CA2032974A1 - Process for the preparation of glycosylanthracyclinones - Google Patents
Process for the preparation of glycosylanthracyclinonesInfo
- Publication number
- CA2032974A1 CA2032974A1 CA002032974A CA2032974A CA2032974A1 CA 2032974 A1 CA2032974 A1 CA 2032974A1 CA 002032974 A CA002032974 A CA 002032974A CA 2032974 A CA2032974 A CA 2032974A CA 2032974 A1 CA2032974 A1 CA 2032974A1
- Authority
- CA
- Canada
- Prior art keywords
- protecting group
- acyl protecting
- acyl
- group
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
BEHRINGWERKE AKTIENGESELLSCHAFT 89/B 050 - Ma 812 Dr. Ha/Sd ABSTRACT OF THE DISCLOSURE
PROCESS FOR THE PREPARATION OF GLYCOSYLANTHRACYCLINONES
A process for the preparation of 7-O-glycosylanthracycli-nones which correspond to the following general formula I
I
is described in which R1 is H or OH
R2 is H, ON or OCH3 R3 is H, COOCH3, OH or an O-acyl protecting group R4 is CH2CH3, COCH3, COCH2OH or a COCHaO-acyl protecting group R5 is NH2, an NH-acyl protecting group, OH or an O-acyl protecting group R6 is H, OH, an O-acyl protecting group, NH2 or an NH-acyl protecting group R7 is H, OH or an O-acyl protecting group, an acyl protecting group being an acetyl, mono-, di- or trihaloacetyl group where halogen = fluorine or chlorine, or a benzoyl or p-nitrobenzoyl group, starting from an anthracyclinone compound of the formula II
II
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3 or an O-acyl protecting group and R4 is CH2CH3, COCH3, or a COCH2-O-acyl protecting group, and a functionalized carbohydrate building block of the formula III
III
in which R5 is an NH-acyl protecting group or an O-acyl protect-ing group R6 is H, an NH-acyl protecting group or an O-acyl protecting group R7 is H or an O-acyl protecting group and R8, R9 and R10 are (C1-C4)-alkyl, an acyl protecting group for amino groups preferably being a trifluoroacetyl group and for hydroxyl groups preferably being an acetyl, trifluoroacetyl, chloroacetyl or p-nitrobenzoyl group, in the presence of a promoter such as trifluoromethanesulfonic acid tri-(C1-C4)alkyl-silyl ester or anhydride or BF3-ether, in an anhydrous organic solvent, if desired in the presence of a base or of an acid entrainer and a drying agent at -50°C to 25°C, a compound of the formula I being formed in which the radicals R1, R2, R3, R4, R5, R6 and R7 retain the meaning defined above and these compounds additionally being subjected to a deacylation step by means of an alkali liquor or an alcoholate for the preparation of cyto-statically active compounds of the formula I
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3 or OH
R4 is CH2CH3, COCH3 or COCH2OH
R5 is NH2 or OH
R6 is H, OH or NH2 and R7 is H or OH.
PROCESS FOR THE PREPARATION OF GLYCOSYLANTHRACYCLINONES
A process for the preparation of 7-O-glycosylanthracycli-nones which correspond to the following general formula I
I
is described in which R1 is H or OH
R2 is H, ON or OCH3 R3 is H, COOCH3, OH or an O-acyl protecting group R4 is CH2CH3, COCH3, COCH2OH or a COCHaO-acyl protecting group R5 is NH2, an NH-acyl protecting group, OH or an O-acyl protecting group R6 is H, OH, an O-acyl protecting group, NH2 or an NH-acyl protecting group R7 is H, OH or an O-acyl protecting group, an acyl protecting group being an acetyl, mono-, di- or trihaloacetyl group where halogen = fluorine or chlorine, or a benzoyl or p-nitrobenzoyl group, starting from an anthracyclinone compound of the formula II
II
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3 or an O-acyl protecting group and R4 is CH2CH3, COCH3, or a COCH2-O-acyl protecting group, and a functionalized carbohydrate building block of the formula III
III
in which R5 is an NH-acyl protecting group or an O-acyl protect-ing group R6 is H, an NH-acyl protecting group or an O-acyl protecting group R7 is H or an O-acyl protecting group and R8, R9 and R10 are (C1-C4)-alkyl, an acyl protecting group for amino groups preferably being a trifluoroacetyl group and for hydroxyl groups preferably being an acetyl, trifluoroacetyl, chloroacetyl or p-nitrobenzoyl group, in the presence of a promoter such as trifluoromethanesulfonic acid tri-(C1-C4)alkyl-silyl ester or anhydride or BF3-ether, in an anhydrous organic solvent, if desired in the presence of a base or of an acid entrainer and a drying agent at -50°C to 25°C, a compound of the formula I being formed in which the radicals R1, R2, R3, R4, R5, R6 and R7 retain the meaning defined above and these compounds additionally being subjected to a deacylation step by means of an alkali liquor or an alcoholate for the preparation of cyto-statically active compounds of the formula I
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3 or OH
R4 is CH2CH3, COCH3 or COCH2OH
R5 is NH2 or OH
R6 is H, OH or NH2 and R7 is H or OH.
Description
~3X~7~
BEElRINGWERRE A:~TI~NGESELLSC:HAFT HOE 89/B 050 - Ma 812 Dr. Ha/Sd Descripkion PRDl,ESS FOB~ T~E Pl~P~ID~ OF ~LYCOSYL~ YCLINONES
- _ ~he pre~en~ invention relates to a proce~s, particularly to a glyco~ylation process, for the preparation o 7-0-~lycosylanthracyclinones which, owing to their cytostatic activity, are ~uitable for the ~reatment of aarcino~e~.
The anthracycline clas~ of substance i6 descri~d in depth in the technic~l litera~urb. Doxorubicin and it~
14-desoxy analog daunorubicin are named here a~ the most successful representative~ of this clas~ of substance, which can be employed in the clinic for ~he treatment of a large number of solid tumor and leukemias. Other analogs which have been modified both in the aglycone moiety and in the carbohydrate unit have recently been introduced in the clinic or are in clinical testing.
The chemical preparation of anthracyclines i8 carried out, starting from a functionali~ed carbohydrat0 building block as a donor and an anthracyclinone as an acceptor, in the presence of a promoter. In thi~ case/ the hydrosyl group on the C7 atom of the anthracyclinone acceptor is glycosylated with a carbohydrate building blsck with the formation of an ~-O-glyco~idic linkage.
~he following functionali~ carbohydrat~ building blocks are u~ed for the glycosylation of anthxacyclinoness 1) Glycosyl halides u~ing ~Llver ~alts as promoters ~F.
Arcamone in hDoxorubicin", Academic Press, 1981, pp.
82-92 and pp. 194-258).
BEElRINGWERRE A:~TI~NGESELLSC:HAFT HOE 89/B 050 - Ma 812 Dr. Ha/Sd Descripkion PRDl,ESS FOB~ T~E Pl~P~ID~ OF ~LYCOSYL~ YCLINONES
- _ ~he pre~en~ invention relates to a proce~s, particularly to a glyco~ylation process, for the preparation o 7-0-~lycosylanthracyclinones which, owing to their cytostatic activity, are ~uitable for the ~reatment of aarcino~e~.
The anthracycline clas~ of substance i6 descri~d in depth in the technic~l litera~urb. Doxorubicin and it~
14-desoxy analog daunorubicin are named here a~ the most successful representative~ of this clas~ of substance, which can be employed in the clinic for ~he treatment of a large number of solid tumor and leukemias. Other analogs which have been modified both in the aglycone moiety and in the carbohydrate unit have recently been introduced in the clinic or are in clinical testing.
The chemical preparation of anthracyclines i8 carried out, starting from a functionali~ed carbohydrat0 building block as a donor and an anthracyclinone as an acceptor, in the presence of a promoter. In thi~ case/ the hydrosyl group on the C7 atom of the anthracyclinone acceptor is glycosylated with a carbohydrate building blsck with the formation of an ~-O-glyco~idic linkage.
~he following functionali~ carbohydrat~ building blocks are u~ed for the glycosylation of anthxacyclinoness 1) Glycosyl halides u~ing ~Llver ~alts as promoters ~F.
Arcamone in hDoxorubicin", Academic Press, 1981, pp.
82-92 and pp. 194-258).
2) Glycosyl halides using mercury ~alts a~ promoters (T.M. Smith et ~1., J. Org. Chem. 42, 3653 (1977), F.
Axcamone et al., Cancer Treat Rep. 60, 829 (1976)).
Axcamone et al., Cancer Treat Rep. 60, 829 (1976)).
3 ) Glycals using acid as a promoter (H. Umezawa et al., J. Antibiotic~ 33, 1581 (1980)).
4~ Glycals u~ing ~-iodosuccinimide ~D. Horton ~t al . in "Anthracycline AntibioticQ", Editor H.S. ~l Khadem, Academic Press, 1982, pp. 197 - 224).
5) l~O-Acyl-carbohydrate donor~ using trimethylsilyl triflate as a promoter (EP O 143,323/1988).
~-Glycosides can be prepared ~electively by methods 1 and 2, but as the glycosyl halides are very un~table, their use in glycoside synthe~i~, above all on the indus~rial scale, is very problematical. ~oreover, expensivs ~ilver salts or toxic mercury salts are used in thi~ c~se.
~-Glycosides can only be prepared as a mixture o tha ~-- and ~-products by method 3. Only 2'-haloanthracyclines can be prepared by method 4.
~-Glycosi~es can be pr~pared selectively by method 5, but as the glycosyl donor is pre~ent a~ a mixture of the ~
and ~-O-acyl derivativ~s, the ~-O-acyl deriva~ives preferably rsacting to completion in the glycosylation, the ~-O-acyl component ufiually remain~ unre~cted during the reaction. Expen~ive chro~atography i8 neCe~8ary i~
the purification of th* desired ~-glyco~ide~.
Surprisi~gly/ ~t has been ~hown in the glyc~ylation of 1 equivalent ~eq.) of ~-rhodomycinone ~th one eq. of l-O-tert.-butyldimethyl8ilyld~unos~mine deriv~tive a~ donor that ~-dauno~aminylrhodomycinone~ are ~electiv21y formed in high yield. In this ~ynthesis of the ~-glyco5yl~nthra-cyclinones, 3 e~. of glyco~ylation co~ponent, (4-O-p-nitrobenzoyl-3-N-trifluoroacetyl~ dauno~minyl _ 3 _ ~ 9 chloride) were formerly re~uired.
Building on this knowledge, the aim has been set for the pre~ent invention of developing a novel process for the glycosylation of anthracyclinone~ using 1-0-trialkylsilyl susars.
This aim is achieved according to the invenkion by the process for the preparation ~f an ~nthracycline of the formula I
Rl OH R3 1~, in which Rl is H or 9H
R2 is H, OH or OCH3 R3 is H, COOCH3, 0~ or an O-acyl protectin~ group R4 i8 CH2CH3, COCH3, COCH20H or a CO-C~20-acyl protecting group R5 i NH2, an NH-acyl protecting group, OH or an O-acyl pxotecting group R~ is H, OH, an O-acyl protecting group, ~H2 or an ~H-acyl protecting group R7 is H, OH or an O-acyl protecting group.
An acyl prot~cting group i~ undsr~tood a~ meaning an ~cyl group customary in carbohydrate chemi~try, which i8 derived fxom a Cl-C4-alkanoic acidt mvno-, di- or trihalo-ac~tic acid or benzoic acid.
~ 4 ~ X~ Z9 An acyl protec ing ~roup is preferably acetyl, mono-, di-or trihaloacetyl where halogen = fluorine or chlorine, or benzoyl or p-nitrobenzoyl.
Preferred compounds of the fonnula I are those in which R1, R2, R3, R4, R5, R~ and R7 retain their above-def ined meaning, an acyl protecting group being acetyl, chloro-acetyl, txifluoroacetyl or p-ni~robenzoyl.
The compounds of the formula I may optionally 1:~3 pre~ent a~ ammonium ~alts.
The proce~s according to the invention for the prepara-tion of a compound of the formula I compriY~s reacting an anthracyclinone compound of the formula II
II
in which R1 i~ H or OH
R2 i8 H, OH or OCH3 R3 is H, COOCH3 ~r an O-acyl protecting group and R4 i~ CH2CH3, COCH3, or a CO-CH2-O-acyl protecting ~roup, wi~h a functionalized carbohydrate building block of the formula III
Ia H3C~ o~ o.Si--~9 R'_~/ Rlo III
R ~5 ~
in which R5 is an NH-acyl pr~tecting group or an O-acyl protect-ing group R6 is H, an NH-acyl protecting group or an O-acyl protecting group R7 is H or an O-acyl protecting group and RB, R~ and Rl are ~Cl-C4~-al~yl, an acyl protecting gr~up for amino ~roups preferably being trifluoroa~etyl and for hydroxyl groups preferably being acetyl, trifluoroacetyl, chloroacetyl or p-nitro-benzoyl, in the presence of a promoter such as a tri-fluoromethanesulfonic acid tri-(Cl-C4)-alkylsilyl ester or anhydride or BF3.ether, in an anhydrous organic ~olvent, if desired in the pre3ence of a base or of an acid entrainer and a drying agent at -50C to 25C to give a compound of the formula I in which the radicals R1~ RZ, R3, R4, R5, R6 and R7 retain the meaning defined above and if appropriate deacylating these compounds preferably by meanæ of an alkali liquor or an alcoholate to give cytostatically active compounds of the formula I
in which Rl is H or OH
R2 is H, OH or OCH3 R3 i~ H, COOCH3 or OH
R4 iB CH2CH3, CQC~I3 or COCH2OH
R5 i~ NH2 or OH
R6 is H, OH or NH2 and R7 is H o~ OH.
In detail, the procedure in this ca~e i~ as iollows:
A glycosyl donor of the formula III i8 prepared ~tar~ing from a carbohydrate pxecur~or, which contains one free hydroxyl group on the Cl atom, and a ~ri- ~C~-C4) ~alkyl-silyl halide in the pre~ence of an organic base such as pyridi~e or imidazole and ~n oxg~nic ~olvent 8~ch as dichloromethane or dichloroeth~ne at 20~-60C.
~-Glycosides can be prepared ~electively by methods 1 and 2, but as the glycosyl halides are very un~table, their use in glycoside synthe~i~, above all on the indus~rial scale, is very problematical. ~oreover, expensivs ~ilver salts or toxic mercury salts are used in thi~ c~se.
~-Glycosides can only be prepared as a mixture o tha ~-- and ~-products by method 3. Only 2'-haloanthracyclines can be prepared by method 4.
~-Glycosi~es can be pr~pared selectively by method 5, but as the glycosyl donor is pre~ent a~ a mixture of the ~
and ~-O-acyl derivativ~s, the ~-O-acyl deriva~ives preferably rsacting to completion in the glycosylation, the ~-O-acyl component ufiually remain~ unre~cted during the reaction. Expen~ive chro~atography i8 neCe~8ary i~
the purification of th* desired ~-glyco~ide~.
Surprisi~gly/ ~t has been ~hown in the glyc~ylation of 1 equivalent ~eq.) of ~-rhodomycinone ~th one eq. of l-O-tert.-butyldimethyl8ilyld~unos~mine deriv~tive a~ donor that ~-dauno~aminylrhodomycinone~ are ~electiv21y formed in high yield. In this ~ynthesis of the ~-glyco5yl~nthra-cyclinones, 3 e~. of glyco~ylation co~ponent, (4-O-p-nitrobenzoyl-3-N-trifluoroacetyl~ dauno~minyl _ 3 _ ~ 9 chloride) were formerly re~uired.
Building on this knowledge, the aim has been set for the pre~ent invention of developing a novel process for the glycosylation of anthracyclinone~ using 1-0-trialkylsilyl susars.
This aim is achieved according to the invenkion by the process for the preparation ~f an ~nthracycline of the formula I
Rl OH R3 1~, in which Rl is H or 9H
R2 is H, OH or OCH3 R3 is H, COOCH3, 0~ or an O-acyl protectin~ group R4 i8 CH2CH3, COCH3, COCH20H or a CO-C~20-acyl protecting group R5 i NH2, an NH-acyl protecting group, OH or an O-acyl pxotecting group R~ is H, OH, an O-acyl protecting group, ~H2 or an ~H-acyl protecting group R7 is H, OH or an O-acyl protecting group.
An acyl prot~cting group i~ undsr~tood a~ meaning an ~cyl group customary in carbohydrate chemi~try, which i8 derived fxom a Cl-C4-alkanoic acidt mvno-, di- or trihalo-ac~tic acid or benzoic acid.
~ 4 ~ X~ Z9 An acyl protec ing ~roup is preferably acetyl, mono-, di-or trihaloacetyl where halogen = fluorine or chlorine, or benzoyl or p-nitrobenzoyl.
Preferred compounds of the fonnula I are those in which R1, R2, R3, R4, R5, R~ and R7 retain their above-def ined meaning, an acyl protecting group being acetyl, chloro-acetyl, txifluoroacetyl or p-ni~robenzoyl.
The compounds of the formula I may optionally 1:~3 pre~ent a~ ammonium ~alts.
The proce~s according to the invention for the prepara-tion of a compound of the formula I compriY~s reacting an anthracyclinone compound of the formula II
II
in which R1 i~ H or OH
R2 i8 H, OH or OCH3 R3 is H, COOCH3 ~r an O-acyl protecting group and R4 i~ CH2CH3, COCH3, or a CO-CH2-O-acyl protecting ~roup, wi~h a functionalized carbohydrate building block of the formula III
Ia H3C~ o~ o.Si--~9 R'_~/ Rlo III
R ~5 ~
in which R5 is an NH-acyl pr~tecting group or an O-acyl protect-ing group R6 is H, an NH-acyl protecting group or an O-acyl protecting group R7 is H or an O-acyl protecting group and RB, R~ and Rl are ~Cl-C4~-al~yl, an acyl protecting gr~up for amino ~roups preferably being trifluoroa~etyl and for hydroxyl groups preferably being acetyl, trifluoroacetyl, chloroacetyl or p-nitro-benzoyl, in the presence of a promoter such as a tri-fluoromethanesulfonic acid tri-(Cl-C4)-alkylsilyl ester or anhydride or BF3.ether, in an anhydrous organic ~olvent, if desired in the pre3ence of a base or of an acid entrainer and a drying agent at -50C to 25C to give a compound of the formula I in which the radicals R1~ RZ, R3, R4, R5, R6 and R7 retain the meaning defined above and if appropriate deacylating these compounds preferably by meanæ of an alkali liquor or an alcoholate to give cytostatically active compounds of the formula I
in which Rl is H or OH
R2 is H, OH or OCH3 R3 i~ H, COOCH3 or OH
R4 iB CH2CH3, CQC~I3 or COCH2OH
R5 i~ NH2 or OH
R6 is H, OH or NH2 and R7 is H o~ OH.
In detail, the procedure in this ca~e i~ as iollows:
A glycosyl donor of the formula III i8 prepared ~tar~ing from a carbohydrate pxecur~or, which contains one free hydroxyl group on the Cl atom, and a ~ri- ~C~-C4) ~alkyl-silyl halide in the pre~ence of an organic base such as pyridi~e or imidazole and ~n oxg~nic ~olvent 8~ch as dichloromethane or dichloroeth~ne at 20~-60C.
- 6 ~ 29~4 The preparation of trimethylsilyl and tert.butyl(di-methyl~ 8ilyl derivative~ of the formula III i~ particu-larly preferred in thi~ case.
1 eq. to 1.5 eq. of glyco~yl donor of the formula III are as a rule required for the glycosylation of 1 eq. of snthracyclinone. Trifluorome~hanesulfonic acid tri-(Cl-C4)-alkylsilyl estPr, preferably tr~methyl~ilyl tri-fluoromethanesulfonate or tert.butyl(dimethyl~ilyl trifluoromethanesulfonate, or BF3-ether i~ preferably employed as the pr~mot~r. The glycosylation i3 carried out in an anhydrous organic solvent such as dichloro-methane, dichloroethane, ether, toluene, acetonitrile or mixtures thereof with acetone or ethyl acetate, as a rule in the presence of a drying agent ~uch as a molecular sieve or barium sulfate at -70aC to 25~C, preferably at -50C to -20C. When using trifluoromethanesulfonic anhydride as the promoter, an organic base such as triethylamine or dimethylaminopyridine may be added.
The deacylation of the glycoside products is carried out by means of an alkali metal ba~e such a~ NaOH or an alcoholate such as sodium methylate.
The following examples illustrate the process ~ccordinq to ~he invention without the latter being restricted ~o the compounds mentioned in the examples.
1 eq. to 1.5 eq. of glyco~yl donor of the formula III are as a rule required for the glycosylation of 1 eq. of snthracyclinone. Trifluorome~hanesulfonic acid tri-(Cl-C4)-alkylsilyl estPr, preferably tr~methyl~ilyl tri-fluoromethanesulfonate or tert.butyl(dimethyl~ilyl trifluoromethanesulfonate, or BF3-ether i~ preferably employed as the pr~mot~r. The glycosylation i3 carried out in an anhydrous organic solvent such as dichloro-methane, dichloroethane, ether, toluene, acetonitrile or mixtures thereof with acetone or ethyl acetate, as a rule in the presence of a drying agent ~uch as a molecular sieve or barium sulfate at -70aC to 25~C, preferably at -50C to -20C. When using trifluoromethanesulfonic anhydride as the promoter, an organic base such as triethylamine or dimethylaminopyridine may be added.
The deacylation of the glycoside products is carried out by means of an alkali metal ba~e such a~ NaOH or an alcoholate such as sodium methylate.
The following examples illustrate the process ~ccordinq to ~he invention without the latter being restricted ~o the compounds mentioned in the examples.
~A~h~S
~ANPL~ 1 Preparation o~ carbohydrate building blocks Methyl 4-0-p-ni~robenzoyl-2,3,6-tride~osy-3-trifluoro-ace~amido-~-L-lyxohexopyrano3ide (~ompound 1) 61 g (237 mmol) of methyl 3-N-trifluoroace~yld~uno~amin-ide were dissolved in 840 ml of dichlorome~hane/pyridine (2:1~ and 33 g (177 ~ol) of p-ni~roben~oyl chloride were added. The reaction mixture was stirred at 35~C for 3 h, then evaporated in vacuo and rediRtilled with toluene.
The residue di~olved in 600 ml of dichloromethane was washed with 0.1 N HCl, then with water. The organic phase was dried over odium sulfat~ and evaporated. The crude product was purified by column chromatography on 600 g of silica gel (eluents chloroform/ethyl ~cetate 15~
Yield: ~2 g (95 %); Rf = 0.76 (6~1 CHC13/EtOAc; melting point: 65-67C; [~]D -183C (c 1.03, chlorofo~m).
4-0-p-Nitrobenzoyl-2,3,6-tridesoxy-3-trifluoroacetamido-L-lyxoh~xopyranose (Compound 2) 25 g (61.5 mmol) of ~e~hyl 4-0-p ni~robenzoyl-3-N-tri-fluoroacetyl-~-L-daunosaminide were suspended in 250 ml of 30 % 6trength trifluoroacetic acid. The reaction mixture wa~ kept undex reflux for 10 min. The cooled reaction solution was extracted twice ~ith ethyl ace~ate.
The organic ph ~e wa~ washed with pho~phate buffer (O.1 mol of ~H~P04 adjusted to pH 7~5 with Q.l mol of NaOH), then with water ~nd dried o~er sodium sulphate.
After evaporating the filtrate, the re~idue (21 g) ~a~
crystallized from ether. The mother liquor (6 g) was purified by column chromatography on 100 g o~ ilica gel (eluent: chloroform/ethyl a~etate 9:1). Yield: 17.4 (72.4 %); Rf = 0.21 (9sl CHCl3/Et~Ac); melting point:
213C; [~1 -192 (c 0.86, ~tOAc)~
~ANPL~ 1 Preparation o~ carbohydrate building blocks Methyl 4-0-p-ni~robenzoyl-2,3,6-tride~osy-3-trifluoro-ace~amido-~-L-lyxohexopyrano3ide (~ompound 1) 61 g (237 mmol) of methyl 3-N-trifluoroace~yld~uno~amin-ide were dissolved in 840 ml of dichlorome~hane/pyridine (2:1~ and 33 g (177 ~ol) of p-ni~roben~oyl chloride were added. The reaction mixture was stirred at 35~C for 3 h, then evaporated in vacuo and rediRtilled with toluene.
The residue di~olved in 600 ml of dichloromethane was washed with 0.1 N HCl, then with water. The organic phase was dried over odium sulfat~ and evaporated. The crude product was purified by column chromatography on 600 g of silica gel (eluents chloroform/ethyl ~cetate 15~
Yield: ~2 g (95 %); Rf = 0.76 (6~1 CHC13/EtOAc; melting point: 65-67C; [~]D -183C (c 1.03, chlorofo~m).
4-0-p-Nitrobenzoyl-2,3,6-tridesoxy-3-trifluoroacetamido-L-lyxoh~xopyranose (Compound 2) 25 g (61.5 mmol) of ~e~hyl 4-0-p ni~robenzoyl-3-N-tri-fluoroacetyl-~-L-daunosaminide were suspended in 250 ml of 30 % 6trength trifluoroacetic acid. The reaction mixture wa~ kept undex reflux for 10 min. The cooled reaction solution was extracted twice ~ith ethyl ace~ate.
The organic ph ~e wa~ washed with pho~phate buffer (O.1 mol of ~H~P04 adjusted to pH 7~5 with Q.l mol of NaOH), then with water ~nd dried o~er sodium sulphate.
After evaporating the filtrate, the re~idue (21 g) ~a~
crystallized from ether. The mother liquor (6 g) was purified by column chromatography on 100 g o~ ilica gel (eluent: chloroform/ethyl a~etate 9:1). Yield: 17.4 (72.4 %); Rf = 0.21 (9sl CHCl3/Et~Ac); melting point:
213C; [~1 -192 (c 0.86, ~tOAc)~
- 8 ~ 29~
3,4~Bi6-(trifluoroacetylamino)-2,3,4,6-tetrade~oxy-1-lyxohexopyranose (Compound 3) Benzyl 3,4-bis-(trifluoroacetylamino)-2,3,4,6-tetrAdes-oxy-~-L-lyxohexopyranoside (6.5 g) was dissolved in S glacial acetic acid and hydrogenated in the pre~ence of 10 ~ strength Pd/C (5.5 g) for 48 hour6. The mixture wa~
then filtered and the filtrate was evaporated in vacuo.
The residue wa~ redistilled with 2sl methanol/toluene.
The re~ulting product was purified by column chromato graphy on Bilica gel ( 120 g) u~ing 3: 1 dichloromethane-methanol. Yield: 4.39 g; 1~D -63.3 (c 1, EtOAc).
2,6-Didesoxy-3,4-di-O-p-nitrobenzoyl-L-lyxohexopyrano6e (Compound 4) 2,3-Didesoxy-1,3,4-tri-O-p-nitrobenzoyl-~ and ~-L-lyxo-hexopyranose (2.5 g, 4.2 mmol) was dissolved in methanol (60 ml) and aminated silica gel (~erck, 3 g) was added.
The reaction mixture was ~tirred at xoom temperature for 3 hours and then filtered. Af~er evaporating the filt-rate, the residue wa~ dissol~ed in dichloromethane (120 ml) and washed with phosphate buffer (pH 8, 60 ml x 2), then wi~h water. The organic phase was dried over magnesium sulfate and evaporated in vacuo. ~he residue was purified by column chromatography on silica gel ~130 g) using 7:1 dichloromethane-acetone. Yield: 1.42 g (76 ~).
~xample 2 Prepara~ion of l-O-trialkyl~ilylcarbohydxate derivativQ~
4-O-p-Nitroben~oyl--2,3,6-tride~o~y 3-trifluoroacetamido-l-O-trimethylsilyl-~-L-lyxohexopyrano~e (comp~und 5) 4.6 g (11,7 mmol) of 4 O-p-~itrobenzoyl-2,3,6-tridesoxy 3-trifluoroacetamido-~-lyxohexopyrano~e were dissolved in 80 ml of pyridine/dichloromethane (1:13 and 4.46 ml (35.1 mmol) of trL~ethyl~ilyl chloride were added at 0~C.
After 16 h, 100 ml of dichloromethane were added ~o the reaction mixture, which was washed twice ~ith 200 ml of Z03~97~
_ g phospha~e buffer (pH 7.5) each tLme. The organic phase was dried over ~odium sulfate and eYaporated in vacuo.
The re~idue was additionally red~stilled with toluene.
The crude product, dried in a high vacuum, wa~ purified by column chromatography on 100 g of silica gel ~eluent:
dichloromethane/pe~roleum ether/acetone 5:5:0.5). ~ield:
5.07 g (93-3 ~) l-O-t-Butyl-dimethylsilyl-4-O-p-nitrobenzoyl-2,3,6-tride~oxy-3-trifluoroacetamido-~ lyxohexopyranose (Compound 6) 4.05 g (10.3 mmol) of 4-O-p-Nitrobenzoyl-3-N-trifluoro-acetyl-L-daunosamine were dis6clved in 160 ml o~ pyrid-ine/1,2-dichloroethane and 7.7 g (51.5 mmol) of t-butyl-dimethylsilyl chloride were added. After stirr~ng at 60C
for 16 h, the reaction mixture wa~ dilu~ed with 200 ml of dichloromethane ~nd washed twice with pho~phate buf~er (O.1 mol of KHzPO4 ad~usted to pH 7.5 with 0.1 mol o~
NaOH) with re-extraction of the aqueou6 phase. The organic phase was dried over sodium ~ulfate and evapora-ted in vacuo. The re~idue was redi6tilled ~everal times with toluene until pyridine was no lon~er presen~, then purified by column chromatography on 150 g of ~ilica gel (eluent:petroleumether/dichloromathane/acetone 10:10:1).
Yields 4.7 g ~90.3 %). Rf = 0.43 (10.10:1 chloroform/pet-roleum ether/acetone); melting point: 72-74C; 1~]D -91 (c 1, chloroform).
3,4-Bis-(trifluoroacetylamino)-l-O-ter~.-bu~yl(dime~hyl)-silyl-2,3,~,6-tetra-de~oxy-L-lyxohexopyranose (Compound 7) Starting from 3,4-bi~-(trifluoroacetylamino)-2,3,4,6-tetradesvxy-L-lyxohexopyTano~eandtert.-butyl(diemthyl~-~ilyl chloride, the ti~le compound was ~ynthe~ized by the procedure for the preparation of compound 6.
2,6-Didesoxy-3,4-di-O-p-nitrobenzoyl-l;~O-tert.-butyl(di-methyl)silyl-L--lyxohexopyrano~e (Compound 8) The title compound wa~ prepared by the procedure for the - lo- ~ 2974 synthesis of compound 6 starting from 2,6-didesoxy-3,4-di-O-p-nitroben~oyl-L-lyx~hexop~ranose and tert.-butyl-(dLmethyl)silyl chloride~
Example 3 S Preparation of 7-O-trimethyl~ilyl~ o)rhodomycinones 7-o-TrLmethyl~ilyl-e-rhodomycinone (Compound 9) 200 mg (0.429 mmol) of ~-rhodomycinone (92 ~ by HPLC) were dissolved in lO ml of pyridine/dichloromethane and 0.180 ml (1.4~ mmol) of trimethyl6ilyl chloride was added at 0C. After stirring for 30 min, the r~action mixture was diluted with 20 ml of dichloromethane and wa~hed twice with phosphate buffer (pH 7.5). ~he organic phase was dried over sodium ~ulfate and then evaporated, and the residue was redistilled with toluene to remove pyridine xesidues. The acid-sensitive product was puri-fied by column chromatography on 20 g of ~ilica g~1 [eluent: chloroform/triethylamine 200:1~. Yield: 180.6 mg (84 ~); t~]D +279~ (c 0.037, ~hloroform).
7-O-Trimethylsilyl-~-isorhodomycinone (Compound lO~
200 mg (O.45 mmol) of ~-isorhodomycinone were dissolYed in 10 ml of pyridine/dichloromethane (1:13 ~nd 0.180 ml (1.398 mmol) of trimethylsilyl chloride was added at 0C.
After ~tirring for 30 min, ~h~ reaction mixture was diluted with 20 ml of dichlorometha~e and washed twice wi h phosphate buffer SpH 7.5). ~he organic pha~e w~s dried over ~odium ulfate, ~hen evaporated in vacuo. The residue was redistill~d with toluene to ramove pyridine residues. The acid-~ensitive product was purified ~y column chromatography on 20 g of ~ilica gel (elue~ts chlorofo~/triethylamine (200~ Yields 180 ~g (82 %);
[3~D ~3~5 (C 0-0061, chloroform~.
~ample 4 Glycosy}ation of anthracyclinones with functionalized 3~74 carbohydrate building blocks 7-0-~4-O-p-Nitrobenzoyl-2,3,~-tridesoxy-3-trifluoroacet-ylamino-~-L-lyxohexopyrano~yl)-~-isorhodomycinone (Compound 11) ~-I60rhodomycinone (6.0 ~, 11.2 mmol), daunosamine donor (compound 6, 8.51 g, 16.8 mmol) and molecular ~ieve 4 A
(6.0 g) were suspended in 5:1 dichloromethane-ethyl acetate (7~Q ml) undex protective ga~. After the addition of trimethylsilyl ~rifluorome~h~ne~ulfona~e (4.97 ~, 22.4 mmol) at -35~C, the reaction mixture ~as stirred for 5 hours. Triethylamine (10 ml) was added to the cooled mixture, which was filtered. The filtra~e was wa~hed twice with citrate buffer (0.1 molar citric acid solution adjusted t~ pH 5 with 0.1 molar NaOH), then with ice-water. The organic ph~se was dried over sodium sulfate and evaporated in vacuo. The residue (12.6 g) wa~ puri-fied ~y column chromatography on silica gel (450 g) uRing 200:10:1 chloroform-ethyl acetate-formic acid. Yield:
7.15 g t78 %); Rf = 0.33 (solvent - see above).
7-0-(4-O-p-Nitrobenzoyl-~,3,6-tridesoxy-3-trifluoroacet~
ylamino-~-L-lyxohexopyranosyl)-~-rhodomycinone (Compound 12) The title compound 12 was synthesized by the procedure for the prep~ration of compound 11 starting from e -rhodomycinone and daunos~mine donor (~ompound 6).
7-0-(4-O-p-Nitrobenzoyl-2,3,6-tride~oxy-3-trif~uoroace~-ylamino-~-L-lyxohexopyranosyl~-daunomycinone (Compound 13) The title compound 13 wa~ prepared by the procedure for th~ ~ynthesis of c~mpound 11 starting from daunomycinone and daunosamine donox (compoulld 6).
7-0-(3,4-Bi~-(trifluoroacetylamino)-2,3,4,6 te~ra-de~oxy-~-L-lyxohexopyranosyl)-4-O-methyl-10-O-p-nitrobenzoylw~-rhodomycinone (Compound 14) 4-O-Methyl-10-O p-nitrobenzoyl-~-rhodomycinone (2.64 g!
4.80 mmol), 3,4-bis-tri1uoroa~etylamino sugar (compound 12 ~ 3Z97~
7, 2.17 g, 4.80 mmol) and 4 A molecular ~ieve (3.0 g) were dissolved in dichloromethane (220 ml) and trimethyl-silyl triflate (1.2 ml3 were added at -35~Co The reaction mixture was stirred at -35C for 3 hours, then triethyl-S amine (2.5 ml) wa~ added and the mixture wa~ filtered.
The filtrate was wa~hed with phosphate buffer ~pH 7, 60 ml x 2), then with water, dried (~odium sulfate) ~nd evaporated in vacuo. The residue was purified by colu~n chroma~ograp~y on silica gel (220 g) u~ing 15:1 chloro-form-acetone. Yield: 3.3S g (81 ~), Rf = 0.37 (15:1 chloro~oxm-a~etone); ~elting point: 222~C; alpha D + 250 (c O.05, chloroform~.
7-~-(3,4-Bis-O-p~nitrobenzoyl-2,6-didesoxy~alpha-L-lyxo-hexopyranosyl)-4-0-methyl-10-0-p-nitrobenzoyl-~-rhodo-mycinone (Compound 15) The title compound was synthesized by the procedure forthe preparation of ~ompound 14 starting from 2-de~oxy-fucose donor (compound 8) and 4-0-methyl-10-0-p-nitro-benzoyl-~-rhodomycinone.
~xample 5 Deblocking of anthxacyclines The anthracycline derivatives described in Example 4 were deblocked by known processes, a~ de6cribed in the follow-ing general procedure:
Protected anthracycline compound was dissolved ~n metha-nol or chloroform-methanol and 1 N NaOH was added at O~C.
After the reaction had taken place, the reaction mixture was neutralized with 1 N HCl. After th~ cu~tomary work-up, the deblocked compound was purified on RP-~8 silica gel or amino 8ilica gel.
The following c~mpounds were prepared by thi~ procedure:
O~'Z~374 _ 13 -7-0-(3-Amino-2,3,6-tridesoxy-alpha-L-lyxohexopyrano~yl)-~-isorhodomycinone (Compound 16) 7-0-(3-Amino-2,3,6-tridesoxy-alpha-L-lyxohexopyranosyl)-~-rhodomycinone (Compound 17) 7-0-(3-Amino-2,3,6-~ride~oxy~ lyxohexopyranosyl)-daunomycinone (Compound 18) 7-0-(3,4-Diamino-2,3,4,6-tetra-deso~y-~-L-lyxohexopyrano-syl)-4-0-methyl-~-rhodomycinone (Compound 19) 7-0-(2,6-Didesoxy-~-L-lyxohexopyranosyl)-4 O-methyl-~-rhodomycinone (Compound 20)
3,4~Bi6-(trifluoroacetylamino)-2,3,4,6-tetrade~oxy-1-lyxohexopyranose (Compound 3) Benzyl 3,4-bis-(trifluoroacetylamino)-2,3,4,6-tetrAdes-oxy-~-L-lyxohexopyranoside (6.5 g) was dissolved in S glacial acetic acid and hydrogenated in the pre~ence of 10 ~ strength Pd/C (5.5 g) for 48 hour6. The mixture wa~
then filtered and the filtrate was evaporated in vacuo.
The residue wa~ redistilled with 2sl methanol/toluene.
The re~ulting product was purified by column chromato graphy on Bilica gel ( 120 g) u~ing 3: 1 dichloromethane-methanol. Yield: 4.39 g; 1~D -63.3 (c 1, EtOAc).
2,6-Didesoxy-3,4-di-O-p-nitrobenzoyl-L-lyxohexopyrano6e (Compound 4) 2,3-Didesoxy-1,3,4-tri-O-p-nitrobenzoyl-~ and ~-L-lyxo-hexopyranose (2.5 g, 4.2 mmol) was dissolved in methanol (60 ml) and aminated silica gel (~erck, 3 g) was added.
The reaction mixture was ~tirred at xoom temperature for 3 hours and then filtered. Af~er evaporating the filt-rate, the residue wa~ dissol~ed in dichloromethane (120 ml) and washed with phosphate buffer (pH 8, 60 ml x 2), then wi~h water. The organic phase was dried over magnesium sulfate and evaporated in vacuo. ~he residue was purified by column chromatography on silica gel ~130 g) using 7:1 dichloromethane-acetone. Yield: 1.42 g (76 ~).
~xample 2 Prepara~ion of l-O-trialkyl~ilylcarbohydxate derivativQ~
4-O-p-Nitroben~oyl--2,3,6-tride~o~y 3-trifluoroacetamido-l-O-trimethylsilyl-~-L-lyxohexopyrano~e (comp~und 5) 4.6 g (11,7 mmol) of 4 O-p-~itrobenzoyl-2,3,6-tridesoxy 3-trifluoroacetamido-~-lyxohexopyrano~e were dissolved in 80 ml of pyridine/dichloromethane (1:13 and 4.46 ml (35.1 mmol) of trL~ethyl~ilyl chloride were added at 0~C.
After 16 h, 100 ml of dichloromethane were added ~o the reaction mixture, which was washed twice ~ith 200 ml of Z03~97~
_ g phospha~e buffer (pH 7.5) each tLme. The organic phase was dried over ~odium sulfate and eYaporated in vacuo.
The re~idue was additionally red~stilled with toluene.
The crude product, dried in a high vacuum, wa~ purified by column chromatography on 100 g of silica gel ~eluent:
dichloromethane/pe~roleum ether/acetone 5:5:0.5). ~ield:
5.07 g (93-3 ~) l-O-t-Butyl-dimethylsilyl-4-O-p-nitrobenzoyl-2,3,6-tride~oxy-3-trifluoroacetamido-~ lyxohexopyranose (Compound 6) 4.05 g (10.3 mmol) of 4-O-p-Nitrobenzoyl-3-N-trifluoro-acetyl-L-daunosamine were dis6clved in 160 ml o~ pyrid-ine/1,2-dichloroethane and 7.7 g (51.5 mmol) of t-butyl-dimethylsilyl chloride were added. After stirr~ng at 60C
for 16 h, the reaction mixture wa~ dilu~ed with 200 ml of dichloromethane ~nd washed twice with pho~phate buf~er (O.1 mol of KHzPO4 ad~usted to pH 7.5 with 0.1 mol o~
NaOH) with re-extraction of the aqueou6 phase. The organic phase was dried over sodium ~ulfate and evapora-ted in vacuo. The re~idue was redi6tilled ~everal times with toluene until pyridine was no lon~er presen~, then purified by column chromatography on 150 g of ~ilica gel (eluent:petroleumether/dichloromathane/acetone 10:10:1).
Yields 4.7 g ~90.3 %). Rf = 0.43 (10.10:1 chloroform/pet-roleum ether/acetone); melting point: 72-74C; 1~]D -91 (c 1, chloroform).
3,4-Bis-(trifluoroacetylamino)-l-O-ter~.-bu~yl(dime~hyl)-silyl-2,3,~,6-tetra-de~oxy-L-lyxohexopyranose (Compound 7) Starting from 3,4-bi~-(trifluoroacetylamino)-2,3,4,6-tetradesvxy-L-lyxohexopyTano~eandtert.-butyl(diemthyl~-~ilyl chloride, the ti~le compound was ~ynthe~ized by the procedure for the preparation of compound 6.
2,6-Didesoxy-3,4-di-O-p-nitrobenzoyl-l;~O-tert.-butyl(di-methyl)silyl-L--lyxohexopyrano~e (Compound 8) The title compound wa~ prepared by the procedure for the - lo- ~ 2974 synthesis of compound 6 starting from 2,6-didesoxy-3,4-di-O-p-nitroben~oyl-L-lyx~hexop~ranose and tert.-butyl-(dLmethyl)silyl chloride~
Example 3 S Preparation of 7-O-trimethyl~ilyl~ o)rhodomycinones 7-o-TrLmethyl~ilyl-e-rhodomycinone (Compound 9) 200 mg (0.429 mmol) of ~-rhodomycinone (92 ~ by HPLC) were dissolved in lO ml of pyridine/dichloromethane and 0.180 ml (1.4~ mmol) of trimethyl6ilyl chloride was added at 0C. After stirring for 30 min, the r~action mixture was diluted with 20 ml of dichloromethane and wa~hed twice with phosphate buffer (pH 7.5). ~he organic phase was dried over sodium ~ulfate and then evaporated, and the residue was redistilled with toluene to remove pyridine xesidues. The acid-sensitive product was puri-fied by column chromatography on 20 g of ~ilica g~1 [eluent: chloroform/triethylamine 200:1~. Yield: 180.6 mg (84 ~); t~]D +279~ (c 0.037, ~hloroform).
7-O-Trimethylsilyl-~-isorhodomycinone (Compound lO~
200 mg (O.45 mmol) of ~-isorhodomycinone were dissolYed in 10 ml of pyridine/dichloromethane (1:13 ~nd 0.180 ml (1.398 mmol) of trimethylsilyl chloride was added at 0C.
After ~tirring for 30 min, ~h~ reaction mixture was diluted with 20 ml of dichlorometha~e and washed twice wi h phosphate buffer SpH 7.5). ~he organic pha~e w~s dried over ~odium ulfate, ~hen evaporated in vacuo. The residue was redistill~d with toluene to ramove pyridine residues. The acid-~ensitive product was purified ~y column chromatography on 20 g of ~ilica gel (elue~ts chlorofo~/triethylamine (200~ Yields 180 ~g (82 %);
[3~D ~3~5 (C 0-0061, chloroform~.
~ample 4 Glycosy}ation of anthracyclinones with functionalized 3~74 carbohydrate building blocks 7-0-~4-O-p-Nitrobenzoyl-2,3,~-tridesoxy-3-trifluoroacet-ylamino-~-L-lyxohexopyrano~yl)-~-isorhodomycinone (Compound 11) ~-I60rhodomycinone (6.0 ~, 11.2 mmol), daunosamine donor (compound 6, 8.51 g, 16.8 mmol) and molecular ~ieve 4 A
(6.0 g) were suspended in 5:1 dichloromethane-ethyl acetate (7~Q ml) undex protective ga~. After the addition of trimethylsilyl ~rifluorome~h~ne~ulfona~e (4.97 ~, 22.4 mmol) at -35~C, the reaction mixture ~as stirred for 5 hours. Triethylamine (10 ml) was added to the cooled mixture, which was filtered. The filtra~e was wa~hed twice with citrate buffer (0.1 molar citric acid solution adjusted t~ pH 5 with 0.1 molar NaOH), then with ice-water. The organic ph~se was dried over sodium sulfate and evaporated in vacuo. The residue (12.6 g) wa~ puri-fied ~y column chromatography on silica gel (450 g) uRing 200:10:1 chloroform-ethyl acetate-formic acid. Yield:
7.15 g t78 %); Rf = 0.33 (solvent - see above).
7-0-(4-O-p-Nitrobenzoyl-~,3,6-tridesoxy-3-trifluoroacet~
ylamino-~-L-lyxohexopyranosyl)-~-rhodomycinone (Compound 12) The title compound 12 was synthesized by the procedure for the prep~ration of compound 11 starting from e -rhodomycinone and daunos~mine donor (~ompound 6).
7-0-(4-O-p-Nitrobenzoyl-2,3,6-tride~oxy-3-trif~uoroace~-ylamino-~-L-lyxohexopyranosyl~-daunomycinone (Compound 13) The title compound 13 wa~ prepared by the procedure for th~ ~ynthesis of c~mpound 11 starting from daunomycinone and daunosamine donox (compoulld 6).
7-0-(3,4-Bi~-(trifluoroacetylamino)-2,3,4,6 te~ra-de~oxy-~-L-lyxohexopyranosyl)-4-O-methyl-10-O-p-nitrobenzoylw~-rhodomycinone (Compound 14) 4-O-Methyl-10-O p-nitrobenzoyl-~-rhodomycinone (2.64 g!
4.80 mmol), 3,4-bis-tri1uoroa~etylamino sugar (compound 12 ~ 3Z97~
7, 2.17 g, 4.80 mmol) and 4 A molecular ~ieve (3.0 g) were dissolved in dichloromethane (220 ml) and trimethyl-silyl triflate (1.2 ml3 were added at -35~Co The reaction mixture was stirred at -35C for 3 hours, then triethyl-S amine (2.5 ml) wa~ added and the mixture wa~ filtered.
The filtrate was wa~hed with phosphate buffer ~pH 7, 60 ml x 2), then with water, dried (~odium sulfate) ~nd evaporated in vacuo. The residue was purified by colu~n chroma~ograp~y on silica gel (220 g) u~ing 15:1 chloro-form-acetone. Yield: 3.3S g (81 ~), Rf = 0.37 (15:1 chloro~oxm-a~etone); ~elting point: 222~C; alpha D + 250 (c O.05, chloroform~.
7-~-(3,4-Bis-O-p~nitrobenzoyl-2,6-didesoxy~alpha-L-lyxo-hexopyranosyl)-4-0-methyl-10-0-p-nitrobenzoyl-~-rhodo-mycinone (Compound 15) The title compound was synthesized by the procedure forthe preparation of ~ompound 14 starting from 2-de~oxy-fucose donor (compound 8) and 4-0-methyl-10-0-p-nitro-benzoyl-~-rhodomycinone.
~xample 5 Deblocking of anthxacyclines The anthracycline derivatives described in Example 4 were deblocked by known processes, a~ de6cribed in the follow-ing general procedure:
Protected anthracycline compound was dissolved ~n metha-nol or chloroform-methanol and 1 N NaOH was added at O~C.
After the reaction had taken place, the reaction mixture was neutralized with 1 N HCl. After th~ cu~tomary work-up, the deblocked compound was purified on RP-~8 silica gel or amino 8ilica gel.
The following c~mpounds were prepared by thi~ procedure:
O~'Z~374 _ 13 -7-0-(3-Amino-2,3,6-tridesoxy-alpha-L-lyxohexopyrano~yl)-~-isorhodomycinone (Compound 16) 7-0-(3-Amino-2,3,6-tridesoxy-alpha-L-lyxohexopyranosyl)-~-rhodomycinone (Compound 17) 7-0-(3-Amino-2,3,6-~ride~oxy~ lyxohexopyranosyl)-daunomycinone (Compound 18) 7-0-(3,4-Diamino-2,3,4,6-tetra-deso~y-~-L-lyxohexopyrano-syl)-4-0-methyl-~-rhodomycinone (Compound 19) 7-0-(2,6-Didesoxy-~-L-lyxohexopyranosyl)-4 O-methyl-~-rhodomycinone (Compound 20)
Claims (10)
1. A process for the preparation of an anthracycline of the formula I
I
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3, OH or an O-acyl protecting group R4 is CH2CH3, COCH3, COCH2OH or a COCH2O-acyl protect-ing group R5 is NH2, an NH-acyl protecting group, OH or an O-acyl protecting group R6 is H, OH, an O-acyl protecting group, NH2 or an NH-acyl protecting group R7 is H, OH or an O-acyl protecting group, which comprises reacting an anthracyclinone compound of the formula II
II
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3 or an O-acyl protecting group and R4 is CH2CH3, COCH3, or a COCH2-O-acyl protecting group, with a functionalized carbohydrate building lock of the formula III
III
in which R5 is an NH-acyl protecting group or an O-acyl protecting group R6 is H, an NH-acyl protecting group or an O-acyl protecting group R7 is H or an O-acyl protecting group and R8, R9 and R10 are (C1-C4)-alkyl, in the presence of a promoter in an anhydrous organic solvent, if desired in the presence of a base or of an acid entrainer and a drying agent at -50°C to 25°C to give a compound of the formula I in which the radicals R1, R2, R3, R4, R5, R6 and R7 retain the meaning defined above for the formulae II and III and if appropriate deacylating there compounds to give cytostatically active compounds of the formula I
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3 or OH
R4 is CH2CH3, COCH3 or COCH2OH
R5 is NH2 or OH
R6 is H, OH or NH2 and R7 is H or OH.
I
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3, OH or an O-acyl protecting group R4 is CH2CH3, COCH3, COCH2OH or a COCH2O-acyl protect-ing group R5 is NH2, an NH-acyl protecting group, OH or an O-acyl protecting group R6 is H, OH, an O-acyl protecting group, NH2 or an NH-acyl protecting group R7 is H, OH or an O-acyl protecting group, which comprises reacting an anthracyclinone compound of the formula II
II
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3 or an O-acyl protecting group and R4 is CH2CH3, COCH3, or a COCH2-O-acyl protecting group, with a functionalized carbohydrate building lock of the formula III
III
in which R5 is an NH-acyl protecting group or an O-acyl protecting group R6 is H, an NH-acyl protecting group or an O-acyl protecting group R7 is H or an O-acyl protecting group and R8, R9 and R10 are (C1-C4)-alkyl, in the presence of a promoter in an anhydrous organic solvent, if desired in the presence of a base or of an acid entrainer and a drying agent at -50°C to 25°C to give a compound of the formula I in which the radicals R1, R2, R3, R4, R5, R6 and R7 retain the meaning defined above for the formulae II and III and if appropriate deacylating there compounds to give cytostatically active compounds of the formula I
in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3 or OH
R4 is CH2CH3, COCH3 or COCH2OH
R5 is NH2 or OH
R6 is H, OH or NH2 and R7 is H or OH.
2. The process as claimed in claim 1, wherein a compound of the fonmula I, in which R1 is H or OH
R2 is H, OH or OCH3 R3 is H, COOCH3, OH or an O-acyl protecting group R4 is CH2CH3, COCH3 or a COCH2O acyl protecting group R5 is an NH-acyl protecting group or an O-acyl protecting group R6 is H,an O-acyl protecting group or an NH-acyl protecting group R7 is H or an O-acyl protecting group is prepared.
R2 is H, OH or OCH3 R3 is H, COOCH3, OH or an O-acyl protecting group R4 is CH2CH3, COCH3 or a COCH2O acyl protecting group R5 is an NH-acyl protecting group or an O-acyl protecting group R6 is H,an O-acyl protecting group or an NH-acyl protecting group R7 is H or an O-acyl protecting group is prepared.
3. The process as claimed in at least one of claims 1 and 2, wherein an acyl protecting group is an acetyl, mono-, di- or trihaloacetyl group where halogen =
fluorine or chlorine, or a benzoyl or p-nitrobenzoyl group.
fluorine or chlorine, or a benzoyl or p-nitrobenzoyl group.
4. The process as claimed in at least one of claim6 1 and 2, wherein a trifluoroacetyl group is used as an acyl protecting group for amino groups and an acetyl, chloroacetyl, trifluoroacetyl, benzoyl or p-nitro-benzoyl group is used as a protecting group for hydxoxyl groups.
5. The process as claimed in claim 1, wherein trifluoro-methanesulfonic acid tri-(C1-C4)-alkylsilyl ester or anhydride or BF3-ether is used as the promoter.
6. The process as claimed in claim 1, wherein trimethyl-silyl or tert.butyl(dimethyl)silyl trifluoroethane-sulfonate is used as the promoter.
7. The process as claimed in claim 1, wherein dichloro-methane, dichloroethane, ether, toluene, acetonitrile or one of their mixtures with acetone or ethyl acetate is used as the organic solvent.
8. The process as claimed in claim 1, wherein deacylation is carried out by means of an alkali liquor or an alcoholate.
9. Functionalied carbohydrate building blocks of the formula III in which R5 is an NH-acyl protecting group or an O-acyl protecting group R6 is H, an NH-acyl protecting group or an O-acyl protecting group R7 is H or an O-acyl protecting group and R8, R9 and R10 are (C1-C4)-alkyl, an acyl protecting group for amino groups being tri-fluoroacetyl and for hydroxyl groups being acetyl, chloroacetyl, trifluoroacetyl, benzoyl or p-nitro-benzoyl.
10. The process for the preparation of an anthracycline as claimed in claim 1 and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3943029.4 | 1989-12-27 | ||
| DE3943029A DE3943029A1 (en) | 1989-12-27 | 1989-12-27 | METHOD FOR PRODUCING GLYCOSYL ANTHRACYCLINONES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2032974A1 true CA2032974A1 (en) | 1991-06-28 |
Family
ID=6396470
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002032974A Abandoned CA2032974A1 (en) | 1989-12-27 | 1990-12-21 | Process for the preparation of glycosylanthracyclinones |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0437820A3 (en) |
| JP (1) | JPH05345794A (en) |
| KR (1) | KR910011879A (en) |
| AU (1) | AU633671B2 (en) |
| CA (1) | CA2032974A1 (en) |
| DE (1) | DE3943029A1 (en) |
| IE (1) | IE904681A1 (en) |
| PT (1) | PT96358A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3842836A1 (en) * | 1988-12-20 | 1990-06-21 | Behringwerke Ag | RHODOMYCINE WITH A MODIFIED CARBOHYDRATE UNIT |
| DE3924655A1 (en) * | 1989-07-26 | 1991-01-31 | Behringwerke Ag | ANTHRACYCLINE DERIVATIVES |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4564674A (en) * | 1983-10-31 | 1986-01-14 | Sagami Chemical Research Center | Process for an anthracycline derivative, and an anthracyclinone derivative useful for the process |
| DE3836122A1 (en) * | 1988-10-22 | 1990-05-31 | Behringwerke Ag | METHOD FOR PRODUCING 4-0-ALKYL RHODOMYCINES |
| MA21995A1 (en) * | 1989-11-13 | 1991-07-01 | Menarini Farma Ind | NOVEL FLUORONAPHTHACENEDIONES, THEIR GLYCOZYL DERIVATIVES AND THEIR MANUFACTURING METHODS. |
| DE4036155A1 (en) * | 1990-11-14 | 1992-05-21 | Behringwerke Ag | SEMISYNTHETIC DIASTEREOMERIC PURE N-GLYCIDYL ANTHRACYCLINE, METHOD FOR THEIR STEREOSELECTIVE PRODUCTION AND THEIR USE AS CYTOSTATICS |
-
1989
- 1989-12-27 DE DE3943029A patent/DE3943029A1/en not_active Withdrawn
-
1990
- 1990-12-21 EP EP19900125272 patent/EP0437820A3/en not_active Withdrawn
- 1990-12-21 IE IE468190A patent/IE904681A1/en unknown
- 1990-12-21 CA CA002032974A patent/CA2032974A1/en not_active Abandoned
- 1990-12-24 AU AU68406/90A patent/AU633671B2/en not_active Ceased
- 1990-12-26 JP JP2418213A patent/JPH05345794A/en active Pending
- 1990-12-26 PT PT96358A patent/PT96358A/en not_active Application Discontinuation
- 1990-12-27 KR KR1019900021904A patent/KR910011879A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR910011879A (en) | 1991-08-07 |
| AU6840690A (en) | 1991-07-04 |
| EP0437820A3 (en) | 1991-07-31 |
| IE904681A1 (en) | 1991-07-17 |
| DE3943029A1 (en) | 1991-07-04 |
| PT96358A (en) | 1991-09-30 |
| EP0437820A2 (en) | 1991-07-24 |
| AU633671B2 (en) | 1993-02-04 |
| JPH05345794A (en) | 1993-12-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0180415B1 (en) | A 6-0-methylerythromycin A derivative | |
| JP2651414B2 (en) | 4-dementoxy-4-amino-anthracyclines | |
| RU2440363C2 (en) | Synthesis of epirubicin from 13-dihydrodaunorubicin | |
| JPS6123200B2 (en) | ||
| US5945518A (en) | Process for the preparation of anthracycline antibiotics | |
| JP2004513131A (en) | Glycosidation of indolocarbazole using phase transfer catalyst | |
| EP0521458B1 (en) | Mono and bis alkylamino-anthracyclines | |
| CA2032974A1 (en) | Process for the preparation of glycosylanthracyclinones | |
| HU198505B (en) | Process for producing antitumour anthracycline glycosides | |
| EP0366973B1 (en) | New 4-substituted anthracyclinones and anthracycline glycosides and the process for preparing them | |
| FI84075C (en) | Process for the preparation of new anthracyclines | |
| US4933439A (en) | Tylosin derivatives and processes for producing the same | |
| AU641644B2 (en) | A process for the preparation of etoposides | |
| EP1140962B1 (en) | Novel derivatives from the class of oleandomycin | |
| CS270411B2 (en) | Method of new 4 halogen anthracycline glycosides production | |
| EP0354995A1 (en) | 4-Substituted anthracyclinones and anthracycline glycosides and their preparation | |
| US4496485A (en) | Asymmetric 7-O-(substituted acetyl)-4-demethoxydaunomycinones | |
| HRP950436A2 (en) | 8-fluoro-anthracyclines, processes for their preparation and pharmaceutical compositions containing them | |
| EP0365973B1 (en) | Process for preparing 4-0-alkyl-rhodomycins | |
| EP0490311B1 (en) | Derivatives of 10,11,12,13-tetra-hydrodesmycosin, processes for preparation, and use thereof in obtaining pharmaceuticals | |
| GB2201419A (en) | Anthracycline-oestrone derivatives | |
| KR0157612B1 (en) | Novel anthrcycline glycoside derivatives | |
| RU2024483C1 (en) | 4-substituted anthracyclinones and anthracycline glycoside | |
| CA1335199C (en) | 14-chlorodaumonycin and process for the preparation of 14-chlorodaunomycin, and process for the preparation of (2"r)-4'-o-tetrahydropyranyladriamycin | |
| WO1994012512A1 (en) | Glucosylglucoside derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |