CA2001087A1 - Process for the preparation of 4-o-alkylrhodomycins - Google Patents
Process for the preparation of 4-o-alkylrhodomycinsInfo
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Abstract
BEHRINGWERKE ARTIENGESELLSCHAFT 88/B 031 - Ma 724 Dr. Ha/Li/Hch Abstract of the disclosure Process for the preparation of 4-O-alkylrhodomycins A process is descried for the preparation of 4-O-alkyl-rhodomycins of the formula I
I
in which R1 denotes H, C1-C4-alkyl or an acyl protective group, R2 denotes OH, COOCH3, O-Si(C1-C4-alkyl)3 or an O-acyl protective group, acyl being acetyl, monohalogeno-acetyl, dihalogenoacetyl or trihalogenoacetyl with fluorine or chlorine as the halogen, benzoyl or p-nitrobenzoyl, R3 denotes C1-C4-alkyl, R4 denotes H or R4 and R5 togethex denote a tetraisopropyldisiloxane-1,3-diyl protective group, and R5 denotes H or a glycosyl radical of the fonmula II
II
in which R6 is OH, acetoxy, NHCOCF3, NH2, a mono-C1-C4-alkylamino group or a di-C1-C4-alkylamino group or a 4-morpho-linyl group and R7 is H, OH or an acetoxy, trifluoroacetoxy or p-nitrobenzoyloxy group, and the use thereof for the preparation of 7-O-glycosyl-rhodomycins which are suitable, by virtue of their cytostatic activity for the treatment of oncoses.
I
in which R1 denotes H, C1-C4-alkyl or an acyl protective group, R2 denotes OH, COOCH3, O-Si(C1-C4-alkyl)3 or an O-acyl protective group, acyl being acetyl, monohalogeno-acetyl, dihalogenoacetyl or trihalogenoacetyl with fluorine or chlorine as the halogen, benzoyl or p-nitrobenzoyl, R3 denotes C1-C4-alkyl, R4 denotes H or R4 and R5 togethex denote a tetraisopropyldisiloxane-1,3-diyl protective group, and R5 denotes H or a glycosyl radical of the fonmula II
II
in which R6 is OH, acetoxy, NHCOCF3, NH2, a mono-C1-C4-alkylamino group or a di-C1-C4-alkylamino group or a 4-morpho-linyl group and R7 is H, OH or an acetoxy, trifluoroacetoxy or p-nitrobenzoyloxy group, and the use thereof for the preparation of 7-O-glycosyl-rhodomycins which are suitable, by virtue of their cytostatic activity for the treatment of oncoses.
Description
BEHRINGWERKE ARTIENGESELLSCHAFT 88/B 031 - ~a 724 Dr. Ha/Li./Hch Process for the preparation of 4-O-alkylrhodomycins The present invention relates to a new process for the preparation of 4-O-alkylrhodomycins, e~pecially 4-O-alkyl-~-rhodomycinone~ and 4-O-alkyl epsilon-rhodomycin-ones, and the use th~reof for the preparation of 7-O-glycosylrhodomycins which, by virtue oP their cytostaticeffectiveness, ~re suitable for the treatmen~ of oncoses.
Anthracyclins are described in the ~pecialist literature.
It is known from the doxorubicin-daunorubicin group of anthracyclin that 4-O-methyl ~ubstitution is necessary in the anthracyclins for antitumoral action and tumor ~electivity. The corre~ponding 4-hydroxy derivativeæ, ~uc~ as carminomycins and ~-rhodomycins, are cytotoxic and les~ tumor-selective.
The invention i~ based on the ob~ect of developing a proce~s which gives 4-O-alkylrhodom~rcinone derivatives in good yield~ and which means a s~nplifi~ation co~pared with ~he known process, as well a~ the elaboration of a protective group chemi~try on 4-O alkylrhodomycinones whi~h make6 it pos~ible to u~e the aglycone for the preparation of 7-O-glycosylrhodomycinones.
The present proce~s for the preparation of 4-O-alkyl-rhodomycin~ i~ based on the surpxising findin~ that an unprotected rhodcmycino~e aglycone can be reacted with 1,3-dichloro-1,1,3 9 3-tetrai~opropyldi6iloxane to ~ive a 6,7-O-(tetraisopropyldisiloxane-1,3 diyl)~rhodomycinone and then with a trialkylsilyl halide to g~ve ~ 10-O-trialkyl~ilyl compound. By thi6 route th~ ~ubseguent alkylation can only t~ke place at the phenoli~ hydroxyl group~ at the C-4 and C~ tom~ alkylation of the phenolic group at the C-4 atom curpri~ingly is mainly taking place.
Anthracyclins are described in the ~pecialist literature.
It is known from the doxorubicin-daunorubicin group of anthracyclin that 4-O-methyl ~ubstitution is necessary in the anthracyclins for antitumoral action and tumor ~electivity. The corre~ponding 4-hydroxy derivativeæ, ~uc~ as carminomycins and ~-rhodomycins, are cytotoxic and les~ tumor-selective.
The invention i~ based on the ob~ect of developing a proce~s which gives 4-O-alkylrhodom~rcinone derivatives in good yield~ and which means a s~nplifi~ation co~pared with ~he known process, as well a~ the elaboration of a protective group chemi~try on 4-O alkylrhodomycinones whi~h make6 it pos~ible to u~e the aglycone for the preparation of 7-O-glycosylrhodomycinones.
The present proce~s for the preparation of 4-O-alkyl-rhodomycin~ i~ based on the surpxising findin~ that an unprotected rhodcmycino~e aglycone can be reacted with 1,3-dichloro-1,1,3 9 3-tetrai~opropyldi6iloxane to ~ive a 6,7-O-(tetraisopropyldisiloxane-1,3 diyl)~rhodomycinone and then with a trialkylsilyl halide to g~ve ~ 10-O-trialkyl~ilyl compound. By thi6 route th~ ~ubseguent alkylation can only t~ke place at the phenoli~ hydroxyl group~ at the C-4 and C~ tom~ alkylation of the phenolic group at the C-4 atom curpri~ingly is mainly taking place.
Thi~ ob~ect is achieved in ~ccordance with the invention by the proces~ for the preparation of a rhodomycin derivative of the formula I
O ORl R
~ ~ E~ I
R30 D OR~ b R 3 in which R~ denotes ~, C~-C4-alkyl or an acyl protecti~e group, R2 denotes OH, COOCH3, O-Si(Cl-C4-alkyl)3 or an O~acyl protective gxoup, acyl being acetyl, monohalogeno-acetyl, dihalosenoac0tyl or trihalogenoacetyl with fluorine or chlorine a6 the halogen, benzoyl or p-nitroben~oyl, R3 deno~e~ Cl-C4-alkyl, R4 denotes H or R4 and R5 together denote a tetrai~opropyldisiloxane-1,3-diyl protective group, and Rs denote H or a glycosyl radical of the formula II
R7 ~ ~
R~ ;
in which R6 i8 OH, ~etoxy, ~HCOCF3, NHz, a mono-C~-C~-alkylamino ~roup or a di-Cl-C~-alkylEmino group or a 4-morpho-linyl group and R7 1~ H9 OH or an acetoxy, trifluoroaceto~y or p-nitrobenzoylo~y group, which compri~e6 reactin~ a rhodomycinone derivati~e of the formula I in which R2 is OH or COOCH3 ~nd R3, R~ and R5 ~re H, with 1,3Ydichloro-1,1,3,3-tetraisopropyldisiloxane a~d, if appropriate, ~ubsequen~ly with a tri-C,-C~alkyl~ilyl halide, pxeferably with a chloride deriv~tive, in the ,, ,~ , , 8~7 presence of a b~se, ~uch as pyricline or dimethylamino-pyridine, and an organic ~olvent, 6uch as methylene dichloride or chloroform, at a tempera ure between 15C
and 80C to give a 6,7 0-(tetrai~opropyldi~iloxans-1,3-diyl)-rhodomycinone compound of the formula I in which R1 and R3 are H, R2 is COOCH3 or O-Si(Cl-C4-alkyl) 3 and R4 and R5 together are a tetrai~opropyldi~iloxane-1/3-diyl group, then etherifying th~ resultin~ compound with an al~ylat-ing agent, pxeferably a Cl-C4-alkyl bromide or iodide, in the presence of an alkali metal carbonat~ and an organic 601vent, such a ace$onP or dioxa~e, at the phenolic hydroxyl group on the C-4 a~om, if appropriate al~o at the phenolic hydkoxyl group on the C-11 atom, then, if appropriate, ~plitting off the trialkyl~ilyl protective group st the C-10 atom by acid hydrolysis, preferably by means of hyckochloric acid, and acylating the resulting compound at the 10-hydroxyl group and, if appropriate, at the ll hydroxyl group by means of an acylating agent, preferably p-nitxobenzoyl chloride, tri~luoroacetic anhydride or ~cetyl chloride, in the pre~ence of a ba~e, ~uch as pyridine, triethylamine or dimethylaminopyridine, and an organic 501vent ~ ~uch as methylene dichloride or chloroform, and ~plitting off the tetrai~opropyldi~
o~ne 1,3-diyl group by means of an ammonium fluoride, preferably tetr~butylammonium fluoride, in a polar organic solvent~ ~uch as tetrahydrofuran or dioxane, in the course of which a compound of the formula III
~ Jo~ III
in which Rl denote~ ~, Cl C4-alkyl or an acyl protective group ~ndicated above, R2 denotes COOCH3 or an O acyl protective group and R3 denotes C,~C4~alkyl i8 formed. .
The proce~s on which ~he inven~ion i~ based i~ illus-trated in Scheme 1.
The use of a rhodomycinone compound of the formula III in a proce6s for the praparation of a 7-0-sl~cos~ rhodomyci-ncne compound of th~ forMula I compri6es reacting acompound of the formula III in a manner known per 6e with a functionalized deoxy ~ugar of the formula IV or V
in which R6 represents an acetoxy or trifluoroacetamido group, R7 repre~ents a hydrogen atom or an acetoxy~ trifluoro-ace~o~y or p-nitrobenzoyloxy group and Y repre~ents an acetoxy or p-nitrobenzoyloxy group or 8 chloride, in the presence o:E a catalyst, such as a tri-C~-C4-alkyl ilyl trifluoromethanesulfonate or the ~ilver ~alt of trifluoromethane6ulfonic acid, to give a 7-0-glycosyl-rhDdomycinone of the formula I in which the radical~ Rl, R2, R3, R6 and R7 retain the meaning defined in formulae III, IV and V, then spli~ting off the acyl protect.ive groups by alkaline hydroly~i~, in the course of which a compound of the formula I in whieh R1 denotes H or Cl-C4-~lkyl, RZ denote6 OH or COOCH3, ~5 ~3 denotes Cl-C4-alkyl, R~ denotes H and R5 denotes a glyco~yl radical of the formula II in which R6 i~ ~H2 or OH and R7 is H or OH i8 fonmed, and, if appropriate, reacting a re~ulting compound of the formula I containing an amino-~ugar under the conditions of reductive alkylation with a C~-C~-aldehyde or diglycol aldehyde in the presence of an alkali metal cyano-borohydride to ~ive a further compound of the formulil I
iLn which .
... , .,. ~ . , .,: ';!. ..
, ~ .: .
';, ' -' ~ , :
': .. : ~, .: , Scheme 1 ~f Et -~~~ OH
6 , ~ r 1 d I~CH z Cl ;~ 6 7 -RMN ~ 5 ~ _ O_ /~
./ Me 3 SiCJ
~e .-~ pyrldine ~1~
rle-Si-~e ~le-Si-Me Mel/ I~a2CO~ 0H
OH O 9 o ~e~D~C~ 2CI 2rqeO O O O
~si-o-sj <~ ~Si-O-Si~
CH 2Cl 2~,/"'/ [~ ~3 q ~J " O H O H O O - p N O z neo o o o Butq~llF~THF ~ ~ = Et ~Si--o--si~ 6 ~7 ~ 1eO O HO OH
pNBzCI I R = H ¦ :
yr/C~I 2Ct z C ¦ R2 = pNBZ ¦
pNBz = p 02N-PtlCO-%~
the radicals R1, R2, R3, R4, R5 and R7 retain the last-mentioned meaning and RB represents a mono-Cl-C4-alkyl-amino or di-Cl C4-alkylamino group or 8 4-morpholinyl group.
S Example6 The present invention is described in greater detail in the following e~ampl~s, without being limited thereto.
~he ~tructure o the compounds described in the following examples was determined by means of NMR and M~ analytical chemistry. ~he progre~ of the reactivns and the chemical purity of the compounds were investigated by thin layer chromatography or by EPLC.
~xample 1 The introduction of silyl protective groups into a rhodomycinone in po~itions 6,7 ~nd, if appropriate, 10.
6,7-0-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-~-rhodomycinone ~Compound 1) 10 g (25.8 mmol) of ~-rhodomycinone were di~solved in 300 ml of 1:1 pyridine/methylene dichloride, and 1202 ml (1.5 equivalents) of 1,3-dichloro~1,1,3,3-tetrai~opropyl-d~iloxane, dis olved in 150 ml of methylene dichloride, were added at 0C with the exclusion of moisture. ~he re~ction mixture wa~ ~tirred for 24 hour~ Bt xoom tem-perature and then for a further 72 hour~ at 60C. After the further addition of 6.5 ml (O.8 equivalent~) of 1,3-dichloro-1,1,3,3-tetraisopropyldi~iloxane, the reaction mixture was ~tirred for a further 72 hours ~t 60~Co 50 ml of methanol were added to the reaction ~i~ture ~nd the product wa~ ev~poratPd in vacuo and ~ubject~d to two further di~tillation~ with toluene. The re~idue which remained was purified by column chromatography t~ilica gel; mobile phase: 20sl chloroform/ethyl acetate)~
, ' '~
Yield: 10.8 g (67%); meltin~ point. 115-117C
~alpha~D = ~425 (C = 0.2 in chloroform) ~H-NMR (90 ~Hz, CDCl3, delta~: 13.91 and 13.07 (~,PhOH), 7.82 (br d, H-l), 7.65 (t, H-2), 7.30 (br d, H-3), 5.28 S (br 6, H-7), 4.9S (8, H-10), 4.75 (6, 9-OH)~ 3.66-3.54 (m, alkyl-Si3 6,7-0-(1 t 1,3,3~Tetrai~opropyldi6iloxane-1,3-diyl)-ep~i-lon-rhodomycinone (Compound 2) 5 g (11.67 mmol) of epsilon-rhodomycinone a~d 9.2 g ~2~5 equivalents) of 1,3-dichloro-1,1,3,3-tetrai~opropyl disiloxane were dissol~ed in 150 ml of 1:1 methylene dichloride/pyTidine. After a reaction time of 8 day~ the title compound wa~ i~olated a de~cribed in the in~truc-tions for ~he preparation of compound 1.
Yield: 6.1 g (78~) 6 t 7-0-~1,1,3,3-Tetraisopropyldi6iloxane~1,3-diyl)-10-O-trimethylsilyl-~-rhodomycinone (Compound 3) 19.0 g (30.2 mmol) of compound 1 were di~solved in 250 ml of methylene dichloride a~d 250 ml of pyridine, and 4.2 g ~1.5 equivalents) o~ chlorotrimethylsilane t di~olved in 50 ml of methylene dichloride, we:re added at 0C. The reaction mixture was ~tirred for 1 hour at room tempera~
ture. The r~sction mixture wa~ then evaporated in vacuo and sub~ected to two further distillation6 ~ith toluene.
The residue wa~ puri~ied by column chromatography (silica gel; mobile phase: 7:3 methylene dichloride/petrol~um ether), Yield: 1~.3 g (77~); ~elting points 194-196C
(alpha)D - +530~ (c = 0.2 in chloroform) H-NMR (300 ~Hz, CDCl3, delt~): 13.87 and 13.12 t~, phOH), 7.79 ~dd, ~-1), 7.61 (t, H-~), 7.25 (dd, H-3), 5.23 ~dd, ~-7), 2.13 (dd, H-8~ .06 (dd, H-8b), 4.86 (br ~, H-10), 1.64 (m, H-13a and H-13b), 1002 (t, H-14), 0.2 and 1.2-1.3 (m, alkyl-Si) Example 2 Alkylation of a rhodomycinone in po~ition 4 or, if appropriate, 11.
4-0-Methyl-6,7-0-(1,1,3,3-~etraisopropyldisiloxane 1,3-diyl)-10-0-trimethylsilyl-~rhodomycinone (Compound 4) and 4,11-Di-0 methyl-6,7~0-(1,1,3,3-tetraisopropyldi~iloxane-1,3-diyl)-10-O-trimethyl6ilyl-~-rhodomycinone (Compound 5) 10 Process a):
0.75 g (1.07 mmol) of compound 3 were di~solved in 30 ml of acetone and 7 ml of methylene dichloride~ and 4.4 g (30 equivalent~) of pota~sium carbonste and 10 ml ~150 equivalent~ Qf methyl io~ide were added. The reaction 15 mixture wa~ ~tirred for 3 day6 at room temperature, the progres~ of the xeaction being followed by thin layer chromatography. Methylene dichloride wa~ added to the reaction mixture and the product was extracted by w~shing succes~ively with water, 1 N hydrochlori~ acid and water.
20 The organic phase was dried over sodium sula~e and evaporated in ~acuo. The ~ompounds 6 and 7, ~hich were present in the residue, were ~eparated by column chroma-tography over 35 g of ~ilica gel u~i.n~ methylene dichlor-ide as the mobile phase.
25 Compound 4:
Yield: 0.46 y (60~); melting point: 213-214C
(alpha~D = ~472 ~c = 0.05 in chloro~orm) lH-NMR (30G MHz, CDCl~, delta): 13.22 (8, PhOH), 7.89 (dd, H-l), 7.65 ($, H-2), 7.29 (dd, H~3), 5.35 (ddt H-7), 2.17 30 (dd, H-8a), 2.07 (dt, H-8h), 4~89 (d, H 10), 1.39 (m, ~-13a~, 1.15 (m, H-13b), 1.05 (t, H-14)~ 3.96 (~, OMe), 0.1 and 1.18-1.33 (m, alkyl-si)~ 4.45 ts~ 9-OH) Compound 5s Yield: 0.27 g (35%); melting point: 103-105C
35 (alpha)D = +124 (c = 0.05 in chloroform) , :
2~ 37 , -- 10 ~
lH-NMR ~400 MHz, CDCl3, delta): 7.72 (dd, H-l~, 7.59 (t/
H-2), 7.21 (ddl H 3), 5.34 (dd, ~ 7), 2.17 (dd, H-8a), 2.05 (dt, H-8b), 4.70 (d, H-10), 1.40 (m, H-13a), 1.31 (m, H-13b), 1.04 ~t, H-14), 3.93 and 3.91 (~, OMe), 0.1 S and 0.9-1.3 (alkyl-Si), 4.50 (æ, 9-OH) Pxocess b):
1 g (1.42 mmol) of compound 3 were dis601ved in 4.5 ml of acetone and 18 ml of methylene dichloride, and 4.2 g (12.9 mmol) of cesium carbonate and 5 ml (71.5 mmol) of methyl iodide were added with ~tirring at 4C. After a reaction time of 3 days the reaction mixture was worked up as described above, compound 4 (yialds 0.76 ~ (75~)) and compound 5 ~yield: 0.1 g (10~)) being isolated.
4 O-Met~yl 6,7-0-(1,1,3,3-tetrai~opropyl-di~iloxsne-1,3-diyl)-epsilon-rhodomycinone (Compound 6) The title compound was prepared by the instructions for the preparation of compound 4, ~tarting ~rom 6.03 g (9 mmol) of compound 2, 37.49 g (30 equi~alent.) of potassium carbonate and 56.5 ml (~00 mmol) of methyl iodide.
Yield: 3.2 g ~52~) Example 3 Selective deblocking of the txialkyl~ilyl protective g~oup 4-0 ~ethyl-6,7-0-(1 t 1,3,3-tetrai~opropyldi6iloxane-1,3-diyl)-~-rhodomycinone (Compound 7) 2 ~ (2.8 ~mol) of compound 4 were di~601ved ~n 100 ml of ~athylane dichloride and 100 ml of msthanol, &nd 20 ml of 0.1 N hydrochloric acid were added. After stirring ~or 30 minutes ~t room temperature, the reaction mixture was diluted with methylene dichloride and extracted by shaking with water. The organic pha e wa~ dried by maans . : .
o~ ~
of sodium ~ulfate and evaporated in vacuo. The r~sidue was also filtered ~hrough 50 g of silica g~l (mobile phase: 20.1 methylene dichloride/acetone).
Yield: 1.7 ~ (96%); melting point: 166-168C
~alpha)D = +386~ (o - 0.05 in chloroform) ~xample 4 ;~
Introduction of acyl protective groups 4-0-~ethyl-10-0-p-nitrobenzoyl-6,7-0~(1,1,3,3-tetraiso-propyldi~iloxane-1,3-diyl)-~-rhvdomycinone (Compound 8) 0.68g (1.05 mmol~ of compound 7 wa~ di~olved in 40 ml of 2:1 chloroform/pyridine, and 0.3 g ~1.5 e~uivalents) of p-nitrobenzoyl chloride was added. After stirring at 0C
for 15 houxs, 10 ml of methanol were added to the reac tion mixture. The reaction mixture was evapora~ed in vacuo and di~tilled again with toluene. The residue was dissolved in chloroform and washed twice with water, and the organic phase was dried over sodium sulfate and evaporated in vacuo~ The crude product which remained was purified fuxther by column chromatography over 120 g of ::.
silica gel (mobile pha~e: 17:10:1 petroleum ether/methyl-ene dichloride/acetone).
Yield: 340 m~ ~81.1g); melting point~ 114-116C
(alpha)~ = ~384D (c = 0.05 in ~hloroform) 1H-NMR (300 ~Hz, CDCl3, delta): 13.02 1~, PhOH), 7.84 (dd, H-l~, 7.~5 (t, H-2~, 7.32 (dd, H~3), 5.51 (dd, H-7~, 2.38 (dt, H-8a), 2.07 (dd, H-8b), 6056 ~d, H-10), 1.50 (m, H-13a), 1.83 (m~ H-13b)~ 1.07 (t, H-14~, 3.98 (8, 4-OMe), 8.08 and 8.22 (m, aryl), 0.64-1.2 (m, alkyl-Si) 10,11-Bis-~-(p-nitrobenzoyl)-4-0-methyl-6,7-0-tl,1,3,3-tetrai~opropyldisiloxane-1,3-diyl~ ~-rhodom~cinone (Compound 9) 0.34 g (0052g mmol) of compound 7 wa~ reacted with 0.3 g (3 eguivalent~ of p nitrobenzoyl chloride as described ~ .
, , ~ , , "
8~
above to give the title compound.
Yi~ld: 0.35 ~72~) Example 5 Deblocking the tetrai~opropyldisil~xane-1,3-diyl protec-tive group 4-O-Methyl-10-O-p-nitrobenzoyl-~-rhodomycinone (Compound 10~
0.6 g (0.76 mmol) of ~ompound 8 was di~solved in 30 ml of THF, and 1 ml of a 1-molar solution in THE of tetrabutyl-ammonium fluoride was add~d at 0C. After the reactionmixture had been ~tirred for 30 minutes, 30 ml of 0.1 N
hydrochloric acid were added and the mixture was extrac-ted twice with chloroform. The or~anic pha~e wa~ dried over ~odi~m sulfate and ~vapora~ed in vacuo. The crude lS product ohtained was purified by chromatography over 65 q of silica gel (mobile pha~e: 15:1 methylene dichloride~
acetone).
Yield: 0.3~8 g (91%); meltins point: 153-155C
(alpha)D = ~275 (c = 0.02 in chlorofonm) 10,11-gis_o_(p-nitxobenzoyl)~4-O-methyl-~-rhodomycinone ~Compound 11) 0.15 g (0.15~ mmol) of compound 9 W~15 reacted with 0.2 ml of a l-~olar ~olution in ~HF of tetrabutylamonium fluor-ide a~ de~cribed above to give the title compound.
Yields 95.8 mg (88%) 4-O-~ethyl epsilon-rhodomycinone (Compound 12) The title compound wa~ prepared by the in~truction~ for the prep~ration of compound 10, starting from 3.2 g (4.6 mmol) of compound 6.
Yield. 1.6 g (83%~; ~AB m/e = 443 ~M~Ht) , :~ .
- ~3 -Example 6 Formation of glycosides of the rhodomycins with function-alized amino-~ugar~
4-0-Methyl-10-0-p-nitrobenzoyl-7-0-(4'-0-p-nitro~enzoyl~
O ORl R
~ ~ E~ I
R30 D OR~ b R 3 in which R~ denotes ~, C~-C4-alkyl or an acyl protecti~e group, R2 denotes OH, COOCH3, O-Si(Cl-C4-alkyl)3 or an O~acyl protective gxoup, acyl being acetyl, monohalogeno-acetyl, dihalosenoac0tyl or trihalogenoacetyl with fluorine or chlorine a6 the halogen, benzoyl or p-nitroben~oyl, R3 deno~e~ Cl-C4-alkyl, R4 denotes H or R4 and R5 together denote a tetrai~opropyldisiloxane-1,3-diyl protective group, and Rs denote H or a glycosyl radical of the formula II
R7 ~ ~
R~ ;
in which R6 i8 OH, ~etoxy, ~HCOCF3, NHz, a mono-C~-C~-alkylamino ~roup or a di-Cl-C~-alkylEmino group or a 4-morpho-linyl group and R7 1~ H9 OH or an acetoxy, trifluoroaceto~y or p-nitrobenzoylo~y group, which compri~e6 reactin~ a rhodomycinone derivati~e of the formula I in which R2 is OH or COOCH3 ~nd R3, R~ and R5 ~re H, with 1,3Ydichloro-1,1,3,3-tetraisopropyldisiloxane a~d, if appropriate, ~ubsequen~ly with a tri-C,-C~alkyl~ilyl halide, pxeferably with a chloride deriv~tive, in the ,, ,~ , , 8~7 presence of a b~se, ~uch as pyricline or dimethylamino-pyridine, and an organic ~olvent, 6uch as methylene dichloride or chloroform, at a tempera ure between 15C
and 80C to give a 6,7 0-(tetrai~opropyldi~iloxans-1,3-diyl)-rhodomycinone compound of the formula I in which R1 and R3 are H, R2 is COOCH3 or O-Si(Cl-C4-alkyl) 3 and R4 and R5 together are a tetrai~opropyldi~iloxane-1/3-diyl group, then etherifying th~ resultin~ compound with an al~ylat-ing agent, pxeferably a Cl-C4-alkyl bromide or iodide, in the presence of an alkali metal carbonat~ and an organic 601vent, such a ace$onP or dioxa~e, at the phenolic hydroxyl group on the C-4 a~om, if appropriate al~o at the phenolic hydkoxyl group on the C-11 atom, then, if appropriate, ~plitting off the trialkyl~ilyl protective group st the C-10 atom by acid hydrolysis, preferably by means of hyckochloric acid, and acylating the resulting compound at the 10-hydroxyl group and, if appropriate, at the ll hydroxyl group by means of an acylating agent, preferably p-nitxobenzoyl chloride, tri~luoroacetic anhydride or ~cetyl chloride, in the pre~ence of a ba~e, ~uch as pyridine, triethylamine or dimethylaminopyridine, and an organic 501vent ~ ~uch as methylene dichloride or chloroform, and ~plitting off the tetrai~opropyldi~
o~ne 1,3-diyl group by means of an ammonium fluoride, preferably tetr~butylammonium fluoride, in a polar organic solvent~ ~uch as tetrahydrofuran or dioxane, in the course of which a compound of the formula III
~ Jo~ III
in which Rl denote~ ~, Cl C4-alkyl or an acyl protective group ~ndicated above, R2 denotes COOCH3 or an O acyl protective group and R3 denotes C,~C4~alkyl i8 formed. .
The proce~s on which ~he inven~ion i~ based i~ illus-trated in Scheme 1.
The use of a rhodomycinone compound of the formula III in a proce6s for the praparation of a 7-0-sl~cos~ rhodomyci-ncne compound of th~ forMula I compri6es reacting acompound of the formula III in a manner known per 6e with a functionalized deoxy ~ugar of the formula IV or V
in which R6 represents an acetoxy or trifluoroacetamido group, R7 repre~ents a hydrogen atom or an acetoxy~ trifluoro-ace~o~y or p-nitrobenzoyloxy group and Y repre~ents an acetoxy or p-nitrobenzoyloxy group or 8 chloride, in the presence o:E a catalyst, such as a tri-C~-C4-alkyl ilyl trifluoromethanesulfonate or the ~ilver ~alt of trifluoromethane6ulfonic acid, to give a 7-0-glycosyl-rhDdomycinone of the formula I in which the radical~ Rl, R2, R3, R6 and R7 retain the meaning defined in formulae III, IV and V, then spli~ting off the acyl protect.ive groups by alkaline hydroly~i~, in the course of which a compound of the formula I in whieh R1 denotes H or Cl-C4-~lkyl, RZ denote6 OH or COOCH3, ~5 ~3 denotes Cl-C4-alkyl, R~ denotes H and R5 denotes a glyco~yl radical of the formula II in which R6 i~ ~H2 or OH and R7 is H or OH i8 fonmed, and, if appropriate, reacting a re~ulting compound of the formula I containing an amino-~ugar under the conditions of reductive alkylation with a C~-C~-aldehyde or diglycol aldehyde in the presence of an alkali metal cyano-borohydride to ~ive a further compound of the formulil I
iLn which .
... , .,. ~ . , .,: ';!. ..
, ~ .: .
';, ' -' ~ , :
': .. : ~, .: , Scheme 1 ~f Et -~~~ OH
6 , ~ r 1 d I~CH z Cl ;~ 6 7 -RMN ~ 5 ~ _ O_ /~
./ Me 3 SiCJ
~e .-~ pyrldine ~1~
rle-Si-~e ~le-Si-Me Mel/ I~a2CO~ 0H
OH O 9 o ~e~D~C~ 2CI 2rqeO O O O
~si-o-sj <~ ~Si-O-Si~
CH 2Cl 2~,/"'/ [~ ~3 q ~J " O H O H O O - p N O z neo o o o Butq~llF~THF ~ ~ = Et ~Si--o--si~ 6 ~7 ~ 1eO O HO OH
pNBzCI I R = H ¦ :
yr/C~I 2Ct z C ¦ R2 = pNBZ ¦
pNBz = p 02N-PtlCO-%~
the radicals R1, R2, R3, R4, R5 and R7 retain the last-mentioned meaning and RB represents a mono-Cl-C4-alkyl-amino or di-Cl C4-alkylamino group or 8 4-morpholinyl group.
S Example6 The present invention is described in greater detail in the following e~ampl~s, without being limited thereto.
~he ~tructure o the compounds described in the following examples was determined by means of NMR and M~ analytical chemistry. ~he progre~ of the reactivns and the chemical purity of the compounds were investigated by thin layer chromatography or by EPLC.
~xample 1 The introduction of silyl protective groups into a rhodomycinone in po~itions 6,7 ~nd, if appropriate, 10.
6,7-0-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-~-rhodomycinone ~Compound 1) 10 g (25.8 mmol) of ~-rhodomycinone were di~solved in 300 ml of 1:1 pyridine/methylene dichloride, and 1202 ml (1.5 equivalents) of 1,3-dichloro~1,1,3,3-tetrai~opropyl-d~iloxane, dis olved in 150 ml of methylene dichloride, were added at 0C with the exclusion of moisture. ~he re~ction mixture wa~ ~tirred for 24 hour~ Bt xoom tem-perature and then for a further 72 hour~ at 60C. After the further addition of 6.5 ml (O.8 equivalent~) of 1,3-dichloro-1,1,3,3-tetraisopropyldi~iloxane, the reaction mixture was ~tirred for a further 72 hours ~t 60~Co 50 ml of methanol were added to the reaction ~i~ture ~nd the product wa~ ev~poratPd in vacuo and ~ubject~d to two further di~tillation~ with toluene. The re~idue which remained was purified by column chromatography t~ilica gel; mobile phase: 20sl chloroform/ethyl acetate)~
, ' '~
Yield: 10.8 g (67%); meltin~ point. 115-117C
~alpha~D = ~425 (C = 0.2 in chloroform) ~H-NMR (90 ~Hz, CDCl3, delta~: 13.91 and 13.07 (~,PhOH), 7.82 (br d, H-l), 7.65 (t, H-2), 7.30 (br d, H-3), 5.28 S (br 6, H-7), 4.9S (8, H-10), 4.75 (6, 9-OH)~ 3.66-3.54 (m, alkyl-Si3 6,7-0-(1 t 1,3,3~Tetrai~opropyldi6iloxane-1,3-diyl)-ep~i-lon-rhodomycinone (Compound 2) 5 g (11.67 mmol) of epsilon-rhodomycinone a~d 9.2 g ~2~5 equivalents) of 1,3-dichloro-1,1,3,3-tetrai~opropyl disiloxane were dissol~ed in 150 ml of 1:1 methylene dichloride/pyTidine. After a reaction time of 8 day~ the title compound wa~ i~olated a de~cribed in the in~truc-tions for ~he preparation of compound 1.
Yield: 6.1 g (78~) 6 t 7-0-~1,1,3,3-Tetraisopropyldi6iloxane~1,3-diyl)-10-O-trimethylsilyl-~-rhodomycinone (Compound 3) 19.0 g (30.2 mmol) of compound 1 were di~solved in 250 ml of methylene dichloride a~d 250 ml of pyridine, and 4.2 g ~1.5 equivalents) o~ chlorotrimethylsilane t di~olved in 50 ml of methylene dichloride, we:re added at 0C. The reaction mixture was ~tirred for 1 hour at room tempera~
ture. The r~sction mixture wa~ then evaporated in vacuo and sub~ected to two further distillation6 ~ith toluene.
The residue wa~ puri~ied by column chromatography (silica gel; mobile phase: 7:3 methylene dichloride/petrol~um ether), Yield: 1~.3 g (77~); ~elting points 194-196C
(alpha)D - +530~ (c = 0.2 in chloroform) H-NMR (300 ~Hz, CDCl3, delt~): 13.87 and 13.12 t~, phOH), 7.79 ~dd, ~-1), 7.61 (t, H-~), 7.25 (dd, H-3), 5.23 ~dd, ~-7), 2.13 (dd, H-8~ .06 (dd, H-8b), 4.86 (br ~, H-10), 1.64 (m, H-13a and H-13b), 1002 (t, H-14), 0.2 and 1.2-1.3 (m, alkyl-Si) Example 2 Alkylation of a rhodomycinone in po~ition 4 or, if appropriate, 11.
4-0-Methyl-6,7-0-(1,1,3,3-~etraisopropyldisiloxane 1,3-diyl)-10-0-trimethylsilyl-~rhodomycinone (Compound 4) and 4,11-Di-0 methyl-6,7~0-(1,1,3,3-tetraisopropyldi~iloxane-1,3-diyl)-10-O-trimethyl6ilyl-~-rhodomycinone (Compound 5) 10 Process a):
0.75 g (1.07 mmol) of compound 3 were di~solved in 30 ml of acetone and 7 ml of methylene dichloride~ and 4.4 g (30 equivalent~) of pota~sium carbonste and 10 ml ~150 equivalent~ Qf methyl io~ide were added. The reaction 15 mixture wa~ ~tirred for 3 day6 at room temperature, the progres~ of the xeaction being followed by thin layer chromatography. Methylene dichloride wa~ added to the reaction mixture and the product was extracted by w~shing succes~ively with water, 1 N hydrochlori~ acid and water.
20 The organic phase was dried over sodium sula~e and evaporated in ~acuo. The ~ompounds 6 and 7, ~hich were present in the residue, were ~eparated by column chroma-tography over 35 g of ~ilica gel u~i.n~ methylene dichlor-ide as the mobile phase.
25 Compound 4:
Yield: 0.46 y (60~); melting point: 213-214C
(alpha~D = ~472 ~c = 0.05 in chloro~orm) lH-NMR (30G MHz, CDCl~, delta): 13.22 (8, PhOH), 7.89 (dd, H-l), 7.65 ($, H-2), 7.29 (dd, H~3), 5.35 (ddt H-7), 2.17 30 (dd, H-8a), 2.07 (dt, H-8h), 4~89 (d, H 10), 1.39 (m, ~-13a~, 1.15 (m, H-13b), 1.05 (t, H-14)~ 3.96 (~, OMe), 0.1 and 1.18-1.33 (m, alkyl-si)~ 4.45 ts~ 9-OH) Compound 5s Yield: 0.27 g (35%); melting point: 103-105C
35 (alpha)D = +124 (c = 0.05 in chloroform) , :
2~ 37 , -- 10 ~
lH-NMR ~400 MHz, CDCl3, delta): 7.72 (dd, H-l~, 7.59 (t/
H-2), 7.21 (ddl H 3), 5.34 (dd, ~ 7), 2.17 (dd, H-8a), 2.05 (dt, H-8b), 4.70 (d, H-10), 1.40 (m, H-13a), 1.31 (m, H-13b), 1.04 ~t, H-14), 3.93 and 3.91 (~, OMe), 0.1 S and 0.9-1.3 (alkyl-Si), 4.50 (æ, 9-OH) Pxocess b):
1 g (1.42 mmol) of compound 3 were dis601ved in 4.5 ml of acetone and 18 ml of methylene dichloride, and 4.2 g (12.9 mmol) of cesium carbonate and 5 ml (71.5 mmol) of methyl iodide were added with ~tirring at 4C. After a reaction time of 3 days the reaction mixture was worked up as described above, compound 4 (yialds 0.76 ~ (75~)) and compound 5 ~yield: 0.1 g (10~)) being isolated.
4 O-Met~yl 6,7-0-(1,1,3,3-tetrai~opropyl-di~iloxsne-1,3-diyl)-epsilon-rhodomycinone (Compound 6) The title compound was prepared by the instructions for the preparation of compound 4, ~tarting ~rom 6.03 g (9 mmol) of compound 2, 37.49 g (30 equi~alent.) of potassium carbonate and 56.5 ml (~00 mmol) of methyl iodide.
Yield: 3.2 g ~52~) Example 3 Selective deblocking of the txialkyl~ilyl protective g~oup 4-0 ~ethyl-6,7-0-(1 t 1,3,3-tetrai~opropyldi6iloxane-1,3-diyl)-~-rhodomycinone (Compound 7) 2 ~ (2.8 ~mol) of compound 4 were di~601ved ~n 100 ml of ~athylane dichloride and 100 ml of msthanol, &nd 20 ml of 0.1 N hydrochloric acid were added. After stirring ~or 30 minutes ~t room temperature, the reaction mixture was diluted with methylene dichloride and extracted by shaking with water. The organic pha e wa~ dried by maans . : .
o~ ~
of sodium ~ulfate and evaporated in vacuo. The r~sidue was also filtered ~hrough 50 g of silica g~l (mobile phase: 20.1 methylene dichloride/acetone).
Yield: 1.7 ~ (96%); melting point: 166-168C
~alpha)D = +386~ (o - 0.05 in chloroform) ~xample 4 ;~
Introduction of acyl protective groups 4-0-~ethyl-10-0-p-nitrobenzoyl-6,7-0~(1,1,3,3-tetraiso-propyldi~iloxane-1,3-diyl)-~-rhvdomycinone (Compound 8) 0.68g (1.05 mmol~ of compound 7 wa~ di~olved in 40 ml of 2:1 chloroform/pyridine, and 0.3 g ~1.5 e~uivalents) of p-nitrobenzoyl chloride was added. After stirring at 0C
for 15 houxs, 10 ml of methanol were added to the reac tion mixture. The reaction mixture was evapora~ed in vacuo and di~tilled again with toluene. The residue was dissolved in chloroform and washed twice with water, and the organic phase was dried over sodium sulfate and evaporated in vacuo~ The crude product which remained was purified fuxther by column chromatography over 120 g of ::.
silica gel (mobile pha~e: 17:10:1 petroleum ether/methyl-ene dichloride/acetone).
Yield: 340 m~ ~81.1g); melting point~ 114-116C
(alpha)~ = ~384D (c = 0.05 in ~hloroform) 1H-NMR (300 ~Hz, CDCl3, delta): 13.02 1~, PhOH), 7.84 (dd, H-l~, 7.~5 (t, H-2~, 7.32 (dd, H~3), 5.51 (dd, H-7~, 2.38 (dt, H-8a), 2.07 (dd, H-8b), 6056 ~d, H-10), 1.50 (m, H-13a), 1.83 (m~ H-13b)~ 1.07 (t, H-14~, 3.98 (8, 4-OMe), 8.08 and 8.22 (m, aryl), 0.64-1.2 (m, alkyl-Si) 10,11-Bis-~-(p-nitrobenzoyl)-4-0-methyl-6,7-0-tl,1,3,3-tetrai~opropyldisiloxane-1,3-diyl~ ~-rhodom~cinone (Compound 9) 0.34 g (0052g mmol) of compound 7 wa~ reacted with 0.3 g (3 eguivalent~ of p nitrobenzoyl chloride as described ~ .
, , ~ , , "
8~
above to give the title compound.
Yi~ld: 0.35 ~72~) Example 5 Deblocking the tetrai~opropyldisil~xane-1,3-diyl protec-tive group 4-O-Methyl-10-O-p-nitrobenzoyl-~-rhodomycinone (Compound 10~
0.6 g (0.76 mmol) of ~ompound 8 was di~solved in 30 ml of THF, and 1 ml of a 1-molar solution in THE of tetrabutyl-ammonium fluoride was add~d at 0C. After the reactionmixture had been ~tirred for 30 minutes, 30 ml of 0.1 N
hydrochloric acid were added and the mixture was extrac-ted twice with chloroform. The or~anic pha~e wa~ dried over ~odi~m sulfate and ~vapora~ed in vacuo. The crude lS product ohtained was purified by chromatography over 65 q of silica gel (mobile pha~e: 15:1 methylene dichloride~
acetone).
Yield: 0.3~8 g (91%); meltins point: 153-155C
(alpha)D = ~275 (c = 0.02 in chlorofonm) 10,11-gis_o_(p-nitxobenzoyl)~4-O-methyl-~-rhodomycinone ~Compound 11) 0.15 g (0.15~ mmol) of compound 9 W~15 reacted with 0.2 ml of a l-~olar ~olution in ~HF of tetrabutylamonium fluor-ide a~ de~cribed above to give the title compound.
Yields 95.8 mg (88%) 4-O-~ethyl epsilon-rhodomycinone (Compound 12) The title compound wa~ prepared by the in~truction~ for the prep~ration of compound 10, starting from 3.2 g (4.6 mmol) of compound 6.
Yield. 1.6 g (83%~; ~AB m/e = 443 ~M~Ht) , :~ .
- ~3 -Example 6 Formation of glycosides of the rhodomycins with function-alized amino-~ugar~
4-0-Methyl-10-0-p-nitrobenzoyl-7-0-(4'-0-p-nitro~enzoyl~
3'-N-trifluoroacetyl-alpha-L-daunosaminyl)-~ rhodomycin-one (Compound 13) 1.84 ~ ~3.36 mmol) of compound 10, 3.64 g (6~72 mmol) of 1,4-di~O-p-nitrobenzoy' 3-N-~rifluoroacetyl-alpha,~
daunosamine and 5 g of mol~cular ~ieve 4 A were ~u~p~n-ded, with the exclu6ion of moisture, in 300 ml of a ~olvent mixture composed of lOtl chloroform/acetone. The reaction mixture wa~ cooled to -50C, 3 ml of trimethyl-fiilyl trifluoromethane~ulfonate were added and ~tirring was continued ~or 4 hours at -45C. The progre~ of the reaction wa~ monitored by thin layer chromatography (mobile phase; 20:1, methylene dichloride/acetone). The reac~ion mi~ture wa~ neutraliz~d (pH 7) with triethyl-amine and was filtered. ~fter the 801vent had been evaporated the residue wa~ purified by column chroma-tography ~6ilica ~el; mobile phase: 20:1 methylene dichloride~acetone).
Yield: 2~3 g (74%) 1H-NMR, HjH-COSY t300 MHz, C6H6~CDCl3 1:1, delta): 7.60 ~d~
H-l), 7.05 (tl H-2), S.58 (d, H-3)~ 5.12 (dd~ H~7)~ 2.29 (d, ~-8a), 1.90 (dd, H-8b) ~ 6.57 (6, H-10), 1.81 (m, H 13a), 1.38 (m, H-13b), 0.99 tt, H-14), 13.93 and 13.17 (8, PhOH~, 3.41 (~, OMe), 3.SO (8, 9~0H), 7.28-7.72 (~, p-N02Bz~, 5.49 (d, H-l'), 1~69 (ddd, H-2'a), 1~85 ~dd, H-2'b), ~.13 (m, H 3~, 5.06 (br ~, H~4'), 4~21 (q, H-5'), 1.00 (d, H 6'), 6.12 (d, NH) 10,11-Bis-0 (p-nitrobenzoyl)-4-0-methyl-7-0-(4'-0-p-~itrokenzoyl~3'-N-trifluoroacetyl-alpha-L-daunosaminyl)-~-rhodomycinone (Compound 14) The ~itle compound was prepared by ~he glyoo6idation process for the preparation of compound 13, starting from the aglycone compound 11 and 1,4-di~O-p-nitroben~oyl-3,N-trifluoroacetyl-alpha,~-L-dauno~amine.
daunosamine and 5 g of mol~cular ~ieve 4 A were ~u~p~n-ded, with the exclu6ion of moisture, in 300 ml of a ~olvent mixture composed of lOtl chloroform/acetone. The reaction mixture wa~ cooled to -50C, 3 ml of trimethyl-fiilyl trifluoromethane~ulfonate were added and ~tirring was continued ~or 4 hours at -45C. The progre~ of the reaction wa~ monitored by thin layer chromatography (mobile phase; 20:1, methylene dichloride/acetone). The reac~ion mi~ture wa~ neutraliz~d (pH 7) with triethyl-amine and was filtered. ~fter the 801vent had been evaporated the residue wa~ purified by column chroma-tography ~6ilica ~el; mobile phase: 20:1 methylene dichloride~acetone).
Yield: 2~3 g (74%) 1H-NMR, HjH-COSY t300 MHz, C6H6~CDCl3 1:1, delta): 7.60 ~d~
H-l), 7.05 (tl H-2), S.58 (d, H-3)~ 5.12 (dd~ H~7)~ 2.29 (d, ~-8a), 1.90 (dd, H-8b) ~ 6.57 (6, H-10), 1.81 (m, H 13a), 1.38 (m, H-13b), 0.99 tt, H-14), 13.93 and 13.17 (8, PhOH~, 3.41 (~, OMe), 3.SO (8, 9~0H), 7.28-7.72 (~, p-N02Bz~, 5.49 (d, H-l'), 1~69 (ddd, H-2'a), 1~85 ~dd, H-2'b), ~.13 (m, H 3~, 5.06 (br ~, H~4'), 4~21 (q, H-5'), 1.00 (d, H 6'), 6.12 (d, NH) 10,11-Bis-0 (p-nitrobenzoyl)-4-0-methyl-7-0-(4'-0-p-~itrokenzoyl~3'-N-trifluoroacetyl-alpha-L-daunosaminyl)-~-rhodomycinone (Compound 14) The ~itle compound was prepared by ~he glyoo6idation process for the preparation of compound 13, starting from the aglycone compound 11 and 1,4-di~O-p-nitroben~oyl-3,N-trifluoroacetyl-alpha,~-L-dauno~amine.
4~0-Methyl-7-0-l4'-0-p~-nitrobenzoyl-3'-N-~rifluroacetyl-alpha-L-dauhosaminyl)-epsilon-rhodomycinone (Compound 153 The title compound was prepared by the glyco~idation proces~ for the preparation of the compvund 13, starting from 4-0-methyl-epsilon-rhodomycinone (compound 12) and 1,4-di-0-p-nitrobenzoyl-3,N~trifluoroacetyl-alpha,~-L-dauno~amine.
~xampl~ 7 Deblocking r~actions 4~0-Methyl-10-0-p-nitrobenzoyl-7-0-(3'-N-trifluoroacetyl alpha-L-daunosami~yl)-~-rhodomycinone (Compound 16) 0.12 g (0.13 ~mol) of compound 13 wa6 di&solved in 2 ml of lol me~hylene dichloride/methano:l, and 0.5 ml of 0.1 N
N~OH was added. The reaction mixture was stirred for 30 minutes at room temperature. The reaction wa~ Etopped by adding O.5 ml of 0.1 N HCl. Chloro:Eorm wa~ added to the mi~ture and it was then extracted by washing with water.
The organic pha~e wa~ dried over ~odium ~ulfate and evaporated in vacuo and the r86 ? d~e which re~ul ed ~as purified by column chrom~tography (6ilica gel; 6:1 methylene dichloride/acetone).
Yield$ 0.08 g (80~), melting point: 186-188C
(alpha)D = ~700 (c = 0.~ in chloroform) 7-0-(~lpha~L~Dauno~aminy~)-4-0-methyl-~-rhodo~ycinone (Compound 17) O.3 g (0.32 mmol) of compound 13 wa~ dis~olved in 10 ml of 1:1 chloroform/methanol, and 3 ml of 1 N NaOH wer~
added with ~tirring. After 2 hour~ the reaction mixture . - ~5 -was neutralized with 3 ml of 1 N HCl, dilu~ed with chloroform and butanol and extracted by washing with water. The organic phase wa~ dried over sodium ~ulfate and evaporated in vacuo. The residue wa~ purified over RP-18 silica gel.
Yield, 0.14 g (83%); MSs F~B m/e = 530 (~H~) 7-O-(alpha-L-Daunosaminyl)-4-O-methyl-ep~ilon-rhodomycin-one (Compound 18) The title compound was prepared by the process for the preparation of compound 16, starting from compound 15.
Example 8 ~odification of the rhodomycins at the 3'-amino group 7-0-(3'-N-DLmethyl-alpha-L-daunosaminyl)-4 O-methyl~-lS rhodomycinon~
(Compound 19) 200 mg [0.37 mmol) of compound 17 were dissolved in 20 ml of methanol, and 0.6 ml of 37~ ~;trength formaldehyde solution wafi added with stirring. After 142 mg of ~odium ~yanoborohydride had ~san added, the reaction mixture was stirred for a further 3 hours. The re~ulting ~rude product ~as purified by column chromatography (silica gel, 3s1 chloroform/methanol).
~ield: 161 mg (78~); MS: FAB m/e = 558 (M+~+) 4 O-~ethyl-7-0-(3'~(morpholin-4-yl)-2~3,6-tri-deoxy-~lpha-~-ly~ohexopyrano~yl~ rhodomycinone (Compound 20) 200 mg (0.37 mmol) of compound 17 were di~olved in 20 ml of 10:1 methanol/chloroformO and 77.2 m~ of 2,2'-hydroxy-bis-acetaldehyde which had been freshly pr~pared from 1~4-anhydroerythritol by periodate oxidation ~ere added.
After 25 mg of ~odiuM syanoborohydride h~d been ~ddedl the rea~tion mixture lwas ~tirred for 2 hours at room temperature and then evaporated in vacuo. The re3idue wa~
8~3 purified by column chro~atography over ~P-18 silica gel.
Yields 165 mg (74%); MS: PAB m/e = 600 (M+H'~
4-O-~ethyl-(3'-morpholin-4-yl)-2,3,6~trideoxy alpha-L-lyxohexopyrano~yl)-ep~ilon-rhodomycinone (Compound 21) The title compound wa~ prepared by the proees~ for the ~:
preparation of compound 20, starting from compound 18 and 2,2'-hydroxybis-acetaldehyde.
~xampl~ 7 Deblocking r~actions 4~0-Methyl-10-0-p-nitrobenzoyl-7-0-(3'-N-trifluoroacetyl alpha-L-daunosami~yl)-~-rhodomycinone (Compound 16) 0.12 g (0.13 ~mol) of compound 13 wa6 di&solved in 2 ml of lol me~hylene dichloride/methano:l, and 0.5 ml of 0.1 N
N~OH was added. The reaction mixture was stirred for 30 minutes at room temperature. The reaction wa~ Etopped by adding O.5 ml of 0.1 N HCl. Chloro:Eorm wa~ added to the mi~ture and it was then extracted by washing with water.
The organic pha~e wa~ dried over ~odium ~ulfate and evaporated in vacuo and the r86 ? d~e which re~ul ed ~as purified by column chrom~tography (6ilica gel; 6:1 methylene dichloride/acetone).
Yield$ 0.08 g (80~), melting point: 186-188C
(alpha)D = ~700 (c = 0.~ in chloroform) 7-0-(~lpha~L~Dauno~aminy~)-4-0-methyl-~-rhodo~ycinone (Compound 17) O.3 g (0.32 mmol) of compound 13 wa~ dis~olved in 10 ml of 1:1 chloroform/methanol, and 3 ml of 1 N NaOH wer~
added with ~tirring. After 2 hour~ the reaction mixture . - ~5 -was neutralized with 3 ml of 1 N HCl, dilu~ed with chloroform and butanol and extracted by washing with water. The organic phase wa~ dried over sodium ~ulfate and evaporated in vacuo. The residue wa~ purified over RP-18 silica gel.
Yield, 0.14 g (83%); MSs F~B m/e = 530 (~H~) 7-O-(alpha-L-Daunosaminyl)-4-O-methyl-ep~ilon-rhodomycin-one (Compound 18) The title compound was prepared by the process for the preparation of compound 16, starting from compound 15.
Example 8 ~odification of the rhodomycins at the 3'-amino group 7-0-(3'-N-DLmethyl-alpha-L-daunosaminyl)-4 O-methyl~-lS rhodomycinon~
(Compound 19) 200 mg [0.37 mmol) of compound 17 were dissolved in 20 ml of methanol, and 0.6 ml of 37~ ~;trength formaldehyde solution wafi added with stirring. After 142 mg of ~odium ~yanoborohydride had ~san added, the reaction mixture was stirred for a further 3 hours. The re~ulting ~rude product ~as purified by column chromatography (silica gel, 3s1 chloroform/methanol).
~ield: 161 mg (78~); MS: FAB m/e = 558 (M+~+) 4 O-~ethyl-7-0-(3'~(morpholin-4-yl)-2~3,6-tri-deoxy-~lpha-~-ly~ohexopyrano~yl~ rhodomycinone (Compound 20) 200 mg (0.37 mmol) of compound 17 were di~olved in 20 ml of 10:1 methanol/chloroformO and 77.2 m~ of 2,2'-hydroxy-bis-acetaldehyde which had been freshly pr~pared from 1~4-anhydroerythritol by periodate oxidation ~ere added.
After 25 mg of ~odiuM syanoborohydride h~d been ~ddedl the rea~tion mixture lwas ~tirred for 2 hours at room temperature and then evaporated in vacuo. The re3idue wa~
8~3 purified by column chro~atography over ~P-18 silica gel.
Yields 165 mg (74%); MS: PAB m/e = 600 (M+H'~
4-O-~ethyl-(3'-morpholin-4-yl)-2,3,6~trideoxy alpha-L-lyxohexopyrano~yl)-ep~ilon-rhodomycinone (Compound 21) The title compound wa~ prepared by the proees~ for the ~:
preparation of compound 20, starting from compound 18 and 2,2'-hydroxybis-acetaldehyde.
Claims (7)
1. A process for the preparation of a rhodomycin derivative of the formula I
I
in which R1 denotes H, C1-C4-alkyl or an acyl protective group, R2 denotes OH, COOCH3, O-Si(C1-C4-alkyl)3 or an O-acyl protective group, acyl being acetyl, monohslogeno-acetyl, dihalogenoacetyl or trihalogenoacetyl with fluorine or chlorine as the halogen, benzoyl or p-nitrobenzoyl, R3 denotes C1-C4-alkyl, R4 denotes H or R4 and R5 together denote a tetraisopropyldisiloxane-1,3-diyl protective group, and R5 denotes H or a glycosyl radical of the formula II
II
in which R6 is OH, ac toxy, NHCOCF3, NH2, a mono-C1-C4-alkylamino group or a di-C1-C4-alkylamino group or a 4-morpho-linyl group and R7 is H, OH or an acetoxy, trifluoroacetoxy or p-nitrobenzoyloxy group, which comprises reacting a rhodomycinone derivative of the formula I in which R1 is H, R2 is OH or COOCH3 and R3, R4 and R5 are H, with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane and, if appropriate, subsequently with a tri-C1-C4-alkylsilyl halide, preferably with a chloride derivative, in the presence of a base, such as pyridine or dimethylamino-pyridine, and an organic solvent, such as methylene dichloride or chloroform, at a temperature between 15°C
and 80°C to give a 6,7-O-(tetraisopropyldisiloxane-1,3-diyl)-rhodomycinone compound of the formula I in which R1 and R3 are H, R2 is COOCH3 or O-Si(C1-C4-alkyl)3 and R4 and R5 together are a tetraisopropyldisiloxane-1,3-diyl group, then etherifying the resulting compound with an alkylat-ing agent, preferably a C1-C4-alkyl bromide or iodide, in the presence of an alkali metal carbonate and an organic solvent, such a acetone or dioxane, at the phenolic hydroxyl group on the C-4 atom, if appropriate also at the phenolic hydroxyl group on the C-11 atom, then, if appropriate, splitting off the trialkylsilyl protective group at the C-10 atom by acid hydrolysis, preferably by means of hydrochloric acid, and acylating the resulting compound at the 10-hydroxyl group and, if appropriate, at the 11-hydroxyl group by means of an acylating agent, preferably p-nitrobenzoyl chloride, trifluoroacetic anhydride or acetyl chloride, in the presence of a base, such as pyridine, triethylamine or dimethylaminopyridine, and an organic solvent, such as methylene dichloride or chloroform, and splitting off the tetraisopropyldisil-oxane-1,3-diyl group by means of an ammonium fluoride, preferably tetrabutylammonium fluoride, in a polar organic solvent, such as tetrahydrfuran or dioxane, in the course of which a compound of the formula III
III
III
in which R1 denotes H, C1-C4 alkyl or an acyl protective group indicated above, R2 denotes COOCH3 or an O-acyl protective group and R3 denotes C1-C4-alkyl is formed.
I
in which R1 denotes H, C1-C4-alkyl or an acyl protective group, R2 denotes OH, COOCH3, O-Si(C1-C4-alkyl)3 or an O-acyl protective group, acyl being acetyl, monohslogeno-acetyl, dihalogenoacetyl or trihalogenoacetyl with fluorine or chlorine as the halogen, benzoyl or p-nitrobenzoyl, R3 denotes C1-C4-alkyl, R4 denotes H or R4 and R5 together denote a tetraisopropyldisiloxane-1,3-diyl protective group, and R5 denotes H or a glycosyl radical of the formula II
II
in which R6 is OH, ac toxy, NHCOCF3, NH2, a mono-C1-C4-alkylamino group or a di-C1-C4-alkylamino group or a 4-morpho-linyl group and R7 is H, OH or an acetoxy, trifluoroacetoxy or p-nitrobenzoyloxy group, which comprises reacting a rhodomycinone derivative of the formula I in which R1 is H, R2 is OH or COOCH3 and R3, R4 and R5 are H, with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane and, if appropriate, subsequently with a tri-C1-C4-alkylsilyl halide, preferably with a chloride derivative, in the presence of a base, such as pyridine or dimethylamino-pyridine, and an organic solvent, such as methylene dichloride or chloroform, at a temperature between 15°C
and 80°C to give a 6,7-O-(tetraisopropyldisiloxane-1,3-diyl)-rhodomycinone compound of the formula I in which R1 and R3 are H, R2 is COOCH3 or O-Si(C1-C4-alkyl)3 and R4 and R5 together are a tetraisopropyldisiloxane-1,3-diyl group, then etherifying the resulting compound with an alkylat-ing agent, preferably a C1-C4-alkyl bromide or iodide, in the presence of an alkali metal carbonate and an organic solvent, such a acetone or dioxane, at the phenolic hydroxyl group on the C-4 atom, if appropriate also at the phenolic hydroxyl group on the C-11 atom, then, if appropriate, splitting off the trialkylsilyl protective group at the C-10 atom by acid hydrolysis, preferably by means of hydrochloric acid, and acylating the resulting compound at the 10-hydroxyl group and, if appropriate, at the 11-hydroxyl group by means of an acylating agent, preferably p-nitrobenzoyl chloride, trifluoroacetic anhydride or acetyl chloride, in the presence of a base, such as pyridine, triethylamine or dimethylaminopyridine, and an organic solvent, such as methylene dichloride or chloroform, and splitting off the tetraisopropyldisil-oxane-1,3-diyl group by means of an ammonium fluoride, preferably tetrabutylammonium fluoride, in a polar organic solvent, such as tetrahydrfuran or dioxane, in the course of which a compound of the formula III
III
III
in which R1 denotes H, C1-C4 alkyl or an acyl protective group indicated above, R2 denotes COOCH3 or an O-acyl protective group and R3 denotes C1-C4-alkyl is formed.
2. The process as claimed in claim 1 for the preparation of a .beta.-rhodomycinone derivative of the formula I in which R1 is H or C1-C4-alkyl, R2 is OH or an O-acyl protective group, R3 is C1-C4-alkyl and R4 and R5 are H.
3. The process as claimed in claim 1 for the preparation of an epsilon-rhodomycinone derivative of the formula I in which R1 is H, R2 is COOMe, R3 is C1-C4-alkyl and R4 and R5 are H.
4. The use of a rhodomycinone compound of the formula III
for the preparation of a 7-O-glycosyl-rhodomycinone compound of the formula I, which comprises reacting a compound of the formula III in a marner known per se with a functionalized deoxy-sugar of the formula IV or V, IV V
in which R6 reprsents an acetoxy or trifluoroacetamido group, R7 represents a hydrogen atom or an acetoxy, trifluoro-acetoxy or p-nitrobenzoyloxy group and Y represents an acetoxy or p-nitrobenzoyloxy group or a chloride, in the presence of a catalyst, such as a tri-C1-C4-alkylylsilyl trif1uoromathaneaulfonate or the silver salt of trifluoromethanesulfonic acid, to give a 7-O-glycosylrhodomycinone of the formula I in which the radicals R1, R2, R3, R6 and R7 retain the meanLng defined in formulae III, IV and V, then splitting off the acyl protective groups by alkaline hydrolysis, in the course of which a compound of the formula I in which R1 denotes H or C1-C4-alkyl R2 denotes OH or COOCH3, R3 denotes C1-C4-alkyl, R4 denotes H and R5 denotes a glycosyl radical of the formula II in which R6 is NE2 or OH and R7 is H or OH is formed, and, if appropriate, reacting a resulting compound of the fommula I containing an amino-sugar under the conditions of reductive alkylation with a C1-C4-aldehyde or diglycol alciehyde ln the presence of an alkali metal cyanoborohyd-ride to give a further compound of the formula I in which the radicalçi R1, R2, R3, R4, R5 and R7 retain the last mentioned meaning and R6 represents a mono-C1-C4-alkyl-amino or di-C1-C4-alkylamino group or a 4-morpholinyl group.
for the preparation of a 7-O-glycosyl-rhodomycinone compound of the formula I, which comprises reacting a compound of the formula III in a marner known per se with a functionalized deoxy-sugar of the formula IV or V, IV V
in which R6 reprsents an acetoxy or trifluoroacetamido group, R7 represents a hydrogen atom or an acetoxy, trifluoro-acetoxy or p-nitrobenzoyloxy group and Y represents an acetoxy or p-nitrobenzoyloxy group or a chloride, in the presence of a catalyst, such as a tri-C1-C4-alkylylsilyl trif1uoromathaneaulfonate or the silver salt of trifluoromethanesulfonic acid, to give a 7-O-glycosylrhodomycinone of the formula I in which the radicals R1, R2, R3, R6 and R7 retain the meanLng defined in formulae III, IV and V, then splitting off the acyl protective groups by alkaline hydrolysis, in the course of which a compound of the formula I in which R1 denotes H or C1-C4-alkyl R2 denotes OH or COOCH3, R3 denotes C1-C4-alkyl, R4 denotes H and R5 denotes a glycosyl radical of the formula II in which R6 is NE2 or OH and R7 is H or OH is formed, and, if appropriate, reacting a resulting compound of the fommula I containing an amino-sugar under the conditions of reductive alkylation with a C1-C4-aldehyde or diglycol alciehyde ln the presence of an alkali metal cyanoborohyd-ride to give a further compound of the formula I in which the radicalçi R1, R2, R3, R4, R5 and R7 retain the last mentioned meaning and R6 represents a mono-C1-C4-alkyl-amino or di-C1-C4-alkylamino group or a 4-morpholinyl group.
5. The use of a .beta.-rhodomycinone compound as claimed in claim 2 for the preparation of a 7-O-glycosyl-,.beta.-rhodomycinone compound of the formula I in which R1 denotes H, C1-C4-alkyl or an acyl protective group, R2 denotes OH or an acyl protective group, R3 denotes C1-C4-alkyl, R4 denotes H and R5 denotes a glycosyl radical of the formula II in which R5 is OH, acetoxy, NHCOCF3, NH2, a mono-C1-C4-alkylamino group or a di-C1-C4-alkylamino group or a 4-morpho-linyl group and R7 is H, OH or an acetoxy, trifluoroacetoxy or p-nitrobenzoyloxy group.
6. The use of an epsilon-rhodomycinone compound as claimed in claim 3 for the preparation of a 7-O-glycosyl-epsilon rhodomycinone compound of the formula I in which R1 denotes H or C1-C4,-alkyl, R2 denotes COOMe, R3 denotes C1-C4-alkyl, R4 denotes H and R5 denotes a glycosyl radical of the formula II in which R6 is OH, acetoxy, NHCOCF3, NH2 or a mono-C2-C4-alkyl-amino group or di-C1-C4-alkylamino group or a 4-morpholinyl group and R7 is H, OH or an acetoxy, trifluoroacetoxy or p-nitrobenzoyloxy group.
7. The process as claimed in claim 1, and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3836122.1 | 1988-10-22 | ||
| DE3836122A DE3836122A1 (en) | 1988-10-22 | 1988-10-22 | METHOD FOR PRODUCING 4-0-ALKYL RHODOMYCINES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2001087A1 true CA2001087A1 (en) | 1990-04-22 |
Family
ID=6365756
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002001087A Abandoned CA2001087A1 (en) | 1988-10-22 | 1989-10-20 | Process for the preparation of 4-o-alkylrhodomycins |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0365973B1 (en) |
| JP (1) | JPH02164840A (en) |
| KR (1) | KR900006358A (en) |
| AT (1) | ATE98626T1 (en) |
| AU (1) | AU4356689A (en) |
| CA (1) | CA2001087A1 (en) |
| DE (2) | DE3836122A1 (en) |
| DK (1) | DK523189A (en) |
| PT (1) | PT92031B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111971842A (en) * | 2018-03-23 | 2020-11-20 | 富山药品工业株式会社 | Electrolyte for electricity storage device and nonaqueous electrolyte |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3943029A1 (en) * | 1989-12-27 | 1991-07-04 | Behringwerke Ag | METHOD FOR PRODUCING GLYCOSYL ANTHRACYCLINONES |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3641835A1 (en) * | 1986-12-08 | 1988-06-16 | Behringwerke Ag | CYTOSTATICALLY EFFECTIVE ANTHRACYCLINE DERIVATIVES |
| DE3641833A1 (en) * | 1986-12-08 | 1988-06-09 | Behringwerke Ag | CYTOSTATICALLY EFFECTIVE ANTHRACYCLINE DERIVATIVES |
| DE3712350A1 (en) * | 1987-04-11 | 1988-10-20 | Behringwerke Ag | SEMISYNTHETIC RHODOMYCINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS CYTOSTATICS |
-
1988
- 1988-10-22 DE DE3836122A patent/DE3836122A1/en not_active Ceased
-
1989
- 1989-10-17 EP EP89119222A patent/EP0365973B1/en not_active Expired - Lifetime
- 1989-10-17 AT AT89119222T patent/ATE98626T1/en not_active IP Right Cessation
- 1989-10-17 DE DE89119222T patent/DE58906440D1/en not_active Expired - Fee Related
- 1989-10-19 PT PT92031A patent/PT92031B/en not_active IP Right Cessation
- 1989-10-20 JP JP1271937A patent/JPH02164840A/en active Pending
- 1989-10-20 CA CA002001087A patent/CA2001087A1/en not_active Abandoned
- 1989-10-20 AU AU43566/89A patent/AU4356689A/en not_active Abandoned
- 1989-10-20 DK DK523189A patent/DK523189A/en not_active Application Discontinuation
- 1989-10-20 KR KR1019890015079A patent/KR900006358A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111971842A (en) * | 2018-03-23 | 2020-11-20 | 富山药品工业株式会社 | Electrolyte for electricity storage device and nonaqueous electrolyte |
| CN111971842B (en) * | 2018-03-23 | 2023-10-10 | 富山药品工业株式会社 | Electrolytes and non-aqueous electrolytes for power storage equipment |
Also Published As
| Publication number | Publication date |
|---|---|
| ATE98626T1 (en) | 1994-01-15 |
| PT92031B (en) | 1995-06-30 |
| EP0365973B1 (en) | 1993-12-15 |
| KR900006358A (en) | 1990-05-08 |
| PT92031A (en) | 1990-04-30 |
| JPH02164840A (en) | 1990-06-25 |
| DK523189D0 (en) | 1989-10-20 |
| DE58906440D1 (en) | 1994-01-27 |
| DE3836122A1 (en) | 1990-05-31 |
| EP0365973A1 (en) | 1990-05-02 |
| DK523189A (en) | 1990-04-23 |
| AU4356689A (en) | 1990-04-26 |
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