A short synthesis of Dronedarone

Article abstract of DOI:10.1016/j.bmc.2018.03.041

A modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine 20 and 1,3-diketone 14 (R = CH₂CH₂CH₂NBu₂) in a two-stage process in almost 55% overall yield. Our results represent significant improvement over other state-of-the-art methods as no extra steps for the decoration of the benzofuran core are required.

Full text of DOI:10.1016/j.bmc.2018.03.041

Accepted Manuscript
A short synthesis of Dronedarone
Barbara Piotrkowska, Sven Nerdinger, Erwin Schreiner, Lovro Selič, Piotr P.
Graczyk
PII:
S0968-0896(18)30560-1
https://doi.org/10.1016/j.bmc.2018.03.041
BMC 14279
DOI:
Reference:
Bioorganic & Medicinal Chemistry
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16 March 2018
26 March 2018
26 March 2018
Please cite this article as: Piotrkowska, B., Nerdinger, S., Schreiner, E., Selič, L., Graczyk, P.P., A short synthesis
of Dronedarone, Bioorganic & Medicinal Chemistry (2018), doi: https://doi.org/10.1016/j.bmc.2018.03.041
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Graphical Abstract
A short synthesis of Dronedarone
B. Piotrkowska a, S. Nerdinger b, Erwin Schreinerb, L Selič c,
P. P. Graczyka
a) Selvita Services Sp. Z o. o., Bobrzynskiego 14, 30-348 Krakow, Poland b) Sandoz GmbH, Biochemiestr. 10,
A-6550 Kundl, Austria c) Lek Pharmaceutical, Kolodvorska 27, 1234 Mengeš, Slovenia

A short synthesis of Dronedarone
Barbara Piotrkowska a, Sven Nerdingerb*, Erwin Schreinerb, Lovro Seličc, and Piotr P.
Graczyka
a) Selvita Services Sp. Z o. o., Bobrzynskiego 14, Krakow, 30-348 Poland b) Sandoz GmbH,
Biochemiestr. 10, Kundl, A-6550 Austria c) Lek Pharmaceutical, Kolodvorska 27, Mengeš,
1234 Slovenia
* Corresponding author. Tel.: +43 (0) 5338 2003341; e-mail: sven.nerdinger@sandoz.com
ABSTRACT
A modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine
15 and 1,3-diketone 18 (R=CH2CH2CH2NBu2) in a two-stage process in almost 55% overall
yield. Our results represent significant improvement over other state-of-the-art methods as no
extra steps for the decoration of the benzofuran core are required.
Keywords: Dronedarone; optimization; Nenitzescu; quinonimine
1. Introduction
Dronedarone (1) is a drug structurally related to amiodarone (2) and developed by Sanofi
Pharma for the treatment of atrial fibrillation and atrial flutter1.
Thanks to its efficacy and only minimal side effects as compared with 2 there has been
constant interest in discovering better synthetic routes to this molecule. This paper describes
the development of a very short process leading to 1 and the outcome of our optimization
efforts.
2. Background

The original method patented over 25 years ago by Gubin et al.2 was based on the
construction of a 2,5-disubstituted benzofuran derivative 5 followed by its benzoylation with
p-anisoyl chloride (Figure 1).
a) PPh3 b) C4H9C(O)Cl, pyridine c) Et3N d) p-MeOC6H4C(O)Cl, SnCl4 e) AlCl3 f)
ClCH2CH2CH2NBu2, K2CO3 g) H2/PtO2 h) MsCl, Et3N i) HCl
Figure 1. The original synthesis of Dronedarone hydrochloride (1.HCl)
The target Dronedarone was obtained as hydrochloride salt 1-HCl in almost 40% overall
yield.
While the yield was acceptable, the synthesis was relatively long (8 steps) and had several
shortcomings, one of which was the formation of large amounts of Ph3P=O during cyclization
to form the key intermediate 5. Alternative approaches to 5, not involving phosphorus
chemistry, were later proposed by others3,4,5,6,7,8,9 and are schematically shown in Figure 2.

Figure 2. Alternative synthetic approaches to 5 not involving phosphorus chemistry.
Other methods could also potentially be used for this purpose.10
Most of the earlier synthetic approaches to Dronedarone had to have the central benzofuran
system benzoylated. Originally, the key intermediate benzofuran 5 was benzoylated in the
presence of SnCl4. Soon, a couple of alternative ways to perform benzoylation of 5 to produce
6 (R=Me or R=CH2CH2CH2NBu2) have been reported (Figure 3). The use of a milder Lewis
acid, FeCl3 (yield 98%) was proposed by Biard (R= CH2CH2CH2NBu2)11 and AlCl3 (yield
88%) by Mohanarangam et al. (R=Me).12
Figure 3. Alternative ways to benzoylate 5

The Friedel-Crafts acylation leading to 6 could also be performed in a highly regioselective
manner (less than 5% of o-acylation) with the functionalities inverted as shown in Figure 413.
a) H2SO4, AcOH b) SOCl2 c) p-anisole, AlCl3
Figure 4. Preparation of 6 through acylation with functionalities inverted
Benzoylation of sulfonamide 11 (Figure 5) using either FeCl3 (yield 86% of 1)14 or SnCl4
(yield 65.9% of 1)15 made the process a little more convergent.
a) FeCl3 or SnCl4 b) HCl
Figure 5. Benzoylation of sulfonamide 11
While in the original route phenolic OH in 6 (R=H) underwent etherification with
dibutylaminochloropropane (Figure 1, step f), in some of the newer approaches the
introduction of the amino group was carried out stepwise. Figure 6 shows the process
developed by Mohanarangam et al.12. Phenolic OH in 6 (R=H) was alkylated with 1-bromo-3-
chloropropane. Following reduction of the nitro group and formation of sulfonamide, the
chloro derivative was subjected to the reaction with dibutylamine.
a) 1-bromo-3-chloropropane, K2CO3 b) HCOONH4, Pd/C c) MsCl, NaHCO3 d) Bu2NH e)
HCl
Figure 6. Stepwise installation of amino groups in 6 (R=H).

An alternative method16 used 3-chloro-1-propanol instead of 1-bromo-3-chloropropane as the
alkylating agent. Subsequent reaction of 7 (R=CH2CH2CH2OH) with mesyl chloride formed
sulfonamide at C(5) and converted the hydroxyl into mesylate, which then could be reacted
with dibutylamine giving 1.
In contrast to the syntheses presented above, some of the newer approaches to Dronedarone
(1.HCl) aimed at achieving the desired substitution pattern already at the stage of the
benzofuran system formation, thus avoiding the Friedel-Crafts acylation. A classic example of
such strategy is based on an oxo variant of the Fisher indole synthesis and involves the
reaction between diketone 14 (R=H) and hydroxylamine derivative 15 (Figure 7).17
a) BuCOOEt, MeONa b) AcOH, 70-100 °C c) AcOH, water, 70 °C
Figure 7. An oxo variant of the Fisher indole synthesis en route to 6 (R=H)
Tautomer 16 (R=H) was then converted into 6 (R=H) by heating in water – acetic acid
mixture.
Intermediate 6 (R=Me) was obtained by researchers from Sanofi18 through cyclization of
ketoester 14 (Figure 8).
a) CH3(CH2)3C(O)Cl, K2CO3 b) Bu3N, molecular sieves
Figure 8. Benzofuran 6 (R=Me) through cyclization of ketoester 14

While additional derivatization of 6 (Figure 8, R=Me) was required to obtain 1.HCl, some of
the more recent methods have focused on providing all the required substituents already at the
stage of the cyclization reaction. An example of such approach based on a Nenitzescu reaction
between quinonimine 15 and enaminone 16 (R=CH2CH2CH2NBu2) was developed by Sanofi-
Aventis and is shown in Figure 9.19
a) Glacial AcOH b) HCl
Figure 9. Nenitzescu reaction between quinonimine 15 and enaminone 16
Instead of 16 (R=CH2CH2CH2NBu2), enaminone 17 (R=CH2CH2CH2NBu2) could also be
used (yield 73%).19
A team from Sandoz and Lek demonstrated that instead of preparing the relevant enaminone,
one could further simplify the process by making use of the parent 1,3-diketone 18
(R=CH2CH2CH2NBu2) instead (Figure 10).20

a) Et3N b) Et3N, ZnCl2
Figure 10. Nenitzescu-like reaction between quinonimine 15 and 1,3-diketone 18
A mixture of retro-Claisen products 20 and 21 was then converted in the presence of Et3N and
ZnCl2 into the final product in 50% yield, which could serve as an elegant proof-of-concept
for such a convergent process.
3. Results and discussion
Recently, our efforts focused on further improvement in the purity and yield of the product.
Initially, the stage of formation of a mixture of retro-Claisen products 20 and 21 was
investigated. Reaction was carried out in dioxane using 1 equivalent of organic base. The
influence of several parameters was checked, among them the quality (dryness) of solvent, the
type of base, reaction time, etc. The results are presented in Table 1.

Table 1. Results of optimization of conditions to produce a mixture of 20 and 21
Run Dioxane dried Base
over MS
Addition time Rxn time [h] Final ratio
[min]
8
10
20
15
18: (20+21): 1
1
2
3
4
5
6
7
8
9
no
no
no
no
yes
yes
yes
yes
yes
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DIPEA 12
DIPEA 17
Et3N
1
2
2
3
2
2
2.5
3
13.8: 80.3: 5.5
7.2: 81.9: 9.1
4.9: 84.3: 9.6
2.8: 83.3: 10.9
2.3: 89.4: 1.0
2.8: 93.1: 1.6
5.9: 84.9: 1.9
97.3a
15
15
16
3
98.3a
a no other compounds except 20 and 21 were isolated
Higher conversion was achieved with longer addition time (runs 3, 8, 9) and longer reaction
time (runs 8 and 9). A high level of conversion (>97%) could be obtained with either base
(DIPEA or Et3N; runs 8 and 9). Unfortunately, in order to achieve purity required for the next
step (formation of 1) the mixture of 20 and 21 had to be cleaned by column chromatography.
The mixture of 20 and 21 was then subjected to the reaction with varying amounts of ZnCl2 in
the presence of tertiary amine such as Et3N or Bu3N in various solvents over periods from 1 to
68 h. The results are shown in Table 2.
Table 2. Results of optimization of conditions to produce Dronedarone from a mixture of 20
and 21
Run
Solvent
Et3N
[eq]
1.5
1.5
1.5b
1.5
1.5b
2
ZnCl2
[eq]
1.1
Reflux time
Purity
[%]
89
Yield of 1
[%]a
[h]
18.5
23
1
19
1
2
3
4
5
6
7
8
dioxane
dioxane
toluene
toluene
p-xylene
dioxane
dioxane
dioxane
88
1.2
64
80
c
d
19e
1.1
78
quant
c
d
21
76e
d
d
0.3
0.3f
20, 45, 68
24, 44
45
63, 79, 81e
79, 95e
75%g
1.5
1.5
0.27 f
99.3%
a Yield based on starting diketone 18, unless stated otherwise b Bu3N used instead of Et3N c
molecular sieves used instead of ZnCl2 product not isolated e respectively, conversion rate
d
based on HPLC f as 1.0 M solution in Et2O g as hydrochloride 1.HCl
The type of amine did not seem to matter much (runs 2 and 5). It was not necessary to use
more than 1 equivalent of ZnCl2, just 0.3 eq. or less was sufficient (runs 6, 7, 8), preferably in
the form of a 1.0 M solution in Et2O (runs 7, 8). A dehydrating agent such as molecular sieves
instead of Lewis acid did not work well (runs 3, 5). To achieve high conversion rates long
reflux time was required (runs 7, 8). Run 8 represents optimized set of conditions for the
process.

4. Summary and conclusions
A modification of the Nenitzescu reaction was used to obtain Dronedarone base from
quinonimine 15 and 1,3-diketone 18 (R=CH2CH2CH2NBu2) in a two-stage process in almost
55% overall yield. Additional work is underway to further simplify the process, in particular
to avoid chromatographic purification of 20 and 21.
5. Experimental
All of the solvents and reagents used were obtained commercially and used as such unless
noted otherwise. Moisture- or air-sensitive reactions were conducted under nitrogen
atmosphere in oven-dried (120 °C) glass apparatus. The solvents were removed under reduced
pressure using standard rotary evaporators. Purity of the final compounds was examined by
LCMS using Waters Symmetry, C18, 3.9 x 150 mm, 5 µm analytical reverse phase C18
column with 0.1 % HCOOH-water solution, and 0.1%HCOOH-acetonitrile solution gradient
and Dionex 3000RS chromatograph with Ultimate DAD-3000 detector at 254 nm. 1H NMR
analysis was performed on Varian UnityPlus 200 MHz in CDCl3 or CD3OD as solvent.
Compounds 15 and 18 were synthesized as published by us earlier.20
5.1. Mixture of 20 and 21
To a solution of 1,3-diketone 18 (R=CH2CH2CH2NBu2) (1.0 g, 2.57 mmol) in anh. dioxane
(dried over molecular sieves), Et3N (0. 356 ml, 2.57 mmol) was added followed by dropwise
addition of the solution of 15 (0.48 g, 2.57 mmol) in dioxane (5 mL) within 16 min. After
addition was completed the brown reaction mixture was stirred for 3 h at RT. The solvent was
evaporated (water bath 40 °C) to provide the crude mixture of 20 and 21 as a brown oil. It was
purified by column chromatography using hexane : ethyl acetate : Et3N (1:1:0.15; v/v/v) as
eluent (product Rf = 0.5). Fractions containing the desired products were combined to provide
a mixture of 20 and 21 as light yellow viscous oil (1.06 g, 72%; purity 98.3%). The mixture
was used directly in the next step.
5.2. Dronedarone base (1)
The mixture of 20 and 21 (1.05 g, 1.83 mmol) was dissolved in anh. dioxane (15 mL).
Triethylamine (0.382 ml, 2.74 mmol) was added followed by 0.5 M solution of ZnCl2 in THF
(1.0 mL, 0.50 mmol). The reaction mixture was then refluxed for 45 h, cooled to RT and
filtered through a pad of Celite. The charcoal was added to the filtrate and the mixture was
stirred for 1 h at 50 °C. Solids were filtered off on a pad of silica and Celite and the cake was
washed with dioxane until all product was eluted. The filtrate was concentrated to provide 1
(0.76 g, 1.365 mmol, 75%, HPLC purity 99.3%) as a yellow oil. 1H NMR (ppm, CDCl3): 7.80
(d, 2H), 7.43 (d, 1H), 7.36 (d, 1H), 7.28 (m, 1H), 6.95 (d, 2H), 4.10 (t, 2H), 2.91 (s, 3H), 2.83
(t, 2H), 2.61 (t, 2H), 2.43 (t, 4H), 1.95 (m, 2H), 1.72 (m, 2H), 1.42 (m, 4H), 1.30 (m, 6H),
0.89 (m, 9H).
5.3. Dronedarone hydrochloride (1.HCl)
The base 1 (0.76 g, 1.365 mmol) converted to hydrochloride by dissolution in EtOAc (10 mL)
followed by dropwise addition of a 2.25 M solution of HCl in Et2O (0.604 ml, 1.36 mmol)
over 5 min. A suspension formed was stirred for 1 h at RT, 1 h at 0 °C. The solid was filtered
off and dried to provide 1.HCl (0.79 g, 98%) as off-white solid, m.p. 142 °C, purity 100%. 1H
NMR (CD3OD, ppm): 7.81 (d, 2H), 7.52 (d, 1H), 7.32 (s, 1H), 7.23 (dd, 1H), 7.10 (d, 2H),
4.26 (t, 2H), 3.43 (m, 2H), 3.23 (m, 4H), 2.90 (m, 5H), 2,30 (m, 2H), 1,79 – 1,71 (m, 6H),
1.50 – 1.42 (m, 4H), 1.37 – 1.30 (m, 2H), 1.03 (t, 6H), 0.89 (t, 3H).

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