Synthesis of an all-cis intermediate of ticagrelor

Article abstract of DOI:10.1016/j.tetlet.2015.09.074

A six step conversion of the common carbocyclic nucleoside precursor 8 into the all-cis key intermediate for the synthesis of ticagrelor analogs is reported. The method involves two oxidation/stereoselective reduction sequences for both the C-O and C-N bonds. Inversion of stereochemistry was confirmed by analysis of spin couplings between the hydrogens at the junction of the 1,3-dioxolane and cyclopentane rings.

Full text of DOI:10.1016/j.tetlet.2015.09.074

Tetrahedron Letters 56 (2015) 6093–6096
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Tetrahedron Letters
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Synthesis of an all-cis intermediate of ticagrelor
Joanna Włodarczyk a, Andrzej Wolan a,b, Marcin Rakowiecki a, Mariusz Jan Bosiak a,b, Marcin Budny a,
⇑
a Synthex Technologies Sp. z o.o., Gagarina 7/134B, 87-100 Torun´, Poland
b Nicolaus Copernicus University, Faculty of Chemistry, Gagarina 7, 87-100 Torun´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2015
Revised 12 September 2015
Accepted 17 September 2015
Available online 21 September 2015
A six step conversion of the common carbocyclic nucleoside precursor 8 into the all-cis key intermediate
for the synthesis of ticagrelor analogs is reported. The method involves two oxidation/stereoselective
reduction sequences for both the CAO and CAN bonds. Inversion of stereochemistry was confirmed by
analysis of spin couplings between the hydrogens at the junction of the 1,3-dioxolane and cyclopentane
rings.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Carbocyclic nucleosides
Ticagrelor
API impurities
NMR spectroscopy
Introduction
previously used in the synthesis of ticagrelor. We considered that
with all-cis 7 in hand, all-cis ticagrelor may also be prepared
Carbocyclic nucleosides (CNs) are compounds possessing
important antiviral, antitumor, and antibiotic activities.1 Naturally
occurring CNs—aristeromycin (1)2 and neplanocin A (2)3 served as
an inspiration for the design and synthesis of many unnatural
analogs.4 Some of these, entecavir (3),5 carbovir (4),6 abacavir
(5),7 and ticagrelor (6),8 have found application as drugs (Fig. 1).
The stereochemistry of many CNs analogs is similar to that of
the natural nucleosides. However, this similarity is not required
to effect biological activities and there are examples of bioactive
nucleoside analogs in which one stereogenic center has been inver-
ted.4b–d,f Interestingly, all-cis CNs, in which two stereocenters are
inverted, have not been broadly investigated. However, these
compounds have occasionally been reported as part of general
synthetic approaches to CNs (Scheme 1).9
These examples show that all-cis CNs can be formed, at least as
minor products, during the synthesis of APIs (active pharmaceuti-
cal ingredients) in the pharmaceutical industry. Therefore, access
to this scaffold is particularly important in drug development pro-
cesses in order to determine their levels in APIs.
During the course of our research aimed at the synthesis of tica-
grelor impurities, we developed a synthesis of all-cis 7 from previ-
ously reported carbocycle 8. All-cis 7, where the C-1 and C-4
stereocenters are inverted, is an analog of 9, a key intermediate
(Scheme 2).
NH2
N
NH2
N
N
N
N
N
N
N
HO
HO
HO
OH
HO
OH
aristeromycin 1
neplanocinA 2
O
N
O
N
NH
NH2
NH
N
N
N
N
HO
HO
NH2
HO
3
4
entecavir
carbovir
HN
F
F
HN
N
OH
N
N
N
N
N
N
O
N
NH2
N
S
HO
HO
OH
ticagrelor 6
abacavir 5
⇑
Corresponding author. Tel.: +48 56 646 19 63; fax: +48 56 654 24 77.
E-mail address: budny@synthex.com.pl (M. Budny).
Figure 1. Selected carbocyclic nucleoside natural products and analogs.
http://dx.doi.org/10.1016/j.tetlet.2015.09.074
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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J. Włodarczyk et al. / Tetrahedron Letters 56 (2015) 6093–6096
a)
ref. 9a
PhCO2
N3
PhCO2
HO
N3
OH
PhCO2
HO
N3
OH
OsO4, NMO
+
wet DCM,
70%
dr = 15:1
b) ref. 9b
Br
BzO
BzO
NHOMe
BzO
NHOMe
NOMe
nBu3SnH, AIBN
+
71%
dr = 80:20
O
O
O
O
O
O
O
c)
ref. 9b
Br
NHOBn
NHOBn
OTBS
nBu3SnH, AIBN
NOBn
O
O
O
+
80%
dr = 64:36
Ph
Ph
O
O
Ph
OTBS
OTBS
Scheme 1. Studies toward all-cis CNs.
1
O
O
4
NH2
Swern
O
OH
HO
NHCbz
NHCbz
HO
HO
Ref. 8
O
oxidation
HO
3
2
ticagrelor
DCM
-78 °C to R.T.
95%
O
O
7 steps
HO OH
O
O
O
O
HO
NHCbz
9
7
10
8
11
NHCbz
O
O
HO
NHCbz
EtO2C
O
NaBH4
Br
CO2Et
4
1
NH2
MeOH
R.T.
NaH, DMF, 0 °C
34%
this work
all-cis
8
O
O
O
O
3
2
ticagrelor
O
O
99%
12
EtO2C
13
Na2WO4×H2O
O
NH2
EtO2C
O
N
Pd/C, H2
(12 mol%)
OH
Scheme 2. An outline of the study.
MeOH
R.T.
H2O2
MeOH/H2O (1:1)
90%
O
O
O
O
O
O
93%
14
7
15
Results and discussion
O
NH2
LiAlH4
HO
Et2O, R.T.
43%
Our strategy for inversion of the configuration at C-1 and C-4
involved oxidation of the CAO and CAN bonds to the ketone and
imine, respectively, followed by reduction with metal hydrides.
We envisioned that steric hindrance induced by the 1,3-dioxolane
ring should preferentially favor exposure of one face of the
cyclopentane ring to hydride attack (Fig. 2).
Scheme 3. Synthesis of all-cis 7.
Our synthesis began with compound 8, which was obtained
from D-ribose (10) in 7 steps according to a previously published
route.8 The C-4 stereochemistry was inverted in two high yielding
Swern conditions before reduction with NaBH4 to exclusively
afford alcohol 12.
steps. First, the secondary alcohol was oxidized to ketone 11 under
Before transformation of the CAN bond to the C@N bond, the
secondary alcohol was needed to be protected. The CH2CO2Et
group was selected because it could be converted into the HOCH2-
CH2 unit present in ticagrelor, during reduction of the C@N bond.
Williamson etherification using ethyl bromoacetate proved to be
a difficult transformation, giving 13 in only 34% yield. Presumably,
both the steric hindrance of the secondary alcohol and the rela-
tively acidic proton of the NHCbz group made this reaction
difficult.
The Cbz protecting group was removed under standard condi-
tions providing amine 14 in 93% yield which was smoothly con-
verted, in a tungsten-catalyzed process10 with hydrogen peroxide
as the external oxidant, to oxime 15 in 90% yield. Reduction of both
oxime and esters moieties in 15 with LiAlH4 provided amine 7 in
43% yield (Scheme 3).
M
a)
b)
H
H
O
CbzHN
CbzHN
O
OH
O
O
O
M
H
M
H
H
N
OH
NH2
RO
M
R'O
O
O
O
H
O
The stereochemistry of compounds 12 and 7 was assigned
according to their 1H and 2D NMR spectra and by comparison with
the spectra of uninverted 8 and 9 (Fig. 3).
R = HOCH2CH2
Figure 2. Proposed stereoselectivity for reduction of the C@O and C@N bonds.

J. Włodarczyk et al. / Tetrahedron Letters 56 (2015) 6093–6096
6095
Figure 3. Stereochemistry determination by 1H NMR.
Hydrogens Hb and Hc from the 1,3-dioxolane ring junction were
Supplementary data
diagnostic for determining the stereochemistry. In uninverted
alcohol 8, protons Hb and Hc gave a broad doublet (J = 4.2 Hz)
and a doublet of doublets (J1 = 5.6 Hz, J2 = 2.1 Hz). Since the broad
doublet at 4.59 ppm was not well resolved, differences between J
coupling values from coupled hydrogens occurred. The COSY spec-
trum of 8 showed that neither Ha–Hb nor Hc–Hd proton pairs were
coupled; therefore we could not determine which peak came from
Hb or Hc (Fig. 3a). In alcohol 12, however, with an inverted sec-
ondary alcohol, the dihedral angles Hc–C–C–Hd and Hc–C–C–Hb
should have similar values and hence, J values for couplings Hc–
Hd and Hc–Hb should also be similar. Indeed, Hc was a broad triplet
with J = 4.9 Hz (Fig. 3b). This assignment was confirmed by 2D
NMR spectra. The comparison of 1H NMR spectra of 9 and 7 led
to the conclusion that protons Hb and Hc in 7 must be cis to Ha
and Hd as both Hb and Hc gave triplets (J = 5.2 Hz) (Fig. 3c and d).
Supplementary data (methods, experimental procedures, and
characterization data, as well as copies of NMR spectra) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2015.09.074.
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in the synthesis of an all-cis analog of ticagrelor. The stereochem-
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Acknowledgement
This work was funded by Synthex Technologies Sp. z o.o.

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