Identification and synthesis of impurities formed during prasugrel hydrochloride preparation

Article abstract of DOI:10.14233/ajchem.2013.14606

Prasugrel hydrochloride (1), an important platelet inhibitor is used for the reduction of thrombotic cardiovascular events. During laboratory I optimization and later 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 characterization of these impurities. Present study will be of immense help to others to obtain chemically pure prasugrel hydrochloride.

Full text of DOI:10.14233/ajchem.2013.14606

Asian Journal of Chemistry; Vol. 25, No. 14 (2013), 7783-7789
http://dx.doi.org/10.14233/ajchem.2013.14606
Identification and Synthesis of Impurities Formed During Prasugrel Hydrochloride Preparation
*
T. UMASANKARA SASTRY , K. NAGESWRARA RAO, T. APPI REDDY and P. GANDHI
R & D Centre, Mylan Laboratories Limited, ANRICH Industrial Estate, Bollaram (Village), Jinnaram (Mandal), Medak-502 325, India
*Corresponding author: E-mail: umasankarasastry.tummalapalli@mylan.in
(Received: 21 September 2012;
Accepted: 15 July 2013)
AJC-13808
Prasugrel hydrochloride (1), an important platelet inhibitor is used for the reduction of thrombotic cardiovascular events. During laboratory
optimization and later 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 characterization of
these impurities. Present study will be of immense help to others to obtain chemically pure prasugrel hydrochloride.
Key Words: Impurity profile, Prasugrel, Related substances.
O
INTRODUCTION
F
O
O
N
Prasugrel hydrochloride is designated chemically as 5-
[1(RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxyethyl]-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine-2-yl acetate hydrochloride (1).
The literature synthesis1,2 (Scheme-I) involves condensation
of 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone (2)
with 5,6,7,7a-tetrahydrothieno[3,2-c]pyridine -2(4H)-one hydro-
chloride (3) in the presence of base and acetonitrile gives 5-
(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-
tetrahydrothieno[3,2-c]pyridin-2(4H)-one (4), on treatment
with acetic anhydride in presence of base and DMF affords
prasugrel base (5) which on reaction with hydrochloric acid
in presence of acetone gives prasugrel hydrochloride (1).
O
S
O
N
S
O
14
17
O
O
O
F
S
O
N
N
.HCl
S
19
22
Fig. 1. Prasugrel hydrochloride (1), process related impurities
During laboratory optimization of prasugrel hydrochlo-
ride (1), many process related impurities were identified. The
guidelines recommended by ICH state that the acceptable
levels for a known and unknown compound (impurity) in the
drug should be less than 0.15 and 0.10 %, respectively3, also
EMEA document state that the acceptable levels for a 3-fluro
prasugrel and desacetyl prasugrel in the drug should be less
than 0.20 %4. In order to meet the stringent regulatory require-
ments, the impurities present in the drug substances must be
identified and characterized. Literature reports5-7 include
impurities formed due to either incomplete acetylation (e.g.,
4) or during conversion of prasugrel hydrochloride (e.g., 7).
However, no synthetic details have been reported. In this
context, the present study described the identification, synthesis
and characterization of impurities formed during prasugrel
hydrochloride synthesis.
O
F
O
F
N
O
N
O
S
O
.HCl
S
1 Prasugrel hydrochloride
4
Cl
O
N
O
F
R
O
O
N
O
. HCl
S
R1
S
O
7
10 R = F, R1 = H
13 R = H, R1 = F

7784 Sastry et al.
Asian J. Chem.
Br
O
N
F
F
NH.HCl
i
O
S
+
O
O
S
5,6,7,7a-tetrahydrothieno[3,2-
c]pyridin-2(4H)-one hydrochloride
2-bromo-1-cyclopropyl-2-(2-
fluorophenyl)ethanone
5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-
5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one
(3)
(4)
(2)
ii
O
N
F
O
N
F
iii
O
.HCl
O
S
O
S
Prasugrel hydrochloride
(1)
O
Prasugrel base
(5)
Scheme-I: Reagents and conditions: (i) K2CO3, acetonitrile, 0-5 ºC; (ii) K2CO3, acetic anhydride, DMF, 0-5 ºC, (iii) acetone, HCl, 40-45 ºC
5-(5-Chloro-1-(2-fluorophenyl)-2-oxopentyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride
(7): To a suspension of 5-(2-cyclopropyl-1-(2-fluorophenyl)-
2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-
one 4 (10 g, 30.17 mmol) in water (50 mL), hydrochloric acid
(13.5 mL) was added and the mixture stirred for 0.5 h at 80-
85 ºC. The pH was adjusted to 7.5 with 10 % NaOH solution
at 25-30 ºC and extracted with toluene (2 × 50 mL) and the
combined organic phases washed with water (2 × 20 mL),
concentrated under reduced pressure afford desacetylchloro
prasugrel 6 (6.2 g, 55.8 % yield) as a brown yellow liquid. Its
mass (ESI-MS) displayed the required molecular ion peak at
m/z 368 and the characteristic chlorine isotopic pattern.
To the residue (6), DMF (40 mL) was added and the mixture
was stirred until clear solution was obtained. Cool the reaction
mixture to 0-5 ºC, charged anhydrous potassium carbonate
(5.24, 37.9 mmol) and slowly added acetic anhydride (3.45 g,
33.7 mmol) and maintain until the TLC revealed the completion
of reaction. Charged toluene (100 mL) and water (100 mL).
The clear biphasic system was stirred for 15 min and then the
layers were separated. The aqueous phase was extracted with
toluene (3 × 50 mL) and the combined organic phases washed
with water (4 × 20 mL). The organic phase was distilled under
vacuum and purified by silica column chromatography. Elution
with 8-10 % ethyl acetate in hexane (v/v) afford pale yellow
oily crude. The resulting crude was dissolved in acetone (60
mL) and slowly added conc. HCl (1.8 mL) at 25-30 ºC and
stirred for 4 h. The obtained material was removed by filtration
and washed with acetone (10 mL). The wet material was dried
under vacuum at 40-45 ºC for 5 h to afford CATP hydrochloride
impurity 7 (4.0 g, 57.8 % yield, HPLC purity 97.55 %) as a
off-white solid. IR (KBr, νmax, cm-1) 2939, 1760, 1614, 1506,
1494, 1409, 1371, 1213, 1157, 1096, 1003, 881,768, 646. 1H
NMR (DMSO-d6): δ 7.37-7.64 (m, 1H), 7.37-7.64 (m, 1H),
7.37-7.64 (m, 1H), 7.37-7.64 (m, 1H), 6.55 (s, 1H), 5.87 (br,
s, 1H), 3.83 (br, s, 2H), 3.83 (br, s, 1H), 3.48-3.64 (m, 2H),
3.01 (br, s, 2H) 2.69-2.80 (m, 1H), 2.43 (br, 1H), 2.29 (s, 3H),
1.86-1.97 (m, 2H). 13C NMR: 201.74, 167.73, 160.82 (d, J =
247.6), 149.71, 133.51, 131.83, 125.86, 124.33, 116.85 (d,
J = 20.9), 112.02, 68.42, 49.52, 44.26, 25.94, 20.46. ESI-MS:
m/z 410 ([M + H]+, C20H21NO3SClF calcd. (%) 410.3).
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on a Bruker
300 MHzAvance NMR spectrometer. The chemical shifts were
reported ppm relative to either residual solvent or tetramethy-
lsilane. The FT-IR spectra were recorded on Perkin-Elmer
spectrum one FT-IR spectrometer and only prominent peaks
are reported. Mass spectra were recorded on a Agilent 1100
series LC-MSD-TRAP-SL system. HPLC analysis was carried
out on WatersAlliance 2487 or WatersAlliance 2695 systems.
All the reagents used were of LR grade and used without
further purification. All the anhydrous reactions were carried
out under a nitrogen atmosphere. Silica gel (120-200 mesh)
was used for column chromatography.
General experimental procedure
5-(2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-
5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one (4): To
a suspension of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-
2(4H)-one hydrochloride (10 g 52.17 mmol) (3) in acetonitrile
(60 mL) was cool to 0-5 ºC, anhydrous potassium carbonate
(14.45 g, 104.5 mmol) was added and charged 2-bromo-1-
cyclopropyl-2-(2-fluorophenyl)ethanone 2 (10.75 g, 41.8
mmol) at 0-5 ºC and the mixture was stirred for 4 h at 0-5 ºC.
The salt was removed by filtration and then washed with
acetonitrile (10 mL). The filtrate acetonitrile was removed by
distillation under vacuum at 40-45 ºC to afford desacetyl
prasugrel 4 as a brown oily liquid. The resulting oily crude
was recrystallized from diisopropylether (100 mL) to afford
desacetyl prasugrel 4 (4.0 g, 23.2 % yield, HPLC purity 95.82
%) as a off-white solid. IR (KBr, νmax, cm-1): 3053, 2968, 2812,
1700, 1640, 1584, 1486, 1440, 1397, 1384, 1222, 1171, 1076,
1055, 877, 845,761,645. 1H NMR(DMSO-d6): δ 7.37-7.44 (m,
1H), 7.37-7.44 (m, 1H), 7.24-7.30 (m, 1H), 7.24-7.30 (m, 1H),
6.22 (s, 1H), 4.86 (s, 1H), 4.42-4.48 (m, 1H), 3.94 (d, J =
12.0, 1H), 3.05 (d, J = 12.0, 1H), 2.96-3.00 (m, 1H), 2.36-
2.42 (m, 1H), 2.24-2.32 (m, 2H), 1.62-1.67 (m, 1H), 0.83-
0.93 (m, 4H). 13C NMR : 206.72, 198.17, 170.11, 160.60 (d,
J = 244.0), 131.36 (d, J = 3.8), 130.29 (d, J = 8.5), 125.40,
124.55 (d, J = 3.0), 121.08 (d, J = 14.8), 115.71 (d, J = 22.5),
70.95, 52.32, 50.50, 47.84, 33.71, 17.94, 11.18, 11.39. ESI-
MS: m/z 332 ([M + H]+, C18H18NO2SF calcd. (%) 332.1).

Vol. 25, No. 14 (2013)
Identification and Synthesis of Impurities Formed During Prasugrel Hydrochloride Preparation 7785
5-(2-Cyclopropyl-1-(3-fluorophenyl)-2-oxoethyl)-
4,5,6,7-tetrahydrothieno [3,2-c]pyridin-2-yl acetate (10):
To a suspension of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-
2(4H)-one hydrochloride 3 (10 g, 52.17 mmol) in acetonitrile
(60 mL) was cooled to 0-5 ºC, anhydrous potassium carbonate
(14.4 g, 104.45 mmol) was added and charged 2-bromo-1-
cyclopropyl-2-(3-fluorophenyl)ethanone) 8 (10.75 g, 41.7
mmol) at 0-5 ºC and the mixture was stirred for 4 h at 0-5 ºC.
The salt was removed by filtration and then washed with aceto-
nitrile (10 mL). The filtrate acetonitrile was removed by
distillation under vacuum at 40-45 ºC to afford desacetyl 3-
fluro prasugrel 9 (14 g) as a brown oily liquid. To the oily
crude (14 g, 42.2 mmol), DMF (120 mL) was charged and stir
until clear solution was obtained. The resulting solution was
cooled to 0-5 ºC, anhydrous potassium carbonate (12.84 g,
92.9 mmol) was added and slowly added acetic anhydride
(10.8 g, 105.60 mmol) at 0-5 ºC and then stirred for 1 h, when
analytical TLC revealed the amount of des acetyl 3-fluro
prasugrel 9 was below 2 %. The reaction mixture was cooled
to 20-25 ºC then charged toluene (90 mL) and water (150 mL).
The mixture was stirred for 15 min and then separated the
layers. The aqueous layer was extracted with toluene (2 ×
30 mL). The combined organic layer was washed with water
(4 × 50 mL) and concentrated under vacuum at 40-45 ºC and
purified by silica column chromatography using 10 % ethyl
acetate in hexane (v/v) afforded 3-fluro prasugrel 10 as a off-
white solid (5 g, 25.6 % yield, HPLC purity 98.82 %) IR (KBr,
νmax, cm-1) : 3011, 2939, 2799, 1766, 1611, 1500, 1444, 1371,
1249, 1194, 1122, 894, 786, 685. 1H NMR (DMSO-d6): δ 7.41-
7.49 (m, 1H) , 7.26-7.31 (m, 1H), 7.26-7.31 (m, 1H), 7.15-
7.22 (m, 1H), 6.44 (s, 1H), 4.43 (1H), 3.43 (d, J = 14.7, 1H),
3.35 (d, J = 14.7, 1H), 2.68-2.77 (2H), 2.68-2.77 (2H), 2.45-
2.48 (1H), 2.26 (s, 3H), 0.71-0.93 (m, 2H), 0.71-0.93 (m, 2H).
13C NMR: 208.19, 167.82, 162.22 (d, J = 242.7), 148.71,
138.48 (d, J = 7.2), 130.66 (d, J = 8.1) 129.34, 125.45, 124.96,
115.41 (d, J = 21.7), 115.08 (d, J = 21.2), 112.42, 78.90,
50.21, 48.22, 24.40, 20.40, 17.49, 11.80, 11.15. ESI-MS: m/z
374 ([M + H]+, C20H20NO3SF, calcd. (%) 374.1).
The aqueous layer was extracted with toluene (2 × 30 mL).
The combined organic layer was washed with water (4 × 50
mL) and concentrated under vacuum at 40-45 ºC and purified
by silica column chromatography using 10 % ethylacetate in
hexane (v/v) afford 4-fluoro prasugrel 13 as a off-white solid
(5 g, 25.6 % yield, HPLC purity 98.97 %) IR (KBr, νmax, cm-1):
3009, 2942, 1761, 1602, 1435, 1373, 1221, 1200, 1158, 898,
832, 653. 1H NMR (DMSO-d6): δ 7.47-7.52 (dd, J = 5.7,8.7,
2H), 7.23 (t, J = 8.9, 2H), 6.43 (s, 1H), 4.39 (s, 1H), 3.36-3.42
(2H), 2.72 (s, 2H), 2.72 (s, 2H), 2.44- 2.48 (1H), 2.26 (s,
3H),0.70-0.91 (m, 2H), 0.70-0.91 (m, 2H). 13C NMR : 208.47,
167.81, 161.89 (d, J = 243.3), 148.70, 131.84, 130.79 (d, J =
8.3), 129.39, 125.44, 115.59 (d, J = 21.2), 112.42, 78.61,
50.20, 48.20, 24.39, 20.40, 17.39, 11.66, 11.01. ESI-MS : m/
z 374 ([M + H]+, C20H20NO3SF, calcd. (%) 374.2).
5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl
acetate (14): To a suspension of 5,6,7,7a-tetrahydrothieno[3,2-
c]pyridin-2(4H)-one hydrochloride 3 (10 g, 52.17 mmol) in
DMF (70 mL) was cooled to 0-5 ºC, anhydrous potassium
carbonate (21.65 g, 156.7 mmol) was added and slowly added
acetic anhydride (16 g, 156.7 mmol) at 0-5 ºC. The reaction
mixture was stirred for 1 h at 0-5 ºC, analytical TLC revealed
the completion of reaction. To the reaction mass ethyl acetate
(100 mL) and water (60 mL) were charged and then stirred
for 15 min. The layers were separated, the aqueous layer was
extracted with ethyl acetate (2 × 20 mL). The combined organic
layer was washed with water (4 × 20 mL). The solvent was
completely removed under vacuum at 45-50 ºC. The residue
was purified by silica column chromatography using 10 %
methanol in dichloromethane (v/v) to afford diacetyl prasugrel
14 (2.5 g, 20.03 % yield, HPLC purity 98.17 %). IR (KBr,
νmax, cm-1): 3001, 2940, 1760, 1582, 1471, 1424, 1373, 1255,
1015, 882, 819, 641. 1H NMR (CDCl3): δ 6.38 (s, 1H), 4.56
(s, 1H), 4.44 (s, 1H), 3.90 (t, J = 5.7, 1H), 3.74 (t, J = 5.7,
1H), 2.81 (t, J = 5.7, 1H), 2.75 (t, J = 5.7, 1H), 2.29 (s, 3H),
2.18 (s, 3H). 13C NMR : 169.30, 167.54, 149.86, 128.31,
124.57, 111.56, 45.97, 44.08, 24.90, 21.45, 20.56. ESI-MS:
m/z 240 ([M + H]+, C11H13NO3S, calcd. (%) 240.0), m/z 262
(([M + Na]+).
5-(2-Cyclopropyl-1-(4-fluorophenyl)-2-oxoethyl)-
4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate (13):
Anhydous potassium carbonate (14.45 g, 104.58 mmol) was
added to stirred suspension of 5,6,7,7a-tetrahydrothieno[3,2-
c]pyridin-2(4H)-one hydrochloride 3 (10 g, 52.17 mmol) in
acetonitrile (60 mL) at 0-5 ºC and then charged 2-bromo-1-
cyclopropyl-2-(4-fluorophenyl)ethanone 11 (12.7 g, 49.6
mmol) at 0-5 ºC and the mixture was stirred for 4 h at 0-5 ºC.
The salt was removed by filtration and then washed with
acetonitrile (10 mL). The filtrate acetonitrile was removed by
distillation under vacuum at 40-45 ºC to afford desacetyl
4-fluro prasugrel 12 (14 g, 42.2 mmol) as a brown oily liquid.
To the oily crude (14 g), DMF (120 mL) was charged and stir
until clear solution was obtained. The resulting solution was
cooled to 0-5 ºC, anhydrous potassium carbonate (12.84 g,
92.9 mmol) was added and slowly added acetic anhydride (10.8
g, 105.60 mmol) at 0-5 ºC and then stirred for 1 h, when analy-
tical TLC revealed the amount of des acetyl 4-fluro prasugrel
12 was below 2 %. The reaction mixture was cooled to 20-25
ºC then charged toluene (90 mL) and water (150 mL). The
mixture was stirred for 15 min and then separated the layers.
5-(1-(2-Fluorophenyl)-2-oxopropyl)-4,5,6,7-tetra-
hydrothieno[3,2-c]pyridin-2-yl acetate (17): Anhydrous
potassium carbonate (7.2 g, 52.11 mmol) was added to stirred
suspension of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-
one hydrochloride 3 (5 g, 26.1 mmol) in acetonitrile (30 mL)
at 0-5 ºC and then charged 1-bromo-1-(2-fluorophenyl)propan-
2-one 15 (5.73 g, 24.8 mmol) at 0-5 ºC and the mixture was
stirred for 4 h at 0-5 ºC. The salt was removed by filtration
and then washed with acetonitrile (5 mL). The filtrate aceto-
nitrile was removed by distillation under vacuum at 40-45 ºC
to afford desacetyl methyl keto prasugre 16 (4 g, 13.09 mmol)
as a brown oily liquid. To the oily crude (4 g), DMF (30 mL)
was charged and stirred until clear solution was obtained. The
resulting solution was cooled to 0-5 ºC, anhydrous potassium
carbonate (3.62 g, 26.2 mmol) was added and slowly added
acetic anhydride (3.34 g, 32.7 mmol) at 0-5 ºC and then stirred
for 1 h, when analytical TLC revealed the amount of desacetyl
methyl keto prasugrel 16 was below 2 %. The reaction mixture
was cooled to 20-25 ºC then charged toluene (45 mL) and
water (150 mL). The mixture was stirred for 15 min and then

7786 Sastry et al.
Asian J. Chem.
separated the layers. The aqueous layer was extracted with
toluene (2 × 15 mL). The combined organic layer was washed
with water (4 × 25 mL) and concentrated under vacuum at 40-
45 ºC. The resulting residue was triturated with methanol (10
mL) for 1 h. The solid obtained was removed by filtration and
washed with methanol (5 mL). The wet material was dried
under vacuum to afford methyl keto prasugrel impurity 17
(1.0 g, 11.6 % yield, HPLC purity 89.82 %) as a pale yellow
solid. IR (KBr, νmax, cm-1): 2954, 2844, 1759, 1613, 1488, 1372,
1217, 1134, 826, 760, 612. 1H NMR (DMSO-d6): δ 7.37-7.47
(m, 1H), 7.37-7.47 (m, 1H), 7.27 (d, J = 7.8, 1H), 7.22 (d, J =
3.0, 1H), 6.41 (s, 1H), 4.72 (s, 1H), 3.40 (s, 2H), 2.62-2.81
(m, 2H), 2.62-2.81 (m, 2H), 2.25 (s, 3H), 2.14 (s, 3H). 13C
NMR: 205.50, 167.77, 160.58 (d, J = 243.5), 148.66, 130.97
(d, J = 3.8), 130.19 (d, J = 8.5), 129.45, 125.30, 124.63 (d, J
= 3.1), 121.53 (d, J = 14.5), 115.71 (d, J = 22.5), 112.29,
71.23, 49.60, 47.74, 26.82, 24.63, 20.37 ESI-MS: m/z 348
([M + H]+, C18H18NO3S, calcd. (%) 348.1), m/z 370 ([M +
Na]+).
carbonate (11.68 g, 84.5 mmol) was added and slowly added
acetic anhydride (11.4 g, 111.8 mmol) at 0-5 ºC and then stirred
for 1 h, when analytical TLC revealed the amount of des
acetylfluoro prasugrel 21 was below 2 %. The reaction mixture
was cooled to 20-25 ºC then charged toluene (90 mL) and
water (150 mL). The mixture was stirred for 15 min and then
separated the layers. The aqueous layer was extracted with
toluene (2 × 30 mL). The combined organic layer was washed
with water (4 × 50 mL) and concentrated under vacuum at 40-
45 ºC. The resulting residue was triturated with methanol (10
mL) for 1 h. The solid obtained was removed by filtration and
washed with methanol (5 mL). The wet material was dried
under vacuum to afford desfluoro prasugrel impurity 22 (3 g,
16.21 % yield, HPLC purity 93.65 %) as a off-white solid. IR
(KBr, νmax, cm-1): 3086, 2989, 1754, 1584, 1495, 1455, 1417,
1369, 1217, 1193, 888, 832, 822, 761, 714, 698, 665. 1H NMR
(DMSO-d6): δ 7.32-7.47 (m, 2H), 7.32-7.47 (m, 2H), 7.32-
7.47(m, 1H), 6.43 (s, 1H), 4.33 (s, 1H), 3.33-3.38 (2H), 2.72
(s, 2H), 2.72 (s, 2H), 2.46-2.48 (1H), 2.26 (s, 3H), 0.68-.91
(m, 2H), 0.68-.91 (m, 2H). 13C NMR: 208.61, 167.84, 148.70,
135.69, 129.46, 128.80, 128.76, 128.20, 125.49, 112.43, 79.86,
50.34, 48.32, 24.44, 20.42, 17.31, 11.62, 11.03. ESI-MS: m/z
356 ([M + H]+, C20H21NO3S, calcd. (%) 356.2).
1-Cyclopropyl-2-(6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-yl)-2-(2-fluorophenyl)ethanone hydrochloride (19):
To a suspension of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine
hydrochloride 18 (20 g, 113.86 mmol) in acetonitrile (120 mL)
was cooled to 0-5 ºC, anhydrous potassium carbonate (31.4 g,
227.2 mmol) was added and charged 2-bromo-1-cyclopropyl-
2-(2-fluorophenyl)ethanone) 2 (23.4 g, 91.0 mmol) at 0-5 ºC
and the mixture was stirred for 4 h at 0-5 ºC. The salt was
removed by filtration and then washed with acetonitrile
(40 mL). The filtrate acetonitrile was removed by distillation
under vacuum at 40-45 ºC. The resulting crude was dissolved
in acetone (200 mL) and slowly added 10 % ethanolic HCl
(20 mL) at 25-30 ºC and stirred for 1 h. The obtained material
was removed by filtration and washed with acetone (30 mL).
The wet material was dried under vacuum at 40-45 ºC for 5 h
to afford thiophene impurity 19 (14 g, 34.8 % yield, HPLC
purity 99.30 %) as a off-white solid. IR (KBr, νmax, cm-1): 3430,
3094, 2937, 1708, 1611, 1492, 1458, 1417, 1383, 1236, 773,
RESULTS AND DISCUSSION
Desacetyl prasugrel (4), a possible contaminant in
prasugrel hydrochloride that can be formed by incomplete
acetylation of desacetyl prasugrel or may be deacetylation of
prasugrel base. The desacetyl prasugrel impurity (4) was synthe-
sized by condensation of (2) with 5,6,7,7a-tetrahydro-
thieno[3,2-c]pyridin-2(4H)-one hydrochloride (3) in the
presence of base and acetonitrile8 (Scheme-I).
During hydrochloride conversion of prasugrel (5), forma-
tion of 0.3-0.5 % of the chloro prasugrel (7) is observed, the
level is reduced to less than 0.1 % during its isolation and
purification. The CATP impurity (7) was prepared by reaction
of HCl/water with (4) and the desacetyl chloro prasugrel
formed (6) was acetylated with acetic anhydride in the presence
of DMF and potassium carbonate, followed by purification
by column chromatography and further treatment with conc.
hydrochloric acid in the presence of acetone (Scheme-II).
In some of commercial samples, 2-bromo-1-cyclopropyl-
2-(2-fluorophenyl)ethanone (2) was found to be contaminated
with traces of 2-bromo-1-cyclopropyl-2-(3-fluorophenyl)-
ethanone (8), although the amount of contamination of the
fluoro analogue (10) in prasugrel hydrochloride (1) was never
more than 0.2 %4. The fluoro analogue of prasugrel9 (10) was
synthesized from 2-bromo-1-cyclopropyl-2-(3-fluorophenyl)-
ethanone (8) following the reaction sequence used to synthe-
size (5), followed by purification by column chromatography
(Scheme-III).
1
614, 598. H NMR (DMSO-d6): δ 10.5-11.5 (br, 1H) 7.58-
7.63 (m, 1H), 7.58-7.63 (m, 1H), 7.38-7.50(m, 1H), 7.38-7.50
(m, 1H), 6.88 (s, 1H), 6.09 (1H), 4.0-4.28 (2H), 3.11 (br, 2H),
1.97 (br, 1H), 0.88-1.07 (m, 2H), 0.88-1.07 (m, 2H). 13C NMR:
201.73, 160.95 (d, J = 248.0), 133.45 (d, J = 8.1), 132.65,
131.47, 128.06, 125.68 (d, J = 3.3), 125.41, 124.95, 116.69
(d, J = 21.5), 115.72, 68.81, 49.95, 47.51, 21.97, 12.69, 12.34,
ESI-MS: m/z 316 ([M + H]+, C18H18NO3S, calcd. (%) 316.1).
5-(2-Cyclopropyl-2-oxo-1-phenylethyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridin-2-yl acetate (22):Anhydous
potassium carbonate (14.4 g, 104.6 mmol) was added to stirred
suspension of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-
one hydrochloride 3 (10 g, 52.17 mmol) in acetonitrile (30
mL) at 0-5 ºC and then charged 2-bromo-1-cyclopropyl-2-
phenylethanone 20 (11.25 g, 47.0 mmol) at 0-5 ºC and the
mixture was stirred for 4 h at 0-5 ºC. The salt was removed by
filtration and then washed with acetonitrile (5 mL). The filtrate
acetonitrile was removed by distillation under vacuum at 40-
45 ºC to afford desacetylfluoro prasugrel 21 (14 g, 44.7 mmol)
as a brown oily liquid. To the oily crude (14 g), DMF (60 mL)
was charged and stirred until clear solution was obtained. The
resulting solution was cooled to 0-5 ºC, anhydrous potassium
In some of commercial samples, 2-bromo-1-cyclopropyl-
2-(2-fluorophenyl)ethanone (2) was found to be contaminated
with traces of 2-bromo-1-cyclopropyl-2-(4-fluorophenyl)-
ethanone (11), although the amount of contamination of the
fluoro analogue (13) in prasugrel hydrochloride (1) was never
more than 0.15 %4. The fluoro analogue of prasugrel9 (13) was
synthesized from 2-bromo-1-cyclopropyl-2-(4-fluorophenyl)-

Vol. 25, No. 14 (2013)
Identification and Synthesis of Impurities Formed During Prasugrel Hydrochloride Preparation 7787
O
Cl
O
N
F
F
i
N
O
O
S
S
5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-
5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one
5-(5-chloro-1-(2-fluorophenyl)-2-oxopentyl)-
5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one
(4)
(6)
ii
O
Cl
F
N
O
. HCl
S
O
5-(5-chloro-1-(2-fluorophenyl)-2-oxopentyl)-
4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate
hydrochloride
(7)
Scheme-II: Reagents and conditions: (i) HCl, water, 80-85 ºC; (ii) (a) K2CO3, acetic anhydride, DMF, 0-5 ºC; (b) column chromotography; (c) acetone, conc.
HCl
Br
O
N
F
NH.HCl
i
O
F
S
+
O
O
S
5-(2-cyclopropyl-1-(3-fluorophenyl)-2-oxoethyl)-
5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one
5,6,7,7a-tetrahydrothieno[3,2-
c]pyridin-2(4H)-one hydrochloride
2-bromo-1-cyclopropyl-2-(3-
fluorophenyl)ethanone
(3)
(9)
(8)
ii
O
N
F
O
S
O
5-(2-cyclopropyl-1-(3-fluorophenyl)-2-oxoethyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridin-2-yl acetate
(
10)
Scheme-III: Reagents and conditions: (i) K2CO3, acetonitrile, 0-5 ºC; (ii) (a) K2CO3, acetic anhydride, DMF, 0-5 ºC; (b) column chromotography
ethanone (11) following the reaction sequence used to synthe-
size (5), followed by purification by column chromatography
(Scheme-IV).
to be contaminated with traces of 4,5,6,7-tetrahydrothieno[3,2-
c]pyridine hydrochloride (18), although the amount of conta-
mination of thiophene impurity (19) in prasugrel hydrochlo-
ride (1) was never more than 0.15 %3. Thiophene impurity
(19) was synthesized from 4,5,6,7-tetrahydrothieno[3,2-
c]pyridine hydrochloride (18) by alkylation with 2-bromo-1-
cyclopropyl-2-(2-fluorophenyl)ethanone (2) in presence
of potassium carbonate and acetonitrile followed by treatment
with etahnolic HCl in the presence of acetone (Scheme-
VII).
During the acetylation reaction there is always the
probability of diacetylation due to presence of excess 5,6,7,7a-
tetrahydrothieno[3,2-c]pyridin-2(4H)-one hydrochloride (3),
hence the diacetyl thieno pyridine (14) was synthesized by
acetylation of thienopyridine (3) with acetic anhydride, follo-
wed by purification by column chromatography (Scheme-V).
In some of commercial samples, 2-bromo-1-cyclopropyl-
2-(2-fluorophenyl)ethanone (2) was founded to be contami-
nated with traces of 1-bromo-1-(2-fluorophenyl)propan-2-one
(15), although the amount of contamination of methylketo
impurity9 (17) in prasugrel hydrochloride (1) was never more
than 0.15 %3. Methylketo impurity (17) was synthesized from
1-bromo-1-(2-fluorophenyl)propan-2-one (15) following the
reaction sequence used to synthesize 5 (Scheme-VI).
In some of the commercial samples, 5,6,7,7a-tetrahydro-
thieno[3,2-c]pyridin-2(4H)-one hydrochloride (3) was found
In some of the commercial samples, 2-bromo-1-cyclopropyl-
2-(2-fluorophenyl)ethanone (2) was found to be contaminated
with traces of 2-bromo-1-cyclopropyl-2-phenylethanone (20),
although the amount of contamination of the desfluoro
analogue (22) in prasugrel hydrochloride (1) was never more
than 0.15 %3. The desfluoro analogue of prasugrel (22) was
synthesized from 2-bromo-1-cyclopropyl-2-phenylethanone
(20) following the reaction sequence used to synthesize 5
(Scheme-VIII).

7788 Sastry et al.
Asian J. Chem.
Br
O
N
NH.HCl
i
O
S
+
O
O
F
S
F
5,6,7,7a-tetrahydrothieno[3,2-
c]pyridin-2(4H)-one hydrochloride
2-bromo-1-cyclopropyl-2-(4-
fluorophenyl)ethanone
5-(2-cyclopropyl-1-(4-fluorophenyl)-2-oxoethyl)-
5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one
(3)
(11)
(12)
ii
O
N
O
S
F
O
5-(2-cyclopropyl-1-(4-fluorophenyl)-2-oxoethyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridin-2-yl acetate
(13)
Scheme-IV: Reagents and conditions: (i) K2CO3, acetonitrile, 0-5 ºC; (ii) K2CO3, acetic anhydride, DMF, 0-5 ºC; (b) column chromotography
O
i
NH.HCl
O
N
O
O
S
S
5,6,7,7a-tetrahydrothieno[3,2-
c]pyridin-2(4H)-one hydrochloride
5-acetyl-4,5,6,7-tetrahydrothieno[3,2-
c]pyridin-2-yl acetate
(3)
(
14)
Scheme-V: Reagents and conditions: (i) (a) K2CO3, acetic anhydride, DMF, 0-5 ºC; (b) column chromotography
O
O
N
F
F
i
NH.HCl
Br
O
+
O
S
S
5,6,7,7a-tetrahydrothieno[3,2-
c]pyridin-2(4H)-one hydrochloride
5-(1-(2-fluorophenyl)-2-oxopropyl)-5,6,7,7a-
tetrahydrothieno[3,2-c]pyridin-2(4H)-one
1-bromo-1-(2-
fluorophenyl)propan-2-one
(
16)
(
15)
(3)
ii
O
N
F
O
S
O
5-(1-(2-fluorophenyl)-2-oxopropyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridin-2-yl acetate
(17)
Scheme-VI: Reagents and conditions: (i) K2CO3, acetonitrile, 0-5 ºC; (ii) K2CO3, acetic anhydride, DMF, 0-5 ºC
O
O
N
F
F
NH.HCl
i
Br
+
S
. HCl
S
4,5,6,7-tetrahydrothieno[3,2-
c]pyridine hydrochloride
2-bromo-1-cyclopropyl-2-(2-
fluorophenyl)ethanone
1-cyclopropyl-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-
(2-fluorophenyl)ethanone hydrochloride
(2)
(18)
(
19)
Scheme-VII: Reagents and conditions: (i) (a) K2CO3, acetonitrile, 0-5 ºC; (b) ethanolic HCl, acetone, 35-40 ºC
Conclusion
ACKNOWLEDGEMENTS
For better knowledge of the synthetic path way of an active
pharmaceutical ingredient (API) it is mandatory to identify
all the impurities formed/anticipated. In this context we have
synthesized and characterized different potential process
related impurities of prasugrel hydrochloride.
The authors thank Mylan Laboratories Limited for sup-
porting this work and also to the authorities of Jawaharlal
Nehru Technological University Hyderabad, Kukatpally,
Hyderabad for research facilities.

Vol. 25, No. 14 (2013)
Identification and Synthesis of Impurities Formed During Prasugrel Hydrochloride Preparation 7789
Br
O
NH.HCl
i
O
S
N
+
O
O
S
5,6,7,7a-tetrahydrothieno[3,2-
c]pyridin-2(4H)-one hydrochloride
2-bromo-1-cyclopropyl-2-
phenylethanone
5-(2-cyclopropyl-2-oxo-1-phenylethyl)-5,6,7,7a-
tetrahydrothieno[3,2-c]pyridin-2(4H)-one
(3)
(21)
(
20)
ii
O
N
O
S
O
5-(2-cyclopropyl-2-oxo-1-phenylethyl)-
4,5,6,7-tetrahydrothieno[3,2- ]pyridin-2-yl
acetate
c
(
22)
Scheme-VIII: Reagents and conditions: (i) K2CO3, acetonitrile, 0-5 ºC; (ii) K2CO3, acetic anhydride, DMF, 0-5 ºC
5. M. Hagihara, T. Inoue, H. Miyata, K. Nakamura,Y. Wada and N.Yokota,
Process for Producing High-Purity Prasugrel and Acid Addition Salt
Thereof, US Patent 2009/0203729 (2009).
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Preparation of Prasugrel and Its Pharmaceutically Acceptable Salts,
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