Methods of obtaining aminoalkylglucosaminidphosphates and disaccharide immunoeffectors and their intermediate compounds

FIELD: chemistry.

SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.

EFFECT: method improvement.

11 cl, 3 ex

 

Cross-reference to related applications This application has priority on the continued application US 60/394487 filed 08.07.02, Indicated continued application is related to US No. 10/137730 filed 30.04.02, which is a partial continuation of US No. 10/043089 filed 08.01.2002, which is a partial continuation of US No. 09/905106 filed 12.07.2001, which is a partial continuation of US No. 09/439839 filed 12.11.1999,, now patent US 6303347, which is a partial continuation of US No. 08/853826 filed 08.05.1997,, now patent US 6113918. The present application also relates to US 09/074720 filed 07.05.1998, to US 6355257, which is a partial continuation of US No. 853826. This application also has the priority application US 60/438585 filed 06.05.2003, All of these patents and references are incorporated into the present application as reference, in their entirety.

The technical field to which the invention relates.

The present invention relates to processes of acquiring aminoalkylindole (AGP) and disaccharide glycosides compounds. Such compounds are disclosed as immunoaffinity, adjuvants for vaccines, and the like, and, in addition, they can have their own therapeutic and/or prophylactic properties. Further, the present invention relates to processes for glycosylating compounds that can serve as PR the intermediate compounds in the synthesis AGP's compounds, disaccharides and related molecular structure.

The level of technology

Aminoalkylindole described in several patents, patent applications and journal articles. Such compounds usually have five or six of the acyl groups in the structure of the molecule, together with the "aglycone" (nitrogen), which may be cyclic or acyclic. AGP's with acyclic aglionby groups are disclosed, for example, in US 6113918; 6303347 and 6355257. AGP's, which is cyclical aglionby groups are disclosed, for example, in WO 02/012258.

The above-mentioned documents describe getting AGP compounds in two alternative ways. In the same way protected 3-O-allocationally glycosylated containing phosphonate side chain, condense with aminoalcohols or aminoalcohols of the type described in the patents. The reaction product is then selectively alleroed to provide additional acyl groups, as described, and the protective groups are removed. In the second way and phosphonate side chain, and fatty acid groups introduced after the condensation reaction. For more information about how to get the AGP compounds contained in Johnson et al., Bioorg. Med. Chem. Lett. 9: 2273 (1999).

Disaccharides that can be obtained using the methods described in this application includes components well known is immunostimulator of monophosphorylated And contained, for example, in MPL® immunostimulant (Corixa Corp.). Other disaccharides that can be accessed, disclosed, for example, in PCT WO 01/90129 and US 6013640; 4987237; 4912094; 4436727 and 4436728. In the US 6103640 disaccharide obtained by condensation of N-allocationand or N-protected glycosylase acceptor link with protected and/or 3-O-allocationand Picatinny donor element. The protective group is benzyl (Bn) and 2,2,2-trichlorocarbanilide (Troc) group. Picatinny acceptor and donor units formed separately using a series of steps to protect and unprotect a Deputy, starting from known initial products benzyl - 2-(trimethylsilyl)ethyl-2-amino-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside, respectively.

Glycosylated used in many processes in the chemistry of sugars, for the introduction of glycosidic residue in the molecule, usually as part of a multi-stage synthesis. They are useful intermediate compounds for the introduction of a large number of groups, usually by reaction of interaction with nucleophiles, especially with nucleophiles such as oxygen, sulfur and nitrogen. It is suitable to support the process of obtaining AGP and disaccharide glycosides compounds using glycosylated as the original product.

Describes the different ways of obtaining glycosylation. How great the ILO they include gorodilova existing glycoside (which may contain customary protective group on reaktionstechnik residues, such as amino or hydroxyl).

In the patent US 6299897, for example, the ethyl ester of the glycoside, which is considered (in this case, for example, N-acetylneuraminic acid)reacts with acetylchloride with the formation of the corresponding glycosilated. In the US 5843463 glycosilated produced by the interaction of the considered glycoside (3-O-allyl-5-O-benzyl-1,2-O-methoxy-benzilidene-alpha-D-ribofuranose) with (trimethylsilyl)-chloride. The reaction is performed by mixing the two reagents or by dissolution of the glycoside in trimethylsilylpropyne.

US 4613590 discloses a method of producing glycosilated when processing glycoside with titanium tetrachloride. In Org. Lett. 2:2713 (2000), Sugiyama et al. glycosylamide get in the interaction of thioglycosides chloride chlorosulfonyl.

The Kovac, Carbohydr. Res. 245: 219 (2993) get glycosilated by the interaction of glycoside with dichlorodimethyl ether and zinc chloride. Takeo et al., Carbohydr. Res. 245: 81 (1993) is glycosilated when interacting with chlorine. Magnusson et al., 55: 3181 (1990) is glycosilated by the reaction of 2-(trimethylsilyl)ethylglycine with 1,1-dichlorodimethyl ether in the presence of catalytic amounts of zinc chloride.

Disclosure invented the I

The present invention relates to a group of relatively new processes aminoalkylindoles and disaccharides, together with the intermediate processes and connections.

In the first aspect of the invention relates to processes for aminoalkylsilane compounds (AGP).

In the second aspect of the invention relates to processes of acquiring glycosylation, which includes the interaction of cilingiroglu with dihalogenoalkane ether in the presence of zinc chloride, zinc bromide, boron TRIFLUORIDE or the like of Lewis acids. This stage also includes the first of a two-stage process stage removal of the anomeric silyl protective group from cilingiroglu by his first interaction with obtaining glycosylated, which then interacts with the silver salt in the presence of water to obtain hemiacetal.

In another aspect of the present invention includes a process in which first receive glycosylated, as described above, with the subsequent interaction of glycosylated monosaccharide in the presence of silver salts, with the formation of the disaccharide.

Another aspect of the present invention includes the process of obtaining disaccharide by the interaction of monosaccharide with simillimum.

Another aspect of the present invention includes a process siciliani the disaccharide and optional subsequent addition of phosphonic side chain to the disaccharide.

Another aspect of the present invention includes the process of obtaining triallylamine disaccharide from disaccharide.

Another aspect of the invention is a process of removal of the protective acetyl groups of the disaccharide.

Still a further aspect of the present invention includes the process of obtaining phosphorylated disaccharide by (a) selective protection of the 6'-hydroxyl substituent of the disaccharide and (b) adding a phosphonic side chain to the disaccharide at the 5'-position.

Another aspect of the present invention includes a process for the simultaneous removal of all based on simile protective groups of the disaccharide having multiple, based on simile protective group.

Other aspects of the present invention include other new processes and new intermediate compounds, and/or they will be apparent from the following description.

The implementation of the invention

Definitions: as used in this application

The term "glycoside" refers to tetrahydropyranol ring bearing Deputy 1-position (i.e. on one of the carbon atoms adjacent to the oxygen atom in the ring), which represents a hydroxy-group, optionally substituted by alkoxygroup or tizamidine similarshow. Glycosides may also have substituents at other positions, usually protected or nezam is protected hydroxyl or amino group.

The term "cellpics" refers to a glycoside in which the group attached at the 1-position, is trisamino silyloxy, such as trimethylsilyloxy, tert-butyldimethylsilyloxy or tert-butyldiphenylsilyl. Silyl component of this group has the formula RaRbRcSi, where Ra, Rband Rcindependently selected from the group consisting of C1-C6of alkyl, C3-C6cycloalkyl and optionally substituted phenyl. Preferably one of Ra, Rband Rcgroup is larger than methyl; a relatively difficult group, such as tert-butyl, phenyl and isopropyl are preferred. Included in the silyl components are killiecrankie, diarylethylene and triarylamine group. Typical examples are triisopropylsilyl, triphenylsilane, tert-butyldimethylsilyl (TBS) and tert-butyldiphenylsilyl (TBDPS) group. Silyl component cilingiroglu is preferable in the form of TBS or TBDPS group.

Cellpics can usually be represented by the formula (II)

where R20represents trisamino silyl group, preferably TBS or TBDPS and W, X, Y and Z independently represent H, optionally protected hydroxy, n is necessarily protected amino or optionally substituted alkyl groups. Typically, Z is an optionally protected hydroxymethylene group.

The term "dihalogenoalkane ether" refers to a compound bearing alkoxygroup and two of the halogen atom on one carbon atom. Typical examples are dichlorodimethyl ether (CHCl2Och3), dichloromethylsilane ether (CHCl2OC2H5), diplomatically ether (CHBr2OCH3), 1,1-diplomatically ether (CH3CCl2OS2H5) and the like. Dichlorodimethyl ether is preferred in the methods of the present invention.

The term "glycosylated" refers to 2-halogenerators connection, for example, 2-chlortetracycline or 2-bromotetradecane. The preferred Halogens are fluoride, chloride and bromide, chloride being more preferred. In addition, glycosylated used in the methods of the present invention may have other substituents similar to those presented in the formula (II)above.

Glycosylated can generally be represented by the formula (III):

where W, X, Y and Z have the same values described above for formula (II), and a represents Cl, Br or F.

The term "aliphatic" means a straight or branched chain or neuroma the systematic cyclic, hydrocarbon radical, or combination thereof, which may be fully saturated or mono - or polyunsaturated and can include di - and multivalent radicals, having the specified number of carbon atoms (i.e. With1-C10means from one to ten carbon atoms). Examples of saturated acyclic aliphatic groups (also defined as "alkyl" groups) include, but without limitation, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec.-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. Unsaturated aliphatic group represents one of the groups which have one or more double or triple bonds. Examples of unsaturated acyclic aliphatic groups include, but without limitation, vinyl, 2-propenyl, Isopropenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethinyl, 1 - and 3-PROPYNYL, 3-butynyl and higher homologs and isomers. Examples of cyclic aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl and the like.

The divalent aliphatic group include saturated and unsaturated groups, such as those mentioned above, for example, methylene, -CH2-; ethylene, -CH2CH2-; n-butylene, -CH2CH2 CH2CH2-; and unsaturated groups such as-CH=CH-, -CH=CH-CH2CH2- and the like.

The terms "accelerations", "aminoantipyrine" and "tolerations" are used in their ordinary sense, and they are related to aliphatic groups attached to the remainder of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively. The terms "alkoxy", "dialkoxy and aminoalkyl" have regard to such groups containing saturated acyclic aliphatic residues.

The term "heteroaromatics," by itself or in combination with another term, means, unless otherwise stated, a group similar aliphatic group, i.e. with a saturated or unsaturated straight or branched chain or a cyclic radical, or combination thereof, containing a fixed number of carbon atoms and also containing at least one heteroatom selected from the group consisting of O, N, Si and S, and where the nitrogen atom and the sulfur atom may optionally be oxidized and the nitrogen heteroatom may be optionally quaternity. Heteroatom(s) O, N and S and Si may be placed at any position heteroaromatics group or the position at which the group attached to the remainder of the molecule. Examples include, but without limitation, -CH2-CH2-O-CH3, -CH2-CH2 -NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3and-CH2-CH=N-och3.

Aliphatic groups can be substituted or unsubstituted. The substituents include different groups selected from: -OR',=O,=NR',=N-OR', -NR'r R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)R NR'r", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NRR'R")=NR"', -NR'r C(R NR'r")=NR"', -NR-C(NR'r R")=NR"', -S(O)R', -S(O)2R', -S(O)2NR'r R", -NRSO2R', -CN and-NO2in number, in the range from 0 to (2m'+1), where m' represents the total number of carbon atoms in such radical. R', R" and R"' each independently may be hydrogen, optionally substituted alkyl, aryl, optionally substituted by 1-3 Halogens, optionally substituted alkoxy, optionally substituted, dialkoxy or optionally substituted aryl-(C1-C4)alkyl groups. When the compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R" and R"' groups, when there is more than one of these groups. When R' and R" are attached to the same nitrogen atom, then they can be combined with the nitrogen atom to form a 5-, 6 - or 7-membered ring. For example, -NR'r R" oznacza the t on 1-pyrrolidinyl and 4-morpholinyl.

The term "aromatic" or "aryl" refers to a typical substituted or unsubstituted alifaticheskimi hydrocarbon groups of this class, i.e., polyunsaturated, typically aromatic hydrocarbon Deputy, who may be in the form of a single ring or multiple rings (up to three rings)which are condensed together or linked covalently, such as phenyl, naphthyl and the like.

The term "arylalkyl" refers to alkyl groups substituted by one or more aryl groups; for example, benzyl, phenetyl, triphenylmethyl and the like.

The term "acyl" refers to a group derived from an organic acid with removal of the hydroxyl group. Acyl compounds can generally be aliphatic, aromatic or heterocyclic in nature. "Aliphatic acyl" refers to such groups derived from saturated or unsaturated aliphatic acids, and includes groups such as acetyl, propionyl, butyryl, hexanoyl, decanoyl, dodecanoyl, deletion and the like. When determining acyl groups through the content of the carbon atoms of the assignment is to the content of carbon atoms in a group. Accordingly, acetyl is a2acyl group; propionyl represents a C3acyl group, the deletion before the hat is 14acyl group, and so on.

The term "alkanoyloxy" refers to groups having a saturated or unsaturated aliphatic group or arylalkyl group, such as benzyl, linked through an oxygen atom to a carbonyl group, i.e. a group having the General formula Alk.-OC(O)-, where Alk. denotes an aliphatic or arylalkyl group, as defined above.

The term "alkanoyloxy" refers to a saturated or unsaturated acyl group, substituted at the indicated position aliphatic group Al.(O)O-, in which Al. denotes an acyclic saturated or unsaturated aliphatic group. In General, alkanoyloxy preferably has from 2 to 24 carbon atoms, more preferably from 6 to 14 carbon atoms. Acyl residue alkanolamine group contains from 6 to 14 carbon atoms. A typical group of this series is a 3-(n-alkanoyloxy)acyl group, where the acyl group is a deletion, and alkanoyloxy containing from 2 to 20, preferably from 6 to 14 carbon atoms inclusive. Similarly, the term "alkanoyl" refers to a group Al.(O)-, where Al. is as defined above.

The term "protective group" refers to any of a large number of groups used to replace one or both of the hydrogen atoms of the reaction is posebnoj group, such as hydroxy, amino or Tolna group, to block, to prevent or reduce the reactivity of the group. Examples of protective groups and a list of commonly used abbreviations for them) can be found in T. W. Green and .G. Puts, "Protective Grups in Organic Chemistry" (Wiley), Beaucage and Iyer, Tetrahedron 48:2223 (1992) and Harrison et al., Compendium of Synthetic Organic Methods, vols. 1-8 (Wiley).

Representatives aminosidine groups include those that form a carbamate or amide with the nitrogen atom, as well as those groups that are brought together in a publication Green and Puts as "special-NH protective groups. Typical examples aminosidine groups include acetyl (AC), trifluoracetyl, benzyloxycarbonyl (Cbz), tert.-butoxycarbonyl (Boc), allyloxycarbonyl (AOC), 9-fluorenylmethoxycarbonyl (Fmoc), nitro-versatiletradersonline (Nvoc), optionally substituted by falola, and the like.

Typical hydroxyamine groups include those where the hydroxy-group is either acylated or alkilirovanny, for which use simple education or esters, for example, acetyl, benzyl, triteleia, alkyl, tetrahydropyranyl, allyl and tizanidine silyl group.

The choice of protective groups for this connection, purpose, or the imposition of conditions is within the skill of a specialist in this field, and e is about doing, to protect, generally or selectively considered reactive group in the prevailing conditions (the presence of other reactive compounds, pH, temperature and so on). Protective groups which can be used in the present invention and which are mentioned include palorinya, acetyl (AC), benzyl (Bn), 2,2,2-trichlorocarbanilide (Troc), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS) and 2,2,2-trichloro-1,1-dimethylethanamine (TSOS) group. As is well known to the average expert, some of the protective groups or types of groups may be more suitable than others for use with private connections or in a particular situation and get advantage from these correspondences in the development of methods, which include compounds with reactive groups such as hydroxy and/or amino groups. Thus, as will be seen below, the reaction scheme can be deployed to obtain or interaction of certain compounds in which a General or selective protect or unprotect (removal of protective groups) performed at some points. For example, to selectively introduced into the reaction of the hydroxyl group in the compound, which also contains the amino group or, conversely, the group that is not desirable to introduce into the reaction at this stage, you may be running the employees blocking protective group, which is not removed under the reaction conditions (for example, cannot be either hydrolyzed by the base when the reaction should be carried out in basic conditions, while the group, which must be introduced into the reaction, can be protected by a group which is hydrolyzed by base, so this group is not blocked and, thus, reactive). Similarly, as will be seen below, to selectively introduced into the reaction group, for example, hydroxyl group, located in one position in the molecule, it is possible to protect the other protecting group that is different from the other hydroxyl in the molecule. As used in this description, the symbol "PG" refers to protective groups, which form esters, ethers or carbonates with hydroxyine groups (that is, an oxygen atom, hydroxylases group) or which form amides or carbamates with amino groups (that is, with the nitrogen atom of the amino group). The designation of "PG'is used in this description to refer to it optionally substituted palorinya group, for example, phthaloyl or tetrachlorophthalic and which, as shown, can be used to protect the amino group. But in any case, the choice of specific protective groups used or demonstrated in the processes described in the present description, in any case, no purpose is, to limit the scope of the invention.

Main products

The main products obtained using the processes and intermediates of the present invention contain a group of compounds that include and AGP connections, which are monosaccharides and disaccharides to some extent similar patterns. As a rule, the products can be described by formulas (I) and (Ia-C):

and their pharmaceutically acceptable salts and derivatives, where Y represents-O - or-NH-; R1and R2each independently is selected from saturated and unsaturated (C2-C24) aliphatic acyl group; R8represents-H or-RO3R11R12where R13and R12each independently is-H or (C1-C4) aliphatic groups; R9represents-H, -CH3or RHO3R13R14where R13and R14each is independently selected from-H and (C1-C4) aliphatic groups and where at least one of R8and R9is fosforsoderzhashchie group, but R8and R9both are phosphorus-containing groups; and X represents a group selected from the formulas:

and

where the indices n, m, p, q, n', t', p' and q' each independently is an integer from 0 to 6, provided that the sum of p' and t' is an integer from 0 to 6; the index r is independently an integer from 0 to 14, and may be the same or different; R3, R11and R12independently represent saturated or unsaturated aliphatic (C2-C24) acyl groups; and when X has the formula (1A) or (1C), one of R, R2, R3, R11and R12optional is hydrogen; R4and R' is independently selected from H and methyl; R6and R7independently selected from H, HE, (C1-C4)oxyaliphatic groups, RHO3H2, ORO3H2, -SO3N, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -Cho, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15and-OSO3R15where R15and R16each is independently selected from H and (C1-C4)aliphatic groups; R10selected from N, CH3, RHO3H2that ω-phosphonooxy(C2-C24)alkyl and ω-carboxy(C1-C24)alkyl; R13independently selected from H, HE, (C1-C4)oxyaliphatic groups, -PO3R17R18, ORO3R17R18, -SO3R17, -OSO3R17, -NR17R18, -SR17, -CN, -NO 2, -Cho, -CO2R17and-CONR17R18where R17and R18each is independently selected from H and (C1-C4)aliphatic groups; and Z represents-O - or-S-.

Processes and intermediate compounds

One of the processes of the present invention relates to the production of glycosylation, which includes the interaction of O-cilingiroglu with dihalogenoalkane ether in the presence of zinc chloride, zinc bromide, boron TRIFLUORIDE or similar Lewis acid. More specifically, in this process glycosylated is formed by the interaction of cilingiroglu formula (II):

where R20represents trisamino silyl group having the formula, R3RbRcSi in which R3, Rb, and Rcindependently selected from the group consisting of C1-C6of alkyl, C3-C6cycloalkyl and optionally substituted phenyl, preferably TBS or TBDPS and W, X, Y and Z independently represent H, optionally protected hydroxy, optionally protected amino, and optionally substituted alkyl groups, with dihalogenoalkane ether, preferably dichlorodimethyl ether, in the presence of zinc chloride, zinc bromide, boron TRIFLUORIDE or similar Lewis acid. The Lewis acid used in p is blithedale in stoichiometric amount relative to cilingiroglu. The reaction of obtaining glycosylated carried out at a temperature from about -30°With up to about 50°C, preferably from about 0°With up to about 30°and in the presence of a solvent, such as chloroform, dichloromethane, dichloroethane, or similar solvents which are inert under the conditions required for implementation of the response. The reaction temperature is selected to allow the reactants to substantially dissolve and prevent excessive boiling dihalogenoalkane ether. The yield of the desired product glycosylated basically has a value from about 50 to about 95%. The choice of these solvents is carried out on the basis of knowledge of the average person skilled in the art. Cilingiroglu usually get in a protected form, which is known to the average person skilled in the art. However, the specific cilingiroglu, such as specific triacetyluridine cilingiroglu and their derivatives, can be obtained through the new intermediate compounds described below, which is an aspect of the invention.

The average person skilled in the art will appreciated that glycosylated may exist in the form of isomers, if the other substituents are glycosylation ring. The invention includes obtaining individual isomers as well as mixtures of both isomers. Conditions for the exercise of reactions the most j of nucleophiles with glycosylceramide well known to the average expert in the field.

Thus obtained glycosylated typically have the formula (III)

where a represents Cl, Br or F, and W, X, Y and Z have the same meanings as described above.

In one preferred embodiment of cellpics and the resulting products substituted at the 3-position (Deputy X) with aliphatic acyl group, preferably alkanolamines group, more preferably 3-n-alkanolamines group, and more preferably 3-alcoholattributable group in which an aliphatic or alcoolica group contains from 2 to 24, preferably from 2 to 18 and preferably from 6 to 14 carbon atoms and protective groups in this connection are preferably of The groups or similar alkanolammonium groups. In such embodiments compounds have the General formula (IV) or (V):

where a represents Cl, Br or F; R20represents trisamino silyl group, and R21represents an aliphatic acyl group, preferably 3-n-alcoholattributable group. It should be noted that in these and in subsequent formulas protective groups more accurately identified to illustrate and/or clarity. However, as is well known to the average expert in the field, the other protective groups, as defined above for "PG", can be used as a suitable hence, for example, more generally, these compounds can be represented by the formula

where PG is a protective group, which form a simple ether, ester or carbonate with an oxygen atom or which form an amide or a carbamate with the nitrogen atom, respectively.

In another preferred embodiment of cellpics has a hydroxyl group at 4-position, substituted phosphatefree group, such as dialkylphosphinate or diarylphosphino group, R21represents alkanoyloxy group, preferably 3-n-alcoholattributable group, and the protective groups are preferably "TSOS" groups derived from 2,2,2-trichloro-1,1-dimethylethanamine, or similar alcoholicsanonymous protective group, such as Troc; that is, cellpics may have a specific formula (VI):

where R20represents trisamino silyl group, preferably TBS or TBDPS; R21represents an aliphatic acyl, preferably alkanoyloxy group; and R22represents alkyl, aryl or arylalkyl, or may have a more General formula that allow you to plug the em to use other suitable protective groups and glycosylated respectively, having the more specific formula (VII):

where R21and R22have the same values as those described above, and a represents Cl, Br or F.

In one aspect of the invention, glycosylamide thus obtained interact with monosaccharide, preferably in the presence of silver salts, to obtain the disaccharide using this two-stage method. Monosaccharides, which can be used as reagents in this way include, for example, those that have formulae (i)to(iii):

(i):

(ii):

or (iii):

where R23represents an aliphatic acyl group, preferably 3-n-alcoholattributable group, as described above.

Disaccharides that may be obtained through such methods include those that have the formula (iA)-(ivA):

(iA):

(iiA):

(iiiA):

(ivA):

where R21, R22and R23have the same values as those described above, and these protective groups are usually those that can be used.

Reactions leading to the synthesis products (iA)-(ivA) in soo is according to the present invention, usually carried out at a temperature of from about -30°With up to about 30°, chlorine or other solvent in the presence of a silver catalyst, such as triftorbyenzola (triplet) silver, and anhydrous conditions, with or without other additives such as molecular sieves or buffer agents, such as tetramethylrhodamine.

In another aspect of the invention, cilingiroglu formula (II) condense directly from a monosaccharide, not through the process of education glycosylated. The resulting product is again a disaccharide having a Deputy in accordance with the original products. This process is usually carried out at a temperature from about -78°With up to about 50°in the presence of a suitable catalyst, a Lewis acid such as trimethylsilyltriflate epirate of boron TRIFLUORIDE with or without additional drying or buffer agents. In another aspect of the present invention, the protective group may actually be removed from cilingiroglu with such groups, by its interaction with dehalogenation ether, to obtain glycosylated and subsequent interaction of glycosylated with a silver salt such as silver oxide or silver carbonate, in the presence of water to obtain the corresponding hemiacetal.

Disaccharides obtained by using any of the processes, could the t to be subjected to the additional siciliani hydroxyl group at 4-position of the restored sugar similitude group, such as TBS, in the presence of imidazole and N,N-dimethylformamide to obtain 3,4-bis-similarvideo connection. Attaching a phosphate group at the 4-position unrestored sugar then performed using the chain stages, including (1) removal of 4.6 protective groups (usually acetate or Troc), (2) N-unprotect/acylation, (3) selective protection of the first 6-position with groups such as TSOS, and (4) interaction of 6-protected disaccharide with fosforiliruyusciye agent such as phosphoramidite reagent, for example, dibenzyldithiocarbamate [ensuring dibenzyltoluene side chain] or chlorophosphate, such as bis(2,2,2-trichlorethyl)chlorophosphate [encore software(2,2,2-trichloroethyl)phosphonic side chain] or diphenylchlorophosphine [ensuring diphenylphosphino side chain].

The invention likewise includes how to get triallylamine disaccharides, such as those which have the formula (viii):

where R21, R23and R24represent an aliphatic acyl, preferably alkanoyloxy group and R22is optionally substituted alkyl, aryl or arylalkyl group, by selective protection of the C-6 hydroxyl group of the corresponding disaccharide using 2,2,2-trichloro-1,1-dimethylethanamine in PR is the absence of a tertiary amine, such as pyridine. Preferably R21, R23and R24represent the (R)-3-hexadecyloxypropyl, (R)-3-octadecatetraenoic and (R)-3-tetradecanoylphorbol respectively, but they may be the same or different depending on the desired substitutions and nature used monosaccharide donor at the stage of glycosylation.

The present invention also relates to processes for aminoalkyl and cyclic aminoalkyl glucosaminide compounds (AGP), which are compounds of formula (I)in which X represents a (Ia) or (Ic), in which the fatty acid and phosphate groups introduced on the main AGP frame after the initial stage of glycosylation (condensation). These processes include the use of new glycosidic trialing intermediates which can be selectively protected at the 6-position of the sugar, until the introduction of complex volatile and midsweden acyloxyacyl residues.

One preferred according to the invention methods teachings AGP compounds shown in scheme 1 below. Scheme 1 raskryvat way to obtain specific compounds of formula (Ia), but is intended to serve only as an example of a specified aspect of the invention, the same or similar method may be used for receiving the Oia other model compounds of formula (Ia), as well as the compounds of formula (Ic).

In the specified process introduction aliphatic acyl, for example (R)-3-n-alkanolamine and phosphate groups in the glucosamine and aglionby components also carry out after the condensation reaction, but, unlike the method disclosed in the prior art, the 3-hydroxyl group is selectively etherification using alanovoy acids, substituted aliphatic acyl group, preferably (R)-3-n-alkanolamines acid, in the presence of unprotected/nefosfaurilirovanna 4-hydroxyl group, with blocking 6-position. It reaches through the protection of the 6-hydroxyl group of the sugar residue resistant protective group at the place of temporary protection 4,6-hydroxyl of the provisions of the acetonide. Preferably β-glycoside 8 or sootvetstvuyshee bis-Troc derivative 9 de-O-acetimidoyl using a suitable base, which gives an intermediate triol 10, which selectively protects 6-position using a hindered silyl group such as tert-butyldimethylsilyl (TBS) in conventional conditions known to the average person skilled in the art that gives silylamine intermediate connection 12. Intermediate triol 10 represents a new connection. 3-O-Acylation 12 using (R)-3-n-alcoholattributable acid, for example, with the subsequent removal of the protection/acylation of sugar and aglionby amino groups, at the same time (PG=Troc) or sequentially (PG=Aoc) using either zinc (PG=Troc) or zinc and Pd(0) (PG=Aoc) under unprotect and (R)-3-n-alcoholattributable acid at the stage of acylation, provides hexachlorophane intermediate connection 13. Pentachlorophenate connection, in which one of the acyl groups, R1, R2, R3, R11or R12is hydrogen, can be obtained by using different protective groups for the two amino groups so that one or the other can be selectively allyawan, for example using AOC group for the first and the Troc group to another.

Phosphorylation of the 4-hydroxyl group performed using techniques well known to the average person skilled in the art, using, preferably, or dibenzyl, or di-tert-butylamine chlorophosphate, or phosphoramidite reagent that gives phosphotriester 14. Phosphate, silyl, and any remaining protective groups in 14 then cleaved under mild acidic conditions or by other appropriate techniques, which gives the compounds of formula (Ia). It is important to note that the order in which you enter phosphate and N-linked (R)-3-n-alcoholattributable group 14 may be addressed through appropriate selection of orthogonal phosphate and aminosidine groups.

Variant of the method is demonstrated on scheme, shown in scheme 2 and involves the use of commercially available glycosylase donor, such as 15, with or acetyl, or phthalimide azatadine groups and either anomeric acetoxy or halide group. On the other hand, this scheme represents the methods of the invention for preparing compounds of formula (Ia) or (Ic).

Figure 2 Picatinny donor 15 condense with the same N-protected acceptor component 16 in the presence of a suitable catalyst, giving β-glycoside 17. As N-acetyl and phthalimide groups usually require strong basic conditions to remove the protection, as a rule, you must use stable in basic conditions, the ether-linked protective group, such as triphenylmethyl (trityl, Tr) 6-position. Accordingly, de-O-acetylation of 17 under normal conditions, followed preferably by selective trailerboat 6-position gives diol 18. Caused by base cleavage of N-acetyl or phthalimide group followed odnovremenno or sequential N - and O - acylation of the obtained intermediate Diamantina using (R)-3-n-alcoholattributable acid in the presence of a suitable reagent(s) condensation gives hexachlorophane derivative 19. Intermediate deamination is formed by processing the connection 18 base with f is rmula:

Phosphorylation of compound 19 chlorophosphate or phosphoramidite reagent as shown in scheme 1, followed by removing protection in mild acidic conditions or by using other suitable techniques gives the compounds of formula (Ia).

SCHEME 1

SCHEME 2

In the above schemes 1 and 2 different groups of R1-R7n, p and q have the meanings as defined above.

The invention, moreover, is illustrated by the following examples. These examples are presented solely as illustrative for the invention and in no case do not limit its definition or boundary.

Example 1: Getting chloride 2-deoxy-4-O-diphenylphosphino-3-O-[(R)-3-tetradecanoylphorbol]-6-O-(2,2,2-trichloro-1,1-dimethylethoxysilane)-2-(2,2,2-trichlorocarbanilide)-α-D-glucopyranosyl

This process is illustrated in scheme a below, and includes new intermediate compounds (iv), (vi) and (vii)that represent aspects of the present invention.

Scheme And

(a) Obtaining tert-butyldiphenylsilyl-2-deoxy-4,6-O-isopropylidene-2-(2,2,2-trichlorocarbanilide)-α-D-glucopyranoside (Scheme A, the compound (vi).

(1) 2,2,2-Trichlorocarbanilide (200 g, 0,944 mol) to ablaut portions into a solution of the hydrochloride of D-glucosamine (v, 200 g 0,927 mol) and NaHCO3(200 g, 2.4 mol) in water (4 l) in a 3-necked round-bottom flask with a volume of 10 l and the resulting mixture was mechanically stirred overnight at room temperature. The precipitate is white, which is formed, collected by filtration, using Pittaway funnel, volume 2 l), washed with ether (2 l) and dried under high vacuum for 3 hours, giving 297 g (90%) of 2-deoxy-2-(2,2,2-trichlorocarbanilide)-D-glucose in the form of a solid white color (mol. weight 354,57).

(2) a Solution of 2-deoxy-2-(2,2,2-trichlorocarbanilide)-D-glucose (297 g, 0,838 mol)obtained above in (1), in a mixture of pyridine (1 l, 12.4 mol) and acetic anhydride (1 l, 10.6 mol) in a round bottom flask with a volume of 10 l mechanically stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure giving an oil which is distilled azeotrope with toluene (2×1 l) and dried under high vacuum overnight, giving 438 g (˜100%; 90% of v) leads to compounds, which in the form of syrup (mol. weight 522,71, TLC (EtOAc) Rf0,75).

(3) leads to compounds, which obtained above in (2) (438 g, 0,838 mol), dissolved in EtOAc (4 l) and transferred into a 3-necked round bottom flask with a volume of 10 l was treated with morpholine (200 ml, to 2.29 mol) and mechanically stirred for 8 hours at room temperature. Completion of reaction was determined by TLC (50% mixture of EtOAc/hexane). We use the t 3 N aqueous solution of HCl (2 l) and the resulting mixture is stirred for 30 minutes. The mixture is transferred into a separate flask a volume of 6 l and the layers separated. The organic phase is washed with saturated aqueous NaCl (1 l), dried (Na2SO4) and concentrated, giving 373 g (93%, 84% v) derived from the taken-protected 1-O-position (hemiacetal) as a white foam (mol. weight 480,67; TLC (50% mixture of EtOAc/hexane) Rf0,22).

(4) the Solution of hemiacetal obtained above in (3) (373 g, 0,776 mol), and imidazole (132 g, 1.94 mol) in N,N-dimethylformamide (DMF, 430 ml, 1.8 M) is treated with tert-butylchloroformate (242 ml, 0,931 mol) and stirred for 48 hours at room temperature. The completion of the reaction is confirmed by TLC (50% mixture of EtOAc/hexane). The reaction mixture was partitioned between ethyl ether (4 l) and water (1 l) in a separate flask a volume of 6 l and the layers separated. The ether layer is washed with water (1 l), dried (Na2SO4) and concentrated, giving painted in a bronze color oil, which crystallized from a mixture of EtOAc-hexane (˜1:2 vol./about.) three portions, which ensures 474 g (85%, 71% of v) tert-butyldiphenylsilyl iv in the form of a solid white color (mol. weight 719,08; TLC (50% mixture of EtOAc/hexane) Rf0,44).

(5) the Solution of cilingiroglu obtained above in (4) (474 g, 0,659 mol), Meon (2 l) in a 3-necked round-bottom flask with a volume of 3 l is treated with ammonium hydroxide (300 ml, 4.5 mol) (some precipitation) and the mix is at room temperature over night, and then treated storm the rest of ammonium hydroxide (50 ml, 0.75 mol) and again stirred overnight. Completion of reaction was determined by TLC (EtOAc). The reaction mixture was concentrated and the resulting residue dissolved in EtOAc (500 ml), placed on a bed of silica gel (1 kg) in Pittaway a glass funnel with a volume of 3 l and elute 50% mixture of EtOAc-hexane (5 l) and EtOAc (7 l). The fractions containing the product are concentrated in a round bottom flask with a volume of 3 l, which gives 329 g (84%, 60% v) Tirol (mol. weight 592,97, TLC (EtOAc) Rf0,35).

(6) Suspension of triol obtained above in (5) (329 g, 0,555 mol), 2,2-dimethoxypropane (1.5 l) in a round bottom flask with a volume of 3 l handle camphorsulfonic acid (6.4 g, 0,028 mol) and stirred with a magnetic stirrer at room temperature over night, receiving the solution is light yellow in color. Add solid NaHCO3(4.6 g, by 0.055 mol) and the resulting mixture is stirred for 2 hours at room temperature, and then concentrated to dryness. The resulting crude product is dissolved in dichloromethane (1.2 l), divided into two equal portions and placed on a silica gel (1 kg, pre-moistened with a 30% mixture of EtOAc/hexane) in two individual mettowee glass funnel with a volume of 3 l and elute 30% mixture of EtOAc/hexane (10 l) and 50% mixture of EtOAc/hexane (8 l). The fractions containing the purified product are pooled and concentrated that d is no connection vi in the form of an amorphous substance. The specified product can be further purified by crystallization from hexane if necessary.

Molecular formula: C28H36Cl3NO7Si

Molecular weight: 633,04

Theoretical output: 587 g (v)

The resulting output: 306 g (87%, 52% v)

TLC: Rfof 0.60 (EtOAc)

(b) Obtaining tert-butyldiphenylsilyl-2-deoxy-4-O-diphenylphosphino-3-O-[(R)-3-tetradecanoylphorbol]-6-O-(2,2,2-trichloro-1,1-dimethylethoxysilane)-2-(2,2,2-trichlorocarbanilide)-α-D-glucopyranoside (Scheme A, the compound (vii).

(1) a Solution of compound vi (141 g, 0,223 mol) in CH2Cl2(1 l) in a round bottom flask with a volume of 2 liters treated with 3-(R)-(tetradecanoate)tetradecanoic acid (101,7 g, 0,224 mol), DCC (55 g, in the form of a melt, 0,267 mol) and 4-pyrrolidineethanol (3.3 grams, of 0.022 mol) and stirred at room temperature overnight. Completion of reaction was determined by TLC (20% mixture of EtOAc/hexane). The reaction mixture was filtered, concentrated to approximately half volume, divided into two equal portions and placed on a silica gel (1 kg, pre-moistened with a 2.5% mixture of EtOAc/hexane) in two individual mettowee glass funnel with a volume of 3 L. the Gradient elution with 2.5%, 5% and 10% mixture of EtOAc/hexane (8 l each) and concentration of the fractions containing the product in a round bottom flask with a volume of 3 l, gives 220 g (92%) ether (mol. weight 106972, TLC (20% mixture of EtOAc/hexane) Rf0,53).

(2) the Ester obtained above in (1) (218 g, 0,204 mol), suspended in 90% aqueous solution Asón (1 l) in a round bottom flask with a volume of 3 l, mix (rotary evaporator) at a temperature of 70°C for 2.5 hours getting the solution a milky appearance. Completion of reaction was determined by TLC (20% mixture of EtOAc/hexane). The reaction mixture was concentrated and the residue Asón remove azeotrope with toluene (2×500 ml). The resulting crude product is dissolved in 10% mixture of EtOAc/hexane (400 ml), divided into two equal portions and placed on a silica gel (1 kg) in two individual mettowee glass funnel with a volume of 3 L. the Gradient elution with 10% mixture of EtOAc/hexane (10 l) and 15%, 20% and 30% mixture of EtOAc/hexane (5 l each) and concentration of the fractions containing the product, give 193 g (92%, 85% of vi) diol (mol. weight 1029,66, TLC (20% EtOAc) Rf0,10)containing a small amount (<5% by TLC) 6-O-acetyl as a by-product (Rf0,25). (Note: 6-acetate by-product is easily separated by means of radial compression chromatography as a derivative of 4-diphenylphosphate obtained below for the stage (3).)

(3) Magnetic stirrer stirred solution of diol obtained above in (2) (193 g, 0,187 mol) in CH2Cl2(1 l) at temperature 0°C, treated with pyridine (18.2 ml, 0,225 mol)and then 1,1-dimethyl-2,2,2-trichlorethylphosphate the (49.5 g, 0,206 mol). The development of the reaction is controlled by TLC (20% mixture of EtOAc/hexane). When the reaction is brought to its end, as shown by TLC (usually 30 to 60 minutes, but may need a longer reaction time), sequentially add triethylamine (55 ml to 0.39 mol), 4-pyrrolidinedione (13,9 g, 0,094 mol) and diphenylchlorophosphine (58,2 ml, 0,281 mol) and the resulting mixture was stirred at room temperature overnight. Completion of reaction was determined by TLC (20% mixture of EtOAc/hexane). The reaction mixture is concentrated to dryness and the resulting residue partitioned between EtOAc (1.5 l) and 1.2 N aqueous solution of HCl (2 l) in a separate flask a volume of 6 l and the layers separated. The EtOAc layer washed with water (2 l), dried (Na2SO4) and concentrate. The resulting residue is dissolved in 10% mixture of EtOAc/hexane (500 ml) and purified using gradient elution on a Biotage system 150 Hi (150 l column) with a 10% mixture of EtOAc/hexane (50 l), collecting 950 ml fractions. The fractions containing the compound vii, unite and concentrate.

Molecular formula: C70H98Cl6NO15Psi

Molecular weight: 1465,30

Theoretical output: 326,8 g (vi)

The resulting output: 211 g (77%, 65% vi)

TLC: Rfto 0.47 (20% mixture of EtOAc/hexane)

(C) Obtaining chloride 2-deoxy-4-O-diphenylphosphino-3-O-[(R)-3-tetradecanoyl-ditetradecyl]-6-O-(2,2,2-trichloro-α-dimethylethoxysilane)-2-(2,2,2-Tr is chloroethoxy-carbylamine)-α -D-glucopyranosyl (Scheme A, the compound (vii).

A solution of compound vii (192 g, 0,131 mol) in CHCl3(2 l) at temperature 0°in round bottom flask with a volume of 5 l process, introducing dropwise from a separating funnel and,and-dichlorodimethyl ether (78 ml, 0.87 mol), and then ZnCl2(1.0 M in ether, 100 ml, 0.1 mol). The cold bath removed and the mixture stirred at room temperature overnight. Completion of reaction was determined by TLC (20% mixture of EtOAc/hexane). The reaction mixture is treated with cold saturated aqueous NaHCO3(1 l), stirred for one hour and the layers are separated in a separate flask a volume of 6 L. the Organic layer is dried (MgSO4) and concentrate. The obtained residue is purified on Biotage system 150 Hi (150 l column), elwira a 10% mixture of EtOAc/hexane (80 l, 950 ml fractions). The fractions containing pure product are pooled and concentrated.

Molecular formula: C54H79Cl7NO14P

Molecular weight: 1245,36

Theoretical output: 163,2 g

The resulting output: 141 g (86%)

TLC: Rf0,42 (20% mixture of EtOAc/hexane)

Example 2 - Getting triethylammonium salt (N-[(R)-3-decanoate the deletion]-O-[2-deoxy-4-O-phosphono-2-[(R)-3-technologytechnology]-3-O-[(R)-3-technologietransfer]-β-D-glyukopiranozil]-L-serine [compound of formula (Ia)in which R1=R2=R3=H-C9H 19CO, Z=Y=O, n=m=p=q=0, r=10, R4=R5=R7=R9=N, R6=CO2N, R8=RHO3H2)], namely

In this example, use the method shown in scheme 1.

(1) a Solution of 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-(2,2,2-trichlorosucrose a melamine)-β-D-glucopyranoside (5,33 g, 10.2 mmol) and benzyl N-(2,2,2-trichlorocyanuric)-L-serine (4,16 g, and 11.2 mmol) in anhydrous CH2Cl3(15 ml) is treated dropwise with efratom of boron TRIFLUORIDE (2,59 ml of 20.4 mmol)and then stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO3(20 ml) and the layers separated. The aqueous layer was extracted with CHCl3(2×10 ml) and the combined organic layers washed with H2O (10 ml), dried (Na2SO4), and then concentrated in vacuo. Flash chromatography on silica gel (gradient elution, 20-50% of a mixture of AcOEt/hexane) gives 7,42 g (87%) of benzyl ester of N-(2,2,2-trichlorocyanuric)-O-[3,4,6-Tetra-O-acetyl-2-deoxy-2-(2,2,2-trichlorocarbanilide)-β-D-glyukopiranozil]-L-serine in a solid white color (compound 9; X=O, n=m=p=q=0, r=10, R4=R5=R7=N, R6=CO2Bn).

(2) Solution of the compound obtained above in (1) (408 mg, 0.49 mmol), in tetrahydrofuran (THF; 20 ml) hydronaut in the presence of 10% palladium on coal (30 mg) at room is temperature and atmospheric pressure for 3 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. Flash chromatography on silica gel with 2% mixture of Meon-CHCl3and then with a 10% mixture of Meon-CHCl3give 347 mg (98%) N-(2,2,2-trichlorocyanuric)-O-[3,4,6-Tetra-O-acetyl-2-deoxy-2-(2,2,2-trichlorocarbanilide)-β-D-glyukopiranozil]-L-serine in a solid white color (compound 9; X=O, n=m=p=q=0, r=10, R4=R5=R7=N, R6=CO2N)

(3) Solution of the compound obtained above in (2) (998 mg, of 1.34 mmol) in methanol (15,5 ml), treated with ammonium hydroxide (of 0.21 ml, 5.37 mmol) at room temperature for 16 hours, and then additional ammonium hydroxide (of 0.21 ml, 5.37 mmol) in 24 hours. The reaction mixture was concentrated in vacuo, giving a solid white color. The suspension is solid white in CH2Cl2(33,5 ml) is treated with benzylbromide (0,80 ml, 6.7 mmol), tetrabutylammonium bromide (432 mg, of 1.34 mmol) and a saturated solution of NaHCO3(33,5 ml) and the resulting biphasic mixture was vigorously stirred at room temperature for 24 hours and the layers separated. The aqueous layer was extracted with CHCl3(2×15 ml) and the combined organic layers washed with N2About (10 ml), dried (Na2SO4) and concentrated in vacuo. The resulting residue is dissolved in anhydrous pyridine (10 ml), treated with tert-BU is ultimatelyimplodes (242 mg, to 1.61 mmol) and stirred at room temperature for 1.5 hours. The reaction mixture was treated with additional tert-butyldimethylsilyloxy (242 mg, of 1.61 mmol) and stirred for 1.5 hours. The reaction mixture was partitioned between CHCl3(10 ml) and N2About (10 ml). The aqueous layer was extracted with CHCl3(2×15 ml) and the combined organic layers washed with N2About (15 ml), dried (Na2SO4) and concentrated in vacuo. Flash chromatography on silica gel using gradient elution (1,0→1,25% CH3HE/CHCl3gives 724 mg (66%) of benzyl ester of N-(2,2,2-trichlorocyanuric)-O-[6-O-tert-butyldimethylsilyl-2-deoxy-2-(2,2,2-trichlorocarbanilide)-β-D-glyukopiranozil]-L-serine in a solid white color (compound 12 PG=Troc, X=0, n=m=p=q=0, r=10, R4=R5=R7=N, R6=CO2H).

(4) Solution of the compound obtained above in (3) (892 mg, of 1.09 mmol)in anhydrous CH2Cl2(10.5 ml) is treated with (R)-3-technologytechnology acid (476 mg, 1.20 mmol), methiodide 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC-MeI; 355 mg, 1.20 mmol) and 4-pyrrolidineethanol (8 mg, 0,054 mmol) at a temperature of 0°within hours. The reaction mixture was treated with additional (R)-3-technologytechnology acid (60 mg) and EDC MeI (60 mg) at a temperature of 0°C, stirred for 30 minutes and the concentration of irout in vacuum. Flash chromatography on silica gel with a mixture of 1:6 AcOEt-hexane give 1.10 g (85%) of benzyl ester of N-(2,2,2-trichlorocyanuric)-O-[6-O-tert-butyldimethylsilyl-3-O-[(R)-3-technologietransfer]-2-deoxy-2-(2,2,2-trichlorocarbanilide)-β-D-glyukopiranozil]-L-serine in the form of a colorless oil.

(5) Solution of the compound obtained above in (4) (1,162 g, 0,967 mmol)in 20% aqueous THF solution (16 ml) is treated with powdered zinc (632 mg, 9,67 mmol) and acetic acid (0,12 ml, 2,13 mmol)and then stirred for one hour at room temperature. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The obtained solid off-white color dissolved in CHCl3(15 ml) and washed successively with portions of 15 ml each of 0,1M HCl, saturated aqueous NaHCO3and H2O. the Organic layer is dried (Na2SO4) and concentrated in vacuo and the resulting residue is dried overnight under high vacuum. A solution of the residue in anhydrous CH2Cl2(9.5 ml) is treated with (R)-3-technologytechnology acid (848 mg, 2,13 mmol) and EDC.MeI (632 mg, 2,13 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue purified using flash chromatography on silica gel (gradient elution; 20→25% AcOEt/hexane), giving of 1.03 g (66%) benzyl the new ester of N-[(R)-3-technologietransfer]-O-[6-O-tert-butyldimethylsilyl-2-deoxy-2-[(R)-3-technologytechnology]-3-O-[(R)-3-technologietransfer]-β -D-glyukopiranozil]-L-serine in the form of a glassy solid (compound 13 R1=R2=R3=n-C9H19CO, X=O, n=m=p=q=0, r=10, R4=R5=R7=N, R6=CO2Bn).

(6) Solution of the compound obtained above in (5) (112 mg, 0,069 mmol)in anhydrous dichloromethane (1 ml) in an argon atmosphere is treated with diisopropylchlorophosphoramidite (39 μl, 0.12 mmol) and tetrazole (12 mg, 0,173 mmol) and stirred at room temperature for one hour. The reaction mixture is cooled to a temperature of 0°and treated With meta-chloroperbenzoic acid (meta-SRV; 33 mg, rate of 0.193 mmol) for 30 minutes. The reaction mixture is quenched with an additional quantity of saturated aqueous NaHCO3(5 ml) and stirred at room temperature for 15 minutes. The aqueous layer was extracted with chloroform (3×5 ml) and the combined organic layers washed with water (5 ml), dried (Na2SO4) and concentrated in vacuo. Flash chromatography with 25% of a mixture of AcOEt-hexane gives the partially purified product, which again chromatographic on silica gel with 20% mixture of AcOEt-hexane, giving 122 mg (93%) of benzyl ester of N-[(R)-3-technologietransfer]-O-[6-O-tert-butyldimethylsilyl-2-deoxy-4-O-diphenylphosphino-2-[(R)-3-technologytechnology]-3-O-[(R)-3-technologietransfer]-β-D-glyukopiranozil]-L-serine as bestsitegames.

(7) Solution of the compound obtained above in (6) (232 mg, 0,124 mmol)in anhydrous THF (10 ml) hydronaut in the presence of 20% palladium hydroxide on coal (46 mg) at room temperature and atmospheric pressure within 36 hours. The reaction mixture was filtered through celite and the filtrate concentrated under vacuum. The obtained oil (181 mg) was dissolved in CH2Cl2(2.5 ml) and treated triperoxonane acid (29 μl) and stirred in an argon atmosphere at room temperature for 18 hours. The reaction mixture was concentrated and co evaporated with hexane (2x5 ml). Flash chromatography on silica gel with a mixture of chloroform-methanol-water-triethylamine (gradient elution; 87:12:0,5:0,5→77:22,5:0,5:0,5) give 102 mg (55%) triethylammonium salt of N-[(R)-3-technologietransfer]-O-[2-deoxy-4-O-phosphono-2-[(R)-3-technologytechnology]-3-O-[(R)-3-technologietransfer]-β-D-glyukopiranozil]-L-serine (RC-527) in the form of a colorless solid.

Example 3 - Getting bis(triethyl)ammonium salt (S)-2-[(R)-3-hexanoyloxyfucoxanthin]-3-phosphonoacetate 2-deoxy-4-O-phosphono-3-O-[(R)-3-hexanoyloxyfucoxanthin]-2-[(R)-3-hexanoyloxyfucoxanthin]-β-D-glucopyranoside [compound of formula (I)in which X represents a (Ia), namely, R1=R2=R3=n-C5H11CO, Z=Y=O, n=m=p=q=0, r=10, R4=R5=R7=R =N, R6=CH2ORO3H2, R8=RHO3H2], namely:

In this example, use the method shown in scheme 1.

(1) In accordance with the similar procedure described for example 2-(3), 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-(2,2,2-trichlorocarbanilide)-β-D-glucopyranosid (0,62 g, 1.18 mmol) and (S)-2-(2,2,2-trichlorocarbanilide)-3-benzyloxy-1-propanol (0,46 g of 1.30 mmol) condense in the presence of epirate of boron TRIFLUORIDE (0.3 ml, 2.4 mmol), giving (R)-2-(2,2,2-cryptgetkeyparam-3-benzyloxy-1-propyl-2-deoxy-3,4,6-Tetra-O-acetyl-2-(2,2,2-trichlorocarbanilide)-β-D-glucopyranosid in the form of a solid light-yellow color (compound 9; X=O, n=m=p=q=0, r=10, R4=R5=R7=N, R6=CH2OBn). A solution of this compound in methanol (15 ml) is treated with ammonium hydroxide (of 0.21 ml, 5.37 mmol) at room temperature for 19 hours, and then additional ammonium hydroxide (0,20 ml, 5.1 mmol) in 25 hours. The reaction mixture was concentrated in vacuo, giving a solid white color. Flash chromatography on silica gel (gradient elution 5→6% CH3HE/CHCl3gives 0,57 g (63%) of 3-benzyloxy-(R)-2-(2,2,2-trichlorocarbanilide)propyl 2-deoxy-2-(2,2,2-trichlorocarbanilide)-β-D-glucopyranoside as the vitreous is solid substances.

(2) Solution of the compound obtained above in (2) (0,57 g, 0.83 mmol)in anhydrous pyridine (8.5 ml) is treated with tert-butyldimethylsilyloxy (0.15 g, 0,99 mmol) and stirred at room temperature for 1.5 hours. Additionally add tert-butyldimethylsilyloxy (0.15 g, 0,99 mmol) and after another 1.5 hours, the reaction mixture was partitioned between CHCl3(10 ml) and N2O (10 ml) and the layers separated. The aqueous layer was extracted with CHCl3(2×10 ml) and the combined organic layers washed with H2O (10 ml), dried (Na2SO4) and concentrated in vacuo. Flash chromatography on silica gel (gradient elution; 80:1→60:1 CHCl3/CH3HE gives 0.65 g (98%) of 3-benzyloxy-(R)-2-(2,2,2-trichlorocarbanilide)propyl 6-O-tert-butyldimethylsilyl-2-deoxy-2-(2,2,2-trichlorocarbanilide)-β-D-glucopyranoside in a solid white color.

(3) In accordance with the similar procedure described for example 2-(4), the compound obtained above in (2) (0,47 g, 0.59 mmol), acelerou (R)-3-hexanoyloxyfucoxanthin acid (0,22 g, 0.64 mmol) in the presence of EDC MeI (0.21 g, 0.70 mmol) and 4-pyrrolidinedione (4 mg, 0.03 mmol), which gives 0,58 g (88%) of 3-benzyloxy-(R)-2-(2,2,2-trichlorocarbanilide)propyl-6-O-tert-butyldimethylsilyl-3-O-[(R)-3-hexanoyloxyfucoxanthin]-2-deoxy-2-(2,2,2-trichlorocarbanilide)-β-D-glucopyranoside in the form of b is izvetnogo oil.

(4) In accordance with the similar procedure described for example 2-(5)with the compound obtained above in (3) (0,58 g, 0.51 mmol), remove protection using zinc (0.34 g, 5,14 mmol) and acelerou (R)-3-hexanoyloxyfucoxanthin acid (0.39 g, 1.13 mmol) in the presence of EDC MeI (0.34 g, 1.13 mmol), which gives 0,41 g (56%) of 3-benzyloxy-(R)-2-[(R)-3 hexanoyloxyfucoxanthin]propyl-6-O-tert-butyldimethylsilyl-3-O-[(R)-3-hexanoyloxyfucoxanthin]2-deoxy-2-[(R)-3-hexanoyloxyfucoxanthin]-β-D-glucopyranoside as a colorless oil (compound 13 R1=R2=R3=n-C3H11WITH, X=O, n=m=p=q=0, r=10, R4=R5=R7=N, R6=CH2OBn).

(5) Solution of the compound obtained above in (4) (0,41 g, 0.29 mmol)in THF (18 ml) hydronaut in the presence of palladium chloride (0.04 g) at room temperature and atmospheric pressure for 17 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. Flash chromatography on silica gel (gradient elution; 1:2→1:8 ethyl acetate/heptane) provides 0.3 g (77%) of 3-hydroxy-(R)-2-[(R)-3-hexanoyloxyfucoxanthin]propyl-6-O-tert-butyldimethylsilyl-3-O-[(R)-3-hexanoyloxyfucoxanthin]-2-deoxy-2-[(R)-3-hexanoyloxyfucoxanthin]-β-D-glucopyranoside as a colorless oil (compound 13 R1=R2=R3=n-C5H11CO, X=O, n=m=p=q=0, r=10, R4=R 5=R7=N, R6=CH2OH).

(6) In accordance with the similar procedure described for example 2-(6), the compound obtained above in (5) (0,30 g, 0.22 mmol), phosphorylate dibenzyldithiocarbamate (0.25 ml, 0.75 mmol), tetrazole (0.08 g, 1.11 mmol) and meta-SRV (0.33 g, of 1.95 mmol), which gives 0,30 g (73%) of 3-dibenzyltoluene-(R)-2-[(R)-3-hexanoyloxyfucoxanthin]propyl 4-dibenzylamino-6-O-tert-butyldimethylsilyl-3-O-[(R)-3-hexanoyloxyfucoxanthin]-2-deoxy-2-[(R)-3-hexanoyloxyfucoxanthin]-β-D-glucopyranoside as a colorless oil.

(7) Solution of the compound obtained above in (6) (302 mg, 0.16 mmol)in anhydrous THF (13 ml) hydronaut in the presence of 20% palladium chloride coal (60 mg) at room temperature and atmospheric pressure for 27 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. A solution of the obtained oil (226 mg) in CH2Cl2(3.5 ml) is treated triperoxonane acid (0.04 ml, 0.49 mmol) and stirred in an argon atmosphere at room temperature for 16 hours. The reaction mixture was concentrated and co evaporated with hexane (2×5 ml) and the obtained residue is dried under high vacuum giving the crude product (226 mg). Part of the crude product (102 mg) was dissolved in a mixture of 1:2 CHCl3/CH3HE (9 ml), placed on a DEAE - cellulose column (15 g, big with what speed (flow), Sigma) and elute with a mixture of 2:3:1 CHCl3:CH3HE:N2O using a salt gradient from 0 to 0.1 M NH2The OAc. The fractions containing the purified product are pooled, washed with a 0.1 N aqueous solution of HCl and concentrated in vacuo. The obtained residue lyophilized of 1% aqueous solution of triethylamine (no pyrogen)that give 82 mg (81%) bis(triethyl)ammonium salt of (S)-2-[(R)-3-hexanoyloxyfucoxanthin]-3-phosphonoacetate 2-deoxy-4-O-phosphono-3-O-[(R)-3-hexanoyloxyfucoxanthin]-2-[(R)-3-hexanoyloxyfucoxanthin]-β-D-glucopyranoside in the form of a white powder: positive FAB-MS calculated for [M+Na]+1407,8534 found 1407,8689;1H NMR (CDCl3/CD3OD): δ (frequent. in million) 5,23-5,16 (m, 4H), of 4.67 (d, 1H), to 4.38 (DD, 1H), 4,19-a 3.83 (m, 7H), 3,49 (m, 2H), 3,06 (m, N), 2,64-2,23, (m, N), 1,58-of 1.56 (m, N), of 1.23 (m, 94 H), 0.88-0.87 (m, N).13With NMR (CDCl3/CD3OD): δ (frequent. per million) 173,7, 173,3, 173,2, 170,3, 170,1, 100.0, 74,6, 74,0, 70,9, 70,8, 70,3, 66,6, 63,5, 60,4, 54,2, 45,8, 41,1, 40,7, 39,3, 34,4, 34,3, 31,9, 31,3, 29,7, 29,4, 25,3, 24,7, 22,7, 22,3, 14,1, 13,9, 8,5.

All publications and patent applications cited in the present description, included in the invention as reference as if each individual publication or description to the patent identified and individually indicated as reference in the present application.

Although the above invention has been described in detail only with the help of illustrations and examples to clear Pont is mania, the average person skilled in the art in light of the study the present invention will be apparent that addition can be done some changes and modifications, without departing from the spirit or scope of the attached claims.

1. The method of obtaining compounds of aminoalkylphosphonic 4-phosphate of the formula

where X represents;

Y represents-O - or-NH-;

R1, R2and R3each is independently selected from hydrogen and saturated and unsaturated (C2-C24)aliphatic acyl groups;

R8represents-H or-RO3R11R11awhere R11and R11aeach independently is-H or (C1-C4)aliphatic groups;

R9represents-H, -CH3or-PO3R13aR14where R13aand R14each is independently selected from-H and (C1-C4)aliphatic groups; and

where the indices n, m, p, q each independently is an integer from 0 to 6, and y independently is an integer from 2 to 10;

R4and R5independently selected from H and methyl;

R6and R7independently selected from H, HE, (C1-C4)oxyaliphatic groups, RHO3H2, ORO 3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -Cho, -CO2R15, -CONR15R16, RHO3R15R16, ORO3R15R16, -SO3R15and-OSO3R15where R15and R16each is independently selected from H and (C1-C4)aliphatic groups, where the aliphatic group is optionally substituted by aryl; and

Z represents-O - or-S-;

provided that at least one of R8and R9is a group containing phosphorus, but R8and R9cannot be simultaneously a group containing phosphorus,

including

(a) selective 6-O-similarobama derivative 2-amino-2-deoxy-β-D-glucopyranose formula

where X represents O or S; and PG is independently represents a protective group which forms an ester, a simple ester or carbonate with an oxygen atom, a hydroxyl group or that forms an amide or carbamate with the nitrogen atom of the amino group, respectively;

using trisemester of CHLOROSILANES RaRbRcSi-Cl, where Ra, Rband Rcindependently selected from the group consisting of C1-C6of alkyl, C3-C6cycloalkyl and optionally substituted phenyl, in the presence of the tvii tertiary amine, that gives 6-Siciliano derived;

(b) selective acylation of 4-HE position obtained 6-0-similarvideo derived using (R)-3-alkanolamines acid or hydroxyamino (R)-3-hydroxyalkanoate acid in the presence of a carbodiimide reagent and a catalytic amount of 4-dimethylaminopyridine or 4-pyrrolidinedione that gives 4-O-acylated derivative;

(c) selective removal of nitrogen protective groups, sequentially or simultaneously, and N,N-diallylamine diamine obtained using (R)-3-alkanolamines acid or hydroxyamino (R)-3-hydroxyalkanoate acid in the presence of the reagent peptide condensation;

(d) the introduction of protective phosphate group at the 3-position with chlorophosphate or reagent of phosphoramidite that gives phosphotriester; and

(e) simultaneous or sequential removal of protection phosphate, silyl and the remaining protective groups.

2. The method according to claim 1, in which PG represents a 2,2,2-trichlorocarbanilide group, and tizamidine horseley reagent represents a tert-butyldimethylchlorosilane.

3. The method according to claim 1, in which the carbodiimide reagent for 3-O-acylation use methodid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and the catalyst is 4-pyrrolidinedione.

4. SPO is about according to claim 1, in which the reagent peptide condensation used for the N-acylation is methodid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

5. The method according to claim 1, in which the phosphate protecting group is benzyl, substituted benzyl, tert-botep, 2,2,2-trichloroethyl, 2-trimethylsilylmethyl or allyl.

6. The method according to claim 1, in which PG represents a 2,2,2-trichlorocarbanilide group, tizamidine horseley reagent represents a tert-BUTYLCARBAMATE and phosphate protecting group is benzyl.

7. The method according to claim 1, in which PG represents a 9-fluorenylmethoxycarbonyl group, tizamidine horseley reagent represents a tert-BUTYLCARBAMATE and phosphate protecting group is benzyl.

8. The method according to claim 1, where the derivative 2-amino-2-deoxy-β-O-glucopyranose has the formula

,

,

or

,

9. The method according to claim 8, in which the derived glucopyranose interacts with tert-butylimidazolium in the presence of a tertiary amine, which gives 6-O-Siciliano derivative of the formula

10. The method according to claim 8, in which the derived glucopyranose interacts with tert-butylimidazolium in the presence of the tvii tertiary amine, that gives 6-O-Siciliano derivative of the formula

11. The method of claim 8, where the derived glucopyranose interacts with tert-butylimidazolium in the presence of pyridine, which gives 6-O-Siciliano derivative of the formula



 

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