Synthesis method of salosamine

Abstract

The invention relates to a synthesis method of salosamine, and belongs to the technical field of chemical synthesis. Methyl-D-rhamnoside is used as a raw material, is subjected to a photooxidation reduction isomerization reaction under illumination, then is subjected to a condensation reaction with hydroxylamine, and then is subjected to an addition reaction and a reduction reaction to obtain the sesalosamine. The method has the advantages of short steps, no need of column chromatography separation of products in all steps, high total yield and large preparation scale; the synthesis method can be applied to continuous flow synthesis and is suitable for large-scale application.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and more specifically, relates to a method for synthesizing cyclosaccharide, and in particular to a method for synthesizing cyclosaccharide using methyl-D-rhamnoside as a raw material. Background Art

[0002] Rare amino sugars with specific structures are the core structural units of many bioactive sugar natural products and drugs, and have an important influence on the biological activity of their parent structures. However, the natural content of these rare sugars is rare and difficult to separate and extract. Chemical synthesis is an effective means to obtain these rare sugars, but due to the complexity of the structure of these rare sugars, there are not many syntheses above the gram level. Saccharomicines are a kind of 17-sugar antibiotics isolated from soil fungi. They have extensive and excellent inhibitory activity against a variety of bacteria, including drug-resistant bacteria, and have the potential to become a new generation of antibiotics. Among the 17 monosaccharide units of saccharomicin, there are 4 rare amino sugars with specific structures, namely saccharosamine. The large-scale acquisition of saccharosamine is a prerequisite for synthesizing saccharomicins and modifying and simplifying their structures to discover new antibiotics. At present, many synthetic methods of saccharomicins have been reported, but most of these methods have lengthy synthetic steps, low efficiency, and very few syntheses above the gram level, which makes it difficult to solve the problem of large-scale acquisition of saccharomicins. Recently, the applicant team (Angew. Chem. Int. Ed., 2017, 56, 5227–5231) reported a method for synthesizing cyclosaccharide with a total yield of 16.5% and a scale of 2 grams using glucalose as a raw material through 12 steps of reaction. However, since the key step of this synthesis route, the C6 deoxygenation step, is cumbersome, the selective oxidation of the C3 position is time-consuming, some steps are inconvenient to operate, and each step requires column chromatography separation, which leads to further difficulty in amplification. Subsequently, the Bennettt group (Angew. Chem. Int. Ed., 2017, 56, 5227–5231) also used glucalose as a raw material to synthesize cyclosaccharide with a total yield of 16% in 15 steps. However, this method also did not solve the above problems, and cyclosaccharide can only be synthesized on a gram scale. Therefore, it is still a major problem to develop a new synthesis method and obtain cyclosaccharide efficiently and on a large scale. Summary of the invention

[0003] In view of the above defects or improvement needs of the prior art, the present invention provides an efficient and large-scale synthesis method of cyclosaccharide. The method uses methyl-D-rhamnoside as a raw material, synthesizes cyclosaccharide through four steps of photooxidation-reduction, condensation, methyl addition and reduction, and realizes the large-scale high-yield synthesis of cyclosaccharide at the hundred-gram level, thereby solving the technical problems of cumbersome steps, low yield and inability to synthesize on a large scale in the prior art synthesis method of cyclosaccharide.

[0004] According to the purpose of the present invention, a method for synthesizing cyclosaccharide is provided, comprising the following steps:

[0005] (1) mixing the methyl-D-rhamnoside of formula I with a carbazole benzonitrile photocatalyst, an oxidant, a base and a Lewis acid, and performing a photo-oxidation-reduction isomerization reaction under visible light irradiation to obtain a compound of formula II;

[0006] (2) the compound represented by formula II undergoes a condensation reaction with methyl-protected hydroxylamine or benzyl-protected hydroxylamine to obtain a compound represented by formula III;

[0007] (3) the compound represented by formula III undergoes an addition reaction with a methylating agent under the action of a Lewis acid to obtain a compound represented by formula IV;

[0008] (4) the compound represented by formula IV is subjected to a reduction reaction under the action of a reducing agent to obtain cyclosamine represented by formula V;

[0009] The chemical reaction formula of the synthesis method is:

[0010]

[0011] Wherein R is methyl or benzyl.

[0012] Preferably, the synthesis process is carried out in a continuous flow reactor or in a tank reactor.

[0013] Preferably, in step (1), the carbazolylbenzonitrile photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile or 4,5-di(9-carbazolyl)-ophthalonitrile.

[0014] Preferably, in step (1), the Lewis acid is tetrabutylammonium acetate, the oxidant is manganese acetate dihydrate, and the base is quinine.

[0015] Preferably, in step (3), the methylating agent is a methyl Grignard reagent or a methyllithium reagent.

[0016] Preferably, in step (3), the Lewis acid is cerium trichloride or boron trifluoride etherate.

[0017] Preferably, in step (3), the temperature of the addition reaction is -78°C to 0°C.

[0018] Preferably, in step (4), the reducing agent is borane.

[0019] Preferably, in step (4), the reduction reaction is carried out in a continuous flow hydrogenation reactor loaded with a transition metal catalyst column.

[0020] Preferably, the transition metal catalyst is a palladium-carbon catalyst or a Raney nickel catalyst, and the hydrogen pressure in the reactor is 10-40 bar.

[0021] In general, the above technical solution conceived by the present invention has the following technical advantages compared with the prior art:

[0022] (1) The present invention reports for the first time a rapid and large-scale synthesis method of cyclosporine on a scale of more than 100 grams. The method rapidly completes the synthesis of cyclosporine in four steps with a total yield of 33%, and the application of flow chemistry technology ensures the expansion of the reaction scale.

[0023] (2) In the present invention, preferably, when the hydroxylamine protecting group is methyl, the obtained product compound III-2 can be purified by recrystallization. The compound IV obtained after methylation of the general formula compound III can be used for the subsequent reduction and deprotection step after simple extraction. The final product compound V, cyclosamine, can also be purified by recrystallization. The whole process does not need to be purified by column chromatography.

[0024] (3) The present invention can efficiently and rapidly synthesize cyclosaccharide on a large scale using only four steps of reaction, three batch reactions or continuous flow chemical reactions.

[0025] (4) The present invention can use flow chemistry technology to assist in the scale-up reaction, has good reproducibility, is suitable for scale-up, and has the potential for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a schematic diagram of the preparation process of the present invention.

[0027] Figure 2 This is the photo-oxidation-reduction isomerization reaction step of the present invention.

[0028] Figure 3 This is the step of synthesizing compound III-1 of the present invention.

[0029] Figure 4 This is the methylation step of the present invention.

[0030] Figure 5 This is the deprotection step of the present invention.

[0031] Figure 6 This is the step of synthesizing imine in the present invention.

[0032] Figure 7 This is the step of synthesizing 100-gram-level imines according to the present invention.

[0033] Figure 8 This is the step of synthesizing 100-gram-level compound IV-2 of the present invention.

[0034] Fig. 9 This is the deprotection step of compound IV-2 of the present invention. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0036] Figure 1 The preparation process of the present invention is shown in FIG. 1 . The preparation method of cyclosamine of the present invention is carried out in a reaction kettle or in a continuous flow reactor, preferably in a continuous flow reactor, and comprises the following steps:

[0037] (1) transporting a mixed solution of methyl-D-rhamnoside (I) as shown in formula I and a photocatalyst, an oxidant, a base and an additive into a first continuous flow reactor, and performing a photoredox isomerization reaction under visible light irradiation to obtain a mixed reaction material comprising formula II and a methylhydroxylamine solution, mixing the mixed reaction material with the methylhydroxylamine solution in a first micro-mixer, and then transporting the mixed reaction material into a second continuous flow reactor for condensation reaction, and the product is recrystallized to obtain a compound as shown in formula III;

[0038] (2) conveying a solution of the compound represented by Formula III to a second micromixer, mixing it with a mixed solution of boron trifluoride etherate and tetramethylethylenediamine, conveying it to a third micromixer to mix it with a methyllithium solution at low temperature, and then inputting it into a third continuous flow reactor to undergo an addition reaction at low temperature, and extracting the product to obtain a compound represented by Formula IV;

[0039] (3) A solution of the compound shown in Formula IV is input into a third micromixer, mixed with a reducing agent solution, and then input into a fourth continuous flow microreactor for reaction, and the product is recrystallized to obtain cyclosamine shown in Formula V.

[0040] In some embodiments, the visible light comes from a 465nm LED lamp.

[0041] In some embodiments, in step (2), the low temperature is -78°C to 0°C, preferably -20°C.

[0042] In some embodiments, the reducing agent in step (3) is borane, the solvent of the solution is tetrahydrofuran, and the reaction temperature of the fourth continuous flow microreactor is 25°C to 80°C, preferably 60°C.

[0043] In some embodiments, the reducing agent in step (3) is hydrogen, the solvent of the solution is methanol, the fourth continuous flow microreactor is a continuous flow hydrogenation reactor loaded with a transition metal catalyst column, the transition metal catalyst is one of palladium / carbon and Raney nickel, preferably Raney nickel, the hydrogen pressure is 10-40 bar, preferably 40 bar, and the reaction temperature is 25°C to 60°C, preferably 60°C.

[0044] The following are specific embodiments

[0045] Example 1: Synthesis of Methyl-D-Rhamnoside (Compound I)

[0046]

[0047] According to the literature (Green Chem., 2019, 21, 1122-1127.), 401.6 g of compound SI was synthesized, and SI was dissolved in methanol (to a concentration of c = 0.5 M), and the resulting solution was pumped into a packing column filled with a basic resin (Ambersep 900OH) containing 10% mass fraction of SI compound at a flow rate of 3.2 ml / min. The solution obtained at the outlet was collected, and after removing methanol under reduced pressure, compound I (235.1 g, equivalent conversion) was obtained. 1 H NMR (400MHz, CDCl3) δ4.93 (s, 1H, H-1), 4.62 (s, 3H, OH), 3.69 (d, J = 8.4Hz, 1H, H-3), 3.56(dq,J=8.4Hz,1H,H-5),3.41(t,J=9.6Hz,1H,H-4),1.28(d,J=6.0Hz,1H,H-6). 13 C NMR (100MHz, CDCl3) δ101.12,72.87,71.74,71.00,68.26,55.01,17.69.

[0048] Example 2: Screening of catalysts for redox isomerization step (with the yield of compound II' as the evaluation standard)

[0049]

[0050] The following Table 1 is the screening data of this embodiment.

[0051] Entry catalyst II' Yield SI 1 4CzIPN 61％ - 2 2C 50％ - 3 Eosin Y - quant. 4 <![CDATA[CF3-4-CzIPN]]> 12％ 31％

[0052]

[0053] The specific operation is as follows: Compound (I), catalyst (0.04 equiv), tetrahydrated manganese acetate (Mn(OAc)2·4H2O, 0.2 equiv), tetrabutylammonium acetate (Bu4NOAc, 0.1 equiv), and quinine (0.1 equiv) are weighed in a reaction bottle, which is sealed and replaced with argon gas to dissolve the air in the reaction bottle. Anhydrous deoxygenated solvent acetonitrile / dimethyl sulfoxide (4:1, v / v) is added to dissolve (so that the concentration of compound I c = 0.2 M). The reaction vessel is placed 1 cm away from a 5W blue LED lamp (465 nm) and cooled with a fan. After stirring at room temperature for 18 hours, triethylamine (Et3N, 3.0 equiv), DMAP (0.1 equiv) and acetic anhydride (Ac2O, 3.0 equiv) are added to the reaction mixture in sequence and stirred at room temperature for 3 hours. After removing most of the solvent under reduced pressure, the mixture is extracted with ethyl acetate. The combined organic layer is washed with saturated sodium bicarbonate and brine and dried with sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel chromatography to give compound II' as a white solid. 1 H NMR (600MHz, CDCl3) δ5.08(d,J=4.2Hz,1H,H-1),4.91(d,J=9.6Hz,1H,H-4),4.10(dq,J=6.6,10.2Hz,1H,H-5),3.36(s,3 H,OMe),2.82(dd,J=4.2,14.4,Hz,1H,H-2a),2.64(d,J=14.4Hz,1H,H-2b),2.18(s,3H,OAc),1.36(d,J=6.6Hz,3H,H-6). 13 C NMR (150MHz, CDCl3) δ198.4,169.8,99.6,78.6,67.8,55.0,46.4,20.6,18.7.HRMS calc.for C9H 14 NaO5[M+Na] + :225.0733,found:225.0732.

[0054] Example 3: Synthesis of Imine Compound III-1 by Tank Reaction

[0055]

[0056] Compound (I) (500 mg, 2.81 mmol), 4CzIPN (88.6 mg, 0.11 mmol, 0.04 equiv), manganese acetate tetrahydrate (Mn(OAc)2·4H2O, 137.6 mg, 0.56 mmol, 0.2 equiv), tetrabutylammonium acetate (Bu4NOAc, 84.7 mg, 0.28 mmol, 0.1 equiv), and quinine (31.2 mg, 0.28 mmol, 0.1 equiv) were weighed into a reaction flask, which was sealed and the air in the reaction flask was replaced with argon. An anhydrous deoxygenated solvent acetonitrile / dimethyl sulfoxide (4:1, v / v, 14 mL) was added to dissolve the mixture (so that the concentration of compound I was c = 0.2 M). The reaction vessel was placed 1 cm away from a 5W blue LED lamp and cooled with a fan. After stirring at room temperature for 18 hours, triethylamine (Et3N, 0.39 mL, 2.81 mmol, 1.0 equiv) and a solution of BnONH2·HCl (493.0 mg, 3.09 mmol, 1.1 equiv) in 7 mL of methanol were added to the reaction mixture (so that the concentration of BnONH2·HCl in methanol was c = 0.4) and stirred at room temperature for 3 hours. After removing most of the solvent under reduced pressure, the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, brine and dried with sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography to give III-1 (322.5 mg, 43.3%). 1 H NMR(600MHz, CDCl3) δ7.34-7.26(m,5H,Ph),5.14(d,J=12.6Hz,1H,PhCH),5.11(d,J=12.6Hz,1H,PhCH),4.83(d,J=4.2Hz,1H,H-1), 3.68(dq,J=9.0,6.0Hz,1H,H-5), 3.40(d,J=14.4Hz,1H,H-2), 3.31(s,3H,OMe), 2.17(dd,J=4.2,14.4Hz,1H,H-2), 1.35(d,3H,H-6). 13 C NMR (150MHz, CDCl3) δ153.8,137.7,128.5,128.5,128.3,128.3,128.0,98.0,76.4,72.5,70.4,54.9,31.1,18.3.HRMS calc.for C 14 H 19 NO4Na[M+Na] + :288.1206,found:288.1209.

[0057] Example 4: Synthesis of Imine Compound III-2 by Tank Reaction

[0058] Referring to Example 3, BnONH2·HCl was replaced with MeONH2·HCl (258.0 mg, 3.09 mmol, 1.1 equiv). A colorless solid compound III-2 (228.6 mg, 43%) was obtained from compound (I) (500 mg, 2.81 mmol). 1 H NMR (600MHz, CDCl3) δ4.85 (d, J=4.8Hz, 1H, H-1), 3.90 (s, 3H, OMe), 3.79 (dd, J=9.6, 5.6Hz, 1H, H-4), 3.68 (dq, J=6.6, 9.6Hz, 1H, H-5), 3.47(d,J=5.6Hz,1H,OH),3.35(d,J=15.0Hz,1H,H-2),3.33(s,3H,OMe),2.16(dd,J=5.6,15.0Hz,1H,H-2),1.38(d,J=6.6Hz,3H,H-6). 13 C NMR (150MHz, CDCl3) δ153.0,97.9,72.3,70.4,62.2,54.8,30.7,18.3.HRMS calc.forC8H 15 NO4Na[M+Na] + :212.0893,found:212.0895.

[0059] Example 5: Tank reaction methylation

[0060]

[0061] Table 2 below shows the yield of the methylation step of the present invention.

[0062]

[0063]

[0064] The specific operations are as follows:

[0065] Methylation condition 1: Dried cerium trichloride (255.5 mg, 1.04 mmol, 5.5 equiv) was suspended in dry tetrahydrofuran (1.9 mL), and methyl lithium (3.1 M diethoxymethane solution, 0.30 mL, 0.94 mmol, 5.0 equiv) was slowly added dropwise to the suspension at -78 ° C. After stirring for 1 hour, a tetrahydrofuran solution (1.9 mL) of compound III (50 mg, 0.19 mmol, 1.0 equiv) was added dropwise. After stirring at -78 ° C for 2.5 h, the reaction mixture was quenched with saturated sodium bicarbonate. After filtration, the resulting organic solvent was removed under reduced pressure and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography to obtain compound IV-1.

[0066] Methylation condition 2: Compound III (50 mg, 0.19 mmol, 1.0 equiv) was dissolved in dry tetrahydrofuran (3.8 mL), and zinc chloride (1.0 M tetrahydrofuran solution, 1.04 mL, 1.04 mmol, 5.5 equiv) was slowly added dropwise at -78 °C, and methyl lithium (3.1 M diethoxymethane solution, 0.30 mL, 0.94 mmol, 5.0 equiv) was slowly added dropwise at the same temperature for 30 minutes. After stirring at -78 °C for 2.5 hours, the reaction mixture was quenched with saturated ammonium chloride solution. After filtering, the solvent in the obtained reaction mixture was removed by drying under reduced pressure, and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography to obtain compound IV-1.

[0067] Methylation condition 3: Compound III (50 mg, 0.19 mmol, 1.0 equiv) was dissolved in dry tetrahydrofuran (3.8 mL), and tetrabutyl titanate (0.35 mL, 1.04 mmol, 5.5 equiv) was slowly added dropwise at -78 ° C. After stirring for 30 minutes at the same temperature, methyl lithium (3.1 M diethoxymethane solution, 0.30 mL, 0.94 mmol, 5.0 equiv) was slowly added dropwise. After stirring at -78 ° C for 2.5 hours, the reaction mixture was quenched with saturated ammonium chloride solution. After filtering, the solvent in the obtained reaction mixture was dried under reduced pressure and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography to obtain compound IV-1.

[0068] Methylation condition 4: Compound III (50 mg, 0.19 mmol, 1.0 equiv) was dissolved in dry tetrahydrofuran (3.8 mL), and trifluoroboron ether (0.13 mL, 1.04 mmol, 5.5 equiv) was slowly added dropwise at -78 °C, and methyl lithium (3.1 M diethoxymethane solution, 0.30 mL, 0.94 mmol, 5.0 equiv) was slowly added dropwise at the same temperature for 30 minutes. After stirring at -78 °C for 2.5 hours, the reaction mixture was quenched with saturated ammonium chloride solution. After filtering, the solvent in the obtained reaction mixture was dried under reduced pressure and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography to obtain compound IV-1.

[0069] Methylation condition 5: Compound III (50 mg, 0.19 mmol, 1.0 equiv) was dissolved in dry tetrahydrofuran (3.8 mL), and tetramethylethylenediamine (0.20 mL, 1.32 mmol, 7.0 equiv) and boron trifluoride ether (0.13 mL, 1.04 mmol, 5.5 equiv) were slowly added dropwise at -78 °C, and methyl lithium (3.1 M diethoxymethane solution, 0.30 mL, 0.94 mmol, 5.0 equiv) was slowly added dropwise at the same temperature for 30 minutes. After stirring at -78 °C for 2.5 hours, the reaction mixture was quenched with saturated ammonium chloride solution. After filtering, the solvent in the obtained reaction mixture was dried under reduced pressure and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography to obtain compound IV-1.

[0070] Methylation condition 6: Compound III (50 mg, 0.19 mmol, 1.0 equiv) was dissolved in dry tetrahydrofuran (3.8 mL), and tetramethylethylenediamine (0.14 mL, 0.94 mmol, 5.0 equiv) and boron trifluoride ether (46.5 uL, 0.38 mmol, 2.0 equiv) were slowly added dropwise at -78 °C, and methyl lithium (3.1 M diethoxymethane solution, 0.18 mL, 0.57 mmol, 3.0 equiv) was slowly added dropwise at the same temperature for 30 minutes. After stirring at -78 °C for 2.5 hours, the reaction mixture was quenched with saturated ammonium chloride solution. After filtering, the solvent in the obtained reaction mixture was dried under reduced pressure and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography to obtain compound IV-1.

[0071] 1H NMR(600MHz, CDCl3) δ7.37-7.29(m,5H,Ph-H),4.70(d,J=11.4Hz,1H,PhCH),4.67(d,J=1 1.4Hz,1H,PhCH),4.63(d,J=4.2Hz,1H,H-1),3.62(dq,J=9.6,6.0Hz,1H,H-5),3.59(d,J =9.6Hz,1H,-OH),3.32(s,3H,-OMe),3.12(dd,J=9.6,9.6Hz,1H,H-4),2.00(d,J=14.4Hz ,1H,H-2),1.61(dd,J=14.4,4.2Hz,1H,H-2),1.36(s,3H,Me),1.29(d,J=6.0Hz,3H,H-6). 13 HRMS calc.for C 15 H 23 NO4Na[M+Na] + :304.1519,found:304.1513.

[0072] Example 6: Synthesis of Compound IV-2 under kettle conditions

[0073]

[0074] Referring to Example 5, compound III-2 (230 mg, 1.22 mmol) was used as a raw material and methylation conditions 1 of Example 5 were used to obtain compound IV-2 (201.7 mg, 81%). Compound III-2 (250 mg, 1.32 mmol) was used as a raw material and methylation conditions 2 of Example 5 were used to obtain compound IV-2 (229.3 mg, 85%). 1H NMR (400MHz, CDCl3) δ4.60(d,J=3.6Hz,1H,H-1),3.62(dq,J=6.0,10.0Hz,1H,H-5),3.57(d,J=8.8Hz,1H,OH),3.50(s,3H,OMe),3.32(s,3H,OMe ),3.10(dd,J=8.8,8.8Hz,1H,H-4),1.93(d,J=14.8Hz,1H,H-2),1.56(dd,J=3.6,14.8Hz,1H,H-2),1.30(s,3H,Me),1.27(d,J=6.0Hz,3H,H-6). 13 C NMR (100MHz, CDCl3) δ98.2,79.2,65.2,63.8,57.9,55.2,38.3,23.2,18.3.HRMS calc.forC9H 19 NO4Na[M+Na] + :228.1206,found:228.1203.

[0075] Example 7: Reduction of Compound IV under autoclave conditions (taking Compound IV-1 as an example)

[0076]

[0077] Table 3 below shows the data for the reduction step.

[0078] Entry Reagent conditions temperature Reaction time Yield 1 <![CDATA[0.1 equivalent of Pd / C, H2]]> 25℃ 12 hours 88％ 2 <![CDATA[5.0 equivalents of BH3·THF]]> 25℃ 4 hours 74％ 3 <![CDATA[5.0 equivalents of BH3·THF]]> 60℃ 4 hours 93％

[0079] Specific operations:

[0080] Reduction condition 1: Compound IV-1 (225.0 mg, 0.82 mmol, 1.0 equiv) was dissolved in 8.2 mL of methanol (to make the concentration c = 0.1 M), and 10% palladium carbon (18.9 mg, 0.08 mmol, 0.1 equiv) was added. The mixture was reacted at 25°C under a hydrogen atmosphere for 12 hours. After filtration, the residue was concentrated and purified by silica gel chromatography to obtain compound V (124.4 mg, 88%).

[0081] Reduction condition 2: Compound IV-1 (50.0 mg, 0.18 mmol, 1.0 equiv) was weighed into a sealed tube, 0.9 mL of tetrahydrofuran was added to dissolve, and then borane tetrahydrofuran complex (0.9 mL, 0.90 mmol, 5.0 equiv) was added (so that the concentration of compound IV after addition was c = 0.1 M), the tube was sealed, and the reaction was carried out at 25°C for 4 hours. Methanol was added to quench the reaction and then concentrated. The residue was purified by silica gel chromatography to obtain compound V (23.0 mg, 74%).

[0082] Reduction condition 2: Compound IV-1 (225.0 mg, 0.82 mmol, 1.0 equiv) was weighed into a sealed tube, 4.1 mL of tetrahydrofuran was added to dissolve, borane tetrahydrofuran complex (4.1 mL, 0.90 mmol, 5.0 equiv) (so that the concentration of compound IV after addition is c = 0.1 M), the tube was sealed, and the reaction was carried out at 60°C for 4 hours. Methanol was added to quench the reaction and then concentrated. The residue was purified by silica gel chromatography to obtain compound V (129.2 mg, 93%).

[0083] 1 H NMR (400MHz, CD3Cl) δ4.64(d,J=3.6Hz,1H,H-1),3.44(dq,J=6.4,9.6Hz,1H,H-5),3.26(s,3H,-OMe),2.82(d,J=10.0Hz,1H,H-4),2.32 (brs,3H,OH,NH2),1.84(d,J=14.4Hz,1H,H-2a),1.72(ddd,J=0.8,4.0,14.4Hz,1H,H-2b),1.23(d,J=6.0Hz,3H,H-6),1.07(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ100.12,77.23,66.70,56.34,51.46,44.11,29.69,19.54.HRMS calc.for C8H 18 NO3[M+H] + :176.1281,found:176.1283.

[0084] Example 8: Synthesis of Compound V from Compound IV-2 under autoclave conditions

[0085]

[0086] Referring to Example 7, compound V (38.8 mg, 91%) was synthesized by using compound IV-2 (50 mg, 0.24 mmol) as a raw material through reduction condition 3 of Example 7.

[0087] Example 9: Oxidation step under flow chemistry conditions (with the yield of compound II' as the evaluation standard)

[0088] Figure 2 This is the photo-oxidation-reduction isomerization reaction step of the present invention.

[0089] Table 4 below shows the yield of the oxidation step of the present invention.

[0090]

[0091] General procedure: Compound (I) (1 g, 5.62 mmol), 4CzIPN (177.2 mg, 0.22 mmol, 0.04 equiv), manganese acetate tetrahydrate (Mn(OAc)2·4H2O, 275.3 mg, 1.12 mmol, 0.2 equiv), tetrabutylammonium acetate (Bu4NOAc, 169.3 mg, 0.56 mmol, 0.1 equiv), and quinine (62.4 mg, 0.56 mmol, 0.1 equiv) were weighed into a three-necked flask, and deoxygenated solvent acetonitrile / dimethyl sulfoxide (v / v, 4:1) (19 mL) was added under argon protection. The mixture was pumped into a PFA coil reactor (1 / 8 inch inner diameter, 30 mL) by a peristaltic pump at a constant flow rate as shown in the table above, and irradiated under a blue LED (465 nm, 200 w). The reaction solution was collected. Triethylamine (Et3N, 1.34 ml, 16.85 mmol, 3.0 equiv), 4-(dimethylamino)pyridine (68.6 mg, 0.56 mmol, 0.1 equiv) and acetic anhydride (1.59 ml, 16.85 mmol, 3.0 equiv) were added to the reaction solution in sequence at room temperature and stirred at room temperature for 3 hours. After removing most of the solvent under reduced pressure, the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography to obtain a white solid compound II'.

[0092] Example 10: Synthesis of Compound III-1 under flow chemistry conditions

[0093] Figure 3 This is the step of synthesizing compound III-1 of the present invention.

[0094] Compound I (2 g, 11.24 mmol), 4CzIPN (354.4 mg, 0.45 mmol, 0.04 equiv), manganese acetate tetrahydrate (Mn(OAc)2·4H2O, 550.5 mg, 2.25 mmol, 0.2 equiv), tetrabutylammonium acetate (Bu4NOAc, 338.6 mg, 1.12 mmol, 0.1 equiv), and quinine (124.9 mg, 1.12 mmol, 0.1 equiv) were weighed into a three-necked flask, and under argon protection, a deoxygenated solvent acetonitrile / dimethyl sulfoxide (v / v, 4:1, 37.5 mL) was added. The above mixture was pumped into the first continuous flow reactor (PFA coil reactor, inner diameter 1 / 8 inch, 30 mL) at 0.1 mL / min by a peristaltic pump, and reacted under irradiation of a blue LED (465 nm, 200 W). After the reaction solution flows out, it is mixed with another methanol solution of BnONH2·HCl (1.97 g, 12.36 mmol, 1.1 equiv) and triethylamine (11.24 mmol, 1.56 mmol, 1.0 equiv) pumped at a flow rate of 0.1 mL / min (making the concentration of BnONH2·HCl c = 0.3 M) in the first mixer (Y-mixer), and continued to be pumped into the second continuous flow reactor (PFA coil reactor, B inner diameter 1 / 8 inch, 3 mL). The reaction mixture was collected, the solvent was removed under reduced pressure and diluted with ethyl acetate. The combined organic phase was washed with saturated sodium bicarbonate and brine and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography to obtain compound III-1 (1.33 g, 45% for two steps) as a colorless syrup.

[0095] Example 11: Methylation under flow chemistry conditions (using compound III-1 as raw material)

[0096] Figure 4 This is the methylation step of the present invention.

[0097] Methylation conditions under flow chemistry conditions:

[0098] Preparation of solution A: Compound III (400 mg, 1.51 mmol) was dissolved in 7.5 ml of anhydrous tetrahydrofuran (to make the concentration c = 0.2 M).

[0099] Solution B was prepared by dissolving anhydrous tetramethylethylenediamine (TMEDA, 1.13 mL, 7.54 mmol, 5.0 equiv) and boron trifluoride etherate solution (BF3·Et2O, 0.38 mL, 3.02 mmol, 2.0 equiv) in 6 mL of anhydrous tetrahydrofuran (so that the boron trifluoride etherate concentration c = 0.4 M).

[0100] Solution C: Dissolve methyllithium (3.1 M MeLi in diethoxymethane, 1.46 mL, 4.53 mmol, 3.0 equiv) in 13.6 mL of anhydrous tetrahydrofuran (to make concentration c = 0.3 M)

[0101] The third continuous flow reactor consists of two parts: pre-reactor A (PFA coil reactor, inner diameter 1 / 8 inch, 4.5 mL) and addition reactor B (PFA coil reactor, inner diameter 1 / 8 inch, 24 mL). Solutions A, B and half of solution C are pumped at the speeds shown in the table below, mixed after precooling at the temperature shown in the table below, and then the entire mixture passes through the pre-reactor A part, which is immersed in a cooling bath at the temperature shown in the table below. It is then mixed with the other half of the precooled solution C pumped at the speed shown in the table below, and passed through the addition reactor B part at the same temperature to obtain the residence time shown in the table below. The mixture is collected in a flask containing a quencher solution. After concentration, the mixture is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After evaporating the solvent, the resulting residue IV-1 can be directly used in the next reaction.

[0102] Table 5 below shows the data of different methylation conditions of the present invention.

[0103]

[0104] When the precooling temperature and reaction temperature are -20°C, the retention time is 15 minutes, the reaction solution is quenched by pumping in methanol, and then neutralized with ammonium chloride solution in a collection bottle, a better yield can be obtained. In subsequent examples, if there is no special explanation, this condition is selected for the reaction.

[0105] Example 12: Screening of deprotection step conditions under flow chemistry conditions (using compound IV-1 as raw material)

[0106] Figure 5 This is the deprotection step of the present invention.

[0107] Deprotection conditions under flow chemistry conditions:

[0108] Preparation of solution A: Compound IV (500 mg, 1.78 mmol) was dissolved in 6 ml of anhydrous tetrahydrofuran (to make the concentration c = 0.3 M).

[0109] Solution B was prepared by diluting 8.9 ml of borane tetrahydrofuran solution with 3.1 ml of anhydrous tetrahydrofuran (to a borane concentration of c = 0.75 M, 8.90 mmol, 5 equiv).

[0110] The fourth continuous flow reactor consists of two parts: reactor A (PFA capillary inner diameter 1 / 8 inch, 4.5 mL), and reactor B (PFA capillary inner diameter 1 / 8 inch, 4.5 mL). Solution A and half of solution B are mixed by injection pumps at the speeds shown in the table below and pumped into the reduction reactor A part (the reactor is at the temperature shown in the table below). The other half of solution B is mixed with the above solution by injection pumps at the speed shown in the table below and pumped to the reactor B part (the reactor is at the temperature shown in the table below) to obtain the total residence time shown in the table below. The mixture is collected in a flask and quenched with methanol, the solvent is evaporated, and the residue is purified by silica gel chromatography to obtain compound V.

[0111] Table 6 below shows the data of different deprotection conditions of the present invention.

[0112] Entry Speed ​​(X) Dwell time Temp. Back pressure valve yield recovery 1 16uL / min 4h rt 5bar 63％ 9％ 2 5ul / min 12h rt 5bar 63％ 7％ 3 16uL / min 4h 60℃ 5bar 78％ 18％ 4 16uL / min 4h 60℃ 20bar 85％ 11％ 5 63uL / min 1h 60℃ 20bar 92％ ND 6 0.25mL / min 15min 60℃ 20bar 92％ ND

[0113] Among them, the best reaction effect and highest efficiency were achieved when the reaction temperature was 60°C, the back pressure valve was 20 bar, and the retention time was 15 minutes. In the subsequent examples, these conditions were selected for deprotection unless otherwise specified.

[0114] Example 13: Synthesis of Imine III-2 under Flow Chemistry Conditions

[0115] Figure 6 This is the step of synthesizing imine in the present invention.

[0116] Compound (I) (119.3 g, 669.92 mmol), 4CzIPN (21.14 g, 26.80 mmol, 0.04 equiv), manganese acetate tetrahydrate (Mn(OAc)2·4H2O, 32.84 g, 133.98 mmol, 0.2 equiv), tetrabutylammonium acetate (Bu4NOAc, 20.20 g, 66.99 mmol, 0.1 equiv), and quinuclidine (7.45 g, 66.99 mmol, 0.1 equiv) were weighed into a three-necked flask, and then 2233 ml of a deoxygenated solvent acetonitrile / dimethyl sulfoxide (v / v, 4:1) was added to dissolve (to make the concentration c = 0.3 M). The flask was kept airtight and the mixture was pumped into the first continuous flow reactor (PFA coil reactor inner diameter 1 / 8 inch, 50 ml) and irradiated under a blue LED (465 nm, 200 W) by a peristaltic pump at a flow rate of 0.14 ml / min, with a retention time of 6 hours. Then, the solution was mixed with another solution of MeONH2·HCl (61.55 g, 736.91 mmol, 1.1 equiv) and triethylamine (93.12 mL, 669.92 mmol, 1.0 equiv) in 1117 ml of methanol (so that the concentration of MeONH2·HCl was c=0.7 M) pumped at a flow rate of 0.07 ml / min through a Y-mixer and continued to be pumped into the second continuous flow reactor (PFA coil reactor inner diameter 1 / 8 inch, 3.2 ml) to obtain a retention time of 15 minutes. The reaction mixture was collected, the solvent was removed under reduced pressure, and water was added. After stirring at room temperature for 30 minutes, it was filtered and the resulting filter residue was washed with water. The obtained aqueous phases were combined and the product was extracted with petroleum ether. After the petroleum ether was removed under reduced pressure, the crude product was crystallized from petroleum ether-ethyl acetate at -20°C to obtain colorless solid III-2 (52.9 g, 42% for two steps).

[0117] Example 14: Synthesis of 100-gram-scale imine III-2 under flow chemistry conditions

[0118] Figure 7 This is the step of synthesizing 100-gram-level imines according to the present invention.

[0119] Compound (I) (235.0 g, 1319.63 mmol), 4CzIPN (41.64 g, 52.79 mmol, 0.04 equiv), manganese acetate tetrahydrate (Mn(OAc)2·4H2O, 64.69 g, 263.93 mmol, 0.2 equiv), tetrabutylammonium acetate (Bu4NOAc, 39.79 g, 131.96 mmol, 0.1 equiv), and quinuclidine (14.67 g, 131.96 mmol, 0.1 equiv) were weighed into a three-necked flask, and then 4.4 liters of deoxygenated solvent acetonitrile / dimethyl sulfoxide (v / v, 4:1) were added to dissolve (to make the concentration c = 0.3 M). The flask was kept airtight and the mixture was pumped into the first continuous flow reactor (PFA coil reactor inner diameter 1 / 8 inch, 200 ml) and irradiated under a blue LED (465 nm, 800 W) by a peristaltic pump at a flow rate of 0.56 ml / min, with a retention time of 6 hours. Then, the solution was mixed with another solution of MeONH2·HCl (121.24 g, 1451.59 mmol, 1.1 equiv) and triethylamine (183.4 mL, 1319.63 mmol, 1.0 equiv) in 2.2 liters of methanol (so that the concentration of MeONH2·HCl was c=0.7 M) pumped at a flow rate of 0.28 ml / min through a Y-mixer and continued to be pumped into the second continuous flow reactor (PFA coil reactor inner diameter 1 / 8 inch, 12.5 ml) to obtain a retention time of 15 minutes. The reaction mixture was collected, the solvent was removed under reduced pressure, and water was added. After stirring at room temperature for 30 minutes, it was filtered and the resulting filter residue was washed with water. The obtained aqueous phases were combined and the product was extracted with petroleum ether. After the petroleum ether was removed under reduced pressure, the crude product was crystallized from petroleum ether-ethyl acetate at -20°C to obtain a colorless solid III-2 (105.39 g, 42% for two steps).

[0120] Example 15: Synthesis of 100-gram-scale compound IV-2 from compound III-2 under flow chemistry conditions

[0121] Figure 8 This is the step of synthesizing 100-gram-level compound IV-2 of the present invention.

[0122] Referring to Example 11, the compound III-2 (158.32 g, 836.7 mmol) obtained in Examples 13 and 14 was used as a raw material for methylation to obtain a colorless oily liquid compound IV-2 (136.43 g, 81%). The crude product obtained after extraction can be directly used for subsequent deprotection without column chromatography.

[0123] Example 16: Deprotection of Compound IV-2 under flow chemistry conditions

[0124] Fig. 9 This is the deprotection step of compound IV-2 of the present invention.

[0125] Referring to Example 12, compound IV-2 (300 mg, 1.48 mmol) was used as a raw material for reduction to obtain a white solid compound V (241.2 mg, 93%).

[0126] Example 17: Condition screening of reduction of compound IV-2 using a reduction hydrogenation apparatus

[0127]

[0128] Specific operation: Weigh compound IV-2 and dissolve it in methanol to obtain a solution with the concentration shown in the table below, and pump it into a continuous flow hydrogenation reactor (ThalesNano, Pro), after the catalyst column is reacted at the temperature shown in the table below and a hydrogen pressure of 40 bar, the solution is collected at the outlet, dried under reduced pressure to remove methanol, and then recrystallized with dichloromethane-petroleum ether to obtain compound V.

[0129] Table 7 below shows the data of the screening of reduction conditions for compound IV-2 according to the present invention.

[0130]

[0131] a THS-01111(30X4 mm). b THS-01112(30X4 mm). c THS-01132(70X4 mm).

[0132] Among them, the best reaction efficiency can be obtained by pumping compound IV-2 with a concentration of 0.2M into a 70X4 mm catalyst column at 60°C at a flow rate of 1.8 mL / min and reacting with hydrogen at a pressure of 40 bar.

[0133] Example 18: Preparation of 100-gram-scale Cyclosamine using a reduction hydrogenation apparatus

[0134]

[0135] Referring to Example 17, compound IV-2 (136.43 g, 664.7 mmol) was used as a raw material for deprotection to synthesize the final product cyclosaccharide V (116.28 g, equivalent conversion). So far, the present invention has completed the synthesis of 100-gram-level compound V (116.3 g, 0.66 mol) using compound I (348.3 g, 1.99 mol) as a raw material, with a total yield of 33%.

[0136] It will be easily understood by those skilled in the art that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing cyclosaccharide, characterized in that: The following steps are involved: (1) mixing the methyl-D-rhamnoside of formula I with a carbazole benzonitrile photocatalyst, an oxidant, a base and a Lewis acid, and performing a photo-oxidation-reduction isomerization reaction under visible light irradiation to obtain a compound of formula II; (2) the compound represented by formula II undergoes a condensation reaction with methyl or benzyl protected hydroxylamine to obtain a compound represented by formula III; (3) the compound represented by formula III undergoes an addition reaction with a methylating agent under the action of a Lewis acid to obtain a compound represented by formula IV; (4) the compound represented by formula IV is subjected to a reduction reaction under the action of a reducing agent to obtain cyclosamine represented by formula V; The chemical reaction formula of the synthesis method is: Wherein R is methyl or benzyl.

2. The method for synthesizing cyclosaccharide according to claim 1, characterized in that: The synthesis process is carried out in a continuous flow reactor or in a tank reactor.

3. The method for synthesizing cyclosaccharide according to claim 1, characterized in that: In step (1), the carbazolylbenzonitrile photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile or 4,5-di(9-carbazolyl)-ophthalonitrile.

4. The method for synthesizing cyclosaccharide according to claim 1, characterized in that: In step (1), the Lewis acid is tetrabutylammonium acetate, the oxidant is manganese acetate dihydrate, and the base is quinine.

5. The method for synthesizing cyclosaccharide according to claim 1, characterized in that: In step (3), the methylating reagent is a methyl Grignard reagent or a methyllithium reagent.

6. The method for synthesizing cyclosaccharide according to claim 1, characterized in that: In step (3), the Lewis acid is cerium trichloride or boron trifluoride etherate.

7. The method for preparing cyclosaccharide according to claim 1, characterized in that: In step (3), the temperature of the addition reaction is -78°C to 0°C.

8. The method for preparing cyclosaccharide according to claim 1, characterized in that: In step (4), the reducing agent is borane.

9. The method for preparing cyclosaccharide according to claim 1, characterized in that: In step (4), the reduction reaction is carried out in a continuous flow hydrogenation reactor loaded with a transition metal catalyst column.

10. The method for preparing cyclosaccharide according to claim 9, characterized in that: The transition metal catalyst is a palladium carbon catalyst or a Raney nickel catalyst, and the hydrogen pressure in the reactor is 10-40 bar.

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