A new and improved synthesis of bidisomide

Article abstract of DOI:10.1021/op010217t

Bidisomide, an antiarrhythmic and defibrillating agent, has been synthesized by a new approach. One of the key intermediates in this synthesis is 2-(N-isopropyl-N-allylamino)ethyl chloride. The distinct advantages of this new process over the existing one are described.

Full text of DOI:10.1021/op010217t

Organic Process Research & Development 2001, 5, 528−530
Technical Notes
A New and Improved Synthesis of Bidisomide
Alok K. Awasthi* and Kalidas Paul
DiscoVery Chemistry, Pharmacia Corporation, 4901 Searle Parkway, Skokie, Illinois 60077, U.S.A.
Scheme 1. Existing process
Abstract:
Bidisomide, an antiarrhythmic and defibrillating agent, has
been synthesized by a new approach. One of the key intermedi-
ates in this synthesis is 2-(N-isopropyl-N-allylamino)ethyl chlo-
ride. The distinct advantages of this new process over the
existing one are described.
Introduction
Bidisomide or (()-R-[2-[acetyl(1-methyl ethyl)amino]-
ethyl]-R-(2-chlorophenyl)-1-piperidinebutanamide is a new
antiarrhythmic and atrial defibrillating agent. Although
currently not in clinical trials, earlier animal and human
studies had indicated that bidisomide may be a promising
drug due to its therapeutic profile.1 This realization triggered
the development of several synthetic routes.1-4 The route
used to prepare development supplies is illustrated by
Scheme 1.
However, associated with this process were two major
flaws that were absolutely unacceptable from a large-scale
production point of view. The first problem was the N-benzyl
protection of 2-aminoethanol in step 1. This, despite exten-
sive efforts, involved an uncontrollable double hydrogenation
and 52 h of reaction time. The second major issue was the
palladium-catalyzed hydrogenation (step 6) to remove the
benzyl-protecting group. This was accompanied by a sig-
nificant amount of undesired deschloro product. Once the
dechlorination occurs, the product cannot be purified in any
known fashion to remove the deschloro impurity. This reality
reduced dramatically the probability of meeting product
specifications and increased the process cost. Thus, there was
a pressing need to design and reduce to practice a new
process for the synthesis of bidisomide, lacking the issues
encountered in the existing process. Replacing the benzyl-
protecting group by a functionality that did not require
hydrogenation for removal was critical to our success.
This report deals with a new synthesis of 1 which
completely eliminates the need of any hydrogenation.
Results and Discussion
Our initial approach involved the use of an allyl group
as an amino-protecting group5 and incorporated this into a
new synthetic route (Scheme 2).
This synthesis started with the condensation of allylbro-
mide (11) with 2-N-isopropylaminoethanol (10) to afford
2-N-isopropyl-N-allylaminoethanol (12) followed by chlo-
rination with thionyl chloride to produce 2-(N-isopropyl-N-
allylamino)ethyl chloride (13) in almost quantitative yield.
The common intermediate 6 in both syntheses was then
alkylated with 13 to produce 14. The cyano intermediate 14
was then hydrolyzed to amide 15. Deallylation of 15 was
then carried out using Wilkinson’s catalyst to generate the
second common intermediate 9. N-Acylation of secondary
amine (9) yielded racemic bidisomide (1).
(1) Desai, B. N.; Fowler, K. W.; Chorvat, R. J.; Frederick, L. G.; Hatley, F.
R.; Kurt, J. R.; Garthwaite, S. M. J. Med. Chem. 1988, 31, 2158.
(2) Desai, B. N.; Chorvat, R. J.; Rorig, K. J. U.S. Patents 4,639,524, 1987 and
5,097,035, 1992.
(3) Dygos, J. M.; Kowar, T. R.; McLaughlin, K. T.; Plume, G.; Prunier, M.
L.; Salzmann, R. J.; Scaros, M. G.; Wieczorek, J. J. Application: WO 94-
US9464 19940826, 1994.
Conclusions
In conclusion, the new and improved synthesis of bidi-
somide offers distinctive advantages over the published
synthesis. This employs mild reaction conditions. Replacing
the benzyl group by a different amino-protecting group that
(4) Kowar, T. R. Application: US 95-433622 19950503, 1998; 455,731,435,
1998.
(5) Moreau, B.; Lavielle, S.; Marquet, A. Tetrahedron Lett. 1977, 30, 2591.
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10.1021/op010217t CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 08/22/2001

Scheme 2
(d, 2H), 4.15 (m, 2H), 3.7 (m, 2H), 3.3 (m, 3H), 1.5 (dd,
6H); 13C NMR (CDCl3) δ 127.17, 125.08, 54.93, 53.71,
50.05, 37.08, 17.00, 16.17; IR (KBr) (cm-1) 3858, 2982,
1545; EI-MS 162 (M+). Anal. Calcd for C8H17Cl2N: C,
48.49; H, 8.65; N, 7.06; Cl, 35.80. Found: C, 47.76; H, 8.74;
N, 7.06; Cl, 35.78.
Preparation of (()-r-(2-Chlorophenyl)-r-[2-[(-methyl-
ethyl)(allyl) amino]ethyl]-1-piperidinebutanenitrile (14).
To a round-bottom flask under argon atmosphere was added
sequentially DMSO (48.3 mL, 0.561 mol), powdered anhy-
drous KOH (31.78 g, 0.566 mol), (()-R-(2-chlorophenyl)-
1-piperidinebutanenitrile (6) (26.8 g, 0.102 mol), and DMSO
(10 mL). A solution of 2-(N-isopropyl-N-allylamino)ethyl
chloride hydrochloride (13) (22.0 g, 0.111 mol) in DMSO
(18 mL) was then added to the above reaction mixture by
maintaining the reaction temperature below 20 °C. This
mixture was then stirred for 10 h at 25 °C and then poured
in to a cold stirred mixture of heptane (60 mL) and water
(100 mL). The flask was rinsed with water (100 mL) and
heptane (60 mL), and both rinses and the reaction mixture
were combined. The layers were separated and the organic
layer was filtered through Celite (2 g). The filter cake was
washed with heptane (40 mL), and the wash was combined
with the organic phase. The combined organic phase was
then washed with water (2 × 50 mL) and dried over
anhydrous MgSO4 for 1 h, filtered, and concentrated to give
the crude product as a yellow oil (30 g, 76% yield). 1H NMR
(CDCl3) δ 7.7 (dd, 1H), 7.4 (dd, 1H), 7.25 (m, 2H), 5.7 (m,
1H), 5.15 (dd, 2H), 3.0 (d, 2H), 2.9-2.5 (m, 5H), 2.4-2.0
(m, 8H), 1.6-1.2 (m, 6H), 0.9 (dd, 6H); 13C NMR (CDCl3)
δ 137.24, 132.39,131.97, 131.17, 129.11, 126.98, 122.33,
116.28, 55.20, 54.61, 53.76, 50.61, 45.65, 36.46, 34.22,
25.82, 24.20, 18.32, 18.19; IR (KBr) (cm-1) 2980, 2240; EI-
MS 388 (M+). Anal. Calcd for C23H34ClN3‚0.5H2O: C,
69.58; H, 8.89; N, 10.58; Cl, 8.93. Found: C, 70.00; H, 9.45;
N, 10.53; Cl, 8.87.
eliminates the need for three hydrogenations significantly
reduces batch cycle times. Towards the end, all of this and
catalytic deallylation, probably via isomerization, offers
potential cost savings and purity advantages.
Experimental Section
All chemicals were reagent grade and used as purchased.
Compound 6 was procured from the Chemical Sciences
department of Searle. All reactions were performed under
an inert atmosphere of dry nitrogen, using distilled dry
1
solvents unless otherwise stated. H and 13C NMR spectra
were obtained on a Varian INOVA-400 instrument. Elemen-
tal analyses were determined by E. Zielinski and associates
in the Physical Methodology department of our company.
HPLC analysis was carried out by the group of J. Wysocki.
Preparation of 2-N-Isopropyl-N-allylaminoethanol (12).
2-(Isopropylamino)ethanol (34.94 g, 0.3 mol) was taken up
in dry CH2Cl2 (100 mL). To this solution triethylamine (44.60
mL, 0.32 mol) and allyl bromide (25.96 mL, 0.3 mol) were
added, and the reaction mixture was stirred at 25 °C. After
2 h of stirring, a saturated solution of NaHCO3 was added
to the reaction mixture. The CH2Cl2 layer was separated,
washed with 2 × 50 mL of water, dried over MgSO4, and
filtered. Evaporation of the CH2Cl2 gave the product as an
Preparation of (()-r-(2-Chlorophenyl)-r-[2-[(-methyl-
ethyl)(allyl)amino]-ethyl]-1-piperidinebutaneamide (15).
To a round-bottom flask under argon was added (()-R-(2-
chlorophenyl)-R-[2-[(-methyl-ethyl)(allyl)amino]ethyl]-1-pi-
peridinebutanenitrile (7) (10.0 g, 0.026 mol) followed by the
cautious addition of concentrated H2SO4 (15 mL). The
reaction mixture was stirred at 85 to 90 °C for 3 h and then
slowly poured into a stirred mixture of water (42 mL) and
toluene (50 mL). The flask was rinsed with water (20 mL),
and this wash was combined with the reaction mixture.
Aqueous NaOH (29 mL, 50 wt %) was then added to the
above reaction mixture, maintained between 35 and 40 °C
to bring the pH to 12. The reaction mixture was then warmed
to 45 °C for 15 min, and the layers were separated. The
aqueous phase was washed with toluene (2 × 15 mL), and
the toluene wash was combined with the organic phase. This
solution was dried over anhydrous Na2SO4 (4.0 g), filtered
through Celite (2.0 g), and concentrated to give the crude
product as a brown oil (9.56 g, 90% yield). 1H NMR (CDCl3)
δ 7.47 (d, 1H), 7.34 (d, 1H), 7.25 (m, 2H), 6.3 (bs, 1H), 5.8
(m, 1H), 5.3 (bs, 1H), 5.05 (dd, 2H), 3.0 (d, 2H), 2.9 (m,
1
oil (22.0 g, 51% yield). H NMR (CDCl3) δ 5.8 (m, 1H),
5.15 (m, 2H), 3.5 (t, 2H), 3.15 (d, 2H), 3.05 (m, 1H), 2.6 (t,
2H), 1.0 (d, 6H).
In further optimization of this procedure, 2-(isopropy-
lamino)ethanol was alkylated with allyl bromide in THF for
1 h to afford the desired product in 97% yield with >97%
GC purity.
Preparation of 2-(N-Isopropyl-N-allylamino)ethyl Chlo-
ride Hydrochloride (13). 2-N-Isopropyl-N-allylaminoethanol
(12) (22.0 g, 0.155 mol) was taken up in CH2Cl2 (50 mL).
To this was added a solution of SOCl2 (15 mL) in CH2Cl2
(50 mL), and the reaction temperature was maintained
between 5 and 10 °C. After the addition was complete, the
reaction mixture was stirred at 20 to 22 °C for 1 h and then
concentrated on a rotary evaporator. The residue was taken
up in CH2Cl2 (100 mL) and again concentrated to completely
remove the SOCl2. The so-obtained residue was taken up in
acetone (300 mL), filtered, and dried to afford the product
(30.0 g, 97% yield). 1H NMR (CDCl3) δ 6.35 (m, 1H), 5.55
1H), 2.5-2.7 (m, 12H), 1.6-1.2 (m, 6H), 0.9 (dd, 6H); 13
NMR (CDCl3) δ 175.95, 138.88, 137.37, 134.48, 131.48,
C
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129.54, 128.41, 126.73, 116.30, 54.80, 54.72, 54.71, 53.67,
50.56, 44.85, 32.66, 30.43, 25.82, 24.30, 18.33, 18.21; IR
(KBr) (cm-1) 2980, 1680; EI-MS 406 (M+). Anal. Calcd
for C23H36ClN3O: C, 68.04; H, 8.94; N, 10.35; Cl, 8.73.
Found: C, 68.34; H, 10.11; N, 9.46; Cl, 8.12.
C20H32ClN3O‚0.5 H2O: C, 64.07; H, 8.87; N, 11.21; Cl, 8.46.
Found: C, 64.14; H, 8.38; N, 10.44; Cl, 9.65.
Preparation of (()-r-[2-[Acetyl(1-methylethyl)amino]-
ethyl]-r-(2-chlorophenyl)-1-piperidinebutaneamide (1) or
(Bidisomide). To a round-bottom flask under argon were
added (()-R-(2-chlorophenyl)-R-[2-[(-methyl-ethyl) amino]-
ethyl]-1-piperidinebutaneamide (1.83 g, 0.005 mol), ethyl
acetate (15 mL), and acetic anhydride (2 mL, 0.02 mol). The
reaction mixture was stirred at 25 °C for 6 h and then diluted
with water (10 mL). The ethyl acetate was removed under
removed pressure, and a solution of K2CO3 (2.5 g) in water
(10 mL) was added to the residue. It was then extracted with
ethyl acetate (3 × 35 mL), and the combined extracts were
dried over anhydrous Na2SO4 (4.0 g) and filtered through
Celite (2.0 g). Evaporation of the ethyl acetate gave the
product as an off-white solid (1.8 g, 88% yield). NMR and
HPLC of the product were identical to those of an authentic
sample of bidisomide. 1H NMR (CDCl3) δ 7.9-7.1 (m, 4H),
3.9 (m, 1H), 2.2 and 1.9 (2 s, 3H), 1.1 (d, 6H); ES-MS 408
(M + H).
Preparation of (()-r-(2-Chlorophenyl)-r-[2-[-(methyl-
ethyl) amino]ethyl]-1-piperidinebutaneamide (9). To a
round-bottom flask under argon were added (()-R-(2-
chlorophenyl)-R-[2-[(-methyl-ethyl)(allyl)amino]ethyl]-1-pi-
peridinebutaneamide (15) (5.88 g, 0.0145 mol), DABCO
(337 mg, 0.003 mol), rhodiumtriphenylphosphine chloride
(925 mg, 0.001 mol), and 10% aqueous ethanol (40 mL).
The reaction mixture was heated at reflux temperature for 5
h and cooled. Ethanol (∼20 mL) was then evaporated, and
water (100 mL) was added. Reaction mixture was extracted
with diethyl ether (3 × 100 mL), and the combined ether
layers were washed with brine (2 × 20 mL) and 1 N HCl
(15 mL). It was then dried over anhydrous MgSO4, filtered,
and evaporated to give a yellow solid. This solid was
recrystallized with 50% ethyl acetate in heptane to give the
desired product (2.5 g, 47% yield). 1H NMR (CDCl3) δ 7.75
(m, 1H), 7.47 (d, 1H), 7.35 (d, 1H), 7.25 (m, 2H), 6.3 (bs,
1H), 5.3 (bs, 1H), 2.8 (m, 1H), 2.5-2.7 (m, 12H), 1.6-1.2
(m, 6H), 1.0 (dd, 6H); 13C NMR (CDCl3) δ 177.02, 139.55,
134.27, 131.58, 129.35, 128.87, 126.33, 54.70, 54.69, 48.65,
42.87, 34.70, 30.47, 25.90, 24.25, 22.77, 22.51; IR (KBr)
(cm-1) 3500, 2980, 1690; EI-MS 366 (M+). Anal. Calcd for
Acknowledgment
We thank Dr. Donald W. Hansen, Jr., Dr. Ashok Narain,
and Mr. Bipin N. Desai.
Received for review May 14, 2001.
OP010217T
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