Efficient synthesis of prasugrel, a novel P2Y12 receptor inhibitor

Article abstract of DOI:10.1016/j.tetlet.2012.07.071

An efficient synthesis of prasugrel, a novel P2Y₁₂ receptor inhibitor, is described. The cyclopropyl-phenylethanone intermediate was prepared by cyanide substitution, bromination, N-substitution, and the Grignard reaction. After acid hydrolyzation of the methyl ether and subsequent acetylation, the title product was obtained with a total yield of 21% after 10 linear steps from simple and commercially available raw materials.

Full text of DOI:10.1016/j.tetlet.2012.07.071

Tetrahedron Letters 53 (2012) 5364–5366
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Tetrahedron Letters
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Efficient synthesis of prasugrel, a novel P2Y12 receptor inhibitor
Xianhua Pan a, , Rui Huang a, , Jianshui Zhang a, , Liping Ding b, , Weijin Li b, , Qunhui Zhang b, , Feng Liu a,
⇑
⇑
a School of Perfume and Aroma Technology, Shanghai Institute of Technology, 100 Haiquan Rd., Shanghai 201418, PR China
b Zhejiang Hisoar Pharmaceutical Co., Ltd, 100 Waisha Branch Rd., Jiaojiang, Taizhou, Zhejiang 318000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of prasugrel, a novel P2Y12 receptor inhibitor, is described. The cyclopropyl-phenyl-
ethanone intermediate was prepared by cyanide substitution, bromination, N-substitution, and the Grig-
nard reaction. After acid hydrolyzation of the methyl ether and subsequent acetylation, the title product
was obtained with a total yield of 21% after 10 linear steps from simple and commercially available raw
materials.
Received 24 April 2012
Revised 10 July 2012
Accepted 17 July 2012
Available online 26 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Prasugrel
Platelet inhibitor
Cyclopropyl
Grignard reaction
Synthesis
Cardiovascular disease is a global epidemic that kills nearly 17
million patients every year and the number is mounting steadily.
It has been found that blockers of the Gi-linked P2Y12 receptor
were promising new treatments for cardiovascular diseases.1
Prasugrel (Fig. 1), a new thienopyridine P2Y12 receptor inhibitor,
which was approved by the US FDA in 2009, is a potent, irrevers-
ible, and selective inhibitor of ADP (adenosine diphosphate)-med-
iated platelet aggregation. In comparison to ticlopidine (trade
name Ticlid, Fig. 1) and clopidogrel (trade name Plavix)2,3 the
best-selling thienopyridine ADP-receptor antagonists, prasugrel
achieved a safer, higher, faster, and more consistent level of inhibi-
tion of platelet aggregation.4 Thus, there exists commercial and
practical interest in the preparation of prasugrel on a large-scale.
Over the past 10 years, several protocols have been reported for
the synthesis of prasugrel (Scheme 1). The original synthetic route
to prasugrel was developed by Kioke and co-workers in 1993,5a in
which the 2-position of 4,5,6,7-tetrahydrothieno [3,2-c]pyridine
hydrochloride was oxidized, and then condensed with 2-bromo-
1-cyclopropyl-2-(2-fluorophenyl) ethanone to construct the core
structure of prasugrel. However, the relatively low condensation
yield (32%) rendered this procedure too inefficient to scale up.
Stepankova and Hajicek,5b chose 2-cyclopropyl-1-(2-fluoro-
phenyl)-2-oxoethyl methanesulfonate and 5,6,7,7a-tetrahydrothi-
eno[3,2-c]pyridin-2(4H)-one hydrochloride as the substrates of
the condensation reaction, but the yield (23%) was still not
satisfactory.
Kikuo et al.5c offered an alternate synthetic route for prasugrel
by condensing 2-bromo-1-cyclopropyl-2-(2-fluorophenyl) etha-
none with 2-((tert-butyldimethylsilyl)oxy)-4,5,6,7-tetrahydrothie-
no[3,2-c]pyridine,
a route which significantly improved the
reaction yield to 72%. Although this process effectively imple-
mented the condensation reaction, the complex operation and
safety risk involved in the usage of n-BuLi, Borate ester in the
Cl
Cl
CO2Me
N
O
F
N
N
OAc
S
S
S
prasugrel
clopidogrel
ticlopidine
Figure 1. Structures of ticlopidine, clopidogrel, and prasugrel.
O
O
F
F
N
N
OR1
OAc
S
S
1
R1= H,TBS, Ac
Prasugrel
O
F
ClH HN
+
O
R2
S
⇑
Corresponding authors.
E-mail address: liufeng@sit.edu.cn (F. Liu).
R2= Br, OMs
These authors contributed equally to this work.
Scheme 1. Reported synthetic route of prasugrel.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.071

X. Pan et al. / Tetrahedron Letters 53 (2012) 5364–5366
5365
F
F
Br
Grignard reaction
F
NaCN, TBAB
Toluene, H2O
Br2, CH2Cl2
0 ºC, 81 %
CN
CN
Br
55 ºC, 85 %
O
O
Nucleophilic
sub stitution
F
F
7
8
9
N
N
OAc
OMe
S
S
F
CN
9, K2CO3
EtOH, 0 ºC
93 %
12
Prasugrel
1
HN
N
F
Br
O
O
HN
S
S
OMe +
+
CN
6
10
MgBr
S
11
6
9
Scheme 4. Synthesis of 2-(2-fluorophenyl)-2-(2-methoxy-6,7- dihydrothieno[3,2-
c]pyridin-5(4H)-yl)acetonitrile 10.
Scheme 2. Retro-synthesis of prasugrel.
cyano substitution and subsequent bromination, we obtained 2-
bromo-2-(2-fluorophenyl)acetonitrile 99 in 69% yield in 2 steps.
Then the bromide group of 9 was quite smoothly substituted by
compound 6 in absolute alcohol at 0 °C to give 109 in 93% yield
(Scheme 4).
With the key compound 10 in hand, we then examined the
Grignard reaction of cyclopropyl-magnesium bromide 11 with 10
at ambient temperature in anhydrous THF. In order to improve
the conversion of 10, a 50% equiv excess of 11 was added, since
its by-products, cyclopropane and 1,10-bi(cyclopropane), were vol-
atile and could be easily removed.
oxidation, as well as the relatively high cost and low atom econ-
omy of TBSCl as the protective group for the 2-position made the
procedure less than ideal for large-scale production.
More recently, Padi et al.5d reported another strategy for the
synthesis of prasugrel, based on the condensation of 2-bromo-1-
cyclopropyl-2-(2-fluorophenyl) ethanone with 4,5,6,7-tetrahydro-
thieno[3,2-c]pyridin-2-yl acetate. However, the yield is quite low
(<10%). These attempts revealed that only proper protection of
the 2-hydroxy of thienopyridine would promote the condensation
reaction.
After a simple work up, the coupling product 129 was collected
as a white powder in 65% yield by recrystallization from isopropyl
alcohol. Then the methoxy group of 12 was hydrolyzed with 0.5 M
hydrochloric acid at 40 °C for 12 h, to form 2-hydroxy-thiophene
139 in 83% yield. It should be noted that a higher temperature or
concentration of hydrochloric acid results in the undesired byprod-
uct 14, which might form by the acidic ring opening of the cyclo-
propane. Finally, the synthesis of prasugrel 1 was accomplished
by treating 13 with NaH and Ac2O in DMF. After easy work up
and recrystallization, the title product 19 was obtained as a white
solid in good yield (Scheme 5).
In summary, we have devised a practical and novel procedure
for the synthesis of prasugrel from simple raw materials. Its ease
of work-up, high yield, and fairly mild reaction conditions provide
a new access to prasugrel. Other applications of this process are
under investigation in our laboratory.
As a part of our continuing interest in developing practical and
efficient processes for the synthesis of active pharmaceutical ingre-
dients (API) and related intermediates, we report in this work a no-
vel and efficient approach to the preparation of prasugrel 1.
As shown in the retrosynthetic procedure in Scheme 2, we have
chosen methoxy as the protecting group, so the final O-acetyl
group was introduced by acid hydrolysis of the corresponding
methoxy of 12, followed by acetylation. Then the cyclopropyl
ketone was formed by the Grignard reaction of cyclopropyl magne-
sium bromide and phenyl-acetonitrile. The latter was prepared by
the nucleophilic substitution of 2-methoxy-4,5,6,7-tetrahydrothie-
no[3,2-c]pyridine 6 and 2-bromo-2-(2-fluorophenyl)acetonitrile 9.
We first prepared intermediate 6 using commercially available
2 (Scheme 3). Bu4NHSO4 assisted benzyl protection was performed
smoothly, to furnish 3 in 97% yield, and this was subsequently
converted into bromide 4 using HBr, H2O2, and AcOH in MeOH
(93%). Then, 2-Br thienopyridine 4 was converted into 2-methoxy
thienopyridine 5 via the CuI–NaI promoted methoxy substitution,
in 85% yield. Finally, the N-benzyl was de-protected with methyl
chloroformate and KOH (91%). In this procedure, 2-methoxy-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine 69 was produced in
hundreds of grams.
O
F
CN
MgBr 11
1.5 eq.
F
THF, 0 ºC to r.t.
N
N
O
O
65 %
S
S
S
We next used 2-fluoro-benzyl bromide 7 as another starting
material. After TBAB (tetrabutyl ammonium bromide) promoted
12
10
O
O
F
F
0.5 M HCl
40 ºC, 12 h.
83 %
HCl
HN
+
HBr, H2O2
BnCl, Bu4NHSO4 BnN
N
N
OH
OH
K2CO3, CH3CN
70 ºC, 97 %
MeOH, AcOH
0-5 ºC, 93 %
S
S
S
3
2
14
13
Ac2O, DMF
BnN
CuI, NaI
Br
NaH, 0 ºC
BnN
OMe
S
85 %
MeONa, MeOH
reflux, 85 %
S
O
4
5
F
O
N
OAc
S
1.
HN
Cl
O
OMe
2. KOH
S
91 %
6
1 prasugrel
Scheme 5. Synthesis of prasugrel 1.
Scheme 3. Synthesis of 2-methoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine 6.

5366
X. Pan et al. / Tetrahedron Letters 53 (2012) 5364–5366
d = 7.73 (td, J = 7.7, 1.5 Hz, 1H), 7.53–7.40 (m, 1H), 7.29 (dd, J = 8.8, 5.7 Hz,
References and notes
1H), 7.16 (t, J = 9.2 Hz, 1H), 5.76 (s, 1H). MS-ESI: m/z(%) = 214 (100) [M+H]+, 216
(98) [M+H]+. Anal. Calcd for C8H5BrFN: C, 44.89; H, 2.35. Found: C, 44.82; H,
2.40.
1. Atsuhiro, S.; Fumitoshi, A.; Kenji, Y.; Ryo, I.; Taketoshi, O.; Kenichi, O.; Hiroyuki,
K. Br. J. Pharmacol. 2001, 132, 47.
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Med. 2001, 345, 494.
2-(2-Fluorophenyl)-2-(2-methoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
yl)acetonitrile (10) 1H NMR (400 MHz, CDCl3): d = 7.52–6.65 (m, 4H), 5.54 (s,
1H), 4.97 (s, 1H), 3.55 (s, 3H), 3.31 (dd, J = 45.6, 13.8 Hz, 2H), 2.85–2.17 (m, 4H).
MS-ESI: m/z(%) = 303 (100) [M+H]+. Anal. Calcd for C16H15FN2OS: C, 63.56; H,
5.00. Found: C, 63.48; H, 5.03.
1-Cyclopropyl-2-(2-fluorophenyl)-2-(2-methoxy-6,7-dihydrothieno[3,2-
c]pyridin-5(4H)-yl)ethanone (12) 1H NMR (400 MHz, CDCl3): d = 7.46–7.11 (m,
4H), 5.79 (s, 1H), 4.82 (s, 1H), 3.98–3.73 (m, 3H), 3.48 (dd, J = 32.6, 14.4 Hz, 2H),
3.06–2.64 (m, 4H), 2.31 (dd, J = 7.9, 4.5, 3.3 Hz, 1H), 1.13–0.94 (m, 2H), 0.95–0.50
(m, 2H). MS-ESI: m/z(%) = 346 (100) [M+H]. Anal. Calcd for C19H20FNO2S: 66.06;
H, 5.84. Found: C, 65.93; H, 5.90.
1-Cyclopropyl-2-(2-fluorophenyl)-2-(2-hydroxy-6,7-dihydrothieno[3,2-
c]pyridin-5(4H)-yl)ethanone (13)7 Mp 120–122 °C. (lit.8 Mp 123–125 °C).1H
NMR (400 MHz, CDCl3): d = 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 (100) [M+H]+.
Prasugrel (1)8 Mp 120–121 °C. (lit.8 Mp 120.5–124.6 °C). 1H NMR (400 MHz,
CDCl3): d = 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 (100) [M+H]+.
3. (a) Wiviott, S. D.; Tantry, U. S.; Gurbel, P. A. Rev. Cardiovasc. Med. 2006, 7, 13; (b)
Wiviott, S. D.; Braunwald, E. Am. Fam. Physician. 2004, 70, 525; (c) Sharis, P. J.;
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9. Spectral data:
2-Methoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6) 1H NMR (400 MHz,
CDCl3): d = 5.82 (s, 1H), 3.82 (s, 3H), 3.75 (s, 2H), 3.14 (t, J = 5.8 Hz, 2H), 2.61
(t, J = 5.6 Hz, 2H), 2.25 (s, 1H). MS-ESI m/z(%) = 170 (100) [M+H]+. Anal. Calcd for
C8H11NOS: C, 56.77; H, 6.55. Found: C, 56.72; H, 6.58.
2-(2-Fluorophenyl)acetonitrile (8)6 1H NMR (400 MHz, CDCl3): d = 7.47 (t,
J = 7.6 Hz, 1H), 7.35 (dd, J = 7.6, 5.8 Hz, 1H), 7.21 (dd, J = 10.8, 4.2 Hz, 1H), 7.12
(dd, J = 9.8, 8.4 Hz, 1H), 3.79 (s, 2H); MS-ESI: m/z(%) = 136 (100) [M+H]+1
.
2-Bromo-2-(2-fluorophenyl)acetonitrile (9) 1H NMR (400 MHz, CDCl3):