Tetrahedron Letters
A facile electrochemical synthesis of suvorexant
Tanay Ghoshal a,b, Tarun M. Patel a, , Sharadsrikar Kotturi b
⇑
a
Shri MM Patel Institute of Sciences and Research, Department of Chemistry, Kadi Sarva Vishwavidyalaya, Gandhinagar 382024, Gujarat, India
Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile, scalable electrochemical method to prepare Suvorexant has been developed. Two different elec-
trochemical routes explored. The route with the high yield and less step taken forward.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 12 February 2021
Revised 13 March 2021
Accepted 16 March 2021
Available online 20 March 2021
Keywords:
Electrochemistry
Facile
Suvorexant
Introduction
tions where moderate temperature needed for conversion. In
continuation to our earlier work [16], we have developed an elec-
Suvorexant also known as MK-405 [1] is a dual orexin receptor
antagonist for treating insomnia [2,3], improved sleep onset and
maintenance [4]. Suvorexant has an appreciative tolerability, low
potential for addiction and limited side effects thus having an edge
over other medicines prescribed for sleep disorder. Given its global
acceptance, many groups have developed different synthetic
routes (Scheme 1). While Wacharasindhu et al used 5-chloro-2-
mercapto benzoxazole coupled with 2-amino ethanol under micro-
wave condition [5], irradiation with white light and Rose Bengal as
photo catalyst [6] is also reported. This intermediate on further
processing afforded Suvorexant. Cox [7] and Chen [8] had devel-
oped a process where the 5 was prepared and coupled with 2,5
dichloro benzoxazole at the final step to get Suvoraxant. To the
best of our knowledge, to date none have reported an electrochem-
ical methodology to prepare Suvorexant. However, Gao et al [9]
and Ackermann et al [10] have previously reported the electro-
chemical CAH amination step in the past, but none have utilised
that for the synthesis of suvorexant.
trochemical method to synthesise Suvorexant in good yields. We
explored two routes. In our first route, we have electrochemically
coupled 5-chloro benzoxazole (7) with tert-butyl (R)-7-methyl-
1,4-diazepane-1-carboxylate (6) in the first step, which was used
further to prepare 14. In the second route, we prepared 5 and elec-
trochemically coupled with 7 in the final step to form 14. Once we
identified the advantages and the overall yields of both the routes,
the best possible route used further to prepare 14 on scale.
Results and discussion
The initial trials were carried out with 7 and 6 as starting mate-
rials using TBAI as a supporting electrolyte with catalytic amount
of acetic acid in dry acetonitrile as a solvent using carbon rod as
anode and an aluminium wire as the cathode. The reaction was
complete in 3 h and 8 isolated in 95% yield. However, a column
purification needed to remove the Tetrabutylammonium part from
the crude material. The insolubility of the electrolytes in water as
well as organic phases needed the crude material to be treated
with resin [17] to ensure removal of TBAI. With an aim to easily
remove the electrolytes by aqueous workup, we screened a few
water-soluble electrolytes (Table 1). Using Ammonium Iodide
and Ammonium Bromide, we achieved 12% and 17% conversion
respectively while with Ammonium perchlorate we observed 23%
conversion. We did not observed the formation of 8 when 5% aque-
ous sodium bromide solution was used.
Electrochemisty as a technique in organic synthesis has started
to gain wide acceptance due to its width of application [11–15].
This methodology offers the advantages of being mostly clean,
green, eliminating formation of side products, good yields, and
ability to control the reaction at the flick of the switch apart from
reducing the bio-burden of effluent treatment. Most electrochem-
ical reactions are carried out at room temperature with few excep-
⇑
The use of acetic acid to open the benzoxazole ring into O-
hydroxyamidine derivative (A) [18,19] is known. The opening of
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