Efficient Synthesis of Dichlorodenafil, an Unapproved Sildenafil Analogue Appearing in Non-prescription Supplements

Abstract

We have developed an efficient synthesis of dichlorodenafil (4), an unapproved sildenafil analogue isolated from dietary supplements. Our sequence employs POCl 3 -mediated chlorination of readily available chloroacetyl compound 7 followed by selective hydrolysis of the chloro-heterocycle function. Our synthesis confirms the structure of the illegal additive, and will provide regulatory agencies with ready access to authentic standard samples of dichlorodenafil (4) to aid in their mission to protect the public from unapproved and potentially harmful erectile dysfunction (ED) drug analogues that are added to herbal and dietary supplements without providing users with appropriate toxicological or pharmacological information.

Pyrazolopyrimidines in ‘all-natural’ products for erectile dysfunction treatment: the unreliable quality of dietary supplements

“…More likely, they are by-products of the synthesis of a sildenafil analogue. For the synthesis of sildenafil and its analogues many different routes are described (Kim et al 2001(Kim et al , 2013Ley et al 2002;Yu et al 2003;Li et al 2004;Xia et al 2005;Abdel-Jalil, Khanfar, Abu-Safieh et al 2005;Medrasi et al 2013). Based on published procedures a hypothetical reaction scheme towards pyrazolopyrimidines bearing an acetyl bridge, explaining the existence of the compounds found in the present study and earlier by others, is shown in Figure 8.…”

“…Seven of them have already been published (piperazinonafil, isopiperazinonafil, oxoacetildenafil, (Z)-/(E)-dichlorodenafil, gendenafil and hydroxyhomoacetildenafil) (Lin et al 2008;Instrumental Analysis Data of Illegal Compounds in Food 2010;Wollein et al 2011;Kim et al 2013). Compound 6 could be assigned to 5-(2-ethoxyphenyl)- Figure 4.…”

“…Compound 6 could be assigned to 5-(2-ethoxyphenyl)- Figure 4. 13 C-NMR spectra of (A) compound 6, (B) compound 12, (C) compounds 9 and 10, (D) compound 11, (E) compound 7 ((Z)-dichlorodenafil (Kim et al 2013)) and compound 13 ((E)-dichlorodenafil (Kim et al 2013)), (F) compound 1, (G) compound 5, (H) compound 4 (oxoacetildenafil; Instrumental Analysis Data of Illegal Compounds in Food 2010), and (I) compound 8 (hydroxyacetildenafil (Hou et al 2006)). *Formate.…”

“…Compared with published NMR data, compounds 4, 7, 8 and 10 could be assigned to oxoacetildenafil (oxohongdenafil) (Instrumental Analysis Data of Illegal Compounds in Food 2010), dichlorodenafil ((Z)-isomer) (Kim et al 2013), hydroxyacetildenafil (hydroxyhongdenafil) (Hou et al 2006), and gendenafil (Lin et al 2008), respectively. Compounds 7 and 13 could not be isolated separately ( Figure 1D).…”

“…Consequently the 1 H-NMR spectrum of compound 7 ( Figure 3E) shows additional signals with very low intensities. While the signal at 6.79 ppm represents the vinyl proton of the (Z)-isomer (main component) the small signal at 6.57 ppm could be assigned to the (E)-isomer of dichlorodenafil (Kim et al 2013). On the basis of the integrals of both vinyl protons a ratio of 96% (Z)-isomer and 4% (E)-isomer could be estimated.…”