摘要
目的合成具有抗肿瘤活性和免疫调节作用的3-氨基-N-(2,6-二氧代-3-哌啶基)-邻苯二甲酰亚胺(pomalidomide,1)。方法 N-Boc-L-谷氨酰胺(2)经羰基二咪唑缩合、脱保护得到3-氨基哌啶-2,6-二酮盐酸盐(4);3-硝基邻苯二甲酸(5)环合得到3-硝基邻苯二甲酸酐(6);4与6在乙酸中缩合,再经甲酸铵/钯炭还原得到目标产物。结果与结论经过5步反应合成目标化合物,总收率为46.5%(以5计),目标化合物结构经1H-NMR和MS谱确证。
Pomalidomide, an analogue of thalidomide, was developed by Celgene corporation. It is known as immunomodulatory drugs（IMIDs） which shows higher TNFα inhibitory activity, a good toxicity profile and specific activity in multiple myeloma （MM）. A synthesis of pomalidomide was reported by Tang, et al. It was prepared from N-tert-butoxycarbonyl-L-glutamin via cyclization with 1-ethyl-3-（ 3-dimethylaminopropyl） carbodiimide （EDCI）, deprotection of tert-butoxycarbonyl group with trifluoroacetic acid in dichlo- romethane, condensation with 3-nitrophthalic acid anhydride and reduction of nitro group using Fe powder. This route was simple and easy to handle, but the reagents used in the steps caused multiple problems, such as two steps of chromatography, expensive trifluoroacetic acid, oil intermediates and so on. The route in this article is the same as the one in the reference, while in each step, we use a different reagent. Here pomalidomide was synthesized from N-tert-butoxycarbonyl-L-glutamin via cyclization using 1,1 ＇-carbonyldiimidazole （CDI）, deprotection by HCl-ethylacetate solution, condensation with 3-nitrophthalic acid anhydride with CH3COONa and f＇mally reduction of nitro group with HCOONH4 catalyzed by 10% Pd/C. Its structure was confirmed by ^1H-NMR and MS. Purifying by chromatography was avoided since every intermediate in this method is solid. The total yield is 46. 5 % （ calculated by 3-nitrophthalic acid）, higher than that of the reference（ 35% ）.
出处
《中国药物化学杂志》
CAS
CSCD
2013年第2期108-110,共3页
Chinese Journal of Medicinal Chemistry
