Convenient synthesis of [3R-(3α,4β,5α,6β)]-2-[7- chloro-1-(4-ethylbenzyl)-5-methyl-1H-indol-3-yl]-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

Article abstract of DOI:10.1007/s00706-010-0350-0

A novel and convenient approach for the preparation of [3R-(3α, 4β,5α,6β)]-2-[7-chloro-1-(4-ethylbenzyl)-5-methyl-1H-indol-3-yl] -6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is developed. It has been achieved in about 72% overall yield. Springer-Verl

Full text of DOI:10.1007/s00706-010-0350-0

Monatsh Chem (2010) 141:913–916
DOI 10.1007/s00706-010-0350-0
ORIGINAL PAPER
Convenient synthesis of [3R-(3a,4b,5a,6b)]-2-[7-chloro-1-
(4-ethylbenzyl)-5-methyl-1H-indol-3-yl]-6-(hydroxy-
methyl)tetrahydro-2H-pyran-3,4,5-triol
•
Yong-Hai Liu Da-Li Li Qin-Hua Li
•
•
•
Jun-Fang Yang Lu-De Lu
Received: 13 April 2010 / Accepted: 9 June 2010 / Published online: 24 July 2010
ꢀ Springer-Verlag 2010
Abstract A novel and convenient approach for the
preparation of [3R-(3a,4b,5a,6b)]-2-[7-chloro-1-(4-ethyl-
benzyl)-5-methyl-1H-indol-3-yl]-6-(hydroxymethyl)tetrahy-
dro-2H-pyran-3,4,5-triol is developed. It has been achieved
in about 72% overall yield.
Results and discussion
The important intermediate 4 was synthesized by bromin-
ation of 3 in dichloromethane at 0 ꢁC. However, the
3-halo- and even more so the 2-haloindoles are unstable
and must be utilized as soon as they are prepared [15].
Accordingly, it is very difficult to handle compound 4 at
scale up level, and it requires more attention to avoid
exposure to air, especially at the time of product filtration
and drying. Moreover, compound 5 was prepared by cou-
pling reaction between 4 and [3R-(3a,4b,5a,6b)]-3,4,5-
tris(benzyloxy)-6-(benzyloxymethyl)tetrahydropyran-2-one
in unsatisfactory yield, and the synthetic route needed seven
steps, which limited a large-scale production according to the
procedure of Yonekubo et al. [14].
Keywords Glycosides Á Halogenation Á Heterocycles
Introduction
Sodium glucose co-transporter 2 (SGLT2) plays a key role
in maintaining glucose equilibrium in the human body
[1–3]. Much attention has been given to SGLT2 as a
molecular target to directly induce glucose excretion and to
safely normalize plasma glucose in the treatment of type 2
diabetes [4–7]. The reformative subset of SGLT2 inhibitors
to be explored was the carbon glycosides in which the bond
between the glucose and aglycone is a carbon–carbon bond
[8–12]. It was reported that [3R-(3a,4b,5a,6b)]-2-[7-chloro-
1-(4-ethylbenzyl)-5-methyl-1H-indol-3-yl]-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (1) may be advancing to
clinical development to directly induce glucose excretion
and to safely normalize plasma glucose in the treatment of
type 2 diabetes [13, 14]. The reported synthetic route of 1 is
shown in Scheme 1 [14].
Herein we report the facile synthesis of 1 by three steps.
The synthetic route is depicted in Scheme 2. Firstly, the
coupling reaction between 2 and 1-(bromomethyl)-4-ethyl-
benzene gave 9 in the presence of cesium carbonate.
Moreover, 10 can be easily prepared by treatment of [2R-(2a,-
3b,4a,5b,6a)]-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-
tetrahydro-2H-pyran-2-ol with trichloroacetonitrile for 4 h
at room temperature. Then the coupling reaction between 9
and 10 in anhydrous dichloromethane for 30 min at -78 ꢁC
afforded 8 in a high yield of 83%, which was hydrogenated
under 0.1 MPa hydrogen at room temperature to produce 1
in about 72% overall yield.
In order to demonstrate the influence of solvent, a series
of solvents were used in this protocol for deprotection of 8,
and the result is shown in Table 1. A mixture of 1 and 1a
was found in benzene, ethyl acetate (EtOAc), chloroben-
zene, and 1,2-dichlorobenzene during deprotection
reaction. However, when 20 equivalents of 1,2-dichloro-
benzene were added to the reaction system, by-product 1a
could not be detected by LC–MS (Table 1, entry 4). A
Y.-H. Liu Á D.-L. Li (&) Á Q.-H. Li Á J.-F. Yang Á L.-D. Lu
School of Chemical Engineering,
Nanjing University of Science and Technology,
Nanjing, China
e-mail: dreamlyh@sohu.com
123

914
Y.-H. Liu et al.
Br
Cl
Cl
S
Cl
a
b
N
O
c
O
OH
N
O
N
O
O
S
O
NH
O
O
O
BnO
BnO
S
BnO
BnO
Cl
OBn
OBn
OBn
OBn
2
3
4
5
Cl
Cl
S
Cl
Cl
g
d
f
e
N
N
O
O
O
O
NH
N
HO
HO
O
O
BnO
BnO
BnO
BnO
BnO
OH
BnO
OBn
OBn
OBn
OH
OBn
OBn
OBn
6
7
8
1
(a) DMF, 4-toluenesulfonyl chloride, 25 °C; (b) dichloromethane, bromine, 0 °C; (c)
n-butyl lithium, [3R-(3α,4β,5α,6β )]-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-
tetrahydropyran-2-one, -78 °C; (d) triethylsilane, acetonitrile, -15 °C; (e)
tetrahydrofuran, potassium hydroxide, 50 °C; (f) DMF, 1-(bromomethyl)-4-
ethylbenzene, 0 °C; (g) 10% Pd-C, MeOH, H2, 25 °C.
Scheme 1
(a) DMF, 1-(bromomethyl)-4-ethylbenzene, Cs2CO3, 60 °C; (b) CH2Cl2, [2S-
(2α,3β,4α,5β,6α)]-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-
yl 2,2,2-trichloroacetimidate (10), -78 °C; (c) 10% Pd-C, 1,2-dichlorobenzene, MeOH,
H2, 25 °C.
Scheme 2
possible reason for the effect of 1,2-dichlorobenzene in this
protocol could be that its chlorine group can be reduced
first, and the resultant hydrochloride can gradually inhibit
the reduction of the chlorine atom of 1.
Experimental
Compound 2 was purchased from Sigma-Aldrich, and all
reagents were obtained from suppliers and were not puri-
fied. Melting points were measured on a PHMK179-2454
apparatus. Elemental analyses (C, H, N) were determined
with a Perkin-Elmer 240c instrument; their results were
In conclusion, a more convenient and effective approach
for synthesis 1 was found. It has been achieved in about
72% overall yield.
123

Synthesis of [3R-(3a,4b,5a,6b)]-2-[7-chloro-1-…]
915
Table 1 Synthesis of compound 1 by deprotection of benzyl group
Cl
Cl
N
O
N
N
O
HO
HO
H2/Pd
O
HO
BnO
BnO
+
EA/MeOH,12 h
OH
OH
HO
OBn
OH
OH
OBn
8
1
1a
Entry
1
Solvent
Equivalents
Product 1 yield (%)a
By-product 1a yield (%)a
Benzene
10
20
10
20
10
20
10
20
51
51
51
51
74
81
92
99
48
49
49
48
25
18
6
2
3
4
a
Ethyl acetate
Chlorobenzene
1,2-Dichlorobenzene
0
Determined by HPLC analysis of crude products before purification
was slowly added. The solution was stirred for 30 min at
-78 ꢁC, quenched with saturated NaHCO3, and extracted
with EtOAc. The organic phase was separated and washed
with brine, dried over anhydrous Na2SO4, and concentrated
in vacuo to give a crude oil. The oil was purified by column
chromatography (petroleum ether/EtOAc, 6:1, v/v) to give
the pure product 8 as colorless oil (5.8 g, 83%). Rf = 0.35
found to be in good agreement ( 0.2%) with the calculated
values. 1H NMR and 13C NMR were measured on a Bruker
AM-300 spectrometer. EI mass spectral measurement was
carried out on a Waters alliance 2695 with acetonitrile and
water as a mobile phase. Column chromatography was
conducted under low pressure by elution of the columns
filled with silica gel (0.040–0.063 mm, Merck).
1
(petroleum ether/EtOAc, 8:1, v/v); H NMR (300 MHz,
7-Chloro-1-(4-ethylbenzyl)-5-methyl-1H-indole
CDCl3): d = 1.17 (3H, t, J = 7.8 Hz), 2.37 (3H, s), 2.60
(2H, q, J = 7.8 Hz), 3.43–3.52 (3H, m), 3.65–3.90 (7H, m),
3.97–4.10 (2H, m), 4.43 (1H, d, J = 9.6 Hz), 4.47–4.99 (8H,
m), 5.26 (2H, s), 6.93–6.96 (3H, m), 7.08 (1H, d,
J = 7.8 Hz), 7.07–7.30 (21H, m), 7.46 (1H, s) ppm;
13C NMR (300 MHz, CDCl3): d = 142.8, 135.4, 131.2,
130.6, 130.4, 129.8, 128.8, 128.6, 128.2, 128.0, 127.8,
127.6, 127.2, 126.6, 120.8, 120.6, 119.4, 118.2, 94.6, 87.8,
79.8, 75.5, 75.1, 75.0, 74.6, 74.3, 73.4, 66.6, 55.2, 28.6, 22.4,
15.5 ppm; MS: m/z = 805 [M]?, 828 [M ? Na]?.
(9, C18H18ClN)
To a solution of 1.66 g 2 (10 mmol) in 10 cm3 anhydrous
DMF, 2.19 g 1-(bromomethyl)-4-ethylbenzene (11 mmol)
was added, and the mixture was stirred for 5 h at 50 ꢁC. Then
the reaction mixture was poured into ice water and extracted
with EtOAc. The organic phase was washed with water and
brine, dried with anhydrous sodium sulfate, and concentrated
in vacuo to give 9 as yellow solid (2.76 g, 97%). M.p.: 61–
62 ꢁC; 1H NMR (300 MHz, CDCl3): d = 1.17 (3H, t,
J = 7.5 Hz), 2.37 (3H, s), 2.57 (2H, q, J = 7.8 Hz), 5.61
(2H, s), 6.49 (1H, m), 6.72–6.83 (2H, m), 6.91–6.94 (1H, m),
[3R-(3a,4b,5a,6b)]-2-[7-Chloro-1-(4-ethylbenzyl)-5-
methyl-1H-indol-3-yl]-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (1, C24H28ClNO5)
6.94–7.04 (2H, m), 7.30 (1H, s), 7.46–7.51 (1H, m) ppm; 13
C
NMR (300 MHz, CD3OD): d = 137.2, 136.6, 134.9, 132.3,
129.2, 129.1, 127.8, 127.7, 120.7, 119.3, 116.2, 102.4, 60.8,
28.6, 20.8, 16.1 ppm; MS: m/z = 283 [M]?, 306 [M ? Na]?.
To a solution of 5 g 8 (6.21 mmol) in 50 cm3 EtOAc/
MeOH (1:4) in a 150 cm3 autoclave reactor, 0.5 g palla-
dium on carbon and 15 cm3 1,2-dichlorobenzene were
added in turn. The air in the reactor was removed by argon,
then 0.1 MPa H2 was added for 12 h at 25 ꢁC. The solvent
was filtrated, the filter cake was washed by EtOAc, and the
filtrate was concentrated in vacuo to give an oil. The oil
was purified by column chromatography (MeOH/EtOAc,
7-Chloro-1-(4-ethylbenzyl)-5-methyl-3-[[3S-(3a,4b,5a,6b)]-
3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-
pyran-2-yl]-1H-indole (8, C52H52ClNO5)
To a stirred solution of 6 g 10 (8.8 mmol) in 150 cm3
anhydrous dichloromethane at -78 ꢁC, 9.9 g 9 (35.1 mmol)
123

916
Y.-H. Liu et al.
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1:4, v/v) to get 1 as light yellow oil (2.46 g, 89%).
1
Rf = 0.30 (MeOH/EtOAc, 1:5, v/v); H NMR (300 MHz,
CD3OD): d = 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 2.57
(2H, q, J = 7.8 Hz), 3.43–3.52 (3H, m), 3.65–3.71 (2H,
m), 3.86–3.91 (1H, m), 4.46 (1H, d, J = 9.6 Hz), 5.26 (2H,
s), 6.93–6.96 (3H, m), 7.08 (2H, d, J = 7.8 Hz), 7.29 (1H,
s), 7.46 (1H, s) ppm; 13C NMR (300 MHz, CD3OD):
d = 142.4, 138.5, 133.3, 130.7, 129.0, 128.6, 128.2, 126.8,
120.6, 119.9, 117.8, 116.2, 90.6, 85.8, 78.8, 71.6, 71.3,
62.6, 55.2, 29.6, 23.2, 16.5 ppm; MS: m/z = 445 [M]?,
468 [M ? Na]?.
14. Yonekubo S, Fushimi N (2007) EU Patent 1813611, Chem Abstr
144:488898
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123