A kind of synthetic method of cyclophosphamide

Abstract

The invention provides a synthetic method for cyclophosphoramide. According to the synthetic method, phosphorus oxychloride is slowly added into a mixed solution of dichloroethane, polyphosphoric acidand acetic anhydride, 3-amino propyl alcohol is dropwise added so as to prepare 2-chloro-2-oxo-[1.3.2] oxygen-nitrogen-phosphorus heterocyclic hexane; and dichloroethane and a 5a molecular sieve areadded, ammonia gas is introduced, heating is carried out at 4 atm to reach 120 DEG C, reaction is carried out for 2-2.5 hours, and treatment is carried out so as to obtain the cyclophosphoramide. Themethod has the advantages that the reaction conditions are relatively mild, and the yield and the content are high.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of cyclophosphamide. Background technique [0002] Cyclophosphamide (Cyclophosphamide, CTX, C7H15C12N2O2P, chemically named N, N-bis-(β-chloroethyl)-N′-(3-hydroxypropyl)phosphoramide lactone)) is a drug that enters the human body and is Nitrogen mustard derivatives that are hydrolyzed by excess phosphoramidase or phosphatase present in the liver or tumor to become activated phosphoramide mustard. It has a broad anti-tumor spectrum and is the first so-called "latent" broad-spectrum anti-tumor drug, which is effective for both leukemia and solid tumors. [0003] This product has no activity in vitro, and it mainly plays its role through the hydrolysis of P450 enzymes in the liver into aldophosphamide and then transported to the tissues to form phosphoramide mustard. Cyclophosphamide can be inactivated by dehydrogenase conversion to carboxy...

AI Technical Summary

Problems solved by technology

The problem of this invention is that the reaction temperature in the first step is too high, and a large amount of triethylamine is used in both steps, which is not conducive to industrial production, and the reaction in the second step cannot be carried out after repeating the above experimental process.

[0009] Chinese Taiwan area patent (TW1546312A) discloses the synthetic method of solvent-free preparation cyclophosphamide, comprises that bis(2-chloroethyl) aminoacid, catalyzer and N-methylmorpholine are placed in the reaction bottle, and in the bottle The reactant was cooled to 4°C, then phosphorus oxychloride (POCl3) was slowly added dropwise, after stirring at room temperature for 5 hours, the temperature was continued to drop to 4°C, 3-amino-1 propanol was added dropwise, and then stirred at room temperature for 15 hours , and then obtain the product through extraction and crystallization. This process has strict requirements on temperature, and different temperatures need to be controlled in different stages. The reaction steps are complicated, the reaction efficiency is low, and the low temperature environment needs to be controlled.

Images