One-step synthesis method of 2 '3'-dideoxynucleoside

A technology of deoxynucleoside and synthesis method, applied in the field of organic chemical industry, can solve the problems of long steps, low efficiency, etc., and achieve the effects of short time, mild reaction conditions and wide selection of ligands

Inactive Publication Date: 2022-03-29
HANGZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method avoids the shortcomings of traditional production methods such as lengthy steps, low efficiency and the need to use toxic and harmful reagents, and is convenient for use in laboratories and industrial production

Method used

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  • One-step synthesis method of 2 '3'-dideoxynucleoside
  • One-step synthesis method of 2 '3'-dideoxynucleoside
  • One-step synthesis method of 2 '3'-dideoxynucleoside

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Put 1mmol 2,6-dichloropurine, 24.7mmol tetrahydrofuran, 5mmol tert-butanol peroxide, 0.1mmol 2,2'-bipyridine, 0.1mmol copper chloride in the reactor, and stir at 70°C for 24 hours. After the reaction, excess tetrahydrofuran was distilled off by rotary distillation, and 191 mg of the product was obtained through silica gel column chromatography. The ratio of the theoretical yield to 258 mg was calculated to give a reaction yield of 74%. The reaction equation is as follows:

[0049]

[0050] The product passed the nuclear magnetic resonance test, and the measured data were: 1 H NMR (400MHz, CDCl 3 ,TMS)δ8.23(s,1H),6.32(t,J=4.2Hz,1H),4.21(dd,J=14.4Hz,7.8Hz,1H),4.10(dd,J=16.0Hz,7.6 Hz,1H),2.56(m,2H),2.17(m,2H); 13 C NMR (100MHz, CDCl 3 )δ152.7, 152.1, 151.6, 144.1, 131.4, 86.7, 70.1, 32.7, 24.2. The product has been tested by high-resolution mass spectrometry, and the test data obtained is: HRMS (EI) Calcd forC 9 h 8 Cl 2 N 4 O:[M] + 258.0075; Found, 258.0079. ...

Embodiment 2

[0052] 1mmol 6-chloropurine, 24.7mmol tetrahydrofuran, 5mmol tert-butanol peroxide, 0.1mmol 2,2'-bipyridine, 0.1mmol copper chloride were placed in the reactor, and stirred at 70°C for 24 hours. After the reaction was completed, excessive THF was evaporated by rotary distillation, and 146 mg of the product was obtained through silica gel column chromatography. The ratio of the theoretical yield to 225 mg was calculated to give a reaction yield of 65%. The reaction equation is as follows:

[0053]

[0054] The product was tested by nuclear magnetic resonance, and the measured data were: 1H NMR (400MHz, CDCl3, TMS) δ8.75(s, 1H), 8.24(s, 1H), 6.36(dd, J=5.6Hz, 2.6Hz, 1H ), 4.32(dd, J=10.8Hz, 6.6Hz, 1H), 4.11 (dd, J=10.8Hz, 7.8Hz, 1H), 2.59(m, 2H), 2.18(m, 2H); 13C NMR (100MHz , CDCl3) δ 151.8, 151.0, 150.9, 143.4, 132.4, 86.6, 69.9, 32.5, 24.2. The product was tested by high-resolution mass spectrometry, and the test data obtained was: HRMS (ESI) Calcd for C 9 h 9 ClN 4 O:...

Embodiment 3

[0056] 1 mmol of bis-Boc-adenine, 24.7 mmol of tetrahydrofuran, 5 mmol of tert-butanol peroxide, 0.1 mmol of 2,2'-bipyridine, and 0.1 mmol of copper chloride were placed in a reactor and stirred at 70°C for 24 hours. After the reaction was completed, excess tetrahydrofuran was distilled off, and 207 mg of the product was obtained through silica gel column chromatography. The ratio of the theoretical yield to 406 mg was calculated to give a reaction yield of 51%. The reaction equation is as follows:

[0057]

[0058] The product passed the nuclear magnetic resonance test, and the measured data were: 1 H NMR (400MHz, d 6 -DMSO)δ8.85(s,1H),8.75(s,1H),6.41(dd,J=6.4Hz,3.6Hz,1H),4.16(dd,J=14.8Hz,7.6Hz,1H),3.94 (dd, J=14.4Hz, 7.0Hz, 1H), 2.44-2.55(m, 2H), 2.23(m, 1H), 2.06(m, 1H), 1.38(s, 18H); 13 C NMR (100MHz, CDCl 3)δ152.5, 151.9, 150.5, 150.2, 142.9, 129.5, 86.2, 83.7, 69.8, 32.4, 27.8, 24.3. The product has been tested by high-resolution mass spectrometry, and the test da...

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Abstract

The invention discloses a one-step synthesis method of 2 '3'-dideoxynucleoside. The method comprises the following steps: directly reacting alkaloid (I) and saturated ether R4OCH2R5 at a certain temperature under the action of a catalyst and an oxidizing agent to synthesize 2 '3'-dideoxynucleoside in one step; according to the synthesis method, ether can be converted into a highly electrophilic carbonyl ylide intermediate under the combined action of a catalyst, a ligand and an oxidizing agent, and alkaloid (I) has better nucleophilic reaction activity due to lone electron pairs on nitrogen atoms, can attack the electrophilic carbonyl ylide intermediate generated in situ in the reaction, and can be used for preparing a high-purity carbonyl ylide intermediate. The 2 '3'-dideoxynucleoside and the 2 '3'-dideoxynucleoside are combined to react to generate a final 2 '3'-dideoxynucleoside product, and reaction byproducts only comprise water and tert-butyl alcohol, so that the environment is not polluted.

Description

technical field [0001] The invention belongs to the field of organic chemical industry and relates to the preparation of a class of organic compound molecules, in particular to a one-step synthesis method of 2'3'-dideoxynucleosides. Background technique [0002] 2'3'-Dideoxynucleoside is the basic skeleton of many drugs, and it is also the core component of dideoxy DNA sequencing reagents, which has been widely valued and applied. For example, 2'3'-dideoxynucleoside is the core structure of many antiviral drugs, especially has a good inhibitory effect on HIV. For example, dideoxyinosine (ddI), dideoxycytidine (ddC), and dideoxythymidine (ddT) have been approved for clinical use in some countries, and dideoxydehydrothymidine (D4T) has entered clinical phase I / II trials . Common drugs such as didanosine, zalcitabine and so on. At the same time, 2'3'-dideoxynucleoside is also the core fragment of the chain reaction terminator in DNA sequencing reagents, which can be used for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/40C07D473/34C07D239/54C07D239/47
CPCC07D473/40C07D473/34C07D239/54C07D239/47
Inventor 解春松吴松
Owner HANGZHOU NORMAL UNIVERSITY
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