Development of a Practical and Reliable Synthesis of Laquinimod

Abstract

Laquinimod (5-chloro-1,2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinoline carboxamide) is a drug candidate for treatment of Multiple Sclerosis. A short and industrially feasible process for the preparation of laquinimod starting from 2-amino-6-chlorobenzoic acid, in essentially four steps, is dis-cussed. The key step is a novel reaction in which a methyl ester is converted to an amide in very high yield and with excellent purity. The present article elucidates the scale-up process along with safety aspects and the impurity profiles of the intermediates and product. Initial laboratory conditions are described as well as the changes made on transfer to pilot-plant scale.

An Efficient Method for the Synthesis of Laquinimod

“…Laquinimod was first synthesized at laboratory scale via a three‐step procedure . However, this process suffered from several major disadvantages from an industrial perspective, including high cost, tedious workup procedures, low yield, and the use of phosgene.…”

“…However, this process suffered from several major disadvantages from an industrial perspective, including high cost, tedious workup procedures, low yield, and the use of phosgene. In 2007, another synthetic route of laquinimod was reported by Johan Wennerberg (Scheme ) .…”

1,3-Dipolar Cycloaddition−Decarboxylation Reactions of an Azomethine Ylide with Isatoic Anhydrides: Formation of Novel Benzodiazepinones

“…Isatoic anhydride 1a was identified as a potential new carbonyl dipolarophile. Isatoic anhydride derivatives are readily available, versatile synthetic intermediates undergoing reactions with a broad range of nucleophiles to afford 2-aminobenzoyl derivatives . Thus, it was thought that the C4-carbonyl moiety within isatoic anhydride 1a may be sufficiently activated that it would undergo cycloaddition with an azomethine ylide 2 to afford the spiro-fused oxazolidine 3 (Scheme ).…”