Hidetoshi Isawa

FIRST FORMATION OF THIEPINO[2,3-b]- AND THIEPINO[3,2-a]-INDOLIZINE DERIVATIVES

The reactions of potassium l,3-bis(ethoxycarbonyl)indolizine-2-thiolates with ethyl 4-bromocrotonate afforded the corresponding indolizine derivatives having (E)-(3-ethoxycarbonyl-2-propenyl)thio, (E)- and (Z)-(3-ethoxycarbonyl-1-propenyl)thio group at the 2-position. The alkaline treatment of these S-alkylated indolizines gave the title compounds in good yields.

O-Glycosylation of 4-(Substituted benzyl)-1,2-dihydro-3H-pyrazol-3-one Derivatives with 2,3,4,6-Tetra-O-acyl-α-D-glucopyranosyl Bromide via N1-Acetylation of the Pyrazole Ring.

A practical preparation of 4-(substituted benzyl)-3-(2,3,4,6-tetra-O-acyl-β-D-glucopyranosyloxy)-1H-pyrazole derivative 2 is described. O-Glycosylation of 4-(substituted benzyl)-1,2-dihydro-3H-pyrazol-3-one derivative 3 was facilitated by introduction of electron-withdrawing substituents, such as an acetyl group, at the N1-position of the pyrazole ring. 1-Acetyl-4-(substituted benzyl)-1,2-dihydro-3H-pyrazol-3-one 10 reacted with 2,3,4,6-tetra-O-acyl-α-D-glucopyranosyl bromide 5 in the presence of potassium carbonate in acetonitrile to provide the 1-acetyl-4-(substituted benzyl)-3-(2,3,4,6-tetra-O-acyl-β-D-glucopyranosyloxy)-1H-pyrazole derivative 11 in high yield. When 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (5b) was used as a glycosyl donor, the resulting O-glycosylated product 11 was N1-deacetylated in the presence of potassium bicarbonate in methanol without unfavorable deprotection of the glycosyl moiety to provide 2 in excellent yield. The synthetic intermediate 2b of Remogliflozin etabonate (1b) was synthesized using this strategy.