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Method for synthesizing chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition

A technology of nucleoside analogs and five-membered carbon rings, which is applied in the fields of chemistry and medicine, can solve the problems of expensive raw materials and complicated processes, and achieve the effect of simple operation, mild reaction conditions, concise and practical synthesis methods

Inactive Publication Date: 2015-11-11
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In order to solve the deficiencies of the prior art, a simple, green and efficient asymmetric cycloaddition method was found to synthesize chiral five-membered carbocyclic nucleoside analogues, based on solving the problem of expensive raw materials in the synthesis process of such compounds, The problem of complex process 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 pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition
  • Method for synthesizing chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition
  • Method for synthesizing chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The asymmetric cycloaddition reaction formula provided by the present invention is as follows:

[0026]

[0027] Take a Shurank tube, under the protection of nitrogen, with 5mol% Pd 2 (dba) 3 and 10 mol% of ligand L in freshly distilled CH 2 Cl 2 As a solvent, stir at room temperature for 20 min, then add α-base-substituted acrylate (0.05 mmol) and allyl cyclopropane (0.075 mmol, 1.5 eq) in sequence, and react at 25 degrees Celsius. Through thin-layer plate detection (TLC); the target product was obtained through column chromatography with a yield of 99%, ee1=91%, ee2=90%.

[0028] 1 HNMR (400MHz, CDCl 3 ):δ8.68(s,1H),8.34(s,1H),5.63-5.57(m,1H),5.02(d,J=17.2Hz,1H),4.93(d,J=10.4Hz,1H) ,4.23-4.16(m,2H),3.86(q,J=7.6Hz,1H),3.80(s,3H),3.72(s,3H),3.60(d,J=14.8Hz,1H),3.40( d, J=15.2Hz, 1H), 2.98(q, J=7.2Hz, 1H), 2.46(q, J=5.6Hz, 1H), 1.13(t, J=7.2Hz, 3H). 13 CNMR (100MHz, CDCl 3 ): δ171.4, 171.2, 169.2, 152.1, 151.5, 151.2, 144.1, 133.4, 131.4, 119.2, 62.9, 57.2, 5...

Embodiment 2

[0030]

[0031] Take a Shurank tube, under the protection of nitrogen, with 5mol% Pd 2 (dba) 3 and 10 mol% of ligand L in freshly distilled CH 2 Cl 2 As a solvent, stir at room temperature for 20 min, then add α-base-substituted acrylate (0.05 mmol) and allyl cyclopropane (0.075 mmol, 1.5 eq) in sequence, and react at 25 degrees Celsius. Through thin-layer plate detection (TLC); the target product was obtained through column chromatography with a yield of 80%, ee1=81.4%, ee2=72.5%.

[0032] 1 HNMR (400MHz, CDCl 3):δ7.87(s,1H),5.61-5.52(m,1H),5.17(s,2H),5.05(d,J=17.2Hz,1H),4.97(d,J=10.4Hz,1H) ,4.23-4.15(m,2H),3.77(s,3H),3.72(s,3H),3.52(d,J=15.2Hz,1H),3.31(d,J=14.8Hz,1H),2.85( q,J=7.2Hz,1H),2.57-2.51(m,2H),1.16(t,J=7.2Hz,3H). 13 CNMR (100MHz, CDCl 3 ): δ171.5, 171.5, 169.6, 158.5, 154.0, 141.2, 133.6, 118.9, 71.9, 62.6, 57.4, 53.4, 53.3, 49.3, 41.8, 37.2, 13.8. HRMS: exactmasscalcdforC 19 h 22 ClN 5 o 6 Na(M+Na) + requiresm / z474.1151, foundm / z474.1149. 1 HNMR (4...

Embodiment 3

[0034]

[0035] Take a Shurank tube, under the protection of nitrogen, with 5mol% Pd 2 (dba) 3 and 10 mol% of ligand L in freshly distilled CH 2 Cl 2 As a solvent, stir at room temperature for 20 min, then add α-base-substituted acrylate (0.05 mmol) and allyl cyclopropane (0.075 mmol, 1.5 eq) in sequence, and react at 25 degrees Celsius. Through thin-layer plate detection (TLC); the target product was obtained through column chromatography with a yield of 93%, ee1=90.5%, ee2=79.5%.

[0036] 1 HNMR (400MHz, CDCl 3 ):δ8.95(s,1H),8.77(d,J=7.6Hz,2H),8.35(s,1H),7.58-7.52(m,3H),5.71-5.63(m,1H),5.05( d,J=17.2Hz,1H),4.95(d,J=10.4Hz,1H),4.26-4.16(m,2H),3.91-3.86(m,1H),3.80(s,3H),3.70(s ,3H),3.65(d,J=15.2Hz,1H),3.43(d,J=15.2Hz,1H),2.98(q,J=6.8Hz,1H),2.54(q,J=5.2Hz,1H ), 1.13(t,J=7.2Hz,3H). 13 CNMR (100MHz, CDCl 3 ): δ171.5, 171.4, 169.7, 154.8, 152.0, 143.1, 133.8, 131.0, 129.7, 128.6, 118.8, 71.9, 70.0, 62.7, 57.3, 53.4, 53.4, 49.7, 42.3, 37.2, 13.9. 25 h 26 N 4 o 6 Na(...

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Abstract

The invention discloses a method for synthesizing a chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition. The reaction equation is as shown in the specification. According to the method for synthesizing a chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition, provided by the invention, a specific chiral catalyst is used, so that the chiral product can be obtained at a high yield and a high enantiomer excess value; besides, the reaction has the advantages that the operation is simple, the reaction condition is mild and the catalyst is inexpensive and easily obtainable, and a simple and practical synthetic method is provided for synthesis of chiral pentabasic carbocyclic nucleoside analogues.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and specifically relates to a method for obtaining chiral five-membered carbocyclic nucleoside analogs through an asymmetric [3+2] cycloaddition reaction. 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. The carbocyclic nucleoside derivatives thus 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 ...

Claims

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Application Information

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IPC IPC(8): C07D473/40C07D473/00C07D473/30C07D473/34C07D209/38C07D487/04C07D209/86C07D235/24C07D209/48C07D233/56C07D239/54
CPCC07D473/40C07B2200/07C07D209/38C07D209/48C07D209/86C07D233/56C07D235/24C07D239/54C07D473/00C07D473/30C07D473/34C07D487/04
Inventor 郭海明韩瑞杰王东超谢明盛王海霞张倩渠桂荣
Owner HENAN NORMAL UNIV
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