During the three years of my Ph.D. I had the opportunity to work on several projects, thanks to the collaboration with Dipharma Francis s.r.l., a chemical company in which I also spent an internship period. These projects can be divided into two branches, the first regarding the academic research, with the aim to develop new sustainable synthesis of substituted amines. The second, with a more industrial character, based on the investigation for alternative synthesis of APIs and on the synthesis of their impurities. The first chapter of this thesis cover the work on sustainable processes, which was faced with the exploit of microwave dielectric heating technology (MW). The simplification of organic syntheses and the development of sustainable protocols are among the main topics of interest for the chemical and pharmaceutical industry. In fact, these aspects can lead to a reduction in production costs, allowing to reach the final product with fewer steps and reducing the production of waste, thus achieving a lower environmental impact. These are fundamental characteristics of the so-called “green chemistry”, whose basic concept is that the planning and the design of a new product must not be casual, but should be rationalized with the intent of obtaining the product through environmentally friendly processes. The MW is a useful tool for green chemistry, actually, microwave-assisted organic synthesis (MAOS) produce higher yields and lower quantities of side-products, with respect to the conventional reactions. This means that the reactions performed in it are reasonably cleaner, producing a smaller amount of waste. Moreover heating by means of microwave radiation is a highly resourceful process, resulting in substantial energy savings. Following the indications of the green chemistry two sustainable processes for the synthesis of substituted amines were developed, both employing the use of MW dielectric heating. First an iron catalysed reductive amination was developed: due to the relatively high price of some common metal catalysts and their corresponding complexes, the search for cheaper and environmentally friendly catalysts is a current and challenging topic. For this reason, iron has been chosen among the various transition metals, as it is the second most abundant metal in the earth's crust and has only been poorly studied for reductive amination reactions. A new one pot process was developed, using both Fe3(CO)12 or Fe2(CO)9 as the catalysts, sodium hydroxide and DMAP as the bases and isopropanol as green solvent and hydrogen donor. After an initial optimization phase, it was possible to obtain various substituted amines by reacting different aldehydes with primary and secondary amines. With this procedure it was possible to use not only aromatic amines, as previously reported for the iron catalyzed reductive amination, but also aliphatic ones. Moreover, thanks to the use of microwave heating it was possible to complete the reactions in just 10 minutes. Subsequently a one-pot domino hydrogenation-reductive amination has been developed using phenol as the starting material, for the production of a very interesting scaffold such as cyclohexylamines, which are present in the structure of various APIs such as anticonvulsants, antidiabetics and antiviral compounds. As seen previously, the reductive amination of carbonyl compounds is one of the most useful methods for preparing substituted amines and a substantial improvement in this transformation is the generation of the carbonyl compound from alcohols under conditions compatible with the reductive amination. However, until now the methods for the formation of cyclohexanone from phenol require high temperatures and high H2 pressures. Therefore, the possibility to perform these reactions in a sustainable way was explored. Water was used as the ecofriendly solvent, sodium formate was chosen as a sustainable source of hydrogen, being among the main products of biomass, and Pd/C was used as the heterogeneous catalyst, which can be recovered by simple filtration and reused. After the initial phase of optimization of the reaction between phenol and butylamine, which led to the obtainment of N-butyl-cyclohexylamine in good yield, it was possible to synthesize several substituted cyclohexylamines, using primary and secondary amines, amino alcohols, and even amino acids as nucleophiles. Also in this case the use of MW dielectric heating led the reaction to finish in only 20 minutes. Moreover all the products were isolated after filtration and acid/basic workup, with no need for flash chromatography. The second chapter of the thesis starts to deal with the industrial side of the work. In fact this section was done in partnership with the chemical company Dipharma Francis, and this collaboration led us to look for a new synthetic way to produce the drug Vildagliptin, a dipeptidyl peptidase-4 inhibitor approved for the treatment of type 2 diabetes mellitus. Its structure is characterized by a cyanopyrrolidine connected to a 3-hydroxy-1-aminoadamantane via an acetyl linker. Looking at the current literature, it was clear that every single work so far was relying on L-prolinamide employed as starting material or synthesis intermediate, to get to the (S)-2-cyanopyrrolidine key intermediate. Then, to bypass this route, it was thought a synthesis where the key (S)-2-cyanopyrrolidine intermediate is obtained from the new intermediate (S)-2-pyrrolidinecarbaldehyde, developing a novel synthetic strategy for the synthesis of Vildagliptin. Starting from the cheap and commercially available L-proline it was possible to produce an original synthesis of Vildagliptin with an overall 20% yield, with a process that could be readly scalable for industrial purpose. Finally, the third chapter is about the internship I held in the research and development laboratories of Dipharma Francis. During this time I had the opportunity to work on the answer to a 'deficiency letter' sent by the Food and Drug Administration about the Drug Master File submitted in 2015 for the product Miglustat. Miglustat, also known as N-butyl-deoxynojirimycin, is a potent inhibitor of glycosidases and glycosyltransferases, belonging to the class of iminosugars, a family of polyhydroxylated heterocycles, similar to sugars in which the endocyclic oxygen is replaced by a nitrogen atom. This substitution gives them significant biological properties due to the ability to mimic carbohydrates, and for this reason Miglustat is used for the treatment of Gaucher disease. The FDA deficiency letter requested the synthesis and characterization of four possible impurities of Miglustat, to be sure, with analytical evidences, that they were not present in the final product. They required the manno and galacto diastereoisomers of Miglustat for the possible presence of galactose and mannose traces in the raw material used for the synthesis of Miglustat, i.e. glucose. In fact these could follow the same synthetic way of glucose and give the final product with a wrong configuration. Then, it was requested to prepare a monobenzylated N-butyl-deoxynojirimycin to control the possible impurities deriving from an incomplete deprotection in the last step of the synthesis. Finally, it was requested to prepare the N-butyl-N-oxide-deoxynojirimycin to verify this possible oxidation by-product. It was therefore my task to prepare analytical standards with high purity of these molecules that were used to respond to the FDA.
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