Zaleplon is a pyrazolopyrimidine sedative-hypnotic agent licensed for the short-term treatment of insomnia. Due to its potential for abuse and addiction, zaleplon is classified as a controlled substance in some countries. Accurate analysis and identification of zaleplon in drug abuse cases requires the use of isotopically labeled internal standards, such as zaleplon-d5.
Here, we present the synthesis of deuterium-labeled zaleplon-d5, which can serve as an internal standard for the GC-MS analysis of zaleplon. Synthesis of Zaleplon-d5 by Scheme 1
Our first route to zaleplon-d5 shown in Scheme 1.
Initially, 3nitroacetophenone 1 was treated with N,N-dimethylformamide dimethylacetal under reflux to yield the intermediate, enamide 2.
Another key intermediate, 5-amino-1H-pyrazole-4-carbonitrile (4) was obtained by refluxing ethoxymethylenemalononitrile (3) and hydrazine hydrate in ethanol.
In the following step, compounds 4 and 2 underwent cyclization under mild acidic condition at reflux to yield 7-(3-nitro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile (5).
An efficient reduction of 5 using 10% Pd/C catalyst at an H pressure of 60 psi gave 7-(3-amino-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile (6).
The 3-amino phenyl pyrazolopyrimidine 6 was treated with an acetic anhydride and pyridine to produce acetamide 7.
Introduction of the isotopic label was attempted by treating acetamide 7 with ethyl iodide-din the presence of sodium hydride, under an inert atmosphere at 50℃.
Unfortunately, the yield of zaleplon-d5 obtained was negligible. Various alternative conditions were tried, but the maximum yield obtained was only 20%. The purification of zaleplon-d5 was also problematic, as zaleplon-d5 could not be successfully crystallized and was difficult to elute from a silica gel column. Therefore, this route was abandoned.
Synthesis of Zaleplon-d5 by Scheme 2
The synthesis started from compound 1, which is readily available and inexpensive. 3'-Nitroacetophenone 1 was reduced to 3'-aminoacetophenone 9.
Subsequently, Acylation to generate acetamide 10, which in turn was treated with N,N-dimethylformamide dimethylacetal to produce enamide 11.
Enamide 11 was alkylated using ethyl iodide-d5 and sodium hydride as base at room temperature to yield the N-ethylated enamide 12.
In the final step, N-ethylenamide 12 was coupled with 5-aminopyrazole 4 in aqueous acid at 50℃ to produce zaleplon-d5 8 in 85% yield.
Further purification by recrystallization of the crude product from 30% aqueous acetic acid yielded colorless crystals of zaleplon-d5 8.
In conclusion, this work provides an elegant route to zaleplon-d5, an internal standard for zaleplon analysis. This synthesis paves the way for the quantitative detection of zaleplon in drug abusers.
Hello! If you are looking for a socializing platform that provides unique opportunities to meet interesting people, BongaCams will be a great choice. With the help of convenient filters and settings, you will always be able to find those who match your interests. The platform is actively used in different regions of the country and continues to gain popularity. User-friendly interface and quick access to the functionality make using the site comfortable for users with different levels of technical literacy.