Effect of deuteration on the metabolism and clearance of some pharmacologically active compounds - Synthesis and in vitro metabolism of deuterated derivatives of dronedadrone

Article abstract of DOI:10.1002/jlcr.3090

The synthesis and in vitro metabolism studies of a family of specifically deuterated derivatives of dronedarone are described. Metabolic stability and clearance of the parent compound are not sensitive to deuterium substitution, irrespective of the position of the heavy label. Copyright

Full text of DOI:10.1002/jlcr.3090

Special Issue Article
Received 2 May 2013,
Revised 13 June 2013,
Accepted 14 June 2013
Published online in 04 September 2013 Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3090
Effect of deuteration on the metabolism and
clearance of some pharmacologically active
compounds—synthesis and in vitro
metabolism of deuterated derivatives of
dronedadrone†
a
a
a
a
*
Joseph Schofield, Denis Brasseur, Béatrice de Bruin, Thierry Vassal,
Sylvie Klieber,b Catherine Arabeyre,b Martine Bourrié,b
Freddy Sadoun,b and Gérard Fabreb
The synthesis and in vitro metabolism studies of a family of specifically deuterated derivatives of dronedarone are described.
Metabolic stability and clearance of the parent compound are not sensitive to deuterium substitution, irrespective of the
position of the heavy label.
Keywords: stable labelled synthesis; deuterium; deuterium labelling; isotope effect; antiarrhythmic; in vitro metabolism
promising candidates once again. Although such efforts have
Introduction
been underway since the 1970s, no deuterated entities have
Recent years have seen a renaissance of interest in the
yet made it to market, the most promising results to date
concern MK-0641 that was withdrawn in clinical phase II,7
development of deuterated drug molecules. Up to the year 2000,
and SD-809 reported to be currently approaching phase III8
patent applications concerning deuterated pharmaceuticals
remained at a low but fairly constant level, but by the end of the
(Figure 1).
first decade of the 21st century, activity in this area had increased
The theoretical considerations outlined above have proved
dramatically.1 For example, in 2002, only two applications for
difficult to translate to in vivo success. In an effort to understand
deuterated drugs were recorded, a number which had risen to
which structural parameters are important to enhance metabolic
64 by 2010. Over the same time period, although the number of
stability of deuterated compounds compared to their unlabelled
new drug entities approved for the market annually remained
parents, we have prepared a series of deuterated analogues of
stable, overall pharmaceutical R&D spending approximately
dronedarone, a compound from our company portfolio and
doubled.2 Clearly, a significant portion of the R&D effort in
studied their metabolic profiles in vitro compared to the
this area is driven by economic considerations: substitution
unlabelled parent.
of hydrogen for deuterium in late-stage or marketed
molecules creates a patentable, usually active chemical
entity without the expense incurred from lengthy discovery
programs to identify hits and transform them to lead
Dronedarone, marketed since 2009 as Multaq ®, is a treatment
for atrial fibrillation and is a substituted benzofuran for which the
aIsotope Chemistry and Metabolite Synthesis, DSAR-DD, Sanofi R&D, 1 Avenue
Pierre Brossolette, 91380 Chilly-Mazarin, France
molecules. Based on this economic model, several start-up
companies have made this activity their core business.3
The scientific rationale behind attempts to improve
absorption, distribution, metabolism and excretion properties
of drug candidates by deuteration has been comprehensively
reviewed4–6 and is based on the primary isotope effect: C-D
bonds are stronger than the corresponding C-H bonds, so that
any oxidative metabolism in which C-H bond-breaking is at least
partially rate-limiting, could theoretically be slowed down if
hydrogen is replaced by deuterium at the metabolic ‘hot-spot’.
The in vivo half-life of, and exposure to the parent molecule
should thus be increased, transforming drug candidates, which
bBioanalysis, Metabolism and In-vitro Methods, DSAR-DD, Sanofi R&D, 371 Rue
du Professeur Joseph Blayac, 34184 Montpellier, France
*Correspondence to: Joseph M. Schofield, Isotope Chemistry and Metabolite
Synthesis, DSAR-DD, Sanofi R&D, 1, Avenue Pierre Brossolette, 91380 Chilly-
Mazarin, France.
E-mail: joseph.schofield@sanofi.com
† This article is published in Journal of Labelled Compounds and
Radiopharmaceuticals as a special issue on IIS 2012 Heidelberg Conference,
edited by Jens Atzrodt and Volker Derdau, Isotope Chemistry and Metabolite
Synthesis, DSAR-DD, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst
had previously failed because of the lack of exposure, into G876, 65926 Frankfurt am Main, Germany.
J. Label Compd. Radiopharm 2013, 56 504–512
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J. Schofield et al.
investigation. These compounds were incubated separately with
human hepatocytes in primary culture under standard conditions,
and the incubates analysed quantitatively for dronedarone over
24h.
Figure 1. Chemical Structures of MK-0641 and SD-809.
metabolic behaviour in man is well established. The major, active
metabolite, SR35021, results from cytochrome P450 (CYP)
mediated debutylation, with the isoform 3A4 of the enzyme
being the major contributor.9 SR35021 is further metabolised
to the inactive carboxylic acid SR95014 by monoamine oxidase-
mediated oxidative deamination.10 Other minor metabolic
pathways involve O-dealkylation to phenol
1 and some
oxidation/hydroxylation to a series of uncharacterised derivatives
2.10 (Scheme 1). In order to investigate the sensitivity of the major
oxidative pathways to deuterium substitution and its effect on
metabolic clearance of dronedarone, we prepared a series of
eight specifically deuterated analogues 3a-h with D atoms in α
positions to the principal sites of metabolism 3a, 3e, 3g and 3h
or with per-deuterated chains 3c, 3b, 3f or with combinations
of both substitution types 3d. The compounds containing per-
deuterated chains, that is, 3c, 3b, 3f and 3d were prepared to
include any minor chain hydroxylation pathways in the
Results and discussions
Chemistry
For the deuterated dronedarone derivatives completely labelled
in the butyl side chains, 3b and 3f, the key per-deuterated di-n-
Scheme 1. Human metabolic pathways for dronedarone, 3.
Scheme 2. Synthesis of deuterated dibutylamine, 5.
Scheme 3. Synthesis of deuterated propyl derivative 13.
J. Label Compd. Radiopharm 2013, 56 504–512
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J. Schofield et al.
buylamine is commercially available, whereas for the compounds In vitro metabolism studies
α-deuterated to nitrogen in the side chains, that is, 3d, 3g and 3h,
With the deuterated analogues 3a-h in hand, each was
incubated separately with two different preparations of human
hepatocytes, as was unlabelled dronaderone. The experiments
were carried out at two different substrate concentrations (0.5
and 5 μM) either alone, in presence of ketaconazole, 22, or in
presence of 1-aminobezotriazole, 23. (Figure 2). These latter
incubations were designed to quantify the contributions of both
CYP3A4, and total CYPs to the overall metabolic clearance of the
analogues, because 22 selectively inhibits the 3A4 isoform15,
whereas 23 inhibits the whole family of p450 enzymes.16 Each
incubate was analysed by liquid chromatography-mass
spectrometry (LC-MS) over time to quantify the concentration
of starting dronedarone analogue remaining.
it was necessary to prepare the D4 amine 5 (Scheme 2). Butyryl
chloride, 6, and butanamide, 7, were condensed under acidic
conditions, using a modification of a literature procedure11 to
yield the imide, 8, which was reduced to 5 in good yield using
lithium aluminium deuteride.
Similarly, for the targets per-deuterated in the central propyl
chain, 3b and 3d, D6-bromopropanol is readily available. For
analogues carrying D atoms α to the phenolic O atom, 3a-d, we
prepared methyl-3-hydroxypropionate, 10, using β-propiolactone,
9, according to a literature procedure.12 O-Protection to 11,12
followed by deuteroreduction of the ester function, gave a
very good yield of the mono-protected deuterated diol, 12,
which was brominated under standard conditions to compound
13 (Scheme 3).
Figure
3 shows a typical time-concentration plot for
dronedarone, 3, and its eight deuterated analogues, 3a-h, over a
24 h incubation with one specific human hepatocyte preparation.
That no significant differences exist in the metabolic stability
of any of the analogues, is supported by the calculated mean
clearance figures for the whole set of incubations (Figure 4),
obtained at two different substrate concentrations (0.5 and 5
μM) with two different human hepatocyte preparations. We
assume that no saturation of clearance occurs, and that there is
no difference in CYP contribution over the concentration range.
Additionally, from the incubations conducted in presence of 22
and 23, no significant differences in either the contribution of
CYP3A4 or total CYP to the overall metabolic clearance could
be discerned (Figure 4).
β-propiolactone, 9, was also used in the synthesis of analogues
3e and 3g carrying D atoms α to the tertiary nitrogen atom.
Starting from the readily available nitro-substituted phenol, 14,
base mediated opening13 gave the propionic acid, 15, which
was deutero-reduced to the intermediate alcohol, 16, prior to
activation as the tosyl derivative 17. Reaction of 17 with the
previously described deuterated amine, 5 or D9-n-butylamine, gave
the two nitro derivatives 18e and 18g respectively. (Scheme 4)
The remaining nitro derivatives 18a-18d, 18f and 18h were all
prepared from 14 using the intermediates described above. Thus,
14 was converted to a series of ethers 19a-c by reaction with
either D6-dibromopropane, dibromopropane or 13 under a
variety of similar conditions. 19c was deprotected and
brominated under standard conditions to bromo derivative 19d.
Alkylation of the three amines 9, d9-di-n-butylamine and di-n-
butylamine with the appropriate bromo derivatives 19a, b or d
gave the nitro derivatives 18a-18d, 18f and 18h (Scheme 5).
All eight nitro compounds 18a-h were converted to their
methylsulphhonylamido derivatives 3a-h by tin(II) chloride
reduction to the primary amines 20a-h, following a literature
procedure.14 The primary amines 20a-h were then sulphonylated
using excess methanesulphonyl chloride in the presence of
aqueous ammonia. This technique is used to ensure that any bis
sulphonylated material, 21, is hydrolysed immediately to the
required 3. All analogues were isolated as their hydrochloride
salts (Scheme 6).
Experimental
All reagents were of commercial quality and were used as received.
Reactions were monitored by thin layer chromatography (TLC) on glass
plates coated with silica gel containing fluorescence indicator (silica gel
60 F254, from Merck KGaA) or by LC/MS (Agilent 1100 Series;
column: Symmetry C18, 5 μm, 4.6 × 50 mm; mass detector: API3000
from AB-SCIEX). Purifications by column chromatography were carried
out on cartridges of pre-packed silica gel 60, (0.063–0.2 mm) from Merck
Chimie or Macherey-Nagel with the described eluents. The 1H NMR and
13C-NMR spectra were recorded on a Bruker AC-200 (200 MHz) or on a
Bruker Avance 600 (600 MHz) nuclear magnetic resonance spectrometer,
13C-NMR spectra being obtained using off-resonance decoupling so that
Scheme 4. Synthesis of nitro derivatives α deuterated in propyl chain 18e, 18g.
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Copyright © 2013 John Wiley & Sons, Ltd.
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J. Schofield et al.
Scheme 5. Synthesis of nitro derivatives 18a-d, 18f and 18h.
Scheme 6. Conversion of nitro compounds, 18 to methylsulphonamido derivatives, 3.
carbon atoms carrying deuterium atoms appeared as multiplets. The 1H on an oil bath at 100°C for 2 h. The reaction mixture was partitioned
NMR data were compared with literature data or checked against an between dichloromethane and saturated sodium carbonate solution,
authentic sample of the corresponding unlabelled compound. Where and the layers separated. The aqueous phase was extracted three times
analytical data is not recorded for a particular analogue, characterisation with dichloromethane, the combined organic phase dried over MgSO4
was achieved by comparison of chromatographic data with a more fully and evaporated to an off white solid.
characterised analogue. The MS spectra were recorded on a Shimadzu
ion trap/time-of-flight mass spectrometer.
The condensation was repeated using 6 (8.70 g, 100 mmol) and 7
(10.4 mL, 100 mmol) and the crude products combined and
recrystallised from diisopropyl ether to provide 8 (8.30 g, 53 mmol,
48%) as a white solid. 1H NMR (CDCl3, 600 MHz) δ 8.37 (bs, 1H),
2.55 (t, 4H), 1.80-1.60 (m, 4H), 1.00 (t, 6H). 13C-NMR (CDCl3,
N-Butyrylbutyramide (8)
A mixture of butyryl chloride, 6 (0.87 g, 10 mmol), butanamide, 7 150 MHz) δ 174, 39, 18, 14; gas chromatography (GC) MS retention
(1.04 mL, 10 mmol), and several drops of concentrated H2SO4 was heated time = 13.42 min, m/z = 158 (M + H+)
J. Label Compd. Radiopharm 2013, 56 504–512
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J. Schofield et al.
(CDCl3, 600 MHz) δ 1.6-1.2 (m, 8H), 0.9 (t, 6H). 13C-NMR (CDCl3, 150 MHz)
δ 49.1(m), 32.3, 20.6, 14.2. MS m/z 134 (M + H+).
Methyl-3-hydroxypropionate (10)11
A solution of β-propiolactone, 9 (20.15 g, 0.28 mol), in MeOH (100 mL)
was treated portionwise at room temperature with sodium methoxide
(1.51 g, 28 mmol) with stirring. The mixture was warmed on an oil bath
at 50°C for 4 h, and after cooling to room temperature, the MeOH was
evaporated and the residue taken up in diethyl ether. Insoluble material
was removed by filtration through a pad of silica gel and the volatiles
removed under reduced pressure at room temperature to give 10 as a
pale yellow oil (23.5 g, 0.23 mol, 82%). 1H NMR (CDCl3, 200 MHz) δ 3.85
(q, 2H), 3.68 (s, 3H), 2.60(t, 2H), 2.38 (t, 1H) used without additional
purification.
Figure 2. Chemical structures of ketoconazole, 22, and 1-aminobenzotriazole, 23.
Methyl -3-(tert-butyldiphenylsilanyloxy)propioniate (11)
A stirred solution of 10 (5.00 g, 48 mmol) in anhydrous dichloromethane
(100 mL) was treated with imidazole (6.54 g, 96 mmol) at room
temperature. Tert-butyldiphenylchlorosilane (15 mL, 58 mmol) was added
dropwise and the reaction mixture allowed to stir for 24 h at room
temperature. Crushed ice was added and the mixture partitioned
between water and dichloromethane. The layers were separated and
the aqueous phase re-extracted twice with dichloromethane. The
combined organic phase was washed with water, dried over anhydrous
sodium sulphate and evaporated to yield a practically colourless, thick oil.
The reaction was repeated using the same quantities of reagents, and
the products combined to give the crude intermediate as a thick oil
(45 g). This was chromatographed on silica gel in 98:2 n-pentane/diethyl
ether to give 11 (27.0 g, 79 mmol, 82%) as a thick oil. 1H NMR (CDCl3,
600 MHz) δ 7.75-7.65 (m, 4H), 7.5-7.35 (m, 6H), 3.90 (t, 2H), 3.70 (s, 3H)
2.60 (t, 2H), 1.06 (s, 9H). 13C-NMR (CDCl3, 150 MHz) δ 172.2, 135.6, 133.5,
129.7, 127.7,127.6, 59.9, 51.6, 37.7, 26.7, 19.2.
Figure 3. Time versus concentration plot during hepatocyte incubation for
dronedarone and its deuterated analogues 3a-h.
[α, α, α', α'-2H4]-dibutylamine (5)
[1-2H2]-3-(tert-Butyldiphenylsilanyloxy)propan-1-ol (12)11
A solution of 11 (5.00 g, 14.6 mmol) in diethyl ether (20 mL) was treated
A solution of 8 (3.00 g, 19 mmol) in anhydrous THF (40 mL) was treated
with LiAlD4 (1.20 g, 29 mmol). After warming for several hours, GC
analysis showed reaction to be incomplete, so further LiAlD4 (1.00 g, portionwise with LiBD4 (188 mg, 7.3 mmol) over 20 min. GC analysis
24 mmol) was added and warming continued for 4 h. The mixture was showed the reaction to be incomplete, so further LiBD4 (311 mg,
quenched by the addition of excess 1 M sodium hydroxide solution, 12 mmol) was added, and the mixture allowed to stir overnight. The
and extracted three times with dichloromethane. The combined extracts mixture was partitioned between water and diethyl ether, the layers
were dried over solid potassium carbonate and carefully evaporated to
separated and the aqueous phase extracted twice with diethyl ether.
dryness at room temperature to avoid loss of volatile product. 5 (2.53 g The combined ethereal phase was dried over MgSO4, and evaporated
containing residual solvent) was recovered as a mobile, practically to a colourless oil, which crystallised on standing as crude 12 (5.76 g
colourless liquid. The yield, as estimated by 1H NMR was 73%. 1H NMR containing some residual solvent), which was used in the next step
Mean Clearance in
mL.h-1.(106 hep)-1
0.141 0.041
% CYP3A4
contribution
% Total CYP
contribution
Compound
3
86
88
84
84
84
85
84
4
3
5
5
3
6
7
94
95
96
95
96
91
97
94
98
4
2
2
2
4
5
5
6
2
3a
3b
3c
3d
3e
3f
0.142 0.042
0.123 0.044
0.133 0.044
0.125 0.039
0.138 0.048
0.127 0.049
0.117 0.032
0.146 0.048
3g
3h
81 10
89
3
Figure 4. Mean total in vitro metabolic clearances, CYP3A4 and total CYP contributions characterizing in vitro metabolism of dronedarone 3 and deuterated analogues 3a-h.
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J. Schofield et al.
without purification. 1H NMR (CDCl3, 200 MHz) δ 7.75–7.35 (m, 10H), 3.97 with water and dried over MgSO4 before being evaporated. The
(t, 2H), 2.60 (bs, 1H), 1.84 (bt, 2H), 1.14(m, 9H).
residue was chromatographed on silica gel in 50:50 chloroform :
n-pentane in a gradient elution up to 60:40 chloroform : n-pentane
to provide 17 (4.00 g, 7.23 mmol, 87%). MS m/z 554 (M + H+); 552
(M-H-). The product was further characterised by comparison of its
TLC properties with the unlabelled analogue.
[3-2H2]-(3-Bromopropoxy)-tert-butyldiphenylsilane (13)11
A mixture of 12 (5.76 g containing solvent, 14.6 mmol based on starting
11) and triphenylphosphine (4.54 g, 17.3 mmol) in dichloromethane
(12 mL) was treated with a solution of carbon tetrabromide (6.69 g,
20.2 mmol) in dichloromethane (15 mL). After 30 min, the mixture was
concentrated, taken up in n-pentane and the insoluble triphenylphosphine
oxide removed by filtration. The solution was concentrated to give crude 13
(7.55 g), which was used without further purification. 1H NMR (CDCl3,
200 MHz) δ 7.73–7.35 (m, 10H), 3.82 (t, 2H), 2.10 (m, 2H), 1.15(m, 9H)
(2-Butyl-5-nitrobenzofuran-3-yl)-[4-(3-dibutylamino-(3-[2H2]-
propoxy)-phenyl]-methanone (18e)
A mixture of 17 (1.25 g, 2.26 mmol) and di-n-butylamine (0.96 mL,
5.6 mmol) in ethanol (30 mL) was heated at reflux for 8 h, with the
addition of further di-n-butylamine (0.8 mL, 4.6 mmol) after 4.5 h. The
reaction mixture was evaporated, and the residue chromatographed
in 98:2 chloroform-MeOH on silica gel to yield, after evaporation 18e
(0.75 g, 66%), characterised by comparison of its TLC properties with
the unlabelled analogue.
3-[4-(2-Butyl-5-nitro-benzofuran-3-carbonyl)phenoxy]-
propionic acid (15)
A
mixture of 14 (1.00 g, 2.95 mmol), β-propiolactone, 9 (0.212 g,
2.95 mmol) and THF (10 mL) was stirred under argon at room
temperature and treated dropwise with a 1 M solution of potassium
tert-butoxide in THF (2.95 mL, 2.95 mmol). The reaction mixture was
heated at reflux for 3 h, allowed to cool overnight, then treated with
further 9 (0.109 g, 1.5 mmol) and 1 M potassium tert-butoxide in THF
(1.5 mL, 1.5 mmol) and heated at reflux for 2.5 h. The mixture was cooled
to room temperature, diluted with water and extracted twice with EtOAc.
The combined extracts were dried over MgSO4 and evaporated to a gum,
which was chromatographed in 98:2 chloroform-MeOH to give 15 as a
waxy solid (0.30 g, 0.72 mmol, 24%) 1H NMR (CDCl3, 600 MHz) δ 9.50 (bs,
1H), 8.28 (d, 1H), 8.20 (dd, 1H), 7.80 (d, 2H), 7.55 (d, 1H), 6.96 (d, 2H),
4.35 (t, 2H), 2.90 (2 x t, 4H), 1.80 (q5, 2H), 1.30 (m, 2H), 0.87 (t, 3H).
The synthesis was repeated using 14 (2.00 g, 5.89 mmol), β-
propiolactone, 9 (0.74 mL, 11.8mmol) and solid potassium t-butoxide
(1.321g, 11.8mmol), both added in two portions. Column chromatography
under the same conditions gave further 15 (0.90 g, 2.19 mmol, 37%).
(2-Butyl-5-nitrobenzofuran-3-yl)-[4-(3-di-1-[2H2]-butylamino-
(3-[2H2]-propoxy)-phenyl]-methanone (18g)
A mixture of 17 (1.25 g, 2.26 mmol) and 5 (0.752 g, 5.64 mmol) in ethanol
(30 mL) was heated at reflux for 8 h, with the addition of further 5 (0.63 g,
4.4 mmol) after 4.5 h. The reaction mixture was evaporated, and the
residue chromatographed in 98:2 chloroform-MeOH on silica gel to yield,
after evaporation 18 g (0.60 g, 52%), characterised by comparison of its
TLC properties with the unlabelled analogue.
[4-(3-Bromo-[2H6]-propoxy)-phenyl]-(2-butyl-5-nitro-
benzofuran-3-yl)-methanone (19a)
To a solution of 14 (3.243 g, 9.56 mmol,) in water (10 mL) was added
[2H6]-1,3-dibromopropane (2.519 g, 12.1 mmol) and sodium hydroxide
(0.352 g, 8.8 mmol). The reaction mixture was stirred at reflux for 8 h,
allowed to warm to room temperature then diluted with water and
dichloromethane. The aqueous layer was extracted three times with
dichloromethane, and the combined organic layers were dried over Na2SO4,
and evaporated. The brown oil so obtained was chromatographed in 9:1
pentane-diethyl ether on silica gel to give 19a as a pale yellow oil
(2.752 g, 62%).1H NMR (CDCl3, 200 MHz) δ 8.3 (s, 1H), 8.1 (d, 1H), 7.8
(m, 2H), 7.5 (d, 1H), 7.0 (d, 2H), 2.9 (t, 2H), 1.75 (q, 2H), 1.3 (q, 2H), 0.9
(t, 3H). MS m/z 466 (M + H+)
(2-Butyl-5-nitrobenzofuran-3-yl)-[4-(3-[2H2]-
3-hydroxypropoxy)phenyl]-methanone (16)
15 (0.90 g, 2.19 mmol) in solution in THF (50 mL) stirred on an ice water
bath under argon, was treated dropwise with a 1 M solution of borane-
D3–THF complex in THF (2.4 mL, 2.4 mmol). After 3 h, further 1 M solution
borane-D3–THF complex in THF (2.4 mL, 2.4 mmol) was added and
stirring continued for 2.5 h. Saturated aqueous potassium carbonate
solution was added, followed by ice water, and the mixture extracted
twice with EtOAc. The combined extracts were washed with water, dried
over MgSO4 and evaporated to an oil.
This experiment was repeated using 14 (4.00 g, 11.8 mmol), water
(16 mL), [2H6]-1,3-dibromopropane (3.11 g, 15.0 mmol) and sodium
hydroxide (0.434 g, 10.8 mmol) to provide a further quantity of 19a as a
pale yellow oil (3.10 g, 6.7 mmol, 56%) identical to the first batch.
The reduction was repeated twice using 15 (0.50 g, 1.22 mmol and
6.71 g, 13.3 mmol) and 1 M solution borane-D3–THF complex in THF
(1.82 mL, 1.82 mmol and 31.5 mL, 31.5 mmol). Similar work-up and
combination of reaction products gave crude 16 (7.38 g), which was
chromatographed in chloroform: MeOH (995:5) on silica gel to yield
purified 16 (3.30 g, 8.26 mmol, 49% overall) as a thick oil, which was used
without further characterisation.
[4-(3-Bromo-propoxy)-phenyl]-(2-butyl-5-nitro-benzofuran-
3-yl)-methanone (19b)
To a solution of 14 (1.000 g, 2.94 mmol) in dimethylformamide (30 mL)
was added 1,3-dibromopropane (0.373 mL, 3.65 mmol) under argon.
The reaction mixture was stirred at room temperature overnight. The
reaction mixture was then diluted with water and EtOAc. The organic
layer was separated, washed with water, dried over Na2SO4 and the
solvent evaporated. The brown oil so obtained was chromatographed
in 90:10 pentane-diethyl ether to give 19b as a light yellow oil (0.625 g,
(2-Butyl-5-nitrobenzofuran-3-yl)-[4-(3-[2H2]-3-
(4-methylphenylsulphonyloxy) propoxy) phenyl]-methanone (17)
16 (3.30 g, 8.26 mmol) dissolved in dichloromethane (100 mL) was 1.36 mmol, 46%). 1H NMR (CDCl3, 200 MHz) δ 8.4 (s, 1H), 8.2 (d, J = 8 Hz,
treated with p-toluenesulphonyl chloride (3.15 g, 16.5 mmol), and 1H), 7.8 (d, J = 8 Hz, 2H), 7.6 (d, 1H), 4.2 (t, 2H), 3.6 (t, 2H), 2.9 (t, 2H), 2.4
the solution stirred on an ice water bath, while triethylamine (q5, 2H), 1.8 (q5, 2H), 1.3 (q6, 2H), 0.9 (t, 3H). MS m/z 461 (M + H+)
(2.3 mL, 16.5 mmol) was added dropwise. After 20 h, further In an alternative reaction, 14 (1.323 g, 3.90 mmol), 1,3-dibromopropane
quantities of p-toluenesulphonyl chloride (3.15 g, 16.5 mmol) and (1.00 g, 4.95 mmol) and solid sodium hydroxide (0.15 g, 3.8 mmol) were
triethylamine (2.3 mL) were added, and after an additional 24 h, more heated together with stirring at reflux for 5 h. The mixture was diluted
p-toluenesulphonyl chloride (1.57 g, 8.23 mmol) and triethylamine with water and extracted three times with dichloromethane. The
(1.15 mL, 8.3 mmol) were again added. The mixture was diluted with combined extracts were dried over MgSO4 and evaporated to a dark oil
water, extracted twice with EtOAc and the combined extracts washed
(2.1 g). This was chromatographed on silica gel in 90:10 n-pentane/diethyl
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J. Schofield et al.
ether to give 19b as a yellow oil (1.15 g, 2.50 mmol, 64%) identical to the
previous batch.
MeOH containing 0.2% concentrated ammonia solution on silica gel.
By this general method the following were obtained:
(2-Butyl-5-nitro-benzofuran-3-yl)-[4-(3-di-butylamino-1-[2H2]-propoxy)-
phenyl]-methanone (18a) (0.72 g, 1.41 mmol, 80%) was isolated as a
yellow oil from 19d (0.82 g, 1.77 mmol) and di-n-butylamine (total of
1.2 mL, 7.0 mmol)
{4-[3-(tert-Butyl-diphenyl-silanyloxy)-3-[2H2]propoxy]-
phenyl}-(2-butyl-5-nitro-benzofuran-3-yl)-methanone (19c)
A mixture of crude 13 (7.55 g, 14.4 mmol based on starting 11), 14
(4.89 g, 14.4 mmol) and caesium carbonate (4.69 g, 14.4 mmol) in DMF
(80 mL) was heated on an oil bath at 110°C. The mixture was
concentrated under reduced pressure and the black residue
chromatographed on silica gel in 95:5 pentane/diethyl ether to give
19c (3.81 g, 6.0 mmol, 41% over the three steps) as a waxy solid, which
was used directly in the next step. 1H NMR (CDCl3, 200 MHz) δ 8.39 (s,
1H), 8.21 (d, 1H), 7.85 (m, 2H), 7.75-7.30 (m, 11H), 6.96 (d, 2H), 3.90 (t,
2H), 2.94 (t, 2H), 2.07 (t, 2H), 1.78 (m, 2H), 1.35 (m, 2H), 1.05 (s, 9H), 0.90
(t, 3H).
(2-Butyl-5-nitro-benzofuran-3-yl)-[4-(3-di-[2H9]-butylamino-[2H6]-
propoxy)-phenyl]-methanone (18b) (0.74 g 1.38 mmol, 65%).1H NMR
(CDCl3, 200 MHz) δ 8.4 (s, 1H) 8.3 (d, 1H), 7.8 (d, 2H), 7.5 (d, 1H), 7.0 (d,
1H), 2.9 (t, 2H), 1.75 (q5, 2H), 1.3 (q5, 2H), 0.9 (t, 3H); m/z: 533 [M + H+]
was isolated as a yellow oil from 19a (0.993 g, 2.13 mmol) and [2H18]-
dibutylamine (total of 1.067 g, 7.24 mmol)
(2-Butyl-5-nitro-benzofuran-3-yl)-[4-(3-di-1-[2H2]-butylamino-1-[2H6]-
propoxy)-phenyl]-methanone (18d) (1.50 g, 2.89 mmol, 80%) was isolated
as a yellow oil from 19a (1.69 g, 3.62 mmol) and 5 (0.964 g, 7.23 mmol).
(2-Butyl-5-nitro-benzofuran-3-yl)-[4-(3-di-[2H9]-butylamino-propoxy)-phenyl]-
[4-(3-[2H2]-3-Bromopropoxy)-phenyl]-(2-butyl-5-
nitro-benzofuran-3-yl)-methanone (19d)
1
methanone (18f) as a yellow oil (0.486 g, 0.92 mmol, 82%). H NMR (CDCl3,
200 MHz) δ 8.3 (s, 1H), 8.2 (d, 1H), 7.8 (d, 2H), 7.6 (d, 1H), 7.0 (d, 1H), 4.1 (t,
2H), 2.9 (t, , 2H), 2.6 (t, 2H), 1.8 (q5, 2H), 1.75 (q5, 2H), 1.4 (q6, 2H), 0.9 (t, 3H).
MS m/z 527 (M + H+) from 19b (0.993 g, 2.13 mmol) and [2H18]-dibutylamine (total
of 0.812 g, 5.52 mmol)
A solution of 19c (3.61 g, 5.7 mmol) in anhydrous THF (100 mL) was
stirred and cooled on an ice-water bath at 0°C. Tetrabutylammonium
fluoride solution (6.8 mL of 1 M in THF, 6.8 mmol) was added, and the
dark mixture stirred at room temperature overnight. The mixture was
poured onto crushed ice and extracted three times with EtOAc. The
combined extracts were dried over magnesium sulphate and evaporated
to yield crude alcohol intermediate (4.0 g) as an orange oil, which was
chromatographed on silica gel in 98:2 dichloromethane/MeOH to
provide the intermediate alcohol (1.00 g, 2.5 mmol, 44%) as a pale yellow
oil, which was transferred to a reaction flask with dichloromethane (20 mL).
Triphenylphosphine (790mg, 3.0mmol) and carbon tetrabromide (1.16 g,
3.5mmol) were added, and the reaction stirred at room temperature. TLC
analysis indicated that the reaction was incomplete, so further
triphenylphosphine (393 mg, 1.5mmol) and carbon tetrabromide (0.581 g,
1.75mmol) were added and the mixture stirred overnight. The volatile
solvents were evaporated, and the residue chromatographed on silica gel
in 9:1 n-pentane/diethyl ether to provide 19d (0.82g, 1.8mmol, 32% from
19c). 1H NMR (CDCl3, 600 MHz) δ 8.34 (1H, d), 8.21 (1H, dd), 7.82 (2H, d),
7.58(1H, d), 7.01 (d, 2H), 4.23 (m, impurity), 3.64 (t, 2H), 2.92 (t, 2H), 2.39 (t,
2H), 1.76 (m, 2H), 1.45-1.34 (m, 4H), 0.90 (t, 3H).
(2-Butyl-5-nitro-benzofuran-3-yl)-[4-(3-di-1-[2H2]-butylaminopropoxy)phenyl]-
methanone (18h) (0.661 g, 1.29 mmol, 80%) from 19b (1.15 g, 2.50 mmol) and
5 (1.06 g, 7.95 mmol) characterised by comparison with analogues.
Synthesis of amines (20a-h) from nitro compounds (18a-h)
A solution of the nitro compound 18 in ethanol (about 35 volume
equivalents) was treated with tin (II) chloride dihydrate (5 mol
equivalents), and the mixture heated at 80°c under argon. When TLC
indicated no starting material to remain, the mixture was quenched with
ice, basified (5% aqueous sodium bicarbonate solution) treated with
excess EtOAc and filtered over a Celite pad. After washing the filter cake
with further EtOAc, the extract was washed with water, and the aqueous
layer extracted twice with the same solvent. The combined organic
phase was dried over Na2SO4 and evaporated. The resultant crude
amines 20 were chromatographed in 98:2 dichloromethane-MeOH
containing 0.2% concentrated ammonia solution over silica gel. By using
this general method, the following were obtained:
(2-Butyl-5-nitro-benzofuran-3-yl)-[4-(3-dibutylamino-[2H6]-
propoxy)-phenyl]-methanone (18c)
(5-Amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-1-[2H2]-propoxy)-phenyl]-
methanone (20a) (0.611 g, 1.27 mmol, 90%) from 18a (0.715 g, 1.40 mmol) as a
pale yellow oil.
A mixture of K2CO3 (0.475 g, 3.44 mmol) and 14 (1.001 g, 2.95 mmol) in
butan-2-one (5.4 mL) was treated with [2H6]-1,3-dibromopropane
(1.238 g, 5.95 mmol) under argon. The reaction mixture was stirred at
reflux for 4.5 h, then allowed to cool to room temperature, diluted with
methyl-tert-butyl-ether (20 mL), filtered and the solvents evaporated to
yield a yellow oil. The oil so obtained was diluted with DMSO (7.5 mL)
and treated with dibutylamine (1.2 mL, 7.06 mmol) and the suspension
stirred at room temperature for 18 h. The reaction mixture was then
partitioned between water and EtOAc. The organic layer was separated,
washed with water, dried over Na2SO4 and evaporated to yield a brown
oil, which was chromatographed in 99:1 dichloromethane-MeOH
containing 0.1% concentrated ammonium hydroxide to give 18c
(0.718 g, 5.9 mmol, 47%) as a light orange oil. MS m/z 515 (M + H+).
(5-Amino-2-butylbenzofuran-3-yl)-[4-(3-di-[2H9]-butylamino-[2H6]-propoxy)-
phenyl]-methanone (20b) (0.605 g, 1.20 mmol, 90%) as a yellow oil. 1H NMR
(CDCl3, 200 MHz) δ 7.85 (d, 2H), 7.3 (m, 1H), 6.95 (d, 2H), 6.6 (m, 2H), 3.55 (bs,
2H,), 2.85 (t, 2H), 1.75 (q5, 2H), 1.3 (m, 2H), 0.9 (t, 3H). MS m/z 503 (M + H+),
from 18b (0.711 g, 1.33 mmol)
(5-Amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-[2H6]-propoxy)-phenyl]-
1
methanone (20c) (0.404 g, 0.85 mmol, 95%) was obtained as a yellow oil. H
NMR (CDCl3, 200 MHz) δ 7.85 (d, 2H), 7.3 (m, 1H), 6.95 (d, 2H), 6.6 (m, 2H), 3.55
(bs, 2H), 2.85 (t, 2H), 2.5 (m, 2 x 2H), 1.85 (m, 2H), 1.0 (m, 5x2H), 0.9 (m, 3 x 3H).
MS m/z 503 (M + H+) from 18c (0.456 g, 0.89 mmol)
Synthesis of other tertiary amines (18a, 18b, 18d, 18f
and 18h) from bromo compounds (19a, 19b and 19d)
(5-Amino-2-butyl-benzofuran-3-yl)-[4-(3-di-1-[2H2]-butylamino-3-[2H6]-
A solution of the bromo derivative 19 in ethanol (~10 volumes) was propoxy)-phenyl]-methanone (20d) (1.177 g, 2.27 mmol, 78%) from 18d
treated with the appropriate dibutylamine (~2.5 molar equivalents)
and heated for 5 h at reflux temperature. Further dibutylamine was
added and heating continued until conversion was complete as shown
by TLC. The reaction mixture was cooled and evaporated to dryness
(1.50 g, 2.9 mmol)
(5-Amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-3-[2H2]-
propoxy)-phenyl]-methanone (20e) (0.51 g, 1.06 mmol, 72%) from 18e
before the crude 18 was chromatographed in 98:2 dichloromethane- (0.75 g, 1.47 mmol)
www.jlcr.org
Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 504–512

J. Schofield et al.
(5-Amino-2-butyl-benzofuran-3-yl)-[4-(3-di-[2H9]-butylaminopropoxy)-phenyl]-
methanone (20f) (0.404 g, 0.81 mmol, 90%) was obtained as a yellow oil. H 7.45 (d, 1H), 7.3 (d, 1H), 7.2 (s, 1H), 6.95 (d, 2H), 2.95 (t, 2H), 2.9 (s, 3H), 1.75
NMR (CDCl3, 200 MHz) δ 7.8 (d, 2H), 7.25 (m, 1H), 6.9 (d, 2H), 6.6 (m, 2H), 4.1 (t,
(m, 2H), 1.4 (m, 2H), 0.9 (m, 3H). MS m/z 581 (M + H+) from 20b (0.573 g,
solid. 1H NMR (CDCl3, 600 MHz) δ 11.9 (bs, 1H), 7.8 (d, 2H), 7.55 (bs, 1H),
1
2H), 3.5 (bs, 2H), 2.9 (t, 2H), 2.6 (t, 2H), 1.8 (m, 2H), 1.75 (m, 2H), 1.3 (m, 2H), 0.9 1.14 mmol)
(t, 3H). MS m/z 497 (M + H+), from 18f (0.473 g, 0.9 mmol)
N-{2-Butyl-3-[4-(3-dibutylamino-[2H6]-propoxy)-benzoyl]-benzofuran-5-
(5-Amino-2-butyl-benzofuran-3-yl)-[4-(3-di-1-[2H2]-butylamino-3-[2H2]-
propoxy)-phenyl]-methanone (20g) (0.33 g, 0.68 mmol, 58%) was solid. 1H NMR (CDCl3, 600 MHz) δ 11.6 (bs, 1H), 7.9 (bs, 1H), 7.8 (m, 2H),
yl}-methanesulfonamide; hydrochloride (3c) (0.480 g, 95%) as a white
obtained as a yellow oil from 19g (0.75 g, 1.47 mmol)
7.4 (d, 1H), 7.3 (d, 1H), 7.2 (s, 1H), 6.9 (d, 2H), 3.05 (bs, 4H), 2.95 (t, 3H),
2.9 (s, 3H), 1.75 (m, 9H), 1.4 (m, 6H), 0.95 (t, 6H), 0.9 (t, 3H). MS m/z 563
[M + H+] from 20c (0.410 g, 0.85 mmol)
(5-Amino-2-butyl-benzofuran-3-yl)-[4-(3-di-1-[2H2]-butylamino-propoxy)-
phenyl]-methanone (20h) (643 mg, 1.33 mmol, 68%) from 18h (1.00 g,
1.95 mmol).
N-{2-Butyl-3-[4-(3-di-1-[2H2]-butylamino-[2H6]-propoxy)-benzoyl]-benzofuran-5-
yl}-methanesulfonamide; hydrochloride (3d) (0.17 g, 0.28 mmol, 14%) as a white
solid. 1H NMR (CDCl3, 200 MHz) δ 7.79 (d, 2H), 7.44 (d, 1H), 7.31 (dd, 1H), 7.18 (d,
1H), 6.94 (d, 2H), 2.98 (m, 2H), 2.92 (s, 3H), 1.77-1.35 (m, 12H), 0.98-0.91 (m, 9H).
MS m/z 567 (M + H+), 565 (M-H-) from 20d (0.974 g, 2.0 mmol)
[2H4]-N-{2-Butyl-3-[4-(3-dibutylamino-propoxy)-benzoyl]-
benzofuran-5-yl}-methanesulfonamide; hydrochloride (3h)
A solution of 20h (0.500 g, 1.04 mmol) in dichloromethane (10 mL) was
treated with triethylamine (210 μL, 1.5 mmol) and methanesulphonyl [2H2]-N-{2-Butyl-3-[4-(3-dibutylamino-3-[2H2]-propoxy)-benzoyl]-benzofuran-5-
chloride (120 μL, 1.54 mmol) and stirred for 20 min at room temperature.
The mixture was diluted with water and extracted three times with
dichloromethane, the combined extracts were dried over MgSO4 and
evaporated to a beige foam shown by LC/MS analysis to consist of a
1:3 mixture of the required 3h, and the disulphonylated compound
(21h). The crude mixture was dissolved in 1:1 MeOH/THF (10 mL),
transferred to a reaction flask and treated with 10% aqueous sodium
carbonate solution (5 mL) and concentrated ammonia solution (5 mL).
The reaction mixture was heated to reflux for 10 h, cooled and extracted
three times with EtOAc. The combined extracts were dried over Na2SO4
and evaporated to a dark oil (500 mg). Column chromatography on silica
gel in 98:2 dichloromethane/MEOH containing 0.2% concentrated
aqueous ammonia gave 3h free base (286 mg, 0.51 mmol, 49%) as an
oil. This was taken up in 2-propanol, and treated with excess of a solution
of HCl in 2-propanol. The solution was concentrated, treated dropwise
with diethyl ether and refrigerated. The 3h (0.22 g, 0.37 mmol, 35%)
was recovered as a white solid by filtration, and dried under vacuum.
1H NMR (CDCl3, 600 MHz) δ 12.06 (1H), 7.80 (d, 2H), 7.44 (d, 1H), 7.31
(dd, 1H), 7.18 (dd, 1H), 6.96 (d, 2H), 4.28 (bt, 2H), 3.24 (bt, 2H), 2.98 (t,
2H), 2.93 (s, 3H), 2.44 (m, 2H), 1.77-1.82 (m, 6H), 1.44-1.38 (m, 6H), 1.00
(t, 6H), 0.92 (t, 3H). MS m/z 561.3255 (M + H+), 559.3171 (M-H-).
yl}-methanesulfonamide; hydrochloride (3e) (0.48 g, 0.81 mmol, 86%) as a white
solid from 20e (0.51g, 1.06mmol). 1H NMR (CDCl3, 600 MHz) δ 7.74 (d, 2H), 7.44
(d, 1H), 7.33 (dd, 1H), 7.18 (d, 2H), 4.26 (t, 3H), 3.15-2.95 (m, 6H), 2.93 (s, 3H), 2.41 (t,
2H), 1.90-1.70 (m, 6H), 1.50-1.30 (m, 6H), 0.99 (t, 6H). MS m/z 559 (M + H+),
557 (M-H-)
N-{2-Butyl-3-[4-(3-di-[2H9]-butylamino-propoxy)-benzoyl]-benzofuran-5-
yl}-methanesulfonamide; hydrochloride (3f) (0.205 g, 41%) as a white
solid. 1H NMR (CDCl3, 600 MHz) δ 11.9 (bs, 1H), 7.8 (m, 3H), 7.4 (d,
J = 12 Hz, 1H), 7.3(d, J = 6 Hz, 1H), 7.2 (s, 1H), 6.9 (d, J = 6 Hz, 2H), 4.2 (m,
2H), 3.2 (bs, 2H), 2.95 (t, 3H), 2.9 (s, 3H), 2.4 (bs, 2H), 1.8 (m, 2H), 1.35
(m, 2H), 0.9 (m, 3H). MS m/z 575 (M + H+) from 20f (0.404 g, 0.81 mmol)
N-{2-Butyl-3-[4-(3-di-1-[2H2]-butylamino-3-[2H2]-propoxy)-benzoyl]-benzofuran-
5-yl}-methanesulfonamide; hydrochloride (3g) (0.270 g, 0.53 mmol, 78%) as a
white solid from 20g (0.33 g, 0.68 mmol) 1H NMR (CDCl3, 600 MHz) δ 11.76(bs,
1H), 7.78(d, 2H), 7.43(d, 1H), 7.38(dd, 1H), 7.19(d, 1H), 6.93(d, 1H), 4.23(t, 2H),
2.96(t, 2H), 2.92(s, 3H), 2.40(t, 2H), 1.79-7.74(m, 6H), 1.50-1.35(m, 6H), 0.98 (t,
6H). MS m/z) 563 (M + H+), 561 (M-H-)
Conclusion
Synthesis of methylsulphonamido hydrochlorides (3a-g)
from amines (20a-h)
Site specific deuteration of dronedarone in a variety of positions
in the metabolically labile part of the molecule had little to no
significant effect on the in vitro behaviour of the parent
compound in the human hepatocyte model. Overall metabolic
clearance of dronedarone is nearly exclusively CYP-dependent
and is dominated by CYP3A4 dependent N-debutylation. These
results confirm previous findings, for example the low (<2)
kinetic isotope effect observed for P450 mediated demethylation
of N,N-dimethylaniline,17, which is explained by invoking a single
electron transfer mechanism—although this remains a subject of
much debate.18 This observation may be of help in determining
which substrates have a greater chance of exhibiting reduced
rates of metabolic clearance once deuterated.
For the other compounds in the series, a solution of amine 20 in THF (about
20 volumes) and t-butylmethyl ether (about 10 volumes) was treated with
methanesulphonyl chloride (1.0 molar equivalent) and 30% aqueous
ammonia solution (1.0 molar equivalent). The mixture was stirred at room
temperature, and if TLC indicated reaction to be incomplete, further
methanesulphonyl chloride (1.0 molar equivalent) and 30% aqueous
ammonia solution were added. Once reaction was complete, the mixture
was partitioned between water and EtOAc, the layers separated and the
aqueous phase re-extracted with EtOAc. The combined organic phase
was dried over Na2SO4 and evaporated. The residue was chromatographed
on silica gel and converted to the hydrochloride salt by treating an ethereal
solution with an anhydrous solution of HCl in ether. Hydrochloride salts
were collected by filtration and dried under vacuum. By using this general
method the following were synthesised:
N-{2-Butyl-3-[4-(3-dibutylamino-1-[2H2]-propoxy)-benzoyl]-benzofuran-5-
Acknowledgements
yl}-methanesulfonamide; hydrochloride (3a) (0.141 g, 21 %) as a white
1
solid. H NMR (CDCl3, 200 MHz) δ 7.79 (d, 2H), 7.55 (bs, 1H), 7.44 (d, 1H),
We wish to thank Dr Serge Perard for NMR and mass spectral
data and their interpretation.
7.32 (dd, 1H), 7.18 (d, 1H), 6.94 (d, 2H), 3.18 (dd, 2H), 3.06-3.00 (m, 6H),
2.39 (dd, 2H), 1.82-1.70 (m, 6H), 1.50-1.25 (m, 6H), 0.98-0.91 (m, 9H). MS
m/z 559 (M + H+); 557 [M-H-] from 20a (0.611 g, 1.27 mmol)
Conflict of Interest
N-{2-Butyl-3-[4-(3-di-[2H9]-butylamino-[2H6]-propoxy)-benzoyl]-benzofuran-
5-yl}-methanesulfonamide; hydrochloride (3b) (0.205g, 41%) as a white
The authors have declared that there is no conflict of interest.
J. Label Compd. Radiopharm 2013, 56 504–512
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org

J. Schofield et al.
[11] K. Baburao, A. M. Costello, R. C. Petterson, G. E. Sender, J. Chem. Soc
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[15] J. H. Lin, A. Y. H. Lu, Clin. Pharmacokinet. 1998, 35, 361–390.
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 504–512