Selective phosphorylation synthesis method

Abstract

The invention discloses a selective phosphorylation synthesis method which comprises the following steps: dispersing a hydroxyl substrate in an aprotic solvent, adding an acid-binding agent, a catalyst and dibenzyl phosphite, reacting at 25-30 DEG C for 10-12 hours, and then concentrating and purifying to obtain a monophosphorylation glycoside product, the catalyst is Fe (dipm) 3; the hydroxyl substrate is an alcohol compound or a glycoside compound containing at least one hydroxyl group. According to the invention, in-situ conversion of dibenzyl phosphite into dibenzyl chlorophosphate in a reaction system is realized by a one-pot method strategy, and high-regioselectivity phosphorylation of an alcohol or glycoside substrate is realized in the presence of an iron catalyst; the complex steps and harsh conditions of synthesizing, separating and purifying the dibenzyl chlorophosphate in advance in the prior art are avoided, the high-regioselectivity phosphorylation of the alcohol or glycoside compound is realized, the process is simple, the yield is high, and the method is suitable for popularization and application.

Description

A selective phosphorylation synthesis method Technical Field

[0001] This invention relates to the field of organic synthetic chemistry, and in particular to a selective phosphorylation synthesis method. Background Technology

[0002] Phosphylation is an important organic transformation that introduces phosphoryl groups and has wide applications in medicinal chemistry, chemical biology, and materials science. Phosphophosphates are commonly used phosphorylation reagents, but they are generally sensitive to moisture, have poor stability, and are inconvenient to store and transport. In particular, dibenzyl chlorophosphate is not stable enough when it exists alone, which limits its widespread use.

[0003] In existing technologies, phosphorylation of polyhydroxy compounds (such as sugars) typically requires the prior synthesis and purification of unstable phosphorylating agents (such as dibenzyl chlorophosphate), a cumbersome process with demanding conditions. Currently, hydroxyl phosphorylation strategies mainly rely on Lewis acids or nucleophilic catalysts (such as pyridine-N-oxides, titanium complexes, 4-(dimethylamino)pyridine, etc.). While these systems can achieve phosphorylation of common alcohols, they generally suffer from poor regioselectivity when dealing with structurally complex sugar molecules, making it difficult to achieve specific monophosphorylation of diols or polyhydroxy substrates. For example, the SnCl2 catalytic system readily undergoes intramolecular cyclization side reactions when acting on glycoside substrates containing 1,2-cis-diols, generating thermodynamically more stable five-membered cyclic phosphate esters rather than the target monophosphorylated product. Although hemiboric acid catalysts can effectively recognize 1,2-cis-diol structures, they struggle to achieve effective phosphorylation modification of 1,2-trans-diols in competitive experiments, and regioselectivity control remains a challenge. In addition, existing methods for the phosphorylation of common monools or simple polyols also face the problem of relying on unstable phosphorylating reagents (such as chlorophosphates). The pre-synthesis, separation and purification steps are cumbersome, which restricts the process of efficient and large-scale preparation.

[0004] Therefore, developing a one-pot phosphorylation strategy that can avoid the pre-preparation of unstable phosphorylation reagents and has both high regioselectivity and broad substrate applicability is of great scientific significance and application prospect. Summary of the Invention

[0005] The purpose of this invention is to provide a selective phosphorylation synthesis method to solve the problems of unstable preparation and poor regioselectivity in existing phosphorylation polyhydroxy compound synthesis methods.

[0006] To address the aforementioned technical problems, this invention provides a selective phosphorylation synthesis method, which includes the following steps: dispersing a hydroxyl substrate in an aprotic solvent, adding an acid-binding agent, a catalyst, and dibenzyl phosphite, reacting at 25–30°C for 10–12 h, followed by concentration and purification to obtain a monophosphorylated glycoside product; the catalyst is tris(2,2,6,6-tetramethyl-3,5-heptanedikelic acid)ferric; the hydroxyl substrate is an alcohol or glycoside compound containing at least one hydroxyl group.

[0007] In some embodiments, the aprotic solvent includes acetonitrile and carbon tetrachloride. More preferably, the aprotic solvent is a mixture of acetonitrile and carbon tetrachloride, and the volume ratio of acetonitrile to carbon tetrachloride is 1:1.

[0008] In some embodiments, the ratio of hydroxyl substrate to aprotic solvent is 1 mmol: (8–12) mL.

[0009] In some embodiments, the molar ratio of the hydroxyl group in the hydroxyl substrate to the acid binder, catalyst, and dibenzyl phosphite is 1:(3-5):(0.05-0.1):(1.2-2.0).

[0010] In some embodiments, the acid-binding agent is N,N-diisopropylethylamine.

[0011] In some embodiments, the hydroxyl substrate includes at least one selected from ethanol, benzyl alcohol, cyclohexanol, 2-methyl-2,4-pentanediol, 6-tert-butyldiphenylsilyl-α-D-mannose, 6-tert-butyldimethylsilyl-α-D-galactosyl, 4,6-benzylidene-α-D-mannose, 2,3-benzyl-β-D-galactosyl, and 2,3-benzoyl-β-D-glucoside.

[0012] In some implementations, the concentration and purification process involves sequentially performing reduced pressure concentration and column chromatography purification.

[0013] Unlike existing technologies, the advantages of this invention are as follows: 1. Avoidance of unstable intermediate separation and mild reaction conditions: This invention employs a highly integrated one-pot strategy, using commercially available and stable dibenzyl phosphite as the starting material. Dibenzyl chlorophosphate intermediate is generated in situ during the reaction, eliminating the need for separation and purification, and can be directly used for subsequent phosphorylation reactions. This process significantly shortens the reaction pathway, is simple and efficient, reduces material loss and operational complexity caused by intermediate instability, and improves reaction efficiency and overall yield. Simultaneously, using moisture-insensitive dibenzyl phosphite instead of the traditional unstable dibenzyl chlorophosphate makes raw material storage and handling safer and more convenient. The entire reaction is carried out at room temperature, requiring no special equipment or stringent control, resulting in low energy consumption and environmentally friendly operation.

[0014] 2. High regioselectivity and strong substrate adaptability: Without any ligands or conventional catalysts, the reaction almost stalls, with very little product formation. However, the phosphorylation reaction catalyzed by Fe(dipm)3 in this invention exhibits optimal catalytic efficiency, demonstrating the crucial role of ligands in driving this reaction. On one hand, the phosphorylation reaction in this invention demonstrates excellent regiorecognition of specific hydroxyl groups (such as primary or secondary hydroxyl groups) on the sugar ring, enabling efficient and highly selective monophosphorylation of complex polyhydroxy substrates. On the other hand, the method of this invention not only solves the problem of selective phosphorylation of complex sugar substrates but is also applicable to the efficient phosphorylation of simple monools (such as ethanol and cyclohexanol) to structural polyols (such as 2-methyl-2,4-pentanediol), significantly expanding the application boundaries of this method.

[0015] 3. The process is economical and practical, with industrialization potential: all reagents used are commercially available and reasonably priced; the one-pot process significantly reduces time and labor costs, the operation process is simple and easy to scale up, providing a reliable technical route for the large-scale preparation of phosphorylated sugar derivatives, and has broad application prospects in drug synthesis, sugar vaccine development and other fields. Attached Figure Description

[0016] Figure 1 is the NMR spectrum of compound 1 prepared in Example 1 of the present invention; Figure 2 is the NMR spectrum of compound 4 prepared in Example 2 of the present invention; Figure 3 is the NMR spectrum of compound 6 prepared in Example 3 of the present invention; Figure 4 is the NMR spectrum of compound 9 prepared in Example 4 of the present invention; Figure 5 is the NMR spectrum of compound 11 prepared in Example 5 of the present invention; Figure 6 is the NMR spectrum of compound 14 prepared in Example 6 of the present invention; Figure 7 is a yield comparison chart of the synthesis using compounds 1-16 as hydroxyl substrates in the present invention. Detailed Implementation

[0017] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0018] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the invention; the terms “comprising” and “having”, and any variations thereof, in the specification, claims, and foregoing description of the invention, are intended to cover non-exclusive inclusion.

[0019] The "range" disclosed in this invention is defined in the form of a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for specific parameters, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this application, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0020] In this invention, the reference to "embodiment" means that a specific feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of the invention. The appearance of this phrase in various places throughout the specification does not necessarily refer to the same embodiment, nor is it a mutually exclusive, independent, or alternative embodiment. It will be explicitly and implicitly understood by those skilled in the art that the embodiments described herein can be combined with other embodiments.

[0021] In existing technologies, phosphorylation of polyhydroxy compounds (such as sugars) typically requires the prior synthesis and purification of unstable phosphorylating agents (such as dibenzyl chlorophosphate), a cumbersome process with demanding conditions. Currently, hydroxy phosphorylation strategies mainly rely on Lewis acids or nucleophilic catalysts (such as pyridine-N-oxides, titanium complexes, 4-(dimethylamino)pyridine, etc.). While these systems can achieve phosphorylation of common alcohols, they generally suffer from poor regioselectivity when dealing with structurally complex sugar molecules, making it difficult to achieve specific monophosphorylation of diols or polyhydroxy substrates.

[0022] To address the aforementioned problems, this invention provides a selective phosphorylation synthesis method, comprising the following steps: dispersing a hydroxyl substrate in an aprotic solvent, adding an acid-binding agent, a catalyst, and dibenzyl phosphite, reacting at 25–30°C for 10–12 h, followed by concentration and purification to obtain a monophosphorylated glycoside product; the catalyst is tris(2,2,6,6-tetramethyl-3,5-heptanedikelic acid)ferric, hereinafter referred to as Fe(dipm)3; the hydroxyl substrate is an alcohol or glycoside compound containing at least one hydroxyl group; the aprotic solvent includes acetonitrile and carbon tetrachloride; the acid-binding agent is preferably N,N-diisopropylethylamine (i.e., DIPEA).

[0023] The reaction formulas for the in-situ reactions in the selective phosphorylation synthesis method of this invention are as follows: Specifically, the above reaction uses highly stable dibenzyl phosphite as the starting material, generating dibenzyl chlorophosphate intermediate in situ during the reaction. This intermediate can be directly used for subsequent phosphorylation reactions without the need for separation and purification. Simultaneously, the excellent catalytic effect of Fe(dipm)3 not only avoids the cumbersome steps and harsh conditions of pre-synthesizing, separating, and purifying dibenzyl chlorophosphate in existing technologies, but also achieves highly regioselective phosphorylation of 1,2-cis-diol structures. This reaction formula only describes some hydroxyl substrates; however, for other similar hydroxyl substrates, such as ethanol, cyclohexanol, and 2-methyl-2,4-pentanediol, the synthetic method of this invention can also exhibit excellent regiorecognition ability for specific hydroxyl groups (such as primary or secondary hydroxyl groups) on the sugar ring, thereby achieving efficient and highly selective monophosphorylation of complex polyhydroxy substrates.

[0024] In some embodiments, the aprotic solvent is a mixture of acetonitrile and carbon tetrachloride, with a volume ratio of acetonitrile to carbon tetrachloride of 1:1. Since the reaction does not occur when using pure acetonitrile, and the reaction is less effective when using pure carbon tetrachloride, a mixture of acetonitrile and carbon tetrachloride is used as the aprotic solvent.

[0025] In some embodiments, the ratio of hydroxyl substrate to aprotic solvent is 1 mmol: (8–12) mL.

[0026] In some embodiments, the molar ratio of the hydroxyl group in the hydroxyl substrate to the acid-binding agent, catalyst, and dibenzyl phosphite is 1:(3-5):(0.05-0.1):(1.2-2.0); more preferably, the molar ratio of the hydroxyl substrate, acid-binding agent, catalyst, and dibenzyl phosphite is 1:3:0.1:1.5.

[0027] In some embodiments, the hydroxyl substrate includes at least one of compounds 1 to 16: In some embodiments, the concentration and purification process involves sequentially performing reduced pressure concentration and column chromatography purification.

[0028] The performance of the selective phosphorylation synthesis method of this invention is tested and analyzed through specific embodiments below. Where specific techniques or conditions are not specified in the embodiments, they were performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0029] I. Preparation Method Example 1 This example uses 6-tert-butyldiphenylsilyl-α-D-mannose as a hydroxyl substrate. The specific preparation steps of its selective phosphorylation synthesis method are as follows: In a reaction flask equipped with a magnetic flask, 43.3 mg (0.1 mmol) of 6-tert-butyldiphenylsilyl-α-D-mannose was weighed and dissolved in 1.0 mL of acetonitrile / carbon tetrachloride (V / V = 1 / 1). 6.0 mg (0.01 mmol) of Fe(dipm)3 and 52.0 μL (0.3 mmol) of DIPEA were added sequentially. Finally, 33.0 μL (0.15 mmol) of dibenzyl phosphite was added, and the reaction was carried out at room temperature for 8 hours. After evaporating the solvent and filtering out the metal, the crude reaction mixture was directly analyzed by 1H and 31P nuclear magnetic resonance spectroscopy. The product 3-O-(dibenzyloxyphosphoryl)-6-tert-butyldiphenylsilyl-α-D-mannosyl methyl glycoside (compound 1) was obtained with an NMR yield of 74%. Subsequently, the product was separated and dried by column chromatography to obtain 29.8 mg of pure 3-O-(dibenzyloxyphosphoryl)-6-tert-butyldiphenylsilyl-α-D-mannosyl methyl glycoside (compound 1), with an actual yield of 43%. Figure 1 further confirms the preparation of the target product.

[0030] Example 2. This example uses 6-tert-butyldimethylsilyl-α-D-galactosylmethyl glycoside as a hydroxyl substrate. The specific preparation steps of its selective phosphorylation synthesis method are as follows: In a reaction flask equipped with a magnetic stir bar, 30.8 mg (0.1 mmol) of 6-tert-butyldimethylsilyl-α-D-galactosylmethyl glycoside was weighed and dissolved in 1.0 mL of acetonitrile / carbon tetrachloride (V / V = 1 / 1). 6.0 mg (0.01 mmol) of Fe(dipm)3 and 52.0 μL (0.3 mmol) of DIPEA were added sequentially, and finally 33.0 μL (0.15 mmol) of dibenzyl phosphite were added. The reaction was carried out at room temperature for 10 hours. The solvent was evaporated to dryness, and the product was separated and dried by column chromatography to obtain 31.8 mg of pure 3-O-(dibenzyloxyphosphoryl)-6-tert-butyldimethylsilyl-α-D-galactosylmethyl glycoside (compound 4), with an actual yield of 56%. Figure 2 further confirms the successful preparation of the target product.

[0031] Example 3. This example uses 4,6-benzyl-α-D-mannosyl methyl glycoside as a hydroxyl substrate. The specific preparation steps of its selective phosphorylation synthesis method are as follows: In a reaction flask equipped with a magnetic stir bar, 28.2 mg (0.1 mmol) of 4,6-benzyl-α-D-mannosyl methyl glycoside was weighed and dissolved in 1.0 mL of acetonitrile / carbon tetrachloride (V / V = 1 / 1). Then, 6.0 mg (0.01 mmol) of Fe(dipm)3, 52.0 μL (0.3 mmol) of DIPEA, and finally 33.0 μL (0.15 mmol) of dibenzyl phosphite were added sequentially, and the reaction was carried out at room temperature for 12 hours. The solvent was evaporated to dryness, and the product was separated and dried by column chromatography to obtain 13.6 mg of pure 3-O-(dibenzyloxyphosphoryl)-4,6-benzyl-α-D-mannosyl methyl glycoside (compound 6), with an actual yield of 25%. Figure 3 further confirms the preparation of the target product.

[0032] Example 4. This example uses 2,3-benzyl-β-D-galactosyl methyl glycoside as a hydroxyl substrate. The specific preparation steps of its selective phosphorylation synthesis method are as follows: In a reaction flask equipped with a magnetic stir bar, 37.4 mg (0.1 mmol) of 2,3-benzyl-β-D-galactosyl methyl glycoside was weighed and dissolved in 1.0 mL of acetonitrile / carbon tetrachloride (V / V = 1 / 1). Then, 6.0 mg (0.01 mmol) of Fe(dipm)3, 52.0 μL (0.3 mmol) of DIPEA, and finally 33.0 μL (0.15 mmol) of dibenzyl phosphite were added sequentially. The reaction was carried out at room temperature for 10 hours. The solvent was evaporated to dryness, and the product was separated and dried by column chromatography to obtain 57.9 mg of pure 6-O-(dibenzyloxyphosphoryl)-2,3-benzyl-β-D-galactosyl methyl glycoside (compound 9), with an actual yield of 91%. Figure 4 further confirms the preparation of the target product.

[0033] Example 5. This example uses 2,3-benzoyl-β-D-glucomethyl glycoside as a hydroxyl substrate. The specific preparation steps of its selective phosphorylation synthesis method are as follows: In a reaction flask equipped with a magnetic stir bar, 40.2 mg (0.1 mmol) of 2,3-benzoyl-β-D-glucomethyl glycoside was weighed and dissolved in 1.0 mL of acetonitrile / carbon tetrachloride (V / V = 1 / 1). Then, 6.0 mg (0.01 mmol) of Fe(dipm)3, 52.0 μL (0.3 mmol) of DIPEA, and finally 33.0 μL (0.15 mmol) of dibenzyl phosphite were added sequentially, and the reaction was carried out at room temperature for 10 hours. The solvent was evaporated to dryness, and the product was separated and dried by column chromatography to obtain 57.6 mg of pure 6-O-(dibenzyloxyphosphoryl)-2,3-benzoyl-β-D-glucomethyl glycoside (compound 11), with an actual yield of 87%. Figure 5 further confirms the preparation of the target product.

[0034] Example 6. This example uses benzyl alcohol as a hydroxyl substrate, and the specific preparation steps of its selective phosphorylation synthesis method are as follows: In a reaction flask equipped with a magnetic stir bar, 6.0 mg (0.1 mmol) Fe(dipm)3 was weighed and dissolved in 1.0 mL acetonitrile / carbon tetrachloride (V / V = 1 / 1), followed by the sequential addition of 52.0 μL (0.3 mmol) DIPEA, 10.5 μL (0.1 mmol) benzyl alcohol, and finally 33.0 μL (0.15 mmol) dibenzyl phosphite. The reaction was carried out at room temperature for 6 hours. The solvent was evaporated to dryness, and the product was separated and dried by column chromatography to obtain 35.0 mg of pure tribenzyl phosphate (compound 14), with an actual yield of 95%. Figure 6 further confirms the preparation of the target product.

[0035] Comparative Example 1 differs from Example 1 only in that no catalyst was added, and the mixture was directly subjected to treatment after 8 hours. 1 H and 31 P-NMR spectroscopy analysis of the crude reaction mixture yielded 3-O-(dibenzyloxyphosphoryl)-6-tert-butyldiphenylsilyl-α-D-mannose methyl glycoside (compound 1) with an NMR yield of 4%.

[0036] Comparative Example 2 differs from Example 1 only in that an equal amount of iron acetylacetonate (Fe(acac)3) is used instead of tris(2,2,6,6-tetramethyl-3,5-heptanedione acid) iron (Fe(dipm)3), and the mixture is directly subjected to treatment after 8 hours. 1 H and 31 P-NMR spectroscopy analysis of the crude reaction mixture yielded 3-O-(dibenzyloxyphosphoryl)-6-tert-butyldiphenylsilyl-α-D-mannose methyl glycoside (compound 1) with an NMR yield of 49%.

[0037] Comparative Example 3 differs from Example 1 only in that an equal amount of potassium carbonate (K2CO3) is used instead of N-ethyldiisopropylamine (DIPEA), and the mixture is directly subjected to oxidation after 8 hours. 1 H and 31 P-NMR spectroscopy analysis of the crude reaction mixture yielded a product, 3-O-(dibenzyloxyphosphoryl)-6-tert-butyldiphenylsilyl-α-D-mannose methyl glycoside (compound 1), with an NMR yield of 22%.

[0038] Comparative Example 4 differs from Example 1 only in that a pure carbon tetrachloride (CCl4) solution is used instead of the acetonitrile / carbon tetrachloride (V / V = 1 / 1) mixed solution. The mixture was directly applied after 8 hours. 1 H and 31P-NMR spectroscopy analysis of the crude reaction mixture yielded 3-O-(dibenzyloxyphosphoryl)-6-tert-butyldiphenylsilyl-α-D-mannose methyl glycoside (compound 1) with an NMR yield of 36%.

[0039] II. Test Results and Analysis The NMR yield results of the samples prepared in Example 1 and Comparative Examples 1 to 4 above were statistically analyzed, and the results are shown in Table 1.

[0040] Table 1 As shown in Table 1, 1) Comparing Example 1 with Comparative Examples 1 and 2, it can be seen that without introducing a catalyst or using other iron catalysts, the NMR yield of Compound 1 prepared is much lower than that of Example 1 of this invention. This is because the unique steric hindrance and electronic effects of the ligands in Fe(dipm)3 jointly optimize the coordination microenvironment of the iron center. The four methyl groups in the ligands generate strong stereoshiking, which may enable them to accurately recognize and activate specific hydroxyl groups on the sugar ring, thereby achieving both high catalytic efficiency and high regioselectivity. This proves that the use of Fe(dipm)3 as a catalyst in this invention can significantly improve catalytic efficiency, and its effect is difficult to be replaced by other iron catalysts.

[0041] 2) Comparing Example 1 and Comparative Example 3, it can be seen that the NMR yield of Compound 1 is significantly reduced when potassium carbonate is used as the base. This is because potassium carbonate, as an inorganic base, has insufficient basicity, solubility, and its mechanism of action in the reaction system to effectively promote the smooth conversion of dibenzyl phosphite and carbon tetrachloride to dibenzyl chlorophosphate, or to maintain the optimal reaction microenvironment required for subsequent phosphorylation reactions, resulting in low reaction efficiency. Therefore, the organic base (DIPEA) in the technical solution of this invention is key to achieving efficient in-situ generation of the active phosphorylation intermediate and smooth subsequent reactions, and its effect is difficult to be replaced by other bases.

[0042] 3) Comparing Example 1 and Comparative Example 4, it can be seen that compared with Example 1 using a mixed solvent of acetonitrile and carbon tetrachloride, the NMR yield of the target product obtained in Comparative Example 4, which used only pure carbon tetrachloride as the solvent, decreased significantly. This is because pure carbon tetrachloride has poor solubility for the reactants (especially polyhydroxy glycoside substrates and polar intermediates), resulting in insufficient contact between reactants and low reaction efficiency. Simultaneously, CCl4 alone may not provide the suitable polarity and solvation environment required for the reaction, thus affecting the stability of the active intermediate formation and the catalytic efficiency of the catalyst. The acetonitrile / CCl4 mixed solvent system used in this invention optimizes the properties of the reaction medium through the complementary effect of the solvents. This aprotic solvent is a crucial factor in ensuring the efficient conduction of the reaction.

[0043] 4) The large differences in yield between Examples 1-6 may stem from the steric accessibility and reactivity of the target hydroxyl group. When the reaction site is a sterically unhindered primary hydroxyl group (e.g., Examples 4, 5, and 6), the yield can reach 87% to 95%. However, when the reaction is forced to occur on a more sterically unhindered secondary hydroxyl group, as in Examples 1-3, where the substrate has a highly hindered silane or rigid ketal structure at the 6- or 4,6-position, these groups may hinder the effective coordination and activation of the target hydroxyl group (e.g., 3-OH) by the catalyst through steric shielding or conformational locking, resulting in a significant decrease in reaction efficiency to 25%–56%. This demonstrates the universally applicable high efficiency of this method for primary hydroxyl groups. Furthermore, the relevant synthetic yields of the aforementioned hydroxyl substrate compounds 1-16 are attached, as shown in Figure 7.

[0044] Therefore, this method is best suited for synthesizing phosphorylated products with the following characteristics, such as primary hydroxyl (-CH2OH) phosphorylation. When the substrate is a sterically unhindered primary hydroxyl group (such as benzyl alcohol in Example 6), it exhibits near-quantitative reaction efficiency and the strongest universality. Secondly, it is suitable for structurally well-defined monophosphorylated glycosides: particularly applicable to glycoside substrates whose hydroxyl competitive environment has been pre-simplified by protecting groups (such as benzyl or benzoyl), enabling efficient and highly selective one-pot preparation of structurally well-defined monophosphorylated derivatives.

[0045] It should be noted that all the above embodiments belong to the same inventive concept, and the descriptions of each embodiment have different focuses. Where the description in a particular embodiment is not detailed, please refer to the description in other embodiments.

[0046] The embodiments described above are merely illustrative of implementation methods of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A selective phosphorylation synthesis method, characterized in that, The process includes the following steps: dispersing a hydroxyl substrate in an aprotic solvent, adding an acid-binding agent, a catalyst, and dibenzyl phosphite, reacting at 25–30 °C for 10–12 h, followed by concentration and purification to obtain a monophosphorylated glycoside product; the catalyst is tris(2,2,6,6-tetramethyl-3,5-heptanedikelic acid)ferric; the hydroxyl substrate is an alcohol or glycoside compound containing at least one hydroxyl group.

2. The selective phosphorylation synthesis method according to claim 1, characterized in that, The aprotic solvents include acetonitrile and carbon tetrachloride.

3. The selective phosphorylation synthesis method according to claim 2, characterized in that, The aprotic solvent is a mixture of acetonitrile and carbon tetrachloride, and the volume ratio of acetonitrile to carbon tetrachloride is 1:

1.

4. The selective phosphorylation synthesis method according to claim 3, characterized in that, The ratio of the hydroxyl substrate to the aprotic solvent is 1 mmol: (8–12) mL.

5. The selective phosphorylation synthesis method according to claim 1, characterized in that, The molar ratio of the hydroxyl group in the hydroxyl substrate to the acid-binding agent, catalyst, and dibenzyl phosphite is 1:(3-5):(0.05-0.1):(1.2-2.0).

6. The selective phosphorylation synthesis method according to claim 1, characterized in that, The acid-binding agent is N,N-diisopropylethylamine.

7. The selective phosphorylation synthesis method according to claim 1, characterized in that, The hydroxyl substrate includes at least one selected from ethanol, benzyl alcohol, cyclohexanol, 2-methyl-2,4-pentanediol, 6-tert-butyldiphenylsilyl-α-D-mannose, 6-tert-butyldimethylsilyl-α-D-galactose, 4,6-benzylidene-α-D-mannose, 2,3-benzyl-β-D-galactose, and 2,3-benzoyl-β-D-glucoside.

8. The selective phosphorylation synthesis method according to claim 1, characterized in that, The concentration and purification process involves sequentially performing reduced pressure concentration and column chromatography purification.

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