20
1
overlap between an aromatic carbon and solvent peaks, not all
apparatus). [α]D +29.4 (c 1.52, MeOH); H NMR (CD3OD) δ
1.19 (3H, t, J = 7.5 Hz), 2.60 (2H, q, J = 7.5 Hz), 3.42−3.48 (1H,
m), 3.64 (1H, dd, J = 6.0, 12.0 Hz), 3.75−3.83 (4H, m), 5.08 (1H,
d, J = 12.5 Hz), 5.14 (1H, d, J = 12.5 Hz), 5.78 (1H, s), 7.14 (2H,
d, J = 8.0 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.0 Hz),
7.39 (1H, s), 7.40 (1H, d, J = 8.5 Hz); 13C NMR (CD3OD) δ 17.2,
30.5, 63.9, 72.9, 74.4, 76.0, 77.3, 77.5, 77.8, 112.6, 122.5, 122.8,
128.9, 129.8, 123.0, 141.0, 142.1, 144.1, 145.6, 147.0; IR (ATR):
3313, 2924, 1701, 1649, 1541, 1099, 1065, 1011 cm−1; HRMS
ACCEPTED MANUSCRIPT
carbons resonances were visible; IR (KBr): 2956, 1591, 1562,
1377, 1252, 1182, 1107, 841 cm−1; HRMS (ESI+) (m/z): Calcd
for C32H65BrNaO8Si5+ [M+Na]+ 819.2601, Found 819.2599.
4.8. (2,3R,4S,5R)-Tetrakis(trimethylsilyloxy)-6R-
trimethylsilyloxymethyl-2-[5-(4-ethylphenyl)hydroxymethyl-2-
(1-methoxy-1-methylethoxymethyl)phenyl]tetrahydropyran (8)
To the solution of 7, which was obtained in the previous step,
was added dropwise a solution of n-BuLi in hexane (1.54 M,
1119 mL, 1724 mmol) at −78 °C. The whole was stirred at –78
°C for 1 h. To the resulting mixture was added dropwise 4-
ethylbenzaldehyde (242 g, 1806 mmol) at –78 °C, and the
mixture was stirred at the same temperature for 2.5 h. After
addition of the mixture to 20%NH4Cl (aq), the organic layer was
washed with water. The solvent was evaporated under reduced
pressure to give a product containing 8 as an oil (879 g). This
product was used in the next step without further purification.
For analytical data of 8, a portion of the oil was purified by
preparative HPLC (column: Inertsil ODS-3, 20 mm I.D. x 250
mm; acetonitrile, 30 mL/min) to give two mixtures (8a and 8b:
each containing diastereomers). 8a: colorless oil. 1H NMR
(CDCl3) δ −0.47 (4.8H, s), −0.40 (4.2H, s), −0.003−0.004 (5H,
m), 0.07−0.08 (13H, m), 0.15−0.17 (18H, m), 1.200 and 1.202
(3H, each t, J = 8.0 Hz), 1.393 and 1.399 (3H, each s), 1.44 (3H,
s), 2.61 (2H, q, J = 8.0 Hz), 3.221 and 3.223 (3H, each s), 3.43
(1H, t, J = 8.5 Hz), 3.54 (1H, dd, J = 8.5, 3.0 Hz), 3.61−3.66 (1H,
m), 3.80−3.85 (3H, m), 4.56 and 4.58 (1H, each d, J = 12.4 Hz),
4.92 and 4.93 (1H, each d, J = 12.4 Hz), 5.80 and 5.82 (1H, each
d, J = 3.0Hz), 7.14 (2H, d, J = 8.0 Hz), 7.28−7.35 (3H, m),
7.50−7.57 (2H, m); HRMS (ESI+) (m/z): Calcd for
(ESI+) (m/z): Calcd for C22H27O7 [M+H]+ 403.1751, Found
+
403.1750, Calcd for C22H26NaO7 [M+Na]+ 425.1571, Found
+
20
425.1591. 9b: colorless amorphous solid. [α]D +11.1 (c 1.44,
MeOH); 1H NMR (CD3OD) δ 1.20 (3H, t, J = 7.4 Hz), 2.61 (2H,
q, J = 7.4 Hz), 3.42−3.48 (1H, m) , 3.65 (1H, dd, J = 5.9, 11.9
Hz), 3.75−3.83 (4H, m), 5.08 (1H, d, J = 12.9 Hz), 5.15 (1H, d, J
= 12.9 Hz), 5.79 (1H, s), 7.14 (2H, d, J = 7.9 Hz), 7.23 (1H, d, J
= 7.4 Hz), 7.28 (2H, d, J = 7.9 Hz), 7.36 (1H, d, J = 8.4 Hz), 7.42
(1H, s); 13C NMR (CD3OD) δ: 17.1, 30.4, 63.7, 72.8, 74.2, 75.8,
77.1, 77.3, 77.5, 112.5, 122.1, 122.5, 128.7, 129.6, 130.0, 140.9,
141.89, 144.0, 145.4, 146.8; IR (KBr): 3367, 2929, 1699, 1649,
1510, 1063, 1007 cm−1; HRMS (ESI+) (m/z): Calcd for
C22H27O7 [M+H]+ 403.1751, Found 403.1747, Calcd for
+
C22H26NaO7+ [M+Na]+ 425.1571, Found 425.1579.
4.10. Tofogliflozin (1)
A part of the oil containing 9 (125 g out of 247 g), which was
obtained in the previous step, was dissolved in 1,2-
dimethoxyethane (400 mL). To the solution were added water
(150 mL) and 5% Pd/C (19 g, water content ratio: 50%). The
mixture was stirred under hydrogen at room temperature for 6 h.
After filtration, the residue was washed with a mixture of 1,2-
dimethoxyethane (250 mL) and water (250 mL). The filtrate and
washings were combined. To this mixture was added 1,2-
dimethoxyethane (500 mL), and the resulting mixture was
washed with n-heptane (1000 mL x 2). To the aqueous layer were
added AcOEt (500 mL) and aqueous 25% NaCl (600 g). The
organic layer was washed with aqueous 15% NaCl (600 g), and
the solvent was removed under reduced pressure. To the resulting
residue was added acetone (500 mL), and the solvent was
removed under reduced pressure to give 1 (106 g; 93.9% purity:
calculated based on the area ratio measured by HPLC; column:
Atlantis dC18, 4.6 mm I.D. x 75 mm, 3 µm; H2O with
acetonitrile, gradient operation 2% to 100%; flow rate, 1.2
mL/min). The purification was carried out in the next step by
way of the synthesis of carbonate derivative.
+
C41H76NaO9Si5 [M+Na]+ 875.4228, Found 875.4238. 8b:
colorless oil. 1H NMR (toluene-d8, 80 °C) δ −0.25 (4H, s), −0.22
(5H, s), 0.13 (5H, s), 0.16 (4H, s), 0.211 and 0.214 (9H, each s),
0.25 (9H, s), 0.29 (9H, s), 1.21 (3H, t, J = 7.5 Hz), 1.43 (3H, s),
1.45 (3H, s), 2.49 (2H, q, J = 7.5 Hz), 3.192 and 3.194 (3H, each
s), 3.91−4.04 (4H, m), 4.33−4.39 (2H, m), 4.93 (1H, d, J = 14.5
Hz), 5.10−5.17 (1H, m), 5.64 and 5.66 (1H, each s), 7.03 (2H, d,
J = 8.0 Hz), 7.28−7.35 (3H, m), 7.59−7.64 (1H, m), 7.87−7.89
+
(1H, m); HRMS (ESI+) (m/z): Calcd for C41H76NaO9Si5
[M+Na]+ 875.4228, Found 875.4272.
4.9. 1,1-Anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-
(hydroxymethyl)phenyl]-β-D-glucopyranose (9)
A part of the oil containing 8 (628 g out of 879 g), which was
obtained in the previous step, was dissolved in THF (991 mL).
To the solution were added water (63 mL) and aqueous 1N HCl
(23 mL), and the whole was stirred at 28 °C for 7 h. After
addition of triethylamine (3.8 mL, 25.8 mmol), the solvent was
removed under reduced pressure. The resulting residue was
dissolved in water (198 mL) and 1,2-dimethoxyethane (396 mL),
and the solution was washed with heptane (595 mL). To the
aqueous layer were added water (99 mL) and 1,2-
dimethoxyethane (198 mL), and the resulting solution was
washed with heptane (595 mL). The solvent was removed under
reduced pressure to give a product containing 9 as an oil (247 g).
This product was used in the next step without further
purification. For analytical data of 9, a portion of the oil was
purified by column chromatography on silica gel (Purif-Pack, 60
µm, dichloromethane/methanol; methanol: 5% to 15%) to give a
mixture of two epimers. After addition of aqueous acetonitrile,
one of the epimers was obtained as a solid (9a). The mother
liquor was evaporated, and the residue was purified by
preparative HPLC (column: Inertsil ODS-3, 20 mm I.D. 250 mm;
20% acetonitrile in water, 20 mL/min) to give another epimer as
an amorphous solid (9b). 9a: white solid, mp 78 °C (DSC
4.11. Purification of tofogliflozin (1)
4.11.1. Synthesis of 1,1-anhydro-1-C-[5-(4-
ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-
2,3,4,6-tetra-O-methoxycarbonyl-β-D-
glucopyranose (10)
The product 1 (106 g), which was obtained in the previous
step, and N-methylimidazole (318 mL, 3994 mmol) were
dissolved in acetone (400 mL). To the solution was added methyl
chloroformate (182 mL, 2367 mmol) at 15 °C. The mixture was
allowed to warm to 18 °C, and then stirred for 3 h. After addition
of water (800 mL), the mixture was extracted with AcOEt (800
mL). The organic layer was washed with aqueous solution of
10% NaHSO3 and 5% NaCl (800 mL), and then washed with
20% NaCl (800 mL x 2). The solvent was removed under
reduced pressure. After addition of ethanol, t-butyl methyl ether
and 2-propanol, the mixture was heated to 74 °C to dissolve the
residue. The solution was stirred at 55 °C for 1 h. After
precipitation of solid, the mixture was cooled to 25 °C over 1.5 h.
To the resulting mixture was added 2-propanol (270 mL), and
then the mixture was stirred at 25 °C for 1 h. Filtration and