A General, One-Step Synthesis of Substituted Indazoles using a Flow Reactor

Abstract

Flow chemistry is a rapidly emerging technology within the pharmaceutical industry, both within medicinal and development chemistry groups. The advantages of flow chemistry, increased safety, improved reproducibility, enhanced scalability, are readily apparent, and we aimed to exploit this technology in order to provide small amounts of pharmaceutically interesting fragments via a safe and scalable route, which would enable the rapid synthesis of multigram quantities on demand. Here we report a general and versatile route which utilises flow chemistry to deliver a range of known and novel indazoles, including 3-amino and 3-hydroxy analogues. ' INTRODUCTIONAs part of an ongoing medicinal chemistry program, we were interested in synthesising a range of 5-and 6-substituted N-methylindazoles (1), which can be synthesised via the condensation of methylhydrazine with the corresponding 2-fluorobenzaldehyde (scheme 1). This approach was particularly attractive to us due to the relatively large set of commercial 2-fluorobenzaldehydes available, but we were surprised to find the reaction is not widely precedented, and we were only able to locate isolated examples in the literature. 1 Condensations with hydrazine are slightly more common, and although recent publications by Lukin 2 and Slade 3 demonstrate the versatility of the reaction, the yields are variable (0-82% and 38-66%, respectively) and the reaction times long (3-36 h). We also reasoned that this approach could be applied to give 3-aminoindazoles (2) and 3-hydroxyindazoles (3) from 2-fluorobenzonitriles and benzoates respectively (scheme 1). Once again, we were surprised to learn that, although the S N Ar condensation between hydrazines and 2-fluorobenzonitriles is fairly well reported, 4 there are very few reported procedures for the synthesis of 3-hydroxyindazoles from 2-fluorobenzoates. 5 Additionally, we hoped to identify a generic route which would utilise unsubstituted hydrazine, thus enabling us to diversify around the 1-position at a later date. However, the hazards with using hydrazines under forcing conditions are well-known, 6 and this issue, together with the long reaction times cited in the literature, pointed towards a potentially scale-limited route.We therefore considered utilising flow chemistry techniques as a means of providing a safe, scalable alternative in order to deliver the small quantities of monomers required, and also to facilitate scale-up on-demand. Flow chemistry reactions are now widely documented in the literature, 7,8 and the technology is becoming increasingly prominent in the pharmaceutical industry. 9 Our group has previously demonstrated the use of flow reactors to safely control reaction exotherms, 10 and also the use of flow microwaves to achieve selective bromination of a substituted benzene. 11 Indeed, one of the perceived advantages of flow chemistry is the ability to safely perform reactions at elevated temperatures and pressures, and as such it is often compared to microwave synthesis. 12 We aimed to exploit this appro...

Silica Supported Polyphosphoric Acid Catalyzed Synthesis of Substituted Indazoles

“…Similar type synthetic protocols were also studied using various acid catalysts such as PTSA, Montmorillonite KSF, Amberlite-15, Zeolite-HY and Montmorillonite K-10, the desired indazoles were obtained in 17, 64, 38, 57 and 85 % yields respectively. [15][16][17][18][19][20][21][22][23] The above-mentioned acid-catalyzed reactions were carried at reflux temperature for 3 h using 20 % weight of catalyst concerning the weight of all the reactant was used. Thus, silica supported polyphosphoric acid was found to be a moderate heterogeneous acid catalyst as compared with the above acid catalyst used for the synthesis of indazole derivatives.…”

Synthesis of indazole motifs and their medicinal importance: An overview

“…However methyl ortho-benzoate react with methyl hydrazine to form 3-amino and 3-hydroxy indazole are reported (Scheme-08) [22]. Regioselective synthesis of 2, 3-disubstituted tetrahydro-1H-indazoles has been reported by using catalyst zirconium sulfophenyl phosphonate methanephosphonate (Scheme-09) [23].…”

“…An emerging technology using flow chemistry is used by pharmaceutical industry for development of novel drugs using indazole derivatives (Scheme-26) [40].…”

Managing Hazardous Reactions and Compounds in Process Chemistry

“…Other heterocycles such as N-aryl pyrazoles (108), 1,2-azoles (4, 109) and substituted indazoles (110). were also prepared by flow reactions.…”