Dinh Chau Phan

: A new, simple method for the synthesis of N,N-diethyl-m-methylbenzamide (DEET) from m-toluic acid and diethylamine using 1,1'-carbonyl-di-(1,2,4-triazole) (CDT) as a coupling agent has been performed. The basic principles of activated carbonyls have been explored with the ability to prepare new amides easily. All reaction by-products are water-soluble as well as removed by filtration, the reaction could be purified easily in an aqueous solution by liquid-liquid extraction, and the product DEET was high purity. This experimental efficiency is about 94-95%, purity (HPLC): 97-98%.

Thalidomide (1) (N-phthalimidogluatarimide) was first marketed in West Germany by Chemie Grunelthal GmbH as a clinically effective non-barbiturate sedative-hypnotic in 1957.1–3 This drug was widely...

Amantadine hydrochloride (1, Scheme 1) is an important antiviral and anti-Parkinson drug.1–5 However, previous methods for its preparation,4–32 in yields as high as 50-58%,4,6,22 have had safety an...

A simple and economical process for producing amantadine hydrochloride (1) on a 250 g scale, an antiviral and anti-Parkinson drug, has been developed. Several methods for the preparation of 1 through intermediate N-(1-adamantyl)-acetamide (4) in four or three steps were reported. These procedures started with adamantine (2) or 1-bromoadamantane (3), acetonitrile, and sulfuric acid by using the Ritter-type reaction to obtain N-(1-adamantyl)-acetamide, which was deacetylated to afford 1-amino-adamantane (5) and then the salt formed with anhydrous HCl gives 1 with the overall yield of 1 being 50–58%. In this article, a two-step procedure for the synthesis of 1 from 1-bromadamantane (3) and formamide via N-(1-adamantyl)-formamide (6) in two steps with an overall yield of 88% was reported. In this procedure, the preparation of 6 from 3 is a key step with a yield of 94%, followed by the hydrolysis of 6 with an aq. solution of HCl to give 1 in high yield (93%). The procedure was also carried out under optimal conditions established to reduce the use of toxic reagents or solvents and was carried out in one pot to make it more environmentally friendly. The procedure can be considered as more suitable for the large-scale production of 1. The structures of product 1 and intermediate 6 were confirmed by IR, MS, ¹H NMR, ¹³C NMR.

This work presents a predominant cost-saving process for the industrial scale synthesis of memantine hydrochloride (1) from 1,3-dimethyladamantane (2) by a two-step method in which both steps were carried out in one-pot. The conversion of 2 to N-(3,5-dimethyladamantane-1-yl)acetylamide (3) was synthesized first in mixture of sulfuric acid 96-98% and nitric acid 64-65% at 25 ºC for 2.5 h and then in acetonitrile at 40 ºC for 3.5 h as a key step. The yield of this process reached to 98%. Next, the deacetylation of 3 with potasium hydroxide in mixture of water-ethylene glycol at 140 ºC for 15 h to get memantine base which was then converted into memantine hydrochloride (1) by aq. HCl 14% (yield of 93%). Overall yield of this synthetic route was 91.65%. The advantages of this process is saving time, solvents, reagents and giving a higher yield as compared to reported procedures.

(2020). An Improved Synthesis of Memantine Hydrochloride. Organic Preparations and Procedures International. Ahead of Print.

Memantine hydrochloride is a medicine used for the treatment of Alzheimer’s disease. A number of methods for the preparation of memantine hydrochloride have been reported. These procedures started from 1,3-dimethyl-adamantane by as many as using three or four reaction steps to produce memantine hydrochloride with overall yields ranging from 54 to 77%. In this article, a simple, concise two-step synthesis of memantine hydrochloride from 1,3-dimethyl-adamantane via N-formamido-3,5-dimethyl-adamantane with an improved overall yield of 83% was developed. In step 1, 3,5-dimethyl-adamantane was reacted with formamide and nitric acid to afford 1-formamido-3,5-dimethyl-adamantane in 98% yield, followed by hydrolysis of 1-formamido-3,5-dimethyl-adamantane with aq hydrochloride to give memantine hydrochloride in 85% yield. The procedure can be easily deployed at an industrial scale.

Reaction of 4-(1-adamantyl)-3-thiosemicarbazide (1) with numerous substituted acetophenones and benzaldehydes yielded the corresponding thiosemicarbazones containing adamantane skeletons. The synthesized compounds were evaluated for their in vitro activities against some Gram-positive and Gram-negative bacteria, and the fungus Candida albicans, and cytotoxicity against four cancer cell lines (Hep3B, HeLa, A549, and MCF-7). All of them showed good antifungal activity against Candida albicans. Compounds 2c, 2d, 2g, 2j and 3a, 3e, 3g displayed significant inhibitory activity against Enterococcus faecalis. Compounds 2a, 2e, 2h, 2k and 3j had moderate inhibitory potency against Staphylococcus aureus. Compounds 2a, 2e and 2g found so good inhibitory effect on Bacillus cereus. Compounds 2d and 2h, which contain (ortho) hydroxyl groups on the phenyl ring, were shown to be good candidates as potential agents for killing the tested cancer cell lines, i.e., Hep3B, A549, and MCF-7. Compounds 2a–c, 2f, 2g, 2j, 2k, 3g, and 3i were moderate inhibitors against MCF-7.