FI78452B - FOERFARANDE FOER FRAMSTAELLNING AV RACEMISKA AGLYKONER OCH () -4-DEMETOXI-6-DEOXIDAUNOMYCINONE. - Google Patents

Description

78 4 52

METHOD FOR THE PREPARATION OF RACEMIC AGLYCONES AND (+) - 4-DEMETOXY-6-DEXXIDAUNIC MYSIN0EN _ FOR THE PREPARATION OF RACEMISAL AGLYCONER WITH (±) -4-DEMETOXY-6 "DEOXIDE

This invention relates to a process for the preparation of racemic aglycones of the general formula

LsXJäLj0 "(i)

1 i2 OH

wherein one of R 1 and R 8 is hydrogen and the other is a hydroxy group.

The tetracyclic aglycones of formula (I) are used in the preparation of new therapeutically active anthracycline glycosides of the general formula

Jf Γ1 co-ch2r3

(HJ

h r2 [lp

NHX

wherein R and R are as defined above, R_, R and 1b v ^

Rg independently represents either hydrogen or a hydroxy group and X is hydrogen or a trifluoroacetyl group, wherein R1 and R8 do not both simultaneously mean a hydroxy group and when R1 is a hydroxy group X is hydrogen. It is prepared by reacting an aglycone of formula (I) with a protected halogen sugar of formula (III)

Y

d (III) NHCOCFg * 6 2 784R? wherein Y represents a halogen atom, preferably a chlorine atom, and R 9 and R 7 independently represent hydrogen or a trifluoroacetoxy group, but not both simultaneously a trifluoroacetoxy group.

From an article by Umezawan et al in Journal of Antibiotics, Vol. 33, no. 12 (1986), pp. 1581-85, a process for the preparation of 4-demethoxy-11-deoxydaunomycinone is known. The starting material for the process of the invention is 2-acetyl-2-hydroxy-4-methoxytetralin, which is subjected to Friedel-Crafts acylation with phthalic anhydride to give a racemic mixture of 4-demethoxy-7,11-dideoxydaunomycinone. This is obtained by treating the ethylene glycates corresponding to the ethylene glycol necessary to protect the 13-carbonyl group, which are brominated with bromine using a method known per se, followed by hydrolysis with 8N hydrochloric acid in acetone to give the desired 4-demethoxy-11-deoxydaunomycinone condensation to give the final glycoside compounds.

The process for the preparation of racemic aglycones according to the invention differs from the above-mentioned known process in that the starting material used is different and in that, in addition to 4-demethoxy-11-deoxydaunomycinone, hitherto unknown 4-demethoxy-6-deoxydaunomycinone is obtained, as will be seen below. The latter compound is also a subject of the present invention.

3 78459

The preparation of the aglycones of formula (I) according to the invention can be represented by the following reaction scheme: 1 ° H-> f ^ Y '"o *. / H + I ^

| ^^ COOH ^> X-COOH

(1) 0 (2) (3) 3 0 - "2> (4) 00¾ ^ l. Pj X (cf3co) 2 ° V jj

(4) +! I -> i f v \ A

^ f CF3C00H ^ (5) 0CH3 Lh3 i 3 (6) 4 / ö 4 ο 2 o

0CK3 II

Ί) “2 2) H2SO4 CH; 3 och3 H2SO4

^ O

O OH II

C0CH3 C0CH3 H (8) O OH

Ί l

O

O OH II

COCHj

Il (10) O OH (11)

O

5 78452

The actual starting materials for the reaction cycles are 1,2,3,6-tetrahydrophthalic anhydride (1) and 1,4-dimethoxynaphthalene (5). Compound (1) is treated with an alcohol of the general formula RHH, wherein R represents lower alkyl, substituted lower alkyl or aryl to give the corresponding monoester (2). This is treated by a Friedel-Crafts reaction with acetyl chloride followed by dilute alkali to give the corresponding L, B-unsaturated ketone (3). Acylation is a regiospecific process that yields only the C-4 acetyl derivative. Catalytic reduction of compound (3) quantitatively gives acid (4), a key compound in tetracyclic chromophone synthesis. The acid (4) is immediately converted to a mixture of both isomers (6) by reaction with 1,4-dimethoxynaphthalene in the presence of trifluoroacetic anhydride and trifluoroacetic acid. Catalytic reduction of the benzyl carbonyl function of mixture (6) followed by treatment with sulfuric acid at room temperature provides a mixture of tetracyclic isomers (7). Treatment of this mixture (7) with sulfuric acid at 80 ° C gives a 1: 1 mixture of racemic anthracyclinones (8) and (9). The coupling of hydroxyl groups to give compounds (10) and (11) is carried out in a manner known per se. By treating the mixture first with boiling acetic anhydride in the presence of P-toluenesulfonic acid and then with m-chloroperbenzoic acid at room temperature for two hours. In fact, the methods for oxidizing ketones (8) and (9) to the corresponding hydroxyketones (10) and (li) are similar to those used for typical 20-ketostereoids ((i) KO-t.Bu /, DMF, -20 ° C, ( ii) (ET0) 3P, DMF, -20 ° C, JN Garden et al., J. Org. Chem. 33, 3294 (1968)) or ((i) Ac 2 O, HCl 4, (ii) m-chloroperbenzoic acid; J. Attenburrow et al., J. Chem. Soc., 4547 (1961)). The result is a diastereomeric mixture of racemic (t) -4-demethoxy-6,7-dideoxydaunomycinone (10) and racemic (-) - 4-demethoxy-7,11-dideoxydaunomycinone (11).

6 78452

Finally, the coupling of the 7-hydroxyl group to compounds (10) and (11) is carried out by benzyl bromination followed by solvolysis fC.M. Wong et al., Can.J.Chem. 51, 466 (1973)). Separately, the mixture is chromatographed on silica gel to separate isomers using a manual separation method (CT Eliel "Stereochemistry of Carbon Compounds", McGraw Hill, 1962, Chapter 4), after which each racemic compound thus obtained is treated separately by boiling with ethylene glycol to give ethylene glycol. is p-toluenesulfonic acid, to give the corresponding 13-ketals, which are then reacted with bromine in carbon tetrachloride in the presence of 2,2'-azo-bis-isobutyronitrile to give benzyl bromination, followed by hydrolysis of the ketal group with aqueous hydrogen chloride in acetone for 3 hours at room temperature. to give racemic (-) - 4-demethoxy-6-deoxydaunomycinone (I; R 1 = OH, R 2 = H) and racemic (-) - 4-demethoxy-11-deoxydaunomycinone (I, R 1 = H, R 2) = OH).

As already mentioned above, the invention also relates to a racemic aglycone, 4-demethoxy-6-deoxydaunomycinone, of the formula

° OH

This compound can be prepared by the method described above and is useful as a starting material for the preparation of therapeutically active anthracycline glycosides.

7 78452

The following examples are intended to illustrate the invention in more detail without limiting it.

EXAMPLE 1: Preparation of monomethyl 1,2,3,6-tetrahydrophthalate (2, R = CH 2)

A solution of 50 g (0.329 mol) of 1,2,3,6-tetrahydrophthalic anhydride (1) in a mixture of 200 ml of methylene chloride and 300 ml of methanol and 1 g of p-toluenesulfonic acid was refluxed for 4 hours. The solvent was then evaporated under reduced pressure, and the residue was dissolved in chloroform, washed with water and evaporated to dryness to give 56 g of the title compound (yield 73%), which was crystallized from petroleum ether (60 ° C); mp. 85 ° C, thin layer chromatography (TLC) on Merck F__ silica gel plates. (chloroform: acetone, 2: 1, calculated from d 54 by volume): Rf 0.28.

EXAMPLE 2: Preparation of monomethyl-4-acetyl-1,2,3,6-tetrahydrophthalate (3, R = CH)

O

A suspension of 85 g (0.64 mol) of anhydrous aluminum trichloride in 1.5 liters of anhydrous methylene dichloride was added dropwise under stirring under nitrogen to 75 ml (1 mol) of acetyl chloride at -5 ° C. 40 g (0.217 mol) of the compound prepared according to Example 1 in 750 ml of anhydrous methylene dichloride were then added over a period of two hours. The reaction mixture was kept at -5 ° C for 6 hours and then at room temperature overnight. After adding 1 kg of ice, the organic phase was separated, washed with water and evaporated to dryness. The residue was treated with 50 g of potassium carbonate dissolved in 500 ml of methanol at room temperature for 5 hours. After filtration, the solvent was evaporated, and the residue, dissolved in water, was washed with chloroform. The pH of the aqueous alkaline solution was adjusted to 3 and re-extracted with chloroform. The residue obtained after evaporation of the solvent was purified by chromatography on silica using a solvent combination of chloroform: acetone (95: 5, by volume). 28 g of the title compound β 78452 (57% of the total yield) were obtained, which compound was crystallized from diethyl ether-petroleum ether, m.p. 94-96 ° C.

TLC on silica gel plates Merck? 254 (chloroform: acetone, 2: 1 by volume): Rf 0.22. IR (Kbr): 1660 cm -1 C = O 0, for β-unsaturated ketone, 1690 cm -1 C = O acid, 1720 cm -1 C = O ester.

NMR (CDCl 3): δ) 2.33 (s, 3H, COCH 3), 2.55-2.95 (m, 4H, CH 2 -C * = CH-CH 2). 3.00-3.30 (m, 2H, CH 3 OCOCH, HCOCOCH), 3.70 (s, 3H, C 10 CH 3), 6.91 (m, 1H, CH =), 9.61 (s, 1H, C00H ).

EI-nS: m / e 226 (M < + >); m / e 208 (M + -H 2 O); m / e 195 (M + -OCH 3); m / e 180 (M + -H 2 / -CO); m / e 121 (M + -H 2 O-CO-COOCH 3).

EXAMPLE 3: Preparation of monomethyl 4-acetyl perhydrophthalate (4, R * CH 3)

A solution of 4.6 g of the compound prepared according to Example 2 in 120 ml of ethanol was hydrogenated at room temperature at a pressure of 1 bar in the presence of 0.6 g of 10% palladium-activated carbon as catalyst.

Evaporation of the solvent gave the title compound in quantitative yield.

IR spectrum (film): 1680 cm -1 CO for acid, 1710 cm 2 CO for ketone, 1730 cm 2 CO for ester.

NMR (CDCl 3): δ 1.5-2.6 (m, ΘΗ), 2.18 (s, 3H, COCH 3), 3.28 (m, 1H), 3.70 (s, 3H, OCH-g ), B, 53 (broad s, 1H, C00H).

EXAMPLE 4: 1,4-Dimethoxy-3- (2'-methoxycarbonyl-4'-acetyl-cyclohexylcarbonate) -naphthalene and 1,4-dimethoxy-3- (2'-methoxycarbonyl-5 '-acetyl-cyclohexylcarbonyl) -naphthalene (6, R = CH3)

A solution of 3.2 g (0.017 mol) of 1,4-dimethoxynaphthalene and 4.0 g (0.017 mol) of the compound prepared according to Example 3 in 50 ml of trifluoroacetic anhydride 9 78452 and 25 trifluoroacetic acid was refluxed for 24 hours. After the solvent was evaporated off under reduced pressure, the obtained residue was dissolved in chloroform and washed with saturated aqueous sodium bicarbonate solution and then with water. The residue obtained after evaporation of the solvent was purified on a silica gel column using chloroform as an eluent; 3.5 g of a mixture of the title isomeric compounds were obtained.

TLC "silica gel plates Merck (chloroform: acetone 98: 2, by volume): Rf 0.3.

FD-NS: M / e 398 (M +) IR (film): 1660 cm -1 with CD &, fb-unsaturated feton, 1710 cm -1 with CO ketone, 1720 cm -1 with CO ester.

NMR (COCl 3) = * 1.5-2.3 (m, 8H), 2.18 (s, 3H, COCH 3), 3.67 (s, 3H, COOCH 3). 3.65 (m, 1H), 4.00-4.02 (two s, 0¾). 7.01 (s, 1 H), 7.5-8.4 (m, 4 H).

EXAMPLE 5: 6,6a, 7,8,9,10,10a, 11-octahydro-5,12-dimethoxy-11-oxo-8-acetyl-naphthasene and 6,6a, 7,8,9,10,10a Preparation of 1,1-octa-hydro-5,12-dimethoxy-11-oxo-9-acetyl-naphthasene (7)

A solution of 0.45 g (1.1 mol) of a mixture of the isomeric compounds prepared according to Example 4 in 40 ml of ethanol and 0.2 ml of concentrated hydrochloric acid was hydrogenated at room temperature in the presence of 0.3 g of 5% strength. palladium on activated carbon. The catalyst was removed by filtration and the solution was evaporated to dryness under reduced pressure. The residue was dissolved in 10 ml of concentrated sulfuric acid.

After standing for 20 minutes, the reaction mixture was poured into cold water and then extracted with chloroform. The organic phase washed with saturated aqueous sodium bicarbonate solution and then with water was evaporated to dryness, and the residue was purified by silica gel column chromatography, eluting with chloroform; 0.2 g of a mixture of the title isomers was obtained.

TLC on silica gel Merck 2 254 (chloroform: acetone 98: 2, by volume): Rf 0.33 EI-MS: m / e 353 (M +), m / e 337 (M - CH-J, m / e 43 (CH ~ C0 +).

-1 ^ J

IR (KBr): 1680 cm-C = O-ir, unsaturated ketone, 1705 cm-C = O-ketone.

NMR (CDCl 3) δ 1.8-2, B (m, ΘΗ), 2.28 (s, 3H, COCH 3), 3.2-3.8 (m, 3H), 3.95 (s, 3H, OCH 2), 4.05 (s, 3H, OCH 2), 7.4-8.4 (m, 4H).

EXAMPLE 6: 5,7,8,9,10,12-hexahydro-5,12-dioxo-11-hydroxy-9-acetylnaphthalene (Θ) and 5,7, Θ, 9,10,12-hexahydro-5, Preparation of 12-dioxo-6-hydroxy-9-acetyl-naphthasene (9)

A solution of 0.05 g of a mixture of the isomeric compounds prepared according to Example 5 in 5 ml of concentrated sulfuric acid was heated at 80 ° C for one hour. The reaction mixture was poured into cold water and extracted with chloroform. The organic phase washed with saturated aqueous sodium bicarbonate solution and then with water was concentrated to a small volume under reduced pressure and chromatographed on a silica gel column, eluting with chloroform; a mixture (1: 1) of the title isomeric compounds was obtained.

TLC on silica gel plates Merck F254 (ΜΟΓΟ-ΡθΓίηϊ: acetone 98: 2, by volume): Rf 0.5.

EI-MS: m / e 320 (M < + >), 227 (M + -CH3CO), 259 (M + -CH3CO-H2O), 43 (CkOCO +).

:: J * IR (KBr): 1625 cm bound C = O-quinone, 1670 cm free -: - a _ λ C = O-quinone, 1710 cm C = O-ketone, 2940 cm bound OH.

NMR (CDCl 3): 1.8-2.3 δ (m. 3H), 2.30 (s, 3H, COCH 3, 2.6-3.1 (m, 4H), 7.4-8.4 (m, 5H), 11.71 and 11.75 (two 2, 1H, OH phenolic).

UV-Vis & CHCl 3): 250, 267, 414 nm.

EXAMPLE 7: Preparation of 4-demethoxy-6,7-dideoxydaunomycinone (10) and 4-demethoxy-7,11-dideoxydaunomycinone (11) 0.32 g of compounds (8) prepared according to Example 6 7845? t and (9) the mixture was dissolved in 3 ml of acetic anhydride and boiled for 1 hour in the presence of 0.19 g of p-toluenesulfonic acid, refluxing. The residue of the reaction mixture obtained by evaporation under reduced pressure was dissolved in 40 ml of methylene dichloride, and the solution was treated with 0.250 g of m-chloroperbenzoic acid. After 2 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium bicarbonate solution and then with water. The residue obtained by evaporating the solvent was dissolved in a mixture of acetone and ethanol, and the solution was treated with 30 ml of 1N sodium hydroxide a at room temperature for 1 hour. After the usual work-up, the crude product was chromatographed on silica gel using chloroform as eluent; the title compounds were obtained in pure form.

Compound (10) TLC on silica gel Merck 1254 (chloroform-acetone 90: 2, v / v): Rf 0.10, EI-MS: m / e 336 (M +), 310 (M - H 2 O), 293 (M - CH 3 CO) , 275 (M - CH 3 CO - H 2 O).

NMR - 00 MHz (CDCl 3): δ 1.95 (m, 2H, H-O), 2.30 (s, 3H, COCH 3), 3.01 (m, 4H, H-7, H-10) , 3.03 (s, 1H, OH-9). 7.64 (s, 1H, H-6), 7.70-8.3 (m, 4H, arom.), 13.03 (s, 1H, OH-11).

IR (KBr): 1620 cm-1 bound C * O-quinone, 1665 cm-1 free -1 C = O-quinone, 1705 cm-1 O-ketone.

UV-Vis (CHCl 3): 250, 267, 414 nm. j

Compound (11) TLC on silica gel plates Merck® 54 (chloroform: acetone 90: 2, by volume): Rf 0.15.

EI-MS: m / e 336 (M < + >). 1 H NMR - 00 MHz (CDCl 3): δ 2.0 (m. 2H, H-8), 2.30 (s, 3H. COCH 6), 2.75-3.20 (two d.> 17.4 Hz , 2H, H-10. 3.0 (M, 2H, H-7), 3.75 (s, 1H, OH-9), 7.51 (s, 1H, H-11). .4 (m, 4H, arom.), 12.99 (s, 1H, OH-6).

UV-Vis (CHCl 3): 250, 267, 414 nm.

IR (KBr): 1625 cm-1 bound C-O-quinone, 1665 cm-1 free C = O-quinone, 1705 cm-1 C = O-ketone.

J i 12 78452 EXAMPLE 8: Preparation of (±) -4-demethoxy-6-deoxydaunomycinone (I, R 2 = OH, R 2 = H)

A solution of 0.5 g of (-) - 4-dematoxy-5,7-dideoxydaunomycinone (10) prepared according to Example 7 in 50 ml of benzene was treated by refluxing with 1.2 ml of ethylene glycol for 4 hours when 0.045 g of p-toluenesulfonic acid was present to give 0.4 g of the corresponding 13-ketal derivative, which crystallized directly from the cooled reaction mixture. This compound was dissolved in 250 ml of carbon tetrachloride and treated with 2 ml of a solution containing 3.2 g of bromine in 32 ml of carbon tetrachloride at 45 ° C for 6 hours in the presence of 0.46 g of 2.2 ' azo-bis-isobutyronitrile. The cooled reaction mixture was extracted with aqueous sodium hydroxide solution, and the pH of the colored aqueous phase was adjusted to 6.5 and extracted with chloroform. From the small volume of evaporated organic extracts, 0.11 g of crystalline 4-demethoxy-6-deoxy-13-ketal daemon was obtained.

TLC on silica gel plates Merck F254 [cHC 13: (CH3) 2 CO 9: 1 v / v]: Rf 0.21. EI-MS: m / e 396 (M +).

NMR (CDCl 2): δ 1.47 (s, 3H, 14-CH 3) 1.53 (s, 1H, GH-9). 2.27 (ddd, 2H, Hh8, 3 = 14.5 Hz, 4.5 Hz, 6.0 Hz), 3.02 (dd, 2H, H-10.3 = 17.5 Hz), 3.90 ( d, 1H, OH-7, 3 = 10.5 Hz), 4.09 (s, 4H, OCH2CH2O), 4.90 (dd, 1H, HH7, 3 = 4.5, 6.0 Hz), 7 , 65, 6.26: (m, 4H, aromatic), 7.96 (s, 1H, H-6), 13.11 (s, 1H, OH-11).

IR (KBr): 1620 cm -1 bound C = O-quinone; 1670 cm 1 free C = O-quinone.

Finally, hydrolysis of the ketal group was performed by treatment with aqueous hydrogen chloride in acetone (300 ml of 0.25N solution) at room temperature for 3 hours.

Compound (I, R 1 = OH, R 2 = H): TLC on silica gel plates Merck using 1 solvent mixture chloroform: acetone (9: 1, by volume): Rf 0.24.

FO-MS: m / z 352 (M < + >).

13 7845 2 NMR-270 MHz (CDCl 3): δ 2.42 (s, 3H, COCH), 2.98 (d, 1H, H = 10, and ax J 17.9 Hz), 3.13 (d , 1H, H -10, J m 17.9 Hz), 4.07 (d, OH-7, gem e J-10 Hz), 4.46 (s, OH-9), 4.93 (m , H -7, J-10 Hz D 0 after addition CQ e Wu = 8 Hz), 7.99 (s, H-6), 13.07 (s, 0H-11).

B

EXAMPLE 9: Preparation of (+) - 4-demethoxy-11-deoxydaunomycinone (I, R 1 = H, R 2 = OH)

Compound (11) prepared as described in Example 7 was converted to the title compound (I, R- = H, R = OH) by the method described in Example 8: TLC on silica gel Merck F._., 1 c 2b4 solvent mixture chloroform: acetone (9: 1, calculated by volume):

Rf 0.34.

NMR-60 MHz (CDCl 3 / DMSO- d 2): δ 2.42 (s, CH 2 CO), 3.08 (d, H -10, 3 o 3 ax

Jgem 18 Hz) '3.28 (d * Heq' 10 'Jgem 18 Hz) * 5.32 (m' Heq_7WH = 1 ° Hz) f 6.62 (s, H-11), 13.24 (s. OH-6), 7.7-8.5 (m, 4 aromatic protons., I 1 f

Claims (4)

1. The process for preparing racemic aglycones whose general formula is 18 78452 - in which formally one of the groups R 1 and R 2 is hydrogen and then the other a hydrox group, characterized in that a 1,2,3,6-tetrahydrophthalic anhydride of formula (1) is reacted with an alcohol of the formula ROH, wherein R is a lower alkyl, a substituted lower alkyl or aryl, so that a monoester obtained in the formula (2) is COOH where R is the same as above, reacted with acetyl chloride at a Friedel-Crafts reaction, and then treated with a dilute alkali, after which a 2, β-O-saturated ketone of formula AA is obtained. 3. From which genon catalytic reduction, a 4-acetyl perhydrophthalate according to the formula el³COOH SO so genon is obtained to react with 1,4-dimethorethaphthalene in the presence of trifluoroacetic anhydride and trifluoroacetic acid to give a mixture of isone compounds of Forms 1 and 3 and OCH3 and which are later catalytically reduced during a benzyl carbonic reaction, and then treated with sulfuric acid at run temperature, a mixture of tetracyclic isons according to Formnel 20 7 8 4 5 2 CH 3 <7 > and 3 are obtained from which, by a subsequent sulfuric acid treatment at 80 ° C for one hour, a 1: 1 mixture of racemic anthracyclinones according to the forals OO OH (8) (9) is obtained, the mixture first being treated with boiling acetanhydride in the presence of p toluene sulfonic acid is then saturated with m-chloroperbentsoic acid at room temperature for two hours to give a diastereomeric fermentation of a racemic (±) -A-demethoxy-6,7-dideoxidaunomycinone of formula 1 x 2: and 3 o