Synthesis of rimonabant regioisomer

Article abstract of DOI:10.1007/s00706-008-0903-7

A novel synthesis route for a rimonabant regioisomer was developed.

Full text of DOI:10.1007/s00706-008-0903-7

Monatsh Chem 139, 1091–1093 (2008)
DOI 10.1007/s00706-008-0903-7
Printed in The Netherlands
Synthesis of rimonabant regioisomer
Kotagiri Vijay Kumar1, Jambula mukunda Reddy1, Sashi Kanth Suthrapu1, Chitneni Prasad Rao2,
P. Pratap Reddy1, Apurba Bhattacharya1, Rakeshwar Bandichhor1
1
Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd., Bachupally, Qutubullapur, A.P., India
2
Department of Chemistry, Osmania University, Hyderabad, A.P., India
Received 23 November 2007; Accepted 16 January 2008; Published online 21 April 2008
# Springer-Verlag 2008
Abstract A novel synthesis route for a rimonabant
regioisomer was developed.
impurities. Despite the synthesis of the desired one,
our affair also involves identifying and characterizing
impurities by means of spectroscopy and other tech-
niques. Since they are present only in traces, the
spectroscopic characterization and documentation are
practically impossible that enforces us to design
route(s) for their synthesis if they are of organic origin.
Keywords Rimonabant; Anti-obesity; Regioisomer.
Introduction
Impurities’ profiling of active pharmaceutical ingre-
dients (APIs) imposes a great challenge in pharma-
ceutical industries and a renaissance for the same is
now seen as an indispensable aspect of drugs and
their process development for the following reasons:
i) to assure that the elicited pharmacological or tox-
icological effects are only due to the API and not due
to impurities, ii) also to ensure that in the due course
of the product formulation and marketing the im-
purities should not be generated or elevated, and
iii) impurities can not be considered always to be
inferior, it may have better pharmacological and in-
ferior toxicological properties [1].
Results and discussion
Synthesis of 1 and their analogs are extensively ex-
plored [2–6]. The only synthesis of regioisomer 2
(Fig. 1) in trace amount (as an impurity) is given in
Ref. [7]. Herein, we report a novel synthesis of 2 in
moderate yield.
As presented in Scheme 1, we were able to
accomplish the synthesis of 2 in three steps. Pre-
paration of the ethyl 4-(4-chlorophenyl)-3-methyl-
2,4-dioxobutanoate (4) was achieved by reacting
When it comes to profiling of impurities generated
from chemistry involved in the synthesis it becomes
more stringent and demanding. In general, during the
synthesis of desired species, traces of certain unde-
sired byproducts used to be observed that we refer
Correspondence: Rakeshwar Bandichhor, Innovation Plaza,
IPD, R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42,
45, 46& 54, Bachupally, Qutubullapur, R. R. Dist. 500073, A.P.,
India. E-mail: rakeshwarb@drreddys.com; Chitneni Prasad
Rao, DepartmentofChemistry, OsmaniaUniversity, Hyderabad
5000007, A.P., India. E-mail: prasadraoch@yahoo.com
Fig. 1 Rimonabant (1) and its regioisomer 2

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K. V. Kumar et al.
Scheme 1
Ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate (4)
A mixture of 300 cm3 methylcyclohexane and 300 cm3 1 M
solution of lithium hexamethyldisilazane (0.32 mol) was
charged into a round-bottom flask under N2 and cooled to
15–25ꢀC. To this solution was added a solution of 50.0 g 3
(0.30 mol) in 125cm3 methylcyclohexane over a period of
45min and stirred about 2.5h, then 47.8g diethyl oxalate
(0.33 mol) were added over a period of 30–45min and stirred
about 17h. On the completion of the reaction (TLC), the solid
material was filtered off and washed with 100cm3 methylcy-
clohexane. The solid was dissolved in 250 cm3 water, filtered,
and the pH of the filtrate was adjusted to 1–2 by adding conc.
hydrochloric acid (24 cm3). Separated solid was filtered off,
the filtrate was extracted with 3Â250 cm3 ethyl acetate, and
the organic layer was dried over anhydrous sodium sulfate
(20 g) followed by distillation of the solvent at about 55–
65ꢀC under reduced pressure of about 700 mmHg to afford
21.5g 4 (identical as described in Ref. [7]) as a residue.
1-(4-chlorophenyl)propane-1-one (3) with ethyl gly-
oxalate in presence of LHMDS followed by treating
the resultant with conc. aq. HCl. Triethylamine me-
diated amidation followed by condensation afforded
the desired regioisomer 2 in moderate yield. This
successful synthesis proved to be advantageous in
identifying the impurity 2 which was formed, in
trace amount, during the synthesis [6] of 1 at large
scale (200 g). Spectroscopic data of 2 is in agree-
ment with literature [7].
In conclusion we accomplished a novel and im-
proved synthesis for 2.
Experimental
Unless otherwise stated, all non-aqueous reactions and dis-
tillations were carried out under an atmosphere of dry N2
in dried glassware. When necessary, solvents and reagents
were dried prior to use. Analytical thin layer chromatogra-
phy (TLC) was performed on EM Reagents 0.25 mm sil-
ica gel aluminum supported plates that have been bought
from Merck. Visualization was accomplished by irradia-
N-(Piperidin-1-yl)-3-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-methyl-1H-pyrazole-5-carboxamide (2)
A mixture of 21.5g 4 (0.08 mol) in 11.0cm3 triethylamine and
8.04g 1-aminopiperdine (0.08 mol) was stirred about 3 h at
ambient temperature. On completion of reaction (TLC),
500 cm3 ethyl acetate were added and the organic layer was
washed with 3Â500 cm3 water, dried over sodium sulfate
followed by distillation of the solvent at about 55–65ꢀC under
reduced pressure of about 700mm Hg to afford 19.5g 5 as a
crude material. A solution of 19.5g 5, and 12.9g 2,4-dichloro-
phenylhydrazine (0.06 mol) in 240 cm3 ethanol was stirred
for 8 h. On completion of the reaction (TLC), the solid was
filtered off, washed with 20cm3 ethanol, and solvent was
1
tion under a 254 nm UV lamp. H NMR spectra were re-
corded on a Varian 400 MHz. Chemical shifts are reported
in ppm from tetramethylsilane or with the solvent reso-
nance as the internal standard (CD3OD 3.31 ppm). IR spec-
tra were taken on Perkin-Elmer equipment. Mass spectra
were obtained on a low resonance Q-trap machine in elec-
tron spray mode. Melting points were obtained on a Polmon
apparatus.

Synthesis of rimonabant regioisomer
1093
removed at about 55–65ꢀC under reduced pressure of about
700 mm Hg to afford a residue (23.2g). This was dissolved in
200 cm3 dichloromethane and stirred about 30 min followed
by filtration of solid that was washed with 10 cm3 dichloro-
methane. Solvent from the resultant filtrate was distilled
completely at about 35–40ꢀC under reduced pressure of about
700 mmHg to afford 21.5g of crude compound. This was
purified by column chromatography to afford 8.5 g 2 (identical
as described in Ref. [7]) in 30% yield. To remove the trace
amount of rimonabant (1) (identical as described in Ref. [7]),
the mixture was separated by dissolving the semi-pure ma-
terial obtained from column in 50 cm3 acetone and stirring
for about 10 min afforded insoluble rimonabant (1) in 0.3 g
quantity.
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Acknowledgements
We thank the management of IPDO, Dr. Reddys Laboratories
for supporting this work.
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