A concise and sequential synthesis of the nitroimidazooxazole based drug,Delamanid and related compounds

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 viz., allylation, selective N-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%.

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.

Imidazoles are present in a wide variety of biologically relevant molecules exhibiting diverse pharmaceutical properties. Specifically, nitroimidazole containing compounds are active therapeutic agents against a wide variety of protozoan, bacterial (anaerobic) and leishmanial infections of humans and animals.¹ The notable examples of drugs are fexindazole,² metronidazole,³ benznidazole,⁴ tinidazole,⁵etc. Nitroimidazole was also well explored in the area of tuberculosis (TB) drug discovery (the structure of nitroimidazole containing drugs and lead compounds shown in Fig. 1).^6–9 CGI-17341 (I, developed by Ciba-Geigy, India) represents one of the very earliest outcomes but was not continued because of mutagenicity.⁶ Continued efforts to overcome the mutagenic liability led to the discovery of Delamanid (II, OPC-67683, a blockbuster against multi-drug resistant-TB, approved in 2014 by the EU)⁷ and Pretomanid^8a (III, PA-824, against multi-drug-resistant-MTB, approved in 2019 by the USFDA).¹⁰ Our involvement in the area of the TB drug discovery program and nitroimidazole chemistry^8b,c motivated us to develop a new concise and improved strategy towards the synthesis of Delamanid. The first synthesis of Delamanid was done by Tsubouchi et al. in 2004 (Otsuka Pharmaceutical Ltd. WO2004033463A1) which involved 16 steps (details shown in Fig. S1 of ESI^†).^11,12 The synthesis involves protection–deprotection strategy and made the process lengthy. Later on, in 2011, Otsuka had developed another concise route for Delamanid with improved yield (upper half of Fig. 2, details shown in Fig. S2 of ESI^†). This method involved the Sharpless epoxidation of 2-methyl allylalcohol followed by ring opening with 4-bromophenol. Then coupling with 4(4-trifluoromethoxy phenyl)piperidine fragment under palladium catalyzed conditions, which in turn was synthesized in 2–5 steps.¹³ Considering the importance of Delamanid, It could be better if more concise route was developed. In this regard, here we devised a route which involves sequential addition of fragments which not only avoid protection and deprotection but also provides the advantages of avoidance of dry conditions and costly intermediates. The lower half of Fig. 2 represents the strategy of the present method used for the synthesis of Delamanid, which involve the sequential coupling with following cascade viz., allylation, selective N-arylation, Mitsunobu ether formation, Sharpless dihydroxylation, epoxidation, ring opening and cyclization using inexpensive and easily available starting materials.Open in a separate windowFig. 1Nitroimidazole containing drugs and leads.Open in a separate windowFig. 2Previous and current approaches.The present synthesis started with 2-methylallyl chloride as first starting material and its selection is because of following reasons (i) as protecting group, (ii) inexpensive (33$ per 100 mL, Sigma) in comparison to 2-methylallyl alcohol (766$ per 100 mL, Sigma) which is used in earlier reported method and (iii) provide double bond functionality to generate epoxide via Sharpless dihydroxylation approach, which operates under open atmosphere conditions and avoids the anhydrous and dry environment as required for Sharpless epoxidation, used in the previous reported methods.^7,11b,12