Conjugate Based Systems For Controlled Drug Delivery
A conjugate and conjugation technology, applied in the direction of drug combination, endocrine system diseases, active ingredients of heterocyclic compounds, etc.
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Embodiment 1
[0487] Example 1 - Synthesis of Azidoethyl Glucose (AzEG)
[0488] a. Synthesis of bromoethylglucose
[0489] DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, MA) was washed with deionized water to remove color. Treat 225 g of D-glucose (1.25 mol; 1 equiv, AlfaAesar) and 140 g of DOWEX50Wx4 with 2.2 L of 2-bromoethanol (30.5 mol, 25 equiv; 124.97 g / mol; 1.762 g / mL; BP=150 °C; AlfaAesar) mixture, and the stirred mixture was heated to 80°C for 4 hours. The reaction was monitored by TLC (20% methanol / dichloromethane (DCM)). After about 4 hours, the reaction was complete and it was cooled to room temperature. The solution was filtered to remove the resin, and the resin was washed with ethyl acetate and DCM. The resulting filtrate was stripped to an amber oil in a rotary evaporator. A total of 400 g was obtained after evaporation.
[0490] The amber oil was purified on silica gel (4 kg silica packed in DCM) in the following manner. The crude product was dissolved in DCM and loaded ...
Embodiment 2
[0496] Example 2 - Synthesis of Azidoethylmannose (AzEM)
[0497] a. Synthesis of Bromoethylmannose
[0498] DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, MA) was washed with deionized water to remove color. Treat 225 g of D-mannose (1.25 mol; 1 equiv, AlfaAesar) and 140 g of DOWEX50Wx4 , and the stirred mixture was heated to 80 °C for 4 hours. The reaction was monitored by TLC (20% methanol / dichloromethane (DCM)). After about 4 hours, the reaction was complete and then cooled to room temperature. The solution was filtered to remove the resin, and the resin was washed with ethyl acetate and DCM. The resulting filtrate was evaporated in a rotary evaporator to an amber oil.
[0499]The amber oil was purified on silica gel (4 kg silica packed in DCM) in the following manner. The crude product was dissolved in DCM and loaded onto the column, then eluted with 2x4L 10% methanol / DCM, 2x4L 15% methanol / DCM, and 3x4L 20% methanol / DCM. Fractions containing product (based on TLC) were...
Embodiment 3
[0505] Example 3 - Synthesis of Azidoethylmannobiose (AzEBM)
[0506] The AzEM compound from Example 2 was selectively protected using xylylene ether, purified by column chromatography, and subsequently reacted with benzyl bromide to afford 1-α-(2-azidoethyl)-4,6- Benzaldehyde Diacetal-3-Benzyl-Mannopyranoside. Subsequent glycosylation of the product with 1-α-bromo-2,3,4,6-tetrabenzoylmannopyranoside under strictly anhydrous conditions using silver trifluoromethanesulfonate chemistry yielded the Protected - azidoethylmannobiose product. The intermediate is then deprotected to remove the benzoyl group to give AzEBM.
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