Sharma Sumit, Anand Radhika, Cham Pankaj Singh, Raina Sushil, Vishwakarma Ram A, Singh Parvinder Pal
Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine Canal Road Jammu-180001 India
Academy of Scientific and Innovative Research (AcSIR) Ghaziabad-201002 India.
RSC Adv. 2020 May 1;10(29):17085-17093. doi: 10.1039/d0ra01662d. eCollection 2020 Apr 29.
A concise, protection-group free and sequential route has been developed for the synthesis of the nitroimidazole based FDA-approved multi-drug resistant anti-tuberculosis drug, Delamanid and anti-leishmanial lead candidate VL-2098. The synthesis required chiral epoxides (11 and 17) as key intermediates. The chiral epoxide 11 was synthesised by sequential reaction cascades , allylation, selective -arylation, Mitsunobu etherification, Sharpless asymmetric dihydroxylation and epoxidation, which do not require any special/dry reaction conditions. The steps involved towards the synthesis of epoxide also worked nicely in gram scales. After the synthesis of epoxide 11, the synthesis of Delamanid was achieved by reaction with 2-bromo-4-nitroimidazole 12 with an overall yield of 27%. Similarly, anti-leishmanial lead candidate VL-2098 was also synthesized in an overall yield of 36%.
已开发出一种简洁、无保护基团且连续的路线，用于合成基于硝基咪唑的、经美国食品药品监督管理局（FDA）批准的多药耐药抗结核药物地拉曼尼以及抗利什曼原虫先导候选药物VL-2098。该合成过程需要手性环氧化合物（11和17）作为关键中间体。手性环氧化合物11通过连续反应串联、烯丙基化、选择性芳基化、光延醚化、夏普莱斯不对称双羟基化和环氧化反应合成，这些反应不需要任何特殊/干燥的反应条件。合成环氧化合物所涉及的步骤在克级规模上也能很好地进行。在合成环氧化合物11之后，通过与2-溴-4-硝基咪唑12反应合成了地拉曼尼，总收率为27%。同样，抗利什曼原虫先导候选药物VL-2098也以36%的总收率合成。
