Concise and efficient synthesis of cinepazide

Article abstract of DOI:10.1080/00397911.2013.848370

An efficient synthesis of cinepazide has been carried out in four steps with an overall yield of 51%. The synthesis was started from a commercially available 3,4,5-tri-methoxy benzaldehyde. All the reactions were very clean and the isolation of products was also very easy.

Full text of DOI:10.1080/00397911.2013.848370

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Concise and Efficient Synthesis of
Cinepazide
B. Nagaiah a & A. Venkat Narsaiah a
a Organic and Biomolecular Chemistry Division , Indian Institute of
Chemical Technology , Hyderabad , India
Accepted author version posted online: 02 Dec 2013.Published
online: 28 Mar 2014.
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To cite this article: B. Nagaiah & A. Venkat Narsaiah (2014) Concise and Efficient Synthesis of
Cinepazide, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:9, 1227-1231, DOI: 10.1080/00397911.2013.848370
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Synthetic Communications®, 44: 1227–1231, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.848370
CONCISE AND EFFICIENT SYNTHESIS OF CINEPAZIDE
B. Nagaiah and A. Venkat Narsaiah
Organic and Biomolecular Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India.
GRAPHICAL ABSTRACT
Abstract An efficient synthesis of cinepazide has been carried out in four steps with an
overall yield of 51%. The synthesis was started from a commercially available 3,4,5-tri-
methoxy benzaldehyde. All the reactions were very clean and the isolation of products was
also very easy.
Keywords: Amide; coupling; hydrolysis; trimethoxybenzaldehyde; Wittig reaction
INTRODUCTION
Cardiovascular diseases (CVDs) are a group of disorders of the heart and
blood vessel, responsible for about 50% of premature deaths in western industrialized
countries and 30% of all global deaths.[1] Therefore, extensive research for new and
better therapeutic agents continues in different pharmaceutical laboratories, institu-
tions, and universities. The drugs used for CVDs are inotropic, diuretics, vasodilators,
angiotensin-converting enzyme inhibitors, and β-blockers. cinepazide has been widely
used as a clinical therapeutic drug and it has a vasodilating action by increasing blood
flow through the brain and peripheral organs such as cardiac muscle, skeletal muscle,
and kidneys.[2]
Cinepazide can inhibit the re-absorption of adenosine and adenosine deami-
nase activity, delay the adenosine metabolism, and then increase the endogenous
adenosine content in local lesions, resulting in the enhancement of the therapeutic
effect of adenosine. In addition, cinepazide can inhibit the phosphodiesterase activity,
Received July 24, 2013.
Address corresspondence to A. Venkat Narsaiah, Organic and Biomolecular Chemistry Division,
Indian Institute of Chemical Technology, Hyderabad 500007, India. E-mail: vnakkirala2001@yahoo.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1227

1228
B. NAGAIAH AND A. V. NARSAIAH
decrease the platelet aggregations, reduce the production of free radicals, decrease the
influence of neutrophils on the vascular endothelial cells, and suppress the calcium
overload, leading to the decrease of myocardial necrosis, protection of myocardial
cells, and improvement of cardiac hemodynamics.[3] Wang and coworkers used mixed
anhydride of (E)-3,4,5-tri methoxycinnamic acid and pivolyl chloride followed by
coupling and alkylation reaction and Othaka et al. used acylation of pyrrolidinocar-
bonylmethylpiperizine with (E)-3,4,5-tri methoxycinnamyl chloride for the synthesis
of cinepazide.[4]
The pharmaceutical importance of cinepazide attracted us and as part of our
research program in design and synthesis of biologically active compounds[5] we
herein report a simple and efficient synthesis for cinepazide.
RESULTS AND DISCUSSION
The synthesis was started from commercially available 3,4,5-trimethoxy
benzaldehyde 2. This aldehyde was subjected to Wittig reaction in benzene to afford
(E)-ethyl 3-(3,4,5-trimethoxyphenyl)acrylate 3in 88% yield. The olefin ester com-
pound 3 on hydrolysis with lithium hydroxide in tetrahydrofuran (THF)–H2O mixture
accomplished (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid 4in 90% yield.
Theamidecouplingwithacrylicacid4andpiperazinewasestablishedinthepresence
of hydroxy benzotriazole (HOBt) and triethyl amine (TEA) in dichloromethane at low
temperature to get (E)-1-(piperazin-1-yl)-3-(3,4,5-trimethoxyphenyl)-prop-2-en-1-one
Scheme 1. Reagents and conditions: (a) Ph3P=CHCO2Et, benzene, rt, 3h, 88%. (b) LiOH, THF–H2O
(2:1), rt, 5h, 90%. (c) Piperazine, EDC, HOBT, TEA,CH2Cl2, 0 °C, 5h, 70%. (d) 2-Bromo-1-(pyrrolidin-1-
yl)-propan-1-one, acetone, K2CO3, PTC, rt, 3h, 92%.

SYNTHESIS OF CINEPAZIDE
1229
5in 70% yield. The amide compound 5 on reaction with 2-bromo-1-(pyrroli din-1-yl)-
ethanone 6 in the presence of potassium carbonate (K2CO3) in acetone afforded the
target molecule, (E)-1-{4-[2-oxo-2-(pyrrolidin-1-yl)-ethyl]-piperazin-1-yl}-3-(3,4,5-
trimethoxyphenyl)-prop-2-en-1-one 1, in excellent yields as shown in Scheme 1. All the
products were confirmed by their spectroscopic analysis.
CONCLUSION
In conclusion, we have demonstrated a simple and efficient synthetic route for
the preparation of cinepazide in four steps with an overall yield in 51%. All the reac-
tions were very clean and the isolation of products is very easy.
EXPERIMENTAL
Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR 240-c spectro
photometer using KBr optics. 1H NMR spectra were recorded on Bruker 300-MHz,
spectrometer in CDCl3 using tetramethylesilance(TMS) as internal standard. Mass
spectra were recorded on a Finnigan MAT 1020 mass spectro meter operating at 70eV.
(E)-Ethyl-3-(3,4,5-trimethoxyphenyl)acrylate (3)
Ethyl-2-(tritylphosphinyli dene)-acetate (2.12g, 6.09mmol) was added to a
stirred solution of 3,4,5-tri methoxybenzaldehyde (1g, 5.1mmol) in benzene and the
resulting reaction mixture was stirred at room temperature. Progress of the reaction
was monitored by thin-layer chromatography(TLC), and the reaction was completed
within 3h. Then the reaction mixture was adsorbed on silica gel (60–120 mesh) and
eluted with ethyl acetate–hexane mixture (1:9). Pure compound was obtained as
colorless liquid, 1.2g (88.4%). IR (KBr, cm−1): 2974, 2939, 1703, 1633, 1583, 1505,
1455, 1416, 1340, 1314, 1278, 1243, 1182, 1152, 1122, 1036, 990, 823cm−1; 1H NMR
(CDCl3): δ 1.35 (t, 3H, J=7.0Hz), 3.84 (s, 3H), 3.88 (s, 6H), 4.25 (q, 2H, J=7.0Hz),
6.29 (d, 1H, J=16Hz), 6.71 (s, 2H), 7.55 (d, 1H, J=16Hz); ESI-MS m/z (%): 289
([M+Na]+, 10), 266 (10), 257 (100), 251 (45), 249 (15), 181 (15), 179 (60), 173 (30).
(E)-3-(3,4,5-Trimethoxyphenyl)acrylic Acid (4)
Lithium hydroxide (0.16g, 6.75mmol) was added to a stirred solution of
(E)-ethyl-3-(3,4,5-trimethoxyphenyl)-acrylate (1.2g, 4.5mmol) in THF–H2O
(12-6mL) at 0°C and continued stirring for 5h at room temperature. After com-
pletion of reaction as indicated by TLC, the solvent was removed under reduced
pressure, and the residue was diluted by adding cooled water and neutralized with
dilute hydrochloric acid. Then the reaction mixture was extracted with ethyl acetate
(2×20mL) and the combined organic layers were washed with brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The crude product was
purified by column chromatography using silica gel (60–120mesh) and eluted with
ethyl acetate–hexane mixture (4:6 ratio). Pure compound was obtained as a white

1230
B. NAGAIAH AND A. V. NARSAIAH
solid, 0.960g (90%). Mp125–126oC. IR (KBr, cm−1): 3106, 3004, 2838, 2651, 1670,
1
1627, 1584, 1505, 1456, 1404, 1332, 1284, 1245, 1121, 994, 828, 729, 616cm−1; H
NMR (CDCl3+DMSO-d6): δ 3.81 (s, 3H), 3.87 (s, 6H), 6.3 (d, 1H, J=15.9Hz), 6.75
(s, 2H), 7.50 (d, 1H, J=15.9Hz); ESI-MS m/z (%): 261 ([M+Na]+, 100), 239 (80), 221
(98), 213 (10), 190 (10), 123 (15), 102 (20).
(E)-1-(Piperazin-1-yl)-3-(3,4,5-trimethoxyphenyl)-prop-2-en-1-one (5)
EDC (0.35g, 1.82mmol) was added to a stirred solution of (E)-3-(3,4,5-
trimethoxyphenyl)-acrylic acid (0.8g, 3.36mmol) in dry CH2Cl2 (5mL) followed by
HOBt (0.25g, 1.85mmol) at room temperature. After 15min of stirring, the reaction
mixture was cooled to 0oC and a mixture in which piperazine (0.29g, 3.37mmol)
was dissolved in dry CH2Cl2 (5mL) and then TEA (0.70mL, 5.04mmol) were slowly
added The resulting reaction mixture was stirred at room temperature for 5h. The
completion of reaction was confirmed by TLC and the reaction mixture was diluted
by adding CH2Cl2 (10mL) followed by saturated ammonium chloride solution
(10mL). The reaction mixture was extracted with CH2Cl2 (2×10mL) and the com-
bined organic layer was washed with brine and dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was purified by column chro-
matography using silica gel (60–120 mesh) and eluted with ethyl acetate-hexane mix-
ture (3:7 ratio) to obtain a pure product as yellow syrup, 0.71g (70%). IR (neat, cm−1):
3429, 2939, 2840, 1644, 1588, 1504, 1458, 1423, 1368, 1337, 1274, 1226, 1126, 1043,
1
1002, 827, 753, 660cm−1.; H NMR (CDCl3): δ 2.80-2.95 (m, 4H), 3.50–3.70 (m,
4H), 3.80 (s, 3H), 3.90 (s, 6H), 4.10-4.20 (br s, 1H), 6.60-6.75 (m, 3H), 7.55 (d, 1H,
J=15Hz).; ESI-MS m/z (%): 329 ([M+Na]+ 20), 307 (100), 221 (75).
(E)-1-{4-[2-Oxo-2-(Pyrrolidin-1-yl)-ethyl]-piperazin-1-yl}-3-
(3,4,5-trimethoxyphenyl)-prop-2-en-1-one (1)
K2CO3 (0.09g, 0.652 mmol) and a catalytic amount of PTC (TBAI) was added
to a stirred solution of (E)-1-(piperazin-1-yl)-3-(3,4,5-trimethoxyphenyl)-prop-2-
en-1-one (0.10g, 0.326mmol) in dry acetone (5mL) After 30min stirring 2-bromo-
1-(pyrrolidin-1-yl)-ethanone (0.074g, 0.39mmol), was added which was dissolved in
dry acetone (5mL). The resulting reaction mixture was stirred for 3h at room temper-
ature and the completion reaction was confirmed by TLC. The solvent was removed
under reduced pressure. The residue was extracted with ethyl acetate (2×15mL) and
the combined organic layers were washed with brine, dried over anhydrous Na2SO4
and concentrated under reduced pressure to afford a crude product, which was
purified by column chromatography using silica gel (60–120mesh) and eluted with
ethyl acetate–hexane mixture (3:7) to obtain a pure product as yellow syrup, 0.124g
(92%). IR (neat, cm−1): 3058, 2925, 1954, 1760, 1701, 1593, 1551, 1515, 1489, 1464,
1
1442, 1393, 1354, 1252, 1179, 1158, 1077, 1025, 884, 819, 761, 697cm−1; H NMR
(CDCl3): δ 1.80-2.01 (m, 4H), 2.50-2.70 (m, 4H), 3.13 (s, 2H), 3.35-3.50 (m, 4H),
3.65–3.80 (m, 4H), 3.82 (s, 6H), 3.90 (s, 3H), 6.50-6.75 (m, 3H), 7.52 (d, 1H, J=15Hz);
13C NMR (CDCl3, 75 MHz): 167.2, 165.3, 153.3, 142.9, 133.2, 122.4, 116,1, 105.3,

SYNTHESIS OF CINEPAZIDE
1231
104.9, 60.9, 56.2, 56.0, 52.7, 46.1, 45.8, 40.8, 26.1, 24.0; EIMS m/z (%): 440 ([M+Na]+,
60), 418 (50), 242 (100), 139 (8).
FUNDING
B. N. is thankful to the University Grants Commission, New Delhi, for provid-
ing a fellowship.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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