A chiral three-membered carbocyclic pyrimidine nucleoside analog and its preparation method

A carbocyclic pyrimidine nucleoside and analog technology, applied in the field of chiral three-membered carbocyclic pyrimidine nucleoside analogs and their preparation, can solve the problems of expensive raw materials, complicated processes, etc. mild conditions

Inactive Publication Date: 2019-04-05
HENAN NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The present invention seeks a simple, green and efficient synthesis method of chiral three-membered carbocyclic pyrimidine nucleoside analogues, based on solving the problems of expensive raw materials and complicated processes in the synthesis process of such compounds, and the development of nucleoside drugs. The synthesis and application provide reference value and provide raw materials for the research of new antiviral and antitumor drugs

Method used

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  • A chiral three-membered carbocyclic pyrimidine nucleoside analog and its preparation method
  • A chiral three-membered carbocyclic pyrimidine nucleoside analog and its preparation method
  • A chiral three-membered carbocyclic pyrimidine nucleoside analog and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027]

[0028] Take a dry 100mL flask, dissolve pyrimidine (10.0mmol, 3.11g) and sodium tetrachloropalladate (1.0mmol, 294mg) in 185mL of vinyl acetate, reflux and stir at 80°C for 12h, then distill off the solvent under reduced pressure. The product was obtained by column chromatography with a yield of 88%. 1 H NMR (400MHz, CDCl 3 ): δ7.76(d, J=7.6Hz, 1H), 7.36(dd, J=8.8, 16.0Hz, 1H), 7.13(d, J=7.6Hz, 1H), 5.26(dd, J=2.0, 16.0Hz, 1H), 5.08(dd, J=2.0, 8.8Hz, 1H), 1.56(s, 18H); 13 C NMR (100MHz, CDCl 3 ): δ162.6, 153.3, 149.4, 142.4, 132.3, 104.5, 97.1, 85.2, 27.7.

Embodiment 2

[0030]

[0031] Take a dry test tube, use dioxane (0.2mL) as solvent, dissolve 1% Ru-pheox in dioxane (0.4mL), and dissolve ethyl diazoacetate (0.2mmol, 4eq) in dioxane In oxane (0.4mL), add the dissolved catalyst (0.1mL) into the reaction tube, then slowly drop ethyl diazoacetate (0.1mL) into the reaction tube, stir at room temperature for 1min, repeat the above operation 3 times , until the reaction of the raw materials is complete. The target product was obtained by column chromatography with a yield of 93%, ee: 99%. 1 HNMR (400MHz, CDCl 3 ):δ7.16(d,J=8.0Hz,1H),5.72(d,J=8.0Hz,1H),4.23-4.14(m,2H),3.51-3.47(m,1H),2.09-2.04( m,1H),1.70-1.65(m,1H),1.60(s,9H),1.47-1.41(m,1H),1.29(t,J=7.2Hz,3H); 13 C NMR (150MHz, CDCl 3 ): δ171.0, 160.4, 149.3, 143.1, 102.4, 100.1, 87.2, 61.6, 38.1, 27.6, 22.3, 15.3, 14.3. HRMS: exact mass calcd for C 15 h 20 N 2 o 6 [M+Na] + requires m / z 347.1214, found m / z 347.1212.

Embodiment 3

[0033]

[0034] Take a dry test tube, use dioxane (0.2mL) as solvent, dissolve 2% Ru-pheox in dioxane (0.4mL), and dissolve ethyl diazoacetate (0.2mmol, 4eq) in dioxane In oxane (0.4mL), add the dissolved catalyst (0.1mL) into the reaction tube, then slowly drop ethyl diazoacetate (0.1mL) into the reaction tube, stir at room temperature for 1min, repeat the above operation 3 times , until the reaction of the raw materials is complete. The target product was obtained by column chromatography with a yield of 96%, ee: 99%. 1 HNMR (400MHz, CDCl 3 ):δ6.99(s,1H),4.21-4.16(m,2H),3.48-3.44(m,1H),2.08-2.04(m,1H),1.92(d,J=0.8Hz,3H), 1.70-1.65(m,1H),1.60(s,9H),1.47-1.42(m,1H),1.29(t,J=7.2Hz,3H); 13 C NMR (150MHz, CDCl 3 ): δ171.1, 161.4, 149.4, 147.9, 139.1, 110.9, 87.1, 61.6, 37.9, 27.6, 22.3, 15.5, 14.3, 12.5. HRMS: exact mass calcd for C 16 h 22 N 2 o 6 [M+Na] + requires m / z 361.1370, found m / z 361.1372.

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Abstract

The invention discloses a chiral tri-carbocyclic pyrimidine nucleoside analogue and a preparation method of the chiral tri-carbocyclic pyrimidine nucleoside analogue. The preparation method comprises the following steps of taking dioxane as a solvent, adding Ru-pheox as a ligand and a catalyst, then adding an ethyl diazoacetate reactant, stirring at a room temperature for 4 minutes, and reacting at the room temperature. The preparation method disclosed by the invention is a simple, convenient, green and efficient method for synthesizing the chiral tri-carbocyclic pyrimidine nucleoside analogue, aims to solve the problems of expensive raw materials and complicated process in the process of synthesizing the kind of compound, and has the advantages that a reference value is provided for the synthesis and application of nucleoside drugs, and the raw material is provided for the research of new antiviral drugs and new antitumor drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a chiral three-membered carbocyclic pyrimidine nucleoside analog and a preparation method thereof. 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. Therefore, the carbocyclic pyrimidine nucleoside analogs have 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 modify various parts of nucleosi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/54C07D239/553C07D239/47
CPCC07D239/47C07D239/54C07D239/553
Inventor 郭海明渠桂荣周鹏谢明胜王东超
Owner HENAN NORMAL UNIV
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