A synthesis process for the key intermediate of methotrexate, methotrexate disodium salt, and conducts optimization research were provided by using zinc salt of p-aminobenzoylglutamic acid and tetraaminopyrimidine sulfate as starting materials, with purified water as the reaction solvent. By adding 1,1,3-tri-bromoacetone dropwise and maintaining the pH vaule of 2.0～2.5, a cyclization reaction was carried out. After the reaction of zinc salt of p-aminobenzoylglutamic acid was completely detected by HPLC, the crude methotrexate filter cake was obtained by suction filtration. Then, an appropriate amount of purified water was added and the pH vaule was adjusted to 11～12. Anhydrous ethanol was slowly added dropwise until crystals precipitate, and the wet product of methotrexate disodium salt was obtained by suction filtration. Finally, the product was dried under vacuum at 50 ℃ to obtain the finished product. The overall process yield was over 40%, and the purity was over 98.0%. The synthesis process is relatively simple, the raw materials are cheap and readily available, and the post-treatment is simple, making it very suitable for industrial production.