wherein R represents a hydrogen atom or a COOR. group in which R _α may be a hydrogen atom or a straight or branched alkyl group having from 1 to 10 carbon atoms optionally substituted at one or more carbon(ε) in the chain with inert groups such as an aryl group, an alkoxy group, an ester or an amido group.

Accordingly, the present invention provides a process for the preparation of an anthracyclinone of formula (I), which process comprises:

(i)(a) reacting a 4-demethyl- -εulfonyl-7-deoxy-13- dioxolanyl daunomycinone of formula (V) :

wherein R' represents an alkyl group having from 1 to 10 carbon atoms optionally substituted by one or more halogen atoms or an aryl group optionally substituted by halogen, alkyl, alkoxy or nitro, in a reducing environment with a catalytic amount of a compound of formula (VIII):

wherein M represents a transition metal atom, L and __' , which may be the same or different, each represent an anion or a neutral molecule and n and m may vary from 0 to , such as to obtain a compound of formula (VII):

wherein R represents hydrogen; or

(b) carbonylating a 4-demethyl-4-εulfonyl-7-deoxy- 13-dioxolanyl daunomycinone of formula (V) as defined above, with carbon monoxide in the presence of a nucleophile R. OH wherein . _χ is as defined above, an organic or inorganic base and as catalyst a compound of formula (VIII) as defined above, such aε to obtain a compound of formula (VII) as shown above wherein R represents a COO _j^ group; and

(ii) introducing an α-hydroxy group at the 7-position and removing the 13-oxo protecting group by acid hydrolysis from the resultant compound of formula (VII).

In the definitions, an alkyl group such aε C.-C ₁₀ alkyl is typically C _χ -C. alkyl, for example methyl. An aryl group is preferably phenyl. An alkoxy group is typically C.-C ₄ alkoxy. An eεter group iε, for example, (C. -C ₄ alkoxy)carbonyl. The amido group iε generally carbamoyl. Halogen includes F, Cl and Br. Typically m+n is at least 1, for example 1, 2, 3 or 4.

The process for the preparation of compounds of general formula (I*) is illustrated by the following reaction scheme 1. The starting material shown there, 4-demethyl-7-deoxy daunomycinone (II), may be prepared by total chemical synthesis as described in US-A-4046878:

(ID

SCHEME 1

(VII)

More conveniently (II) can be obtained by C4-0CH ₃ demethvlation of the naturally occurring daunomycinone (III) followed by hydrogenolysis of the 7α-hydroxyl group

Compound (II) is then protected at the C13 keto group by reaction with ethylene glycol to give (IV)

and selectively sulfonated in position C4-0H (V)

The sulfonating agent is a sulfonyl compound of formula (VI)

R'SOaX (VI)

wherein X may be a halogen atom, a OSOR' group, an imidazolide, a

NH(C ₆ H_. ) (R'SOz) or another group capable of reacting with a phenol to give a sulfonate, and R' represents an alkyl group having from 1 to 10 carbon atoms , a halo or polihalo alkyl group or an aryl group optionally substituted by halogen atom(s), alkyl, alkoxy or nitro groups. Preferred groups which R' may represent are: trifluoromethyl, 4-fluorophenyl and 4- tolyl.

According to the process of the invention compound of formula (V) is

transformed into (VII) by treatment in an appropriate solvent with a compound of formula (VIII) (hereunder referred to as catalyst): —

wherein M represents a transition metal atom, L and L' , same or different, may be an anion as Cl ^_ or CHsCOO- or a neutral molecule as a solvent molecule, a mono or a di-phosphine, a phosphite or a diamine; n and may vary from 0 to 4. Preferred transition metal atoms which M may represent are palladium or nickel. Preferred groups which L and/or L' may represent are triaryl phosphines such as triphenyl phosphine and tritolyl phosphine or chelating diphosphines such as 1,3 diphenylphosphino propane and 1,1' bis-(diphenylphosphino)ferrocene

In particular, 4-demethoxy-7-deory-13-dioxolanyl daunomycinone ((VII), R-H) is obtained by treating (V), under an inert atmosphere, with the

catalyεt, either preformed or generated "in εitu" from suitable precursorε, in the preεence of a reducing εyεte which iε able to act as a formal hydride donor, A suitable reducing system, under the conditions of the invention is a trialkylammonium formate formed "in εitu" by addition of formic acid and a trialkylamine. Reaction is typically at 60°C.

Alternatively compounds of formula ((VII), R»COOR _χ ) are obtained by treating (V) under a carbon monoxide atmosphere, with the catalyst, either preformed or generated "in situ" from suitable precursorε, in the preεence of a nucleophile _j^ OH, wherein _χ iε aε defined above, and a baεe. Suitable baεeε are trialkylamineε and alkali or alkaline earth carbonates or hydroxides.

The temperature of the reaction iε typically from 0 to 150°C. The catalyεt (VIII) is generally uεed in a molar ratio with reεpect to (V) from 1:1 to 1:10000, preferably from 1:20 and 1:1000. The CO preεεure may vary from 1 to 100 atm. , preferably from 1 to 10 atm.

The 7α-hydroxyl. group iε then introduced into the compoundε of formula (VII) and the ketal group removed to give the final compounds of formula (I). The introduction of the 7α-hydroxyl group may be performed according to the method described by CM. Wong e_t al_. , Can. J. Chem. 5L, 446, (1973): brominating compounds (VII) at the C7 position and hydrolysing the 7-bromo and the 13-ketal groups to give compounds of formula (I) .

Typically the o-hydroxy group is introduced at the 7-position of the compound of formula (VII), the 13-dioxolanyl protecting group is removed by acid hydrolysis at 0°C with trifluoroacetic acid, and the obtained crude product is purified by chromatography on a silica gel column using as eluent system chloroform-acetone. When R is hydrogen, the eluent system may be chloroform-acetone (9:1 v/v). For R as COOR, , the system may be chloroform-acetone

(95:5 v/v).

Although the use of tranεition metal catalysis for both hydrogenolysiε and carbonylation of aryl εulfonateε haε been known for yearε it iε new in anthracycline chemistry. The process of the present invention, starting from a common εulfonate of formula (V) allows εeveral valuable intermediateε of general formula (I) to be synthesised which are otherwise accessible only by individual total εynthesiε. Moreover, when the starting material (II) iε obtained from the naturally occurring daunomycinone (V) , the present invention allows to the target molecules of general formula (I) to be syntheεiεed in high yield and without optical reεolution εtepε. The compounds (I) are intermediateε in the preparation of antitumor anthracycline glycoεideε.

The preεent invention will be now more fully deεcribed by meanε of the following Exampleε, which are provided merely for purpoεeε of illuεtration and are not intended to limit the preεent invention. Example 1

4-Demethyl-7-deoxy-13-dioxolanyl daunomycinone (IV). To a εuspenεion of 13g (35.3 mmol) of 4-demethyl-7-deoxy daunomycinone in 400 mL of benzene were added 30 mL of ethylene glycol and 0.3 g of para-toluenεulfonic acid. The reaction mixture waε refluxed with azeotropic removal of water for ca. 6 hourε, then cooled to room temperature. The solid was recovered by filtration and washed with water and ethanol to give, after drying, 13.1 g of (IV). The product showed on HP C analysis to be of 98.6% purity. HPLC analysis:

Column: MERCK RP 18/7 m (250 x 4.2 mm). Mobile phase: A-0.01 M sodium heptansulfonate/0.02 M phosphoric acid 6

Acetonitrile 4

B-Methanol 7

Acetonitrile 3

Gradient: from 201 B to 70Z B in 25 in, Flow rate: 1.5 mL/min, Detector: UV at 254 nm.

^H-NMR 300 MHz (in CDC1 ₃ ): δ= 1.46 (3H, s), 1.50-2.20 (3H, m) , 2.71-3.22

(4H, m), 4.08 (4H, s), 7.28 (1H, dd, J-8.2,1.2 Hz), 7.67 (1H, t, J=8.2

Hz), 7.86 (lH,dd, J-8.2,1.2 Hz), 12.31 (lH,s), 12.84 (lH,s), 13.67 (lH,s)

M.S. : m/z - 412 (M~, base peak). αj (c » 0.1 in dioxane) «= - 76°. ϋ.V. (in EtOH): A- 528,514,492,293,255,236,204 nm; max = 255 nm.

I.R. (Nujol mull) :3420,1590,1518 cπr ¹

TLC on Kieselgel plate F 254 (Merck) using chloroform/acetone (9/1 by volume) : Rf - 0.62

Example 2

4-Demethyl-4-trifluoromethansulfonyl-7-deoxγ-13-dioxolan yl daunomycinone (V: ?.'- CF-)

To a solution in pyridine (110 mL) of 1.1 g (2.7 rαmol) of (IV), 2.3 mL (13.2 mmol) of diisopropylethylamine and 0.33 g (2.7 iπmol) of 4- dimethylaminopyridine, cooled at 0 °C, were added 1.4 mL (8.3 mmol) of trifluoro ethansulfonyl anhydride and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then cooled to 0°C and added with 500 mL of methylene chloride and 300 mL of 10Z hydrochloric acid. The organic phase was washed with water, dried over sodium sulfate and the solvent evaporated under reduced pressure to leave a solid which was refluxed for 15 minutes in methanol (35 mL) and

filtered obtaining 0.95 g (65Z from IV) of (V; R'= CF ₃ ), (HPLC: 942, conditions as described in example 1);

^H-NMR 200 MHz (in CDC1 ₃ ): δ= 1.46 (3H, s), 1.50 - 2.20 (3H, m) , 2.68 -

3.27 (4H, m), 4.08 (4H, s) 7.60 (1H, d, J-8.1 Hz), 7.88 (1H, t, J=8.0

Hz), 8.48 (1H, dd, J-l.2 _. 8.0 Hz), 13.45 (2H, s).

M.S : m/z - 544 (M*, base peak).

U.V. (in EtOH): λ - 531,496,255,206 nm; Λ max - 255 nm.

I.R. (Nujol mull): __/ - 3525,1615,1585 cm- ³ - r -ι2o αj (c = 0.1 in dioxane) = - 62.5°

TLC on ielsegel plate F 254 (Merck) using chlrofoπn/acetone (9/1 by volume) : Rf=0.58

Example 3

4-Demethyl-4-(4 ^, fluorobenzensulfonyl)-7-deoxy-13-dioxolanyl daunomycinone (V: R' - 4-FfC«H_.n

To a solution in pyridine (110 mL) of 1.1 g (2.7 mmol) of (IV), 2.3 L (13.2 mmol) of diisopropylethylamine and 0.33 g (2.7 mmol) of 4- dimethylaminopyridine, ,.cooled to 0 °C were added 0.58 g (3.0 mmol) of 4- fluorobenzensulfonyl chloride and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then cooled to 0 °C and added with 500 mL of methylene chloride and 300 mL of 10Σ hydrochloric acid. The organic phase was washed with water, dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue was chromatographated on silica gel (toluene/acetone 8:2 by volume as eluant) obtaining 1.0 g (70.0 Z from IV) of (V, R' - 4- F(C.H_)), (HPLC: 98.3Z);

a-H-MM 300 MHz (in CDC1 ₃ ): δ= 1.46 (3H, s), 1.50 - 1.87 (2H, m) , 2.05 (IH, dd, J-2.4;6.1 Hz), 2.70 - 3.18 (4H, m) , 4.08 (4H, s), 7.10 - 7.25 (2H, m), 7.63 (IH, d, J-8.0 Hz), 7.78 (IH, t, J-8.0 Hz), 7.96 - 8.01 (2H, m), 8.37 (IH, dd, J-1.3;7.8 Hz), 13.39 (IH, s), 13.45 (IH, s).

M.S. : m/z - 570 (M ^÷ , base peak).

Irα-ι1* ^β (c - 0.1 in dioxane) - - 34.4°. ϋ.V. (in EtOH): Λ - 528,493,254,206 nm; λmax - 254 nm.

I.R. (Nujol mull): U - 3500,1610,1580 cm" ¹

TLC on Kieselgel plate F 254 (Merck) using chloroform/acetone (9/1* by volume) : Rf - 0.61

Example 4

4-Demethyl-4-(4'toluensulfonyl)-7-deoxy-13-dioxolanyl daunomycinone (V; ' _ 4-.H-_.C__H-.))

The synthesis was carried out as described in example 3 except that 4- toluensulfonyl chloride was used as sulfonating agent. The reaction crude was chromatographated on silica gel (toluene/acetone 8:2 by volume as eluant) obtaining 1.0 g (67.0 Z from IV) of (V, R' - 4-CH_(C_H_) ) , (HPLC:

97.5Z),

^■ ' ^■ H- MR 300 MHz (in CDC1_): δ« 1.46 (3H, s), 1.50 - 1.85 (2H, m) , 2.05

(IH, dd, J-2,4;6.1 Hz), 2.40 (3H, s), 2.70 - 3.14 (4H, m) , 4.08 (4H, s),

7.30 (2H, d, J-8.4 Hz), 7.59 (IH, d, J-7.5 Hz), 7.76 (IH, t, J-7.9 Hz)

7.80 (2H, d, J-8.4 Hz), 8.36 (IH, dd, J-1.2;7.8 Hz), 13.40 (IH, s), 13.42

(IH, β).

M.S. : m/z - 566 (M*. base peak)

^α (c - 0.1 in dioxane) « - 68.l ^e

U.V. ( in EtOH) : A ^« 528 , 493 , 254 , 228 , 205 nm; Λ max - 254 nm. l.R. (Nujol mull): JJ - 3430,1610,1575 cm.- ³ -

TLC on Kieselgel plate F 254 (Merck) using chloroform/acetone (9/1 by volume) : Rf - 0.57

Example 5

4-Demethoxy daunomycinone (I, R- H)

To a solution of 2 g of (V; R'- CF _S ), (3.6 mmol) in 50 mL of dimethylformamide under an inert atmosphere, were successively added 2 mL of triethylamine, 0.6 mL of formic acid, 110 g of l,l'-bis- (diphenylphosphino) ferrocene (0.178 mmol) and 40 mg of palladium acetate (0.178 mmol). The reaction mixture was stirred for 30 minutes at 60 °C, then cooled to 0 °C, acidified with 10Z hydrochloric acid and extracted with methylene chloride. The organic phase was evaporated to dryness and the residue chromatographated on silica gel (toluene/acetone 8:2 by volume as eluant) obtaining 1.24 g (86.9 Z) of 4-demethoxy-7-deoxy-13- dioxolanyl daunomycinone (VII; R - H), (HPLC: 98.4 Z),

'-H-NMR 200 MHz (in CDC1_): δ-1.45 (3H, β), 1.6 -2.15 (3H, m) , 2.70 - 3.16 (4h, m), 4.08(4H, s), 7.76 -7.85 (2H, m) , 8.3 - 8.36(2h. m) , 13.52(lh, s), 13,54(1H, s)

M.S. : m/z - 396 (M*. base peak). α (c-0.1 in dioxane) - -52.5°

U.V. (in EtOH): λ -516,482,288,252,204 run; max-252 l.R. (Nujol mull): U -3415,1612,1580 cπr ¹

TLC on Kieselgel plate F 254 (Merck) using chloroform/acetone (9/1 by volume) : Rf - 0.59

The compound described above (VII, R = H) , (lg, 2.5 mmol) was dissolved in 160 mL of carbon tetrachloride, heated at reflux temperature and added with 2,2*-azo-isobutyronitrile (0.55 g) and 160 mL of water. To the reaction mixture, vigorously stirred, were added dropwise over 30 min. 4.8 mL of a 0.6 M solution of bromine in carbon tetrachloride. After 1 hour the mixture was cooled and the organic phase was washed with water and extracted with IN sodium hyroxide. The pH of the aqueous alkaline solution was adjusted to 8.2 with 2N hydrochloric acid and the mixture extracted with methylene chloride. The solution was dried over sodium sulfate and the solvent evaporated in vacuo. The residue was dissolved in 30 mL of trifluoroacetic acid and 3 mL of water at 0 °C and stirred for 1 hour; the reaction mixture was then diluted with 50 mL of water and extracted with methylene chloride. The organic phase was washed with aqueous sodium hydrogen carbonate and water and dried over sodium sulfate. The solvent was removed in vacuo and the residue chromatographated on silica gel (chloroform/acetone 9:1 by volume as eluant) obtaining 0.52 g (56.5. Z from VII, R - H) of (I, R - H) , (HPLC: 99.l∑),

^H-NMR 300 MHz (in CDC1,): 6- 2.19 (IH, dd, J-4.8,14.5 Hz), 2.37 (IH, ddd, J-2.0, 2.0, 14.5 Hz), 2.43 (3H. s), 2.95 (IH, d, J-18.6 Hz), 3.20 (IH, dd, J-2.0, 18.6 Hz), 3.83 (IH, d, J-4.8 Hz), 4.55 (IH, s), 5.32 (IH, ddd, J-2.0, 4.8, 4.8 Hz), 7.84-7.86 (2H, m) , 8.33-8.36 (2H, m), 13.30 (IH, s), 13.60 (IH, s).

U.V. (in EtOH): A - 208,252,257,285,480,500,514 nm; Am x - 252 nm. l.R. (KBr pellet): V - 3450, 1715, 1652, 1585 cm- ³ -. (αj (c - 0.1 in dioxane) - + 159°

M. S . : m/z - 368 (M* , base peak) .

TLC o Kieselgel plate F 254 (Merck) using chloroform/acetone (8:2 by volume) : Rf - 0.70.

Example 6

4-Demethoχv daunomycinone (I; R - H)

The reaction was carried out as described in example 5 except that dioxane (50 mL) was used as solvent and 1,3-diphenylphosphinopropane (74 mg, 0.178 mmol) as ligand for palladium.

After 1 hour at 60 °C the reaction mixture was worked up as described in example 5 obtaining 1.17 g (82.0 Z) of 4-demethoxy-7-deoxy-13-dioxolanyl daunomycinone (VII; R - H) , (HPLC 99.1 Z).

Compound (VII; R - H) was then converted into 4-de_.eth.oxy daunomycinone

(I; R - H) as described in example 5.

Example 7

4-Demethoxy daunomycinone (I; R - H)

The reaction was carried out as described in example 5 except that tri-p- tolylphosphine (108 mg, 0.356 mmol) was used as ligand for palladium.

After 1 hour at 60 °C the reaction mixture was worked up as described in example 5 obtaining 1.21 g (84.8 Z) of 4-demethoxy-7-deo__y-13-dioxolanyl daunomycinone (VII; R - H), (HPLC 98.9 Z).

Compoimd (VII; R - H) was then converted into 4-demethoxy daunomycinone

(I; R - H) as described in example 5.

Example 8

4-Demethoxy daunomycinone (I: R - H)

The reaction was carried out as described in example 5 except that 4- demethyl-4-(4'fluorobenzensulfonyl)-7-deoxy-13-dioxolanyl daunomycinone

(V; R'» 4-F(C ₆ H_.)), (2.07 g, 3.6 mmol) was used as substrate. The reaction mixture was stirred for 7 hours at 90 °C, then worked up as described in example 5 obtaining 1.05 g (73.6 Z9 of 4-demethoxy-7-deoxy-

13-dioxolanyl daunomycinone (VII; R - H), (HPLC: 98.7 Z).

Compound (VII; R - H) was then converted into 4-demethoxy daunomycinone

(I; R = H) as described in example 5.

Example 9

4-Demethoxy daunomycinone (I: R - H)

The reaction was carried out as described in example 5 except that 4- demethyl-4-(4'toluensulfonyl)-7-deoxy-13-dioxolanyl daunomycinone (V; R'-

4-CH__(C _β H_.)) , (2.04 g, 3.6 mmol) was used as substrate, dioxane (50 mL) as solvent and 1,3-diphenylphosphinopropane (74 mg, 0.178 mmol) as ligand for palladium. The reaction mixture was stirred for 7 hours at 90 °C, then worked up as described in example 5 obtaining 1.0 g (70 Z) of 4- demethoxy-7-deoxy-13-dioxolanyl daunomycinone (VII; R-H) , (HPLC: 99.0 Z)

Compound (VII; R - H) was then converted into 4-demethoxy daunomycinone

(I; R - H) as described in example 5.

Example 10

4-Demethoxy-4-methoxycarbonyl daunomycinone (I: R - COOCH

To a solution of 2 g of (V; R* - CF_»), (3.6 mmol) in 50 mL of dioxane,

under a carbon monoxide atmosphere, were successively added 1 mL of triethylamine, 3 mL of methanol, 74 mg of 1,3 diphenylphosphinopropane (0.178 mmol) and 40 mg of palladium acetate (0.178 mmol). The reaction mixture was stirred at 60 °C until the CO absorption stopped, then cooled to 0 °C, acidified with 10Z hydrochloric acid and extracted with methylene chloride. The organic phase was evaporated to dryness leaving 1.44 g (88.1Z) of crude 4-demethoxy-4-methoxycarbonyl-7-deoxy-13 -dioxolanyl daunomycinone (VII; R - C00CH-), (HPLC : 95.1Z). ^a -H-NMR 300 MHz (in CDC1 ₃ ): δ - 1.46 (3H,s), 1.58-1.90 (2H,m) , 2.00-2.08 (lH. ^' ), 2.75-3.12 (4H,m), 4.02 (3H,s), 4.06 (4H,s), 7.68 (lH.dd,J-7.5,1.3 Hz), 7.82 (lH,t,J-7.6 Hz), 8.41 (lH,dd,J-7.8,1.3 Hz), 13.07 (lH.s), 13.40 (lH.s). ϋ.V. (in EtOH): A- 523,489,256,206 nm; Λmax - 206 nm. l.R. (Nujol mull): " - 3490,1725,1615,1570 cm" ³ -.

■ r (c - 0.1 in dioxane) - -51°.

M.S.: m/z - 454 (M*. base peak).

TLC on Kieselgel plate F 254 (Merck) using chloroform/acetone (9/1 by volume): Rf - 0.54

The compound described above (VII; R - C00CH_), (1.4 g; 3.08 mmol) was dissolved in 200 L of carbon tetrachloride, heated at reflux temperature and added with 2,2'-azo-iεobutyronitrile (0.68 g) and 200 mL of warer. To the reaction mixture, vigorously stirred, were added dropwise.σver 30 min, 5.9 mL of a 0.6 M solution of bromine in carbon tetrachloride. After 1 hour the mixture was cooled and the organic phase was washed with water and extracted with IN sodium hydroxide. The pH of the aqueous alkaline

solution was adjusted to 8.2 with 2N hydrochloric acid and the mixture extracted with methylene chloride. The solution was dried over sodium sulfate and the solvent evaporated in vacuo. The residue was dissolved in 37 mL of trifluoroacetic acid and 4 mL of water at 0 °C and stirred for 1 hour; the reaction mixture was then diluted with 60 L of water and extracted with methylene chloride. The organic phase was washed with aqueous sodium hydrogen carbonate and water and dried over sodium sulfate. The solvent was removed in vacuo and the residue chromatographated on silica gel (chloroform/acetone 95:5 by volume as eluant) obtaining 0.71 g (54.1Z from VII, R - C00CH ₃ ) of (I; R - C00CH ₃ ), (HPLC: 98.7Z)

^-NMR 300 MHz (in CDC1 ₃ ): δ - 2.04 (lH.dd,J-14.5;4.7 Hz), 2.32 (lH,d,J-14.5 Hz), 2.45 (3H,s), 2.87 (lH,d,J-19 Hz), 3.08 (lH.dd,J=19;1.8 Hz), 4.02 (3H,S), 4.21 (lH.bs), 4.76 (lH.s), 5.21 (lH.bs), 7.71 (lH,dd,J-7.7;1.2 Hz), 7.87 (lH,t,J-7.7 Hz), 8.38 (lH.dd,J-7.7;1.2 Hz), 12.88 (1H,S), 12.98 (1H,S). U.V. (in EtOH): - 522,489,461,285,253,206 nm; /max - 253 nm. l.R. (Nujol mull): - 3440,1735,1713,1622,1576 c .- ³ - r -V*° αj (c - 0.1 in dioxane) - + 145°

M.S. m/z - 426 (M÷, base peak)

TLC on Kieselgel plate F 254 (Merck) using chloroform/acetone (9:1 by volume) Rf - 0.40

Example 11

4-Demethoxydaunomycinone-4-carboxylic acid (I; R » C00H)

The reaction was carried out as described in example 10 except that 4-

methoxybenzyl alcohol (9.8 g ; 72 m ol) was used instead of methanol.

After the CO absorption ceased the reaction mixture was worked up as described in example 10 to give 1.65 g (81.8Z) of crude 4-demethoxy-4-

(4*-methoxybenzyl)carbonyl-7-deoxy-13-dioxolanyl daunomycinone (VII; R -

C00CH_(C_H_)0CH ₃ ), (HPLC: 96.3Z).

^H-NMR 300 MHz (in CDCls): δ - 1.45 (3H,s), 1.60-2.10 (3H,m), 2.75-3.22

(4H,m), 3.95 (3H,s), 4.08 (4H,s), 5.23 (2H,s), 6.86 (2H,d,J=8.7 Hz), 7.39

(2H,d,J=8.7 Hz) , 7.69 (lH.dd,J-7.5,1.3 Hz) , 7.81 (lH,t,J-7.6 Hz) , 8.38

(lH,dd,J=7.8,1.3 Hz), 13.03 (lH.s), 13.42 (lH.s)

U.V. (in EtOH): A- 522,488,257,206 nm; /max - 206 nm. l.R. (Nujol mull): t - 3400,1730,1610,1570 arr ³ -

/ cti (c - 0.1 in dioxane) - - 58°

M.S. m/z - 560 (M*, base peak)

TLC on Kieselgel plate F 254 (Merck) using chloroform/acetone (9/1 by volume): 0.55

The compound described above (VII; R - C00CH ₂ (C _β H_)0CH_) was then converted into 4-demethoxydaunomycinone-4-carboxylic acid (I; R - COOH) as described in example 10.

' ^• H-NMR 300 MHz (in DMSO d6): δ - 1.90-2.08 (lH,m), 2.20-2.28 (lH,m), 2.38

(3H,s), 2.96 (lH,d,J-18.7 Hz), 3.08 (lH,d,J-18.7 Hz), 5.10 (lH.bs), 5.38

(lH,d,J-6.6 Hz), 6.17 (IH, bs), 7.94 (lH,d,J-7.3 Hz), 8.07 (lH.t,J-7.6

Hz), 8.39 (lH,d,J-7.5 Hz), 13.15 (lH.s), 13.25 (1H,S), 13.40 (lH.bs).

U.V. (in EtOH): A- 486,287,251,205 nm; λmax - 251 n . l.R. (Nujol mull): 1/ -3340,1695,1610,1565 cm- ³ -

[ a] (c - 0.1 in dioxane) - + 146" M.S. m/z - 412 (M~, base peak)