An improvement to the preparation of prasugrel hydrochloride

Article abstract of DOI:10.3184/174751913X13687269227225

An efficient synthesis of prasugrel, a thienopyridine ADP-receptor antagonists, is described. A thienopyridine intermediate was prepared by N-protection, boric acid substitution and N-substitution. After acid hydrolysis of the methyl ether and subsequent acetylation, prasugrel was obtained with a total yield of 50% after seven linear steps from 4,5,6,7-tetrahydrothieno [3,2-c]pyridine and 2-bromo-1-cyclopropyl-2-(2- fluorophenyl)ethan-1-one as raw materials.

Full text of DOI:10.3184/174751913X13687269227225

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 369
JUNE, 369–371
An improvement to the preparation of prasugrel hydrochloride
Wenhua Ou*, Weiyin Yi, Feng Liu, Xianhua Pan and Xijiang Peng
School of Perfume and AromaTechnology, Shanghai Institute ofTechnology, 100 Haiquan Rd. Shanghai, 201418, P. R. China
An efficient synthesis of prasugrel, a thienopyridine ADP-receptor antagonists, is described. A thienopyridine inter-
mediate was prepared by N-protection, boric acid substitution and N-substitution. After acid hydrolysis of the methyl
ether and subsequent acetylation, prasugrel was obtained with a total yield of 50% after seven linear steps from
4,5,6,7-tetrahydrothieno [3,2-c]pyridine and 2-bromo-1-cyclopropyl-2-(2- fluorophenyl)ethan-1-one as raw materials.
Keywords: prasugrel, boric acid substitution, platelet inhibitor
Prasugrel is a novel thienopyridine prodrug that is rapidly
metabolised to its active platelet-inhibitory metabolite (R-
138727) which exerts antiplatelet activity through antagonism
of P2Y (12) receptors.1 Prasugrel has found extensive use as a
major thienopyridine ADP-receptor antagonist with a safer,
higher, faster, and more consistent level of inhibition of
platelet aggregation compared to similar drugs that are used
for the treatment of cardiovascular disease such as ticlopidine
and clopidogrel.2–7 Due to the sharp increase in the number
of people suffering from cardiovascular disease, the need
for prasugrel to treat cardiovascular disease is growing.
Considerable effort has been spent on developing simple and
practical synthetic routes for the preparation of prasugrel 1
(Scheme 1).8–11 In 1993, Hiroyuki synthesised prasugrel 1
from the C-2 enol 4,5,6,7-tetrahydrothieno [3,2-c]pyridine
hydrochloride and 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)
ethanone.8 Stepankova synthesised this compound from 2-
cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl methanesulfonate
and 5,6,7,7a-tetrahydrothieno [3,2-c]pyridin-2(4H)-one hydro-
chloride.9 Given the relatively low yield and unavoidable
impurities (Scheme 2),8–12 there is still room for improvement.
We report here an improved synthetic route for the preparation
of prasugrel hydrochloride.
N-protection reaction with triphenylchloromethane in CH2Cl2.
Compound 8 was converted to compound 9 in 96% yield by
reacting with trimethyl borate. Removal of the triphenylmethyl
protecting group was performed at r.t. (TsOH, THF), to give
compound 10 in 89% yield. Compound 10 was then reacted
with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethan-1-one
12 which was prepared according to the procedure of H.
Stepankova, and J. Hajicek.9 Compound 11 was obtained in
93% yield after purification. Compound 11 was then oxidised
and acetylated to give prasugrel 1 in 85% yield via the key
intermediate 4. After treatment with an acetone solution of
hydrogen chloride, prasugrel hydrochloride was isolated in
88% yield.
In conclusion, a highly efficient and practical approach to
prasugrel hydrochloride has been developed by borate esterifi-
cation. In this process, the boronate group was successfully
used to generate the 2-oxo group to avoid the formation of
by-products attached to the oxo group. Its ease of work-up,
high yield, fairly mild reaction conditions and no unavoidable
impurities provide an improved access to prasugrel. The over-
all yield of the route is 50% for seven steps. Other applications
of this process are under investigation in our laboratory.
The synthesis started from 4,5,6,7-tetrahydrothieno[3,2-c]-
pyridine 7 (Scheme 3) which was obtained from Sigma-
Aldrich Co. compound 8 was prepared in 92% yield8,13 after
Experimental
Melting points were determined with a SGW X-4 micro melting point
1
apparatus. H NMR spectras were recorded using Avance 400 MHz
Scheme 1
Scheme 2
* Correspondent. E-mail: ouwenhua@sit.edu.cn

370 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 3
spectrometer. ESI-MS were recorded on Dionex MSOPlus mass spec-
trometer. High resolution mass spectra were recorded on Finnigan
MAT XL95 mass spectrometer.
12 (22.6 g, 0.088 mol) in absolute ethanol (50 mL) was added. The
mixture was stirred for another 8 h at 50 °C. After cooling to room
temperature, the reaction mixture was concentrated under vacuum to
remove enthanol, saturated NaCl solution (300 mL) and ethyl acetate
(400 mL) were added, and the layers were separated. The organic
layer was washed with saturated NaCl (50 mL), dried over anhydrous
Na2SO4, filtered and concentrated to provide the crude product. This
was recrystallised from a mixture of EtOAc and petroleum ether
to give compound 11 (26.8 g) as a pale yellow solid in 93% yield.
M.p. 125–127 °C. 1H NMR (400 MHz, CDCl3) δ 7.80–6.91 (m, 4H),
5.33 (s, 1H), 4.89 (s, 1H), 3.66 (d, J = 24.7 Hz, 2H), 3.19–1.88 (m,
4H), 1.66 (s, 1H), 0.97–0.56 (m, 4H). MS-ESI (m/z): 360 [M+H]+.
HRMS Calcd for C18H19BFNO3S (M + H)+ requires 360.2224, found
360.2217.
5-Trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8): The hydro-
chloride of 4,5,6,7-tetrahydrothieno [3,2-c]pyridine 7 (140.4 g, 0.8 mol)
was added to a mixture of CH2Cl2 (500 mL) and 4M sodium hydrox-
ide solution (420 mL, 1.68 mol), and stirred at room temperature for
15 min. This solution was kept at room temperature while triphenyl-
chloromethane (234.0 g, 0.84 mol) was added in portions. After the
addition, the mixture was stirred at room temperature for 8 h. Then
H2O (500 mL) was added to the reaction mixture. The layers were
separated, the organic layer was washed with sat. NaCl, dried over
anhydrous MgSO4, filtered and concentrated to provide the crude
product. This was recrystallised from EtOAc to give compound 8
(280.4 g) as a white solid in 92% yield. M.p. 162–164 °C. (lit 13 150–
1-Cyclopropyl-2-(2-fluorophenyl)-2-(2-hydroxy-6,7-dihydrothi-
eno[3,2-c]pyridin-5(4H)-yl)ethan-1-one (4): Acetic acid was added
until a pH of 5 was reached to a solution of compound 11 (18.0 g,
0.05 mol) in absolute ethanol (100 mL) under a nitrogen atmosphere
below 4 °C. Then 30% hydrogen peroxide (6.8 g, 0.06 mol) was added
slowly. After the addition, the mixture was stirred and warmed slowly
to room temperature for 4 h. The reaction was quenched with
saturated sodium thiosulfate solution (50 mL). Then the reaction mix-
ture was concentrated under vacuum to remove enthanol. Saturated
NaHCO3 (100 mL) and ethyl acetate (100 mL) were added, and the
layers were separated. The organic layer was washed with saturated
NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to
provide the crude product. This was recrystallised from isopropyl
ether to give compound 4 (15.2 g) as a pale yellow solid in 92% yield.
1
151 °C). H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.3 Hz, 6H),
7.39–7.24 (m, 6H), 7.19 (t, J = 7.3 Hz, 3H), 7.06 (d, J = 5.0 Hz, 1H),
6.67 (d,J = 5.1 Hz, 1H), 3.45 (s, 2H), 3.01 (s, 2H), 2.63 (s, 2H). ESI-
MS m/z: 382.2 (M+H)+.
(5-Trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)boronic acid
(9):14 A magnetically stirred solution containing compound 8 (19 g,
50 mmol) in THF (50 mL) was treated with 2.5M hexane solution of
n-BuLi (30 mL, 0.075 mol) at 0 °C under a nitrogen atmosphere. The
mixture was stirred at –10 °C for two hours, and then trimethylborate
(19 mL, 0.075 mol) in THF (50 mL) was added slowly over half hour.
The mixture was stirred at –10 °C for 1 h before EtOAc (100 mL) was
added. The layers were separated, the organic layer was washed first
with sat. NaHCO3, and then with sat. NaCl, dried over anhydrous
Na2SO4, filtered and concentrated to provide the product (20.4g) as a
8
1
M.p. 124–126 °C. (lit 123–125 °C). H NMR (400 MHz, CDCl3)
δ 7.46–7.11 (m, 4H), 6.05 (d, J = 8.7 Hz, 1H), 4.87 (t, J = 7.9 Hz, 1H),
4.10 (ddd, J = 12.5, 5.7, 1.3 Hz, 1H), 3.95 (ddd, J = 15.6, 12.3, 1.9 Hz,
1H), 3.10 (ddd, J = 12.0, 9.8, 3.5 Hz, 1.5H), 2.85 (d, J = 12.3 Hz,
0.5H), 2.54 (td, J = 12.2, 1.6 Hz, 0.5H), 2.43–2.22 (m, 1.5H), 2.16–
2.00 (m, 1H), 2.01–1.74 (m, 1H), 1.11–1.00 (m, 2H), 0.97–0.71 (m,
2H). MS-ESI (m/z): 332 [M+H]+.
1
pale yellow viscous liquid in 96% yield. H NMR (δ, CDCl3): 7.55–
7.57 (m, 6H), 7.29–7.34 (m, 7H), 7.09–7.20 (m, 3H), 3.25–3.48 (m,
2H), 3.06–3.10 (m, 2H), 2.61–2.68 (m, 2H). ESI-MS m/z: 426.4
(M+H)+.
TsOH salt of (4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)boronic
acid (10): p-Toluenesulfonic acid (17.2 g, 0.1 mol) was added to a
solution of compound 9 (42.5 g, 0.1 mol) in 300 mL of THF, while
keeping the internal temperature between 0 and 5 °C. After the addi-
tion was complete, stirring was continued for another hour at room
temperature. The white solid which formed was filtered, and washed
with THF. After drying below 60 °C, compound 10 (31.6 g) was
Prasugrel (1): 60% Sodium hydride (0.44 g, 0.011 mo1) was added
to a magnetically stirred solution containing compound 4 (3.31 g,
10 mmol) in DMF (20 mL) and Ac2O (0.38 mL, 40mmol) at 0 °C
under a nitrogen atmosphere. The mixture was stirred at room
temperature for 1 h. The white solid was formed after adding 100 mL
of ice-water. The white solid was filtered, and washed with Et2O. After
drying under 60 °C, prasugrel 1 (3.2 g) was obtained in 85% yield.
1
obtained in 89% yield. H NMR (400 MHz, CDCl3) δ 8.98 (s, 2H),
8.25 (s, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.11 (d, J =
7.9 Hz, 2H), 4.21 (s, 2H), 3.53–3.17 (m, 2H), 3.04 (t, J = 5.8 Hz,
2H), 2.29 (s, 3H). MS-ESI (m/z): 378.3 [M+Na]+.
(5-(2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahy-
drothieno[3,2-c]pyridin-2-yl)boronic acid (11): Triethylamine (34.5 g,
0.25 mol) was added to a solution of compound 10 (28.4 g, 0.08 mol)
in 150 mL of absolute ethanol under a nitrogen atmosphere. The
mixture was stirred vigorously at 50 °C, and a solution of compound
13
1
M.p. 120–121 °C. (lit 119–121 °C). H NMR (400 MHz, CDCl3)
δ 7.53–7.02 (m, 4H), 6.26 (s, 1H), 4.83 (s, 1H), 3.52 (q, J = 14.3 Hz,
2H), 2.95–2.59 (m, 4H), 2.32–2. 25 (m, 1H), 2.24 (s, 3H), 1.11–0.91
(m, 2H), 0.91–0.59 (m, 2H). MS: ESI (m/z): 374 [M+ H]+.
Prasugrel hydrochloride (1)·HCl: acetone solution of hydrogen
chloride was added to a magnetically stirred solution containing

JOURNAL OF CHEMICAL RESEARCH 2013 371
3
4
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reached at 0 °C under a nitrogen atmosphere. The reaction was stirred
for another 12 h at 0 °C. The white solid which formed was filtered,
and washed with Et2O. After drying under 40 °C, 3.6 g of prasugrel
hydrochloride 1·HCl was obtained in 88% yield. The purity of the
product was higher than 99.7%.
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Received 19 February 2013; accepted 12 April 2013
Paper 1301801 doi: 10.3184/174751913X13687269227225
Published online: 12 June 2013
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