An alternative synthetic route for an antidiabetic drug, rosiglitazone

Article abstract of DOI:10.1016/j.bmcl.2011.12.020

A convenient and scalable four-step novel route has been developed for the synthesis of rosiglitazone (8), an antidiabetic drug. This multistep route requires 4-fluoro benzaldehyde (4), 2,4-thiazolidinedione (6) and 2-chloro pyridine (1) as key reactants and gives overall better yield of rosiglitazone. In addition, some steps have been accelerated, which leads to an overall time saving of 10 h.

Full text of DOI:10.1016/j.bmcl.2011.12.020

Bioorganic & Medicinal Chemistry Letters 22 (2012) 924–928
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
An alternative synthetic route for an antidiabetic drug, rosiglitazone
⇑
Dhanaji V. Jawale, Umesh R. Pratap, Ramrao A. Mane
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and scalable four-step novel route has been developed for the synthesis of rosiglitazone (8),
an antidiabetic drug. This multistep route requires 4-fluoro benzaldehyde (4), 2,4-thiazolidinedione (6)
and 2-chloro pyridine (1) as key reactants and gives overall better yield of rosiglitazone. In addition, some
steps have been accelerated, which leads to an overall time saving of 10 h.
Received 3 November 2011
Revised 29 November 2011
Accepted 3 December 2011
Available online 9 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2,4-Thiazolidinedione
Deep eutectic solvent
Rosiglitazone
Diabetes mellitus
Type 1 diabetes mellitus (DM) is a widespread metabolic dis-
ease.1 The causes of diabetes mellitus have been well recognized.
This is complex, chronic and progressive disease,2 which is consid-
ered by World Health Organization (WHO) as refractory disease.3
Considering the seriousness of Type 2 diabetes mellitus (Type 2
DM) various clinical agents are developed and are in use.4 Recently
2,4-thiazolidinediones (TZD’s) are gaining more importance as
antidiabetic agents and their mechanism of action has been thor-
oughly investigated.5 Thiazolidinediones viz. pioglitazone, rosiglit-
azone, netoglitazone and ciglitazone are found to display
significant antidiabetic activity.6 Among them rosiglitazone dis-
plays superior antihyperglycemic activity and therefore used to
treat type 2 diabetes mellitus.7,8 Rosiglitazone activates the perox-
isome proliferator activated nuclear receptor subtype PPAR gamma
and this substrates has been found to bind to this PPAR isoform
with a kd of 40 nM.5b
In view of the significance of rosiglitazone several efforts have
been made which leads to provide better and cost effective syn-
thetic routes for rosiglitazone. Following are some important syn-
thetic methods which are practiced to prepare rosiglitazone.
Cantello et al.7 have reported the synthesis of rosiglitazone, BRL
49653 using the reactants, 4-fluoro benzaldehyde, 2,4-thiazolidin-
edione and 2-Cl-pyridine. The route is depicted in Scheme 1. It
seems that though this is four-step synthetic route but it needs
more than 36 h for generating rosiglitazone. This route also requires
toxic/hazardous chemicals like NaH, piperidine and toluene. Solid
phase synthesis of rosiglitazone has been attempted by Brummond
and Lu.9 This route also requires 4-hydroxy benzaldehyde, 2-fluoro
pyridine, trifluoroacetic acid, and [(Ph3P) CuH]6 as reactants. More-
over, it lacks scalability and is associated with additional steps like
linking and delinking.
Recently polymer assisted synthesis of rosiglitazone has been
developed by Ladlow and co-workers.10 The synthetic route is de-
picted in Scheme 2.
The overall yield of this route is 46% and has seven steps. The
conversions of compound (13) to (5) and (5) to (7) have been done
using toxic and hazardous polymer supported reagents like Ps-CrO3
and piperazinomethyl polystyrene.
Shimizu and Gaonkar11 have developed a simple, rapid and high
yielding synthetic protocol for rosiglitazone (Scheme 3). The rates
of most of the steps of this protocol have been accelerated by
microwave irradiation. Hence the route is not easily scalable.
Considering the lacunas of the reported synthetic routes here
we thought that there is still scope to improve cost efficiency of
rosiglitazone production by providing relatively rapid and non te-
dious work up protocols with the ability to obtain rosiglitazone
with overall high yield.
Here an alternative scalable synthetic route for the synthesis of
rosiglitazone has been developed, which leads to better/higher
yield of rosiglitazone. Steps involved in the route are drawn in
Scheme 4.
The developed route has overall four steps. The first step deals
with Knoevenagel condensation of 4-fluorobenzaldehyde (4) and
2,4-thiazolidinedione (6), carried for obtaining 5-(4-fluorobenzy-
lidene) thiazolidine-2,4-dione (9). This condensation was carried
out using a safer nonvolatile solvent, freshly prepared deep eutec-
tic solvent (16). The condensation was found to be completed
within 2 h at 80 °C. In the second step the intermediate
2-(N-ethyl-N-(pyridin-2-yl) amino) ethanol (3) has been synthe-
sized using literature procedure.7 The compound (3) was then
⇑
Corresponding author. Tel.: +91 240 2403313; fax: +91 240 2403335.
E-mail addresses: manera2011@gmail.com, manera@indiatimes.com(R.A. Mane).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.020

D. V. Jawale et al. / Bioorg. Med. Chem. Lett. 22 (2012) 924–928
925
i) NaH, DMF,
OH
120ºC
14-15h
N
H
80ºC, 10-12h
OH
N
Cl
O
N
N
N
N
2
F
ii)
1
3
5
CHO
i ) Piperidine
CHO
4
O
ii)
Toluene,
NH
reflux, 7-8h
O
S
6
O
O
NH
O
Mg, Methanol, iodine
Reflux, 3h
N
O
N
NH
N
N
O
O
S
S
7
Rosiglitazone
8
Scheme 1. Synthesis of rosiglitazone drug.
O
O
O
O
O
OH
N
H
ethyl iodoacetate
i) MeNH2, H-15, THF
HO
HO
K2CO3, DMF, 90ºC
11
10
9
i) BH3,THF, 65ºC
ii)Et2NH
HO
iii) SCX-2
NH
N
N
O
O
N
N
O
HO
2-fluoropyridine
12
PS-CrO3, THF
OHC
13
120ºC
5
O
NH
piperazinomethyl
i)
ii) SCX-2
polystyrene, PhMe, 88ºC
O
HO
O
S
6
N
N
O
N
N
H2, Pd (OH)2
O
S
1,4-dioxane, 80ºC
7
HN
8
O
O
S
HN
O
Scheme 2. Polymer assisted synthesis of rosiglitazone.
condensed with 5-(4-fluorobenzylidene) thiazolidine-2,4-dione (9)
in dimethyl sulfoxide in presence of potassium carbonate and ob-
tained (Z)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]-
methylene]-2,4-thiazolidinedione 7 within 4 h. The compound 7
on reduction with methanol–Mg gave rosiglitazone 8. This route
avoids the use of sodium hydride, piperidine, N,N-dimethyl form-
amide and steps required for linking and delinking of the re-
ported/practiced routes.
reaction media and organic/inorganic bases. The results are pre-
sented in Table 1.
Deep eutectic solvent12 (16) composed wholly of biomaterials
referred as Bio-ILs, synthesized with 100% atom economy (Scheme
5). Choline chloride (14) when reacted with urea (15) at 80 °C gave
the molten salt, deep eutectic solvent and this molten salt has been
used for condensing 4-fluorobenzalehyde (4) and 2,4-thiazolidin-
edione (6) leading to 5-(4-fluorobenzylidene) thiazolidine-2,4-
dione (9) following Knoevenagel condensation.
Attempts have been made to optimize the reaction conditions
for the condensation of 4-fluorobenzaldehyde (4) and 2,4-thiazo-
lidinedione (6) by carrying out the condensation using various
After knowing that freshly prepared deep eutectic solvent
worked as better medium and catalyst then focus was directed

926
D. V. Jawale et al. / Bioorg. Med. Chem. Lett. 22 (2012) 924–928
CHO
O
i) KOH, H2OPhMe,
DMF, 85ºC, TBAHS,
OH
20 min, MW
140
20 min.
ºC, MW
N
H
OH
N
Cl
N
N
F
N
N
1
2
3
5
ii)
CHO
4
i ) Piperidine,
Acetic acid, SiO2
O
NH
ii)
Toluene,130ºC,
O
S
10 min, MW
6
O
O
NH
N
N
Mg, Methanol
Reflux
O
O
O
S
N
N
S
8
NH
7
O
Scheme 3. Microwave assisted synthesis of rosiglitazone.
O
F
F
NH
O
Deep eutectic solvent
S
O
CHO
S
80ºC, 2h
NH
4
6
9
O
2
H
N
OH
OH
DMSO, K2CO3
100ºC,4h
N
1
Cl
N
N
3
120ºC, 13h
O
O
CH3 OH, Mg, Iodine
Reflux, 3h
NH
O
S
N
N
O
O
N
N
S
NH
7
8
O
Scheme 4. A convenient present synthetic route for the synthesis of rosiglitazone drug.
phenyl]-methylene]-2,4-thiazolidinedione (7), avoiding the use
of toluene and piperidine (Scheme 6).
Table 1
Optimization of different catalysts for the synthesis of 5-(4-fluorobenzylidene)
thiazolidine-2,4-dione (9)
To investigate the choice of the base in the above condensation
it was separately carried in dimethyl sulfoxide (DMSO) using dif-
ferent bases to obtain (Z)-5-[[4-[2-(methyl-2- pyridinylamino) eth-
oxy] phenyl]-methylene]-2,4-thiazolidinedione (7). When the
above condensation was run in DMSO in presence of NaH, it was
observed that the yield of the product (7) after 4 h was about
63%. Then the condensation was performed using bases, like
K2CO3, NaOH and KOH and the results are summarized in Table
4. It was noted that the condensation when carried in DMSO using
K2CO3 gave satisfactory yield of (7) within 4 h.
Entry
Catalytsa
Time (h)
Yieldb (%)
1
2
3
4
5
7
Piperidine in toluene
Pyrrolidine in EtOH
Piperidine in ethanol
Piperidine and acetic acid
Sodium acetate in acetic acid
Deep eutectic solvent
2
2
2
2
2
2
54
57
59
76
81
93
a
Reactions were carried at 80 °C.
Isolated yields of product (9).
b
The condensation of 2-(N-methyl-N-(pyridin-2-yl) amino) etha-
nol (3) and 5-(4-fluorobenzylidene) thiazolidine-2,4-dione (9) has
been carried in DMSO using K2CO3 by varying temperature. It
was noted that the condensation was found to give high yield of
(7) within 4 h when performed at 100 °C (Table 5).
to optimize temperature required for the condensation. No in-
creased conversion was obtained at temperatures above 80 °C,
(9) within 2 h (Table 2).
Furthermore we attempted to provide a better protocol for syn-
thesizing one of the intermediates, (Z)-5-[[4-[2-(methyl-2-pyridi-
nylamino) ethoxy] phenyl]-methylene]-2,4-thiazolidinedione (7)
required for obtaining rosiglitazone by following Cantello et al.7
route.
It was also noted that deep eutectic solvent can be recovered
and recycled for another batch of the condensation leading to
(9). Observations are recorded in Table 3.
The condensation of 4-[2-(methyl-2-pyridinylamino) ethoxy]
benzaldehyde (5) and 2,4-thiazolidinedione (6) has also been
carried in deep eutectic solvent at 80 °C for 2 h and obtained
better yields of (Z)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]
Intermediate (7) has been synthesized by this group via con-
densation of 4-[2-(methyl-2-pyridinylamino) ethoxy] benzalde-

D. V. Jawale et al. / Bioorg. Med. Chem. Lett. 22 (2012) 924–928
927
Table 4
O
O
80
º
C
Synthesis of (7) using fluoride displacement method
N
Cl
N
Cl
OH
H2N
NH2
OH
H2N
NH2
Entry
Basea
Time (h)
Yieldb (%)
30min.
15
1
2
3
4
NaH
NaOH
KOH
4
4
4
4
63
75
80
87
14
16
Scheme 5. Preparation of deep eutectic solvent.
K2CO3
a
Reaction carried in DMSO at 100 °C amount of base two equivalent of (9).
Isolated yield of product (7).
b
Table 2
Optimization of reaction temperature
Entry
Temperature
Time (h)
Yielda (%)
Table 5
1
2
3
4
5
6
rt
40
60
80
100
120
>24
21
8
2
2
58
63
79
93
91
92
Optimization of the reaction temperature for the synthesis of (7)
Entry
Tempa (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
rt
50
60
80
100
120
>24
20
13
9
4
4
None
47
58
2
a
74
Isolated yield of product.
87
86
a
Reaction of (3) and (9) were carried in DMSO using base K2CO3.
Isolated yield of product (7).
b
Table 3
Recovery and recycling of deep eutectic solvent
Entrya
Yieldb (%)
displacement reaction (9) to (7) potassium carbonate and DMSO
has been used in place of NaH.
With these merits the developed route is more convenient and
practicable.
Fresh
I
II
III
93
91
90
92
a
Solvents and reagents were obtained from commercial sources
and used without further purification. 1H NMR spectra were re-
corded at 300 MHz on Bruker DRX-300. 13C NMR spectra were re-
corded at 100 MHz on Jeol. The mass spectra were recorded on
JEOL—Accu TOF DART-MS-T 100Lc. Melting points are taken in
open capillary method and are uncorrected.
2-(N-Methyl-N-(pyridin-2-yl) amino) ethanol (3): A neat mixture
of 2-chloro pyridine (1) (0.13 mole) and N-methyl ethanol amine
(2) (0.13 mole) was allowed to interact at 120 °C. The progress of
the reaction was monitored by thin layer chromatography. After
13 h of the reaction, the reaction mass was allowed to cool to rt
and it was poured on ice cold water (300 mL). To aqueous mass
ammonium chloride (4 g) was added. The reaction content was
then extracted with ethyl acetate (250 mL). The separated organic
layer was washed with brine solution. Solvent was removed under
vacuum from the extract. Thus obtained (3) was directly used in
the next step without further purification.
2-(N-Methyl-N-(pyridin-2-yl) amino) ethanol (3): Yield 90%; li-
quid; bp 113–111 °C; 1H NMR (300 MHz, DMSO-d6): d ppm 3.01
(s, 3H, NCH3), 3.37–3.55 (m, 4H, CH2CH2), 4.71 (s, 1H, –OH
exchangeable with D2O), 6.50 (m, 1H, ArH), 6.57 (m, 1H, ArH),
7.45 (m, 1H, ArH), 8.03 (m, 1H, ArH); 13C NMR (100 MHz, DMSO-
d6): 34.89, 54.30, 62.93, 106.29, 112.23, 137.77, 146.98, 159.24;
DART-MS (ESI+, m/z): 153 (M+).
5-(4-Fluorobenzylidene) thiazolidine-2,4-dione (9): A mixture of
4-fluorobenzaldehyde (4) (0.14 mole) and 2,4-thiazoldinedione (6)
(0.14 mole) was heated in deep eutectic solvent ( 8) (40 mL) at
80 °C. Progress of the reaction was monitored by thin layer
Reaction carried at 80 °C.
Isolated yield.
b
hyde (5) and 2,4-thiazolidinedione (6) in refluxing toluene in pres-
ence of piperidine. It was observed that the time required for con-
densation is more than 7 h yielding moderate yield. Therefore
following efforts are made for obtaining the intermediate.
Here condensation of 4-[2-(methyl-2-pyridinylamino) ethoxy]
benzaldehyde (5) and 2,4-thiazolidinedione (6) has been carried
in deep eutectic solvent at 80 °C and obtained better yields of
(Z)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]-methy-
lene]-2,4-thiazolidinedione (7) within 2 h, avoiding the use of
toluene and piperidine (Scheme 7).
In conclusion, By employing the above optimized reaction con-
ditions the syntheses of 5-(4-fluorobenzylidene) thiazolidine-2,4-
dione (9) and (Z)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phe-
nyl]-methylene]-2,4-thiazolidinedione (7) have been carried. An
alternative four-step and scalable synthetic route for the synthesis
of rosiglitazone drug has been thus developed and depicted in
Scheme 4. The developed alternative route for the synthesis of ros-
iglitazone has following advantages over the existing routes.
(i) The overall yield of rosiglitazone obtained is relatively high-
er, 58%. (ii) The total reaction time required for getting rosiglitaz-
one is considerable reduced and for all the four steps it is 22 h.
(iii) Recyclable, nonvolatile Deep eutectic solvent has been utilized
for the Knoevenagel condensation reaction replacing less attractive
solvents such as toluene, acetic acid, etc. (iv) For the fluoride
O
Deep eutectic solvent
80ºC, 2h
NH
O
O
O
N
N
N
N
S
O
S
6
NH
5
CHO
7
O
Scheme 6. Synthesis of (Z)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]-methylene]-2,4-thiazolidinedione.

928
D. V. Jawale et al. / Bioorg. Med. Chem. Lett. 22 (2012) 924–928
F
O
O
O
S
OH
DMSO, K2CO3
N
N
S
N
N
NH
NH
7
100ºC, 4h
9
3
O
O
Scheme 7. Synthesis of (Z)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]-methylene]-2,4-thiazolidinedione.
chromatography. After 2 h of the reaction, the reaction mass was
allowed to cool to rt. and it was poured on ice cold water
(250 mL). Thus obtained solid 9 was filtered and washed with
water. It was crystallized using ethanol. 5-(4-Fluorobenzylidene)
thiazolidine-2,4-dione (9): Yield 93%; Pale yellow solid; mp
219–220 °C; 1H NMR (300 MHz, DMSO-d6) d ppm: 7.34–7.74 (m,
4H, ArH), 7.79 (s, 1H, C6H4CH@C), 12.63 (br s, 1H, NH, exchange-
able with D2O); 13C NMR (100 MHz, DMSO-d6): 116.59, 123.25,
129.71, 130.70, 132.50, 164.09, 167.28, 167.76; DART-MS (ESI+,
m/z): 224 (M+).
J = 4.80 Hz, ArH), 11.99 (br s, 1H, NH, exchangeable with D2O);
13C NMR (100 MHz, DMSO-d6): 36.19, 37.30, 39.91, 53.0, 65.14,
114.27 (2C), 128.48 (2C), 130.40, 147.10, 157.34, 166.81, 171.68,
175.70; DART-MS (ESI+, m/z): 358 (M+).
4-[2-(Methyl-2-pyridinylamino) ethoxy] benzaldehyde (5): Yield;
viscous liquid; 1H NMR (300 MHz, DMSO-d6): d ppm 3.06 (s, 3H,
NCH3), 3.95 (t, 2H, J = 5.7 Hz, –CH2CH2–), 4.25 (t, 2H, J = 6.0 Hz, –
CH2CH2–), 6.65 (d, 1H, J = 6.7 Hz, ArH), 6.58 (m, 1H, ArH), 7.13 (d,
2H, J = 8.7 Hz, ArH), 7.49 (m, 1H, ArH), 8.09 (d, 2H, J = 3.0 Hz,
ArH), 9.85 (s, 1H, –CHO). 13C NMR (100 MHz, DMSO-d6): 33.02,
44.70, 61.74, 109.87, 107.06, 109.87, 125.04 (2C), 127.38 (2C),
132.99, 143.70, 153.54, 159.75, 186.01. DART-MS (ESI+, m/z): 257
(M+).
(Z)-5-[[4-[2-(Methyl-2-pyridinylamino) ethoxy] phenyl]-methy-
lene]-2,4-thiazoldinedione (7): A mixture of 5-(4-fluorobenzylidene)
thiazolidine-2,4-dione (9) (0.05 mole), 2-(N-methyl-N-(pyridin-2-
yl) amino) ethanol (3) (0.05 mole) and K2CO3 (0.1 mole) was stirred
in DMSO (90 mL) at 100 °C. Progress of the reaction was monitored
by thin layer chromatography. After 4 h of the reaction, the reac-
tion mass was allowed to cool at rt. and it was poured on crushed
ice cold. The reaction mass was neutralized by adding HCl. Thus
obtained yellow solid (9) was filtered and washed with water.
Crystallized using ethanol. (Z)-5-[[4-[2-(Methyl-2-pyridinylamino)
ethoxy] phenyl]-methylene]-2,4-thiazoldinedione (7): Yield, 80% ;
white solid; mp 196–197 °C; 1H NMR (300 MHz, DMSO-d6): d
ppm 3.05 (s, 3H, NCH3), 3.91 (t, 2H, J = 5.4 Hz, –CH2CH2–), 4.20 (t,
2H, J = 5.4 Hz, –CH2CH2), 6.80 (d, 2H, J = 8.14 Hz, ArH), 7.1 (m, 1H,
ArH), 7.33–7.38 (m, 5H, ArH), 12.58 (br s, 1H, NH, exchangeable
with D2O); 13C NMR (100 MHz, DMSO-d6): 37.10, 48.32, 65.72,
105.8, 115.60, 155.40, 120.30, 125.60, 131.80, 132.15, 137.23,
147.51, 157.92, 165.77, 167.80; DART-MS (ESI+, m/z): 356 (M+).
5-[[4-[2-(Methyl-2-pyridinylamino) ethoxy] phenyl]-methyl]-2,4-
thiazoldinedione, rosiglitazone (BRL 49652) (8): To the solution of
(Z)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]-methy-
lene]-2,4-thiazoldinedione (7) (0.02 mole) in methanol (80 mL),
Mg (0.31 mmol) and crystal of iodine (0.5 g) was added. The reac-
tion mass was refluxed and stirred. The progress of the reaction
was monitored by thin layer chromatography. After 3 h of reflux
the reaction mass was allowed to cool at rt. The reaction mass
was then added in ice and it was neutralized by HCl. Aqueous layer
was extracted using DCM (130 Â 2 mL). The combined organic lay-
ers were dried over magnesium sulphate. The dried organic layer
was concentrated under vacuum. The obtained white product
was crystallized using ethanol. 5-[[4-[2-(Methyl-2-pyridinylamino)
ethoxy] phenyl]-methyl]-2,4-thiazoldinedione, rosiglitazone (BRL
49652) (8): Yield, 80%; white solid; mp 152–153 °C; 1H NMR
(300 MHz, DMSO-d6): d ppm 3.10 (s, 3H, NCH3), 3.30 (dd, 2H,
J = 7. 8 Hz, J = 10.2 Hz, C6H5CH2CH),3.91 (t, 2H, J = 5.4 Hz, CH2CH2),
4.12 (t, 2H, J = 5.4 Hz, CH2CH2), 4.83 (m, 1H, C6H5CH2CH), 6.19 (d,
2H, J = 8.14 Hz, ArH), 6.65 (m, 1H, ArH), 6.86 (d, 1H, J = 8.1 Hz,
ArH), 7.13 (d, 2H, J = 8.1 Hz, ArH), 7.62 (m, 1H, ArH), 8.04 (d, 1H,
Acknowledgments
Authors are thankful to Professor D.B. Ingle for his invaluable
discussions and guidance. One of the authors, D.V. Jawale is also
grateful to U.G.C., New Delhi, India for Research Fellowship in Sci-
ences for Meritorious Students.
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