CA2654424A1

CA2654424A1 - Tetra-benzyl voglibose in crystalline form and a method for preparing the same

Info

Publication number: CA2654424A1
Application number: CA002654424A
Authority: CA
Inventors: Ligang Liu; Ruiwen Li
Original assignee: Individual
Current assignee: PHARMAXYN LABORATORIES Ltd
Priority date: 2006-07-17
Filing date: 2007-06-18
Publication date: 2008-01-31
Also published as: KR101379988B1; KR20090031376A; WO2008011791A1; JP2009543814A; CN1931826A; JP5216006B2; CN100393694C

Abstract

The present invention provides crystalline tetrabenzyl voglibose with the following physical properties: there are peaks at 2.theta.=16.84±0.20°C, 18.99±0.20°and 24.11±0.20°of its Cu X-ray powder diffraction spectrum, and its melting point is 88.0°C~90.8°C. The present invention also provides a method for preparing the said crystal and a method of using the said crystal to prepare voglibose with high purity. Since the crystalline tetrabenzyl voglibose has higher purity and content than the oily tetrabenzyl voglibose, it can be stored and transported more easily, can be fetched and weighed more conveniently and when it is used to prepare voglibose, less impurity would be introduced or produced in the reaction.

Description

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 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 ~

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.

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 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 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;

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 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 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 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:

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

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 -1~

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) 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) 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 - ~~

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 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) - - - ~

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 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.

Claims

1. A tetra-benzyl voglibose in crystalline form having the following molecular structure:

characterized by the following physical property:
in Cu X-ray powder diffraction, there are characteristic peaks where 2.theta.
is 16.84~0.20°, 18.99~0.20° and 24.11~0.20°.

2. The tetra-benzyl voglibose in crystalline form as claimed in claim 1, characterized in that in Cu X-ray powder diffraction, there are further characteristic peaks where 2.theta. is 8.39~0.20°, 11.91~0.20°, 22.11~0.20°, 23.37~0.20°, 24.53~0.20°, 25.63~0.20° and 25.99~0.20°.

3. The tetra-benzyl voglibose in crystalline form as claimed in claim 1, characterized in that endothermic value of the tetra-benzyl voglibose is about 89.7°C
in differential scanning calorimetry analysis.

4. The tetra-benzyl voglibose in crystalline form as claimed in claim 1, characterized in that infrared spectrum of the tetra-benzyl voglibose in crystalline form is as shown in Fig. 9 in the infrared spectrum analysis.

5. The tetra-benzyl voglibose in crystalline form as claimed in claim 1, characterized in that melting point of the tetra-benzyl voglibose in crystalline form is 88.0~90.8°C .

6. The tetra-benzyl voglibose in crystalline form as claimed in claim 1, characterized in that single crystal of said tetra-benzyl voglibose in crystalline form has a molecular stereo-structure as shown in Fig. 5 in single crystal X-ray diffraction.

7. The tetra-benzyl voglibose in crystalline form as claimed in claim 1, characterized in that said tetra-benzyl voglibose in crystalline form belongs to orthorhombic system among the space group P2(1)2(1)2(1), and unit cell parameters are a=7.8487.ANG., b=20.746.ANG., c=20.988.ANG., and R value=0.0748.

8. The tetra-benzyl voglibose in crystalline form as claimed in claim 1, characterized in that molecules of said tetra-benzyl voglibose in crystalline form are linked with each other by force of hydrogen bond.

9. The tetra-benzyl voglibose in crystalline form as claimed in claim 1, characterized in that content of said tetra-benzyl voglibose in crystalline form is more than 95%.

10. A method for preparing tetra-benzyl voglibose in crystalline form, which comprises the following steps:
step 1) dissolving tetra-benzyl voglibose in oily form into polar nonprotic solvent, wherein the volume-to-weight ratio of said polar nonprotic solvent to said tetra-benzyl voglibose in oily form is 0.5~5:1;
step 2) adding nonpolar solvent into the said solution of tetra-benzyl voglibose to produce crystal while stirred at room temperature, wherein the volume-to-weight ratio of said nonpolar solvent to said tetra-benzyl voglibose in oily form is 2~20:1;
step 3) after cooling down, filtering and drying so as to obtain the tetra-benzyl voglibose in crystalline form.

11. The method as claimed in claim 10, characterized in that in step 1), said polar nonprotic solvent is one or more selected from the group consisting of ethyl acetate, isopropyl ether, ethyl ether and tetrahydrofuran.

12. The method as claimed in claim 11, characterized in that said polar nonprotic solvent is ethyl acetate and/or isopropyl ether.

13. The method as claimed in claim 10, characterized in that in step 1), said volume-to-weight ratio of said polar nonprotic solvent to said tetra-benzyl voglibose in oily form is 1~3:1.

14. The method as claimed in claim 10, characterized in that in step 2), said nonpolar solvent is one or more selected from the group consisting of cyclohexane, n-hexane, carbon tetrachloride and petroleum ether.

15. The method as claimed in claim 14, characterized in that said nonpolar solvent is cyclohexane and/or n-hexane.

16. The method as claimed in claim 10, characterized in that in step 2), said volume-to-weight ratio of said nonpolar solvent to said tetra-benzyl voglibose in oily form is 2~10:1.

17. The method as claimed in claim 10, characterized in that in step 3), setting the solution aside for 1 to 5 hours, then setting aside for 1 to 5 hours at temperature of 0°C to 5°C, drying the crystal after filtration for 10 to 12 hours in vacuum to obtain the tetra-benzyl voglibose in crystalline form.

18. A method for preparing voglibose, characterized in that the voglibose is prepared by use of said tetra-benzyl voglibose in crystalline form as claimed in claim 1.