Synthesis of 3-Aminopyrazinone Mediated by 2-Pyridylthioimidate−ZnCl₂ Complexes. Development of an Efficient Route to a Thrombin Inhibitor

Abstract

A six-step preparation of thrombin inhibitor drug candidate 1 from pyrazinone 7 in 47% overall yield is described. The problem of low reactivity between weak amine nucleophile 4 and poor electrophile 3-bromopyrazinone 17 was overcome with the use of pyridinylthioimidate 27 in the presence of ZnCl(2) to afford adduct 3 in high yield. Several zinc complexes were characterized by solution and solid-state NMR and X-ray crystallographic analyses, and provided insight into the reaction mechanism. Preparation of pyridine N-oxide amine 4 was accomplished via a selective oxidation of the corresponding pyridinylamine 6. Pyridinylthioimidate 27 was prepared from pyrazinone 7 via a two-step one-pot process in near quantitative yield. Chlorination of the pyrazinone ring in 3 followed by hydrolysis and amide coupling completed the synthesis of 1. This chromatography-free synthesis was used successfully to prepare multikilogram quantities of the drug with reproducibility and high purity.

New Synthesis of 2‐Heteroarylperfluoropropionic Acids Derivatives by Reaction of Azine N‐Oxides with Hexafluoropropene

“…These side-products were probably formed by means of a cine nucleophilic substitution in the N-oxide with MeOH acting as a nucleophile and probably HFP or other electrophilic species transforming the N-oxide oxygen atom into a good leaving group. Increasing the temperature to 80 8C raised the yield to 61 % (entry 2). Considering that during the reaction 2 equiv of HF are produced, we attempted to neutralise the mixture by adding various bases (entries 3-5).…”

“…Such compounds could be used, for example, as precursors in the synthesis of new pharmaceuticals that incorporate a heterocyclic subunit with a side-chain bearing functional groups responsible for the biological activity and fluorine atoms that prevent metabolic oxidative and/or hydrolytic decomposition of the drug. [2] In particular, there is a growing interest in the new sidechain-fluorinated derivatives of 2-arylpropionic acids-the "profen" family of non-steroidal anti-inflammatory drugs. The presence of a fluorine atom in the a position was expected to prevent racemisation of the compound under physiological conditions and to modify its metabolism and interactions with the receptor.…”

“…1 JA C H T U N G T R E N N U N G (C,F) = 197. 4 Hz,2 JA C H T U N G T R E N N U N G (C,F) = 31.0 Hz), 121.1 (qd, 1 JA C H T U N G T R E N N U N G (C,F) = 286.2 Hz, 2 JA C H T U N G T R E N N U N G (C,F) = 29.3 Hz), 121.7 (d, 3 JA C H T U N G T R E N N U N G (C,F) = 7.8 Hz), 124.9, 137.6 (d, 4 JA C H T U N G T R E N N U N G (C,F) = 1.7 Hz), 148.8 (d, 4 JA C H T U N G T R E N N U N G (C,F) = 1.7 Hz), 150.1 (d, 2 JA C H T U N G T R E N N U N G (C,F) = 24.1 Hz), 161.5 ppm (d, 2 JA C H T U N G T R E N N U N G (C,F) = 21.6 Hz); 19 F NMR (376.4 MHz): d = À175.09 (q, 3 JA C H T U N G T R E N N U N G (F,F) = 8.8 Hz, 1 F, CF), À76.81 …”

Expanding the substitution pattern of 2(1H)-pyrazinones via Suzuki and Heck reactions

“…Not even a trace of the 5-aryl substituted compounds was formed. Other conditions involving the use of Pd 2 (dba) 3 , combined with P(t-Bu) 3 and CsF or KF in THF or dioxane, i.e. the conditions used for the synthesis of biaryl compounds starting from an aryl chloride, 24 were also unsuccessful.…”

“…1). A pyrazinone was introduced at the P2-P3 (modified amino acid) positions of tryptase inhibitors (e.g., 1), 1 thrombin inhibitors (e.g., 2) 2-6 and caspase-3 inhibitors (e.g., 3). 7 In all these cases, variation of the pyrazinone substituents representing the P1 and P4 residues led to potent compounds.…”