KR20090031376A - Crystalline tetrabenzyl voglibose and their preparation - Google Patents

Abstract

The present invention provides crystalline tetrabenzyl voglibose with the following physical properties: there are peaks at 2Theta=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

Tetrabenzyl bogglibose in crystalline phase and its preparation method {CRYSTALLINE TETRABENZYL VOGLIBOSE AND THEIR PREPARATION}

The present invention relates to tetrabenzyl boglybose in the crystalline phase and to a process for producing tetrabenzyl boglybose in the crystalline phase.

Bogliose, an alpha-glucosidase inhibitor developed by Takeda Pharmaceutical Company (Japan) (EP56194), is used for the treatment of diabetes and is currently available in Japan, Korea, and China. . It has a molecular structure of formula (1).

Boglybose's chemical name

(1S)-(1 (OH), 2,4,5 / 1, 3) -5-[(2-hydroxy-1- (hydroxymethyl) ethyl) amino] -1-C-hydroxymethyl- 1,2,3,4-cyclohexanetetrol ((1S)-(1 (OH), 2,4,5 / 1, 3) -5-[(2-hydroxy-1- (hydroxymethyl) ethyl) amino ] -1-C-hydroxymethyl-1,2,3,4-cyclohexanetetrol). There are several methods for the production of bolibos, the earliest method being the chemical synthesis of bolibos by the use of valienamine produced by fermentation of raw materials (EP56194). However, the process for the preparation and separation of the valenamine is complex, requires considerable manpower and energy consumption, and it is difficult to remove impurities in the product obtained by this method, which is complicated column chromatography for purification. Is required. Later, European Patent No. EP260121, J. Org. Chem. Some methods of telesynthesis by using D-glucose as a raw material as described in 1992, 57, 3651, WO 03/080561 and WO 2005/030698 Are present.

Among these, one typical process procedure is described in EP 260 121 and in J. Org. Chem. The same process as published in 1992, 57, 3651 (FIG. 10). In this step, (1S)-(1 (OH), 2,4,5 / 1,3) -2,3,4-tri-O-benzyl-5-[(2- Hydroxy-1- (hydroxymethyl) ethyl) amino] -1-C-benzyloxymethyl-1,2,3,4-cyclohexanetetrol ((1S)-(1 (OH), 2,4, 5 / 1,3) -2,3,4-tri-O-benzyl-5-[(2-hydroxy-1- (hydroxymethyl) ethyl) amino] -1-C-benzyloxymethyl-1,2,3,4 -cyclohexanetetrol (hereinafter referred to as 'tetrabenzyl boglybose') is a key intermediate, and vogliose is produced directly by the tetrabenzyl boglybose through debenzylation. Therefore, its quality directly affects the quality of Boglybose, a drug for the treatment of diabetes.

The intermediate described in both current documents and methods (such as European Patent Nos. EP260121, J. Org. Chem. 1992, 57, 3651, and WO 2005/030698, etc.), etc. Is the product of (oily product).

Tetrabenzyl bogglibose in oil form is difficult to store and transport, is not easy to take in use and weighs, and is inconvenient to change materials and to work during manufacture. At the same time, due to the low purity and content of the tetrabenzyl boglybose in the oil form, impurities are easily introduced or produced during the reaction when making it using the same, which makes it difficult to produce high quality boglybose. .

In order to overcome the shortcomings of the current oil form tetrabenzyl boglybose, a technical problem to be solved by the present invention is to provide tetrabenzyl boglybose in crystalline phase and a method for preparing the same.

During the study of the manufacturing process of bolibos, we discovered and prepared the core intermediate tetrabenzyl boliboss. Typically, all the literature and information of the prior art said tetrabenzyl bogglibose appeared only as an oily substance. Through the study of this material, tetrabenzyl boglybose in crystalline form was successfully obtained. Crystals of this kind are stable in their crystalline state under normal conditions under room temperature.

Tetrabenzyl boglybose in the crystalline form can be used for the preparation of boglybose, a high purity alpha-glucosidase inhibitor, and is easy to store, transport and work in the preparation. This manufacturing method has the advantages of less processes, conventional and obtainable reagents, less contamination, simple operation and high purity products.

The present invention also provides a process for the preparation of boglybose by the use of tetrabenzyl boglybose in the above crystalline form. The content of boglybose produced by this crystal can reach up to 99.9%. Dosage forms made with such boligose may have higher therapeutic effect and fewer side effects.

Accordingly, the present invention provides tetrabenzyl boglybose in crystalline form having the following physical properties:

In the Cu X-ray powder diffraction map, there are characteristic peaks with 2θ of 16.84 ± 0.20 °, 18.99 ± 0.20 ° and 24.11 ± 0.20 °.

The melting point of tetrabenzyl boglybose in crystalline form is 88.0 to 90.8 ° C.

Furthermore, in the copper X-ray powder diffraction plot, the characteristic peaks of tetrabenzyl boglybose in the crystalline form of the present invention have a 2θ of 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 °.

The endothermic peak value of the differential scanning calorimeter of tetrabenzyl boglybose of the present invention is about 89.7 ° C.

In single crystal X-ray diffraction, the single crystal of tetrabenzyl boglybose in the crystalline form has a molecular stereo-structure as shown in FIG.

Moreover, the tetrabenzyl bogglibose of the crystalline form belongs to the orthorhombic system among the space groups of P2 (1) 2 (1) 2 (1), and the unit cell parameters are a = 7.8487 ms, b = 20.746 ms, c = 20.988 ms and R value = 0.0748.

The molecules of the tetrabenzyl boglybose in the crystalline form are connected to each other by the force of hydrogen bonding.

In the analysis of the infrared spectrum, tetrabenzyl bogglibose in the crystalline form exhibits its infrared spectrum as shown in FIG. 9.

The content of tetrabenzyl boglybose in the crystalline form provided through the method of the present invention may be 95% or more, in particular the content may be between 95 and 99.5% by high performance liquid chromatography (HPLC), This is markedly higher than the content of tetrabenzyl boglybose in oil form.

The present invention also provides a process for the preparation of tetrabenzyl boglybose in crystalline form. In this process, the first step is to dissolve tetrabenzyl boglybose in oil form in a solvent in polar aprotic form, such as ethyl acetate, isopropyl ether, ethyl ether or tetrahydrofuran. The second step is the addition of other types of nonpolar solvents such as cyclohexane, normal-hexane, carbon tetrachloride or petroleum ether. Subsequently, the solution is stirred at room temperature to produce crystals, and then, after sufficiently cooling, the solution is filtered and dried to obtain tetrabenzyl boglybose in the crystalline form of the present invention.

In particular, the preparation method dissolves 1 part of tetrabenzyl boglybose in oil form in 0.5 to 5 parts (volume to weight ratio), preferably 1 to 3 parts, of a polar aprotic solvent; Then, 2 to 20 parts (volume to weight ratio) of one or more nonpolar solvents are added, preferably 2 to 10 parts. The polar aprotic solvent may be selected from the group consisting of ethyl acetate, isopropyl ether, ethyl ether and tetrahydrofurans, preferably ethyl acetate and / or isopropyl ether; The nonpolar solvent may be selected from the group consisting of cyclohexane, normal-hexane, carbon tetrachloride and petroleum ethers, preferably cyclohexane and / or normal-hexane. Subsequently, crystals are produced by stirring the obtained solution at room temperature. Subsequently, it is cooled, filtered and dried. For example, the obtained solution is first left to cool for 1 to 5 hours, then it is left to stand for 1 to 5 hours at a temperature of 0 to 5 ° C., and the solution is filtered to filter the crystals in a vacuum. Dry for 10-12 hours. The above crystals of the tetrabenzyl boglybose can be obtained.

Subsequent debenzylation allows the preparation of high purity boglybose with the advantages of the tetrabenzyl boglybose obtained above.

By testing the single crystal state and the powder state of the crystal, the features and characteristics of the crystal of the present invention are defined below. Accordingly, single crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry (DSC) analysis, infrared (IR) spectra and data of tetrabenzyl boglybose in the above crystalline form according to the present invention are described for explanation.

Testing of single crystal X-ray diffraction of the crystal indicates that the empirical formula is C ₃₈ H ₄₅ NO ₇ ; It belongs to the tetragonal system among the space groups of P2 (1) 2 (1) 2 (1), whose unit lattice factors are a = 7.8487 Å, b = 20.746 Å, c = 20.988 Å and R value = 0.0748. In general, the crystal also has its powder X-ray diffraction data, in particular X-ray diffraction peaks with 2θ of 16.84 ± 0.20 °, 18.99 ± 0.20 ° and 24.11 ± 0.20 °, in particular 2θ of 8.39 ± 0.20 °, 11.91 ± 0.20 Can be specified by X-ray diffraction peaks at 22.11 ± 0.20 °, 23.37 ± 0.20 °, 24.53 ± 0.20 °, 25.63 ± 0.20 ° and 25.99 ± 0.20 °.

Moreover, the crystal can be characterized by endothermic properties through a differential scanning calorimeter, the endothermic value of which is 89.7 ° C.

Advantageous effects of the present invention include the following; Tetrabenzyl boglybose in the crystalline form is easy to store and transport, take it in use, and is easy to weigh, thus making it easier to modify and work with materials during manufacture compared to tetrabenzyl boglybose in oil form. Do. At the same time, due to the high purity and high content of tetrabenzyl boglybose in crystalline form as compared to tetrabenzyl boglybose in oil form, less impurities can be introduced or produced during the reaction when making it to be used. . By taking advantage of such a determination, higher purity boliboses can be produced, and therefore, bolibos, prepared in dosage form, can have a higher therapeutic effect and fewer side effects.

Although more details of the invention may be included in the following figures and embodiments, the description of these embodiments should not be understood as limiting the aspects of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an X-ray powder diffraction diagram of tetrabenzyl boglybose in the crystalline form of Example 2 according to the present invention.

FIG. 2 is an X-ray powder spinning plot of tetrabenzyl boglybose in crystalline form of Example 3 according to the present invention. FIG.

FIG. 3 is an X-ray powder rotating plot of tetrabenzyl boglybose in crystalline form of Example 4 according to the present invention.

FIG. 4 is an X-ray powder rotating plot of tetrabenzyl boglybose in crystalline form of Example 5 according to the present invention.

FIG. 5 is a diagram showing the molecular conformation of tetrabenzyl bolibos in crystalline form by single crystal X-ray diffraction according to the present invention.

FIG. 6 is a view showing molecular unit cell packing of tetrabenzyl bogliboss in crystalline form according to the present invention. FIG.

7 is a schematic diagram of the molecules of tetrabenzyl boglybose in crystalline form having molecules connected to each other by the force of hydrogen bonding according to the present invention.

8 is a diagram for the differential scanning calorimetry of tetrabenzyl boglybose in crystalline form according to the present invention.

FIG. 9 is an infrared spectrogram of tetrabenzyl bogliboss in crystalline form according to the present invention. FIG.

FIG. 10 is a process flow diagram for the production of boliboses with the advantage of tetrabenzyl bogglibose in crystalline form according to the invention.

Detailed Description of the Preferred Embodiments

The raw materials used in the following embodiments are all obtainable on the market unless otherwise indicated in the present document.

Preparation of Tetrabenzyl Boglybose in Oil Form

Example 1 Preparation of Tetrabenzyl Boglybose in Oil Form (as in the production process described in J. Org. Chem. 1992, 57, 3642)

(1S)-(1 (OH), 2,4,5 / 1,3) -2,3,4-tri-O-benzyl-1-C-benzyloxymethyl-5-O-1,2,3 , 4-cyclohexanetetrol ((1S)-(1 (OH), 2,4,5 / 1,3) -2,3,4-tri-O-benzyl-1-C-benzyloxymethyl-5-O -1,2,3,4-cyclohexanetetrol (6.0 g, 10.8 mmol) and 2-amino-1,3-propanediol (3.0 g, 33 mmol) are dissolved in 30 ml of methanol and placed there at room temperature As a batch, sodium cyanoborohydride (1.5 g, 24 mmol) was added. The reaction solution was concentrated. The residue was dissolved in 300 ml of ethyl acetate, washed with 100 ml of water, then washed twice with 100 ml of 1% hydrochloric acid solution, washed twice with 100 ml of 5% sodium carbonate solution, Washed with 100 ml brine and dried over anhydrous sodium sulfate. Ethyl acetate was recovered and the residue was subjected to silica gel (150 mL) column chromatography eluting with ethyl acetate. The composition containing ethyl acetate was concentrated to give 5.2 g of a straw yellow oily material having a content of 89.4% by high performance liquid chromatography.

Preparation of Tetrabenzyl Boglybose in Crystal Form

Example 2

1 g of tetrabenzyl boglybose (prepared in Example 1) in oil form was dissolved in 2.5 ml of ethyl acetate, and 6 ml of cyclohexane was added thereto while stirring. The solution was then stirred at room temperature for 1.5 hours to produce white crystals. It was left at room temperature for 5 hours and then left at a temperature of 0-5 ° C. for 5 hours. After filtration, the crystals were dried under vacuum at room temperature for 12 hours to give 0.76 g of white crystals having a content of 98.5% by high performance liquid chromatography. Melting point: 88.2 to 90.8 ° C .; [α] ²² _D + 30.8 ° (cl, chloroform); Proton nuclear magnetic resonance spectroscopy ( ¹ H NMR) (CDCl ₃ , 500 Hz), δ: 1.63 (1H, dd, J = 2.8, 15.1 Hz), 1.91 (1H, dd, J = 2.9, 15.1 Hz), 2.78 (1H, m), 3.19 (1H, d, J = 8.6 Hz), 3.39 (1H, m), 3.54 (1H, d, J = 8 Hz), 3.62-3.73 (6H, m), 4.13 (1H, t, J = 9.6 Hz), 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).

The crystal powder was analyzed by using a copper target X-ray diffractometer (D / max-2500 / PC, RIGAKU INTERNATIONAL CORP., Japan) (Nanjing Normal University). Experiment by))). The conditions of diffraction are as follows:

Divergence: 1 °

Receiving Slit: 0.3mm

Scattering degree: 1 °

Voltage: 40 ㎸, Current: 100 ㎃

Scanning speed: 5 ° / min, time interval 0.02 ° (deg)

1 is an X-ray powder diffraction diagram of tetrabenzyl boglybose in crystalline form, and the data of X-ray powder diffraction is shown in Table 1 (data of X-ray powder diffraction of tetrabenzyl boglybose in crystalline form).

number 2θ value d value I / I _o value One 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 10 26.00 3.4242 11

Example 3

3.0 g of tetrabenzyl boglybose (prepared in Example 1) in oil form was dissolved in 10 ml of isopropylether, and 25 ml of normal-hexane was added thereto while stirring. The solution was then stirred at room temperature for 1 hour to produce crystals in powder form. It was left to stand again for 5 hours at room temperature and then left for 5 hours at a temperature of 0 to 5 ° C. Subsequently, after filtration, the crystals were dried under vacuum at room temperature for 12 hours to obtain 2.5 g of white crystals having a content of 98.7% by high performance liquid chromatography. Melting point: 88.5 to 90.7 ° C .; [α] ²² _D + 30.6 ° (cl, chloroform). Its proton nuclear magnetic resonance spectroscopy data was the same as that of Example 2.

The crystal powder was analyzed by using a copper target X-ray diffractometer (D / max-2500 / PC, Rigaku International Corporation, Japan) (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 plot of tetrabenzyl boglybose in crystalline form, and the data of X-ray powder diffraction is shown in Table 2 (data of X-ray powder diffraction of tetrabenzyl boglybose in crystalline form).

number 2θ value d value I / I _o value One 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

Example 4

3.0 g of tetrabenzyl boglybose (prepared in Example 1) in oil form was dissolved in 1.5 ml of ethyl ether, and 6 ml of petroleum ether was added thereto while stirring. The solution was then stirred at room temperature for 1 hour to produce crystals. It was left to stand at room temperature again for 1 hour and then left at a temperature of 0 to 5 ° C for 1 hour. Subsequently, after filtration, the crystals were dried under vacuum at room temperature for 10 hours to give 2.3 g of white crystals having a content of 98.5% by high performance liquid chromatography. Melting point: 88.1 to 90.6 ° C .; [α] ²² _D + 30.5 ° (cl, chloroform). Its proton nuclear magnetic resonance spectroscopy data was the same as that of Example 2.

The crystal powder was analyzed by using a copper target X-ray diffractometer (D / max-2500 / PC, Rigaku International Corporation, Japan) (tested by Nanjing Normal University). . The conditions of diffraction were the same as those of Example 2. 3 is an X-ray powder diffraction plot of tetrabenzyl boglybose in crystalline form, and the data of X-ray powder diffraction is shown in Table 3 (data of X-ray powder diffraction of tetrabenzyl boglybose in crystalline form).

number 2θ value d value I / I _o value One 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 g of tetrabenzyl boglybose (prepared in Example 1) in oil form was dissolved in 10 ml of tetrahydrofuran, and 40 ml of carbon tetrachloride was added thereto while stirring. The solution was then stirred at room temperature for 1 hour to produce white crystals. It was left at room temperature for 5 hours and then left at a temperature of 0-5 ° C. for 5 hours. After filtration, the crystals were dried under vacuum at room temperature for 12 hours to give 1.2 g of white crystals having a content of 98.6% by high performance liquid chromatography. Melting point: 88.0 to 90.5 ° C .; [α] ²² _D + 30.7 ° (cl, chloroform). Its proton nuclear magnetic resonance spectroscopy data was the same as that of Example 2.

The crystal powder was analyzed by using a copper target X-ray diffractometer (D / max-IIIB, Rigaku International Corporation, Japan) (tested by Zhengzhou University). The conditions of diffraction are as follows:

Divergence: 1 °

Receiving Slit: 0.15mm

Scattering degree: 1 °

Voltage: 35 ㎸, Current: 30 ㎃

Scan speed: 4 ° / min, time interval 0.02 ° (deg)

4 is an X-ray powder diffraction diagram of tetrabenzyl boglybose in crystalline form, and the data of X-ray powder diffraction is shown in Table 4 (data of X-ray powder diffraction of tetrabenzyl boglybose in crystalline form).

number 2θ value d value I / I _o value One 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

Test of Tetrabenzyl Boglybose in Crystal Form

Example 6

A. Conditions of the test

1. Single Crystal X-ray Diffraction

Model of the instrument: AXIS-IV X-ray image-plate system (produced by Rigaku International Corporation, Japan)

2. Infrared Spectroscopy (IR)

NEXUS-470 infrared spectrometer (Nicolet), measured by KBr pellet method

3. Differential scanning calories

DSC204 Differential Scanning Calorimeter (NETZSCH)

Injection: 3 mg;

Temperature range: 30 to 200 ° C;

Heating rate: 3 ℃ / min

B. Sample to be tested

Tetrabenzyl Boglybose in Crystal Form Prepared According to Example 5

C. Results

Single crystal X-ray diffraction data indicates that the empirical formula is C ₃₈ H ₄₅ NO ₇ ; The crystals belong to the tetragonal system among the space groups of P2 (1) 2 (1) 2 (1), and the unit lattice factors were a = 7.8487 Å, b = 20.746 Å, c = 20.988 Å and R value = 0.0748. . Its molecular conformation is shown in FIG. 5. The perspective view of the unit grid packing in the direction A is shown in FIG. 7 shows that molecules are connected to each other by the force of hydrogen bonding. Tables 5 to 10 below show crystal data, atomic coordinates, bond lengths, bond angles, torsion angles and hydrogen bond lengths and angles, respectively.

FIG. 8 is a diagram of differential scanning calorimetry of tetrabenzyl boglybose in crystalline form. FIG. 8 shows that the endothermic characteristic will be an endothermic value of 89.7 ° C.

9 is an infrared spectrogram of tetrabenzyl boglybose in crystalline form.

Table 5 below shows those for crystal data and structure modifications.

Experimental formula C ₃₈ H ₄₅ NO ₇ Formula weight 627.75 Temperature 291 (2) K wavelength 0.71073Å Crystal system, space group Orthorhombic, P2 (1) 2 (1) 2 (1) Unit grid standard a = 7.8487 (16) Å, α = 90 ° b = 20.746 (4) Å, β = 90 ° c = 20.988 (4) Å, γ = 90 ° volume 3417.4 (12) Å ³ Calculated Density 4, 1.220mg / ㎥ Absorption coefficient 0.083 mm ^-1 F (000) 1344 Crystal size 0.20 * 0.18 * 0.18mm Theta (θ) range for data correction 1.38 to 25.00 ° Instruction range -9≤h≤9, -24≤k≤0, -24≤l≤24 Collected Fire Rate / Independent Fire Score (reflections collected / unique) 9647/3327 [R (int) = 0.0833 Completeness for theta (θ) = 25 97.3% Absorption correction Semi-empirical from equivalents Max and Min Projection 0.9852 and 0.9835 Refinement method Least squares around the matrix for the ^{F 2 (full-matrix least-} squares on F 2) Burst Score / Constraints / Parameters (data / restraints / parameters) 3327/3/432 Suitability for ^{F 2 (goodness-of-fit} on F 2) 1.051 Final R indices [I> 2 sigma (I)] R1 = 0.0748, wR2 = 0.1538 R indicators (all data) R1 = 0.1289, wR2 = 0.1740 Absolute structure parameter 0 (10) Extinction coefficient 0.0011 (6) Peak and hole deviations (largest diff. Peak and hole) 0.329 and-0.172e.Å ³

Table 6 below shows the atomic loci (* 10 ⁴ ) and equivalent isotropic displacement factors (Å ² * 10 ³ ). U (eq) is defined as one third of the trace amount of orthogonalized Uij.

atom X y z U (eq) N (1) 5785 (6) -985 (2) 9877 (2) 40 (1) O (1) 9116 (5) -631 (1) 10222 (2) 40 (1) 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) 101 (2) O (7) 2146 (5) -1327 (2) 9956 (2) 57 (1) C (1) 8413 (6) -50 (3) 10476 (2) 34 (1) 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) 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 (11) 7396 (13) 1763 (5) 13246 (4) 96 (3) C (12) 6883 (12) 2316 (5) 12911 (5) 103 (3) C (13) 7275 (13) 2360 (4) 12273 (4) 94 (3) C (14) 8130 (10) 1869 (4) 11977 (4) 72 (2) C (15) 10541 (9) 1324 (4) 9762 (6) 110 (4) C (16) 12286 (7) 1518 (3) 9942 (3) 43 (2) C (17) 12841 (10) 1457 (4) 10561 (4) 71 (2) C (18) 14385 (15) 1641 (4) 10758 (6) 109 (3) C (19) 15420 (11) 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 below shows the bond lengths.

Atom-atomic Length Atom-atomic Length Atom-atomic 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 O (1) -C (1) 1.429 (6) C (9) -C (14) 1.361 (9) C (25) -C (26) 1.376 (13) O (1) -H (1E) 0.907 (11) C (9) -C (10) 1.364 (9) C (25) -H (25A) 0.9300 O (2) -C (8) 1.409 (7) C (10) -C (11) 1.385 (12) C (26) -C (27) 1.315 (12) O (2) -C (7) 1.418 (7) C (10) -H (10A) 0.9300 C (26) -H (26A) 0.9300 O (3) -C (15) 1.400 (8) C (11) -C (12) 1.405 (13) C (27) -C (28) 1.384 (13) O (3) -C (2) 1.424 (6) C (11) -H (11A) 0.9300 C (27) -H (27A) 0.9300 O (4) -C (22) 1.390 (6) C (12) -C (13) 1.377 (13) C (28) -H (28A) 0.9300 O (4) -C (3) 1.434 (6) C (12) -H (12A) 0.9300 C (29) -C (30) 1.498 (9) O (5) -C (29) 1.425 (8) C (13) -C (14) 1.371 (11) C (29) -H (29A) 0.9700 O (5) -C (4) 1.446 (6) C (13) -H (13A) 0.9300 C (29) -H (29B) 0.9700 O (6) -C (37) 1.422 (8) C (14) -H (14A) 0.9300 C (30) -C (35) 1.319 (11) O (6) -H (6E) 0.911 (11) C (15) -C (16) 1.477 (9) C (30) -C (31) 1.338 (11) O (7) -C (38) 1.413 (8) C (15) -H (15A) 0.9700 C (31) -C (32) 1.318 (13) O (7) -H (7E) 0.914 (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) -H (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 C (3) -H (3A) 0.9800 C (19) -C (20) 1.351 (13) C (35) -H (35A) 0.9300 C (4) -C (5) 1.533 (7) C (19) -H (19A) 0.9300 C (36) -C (37) 1.494 (9) C (4) -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) -H (6A) 0.9700 C (22) -C (23) 1.507 (9) C (37) -H (37B) 0.9700 C (6) -H (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 below shows the coupling angle [° (deg)].

Atom-atom-atom Angle Atom-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 (1E) 108 (5) C (18) -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 (1) -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 (1) 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 O (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 O (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) 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 (31) -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 (11) -C (10) -H (10A) 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 (l1) -H (11A) 120.2 N (1) -C (36) -C (37) 107.5 (5) C (12) -C (11) -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 (13) -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) -H (15B) 107.7 C (36) -C (38) -H (38B) 109.2 C (17) -C (16) -C (21) 118.1 (7) H (38A) -C (38) -H (38B) 107.9

Table 9 below shows the torsion angle [° (deg)].

Atom-Atom-Atom-Atom Angle Atom-Atom-Atom-Atom Angle C (15) -O (3) -C (2) -C (3) 93 .1 (7) C (10) -C (9) -C (14) -C (13) 0.3 (12) C (15) -O (3) -C (2) -C (1) -142.2 (6) C (8) -C (9) -C (14) -C (13) 179.9 (7) O (1) -C (1) -C (2) -O (3) -66 .1 (5) C (12) -C (13) -C (14) -C (9) -0.5 (14) C (7) -C (1) -C (2) -O (3) 51.2 (6) C (2) -O (3) -C (15) -C (16) 151.8 (7) C (6) -C (1) -C (2) -O (3) 172 .3 (4) O (3) -C (15) -C (16) -C (17) -62. 6 (11) O (1) -C (1) -C (2) -C (3) 58.9 (5) O (3) -C (15) -C (16) -C (21) 119. 3 (8) C (7) -C (1) -C (2) -C (3) 176 .1 (4) C (21) -C (16) -C (17) -C (18) 0.2 (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) -O (4) -C (3) -C (2) 127 .2 (5) C (16) -C (17) -C (18) -C (19) 1.8 (14) C (22) -O (4) -C (3) -C (4) -112 .6 (5) C (17) -C (18) -C (19) -C (20) -4.2 (15) O (3) -C (2) -C (3) -O (4) -60.8 (5) C (18) -C (19) -C (20) -C (21) 4.0 (13) C (1) -C (2) -C (3) -O (4) 175 .0 (4) C (17) -C (16) -C (21) -C (20) -0.3 (9) O (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) -O (5) -C (4) -C (3) -159.2 (6) C (3) -O (4) -C (22) -C (23) 168.8 (5) C (29) -O (5) -C (4) -C (5) 73. 1 (7) O (4) -C (22) -C (23) -C (28) -143.2 (7) O (4) -C (3) -C (4) -O (5) 67.9 (5) O (4) -C (22) -C (23) -C (24) 38.7 (9) C (2) -C (3) -C (4) -O (5) -172 .3 (4) C (28) -C (23) -C (24) -C (25) 2.6 (11) O (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) O (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) O (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) -O (5) -C (29) -C (30) 155. 2 (6) O (1) -C (1) -C (6) -C (5) -60 .5 (6) O (5) -C (29) -C (30) -C (35) 118 .7 (8) C (7) -C (1) -C (6) -C (5) -178.2 (5) O (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) -O (2) -C (7) -C (1) 171.0 (5) C (31) -C (32) -C (33) -C (34) -4.8 (19) O (1) -C (1) -C (7) -O (2) -177 .2 (4) C (32) -C (33) -C (34) -C (35) 4.2 (18) C (6) -C (1) -C (7) -O (2) -56.2 (6) C (31) -C (30) -C (35) -C (34) 0.7 (12) C (2) -C (1) -C (7) -O (2) 62.6 (6) C (29) -C (30) -C (35) -C (34) 175.5 (8) C (7) -O (2) -C (8) -C (9) -171 .9 (5) C (33) -C (34) -C (35) -C (30) -2.0 (14) O (2) -C (8) -C (9) -C (14) -42 .9 (9) C (5) -N (1) -C (36) -C (37) 170.8 (5) O (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 (11) -0.2 (11) N (1) -C (36) -C (37) -O (6) 172 .6 (6) C (8) -C (9) -C (10) -C (ll) -179.9 (7) C (38) -C (36) -C (37) -O (6) -60 .2 (7) C (9) -C (10) -C (11) -C (12) 0.4 (13) N (1) -C (36) -C (38) -O (7) 53 .3 (7) C (10) -C (ll) -C (12) -C (13) -0.6 (14) C (37) -C (36) -C (38) -O (7) -69.2 (7) C (11) -C (12) -C (13) -C (14) 0.7 (14)

Table 10 below shows hydrogen bond lengths [mm] and angles [degrees].

D-H… A d (D-H) d (H… A) d (D… A) Angle of DHA O (7) -H (7E)... O (1) # 1 0.914 (11) 1.931 (18) 2.837 (5) 171 (8) O (6) -H (6E)... O (7) # 2 0.911 (11) 1.98 (3) 2.836 (7) 156 (6) 0 (1) -H (1E)... N (1) 0.907 (11) 1.98 (4) 2.810 (6) 151 (7)

Manufacture of Bogliboss

Example 7

10 shows a process for the preparation of boliboss by using tetrabenzyl boliboss. Tetrabenzyl boglybose (3.0 g, 4.8 mmol) in the prepared crystalline form was dissolved in 90% formic acid / methanol (1:19, 60 mL), to which palladium black (0.6 g) was added, The reaction was carried out at room temperature under nitrogen atmosphere for 12 hours. The reaction product was filtered and washed with 20 ml of methanol / water (1: 1). The filtrate was concentrated. The residue was adsorbed onto strong-acid ion exchange resin (250 mL), washed with water, and then eluted with 0.5N ammonia. After eluent was concentrated, 50 mL of anhydrous alcohol was added, boiled, cooled slightly, active carbon was added thereto, heated for 10 minutes, and further filtered. The filtrate was naturally cooled to room temperature, yielding white crystals. It was left for 1 to 3 hours at a temperature of 0 to 5 ° C., filtered, washed with a small amount of anhydrous alcohol and dried for 12 hours under vacuum to give 1.1 g of white crystals having a purity of 99.9% by high performance liquid chromatography. Obtained. Melting point: 164-166 degreeC. It was confirmed that the spectral data of the structure is consistent with the reported data.

Of course, the present invention may have other embodiments. Modifications, variations or applications of the invention may be made within the scope of the principles of the invention. This application is intended to cover all such departures from this description as come within the scope of the known or commercially available embodiments of the invention and also within the limits of the appended claims.

The tetrabenzyl boglybose in crystalline form is easy to store and transport, take it in use, and is easy to weigh, thus making it easier to change materials and work during manufacturing compared to the tetrabenzyl boglybose in oil form. Do. At the same time, due to the high purity and high content of tetrabenzyl boglybose in crystalline form as compared to tetrabenzyl boglybose in oil form, less impurities can be introduced or produced during the reaction when making it to be used. . The use of such crystals can produce higher quality boliboses, and thus the bolibos made in dosage form can have a higher therapeutic effect and fewer side effects.

Claims (18)

It has a molecular structure of formula (2), and in the copper X-ray powder diffraction, characterized in that the physical properties in which the characteristic peaks are 2θ is 16.84 ± 0.20 °, 18.99 ± 0.20 ° and 24.11 ± 0.20 ° Tetrabenzyl boglibosses in the form: [Formula 2]

The method of claim 1, For copper X-ray powder diffraction, the characteristic peaks with 2θ are 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 ° Tetrabenzyl bolibos in crystalline form, characterized by being present. The method of claim 1, Tetrabenzyl bolibosose in crystalline form, characterized in that the endothermic value of the tetrabenzyl bolibos is about 89.7 ° C in differential scanning calorimetry. The method of claim 1, Tetrabenzyl bolibos in crystalline form, characterized in that the infrared spectrum of the crystalline form of tetrabenzyl bolibos is as shown in Figure 9 in the infrared spectrum analysis. The method of claim 1, Tetrabenzyl bolibos in crystalline form, characterized in that the melting point of the tetrabenzyl bogglibose in the crystalline form is 88.0 ~ 90.8 ℃. The method of claim 1, Tetrabenzyl bolibosose in crystalline form, characterized in that the single crystal of tetrabenzyl bolibosose in crystalline form has a molecular stereostructure as shown in FIG. 5 in single crystal X-ray hysteresis. The method of claim 1, Tetrabenzyl Boglybose in the crystalline form belongs to a tetragonal system among the space groups of P2 (1) 2 (1) 2 (1), and its unit lattice factors are a = 7.8487 Å, b = 20.746 Å, c = 20.988 Å and Tetrabenzyl bogglibose in crystalline form, characterized in that R value = 0.0748. The method of claim 1, Tetrabenzyl bolibos in crystalline form is characterized in that connected to each other by the force of hydrogen bonding. The method of claim 1, Tetrabenzyl bolibos in a crystalline form, characterized in that the content of the tetrabenzyl boglybose in the crystalline form is 95% or more. Step 1) dissolving tetrabenzyl boglybose in oil form in a polar aprotic solvent, wherein the volume to weight ratio of the polar aprotic solvent to the tetrabenzyl boglybose is from 0.5 to 5: 1; Step 2) adding a nonpolar solvent to the solution of tetrabenzyl boglybose with stirring at room temperature to form crystals, wherein the volume to weight ratio of the nonpolar solvent to tetrabenzyl boglybose in oil form is from 2 to 20 : 1 person step; Step 3) after cooling, filtration and drying to obtain tetrabenzyl boglybose in crystalline form; Method for producing tetrabenzyl boglybose in a crystalline form, characterized in that comprises a. The method of claim 10, Preparation of tetrabenzyl boglybose in crystalline form according to step 1), wherein said polar aprotic solvent is one or more selected from the group consisting of ethyl acetate, isopropyl ether, ethyl ether and tetrahydrofuran. Way. The method of claim 11, wherein The polar aprotic solvent is ethyl acetate and / or isopropyl ether. The method of claim 10, The process for preparing tetrabenzyl bolibos in crystalline form according to step 1), wherein the volume-to-weight ratio of the polar aprotic solvent to tetrabenzyl bolibos is 1 to 3: 1. The method of claim 10, The method of claim 2), wherein the nonpolar solvent is one or more selected from the group consisting of cyclohexane, normal-hexane, carbon tetrachloride and petroleum ether. The method of claim 14, The non-polar solvent is cyclohexane and / or normal-hexane manufacturing method of tetrabenzyl bolibos in the crystal form. The method of claim 10, The process for preparing tetrabenzyl bolibos in crystalline form according to step 2), characterized in that the volume-to-weight ratio of the nonpolar solvent to the tetrabenzyl boligose in oil form is from 2 to 10: 1. The method of claim 10, In step 3), the solution is left for 1 to 5 hours, then left for 1 to 5 hours at a temperature of 0 to 5 ° C., and after filtration the crystals are dried in vacuo for 10 to 12 hours to form tetra A process for preparing tetrabenzyl boglybose in crystalline form, characterized by obtaining benzyl boglybose. A method for producing bolibos, wherein bolibos is prepared by the use of tetrabenzyl bolibos in the crystalline form as claimed in claim 1.

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