Tetrahedron Letters
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.
Figure 1. Selected carbocyclic nucleoside natural products and analogs.
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.