![]() Method of preparing anthracycline glycosides
专利摘要:
1506200 Daunomycin and adriamycin derivatives SOC FARMACEUTICI ITALIA SpA 21 April 1976 [30 April 1975] 18098/75 Heading C2C Daunomycin and the 4<SP>1</SP>-epi derivatives and the novel 3<SP>1</SP>,4<SP>1</SP>-epi, 3<SP>1</SP>,4<SP>1</SP>-epi-6<SP>1</SP>-hydroxy and 4 - demethoxy - 41 - epi derivatives of daunomycin and adriamycin (in α-anomer form) are prepared by reacting daunomycinone or its 4- demethoxy derivative with the appropriate N 1 O- protected 1-halo-daunosamine in an organic solvent in the presence of a soluble silver salt catalyst and a molecular sieve as dehydrating agent, removing the protecting groups and, if necessary, brominating or iodinating the resulting daunomycin or derivative thereof and hydrolysing the resulting 14-bromo or -iodo derivative with an alkali metal formate to form the corresponding adriamycin. 2,3 - Dideoxy - 4,6 - di - O - p - nitrobenzoyl - 3- N - trifluoro - acetyl - α - L - ribo - hexopyranosyl chloride is prepared by reacting 4,6-O- benzylidene - 2 - deoxy - α - L - erythro - hexopyranosoid-3-ulose with methanolic hydroxylamine, reducing the resulting oxime with LiAlH 4 , treating the resulting amine with methanolic HCl and then trifluoroacetic anhydride, reacting the resulting methyl 2,3- dideoxy - 3 - N - trifluoroacetyl - α - L - ribohexapyranoside with p-nitrobenzoyl chloride, treating the resulting di-p-nitrobenzoate with HCl, reacting the resulting pyranose with p-nitrobenzoyl chloride and chlorinating the resulting tri-O-p-nitrobenzoyl derivative. 2,3,6 - Trideoxy - 3 - N - trifluoroacetyl - 4- O - p - nitro - benzoyl - α - L@- ribo - hexopyranosyl chloride is prepared by brominating methyl 2,3 - dideoxy - 3 - N - trifluoroacetyl - α - L- ribopyranoside with N-bromosuccinimide, reducing the resulting 6-bromo derivative with Pd-C, treating the resulting methyl 2,3,6- trideoxy - 3 - trifluoroacetamido - α - L - ribohexopyranoside with p-nitrobenzoyl chloride, treating the resulting 4-O-p-nitrobenzoyl derivawith HCl, reacting the resulting pyranose with p-nitrobenzoyl chloride and chlorinating the resulting di-p-nitrobenzoyl derivative with HCl. 公开号:SU728719A3 申请号:SU762353457 申请日:1976-04-26 公开日:1980-04-15 发明作者:Аркамоне Федерико;Барджотти Альберто;Ди Марко Аурелио;Пенко Серджо 申请人:Сочиета Фармасьютичи Италиа С.П.А. (Фирма); IPC主号:
专利说明:
groups by soft alkaline hydrolysis of 0.1 n. pacTBOpON. sodium hydroxide and processing the resulting free glycoside compound with a methanol solution of hydrogen chloride. The target product is isolated by known techniques. The solubility of the silver salt in an organic solvent allows condensation to occur in the homogeneous phase, eliminating the well-known complexity of the Konig-Knorr reaction in the presence of insoluble silver compounds or mercury. The reaction goes to completion in a short time (usually from 1 to 8 hours), and protected glycosides can be obtained in good yields. In addition, it is important that the reaction is stereospecific, only alpha anomers are formed. 1, 3, 4-Epi-b-oxy Example daunomycin (I). A solution of 1.1 g of daunomycin (E) {R-methoxy) in 110 ml of anhydrous methylene dichloride is mixed with 0.8 g of 1-chloro 2,3-dideoxy-3-M-trifluoroacetate-4, b-di-p- para-nitro6-benzoyl-alpha-L-ribohexapyranose (m) in the presence of 12 g of molecular sieve (4A Merck) and treated with 0.37 g with vigorous stirring for 10-15 hours at room temperature. The reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. Separate the organic phase and evaporate in vacuo. The stat is purified by chromatography on a silica column using 2: 1 (v / v) benzene-ethyl acetate system as eluent. 1.3 g (yield 80%) of the assigned glycoside are obtained; 241-243 ° C (oO2P -: - 24l (from 0.07 in the SNA,). A solution of 0.7 g of the obtained compound in 45 ml of acetone is prepared is mixed with 50 ml of 0.2N. an aqueous solution of caustic soda at. After 40 min, the solution was adjusted to pH 4 with 1 I. hydrogen chloride and extracted with chloroform to remove aglycones. The aqueous solution, adjusted to pH 8.5, is re-extracted with chloroform. The extracts are combined, dried over anhydrous sodium sulfate, evaporated to a volume of 10 ml. A stoichiometric amount of anhydrous methanolic hydrogen chloride and an excess of ethyl ether are poured in to obtain O, 36 g (83%) of 3,4-epi-6-oxideunomycin-; read-rochloride (I). M.p. 183-185C (cC) g 4-2l5 ° (from 0.02 to MeOH). Thin-layer chromatogram on Merck NG silica gel, buffered at pH 7 M / 15-phosphate, using (as eluent) chloroform-methanol-water system (13: 6: 1 by volume), R 0.43. Example 2, 3, 4-E11I-dauno1Micin. A solution of 0.29 g of aunomycin (R-methoxy) in 3Q MP of anhydrous methylene chloride is mixed with 0.15 g of pyranosyl chloride and treated with 0.1 g with vigorous stirring for 10-15 hours at room temperature. The compound is treated as indicated in example 1 to receive. O, 185 g (65%) of the protected glycoside, m.p. 245 (;. With thin layer chromatography of silica gel Merck 60f 254 using benzene-ethyl acetate (2: 1 by volume), RC 0.3. During the treatment to remove the protecting groups as described in Example 1, the desired product is obtained in a quantitative yield, mp. 180-181 C (s), (c 0.05 MeOH). With a thin-layer chromatogram on Merck silica gel, buffered to pH 7 with help, and M / 15 phosphate buffer, with a chloroform-methanol-water solvent system (13: 6: 1 by volume) Kg 0.55. Daunomycin under the same conditions has 0.43. R PRI me R 3. 4 Dimethoxy 4-epi-daunomycin. 1 g of 4-dimethoxy, caunomycin () is dissolved in 100 ml of anhydrous methylene chloride, containing 1.2 g of l-hlop-N, 0-trifetropacetyl-4-epida unosamine, and treated in 10 minutes of 10 g of molecular sct (4 A Merck) ,, 0.86 g, j dissolved in 40 ml of diethyl ether. Through i20 at room temperature, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate, the organic phase is separated and evaporated under vacuum; The S, O-protected residue is treated with 200 ml of methanol for 15 minutes at room temperature and 1.3 g of the crude product are obtained after stitching the solvent. Chromatograph in a column of silica with chloroform-benzene-meth acol as an eluent (100: 34: 4 by volume) get 0.5 g of pure M-trifluoroace tyl-4-dimethoxy-4-epi-daun} P.gin. Thin-layer chromagogra -1 -1a on Merck silica gel f 254 using the chloroform-benzene-methanop system (100: 34: 4 by volume), to 0.17.
权利要求:
Claims (1) [1] The resulting M-triftoch acetyl derivative is dissolved in 5 ml of acetone and treated at 50 ml of 0.1 N. caustic soda solution. After 20 minutes, the solution is adjusted to pH 8, .3 and re-extracted (repeatedly) with chloroform. The combined extracts are dried and evaporated to a small volume (about 15 ml) and acidified to pH 3.5 (round) with anhydrous methanolic hydrogen chloride. Pour excess diethyl ether. Obtain 0.35 g of 4-dimethoxy-4-epi-daunomycin as hydrochloride Thin layer chromatogram on Merkel f 254 gel caps using the chlorofor-methanol-water system (12-20: 2), R 0.25, Formula 1 invention. Method the preparation of glycoeno anthracycline of the general formula O OH where R is hydrogen; HCH is X is a group of the formula HOOH - OH I & R 5 V / V /, characterized by the general formula where R has the indicated values, is reacted in anhydrous methylene chloride, in the presence of silver trifluoromethanesulfonate as a catalyst and molecular sieves as a dehydrating agent with a protected sugar derivative of the formula (g) or (e) B oeoCFj) °) NHCiOCF, where the group —o — C R is hydrogen, the C — O — C group, followed by removal of the zaptny groups by 0.1 alkaline hydrolysis of 0.1 and . with sodium hydroxide solution and the resulting free glycoside compound is treated with a methanolic solution of hydrogen chloride. Sources of information taken into account during the examination 1. USSR patent for application No. 214133.8 / 23-04, cl. C 07 H 15/24, 1974.
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同族专利:
公开号 | 公开日 SE436884B|1985-01-28| DK189676A|1976-10-31| AU500439B2|1979-05-24| BE841266A|1976-10-29| AT345457B|1978-09-25| FR2309234A1|1976-11-26| SE431875B|1984-03-05| US4112076A|1978-09-05| NL179587B|1986-05-01| DK150203B|1987-01-05| GB1506200A|1978-04-05| ES447433A1|1977-07-01| ATA302676A|1978-01-15| JPS51133262A|1976-11-18| CA1061335A|1979-08-28| SE7604908L|1976-10-31| CH624125A|1981-07-15| DE2618822C3|1983-04-28| AU1339076A|1977-11-03| ZA762562B|1977-04-27| DE2618822B2|1982-09-16| NL7604049A|1976-11-02| DE2618822A1|1976-11-11| NL179587C|1986-10-01| CH541176A4|1981-07-15| SE8001615L|1980-02-29| FR2309234B1|1978-08-25| JPS5619878B2|1981-05-09| DK150203C|1987-11-02|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 US3803124A|1968-04-12|1974-04-09|Farmaceutici It Soc|Process for the preparation of adriamycin and adriamycinone and adriamycin derivatives| GB1467383A|1974-06-12|1977-03-16|Farmaceutici Italia|Daunomycin analogues| GB1470860A|1974-10-29|1977-04-21|Farmaceutici Italia|Anthracycline glycosides|FR2374333B1|1976-12-20|1981-03-20|Inst Int Pathologie Cellulaire| GB1550879A|1976-12-22|1979-08-22|Farmaceutici Italia|Antitumour glycosides| GB1567392A|1977-02-22|1980-05-14|Farmaceutici Italia|Daunorubicin derivatives| US4201773A|1978-07-26|1980-05-06|The United States Of America As Represented By The Department Of Health, Education And Welfare|7-O--daunomycinone, desmethoxy daunomycinone, adriamycinone, and carminomycinone| IT1196402B|1978-11-21|1988-11-16|Erba Farmitalia|ANTI-TUMORAL ANTIBIOTICS| NL8001417A|1979-03-17|1980-09-19|Erba Farmitalia|ANTITUMORGLYCOSIDES.| JPH0135813B2|1979-08-20|1989-07-27|Efu Hofuman Ra Roshu Unto Co Ag| AT1101T|1979-09-01|1982-06-15|Farmitalia Carlo Erba S.P.A.|ANTHRACYCLIN GLYCOSIDES, METHOD FOR THE PRODUCTION THEREOF AND THE PHARMACEUTICAL COMPOSITION CONTAINING THE SAME.| US4345068A|1979-11-22|1982-08-17|Farmitalia Carlo Erba S.P.A.|Process for the preparation of 4'-epidaunorubicin, 3',4'-diepidaunorubicin, their doxorubicin analogs, and intermediates used in said process| US4298726A|1980-03-07|1981-11-03|Purdue University|Synthesis of N-benzoyl-L-ristosamine and intermediates used in its preparation| US4301276A|1980-03-07|1981-11-17|Purdue University|Synthesis of daunosamine hydrochloride and intermediates used in its preparation| US4345070A|1980-09-29|1982-08-17|Farmitalia Carlo Erba S.P.A.|Process for the preparation of 4'-deoxy-daunorubicin and 4'-deoxy-doxorubicin| US5138042A|1981-05-28|1992-08-11|Farmitalia Carlo Erba S.P.A.|6-deoxyanthracyclines| DE3233898C2|1981-09-18|1988-01-28|Farmitalia Carlo Erba S.P.A., Mailand/Milano, It| GB8426672D0|1984-10-22|1984-11-28|Erba Farmitalia|Pharmaceutical compositions| GB2196626B|1986-10-15|1990-09-19|Erba Farmitalia|Antitumor anthracycline glycosides, their preparation, intermediates thereof, and compositions and use therefor| DE3641835A1|1986-12-08|1988-06-16|Behringwerke Ag|CYTOSTATICALLY EFFECTIVE ANTHRACYCLINE DERIVATIVES| GB8803076D0|1988-02-10|1988-03-09|Erba Carlo Spa|3'-deamino-4'-deoxy-4'-amino anthracyclines| GB9216962D0|1992-08-11|1992-09-23|Erba Carlo Spa|Therapeutically active naphthalenesulfonic-pyrrolecarboxamido derivatives| US7485707B2|2003-07-02|2009-02-03|Solux Corporation|Thermally stable crystalline epirubicin hydrochloride and method of making the same| US20090099346A1|2003-07-02|2009-04-16|Victor Matvienko|Thermally stable crystalline epirubicin hydrochloride| US7388083B2|2005-03-07|2008-06-17|Solux Corporation|Epimerization of 4′-C bond and modification of 14-CH3--fragment in anthracyclin antibiotics| CN101331147B|2005-12-13|2011-11-30|苏洛克股份有限公司|Method for preparing 4-demethyldaunorubicin| US8802830B2|2005-12-20|2014-08-12|Solux Corporation|Synthesis of epirubicin from 13-dihydrodaunorubicine| US8357785B2|2008-01-08|2013-01-22|Solux Corporation|Method of aralkylation of 4′-hydroxyl group of anthracylins| EP2301943B1|2009-09-08|2014-01-08|Heraeus Precious Metals GmbH & Co. KG|Crystallization of epidaunorubicin x HCI| DE102011103751A1|2011-05-31|2012-12-06|Heraeus Precious Metals Gmbh & Co. Kg|Crystallization of epirubicin hydrochloride| DE102011111991A1|2011-08-30|2013-02-28|Lead Discovery Center Gmbh|New cyclosporin derivatives| CN103204888B|2012-01-15|2016-08-17|山东新时代药业有限公司|A kind of preparation method of intermediate of epirubicin hydrochloride| US10301343B2|2015-03-30|2019-05-28|Meiji Seika Pharma Co., Ltd.|Method of producing epirubicin and novel production intermediate thereof|
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申请号 | 申请日 | 专利标题 GB18098/75A|GB1506200A|1975-04-30|1975-04-30|Glycosides| 相关专利
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