Background technology
Amifostine is a broad-spectrum cytoprotective agent that was first screened by the Walter Reed Army Medical Research Institute in the United States in the 1960s. It is a radioprotective agent with highly effective anti-radiation effects and safe use. It has been used until now. The code name used by the institute at that time was WR-2721. It is currently used clinically to reduce the side effects caused by radiation and drugs during radiotherapy and chemotherapy, and was approved by the FDA in 1996 as the first cell protective agent. Amifostine is an organic phosphorylated amine sulfur-based prodrug, which is hydrolyzed by alkaline phosphatase in normal tissues into an active metabolite, code-named WR-1065. It can scavenge free radicals generated during radiation or drug chemotherapy. This protects normal cells and does not significantly affect the therapeutic effect of the combined drugs.
At present, there are a large number of documents related to the preparation of amifostine in this technical field. The methods generally include the following: The earliest document (J Med Chem: 1969, 12 (2): 236-43) reported that its synthesis was through ethylene oxide. Alkane reacts with 1,3-propanediamine to obtain N-hydroxyethyl-1,3-propanediamine, and then undergoes one-step bromination to obtain the dihydrobromide salt of N-bromoethyl-1,3-propanediamine. , the dihydrobromide of N-bromoethyl-1,3-propanediamine reacted with sodium thiophosphate in the polar aprotic solvent DMF as the accelerator, and then added a large amount of methanol to crystallize to obtain the product, the overall yield 29.4%. This route has low yield and many steps. Medicinal amifostine needs to control the DMF residue. Domestic literature such as Zeng Tongshou, Li Lu, Synthesis of Aminoalkyl Phosphorothioate Compounds, Acta Pharmaceutical Sinica: 1981, 16(4): 303-305 and Li Jiaming, Research on the Synthesis Process of the Anti-radiation Drug Amifostine, Anhui Chemical Industry: 2000(2):17-19 also reported this synthetic route. The difference is that in the final reaction to prepare amifostine, Zeng Tongshou et al. used DMSO as the accelerator and needed to add 3.4 times of reactants. Methanol with the mass of dihydrobromide of N-bromoethyl-1,3-propanediamine was added into the reaction system as a crystallizing agent to precipitate the amifostine product. Li Jiaming et al. used 3.0 times of the reactants. Ethanol with the mass of dihydrobromide of N-bromoethyl-1,3-propanediamine was used as a crystallizing agent to precipitate the product amifostine.
In recent years, the patent CN2011104318448 directly uses N-hydroxyethyl-1,3-propanediamine as raw material to obtain dihydrobromide of N-bromoethyl-1,3-propanediamine through bromination, and then Amifostine is obtained by condensation with sodium thiophosphate in potassium iodide solution, but post-processing requires the addition of ethanol for crystallization at low temperature of 0~5°C. Patent CN200810146538.8 directly reacts N-bromoethyl-1,3-propanediamine with dihydrobromide and sodium thiophosphate in one step, with the promotion of DMSO adding 1.0~2.8 times the mass of the reactant bromide salt, without The lower alcohol is crystallized to obtain the product. Patent US2006042761 uses DMF as the accelerator and adds methanol as the crystallizing agent. The crude product is purified through at least one ion exchange resin column or one activated carbon column, and the operation is complicated.
It can be seen that the last step of the above methods involves phosphorothiolation of ω-(aminoalkylamino)alkyl halide to obtain amifostine, but the reaction system requires a polar aprotic solvent. Such polar aprotic solvents such as DMSO and DMF have high boiling points and are difficult to recover and recycle; in addition, these solvents are not conventional green solvents and have certain environmental pollution. The key is the residual high boiling point solvent in amifostine products. Need to control. The standards of pure products purified by relevant literature methods vary. Except for the patent CN200810146538.8, which mentions meeting the USP29 version requirements, there are no relevant literature and patent reports on the quality achieved by refined amifostine. The present invention directly reacts with N-bromoethyl-1,3-propanediamine and sodium thiophosphate, with low carbon alcohols as accelerator, especially with low boiling point methanol, ethanol, etc. as accelerator, reaction After completion, the product is directly filtered without treatment and reaches the standard of pharmaceutical injection after recrystallization. It is easy to operate, amifostine products do not contain high boiling point solvent residues, are of high quality, the solvent is recyclable, green and environmentally friendly, and energy saving, which is of great significance for reducing costs and protecting the environment.
Content of the invention
Therefore, the present invention provides a green and recyclable cleaning process, which is characterized by dropwise addition of green solvent alcohols, especially low boiling point methanol as an auxiliary agent, which is easy to operate, recyclable solvent, green, environmentally friendly, efficient, and convenient Purification, the purified amifostine does not contain boiling point solvent residues, and the quality is improved.
The present invention is realized through the following technical solutions:
A method for preparing green amifostine trihydrate, in an aqueous solution, the mass percentage of N-bromoethyl-1,3-propanediamine dihydrobromide and sodium thiophosphate is 10-70% , the molar ratio of the two is 1:0.8~1.2, preferably 1:0.95~1.05; low carbon alcohol or polyol Cabot conductive carbon black is the accelerator, the reaction temperature is 5-60°C, the preferred temperature is 15~ 35°C, reaction time is 1.0~5.0 hours. The crude amifostine trihydrate is obtained by direct filtration; the crude amifostine trihydrate is purified by twice recrystallization to obtain medicinal amifostine trihydrate.
The dosage of the accelerator is 0.10~10.0 of the purified water used, and the purified water is the water used in the aqueous solution.
The accelerator is lower alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and their mixtures; polyhydric alcohols are 1,2-propanediol, 1,3-propanediol, 1,3-butanol Diol, 1,4-butanediol, diethylene glycol or diethylene glycol.
The solvent used in the recrystallization purification is methanol, ethanol, acetone, isopropyl alcohol or their mixed solutions, preferably the crude product is recrystallized once from methanol and twice from ethanol.
The specific steps are as follows:
① Dissolve the reactants N-bromoethyl-1,3-propanediamine dihydrobromide and sodium thiophosphate in water at a ratio of 1.0:0.8~1.2 at 5-60°C, and add Low-carbon alcohol or polyol accelerator, cool after completion of the reaction, and filter to obtain crude amifostine.
② Distill the transparent liquid obtained by solid-liquid separation in step I under normal pressure, recover methanol, and reuse it. The crude product in step 1 and step 2 is purified by recrystallization. The crude amifostine is dissolved in water 2.0 to 3.5 times its weight. After decolorization and filtration with activated carbon, low carbon alcohols (methanol, ethanol, isopropyl, respectively) are added. Alcohol and its mixed solution) or acetone (acetone and its mixed solution of the above alcohols), precipitate the product.
③ Carry out secondary recrystallization and purification of the crude product in step 2, dissolve amifostine into water 2.0 to 3.5 times its weight, then add ethanol to precipitate amifostine trihydrate, its purity is >99.5%. Thiol content <0.1%, other related substances <0.1%, total impurities <0.3%.
The present invention uses methanol as the accelerator, and has the characteristics of recyclable solvent, green environmental protection, energy saving, and convenient purification.
Operation steps
The detailed preparation steps for synthesizing crude amifostine using methanol as accelerator are as follows:
Take 140g of purified water, 68.0g of N-bromoethyl-1,3-propanediamine dihydrobromide (0.2mol), and 75.2g of sodium thiophosphate (0.19mol) as raw materials and add them to 250mL in sequence. In the flask, stir to dissolve and control the temperature not to exceed 35°C. Add 150g of methanol dropwise at a constant speed, react for 3.5 hours and then cool down. When the temperature drops to 0°C with frozen brine, stop stirring and let it sit overnight. The next day, filter under reduced pressure, dry, and weigh to obtain 36.38g of crude amifostine. The main content is greater than 96.00% measured by the USP35 version method and the external standard method.
