Hydroxyl selective phosphorylation protection method based on iron catalyst and application

Abstract

The invention relates to a hydroxyl selective phosphorylation protection method based on an iron catalyst and application, and the method comprises the following steps: mixing a polyhydroxy substrate, an aprotic solvent, the iron catalyst, an acid-binding agent and a phosphorylation reagent, carrying out phosphorylation reaction, and carrying out post-treatment to obtain a selective phosphorylation protection product. Under the action of the iron catalyst, the polyhydroxy substrate reacts with the phosphorylation reagent, so that one or two hydroxyl groups in the polyhydroxy substrate can be protected by phosphoryl groups with high selectivity, the efficient and high-selectivity phosphorylation process of the polyhydroxy substrate is realized, the yield of the obtained product is high, the reaction conditions are mild, and the method is suitable for industrial production. Operation is simple, convenient and efficient, and industrial production is achieved.

Description

Technical Field

[0001] The invention relates to the field of organic synthetic chemistry, and in particular to a hydroxyl selective phosphorylation protection method based on an iron catalyst and an application thereof. Background Art

[0002] Sugar molecules, as one of the widely existing biological molecules in nature, play a vital role in life activities. On the other hand, organophosphorus compounds, with their unique chemical properties, have shown broad application prospects in organic synthesis, materials science, life sciences and other fields. By cleverly introducing phosphate groups into the structure of sugar molecules, not only new chemical and biological activities are added to sugar compounds, but also their application range in multiple fields is greatly expanded. However, since sugar molecules contain multiple hydroxyl functional groups, multiple potential sites with similar reactivity are formed, which makes it particularly difficult to introduce phosphate groups at specific sites.

[0003] Traditional chemical synthesis methods often cannot directly complete this complex modification process, but require cumbersome protection and deprotection strategies to achieve phosphorylation of hydroxyl groups at specific sites and achieve precise control of site selectivity. For example, Kobayashi, S. et al. first used protection and deprotection strategies to pre-protect the 2,3 hydroxyl groups of riboside, and obtained a 2,3-benzyl protected substrate with a total yield of about 60% in three steps, and then phosphorylated the 5 hydroxyl group to obtain the corresponding 5 hydroxyl phosphorylated product under the catalysis of zinc salt. The synthetic route is as follows:

[0004] In addition, although phosphitylation is a type of acylation, its reaction activity is much lower than that of ordinary acyl chlorides and its synthesis is difficult. At the same time, due to the specificity and selectivity of the catalyst, the catalysts commonly used in acylation reactions, such as stannous chloride, are not necessarily suitable for phosphitylation reactions, and stannous chloride is highly toxic. Summary of the invention

[0005] The purpose of the present invention is to overcome the above technical deficiencies, provide a hydroxyl selective phosphorylation protection method based on an iron catalyst and its application, and solve the technical problems of complex synthesis steps, low selectivity or low yield of phosphorylation of polyhydroxy glycoside substrates in the prior art.

[0006] In order to achieve the above technical purpose, the technical solution provided by the present invention is: In a first aspect, the present invention provides a selective phosphorylation protection method based on an iron catalyst, comprising the following steps: mixing a polyhydroxy substrate, an aprotic solvent, an iron catalyst, an acid binding agent and a phosphorylation agent, performing a phosphorylation reaction, and obtaining a selective phosphorylation protection product through post-treatment.

[0007] Preferably, the molar volume ratio of the polyhydroxy substrate to the aprotic solvent is 1 mmol: (5-10) mL.

[0008] Preferably, the polyhydroxy substrate comprises a glycoside derivative containing more than two hydroxyl groups.

[0009] Further preferably, the glycoside derivative includes a mannoside derivative, a galactoside derivative, a rhamnoside derivative, a fucoside derivative or a glucoside derivative.

[0010] More preferably, the glycoside derivatives include methyl-6-tert-butyldimethylsilyl-α-D-pyranoside, methyl 4,6- O -Benzylidene-α-D-mannopyranoside, p-methylphenylthio-6-tert-butyldimethylsilyl-α-D-mannopyranoside, methyl-6-tert-butyldimethylsilyl-β-D-galactopyranoside, methyl-2,6- O -Benzyl-α-D-galactopyranoside, methyl-α-L-rhamnopyranoside, p-methylphenylthio-β-L-fucoside, methyl 4,6- O -Benzylidene-α-D-glucopyranoside, methyl-4,6- O -Benzylidene-β-D-glucopyranoside, methyl-2,3- O -Benzyl-α-D-mannoside, methyl-β-D-galactopyranoside, methyl-α-D-mannoside.

[0011] Preferably, the aprotic solvent includes acetonitrile, dichloromethane or N,N -Dimethylformamide.

[0012] Preferably, the molar ratio of the polyhydroxy substrate to the iron catalyst is 1:(0.05-0.1).

[0013] Preferably, the iron catalyst includes tris(2,2,6,6-tetramethyl-3,5-heptanedione)iron, or the iron catalyst is prepared from an iron salt and a ligand in an alkaline environment; when the iron catalyst is tris(2,2,6,6-tetramethyl-3,5-heptanedione)iron, the polyhydroxy substrate is dissolved in an aprotic solvent, and then the iron catalyst, an acid binding agent and a phosphating agent are added to carry out a phosphating reaction; when the iron catalyst is prepared from an iron salt and a ligand in an alkaline environment, the iron salt and the ligand are first mixed in a molar ratio of 1: (2 to 3), and then the acid binding agent and the aprotic solvent are added and stirred to generate the iron catalyst in situ; then the polyhydroxy substrate and the phosphating agent are added and mixed to carry out a phosphating reaction.

[0014] Preferably, the molar ratio of the polyhydroxy substrate to the acid binding agent is 1:(1.2-4).

[0015] Preferably, the acid binding agent comprises N,N-Diisopropylethylamine or triethylamine.

[0016] Preferably, the molar ratio of the polyhydroxy substrate to the phosphating agent is 1:(1-3).

[0017] Preferably, the phosphating agent comprises diphenylphosphinoyl chloride or diisopropyl chlorophosphate.

[0018] Preferably, the phosphorylation reaction is carried out at room temperature for 2 to 8 hours.

[0019] Preferably, the post-treatment comprises evaporating the solvent under reduced pressure, separating by column chromatography and drying.

[0020] In a second aspect, the present invention provides an application of a selective phosphorylation protection method based on an iron catalyst in the synthesis of phosphorylated protected glycosides.

[0021] Compared with the prior art, the beneficial effects of the present invention include: The present invention dissolves a polyhydroxy substrate containing more than two hydroxyl groups in an aprotic solvent, then adds an iron catalyst, an acid binding agent and a phosphating agent to complete the raw material mixing, and under the action of the iron catalyst, the polyhydroxy substrate reacts with the phosphating agent, so that one or two hydroxyl groups in the polyhydroxy substrate can be protected by the phosphoryl group with a high degree of selectivity; the present invention successfully realizes an efficient and highly selective phosphorylation process for polyhydroxy substrates, and is particularly suitable for glycoside substrates, and the obtained product has high purity, clear structure and high yield. The iron catalyst and the phosphating agent are economical, paving the way for industrial production, and the reaction conditions of the present invention are mild, the operation is simple and efficient, and it is conducive to realizing industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The product obtained in Example 1 of the present invention 1 H-NMR spectrum; Figure 2 The product obtained in Example 1 of the present invention 13 C-NMR spectrum; Figure 3 The product obtained in Example 1 of the present invention 31 P-NMR spectrum; Figure 4 The product obtained in Example 2 of the present invention 1 H-NMR spectrum; Figure 5 The product obtained in Example 2 of the present invention 13 C-NMR spectrum; Figure 6 The product obtained in Example 2 of the present invention 31 P-NMR spectrum; Figure 7 The product obtained in Example 3 of the present invention1 H-NMR spectrum; Figure 8 The product obtained in Example 3 of the present invention 13 C-NMR spectrum; Fig. 9 The product obtained in Example 3 of the present invention 31 P-NMR spectrum; Fig.10 The product obtained in Example 4 of the present invention 1 H-NMR spectrum; Fig.11 The product obtained in Example 4 of the present invention 13 C-NMR spectrum; Fig.12 The product obtained in Example 4 of the present invention 31 P-NMR spectrum; Fig.13 The product obtained in Example 5 of the present invention 1 H-NMR spectrum; Fig.14 The product obtained in Example 5 of the present invention 13 C-NMR spectrum; Fig.15 The product obtained in Example 5 of the present invention 31 P-NMR spectrum; Fig.16 The product obtained in Example 6 of the present invention 1 H-NMR spectrum; Fig.17 The product obtained in Example 6 of the present invention 13 C-NMR spectrum; Fig.18 The product obtained in Example 6 of the present invention 31 P-NMR spectrum; Fig.19 The product obtained in Example 7 of the present invention 1 H-NMR spectrum; Fig. 20 The product obtained in Example 7 of the present invention 13 C-NMR spectrum; Fig.21 The product obtained in Example 7 of the present invention 31 P-NMR spectrum; Fig. 22 The product obtained in Example 8 of the present invention 1 H-NMR spectrum; Fig.23 The product obtained in Example 8 of the present invention 13 C-NMR spectrum; Fig.24 The product obtained in Example 8 of the present invention31 P-NMR spectrum; Fig.25 The product obtained in Example 9 of the present invention 1 H-NMR spectrum; Fig.26 The product obtained in Example 9 of the present invention 13 C-NMR spectrum; Fig. 27 The product obtained in Example 9 of the present invention 31 P-NMR spectrum. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0024] The present invention provides a method for selectively phosphating hydroxyl groups based on an iron catalyst and application thereof. The method is a method for selectively protecting hydroxyl groups, which is not only environmentally friendly but also has mild reaction conditions, simple and efficient operation.

[0025] In a first aspect, the present invention provides a selective phosphorylation protection method based on an iron catalyst, comprising the following steps: The polyhydroxy substrate, a non-protonic solvent, an iron catalyst, an acid binding agent and a phosphorylation agent are mixed to carry out a phosphorylation reaction, and a selective phosphorylation protection product is obtained through post-treatment.

[0026] In some preferred embodiments, the molar volume ratio of the polyhydroxy substrate to the aprotic solvent is 1 mmol: (5-10) mL, including but not limited to 1 mmol: 5 mL, 1 mmol: 6 mL, 1 mmol: 7 mL, 1 mmol: 8 mL, 1 mmol: 9 mL or 1 mmol: 10 mL, etc.

[0027] In some preferred embodiments, the polyhydroxy substrate comprises a glycoside derivative containing more than two hydroxyl groups.

[0028] Further preferably, the glycoside derivative includes a mannoside derivative, a galactoside derivative, a rhamnoside derivative, a fucoside derivative or a glucoside derivative.

[0029] More preferably, the glycoside derivatives include methyl-6-tert-butyldimethylsilyl-α-D-pyranoside, methyl 4,6- O -Benzylidene-α-D-mannopyranoside, p-methylphenylthio-6-tert-butyldimethylsilyl-α-D-mannopyranoside, methyl-6-tert-butyldimethylsilyl-β-D-galactopyranoside, methyl-2,6-O -Benzyl-α-D-galactopyranoside, methyl-α-L-rhamnopyranoside (CAS: 14917-55-6), p-methylphenylthio-β-L-fucoside, methyl 4,6- O -Benzylidene-α-D-pyranoglucoside (CAS: 3162-96-7), methyl-4,6- O -Benzylidene-β-D-glucopyranoside, methyl-2,3- O -Benzyl-α-D-mannoside methyl, methyl-β-D-galactopyranoside (CAS: 1824-94-8), methyl-α-D-mannopyranoside (CAS: 617-04-9). The above glycoside derivatives are all prepared by known preparation methods of those skilled in the art or can be purchased.

[0030] In some preferred embodiments, the aprotic solvent includes acetonitrile, dichloromethane or N,N -Dimethylformamide.

[0031] In some preferred embodiments, the molar ratio of the polyhydroxy substrate to the iron catalyst is 1:(0.05-0.1), including but not limited to 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09 or 1:0.1, etc.; more preferably 1:0.1.

[0032] In some preferred embodiments, the iron catalyst includes tris(2,2,6,6-tetramethyl-3,5-heptanedione)iron, or the iron catalyst is prepared from an iron salt and a ligand in an alkaline environment.

[0033] More preferably, when the iron catalyst is tris(2,2,6,6-tetramethyl-3,5-heptanedione)iron, the polyhydroxy substrate is dissolved in an aprotic solvent, and then the iron catalyst, acid binding agent and phosphating agent are added to carry out the phosphating reaction.

[0034] Further preferably, when the iron catalyst is prepared from an iron salt and a ligand in an alkaline environment, the iron salt and the ligand are first mixed in a molar ratio of 1: (2-3), and then an acid binding agent and a non-protonic solvent are added and stirred to generate an iron catalyst in situ; then a polyhydroxy substrate and a phosphating agent are added and mixed to carry out a phosphating reaction.

[0035] More preferably, the iron salt includes ferric chloride, and the ligand includes 2,2,6,6-tetramethyl-3,5-heptanedione; and the molar ratio of ferric chloride to 2,2,6,6-tetramethyl-3,5-heptanedione is 1:2.

[0036] In some preferred embodiments, the molar ratio of the polyhydroxy substrate to the acid binding agent is 1:(1.2-4), including but not limited to 1:1.2, 1:1.5, 1:1.7, 1:2, 1:2.4, 1:2.8, 1:3, 1:3.2, 1:3.5 or 1:4, etc.; more preferably 1:1.5.

[0037] In some preferred embodiments, the acid binding agent comprises N,N -Diisopropylethylamine or triethylamine.

[0038] In some preferred embodiments, the molar ratio of the polyhydroxy substrate to the phosphating agent is 1:(1-3), including but not limited to 1:1, 1:1.2, 1:1.3, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8 or 1:3, etc.; more preferably 1:1.2.

[0039] In some preferred embodiments, the phosphating agent includes diphenylphosphinoyl chloride or diisopropyl chlorophosphate.

[0040] In some preferred embodiments, the phosphitylation reaction is carried out at room temperature for 2 to 8 hours, and the reaction time includes but is not limited to 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h or 8h.

[0041] In some preferred embodiments, the post-treatment comprises evaporating the solvent under reduced pressure, separating by column chromatography and drying.

[0042] In a second aspect, the present invention provides an application of a selective phosphorylation method based on an iron catalyst in the synthesis of phosphorylated protected glycosides.

[0043] The main mechanism of action and advantages of the present invention: (1) The present invention dissolves a polyhydroxy substrate containing more than two hydroxyl groups, especially a sugar substrate, in an appropriate amount of aprotic solvent, then adds an acid-binding agent in an amount equivalent to or slightly in excess of the substrate, and reacts the polyhydroxy substrate with a phosphating agent under the action of an iron catalyst, so that one or two hydroxyl groups in the polyhydroxy substrate can be protected by phosphoryl groups with high selectivity; (2) The iron catalyst used in the present invention is preferably tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron [Fe(dipm)3], which is green, non-toxic, cost-effective and easily available. It is further combined with the phosphating agent diphenylphosphinoyl chloride to achieve efficient and highly selective phosphating of glycoside substrates under mild reaction conditions. This method cleverly avoids the cumbersome multi-step protection and deprotection steps in the traditional process, thereby greatly improving the reaction efficiency and product yield; (3) The present invention selectively phosphates with an iron catalyst to efficiently and selectively introduce organic phosphorus groups into polyhydroxy substrates such as glycosides, and the resulting products are of high purity and clear structure. More importantly, this technology has shown extremely high applicability and flexibility in treating polyhydroxy substrates, especially sugar substrates, greatly broadening its scope of application; (4) The iron catalyst and the phosphating agent of the present invention are economical, paving the way for industrial production. The entire reaction process of the present invention is carried out at room temperature. After the reaction is completed, the solvent is removed by decompression operation, and the product is separated to easily obtain a product in which the hydroxyl group is highly selectively protected. The operation steps are simple, which is conducive to industrial production and shows huge market potential and commercial value.

[0044] Therefore, the present invention adopts the strategy of iron catalyst to realize the selective phosphorylation process of polyhydroxy substrates, filling the gap in the prior art for the selective phosphorylation method of 1,2-diols (including sugar substrates). It is an efficient, environmentally friendly and highly selective new approach, which is both green and economical, and has high selectivity and wide substrate applicability. It can be used for the selective phosphorylation of ortho-hydroxyl and polyhydroxyl substrates, especially for the efficient introduction of phosphorus groups into glycoside substrates to synthesize partially phosphoryl-protected glycosides.

[0045] The present invention is further described in detail below through specific examples.

[0046] Example 1

[0047] 30.8 mg (0.1 mmol) of methyl-6-tert-butyldimethylsilyl-α-D-pyranoside was dissolved in 1.0 ml of acetonitrile, and 0.01 mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company) was added, as well as 0.15 mmol N,N-diisopropylethylamine and 0.12 mmol diphenylphosphinoyl chloride. The reaction mixture was stirred at room temperature for 2 hours. After that, the solvent was evaporated under reduced pressure, separated and dried by column chromatography, and finally 50.3 mg of compound 1: 3-diphenylphosphinoyl-methyl-6-tert-butyldimethylsilyl-α-D-pyranoside was obtained, with a yield of 99%.

[0048] Its NMR spectrum data is as follows Figures 1 to 3 As shown, NMR analysis confirmed that the product was a single 3-diphenyloxyphosphinoyl derivative.

[0049] Example 2

[0050] 30.8 mg (0.1 mmol) of methyl-6-tert-butyldimethylsilyl-α-D-pyranoside was dissolved in 1.0 ml of acetonitrile, and 0.01 mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company) was added, as well as 0.20 mmol N,N-diisopropylethylamine and 0.15 mmol diisopropyl chlorophosphate. The reaction mixture was stirred at room temperature for 2 hours. After that, the solvent was evaporated under reduced pressure, separated and dried by column chromatography, and finally 36.8 mg of compound 2: 3-diisopropoxyphosphino-methyl-6-tert-butyldimethylsilyl-α-D-pyranoside was obtained, with a yield of 78%.

[0051] Its NMR spectrum data is as follows Figures 4 to 6 As shown, NMR analysis confirmed that the product was a single 3-position diisopropoxyphosphoyl derivative.

[0052] Example 3

[0053] Take 28.2 mg (0.1 mmol) of methyl 4,6- O -benzylidene-α-D-pyranoside was dissolved in 1.0 ml of acetonitrile, and 0.01 mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company) was added, as well as 0.15 mmol N,N-diisopropylethylamine and 0.12 mmol diphenylphosphinoyl chloride. The reaction mixture was stirred at room temperature for 2 hours. After that, the solvent was evaporated under reduced pressure, separated and dried by column chromatography, and finally 43.5 mg of compound 3 was obtained: 3-diphenyloxyphosphinoyl-methyl 4,6- O -Benzylidene-α-D-pyranoside, yield 90%.

[0054] Its NMR spectrum data is as follows Figures 7 to 9 As shown, NMR analysis confirmed that the product was a single 3-diphenyloxyphosphinoyl derivative.

[0055] Example 4

[0056] Take 0.1mmol of p-methylphenylthio-6-tert-butyldimethylsilyl-α-D-pyranoside, dissolve it in 1.0ml of acetonitrile, add 0.01mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company), 0.15mmol N,N-diisopropylethylamine and 0.12mmol diphenylphosphinoyl chloride. The reaction mixture is stirred at room temperature for 2 hours. After that, the solvent is evaporated under reduced pressure, separated and dried by column chromatography, and finally 56.5mg of compound 4: 3-diphenyloxyphosphinoyl-p-methylphenylthio-6-tert-butyldimethylsilyl-α-D-pyranoside is obtained, with a yield of 94%.

[0057] Its NMR spectrum data is as follows Figures 10 to 12 As shown, NMR analysis confirmed that the product was a single 3-diphenyloxyphosphinoyl derivative.

[0058] Example 5

[0059] Take 0.1mmol of methyl-6-tert-butyldimethylsilyl-β-D-pyranogalactoside, dissolve it in 1.0ml of acetonitrile, add 0.01mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company), 0.15mmol N,N-diisopropylethylamine and 0.12mmol diphenylphosphinoyl chloride. The reaction mixture is stirred at room temperature for 2 hours. After that, the solvent is evaporated under reduced pressure, separated and dried by column chromatography, and finally 47.3mg of compound 5: 3-diphenylphosphinoyl-methyl-6-tert-butyldimethylsilyl-β-D-pyranogalactoside is obtained, with a yield of 93%.

[0060] Its NMR spectrum data is as follows Figures 13 to 15 As shown, NMR analysis confirmed that the product was a single 3-diphenyloxyphosphinoyl derivative.

[0061] Example 6

[0062] Take 0.1mmol methyl-2,6- O-benzyl-α-D-galactopyranoside was dissolved in 1.0 ml of acetonitrile, and 0.01 mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company) was added, as well as 0.15 mmol N,N-diisopropylethylamine and 0.12 mmol diphenylphosphinoyl chloride. The reaction mixture was stirred at room temperature for 2 hours. After that, the solvent was evaporated under reduced pressure, separated and dried by column chromatography, and finally 54.0 mg of compound 6 was obtained: 3-diphenylphosphinoyl-methyl-2,6- O -Benzyl-α-D-galactopyranoside, yield 94%.

[0063] Its NMR spectrum data is as follows Figures 16 to 18 As shown, NMR analysis confirmed that the product was a single 3-diphenyloxyphosphinoyl derivative.

[0064] Example 7

[0065] Take 0.1mmol of methyl-α-L-rhamnoside and dissolve it in 1.0ml of acetonitrile, add 0.01mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company), 0.25mmol N,N-diisopropylethylamine and 0.20mmol diphenylphosphinoyl chloride. The reaction mixture was stirred at room temperature for 4 hours. After that, the solvent was evaporated under reduced pressure, separated and dried by column chromatography, and finally 37.0mg of compound 7: 3-diphenylphosphinoyl-methyl-α-L-rhamnoside was obtained, with a yield of 97%.

[0066] Its NMR spectrum data is as follows Figures 19 to 21 As shown, NMR analysis confirmed that the product was a single 3-diphenyloxyphosphinoyl derivative.

[0067] Example 8

[0068] 0.1 mmol of p-methylphenylthio-β-L-fucoside was dissolved in 1.0 ml of acetonitrile, and 0.01 mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company) was added, as well as 0.25 mmol of N,N-diisopropylethylamine and 0.20 mmol of diphenylphosphinoyl chloride. The reaction mixture was stirred at room temperature for 4 hours. After that, the solvent was evaporated under reduced pressure, separated and dried by column chromatography, and finally 42.0 mg of compound 8: 3-diphenyloxyphosphinoyl-p-methylphenylthio-β-L-fucoside was obtained, with a yield of 89%.

[0069] Its NMR spectrum data is as follows Figure 22 to Figure 24 As shown, NMR analysis confirmed that the product was a single 3-diphenyloxyphosphinoyl derivative.

[0070] Example 9

[0071] Take 0.1mmol methyl 4,6- O -benzylidene-α-D-pyranoglucoside was dissolved in 1.0 ml of acetonitrile, and 0.01 mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company) was added, as well as 0.25 mmol N,N-diisopropylethylamine and 0.20 mmol diphenylphosphinoyl chloride. The reaction mixture was stirred at room temperature for 4 hours. After that, the solvent was evaporated under reduced pressure, separated and dried by column chromatography, and finally 44.0 mg of compound 9 was obtained: 2-diphenyloxyphosphinoyl-methyl 4,6- O -Benzylidene-α-D-pyranoglucoside, yield 91%.

[0072] Its NMR spectrum data is as follows Figure 25 to Figure 27 As shown, NMR analysis confirmed that the product was a single 2-diphenyloxyphosphinoyl derivative.

[0073] Example 10

[0074] Take 0.2mmol methyl-4,6- O -benzylidene-β-D-pyranoglucoside was dissolved in 2.0 ml of acetonitrile, and 0.02 mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company) was added, as well as 0.25 mmol N,N-diisopropylethylamine and 0.20 mmol diphenylphosphinoyl chloride. The reaction mixture was stirred at room temperature for 4 hours. After that, the solvent was evaporated under reduced pressure, separated and dried by column chromatography, and finally 53.0 mg of compound 10a was obtained: 2-diphenyloxyphosphinomethyl-4,6- O -benzylidene-β-D-pyranoglucopyranoside, yield 55%; and 34.5 mg of compound 10b: 3-diphenylphosphinoyl-methyl-4,6- O -Benzylidene-β-D-pyranoglucoside, yield 35%.

[0075] Its NMR spectrum data are as follows: Compound 10a: 11H NMR (400 MHz, Chloroform- d ) δ 7.94 - 7.81 (m, 4H), 7.59 – 7.43 (m, 8H), 7.36 - 7.31 (m, 3H), 5.72 (s, 1H), 5.51 (s, 1H), 4.58 (d, J = 7.5Hz, 1H), 4.38 – 4.31 (m, 1H), 4.11 (q, J = 7.1 Hz, 1H), 4.05 (t, J = 8.1 Hz, 1H), 3.89 (q, J = 7.6 Hz, 1H), 3.72 (t, J = 9.9 Hz, 1H), 3.58 (s, 3H), 3.53 – 3.50 (m, 1H). 13 13C NMR (101 MHz, Chloroform- d ) δ 137.1, 133.0, 132.9 (d, J = 4.3 Hz), 132.7(d, J = 2.9 Hz), 131.5 (d, J = 10.5 Hz), 130.1, 129.2, 128.8 (d, J = 3.8 Hz), 128.7(d, J = 4.2 Hz), 128.3, 127.9, 126.4, 102.8 (d, J = 9.7 Hz), 102.0, 80.6 (d, J =7.5 Hz), 80.2, 72.4, 68.6, 66.3, 57.5. 31 31P NMR (162 MHz, Chloroform- d ) δ 36.61. Compound 10b: 1 1H NMR (400 MHz, Chloroform- d) δ 7.92-7.86 (m, 2H), 7.79 –7.74 (m, 2H), 7.54 – 7.40 (m, 9H), 7.31 – 7.25 (m, 2H), 5.91 (s, 1H), 5.59(s, 1H), 4.38 – 4.24 (m, 3H), 3.85 – 3.73 (m, 3H), 3.59 (s, 3H), 3.40-3.34(m, 1H). 13 C NMR (101 MHz, Chloroform- d ) δ 137.2, 133.1, 133.0, 133.0 (d, J = 3.0Hz), 132.7 (d, J = 2.9 Hz), 131.4, 131.3, 129.4, 128.8, 128.7, 128.4, 126.4,104.7, 101.8, 80.2 (d, J = 6.9 Hz), 79.0 (d, J = 7.2 Hz), 73.7, 68.8, 65.9,57.7. 31 P NMR (162 MHz, Chloroform- d ) δ 37.59. NMR analysis confirmed that product 10a was a 2-diphenyloxyphosphinoyl derivative, and product 10b was a 3-diphenyloxyphosphinoyl derivative.

[0076] Embodiment 11

[0077] Take 0.1mmol methyl-2,3- O Benzyl-α-D-mannose methyl glycoside was dissolved in 1.0 ml of acetonitrile, and 0.01 mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company) was added, as well as 0.15 mmol N,N-diisopropylethylamine and 0.12 mmol diphenylphosphinoyl chloride. The reaction mixture was stirred at room temperature for 2 hours. After that, the solvent was evaporated under reduced pressure, separated and dried by column chromatography, and finally 57.0 mg of compound 11 was obtained: 6-diphenylphosphinoyl-methyl-2,3- O -Benzyl-α-D-mannose methyl glycoside, yield 99%.

[0078] Its NMR spectrum data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.88-7.78 (m, 4H), 7.54 (t, J = 7.4Hz, 1H), 7.49 – 7.41 (m, 3H), 7.40 – 7.25 (m, 12H), 4.82 – 4.72 (m, 3H), 4.68(dd, J = 12.1, 4.7 Hz, 2H), 4.50 – 4.42 (m, 1H), 4.30 (t, J = 9.6 Hz, 1H), 4.23-4.17 (m, 1H), 4.04 – 3.97 (m, 1H), 3.83 – 3.76 (m, 2H), 3.70 (dt, J = 9.9, 2.7Hz, 1H), 3.32 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 138.8, 138.6, 132.5(d, J = 2.9 Hz), 132.3 (d, J = 2.9 Hz), 132.2, 132.1, 131.7, 131.6, 130.4, 130.3,128.8, 128.7 (d, J = 4.0 Hz), 128.5, 128.4 (d, J = 5.0 Hz), 127.8, 127.6 (d, J =5.8 Hz), 99.8, 79.2, 75.5, 73.1, 72.8, 72.4 (d, J = 4.9 Hz), 66.5, 64.1 (d, J =5.8 Hz), 54.9. 31 P NMR (162 MHz, Chloroform- d ) δ 35.14. NMR analysis confirmed that the product was a single 6-diphenyloxyphosphinoyl derivative.

[0079] Example 12

[0080] Take 0.1mmol of methyl-β-D-galactopyranoside, dissolve it in 1.0ml of acetonitrile, add 0.01mmol of commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company), 0.40mmol of N,N-diisopropylethylamine and 0.30mmol of diphenylphosphinoyl chloride. The reaction mixture is stirred at room temperature for 4 hours. After that, the solvent is evaporated under reduced pressure, separated and dried by column chromatography, and finally 57.0mg of compound 12: 3,6-bis(diphenyloxyphosphinoyl)-methyl-β-D-galactopyranoside is obtained, with a yield of 96%.

[0081] Its NMR spectrum data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.90 – 7.71 (m, 8H), 7.55 – 7.38(m,12H), 4.31 – 4.24 (m, 1H), 4.21 – 4.05 (m, 4H), 3.94 (dd, J = 9.2, 7.5 Hz, 1H), 3.69 – 3.59 (m, 2H), 3.48 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 132.7,132.6, 132.1, 132.0, 132.0, 131.9, 131.9, 131.8, 131.6, 131.5, 131.1, 130.2,129.8, 128.9, 128.8, 128.7, 104.1, 79.3, 72.9, 69.9, 67.4, 62.9, 57.0. 31 P NMR (162 MHz, Chloroform- d ) δ 35.23, 34.48. NMR analysis confirmed that the product was a single 3,6-bis(diphenyloxy)phosphinoyl derivative.

[0082] Embodiment 13

[0083] Take 0.1mmol methyl-α-D-pyranoside, dissolve it in 1.0ml acetonitrile, add 0.01mmol commercially purchased tris(2,2,6,6-tetramethyl-3,5-heptanedione) iron catalyst (source: Adamas Reagent Company), 0.40mmol N,N-diisopropylethylamine and 0.30mmol diphenylphosphinoyl chloride. The reaction mixture is stirred at room temperature for 4 hours. After that, the solvent is evaporated under reduced pressure, separated and dried by column chromatography, and finally 53.5mg of compound 13: 3,6-bis(diphenyloxyphosphinoyl)-methyl-α-D-pyranoside is obtained, with a yield of 90%.

[0084] Its NMR spectrum data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.93 – 7.77 (m, 8H), 7.55 – 7.39 (m,12H), 4.72 (s, 1H), 4.50 – 4.34 (m, 2H), 4.31 – 4.16 (m, 2H), 4.05 (s, 1H), 3.63-3.60 (m, 1H), 3.19 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 132.6 (dd, J =5.8, 2.9 Hz), 132.4 (t, J = 2.5 Hz), 132.0 (d, J = 1.8 Hz), 132.0, 131.9 (d, J =2.0 Hz), 131.9, 131.3 (d, J = 3.9 Hz), 131.2, 130.5, 129.9 (d, J = 5.3 Hz),129.8, 128.9, 128.7 (d, J = 2.7 Hz), 128.7, 128.6 (d, J = 2.7 Hz), 128.5, 101.1,78.6 (d, J = 7.1 Hz), 71.6 (d, J = 4.6 Hz), 70.2 (d, J = 4.6 Hz), 65.3 (d, J = 3.8Hz), 65.1 (d,J = 6.5 Hz), 54.8. 31 P NMR (162 MHz, Chloroform- d ) δ 35.06, 33.86. NMR analysis confirmed that the product was a single 3,6-bis(diphenyloxy)phosphinoyl derivative.

[0085] The substrates, products, yields and reaction conditions of the above examples were statistically analyzed and the results are shown in Table 1 below.

[0086] Table 1 Substrates, products and reaction conditions of Examples 1-13

[0087] Embodiment 14 Compared with Example 1, the difference is only that: replace N,N -diisopropylethylamine was used as an acid-binding agent, and the other steps and conditions were the same as those in Example 1. It was found that the target compound could be obtained with an isolated yield of 90%.

[0088] Embodiment 15 Compared with Example 1, the only difference is that: using dichloromethane or N,N -Dimethylformamide was used as the reaction solvent instead of acetonitrile, and the other steps and conditions were the same as those in Example 1. It was found that the target compound could be obtained with an isolation yield of more than 90%.

[0089] Example 16 Compared with Example 1, the only difference is that: a mixture obtained by mixing 0.01 mmol of ferric chloride and 2,2,6,6-tetramethyl-3,5-heptanedione (CAS: 1118-71-4) in a molar ratio of 1:2 is used to replace tris(2,2,6,6-tetramethyl-3,5-heptanedione)ferric acid, and the mixture is stirred in acetonitrile solvent for 0.5 hour with an acid binding agent (increased by 0.3 equivalents relative to Example 1) to generate an iron complex catalyst in situ, and then 0.1 mmol of methyl-6-tert-butyldimethylsilyl-α-D-pyranoside and 0.12 mmol of diphenylphosphinoyl chloride (the acid binding agent is no longer repeatedly added in the system) are added to react, and the other steps and conditions are the same as those in Example 1.

[0090] The results showed that the target compound could be obtained with an isolated yield of 88%.

[0091] Comparative Example 1 Compared with Example 1, the only difference is that the tris(2,2,6,6-tetramethyl-3,5-heptanedione)iron catalyst is removed, and the other steps and conditions are the same as those of Example 1. It was found that almost no target compound was obtained, and almost all the raw materials were recovered.

[0092] Comparative Example 2 Compared with Example 1, the only difference is that ferric chloride is used instead of tris(2,2,6,6-tetramethyl-3,5-heptanedione)iron catalyst, and the other steps and conditions are the same as those of Example 1. As a result, the target compound is obtained with an isolated yield of only 38%.

[0093] Comparative Example 3 Compared with Example 1, the only difference is that potassium carbonate is used instead of N,N -Diisopropylethylamine was used as the acid-binding agent, and the other steps and conditions were the same as those in Example 1. As a result, the target compound was obtained with an isolated yield of only 42%.

[0094] Comparative Example 4 Compared with Example 1, the only difference is that ethyl acetate is used instead of acetonitrile as the reaction solvent, and the other steps and conditions are the same as those of Example 1. It was found that the target compound was obtained with an isolated yield of only 31%.

[0095] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for selective phosphorylation protection of hydroxyl groups based on an iron catalyst, characterized in that: The following steps are involved: The polyhydroxy substrate, a non-protonic solvent, an iron catalyst, an acid binding agent and a phosphorylation agent are mixed to carry out a phosphorylation reaction, and a selective phosphorylation protection product is obtained through post-treatment.

2. The method for selective phosphating of hydroxyl groups based on an iron catalyst according to claim 1, characterized in that: The molar volume ratio of the polyhydroxy substrate to the aprotic solvent is 1 mmol: (5-10) mL.

3. The method for selective phosphating of hydroxyl groups based on an iron catalyst according to claim 1, characterized in that: The polyhydroxy substrate includes glycoside derivatives containing more than two hydroxyl groups.

4. The method for selective phosphating of hydroxyl groups based on an iron catalyst according to claim 3, characterized in that: The glycoside derivatives include mannoside derivatives, galactoside derivatives, rhamnoside derivatives, fucoside derivatives or glucoside derivatives.

5. The method for selective phosphating of hydroxyl groups based on an iron catalyst according to claim 1, characterized in that: The aprotic solvent includes acetonitrile, dichloromethane or N,N -Dimethylformamide.

6. The method for selective phosphating of hydroxyl groups based on an iron catalyst according to claim 1, characterized in that: The molar ratio of the polyhydroxy substrate to the iron catalyst is 1:(0.05-0.1).

7. The method for selective phosphating protection of hydroxyl groups based on an iron catalyst according to claim 1, characterized in that: The iron catalyst includes tris(2,2,6,6-tetramethyl-3,5-heptanedione)iron, or the iron catalyst is prepared from an iron salt and a ligand in an alkaline environment; When the iron catalyst is tris(2,2,6,6-tetramethyl-3,5-heptanedione)iron, the polyhydroxy substrate is dissolved in an aprotic solvent, and then the iron catalyst, an acid binding agent and a phosphating agent are added to carry out a phosphating reaction; When the iron catalyst is prepared from an iron salt and a ligand in an alkaline environment, the iron salt and the ligand are first mixed in a molar ratio of 1: (2-3), and then an acid-binding agent and a non-protonic solvent are added and stirred to generate an iron catalyst in situ; then a polyhydroxy substrate and a phosphating agent are added and mixed to carry out a phosphating reaction.

8. The method for selective phosphating of hydroxyl groups based on an iron catalyst according to claim 1, characterized in that: The molar ratio of the polyhydroxy substrate to the acid binding agent is 1:(1.2-4); The acid binding agent comprises N,N -Diisopropylethylamine or triethylamine.

9. The method for selective phosphating protection of hydroxyl groups based on an iron catalyst according to claim 1, characterized in that: The molar ratio of the polyhydroxy substrate to the phosphorylation agent is 1:(1-3); The phosphating agent includes diphenylphosphinoyl chloride or diisopropyl chlorophosphate; The phosphorylation reaction is carried out at room temperature for 2 to 8 hours.

10. Use of the hydroxyl selective phosphorylation protection method based on an iron catalyst as claimed in any one of claims 1 to 9 in the synthesis of phosphorylated protected glycosides.

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