Improved Process for the Synthesis of 3-(3-Trifluoromethylphenyl)propanal for More Sustainable Production of Cinacalcet HCl.

Cinacalcet (I), sold as hydrochloride salt, is a calcimimetic drug which has been approved for the treatment of secondary hyperparathyroidism in patients with chronic renal disease and for the treatment of hypercalcemia in patients with parathyroid carcinoma. Here, an improved method for the synthesis of 3-(3-trifluoromethylphenyl)propanal (II), a key intermediate for the preparation of I, is described. The protocol required a Mizoroki-Heck cross-coupling reaction between 1-bromo-3-(trifluoromethyl)benzene and acroleine diethyl acetal, catalyzed by Pd(OAc)2 in the presence of nBu4NOAc (tetrabutylammonium acetate), followed by the hydrogenation reaction of the crude mixture of products in a cascade process. Palladium species, at the end of the reaction, were efficiently recovered as Pd/Al2O3. The procedure was developed under conventional heating conditions as well as under microwave-assisted conditions. The obtained mixture of 1-(3,3-diethoxypropyl)-3-(trifluoromethyl)benzene (III), impure for ethyl 3-(3-trifluoromethylphenyl) propanoate (IV), was finally treated, under mild conditions, with potassium diisobutyl-tert-butoxyaluminum hydride (PDBBA) to obtain after hydrolysis 3-(3-trifluoromethylphenyl)propanal (II), in an excellent overall yield and very high purity. Microwave conditions permitted a reduction in reaction times without affecting selectivity and yield. The final API was obtained through reductive amination of (II) with (R)-(+)-1-(1-naphthyl)ethylamine (V) using a catalyst prepared by us with a very low content of precious metal.

1 H-15 N HMBC NMR as a tool for rapid identification of isomeric azaindoles: The case of 5F-MDMB-P7AICA.

The high frequency of the synthetic cannabinoid receptor agonists (SCRAs) emergence renders this group of new psychoactive compounds particularly demanding in terms of detection, identification, and responding. Without the available reference material, one of the specific problems is differentiation and structure elucidation of constitutional isomers. Herein, we report a simple and efficient flow chart diagram applicable for a rapid nuclear magnetic resonance (NMR) identification and differentiation between azaindoles, 4-, 5-, 6-, and 7-azaindole, which is a common structural motif of synthetic cannabinoids. The flow chart diagram is based on 1 H NMR and 1 H-15 N NMR spectra, and to prove the concept, it has been tested on 5F-MDMB-P7AICA (1). Spectral and analytical data including standard 1D and 2D NMR spectra, gas chromatography-mass spectrometry (GC-MS), Fourier transform infrared-attenuated total reflectant (FTIR-ATR), Raman, melting point, and combustion analysis are provided for compound 1.

Seasonal and spatial variations in the occurrence, mass loadings and removal of compounds of emerging concern in the Slovene aqueous environment and environmental risk assessment.

This study reports the development of a multi-residue method for determining 48 compounds of emerging concern (CEC) including three diclofenac transformation products (TP) in Slovenian wastewater (WW) and surface water (SW). For solid-phase extraction (SPE), Oasis™ Prime cartridges were favoured over Oasis HLB™. The validated method was then applied to 43 SW and 52 WW samples collected at nine locations. Ten bisphenols in WW and 14 bisphenols in SW were traced in Europe for the first time. Among all of the 48 targeted CEC, 21 were >LOQ in the influents and 20 in the effluents. One diclofenac TP was also quantified in WWs (3.04-78.1 ng L-1) for the first time. As expected, based on mass loads in the wastewater treatment plant influents, caffeine is consumed in high amounts (105,000 mg day-1 1000 inhab.-1) in Slovenia, while active pharmaceutical ingredients (APIs) are consumed in lower amounts compared to other European countries. Removal was lower in winter in the case of four bisphenols (17-78%), one preservative (36%) and four APIs (-14-91%), but remained constant for caffeine, one API, two UV-filters and three preservatives (all >85.5%). Overall, a constructed wetland showed the lowest (0-80%) and most inconsistent removal efficiencies (SD > 40% for some CECs) of CECs including caffeine, two UV-filters, two preservatives and two APIs compared to other treatment technologies. The method was also able to quantify Bisphenol S in SW (<36.2 ng L-1). Environmental risk was assessed via risk quotients (RQs) based on WW and SW data. Two UV-filters (oxybenzone and dioxybenzone), estrone and triclosan, despite their low abundance posed a medium to high environmental risk with RQs between 0.282 (for HM-BP) and 15.5 (for E1).

En Route to 2-(Cyclobuten-1-yl)-3-(trifluoromethyl)-1H-indole.

A six-step synthetic route from 4-chloro-2-methylaniline to 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole (1) has been reported. Compound 1a is a key impurity of reverse transcriptase inhibitor efavirenz, an important anti-HIV/AIDS drug. Synthetic challenges, dead ends, and detours are discussed.

Regioselective Hydrolysis and Transesterification of Dimethyl 3-Benzamidophthalates Assisted by a Neighboring Amide Group.

An efficient, highly regioselective hydrolysis and transesterification of dimethyl 3-benzamidophthalates into the corresponding carboxylic acid monoesters and mixed esters (including tert-butyl esters) under basic conditions is presented. The selectivity is governed by the neighboring 3-benzamido moiety's participation and by the nature of the solvent. In alcohols the reaction occurred exclusively at the ortho-position to the benzamido functionality, in pyridine or acetonitrile at both ester groups. An insight into the mechanistic pathway was obtained from a (1)H NMR study in perdeuteromethanol.

A way to avoid using precious metals: the application of high-surface activated carbon for the synthesis of isoindoles via the Diels-Alder reaction of 2H-pyran-2-ones.

The application of activated carbon (Darco KB) for the acceleration and direction of the transformation of various 2H-pyran-2-ones with N-substituted maleimides toward isoindole derivatives through the reaction sequence cycloaddition/elimination/dehydrogenation is described. In this reaction, the catalyst mainly influences the dehydrogenation step, which is essential to avoid the formation of bicyclo[2.2.2]octenes as the other possible products. We found that the combination of Darco KB, as the metal-free catalyst, and decalin, as the solvent in a closed vessel, represents the most successful conditions. A comparison of the effect of various dehydrogenation catalysts and reaction conditions is also presented. In addition, we have proven that the aromatization occurs via a hydrogen transfer from the cyclohexadiene intermediate to the maleimide derivative (therefore producing succinimides). This transfer is facilitated by the active surface of the heterogeneous carbon-based catalyst.