Download PDF, 163 kB

Design and synthesis of
morpholine analogues
Mykhailiuk P.; Denisenko O.; Garbuz P.; Datcenko O.; Martirosov R.; Artemenko A.; Tkachuk G.;
Parhomenko, O.; Radchenko D.; Gorulia O.; Andrushko O.; Kondratov I.; Shcherbatiuk A.; Shyshlyk O.; Tolmachev A.
Introduction
Aim
More than 20 FDA-approved drugs contain the residue of morpholine. The fragment of morpholine, however, is often metabolically labile.3 Therefore, in recent
time analogues of morpholine became widespread in drug discovery.
To synthesize a library of
analogues of morpholine.
O
Merck, 2004
SERM
N
N
N
O
N
H
HO
N
H
S
N
N
CO2H
F
O
N
cyclic
aliphatic
core
N
O
O
Merck Sharp &
Dohme, 2002
NK1 antagonist
O
MeO
N
O
N
CF3
O
O
F3C
O
CF3
O
OH
N
HN
H
N
Ph
Wyeth, 2009
mTOR inhibitor
HN
ETH Zürich, 2010
antibacterial agent
Synthesis
CF3
HO
CF3
O
70%
CF3
PPh3, CCl4
Et3N
BnNH2
N
30%
HN
O
N
CF3
N
CN
89%
CF3
N
H
Ph
Ph
CO2Et
O
O
NaH,DMF
61%
CF3
OH
LiAlH4
Et2O
75%
CN
NH2
OMe
Me3SiCl
MeOH
O
CF3
O
O
2. KOtBu, THF
67%
N
O
NH
N
Ph
EtO2C
MeOH
91%
Ph
EN300-113203
EN300-82709
EN300-173715
EN300-135658
O
Pd/H2
MeOH
94%
EtO2C
O
N
H
O
N
H
EN300-96084
O
O O
S
EN300-97807
O
EN300-121878
EN300-93931
EN300-56462
O
O
O
O
N
H
N
H
N
H
S
NBoc
EN300-108154
EN300-170553
O
N
H
EN300-111660
F
EN300-52620
O
O
O
N
H
N
H
EN300-102280
F
N
H
HN
N
H
N
H
N
H
EN300-140486
O
O
F
N
H
EN300-111595
EN300-123162
F
O
O
O
O
N
H
EN300-102855
N
H
O
O
N
H
O
N
H
EN300-99316
O
O
N
H
EN300-110174
N
H
N
H
EN300-86476
N
H
EN300-114690
EN300-53600
N
H
O
EN300-122734
N
H
EN300-119630
O
O2N
O
O
N
H
N
H
N
H
N
H
O
EN300-91609
O
O
O
N
H
N
H
O
N
H
EN300-132632
O
O
MeNO2
DBU
CO2Et
EN300-131681
O
N
H
O
N
H
EN300-131681
O
O
Ph
and
also
THF
76%
N
H
Ph
N
O
EN300-133936
89%
BH3*Me2S
MeOH
82%
67%
61%
(2 steps)
and
also
N
H
O
O
N
O
PO(OEt)2
NaH, DMF
81%
O
Pd/H2
THF
91%
Ph
EN300-89737
O
O
BH3*Me2S
N
O
OH
THF
73%
N 2H 4
KOH
Pd/H2
N
H
PhCHO
NaH(OAc)3
O
O
HCl
Ph
1. ClCH2COCl
THF, NEt3
O
EN300-83277
EN300-81684
CO2Et
BrCH2CH2Br
and
also
N
Ph
NEt3
63%
Ph
Pd/C, H2
73%
CF3
HN
76%
O
Et2O*BF3
NaBH4
1. ClOCCH2Cl
2. K2CO3
Ph
Ph
O
HO
H2SO4
H 2O
EN300-110343
S
EN300-115251
EN300-114659
O O
S
O O
S
N
H
N
H
N
H
EN300-102867
EN300-75219
EN300-103738
HN
N
H
EN300-118087
O
N
H
EN300-79411
Conclusions
Contact
References
A library of novel and/or previously scarcely
accessible morpholine analogues have been
synthesized in multigram amounts.4
All compounds are on stock.
Pavel Mykhailiuk, PhD
Enamine LTD, Ukraine, Kyiv
[email protected]
www.enamine.net
1.
2.
3.
4.
EN300-116514
O
O S
N
H
EN300-88855
www.drugbank.ca
Bissantz, B. et al. J. Med. Chem. 2010, 5061.
Wuitschik, G. et al. J. Med. Chem. 2010, 3227.
Shcherbatiuk, A. et al. Tetrahedron 2013, 3746.

Download Report