The regioselective bromine-lithium exchange reaction of alkoxymethyldibromobenzene: A new strategy for the synthesis of tofogliflozin as a SGLT2 inhibitor for the treatment of diabetes

Article abstract of DOI:10.1016/j.tet.2016.12.028

The regioselective bromine-lithium exchange reaction of 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (2), which resulted in optimized selectivity of 220:1, is described. Applying this method to the synthesis of tofogliflozin (1) as a SGLT2 inhibi

Full text of DOI:10.1016/j.tet.2016.12.028

Accepted Manuscript
The regioselective bromine-lithium exchange reaction of
alkoxymethyldibromobenzene: A new strategy for the synthesis of tofogliflozin as a
SGLT2 inhibitor for the treatment of diabetes
Masatoshi Murakata, Takuma Ikeda, Nobuaki Kimura, Akira Kawase, Masahiro
Nagase, Masahiro Kimura, Kenji Maeda, Akie Honma, Hitoshi Shimizu
PII:
S0040-4020(16)31306-0
10.1016/j.tet.2016.12.028
TET 28320
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 October 2016
Revised Date: 9 December 2016
Accepted Date: 13 December 2016
Please cite this article as: Murakata M, Ikeda T, Kimura N, Kawase A, Nagase M, Kimura
M, Maeda K, Honma A, Shimizu H, The regioselective bromine-lithium exchange reaction of
alkoxymethyldibromobenzene: A new strategy for the synthesis of tofogliflozin as a SGLT2 inhibitor for
the treatment of diabetes, Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.028.
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alkoxymethyldibromobenzene: a new strategy for the
synthesis of tofogliflozin as a SGLT2 inhibitor for the
treatment of diabetes
Masatoshi Murakata, Takuma Ikeda, Nobuaki Kimura, Akira Kawase, Masahiro Nagase, Masahiro Kimura, Kenji Maeda, Akie Honma,
Hitoshi Shimizu
API Process Development Department, Pharmaceutical Technology Division, Chugai Pharmaceutical Co., LTD. 5-5-1 Ukima, Kita-ku, Tokyo 115-8543,
Japan
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Tetrahedron
journal homepage: www.elsevier.com
The regioselective bromine-lithium exchange reaction of
alkoxymethyldibromobenzene: a new strategy for the synthesis of tofogliflozin as a
SGLT2 inhibitor for the treatment of diabetes
Masatoshi Murakata,* Takuma Ikeda, Nobuaki Kimura, Akira Kawase, Masahiro Nagase, Masahiro
Kimura, Kenji Maeda, Akie Honma, Hitoshi Shimizu
API Process Development Department, Pharmaceutical Technology Division, Chugai Pharmaceutical Co., LTD. 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The regioselective bromine-lithium exchange reaction of 2,4-dibromo-1-(1-methoxy-1-
methylethoxymethyl)benzene (2), which resulted in optimized selectivity of 220:1, is described.
Applying this method to the synthesis of tofogliflozin (1) as a SGLT2 inhibitor is also described.
Selective and sequential metalation-functionalization of 2 led to the synthesis of 1 in 47%
overall yield.
Available online
Keywords:
Bromine-lithium exchange reaction
Regioselective
2009 Elsevier Ltd. All rights reserved
.
Sequential metalation-functionalization
Tofogliflozin
1. Introduction
Metalation of aromatic compounds has become a well-known
and powerful tool in synthetic organic chemistry. In particular,
extensive research on halogen-metal exchange reactions of aryl
halides has been reported.1 We became interested in the halogen-
metal exchange reaction of a dihalobenzene derivative, because
selective and sequential metalation-functionalization would
enable us to form two carbon-carbon bonds regioselectively at
the desired positions. Taking into account substrate availability,
we focused our attention on the reaction of homo-dihalogenated
benzene derivatives (Figure 1). We also envisioned that use of
alkoxymethyl-2,4-dihalobenzene as a substrate would lead to the
efficient synthesis of a carbon backbone of tofogliflozin (1),
which is a sodium glucose cotransporter 2 (SGLT2) inhibitor for
the treatment of diabetes (Figure 2).2,3
Figure 2. Synthesis of tofogliflozin.
To simplify the metalation process, we decided to use BuLi
alone as a reagent for halogen-metal exchange.4 There are several
reports of
selective metalation of homo-dihalobenzene
derivatives with BuLi alone,5 however, little is known about the
sequence of regioselective halogen-metal exchange followed by
anion trap beginning with alkoxymethyl-2,4-dihalobenzene.
Herein, we describe the efficient sequential bromine-lithium
exchange reactions of alkoxymethyl-2,4-dibromobenzene 2 and
Figure 1. C-C bonds formation by selective and sequential
metalation-functionalization.

2
Tetrahedron
application of the reaction to the synthesis of tofogliflozin (1)
To develop a system that would achieve better coordination
ACCEPTED MANUSCRIPT
as three-component coupling process.
control for the ortho-selectivity, next we examined the reaction in
a non-coordinating solvent, in which BuLi would exist in a
highly aggregated state and the reactivity would be reduced,7
while the coordination of the oxygen of 2 would enhance the
reactivity. Thus, toluene was used as a non-coordinating solvent;
however, the reaction mixture became a suspension due to the
insolubility of lithated compounds. After screening several
solvents, it was found that the addition of a small amount of tert-
butyl methyl ether (MTBE) was effective in keeping the mixture
homogeneous. When the reaction was carried out in a mixture of
toluene and MTBE (7.3:0.7) at −80°C, the selectivity was
improved, and the ratio of 3 to 4 was 9:1 (entry 1 in Table 2).
Although the selectivity did not change between −80°C and −30
°C, the reaction at 0 °C afforded the desired product 3 in a ratio
of 16:1 (entry 4 in Table 2). Although the selectivity was
independent of the mixing time at 0 °C, the effects of the length
of time taken to add BuLi were remarkable. When BuLi was
introduced slowly over 30 min at 0 °C, the ratio of 3 to 4 reached
40:1 (entry 6 in Table 2).
2. Results and discussion
2.1. Regioselective protonation via bromine-lithium exchange
As shown in Scheme 1, 2,4-dibromo-1-(1-methoxy-1-
methylethoxymethyl)benzene 2, which was readily prepared
from a commercially available dibromobenzyl alcohol, was
chosen as a substrate for the bromine-lithium exchange reaction.
It was anticipated that the oxygen atoms of the methoxymethoxy
group would coordinate with a lithium atom, and the bromine-
lithium exchange at the ortho-position driven by proximity effect
would be favorable.6
Scheme 1. Regioselective protonation via bromine-lithium
exchange.
To explore the regioselectivity of the bromine-lithium
exchange reaction of 2, the reactions with BuLi were quenched
with aqueous NH4Cl to afford para-bromobenzene 3 and ortho-
bromobenzene 4 (Scheme 1). The results are listed in Tables 1
and 2.
Table 1. Bromine-lithium exchange of 2 in THF.a
Figure 3. Mechanistic rationale for bromine-lithium exchange of 2.
Entry Temp.
Addition of
BuLi (min)
Mixing
(min)
Yield
Selectivity
(3/4)c
(oC)
(%)b
A mechanistic rationale for this interesting phenomenon is
depicted in Figure 3. The slow addition of BuLi would give time
for further bromine-lithium exchange reaction between para-
lithiated product 6 and the remaining starting material 2.8 This
process could allow for the conversion of the undesired para-
lithiated product 6 to the desired ortho-lithiated product 5,
because para-lithiated product 6 would be converted back to 2,
which then could produce ortho-lithiated product 5 as a major
product. Thus, the dibromide is presumably acting as a mediator
to increase the overall regioselectivity.
3
4
1
2
−78
−80
3
2
1
66
65
23
20
3:1
3:1
60
aAll reactions were carried out with 1.48 mmol of 2 and 1.1 equivalent of
BuLi. Volume of THF was 8 v/w. Determined by crude H NMR spectra,
with durene as an internal standard. cDetermined by crude 1H NMR spectra.
b
1
When the reaction was carried out by using a 1.1 equivalent of
BuLi in THF at −78 C, the ratio of 3 to 4 was only 3:1, and the
o
Table 3. Bromine-lithium exchange of 2 in toluene-MTBE, with
additional 0.3 equivalent of 2.a
starting material 2 was not fully consumed (entry 1 in Table 1).
Even with prolonged mixing after adding BuLi, the reaction did
not reach completion (the amount of starting material 2
remaining; with entry 1 was 2% and with entry 2 was 4%) and
the selectivity did not change either (entry 2 in Table 1). This
pattern of selectivity implied that when BuLi coordinated with
THF it could easily react with the para-position without
interacting with the methoxymethoxy group.
Entry
Temp.
Addition of
BuLi (min)
Mixing
(min)
Additional
Selectivity
(oC)
mixing (min)b
(3/4)c
1
2
3
−78
−30
0
3
3
3
30
30
1
30
30
30
8:1
10:1
220:1
Table 2. Bromine-lithium exchange of 2 in toluene-MTBE.a
aAll reactions were carried out with 1.1 equivalent of BuLi for the initial
amount of 2. Total volume of toluene-MTBE was 10.4 v/w (9.5:0.9). bMixing
time after adding 0.3 equivalent of 2 to a reaction mixture of 2 and BuLi.
cDetermined by crude NMR spectra.
Entry
Temp. (oC)
Addition of
BuLi (min)
Mixing
(min)
Selectivity
(3/4)b
1
2
3
4
5
6
−80
−80
−30
0
3
2
30
60
30
1
9:1
To test this working hypothesis, we added an additional 0.3
equivalent of 2 to the reaction mixture that had been treated with
BuLi. Although the selectivity at both −78 °C and −30 °C was
similar to that in previous conditions (entries 1 and 2 in Table 3
vs entries 1 and 3 in Table 2), raising the reaction temperature to
0 °C was found to enhance the ortho-selectivity dramatically.
The product ratio of 3 to 4 from the reaction with an additional
0.3 equivalent of 2 at 0 °C reached 220:1, which shows that use
of an additional amount of 2 resulted in high selectivity (entry 3
in Table 3).
9:1
9:1
3
3
16:1
16:1
40:1
0
3
30
0
0
30
aAll reactions were carried out with 1.48 mmol of 2 and 1.1 equivalent of
b
BuLi. Volume of toluene-MTBE was 8 v/w (7.3:0.7). Determined by crude
NMR spectra.

OH
2.2. Practical double additions via selective bromine-lithium
exchange
ACCEPTED MANUSCRIPT
H2, 5%Pd-C
HCl aq
crude-1
Et
8
Next, we turned our attention to applying this selective
DME-H2O
99% conv.
THF-H2O
O
OH
OH
O
lithiation method to the synthesis of tofogliflozin (1).
Considering a cost-effective synthetic procedure for practical
production, the reaction conditions were modified to incorporate
the split addition of BuLi to avoid excessive use of 2. As shown
in Scheme 2, to create and maintain an environment in which 2
exists during lithium-bromine exchange, 0.8 equivalent of BuLi
was added first. After stirring for 30 min at −10 to 0 °C, another
0.3 equivalent of BuLi was introduced to drive the reaction to
completion. This resulting mixture was added to
trimethylsilylgluconolactone, and then alkoxide generated was
trapped by trimethylsilyl chloride to afford 7 as an epimeric
mixture. The second lithiation using BuLi was followed by the
addition of 4-ethylbenzaldehyde to afford double 1,2-additions
product 8. The sequence of these 1,2-additions were achieved in
a one-pot process.9 The ortho-regioselectivity of the first
lithiation was attained at a ratio of 53:1 (98% conversion). It is of
note that when the addition of BuLi was split, the regioselectivity
of the bromine-lithium exchange was high enough in practical
production to form double carbon-carbon bonds at the desired
positions.
97% conv.
HO
OH
9
1) ClCO2Me
N-methylimidazole
acetone
1) NaOH aq
DME
Et
quant.
O
OCO2Me
OCO2Me
1
O
2) crystallization
EtOH-MTBE-iPrOH
57%
from dibromobenzyl alcohol
(precusor of 2)
2) crystallization
acetone-H2O
82%
MeO2CO
OCO2Me
10
Scheme 3. Synthesis and purification of 1.
Purification was achieved by way of recrystallizing its
carbonate derivative; namely, the crude product 1 was treated
with methyl chloroformate and N-methylimidazole as a base
followed by recrystallization (EtOH-MTBE-iPrOH) to afford
tetracarbonate 10, isolated yield of which reached 57% from the
primus dibromobenzyl alcohol (precursor of 2). Hydrolysis of 10
by aqueous sodium hydroxide followed by crystallization
(acetone-H2O) afforded tofogliflozin (1) in 82% isolated yield.
Thus, a high overall yield of 47% (isolated yield) was achieved.
Br
Br
1) BuLi (0.8 eq) at –10 °C
2) stirring for 0.5 h at –10 °C
3) BuLi (0.3 eq) at –10 °C
4) stirring for 1 h at –10 °C
O
Li
O
Br
3. Conclusion
OMe
OMe
toluene-MTBE
98 % conversion
ortho : para = 53 : 1
2
In summary, bromine-lithium exchange reaction of 2,4-
dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene 2 in a
highly regioselective manner was realized by use of BuLi alone.
Dibromide as a starting material was found to be a mediator that
increased the selectivity of the reaction. Furthermore, the
efficient three-component coupling process was accomplished,
which ultimately led to the synthesis of tofogliflozin (1). The
method of selective lithiation mentioned here should be useful
for the preparation of unsymmetrical trisubstituted benzene
derivatives.
O
OTMS
O
Br
TMSO
OTMS
OTMS
O
TMSO
1)
–70 °C
MeO
OTMS
OTMS
O
2) TMSCl, Et3N
toluene-MTBE
TMSO
OTMS
7
4. Experimental section
OH
4.1. General
O
Et
1) BuLi, –78 °C
2)
TMSO
O
All reactions were carried out under a nitrogen atmosphere
unless otherwise noted. All reagents were purchased from
commercial sources and used without further purification unless
otherwise noted. Melting points were measured on a capillary
melting point apparatus (Büchi) or a differential scanning
calorimetry (DSC) apparatus (Mettler Toledo). FT-IR spectra
were performed with a FT/IR-480 plus (JASCO) spectrometer.
1H NMR (500 MHz) and 13C NMR (125 MHz) were recorded on
MeO
OTMS
OTMS
OHC
Et
TMSO
toluene-MTBE
OTMS
8
Scheme 2. Practical double additions via selective bromine-lithium
exchange.
2.3. Synthesis and purification of tofogliflozin
a
JNM-ECP
500
(JEOL)
spectrophotometer
with
tetramethylsilane or the solvent resonance as an internal standard.
Mass spectra were measured on a LCT Premier XE (Waters)
spectrophotometer. Specific rotation was measured on a P-2200
(JASCO) digital polarimeter. Column chromatography was
performed on silica gel. HPLC analysis was performed on
Agilent 1100 (Agilent). Preparative reversed-phase HPLC was
performed on PLC761 system (GL Science).
After we had established an efficient method of achieving
highly selective and sequentially controlled lithiation-
functionalization, 1,2-additions adduct 8 was converted to
tofogliflozin (1), as shown in Scheme 3. To attain telescoping
process for practical production, the crude 8 was treated with
aqueous hydrochloric acid to construct a spiro-ring and also to
remove both the methoxymethylethyl group and the
trimethylsilyl group to afford benzhydrol 9 (97% conversion).
Hydrogenolysis of 9 using 5% Pd-C afforded tofogliflozin (1) as
a crude product in 99% conversion.
4.2. 2,4-Dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene
(2)
Under
a nitrogen atmosphere, to a solution of 2,4-
dibromobenzyl alcohol (40 g, 0.15 mol) and 2-methoxypropene

4
Tetrahedron
ACCEPTED MANUSCRIPT
(144 mL, 1.5 mol) in THF (300 mL) was added pyridinium p-
was added a solution of n-BuLi in hexane (1.6 M, 1.01 mL, 1.62
toluenesulfonic acid (75 mg, 0.30 mmol) at 0 °C, and the whole
was stirred for 1 h. The reaction mixture was poured into
saturated NaHCO3 at 0 °C. The resulting mixture was extracted
with toluene. The organic layer was washed with saturated NaCl,
and dried over Na2SO4. The solvent was removed under reduced
pressure to give 2 as an oil quantitatively. The product was used
mmol) at 0 °C over 3 min, and then the mixture was stirred for 1
min. To the resulting mixture was added a solution of 2,4-
dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (2) (150
mg, 0.44 mol) in toluene (1.1 mL) and tert-butyl methyl ether
(0.11 mL), and then the whole was stirred at 0 °C for 30 min. The
reaction was quenched with saturated NH4Cl. The resulting
mixture was extracted with AcOEt. The organic layer was
washed with saturated NaCl, and dried over Na2SO4. The solvent
was removed under reduced pressure to give a mixture of 4-
bromo-1-(1-methoxy-1-methylethoxymethyl)benzene (3) and 2-
bromo-1-(1-methoxy-1-methylethoxymethyl)benzene (4). The
ratio of 3 to 4 was estimated to be 220/1 through the integration
of a benzylic proton in 3 [δ 4.43 (2H)] and a benzylic proton in 4
[δ 4.55 (2H)] in 1H NMR.
1
in the next step without further purification. H NMR (CDCl3) δ
1.44 (6H, s), 3.22 (3H, s), 4.48 (2H, s), 7.42 (1H, d, J = 8.0 Hz),
7.44 (1H, dd, J = 1.5, 8.0 Hz), 7.68 (1H, d, J = 1.5 Hz); 13C NMR
(CDCl3) δ 24.82, 49.16, 62.26, 101.01, 121.32, 122.99, 129.94,
130.85, 134.90, 137.98; IR (KBr) 2989, 2941, 1581, 1464, 1375,
1080, 1059, 814 cm−1; HRMS (APPI+) (m/z): Calcd for
C11H14Br2NaO+ [M+Na] + 358.9253, Found 358.9244.
4.3. Synthesis of 4-bromo-1-(1-methoxy-1-methylethoxymethyl)
benzene (3)
4.7. (2,3R,4S,5R)-Tetrakis(trimethylsilyloxy)-6R-
trimethylsilyloxymethyl-2-[5-bromo-2-(1-methoxy-1-
methylethoxymethyl)phenyl]tetrahydropyran (7)
To a solution of 4-bromobenzyl alcohol (7.48 g, 40.0 mmol)
and pyridinium p-toluenesulfonic acid (20.1 mg, 0.08 mmol) in
THF (60 mL) was added 2-methoxypropene (38.3 mL, 400
mmol) at −20 °C, and the whole was stirred at the same
temperature for 15 h. The reaction mixture was poured into
saturated NaHCO3 at 0 °C. The resulting mixture was extracted
with toluene. The organic layer was washed with water, and dried
over Na2SO4. The solvent was removed under reduced pressure
to give 3 as an oil quantitatively. 1H NMR (CDCl3) δ 1.41 (6H, s),
3.24 (3H, s), 4.43 (2H, s), 7.21−7.24 (2H, m), 7.44−7.47 (2H, m).
To
a
solution
of
2,4-dibromo-1-(1-methoxy-1-
methylethoxymethyl)benzene 2 (277 g, 820 mmol) in toluene
(2616 mL) and t-butyl methyl ether (262 mL) was added
dropwise a solution of n-BuLi in hexane (1.54 M, 426 mL, 656
mmol) at −10 °C. The whole was stirred at −10 °C for 0.5 h. To
the resulting mixture was added a solution of n-BuLi in hexane
(1.54 M, 160 mL, 246 mmol) at −10 °C. The whole was stirred
for 1 h at the same temperature. The mixture was cooled to
−48 °C and added dropwise to
tris(trimethylsilyloxy)-6-
a solution of 3,4,5-
4.4. Synthesis of 2-bromo-1-(1-methoxy-1-methylethoxymethyl)
benzene (4)
(trimethylsilyloxymethyl)tetrahydropyran-2-one (402 g, 862 mol)
in THF (2012 mL) at −77 °C. After the reaction mixture was
stirred at −70 °C for 1.5 h, triethylamine (24 mL, 172 mmol) and
trimethylsilyl chloride (98 g, 903 mmol) were added successively,
and the resulting mixture was warmed to 0 °C to give a solution
containing the compound 7. This solution was used in the next
step. To determine the regioselectivity of bromine-lithium
exchange reaction, a small portion of the reaction mixture was
taken before addition of lactone, and quenched with saturated
NH4Cl. The selectivity (3/4 = 53/1) was calculated based on the
area ratio measured by HPLC (column: Ascentis Express C18,
3.0 mm I.D. x 100 mm, 2.7 µm ; 2mM AcONa/H2O with
acetonitrile, gradient operation 30% to 98%; flow rate, 1.0
mL/min). For analytical data of 7, the solvent was removed and
the resulting residue was purified by preparative HPLC (column;
Inertsil ODS-3, 20 mm I.D. x 250 mm; acetonitrile, 30 mL/min)
to give 7 as two isolated epimers (7a and 7b). 7a: colorless oil.
To a solution of 2-bromobenzyl alcohol (1.90 g, 10.2 mmol)
and pyridinium p-toluenesulfonic acid (2.0 mg, 0.008 mmol) in
THF (20 mL) was added 2-methoxypropene (10 mL, 104 mmol)
at 0 °C, and the whole was stirred at the same temperature for 1 h.
The reaction mixture was poured into saturated NaHCO3. The
resulting mixture was extracted with AcOEt. The organic layer
was washed with NaCl, and dried over Na2SO4. The solvent was
removed under reduced pressure to give 4 as an oil quantitatively.
1H NMR (CDCl3) δ 1.46 (6H, s), 3.24 (3H, s), 4.55 (2H, s),
7.10−7.14 (1H, m), 7.29−7.33 (1H, m), 7.51−7.55 (2H, m).
4.5. Typical procedure for bromine-lithium exchange followed
by protonation (Entry 4 in Table 2)
Under a nitrogen atmosphere, to a solution of 2,4-dibromo-1-
(1-methoxy-1-methylethoxymethyl)benzene (2) (500 mg, 1.48
mol) in toluene (3.65 mL) and tert-butyl methyl ether (0.35 mL)
was added a solution of n-BuLi in hexane (1.6 M, 1.01 mL, 1.62
mmol) at 0 °C over 3 min, and then the mixture was stirred for 1
min. The reaction was quenched with saturated NH4Cl. The
resulting mixture was extracted with AcOEt. The organic layer
was washed with saturated NaCl, and dried over Na2SO4. The
solvent was removed under reduced pressure to give a mixture of
4-bromo-1-(1-methoxy-1-methylethoxymethyl)benzene (3) and
2-bromo-1-(1-methoxy-1-methylethoxymethyl)benzene (4). The
ratio of 3 to 4 was estimated to be 16/1 through the integration of
a benzylic proton in 3 [δ 4.43 (2H)] and a benzylic proton in 4 [δ
20
1
[α]D +19.2 (c 1.5, MeCN); H NMR (CDCl3) δ −0.30 (9H, s),
0.10 (9H, s), 0.10 (9H, s), 0.16 (9H, s), 0.17 (9H, s), 1.41 (3H, s),
1.43 (3H, s), 3.20 (3H, s), 3.39 (1H, t, J = 9.0 Hz), 3.43 (1H, d, J
= 9.0 Hz), 3.62 (1H, dd, J = 10.5, 7.5Hz), 3.81−3.89 (3H, m),
4.62 (1H, d, J = 13.2 Hz), 4.81 (1H, d, J = 13.2 Hz), 7.38 (1H, dd,
J = 8.8, 2.5Hz), 7.46 (1H, d, J = 8.8 Hz), 7.70 (1H, d, J = 2.5
Hz); 13C NMR(CDCl3) δ −0.3, 0.4, 1.3, 1.4, 2.1, 25.0, 25.2, 48.9,
61.3, 63.2, 73.0, 74.6, 76.4, 77.3, 100.6, 102.9, 120.1, 130.2,
131.1, 133.8, 136.4, 142.7; IR (KBr) 2956, 1593, 1562, 1377,
1252, 1151, 1082, 841 cm−1; HRMS (ESI+) (m/z): Calcd for
+
1
C32H65BrNaO8Si5 [M+Na]+ 819.2601, Found 819.2595. 7b:
4.55 (2H)] in H NMR. The yield was calculated with durene as
20
1
colorless oil. [α]D +5.6 (c 1.5, MeCN); H NMR (toluene-d8,
80 °C) δ −0.16 (9H, s), 0.18 (9H, s), 0.22 (9H, s), 0.23 (9H, s),
0.29 (9H, s), 1.405(3H, s), 1.412 (3H, s), 3.16 (3H, s), 3.87 (1H,
dd, J = 10.5, 4.3 Hz), 3.98 (1H, dd, J = 4.3, 1.5 Hz), 4.02 (1H, dd,
J = 10.5, 2.5 Hz), 4.14 (1H, brs), 4.26−4.28 (1H, m), 4.39−4.41
(1H, m), 4.90−4.96 (2H, m), 7.34 (1H, dd, J = 8.5, 1.5 Hz), 7.70
(1H, d, J = 8.5 Hz), 7.97 (1H, brs); 13C NMR(toluene-d8, 80 °C) δ
0.7, 1.1, 1.9, 2.3, 3.0, 26.95, 26.04, 49.7, 62.0, 64.0, 65.0, 75.7,
75.9, 83.0, 101.7, 103.6, 121.5, 132.0, 132.1, 133.3, 145.4, due to
an internal standard.
4.6. Typical procedure for bromine-lithium exchange, with
additional 0.3 equivalent of 2, followed by protonation (Entry 3
in Table 3)
Under a nitrogen atmosphere, to a solution of 2,4-dibromo-1-
(1-methoxy-1-methylethoxymethyl)benzene (2) (500 mg, 1.48
mol) in toluene (3.65 mL) and tert-butyl methyl ether (0.35 mL)

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
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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

6
Tetrahedron
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Nutrition & Diabetes 2014, 4, e125; (e) Suzuki, M.; Hiramatsu,
dryness under reduced pressure to give 10 [104 g; total yield
M.; Fukazawa, M.; Matsumoto, M.; Honda, K.; Suzuki, Y.;
Kawabe, Y. Diabetes Obes. Metab. 2014, 16, 622−627; (f)
Yamane, M.; Kawashima, K.; Yamaguchi, K.; Nagao, S.; Sato,
M.; Suzuki, M.; Honda, K.; Hagita, H.; Kuhlmann, O.; Poirier, A.;
Fowler, S.; Funk, C.; Simon, S.; Aso, Y.; Ikeda, S.; Ishigai, M.
Xenobiotica 2015, 45, 230−238.
from 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene
2, 57%] as a white solid; mp 129−130 °C (capillary melting point
apparatus). Spectra data spectra data were identical to those
reported previously.3c
4.11.2. Conversion of 10 to tofogliflozin (1)
3. Synthesis of tofogliflozin: (a) Ohtake, Y.; Sato, T.; Kobayashi, T.;
Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori,
M.; Yamaguchi, M.; Takami, K.; Yeu, S.-Y.; Ahn, K.-H.;
Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.;
Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55,
7828−7840; (b) Murakata, M.; Ikeda, T.; Kawase, A.; Nagase, M.;
Kimura, N.; Takeda, S.; Yamamoto, K.; Takano, K.; Nishimoto,
M.; Ohtake, Y.; Emura, T.; Kito, Y. PCT Int. Appl. WO
2011074675, 2011; Chem. Abstr. 2011, 155, 785683; (c) Ohtake,
Y.; Emura, T.; Nishimoto, M.; Takano, K.; Yamamoto, K.;
Tsuchiya, S.; Yeu, S.-Y.; Kito, Y.; Kimura, N.; Takeda, S.;
Tsukazaki, M.; Murakata, M.; Sato, T. J. Org. Chem. 2016, 81,
2148−2153; (d) a patent regarding the present paper, Murakata,
M.; Ikeda, T.; Kimura, N.; Kawase, A.; Nagase, M.; Yamamoto,
K.; Takata, N.; Yoshizaki, S. PCT Int. Appl. WO2009154276,
2009; Chem. Abstr. 2009, 152, 1598414; (e) Yang, X.-D.; Pan, Z.-
X.; Li, D.-J.; Wang, G.; Liu, M.; Wu, R.-G.; Wu, Y.-H.; Gao, Y.-
C. Org. Process Res. Dev. 2016, 20, 1821−1827.
To a solution of 10 (82 g) in 1,2-dimethoxyethane (328 mL)
was added dropwise aqueous 4N NaOH (265 mL, 1060 mmol) at
40 °C. The mixture was stirred at the same temperature for 4.5 h.
After addition of water (82 mL), the organic layer was washed
with
a
solution
of
18%
NaH2PO4·2H2O
and
12%Na2HPO4·12H2O (410 mL). After addition of AcOEt (410
mL), the organic layer was washed with 25% NaCl. (410 mL x 2).
The solvent was removed under reduced pressure. To the
resulting residue were added acetone and water, and then the
solvent was evaporated under reduced pressure. After
recrystallization from acetone and water, to the resulting crystal
was added water (246 mL), and then the mixture was stirred at
4 °C for 1 h. Filtration and dryness under reduced pressure to
give 1 as monohydrate crystal (44g, water content 4.47%; 82%);
white powder, mp 71−92 °C (capillary melting point apparatus).
Spectra data were identical to those reported previously.3a
4. As for metalation methods other than BuLi alone; see ref 1.
5. For selected examples of the regioselective bromine-lithium
exchange of dibromobenzene derivatives by use of BuLi alone: (a)
Sunthankar, S. V.; Gilman, H. J. Org. Chem. 1951, 16, 8−16; (b)
Barluenga, J.; Montserrat, J. M.; Flórez, J. J. Org. Chem. 1993,
58, 5976−5980; (c) Hardcastle, I. R.; Hunter, R. F.; Quayle, P.
Tetrahedron Lett. 1994, 35, 3805−3808; (d) Stanetty, P.;
Krumpak, B.; Rodler, I. K. J. Chem. Res. (S) 1995, 342−343; (e)
Dąbrowski, M.; Kubicka, J.; Luliński, S.; Serwatowski, J.
Tetrahedron 2005, 61, 6590−6595; (f) Menzel, K.; Dimichele, L.;
Mills, P.; Frantz, D. E.; Nelson, T. D.; Kress, M. H. Synlett 2006,
1948−1952; (g) Kurach, P.; Luliński, S.; Serwatowski, J. Eur. J.
Org. Chem. 2008, 3171−3178.
Acknowledgments
M.M. thanks Dr. Kunio Ogasawara, Professor Emeritus,
Tohoku University, for helpful suggestions for this study. We
thank Mr. Hiroaki Takao for mass spectrometry measurements.
Thanks are also due to Ms. Sally Matsuura and Editing Services
at Chugai Pharmaceutical Co., Ltd. for assistance with English
usage.
6. Cf. an example of coordination of methoxymethoxy group to
lithium atom: Winkle, M. R.; Ronald, R. C. J. Org. chem. 1982,
47, 2101−2108.
Supplementary data
7. Brown, T. L. Acc. Chem. Res. 1968, 1, 23−32.
Supplementary data associated with this article can be found,
in the online version, at
8. Halogen transfer of poly halobenzene initiated by deprotonation
was reported: (a) Bunnett, J. F. Acc. Chem. Res. 1972, 5, 139−147;
(b) Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376−393; (c)
Schnürch, M.; Spina, M.; Khan, A. F.; Mihovilovic, M. D.;
Stanetty, P. Chem. Soc. Rev. 2007, 36, 1046−1057; (d) Miller, R.
E.; Rantanen, T.; Ogilvie, K. A.; Groth, U.; Snieckus, V. Org. Lett.
2010, 12, 2198−2201 and references cited therein. A recent
example of thermodynamically controlled arylbromide-aryllithium
exchange reaction: (e) Kojima, T.; Hiraoka, S. Org. Lett. 2014, 16,
1024−1027 and references cited herein.
References and notes
1. (a) Nájera, C.; Sansano, J. M.; Yus, M. Tetrahedron 2003, 59,
9255−9303; (b) Tilly, D.; Chevallier, F.; Mongin, F.; Gros, P. C.
Chem. Rev. 2014, 114, 1207−1257 and references cited therein.
2. Pharmacology: (a) Suzuki, M.; Honda, K.; Fukazawa, M.; Ozawa,
K.; Hagita, H.; Kawai, T.; Takeda, M.; Yata, T.; Kawai, M.;
Fukuzawa, T.; Kobayashi, T.; Sato, T.; Kawabe, Y.; Ikeda, S. J.
Pharmacol. Exp. Ther. 2012, 341, 692−701; (b) Nagata, T.;
Fukuzawa, T.; Takeda, M.; Fukazawa, M.; Mori, T.; Nihei, T.;
Honda, K.; Suzuki, Y.; Kawabe, Y. Br. J. Pharmacol. 2013, 170,
519−531; (c) Yamaguchi, K.; Kato, M.; Suzuki, M.; Hagita, H.;
Takada, M.; Ayabe, M.; Aso, Y.; Ishigai, M.; Ikeda, S. J.
Pharmacol. Exp. Ther. 2013, 345, 52−61; (d) Suzuki, M.; Takeda,
M.; Kito, A.; Fukazawa, M.; Yata, T.; Yamamoto, M.; Nagata, T.;
Fukuzawa, T.; Yamane, M.; Honda, K.; Suzuki, Y.; Kawabe, Y.
9. For one-pot synthesis: (a) Anderson, N. G. Practical Process
Research & Development-A Guide For Organic Chemists, 2nd ed.,
Academic Press: New York 2012; (b) Hayashi, Y. Chem. Sci.
2016, 7, 866−880 and references cited therein.
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Highlights
●
●
●
Highly regioselective bromine-lithium exchange reaction of dibromobenzene
derivative was realized.
Dibromide as a starting material was found to be a mediator that increased the
selectivity.
Tofogliflozin was synthesized via three-component coupling.