FR2495150A1 - TETRAHYDRONAPHTACENE DERIVATIVES - Google Patents

Abstract

Prepn. of 8-R1-8-R2-7,8,9,10- tetrahydro-1,6,11- trimethoxy- 5,12-dioxo-naphthacenes of formula (VII) from new 2-R1-2-R2-1,2,3,4- tetrahydro-5- hydroxy-8- methoxynaphthalenes of formula (I) via new intermediates ; is claimed, (where R1 is COOR or CXMe; R is lower alkyl; X is opt. protected oxo; R2 is H or OH; R5 is lower alkyl; R10 is COOH or CXMe). . The steps in the process are carried out as follows: (a) reaction of (I) with (II) in the presence of an aromatic boronic acid and treatment of the resulting boronate ester with a diol; (b) reductive cleavage of the phthalide ring; (c) methylation and saponification; (d) cylisation and, if necessary, esterification; (e) oxidn. The cpds. are intermediates for antibacterial and antitumour activity, e.g. adriamycin and daunohydrin.

Description

 The present invention relates to polycyclic compounds. More particularly, the invention relates to a process for the preparation of tetrahydronaphthacene derivatives and their intermediates as well as some of said derivatives and intermediates in themselves.

ou R1 représente un groupe alcoxycarbonyle inférieur ou un groupe de formule

The process provided by the invention consists in reacting a compound of general formula

or R1 represents a lower alkoxycarbonyl group or a group of formula

où R5 représente un groupe alcoyle inférieur, en présence d'un acide boronique aromatique et a' transformer l'ester d'acide boronique obtenu en un composé de formule générale

où R1 et R2 ont la signification donnée ci-dessus, si on le désire, à cliver de façon réductrice le noyau phtaiide dans un composé de formule III pour donner un composé de formule générale

où R2 a la signification donnée ci-dessus et où R10 représente un groupe carboxy ou un groupe de formule (a) ci-dessus, si on le désire, à méthyler un composé de formule IV et à saponifier le monoester ou diester obtenu pour donner un composé de formule générale

où R2 et R10 ont la signification donnée ci-dessus, si on le désire, à cycliser un composé de formule V et, lorsque R représente un groupe carboxy, à transformer ledit groupe en un groupe alcoxycarbonyle inférieur par estérification pour donner un composé de formule générale

où R1 et R2 ont la signification donnée ci-dessus, et, si on le désire, à oxyder un composé de formule
VI pour donner un composé de formule générale

où R1 et R2 ont la signification donnée ci-dessus.R2 represents a hydrogen atom or a hydroxyl group and R3 and R4 together represent an oxo group or a protected oxo group, with an aldehyde of general formula

where R5 represents a lower alkyl group in the presence of an aromatic boronic acid and transforming the resulting boronic acid ester into a compound of the general formula

where R 1 and R 2 have the meaning given above, if desired, to reductively cleave the phthalide ring in a compound of formula III to give a compound of the general formula

where R 2 has the meaning given above and wherein R 10 represents a carboxy group or a group of formula (a) above, if desired, to methylate a compound of formula IV and to saponify the monoester or diester obtained to give a compound of the general formula

wherein R2 and R10 have the meaning given above, if desired, to cyclize a compound of formula V and, when R is carboxy, to convert said group to a lower alkoxycarbonyl group by esterification to give a compound of formula General

where R1 and R2 have the meaning given above, and, if desired, to oxidize a compound of formula
VI to give a compound of the general formula

where R1 and R2 have the meaning given above.

 As used in this specification, the term "lower alkyl" denotes a straight or branched chain alkyl group which preferably contains from 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, tert. butyl, pentyl, hexyl, etc.). The lower alkyl moiety of a lower alkoxycarbonyl group has the same meaning, the lower alkoxycarbonyl examples being methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and the like. A protected oxo group can be any conventional protected oxo group. Preferably, however, an oxo group is protected in the form of a ketal, particularly an alkylene ketal and most preferably ethylene ketal.

 The reaction of a compound of formula II with an aldehyde of formula III, preferably methyl 2-formyl-3-methoxybenzoate, is conveniently carried out in the presence of an inert organic solvent. Preferred solvents are aromatic hydrocarbons such as benzene, toluene, xylenes and the like. Benzeneboronic acid is the preferred aromatic boronic acid for use in this reaction, although other aromatic boronic acids such as toluene-boronic acid, xylene-boronic acid, nitrobenzene acid, and the like can also be used. boronic, methoxybenzene-boronic acid, pyridine-boronic acid-, etc.The reaction is conveniently carried out in the presence of a catalytic amount of a carboxylic acid, preferably a lower alkanecarboxylic acid such as acetic acid, propionic acid, etc. It is advantageous for the reaction to proceed at an elevated temperature, preferably at the reflux temperature of the reaction mixture.

The above reaction yields a boronic acid ester which is converted to a compound of formula
III. This transformation is preferably carried out by treating the boronic acid ester with a 1,3-diol in the presence of an acid, and it is convenient to use the excess 1,3-diol. 2-methyl-2,4-pentanediol is a particularly preferred 7,3-diol. Of the acids that can be used, lower alkanecarboxylic acids such as acetic acid, propionic acid and the like are preferred. It is convenient to carry out the treatment in the presence of an inert organic solvent such as a halogenated hydrocarbon (for example dichloromethane, etc.) and at about ambient temperature. It is also possible to carry out the transformation of a boronic acid ester. to a compound of formula III by heating the ester in the presence of an acid such as a lower alkanecarboxylic acid.

 The reducing cleavage of the phthalide ring in a compound of formula III to give a compound of formula R can be effected in a generally known manner, for example, reductive cleavage can be carried out using zinc under alkaline conditions which It can be obtained, for example, by the use of an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc. This process for performing the reducing cleavage preferably takes place at an elevated temperature. Reductive cleavage can also be carried out by hydrogenation in the presence of a suitable catalyst.

 The methylation of a compound of formula IV can be carried out in a conventional manner; for example, using methyl iodide in the presence of a base such as potassium carbonate.

 The saponification of a monoester or diester obtained (the latter in the case where a compound of formula r wherein R10 represents a carboxy group is methyl) can be carried out in a conventional manner, for example by treatment with a hydroxide hydroxide. alkali metal such as sodium hydroxide.

 The cyclization of a compound of formula V can be carried out according to known methods; for example, in the presence of concentrated sulfuric acid or a trihaloacetic acid anhydride, preferably trifluoroacetic acid anhydride. When a trihaloacetic acid anhydride is used, it is convenient to carry out the cyclization in the presence of an inert organic solvent such as a chlorinated hydrocarbon (for example dichloromethane, etc.) and at about room temperature.

 When cyclizing a compound of formula V wherein is a carboxy group, the cyclization product (a compound corresponding to formula VI, but wherein R 1 represents a carboxy group) is esterified to give a compound of formula VI wherein R is a group lower alkoxycarbonyl. This esterification is carried out in a conventional manner, for example using a lower alkanol such as methanol.

 The oxidation of a compound of formula VI can be carried out using known oxidation methods. For example, the oxidation can be carried out using hydrogen peroxide or a chromic oxidizing agent such as chromium letrioxide in the presence of acetic acid.

 It will be appreciated that the product obtained in any of the above mentioned steps of the process need not be isolated and purified before being subjected to the subsequent process step.

In particular, a compound of formula R can be conveniently converted to a compound of formula VII without isolating or purifying compounds of formulas V and VI and, when formed, compounds of formula VI, but wherein R1 represents a carboxy group.

 The starting materials of formula I above can be prepared in various ways depending on the nature of the substituents R 1 and R 2 present.

où R11 représente un groupe alcoxycarbonyle inférieur, avec du trichlorure de bore et en hydrogénant de façon catalytique le composé de formule générale

obtenu, où R11 a la signification donnée ci-dessus.Thus, the starting materials of formula I wherein R 1 represents a lower alkoxycarbonyl group and wherein R 2 represents a hydrogen atom can be prepared by treating a compound of the general formula

wherein R 11 represents a lower alkoxycarbonyl group, with boron trichloride and catalytically hydrogenating the compound of the general formula

obtained, where R11 has the meaning given above.

 The treatment of a compound of formula VIII, which is a known compound or an analogue of a known compound, with boron trichloride is carried out at low temperature (for example -700C) and it is convenient to proceed in the presence an inert organic solvent (for example a halogenated hydrocarbon such as dichloromethane).

où R11 a la signification donnée ci-dessus, peut s'effectuer de façon classique; par exemple, en utilisant de l'hydrogène en présence d'un catalyseur au platine (par exemple l'oxyde de platine) dans un solvant approprié (par exemple un alcanol inférieur comme le méthanol, etc). Là encore, par exemple, on peut préparer les produits de départ de formule I où R1 représente un groupe de formule (a) ci-dessus et où R2 représente un atone d'hydrogène, selon le schéma de formules
I ci-dessous où R6 représente un groupe hydroxy éthérifié facilement clivable en un groupe hydroxy (par exemple benzyloxy) et où R30 et R40 ensemble représentent un groupe oxo protégé. Catalytic hydrogenation of a compound of formula ni to give a compound of general formula

where R11 has the meaning given above, can be carried out conventionally; for example, using hydrogen in the presence of a platinum catalyst (eg platinum oxide) in a suitable solvent (for example a lower alkanol such as methanol, etc.). Again, for example, the starting materials of formula I wherein R 1 represents a group of formula (a) above and where R 2 represents a hydrogen atom, according to the formula scheme, can be prepared.
I below where R6 is an etherified hydroxy group readily cleavable to a hydroxy group (eg benzyloxy) and wherein R30 and R40 together represent a protected oxo group.

Scheme of formulas I

 If one considers the scheme of formulas I, the hydroxy group is replaced in a compound of formula Ia by an etherified hydroxy group which is easily cleavable to a hydroxy group. This step can be done conventionally. For example, a compound of formula Ia can be reacted with a benzyl halide, especially benzyl chloride, in the presence of a suitable base (for example an alkali metal carbonate such as potassium carbonate) to give a compound of formula I wherein R6 is benzyloxy.

 A compound of formula X is converted into an acid of formula XI by saponification in a conventional manner; for example, using sodium hydroxide in aqueous alcoholic solution (for example an aqueous methanolic solution).

 An acid of formula XI is then converted into a compound of formula XII by treatment with methyl lithium in a conventional manner; for example, in an inert organic solvent such as an ether (eg diethyl ether, etc.) at about room temperature.

The transformation of a compound of formula
XII to a compound of formula Ib is also carried out conventionally. Thus, when R 6 is benzyloxy, this group can be converted to a hydroxy group by hydrogenation in the presence of a suitable catalyst (for example a palladium catalyst) and in the presence of an inert organic solvent (e.g. 'ethyl acetate).

 A compound of formula Ib can be converted to a compound of formula Ic in a conventional manner for the protection of an oxo group. In a preferred embodiment, this transformation comprises a ketalization which can be carried out, for example, using a suitable alkylene or alkylene diol in the presence of toluene-4-sulfonic acid and in the presence of a suitable inert organic solvent such as an aromatic hydrocarbon (eg, benzene, toluene, etc.) at an elevated temperature (e.g. the reflux temperature of the reaction mixture). A compound of formula Ic in which R 30 and R 40 are together is preferably an alkylene dioxy group, especially the ethylene dioxy group, is preferably prepared.

 Again, for example, the starting materials of formula I wherein R 1 represents a group of formula (a) above and where R is a hydroxy group according to formula II below where R 6, R 11, R30 and R40 have the meaning given above.

Scheme of formulas II

 If one considers the scheme of formulas II, a compound of formula X is converted into a compound of formula XIII by first forming the lithium enolate of a compound of formula X and then treating the enolate or with diperoxo-oxohexamethylphosphoramidomolybdenum (VI) pyridine (MoO5.py.H22) or with oxygen in the presence of a trialkylphosphite.

The conversion of a compound of formula X into a lithium enolate is carried out in a conventional manner; for example, using lithium diisopropylamide in an inert organic solvent such as tetrahydrofuran at low temperature (for example -780C),
The lithium enolate is then treated, preferably in situ, with diperoxo-oxohexamethyl phosphoramidomolybdenum (VI) pyridine, if possible at a temperature between about room temperature and -780 ° C, or with oxygen in the presence of a trialkylphosphite (for example triethylphosphite), which is convenient to do by passing gaseous oxygen through a mixture of enolate and trialkylphosphite in an inert organic solvent such as tetrabydrofuran at low temperature (for example - 78 C).

A compound of formula
XIII to a ss-ketosulfoxide of formula XIV by treatment with an alkali metal salt of dimethylsulfoxide.

It is convenient to carry out this treatment using the sodium salt of dimethylsulfoxide and in the presence of an inert organic solvent (eg tetrahydrofuran) at about 0 ° C.

A p-ketosulfoxide of formula
XIV to a compound of formula XV by treatment with aluminum amalgam. This treatment is conveniently carried out in the presence of an inert solvent (for example aqueous tetrahydrofuran) at a temperature between about 10 C and 200 C.

 A compound of formula XV may be converted to a compound of formula XVI in a manner analogous to that described above with respect to the conversion of a compound of formula Ib to a compound of tO 2 -mol Ic.

 Transformation of a compound of formula XVI into a compound of formula Id s1 is carried out analogously to what has been described above with respect to the conversion of a compound of formula XII into a compound of formula Ib.

 Finally, a compound of formula Id can be converted into a compound of formula Ic in a conventional manner for the conversion of a protected oxo group to an oxo group. thus, an oxo group can be converted into an oxo group by treatment with an acid (for example hydrochloric acid) in a suitable inert organic solvent (for example dioxane).

 The starting aldehydes of formula II above are known compounds or analogs of known compounds which can be conventionally prepared.

 the compounds of formulas I, III, IV, V and VI, certain compounds of formula VII and certain compounds which are present in the preparation of the compounds of formula I are new and it will be appreciated that these new compounds also form part of the invention.

 the bicyclic and tetracyclic compounds formulated herein may exist not only in racemic form but also in optically active form and it will be appreciated that the invention includes racemates and optical isomers. It will also be appreciated that when an optical isomer is used in the above process, the optical configuration is retained throughout the reaction sequence.

 The invention provides a regiospecific synthesis of the compounds of formula VII above which are useful intermediates in the preparation of anthracyclines having antibiotic and antineoplastic activity, adriamycin, daunomycin and carminomycin being examples of such anthracyclines.

où R2 a la signification donnée plus haut et où R14 représente un groupe alcoxycarbonyle inférieur ou acétyle, par traitement avec du trichlorure de bore, après enlèvement de la protection de tout groupe oxo éventuellement présent.The conversion of compounds of formula VII into therapeutically useful anthracyclines can be carried out, for example, by means of compounds of general formula

where R 2 has the meaning given above and where R 14 represents a lower alkoxycarbonyl or acetyl group, by treatment with boron trichloride, after removal of the protection of any oxo group possibly present.

 Transformation of compounds of formula VII into compounds of formula XVII, of which 7-deoxydaunomycinone is an example, is also part of the invention.

 The removal of the protection given by a protecting group which may be present in a compound of formula VII before treatment with boron trichloride is carried out in a manner analogous to that described above in connection with the transformation of a compound of formula Id in a compound of formula Ie.

 The treatment with boron trichloride is conveniently carried out in an inert organic solvent such as a halogenated hydrocarbon (eg dichloromethane, etc.) and at about 00.degree.

 The subsequent conversion of compounds of formula XVII to anthracyclines can be carried out according to generally known methods.

où R2 et R14 ont la signification donnée plus haut, selon des procédés classiques; cf, par exemple Kende et coll.J.A.C.S. (176), 98, 1967, et Smith et colt. Thus, a compound of formula XVII can be converted into a compound of the general formula

where R2 and R14 have the meaning given above, according to conventional methods; cf, eg Kende et al., JACS (176), 98, 1967, and Smith et al.

JACS (176), 98, 1969. A compound of formula XVIII can then be converted into an anthracycline by glycosidation in a conventional manner; see, for example,
Smith et al. JBCS (1976), 98, 1969.

 It is also possible to convert compounds of formula VII -en compounds of formula XVIII above according to another embodiment of the invention.

où R1 et R2 ont la signification donnée plus haut, de traiter ledit bromure de formule XIX avec de l'acétate d'argent en présence.d'acide acétique, de désacétyler l'acétate de formule générale

obtenu, où R1 et R2 ont la signification donnée plus haut, et, après avoir retiré la protection d'un éventuel groupe oxo protégé présent, de traiter le composé de formule générale

obtenu, où R2 et R14 ont la signification donnée plue haut, avec du trichlorure de bore.This transformation involves brominating a compound of formula VII to give a bromide of the general formula

where R1 and R2 have the meaning given above, to treat said bromide of formula XIX with silver acetate in the presence of acetic acid, to deacetylate the acetate of general formula

obtained, where R1 and R2 have the meaning given above, and, after removing the protection of any protected oxo group present, to treat the compound of general formula

obtained, where R2 and R14 have the meaning given above, with boron trichloride.

 The bromination of a compound of formula VII can be carried out conventionally for benzyl bromurations. Thus, the bromination can be carried out using N-bromosuccinimide and a free-radical inducer (eg benzoyl peroxide or α-azoisobutyronitrile) or using elemental bromine and a free-radical inducer (see for example Wong and Can J. Chem 1971, 49, 2712).

When R2 represents a hydroxy group, the bromination gives a mixture of cis-trans bromides of formula
XIX in approximately equal proportions.

It is convenient to treat a bromide of formula XIX with silver acetate in the presence of acetic acid at about room temperature for about 16 hours. When using a mixture of cis and trans bromides of formula
XIX, a mixture of cis and trans acetates of formula XX wherein the cis acetate predominates in a ratio of about 8: 1 is obtained.

 The deacetylation of an acetate of formula XX can be carried out in a conventional manner; for example, using a lower alkali metal alkoxide in a corresponding lower alkanol (for example, sodium methoxide in methanol). A trans-diol obtained at this stage can be converted to a cis-diol by reaction with an aromatic boronic acid and subjecting the obtained cis boronic acid ester to diol exchange with a suitable 1,3-diol. The reaction of a trans-diol with an aromatic boronic acid (for example tolueneboronic acid, xyleneboronic acid, methoxybenzeneboronic acid, nitrobenzeneboronic acid, pyridineboronic acid, preferably benzeneboronic acid) is carried out in the presence of an organic sulphonic acid, preferably toluene-4-sulphonic acid, and in the presence of an inert organic solvent, preferably an aromatic hydrocarbon such as benzene, toluene, etc., in the vicinity the ambient temperature. The cis-boronic acid ester obtained is then treated with a 1,3-diol, preferably 2-methyl-2,4-pentanediol, in the presence of an organic carboxylic acid, preferably acetic acid. to give a cis-diol. It is convenient to carry out this treatment in an inert organic solvent, preferably a halogenated hydrocarbon such as dichloromethane and at about room temperature.

 Bye removal of the protection of a protected oxo group optionally present in the product obtained after the deacetylation can be carried out in a manner analogous to that described above in connection with the conversion of a compound of formula Id into a compound of formula Ie.

 The conversion of a compound of formula XXI to a compound of formula XVIII by treatment with boron trichloride may be carried out in a manner analogous to that described above in connection with the preparation of compounds of formula XVII starting from of compounds of formula VII.

 Certain compounds of formulas XVII, XVIII, IX, XX and XXI are new and are also part of the invention.

 The following examples illustrate the invention.

Example 7 (A) A mixture of 1.1 g of 2-acetyl-1,2,3,4-tetrahydro-5-hydroxy-8-methoxynaphthalene, 1.5 g of α-formyl is heated under reflux for 20 hours. Methyl 3-methoxybenzoate, 0.7 g of benzeneboronic acid, 0.5 ml of acetic acid and 50 ml of benzene. The solvent is removed by evaporation and the residue is dissolved in a mixture of 10 ml of dichloromethane, 70 ml of 2-methyl-2,4-pentanediol and 0.1 ml of acetic acid. The solution is stirred at room temperature for 20 hours and then extracted with 2 portions of 50 ml of dichloromethane. The combined dichloromethane extracts are washed with 4 x 50 ml portions of water, dried and evaporated to give a yellow oil. Crystallization from acetone / diethyl ether gives 1.6 g (83%) of 3- (6-acetyl-5,6,7,8-tetrahydro-1-hydroxy-4-methoxy-2-naphthyl) -4-methoxyphthalide as colorless crystals of Pf 184-1870C.

 (B) A mixture of 0 ml of water, 5.0 g of sodium hydroxide and 5.0 g of zinc powder was refluxed under a nitrogen atmosphere while stirring vigorously. 1.0 g of 3- (6-acetyl-5,6,7,8-tetrahydro-1-hydroxy-methoxy-2-naphthyl) -4-methoxophthalide are added to the mixture and the mixture is stirred and heated for 2 hours. hours the mixture obtained. Cool and filter the solution.

The filtrate is acidified with 2M hydrochloric acid and extracted with 3 x 50 ml portions of ethyl acetate. The combined ethyl acetate extracts are washed with water, dried and evaporated to give a pale yellow gum. Trituration of this gum with diethyl ether / hexane affords 0.82 g (82%) of 2-E-acid (6-acetyl-5,6,7,8-tetrahydro-1-hydroxy-4-methoxy) naphthyl) methyl] -3-methoxybenzoic acid in the form of colorless crystals of Pf 165166CC.

(C) A mixture of 0.5 g of 2 - [(6-acetyl-5,6,7,8-tetranydro-1-hydroxy-4-methoxy-2-naphthyl) acid is refluxed with stirring) methyl] -3-methoxybenzoic acid, 5.0 g of anhydrous potassium carbonate, 2 ml of methyl iodide and 50 ml of acetone. Fractions of 2 ml of methyl iodide were added after 3 hours and after 6 hours, and the mixture was refluxed and stirred for a total of 24 hours. Cool and filter the mixture, and evaporate the filtrate. The residue is dissolved in a mixture of 30 ml of methanol, 30 ml of water and 0.6 g of sodium hydroxide, and the mixture obtained is refluxed for 4 hours.

Most of the methanol is removed by evaporation, the residue is diluted with 50 ml of water, acidified with 2M hydrochloric acid and extracted with 3 50 ml portions of acetate. ethyl. The combined ethyl acetate extracts are washed with 2 x 50 ml portions of water, dried and evaporated to give a yellow gum which is dissolved in concentrated sulfuric acid. After 15 minutes, the solution is poured into 50 g of crushed ice and the product is extracted with 3 fractions of 50 ml of ethyl acetate. The combined ethyl acetate extracts are washed with 3 x 50 ml portions of water and evaporated to give a brown crystalline residue which is dissolved in 40 ml of acetic acid. A solution of 0.34 g of chromium trioxide in 20 ml of 80% aqueous acetic acid is added with stirring, the mixture is stirred at room temperature for 20 minutes and then poured into 300 ml of water. The product is extracted with 3 fractions of 100 ml of dichloromethane, the combined dichloromethane extracts are washed with 2 fractions of 200 ml of water and with 3 fractions of 300 ml of 10% aqueous potassium hydrogen carbonate, dried and evaporates. Crystallization of the residue from ethyl acetate / isopropanol gives 150 mg (29%) of 8-acetyl-7,8,9,10-tetrahydro-1,6,11-trimethoxy-5,12-naphtacenedione under the shape of yellow needles of Pf 183-184 C.

 The 2-acetyl-1,2,3,4-tetrahydro-5-hydroxy-8-methoxy-naphthalene used as starting material can be prepared in the following manner: (i) 5.0 g of 1, Methyl 2,3,4-tetrahydro-5,8-dimethoxy-1-oxo-3-naphthalenecarboxylate in 50 ml of dichloromethane and the solution was cooled to -700 ° C. under a nitrogen atmosphere. of boron trichloride in 40 ml of dichloromethane with stirring and the resulting solution is allowed to warm to room temperature, stirred at this temperature for 10 minutes and then poured while stirring into 200 ml of 1M hydrochloric acid at room temperature. the temperature of the ice. The dichloromethane layer is separated, washed with 4 fractions of 300 ml of water and with 300 ml of saturated aqueous sodium chloride, dried and evaporated to give a pale yellow crystalline mud.The recrystallization of this mass from dichloromethane / hexane gives 3.0 g (63) of methyl 1,2,3,4-tetrahydro-8-hydroxy-5-methoxy-1-oxo-3-naphthalenecarb xylate as yellow needles pale Pf 83-83.5 C.

(ii) 8 g of 1sk, 3,4-tetrahydro-8-hydroxy-5-methoxy-1-oxo-13-naphthyl alenecarboxylate are suspended in 500 ml of methanol containing 1 ml of hydrochloric acid. concentrated. 0.6 g of platinum oxide catalyst are added and the mixture is stirred in an atmosphere of hydrogen until the hydrogen uptake ceases. The catalyst is filtered off through diatomaceous earth and the filtrate is evaporated. The residue is taken up in 300 ml of diethyl ether, washed with 50 ml of 5% potassium hydrogen carbonate, dried and evaporated. Trituration of the residue with hexane gives 6.1 g. of methyl 1,2,3,4-tetrahydro-5-hydroxy-8-methoxy-2-naphthoate as off-white crystals. Recrystallization from diethyl ether / hexane gives colorless crystals of mp 129.5-130 ° C.

(iii) A mixture of 5.0 g of methyl 1,2,3,4-tetrahydro-5-hydroxy-8-methoxy-2-naphthoate and 12.0 g of carbonate is stirred at 80 ° C. for 4 hours under nitrogen. of potassium, 5 ml of benzoyl chloride and 120 ml of dimethylformamide. The solvent is removed by evaporation, the residue is dissolved in 200 ml of ethyl acetate and the solution is washed with 5 parts of 200 ml of water, dried and evaporated to give the crude product in the form of pink crystals. Purification by silica gel chromatography using 1: 1 ethyl acetate / hexane for elution yields 5.63 g (82.5%) of 5-benzyloxy-1,2,3,4 methyl tetrahydro-8-methoxy-2-naphthoate in the form of colorless crystals of Pf 78-800.

(iv) A mixture of 5.63 g of methyl 5-benzyloxy-1,2,3,4-tetrahydro-8-methoxy-2-naphthoate, 150 ml of water, 150 ml is refluxed for 3 hours. of methanol and 5.0 g of sodium hydroxide. The methanol is removed by evaporation and the residue is diluted with 150 ml of water and then acidified to pH 3 with 2M hydrochloric acid. The product is extracted with 3 portions of 100 ml of ethyl acetate and the combined ethyl acetate extracts are washed with 2 portions of 100 ml of water, dried and evaporated. Trituration of the residue with diethyl ether / hexane gives 5.0 g of 5-benzyloxy-1,2,3,4-tetrahydro-8-methoxy-2-naphthoic acid as colorless crystals of Pf 1471490 C.

(v) 34 ml of a 1.7 M solution of methyllithium in diethyl ether is added to a stirred solution of 7.8 g of 5-benzyloxy-1,2,3,4-tetrahydro-8-methoxy- 2-naphthoic in 500 ml dry diethyl ether under a nitrogen atmosphere. The mixture is stirred at room temperature for 4 hours and then poured into 500 ml of 5% aqueous ammonium chloride. The diethyl ether layer is separated, washed successively with 200 ml of water, 200 ml of 5% aqueous potassium carbonate and 100 ml of water, dried and evaporated to give 6.0 g. 5, 6, 5-benzyloxy-1,2,3,4-tetrahydro-8-methoxy-2-acetonaphthon in the form of colorless crystals of Pf 75-760C (from diethyl ether / hexane).

(vi) A solution of 1.5 g of 5-benzyloxy-1,2,3,4-tetrahydro-8-methoxy-2-acetonaphthonate in 100 ml of ethyl acetate is stirred in a hydrogen atmosphere. in the presence of 0.2 g of palladium at 100 carbon.

After hydrogen uptake ceased, the catalyst was removed by filtration through diatomaceous earth and the filtrate evaporated to give 0.98 g (91.5%) of 2-acetyl-1,2 3,4-tetrahydro-5-hydroxy-8-methoxynaphthalene as colorless crystals of Pf 143-144 ° C.

Example a (A) In a manner analogous to that described in Part (A) of Example 1, starting from 2.63 g of 1,2,3,4-tetrahydro-5-hydroxy-8-methoxy 2-methyl naphthoate (prepared as described in part (ii) of Example 1), 1.5 g of benzeneboronic acid and 2.2 g of methyl 2-formyl-3-methoxybenzoate, 2 96 g of methyl 1,2,3,4-tetrahydro-5-hydroxy-8-methoxy-6- (3-methoxyphthalidyl) -2-naphthoate in the form of colorless crystals of Pf 206-2080C (from ethyl acetate / hexane).

 (B) In a manner analogous to that described in Part (3) of Example 1, starting from 1.0 g of 1,2,3,4-tetrahydro-5-hydroxy-8-methoxy-6 Methyl (3-methoxy phthalidyl) -2-naphthoate gives 0.81 g (83.5%) of 6- (2-carboxy-6-methoxybenzyl) -1,2,3,4-tetrahydroic acid. -hydroxy-8-methoxy-2-naphthoic in the form of colorless crystals of Mp 237-240 ° C (from ethyl acetate).

(C) In a manner analogous to that described in part (C) of Example I except that after cyclization with sulfuric acid the mixture is poured into methanol at ice-temperature and heated to 60.degree. s the solution obtained to reform the methyl ester, starting from 0.4 g of 6- (2-carboxy-6-methoxy-benzyl) -1,2,3,4-tetrahydro-5-hydroxy-8-methoxy acid 2-Naphthalene gives 0.165 g (39%) of methyl 7,8,9,10-tetrahydro-1,6,11-trimethoxy-5,12-naphtacenedione-8-carboxylate in the form of of yellow needles from Pf 192 19300.

Example 3 (1k) In a manner analogous to that described in Part (A) of Example 1, starting with 2.5 g of 6- (1,1-ethylenedioxyethyl) -5,6,7,8 tetrahydro-4-methoxis-1-yl-6-naphthalenediol, 1.8 g of methyl 2-formyl-3-methoxybenzoate and 1.75 g of benzeneboronic acid give 2.68 g (67%) of 3-6 g. - (1,1-Ethylenedioxyethyl) 5,6,7,8-tetrahydro-1,6-dihydroxy-4-methoxy-2-naphthyl] -4-methoxyphthalide in the form of colorless crystals of Feb 197-205 C (at from diethyl ether / hexane).

(B) In a manner analogous to that described in Part (B) of Example 1, starting from 2.0 g of 3- [6 (1,1-ethylenedioxyethyl) -5,6,7,8 tetrahydro-1,6-dihydroxy-4-methoxy-2-naphthyl-4-methoxyphthalide gives 1.55 g (77%) of 2- [6- (1,1-ethylenedioxyethyl) 5, 6,7,8-tetrahydro-1,6-dihydro-4-methoxy-2-naphthyl] methyl-3-methoxybenzoate in the form of a white powder of mp 200-202 ° C.

 (C) A mixture of 1.0 g of 2 - [[6- (1,1-ethylenedioxyethyl) -5,6,7,8-tetrahydro-1,6-dihydro acid is refluxed with stirring; 4-methoxy-2-naphthyl] methyl] -3-methoxybenzoic acid, 10 g of anhydrous potassium carbonate, 4 g of methyl iodide and 80 ml of acetone. 4 ml of methyl iodide are added after 3 hours and after 6 hours, and the mixture is heated and stirred for a total of 24 hours. Cool and filter the mixture, and evaporate the filtrate. The residue is dissolved in a mixture of 30 ml of methanol, 50 ml of water and 1.5 g of sodium hydroxide and refluxed for 1 1/2 hours.

Most of the methanol is then removed by evaporation, the residue is diluted with 50 ml of water, acidified with 2M hydrochloric acid and extracted with 3 fractions of 100 ml of ethyl acetate. ethyl.

The combined ethyl acetate extracts are washed with 2 x 50 ml portions of water, dried and evaporated to give 0.85 g (82%) of a white powder which is used in the next step without further purification.

 0.85 g of the above powder are suspended in 30 ml of dichloromethane and 5 ml of trifluoroacetic acid anhydride are added with stirring. The mixture is stirred at room temperature for 1/2 hour and then poured into 30 ml of water. The dichloromethane is separated, washed with 2 x 30 ml portions of water and evaporated to give a yellow crystalline residue which is dissolved in a mixture of 50 ml of ethanol, 5 ml of water and 0 ml. 3 g of sodium hydroxide. 10 ml (100 vol.) Of hydrogen peroxide are added and the mixture is heated to 80 ° C. 10 ml portions of hydrogen peroxide are added after 20 minutes and after 40 minutes, and then the mixture in 200 ml of water and extracted with 3 fractions of 50 ml of dichloromethane. The combined dichloromethane extracts are washed with water, dried and evaporated to give a yellow residue which is purified by column chromatography on silica gel using ethyl acetate / hexane for elution.

490 mg (58%) of 8- (1,1-ethylenedioxyethyl) 7,8,9,10-tetrahydro-8-hydroxy-1, 6,11-tetramethoxy-5,12-naphtacenedione are obtained in the form of of yellow crystals of 194-1960 ° C (from ethyl acetate).

The 6- (1,1-ethylenedioxyethyl) -5,6,7,8-tetrahydro-4-methoxy-1,6-naphthalenediol used as starting material can be prepared as follows
(i) 56.9 ml of a 1.6 M solution of butyllithium in hexane is added with stirring to a solution of 11.86 ml of diisopropylamine in 160 ml of dry tetrahydrofuran under an argon atmosphere. at -780 ° C. After 20 minutes, 20.4 g of methyl 5-benzyloxy-1,2,3,4-tetrahydro-8-methoxy-2-naphthoate (prepared as described in part ( iii) of Example 1) in 160 ml of tetrahydrofuran and the mixture is stirred at -780C for 1 hour. The resulting lithium enolate solution is then transferred by increasing the argon pressure, through a syringe needle. open at both ends, in a flask containing a stirred solution of 22.1 ml of triethylphosphite in 160 ml of dry tetrahydrofuran at -780 ° C through which a strong oxygen stream was passed.

 After the end of the lithium enolate transfer, the flow of oxygen is continued for 80 minutes. The mixture is then quenched by the addition of 17.4 ml of acetic acid. The mixture is allowed to reach 0 ° and stirred at this temperature for 5 minutes. 600 ml of water are added, the solution is stirred at 0 ° C. for 1 hour and then the larger part of the tetrahydrofuran is removed by evaporation. The residue is extracted with 3 fractions of 200 ml of ethyl acetate, the combined ethyl acetate extracts are washed with 2 portions of 100 ml of 10% aqueous potassium hydrogen carbonate, dried and evaporated. . The residue is subjected to column chromatography on silica gel using ethyl acetate / hexane (1: 1) for elution. 13.75 g (64%) of methyl 5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-naphthoate are obtained in the form of colorless crystals of Pf 96-97 C. (from diethyl ether / hexane).

 (ii) A mixture of 9.9 g of 50% sodium hydride and 120 ml of dimethylsulfoxide is heated at 70 ° C. under a nitrogen atmosphere while stirring for 95 minutes. The mixture is cooled to OOC and 120 ml of dry tetranydrofuran are added followed by a solution of 14.58 g of 5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-naphthoate. methylated in 120 ml of dry tetrahydrofuran. The mixture is stirred at 0 ° C. for 3/4 hour and poured into 600 μl of water, the solution is acidified to pH 4 with orthophosphoric acid and extracted with 4 fractions of 300 ml of water. dichloromethane. The combined dichloromethane extracts are washed with water, dried and evaporated to give the crude crystalline α-ketosulfoxide which is used directly in the next step.

(iii) The crude α-ketosulfoxide above above was dissolved in a mixture of 510 ml of tetrahydrofuran and 57 ml of water, and the solution was cooled to 1000 under a nitrogen atmosphere. Aluminum amalgam (prepared from 18.0 g foil foil) is added and the mixture is stirred for 4 1/2 hours while maintaining the temperature at 1200. Filter and evaporate The mixture. The oily residue is taken up in 200 μl of dichloromethane, washed with 2 × 100 ml portions, dried and evaporated. Column chromatography of the residue on silica gel using ethyl acetate / hexane (1: 1) for elution gives 10.9 g (7E, 4%) of 5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-acetonaphthon in the form colorless crystals of
Mp 71-72C.

(iv) A mixture of 10.2 g of 5-benzyloxy-1,2,3,4-tetrahydro-2-hydro-8-methoxy-2-acetonaphthon, 790 ml of benzene, 27 ml of sodium hydroxide was heated under reflux. acetone, 78.5 ml of ethylene glycol and 0.4 g of toluene-4-sulfonic acid using a Dean trap
Stark for 6 1/2 hours. The solution is cooled, washed with 2 x 300 ml portions of 0% aqueous potassium hydrogen carbonate, dried and evaporated. Crystallization of the residue from diethyl ether gives 9.85 g (85%) of 5-benzyloxy-2- (1,1-ethylenedioxyethyl) -1,2,3,4-tetrahydro-8-methoxy-2-naphthol under the form of colorless crystals of Pf 99 10000.

 (v) A solution of 5.0 g of 5-benzyloxy-2- (1,1-ethylenedioxyethyl) -1,2,3,4-tetrahydro-8-methoxy-2-naphthol is stirred. in 500 ml of ethyl acetate with 0.8 g of 10% palladium / carbon in a hydrogen atmosphere. After the hydrogen uptake has ceased, the catalyst is filtered off through diatomaceous earth and the filtrate is evaporated to give 3-79 g (100%) of 6- (1,1- ethylene-dioxyethyl) -5,6,7,8-tetrahydro-4-methoxy-1,6-naphthalenediol in the form of colorless crystals of Pf 122 12300.

The methyl 5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-naphthoate, prepared as described in part (i) of this example, can be resolved as follows
(a) 30 g of methyl 5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-naphthoate are dissolved in 625 ml of methanol, 325 ml of a solution of 5% sodium hydroxide. and the mixture is stirred at room temperature for 95 minutes. Most of the methanol is removed by evaporation and the residue is diluted with 500 ml of water. The pH of the solution is adjusted to about 2 with concentrated hydrochloric acid and the mixture is extracted with 3 fractions of 100 ml of ethyl acetate. The combined methyl acetate extracts are washed with 2 parts of ethyl acetate. 100 ml of water and with 100 ml of saturated sodium chloride solution, dried and evaporated to give 27.35 g (95 G%) of 5-benzyloxy-1,2,3,4-tetrahydro acid -2-hydroxy-8-methoxynaphthalene-2-carboxylic acid in the form of a white powder of 148-150 ° C.

 (b) 5.0 g of the foregoing carboxylic acid are dissolved in 750 ml of absolute methanol under reflux. 2.05 g of B (-) - methylbenzylamine are added and the mixture is allowed to cool and crystallize, while seeding, overnight. The crystalline product was collected and dried in vacuo at 35 ° C. 2.15 g of the above-described salt of S (-) - α-methylbenzylamine of the above-mentioned carboxylic acid was obtained in the form of colorless crystals of Fi 208-210; Ea] = +7.4 (c = 1 in acetic acid).

 The mother liquors are evaporated from the previous crystallization and the residue is dissolved in 25 ml of 2M hydrochloric acid and 100 ml of ethyl acetate. The mixture is stirred and the layers are separated.

The aqueous layer is extracted with 2 fractions of 100 ml of methyl acetate. The ethyl acetate solutions were combined, washed with 2 x 500 ml portions of water, dried and evaporated to give 4.2 g of a gum-like residue. The residue is dissolved in 420 ml of refluxing methanol, the resulting solution is treated with 1.72 g of R (+) - α-methylbenzylamine and the resulting solution is allowed to crystallize, while being seeded. the night. The crystalline product was collected and dried to give 2.74 g of the R (+) α-methylbenzylamine salt of the foregoing acid as colorless crystals of mp 208-210 ° C [α] D 2 O. = -7.4 (c = 1% in acetic acid).

 (c) The above mentioned salts are separately converted into the corresponding carboxylic acids by first dissolving 2.5 g of the salt in 25 ml of hydrochloric acid (2 ml) and 100 ml of ethyl acetate. The solution is then stirred and the organic layer is separated. The aqueous layer is extracted with 2 fractions of 250 ml of ethyl acetate. The combined organic layers are washed with 2 fractions of 500 ml of water and with 50 ml of saturated sodium chloride solution, and dried. evaporated to give the carboxylic acid, i.e. S - (+) - 5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxynaphthalene-2-carboxylic acid or R - (-) - 5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxynaphthalen-2-carboxylic acid, in the form of a gum.

 (d) The preceding carboxylic acids are separately converted to give the corresponding methyl esters. For this purpose, 1.5 g of the carboxylic acid is dissolved in 10 ml of methanol and 1 ml of boron trifluoride-methanol complex is added. After stirring at room temperature for 3 hours, the mixture is poured into 25 ml of water and extracted with 2 25 ml portions of dichloromethane. The combined dichloromethane extracts are washed with 3 x 10 ml portions of 10% potassium hydrogen carbonate solution and with 10 ml of water, dried and evaporated to give 1.5 g of the respective ester under In this way, S - (+) - methyl-5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-2 is obtained. naphthoate of Pf 10701080 c [(α] D20 = +33.80 (c = 0.5% in chloroform) ~ 7 and R - (-) methyl-5-benzyloxy-1,2,3,4- tetrahydro-2-hydroxy-8-methoxy-2-naphthoate, mp 107 ° -108 ° C. [(α)] D 2 O = -33.9 (c = 0.5% in chloroform). optically active starting materials for use in the invention.

Example 4
0.25 g of boron trichloride in 3 ml of dichloromethane are poured into a stirred solution of 50 mg of 8-acetyl-7,8,9,10-tetrahydro-1,6,11-trimethoxy-5,12. -naphtacenedione (prepared as described in part (c) of Example 1) in 20 ml of dichloro methane at 0 ° C. The solution is stirred for 5 minutes, quenched by slowly adding 5 ml of methanol and then poured into 50 ml of water. The dichloromethane layer is separated, dried and evaporated to give a red crystalline residue. Recrystallization from dichloromethane / methanol gives 40 mg (86%) of 8-acetyl-7,8,9,10-tetrahydro-6,11-dihydroxy-1-methoxy-5,12-naphtacenedione under the Red needles shape of Pf 243-2450C.

Example 5
In a similar way to what is. described in Example 4, from methyl 7,8,9,10-tetrahydro-1,6,11-trimethoxy-5,12-naphtacenedione-8-carboxylate (prepared as described in part (C)). ) of Example 2) there is obtained 7,8,9,10-tetrahydro-6,11-dihydroxy-1-methyl-5-methoxy-1-naphthalenedi-8-methyl-arboxylate under the shape of brilliant red needles of Pf 262-2630C (from tetrahydrofuran / isopropanol).

Example 6
36 mg of 8- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8-hydroxy-1,6,11,6,1,1-trimethoxy-5,12-naphthalenedione are prepared (prepared as is mentioned in part (c) of Example 3) in 10 ml of dioxane and 8 ml of 5 M hydrochloric acid are added with stirring.

After 30 minutes, the mixture is poured into 100 ml of water and the product is extracted with 2 portions of 50 ml of dichloromethane. The combined dichloromethane extracts are washed with 2 x 50 ml portions of water, dried and evaporated. The yellow residue is dissolved in 10 ml of dichloromethane and 0.2 g of boric trichloride in 3 ml of dichloromethane are added with stirring. After 10 minutes, the red solution is poured into 50 ml of water and the mixture is stirred.

The dichloromethane layer is separated, dried and evaporated to give a red crystalline residue.

Recrystallization from tetrahydrofuran / ethyl acetate yields 20 mg (66%) of 8-acetyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12- naphthacenedione in the form of red prisms of Pf 228-229 C.

EXAMPLE 7 (A) 452 μl of 8- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8-hydroxy-1,6,11-trimethoxy-5,12-naphtacenedione (prepared as it is said in part (c) of Example 3) in 44 ml of carbon tetrachloride by heating at reflux for 30 minutes.

200 mg of N-bromosuccinimide and 10 mg of azoisobutyronitrile are added to the solution which is kept under reflux. The mixture is heated under reflux for a further 1 hour under nitrogen and, with stirring, another 36 mg of N-bromosuccinimide and another 5 mg of a-azoisobutyronitrile are added and the mixture is heated at reflux for 1 hour. After cooling and evaporation, a yellow residue is obtained which is dissolved in 50 ml of glacial acetic acid. The resulting solution is treated with 0.5 g of silver acetate, the mixture is stirred in the dark for 18 hours under nitrogen and the solvent is then removed by evaporation. The residue is treated with 100 ml of dichloromethane, the mixture is filtered, the filtrate is washed with 10% potassium hydrogen carbonate solution, dried over anhydrous sodium sulphate and evaporated to give a yellow gol. Crystallization of this gum from ethyl acetate / diethyl ether gives 273 mg (53.5%) of rac-cis-10-acetoxy-8- (1,1-ethylenedioxyethyl) -7.8.9, 10-Tetrahydro-8-hydroxy-1,6,11-trimethoxy-5,12-naphtacenedione in the form of yellow crystals of mp 220 ° -220 ° C. This product is pure according to thin layer chromatography.

 Chromatography of the mother liquors from the previous crystallization using ethyl acetate for elution gives 40 mg (8%) of rac-trans-10-acetoxy-8- (1,1-ethylenedioxyethyl) 7,8,9,10-tetrahydro-8-hydroxy-1, 6,11-trimethoxy-5,12-naphtacenedione in the form of yellow crystals of 223-224 ° C (from tetrahydrofuran / methanol) ) then another 25 mg (5%) of rac-cis-10-acetoxy-8- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8-hydroxy-1,6,11- trimethoxy-5,12-naphtacenedione which is identical to the product obtained as described in the previous paragraph.

(B) (i) 100 mg of rac-cis-10-acetoxy-8- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8-hydroxy-1,6,11 is dissolved -trimethoxy-5,12-naphtacenedione in 2 ml of dichloromethane and the solution is diluted with 25 ml of methanol. 30 ml of 50% sodium hydride are added and the mixture is stirred at room temperature for 1 hour. 0.25 ml of acetic acid is added and most of the solvent is removed by evaporation.

The residue is dissolved in 50 ml of dichloromethane and the solution is washed with 2 x 50 ml of water, dried over anhydrous sodium sulphate and evaporated to give a yellow crystalline product which, after trituration with diethyl ether, gives 85 mg (92.5%) of rac-cis-8- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8,10-dihydroxy-1,6,11-trimethoxy-5 12-naphthacenedione in the form of a yellow powder of 215-216 ° C, (B) (ii) 20 mg of rac-trans-10-acetoxy-8- (1,1-ethylenedioxyethyl) are converted into ) -7,8,9,10-tetrahydro-8-hydroxy-1,6,11-trimethoxy-5,12-naphtacenedione similar to that described in the previous paragraph in rac-trans-8- ( 1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8-yl) dihydroxy-1H-6,11-trimethoxy-5H-12-naphthenedenedione which is obtained in the form of a yellow gum. dissolved in 20 ml of toluene, 15 mg of benzeneboronic acid and 2 mg of toluene-4-sulphonic acid are added and The mixture is stirred at room temperature for 16 hours. The solution is washed with 10 ml of 10% sodium bicarbonate solution, dried and evaporated to give a yellow residue which is dissolved in a mixture of 2 ml of dichloromethane, 2 ml of 2, 4-pentanediol and 1 ml of acetic acid. The mixture is allowed to stand at room temperature for 30 hours, diluted with 25 ml of dichloromethane and washed with 3 fractions of 25 ml of water. after drying, the solvent is removed by evaporation and the residue is purified by silica gel chromatography using ethyl acetate for elution. 10 mg of rac-cis-8-Cl, 1-ethylenedioxyethyl) 7,8,9,10-tetrahydro-8,10-dihydroxy-1,6,11-trimethoxy-5,12-naphtacenedione are obtained in the form of yellow crystals of Pf 215-2160C.

 Cc) 50 mg of rac-cis-8- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8,10-dihydroxy-1,6,11-trimethoxy-5,12 are dissolved. The naphthacenedione in 25 ml of warm dioxane is cooled to 0OC, 25 ml of 5M hydrochloric acid are added and the mixture is stirred at room temperature for 3 1/2 hours. The mixture is poured into 100 ml of dichloromethane and the organic layer is separated, washed with 2 x 50 ml portions of water, dried and evaporated. Trituration of the yellow residue with diethyl ether / ethyl acetate gives 35 mg (77%) of rac-cis-8-acetyl-7,8,9,10-tetrahydro-8,10-dihydroxy-1, 6, 11-trimethoxy-5,12-naphtacenedione. in the form of yellow crystals of mp 214-215 C.

(D) Treatment of rac-cis-8-acetyl-7,8,9,10-tetrahydro-8,10-dihydroxy-1,6,11-trimethoxy-5,12-naphtacenedione with boron trichloride the manner described in Example 6 gives rac-cis-8 acetyl-7,8,9,10-tetrahydro-6,8,10,11-tetrahydroxy-1-methoxy-5,12-naphtacenedione (racemic daunomycinone). ) in the form of red crystals having a thin layer chromatogram and a nuclear magnetic resonance spectrum identical to those of authentic daunomycinone from natural sources.

 (E) Racemic daunomycinone can also be prepared from rac-1- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8,10-dihydroxy-1, 6,11-trimethoxy - 5,12-naphtacenedione (prepared as described in paragraph (B) of this example) by treatment with boron trichloride or according to the method described in Example 6 leaving the necessary time for the decetalization step.

Claims (2)

 1-rac-cis-8- (1,1-ethylene-dioxyethyl) -7,8,9,10-tetrahydro-8,10-dAhydroxy-1,6,11-trimethoxy-5,12-naphthaenedione.  2-rac-trans-8- (1,1-ethyldne-dioxyethyl) -7,8,9,10-tetrahydro-8,10-dihydroxy-1,6,11-trimethoxy-5,12-napthacenedione.