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本文研究了治疗骨髓增殖性肿瘤药物TG101209的合成工艺。以2,4-二羟基-5-甲基嘧啶为起始原料,与三氯氧磷、氨水发生氯化、取代反应生成2-氯-4-氨基-5-甲基嘧啶(B),B再与N-叔丁基-3-溴苯磺酰胺(C)发生Buchwald偶联反应得到3-[(2-氯-5-甲基-4-嘧啶基)胺基]-N-(叔丁基)苯磺酰胺(D)。以甲醇为溶剂,D与CH3OH-HCl反应得到3-[(2-氯-5-甲基-4-嘧啶基)胺基]-N-(叔丁基)苯磺酰胺盐酸盐(E),E与1-甲基-4-(4-氨基苯基)哌啶(G)发生亲核取代反应得到N-叔丁基-3-(5-甲基-2-[4-(4-甲基-1-哌嗪)苯胺基]-4-胺基嘧啶)-苯磺酰胺(TG101209)。总收率达到30.9%,HPLC测得纯度达到99.7%。
This article studies the synthesis of myeloproliferative tumor drug TG101209. 2,4-Dihydroxy-5-methylpyrimidine as the starting material, with phosphorus oxychloride, ammonia chlorination, substitution reaction 2-chloro-4-amino-5-methylpyrimidine (B), B Buchwald coupling reaction with Nt-butyl-3-bromobenzenesulfonamide (C) gave 3 - [(2-chloro-5-methyl-4-pyrimidinyl) amino] -N- Yl) benzenesulfonamide (D). Reaction of D with CH3OH-HCl with methanol as solvent gave 3 - [(2-chloro-5-methyl-4- pyrimidinyl) amino] -N- (tert- butyl) benzenesulfonamide hydrochloride (E) , Nucleophilic substitution reaction of E with 1-methyl-4- (4-aminophenyl) piperidine (G) gave Nt-butyl-3- Methyl-1-piperazine) anilino] -4-aminopyrimidine) -benzenesulfonamide (TG101209). The total yield of 30.9%, HPLC purity of 99.7%.