Simple one-pot green method for large-scale production of mesalamine, an anti-inflammatory agent

1 Introduction

Inflammation is a protecting mechanism utilised by tissues against endogenous and exogenous antigens, induced by microbial infection or tissue injury and is characterised by redness, enema, fever, pain, and loss of performance. Inflammation associated with various chronic diseases including arterial sclerosis, obesity, diabetes, neurodegenerative diseases and even cancer, is a serious health concern [1], [2]. Non-steroidal medication (NSAIDs) is widely used for the treatment of inflammatory and painful conditions, as well as autoimmune disease, soft tissue lesions, fever and urinary tract infections [3], [4]. The activity of NSAIDs results from protein inhibition of cyclooxygenase (COX) mediated production of pro-inflammatory prostaglandins and thromboxanes [5]. COX enzymes exist in three isoforms: COX-1, COX-2 and COX-3 [6], [7]. COX-1 is the constitutional enzyme in most cells and plays an important role in the protection of the stomach tissue layer, protoplasm aggregation and nephritic blood flow. The COX (COX-1 and COX–2) is associated with nursing inducible isozyme system, and is considerably expressed throughout inflammation, pain, and oncogenesis [7], whereas COX-3, a splice variant of COX-1, is taken into account as another target for drugs [6], [7], [8]. Conventional NSAIDs inhibit COX-1 and COX-2 and therefore their administration usually causes epithelial duct [9], [10], renal [11], [12], and hepatic effects [13].

Mesalamine belongs to the class of salicylates, which are known to exhibit anti-inflammatory activity. It is also a key intermediate for sulphasalazine, olsalazine and balsalazide [14]. It is slightly soluble in dehydrated alcohol and methyl alcohol and insoluble in chloroform, ether, n-hexane and ester. It is prescribed for the treatment and management of colitis. It primarily provides relief from pain to some extent in patients affected by this disease [15], [16], [17], [18], [19], [20], [21]. 5-Aminosalicylic acid is an active medicine for colitis due to its multiple actions on numerous functions of the immune system [22], [23].

Mesalamine is a simple compound, but is difficult to prepare in high purity and in good yields, especially on a large scale. Few synthetic routes for mesalamine are reported in the literature, such as the coupling of diazonium salt derived from sulfanilic acid with salicylic acid [24]. In this method, the product undergoes hydrogenation, resulting in low purity and yield. Another method based on the condensation of phenyl diazonium salt with salicylic acid, followed by hydrogenation to give the desired mesalamine, is also reported [25]. A protocol involving the nitration of salicylic acid followed by reduction to form the target compound is also described, but with low purity and yield [26]. A two-step procedure involving carboxylation of p-acetaminophenol or p-aminophenol in the presence of a solid base catalyst is reported to give a 63% yield [27]. Generally, upscaling the laboratory experiments and their large-scale production is challenging [28], [29].

Motivated by the application of mesalamine in inflammation control, we attempted the one-pot synthesis of mesalamine from 2-chloro-5-nitrobenzoic acid, to broaden its scope for industrial scale production. In this communication, we describe an efficient one-pot method in which 2-chloro-5-nitrobenzoic acid is converted to 2-hydroxy-5-nitrobenzoic acid using excess aqueous KOH (4.0 equivalents) to ensure completion of hydrolysis; this is further converted to the desired product, mesalamine, under hydrogen atmosphere using 10% Pd/C as the catalyst. By this strategy, the target compound, mesalamine, was obtained in an excellent yield (93%). Tables 1 and 2 summarise the results of the optimisation of the reaction conditions.

Table 1:

Optimisation of reaction conditions for the preparation of 2-hydroxy-5-nitrobenzoic acid (2).