DESCRIPTION
METHOD FOR PRODUCING C-GLYCOSIDE DERIVATIVE AND INTERMEDIATE
FOR SYNTHESIS THEREOF
TECHNICAL FIELD
[0001]
The present invention relates to a method for producing
a C-glycoside derivative which is useful as a Na+-glucose
cotransporter inhibitor for treating and preventing, in
particular, diabetes such as insulin-dependent diabetes (type
1 diabetes), non-insulin-dependent diabetes (type 2 diabetes)
and the like and various diabetes-related diseases including
insulin-resistant diseases and obesity; as well as to an
intermediate used for synthesis of the C-glycoside derivative.
BACKGROUND ART
[0002]
The C-glycoside derivative represented by the formula
(1) and its salt [hereinafter, they are referred to as
"compound (1)" or "compound of formula (1)" in some cases] is
known to be useful for treatment and prevention of diabetes
such as insulin-dependent diabetes (type 1 diabetes), non-
insulin-dependent diabetes (type 2 diabetes) and the like and
various diabetes-related diseases including insulin-resistant
diseases and obesity (Patent Literature 1).
[0003]
[Formula 1]


[0004]
The method for producing the C-glycoside derivative
represented by the formula (1), described in the Patent
Literature 1 is understood to be represented by the below-
shown reaction formula (I), by referring to the Examples and
Reference Examples, described in the Patent Literature 1.
Roughly explaining, it is a method which comprises reacting
[l-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy]tert-
butyl)dimethylsilane (synthesized in accordance with
Reference Example 37 of the Literature) in a manner shown in
Example 65 of the Literature, to obtain (IS)-1,5-anhydro-l-
[3-(l-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-0-
benzyl-D-glucitol and then reacting the obtained compound in
accordance with Example 100 of the Literature to synthesize
intended (IS)-1,5-anhydro-l-C-[3-(l-benzothiophene-2-
ylmethyl)-4-fluorophenyl]-D-glucitol.
[0005]
[Formula 2]
Reaction formula (I)


[0006]
However, the method for producing the C-glycoside
derivative of the formula (1), disclosed in the Patent
Literature 1 is not industrially satisfactory in yield and
cost, as is seen in later-shown Reference Example 1 of the
present Description.
[0007]
For example, as described later, the method includes a
step of low product yield (for example, a step of about 50%
or lower yield) and the overall yield of the C-glycoside
derivative (final product) represented by the formula (1)
from the compound (8) (starting raw material) is below 7%;
therefore, the method has problems in yield and cost from the
standpoint of medicine production and has not been
satisfactory industrially. In addition, the method includes
an operation of purification by column chromatography which
uses chloroform as part of purification solvents; use of such

a solvent poses a problem in environmental protection and
there are various restrictions in industrial application of
such an operation; thus, the method has problems in providing
an effective medicine.
[0008]
Also, an improved method of conducting an addition
reaction with trimethylsilyl carbohydrate instead of benzyl
carbohydrate and then conducting deprotection for acetylation,
is known for a compound which has a structure different from
that of the compound of the formula (1) but has a structure
common to that of the compound of the formula (1) (Patent
Literature 2). It is described in the Patent Literature 2
that the improved method enhances the overall yield to 6.2%
from 1.4%. Even in the improved method, however, the yield
is low at 6.2% which is far from satisfaction in industrial
production.
Patent Literature 1: WO 2004/080990 Pamphlet
Patent Literature 2: WO 2006/006496 Pamphlet
DISCLOSURE OF THE INVENTION
[0009]
The present invention aims at providing a method for
producing a C-glycoside derivative represented by the formula
(1), which enables production of the C-glycoside derivative
at a high yield and at a low cost, which conforms to
environmental protection, and which is advantageous
industrially; and an intermediate useful for production of
the C-glycoside derivative.
[0010]
In order to achieve the above aim, the present

inventors made a study on the method for industrial
production of the compound (1). As a result, the present
inventors found, by using a particular intermediate for
synthesis, a method for producing a C-glycoside derivative,
which requires no purification by column chromatography,
which can avoid the use of chlorine-based solvent, which
enables production of the C-glycoside derivative at a high
yield (an improved overall yield) and at a low cost, which
conforms to environmental protection, and which is
advantageous industrially. The finding has led to the
completion of the present invention. Thus, the present
invention provides a method for producing a C-glycoside
derivative and an intermediate for synthesis of the
C-glycoside derivative, both shown below.
[0011]
[1] A compound represented by the following formula (2d)
[formula 3]

[in the formula, B1s may be the same or different from each
other and are each H or C(=0)R1 (R1s may be the same or
different from each other and are each lower alkyl), with a
proviso that at least one of B1s is C(=0)R1].
[0012]
[2] A compound according to [1], wherein each R1 is methyl.
[0013]
[3] A compound represented by the following formula (Ia)


(in the formula, R2 is H or halogen and Y is Br or I).
[0014]
[4] A method for producing a compound represented by the
following formula (1),
[formula 5]

characterized by subjecting the compound set forth in [1] to
a reaction for elimination of acyl group.
[0015]
[5] A method for producing a compound set forth in [1],
characterized by allowing a compound selected from the group
consisting of triethylsilane, triisopropylsilane, tert-
butyldimethylsilane, sodium borohydride and sodium
tri(acetoxy)borohydride to act on a compound represented by
the following formula (2c)
[formula 6]


[in the formula, B1s may be the same or different from each
other and are each H or C(=0)R1 (R1s may be the same or
different from each other and are each lower alkyl) and Me is
methyl, with a proviso that at least one of B1s is C(=O)R1],
to reduce the compound of the formula (2c).
[0016]
[6] A method according to [4], wherein the compound set
forth in [1] is a compound produced by the method set forth
in [5].
[0017]
[7] A method for producing a compound represented by the
following formula (1),
[formula 7]

characterized by subjecting the compound set forth in [2] to
a reaction for elimination of acetyl group.
[0018]
[8] A method for producing a compound set forth in [2],
characterized by allowing a compound selected from the group
consisting of triethylsilane, triisopropylsilane, tert-
butyldimethylsilane, sodium borohydride and sodium
tri(acetoxy)borohydride to act on a compound represented by
the following formula (2b)
[formula 8]


[in the formula, B2s may be the same or different from each
other and are each H or C(=0)Me and Me is methyl, with a
proviso that at least one of B2s is C(=0)Me], to reduce the
compound of the formula (2b).
[0019]
[9] A method according to [7], wherein the compound set
forth in [2] is a compound produced by the method set forth
in [ 8] .
[0020]
[10] A method for producing a compound represented by the
following formula (1),
[formula 12]

characterized by subjecting a compound represented by the
following formula (4)
[formula 9]


(in the formula, Y is Br or I) and a compound represented by
the following formula (3)
[formula 10]

(in the formula, As may be the same or different from each
other and are each lower alkyl), to an addition reaction,
eliminating tri-lower alkyl silyl, and being acylated, then
conducting reduction to obtain a compound represented by the
following formula (2d)
[formula 11]

[in the formula, B1s may be the same or different from each
other and are each H or C(=O)R1 (R1s may be the same or
different from each other and are each lower alkyl), with a
proviso that at least one of B1s is C(=0)R1], and subjecting
the compound to a reaction for elimination of acyl group.
[0021]
[11] A method according to [10], wherein the compound
represented by the formula (4) is a compound of the formula
(4) obtained by subjecting a compound represented by the
following formula (5)


(in the formula, X is halogen and Y is Br or I) to a
reduction reaction.
[0022]
[12] A method for producing a compound represented by the
following formula (1),
[formula 17]

characterized by subjecting a compound represented by the
following formula (4)
[formula 14]

(in the formula, Y is Br or I) and a compound represented by
the following formula (3a)
[formula 15]


(in the formula, TMS is trimethylsilyl) to an addition
reaction, eliminating trimethylsilyl in methanol, and being
acetylated, then conducting reduction to obtain a compound
represented by the following formula (2a)
[formula 16]

[in the formula, B2s may be the same or different from each
other and are each H or C(=0)Me (Me is methyl), with a
proviso that at least one of B2s is C(=0)Me], and subjecting
the compound to a reaction for elimination of acetyl group.
[0023]
[13] A method according to [12], wherein the compound
represented by the formula (4) is a compound of the formula
(4) obtained by subjecting a compound represented by the
following formula (5)
[formula 18]

(in the formula, X is halogen and Y is Br or I) to a
reduction reaction.
[0024]
According to the present invention, there are provided
a method for producing a C-glycoside derivative, which

enables production of the C-glycoside derivative at a high
yield and at a low cost, which conforms to environmental
protection, and which is advantageous industrially; and an
intermediate for synthesis, which is useful for production of
the C-glycoside derivative.
BEST MODE FOR CARRYING OUT THE INVENTION
[0025]
An embodiment (the first step to the fifth step) of the
method for producing a C-glycoside derivative, of the present
invention is shown in the following reaction formula (II).
Then, each step is described specifically in the order of the
first step to the fifth step.
[0026]
[Formula 19]
Reaction formula (II)

[0027]
First step
The first step shown in the reaction formula (II) is a

step of conducting an addition reaction with a compound of
formula (7) [hereinafter, this compound may be referred to as
"compound (7)"] and a compound of formula (8) [hereinafter,
this compound may be referred to as "compound (8)". In the
reaction formula (II), Y is Br or I and, in an embodiment, is
Br. The same applies to hereinafter.] in the presence of an
alkyl lithium reagent in an appropriate solvent to obtain a
compound of formula (6) [hereinafter, this compound may be
referred to as "compound (6)"]-
[0028]
In the addition reaction, as the alkyl lithium reagent,
there can be mentioned n-butyl lithium, sec-butyl lithium,
tert-butyl lithium, etc.; and, in an embodiment, n-butyl
lithium is used. As the solvent, there can be mentioned
ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, 1,4-dioxane, diglyme and the like, and
aromatic hydrocarbons such as benzene, toluene, xylene and
the like; and, in an embodiment, tetrahydrofuran is used.
The reaction can be conducted by adding, to a tetrahydrofuran
solution of a compound (7), about 1 equivalent, for example,
0.95 to 1.20 equivalents of n-butyl lithium and conducting a
reaction at -80 to -10°C (-35 to -10°C in an embodiment)
ordinarily for 30 minutes, and adding, to the reaction
mixture, about 1 equivalent, for example, 0.95 to 1.20
equivalents of a compound (8) at -80 to -10°C (-35 to -10°C
in an embodiment). The reaction is complete at -20°C
ordinarily in 1 to 3 hours. To the reaction mixture are
added water and hydrochloric acid, followed by extraction;
the organic layer is washed with water and subjected to
distillation under reduced pressure; to the residue are added

toluene and n-heptane; the separated-out crystals are
collected by filtration and dried; thereby, a compound (6)
can be obtained.
[0029]
Second step
The second step shown in the reaction formula (II) is a
step of producing a compound of formula (5) [hereinafter,
this compound may be referred to as "compound (5)"] from the
compound (6) which is a raw material. More particularly, the
second step is a step of halogenating the compound (6) (the
halogen used in the halogenation is F, C1, Br or I and, in an
embodiment, is C1) to produce a compound (5). The
halogenation is conducted using an appropriate halogenating
agent, in an appropriate solvent. As the halogenating agent,
there can be mentioned thionyl chloride, thionyl bromide,
methanesulfonyl chloride, methanesulfonyl bromide, bromine,
iodine, etc., and, in an embodiment, thionyl chloride is used.
As the solvent, there can be mentioned aromatic hydrocarbons,
ethers, acetonitrile, etc. and, in an embodiment,
acetonitrile is used. A pyridine derivative such as pyridine,
lutidine or the like, or a tertiary amine such as
triethylamine, diisopropylamine or the like may be added.
Specifically, the second step can be conducted by dropping,
into an acetonitrile solution of the compound (6), an
equivalent to excess equivalents, for example, 1 to 1.5
equivalents of thionyl chloride at room temperature to a
reflux temperature, at room temperature in an embodiment,
followed by stirring ordinarily for 1 to 2 hours.
[0030]
Third step

The third step shown in the reaction formula (II) is
step of producing a compound of formula (4) [hereinafter,
this compound may be referred to as "compound (4)"] from the
compound (5) which is a starting material. More particularly,
the third step is a step of reducing the compound (5) to
produce a compound (4). The reduction is conducted using an
appropriate reducing agent, in the presence of a base in an
appropriate solvent. As the reducing agent, there can be
mentioned sodium borohydride, sodium tri(acetoxy)borohydride
etc. and, in an embodiment, sodium borohydride is used. As
the base, there can be mentioned metal hydroxides such as
sodium hydroxide, potassium hydroxide and the like and, in an
embodiment, sodium hydroxide is used. As the solvent, there
can be mentioned aromatic hydrocarbons, ethers, acetonitrile,
water and mixtures thereof and, in an embodiment, a mixed
solvent of acetonitrile and water is used. Specifically, the
reaction is conducted by dropping a solution of the compound
(5) into an aqueous solution of 0.1 to 2.5 equivalents of
sodium hydroxide and an excess amount, for example, 2 to 4
equivalents of sodium borohydride at room temperature to
reflux temperature (in an embodiment, at 50 to 70°C) ,
followed by stirring ordinarily for 1 to 5 hours.
[0031]
Fourth step
The fourth step shown in the reaction formula (II) is a
step of conducting an addition reaction with the compound (4)
and a compound of formula (3) [hereinafter, this compound may
be referred to as "compound (3)". In the formula (3), As may
be the same or different from each other and are each a
linear or branched lower alkyl group of 1 to 6 carbon atoms

and, in an embodiment, are each methyl] in the presence of an
alkyl lithium reagent in an appropriate solvent, then
treating the addition product with an acid in the presence of
methanol to remove tri-lower alkylsilyl, then treating the
resulting compound with an acylating agent capable of
introducing a group represented by formula R1C(=0) (in the
formula, R1 is a linear or branched lower alkyl of 1 to 6
carbon atoms and, in an embodiment, is methyl), to give rise
to acylation, then conducting reduction to obtain a compound
of formula (2) [hereinafter, this compound may be referred to
as "compound (2)"]. Here, the linear or branched lower alkyl
of 1 to 6 carbon atoms refers to methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,
n-hexyl, isohexyl, or the like. In this step, there may be
formed, besides the compound (2), such compounds as, in the
compound (2), at least one 0C(=0)R1 group of the four
0C(=0)R1 groups is OH group, and a compound (1) can be
obtained also from such compounds by conducting the treatment
of fifth step.
[0032]
In the addition reaction, as the alkyl lithium reagent,
there can be mentioned n-butyl lithium, sec-butyl lithium,
tert-butyl lithium, etc. and, in an embodiment, n-butyl
lithium is used. As the solvent, there can be mentioned
ethers and aromatic hydrocarbons and, in an embodiment, a
mixed solvent of diisopropyl ether and toluene is used. The
reaction can be conducted by adding, to a toluene-diisopropyl
ether (1.3:1) solution of the compound (4), about 1
equivalent, for example, 0.95 to 1.20 equivalents of an alkyl
lithium reagent, reacting them at -80 to -10°C (-35 to -20°C

in an embodiment) ordinarily for 0.1 to 5 hours, and adding
the reaction mixture to a toluene.solution of about 1
equivalent, for example, 0.95 to 1.20 equivalents of a
compound (3), in an embodiment, at -80 to -50°C. The
reaction is complete at -80 to -50°C ordinarily in 2 to 24
hours.
[0033]
In the subsequent step of acid treatment in the
presence of methanol, as the acid, there can be mentioned
hydrogen chloride, sulfuric acid, acetic acid,
trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic
acid, etc. and, in an embodiment, hydrogen chloride is used.
The acid treatment by the above acid can be conducted at
-5 to 5°C ordinarily for 1 to 48 hours.
[0034]
The subsequent acylation step including an acetylation
step using an acetylating agent is conducted by conducting a
reaction in an appropriate solvent in the presence of an
appropriate base, using an acylating agent capable of
introducing a group represented by formula R1C(=O) (in the
formula, R1 has the same definition as given above) . As the
solvent, there can be mentioned ketones such as acetone,
2-butanone and the like; aromatic hydrocarbons; acetic acid
esters such as ethyl acetate, isopropyl acetate and the like;
aprotic polar solvents such as dimethylformamide,
dimethylacetamide and the like; halogenated hydrocarbons such
as methylene chloride, chloroform, 1,2-dichloroethane and the
like; pyridine; water; and so forth. In an embodiment,
toluene is used. As the base, there can be mentioned metal
hydroxides such as sodium hydroxide, potassium hydroxide and

the like; metal carbonates such as sodium carbonate,
potassium carbonate and the like; metal alkoxides such as
sodium methoxide, sodium ethoxide, tert-butoxy potassium and
the like; metal hydrides such as sodium hydride and the like;
tertiary amines such as triethylamine, diisopropylethylamine
and the like; pyridine derivatives such as pyridine, lutidine
and the like; and so forth. In an embodiment, pyridine is
used. As the acylating agent capable of introducing a group
represented by formula R1C(=O) (in the formula, R1 has the
same definition as given above), there can be mentioned
alkanoic acid anhydrides such as propionic anhydride,
propionyl chloride, butyric anhydride and the like; and alkyl
halides such as acetyl chloride, acetyl bromide and the like.
Of them, preferably used is an acylating agent wherein R1 is
methyl of 1 carbon atom, that is, an acetylating agent. As
the acetylating agent, there can be mentioned acetyl chloride,
acetyl bromide, acetic anhydride, etc. and, in an embodiment,
acetic anhydride is used.
[0035]
The reaction is conducted by adding toluene to the
above-mentioned concentration residue and then reacting with
an excess amount, for example, 5 equivalents of acetic
anhydride in the presence of an excess amount, for example, 6
equivalents of pyridine with cooling or at room temperature.
The reaction is complete ordinarily in 1 to 24 hours. A
catalytic amount of 4-dimethylaminopyridine may be added for
promotion of the reaction.
[0036]
The subsequent reduction reaction is conducted with an
appropriate reducing agent in the presence of an acid

catalyst in an appropriate solvent. As the reducing agent,
there can be mentioned triethylsilane, triisopropylsilane,
tert-butyldimethylsilane, sodium borohydride, sodium
tri(acetoxy)borohydride etc. and, in an embodiment, tert-
butyldimethylsilane is used. As the acid, there can be
mentioned Lewis acids such as boron trifluoride-diethyl ether
complex, trimethylsilyl trifluoromethanesulfonate and the
like; and Br$nsted acids such as acetic acid,
trifluoroacetic acid, trifluoromethanesulfonic acid and the
like. In an embodiment, trifluoromethanesulfonic acid is
used. As the solvent, there can be mentioned halogenated
hydrocarbons, ethers, acetonitrile, etc. and, in an
embodiment, acetonitrile is used.
[0037]
Specifically, the reaction is conducted in the presence
of an equivalent amount to an excess amount, for example,
1 to 2 equivalents of tert-butyldimethylsilane and an excess
amount, for example, 2 equivalents of
trifluoromethanesulfonic acid, in an appropriate solvent
under cooling or at room temperature, for example, at -5 to
5°C. The reaction is complete ordinarily in 1 to 5 hours.
[0038]
Fifth step
The fifth step shown in the reaction formula (II) is a
step of obtaining an intended compound of formula (1) from
the compound (2) which is a starting material. More
particularly, the fifth step is a step of removing acyl group
from the compound (2) to produce a compound (1). This
reaction is conducted in the presence of an appropriate base
in an appropriate solvent. As the base, there can be

mentioned metal hydroxides such as sodium hydroxide,
potassium hydroxide and the like; metal alkoxides such as
sodium methoxide, sodium ethoxide and the like; and so forth.
In an embodiment, sodium hydroxide is used. As the solvent,
there can be mentioned alcohols such as methanol, ethanol,
isopropanol and the like; aromatic hydrocarbons; ethers;
water; and mixed solvents thereof. In an embodiment, a
methanol—water mixed solvent is used. Specifically, this
deprotection reaction is conducted by reacting the compound
(2) with, for example, 5 equivalents of sodium hydroxide in
an appropriate solvent, for example, a methanol-water mixed
solvent at room temperature to a reflux temperature, for
example, at 40 to 50°C. The reaction is complete ordinarily
in 1 to 5 hours.
[0039]
Incidentally, the compound (5) and the compound (4)
obtained in the second step and the third step, respectively,
are both shown by the following formula (la).
[0040]
[Formula 20]

(In the formula, R2 is H or halogen.)
[0041]
Next, the known method for producing the C-glycoside
derivative represented by the formula (1), shown in the
reaction formula (I) is explained specifically in the
following Reference Example 1.

[0042]
(Reference Example 1)
First step: synthesis of l-benzothien-2-yl(5-bromo-2-
fluorophenyl)methanol
Into a tetrahydrofuran (20 ml) solution of
benzo[b]thiophene (5.0 g) was dropwise added a n-hexane
solution (25 ml) of n-butyl lithium (1.58 M) at -78°C in an
argon atmosphere, followed by stirring at -78°C for 10
minutes. Into this solution was dropwise added a
tetrahydrofuran (80 ml) solution of 5-bromo-2-
fluorobenzaldehyde (8.0 g), followed by stirring at -78°C for
2.5 hours. The temperature of the reaction mixture was
elevated to room temperature. Water was added thereto,
followed by extraction with ethyl acetate. The organic layer
was washed with a saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate) to obtain
l-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (10.5 g,
yield: 83.6%).
XH-NMR (CDC13) : 8
2.74 (1H, d), 6.35 (1H, d), 6.93 (1H, dd), 7.14 (1H, s),
7.27-7.38 (2H, m), 7.39 (1H, m), 7.68 (1H, dd),
7.74 (2H, m)
[0043]
Second step: synthesis of [l-benzothien-2-yl(5-bromo-2-
fluorophenyl)methoxy](tert-butyl)dimethylsilane
To a dimethylformamide (20 ml) solution of
l-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (5.0 g)
were added imidazole (1.3 g), a catalytic amount of

4-(dimethylamino)pyridine and tert-butyldimethylchlorosilane
(2.7 g), followed by stirring at room temperature for 7 hours.
To the reaction mixture was added a saturated aqueous
ammonium chloride solution, followed by extraction with ethyl
acetate. The organic layer was washed with a saturated
aqueous ammonium chloride solution and a saturated aqueous
sodium chloride solution, dried over anhydrous magnesium
sulfate, filtered and concentrated. The residue was purified
by silica gel column chromatography (n-hexane/ethyl acetate)
to obtain [l-benzothien-2-yl(5-bromo-2-
fluorophenyl)methoxy](tert-butyl)dimethylsilane (5.22 g,
yield: 78.0%).
MS: 451 (M+)
1H-NMR (CDC13) : 8
0.05 (3H, s), 0.11 (3H, s), 0.95 (9H, s), 6.34 (1H, s),
6.91 (1H, t), 7.08 (1H, d), 7.23-7.38 (2H, m) ,
7.64-7.68 (1H, m), 7.75-7.28 (2H, m)
[0044]
Third step: Synthesis of 1-C-[3-(l-benzothien-2-yl{[tert-
butyl- (dimethyl)silyloxyjmethyl)4-fluorophenyl]-2,3,4,6-
tetra-O-benzyl-D-glucopyranose
Into a tetrahydrofuran (15 ml) solution of
[l-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy] (tert-
butyl) dimethylsilane (1.5 g) was dropwise added a n-hexane
solution (2.2 ml) of n-butyl lithium (1.58 M) in an argon
atmosphere at -78°C, followed by stirring at -78°C for 30
minutes. Into the solution was dropwise added a
tetrahydrofuran (20 ml) solution of 2,3,4,6-tetra-O-benzyl-D-
glucono-1,5-lactone (1.9 g), followed by stirring at -78°C
for 15 minutes and then at 0°C for 1.5 hours. To the

reaction mixture was added a saturated aqueous ammonium
chloride solution, followed by extraction with ethyl acetate.
The organic layer was washed with a saturated aqueous
ammonium chloride solution and a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium sulfate,
filtered and concentrated. The residue was purified by
silica gel column chromatography
(n-hexane/chloroform/acetone) to obtain 1-C-[3-(1-benzothien-
2-yl{[tert-butyl-(dimethyl)silyloxy}methyl)-4-fluorophenyl]-
2,3,4,6-tetra-O-benzyl-D-glucopyranose (1.52 g, yield: 50.2%).
MS: 933 (M+Na)
[0045]
Fourth step: Synthesis of 1-C-{3-[l-benzothien-2-
yl(hydroxy)methyl]-4-fluorophenyl}-2,3,4,6-tetra-O-benzyl-D-
glucopyranose
To a tetrahydrofuran (15 ml) solution of l-C-[3-(l-
benzothien-2-yl{[tert-butyl-(dimethyl)silyloxy}methyl)-4-
fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose (1.52 g)
was added a tetrahydrofuran solution (2.0 ml) of
tetrabutylammonium fluoride (1.0 M), followed by stirring at
room temperature for 1 hour. The reaction mixture was
concentrated per se. The residue was purified by silica gel
column chromatography (n-hexane/ethyl acetate) to obtain
1-C-{3-[l-benzothien-2-yl(hydroxy)methyl]-4-fluorophenyl}-
2,3,4,6-tetra-O-benzyl-D-glucopyranose (0.99 g, yield: 74.7%).
MS: 819 (M+Na), 779 (M+H-H20)
[0046]
Fifth step: Synthesis of (IS)-1,5-anhydro-l-[3-(1-benzothien-
2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol
To an acetonitrile (5.0 ml) solution of l-C-{3-[l-

benzothien-2-yl(hydroxy)methyl]-4-fluorophenyl}-2,3,4,6-
tetra-Obenzyl-D-glucopyranose (500 mg) were added
triethylsilane (175 mg) and boron trifluoride-diethyl ether
complex (196 mg) in an argon atmosphere at -20°C, followed by
stirring at -20°C for 5 hours. To the reaction mixture was
added a saturated aqueous sodium bicarbonate solution,
followed by extraction with chloroform. The organic layer
was washed with a saturated aqueous sodium bicarbonate
solution and a saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, filtered and
concentrated. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate) to obtain (IS)-1,5-
anhydro-1-[3-(l-benzothien-2-ylmethyl)-4-fluorophenyl]-
2,3,4,6-tetra-O-benzyl-D-glucitol (150 mg, yield: 30.2%)
MS: 787 (M+Na)
^-NMR (CDC13) : S
3.42-3.48 (1H, m), 3.55-3.58 (1H, m) , 3.72-3.78 (4H, m),
3.83 (1H, d), 4.14-4.30 (3H, m), 4.39 (1H, d),
4.51-4.67 (4H, m), 4.83-4.94 (2H, m) , 6.86-6.90 (1H, m) ,
6.98 (1H, brs), 7.06-7.37 (24H, m), 7.57-7.60 (1H, m),
7.66-7.69 (1H, m)
[0047]
Sixth step: Synthesis of (IS)-1,5-anhydro-l-C-[3- (1-
benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol
To a dichloromethane (10 ml) solution of (IS)-1,5-
anhydro-1-[3-(l-benzothien-2-ylmethyl)-4-fluorophenyl]-
2,3,4,6-tetra-O-benzyl-D-glucitol (137 mg) were added
pentamethylbenzene (382 mg) and a n-heptane solution (0.75
ml) of boron trichloride (1.0 M) in an argon atmosphere at
-78°C, followed by stirring at -78°C for 3 hours. Methanol

was added to the reaction mixture, the temperature of the
resulting mixture was elevated to room temperature, and the
mixture was concentrated per se. The residue was purified by-
silica gel column chromatography (chloroform/methanol) to
obtain (IS)-1,5-anhydro-l-C-[3-(l-benzothiophene-2-ylmethyl)-
4-fluorohenyl]-D-glucitol (63 mg, yield: 87.8%).
1H-NMR (CD3OD) : 8
3.29-3.48 (4H, m), 3.68 (1H, dd), 3.87 (1H, dd),
4.11 (1H, d), 4.20-4.29 (2H, m), 7.03 (1H, s),
7.08 (1H, dd), 7.19-7.29 (2H, m), 7.35 (1H, m),
7.42 (1H, dd), 7.64 (1H, d), 7.72 (1H, d)
[0048]
(Reference Example 2)
Synthesis of 2-(5-bromo-2-fluorobenzyl)-1-benzothiophene
[synthesis of compound (4)]
In the third step of the production method of the
present invention, when a compound (4) is separated out as
crystals, a seed crystal of 2-(5-bromo-2-fluorobenzyl)-1-
benzothiophene may be added. The seed crystal added in this
case can be produced as follows.
[0049]
A dioxane (1.1 liters) solution of 2-[(5-bromo-2-
fluorophenyl)(chloro)methyl]-1-benzothiophene (551 g) was
added to a dioxane (3.3 liters)-water (1.6 liters) solution
of sodium borohydride (410 g) and sodium hydroxide (31 g) at
60 to 66°C, followed by stirring at 52 to 60°C for 39 hours.
To the reaction mixture was added toluene (5.5 liter), water
(3.8 liters) and 36% hydrochloric acid (620 ml) to conduct
extraction. The organic layer was subjected to distillation
under reduced pressure to distil off the solvent. The

residue was dried under reduced pressure. The obtained
crystals were dissolved in 2-propanol (1 liter) and methanol
(1 liter) with heating, followed by stirring at 0°C for 20.5
hours. The separated-out crystals were collected by
filtration, washed with methanol (500 ml), and dried under
reduced pressure to obtain 2-(5-bromo-2-fluorobenzyl)-1-
benzothiophene [373 g, yield: 75.0%, purity: 99% (HPLC)] as
white crystals. Incidentally, the 2-[(5-bromo-2-
fluorophenyl)(chloro)methyl]-1-benzothiophene is the same as
the compound (5) obtained in the second step of the
production method of the present invention.
[0050]
Next, the present invention method for producing a
C-glycoside derivative represented by the formula (1), shown
in the reaction formula (II) is described by way of Example.
However, the present invention is not restricted to the
Example; it can be easily modified or changed by those
skilled in the art, as long as there is no deviation from the
gist of the present invention; and, needless to say, modified
or changed ones are included in the scope of the present
invention.
EXAMPLE
[0051]
(Example)
First step: Synthesis of l-benzothien-2-yl(5-bromo-2-
fluorophenyl)methanol
Into a tetrahydrofuran (100 liters) solution of
benzo[b]thiophene (17.4 kg ) was dropwise added a n-hexane
solution (56.2 kg) of n-butyl lithium (15.08%) in an argon

atmosphere at -24.2 to -13.5°C, followed by stirring at -22.1
to -13.5°C for 40 minutes. Into this solution was dropwise
added a tetrahydrofuran (18 liters) solution of 5-bromo-2-
fluorobenzaldehyde (25.5 kg) at -22.1 to -11.8°C, followed by
stirring at -23.5 to -16.1°C for 2 hours. To the reaction
mixture were added water (100 liters), toluene (130 liters)
and 38% hydrochloric acid (12.3 kg), and extraction was
conducted. The organic layer was washed with water (130
liters) and then subjected to distillation at normal
pressure to distill off the solvent until the residue became
100 liters. Toluene (130 liters) was added to the residue
and the mixture was subjected to distillation at normal
pressure to distil off the solvent until the residue became
100 liters. The operation of adding toluene to the residue
and subjecting the mixture to distillation under reduced
pressure to distill off the solvent, was repeated twice:
Then, n-heptane (310 liters) was added to the residue,
followed by heating to dissolve the residue. To the solution
was added, as a seed crystal, about 26 g of the 1-benzothien-
2-yl(5-bromo-2-fluorophenyl)methanol produced in the same
manner as that shown in the first step of Reference Example 1,
followed by stirring at 1.2 to 5.0°C for 13 hours. The
separated-out crystals were collected by filtration, washed
twice with a toluene-n-heptane (1:6) mixed solvent (26
liters), and subjected to vacuum drying to obtain, as white
crystals, l-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol
[35.91 kg, yield: 84.8%, purity: 99% (HPLC)].
1H-NMR (CDC13) : 5
2.74 (1H, d), 6.35 (1H, d), 6.93 (1H, dd), 7.14 (1H, s),
7.27-7.38 (2H, m), 7.39 (1H, m), 7.68 (1H, dd),

7.74 (2H, m)
[0052]
Second step: Synthesis of 2-[(5-bromo-2-
fluorophenyl)(chloro)methyl]-1-benzothiophene
Into an acetonitrile (10 ml) solution of 1-benzothien-
2-yl(5-bromo-2-fluorophenyl)methanol (1.0 g) was dropwise
added thionyl chloride (706 mg) at a temperature of 5°C or
lower, followed by stirring at 5.0 to 25.0°C for 3.5 hours.
The reaction mixture was subjected to distillation under
reduced pressure to distill off the solvent and the residue
was subjected to vacuum drying to obtain 2-[(5-bromo-2-
fluorophenyl)(chloro)methyl]-1-benzothiophene [1.05 g, yield:
100%, purity: 99% (HPLC)].
1H-NMR (CDC13) : 8
6.62 (1H, s), 6.98 (1H, dd), 7.22 (1H, s),
7.30-7.37 (2H, m), 7.45 (1H, m), 7.71 (1H, dd),
7.77 (1H, m), 7.81 (1H, dd)
[0053]
Third step: Synthesis of 2-(5-bromo-2-fluorobenzyl)-1-
benzothiophene
Acetonitrile (1,260 ml)was added to 2-[(5-bromo-2-
fluorophenyl)(chloro)methyl]-1-benzothiophene (265.69 g) and
the mixture was heated to 40°C. The resulting solution was
added to a water (1,260 ml) solution of sodium borohydride
(113.0 g) and sodium hydroxide (14.9 g) at 59.0 to 67.9°C,
followed by stirring at 24.1 to 67.5°C for 17.5 hours. To
the reaction mixture were added 36% hydrochloric acid (340.5
g), water (1,260 ml) and toluene (1,260 ml), and extraction
was conducted. The organic layer was washed with a 5%
aqueous sodium hydrogencarbonate solution (1,260 ml) and

subjected to vacuum distillation to distil off the solvent.
To the residue were added 2-propanol (378 ml) and methanol
(756 ml), and the residue was dissolved with heating. To the
solution was added, as a seed crystal, 2.7 g of the 2-(5-.
bromo-2-fluorobenzyl)-1-benzothiophene produced by the method
of Reference Example 2, at 39.7°C, followed by stirring at
0.7 to 5.0°C for 13 hours. The separated-out crystals were
collected by filtration, washed with methanol (251 ml), and
vacuum-dried to obtain, as white crystals, 2-(5-bromo-2-
fluorobenzyl)-1-benzothiophene [194.05 g, yield: 80.9%,
purity: 99% (HPLC)].
1H-NMR (CDC13) : 5
4.18 (2H, s), 6.90-6.97 (1H, dd), 7.17 (1H, s),
7.22-7.40 (4H, m), 7.67 (1H, d) , 7.74 (1H, d)
[0054]
Forth step: Synthesis of (IS) -2, 3, 4, 6-tetra-O-acetyl-l,5-
anhydro-1-[3-(l-benzothien-2-ylmethyl)-4-
fluorophenyl]glucitol
To a toluene (32.5 ml)-diisopropyl ether (25 ml)
solution of 2-(5-bromo-2-fluorobenzyl)-1-benzothiophene (5.0
g) was dropwise added a n-hexane solution (10 ml) of n-butyl
lithium (1.6 M) at -43.5 to -33.3°C, followed by stirring for
10 minutes. To the reaction mixture was added, at -72.6 to
-65.0°C, a toluene (17.5 ml) solution of 2,3,4,6-tetrakis-O-
(trimethylsilyl)-D-glucono-1,5-lactone (8.0 g), followed by
stirring for 6 hours. The reaction mixture was added to a
methanol (25 ml) solution of an ethyl acetate solution (7.8
ml) of hydrogen chloride (4 M) at a temperature of 0°C or
lower, followed by stirring at 0°C for 17 hours. The
reaction mixture was added to a water (35 ml) solution of

potassium carbonate (1.29 g). Thereto was added ethyl
acetate, followed by extraction. The aqueous layer was
extracted with toluene (20 ml)-ethyl acetate (10 ml). The
organic layers obtained by extraction were combined and
subjected to vacuum distillation to distil off the solvent
until the reside became 40 ml. Toluene (25 ml) was added to
the residue and the mixture was subjected to vacuum
distillation to distil off the solvent until the residue
became 40 ml. This operation of adding toluene to the
residue and subjecting the mixture to vacuum distillation to
distil off the solvent, was repeated twice to obtain methyl
1-C-[3-(l-benzothien-2-ylmethyl)-4-fluorophenyl]- a -
glucopyranoside as a toluene solution.
^-NMR (CD3OD) : 8
3.08 (3H, s), 3.10 (1H, m), 3.42 (1H, dd), 3.58 (1H, m),
3.75 (1H, dd), 3.82 (1H, m), 3.92 (1H, dd),
4.23 (1H, d), 4.32 (1H, d), 7.05 (1H, s), 7.09 (1H, dd),
7.22 (1H, m), 7.27 (1H, m), 7.54 (1H, m),
7.64-7.65 (2H, m), 7.72 (1H, d)
[0055]
To the above-obtained toluene solution of methyl 1-C-
[3-(l-benzothien-2-ylmethyl)-4-fluorophenyl]- a -
glucopyranoside were added pyridine (7.39 g) and
4-dimethylaminopyridine (19 mg). Thereto was added acetic
anhydride (7.94 g) at 1.7 to 3.3°C, followed by stirring at
room temperature for 12 hours. To the reaction mixture was
added hydrochloric acid (2 M, 50 ml), followed by extraction.
The organic layer was washed with a 5% aqueous sodium
hydrogencarbonate solution (75 ml) and successively with an
aqueous sodium chloride solution (25%, 50 ml), and subjected

to vacuum distillation to distil off the solvent until the
residue became 15 ml, to obtain, as a toluene solution,
methyl 2,3,4,6-tetra-O-acetyl-l-C-[3-(l-benzothien-2-
ylmethyl) -4-fluorophenyl] - a -glucopyranoside .
1H-NMR (CD3OD): 5
1.67 (3H, s), 1.90 (3H, s), 2.02 (3H, s), 2.03 (3H, s),
3.13 (3H, s), 4.07 (1H, m), 4.25-4.32 (2H, m),
4.37-4.40 (2H, m), 4.86 (1H, m), 5.15 (1H, dd),
5.51 (1H, dd), 7.00 (1H, s), 7.15 (1H, dd),
7.24 (1H, dd), 7.29 (1H, dd), 7.42 (2H, m),
7.66 (1H, d), 7.72 (1H, d)
[0056]
Acetonitrile (10 ml) was added to the residue obtained
above. The solution was added to an acetonitrile (20 ml)
solution of trifluoromethanesulfonic acid (4.67 g) and tert-
butyldimethylsilane (3.62 g) at -9.2 to 1.0°C, followed by
stirring at 0°C for 3 hours. To the reaction mixture were
added tetrahydrofuran (70 ml) and toluene (25 ml). The
solution was added to a solution of potassium carbonate (2.8
g), sodium chloride (1.5 g) and water (30 ml) at 5.0 to 9.0°C,
followed by extraction at 30 to 40°C. The organic layer was
washed with a 25% aqueous sodium chloride solution (25 ml)
and subjected to distillation at normal pressure to distil
off the solvent until the residue became 55 ml. The residue
was cooled slowly and stirred at 0°C for 50 hours. The
separated-out crystals were collected by filtration, washed
twice with toluene (5 ml) and vacuum-dried to obtain, as
white crystals, IS)-2,3,4,6-tetra-O-acetyl-l,5-anhydro-l-[3-
(l-benzothien-2-ylmethyl)-4-fluorophenyl] glucitol [6.66 g,
yield: 74.7%, purity: 99% (HPLC)].

1H-NMR (CDCI3) : 8
1.70 (3H, s), 1.98 (3H, s), 2.04 (3H, s), 2.05 (3H, s) ,
3.78 (1H, m), 4.12-4.38 (5H, m) , 5.07 (1H, m),
5.18-5.31 (2H, m) , 6.99 (1H, dd), 7.07 (1H, dd) ,
7.20-7.32 (4H, m), 7.66 (1H, d), 7.73 (1H, d)
[0057]
Fifth step: Synthesis of (IS) -1, 5-anhydro-l-O [3- (1-
benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol
To a methanol (427.4 kg) solution of (IS)-2, 3, 4, 6-
tetra-O-acetyl-1,5-anhydro-l-[3-(l-benzothien-2-ylmethyl)-4-
fluorophenyl] glucitol (76.9 kg) was added a water (230
liters) solution of sodium hydroxide (26.9 kg) at a
temperature of 25°C or lower, followed by stirring at 40.0 to
49.1°c for 4 hours. Water (850 liters) was added to the
reaction mixture, and 12.9 kg of 38% hydrochloric acid was
added thereto at a temperature of 25°C or lower. The mixture
was heated to 60°C, followed by stirring at 20.2 to 25.0°C
for 9.5 hours. The separated-out crystals were collected by
filtration, washed with tap water (80 liters), and vacuum-
dried to obtain, as white crystals, (IS)-1,5-anhydro-l-C-[3-
(l-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol
[52.7 kg, yield: 97.0%, purity: 99% (HPLC)].
^-NMR (CD3OD) : 8
3.29-3.48 (4H, m), 3.68 (1H, dd), 3.87 (1H, dd) ,
4.11 (1H, d), 4.20-4.29 (2H, m), 7.03 (1H, s),
7.08 (1H, dd) , 7.19-7.29 (2H, m) , 7.35 (1H, nt) ,
7.42 (1H, dd), 7.64 (1H, d), 7.72 (1H, d)
[0058]
The yield of the production method of the present
invention, in Example is shown in the following Table 1.


[0060]
Meanwhile, the yield of the known production method of
C-glycoside derivative represented by the formula (1), in
Reference Example 1 is shown in the following Table 2.
[0061]
[0062]
As is understood from Table 1 and Table 2, the present
invention method, as compared with the known method, includes
no step giving a yield of 50% or lower; therefore, the
present invention method can give a high total yield and is
advantageous in cost. Further, the present invention method
has no need of using a column or chloroform. For these
reasons, the present invention method, as compared with the

known method, is extremely superior industrially. In
particular, the present invention method has achieved a high
overall yield of 49.7%, whereby an industrially applicable
production method has been established. Incidentally, the
first step in Example and the first step in Reference Example
1 conduct the same reaction; however, they give slightly
different yields. Even if the yield of the first step of
Example is used as the yield of the first step of Reference
Example 1 and the overall yield of the Reference Example 1 is
calculated, the overall yield thereof becomes 6.58%; thus,
the overall yield of Example is overwhelmingly superior and
there has been established, by the present invention method,
an industrially applicable production method of C-glycoside
derivative represented by the formula (1).
INDUSTRIAL APPLICABILITY
[0063]
The present invention provides a method for producing a
C-glycoside derivative, which enables the production at a
high yield at a low cost, which conforms to environmental
protection, and which is advantageous industrially; and an
intermediate for synthesis, useful in the production step of
the method.

Claims
[1] A compound represented by the following formula (2d)
[formula 1]

[in the formula, B1s may be the same or different from each
other and are each H or C(=0)R1 (R1s may be the same or
different from each other and are each lower alkyl), with a
proviso that at least one of B1s is C(=0)R1].
[2] A compound according to Claim 1, wherein each R1 is
methyl.
[3] A compound represented by the following formula (la)
[formula 2]

(in the formula, R2 is H or halogen and Y is Br or I).
[4] A method for producing a compound represented by the
following formula (1),
[formula 3]

characterized by subjecting the compound set forth in Claim 1,

to a reaction for elimination of acyl group.
[5] A method for producing a compound set forth in Claim 1,
characterized by allowing a compound selected from the group
consisting of triethylsilane, triisopropylsilane, tert-
5 butyldimethylsilane, sodium borohydride and sodium
tri(acetoxy)borohydride to act on a compound represented by
the following formula (2c)
[formula 4]

10 [in the formula, B1s may be the same or different from each
other and are each H or C(=O)R1 (R1s may be the same or
different from each other and are each lower alkyl) and Me is
methyl, with a proviso that at least one of B1s is C(=O)R1],
to reduce the compound of the formula (2c).
15 [6] A method according to Claim 4, wherein the compound set
forth in Claim 1 is a compound produced by the method set
forth in Claim 5.
[7] A method for producing a compound represented by the
following formula (1),
20 [formula 5]

characterized by subjecting the compound set forth in Claim 2,

to a reaction for elimination of acetyl group.
[8] A method for producing a compound set forth in Claim 2,
characterized by allowing a compound selected from the group
consisting of triethylsilane, triisopropylsilane, tert-
5 butyldimethylsilane, sodium borohydride and sodium
tri(acetoxy)borohydride to act on a compound represented by
the following formula (2b)
[formula 6]

10 [in the formula, B2s may be the same or different from each
other and are each H or C(=0)Me and Me is methyl, with a
proviso that at least one of B2s is C(=0)Me], to reduce the
compound of the formula (2b).
[9] A method according to Claim 7, wherein the compound set
15 forth in Claim 2 is a compound produced by the method set
forth in Claim 8.
[10] A method for producing a compound represented by the
following formula (1),
[formula 10]
20
characterized by subjecting a compound represented by the
following formula (4)


(in the formula, Y is Br or I) and a compound represented by
the following formula (3)
5 [formula 8]

(in the formula, As may be the same or different from each
other and are each lower alkyl), to an addition reaction,
eliminating tri-lower alkyl silyl, and being acylated, then
10 conducting reduction to obtain a compound represented by the
following formula (2d)
[formula 9]

15 [in the formula, B1s may be the same or different from each
other and are each H or C(=0)R1 (R1s may be the same or
different from each other and are each lower alkyl), with a
proviso that at least one of B1s is C(=0)R1], and subjecting
the compound to a reaction for elimination of acyl group.
20 [11] A method according to Claim 10, wherein the compound
represented by the formula (4) is a compound of the formula

(4) obtained by subjecting a compound represented by the
following formula (5)
[formula 11]

5 (in the formula, X is halogen and Y is Br or I) to a
reduction reaction.
[12] A method for producing a compound represented by the
following formula (1),
[formula 15]
10
characterized by subjecting a compound represented by the
following formula (4)
[formula 12]

15 (in the formula, Y is Br or I) and a compound represented by
the following formula (3a)
[formula 13]


(in the formula, TMS is trimethylsilyl) to an addition
reaction, eliminating trimethylsilyl in methanol, and being
acetylated, then conducting reduction to obtain a compound
represented by the following formula (2a)
5 [formula 14]

[in the formula, B2s may be the same or different from each
other and are each H or C(=0)Me (Me is methyl), with a
proviso that at least one of B2s is C(=0)Me], and subjecting
10 the compound to a reaction for elimination of acetyl group.
[13] A method according to Claim 12, wherein the compound
represented by the formula (4) is a compound of the formula
(4) obtained by subjecting a compound represented by the
following formula (5)
15 [formula 16]

(in the formula, X is halogen and Y is Br or I) to a
reduction reaction.

The present invention provides a method for producing a C-glycoside derivative, which can produce the C-glycoside derivative at a high yield and at a low cost, which conforms to environmental protection, and which is applicable
industrially. The C-glycoside derivative is useful for treating and preventing diabetes such as insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes) and the like and various diabetes-related
diseases including insulin-resistant diseases and obesity.