Preparation and purification of desethylamiodarone hydrochloride

Article abstract of DOI:10.1080/00397910600941406

Reaction of the free base of amiodarone with 1-chloroethyl chloroformate in toluene gives desethylamiodarone, which can be easily purified and converted to the hydrochloride salt. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600941406

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Preparation and Purification of
Desethylamiodarone Hydrochloride
a
a
a
Anthony N. Lucas , Mehmet Tanol , Michelle P. McIntosh & Roger A.
a
Rajewski
a
Center for Drug Delivery Research, University of Kansas , Lawrence,
Kansas, USA
Published online: 23 Nov 2006.
To cite this article: Anthony N. Lucas , Mehmet Tanol , Michelle P. McIntosh & Roger A. Rajewski (2006)
Preparation and Purification of Desethylamiodarone Hydrochloride, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:22, 3371-3376, DOI:
10.1080/00397910600941406
To link to this article: http://dx.doi.org/10.1080/00397910600941406
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Synthetic Communications , 36: 3371–3376, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600941406
Preparation and Purification of
Desethylamiodarone Hydrochloride
Anthony N. Lucas, Mehmet Tanol, Michelle P. McIntosh,
and Roger A. Rajewski
Center for Drug Delivery Research, University of Kansas, Lawrence,
Kansas, USA
Abstract: Reaction of the free base of amiodarone with 1-chloroethyl chloroformate in
toluene gives desethylamiodarone, which can be easily purified and converted to the
hydrochloride salt.
Keywords: Amiodarone, chloroethyl chloroformate, dealkylation, desethylamiodar-
one, metabolite
INTRODUCTION
Amiodarone [(2-butylbenzofuran-3-yl) (4-[2-(diethylamino) ethoxy)]-3,5-diio-
dophenyl)methanone] is indicated for the treatment of acute and chronic
[1]
atrial and ventricular arrhythmias in humans and is seeing a resurgence of
2,3]
[
use for atrial fibrillation.
desethylamiodarone [(2-butylbenzofuran-3-yl)(4-[2-(ethylamino)ethoxy]-3,5-
Both amiodarone and its major metabolite,
[
4]
[5–7]
diiodophenyl)methanone], are pharmacologically active,
pounds have been implicated in the prolongation of the duration of activation
and both com-
[8–12]
and recovery of the ventricular myocardium (QT interval),
which is a
major side effect of chronic amiodarone administration. Desethylamiodarone
is not commercially available, thereby limiting investigation into the in vivo
behavior of both amiodarone and desethylamiodarone. The present work
describes a facile method to prepare desethylamiodarone from the commercially
available amiodarone hydrochloride salt. The method for de-ethylation of
Received in the USA April 20, 2006
Address correspondence to Roger A. Rajewski, Center for Drug Delivery Research,
University of Kansas, Lawrence, KS 66047, USA. E-mail: rajewski@ku.edu
3
371

3
372
A. N. Lucas et al.
amiodarone to give desethylamiodarone is based on the work of Olofson et al.
for the dealkylation of N-ethylpiperidine, N,N-diethylaniline, and various drugs
[13]
with l-chloroethyl chloroformate.
During our evaluation of the optimal reagents and conditions for generation
of desethylamiodarone, we evaluated various chloroformic acid derivatives for
their ability to dealkylate amiodarone. 1-Chloroethyl chloroformate proved to
be the only chloroformic acid derivative of the compounds we studied that
provided facile dealkylation. In addition to the work of Olofoson et al., this
reagent has previously been used to prepare the N-demethylated metabolites
[
14]
of tamoxifen,
and chloroprothixene,
promazine, levomepromazine, orphenadrine, clomipramine
[16]
[
15]
[17]
various erythromycins,
and zopicione.
The
mild reaction conditions involved when using 1-chloroethyl chloroformate for
dealkylation of tertiary amines is especially useful for compounds with other
acid labile functional groups.
RESULTS AND DISCUSSION
Commercially available amiodarone hydrochloride (1) was converted to the free
base (la) in saturated aqueous sodium bicarbonate, followed by extraction into
ethylacetate Scheme 1. The ethylacetate solution was dried with sodium sulfate
and filtered, and la was isolated by rotary evaporation of the solvent. Refluxing
la and 1-chloroethyl chloroformate (3, 5 equivalents) in toluene for 16 h
resulted in nearly quantitative conversion of 1a to desethylamiodarone (2) with
minimal side-product formation. The rate of the reaction was enhanced with
increased equivalents of 3; however, the amount of by-products increased also.
Various other chloroformic acid derivatives were also evaluated for conver-
sion of la to 2. None of the seven other chloroformic acid derivatives attempted
(Table 1) resulted in formation of 2. For those derivatives that provided evidence
ofa stable tertiaryorquarternarycarbamate intermediate (liquidchromatography
with mass detection, LC/MS analysis) followiong 16 h at reflux, additional
workup in solution with bubbling HCI gas did not convert the carbamates to 2,
and all the intermediates were recovered unchanged.
Because 2a was to be used in vivo studies and as an analytical standard,
having a pure and well-characterized product was important. To obtain a pure
product, the crude product 2 was subjected to flash chromatography and
converted to 2a with gas HCI. Compound 2a was recrystallized twice to
give the highly pure product in good yield (75%) based on the original
1
13
amount of 1. The identity of 2a was confirmed with H and C NMR,
elemental analysis, and FAB mass-spectral analysis. The purity of 2a was
determined using thermogravimetric analysis (TGA), differential scanning
calorimetry (DSC), Karl Fisher titration, and reverse-phase LC/MS.
The NMR spectra of 2a were in excellent agreement with the corres-
ponding spectra of 1 and were consistent with the loss of one ethyl group in
2
a. Fast atom bombardment (FAB) positive mass spectral analysis gave a

Desethylamiodarone Hydrochloride
3373
Scheme 1.
major Mþl ion peak of 618.1 amu, consistent with the exact mass of 2.
Compound 2a did not contain residual volatile solvents based on Karl
Fisher and TGA analysis. It exhibited a single sharp endotherm on DSC
analysis and a single peak on LC/MS analysis with an Mþl peak of 618
amu, indicating the high purity of the product. The procedure described
provides for the facile preparation of pure 2a from 1 in high yield.
EXPERIMENTAL
All chemicals were purchased from commercial suppliers and used without
further purification. NMR spectra were recorded on a Bruker Avance
4
00-MHz spectrometer. FAB mass-spectral analysis was performed on a VG
MicroMass) ZAB HS spectrometer in a matrix of nitrobenzyl alcohol in
(

3
374
A. N. Lucas et al.
Table 1. Chloroformic acid derivatives attempted for the de-ethylation of
amiodarone
Desethyl-
amiodarone
Stable
intermediate
No
reaction
þ
þ
þ
þ
þ
þ
þ
þ
þ
Note: Reaction conditions: 5 eq. choloroformic acid derivative refluxed in toluene
for 16 h.
methanol. TGA and DSC analyses were performed on a Perkin Elmer TGA7
gravimetric analyzer and Pyris 1 calorimeter, respectively. Karl Fisher analysis
was performed on a Brinkman 652 KF-coulometer. For LC/MS analysis, the
sample was fractionated on a Zorbax column (5 mm, SB-18, 2.1 ꢀ 50 mm)
using a modular Shimadzu system consisting of a LCMS-2010 detector in
elctrospray positive mode, a SIL-10 ADVP auto injector, LC-10 ADVP
pumps, DGV-14A degasser, and SL-10AVP system controller, with data collec-
tion and analysis performed by LCMS solution ver. 2.04 software. The mobile
phase consisted of 0.4:99.6 parts ammonium hydroxide (30%)–methanol at a
flow rate of 200 mL/min.
The free base 1a was prepared from commercially available 1 by dissol-
ving 1 (3.0 gm, 4.4 mmol) in saturated aqueous sodium bicarbonate (200 mL)
and mixing the resulting solution vigourously with ethylacetate (200 mL) for
3
0 min. The organic layer was isolated, dried with sodium sulfate, filtered, and
evaporated to dryness to give a yellow liquid. The residue was dissolved in
toluene (10 mL) and 1-chloroethyl chloroformate (5 equivalents; 2.4 mL)
was added with stirring. The mixture was refluxed for 16 h, cooled to room

Desethylamiodarone Hydrochloride
3375
temperature, and evaporated to dryness under vacuum. The resulting residue
was dissolved in ethyl acetate and washed with saturated aqueous sodium
bicarbonate. The organic phase was isolated, dried with sodium sulfate,
filtered, and evaporated to dryness under vacuum. The crude product was
purified by flash chromatography on silica gel via elution of impurities with
ethyl acetate–hexanes (10:90 V/V) followed by elutuion of 2 with
methanol. Compound 2 was converted to 2a by bubbling HCl gas through
the pooled methanol fractions that were then evaporated to dryness. The
product were recrystallized twice in acetone to give 2.17 g of 2a (75%
1
13
yield) as a white solid. The H and C NMR (400 MHz, CDC1 ) spectra of
3
2
a were compared to those of 1, and chemical shifts were within 0.1 ppm.
The integration of the ethyl protons (3.47 and 1.58 ppm) corresponds to the
loss of one ethyl group in 2a. FAB positive: Mþl peak 618.1 amu; 2 exact
mass 616.99 amu. Karl Fisher analysis: 0% water. DSC analysis: single,
sharp endotherm at 186.78C. Anal. calcd. for C H ClI NO : C, 42.26; H,
2
3
26
2
3
4
.01; N, 2.14. Found: C, 42.47; H, 4.00; N, 2.22.
ACKNOWLEDGMENT
This work was supported in part by a grant from the Kansas Technology
Enterprise Corporation through the Centers for Excellence Program.
REFERENCES
1
. Malpartida, F.; Mola, M.; Huguet, R.; Sala, J.; Noguera, J.; Cordeiro, B. Clinical
evaluation of amiodarone hydrochloride as an anti-arrhythmia agent. Rev. Md.
Univ. Navarra 1975, 19, 143–149.
2
. Roy, D.; Talajic, M.; Dorian, P.; Connolly, S.; Eisenberg, M. J.; Green, M.;
Kus, T.; Lambert, J.; Dubuc, M.; Gagne, P.; Nattel, S.; Thibault, B. Amiodarone
to prevent recurrence of atrial fibrillation: Canadian trial of atrial fibrillation
investigators. N. Engl. J. Med. 2000, 342, 913–920.
3
. Shinagawa, K.; Shiroshita-Takeshita, A.; Schram, G.; Nattel, S. Effects of anti-
arrhythmic drugs on fibrillation in the remodeled atrium: Insights into the
mechanism of the superior efficacy of amiodarone. Circulation 2003, 107, 1440–1446.
. Flanagan, R. J.; Storey, G. C.; Holt, D. W.; Farmer, P. B. Identification
and measurement of desethylamiodarone in blood plasma specimens from
amiodarone-treated patients. J. Pharm. Pharmacol. 1982, 34, 638–643.
. Nattel, S. Pharmacodynamic studies of amiodarone and its active n-desethyl
metabolite. J. Cardiovasc. Pharmacol. 1986, 8, 771–777.
4
5
6
. Kharidia, J.; Eddington, N. D. Effects of desethylamiodarone on the electrocardio-
gram in conscious feely moving animals: Pharmacokinetic and pharmacodynamic
modeling using computer-assisted radio telemetry. Biopharm. Drug Dispos. 1996,
17, 93–106.

3
376
A. N. Lucas et al.
7
8
9
. Pollak, P. T.; Sharma, A. D.; Carruthers, S. G. Correlation of amiodarone dosage,
heart rate, QT interval and corneal microdeposits with serum amiodarone and
desethylamiodarone concentrations. Am. J. Cardiol. 1989, 64, 1138–1143.
. Torres, V.; Tepper, D.; Flowers, D.; Wynn, I.; Lam, S.; Keefe, D.; Miura, D. S.;
Somberg, J. C. QT prolongation and the antiarrhythmic efficacy of amiodarone.
J. Am. Coll. Cardiol. 1986, 7, 142–147.
. Stark, G.; Stark, U.; Windisch, M.; Vicenzi, M.; Eggemeich, U.; Nagl, S.; Kral, K.;
Pilger, E.; Tritthart, H. A. Comparison of acute electrophysiological effects of
amiodarone and its metabolite desethylamiodarone in Langendorff perfused
guinea pig hearts. Basic Res. Cardiol. 1991, 86, 136–147.
1
0. Baerman, J. M.; Annesley, T.; DiCarlo, L. A., Jr.; Foley, M. K.; Nicklas, J. M.;
Crevey, B. J.; Morady, F. Interrelationships between serum levels of amiodarone,
desethylamiodarone, reverse t3 and the QT interval during long-term amiodarone
treatment. Am. Heart. J. 1986, 111, 644–648.
1
1. Burgess, C. D.; Siebers, R. W.; Purdie, G. L.; Taylor, C.; Maling, T. J. The
relationship between the QT interval and plasma amiodarone concentration in
patients on long-term therapy. Eur. J. Clin. Pharmacol. 1987, 33, 115–118.
2. Cubeddu, L. X. QT prolongation and fatal arrhythmias: A review of clinical impli-
cations and effects of drugs. Am. J. Ther. 2003, 10, 452–457.
1
1
3. Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau, M.; Malfroot, T. A new reagent for
the selective, high-yield n-dealkylation of tertiary-amines—improved syntheses of
naltrexone and nalbuphine. J. Org. Chem. 1984, 49, 2081–2082.
1
1
4. da Costa, G. G.; McDaniel-Hamilton, L. P.; Heflich, R. H.; Marques, M. M.;
Beland, F. A. DNA adduct formation and mutant induction in-Sprague-Dawley
rats treated with tamoxifen and its derivatives. Carcinogenesis 2001, 22,
1
5. Pelander, A.; Ojanpera, I.; Hare, T. A. Preparation of n-demethylated drug metab-
307–1315.
olites for analytical purposes using 1-chloroethyl chloroformate. Forensic Sci. Int.
1
997, 85, 193–198.
6. Hengeveld, J. E.; Gupta, A. K.; Kemp, A. H.; Thomas, A. V. Facile n-demethyla-
tion of erythromycins. Tetrahedron Lett. 1999, 40, 2497–2500.
7. Hong, Y. P.; Bakale, R. P.; Fang, Q. K.; Xiang, T. J.; McConville, F. X.;
Senanayake, C. H.; Wald, S. A. Synthesis of enantiomerically pure desmethylzo-
piclone and determination of its absolute configuration. Tetrahedron: Asymmetry
1
1
2
000, 11, 4623–4627.