Catalytic synthesis of pyrazinamide from 2,5-dimethylpyrazine

Abstract

Compounds of the pyrazine series, including pyrazinecarboxylic acid amides, are widely used in the production of various drugs. One of the well known compounds in this seties is 2-pyrazinecarboxylic acid amide, known as the antituberculous drug pyrazinamide. We have established that this drug can be synthesized with a high yield by oxidative ammonolysis of 2-methylpyrazine [1]. It was found that the process, proceeding in an aqueous ammonia solution, involves oxidation of the methyl group to nitrile, followed by its conversion into amide in the course of high-temperature hydrolysis. By the same token, during oxidative ammonolysis of 2,5-dimethylpyrazine (I) on a molybdenum-cerium -titanium mixed oxide catalyst, the initial compound converted sequentially into 5-methylpyrazine-2-carboxamide (II) and 2,5-pyrazinedicarboxamide (III) [2].Below we present the results of investigation of the oxidative ammonolysis of compound I in the presence of three samples of catalysts representing a molybdenum-antimony -titanium mixed oxide system. The samples had the same molar ratio MoO3/Sb203 = 1 : 0.5 and a variable relative content of TiO2: 0.25, 0.50, and 0.75 mole TiO2 per mole MoOs.Selection of this catalyst system was based on the known facts evidencing that the presence of antimony oxides markedly facilitates the oxidative ammonolysis of organic compounds [3,4]. Antimony oxides favor the activation of oxygen supplied from the gas phase to the contact zone [5] and, under certain conditions, may generate or regenerate active centers on the surface of MOO3, acting by a mechanism of the "remote control" type [6].The results obtained in our experiments indicate that the oxidative ammonolysis of compound I involves both the for- mation of partial oxidation products and products of more profound transformations. The oxidative ammonolysis of 2,5-dimethylpyrazine (I) with the formation of amides II and III is accompanied by the demethylation of compound I with the formation of 2-methylpyrazine (IV) and pyrazine (VI). Compound IV converts into the target 2-pyrazinecarboxylic acid amide (V). Also observed, albeit in trace amounts, was 2,5-pyrazine polyamide (VII). All the above substances were isolated from the reaction mixture and identified. 381 VIQualitative composition of the products of oxidative ammonolysis of compound I was the same for all the three catalysts. However, the quantitative ratio of the products was markedly different, depending on the content of titanium dioxide in the sample and on the temperature (Table 1).The first catalyst sample had the oxide component ratio degree of conversion increased from 25 to 100% when the process temperature rose from 320 to 420~ The main reaction product was pyrazinamide (V), the yield of which also increased in the temperature range studied to reach 76% at 420~ Analysis of the reaction mixture revealed, besides amide V, the presence of pyrazines II, III, IV, and VI. The maximum yield of diamide III did not exceed 5-6%, being virtually independent of the temperature. Approximately...

Catalytic Performance of Lanthanum Vanadate Catalysts in Ammoxidation of 2-Methylpyrazine

“…It allows the manufacture of 2-cyanopyrazine (CP) in a single step and is an industrially important reaction as well. In detail, CP is an intermediate compound to synthesize pyrazinamide (PyA) that is globally used as an effective anti-tubercular drug [8].…”

Ammoxidation of 2-methylpyrazine to 2-cyanopyrazine over Nb–V oxides: marked effect of the Nb/V ratio on the catalytic performance

“…1 For instance, 2-cyanopyrazine (CP), which is also prepared by the ammoxidation of 2-methylpyrazine (MP), is a valuable intermediate for the production of pyrazinamide, an effective "anti-tubercular drug". [1][2][3][4][5][6] According to a World Health Organization (WHO) report published in 2012, 7 tuberculosis (TB) still remains an immense global problem. The report claims that there were approximately 8.7 million new cases of TB in 2011 and about 1.4 million deaths across the globe.…”

Tuning the surface composition of novel metal vanadates and its effect on the catalytic performance

“…2 In particular, ammoxidation of 2-methylpyrazine (MP) to 2-cyanopyrazine (CP) is of special commercial interest because CP is an intermediate to produce pyrazinamide (PyA), an effective anti-tubercular drug. 3 To date, a variety of catalysts, e.g. V-Sb-Mn-O, 4 V-Ti-O, 5 heteropolyacids 6 and FePO 4 , 7 have been examined.…”