Process for preparing anthracyclinones

Details Process for preparing anthracyclinones Process for preparing anthracyclinones

1991-08-26

1993-01-19

Cintins, Marianne M.

Organic compounds -- part of the class 532-570 series

Organic compounds

Tetracyclo naphthacene configured ring system having at...

552206, C07C 5022

Patent

active

051807580

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for preparing anthracyclinones of the general formula (I): ##STR4## wherein R represents a hydrogen atom or a COOR.sub.1 group in which R.sub.1 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(s) 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-4-sulfonyl-7-deoxy-13-dioxolanyl daunomycinone of formula (V): ##STR5## 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): same or different, each represent an anion or a neutral molecule and n and m may vary from 0 to 4, such as to obtain a compound of formula (VII): ##STR6## wherein R represents hydrogen; or
(b) carbonylating a 4-demethyl-4-sulfonyl-7-deoxy-13-dioxolanyl daunomycinone of formula (V) as defined above, with carbon monoxide in the presence of a nucleophile R.sub.1 OH wherein R.sub.1 is as defined above, an organic or inorganic base and as catalyst a compound of formula (VIII) as defined above, such as to obtain a compound of formula (VII) as shown above wherein R represents a COOR.sub.1 group; and
(ii) introducing an .alpha.-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 as C.sub.1 -C.sub.10 alkyl is typically C.sub.1 -C.sub.4 alkyl, for example methyl. An aryl group is preferably phenyl. An alkoxy group is typically C.sub.1 -C.sub.4 alkoxy. An ester group is, for example, (C.sub.1 -C.sub.4 alkoxy)carbonyl. The amido group is 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 U.S. Pat. No. 4,046,878: ##STR7##
More conveniently (II) can be obtained by C4--OCH.sub.3 demethylation of the naturally occurring daunomycinone (III) followed by hydrogenolysis of the 7.alpha.-hydroxyl group ##STR8##
Compound (II) is then protected at the C13 keto group by reaction with ethylene glycol to give (IV) ##STR9## and selectively sulfonated in position C4--OH (V): ##STR10##
The sulfonating agent is a sulfonyl compound of formula (VI): NH(C.sub.6 H.sub.5)(R'SO.sub.2) 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 ##STR11## transformed into (VII) by treatment in an appropriate solvent with a compound of formula (VIII) (hereunder referred to as catalyst): may be an anion as Cl.sup.- or CH.sub.3 COO.sup.- or a neutral molecule as a solvent molecule, a mono or a di-phosphine, a phosphite or a diamine; n and m 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-deoxy-13-dioxolanyl daunomycinone ((VII), R=H) is obtained by treating (V), under an inert atmosphere, with the catalyst, either preformed or gene

REFERENCES:
patent: 5103029 (1992-04-01), Cabri et al.
J. Chem. Soc., Chem. Commun., 1987, R. E. Dolle et al.: "Palladium catalysed alkoxycarbonylation of phenols to benzoate ester", pp. 904-905.
Tetrahedron Letters, vol. 27, No. 45, 1986, Pergamon Journals Ltd, (GB), S. Cacchi et al.: "Palladium-catalyzed triethylammonium formate reduction of aryl triflates. A selective method for the deoxygenation of phenols", pp. 5541-5544.

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