Method for synthesizing glycosyl sulfenamide by constructing S-N bond through electrochemical oxidation of glycosyl thiol and amine compound

Abstract

The invention discloses a method for synthesizing glycosyl sulfenamide by constructing an S-N bond through electrochemical oxidation of glycosyl thiol and an amine compound, and belongs to the technical field of synthesis of drug intermediates. The method comprises the following steps: taking an organic solution containing glycosyl thiol, an amine compound and an electrolyte salt as an electrolyte, placing an anode and a cathode in the electrolyte, introducing direct current, and carrying out electrochemical reaction to obtain the glycosyl sulfenamide compound. The method has the advantages of strong reaction universality, high target product yield, realization through one-step chemical reaction, mild reaction conditions and no need of any transition metal catalyst.

Description

Technical Field

[0001] The invention relates to a method for constructing an SN bond, in particular to a method for synthesizing glycosyl sulfenamide by constructing an SN bond through electrochemical oxidation of glycosyl thiol and amine compounds, and belongs to the technical field of drug intermediate synthesis. Background Art

[0002] Thioglycosides are a class of glycoside compounds that connect sugar groups to aglycones through sulfur atoms, and they have a variety of important biological activities and physiological functions in vivo. This type of compound has important biological activities in vivo, including antioxidant, anti-inflammatory, antibacterial, antiviral and other effects. Therefore, thioglycosides have broad application prospects in the fields of health care and medicine, and the synthesis and biological activity research of this type of compound has become one of the research hotspots in the fields of biochemistry and medicinal chemistry. Compared with oxygen glycosides that are easily hydrolyzed, thioglycosides have stronger acid-base and enzymatic hydrolysis tolerance. It has good glycosidase inhibitory activity. And because of its weak bond energy of CS bond, this feature makes it can be used as both a donor and an acceptor, and is widely used in the synthesis of N-glycosides, C-glycosides, oligosaccharides and polysaccharides. In addition, thioglycosides are widely present in drugs, natural products and bioactive substances. For example, Auranofin is widely used in the treatment of arthritis and also exhibits anticancer activity. hSGLT1 inhibitors can effectively inhibit the absorption of glucose and galactose by the human body and are commonly used diabetes drugs in clinical practice. Calichemicin gamma and Hsp 90 have good antitumor activity. Afrostyraxthioside A is clinically used for its efficacy against nematode parasites. MUS-CB is a fluorescent non-hydrolyzable analog of cellulase, etc. Among the various thioglycosides developed so far, glycosylsulfenamides are particularly eye-catching. This class of stable thioglycoside compounds is widely used in industry and medicinal chemistry. However, so far, there are only a few reports on the preparation of S-glycosylsulfonamides. Itzstein and his colleagues reported a method for preparing thioglycosylsulfenamides from glycosylthiols and secondary amines catalyzed by alkyl halides (Owen, DJ; von Itzstein, M., A one-pot synthesis of novel N,N-dialkyl-S-glycosylsulfenamides. Carbohydrate Research 2000, 328, 287-292.). Szilagyi and colleagues reported a silver-catalyzed reaction of disulfide compounds with amine compounds to synthesize glycosyl sulfenamides (Illyés, T.-Z.; Molnár-Gábor, D.; Szilagyi, L., Novel approaches to the syntheses of N-substituted S-glycosyl-sulfenamides. Carbohydrate Research 2004, 339, 1561-1564.).Misra and colleagues reported the NBS-catalyzed reaction of glycosyl thiols and amine compounds to synthesize sulfenamides, but this method needs to be carried out at a low temperature of -40°C (Gucchait, A.; Jana, K.; Misra, AK, Convenient preparation of thioglycomimetics: S-glycosylsulfenamides, sulfinamides and sulphonamides. RSC Advances 2017, 7, 32478-32487.). Gang He and colleagues reported a copper-catalyzed method for synthesizing sulfenamides from glycosyl thiols and 3-methyldioxazolone (Bai, Z.; Zhu, S.; Hu, Y.; Yang, P.; Chu, X.; He, G.; Wang, H.; Chen, G., Synthesis of N-acyl sulfenamides via copper catalysis and their useas S-sulfenylating reagents of thiols. Nature Communications 2022, 13.). However, the above methods still require the use of metal catalysts and oxidants. Therefore, it is of great significance to develop a green and environmentally friendly method to synthesize this type of compound.

[0003] Summary of the invention

[0004] In order to solve the technical problems existing in the prior art, the purpose of the present invention is to provide a method for synthesizing glycosyl sulfonamide by efficiently constructing SN bonds between glycosyl thiols and amine compounds through electrochemical oxidation. The method is completed by a one-step electrochemical reaction, has a high yield of the target product, is simple to operate, has mild conditions, has strong substrate universality, does not require the addition of any metal catalysts, oxidants, reducing agents and other environmentally unfavorable chemical reagents, and is conducive to the efficient synthesis of glycosyl sulfonamide.

[0005] In order to achieve the above technical objectives, the present invention provides a method for electrochemically oxidizing glycosyl thiol and amine compounds to construct SN bonds to synthesize glycosyl sulfenamides.

[0006] An organic solution of a substance and an electrolyte salt is used as an electrolyte, an anode and a cathode are placed in the electrolyte, a direct current is passed, and an electrochemical reaction is carried out to obtain a glycosyl sulfenamide compound.

[0007] As a preferred embodiment, the glycosyl thiol has a structure of Formula 1:

[0008] R-SH

[0009] Formula 1

[0010] Wherein, R is a five-membered sugar ring, a six-membered sugar ring or a polybasic sugar ring. The polybasic sugar ring is composed of two or more five-membered sugar rings or six-membered sugar rings bonded together, and the preferred polybasic sugar ring is a two-membered sugar ring. The six-membered sugar ring is, for example, glucose.

[0011] As a preferred embodiment, the amine compound has a structure of Formula 2:

[0012]

[0013] Among them, R 1 and R 2 are independently selected from hydrogen, primary carbon, secondary carbon or quaternary carbon, and R 1 and R 2 Not hydrogen at the same time.

[0014] As a preferred embodiment, the glycosyl sulfenamide compound has a structure of Formula 3:

[0015]

[0016] in,

[0017] R is a five-membered sugar ring, a six-membered sugar ring or a polyvalent sugar ring;

[0018] R 1 and R 2 are independently selected from hydrogen, primary carbon, secondary carbon or quaternary carbon, and R 1 and R 2 Not hydrogen at the same time.

[0019] In the amine compounds and glycosyl sulfenamide compounds of the present invention, R 1 and R 2 It can be selected from hydrogen, primary carbon, secondary carbon or quaternary carbon, and the sources of primary carbon, secondary carbon or quaternary carbon are relatively wide, and can be derived from aliphatic hydrocarbon groups and their derivatives, aromatic groups and their derivatives, etc. Aliphatic hydrocarbon groups such as C1~C 10 Alkyl groups. Aliphatic hydrocarbon derivatives such as C1 to C 10 The alkyl group of the present invention is further substituted with some conventional small molecule substituents, such as halogen substituents, hydroxyl groups, phenyl groups, etc. Aromatic groups include phenyl groups, naphthyl groups, etc. Aromatic derivatives include further substituted conventional small molecule substituents on the benzene ring, such as short-chain alkyl groups, alkoxy groups, halogen substituents, etc. 1 and R 2 It can be a closed ring structure, such as a five-membered or six-membered ring structure, and the closed ring structure can be doped with heteroatoms, such as oxygen, sulfur, etc. The closed ring structure can be further substituted with small molecule substituents, such as phenyl, hydroxyl, etc. 1 and R2 It is a group introduced by an amine compound. Common primary amines or secondary amines in the prior art are all suitable for the synthesis of glycosyl sulfenamide compounds.

[0020] The glycosyl sulfenamide compound of the present invention has the following structure:

[0021]

[0022]

[0023] The glycosyl sulfenamide compound of the present invention mainly utilizes sugars to carry out thioglycosidation on existing drugs (such as reboxetine), thereby introducing thioglycoside fragments on the amine group.

[0024] As a preferred embodiment, the molar ratio of the glycosyl thiol to the amine compound is 1:1.5 to 2.5. The molar ratio of the glycosyl thiol to the amine compound is more preferably 1.0:2.0.

[0025] As a preferred embodiment, the molar ratio of the glycosyl thiol to the electrolyte salt is 1.0:0.5-1.5.

[0026] As a preferred solution, the electrolyte salt includes sodium iodide and / or potassium iodide. The most preferred electrolyte salt is sodium iodide. The electrolyte salt sodium iodide has a significant promoting effect on the reaction. For example, if other electrolyte salts are used instead, the yield of the glycosyl sulfenamide compound will be significantly reduced.

[0027] As a preferred solution, the electrolyte uses acetonitrile and water as a mixed solvent. The electrolyte is further preferably acetonitrile / water (combined in a volume ratio of 80-90% / 10-20%). The use of a combined solvent of acetonitrile and water can improve the solubility of the reaction raw materials and the electrolyte, and can also improve the conductivity, thereby increasing the reaction yield of the glycosyl sulfenamide compound.

[0028] As a preferred solution, the anode is a carbon rod anode or a platinum sheet anode; the cathode is a platinum sheet cathode, a carbon rod cathode or a nickel sheet cathode. Experiments show that the most preferred electrode combination is: the anode is a carbon rod anode and the cathode is a platinum sheet cathode, which can significantly improve the yield of the glycosyl sulfenamide compound compared to other electrode combinations.

[0029] As a preferred solution, the conditions of the electrochemical reaction are: under air conditions, the current of the direct current is 5-15 mA, the temperature is 20-30° C., and the time is 40-50 min. A further preferred direct current current is 10-15 mA. Within the selected direct current current range, as the direct current increases, the yield of the glycosyl sulfenamide compound can be significantly improved, and the direct current is 10-15 mA and by optimizing other reaction conditions, the yield of the glycosyl sulfenamide compound can be ensured to reach more than 85%.

[0030] The present invention provides a method for synthesizing glycosyl sulfenamide by constructing SN bond with amine compounds through electrochemical oxidation. The reaction between glycosyl thiol and morpholine is used as an example for illustration: the reaction mechanism is as follows: glycosyl thiol undergoes an oxidation reaction at the anode to lose an electron and be converted into a carbon-based thiol free radical. Meanwhile, morpholine also undergoes an oxidation reaction at the anode to be converted into a nitrogen free radical. Then, the carbon-based thiol free radical and the nitrogen free radical undergo cross-coupling to form a sulfenamide compound 3a. Meanwhile, hydrogen protons undergo a reduction reaction at the cathode to be converted into hydrogen.

[0031]

[0032] The method for synthesizing glucosinolates of the present invention comprises the following specific steps:

[0033] 1) At room temperature, glycosyl thiol (0.2 mmol, 1.0 equiv), amine compound (0.4 mmol, 2 equiv), NaI (0.2 mmol, 1 equiv), and CH3CN / H2O (2.6 mL / 0.4 mL) were added into an integrated electrolytic cell, a carbon rod electrode was used as the anode of the electrochemical system, a platinum sheet electrode was used as the cathode of the electrochemical system, and 15 mA direct current was applied.

[0034] 2) At the same time, the glycosyl thiol was dissolved in 1 mL CH3CN, and added dropwise into the electrochemical reaction system within 30 minutes. After the addition was completed, the reaction was continued for another 10 minutes. After the reaction was completed, the crude product was concentrated under reduced pressure and the target product was obtained by column chromatography separation.

[0035] Compared with the prior art, the technical solution of the present invention has the following beneficial technical effects:

[0036] 1) The reaction conditions are mild and no heating is required.

[0037] 2) Avoid the use of environmentally unfriendly chemical reagents such as transition metal catalysts, oxidants, and reducing agents.

[0038] 3) The substrates are highly universal, and both electron-withdrawing and electron-donating protecting groups are well compatible with the reaction. At the same time, primary amines, secondary amines, cyclic amines, and chain amines can also obtain medium or higher yields. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 For compound 1 1 H NMR.

[0040] Figure 2 For compound 1 13 C NMR.

[0041] Figure 3 For compound 2 1 H NMR.

[0042] Figure 4 For compound 2 13 C NMR.

[0043] Figure 5 For compound 3 1 H NMR.

[0044] Figure 6 For compound 3 13 C NMR.

[0045] Figure 7 For compound 4 1 H NMR.

[0046] Figure 8 For compound 4 13 C NMR.

[0047] Fig. 9 For compound 5 1 H NMR.

[0048] Fig.10 For compound 5 13 C NMR.

[0049] Fig.11 Thioglycosylated reboxetine 1 H NMR.

[0050] Fig.12 Thioglycosylated reboxetine 13 C NMR. DETAILED DESCRIPTION

[0051] The following specific examples are intended to further illustrate the present invention rather than to limit the scope of protection of the claims.

[0052] The present invention is specifically described by taking the reaction of synthesizing glycosyl sulfenamide compounds by electrochemical reaction of glycosyl thiol and morpholine as an example, and taking the screened optimal reaction conditions as standard reaction conditions. The specific reaction formula is as follows:

[0053]

[0054] At room temperature, 1a (0.2 mmol, 1.0 equiv), 3a (0.4 mmol, 2 equiv), NaI (0.2 mmol, 1 equiv), and CH3CN / H2O (2.6 mL / 0.4 mL) were added to an integrated electrolytic cell. A carbon rod electrode was used as the anode of the electrochemical system, and a platinum electrode was used as the cathode of the electrochemical system. A 15 mA direct current was applied. At the same time, the glycosyl thiol 1a was dissolved in 1 mL of CH3CN and added dropwise into the electrochemical reaction system within 30 min. After the addition was completed, the reaction was continued for 10 min. After the reaction was completed, the crude product was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography to obtain the target product.

[0055] The following control experimental groups 1 to 12 are based on standard reaction conditions for comparison and explanation:

[0056]

[0057] Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 3a (0.4 mmol, 2.0 equiv), NaI (0.2 mmol, 1.0 equiv), solvent (4 mL), 40 min.

[0058] Experimental groups 1 to 4 in the above table investigated the effects of different solvents on the dehydrogenation and oxidation coupling reaction. The experiments showed that the solvent had a certain influence on the reaction. In polar organic solvents such as DMAc and CH3CN, the reaction could proceed smoothly, while in non-polar organic solvents such as DCM, the reaction effect was relatively poor. The introduction of a small amount of water into the polar organic solvent could improve the reaction effect. The best reaction solvent was a mixed solvent of CH3CN and water.

[0059] Experimental groups 1 and 5-6 in the above table investigated the effects of different electrodes on the dehydrogenation and oxidation coupling reaction. The experiments showed that the electrode pair had a certain influence on the reaction. Any combination of platinum sheet electrode, carbon rod electrode, nickel sheet electrode, etc. into an electrode pair could make the reaction proceed smoothly. The best reaction electrode pair was the carbon rod as the anode and the platinum sheet electrode as the cathode.

[0060] In the above table, experimental groups 1 and 7-8 investigated the effects of different current sizes on the dehydrogenation and oxidation coupling reaction. The experiments showed that the current size had a certain influence on the reaction. The yield of the target product was significantly improved with the increase of the current. The preferred reaction current was 10-15 mA, and the best reaction current was 15 mA.

[0061] In the above table, experimental groups 1 and 9-10 investigated the effects of different electrolytes on the dehydrogenation and oxidation coupling reaction. The experiments showed that the electrolyte salt had a certain influence on the reaction. The electrolyte salt was preferably an iodine salt, and the best electrolyte salt was NaI.

[0062] In the above table, experimental groups 1 and 11 investigated the effect of direct current on the dehydrogenation and oxidation coupling reaction. If direct current is not applied, the reaction cannot proceed smoothly.

[0063] Experimental groups 1 and 12 in the above table investigated the effect of nitrogen atmosphere on the dehydrogenation and oxidation coupling reaction. The experiments showed that nitrogen had a huge impact on the reaction and the best reaction condition was an air atmosphere.

[0064] The following examples examine the reaction effects of different substrates under optimal reaction conditions.

[0065] Example 1

[0066]

[0067] At room temperature, 3a (0.4mmol, 2equiv), NaI (0.2mmol, 1equiv), CH3CN / H2O (2.6mL / 0.4mL) were added to an integrated electrolytic cell, a carbon rod electrode was used as the anode of the electrochemical system, a platinum sheet electrode was used as the cathode of the electrochemical system, and a 15mA direct current was applied. At the same time, 1a was dissolved in 1mL CH3CN and added dropwise into the electrochemical reaction system within 30min. After the addition was completed, the reaction was continued for another 10min. After the reaction was completed, the crude product was concentrated under reduced pressure. The target product 1 (4a, 84.4mg) was obtained by column chromatography separation with a yield of 94%.

[0068]

[0069] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(morpholinothio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0070] Yield: 94%

[0071] The characterization data of the compound are as follows: 1H NMR (400MHz, DMSO-d6) δ5.34(t,J=9.4Hz,1H),5.24(d,J=10.2Hz,1H),4.95-4.82(m,2H),4.19-3.96(m, 3H), 3.56 (t, J = 4.5Hz, 4H), 3.04-2.93 (m, 2H), 2.90-2.84 (m, 2H), 2.00 (s, 3H), 2.00 (s, 6H), 1.94 (s, 3H). 13 C NMR (101MHz, DMSO-d6) δ169.93,169.54,169.31,169.08,82.78,73.97,73.16,68.16,67.49,66.87,62.03,56.67,20.46,20.44,20.38,20.29.

[0072] Example 2

[0073] At room temperature, 3a (0.4mmol, 2equiv), NaI (0.2mmol, 1equiv), CH3CN / H2O (2.6mL / 0.4mL) were added to an integrated electrolytic cell, a carbon rod electrode was used as the anode of the electrochemical system, a platinum sheet electrode was used as the cathode of the electrochemical system, and a 15mA direct current was applied. At the same time, 1b was dissolved in 1mL CH3CN and added dropwise into the electrochemical reaction system within 30min. After the addition was completed, the reaction was continued for 10min. After the reaction was completed, the crude product was concentrated under reduced pressure. The target product 2 (84.4mg) was obtained by column chromatography separation with a yield of 94%.

[0074]

[0075] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(thiomorpholinothio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0076] Yield: 94%

[0077] The characterization data of the compound are as follows: 1H NMR (400MHz, DMSO-d6) δ5.30(d,J=3.4Hz,1H),5.26(d,J=4.3Hz,1H),5.23(d,J=3.9Hz,1H),4.96(t,J=8.0Hz,1H),4.30(t,J= 6.3Hz,1H),4.09-3.95(m,2H),3.56(t,J=4.5Hz,4H),3.04-2.84(m,4H),2.12(s,3H),2.02(s,3H),1.99(s,3H),1.92(s,3H). 13 C NMR (101MHz, DMSO-d6) δ169.98,169.87,169.53,169.36,82.99,73.09,71.18,67.61,66.97,64.92,61.72,56.55,20.59,20.50,20.44,20.40.

[0078] Example 3

[0079] At room temperature, 3a (0.4mmol, 2equiv), NaI (0.2mmol, 1equiv), CH3CN / H2O (2.6mL / 0.4mL) were added to an integrated electrolytic cell, a carbon rod electrode was used as the anode of the electrochemical system, a platinum sheet electrode was used as the cathode of the electrochemical system, and a 15mA direct current was applied. At the same time, 1c was dissolved in 1mL CH3CN and added dropwise into the electrochemical reaction system within 30min. After the addition was completed, the reaction was continued for 10min. After the reaction was completed, the crude product was concentrated under reduced pressure. The target product 3 (45.8mg) was obtained by column chromatography separation with a yield of 61%.

[0080]

[0081] (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-(morpholinothio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0082] Yield: 61%

[0083] The characterization data of the compound are as follows: 1H NMR(400MHz,DMSO-d6)δ5.85(d,J=1.2Hz,1H),5.21(dd,J=3.4,1.5Hz,1H),5.11(t, J=10.0Hz,1H),4.79(dd,J=10.0,3.5Hz,1H),4.38(ddd,J=10.0,5.8,2.5Hz,1H),4.1 9(dd,J=12.2,5.9Hz,1H),4.06(dd,J=12.3,2.5Hz,1H),3.56(t,J=4.6Hz,4H),3.02 (dtd,J=16.4,11.6,4.4Hz,4H),2.12(s,3H),2.04(s,3H),2.00(s,3H),1.94(s,3H). 13 C NMR (101MHz, DMSO-d6) δ170.02,169.69,169.67,169.54,81.92,69.35,69.32,68.52,66.93,65.69,62.09,56.07,20.68,20.46,20.45,20.37.

[0084] Example 4

[0085] At room temperature, 3b (0.4mmol, 2equiv), NaI (0.2mmol, 1equiv), CH3CN / H2O (2.6mL / 0.4mL) were added to an integrated electrolytic cell, a carbon rod electrode was used as the anode of the electrochemical system, a platinum sheet electrode was used as the cathode of the electrochemical system, and a 15mA direct current was applied. At the same time, 1a was dissolved in 1mL CH3CN and added dropwise into the electrochemical reaction system within 30min. After the addition was completed, the reaction was continued for 10min. After the reaction was completed, the crude product was concentrated under reduced pressure. The target product 4 (85.5mg,) was obtained by column chromatography separation with a yield of 92%.

[0086]

[0087] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(thiomorpholinothio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0088] Yield: 92%

[0089] The characterization data of the compound are as follows: 1H NMR(400MHz,CD3OD)δ5.31(t,J=9.3Hz,1H),5.10-5.03(m,1H),4.87(d,J=10 .1Hz,1H),4.25(dd,J=12.3,5.1Hz,1H),4.15(dd,J=12.3,2.3Hz,1H),3.92( ddd,J=10.1,5.0,2.3Hz,1H),3.37-3.32(m,1H),3.29(s,1H),3.27-3.20(m, 2H),2.72-2.58(m,4H),2.06(s,3H),2.02(s,3H),2.02(s,3H),1.98(s,3H). 13 C NMR (101MHz, CD3OD) δ172.26,171.66,171.28,171.12,86.41,76.52,75.61,69.66,69.26,63.39,60.87,29.40,20.73,20.61,20.58.

[0090] Example 5

[0091] At room temperature, 3c (0.4mmol, 2equiv), NaI (0.2mmol, 1equiv), CH3CN / H2O (2.6mL / 0.4mL) were added to an integrated electrolytic cell, a carbon rod electrode was used as the anode of the electrochemical system, a platinum sheet electrode was used as the cathode of the electrochemical system, and a 15mA direct current was applied. At the same time, 1a was dissolved in 1mL CH3CN and added dropwise into the electrochemical reaction system within 30min. After the addition was completed, the reaction was continued for 10min. After the reaction was completed, the crude product was concentrated under reduced pressure. The target product 5 (85.5mg,) was obtained by column chromatography separation with a yield of 92%.

[0092]

[0093] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((4-hydroxypiperidin-1-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0094] Yield: 92%

[0095] The characterization data of this compound are as follows: 1H NMR (400MHz, DMSO-d6) δ5.33(t,J=9.4Hz,1H),5.12(d,J=10.2Hz,1H),4.86(t,J =9.8Hz,2H),4.58(d,J=4.2Hz,1H),4.17-4.08(m,1H),4.07-3.99(m,2H),3.44(d q,J=8.5,4.3Hz,1H),3.12-3.02(m,1H),3.00-2.92(m,1H),2.92-2.77(m,2H),2 .00(s,3H),1.99(s,6H),1.94(s,3H),1.69(d,J=11.0Hz,2H),1.51-1.33(m,2H). 13 C NMR (101MHz, DMSO-d6) δ169.92,169.56,169.32,169.04,83.31,73.98,73.29,68. 13,67.57,64.75,61.96,55.33,54.74,35.44,35.28,20.47,20.46,20.40,20.31.

[0096] Example 6

[0097] Thioglycosidation of reboxetine: Reboxetine is a norepinephrine reuptake inhibitor, which is used clinically to treat depression. Reboxetine and its derivative reboxetine mesylate are both approved antidepressants. Therefore, the synthesis of reboxetine derivatives is of great significance for the development of such drugs. The inventors successfully introduced the thioglycoside fragment on the amino group using this electrochemistry to obtain the thioglycosidated reboxetine derivative, and harvested the target compound with a yield of 42%.

[0098]

[0099] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((S)-2-((S)-(2-ethoxyphenoxy)(phenyl)methyl)morpholino)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0100] The characterization data of this compound are as follows: 1H NMR(400MHz,DMSO-d6)δ7.40(d,J=7.5Hz,1H),7.32(t,J=7.3Hz,2H),7.26(d,J=7.1Hz,1H),6.88(dd,J=15.5,7.9Hz,2H),6.80(t,J=7.7Hz,1H),6.71(t,J=7.8Hz,1H),5.32(t,J=9.5Hz,1H),5.27(d,J=6.0Hz,1H),5.14(d,J=10.2Hz,1H),4.85(q,J=11.2,10.6Hz,2H),4.02(q,J=12.4,11.5Hz,5H),3.81(d,J=10.0Hz,2H),3.49(t,J=11.1Hz,1H),3.04-2.77(m,3H),2.45(d,J=11.7Hz,1H),1.99(s,6H),1.93(s,3H),1.82(s,3H),1.41-1.28(m,3H). 13 C NMR(101MHz,DMSO-d6)δ169.94,169.55,169.29,168.77,149.13,147.27,137.58,128.17,127.96,127.36,121.74,120.69,117.02,114.44,83.18,80.89,78.53,74.04,73.15,68.08,67.48,66.58,64.07,62.02,57.24,56.69,20.46,20.38,20.30,20.25。

Claims

1. A method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to construct SN bonds, characterized in that: An organic solution containing glycosyl thiol, amine compounds and electrolyte salts is used as an electrolyte, an anode and a cathode are placed in the electrolyte, a direct current is passed through, and an electrochemical reaction is performed to obtain a glycosyl sulfonamide compound.

2. The method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to form SN bonds according to claim 1, characterized in that: The glycosyl thiol has a structure of Formula 1: R--SH Formula 1 Wherein, R is a five-membered sugar ring, a six-membered sugar ring or a polyvalent sugar ring.

3. The method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to form SN bonds according to claim 1, characterized in that: The amine compound has a structure of Formula 2: Among them, R 1 and R 2 are independently selected from hydrogen, primary carbon, secondary carbon or quaternary carbon, and R 1 and R 2 Not at the same time as hydrogen.

4. The method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to form SN bonds according to claim 1, characterized in that: The glycosyl sulfenamide compound has a structure of Formula 3: in, R is a five-membered sugar ring, a six-membered sugar ring or a polyvalent sugar ring; R 1 and R 2 are independently selected from hydrogen, primary carbon, secondary carbon or quaternary carbon, and R 1 and R 2 Not at the same time as hydrogen.

5. A method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to form SN bonds according to any one of claims 1 to 4, characterized in that: The molar ratio of the glycosyl thiol to the amine compound is 1:1.5-2.

5.

6. A method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to form SN bonds according to any one of claims 1 to 4, characterized in that: The molar ratio of the glycosyl thiol to the electrolyte salt is 1.0:0.5-1.

5.

7. The method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to form SN bonds according to claim 6, characterized in that: The electrolyte salt includes sodium iodide and / or potassium iodide.

8. The method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to form SN bonds according to any one of claims 1 to 4, characterized in that: The electrolyte uses acetonitrile and water as a mixed solvent.

9. A method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to form SN bonds according to any one of claims 1 to 4, characterized in that: The anode is a carbon rod anode or a platinum sheet anode; the cathode is a platinum sheet cathode, a carbon rod cathode or a nickel sheet cathode.

10. A method for synthesizing glycosyl sulfenamide by electrochemically oxidizing glycosyl thiol and amine compounds to form SN bonds according to any one of claims 1 to 4, characterized in that: The conditions of the electrochemical reaction are: under air or protective atmosphere, the current of direct current is 5-15 mA, the temperature is 20-30° C., and the time is 40-50 min.

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