Synthesis method of alpha fused ring C-glycoside and application of alpha fused ring C-glycoside in pharmacy

Abstract

The invention provides a synthesis method of alpha condensed ring C-glycoside, which comprises the following steps: mixing a catalyst, a ligand, an additive, a 1, 3-dicarbonyl compound and a 2, 3-unsaturated glycosyl donor, adding an organic solvent, reacting at room temperature, monitoring the reaction process by TLC (Thin Layer Chromatography), and terminating the reaction when the 1, 3-dicarbonyl compound completely disappears, thereby obtaining the alpha condensed ring C-glycoside. The catalyst Co (THMD) 3 used in the invention can catalytically generate a carbon glycoside product with high yield.

Description

Technical Field

[0001] The invention provides a method for synthesizing an α-condensed ring carbon glycoside compound, belonging to the technical field of organic synthesis. Background Art

[0002] Carbohydrates, as one of the four basic substances for life activities, are widely present in many natural products. They play an important role in biological cells and in the medical field, and they also play an important role in the medical field. First, they serve as nutrients and skeleton components for animals and plants. Secondly, they also shoulder many complex biological functions, such as intercellular communication recognition, signal transmission, immune regulation and other important physiological functions. For example, glycoconjugate vaccines are covalently linked to polysaccharides and carrier proteins, and their immunogenicity is deeply affected by glycosylation reaction sites. As carbohydrate compounds are increasingly gaining widespread attention, more glycoside drugs are constantly being used in drugs, laying a certain foundation for future drug research and development, disease treatment and the development of related vaccines. In addition, more and more glycoside drugs that have been marketed are appearing in our lives, protecting our lives.

[0003] Carbon glycosides are a class of compounds connected to another carbohydrate unit through a CC bond. Compared with traditional oxygen glycosides, they have extremely excellent stability in the process of enzyme or acid degradation. Therefore, they are widely used as substitutes for natural oxygen glycosides in the development of new biochemical probes and drugs. For example, some condensed ring carbon glycoside natural products extracted from oolong tea and marine organisms and Malayamycin A have certain biological activities, so the synthesis of compounds with such skeletons has certain value and biological significance. In this regard, we conducted a literature survey on the synthesis of condensed ring carbon glycosides. Although methods for synthesizing condensed ring carbon glycosides have been reported, the yield is low and the steps are long. For example, Toshiyuki Kan's research group used trichloroimide to guide benzyl-protected glucose to synthesize flavonoid natural products containing a bicyclic structure with a total yield of 26% and 15% through 7 steps. Although this method can obtain condensed ring carbon glycoside products through a total synthesis method, its synthesis steps are long and the yield is relatively low. Therefore, it is a great challenge to simply and directly synthesize fused-ring carbon glycoside products, which is also the problem that the present invention focuses on solving. Summary of the invention

[0004] In view of the above technical problems, the present invention provides an α-fused ring carbon glycoside compound, the structural formula of which is: , the R 1 is triisopropylsilyl TIPS, tert-butyldiphenylsilyl TBDPS, or tert-butyldimethylsilyl TBS; the R 2 , R 3The structural formula is an alkane, a benzene ring, a heterocycle or a substituted benzene ring; the heterocycle is selected from one or more of thiophene, furan, pyridine, pyrrole, and imidazole; the substituents of the substituted benzene ring include o-methyl, m-methyl, o-methoxy, m-methoxy and the like.

[0005] Another method of the present invention is to provide a method for synthesizing α-condensed ring carbon glycosides, comprising the following steps: mixing a catalyst, a ligand, an additive, a 1,3-dicarbonyl compound and a 2,3-unsaturated glycosyl donor, adding an organic solvent, reacting at room temperature, monitoring the reaction progress by TLC, and terminating the reaction when the 1,3-dicarbonyl compound completely disappears, thereby obtaining α-condensed ring carbon glycosides. The reaction formula is as follows: .

[0006] The sugar receptor R 2 , R 3 The structural formula is alkane, benzene ring, heterocycle, substituted benzene ring, and the substituents of the substituted benzene ring include o-methyl, m-methyl, thiophene and the like.

[0007] The glycosyl donor R 1 The groups represented are triisopropylsilyl TIPS, tert-butyldiphenylsilyl TBDPS, and tert-butyldimethylsilyl TBS.

[0008] The catalyst includes Co(acac) 3 、Co(BF 4 ) 2 、Co(PPh 3 )Cl 2 ,CoBr 2 、Co(TMHD) 3 The ligand includes PPh 3 The solvent includes any one of dichloromethane, chloroform, acetonitrile, toluene and tetrahydrofuran.

[0009] In this patent, after screening, the catalyst Co(TMHD) used 3 It can generate high yield of α-fused ring carbon glycosides, and the large steric hindrance of the coordinated ligand Xantphos and the No. 1 protecting group in the raw material can ensure the generation of carbon glycoside products with α configuration as the main component.

[0010] Another object of the present invention is to provide the α-fused ring carbon glycoside compound in inhibiting α -Application of glucosidase activity in vitro.

[0011] Another object of the present invention is to provide the use of an α-fused ring carbon glycoside compound in the preparation of a drug for inhibiting the in vitro activity of α-glucosidase.

[0012] The present invention provides a fast and efficient method for synthesizing condensed-ring carbon glycosides. The present invention can circumvent the traditional multi-step experimental operation and synthesize bicyclic carbon glycosides by a direct one-step method, and has the characteristics of high yield and excellent stereoselectivity.

[0013] The compound provided by the present invention has good anti-sugar activity, can effectively inhibit α-glucosidase, and has anti-diabetic pharmaceutical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 is the hydrogen spectrum of compound 3a.

[0015] Figure 2 This is the carbon spectrum of compound 3a. DETAILED DESCRIPTION

[0016] Experimental reagents Co(TMHD) 3 (Jiangsu Xinnoko Catalyst Co., Ltd.), petroleum ether (boiling range 60-90 ℃, 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, Switzerland ARMAR Company); nuclear magnetic resonance tube (5mm 100 / pk 2 ST500-8, American Norell Company).

[0017] 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) Example 1 The catalyst, ligand, additive, 1,3-dicarbonyl compound and 2,3-unsaturated glycoside donor are mixed, an organic solvent is added, the reaction is carried out at room temperature, and the reaction progress is monitored by TLC. When the 1,3-dicarbonyl compound disappears completely, the reaction is terminated to obtain α-fused ring carbonyl glycoside. The catalyst Co(THMD) used in the present invention is 3 It can catalyze the production of carbonyl glycoside products with high yields. The optimized experimental schemes of different catalysts, ligands and solvents are analyzed as follows:

[0018] Note: All experiments used 0.12 mmol 2,3-unsaturated glycosyl donor and 0.1 mmol 1,3-dicarbonyl compound, 10 mol% Pd catalyst, 15 mol% ligand, 20 mol% additive in 2 mL solvent and stirred at room temperature; isolated yield; stereoselectivity was measured by H NMR. DPPf: 1,1'-bis(diphenylphosphino)ferrocene, DPPBZ: 1,2-bis(diphenylphosphino)benzene, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, DPEphos: diphenyl(4-vinylphenyl)phosphine.

[0019] The technical solution of the present invention screens and optimizes the reaction conditions. Under the conditions of MeCN as solvent, Xantphos as ligand, and zinc powder as additive, the catalyst is first screened (Entries 1-5). It is found that when Co(BF 4 ) 2When used as a catalyst, carbon glycoside products were generated, but the yield was only 51%. When Co(TMHD) 3 When used as a catalyst, the yield reached 74% and the selectivity was excellent (dr>20:1). The ligand was then replaced (Entries 6-8), and the yield and selectivity of the product were found to be moderate. Subsequently, the solvent was changed (Entries 9-13), and it was found that the yield and selectivity of carbon glycosides were moderate in DCM, Toluene, DCE, and THF. Summarizing the experimental results, the optimal conditions for the reaction of 1,3-dicarbonyl compounds with 2,3-unsaturated glycosyl donors were obtained. In Co(TMHD) 3 As a catalyst, Xantphos as a ligand, zinc powder as an additive, and MeCN as a solvent, the reaction effect is best at room temperature.

[0020] In the case of the above route, the present invention uses 2,3-unsaturated glycosyl donor as raw material to prepare carbonyl glycoside, and the technical route is as follows:

[0021] 2, 3-unsaturated glycosyl donor (0.1 mmol, 35.85 mg), diketone reagent (0.1 mmol, 22.41 mg), Co(TMHD) 3 (0.01 mmol, 6.1 mg), xantphos (0.015 mmol, 8.7 mg), Zn (0.02 mmol, 2 mg) and 2 mL of acetonitrile were added to the reaction bottle for reaction. The reaction progress was detected by TLC. When the diketone was completely reacted, the reaction was quenched, the organic phase was extracted and collected, and the solvent was removed by vacuum distillation to obtain a crude product. Then, petroleum ether / ethyl acetate / dichloromethane solution was used as the mobile phase for column chromatography to obtain the oxygen glycoside product (yield was 74%, α:β = 15:1). 1 H NMR (400 MHz, CDCl 3 ) δ 7.63 – 7.58 (m, 2H), 7.36 – 7.30 (m, 3H), 7.30 – 7.22 (m, 1H), 7.22 –7.11 (m, 4H), 5.87 (d, J = 8.2 Hz, 1H), 5.34 (dt, J = 8.1, 3.4 Hz, 1H), 4.08 –3.99 (m, 2H), 3.99 – 3.89 (m, 1H), 3.09 (dd, J = 15.4, 3.5 Hz, 1H), 2.99 (dd, J=15.4, 3.3 Hz, 1H), 0.83 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H). 13 C{ 1 H} NMR (100MHz, CDCl 3 ) δ 208.2, 192.2, 167.8, 138.3, 132.0, 131.0, 129.1, 129.0, 128.7,128.1, 128.0, 109.7, 79.8, 79.3, 79.0, 63.2, 40.7, 25.8, 18.3, -5.4, -5.5.HRMS (ESI) m / z : calcd for C 27 H 33 O 5 Si + (M + H) + , 465.2092; found, 465.2077; =119.34 ( c = 1.0, CHCl 3 ). The following products were also prepared under the reaction conditions:

[0022] Activity evaluation The enzyme α-glucosidase was used in the experiment to inhibit the activity of the enzyme in vitro, and the inhibitory activity of multiple compounds on α-glucosidase was detected. Acarbose was used as a positive drug. The reaction solution was prepared, and the sample and positive drug were dissolved in DMSO, and the compound concentrations were 90, 30, and 10 μM, respectively.

[0023] α-glucosidase in vitro inhibitory activity, detect the inhibitory activity of multiple compounds on α-glucosidase. The experiment was divided into enzyme activity group (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 with dimethyl sulfoxide (DMSO) respectively, and then dilute the sample solution to the corresponding concentration with PBS buffer solution (0.1 mol / mL, pH = 6.8); second: use a standard pipette to accurately measure 15 μL of sample and 45 μL of α-glucosidase solution (0.3 μL / mL) and add them to a 96-well plate, shake and mix for 4 minutes to mix them completely. Then preheat at 37°C, add 20 μL of substrate (PNPG) solution, shake and mix evenly, and react at 37°C for half an hour; third: add 100 μL of Na 2 CO 3 The reaction was terminated by adding 405 nm absorbance OD to obtain the inhibitory activity of the sample. Table 1 shows the test results of the compound, which shows that the polycyclic carbon glycoside compound we obtained has a certain in vitro inhibitory activity of α-glucosidase and has anti-diabetic potential.

[0024] Table 1. In vitro α-glucosidase inhibitory activity results of the compounds .

Claims

1. An α-fused ring carbon glycoside compound, characterized in that: The structural formula is: , the R 1 is triisopropylsilyl TIPS, tert-butyldiphenylsilyl TBDPS, or tert-butyldimethylsilyl TBS; the R 2 , R 3 The structural formula is an alkane, a benzene ring, a heterocycle or a substituted benzene ring; the substituent of the substituted benzene ring includes any one of o-methyl, m-methyl and thiophene.

2. The α-fused ring carbon glycoside compound according to claim 1, characterized in that The heterocycle is selected from one or more of thiophene, furan, pyridine, pyrrole and imidazole; The substituents of the substituted benzene ring include o-methyl, m-methyl, o-methoxy and m-methoxy substituted phenyl.

3. The α-fused ring carbon glycoside compound according to claim 2, characterized in that: The α-fused ring carbon glycoside compound is selected from any one of the following: 。 4. A method for synthesizing an α-fused ring carbon glycoside, characterized in that: The method comprises the following steps: mixing a catalyst, a ligand, an additive, a 1,3-dicarbonyl compound and a 2,3-unsaturated glycoside donor, adding an organic solvent, reacting at room temperature, monitoring the reaction progress by TLC, and terminating the reaction when the 1,3-dicarbonyl compound completely disappears, thereby obtaining the α-fused ring carbonyl glycoside, and the reaction formula is as follows: 。 5. The method for synthesizing the α-fused ring carbon glycoside according to claim 4, characterized in that: The glycosyl donor R 1 The groups represented are triisopropylsilyl TIPS, tert-butyldiphenylsilyl TBDPS, and tert-butyldimethylsilyl TBS.

6. The method for preparing the α-fused ring carbon glycoside compound according to claim 4, characterized in that: The catalyst includes any one of Co(acac)3, Co(BF4)2, CoBr2, and Co(TMHD)3.

7. The method for synthesizing the α-fused ring carbon glycoside according to claim 1, characterized in that: The ligand includes any one of DPPB, Brettphos, Xantphos, tBuXPhos, DPPP, and Johnphos, and the additive includes one of zinc powder, cesium carbonate, and potassium carbonate.

8. The method for synthesizing the α-fused ring carbon glycoside according to claim 1, characterized in that: The solvent includes any one of dichloromethane, chloroform, acetonitrile, toluene and N,N-dimethylformamide.

9. The α-fused ring carbon glycoside compound according to any one of claims 1 to 2 inhibits α -Application of glucosidase activity in vitro.

10. Use of the α-fused ring carbon glycoside compound according to any one of claims 1 to 2 in the preparation of a drug for inhibiting the in vitro activity of α-glucosidase.

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