Efficient, Economic, and Large-scale Synthesis of 2, 4-Dichloro-10,11-dihydro-5H-dibenzo[a, d][7]annulen-5-one

Abstract

Dibenzosuberone-based tricyclic compounds are promising anti-fungal and anti-histaminic agents, 1 – 6 exemplified by the dichloro-substituted 1-(5H-dibenzo [a, d] cyclohepten-5-yl)- 1H-imidazole compound, Eberconazole (Figure 1). A key intermediate in the manufacture of Eberconazole is compound 1 (Scheme 1). Unfortunately, the synthesis methods reported to date for such substituted dibenzosuberones 7 – 13 are difficult to apply on industrial scale. The disadvantages of the reported methods include reaction at -78 (cid:1) C and the handling of pyrophoric organometallic reagents. In addition, any cyclization using poly-phosphoric acid at 150 (cid:1) C may lead to degradation of the product. We now disclose an efficient and scalable process for the preparation of key intermediate 1 by an alternative route, which minimizes the number of steps and improves both quality and yield. The present process is simple, convenient and cost effective for large-scale production. The synthetic route is shown in Scheme 1 and detailed in the Experimental section