Convergent Kilo-Scale Synthesis of a Potent Renin Inhibitor for the Treatment of Hypertension

Abstract

Process research and development of a synthetic route towards a novel renin inhibitor (1) is described. The highly convergent synthetic route provided 1 in 15% yield on multikilogram scale with a longest linear sequence of 11 steps. The use of catalytic hydrogenation features prominently in our design. The proper choice of N-methylpyridone surrogate was also important, and we describe a method for the easy conversion of 2-methoxypyridines to N-methylpyridones using cheap and readily available reagents.

Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation

“…If successful, this would enable the introduction of two stereogenic centers from an achiral starting material in a single step, bringing benefits to throughput and potentially cost of goods over their initial racemic installation. Initial attempts to hydrogenate the pyridine ring suffered from excessive amounts of hydrodefluorination, an issue which plagues even the state-of–the-art dearomatization–hydrogenation method of Nairoukh et al The use of a more easily reduced hydrogenation substrate was sought, with attention turning to the hydrogenation of an olefin bearing a double bond between the two prostereogenic centers. − Providing the exocyclic nitrogen of the hydrogenation substrate with a carbamate protecting group was targeted in the hope that the coordination of its carbonyl to the metal of a chiral hydrogenation catalyst would enable the highly enantioselective delivery of hydrogen. Notably, such behavior has been observed with the enantioselective hydrogenation of structurally related fluoroenamides. , …”

Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold

“…The pinacol borate intermediate 42 was prepared by triflation of βketoester, 21 followed by Miyaura borylation. 22 Under Suzuki coupling conditions between o-bromophenol and 42, Pdcatalyzed coupling and the following 6-membered lactone formation simultaneously proceeded. This tandem reaction and the subsequent deprotection yielded the tricyclic coumarin intermediate 39 as a single product.…”

Synthesis of Colibactin Pyrrolidono[3,4-d]pyridones via Regioselective C(sp3)–H Activation

“…DMF), subsequent addition of 8 in the presence of triethylamine furnished amide 10 (91%). [18] With the intermediate 10 in hand, the stage for the C-H functionalization was set and the results are summarized in Table 1 Literature reports suggest that the role of the ligand has the strongest influence on the outcome of the reaction, while other parameters such as Pd source, base, additive, and solvent were based on recent findings. [14][15] The following parameters were set, Pd2dba3, Cs2CO3, CsOPiv as soluble organic base, toluene as solvent and generally a temperature of 100 °C was kept, since it was sufficient for the reactivity.…”

“…2,4-Dichloropyridine (12) was found to be a suitable starting material, and nucleophilic aromatic substitution with 2-(trimethylsilyl)ethanol provided the 2-substitued product 13 with high regioselectivity in 77% yield. 18 Selective ortho bromination was achieved with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) and catalytic AgNO 3 to yield dihalogenated pyridine 14 (77%). Silver(I) was found to shorten the reaction time significantly.…”