Organic Process Research & Development最新文献

An efficient gram-scale synthesis of the antituberculosis agent pretomanid using straightforward chemistry, mild reaction conditions, and readily available starting materials is reported. Four different protecting groups on the glycidol moiety were investigated for their technical feasibility and ability to suppress side reactions. Starting from readily available protected (R)-glycidols and 2-bromo-4-nitro-1H-imidazole, pretomanid could be prepared in a linear three-step synthesis in up to 40% isolated yield. In contrast to most syntheses reported so far, deprotection and cyclization were performed in a one-pot fashion without any hazardous steps or starting materials.

This article reports a rare example of the crystallization of a cocrystal of an organic molecule with its epimer. In this case, belzutifan, a novel treatment for von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC), crystallizes as a 1:1 cocrystal with one of its epimers (inversion of stereochemistry at the hydroxyl position). This observation is of particular importance to controlling the purity of the API in the commercial manufacturing process. After the discovery of this cocrystal, the crystalline structure was determined through a combination of crystal structure prediction (CSP) and powder X-ray diffraction followed by single-crystal X-ray diffraction structure determination. The only lattice interaction that exists between the two epimers is a π–π stacking arrangement created by the alternating fluorobenzonitrile aryl groups of each epimer. The formation of this complex, while unexpected, is a reminder that unexplored crystal forms can pose a significant risk to the robustness of chemical manufacturing processes. At present, the cost of leveraging CSP tools across the entirety of a synthetic process is significant. However, discoveries such as the belzutifan:hydroxy epimer cocrystal highlight why current investments in in silico tools are needed and justify expanding their use to de-risk commercial synthetic routes to expedite the development of life-saving medications.

An industry-ready approach for the synthesis of terlipressin is developed: the entire peptide chain assembly and subsequent disulfide bond closure are carried out on a polymeric carrier with a specific precaution for the protection of the N-terminal α-amino group. The effect of various factors on the purity of crude disulfide was studied, and the solid-phase cyclization process was optimized. The designed approach has high fidelity and reproducibility and is applicable for a large-scale peptide synthesis (we show it up to 15 g of the pure product). Using molecular modeling, we have found that the state of the N-terminal amino group (free or protected) has a significant influence on the ability of two cysteine side chains to reach each other, paving the way to a rational choice of protecting groups in peptide synthesis.

A concise methodology for the synthesis of acid hydrazides from carboxylic acids via a continuous flow process in yields ranging from 65 to 91% is described. Using short residence times of between 13 and 25 mins, the conditions proved amenable to a variety of mono- and diacids, including aliphatic, aromatic, and heteroaromatic functionalities. To demonstrate scalability, a large-scale (200 g) synthesis of azelaic dihydrazide was conducted over a continuous run of 9 h with an 86% overall yield, equating to a 22 g/h output.

Agglomeration is an issue that causes many problems during secondary processing for pharmaceutical companies, causing material to need further processing and costing additional time and resources to ensure a satisfactory outcome. A potential source of agglomeration arises from the particle contacts established during filtration that lead to robust agglomerates forming during drying, so that a necessary first step toward understanding agglomeration is to study the packing properties of filtration beds. Here, we present two and three-dimensional models simulating the formation of packed bed structures during filtration. The models use circular and spherical particles of different sizes, mimicking the bimodal particle size distributions sometimes encountered in industrial practice. The statistics of packing and void formation, along with the distribution of interparticle contacts and percolation structures, are presented and discussed in the context of filtration, drying, and agglomeration. The model paves the way for predictive capabilities that can lead to the rational design of processes to minimize the impact of agglomeration.

A persistent and severe mental illness called Schizophrenia affects 20 million people globally. There is not a single component that causes Schizophrenia, according to research. Schizophrenia is hypothesized to result from genetic and environmental interactions, among other things. Antipsychotic medications, including Clozapine, Aripiprazole, Asenapine, Olanzapine, Quetiapine, Risperidone, and Cariprazine, are used to treat the majority of Schizophrenia cases. Clozapine is the first atypical antipsychotic and psychiatric medication (also called a second-generation antipsychotic, SGA). Clozapine was authorized in the US in December 2002 to lower the risk of suicide in individuals with Schizophrenia or schizoaffective disorder who were considered to be at chronic risk for suicidal behavior. It is mostly used to treat individuals with Schizophrenia and schizoaffective disorders who have not responded well to other antipsychotic medications or are unable to tolerate other medications because of extrapyramidal side effects. A brief background of recent developments in the synthesis of the Clozapine drug molecule is provided in this review.

4H,8H-Difurazano[3,4-b:3′,4′-e]pyrazine (DFP) is an important heat-resistant explosive intermediate, but its current synthesis process is still not scalable due to the low yields and acidic smokes in an internal chlorination step to give the intermediate DHFP. In this work, a DMA-promoted chlorination method to synthesize 5,6-dichlorofurazano[3,4-b]pyrazine is described to solve the bottleneck of DFP synthesis. The best reaction conditions were confirmed to be DMA, DHFP, and POCl₃ (2:1:40) at 120 °C for 3 h, with an increased yield of 62%. This new method not only increases the yield but also eliminates the acid smokes during postprocessing, and it is likely to find practical applications in the synthesis of DFP and other heat-resistant explosives.

In 1948, the first kilograms of synthetic vitamin A (acetate) were produced by F. Hoffmann-La Roche, eliminating the need to extract this vital compound from natural sources; this year marks 75 years of successful production. Since then, a number of chemical routes have been commercialized. Of these, three processes have stood the test of time and are still in use today, with only minor modifications. This review covers both the historical and scientific developments in the production of vitamin A derivatives from their beginnings up until recent developments including a fully catalytic process and the successful pilot-scale production via fermentation. In addition, the development of formulation technologies, which have gone hand-in-hand with chemical process development, is described; correct formulation is essential for stabilizing vitamin A derivatives which are sensitive to light and oxidation.

Selective crystallization of a pure product from complex mixtures is challenging due to the variety of impurities which can potentially affect the crystallization process and hence dramatically increase the complexity of the separation task. Focusing on specific mechanisms of product contamination, we demonstrate that suitable operating parameters for efficient purification can be derived in experiments with simplified crystallization systems and transferred to crystallization from complex mixtures. Systematic investigations were carried out for the selective crystallization of linear 1,12-dimethyl dodecanedioate (l-C₁₂-DME) from reaction mixtures as the model system. In the reference binary system l-C₁₂-DME/methanol, we observed the preferential formation of inclusions in platelet-shaped crystals at a low cooling rate κ = 0.1 K·min^–1, whereas pure crystals were obtained at faster cooling with κ = 0.5 K·min^–1. Furthermore, we verified that the structurally similar reaction substrate strongly promotes agglomeration, indicating that the isolation of a pure product from the reaction mixture requires sufficient conversion in the preceding reaction step. Finally, we demonstrate that in crystallization from complex mixtures, the introduction of gas bubbles enables controlled nucleation, improving product purity and reproducibility compared to simple cooling crystallization with uncontrolled nucleation. Using suitable operating parameters derived from simplified crystallization systems, by means of gassing crystallization with inert argon, l-C₁₂-DME can be purified from a complex reaction mixture with multiple impurities at a target purity of >99.9% and simultaneously high yield.