Solid-Phase Synthesis of Lidocaine and Procainamide Analogues Using Backbone Amide Linker (BAL) Anchoring

Abstract

New solid-phase strategies have been developed for the synthesis of lidocaine (1) and procainamide (2) analogues, using backbone amide linker (BAL) anchoring. Both sets were prepared starting from a common resin-bound intermediate, followed by four general steps: (i) attachment of a primary aliphatic or aromatic amine to the solid support via reductive amination (as monitored by a novel test involving reaction of 2,4-dinitrophenylhydrazine with residual aldehyde groups); (ii) acylation of the resultant secondary amine; (iii) displacement of halide with an amine; and (iv) trifluoroacetic acid-mediated release from the support. A manual parallel strategy was followed to provide 60 novel compounds, of which two dozen have not been previously described. In most cases, initial crude purities were >80%, and overall isolated yields were in the 40-88% range.

Mechanochemical Catalytic Transfer Hydrogenation of Aromatic Nitro Derivatives

“…The first example describes a successful two-step preparation of an API procainamide ( 5 ). Procainamide is classified as a sodium channel blocker used in treatment of cardiac arrhythmia, administered orally or intravenously [69]. Previously, there have been several attempts at utilizing mechanochemistry for the synthesis of biologically active compounds and APIs [70], for example teriflunomide [71], Leu-enkephalin [72], atorvastatin [73] and several sulfonylureas [74].…”

Mesoporous Niobium Oxide Spheres as an Effective Catalyst for the Transamidation of Primary Amides with Amines

“…N ‐[2‐(Diethylamino)ethyl]benzamide (3q): 23 White solid; yield: 406 mg (92%); 1 H NMR (400 MHz, CDCl 3 ): δ =7.80–7.74 (m, 2 H), 7.51–7.35 (m, 3 H), 7.01 (s, 1 H), 3.47 (dd, J =6.3, 5.5 Hz, 2 H), 2.67–2.62 (m, 2 H), 2.56 (q, J =7.1 Hz, 4 H), 1.03 (t, J =7.1 Hz, 6 H); 13 C NMR (100 MHz, CDCl 3 ): δ =167.4, 134.9, 131.3, 128.6, 127.0, 51.5, 46.9, 37.4, 12.0; HR‐MS (ESI): m/z =243.1479 [M+Na] + , calcd. for C 13 H 20 N 2 NaO: 243.1473.…”

Preparation of Biphenyl Array using Aryl Sulfide as a Safety Catch Linker for Solid Phase Organic Synthesis

“…73mmol) containing a drop of 4-dimethylaminopyridyne (DMAP) in DMF ( 4 ml) by using 1-ethyl-3-(3 '-dimethylaminopropyl)carbodiimide hydrochloride (WSC, 0. 73mmol, 14mg) and 1,3-diisopropylcarbodiimide (DIC, 0.073mmo1, 92 mg) as condensing agents at rt for 20h [6]. The solution was removed by filtration, the derivatized resin was washed with DMF, H 2 0, THF, ethanol, and hexane, and the resin was dried in vacuo (Scheme 1 ).…”