FIELD OF THE INVENTION The present invention relates generally to chemical methods for the preparation of tetracyclic compounds useful in the synthesis of therapeutic compounds. More particularly, the present invention relates to a method for the preparation of compounds and derivatives thereof useful in the synthesis of anthracyclines and related compounds.

BACKGROUND OF THE INVENTION The natural anthracycline antibiotics daunomycin (1) and adriamycin (2) are widely employed as antineoplastic agents. However, their clinical use has been hampered by a number of undesirable side effects, in particular a dose-related and irreversible cardiotoxicity. This has stimulated considerable research to develop synthetic anthracycline analogs which are ideally less toxic, more potent and have a broader spectrum of antineoplastic activity. Idarubicin (3), the 4-demethoxy analog of daunomycin (1), is one such compound which is now in clinical use.

(1) Daunomycin Rl = OCH3, R2 = H (2) Adriamycin R'= OCH3, RZ = OH (3) Idarubicin R'= H, R = H.

A number of general approaches to the synthesis of idarubicin are known. These include a total synthesis via Diels-Alder A-ring formation and a total synthesis via Friedel-Crafts C-ring formation. A key intermediate in each of these total synthetic approaches is the tetracyclic compound demethoxydaunomycinone (4).

Conjugation of (4) with the sugar daunosamine, provides access to idarubicin (3).

However, whilst providing a total synthetic route to idarubicin these approaches have limited commercial applicability due to the large number of synthetic manipulations required to form the tetracyclic frame work of (4).

A more desirable route to (4), which eliminates the need for a synthetic construction of the tetracyclic framework, involves a semi-synthetic approach wherein the D-ring of daunomycinone (5), the aglycone of daunomycin, is demethoxylated.

Currently, this is achieved by demethylation of (5) to form (6) and subsequent formation of a sulfonate, eg., the triflate, followed by reduction thereof (References 1,19 and 20).

Notwithstanding that this approach overcomes the disadvantages associated with the total synthesis approaches, the nature of the reagents employed, such as trifluoromethane sulphonic anhydride, which is expensive, corrosive, moisture sensitive and a liquid at ambient temperature, may impose further cost and handling difficulties.

Accordingly, there exists a need for further procedures for deoxygenation of the D-ring of daunomycinone to provide access to demethoxydaunomycinone (4) or derivatives thereof.

SUMMARY OF THE INVENTION Throughout this specification and the claims which follow, unless the context requires otherwise, the word"comprise", and variations such as"comprises"and"comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The present invention relates to the use of a thione compound capable of undergoing nucleophilic attack by the tetracyclic (D-ring)-OH group, with elimination of a leaving group, to form a thiono ester derivative, and subsequent rearrangement and reduction thereof in the preparation of 4-deoxy-anthracyclines such as idarubicin, or intermediates useful therefor. Accordingly, the present invention provides a process for the preparation of a compound of Formula (I), or protected derivative thereof,

wherein R is H or optionally protected OH, comprising: a) rearranging a thiono ester compound of Formula (II), or a protected derivative thereof

wherein R is as defined above, and Y is a group selected from: (i) NR'R, wherein R'and R2 are independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl ; or R'and R2 together with nitrogen atom to which they are attached form a five- or six-membered optionally substituted N-containing heterocyclic group wherein one or more carbon atoms may be further optionally replaced by a heteroatom;

(ii) OR3, wherein R3 is selected from the group consisting of an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group; or (iii) R4, wherein R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl. to provide a thiol compound of Formula (III), or protected derivative thereof, wherein R and Y are as defined above; and b) hydrogenolysing the thiol group.

It will be recognised that deacylation of the thiol compound of Formula (III) will provide a compound of Formula (IIIa) wherein the resulting-SH group may also be hydrogenolysed to provide access to compounds of Formula (I) or protected derivatives thereof.

Accordingly, in another aspect, the present invention relates to a process for the preparation of a compound of Formula (I), as defined above, or protected derivative thereof, comprising hydrogenolysing the thiol group of a compound of Formula (IIIa), or optionally protected derivative thereof

wherein R is H or optionally protected OH.

In another aspect, the present invention provides a compound of Formula (II) as defined above, or wherein Rl and/or R2 is hydrogen, or protected derivatives thereof, which may be useful in the preparation of 4-demethoxy anthracyclines.

In yet a further aspect, the present invention provides a compound of Formula (III) as defined above, or protected derivative thereof, which may be useful in the preparation of 4-demethoxy anthracyclines.

In still another aspect, the present invention provides a compound of Formula (IIIa) as defined above, or protected derivative thereof, which may be useful in the preparation of 4-demethoxy anthracyclines.

DESCRIPTION OF THE PREFERRED EMBODIMENTS As used herein, the term"alkyl"denotes straight chain, branched, cyclic or fully saturated hydrocarbon residues, preferably containing from 1 to 10 carbon atoms. Preferred alkyl are Ci- C6 alkyl which include methyl, ethyl, n-propyl, isopropyl butyl (n-, sec-and iso-) pentyl and hexyl, and the cyclo forms thereof, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term"alkenyl"is taken to refer to a straight chain, branched or cyclic residue preferably containing from 2-10 carbon atoms wherein the residue contains at least one carbon-carbon

double bond. Examples include vinyl, allyl, butenyl, pentenyl, cyclopentenyl, hexenyl and cyclohexenyl.

The term"alkynyl"is taken to refer to a straight chain, branched or cyclic residue preferably containing from 2-10 carbon atoms wherein the residue contains at least one carbon-carbon triple bond. Examples include ethynyl, propynyl, butynyl, pentynyl and hexynyl.

As used herein,"heteroatom"refers to any atom other than a carbon atom which may be a member of a cyclic organic residue. Examples of suitable heteroatoms include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, arsenic, sellenium and telluruim. Particularly preferred heteroatoms are nitrogen, oxygen and sulfur.

The term"halo"or"halogen"refers to F, Cl, Br or I.

As used herein, the term"leaving group"refers to a chemical group which is displaced by a nucleophile. Suitable leaving groups will be known to those skilled in the art and include those with the ability to stabilize the negative charge which it carries such as the halogens; imidazolyl, sulfates; sulphonates, such as tosylate, brosylate, nosylate, mesylate, triflate, nonaflate, tresylate; protonated alcohols and ethers; pyridinium salts; iminium salts, such as derived from dicyclohexylcarbodiimide (DCC), and diazonium ions.

The term"aryl"denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl, chrysenyl. Particularly preferred aryl is phenyl.

The term"aralkyl"is taken to refer to an aryl group when linked by an alkylene group. An example of an aralkyl groups is (CH2) n-phenyl where n is an integer from 1 to 6. Particularly preferred aralkyl are where n is 1 (benzyl) or 2.

In this specification"optionally substituted"is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, hydroxylalkyl, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboxy, carboxyalkylester, carboxyarylester, mercapto, alkylthio, benzylthio, acylthio, cyano, nitro, sulfate and phosphate groups.

Particularly preferred substituents include: hydroxy, Cl 6alkyl (eg methyl, ethyl, propyl), Cl 6alkoxy (eg methoxy, ethoxy, propoxy), phenyl, benzyl, halo, amino, C, 6alkylamino (eg. methylamino, ethylamino), di-C, 6alkylamino (eg dimethylamino, diethylamino, dipropylamino), hydroxyalkyl (eg hydroxymethyl, hydroxyethyl), trifluoromethyl, tribromomethyl, trichloromethyl, C (O)-C, 6alkyl (eg. acetyl),-OC (O)-C, 6alkyl (eg acetoxy), oxo (where a CH2 group is replaced by C=O), carboxy (C02H), carboxy C, 6alkyl ester, phenoxy, benzyloxy, mercapto, Cl 6alkylthio, nitro and cyano.

The term"N-containing heterocyclic"denotes mono-or polycarbocyclic groups wherein at least one carbon atom is replaced by a nitrogen atom, and where optionally, one or more further carbon atoms are replaced by a heteroatom, preferably selected from nitrogen, sulphur and oxygen. Suitable heterocyclic groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl or piperazinyl; condensed saturated or unsaturated heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, purinyl;

unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as dioxazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiomorphinyl ; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl.

The term"acyl"preferably denotes a group of the formula C (O)-R where R is a substituent in which a carbon or sulfur atom is directly bonded to the carbonyl group, ie an aliphatic acyl group or acyl group containing an aromatic ring, which is referred to as aromatic acyl, or a heterocyclic ring, which is referred to as heterocyclic acyl. Preferred acyl are C (O) Cl 20alkyl, more preferably C (O) C, 6alkyl. Examples of suitable acyl include straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t- butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl ; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl ; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aromatic acyl (aroyl) such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e. g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e. g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]; aralkenoyl such as phenylalkenoyl (e. g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e. g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e. g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and napthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl ; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl ;

arylsulfonyl such as phenylsulfonyl and napthylsulfonyl ; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienylglyoxyloyl.

The skilled addressee will recognise that certain protections/deprotections of potentially reactive groups of Formulae (I)- (IV), other than at the 4-position, when carried out at particular steps of the inventive process may assist in performing any one step by, for example, enhancing reaction rate, directing specificity of the reaction, reducing or eliminating side reactions or improving the yield of the desired product. Thus, the present invention also relates to compounds and processes as described herein wherein reactive groups other than at the 4-positions, of Formulae (I)- (IV) may be protected by a suitable protecting group.

The term"protected derivative"or"optionally protected"is taken to mean a compound which can be obtained by synthetic manipulation of, or protection of, one or more oxy (carbonyl or hydroxy) reactive groups on the tetracyclic framework of the compounds of Formulae (I)- (IV) excluding the 4-OH group which is to be reacted with the thione compound. Suitable protective groups are known to the person skilled in the art and may be found, for example, in Protective Groups in Organic Synthesis by T. W. Greene & P. Wuts, 2nd Edition, 1991, John Wiley and Son, the contents of which are incorporated herein by reference. For example, the hydroxy groups on the A and B rings of Formulae (I)- (IV) may be protected as their alkyl ethers, such as methyl, ethyl, propyl and butyl ethers; silyl ethers; acyl ethers such as acetoxy and benzoyl; and their aralkyl ethers such as benzyl. The 1, 3,-dihydroxy substitution in the A (C7 and C9- OH) ring may also be conveniently protected as acetals or boronates or borate esters. Carbonyl groups (eg C13 carbonyl) may also be protected as acetals, for example by reaction with an alcohol eg., methanol or ethanol, including cyclic acetals derived by reacting the carbonyl group with alkylene glycols such as ethylene glycol and propylene glycol etc. The skilled person would also recognise how these protecting groups may be removed at the appropriate stage.

Suitable methods therefor are described in Greene & Wuts supra.

It will be recognised that the deoxygenation of the 4-position of the D-ring of the tetracyclic system in accordance with the present invention may be performed on tetracyclic compounds which are derived from natural sources, eg., daunomycinone obtained by removing the sugar group from naturally obtained daunomycin, or tetracyclic compounds where the tetracyclic framework has been installed by synthetic routes, eg., FriedelCrafts or Diels-Alder approaches.

Thus, where the tetracyclic framework is installed via a synthetic approach, one or more (ie, 1, 2 or 3) further substituents may be incorporated into the D-ring. Examples of such substituents may include alkyl (eg. methyl, ethyl, propyl), halo (eg chloro, bromo), hydroxy, alkoxy (eg, methoxy, ethoxy), acetoxy, amino, alkylamino, dialkylamino, carboxy (including esters such as alkyl esters, phenyl ester, benzyl ester and corresponding amides), and where appropriate, their protected derivatives. Suitable protecting groups for these substituents eg. amino, carboxy are also described in Greene & Wutz supra.

The thiono ester compound of Formula (In, or protected derivative thereof, may be obtained by reacting an optionally protected compound of Formula (IV) where R is H or optionally protected OH, with a suitable thione compound. Access to the compounds of Formula (IV) may be achieved by demethylation of daunomycinone. Any thione compound which can undergo nucleophilic attack by the 4-OH group may be suitable.

As used herein, the term thione compound refers to a compound containing the moiety C=S.

In one embodiment, the thione compound has the general Formula (i) :

where L is a leaving group, for example, a halo group such as chloro, bromo or iodo or imidazolyl, and Y is a group selected from: (i) NRlR2, wherein R'and Rz are independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl ; or R'and R 2 together with nitrogen atom to which they are attracted form a five-or six-membered optionally substituted heterocyclic group wherein a- CH2-group may be optionally further replaced by a heteroatom; (ii) OR3 wherein R is selected from the group consisting of an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group; (iii) R4, wherein R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl.

In a preferred form of NRIRz, R'and R2 are independently optionally substituted alkyl, for example, optionally substituted methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted phenyl or optionally substituted benzyl. Particularly preferred NRlR2 are NMe2, NEt2 ; NPr2, NBu2 and PhNMe. In another preferred form, R'and , together with the nitrogen atom to which they are attached form an optionally substituted 5-or 6-membered saturated or unsaturated (including aromatic) N-containing heterocyclic ring, wherein one carbon atom may optionally be replaced by a further heteroatom, for example, form an optionally substituted heterocyclyl group selected from:

wherein Z is selected from CH2, O, S, NH or NR (where R is alkyl, eg. methyl, or ethyl; or acyl, eg acetyl or benzoyl).

Optionally, where valency constraints allow, each heterocyclyl group may contain one or more double bonds to form an unsaturated or aromatic heterocyclic group. It will be recognised that where Z and the adjacent C atom form a double bond, Z will represent N or CH rather than NH, NR or CH2 respectively. It will also be recognised that the optional substitution may form a fused bicyclic group wherein the second cyclic group may be a 5 or 6-membered carbocyclic group, either saturated or non-saturated or aromatic or non-aromatic, or a 5 or 6-memebered heterocyclic group which may or may not be aromatic. Suitable heterocyclic groups for NRlR2 may include pyrrolyl, imidazolyl, pyrazolyl, indolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, morpholino, thiomorpholino, piperidyl, piperazinyl, pyrazolidinyl, pyrazolinyl, isoxazinyl, indazolyl, purinyl etc. Particularly preferred substituted or unsubstituted NRlR2 include morpholino, piperidinyl, N-methylpiperazinyl and pyrrolidinyl.

In another preferred form, Y is OR3 wherein R3 is selected from methyl, ethyl, n-propyl, i- propyl, butyl (n-, sec-or t-), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 2-phenylethyl, each of which may optionally be substituted by a substituent described herein.

In another preferred form, Y is R4 wherein R4 is selected from methyl, ethyl, n-propyl, i-propyl, butyl (n-, sec-or t-), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 2-phenylethyl, each of which may optionally be substituted by a substituent described herein.

The thione compounds may be prepared by a variety of methods which are well known to persons skilled in the field.

Thione compounds of Formula (i)- (i), i. e., L-C (S)-NR'R 2, may be prepared, for example, by chlorination of the corresponding thiuram disulphides or reaction of an amine or amine hydrochloride with thiophosgene (see, References 2-5) or with 1, 1'-thiocarbonyldiimidazole (see Reference 16).

Thione compounds of Formula (i)- (ii), i. e., L-C (S)-oR3 may be prepared for example, by reacting thiophosgene or 1, 1'-thiocarbonyldiimidazole with a suitable alcohol (see References 8,13,15,17 and 18).

Thione compounds of Formula (i)- (iii) i. e., L-C (S)-R4 may be prepared from the corresponding thionoacid (see Reference 6).

The tetracyclic thionoester compounds of Formula (II) may be prepared by reaction of ArOH, or an optionally protected derivative, with a suitable thione compound, by any suitable means.

As used herein, the group"Ar"is taken to refer to the Formula (I) radical, or protected derivative thereof, wherein the electron deficient position is the 4-position.

Thus, the salt of an optionally protected compound of Formula (IV) may be formed and reacted with (i) according to wherein B+ is a suitable counterion, eg., Na+, K+, Li+, ammonium salts etc.

In another method for providing compounds of Formula (II), the optionally protected compound of Formula (IV) can be treated with (i) in the presence of a base according to

Suitable examples of bases which may be used in this process include DMAP, pyridine, N- ethyldiisopropylamine, 1, 4-diazabicyclo [2,2,2] octane, triethylamine and other tertiary amines.

Another means of providing a compound of Formula (II) includes preforming a thioformate compound and treating it with an appropriate reagent according to where X is a halogen or any other leaving group, such as imidazole.

Means for carrying out processes for the formation of thiono ester compounds are known to those skilled in the art, for example, see References 7-10 for where Y is (i), References 11-14 where Y is (ii), and References 6 and 7 where Y is (iii).

Rearrangement of ArO-C (S)-Y (II) to form ArS-C (O)-Y (III) can be effected by heating the thiono ester compound, optionally in the presence of a suitable solvent, at an elevated temperature for a time long enough to effect the rearrangement. Suitably, the optionally protected compound ArO-C (S)-Y can be heated at a temperature of about 100°-200°C for about 15 min to about several days, or until no more rearrangement occurs. The skilled addressee will be able to determine suitable conditions by routine methods and will recognise that the duration of heating may depend upon the temperature employed. Suitable solvents are those which are inert and allow the appropriate temperatures to be attained and include N, N- dimethylaniline xylene, toluene, O-dichlorobenzene and diphenyl ether. Alternatively, Lewis acids may be employed to effect the rearrangement from the thionoester derivative ArO-C (S)-Y to thiol derivative ArS-C (O)-Y. Examples of suitable Lewis acids include BF3, BC13, A1C13, AlBr3, Me3B, FeCl3, FeBr3, Ph5Sb and SnCl4.

Hydrolysis (deacylation) of the-S-C (O)-Y group to provide the compound Ar-SH may be carried out by any suitable means known to the skilled person, such as acid or base mediated hydrolysis.

The hydrogenolysis step to effect the 4-position desulfurization is carried out in the presence of a reducing agent. The reducing agent is preferably such that under appropriate conditions it can substantially promote selective desulfurization at the 4-position and preferably does not to any great extent result in hydrogenolysis (for example, less than about 50%) of the optionally protected hydroxy group at the 7-position in the A ring. Optional protection of the 7-OH group, (for example by forming a cyclic group with the 9-OH group) may assist in promoting desulfurization. Reducing agents which may be suitable for the hydrogenolysis of the 4 position carbon-sulfur bond are those which may contain one or more transition metal (s), eg., palladium, nickel, cobalt, ruthenium, rhodium, molybdenum, tungsten, osmium, iridium, iron, copper, zinc etc,.

Particularly preferred reagents include nickel palladium-, cobalt-, iron-, molybdenum or tungsten-containing reagents. Exemplary reagents include Raney Nickel, Nickel boride, soluble nickel complexes and nickel-, palladium-, cobalt-, iron-, molybdenum-and tungsten-phosphine chelates.

Preferred phosphine chelating ligands include triphenylphosphine; bis (diphenylphosphino) methane; bis (diphenylphosphino) ethane; bis (dimethylphosphino) ethane; bis (diphenylphosphine) propane; bis (diphenylphosphino) butane; bis (diphenylphosphino) pentane; bis (diphenylphosphino) hexane; bis (diphenylphosphino) ethylene; bis (diphenylphosphino) hexane; bis (diphenylphosphino) benzene; bis (diphenylphosphino) acetylene; bis (diphenylphosphino) benzene; bis (diphenylphosphino) maleic acid diethyl ester; bis (diphenylphosphinoethyl)- phenylphosphine; bis (diphenylphosphino) ferrocence; etc.

Whilst it is possible to carry out the methods of the present invention on the unprotected forms of the compounds of Formulae (II)- (IV), preferably the reactions are carried out on protected derivatives thereof so as to reduce or eliminate reactivity of other reactive groups on the tetracyclic framework.

Thus, in one preferred form, the a-carbonyl group on the A-ring (C13 carbonyl) is protected before the 4-position hydroxy group is reacted with the appropriate thione compound. A suitable protecting group for protection of the a-carbonyl group of the A-ring is the dioxolanyl group, which can be formed by reacting the carbonyl group with ethylene glycol. Other suitable protecting groups are described hereinbefore and in Greene and Wuts supra.

In another preferred form, the 7,9-dihydroxy groups of the A-ring are protected before rearrangement of the ArO-C (S)-Y group is effected. A suitable protecting group therefor is a boronic ester such as a phenylboronic ester, which can be formed by reacting the hydroxy groups with phenyl boronic acid. Other suitable protecting groups are described in Greene and Wuts supra.

An example of a synthesis of (I) is illustrated in Scheme 1.

SCHEME 1

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

The invention will now be further described in the following Examples which are presented for the purpose of illustration only and are not to be construed as limiting the scope of the invention.

Example 1 Step 1 Daunomycinone A solution of daunomycin (3 g, 5.32 mmole) in 60 ml of 30% acetic acid was stirred at reflux for about 5 h under nitrogen. After the completion of the hydrolysis as shown on TLC, the mixture was cooled on ice. An orange solid was collected by filtration and washed with water and dried at 60°C under vacuum for 2 days, to provide daunomycinone (1.99 g). Yield >94 %.

Daunosamine (0.89 g) was recovered from the above filtrate for later use.

1HNMR (daunomycinone) 400 MHz (DMSO-d6): 6 = 1.88 (1H, dd), 2.12 (1H, d), 2. 28 (3H, s), 2.73 (1H, d), 2.89 (1H, d), 3.91 (3H, s), 4.94 (1H, bs), 5.25 (1H, d, exchangeable), 6.02 (1H, s, exchangeable), 7.52 (1H, d), 7.73 (1H, d), 7.78 (1H, t), 13.09 (1H, s, exchangeable), 13.81 (1H, s, exchangeable).

1HNMR (daunomycinone) 400 MHz (CDCI3) : 6 = 2.14 (1H, dd), 2.33 (1H, d), 2.40 (3H, s), 2.91 (1H, d), 3.16 (1H, dd), 3.70 (1H, d, exchangeable), 4.07 (3H, s), 4.53 (1H, s, exchangeable), 5. 30 (1H, d), 7. 37 (1H, d), 7.76 (1H, t), 8.01 (1H, d), 13.24 (1H, s, exchangeable), 13.95 (1H, s, exchangeable).

Step 2 4-Demethyldaunomycinone (ref. C. M. Wong, et al, Can. J. Chem. 49,2712,1971) Daunomycinone (1.43g, 5 mmole) was dissolved in 200 ml of dry dichloromethane and cooled on ice. Under nitrogen, 10 equivalents of anhydrous aluminum chloride were added portion wise to the stirred solution. After completion of the addition, the mixture was heated to reflux for 4 h. It was cooled to room temperature and slowly poured into 200 ml of ice water. The

mixture was acidified to pH 1-2 and the aqueous layer was allowed to stand at room temperature until the product fully precipitated. Yield 1.35 g (greater than 95 %) after filtration and drying.

1HNMR 400 MHz (DMSO-d6) : # = 1.93 (1H, d), 2.14 (1H, d), 2.28 (3H, s), 2.85 (1H, d), 2.97 (1H, d), 4.76 (1H, bs), 5.27 (1H, bs), 6.08 (1H, t), 7.34 (1H, d), 7.72 (1H, t), 7.77 (1H, d), 11.94 (1H, bs), 12.71 (1H, bs), 13.34 (1H, s).

Step 3 4-Demetllyl-l3-dioxolanyl-daunomycinone (ref. K. Tamota, et al, Tetrahedron, 40 (22) 4617, 1984).

To the suspension of 4-demethyldaunomycinone (740 mg, 1.93 mmole) in 30 ml of dry benzene were added 10 equivalents of distilled ethylene glycol and 0.2 equivalent of toluenesulfonic acid. The mixture was stirred at reflux under nitrogen and the reaction was monitored by TLC on Merck Kieselgel 60 F254 plates using CH2CL2 : MeOH=40 : 1 as solvent. After completion of the reaction and cooling, the solid was filtered, rinsed with methanol and dried at 60 °C under vacuum, yielding 716.3 mg (87%).

'HNMR 300 MHz (CDC13): 6 = 1.46 (3H, s), 1.96 (1H, dd), 2.45 (1H, d), 2.79 (1H, d), 3.02 (1H, s), 3.23 (1H, dd), 3.81 (1H, d), 4.07 (4H, s), 5.24 (1H, t), 7.29 (1H, d), 7.68 (1H, t), 7.86 (1H, d), 12.02 (1H, s), 12.95 (1H, s), 13.35 (1H, s).

Step 4 4-Demethyl-13-dioxlanyl-4-dimethylthiocarbamoyl-0-daunomycin one The suspension of 4-demethyl-13-dioxolanyl-daunomycinone (688 mg, 1.61 mmole) in 8 ml of DMF was stirred in an ice bath under nitrogen and 1, 4-diazabicyclo [2,2,2] octane (3.22 mmole) and p-dimethylaminopyridine (0.16 mmole) were added portion wise. After 0.5 h stirring, dimethylthiocarbamoyl chloride was added. The mixture was kept stirring at room temperature overnight and then cooled on ice. An orange solid was filtered and rinsed with methanol and water to give the O-thiocarbamate 700 mg after drying (>85 %).

'HNMR 400 MHz (CDC13) : 6 = 1.45 (3H, s), 1.97 (1H, dd), 2.44 (1H, d), 2.78 (1H, d), 3.02 (1H, s), 3. 23 (1H, dd), 3.48 (3H, s), 3.50 (3H, s), 3.76 (1H, d), 4.07 (4H, s), 5.24 (1H, bs), 7.43 (1H, d), 7.81 (1H, t), 8.32 (1H, d), 13.37 (1H, s), 13.76 (1H, s).

Step 5 4-Demethyl-13-dioxolanyl-4-dimethyltliiocarbamoyl-S-daunomyc inone and 4-Demethyl-13-dioxolanyl-7, 9-dehydroxyl-7, 8,9,10-deltydro-4-dimetlzylthiocarbamoyl-S- daunomycinone The solution of the O-thiocarbamate (90 mg), obtained as described as in step 4, in N, N- dimethylaniline (6ml) was heated in an oil bath at 150 °C-160 °C for 4 h under nitrogen. After cooling, the reaction mixture was diluted with dichloromethane and the solution was washed with 10% HCl, water and brine before drying over MgS04. The residue obtained after filtration and evaporation was solidified by trituration with cold ethyl acetate and filtered to give the S- thiocarbamate (50 mg). Yield ca. 56 %.

'HNMR 300 MHz (CDCl3) : # = 1.46 (3H, s), 1.97 (1H, dd), 2.45 (1H, d), 2.78 (1H, d), 3.06 (3H, bs), 3.10 (1H, s), 3.23 (1H, dd), 3.24 (3H, bs), 3.76 (1H, d), 4.07 (4H, s), 5.26 (1H, t), 7.73 (1H, t), 8.04 (1H, d), 8.40 (1H, d), 13.29 (1H, s), 13.46 (1H, s).

'HNMR 400 MHz (DMSO-d6, 367 K): 6 = 1.33 (3H, s), 1. 85 (1H, d), 2.22 (1H, d), 2.73 (1H, d), 3.07 (6H, s), 3.95 (4H, s), 5.11 (1H, s), 7.86 (1H, t), 8.05 (1H, d), 8. 33 (1H, d), 13.14 (1H, s), 13.18 (1H, s).

Concentration of the above filtrate and filtration of the resulted solid with hexane, afforded the 7,9-dehydrated S-thiocarbamate (29 mg) in 35 % yield.

'HNMR 300 MHz (CDC13) : 3 = 1.73 (3H, s), 3.07 (3H, bs), 3.24 (3H, bs), 3.79-4.85 (2H, m), 4.08-4.13 (2H, m), 7.74 (1H, t), 7.90 (1H, dd), 8.03 (1H, dd), 8.46 (1H, d), 8.53 (1H, d), 8.59 (1H, d), 13.88 (1H, s), 14.02 (1H, s).

Example 2 4-Demethyl-4-dimethyltlziocarbamoyl-O-daunomycinone The mixture of 4-demethyldaunomycinone (0.1 mmole), 1, 4-diazabicyclo [2,2,2] octane (0.2 mmole), dimethylthiocarbamoyl chloride (0.2 mmole) and DMF (0.5 ml) were stirred at room temperature overnight under nitrogen. The solid was removed by filtration and washed with methanol. The combined filtrate was poured into water and the resulted solid was collected by filtration The solid was re-dissolved in CH2C12, washed with 10% HCI, water and brine before drying over MgS04. Removal of the solvent after filtration gave a red solid. Yield 27 mg (ca.

60%).

'HNMR 400 MHz (CDC13) : 6 = 2.16 (1H, dd), 2.31 (1H, d), 2.40 (3H, s), 2.93 (1H, d), 3.17 (1H, d), 3.48 (3H, s), 3.50 (3H, s), 3.70 (1H, bs), 4.49 (1H, bs), 5.28 (1H, d), 7.44 (1H, d), 7.83 (1H, t), 8.32 (1H, d), 13.27 (1H, s), 13.71 (1H, s).

Example 3 Step 1 -Demethyl-13-dioxolanyl-4-dimethylthiocarbaoyl-O-daunomycino ne-7,9-diyl Benzeneboronate The O-thiocarbamate (1 mmole) prepared as described in step 4 of example 1 was mixed with phenylboronic acid (1 mmole) and toluenesulfonic acid (0.05 mmole) in dry benzene (15 ml) under nitrogen. The reaction was monitored by TLC on Merck Kiesegel 60 F254 plates using ethyl acetate: hexane (1 : 1) as the solvent. After completion of the reaction, the mixture was filtered and rinsed with benzene. The combined filtrate was evaporated to dryness. The solid was washed with hexane and filtered to supply the boronated O-thiocarbamate in 100% yield.

'HNMR 400 MHz (CDC13) : 6 =1. 57 (3H, s), 2.02 (1H, dd), 2.47 (1H, bd), 3.08 (1H, d), 3.35 (1H, d), 3.49 (3H, s), 3.51 (3H, s), 4.05-4.16 (4H, m), 5.76 (1H, d), 7.23-7.50 (5H, m), 7.70-7.81 (3H, m), 8.30 (1H, d), 13.26 (1H, s), 13.66 (1H, s).

Step 2 <BR> 4-Demethyl-13-dioxolanyl-4-dimetlzylthiocarbamoyl-S-daunomyc inone-7, 9-diyl<BR> Benzeneboronate The crude boronated O-thiocarbamate (220 mg) supplied as described in step 1 above, was heated and stirred in 3 ml of o-dichlorobenzene at 180 °C, under nitrogen. The temperature was maintained for about 30 min before cooled to room temperature. The mixture was passed through a small silica column to remove the solvent and the absorbed product was eluted with 10% methanol in dichloromethane. The solid obtained after evaporation was washed with hexane and collected by filtration to give the required boronated S-thiocarbamate containing a little of the de-boronated S-thiocarbamate. The yield of the crude product was greater than 95 %.

1HNMR 400 MHz (CDCl3) : 6 = 1.57 (3H, s), 2.03 (1H, dd), 2.48 (1H, bd), 3.06 (3H, bs), 3.09 (1H, d), 3.25 (3H, bs), 3. 36 (1H, d), 4.03-4.15 (4H, m), 5.78 (1H, t), 7.26 (2H, t), 7.34 (1H, t), 7.71 (1H, t), 7.75 (2H, d), 8.04 (1H, d), 8.37 (1H, d), 13.19 (1H, s), 13.36 (1H, s).

Example 4 4-Demethyl-13-dioxolanyl-4-dimethylthiocarbamoyl-S-daunomyci none-7, 9-diyl Benzeneboronate The reaction was carried out as described in step 2 of example 3 except that xylene (3 ml) was used as solvent. After refluxing for 2 h. under nitrogen, the reaction mixture was worked up as stated in example step 2 of example 2 to give the crude rearranged product in greater than 95 % yield.

Example 5 <BR> <BR> 4-Demethyl-13-dioxolanyl-4-dimethyltlziocarbamoyl-S-daunomyc inone-7, 9-diyl<BR> Benzeneboronatel The reaction was conducted as described in step 2 of example 3 except that 4 ml of toluene was used as solvent. After the reaction mixture was stirred at reflux for 3 days, it was worked up as described in step 2 of example 2, giving the desired product in about 94 % yield.

Example 6 4-Demethyl-13-dioxolanyl-daunomycinone-7, 9-diyl Benzeneboronate The crude boronated S-thiocarbamate (0.1 mmole) prepared in above examples 3 to 5 was dissolved in 1 ml of DMF. Triethylamine (0.4 mmole), formic acid (0.4 mmole), palladium acetate (0.001 mmole) and 1, 1=-bis (diphenylphosphino) ferronce (0.001 mmole) were added with stirring under nitrogen. After stirred at 40-44 °C for 2 days, the mixture was diluted with dichloromethane and washed with 10 % HCl and water. The organic phase was then washed with brine before drying over MgS04. After removal of the solvent, the residue was purified by TLC to give the title compound in ca. 20 % yield.

'HNMR 400 MHz (CDC13) : 6 = 1.57 (3H, s), 2.04 (1H, d), 2.49 (1H, d), 3.10 (1H, d), 3. 37 (1H, d), 4.07-4.14 (4H, m), 5.78 (1H, d), 7.26 (2H, t), 7.35 (1H, dd), 7.76 (2H, d), 7.78-7.81 (2H, m), 8.28-8.36 (2H, m), 13.19 (1H, s), 13.36 (1H, s).

Example 7 4-Demethyl-13-dioxolanyl-daunomycinone-7, 9-diyl Benzeneboronate The settled catalyst from 20 ml of Raney nickel was washed with water and ethanol. To the boiled suspension of catalyst in 20 ml of acetone was dropwise added a solution of the crude boronated S-thiocarbamate (0. 2 mmole) in 20 ml of acetone in 5 min. After stirred at reflux for about 1 h, the reaction was completed as indicated by TLC. The mixture was filtered after cooling and the catalyst was extracted with acidic ethanol. The combined filtrate was evaporated to dryness and the residue was re-dissolved in dichloromethane. The solution was washed with water and brine before drying over MgS04. Removal of the solvent after filtration gave the desulfurized product in about 70 % yield.

Example 8 4-Demetllyldaunomycinone (Idarubicinone) The desulfurized compound (0.1 mmole) prepared in example 6 or 7 was mixed with 0.2 ml of trifluoroacetic acid in an ice bath under nitrogen and stirred at room temperature for 1 h. To the mixture were added 10 equivalents of 2-methyl-pentane-2,4-diol and 0.5 ml of acetone or dichloromethane and the mixture was stirred at room temperature for 24 h. After completion of the reaction as shown on TLC and removal of solvent, water was added and the orange solid was filtered and washed with water to give the desired 4-demethyldaunomycinone in ca. %.

The crude product could be purified by chromatography.

IHNMR 400 MHz (CDC13) : 6 = 2.18 (1H, dd), 2.34 (1H, d), 2.41 (3H, s), 2.96 (1H, d) 3.20 (1H, dd), 3.75 (1H, bs), 4.50 (1H, s), 5.32 (1H, bs), 7.81-7.87 (2H, m), 8.30-8.37 (2H, m), 13.32 (1H, s), 13.60 (1H, s).

Example 9 4-Demetllyldaunomycinone (Idarubicinone) The desulfurized compound obtained in example 6 or 7 was mixed with 10 equivalents of 2- methylpentane-2,4-diol in acetone and stirred under nitrogen at about 45 °C for 2 days. The solvent was removed and triflouroacetic acid was added at 0 °C. After the mixture was stirred at room temperature for 30h, the mixture was worked up as described in example 8 to give the desired 4-demethyldaunomycinone.

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