Glycosylation reaction method with elementary substance iodine as accelerant

Abstract

The invention provides a glycosylation reaction method using elemental iodine as an accelerant, which comprises the following steps: carrying out glycosylation reaction on raw materials containing a glycosylation donor, a glycosylation receptor and an accelerant to obtain a glycosylation reaction product; wherein the accelerant is elemental iodine; the chemical formula of the glycosylation donor is shown as a formula I, wherein Sugar in the formula I is substituted or non-substituted glycosyl; the glycosylation receptor comprises at least one of a hydroxyl-containing compound, an amide compound, a sulfonamide compound or a pyrimidine compound. The glycosylation reaction method taking the elemental iodine as the accelerant disclosed by the invention is low in cost, simple and convenient to operate and mild in condition, and is widely applicable to synthesis of various oxyglycosides, nitroglycosides and carbohydrate drugs.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and in particular relates to a glycosylation reaction method using elemental iodine as a promoter. Background Art

[0002] Important goals of carbohydrate chemistry research include developing new synthetic technologies for polysaccharide and oligosaccharide derivatives, developing new carbohydrate drugs and polysaccharide vaccines, etc. The core theme of synthetic carbohydrate chemistry is the construction of glycosidic bonds, so a universal synthetic method for complex carbohydrates remains a challenging goal for synthetic chemists. Over the past century, efforts have been made to develop new glycosylation methods to efficiently synthesize different glycans and glycoconjugates. However, finding an efficient and generally applicable glycosylation method remains challenging.

[0003] Since Arthur Michael first reported the glycosylation reaction of glycosyl chloride with alcohol in 1879, glycosyl halides have received extensive attention and in-depth research in the field of carbohydrate chemical synthesis. Many glycosyl halides have been developed for glycosylation reactions. Due to the relatively simple preparation and high reactivity of glycosyl halides, they are still common glycosyl donors in glycosylation reactions. Different types of glycosyl halides (including fluorides, chlorides, bromides and iodides) have different reactivity and preparation methods. Traditional glycosylation reactions require the preparation of glycosyl halides with sugar hemiacetals or various glycosides, which are then activated by activators and further substituted by nucleophiles (such as alcohols or amines) to generate the corresponding glycosides. Overall, the diversity and high reactivity of glycosyl halides provide a variety of options for the synthesis of carbohydrates. Although significant progress has been made in the application of glycosyl halides in glycosylation reactions, many known glycosylation schemes still need further research and improvement.

[0004] Chinese patent CN 111018927 A proposes a glycosylation donor of o-(1-phenylvinyl)benzoate, and proposes a glycosylation reaction scheme of the glycosylation donor. However, in the glycosylation reaction mode proposed, the reaction is catalyzed by a combination of a promoter NIS and a Lewis acid TMSOTf. When a weak nucleophilic reagent is used as a glycosylation acceptor, the succinimide generated in the system will bring about unfavorable nucleophilic competition, which may lead to the formation of one or more by-products, thereby affecting the efficiency and selectivity of the glycosylation reaction; and the glycosylation reaction needs to be carried out at a low temperature of 0 to -20°C, the reaction steps are relatively complicated, the reaction conditions are relatively harsh, and the overall cost is relatively high. Summary of the invention

[0005] The present invention provides a method for activating glycosyl o-(1-phenylvinyl) benzoate donors by using a single promoter elemental iodine, so as to solve the problems of complicated glycosidation reaction process and high cost in the prior art.

[0006] A glycosylation reaction method using elemental iodine as a promoter comprises the following steps:

[0007] Carrying out a glycosylation reaction on a raw material including a glycosylation donor, a glycosylation acceptor and a promoter to obtain a glycosylation reaction product;

[0008] Wherein, the promoter is elemental iodine;

[0009] The chemical formula of the glycosylation donor is shown in Formula I:

[0010]

[0011] In formula I, Sugar is a substituted or unsubstituted saccharide;

[0012] The glycosylated receptor comprises at least one of a hydroxyl-containing compound, an amide compound, a sulfonamide compound or a pyrimidine compound.

[0013] Optionally, the Sugar has a structural formula of:

[0014]

[0015] Wherein, PG is one or more hydroxyl protecting groups, glycosyl groups or sugar chains;

[0016] Preferably, the hydroxyl protecting group is selected from any one of a substituted or unsubstituted aromatic acyl group, a substituted or unsubstituted C2-C6 alkanoyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted C1-C6 alkyl group.

[0017] Preferably, the hydroxyl protecting group is selected from any one of acetyl (Ac), benzyl (Bn), and benzoyl (Bz).

[0018] The method for preparing the glycosylation donor of formula I comprises the following steps:

[0019] The compound shown in formula S is subjected to an esterification reaction with 2-(1-phenylvinyl)benzoic acid.

[0020]

[0021] Among them, the Sugar structure is as described above.

[0022] The esterification reaction comprises the following steps: dissolving compound S and 2-(1-phenylvinyl)benzoic acid in a dichloromethane solvent at room temperature, adding DMAP, EDCI and DIPEA under an inert gas atmosphere, stirring the mixture at room temperature until TLC shows that the reaction is complete, and obtaining a structure of formula I by rapid column chromatography.

[0023] The molar ratio of the compound S, 2-(1-phenylvinyl)benzoic acid, DMAP, EDCI and DIPEA is 1:1 to 1.5:1:1.5 to 2:3;

[0024] Preferably, it is 1:1.2:1:1.8:3; the concentration of compound S in the dichloromethane solvent is 0.01-1 mol / L, preferably 0.1-0.5 mol / L.

[0025] Optionally, the glycosylation donor is selected from at least one of I-1, I-2, and I-3:

[0026]

[0027] Optionally, the glycosylation receptor is at least one of the compounds shown in chemical formulas II-1 to II-12:

[0028]

[0029] Optionally, the molar ratio of the glycosylation donor to the glycosylation acceptor is 1 to 2.0:1;

[0030] The molar ratio of the glycosylated receptor to elemental iodine is 1:1.2-2.5.

[0031] Optionally, the solvent is at least one of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a ketone solvent, an amide solvent, an ether solvent, and a nitrile solvent;

[0032] Preferably, the solvent is at least one of toluene, dichloromethane, ether, acetone, N,N-dimethylformamide, tetrahydrofuran, and acetonitrile;

[0033] Preferably, the solvent is acetonitrile;

[0034] Preferably, the concentration of glycosylated receptors in the raw material is 0.033-0.1 mol / L;

[0035] Optionally, the raw material further comprises a desiccant;

[0036] The desiccant is selected from Molecular sieves, Molecular sieves, at least one of molecular sieves;

[0037] Optionally, the amount of the desiccant added is 2 to 5 grams per millimole of the glycosylated receptor.

[0038] Optionally, the reaction temperature of the raw materials is 0°C to room temperature, and the reaction time is 1.5 to 24 hours;

[0039] Optionally, the reaction is carried out under an inert atmosphere;

[0040] Optionally, the inert atmosphere is argon or nitrogen.

[0041] Optionally, the method further comprises the following steps:

[0042] After the glycosylation reaction is completed, quenching is performed to obtain a glycosylation reaction product, and then the glycosylation reaction product is purified.

[0043] Optionally, the glycosylation reaction product is at least one of the compounds represented by chemical formulas P1 to P14:

[0044]

[0045] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0046] The glycosylation process of the present invention uses only elemental iodine as a promoter, does not involve metals, and does not require additional strong acid catalysis. It operates under relatively mild conditions (room temperature reaction), and can use sulfonamide compounds as reaction substrates. The substrate range is wider than that of the prior art, and a high yield can be obtained.

[0047] The invention can realize the high stereoselective construction of 1,2-cis glycosidic bonds through mixed solvents, and has a wider application range. It also realizes the synthesis of the carbohydrate drug PG545 by the iodine-promoted glycosyl o-(1-phenylvinyl) benzoate donor activation method. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0049] Figure 1 Glycosylation reactions under different conditions. Trace and Quantitative represent trace reaction and quantitative reaction; the yield of 3a is the isolated yield; and the ratio of α:β is determined by NMR. DETAILED DESCRIPTION

[0050] Now, various exemplary embodiments of the present invention are described in detail, and this detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention. It should be understood that the terms described in the present invention are only for describing specific embodiments and are not used to limit the present invention.

[0051] In addition, for the numerical range in the present invention, it is understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0052] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0053] The raw materials, reagents and other materials used in the following examples are all commercially available products. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art in the art described in the present invention. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention.

[0054] The present invention provides a glycosidation reaction method using elemental iodine as a promoter, comprising the following steps:

[0055] Carrying out a glycosylation reaction on a raw material including a glycosylation donor, a glycosylation acceptor and a promoter to obtain a glycosylation reaction product;

[0056] Wherein, the promoter is elemental iodine;

[0057] The chemical formula of the glycosylation donor is shown in Formula I:

[0058]

[0059] In formula I, Sugar is a substituted or unsubstituted saccharide;

[0060] The glycosylated receptor comprises at least one of a hydroxyl-containing compound, an amide compound, a sulfonamide compound or a pyrimidine compound.

[0061] All compounds of formula I used in the examples were prepared according to the method described in Chinese patent CN 111018927 A. The specific preparation process is as follows: Route 1:

[0062]

[0063] Wherein Sugar is a substituted or unsubstituted sugar group. Compound S-1 (1.0 equivalent) and 2-(1-phenylvinyl)benzoic acid (1.2 equivalent) were dissolved in anhydrous DCM (c=0.1M), and 4-dimethylaminopyridine (DMAP) (1.0 equivalent), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (1.8 equivalent) and N, N-diisopropylethylamine (DIPEA) (3.0 equivalent) were added. The mixture was stirred at room temperature until TLC analysis showed that the reaction was complete. Then, the mixture was directly purified by silica gel flash column chromatography to obtain the glycosylation donor shown in Formula I.

[0064] According to the method of route 1, compound I-1 was prepared from the raw material S-1 (400 mg, 0.74 mmol) corresponding to I-1. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain I-2 (532 mg, 96%, α:β = 1:3.5) as a colorless syrup. 1H NMR(400MHz, CDCl3)δ7.96(dd,J=7.9,1.4Hz,3.5H),7.90(dd,J=7.8,1.4Hz,1H),7.59-7.32(m,21H),7.30-7.15(m,106H),6.40(d,J=3.4Hz,1H),5 .69(d,J=3.4Hz,4.5H),5.63(d,J=8.0Hz,3.5H),5.30(s,1H),5.16(d,J=8 .1Hz,4.5H),4.87-4.74(m,13H),4.66-4.40(m,26H),3.76-3.43(m,30H).

[0065] The structure of compound I-1 is as follows:

[0066]

[0067] According to the method of route 1, compound I-2 was prepared from the raw material S-2 (200 mg, 0.36 mmol) corresponding to I-2. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain I-1 (265 mg, 97%, α:β = 1:8.5) as a colorless syrup. β configuration: 1H NMR (400MHz, CDCl3) δ7.95-7.85 (m, 3H), 7.53 (t, J = 7.4 Hz, 1H), 7.49-7.43 (m, 1H), 7.41-7.05 (m, 24H), 5.78 (d, J = 8.2 Hz, 1H), 5.57 (s, 1H), 5.00 (s, 1H), 4.80 (d, J = 10.8 Hz, 1H), 4.73 (d, J = 1 1.2Hz,1H),4.67-4.56(m,3H),4.47(d,J=12.1Hz,1H),3.90(t,J=9.2Hz,1H),3.83(t,J=9.0Hz ,1H), 3.75(dd,J=11.1,3.5Hz,1H), 3.68(dd,J=11.1,2.0Hz,1H), 3.61(dt,J=9.6,2.7Hz,1H).

[0068] The structure of compound I-2 is as follows:

[0069]

[0070] According to the method of route 1, compound I-3 was prepared from the raw material S-3 (500 mg, 0.92 mmol) corresponding to I-3. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10: 1) to obtain I-3 (658 mg, 95%, α: β = 1: 3.3) as a colorless syrup. β configuration: 1H NMR (600MHz, CDCl3) δ7.94 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.36-7.27 (m, 14H), 7.25-7.10 (m, 12H), 5.66 (d, J = 1.0 Hz, 1H), 5.58 (d, J = 8.0 Hz, 1H, H-1), 5.13 (d, J = 1.0 Hz,1H),4.94(d,J=11.4Hz,1H),4.72-4.66(m,3H),4.61(dd,J=11.2,9.4Hz,2H),4.41(d,J=11.8H z, 1H), 4.38 (d, J = 11.7Hz, 1H), 3.97-3.92 (m, 2H), 3.65-3.55 (m, 3H), 3.47 (dd, J = 9.0, 4.9Hz, 1H).

[0071] The structure of compound I-3 is as follows:

[0072]

[0073] Embodiment 2:

[0074] Some compounds of formula P of the present invention are prepared according to the following route 2:

[0075]

[0076] Wherein, NuH is at least one of any hydroxyl-containing compound, pyrimidine compound, amide compound, and sulfonamide compound. The specific steps are as follows:

[0077] At room temperature, the glycosylated donor of formula I (1.5 equivalents) and the acceptor of formula II (1.0 equivalents) were dissolved in anhydrous MeCN (c = 0.033M), and dry MS (3.0 g / mmol) was stirred at room temperature for 10 minutes. Then iodine (2.0 equivalents) was added thereto, and the reaction mixture was stirred at room temperature (25°C) for 1.5-24 hours. Then Et3N was added to quench the reaction, and the product of formula P was obtained by direct purification by silica gel column chromatography.

[0078] 2-1 Preparation of glycosylated product P1:

[0079]

[0080] According to the general method of route 2, I-1 (43.4 mg, 0.06 mmol) was glycosylated with II-1 (18 mg, 0.04 mmol) for 2 hours to obtain P1 (38 mg, 99%, α:β=1:4) as a syrup: 1H NMR (400 MHz, CDCl3) δ7.34-7.22 (m, 37H), 7.17 (ddd, J=9.8,5.6,2.6 Hz, 6.5H), 7.11 (dd, J=7.1,2.5 Hz, 0.5H), 4.96 (dd, J=10.9,3.8 Hz, 2.5H), 4.93-4.87 (m, 1.5H), 4.83-4.68 (m, 7H), 4.66-4.56 (m, 4H), 4.55-4.48 (m,3.5H),4.44(d,J=12.1Hz,0.5H),4.34(d,J=7.7Hz,1H),4.17(dd,J=10.8,2.0Hz,1H),3.97(dt,J=14.7 ,9.5Hz,1.5H),3.85-3.80(m,1H),3.77-3.48(m,10H),3.47-3.40(m,1.5H),3.34(s,0.75H),3.32(s,3H).

[0081] 2-2 Preparation of glycosylation product P2:

[0082]

[0083] According to the general method of route 2, I-1 (50 mg, 0.07 mmol) and II-8 (17.4 mg, 0.13 mmol) were subjected to glycosylation reaction for 16 hours to obtain P2 (35 mg, 80%, β:α>10:1) as a syrup: 1H NMR (600MHz, CDCl3) δ8.90(s,1H),7.38-7.26(m,16H),7.18(d,J=7.2Hz,4H),6.76(d,J=5.6Hz,1H),5.55(d,J=9.1Hz,1H,H-1),4.94(s,2H), 13C NMR (151MHz, CDCl3) δ156.6,156.4,149.0,140.8,139.2,138.1,137.8,137.7,137.0,129.0,129.0,128.8,128.7,128.7,1 28.6,128.6,128.3,128.1,128.1,128.0,127.9,127.8,86.0,81.7(C-1β),77.8,77.6,77.3,76.1,75.3,74.6,73.6,68.3.

[0084] 2-3 Preparation of glycosylated product P3:

[0085]

[0086] According to the general method of route 2, I-1 (60 mg, 0.08 mmol) and II-9 (6.9 mg, 0.04 mmol) were subjected to glycosylation reaction for 24 hours to obtain P3 (13.5 mg, 48%, α:β=1:5) as syrup: 1H NMR (600MHz, CDCl3): δ7.76(d,J=7.9Hz,2H),7.36-7.27(m,19H),7.25-7.20(m,3H),7.18-7.09(m,5H),4.97(d,J=9 13C NMR (151MHz, CDCl3) δ143.5,138.6,138.4,138.1,138.0,137.6,129.6,129.5,128.7,128.7,128.7,128.6,128.5,128.3,128.2,128.0,128.0, 128.0,128.0,127.9,127.9,127.9,127.7,127.4,85.7,84.4,82.1,80. 5(C-1β),76.5,75.9,75.1,75.0,73.7,68.3,29.9(CH3α),21.6(CH3β).

[0087] 2-4 Preparation of glycosylated product P4:

[0088]

[0089] According to the general method of route 2, I-2 (59.0 mg, 0.08 mmol) and II-1 (18.0 mg, 0.04 mmol) were subjected to glycosylation reaction for 2 hours to obtain P (35.0 mg, 90%) as a syrup: 1H NMR (400 MHz, CDCl3) δ7.89-7.80 (m, 2H), 7.39-7.33 (m, 1H), 7.25-7.03 (m, 30H), 6.96-6.91 (m, 2H), 5.27 (dd, J = 9.4, 8.0 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 4.73 (d, J = 10.8 Hz, 1H), 4.65 (dd, J = 11.6, 4.4 Hz, 2H), 4.61-4.54 (m, 2H), 4 .53-4.44(m,5H),4.39(d,J=3.5Hz,1H),4.36(d,J=11.1Hz,1H),4.20(d,J=11.0Hz,1H),4.08-4.03(m,1H),3.82 -3.56(m,7H),3.48(ddd,J=9.7,5.2,2.0Hz,1H),3.35(dd,J=9.6,3.6Hz,1H),3.29(t,J=9.3Hz,1H),3.11(s,3H).

[0090] 2-5 Preparation of glycosylated product P5:

[0091]

[0092] According to the general method of route 2, I-3 (50 mg, 0.07 mmol) and II-2 (23.2 mg, 0.05 mmol) were subjected to glycosylation reaction for 2 hours to obtain P5 (43 mg, 95%, β only) as a syrup: 1H NMR (600MHz, CDCl3): δ8.03(dd,2H),7.87(dd,2H),7.83(dd,2H),7.56-7.50(m,3H),7.36(q,J=8.2Hz,4H),7.32-7.26(m,13H), 7.20(t,J=7.1Hz,1H),7.11-7.07(m,2H),7.07-7.03(m,1H),5.75(dd,J=6.5,4.8Hz,1H),5.72(d,J=1.8Hz,1H,H-1),5.70-5.66( m,1H),4.98(d,J=10.9Hz,1H),4.78(d,J=10.9Hz,1H),4.72(d,J=12.2Hz,1H),4.61-4.55(m,5H),4.47-4.41(m,2H),3.93(t,J= 13C NMR (151MHz, CDCl3) δ166.2,165.4,165.1,138.5,138.4,138.1,133.5,133.3,129.9,129.7,129.3,129.1,128.6,128.5,128.4,128. 3,128.1,127.8,127.7,127.5,107.3(C-1),98.0,81.2,80.1,78.7,77.6,75.9,75.7,73.5,73.4,72.1,69.6,68.7,64.8,55.4,29.9.

[0093] 2-6 Preparation of glycosylated product P6:

[0094]

[0095] According to the general method of route 2, I-3 (50 mg, 0.07 mmol) and II-3 (24 mg, 0.05 mmol) were subjected to glycosylation reaction for 2 hours to obtain P6 (45 mg, 97%, β only) as a syrup: 1H NMR (600MHz, CDCl3): δ7.98(t,J=7.7Hz,4H),7.88(d,J=8.0Hz,2H),7.58-7.54(m,1H),7.52-7.46(m,2H),7.42-7.39(m,4H),7 .34-7.21(m,14H),7.16-7.11(m,3H),5.79(dd,J=7.1,4.8Hz,1H),5.72(d,J=4.8Hz,1H),5.44(s,1H),5.02(d,J=2.6Hz,1H),4. 98(d,J=10.8Hz,1H),4.84(d,J=10.8Hz,1H),4.80(d,J=10.8Hz,1H),4.70(q,J=5.9Hz,1H),4.63(d,J=12.1Hz,1H),4.56-4.46( 13C NMR (151MHz, CDCl3) δ166.1,165.3,165.3,138.6,138.3,138.1,133.6,133 .4,133.1,129.9,129.9,129.8,129.7,129.3,129.1,128.6,128.5,128.5,1 28.5,128.4,128.2,128.0,128.0,127.8,127.8,127.7,103.9(C-1),97.2,8 0.9,78.8,77.9,76.8,76.0,75.8,75.2,73.6,72.8,70.3,68.6,65.4,55.3.

[0096] 2-7 Preparation of glycosylated product P7:

[0097]

[0098] According to the general method of route 2, I-3 (50 mg, 0.07 mmol) and II-4 (7.8 mg, 0.05 mmol) were subjected to glycosylation reaction for 2 hours to obtain P7 (29.7 mg, 99%, β only) as a syrup: 1H NMR (600MHz, CDCl3): δ8.07(d,J=6.8Hz,2H),8.02(d,J=6.8Hz,2H),7.90(d,J=6.8Hz,2H),7.60-7.55(m,1H),7.54-7.49(m,2H),7.42(t,J=7 .8Hz,2H),7.38(t,J=7.7Hz,2H),7.33(t,J=7.8Hz,2H),5.85(dd,J=6.6,4.8Hz,1H),5.62(dd,J=4.7,1.1Hz,1H),5.34(d,J=1.1Hz,1H,H-1),4 .74-4.67(m,2H),4.55(dd,J=11.3,5.2Hz,1H),3.38(td,J=10.7,4.3Hz,1H),2.22-2.15(m,2H),1.63-1.58(m,2H),1.37-1.31(m,1H),1.22- 1.16(m,1H),1.02-0.92(m,2H),0.90(d,J=7.0Hz,3H),0.88-0.82(m,1 H),0.81(d,J=6.6Hz,3H),0.79(d,J=6.9Hz,3H),0.78-0.72(m,1H); 13C NMR (151MHz, CDCl3) δ166.3,165.6,165.5,133.5,133.5,133.2,130.0,129.9,129.9,129.9,129.5,129.2,128. 6,128.5,128.4,107.1(C-1),82.0,78.6,76.1,72.8,65.2,48.3,43.0,34.4,31.7,25.8,23.4,22.3,21.1,16.3.

[0099] 2-8 Preparation of glycosylated product P8:

[0100]

[0101] According to the general method of route 2, I-3 (50 mg, 0.07 mmol) and II-5 (19.4 mg, 0.05 mmol) were subjected to glycosylation reaction for 2 hours to obtain P8 (41 mg, 99%, β only) as a colorless syrup: 1H NMR (600 MHz, CDCl3): δ8.07 (d, J = 7.7 Hz, 2H), 8.02 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 7.8 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.54-7.48 (m, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H). ,2H),7.32(t,J=7.7Hz,2H),5.88(dd,J=7.0,4.8Hz,1H),5.63(d,J=4.7Hz,1H),5.41( s,1H,H-1),4.73(dd,J=11.5,4.3Hz,1H),4.69(dt,J=6.9,4.8Hz,1H),4.52(dd,J=11. 5,5.1Hz,1H),3.65-3.58(m,1H),1.95(dt,J=12.7,3.4Hz,1H),1.92-1.87(m,1H),1.8 5-1.77(m,1H),1.70(dt,J=13.4,3.7Hz,1H),1.62(dt,J=12.8,3.9Hz,1H),1.57-1.50 (m,3H),1.49-1.44(m,1H),1.42-1.21(m,9H),1.16-0.95(m,11H),0.92-0.85(m,10H) ,0.84-0.79(m,1H),0.74(s,3H),0.64(s,3H),0.58(ddd,J=14.0,10.6,4.0Hz,1H); 13C NMR (151MHz, CDCl3) δ166.3,165.5,133.5,133.4,133.2,130.0,129.9,129. 5,129.2,128.6,128.5,128.4,103.9(C-1),78.6,77.8,76.3,72.8,65.1,56 .6,56.4,54.5,45.0,42.7,40.2,39.7,37.0,36.3,36.1,35.9,35.7,35.6,32.2,28.8,28.4,28.2,27.8,24.4,24.0,23.0,22.7,21.4,18.8,12.4,12.2.

[0102] Embodiment 3:

[0103] Some compounds of formula P of the present invention are prepared according to the following route 3:

[0104]

[0105] Wherein, NuH is any hydroxyl-containing compound or a pyrimidine compound or an amide compound.

[0106] The specific steps are as follows:

[0107] At room temperature, the glycosylation donor of formula I-1 (1.5 equivalents) was dissolved in a dry DCM / DMF mixed solvent (0.033 M, v / v 15:1), and dry MS (3.0 g / mmol) was stirred at room temperature for 10 minutes. At 0°C, iodine I2 (2.0 equivalents) was added thereto and stirred for 1 hour until TLC thin layer chromatography analysis showed that the donor was completely activated, and then the receptor of formula II (1.0 equivalents) was added to the reaction system, slowly heated to room temperature and stirred for 1.5-24 hours until TLC showed that the receptor was completely converted. Then Et3N was added to quench the reaction, and the glycosylation product shown in formula P was obtained directly by silica gel column chromatography.

[0108] 3-1 Preparation of glycosylated product P9:

[0109]

[0110] According to the general method of route 3, I-1 (43.4 mg, 0.06 mmol) and II-3 (18 mg, 0.04 mmol) were glycosylated to obtain P9 (34.5 mg, 90%, α:β>20:1) as a colorless syrup: 1H NMR (600MHz, CDCl3): δ7.30 (d, J = 6.9Hz, 2H), 7.27-7.15 (m, 27H), 7.08-7.01 (m, 4H),6.93(t,J=7.5Hz,2H),4.91(d,J=10.8Hz,1H),4.87(dd,J=10.9,3.5Hz,2H) ,4.84(d,J=10.3Hz,1H),4.78-4.71(m,4H),4.69(d,J=10.4Hz,1H),4.64(d,J=1 2.2Hz,1H),4.54(d,J=12.1Hz,1H),4.48(d,J=12.1Hz,1H),4.45-4.39(m,2H),4 .36(d,J=11.0Hz,1H),4.25(d,J=12.1Hz,1H),4.02(d,J=9.4Hz,1H),3.99(d,J= 9.5Hz,1H),3.93(dt,J=10.2,2.5Hz,1H),3.77(dd,J=9.9,3.4Hz,1H),3.71(dt, J=10.1,3.9,2.1Hz,1H),3.67-3.58(m,3H),3.55(t,J=9.5Hz,1H),3.51(dd,J=9 .6,3.6Hz,1H),3.46(dd,J=10.9,2.9Hz,1H),3.41-3.38(m,1H),3.38(s,3H); 13C NMR (151MHz, CDCl3) δ138.9,138.9,138.6,138.5,138.3,138.1,138.1,128.6,128 .5,128.5,128.5,128.4,128.4,128.3,128.2,128.1,128.0,128.0,127.8,127.8,1 27.7,127.7,127.7,127.6,127.5,96.5(C-1),94.3(C-1'),82.3,80.9,79.2,78.2, 77.8,76.3,75.8,75.1,75.0,74.9,73.7,73.5,73.0,70.4,70.3,68.7,68.3,55.0.

[0111] 3-2 Preparation of glycosylated product P10:

[0112]

[0113] According to the general method of route 3, I-1 (43 mg, 0.06 mmol) and II-6 (10 mg, 0.04 mmol) were glycosylated to obtain P10 (29.5 mg, 98%, α:β>20:1) as a colorless syrup: 1H NMR (600MHz, CDCl3): δ7.35-7.26(m,18H),7.12(d,J=7.3Hz,2H),5.87(d,J=3.5Hz,1H,H-1'),5.24(d,J=3.5Hz,1H,H-1),4.96(d,J=10.9H z,1H),4.82(d,J=10.6Hz,1H),4.80(d,J=10.8Hz,1H),4.74(d,J=11.8Hz,1H),4.69(d,J=11.8Hz,1H),4.66(d,J=3.6Hz,1H),4.60(d,J=12. 1Hz,1H),4.51-4.41(m,3H),4.22(d,J=2.8Hz,1H),4.12(dd,J=8.1,2.7Hz,1H),4.07-4.01(m,2H),3.93(t,J=9.4Hz,1H),3.79(dt,J=10.2 13C NMR (151MHz, CDCl3) δ138.8,138.3,138.1,138.0,128.6,128.5,128.5,128.2,128.1,128.0,128.0,127.9,127.8,127.7,127.7,111.9,10 9.2,105.3(C-1'),98.1(C-1),83.8,81.7,81.3,80.9,80.1,77.9,75 .8,75.4,73.7,73.2,72.5,71.4,68.8,67.2,27.1,26.9,26.3,25.6.

[0114] 3-3 Preparation of glycosylated product P11:

[0115]

[0116] According to the general method of route 3, I-1 (44 mg, 0.06 mmol) and II-7 (20 mg, 0.04 mmol) were glycosylated to obtain P11 (35.6 mg, 87%, α:β>20:1) as a white solid: 1H NMR (600MHz, CDCl3): δ8.04(d,J=7.2Hz,2H),7.95(d,J=7.5Hz,2H),7.93(d,J=7 .7Hz,2H),7.59(d,J=7.5Hz,2H),7.39-7.25(m,23H),7.12(d,J=7.6Hz,2H),7.0 9(d,J=5.7Hz,2H),5.70(dd,J=10.9,3.0Hz,1H),5.62(dd,J=10.9,3.6Hz,1H),5 .24(d,J=3.7Hz,1H,H-1'),5.03(d,J=11.0Hz,1H),4.93(d,J=10.9Hz,1H),4.91( d,J=3.5Hz,1H,H-1),4.81(d,J=11.8Hz,1H),4.78(d,J=11.0Hz,1H),4.74-4.67 (m,3H),4.47-4.45(m,1H),4.40-4.32(m,3H),4.15-4.11(m,1H),4.08(dt,J=10. 1,2.1Hz,1H),4.05-4.04(m,1H),3.70(t,J=9.6Hz,1H),3.55(dd,J=9.9,3.5Hz, 1H), 3.41 (s, 3H), 3.24 (dd, J=11.0, 2.3Hz, 1H), 2.85 (dd, J=11.0, 2.0Hz, 1H); 13C NMR (151MHz, CDCl3) δ166.3,166.2,166.0,139.0,138.6,138.0,133.3,133. 3,130.1,129.9,129.8,128.6,128.5,128.5,128.4,128.4,128.3,128.1,128 .0,127.9,127.9,127.7,127.6,127.6,100.3(C-1),97.5(C-1'),82.0,79.8, 77.8,76.7,75.7,75.0,74.3,73.5,71.4,70.6,69.4,68.5,67.9,63.1,55.5.

[0117] 3-4 Preparation of glycosylated product P12:

[0118]

[0119] According to the general method of route three, I-1 (39 mg, 0.05 mmol) was glycosylated with II-10 (23 mg, 0.03 mmol) to obtain P12 (34.5 mg, 83%, α:β>20:1) as a colorless syrup: 1H NMR (600 MHz, CDCl3): δ7.94 (d, J=7.9 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.39 (t, J=7.4 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.26-7.15 (m, 35H), 7.11-7.05 (m, 4H), 5.71-5.67 (m, 2H, H-1 and CCHH),5.62(d,J=3.6Hz,1H,H-1'),5.15(s,1H),4.86(d,J=10.8Hz,1H),4.82-4.72(m,4H),4.5 8(d,J=11.9Hz,1H),4.55-4.41(m,7H),4.27(d,J=12.1Hz,1H),4.17(t,J=9.1Hz,1H),3.90(t,J =9.4Hz,1H),3.84(dd,J=11.4,3.3Hz,1H),3.80(t,J=8.5Hz,1H),3.76(dt,J=10.1,2.5Hz,1H), 3.64(dt,J=8.9,3.8Hz,3H),3.59(t,J=8.0Hz,1H),3.53-3.46(m,2H),3.37(d,J=9.7Hz,1H); 13C NMR (151MHz, CDCl3) δ165.2,149.1,143.8,140.6,138.9,138.7,138.6,138.6,138.15,138.1,1 37.9,132.3,131.7,130.6,129.8,128.4,128.4,128.3,128.3,128.1,128.0,127.9,127.8,127. 8,127.8,127.7,127.7,127.6,127.5,127.3,126.9,126.8,114.5,97.0(C-1'),94.5(C-1),84.9 ,82.1,80.7,79.6,77.8,75.6,75.5,75.1,74.5,74.0,73.6,73.5,73.4,72.5,71.1,68.8,68.4.

[0120] Embodiment 4:

[0121] The preparation route of formula P13 of the present invention is as follows:

[0122]

[0123] Among them, OPTFAI is N-phenyl trifluoroacetimidate; OPVB is o-(1-phenylvinyl) benzoate; and OMP is p-methoxyphenyl ether.

[0124] The specific steps are as follows:

[0125] Donor S4 (50 mg, 0.07 mmol) was dissolved in dry DCM / DMF (1.4 mL, v / v 15:1) and precipitated with fresh flame-dried molecular sieves. Stir at room temperature for 10 minutes. The reaction solution was cooled to 0°C, and TfOH (8.3 μL, 0.09 mmol) was then added. After 30 min, receptor II-10 (30.8 mg, 0.05 mmol) was added and the reaction was stirred at 0°C until TLC analysis showed that the receptor was completely converted. Receptor II-12 (26 mg, 0.05 mmol) and iodine (18 mg, 0.07 mmol) were then added to the reaction. The resulting mixture was stirred at 0°C to room temperature until TLC analysis showed that the reaction was complete. The solution was diluted with dichloromethane and quenched with saturated sodium thiosulfate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, vacuum filtered and concentrated.Purification by flash chromatography (hexane:ethyl acetate, 10:1) gave P13 (57.5 mg, 81%) as a colorless syrup: 1H NMR (600MHz, CDCl3): δ7.26-7.06(m,50H),7.04(d,J=8.7Hz,2H),6.81(d,J= 8.8Hz,2H),5.64(d,J=3.6Hz,1H),5.56(d,J=3.7Hz,1H),5.02(d,J=10.9Hz, 1H),4.96(d,J=11.6Hz,1H),4.92(d,J=7.6Hz,1H),4.89(d,J=11.5Hz,1H),4 .85(d,J=10.9Hz,1H),4.82(d,J=11.6Hz,1H),4.80-4.77(m,2H),4.76(d,J= 10.9Hz,1H),4.73(d,J=11.0Hz,1H),4.56-4.50(m,5H),4.47-4.42(m,5H),4 .29(d,J=12.1Hz,1H),4.10(d,J=9.0Hz,1H),4.06-4.00(m,2H),3.94-3.90( m,2H),3.86-3.83(m,2H),3.77(s,3H),3.77-3.72(m,3H),3.70-3.64(m,3H) ,3.57-3.52(m,3H),3.49(dd,J=9.9,3.6Hz,1H),3.41(d,J=10.6Hz,1H); 13C NMR (151MHz, CDCl3) δ155.5,151.6,139.0,138.9,138.6,138.4,138.3,138.3,138.1,137.9,128.5,128.4, 128.4,128.4,128.4,128.4,128.3,128.3,128.1,128.0,127.9,127.8,127.8,127.7,127.6,127.6,127.5,1 27.5,127.3,127.1,126.9,126.7,118.7,114.7,102.9,97.1,96.8,84.7,82.2,82.1,81.6,79.7,79.5,77.8,75.6,75.1,75.0,74.9,74.3,74.2,73.9,73.6,73.5,73.4,73.2,73.2,71.2,71.1,69.2,69.1,68.4,55.8.

[0126] Embodiment 5:

[0127] The preparation route of formula P14 of the present invention is as follows:

[0128]

[0129] Among them, OPTFAI is N-phenyl trifluoroacetimidate; OPVB is o-(1-phenylvinyl) benzoate.

[0130] The specific steps are as follows:

[0131] At 0 ° C, cerium ammonium nitrate CAN (272 mg, 0.51 mmol) was added to a mixed solution of DCM (1.0 mL) / MeCN (1.7 mL) / H2O (1.0 mL) of P13 (155 mg, 0.10 mmol). The mixture was stirred at room temperature for 4 hours. The reaction solution was then spin-dried and diluted with ethyl acetate, and washed with saturated sodium bicarbonate aqueous solution, water and saturated brine in sequence. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (n-hexane: ethyl acetate, 4: 1 to 2: 1) gave a brown solid (98.0 mg, 68%). The above brown solid (98.0 mg, 0.07 mmol) and 2,2,2-trifluoro-N-phenylacetimidyl chloride (22.0 mg, 0.10 mmol) were dissolved in acetone (1.0 mL), and anhydrous K2CO3 (29.0 mg, 0.21 mmol) was added. The reactants were stirred at room temperature overnight, then filtered and concentrated in vacuo. The residue was purified by flash column chromatography (hexane:ethyl acetate, 30:1 to 20:1, containing 1% Et3N) to give S5 (88.0 mg, 80%).

[0132] Under nitrogen protection, glycosylation donor S5 (85.0 mg, 0.05 mmol) was dissolved in dry DCM / DMF (1.1 mL, v / v 15:1) and mixed with fresh flame-dried Molecular sieves were stirred at room temperature for 10 minutes. The reaction solution was cooled to 0 ° C, and TfOH (6.3 μL, 0.07 mmol) was added. After 30 minutes, receptor II-11 (24.0 mg, 0.04 mmol) was added to the solution, and the reaction was slowly heated to room temperature at 0 ° C and stirred until TLC analysis showed that the receptor was completely converted. Then at 0 ° C, receptor II-5 (14.0 mg, 0.04 mmol) and iodine (13.7 mg, 0.05 mmol) were added to the solution. The resulting mixture was stirred at 0 ° C to room temperature until TLC analysis showed that the reaction was complete. The solution was diluted with dichloromethane and the reaction was quenched with saturated sodium thiosulfate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (hexane: ethyl acetate, 20: 1) to give the precursor compound P14 of drug PG545 (36.0 mg, 45%): 1H NMR (600 MHz, CDCl3): δ 8.00 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.30-7.19 (m, 39H), 7.12 (dd, J = 15.7, 7.3 Hz, 2 1H),5.69(d,J=3.6Hz,1H),5.56(d,J=3.5Hz,1H),5.44(d,J=3.6Hz,1H),5.33(t,J=8.4Hz,1H),4.91(dd, J=11.7,2.3Hz,2H),4.85-4.73(m,6H),4.68-4.63(m,2H),4.54-4.39(m,14H),4.26(d,J=12.2Hz,1H),4.1 5(t,J=8.9Hz,1H),4.11-3.99(m,5H),3.95-3.86(m,4H),3.84-3.74(m,4H),3.70-3.64(m,2H),3.57-3.4 8(m,7H),3.38(d,J=10.5Hz,1H),1.95(dt,J=12.8,3.6Hz,1H),1.90-1.84(m,1H),1.83-1.75(m,1H),1.65 -1.42(m,8H),1.33-1.19(m,7H),1.14-0.95(m,11H),0.89(d,J=6.4Hz,3H),0.86(d,J=2.8Hz,3H),0.85( 13C NMR (151MHz, CDCl3) δ165.3,139.1,139.0,138.9,138.7,138.5,138.5,138.3,138.3,138.2,138.1,138.1,137.9,133.0,130.4,129.9,128.4,128.4,128.4,128.3,128.3,128.3,128.3,128.2,128.2,1 28.1,128.0,127.9,127.8,127.7,127.7,127.7,127.6,127.6,127.6,127.5,127.5,127.4,127.2,127.1,126.8,126.7,99.9,97.0,96.9,96.7,83.0,82.3,81.8 ,81.5,79.8,79.7,79.4,79.3,77.8,75.6,75.2,75.1,74.2,74.2,74.1,73.7,73.6,73.5,73.4,73.4,73.2,73.0,72.8,72.6,71.2,71.1,71.0,69.3,69.1,68.9 ,68.4,56.6,56.5,54.5,44.8,42.7,40.2,39.7,37.2,36.3,35.9,35.7,35.6,34.8,32.2,29.5,28.8,28.4,28.2,24.3,24.0,23.0,22.7,21.4,18.8,12.3,12.2. .

[0133] Test example

[0134] In order to verify the effect of using iodine as a promoter in the present invention, the present invention is based on Figure 1 The synthetic route in the experiment was used to carry out 13 reaction experiments with different promoters and solvents (the solvent in experiment 13 was a mixture of DCM and DMF in a molar ratio of 15:1). The product P1 was synthesized from I and II-1. It can be seen that the method of the present invention can be operated under relatively mild conditions (room temperature reaction) and provides a wide substrate range and high yield.

[0135] The participation of weak nucleophilic reagents is an economical and environmentally friendly strategy for adjusting the stereoselectivity of glycosylation, which does not require additional synthesis steps and is easily removed after the reaction. The present invention can achieve high stereoselective construction of 1,2-cis glycosidic bonds through mixed solvents and has a wide range of applications.

[0136] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A glycosylation reaction method using elemental iodine as a promoter, characterized in that: The steps include: Carrying out a glycosylation reaction on a raw material including a glycosylation donor, a glycosylation acceptor and a promoter to obtain a glycosylation reaction product; Wherein, the promoter is elemental iodine; The chemical formula of the glycosylation donor is shown in Formula I: In formula I, Sugar is a substituted or unsubstituted saccharide; The glycosylated receptor comprises at least one of a hydroxyl-containing compound, an amide compound, a sulfonamide compound or a pyrimidine compound.

2. The saccharification reaction method using elemental iodine as a promoter according to claim 1, characterized in that: The Sugar has a structural formula of: Wherein, PG is one or more hydroxyl protecting groups, glycosyl groups or sugar chains; Preferably, the hydroxyl protecting group is selected from any one of a substituted or unsubstituted aromatic acyl group, a substituted or unsubstituted C2-C6 alkanoyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted C1-C6 alkyl group.

3. The saccharification reaction method using elemental iodine as a promoter according to claim 1, characterized in that: The glycosylation donor is selected from at least one of I-1, I-2, and I-3:

4. The glycosylation reaction method using elemental iodine as a promoter according to claim 1, characterized in that: The glycosylated receptor is at least one of the compounds shown in chemical formulas II-1 to II-12:

5. The saccharification reaction method using elemental iodine as a promoter according to claim 1, characterized in that: The molar ratio of the glycosylation donor to the glycosylation acceptor is 1 to 2.0:1; The molar ratio of the glycosylated receptor to elemental iodine is 1:1.2-2.

5.

6. The saccharification reaction method using elemental iodine as a promoter according to claim 1, characterized in that: The raw material further comprises a solvent, and the solvent is at least one of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a ketone solvent, an amide solvent, an ether solvent, and a nitrile solvent; Preferably, the solvent is at least one of toluene, dichloromethane, ether, acetone, N,N-dimethylformamide, tetrahydrofuran, and acetonitrile; Preferably, the solvent is acetonitrile; Preferably, the concentration of glycosylation receptor in the raw material is 0.033-0.1 mol / L.

7. The saccharification reaction method using elemental iodine as a promoter according to claim 1, characterized in that: The raw material also includes a desiccant; The desiccant is selected from Molecular sieves, Molecular sieves, at least one of molecular sieves; Preferably, the amount of the desiccant added is 2-5 g per millimole of glycosylated receptor.

8. The saccharification reaction method using elemental iodine as a promoter according to claim 1, characterized in that: The reaction temperature of the raw materials is 0°C to 25°C, and the reaction time is 1.5 to 24 hours; Preferably, the reaction is carried out under an inert atmosphere; Preferably, the inert atmosphere is argon or nitrogen.

9. The saccharification reaction method using elemental iodine as a promoter according to claim 1, characterized in that: The following steps are also included: After the glycosylation reaction is completed, quenching is performed to obtain a glycosylation reaction product, and then the glycosylation reaction product is purified.

10. The saccharification reaction method using elemental iodine as a promoter according to claim 1, characterized in that: The glycosylation reaction product is at least one of the compounds represented by chemical formulas P1 to P14:

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