WO2023109057A1 - S-configuration pro-xylane crystal form compound and preparation method therefor - Google Patents

Abstract

Provided in the present invention is an S-configuration pro-xylane crystal form compound, which is a crystalline hydrate, and has a molecular formula of C8H16O5·H2O. Compared with the prior art, the S-configuration pro-xylane crystal form compound provided in the present invention has a relatively high stability.

Description

A kind of S-configuration Bosein crystal compound and preparation method thereof

This application claims the priority of the Chinese patent application submitted to the China Patent Office on December 17, 2021, with the application number 202111556250.X, and the title of the invention "An S-configuration Bosein crystal compound and its preparation method" , the entire contents of which are incorporated in this application by reference.

technical field

The invention belongs to the technical field of medicine, and in particular relates to an S-configuration Bosein crystal compound and a preparation method thereof.

Background technique

The INCI (International Cosmetic Ingredient Nomenclature) name of Bosein is hydroxypropyltetrahydropyrantriol, which is a glycoprotein mixture derived from xyloside. It was first developed by the French L'Oreal Paris company. , has anti-aging effects. Its structural formula is:

Boseine works in two ways. On the one hand, it can stimulate the synthesis of glycosaminoglycans (GAGs), so as to restore the function of the extracellular matrix. Simply put, glycosaminoglycans (GAGs) are networks with strong water absorption capacity. During our aging process, the synthesis of this network It becomes difficult and the water absorption capacity becomes poor, and the skin will lose its plump state when it was young, and Bosein can stimulate the synthesis of glycosaminoglycans GAGs to improve this state; The junction of the dermis plays a role (promoting the synthesis of collagen VII and collagen IV), making the epidermis and dermis fit closer together, and the skin becomes firmer and more elastic.

The preparation method of Bosene can be found in Bioorg.Med.Chem.Lett, 2009, 19:845-849. Since Bose absorbs moisture easily in the air, crystal stability is very important. A crystal form of Bosene is disclosed in the above literature, but the corresponding preparation method is not reported, and the stability of Bosene still needs to be improved.

Contents of the invention

In view of this, the technical problem to be solved by the present invention is to provide an S-configuration Bosein crystal compound with high stability and a preparation method thereof.

The invention provides an S-configuration Bosein crystal compound, the S-configuration Bosein crystal compound is a crystalline hydrate, and its molecular formula is C ₈ H ₁₆ O ₅ ·H ₂ O.

Preferably, the Bosein compound is a monoclinic crystal system with a space group of P21, and the unit cell parameters are

α=90°, β=103.221(4)°, γ=90°.

Preferably, the unit cell volume of the Bosein crystal compound

Preferably, the number of molecules in the unit cell of the Bosein crystal compound is Z=2.

Preferably, the Bosein crystal compound has a density of 1.288 g/cm ³ .

Preferably, the S-configuration Bosein crystal compound has the characteristics of X-ray powder diffraction spectrum as described in the following table, wherein the error of 2θ and interplanar spacing is ±0.2:

The present invention also provides a preparation method of an S-configuration Bosein crystal compound, comprising:

Mix and dissolve the S-configuration Bosein with water or alcohol solvent, let stand, filter and dry to obtain the Bosein crystal compound.

Preferably, the ratio of the S-configuration Bosene to water or alcohol solvent is 1 mg: (0.05-0.2) mL.

Preferably, the mixing and dissolving is carried out under heating; the heating temperature is greater than or equal to 50°C.

The present invention also provides the application of the above-mentioned S-configuration Bosein crystal compound in the preparation of cosmetics.

The invention provides an S-configuration Bosein crystal compound, the S-configuration Bosein crystal compound is a crystalline hydrate, and its molecular formula is C ₈ H ₁₆ O ₅ ·H ₂ O. Compared with the prior art, the S-configuration Bosein crystal compound provided by the present invention has higher stability.

Description of drawings

Fig. 1 is the molecular structure diagram of the S-configuration Bosein crystal compound obtained in Example 1 of the present invention;

Figure 2 is a unit cell packing diagram of the S-configuration Bosein crystal compound obtained in Example 1 of the present invention;

Fig. 3 is the X-ray powder diffraction pattern of the S-configuration Bosein crystal compound obtained in Example 1 of the present invention;

Figure 4 is a list of diffraction peaks of the X-ray powder diffraction of the S-configuration Bosein crystal compound obtained in Example 1 of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

The invention provides an S-configuration Bosein crystal compound, the S-configuration Bosein crystal compound is a crystalline hydrate, and its molecular formula is C ₈ H ₁₆ O ₅ ·H ₂ O.

Further specifically, the S-configuration Bosein compound is a monoclinic crystal system with a space group of P21, and the unit cell parameters are

α=90°, β=103.221(4)°, γ=90°.

Further specifically, the unit cell volume of the S-configuration Bosein crystal compound

The number of molecules in the unit cell of the S-configuration Bosein crystal compound is Z=2; the density of the S-configuration Bosein crystal compound is 1.288g/cm ³ ; the S-configuration The C7 atom in the Bosein crystal compound is in the S configuration.

The invention adopts the internationally recognized X-ray diffraction method (XRD) to study and characterize the crystal structure of the S-configuration Bosein crystal compound. Equipment: Bruker Apex II CCD single crystal X-ray diffractometer. The ray Kα of the Mo target selected for graphite monochromatization

by

The crystal diffraction data were collected in the range of θ=1.884°～25.082°. A total of 4845 diffraction points were collected, of which 1672 diffraction points (I>2σ(I)) were observed and used for structure correction. Diffraction data were corrected for LP factors and empirical absorption. Using the direct method and several rounds of differential Fourier synthesis, all non-hydrogen atoms were found, and the coordinates of the hydrogen atoms were obtained by geometric hydrogenation. All non-hydrogen atoms in the structure were corrected by full-matrix least squares, and anisotropic thermal parameters were used. The software program used for structural analysis and refinement is SHELXTL Version 6.14. See Table 1 for the crystal data of the S-configuration Bosein crystal compound, see Table 2 for some bond lengths, and see Table 3 for some bond angles.

Table 1 Crystal data of S-configuration Bosein compound

Table 2 Some bond lengths in crystals of S-configuration Bosein compounds

Table 3 Some bond angles in crystals of S-configuration Bosein compounds

atom-atom-atom	Bond angle (°)	atom-atom-atom	Bond angle (°)
C(1)-O(1)-C(5)	112.6(3)	C(3)-C(4)-C(5)	111.9(4)
O(1)-C(1)-C(2)	110.1(4)	O(1)-C(5)-C(6)	108.1(4)
O(2)-C(2)-C(3)	111.1(4)	O(1)-C(5)-C(4)	108.3(4)
O(2)-C(2)-C(1)	110.9(4)	C(6)-C(5)-C(4)	113.5(4)
C(3)-C(2)-C(1)	111.0(4)	C(7)-C(6)-C(5)	115.2(4)
C(2)-C(3)-C(4)	110.9(4)	O(4)-C(7)-C(8)	107.8(4)
O(3)-C(4)-C(3)	107.4(4)	O(4)-C(7)-C(6)	111.0(4)
O(3)-C(4)-C(5)	110.5(4)	C(8)-C(7)-C(6)	113.0(5)

O(003)-C(3)-C(2)

107.1(4)

O(003)-C(3)-C(4)

111.0(4)

The invention adopts the internationally recognized X-ray powder diffraction method (XRPD) to study and characterize the crystal form of the S-configuration Bosein crystal compound.

Equipment: RIGAKU TTR III type X-ray powder diffractometer.

Measurement conditions and methods: scan axis Gonio; start position [°2Th.] 3.0131; end position [°2Th.] 60.0051; step size [°2Th.] 0.0260; scan time per step [s] 93.8400; scan type Continuous; PSD mode scanning; PSD length [°2Th.] 3.35; offset [°2Th.] 0.0000; divergence slit type fixed; divergence slit size [°] 0.4354; sample length [mm] 10.00; measurement temperature [°C] 25.00 ; light pipe target Cu; K-Alpha1

1.54060; K-Alpha2

1.54443; K-Beta

1.39225; K-Alpha2/K-Alpha1 ratio 0.50000; high voltage generator setting 40mA, 45kV; diffractometer type 0000000011191334; goniometer radius [mm] 240.00; diverging slit bull center distance [mm] 100.00; incident light path monochromator No ;Rotate no.

The X-ray powder diffraction pattern of the S-configuration Bosein crystal compound provided by the present invention is shown in Figure 3, and has the characteristics of the X-ray powder diffraction pattern described in the table below, wherein the error of 2θ and interplanar spacing ± 0.2:

The S-configuration Bosein crystal compound provided by the invention has relatively high stability.

The present invention also provides a preparation method of the above-mentioned S-configuration Bosein crystal form compound, comprising: mixing and dissolving the S-configuration Boseine and water, standing, filtering, and drying to obtain the Bosein crystal form compound.

Wherein, the present invention has no special limitation on the source of all raw materials, and the purity of the compound can reach more than 99%. In the examples provided by the present invention, specifically, it is S-configuration Bosene with an HPLC purity of 99.01% obtained by the preparation method described in the literature Bioorg.Med.Chem.Lett, 2009, 19:845-849.

Mix and dissolve the S-configuration Boseine with water or alcohol solvent; the ratio of the S-configuration Boseine to water or alcohol solvent is preferably 1 mg: (0.05-0.2) mL, more preferably 1 mg: (0.08 ～0.15) mL, more preferably 1mg: 0.1mL; The alcohol solvent is an alcohol solvent well known to those skilled in the art, and there is no special limitation. In the present invention, it is preferably anhydrous alcohol solvent, more preferably anhydrous alcohol solvent. One or more of water methanol, absolute ethanol and anhydrous n-butanol; the mixing and dissolving is preferably carried out under the condition of heating and stirring; the temperature of the heating and stirring is preferably greater than or equal to 50°C; the heating and stirring The time is preferably 2-10 minutes, more preferably 4-7 minutes, until the solid is dissolved and clarified; in the example provided by the present invention, it is specifically heating and stirring for 5 minutes.

After mixing and dissolving, it is preferably cooled to room temperature and allowed to stand; the standing time is preferably more than 20 hours, more preferably equal to or greater than 24 hours. It is necessary to prevent vibration during the static growth of single crystal.

When the solvent used is an alcohol solvent, it is preferred to add a non-polar solvent dropwise after dissolving, and leave it to stand after solids appear; the non-polar solvent is preferably dichloromethane and/or sherwood oil; The time is preferably more than 20h, more preferably equal to or greater than 24h. It is necessary to prevent vibration during the static growth of single crystal.

The system is in a non-closed state during the standing process, so when the solvent used is anhydrous alcohol solvent, due to the hygroscopicity of the S-configuration Boseine, it will absorb moisture from the air, thereby obtaining crystals containing crystal water.

After standing still, crystals are precipitated, filtered, preferably washed and dried, to obtain the S-configuration Bosein crystal compound; the washing is preferably an alcohol solvent, more preferably ethanol and/or methanol; the drying is preferably vacuum Drying; the drying temperature is preferably 30°C to 40°C.

The present invention also provides an application of the above-mentioned S-configuration Bosein crystal compound in the preparation of cosmetics.

In order to further illustrate the present invention, an S-configuration Bosein crystal compound provided by the present invention and its preparation method are described in detail below in conjunction with the examples.

The reagents used in the following examples are all commercially available.

Example 1

Add 10 mg of S-configuration Bosein solid to 1 mL of purified water, stir at 50°C for 5 min until the solid is completely dissolved and clear, stop heating and let it cool down to room temperature for 24 h (avoid vibration during single crystal growth). Crystallize, filter, wash with ethanol, and dry under vacuum at 40°C to obtain 9 mg of S-configuration Bosein single crystal, with a yield of 90%.

Example 2

Add 15 mg of S-configuration Bosein solid to 2 mL of absolute ethanol, stir at 50°C for 5 min until the solid is completely dissolved and clear, stop heating and let it cool down to room temperature, and let it stand still for 24 hours (prevent vibration during single crystal growth) ). Crystallization, filtration, washing, and vacuum drying yielded 14.3 mg of S-configuration Bosene single crystal with a yield of 95%.

Example 3

Add 10mg of S-configuration Bosein solid to 2mL of anhydrous methanol, stir at 50°C for 5min until the solid is completely dissolved and clear, stop heating and let it cool down to room temperature, and let it stand still for 24h (prevent vibration during single crystal growth) ). Crystallize, filter, wash with ethanol, and dry under vacuum at 40°C to obtain 9.4 mg of S-configuration Bosene single crystal, with a yield of 94%.

Example 4

Add 15 mg of S-configuration Bosein solid to 2 mL of n-butanol, stir at 50°C for 5 min until the solid is completely dissolved and clear, stop heating and let it cool down to room temperature, and let it stand still for 24 hours (prevent vibration during single crystal growth) ). Crystallize, filter, wash with ethanol, and dry under vacuum at 40°C to obtain 13.8 mg of S-configuration Bosene single crystal, with a yield of 92%.

Example 5

Add 10mg of S-configuration Bosein solid to 2mL of anhydrous methanol, and place it statically at -20°C for 24h (avoid vibration during single crystal growth). Crystallize, filter, wash, and dry under vacuum at 40°C to obtain 8.2 mg of S-configuration Bosene single crystal, with a yield of 82%.

Example 6

Add 10 mg of S-configuration Bosein solid to 2 mL of anhydrous methanol, add dichloromethane dropwise under slow stirring until the solid appears, and then continue to stand for 24 h (to prevent vibration during the growth of the single crystal). Crystallize, filter, wash, and dry under vacuum at 40°C to obtain 8.6 mg of S-configuration Bosene single crystal, with a yield of 86%.

Example 7

Add 10 mg of S-configuration Bosein solid to 2 mL of anhydrous methanol, add petroleum ether dropwise under slow stirring until the solid appears, and then continue to stand for 24 hours (to prevent vibration during the growth of single crystal). Crystallize, filter, wash, and vacuum-dry at 40°C to obtain 8.5 mg of S-configuration Bosene single crystal, with a yield of 85%.

The size of 0.230mm × 0.140mm × 0.090mm white prismatic crystals prepared according to the method in Example 1 is selected and placed on the glass fiber, and X-ray diffraction analysis is carried out at a temperature of 2969 (2) K to obtain its molecular structure as shown in As shown in Figure 1, the unit cell packing diagram is obtained, as shown in Figure 2. MoKa monochromated with graphite on a single crystal X-ray diffractometer

ray to

The crystal diffraction data were collected in the range of θ=1.884°～25.082°. A total of 4845 diffraction points were collected, of which 1672 diffraction points (I>2σ(I)) were observed and used for structure correction. Diffraction data were corrected for LP factors and empirical absorption. The direct method and several rounds of differential Fourier synthesis were used to find all non-hydrogen atoms, and the coordinates of the hydrogen atoms were obtained by geometric hydrogenation. All non-hydrogen atoms in the structure were corrected by full-matrix least squares and anisotropic thermal parameters were used.

See Table 1 for the crystal data of the S-configuration Bosein crystal compound, see Table 2 for some bond lengths, and see Table 3 for some bond angles.

Table 1 Crystal data of S-configuration Bosein compound

Table 2 Some bond lengths in crystals of S-configuration Bosein compounds

Table 3 Some bond angles in crystals of S-configuration Bosein compounds

atom-atom-atom	Bond angle (°)	atom-atom-atom	Bond angle (°)
C(1)-O(1)-C(5)	112.6(3)	C(3)-C(4)-C(5)	111.9(4)

O(1)-C(1)-C(2)	110.1(4)	O(1)-C(5)-C(6)	108.1(4)
O(2)-C(2)-C(3)	111.1(4)	O(1)-C(5)-C(4)	108.3(4)
O(2)-C(2)-C(1)	110.9(4)	C(6)-C(5)-C(4)	113.5(4)
C(3)-C(2)-C(1)	111.0(4)	C(7)-C(6)-C(5)	115.2(4)
C(2)-C(3)-C(4)	110.9(4)	O(4)-C(7)-C(8)	107.8(4)
O(3)-C(4)-C(3)	107.4(4)	O(4)-C(7)-C(6)	111.0(4)
O(3)-C(4)-C(5)	110.5(4)	C(8)-C(7)-C(6)	113.0(5)
O(003)-C(3)-C(2)	107.1(4)	O(003)-C(3)-C(4)	111.0(4)

The S-configuration boson single crystal obtained in embodiment 1 is carried out stability test, obtains following result:

At 2-8°C, sealed and stored for half a year, there is no obvious change in appearance, no obvious moisture absorption, and the properties and optical rotation of the product have not changed after testing;

At 20°C, there is no obvious change in appearance within 48 hours, no obvious moisture absorption phenomenon, and the product properties and optical rotation have not changed after testing;

At 40°C, there is no obvious change in appearance within 24 hours, no obvious moisture absorption phenomenon, and the product properties and optical rotation have not changed after testing.

At 50°C, there is no obvious change in appearance within 8 hours, no obvious moisture absorption phenomenon, and the product properties and optical rotation have not changed after testing.

Application performance:

The S-configuration Bosein single crystal obtained in Example 1 is mixed with common cosmetic raw materials (water, ethanol, glycerin) at room temperature and miscible, and the properties of the product do not change.

The S-configuration Bosein single crystals obtained in Examples 2 to 7 were detected by the above method, and the results obtained were the same as those in Example 1, and it was confirmed that the obtained compounds were of the same crystal form.

The S-configuration Bosein single crystal obtained in Example 1 is detected by X-rays, and its X-ray powder diffraction pattern is obtained as shown in Figure 3; the diffraction peak list diagram of its X-ray powder diffraction is obtained as shown in Fig. 4.

Claims (10)

1. An S-configuration Bosein crystal compound, characterized in that the S-configuration Bosein crystal compound is a crystalline hydrate, and its molecular formula is C ₈ H ₁₆ O ₅ ·H ₂ O.
2. The S-configuration Bosein crystal compound according to claim 1, wherein the Bosein crystal compound is a monoclinic crystal system, P21 space group, and the unit cell parameter is

   

   

   α=90°, β=103.221(4)°, γ=90°.
3. The S-configuration Bosein crystal compound according to claim 1, wherein the unit cell volume of the Bosein crystal compound is

   
4. The S-configuration Bosein crystal compound according to claim 1, characterized in that the number of molecules in the unit cell of the Bosein crystal compound is Z=2.
5. The S-configuration Bosein crystal compound according to claim 1, characterized in that the density of the Bosein crystal compound is 1.288 g/cm ³ .
6. The S-configuration Bosein crystal form compound according to claim 1, wherein the S-configuration Bosein crystal form compound has the X-ray powder diffraction spectrum characteristics as described in the following table, wherein 2θ and interplanar spacing error ±0.2:

   
7. A method for preparing an S-configuration Bosein crystal compound, characterized in that it comprises:

   Mix and dissolve the S-configuration Bosein with water or alcohol solvent, let stand, filter and dry to obtain the Bosein crystal compound.
8. The preparation method according to claim 7, characterized in that the ratio of the S-configuration Bosene to water or alcohol solvent is 1 mg: (0.05-0.2) mL.
9. The preparation method according to claim 7, characterized in that the mixing and dissolving is carried out under the condition of heating; the heating temperature is greater than or equal to 50°C.
10. The S-configuration Bosein crystal compound described in any one of claims 1 to 6 or the S-configuration Bosein crystal compound prepared by the preparation method of any one of claims 7 to 9 in the preparation of cosmetics application.

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