A scalable synthesis of a histamine H3 receptor antagonist

Article abstract of DOI:10.1021/jo040225i

Starting from 1-methylimidazole, a concise, scalable, three-step synthesis of the title compound is described. The required 2-chloroimidazole was prepared in very good yield by halogen-metal exchange between the 2-lithio derivative and hexachloroethane.

Full text of DOI:10.1021/jo040225i

SCHEME 1
A Scalable Synthesis of a Histamine H3
Receptor Antagonist
Neelakandha S. Mani,* Jill A. Jablonowski, and
Todd K. Jones
Department of Drug Discovery, Johnson & Johnson
Pharmaceutical Research and Development, L.L.C.,
3210 Merryfield Row, San Diego, California 92121
nmani@prdus.jnj.com
Received June 28, 2004
Abstract: Starting from 1-methylimidazole, a concise,
scalable, three-step synthesis of the title compound is
described. The required 2-chloroimidazole was prepared in
very good yield by halogen-metal exchange between the
2-lithio derivative and hexachloroethane.
The third histamine (H3) receptor was first described
as a presynaptic autoreceptor located in the central
nervous system.1 Subsequently, H3 receptors were also
shown to be located presynaptically as heteroreceptors
on nonhistamine-containing neurons.2 A number of po-
tential therapies for disorders associated with sleep-
wake cycle, cognition, memory, food intake, and thermo-
regulation using modulators of H3 receptors have been
proposed on the basis of animal pharmacology experi-
ments. The successful cloning of the human histamine
H3 receptor3 led to an intensive medicinal chemistry effort
in this area, and a number of novel H3 antagonists have
been identified in our laboratories. Compound 1 was
identified as one of the most promising among a number
of potent H3 antagonists for further pharmacological
evaluation.4 Toward this purpose, multigram quantities
of 1 were needed. Our initial laboratory synthesis ap-
peared to be unsuited for this purpose. As outlined in
the Scheme 1, it involved a six-step synthetic sequence
including reagents undesirable for large-scale work,
hazardous reaction conditions, and chromatographic
purifications. Herein we describe a shorter, more ef-
ficient, and scalable synthesis of 1.
SCHEME 2
and oxidation steps, the thiol moiety at the C-2 position
was then transformed to a reactive propylsulfonyl leaving
group, which underwent nucleophilic substitution with
(1-isopropylpiperiden-4-yl)methanol (7) to furnish the
final product.
In the scale-up synthesis, our strategy relied on regio-
selective metalation of an imidazole to install the 4-
chlorobenzoyl group at the C-5 position. Since metalation
at C-5 requires masking the C-2 position of the imidazole,
our concept was to employ a suitable group that not only
blocked the C-2 position during the metalation at C-5 but
also functioned as a reactive leaving group in a nucleo-
philic substitution reaction directly in the next step as
depicted in Scheme 2. Among the halogens, chlorine and
fluorine were considered to play this dual role since they
are most likely to be stable to metalating reagents such
as n-butyllithium.6 Chlorine appeared most suitable, due
The discovery synthesis started from N-methylimid-
azole-2-thiol and employed a selective metalation strat-
egy5 to install the required 4-chlorobenzoyl group at the
C-5 position (Scheme 1). Through a sequence of alkylation
(1) Arrang, J.-M.; Garbarg, M.; Schwartz, J.-C. Nature 1983 302,
832-836.
(2) The Histamine H3 Receptor; Leurs, R., Timmerman, H., Eds.;
Elsevier: Amsterdam, 1998.
(3) Lovenberg, T. W.; Roland, B. L.; Wilson, S. J.; Jiang, X.; Pyati,
J.; Huvar, A.; Jackson, M. R.; Erlander, M. G. Mol. Pharmacol. 1999,
55, 1101-1107.
(4) Bogenstaetter, M.; Carruthers, N. I.; Lovenberg, T. W.; Ly, K.
S.; Jablonowski, J. A. WO 2002079168, 2002; Chem. Abstr. 2002, 137,
279192.
(5) Comprehensive Heterocyclic Chemistry II; Shinkai, I., Eds.;
Pergamon: New York, 1996; Vol. 3, pp 136-138 and references therein.
(6) Gilman, H.; Moore, F. W. J. Am. Chem. Soc. 1940, 62, 1843-
1846.
10.1021/jo040225i CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/19/2004
J. Org. Chem. 2004, 69, 8115-8117
8115

SCHEME 3
SCHEME 4
TABLE 1. Preparation of
2-Chloro-1-methyl-1H-imidazole (11)
chlorine source
solvent
T (°C)
yield (%)
CCl3COCl
Cl2
THF
THF
THF
THF
-78
0
-78
-78
20
10
38
80
CCl4
C2Cl6
sodium salt of 4-piperidinylmethanol 711 proceeded
smoothly to furnish the free base of 1 in 78% yield
(Scheme 4).
to the ease of its introduction, particularly when required
in large scale. In addition, use of chlorine as a protecting
group at C-2 during lithiation at C-5 of some imidazole
derivatives has been reported.7,8c Thus, 2-chloro-1-methyl-
imidazole was chosen as the key synthon for preparing
1 and related analogues.
In conclusion, we have developed a concise, three-step
synthesis of 1 starting from 1-methylimidazole. Consist-
ently good to excellent yields were obtained in all steps,
and all the intermediates were purified by distillation
and/or crystallization. Use of a 2-chloroimidazole deriva-
tive, in which the chlorine plays a dual rolesblocking the
C-2 position during metalation and reacting as a leaving
group in subsequent stepsas illustrated in our synthesis,
provides a unique and general strategy to a range of
substituted imidazoles.
Preparation of 2-chloroimidazole derivatives has been
reported.8 The most efficient method appeared to be
lithiation of N-methylimidazole and reaction of the
2-lithio derivative with a positive halogen source (Scheme
3). The reported procedures using trichloroacetyl chloride
and carbon tetrachloride8b,c gave moderate yields (30-
40%) of the required 2-chloro derivative in our hands
(Table 1). In addition, these reagents posed significant
difficulties for large-scale preparations. Both trichloro-
acetyl chloride and CCl4 generated highly reactive inter-
mediates (dichloroketene and dichlorocarbene, respec-
tively), which decomposed under the reaction and workup
conditions and made isolation very difficult. Hexachlo-
roethane, readily available and inexpensive, proved a
more useful chlorine source for the halogen-metal
exchange reaction. Tetrachloroethylene, the byproduct
formed during the reaction, was quite stable to the
reaction and workup conditions and was easily removed
by distillation (bp 121 °C).
Thus, treatment of N-methylimidazole with n-butyl-
lithium generated the 2-lithio derivative, which on
quenching with hexachloroethane gave the 2-chloro
derivative in very good yield as a colorless liquid.
Introduction of the 4-chlorobenzoyl substituent at C-5
by regioselective lithiation strategy also worked ef-
ficiently. Thus, treatment of 2-chloro derivative 11 with
n-butyllithium generated the 5-lithio derivative, which
on treatment with Weinreb amide 129 furnished the
desired 4-chlorobenzoyl analogue 13 in excellent overall
yield as a crystalline solid. Nucleophilic substitution10 of
the activated 2-chloro-5-benzoylimidazole 13 with the
Experimental Section
Preparation of 2-Chloro-1-methyl-1H-imidazole (11). To
a 300-mL, three-necked, round-bottomed flask equipped with a
magnetic stirrer and nitrogen inlet were added N-methyl-
imidazole (4.1 g, 0.05 mol) and anhydrous THF (25 mL). The
stirrer was started, and the solution was cooled to -78 °C.
n-BuLi (2.5 M in hexanes, 22 mL, 0.055 mol) was added via
syringe resulting in a golden yellow solution. This solution was
stirred for 30 min whereupon a solution of hexachloroethane (13
g, 0.055 mol) in THF (25 mL) was added dropwise via syringe.
The reaction mixture was stirred for 1 h and then quenched with
saturated aqueous ammonium chloride (25 mL). The cooling bath
was removed, and when the reaction flask reached room tem-
perature the contents were transferred to a 500 mL separatory
funnel, washing with ethyl acetate (150 mL). The organic layer
was separated, washed with water and brine, and dried over
anhydrous sodium sulfate. After filtration, the solvents were
evaporated under reduced pressure resulting in an oily residue.
This crude product was distilled under reduced pressure to afford
2-chloro-1-methyl-1H-imdazole (4.75 g, 80%) as a colorless liquid,
bp 136 °C/5 Torr. Purity was determined to be 97.3% by GC
analysis (HP-5MS 30 m × 0.25 mm × 0.25 µm column; oven
temperature 55 °C; ramp 10 °C/min; final temperature 270 °C;
mass selective detector; retention time 5.6 min). IR (film): 1515,
1
1420, 1367, 1277, 1127, 912, 740, 689, 665 cm-1. H NMR (400
MHz, CDCl3): δ 6.93 (d, J ) 1.6 Hz, 1 H), 6.89 (d, J ) 1.6 Hz,
1 H), 3.55 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 132.2, 127.9,
121.8, 33.1. HRMS (EI): m/z calcd for C4H6ClN2 [M + H]+
117.0223, found 117.0220.
(7) (a) Suzuki, M.; Tanaka, H.; Miyasaka, T. Chem. Pharm. Bull.
1987, 35, 4056-4063. (b) Tanaka, H.; Hirayama, M.; Suzuki, M.;
Miyasaka, T.; Matsuda, A.; Ueda, T. Tetrahedron 1986, 42, 1971-1980.
(c) Eriksen, B. L.; Vedsø, P.; Begtrup, M. J. Org. Chem. 2001, 66, 8344-
8348.
(8) (a) Imbach, J. L.; Jacquier, R.; Romane, A. J. Heterocycl. Chem.
1967, 4, 451-454. (b) Boga, C.; Del Vecchio, E.; Forlani, L.; Milanesi,
L.; Todesco, P. E. J. Organomet. Chem. 1999, 588, 155-159. (c) Boga,
C.; Del Vecchio, E.; Forlani, L.; Todesco, P. E. J. Organomet. Chem.
2000, 601, 233-236.
(9) Piotrowski, D. W. Synlett 1999, 7, 1091-1093.
(10) Jarosinski, M. A.; Anderson, W. K. J. Org. Chem. 1991, 56,
4058-4062.
Preparation of 4-Chloro-N-methoxy-N-methylbenz-
amide (12). A 1-L, three-necked, round-bottomed flask equipped
with a magnetic stirrer, a nitrogen inlet, and an addition funnel
was charged with N,O-dimethylhydroxylamine hydrochloride (20
g, 0.20 mol) and dichloromethane (250 mL). The mixture was
cooled to 0 °C, and triethylamine (24 g, 0.20 mol) was added,
followed by a solution of 4-chlorobenzoyl chloride (35.8 g, 0.2
(11) Compound 7 was prepared by treating 4-piperidenemethanol
with acetone and sodium triacetoxyborohydride. For detailed experi-
mental procedures, see the Supporting Information.
8116 J. Org. Chem., Vol. 69, No. 23, 2004

mol) in dichloromethane (100 mL). After the addition was
complete, the cooling bath was removed, and the reaction was
allowed to warm to room temperature and was stirred overnight.
The reaction mixture was quenched with saturated aqueous
ammonium chloride (200 mL). The mixture was transferred to
a separatory funnel, the layers were separated, and the aqueous
layer was extracted with dichloromethane (200 mL). The com-
bined organic layers were washed with aqueous sodium bicar-
bonate and brine and then dried over anhydrous magnesium
sulfate. After filtration, the solvents were evaporated under
reduced pressure to afford the benzamide 12 (37 g, 92%) as a
colorless oil. IR (film): 2935, 1639, 1593, 1460, 1415, 1212, 1090,
every 4-8 h. After 36 h, the reaction was judged complete. The
reaction mixture was cooled to room temperature, poured into
ice-cold water, and extracted with ethyl acetate (2 × 250 mL).
The combined organic extracts were dried over anhydrous
sodium sulfate, filtered, and evaporated under reduced pressure
to provide the crude material as a brown solid. Recrystallization
from ethyl acetate afforded the desired product (17.5 g, 78%) as
a white crystalline solid. Mp: 126-127 °C. IR (film): 2963, 1615,
1585, 1529, 1481, 1362, 1287, 1213, 1173, 1104, 1020, 897,846,
1
727, 698 cm-1. H NMR (400 MHz, CDCl3): δ 7.67 (d, J ) 8.6
Hz, 2 H), 7.38 (d, J ) 8.6 Hz, 2 H), 7.13 (s, 1 H), 4.22 (d, J ) 6.0
Hz), 3.68 (s, 3 H), 2.84 (m, 2 H), 2.61 (m, 1 H), 2.09 (m, 2 H),
1.74 (m, 3 H), 1.30 (m, 2 H), 0.97 (d, J ) 6.5 Hz, 6 H). 13C NMR
(100 MHz, CDCl3): δ 183.4, 157.0, 138.3, 138.2, 137.3, 130.2,
128.7, 127.1, 74.9, 54.6, 48.4, 35.9, 30.7, 29.1, 18.3. HRMS (EI):
m/z calcd for C20H27ClN3O2 [M + H]+ 376.1792, found 376.1801.
Anal. Calcd for C20H26ClN3O2: C, 63.91; H, 6.97; N, 11.17.
Found: C, 63.55; H, 6.77; N, 11.05.
1015, 887, 838, 747, 730 cm-1 1H NMR (400 MHz, CDCl3): δ
.
7.58 (d, J ) 8.6 Hz, 2 H), 7.32 (d, J ) 8.6 Hz, 2 H), 3.55 (s, 3 H),
3.11 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 169.2, 137.3, 132.9,
130.5, 128.8, 61.7, 34.1. HRMS (EI): m/z calcd for C9H11ClNO2
[M + H]+ 200.0478, found 200.0484.
(2-Chloro-3-methyl-3H-imidazol-4-yl)(4-chlorophenyl)-
methanone (13). To a 1-L, three-necked, round-bottomed flask
equipped with a magnetic stirrer, a nitrogen inlet, and an
addition funnel were added 2-chloro-1-methyl-1H-imidazole (15
g, 0.128 mol) and THF (250 mL). The reaction mixture was
cooled to -78 °C, and n-BuLi (2.5 M in hexanes, 54 mL, 0.135
mol) was added. The pale yellow suspension that formed was
stirred for 1 h, and a solution of 4-chloro-N-methoxy-N-methyl-
benzamide (27 g, 0.135 mol) in THF (50 mL) was then added
dropwise. After the addition was complete, the cooling bath was
removed, and the reaction was allowed to warm to room
temperature. The reaction mixture was quenched with saturated
aqueous ammonium chloride (150 mL), transferred to a sepa-
ratory funnel, and extracted with ethyl acetate (1.5 L). The
organic layer was washed with water, brine and dried over
anhydrous sodium sulfate. After filtration, the solvents were
evaporated under reduced pressure to yield the product as a
crystalline solid. Recrystallization from ethyl acetate-hexanes
afforded the desired ketone (31.2 g, 97%) as a white crystalline
solid. Mp: 173-174 °C. IR (film): 1639, 1589, 1517, 1395, 1377,
(4-Chlorophenyl)-[2-(1-isopropylpiperidin-4-ylmethoxy)-
3-methyl-3H-imidazol-4-yl]methanone (1) Maleate Salt. A
500-mL, three-necked, round-bottomed flask equipped with a
magnetic stirrer, nitrogen inlet, reflux condenser, and an addi-
tion funnel was charged with (4-chlorophenyl)[2-(1-isopropyl-
piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]methanone
(15.4 g, 40.96 mol), ethanol (170 mL), and maleic acid (4.75 g,
40.96 mol). The mixture was heated on a heating mantle at 70-
75 °C until a clear solution was obtained. The heat source was
removed, and the reaction mixture was cooled to room temper-
ature. The solution was transferred to a 2-L beaker, washing
with 25 mL of ethanol. The solution was diluted with 750 mL of
ether with vigorous stirring. The white precipitate that formed
was filtered and dried in vacuo to afford the maleate salt as a
white powder. Recrystallization from water afforded the maleate
salt (18.8 g, 93%) as colorless needles. Mp: 161-162 °C. IR
(film): 2963, 1625, 1586, 1532, 1466, 1361, 1257, 1172,1087,
1025, 956, 757, 698 cm-1 1H NMR (400 MHz, CDCl3): δ 7.71
.
(d, J ) 8.6 Hz, 2 H), 7.43 (d, J ) 8.6 Hz, 2 H), 7.17 (s, 1 H), 6.27
(s, 2 H), 4.36 (d, J ) 6.0 Hz, 2 H), 3.73 (s, 3 H), 3.53 (m, 3 H),
2.74 (bt, J ) 11.6 Hz, 2 H), 2.24-1.92 (m, 5 H), 1.34 (d, J ) 6.8
Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ 183.9, 169.7, 156.6,
138.8, 138.2, 137.5, 136.0, 130.6, 129.1, 127.7, 73.2, 57.9, 48.3,
34.4, 31.1, 26.0, 17.0. Anal. Calcd for C24H30ClN3O6: C, 58.21;
H, 6.07; N, 8.35. Found: C, 58.6; H, 6.07; N, 8.35.
1253, 1186, 902, 841, 756, 738, 695, 676 cm-1 1H NMR (400
.
MHz, CDCl3): δ 7.78 (d, J ) 8.6 Hz, 2 H), 7.44 (s, 1 H), 7.44 (d,
J ) 8.6 Hz, 2 H), 3.97 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ
183.3, 140.3, 139.5, 139.2, 136.3, 131.2, 130.4, 128.9, 33.5. HRMS
(EI): m/z calcd for C11H9Cl2N2O [M + H]+ 255.0092, found
255.0104. Anal. Calcd for C11H8Cl2N2O: C, 51.8; H, 3.06; N,
10.93. Found: C, 52.08; H, 3.16; N, 10.90.
(4-Chlorophenyl)-[2-(1-isopropylpiperidin-4-ylmethoxy)-
3-methyl-3H-imidazol-4-yl]methanone (1). To a 1-L, three-
necked, round-bottomed flask equipped with a magnetic stirrer,
nitrogen inlet, and an addition funnel were added NaH (1.45 g,
0.061 mol) and THF (300 mL). The stirred suspension was cooled
to 0 °C, and (1-isopropylpiperidin-4-yl)methanol (9.5 g 0.06 mol)
was added. The cooling bath was removed and the reaction
mixture warmed to room temperature. After 2 h, a solution of
(2-chloro-3-methyl-3H-imidazol-4-yl)(4-chloro-phenyl)metha-
none (15.56 g, 0.061 mol) in dry THF (100 mL) was added. The
reaction mixture was stirred at 60 °C and monitored by HPLC
Acknowledgment. We thank Dr. Jiejun Wu and
Heather McAllister for Mass Spectra, and Dr. Scott E.
Denmark for useful discussions.
Supporting Information Available: General experimen-
tal methods, experimental details for the preparation of 7, and
copies of 1H and 13C NMR spectra for compounds 1, 7, 11, 12,
and 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO040225I
J. Org. Chem, Vol. 69, No. 23, 2004 8117