Process for the production of peracylated 1-0-glycosides

Details Process for the production of peracylated 1-0-glycosides Process for the production of peracylated 1-0-glycosides

2002-07-11

2004-12-14

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S018500, C536S018600, C536S124000

Reexamination Certificate

active

06831164

ABSTRACT:

The invention relates to a new process for the production of peracylated 1-O-glycosides of general formula I, which is cited in more detail in the claims. The process according to the invention starts from economical starting materials, provides good yields, and allows the production of peracylated saccharides with 1-O-functionalized side chains on an enlarged scale.
Peracylated saccharide derivatives are valuable intermediate products in synthetic chemistry. Pharmaceutical chemistry primarily uses such components very frequently, since many highly potent and selective pharmaceutical agents carry sugar radicals. Thus, for example, in the Journal of Drug Targeting 1995, Vol. 3, pp. 111-127, applications of the so-called “glycotargeting” are described. So-called “multi-antennary sugar chains” are described in Chemistry Letters 1998, p. 823. By clustering sugar units, the carbohydrate-receptor-interaction in the case of the cell-cell-interaction is considerably improved. The synthesis of galactosides with high affinity to the asialoglycoprotein receptor was 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 then can be suspended on various other molecules. A good survey on the use of saccharides as a basis of glycobiology was provided in Acc. Chem. Res. 1995, 321. Also, for the synthesis of LewisX mimetic agents (Tet. Lett. Vol. 31, 5503), functionalized monosaccharides are used as precursors (see also JACS 1996, 118, 6826).
The use of derivatized monosaccharides as intermediate stages for potential pharmaceutical agents was well represented in Current Medicinal Chemistry, 1995, 1, 392. Perbenzylated-1-OH-sugar derivatives (galactose, glucose) are also used in the synthesis of heart-active glycosides (digitoxin-conjugates). The 1-O-glycosylation is carried out here via trichloroacetimidate and BF
3
-catalysis (J. Med. Chem. 1986, 29, p. 1945). For the production of immobilized sugar ligands (e.g., linkage to HSA), functionalized, protected monosaccharides are used (Chemical Society Reviews 1995, p. 413).
It is the purpose of a group of syntheses to introduce additional functionality into a sugar molecule via a 1-O-glycosylation reaction. Here, primarily terminal COOH—, amino- or OH— groups are of interest, since the latter can be further reacted in subsequent steps.
The production of 1-O-glycosides is carried out in most cases according to standard methods, such as, e.g., according to the trichloroacetimidate methods described by Koenigs-Knorr, Helferich or 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. Ber. 94 (1961), 491; B. Helferich and W. M. Müller, Chem. Ber. 1970, 103, 3350; G. Wulff, G. Röhle and W. Krüger, Ang. Chem. Internat. Edn., 1970, 9, 455; J. M. Berry and G. G. S. Duthon, Canad. J. Chem. 1972, 50, 1424; R. R. Schmidt, Angew. Chem. [Applied Chemistry] 1986, 98, 213.]
A feature that is common to all of these methods is that the 1-hydroxyl group is converted into a reactive form that is ultimately used as a leaving group. Under Lewis acid catalysis (partially in stoichiometric amount), the actual reaction is carried out with an alcohol to form 1-O-glycoside. For such reactions, numerous examples are provided in the literature.
In the production of immunostimulant KRN-7000 (Kirin Brewery), the condensation of tetra-O-benzyl-&bgr;-D-galactopyranosyl-bromide with a primary alcohol, whose hydroxyl group sits at the end of a di-hydroxy-amido-C-chain (in DMF/toluene under Lewis acid catalysis), is thus a central step (Drug of the Future 1997, 22(2), p. 185). In Japanese Patent JP 95-51764, the reaction of 1-O-acetyl-2,3,4-tri-O-benzyl-L-fucopyranose with polyoxyethylene-30-phytosterol (BPS-30, NIKKO Chem., Japan) under trimethyl-silylbromide/zinc triflate catalysis was described. In Bull. Chem. Soc. 1982, 55(4), pp. 1092-6, 1-O-glycosylations of perbenzyl-sugars under titanium tetrachloride catalysis in dichloromethane are described.
In Liebigs Ann. Org. Bioorg. Chem.; EN; 9; 1995; 1673-1680, the production of 3,4,5-trisbenzyloxy-2-benzyloxymethyl-6-(2-hexadecyloxyethoxy)-tetrahydropyran is described. Starting from 2,3,4,6-tetra-O-benzyl-D-glucopyranose, the 1-O-glycosylation is performed with use of Bu
4
NBr, CoBr
2
, Me
3
SiBr and a molecular sieve in methylene chloride within 60 hours.
A tetrabenzyl derivative, which contains a terminal carboxyl group that is protected as a methyl ester, is described in Carbohydr. Res.; EN; 230; 1; 1992; 117. The carboxyl group can then be released and further reacted. For glycosylation, silver carbonate is used in dichloromethane. The use of expensive silver carbonate limits the batch size and makes an economical up-scaling almost impossible. The same problem applies for the compound below, which was described in Tetrahedron Lett. 30, 44, 1989, p. 6019. Here, 2,3,4,6-tetra-O-benzyl-D-mannosyl-bromide in nitromethane is reacted with 2-benzyloxyethanol with the aid of mercury cyanide to form 1-O-glycoside. The use of mercury cyanide in pilot-plant installations is problematical in nature and can be rejected from the environmental-political standpoint.
The substance libraries for the high-capacity-screening described most recently very frequently use saccharides (Angew. Chemie 1995, 107, 2912). Here, the purpose is to have present sugar components in protected form, which carry a functional group, such as, e.g., —COOH, or —NH
2
, which can be reacted in, e.g., an automated synthesis. The components that are used in this respect were described by Lockhoff, Angew. Chem. 1998, 110 (24), p. 3634. Primarily the 1-O-acetic acid of perbenzyl-glucose is important here. The production is carried out over two stages, via trichloroacetimidate and reaction with hydroxyacetic acid ethyl ester, BF
3
catalysis in THF and subsequent saponification with NaOH in MeOH/THF. The total yield over two stages is only 59%, however.
In the same publication, the production of a 1-O-(aminoethyl)-glycoside of the perbenzylated glucose is also described. The reaction is carried out, also starting from trichloroacetimidate, by reaction with N-formylaminoethanol under BF3-catalysis in THF and subsequent saponification in MeOH/THF. The total yield is also relatively low here; it is 45%.
A 1-O-(aminoethyl) derivative of perbenzylxylose passes through as an intermediate product in Carbohydrate Research 1997, 298, p. 173. The synthesis is very lengthy, however, since it starts from 1-bromo-peracetate of xylose. The actual 1-O-glycosylation is carried out via a 1-phenylthioether, which is reacted with 2-azidoethanol under DMTST catalysis (=dimethyl (methylthio)-sulfonium-triflate) in dichloromethane (total number of stages: 7). The total yield is not suitable for an industrial application with less than 40%.
In the survey article by R. R. Schmidt in Angew. Chem. 1986, 98, pp. 213-236, direct reactions of 1-OH-perbenzyl-glucose and -ribose with 2-haloesters and triflates are described. As a base, sodium hydride in THF or benzene is used (Chem. Ber. 1982, 115); the yields are between 40 and 55%. The use of sodium hydride in dioxane or potassium-tert-butylate in THF (both at room temperature) is also described for 1-O-alkylation with triflates (Angew. Chem. 1986, 98, p. 218). The anhydrous reaction conditions that are to be followed most strictly represent a large hurdle in up-scaling such alkylations.
All processes known to date have the great disadvantage that an up-scaling of the process cannot be achieved easily. The use of Lewis acids in 1-O-glycosylation as well as sodium hydride in 1-O-alkylation already requires anhydrous reaction conditions, which in large batches is always associated with difficulties. The working-up and disposal of reaction adjuvants (Hg/cyanide/etc.) is also a problem in many cases.
The object of the invention was therefore to provide a process

Affiliated with

Also associated with

Rating

Process for the production of peracylated 1-0-glycosides does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the production of peracylated 1-0-glycosides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the production of peracylated 1-0-glycosides will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3281841