Preparation method of oxime glucoside

Abstract

The invention relates to a preparation method of oxime glucoside. According to the method, unprotected fluoroglycoside and oxime are taken as substrates, alkali is taken as an accelerant, and the substrates and the alkali are stirred to react in a solvent to obtain an oxime glycoside product. The novel preparation method of the oxime glucoside is simple in reaction condition, convenient to operate and wide in substrate applicability, meanwhile, the substrate glucoside does not need to be protected, the problems of upper protection and deprotection processes are avoided, one-step synthesis is achieved, and the yield of the oxime glucoside is remarkably increased. Moreover, the method takes cheap and environment-friendly alkali as an accelerant, has the characteristics of low cost, environment friendliness and the like, and is more suitable for industrial production. Besides, the preparation method disclosed by the invention can be suitable for amplification reaction, a relatively high yield is kept, and a brand-new solution is provided for large-scale industrial production of oxime glucoside.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and relates to a method for preparing oxime glycosides, specifically to a method for directly coupling fluorinated glycosides and oximes to obtain oxime glycosides. Background Art

[0002] Oxime glycosides have important values in multiple fields. In biology, it is a key substance in the plant defense mechanism. For example, phenylacetaldehyde oxime glucoside can help plants resist the invasion of pathogenic bacteria and insects, etc., and also participates in the regulation of plant growth and development and affects the interaction between plants and microorganisms. In the medical field, oxime glycosides and their degradation products have various biological activities such as antibacterial, antiviral, antitumor, antioxidant and anti-inflammatory, and can be used to develop new drugs, providing potential means for the treatment of various diseases. In chemical and drug research and development, oxime glycosides are important synthetic intermediates and can be used as lead compounds to develop drugs with higher activity and lower toxicity. In addition, in the food field, oxime glycosides and their degradation products can endow food with special flavors, and can also be used for food preservation and anti-corrosion to extend the shelf life of food. Currently, there are several methods for synthesizing oxime glycosides. The classic method is a multi-step reaction of O-glycosylation - deprotection - oxime formation of N-protected hydroxylamine. Recently, Yu Biao's group developed a direct glycosylation reaction of protected glycosyl donors and oxime sugars. Dai Yuanwei's group reported the synthesis reaction of oxime glycosides through palladium-catalyzed allylation reaction. However, the reaction of directly synthesizing oxime from unprotected glycosylation donors has not been developed. Summary of the Invention

[0003] The purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art and provide a method for preparing oxime glycosides. The present invention provides a novel method for preparing oxime glycosides, which has simple reaction conditions, convenient operation, wide substrate applicability, and at the same time does not require protection of the substrate glycoside, avoiding the problems in the processes of protection and deprotection, realizing one-step synthesis, and significantly improving the yield of oxime glycosides. Moreover, the present invention uses an inexpensive and environmentally friendly base as a promoter, with characteristics such as low cost and environmental friendliness, and is more suitable for industrial production. In addition, the preparation method of the present invention can be applied to scale-up reactions and maintain a high yield, providing a brand-new solution for large-scale industrial production of oxime glycosides.

[0004] The purpose of the present invention can be achieved through the following solutions:

[0005] In the first aspect, the present invention provides a method for preparing oxime glycosides, using the unprotected fluorinated glycoside shown in Formula I and the oxime shown in Formula II as substrates, a base as a promoter, and stirring and reacting in a solvent to obtain the oxime glycoside product shown in Formula III;

[0006]

[0007] wherein, R 1, R 2 Each independently selected from an alkyl or cycloalkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted anthracenyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted indolyl group, and a hydrogen atom;

[0008] The substituted group is selected from one or more of a C1-C6 lower alkyl group, a C1-C6 lower alkoxy group, and a halogen.

[0009] As an embodiment of the present invention, R 1 is selected from any one of a phenyl group, a methyl group, and a hydrogen atom;

[0010] R 2 is selected from any one of a phenyl group, a phenyl group substituted with a methoxy group, a naphthyl group, and a cyclopentyl group.

[0011] As an embodiment of the present invention, the oxime is selected from the following:

[0012]

[0013] Preferably, the oxime is selected from the following:

[0014] More preferably, the oxime is

[0015] As an embodiment of the present invention, the glycosyl group in the fluoroglycoside is a hexose monosaccharide group. The monosaccharide group in the present invention is an unprotected monosaccharide group.

[0016] Preferably, the fluoroglycoside is an unprotected α-fluoroglucoside, and its structural formula is

[0017] As an embodiment of the present invention, the molar ratio of the fluoroglycoside to the oxime is 1:5 - 5:1.

[0018] As an embodiment of the present invention, the base is an organic base or an inorganic base, including any one of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, triethylamine, trimethylamine, and diisopropylethylamine.

[0019] As an embodiment of the present invention, the molar ratio of the base to the oxime is 1:3 - 3:1.

[0020] As an embodiment of the present invention, the solvent includes any one of water, an organic solvent, a mixture of water and an organic solvent, and a mixture of organic solvents; wherein, the organic solvent includes one or more of methanol, ethanol, isopropanol, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

[0021] Preferably, the solvent includes one or more of water, methanol, ethanol, isopropanol, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

[0022] In some embodiments, the mixture of water and organic solvent includes a mixture of water and methanol, a mixture of water and ethanol, a mixture of water and N,N-dimethylformamide, and a mixture of water and acetonitrile; wherein, the volume ratio of water to organic solvent is 5:95 - 95:5. Preferably, it is 1:5.

[0023] As an embodiment of the present invention, the temperature of the reaction is 0 to 150 °C.

[0024] As an embodiment of the present invention, the stirring is carried out using a magnetic stirrer or a mechanical stirrer, and the rotation speed is 300 to 3000 revolutions per minute.

[0025] In a second aspect, the present invention provides an oxime glycoside obtained by the above preparation method.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1. The present invention provides a novel preparation method for oxime glycosides. Creatively, using fluorinated glycosides and oximes as substrates and a base as a promoter, the oxime glycoside product is synthesized in one step. Compared with the traditional multi-step synthesis route, the preparation method of the present invention has simple reaction conditions, convenient operation, wide substrate applicability, and at the same time, there is no need to protect the substrate glycoside, avoiding the problems in the processes of protection and deprotection, realizing one-step synthesis, and significantly improving the yield of oxime glycosides.

[0028] 2. The preparation method of the present invention uses an inexpensive and environmentally friendly base as a promoter. Compared with the precious metal catalysts such as gold and palladium used in traditional synthesis methods, it has the characteristics of low cost and environmental friendliness, and is more suitable for industrial production.

[0029] 3. The preparation method of the present invention can be applied to scale-up reactions and maintain a high yield, and the raw materials are simple and easily available, which is conducive to large-scale production, providing a new solution for the large-scale industrial production of oxime glycosides. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] By reading the following detailed description of non-limiting embodiments with reference to the accompanying drawings, other features, objects, and advantages of the present invention will become more apparent:

[0031] Figure 1 It is a schematic diagram of the synthesis route of the oxime glycoside of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments. The following examples are implemented on the premise of the technical solution of the present invention, providing detailed implementation manners and specific operation processes, which will help those skilled in the art to further understand the present invention. It should be noted that the protection scope of the present invention is not limited to the following embodiments. Several adjustments and improvements made on the premise of the concept of the present invention all fall within the protection scope of the present invention.

[0033] The raw materials involved in the embodiments of the present invention are all commercially available products, and the specific preparation operations and characterization tests are conventional technologies.

[0034] Example 1

[0035] Reference Figure 1 the shown synthetic route, add (197 mg, 1 mmol), calcium hydroxide (148 mg, 2.0 mmol, 2.0 eq.), into a mixed solvent of methanol / water (6 mL) with a volume ratio of 5:1 for dissolution. After stirring at room temperature for 10 minutes, add α-fluorosugar (i.e., α-fluoroglucoside) (364 mg, 2.0 mmol, 2.0 eq.), and react under heating and stirring at 35 °C for 24 hours. After the reaction is completed, evaporate and concentrate the reaction solution, adsorb the reactants with silica gel, and place them on a silica gel column for chromatography separation and purification to obtain the corresponding β-configured coupling product 194 mg, which is a white solid with a yield of 54%. NMR spectral data: 1 H NMR(600MHz,MeOD)δ7.48–7.38(m,8H),7.41–7.32(m,2H),5.10(d,J=8.3Hz,1H),3.90(dd,J=12.1,2.2Hz,1H),3.71(dd,J=12.0,5.5Hz,1H),3.46–3.37(m,2H),3.35–3.32(m,2H). 13 C NMR(151MHz,MeOD)δ160.6,137.6,134.4,130.9,130.8,130.2,129.4,129.3,129.1,106.4,78.5,78.4,73.4,71.2,62.6.

[0036] Example 2

[0037] Add (121 mg, 1 mmol), calcium hydroxide (148 mg, 2.0 mmol, 2.0 eq.), into a mixed solvent of methanol / water (6 mL) with a volume ratio of 5:1 for dissolution. After stirring at room temperature for 10 minutes, add α-fluorosugar (364 mg, 2.0 mmol, 2.0 eq.) was reacted with stirring at 35 °C for 24 h. After completion of the reaction, the reaction solution was concentrated by evaporation. The reactants were adsorbed on silica gel and separated and purified by silica gel column chromatography to obtain the corresponding β-configured coupling product. 258 mg, a white solid, with a yield of 90%. NMR spectral data: 1 H NMR(600 MHz, MeOD) δ 8.26(s, 1H), 7.66–7.59(m, 2H), 7.45–7.36(m, 3H), 5.04(dd, J = 8.1, 1.4 Hz, 1H), 3.88(dd, J = 12.1, 2.2 Hz, 1H), 3.70(dd, J = 12.1, 5.2 Hz, 1H), 3.49–3.32(m, 4H). 13 C NMR(151 MHz, MeOD) δ 152.7, 133.1, 131.5, 129.8, 128.4, 106.1, 78.3, 78.2, 73.6, 71.3, 62.5.

[0038] Example 3

[0039] Dissolve (135 mg, 1 mmol) and calcium hydroxide (148 mg, 2.0 mmol, 2.0 eq.) in a mixed solvent of methanol / water (6 mL) with a volume ratio of 5:1. After stirring at room temperature for 10 min, α-fluorosugar (364 mg, 2.0 mmol, 2.0 eq.) was added, and the reaction was carried out with stirring at 35 °C for 24 h. After completion of the reaction, the reaction solution was concentrated by evaporation. The reactants were adsorbed on silica gel and separated and purified by silica gel column chromatography to obtain the corresponding β-configured coupling product 134 mg, a white solid, with a yield of 45%. NMR spectral data: 1 H NMR(600 MHz, Methanol-d4) δ 7.68(dtd, J = 5.3, 4.1, 1.9 Hz, 2H), 7.39(qd, J = 4.1, 1.7 Hz, 3H), 5.09–5.03(m, 1H), 3.87(dd, J = 12.1, 2.2 Hz, 1H), 3.69(dd, J = 12.0, 5.4 Hz, 1H), 3.50–3.43(m, 2H), 3.42–3.32(m, 2H), 2.32(s, 3H). 13 C NMR(151 MHz, Methanol-d4) δ 159.1, 137.4, 130.6, 129.5, 127.4, 105.9, 78.3, 78.3, 73.6, 71.3, 62.6, 13.6.

[0040] Example 4

[0041] Put (165 mg, 1 mmol), calcium hydroxide (148 mg, 2.0 mmol, 2.0 eq.), into a mixed solvent of methanol / water (6 mL) with a volume ratio of 5:1 and dissolve. After stirring at room temperature for 10 minutes, add α-fluorosugar (364 mg, 2.0 mmol, 2.0 eq.), and react under heating and stirring at 35 °C for 24 hours. After the reaction is completed, evaporate and concentrate the reaction solution, adsorb the reactants with silica gel, and place them on a silica gel column for chromatography separation and purification to obtain the corresponding β-configured coupling product 121 mg, a white solid, with a yield of 37%. NMR spectral data: 1 HNMR(600 MHz, Methanol-d4) δ7.66–7.60(m, 2H), 6.96–6.90(m, 2H), 5.07–5.00(m, 1H), 3.87(dd, J=12.0, 2.2 Hz, 1H), 3.81(s, 3H), 3.69(dd, J=12.0, 5.5 Hz, 1H), 3.51–3.42(m, 2H), 3.42–3.33(m, 2H), 2.29(s, 3H). 13 CNMR(151 MHz, Methanol-d4) δ162.4, 158.8, 129.6, 128.9, 114.8, 105.8, 78.3, 78.3, 73.6, 71.3, 62.7, 55.8, 13.5.

[0042] Example 5

[0043] Put (185 mg, 1 mmol), calcium hydroxide (148 mg, 2.0 mmol, 2.0 eq.), into a mixed solvent of methanol / water (6 mL) with a volume ratio of 5:1 and dissolve. After stirring at room temperature for 10 minutes, add α-fluorosugar (364 mg, 2.0 mmol, 2.0 eq.), and react under heating and stirring at 35 °C for 24 hours. After the reaction is completed, evaporate and concentrate the reaction solution, adsorb the reactants with silica gel, and place them on a silica gel column for chromatography separation and purification to obtain the corresponding β-configured coupling product 142 mg, a white solid, with a yield of 41%. NMR spectral data: 1HNMR(600MHz, Methanol-d4) δ 8.12 (s, 1H), 7.92–7.88 (m, 2H), 7.88–7.81 (m, 2H), 7.53–7.47 (m, 2H), 5.12 (d, J=7.5Hz, 1H), 3.88 (dd, J=12.1, 2.3Hz, 1H), 3.70 (dd, J=12.1, 5.5Hz, 1H), 3.53–3.45 (m, 2H), 3.44–3.33 (m, 2H), 2.43 (s, 3H). 13 CNMR(151MHz, Methanol-d4) δ 158.8, 135.3, 134.7, 134.6, 129.6, 129.0, 128.6, 127.9, 127.5, 127.4, 124.5, 106.1, 78.4, 78.3, 73.7, 71.4, 62.7, 13.3.

[0044] Example 6

[0045] Place (99 mg, 1 mmol), calcium hydroxide (148 mg, 2.0 mmol, 2.0 eq.), in a mixed solvent of methanol / water (6 mL) with a volume ratio of 5:1 and dissolve. After stirring at room temperature for 10 minutes, add α-fluorosugar (364 mg, 2.0 mmol, 2.0 eq.), and react under heating and stirring at 35 °C for 24 hours. After the reaction is completed, evaporate and concentrate the reaction solution, adsorb the reactants with silica gel, and place them on a silica gel column for chromatography separation and purification to obtain the corresponding β-configured coupling product 52 mg, as a white solid, with a yield of 20%. NMR spectral data: 1 HNMR(600MHz, Methanol-d4) δ 4.85 (d, J=8.2Hz, 1H), 3.86 (dd, J=12.0, 1.9Hz, 1H), 3.68 (dd, J=12.0, 5.0Hz, 1H), 3.42 (t, J=8.7Hz, 1H), 3.39–3.32 (m, 3H), 2.62–2.43 (m, 2H), 2.39 (td, J=6.8, 2.6Hz, 2H), 1.84–1.73 (m, 4H). 13 CNMR(151MHz, Methanol-d4) δ 171.4, 105.3, 78.2, 78.2, 73.5, 71.3, 62.7, 31.8, 29.1, 26.1, 25.5.

[0046] Example 7

[0047] Scale up the reaction by 10 times:

[0048] Put (1.97 g, 10 mmol), calcium hydroxide (1.48 g, 20 mmol, 2.0 eq.) into a mixed solvent of methanol / water (60 mL) with a volume ratio of 5:1 for dissolution. After stirring at room temperature for 10 minutes, add α-fluorosugar (3.64 g, 2 mmol, 2 eq.), and react under heating and stirring at 35 °C for 24 hours. After the reaction is completed, evaporate and concentrate the reaction solution, adsorb the reactants with silica gel, and place them on a silica gel column for chromatography separation and purification to obtain the corresponding β-configured coupling product 2.24 g, which is a white solid with a yield of 62%.

[0049] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various deformations or modifications within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for preparing an oxime glycoside, characterized in that, Using the fluoroglycoside represented by formula I and the oxime represented by formula II as substrates, and a base as a promoter, stirring and reacting in a solvent to obtain an oxime glycoside product represented by formula III; Among them, R 1 , R 2 are each independently selected from any one of C1-C8 alkyl or cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted furyl, substituted or substituted pyridyl, substituted or unsubstituted indolyl, and hydrogen atom; The substituted group is selected from one or more of C1-C6 lower alkyl, C1-C6 lower alkoxy, and halogen.

2. The preparation method according to claim 1, wherein R 1 is selected from any one of phenyl, methyl, and hydrogen atom; R 2 is selected from any one of phenyl, phenyl substituted with methoxy, naphthyl, cyclopentyl, and hydrogen atom.

3. The preparation method according to claim 1, wherein The oxime is selected from the following:

4. The preparation method according to claim 1, characterized in that, The sugar group in the fluoroglycoside is a hexose monosaccharide group.

5. The preparation method according to claim 1, wherein The fluorinated glycoside is an α-fluorinated glucoside, and its structural formula is 6. The preparation method according to claim 1, characterized in that The molar ratio of the fluoroglycoside to the oxime is 1:5 - 5:

1.

7. According to the preparation method described in claim 1, characterized in that, The base includes any one of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, triethylamine, trimethylamine, and diisopropylethylamine; the molar ratio of the base to the oxime is 1:3 - 3:

1.

8. The preparation method according to claim 1, characterized in that, The solvent includes any one of water, an organic solvent, and a mixture of water and an organic solvent; wherein, the organic solvent includes one or more of methanol, ethanol, isopropanol, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

9. According to the preparation method described in claim 1, characterized in that, The temperature of the reaction is 0 to 150 °C; the rotation speed of the stirring is 300 to 3000 revolutions per minute.

10. An oxime glycoside prepared by the preparation method according to any one of claims 1-9.

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