) the manufacture of the following compounds of Formula I: 8-chloro - 1,2,3,4,4a,9,9a,10 - octahydro - 4,10-dioxo - 5 - hydroxy - 2 - a  - cyano - N - formyl-anthraceneglycine ethyl ester and the corresponding 3 - carbethoxy and 3 - carbobenzyl-oxy compounds, 8 - chloro - 1,2,3,4,4A,9,9A,10-octahydro - 4,10 - dioxo - 5 - hydroxy - 2-anthraceneglycine, 8 - chloro - 3 - carbobenzyl-oxy - 1,2,3,4,4a,9,9a,10 - octahydro - 4,10 - dioxo - 5 - hydroxy - 2 - a - dimethylamino-anthracenemalononitrile, 8 - chloro - 1,2,3,4, 4a,9,9a,10 - octahydro - 4,10 - dioxo - 5 - hydroxy - 2 - a  - dimethylaminoanthracenemalononitrile ethyl 8 - chloro - 3 - carbobenzyloxy-4,10 - dioxo - 5 - hydroxy - 1,2,3,4,4a,9,9a,10-octahydroanthryl - 2 - nitroacetate, 8 - chloro-3 - carbobenzyloxy - 2 - nitromethyl - 4,10-dioxo - 5 - hydroxy - 1,2,3,4,4a,9,9a,10 - octahydroanthracene and the corresponding 3-carboxy compound; (2) the manufacture of the following compounds of Formula II: ethyl 8-chloro - 5 - methoxy - 1,4,4a,9,9a,10 - hexahydro - 4,10 - dioxoanthracene - 3 - carboxylate and the corresponding 5-hydroxy compound, benzyl 8 - chloro - 5 - hydroxy - 1,4,4a,9,9a,10-hexahydro 4,10 - dioxoanthracene - 3 - carboxylate and 8 - chloro - 5 - hydroxy - 1,4,4a, 9,9a,10 - hexahydro - 4,10 - dioxoanthracene-3-carboxamide; and (3) the manufacture of the following intermediates:  8-chloro-1,4,4a,9, 9a,10 - hexahydro - 4,10 - dioxo - 5 - hydroxyanthracene, diethyl 8 - chloro - 1,2,3,4 - tetrahydro - 5 - methoxy - 4 - oxo - 2 - naphthyl ethylidene malonate and the corresponding 5-hydroxy compound, dibenzyl 8 - chloro - 1,2,3, 4 - tetrahydro - 5 - hydroxy - 4 - oxo - 2 - naphthylethylidene malonate, the cyclopentadiene adducts of diethyl 8-chloro-1,2,3,4-tetrahydro-5 - methoxy - 4 - oxo - 2 - naphthylethylidene malonate and of the corresponding 5-hydroxy compound and of dibenzyl 8-chloro-1,2,3,4-tetrahydro - 5 - hydroxy - 4 - oxo - 2 - naphthylethylidene malonate, ethyl 10-chloro-1,4,11, 11a,12,12a - hexahydro - 5 - hydroxy - g  - methoxy - 6 - oxo - 1,4 - methanonaphthacene-4a(6H)-carboxylate and the corresponding g -hydroxy compound, benzyl 10 - chloro - 1,4, 11,11a,12,12a - hexahydro - 5,7 - dihydroxy - 6-oxo - 1,4 - methanonaphthacene - 4a(6H) - carboxylate, and the corresponding carboxylic acid and acid chloride.  The products of Formula I are useful as chelating, complexing or sequestering agents for polyvalent metal ions and as bactericides.  They are useful also in the synthesis of antibiotics of the tetracycline by any of the following processes: (1) A compound of the formula <FORM:1003648/C2/3> in which X is hydrogen or halogen and R3 and R4 are each hydrogen or methyl, is converted into a compound of the formula <FORM:1003648/C2/4> by reactions involving (a) the conversion of the acid into an acyl halide; (b) conversion of the acyl halide into the corresponding acyl malonate by reaction with sodium or magnesium diethyl malonate; and (c) cyclization of the acyl malonate by treatment with a strongly basic condensing agent.  The product may then be treated to remove the carbethoxy group or may be converted into a 2-carboxamino derivative. (2) A compound of Formula I in which Z is hydrogen and R is lower carbalkoxy or phenyl lower carbalkoxy may be hydrolysed and the product successively converted into an acyl halide, treated with sodium or magnesium diethyl malonate and cyclized as described above; the nitro group may then be reduced and methylated, and the product finally treated to remove the carbethoxy group or convert it into a 2-carboxamino group.  (3) A compound of Formula I in which Z is lower carbalkoxy or lower alkanoyl may be treated by processes involving (a) reduction of the nitro group; (b) methylation of the resulting amino group; (c) hydrolysis of the carbalkoxy or alkanoyl group; and (d) successive conversion into an acyl halide, treatment with sodium or magnesium diethyl malonate and cyclization as described above; the product may then be treated to remove the carbethoxy group or may be converted into a 2-carboxamino derivative.  The products of Formula II are useful as chelating, complexing or sequestering agents for polyvalent metal ions, as bactericides, and as intermediates for the preparation of compounds of Formula I.