Background and overview[1]
Azide-dipolyethylene glycol can be used as a pharmaceutical synthesis intermediate.
Preparation[1]
Azide-dipolyethylene glycol is prepared as follows:
Step 1: Add 50g diethylene glycol and 34g triethylamine to 500ml methylene chloride, stir, weigh 54g p-toluenesulfonyl chloride and dissolve it in 150ml methylene chloride, add it dropwise to the reaction system under ice-water bath conditions medium, complete the dripping, and react at 20°C for 12 hours. TLC shows that the reaction is completed, add ml of water to wash, separate the layers, dry the organic phase over anhydrous sodium sulfate, spin to dryness, and then undergo column chromatography separation and purification to obtain 55g of intermediate A, yield: 90%. The nuclear magnetic data are as follows: 1HNMR (MHz, CDCl3): δ: 7.792 (d, J=8.4Hz, 2H); 7.350 (d, J=8.4Hz, 2H); 4.158 (t, J=4.4Hz, 2H); 3.702 ~3.567 (m, 6H); 2.818 (s, 1H); 2.435 (s, 3H).
Step 2: Add 55g of intermediate A obtained in step (1) to 300ml of ethanol, then add 18g of sodium azide, raise the temperature to 80°C, and stir for 10h. After the reaction is completed, cool to room temperature, add 200 ml of water, extract with 500 ml of dichloromethane, dry the dichloromethane phase with anhydrous sodium sulfate, and spin to dryness to obtain 28 g of intermediate B, yield: 95%. The nuclear magnetic data are as follows: 1HNMR (MHz, CDCl3): δ: 3.740～3.542 (m, 6H); 3.342 (t, J=4.8Hz, 2H); 3.026 (s, 1H).
Application
Azide-dipolyethylene glycol can be used to prepare a terminal thiol polyethylene glycol amino group (NH2-PEGn-SH, n=1-24), as follows;
Step 1: Add 28g azide-dipolyethylene glycol to 300ml methylene chloride, then add 18g triethylamine, dropwise add 19g methylsulfonyl chloride under ice-water bath conditions, and react for 12 hours at 20°C. . At the end of the reaction, add ml of water to wash, separate the layers, dry the organic phase with anhydrous sodium sulfate, and spin to dryness to obtain 32g of intermediate C, yield: 90%. The nuclear magnetic data are as follows: 1HNMR (MHz, CDCl3): δ amino silicone oil emulsion: 4.373 (t, J=4.0Hz, 2H); 3.778~3.644 (m, 4H); 3.389 (t, J=4.8Hz, 2H); 3.098 (s, 3H).
Step 2: Add 32g of the intermediate obtained in step (1) to 250ml of DMF, then add 20g of thioacetic acid, add 33g of potassium carbonate in batches under ice-water bath conditions, and stir at room temperature for 12h. At the end of the reaction, add 700 ml of water, extract with 500 ml of dichloromethane, dry the dichloromethane phase with anhydrous sodium sulfate, spin to dryness, and then undergo column chromatography separation and purification to obtain 28 g of intermediate D from eva resin, yield: 92%. The nuclear magnetic data are as follows: 1HNMR (MHz, CDCl3): δ: 3.683～3.585 (m, 4H); 3.396 (t, J=4.8Hz, 2H); 3.101 (t, J=4.8Hz, 2H); 2.329 (s, 3H).
Step 3: Add 28g of the intermediate obtained in step (2) to 200ml of methanol, then add 9.8g of sodium methoxide, and stir at room temperature for 12h. At the end of the reaction, add 300 ml of water, extract with ml of dichloromethane, dry the dichloromethane phase with anhydrous sodium sulfate, spin to dryness, and then separate and purify by column chromatography to obtain 20 g of intermediate E, yield: 93%. The nuclear magnetic data are as follows: 1HNMR (MHz, CDCl3): δ: 3.690~3.570 (m, 6H); 3.096 (t, J=4.8Hz, 2H); 1.682 (t, J=4.0Hz, 1H).
Step 4: Add 20g of the intermediate obtained in step (:4) to 150ml of tetrahydrofuran, add 4.0g of lithium aluminum hydride in batches under an ice bath, and stir at room temperature for 3h. At the end of the reaction, add 2 ml of water and 35% sodium hydroxide solution, filter with suction, spin the filtrate to dryness, and then separate and purify by column chromatography to obtain 16 g of the final product, yield: 96%. The nuclear magnetic data are as follows: 1HNMR (MHz, CDCl3): δ: 3.677～3.556 (m, 4H); 2.822 (t, J=4.8Hz, 2H); 2.682 (t, J=4.0Hz, 2H); 2.112 (s, 2H); 1.602 (t, J=4.0Hz, 1H).
Main reference materials
[1] CN201710531334.5 A method for preparing thiol-terminated polyethylene glycol amino groups
