Assessment of the cardiovascular risks and health benefits of rosiglitazone
Isolation, Synthesis and Characterization of Rosiglitazone...
Transcript of Isolation, Synthesis and Characterization of Rosiglitazone...
ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
http://www.e-journals.net Vol. 5, No.3, pp. 562-566, July 2008
Isolation, Synthesis and Characterization of
Rosiglitazone Maleate Impurities
SINGAMSETTY RADHA KRISHNA§, MANDAVA VENKATA NAGA
BRAHMESHWAR RAO§, TIRMALARAJU SATYANARYANA RAJU
§,
VURIMIDI HIMABINDU# and GHANTA MAHESH REDDY
§*
§Research and Development, Dr. Reddy’s Laboratories Ltd.,
Integrated Product and Development, Unit-III, Plot No. 116, S V Co-Op.
Ind. Estate, Bollaram, Jinnaram, Medak Dist 502 325; A P, India #Institute of Sciences and Technology, Center for Environmental Sciences,
J.N.T. University, Kukatpally, Hyderabad-500072, India Dr. Reddy’s communication No. DRL-IPDO-IPM - 00074
Received15 November 2007; Accepted 2 January 2008
Abstract: Three unknown impurities in rosiglitazone maleate 1 bulk drug at
level below 0.1% (ranging from 0.05 to 0.1%) were detected by simple
reverse phase high performance liquid chromatography. These impurities
were preliminarily identified with LC-MS and characterized by the mass
number of the impurities. Different experiments were conducted and finally
synthesized and characterized the unknown impurities.
Keywords: Rosiglitazone, Drug, Impurities, Synthesis, HPLC and LC-MS
Introduction
Rosiglitazone maleate 1, is an anti diabetic drug, which is a choice of non insulin dependent
diabetes mellitus (NIDDM)1-5
, during the process development of rosiglitazone maleate 1, three
unknown impurities were identified in the analysis of different batches whose percentage area
ranged from 0.05 to 0.1% by HPLC. A comprehensive study has been carried out to isolate or to
prepare and characterize those impurities, due to the importance of the stringent requirement of
regulatory authorities and all the impurities should be at the levels of >0.1% must identified and
characterized. The present paper aims to isolate or prepare impurities and characterization.
Experimental
Samples The investigated samples of Rosiglitazone maleate bulk drug material were prepared in
Dr. Reddy’s Laboratories Ltd., Active Pharmaceutical Ingredient, Hyderabad, India.
Isolation, Synthesis of Rosiglitazone Maleate Impurities 563
High performance liquid chromatography (HPLC)
An in-house LC isocratic method was developed for the analysis of rosiglitazone maleate
and its impurities, where a column (Inertsil ODS 3V, 250 x 4.6 mm, 5 µ) with a mobile
phase consisting of buffer (4.14 g of sodium dihydrogen phosphate in 1000 mL of water,
adjusted the pH to 6.2 with diluted sodium hydroxide), and acetonitrile in the ratio of
50:50 (v/v) with a flow rate of 1.0 mL/min, UV detection at 245 nm was used. This LC
method was able to detect all these impurities.
Liquid chromatography-Mass spectrometry (LC-MS)
LC-MS/MS compatible method was developed for the analysis of Rosiglitazone maleate and
its impurities, where a column (Inertsil ODS 3V 250 X 4.6 X 5.0 µ) with a mobile phase
consisting of 0.01M ammonium acetate (pH=6.0) adjusted with dilute acetic acid and
acetonitrile in the ratio of 65:35, with a flow rate of 1.0 mL/min, UV detection at 280 nm
was used. This LC method was able to detect all the impurities. The mass spectrum of
impurities was recorded on AB-4000 Q-trap LC-MS/MS mass spectrometer.
Mass spectrometry
The electro spray ionization and MS-MS studies were performed on AB-4000 LC-MS/MS
mass spectrometer. The positive and negative electro spray MS data was obtained by
switching the capillary voltage between n+5000 and -4500V respectively.
NMR spectroscopy
The 1H NMR experiments of rosiglitazone maleate were done at 400 MHz and 100 MHz on
Varian Mercury plus 400 MHz FT NMR Spectrometer and similar experiments for
impurities 1, 2 and 3 were performed on Gemini-2000 (200 MHz) in DMSO-d6. The 1H
chemical shift values were reported on the δ scale in ppm relative to TMS (δ=0.00ppm) and
the chemical shift values were reported relative to CDCl3 (δ=77.00ppm) and DMSO-d6
(δ=39.50ppm) as internal standards respectively. DEPT spectra revealed the presence of
methyl and methane groups as positive peaks and methylenes as negative peaks.
FT IR spectroscopy
The IR spectra were recorded in the solid state as KBr dispersion medium using Perkin
Elmer Spectrum One FT IR spectrophotometer.
Synthesis of impurities
Synthesis of impurity 1 (desmethyl impurity)
To a mixture of 2-chloropyridine, (2, 40.0 g, 0.352 mol) and 2-aminoethanol (3, 48.2 g,
0.790 mol) heated to 145-155OC and maintained for 10-12 h, the reaction was monitored by
TLC, after completion of the reaction, cool to 25-35OC, added saturated sodium chloride
solution (~ 98 mL), and extracted with toluene (4 x 50 mL), the combined organic layer was
distilled, yielded 14 g of crude 4, proceeded to next step with out further purification. The
crude compound 4 (10 g), potassium tert- butoxide (29.5 g), and DMF (30 mL) were stirred
for 10 h at 25-35OC temperature, after completion of the reaction (monitored by TLC) water
(500 mL) was added and stirred for 2-4 h, the obtained solid was filtered and washed with
water suck dry for 1-1.5 h, the wet material was taken into the RBF, added thiazolidine-2,4-
dione (6, 5.5 g, 0.047 mol), benzoic acid (0.6 g), piperdine (0.5 g), toluene (82.0 mL) were
heated to azotropically reflux for 4-8 h, cool to 25-35OC filtered the solid and washed with
toluene, obtained compound 7, dried at 60-70OC, yield 7.0 g.
564 G. MAHESH REDDY et al.
The above compound 7(6.0 g), acetic acid and water mixture 100 mL (8:2) and wet
palladium carbon (10 g) under hydrogen pressure 2.0 kg/cm in hydrogenation rector for 12
h, the reaction mass was filtered through hyflow, washed with acetic acid and pH was adjust
to 6-7 with caustic lye, followed by extracted with dichloromethane (60 mL), the organic
layer was distilled completely and product was isolated in isopropyl alcohol, yield 2.5 g,
mass m/z 344, IR (KBr): 3333,1698, 1H NMR: 12.0(1H), 7.9-8.0(1H), 7.0-7.5(1H), 6.5-
7.5(2H), 6.5-7.0(2H), 4.8-5.0(1H), 3.8-4.2(2H), 3.6-3.8(2H), 3.2-3.4(3H), 2.8-3.2(1H).
Synthesis of impurity 1 (dimer impurity)
To a solution of 5-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-benzylidene}-thiazolidine-
2,4-dione (8, 300 g, 0.845.mol) in THF (1010 mL), cool the reaction mass to -5 to 0 °C and
slowly added L-slectride (186 mL) using dropping funnel at -5 to 0 OC the reaction
maintained for 40 minutes, then reaction was further cooled -10 O
C and added 10% aqueous
sodium hydroxide (338 mL) solution, followed by 27% hydrogen peroxide solution (84 mL)
was added. The solvent was distilled below 0OC and pH was adjusted to 7 with 2M HCl
solution (370 mL), the reaction mass was extracted with dichloromethane (3 x 150 mL), the
separated organic layer was distilled completely, the crude was purified by column
chromatography using dichloromethane and methanol as eluents, yield 4.0 g with 98%
purity by HPLC, mass m/z 712, IR (KBr): 3434, 2927, 1753, 1702; 1HNMR: 7.94(1H),
7.9(1H), 7.37(1H), 6.46-7.39(4H), 3.97-4.61(2H), 3.82-3.95(4H), 2.4-3.5(2H).
Synthesis of impurity 2 (succinate impurity)
A mixture of Rosiglitazone maleate (1, 10 g) and water (2 mL) were heated to 95-100OC for
120 h with out stirring, the reaction mass cooled to 25-35OC scratched 8.4 grams. Take this
material and methanol (160 mL) heat to 60-65OC, stirred for 20-30 minutes and cool to 40-
45OC, filter the solid and dried at 50-55
OC, yield 3.9 g with 99% purity by HPLC, MS : m/z
473, IR(KBr): 3547, 3422 and 1755,1715; 1HNMR: 4.97(dd,1H), 3.05(dd,1H), 3.38(m,1H),
7.15(d,1H), 6.86(d,1H), 4.11(t,2H), 3.89(t,2H), 3.06(s,3H), 8.07(d,1H), 6.56(t,1H), 7.50
(t,1H) 6.65(d,1H), 5.07(t,1H), 2.65(d,1H), 3.02(m,1H).
Figure 1. Blend chromatogram of rosiglitazone and its impurities
Table 1. IR and mass spectral data of impurities 1, 2 & 3.
S.No. compound IR cm-1
MS
1 Impurity 1 3434(NH), 2927(OH)
1753(C=O), 1702 (C=O)
protonated molecular ion
+ve ES m/z = 713
2 Impurity 2 3547(NH), 3422(OH)
1755(C=O), 1715 (C=O)
protonated molecular ion
+ve ES m/z = 473
3 Impurity 3 3333(NH), 1698(OH)
1753(C=O), 1702 (C=O)
protonated molecular ion
+ve ES m/z = 344
Isolation, Synthesis of Rosiglitazone Maleate Impurities 565
Table 2. 1H NMR spectral date of impurities 1,2&3
Impurity 1 Impurity 2 Impurity 3 S.No.
H ppm H ppm H ppm
1 1H 7.94 1H 4.97 2H 11.0
2 1H 7.90 1H 3.05 1H 7.9
3 1H 7.37 1H 3.38 1H 7.0
4 4H 6.46 1H 7.15 4H 6.5
5 2H 3.97 1H 6.86 1H 4.8
6 4H 3.82 2H 4.11 2H 3.8
7 2H 2.4 2H 3.89 2H 3.6
8 3H 3.06 3H 3.2
9 1H 6.56 1H 2.8
10 1H 5.07
11 1H 2.65
12 1H 3.02
Results and Discussion
In our approach based on the mass information from LC-MS we have proposed structures
and synthetic schemes (1-3) for the impurities. We have also designed different experiment
and synthesized these compounds and characterized. The isolated compounds RRT’s are
matching with of unknown impurities. The same impurities were enriched from the filtrates
of the isolated compounds, by keeping compound stability at variable temperatures.
Synthesis of rosiglitazone impurities
N Cl N NOH
H
N NO
HS
NH
O
O
N NH
O
S
NH
O
O
N NO
H
CHO+
OHH2N
(Desmethyl Rosiglitazone)
Impurity 1
Toluene F CHO
DMF/ tBuOK
Pd/C, AcOH
2 34
6
S
NH
O
O
5
7
Scheme 1
N NO
CH3S
NH
O
O
N NO
CH3 O
S
HN
NS
NH
L-slectrideN
Impurity 2
(Dimer impurity)
O
O
O
O
H3C
8
Scheme 2
566 G. MAHESH REDDY et al.
COOH
COOH.
Rosiglitazone Maleate (1)
water
Impurity 3
(succinate impurity)
N NO
CH3
S
NH
O
O COOH
COOH
N NO
CH3
S
N
O
O
Scheme 3
Conclusion
The results from various physio-chemical techniques confirm the structures of three
impurities of Rosiglitazone maleate 1. Based on the through analytical and the sequence of
preparations, the structures of three impurities were established with well characterization.
Acknowledgement
We thank the management of Dr. Reddy’s laboratories Ltd. for supporting this work. Co-
operation extended by all college of Analytical Research and Development division is
gratefully acknowledged.
References
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A L, Stephen A S and Peter L H, J. Med. Chem. 1994, 37, 3977.
2. DeFronzo R A, Ferrannini E and Koivisto V, Am. J. Med 1983, 17, 74(1A) 52.
3. Meguro K and Fujita T, US 4687777, 1987; Chem. Abstr. 1986,105:226543.
4. Momose Y, Meguro K, Ikeda H, Hatanaka C, Oi S and Sohda T, Chem. Pharm Bull.
1991, 39(6), 1440.
5. Barrie C C C, Drake S E, David H, Curtis H R, Catherine M H, Richard M H, Keith R
J, John T S and Stefan R W, J. Chem. Soc., Perkin Trans-1, 1994, 3319.
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