CH644836A5 - POLYCYCLIC COMPOUNDS. - Google Patents

Description

The present invention relates to polycyclic compounds, in particular a process for the preparation of tetrahydronaphthaene derivatives and intermediates therefor, and certain such derivatives and intermediates themselves.

The process according to the invention is characterized in that a compound of the formula

OCH

• R ~

OH

wherein R1 is lower alkoxycarbonyl or a group of the formula

R3 R4 \ /

C — CH, (a)

t

R2 represents hydrogen or hydroxy and R3 and R4 together represent oxo or a protected oxo group,

with an aldehyde of the formula

• COOR

CHO

OCH

where R5 is lower alkyl,

in the presence of an aromatic boronic acid and the boronic ester obtained in a compound of the formula

OCH

CCH

OH

III

wherein R1 and R2 have the above meaning, converts the phthalide ring in the compound of formula III to a compound of formula

OCH

10th

COOH

IV

CCH

CH

in which R2 has the meaning given above and R10 denotes carboxy or a group of the formula (a) given above,

to get the compound of formula IV methylated and the mono- or diester obtained to a compound of formula

OCH

10th

COOH

OCH

OCH

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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where R2 and R10 have the meaning given above,

saponifies the compound of the formula V cyclizes and, if R10 is carboxy, this group is esterified to a lower alkoxycarbonyl group and the compound of the formula thus obtained

OCH

OCH

OCH

wherein R1 and R2 have the above meaning, to a compound of formula

OCH

OCH

0

OCH

where R1 and R2 have the above meaning,

oxidized.

The term "lower alkyl" used here means a straight-chain or branched alkyl group with preferably 1-6 C atoms, e.g. Methyl, ethyl, propyl, isopropyl, butyl, tert. Butyl, pentyl and hexyl. The lower alkyl radical of a lower alkoxycarbonyl group has the same meaning. Examples of lower alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl. A protected oxo group can be any conventional protected oxo group, but the oxo group is preferably protected in the form of a ketal, in particular an alkylene ketal, especially as an ethylene ketal.

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

The above reaction provides a boronic ester which is converted to a compound of Formula III. This conversion is preferably carried out by treating the boronic acid ester with a 1,3-diol in the presence of an acid, the 1,3-diol advantageously being used in excess. A particularly preferred 1,3-diol is 2-methyl-2,4-pentanediol. Preferred acids in this reaction are lower alkane carboxylic acids such as acetic acid and propionic acid. The reaction is conveniently carried out in the presence of an inert organic solvent such as a halogenated hydrocarbon, e.g. B. dichloromethane, and carried out at about room temperature. Alternatively, the conversion of a boronic acid reester into a compound of formula III can be accomplished by heating the ester in the presence of an acid such as a lower alkane carboxylic acid.

The reductive cleavage of the phthalide ring in a compound of formula III to a compound of formula IV can be carried out in a manner known per se. For example, reductive cleavage using zinc under alkaline conditions, e.g. can be brought about by an alkali metal hydroxide such as sodium or potassium hydroxide. This reductive cleavage method is preferably carried out at elevated temperature. Alternatively, the 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 manner known per se, for example by means of methyl iodide in the presence of a base such as potassium carbonate.

The saponification of a mono- or diester thus obtained (in the latter case a compound of formula IV, in which R10 represents a methylated carboxy group) can be carried out in a manner known per se, e.g. by treatment with alkali metal hydroxide such as sodium hydroxide.

The cyclization of a compound of formula V can be carried out by methods known per se, for example in the presence of concentrated sulfuric acid or a trihaloacetic anhydride, preferably trifluoroacetic anhydride. If a trihaloacetic anhydride is used, the cyclization is conveniently carried out in the presence of an inert organic solvent such as a chlorinated hydrocarbon, e.g. Dichloromethane, carried out at about room temperature.

When a compound of formula V in which R10 is carboxy is cyclized, the cyclization product (a compound of formula VI but in which R1 is carboxy) is esterified to a compound of formula VI in which R1 is lower alkoxycarbonyl. The esterification is carried out in a manner known per se, for example using a lower alkanol, such as methanol.

The oxidation of a compound of formula VI can be accomplished using known oxidation processes. For example, the oxidation can be carried out using hydrogen peroxide or a chromium (VI) oxidizing agent such as chromium trioxide in the presence of acetic acid.

It goes without saying that each of the products obtained in the process steps described above does not need to be isolated and purified before it is used in the next reaction step. In particular, a compound of the formula IV can advantageously be converted into a compound of the formula VII without isolation and purification of the compounds of the formulas V and VI and, if appropriate, of compounds which correspond to the formula VI but in which R1 is carboxy.

The starting materials of the formula I can be prepared in various ways, depending on the nature of the substituents R1 and R2 present.

For example, a starting material of formula I, wherein R1 is lower alkoxycarbonyl and R2 is hydrogen, can be prepared by using a compound of formula

4th

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

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OCH

Vili where R11 is lower alkoxycarbonyl,

treated with boron trichloride and the compound of the formula obtained

OCH

IX

10th

15

20th

25th

where R11 has the above meaning,

catalytically hydrogenated.

The treatment of a compound of formula VIII, which is a known compound or an analog of a known compound, with boron trichloride is carried out at low temperature (e.g. -70 ° C) and conveniently in the presence of an inert organic solvent, e.g. B. a halogenated hydrocarbon such as dichloromethane.

The catalytic hydrogenation of a compound of formula IX, which is a compound of formula

OCH

Ia in which R11 has the meaning given above,

provides, can in a conventional manner, for. B. using hydrogen in the presence of a platinum catalyst, e.g. B. platinum oxide in a suitable solvent, e.g. B. a lower alkanol such as methanol.

Starting materials of the formula I, in which R1 is a group of the formula (a) and R2 are hydrogen, can be obtained according to the reaction scheme I below, where R6 represents an etherified hydroxy group which is easily cleavable to a hydroxy group, e.g. Benzyloxy and R30 and R40 together represent a protected oxo group.

Formula scheme I

OCH

->

V

x

OCH

OCH

COCH.

«-

V

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6

COCH.

OCK

Ib

In the reactions shown in formula scheme I, the hydroxyl group in a compound of the formula Ia is replaced by an etherified hydroxyl group which can easily be split into a hydroxyl group. This can be done in a manner known per se. For example, a compound of formula la with a benzyl halide, especially benzyl chloride in the presence of a suitable base, e.g. an alkali metal carbonate such as potassium carbonate, to give a compound of formula X in which R6 is benzyloxy.

The compound of formula X is converted into an acid of formula XI by saponification in a manner known per se, for example using sodium hydroxide in aqueous alcoholic solution, e.g. aqueous methanol.

An acid of formula XI is then converted into a compound of formula XII by treatment with methyl lithium in a manner known per se, for example in an inert organic solvent such as an ether, e.g. Diethyl ether, at about room temperature.

The conversion of a compound of formula XII into a compound of formula Ib is also carried out in a manner known per se. For example, if R6

20th

25th

30th

35

Ic

Benzyloxy, this group can be converted into a hydroxy group by hydrogenation and in the presence of a suitable catalyst, e.g. a palladium catalyst in the presence of an inert organic solvent, e.g. Ethyl acetate.

A compound of the formula Ib can be converted into a compound of the formula Ic in a manner known per se for the protection of oxo groups. In a preferred embodiment, this conversion consists of catalysis, for example by reaction with an appropriate alcohol 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, e.g. Benzene or toluene, at elevated temperature, e.g. at the reflux temperature of the reaction mixture. A compound of the formula Ic is preferably prepared in which R30 and R40 together are alkylenedioxy, in particular ethylenedioxy.

Starting materials of the formula I, in which R1 is a group of the formula (a) and R2 are hydroxy, can be prepared in accordance with formula scheme II, where R6, R11, R30 and R40 have the meaning given above.

Formula scheme II

OCH

OCH.

OCH

XIII

COCH2SOCH3

XIV

7

644836

V

OGH

OCH

XVI

In the reaction shown in Formula Scheme II, a compound of Formula X is converted to a compound of Formula XIII by first forming the lithium enolate of a compound of Formula X and the enolate either with diperoxo-oxohexamethylphosphoramidomolybdenum (VI) pyridine ( Mo05 • py • HMPT) or treated with oxygen in the presence of a trialkyl phosphite.

The conversion of a compound of formula X into a lithium enolate is carried out in a manner known per se, for example using lithium diisopropylamide in an inert organic solvent such as tetrahydrofuran at low temperature, for. B. - 78 ° C.

The lithium enolate is then preferably in situ either with MoOs py • HMPT appropriately at temperatures between room temperature and -78 ° C or with oxygen in the presence of a trialkyl phosphite, e.g. Triethyl phosphite, reacted, preferably by gaseous oxygen by mixing the enolate and trialkyl phosphite in an inert organic solvent such as tetrahydrofuran at low temperatures, e.g. —78 ° C.

A compound of formula XIII can be converted to a β-keto sulphoxide of formula XIV by treatment with an alkali metal salt of dimethyl sulfoxide. This reaction is preferably carried out using the sodium salt of dimethyl sulfoxide and in the presence of an inert organic solvent, e.g. Tetrahydrofuran, made at about 0 ° C.

The β-ketosulfoxide of formula XIV is converted into a compound of formula XV by treatment with aluminum amalgam. This treatment is conveniently carried out in the presence of an inert organic solvent, e.g. aqueous tetrahydrofuran, carried out at temperatures between about 10 ° and 20 ° C.

A compound of the formula XV can be converted into a compound of the formula XVI in analogy to that described earlier35

45

50

55

60

65

NEN conversion of a compound of formula Ib can be converted into a compound of formula Ic.

The conversion of a compound of the formula XVI to a compound of the formula Id is carried out in analogy to the conversion of a compound of the formula XII described above to a compound of the formula Ib.

Finally, a compound of the formula Id can be converted into a compound of the formula Ie in the manner customary for the conversion of protected oxo groups into oxo groups. For example, a ketalized oxo group can be converted into an oxo group by treatment with an acid, e.g. Hydrochloric acid, in a suitable inert organic solvent, e.g. Dioxane.

The aldehydes of the formula II are known compounds or analogs to known compounds which can be prepared in a known manner.

The compounds of the formulas I and certain compounds of the formula VII are new and also a subject of the present invention.

The bicyclic and tetracyclic compounds described here can occur not only in racemic but also in optically active form. The present invention therefore includes both the racemates and the optical isomers. If an optical isomer is used in any of the above processes, the optical configuration is maintained throughout the reaction sequence.

The present invention provides a region-specific synthesis of compounds of formula VII, which are of value as intermediates in the production of anthracyclines with antibiotic and antineoplastic properties. Examples of such anthracyclines are adriamycin, daunomycin and carminomycin.

The conversion of compounds of the formula VII into therapeutically valuable anthracyclines can be carried out, for example, via compounds of the formula

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0 OH

14

OCH

OH

XVII

in which R2 has the meaning given above and R14 is lower alkoxycarbonyl or acetyl,

by treatment with boron trichloride, after splitting off any oxo protecting groups that may be present.

The invention also relates to the use of new compounds of the formula VII for the preparation of new compounds of the formula XVII.

The removal of a protective group in a compound of the formula VII before the treatment with boron trichloride is carried out in analogy to the conversion of a compound of the formula Id described above into a compound of the formula Ie.

Treatment with boron trichloride is conveniently carried out in an inert organic solvent such as a halogenated hydrocarbon, e.g. Dichloromethane, carried out at about 0 ° C.

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

For example, a compound of formula XVII can be converted into a compound of formula

O OH

, 14

OH

OH

OCH

0

XVIII

where R2 and R14 have the meaning given above,

can be converted by methods known per se, for example according to Kende et al J.A.C.S. (1976), 98, 1967, and Smith et al J.A.C.S. (1976), 98, 1969. A compound of the formula XVIII can subsequently be converted into an anthracycline by glycosidation in a known manner, for example according to Smith et al J.A.C.S. (1976), 98, 1969.

Alternatively, a compound of formula VII can be converted into a compound of formula XVIII according to the present invention. This conversion consists in brominating a compound of formula VII, giving a bromide of formula

OCH

Br

OCH

0

CCH

where R1 and R2 have the above meaning,

receives, the bromide of the formula XIX treated with silver acetate in the presence of acetic acid, the acetate of the formula obtained

OCH

OCOCH

CCH

0

OCH

wherein R1 and R2 have the above meaning, deacetylated and, after splitting off any oxo protecting groups, the compound of the formula obtained

CCH

14

OH

OCH

OCH

wherein R2 and R14 have the above meaning, treated with boron trichloride.

The bromination of a compound of formula VII can be carried out in a manner known per se for benzylic bromination. For example, bromination can be carried out using N-bromosuccinimide and a free radical generator, e.g. B. benzoyl peroxide or a-azoisobutyro-nitrile or using elemental bromine and a free radical generator (see. Can. J. Chem. 1971,49, 2712). When R2 is hydroxy, the bromination yields a mixture of ice and trans bromides of formula XIX in approximately equal parts.

The treatment of a bromide of the formula XIX with silver acetate in the presence of acetic acid is conveniently carried out at about room temperature for 16 hours. If a cis / trans mixture of bromides of the formula XIX is used, a mixture of cis and trans acetates of the formula XX is obtained, in which the cis acetate predominates in an 8: 1 ratio.

The deacetylation of an acetate of formula XX can be carried out in a manner known per se, for example by means of an alkali metal lower alkoxide in a corresponding lower alkanol, e.g. Sodium methoxide in methanol. A trans-diol obtained at this stage can be converted into a cis-diol by reaction with an aromatic boronic acid and reaction of the cis-boronic acid ester obtained with a suitable 1,3-diol with exchange of the diol. The reaction of the trans diol with an aromatic boronic acid, e.g. Toluene boronic acid, xylene boronic acid, methoxybenzoeboronic acid, nitrobenzoic acid, pyridine boronic acid, and preferably benzene boronic acid. is advantageously in the presence of an organic sulfonic acid, preferably p-toluenesulfonic acid in the presence of an inert organic solvent, preferably an aromatic hydrocarbon such as benzene or toluene

8th

s

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

about room 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, and gives a cis-diol. This treatment is expediently carried out in an inert organic solvent, preferably a halogenated hydrocarbon such as dichloromethane, and at room temperature.

The cleavage of oxo protecting groups, which may be present in the product obtained after the deacetylation, can be carried out in a manner analogous to that described earlier in connection with the conversion of a compound of the formula Ic into a compound of the formula Ie.

The conversion of a compound of formula XXI into a compound of formula XVIII by means of boron trichloride can be accomplished in analogy to the manner described for the preparation of compounds of formula XVII from compounds of formula VII.

The following examples illustrate the invention.

example 1

A) A mixture of 1.1 g of 2-acetyl-l, 2,3,4-tetrahydro-5-hydroxy-8-methoxynaphthalene, 1.5 g of 2-formyl-3-meth-oxy-benzoic acid methyl ester, 0 , 7 g of benzene boronic acid, 0.5 ml of acetic acid and 50 ml of benzene were heated to reflux for 20 hours. The solvent was evaporated and the residue was dissolved in a mixture of 10 ml dichloromethane, 10 ml 2-methyl-2,4-pentanediol and 0.1 ml acetic acid. The solution was stirred at room temperature for 20 hours and then extracted with two 50 ml portions of dichloromethane. The dichloromethane extracts were washed with four 50 ml portions of water, dried and evaporated to a yellow oil. Crystallization from acetone / diethyl ether gave 1.6 g of 3- (6-acetyl-5,6,7,8-tetra-hydro-1-hydroxy-4-methoxy-2-naphthyl) -4-methoxy-phthalide in Form of colorless crystals with a melting point of 184-187 ° C.

B) A mixture of 50 ml of water, 5 g of sodium hydroxide and 5 g of zinc powder was heated to reflux with vigorous stirring under a nitrogen atmosphere. Then 1 g3- (6-acetyl-5,6,7,8-tetrahydro-l-hydroxy-4-meth-oxy-2-naphthyl) -4-methoxyphthalide was added and the mixture was heated with stirring for 2 hours. The solution was cooled and filtered, the filtrate acidified with 2M hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The combined ethyl acetate extracts were washed with water, dried and evaporated to a light yellow gum. Trituration of this gum with diethyl ether / hexane gave 0.82 g of 2 - [(6-acetyl-5,6,7,8-tetrahydro-l-hydroxy-4-methoxy-2-naphthyl) methyl] -3-methoxybenzoic acid in the form colorless crystals with a melting point of 165-166 ° C.

C) A mixture of 0.5 g of 2 - [(6-acetyl-5,6,7,8-tetrahy-dro-l-hydroxy-4-methoxy-2-naphthyl) methyl] -3-methoxy-benzoic acid, 5 g of anhydrous potassium carbonate, 2 ml of methyl iodide and 50 ml of acetone were heated to reflux with stirring. After 3 and 6 hours, 2 ml portions of methyl iodide were added and the mixture was heated to reflux with stirring for a total of 24 hours. The mixture was cooled and filtered, and the filtrate was evaporated. The residue was dissolved in a mixture of 30 ml of methanol, 30 ml of water and 0.6 g of sodium hydroxide and heated to reflux for 4 hours. Most of the methanol was then evaporated, the residue diluted with 50 ml of water, acidified with 2N hydrochloric acid and extracted with three times 50 ml of ethyl acetate. The combined ethyl acetate extracts were washed with twice 50 ml of water, dried and evaporated to a yellow gum, which in

644 836

concentrated sulfuric acid was dissolved. After 15 minutes the solution was poured into 50 g of poured ice and the product extracted with three times 50 ml of ethyl acetate. The combined extracts were washed three times with 50 ml of water and evaporated to a brown crystalline residue which was dissolved in 40 ml of acetic acid. A solution of 0.34 g of chromium trioxide in 20 ml of aqueous 80% acetic acid was added with stirring, the mixture was stirred at room temperature for 20 minutes and then poured into 300 ml of water. The product was extracted with three times 100 ml of dichloromethane, the extracts were washed with two times 200 ml of water and three times with 300 ml of aqueous 10% potassium hydrogen carbonate solution, dried and evaporated. Crystallization of the residue from ethyl acetate / isopropanol gave 150 mg of 8-acetyl-7,8,9,10-tetra-hydro-1,6,1 l-trimethoxy-5,12-naphthacendione in the form of yellow needles with melting point 183- 184 ° C.

The 2-acetyl-l, 2,3,4-tetrahydro-5-hydroxy-8-methoxynaphthalene used as the starting material can be prepared as follows:

(i) 5 g of methyl l, 2,3,4-tetrahydro-5,8-dimethoxy-l-oxo-3-naphthalinecarboxylic acid was dissolved in 50 ml of dichloromethane and cooled to -70 ° C under nitrogen. The solution was mixed with 5 g of boron trichloride in 40 ml of dichloromethane with stirring and allowed to warm up to room temperature, stirred at this temperature for 10 minutes and then added to 200 ml of ice-cold IN hydrochloric acid with stirring. The dichloromethane layer was separated, washed with four times 300 ml of water and 300 ml of saturated aqueous sodium chloride solution, dried and evaporated to a light yellow crystals. Recrystallization from dichloromethyl / hexane gave 3 gl, 2,3,4-tetrahydro-8-hydroxy-5-methoxy-1-oxo-3-naphthalenecarboxylic acid methyl ester in the form of light yellow needles with a melting point of 83-83, 5 ° C.

(ii) 8 g of l, 2,3,4-tetrahydro-8-hydroxy-5-methoxy-l-oxo-3-naphthalenecarboxylic acid methyl ester was suspended in 500 ml of methanol containing 1 ml of concentrated hydrochloric acid. After adding 0.6 g of platinum oxide catalyst, the mixture was shaken in a hydrogen atmosphere until the hydrogen uptake ceased. The catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was taken up in 300 ml of diethyl ether, washed with 50 ml of aqueous 5% potassium hydrogen carbonate solution, dried and evaporated. Trituration of the residue with hexane gave 6.1 g of l, 2,3,4-tetrahydro-5-hydroxy-8-methoxy-2-naphthoic acid methyl ester in the form of gray-white crystals. Recrystallization from diethyl ether / hexane gave colorless crystals with a melting point of 129.5-130 ° C.

(iii) A mixture of 5 gl, 2,3,4-tetrahydro-5-hydroxy-8-methoxy-2-naphthoic acid methyl ester, 12 g of potassium carbonate, 5 ml of benzyl chloride and 120 ml of dimethylformamide were 4 hours under nitrogen at 80 ° C stirred. The solvent was evaporated, the residue was dissolved in 200 ml of ethyl acetate and the solution was washed three times with 200 ml of water, dried and evaporated to a crude product in the form of pink crystals. Purification and chromatography on silica gel with ethyl acetate / hexane (1: 1) gave 5.63 g of 5-benzyloxy-1,2,3,4-tetrahydro-8-methoxy-2-naphthoic acid methyl ester as colorless crystals with a melting point of 78-80 ° C. .

(iv) A mixture of 5.63 g of 5-benzyloxy-1,2,3,4-tetrahy-dro-8-methoxy-2-naphthoic acid methyl ester, 150 ml of water, 150 ml of methanol and 5 g of sodium hydroxide was used for 3 hours heated to reflux. The methanol was evaporated and the residue was diluted with 150 ml of water and adjusted to pH 3 with 2N hydrochloric acid. The product came with

9

s io

15

20th

25th

30th

35

40

45

50

55

60

65

644836

extracted three times 100 ml of ethyl acetate and the extracts were washed with two 100 ml of water, dried and evaporated. Trituration of the residue with diethyl ether / hexane gave 5 g of 5-benzyîoxy-1,2,3,4-tetrahydro-8-meth-oxy-2-naphthoic acid in the form of colorless crystals with a melting point of 147-149 ° C.

(v) 34 ml of a 1.7M solution of methyl lithium in diethyl ether became a stirred solution of 7.8 g of 5-benzyloxy-l, 2,3,4-tetrahydro-8-methoxy-2-naphthoic acid in 500 ml of dry diethyl ether given under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours, poured into 500 ml of an aqueous 5% ammonium chloride solution. The ethereal layer was separated, washed successively with 200 ml of water, 200 ml of aqueous 5% potassium carbonate solution and 200 ml of water, dried and evaporated. 6 g of 5-benzyloxy-1,2,3,4-tetra-hydro-8-methoxy-2-acetonaphthone were obtained as colorless crystals with a melting point of 75-76 ° C. (diethyl ether / hexane).

(vi) A solution of 1.5 g of 5-benzyloxy-l, 2,3,4-tetrahy-dro-8-methoxy-2-acetonaphthone in 100 ml of ethyl acetate was added under a hydrogen atmosphere in the presence of 0.2 g of 10% Palladium / carbon catalyst shaken. After the hydrogen uptake had ceased, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. 0.98 g of 2-acetyI-l, 2,3,4-tetrahydro-5-hydroxy-8-methoxynaphthalene was obtained as colorless crystals with a melting point of 143-144 ° C.

Example 2

A) Analogously to Example 1, paragraph A), 2.63 g of 1,2,3,4-tetrahydro-5-hydroxy-8-methoxy-2-naphthoic acid methyl ester (prepared according to section (ii) of Example) 1) 1.5 g of benzene boronic acid and 2.2 g of 2-formyl-3-methoxybenzoic acid methyl ester, 2.96 gl, 2,3,4-tetrahydro-5-hydroxy-8-methoxy-6- (3- methoxyphthalidyl) -2-naphthoic acid methyl ester as colorless crystals of melting point 206-208 ° C (from ethyl acetate / hexane).

B) In analogy to Example 1, part B) 1 gl, 2,3,4-tetrahydro-5-hydroxy-8-methoxy-6- (3-methoxy-phthalidyl) -2-naphthoic acid methyl ester became 0.81 g 6- (2-carboxy-6-methoxybenzyl) -1,2,3,4-tetrahydro-5-hydroxy-8-methoxy-2-naphthoic acid in the form of colorless crystals with a melting point of 237-240 ° C (from ethyl acetate ).

C) In analogy to Example 1, Section C) (but after the cyclization with sulfuric acid, the mixture was poured into ice-cold methanol and the solution obtained was heated to 60 ° C. in order to reconstitute the methyl ester) from 6 g - (2-Carboxy-6-methoxybenzyl) -l, 2,3,4-tetrahydro-5-hydroxy-8-methoxy-2-naphthoic acid 0.165 g 7,8,9,10-tetrahydro-l, 6,1 l -trimethoxy-5,12-naph-thacendione-8-carboxylic acid methyl ester in the form of yellow needles with a melting point of 192-193 °.

Example 3

A) Analogously to Example 1, paragraph A), 2.5 g of 6- (1,1-ethylenedioxyethyl) -5,6,7,8-tetrahydro-4-methoxy-1,6-naphthalenediol, 1.8 methyl g-formyl-3-methoxybenzoate and 1.75 g of benzene boronic acid 2.68 g of 3- [6- (l, l-ethylenedioxyethyl) -5,6,7,8-tetrahydro-l, 6-dihydroxy- 4-methoxy

2-naphthyl] -4-methoxyphthalide as colorless crystals with a melting point of 197-205 ° C. (from diethyl ether / hexane).

B) In analogy to Example 1, paragraph B) from 2 g

3- [6- (1,1-ethylenedioxyethyI) -5,6,7,8-tetrahydro-1,6-dihydroxy-4-methoxy-2-naphthyl] -4-methoxyphthalide 1.55 g 2- / [6- (1,1-ethylenedioxyethyl) -5,6,7,8-tetrahydro-1,6-dihydro-

4-methoxy-2-naphthylmethyl / -3-methoxybenzoic acid obtained in the form of a white powder with a melting point of 200-202 ° C.

C) A mixture of 1.0 g of 2 - / [6- (l, l-ethylenedioxyethyl) -5,6,7,8-tetrahydro-1-6-dihydroxy-4-methoxy-2-naphthylJ-methyl / - 3-methoxybenzoic acid, 10 g of anhydrous potassium carbonate, 4 ml of methyl iodide and 80 ml of acetone were heated to reflux with stirring. After 3 and 6 hours, 4 ml each of methyl iodide was added and the mixture was heated to reflux for a total of 24 hours. The mixture was then cooled, filtered and the filtrate evaporated. The residue was dissolved in a mixture of 30 ml of methanol, 50 ml of water and 1.5 g of sodium hydroxide and heated to reflux for 1.5 hours. Most of the methanol was evaporated, the residue was diluted with 50 ml of water, acidified with 2M hydrochloric acid and extracted with three times 100 ml of ethyl acetate. The extracts were washed with twice 50 ml of water, dried and evaporated and yielded 0.85 g of a white powder which was used in the next step without further purification.

0.85 g of this powder was suspended in 30 ml of dichloromethane and 0.5 ml of trifluoroacetic anhydride was added with stirring. The mixture was stirred for half an hour at room temperature and then poured into 30 ml of water. The dichloromethane phase was separated, washed with 30 ml of water and evaporated to a yellow crystalline solid which was dissolved in 50 ml of ethanol, 5 ml of water and 0.3 g of sodium hydroxide. Then 10 ml of hydrogen peroxide were added and the mixture was heated to 80.degree. Another 10 ml of hydrogen peroxide was added after 20 and 40 minutes, and the mixture was then poured into 200 ml of water and extracted with three times 50 ml of dichloromethane. The combined extracts were washed with water, dried and evaporated to a yellow solid which was purified by column chromatography on silica gel with ethyl acetate / hexane. 490 mg of 8- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8-hydroxy-1,6,1 l-trimethoxy-5,12-naphthacenedione were obtained in the form of yellow crystals with a melting point of 194- 196 ° (from ethyl acetate).

The 6- (l, l-ethylenedioxyethyl) -5,6,7,8-tetrahydro-4-methoxy-l, 6-naphthalenediol used as starting material was prepared as follows:

(i) 56.9 ml of a 1.6M solution of butyllithium in hexane was added with stirring to a solution of 11.86 ml of diisopropylamine in 160 ml of dry tetrahydrofuran under an argon atmosphere at -78 ° C. After 30 minutes, 20.4 g of 5-benzyloxy-1,2,3,4-tetrahydro-8-methoxy-2-naphthoic acid methyl ester (prepared according to Example 1, paragraph (iii)) were added to 160 ml of tetrahydrofuran, and the mixture was stirred at -78 ° C for 1 hour. The resulting solution of the lithium enolate was then brought into a flask by means of an injection needle, which contained a stirred solution of 22.1 ml of triethyl phosphite in 160 ml of dry tetrahydrofuran at -78 ° C., into which a vigorous flow of oxygen was introduced. After all of the lithium enolate had been transferred, the passage of oxygen was continued for 80 minutes. The reaction was then brought to an end by the addition of 17.4 ml of acetic acid, the mixture was allowed to warm to 0 ° C. and stirred at this temperature for 5 minutes. Then 600 ml of water was added, the solution was stirred at 0 ° C for 1 hour and most of the tetrahydrofuran was then evaporated. The residue was extracted three times with 200 ml of ethyl acetate, the extracts were washed with twice 100 ml of aqueous 10% potassium hydrogen carbonate solution, dried and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexane (1: 1). 13.75 g were obtained

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5-Benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-naphthoic acid methyl ester as colorless crystals with a melting point of 96-97 ° C (from diethyl ether / hexane).

(ii) A mixture of 9.9 g 50% sodium hydride and 120 ml dimethyl sulfoxide was heated to 70 ° C under nitrogen and with stirring for 95 minutes. The mixture was cooled to 0 ° C and successively with 120 ml of dry tetrahydrofuran and a solution of 14.58 g of 5-benzyloxy-l, 2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-naphthoic acid methyl ester added in 120 ml of dry tetrahydrofuran. The mixture was stirred at 0 ° C. for 45 minutes and poured into 600 ml of water, the solution was acidified to pH 4 by adding orthophosphoric acid and extracted with four times 300 ml of dichloromethane. The combined extracts were washed with water, dried and evaporated to give a crude crystalline β-keto sulfoxide which was used directly in the next step.

(iii) The above-mentioned crude β-keto sulfoxide was dissolved in a mixture of 510 ml of tetrahydrofuran and 57 ml of water, the solution was cooled to 10 ° C. under nitrogen and aluminum amalgam made from 18 g of aluminum foil was added. The mixture was stirred for 4.5 hours while maintaining a temperature of 10-12 ° C. It was then filtered and evaporated. The oily residue was taken up in 200 ml of dichloromethane, washed with twice 100 ml of water, dried and evaporated. Column chromatography of the residue on silica gel with ethyl acetate / hexane (1: 1) gave 10.9 g of 5-benzyloxy-l, 2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-acetonaphthone as colorless crystals of melting point 71 -72 ° C.

(iv) A mixture of 10.2 g of 5-benzyloxy-I, 2,3,4-tetrahy-dro-2-hydroxy-8-methoxy-2-acetonaphthone, 790 ml of benzene, 27 ml of acetone, 78.5 ml Ethylene glycol and 0.4 g of p-toluenesulphonic acid were heated to reflux under a Dean-Stark attachment for 6.5 hours. The solution was cooled, washed with twice 300 ml of aqueous 10% potassium hydrogen carbonate solution, dried and evaporated. Crystallization of the residue from diethyl ether yielded 9.85 g of 5-benzyloxy-2- (1,1-ethylenedioxyethyl) -1,2,3,4-tetra-hydro-8-methoxy-2-naphthol as colorless crystals with a melting point of 99- 100 ° C.

(v) A solution of 5 g of 5-benzyloxy-2- (l, l-ethylenedi-oxyethyl) -l, 2,3,4-tetrahydro-8-methoxy-2-naphthol in 500 ml of ethyl acetate was treated with 0.8 g 10% palladium / carbon catalyst shaken in a hydrogen atmosphere. After the hydrogen uptake had ceased, the catalyst was filtered off over diatomaceous earth and the filtrate was concentrated, 3.79 g of 6- (l, l-ethylenedioxyethyl) -5,6,7,8-tetrahydro-4-methoxy-l, 6-naphthalenediol in Form of colorless crystals of melting point 122-123 ° C were obtained.

The 5-benzyloxy-l, 2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-naphthoic acid methyl ester prepared according to paragraph (i) of this example can be cleaved as follows:

a) 30 g of 5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-naphthoic acid methyl ester were dissolved in 625 ml of methanol, the solution was mixed with 325 ml of 5% sodium hydroxide solution and 95 Minutes at room temperature. Most of the methanol was evaporated and the residue was diluted with 500 ml of water. The pH of the solution was adjusted to 2 by adding concentrated hydrochloric acid and the mixture was extracted three times with 100 ml of ethyl acetate. The combined extracts were washed with twice 100 ml of water and with 100 ml of saturated sodium chloride solution, dried and evaporated to give 27.35 g of 5-benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-naphthalene 2-carboxylic acid as a white powder with a melting point of 148-150 ° C.

644 836

b) 5 g of the above-mentioned carboxylic acid were dissolved in 750 ml of absolute ethanol under reflux. 2.05 g of S (-) - a-methylbenzylamine was added to the solution and the mixture was cooled and allowed to crystallize overnight after inoculation. The crystalline product was collected and dried at 35 ° C under reduced pressure. 2.15 g of the S (-) - a-methylbenzylamine salt of the above-mentioned carboxylic acid were obtained in the form of colorless crystals of melting point 208-210 ° C., [a] D20 = + 7.4 (c = 1% in acetic acid) .

The mother liquors from the above crystallization were evaporated and the residue was dissolved in 25 ml of 2M hydrochloric acid and 100 ml of ethyl acetate. The mixture was shaken and the layers separated. The aqueous layer was extracted with twice 100 ml of ethyl acetate. The ethyl acetate solutions were combined, washed with twice 500 ml of water, dried and evaporated to give 4.2 g of a gummy residue. This residue was dissolved in 420 ml of ethanol under reflux, the solution was treated with 1.72 g of R (+) - a-methylbenzylamine and, after inoculation, allowed to crystallize overnight. The crystalline product was collected and dried and yielded 2.74 g of the R (+) - a-methylbenzylamine salt of the acid in the form of colorless crystals with a melting point of 208-210 ° C., [a] D20 = —7.4 (c = 1% in acetic acid).

c) The salts mentioned above were individually converted into the corresponding carboxylic acids as follows: First, 2.5 g of salt were dissolved in 25 ml of 2M hydrochloric acid and 100 ml of ethyl acetate. The solution was shaken and the organic phase separated. The aqueous phase was extracted with twice 250 ml of ethyl acetate. The combined organic phases were washed twice with 500 ml of water and with 50 ml of saturated sodium chloride solution, dried and evaporated and gave the carboxylic acid, i.e. S-

(+) - 5-Benzyloxy-1,2,3,4-tetrahydro-2-hydroxy-8-methoxy-naphthalene-2-carboxylic acid and the corresponding R - (-) - carboxylic acid in the form of a rubber.

d) The above carboxylic acids were individually converted into the corresponding methyl esters. To do this

1.5 g of carboxylic acid dissolved in 10 ml of methanol and the solution was mixed with 1 ml of boron trifluoride-methanol. After stirring for 3 hours at room temperature, the mixture was poured into 25 ml of water and extracted with twice 25 ml of dichloromethane. The combined extracts were washed with three times 10 ml of 10% potassium hydrogen carbonate solution and 10 ml of water, dried and evaporated and yielded 1.5 g of the corresponding ester in the form of an off-white solid. In this way, S - (+) - 5-benzyloxy-l, 2,3,4-tetrahydro-2-hydroxy-8-methoxy-2-naphthoic acid methyl ester of melting point 107-108 ° C was obtained, [o (fD20 = +33.8 (c = 0.5% in chloroform) and the corresponding R - (-) - methyl ester with a melting point of 107-108 ° C, [a] D20 = --33.9 (c = 0.5% in Chloroform) These esters can be used to prepare optically active starting materials for the present invention.

Example 4

0.25 g of boron trichloride in 3 ml of dichloromethane was added to a stirred solution of 50 mg of 8-acetyl -?, 8,9,10-tetrahy-dro-l, 6, ll-trimethoxy-5,12-naphthacendione (prepared according to Example 1, paragraph c)) in 20 ml dichloromethane at 0 ° C. The solution was stirred for 5 minutes, slowly added 5 ml of methanol and then added to 50 ml of water. The dichloromethane layer was separated, dried and evaporated to give a red crystalline residue. Recrystallization from dichloromethane / methanol gave 40 mg of 8-acetyl-7,8,9,10-tetrahydro-6,1 l of I-dihydroxy-1-

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644 836

methoxy-5,12-naphthacendione in the form of red needles with a melting point of 243-245 ° C.

Example 5

In analogy to Example 4, 6,8,9,10-tetrahydro-1,6,11-trimethoxy-5,12-naphthacendione-8-carboxylic acid methyl ester (prepared according to Example 2, Part C) gave 7.8, 9,10-tetrahydro-6.1 l-dihydroxy-l-methoxy-5.12-naph-thacendione-8-carboxylic acid methyl ester in the form of light red needles with a melting point of 262-263 ° C. (from tetrahydrofuran / isopropanol) .

Example 6

36 mg of 8- (l, l-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8-hydroxy-1,6,11-trimethoxy-5,12-naphthacendione (prepared according to Example 3, paragraph c)) dissolved in 10 ml of dioxane and mixed with 8 ml of 5M hydrochloric acid with stirring. After 30 minutes the mixture was poured into 100 ml of water and extracted with twice 50 ml of dichloromethane. The combined dichloromethane extracts were washed with twice 50 ml of water, dried and evaporated. The yellow residue was redissolved in 10 ml of dichloromethane and 0.2 g of boron trichloride in 3 ml of dichloromethane was added with stirring. After 10 minutes the red solution was poured into 50 ml of water and the mixture was shaken. The dichloromethane layer was separated, dried and evaporated to give a crystalline residue. Recrystallization from tetrahydrofuran / ethyl acetate gave 20 mg of 8-acetyl-7,8,9,10-tetrahydro-6,8,11 -trihydroxy-1-methoxy-5,12-naphthacendione as red prisms with a melting point of 228-229 ° C.

Example 7

A) 452 mg of 8- (l, l-ethylenedioxyethyl) -7,8,9, lö-tetrahy-dro-8-hydroxy-1,6,11-trimethoxy-5,12-naphthacendione (prepared according to Example 3, paragraph c)) were refluxed in 44 ml of carbon tetrachloride for 30 minutes. 200 mg of N-bromosuccinimide and 10 mg of a-azoisobutyronitrile were added to the solution under reflux. The mixture was then heated to reflux for a further hour with nitrogen and stirring, 36 mg of N-bromosuccinimide and 5 mg of a-azoisobutyronitrile were added and the mixture was heated to reflux for a further hour. After cooling by evaporation, a yellow residue was obtained, which was dissolved in 50 ml of glacial acetic acid. 0.5 g of silver acetate was added to the solution, the mixture was stirred in the dark under nitrogen for 18 hours and then evaporated. The residue was mixed with 100 ml of dichloromethane, the mixture was filtered and the filtrate was washed with 10% potassium hydrogen carbonate solution, dried and evaporated. The yellow gum thus obtained was crystallized from ethyl acetate / diethyl ether and gave 273 mg of rac-cis-10-acetoxy-8- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8-hydroxy-1,6 , 11-trimethoxy-5,12-naphthacendione in the form of yellow crystals with a melting point of 220-222 ° C. This product was pure by thin layer chromatography.

Chromatography of the mother liquors from the previous crystallization using ethyl acetate for elution gave 40 mg rac-trans-10-acetoxy-8- (l, l-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8-hydroxy- 1,6, tri-methoxy-5,12-naphthacendione as yellow crystals with a melting point of 223-224 CC (from tetrahydrofuran / methanol) and a further 25 mg of rac-cis-10-acetoxy-8- (1,1-ethylenedioxy -ethyl) -7,8,9, lO-tetrahydro-8-hydroxy-l, 6,11-trimethoxy-5,12-naphthacendione, which were identical to the product obtained in the previous section.

B) (i) 100 mg rac-cis-10-acetoxy-8- (l 1-ethylenedioxy-ethyl) -7,8,9,10-tetrahydro-8-hydroxy-1,6,11-trimethoxy-5, 12-naphthacenedione was dissolved in 2 ml of dichloromethane and the solution was diluted with 25 ml of methanol. 30 mg of 50% sodium hydride were then added and the mixture was stirred at room temperature for 1 hour. After adding 0.25 ml of acetic acid, most of the solvent was evaporated, the residue was dissolved in 50 ml of dichloromethane, the solution was washed with twice 50 ml of water, dried and evaporated. The yellow crystalline residue thus obtained was, after trituration with diethyl ether, 85 mg of rac-cis-8- (l, l-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8,10-dihydroxy-1,6,11-trimethoxy -5,12-naphthacendione as a yellow powder with a melting point of 215-216 ° C.

B) (ii) 20 mg rac-trans-10-acetoxy-8- (1,1-ethylenedioxy-ethyl) -7,8,9,10-tetrahydro-8-hydroxy-l, 6, ll-trimethoxy-

5,12-Naphthacenedione were converted to crude rac-trans-8- (1,1-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8,10-dihydro-xy-1 in the same manner as described in the previous section , 6,11-trimethoxy-5,12-naphthacendione, which was obtained as a yellow gum. This gum was dissolved in 20 ml of toluene, 15 mg of benzene boronic acid and 2 ml of p-toluenesulfonic acid and stirred for 16 hours at room temperature. The solution was washed with 10 ml of 10% sodium hydrogen carbonate solution, dried and evaporated to a yellow residue which was dissolved in a mixture of 2 ml of dichloromethane, 2 ml of 2-methyl-2,4-pentanediol and 1 ml of acetic acid. The mixture was left to stand at room temperature for 30 hours, diluted with 25 ml of dichloromethane and washed with three times 25 ml of water. After drying, the solvent was evaporated and the residue was chromatographed on silica gel with ethyl acetate. 10 mg of rac-cis-8- (l, l-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8,10-dihydroxy-l, 6,11-trimethoxy-5,12-naphthacenedione were obtained as yellow crystals melting point 215-216 ° C.

C) 50 mg of rac-cis-8- (l, l-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8,10-dihydroxy-1,6,11-trimethoxy-5,12-naphthacenedione were obtained in 25 ml of warm dioxane dissolved, the solution cooled to 0 ° C, mixed with 25 ml of 5N hydrochloric acid and stirred for 3.5 hours at room temperature. The mixture was poured into 100 ml of dichloromethane, the organic phase was separated off, washed with twice 50 ml of water, dried and evaporated. Trituration of the yellow residue with diethyl ether / ethyl acetate yielded 35 mg rac-cis-8-acetyl-7,8,9,10-tetrahydro-8,10-dihydroxy-1,6,11-trimethoxy-5,12-naphthacendione as yellow crystals with a melting point of 214-215 ° C.

D) Treatment of rac-cis-8-acetyl-7,8,9,10-tetrahydro-8, 10-dihydroxy-1,6,11-trimethoxy-5,12-naphthacenedione with boron trichloride according to Example 6 gave rac-cis -8-AcetyI-

7,8,9,10-tetrahydro-6,8,10, ll-tetrahydroxy-l-methoxy-5,12-naphthacendione (racemic daunomycinone) in the form of red crystals with an identical thin layer chromatogram and NMR spectrum compared to the authentic one Daunomycinon from natural sources.

E) Racemic daunomycinone can also rac-cis-8- (l, l-ethylenedioxyethyl) -7,8,9,10-tetrahydro-8,10-dihydro-xy-1,6,11-trimethoxy-5,12- naphthacendione (prepared according to section B) of this example) can be obtained by treatment with boron trichloride according to example 6, sufficient time being provided for the decetalation.

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Claims (8)

644 836 2nd PATENT CLAIMS î. Process for the preparation of polycyclic compounds of formula VII CCH. wherein R1 and R2 have the above meaning, converts the phthalide ring in the compound of formula III to a compound of formula CCH. 10th VII 0CH3 O OCK. IV 15 wherein R1 is lower alkoxycarbonyl or a group of the formula —R R \ / C — CH in which R2 has the meaning given above and R10 denotes carboxy or a group of the formula (a) given above, to get the compound of formula IV methylated and 2Q the mono- or diester obtained to a compound of formula 3,7,8,9, 10-tetrahydro-1,6,1 l-trimethoxy-5,12-naphthacendione-8-carboxylic acid methyl ester as compound according to claim 2. 3rd 644836 wherein R12 is lower alkoxycarbonyl and Rz has the meaning given in claim 1. 3, U) OCß. R2 represents hydrogen or hydroxy and R3 and R4 together represent oxo or a protected oxo group, characterized in that a compound of the formula 25th s ^ CCOH OCH 30th OCH. OCH. wherein R1 and R2 have the above meaning, with an aldehyde of the formula ^ X ^ COOR 35 in which R2 and R10 have the above meaning, saponified, the compound of the formula V cyclized and, if R1 & carboxy, this group is esterified to a lower alkoxycarbonyl group, and the compound of the formula thus obtained 40 45 II CHO 50 VI OCH. OCH. OCH. where R5 is lower alkyl, in the presence of an aromatic boronic acid, the boronic ester obtained in a compound of the formula in which R1 and R2 have the meaning given above, oxidized to a compound of the formula VII. 2. Compounds of the formula 60 65 III 4. Compounds of the formula OCH OH wherein R1 and R2 have the meaning given in claim 1, as means for carrying out the method according to claim 1. 5. 2-acetyl-l, 2, 3,4-tetrahydro-5-hydroxy-8-methoxy-naphthalene as a compound according to claim 4. 6. 1,2,3,4-tetrahydro-5-hydroxy-8-methoxy-2-naphthoic acid methyl ester as a compound according to claim 4. 7. 6- (I, l-ethylenedioxyethyl) -5,6,7,8-tetrahydro-4-meth-oxy-l, 6-naphthalenediol as a compound according to claim 4. 8. Use of compounds of the formula VIIa of claim 2 for the preparation of compounds of the formula XVIIa O OH XVIIa OCH OH wherein R2 and R12 have the meaning given in claims 1 and 2, by treatment with boron trichloride.