New Synthetic Routes for Natural and Synthetic Fragrance Ingredients

Research & development of alternative routes for fragrance ingredients currently produced by International Flavours & Fragrances Inc. (IFF) in Benicarlò, Spain is reported herein. Past and current industrial syntheses of these ingredients are initially summarised as well as their primary role in the industry. The research disclosed has focused on designing and developing sustainable and safe methods for their industrial preparation and, where possible, evaluation to/of continuous flow approaches. The first target was the musky, earthy natural ingredient known as Veramoss. For this molecule, three alternative synthetic pathways were explored starting with cheap and widely available raw materials such as butanone, dimethyl malonate, methyl acetoacetate, methyl crotonate, and acetaldehyde. Despite being unable to achieve the final compound, the study enabled the development of a continuous-flow Knoevenagel reaction employing polymer-supported dimethylamine catalyst to obtain dimethyl ethylidene malonate in moderate yields (38%) as well as an interesting one-pot methodology for the preparation of 4-chlorohex-4-en-3-one from dimethyl oxalate and butanone in good yields (76%). These developed methodologies could become interesting starting points for future works. Along with route scouting, the main goal of the project was to propose an improved “green” alternative to the currently employed toxic elemental chlorine. To this aim, four main alternative chlorination processes were investigated, one of which proved to be the candidate of choice: trichloroisocyanuric acid (TCCA). An optimisation based on utilizing TCCA was carried out by employing one-factor-at-the-time (OFAT) and design of experiment (DoE) approaches. The optimised one-pot procedure was scaled up to multi-grams quantities allowing the isolation of Veramoss whose quality was validated for commercial purposes. Furthermore, the study also proposed a de novo procedure for the purification of discoloured Veramoss obtained from mischarge and side reactions during chlorination. The methodology based upon selective phenol-amine H-bonded complex formation allowed the recovery of purified white material in 60% overall yield, reducing waste and the need to dispose of discoloured batches. The second target molecule was the newly established IFF compound Ambertonic™, a synthetic tricyclic musk odorant featuring a pyrimidine scaffold. The investigation focused on finding valuable alternative routes starting from a readily available intermediate: Cashmeran. Five viable methods were explored, however, only one allowed the ultimate cyclisation to occur. The effective strategy was then optimised for the preparation of the material. Hence, a two steps one-pot synthesis was developed to yield Ambertonic™ in good yield (53%). The methodology consists in the formylation of the dihydro-cashmeran material with subsequent pyrimidine formation inspire by a publication by Bredereck et al. The optimisation of both stages were initially found to be challenging presenting low yields, solid precipitation, and formation of impurities. Scouting different reaction conditions and parameters, the issues were tackled and eventually solved. Additionally, the first SCXRD structure and racemic resolution of the trans-isomer was carried out allowing us to gain a deeper understanding of the absolute configuration of the active odorant species. The final target investigated was dehydroherbac, a key intermediate for the preparation of the fresh, green odorant known as Galbascone. Three synthetic routes were envisioned starting from different raw materials such as acrylonitrile, 4,4-dimethylcyclohexanone, 5-methyl-hexan-2-one, and 3-carene. Two of the proposed strategies aimed at preparing an enaminone intermediate which undergoes de-amination through selective enamine reduction and elimination. The latter procedure ultimately proved to be impracticable on the desired scaffold. Regardless of the outcomes, a continuous-flow photo-catalysed method for the preparation of a cyano-ketone was optimised to yield 630 mg h-1 of material in 63% isolated yield as a proof-of-concept study. Employing 3-carene as a precursor was also considered through catalytic hydrogenolysis and CH activation of a tertiary carbon. Such a strategy allowed access to three possible oxidative hydroxylation methods as described in the literature utilising dioxiranes, and peracids. Due to the lack of time, the investigation was not completed, however it has established a solid foundation for future work. The project also involved the optimisation of a previously designed route to Galbascone via a Henry-Nef reaction. Kinetic studies performed on the amine-catalysed Henry reaction enabled establishment of a better understanding of the latter and reduced the amount of nitroethane employed for the reaction. In summary, potential preparative routes to the three fragrance ingredients were developed and optimised. The process utilised known chemistry which employs safe and cheap raw materials. Both the developed methodologies for Veramoss and Galbascone have also been considered for scale up at IFF in Benicarlò, achieving interesting manufacturing results

Continuous-Flow Hofmann Rearrangement Using Trichloroisocyanuric Acid for the Preparation of 2-Benzoxazolinone

A continuous-flow preparation of 2-benzoxazolinone via the Hofmann rearrangement of salicylamide has been implemented employing trichloroisocyanuric acid as the stable and atom-economic chlorinating agent. The system was optimized to avoid solid accumulation and allow the preparation of hundreds of grams of the pure desired material over a working day. Furthermore, a trichloroisocyanuric acid (TCCA)-based chlorination of 2-benzoxazolone to the corresponding 5-chloro derivative was also carried out under batch conditions

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

Due to their intrinsic physical properties, which includes being able to perform as volatile liquids at room and biological temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a multibillion dollar industry and the flourishing sub-field of flow chemistry evolving within the discipline of organic synthesis. This is illustrated through selected examples of industrially important transformations specific to the fragrances and flavours industry and by highlighting the advantages of conducting these transformations by using a flow approach. This review is designed to be a compendium of techniques and apparatus already published in the chemical and engineering literature which would constitute a known solution or inspiration for commonly encountered procedures in the manufacture of fragrance and flavour chemicals

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase.

Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies. Following an in-depth analysis of a library of synthesized benzylimidazole derivatives, compound was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC values of 2.3 and 29 nM, respectively. Remarkably, the compound showed high selectivity with respect to 11β-hydroxylase (CYP11B1), as well as CYP3A4 and CYP1A2. When tested in cells, showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC of 0.26 ± 0.03 μM at 72 h), and a remarkable pro-apoptotic effect. In addition, the compound significantly inhibited mTOR phosphorylation at its IC concentration, thereby negatively modulating the PI3K/Akt/mTOR axis, which represents an escape for the dependency from ER signaling in BC cells. The compound was further investigated for cytotoxicity on normal cells and potential cardiotoxicity against ERG and Nav1.5 ion channels, demonstrating a safe biological profile. Overall, these assays demonstrated that the compound is potent and safe, thus constituting an excellent candidate for further evaluation. [Abstract copyright: © 2023 The Authors. Published by American Chemical Society.

A simple one-pot oxidation protocol for the synthesis of dehydrohedione from Hedione

A new method for the oxidation of Hedione 1 to dehydrohedione 2, a high value intermediate in the flavour and fragrance industry, has developed based upon one pot α-chlorination-elimination sequence which can be readily scaled. The spontaneous elimination of the α-chloro in methanol was unprecedented and has allowed for the oxidation, typically performed in multiple steps/reactions, to be carried out as a one-pot protocol. A continuous flow process for performing the reaction utilising sulfuryl chloride has also demonstrated allowing for steady, safe evolution of SO2 gas during the reaction

Nomogram predicting response after chemoradiotherapy in rectal cancer using sequential PETCT imaging: a multicentric prospective study with external validation.

Abstract Purpose To develop and externally validate a predictive model for pathologic complete response (pCR) for locally advanced rectal cancer (LARC) based on clinical features and early sequential 18 F-FDG PETCT imaging. Materials and methods Prospective data (i.a. THUNDER trial) were used to train ( N =112, MAASTRO Clinic) and validate ( N =78, Universita Cattolica del S. Cuore) the model for pCR (ypT0N0). All patients received long-course chemoradiotherapy (CRT) and surgery. Clinical parameters were age, gender, clinical tumour (cT) stage and clinical nodal (cN) stage. PET parameters were SUV max , SUV mean , metabolic tumour volume (MTV) and maximal tumour diameter, for which response indices between pre-treatment and intermediate scan were calculated. Using multivariate logistic regression, three probability groups for pCR were defined. Results The pCR rates were 21.4% (training) and 23.1% (validation). The selected predictive features for pCR were cT-stage, cN-stage, response index of SUV mean and maximal tumour diameter during treatment. The models' performances (AUC) were 0.78 (training) and 0.70 (validation). The high probability group for pCR resulted in 100% correct predictions for training and 67% for validation. The model is available on the website www.predictcancer.org. Conclusions The developed predictive model for pCR is accurate and externally validated. This model may assist in treatment decisions during CRT to select complete responders for a wait-and-see policy, good responders for extra RT boost and bad responders for additional chemotherapy

Synthesis of 7-Chloroquinoline Derivatives Using Mixed Lithium-Magnesium Reagents

We have prepared a library of functionalized quinolines through the magnesiation of 7-chloroquinolines under mild conditions, employing both batch and continuous flow conditions. The preparation involved the generation of mixed lithium-magnesium intermediates, which were reacted with different electrophiles. Mixed lithium-zinc reagents allowed the synthesis of halogenated and arylated derivatives. Some of the synthesized 4-carbinol quinolines have shown interesting antiproliferative properties, their hydroxyl group being a suitable amino group bioisostere. We also report a two-step approach for optically active derivatives

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 \ub1 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys