Alkyl N-glycoside compound and synthesis method thereof

Abstract

The 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 the following steps: uniformly dispersing manganese powder, a nickel catalyst and an organic ligand as shown in a formula 1 in a reaction solvent in an inert atmosphere, and uniformly mixing to obtain a reaction medium solution; a compound 1 as shown in a formula 1 and a compound 2 as shown in a formula 2 are sequentially dispersed in a reaction medium solution, stirred at room temperature and purified, and the alkyl N-glycoside compound as shown in a formula 3 is obtained. The synthesis method is simple and easy to operate, the synthesis condition is mild, the synthesis method can be suitable for different substrates, modular synthesis of the alkyl N-glycoside compound can be achieved, and the synthesis method is suitable for industrial production. The technical defects that in the prior art, reaction conditions of high temperature, strong base and the like are harsh, substrate synthesis is complex, the range is limited, and expensive photocatalysts are used are effectively overcome. # 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, it is of great significance to develop efficient methods for the synthesis of azaglycosides.

[0003] The traditional synthesis method of glycoside compounds is to generate the corresponding glycoside compounds by forming an oxygen cation from the sugar donor under acidic conditions and then reacting with nucleophiles such as O, N and S in a polar reaction. However, since the nucleophilicity of the N nucleophile is weakened under acidic conditions, the reactivity is poor, that is, the traditional synthesis method of glycoside compounds based on the acid-promoted glycosylation system is difficult to prepare nitrogen glycoside compounds.

[0004] In order to solve the above technical problems, the prior art (DOI No. 10.1038 / s41467-024-47711-9) and the prior art (DOI No. 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] It can be seen from Reaction Equations 1 and 2 that the above method for preparing nitrogen glycoside compounds through the copper-photosynergistic catalytic strategy not only needs to be carried out in a strong alkaline environment, the reaction conditions are harsh, and 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] An alkyl N-glycoside compound and a 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 preferably uses manganese powder as a reducing agent, which can not only reduce the metal nickel provided by the nickel catalyst in the reaction medium system, but also improve the subsequent nickel catalyst to promote the reaction of the glycosyl donor and the electrophilic amine reagent to form an alkyl N-glycoside compound. In addition, the present invention has found in the process of exploration that when a metal reducing agent other than manganese powder is used, such as potassium powder, the target product cannot be obtained.

[0015] The organic ligand used in the present invention is a compound having a structure as shown in Formula 4. The organic ligand is not only cheap and readily available, which can reduce the synthesis cost, but also has multiple coordination chelating sites, which can promote coordination with the metal nickel provided by the nickel catalyst, thereby facilitating the subsequent reaction of 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 used is nickel chloride dimethoxyethane, which is not only low in toxicity and cheap and readily available, but also can achieve the effect of transition metal catalytic reduction coupling to promote the reaction of glycosyl donors and electrophilic amine reagents to form alkyl N-glycoside compounds. In addition, the present invention found in the exploration process that when other metal catalysts are used, such as cobalt catalysts and iron catalysts, no target product is detected.

[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 of 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 each 1 L of the reaction solvent, and the manganese powder, the nickel catalyst and the organic ligand are uniformly dispersed in the reaction solvent to achieve the effect of coordinating the organic ligand and the metal nickel in advance. In some preferred embodiments of the present invention, the manganese powder, the nickel catalyst and the 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 reduction coupling reaction: 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, the compound 1 and the compound 2 are sequentially dispersed in the reaction medium solution under an inert atmosphere, 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; 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, 1H-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-(((2-(10-oxo-10,11-dihydrodibenzo[b,f]thien-2-yl)propanoyl)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 nitrogen-containing components into the target product to obtain alkyl N-glycoside compounds.

[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] Wherein, the compound 2a is O-benzoyl-N,N-dibenzylhydroxylamine; the compound 2b is O-benzoyl-N-benzyl-N-(4-chlorobenzyl)hydroxylamine; the compound 2c is O-benzoyl-N-benzyl-N-(2-fluorobenzyl)hydroxylamine; the compound 2d is O-benzoyl-N-benzyl-N-(4-(trifluoromethyl)benzyl)hydroxylamine; the compound 2e is 4-(((benzoyloxy)(benzyl)amino)methyl)benzonitrile; the 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 21 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 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 evenly 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 a 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 improve 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 react fully.

[0037] In some preferred embodiments of the present invention, the purification is column chromatography separation and purification to achieve the effect 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 reduction coupling strategy, with 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 a nickel catalyst in a reaction solvent as a reaction medium solution, and using a stable, simple and easily available compound 1 as shown in Formula 1 and a compound 2 as shown in Formula 2 as a glycosyl donor and an electrophilic amine reagent, respectively, and dispersing compound 1 and compound 2 in the reaction medium solution by stirring, and during the stirring process, compound 2 first undergoes an oxidative addition reaction with a metal nickel complex formed by coordination of the organic ligand and the nickel catalyst, and then undergoes a free radical addition reaction with the glycosyl free radical generated by compound 1 in the system, and finally undergoes reduction elimination under the action of metal manganese to obtain a 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 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 reaction medium solution: tetrahydrofuran and toluene are mixed in a volume ratio of 4:1 to obtain a reaction solvent. In a nitrogen atmosphere of a glove box, 0.3 mmol manganese powder, 0.01 mmol nickel chloride dimethoxyethane, 0.012 mmol organic ligand L1 and 1 mL of the above-prepared reaction solvent are added to a 10 mL reaction tube, and stirred at room temperature for 15 min to obtain a reaction medium solution.

[0048] Step 2, transition metal catalyzed reduction 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 are sequentially added to the reaction medium solution obtained above under a nitrogen atmosphere, and the mixture is stirred and reacted at room temperature for 12 h. Compound 3a is obtained by separation and purification by column chromatography. The synthesis route thereof 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 performs NMR test on compound 3a, and the test results are as follows: Figure 1 and Figure 2 shown.

[0053] in, Figure 1 Compound 3a prepared in Example 1 1 H NMR (400MHz, 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 It can be seen from the test results 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 route 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 route 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 route 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 route 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 route 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 Formula 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 route of this embodiment is shown in reaction formula 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 route of this embodiment is shown in reaction formula 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 route of this embodiment is shown in reaction formula 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] Embodiment 11

[0110] This embodiment provides a method for synthesizing compound 3k. The reaction route 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 route of this embodiment is shown in reaction formula 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 route of this embodiment is shown in Reaction Scheme 15.

[0123]

[0124] Reaction 15.

[0125] The only difference between this example and Example 1 is that in this example, compound 1a is used as a glycosyl donor and compound 2m is used as an 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] Embodiment 14

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

[0129]

[0130] Reaction 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] Embodiment 15

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

[0135]

[0136] Reaction 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 Formula 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 route 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] Embodiment 17

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

[0147]

[0148] Reaction 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] Embodiment 18

[0152] This embodiment provides a method for synthesizing compound 3r. The reaction route of this embodiment is shown in reaction formula 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] Embodiment 19

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

[0159]

[0160] Reaction 21.

[0161] The difference between this example and example 1 is that in this example, compound 1a is used as a glycosyl donor and compound 2s is used as an electrophilic amine reagent. In addition, compound 3s obtained in this example is a yellow liquid with a β configuration and a yield of 52%.

[0162] Embodiment 20

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

[0164]

[0165] Reaction equation 22.

[0166] The only difference between this example and Example 1 is that in this example, compound 1a is used as a glycosyl donor and compound 2t is used as an 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] Embodiment 21

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

[0170]

[0171] Reaction equation 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] Embodiment 22

[0175] This embodiment provides a method for synthesizing compound 3v. The reaction route of this embodiment is shown in reaction formula 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 a glycosyl donor and Compound 2k is used as an 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] Embodiment 23

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

[0182]

[0183] Reaction 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] Embodiment 24

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

[0188]

[0189] Reaction 26.

[0190] The only difference between this example and Example 1 is that in this example, compound 1c is used as a glycosyl donor and compound 2m is used as an 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] Embodiment 25

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

[0194]

[0195] Reaction 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] Embodiment 26

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

[0200]

[0201] Reaction equation 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] Embodiment 27

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

[0206]

[0207] Reaction equation 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] Embodiment 28

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

[0212]

[0213] Reaction 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] Embodiment 29

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

[0218]

[0219] Reaction 31.

[0220] The only difference between this example and Example 1 is that in this example, compound 1e is used as a glycosyl donor and compound 2e is used as an 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] Embodiment 30

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

[0224]

[0225] Reaction equation 32.

[0226] The difference between this example and example 1 is that in this example, compound 1f is used as a glycosyl donor and compound 2e is used as an electrophilic amine reagent. The reaction route of this example is shown in reaction formula 32, and compound 3ad obtained in this example is a white solid with a β configuration and a yield of 35%.

[0227] Embodiment 31

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

[0229]

[0230] Reaction equation 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 Formula 33, and the compound 3ae obtained in this example is a white solid with a β configuration and a yield of 52%.

[0233] Embodiment 32

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

[0235]

[0236] Reaction equation 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] Embodiment 33

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

[0241]

[0242] Reaction 35.

[0243] The only difference between this example and Example 1 is that in this example, compound 1g is used as a glycosyl donor and compound 2q is used as an 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] Embodiment 34

[0246] This embodiment provides a method for synthesizing compound 3ah. The reaction route of this embodiment is shown in reaction formula 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 a glycosyl donor and compound 2q is used as an 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] Embodiment 35

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

[0253]

[0254] Reaction 37.

[0255] The difference between this example and example 1 is that in this example, compound 1i is used as a glycosyl donor and compound 2q is used as an electrophilic amine reagent. In addition, compound 3ai obtained in this example is a white solid with a β configuration and a yield of 77%.

[0256] Embodiment 36

[0257] This embodiment provides a method for synthesizing compound 3aj. The reaction route of this embodiment is shown in reaction formula 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] Embodiment 37

[0263] This embodiment provides a method for synthesizing compound 3ak. The reaction route of this embodiment is shown in reaction formula 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] Embodiment 38

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

[0270]

[0271] Reaction 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 is a white solid with a β configuration and a yield of 63%.

[0274] Embodiment 39

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

[0276]

[0277] Reaction 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] Embodiment 40

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

[0282]

[0283] Reaction equation 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] Embodiment 41

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

[0288]

[0289] Reaction 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 the above Examples 1 to 21, 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 present invention organizes the alkyl N-glycoside compounds synthesized in the above-mentioned Examples 22 to 41 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 reduction coupling strategy, uses a stable glycosyl donor and a simple and readily available electrophilic amine reagent as starting materials, overcomes obstacles 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, and efficiently, mildly and conveniently synthesizes a series of alkyl N-glycoside compounds. The synthesized alkyl N-glycosides have potential active value in the field of biopharmacology.

[0299] Obviously, the above embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without 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, uniformly dispersing the manganese powder, the nickel catalyst and the organic ligand in a reaction solvent, and mixing them to obtain a reaction medium solution; 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, the compound 1 and the compound 2 are sequentially dispersed in the reaction medium solution under an inert atmosphere, 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. In the formula, GPO is selected from any one or more groups of acetoxy, benzoyl, pivaloyloxy and benzyloxy; R1 is selected from any one of substituted benzyl, naphthyloxy, furanyloxy, thienyloxy, indoleoxy, phenyl, allyl, cyclopropyloxy and ethyl; R2 is selected from any one of substituted benzyl, naphthyloxy, furanyloxy, thienyloxy, indolyloxy, phenyl, allyl, cyclopropyloxy and ethyl.

2. The method for synthesizing an alkyl N-glycoside compound according to claim 1, characterized in that: The nickel catalyst is nickel chloride dimethoxyethane.

3. The method for synthesizing an alkyl N-glycoside compound according to claim 1, characterized in that: 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.

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

1.

5. The method for synthesizing an alkyl N-glycoside compound according to claim 1, characterized in that: The added amount of the compound 1 is 17 to 19 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, characterized in that: The added amount of the compound 2 is 9 to 11 times the molar amount of the nickel catalyst in the reaction medium solution.

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

8. The method for synthesizing an alkyl N-glycoside compound according to claim 1, characterized in that: The purification is column chromatography separation and purification.

9. An alkyl N-glycoside compound synthesized by the synthesis method according to any one of claims 1 to 8.

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