Development of a fast and flexible generic process for the reduction of nitro compounds

The hydrogenation of aromatic nitro substrates is a frequently used reaction in the multi-step fabrication of active pharmaceutical ingredients (APIs). Today most pharmaceutical production processes are performed in batch mode. In the frame of the C2-campaign speed is an important factor during the production of a multitude of possible API’s. A generic reactor set-up able to be adapted for the transformation of a specific substrate would reduce the development time and thereby the campaign time significantly. In the frame of the EU-project F3-Factory such a flexible and continuous reaction system for this important reaction class able to produce 1-5 kg API is being developed. To allow for an easy and fast adaptation of this process for a range of nitro substrates a substrates adoption methodology (SAM) is also being developed. A literature study of the nature of different reduction methods (H2 gas, H-Donor, CO gas, etc.) led to the conclusion that the liquid phase reduction of aromatic nitro substrates by either hydrogen gas or an H-donor is the most selective method. Following the requirements of that reaction type a flexible and modular reactor for the liquid phase reduction with a heterogeneous slurry catalyst was designed that can be adapted for reduction of a range of nitro compounds. The generic process provides the possibilities of swapping out a reactor or work up technology as required. The equipments of the generic process should be also able to operate at wider range of operational variables making it suitable for a range of substrates. The SAM identifies the necessary changes to a generic process and plant in order to adapt it for a given substrate. The objectives of this presentation is to highlight the design of a generic nitro reduction process and to demonstrate the application of this generic process on a pharmaceutical manufacturing case study involving the nitro reduction of 6-Nitroquinoline

Preparation of organic hydrazides

Thesis (M.A.)--Boston UniversityDue to the actual high price of hydrazine, this chemical cannot be used in an economical preparation of organic hydrazides. A synthesis of such hydrazides can be envisaged by the reduction of N-nitroamides. The problem is then to find a set of conditions under which no hydrogenolysis of the nitrogen-nitrogen bond occurs. This had been done with N-nitrocarbamates and it was hoped that the results could be extended to N-nitroamides: N-Nitro-N-methylamides were actually used in order to have a more stable N-nitro group. Dimethylation of the hydrazine could be performed either by acid hydrolysis of the addition product obtained with diethyl azodicarboxylate or by heating with pyridinium chloride. After failure to reduce p-N-dinitro-N-methylbenzamide to hydrazine, a new technique was experienced by which the amide was nitrated and reduced directly without isolation of the N-nitroamide. Preliminary results suggested that the electron shifting ability of the R group in molecules of the type R CO-N(NO2)CH3 is very important in their reduction to hydrazine. Several molecules were then reduced with different R. It was found that the yield of hydrazine increases with the electron repelling ability if R. A mechanism involving formation of an unstable platinum hydride is proposed for the reaction. A survery of the addition reactions of azodicarboxylic esters is given with the description of an attempt of "Azo reaction" between diethyl azodicarboxylate and p-N-dinitro-N-methylbenzamide

New insight into 4-nitrobenzene diazonium reduction process: Evidence for a grafting step distinct from NO2 electrochemical reactivity

Electrochemical and spectroscopic investigations were performed in order to clarify the mechanism of 4-nitrobenzene diazonium reduction on glassy carbon in protic medium. The number and nature of the electron transfer processes were found to be strongly correlated to the electrode surface state. On polished electrode two different reduction peaks were observed. Selective electrolyses realized at the corresponding potential definitely proved that the grafting process actually occurs at a potential distinct from NO2 electroreduction, this latter inducing the presence of the quasi-reversible NO/NHOH redox couple at the electrode surface. These results were confirmed by XPS analyses. Furthermore, voltammetric experiments using Fe(CN)63- showed that the electrochemical properties of the modified electrode strongly depend on the potential applied for grafting, which modulates the nitro group oxidation state. All the results suggested that the electrode functionalization was more efficient when grafting and NO2 reduction were performed separately

Formation of a gold-carbon dot nanocomposite with superior catalytic ability for the reduction of aromatic nitro groups in water

We report the synthesis of a gold-carbon dot nanocomposite and its utility as a recyclable catalyst for the reduction of aromatic nitro groups. The presence of carbon dots on gold nanosurfaces enhanced the reduction rate by two-fold

Preparation of substituted hydrazines

Thesis (M.A.)--Boston UniversityAlthough a large number of substituted hydrazines are known, the preparation of simple monoalkylhydrazines in a manner suitable for the large-scale economical synthesis has never been developed. Three methods commonly employed in the laboratory i.e. the direct alkylation of hydrazine by an alkyl halide, the alkylation of benzalazine with alkyl sulfates and the catalytic reduction of hydrazones all have serious limitations. It appears that the reduction of an N-nitro or N-nitroso group should give a hydrazine derivative if the reduction could be carried out under conditions which would reduce these groups without scission of the nitrogen to nitrogen bond. Such reductions of a few compounds, notably N-methyl-N-nitrosourea, have been known for some time but the yields are either low or not given in the literature in most cases. The current research project was directed toward the development of suitable conditions for this desired reduction without hydrogenolysis of the N-N bond. Many possible reducing agents are known and should be investigated; the present paper deals only with the reduction of these compounds with zinc dust and dilute acetic acid [TRUNCATED

Phosphorus-containing imide resins

Bis- and tris-imides derived from tris (m-aminophenyl) phosphine oxides by reaction with maleic anhydride or its derivatives, and addition polymers of such imides, including a variant in which a mono-imide is condensed with a dianhydride and the product is treated with a further quantity of maleic anhydride. Such monomers or their oligomes may be used to impregnate fibers and fabrics which when cured, are flame resistant. Also an improved method of producing tris (m-aminophenyl) phosphine oxides from the nitro analogues by reduction with hydrazine hydrate using palladized charcoal or Raney nickel as the catalyst is described

Application of nitroarene dioxygenases in the design of novel strains that degrade chloronitrobenzenes.

Widespread application of chloronitrobenzenes as feedstocks for the production of industrial chemicals and pharmaceuticals has resulted in extensive environmental contamination with these toxic compounds, where they pose significant risks to the health of humans and wildlife. While biotreatment in general is an attractive solution for remediation, its effectiveness is limited with chloronitrobenzenes due to the small number of strains that can effectively mineralize these compounds and their ability to degrade only select isomers. To address this need, we created engineered strains with a novel degradation pathway that reduces the total number of steps required to convert chloronitrobenzenes into compounds of central metabolism. We examined the ability of 2-nitrotoluene 2,3-dioxygenase from Acidovorax sp. strain JS42, nitrobenzene 1,2-dioxygenase (NBDO) from Comamonas sp. strain JS765, as well as active-site mutants of NBDO to generate chlorocatechols from chloronitrobenzenes, and identified the most efficient enzymes. Introduction of the wild-type NBDO and the F293Q variant into Ralstonia sp. strain JS705, a strain carrying the modified ortho pathway for chlorocatechol metabolism, resulted in bacterial strains that were able to sustainably grow on all three chloronitrobenzene isomers without addition of co-substrates or co-inducers. These first-generation engineered strains demonstrate the utility of nitroarene dioxygenases in expanding the metabolic capabilities of bacteria and provide new options for improved biotreatment of chloronitrobenzene-contaminated sites

Nitroheterocyclic drug resistance mechanisms in <i>Trypanosoma brucei</i>

OBJECTIVES: The objective of this study was to identify the mechanisms of resistance to nifurtimox and fexinidazole in African trypanosomes. METHODS: Bloodstream-form Trypanosoma brucei were selected for resistance to nifurtimox and fexinidazole by stepwise exposure to increasing drug concentrations. Clones were subjected to WGS to identify putative resistance genes. Transgenic parasites modulating expression of genes of interest were generated and drug susceptibility phenotypes determined. RESULTS: Nifurtimox-resistant (NfxR) and fexinidazole-resistant (FxR) parasites shared reciprocal cross-resistance suggestive of a common mechanism of action. Previously, a type I nitroreductase (NTR) has been implicated in nitro drug activation. WGS of resistant clones revealed that NfxR parasites had lost >100 kb from one copy of chromosome 7, rendering them hemizygous for NTR as well as over 30 other genes. FxR parasites retained both copies of NTR, but lost >70 kb downstream of one NTR allele, decreasing NTR transcription by half. A single knockout line of NTR displayed 1.6- and 1.9-fold resistance to nifurtimox and fexinidazole, respectively. Since NfxR and FxR parasites are ∼6- and 20-fold resistant to nifurtimox and fexinidazole, respectively, additional factors must be involved. Overexpression and knockout studies ruled out a role for a putative oxidoreductase (Tb927.7.7410) and a hypothetical gene (Tb927.1.1050), previously identified in a genome-scale RNAi screen. CONCLUSIONS: NTR was confirmed as a key resistance determinant, either by loss of one gene copy or loss of gene expression. Further work is required to identify which of the many dozens of SNPs identified in the drug-resistant cell lines contribute to the overall resistance phenotype

Crystallographic Distinction between “Contact” and “Separated” Ion Pairs: Structural Effects on Electronic/ESR Spectra of Alkali-Metal Nitrobenzenides

The classic nitrobenzene anion-radical (NB-• or nitrobenzenide) is isolated for the first time as pure crystalline alkali-metal salts. The deliberate use of the supporting ligands 18-crown-6 and [2.2.2]cryptand allows the selective formation of contact ion pairs designated as (crown)M+NB-•, where M+ = K+, Rb+, and Cs+, as well as the separated ion pair K(cryptand)+NB-•both series of which are structurally characterized by precise low-temperature X-ray crystallography, ESR analysis, and UV−vis spectroscopy. The unusually delocalized structure of NB-• in the separated ion pair follows from the drastically shortened N−C bond and marked quinonoidal distortion of the benzenoid ring to signify complete (95%) electronic conjugation with the nitro substituent. On the other hand, the formation of contact ion pairs results in the substantial decrease of electronic conjugation in inverse order with cation size (K+ \u3e Rb+) owing to increased localization of negative charge from partial (NO2) bonding to the alkali-metal cation. Such a loss in electronic conjugation (or reverse charge transfer) may be counterintuitive, but it is in agreement with the distribution of odd-electron spin electron density from the ESR data and with the hypsochromic shift of the characteristic absorption band in the electronic spectra. Most importantly, this crystallographic study underscores the importance of ion-pair structure on the intrinsic property (and thus reactivity) of the component ions - as focused here on the nitrobenzenide anion