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The synthesis of peptides by amide bond formation between suitably protected amino acids is a fundamental part of the drug discovery process. However, the required coupling and deprotection reactions are routinely carried out in dichloromethane and DMF, both of which have serious toxicity concerns and generate waste solvent which constitutes the vast majority of the waste generated during peptide synthesis. In this work, propylene carbonate has been shown to be a green polar aprotic solvent which can be used to replace dichloromethane and DMF in both solution- and solid-phase peptide synthesis. Solution-phase chemistry was carried out with Boc/benzyl protecting groups to the tetrapeptide stage, no epimerisation occurred during these syntheses and chemical yields for both coupling and deprotection reactions in propylene carbonate were at least comparable to those obtained in conventional solvents. Solid-phase peptide synthesis was carried out using Fmoc protected amino acids on a ChemMatrix resin and was used to prepare the biologically relevant nonapeptide bradykinin with comparable purity to a sample prepared in DMF.
Essentially all medicines and current drug candidates contain at least one basic nitrogen atom. A common approach to the synthesis of amines is to reduce the corresponding amide with a hydride reagent such as LiAlH4, DIBAL, RedAl, B2H6, Et3SiH, or polymethylhydroxysilane (PMHS).
The reaction survey reported that reduction of amides to amines was used in only 0.6% of chemical transformations; this number would surely be higher if safer methods for use on scale were available. The survey indicated that the number of amide reductions was equally split between diborane and hydride reagents.
Lithium aluminium hydride,
having a molecular weight of 38 and four hydrides per molecule, has the highest hydride density and is frequently used, even though it co-generates an inorganic by-product (lithium aluminum hydroxide) which is difficult to separate from the product. The workup procedure recommended by one bulk supplier (Chemetall) is to precipitate and filter the aluminum hydroxide salts. However, slow filtrations and product loss through occlusion or adsorption are typical problems that can be encountered.
Options for disposal of the cake include dissolving in water and sending to a waste water treatment plant or drying the cake and sending to a chemical waste dump that accepts solids.1 Both options have an environmental impact. Therefore, a generally applicable, safe, environmentally benign and economically viable method for the reduction of amides to amines would have an appreciable benefit to numerous processes.
Hydrogen gas is the ideal reductant because the only by-product is water. Thus, much research has been directed towards discovery of a transition metal catalyst selective for hydrogenation of amides. However, even with the best catalysts, both high temperature (150 °C) and pressure (>100 bar) are required. These conditions involve expensive high pressure hydrogenation equipment not typically available in a common pharmaceutical manufacturing plant.
The harsh conditions also preclude the use of these catalysts with substrates that contain other reducible or thermally labile functional groups. Recent research has led to the discovery of catalysts that are effective at lower temperature and pressure, giving encouragement that the goal of finding a selective, low pressure/temperature catalyst is realistic.2
Another approach would be to use a biotransformation to reduce the amide. It is notable that a number of bacteria and fungi reduce carboxylic acids to aldehydes or ketones.3 The usual fate of amides in biological pathways is hydrolysis. However, an anaerobic bacteria, Clostridium sporogenes, has been reported to reduce benzamide to benzylamine. 4
A key challenge in this technology area is gaining a detailed understanding of these complex enzyme-catalysed processes that require ATP/NADPH co-factor recycling, and getting the enzymes cloned and produced on a large scale in suitable expression systems.
The acylation/reduction strategy for N-alkylation avoids the need to handle alkylating agents and would be more widely used if a safer, more atom economical or preferably catalytic method for amide reduction were developed. The solution to this problem could be either chemical or biochemical.
- Chemetall brochures, Lithium Aluminum Hydride… strong, concentrated and economical, Oct. 2000, pp. 18–19 Search PubMed .
- A. A. Smith, P. Dani, P. D. Higginson and A. J. Pettman, World Pat., WO2005/066112 A1, 2005 Search PubMed .
- (a) A. Hage, H. E. Schoemaker and J. A. Field, Appl. Microbiol. Biotechnol., 1999, 52, 834–838 CrossRef CAS Search PubMed ; (b) A. He, T. Li, L. Daniels, I. Fotheringham and J. P. N. Rosazza, Appl. Environ. Microbiol., 2004, 70, 1874–1881 CrossRef CAS Search PubMed .
- O. Dipeolu, J. Gardiner and G. Stephens, Biotechnol. Lett., 2005, 27, 1803–1807 CrossRef CAS Search PubMed .