治疗骨髓增殖性肿瘤药物TG101209的合成

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%。

Synthetic Technique of TG101209 for Treating Bone Marrow Hyperplastic Tumor

The synthetic technique of TG101209 for treating bone marrow hyperplastic tumor was studied.2-Chloro-4-amino-5-methyl-pyrimidine(B) was prepared by chlorination and substitution reaction of 2,4-dihydroxy-5-methylpyrimidinnel, phosphorus oxychloride and ammonium hydroxide.B reacted with 3-bromo-N-t-butyl benzenesulfonic amide (C) to give 3-(2-chloro-5-methyl-4-pyrimidinyl) amino]-N-t-butylbenzenesulfonic amide (D) by Buchwald coupling reaction.D reacted with CH3OH-HCl in the methanol to afford 3- (2-chloro-5-methyl-4-pyrimidinyl) amino]-N-tert-butylbenzenesuiphonamide hydrochloride (E). (N-tert-butyl-3-(5-methyl-2-4-(4-methyl-1-piperazinyl)-phenylamino]-pyrimidine-4-ylamino)-benzenesulfonamide)(TG101209) was synthesized by nucleophilic substitution reaction of the intermediate (E) and 1-methyl-4-(4-aminophenyl)piperidine (G). The overall yield was 30.9%. HPLC purity was 99.7%. (N-tert-butyl-3-(5-methyl-2-4-(4-methyl-1-piperazinyl)-phenylamino]-pyrimidin-4-ylamino)-benzenesulfonamide)(TG101209) was synthesized by nucleophilic substitution reaction of the intermediate (E) and (G).The overall yield was 30.9%.HPLC purity is 99.7%.