Crystalline insulin-conjugates
A conjugate and insulin technology, applied in the direction of insulin, carrier binding/immobilization peptide, hormone peptide, etc.
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Embodiment 1
[0412] Example 1 - Synthesis of Azidoethyl Glucose (AzEG)
[0413] a. Synthesis of bromoethylglucose
[0414] DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, MA) was washed with deionized water to remove color. 225 g of D-glucose (1.25 mol; 1 equiv, Alfa Aesar) and 140 Gram the mixture of DOWEX 50Wx4 and heat the stirred mixture 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.
[0415] The amber oil was purified on silica gel (4 kg silica packaged in DCM) in the manner described below. The crude product was dissolved in DCM and loaded onto the column, then eluted with 2 x 4L 10% methanol / DCM, 2 x 4L 15% methanol / DCM and 3 x 4L ...
Embodiment 2
[0421] Example 2 - Synthesis of Azidoethylmannose (AzEM)
[0422] a. Synthesis of bromoethylmannose
[0423] DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, MA) was washed with deionized water to remove color. 225 g of D-mannose (1.25 mol; 1 eq, Alfa Aesar) and A mixture of 140 grams of DOWEX 50Wx4 was added 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.
[0424] The amber oil was purified on silica gel (4 kg silica packaged in DCM) in the manner described below. The crude product was dissolved in DCM and loaded onto the column, then eluted with 2 x 4L 10% methanol / DCM, 2 x 4L 15% methanol / DCM, and 3 x 4L 20% methanol / DCM. Fractions contai...
Embodiment 3
[0430] Example 3 - Synthesis of Azidoethylmannobiose (AzEBM)
[0431] 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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