Alkyl N-glycoside compound and synthesis method thereof

Abstract

The present invention belongs to the technical field of synthesis of alkyl nitrogen glycoside compounds, and discloses an alkyl N-glycoside compound and a synthesis method thereof. The synthesis method comprises: under an inert atmosphere, uniformly dispersing the manganese powder, nickel catalyst, and organic ligand as shown in Formula 1 in a reaction solvent, and mixing to obtain a reaction medium solution; sequentially dispersing compound 1 as shown in Formula 1 and compound 2 as shown in Formula 2 in the reaction medium solution, stirring at room temperature, and purifying to obtain an alkyl N-glycoside compound as shown in Formula 3. The synthesis method of the present invention is simple and easy to operate, and the synthesis conditions are mild. The synthesis method of the present invention is applicable to different substrates, and can achieve modular synthesis of alkyl N-glycoside compounds, effectively overcoming technical defects in the prior art such as harsh reaction conditions such as high temperature and strong base, complex and limited scope of substrate synthesis, and the use of relatively expensive photocatalysts. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the technical field of synthesis of alkyl nitrogen glycoside compounds, in particular to an alkyl N-glycoside compound and a synthesis method thereof. Background Art

[0002] Azaglycosides have a wide range of biological and pharmacological activities and play a significant role in the exploration of life processes and drug development. Therefore, the development of efficient methods for the synthesis of azaglycosides is of great significance.

[0003] The traditional synthesis of glycosides involves reacting a sugar donor with an oxygen cation under acidic conditions, which then undergoes a polar reaction with nucleophiles such as O, N, and S to produce the corresponding glycosides. However, acidic conditions weaken the nucleophilicity of the N nucleophile, resulting in poor reactivity. This means that traditional acid-promoted glycosylation-based glycoside synthesis methods are difficult to produce nitrogen glycosides.

[0004] In order to solve the above technical problems, the prior art (DOI number 10.1038 / s41467-024-47711-9) and the prior art (DOI number 10.1038 / s44160-024-00496-7) both provide a copper-photosynergistic catalytic strategy for preparing nitrogen glycoside compounds, and the preparation ideas of the above two prior arts are shown in Reaction Formulas 1 and 2, respectively.

[0005]

[0006] Reaction formula 1.

[0007]

[0008] Reaction formula 2.

[0009] As can be seen from Reaction Equations 1 and 2, the above-mentioned method for preparing nitrogen glycoside compounds through the copper photocatalytic strategy not only needs to be carried out in a strong alkaline environment and has harsh reaction conditions, but also the photocatalyst used is relatively expensive. In addition, the substrates targeted are limited to heterocycles, which is not conducive to promotion and use. Summary of the Invention

[0010] In order to solve the above technical problems, the present invention provides an alkyl N-glycoside compound and a synthesis method thereof.

[0011] The alkyl N-glycoside compound and the synthesis method thereof of the present invention are achieved by the following technical scheme:

[0012] The first object of the present invention is to provide a method for synthesizing an alkyl N-glycoside compound, characterized in that it comprises the following steps:

[0013] Step 1, preparation of a reaction medium solution: under an inert atmosphere, manganese powder, nickel catalyst and organic ligand are uniformly dispersed in a reaction solvent and mixed to obtain a reaction medium solution.

[0014] It should be noted that the present invention prefers manganese powder as a reducing agent. This not only reduces the metallic nickel provided by the nickel catalyst in the reaction medium, thereby enhancing the subsequent nickel catalyst-promoted reaction between the glycosyl donor and the electrophilic amine reagent to form an alkyl N-glycoside compound, but also, during the present invention's exploration, it was discovered that the target product could not be obtained when a metal reducing agent other than manganese powder, such as potassium powder, was used.

[0015] The organic ligand used in the present invention is a compound having a structure as shown in Formula 4. This organic ligand is not only inexpensive and readily available, reducing synthesis costs, but also has multiple coordination and chelation sites, which can promote coordination with the metallic nickel provided by the nickel catalyst, thereby facilitating the subsequent reaction between the glycosyl donor and the electrophilic amine reagent. In Formula 4, Me represents a methyl group, and tBu represents a tert-butyl group.

[0016]

[0017] The present invention uniformly disperses manganese powder, a nickel catalyst and an organic ligand in a reaction solvent, so that the components are fully in contact with each other. During the contact process, the manganese powder first reduces the divalent metal nickel in the nickel catalyst to a zero-valent state, and the catalyst and the organic ligand are fully coordinated, which can help the glycosyl donor and the electrophilic amine reagent to react to form an alkyl N-glycoside compound in the subsequent reaction process.

[0018] In some preferred embodiments of the present invention, the nickel catalyst employed is nickel chloride dimethoxyethane. Nickel chloride dimethoxyethane is not only low in toxicity, inexpensive, and readily available, but also enables transition metal-catalyzed reductive coupling to promote the reaction between the glycosyl donor and the electrophilic amine reagent to form alkyl N-glycoside compounds. Furthermore, during the present invention's exploration process, it was discovered that no target product was detected when other metal catalysts, such as cobalt and iron catalysts, were used.

[0019] In some preferred embodiments of the present invention, the reaction solvent used is a mixed solution of tetrahydrofuran and toluene, and the volume ratio of tetrahydrofuran to toluene is 4 to 4.5:1, so as to promote the full dissolution of each preparation raw material, thereby improving the direct contact and reaction effect of each preparation raw material, and promoting the reaction between the glycosyl donor and the electrophilic amine reagent to form an alkyl N-glycoside compound.

[0020] In some preferred embodiments of the present invention, 0.01 mol of nickel catalyst, 0.02 mol to 0.03 mol of organic ligand, and 0.25 mol to 0.35 mol of manganese powder are added to 1 L of the reaction solvent, and the manganese powder, nickel catalyst, and organic ligand are uniformly dispersed in the reaction solvent to achieve the effect of pre-coordinating the organic ligand to the metallic nickel. In some preferred embodiments of the present invention, the manganese powder, nickel catalyst, and organic ligand are uniformly dispersed in the reaction solvent by stirring, and the stirring temperature during stirring is room temperature and the stirring time is 10 min to 20 min.

[0021] Step 2, transition metal-catalyzed reductive coupling reaction: Compound 1 as shown in Formula 1 is used as a glycosyl donor, and Compound 2 as shown in Formula 2 is used as an electrophilic amine reagent. Under an inert atmosphere, Compound 1 and Compound 2 are sequentially dispersed in the reaction medium solution, and stirred to react at room temperature. After purification, Compound 3 as shown in Formula 3, i.e., the alkyl N-glycoside compound, is obtained.

[0022]

[0023] It should be noted that in the above Formulas 1 to 3, GPO is selected from any one or more of OAc-acetoxy, OBz-benzoyl, OPiv-pivaloyloxy and OBn-benzyloxy; R1 is selected from any one of substituted benzyl, naphthyloxy, furanyloxy, thienyloxy, indoleoxy, phenyl, allyl, cyclopropyloxy and ethyl; and R2 is selected from any one of substituted benzyl, naphthyloxy, furanyloxy, thienyloxy, indoleoxy, phenyl, allyl, cyclopropyloxy and ethyl.

[0024] The present invention uses compound 1 having a structure as shown in Formula 1 as a glycosyl donor. That is, the glycosyl donor used in the present invention has a stable structure, a simple structure and is easy to synthesize, so that it can achieve mild and efficient synthesis of the target product.

[0025] In some preferred embodiments of the present invention, the compound 1 is selected from compound 1a ((2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate), compound 1b ((2R,3R,4S,5R,6R)-2-(benzoyloxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl tribenzoate), compound 1c ((2R,3R,4S,5R)-2-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate), compound 1d ((2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate), Compound 1e ((2R,3R,4S,5R,6R)-2-bromo-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tris(2,2-dimethylpropionate)), Compound 1f ((2R,3S,4S,5R,6R)-2-(benzoyloxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl tribenzoate), Compound 1g ((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-bromotetrahydro-2H-pyran), Compound 1h ((2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-((2R,3R,4S,5R,6R)-4,5- diacetoxy-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate), compound 1i ((2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate), compound 1j ((2R,3R,4S,5R)-2-bromo-6-(((4-((5S,8R,9S,10S,13R,14S,17S)-10,13-dimethyl-3,7, 5-triyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate), compound 1k ((2R,3R,4S,5R,6R)-2-bromo-6-(((2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropanoyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate), compound 1l ((2S,3S,4R,5S,6S)-2-(((N-(benzyloxycarbonyl)-N-methyl-D-leucyl)oxy)methyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate), compound 1m ((2S,3S,4R,5S,any one of compound 1o ((2R,3R,4S,5R,6R)-2-bromo-6-((((S)-2-(6-methoxynaphthalen-2-yl)propionyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate), compound 1n ((2S,3S,4R,5S,6S)-2-bromo-6-(((4-(N,N-dipropylsulfamoyl)benzoyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate), and compound 1o ((2R,3R,4S,5R,6R)-2-bromo-6-(((2-(10-oxo-10,11-dihydrodibenzo[b,f]thiapin-2-yl)propionyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate). The chemical structural formulas of the compounds used in the above compound 1 are shown in Table 1.

[0026] Table 1 Compound 1 and its corresponding chemical structure

[0027]

[0028] It should also be noted that the compound 2 having a structure as shown in Formula 2 of the present invention is used as an electrophilic amine reagent, that is, the electrophilic amine reagent used in the present invention has polarity reversal, so that N can be converted from nucleophilic to electrophilic, so that the synthesis process of the present invention does not require a harsh alkaline environment, and can introduce a nitrogen-containing component into the target product to obtain an alkyl N-glycoside compound.

[0029] In some preferred embodiments of the present invention, the compound 2 is selected from any one of compound 2a, compound 2b, compound 2c, compound 2d, compound 2e, compound 2f, compound 2g, compound 2h, compound 2i, compound 2j, compound 2k, compound 2l, compound 2m, compound 2n, compound 2o, compound 2p, compound 2q, compound 2r, compound 2s, compound 2t and compound 2u.

[0030] Among them, the compound 2a is O-benzoyl-N,N-dibenzylhydroxylamine; compound 2b is O-benzoyl-N-benzyl-N-(4-chlorobenzyl)hydroxylamine; compound 2c is O-benzoyl-N-benzyl-N-(2-fluorobenzyl)hydroxylamine; compound 2d is O-benzoyl-N-benzyl-N-(4-(trifluoromethyl)benzyl)hydroxylamine; compound 2e is 4-(((benzoyloxy)(benzyl)amino)methyl)benzonitrile; compound 2f is O-benzoyl-N-benzyl-N-(4-fluoro-2 -methylbenzyl)hydroxylamine; Compound 2g is O-benzoyl-N-benzyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)hydroxylamine; Compound 2h is O-benzoyl-N-benzyl-N-(2,4-dimethylbenzyl)hydroxylamine; Compound 2i is O-benzoyl-N-benzyl-N-(4-(methylthio)benzyl)hydroxylamine; Compound 2j is O-benzoyl-N-benzyl-N-(3,4,5-trimethoxybenzyl)hydroxylamine; Compound 2k is O-benzoyl-N-benzyl-N-(2-methylbenzyl)hydroxylamine; compound 2l is O-benzoyl-N-benzyl-N-(naphthalen-1-ylmethyl)hydroxylamine; compound 2m is N-(benzo[d][1,3]dioxol-4-ylmethyl)-O-benzoyl-N-benzylhydroxylamine; compound 2n is O-benzoyl-N-benzyl-N-((1-methyl-1H-indol-2-yl)methyl)hydroxylamine; compound 2o is O-benzoyl-N-benzyl-N-(thiophen-2-ylmethyl)hydroxylamine Compound 2p is O-benzoyl-N-benzyl-N-(furan-2-ylmethyl)hydroxylamine; Compound 2q is N-(4-(1H-pyrazol-1-yl)benzyl)-O-benzoyl-N-benzylhydroxylamine; Compound 2r is O-benzoyl-N-benzyl-N-(cyclopropylmethyl)hydroxylamine; Compound 2s is N-allyl-O-benzoyl-N-benzylhydroxylamine; Compound 2t is O-benzoyl-N-benzyl-N-ethylhydroxylamine; Compound 2u is N-allyl-O-benzoyl-N-phenylhydroxylamine. The chemical structural formulas of the compounds used in the above-mentioned compound 2 are shown in Table 2.

[0031] Table 2 Compound 2 and its corresponding chemical structure

[0032]

[0033] The present invention adds the compound 1 and the compound 2 to the reaction medium solution in sequence, and stirs the solution at room temperature so that the compound 1 and the compound 2 are uniformly dispersed in the reaction medium solution. During the stirring process, the compound 2 first undergoes an oxidative addition reaction with a metal nickel complex formed by coordination of an organic ligand and a nickel catalyst, then undergoes a free radical addition reaction with a glycosyl free radical generated by the compound 1 in the system, and finally undergoes reduction and elimination under the action of metal manganese to obtain the target product, that is, an alkyl N-glycoside compound.

[0034] In some preferred embodiments of the present invention, the added amount of the compound 1 is 17 to 19 times the molar amount of the nickel catalyst in the reaction medium solution, so as to increase the reaction yield by providing an excess of glycosyl donor.

[0035] In some preferred embodiments of the present invention, the added amount of the compound 2 is 9 to 11 times the molar amount of the nickel catalyst in the reaction medium solution, so as to completely convert the electrophilic amine.

[0036] In some preferred embodiments of the present invention, the stirring reaction time is 8 h to 16 h, so that compound 1 and compound 2, ie, the glycosyl donor and the electrophilic amine reagent, can fully react.

[0037] In some preferred embodiments of the present invention, the purification is column chromatography separation and purification to achieve the purpose of separating and purifying the target compound.

[0038] The present invention also provides an alkyl N-glycoside compound synthesized by the above synthesis method.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] The present invention is based on a nickel-catalyzed reductive coupling strategy, using manganese powder as a reducing agent, a compound as shown in Formula 4 as an organic ligand, and a mixed solution obtained by dispersing it and the nickel catalyst in a reaction solvent as a reaction medium solution. Compound 1 as shown in Formula 1 and compound 2 as shown in Formula 2, which are structurally stable and easily available, are used as glycosyl donors and electrophilic amine reagents, respectively. Compound 1 and compound 2 are dispersed in the reaction medium solution by stirring. During the stirring process, compound 2 first undergoes an oxidative addition reaction with a metal nickel complex formed by coordination with the organic ligand and the nickel catalyst, then undergoes a free radical addition reaction with the glycosyl free radical generated by compound 1 in the system, and finally undergoes a reduction elimination under the action of metal manganese to obtain the target product. That is, the present invention can realize the synthesis of alkyl N-glycoside compounds by the reaction of the glycosyl donor and the electrophilic amine reagent at room temperature.

[0041] The synthesis method of the present invention is simple and easy to operate, and the synthesis conditions are mild. The synthesis method of the present invention is applicable to different substrates and can realize the modular synthesis of alkyl N-glycoside compounds, effectively overcoming the technical defects of the prior art, such as harsh reaction conditions such as high temperature and strong base, complex and limited scope of substrate synthesis, and the use of relatively expensive photocatalysts. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 Compound 3a prepared in Example 1 1 H NMR (400 MHz, CDCl3) chart.

[0043] Figure 2 Compound 3a prepared in Example 1 13 C NMR (101 MHz, CDCl3) chart. DETAILED DESCRIPTION

[0044] The technical solutions in the embodiments of the present invention will be described clearly and completely below.

[0045] Example 1

[0046] This embodiment provides a method for synthesizing compound 3a, comprising the following steps:

[0047] Step 1, Preparation of the Reaction Medium Solution: Mix tetrahydrofuran and toluene in a 4:1 volume ratio to obtain a reaction solvent. Under a nitrogen atmosphere in a glove box, add 0.3 mmol of manganese powder, 0.01 mmol of nickel chloride (dimethoxyethane), 0.012 mmol of organic ligand L1, and 1 mL of the prepared reaction solvent to a 10 mL reaction tube. Stir at room temperature for 15 minutes to obtain a reaction medium solution.

[0048] Step 2, transition metal-catalyzed reductive coupling reaction: Using compound 1a as a glycosyl donor and compound 2a as an electrophilic amine reagent, 0.18 mmol of compound 1a and 0.1 mmol of compound 2a were sequentially added to the reaction medium solution obtained above under a nitrogen atmosphere. The reaction was stirred at room temperature for 12 hours, and then separated and purified by column chromatography to obtain compound 3a. The synthetic route is shown in Reaction Scheme 3:

[0049]

[0050] Reaction formula 3.

[0051] The compound 3a synthesized in this example is a white solid with a β-configuration and a yield of 81%.

[0052] The present invention conducted nuclear magnetic resonance testing on compound 3a, and the test results were as follows: Figure 1 and Figure 2 shown.

[0053] in, Figure 1 Compound 3a prepared in Example 1 1 H NMR (400 MHz, CDCl3) chart, Figure 2 Compound 3a prepared in Example 1 13 C NMR (101 MHz, CDCl3) chart.

[0054] according to Figure 1 and Figure 2 The test results show that compound 3a was successfully synthesized by the synthesis method of the present invention.

[0055] Example 2

[0056] This embodiment provides a method for synthesizing compound 3b. The reaction scheme of this embodiment is shown in Reaction Scheme 4.

[0057]

[0058] Reaction formula 4.

[0059] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2b is used as the electrophilic amine reagent.

[0060] The compound 3b obtained in this example is a white solid with a β configuration and a yield of 61%.

[0061] Example 3

[0062] This embodiment provides a method for synthesizing compound 3c. The reaction scheme of this embodiment is shown in Reaction Scheme 5.

[0063]

[0064] Reaction formula 5.

[0065] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2c is used as the electrophilic amine reagent.

[0066] The compound 3c obtained in this example is a yellow liquid with a β configuration and a yield of 77%.

[0067] Example 4

[0068] This embodiment provides a method for synthesizing compound 3d. The reaction scheme of this embodiment is shown in Reaction Scheme 6.

[0069]

[0070] Reaction formula 6.

[0071] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2d is used as the electrophilic amine reagent.

[0072] The compound 3d obtained in this example is a white solid with a β configuration and a yield of 65%.

[0073] Example 5

[0074] This embodiment provides a method for synthesizing compound 3e. The reaction scheme of this embodiment is shown in Reaction Scheme 7.

[0075]

[0076] Reaction formula 7.

[0077] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2e is used as the electrophilic amine reagent.

[0078] The compound 3e obtained in this example is a white solid with a β configuration and a yield of 40%.

[0079] Example 6

[0080] This embodiment provides a method for synthesizing compound 3f. The reaction scheme of this embodiment is shown in Reaction Scheme 8.

[0081]

[0082] Reaction formula 8.

[0083] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2f is used as the electrophilic amine reagent.

[0084] The compound 3f obtained in this example is a white solid with a β configuration and a yield of 61%.

[0085] Example 7

[0086] This example provides a method for synthesizing compound 3g.

[0087]

[0088] Reaction formula 9.

[0089] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2g is used as the electrophilic amine reagent.

[0090] The reaction route of this example is shown in Reaction Scheme 9, and the compound 3g obtained in this example is a white solid with a β configuration and a yield of 72%.

[0091] Example 8

[0092] This embodiment provides a method for synthesizing compound 3h. The reaction scheme of this embodiment is shown in Reaction Scheme 10.

[0093]

[0094] Reaction formula 10.

[0095] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2h is used as the electrophilic amine reagent.

[0096] The compound 3h obtained in this example is a colorless liquid with a β configuration and a yield of 73%.

[0097] Example 9

[0098] This embodiment provides a method for synthesizing compound 3i. The reaction scheme of this embodiment is shown in Reaction Scheme 11.

[0099]

[0100] Reaction formula 11.

[0101] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2i is used as the electrophilic amine reagent.

[0102] The compound 3i obtained in this example is a white solid with a β configuration and a yield of 64%.

[0103] Example 10

[0104] This embodiment provides a method for synthesizing compound 3j. The reaction scheme of this embodiment is shown in Reaction Scheme 12.

[0105]

[0106] Reaction formula 12.

[0107] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2j is used as the electrophilic amine reagent.

[0108] The compound 3j obtained in this example is a white solid with a β configuration and a yield of 74%.

[0109] Example 11

[0110] This embodiment provides a method for synthesizing compound 3k. The reaction scheme of this embodiment is shown in Reaction Scheme 13.

[0111]

[0112] Reaction formula 13.

[0113] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2k is used as the electrophilic amine reagent.

[0114] The compound 3k obtained in this example is a white solid with a β configuration and a yield of 50%.

[0115] Example 12

[0116] This embodiment provides a method for synthesizing compound 31. The reaction scheme of this embodiment is shown in Reaction Scheme 14.

[0117]

[0118] Reaction formula 14.

[0119] The only difference between this example and Example 1 is that in this example, Compound 1a is used as the glycosyl donor and Compound 21 is used as the electrophilic amine reagent.

[0120] The compound 31 obtained in this example is a yellow liquid with a β configuration and a yield of 63%.

[0121] Example 13

[0122] This embodiment provides a method for synthesizing compound 3m. The reaction scheme of this embodiment is shown in Reaction Scheme 15.

[0123]

[0124] Reaction formula 15.

[0125] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2m is used as the electrophilic amine reagent.

[0126] The compound 3m obtained in this example is a red solid with a β configuration and a yield of 52%.

[0127] Example 14

[0128] This embodiment provides a method for synthesizing compound 3n. The reaction scheme of this embodiment is shown in Reaction Scheme 16.

[0129]

[0130] Reaction formula 16.

[0131] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2n is used as the electrophilic amine reagent.

[0132] The compound 3n obtained in this example is a yellow liquid with a β configuration and a yield of 56%.

[0133] Example 15

[0134] This example provides a method for synthesizing compound 3o.

[0135]

[0136] Reaction formula 17.

[0137] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2o is used as the electrophilic amine reagent.

[0138] The reaction route of this example is shown in Reaction Scheme 17, and the compound 3o obtained in this example is a white solid with a β configuration and a yield of 76%.

[0139] Example 16

[0140] This embodiment provides a method for synthesizing compound 3p. The reaction scheme of this embodiment is shown in Reaction Scheme 18.

[0141]

[0142] Reaction formula 18.

[0143] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2p is used as the electrophilic amine reagent.

[0144] The compound 3p obtained in this example is a white solid with a β configuration and a yield of 65%.

[0145] Example 17

[0146] This embodiment provides a method for synthesizing compound 3q. The reaction scheme of this embodiment is shown in Reaction Scheme 19.

[0147]

[0148] Reaction formula 19.

[0149] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2q is used as the electrophilic amine reagent.

[0150] The compound 3q obtained in this example is a white solid with a β configuration and a yield of 72%.

[0151] Example 18

[0152] This embodiment provides a method for synthesizing compound 3r. The reaction scheme of this embodiment is shown in Reaction Scheme 20.

[0153]

[0154] Reaction formula 20.

[0155] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2r is used as the electrophilic amine reagent.

[0156] The compound 3r obtained in this example is a white solid with a β configuration and a yield of 67%.

[0157] Example 19

[0158] This embodiment provides a method for synthesizing compound 3s. The reaction scheme of this embodiment is shown in Reaction Scheme 21.

[0159]

[0160] Reaction formula 21.

[0161] The only difference between this example and Example 1 is that this example uses compound 1a as the glycosyl donor and compound 2s as the electrophilic amine reagent. Compound 3s obtained in this example is a yellow liquid with a β configuration and a yield of 52%.

[0162] Example 20

[0163] This embodiment provides a method for synthesizing compound 3t. The reaction scheme of this embodiment is shown in Reaction Scheme 22.

[0164]

[0165] Reaction formula 22.

[0166] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2t is used as the electrophilic amine reagent.

[0167] The compound 3t obtained in this example is a white solid with a β configuration and a yield of 59%.

[0168] Example 21

[0169] This embodiment provides a method for synthesizing compound 3u. The reaction scheme of this embodiment is shown in Reaction Scheme 23.

[0170]

[0171] Reaction formula 23.

[0172] The only difference between this example and Example 1 is that in this example, compound 1a is used as the glycosyl donor and compound 2u is used as the electrophilic amine reagent.

[0173] The compound 3u obtained in this example is a white solid with a β configuration and a yield of 46%.

[0174] Example 22

[0175] This embodiment provides a method for synthesizing compound 3v. The reaction scheme of this embodiment is shown in Reaction Scheme 24.

[0176]

[0177] Reaction formula 24.

[0178] The only difference between this example and Example 1 is that in this example, compound 1b is used as the glycosyl donor and compound 2k is used as the electrophilic amine reagent.

[0179] The compound 3v obtained in this example is a white solid with a β configuration and a yield of 34%.

[0180] Example 23

[0181] This embodiment provides a method for synthesizing compound 3w. The reaction scheme of this embodiment is shown in Reaction Scheme 25.

[0182]

[0183] Reaction formula 25.

[0184] The only difference between this example and Example 1 is that in this example, compound 1c is used as the glycosyl donor and compound 2i is used as the electrophilic amine reagent.

[0185] The compound 3w obtained in this example is a colorless liquid with a β configuration and a yield of 50%.

[0186] Example 24

[0187] This embodiment provides a method for synthesizing compound 3x. The reaction scheme of this embodiment is shown in Reaction Scheme 26.

[0188]

[0189] Reaction formula 26.

[0190] The only difference between this example and Example 1 is that in this example, compound 1c is used as the glycosyl donor and compound 2m is used as the electrophilic amine reagent.

[0191] The compound 3x obtained in this example is a white solid with a β configuration and a yield of 54%.

[0192] Example 25

[0193] This embodiment provides a method for synthesizing compound 3y. The reaction scheme of this embodiment is shown in Reaction Scheme 27.

[0194]

[0195] Reaction formula 27.

[0196] The only difference between this example and Example 1 is that in this example, compound 1d is used as the glycosyl donor and compound 2i is used as the electrophilic amine reagent.

[0197] The compound 3y obtained in this example is a white solid with a β configuration and a yield of 76%.

[0198] Example 26

[0199] This embodiment provides a method for synthesizing compound 3z. The reaction scheme of this embodiment is shown in Reaction Scheme 28.

[0200]

[0201] Reaction formula 28.

[0202] The only difference between this example and Example 1 is that in this example, compound 1d is used as the glycosyl donor and compound 2o is used as the electrophilic amine reagent.

[0203] The compound 3z obtained in this example is a yellow solid with a β configuration and a yield of 56%.

[0204] Example 27

[0205] This embodiment provides a method for synthesizing compound 3aa. The reaction scheme of this embodiment is shown in Reaction Scheme 29.

[0206]

[0207] Reaction formula 29.

[0208] The only difference between this example and Example 1 is that in this example, compound 1d is used as the glycosyl donor and compound 2n is used as the electrophilic amine reagent.

[0209] The compound 3aa obtained in this example is a yellow liquid with a β configuration and a yield of 41%.

[0210] Example 28

[0211] This embodiment provides a method for synthesizing compound 3ab. The reaction scheme of this embodiment is shown in Reaction Scheme 30.

[0212]

[0213] Reaction formula 30.

[0214] The only difference between this example and Example 1 is that in this example, compound 1e is used as a glycosyl donor and compound 2k is used as an electrophilic amine reagent.

[0215] The compound 3ab obtained in this example is a white solid with a β configuration and a yield of 59%.

[0216] Example 29

[0217] This embodiment provides a method for synthesizing compound 3ac. The reaction scheme of this embodiment is shown in Reaction Scheme 31.

[0218]

[0219] Reaction formula 31.

[0220] The only difference between this example and Example 1 is that in this example, compound 1e is used as the glycosyl donor and compound 2e is used as the electrophilic amine reagent.

[0221] The compound 3ac obtained in this example is a white solid with a β-configuration and a yield of 50%.

[0222] Example 30

[0223] This example provides a method for synthesizing compound 3ad.

[0224]

[0225] Reaction equation 32.

[0226] This example differs from Example 1 only in that compound 1f is used as the glycosyl donor and compound 2e is used as the electrophilic amine reagent. The reaction scheme of this example is shown in Reaction Scheme 32, and compound 3ad is obtained as a white solid with a β-configuration in a 35% yield.

[0227] Example 31

[0228] This embodiment provides a method for synthesizing compound 3ae.

[0229]

[0230] Reaction formula 33.

[0231] The only difference between this example and Example 1 is that in this example, compound 1f is used as the glycosyl donor and compound 2h is used as the electrophilic amine reagent.

[0232] The reaction route of this example is shown in Reaction Scheme 33, and the compound 3ae obtained in this example is a white solid with a β configuration and a yield of 52%.

[0233] Example 32

[0234] This embodiment provides a method for synthesizing compound 3af. The reaction scheme of this embodiment is shown in Reaction Scheme 34.

[0235]

[0236] Reaction formula 34.

[0237] The only difference between this example and Example 1 is that in this example, compound 1f is used as the glycosyl donor and compound 2q is used as the electrophilic amine reagent.

[0238] The compound 3af obtained in this example is a white solid with a β configuration and a yield of 51%.

[0239] Example 33

[0240] This embodiment provides a method for synthesizing compound 3ag. The reaction scheme of this embodiment is shown in Reaction Scheme 35.

[0241]

[0242] Reaction formula 35.

[0243] The only difference between this example and Example 1 is that in this example, compound 1g is used as the glycosyl donor and compound 2q is used as the electrophilic amine reagent.

[0244] The compound 3ag obtained in this example is a white solid with a β configuration and a yield of 52%.

[0245] Example 34

[0246] This embodiment provides a method for synthesizing compound 3ah. The reaction scheme of this embodiment is shown in Reaction Scheme 36.

[0247]

[0248] Reaction equation 36.

[0249] The only difference between this example and Example 1 is that in this example, compound 1h is used as the glycosyl donor and compound 2q is used as the electrophilic amine reagent.

[0250] The compound 3ah obtained in this example is a white solid with a β configuration and a yield of 74%.

[0251] Example 35

[0252] This embodiment provides a method for synthesizing compound 3ai. The reaction scheme of this embodiment is shown in Reaction Scheme 37.

[0253]

[0254] Reaction formula 37.

[0255] The only difference between this example and Example 1 is that this example uses compound 1i as the glycosyl donor and compound 2q as the electrophilic amine reagent. Compound 3ai obtained in this example is a white solid with a β configuration and a yield of 77%.

[0256] Example 36

[0257] This embodiment provides a method for synthesizing compound 3aj. The reaction scheme of this embodiment is shown in Reaction Scheme 38.

[0258]

[0259] Reaction equation 38.

[0260] The only difference between this example and Example 1 is that in this example, compound 1j is used as a glycosyl donor and compound 2h is used as an electrophilic amine reagent.

[0261] The compound 3aj obtained in this example is a white solid with a β configuration and a yield of 65%.

[0262] Example 37

[0263] This embodiment provides a method for synthesizing compound 3ak. The reaction scheme of this embodiment is shown in Reaction Scheme 39.

[0264]

[0265] Reaction equation 39.

[0266] The only difference between this example and Example 1 is that in this example, compound 1k is used as the glycosyl donor and compound 2h is used as the electrophilic amine reagent.

[0267] The compound 3ak obtained in this example is a white solid with a β configuration and a yield of 61%.

[0268] Example 38

[0269] This embodiment provides a method for synthesizing compound 3a1. The reaction scheme of this embodiment is shown in reaction formula 40.

[0270]

[0271] Reaction formula 40.

[0272] The only difference between this example and Example 1 is that in this example, compound 11 is used as a glycosyl donor and compound 2h is used as an electrophilic amine reagent.

[0273] The compound 3a1 obtained in this example was a white solid with a β-configuration and a yield of 63%.

[0274] Example 39

[0275] This embodiment provides a method for synthesizing compound 3am. The reaction scheme of this embodiment is shown in Reaction Scheme 41.

[0276]

[0277] Reaction formula 41.

[0278] The only difference between this example and Example 1 is that in this example, compound 1m is used as a glycosyl donor and compound 2h is used as an electrophilic amine reagent.

[0279] The compound 3am obtained in this example is a white solid with a β configuration and a yield of 68%.

[0280] Example 40

[0281] This embodiment provides a method for synthesizing compound 3an. The reaction scheme of this embodiment is shown in Reaction Scheme 42.

[0282]

[0283] Reaction formula 42.

[0284] The only difference between this example and Example 1 is that in this example, compound 1n is used as the glycosyl donor and compound 2a is used as the electrophilic amine reagent.

[0285] The compound 3an obtained in this example is a white solid with a β configuration and a yield of 61%.

[0286] Example 41

[0287] This embodiment provides a method for synthesizing compound 3ao. The reaction scheme of this embodiment is shown in Reaction Scheme 43.

[0288]

[0289] Reaction formula 43.

[0290] The only difference between this example and Example 1 is that in this example, compound 1o is used as the glycosyl donor and compound 2a is used as the electrophilic amine reagent.

[0291] The compound 3ao obtained in this example is a white solid with a β configuration and a yield of 55%.

[0292] The present invention uses the alkyl N-glycoside compounds synthesized in Examples 1 to 21 above, that is, using Compound 1a as a glycosyl donor and Compounds 2a to 2u as electrophilic amine reagents, to obtain Compounds 3a to 3u and their corresponding chemical structures, as shown in Table 3.

[0293] Table 3 Compound 3 synthesized in Examples 1 to 21 and its corresponding chemical structure

[0294]

[0295] The alkyl N-glycoside compounds synthesized in Examples 22 to 41 of the present invention are summarized as shown in Table 4.

[0296] Table 4 Compound 3 synthesized in Examples 22 to 41 and its corresponding chemical structure

[0297]

[0298] As can be seen from Tables 3 and 4, the present invention is based on a transition metal-catalyzed reductive coupling strategy, using a stable glycosyl donor and a readily available electrophilic amine reagent as starting materials. This overcomes obstacles such as harsh reaction conditions such as high temperature and strong base, the complex and limited scope of substrate synthesis, and the use of relatively expensive photocatalysts, and effectively and mildly synthesizes a series of alkyl N-glycoside compounds. These synthesized alkyl N-glycosides have potential active value in the field of biopharmacology.

[0299] Obviously, the above embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

Claims

1. A method for synthesizing an alkyl N-glycoside compound, characterized in that: The following steps are involved: Using manganese powder as a reducing agent and a compound as shown in Formula 4 as an organic ligand, under an inert atmosphere, the manganese powder, nickel catalyst and the organic ligand are uniformly dispersed in a reaction solvent and mixed to obtain a reaction medium solution; the nickel catalyst is nickel chloride dimethoxyethane; Using compound 1 as shown in formula 1 as a glycosyl donor and compound 2 as shown in formula 2 as an electrophilic amine reagent, under an inert atmosphere, the compound 1 and the compound 2 are sequentially dispersed in the reaction medium solution, stirred and reacted at room temperature, and after purification, a compound 3 as shown in formula 3, i.e., the alkyl N-glycoside compound, is obtained; The compound 3 shown in formula 3 is any one of the following: The definitions of the groups in the compounds represented by Formula 1 and Formula 2 are as shown in the structure of the compound represented by Formula 3.

2. The method for synthesizing an alkyl N-glycoside compound according to claim 1, wherein: When preparing the reaction medium solution, 0.01 mol of the nickel catalyst, 0.02 mol to 0.03 mol of the organic ligand, and 0.25 mol to 0.35 mol of the manganese powder are added to every 1 L of the reaction solvent.

3. The method for synthesizing an alkyl N-glycoside compound according to claim 1, wherein: The reaction solvent is a mixed solution of tetrahydrofuran and toluene; The volume ratio of tetrahydrofuran to toluene is 4.0-4.5:

1.

4. The method for synthesizing an alkyl N-glycoside compound according to claim 1, wherein The added amount of the compound 1 is 17 to 19 times the molar amount of the nickel catalyst in the reaction medium solution.

5. The method for synthesizing an alkyl N-glycoside compound according to claim 1, wherein: The added amount of the compound 2 is 9 to 11 times the molar amount of the nickel catalyst in the reaction medium solution.

6. The method for synthesizing an alkyl N-glycoside compound according to claim 1, wherein: The stirring reaction time is 8h to 16h.

7. The method for synthesizing an alkyl N-glycoside compound according to claim 1, wherein: The purification is column chromatography separation and purification.

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