Preparation of indolizine derivatives via aza-Baylis-Hillman intermediates
Scheme 43. Representation of activation-based synthesis of desired targets
A new range of catalytic strategies that involve the use of propyl phosphonic anhydride (T3P) have been developed to provide efficient, practicable and reproducible approaches to amide synthesis under mild conditions and with broad substrate scope. The functional group tolerance and potency of the T3P-catalysed approach is a “trademark” feature and, consequently, attention was turned to the use of this coupling agents.
95 2.2.5. T3P-catalysed synthesis of amides.
Using T3P as a catalyst, we were successful in synthesising a series of amides from indolizine- 2-carboxylic acid and commercially available primary, secondary or sterically hindered aromatic and aliphatic amines. The catalytic efficacy of T3P was examined by initially coupling indolizine-2-carboxylic acid with 2,4-imidazolidinedione 148 (commonly known as hydantoin) and its N-methylated derivative under various reaction conditions (Scheme 49, p108). Firstly, the coupling of indolizine-2-carboxylic acid and 2,4-imidazolidinedione 148 in a mixture of anhydrous ethyl acetate and pyridine (1:2) did not furnish the desired product.
Replacement of ethyl acetate with anhydrous chloroform, however, led to the formation of two products according to TLC analysis. Refluxing the reaction mixture to accelerate the reaction rate resulted in an intractable product. Lastly, replacement of pyridine with the easy to handle and relatively benign diisopropylethylamine (DIPEA) drastically improved the reaction. The latter condition was applied in all subsequent reactions, including reactions involving relatively non-nucleophilic amines and, where necessary, under reflux. The desired products were obtained in moderate yields. As indicated in the following pages, the reaction was executed with a wide range of amines and either indolizine-2-carboxylic acid or 3-acetylindolizine-2- carboxylic acid.
2.2.6. Preparation of secondary amides.
Several procedures for attaining indolizine ester intermediates have been examined over the past years in our group, including (i) conversion of BH alcohols to corresponding acetoxy derivatives and subsequent thermal cyclisation of the acetylated BH adduct and (ii) direct distillation of the alcohol.145, 215, 218 The seminal discovery that thermal conversion of methyl 3-hydroxy-2-methylene-3-(2-pyridinyl)propanoate 88 into the crystalline methyl indolizine-2- carboxanoate 90 was found to occur at ca. 140 °C with a maximum of 22% yield. Thermal cyclisation was presumed to follow the intramolecular addition-elimination sequence and, clearly, conversion of the alcohol 88 to a corresponding acetate 89 drastically improved the process. Acetylation of the product has been achieved either by refluxing the alcohol in acetic anhydride for 30 minutes or by reaction of the alcohol 88 with acyl chloride in the presence of pyridine at room temperature.218
96 Scheme 44. Brief demonstration for the preparation of synthetic substrate.
In this research, indolizine esters were obtained from the BH alcohol, i.e. without isolating the acetylated intermediate. The alcohol was refluxed in acetic anhydride for two to seven days to obtain methyl indolizine-2-carboxylate or 3-acetylindolzine-2-caboxylate in excellent yield.
Subsequent hydrolysis of the esters (see section 2.2.2 and 2.2.3) provided the carboxylic acids required for the synthesis of the target amides.
Particular attention was given to the selection of the amines required in exploring the potential synergy of coupling the indolizine moiety to a medicinally significant amine moiety. According to Ortona and Antinori,249 the standard six-month TB therapy usually includes administration of a cocktail of isoniazid 168, rifampicin 169 and pyrazinamide 171 in the first two months, with the addition of ethambutol 167 in case resistance is encountered, followed by completion of the course with isoniazid 168 and rifampicin 169. Prolonged therapy has frequently led to patient non-compliance and, in turn, contributed to the emergence of multi-drug resistant TB (MDR-TB) which is difficult and expensive to treat. The hard-to-treat MDR-TB strains are being found increasingly, thus emphasising the need for the ongoing development of new and potent drugs including the possibility of incorporating the well-known anti-TB drugs ethambutol 167, isoniazid 168 and rifampicin 169 (Figure 57.).250
The FDA approved anti-tuberculosis amines, such as pyrazinamide 171, cycloserine 170, and ethambutol 167 and its truncates, such as 2-(2-aminoethoxy)ethanol 172, 2-amino-1-butanol 173 and 4-amino-1-butanol 174 (Figure 58), were thus considered for coupling with the carboxylic acids.
97 Figure 57. FDA approved anti-TB drugs.
The target mycobacteria in TB therapy have a unique cell wall in which mycolic acid confers resistance to chemical attack and dehydration, and inhibits the permeability of hydrophobic antibiotics. The design of new anti-mycobacterials therefore requires molecules with high lipophilicity to facilitate permeability through the cell wall of the mycobacteria. Also, to be taken into consideration is the development of affordable drugs that can suppress or eradicate the extensive drug-resistant TB (XDR-TB) strain. XDR-TB is an MDR-TB with additional resistance to fluoroquinolone and any of the second-line regimen drugs.251 After treatment initiation, MDR-TB therapy, coupled with close monitoring for adverse drug reactions, spans at least 20 months, and the global success rate was reported to average ca. 48% in 2011.252 In 2012, an assessment of 107 XDR-TB patients treated in South Africa revealed a very dismal success rate with a mortality rate of ca. 78%.253 Drug-resistant TB is a particular risk to individuals with HIV and this often leads to rapid transmission of the disease and heightened mortality rate among sufferers.254 The physiological adversities associated with drug-drug interactions (DDIs) between anti-TB drugs and antiretroviral therapy (ART) renders the development of multitherapy drugs imperative.252 This, in turn, addresses the complexities of managing HIV-TB co-infections, including other simultaneous infections such as malaria.
Unfortunately, the attempted preparation (Scheme 45) of amides containing the ethambutol truncates 172-174 (Figure 58) produced insoluble white solids, TLC analysis of which revealed the presence of starting materials. Also, attempted coupling of the indolizine-2- carboxylic acid 138 with each of the nucleotide nitrogenous bases adenine 175, guanosine 176, thymidine 177 and adenosine 178 was not successful. Encouraged by the observation that T3P- catalysed synthesis of N-(2-thiazolyl)indolizine-2-carboxamide 154 improved the yield thirteen folds (Scheme 51) compared to the tris(2,2,2-trifluoroethyl)borate-catalysed reaction (Scheme 35), we proceeded to explore the T3P-mediated coupling of indolizine-2-carboxylic
98 acid with pyrazinamide 171 (Section 2.2.6.1) and cycloserine 170 (Section 2.2.6.2), respectively.
Scheme 45. Schematic representation for attempted coupling of indolizine-2-carboxylic acid