Effective preparation of cycloheptimidazol-4-one compounds

Article abstract of DOI:10.1248/cpb.54.703

Effective preparation of cycloheptimidazol-4-ones was developed. The reactions of 2-tosyloxytropone (5) with amidines (6) carried out under simple conditions such as aq. NaOH in toluene at 35°C afforded the corresponding cycloheptimidazol-4-ones (3) in low yield. However, by adding tetra-n-butylammonium bromide (n-Bu₄NBr) to this reaction system, the yield was improved dramatically. The reaction conditions were screened in detail.

Full text of DOI:10.1248/cpb.54.703

May 2006
Notes
Chem. Pharm. Bull. 54(5) 703—705 (2006)
703
Effective Preparation of Cycloheptimidazol-4-one Compounds
Motoharu SONEGAWA,* Yoshinori IWAI, Hiroshi TOMIYAMA, and Tsuyoshi TOMIYAMA
Kotobuki Research Laboratories, Kotobuki Seiyaku Company, Ltd.; 6351 Sakaki-Machi, Nagano 389–0697, Japan.
Received October 29, 2005; accepted February 2, 2006; published online February 7, 2006
Effective preparation of cycloheptimidazol-4-ones was developed. The reactions of 2-tosyloxytropone (5)
with amidines (6) carried out under simple conditions such as aq. NaOH in toluene at 35 °C afforded the corre-
sponding cycloheptimidazol-4-ones (3) in low yield. However, by adding tetra-n-butylammonium bromide (n-
Bu4NBr) to this reaction system, the yield was improved dramatically. The reaction conditions were screened in
detail.
Key words cycloheptimidazolone; phase transfer catalyst (PTC); angiotensin II
The renin-angiotensin system (RAS) plays a critical role in 3).5) It seems that in this homogeneous reaction system hy-
blood pressure control.1) Angiotensin II (AII), the active hor- drolysis of the substrates occurs. Therefore, the yield was not
mone generated in RAS, shows a potent vasoconstrictive ef- always satisfactory. Another problem in the industrial-scale
fect which is thought to be the etiology of hypertension and manufacture would be not only how to achieve easy recovery
congestive heart failure. Blocking the action of AII at the AII of the solvents, but also to avoid highly inflammable opera-
receptor level is a more effective approach and considerable tion. In order to prevent the hydrolysis and to use recoverable
effort has been made in the search for nonpeptide AII recep- solvents, biphasic reaction conditions were examined. The
tor antagonists in recent years.
cyclization of 2-tosyloxytropone with amidine in the combi-
We have recently described the identification of Pratosar- nation of aq. NaOH and toluene provided cycloheptimidazol-
tan and KT3-866, which are orally active, competitive AII re- 4-one in only 16% yield (Table 1). The details of the reaction
ceptor antagonists.2,3) Tellew et al. have reported that com- conditions were examined because better yield was obtained
pound (1) acts as a dual antagonist both of AII and endothe- when phase transfer catalyst (tetra-n-butylammonium bro-
lin subtype A (ETA).4) These antagonists include a 5,6,7,8- mide (n-Bu4NBr)) was added to this reaction mixture.
tetrahydrocycloheptimidazole skeleton (2) as a major compo-
nent (Chart 1). Therefore, 5,6,7,8-tetrahydrocycloheptimida- Results and Discussion
zole is considered to be a biologically important molecular
In the first step of examination of reaction conditions, in-
part. 5,6,7,8-Tetrahydrocycloheptimidazol-4-one (4), in the fluence of the aqueous alkaline solution in order to decrease
case of XꢀO in the skeleton (2), could be easily obtained the formation of different products was checked (Table 2).6,7)
from cycloheptimidazol-4-one (3) by partial hydrogenation By changing the base concentration with the constant equiva-
(Chart 2).
lent of the base against 5a, the best yield was observed in the
Cycloheptimidazol-4-one compound (3a) has been hith- use of 30% aqueous NaOH solution. NaOH showed the most
erto prepared by the treatment of 2-tosyloxytropone (5a) efficacy among alkali hydroxides under these conditions.
with acetamidine under alkaline reaction condition (Chart
In the second step, reaction temperature was tested be-
cause it could be an important factor to control the produc-
Chart 3. Preparation of 2-Methyl-3H-cycloheptimidazol-4-one (3a) in aq.
NaOH/1,4-Dioxane
Table 1. Reaction of n-Butyramidine (6c) with Tosyloxytropone (5a)
Chart 1. Structure of Biological Active Tetrahydrocycloheptimidazole
Analogs
Yielda)
(%)
Entry
Reaction conditions
1
2
20% aq. NaOH, toluene, 30 °C, 9 h
20% aq. NaOH, n-Bu4NBr (0.4 eq), toluene, 20 °C, 18 h
16
53
Chart 2. Preparation of Tetrahydrocycloheptimidazol-4-one (4)
a) Isolated yield of the compound (3c).2)
∗ To whom correspondence should be addressed. e-mail: ktb-g121@kotobuki-pharm.co.jp
© 2006 Pharmaceutical Society of Japan

704
Vol. 54, No. 5
Table 2. Effect of Concentration of Aqueous Alkaline Solution
Table 4. Effect of Phase Transfer Catalyst
Reaction time
(h)
Yielda)
(%)
Yielda)
(%)
Entry
Base
Phase transfer
catalyst (PTC)
Reaction time
Entry
(h)
1
2
3
4
5
6
7
10% aq. NaOH
20% aq. NaOH
30% aq. NaOH
40% aq. NaOH
50% aq. NaOH
30% aq. KOH
30% aq. LiOH
24
18
10
8
5
10
12
25
53
72
68
62
64
65
1
2
3
4
5
6
n-Bu4NCl
n-Bu4NBr
n-Bu4NI
n-Et4NBr
n-Pr4NBr
n-Hex4NBr
5
5
5
40
8
1
80
82
74
52
69
b)
—
a) Isolated yield of the compound (3c)2). b) Mixture with n-Hex4NBr was ob-
tained.
a) Isolated yield of the compound (3c)2).
Table 3. Effect of Reaction Temperature
Table 5. Reaction of Amidines (6) with 2-Tosyloxytropones (5)
Temp.
(°C)
Reaction time
(h)
Yielda)
(%)
Entry
6c equiv. vs. 5a
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
20
30
40
50
20
30
40
50
8
8
8
8
5
5
5
5
57
62
61
50
72
82
76
65
Compd.
R1
R2
Yielda) (%)
3a5)
3b2)
3d
H
H
H
H
H
H
6-iPr
7-iPr
Me
Et
i-Pr
Bu
i-Bu
Ph
72
77
80
81
80
81
74
75
3e2)
3f
3g5)
3h
a) Isolated yield of the compound (3c)2).
Pr
Pr
3i
a) Isolated yield of the compound (3).
tion of 3c and decomposition of substrates (Table 3). The
highest yield was observed at 30 °C in the range of 20—
50 °C. In addition, the use of 1.5 eq of the amidine (6c) re-
sulted in better yield.
Next, the effectiveness of several kinds of phase transfer
catalyst was examined (Table 4). A similar yield was ob-
tained in the phase transfer catalyst that consists of a butyl
group. However, when a tetra-n-hexylammonium bromide
(n-Hex4NBr) was used, the accurate isolation yield was not one
obtained because the n-Hex4NBr was contaminated into the
products. When 0.2 eq of the phase transfer catalyst was used
in this reaction, prolonged reaction time was required.
Chart 4. Reaction Mechanism for the Formation of Cycloheptimidazol-4-
liberated from the reaction8) and besides, a small amount of
Various kinds of amidines were treated with 2-tosyloxytro- 5-isopropylcycloheptimidazole as a by-product was obtained.
pone (5a) and butyramidine was reacted with 2-tosyloxytro- From these results, it could be considered that the cyclization
pones (5b or 5c) under optimized reaction conditions (Table occurs after an anion of amidine attacks at the 7-position of
5). The reactions with acetamidine or propionamidine af- tosyloxytropone and then followed by the cleavage of the
forded the corresponding products in modest yields. In con- O–S bond takes place preferentially similar to the formation
trast, use of benzamidine and pentanamidine resulted in even of 2-amino-3-carbamoylcyclohepta[b]furan-8-one.9)
higher yields. This would be considered due to the lipophilic-
Regioselective alkylation to cycloheptimidazol-4-ones re-
ity of the amidines, because the lipophilic amidine increases ported in this paper provided Pratosartan as shown in the
the solubility to toluene.
successive paper.10)
The reaction mechanism of this interesting cyclization is
demonstrated in Chart 4. It should be noted that if the same Conclusion
reaction with 2-chlorotropone instead of 2-tosyloxytropone is
The reaction of 2-tosyloxytropone with amidines in the
carried out under similar conditions, no expected products presence of n-Bu4NBr as a phase transfer catalyst in aq.
were obtained. On the other hand, the reaction with 4-iso- NaOH/toluene under industrially useful conditions provided
propyl-2-tosyloxytropone (5b) afforded not only 6-isopropyl- cycloheptimidazol-4-ones in high yield.
cycloheptimidazol-4-one (3h), but also p-toluenesulfinic acid

May 2006
705
1H-NMR (CDCl3) d: 1.50 (6H, d, Jꢀ7.2 Hz), 3.39 (1H, m), 7.07 (1H, dd,
Jꢀ8.8, 11.2 Hz), 7.30 (1H, d, Jꢀ12.0 Hz), 7.40—7.46 (1H, m), 7.86 (1H, d,
Jꢀ10.8 Hz). MS m/z: 188 (Mꢂ), 173 (B.P.), 145.
Experimental
Melting points were determined on Yamato melting point apparatus and
are uncorrected. Infrared (IR) spectra were recorded on a Hitachi 270-30.
Proton nuclear magnetic resonance (1H-NMR) spectra were measured at
400 MHz on a JEOL EX-400 Fourier-transform NMR spectrometer. Chemi-
cal shifts are quoted in part per million (ppm) with tetramethylsilane as an
internal standard. Coupling constants (J) are given in Hz. The following ab-
breviations are used: s, singlet; d, doublet; t, triplet; q, quartet; br s, broad
singlet; dd, doublet of doublet; m, multiplet. Mass spectra (MS) were taken
on a Hitachi M-80B spectrometer. For column chromatography, silica gel
(Merck, Kieselgel 60, 70—230 mesh) was used.
2-Butyl-3H-cycloheptimidazol-4-one (3e): mp 132—134 °C (iPrOH, pale
1
yellow needles). IR (KBr) cmꢁ1: 3070, 2938, 1620, 1575, 1524, 1488. H-
NMR (CDCl3) d: 0.96 (3H, t, Jꢀ7.2 Hz), 1.40—1.51 (2H, m), 1.82—1.91
(2H, m), 3.03 (2H, t, Jꢀ7.6 Hz), 7.07 (1H, dd, Jꢀ8.8, 10.8 Hz), 7.30 (1H, d,
Jꢀ12.4 Hz), 7.40—7.47 (1H, m), 7.85 (1H, d, Jꢀ11.2 Hz). MS m/z: 202
(Mꢂ), 173, 160 (B.P.).
2-Isobutyl-3H-cycloheptimidazol-4-one (3f): mp 153—154 °C (iPrOH,
pale yellow needles). IR (KBr) cmꢁ1: 3070, 2944, 1620, 1569, 1524, 1488,
1272. 1H-NMR (CDCl3) d: 1.02 (6H, d, Jꢀ6.4 Hz), 2.29 (1H, m), 2.89 (2H,
d, Jꢀ7.4 Hz), 7.08 (1H, dd, Jꢀ8.8, 11.2 Hz), 7.30 (1H, d, Jꢀ12.4 Hz), 7.44
(1H, dd, Jꢀ8.8, 12.4 Hz), 7.85 (1H, d, Jꢀ11.2 Hz). MS m/z: 202 (Mꢂ), 187,
160 (B.P.).
2-Propyl-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (4c)2) To a
solution of 2-propyl-3H-cycloheptimidazol-4-one (3c, 4.00 g) in MeOH
(80 ml) was added 10% Pd on carbon (0.40 g) and the mixture was stirred
for 24 h under an atmosphere of hydrogen (1 atm) at 55 °C. After filtration of
the catalyst, the filtrate was concentrated under the reduced pressure. Then,
the residue was purified by silica gel column chromatography (EtOAc/
MeOHꢀ20/1), affording 4c (4.03 g, 99%) as a colorless solid. Recrystalliza-
2-Phenyl-3H-cycloheptimidazol-4-one (3g): mp 227—230 °C (iPrOH,
pale yellow needles, Lit. 212 °C). IR (KBr) cmꢁ1: 3040, 1623, 1569, 1545,
1
1464, 1278. H-NMR (CDCl3) d: 7.12 (1H, dd, Jꢀ8.4, 10.8 Hz), 7.36 (1H,
tion from EtOAc gave colorless crystals. mp 76—77 °C. IR (KBr) cmꢁ1
:
d, Jꢀ12.0 Hz), 7.47 (1H, dd, Jꢀ8.4, 12.0 Hz), 7.51—7.56 (3H, m), 7.95
(1H, d, Jꢀ10.8 Hz), 8.39 (2H, d, Jꢀ8.0 Hz). MS m/z: 222 (Mꢂ), 194 (B.P.),
64.
3236, 2916, 1608, 1542, 1522, 1458, 1408. 1H-NMR (CDCl3) d: 0.98 (3H, t,
Jꢀ7.2 Hz), 1.77 (2H, m), 1.88—2.08 (4H, m), 2.65—2.75 (4H, m), 2.99
(2H, t, Jꢀ7.2 Hz), 10.10—10.40 (1H, br). MS m/z: 192 (Mꢂ), 177, 164
(B.P.).
2-Propyl-7-isopropyl-3H-cycloheptimidazol-4-one (3i): mp 135—136 °C
(iPrOH, pale yellow needles). IR (KBr) cmꢁ1: 3064, 2944, 1623, 1572,
1515, 1482. 1H-NMR (CDCl3) d: 1.03 (3H, t, Jꢀ7.2 Hz), 1.31 (6H, d,
Jꢀ6.8 Hz), 1.82—1.99 (2H, m), 2.80—2.99 (1H, m), 2.98 (2H, t,
Jꢀ7.6 Hz), 7.28 (1H, d, Jꢀ12.8 Hz), 7.38 (1H, d, Jꢀ12.8 Hz), 7.75 (1H, s).
MS m/z: 230 (Mꢂ), 215, 202 (B.P.).
General Procedure for 2-Propyl-6-isopropyl-3H-cycloheptimidazol-4-
one (3h) To a mixture of 30% NaOH (6.85 g) and toluene (25 ml), 4-iso-
propyl-2-tosyloxytropone (5b, 3.18 g), butyramidine hydrochloride (6c,
1.84 g) and tetra-n-butylammonium bromide (1.61 g) were added succes-
sively and the mixture was stirred at 30 °C for 5 h. The reaction mixture was
treated with excess saturated aqueous ammonium chloride and extracted
with EtOAc (3ꢃ20 ml). The combined extract layers were washed with brine
and dried over Na2SO4. The solvent was removed under the reduced pres-
Acknowledgments We thank Professor S. Ikegami, Teikyo University,
for his generous and helpful discussions.
sure. Then, the residue was purified by silica gel column chromatography References and Notes
(EtOAc/MeOHꢀ50/1), affording 3h (1.71 g, 74%). Recrystallization from
iPrOH gave pale yellow needles. mp 166—168 °C. IR (KBr) cmꢁ1: 3064,
2944, 1620, 1575, 1527, 1491. 1H-NMR (CDCl3) d: 1.03 (3H, t, Jꢀ7.2 Hz),
1.31 (6H, d, Jꢀ6.8 Hz), 1.91 (2H, m), 2.85—2.98 (1H, m), 2.99 (2H, d,
Jꢀ7.4 Hz), 7.02 (1H, d, Jꢀ11.6 Hz), 7.25 (1H, s), 7.77 (1H, d, Jꢀ11.6 Hz).
MS m/z: 230 (Mꢂ), 202 (B.P.), 187.
1) Duncia J. V., Chiu A. T., Carini D. J., Gregory G. B., Johnson A. L.,
Price W. A., Wells G. J., Wong P. C., Calabrese J. C., Timmermans P.
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2-Methyl-3H-cycloheptimidazol-4-one (3a): mp 191—193 °C (iPrOH,
3) Ueyama N., Yanagisawa T., Baba H., Kuroiwa K., Hayashi H., Sone-
gawa M., Tomiyama T., Bioorg. Med. Chem. Lett., 4, 1637—1642
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Murugesan N., Ryan C. S., Valentine M. T., Yang Y., Macor J. E.,
Bioorg. Med. Chem. Lett., 13, 1093—1096 (2003).
pale yellow needles, Lit. 191 °C). IR (KBr) cmꢁ1: 3076, 1623, 1572, 1530,
1
1488, 1293, 1272. H-NMR (CDCl3) d: 2.75 (3H, s), 7.10 (1H, dd, Jꢀ8.8,
11.2 Hz), 7.35 (1H, d, Jꢀ12.0 Hz), 7.43—7.49 (1H, m), 7.85 (1H, d,
Jꢀ11.2 Hz). MS m/z: 160 (Mꢂ), 132 (B.P.), 63.
2-Ethyl-3H-cycloheptimidazol-4-one (3b): mp 160—164 °C (iPrOH, pale
1
yellow needles). IR (KBr) cmꢁ1: 3070, 1620, 1566, 1527, 1488, 1281. H-
NMR (CDCl3) d: 1.48 (3H, t, Jꢀ7.6 Hz), 3.07 (2H, t, Jꢀ7.6 Hz), 7.08 (1H,
dd, Jꢀ8.8, 10.8 Hz), 7.33 (1H, d, Jꢀ12.0 Hz), 7.41—7.49 (1H, m), 7.86
(1H, d, Jꢀ11.2 Hz). MS m/z: 174 (Mꢂ, B.P.), 145, 63.
2-Propyl-3H-cycloheptimidazol-4-one (3c): mp 142—144 °C (iPrOH,
pale yellow needles). IR (KBr) cmꢁ1: 3070, 1617, 1569, 1524, 1485, 1269.
1H-NMR (CDCl3) d: 1.04 (3H, t, Jꢀ7.2 Hz), 1.82—1.99 (2H, m), 3.01 (2H,
t, Jꢀ7.6 Hz), 7.08 (1H, dd, Jꢀ8.8, 11.2 Hz), 7.31 (1H, d, Jꢀ12.4 Hz),
7.40—7.49 (1H, m), 7.85 (1H, d, Jꢀ11.2 Hz). MS m/z: 188 (Mꢂ), 173, 160
(B.P.).
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showed m/z 156 mass of p-toluensulfinic acid.
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(1971).
2-Isopropyl-3H-cycloheptimidazol-4-one (3d): mp 183—186 °C (iPrOH, 10) Sonegawa M., Yokota M., Tomiyama H., Tomiyama T., Chem. Pharm.
pale yellow needles). IR (KBr) cmꢁ1: 3070, 1620, 1572, 1521, 1491, 1275.
Bull., 54, 706—710 (2006).