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Method for synthesizing chiral ternary purine carbocyclic nucleoside analogue through intramolecular asymmetric cycloaddition

A carbocyclic nucleoside, asymmetric technology, applied in the field of intramolecular asymmetric cycloaddition synthesis of chiral three-membered purine carbocyclic nucleoside analogs, can solve the problems of expensive raw materials, complicated processes, etc. The effect of simple operation and cheap and easy-to-obtain catalysts

Inactive Publication Date: 2016-06-22
HENAN NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In order to solve the deficiencies of the existing technology, a new substrate was found, and a multi-substituted chiral three-membered purine carbocyclic nucleoside analogue was synthesized by a simple, green, and efficient asymmetric cycloaddition method, based on the solution The problem of expensive raw materials and complicated process in the synthesis of such compounds provides reference value for the synthesis and application of nucleoside drugs, and provides raw materials for the research of new antiviral and antitumor drugs

Method used

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  • Method for synthesizing chiral ternary purine carbocyclic nucleoside analogue through intramolecular asymmetric cycloaddition
  • Method for synthesizing chiral ternary purine carbocyclic nucleoside analogue through intramolecular asymmetric cycloaddition
  • Method for synthesizing chiral ternary purine carbocyclic nucleoside analogue through intramolecular asymmetric cycloaddition

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023]

[0024] Take a 100mL flask, weigh III (206mg, 1.0mmol), K 2 CO 3 (691mg, 5.0mmol) and bromoacetyl bromide (262μL, 3.0mmol), then add 60mL of dichloromethane solution, react for 1h, quench, extract, and spin dry. Dissolve the obtained intermediate in tetrahydrofuran (50 mL), add N, N'-bis-p-toluenesulfonyl hydrazide, the reaction is lowered to 0 ° C, and DBU (750 μL, 5.0 mmol) is added dropwise. After the reaction is complete, quench , extracted, spin-dried, and column chromatography (PE / EA=1:1) gave a yellow solid. 1 HNMR (400MHz, CDCl 3 ):δ8.50(s,1H),8.08(s,1H),7.26(d,J=14.4Hz,1H),6.65-6.62(m,1H),4.81-4.79(m,2H),4.12( s,3H). 13 CNMR (100MHz, CDCl 3 ): δ161.4, 153.0, 151.3, 139.9, 124.7, 122.2, 115.3, 62.7, 54.5, 46.6. HRMS (ESI): m / zcalcd.forC 11 h 10 N 6 NaO 3 [M+Na] + :297.0707,found297.0713.

Embodiment 2

[0026]

[0027] Take IV (1.53g, 5.0mmol) and p-toluenesulfonyl azide (1.18g, 6.0mmol) into a 100mL flask, and add 50mL of acetonitrile. At 0 °C, DBU (2.24 mL, 15.0 mmol) was added dropwise and monitored by TLC. After the reaction was complete, it was quenched, extracted, spin-dried, and passed through a column (PE / EA=1:1) to obtain a white solid. 1 HNMR (400MHz, CDCl 3 ):δ8.53(s,1H),8.09(s,1H),7.34(d,J=14.4Hz,1H),6.76-6.69(m,1H),4.91(d,J=6.8Hz,2H) ,4.15(s,3H),3.18(s,3H). 13 CNMR (100MHz, CDCl 3 ): δ161.3, 161.0, 153.0, 151.3, 140.0, 125.5, 122.2, 114.4, 63.5, 54.5, 52.8. HRMS (ESI): m / zcalcd.forC 13 h 13 N 6 o 5 [M+H] + :333.0942,found333.0950.

Embodiment 3

[0029]

[0030] Take a 100mL flask, weigh V (3.38g, 10.0mmol), TsNHNH 2 (1.86g, 10.0mmol) was dissolved in 50mL toluene, the reaction was refluxed for 9h, spin-dried, then dissolved in dichloromethane, the reaction was transferred to 0°C and Et 3 N (1.02g, 10.0mmol), after the completion of the reaction was detected by TCL, extracted, spin-dried, and passed through the column (PE / EA=1:1) to obtain a yellow solid. 1 HNMR (400MHz, CDCl 3 ):δ8.60(s,1H),8.11(s,1H),7.50-7.32(m,5H),7.20(t,J=7.2Hz,1H),6.79-6.72(m,1H),4.99( d,J=6.8Hz,2H),4.20(s,3H). 13 CNMR (150MHz, CDCl 3 ): δ161.4, 153.0, 151.3, 139.9, 129.2, 126.2, 125.3, 125.1, 124.2, 122.2, 115.2, 62.9, 54.5. HRMS (ESI): m / zcalcd.forC 17 h 15 N 6 o 3 [M+H] + :351.1200,found351.1208.

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Abstract

The invention discloses a method for synthesizing chiral three-membered purine carbocyclic nucleoside analogues through intramolecular asymmetric cycloaddition. Specifically, the N-9 intramolecular diazonium nucleoside is used as a raw material, through intramolecular asymmetry Cycloaddition Synthesis of Chiral Three-membered Purine Carbocyclic Nucleoside Analogues. In the present invention, the raw materials are easy to obtain, and the operation is simple. By using specific chiral catalysts and reaction conditions, the reaction can obtain chiral products with high yield and high enantiomeric excess value, and the reaction can be achieved in gram-level, still up to High yields and high enantiomeric excess values ​​are maintained. This reaction has several advantages such as novel and easy-to-obtain raw materials, mild reaction conditions, and cheap and easy-to-obtain catalysts. It provides a simple and practical synthetic method for the synthesis of chiral three-membered purine carbocyclic nucleoside analogues.

Description

technical field [0001] The invention relates to the technical fields of chemistry and medicine, in particular to a method for synthesizing chiral three-membered purine carbocyclic nucleoside analogues through intramolecular asymmetric cycloaddition. Background technique [0002] Nucleoside drugs play a very important role in antiviral and antitumor chemotherapy drugs, especially in the past ten years, the development of drugs in this area is very fast. The structural modification of natural nucleosides is an important means to find new and more effective antiviral drugs. Among the antiviral drugs currently on the market and in clinical trials, most of them are nucleoside derivatives. Nucleoside derivatives therefore become the compounds with the most antiviral potential. However, such drugs still generally have many adverse reactions, low bioavailability, easy to produce drug resistance, fast metabolism and other problems. Therefore, it is of great significance to improve ...

Claims

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Application Information

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IPC IPC(8): C07D473/30C07D473/34C07D473/40C07D473/00
CPCC07D473/30C07D473/00C07D473/34C07D473/40
Inventor 郭海明黄可心谢明胜王东超王海霞渠桂荣
Owner HENAN NORMAL UNIV
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