NO323684B1 - Process for Preparation of Perbenzylated 1-O-Glycosides - Google Patents

Abstract

The invention relates to a method for the production of perbenzylated 1-O glycosides of general formula (I), or the salts thereof, where Zucker<1> = a monosaccharide with a 1-OH functionality, R = benzyl, n = 2, 3 or 4, X = -O-, -S-, -COO- or NH- and L = a straight or branched chain, saturated or unsaturated C1-C30 hydrocarbon, optionally substituted or interrupted by groups. According to the invention, the method uses cheap starting materials, gives good yields and can be used for the large-scale production of perbenzylated saccharides with 1-O functionalised side chains.

Description

Description

The invention relates to a new process for the production of perbenzylated 1-O-glycosides with the general formula I which is characterized in more detail in the patent claims. The process according to the invention starts with inexpensive starting materials, delivers good yields and allows the production of perbenzylated saccharides with 1-0-functionalized side chains on a large scale.

Perbenzylated saccharide derivatives are valuable intermediates in synthetic chemistry. Above all, pharmaceutical chemistry uses such building blocks very frequently, as many highly potent and selective pharmaceuticals contain sugar residues. Thus, e.g. in Journal of Drug Targeting 1995, vol. 3, pp. 111-127, applications of the so-called "Glycotargetings" described. So-called "multi-antennary sugar chains" are described in Chemistry Letters 1998, p. 823. By means of "clustering" of sugar units, the carbohydrate receptor interaction during the cell-cell interaction is significantly improved. The synthesis of galactosides with high affinity for the asialoglycoprotein receptor has been published in J. Med. Chem. 1995, 38, p. 1538 (see also Int. J. Peptide Protein Res. 43, 1994, p. 477). Here, derivatized galactoses with functionalized side chains are produced which can then be attached to various other molecules. A good overview of the use of saccharides as a basis for glycobiology is given in Acc. Chem. Res. 1995, 321. Also for the synthesis of LewisX Mimetika {Tet. Easy. Vol. 31, 5503) functionalized monosaccharides serve as precursors (see also JACS 1996, 118, 6826).

The use of derivatized monosaccharides as intermediates for potential pharmaceuticals is well explained in Current Medicinal Chemistry, 1995, 1, 392. Perbenzylated 1-OH sugar derivatives (galactose, glucose) are also used in the synthesis of cardiac active glycosides (digitoxin conjugates). l-O-glycosides none take place here via trichloroacetimidate and BF3 catalysis <J. With. Chem. 1986, 29, p. 1945). For the preparation of immobilized sugar ligands (e.g. for connection to HSA)

functionalized, protected monosaccharides are used

(Chemical Society Reviews 1995, p. 413).

One group of syntheses aims to introduce additional functionality into the sugar molecule via an 1-O-glycosidation reaction. Above all, terminal COOH, amino or OH groups are of interest here, as these can be converted further in subsequent steps.

The production of l-O-glycosides takes place in most cases according to classical methods, such as e.g. according to the method of Koenigs-Knorr, Helferich, or the trichloroacetimidate method described by R.R. Schmidt [W. Koenigs and E. Knorr, Ber. dtsch. chem. Ges. 34 (1901) 957; B. Helferich and J. Goendeler, Ber. dtsch. Chem. Ges. 73 (1940) 532; B. Helferich, W. Piel and F. Eckstein, Chem. Pray. 94 (1961), 491; B. Helferich and W..M. Muller, Chem. Pray. 1970, 103, 3350; G. Wulff, G. Rohle and W. Kriiger, Ang. Chem. Boarding school. Edn., 1970, 9, 455; J.M. Berry and G.G.S. Duthon, Canada. J. Chem. 1972, 50, 1424; R. R. Schmidt, Angew. Chem. 1986, 98, 213].

All these methods have in common that the 1-hydroxyl group is transferred to a reactive form which ultimately serves as a leaving group. The actual reaction with an alcohol to 1-0-glycoside takes place under Lewis acid catalysis (partially in stoichiometric amount). There are numerous examples of such transactions in the literature.

Thus, in the preparation of the immunostimulant KRN-7000 (Kirin Brewery) the condensation of tetra-O-benzyl--D-galac-topyranosyl bromide with a primary alcohol whose hydroxyl group sits at the end of a di-hydroxyamido-C chain (in DMF/toluene during Lewis acid catalysis) a key step (Drug of the Future 1997, 22(2), p. 185). In the Japanese patent JP 95-51764, the reaction of 1-0-acetyl-2,3,4-tri-O-benzyl-L-fucopyranose with polyoxyethylene-30-phytosterol (BPS-30, NIKKO Chem., Japan) under trimethylsilyl bromide/zinc triflate catalysis has been described. In Bull. Chem. Soc. 1982, 55(4), pp. 1092-6, 1-O-glycosidations of perbenzyl sugars under titanium tetrachloride catalysis in dichloromethane are described.

In Liebig's Ann. Org. Bioorg. Chem.; ONE; 9; 1995; 1673-1680, the preparation of 3,4,5-trisbenzyloxy-2-benzyloxy-methyl-6-(2-hexadecyloxyethoxy)-tetrahydropyran is described. Starting from 2,3,4,6-tetra-O-benzyl-D-glucopyranose, 1-O-glycosides are not obtained using Bu 4 NBr, CoBr 2 , Me 3 SiBr and molecular sieve in methylene chloride carried out within 60 hours.

A tetrabenzyl derivative containing a terminal carboxyl group protected as a methyl ester is described in Carbohydr. Res.; ONE; 230; 1; 1992; 117. The carboxyl group can then be released and reacted further. For the glycosidation, silver carbonate in dichloromethane is used. The use of the expensive silver carbonate limits the charge size and makes an economic scale-up almost impossible. The same problem applies to the subsequent compound which has been described in Tetrahedron Lett. 30, 44, 1989, p. 6019. Here, 2,3,4,6-tetra-O-benzyl-D-mannosyl bromide in nitromethane is converted to the 1-O-glycoside with 2-benzyloxyethanol with the aid of mercuric cyanide. The use of mercuric cyanide in test facilities is problematic and must be discouraged for environmental protection reasons.

The substance libraries for high-throughput screening that have been described in recent times very frequently use saccharides (Angew. Chemie 1995, 107, 2912). Here, the goal is for sugar building blocks to be available in a protected form that carries a functional group, such as e.g. -COOH or -NH2, such as can be implemented in an automated synthesis. The building blocks that find use for this have been described in Lockhoff, Angew. Chem. 1998, 110(24), p. 3634. Above all, the 1-O-acetic acid of perbenzylglucose is important here. The preparation takes place in 2 steps, via trichloroacetimidate and reaction with hydroxyacetic acid ethyl ester, BF3 catalysis in THF and subsequent saponification with NaOH in MeOH/THF. However, the overall yield over 2 stages amounts to only 59%.

The 1-0-acetic acid ethyl ester which is then passed through transiently is, according to EP 882733, obtained by reacting 2,3,4,6-tetra-O-benzylglucose with hydroxyacetic acid ethyl ester in the presence of catalytic amounts of p-toluenesulfonic acid by boiling in benzene in the event of a return, but admittedly without specifying the dividend.

In the same publication, the preparation of a 1-O-(aminoethyl)-glycoside of the perbenzylated glucose is also described. The reaction takes place, again starting from the trichloroacetimidate, by reaction with N-formylaminoethanol under BF3 catalysis in THF and subsequent saponification in MeOH/THF. The overall dividend is also relatively low here and amounts to 45%.

A 1-O-(aminoethyl) derivative of perbenzylxylose is passed according to Carbohydrate Research 1997, 298, p. 173, as an intermediate product. However, the synthesis is very complicated as it starts from the 1-bromoacetate of xylose. The actual 1-O-glycosidation takes place via a 1-phenylthioether which is reacted with 2-azido-ethanol under DMTST catalysis (= dimethyl (methylthio)-sulfonium triflate) in dichloromethane (total number of steps: 7). At less than 40%, the total yield is not suitable for an industrial application.

In the review article by R.R. Schmidt in Angew. Chem. 1986, 98, pp. 213-236, direct reactions of 1-OH-perbenzylglucose and -ribose with 2-halogenesters and triflates are described. Sodium hydride in THF or benzene is used as a base (Chem. Ber. 1982, 115). The yields are between 40 and 55%. Also the use of sodium hydride in dioxane or potassium tert.-butylate in THF (both at room temperature) is described for the 1-0-alkylation with triflates (Angew. Chem. 1986, 98, p. 218). The anhydrous reaction conditions, which must be strictly adhered to, represent a major obstacle in scaling up such alkylations.

All previously known methods are burdened with the major disadvantage that scaling up the process cannot be realized without further ado. The use of Lewis acids in 1-O-glycosides none as well as of sodium hydride in the 1-O-alkylation always requires anhydrous reaction conditions, which is always associated with difficulties with large charges. The processing and removal of the reaction aids (Hg/cyanide/etc.) is also a problem in several cases.

It was therefore the task of the invention to provide a method by means of which perbenzylated saccharides with a 1-0-functionalized side chain could be produced economically and environmentally friendly on a larger scale.

The task of the invention is solved according to the method stated in the patent claims, by means of which perbenzylated 1-O-glycosides of the general formula I

will be able to be produced. According to the invention's definition, sugar<1> in the general formula I means a monosaccharide functionalized in the 1-OH position, whereby it can also refer to

deoxysugars which instead of one or more OH groups contain an H atom. According to a preferred embodiment of the invention, the sugar in the general formula I means a monosaccharide with 5 or 6 C atoms, e.g. glucose, mannose, galactose, ribose, arabinose or xylose or their deoxysugars, such as e.g. €-deoxygalactose (fucose) or 6-deoxy-mannose (rhamnose).

The residue R represents the benzyl group which, depending on the monosaccharide used or its deoxyform, is present at least twice and when using di-, tri- or polysaccharides is correspondingly present several times.

The residue X means -O-, -S-, -C00- or -NH-. As a result of the method according to the invention, alcohols, carboxylic acids or amines with the general formula I are consequently obtained.

The residue L can mean a straight-chain, branched, saturated or unsaturated Cj-Cjo carbon chain which is optionally interrupted by 1-10 oxygen atoms, 1-3 sulfur atoms, 1-2 phenylene, 1-2 phenyleneoxy, 1-2 phenylenedioxy groups, a thiophene, pyrimidine or pyridine residue and/or is optionally substituted with 1-3 phenyl-,. 1-3 carboxyl, 1-5 hydroxy, 1-5 O-Cj-Gj-alkyl, 1-3 amino groups, 1-3 CF3 groups or 1-10 fluorine atoms. According to the invention, preferred residues are L whereby Y means the site of attachment to the sugar, and c is the site of attachment to the residue X. A particularly preferred means of attachment is. L is the -CHa group. For the preparation of the perbenzylated 1-O-glycosides of the general formula I, a perbenzylated 1-0H-sugar of the general formula II in which sugar, R and n have the above meaning is dissolved in an organic solvent that is not miscible with water, and reacted with an alkylating reagent of the general formula III in which Nu means a nucleofuge, L and X have the aforementioned meaning, and Bg is a protecting group, in the presence of a base and optionally a phase transfer catalyst. As a nucleofuge, e.g. the residues -Cl, -Br, -J, -OTs, -OMs, -OSOjCFj, -OSO 2 CtF 9 or -OSO 3 C 8 F 17 be contained in the alkylating reagent of the general formula III.

For the protecting group Bg, it is a common acid or amine, hydroxy or thiol protecting group, depending on whether X means the residue -0-, -C00- or -NH-. These protective groups are well known to the person skilled in the art (Protective Groups in Organic Syntheses, 2nd ed., T.W. Greene and P.G.M. Wuts, John Wiley&Sons, Inc., New York 1991).

The reaction according to the invention can take place at temperatures from 0-50 °C, preferably from 0 °C to room temperature. The reaction times are from 10 minutes to 24 hours, preferably from 20 minutes to 12 hours.

The base is added either in solid form, preferably finely powdered, or as a 10-70%, preferably 30-50%, aqueous solution. NaOH and KOH serve as preferred bases.

As organic solvents that are not miscible with water, for the alkylation process according to the invention, e.g. toluene, benzene, CF3-benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or mixtures thereof are used.

Quaternary ammonium or phosphonium salts known for this purpose or also crown ethers, such as e.g. [15]-krona-5- or [18]-krona-6. Preferably, quaternary ammonium salts with four identical or different hydrocarbon groups on the cation selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl are mentioned. The hydrocarbon groups on the cation must be sufficiently large to ensure good solubility of the alkylating reagent in the organic solvent. According to the invention, N(butyl)4<+->Cl", N (butyl) 4+-HS04", but also N (methyl) 4*-Cl" are preferably used. After the reaction has taken place, work-up can the reaction mixture takes place by isolation of the still protected end product and with subsequent normal cleavage of the protecting group to the end product with the general formula I. However, it is preferred that the still protected end product is not isolated, but that the solvent is removed, that the residue is taken up in a new solvent which is suitable for the removal of the protecting group and that the removal is carried out here. The procedure for removing the protective group and for the regeneration of the acid, amino, hydroxy or thiol group is well known to the person skilled in the art. an acid protecting group that blocks the acidic proton of the carboxyl group, i.e. for example if methyl, ethyl, benzyl or tert.-butyl, the acid is regenerated in the usual way with the help of alkaline hyd Rolyse. In the method according to the invention, in this case the residue, after removal of the solvent from the alkylation reaction, is taken up in a new solvent, e.g. methanol, ethanol, tetrahydrofuran, isopropanol, butanol or dioxane. An aqueous solution of a base is then added, and the alkaline hydrolysis is carried out at temperatures from 0-100 °C. As hydroxy protecting groups, e.g. benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-tert-butylsilyl or diphenyl-tert-butylsilyl groups in question. The hydroxy groups can also be present, e.g. as THP ether, t-Alkoxyethyl ether, MEM ether or also as ester with aromatic or aliphatic carboxylic acids, such as e.g. acetic acid or benzoic acid. In the case of polyols, the hydroxy groups can also be protected in the form of ketals with e.g. acetone, acetaldehyde, cyclohexanone or benzaldehyde. The hydroxy protecting groups can according to literature methods known to the person skilled in the art, e.g. by hydrogenolysis, acid treatment of the ethers and ketals, alkali treatment of the esters, or treatment of the silyl protecting groups with fluoride, are released (see, e.g., Protective Groups in Organic Syntheses, 2nd ed., T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1991). ;The thiol groups can be protected as benzyl ethers which are cleavable with sodium in ammonia or boiling ethanol (W.J. Patterson, v. du Vigneaud, J. Biol. Chem. 111:393, 1993). S-tert-butyl ethers are readily cleaved with hydrogen fluoride/anisole at room temperature (S. Salzakibona et al., Bull. Chem. Soc. Japn., 40:2164 (1967)]. S-benzyloxycarbonyl derivatives can be conveniently cleaved with concentrated ammonia solution at room temperature (A. Berger et al., J. Am. Chem. Soc, 78:4483, 1956). Only at boiling temperatures that ur, S-benzyloxycarbonyl derivatives of trifluoroacetic acid are cleaved [L. Zervas et al., J. Am . Chem. Soc, 85:1337 (1963)]. The NH 2 groups can be protected in many ways and again released. The N-trifluoroacetyl derivative is cleaved with potassium or sodium carbonate in water [H. Newman, J. Org. Chem. , 30:287 (1965), M.A. Schwartz et al., J. Am. Chem. Soc, 95 G12 (1973)] or simply by ammonia solution [M. Imazama and F. Eckstein, J. Org. Chem. , 44:2039 (1979)]. Likewise, the tert-butyloxycarbonyl derivative is easily cleaved. Stirring with trifluoroacetic acid is sufficient [B.F. Lundt et al., J. Org. Chem., 43:2285 (1978)]. The group ofNH2 protecting groups that can be cleaved hydrogenolytically or reductively are very large: the N-benzyl group can be conveniently cleaved with hydrogen/Pd-C [W.H. Hartung and R. Simonoff, Org. Reactions VII, 263 (1953)], which also applies to the trityl group [L. Zervas et al., J. Am. Chem. Soc, 78:1359 (1956)] and the benzyloxycarbonyl group [M. Bergmann and L. Zervas, Ber. 65:1192 (1932)]. Of the silyl derivatives, the easily cleavable tert-butyldiphenyl-silyl compounds [L.E. Overman et al., Tetrahedron Lett., 27:4391 (1986)] as well as the 2-(trimethylsilyl)-ethyl carbamates [L. Grehn et al., Angew. Chem. Int Ed. Engl., 23:296 (1983)] and the 2-trimethylsilyletanesulfonamides [R.S. Garigipati and S.M. Weinreb, J. Org. Chem., 53:4134 (1988)] used, which can be cleaved with fluoride ions. 9-Fluorenylmethylcarbamate is particularly easily cleavable. The cleavage takes place with amines, such as piperidine, morpholine, 4-dimethylaminopyridine, but also with tetrabutylammonium fluoride [L.A. Corpino et al., J. Org. Chem., 55:1673 (1990); M. Ueki and M. Amemiya, Tetrahedron Lett., 28:6617 (1987)]. The isolation of the final product obtained with the general formula I (alcohol, thiol, amine or carboxylic acid) also takes place - according to usual methods which are well known to the person skilled in the art. Thus, e.g. in the case of the acid protecting group, the solvent evaporated from the hydrolysis reaction and the residue taken up in an aprotic solvent. When acidifying with an aqueous acid solution, the pH is set to approx. 2-4, and then the organic phase is separated. The perbenzylated 1-0-glycoside can now be recovered by crystallization or chromatography. Optionally, the obtained compounds of the general formula I can also be converted to their salts in the usual way. The yields of the compounds of the general formula I, which can be obtained with the method according to the invention, are good. For known compounds, for which a comparison with the state of the art is possible, they lie above the yields according to the state of the art. Thus, e.g. for 1-0-acetic acid of perbenzylated glucose an overall yield of 59% described in Angew. Chem. 1998, 110 (24), p. 3634, with the method mentioned there, while according to the invention the yield for this compound over 2 steps amounts to 82% (cf. example 7 in the present patent application). The preparation of the compound according to example 12 in the present patent application is also described in this publication. While the yield of this compound is 78% according to the invention over 2 steps, with the method described in the publication, only 45% is obtained. In addition to the high yields, the method according to the invention also offers the advantage that it starts from inexpensive starting materials, that an upscaling of the process is possible and that it allows easy isolation of the end products. The starting materials are commercial goods or easy to obtain from purchasable precursors. Thus, tetra-2,3,4,6-0-benzyl-D-glucopyranose can be obtained from Fluka AG, Buchs, Switzerland. At Fluka, methyl-D-mannopyranoside and methyl-D-galactopyranoside are also catalog items. By benzylation and cleavage of the glycoside, 2,3,4,6-tetra-O-benzyl-D-mannose or -galactose is obtained. ;Via the sequence methylglycoside-perbenzyl-methylglycoside-perbenzyl-1-OH-saccharide, the perbenzyl-l-OH derivatives of the pentoses ribose, arabinose), the hexoses and the deoxyhexoses (rhamnose, fucose) can be recovered. The compounds produced according to the invention are valuable intermediates in synthetic chemistry. Thus, they can e.g. find application for the construction of carbohydrate dendrimers, for the synthesis of NMR contrast agents and for the introduction of sugar residues in pharmaceuticals. The invention thus relates to a process for the production of perbenzylated 1-O-glycosides with the general formula I; ; 1 which ;sugar<1>is a monosaccharide functionalized in the 1-OH position, ;R represents benzyl, ;n means 2, 3 or 4, ;X means -0-, -S-, -C00- or - NH-, ;and ;L means a straight-chain, branched, saturated or unsaturated Ci-Cj carbon chain which is optionally interrupted by 1-10 oxygen atoms, 1-3 sulfur atoms, 1-2 phenylene-, 1-2 phenyleneoxy-, 1- 2 phenylenedioxy groups, a thiophene, pyrimidine or pyridine residue and/or is optionally substituted with 1-3 phenyl-, 1-3 carboxyl-, 1-5 hydroxy-, 1-5 O-C^-CV alkyl-, 1-3 amino groups, 1- ;3 CF3 groups or 1-10 fluorine atoms, ;or their salts, characterized in that a perbenzylated 1-OH-sugar of the general formula II ; ; wherein sugar<1>, R and ri have the indicated meaning, ;is reacted with an alkylating reagent of the general formula ;(III) ; ; wherein Nu means a nucleofuge, L and X have the aforementioned meaning, and Bg represents a protecting group, in an organic solvent in the presence of a base and optionally a phase transfer catalyst at a temperature from 0-50 °C, after which the protecting group is cleaved of and the reaction product obtained is optionally transferred to a salt. The method according to the invention will be explained in more detail in the following with the help of design examples. ;Example 1 ;2,3,4,6-tetra-O-benzyl-1-O-carboxymethyl- mannopyranose ;A mixture of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl -mannopyrano se , 1.70 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) of finely powdered potassium hydroxide in 350 ml of toluene are cooled to 0 °C. At 0 °C, 29.3 g (150 mmol) of bromoacetic acid tert-butyl ester are added dropwise over the course of 10 minutes with vigorous stirring. The mixture is stirred for 1 hour at 0 °C. 250 ml MTB (methyl tert-butyl ether) is added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The residue is taken up in 500 ml of ethanol. 40 ml of 50% aqueous caustic soda is added and boiled for 0.5 hour under reflux. It is cooled to 0 °C, the pH is adjusted to 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml water, 500 ml acetic acid ethyl ester and the pH value for the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated and the aqueous phase is once again post-extracted with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid = 20:5:3:0.5). The fractions containing product are evaporated, dissolved in 400 ml ethyl acetate and shaken out 3 times with 200 ml water. The organic phase is then separated and evaporated to dryness in a vacuum. ;Yield: ;50.9 g (85% of theoretical, over 2 steps) of a colorless, viscous oil. ;Elementary analysis: ; ; Example 2; 2, 3, 4, 6-tetra-O-benzyl-1-O-carboxymethyl-mannopyranose; A mixture of 54.1 g (100 mmol) 2,3,4,6-tetra-O-benzyl - mannopyranose, 1.7 g (5 mmol) tetrabutylammonium hydrogen sulfate and 24 g (600 mmol) finely powdered sodium hydroxide in 350 ml toluene are cooled to 0 °C. At 0 °C, 29.3 g (150 mmol) of bromoacetic acid ethyl ester are added dropwise over 10 minutes with vigorous stirring. The mixture is stirred for 1 hour at 0 °C. 250 ml MTB (methyl tert-butyl ether) is added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The remainder is taken up in 500 ml ethanol/50 ml water. 60 ml of 50% aqueous caustic soda is added and boiled for 4 hours under reflux. It is cooled to 0 °C, the pH is adjusted to 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of acetic acid ethyl ester and the pH value of the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated, and the aqueous phase is once again post-extracted with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, and the solvent is distilled off in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid = 20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 400 ml ethyl acetate and shaken out 3 times with 200 ml water. The organic phase is then separated and evaporated to dryness in a vacuum. Yield: 48.5 g (81% of theory, over 2 steps) of a colorless viscous oil. ;Elementary analysis: ; ; Example 3; 2, 3, 4, 6-tetra-O-benzyl-1-O-carboxymethyl-mannopyranose; A mixture of 54.1 g (100 mmol) 2,3,4,6-tetra-O-benzyl - mannopyranose, 0.55 g (5 mmol) tetramethylammonium chloride and 33.7 g (600 mg) finely powdered potassium hydroxide in 350 ml benzene are cooled to 10 °C. At 10 °C, 35.7 g (160 mmol) 6-bromohexanoic acid ethyl ester is added dropwise during 10 minutes under vigorous stirring. Stir for 2 hours at 10 °C. Add 250 ml of MTB (methyl tert-butyl ether), filter off the solid and evaporate the filtrate to dryness in vacuo. The residue is taken up in 500 ml of ethanol/50 ml of water. 60 ml of 50% aqueous sodium hydroxide solution is added and refluxed for 4 hours. It is cooled to 0 °C, and the pH is adjusted to 8 with 10% aqueous hydrochloric acid, and then the solvent distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of acetic acid ethyl ester and the pH value of the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated and d an aqueous phase then extracted once more with 200 ml ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid = 20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 400 ml ethyl acetate and shaken out 3 times with 200 ml water. The organic phase is then separated and evaporated to dryness in a vacuum. Yield: 51.7 g (79% of theory, over 2 steps) of a colorless solid. ;Elementary analysis: ; ; Example 4: 2, 3, 4, 6-tetra-O-benzyl-1-0-(1-phenyl-1-carboxy-et-2-yl)-mannopyrano s e ; A mixture of 54.1 g (100 mmol ) 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.39 g (5 mmol) tetrabutylammonium chloride and 24 g (600 mmol) finely powdered sodium hydroxide in 350 ml toluene are cooled to 0 °C. At 0 °C, 38.6 g (150 mmol) of 2-phenyl-3-bromopropionic acid ethyl ester dissolved in 30 ml of toluene are added dropwise over 10 minutes with vigorous stirring. The mixture is stirred for 1 hour at 0 °C. 250 ml MTB (methyl tert-butyl ether) is added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The remainder is taken up in 500 ml ethanol/50 ml water. 60 ml of 50% aqueous caustic soda is added and boiled for 4 hours under reflux. It is cooled to 0 °C, adjusted to pH 8 with 10% aqueous hydrochloric acid and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of acetic acid ethyl ester and the pH value of the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid 20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 400 ml ethyl acetate and shaken out 3 times with 200 ml water. The organic phase is then separated and evaporated to dryness in a vacuum. Yield: 54.4 g (79% of theory, over 2 steps) of a colorless solid. ;Elementary analysis: ; ; Example 5; 2, 3, 4, 6-tetra-O-benzyl-1-O-carboxymethyl-mannopyranose; A mixture of 54.1 g (100 mmol) 2,3,4,6-tetra-O-benzyl - mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride in 350 ml of toluene and 150 ml of 50% aqueous potassium hydroxide are cooled to 0 °C. At 0 °C, 30.12 g (200 mmol) of chloroacetic acid tert-butyl ester are added dropwise over the course of 20 minutes with vigorous stirring. The mixture is stirred for 1 hour at 10 °C. 250 ml of methyl tert-butyl ether is added, the organic phase is separated and the aqueous phase is extracted twice with 250 ml of water. The solvent of the combined organic phases is distilled off in vacuo and the residue taken up in 500 ml of ethanol. 40 ml of 50% aqueous caustic soda is added and boiled for 0.5 hour under reflux. It is cooled to 0 "C, with 10% hydrochloric acid it is adjusted to pH 8, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of acetic acid ethyl ester and the pH value of the aqueous phase is adjusted at pH 2 (10% aqueous hydrochloric acid) with stirring. The organic phase is separated and the aqueous phase is extracted once more with 200 ml ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid = 20:5:3:0.5).The product-containing fractions are evaporated, dissolved in 400 ml of ethyl acetate and shaken out 3 times with 200 ml of water. The organic phase is then separated and evaporated to dryness in vacuo. ;Yield: ;41.1 g (82% of the theoretical, over 2 steps) of a colorless, viscous oil. ;Elementary analysis: ; ;Example 6 ;2, 3 , 4, 6- tetra- O- benzyl- l- O- carboxymethyl- glucopyranose; A mixture of 54, 1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 24 g (600 mmol) of finely powdered sodium hydroxide in 300 ml of tetrahydrofuran are cooled to 0 °C. At 0 °C, 78 g (150 mmol) of 5-tosyloxy-pentanecarboxylic acid tert-butyl ester dissolved in 40 ml of tetrahydrofuran are added dropwise over the course of 30 minutes with vigorous stirring. The mixture is stirred for 3 hours at 0 °C. 300 ml MTB (methyl tert-butyl ether) is added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The residue is taken up in 500 ml of methanol. Add 50 ml of 50% aqueous caustic soda and boil for 1 hour under reflux. It is cooled to 0 °C, the pH is adjusted to 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up with 1,300 ml of water, 500 ml of acetic acid ethyl ester and the pH value in the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid = 20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 400 ml ethyl acetate and shaken out 3 times with 200 ml water. The organic phase is then separated and evaporated to dryness in a vacuum. ;Yield: ;50 g (78% of theoretical, over 2 steps) of a colorless solid. ;Elementary analysis: ; ; Example 7; 2, 3, 4, 6-tetra-O-benzyl-1-O-carboxymethyl-glucopyranose; A mixture of 54.1 g (100 mmol) 2,3,4,6-tetra-O-benzyl - glycopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride in 350 ml of toluene and 200 ml of 50% aqueous sodium hydroxide solution are cooled to 0 °C. At 0 °C, 29.3 g (150 mmol) of bromoacetic acid tert-butyl ester are added dropwise over the course of 20 minutes with vigorous stirring. The mixture is stirred for 0.5 hour at 0 °C. 250 ml of toluene is added, the organic phase is separated and the aqueous phase is extracted twice with 150 ml of toluene. The solvent in the combined organic phases is distilled off in vacuo and the residue taken up in 400 ml of methanol. Add 50 ml of 50% aqueous caustic soda and boil for 0.5 hour under reflux. It is cooled to 0 °C, the pH is adjusted to 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of dichloromethane and the pH value of the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated and the aqueous phase once more post-extracted with 200 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid = 20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 400 ml of ethyl acetate and shaken out 3 times with 200 ml of water. The organic phase is then separated and evaporated to dryness in a vacuum. ;Yield: ;49.1 g (82% of theoretical, over 2 steps) of a colorless, viscous oil. ;Elementary analysis: ; ; Example 8; 2, 3, 4, 6-tetra-O-benzyl-1-O-carboxymethyl-glucopyranose; A mixture of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl- glucopyranose, 0.55 g (5 mmol) tetramethylammonium chloride and 33.7 g (600 mmol) finely powdered potassium hydroxide in 350 ml benzene are cooled to 0 °C. At 0 °C, 44 g (150 mmol) of 11-bromodecanoic acid ethyl ester dissolved in 50 ml of benzene are added dropwise over the course of 30 minutes with vigorous stirring. The mixture is stirred for 2 hours at 20 °C. 250 ml of methyl tert-butyl ether is added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The remainder is taken up in 500 ml ethanol/50 ml water. 60 ml of 50% aqueous caustic soda is added and boiled for 5 hours under reflux. It is cooled to 0 °C, adjusted to pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of dichloromethane and the pH value of the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid = 20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 400 ml ethyl acetate and shaken out 3 times with 200 ml water. The organic phase is then separated and evaporated to dryness in a vacuum. Yield: 58.4 g (78% of theory, over 2 steps) of a colorless solid. ;Elementary analysis: ; ; Example 9; 2, 3, 4, 6-tetra-O-benzyl-1-O-carboxymethyl-galactopyranose; A mixture of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl -mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride in 350 ml of toluene and 150 ml of 50% aqueous potassium hydroxide are cooled to 0 °C. At 0 °C, 3 0.12 g (200 mol) of chloroacetic acid tert-butyl ester are added dropwise over the course of 20 minutes with vigorous stirring. The mixture is stirred for 1 hour at 10 °C. 250 ml of methyl tert-butyl ether is added, the organic phase is separated and the aqueous phase is extracted twice with 250 ml of water. The solvent in the combined organic phases is distilled off in vacuo and the residue taken up in 500 ml of ethanol. 40 ml of 50% aqueous caustic soda is added and boiled for 0.5 hour under reflux. It is cooled to 0 °C, adjusted to pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of acetic acid ethyl ester and the pH value of the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid - 20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 400 ml ethyl acetate and shaken out 3 times with 200 ml water. The organic phase is then separated and evaporated to dryness in a vacuum. Yield: 41.1 g (82% of theory, over 2 steps) of a colorless viscous oil. ;Elementary analysis: ; Example 10; 2, 3, 4, 6-tetra-O-benzyl-1-O-[1-(4-carboxy)-phenyl-prop-3-yl-galactopyranose; A mixture of 54.1 g (100 mol ) 2,3,4,6-tetra-O-benzyl-galactopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 24 g (600 mmol) of finely powdered sodium hydroxide in 300 ml of tetrahydrofuran are cooled to 10 °C. At 10 °C, 43 g (150 mol) of 4-(3-methanesulfonyloxy-propyl)-benzoic acid ethyl ester dissolved in 50 ml of tetrahydrofuran are added dropwise over the course of 30 minutes with vigorous stirring. The mixture is stirred for 2 hours at 10 °C. 300 ml MTB (methyl tert-butyl ether) is added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The remainder is taken up in 500 ml methanol/50 ml water. 60 ml of 50% aqueous caustic soda is added and boiled for 5 hours under reflux. It is cooled to 0 °C, adjusted to pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of acetic acid ethyl ester and the pH value of the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid = 20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 400 ml ethyl acetate and shaken out 3 times with 200 ml water. The organic phase is then separated and evaporated to dryness in a vacuum. Yield: 54.1 g (77% of theory, over 2 steps) of a colorless solid. ;Elementary analysis: ; ; Example 11; 2, 3, 5-tri-Q-benzyl-1-O-carboxymethyl-ribo£uranose; A mixture of 42.1 g (100 mmol) 2,3,5-tri-O-ribofuranose, 1, 39 g (5 mmol) of tetrabutylammonium chloride in 350 ml of toluene and 200 ml of 50% aqueous caustic soda are cooled to 0 °C. At 0 °C, 29.3 g (150 mmol) of bromoacetic acid tert-butyl ester are added dropwise over the course of 20 minutes with vigorous stirring. The mixture is stirred for 1 hour at 0 °C. 250 ml of methyl tert-butyl ether are added, the organic phase is separated and the aqueous phase is extracted twice with 200 ml of methyl tert-butyl ether. The solvent in the combined organic phases is distilled by 1 vacuum and the residue taken up in 500 ml of ethanol. Add 50 ml of 50% aqueous caustic soda and boil for 0.5 hour under reflux. It is cooled to 0 °C, adjusted to pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of acetic acid ethyl ester and the pH value of the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid * 20:5:3:0.5). The product-containing fractions are evaporated, dissolved in 200 ml of acetic acid ethyl ester and shaken out 3 times with 200 ml of water. The organic phase is then separated and evaporated to dryness in vacuo. Yield: 39.2 g (82% of the theoretical, over 2 steps) of a colourless, viscous oil.

Elemental analysis:

Example 12

2, 3, 5- tri- O- benzyl- l- O-( l-amino-et- 2- yl)- ribofuranose

A mixture of 42.1 g (100 mmol) 2,3,5-tri-O-benzyl-ribof uranose, 3.40 g (10 mmol) tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) finely powdered potassium hydroxide in 350 ml benzene cool to 10 °C. At 10 °C, 38.1 g is added

(150 mmol) of N-(2-bromomethyl)-phthalimide dissolved in 100 ml of benzene dropwise over 40 minutes with vigorous stirring. The mixture is stirred for 3 hours at 10 °C. 300 ml of benzene are added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The filtrate residue is dissolved in 500 ml of ethanol, 25.03 g of hydrazine hydrate (500 mmol) is added, and it is heated for 6 hours under reflux. It is allowed to cool to 0 "C, the precipitate that has formed is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 400 ml of dichloromethane, and this solution is washed twice with 5% aqueous sodium hydroxide solution and then once with water ( each time 300 ml). The organic phase is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/ethanol/triethylamine = 20:2:0.1). Yield: 36.2 g (78% of the theoretical , over 2 steps) of a colorless solid.

Elemental analysis:

Example 13 2,3,4,6-tetra-O-benzyl-1-O-(1-amino-prop-3-yl)-galactopyranose A mixture of 42.1 g (100 mmol) 2,3,4, 6-tetra-O-benzyl-galactopyranose, 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) of finely powdered potassium hydroxide in 350 ml of benzene are cooled to 10 °C. At 10 °C, 40.2 g (150 mmol) of N-(3-bromopropyl)-phthalimide dissolved in 100 ml of benzene are added dropwise over the course of 40 minutes with vigorous stirring. The mixture is stirred for 3 hours at 10 °C. 300 ml of benzene are added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The filtrate residue is dissolved in 500 ml of ethanol, and 25.03 ml of hydrazine hydrate (500 mmol) is added, and it is heated for 6 hours under reflux. Allow to cool to 0 °C, filter off the precipitate and evaporate the filtrate to dryness in a vacuum. The residue is dissolved in 400 ml of dichloromethane, and this solution is washed twice with 5% aqueous caustic soda and then once with water (each time 300 ml). The organic phase is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/ethanol/triethylamine = 20:2:0.1).

Dividend:

46 g {77% of theory, over 2 steps) of a colorless solid.

Elemental analysis:

Example 14

2,3,4,6-tetra-O-benzyl-1-O-{1-amino-hex-6-yl)-mannopyranose

A mixture of 54.1 g (100 mmol) of 2,3,4,6-tetra-0-benzyl-mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride in 350 ml of dichloromethane and 200 ml of 60% aqueous potassium hydroxide is cooled to 0 °C. At 0 °C, 60.3 g (150 mmol) of 6-bromohexylamine-N-(9-fluorenylmethoxycarbonyl) are added dropwise over the course of 30 minutes with vigorous stirring. The mixture is stirred for 1 hour at 0 °C. 300 ml of dichloromethane is added, the organic phase is separated and the aqueous phase is extracted twice with 200 ml of dichloromethane. The solvent in the combined organic phases is distilled off in a vacuum. The residue is taken up in 250 ml of ethanol, and 100 g (1.17 mol) of piperidine are added. The mixture is stirred for 5 hours at 40 °C. The solution is evaporated to dryness, and the residue is chromatographed on silica gel (eluent: dichloromethane/ethanol/triethylamine 20:2:0.1).

Dividend:

41.1 g (79% of theory, over 2 steps) of a colorless solid.

Elemental analysis:

Example 15

2, 3, 4-tri-O-benzyl-6-deoxy-1-O-(1-amino-but-4-yl)-fucopyranose

A mixture of 43.5 g (100 mmol) of 2,3,4-tri-O-benzyl-e-deoxy-fucopyranose, 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate in 350 ml of dichloromethane and 200 ml of 60%-ig aqueous caustic soda is cooled to 0 °C. At 10 °C, 47.4 g (150 mmol) of 2-(trimethylsilyl)-ethylsulfonic acid-N-(4-bromobutyl)-amide dissolved in 100 ml of dichloromethane are added dropwise over the course of 30 minutes with vigorous stirring. The mixture is stirred for 2 hours at 10 °C. 300 ml of dichloromethane is added, the organic phase is separated and the aqueous phase is extracted twice with 200 ml of dichloromethane. The solvent in the combined organic phases is distilled off in a vacuum. The residue is taken up in 350 ml of acetonitrile, and 52.3 g (200 mmol) of tetrabutylammonium fluoride as monohydrate is added. The mixture is stirred for 3 hours at 50 °C. The solution is concentrated to dryness, and the residue is chromatographed on silica gel (eluent: dichloromethane/ethanol/triethylamine = 20:2:0.1).

Dividend:

39.4 g (78% of theory, over 2 steps) of a colorless solid.

Elemental analysis:

Example 16

2, 3, 4, 6- tetra- O- benzyl- 1- 0-( 3, 6, 9, 12, 15- pentaoxa- l- carboxy- hexadecyl- 16- yl)- glucopyranose

A mixture of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 24 g (600 mmol) of finely powdered sodium hydroxide in 350 ml of toluene cool to 0 °C. At 0 °C, 64.3 g (130 mmol) of 17-tosyloxy-3,6,9,12,15-pentaoxaheptadecanoic acid ethyl ester dissolved in 100 ml of tetrahydrofuran are added dropwise over the course of 50 minutes with vigorous stirring. The mixture is stirred for 3 hours at 0 °C. 300 ml of dichloromethane is added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The remainder is taken up in 500 ml ethanol/100 ml water. 60 ml of 60% aqueous caustic soda is added and boiled for 5 hours under reflux. It is cooled to 0 °C, and with 10% aqueous hydrochloric acid it is adjusted to pH 8, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 400 ml of acetic acid ethyl ester and the pH value of the aqueous phase is adjusted to pH 2 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated, and the aqueous phase is then extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol/acetic acid = 20:8:5:0.5). The product-containing fractions are evaporated, dissolved in 400 ml ethyl acetate and shaken out 3 times with 200 ml water. The organic phase is then separated and evaporated to dryness in a vacuum.

Dividend:

64.3 g (77% of the theoretical, over 2 steps) of a colorless oil.

Elemental analysis:

Example 17

2, 3, 4, 6- tetra- O- benzyl- l- O-( l- hydroxy- et- 2- yl)- mannopyranose

A mixture of 54.1 g (100 mmol) 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.7 g (5 mmol) tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) finely powdered potassium hydroxide in 350 ml benzene is cooled to 0 °C. At 0 °C, 31.4 g (150 mmol) of 2,2-dimethyl-propionic acid-2-bromomethyl ester are added dropwise over the course of 30 minutes with vigorous stirring. He stirs for 2 hours at 0 °C. 300 ml of benzene are added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The remainder is taken up in 500 ml ethanol/100 ml water. 100 ml of 50% aqueous lye is added and boiled for 8 hours under reflux. It is cooled to 0 °C, adjusted to pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 400 ml of acetic acid ethyl ester and the pH value of the aqueous phase is adjusted to pH 5 (10% aqueous hydrochloric acid) while stirring. The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel (eluent: dichloromethane/n-hexane/ethanol = 20:8:2). The product-containing fractions are evaporated.

Dividend:

45.6 g (78% of the theoretical, over 2 steps) of a colorless,

tough oil.

Elemental analysis:

Example 18

2, 3, 4, 6- tetra- O- benzyl- 1- O-( l- hydroxy- hex- 6- yl)- glucopyranose

A mixture of 54.1 g (100 mmol) of 2,3,4,6-tetra-0-benzyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 24 g (600 ml) of finely powdered sodium hydroxide in 350 ml of dichloromethane is cooled to 10 °C. At 10 °C, 41.3 g (140 mmol) of 1-(dimethyl-tert-butylsilyloxy)-6-bromohexane dissolved in 100 ml of dichloromethane are added dropwise over 50 minutes with vigorous stirring. The mixture is stirred for 3 hours at 10 °C. 350 ml of dichloromethane is added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The residue is taken up in 350 ml of acetonitrile, and 52.3 g (200 ml) of tetrabutylammonium fluoride (as monohydrate) is added. The mixture is stirred for 3 hours at 50 °C. The solution is concentrated to dryness and the residue chromatographed on silica gel (eluent: dichloromethane/ethanol = 20:1). Yield: 49.3 g (77% of theory, over 2 steps) of a colorless solid.

Elemental analysis:

Example 19

2, 3, 4, 6- tetra- O- benzyl- l- O-( l- hydroxy- et- 2- yl)- galactopyranose

A mixture of 54.1 g (100 mmol) 2,3,4,6-tetra-O-benzyl -benzylgalact opyranose, 1.64 g (15 mmol) tetramethylammonium chloride in 350 ml toluene and 200 ml 60% aq. lye is cooled to 0 °C. At 0 °C, 52.7 g (130 mmol) of 2-(4,4'-dimethoxytriphenylmethyloxy)-ethyl bromide dissolved in 100 ml of toluene are added dropwise over the course of 30 minutes with vigorous stirring. The mixture is stirred for 3 hours at 0 °C. 300 ml of toluene is added, the organic phase is separated and the aqueous phase is extracted twice with 200 ml of toluene. The solvent is distilled off in a vacuum. The residue is taken up in 500 ml of dichloromethane, and 25 g (194 mmol) of dichloroacetic acid are added. The mixture is stirred for 3 hours at 35 °C. The solution is washed 3 times with 300 ml of 10% aqueous sodium hydroxide solution, and the organic phase is concentrated to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane/ethanol 20:1).

Dividend:

46.29 (79% of theoretical, over 2 steps) of a colorless, viscous oil.

Elemental analysis:

Example 20

2, 3, 4- tri- 0- benzyl- 6- deoxy- 1- 0-( 1- hydroxy- 3, 6, 9, 12- tetraaza- tetradec- 14- yl)- galactopyranose

A mixture of 43.5 g (100 mmol) of 2,3,4-tri-0-benzyl-6-deoxygalactopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 24 g (600 mmol) of finely powdered sodium hydroxide in 350 ml of tetrahydrofuran is cooled to 0 °C. At 0 °C, 66.1 g (130 mmol) of 14-tosyloxy-3,6,9,12-tetraaza-1-(dimethyl-tert-butylsilyloxy)-tetradecane, dissolved in 100 ml of tetrahydrofuran, are added dropwise in the course of 40 minutes under vigorous stirring. The mixture is stirred for 3 hours at 10 °C. 300 ml of dichloromethane is added, the solid is filtered off and the filtrate is evaporated to dryness in a vacuum. The residue is taken up in 350 ml of acetonitrile, and 52.3 g (200 ml) of tetrabutylammonium fluoride is added as monohydrate. The mixture is stirred for 3 hours at 50 °C. The solution is concentrated to dryness, and the residue is chromatographed on silica gel (eluent: dichloromethane/ethanol = 20:1).

Dividend:

51.1 g (78% of theory, over 2 steps) of a colorless, viscous oil.

Elemental analysis:

Claims (8)

1. Process for the preparation of perbenzylated l-O-glycosides of the general formula I 1 which one sugar<1> is a monosaccharide that is functionalized in the 1-OH position, R represents benzyl, n means 2, 3 or 4, X means -0-, -S-, -COO- or -NH-, and L means a straight-chain, branched, saturated or unsaturated Ci-Cjp carbon chain which is optionally interrupted by 1-10 oxygen atoms, 1-3 sulfur atoms, 1-2 phenylene-, 1-2 phenyleneoxy-, 1-2 phenylenedioxy groups, a thiophene- , pyrimidine or pyridine residue and/or is optionally substituted with 1-3 phenyl-, 1-3 carboxyl-, 1-5 hydroxy-, 1-5 O-Ci-^-alkyl-, 1-3 amino groups, 1-3 CF3 groups or 1-10 fluorine atoms, or their salts, characterized by a perbenzylated 1-OH sugar of the general formula II wherein sugar<1>, R and n have the stated meaning, is reacted with an alkylating reagent of the general formula (III) wherein Nu means a nucleofuge, L and X have the said meaning, and Bg represents a protecting group, in an organic solvent in the presence of a base and optionally a phase transfer catalyst at a temperature from 0-50 °C, after which the protective group is cleaved off and the resulting reaction product is optionally transferred to a salt. 2. Process according to claim 1, characterized in that a perbenzylated monosaccharide with 5 to 6 C atoms or its deoxy compound is used as perbenzylated 1-OH-sugar of the general formula II. 3. Method according to claim 1 or 2, characterized in that perbenzylated glucose, mannose, galactose, ribose, arabinose, xylose, fucose or rhamnose are used as perbenzylated 1-OH-sugar of the general formula II. 4. Process according to one of the claims 1 to 3, characterized in that the alkylation reagent with the general formula III is used in which the nucleofugen means the residues -Cl, -Br, -J, -OTs, -OMs, -OSOaCF3, -OSOsC« F9or -OS02C„F17. 5. Method according to one of claims 1 to 4, characterized in that the alkylation reagent with the general formula III is used in which the residue L means where means the site of attachment to the sugar, and is the site of attachment to the residue X. 6. Method according to one of claims 1 to 5, characterized in that the organic solvent used is a solvent that is not miscible with water, preferably toluene, benzene, CF3-benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or their mixtures. 7. Method according to one of claims 1 to 6, characterized in that a quaternary ammonium or phosphonium salt or a crown ether, preferably a quaternary ammonium salt, is used as phase transfer catalyst. 8. Method according to one of claims 1 to 7, characterized in that the base is added in solid form or as a 10-70% aqueous solution.