One-Pot Synthesis of Trifluoromethylated Quinazolin-4(3 H)-ones with Trifluoroacetic Acid as CF Source.

A novel and convenient one-pot sequential cascade method for the preparation of 2-trifluoromethylquinazolin-4(3 H)-ones is described. Trifluoroacetic acid (TFA) was employed as inexpensive and readily available CF source, which in the presence of T3P was condensed with a variety of anthranilic acids and amines to provide the products in up to 75% yield. The protocol was proved to be robust on 80 g scale, and the synthetic versatility of the prepared quinazolinon-4-ones was demonstrated by derivatization to further useful building blocks.

Scalable Synthesis of Trifluoromethylated Imidazo-Fused N-Heterocycles Using TFAA and Trifluoroacetamide as CF-Reagents.

A scalable synthesis of trifluoromethylated imidazo-fused N-heterocyles from heterocyclic benzylamines using TFAA as trifluoromethylating reagent is presented. The reaction proceeds via intermediate benzylic N-trifluoroacetamides followed by dehydrative cyclization to the products. To further broaden the scope and practicality, a new method for the preparation of benzylic N-trifluoroacetamides via alkylation of trifluoroacetamide with benzyl (pseudo)halides was developed.

Daring the Challenge and Thinking Big: The Value of Early Process R&D.

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block.

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold-Hopping Approach.

Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold-hopping approach. Structure-activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux. Compound 80 c [{(1S,6R)-3-(6,7-difluoroquinoxalin-2-yl)-3,8-diazabicyclo[4.

Novel S1P(1) receptor agonists--part 3: from thiophenes to pyridines.

In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P1 agonists such as the thiophene derivative 1. As a continuation of these efforts, we replaced the thiophene in 1 by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P1 agonists (e.g.

Novel S1P1 receptor agonists--part 1: From pyrazoles to thiophenes.

From a high-throughput screening campaign aiming at the identification of novel S1P1 receptor agonists, the pyrazole derivative 2 emerged as a hit structure. Medicinal chemistry efforts focused not only on improving the potency of the compound but in particular also on resolving its inherent instability issue. This led to the discovery of novel bicyclo[3.

Industrial applications of the Diels-Alder reaction.

The Diels-Alder reaction is one of the most popular transformations for organic chemists to generate molecular complexity efficiently. Surprisingly, little is known about its industrial application for the synthesis of pharmacologically active ingredients, agrochemicals, and flavors and fragrances. This Review highlights selected examples, with a focus on large-scale applications (>1 kg) from a process research and development perspective.

Scalable synthesis of enantiomerically pure bicyclo[2.2.2]octadiene ligands.

An operationally simple and scalable synthesis of enantiomerically pure bicyclo[2.2.2]octadiene (bod*) ligands relying on an organocatalytic one-pot Michael addition-aldol reaction with cheap 2-cyclohexenone and phenylacetaldehyde is presented.

A practical synthesis of renin inhibitor MK-1597 (ACT-178882) via catalytic enantioselective hydrogenation and epimerization of piperidine intermediate.

A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.

2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists.

Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P(1) through S1P(5). Agonists of the S1P(1) receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders.

Pleated Sheets and Turns of β-Peptides with Proteinogenic Side Chains.

Components of a toolbox with predictable secondary structural elements: β-peptides. The β-peptide shown here with proteinogenic side chains adopts a parallel pleated sheet structure in the solid state upon incorporation of suitably configured β-amino acids. When a β-dipeptide turn segment is incorporated in the center, a hairpin is formed in solution.