CA2015074A1 - Process for the preparation of etoposides - Google Patents
Process for the preparation of etoposidesInfo
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- CA2015074A1 CA2015074A1 CA002015074A CA2015074A CA2015074A1 CA 2015074 A1 CA2015074 A1 CA 2015074A1 CA 002015074 A CA002015074 A CA 002015074A CA 2015074 A CA2015074 A CA 2015074A CA 2015074 A1 CA2015074 A1 CA 2015074A1
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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Abstract
BEHRINGWERKE AKTIENGESELLSCHAFT HOE 89/B 014 - Ma 763 Dr. Ha/Sd Abstract of the disclosure A process for the preparation of etoposides The invention relates to a process for the preparation of a beta-glucopyranose derivative of the formula I
I
in which R1 and R2 are H or an acyl protective group and R3 is H, benzyl or a radical of the formula II
II
with R4 being H or a benzyloxycarbonyl or chloroacetyl protective group and A being C1-C4-alkyl, which comprises eliminating the benzyl group in a benzylglucopyranoside of the formula I in which R1 and R2 are an acyl protective group, R3 is a benzyl protective group and A is C1-C4-alkyl, by hydrogenolysis in the presence of a hydrogenation catalyst and of an organic solvent, there being formation of a glucopyranose derivative of the formula I which is in the beta-hydroxy form and in which R1, R2 and A retain their meaning, and R3 is a hydrogen atom, subsequently reacting this glycosi-dation component with an epi-podophyllotoxin derivative of the formula III
III
in which R4 is benzyloxycarbonyl or chloroacetyl protective group, in the presence of a promoter such as, preferably, BF3.ether or of a tri-(C1-C4)-alkylsilyl trifluorome-thanesulfonate and of an organic solvent, where appro-priate in the presence of a desiccant at -30°C to 0°C, there being formation of a beta-glycoside of the formula I in which R1, R2, R4 and A retain their meaning, and R3 is a radical of the formula II, and eliminating in a product which is formed the benzyloxycarbonyl protective group by hydrogenolysis and the acyl protective group using basic ion exchangers in the presence of a polar solvent, there being formation of a product of the formula I in which R1 and R2 are hydrogen, R3 is a radical of the formula II with R4 equal to hydro-gen, and A is C1-C4-alkyl.
I
in which R1 and R2 are H or an acyl protective group and R3 is H, benzyl or a radical of the formula II
II
with R4 being H or a benzyloxycarbonyl or chloroacetyl protective group and A being C1-C4-alkyl, which comprises eliminating the benzyl group in a benzylglucopyranoside of the formula I in which R1 and R2 are an acyl protective group, R3 is a benzyl protective group and A is C1-C4-alkyl, by hydrogenolysis in the presence of a hydrogenation catalyst and of an organic solvent, there being formation of a glucopyranose derivative of the formula I which is in the beta-hydroxy form and in which R1, R2 and A retain their meaning, and R3 is a hydrogen atom, subsequently reacting this glycosi-dation component with an epi-podophyllotoxin derivative of the formula III
III
in which R4 is benzyloxycarbonyl or chloroacetyl protective group, in the presence of a promoter such as, preferably, BF3.ether or of a tri-(C1-C4)-alkylsilyl trifluorome-thanesulfonate and of an organic solvent, where appro-priate in the presence of a desiccant at -30°C to 0°C, there being formation of a beta-glycoside of the formula I in which R1, R2, R4 and A retain their meaning, and R3 is a radical of the formula II, and eliminating in a product which is formed the benzyloxycarbonyl protective group by hydrogenolysis and the acyl protective group using basic ion exchangers in the presence of a polar solvent, there being formation of a product of the formula I in which R1 and R2 are hydrogen, R3 is a radical of the formula II with R4 equal to hydro-gen, and A is C1-C4-alkyl.
Description
~2 ~ 7 ~
BEHRIN~WERKE AKTIENGESELLSCHAFT HOE 89/B 014 - Ma 763 Dr. Ha/Sd A ~rocess for the Preparation-of etoposides ~he invention relates to a process for the preparation of 4-0-~4,6-0-alkylidene-beta-D-glucopyranosyl)-4'-0-de-methyl-4-epi-podophyllotoxins, which are called etopo-sides, especially of etoposide (VP-16~ which, by reason of its cytostatic a~tivity, i~ ~ui~able for the treatment of cancexs. The invention particularly relates to a process for the preparation of 4,6-0-alkylidene-2,3-di-O-acyl-beta-D-glucopyranoses which are used a8 glycosyl donors for the synthesis of 4-0-beta-D-glucopyranosyl-epi-podophyllotoxins, and to a process for the deacyl-ation of the glycoside intermediates.
Etoposide (VP-16) and the closely structurally related teniposide (VM-26) have been introduced as pharmaceuti-cals. They are particularly valuable for the treatment of small-cell lung cancer and testicular cancer.
The preparation, action and clinical use of etoposides has been described by T.W. Doyle in "Etoposide ~VP-16) -current status and new developments" (Editor. B.F. Issell, F.M. Muggia and S.K. Carter; Academic Press, 1984, pp.
15-32).
Etoposides are usually prepared starting from a function-alized glucopyranose building block and a 4'-0-protected epi-podophyllotoxin dPrivative.
The synthesis of etoposides starting from the glycosyl donors 2,3-di-0-acetyl-4,6-0-ethylidene-D-glucose or 2,3-di-O-halogenoacetyl-4,6-0-ethylidene-D-gluco~e has been described in Swi8s Patent No. 514,578 (GB 823,06B) or EP 0,111,058. The preparakion described therein of these donors, which are obtained from 1-0-benzyloxycarbonyl-beta-glucose precursors, is costly and, because of the use of benzyl chloroformate as reagent, ha~ardous ko 2 ~ 7 ~
~ 2 -health. In addition, these precursors in the beta fonm must be isolated from an alpha,beta mixture because only the beta form provides the beta-hydroxyglucopyranose donors required for the glycoside synthesis.
EP 0,226,202 A2 describes the preparation of etoposides using 1-O-trialkyltin-glucose donors.
Because of the chemical in~tability of the podophyl-lotoxin aglycone, by~products are formed during the conventional deblocking of the etoposide precursoxs.
Deace~ylation as described in the abovementioned patent applications is effected by methanolysis catalyzed by ~inc(II) salts. The by-products occurring in this case are the corresponding methyl esters of the hydroxy acid formed by opening of the lactone ring, as well as a picro lS compound, which comprise up to about 30 % of the xeaction product.
Because of the disadvantages which have been described, there is a need for a straightforward and low-cost process for the preparation of etoposides.
It has been found, surprisingly, that hydrogenolysis of benzyl 2,3-di-O-acyl-4,6-O-ethylidene-beta-D-glucopyrano-side provides the glycosyl donor with retention of the beta con$iguration. Since the alpha-hydroxy form of the glucose unit does not occur in this reaction, the ~ubse-quent glycosylation of the epi-podophyllotoxin deriva-tives takes place selectively to give the desired beta-glycosides. It has furthermore been found that ~he deacylation of the etoposide precursors using a basic ion exchanger takes place without formation of the by-products described above.
~he invention has the ob~ect of developing a process which provide~ the glycosylation component 4,6-O-alkylidene-2,3-di-O-acyl-beta-D-glycopyranose in improved yields and in pure beta-hydroxy form, and signifies a simplification 2 ~
compared with the known processes, the use thereof for the glycosylation of (epi)-podophyllokoxin derivatives and the working out of an improved protective-group chemistry on acylated 4-0-glucosyl-epi-podophyllotoxins which permits preparation of etoposides without the formation of by-products.
This object i5 achieved by the process for the prepara-tion of a beta-glucopyranose derivative of the formula I
o \ \~n ,0 ~ ~ oR3 Rl R2 0, in which Rl and R2 are H or an acyl protective group and - R3 is H, benzyl or the radical of the formula II
<0~, ~ Orle with R4 being H or a benzyloxycarbonyl or chloroacetyl protective group and A being Cl-C4-alkyl, which compri~es eliminating the benzyl group in a benzyl glucopyranoside of the formula I in which Rl and R2 are an acyl protective group, R3 iS a benzyl protective group and A is C1-C4-alXyl, 2 ~ 7 ~
by hydrogenolysis in the presence of a hydrogenation catalyst and of an or~anic sol~ent, there being formation of a glucopyrano~e derivative of the formula I which is in the beta-hydro~y form and in which Rl, RZ and A retain their meaning, and R3 is a hydrogen atom, subsequently reacting this ~lycosidation component with an epi-podo-phyllotoxin derivative of the formula III
OH
<0~
~ O
MeO ~~ Olte o-R4 in which R4 is benzyloxycarbonyl or chloroacetyl protective group, in the presence of a promoter ~uch as, preferably, BF3.ether or of a tri-(Cl-C4)-alkylsilyl trifluoromethane-sulfonate and of an organic ~olvent, where appropriate in the presence of a desiccant at -30C to 0C, there being formation of a beta-glycoside of the formula I in which R1, R2, R4 and A retain their meaning/ and R3 is a radical of the formula II, and eliminating in the product which is formed the benzyloxycarbonyl protective group by hydrogenolysis and the acyl protective group using basic ion exchangers in the presence of a polar ~olvent, there being formation of a product of the formula I in which and * are hydrogen, R3 is a radical of the formula II
with R4 equal to hydrogen, and A i~ Cl-C4-alkyl.
Preferably prepared by the process according to the invention ar~ compounds of the formula I in which R1 and R2 are H, the acetyl or chloroacetyl protective group, R3 is H, benzyl or a radical of the formula II with R4 being 2 ~
H or a benzyloxycarbonyl or chloroacetyl protective group, and A is methyl.
The detailed procedure for this is as follows;
The ~tarting compound benzyl 2,3-di-O-acyl-4,6-O-alkyli-dene-beta-D-glucopyranoside can be prepared by the proce~ses customary in carbohydrate chemis~ry. ~tarting ~rom 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl fluoride, which is easily obtainable industrially, and benzyl alcohol, the ~eta-benzylglucoside is selectively prepared in the pxesence of a Lewis acid such as BF3.ether. The product is deacetylated with sodium methy-late and sub~equently con~erted with a Cl-C4-aldehyde under acid catalysis into a 4,6-0-alkylidene compound which is finally reacted at ~-2 and 0-3 u~ing an acid anhydride or halide in the presence of a base such as pyridine or triethylamine at -40C to O~C to give a benzyl 2,3-di-O-acyl-4,6-O-alkylidene-beta-D-glucopyrano-side.
The glucopyranose glycosylation component which is in the 2V beta-hydroxy form can be prepared in the following manner: benzyl 2,3-di-O-acyl-4,6-O-alkylidene-beta-D-glucopyranoside is hydrogenated in the presence of palladium/carbon or palladium/barium sulfate and of a solvent such as methanol, ethanol, acetone or ethyl acetate or mixtures thereof, preferably acetone/ethanol mixture~, preferably under atmospheric pre~sure, there being quantitative formation of the qlucopyranose com-ponent in the beta-hydroxy form.
The reaction of the beta ~ydroxy donors with a 4'-O-protected 4'-O-demethyl-4-epi-podophyllotoxin deri~ati~e of the formula III i carried out using a promoter such as BF3.ether or of a tri-(Cl-C4)-alkylsilyl trifluoro-methanesulfonate in an anhydrous organic solvent such as dichloromethane, ethyl acetate, ether, acetone or aceto-nitrile, where appropriate in the presence of a desiccant 2 ~ 7 ~
such as a molecular sieve at -30~C to 0C. It is particu-larly advantageous to employ the promoter trimethylsilyl trifluoromethanesulonate.
~he benzyloxycarbonyl protective group is eliminated in 5 a customary manner by hydxogenolysis in the pre~ence of palladium/carbon or palladium/barium sulfate. The acyl protective groups in the c~rbohydrate moiety and, where appropriate, on the aglycone of the etoposide derivatives of the formula I are eliminated usin~ a basic ion lD exchanger, preferably Dowex lx8 in an organic solvent such as methanol, ethanol, propanol, ethyl acetate, dichloromethane, chloroform or mixtuxes thereof. Deacyl-ation of chloroacetyl derivatives of the formula I u~ing the ion exchanger Dowex lx8 is particularly preferred and takes place quantitatively in methanol/chloroform as solvent to give etoposides without the formation of by-products.
Acyl protective groups are, in particular, acetyl or mono-, di- or trihalogenoacetyl protective groups with fluorine, chlorine or bromine as halogen, preferably the chloroacetyl protective group.
The examples which follow are intended to illustrate the invention without, however, confining it to the compounds mentioned.
Example 1 Preparation of benzyl beta-D-glucoside ` - Benzyl beta-D-glucopyranoside (Compound 1) 5 g (14.2 mmol) of 2,3,4,6-tetra O-acetyl-alpha-D-gluco-pyranosyl fluoride were dissolved in 50 ml of dry aceto-nitrile, and 2.2 ml (1.5 eq) of benzyl alcohol wereadded. The reaction mixture was cooled to 0C and, while stirring, 2.1 ml of BF3.ether were added dropwise. After 2 0 ~
2.5 h (TLC- hexane/ethyl acetate), 2.5 ml of ~riethyl-amin~ were added to the reaction mixture, which was then concentrated in vacuo. ~he residue was dissolved in chloro-form, and the solution was washed with phosphate buffer, pH 7.5, and then with ~aturated brine, dried over sodium sulfate and evaporated in vacuo. The product ~6.3 g) was dissolved in 50 ml of dry methanol, and the ~olution was adjusted to pH 11 with sodium methylate. After 4 h, it was neutralized with Dowex ~x8 and evaporated in vacuo.
The resulting product, which is identical (lH NMR, rotation~
to the product described in the literature, was employed without further purification steps in the next stage.
Exam~le 2 Preparation of the 2,3-di-O-acyl-4,6 ethylidene-gluco-sides Benzyl 4,6-O-ethylidene-beta-D-glucopyranoside (Compound 2) 58.8 g (157.0 mmol) of compound 1 were suspended in 600 ml of dioxane. 17.7 ml of acetaldehyde were added, and then the mixture was cooled to 10C and, while stir-ring, 2 ml of concentrated H2SO4 were added dropwise.
After 1.5 h, a further 9 ml of acetaldehyde and 0.5 ml of concentrated HaSO4 were added. The reaction mixture was then stirred at room temperature for 12 h. The re~ulting red-brown ~olution was adjusted to pH 7 with methanolic sodium methylate solution ~ evaporated in vacuo and then distilled with toluene. ~he residue was taken up in ethyl acetate, and the solution was thoroughly washed with ice-water. The organic phase was dried over sodium sulfate and evaporated. The product was dissolved in chloroform/
me~hanol 7:1 and filtered through 150 g of silica gel, and the residue after evaporation of the solvent was crystallized from ether~
Yield: 52.5 g (81 %), ~23 = -79.1 (c = 1 in chloroform) Melting point = 150C
2 ~ 7 ~
Ben~yl 2,3-di-0-acetyl-4,6-0-ethylidene-be~a-D-gluco-pyranoside ICompound 3) 3.51 g (11.8 mmol) of compound 2 were dissolved in 30 ml of dichloromethane and 30 ml of pyridine and, at 0C, 5.3 ml of acetic anhydride were added. The reaction mixture was stirred for 12 h and then worked up as customary in carbohydrate ch~mistry.
Yield: 5.28 g (100 %), ~]D3 Y -87 (c = 1 in rhloroform) Melting point = 155C
Benzyl 2,3-di-0-chloroacetyl-4,6-0-ethylidene-beta-D-glucopyranose (Compound 4) 25 g ~54.3 mmol) of compound 2 were dissolved in 350 ml dry dichloromethane, and 56 ml of triethylamine were added.
The mixture was cooled to -20C and 20 ml of chloroacetyl chloride dissol~ed in 250 ml of dichloromethane were added in portions. After 4 h, a further 11 ml of tri-ethylamine and 3.5 ml of chloroacetyl chloride were added to the reaction mixture. After a further 4 h, the mixture was filtered, and the organic phase was thoroughly washed ~0 with ice-cold phosphate buffer, pH 7Ø The organic phase was dried over magnesium sulfate and evaporated in vacuo.
The residue was dissolved in chloroform/ethyl acetate and filtered through 100 g of silica gel. The product from evaporation crystallized from chloroform and petroleum ether. ~ield: 31.0 g (82 ~), [~ ID = -54 . 9 ( C = 1 in dichloromethane) E~amPle 3 Preparation of beta-hydroxy-glycosylation components 2,3-Di-0-acetyl-4,6-~-ethylidene beta-D-glucopyranose (Compound 5) 1 g (2.6 ~mol) of compound 3 were dissolved in 40 ml of ethyl acetate, and 1 g of palladium/carbon was added. The 20~5~ ~
g reaction mixture was hydrogenated under atmospheric preæsure at room t~mperature for 1 h. The cataly~t was filtered off and the solution was evaporated in vacuo at 35C, and the residue was then dis~illed with toluene, The resulting produc$ was employed without further purification steps in the next reaction stage. Yield:
0.76 g (99 %), [~] 23 = - 16.4 (c = 1 in ethyl acetate) 2,3-Di-O-chloroacetyl-4,6-O-ethylidene-beta-D-gluco-pyranose (Compound 6) 25 g (55.6 mmol) of compound 4 were dissolved in 600 ml of acetone and 60 ml o~ ethanol. 15 g of palladium/carbon were added and then the mixture was hydrogenated for l.S h. ~he catalyst was then filtered off and the organic phase was evaporated at 35C. The residue was distilled 1~ with toluene and employed without further purification steps in the next reaction stage.
Yield: 19.8 g (98 %), [~]23 = -19.8 ~c = 1 in acetone~
Example 4 Glycosylation of podophyllotoxin derivatives 4'-O-Benzyloxycarbonyl-4 O-(2,3-di-O-chloroacetyl-4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-O-demethyl-4-epi-podophyllotoxin (Compollnd 7) Process A:
15.2 g (42.3 mmol) of compound 6, 22.6 g ~4~.3 mmol) of 4'-O benzyloxycarbonyl-4'~0-demethyl-4-epi-podophyl~
lotoxin and 20 g of 4 A molecular sieves were suspended in 1000 ml of dichloxomethane and, at -20C under protec-tive gas, 45.5 ml of BF3~ether were added. The mixture was fitirred at -20~C for 17 h, then 46 ml of ~riethylamin~
were added and the mixture was fil~ered. The ~iltrate wa~
evaporated in vacuo, and the residue was then distilled with toluene. The resulting crude product was dissolved 20~7~
in chloroform and then thoroughly washed with phosphate buffer, pH 7.5. The organic phase wa~ dried over ~odium 8ulfate and evaported in vacuo. The residue was dissolved in a dichloromethane/petroleum ether/acetone 8:2~1 ~olvent mixture and filtered through lO0 y of ~ilica gel.
The product from evaporation of the solvent was crystallized from chloroform/petroleum ether. Yield:
31.8 g (56 %)~ 23 = _37.9D (C = 1 in chloroform) Process B:
15.2 g (42.3 mmol) of compound 6, 22.0 g (42.3 mmol) of 4'-0-benzyloxycarbonyl-4'-0-demethyl-4-epi-podophyl-lotoxin and 20 g of 4 A molecular sieves were suspended in 550 ml of dichloxomethane~acetone 10:1 and, at -30C
under protective gas, 9.4 g of trimethylsilyl trifluoro-methanesulfonate were added. The reaction mixture wa~
stirred at -25C for 6 h, and then 50 ml of triethylamine wers a~ded and the mixture was filtered. The subseguent working up was carried out as described in process A.
Yield: 34 g (92 ~) 4'-0 Benzyloxycarbonyl~4-0-t2,3-di-0-acetyl 4,6-0-ethyl-ide~e-beta-D-glucopyranosyl3-4'-0-demethyl-~-epi-podo-phyllotoxin (Compound 8) 1.22 g ~4.23 mmol) of compound 5, 2.20 g ~4.23 mmol) of 4'-0-benzyloxycarbonyl-4'-0-demethyl-4-epi-podophyl-lotoxin and 2.5 g of 4 ~ molecular ~ieve~ wer~ ~uspende~
in 60 ml of dichloromethane/acetone 10:1 and, at -30C
under protective gas, 0.94 g of trimethyl~ilyl trifluoro-methanesulfonate was added. The reaction mixture was stirred at -25C for 8 h and then 5 ml of tri~thyl~mine were added, and the working up was as for the preparation of compound 7~
YIeld: 2.8 g tB2 ~) 4'-0-Chloroacetyl-4-0-(2,3-di-0-chloroacetyl-4~6~0-ethylidene-beta-D-glucopyranosyl)-4'-0-demethyl-4-epi-2 ~ 7 ~
podophyllotoxin (Compound 9) 11 g (30.6 mmol) of compound 6, 14.6 g (30.6 mmol) of 4'-0-chlsroacetyl-4'-0-dem~thyl-4-epi-podophyllotoxin and 20 g of molecular sieves were stirred in 330 ml of dichloromethane/acetone 10:1 and, at -30C, 6.~ g of trimethylsilyl trifluoromethanesulfonate were added.
After 7 h the reac~ion mixturs was worked up as described for the preparation of compound 7.
Yield: 21.3 g (86 ~) Example 5 Deacylation of the etoposide precursors 4' 0-Benzyloxycarbonyl-4'-0-demethyl-4-epi-4-0-(4,6-0-ethylidene-beta-D-glucopyranosyl)-podophyllotoxin (Compound 10) 27.5 g (31 mmol) of compound 7 were dissolved in 780 ml of dichloromethane and 1225 ml of methanol. 50 g of Dowex lx8 ion exchanger were added and then the reaction mixture was stirred at room temperature for 1 h. The suspension was filtered, and the resin was washed with methanol. ~he filtrates were evaporated, the residue was dis~olved in chloroform, and the solution was thoroughly wa~hed with phosphate buffer, pH 7.5, and then with water. The organic phase was dried over sodium ~ulfate and evaporated in vacuo. The residue crystallized from ether/petroleum ether.
Yield: 21.5 g (96 %~
4'-0-Demethyl-4-epi-4-0-(4,6-0-ethylidene-beta-D gluco-- pyranosyl3-podophyllotoxin (Compound 11) ~0 g (24.6 mmol~ of compound 9 were dissolved in S00 ml of dichloromethane ~nd 900 ml of methanol, and 50 g of Dowex lx8 wsre added. The reactisn mixture was stirred at room temperature for 2 h and then filtered, washing the resin with methanol. The combined filtrates were e~aporated 2 ~
in vacuo. The residue was taken up in dichloromethane, and the solution was then washed with phospha~e buffer, pH 7.5, and with water. The organic phase was dried over sodium 8ul fate and evaporated in vacuo. The product crystallizes from dichloromethane and hexane.
Yield: 13.6 g (94 ~) Example 6 Elimination of the benzyloxycarbonyl group by hydrogenolysis 4'-0-Demethyl-4-epi-4-0-(4,6-0-ethylidene-beta D-gluco pyranosyl)-podophyllotoxin (Compound 11) 9.7 g (13.4 mmol~ o~ compound 10 were di6solved in 260 ml of methanol and hydrogenated with 5 g of palladium/car-bon~ After 40 min, the catalyst was filtered off, and the solution was evaporated in vacuo. The residue was dis-solved in dichloromethane and thoroughly washed with phosphate buffer, pH 7.5, and then with water. The organi~
phase was dri~d over sodium sulfate and evaporated in vacuo. The product crystallizes from dichloromethane and hexane.
Yield: 7.25 g (92 %)
BEHRIN~WERKE AKTIENGESELLSCHAFT HOE 89/B 014 - Ma 763 Dr. Ha/Sd A ~rocess for the Preparation-of etoposides ~he invention relates to a process for the preparation of 4-0-~4,6-0-alkylidene-beta-D-glucopyranosyl)-4'-0-de-methyl-4-epi-podophyllotoxins, which are called etopo-sides, especially of etoposide (VP-16~ which, by reason of its cytostatic a~tivity, i~ ~ui~able for the treatment of cancexs. The invention particularly relates to a process for the preparation of 4,6-0-alkylidene-2,3-di-O-acyl-beta-D-glucopyranoses which are used a8 glycosyl donors for the synthesis of 4-0-beta-D-glucopyranosyl-epi-podophyllotoxins, and to a process for the deacyl-ation of the glycoside intermediates.
Etoposide (VP-16) and the closely structurally related teniposide (VM-26) have been introduced as pharmaceuti-cals. They are particularly valuable for the treatment of small-cell lung cancer and testicular cancer.
The preparation, action and clinical use of etoposides has been described by T.W. Doyle in "Etoposide ~VP-16) -current status and new developments" (Editor. B.F. Issell, F.M. Muggia and S.K. Carter; Academic Press, 1984, pp.
15-32).
Etoposides are usually prepared starting from a function-alized glucopyranose building block and a 4'-0-protected epi-podophyllotoxin dPrivative.
The synthesis of etoposides starting from the glycosyl donors 2,3-di-0-acetyl-4,6-0-ethylidene-D-glucose or 2,3-di-O-halogenoacetyl-4,6-0-ethylidene-D-gluco~e has been described in Swi8s Patent No. 514,578 (GB 823,06B) or EP 0,111,058. The preparakion described therein of these donors, which are obtained from 1-0-benzyloxycarbonyl-beta-glucose precursors, is costly and, because of the use of benzyl chloroformate as reagent, ha~ardous ko 2 ~ 7 ~
~ 2 -health. In addition, these precursors in the beta fonm must be isolated from an alpha,beta mixture because only the beta form provides the beta-hydroxyglucopyranose donors required for the glycoside synthesis.
EP 0,226,202 A2 describes the preparation of etoposides using 1-O-trialkyltin-glucose donors.
Because of the chemical in~tability of the podophyl-lotoxin aglycone, by~products are formed during the conventional deblocking of the etoposide precursoxs.
Deace~ylation as described in the abovementioned patent applications is effected by methanolysis catalyzed by ~inc(II) salts. The by-products occurring in this case are the corresponding methyl esters of the hydroxy acid formed by opening of the lactone ring, as well as a picro lS compound, which comprise up to about 30 % of the xeaction product.
Because of the disadvantages which have been described, there is a need for a straightforward and low-cost process for the preparation of etoposides.
It has been found, surprisingly, that hydrogenolysis of benzyl 2,3-di-O-acyl-4,6-O-ethylidene-beta-D-glucopyrano-side provides the glycosyl donor with retention of the beta con$iguration. Since the alpha-hydroxy form of the glucose unit does not occur in this reaction, the ~ubse-quent glycosylation of the epi-podophyllotoxin deriva-tives takes place selectively to give the desired beta-glycosides. It has furthermore been found that ~he deacylation of the etoposide precursors using a basic ion exchanger takes place without formation of the by-products described above.
~he invention has the ob~ect of developing a process which provide~ the glycosylation component 4,6-O-alkylidene-2,3-di-O-acyl-beta-D-glycopyranose in improved yields and in pure beta-hydroxy form, and signifies a simplification 2 ~
compared with the known processes, the use thereof for the glycosylation of (epi)-podophyllokoxin derivatives and the working out of an improved protective-group chemistry on acylated 4-0-glucosyl-epi-podophyllotoxins which permits preparation of etoposides without the formation of by-products.
This object i5 achieved by the process for the prepara-tion of a beta-glucopyranose derivative of the formula I
o \ \~n ,0 ~ ~ oR3 Rl R2 0, in which Rl and R2 are H or an acyl protective group and - R3 is H, benzyl or the radical of the formula II
<0~, ~ Orle with R4 being H or a benzyloxycarbonyl or chloroacetyl protective group and A being Cl-C4-alkyl, which compri~es eliminating the benzyl group in a benzyl glucopyranoside of the formula I in which Rl and R2 are an acyl protective group, R3 iS a benzyl protective group and A is C1-C4-alXyl, 2 ~ 7 ~
by hydrogenolysis in the presence of a hydrogenation catalyst and of an or~anic sol~ent, there being formation of a glucopyrano~e derivative of the formula I which is in the beta-hydro~y form and in which Rl, RZ and A retain their meaning, and R3 is a hydrogen atom, subsequently reacting this ~lycosidation component with an epi-podo-phyllotoxin derivative of the formula III
OH
<0~
~ O
MeO ~~ Olte o-R4 in which R4 is benzyloxycarbonyl or chloroacetyl protective group, in the presence of a promoter ~uch as, preferably, BF3.ether or of a tri-(Cl-C4)-alkylsilyl trifluoromethane-sulfonate and of an organic ~olvent, where appropriate in the presence of a desiccant at -30C to 0C, there being formation of a beta-glycoside of the formula I in which R1, R2, R4 and A retain their meaning/ and R3 is a radical of the formula II, and eliminating in the product which is formed the benzyloxycarbonyl protective group by hydrogenolysis and the acyl protective group using basic ion exchangers in the presence of a polar ~olvent, there being formation of a product of the formula I in which and * are hydrogen, R3 is a radical of the formula II
with R4 equal to hydrogen, and A i~ Cl-C4-alkyl.
Preferably prepared by the process according to the invention ar~ compounds of the formula I in which R1 and R2 are H, the acetyl or chloroacetyl protective group, R3 is H, benzyl or a radical of the formula II with R4 being 2 ~
H or a benzyloxycarbonyl or chloroacetyl protective group, and A is methyl.
The detailed procedure for this is as follows;
The ~tarting compound benzyl 2,3-di-O-acyl-4,6-O-alkyli-dene-beta-D-glucopyranoside can be prepared by the proce~ses customary in carbohydrate chemis~ry. ~tarting ~rom 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl fluoride, which is easily obtainable industrially, and benzyl alcohol, the ~eta-benzylglucoside is selectively prepared in the pxesence of a Lewis acid such as BF3.ether. The product is deacetylated with sodium methy-late and sub~equently con~erted with a Cl-C4-aldehyde under acid catalysis into a 4,6-0-alkylidene compound which is finally reacted at ~-2 and 0-3 u~ing an acid anhydride or halide in the presence of a base such as pyridine or triethylamine at -40C to O~C to give a benzyl 2,3-di-O-acyl-4,6-O-alkylidene-beta-D-glucopyrano-side.
The glucopyranose glycosylation component which is in the 2V beta-hydroxy form can be prepared in the following manner: benzyl 2,3-di-O-acyl-4,6-O-alkylidene-beta-D-glucopyranoside is hydrogenated in the presence of palladium/carbon or palladium/barium sulfate and of a solvent such as methanol, ethanol, acetone or ethyl acetate or mixtures thereof, preferably acetone/ethanol mixture~, preferably under atmospheric pre~sure, there being quantitative formation of the qlucopyranose com-ponent in the beta-hydroxy form.
The reaction of the beta ~ydroxy donors with a 4'-O-protected 4'-O-demethyl-4-epi-podophyllotoxin deri~ati~e of the formula III i carried out using a promoter such as BF3.ether or of a tri-(Cl-C4)-alkylsilyl trifluoro-methanesulfonate in an anhydrous organic solvent such as dichloromethane, ethyl acetate, ether, acetone or aceto-nitrile, where appropriate in the presence of a desiccant 2 ~ 7 ~
such as a molecular sieve at -30~C to 0C. It is particu-larly advantageous to employ the promoter trimethylsilyl trifluoromethanesulonate.
~he benzyloxycarbonyl protective group is eliminated in 5 a customary manner by hydxogenolysis in the pre~ence of palladium/carbon or palladium/barium sulfate. The acyl protective groups in the c~rbohydrate moiety and, where appropriate, on the aglycone of the etoposide derivatives of the formula I are eliminated usin~ a basic ion lD exchanger, preferably Dowex lx8 in an organic solvent such as methanol, ethanol, propanol, ethyl acetate, dichloromethane, chloroform or mixtuxes thereof. Deacyl-ation of chloroacetyl derivatives of the formula I u~ing the ion exchanger Dowex lx8 is particularly preferred and takes place quantitatively in methanol/chloroform as solvent to give etoposides without the formation of by-products.
Acyl protective groups are, in particular, acetyl or mono-, di- or trihalogenoacetyl protective groups with fluorine, chlorine or bromine as halogen, preferably the chloroacetyl protective group.
The examples which follow are intended to illustrate the invention without, however, confining it to the compounds mentioned.
Example 1 Preparation of benzyl beta-D-glucoside ` - Benzyl beta-D-glucopyranoside (Compound 1) 5 g (14.2 mmol) of 2,3,4,6-tetra O-acetyl-alpha-D-gluco-pyranosyl fluoride were dissolved in 50 ml of dry aceto-nitrile, and 2.2 ml (1.5 eq) of benzyl alcohol wereadded. The reaction mixture was cooled to 0C and, while stirring, 2.1 ml of BF3.ether were added dropwise. After 2 0 ~
2.5 h (TLC- hexane/ethyl acetate), 2.5 ml of ~riethyl-amin~ were added to the reaction mixture, which was then concentrated in vacuo. ~he residue was dissolved in chloro-form, and the solution was washed with phosphate buffer, pH 7.5, and then with ~aturated brine, dried over sodium sulfate and evaporated in vacuo. The product ~6.3 g) was dissolved in 50 ml of dry methanol, and the ~olution was adjusted to pH 11 with sodium methylate. After 4 h, it was neutralized with Dowex ~x8 and evaporated in vacuo.
The resulting product, which is identical (lH NMR, rotation~
to the product described in the literature, was employed without further purification steps in the next stage.
Exam~le 2 Preparation of the 2,3-di-O-acyl-4,6 ethylidene-gluco-sides Benzyl 4,6-O-ethylidene-beta-D-glucopyranoside (Compound 2) 58.8 g (157.0 mmol) of compound 1 were suspended in 600 ml of dioxane. 17.7 ml of acetaldehyde were added, and then the mixture was cooled to 10C and, while stir-ring, 2 ml of concentrated H2SO4 were added dropwise.
After 1.5 h, a further 9 ml of acetaldehyde and 0.5 ml of concentrated HaSO4 were added. The reaction mixture was then stirred at room temperature for 12 h. The re~ulting red-brown ~olution was adjusted to pH 7 with methanolic sodium methylate solution ~ evaporated in vacuo and then distilled with toluene. ~he residue was taken up in ethyl acetate, and the solution was thoroughly washed with ice-water. The organic phase was dried over sodium sulfate and evaporated. The product was dissolved in chloroform/
me~hanol 7:1 and filtered through 150 g of silica gel, and the residue after evaporation of the solvent was crystallized from ether~
Yield: 52.5 g (81 %), ~23 = -79.1 (c = 1 in chloroform) Melting point = 150C
2 ~ 7 ~
Ben~yl 2,3-di-0-acetyl-4,6-0-ethylidene-be~a-D-gluco-pyranoside ICompound 3) 3.51 g (11.8 mmol) of compound 2 were dissolved in 30 ml of dichloromethane and 30 ml of pyridine and, at 0C, 5.3 ml of acetic anhydride were added. The reaction mixture was stirred for 12 h and then worked up as customary in carbohydrate ch~mistry.
Yield: 5.28 g (100 %), ~]D3 Y -87 (c = 1 in rhloroform) Melting point = 155C
Benzyl 2,3-di-0-chloroacetyl-4,6-0-ethylidene-beta-D-glucopyranose (Compound 4) 25 g ~54.3 mmol) of compound 2 were dissolved in 350 ml dry dichloromethane, and 56 ml of triethylamine were added.
The mixture was cooled to -20C and 20 ml of chloroacetyl chloride dissol~ed in 250 ml of dichloromethane were added in portions. After 4 h, a further 11 ml of tri-ethylamine and 3.5 ml of chloroacetyl chloride were added to the reaction mixture. After a further 4 h, the mixture was filtered, and the organic phase was thoroughly washed ~0 with ice-cold phosphate buffer, pH 7Ø The organic phase was dried over magnesium sulfate and evaporated in vacuo.
The residue was dissolved in chloroform/ethyl acetate and filtered through 100 g of silica gel. The product from evaporation crystallized from chloroform and petroleum ether. ~ield: 31.0 g (82 ~), [~ ID = -54 . 9 ( C = 1 in dichloromethane) E~amPle 3 Preparation of beta-hydroxy-glycosylation components 2,3-Di-0-acetyl-4,6-~-ethylidene beta-D-glucopyranose (Compound 5) 1 g (2.6 ~mol) of compound 3 were dissolved in 40 ml of ethyl acetate, and 1 g of palladium/carbon was added. The 20~5~ ~
g reaction mixture was hydrogenated under atmospheric preæsure at room t~mperature for 1 h. The cataly~t was filtered off and the solution was evaporated in vacuo at 35C, and the residue was then dis~illed with toluene, The resulting produc$ was employed without further purification steps in the next reaction stage. Yield:
0.76 g (99 %), [~] 23 = - 16.4 (c = 1 in ethyl acetate) 2,3-Di-O-chloroacetyl-4,6-O-ethylidene-beta-D-gluco-pyranose (Compound 6) 25 g (55.6 mmol) of compound 4 were dissolved in 600 ml of acetone and 60 ml o~ ethanol. 15 g of palladium/carbon were added and then the mixture was hydrogenated for l.S h. ~he catalyst was then filtered off and the organic phase was evaporated at 35C. The residue was distilled 1~ with toluene and employed without further purification steps in the next reaction stage.
Yield: 19.8 g (98 %), [~]23 = -19.8 ~c = 1 in acetone~
Example 4 Glycosylation of podophyllotoxin derivatives 4'-O-Benzyloxycarbonyl-4 O-(2,3-di-O-chloroacetyl-4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-O-demethyl-4-epi-podophyllotoxin (Compollnd 7) Process A:
15.2 g (42.3 mmol) of compound 6, 22.6 g ~4~.3 mmol) of 4'-O benzyloxycarbonyl-4'~0-demethyl-4-epi-podophyl~
lotoxin and 20 g of 4 A molecular sieves were suspended in 1000 ml of dichloxomethane and, at -20C under protec-tive gas, 45.5 ml of BF3~ether were added. The mixture was fitirred at -20~C for 17 h, then 46 ml of ~riethylamin~
were added and the mixture was fil~ered. The ~iltrate wa~
evaporated in vacuo, and the residue was then distilled with toluene. The resulting crude product was dissolved 20~7~
in chloroform and then thoroughly washed with phosphate buffer, pH 7.5. The organic phase wa~ dried over ~odium 8ulfate and evaported in vacuo. The residue was dissolved in a dichloromethane/petroleum ether/acetone 8:2~1 ~olvent mixture and filtered through lO0 y of ~ilica gel.
The product from evaporation of the solvent was crystallized from chloroform/petroleum ether. Yield:
31.8 g (56 %)~ 23 = _37.9D (C = 1 in chloroform) Process B:
15.2 g (42.3 mmol) of compound 6, 22.0 g (42.3 mmol) of 4'-0-benzyloxycarbonyl-4'-0-demethyl-4-epi-podophyl-lotoxin and 20 g of 4 A molecular sieves were suspended in 550 ml of dichloxomethane~acetone 10:1 and, at -30C
under protective gas, 9.4 g of trimethylsilyl trifluoro-methanesulfonate were added. The reaction mixture wa~
stirred at -25C for 6 h, and then 50 ml of triethylamine wers a~ded and the mixture was filtered. The subseguent working up was carried out as described in process A.
Yield: 34 g (92 ~) 4'-0 Benzyloxycarbonyl~4-0-t2,3-di-0-acetyl 4,6-0-ethyl-ide~e-beta-D-glucopyranosyl3-4'-0-demethyl-~-epi-podo-phyllotoxin (Compound 8) 1.22 g ~4.23 mmol) of compound 5, 2.20 g ~4.23 mmol) of 4'-0-benzyloxycarbonyl-4'-0-demethyl-4-epi-podophyl-lotoxin and 2.5 g of 4 ~ molecular ~ieve~ wer~ ~uspende~
in 60 ml of dichloromethane/acetone 10:1 and, at -30C
under protective gas, 0.94 g of trimethyl~ilyl trifluoro-methanesulfonate was added. The reaction mixture was stirred at -25C for 8 h and then 5 ml of tri~thyl~mine were added, and the working up was as for the preparation of compound 7~
YIeld: 2.8 g tB2 ~) 4'-0-Chloroacetyl-4-0-(2,3-di-0-chloroacetyl-4~6~0-ethylidene-beta-D-glucopyranosyl)-4'-0-demethyl-4-epi-2 ~ 7 ~
podophyllotoxin (Compound 9) 11 g (30.6 mmol) of compound 6, 14.6 g (30.6 mmol) of 4'-0-chlsroacetyl-4'-0-dem~thyl-4-epi-podophyllotoxin and 20 g of molecular sieves were stirred in 330 ml of dichloromethane/acetone 10:1 and, at -30C, 6.~ g of trimethylsilyl trifluoromethanesulfonate were added.
After 7 h the reac~ion mixturs was worked up as described for the preparation of compound 7.
Yield: 21.3 g (86 ~) Example 5 Deacylation of the etoposide precursors 4' 0-Benzyloxycarbonyl-4'-0-demethyl-4-epi-4-0-(4,6-0-ethylidene-beta-D-glucopyranosyl)-podophyllotoxin (Compound 10) 27.5 g (31 mmol) of compound 7 were dissolved in 780 ml of dichloromethane and 1225 ml of methanol. 50 g of Dowex lx8 ion exchanger were added and then the reaction mixture was stirred at room temperature for 1 h. The suspension was filtered, and the resin was washed with methanol. ~he filtrates were evaporated, the residue was dis~olved in chloroform, and the solution was thoroughly wa~hed with phosphate buffer, pH 7.5, and then with water. The organic phase was dried over sodium ~ulfate and evaporated in vacuo. The residue crystallized from ether/petroleum ether.
Yield: 21.5 g (96 %~
4'-0-Demethyl-4-epi-4-0-(4,6-0-ethylidene-beta-D gluco-- pyranosyl3-podophyllotoxin (Compound 11) ~0 g (24.6 mmol~ of compound 9 were dissolved in S00 ml of dichloromethane ~nd 900 ml of methanol, and 50 g of Dowex lx8 wsre added. The reactisn mixture was stirred at room temperature for 2 h and then filtered, washing the resin with methanol. The combined filtrates were e~aporated 2 ~
in vacuo. The residue was taken up in dichloromethane, and the solution was then washed with phospha~e buffer, pH 7.5, and with water. The organic phase was dried over sodium 8ul fate and evaporated in vacuo. The product crystallizes from dichloromethane and hexane.
Yield: 13.6 g (94 ~) Example 6 Elimination of the benzyloxycarbonyl group by hydrogenolysis 4'-0-Demethyl-4-epi-4-0-(4,6-0-ethylidene-beta D-gluco pyranosyl)-podophyllotoxin (Compound 11) 9.7 g (13.4 mmol~ o~ compound 10 were di6solved in 260 ml of methanol and hydrogenated with 5 g of palladium/car-bon~ After 40 min, the catalyst was filtered off, and the solution was evaporated in vacuo. The residue was dis-solved in dichloromethane and thoroughly washed with phosphate buffer, pH 7.5, and then with water. The organi~
phase was dri~d over sodium sulfate and evaporated in vacuo. The product crystallizes from dichloromethane and hexane.
Yield: 7.25 g (92 %)
Claims (8)
1. A process for the preparation of a beta-glucopyranose derivative of the formula I
in which R1 and R2 are H or an acyl protective group and R3 is H, benzyl or a radical of the formula II
with R4 being H or a benzyloxycarbonyl or chloroacetyl protective group and A being C1-C4-alkyl, which comprises eliminating the benzyl group in a benzyl glucopyranoside of the formula I in which R1 and R2 are an acyl protective group, R3 is a benzyl protective group and A is C1-C4-alkyl, by hydrogenolysis in the presence of a hydrogenation catalyst and of an organic solvent, there being formation of a glucopyranose derivative of the formula I which is in the beta-hydroxy form and in which R1, R2 and A retain their meaning, and R3 is a hydrogen atom, subsequently reacting this glycosidation component with an epi-podo-phyllotoxin derivative of the formula III
III
in which R4 is benzyloxycarbonyl or chloroacetyl protective group, in the presence of a promoter such as BF3.ether or of a tri-(C1-C4)-alkylsilyl trifluoromethanesulfonate and of an organic solvent where appropriate in the presence of a desiccant at -30°C to 0°C, there being formation of a beta-glycoside of the formula I in which R1, R2, R4 and A
retain their meaning, and R3 is a radical of the formula II, and eliminating in a product which is formed the benzyloxycarbonyl protective group by hydrogenolysis and the acyl protective group using basic ion exchangers in the presence of a polar solvent, there being formation of a product of the formula I in which R1 and R2 are hydrogen, R3 is a radical of the formula II with R4 equal to hydro-gen, and A is C1-C4-alkyl
in which R1 and R2 are H or an acyl protective group and R3 is H, benzyl or a radical of the formula II
with R4 being H or a benzyloxycarbonyl or chloroacetyl protective group and A being C1-C4-alkyl, which comprises eliminating the benzyl group in a benzyl glucopyranoside of the formula I in which R1 and R2 are an acyl protective group, R3 is a benzyl protective group and A is C1-C4-alkyl, by hydrogenolysis in the presence of a hydrogenation catalyst and of an organic solvent, there being formation of a glucopyranose derivative of the formula I which is in the beta-hydroxy form and in which R1, R2 and A retain their meaning, and R3 is a hydrogen atom, subsequently reacting this glycosidation component with an epi-podo-phyllotoxin derivative of the formula III
III
in which R4 is benzyloxycarbonyl or chloroacetyl protective group, in the presence of a promoter such as BF3.ether or of a tri-(C1-C4)-alkylsilyl trifluoromethanesulfonate and of an organic solvent where appropriate in the presence of a desiccant at -30°C to 0°C, there being formation of a beta-glycoside of the formula I in which R1, R2, R4 and A
retain their meaning, and R3 is a radical of the formula II, and eliminating in a product which is formed the benzyloxycarbonyl protective group by hydrogenolysis and the acyl protective group using basic ion exchangers in the presence of a polar solvent, there being formation of a product of the formula I in which R1 and R2 are hydrogen, R3 is a radical of the formula II with R4 equal to hydro-gen, and A is C1-C4-alkyl
2. The process as claimed in claim 1, wherein R1 and R2 are H or the acetyl or chloroacetyl protective group, R3 is H or benzyl or a radical of the formula II with R4 being H or a benzyloxycarbonyl or chloroacetyl protective group, and A is methyl.
3. A process for the preparation of a beta-hydroxy-glucopyranose derivative of the formula I as claimed in claim 1, wherein R1 and R2 are an acyl protective group, R3 is hyrogen atom and A is C1-C4-alkyl, which comprises hydrogenating a beta-benzylglucoside of the formula I in which R1 and R2 are an acyl protective group, R3 is benzyl and is C1-C4-alkyl, in the presence of a hydrogenating agent such as pal-ladium/carbon or palladium/barium sulfate in an organic solvent such as methanol, ethanol, acetone, ethyl acetate or mixtures thereof, preferably acetone/ethanol mixtures, there being formation of a product of the formula I which is in the beta-hydroxy form and in which R1, R2 and A are unchanged and R is a hydrogen atom.
4. The use of a compound prepared as claimed in claim 3 in a process for the preparation of etoposides, which comprises this compound being reacted with a 4'-0-pro-tected 4'-0-demethyl-4-epi-podophyllotoxin using a promoter such as BF3.ether or tri-(C1-C4)-alkylsilyl trifluoromethanesulfonate in an anhydrous organic sol-vent, where appropriate in the presence of a desiccant such as a molecular sieve at -30°C to 0°C to give a beta-glycoside of the formula I where R1 and R2 are an acyl protective group, R3 is an epi-podophyllotoxin residue of the formula II
with R4 being benzyloxycarbonyl or an acyl protective group and A being C1-C4-alkyl.
with R4 being benzyloxycarbonyl or an acyl protective group and A being C1-C4-alkyl.
5. The use as claimed in claim 4, wherein a tri-(C2-C4)-alkylsilyl trifluoromethanesulfonate is used in the process.
6. A process for the deacylation of a 4-O-glucosyl-epi-podophyllotoxin derivative of the formula I in claim 1, which comprises treating an acylated compound with a basic ion exchanger in a solvent such as methanol, ethanol, propanol, methyl acetate, dichloromethane, chloroform or mixtures thereof, preferably with a metha-nol/chloroform mixture, there being formation of a compound of the formula I in which the radicals R1, R2 and R4 are hydrogen, R3 is an epi-podophyllotoxin residue of the formula II
and A is (C1-C4)-alkyl.
and A is (C1-C4)-alkyl.
7. The process as claimed in claim 6, wherein Dowex 1x8 is preferably used as ion exchanger.
8. The process as claimed in claim 1 and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3913326.5 | 1989-04-22 | ||
| DE3913326A DE3913326A1 (en) | 1989-04-22 | 1989-04-22 | METHOD FOR PRODUCING ETOPOSIDES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2015074A1 true CA2015074A1 (en) | 1990-10-22 |
Family
ID=6379257
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002015074A Abandoned CA2015074A1 (en) | 1989-04-22 | 1990-04-20 | Process for the preparation of etoposides |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0394907A1 (en) |
| JP (1) | JPH02292295A (en) |
| KR (1) | KR900016244A (en) |
| AU (1) | AU641644B2 (en) |
| CA (1) | CA2015074A1 (en) |
| DE (1) | DE3913326A1 (en) |
| PT (1) | PT93799A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5034380A (en) * | 1989-11-20 | 1991-07-23 | Bristol-Myers Squibb Company | Alkoxymethylidene epipodophyllotoxin glucosides |
| TW260671B (en) * | 1991-04-29 | 1995-10-21 | Bristol Myers Squibb Co | |
| IL119749A (en) | 1995-12-04 | 2001-03-19 | Nippon Kayaku Kk | Process for producing etoposide |
| KR100519498B1 (en) * | 1997-06-02 | 2005-10-07 | 브리스톨-마이어즈 스퀴브 컴페니 | Process for preparing etoposide |
| WO2006126633A1 (en) * | 2005-05-26 | 2006-11-30 | National University Corporation Obihiro University Of Agriculture And Veterinary Medicine | Deacylation |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0111058B1 (en) * | 1982-11-26 | 1987-11-04 | Nippon Kayaku Kabushiki Kaisha | Process for producing 4'-demethyl-epipodophyllotoxin-beta-d-ethylidene-glucoside and acyl-derivative thereof |
| JPS60246393A (en) * | 1984-05-22 | 1985-12-06 | Nippon Kayaku Co Ltd | Novel preparation of etoposide |
| IL77334A (en) * | 1985-12-16 | 1991-04-15 | Univ Bar Ilan | Synthesis of 9-epipodophyllotoxin glucoside derivatives and some novel intermediates therefor |
| DE3913327A1 (en) * | 1989-04-22 | 1990-10-25 | Behringwerke Ag | METHOD FOR PRODUCING GLUCOSAMINYL-EPI-PODO-PHYLLOTOXIN DERIVATIVES |
-
1989
- 1989-04-22 DE DE3913326A patent/DE3913326A1/en not_active Withdrawn
-
1990
- 1990-04-19 PT PT93799A patent/PT93799A/en not_active Application Discontinuation
- 1990-04-20 CA CA002015074A patent/CA2015074A1/en not_active Abandoned
- 1990-04-20 JP JP2103208A patent/JPH02292295A/en active Pending
- 1990-04-20 KR KR1019900005533A patent/KR900016244A/en not_active Application Discontinuation
- 1990-04-23 AU AU53715/90A patent/AU641644B2/en not_active Ceased
- 1990-04-23 EP EP90107637A patent/EP0394907A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU641644B2 (en) | 1993-09-30 |
| JPH02292295A (en) | 1990-12-03 |
| DE3913326A1 (en) | 1990-11-08 |
| EP0394907A1 (en) | 1990-10-31 |
| AU5371590A (en) | 1990-10-25 |
| KR900016244A (en) | 1990-11-13 |
| PT93799A (en) | 1991-01-08 |
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