A new route for the synthesis of ozagrel hydrochloride

Full text of DOI:10.1080/00304941003699723

This article was downloaded by: [Moskow State Univ Bibliote]
On: 22 January 2014, At: 11:37
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
A New Route for the Synthesis of Ozagrel
Hydrochloride
Chenglong Yu a , Baohai Zhao a , Yihong Zhao a & Jimao Lin a
a School of Chemistry and Chemical Engineering , Shandong
University , Jinan, P. R. China
Published online: 07 Apr 2010.
To cite this article: Chenglong Yu , Baohai Zhao , Yihong Zhao & Jimao Lin (2010) A New Route for
the Synthesis of Ozagrel Hydrochloride, Organic Preparations and Procedures International: The New
Journal for Organic Synthesis, 42:2, 183-185, DOI: 10.1080/00304941003699723
To link to this article: http://dx.doi.org/10.1080/00304941003699723
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Organic Preparations and Procedures International, 42:183–185, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304941003699723
A New Route for the Synthesis of
Ozagrel Hydrochloride
Chenglong Yu, Baohai Zhao, Yihong Zhao, and Jimao Lin
School of Chemistry and Chemical Engineering, Shandong University,
Jinan, P. R. China
(E)-3-[4-(1H-Imidazol-1-ylmethyl)phenyl]-2-propenoic acid hydrochloride (ozagrel hy-
drochloride) is a highly selective inhibitor of thromboxane A2 (TXA2). The beneficial
effects of TXA2 inhibition by ozagrel include improved motor coordination after experi-
mental stroke and antihypertensive effects in spontaneously hypertensive rats. Since 1988,
ozagrel hydrochloride has been marketed as an antithrombotic drug in Japan.1 Therefore,
the development of an efficient synthetic method is of great interest.
The reported preparations of ozagrel hydrochloride involve the reaction of alkyl 4-
bromomethylcinnamate with N-acetylimidazole2 or with imidazole.3 However, both the
methods are costly as the result of either the price of the starting material in the case of N-
acetylimidazole procedure and the low yield (34%) of the reaction in the imidazole method.
We now describe a new cost efficient synthetic route to prepare ozagrel hydrochloride using
low-priced reagents, under mild reaction conditions and in high overall yield.
Ozagrel hydrochloride was obtained through a three-step sequence starting from com-
mercially available p-tolualdehyde by bromination with elemental bromine to afford 4-
(bromomethyl)benzaldehyde 2 in 88% yield. Although bromine was selected as the bromi-
nating agent because of its lower price in China, the reaction works equally well (90% yield)
by bromination with NBS which had to be used in the bromination of alkyl bromethylcin-
namate because the use of bromine lead to reaction at the double bond.4 The subsequent
substitution of 2 with imidazole proceeded smoothly in 92% yield to give 4-(1H-imidazol-
1-ylmethyl)benzaldehyde (3) in the presence of potassium carbonate instead of the much
stronger base NaH.3 The final condensation of 3 with malonic acid5 in toluene followed
by treatment with hydrochloric acid successfully provided ozagrel hydrochloride in 87%
yield. The overall yields of ozagrel hydrochloride using bromine and NBS from 1 are 70%
and 72%, respectively.
Although intermediates 2 and 3 were purified by chromatography in this article, in a
larger scale preparation (30 g), the crude materials are sufficiently pure to be used in the
Submitted January 29, 2010.
Address correspondence to Jimao Lin, School of Chemistry and Chemical Engineering, Shan-
dong University, Jinan 250100, P. R. China. E-mail: linjm@sdu.edu.cn
183

184
Lin et al.
a
b
BrCH2
CHO
CH3
CHO
1
CH2
3
2
c
N
CH2
N
CHO
COOH
N
N
d
.
HCl
4
a. Br2 or NBS/CCl4/reflux;
c. CH2(COOH)2/C6H5CH3/C5H5N;
b. imidazole/K2CO3/CHCl3 /rt;
d. HCl/H2O.
next steps without chromatography; the excess imidazole in the chloroform solution of 3
was removed by simple washing with water.
Experimental Section
Mps were determined on a Beijing XT-4 melting apparatus and are uncorrected. p-
Tolualdehyde was purchased from Beijing Ouhe Technology Co. Ltd and the other chemical
were obtained from Sinopharm Chemical Reagents Co. Ltd. All NMR experiments were
performed on a 400 MHz Bruker Avance spectrometer in CDCl3 using TMS as an internal
standard. IR spectra were recorded as potassium bromide pellets on a Bruker VERTEX-70
spectrometer.
4-(Bromomethyl)benzaldehyde using Bromine
To a three-necked flask equipped with a condenser, an addition funnel, compound 1 (2.40 g,
0.02 mol) and carbon tetrachloride (20 ml) were added. After the reaction mixture was
heated to reflux, bromine (3.04 g, 0.019 mol) was added dropwise under the light irradiation.
The hydrogen bromide generated in the reaction was absorbed in water. After refluxing
for 2 h, carbon tetrachloride was removed by distillation (and recycled) and the resulting
mixture was purified by chromatography (silica gel. 12/1 petroleum ether/ethyl acetate) to
afford 2 (3.50 g, 88%) as a white solid, mp. 95–97◦C, lit.6 mp. 95–95.5◦. 1H-NMR (CDCl3):
δ 4.516 (s, 2H), 7.561 (d, 2H), 7.869 (d, 2H), 10.018 (s, 1H). IR: 3085 cm−1, 1695 cm−1
1532 cm−1, 675 cm−1
,
.
4-(Bromomethyl)benzaldehyde using NBS
Compound 1 (2.40 g, 0.02 mol), benzoyl peroxide (0.05 g, 0.21 mmol) and carbon tetra-
chloride (20 ml) were mixed and heated to reflux. NBS (3.56 g, 0.02 mol) was added in 1 h
and then refluxed for 2 h. After the reaction was complete, succinimide was collected
by filtration, and carbon tetrachloride was removed by distillation (and recycled) and the
resulting mixture was purified by chromatography (silica gel. 12/1 petroleum ether/ethyl
acetate) to afford 2 (3.58 g, 90%) as a white solid, mp. 96–97◦C.

Synthesis of Ozagrel Hydrochloride
4-(1H-Imidazol-1-ylmethyl)benzaldehyde (3)
185
To a well-stirred mixture of 2 (2.99 g, 0.015 mol) and potassium carbonate (4.15 g, 0.03
mol) in chloroform (25 ml) was added imidazole (2.18 g, 0.032 mol) and stirred for 2 h
at room temperature. The solid was colletedand chloroform was removed by distillation
(and recycled). The resulting crude product was purified by chromatography (silica gel,
ethyl acetate) to afford 3 (2.57 g, 92%) as a colorless oil, bp. 149–151◦C/0.2 mm, lit.7 bp.
1
150◦C/0.2 mm. H-NMR (CDCl3): δ 5.247 (s, 2H), 6.956 (s, 1H), 7.098 (d, 1H), 7.296
(d, 2H), 7.60 (s, 1H), 7.850 (d, 2H), 9.980 (s, 1H). IR: 1695 cm−1, 1638 cm−1, 1515 cm−1
.
Ozagrel Hydrochloride (4)
To a solution of 3 (1.86 g, 0.01 mol) in toluene (10 ml) was added malonic acid (2.08 g, 0.02
mol) and pyridine (10 ml). The mixture was heated at 95◦C for 2 h. The mixture was cooled
to room temperature and then 10 ml (5 mol/L) hydrochloric acid was added to give a white
precipitate which was collected and recrystallized from ethanol to give pure 4 (2.30 g,
1
87%) as a white solid, mp. 215–217◦C, lit.3 mp. 214–217◦C. H-NMR (D2O): δ 5.291
(s, 2H), 6.255 (d, 1H), 7.241 (d, 2H), 7.370 (d, 1H), 7.432 (d, 2H), 7.451 (m, 2H), 8.677
(s, 1H). IR: 3000–2250 cm−1, 1688 cm−1, 1600 cm−1
.
References
1. R. Felist, D. Delebase and M. F. Simon, J. Throm. Res., 48, 403 (1987).
2. T. Kamijo, R. Yamamoto et al., Chem. Pham. Bull., 31, 1213 (1983).
3. K. Iizuka, K. Akahane and D. Momose, J. Med. Chem., 24, 1139 (1981).
4. R. Rajagopal, S. A. Siddiqui et al., J. Mol. Catal. A: Chem., 210, 165 (2004).
5. J. K. Augustine, Y. A. Naik et al., J. Org. Chem., 72, 9854 (2007).
6. D. Gunther and P. Gerhard, Chem. Ber., 94, 907 (1961).
7. I. Hiroshi, K. Akihito and K. Yasuko, Jpn Kokai Tokkyo Koho, JP 4041480 (1992); Chem. Abstr.,
117, 26569 (1992).