CA1239638A - 6-deoxyanthracyclines - Google Patents
6-deoxyanthracyclinesInfo
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- CA1239638A CA1239638A CA000520911A CA520911A CA1239638A CA 1239638 A CA1239638 A CA 1239638A CA 000520911 A CA000520911 A CA 000520911A CA 520911 A CA520911 A CA 520911A CA 1239638 A CA1239638 A CA 1239638A
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Abstract
- Abstract of the Disclosure -A new process for the preparation of 6-deoxyanthracyclinones of general formula I:
I
wherein R represents a hydrogen atom, a hydroxy group or a lower alkoxy group is described. The process provides a total synthesis of the 6-deoxyanthracyclinores of formula I using a 1,2,3,6-tetrahydro-phthalate as starting material;
The obtained racemic mixture of the compounds of formula I, if desired, can be submitted to optical resolution by the conventional method of conversion to diastereomeric deri-vatives using a chiral resolving agent. Alternatively, the racemic mixture can be used as such for the condensation with a suitably protected halosugar derivative to obtain alpha glycosidic derivatives of formula XV:
XV
wherein R1 represents a hydrogen atom or a hydroxy group, one of R2 and R3 represents a hydrogen atom, the other of R2 and R3 represents a hydrogen atom or a hydroxy group and X is a hydrogen atom or a trifluoro acetyl group. The N-trifluoroacetyl 75:9S and 7R:9R deri vatives of the ?-glycosides of formula XV can be separa ted by chromatography on silica gel to obtain, after mild alkaline hydrolisis the wanted 75:9S ? -glycosides (R1=H) as free bases and can eventually be transformed into their corresponding doxorubicin derivatives (R1=OH) by known procedures. These .alpha.-glycoside deriva-tives have anti-tumour properties.
I
wherein R represents a hydrogen atom, a hydroxy group or a lower alkoxy group is described. The process provides a total synthesis of the 6-deoxyanthracyclinores of formula I using a 1,2,3,6-tetrahydro-phthalate as starting material;
The obtained racemic mixture of the compounds of formula I, if desired, can be submitted to optical resolution by the conventional method of conversion to diastereomeric deri-vatives using a chiral resolving agent. Alternatively, the racemic mixture can be used as such for the condensation with a suitably protected halosugar derivative to obtain alpha glycosidic derivatives of formula XV:
XV
wherein R1 represents a hydrogen atom or a hydroxy group, one of R2 and R3 represents a hydrogen atom, the other of R2 and R3 represents a hydrogen atom or a hydroxy group and X is a hydrogen atom or a trifluoro acetyl group. The N-trifluoroacetyl 75:9S and 7R:9R deri vatives of the ?-glycosides of formula XV can be separa ted by chromatography on silica gel to obtain, after mild alkaline hydrolisis the wanted 75:9S ? -glycosides (R1=H) as free bases and can eventually be transformed into their corresponding doxorubicin derivatives (R1=OH) by known procedures. These .alpha.-glycoside deriva-tives have anti-tumour properties.
Description
lZ39~3~
TITLE
6-Deoxyanthracyclines DESCRIPTION
The invention re~ates to a process for the preparation of 6-deoxy-anthracyclinones, to certain of the 6-deoxy-anthracyclinones, to certain anthracycline glycosides prepared from them, to those anthracyclic glycosides in pharmaceutical compositions and to the preparation of those anthracycline glycosides.
This applica-ion is a divisional of Canadian Patent Application 157,258 filed June 22, 19~4.
The invention provides a process for the preparation of 6-deoxyanthracyclinones having the general formula I:
O 0~ 0 ~ Cll R ' }~
wherein R represents a hydrogen atom, a hydroxy group or a lower alkoxy group. The process, which is illu-strated in the following reaction scheme, comprises , ~L~39~;3~3 - la -(i) acetylating dimethyl 1,2,3,6-tetrahydro-phthalate (II) by treatment with acetic anthydride in the presence of tin tetrach-loride, followed by treatment with a mild base or a mild acid, (ii) reacting the resultant dimethyl 1,2,3,6-tetrahydro-4-acetyl-phthalate (III) with tosylhydrazine, 1~39~38 ~iii)reducing the resultant dimethyl 1,2,3,6-tetra-hydr~4- (1-tosylhydrazono-ethYl) phthalate (IV?
with catechol borane and subsequently re-arranging the double bond from an enaocyclic to an exocyclic po~ition in the presence ~f sodium acetate, (iv)oxidizing the resultant 1,2-di-(methoxycarbonyl1--4-ethylidene-cyclohex~ne ~V) with potassium permanganate and treatin~ the resultant ~-hydroxy--ket~ne with ethylene glycol ~n the presence 10 a catalytic amount of ~-toluenesulphonic acid (~v) condensing the resultant 2-methoxycarbonyl-5- ~ --methyl-dioxolan-2-yl7-6-oxa-bicyclo/3,2,170ctan-~7-one (~I~ with ~ compound of the general formula ~III wherein R is as a~ove defined (obtained by the acti~n of an alkyllithium on a . co~p~und of the general formula VII wherein R is I as above defined), ¦ ~vi) opening the lactone ring and deprotectino the dioxolan protected keto gr~up in the resultant compound ~f the general formula IX wherein R is as above defined by methanolysis.
(vii) reducing the keto groups of the resultant compound the general formula X wherein ~ is as above defined by treatment with a pyridine-borane complex in the presence of trifluoroacetic acid and c~nVerting the methoxvcarbonyl group to a benzylo~ycarb~nyl group by treatment with phenyl-di~zo~ethane, (viii) e5terifying ~he hydrvxy groups and deestexifying the benzyloxycarbonyl group in the resultant compound of the general formula XI wherein R ls- ss aboye defined by treatment with acetic anhydride in pyridine in the presence ~f 4-dimethylamino--pyridine followed by refluxing with cyclohexene in the presence of a pallad~um-on-carbon catalyst, lix) cyclizing the result~nt c~D~una of the general -fo~ul~ XII ~herein R~ repres~nts a hydrogen atom, an Rcetoxy group or a lower alkoxy group by trea~ment with a mixture of ~rifluoroacetic anhydride and trifluQroacetic acid, and hydrolyzing the ~cetoxy groups with soaium methylate, (x~ oxidizing the l-hydroxyethyl group of the resultant compound of the general formula XIII wherein R is as above definea with silver car~onate, and oxida~ively demethylating the resultant c~mDound with aluminium trichloride in nitrobenzene, and (xi)protecting the 13-keto group of the resultant compound of the general formula XIV by treatment ~ith ethylene glycol, brominating the resultant comp~una at C-7 by txeatment in the presence of
TITLE
6-Deoxyanthracyclines DESCRIPTION
The invention re~ates to a process for the preparation of 6-deoxy-anthracyclinones, to certain of the 6-deoxy-anthracyclinones, to certain anthracycline glycosides prepared from them, to those anthracyclic glycosides in pharmaceutical compositions and to the preparation of those anthracycline glycosides.
This applica-ion is a divisional of Canadian Patent Application 157,258 filed June 22, 19~4.
The invention provides a process for the preparation of 6-deoxyanthracyclinones having the general formula I:
O 0~ 0 ~ Cll R ' }~
wherein R represents a hydrogen atom, a hydroxy group or a lower alkoxy group. The process, which is illu-strated in the following reaction scheme, comprises , ~L~39~;3~3 - la -(i) acetylating dimethyl 1,2,3,6-tetrahydro-phthalate (II) by treatment with acetic anthydride in the presence of tin tetrach-loride, followed by treatment with a mild base or a mild acid, (ii) reacting the resultant dimethyl 1,2,3,6-tetrahydro-4-acetyl-phthalate (III) with tosylhydrazine, 1~39~38 ~iii)reducing the resultant dimethyl 1,2,3,6-tetra-hydr~4- (1-tosylhydrazono-ethYl) phthalate (IV?
with catechol borane and subsequently re-arranging the double bond from an enaocyclic to an exocyclic po~ition in the presence ~f sodium acetate, (iv)oxidizing the resultant 1,2-di-(methoxycarbonyl1--4-ethylidene-cyclohex~ne ~V) with potassium permanganate and treatin~ the resultant ~-hydroxy--ket~ne with ethylene glycol ~n the presence 10 a catalytic amount of ~-toluenesulphonic acid (~v) condensing the resultant 2-methoxycarbonyl-5- ~ --methyl-dioxolan-2-yl7-6-oxa-bicyclo/3,2,170ctan-~7-one (~I~ with ~ compound of the general formula ~III wherein R is as a~ove defined (obtained by the acti~n of an alkyllithium on a . co~p~und of the general formula VII wherein R is I as above defined), ¦ ~vi) opening the lactone ring and deprotectino the dioxolan protected keto gr~up in the resultant compound ~f the general formula IX wherein R is as above defined by methanolysis.
(vii) reducing the keto groups of the resultant compound the general formula X wherein ~ is as above defined by treatment with a pyridine-borane complex in the presence of trifluoroacetic acid and c~nVerting the methoxvcarbonyl group to a benzylo~ycarb~nyl group by treatment with phenyl-di~zo~ethane, (viii) e5terifying ~he hydrvxy groups and deestexifying the benzyloxycarbonyl group in the resultant compound of the general formula XI wherein R ls- ss aboye defined by treatment with acetic anhydride in pyridine in the presence ~f 4-dimethylamino--pyridine followed by refluxing with cyclohexene in the presence of a pallad~um-on-carbon catalyst, lix) cyclizing the result~nt c~D~una of the general -fo~ul~ XII ~herein R~ repres~nts a hydrogen atom, an Rcetoxy group or a lower alkoxy group by trea~ment with a mixture of ~rifluoroacetic anhydride and trifluQroacetic acid, and hydrolyzing the ~cetoxy groups with soaium methylate, (x~ oxidizing the l-hydroxyethyl group of the resultant compound of the general formula XIII wherein R is as above definea with silver car~onate, and oxida~ively demethylating the resultant c~mDound with aluminium trichloride in nitrobenzene, and (xi)protecting the 13-keto group of the resultant compound of the general formula XIV by treatment ~ith ethylene glycol, brominating the resultant comp~una at C-7 by txeatment in the presence of
2,2'-~zo-bis(isobutyron~trile~ w~th bromine or N-bro~osuccinimide, and hydr~lysing the 7-bromo and 13-ketal groups.
~ .
. lZ~39~j3~ ' NNHTs ~3COOC~ H3COO~ J~C~l 3 ~X~\CH3 Il III IV
. ~/
O l l H3COO ~ O~ O
H3cOOCx~7~ CH30~ H3 V VI
X~Br ~ L
R OCH3 ~ R OCH3 ~VI ) VII ~c/ VIII
IX
;..; ~j ~5- 1Z~ ;3~
OCH OCH `
J¢ J I `: CH3 X
: . OCH3 ()CH2C6H5 I H
~X ~ ~ CH3 Xl )CH 3 o OCOCEl 3 ) ~ C i33 R ' OCH3 OCH O OH
~ J ~f CH3 >11~
R CH~
O t)~3 0 P' ' 1 123~38 - 5a -The above reaction scheme is principally useful for the preparation of 6-deoxyanthracyclinones having the general formula I wherein R represents a hydrogen atom or a hydroxy group, in which R represents a hydrogen atom, a hydroxy group or a lower aIkoxy group (pre-ferably a methoxy group) in compounds of formulas VII
to XIII in steps (i) to (xi) of the reaction scheme ¦ and in which R represents a hydrogen atom or a hydroxy group in the compound of the formula XVI resultant from step (x) of the reaction scheme. This is to be appreclated by reason o the demethylating of step ( x ) .
In a first aspect, the present invention provldes a ! process for the preparation of 6-deoxyanthracycli- .
nones having the general formula I:
O OH o 1~39~8 - 5b -wherein R" represents a hydrogen atom or a hydroxy group characterized in that a dimethyl 1,2,3,6-tetrahydro-phthalate of i-ormula II:
H3COOC ~ II
by treatment with acetic anhydride in the presence of tin tetrachloride, followed by treatment with a milcl base or a milcl acid, is transformed into dimethyl 1,2,3, 6-tetrahydro-~l-acetyl-phthalate III:
C~
~.3COO~cl,,3 ¦ . III
~3cooc /
lZ~ 3~ -- 5c -which, when reacted with tosylhydrazine gives the corre-sponding dimethyl 1,2,3,6-te-trahydro-4-(1-tosylhydraæono-ethyl~-phthalate IV:
s .3COOC ~ C~ IV
~3CO~C
reducing the compound IV with catechol borane and sub-sequent rearranging the dcuble bond from an endocyclic l:o an exocyclic position in the presence o~ sodium ace-l:ate, to obtain 1,2-di-(methoxycarbonyl)-4-ethylldene-cyclohe~ne V:
H3C00 ~ ~3 V
H 3COt)~:~
trom which, after an oxidative treatment with potassium permanganate, the corresponding ~-hydroxy ketone is obtained and subsequently reacted with ethylene glycol~
in the presence of catalit.ic amount of p-toluensulphonic acid, to give 2-methoxy-5-~ 2-methyl-dioxolan-2-yl/-5-oxa-bicycla/ 3j2,1/octan-7-one VI:
~ 0 ~
. ~ ~ VI
CH30 ~
1~3g~;~8 - 5d -which, dissolved in anhydrous tetrahydrofuran is con-densed, at a temperature of -78C and for 1 hour, ~ith an alkyltium derivative of formula VIII:
VIII
0 R ~C`113 wherein R represents a hydrogen atom, a hydroxy group or a louer alkoxy group, to obtain the lactone IX:
. o ~1 ~ ~ ~ ,3 IX
~. OC~13 C>
wherein R is as above defined, opening the lactone ring of compound IX by methanolysis and contemporaneously deprotecting the dioxolan protected keto group by acidic treatment to obtain the compound of formula X:
OCH OCH`
Z ~ ~ CH3
~ .
. lZ~39~j3~ ' NNHTs ~3COOC~ H3COO~ J~C~l 3 ~X~\CH3 Il III IV
. ~/
O l l H3COO ~ O~ O
H3cOOCx~7~ CH30~ H3 V VI
X~Br ~ L
R OCH3 ~ R OCH3 ~VI ) VII ~c/ VIII
IX
;..; ~j ~5- 1Z~ ;3~
OCH OCH `
J¢ J I `: CH3 X
: . OCH3 ()CH2C6H5 I H
~X ~ ~ CH3 Xl )CH 3 o OCOCEl 3 ) ~ C i33 R ' OCH3 OCH O OH
~ J ~f CH3 >11~
R CH~
O t)~3 0 P' ' 1 123~38 - 5a -The above reaction scheme is principally useful for the preparation of 6-deoxyanthracyclinones having the general formula I wherein R represents a hydrogen atom or a hydroxy group, in which R represents a hydrogen atom, a hydroxy group or a lower aIkoxy group (pre-ferably a methoxy group) in compounds of formulas VII
to XIII in steps (i) to (xi) of the reaction scheme ¦ and in which R represents a hydrogen atom or a hydroxy group in the compound of the formula XVI resultant from step (x) of the reaction scheme. This is to be appreclated by reason o the demethylating of step ( x ) .
In a first aspect, the present invention provldes a ! process for the preparation of 6-deoxyanthracycli- .
nones having the general formula I:
O OH o 1~39~8 - 5b -wherein R" represents a hydrogen atom or a hydroxy group characterized in that a dimethyl 1,2,3,6-tetrahydro-phthalate of i-ormula II:
H3COOC ~ II
by treatment with acetic anhydride in the presence of tin tetrachloride, followed by treatment with a milcl base or a milcl acid, is transformed into dimethyl 1,2,3, 6-tetrahydro-~l-acetyl-phthalate III:
C~
~.3COO~cl,,3 ¦ . III
~3cooc /
lZ~ 3~ -- 5c -which, when reacted with tosylhydrazine gives the corre-sponding dimethyl 1,2,3,6-te-trahydro-4-(1-tosylhydraæono-ethyl~-phthalate IV:
s .3COOC ~ C~ IV
~3CO~C
reducing the compound IV with catechol borane and sub-sequent rearranging the dcuble bond from an endocyclic l:o an exocyclic position in the presence o~ sodium ace-l:ate, to obtain 1,2-di-(methoxycarbonyl)-4-ethylldene-cyclohe~ne V:
H3C00 ~ ~3 V
H 3COt)~:~
trom which, after an oxidative treatment with potassium permanganate, the corresponding ~-hydroxy ketone is obtained and subsequently reacted with ethylene glycol~
in the presence of catalit.ic amount of p-toluensulphonic acid, to give 2-methoxy-5-~ 2-methyl-dioxolan-2-yl/-5-oxa-bicycla/ 3j2,1/octan-7-one VI:
~ 0 ~
. ~ ~ VI
CH30 ~
1~3g~;~8 - 5d -which, dissolved in anhydrous tetrahydrofuran is con-densed, at a temperature of -78C and for 1 hour, ~ith an alkyltium derivative of formula VIII:
VIII
0 R ~C`113 wherein R represents a hydrogen atom, a hydroxy group or a louer alkoxy group, to obtain the lactone IX:
. o ~1 ~ ~ ~ ,3 IX
~. OC~13 C>
wherein R is as above defined, opening the lactone ring of compound IX by methanolysis and contemporaneously deprotecting the dioxolan protected keto group by acidic treatment to obtain the compound of formula X:
OCH OCH`
Z ~ ~ CH3
3~3 - 5e -wherein R is as above defined, reducing the keto group of compound X by treatment with a pyridine-borane com-plex in ~he presence of trifluoroacetic acid and con-verting the methoxycarbonyl group into a benzyloxycar-bonvl group by treatment with phenyldiaxomethane to obtain the compound of formula XI:
OC~3 OCH2c~H5 OH
~ ~ C3 XI
" ~ ocH3, wherein R is as above defi.ned, esterifying the hydroxy groups and deesterifying t:he benzyloxycarbon~l group of compound XI, wherein R is above defined, by ~reatment, with acetic anhydride in pyridine in l:he presence of
OC~3 OCH2c~H5 OH
~ ~ C3 XI
" ~ ocH3, wherein R is as above defi.ned, esterifying the hydroxy groups and deesterifying t:he benzyloxycarbon~l group of compound XI, wherein R is above defined, by ~reatment, with acetic anhydride in pyridine in l:he presence of
4-dimethylamino-pyridine i',o].lowed by refluxing with' cyclohexene in the presence of.a palladium-on--carbon catalyst, to give the compound of formula XII:
OCH3 O OCt)CH3 R' O~H3 wherein R' represents a hydrogen atom, an acetoxy group or a lower.alkoxy group, which is submitted to a cycliza-tion by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid and to a subsequent ~3~3~3 -- 5f -hydrolysis of the acetoxy groups with sodium methylate to obtain compound XIII:
`'I '~ "3 ~ CH3 wherein R is above defined, from which after an oxidative tr~atment of the l-hydrox~ethyl group with silver car-bonate an.d demethylation of the resultant compound with aluminium trichloride in nitrobenzene, the compound of formula XIV is obtained:
~CH3 XIV
wherein R" is as above defined, from which, after pro-tection of the 13-keto group by treatment with ethylene glycol, bromination of the resultant compound at C-7 with bromine in the presence of 2,2-azo-bis(isobutyroni-trile) followed by hydrolysis of the 7-bromo derivative and removal of the ketal group by acid treatment, or alternatively by bromination with N-bromo-succinimide in the presence of 2,2'-azo-bis(isobutironitrile), by ir-radiation, treatment with silver acetate, hydrolysis lZ3~3~38 - - 5g -of the ketal by acid treatment and finally hydrolysis of the ace-tate with sodium methoxide, the desired compounds of for~mla I are finally obtained.
In a second aspect, the present invention provides a process in accordance with the first aspect wherein R, R' and R" each represe~t hydrogen to prepare 4-demethoxy-6-deoxy-daunomy-inone.
In a third aspect, the present invention provides a process in accordance with the first aspect wherein R and R' each represent a hydroxy group and R' re-presents a methoxy group -to produce 4-demethyl-6-deoxy-daunomycinone.
-6 - ~
The startln~ c~mpounas for the process according to the lnven~ion are known. 2-Brom~-1,4,5-trimethoxy--naphthalene (VII, ~=OC~3) was described by R.L. Haman, ~B Baxbe.r and H. Rapoport, J. Org. Chem., 44, 2153 (1979). The coupling reaction be~ween the compounds VIII and ~I p~oceeds regioselectivelY in high yield t~ qive the key intermediate IX. The organometallic species affects only the caxbonyl group of the methyl ester ana not that of ~he lactone.
- 10 Step (xi) may be performed acco~ding ~o the method descr~bed by (.M. Wona et al., Can J. Chem., ~ 46 (1973), that is by bromination with ~romine .~n the presence of 2,2~-azo~bis(isobutyronitrile) followed:by hyarolysis of the 7-bromo-~eri~ative and removal ~f the ket~l group by ~cid treatment, or alternati~ely by bromination w.ith N-bromo-succinimide in the presence of 2,~'-azo-b.is(isobutyronitrile), by ixradiation, treatment wit;- silver acetate, hydrolysis of the ketal by acidic txeatment and finally hydrolysis of the acetate with so~ium methDxide, The optical resolution o~ the co~poun~ IX may be carried out by the conventional methoa of conversion to dias~ereoisomexic derivatiYes usin9 a chiral resQlving ayent, Resolutiun At this point enables (~)-4-demethoxy--6-deoxy--4~ substituted)-daunomycinones I to be obtained, The 6-deoxyanthracyclinones I, except that in which ~ repxe~ents a hydrogen atom, are novel and are lncluded ~ithin t~e scope of the in~ention. ~-Demethoxy--6-deoxydauno~ycinone, prepared by a different process, was aescr~bed in our British Patent Specification-No.
2100257, The present process is more efficient and more amenable to large scale production than the pre~ious described process The invention also provides anthxacycline glycosides having the general ~ormula XV
- O OH o ~ J~CH2R1 OH
O XV
R _ 7~-- J
- . NHX
wherein Rl represents a hydrogen atom or a hydroxy group, ~ne ~f R2 and R3 represents a hydrogen atom, the other of ~2 and ~3 represents a hydrogen atom or a hydroxy group, and X represents a hydrogen atom or a trifluoro-acetyl group, with the proviso that if X represents a trifluoroacetyl group then Rl represents a hydrogen ;3~
_B_ atom. These compounds may be named as follows:
XVa Rl R3 ~, R2 OH, X ~CF~
4-demethyl-6-deoxy-N-trifluoroacetyl-daunorubic~n.
XVb: ~l=R3=H, R2=OH, X=H
4-demethyl-6-deoxy-daunorubicin.
XVc ~l=R2=H~ R3=H, X=H
4-demethyl-6-deoxv-doxorubicin.
I 1 R2 ~ R3 OH, X COCF3 J 4-demethyl-6-deoxy~N-trifluoroacetyl-4~-epi--daunorubicin XVe~ R2=H, R3=O~, X2H
4-demethyl-6-deoxy-4~-epi-daunorubciin ~ 3 OH~ R2=H, X=H
j 4-demethyl-6-deoxy-4'-epi-doxorubicin XVg: R~ =R3=H, X=COCF3 4-demethyl-6,4'-di~eoxy-N-trifluoroace~yl--daunorubicin XVh: ~i ~2 R3 X H
. 4-demethyl-6,4' -~î deoxy-daunorubicin 20 XVi: Rl=OH, R2=R3=X=H
4-demethyl-6,4'-dideoxy-doxorubicin.
These ~nthracycline glycoside5 may be prepared f~m 4-demethyl-6-deoxy-daunomycinone (I, ~=OH) by condensa~ion thereof with a protected halosugar having 2S the general formula X~I
_g L ~ ~ al NHcocF3 wherein one of R2 and ~3 represents a hydrogen atom and the other ~f ~2 and R3 represents a hydrogen atom or a trifluoroacetoxy group, and Hal represents a halogen at~m, preferablv a chlorine atom, This condensation proceeds in the presence of silver trifluoromethane ~ulphonate according to the metho~
described in ~nited States Patent Specification No.
4l07423, giVing an easily separable mixture of the 7S:9S and 7R:9R 0-trifluor~acetyl protected derivatives ~f the ~-glycosides, XVa, XVd and XVy according to 1he halosugar XVI selected for the reacti~n.
~he O-trifluoroacetyl group may ~e removed ~y methanolysis tG ~ive the compounds XVa, XVd and XVg which by mild alkaline hydrolysis can be converted to the glycosides XVb, XYe and XVh respec~ively.
These, by 14-bromi~ation and ~reatment with aqueous sodium formate in accordance with the metho~ described in United States Patent Specification No. 3803124, give the coxresponding ~oxor~bicin derivatives XVc, 25 XVf and XVi,~ ~hese processes are within the scope ;~
~.
3~;38 of the invention.
A protected halosugar of the formula XVI tv produce com-pound XVa is l-chloro-N,0-ditrifluoroacetyl-daunosamine.
Halosugars of the formula XVI to produce compounds XVd and XVg are, respectively, l-chloro-N,0-ditrifluoro-ace~yl-4'-epi-daunosamine and l-chloro-N,0-ditrifluoro-acetyl-4'-deoxy-daunosamine.
The anthracycline glycosides XV have ~nti-tumour pro-perties and accordingly the invention additionally provides a pharmaceutical composition comprising an anthracycline glycoside having the general formula XV
or a pharmaceutically acceptable salt of such a gly-coside in which X represents a hydrogen atom in admix-ture with a pharmaceutically acceptable dlluent or carrier.
The-invention is illustrated by the f~llowing Examples.
, ' :. , ' .
~Z~ ;31~3 Dimethyl 1,2,3,6-tetrahydro-4-acetyl-ehthalate (III~
10 g of di~ethyl 1,2,3,6-tetrahydrv-p~thalate (II) was treated at ~5C with 25 ml ~f acetic anhydride in the presence ~f 9 ml of tin tetrachloride. The reaction mixture was poured into iced water and extracted with diethyl ether. The organic phase was was~ed with a saturated a~ueous s~lution of sodium bicarb~nate and then with wate~, and was then evaporated 1~ to dryness under vacuum. The ~btain~d oil was dissolved in benzene, treated with a methanolic solution of hydrogen chloriae~ The solution was evaporated to aryness and the xesidue was purified by chromatography on column of silica gel to gi~e 9 g of the title comp~und in 75~ overa~ yield.
mass spectrum: m~z 240 (M
IR (K~r): 1720 cm 1 (C=O of ester); 1660 cm 1 (C=o of d,~ unsaturated ketone) PMR (CDC13): interalia ~ 2.33 ts, COCH3), 3.70 ~s, -COOC 3) and 6.91 (m, HC=C) _ 1,2-Di-(methoxycarbonyl)-4-ethylidene-Cyclohexane (V~
17 g of dimethyl 1,2,3,6-tetrahydrv-~-acetyl-phthalate, prepared as described in Example 1, was refluxed in anhydrous e~hanol with 14.6 g of tosylhydrazine. After ~emoval of the sol~ent, 24 ~ of dimethyl 1,2,3,6--tetrahydro-4~ tosylhydrazono-ethyl)-phthalate ~IV) 1~3~;3~3 crystallized from water: m.p. 162-163C m/z 408 (~ ).
This cc:mpvund was aissol~ea in chloroform, and treatea at 0C with 14 ml of catechol borane. Sodium acetate was added to the reac~ion mixture, which was then refluxed. ~fter washing with water, the solvent was evaporated off and the residue w~s purified by chxomatography on a column of silica gel giving 1~ g of the title compound (yield 8~%): m/z 226 (M ~;
PMR (CDC13): inter alia 6 1.6 (d, J-8Hz, CH3-CH=), 5,3 (q, 3=8Hz, CH3-CH=).
2-Methoxycarbonyl-5-(2-methyldioxolan-2-yl)-6-oxa--bicyclo/3,2,1/octan-7-one tVI ) 8 g of 1,2~di;(methoxycarbonyl)-4-ethylidene-cyclohexane~
prepared as described in Example 2, was dissolved in agueous acetone containing 4.8 ml of acetic acid. An aqueous solution of potassium permanganate was addea, and the mixture was allo~ed to stand fsr 60 minutes at room tempera~ure. The excess oxidant was then destroyed and the reaction mixture, diluted with water, was extracted with ethyl acetate. The ~raanic phase, washed with water and dr~ed over ~nhydrous sodiu~
sulphate, was evapDrated to dryness under Vacuum- The residue (9 g) was dissol~ed in-benzene and refluxed for ~ ~lnutes in the presence of a catalytic amount of p-toluenesulphonic acid. 4 ml of ethylene glycol was _13-added and the reacti~n mixture was xe~lxed for a furthex 2 hours. ~fter c~nvention~l wor~-up, the residue, obtained by evaporating off the solvent, was purified by chromatography on a column of silica gel using as eluent a toluene:acetone mixture 115:1 by volume).
3.0 9 of the title compound was isolated (yiela 33%):
~ p 69-71C; m/z 271 (MH ~.
IR (~Br): 1790 cm 1 (C=O five membered ring lactone3 1735 Gm 1(C=o ester); 1720 cm 1 (C=O
ketone) PMR (CDC13): in r_alia 1~25 (s, CH3), 3.65 (s, 3), an~ 3~9 ~s, O CH2 C 2 . _ ~ 2-(1,4,5-~ximethoxy-3-~phthylcarb~nyl)-5-(2-meth ¦ 15 -dioxolan-2-y.l)-6-oxa-bicyclo~ ,2,170ctan-7-one (IX, _ _ R=OC~3) 7 ml of a 1. 65 M hexane solution of n-butyllithium was dissolved in 30 ml of anhydrous tetrahydrofuran. To the solution was added at -78C a solution of 3,3 g of 1,4,5-trimethoxy-3-bromo-naphthalene (VI, R=OCH3) in 30 ml of anhydrous tetrahydr~furan. 2,5 g of 2-methoxy-carbonyl-5-(2-methyl-dioxolan-2-yl)-6-oxa-bicyclo~3~2,1/-octan-7-one, prepared ~s described in Example 3, was dissolved in 50 ml of anhydrous tetrahydrofuran and ~dded to the reaction mixture. The reaction mixture was stood for 1 hour ~t -78C and then quenched with acetic acld.
~, .
12~3~;38 The sol~ent was rem~vea in vacuo. The residue was purified by silica gel column chromatograhy, gi~ing 3 9 (73~ yield) of the title compound.
m/z 456 ~M '~.
IR (KBr~: 1775 cm 1 (C=O five membered ring lact~ne) 1680 cm (C=O benzylic ketone) PMR (CDC13~: inter alia 1.3 (s, CH3), 3.75 ~s, OCH3), 3.95-4.05 (m,two OCH3 and -0-~H2 CH2 0 ), 6.8 (s~ aromatic ~H) and 6.~-8.1 Im, ~ 10 three H).
1-(1,4,5-trimethoxy-3-naphthylmethyl-2-ben~yloxycarbonyl--4-~1-hydroxyethyl)-4-hydroxy-cyclohexane (XI, R=OCH3) 1.6 g of 2-(1,4,5-trimethoxy-2-naphthylcarbonyl)-5-(2--methyl-dioxolan-2-yl)-6-oxa-bicyclo/3,2,17~ctan-7-one, prepared ~s described in Example 4, was dissolved in methanol and treated at ro~m temperature f~r 1 hour with a lN solution of hydr~gen chloride in anhydr~us methanol. After evaporating off the solvent, there was obtained in akx~t quantitative yield 1.5 g of 1-(1,4,5--trimethoxy-3-naphthylcarbonyl)-2-methoxycarb~nyl-4--acetyl-q-hydroxy-cyclohexane (X, R=OCH3). m/z 444 (~ ');
IR (film):3460 cm ~OH), 1730 cm (C=O ester), 1710 cm 1 (C=O ketone) and 1665 cm i (C=O benzylic ketone).
PMR (CDC13): inter alia 2.~3 (s, CH3CO) 1 3.75-4.05 (s, four OCH3) ~ 6.8 (s, ar~matic H) and ~ . 85-8~0 ~m, three 1~39t;38 aromatic H~, 1.5 g ~f this compound was dissolved in 15 ml of trifluc>roacetic acid and refluxed with 1. 4 ml of pyridine-borane complex~ After removal of th~
sol~ent, the residue was treated with a 10~ aqueous
OCH3 O OCt)CH3 R' O~H3 wherein R' represents a hydrogen atom, an acetoxy group or a lower.alkoxy group, which is submitted to a cycliza-tion by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid and to a subsequent ~3~3~3 -- 5f -hydrolysis of the acetoxy groups with sodium methylate to obtain compound XIII:
`'I '~ "3 ~ CH3 wherein R is above defined, from which after an oxidative tr~atment of the l-hydrox~ethyl group with silver car-bonate an.d demethylation of the resultant compound with aluminium trichloride in nitrobenzene, the compound of formula XIV is obtained:
~CH3 XIV
wherein R" is as above defined, from which, after pro-tection of the 13-keto group by treatment with ethylene glycol, bromination of the resultant compound at C-7 with bromine in the presence of 2,2-azo-bis(isobutyroni-trile) followed by hydrolysis of the 7-bromo derivative and removal of the ketal group by acid treatment, or alternatively by bromination with N-bromo-succinimide in the presence of 2,2'-azo-bis(isobutironitrile), by ir-radiation, treatment with silver acetate, hydrolysis lZ3~3~38 - - 5g -of the ketal by acid treatment and finally hydrolysis of the ace-tate with sodium methoxide, the desired compounds of for~mla I are finally obtained.
In a second aspect, the present invention provides a process in accordance with the first aspect wherein R, R' and R" each represe~t hydrogen to prepare 4-demethoxy-6-deoxy-daunomy-inone.
In a third aspect, the present invention provides a process in accordance with the first aspect wherein R and R' each represent a hydroxy group and R' re-presents a methoxy group -to produce 4-demethyl-6-deoxy-daunomycinone.
-6 - ~
The startln~ c~mpounas for the process according to the lnven~ion are known. 2-Brom~-1,4,5-trimethoxy--naphthalene (VII, ~=OC~3) was described by R.L. Haman, ~B Baxbe.r and H. Rapoport, J. Org. Chem., 44, 2153 (1979). The coupling reaction be~ween the compounds VIII and ~I p~oceeds regioselectivelY in high yield t~ qive the key intermediate IX. The organometallic species affects only the caxbonyl group of the methyl ester ana not that of ~he lactone.
- 10 Step (xi) may be performed acco~ding ~o the method descr~bed by (.M. Wona et al., Can J. Chem., ~ 46 (1973), that is by bromination with ~romine .~n the presence of 2,2~-azo~bis(isobutyronitrile) followed:by hyarolysis of the 7-bromo-~eri~ative and removal ~f the ket~l group by ~cid treatment, or alternati~ely by bromination w.ith N-bromo-succinimide in the presence of 2,~'-azo-b.is(isobutyronitrile), by ixradiation, treatment wit;- silver acetate, hydrolysis of the ketal by acidic txeatment and finally hydrolysis of the acetate with so~ium methDxide, The optical resolution o~ the co~poun~ IX may be carried out by the conventional methoa of conversion to dias~ereoisomexic derivatiYes usin9 a chiral resQlving ayent, Resolutiun At this point enables (~)-4-demethoxy--6-deoxy--4~ substituted)-daunomycinones I to be obtained, The 6-deoxyanthracyclinones I, except that in which ~ repxe~ents a hydrogen atom, are novel and are lncluded ~ithin t~e scope of the in~ention. ~-Demethoxy--6-deoxydauno~ycinone, prepared by a different process, was aescr~bed in our British Patent Specification-No.
2100257, The present process is more efficient and more amenable to large scale production than the pre~ious described process The invention also provides anthxacycline glycosides having the general ~ormula XV
- O OH o ~ J~CH2R1 OH
O XV
R _ 7~-- J
- . NHX
wherein Rl represents a hydrogen atom or a hydroxy group, ~ne ~f R2 and R3 represents a hydrogen atom, the other of ~2 and ~3 represents a hydrogen atom or a hydroxy group, and X represents a hydrogen atom or a trifluoro-acetyl group, with the proviso that if X represents a trifluoroacetyl group then Rl represents a hydrogen ;3~
_B_ atom. These compounds may be named as follows:
XVa Rl R3 ~, R2 OH, X ~CF~
4-demethyl-6-deoxy-N-trifluoroacetyl-daunorubic~n.
XVb: ~l=R3=H, R2=OH, X=H
4-demethyl-6-deoxy-daunorubicin.
XVc ~l=R2=H~ R3=H, X=H
4-demethyl-6-deoxv-doxorubicin.
I 1 R2 ~ R3 OH, X COCF3 J 4-demethyl-6-deoxy~N-trifluoroacetyl-4~-epi--daunorubicin XVe~ R2=H, R3=O~, X2H
4-demethyl-6-deoxy-4~-epi-daunorubciin ~ 3 OH~ R2=H, X=H
j 4-demethyl-6-deoxy-4'-epi-doxorubicin XVg: R~ =R3=H, X=COCF3 4-demethyl-6,4'-di~eoxy-N-trifluoroace~yl--daunorubicin XVh: ~i ~2 R3 X H
. 4-demethyl-6,4' -~î deoxy-daunorubicin 20 XVi: Rl=OH, R2=R3=X=H
4-demethyl-6,4'-dideoxy-doxorubicin.
These ~nthracycline glycoside5 may be prepared f~m 4-demethyl-6-deoxy-daunomycinone (I, ~=OH) by condensa~ion thereof with a protected halosugar having 2S the general formula X~I
_g L ~ ~ al NHcocF3 wherein one of R2 and ~3 represents a hydrogen atom and the other ~f ~2 and R3 represents a hydrogen atom or a trifluoroacetoxy group, and Hal represents a halogen at~m, preferablv a chlorine atom, This condensation proceeds in the presence of silver trifluoromethane ~ulphonate according to the metho~
described in ~nited States Patent Specification No.
4l07423, giVing an easily separable mixture of the 7S:9S and 7R:9R 0-trifluor~acetyl protected derivatives ~f the ~-glycosides, XVa, XVd and XVy according to 1he halosugar XVI selected for the reacti~n.
~he O-trifluoroacetyl group may ~e removed ~y methanolysis tG ~ive the compounds XVa, XVd and XVg which by mild alkaline hydrolysis can be converted to the glycosides XVb, XYe and XVh respec~ively.
These, by 14-bromi~ation and ~reatment with aqueous sodium formate in accordance with the metho~ described in United States Patent Specification No. 3803124, give the coxresponding ~oxor~bicin derivatives XVc, 25 XVf and XVi,~ ~hese processes are within the scope ;~
~.
3~;38 of the invention.
A protected halosugar of the formula XVI tv produce com-pound XVa is l-chloro-N,0-ditrifluoroacetyl-daunosamine.
Halosugars of the formula XVI to produce compounds XVd and XVg are, respectively, l-chloro-N,0-ditrifluoro-ace~yl-4'-epi-daunosamine and l-chloro-N,0-ditrifluoro-acetyl-4'-deoxy-daunosamine.
The anthracycline glycosides XV have ~nti-tumour pro-perties and accordingly the invention additionally provides a pharmaceutical composition comprising an anthracycline glycoside having the general formula XV
or a pharmaceutically acceptable salt of such a gly-coside in which X represents a hydrogen atom in admix-ture with a pharmaceutically acceptable dlluent or carrier.
The-invention is illustrated by the f~llowing Examples.
, ' :. , ' .
~Z~ ;31~3 Dimethyl 1,2,3,6-tetrahydro-4-acetyl-ehthalate (III~
10 g of di~ethyl 1,2,3,6-tetrahydrv-p~thalate (II) was treated at ~5C with 25 ml ~f acetic anhydride in the presence ~f 9 ml of tin tetrachloride. The reaction mixture was poured into iced water and extracted with diethyl ether. The organic phase was was~ed with a saturated a~ueous s~lution of sodium bicarb~nate and then with wate~, and was then evaporated 1~ to dryness under vacuum. The ~btain~d oil was dissolved in benzene, treated with a methanolic solution of hydrogen chloriae~ The solution was evaporated to aryness and the xesidue was purified by chromatography on column of silica gel to gi~e 9 g of the title comp~und in 75~ overa~ yield.
mass spectrum: m~z 240 (M
IR (K~r): 1720 cm 1 (C=O of ester); 1660 cm 1 (C=o of d,~ unsaturated ketone) PMR (CDC13): interalia ~ 2.33 ts, COCH3), 3.70 ~s, -COOC 3) and 6.91 (m, HC=C) _ 1,2-Di-(methoxycarbonyl)-4-ethylidene-Cyclohexane (V~
17 g of dimethyl 1,2,3,6-tetrahydrv-~-acetyl-phthalate, prepared as described in Example 1, was refluxed in anhydrous e~hanol with 14.6 g of tosylhydrazine. After ~emoval of the sol~ent, 24 ~ of dimethyl 1,2,3,6--tetrahydro-4~ tosylhydrazono-ethyl)-phthalate ~IV) 1~3~;3~3 crystallized from water: m.p. 162-163C m/z 408 (~ ).
This cc:mpvund was aissol~ea in chloroform, and treatea at 0C with 14 ml of catechol borane. Sodium acetate was added to the reac~ion mixture, which was then refluxed. ~fter washing with water, the solvent was evaporated off and the residue w~s purified by chxomatography on a column of silica gel giving 1~ g of the title compound (yield 8~%): m/z 226 (M ~;
PMR (CDC13): inter alia 6 1.6 (d, J-8Hz, CH3-CH=), 5,3 (q, 3=8Hz, CH3-CH=).
2-Methoxycarbonyl-5-(2-methyldioxolan-2-yl)-6-oxa--bicyclo/3,2,1/octan-7-one tVI ) 8 g of 1,2~di;(methoxycarbonyl)-4-ethylidene-cyclohexane~
prepared as described in Example 2, was dissolved in agueous acetone containing 4.8 ml of acetic acid. An aqueous solution of potassium permanganate was addea, and the mixture was allo~ed to stand fsr 60 minutes at room tempera~ure. The excess oxidant was then destroyed and the reaction mixture, diluted with water, was extracted with ethyl acetate. The ~raanic phase, washed with water and dr~ed over ~nhydrous sodiu~
sulphate, was evapDrated to dryness under Vacuum- The residue (9 g) was dissol~ed in-benzene and refluxed for ~ ~lnutes in the presence of a catalytic amount of p-toluenesulphonic acid. 4 ml of ethylene glycol was _13-added and the reacti~n mixture was xe~lxed for a furthex 2 hours. ~fter c~nvention~l wor~-up, the residue, obtained by evaporating off the solvent, was purified by chromatography on a column of silica gel using as eluent a toluene:acetone mixture 115:1 by volume).
3.0 9 of the title compound was isolated (yiela 33%):
~ p 69-71C; m/z 271 (MH ~.
IR (~Br): 1790 cm 1 (C=O five membered ring lactone3 1735 Gm 1(C=o ester); 1720 cm 1 (C=O
ketone) PMR (CDC13): in r_alia 1~25 (s, CH3), 3.65 (s, 3), an~ 3~9 ~s, O CH2 C 2 . _ ~ 2-(1,4,5-~ximethoxy-3-~phthylcarb~nyl)-5-(2-meth ¦ 15 -dioxolan-2-y.l)-6-oxa-bicyclo~ ,2,170ctan-7-one (IX, _ _ R=OC~3) 7 ml of a 1. 65 M hexane solution of n-butyllithium was dissolved in 30 ml of anhydrous tetrahydrofuran. To the solution was added at -78C a solution of 3,3 g of 1,4,5-trimethoxy-3-bromo-naphthalene (VI, R=OCH3) in 30 ml of anhydrous tetrahydr~furan. 2,5 g of 2-methoxy-carbonyl-5-(2-methyl-dioxolan-2-yl)-6-oxa-bicyclo~3~2,1/-octan-7-one, prepared ~s described in Example 3, was dissolved in 50 ml of anhydrous tetrahydrofuran and ~dded to the reaction mixture. The reaction mixture was stood for 1 hour ~t -78C and then quenched with acetic acld.
~, .
12~3~;38 The sol~ent was rem~vea in vacuo. The residue was purified by silica gel column chromatograhy, gi~ing 3 9 (73~ yield) of the title compound.
m/z 456 ~M '~.
IR (KBr~: 1775 cm 1 (C=O five membered ring lact~ne) 1680 cm (C=O benzylic ketone) PMR (CDC13~: inter alia 1.3 (s, CH3), 3.75 ~s, OCH3), 3.95-4.05 (m,two OCH3 and -0-~H2 CH2 0 ), 6.8 (s~ aromatic ~H) and 6.~-8.1 Im, ~ 10 three H).
1-(1,4,5-trimethoxy-3-naphthylmethyl-2-ben~yloxycarbonyl--4-~1-hydroxyethyl)-4-hydroxy-cyclohexane (XI, R=OCH3) 1.6 g of 2-(1,4,5-trimethoxy-2-naphthylcarbonyl)-5-(2--methyl-dioxolan-2-yl)-6-oxa-bicyclo/3,2,17~ctan-7-one, prepared ~s described in Example 4, was dissolved in methanol and treated at ro~m temperature f~r 1 hour with a lN solution of hydr~gen chloride in anhydr~us methanol. After evaporating off the solvent, there was obtained in akx~t quantitative yield 1.5 g of 1-(1,4,5--trimethoxy-3-naphthylcarbonyl)-2-methoxycarb~nyl-4--acetyl-q-hydroxy-cyclohexane (X, R=OCH3). m/z 444 (~ ');
IR (film):3460 cm ~OH), 1730 cm (C=O ester), 1710 cm 1 (C=O ketone) and 1665 cm i (C=O benzylic ketone).
PMR (CDC13): inter alia 2.~3 (s, CH3CO) 1 3.75-4.05 (s, four OCH3) ~ 6.8 (s, ar~matic H) and ~ . 85-8~0 ~m, three 1~39t;38 aromatic H~, 1.5 g ~f this compound was dissolved in 15 ml of trifluc>roacetic acid and refluxed with 1. 4 ml of pyridine-borane complex~ After removal of th~
sol~ent, the residue was treated with a 10~ aqueous
5 soluti~n of sodium hydroxide. ~fter mild acidification the free acid was extracted with ethyl acetate. The s~lvent was e~aporated off and ~e residue was directly treated with ~,n ethexeal solution o~ phenyldiazomethane t~ give the title product. This was purified by chromatography: m/z 508 (M ); PMR ~CDC13): inter al~ia 1. 25 (d, ~H3 - C~), 3. 70-3. 95 (s , three OCH3), 5.15 ~d, CH2Ph) ~nd 6.4~ m, nine aromatic H).
__ EX~PL~E: 6 1, 2, 3, 4, 4a, 5,12,12a-Octahydro-2 (1-h~droxyethyl)-2--hydroxy-6, 7,11-trimethoxy-12-~x~na ~ thacene (XIII, -R=OCH3) -0.48 g of 1~(1,4,5-trimethoxy-3-naph hylmethyl)-~-~
-benzyl~xycarb~nyl-4-(1-hydroxyethyl) -4 -hydroxy-cyclo-hexane, prepared as described in Example 5, was treated with acetic anhydride and pyridine in the presence of 4-dimethylamino-pyridine. After a night at room tempera-ture the reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The crude product was dissolved in methanol and refluxed with cyclohexene in the presence of 10% by weight .
391~3~
palladium-on-carbDn. The catalyst was then filtered off and the solution, concentrated to a small ~olume, was treated ~t ~C for 60 minutes wlth trifluoroacetic an~ydride and tri~luoroacetic acid. Then the ~olution was diluted ~ith ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and wlth water, dried and concentrated to dxyness under Vacuum.
~he residue was d~ssolved in methanol in the presence of catalytic amount of sodium methylate. After conventional work-up and purification by chromatography 0.18 g of the title compound was obtained (yield 49%):
m/z 40~ (M '); IR (KBr) : 3450 cm (OH), 1675 cm 1 (C=
O benzylic ~etone); PMR lCDC13): inter alia ~ (1.2 (d, CH3-CH), 3.7-3.9 (s, three ~CH3) and 6.4-8.0 (m, tXree aromatic hydxogen).
1,2,3,4,4a,5,12,12a-Octahydro-2-acetyl-2-hydrox~-6,7,11--trimethoxy-12-oxo-naphthacene 0.8 9 of sil~er carbonate was added to a solution in benzene of 0.09 g of 1,2,3,4,4a,5,12,12a-Octrahydro-2--(l-hydroxyethyl)-2-hydroxy-6,7,11-trimethoxy-12-oxo--naphtacene, prepared as described in Example 6, and the mixture WAS refluxed. After filtering ~ff the solid and evaporating off the sol~ent in Vacuo, 0.08 g of the title compound was obtained (90% yield).
1~ 39~;3~3 _ IR (KBr ): 3360 cm (OH), 1705 cm (C-O ketone~, 1680 cm ~ (C=O, b~enzylic ketone) PMR (CDC13): inter alia ~ 2.2 (s, CH3CO), 3.65-3.90 (s, ~hree OCH3).
__ EX~PL~E: 6 1, 2, 3, 4, 4a, 5,12,12a-Octahydro-2 (1-h~droxyethyl)-2--hydroxy-6, 7,11-trimethoxy-12-~x~na ~ thacene (XIII, -R=OCH3) -0.48 g of 1~(1,4,5-trimethoxy-3-naph hylmethyl)-~-~
-benzyl~xycarb~nyl-4-(1-hydroxyethyl) -4 -hydroxy-cyclo-hexane, prepared as described in Example 5, was treated with acetic anhydride and pyridine in the presence of 4-dimethylamino-pyridine. After a night at room tempera-ture the reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The crude product was dissolved in methanol and refluxed with cyclohexene in the presence of 10% by weight .
391~3~
palladium-on-carbDn. The catalyst was then filtered off and the solution, concentrated to a small ~olume, was treated ~t ~C for 60 minutes wlth trifluoroacetic an~ydride and tri~luoroacetic acid. Then the ~olution was diluted ~ith ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and wlth water, dried and concentrated to dxyness under Vacuum.
~he residue was d~ssolved in methanol in the presence of catalytic amount of sodium methylate. After conventional work-up and purification by chromatography 0.18 g of the title compound was obtained (yield 49%):
m/z 40~ (M '); IR (KBr) : 3450 cm (OH), 1675 cm 1 (C=
O benzylic ~etone); PMR lCDC13): inter alia ~ (1.2 (d, CH3-CH), 3.7-3.9 (s, three ~CH3) and 6.4-8.0 (m, tXree aromatic hydxogen).
1,2,3,4,4a,5,12,12a-Octahydro-2-acetyl-2-hydrox~-6,7,11--trimethoxy-12-oxo-naphthacene 0.8 9 of sil~er carbonate was added to a solution in benzene of 0.09 g of 1,2,3,4,4a,5,12,12a-Octrahydro-2--(l-hydroxyethyl)-2-hydroxy-6,7,11-trimethoxy-12-oxo--naphtacene, prepared as described in Example 6, and the mixture WAS refluxed. After filtering ~ff the solid and evaporating off the sol~ent in Vacuo, 0.08 g of the title compound was obtained (90% yield).
1~ 39~;3~3 _ IR (KBr ): 3360 cm (OH), 1705 cm (C-O ketone~, 1680 cm ~ (C=O, b~enzylic ketone) PMR (CDC13): inter alia ~ 2.2 (s, CH3CO), 3.65-3.90 (s, ~hree OCH3).
6,7-Dideoxycarminomycinone (XIV , R=OH) 0.06 g of 1,2,3,4,4a,5,12,12a octahydro-2-acetyl-2--hydroxy-6,7,11-trimethoxy-12-oxon~phthacene, prep~red as described in Example 7, was ais~olved in nitrobenzene an~ treate2 with 0.12 g of aluminium trichloride The mixture was kept at 70 C until no ~ore starting material was detectable. The xeaction mixture ~as poure~ into an aqeuous ~aturated s~luti~n of oxalic acid and extractea with ethyl acetate. The oxganic phase was separated, washed with wate~, dried and evaporated to dryness. The residue, purifie~ ~n a col D of silica gel, afforded pure 6,7-dideoxycarminvmycinone, yiel~ 40~:
m/z 352 (M ~; IR (KBr): 3420 cm l ~OH), 1705 cm 1 (C=O
ketone) and 1625 cm 1 (C=O, chelated quinone). PMR
2~ (CDC13): lnter alia ~ 1.7-2.2 ~m, CH2~, 2.3 (2, CH3CO), 2.8-3.2 (m, two benzylic CH2), 7.0-7.9 (m, four aromatic H~, 12.6 (s, phenolic OH) and 12.9 (s, phen~lic OH~.
6-Deoxycarminomycinone (I: R=OH) A solut.ion of 6,7-dideoxycarmin~mycinone, prepared as .,:, -` lZ~9~;~8 described in Example 8, ln benzene was treated at refluxing temperature for 4 hours with 1.2 ml of ethylene glycol in the presence of a catalytic ~mount of ~-toluenesulphonic ~cid, affoxding the corresponding 13-ketal derivative. This compound was dissolved ln carbon tetrachloride and treated with 2 ml of a solution of 3,2 g of bromine in 32 ~1 of carbon tetrachloxide at 45~C for 6 hours in ~he presence of 2,2'-azo-bis (isobutyronitrile). The cooled reaction mixture was extracted with lN aque~us sodium hydroxide and the c~loured aqueous phase was adjusted to pH 8,5 and extxacted ~ith chloroform. The organic extracts, evapoxated to dryness, afforded 6-deoxy-13-ketal--car~inomycinone, ~his was dissolved in acetone containing hydro~en chloride (300 ml of a 0.?5 N
solution) and kept at room temperature for 3 hours in order to hydrolyze the ketal group. The desired 6--deoxycarminomycinone was obtained.
~lternatiye Method A ~olution of 50 mg ~0.125 ~m~l) of the 13-ketal aerivative of 6,7~dideoxycarmino~ycinone in 2~ ml of carb~n tetrachloride containin~ 0.14 mmol of N-bromo--succinimide and 0.06 mmol of 2,2'-azo-bis(isobutyro nitrile) was refluxed for 25 minutes. The residue, obtained by evaporating off the solvent under vacuum was dissolved in glacial acetic acid and treated with 80 ~f 1~3~;38 --mg ~f s~lver acetate. The mixture ~s stirred at room temperature ~or five h~urs. The s~l~ent was eY~pbrated off, and the residue was dissolved in ethyl acet~te ~nd fl~te~e~. The filtrate was ~ashed with a satur~tea aqueous solution of s~dium bicarb~nate and with water, dried and concentrated. The residue was dissolved in ~queous acetic acid (90~ by vol~me) at 0C and stirred for 90 ~lnutes. After sol~ent re~v~l, the residue was d~ssol~ed in methanol, s~dium meth~xide was ad~ea and the mixture w~s stirre~ for 90 minutes. After neutralization, extraction an~ ~ashing with water, ~he residue ~as .purified by fl~sh chromatography with methylene dichloride:acetone (.16:1 by ~olume).
The deslred 6-deoxycarmlnomycin~ne was ~btained in 34%
15 overall yield. m/z 368 (M '), ~.p. 211-213C, TLC
on Kieselgel plates (Merck* Trade Mark F254) using as eluent s~l~ent toluene:acetone 4:1 by ~olume, Rf=0.3.
PMR (200 MHz, CDC13): ~ 2,1-2.3 tm, 2H, H-8), 2.3 (s, 3H, -COCH3), 2.7-3.1 (q, 2H, H-10), 4.1 (d, lH, OH-7), 20 4.4 (s, lH, OH-9), 4.8 (d, lH, H-7), 7.3 (d, lH, ~-3),
m/z 352 (M ~; IR (KBr): 3420 cm l ~OH), 1705 cm 1 (C=O
ketone) and 1625 cm 1 (C=O, chelated quinone). PMR
2~ (CDC13): lnter alia ~ 1.7-2.2 ~m, CH2~, 2.3 (2, CH3CO), 2.8-3.2 (m, two benzylic CH2), 7.0-7.9 (m, four aromatic H~, 12.6 (s, phenolic OH) and 12.9 (s, phen~lic OH~.
6-Deoxycarminomycinone (I: R=OH) A solut.ion of 6,7-dideoxycarmin~mycinone, prepared as .,:, -` lZ~9~;~8 described in Example 8, ln benzene was treated at refluxing temperature for 4 hours with 1.2 ml of ethylene glycol in the presence of a catalytic ~mount of ~-toluenesulphonic ~cid, affoxding the corresponding 13-ketal derivative. This compound was dissolved ln carbon tetrachloride and treated with 2 ml of a solution of 3,2 g of bromine in 32 ~1 of carbon tetrachloxide at 45~C for 6 hours in ~he presence of 2,2'-azo-bis (isobutyronitrile). The cooled reaction mixture was extracted with lN aque~us sodium hydroxide and the c~loured aqueous phase was adjusted to pH 8,5 and extxacted ~ith chloroform. The organic extracts, evapoxated to dryness, afforded 6-deoxy-13-ketal--car~inomycinone, ~his was dissolved in acetone containing hydro~en chloride (300 ml of a 0.?5 N
solution) and kept at room temperature for 3 hours in order to hydrolyze the ketal group. The desired 6--deoxycarminomycinone was obtained.
~lternatiye Method A ~olution of 50 mg ~0.125 ~m~l) of the 13-ketal aerivative of 6,7~dideoxycarmino~ycinone in 2~ ml of carb~n tetrachloride containin~ 0.14 mmol of N-bromo--succinimide and 0.06 mmol of 2,2'-azo-bis(isobutyro nitrile) was refluxed for 25 minutes. The residue, obtained by evaporating off the solvent under vacuum was dissolved in glacial acetic acid and treated with 80 ~f 1~3~;38 --mg ~f s~lver acetate. The mixture ~s stirred at room temperature ~or five h~urs. The s~l~ent was eY~pbrated off, and the residue was dissolved in ethyl acet~te ~nd fl~te~e~. The filtrate was ~ashed with a satur~tea aqueous solution of s~dium bicarb~nate and with water, dried and concentrated. The residue was dissolved in ~queous acetic acid (90~ by vol~me) at 0C and stirred for 90 ~lnutes. After sol~ent re~v~l, the residue was d~ssol~ed in methanol, s~dium meth~xide was ad~ea and the mixture w~s stirre~ for 90 minutes. After neutralization, extraction an~ ~ashing with water, ~he residue ~as .purified by fl~sh chromatography with methylene dichloride:acetone (.16:1 by ~olume).
The deslred 6-deoxycarmlnomycin~ne was ~btained in 34%
15 overall yield. m/z 368 (M '), ~.p. 211-213C, TLC
on Kieselgel plates (Merck* Trade Mark F254) using as eluent s~l~ent toluene:acetone 4:1 by ~olume, Rf=0.3.
PMR (200 MHz, CDC13): ~ 2,1-2.3 tm, 2H, H-8), 2.3 (s, 3H, -COCH3), 2.7-3.1 (q, 2H, H-10), 4.1 (d, lH, OH-7), 20 4.4 (s, lH, OH-9), 4.8 (d, lH, H-7), 7.3 (d, lH, ~-3),
7.7 (t, lH, H-2), 7.8 (d, lH, H-l) 8.1 (s, lH, H-6), 12.8 ts, lH, OH-4), 13.2 (s, lH, OH-ll).
2-(1,4-Dimethoxy-3-naphthylcarbonyl)-5-(2-methyl-dioxolan--2-yl)-6-oxa~bicyclo/3,2,17 octan-7-one (IX, R=H) _ Following the ~e~hod describea in Example 4, a solution .
2~39t;31~ .
of 3.2 g of 1 4-dimeth~xy-3-bromo-naphthalene in anhydrous tetrahydrofuran was treated at -78~C with n-butyllithium and then added to a solution in anhydrous tetrahydrofuran of 2.7 9 of the comp~und prepaxed in Exam~le 3. After silica gel column purification 2.8 g of the title com~ound was obtaine~ (65~ yield) m/z 426 (M ): IR (film)~
1780 cm 1 (C=O five membered ring lactone) 1670 cm 1 ~C=~ benzylic ketone) PMR (C~C13): inter alia:
~ 1.4 (s CH3) 3.85 ls two OCH3) 3.9 (s -~-CH2--CH2-0-) 6.9 (s aromatic H) and 7.4-8.4 ~m four ~romatic H).
EXP~lPLE 11 1-(1 4-dimethoxy-3-naphthylmethyl)- -benzyloxycarb~nyl--4-(l-hydroxyethyl)-4-hYdroxy-cyclohexane (XI R=H) Operating as described in Example 5 the treatment of 2-(1 4-dimethoxy-3-naphthylcarbonyl~-5-(2-methyl--dioxolan-2-yl)-6-oxa-bicyclol3 2 lloctan-7-one prepared as described in Example 109. with a solution o~ hydrogen chloride in me~hanol afi.orde~ 1,4--dimethoxy-3-naphthylcarbonyl)-2-meth~xycarb~nyl-4--acetyl 4-hydroxy-cyclohexane (X R-H) in almos$
quantitatlve yield. m/z 414 (M ): IR (filml: 3460 cm 1 (OH) 1730 cm 1 (C=0 ester) 1710 cm 1 (C=0 ketone) and 1670 cm ~ (C=0, benzylic ketone).
PMR (CDC13). inter alia: ~ 2.3 (s CH3C0~ 2.9-3.6 12~ 8 (m, two H), 3.7-3.9 (s, three OCH3), 6.9 (s, aromatic H) and 7.4-8.4 (m, four aromatic H~.
1 y of this compouna, by reduction with pyridine--borane complex, basic treatment and finally esterlfication with phenyldiazomethane was converted to the title compound ~0.7 9, overall yield 63%).
m/z 478 ~M ): IR (film)~: 3450 cm 1 (OH~, 1725 cm 1 (C=O, ester). PMR ~CDC13)~ nter alia ~ 1.3 Id, J=
4Hz r CH3-CH), 3.85-3.9 ~s, two OCH3), 5.1 ~s, CH2--benzylic), 6.6 (s, aromatic ~) and 7.2-8.~ (m, nine aromatic hydrogens).
~,2,3,4,4a,5,12,12a-Octahydro-2-~l-hYaroxyethyl)-2--hydr_xy-6,11-dimethoxy-12-oxo-naphthacene ~Xl~lI, R=H) Operating as described in Example 6, 0.44 9 of 1-(1,4--dimethoxy-3-naphthylmethy])-2-benzyloxycarbonyl-4--(l-hydroxyethyl)-4-hydroxy-cyciohexane, prepared as described in Example 11, was treated with acetic anhydride in presence of 4-dimethylamino-pyridine and pyridine. The corresponding acetate was treated with cyclohexone in the presence of 10% by weight palladium-on-carbon in order to remove the benzly group.
The acid was cyclized by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid at 0C. Finally the removal of the acetyl 0-protecting groups by treatment with sodium methylate afforded, 1~39~;3~3 after purification by chromatogr~phy on a silica gelc~lumn, 0.225 g of the title compound (overallyield 66%), IR (~ilm): 3450 cm (OH), ~675 cm (C=O, benzylic ketone). PMR (CDCl3): inter alia ~ 1.3 (d, J=4Hz, CH3-CH), 1.6-3.5 (m, 3H), 3.85 (s, OCH3), 3.90 (s, OCH3), 7.2-8 4 (m, f~ur aromatic H).
r ~
1,2,3,4,4a,5,12,12a-Octahydro -2- acetyl-2-hydroxy-6,11--dimetho~y-12-ox~-naphthacene .
0.1 g of 1,2,3,4,4a,5,12,12a-oc~hydro-2~ hydr~xyethyl)--2-hydrox~6,11-dimethoxy-12-ox~-napbthacene, prepared as described ~n Exa~ple 12, in benzene was treated wi~h 1 9 of silver carb~nate at refluxing temperature. After filtering ~ff the inorganic s~lids and remc~ving the s~lYent, 0.1 g of the title product was ~btained.
IR (film): 3460 cm 1 ~OH), 1710 cm 1 (C=O ketone~, 1680 cm 1 (C=O benzylic ketone) PMR ICDCl3): Inter alia ~ 2,4 (s, CH3CO), 3.~5 (s, OCH3), 3.90 (s, OCB31, 7. 2~ (m, four aromatic 2~
4-Demethoxy-6,7-dideoxydaunomycinone (XIV, R=H) Operating as described in Example 8, a solution of 0.1 g of 1,2,3,4,4a,5,12,12a-octahydro-2-acetyl-2-hydroxy-6,11-25 -dimethoxy-12-~xo-naphthacene, prepared as described in lZ39t;38 Example 13, in 3 ml of nitxobenzene was treated with 0.25 g of aluminium trichloride ove~nlght at ro~m temperature. After silica gel column chromatography, 0.055 g (63% y~eld) of the title compound was obt~ined, m.p. 2o3-2o4 .
6-Deoxy-4-demethyl daunorubicin (XVb) 90 ~g (0.2~ mmol~ of racemic 6-de~xy-carminomycinone, preparea ~s aescribed in Example 9 was dissol~ed in anhydrous dichloromethane and the solution was cooled to 5-10C. A s~luti~n of 2.4 mg to.6 mmol) of l-chloro--N~0-ditrifluor~acetvl-daunosamine, prepared foll`owinq the pr~cedure described in Cancer Chemo~herapy ~eports, Part 3~ ~ol. 6, N~. 2, p. 123, in diethyl ether and a solution of 154 mg (~6 mmol) of silver trifluo~m~thanesulphonate in dichlorometh~ne were added simultane~usly and rapidly under vigorous stirring.
After 5 ~inutes, a further 0.3 mmol of the halosugar and 0.3 mmol or sil~er trifluoromethane sulphonate were added. After 5 minutes, the reaction was quenched with collidine, The mixture was filtered, washed with a saturAted aqueDus solution of sodium bicarbonate and with watex, dried and concentrated under vacuu~. The reddish o~l ob~tained was diluted with 100 ml ~f ~239~3~3 . - 24-methanol and allowed t~ stand overnight at ro~m temperature to remove the O-trifluoroacetyl group.
The resultin~ crude product was puriflea by flas~
chro~atography on silica gel with dichl~romethane:
methanol:acetone 20~ y ~clume to afford the an~hracycline ~-glycosides XVaO
7S:9S, 20 mg, m.p. 210-212 & .
TLC ~n kieselgel plates (Mexck F254), using as eluent methylene-dichloride:acetone 4:1 by ~olume, Rf= 0.27.
10 m/z 5~3 (M~
PMR (2000 MHz, CDC13): inter alia ~ 1.44 (d, J=6.6Hz, 3H, CH3-S~, 2.42 (s, 3H, COCH3), 3.25-3.05 (two d, J=19Hz, 2H, H-lO), 4.22 (s, lH~ OH-9~, 5.01 (t, J=3 Hz, lH, H-7~, 5,20 (t, J=2.7Hz, lH, H-l'), 6.66 (bd, J=9Hz, lH, NH), 7,80 (s, lH, H-6), 12.62 (s, lH, OH-4), 13~06 (~, lH, OH-ll); m/z 593 (M ' ) 7R:9~ 25 mg, m.p. 174-178C.
TLC on kieseigel plates (Merck F254) using as eluent methylene dichloride:acetone 4:1 by Yolume, Rf=0.23.
m/z 59 3 (M~
PMR (200 MHz, CDC13): inter alia ~ 1.44 (d, J=6.5Hz, 3H
CH3--S'~, 2~41 (s, 3H! COCH3), 2.96 (d, J=19Rz, lH, H--10 ax), 3.30 (dd, J=l, l9Hz~ lH, H-10 eq), 4.25 (s, lH, OH-9), 5,07 (t, J=3.3Hz, lH, H-7), 5.27 (t, J=l.~Hz, lH, H-l'), 6.64 (bd, J=9Hz, lH, NH), 7.74 (s, lH, H-6), 12,66 (s, lH, 0~-4~, 13.10 (s, ~H, OH-ll).
Mild alkaline hydrolysis of XVa removes the N-trifluoroacetyl lZ39f~38 1 group to yive the title compound in quantitative yield.
TLC on kieselgel plates (Merck F254) using as eluent methylene dichloride:methanol:acetic acid:water 80:20:7:3 by volume, Rf 0.47.
6-deoxy-4-demethyl-doxor7lbicin (XVc) A solution of 6-deoxy-4-demethyl-daunorubicin prepared as described in Example 15 in a mixture of methanol and dioxane was treated with bromine to form the 14-bromo derivative. Treatment of the 14-bromo derivative with an aqueous solution of sodium formate at room temperature for 100 hours gave 6-deoxy-4-demethyl-doxorubicin.
m.p. 167-170C
Chromatography on TLC (Merck F254) using solvent system CH2cl2:MeoH:AcoH:H2o (8:2:0.7:0.3 v/v) Rf = 0.47 1~3':~;38 SUPPLEMENTARY DISCLOSURE
4-Demethoxy-6-deoxydaunomycinone (I:R = H) A solution of 0.5 g of 4-demethoxy-6, 7-dideoxydau-nomycinone, prepared as described in Example 14, 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 p-toluenesulphonic acid, affording the corresponding 13-ketal derivative (0.4 g) which cry-stallized directly from the cooled reaction mixture.
This cvmpound was dissolved in 250 ml of carbon tet-rachloride 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-iso-butyronitrile. The cooled reaction mix-ture was extracted with 1 N aqueous sodium hydroxide and the coloured aqueous phase was adjusted to pH
¦ 8.5 and extracted with chloroform. The organic ex-tracts, evaporated to a small volume, afforded 0.11 g of crystalline 4-demethoxy-6-deoxy-13-ketal daunomy~
cinone.
J
lLC on kieselgel plates (Merck F254) solvent system CHC13-(CH3)2CO (9:1 v/v): Rf 0.21 EI-MS:
~Z3~3ti3~3 m/e 396(M~) PMR(CDC13):
1.47 ~ (s, 3H, 14-CH3) 1.53 (s, lH, OH-9) 2.27 (ddd, 2H, H-8) J=14.5 Hz, 4.5 Hz, 6.0 Hz i 3.02 (dd, 2H, H-10) J=17.5 Hz 3.90 (d, lH, OH-7) J=10.5 Hz 4.09 (s, 4H, OCH2CH2O) 4.90 (dd, lH, H-7) J=4,5, 6.0 Hz 7.85, 8.26 (m, 4H, aromatic) 7.98 ~s, lH, H-6) 13.11 (s, lH, OH-ll) ! 15 IR (KBr):
1620 cm 1 bonded C=O quinone 1670lcm~l free C=O quinone Finally the hydrolysis of the ketal group was performed by treatment with an aqueous solution of hydrogen chloride in acetone (300 ml of a 0.25 N solution) at room temperature for 3 hours.
The title compound is obtained: TLC on kieselgel plates (Merck F 254) using solvent system chloroform:acetone (9:1 by volume): Rf 0.24 FD-MS:
i2~ ti3~
m/z 352 (M+) PMR 270 MHz (CDC13):
2.42 (s, 3H, COCH3) 2.98 (d, lH, HaX-10, Jge 17.9 Hz) 3.13 (d, lH, He-10, Jgem 17.9 Hz) 4.07 (d, OH-7, J=10 Hz) 4.46 (s, OH-9) 4.93 (m, Heq~7, J=10 Hz after D20 addltion WH= 8 Hz) 7.99 (s, H-6) 13.07 (s, OH-ll) In addition to the original disclosure, the present invention provides a further process 'or the prepara-tion of 6-deoxyanthroclinones having the gene~al forumla I above wherein R represents a lower alkoxy group. This process comprises the reaction scheme disclosed in the original disclosure on pages 1 to 3, as by steps~(i) to (xi) with the exception that original step (x) is replaced by an a:Lternate step as follows: -(x alternate) protecting the l-hydroxyethyl group of the compound of formula XIII wherein R is a methoxy group, with 2,2'-dimethoxy-propane, oxidatively demethylàting the resultant compound with cerium ammonium nitrate and pyridinium bromide perbromide, lZ~3~38 _ 29 -splitting off the 9t13-isopropylidene group with CF300H and oxidizing the free hydrogen group in the 13-position with triethylamine sulfide complex in dimethyl sulfoxide (~MS0) to provide a compound of the formula XIV
wherein R is a me hoxy group.
This alternate step prov:ides a weaker demethylation ¦ 10 step to facilitate maintaining the methoxy group .in ¦ the 4-position.
Accordingly, in a fourth of its aspects, the present invention provides a process for ~he preparation of 6-deoxyanthracyclinones having the general formula-I:
~ ~ ~ CH
~ R n 0~
j wherein R represents a hydrogen atom, a hydroxy group or a lower alkoxy group, characterized in that a dimethyl 1,2,3,6-tetrahydro-phthalate of formula II:
.
~3~00C
~3C00 ~3~ 8 by treatment with acetic anhydride in `the presence of -tin te-trachloride, followed by treatment with a mild base or a mild acid, is transformed into dimethyl 1, 2,3,6-tetrahydro-4-acetyl-phthalate III
~, .
H3COO ~ 3 III
H3C.OOC
-which, when reacted with tosylhydrazine gives the corresponding dimethyl 1,2,3,6-tetrahydro-4-(1-' tosylhydrazono-ethyl)-phthalate IV: .
~H5 s P.3COOC~ 3 1v ~'. 3COOC
Reducing the compound IV with catechol borane and subsequent rearranging the double bond from an en-docyclic to an exocyclic position in the presence.
of sodium acetate, to obtain 1,2,di-(methoxycarbonyl)-4-ethylidene-cyclohexane V:
- 31 -~ 38 H, ~COOC~CH3 V
~3CQOC
from which, after an oxidative treatment with potas-sium permanganate, the corresponding ~.-hydroxy ketone is obtained and subsequently reacted ~lith ethylene glycol, in the presence of catalitic amount of p-toluensulphonic acid, to give 2-methoxy-5-/ 2-methyl-dioxolan-2-yl/-6-oxa-bicyclo/ 3,2,1/octan-70ne v r:
~/ o. ' ~
t ~ CH~
. 15 : 11 j which, dissolved in anhydrous tetrahyclrofuran in ~on-i densed, at a temperature of -78C-and for lh, with an alkyltium derivative of formula VIII:
~ Li VIII
wherein R is as above defined, to obtain the lactone IX:
~,3~f~38 . ~ 3 IX
wherein R is as above defined, opening the lactone - ring of compound IX by methanolysis and contemporan-eously deprotecting the dioxolan pxot:ected keto group by acidic treatment to obtain the compound of formula X:
~CH3 OCH3 O .
1S ~J~ c~3 ~
' wherein R is as above defined, reduci.ng the keto ¦ 20 group of compound X by treatment with a pyridine-! borane complex in the presence of tri.fluoroacetic acid and converting the methoxycarbonyl group into a benzyloxycarbonyl group by treatment with phenyl-diazomethane to obtain the compound of formula XI:
1~39~3~3 OCH ~CH C H OH
= CH3 R ~13 wherein ~ is as above defined, esterifying the hydroxy groups and deesterifying the benzyloxycarbonyl group of compound XI, wherein R is above defined, by treat-ment with acetic anhydride in pyridine in the presence of 4-dimethylamino-pyridine followed by refluxing with cyclohexene in the presence of a pal:Ladium-on-carbon catalyst, to give the compound of fo:mula XII:
OCH3 o OC'/~CH3 CH3 X~l R' OCH3 ¦ wherein R' represents a hydrogen atom, an acetoxy group or a lower alkoxy group, which is submitted to a cyclization by treatment with a mixture of trifluo-roacetic anhydride and trifluoroacetic acid and to a subsequent hydrolysis of the acetoxy groups with sodium methylate to obtain compound XIII:
C~3 11 OH
wherein R is above defined, from which by protecting the l-hydroxyethyl group of the compound XIII with 2,2'dimethoxypropane, oxidatively demethylating the resulting compound with cerium ammonium nitrate and pyridinium bromide perbromide, splitting off the 9,13-isopropylidene group with CE' COCH and oxidizing the free hydroxy group in the 13-position with triethylamine sulfide complex in dimethyl sulfoxide, the compound of the formula XIV is o~tained:
O OH O
R O
wherein R is as above defined, from which, after pro-tection of the 13-keto group by treatment with ethylene glycol, bromination of the resultant compound at C-7 with bromine in the presence of 2,2-azo-bis(isobutyroni-123~3~38 trile) followed by hydrolysis of the 7 bromo deriva-tive and removal of the ketal group by acid treatment, or alternatively by bromination with N-bromo-succinimide in the presence of 2,2'-azo-bis(isobutironitrile, by irradiation, treatment with silver acetate, hydrolysis of the aceta-te with sodium methoxide, the desired com-pounds of fo.-mula I are finally obtai.ned.
123~3~3 In a fifth aspect, the present invention provides a process in accordance with the fourth aspect for the preparation of 6~deoxydaunomycinone wherein throughout said process R and R' each represent a methoxy group.
In a sixth aspect, the present invention provides a process in accordance with the fourth aspect wherein throughout said process R and R' each comprise a .
lower alkoxy group.
.
6,7-Dideoxydauncomycinone (XIV : R = OCH3) 2.77 g of 1,2,3,4,4a,5,12,12a-octahydro-2-(1-hydroxy-ethyl)-2-hydroxy-6,7,11-trimethoxy-12-oxonaphthacene - (XIII, R = OCH3) prepared according to the Example 6, disso1ved in dloxan ~160 ml) was treatment with 2'2-dimethoxypropane (8.47 g) in presence of p-toluensul-2~ fonic acid (PTSA) (0.07 g) at room temperature for 3.5 hrs. The.solution was diluted wlth water and ex- i tracted with me~thylene chloride to give, after evapora-tion of the solvent, 2.93 g of solid material.
The residue was dissolved in acetonitrile (lC0 ml), cooled at 0C and treated with a solution of cerium ammonium nitrate (CAN) (9.87 g) in water (30 ml).
. After standing for 30 minutes, water was added (200 ml) and extracted thoroughly with CHzCl2. The 12';~3t;38 organic layer was washed with a solu-tion of Na2S2O3, water, dried over Na2SO4 and the solvent removed in vacuo to give 2.57 g of solid material. The residue, dissolved in CH2Cl~ (275 ml) and cooled at 0C was treated wi-th PyHBr-Br2 complex (2.01 g). After 1 hr at 0C triethylamine (TEA) was added (1.75 ml), the mix-ture stirred for 1.5 hr and -then extracted with CH2C12. The organic layer was washed with 5% Na2',2O3 aqueous solution, water, dried over Na2SO4 and con-centrated. The solid material was chromatographecl on kieselgel to give (1.08! overall yield 36%) of 6,7-dideoxy-13-dihydro-9,13-isopropyliden daunomycinone.
m.p. 135--138C (dec.); m!z 408 (M+'), PMR ~CDC13) :nter alia c~ : 1.45, 1.39, 1.24 (s, 6H), 4.04, (s, 3H, ()CH3), 4.07, 4.16 (q, J = 6.4 Hz, lH, CH-CH3), 7.54-7.57 (s, lH, 6-H), 7.35-7.79 (m, 3H), 12.92 (s, lH, ll-OH), The purified product was treated at 0C with~90%
CF3CQOH (50 ml) for 2 hrs. The solution was neutralized with solid NaHCO3 and extracted with methylene ch:Loride.
The solvent was removed in vacuo and the residue dis-solved in DMSO (20 ml). TEA (4 ml) and a solu-tion of TEA-SO3 complex (1.5 g) in DMSO (5 ml) were added.
The mixture was stirred for 40 minutes at room tempera-ture, poured in 1 N HCl and extracted with CH2C12.
The organic phase was washed with NaHCO3 saturated aqueous solution, with water, drled over Na2SO4 and .
~Z;3~j3~
the solvent removed in vacuo~ The crude ma-terial was purified by kieselgel chromatography affording XIV,- R = OCH3(0.72 g, yield 80%).
m.p. 149-151C (dec.): m/z 366 (M+'); PMR (CDC13) inter alia: ~ 1.8-2.2 ~m, 2H, 8-CH2), 2.37 (5, 3H, COCH3), 2.8-3.4 (m, 4H, 10-CH2, 7-CH2), 4.04 (s, 3H, OCH3), 7.35 (dd, J = 1.0, 8.0 Hz, lH, 3-H), 7.58 (s, lH, 6-H), 7.72 (t, J = 8.0 H~, lH, 2-ll), 7.97 (dd, J = 1.0, 8.0 Hz, lH, l-H), 12.90 (s, lH~ ll-OH); UV and visible spectra: 228, 261, 394, 412 nm.
.
6-Deoxydaunomycinone (I, R = OCH3) Product XIV (R = OCH3) (0.6 g?, following the sequence of reactions described in example 9, was transformed to product I (R = OCH3) (0.210 g, yield 33%).
m.p. 268-270DC; m/z 382 (M+ ); PMR (CDC13) inter alia: ~ 2.3 (m, 2H, 8-CH2), 2.42 (s, 3H, COCH3), 3.00 (d, J = 18 Hz, lH, 10-HaX), 3-15 (d, J = 18-0 Hz, lH, 10~Heq), 4.06 (s, 3H, OCH3), 4.96 (m, lH, 7-H~, 7.40 (d, J = 8.0 Hz, lH, 3 H), 7.80 (t, J =
2-(1,4-Dimethoxy-3-naphthylcarbonyl)-5-(2-methyl-dioxolan--2-yl)-6-oxa~bicyclo/3,2,17 octan-7-one (IX, R=H) _ Following the ~e~hod describea in Example 4, a solution .
2~39t;31~ .
of 3.2 g of 1 4-dimeth~xy-3-bromo-naphthalene in anhydrous tetrahydrofuran was treated at -78~C with n-butyllithium and then added to a solution in anhydrous tetrahydrofuran of 2.7 9 of the comp~und prepaxed in Exam~le 3. After silica gel column purification 2.8 g of the title com~ound was obtaine~ (65~ yield) m/z 426 (M ): IR (film)~
1780 cm 1 (C=O five membered ring lactone) 1670 cm 1 ~C=~ benzylic ketone) PMR (C~C13): inter alia:
~ 1.4 (s CH3) 3.85 ls two OCH3) 3.9 (s -~-CH2--CH2-0-) 6.9 (s aromatic H) and 7.4-8.4 ~m four ~romatic H).
EXP~lPLE 11 1-(1 4-dimethoxy-3-naphthylmethyl)- -benzyloxycarb~nyl--4-(l-hydroxyethyl)-4-hYdroxy-cyclohexane (XI R=H) Operating as described in Example 5 the treatment of 2-(1 4-dimethoxy-3-naphthylcarbonyl~-5-(2-methyl--dioxolan-2-yl)-6-oxa-bicyclol3 2 lloctan-7-one prepared as described in Example 109. with a solution o~ hydrogen chloride in me~hanol afi.orde~ 1,4--dimethoxy-3-naphthylcarbonyl)-2-meth~xycarb~nyl-4--acetyl 4-hydroxy-cyclohexane (X R-H) in almos$
quantitatlve yield. m/z 414 (M ): IR (filml: 3460 cm 1 (OH) 1730 cm 1 (C=0 ester) 1710 cm 1 (C=0 ketone) and 1670 cm ~ (C=0, benzylic ketone).
PMR (CDC13). inter alia: ~ 2.3 (s CH3C0~ 2.9-3.6 12~ 8 (m, two H), 3.7-3.9 (s, three OCH3), 6.9 (s, aromatic H) and 7.4-8.4 (m, four aromatic H~.
1 y of this compouna, by reduction with pyridine--borane complex, basic treatment and finally esterlfication with phenyldiazomethane was converted to the title compound ~0.7 9, overall yield 63%).
m/z 478 ~M ): IR (film)~: 3450 cm 1 (OH~, 1725 cm 1 (C=O, ester). PMR ~CDC13)~ nter alia ~ 1.3 Id, J=
4Hz r CH3-CH), 3.85-3.9 ~s, two OCH3), 5.1 ~s, CH2--benzylic), 6.6 (s, aromatic ~) and 7.2-8.~ (m, nine aromatic hydrogens).
~,2,3,4,4a,5,12,12a-Octahydro-2-~l-hYaroxyethyl)-2--hydr_xy-6,11-dimethoxy-12-oxo-naphthacene ~Xl~lI, R=H) Operating as described in Example 6, 0.44 9 of 1-(1,4--dimethoxy-3-naphthylmethy])-2-benzyloxycarbonyl-4--(l-hydroxyethyl)-4-hydroxy-cyciohexane, prepared as described in Example 11, was treated with acetic anhydride in presence of 4-dimethylamino-pyridine and pyridine. The corresponding acetate was treated with cyclohexone in the presence of 10% by weight palladium-on-carbon in order to remove the benzly group.
The acid was cyclized by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid at 0C. Finally the removal of the acetyl 0-protecting groups by treatment with sodium methylate afforded, 1~39~;3~3 after purification by chromatogr~phy on a silica gelc~lumn, 0.225 g of the title compound (overallyield 66%), IR (~ilm): 3450 cm (OH), ~675 cm (C=O, benzylic ketone). PMR (CDCl3): inter alia ~ 1.3 (d, J=4Hz, CH3-CH), 1.6-3.5 (m, 3H), 3.85 (s, OCH3), 3.90 (s, OCH3), 7.2-8 4 (m, f~ur aromatic H).
r ~
1,2,3,4,4a,5,12,12a-Octahydro -2- acetyl-2-hydroxy-6,11--dimetho~y-12-ox~-naphthacene .
0.1 g of 1,2,3,4,4a,5,12,12a-oc~hydro-2~ hydr~xyethyl)--2-hydrox~6,11-dimethoxy-12-ox~-napbthacene, prepared as described ~n Exa~ple 12, in benzene was treated wi~h 1 9 of silver carb~nate at refluxing temperature. After filtering ~ff the inorganic s~lids and remc~ving the s~lYent, 0.1 g of the title product was ~btained.
IR (film): 3460 cm 1 ~OH), 1710 cm 1 (C=O ketone~, 1680 cm 1 (C=O benzylic ketone) PMR ICDCl3): Inter alia ~ 2,4 (s, CH3CO), 3.~5 (s, OCH3), 3.90 (s, OCB31, 7. 2~ (m, four aromatic 2~
4-Demethoxy-6,7-dideoxydaunomycinone (XIV, R=H) Operating as described in Example 8, a solution of 0.1 g of 1,2,3,4,4a,5,12,12a-octahydro-2-acetyl-2-hydroxy-6,11-25 -dimethoxy-12-~xo-naphthacene, prepared as described in lZ39t;38 Example 13, in 3 ml of nitxobenzene was treated with 0.25 g of aluminium trichloride ove~nlght at ro~m temperature. After silica gel column chromatography, 0.055 g (63% y~eld) of the title compound was obt~ined, m.p. 2o3-2o4 .
6-Deoxy-4-demethyl daunorubicin (XVb) 90 ~g (0.2~ mmol~ of racemic 6-de~xy-carminomycinone, preparea ~s aescribed in Example 9 was dissol~ed in anhydrous dichloromethane and the solution was cooled to 5-10C. A s~luti~n of 2.4 mg to.6 mmol) of l-chloro--N~0-ditrifluor~acetvl-daunosamine, prepared foll`owinq the pr~cedure described in Cancer Chemo~herapy ~eports, Part 3~ ~ol. 6, N~. 2, p. 123, in diethyl ether and a solution of 154 mg (~6 mmol) of silver trifluo~m~thanesulphonate in dichlorometh~ne were added simultane~usly and rapidly under vigorous stirring.
After 5 ~inutes, a further 0.3 mmol of the halosugar and 0.3 mmol or sil~er trifluoromethane sulphonate were added. After 5 minutes, the reaction was quenched with collidine, The mixture was filtered, washed with a saturAted aqueDus solution of sodium bicarbonate and with watex, dried and concentrated under vacuu~. The reddish o~l ob~tained was diluted with 100 ml ~f ~239~3~3 . - 24-methanol and allowed t~ stand overnight at ro~m temperature to remove the O-trifluoroacetyl group.
The resultin~ crude product was puriflea by flas~
chro~atography on silica gel with dichl~romethane:
methanol:acetone 20~ y ~clume to afford the an~hracycline ~-glycosides XVaO
7S:9S, 20 mg, m.p. 210-212 & .
TLC ~n kieselgel plates (Mexck F254), using as eluent methylene-dichloride:acetone 4:1 by ~olume, Rf= 0.27.
10 m/z 5~3 (M~
PMR (2000 MHz, CDC13): inter alia ~ 1.44 (d, J=6.6Hz, 3H, CH3-S~, 2.42 (s, 3H, COCH3), 3.25-3.05 (two d, J=19Hz, 2H, H-lO), 4.22 (s, lH~ OH-9~, 5.01 (t, J=3 Hz, lH, H-7~, 5,20 (t, J=2.7Hz, lH, H-l'), 6.66 (bd, J=9Hz, lH, NH), 7,80 (s, lH, H-6), 12.62 (s, lH, OH-4), 13~06 (~, lH, OH-ll); m/z 593 (M ' ) 7R:9~ 25 mg, m.p. 174-178C.
TLC on kieseigel plates (Merck F254) using as eluent methylene dichloride:acetone 4:1 by Yolume, Rf=0.23.
m/z 59 3 (M~
PMR (200 MHz, CDC13): inter alia ~ 1.44 (d, J=6.5Hz, 3H
CH3--S'~, 2~41 (s, 3H! COCH3), 2.96 (d, J=19Rz, lH, H--10 ax), 3.30 (dd, J=l, l9Hz~ lH, H-10 eq), 4.25 (s, lH, OH-9), 5,07 (t, J=3.3Hz, lH, H-7), 5.27 (t, J=l.~Hz, lH, H-l'), 6.64 (bd, J=9Hz, lH, NH), 7.74 (s, lH, H-6), 12,66 (s, lH, 0~-4~, 13.10 (s, ~H, OH-ll).
Mild alkaline hydrolysis of XVa removes the N-trifluoroacetyl lZ39f~38 1 group to yive the title compound in quantitative yield.
TLC on kieselgel plates (Merck F254) using as eluent methylene dichloride:methanol:acetic acid:water 80:20:7:3 by volume, Rf 0.47.
6-deoxy-4-demethyl-doxor7lbicin (XVc) A solution of 6-deoxy-4-demethyl-daunorubicin prepared as described in Example 15 in a mixture of methanol and dioxane was treated with bromine to form the 14-bromo derivative. Treatment of the 14-bromo derivative with an aqueous solution of sodium formate at room temperature for 100 hours gave 6-deoxy-4-demethyl-doxorubicin.
m.p. 167-170C
Chromatography on TLC (Merck F254) using solvent system CH2cl2:MeoH:AcoH:H2o (8:2:0.7:0.3 v/v) Rf = 0.47 1~3':~;38 SUPPLEMENTARY DISCLOSURE
4-Demethoxy-6-deoxydaunomycinone (I:R = H) A solution of 0.5 g of 4-demethoxy-6, 7-dideoxydau-nomycinone, prepared as described in Example 14, 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 p-toluenesulphonic acid, affording the corresponding 13-ketal derivative (0.4 g) which cry-stallized directly from the cooled reaction mixture.
This cvmpound was dissolved in 250 ml of carbon tet-rachloride 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-iso-butyronitrile. The cooled reaction mix-ture was extracted with 1 N aqueous sodium hydroxide and the coloured aqueous phase was adjusted to pH
¦ 8.5 and extracted with chloroform. The organic ex-tracts, evaporated to a small volume, afforded 0.11 g of crystalline 4-demethoxy-6-deoxy-13-ketal daunomy~
cinone.
J
lLC on kieselgel plates (Merck F254) solvent system CHC13-(CH3)2CO (9:1 v/v): Rf 0.21 EI-MS:
~Z3~3ti3~3 m/e 396(M~) PMR(CDC13):
1.47 ~ (s, 3H, 14-CH3) 1.53 (s, lH, OH-9) 2.27 (ddd, 2H, H-8) J=14.5 Hz, 4.5 Hz, 6.0 Hz i 3.02 (dd, 2H, H-10) J=17.5 Hz 3.90 (d, lH, OH-7) J=10.5 Hz 4.09 (s, 4H, OCH2CH2O) 4.90 (dd, lH, H-7) J=4,5, 6.0 Hz 7.85, 8.26 (m, 4H, aromatic) 7.98 ~s, lH, H-6) 13.11 (s, lH, OH-ll) ! 15 IR (KBr):
1620 cm 1 bonded C=O quinone 1670lcm~l free C=O quinone Finally the hydrolysis of the ketal group was performed by treatment with an aqueous solution of hydrogen chloride in acetone (300 ml of a 0.25 N solution) at room temperature for 3 hours.
The title compound is obtained: TLC on kieselgel plates (Merck F 254) using solvent system chloroform:acetone (9:1 by volume): Rf 0.24 FD-MS:
i2~ ti3~
m/z 352 (M+) PMR 270 MHz (CDC13):
2.42 (s, 3H, COCH3) 2.98 (d, lH, HaX-10, Jge 17.9 Hz) 3.13 (d, lH, He-10, Jgem 17.9 Hz) 4.07 (d, OH-7, J=10 Hz) 4.46 (s, OH-9) 4.93 (m, Heq~7, J=10 Hz after D20 addltion WH= 8 Hz) 7.99 (s, H-6) 13.07 (s, OH-ll) In addition to the original disclosure, the present invention provides a further process 'or the prepara-tion of 6-deoxyanthroclinones having the gene~al forumla I above wherein R represents a lower alkoxy group. This process comprises the reaction scheme disclosed in the original disclosure on pages 1 to 3, as by steps~(i) to (xi) with the exception that original step (x) is replaced by an a:Lternate step as follows: -(x alternate) protecting the l-hydroxyethyl group of the compound of formula XIII wherein R is a methoxy group, with 2,2'-dimethoxy-propane, oxidatively demethylàting the resultant compound with cerium ammonium nitrate and pyridinium bromide perbromide, lZ~3~38 _ 29 -splitting off the 9t13-isopropylidene group with CF300H and oxidizing the free hydrogen group in the 13-position with triethylamine sulfide complex in dimethyl sulfoxide (~MS0) to provide a compound of the formula XIV
wherein R is a me hoxy group.
This alternate step prov:ides a weaker demethylation ¦ 10 step to facilitate maintaining the methoxy group .in ¦ the 4-position.
Accordingly, in a fourth of its aspects, the present invention provides a process for ~he preparation of 6-deoxyanthracyclinones having the general formula-I:
~ ~ ~ CH
~ R n 0~
j wherein R represents a hydrogen atom, a hydroxy group or a lower alkoxy group, characterized in that a dimethyl 1,2,3,6-tetrahydro-phthalate of formula II:
.
~3~00C
~3C00 ~3~ 8 by treatment with acetic anhydride in `the presence of -tin te-trachloride, followed by treatment with a mild base or a mild acid, is transformed into dimethyl 1, 2,3,6-tetrahydro-4-acetyl-phthalate III
~, .
H3COO ~ 3 III
H3C.OOC
-which, when reacted with tosylhydrazine gives the corresponding dimethyl 1,2,3,6-tetrahydro-4-(1-' tosylhydrazono-ethyl)-phthalate IV: .
~H5 s P.3COOC~ 3 1v ~'. 3COOC
Reducing the compound IV with catechol borane and subsequent rearranging the double bond from an en-docyclic to an exocyclic position in the presence.
of sodium acetate, to obtain 1,2,di-(methoxycarbonyl)-4-ethylidene-cyclohexane V:
- 31 -~ 38 H, ~COOC~CH3 V
~3CQOC
from which, after an oxidative treatment with potas-sium permanganate, the corresponding ~.-hydroxy ketone is obtained and subsequently reacted ~lith ethylene glycol, in the presence of catalitic amount of p-toluensulphonic acid, to give 2-methoxy-5-/ 2-methyl-dioxolan-2-yl/-6-oxa-bicyclo/ 3,2,1/octan-70ne v r:
~/ o. ' ~
t ~ CH~
. 15 : 11 j which, dissolved in anhydrous tetrahyclrofuran in ~on-i densed, at a temperature of -78C-and for lh, with an alkyltium derivative of formula VIII:
~ Li VIII
wherein R is as above defined, to obtain the lactone IX:
~,3~f~38 . ~ 3 IX
wherein R is as above defined, opening the lactone - ring of compound IX by methanolysis and contemporan-eously deprotecting the dioxolan pxot:ected keto group by acidic treatment to obtain the compound of formula X:
~CH3 OCH3 O .
1S ~J~ c~3 ~
' wherein R is as above defined, reduci.ng the keto ¦ 20 group of compound X by treatment with a pyridine-! borane complex in the presence of tri.fluoroacetic acid and converting the methoxycarbonyl group into a benzyloxycarbonyl group by treatment with phenyl-diazomethane to obtain the compound of formula XI:
1~39~3~3 OCH ~CH C H OH
= CH3 R ~13 wherein ~ is as above defined, esterifying the hydroxy groups and deesterifying the benzyloxycarbonyl group of compound XI, wherein R is above defined, by treat-ment with acetic anhydride in pyridine in the presence of 4-dimethylamino-pyridine followed by refluxing with cyclohexene in the presence of a pal:Ladium-on-carbon catalyst, to give the compound of fo:mula XII:
OCH3 o OC'/~CH3 CH3 X~l R' OCH3 ¦ wherein R' represents a hydrogen atom, an acetoxy group or a lower alkoxy group, which is submitted to a cyclization by treatment with a mixture of trifluo-roacetic anhydride and trifluoroacetic acid and to a subsequent hydrolysis of the acetoxy groups with sodium methylate to obtain compound XIII:
C~3 11 OH
wherein R is above defined, from which by protecting the l-hydroxyethyl group of the compound XIII with 2,2'dimethoxypropane, oxidatively demethylating the resulting compound with cerium ammonium nitrate and pyridinium bromide perbromide, splitting off the 9,13-isopropylidene group with CE' COCH and oxidizing the free hydroxy group in the 13-position with triethylamine sulfide complex in dimethyl sulfoxide, the compound of the formula XIV is o~tained:
O OH O
R O
wherein R is as above defined, from which, after pro-tection of the 13-keto group by treatment with ethylene glycol, bromination of the resultant compound at C-7 with bromine in the presence of 2,2-azo-bis(isobutyroni-123~3~38 trile) followed by hydrolysis of the 7 bromo deriva-tive and removal of the ketal group by acid treatment, or alternatively by bromination with N-bromo-succinimide in the presence of 2,2'-azo-bis(isobutironitrile, by irradiation, treatment with silver acetate, hydrolysis of the aceta-te with sodium methoxide, the desired com-pounds of fo.-mula I are finally obtai.ned.
123~3~3 In a fifth aspect, the present invention provides a process in accordance with the fourth aspect for the preparation of 6~deoxydaunomycinone wherein throughout said process R and R' each represent a methoxy group.
In a sixth aspect, the present invention provides a process in accordance with the fourth aspect wherein throughout said process R and R' each comprise a .
lower alkoxy group.
.
6,7-Dideoxydauncomycinone (XIV : R = OCH3) 2.77 g of 1,2,3,4,4a,5,12,12a-octahydro-2-(1-hydroxy-ethyl)-2-hydroxy-6,7,11-trimethoxy-12-oxonaphthacene - (XIII, R = OCH3) prepared according to the Example 6, disso1ved in dloxan ~160 ml) was treatment with 2'2-dimethoxypropane (8.47 g) in presence of p-toluensul-2~ fonic acid (PTSA) (0.07 g) at room temperature for 3.5 hrs. The.solution was diluted wlth water and ex- i tracted with me~thylene chloride to give, after evapora-tion of the solvent, 2.93 g of solid material.
The residue was dissolved in acetonitrile (lC0 ml), cooled at 0C and treated with a solution of cerium ammonium nitrate (CAN) (9.87 g) in water (30 ml).
. After standing for 30 minutes, water was added (200 ml) and extracted thoroughly with CHzCl2. The 12';~3t;38 organic layer was washed with a solu-tion of Na2S2O3, water, dried over Na2SO4 and the solvent removed in vacuo to give 2.57 g of solid material. The residue, dissolved in CH2Cl~ (275 ml) and cooled at 0C was treated wi-th PyHBr-Br2 complex (2.01 g). After 1 hr at 0C triethylamine (TEA) was added (1.75 ml), the mix-ture stirred for 1.5 hr and -then extracted with CH2C12. The organic layer was washed with 5% Na2',2O3 aqueous solution, water, dried over Na2SO4 and con-centrated. The solid material was chromatographecl on kieselgel to give (1.08! overall yield 36%) of 6,7-dideoxy-13-dihydro-9,13-isopropyliden daunomycinone.
m.p. 135--138C (dec.); m!z 408 (M+'), PMR ~CDC13) :nter alia c~ : 1.45, 1.39, 1.24 (s, 6H), 4.04, (s, 3H, ()CH3), 4.07, 4.16 (q, J = 6.4 Hz, lH, CH-CH3), 7.54-7.57 (s, lH, 6-H), 7.35-7.79 (m, 3H), 12.92 (s, lH, ll-OH), The purified product was treated at 0C with~90%
CF3CQOH (50 ml) for 2 hrs. The solution was neutralized with solid NaHCO3 and extracted with methylene ch:Loride.
The solvent was removed in vacuo and the residue dis-solved in DMSO (20 ml). TEA (4 ml) and a solu-tion of TEA-SO3 complex (1.5 g) in DMSO (5 ml) were added.
The mixture was stirred for 40 minutes at room tempera-ture, poured in 1 N HCl and extracted with CH2C12.
The organic phase was washed with NaHCO3 saturated aqueous solution, with water, drled over Na2SO4 and .
~Z;3~j3~
the solvent removed in vacuo~ The crude ma-terial was purified by kieselgel chromatography affording XIV,- R = OCH3(0.72 g, yield 80%).
m.p. 149-151C (dec.): m/z 366 (M+'); PMR (CDC13) inter alia: ~ 1.8-2.2 ~m, 2H, 8-CH2), 2.37 (5, 3H, COCH3), 2.8-3.4 (m, 4H, 10-CH2, 7-CH2), 4.04 (s, 3H, OCH3), 7.35 (dd, J = 1.0, 8.0 Hz, lH, 3-H), 7.58 (s, lH, 6-H), 7.72 (t, J = 8.0 H~, lH, 2-ll), 7.97 (dd, J = 1.0, 8.0 Hz, lH, l-H), 12.90 (s, lH~ ll-OH); UV and visible spectra: 228, 261, 394, 412 nm.
.
6-Deoxydaunomycinone (I, R = OCH3) Product XIV (R = OCH3) (0.6 g?, following the sequence of reactions described in example 9, was transformed to product I (R = OCH3) (0.210 g, yield 33%).
m.p. 268-270DC; m/z 382 (M+ ); PMR (CDC13) inter alia: ~ 2.3 (m, 2H, 8-CH2), 2.42 (s, 3H, COCH3), 3.00 (d, J = 18 Hz, lH, 10-HaX), 3-15 (d, J = 18-0 Hz, lH, 10~Heq), 4.06 (s, 3H, OCH3), 4.96 (m, lH, 7-H~, 7.40 (d, J = 8.0 Hz, lH, 3 H), 7.80 (t, J =
8.0 Hz, IH, 2-H), 7.96 (s, lH, 6-H), 8.04 (d, J =
8.0 Hz, lH, l-H).
lZ39~3~
While the invention has been described with reference to preferred examples, the invention is not so limited.
Many varations and modifications will now occur to those skilled in the art. For a definition of the invention, reference lS made to the following claims.
'' , "
.
. ' ' .
,, , .
' . ,:
.
.
8.0 Hz, lH, l-H).
lZ39~3~
While the invention has been described with reference to preferred examples, the invention is not so limited.
Many varations and modifications will now occur to those skilled in the art. For a definition of the invention, reference lS made to the following claims.
'' , "
.
. ' ' .
,, , .
' . ,:
.
.
Claims (17)
- Claim 1 continued...
of the ketal by acid treatment and finally hydrolysis of the ace-tate with sodium methoxide, the desired compounds of forumla I are finally obtained. - 2. A process for the preparation of 4-demethoxy-6-deoxy-daunomycinone comprising the process of claim 1 wherein R, R' and R" each represent hydrogen.
- 3. 4-Demethoxy-6-deoxy-daunomycinone when prepared by the process of claim 2 or an obvious chemical equivalent.
- 4. A process for the preparation of 4-demethyl-6-deoxy-daunomycinone comprising the process of claim 1 wherein R and R"
each represents a hydroxy group and R' represents a methoxy group. - 5. 4-Demethyl-6-deoxy-daunomycinone when prepared by the process of claim 4 or an obvious chemical equivalent.
- 6. A process for the preparation of 4-demethyl-6-deoxy-daunomycinone comprising the process of claim 1 wherein R repre-sents a hydroxy group or a methoxy group, R' represents a methoxy group, and R" represents a hydroxy group.
- 7. 4-Demethyl-6-deoxy-daunomycinone when prepared by the process of claim 6 or an obvious chemical equivalent.
8. 6-Deoxyanthracyclinones having the general formula I:
I - Claim 8 continued...
wherein R represents a hydroxy group. - 9. 4-Demethyl-6-deoxy-daunomycinone.
CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE - 10. 6-Deoxyanthracyclinones having the general formula I as defined in claim 8 wherein R represents a hydroxy group or a lower alkoxy group.
- 11. 6-Deoxyanthracyclinones of the formula I as claimed in claim 10 wherein R represents a lower alkoxy group.
12. A process for the preparation of 6-deoxyanthracyclinones having the general formula I:
I
Claim 12 continued...
wherein R represents a hydrogen atom, a hydroxy group or a lower alkoxy group, characterized in that a dimethyl 1,2,3,6-tetrahydro-phthalate of formula II:
II
by treatment with acetic anhydride in the presence of tin tetrachloride, followed by treatment with a mild base or a mild acid, is transformed into dimethyl 1,-2,3,6-tetrahydro-4-acetyl-phthalate III:
III
which, when reacted with tosylhydrazine gives the corresponding dimethyl 1,2,3,6-tetrahydro-4-(1-tosylhydrazono-ethyl)-phthalate IV:
IV
reducing the compound IV with catechol borane and sub-sequent rearranging the double bond from an endocyclic to an exocyclic position in the presence of sodium ace-tate, to obtain 1,2-di-(methoxycarbonyl)-4-ethylidene-cyclohexane V:
Claim 12 continued...
V
from which, after an oxidative treatment with potas-sium permanganate, the corresponding .alpha.-hydroxy ketone is obtained and subsequently reacted with ethylene glycol, in the presence of catalitic amount of p-toluensulphonic acid, to give 2-methoxy-5-?2-methyl-dioxolan-2-yl?-6-oxa-bicyclo?3,2,1?octan-7one VI:
VI
which, dissolved in anhydrous tetrahydrofuran in con-densed, at a temperature of -78°C and for 1 hour, with an alkyltium derivative of formula VIII:
VIII
wherein R is as above defined, to obtain the lactone IX:
Claim 12 continued...
IX
wherein R is as above defined, opening the lactone ring of compound IX by methanolysis and contemporan-eously deprotecting the dioxolan protected keto group by acidic treatment to obtain the compound of formula X:
X
wherein R is as above defined, reducing the keto group of compound X by treatment with a pyridine-borane complex in the presence of trifluoroacetic acid and converting the methoxycarbonyl group into a benzyloxycarbonyl group by treatment with phenyl-diazomethane to obtain the compound of formula XI:
Claim 12 continued...
XI
wherein R is as above defined, esterifying the hydroxy groups and deesterifying the benzyloxycarbonyl group of compound XI, wherein R is above defined, by treat-ment with acetic anhydride in pyridine in the presence of 4-dimethylamino-pyridine followed by refluxing with cyclohexene in the presence of a palladium-on-carbon catalyst, to give the compound of formula XII:
XII
wherein R' represents a hydrogen atom, an acetoxy group or a lower alkoxy group, which is submitted to a cyclization by treatment with a mixture of trifluo-roacetic anhydride and trifluoroacetic acid and to a subsequent hydrolysis of the acetoxy groups with sodium methylate to obtain compound XIII:
Claim 12 continued...
XIII
wherein R is above defined, from which by protecting the 1-hydroxyethyl group of the compound XIII with 2,2'dimethoxypropane, oxidatively demethylating the resulting compound with cerium ammonium nitrate and pyridinium bromide perbromide, splitting off the 9,13-isopropylidene group with CF3COOH and oxidizing the free hydroxy group in the 13-position with triethylamine sulfide complex in dimethyl sulfoxide, the compound of the formula XIV is obtained:
XIV
wherein R is as above defined, from which, after pro-tection of the 13-keto group by treatment with ethylene glycol, bromination of the resultant compound at C-7 with bromine in the presence of 2,2-azo-bis(isobutyroni- - Claim 12 continued...
trile) followed by hydrolysis of the 7-bromo derivative and removal of the ketal group by acid treatment, or alternatively by bromination with N-bromo-succinimide in the presence of 2,2'-azo-bis(isobutironitrile, by irradiation, treatment with silver acetate, hydrolysis of the acetate with sodium methoxide, the desired compounds of formula I are finally obtained. - 13. A process for the preparation of 6-deoxy-daunomycinone comprising the process of claim 12 where-in each of R and R' represents a methoxy group.
- 14. 6-Deoxy-daunomycinone when prepared by the process of claim 13 or an obvious chemical equivalent.
- 15. The process of claim 12wherein R and R' each represents a lower alkoxy group.
- 16. The process of claim 12 wherein the lower alkoxy group which may comprise R and R' consists of a methoxy group.
- 17. 6-Deoxyanthracyclinones having the general formula I:
wherein R represents a hydrogen atom, a hydroxy group or a lower alkoxy group, when prepared by the process of claim 12 or an obvious chemical equivalent.
1. A process for the preparation of 6-deoxyanth-racyclinones having the general formula I:
I
wherein R" represents a hydrogen atom or a hydroxy group characterized in that a dimethyl 1,2,3,6-tetrahydro-phthalate of formula II:
II
by treatment with acetic anhydride in the presence of tin tetrachloride, followed by treatment with a mild base or a mild acid, is transformed into dimethyl 1,2,3, 6-tetrahydro-4-acetyl-phthalate III:
III
which, when reacted with tosylhydrazine gives the corre-sponding dimethyl 1,2,3,6-tetrahydro-4-(1-tosylhydrazono-ethyl)-phthalate IV:
IV
reducing the compound IV with catechol borane and sub-sequent rearranging the double bond from an endocyclic to an exocyclic position in the presence of sodium ace-tate, to obtain 1,2-di-(methoxycarbonyl)-4-ethylidene-cyclohexane V:
V
from which, after an oxidative treatment with potassium permanganate, the corresponding .alpha.-hydroxy ketone is obtained and subsequently reacted with ethylene glycol, in the presence of catalitic amount of p-toluensulphonic acid, to give 2-methoxy-5-? 2-methyl-dioxolan-2-yl?-6-oxa-bicycla?=3,2,1?octan-7-one VI:
VI
which, dissolved in anhydrous tetrahydrofuran is con-densed, at a temperature of -78°C and for 1 hour, with an alkyltium derivative of formula VIII:
VIII
wherein R represents a hydrogen atom, a hydroxy group or a lower alkoxy group, to obtain the lactone IX:
IX
wherein R is as above defined, opening the lactone ring of compound IX by methanolysis and contemporaneously deprotecting the dioxolan protected keto group by acidic treatment to obtain the compound of formula X:
wherein R is as above defined, reducing the keto group of compound X by treatment with a pyridine-borane com-plex in the presence of trifluoroacetic acid and con-verting the methoxycarbonyl group into a benzyloxycar-bonyl group by treatment with phenyldiazomethane to obtain the compound of formula XI:
XI
wherein R is as above defined, esterifying the hydroxy groups and deesterifying the benzyloxycarbonyl group of compound XI, wherein R is above defined, by treatment with acetic anhydride in pyridine in the presence of 4-dimethylamino-pyridine followed by refluxing with cyclohexene in the presense of a palladium-on-carbon catalyst, to give the compound of formula XII:
XII
wherein R' represents a hydrogen atom, an acetoxy group or a lower alkoxy group, which is submitted to a cycliza-tion by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid and to a subsequent hydrolysis of the acetoxy groups with sodium methylate to obtain compound XIII:
XIII
wherein R is above defined, from which after an oxidative treatment of the 1-hydroxyethyl group with silver car-bonate and demethylation of the resultant compound with aluminium trichloride in nitrobenzene, the compound of formula XIV is obtained:
XIV
wherein R" is as above defined, from which, after pro-tection of the 13-keto group by treatment with ethylene glycol, bromination of the resultant compound at C-7 with bromine in the presence of 2,2-azo-bis(isobutyroni-trile) followed by hydrolysis of the 7-bromo derivative and removal of the ketal group by acid treatment, or alternatively by bromination with N-bromo-succinimide in the presence of 2,2'-azo-bis(isobutironitrile), by ir-radiation, treatment with silver acetate, hydrolysis
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000520911A CA1239638A (en) | 1983-06-23 | 1986-10-20 | 6-deoxyanthracyclines |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB838317037A GB8317037D0 (en) | 1983-06-23 | 1983-06-23 | 6-deoxyanthracyclines |
| GB8317037 | 1983-06-23 | ||
| CA000457254A CA1234104A (en) | 1983-06-23 | 1984-06-22 | 6-deoxyanthracyclines |
| CA000520911A CA1239638A (en) | 1983-06-23 | 1986-10-20 | 6-deoxyanthracyclines |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000457254A Division CA1234104A (en) | 1983-06-23 | 1984-06-22 | 6-deoxyanthracyclines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1239638A true CA1239638A (en) | 1988-07-26 |
Family
ID=25670423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000520911A Expired CA1239638A (en) | 1983-06-23 | 1986-10-20 | 6-deoxyanthracyclines |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1239638A (en) |
-
1986
- 1986-10-20 CA CA000520911A patent/CA1239638A/en not_active Expired
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