B. Vu, Thi Phuong Dung Phan, T. Tran
Feb 17, 2022
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Organic Preparations and Procedures International
Abstract
Amantadine hydrochloride (1, Scheme 1) is an important antiviral and anti-Parkinson drug. However, previous methods for its preparation, in yields as high as 5058%, have had safety and environmental concerns. We now report a convenient procedure for the synthesis of 1 from 1-bromoadamantane and formamide via N-(1adamantyl)-formamide, with an overall yield of 81%. The procedure was established with optimal conditions to reduce the use of toxic reagents and solvents to make it safer and more environmentally friendly and thus more suitable for reactions at scale. Despite their usefulness, previous procedures do have several disadvantages, particularly when considering large-scale production: (a) several experimental steps have the potential to decrease the overall yield; (b) the use of benzene as a solvent in the extraction of compound 4 presents toxicity and environmental issues; (c) in the deacetylation of 4 diethylene glycol (DEG) is poisonous and when heated to 240-250 C with sodium hydroxide can lead to an exothermic decomposition reaction with the release of hydrogen gas, acidic vapor, and irritating fumes; (d) the use of ether constitutes a safety risk because of its high inflammability and the potential to form peroxides. To overcome these issues, we now report the preparation of 1 in two steps (Scheme 2) via N-(1-adamantyl)formamide (6) from 3a and formamide. The reaction is done in sulfuric acid at 90 C for 4 hours. Thereafter, the mixture is poured into ice-cold water, and a white solid is precipitated, filtered, and washed with cool water. The obtained 6 is then hydrolyzed using an aqueous solution of KOH in water and propylene glycol to obtain 5, which is finally treated with aqueous HCl to yield 1. The conversion of 3a directly into 6 is a key step in this preparation. The process is summarized below, and complete details are provided in the Experimental section. In this new process, adopting formamide instead of acetonitrile results in compound 6 with a high yield (92%), and it is hydrolyzed easily to 1 under mild conditions (see Experimental section). The preparation of 6 from 3a removes the use of a large amount of fuming sulfuric acid or nitric acid in the previous procedures. This will help to decrease environmental pollution. In addition, extracting amide 6 without the use of