Improved Preparation on Decagram Scale of 5,8-Dihydro-4,6-dihydroxy-5,8-dioxoquinoline-2-carboxylic Acid, a Key Intermediate of Pirenoxine

Abstract

Pirenoxine (Scheme 1, (1)) is a medication used in the treatment and prevention of cataracts. Pirenoxine is sold under the trade name Catalin. Pirenoxine (1) is prepared by the condensation of 5,8-dihydro-4,6-dihydroxy-5,8-dioxoquinoline-2-carboxylic acid (2) with 2-aminophenol in acetic acid as shown in Scheme 1. According to the literature, 5,8-dihydro-4,6-dihydroxy-5,8-dioxoquinoline-2-carboxylic acid (2) is in turn prepared by the oxidation of 4,5,6,8-tetrahydroxyquinoline-2carboxylic acid (4) in the presence of potassium ferricyanide and sulfuric acid in water as shown in Scheme 2 (a). However, the major disadvantage of this synthesis is the use of potassium ferricyanide. Along with the high cost, the reaction between potassium ferricyanide and sulfuric acid may lead to the production of inherently hazardous hydrogen cyanide gas. Hence, this synthesis is not preferable for large scale production. In this context, a facile, economical, safe and industrially viable preparation of 2 has been developed from 4,5,6,8-tetrahydroxyquinoline-2-carboxylic acid (4) under solvent free conditions, and the preparation forms the basis of this report. In our approach, compound 4 is treated with inexpensive ferric chloride with sulfuric acid in water at 20-30 C as shown in Scheme 2 (b) (see Experimental section). On 50 gram scale, the product was obtained in 85% yield as a solid. This method produced a greater yield compared to that of the conventional method (64.5%). During the initial development, several reagents such as chromium trioxide, manganese dioxide, and potassium dichromate had also been tested for this oxidation reaction, but the oxidation reaction of 4 with ferric chloride in aqueous sulfuric acid was superior in forming the desired compound 2. Summing up, this new procedure replaces inherently hazardous and expensive potassium ferricyanide with inexpensive and eco-friendly ferric chloride for the preparation on decagram scale in very good yield of a key intermediate in the synthesis of Pirenoxine.