Identification and synthesis of impurities formed during sertindole preparation

Article abstract of DOI:10.3762/bjoc.7.5

Sertindole (1), an atypical anti-psychotic drug is used for the treatment of schizophrenia. During the laboratory optimization and later during its bulk synthesis the formation of various impurities was observed. The impurities formed were monitored and t

Full text of DOI:10.3762/bjoc.7.5

Identification and synthesis of impurities
formed during sertindole preparation
I. V. Sunil Kumar*1, G. S. R. Anjaneyulu1 and V. Hima Bindu2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 29–33.
1Research and Development Centre, Aptuit Laurus Private Limited,
ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad-500078,
India and 2Institute of Science and Technology, JNTU,
Hyderabad-500072, India
doi:10.3762/bjoc.7.5
Received: 29 September 2010
Accepted: 23 November 2010
Published: 07 January 2011
Email:
I. V. Sunil Kumar* - sunil.indukuri@aptuitlaurus.com
Associate Editor: N. Sewald
* Corresponding author
© 2011 Sunil Kumar et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
impurity profile; related substances; sertindole
Abstract
Sertindole (1), an atypical anti-psychotic drug is used for the treatment of schizophrenia. During the laboratory optimization and
later during its bulk synthesis the formation of various impurities was observed. The impurities formed were monitored and their
structures were tentatively assigned on the basis of their fragmentation patterns in LC-MS. Most of the impurities were synthesized
and their assigned constitutions confirmed by co-injection in HPLC. We describe herein the formation, synthesis and characteriza-
tion of these impurities. Our study will be of immense help to others to obtain chemically pure sertindole.
Introduction
The safety of a drug product is not only dependent on the toxi- then design a synthesis, which is time consuming. The develop-
cological properties of the active drug substance (or API), but ment of a drug substance is incomplete without the identifica-
also on the impurities formed during the various chemical trans- tion of an impurity profile involved in the process. Furthermore,
formations. Therefore, identification, quantification, and control it is not mandatory to design synthetic routes for the impurities.
of impurities in the drug substance and drug product are impor- Thus, in our study we explored the formation, identification,
tant parts of drug development for obtaining marketing synthesis and characterization of impurities found in the prepar-
approval. It is more challenging for an organic chemist to iden- ation of sertindole. This study will be of immense help for
tify the impurities which are formed in very small quantities in organic chemists to understand the potential impurities in sertin-
a drug substance. Since most of the time it is very difficult to dole synthesis and thereby obtain the pure compound.
identify and control impurities within acceptable levels in the
process, extra purification steps may then be necessary thereby Sertindole (1) (Figure 1), displays broad pharmacological
making the process less competitive. More often than not, the profile and mainly affects dopamine D2, serotonin 5-HT2 and
syntheses of impurities are not described in the literature which α1-adrenergic receptors [1-5]. It is a potent centrally acting
makes it even more difficult for the organic chemist who must 5-HT2 receptor antagonist in vivo and finds application in the
29

Beilstein J. Org. Chem. 2011, 7, 29–33.
Figure 1: Sertindole (1), process related impurities and metabolites.
treatment of anxiety, hypertension, drug abuse and cognitive known and unknown compound (impurity) in the drug should
disorders. It has been reported to show antipsychotic effect in be less than 0.15 and 0.10%, respectively [6]. In order to meet
clinical studies. In contrast to other antipsychotics, sertindole the stringent regulatory requirements, the impurities present in
has no associated sedative effects; sedation may add to the the drug substance must be identified and characterized. Litera-
cognitive problems inherent in schizophrenia.
ture reports [5,7-9] include impurities formed due to either over
reduction (e.g., 2, 3 and 6) [5,7], incomplete reduction (e.g., 4
Sertindole is designated chemically as 1-[2-[4-[5-chloro-1-(4- and 5) [5,8] or due to incomplete alkylation (e.g., 9 and 10)
fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazo- [5,7]. However, no synthetic details have been reported. In this
lidinone. Its literature synthesis (Scheme 1) [1-5] involves the context, the present study describes identification, synthesis and
copper catalyzed N-arylation of 5-chloroindole (11) with 4-fluo- characterization of impurities formed during sertindole syn-
robromobenzene (12). The product, 5-chloro-1-(4- thesis.
fluorophenyl)indole (13), on treatment with 4-piperidinone
hydrochloride monohydrate (14) under acidic conditions affords Results and Discussion
5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)- During the catalytic hydrogenation of indole 15, formation of
1H-indole hydrochloride (15). Reduction of 15 in the presence 0.5–1.0% of the des-chloro indole 17 is observed; the level is
of platinum oxide yields 5-chloro-1-(4-fluorophenyl)-3-(4- reduced to less than 0.1% during its isolation and purification. It
piperdinyl)-1H-indole (9) which on condensation with 1-(2- is necessary to remove the impurity at this stage because after
chloroethyl)imidazolidinone (16) in the presence of a base gives condensation with imidazolidinone 16, it is difficult to remove
sertindole (1).
the des-chloro sertindole 2, from sertindole, without significant
loss in yield. The impurity 2 was prepared by palladium
During the laboratory optimization of sertindole (1), many catalyzed hydrogenation of indole 9 and the des-chloro indole
process related impurities were identified. The guidelines 17 formed was condensed with imidazolidinone 16, under
recommended by ICH state that the acceptable levels for a Finkelstein conditions (Scheme 2).
30

Beilstein J. Org. Chem. 2011, 7, 29–33.
Scheme 1: Reagents and conditions: i) K2CO3, CuBr, ethylenediamine, DMF 130–135 °C; ii) CH3COOH, CF3COOH, 100–110 °C; iii) PtO2/H2,
methanol, 30–35 °C; iv) K2CO3, KI, methylisobutyl ketone (MIBK),110–115 °C.
The platinum catalyzed reduction of indole 15 is a critical reac- bromophenyl) indole (18) along with the desired indole 13 was
tion, whilst a prolonged reaction time leads to dehalogenated observed. A detail study of this coupling reaction revealed
product 2, termination without complete reduction leads to significant formation of this undesired indole in the absence of a
indole 9 contaminated with 15. This contaminated material transition metal, especially when cesium carbonate was used for
upon condensation with imidazolidinone 16 results in sertin- the coupling reaction. Sertindole (1) synthesized from this cont-
dole (1) contaminated with 5. The degree of contamination was aminated material was found to contain impurity 21 at levels of
0.02–0.10% [10]. It is difficult to remove the impurity 5 from 0.05–0.25% [10]. In order to quantify and limit the impurities in
sertindole (1). Indole 5 was prepared by condensation of 15 the final drug substance, indole 18 was converted to the corres-
with 1-(2-chloroethyl)imidazolidinone (16) in the presence of ponding N-(4-bromophenyl)-impurity 21 (Scheme 4). The
base (Scheme 3).
catalytic hydrogenation of indole 19 proved to be a difficult
reaction as significant formation of the dehalogenated products
During the N-arylation of 5-chloroindole (11) with 1-bromo-4- was observed, repeated recrystallization from MeOH afforded
fluorobenzene (12), formation of traces of 5-chloro-1-(4- pure indole 20.
Scheme 2: Reagents, conditions (and yields): i) (a) pH adjusted to 6;
(b) Pd/C, HCOONH4, AcOH, MeOH, reflux (77.6%); ii) 16, K2CO3, KI,
Scheme 3: Reagents, conditions (and yields): i) 16, K2CO3, KI, MIBK,
MIBK, reflux (44.5%).
reflux (73.9%).
31

Beilstein J. Org. Chem. 2011, 7, 29–33.
Scheme 6: Reagents, conditions (and yields): i) 12, K2CO3, Cu(II)Br,
ethylenediamine, DMF, 130–135 °C, (51%); ii) 14, CH3COOH,
CF3COOH, 100–105 °C (57%); iii) (a) pH adjusted to 6–7; (b) PtO2/H2,
MeOH, 30–35 °C; (c) column chromatography (33.3%); iv) 16, K2CO3,
KI, MIBK, reflux (64.3%).
Scheme 4: Reagents, conditions (and yields): i) Cs2CO3, DMF,
130–135 °C; ii) 14, CH3COOH, CF3COOH, 100–105 °C (43.4% from
11); iii) (a) pH adjusted to 6–7; (b) H2, PtO2, MeOH, AcOH, 30–35 °C;
(c) crystallization (24.7%); iv) 16, K2CO3, KI, MIBK, reflux (65% yield).
Since dehalogenation was observed during the platinum oxide sertindole (27) was synthesized from 5-bromoindole (23)
reduction of the tetrahydropyridinyl moiety in indole 19, this following the reaction sequence used to synthesize 1
reaction was utilized to synthesize the des-fluoro sertindole 3. (Scheme 6).
Thus prolonged hydrogenation of 19 afforded des-fluoro indole
22, which on condensation with imidazolidinone 16 afforded During the N-alkylation reaction there is always the probability
the desired compound 3 (Scheme 5). The contamination by 3 in of dialkylation, hence the dialkylated piperidine 28 was synthe-
sertindole (1) was 0.20–0.50% [10].
sized by prolonged condensation of imidazolidinone 16 with
sertindole (1), followed by purification by column chromato-
In some of commercial samples, 5-chloroindole was found to be graphy (Scheme 7). The contamination by 28 in sertindole (1)
contaminated with traces of 5-bromoindole (23), although the was 0.25–0.45% [10].
amount of contamination of the bromo analogue 27 in sertin-
dole (1) was never more than 0.02%. The bromo analogue of
Scheme 5: Reagents, conditions (and yields): i) (a) pH adjusted to
6–7; (b) H2, PtO2, MeOH, AcOH, 30–35 °C (73% yield); ii) 16, K2CO3,
Scheme 7: Reagents, conditions (and yield): i) (a) 16, Et3N, NaI,
KI, MIBK, reflux (52%).
CH3CN, reflux; (b) column chromatography (19.1%).
32

Beilstein J. Org. Chem. 2011, 7, 29–33.
Sertindole N-oxide 29, a possible contaminant that can be Acknowledgements
formed by air oxidation, was prepared by oxidation of sertin- The authors wish to thank AptuitLaurus Private Limited for
dole (1) with m-chloroperbenzoic acid (Scheme 8). The con- supporting this work.
tamination by 29 in sertindole (1) was <0.05% [10].
References
1. Perregaard, J. K. Heterocyclic compounds. EP0200322, Nov 5, 1986.
2. Perregaard, J. K. 1-(4'-fluorophenyl)-3,5-substituted indoles useful in
the treatment of psychic disorders and pharmaceutical compositions
thereof. U.S. Patent 4710500, Dec 1, 1987.
3. Perregaard, J. K.; Skarsfeldt, T. Use of sertindole for the treatment of
schizophrenia. EP0392959, Oct 17, 1990.
4. Zanon, J.; Villa, M.; Ciardella, F. Method for manufacture of sertindole.
WO03/080597, Oct 2, 2003.
U.S. Patent Application 2009264656, Oct 22, 2009.
5. Perregaard, J.; Arnt, J.; Bøgesø, K. P.; Hyttel, J.; Sanchez, C.
J. Med. Chem. 1992, 35, 1092–1101. doi:10.1021/jm00084a014
6. ICH guidelines, Q3A (R): Impurities in new drug products: The quality
guidelines for active pharmaceutical ingredients related to impurities
Scheme 8: Reagents, conditions (and yield): i) (a) mCPBA, MeOH,
40–45 °C; (b) column chromatography (52.2%).
according to the International Conference of Harmonization. 2002;
http://www.ich.org.
7. Pearlstein, R. A.; Vaz, R. J.; Kang, J.; Chen, X. L.;
Preobrazhenskaya, M.; Shchekotikhin, A. E.; Korolev, A. M.;
Lysenkova, L. N.; Miroshnikova, O. V.; Hendrix, J.; Rampe, D.
Bioorg. Med. Chem. Lett. 2003, 13, 1829–1835.
Conclusion
For the better understanding of the synthetic pathway of an
active pharmaceutical ingredient (API) it is necessary to iden-
tify all the impurities formed/anticipated. In this regard we have
synthesized and characterized different potential process-related
impurities of sertindole.
doi:10.1016/S0960-894X(03)00196-3
8. Andersen, K.; Liljefors, T.; Gundertofte, K.; Perregaard, J.;
Bøgesø, K. P. J. Med. Chem. 1994, 37, 950–962.
doi:10.1021/jm00033a013
9. Tzeng, T.-B.; Stamm, G.; Chu, S.-y. J. Chromatography B 1994, 661,
299–306. doi:10.1016/0378-4347(94)00356-4
10.The degree of formation of the impurities and the HPLC chromatogram
included in the Supporting Information File S2, page 29, is for samples
of sertindole (1) obtained before laboratory optimization.
Supporting Information
Experimental procedure (Supporting Information File 1);
HPLC chromatograms, 1H and 13C NMR spectra of
compounds 2, 3, 5, 9, 21, 27, 28 and 29 (Supporting
Information File 2). HPLC chromatogram containing
sertindole (1) spiked with process related impurities and
LC-MS fragmentation data [10] is included in Supporting
Information File 2.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Supporting Information File 1
Full experimental details and characterization data for all
new compounds.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-5-S1.pdf]
(http://www.beilstein-journals.org/bjoc)
Supporting Information File 2
1H and 13C NMR spectral data and HPLC chromatograms
for all new compounds.
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.7.5
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-5-S2.pdf]
33