2
C. Picken et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 2. Structure of the prodrug selexipag 3 that is cleaved by hepatic enzymes to give the metabolite ACT-333679 4 which is a potent IP receptor agonist.
amide 6 (Scheme 1) using either carbodimidazole (CDI) or N-(3-
0
dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride (EDCI)
resulted in multiple products as determined by TLC analysis, which
1
were difficult to isolate. H NMR and HPLC analysis of the crude
product mixtures suggested that a significant amount of trepros-
tinil 2 had not undergone reaction. Efforts to prepare the
N-hydroxysuccinimide ester of treprostinil were similarly unsuc-
1
cessful (determined by TLC and H NMR). A protecting group
strategy appeared to be necessary to avoid possible side reactions
due to the treprostinil secondary hydroxyls.
Treprostinil protecting group strategies have been described in
the patent literature [32–35]. These strategies rely on the simulta-
neous protection of the carboxylic acid and the two secondary
hydroxyls, which would then be followed by subsequent selective
deprotection of the carboxylic acid. Several methods were evalu-
ated (ESI Table S1) but did not generate sufficient yields of pure
product. One strategy to per-trimethylsilylate treprostinil [35]
using N,O-bis(trimethysilyl)acetimidate to give the tri-silylated
treprostinil adduct, relied on the lability of the trimethylsilyl ester
to allow coupling of methanesulfonamide 6 to give the desired tre-
prostinil N-acyl methylsulfonamide 5. A treprostinil-derived pro-
Fig. 3. Structure of treprostinil N-acyl methylsulfonamide 5.
The orally administered non-prostanoid, N-acyl methylsulfon-
amide pro-drug called selexipag 3 (marketed as UPTRAVI) [25]
had a 13-fold lower affinity for the IP-receptor than the active form
of the drug (ACT-333679 4; Fig. 2) [26,27]. Upon absorption of
selexipag 3 into the bloodstream, the N-acyl methylsulfonamide
moiety is cleaved by hepatic carboxyesterases to unmask the
active drug 4 exhibiting efficacy for treating PAH [28–30]. Selexi-
pag 3 was designed to reduce side effects caused by the direct acti-
vation of IP receptors before absorption into the bloodstream [28].
N-Acylsulfonamides are known to exhibit chemical and biolog-
ical stability making them desirable candidates for prodrug struc-
tures [31]. We considered that a N-acyl methylsulfonamide form
of treprostinil would combine the extended-release characteristics
of a drug such as selexipag with the desirable pharmacological pro-
file of treprostinil to reduce unwanted activity upon administra-
tion and ultimately achieve greater tolerability. We sought to
prepare treprostinil N-acyl methylsulfonamide 5, which we
hypothesise will have lower activity at the IP receptor compared
to treprostinil 2 (see Fig. 3).
1
duct was isolated but analysis by H NMR did not confirm the
presence of the desired product.
Attempts to directly benzylate the two hydroxyls in treprostinil
2
using an excess of different bases and benzyl bromide, resulted in
no reaction or the formation of several products within which the
desired bis-hydroxyl benzylate treprostinil product was observed
in small amounts. To avoid competitive reactions with the trepros-
tinil carboxylic acid moiety, treprostinil ethyl ester 7 could be pre-
pared in good yield (88%) by Fisher esterification, allowing for
benzylation of the secondary alcohols to again be examined (ESI
Table S1). Benzylation of treprostinil and the corresponding ethyl
ester proved difficult owing to the poor nucleophilicity of the sec-
ondary alcohols. It was found that when treprostinil ethyl ester 7
was treated with the Dudley reagent (2-benzyloxy-1-methylpri-
dinium triflate) [36] dissolved in dichloromethane (DCM) the
desired bis-benzyl treprostinil ethyl ester 8 (Scheme 2) was formed
as a yellow oil in 49% yield following isolation by column chro-
matography. Following successful benzylation, direct benzylation
of treprostinil using the Dudley reagent was also attempted and
showed efficient conversion as determined by TLC.
Results and discussion
The preparation of treprostinil N-acyl methylsulfonamide 5 by
directly coupling treprostinil 2 (50 mg scale) and methylsulfon-
Scheme 1. Proposed direct conversion of treprostinil 2 to treprostinil N-acyl methylsulfonamide 5.