Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02654424 2008-12-04
TETRA-BENZYL VOGLIBOSE IN CRYSTALLINE FORM AND A METHOD
FOR PREPARING THE SAME
FIELD OF THE INVENTION
The present invention relates to a tetra-benzyl voglibose in crystalline form,
and a method for preparing said tetra-benzyl voglibose in crystalline form.
BACKGROUND OF THE INVENTION
Voglibose, an a-glucosidase inhibitor developed by Takeda Pharmaceutical
Company (Japan)(EP56194), is used for treating diabetes and presently on the
market
in Japan, Korea and China. It has a molecular structure as in formula ( I):
H OH
H
HO ~
H
HO OI H OH OH
H H N-----F
\-O H
(1>,
The chemical name of Voglibose is (1S)-(1(OH),2,4,5/1, 3)-5-[(2-hydroxy-
1-(hydroxymethyl) ethyl) amino]-1-C-hydroxymethyl-1,2,3,4-cyclohexanetetrol.
There exist several methods for preparing voglibose, the earliest one being
chemical
synthesis of voglibose by using valienamine produced by fermentation as raw
material(EP56194). However, the process for preparation and separation of
valienamine is complicated and requires substantive manpower and energy
consunlption, and it is difficult to remove impurities in the product obtained
by this
method, which needs complicated columri chromatography for refinement.
L,,ater,
there are also some methods of total chenlical synthesis by using D-glucose as
raw
material, such as those disclosed in E112160 t21, .1. Org. Chem. 1992, 57, 367
l,
W003/080561 and W02005/030698 etc.
Among them, one typical process route is the process as disclosed in
.
1;P260121 and the one as published in .t. Oro. Chem. 1992, 57, 3651 (sllown in
l~ io
1
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10). In this process, (1S)-(1(OH),2,4, 5/1,3)-2,3,4-tri-O-benzyl-5-[(2-hydroxy-
l-
(hydroxymethyl) ethyl) amino]-1-C-benzyloxymethyl-1,2,3,4-cyclohexanetetrol
(hereinafter abbreviated as tetra-benzyl voglibose), a compound of formula (
II ), is a
key intermediate, for voglibose is prepared directly by this tetra-benzyl
voglibose
through debenzylation. Therefore, its quality directly affects the quality of
voglibose,
the drug for treating diabetes.
H OBn
H
BnO H
OH
BnO IOH OBn ~Xr
H HN
OH
(II)
Said intermediate disclosed in all of the current documents and methods
(such as patent document EP260121, J. Org. Chem. 1992, 57, 3651,
W02005/030698) is oily product.
Tetra-benzyl voglibose in oily form is difficult to be preserved and
transported, and is not easy to be taken out and weighed in use, being
inconvenient for
material charging and operation during the production. At the same time, due
to the
low purity and content of tetra-benzyl voglibose in oily form, it is easy to
introduce or
produce impurities during reaction when using it to prepare voglibose, thus
making it
difficult to prepare voglibose of higher quality.
SUMMARY OF THE INVENTION
In order to overcome the disadvantages of the current tetra-benzyl voglihose
in oily form, the technical problem to be solved by the present invention is
to provide
a tetra-benzyl voglibose in crystalline form and a method for preparing the
same.
When studying the process for preparation of voglibose, the inventor found
out and pi-cpared a key intet-mediate, tetra-benzyl vo ibose. Normally, in
all
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documents and information of prior arts, the tetra-benzyl voglibose is only
shown as
an oily substance. Through the study of this substance, a tetra-benzyl
voglibose in
crystalline form is successfully obtained. This kind of crystal is stable in
its crystalline
state under the room temperature at common condition.
Said tetra-benzyl voglibose in crystalline form can be used to prepare high
purity a-glucosidase inhibitor, voglibose, and is easy to be preserved,
transported and
operated in the production. This preparation method is of the advantages of
fewer
steps, ordinary and available reagents, less pollution, sinlple operation and
high purity
of product etc.
The present invention also provides a method for preparing voglibose by use
of the tetra-benzyl voglibose in crystalline form. The content of the
voglibose
produced by this crystal can be up to more than 99.9%. Dosage forms made with
such
voglibose will have better treating effect and less side-effect.
Therefore, the present invention is to provide a tetra-benzyl voglibose in
crystalline form having following physical properties:
In Cu X-ray powder diffraction map, there are characteristic peaks where 20
is 16.84t0.20 , 18.99f0.20 and 24.11f0.20 ;
Melting point of the tetra-benzyl voglibose in crystalline form is
88.0-90.8 C
Further, in Cu X-ray powder diffraction map, there are characteristic peaks
of the tetra-benzyl voglibose in crystalline form of the present invention,
where 20 is
8.39f0.200, 11.91 0.20 , 22.11 0.20 , 23.37f0.20 , 24.53 0.20 , 25.63i0.20
and
25.99f0.20 .
DSC endotlletmic peak value of the tetra-benzyl voglibose of the present
invention is about 89.7 C.
In single crystal X-ray diffraction, single crystal of said tetra-benzyl.
voglibose in crystalline form has a molecular stereo-sti-uctui-e as shown in
Fig. 5.
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Further, said tetra-benzyl voglibose in crystalline form belongs to the
orthorhombic system among space group of P2(1)2(1)2(1), the unit cell
parameters
being a=7.8487A, b=20.746A, c=20.988A, and R value=0.0748.
Molecules of said tetra-benzyl voglibose in crystalline form are linked with
each other by force of hydrogen bond.
In analysis of infrared spectrum, the said tetra-benzyl voglibose in
crystalline form exhibits its infrared spectrum as shown in Fig. 9.
Content of the tetra-benzyl voglibose in crystalline form being provided
through the method of the present invention may be more than 95%, and in
particular,
the content is between 95- 99.5% by HPLC, which is markedly higher than that
of the
tetra-benzyl voglibose in oily form.
The present invention also provides a method for preparing tetra-benzyl
voglibose in crystalline form. In this method, the first step is dissolving
tetra-benzyl
voglibose in oily form in a type of polar nonprotic solvent such as ethyl
acetate,
isopropyl ether, ethyl ether or tetrahydrofuran, etc. The second step is
adding another
type of nonpolar solvent such as cyclohexane, n-hexane, carbon tetrachloride
or
petroleum ether etc. Then, after stirring the said solution at room
temperature to
produce crystal, filtering the solution after it's fully cooled down and
drying, the tetra-
benzyl voglibose in crystalline form of the present invention will be
obtained.
Particularly, said preparation method is to dissolve I share of the tetra-
benzyl voglibose in oily fornl in 0.5-5 shares (by volume-to-weight ratio) of
polar
nonprotic solvent, preferably 1-3 shares; then add 2-20 shares (by volume-to-
wcight
ratio) of one or more kinds of nonpolar solvent, preferably 2-10 shares.. Said
polar
nonprotic solvent may be selected from the group consisting of ethyl acetate,
isopropyl ether, ethyl ether and tetrahydrofuran, etc., preferably ethyl
acetat.e and/or
isopropyl ether; said nonpolar solvent niay be selected from the gl-oup
consisting of
cycloliexane, n-hexanc:, cai-bon teti-achloride and petroleuni ether, ctc.,
preferably
cyclohexane and/or n-hexane. Then crystal is produced by stirring the obtained
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solution at room temperature. Then cool it down, filter it and dry it. For
example, first
set the obtained solution aside for cooling down for 1 to 5 hours, then set it
aside for I
to 5 hours at the temperature of 0 to 5 C, and dry the crystal filtered out of
the
solution for 10 to 12 hours in vacuum. The crystal of the above said tetra-
benzyl
voglibose will be obtained.
High purity voglibose can be prepared taking advantage of the obtained
tetra-benzyl voglibose through further debenzylation.
By testing single crystal state and powder state of the crystal, features and
characteristics of said crystal of the present invention are set forth here.
The single
crystal X-ray diffraction, powder X-ray diffraction, differential scanning
calori;.netry
(DSC) analysis, infrared (IR) spectrum and data of the tetra-benzyl voglibose
iri
crystalline form in accordance with the present invention are therefore
illustratively
presented herein for description.
The test of single crystal X-ray diffraction of the crystal sliows that the
empirical formula of said crystal is C3RH45N07; it belongs to orthorhombic
system
among the space group P2(1)2(1)2(1), and the unit cell parameters are
a=7.8487A,
b=20.746A, c=20.988A, and R value=0.0748. Generally, the crystal can also be
characterized by its power X-ray diffraction data, specifically by X-ray
diffraction
peaks where 20 is 16.84f0.20 , 18.99 0.20 and 24.11 0.20 , and further by X-
ray
diffraction peaks where 20 is 8.39 0.20 , 11.91 0.20 , 22.1 1 0.20 , 23.37
0.20 ,
24.53 0.20 , 25.63 0.20 and 25.99 0.20 .
In addition, the crystal can be characterized by thermodynamic
characteristics via DSC, and its endothermie value is 89.TC.
The advantageous effects of the present invention include: tl-ke tetra-benzyl
voglibose in crystalline form is easier to be preserved and transported, and
is niore
convenient to be taken out and weighed in use, thus easy for rnaterial
charging and
operation during the production than that of the teUra-benzyl voglibose in
oily form.
At the same tiine, due to higher purity and higher content of the tetra-benzyl
voglibose
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in crystalline form in comparison with the tetra-benzyl voglibose in oily
form, less
impurity will be introduced or produced during reaction when preparing
voglibose by
use of it. Higher quality of voglibose can be produced by taking advantage of
this
crystal, thus voglibose being prepared into dosage forms will have better
effect of
treatment and less side-effect.
Further details of the present invention will be incorporated with the
following figures and embodiments; however the description of those
embodiments
should not be understood as the limitation to the scope of the present
invention.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is an X-ray powder diffraction map of the tetra-benzyl voglibose in
crystalline form of Example 2 according to the present invention;
Fig. 2 is an X-ray powder diffraction map of the tetra-benzyl voglibose in
crystalline form of Example 3 according to the present invention;
Fig. 3 is an X-ray powder diffraction map of the tetra-benzyl voglibose in
crystalline form of Example 4 according to the present invention;
Fig. 4 is an X-ray powder diffraction map of the tetra-benzyl voglibose in
crystalline form of Example 5 according to the present invention;
Fig. 5 shows a molecular stereo-structure of the tetra-benzyl voglibose in
crystalline form by single crystal X-ray diffraction according to the present
invention;
Fig. 6 is a view of molecular unit cell packing of the tetra-benzyl voglibose
in crystalline form according to the present invention;
Fig. 7 is a schematic view of molecules of the tetra-benzyl voglibose in
crystalline form with the molecules being linked with each other by force of
hydrogen
bond according to the present invention;
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Fig. 8 is a figure for differential scanning calorimetry analysis of the tetra-
benzyl voglibose in crystalline form according to the present invention;
Fig. 9 is an infrared spectrogram of the tetra-benzyl voglibose in crystalline
form according to the present invention; and
Fig. 10 is a process route for preparing voglibose by taking advantage of tlle
tetra-benzyl voglibose in crystalline form according to the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Raw materials used in following embodiments are all available in the market,
if there is no specific indication in the text.
Preparation of the tetra-benz l~glibose
in oily form
Example 1-- Preparation of the tetra-benzyl voglibose in oily form (as seen in
the
method disclosed in J. Org. Chem. 1992, 57, 3642)
(1 S)-(1(OH),2,4,5/ 1,3)-2,3,4-tri-O-benzyl-l-C-benzyloxytnethyl-5-O-
1,2,3,4-cyclohexanetetrol(6.0g, 10.8mmol) and 2-amino-1,3-propanediol(3.Og,
33mmol) were dissolved into 30mL of methanol, into which sodium
cyanoborohydride (1.5g, 24mmol) was added in batches at room temperature, and
it
was continuously stirred for 16 hours at room temperature. The reaction
solution was
concentrated. The residue was dissolved by 300mL of ethyl acetate, washed by
lOOmL of water, then washed by l 00mL of 1% hydrochloric acid solution twice,
washed by 100mL of 5% sodiuni carbonate solution twice, washed by 100mL of
brine
twice, and dried by anllydrous sodium sulfate. Ethyl acetate was recovered and
the
residue was perfor-med by silica gel (150m1) column chromatography with
elution by
ethyl acetate. The constituent containing ethyl acetate was coi:centrated to
obtain 5.2g
of straw yellow oily substance with content of 89.4% by HPLC.
Preparation of the tetra-benzytvoglibose
in cr ystalline foi-m
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Example 2
1.Og of the tetra-benzyl voglibose in oily form (prepared in Example 1) was
dissolved in 2.5mL of ethyl acetate, into which 6mL of cyclohexane was added
while
stirring. Afterward, the solution was stirred at room temperature for 1.5
hours to
produce white crystal. It was set aside for another 5 hours at room
teinperature, and
then set aside for 5 hours at the temperature of 0-5 C . After filtering, the
crystal was
dried for 12 hours at room temperature under vacuum to obtain 0.76g of white
crystal
with content of 98.5% by HPLC. Mp: 88.2-90.8 C;[a]22D+30.8 (cl, chloroform);
'H
NMR(CDC13, 500Hz), b: 1.63(1H, dd, J=2.8, 15.1 Hz), 1.91 (1H, dd, J=2.9,
15.1Hz) ,
2.78 (1H, m), 3.19 (1H, d, J=8.6 Hz), 3.39 (1H, m), 3.54 (1H, d, J=8.6Hz),
3.62-3.73 (6H, m), 4.13 (1H, t, J=9.6Hz), 4.39 (2H, s), 4.59 (1H, d, J=11..1),
4.64 (1H, d,
J=11.4), 4.72 (1H, d, J=11.4), 4.82 (1H, d, J=10.6), 4.91 (1H, d, J=11.2),
4.93 (1H, d,
J=10.7), 7.24-7.35 (20H, m). 15 By use of copper target X-Ray Diffractometer
(D/max-2500/PC, RIGAKU
INTERNATIONAL CORP., JAPAN), the crystal powder was analyzed (tested by
Nanjing Normal University). The conditions of diffraction were as follows:
Divergence: 1
Receiving Slit: 0.3 mm
Scattering degree: 1
Voltage: 40 KV, Electric Current: 100 mA
Scanning speed: 5deg/min, Space of Time 0.02 deg
Fig. I is an X-ray powder diffraction map of the tetra-benzyl voglibose in
crystalline form, and the data of X-ray powder diffraction are shown in table
1.
Table 1--the data of X-ray powder diffraction of the tetra-benzyl voglibose
in crystalline form
Number 20 value d value I/I value
1 8.44 10.4677 38
2 11.96 7.3937 12
3 16.86 5.2543 40
4 19.02 4.6622 100
5 22.16 4.0081 14
6 23.42 3.7953 9
7 24.14 3.6837 35
8 24.58 3.6187 21
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9 25.68 3.4662 10
26.00 3.4242 11
Example 3
3.Og of the tetra-benzyl voglibose in oily form (prepared in Example 1) was
dissolved in I OmL of isopropyl ether, into which 25mL of n-hexane was added
while
5 stirring. Afterward, the solution was stirred at room temperature for 1 hour
to produce
crystal in powder form. It was set aside for another 5 hours at room
temperature, and
then set aside for 5 hours at the temperature of 0-5 C . Then the crystal was
dried for
12 hours at room temperature under vacuum after filtering to obtain 2.5g of
white
crystal with content of 98.7% by HPLC. Mp: 88.5-90.7 C; [a]22D+30.6 (cl,
10 chloroform). Its 'H NMR data were the same as those of E.xample 2.
By use of copper target X-Ray Diffractometer (D/max-2500/PC, RIGAKU
INTERNATIONAL CORP., JAPAN), the crystal powder was analyzed (tested by
Nanjing Normal University). The conditions of diffraction were the same as
those of
Example 2. Fig. 2 is an X-ray powder diffraction map of the tetra-benzyl
voglibose in
crystalline form, and the data of X-ray powder diffraction are shown in table
2.
Table 2--the data of X-ray powder diffraction of the tetra-benzyl voglibose
in crystalline form
Number 20 value d value I/Ia value
1 8.44 10.4677 60
2 11.96 7.3936 20
3 16.86 5.2543 50
4 19.02 4.6622 100
5 22.16 4.0081 16
6 23.42 3.7953 7
7 24.14 3.6837 29
8 24.58 3.6187 21
9 25.66 3.4688 9
10 26.04 3.4190 9
Exampte 4
3.0g of the tetra-benzyl voglibose in oily foim (prepared in Exaniple 1) was
dissolved in 1.5mL of ethyl ether, into wliich 6mL of petroleum ether was
added
while stirring. Afterward, the solution was stirred at room temperature for 1
hour to
produce crystal. It was set aside foi- another hour at roo1'i1 temperatU-e,
and then set
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aside for 1 hour at the temperature of 0-5 C . Then the crystal was dried for
10 hours
at room temperature under vacuum after filtering to obtain 2.3g of white
crystal with
content of 98.5% by HPLC. Mp: 88.1-90.6C; [a]22 p+30.5 (cl, chloroform). Its
IH
NMR data were the same as those of Example 2.
By use of copper target X-Ray Diffractometer (D/max-2500/PC, RIGAKU
INTERNATIONAL CORP., JAPAN), the crystal powder was analyzed (tested by
Nanjing Normal University). The conditions of diffraction were the same as
those of
Example 2. Fig. 3 is an X-ray powder di ffraction map of the tetra-benzyl
voglibose in
crystalline form, and the data of X-ray powder diffraction are shown in table
3.
Table 3--the data of X-ray powder diffraction of the tetra-benzyl voglibose
in crystalline form
Number 20 value d value I/I o value
1 8.44 10.4677 57
2 11.96 7.3936 20
3 16.86 5.2543 48
4 19.02 4.6622 100
5 22.16 4.0081 15
6 23.42 3.7953 9
7 24.14 3.6837 32
8 24.58 3.6187 22
9 25.68 3.4662 10
10 26.04 3.4190 11
Example 5
2.Og of the tetra-benzyl voglibose in oily form (prepared in Example 1) was
dissolved in l OmL of tetrahydrofuran, into which 40mL of carbon tetrachloride
was
added while stirring. Afterward, the solution was stirred at room temperature
for 1
hour to produce crystal. It was set aside for another 5 hours at room
temperature, and
then set aside for 5 hours at the teniperature of 0-5 C. The crystal was dried
for 12
hours at room temperature undet- vacuum after filtering to obtain 1.2g of
white crystal
with content of 98.6% by HPLC. Mp: 88.0-90.5 C; [a]"p+30.7 (cl, chloroform).
Its
~H NMR data were the sanie as those of Example 2.
By use of copper target X-Ray Diffractometer (D/max-IIIB, RIGAKU
INTERNATIONAL CORP., JAPAN), the ci-ystal powder was analyzed (tested by
ZhengThou University). Tlle conditions of diffractiotlwere as follows:
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Divergence: 1
Receiving Slit: 0.15 mm
Scattering degree: 1
Voltage: 35 KV, Electric Current: 30 mA
Scanning speed: 4deg/min, Space of Time 0.02 deg
Fig. 4 is an X-ray powder diffraction map of the tetra-benzyl voglibose in
crystalline form, and the data of X-ray powder diffraction are shown in table
4.
Table 4--the data of X-ray powder diffraction of the tetra-benzyl voglibose
in crystalline form
Number 20 value d value 1/Io value
1 8.24 10.7216 16
2 11.76 7.5191 15
3 16.76 5.2855 35
4 18.90 4.6916 100
5 21.94 4.0479 15
6 23.22 3.8275 17
7 24.00 3.7049 39
8 24.36 3.6509 15
9 25.50 3.4902 12
10 25.88 3.4399 16
The test of the tetra-benzyl vo lig bose
in crystalline form
Example 6
A. Conditions of Test
1. Single crystal X-ray diffraction
Model of instrument: AXIS-IV X-ray image-plate system (manufactured by
RIGAKU INTERNATIONAL CORP., JAPAN)
2. Infrared spectrum (IR)
NEXUS-470 infrared spectrometer (Nicolet), measured by KBr pellet
method
3. Differential scanning calorimetry
DSC204 Differcntial Scanning Calorinieter (NETZSCH)
Injection: 3mg;
"I'emperature range: 30 C-200 C;
(I
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Heating speed: 3 C/min
B. Sample to be tested
The tetra-benzyl voglibose in crystalline form prepared according to
Example 5
C. Results
Single crystal X-ray diffraction data shows that empirical fonnula of the
crystal is C38H4;NO7; and the crystal belongs to orthorhombic system among the
space group P2(1)2(1)2(1), and unit cell parameters are a=7.8487A, b=20.746A,
c=20.988A, and R value=0.0748. Its molecular stereo-structure is shown in Fig.
5. A
perspective view of unit cell packing in the direction A is shown in Fig. 6.
Fig. 7
shows that molecules were linked with each other by force of hydrogen bond.
The
following Tables 5-10 show crystal data, atomic coordinates, bond lengths,
bond
angles, torsion angles and hydrogen-bond lengths and angles respectively.
Fig. 8 is a figure of differential scanning calorimetry analysis of the tetra-
benzyl voglibose in crystalline form. Fig. 8 shows its thermodynamic property
to be
an endothermic value of 89.7 C .
Fig. 9 is an infrared spectrogram of the tetra-benzyl voglibose in crystalline
form.
Table 5--Crystal data and structure refinement
Einpirical formula C38H45NO7
Formula weight 627.75
Temperature 291(2)K
Wavelength 0.71073 A
Crystal system, space group Orthorhombic, P2(1)2(1)2(l) Unit cell dimensions
a=7.8487(16) A, a=90
b=20.746 (4)A, ~=90
c=20.988 (4)A y=90
Volume 3417.4(12) A
Calculated density 4, 1.220 Mg/m
Absorption coefficient 0.083mm_'~
F(000) 1344
---- -- - - - - - -
Crystal sizc 0.20X0.18X0.18mm
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Theta range for data collection 1.38 to 25.00 deg.
Index ranges -9<h<9, -24<k<0, -24<1<24 _
Reflections collected/uni ue 9647/3327 [R(int)=0.0833
Completeness to theta = 25 97.3% _ _ _
Abso tion correction Semi-empirical from equivalents
Max. and min. transmission 0.9852 and 0.9835
Refinement method Full-matrix least-squares on F
Data/restraints/parameters 3327/3/432 _
Goodness-of-fit on F 1.051 _
Final R indices [I>2sigma (I)] R1 =_0.0748, wR2 = 0.1538 ~
R indices (all data) Rl = 0.1289, wR2 = 0.1740 _ ~
Absolute structure parameter 0(10) _ _
Extinction coefficient 0.0011(6) _ _ _ _
Largest diff. peak and hole 0.329 and -0.172 e_t~~- _
Table 6--Atomic coordinates (X 104) and equivalent isotropic displacement
parameters( ~~ X 103 ). U(eq) is defined as one third of the trace of the
orthogon.alized
Uij tensor.
Atom X y ~z q)
N(1) 5785(6) _ -985 (2) 987_7 (2) 40 (1) _
O(1) 9116 (5) -631(1) 10_222(2) _ 40 (l)
O(2) 8817(6) 667 (2) 11368 (2)_ _ 56 (1) _~
O(3) 10227(4) 666(2) 9853 (2) _ 42 (1)
O(4) 7531(5) 865 (2) 8953 (2) 41 (1) ~
O(5) 4948(4) -87 (2) _ 8950 (2) ---~ -41 (1) _~
O(6) 4900 (8) -2648 (2) 10350 (3) _ I 101 (2)
-J
O(7) 2146(5) -1327(2) ~ 9956 (2) _~ 1) ~
C(1) 8413(6) -50(3) 10476 (2) _ 3~(l)__ _~
C(2) 8503 (6) 498 (3) 9981(2) 34 (1) _
C(3) 7546(7) 324 (2) 9378(2) _ 31 (1) ~
C(4) 5704(7) 156(3) 9531(2) 35 (1)
C(5) 5419 (6) -317(3) 10082 (3) 34 (1) I
C(6) 6530(7) -135 (3) 10654 (2) 38(1)
C(7) 9481 (7) 109 (3) 11065 (3) 45(2)_
C(8) 9567 (9) 789 (3) 11965 (3)_ 62 (2) _~
C(9) 8629 (8) 1328(3) 12296(3) 47 (2) ~
C(10) 8259 (10) 1277(4) ~ 12928(3) 71 (2) ~
~C(l 1) 7396 (13) 1763(5) ~_3246 (4)___ ~ 96 (3)
C(12) _ 6883 (12) 2316 (5) 1291 1(5) ~ 103(3) ~
C 1 3 _ 7275 13 2360 4) ~12273i4)_ 94 3 ~
( ) ( ) ( . ~ ) ---~
C(14) 8130 (10) 1869 (4) ~11977(4)_ 72 (2) ~
r C( I 5) 10541 (9) 1324 (4) 9762(6) 110 (4) I,
~_C(16) _ 1.2286(7) _ 1518 (3) _ 9942 (3) 43 (2)
~ C(17) 12841(10) 1457(4) _ _ 10561 (4)_ 71 (2) _ i
; C(18) _14385 (15) 1641 (4) 10758 (6) 109 (3) _ __
~ ------ - - -
C(19) 15420 (1 I) 1910 (4) 10347(6) --~89 (3)
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C(20) 15112(12) 1989 (3) 9718(6) 89(3)
C(21) 13399(11) 1785(3) 9497 (4) 71 2)
C(22) 8099 (9) 752(3) 8335 (3) 59 (2)
C(23) 7695 (7) 1317(3) 7910 (3) 46(2)
C(24) 7829 (10) 1947 (4) 8117 (4) 71 (2)
C(25) 7430 (14) 2454 (4) 7715 (4) 93 (3)
C(26) 6907(12) 2320 (6) 7103 (5) 98(3)
C(27) 6868(14) 1723(6) 6893 (5) 106 (3)
C(28) 7229 (12) 1211 (5) 7295 (4) 87 (3)
C(29) 3134 (9) -57(5) 8936 (4) 99 (3)
C(30) 2531 (8) -35(4) 8259(3) 47(2)
C(31) 2904 (12) 484 (5) 7907 (5) 96(3)
C(32) 2326 (16) 551(8) 7321 (6) 151 (6)
C(33) 1265(13) 70(8) 7107(5) 142(7)
C(34) 793 (13) -494 (8) 7395(8) 164 (8)
C(35) 1548(11) -504 (5) 8048 (5) 94(3)
C(36) 5090(8) -1500(3) 10286(3) 44(2)
C(37) 5345 (9) - 2125(3) 9945(4) 66(2)
C(38) 3232 (8) -1421 (3) 10485 (3) 53(2)
Table 7--Bond lengths [A]
Atom-atom Length Atom-atom Length Atom-atom Length
N(1) -C(36 1.475(7) C(8) -C(9) 1.508 (9) C(23)-C(24) 1.380 (10)
N(1) -C(5) 1.480(7) C(8) -H(8A) 0.9700 C(24)-C(25) 1.384(11)
N(1) -H(1B) 1.01(6) C(8) -H(8B) 0.9700 C(24)-H(24A) 0.9300
0(1) -C(1) 1.429(6) C(9) -C(14) 1.361 (9) C(25)-C(26) 1.376(13)
0(1) -H(lE) 0.907 (11 C(9) -C(10) 1.364 (9) C(25)-H(25A) 0.9300
0(2) -C(8) 1.409 (7) C(10) -C(11) 1.385 (12) C(26)-C(27) 1.315 (12)
0(2) -C(7) 1.418 (7) C(10)-H(l0A) 0.9300 C(26)-H(26A) 0.9300
0(3) -C(15) 1.400 (8) C (11) -C(12) 1.405 (13) C(27)-C(28) 1.384(13)
0(3) -C(2) 1.424 (6) C(11)-H(11A) 0.9300 C(27)-H(27A) 0.9300
0(4) -C (22) 1.390(6) C(12)-C(13) 1.377 (13) C(28)-H(28A) 0.9300
0(4) -C(3) 1.434(6) C(12)-H(12A) 0.9300 C(29)-C(30) 1.498 (9)
0(5) -C (29) 1.425 (8) C (13) -C(14) 1.371 (11) C(29)-H(29A) 0.9700
0(5) -C(4) 1.446 (6) C(13)-H(13A) 0.9300 C(29)-H(29B) 0.9700
0(6) -C(37) 1.422 (8) C(14)-H(14A) 0.9300 C(30)-C(35) 1.319(11)
0(6) -H(6E) 0.911 (11) C(15)-C(16) 1.477 (9) C(30)-C(31) 1.338(11)
0(7) -C(38) 1.413(8) C(15)-H(15A) 0.9700 C(31)-C(32) 1.318 (13)
0(7) -H(7E) 0914 (11) C(15)-H(15B) 0.9700 C(31)-H(31A) 0.9300
C(1) -C(7) 1.529 (7) C (16) -C(17) 1.376 (9) C(32)-C(33) 1.374 (19)
C(1)_C(6) 1.534 (7) C(16)-C(21) 1.394 (10) C(32)-H(32A) 0.9300
C(1) -C(2) 1.542 (7) C (17) -C(18) 1.336 (12) C(33)-C(34) 1.369(19)
C(2) -C(3) 1.517 (7) C(17)-FI(17A) 0. 9300 C(31)-H(33A) 0.9300
C(2) -H(2A) 0.9800 C(18)-C(19) 1.311 (13) C(34)-C(35) 1.492 (16)
C(3) -C(4) 1.522(8) C(18)-H(18A) 0. 9300 C(34)-H(34A) 0.9300
r------
C(3) -H(3A) 0.9800 C(19)-C(20) 1.351 (13) C(35)-11(35A) 0.9300
C(-l) -C(5) 1.533 (7) C(19)-11(19A) 0.9300 C(36)=C(37) 1.494 (9)
---
( (-1)_H(4A) 0.9800 C (20)-C(21) 1.484 (13) C(36)-C(38) 1.526 (9)
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C 5) -C 6 1.531(7) C 20 H 20A 0.9300 C(36)-H(36A) 0.9800
C 5-H 5A 0.9800 C 21 -H 21A 0.9300 C(37)-H(37A) 0.9700
C(6) 6A 0.9700 C(22)-C(23) 1.507(9) C(37)-H(37B) 0.9700
C(6) 6B 0.9700 C(22)-H(22A) 0.9700 C(38)-H(38A) 0.9700
C(7) -H(7A) 0.9700 C(22)-H(22B) 0.9700 C(38)-H(38B) 0.9700
C(7) -H 7B) 0.9700 C(23)-C (28) 1.359 (10)
Table 8--Bond angles [ (deg)]
Atom-atom-atom Angle Atoin-atom-atom Angle
C(36)-N(1)-C(5) 115,9(4) C(17)-C(16)-C(15) 120.6(7)
C(36)-N(1)-H(1B) 105 (4) C(21)-C(16)-C(15) 121.2(7)
C(5)-N(1) -H(1B) 108 (4) C(18)-C(17)-C(16) 123.6(9)
C(1)-O(1)-H(lE) 108 (5) C(l8)-C(17)-H(17A) 118.2
C(8)-O(2)-C(7) 113.1(4) C(16)-C(17)-H(17A) 118.2
C(15)-O(3)-C(2) 115.6(5) C(19)-C(18)-C(17) 118.7(10)
C(22)-O(4)-C(3) 116.4 (4) C(19)-C(18)-H(18A) 120.7
C(29)-O(5)-C(4) 114.3(5) C(17)-C(18)-H(18A) 120.7 C(37)-O(6)-H(6E) 121(5)
C(18)-C(19)-C(20) 125.7(10)
C(38)-O(7)-H(7E) 112 (5) C(18)-C(19)-H(19A) 117.2
O(l)-C(1) -C(7) 105.8 (4) C(20)-C(19)-H(19A) 117.2
O(1)-C(1) -C(6) 111.5 (4) C(19)-C(20)-C(21) 115.7(8)
O(7)-C(1) -C(6) 110.9(4) C (19)-C (20)-H(20A) 122.2
O(1)-C(1) -C(2) 110.7 (4) C(21)-C(20)-H(20A) 122.2
C(7)-C(1) -C(2) 111.1 (4) C(16)-C(21)-C(20) 118.1(8)
C(6)-C(1)-C(2) 107.0 (4) C(16)-C(21)-H(21A) 120.9
O(3)-C(2)-C(3) 111.8(4) C(20)-C(21)-H(21A) 120.9
O(3)-C(2) -C(1) 110.6 (4) O(4)-C(22)-C(23) 110.7(5)
C(3)-C(2) -C(l) 111.4(4) O(4)-C(22)-H(22A) 109.5
O(3)-C(2) -H(2A) 107.6 C(23)-C(22)-H(22A) 109.5
C(3)-C(2) -H(2A) 107.6 O(4)-C(22)-H(22B) 109.5
C(1)-C(2) -H(2A) 107.6 C(23)-C(22)-H(22B) 109.5
O(4)-C(3) -C(2) 109.8 (4) H(22A)-C(22)-H(22B) 108.1
0(4)-C(3 -C(4) 107.6 (4) C(28)-C(23)-C(24) 118.2(7)
C(2)-C(3)-C(4) 110.4(4) C(28)-C(23)-C(22) 119.6(7)
O(4)-C(3) -H(3A) 109.7 C(24)-C(23)-C(22) 122.2(6)
C(2)-C(3) -H(3A) 109.7 C(23)-C(24)-C(25) 120.7(7)
C(4)-C(3) -H(3A) 109.7 C(23)-C(24)-H(24A) 119.7
O(5)-C(4)-C(3) 107.0(4) C(25)-C(24)-H(24A) 119.7
O(5)-C(4)-C(5) 110.6(4) C(26)-C(25)-C(24) 118.8(9)
C(3)-C(4)-C(5) 116.4(4) C(26)-C(25)-H(25A) 120.6
0(5)-C(4)-H(4A) 107.5 C(24)-C(25)-H(25A) 120.6
C(3)-C(4)-H(4A) 107.5 C(27)-C(26)-C(25) 120.7(9)
C(5)-C(4)-H(4A) 107.5 C(27)-C(26)-H(26A) 119.7
N(1)-C(5)-C(4) 110.6(4) C(25)-C(26)-H(26A) 119.7
N(1)-C(5)-C(6) ~110.4(4) C(26)-C(27)-C(28) 120.8(9)
-_--- - T_-
C(4)-C(5)-C(6) 110.5(4) C(26)-C(27)-H(27A) 119.6
N(1)-C(5)-H(5A) , 108.4 ~ C(28)-C(27)-H(27A) 119.6 - ~~
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C(4)-C(5)-H(5A) 108.4 C(23)-C(28)-C 27) 120.6(9)
C(6)-C(5)-H(5A) 108.4 C(23)-C(28)-H(28A) 119.7
C(1)-C(6)-C(5) 112.7(4) C(27)-C(28)-H(28A) 119.7
C(1)-C(6)-H(6A) 109.0 O(5)-C(29)-C(30) 109.6(6)
C(5)-C(6)-H(6A) 109.0 O(5)-C(29)-H(29A) 109.7
C(1)-C(6)-H(6B) 109.0 C(30)-C(29)-H(29A) 109.7
C(5)-C(6)-H(6B) 109.0 O(5)-C(29)-H(29B) 109.7
H(6A)-C(6)-H(6B) 107.8 C(30)-C(29)-H 29B) 109.7
O(2)-C(7)-C(1) 109.7(4) H(29A)-C(29)-H(29B) 108.2
O(2)-C(7)-H(7A) 109.7 C(35)-C(30)-C(31) 122.4(8)
C(1)-C(7)-H(7A) 109.7 C(35)-C(30)-C(29) 118.8(8)
O(2)-C(7)-H(7B) 109.7 C(31)-C(30)-C(29) 118.6(8)
C(1)-C(7)-H(7B) 109.7 C(32)-C(3l)-C(30) 121.6(12)
H(7A)-C(7)-H(7B) 108.2 C(32)-C(31)-H(31A) 119.2
O(2)-C(8)-C(9) 109.9(5) C(30)-C(31)-H(31A) 119.2
O(2)-C(8)-H(8A) 109.7 C(31)-C(32)-C(33) 115.9(13)
C(9)-C(8)-H(8A) 109.7 C(31)-C(32)-H(32A) 122.0
O(2) -C(8) -H(8B) 109.7 C(33)-C(32)-H(32A) 122.0
C(9)-C(8)-H(8B) 109.7 C(32)-C(33)-C(34) 129.8(12)
H(8A)-C(8)-H(8B) 108.2 C(32)-C(33)-H(33A) 115.1
C(14)-C(9)-C(10) 118.8(7) C(34)-C(33)-H(33A) 115.1
C(14)-C(9)-C(8) 121.6(6) C(33)-C(34)-C(35) 108.0(10)
C(10)-C(9)-C(8) 119.7(7) C(33)-C(34)-H(34A) 126.0
C(9)-C(10)-C(11) 121.1(8) C(35)-C(34)-H(34A) 126.0
C(9)-C(10)-H(10A) 119.4 C(30)-C(35)-C(34) 122.1(10)
C(1I)-C(10)-H(l0A) 119.4 C(30)-C(35)-H(35A) 119.0
C(10)-C(11)-C(12) 119.6(8) C(34)-C(35)-H(35A) 119.0
C(10)-C lI)-H(11A) 120.2 N(l) -C(36) -C(37) 107.5(5)
C(I2)-C(Il)-H(11A) 120.2 N(1)-C(36)-C(38) 115.8(5)
C(13)-C(12)-C(11) 118.4(8) C(37)-C(36)-C(38) 110.6(5)
C(13)-C(12)-H(12A) 120.8 N(1)-C(36)-H(36A) 107.6
C(11)-C(12)-H(12A) 120.8 C(37)-C(36)-H(36A) 107.6
C(14)-C(13)-C 12) 120.1(9) C(38)-C(36)-H(36A) 107.6
C(14)-C(13)-H(13A) 119.9 O(6)-C(37)-C(36) 110.1(6)
C(12)-C(13)-H(13A) 119.9 O(6)-C(37)-H(37A) 109.6
C(9)-C(14)-C(13) 122.0(7) C(36)-C(37)-H(37A) 109.6
C(9)-C(14)-H(14A) 119.0 O(6)-C(37)-H(37B) 109.6
C(l3)-C(14)-H(14A) 119.0 C(36)-C(37)-H(37B) 109.6
O(3)-C(15)-C(16) 113.2(6) H(37A)-C(37)-H(37B) 108.2
O(3)-C(15)-H(15A) 108.9 O(7)-C(38)-C(36) 112.1(5)
C(16)-C(15)-H(15A) 108.9 O(7)-C(38)-H(38A) 109.2
O(3)-C(15)-H(15B) 108.9 C(36)-C(38)-H(38A) 109.2
C(16)-C(15)-H(15B) 108.9 O(7)-C(38)-H(38B) 109.2
H(15A)-C(15)- 107.7 C(36)-C(38)-H(38B) 109.2
H(15B)
C(17)-C(16)-C(21) 118.1(7) H(38A)-C(38)-H(38B) 1079
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Table 9--Torsion angles [ (de )]
Atom-atom-atom-atom Angle Atom-atom-atom-atom Angle
C(15) -0(3) -C(2) -C(3) 93.1(7) C(10) -C(9) -C(14) -C(13) 0.3(12)
C(15) -0(3) -C(2) -C(1) -142.2 (6) C(8) -C(9) -C(14) -C(13) 179.9 (7)
0(1) -C(1) -C(2) -0(3) -66.1(5) C(12)-C(13)-C(14)-C(9) -0.5(14)
C(7) -C(l) -C(2) -0(3) 51.2 (6) C(2) -0(3) -C(15) -C(16) 151.8(7)
C(6) -C(1) -C(2) -0(3) 172.3(4) 0(3) -C(15) -C(16) -C(17) -62. 6 (11)
0(1) -C(1) -C(2) -C(3) 58.9 (5) 0(3) -C(15) -C(16) -C(21) 119. 3 (8)
C(7) -C(l) -C(2) -C(3) 176.1(4) C(21)-C(16) -C(17) -C(18) o .2 (11)
C(6) -C(1) -C(2) -C(3) -62.8(5) C(15)-C(16) -C(17) -C(18) -178.0(8)
C(22) -0(4) -C(3) -C(2) 127.2(5) C(16)-C(17)-C(18)-C(19) 1.8(14)
C (22) -0(4) -C(3) -C(4) -1 12 .6 (5) C(17) -C(18) -C(19)-C(20) -4.2(15)
0(3) -C(2) -C(3) -0(4) -60.8 (5) C(18)-C(19) -C(20) -C(21) 4.0(13)
C(1) -C(2) -C(3) -0(4) 175.0(4) C(17)-C(16)-C(21)-C(20) -0.3(9)
0(3) -C(2) -C(3) -C(4) -179.2(4) C(15)-C(16) -C(21) -C(20) 177.9(6)
C(1) -C(2) -C(3) -C(4) 56 .5(6) C(19)-C(20)-C(21)-C(16) -1.7 (10)
C (29) -0(5) -C(4) -C(3) -159.2(6) C(3) -0(4) -C(22) -C(23) 168.8 (5)
C(29) -0(5) -C(4) --C(5) 73. 1(7) 0(4)-C(22)-C (23) -C (28) -143.2 (7)
0(4) -C(3) -C(4) -0(5) 67.9(5) 0(4) -C(22) -C(23) -C(24) 38.7 (9) C(2) -C(3) -
C(4) -0(5) -172.3(4) C(28)-C(23) -C(24) -C(25) 2.6(11)
0(4) -C(3) -C(4) -C(5) -167.8(4) C(22)-C(23)-C(24)-C(25) -179.3(7)
C(2) -C(3) -C(4) -C(5) -48.1(6) C(23)-C(24)-C(25)-C(26) -0.4 (14)
C(36) -N(1) -C(5) -C(4) -162.5(4) C(24)-C(25)-C(26)-C(27) -3.4 (15)
C(36) -N(1) -C(5) -C(6) 74.9 (5) C(25)-C(26) -C(27) -C(28) 4.8(17)
0(5) -C(4) -C(5) -N(1) 45.3(5) C(24)-C(23) -C(28) -C(27) -1.3 (12)
C(3) -C(4) -C(5) -N(1) -77.1(5) C(22)-C(23) -C(28) -C(27) -179.4 (8)
0(5) -C(4) -C(5) -C(6) 167.8(4) C(26)-C(27) -C(28) -C(23) -2.5(16)
C(3) -C(4) -C(5) -C(6) 45.5(6) C (4)-0(5) -C (29) -C (30) 155.2(6)
0(1) -C(1) -C(6) -C(5) -60.5(6) 0(5) -C(29) -C(30) -C(35) 118.7(8)
C(7) -C(1) -C(6) -C(5) -178.2 (5) 0(5) -C(29) -C(30) -C(31) -66.3 (10)
C(2) -C(1) -C(6) -C(5) 60.6(6) C(35)-C(30) -C(31) -C(32) -1.1(13 )
N(1) -C(5) -C(6) -C(1) 70.7(6) C(29)-C(30) -C(31) -C(32) -175.9(8)
C(4) -C(5) -C(6) -C(1) -52 . 0 (6) C(30)-C(31) -C(32) -C(33) 2.7(14)
C(8) -0(2) -C(7) -C(1) 171.0 (5) C(31)-C(32) -C(33) -C(34) -4.8(19)
0(1) -C(l) -C(7) -0(2) -177.2(4) C(32)-C(33) -C(34) -C(35) 4.2(18)
C(6) -C(1) -C(7) -0(2) -56.2 (6) C(31)-C(30) -C(35) -C(34) 0.7(12)
C(2) -C(1) -C(7) -0(2) 62.6 (6) C(29)-C(30) -C(35) -C(34) 175.5 (8)
C(7) -0(2) -C(8) -C(9) -171 .9(5) C(33)-C(34) -C(35) -C(30) -2.0(14)
0(2) -C(8) -C(9) -C(14) -42 .9 (9) C(5) -N(1) -C(36) -C(37) 170.8 (5)
0(2) -C(8) -C(9) -C(10) 136.8(6) C(5) -N(1) -C(36) -C(38) 46.7 (7) ~
C(14)-C (9)-C(10)-C(1 1) -0.2(11) N(1) -C(36) -C(37) -0(6) 172 .6(6)
C(8)-C(9)-C(10)-C(11) ~ -179.9(7) C(38) -C(36) -C(37) -0(6) -60 .2 (7)
C(9)-C(10)-C (I1)-C(l2 ) 0.4 (13) N(l) -C(36) -C(38) -0(7) 53 .3(7) ~
C(10) C(11) C(12) C(l3) 0.6(14) C(37) -C(36) C(38) -0(7) 6 ~~._(7)
C(11)-C(12)-C(I3)-C(14) 0.7 (14) - - - ~
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Table 10--Hydrogen-bond lengths [A ] and angles [ (deg)]
D-H===A d (D-H) d(H===A) d(D===A) angles (DHA)
O(7)-H(7E) ... 0(1)#1 0.914(11) 1.931 18) 2.837(5) 171(8)
O(6)-H(6E) ... 0(7)#2 0.911(11) 1.98(3) 2.836(7) 156(6)
O(1)-H(lE) ... N(1) 0.907(11) 1.98(4) 2.810(6) 151(7)
Preparation of voglibose
Example 7
A process route for preparation of voglibose by use of the tetra-benzyl
voglibose is shown in Fig. 10. The above prepared tetra-benzyl voglibose in
crystalline form (3.0g, 4.8mmol) was dissolved into 90% of formic acid
/methanol
(1:19, 60mL), into which palladium black (0.6g) was added, reacting for 12
hours at
room temperature in the nitrogen atmosphere. The reaction product was filtered
and
was washed by 20mL of methanol/water (1:1). The filtrate was concentrated. The
residue was absorbed by strong-acid ion exchange resin (250mL), and washed by
water, then eluted by 0.5N of ammonia. After the elute was concentrated, 50mL
of
anhydrous alcohol was added, boiled, and cooled down slightly, into which
active
carbon was added, heated for another 10 minutes, and then filtered. The
filtrate was
cooled down naturally to room temperature to produce white crystal. It was set
aside
for 1-3 hours at the temperature of 0-5C, filtered, washed with a small
quantity of
anhydrous alcohol, and dried for 12 hours under vacuum to obtain 1.1g of white
crystal with purity of 99.9% by HPLC. Mp: 164-166 C. It is proved that
spectral data
of the structure are consistent with those reported.
Of course, the present invention can have other embodiments. Modifications,
variations or adaptations of the invention can be made within the principles
of the
invention. This application is intended to cover such departures from the
present
disclosure as come within known or customary practice in the art to which this
invention pertains and which fall within the limits of the appended clainis.
INDUSTRIAL APPLICATION
The tetra-benzyl voglibose in crystalline form is easier to be preserved and
transported, and is more convenient to be taken out and weighed in use, thus
being
easier for niaterial charging and operation during the production than the
tetra-benzyl
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voglibose in oily form. At the same time, due to generally higher purity and
higher
content of the tetra-benzyl voglibose in crystalline form than the tetra-
benzyl
voglibose in oily form, less impurity will be introduced or produced during
reaction
when preparing voglibose by use of it. Higher quality of voglibose can be
produced
by use of this crystal, thus voglibose being prepared into a dosage form will
have
better effect of treatment and less side-effect.
19
