Presented at 24th Lakeland Symposium on Heterocyclic chemistry in Grasmere, May 2019 and ESOC-19 in Vienna, July 2019 by our Head of Research and Production UK Achim Porzelle and our Senior Production Chemist Ben Llewellyn.


Abstract: A new range of chiral and non chiral N-Boc 7-azaindolines have been synthesised following a two step synthesis from commercially available 2-fluoropyridines on 50 g scale. Cyclisation to the 7-azaindolines was carried out in a flow reactor with comparable results to the conventional batch approach. The scope of the procedure was also evaluated for the synthesis of tetrahydro-1,8-naphthyridines under batch and flow conditions.

Background: Fused saturated/aromatic heterocycles are playing an increasing role  in the development of new drug candidates. 7-Azindolines are a known structural motif,1 but only a couple of general methods have been developed to synthesise these compounds. N-Boc protected 7-azaindoline building blocks with a variety of substituents have only been reported a few times mainly through reduction of azaindoles 22 or the alkylation of N-Boc protected 2-aminopyridines 3 (Scheme 1).3 Introducing chirality on the 2-position is difficult following these methods.


In our ongoing efforts to make new chiral building blocks for the pharmaceutical and agricultural industries, as well as academia, we have developed a general method from commercially available pyridines 4 and N-Boc 1,2,3-oxathiazolidine-2,2-dioxides 5 to make chiral and non chiral N-Boc 7-azaindolines 6 in a 2 step procedure (Scheme 1, only one enantiomer shown for clarity).4

Results: We started our investigation with 4a and the alkylation with 5a gave 7a in a reasonable yield. However, cyclisation of 7a using LiHMDS gave an inseparable mixture of 6a and 8a. Changing the base, solvent and temperature did not improve the result. We also deprotected 7a and attempted to cyclise the free amine, but the results were similar to the Boc protected compound. Enhancing the reactivity of the 2-position using the fluoropyridine 4b disappointingly gave the same results as 4a.


We therefore turned to iodopyridine 4c to further increase the difference in reactivity and pleasingly 6b was obtained albeit in a low yield (Scheme 2). Encouraged by this result we optimised the reaction conditions for the first step with regards to temperature, equivalents of LDA and oxathiazolidine (1.3 eq. LDA, 1.1 eq of oxathiazolidine, -78 °C for 30 min then rt for 3 h). With optimised conditions in hand we synthesised a series of 3-alkyl-2-fluoro-4-iodopyridnes and expanded the range to different substituted pyridines in moderate to good yields. Interestingly the 5-bromo-2-fluoropyridine gave mixtures of isomers which were impossible to separate on scale (Table 1).

Cyclisations in the flow reactor were conducted with a 0.5 M solution of 7 in THF and a residence time of 2.2 min. The deprotonation step worked efficiently at -20 °C but cyclisation needed different temperatures depending of the substitution pattern (0 to 40 °C), which was realised in a two reactor set-up (Figure 1). We also carried out the reactions in a one reactor set-up using the same temperature (40 °C) for deprotonation and cyclisation. The set-up gave mixed results and was only beneficial for some.


Figure 1. Two reactor set-up on the flow reactor.


In all cases it was important to achieve full conversion of the starting material, because any unreacted material is difficult to remove from the products due to similar solubility properties and  Rf-values of the compounds. However, this resulted in the formation of by-products so a trade-off had to be made. After the optimisation process was completed the reactions were carried out in a 10 min run allowing for 4-5 g of material to be cyclised. Expanding the scope to tetrahydro-1,8-naphthyridines in the flow reactor was so far unsuccessful




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