A convenient synthesis of ezetimibe analogs as cholesterol absorption inhibitors

Article abstract of DOI:10.1016/j.cclet.2009.08.009

A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was described. The key step in the synthesis was the intramolecular ring formation through Mitsunobu reaction. Furthermore, a new series of analogs was designed and synthesized.

Full text of DOI:10.1016/j.cclet.2009.08.009

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 67–69
www.elsevier.com/locate/cclet
A convenient synthesis of ezetimibe analogs as cholesterol
absorption inhibitors
a,
b
Jian Feng Ji a, Hui Bin Zhang a, Wen Long Huang a, , Hai Qian , Jin Pei Zhou
*
*
a Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
b Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
Received 8 May 2009
Abstract
A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was described. The key step in
the synthesis was the intramolecular ring formation through Mitsunobu reaction. Furthermore, a new series of analogs was designed
and synthesized.
# 2009 Wen Long Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Ezetimibe; Synthesis; Cholesterol absorption inhibitor
Ezetimibe [1], as shown in Fig. 1, is the first of the cholesterol absorption inhibitors, a novel class of lipid modifying
drugs, which inhibits the absorption of dietary or recycled cholesterol in the intestine and can be used either alone or in
combination with a statin. Some approaches have been reported for the synthesis of ezetimibe. The significant
difference of various synthesis methods was the lactam ring formation step. One general synthesis was afforded by
reaction of acyl chloride and imine which was synthesized from aromatic amine and aromatic aldehyde, to give trans
b-lactams.
Through retrosynthesis of ezetimibe, a new convenient route was proposed, which contained general reagents and
moderate conditions. The key intermediate 6, was synthesized through this method (Scheme 1).
In the previous work of our laboratory, the polarity and the length of C-3 side chain was modified by introducing
ester or amide groups to the C-3 side chain. And several ester or amide analogs have shown some interesting
cholesterol absorption inhibition activity [2]. In order to further investigate the effect of these groups, the ester analogs
(8a–g) with substituents of different polarity or electrophilicity on phenyl groups were designed and synthesized, as
shown in Scheme 2.
General procedure for synthesis of compound 6 was as follows: 4-Methoxybenzoyl chloride 1 and ethyl
acetoacetate were disposed with NaOH (33% aq.) in petroleum ether and then treated with NH4Cl to provide b-
ketoester 2 [3]. Then the ketoester was heated on an oil bath at 140 8C together with 4-fluorobenzenamine in xylene by
continuously distilling ethanol to give amide 3. The Michael addition of amide 3 and methyl acrylate was quite fast,
within 2 h. In anhydrous THF, the yield was 99%, which was a little higher than in THF containing about 2% water,
* Corresponding authors.
E-mail addresses: ydhuangwenlong@126.com (W.L. Huang), qianhai24@126.com (H. Qian).
1001-8417/$ – see front matter # 2009 Wen Long Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.08.009

68
J.F. Ji et al. / Chinese Chemical Letters 21 (2010) 67–69
Fig. 1. Structure of ezetimibe.
Scheme 1. Reagents and conditions: (a) (1) ethyl acetoacetate, NaOH (33% aq.), petroleum ether, (2) NH4Cl, total 35%; (b) 4-fluorobenzenamine,
xylene, 140 8C, 4 h, 72%; (c) methyl acrylate, NaOC2H5, THF, 75 8C, 2 h, 96%; (d) NaBH4, CH3OH, 0 8C, 8 h, 92%; (e) Ph3P, diethyl
azodicarboxylate (DEAD), THF, 8 h, 32.7%.
Scheme 2. Reagents and conditions: (a) LiOH, acetone, H2O, rt, 99.2%; (b) substituted phenols, DMAP, DCC, CH2Cl2, rt.
yielding 96%. Reduction of compound 4 by NaBH4 in CH3OH gave alcohol 5. Under Mitsunobu [4] condition, the
lactam ring was formed, to give compound 6 [5]. Between 0 and 80 8C, the yields of ring formation were quite stable,
from 32% to 34%.
Spectral data of compound 6 indicated that the reaction under Mitsunobu condition afforded the trans b-lactam [6]
because the coupling constant of C3 and C4 proton was 2.1 Hz, which showed significant difference compared to that
of cis b-lactams (5–6 Hz).

J.F. Ji et al. / Chinese Chemical Letters 21 (2010) 67–69
69
Table 1
Results of in vivo bioactivities.
Compoundsa
R1
TC or reduction (%)b
8a
8b
4-COOCH3
10.3
18.7**
4-COOC2H5
8c
8d
4-Cl
4-Br
4-OCH3
2,6-CH3
4-NO2
–
31.2
12.5
NE#
8e
8f
8g
NE#
28.5*
High-cholesterol diet
Normal diet
Ezetimibe
13.26 Æ 1.59c
45.1**
39.1**
–
–
*
P < 0.05.
P < 0.01.
NE: No effect.
**
#
a
8 rats per group.
b
Compared to High-cholesterol diet animal group.
Concentration in serum: mmol/L.
c
Cholesterol absorption inhibition activity was investigated in a rat model [7]. Serum cholesterol levels were
determined in a kit form. The results were presented in Table 1. As can be seen from the data, some of the target
compounds showed moderate effect in lowering total serum cholesterol content. Substitution of alkoxy and 2,6-
dimethyl for R1 as in compound (8e) and compound (8f) resulted in significant decrease in potency. Substitution of
electrophilic groups for R1 as in compounds 8a, 8b, 8c, 8d and 8g results in promising activity in lowering total serum
cholesterol content. These SAR trends may provide insights into the further research on novel cholesterol absorption
inhibitors.
In summary, a mild and convenient procedure for the monocyclic b-lactams through Mitunobu reaction was
developed. The present procedure described here offered moderate yields of products, short reaction time, and
operational simplicity. Bioactivity data indicated that some of the target compounds showed moderate effect in
lowering total serum cholesterol level.
Acknowledgments
We wish to thank Prof Yun Man Li, Dr Wei Rong Fang and Jing Kong for their assistance in bioactivities test. We
also thank Jie Shen from Nanjing Normal University for the help with data analysis and language editing.
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