IE53121B1 - Anthracyclinones - Google Patents
AnthracyclinonesInfo
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- IE53121B1 IE53121B1 IE1909/87A IE190987A IE53121B1 IE 53121 B1 IE53121 B1 IE 53121B1 IE 1909/87 A IE1909/87 A IE 1909/87A IE 190987 A IE190987 A IE 190987A IE 53121 B1 IE53121 B1 IE 53121B1
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- acetyl
- acid
- treatment
- demethoxy
- resultant
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
The invention relates to a process for the preparation of anthracyclinones of the general formula I
wherein one of R^ and Rj represents a hydrogen atom and the other of R^ and Rj represents a hydroxy group.
The invention provides a process for the preparation of anthracyclinones of the general formula I as above defined, the process comprising reacting 1,2,3,6-tetrahydrophthalic anhydride (1) with an alcohol of the general formula ROH, wherein R represents an alkyl, substituted alkyl or aryl group, subjecting the resultant 1,2,3,6-tetrahydrophthalic acid monoester (2) to a Friedel Crafts reaction with acetyl chloride followed by mild alkaline treatment, catalytically reducing the resultant 4-acetyl-l,2,3,6-tetrahydrophthalic acid monoester (3), condensing the resultant
4-acetyl-perhydrophthalic acid monoester (4) with 1,4-dimethoxy-naphthalene (5) in the presence of trifluoro
-2acetic anhydride and trifluoroacetic acid, catalytically reducing the benzylic carbonyl function in the resultant mixture of 2-(1',4'-dimethoxy-naphthalenyl-3'-carbonyl)-4-acetyl-cyclohexyl-l-carboxylic acid ester and 2-(l',4’-dimethoxy-naphthalenyl-3'-carbonyl)-5-acetyl-cyclohexyl-1-carboxylic acid ester (¢) and cyclising the products by treatment with sulphuric acid at ambient temperature, treating the resultant mixture of 6,6o<,7,8,9,10,10«, 11-octahydro-5,12-dimethoxy-ll-oxo-8-acetyl-naphthacene and 6,6oi,7,8,9,10,l 0o<, 1 l-octahydro-5,12-dimethoxy-l1 -oxo-9-aeetyl-naphthacene (7) with sulphuric acid at 80’C, converting the resultant mixture of 5,7,8,9,10,12-hexahydro-5,12-dioxo-ll-hydroxy-9-acetyl-naphthacene (8) and 5,7,8,9,10,12-hexahydro-5,12-dioxo-6-hydroxy-9-acetyl-naphthacene (9, to a diastereomeric mixture of 4-demethoxy-6,7-dideoxy-daunomycinone (10) and 4-demethoxy-7,ll-dideoxy-daunomycinone (11) by (a) treatment with boiling acetic anhydride in the presence of jj-toluenesulphonic acid, followed by treatment with m-chloroperbenzoic acid at ambient temperature or (b) treatment with oxygen and potassium t-butoxide in dimethylformamide at-20°C followed by treatment with phosphorus triethoxide in dimethylformamide at -20°C, chromatographically separating the diastereomers, separately treating each diastereomer with ethylene glycol in refluxing benzene in the presence of £-toluenesulphonic acid, treating the resultant 13-ketal
-3with bromine in carbon tetrachloride in the presence of 2,2’-azo-bis-isobutyronitrile, and hydrolysing the ketal group by treatment with hydrochloric acid in acetone to obtain, separately, (±)-4-demethoxy-6-deoxy5 -daunomycinone (I,R1=OH,R2=H) and (+)-4-demethoxy-ll-deoxy daunomycinone (I,R =H,R2=oH).
The compound 4-demethoxy-6-deoxy-daunomycinone is novel and is included within the scope of the invention.
The process is illustrated by the following reaction 10 scheme, to which the compound numbers in the last preceding paragraph refer.
KR^OH.R^H) I (R1=H,R2=OH)
-5The actual starting materials for the reaction sequences are 1,2,3,6-tetrahydrophthalic anhydride (1) and 1,4-dimethoxy-naphthalene (5). The Friedel-Crafts acetylation of the monoester (2) is a regiospecific process giving only the C-4 acetyl derivative. The procedures (a) and (b) followed for the oxidation of the ketones (8) and (9) to the corresponding hydroxyketones (10) and (11) are those employed with representative 20-ketosteroids. Procedure (1) is described by
J. Attenburrow et al. in J. Chem. Soc., 4547 (1961) and procedure (b, by J.N. Garden et al. in J. Org.
Chem., 33, 3294 (1968). The introduction of the 7-hydroxy group into compounds (10) and (11) is accomplished by benzylic bromination followed by solvolysis (C.M. Wong et al., Can. J. Chem. 51, 446, (1973)].
Optical resolution of the products may be carried out by the conventional method of conversion to diastereoisomeric derivatives using a chiral resolving agent (C.T. Eliel, Stereochemistry of Carbon compounds,
McGraw Hill, 1962, Chapter 4).
The anthracyclinones I are useful intermediates for the preparation of anthracycline glycosides having antitimour properties, for example as described in our
Irish Patent Application No. 1260/82 Specification No.
( ) from which
-6this Application is divided.
The following Examples, in which all temperatures are in degrees Centigrade, illustrate the invention.
Example I - Preparation of monomethyl 1,2,3,6-tetra5 hydrophthalate (2, R’CHg).
- (
A solution of 50 g (0.329 mol) of 1,2,3,6-tetrahydrophthalie anhydride (1) in a mixture of methylene dichloride (200 ml) and methanol (300 ml), containing 1 g of p-toluenesulphonic acid was refluxed for 4 hours.
The solvents were then evaporated off 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 63%), which was recrystallized from petroleum ether (60°); m.p. 85°;
TLC on kieselgel plates Merck Fj54 (chloroform:acetone, 2:1 by volume): Rf 0.28. Merck is a Trade Mark.
Example II - Preparation of monomethyl 4-acetyl-l,2,3,6tetrahydrophthalate (3, R=CHg)
To a suspension of anhydrous aluminium trichloride (85 g,
0.64 mol) in 1.5 litres of anhydrous methylene dichloride under stirring, in a nitrogen atmosphere 75 ml (1 mol) of acetyl chloride were added dropwise at -5°C. Consecutively 40 g (0.217 mol) of the compound prepared in Example I in 750 ml of anhydrous methylene
-710 dichloride were added over a period of 2 hours. The reaction mixture was kept at -5eC for 6 hours and then at room temperature overnight. After the addition of ice (1 kg), the organic phase was separated off, washed with water, and evaporated to dryness. The residue, dissolved in 500 ml of methanol, was treated with 50 g of potassium carbonate at room temperature for five hours. After filtration, the solvent was evaporated off and the residue, dissolved in water, was washed with chloroform. The aqueous alkaline solution was adjusted to pH 3 and extracted repeatedly with chloroform. The residue obtained by evaporation off of solvent was purified by chromatography on a column of silicic acid using the solvent system chloroform:acetone (95:5 by volume,.
g (57% overall yield) of the title compound was obtained and was xecrystallized from diethyl ether: petroleum ether, m.p. 94e-96°.
TLC on kieselgel plates Merck F254 Chloroform:acetone 2:1 by volume): Rf 0.22
IR (KBr): 1660 cm 1 C=0 of ιΐβ-unsaturated ketone
1690 cm-1 C=0 of acid 1720 cm 1 C=0 of ester
PMR (CDC13): 2.33 8 (s, 3H, COCg3)
2.55-2.95 (m, 4H, CHj-C·=CH-CH2)
3.00-3.30 (m, 2H, CH3OCOCH, HOCOCH)
3.70 (s, 3H, COOCg3)
6.91 (m, IH, CH=)
9.81 . (s, , 1H, COOH) m/e 226 (M?) m/e 208 (ΜΪ - h2o> m/e 195 (Mt - och3) m/e 180 (ΜΪ - h2o - CO) m/e 121 (ΜΪ - HjO - CO - COOCHj)
Example III - Preparation of monomethyl 4-acetyl-perhydrophthalate (4, R-CHj).
A solution of 4.6 g of the compound prepared in Example 10 II in 120 ml of ethanol was hydrogenated at room temperature and at 1 atm. in the presence of 0.6 g of 10% palladium-on-charcoal as catalyst. Evaporation off of the solvent afforded the title compound in quantitative yield.
IR spectrum (film): 1680 cm-1 CO of acid 1710 cm-1 CO of ketone 1730 cm-1 CO of ester PMR (CDC13): 1.5-2.6 6 (m, 8H) 2.18 (s, 3H, COCHj) 20 3.28 (m, IH) 3.70 (s, 3H, OCH3) 8.53 (bs. IH, COOH)
Example IV - Preparation of l,4-dimethoxy-3-(2'-methoxycarbonyl-4'-acetyl-cyclohexylcarbonyl)-naphthalene. and
1,4-dimethoxy-3-(2'-methoxyearbonyl)-51-acetyl-cyclo53121
-9hexylcarbonyl)-naphthalene (6, R=CH2)
A solution of 1,4-dimethoxynaphthalene (3.2 g, 0.017 mol) and of the compound prepared in Example III (4.0 g, 0.017 mol) in 50 ml of trifluoroacetic anhydride and
ml of trifluoroacetic acid was refluxed for 24 hours.
The residue, obtained by evaporating off the solvents under reduced pressure, was dissolved in chloroform and washed with an aqueous saturated solution of sodium bicarbonate and then with water. The residue, obtained by evaporation off of the solvent, was purified on a column of silica gel, using chloroform as eluting solvent, to give 3.5 g of a mixture of the isomeric title compounds. TLC on kieselgel plates Merck F254 (chloroform:acetone 98:2 by volume): Rf 0.3
FD-MS: m/e 398 (mT) IR (film): 1660 cm”l CO of W,p-unsaturated ketone 1710 cm 1 CO of ketone 1720 cm-1 CO of ester PMR (CDClj) is 1.5-2.3 6 (m, 8H) 20 2.18 (S, 3H, COCHj) 3.67 (s, 3H, COOCHj) 3.65 (m, IH) 4.00-4.02 (two s, OCH3) 7.01 (s, IH)
7.5-8.5 (m, 4H)
53.131
-10IR (KBr):
Example V - Preparation of 6,6&,7,8,9,10,10rt,ll-octahydro-5,12-dimethoxv-ll-oxo-8-acetyl-naphthacene and 6.6ct, 7,8,9,10.1 Oat, 1l-octahydro-5,12-dimethoxy-11 -oxo-9-aeety1-naphthacene (7)
A solution of the mixture of isomeric compounds prepared in Example IV (0.45 g, 1.1 mmol) 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% palladium-on-charcoal as catalyst. The catalyst was filtered off and the solution was evaporated to dryness under reduced pressure. The residue was dissolved in 10 ml of concentrated sulphuric acid. After standing for 20 minutes the t
reaction mixture was poured into cold water, and then extracted with chloroform. The organic phase, washed with an aqueous saturated solution of sodium bicarbonate and then with water, was evaporated to dryness and the residue was purified by chromatography on a column of silica gel, eluting with chloroform, to give 0.2 g of a mixture of the isomeric title compounds. TLC on kieselgel plates Merck P254 (chloroform:acetone 98:2 by volume): Rf 0.33
EI-MS: m/e 352 (mT) m/e 337(mT-CH3) m/e 43 (CH3CO+)
1680 cm-1 C=0 of a(,J}-unsaturated ketone 1705 cm-1 C»0 of ketone i
-11PMR (CDClg): 1.8-2.8 6 (m, 8H)
2.28 (s, 3Η, COCH3) 3.2-3.8 (m, 3Η)
3.95 (s, 3Η, OCH3) 4.05 (s, 3H, OCH3)
7.4-8.4 (m, 4H)
Example VI - Preparation of 5,7,8,9,10,12-hexahydro-5,12-dioxo-ll-hydroxy-9-acetyl-naphthaeene (8) and
,7,8,9,10,12-hexahydro-5,12-dioxo-6-hydroxy-9-acetvlnaphthacene (9)
A solution of 0.05 g of the mixture of isomeric compounds prepared in Example V in 5 ml of concentrated sulphuric 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 an ageuous saturated solution of sodium bicarbonate and then with water, was concentrated to small volume under reduced pressure and chromatographed on a column of silica gel, eluting with chloroform, to give a mixture (1:1) of the isomeric title compounds. TLC on silica gel plates Merck F254 (chloroform:acetone 98:2 by volume): Rf 0.5 EI-MS: m/e 320 (Mt)
IR (KBr):
1625 cm (Mt - CHjCO) (Mt - CHjCO - H2O) (ch3co+) 1 bonded C*0 quinone
277
259
1670 cm”1 freeOO quinone 1710 cm”1 C-0 ketone 2940 cm”1 bonded OH
PMR (CDC13): 1.8-2.3 S (m, 3H)
2.30 (s, 3H, COCH3)
2.6-3.1 (m, 4H)
7.4-8.4 (m, 5H)
11.71 and 11.75 (two s, IH, OH phenolic) UV-Vis (CHC13): 250, 267? 414 nm
Example VII — Preparation· of 4-demethoxy-6,7-dideoxydaunomycinone (10) and 4-demethoxy-7,ll-dideoxydaunomycinone (11) . «
A mixture (0.32 g ) of compounds 8 and 9 prepared as described in Example VI, was dissolved in 38 ml of acetic anhydride and refluxed for 18 hours in the presence of
0.19 g of p-toluenesulphonic acid. The residue, obtained by evaporation under reduced pressure of the reaction mixture, was dissolved in 40 ml of methylene dichloride and treated with 0.258 g of chloroperbenzoic acid.
After 2 hours at room temperature the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and then with water. The residue, obtained by evaporation off of the solvent, was dissolved in a mixture of acetone and ethanol and treated with 30ml of 1 N sodium hydroxide for 1 hour at room temperature. After conventional processing the crude product was
-13chromatographed on a column of silica gel, using chloroform as eluting agent, to afford the title compounds in pure form. Compound 10 TLC on kieselgel plates Merck £*254 (chloro£orm:acetone 98:2 by volume): Rf 0.18
EI-MS: m/e 336 (wt, 318 (MrHjO) 293 (MrCHjCO, 275 (MrCH3CO-H2O)
PMR-80 MHz (CDC13): 1.95 6 (m, 2H, H-8)
2.38 (s, 3H, COCH3)
3.01 (m, 4H, H-7, H-10)
3.83 (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~^ bonded C=0 quinone
1665 cm”l free C=0 quinone 1705 cm 1 C=0 ketone
UV-Vis (CHCl3): 250, 267, 414 nm
Compound 11 TLC on kieselgel plates Merck F254 (chloroform:acetone 98:2 by volume): Rf 0.15 EI-MS: m/e 336 (M+)
PMR-80 MHz (CDC13):2.0 8 (m, 2H, H-8)
2.38 (s, 3H, COCH )
2.75-3.28 (two d, J=17.4 Hz, 2H, H-10) 3.0 (m, 2H, H-7,
S 31 31
-14UV-Vis (CHClj): IR (KBr):
3.75 (s, IH, OH-9)
7.51 (s, IH, H-ll)
7.7-Θ.4 (m, 4H, arom)
12.99 (s, IH, OH-6)
250, 267, 414 nm 1625 cm-1 bonded OO quinone 1665 cm-1 free OO quinone 1705 cm*1 OO ketone
Example VIII - Preparation of (+)-4-demethoxy-6-deoxydaunomycinone (I: R^^OH, R2»H)
A solution of 0.5 g of (±)4-demethoxy-6,7-dideoxydaunomycinone 10, prepared as described in Example VII, in 50 ml of benzene was treated at refluxing temperature for 4 hours with 1.2 ml of ethylene glycol in presence of 0.045 g of jj-toluenesulphonic acid, affording the corresponding 13-ketal derivative (0.4 g) 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 of
3.2 g of bromine in 32 ml of carbon tetrachloride at 45° for 6 hours in the presence of 0.46 g of 2,2'-azo-bis-isobutyronitrile. The cooled reaction mixture was extrated with IN aqueous sodium hydroxide and the coloured aqueous phase was adjsuted to pH 8.5 and extracted with chloroform. The organic extracts, evaporated to a small volume, afforded 0.11 g
-1510 of crystalline 4-demethoxy-6-deoxy-13-ketal daunomycinone.
TLC on kieselgel plates Merck £354 (chloroform:acetone 9:1 by volume) Rf 0.21 EI-MS: m/e 396 (M+)
PMR (CDC13): 1.47 S (s, 3H, 14-CHj)
1.53 (s, IH, OH-9)
2.27 (ddd, 2H, H-8, J=14.5Hz, 4.5Hz, 6.0Hz) 3.02 (dd, 2H, H-10| J»17.5Hz)
3.90 (d, IH, OH-7, J»10.5Hz)
4.09 (s, 4H, OCH^CH^O
4.90 (dd, IH, H-7 J=4.5, 6.0Hz)
7.85, 8.26 (m, 4H, aromatic)
7.98 (s, 1H, H-6)
13.11 (s, lH, OH-11)
IR (KBr): 1620 cm”^ bonded C=0 quinone
1670 cm”l free C=0 quinone
Finally the hydrolysis of the ketal group was performed by treating with an aqueous solution of hydrogen chloride in acetone (300 ml of a 0.25 N solution) at room temperature for 3 hours.
TLC on kieselgel plates Merck ^54 (chloroform:acetone 9:1 by volume): Rf 0.24 FD-MS: m/e 352 (ΜΪ)
PMR 270 MHz (CDClj):2.42S(s, 3H, COCH-,)
2.98 (d, IH, Hax-10, Jgem17.9Hz)
3.13 (d, IH, H.-10, Jgem 17.9Hz) 4.07 (d, OH-7, J-lOHz) 4.46 (s, OH-9) 4.93 (m, Heg-7, J-lOHz after DjO addition Wh=8Hz) 7.99 (s, H-6) 13.07 (s, , OH-11)
Example IX - Preparation of (~)4-demethoxy-ll-deoxydaunomycinone (I: R^-H, R^-OH)
The compound 11, prepared as described in Example VII, was converted to the title compound following the procedure described in Example VIII.
TLC on silica gel plates Merck ^54 (chloroforni;acetone 9:1 by volume): Rf 0.34
MHZ (CDClj/DMSO-dg)s 2.428(s, ch3coj 3.08 Id,Hax”10* J 18Hz) gem ' 3.28 (d,Heq10' Joem 18Hz) gem • 5.32 (m, H -7 W -10HZ) eo η 6.62 (s, H-ll)
13.24 (s, OH-6)
7.7-8.5 (m, 4 aromatic protons)
Claims (4)
1. A process for the preparation of anthracyclinones of the general formula I as herein defined, the process comprising reacting 1,
2. ,3,6-tetrahydrophthalic anhydride with an alcohol of the general formula ROH, wherein R represents an alkyl, substituted alkyl or aryl group, subjecting the resultant 1,2,3,6-tetrahydrophthalic acid monoester to a Friedel-Crafts reaction with acetyl chloride followed by mild alkaline treatment, catalytically reducing the resultant 4-acetyl-l,2,3,6-tetrahydrophthalic acid monoester, condensing the resultant 4-acetyl-perhydrophthalic acid monoester with
3.
4. -Demethoxy-6-deoxydaunomycinone.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8116264 | 1981-05-28 | ||
| GB8125949 | 1981-08-22 | ||
| IE1260/82A IE53120B1 (en) | 1981-05-28 | 1982-05-26 | Anthracyclines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE871909L IE871909L (en) | 1982-11-28 |
| IE53121B1 true IE53121B1 (en) | 1988-07-06 |
Family
ID=27261194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1909/87A IE53121B1 (en) | 1981-05-28 | 1982-05-26 | Anthracyclinones |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IE53121B1 (en) |
-
1982
- 1982-05-26 IE IE1909/87A patent/IE53121B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE871909L (en) | 1982-11-28 |
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