Overview[1]
Amifostine is a broad-spectrum cell protective agent that was once used as a military anti-radiation agent and is now used as a protective agent for radiotherapy and chemotherapy. It is highly effective in reducing the side effects of anti-cancer drugs such as cyclophosphamide, chloramphenicol, doxorubicin and anti-HIV drugs such as 3-azido-3-deoxythymidine, and does not affect the efficacy of anti-cancer drugs or anti-HIV drugs. Efficacy. Amifostine products currently on the market include freeze-dried powder for injection produced by American Life Sciences Co., Ltd., with the trade name ETHYOL.
This product is only available as a lyophilized powder for injection, but the amorphous form produced by low-pressure lyophilization is thermally unstable. Such lyophilized formulations must be maintained at a temperature of approximately -20°C and transported at a temperature of approximately -70°C to -20°C to avoid degradation of the formulated product, which is not only inconvenient but also requires special packaging. And a lot of shipping costs. American Life Sciences Co., Ltd. believes that “amifostine non-lyophilized powder for injection “dry packaging” or “powder packaging” involves a large number of practical problems when packaging solid amifostine in bulk. Such problems include: powder packaging Difficulties in manual handling methods, the need to grind the powder to acceptable particle size and flowability, difficulties in maintaining dust-free, sterile conditions, and difficulties in loading precise doses of solid amifostine into each vial. ”
Preparation[2]
Step 1: Synthesis
Add 13.6kg of pure water and 19.2mol (7.6kg) of sodium thiophosphate dodecahydrate into a 50L stainless steel reactor, and add N-(2-bromoethyl)-1,3-propanediamine bis under stirring. 19.8 mol of hydrobromide (6.8 kg, 3% excess), slowly add 11.0 kg DMSO while maintaining the reaction temperature not exceeding 25°C. After DMSO is added dropwise, monitor the reaction solution with silver nitrate solution until no black precipitate is precipitated. When the reaction is completed, cool the reaction solution to 0°C and stir for 5 minutes every hour for 18 hours. Centrifuge and filter to obtain 6.1kg of crude amifostine trihydrate.
Step 2: First recrystallization and purification
Add 22.0kg of pure water to the 50L stainless steel crystallization kettle, add 6.1kg of the crude 3-aminopropylamineethylthiophosphate prepared in the previous step, dissolve it at room temperature, add 95.0g of activated carbon, and stir at room temperature for 15 minutes , filter, add 8.7kg of methanol to the mother liquor, cool it to 0°C with cooling water, maintain it for 18 hours, centrifuge and filter, and obtain 4.8kg of 3-aminopropylamine ethyl thiophosphoric acid, which is purified by one recrystallization and has no crystallization water.
Step 3: Second recrystallization and purification
Add 20.0 kg of diluent pure water to the 50L stainless steel crystallization kettle, add 4.8 kg of 3-aminopropylamine ethyl thiophosphoric acid without crystal water obtained from the first recrystallization, stir and dissolve at room temperature, and add activated carbon 75.0g, stir at room temperature for 15 minutes, filter, add 3.2kg of ethanol to the mother liquor, cool to 0°C with cooling water, maintain for 18 hours, centrifuge, filter, and vacuum dry at 30°C to obtain 3.6kg of amifostine trihydrate. Analyzed by HPLC method (according to the 29th edition of the US Pharmacopoeia method), the purity is 99.81%, the thiol content is 0.021%, and other related substances are 0.078%.
