Functionalized Beta 1,6 Glucosamine Disaccharides and Process for Their Preparation

A process for the preparation of an asymmetrically or symmetrically substituted β-(1→6)-linked glucosamine disaccharide comprising reacting a compound of the formula 10:

• wherein:
• R1 is a group selected from a (C3-C6) alkenyl, such as a C3 or C4 alkenyl, preferably 2-propenyl or 1-propenyl;
• X is a hydrogen, a group selected from benzyl or a substituted benzyl, such as 4-methoxybenzyl or 3,4-dimethoxybenzyl or 2,5-dimethoxybenzyl or 2,3,4-trimethoxybenzyl or 3,4,5-trimethoxybenzyl;
• R0 is selected from R5 or R2, wherein R5 is selected from:
• (i) an acyl group derived from a, straight chain-carboxylic acid having from 2 to 24 carbon atoms, preferably a hydroxy acyl group, such as a 3-hydroxy acyl group, an oxo acyl group such as a 3-oxo acyl group, an amino acyl group such as a 3-amino acyl group;
• (ii) an acyloxyacyl group, preferably a 3-acyloxyacyl group, an acylaminoacylgroup, preferably a 3-acylaminoacyl group, an acyl thioacyl group, preferably a 3-acylthioacyl group;
• (iii) an alkyloxyacyl group, preferably a (C2-C24) alkyloxyacyl group, an alkenyloxyacyl group, preferably a (C2-C24) alkenyloxyacyl group, an alkynyloxyacyl group, preferably a (C2-C24) alkynyloxyacyl group an alkyl aminoacyl group, preferably a (C2-C24) alkylaminoacyl group, an alkenylaminoacyl group, preferably a (C2-C24) alkenylaminoacyl group, an alkynylaminoacyl group, preferably a (C2-C24) alkynylaminoacyl group, an alkylthioacyl group, preferably a (C2-C24) alkylthioacyl group, an alkenylthioacyl group, preferably a (C2-C24) alkenylthioacyl group, an alkynylthioacyl group, preferably a (C2-C24) alkynylthioacyl group, an acyl group derived from a branched chain-carboxylic acid having from 2 to 48 carbon atoms, preferably a carboxylic acid branched at the 3-position;
• wherein in the groups (i), (ii), (iii) the hydrocarbon chain of the acyl may be saturated or unsaturated and the hydrocarbon chain of the acyl, alkyl, alkenyl, alkynyl may be branched or straight and optionally may be substituted with one or more groups independently selected from halogen such as fluoro, chloro, bromo, or iodo;
• a hydroxyl or hydroxyl derivative —OY, wherein Y is as defined below;
• an amine or amine derivative —NHW, wherein W is as defined below;
• a group —OZ, wherein Z is selected from (f), (g), (h), (i), (j), (k) as defined below;
• and R2 is a group selected from a (C1-C6) halogenated alkoxy carbonyl, such as 2,2,2-trichloroethoxycarbonyl (TROC) or a 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TCBOC);
• with a compound of the formula 7:
• wherein R4 is selected from:
• (a) an acyl group as defined in (i), (ii) or (iii) for R5;
• (b) a branched or straight alkyl group, preferably a branched or straight (C1-C24) alkyl group;
• a branched or straight alkenyl group, preferably a branched or straight (C1-C24) alkenyl group;
• a branched or straight alkynyl group, preferably a a branched or straight (C1-C24) alkynyl group;
• (c) a group —[(C1-C24) alkyl]-COOX, —[(C2-C24) alkenyl]-COOX or —[(C2-C24) alkynyl]-COOX wherein X is as defined below
• (d) a group —[(C1-C24) alkyl]-NHW, —[(C1-C24) alkenyl]-NHW or —[(C1-C24) alkynyl]-NHW wherein W is as defined below;
• (e) a formyl alkyl group, preferably a formyl [(C1-C24) alkyl] group;
• a formyl alkenyl group, preferably a formyl [(C1-C24) alkenyl] group;
• a formyl alkynyl group, preferably a formyl [(C1-C24) alkynyl] group;
• (f) a dimethoxyphosphoryl group;
• (g) a group —P(O)(OY)2, wherein Y is as defined below;
• (h) a group —P(O)(OH)—O[(C1-C24) alkyl]-NHW, —P(O)(OH)—O[(C1-C24) alkenyl]-NHW or —P(O)(OH)—O[(C1-C24) alkynyl]-NHW wherein W is as defined below;
• (i) a group —P(O)(OH)—O[(C1-C24)alkyl], —P(O)(OH)—O[(C1-C24) alkenyl], or —P(O)(OH)—O[(C1-C24)alkynyl];
• (j) a group —P(O)(OH)—O[(C1-C24) alkyl]-COOX, —P(O)(OH)—O[(C1-C24) alkenyl]-COOX, —P(O)(OH)—O[(C1-C24) alkynyl]-COOX, wherein X is as defined above;
• (k) a group —S(O)(OH)2;
• (l) a protective group selected from benzyl or a substituted benzyl, such as 4-methoxybenzyl or 3,4-dimethoxybenzyl or 2,5-dimethoxybenzyl or 2,3,4-trimethoxybenzyl or 3,4,5-trimethoxybenzyl;
• or from a (C3-C6) alkenyl, such as a C3 or C4 alkenyl, preferably 2-propenyl or 1-propenyl;
• wherein alkyl, alkenyl, alkynyl groups may be branched or straight and may be unsubstituted or optionally are substituted with one or more groups independently selected from halogen such as fluoro, chloro, bromo, or iodo;
• a hydroxyl or hydroxyl derivative —OY, wherein Y is as defined below;
• an amine or amine derivative —NHW, wherein W is as defined below;
• or a group —OZ, wherein Z is selected from (f), (g), (h), (j), (k);
• and wherein Y is selected from hydrogen;
• an (C3-C6) alkenyl, such as a C2 or C3 alkenyl, preferably 2-propenyl or 1-propenyl group;
• a group selected from benzyl or a substituted benzyl, such as 4-methoxybenzyl or 3,4-dimethoxybenzyl or 2,5-dimethoxybenzyl or 2,3,4-trimethoxybenzyl or 3,4,5-trimethoxybenzyl;
• a O-Xylylene group;
• and wherein W is selected from hydrogen;
• a benzyloxycarbonyl group or a 9-fluorenylmethyloxycarbonyl;
• and wherein R6 is a group selected from trichloroacetimidate, fluoride, chloride, bromide, and X and R2 are as defined above, under reaction conditions suitable for forming a compound of the formula 11h:
• wherein R1, R2, R4, R0 and X are as defined above,
• which process optionally further comprises one or more of the following steps (2)-(11):
• (2) reacting the compound of the formula 11h under reaction conditions suitable for the hydrolytic removal of a number of groups R2 of said compound of the formula 11h, while forming a compound of the formula 12a:
• wherein R1, R4, R5 and X are as defined above, when Ro is selected as R5 in formula 11h, or a compound of the formula 12b:
• wherein R1, R4, and X are as defined above, when Ro is selected as R2 in formula Ia;
• (3) reacting the compound of the formula 12a or 12b under reaction conditions suitable for forming an amide bond between a free amino group of said compound of the formula 12a or 12b and a carboxy group of a (activated) carboxylic acid of the formula R5OH, wherein R5 is as defined above, preferably in the presence of a coupling agent such as isobutyl chloroformate or 1-isobutyloxy 2-isobutyloxycarbonyl-1,2-dihydroquinoleine or a carbodiimide under formation of a compound of the formula 13:
• wherein R1, R4, R5, and X are as defined above;
• (4) forming a hemiacetal of the formula 14:
• wherein R4, R5, and X are as defined above, by removal under suitable reaction conditions of the group R1 from the compound of the formula 13, as defined above;
• (5) phosphorylation of the free hydroxyl group of compound 14 preferably with tetrabenzyl pyrophosphate in the presence of a suitable base, such as lithium bis(trimethylsilyl)amide, in a polar solvent such as THF, under reaction conditions suitable for forming a compound of the formula 15a:
• (6) sulfatation of the free hydroxyl group of compound 14, for example by reaction with a sulfur trioxide complex such as trimethyl amine sulfur trioxide complex in a solvent such as DMF, under reaction conditions suitable for forming a compound of formula 15b:
• (7) reacting the free hydroxyl group of compound 14 with an (activated) carboxylic acid of the formula RsOH, wherein R8 is as defined above for R4, preferably in the presence of a coupling agent such as isobutyl chloroformate or 1-isobutyloxy 2-isobutyloxycarbonyl-1,2-dihydroquinoleine or a carbodiimide under formation of a compound of the formula 15c:
• wherein R4, R5, and X are as defined before, and R8 is selected as defined above for R4;
• (8) coupling of an leaving group such as a trichloroacetimidate group to the free hydroxyl group of compound 14, such as by reaction of compound 14 with trichloacetonitrile in the presence of a mineral base, such as cesium carbonate or potassium carbonate, in a polar solvent, preferably an aprotic polar solvent such as dichloromethane under reaction conditions suitable for forming a compound of the formula 24:
• wherein R4, R5, and X are as defined above;
• (9) reacting compound 24 of step (8) with an organic molecule Rs011, wherein R8 is selected from (b), (c), (d) or (e) as defined above for R4, under reaction conditions suitable for forming a compound of the formula 15d:
• (10) reacting, under suitable reaction conditions, reactive groups, such as hydroxyl groups, amine groups, carboxy groups, or carbon double bonds, on a compound of the formula 15a, 15b, 15c, 15d or 13 for example in a reaction selected from esterification, methylation, amidation, oxidation, hydrogenation or α, β hydroxylation with osmium tetroxide, and wherein said reacting of reactive groups optionally is preceded by removing protective groups, such as the groups Y or W to liberate said reactive groups;
• (11) removing a number of protecting groups X from a compound of the formula 13, 14, 15a, 15b, 15c or 15d, preferably by means of hydrogenolysis of said protecting group X, more preferably hydrogenolysis in the presence of a high-grade metal such as palladium on carbon, under reaction conditions suitable for forming of a compound of the formula 1:
• wherein R′4, R′5 and R′7 are as defined above for R4, R5 and R7, respectively, and R′5 is selected from (a), (b), (c), (d), (e), (f), (g), (h), (i) (j) or (k) as defined above for R4, or is selected as H, and wherein Y and W preferably are H.