WO1999058543A1 - New n-alkyloxycarbonyl derivatives of monosaccharides l-acosamine and l-daunosamine - Google Patents

New n-alkyloxycarbonyl derivatives of monosaccharides l-acosamine and l-daunosamine Download PDF

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WO1999058543A1
WO1999058543A1 PCT/PL1999/000015 PL9900015W WO9958543A1 WO 1999058543 A1 WO1999058543 A1 WO 1999058543A1 PL 9900015 W PL9900015 W PL 9900015W WO 9958543 A1 WO9958543 A1 WO 9958543A1
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alkyl
general formula
optionally substituted
group
allyl
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PCT/PL1999/000015
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French (fr)
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Jan Ramza
Grzegorz Grynkiewicz
Ewa Chojecka-Koryn
Ewa Niewiadomska
Iwona Malinowska
Waldemar Priebe
Alicja WIŚNIEWSKA
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Instytut Farmaceutyczny
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Priority claimed from PL98326262A external-priority patent/PL187092B1/en
Priority claimed from PL98326263A external-priority patent/PL188127B1/en
Priority claimed from PL98326261A external-priority patent/PL187153B1/en
Application filed by Instytut Farmaceutyczny filed Critical Instytut Farmaceutyczny
Publication of WO1999058543A1 publication Critical patent/WO1999058543A1/en

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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
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • 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
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins

Definitions

  • the invention relates to the new N-alkyloxycarbonyl derivatives of monosacharides L-acosamine and L-daunosamine, the method of preparation thereof and their use for the preparation of the anthracycline antibiotics.
  • Natural anthracycline antibiotics (Daunomycin, Doxorubicin) and their clinically useful semisynthetic analogs (Epirubicin, Idarubicin) are believed to exert their cytotoxic action mainly through DNA intercalation, but it is well known, that a sugar moiety which does not engage directly in such process, is indispensible for their activity.
  • Prototype anthracycline antibiotics are manufactured by fermentation, but significance of chemical synthesis is growing with successful clinical trials and launches of new analogs.
  • One of principal approaches to new analogs of natural cytotoxic antibiotics, which offers more structural flexibility involves de novo synthesis of the glycosidic bond. Hence, aminosugar constituents of antibiotics have attracted considerable attention as synthetic targets.
  • the key step of the chemical synthesis of anthracycline antibiotics is the formation of the glycosidic bond between anthracycline aglycone and suitable protected aminosugar derivative (glycosyl donor) in the presence of appropriate activating agents (glycosylation promotore) .
  • suitable protected aminosugar derivative glycosyl donor
  • activating agents glycosylation promotore
  • L-acosmine and L-daunosamine are unusual, when compared to most common natural carbohydrates.
  • the L-configuration, absence of hydroxyl groups at positions 2, 3, and 6 and presence of amino group at position 3 considerably limit the choice of starting materials for the synthesis.
  • the configuration of 4-hydroxyl group is axial for L-daunosamine, and equatorial for L-acosamine.
  • Jpn., 59, 1986, 663-664 consists of condensation of hydrazoic acid to the 3, 4-di-O-acetyl-L- rhamnal and subsequent reduction of obtained azide derivative followed by protection of amino group.
  • the L-daunosamine derivative can be obtained according to the same method by subsequent inversion of configuration of C-4 hydroxyl group via oxidation and stereoselective reduction of obtained ketone, or via nucleophilic substitution of active derivative of C-4 hyroxyl group (Synlett., 1995, 272-274).
  • the low stereoselectivity of the condensation of hydrazoic acid to L- rhamnal is the main disadvantage of above methods .
  • L-daunosamine derivative from natural sources known in the art consist of appropriate protection of 3' -amino and/or 4 ' -hydroxy groups in daunomycin (from fermentation process), solvolysis of glycosidic bond and conversion of obtained L-daunosamine derivative into active glycosyl donor (e.g. bromide) .
  • the present invention resolves the problem of stereoselective introduction of protected amino group into the 4
  • the invention provides the new N-alkyloxycarbonyl derivatives of L-acosaminal of formula 3, wherein R' is a protecting group, such as alkyl, alkylcarbonyl, alkylsilyl or alkilarylsilyl group, and R is alkyl, alcoxyalkyl, allyl or arylalkyl group optionally substituted by halogen atom.
  • R is an allyl group.
  • the invention also includes a method of preparation of N- alkyloxycarbonyl derivatives of L-acosaminal of formula 3 comprising transformation of L-rhamnal derivative of the general formula 1 into 2, 3-unsaturated pyranoside by the Ferrier rearangement reaction and, after separation, further reaction with reactive isocyanate.
  • the acosaminal derivative of the general formula 3 may further be transformed to the glycoside of the formula 4 by subsequent glycosylation reaction, using glycosyl acceptor in the presence of an acidic promotore.
  • the acosaminal intermediate 3 may be next used to prepare N- alkyloxycarbonyl derivatives of daunosaminal of formula 8, wherein R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom and R 3 is alkylcarbonyl or arylcarbonyl group, optionally substituted with halogen atom.
  • R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom and R 3 is alkylcarbonyl or arylcarbonyl group, optionally substituted with halogen atom.
  • Another aspect of the invention is the use of the above mentioned N-alkyloxycarbonyl derivatives of acosaminal of formula 3 for the preparation of (thio) glycosides of daunosamine by two different methods involving inversion of configuration at C-4 of acosaminal. 5
  • the method of preparation of (thio) glycosides of daunosamine comprises the steps of deprotection of the acosaminal derivative of the general formula 3, yielding hydroxy derivative of the general formula 5; further reaction with alkyl- or aryl sulphonyl chloride and (A) glycosylation reaction of acosaminal derivative of the general formula 6 with the glycosyl acceptor in the presence of an acidic promotore, separation of yielding product of the general formula of 7 and nucleophilic substitution reaction with the salt of alkyl- or aryl carboxylic acid yielding desired daunosamine derivative of the general formula 8; or comprising (B) conversion of the acosaminal sulfonyl ester 6 into a (thio) glycoside before carrying out the nucleophilic displacement reaction.
  • L-daunosamine derivatives of formula 8 and 9 are versatile chiral synthons, which can be directly applied as daunosamine glycosyl donor.
  • the scope of the invention further comprises the use of glycals of formula 8 and (thio) glycosides of daunosamine of formula 9 for the preparation of anthracycline antibiotics.
  • New N-alkyloxycarbonyl derivatives of acosaminal are of the general formula 3, wherein R* is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group;
  • R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom.
  • New derivatives are of the proper configuration of the sugar moiety for further preparation of the analogs of Epirubicin.
  • Especially useful in the synthesis of semisynthetic analogs of antibiotics are the derivatives of acosaminal of formula 3, wherein R' is a protecting group as defined above and R is allyl, such as 4-0-acetyl-3-amine-3-N-allyloxycarbonyl-l, 2, 3, 6- 6 tetradeoxy-L-ara ⁇ ino-hex-1-enopyranose.
  • Allyloxycarbonylamino group at the position C-4 of the sacharide may be conveniently deprotected in the presence of Pd complexes in the next steps of the process.
  • the method of preparation of N-alkyloxycarbonyl derivatives of acosaminal of the general formula 3, wherein R' is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group; R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom, comprises the reaction of L-rhamnal derivative of the general formula 1 with an alcohol of the formula ROH, known in the art as the Ferrier rearangement reaction (J.Chem. Soc. , 1969, p.570).
  • the reaction is carried out in the aprotic solvent in the presence of a Lewis acid-type catalyst, e.g. tin tetrachloride or trifluoroboride e
  • the crude mixture of 2, 3-unsaturated pyranosides of the general formula 2 is reacted with reactive isocyanate consisting electronwithdrawing substituent, especially chlorosulphonyl isocyanate.
  • the reaction is carried out in an aprotic solvent, such as dichloromethane, toluene, acetonitrile, ethyl ether, methyl- t-buthyl ether, dioxan, tetrahydrofuran or the mixture thereof, especially in dioxan or tetrahydrofuran.
  • the isocyanate adduct is separated by hydrolysis in the aqueous solution of basic and reducing salts, especially in sodium bicarbonate and potassium iodide solution and then extracted with organic solvent.
  • organic solvent ethyl acetate may be used.
  • the acosaminal derivative of the general formula 3 may further be transformed to the glycoside of the formula 4 by subsequent glycosylation reaction, using glycosyl acceptor in the presence of an acidic promotore.
  • glycosylation are known for the persons skilled in the art. The methods and conditions of the reactions are described by for 7 example V.Bollit, C.Mioskowski, J. Org. Chem. , 1990, 55, p.5812).
  • RiXH As a glycosyl acceptor the compound of formula RiXH, wherein Ri is Ci-Ce alkyl, aryl, alkylaryl group optionally substituted with halogen atoms, nitro-, alkyl-, alkoxyl- groups or daunomycinon-7-yl is applied.
  • the reaction is carried out in a aprotic solvent, such as dichloromethane, toluene, acetonitrile, diethyl ether, methyl- t-buthyl ether or the mixture thereof.
  • a aprotic solvent such as dichloromethane, toluene, acetonitrile, diethyl ether, methyl- t-buthyl ether or the mixture thereof.
  • the organic compound of phosphor as a glycosylation promotor is applied.
  • the acosaminal intermediate 3 may also be converted into (thio) glycosides of N-alkyloxycarbonyl derivatives of daunosamine of the general formula 9, wherein R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom; Rx is C ⁇ C 6 alkyl, aryl, alkylaryl group, optionally substituted with halogen atoms, nitro-, alkyl- and alkoxyl- groups; R 3 is alkylcarbonyl or arylcarbonyl group, optionally substituted with halogen atom; X means oxygen or sulphur atom, by the method comprising deprotection of the acosaminal derivative of the formula 3, reaction of yielding hydroxy derivative of the general formula 5 with alkyl- or arylsulphonyl chloride and (A) : glycosylation of acosaminal derivative of the general formula 6 with the glycosyl acceptor of the general formula R
  • the step of deprotection is carried out in the presence of basic reagent chosen from the group consisting of amines, salts, hydroxides and alkyl alcoholates. Especially, triethylamine, potassium carbonate or sodium methanolate is chosen.
  • the deprotection step is carried out in alcohol, water, or a mixture of water and water-soluble solvent.
  • Acosaminal derivative of the general formula 5 is then sulphonylated by the use of alkyl- or aryl-, optionally substituted by halogen atoms, by sulphonyl chloride or sulphonyl anhydride, especially with methanesulphonyl chloride, or methanesulphonyl anhydride.
  • the sulphonylation reaction is carried out in the presence of a basic compound, chosen from the group consisting of amines, hydroxides, or basic salts in an aprotic solvent.
  • a basic compound chosen from the group consisting of amines, hydroxides, or basic salts in an aprotic solvent.
  • a basic compound triethylamine, pyridine or sodium bicarbonate is applied.
  • 4-O-sulphonyl derivative of protected l-acosaminal derivative of formula 6 is then reacted with an oxygen nucleophile, such as carboxilic acid salt, where an acid can contain an alkyl, alkenyl, optionally substituted with halogen atom, especially cesium acetate and cesium 4-nitrobenzoate.
  • an oxygen nucleophile such as carboxilic acid salt, where an acid can contain an alkyl, alkenyl, optionally substituted with halogen atom, especially cesium acetate and cesium 4-nitrobenzoate.
  • Aprotic solvent is used for nucleophilic substitution reaction, especially dimethylformamide or dimethylsulphoxide .
  • Displacement of a sulfonyl ester group by an oxygen nucleophile has been known to proceed with difficulty in case of many pyranosyl substrates. Additionally, possibility of intramolecular participation by vicinal amino group or pyranoside ring oxygen, can lead to various side products. Unexpectedly, we have found reaction conditions, under which direct displacement of a 4-sulfonyl esters can be performed. The reaction is stable and amenable for a scale up.
  • glycosylation is carried out in aprotic solvent, such as dichloromethane, toluene, acetonitrile, diethyl ether, methyl-t-butyl ether or the mixture thereof, in the presence of organic phosphorous derivative as glycosylation promotore.
  • aprotic solvent such as dichloromethane, toluene, acetonitrile, diethyl ether, methyl-t-butyl ether or the mixture thereof.
  • organic phosphorous derivative as glycosylation promotore.
  • triphenylphosphine hydrobromide is used as glycosylation promotore in step (A) .
  • the second method of preparation of (thio) glycosides of N- alkyloxycarbonyl derivatives of daunosamine of the general formula 9 comprises the steps of conversion of the acosaminal sulfonyl ester of formula 6 into a glycoside or thioglycoside first, and carrying out the nucleophilic displacement reaction.
  • Acosaminal of formula 6 is converted to daunosaminal of formula 8 with metal, or ammonium salt of carboxylic acid, optionally substituted with alkyl or aryl, halogen atoms, nitro-, alkyl- and alkoxy- groups as the nucleophilic reagent.
  • Cesium acetate or cesium 4-nitrobenzoate is used as the nucleophilic reagent in step (B) .
  • the nucleophilic substitution reaction is carried out in the aprotic solvent, especially dimethylformamide or dimethylsulphoxide .
  • the daunosaminal of formula 8 is combined with the compound of the general formula R]XH as glycosyl acceptor in the glycosylation reaction in step (B) .
  • glycosylation promotore organic phosphorous derivative is used, especially triphenylphosphine hydrobromide.
  • the reaction is carried out in an aprotic solvent, such as dichloromethane, toluene, acetonitrile, diethyl ether, methyl-t-buthyl ether, dimethylformamide, dimethylsulphoxide or the mixture thereof, in the presence of acidic catalyst, especially triphenylphosphine hydrobromide. 10
  • the method of the invention allows to obtain anomerically pure (thio) glycosides of daunosamine without any need of further anomers distribution.
  • (Thio) glycosides of daunosamine are particularly useful as stable, versatile chiral synthons, which can be directly applied as daunosamine glycosyl donors .
  • the resulting solution was stirred for 24 h. at room temperature.
  • the mixture was diluted with dichloromethane (20 mL) and was poured into stirred saturated aqueous NaHC0 3 .
  • Organic layer was separated and the water layer was extracted with dichloromethane (2 x 25 mL) . Combined organic layers were washed with water, dried and concentrated.

Abstract

The invention provides the new N-alkyloxycarbonyl derivatives of acosaminal of the general formula (3) and N-alkyloxycarbonyl derivatives of daunosaminal of the formula (8), the methods of their preparation and their use for the preparation of the anthracycline antibiotics.

Description

New N-alkyloxycarbonyl derivatives of monosacharides L- acosamine and L-daunosamine
The invention relates to the new N-alkyloxycarbonyl derivatives of monosacharides L-acosamine and L-daunosamine, the method of preparation thereof and their use for the preparation of the anthracycline antibiotics.
Background of the invention
Natural anthracycline antibiotics (Daunomycin, Doxorubicin) and their clinically useful semisynthetic analogs (Epirubicin, Idarubicin) are believed to exert their cytotoxic action mainly through DNA intercalation, but it is well known, that a sugar moiety which does not engage directly in such process, is indispensible for their activity. Prototype anthracycline antibiotics are manufactured by fermentation, but significance of chemical synthesis is growing with successful clinical trials and launches of new analogs. One of principal approaches to new analogs of natural cytotoxic antibiotics, which offers more structural flexibility involves de novo synthesis of the glycosidic bond. Hence, aminosugar constituents of antibiotics have attracted considerable attention as synthetic targets.
The key step of the chemical synthesis of anthracycline antibiotics is the formation of the glycosidic bond between anthracycline aglycone and suitable protected aminosugar derivative (glycosyl donor) in the presence of appropriate activating agents (glycosylation promotore) . The broad spectrum of synthetic glycosylation methods, protection and deprotection of functional groups makes the synthetic approach more 2 effective for preparation of modified anthracycline antibiotic analogs. The critical point of above strategy is availability of conveniently protected aminosugar derivatives suitable for glycosylation reaction. In the known methods of anthracycline antibiotics synthesis anomeric halogenides, 1-O-silyl ethers, 1-O-esters and glycals with conveniently protected 3-amino group, are commonly used as glycosyl donors. Basic hydrolysis is the most commonly used method for deprotection of 3-amino derivatives. These methods were reviewed by K. Toshima and K. Tatsuta: Recent Progress in O-Glycosylation Methods and its Application to Natural Product Synthesis, Chem. Rev. 1993, 93, 1503-1531.
A number of synthetic methods for preparation of L- acosamine and L-daunosamine have been described in original chemical literature and critically reviewed in some monographs
(I.F. Pelyvas et al., Synthetic Aspects of Aminodeoxy Sugars of
Antibiotics, Springer Verlag, Berlin, 1988; L.A. Otsooma et al. Progr. Chem. Org. Natur. Prod. v. 74, 197, (1998); and the references cited therein) . The structures of L-acosmine and L-daunosamine are unusual, when compared to most common natural carbohydrates. The L-configuration, absence of hydroxyl groups at positions 2, 3, and 6 and presence of amino group at position 3 considerably limit the choice of starting materials for the synthesis. The configuration of 4-hydroxyl group is axial for L-daunosamine, and equatorial for L-acosamine.
Derivatives of D-mannose and L-rhamnose are used for known methods of both aminosugars synthesis.
The method of synthesis of L-acosamine from D-mannose as starting material described in the literature (Carbohydr. Res. 44, 1975, 227-240) consists of selective oxidation of 3- hydroxyl group, conversion of corresponding ketone into the oxyme, stereoselective reduction and protection of obtained 3 amino group. Successive steps consist removal of the C-6 hydroxyl group, reverse of configuration of C-4 hydroxyl group and removal of C-2 hydroxyl group. This method is multistep, time-consuming and low effective. Other method of synthesis of L-acosamine from L-rhamnose described in the literature (J. Chem. Soc. Comm., 13(24), 1987, 1171-1172, Bull. Chem. Soc. Jpn., 59, 1986, 663-664) consists of condensation of hydrazoic acid to the 3, 4-di-O-acetyl-L- rhamnal and subsequent reduction of obtained azide derivative followed by protection of amino group. The L-daunosamine derivative can be obtained according to the same method by subsequent inversion of configuration of C-4 hydroxyl group via oxidation and stereoselective reduction of obtained ketone, or via nucleophilic substitution of active derivative of C-4 hyroxyl group (Synlett., 1995, 272-274). The low stereoselectivity of the condensation of hydrazoic acid to L- rhamnal is the main disadvantage of above methods .
The methods of preparation of L-daunosamine derivative from natural sources known in the art consist of appropriate protection of 3' -amino and/or 4 ' -hydroxy groups in daunomycin (from fermentation process), solvolysis of glycosidic bond and conversion of obtained L-daunosamine derivative into active glycosyl donor (e.g. bromide) .
Though the known methods are very ingenious, in general they lack technical feasibility (e.g. exotic or expensive reagents, difficult reaction conditions, low selectivity and difficult separations, poor yields etc.) and consequently these important and much sought materials are absent from the market of pharmaceutical intermediates and even chemical reagents.
Summary of the invention
The present invention resolves the problem of stereoselective introduction of protected amino group into the 4
C-3 position of L-carbohydrate derivative easy available from natural sources and the application of obtained active glycosyl donors for the preparation of their glycosides, including anthracycline antibiotics. The invention provides the new N-alkyloxycarbonyl derivatives of L-acosaminal of formula 3, wherein R' is a protecting group, such as alkyl, alkylcarbonyl, alkylsilyl or alkilarylsilyl group, and R is alkyl, alcoxyalkyl, allyl or arylalkyl group optionally substituted by halogen atom. In the specific embodiment of the invention R is an allyl group.
The invention also includes a method of preparation of N- alkyloxycarbonyl derivatives of L-acosaminal of formula 3 comprising transformation of L-rhamnal derivative of the general formula 1 into 2, 3-unsaturated pyranoside by the Ferrier rearangement reaction and, after separation, further reaction with reactive isocyanate.
The acosaminal derivative of the general formula 3 may further be transformed to the glycoside of the formula 4 by subsequent glycosylation reaction, using glycosyl acceptor in the presence of an acidic promotore.
The acosaminal intermediate 3 may be next used to prepare N- alkyloxycarbonyl derivatives of daunosaminal of formula 8, wherein R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom and R3 is alkylcarbonyl or arylcarbonyl group, optionally substituted with halogen atom. These daunosaminal derivatives also are in the scope of the invention.
Another aspect of the invention is the use of the above mentioned N-alkyloxycarbonyl derivatives of acosaminal of formula 3 for the preparation of (thio) glycosides of daunosamine by two different methods involving inversion of configuration at C-4 of acosaminal. 5
The method of preparation of (thio) glycosides of daunosamine comprises the steps of deprotection of the acosaminal derivative of the general formula 3, yielding hydroxy derivative of the general formula 5; further reaction with alkyl- or aryl sulphonyl chloride and (A) glycosylation reaction of acosaminal derivative of the general formula 6 with the glycosyl acceptor in the presence of an acidic promotore, separation of yielding product of the general formula of 7 and nucleophilic substitution reaction with the salt of alkyl- or aryl carboxylic acid yielding desired daunosamine derivative of the general formula 8; or comprising (B) conversion of the acosaminal sulfonyl ester 6 into a (thio) glycoside before carrying out the nucleophilic displacement reaction.
The resulting L-daunosamine derivatives of formula 8 and 9 are versatile chiral synthons, which can be directly applied as daunosamine glycosyl donor. The scope of the invention further comprises the use of glycals of formula 8 and (thio) glycosides of daunosamine of formula 9 for the preparation of anthracycline antibiotics.
Detailed description of the invention
New N-alkyloxycarbonyl derivatives of acosaminal are of the general formula 3, wherein R* is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group;
R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom.
New derivatives are of the proper configuration of the sugar moiety for further preparation of the analogs of Epirubicin. Especially useful in the synthesis of semisynthetic analogs of antibiotics are the derivatives of acosaminal of formula 3, wherein R' is a protecting group as defined above and R is allyl, such as 4-0-acetyl-3-amine-3-N-allyloxycarbonyl-l, 2, 3, 6- 6 tetradeoxy-L-araώino-hex-1-enopyranose.
Allyloxycarbonylamino group at the position C-4 of the sacharide may be conveniently deprotected in the presence of Pd complexes in the next steps of the process. The method of preparation of N-alkyloxycarbonyl derivatives of acosaminal of the general formula 3, wherein R' is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group; R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom, comprises the reaction of L-rhamnal derivative of the general formula 1 with an alcohol of the formula ROH, known in the art as the Ferrier rearangement reaction (J.Chem. Soc. , 1969, p.570). The reaction is carried out in the aprotic solvent in the presence of a Lewis acid-type catalyst, e.g. tin tetrachloride or trifluoroboride eterate.
The crude mixture of 2, 3-unsaturated pyranosides of the general formula 2 is reacted with reactive isocyanate consisting electronwithdrawing substituent, especially chlorosulphonyl isocyanate. The reaction is carried out in an aprotic solvent, such as dichloromethane, toluene, acetonitrile, ethyl ether, methyl- t-buthyl ether, dioxan, tetrahydrofuran or the mixture thereof, especially in dioxan or tetrahydrofuran. The isocyanate adduct is separated by hydrolysis in the aqueous solution of basic and reducing salts, especially in sodium bicarbonate and potassium iodide solution and then extracted with organic solvent. As organic solvent ethyl acetate may be used.
The acosaminal derivative of the general formula 3 may further be transformed to the glycoside of the formula 4 by subsequent glycosylation reaction, using glycosyl acceptor in the presence of an acidic promotore. The methods of glycosylation are known for the persons skilled in the art. The methods and conditions of the reactions are described by for 7 example V.Bollit, C.Mioskowski, J. Org. Chem. , 1990, 55, p.5812).
As a glycosyl acceptor the compound of formula RiXH, wherein Ri is Ci-Ce alkyl, aryl, alkylaryl group optionally substituted with halogen atoms, nitro-, alkyl-, alkoxyl- groups or daunomycinon-7-yl is applied.
The reaction is carried out in a aprotic solvent, such as dichloromethane, toluene, acetonitrile, diethyl ether, methyl- t-buthyl ether or the mixture thereof. The organic compound of phosphor as a glycosylation promotor is applied. The acosaminal intermediate 3 may also be converted into (thio) glycosides of N-alkyloxycarbonyl derivatives of daunosamine of the general formula 9, wherein R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom; Rx is Cι~C6 alkyl, aryl, alkylaryl group, optionally substituted with halogen atoms, nitro-, alkyl- and alkoxyl- groups; R3 is alkylcarbonyl or arylcarbonyl group, optionally substituted with halogen atom; X means oxygen or sulphur atom, by the method comprising deprotection of the acosaminal derivative of the formula 3, reaction of yielding hydroxy derivative of the general formula 5 with alkyl- or arylsulphonyl chloride and (A) : glycosylation of acosaminal derivative of the general formula 6 with the glycosyl acceptor of the general formula Rj.XH in the presence of an acidic promotore, separation of yielding product of the general formula 7 and its nucleophilic substitution with the salt of alkyl- or aryl carboxylic acid, or (B) : nucleophilic substitution of acosaminal derivative of the general formula 6 with the nucleophilic reagent (salt of alkyl- or aryl carboxylic acid) and glycosylation reaction of daunosaminal derivative of the general formula 8 with the glycosyl acceptor of the general formula Rj.XH in the presence of an acidic promotore, yielding desired product of the general formula 9. 8
The step of deprotection is carried out in the presence of basic reagent chosen from the group consisting of amines, salts, hydroxides and alkyl alcoholates. Especially, triethylamine, potassium carbonate or sodium methanolate is chosen. The deprotection step is carried out in alcohol, water, or a mixture of water and water-soluble solvent. Acosaminal derivative of the general formula 5 is then sulphonylated by the use of alkyl- or aryl-, optionally substituted by halogen atoms, by sulphonyl chloride or sulphonyl anhydride, especially with methanesulphonyl chloride, or methanesulphonyl anhydride. The sulphonylation reaction is carried out in the presence of a basic compound, chosen from the group consisting of amines, hydroxides, or basic salts in an aprotic solvent. As a basic compound triethylamine, pyridine or sodium bicarbonate is applied.
4-O-sulphonyl derivative of protected l-acosaminal derivative of formula 6 is then reacted with an oxygen nucleophile, such as carboxilic acid salt, where an acid can contain an alkyl, alkenyl, optionally substituted with halogen atom, especially cesium acetate and cesium 4-nitrobenzoate. Aprotic solvent is used for nucleophilic substitution reaction, especially dimethylformamide or dimethylsulphoxide .
Displacement of a sulfonyl ester group by an oxygen nucleophile, routinely applied for such purpose in organic sythesis, has been known to proceed with difficulty in case of many pyranosyl substrates. Additionally, possibility of intramolecular participation by vicinal amino group or pyranoside ring oxygen, can lead to various side products. Unexpectedly, we have found reaction conditions, under which direct displacement of a 4-sulfonyl esters can be performed. The reaction is stable and amenable for a scale up.
The obtained compound of formula 7 is a glycosyl donor, which TTIΛV h<=» rπmhi ΠPΓI in t-h<=» πl \/r:o<5\/l a t i <~>n rMrfinn with thf» 9 compound of the general formula RtXH used as glycosyl acceptor.
Such a reaction is known for the person skilled in the art.
(see e.g. Bolit, Mioskowski, J.Org.Chem., 1990, 55, p.5812).
The reaction of glycosylation is carried out in aprotic solvent, such as dichloromethane, toluene, acetonitrile, diethyl ether, methyl-t-butyl ether or the mixture thereof, in the presence of organic phosphorous derivative as glycosylation promotore. Especially, triphenylphosphine hydrobromide is used as glycosylation promotore in step (A) . The second method of preparation of (thio) glycosides of N- alkyloxycarbonyl derivatives of daunosamine of the general formula 9 according to the invention, comprises the steps of conversion of the acosaminal sulfonyl ester of formula 6 into a glycoside or thioglycoside first, and carrying out the nucleophilic displacement reaction. Acosaminal of formula 6 is converted to daunosaminal of formula 8 with metal, or ammonium salt of carboxylic acid, optionally substituted with alkyl or aryl, halogen atoms, nitro-, alkyl- and alkoxy- groups as the nucleophilic reagent. Cesium acetate or cesium 4-nitrobenzoate is used as the nucleophilic reagent in step (B) .
The nucleophilic substitution reaction is carried out in the aprotic solvent, especially dimethylformamide or dimethylsulphoxide .
Then the daunosaminal of formula 8 is combined with the compound of the general formula R]XH as glycosyl acceptor in the glycosylation reaction in step (B) . As glycosylation promotore organic phosphorous derivative is used, especially triphenylphosphine hydrobromide. The reaction is carried out in an aprotic solvent, such as dichloromethane, toluene, acetonitrile, diethyl ether, methyl-t-buthyl ether, dimethylformamide, dimethylsulphoxide or the mixture thereof, in the presence of acidic catalyst, especially triphenylphosphine hydrobromide. 10
The method of the invention allows to obtain anomerically pure (thio) glycosides of daunosamine without any need of further anomers distribution. (Thio) glycosides of daunosamine are particularly useful as stable, versatile chiral synthons, which can be directly applied as daunosamine glycosyl donors .
The use of glycals in the synthesis of biologically important glycosides is reviewed by P.H. Seeberger et al., Aldrichim. Acta, 30, 75 (1997). Additional references can be found in: D.Y. Gin et al., J. Am. Chem. Soc, 120, 13515 (1998). The following examples are provided to further define the invention without, however, limiting the scope of the invention.
Example I . 4-0-Acetyl-3-amine-3-N-allyloxycarbonyl-l, 2, 3, 6-tetradeoxy-L- araJbino-hex-1-enopyranose ( -0-acetyl-3-N-allyloxycarbonyl-L- acosaminal) 3 (R = allyl, R' = acetyl) :
Allyl alcohol (12 mL) and tin tetrachloride (mol 5%.) were added to the solution of 3, 4-di-O-acetyl-L-rhamnal 1 (25 g) in dichloromethane (100 mL) at 0°C and the mixture was stirred for 12 h. at room temperature. The mixture was diluted with dichloromethane (200 mL) and was poured into stirred saturated aqueous NaHC03 . Organic layer was separated and the water layer was extracted with dichloromethane (2 x 100 mL) . Combined organic layers were washed with water, dried and concentrated. Crude compound 2 (R = allyl, R' = acetyl) was dissolved in dry dichloromethane (50 mL) and chlorosulphonyl isocyanate (1.2 eq. ) was added at 0°C. Resulted mixture was stirred at 0°C for additional 1 h. and then poured into stirred aqueous solution of KI and NaHC03 . After 15 minutes the mixture was extracted with ethyl acetate (3 x 50 mL) . Combined organic layers were washed with water, dried and concentrated. The residue was crystalized (hexane and ethyl acetate) affording compound 3 (R 11 = allyl, R' = acetyl) in 45 % yield. mp. = 103-104 °C; xti NMR, (200MHz), CDC13 δ: 6.35 (dd, J 1/2 5.9, J lι3 2.0, IH, H-
1), 5.9 ( , IH, -CH=) 5.26 (m, 2H, =CH2) , 4.80 (dd, J3f48.4, J4,5 9.7, IH, H-4), 4.67 (dd, J2(32.2, IH, H-2), 4.55 (m, 3H, NH, CH2 ami), 4.46 (m, J3,NH 8.8, IH, H-3), 4.04 (dq, J5,6 6.2, J4/5 9.7,
IH, H-5), 2.1 (s, 3H, Oac) , 1.28 (d, J5,66.2, 3H, H-6) .
Example II. 4-0-Acetyl-3-amine-3-N-benzyloxycarbonyl-l, 2,3, 6-tetradeoxy-L- arajbino-hex-1-enopyranose ( 4-0-acetyl-3-N-benzyloxycarbonyl-L- acosaminal) 3 (R = benzyl, R* = acetyl)
Operating as in Example I, but employing benzyl alkohol, compound 3 (R = benzyl, R' = acetyl) was obtained in 39 % yield as an oil.
LH NMR, (200MHz), CDC13 δ: 7.33 (m, 5H, Ph) , 6.34 (dd, J ι,25.9, J 1,31.9, IH, H-l), 5.9 (m, IH, -CH=) 5.08 (m, 2H, CH2Ph) , 4.80 (dd, J3r4 8.3, J4,5 9.5, IH, H-4), 4.65 (dd, J2,3 2.1, IH, H-2), 4.48 (m, J3,NH 8.2, IH, H-3), 4.03 (dq, J5,6 6.3, J4/5 9.5, IH, H- 5), 2.01 (s, 3H, Oac), 1.25 (d, J5t66.3, 3H, H-6) .
Example III.
4' -Methoxybenzyl 4-0-acetyl-3-N-allyloxycarbonyl-3-amine-2, 3, 6- trideoxy-α-L-arabino-hexopyranoside (4' -methoxybenzyl 4-0- acetyl-3-N-allyloxycarbonyl-α-L-acosaminide) 4 (R = allyl, X = O, R' = acetyl, Ri = 4-methoxybenzyl) :
4-Methoxybenzyl alcohol (25 mL) and triphenylphosphine hydrobromide (5% mol.) were added to the solution of compound 3 (R = allyl, R' = acetyl) (25 g) in dichloromethane (100 mL) . The resulting solution was stirred for 24 h. at room temperature. The mixture was then diluted with dichloromethane (200 mL) and poured into stirred saturated aqueous NaHC03. Organic layer was separated and the water layer was extracted 12 with dichloromethane (2 x 100 mL) . Combined organic layers were washed with water, dried and concentrated. The residue was purified at chromatography column yielding 78 % of compound 4 (R = allyl, X = O, R* = acetyl, R,. = 4-methoxybenzyl) , as an oil.
XH NMR, (200MHz), CDC13 δ: 7.12 (m, 4H, Ar) , 5.88 (m, IH, -CH=) , 5.26 (m, 2H, =CH2) , 5.01 (bd, J3/N„6.0, IH, NH) , 4.84 (dd, J 1#2a
3.5, J ι,2e <0.5, IH, H-l), 4.54 (m, 2H, CH2 auyι) , 4.48 (ABq, J,_ 11.5, 2H, CH2Ar), 4.24 (m, 2H, H-4, H-3), 3.95 (dq, J5(66.2, J4,5 9.2, IH, H-5), 2.23 (ddd, J 2e.2al3.0, J ι,2e<0.5, J 2θ(34.4, IH, H-2e), 2.01 (s, 3H, OAc) , 1.75 (ddd, J 2β,2a = J 2a,3 13.0, J 1>2a
3.6, , IH, H-2a), 1.32 (d, J5,66.2, 3H, H-6) .
Example IV. 3-N-Allyloxycarbonyl-3-amine-l, 2,3, 6-tetradeoxy-L-ara±ιino-hex- 1-enopyranose (3-N-allyloxycarbonyl-L-acosaminal) 5 (R = allyl) :
Potassium carbonate (25 mg) was added to the solution of compound 3 (R = allyl, R' = acetyl) (1 g) in methanol (20 mL) and the resulting mixture was stirred for 2 h. at room temperature. After neutralization with acetic acid the solvent was evaporated and the residue was dissilved in dichloromethane (50 ml) and washed with water. The organic layer was dried and concentrated yielding compound 5 (R = allyl) in quantitative yield.
XH NMR, (200MHz), CDC13 δ: 6.40 (dd, J 1(2 6.0, J ι,3 2.0, IH, H- 1), 5.91 (m, IH, -CH=) 5.29 (m, 2H, =CH2) , 4.60 (m, 2H, CH2 aim)/ 4.48 (dd, J2<32.0, IH, H-2), 4.30 (bs, IH, OH), 4.23 (m, 2H, NH, H-3), 3.84 (dq, J5/6 6.2, J4f5 9.7, IH, H-5), 3.42 (dd, J3,48.1, J4,59-7, IH, H-4), 1.40 (d, J5( 6.2, 3H, H-6) .
Example V. 3-N-Allyloxycarbonyl-3-amine-4-0-methanesulphonyl-l, 2,3,6- 13 tetradeoxy-L-araj ino-hex-1-enopyranose ( 3-N-allyloxycarbonyl-4-
O-methanesulphonyl-L-acosaminal ) 6 ( R = allyl, R2 methanesulphonyl) :
Pyridine (1.2 eq.) and methanesulphonyl chloride (1.2 eq.) were added to the solution of compound 5 (R = allyl) (5g) in dichloromethane (50 mL) at room temperature. The resulting mixture was stirred for 12 h. at room temperature. The mixture was poured into ice water and extracted with dichloromethane
(3 x 100 mL) . Combined organic layers were washed with water, dried and concentrated. The residue was crystalized (hexane/ethyl acetate), yielding 6 (84 %) . Mp. = 142-143.5 °C; lH NMR, (200MHz), CDC13 δ: 6.38 (dd, J 1/25.8, J lr3 1.5, IH, H- 1), 5.90 (m, IH, -CH=) 5.48 (bd, J3,NH 7.7, 1H,NH), 5.26 (m, 2H, =CH2), 4.67 (dd, J2,32.4, IH, H-2), 4.55 (m, 4H, H-3, H-4, CH2 aiiyi), 4.10 (dq, J5,e6.2, J4,52.5, IH, H-5), 3.12 (s, 3H, CH3S02) , 1.40 (d, J5,66.2, 3H, H-6) .
Example VI. Phenyl 3-N-allyloxycarbonyl-3-amine-4-0-methanesulphonyl-2, 3, 6- trideoxy-1-S-α-L-arajino-hexopyranoside (phenyl 4-0- methanesulphonyl-3-N-allyloxycarbonyl-l-S-α-L-acosaminide) 7 (R = allyl, Ri = phenyl R2 = methanesulphonyl, X = S) :
Thiophenol (2 eq.) and triphenylphosphine hydrobromide (mol 5%.) were added to the solution of compound 6 (R = allyl, R2 = methanesulphonyl) (95 g) in dichloromethane (800 mL) . The resulting mixture was stirred for 24 h. at -5°C. On the next day the mixture was poured into stirred saturated aqueous NaHC03. Organic layer was separated and the water layer was extracted with dichloromethane (2 x 500 mL) . Combined organic layers were washed with water, dried and concentrated. The residue was purified on chromatography column affording compound 7 (R = allyl, Ri = phenyl R2 = methanesulphonyl, X = S) 14 as an amorphous solid. lH NMR, (200MHz), CDC13 δ: 7.38 (m, 5H, Ar) , 5.89 (m, IH, -CH=) ,
5.55 (bd, J 1(2a 5.0, J lf2β <0.5, IH, H-l), 5.30 (m, 3H, NH,
=CH2), 4.58 (m, 2H, CH2 aUyι) , 4.43 (dq, J5,6 6.0, J4,58.8, IH, H- 5), 4.23 (m, 2H, H-4, H-3) , 3.06 (s, 3H, CH3S02) , 2.44 (ddd, J
2θ,2a 14.0, J ι,2β<0.5, J 2e,34.4, IH, H-2e) , 2.16 (ddd, J 2a,311.9,
J 1/2a5.5, J 2e,2al4.0, IH, H-2a), 1.32 (d, J5f66.1, 3H, H-6) .
Example VII. Phenyl 3-N-allyloxycarbonyl-3-amine-4-0-4' -nitrobenzoyl-2, 3, 6- trideoxy-l-S-a-L-lifcso-hexopyranoside (phenyl 3-N- allyloxycarbonyl-4-0-4' -nitrobenzoyl-1-S-α-L-daunosaminide) 9 (R = allyl, Ri = phenyl R3 = 4-nitrobenzoyl, X = S) : Method A. Cesium 4-nitrobenzoate (3 eq.) was added to the solution of compound 7 (R = allyl, Ri = phenyl R2 = methanesulphonyl, X = S) (2.5 g) in dimethlformamide (10 mL) . The resulting mixture was stirred for 24 h. at 90-100°C. After cooling down the mixture was poured into water and resulting solution was extracted with ethyl acetate. Combined organic layers were washed with water, dried and concentrated. The residue was purified by column chromatography yielding compound 9 (R = allyl, Rx = phenyl R = 4-nitrobenzoyl, X = S) as amorpous solid. LH NMR, (200MHz), CDC13 δ: 8.23 (m, 5H, Ar) , 7.15 (m, 4H, Ar) ,
5.88 (m, IH, -CH=) , 5.78 (dd, J x,2a .9, J 1(2e <0.5, IH, H-l), 5.26 (m, 2H, =CH2) , 5.01 (bd, J3,NH <5.0, IH, NH) , 4.84 (dd, J X 2a 3.5, J ι,2e <0.5, IH, H-l), 5.50 (bd, IH, H-4), 4.63 (m, 4H, H-5, NH, CH2 aiiyi)/ 4.41 (m,lH, H-3),2.33 (ddd, J 2e,2a 13.2, J l 2a 5.5, J 2a,3 13.0, IH, H-2a), 2.16 (ddd, J 2e,2a 13.8 J 2e,3 4.9, J 1(2e
<0.5, , IH, H-2e), 1.18 (d, J5,66.2, 3H, H-6) .
Method B. 15 Compound 9 (R = allyl, Ri = phenyl R3 = 4-nitrobenzoyl, X
= S) was also obtained using daunosaminal 8 (R = allyl, R3 = 4- nitrobenzoyl) as a substrate. Thiophenol (10 mL) and triphenylphosphine hydrobromide (5% mol.) were added to the solution of substrate 8 (R = allyl, R3 = 4-nitrobenzoyl) (5 g) in dichloromethane (50 mL) . The resulting mixture was stirred for 24 h. at room temperature. The mixture was poured into stirred saturated aqueous NaHC03 . Organic layer was separated and the water layer was extracted with dichloromethane (2 x 50 mL) . Combined organic layers were washed with water, dried and concentrated. The residue was purified by column chromatography yielding 63 % of compound 9 (R = allyl, Rx = phenyl R3 = 4- nitrobenzoyl, X = S) as above.
Example VIII.
3-N-Allyloxycarbonyl-amine-4-0-4' -nitrobenzoyl-1, 2,3,6- tetradeoxy-L-liJrso-hex-1-enopyranose (3-N-allyloxycarbonyl-4-0- 4' -nitrobenzoyl-L-daunosaminal) 8 (R = allyl, R3 = 4- nitrobenzoyl) : Cesium 4-nitrobenzoate (3 eq.) was added to the solution of compound 6 (R = allyl, R2 = methanesulphonyl) (2.5 g) in dimethlformamide (10 mL) . The resulting mixture was stirred for 10 h. at 125°C. After cooling down the mixture was poured into water and resulting solution was extracted with dichloromethane. Combined organic layers were washed with water, dried and concentrated. The residue was purified by column chromatography yielding compound 8 (R = allyl, R3 = 4- nitrobenzoyl) as an oil. IH NMR(200MHz) δ: 8.27 (m, 4H, Ar-C6H4) , 6.47 (dd, J 1#: 6.2, J ι,32.3, IH, H-l), 5.83 (m, IH, -CH=) , 5.58 (bd, J3(43.9, IH, H- 4), 5.22 (m, 2H, =CH2) , 4.60 (m, 5H, H-2, H-3, NH, CH2 allyl) , 4.31 (bq, J5(66.6, J4,5 < 0.5, IH, H-5), 1.28 (d, J5,66.6, 3H, H-* 6). 16
Example IX .
Daunomycinon-7-yl 4-0-acetyl-3-N-allyloxycarbonyl-3-amine- 2, 3, 6-trideoxy-α-L-ara ino-hexopyranoside (daunomycinon-7-yl 4- θ-acetyl-3-N-allyloxycarbonyl-α-L-acosaminide) 4 (R = allyl, X = 0, R' = acetyl, Ri = daunomycinon-7-yl) :
Daunomycinone (0,5 g) and triphenylphosphine hydrobromide (mol 5%.) were added to the solution of compound 3 (R = allyl, R' = acetyl) (1 g) in dichloromethane (20 mL) . The resulting solution was stirred for 24 h. at room temperature. The mixture was diluted with dichloromethane (20 mL) and was poured into stirred saturated aqueous NaHC03 . Organic layer was separated and the water layer was extracted with dichloromethane (2 x 25 mL) . Combined organic layers were washed with water, dried and concentrated. The residue was purified by column chromatography yielding compound 4 (R = allyl, X = O, R' = acetyl, Ri = daunomycinon-7-yl) , as an amorphous red powder. H NMR, (200MHz), CDC13 δ: 14.0, 13.3 (2 x s, 2 x IH, 6-OH, 11- OH), 8.2 (dd, J 1(2=8.2Hz, J 1#3=1.0Hz, IH, H-l), 7.79 (t, J lf 2 = J 2,3=8.2Hz, IH, H-2), 7.4 (dd, IH, H-3) , 5.99 (m, IH, -CH=) , 5.5 (d, J V lV =3.5Hz, IH, H-l'), 5.3-5.1 (m, 3H, =CH2, H-7), 5.05 (bd, IH, NH), 4.58-4.44 (m, 3H, -OCH2-, 9-OH) , 4.4-4.06 (m, 4H, -CH2-, H-4', H-5' ) , 4.08 (s, 3H, OMe) , 3.8 (m, IH, H- 3'), 3.25, 2.92 (ABq, J=19.4Hz, 2 x IH, 2 x H-10) , 2.5-2.14 (m, 2H, 2 x H-8), 2.08 (2 x s, 2 x 3H, 2 x Ac), 2.08, 1.65 (2 x m, 2 x IH, H-2'a, H-2'e), 1.22 (d, J5,6=6.2Hz, 3H, H-6' ) .

Claims

17Claims
1. New N-alkyloxycarbonyl derivatives of acosaminal of the general formula 3, wherein
R' is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group; R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom.
2. New N-alkyloxycarbonyl derivatives of acosaminal of the general formula 3, wherein
R' is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group; R is allyl.
3. 4-0-acetyl-3-amine-3-N-allyloxycarbonyl-l, 2,3,6- tetradeoxy-L-araJino-hex-1-enopyranose .
4. A process for the preparation of N-alkyloxycarbonyl derivatives of acosaminal of the general formula 3, wherein R' is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group and R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom, comprising the reaction of L-rhamnal derivative of the general formula 1 with an alcohol of the formula ROH by the Ferrier rearangement reaction and, after separation, further reaction of 2, 3-unsaturated pyranoside of the general formula 2 with reactive isocyanate and separation of the resulting product.
5. A process according to claim 4, in which isocyanate consisting electronwithdrawing substituent, especially chlorosulphonyl isocyanate is used.
6. A process according to claim 4 or 5, in which the product of the reaction with isocyanate is separated by hydrolysis and extraction with organic solvent.
7. A process according to any of the claims 4-6, in which the water solution of basic and reducing salts are used for the hydrolysis, preferable sodium bicarbonate and potassium iodide.
8. A process according to any of the claims 4-7, in which ethyl acetate is used for the extraction.
9. New N-alkyloxycarbonyl derivatives of daunosaminal of formula 8, wherein R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom;
R3 is alkyl- or arylcarbonyl group optionally substituted with halogen atom.
10. New (thio) glycosides of daunosamine of formula 9, wherein R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom;
Ri is C╬╣-C6 alkyl, aryl, alkylaryl group optionally substituted with halogen atoms, nitro-, alkyl- and alkoxyl- groups;
R3 is alkyl- or arylcarbonyl group optionally substituted with halogen atom;
X means oxygen or sulphur atom.
11. A method of preparation of (thio) glycosides of N- alkyloxycarbonyl derivatives of daunosamine of the general formula 9, wherein R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom;
Ri is Ci-Cg alkyl, aryl, alkylaryl group optionally substituted with halogen atoms, nitro-, alkyl- and alkoxyl- groups; R3 is alkyl- or arylcarbonyl group optionally substituted with halogen atom;
X means oxygen or sulphur atom, comprising deprotection of the acosaminal derivative of the formula 3, reaction of yielding hydroxy derivative of the general formula 5 with alkyl- or arylsulphonyl chloride and (A) glycosylation of acosaminal derivative of the general formula 6 with the glycosyl acceptor of the general formula RiXH in the presence of an acidic promotore, separation of yielding product of the general formula of 7 and its nucleophilic substitution with the salt of alkyl- or aryl carboxylic acid, or (B) nucleophilic substitution of acosaminal derivative of the general formula 6 with the salt of alkyl- or aryl carboxylic acid and glycosylation reaction of daunosaminal derivative of the general formula 8 with the glycosyl acceptor of the general formula RiXH in the presence of an acidic promotore yielding desired product of the general formula 9.
12. A method according to claim 11, in which the step of deprotection is carried in the presence of basic reagent chosen from the group consisting of amines, salts, hydroxides and alcoholates .
13. A method according to claim 11 or 12, in which alcohol, or water, or a mixture of water and water-soluble solvent is used as a solvent for the deprotection step.
14. A method according to any of the claims 11-13, in which acosaminal derivative of the general formula 5 is sulphonylated by the use of alkyl- or aryl-, also substituted by halogen atoms, suphonyl chloride or anhydride, especially with methanesulphonyl chloride or methanesulphonyl anhydride.
15. A method according to any of the claims 11-14, in which sulphonylation reaction is carried out in the presence of amine, hydroxide, or basic salt in an aprotic solvent.
16. A method according to any of claims 11-15, in which the compound of the general formula RxXH is used as glycosyl acceptor for the glycosylation reaction in step (A) .
17. A method according to any of the claims 11-16, in which organic phosphorous derivative is used as glycosylation promotore in step (A) .
18. A method according to any of the claims 11-17, in which triphenylphosphine hydrobromide is used as glycosylation promotore in step (A) .
19. A method according to any of the claims 11-18, in which aprotic solvent is used for glycosylation reaction in step (A) .
20. A method according to any of the claims 11-19, in which metal, or ammonium salt of carboxylic acid with alkyl or aryl substituent, also substituted with halogen atoms, nitro-, alkyl- and alkoxy- groups is used as the nucleophilic reagent in step (A) .
21. A method according to any of the claims 11-20, in which cesium acetate is used as the nucleophilic reagent in step (A) .
22. A method according to any of the claims 11-20, in which cesium 4-nitrobenzoate is used as the nucleophilic reagent in step (A) .
23. A method according to any of the claims 11-20, in which aprotic solvent is used for nucleophilic substitution reaction, especially dimethylformamide, or dimethylsulphoxide.
24. A method according to any of claims 11-20, in which metal, or ammonium salt of carboxylic acid with alkyl or aryl substituent, also substituted with halogen atoms, nitro-, alkyl- and alkoxy- groups is used as the nucleophilic reagent in step (B) .
25. A method according to any of the claims 11-23, in which cesium acetate is used as the nucleophilic reagent in step (B) .
26. A method according to any of the claims 11-23, in which cesium 4-nitrobenzoate is used as the nucleophilic reagent in step (B) .
27. A method according to any of the claims 11-24, in which aprotic solvent is used for nucleophilic substitution reaction in step (B) , especially dimethylformamide, or dimethylsulphoxide .
28. A method according to claim 11 in which the compound of the general formula RiXH is used as glycosyl acceptor for the glycosylation reaction in step (B) .
29. A method according to claim 11, in which organic phosphorous derivative is used as glycosylation promotore in step (B) .
30. A method according to claim 11, in which triphenylphosphine hydrobromide is used as glycosylation promotore in step (B) .
31. A method according to claim 11, in which aprotic solvent is used for glycosylation reaction in step (B) .
32. The use of the acosaminal derivatives according to claim 1 for the preparation of N-alkyloxycarbonyl
(thio) glycosides of acosamine of formula 4, wherein R and R' have the above mentioned meaning and Rx is R╬╗ is C!-C6 alkyl, aryl, alkylaryl group optionally substituted with halogen atoms, nitro-, alkyl-, alkoxyl- groups or daunomycinon-7-yl, X means oxygen or sulphur atom, by the method of glycosylation using glycosyl acceptor of the formula RXXH in the presence of an acidic promotore.
33. The use of N-alkyloxycarbonyl derivatives of acosaminal of the general formula 3, wherein
R' is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group;
R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom, for the preparation of N-alkyloxycarbonyl derivatives of daunosamine of the general formula 8 according to claim 9.
34. The use of N-alkyloxycarbonyl derivatives of acosaminal of the general formula 3, wherein
R' is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group;
R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom according to claim 1 for the preparation of anthracycline antibiotics.
35. The use of N-alkyloxycarbonyl derivatives of acosaminal of the general formula 3, wherein
R' is a protecting group, especially alkyl, alkylcarbonyl, alkylsilil or arylalkylsilyl group;
R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom, for the preparation of (thio) glycosides of N-alkyloxycarbonyl derivatives of daunosamine of the general formula 9 according to claim 14.
36. The use of N-alkyloxycarbonyl derivatives of daunosaminal of formula 8, wherein R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom;
R3 is alkyl- or arylcarbonyl group optionally substituted with halogen atom, according to claim 9 for the preparation of anthracycline anibiotics.
37. The use of (thio) glycosides of N-alkyloxycarbonyl derivatives of daunosamine of the general formula 9, wherein R is alkyl, alkoxyl, allyl or arylalkyl group, optionally substituted with halogen atom;
Rx is C╬╣-C6 alkyl, aryl, alkylaryl group optionally substituted with halogen atoms, nitro-, alkyl- and alkoxyl- groups;
R3 is alkyl- or arylcarbonyl group optionally substituted with halogen atom, X is oxygen or sulphur atom, according to the claim 10 for the preparation of anthracycline antibiotics.
PCT/PL1999/000015 1998-05-13 1999-05-12 New n-alkyloxycarbonyl derivatives of monosaccharides l-acosamine and l-daunosamine WO1999058543A1 (en)

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PL98326262A PL187092B1 (en) 1998-05-13 1998-05-13 Method of manufacturing of glycales and/or glycosides of n-alkiloxycarbonyl derivatives of daunosamine
PLP.326263 1998-05-13
PL98326263A PL188127B1 (en) 1998-05-13 1998-05-13 Method of manufacturing of thioglycosides of n-alkiloxycarbonyl derivatives of l-daunosamine
PL98326261A PL187153B1 (en) 1998-05-13 1998-05-13 Method of manufacturing of glycosides of n-alkiloxycarbonyl derivatives of l-acosamine
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CN102391325A (en) * 2011-09-27 2012-03-28 华东师范大学 Method for preparing 4,6-dibenzyl 2,3-unsaturated glucoside
CN102603820A (en) * 2012-02-16 2012-07-25 华东师范大学 Preparation method of 4, 6-dibenzyl 2, 3-unsaturated glucoside
CN108525664A (en) * 2018-03-28 2018-09-14 华东师范大学 A kind of preparation and its application of magnetic Nano nucleocapsid catalyst

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