Prodrug of taxol or polyene-taxol with carbowax as carrier

[0039] Example 1: Synthesis of polyethylene glycol 5000-succinic acid-glycolic acid-paclitaxel

[0040] 1. Functionalization of methoxy-terminated polyethylene glycol

[0041] In a 100ml there-necked flask, equipped with a reflux condensing device and a magnetic stirrer, the baking reaction device is ventilated three times (high-purity argon), under gas protection, add 10g of polymer and 1g of pre-weighed succinic anhydride, and An equimolar amount of dimethylaminopyridine (DMAP) was added to 60 ml of anhydrous and oxygen-free tetrahydrofuran, and the mixture was refluxed for 72 hours. After completion of the reaction, concentrate the solvent, then add 10ml of 0.1M aqueous sodium bicarbonate solution to the residue, acidify the filtrate with 10ml of 0.1N hydrochloric acid, adjust the pH value of the solution to 3-4 with hydrochloric acid, and then use 100ml of ethyl acetate to Wash the water layer three times with ester, combine the ethyl acetate solution and wash twice with saturated sodium chloride solution, add anhydrous magnesium sulfate to dry, then filter the desiccant, concentrate the solvent to 2ml, add 100ml of anhydrous ether to precipitate the product, and obtain a white precipitate , dried under vacuum at room temperature and used for the next reaction.

[0042] 2. Preparation of carboxyl-protected glycolic acid

[0043] In a 100ml three-necked flask, weigh 9g of glycolic acid, add 500ml of ether, after it is fully dissolved, add 5ml of tert-butyl bromide, keep away from light, then add catalyst, react for 24 hours, then filter out the precipitate in the reaction system, The solvent was concentrated until all the anhydrous ether was sucked away. The resulting residue was adjusted to alkaline with an alkaline solution, then extracted three times with dichloromethane, dried over anhydrous magnesium sulfate, filtered and the solvent was concentrated, and then subjected to column separation. The developing solvent was ethyl acetate:petroleum ether=1 : 4.

[0044] 3. Linkage of functionalized polyethylene glycol and glycolic acid

[0045] In a 100ml three-necked flask, add 2g of functionalized methoxy-terminated polyethylene glycol, 0.3g of carboxyl-protected glycolic acid, dissolve in 15ml of dichloromethane, add 0.5g of DCC and a catalytic amount of DMAP under ice-bath conditions , and then reacted at room temperature for 24 hours. After the reaction was completed, the resulting precipitate was filtered off, and then the solvent was concentrated to 1 ml, and 100 ml of anhydrous ether was added to obtain a white precipitate, which was vacuum-dried at room temperature. Add the obtained polymer to a 100ml three-neck flask, add 20ml of dichloromethane and 10ml of trifluoroacetic acid, react for 2 hours, then concentrate the solvent to 1ml, then add 100ml of anhydrous ether to precipitate the product, and obtain a white precipitate, which is vacuum-dried at room temperature .

[0046] 4. Synthesis of methoxy-terminated polyethylene glycol 5000-succinic acid-glycolic acid-paclitaxel

[0047]In a 100ml three-neck flask, add 1.5g of polymer, 1.0g of paclitaxel, dissolve in 20ml of dichloromethane, add 0.25g of DCC and a catalytic amount of DMAP under ice bath conditions, and then react at room temperature for 24 hours. After the reaction was completed, the resulting precipitate was filtered off, and then the solvent was concentrated to 1 ml, and 100 ml of anhydrous ether was added to obtain a white precipitate, which was vacuum-dried at room temperature. The resulting precipitate was redissolved in dichloromethane, then concentrated to 1 ml, then 100 ml of isopropanol was added for freeze crystallization, and filtered under reduced pressure to obtain a white solid, which was washed with ether and dried in vacuo at room temperature. Paclitaxel content is 28%.