Study On The Synthesis Of Balsalazide Disodium

World Health Organization has ranked ulcerative colitis, a kind of chronic inflammation whose pathogenesis we have not known, as one of the modern cureless diseases because of the high incidence.Sulfasalazine is the first clinical medicine and has been used until now. But it has toxic side effect, which causes the patients to suffer a series of ill reactions, such as bellyache, headache, nausea and even the sterility. And near one third of the patients can't tolerate it. Balsalazide is the new-style anti-inflammatory medicament, which can treat ulcerative colitis, rectitis and Crohn's disease. Compared with other 5-ASA medicines, balsalazide is characterized by the instant effect, good curative effect and little side effect.It is foretold that balsalazide will be the substitute product of this kind of medicines. The purpose of this article is to study on the synthesis of balsalazide, to improve the former synthesis process, to optimize the reaction conditions, and increase the total yield.According to the counterreaction synthesis analytical method,balsalazide disodium is synthesized from 4-nitrobenzyl chloride and β -alanine via acylation, reduction, diazotization, coupling and salt formation.The intermediate 1, N-p-nitrobenzoyl- β - alanine, is synthesized from p-nitrobenzoyl chloride, the acylate reagent, with β - alanine under the condition of the temperature 0℃ for 2 hours. N-p-nitrobenzoyl- β -alanine is reduced into N-p-aminobenzoyl- β - alanine using four different reductants, such as iron, hydrogen, hydrazine hydrate and hydrazinium monoformate. Comparing with the four methods, the author adopts the catalytic transfer hydrogenation, using hydrazine hydrate as the hydrogen donator with the Pt/C or FeCl₃· 6H₂O/C as the catalyst. The optimum reaction conditions are that the molar ratio of nitro compound: hydrazine hydrate is 1: 2.5 catalyzed by mass 5% of Pt/C or FeCl₃ · 6H₂O/C at the reflux temperature of alcohol for 3-4 hours. The author studies the effects on the reduction with compared hydrazinium monoformate as the hydrogen donator, and successfully substitutes dichloromethane for ether as crystal solvent, and reclaims the solvent to reuse. N-p-aminobenzoyl-β - alanine is diazotized and coupled with salicylic acid, the molar radio of 1:1.05, at -5-0℃ for hours to give coarse balsalazide acid, which is then crystallized from 70% acetic acid to get the purify one. The balsalazide acid is dissolved in warm ethanol and treated with a solution of sodium hydroxide to adjust to a pH of about 7.5. Stirred for 4 hours,balsalazide disodium is obtained.The target compound is obtained via five reactions above and the total yield is 67.9%. The structure of balsalazide sodium is identified by TLC, IR and 'HNMR. The content of balsalazide disodium determined by the HPLC method is above 98.9%, which reaches a set standard of medicine.