Tetrahedron Letters
Practical synthesis of Vistusertib (AZD2014), an ATP competitive mTOR
inhibitor
b,
Guobing Shen a, Miaoqing Liu a, Jianjun Lu a, , Tao Meng
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a Key Laboratory of Coal Science and Technology of Ministry of Education and Shanxi Province, Taiyuan University of Technology, Taiyuan 030024, PR China
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Vistusertib (AZD2014) is a potent, selective inhibitor of mTOR kinase. Prompted by its fascinating biolog-
ical activity, an efficient and practical synthesis of Vistusertib has been developed from 3-acetylbenzoic
acid through six steps in 48% overall yield.
Received 18 September 2019
Revised 22 October 2019
Accepted 25 October 2019
Available online 5 November 2019
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Vistusertib
AZD2014
mTOR inhibitor
3-Acetylbenzoic acid
Introduction
The mechanistic target of rapamycin (mTOR) is a serine/thre-
onine kinase plays an integral role in the coordination of protein
synthesis, cell growth and proliferation, autophagy, cell metabo-
lism. Dysregulation of mTOR signal pathway is closely related to
many human diseases, including cancer. The limitations of
rapamycin-based therapies have led to the development of a sec-
ond generation of mTOR inhibitors known as ATP-competitive
mTOR kinase inhibitors [1]. Among those, Vistusertib (AZD2014)
is a novel ATP-competitive selective inhibitor of mTOR shows very
good antitumor activity in vivo, good pharmacokinetic and safety
properties [2], which is currently in clinical trials for a wide variety
of cancers [2b,3] (Fig. 1).
The method for preparation AZD2014 described in the prior art
is shown in Scheme 1 [2a]. Reaction of 2,6-dichloronicotinic acid
with liquid ammonia at elevated temperature and pressure
results in the selective introduction of an amino group into the
C2 position and subsequent conversion of the carboxylic acid to
the primary amide, which then cyclized with oxalyl chloride to
afford the pyridopyrimidine scaffold. Chlorination with
phosphorous oxychloride results in the 2,4,7-trichloropyrido[2,3-
d]pyrimidine, the introduction first of a morpholino substituent
at position C-4, followed by C-2 substitution of the second
morpholine ring. Then reaction of 4-aminophenylboronic acid in
Fig. 1. The chemical structure of Vistusertib (AZD2014).
the presence of Pd(PPh3)4 at position C-7 afforded compound VI
(AZD2014) in about 10% overall yield. Owing to the strict
condition, high cost and difficulties on large-scale preparation, an
efficient and practical synthetic method for AZD2014 is desirable.
We have recently developed a synthetic process of low cost,
high purity and suitable for industrial production of this com-
pound, and also suitable for its analogues synthesis [4]. Herein,
we wish to report the details of this improved synthetic procedure
(shown in Scheme 2).
Result and discussion
It is found that AZD2014 contains a methylbenzamide struc-
tural fragment, which brought significant improvement to the
pharmacokinetic properties [2a]. However, Suzuki coupling was
used in the final step to introduce this group in the original
synthetic route, which increases the cost of removing palladium
from Active Pharmaceutical Ingredient (API). We envisioned that
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Corresponding authors.
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.