A method for the preparation of nicotinic acid and its amide from 2-methyl-5-ethylpyridine

Abstract

Potassium permanganate is a suitable agent for the preparative-scale synthesis of carbonic acids with a variety of structures. Such agents are also quite frequently used in technology, for example, for the preparation of nicotinic acid from 13picoline. We have shown that the permanganate method of oxidation can successfully be used for preparing nicotinic acid from such widely available raw materials as 2-methyl-5-ethylpyridine (MEP), although additional stages must be included, to extract and decarboxylate isocinchomeronic acid (ICA). The first stage of the reaction is carried out using 6 moles of KMnO 4 for each mole of MEP. Addition of the correct quantity of oxidizing agent to the reaction vessel in a single aliquot or as 2-3 portions results in the reaction occurring too violently and with excessively low selectivity, and ICA is then formed with yields close to those described in the literature, i.e., not greater than 45% [1]. During experiments to identify the optimal reaction conditions it was found that the KMn04 dosing should be changed, reducing the amount of oxidizing agent to 0.5-1 moles per mole of pyridine base, and each portion should only be added after complete utilization of the preceding portion, which is easily detected because of the decolorization of the reaction solution. MEP itself has an extensive tendency to oxidize: even at 80~ the first 2-3 portions of KMnO 4 are entirely utilized within 10-15 min. As shown in Table 1, the reaction product at this time point consists of three pyridinecarboxylic acids, namely, 6-methylnicotinic, 5-ethylpicolinic, and isocinchomeronic acids, though the ftrst of these is predominant. As more oxidizing agent is added, the total rate of the process decreases, and the content of 6-methylnicotinic acid in the reaction mix decreases, and the proportion of isocinchomeronic acid increases. Side reactions occur simultaneously, accompanied by breakage of the pyrimidine ring, profound oxidation of the organic material, and correspondingly unexpected degradation of the oxidizing agent. Thus, both 6-methylnicotinic acid and the initial MEP are present in the decolorized oxidation reaction after addition of 6 moles of KMnO4. Increasing the temperaatre of the reaction and addition of excess oxidizing agent promote ICA accumulation. At 90~ and at boiling temperature, addition of 7 moles of KMnO 4 results in completion of the oxidation process within 3-3.5 h. By this time, MEP and pyrimidine monocarboxylic acids are completely consumed, and the ICA yield is 68-72% of the theoretical maximum. Excess utilization of the oxidizing agent is no more than 15% of the amount required for the quantity of MEP used. Experiments with greater excess quantities of KMnO 4 did not give positive results: oxidation of the ICA product started, though all sources of ICA were exhausted before this started. Experiments with increased quantities of oxidizable material and oxidizing agent present risks of overheating, especially in the initial phases of the reaction. In order to avoid complications, the first portions of KMnO 4 should be made smaller, the intervals between addition of KMn04 portions should be increased, the mixing of the reaction should be improved, removal of heat from the reaction area should be efficient, and the oxidizing agent should be added as an aqueous solution. It should also be noted that losses during extraction of ICA from the reaction are small, because its water solubility is low, i.e., 0.05-0.1 at pH 1.3-2.8 [2]. The stage producing nicotinic acid consists of decarboxylation of ICA, which is carried out by heating ICA in a steel autoclave at 230-250~ for 2 h in the presence of a minimal quantity of water: up to 15 mmoles per mole of initial substance [3]. In these conditions, the desired product is obtained with a yield of 98-99%.