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http://www.google.com/patents/WO2013068850A2?cl=en
EXAMPLE 24 - Synthesis of
2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(4-chloro-3-(4-
ethoxybenzyl)phenyl)- -D-glucopyranoside
2,4-di-6>-TBDPS-dapagliflozin; (IVj"))
[0229] l-(5-Bromo-2-chlorobenzyl)-4-ethoxybenzene
(1.5 g, 4.6 mmol) and magnesium powder (0.54 g, 22.2 mmol) were placed
in a suitable reactor, followed by THF (12 mL) and 1,2- dibromoethane
(0.16 mL). The mixture was heated to reflux. After the reaction had
initiated, a solution of l-(5-bromo-2-chlorobenzyl)-4-ethoxybenzene (4.5
g, 13.8 mmol) in THF (28 mL) was added dropwise. The mixture was
allowed to stir for another hour under reflux, and was
then cooled to ambient temperature, and then titrated to determine the
concentration. The above prepared
4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl magnesium bromide (31 mL, 10
mmol, 0.32 M in THF) and A1C1
3 (0.5 M in THF, 8.0 mL, 4.0
mmol) were mixed at ambient temperature to give a black solution, which
was stirred at ambient temperature for 1 hour. To a solution of
I, 6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl-
-D-glucopyranose (0.64 g, 1.0 mmol) in PhOMe (3.0 mL) at ambient
temperature was added phenylmagnesium bromide (0.38 mL, 1.0 mmol, 2.6 M
solution in Et
20). After stirring for about 5 min the
solution was then added into the above prepared aluminum mixture via
syringe, followed by additional PhOMe (1.0 mL) to rinse the flask. The
mixture was concentrated under reduced pressure (50 torr) at 60 °C
(external bath temperature) to remove low-boiling point ethereal
solvents and then PhOMe (6mL) was added. The reaction mixture was heated
at 130 °C (external bath temperature) for 8 hours at which time HPLC
assay analysis indicated a 51% yield of
2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(4-chloro-3-
(4-ethoxybenzyl)phenyl)- -D-glucopyranoside. After cooling to ambient
temperature, the reaction was treated with 10% aqueous NaOH (1 mL), THF
(10 mL) and diatomaceous earth at ambient temperature, then the mixture
was filtered and the filter cake was washed with THF. The combined
filtrates were concentrated and the crude product was purified by silica
gel column chromatography (eluting with 1:30 EtOAc/77-heptane)
affording the product 2,4-di-6>- ieri-butyldiphenylsilyl- 1 -
-(4-chloro-3 -(4-ethoxybenzyl)phenyl)- β-D-glucopyranoside (0.30 g, 34%)
as a white powder.
1H NMR (400 MHz, CDC1
3) δ 7.56-7.54 (m,
2H), 7.43-7.31 (m, 13H), 7.29-7.22 (m, 6H), 7.07- 7.04 (m, 2H), 7.00 (d,
J= 2.0 Hz, IH), 6.87 (dd, J= 8.4, 2.0 Hz, IH), 6.83-6.81 (m, 2H), 4.18
(d, J= 9.6 Hz, IH), 4.02 (q, J= 6.9 Hz, 2H), 3.96 (d, J= 10.8 Hz, 2H),
3.86 (ddd, J= 11.3, 7.7, 1.1 Hz, IH), 3.76 (ddd, J= 8.4, 8.4, 4.8 Hz,
IH), 3.56 (ddd, J= 9.0, 6.4, 2.4 Hz, IH), 3.50 (dd, J=
I I.4, 5.4 Hz, IH), 3.44 (dd, J= 9.4, 8.6 Hz, IH),
3.38 (dd, J= 8.8, 8.8 Hz, IH), 1.70 (dd, J= 7.8, 5.4 Hz, IH, OH), 1.42
(t, J= 6.8 Hz, 3H), 1.21 (d, J= 5.2 Hz, IH, OH), 1.00 (s, 9H), 0.64 (s,
9H);
13C NMR (100 MHz, CDC1
3) δ 157.4 (C), 138.8
(C), 137.4 (C), 136.3 (CH x2), 136.1 (CH x2), 135.2 (CH x2), 135.0 (C),
134.9 (CH x2), 134.8 (C), 134.2 (C), 132.8 (C), 132.0 (C), 131.6 (CH),
131.1 (C), 129.9 (CH x2), 129.7 (CH), 129.6 (CH), 129.5 (CH), 129.4
(CH), 129.2 (CH), 127.58 (CH x2), 127.57 (CH x2), 127.54 (CH x2), 127.31
(CH), 127.28 (CH x2), 114.4 (CH x2), 82.2 (CH), 80.5 (CH), 79.3 (CH),
76.3 (CH), 72.7 (CH), 63.4 (CH
2), 62.7 (CH
2), 38.2 (CH
2), 27.2 (CH
3 x3), 26.6 (CH
3 x3), 19.6 (C), 19.2 (C), 14.9 (CH
3).
EXAMPLE 25 -Synthesis of dapagliflozin
((25,3R,4R,55,6/?)-2-[4-chloro-3-(4-
ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(Ij))
IVj' U
[0230] A solution of the
2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(4-chloro-3-(4-
ethoxybenzyl)phenyl)- -D-glucopyranoside (60 mg, 0.068 mmol) in THF (3.0
mL) and TBAF (3.0 mL, 3.0 mmol, 1.0 M in THF) was stirred at ambient
temperature for 15 hours. CaC0
3 (0.62 g), Dowex
^
50WX8-400 ion exchange resin (1.86 g) and MeOH (5mL) were added to the
product mixture and the suspension was stirred at ambient temperature
for 1 hour and then the mixture was filtrated through a pad of
diatomaceous earth. The filter cake was rinsed with MeOH and the
combined filtrates was evaporated under vacuum and the resulting residue
was purified by column chromatography (eluting with 1 : 10 MeOH/DCM)
affording dapagliflozin (30 mg).
1H NMR (400 MHz, CD3OD) δ 7.37-7.34 (m,
2H), 7.29 (dd, J= 8.2, 2.2 Hz, 1H), 7.12-7.10 (m, 2H), 6.82-6.80 (m,
2H), 4.10 (d, J= 9.6 Hz, 2H), 4.04 (d, J= 9.2 Hz, 2H), 4.00 (q, J= 7.1
Hz, 2H), 3.91-3.87 (m, 1H), 3.73-3.67(m, 1H), 3.47-3.40 (m, 3H),
3.31-3.23 (m, 2H), 1.37 (t, J= 7.0 Hz, 3H);
13C NMR (100 MHz, CD3OD)
δ 157.4 (C), 138.6 (C), 138.5 (C), 133.1 (C), 131.5 (C), 130.5 (CH),
129.4 (CH x2), 128.7 (CH), 126.8 (CH), 114.0 (CH x2), 80.5 (CH), 80.8
(CH), 78.3 (CH), 75.0 (CH), 70.4 (CH), 63.0 (CH2), 61.7 (CH2), 37.8 (CH2), 13.8 (CH3);
LCMS (ESI) m/z 426 (100, [M+NH4]+), 428 (36, [M+NH4+2]+), 447 (33, [M+K]+).
Example 1 - Synthesis of l,6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (II")
III II"
[0206] To a suspension solution of l,6-anhydro-
-D-glucopyranose (1.83 g, 11.3 mmol) and imidazole (3.07 g, 45.2 mmol)
in THF (10 mL) at 0 °C was added dropwise a solution of
TBDPSC1 (11.6 mL, 45.2 mmol) in THF (10 mL). After the
l,6-anhydro-P-D-gJucopyranose was consumed, water (10 mL) was added and
the mixture was extracted twice with EtOAc (20 mL each), washed with
brine (10 mL), dried (Na
2S0
4) and concentrated. Column
chromatography (eluting with 1 :20 EtOAc/rc-heptane)
afforded 2,4-di-6>-ieri-butyldiphenylsilyl- l,6-anhydro-
"D-glucopyranose (5.89 g, 81%).
1H NMR (400 MHz, CDC1
3) δ 7.82-7.70 (m,
8H), 7.49-7.36 (m, 12H), 5.17 (s, IH), 4.22 (d, J= 4.8 Hz, IH),
3.88-3.85 (m, IH), 3.583-3.579 (m, IH), 3.492-3.486 (m, IH), 3.47-3.45
(m, IH), 3.30 (dd, J= 7.4, 5.4 Hz, IH), 1.71 (d, J= 6.0 Hz, IH), 1.142
(s, 9H), 1.139 (s, 9H);
13C NMR (100 MHz, CDCI
3) δ
135.89 (CH x2), 135.87 (CH x2), 135.85 (CH x2), 135.83 (CH x2), 133.8
(C), 133.5 (C), 133.3 (C), 133.2 (C), 129.94 (CH), 129.92 (CH), 129.90
(CH), 129.88 (CH), 127.84 (CH
2 x2), 127.82 (CH
2 x2), 127.77 (CH
2 x4), 102.4 (CH), 76.9 (CH), 75.3 (CH), 73.9 (CH), 73.5 (CH), 65.4 (CH
2), 27.0 (CH
3 x6), 19.3 (C x2).
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