Efficient synthesis of antihistamines clocinizine and chlorcyclizine

Article abstract of DOI:10.1007/s00044-011-9556-x

A simple and efficient route has been developed for the synthesis of anti-histamine drugs clocinizine and chlorcyclizine. The common intermediate 1-[(4-chloro phenyl) (phenyl)-methyl]-piperazine (8), is prepared from (4-chlorophenyl) (phenyl)-methanone (5), in three steps with excellent yields. All the reactions proceeded smoothly and the products were also isolated easily. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9556-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:538–541
DOI 10.1007/s00044-011-9556-x
ORIGINAL RESEARCH
Efficient synthesis of antihistamines clocinizine and chlorcyclizine
•
A. Venkat Narsaiah P. Narsimha
Received: 12 August 2010 / Accepted: 7 January 2011 / Published online: 23 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A simple and efficient route has been devel-
oped for the synthesis of anti-histamine drugs clocinizine
and chlorcyclizine. The common intermediate 1-[(4-chloro
phenyl) (phenyl)-methyl]-piperazine (8), is prepared from
(4-chlorophenyl) (phenyl)-methanone (5), in three steps
with excellent yields. All the reactions proceeded smoothly
and the products were also isolated easily.
clocinizine (1) (Wright and Martins, 1968) and chlorcyc-
lizine (2) (Hamlin et al., 1949, Albro et al., 1949, Baltzly
et al., 1949, Sengmany et al., 2007) are the first generation
antihistamine agents belong to diaryl piperazine group
(Fig. 1).
In view of their pharmacological importance and as part
of our research program in design and synthesis of bio-
logically active compounds (Bose and Narsaiah, 2005;
Narsaiah, 2006, 2008; Yadav et al., 2009, Narsaiah et al.,
2010a, b; Narsaiah and Kumar, 2010a, b; Narsaiah and
Nagaiah, 2010) in this article, the synthesis of clocinizine
and chlorcyclizine through a common intermediate (7) as
shown in the Scheme 1 is described.
Keywords Reduction ꢀ Chlorination ꢀ Clocinizine ꢀ
Chlorcyclizine ꢀ Piperazine
Introduction
Our synthetic approach was started from a commercially
available compound (4-chloro phenyl) (phenyl)-methanone
(5). The keto compound 5 was treated with sodium boro-
hydride in methanol at room temperature to afford the
corresponding derivative of (4-chlorophenyl) (phenyl)-
methanol (6) in excellent yields.
Diarylpiperazine derivatives constitute an important class
of compounds, which exhibit a broad spectrum of thera-
peutic activities such as antiemetic, anticholinergic, urti-
caria sedation, anxiolytic, antiserotonergic, opioid agonists,
and bradykinin antagonists. However, they are more
commonly known for their activity as antihistamine agents.
Chemically diverse group of drugs that competitively
antagonize physiologic effects of histamine, an endogenous
agonist at histamine receptor sites. These agents that can
antagonize most effects of histamine are classified
according to the type of histamine receptor they block
(Hardmann et al., 1996). The different substitutions on the
lipophilic or hydrophilic parts of the molecule can modify
pharmacologic profile as well as pharmacokinetics of the
compounds. Antihistamine drugs are commonly used for
relief of allergies caused by intolerances of proteins. The
The above alcoholic compound (4-chlorophenyl) (phe-
nyl)-methanol (6) was reacted with hydrochloric acid in the
presence of calcium chloride to obtain the corresponding
derivative of 1-chloro-4-[chloro-(phenyl)-methyl]-benzene
(7) in excellent yields. The chloro compound 7 thus
obtained was treated with piperazine in the presence of
potassium carbonate and PTC in tetrahydrofuran to pro-
duce the corresponding product of 1-[(4-chlorophenyl)
(phenyl)-methyl]-piperazine (8), in excellent yield as
shown in the Scheme 1, and the overall yield of this
intermediate was obtained in 76.8%.
The above-afforded piperazine compound 8 was reacted
with two different substrates to yield the two different
drugs as shown in the Scheme 2. At first, the compound 8
was treated with cinnamyl bromide the in presence of
sodium hydroxide in THF-water mixture at 60–70°C to
A. Venkat Narsaiah (&) ꢀ P. Narsimha
Organic Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad 500007, India
e-mail: vnakkirala2001@yahoo.com
123

Med Chem Res (2012) 21:538–541
539
Fig. 1
Me
Ph
Me
N
N
N
N
N
N
N
N
Cl
Cl
Cl
Cl
1
2
3
4
Scheme 1 Reagents and
reaction conditions a NaBH4,
MeOH, 0-RT, 1 h, 95%.
N
Cl
OH
O
N
b
c
b CaCl2, HCl, 80–90°C, 4 h,
93%. c Piperazine, K2CO3,
PTC, THF, reflux, 8 h, 87%
a
Cl
Cl
Cl
Cl
5
6
7
8
afford the corresponding product, 1-[(4-chlorophenyl)
(phenyl)-methyl]-4-cinnamylpiperazine (1) in 92% yield.
In another experiment, the compound of 1-[(4-chloro-
phenyl) (phenyl)-methyl]-piperazine (8) was treated with
methyl iodide in the presence of sodium hydroxide in THF-
water mixture at 60–70°C to obtain the corresponding
product of 1-[(4-chlorophenyl) (phenyl)-methyl]-4-meth-
ylpiperazine (2) in 95% yield. In all the cases, the reactions
were very clean, and the isolation of products also was very
easy. All the products were characterized by their 1HNMR,
13CNMR, IR, and mass spectral data.
In summary, we have demonstrated a simple and effi-
cient route for the synthesis of clocinizine and chlorcycli-
zine from a common intermediate in excellent yields. This
synthetic pathway is very convenient for bulk preparation
of the above said drugs under mild reaction conditions.
Experimental section
General
Melting points were recorded on Buchi R-535 apparatus.
IR spectra were recorded on a Perkin-Elmer FT-IR 240-c
spectrophotometer using KBr optics. 1H NMR spectra were
recorded on Bruker-300 MHz, spectrometer in CDCl3
using TMS as internal standard. Mass spectra were recor-
ded on a Finnigan MAT 1020 mass spectrometer operating
at 70 eV.
a
N
N
[4-Chlorophenyl-(phenyl)]-methanol (6)
H
N
To a stirred solution of (4-chlorophenyl (phenyl)-metha-
none, 5 (5 g, 23.1 mmol) in methanol (25 ml) was added
sodium borohydride (1.3 g, 34.6 mmol) in portions at 0°C
for a period of 15 min and the stirring continued at room
temperature for 1 h. The progress of the reaction was
monitored by TLC. After completion of the starting
material as indicated by TLC, the reaction mixture was
quenched by adding crushed ice. The solvent was removed
under reduced pressure, and the residue was extracted with
ethyl acetate (2 9 25 ml). The combined organic layers
were washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The crude product was
purified by column chromatography using silica gel 60–120
mesh and ethyl acetate-hexane mixture in 2:8 ratio as
Cl
N
1
Cl
Me
N
8
N
b
Cl
2
Scheme 2 Reagents and reaction conditions: a Cinnamyl bromide,
NaOH, THF-H2O (2:1), 60–70°C, 2 h, 92%. b Methyl iodide, NaOH,
THF-H2O (2:1), 60–70°C, 2 h, 95%
123

540
Med Chem Res (2012) 21:538–541
1-[(4-Chlorophenyl) (phenyl)-methyl]-4-
eluent. The pure product was obtained as a white solid,
yield 4.8 g (95%). MP, 55–56°C. IR (KBr): t 3360, 3062,
3030, 2899, 1594, 1486, 1452, 1401, 1340, 1282, 1188,
cinnamylpiperazine (1)
1
1086, 1015, 918, 846, 797, 761, 700, 620 cm-1; H NMR
To a stirred solution of 1-[(4-chlorophenyl) (phenyl)-
methyl]-piperazine, 8 (0.5 g, 1.7 mmol) in THF-H2O (2:1,
6 ml) was added sodium hydroxide (70 mg, 1.7 mmol),
and after 15 min, was added cinnamyl bromide (0.36 g,
1.7 mmol) at room temperature. The resulting reaction
mixture was heated at 60–70°C for 2 h. After completion
of the reaction as indicated by TLC, the reaction mixture
was concentrated under reduced pressure, the residue
was extracted with ethyl acetate (2 9 10 ml). The com-
bined organic layers was washed with brine and dried
over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude product was purified by column
chromatography using silica gel 60–120 mesh and ethyl
acetate–hexane mixture in 2:8 ratio as eluent. The pure
product was obtained as yellow syrup, yield 0.64 g (92%).
IR (KBr): t 3027, 2924, 2854, 2810, 1488, 1455, 1290,
1139, 1089, 1006, 968, 862, 804, 749, 696 cm-1; 1H NMR
(CDCl3): d 2.45 (brs, 4H), 2.55 (brs, 4H), 3.15 (d, 2H,
J = 6.0 Hz), 4.19 (s, 1H), 6.14–6.26 (m, 1H), 6.45 (d, 1H,
J = 14.0 Hz), 7.12–7.48 (m, 14H); 13C NMR (75 MHz): d
141.1, 136.6, 133.8, 132.5, 129.1, 128.6, 128.5, 127.7,
127.6, 127.1, 126.3, 125.2, 75.2, 53.1, 51.3, 29.6; EIMS m/
z (%): 403 (M? 100), 203 (10), 201 (30).
(CDCl3): d 5.75 (d, 1H, J = 5.5 Hz), 7.20–7.35 (m, 9H).
EIMS m/z (%): 220 (M?1 15), 201 (85), 182 (100), 167
(30), 102 (35), 65 (10).
1-Chloro-4-[chloro-(phenyl)-methyl]-benzene (7)
To a stirred solution of [4-chloro phenyl-(phenyl)]-metha-
nol, 6 (4.5 g, 20.6 mmol) in hydrochloric acid (20 ml) was
added calcium chloride (3.2 g, 28.8 mmol) at room tem-
perature. The resulting reaction mixture was refluxed for
4 h. After completion of the reaction as indicated by TLC,
the reaction mixture was cooled to room temperature and
extracted with ethyl acetate (2 9 25 ml). The combined
organic layers were washed with brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure.
The crude product was obtained as a light brown liquid,
yield 4.5 g (93%). IR (neat): t 3450, 3062, 3030, 2926,
2812, 1596, 1490, 1452, 1405, 1289, 1227, 1182, 1089,
1
1013, 846, 803, 756, 700, 603 cm-1; H NMR (CDCl3): d
6.02 (s, 1H), 7.25–7.38 (m, 9H). EIMS m/z (%): 237 (M?
10), 203 (40), 201 (100), 166 (20) 124 (15), 109 (15), 91
(10), 71 (25), 56 (10).
1-[(4-Chlorophenyl)(phenyl)-methyl]-4-
methylpiperazine (2)
1-[(4-Chlorophenyl) (phenyl)-methyl]-piperazine (8)
To a stirred solution of 1-[(4-chlorophenyl) (phenyl)-
methyl]-piperazine, 8 (0.5 g, 1.7 mmol) in in THF-H2O
(2:1, 6 ml) was added sodium hydroxide (70 mg,
1.7 mmol) and methyl iodide (0.38 g, 2.6 m mol). The
resulting reaction mixture was heated at 60–70°C for 2 h.
After completion of the reaction as indicated by TLC, the
reaction mixture was concentrated under reduced pressure,
and the residue was extracted with ethyl acetate
(2 9 10 ml). The combined ethyl acetate layers were
washed with brine and dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product
was purified by column chromatography using silica gel
60–120 mesh and ethyl acetate-hexane mixture in 2:8 ratio
as eluent. The pure product was obtained as white solid,
yield 0.5 g (95%). IR (KBr): t 3060, 3024, 2928, 2854,
1598, 1514, 1457, 1418, 1262, 1235, 1140, 1028, 908, 859,
To a stirred solution of 1-chloro-4-[chloro-(phenyl)-
methyl]-benzene, 7 (4 g, 16.9 mmol) in tetrahydrofuran
(40 ml) was added potassium carbonate (4.3 g, 33.7 mmol),
piperazine (1.5 g, 16.9 mmol) and a catalytic amount of
phasetransfer catalyst (tetrabutylammonium iodide). The
resulting reaction mixture was refluxed for 8 h. After
completion of the reaction as indicated by TLC, the reac-
tion mixture was filtered, and the cake was washed with
ethyl acetate (2 9 15 ml). The combined filtrate was
concentrated under reduced pressure, and the residue was
acidified by adding HCl to pH = 4. At this stage, the
compound was washed with hexane (2 9 15 ml) and the
reaction mixture was basified to pH = 8, and extracted
with ethyl acetate (2 9 25 ml). The combined ethyl acetate
layers were washed with brine and dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The
crude product was obtained as a light yellow syrup, yield
4.2 g (87%). IR (KBr): t 3422, 2924, 2854, 1458, 1282,
1090, 1004, 804, 759, 703 cm-1; 1H NMR (CDCl3): d 2.55
(brs, 4H), 3.55 (brs, 4H), 4.25 (s, 1H), 7.15–7.35 (m, 9H).
EIMS m/z (%): 289 (M?2 30), 287 (M? 60), 203 (40), 201
(100), 103 (10) 87 (15), 76 (10).
1
811, 753, 701, 647 cm-1; H NMR (CDCl3): d 2.75 (s,
3H), 2.95 (brs, 4H), 3.05 (brs, 4H), 4.12 (s, 1H), 7.15–7.40
(m, 9H); 13C NMR (75 MHz): d 141.2, 140.8, 131.7, 129.2,
128.8, 128.7, 127.4, 72.3, 60.7, 44.6; EIMS m/z (%): 301
(M? 20), 281 (20), 242 (10), 228 (10), 201 (100), 165 (30),
153 (10).
123

Med Chem Res (2012) 21:538–541
541
Acknowledgments One of the authors, PN is thankful to CSIR-
New Delhi for providing with fellowship.
Narsaiah AV (2008) Microwave promoted alkylation of halonitro-
benzene with malonates in solvent-free medium. Catal Lett
121:81–84
Narsaiah AV, Kumar JK (2010a) A simple and efficient synthesis of
anti-migraine drug Lomerizine. Synthesis 12:1989–1991
Narsaiah AV, Kumar JK (2010b) A simple and efficient enantiose-
lective synthesis of (S)-Esmolol. Int J Ind Chem 1:1–4
Narsaiah AV, Nagaiah B (2010) A simple and efficient synthesis of
anti-migraine drug Lomerizine. Synthesis 16:2705–2709
Narsaiah AV, Narsimha P, Navitha G (2010a) A simple and
straightforward synthesis of antihistaminic drug Cetirizine. Int
J Appl Biol Pharm Tech 1:736–740
Narsaiah AV, Narsimha M, Haritha B (2010b) A concise enantiose-
lective synthesis of a b1-adrenoceptor antagonist (S)-Bevantolol.
Org Synth Med Chem 1:1–3
Sengmany S, Gall EL, Jean CL, Troupel M, Nedelec JY (2007)
Straightforward three- component synthesis of diarylmethylpipera-
zines and 1,2-diarylethylpiperazines. Tetrahedron 63:3672–3681
Wright HB, Martins DL (1968) Hypocholesteremic agents. IV.
Substituted piperazines. J Med Chem 11:390–391
References
Albro LP, Baltzly R, Phillips AP (1949) Unsymmetrically disubsti-
J Org Chem
tuted piperazines II. Histamine antagonists.
14:771–774
Baltzly R, Dubreuil S, Ide WS, Lorz E (1949) Unsymmetrically
disubstituted piperazines. III. N-Methyl-N0-benzhydrylpipera-
zines as histamine antagonists. J Org Chem 14:775–782
Bose DS, Narsaiah AV (2005) An efficient asymmetric synthesis of
(S)-Atenolol: using hydrolytic kinetic resolution. Bioorg Med
Chem. 13:627–630
Hamlin KE, Weston AW, Fischer FE, Michaels RJ Jr (1949)
Histamine antagonists.II. Unsymmetrical 1,4-disubstituted piper-
azines. J Am Chem Soc 71:2731–2734
Hardmann JD, Limbird LE, Molinoff PB, Ruddon RW, Gilmann AG
(eds) (1996) Goodman & Gilman’s the pharmacological basis of
therapeutics. Mc Graw-Hill, New York
Narsaiah AV (2006) Asymmetric synthesis of (S)-1-(3, 4-dihydroxy-
phenoxy)-3-(30,40- dimethoxyphenoxy) ethylamino-2-propanol
hydrochloride (RO363). Synth Commun 36:1897–1901
Yadav JS, Reddy BVS, Rao YG, Ravindar K, Narsaiah AV (2009)
Total synthesis of Xestodecalactone C from L-malic acid.
Synthesis 18:3157–3161
123