Alpha-carbon glycoside based on organic trifluoroborate, synthesis method and application of alpha-carbon glycoside in pharmacy

Abstract

The invention provides a method for stereoselectively synthesizing C-glycoside based on organic trifluoroborate, which comprises the following steps: mixing a catalyst, organic trifluoroborate and 3, 4-O-carbonate glycal, adding an organic solvent, reacting at room temperature, monitoring the reaction process by TLC (Thin Layer Chromatography), and terminating the reaction when the 3, 4-O-carbonate glycal completely disappears, thereby obtaining alpha-carbon glycoside. The catalyst Pd (MeCN) 2Cl2 used in the invention can be used for catalyzing to generate a carbon glycoside product with high yield.

Description

Technical Field

[0001] The present invention provides a kind of organic trifluoroborate-based α The invention discloses a method for synthesizing carbon glycoside compounds, belonging to the technical field of organic synthesis. Background Art

[0002] C The stereoselective synthesis of α-glycosides has attracted extensive attention due to their key roles in various bioprocesses and pharmaceutical applications. C -Glycosides have carbon glycosidic bonds, O -glycosidic bonds exhibit greater stability to enzymatic degradation than glycosides, thus providing improved pharmacokinetic properties. These unique glycosidic bonds are present in a large number of natural products and are known to modulate protein-glycan interactions, making them valuable backbones for drug development. Since sugar moieties with olefinic groups provide an easily accessible platform for the introduction of a wide range of functional groups, it leads to stereoselective C - Development of various synthetic strategies in the field of glycosylation.

[0003] Recently, Professor Brown and Professor Qian reported the synthesis of sugar-based polymers via nickel catalysis. C -glycosides. These effective methods can be used in anhydrous THF under an inert atmosphere using 3.0 equivalents of aryl iodide and [ t -BuLi-(Bpin)2] as the receptor, quickly obtain 2-Bpin- α - C When Professor Liu used thiocarbazine salt (2.0 equivalents) as the acceptor, it could be obtained stereoselectively with a yield of 54% to 91% under heating at 90 °C. α - C -Glycoside. Most reactions previously required strict operation under anhydrous and oxygen-free conditions, or high-temperature reactions, which were harsh and complicated. Summary of the invention

[0004] In view of the above technical problems, the present invention provides a method for using 3,4- O -carbonate glycalol donor and aryl trifluoroborate C -glycosylation method, the structural formula is: , the R is methyleneoxy tert-butyldiphenylsilyl (-CH2OTBDPS), methyleneoxy tert-butyldimethylsilyl (-CH2OTBS), methyleneoxy pivaloyl (-CH2OPiv), methyleneoxybenzoyl (-CH2OBz), methyl (Me) or R = H; the structural formula of the Ar is a benzene ring, a heterocycle or a substituted benzene ring; the substituent of the substituted benzene ring includes any one of p-methyl, p-methoxy and 3,5-trifluoromethyl; the heterocycle is selected from two of 2-thiophene and 2-naphthalene.

[0005] The substituents of the substituted benzene ring include any one of o-methyl, m-methyl, o-methoxy and m-methoxy substituted benzene ring.

[0006] The α The carbon glycoside compound is selected from any one of the following:

[0007] .

[0008] Another object of the present invention is to provide a trifluoroborate-based α The synthesis method of carbon glycoside comprises the following steps: a catalyst, an organic trifluoroborate and 3,4- O -carbonate ester sugars were mixed, organic solvents were added, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC. O -After the carbonate ester sugar disappears completely, terminate the reaction and you can get α Carbon glycoside. The reaction formula is as follows:

[0009] The structural formula of Ar in the sugar acceptor is a benzene ring, a heterocycle and a substituted benzene ring, and the substituents of the substituted benzene ring include o-methyl, m-methyl, thiophene and the like.

[0010] The R is methyleneoxy tert-butyldiphenylsilyl (-CH2OTBDPS), methyleneoxy tert-butyldimethylsilyl (-CH2OTBS), methyleneoxy pivaloyl (-CH2OPiv), methyleneoxybenzoyl (-CH2OBz), methyl (Me) or R = H; the structural formula of Ar is a benzene ring, a heterocycle or a substituted benzene ring.

[0011] The catalyst includes any one of PdCl2, Pd(OAc)2, White catalyst, and Pd(MeCN)2Cl2. The solvent includes any one of dichloromethane, chloroform, acetonitrile, toluene, and dimethyl sulfoxide.

[0012] In this patent, after screening, the catalyst Pd(MeCN)2Cl2 used can generate high yield α Carbon glycoside.

[0013] The α The carbon glycoside compound is selected from any one of the following:

[0014] .

[0015] The advantage of this patent is that the use of organic trifluoroborate as a sugar acceptor has the potential to achieve transition metal-catalyzed glycosidation reactions under mild conditions due to its unique properties (such as air and moisture stability). In addition, organic trifluoroborate, as a substitute for boric acid, boric ester and organic boric ester, has been shown to improve the reactivity of nucleophiles, solving the problem of harsh conditions and insufficient reactivity of general carbon glycosidation.

[0016] Another object of the present invention is to provide α Application of carbon glycoside compounds in the development of drugs for inhibiting the in vitro activity of α-glucosidase.

[0017] The present invention provides a fast and efficient method for synthesizing α Carbon glycosides can be directly synthesized in an open system and under mild conditions. α Carbon glycosides have the characteristics of high yield and excellent stereoselectivity.

[0018] Certain compounds provided by the present invention have good inhibitory α -Glucosidase, which can be used for anti-diabetic pharmaceutical purposes. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is the hydrogen spectrum of compound 3c.

[0020] Figure 2 This is the carbon spectrum of compound 3c. DETAILED DESCRIPTION

[0021] Experimental reagents Pd(MeCN)2Cl2 (Jiangsu Xinnoko Catalyst Co., Ltd.), petroleum ether (boiling range 60-90 °C, Tianjin Hengxing Chemical Reagent Manufacturing Co., Ltd.), ethyl acetate (analytical grade, Tianjin Komiou Chemical Reagent Co., Ltd.), anhydrous sodium sulfate (analytical grade, Sinopharm Chemical Reagent Co., Ltd.), deuterated chloroform (deuterium atomic content 99.8%, TMS content 0.03% V / V, 10*0.5 mL / box, ARMAR, Switzerland); nuclear magnetic resonance tube (5mm 100 / pk 2 ST500-8, Norell, USA).

[0022] Experimental instruments ZXZ-4 rotary vane vacuum pump (Linhai Tanshi Vacuum Equipment Co., Ltd.), DZF-6020 vacuum drying oven (Shanghai Xinmiao Medical Equipment Manufacturing Co., Ltd.), SHB-IIIA circulating water multi-purpose vacuum pump (Shanghai Yukang Science and Education Instrument Equipment Co., Ltd.), CL-4 flat magnetic stirrer (Zhengzhou Great Wall Science and Technology Industry and Trade Co., Ltd.), EYELA SB-1100 rotary evaporator (Shanghai Ailang Instrument Co., Ltd.), FA2104B analytical balance (Shanghai Yueping Science and Technology Instrument Co., Ltd.), XRC-1 micro melting point tester (Sichuan University Science and Technology Instrument Factory), DF-101S collector constant temperature heating magnetic stirrer (Gongyi Yingyu Yuhua Instrument Factory), GZX-9240MBE digital display blast drying oven (Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory), ZF-6 three-purpose UV analyzer (Shanghai Jiapeng Technology Co., Ltd.), Ultrashied 400 MHz Plus nuclear magnetic resonance instrument (Swiss Bruker Company), API 4000 LC-MS / MS mass spectrometer (Bruker Daltonics, Germany).

[0023] Example 1 The catalyst, organic trifluoroborate and 3,4- O -carbonate ester sugars were mixed, organic solvents were added, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC. O -After the carbonate ester sugar disappears completely, terminate the reaction and you can get α The catalyst Pd(MeCN)2Cl2 used in the present invention can catalyze the generation of carbon glycoside products with high yield. The optimized experimental schemes of different catalysts, ligands and solvents are analyzed as follows:

[0024]

[0025] Note: All experiments were performed with 0.10 mmol of 3,4- O -Carbonate glycans react with 0.2 mmol of organic trifluoroborate, 10 mol% of Pd catalyst, and 20 mol% of ligand in 2 mL of solvent at room temperature with stirring; isolated yield; stereoselectivity determined by H NMR. NR = no reaction.

[0026] The technical solution of the present invention screens and optimizes the reaction conditions. Under the condition of MeCN as solvent, the catalyst is first screened (Entries 1-4). When PdCl2 is used as the catalyst, C -glycoside was successfully formed with a yield of 77%, and only αIsomers (Entry 3). When further optimization was performed using different Pd(II) catalysts, it was found that Pd(MeCN)2Cl2 was the most effective, obtaining a yield of 94% of the desired product (Entry 4). The ligands were then replaced (Entries 5-6), and the yield and selectivity of the product were found to be moderate. Subsequently, screening of 6 solvents (Entries 7-12) also failed to exceed the yield obtained with acetonitrile. Based on all the experimental results, Entry 4 was finally determined to be the optimal condition, with Pd(MeCN)2Cl2 as the catalyst and acetonitrile as the solvent, in an open system and at room temperature. α - C -Aryl glycosides.

[0027] In the case of the above route, the present invention uses 3,4- O -Carboglycosides were prepared using carbonate ester glycans and organic trifluoroborate as raw materials. The technical route is as follows:

[0028] (3a R ,4 R )-4-((tert-butyldiphenylsilyl)oxy)methyl)-3a,7a-dihydro-4-((tert-butyldiphenylsilyl)oxy)methyl)- H -[1,3]dioxadioxadi[4,5- c ]pyran-2-one (0.1 mmol, 41.1 mg), potassium trifluoro(4-methylphenyl)borate (0.2 mmol, 39.6 mg), Pd(MeCN)2Cl2 (0.01 mmol, 2.6 mg) and 2 mL of acetonitrile were added to the reaction bottle for reaction. The reaction progress was monitored by TLC. When 3,4- O After the -carbonate glycan is completely reacted, the reaction is quenched, the organic phase is extracted and collected, and the solvent is removed by distillation under reduced pressure to obtain a crude product, which is then subjected to column chromatography using petroleum ether / ethyl acetate solution as the mobile phase to obtain the carbonyl glycoside product (yield is 94%). 1 H NMR (400 MHz, CDCl3) d 7.65 – 7.61 (m, 4H), 7.43 – 7.38 (m, 2H), 7.37 – 7.32 (m, 4H), 7.29 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 6.29 –6.20 (m, 2H, H-3, H-2), 5.32 (d, J = 2.0 Hz, 1H, H-1), 3.92 (ddd, J= 9.3, 4.7,2.1 Hz, 1H, H-4), 3.88 – 3.81 (m, 2H, H-6), 3.71 (td, J = 6.2, 2.1 Hz, H-5),2.37 (s, 3H), 2.00 (d, J = 9.0 Hz, 1H), 1.03 (s, 9H); 13 C{ 1 H} NMR (100 MHz,CDCl3) d 137.6, 136.1, 135.8, 135.7, 133.5, 133.4, 131.6, 129.8, 129.7, 129.1,127.8, 127.8, 127.7, 74.0, 72.3, 63.8, 62.5, 26.9, 21.2, 19.2; HRMS (ESI) m / z:[M + Na] + Calculate for C 29 H 34 O3SiNa + 481.2169; found 481.2171; = -128.4 (c =1.0, CHCl3). The range of C-glycoside substrates generated by the reaction of potassium arylborate and cyclic carbonate galactenose (obtained according to the conditions of Example 1): .

[0029] The C-glycoside substrate ranges for the synthesis of different types of carbonate glycans (refer to the conditions of Example 1) are as follows: .

[0030] Activity evaluation Enzymes used in the experiment α -glucosidase inhibitory activity in vitro, testing multiple compounds α -glucosidase inhibitory activity, acarbose as the positive drug. Preparation of reaction solution, sample and positive drug were dissolved in DMSO.

[0031] α -glucosidase inhibitory activity in vitro, testing multiple compounds α -glucosidase inhibitory activity. The experiment was divided into enzyme activity groups ( α -glucosidase solution and buffer solution), enzyme blank group (buffer and sample), positive group ( α-glucosidase solution and positive drug solution), positive blank group (buffer solution and positive drug solution), sample group ( α -glucosidase solution and sample) and sample blank group (buffer solution and sample). For the above groups, we carried out corresponding research. First: accurately weigh 1-2 mg of sample and positive drug (acarbose), dissolve them in dimethyl sulfoxide (DMSO), and then dilute the sample solution with PBS buffer solution (0.1 mol / mL, pH = 6.8); second: use a standard pipette to accurately measure 20 m L, 50 m L's α -glucosidase solution (0.2 U / mL) was added to the 96-well plate and shaken for 2 minutes to mix thoroughly. Then, the plate was incubated at 37°C. After 10 minutes, 25 m L substrate (PNPG) solution, shake and mix evenly, and incubate at 37°C for half an hour; third: add 100 m L of Na2CO3 solution to terminate it. Finally, the absorbance value OD at 405 nm was measured and the inhibitory activity of the sample was calculated. Table 1 shows the determination results of the compounds. It can be seen that the carbonyl glycoside compounds we obtained have certain α -glucosidase inhibitory activity in vitro and has antidiabetic potential.

[0032] Table 1. Compounds α -Glucosidase Inhibitory Activity Results in vitro

Claims

1. A α A carbon glycoside compound, characterized in that The structural formula is: , the R is methyleneoxy tert-butyldiphenylsilyl - CH2OTBDPS, methyleneoxy tert-butyldimethylsilyl - CH2OTBS, methyleneoxy pivaloyl - CH2OPiv, methyleneoxybenzoyl - CH2OBz, methyl Me or H; the structural formula of the Ar is a benzene ring, a heterocycle or a substituted benzene ring.

2. according to claim 1 α A carbon glycoside compound, characterized in that The heterocyclic ring is selected from any one of 2-thiophene and 2-naphthalene; The substituents of the substituted benzene ring include any one of o-methyl, m-methyl, o-methoxy and m-methoxy substituted benzene rings.

3. The method according to claim 1 or 2 α A carbon glycoside compound, characterized in that The α The carbon glycoside compound is selected from any one of the following: 。 4. A α A method for synthesizing carbon glycosides, characterized in that: The method comprises the following steps: preparing a catalyst, an organic trifluoroborate and 3,4- O -carbonate ester sugars were mixed, organic solvents were added, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC. O -After the carbonate ester sugar disappears completely, terminate the reaction and you can get α Carbon glycoside, the reaction formula is as follows: 。 5. According to claim 4 α A method for synthesizing carbon glycosides, characterized in that: The R is methyleneoxy tert-butyldiphenylsilyl - CH2OTBDPS, methyleneoxy tert-butyldimethylsilyl - CH2OTBS, methyleneoxy pivaloyl - CH2OPiv, methyleneoxybenzoyl - CH2OBz, methyl Me or R=H.

6. According to claim 4 α The method for preparing a carbon glycoside compound is characterized in that: The catalyst includes any one of PdCl2, Pd(OAc)2, White catalyst, and Pd(MeCN)2Cl2.

7. According to claim 1 α A method for synthesizing carbon glycosides, characterized in that: The solvent includes any one of dichloromethane, chloroform, acetonitrile, toluene and dimethyl sulfoxide.

8. The method according to any one of claims 1 to 3 α Application of carbon glycoside compounds in the preparation of drugs for inhibiting the in vitro activity of alpha-glucosidase.

9. A drug for inhibiting the in vitro activity of α-glucosidase, characterized in that: Including any one of claims 1 to 3 α A carbon glycoside compound or a compound synthesized by any one of the methods of any one of claims 4 to 7 α Carbon glycoside compounds.

10. An anti-diabetic drug, characterized in that: Including any one of claims 1 to 3 α A carbon glycoside compound or a compound synthesized by any one of the methods of any one of claims 4 to 7 α Carbon glycoside compounds.

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