An investigation into formation of impurities during synthesis of blonanserin

Article abstract of DOI:10.14233/ajchem.2014.16331

During the process development of Blonanserin (1 ), we have observed formations of unknown impurities are in the final product at enhanced levels which was identified as Des ethyl impurity, di-N-ethylpiperazine impurity, Chloro impurity and des-fluoro impurity. The present work involves detailed optimization studies directed toward the development of an efficient process for the commercial production of Blonanserin substantially free from the chloro impurity and other impurities.

Full text of DOI:10.14233/ajchem.2014.16331

Asian Journal of Chemistry; Vol. 26, No. 18 (2014), 5928-5930
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16331
An Investigation into Formation of Impurities During Synthesis of Blonanserin
1
,2,*
1
2
2
1
K. SUDARSHAN RAO , K. NAGESWARA RAO , T. UMA SANKARA SASTRY , P. MURALIKRISHNA and A. JAYASHREE
1
2
Centre for Chemical Sciences and Technology, IST, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 085, India
Mylan Laboratories Limited, Hyderabad, Telangana, India
*
Corresponding author: sudarshan_kotha@yahoo.co.in
Received: 11 September 2013; Accepted: 1 January 2014;
Published online: 1 September 2014;
AJC-15824
During the process development of Blonanserin (1), we have observed formations of unknown impurities are in the final product at
enhanced levels which was identified as Des ethyl impurity, di-N-ethylpiperazine impurity, Chloro impurity and des-fluoro impurity. The
present work involves detailed optimization studies directed toward the development of an efficient process for the commercial production
of Blonanserin substantially free from the chloro impurity and other impurities.
Keywords: Blonanserin, Synthesis, Impurities, Characterization.
INTRODUCTION
EXPERIMENTAL
Blonanserin, (2-(4-ethyl-l-piperazinyl)-4-(4-fluorophenyl)-
,6,7,8,9,10-hexahydrocycloocta[b]pyridine) is a novel anti-
Preparation of 4-(4-fluorophenyl)-5,6,7,8,9,10-hexa-
hydrocyclooctane[b]pyridine-(1H) ketone (3): To a mixture
of 4-fluorobenzoylacetonitrile (100 g), methane sulfonic acid
(230.6 g) and water (14 mL) was heated to 65-70 °C, stirred
for 3 h and added a cyclooctanone (85 g) at same temperature
then heated to 110 to 115 °C stirred for 2 h, cool to room tempe-
rature then diluted with dichloromethane and water, organic
layer was separated and washed organic layer with water, then
distilled under vacuum solid obtained and purified with acetone
to get pure compound. Yield: 120 g; 73 %.
5
psychotic agent, researched and developed by the Japanese
Zhu You Pharmaceutical Co Ltd. and was marketed for the
first time in Japan in April 2008. Dopamine D
2
and serotonin
1-6
5-HT2A receptor antagonist properties . It is one of the second-
generation antipsychotic agents, together with risperidone and
olanzapine, it is effective in the treatment of both positive and
negative symptoms of schizophrenia without extra-pyramidal
symtoms, but has original properties of affinity higher for the
7
receptor than for the serotonin 5-HT2A receptor .
dopamine D
On the other hand, blonanserin is much less potent in adrener-
2
Preparation of 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-
hexahydrocycloocta[b]pyridine (2): To a mixture of phenyl
phosphine dichloride and 73 g of 3 was heated to 155-160 °C
for 4 h and TLC monitored complete the reaction and cool the
reaction mass at ambient temperature then dichloromethane
700 mL and water 30 mL was added, adjusted pH 8.5 with liq
ammonia then organic layer separated, washed the organic
layer with water distilled under vacuum solid obtained and
purified with acetone to get pure compound. Yield: 66 g;
85 %.
6
gic-α
Such a pharmacological profile shows that blonanserin is more
specific to the dopamine D and serotonin 5-HT2A receptors
with fewer side effects; its excellent effects on schizophrenia
1 1 1
, histamine H and muscarinic M antagonist activities .
2
8
-10
have been reported in many reports . There is a possibility
that this drug gain popularity for treatment of schizophrenia
throughout the world.
In the literature, references, carry out cyclization using
4
-fluorobenzoylacetonitrile (4) and cyclooctanone in the pre-
sence of polyphosphoric acid (PPA) to get 4-(4-fluorophenyl)-
,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(1H)-one (3),
Preparation of 2-(4-ethylpiperazine-1-yl)-4-(4-fluoro-
phenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (1): To
a mixture of potassium iodide 35.7 g, N-ethylpiperazine 78 g
and 65 g of 2 was heated to 165-170 °C for 8 h, cool to room
temperature then water 200 mL and ethylacetate 1000 mL was
added stirred reaction mass for 15 min separated organic layer
then extracted with water using of hydrochloric acid solution
5
yield 60 %. Undergo chlorination of 3 to get 2-chloro-4-(4-
fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine
(2), finally carry out substitution reaction with N-ethyl-
piperazine to get 1. Total yield is 24.4 %.

Vol. 26, No. 18 (2014)
An Investigation into Formation of Impurities During Synthesis of Blonanserin 5929
1
20 mL, layers separated product in aqueous, then adjusted
Desfluoro and Chloro impuries were prepared according
to procedure of 3, 2 and 1.
2-(4-Ethylpiperazine-1-yl)-4-(4-chlorophenyl)-
pH 9 with 30 % NaOH Solution then extracted compound
with ethylacetate 2 × 500 mL, combined organic layer washed
with water, distilled organic layer a white crystalline compound
obtained, the crude purified with isopropyl alcohol to get 71.5 g,
yield 86 % obtained.
1
5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (5): H NMR
(DMSO-d
6
) δ: 7.19-7.36 (4H, d), 2.56 (2H, t), 1.37-1.42 (6H,
m), 2.88 (2H, t), 6.28 (1H, s), 3.53 (4H, t), 2.56 (4H, t), 2.43-
–1
2
-(Piperazine-1-yl)-4-(4-fluorophenyl)-5,6,7,8,9,10-
hexahydrocycloocta[b]pyridine (Des ethyl impurity) (8):
2.50 (2 H, q), 1.13 (3H, t). IR (KBr, νmax, cm ): 3074, 3040,
2950, 2920, 2844, 2832, 2814, 1600, 1585, 1541, 1493, 1468,
1444, 1408, 1260, 1241, 997, 950, 885, 844, 831, 776. m/z :
To a mixture of potassium iodide 5.5 g, piperazine 18.6 g and
1
+
0 g of 2 was heated to 165-170 °C for 8 h, cool to room
384 [M + H] .
temperature then water 30 mL and ethylacetate 150 mL was
added stirred reaction mass for 15 min separated organic layer
then extracted with water using of hydrochloric acid solution
2-(4-Ethylpiperazine-1-yl)-4-phenyl-5,6,7,8,9,10-
1
hexahydrocycloocta[b]pyridine (6): H NMR (DMSO-d
6
) δ:
7.24-7.27 (3H, m), 7.32-7.42 (2H, m), 2.55-2.60 (2H, m), 1.38-
1.43 (6H, m), 1.75-1.80 (2H, m), 2.89 (2H, t), 6.33 (1H, s),
3.53 (4H, t), 2.55-2.60 (4H, m), 2.43-2.50 (2H, q), 1.13 (3H,
1
8.5 mL, layers separated product in aqueous, then adjusted
pH 9 with 30 % NaOH solution then extracted compound with
ethylacetate 2 × 150 mL, combined organic layer washed with
water, distilled organic layer a white crystalline compound
-1
t). IR (KBr, νmax, cm ): 3077, 3055, 3026, 2942, 2923, 2849,
2826, 1585, 1546, 1493, 1456, 1450, 1410, 1264, 1245, 1167,
1
+
1127, 1000, 925, 886, 833, 769, 703. m/z: 350 [M + H] .
obtained, the crude purified with ethanol to get yield 8.5 g. H
NMR (DMSO-d
.57(2H, t(5.4)), 1.37-1.44 (6H, m), 1.74-1.78 (2H, m), 2.88
2H, t(6.2)), 6.29 (1H, s), 3.49 (4H, t(5.1)), 3.01 (4H, t(5.0)),
6
) δ: 7.05-7.10 (2H, m), 7.19-7.24 (2H, m),
RESULTS AND DISCUSSION
2
(
4-Fluorobenzoyl acetonitrile (4) is treated with methane
sulphonic acid and water at 70 °C to form in situ 3-(4-fluoro-
phenyl)-3-oxopropanamide which is further treated with cyclo-
octanone to obtain 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-
cyclooctane[b]pyridine-(1H)ketone (3), intermediate 2 was
prepared by using of 3 and phenyl phosphine dichloride finally
condensation of intermediate 2 with N-ethyl piperazine in the
presence of potassium iodide to give Blonanserin (1) (Scheme-
I).
-1
2
3
1
.28 (1H, br,s). IR (KBr, νmax, cm ): 3416, 3330, 3261, 3068,
045, 2922, 2849, 1606, 1590, 1543, 1507, 1470, 1449, 1411,
293, 1273, 1245, 1218, 1192, 1154, 998, 944, 887,836, 788
+
m/z: 340 [M + H] .
(2-(4-Ethylpiperazine-1-yl)-4-[4-(4-ethylpiperazine-1-
yl)phenyl]-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine)
(
Di-N-ethyl piperazine impurity) (7): Taken blonanserin
filtered mother liquor 100 mL, distilled under vacuum, the
residue was in column chromatography, elute the impurity with
During our preliminary optimization studies, we have
observed four major impurity in the final product and the mole-
cular weights of these impurities were identified by LC-MS
2:98 of methanol and dichloromethane, collect the fraction
distilled under vacuum 2 g of the title compound 7 obtained.
Scheme-I: Commercial synthesis of Blonanserin

5
930 Rao et al.
Asian J. Chem.
F
F
dose requiring the lower qualification threshold, identification
was again attempted. Improved isolation equipment and NMR
techniques resulted in the successful identification of the
impurity.
a
Des ethyl impurity (8) was formed a small amount of ethyl
piperazine present in N-ethylpiperazine, that impurity was
prepared by using of piperazine in the presence of potassium
iodide to get des ethyl impurity (Scheme-II), Di-N-ethyl-
piperazine (7) impurity was formed by using excess of N-ethyl-
piperazine and carryover of chloro and desfluoro instead of
fluoro in 4-fluorobenzoyl acetonitrile, that two impurities chloro
impurity 5 and desfluoro impurity 6 was formed up to final
stage (Scheme-I).
N
Cl
N
N
NH
8
Reaction conditions: (a) piperazine, KI, ethyl acetate
Scheme-II
ACKNOWLEDGEMENTS
analysis as 339, 461, 383 & 385 and 349 were identified as
Des ethyl impurity, di-N-ethylpiperazine impurity, chloro
impurity and des-fluoro impurity respectively. The structure
was further confirmed through synthesis/isolation from mother
liquor, characterization and HPLC spike studies. The content
of compounds 5, 6, 7 and 8 in the final product varied depen-
ding upon the various process parameters and the control of
these impurities could be accomplished by employing appro-
priate controls in the process and temperature in the process.
Detailed investigation and careful mapping of the impurities
at all the stages indicated that the impurity was formed during
the penultimate
The authors Management, the Analytical Research
Department and IPM groups of Mylan Laboratories Limited
for their generous support.
REFERENCES
1
2
.
.
H. Oka, Y. Noda, Y. Ochi, K. Furukawa, T. Une, S. Kurumiya, K. Hino
and T Karasawa, J. Pharmacol. Exp. Ther., 264, 158 (1993).
Y. Noda, S. Kurumiya,Y. Miura and M. Oka, J. Pharmacol. Exp. Ther.,
2
65, 745 (1993).
A. Prakash and A.J. Wagstaff, Drugs, 56, 429 (1998).
3
4
.
.
T. Nagai, Y. Noda, T. Une, K. Furukawa, H. Furukawa, Q.M. Kan and
T. Nabeshima, Neuroreport, 14, 269 (2003).
5
6
.
.
T. Ochi, M. Sakamoto, A. Minamida, K. Suzuki, T. Ueda, T. Une, H.
Toda, K. Matsumoto and Y. Terauchi, Bioorg. Med. Chem. Lett., 15,
A key portion of the development of a commercial synthesis
is the identification of all impurities in the drug substance and
later intermediates. From the outset, identification of the
unknown impurity had proven problematic. No samples of
Blonanserin with > 0.05 % of the impurity were available, but
we were unable to draw a structure to fit this mass, without a
structure it is impossible to determine the source of an impurity
in a complex synthetic route; the mass expected for earlier
steps cannot be predicted. Given the possibility of a higher
1
055 (2005).
T. Ishibashi, H. Nishikawa, T. Une and H. Nakamura, Folia Pharmacol.
Jpn, 132, 351 (2008).
7
8
9
.
.
.
E.D. Deeks and G.M. Keating, CNS Drugs, 24, 65 (2010).
R. Kumagai andY. Ichimiya, Psychiatry Clin. Neurosci., 63, 593 (2009).
E. Garcia, M. Robert, F. Peris, H. Nakamura, N. Sato and Y. Terazawa,
CNS Drugs, 23, 615 (2009).
10. T. Furuse and K. Hashimoto, Ann. Gen. Psychiatry, 9, 17 (2010).