Synthesis of metabolites of dapagliflozin: an SGLT2 inhibitor

Article abstract of DOI:10.1007/s12039-020-1747-x

Abstract: Dapagliflozin is one of the gliflozin class drugs, useful for the treatment of type-2 diabetes. Dapagliflozin undergoes extensive metabolism and transforms to metabolites in humans. The contribution of pharmacologically active metabolites in drug discovery and development is significant. A streamlined synthetic approach is devised to access three metabolites of dapagliflozin namely, benzylic hydroxy dapagliflozin, oxo dapagliflozin and desethyl dapagliflozin. Two synthetic protocols have been proposed for the synthesis of benzylic hydroxy dapagliflozin and oxo dapagliflozin. An enantioselective deethylation of dapagliflozin is also reported. Graphic abstract: Synthesis of three metabolites of Dapagliflozin namely benzylic hydroxy dapagliflozin, oxo dapagliflozin and desethyl dapagliflozin is reported from commercially accessible raw materials.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-020-1747-x

J. Chem. Sci.
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Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-020-1747-x) contains
supplementary material, which is available to authorized users.

4
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J. Chem. Sci.
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Scheme 2.
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(4
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2 . 5 Preparation of tetraacetyl oxodapagliflozin
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7 Preparation of benzylic hydroxy dapagliflozin
(2) (Scheme 3)
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3. Results and Discussion
?
C
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(
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:
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.
(2) (Scheme 1)
1
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2
(Scheme 3)
.
6
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.
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h
p
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r
n
w
a
s
a
a
s
a
o v e) .
g
l
a
s
s
y
o
f
f
-
w
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t
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3
.
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g
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4
%
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(
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D
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a
l
b
Cl
O
CH3
Cl
O
CH3
MnO2 / CHCl3
Reflux, 16 h
O
O
AcO
AcO
AcO
AcO
O
OAc
OAc
OAc
5
OAc
7
LiOH.H2O /
MeOH / THF / H2O
20-30 °C, 16 h
Cl
O
CH3
Cl
O
CH3
O
O
HO
HO
NaBH4 / MeOH
20-30 °C, 16 h
HO
HO
O
OH
OH
OH
OH
3
OH
2
Scheme 3.
A
l
t
e
r
n
a
t
i
v
e
s
y
n
t
h
e
s
i
s
o
f
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y
l
i
c
h
y
d
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x
y
d
a
p
a
g
l
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fl
o
z
i
n
(
2
)
a
n
d
o
x
o
d
a
p
a
g
l
i
fl
o
z
i
n
(
3
)
.

4
2
P
a
g
e
6
o
f
8
J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 4 2
Cl
OH
OH
Cl
O
CH3
O
O
HO
HO
BBr3 / DCM
HO
HO
OH
OH
OH
OH
4
OH
1
+
Cl
O
HO
HO
OH
4a
Scheme 4.
R
e
p
o
r
t
e
d
s
y
n
t
h
e
s
i
s
o
f
d
e
s
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t
h
y
l
d
a
p
a
g
l
i
fl
o
z
i
n
(
4
)
.
Cl
OH
Cl
O
CH3
O
O
HO
HO
Aqueous HBr
Reflux, 16h
HO
HO
OH
OH
OH
4
OH
1
Scheme 5.
P
r
o
p
o
s
e
d
s
y
n
t
h
e
s
i
s
o
f
d
e
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d
a
p
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g
l
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fl
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z
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n
(
4
)
.
d
5
e
w
v
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f
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2
d
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l
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fl
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(
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D
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e 3
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p
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-
-
3
. 2 Preparation of oxo dapagliflozin (3)
(Scheme 2)
t
,
a
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r
2
-
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(
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(8
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-
3 3 Alternative synthesis of benzylic hydroxy
dapagliflozin (2) and oxo dapagliflozin (3)
.
1
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(
S
c
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3
)
.

J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
4
2
P
a
g
e
7
o
f
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( 2
a
l
d
Acknowledgements
t
a
s
m
M
T
b
T
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t
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A
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a c
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a p a g l i fl o z i n ( 5) w i t h
f
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