Asian Journal of Chemistry; Vol. 26, No. 22 (2014), 7587-7590
ASIAN JOURNAL OF CHEMISTRY
Synthesis, Characterization of 3-(Bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline
and Its Crystal Structure
1,*
2
2
2
3
JIA-YING XU , WEI-HUA CHENG , LAN WANG , JIAN-GUO WU and KAI WANG
1College of Chemical and Biological Engineering,Yancheng Institute of Technology,Yancheng 224051, Jiangsu Province, P.R. China
2Department of Light Chemical Engineering,Yancheng Institute of Industry Technology,Yancheng 224051, Jiangsu Province, P.R. China
3High Technology Research Institute of Nanjing University, Changzhou, 213162, Jiangsu Province, P.R. China
*Corresponding author: E-mail: xujiaying-1984@163.com
Received: 21 December 2013;
Accepted: 22 March 2014;
Published online: 6 November 2014;
AJC-16189
3-(Bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline (I), an important intermediate to synthesize pitavastatin calcium. It was prepared
from ethyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylate via reduction by KBH4/ZnCl2 and then bromide by PBr3. The product
was characterized by NMR and LC-MS. The crystal structure of compound I was investigated using X-ray diffraction and SHELXTL-97
software. The result indicated that compound I crystallized in the triclinic system, space group P-1 with a = 9.6150(19), b = 9.868 (2), c =
10.060(2) Å, V = 783.3 (4) Å3; Z 2.
Keywords: 3-(Bromomethy)-2-cyclopropy-4-(4-fluorophenyl)quinolone, Synthesis, Characterization, Crystal structure.
INTRODUCTION
EXPERIMENTAL
Pitavastatin calcium, a new treatment of high cholesterol
statins1,2. It is used as HMG CoA reductase inhibitor by Nissan
Chem Corporation and sold in Japan in 2003. It was proved to
be a kind of long duration, good tolerance and high security
drug to treat hyperlipidemia and high cholesterol statins, which
have a broad market prospect.
3-(Bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-
quinoline(I) is widely concerned as the most important
intermediate to synthesize pitavastatin calcium3. Now, some
synthetic routes are reported about (I) in the literatures, such
as, (I) could be prepared from 2-cyclopropyl-4-(4-fluoro-
phenyl)-3-methylquinoline by NBS bromide in MeCN and
CCl4. But the yield is not high. Herein, we report the synthesis
of (I) from ethyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-
3-carboxylate (1) with an overall yield of about 58.5 %. Mean-
while, the crystal structure of (I) was also investigated. The
synthetic route of compound I was presented as Scheme-I.
Ethyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-
carboxylate (1) was supplied by Well Chemical Co. Ltd of
Jiangsu (Yancheng, People's Republic of China), its mass
content is 98.5 % determined by GC. KBH4, ZnCl2 and PBr3
was supplied by Sinopharm Chemical Reagent Co. Ltd of China.
All other chemicals were of reagent grade and used without
purification as received.
1H NMR spectrum was obtained with Bruker AV-500
spectrometer at 500.13 MHz and measured in CD3OD solution
at 25 0.5 °C. The sample was dissolved in a 5 mm diameter
tube at a concentration of 20 mg/mL. X-ray diffraction was
performed on a Bruker APEXII CCD diffractometer. Mass
spectrum of (I) was analyzed using Trace DSQ LC/MS (Thermo
Electron Co., USA).
Synthesis of compound I: In a 2 L four-necked flask,
THF (30 mL), ZnCl2 (3.15 g, 0.023 mol) and KBH4 (2.45 g,
0.045 mol) were added, stirred for 2 h at room tempeature.
ethyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbo-
xylate (1) (4.9 g, 0.015 mol) was dissolved in toluene and
then it was added into the reaction vessel. The reaction system
was heated slowly to the refluxing temperature. After 20 h,
the system was cooled and filtered. The filter cake was washed
and extracted by toluene. The organic layer was combined
and washed with 0.1 mol/L sodium hydroxide solution and
saturated brine until neutral. The product was collected by
F
F
F
KBH4,ZnCl2
PBr3
COOEt
OH
Br
N
1
N
N
2
I
Scheme-I: Route for the synthesis of compound I
Xu, Jia-Ying
