Synthesis of 5,6‐dihydroxy‐2‐phenyl‐4‐pyrimidinecarboxylic acid, methyl ester, a corrected structure

Abstract

Pyrolysis of the adduct of benzamide oxime and dimethyl acetylenedicarboxylate leads to 5,6‐dihydroxy‐2‐phenyl‐4‐pyrimidinecarboxylic acid methyl ester (4a) rather than 4,5‐dihydro‐α,4‐dioxo‐2‐phenyl‐1H‐imidazole‐5‐acetic acid, methyl ester (1).

A Facile Synthesis of Raltegravir Potassium—An HIV Integrase Inhibitor

“…After completion of the reaction, DMAD adduct ( 5 ) was isolated by evaporating methanol under vacuum as an isomeric mixture. Thermal rearrangement of the above obtained isomeric residue at high temperature (120–125°C for 2 h followed by 130–135°C for 5 h) afforded 6 . After studying the key process parameters for the thermal rearrangement, we shifted our attention on isolation of pure product.…”

“…Coupling reaction of 6 with 4-fluoroben zylamine in the presence of triethylamine produced N-[(4fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-2-[(1-methyl -1-[[(methoxy)carbonyl]amino]ethyl-6-oxo-4-pyrimidine carboxamide (7). (9). The amidation of 9 with oxadiazole carbonyl chloride (10) in the presence of N-methylmorpholine produced Raltegravir (11).…”

“…After completion of the reaction, DMAD adduct (5) was isolated by evaporating methanol under vacuum as an isomeric mixture. Thermal rearrangement [8,9] of the above obtained isomeric…”

“…Another literature report [3] describes the secondgeneration manufacturing route for the preparation of 1 by the condensation of pivaloyl-protected amine intermediate (9) with oxadiazole carbonyl chloride (10). The synthesis of key amine intermediate (9) is also started from the benzylchloroformate protection of acetone cyanohydrin [1]. And in the end, the debenzylation is performed by Pd/C-catalyzed hydrogenation.…”

Rapid Catalyst Identification for the Synthesis of the Pyrimidinone Core of HIV Integrase Inhibitors

“…thermal dissociation/recombination event to afford the key pyrimidinone scaffold, typically in 15-50 % overall yield. [15][16][17][18][19][20] This thermal rearrangement requires elevated temperatures (140 8C) to convert both E and Z isomers into product, thus leading to significant decomposition and low to moderate yields. To date, there has been no report of using catalysis to improve the yields of these reactions, or to decrease the reaction temperatures.…”