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Method for synthesizing chiral non-cyclic and carbocyclic nucleoside analogues

A technology for nucleoside analogs and carbocyclic nucleosides, which is applied in the field of synthesizing chiral acyclic and carbocyclic nucleoside analogs, can solve problems such as complex process control, and achieve easy-to-obtain raw materials, mild reaction conditions, and simple operations Effect

Active Publication Date: 2017-12-22
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In order to solve the deficiencies of the existing technology, a new synthetic route was found, and chiral acyclic and carbocyclic nucleoside analogs were synthesized through a simple, green and efficient asymmetric allyl amination reaction, based on solving this problem It provides reference value for the synthesis and application of nucleoside drugs, and provides raw materials for the research of new antiviral and anticancer active drugs.

Method used

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  • Method for synthesizing chiral non-cyclic and carbocyclic nucleoside analogues
  • Method for synthesizing chiral non-cyclic and carbocyclic nucleoside analogues
  • Method for synthesizing chiral non-cyclic and carbocyclic nucleoside analogues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042]

[0043]Take a Schurunk reaction tube, add 1h (46.2mg, 0.3mmol), SKP (3.6mg, 5mol%) and Pd2(dba)3 (1.8mg, 2.5mol%), cover with a rubber stopper, and replace nitrogen for many times Afterwards, 0.5 mL DCM was added, reacted at room temperature for 30 min, put 2n (34.6 mg, 0.1 mmol) dissolved in 0.5 mL DCM into ultrasound at -20°C, and reacted for 6 h, and the reaction was complete as detected by TLC. Post-processing method: After the reaction is complete, extract with CH2Cl2 (3×10mL), dry over anhydrous Na2SO4, spin dry, and pass through the column to obtain a colorless oil. 89% yield, 79:21B / L, 78:22N9 / N7, 98%ee. 1H NMR (600MHz, CDCl3) δ (ppm) 8.73 (s, 1H), 8.27 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H), 5.80-5.69 (m, 1H), 5.65- 5.55(m,1H),5.65-5.55(m,3H),2.60-2.47(m,1H),2.60-2.47(m,1H),2.05-1.90(m,5H),1.89-1.80(m,5H ),1.79-1.70(m,4H),1.55(t,J=14.4Hz,2H).13C NMR(150MHz,CDCl3)δ(ppm)164.5,151.92,151.89,151.1,145.2,138.1,136.0,131.9, 128.9,116.7,78.7,55.6,37.3,36.32,36.31,...

Embodiment 2

[0045]

[0046] Take a Shourunk reaction tube, add 1j (49.2mg, 0.3mmol), SKP (3.6mg, 5mol%) and Pd2(dba)3 (1.8mg, 2.5mol%), cover with a rubber stopper, and replace nitrogen for many times Afterwards, 0.5 mL DCM was added, reacted at room temperature for 30 min, put 2n (34.6 mg, 0.1 mmol) dissolved in 0.5 mL DCM into ultrasound at -20°C, and reacted for 6 h, and the reaction was complete as detected by TLC. Post-processing method: After the reaction is complete, extract with CH2Cl2 (3×10mL), dry over anhydrous Na2SO4, spin dry, and pass through the column to obtain a colorless oil. 86% yield, 82:18B / L, 84:16N9 / N7, 96%ee. 1H NMR (400MHz, CDCl3) δ (ppm) 8.67 (s, 1H), 8.06 (s, 1H), 6.51 (s, 1H), 6.00 (s, 1H), 5.80-5.6 (m, 1H), 5.58 ( dd,J=9.6,5.6Hz,1H),5.03-4.88(m,3H),3.35(t,J=7.2Hz,2H),2.54-2.25(m,1H),2.35-2.25(m,1H) ,2.02-1.86(m,5H),1.87-1.77(m,7H),1.76-.66(m,4H),1.53(t,J=11.6Hz,2H),1.07(t,J=7.2Hz, 3H).13C NMR (100MHz, CDCl3) δ (ppm) 164.6, 161.5, 151.9, 148.5, 142.3, 138...

Embodiment 3

[0048]

[0049] Take a Shourunk reaction tube, add 1l (60.9mg, 0.3mmol), SKP (3.6mg, 5mol%) and Pd2(dba)3 (1.8mg, 2.5mol%), cover with a rubber stopper, and replace nitrogen for many times Afterwards, 0.5 mL DCM was added, reacted at room temperature for 30 min, put 2n (34.6 mg, 0.1 mmol) dissolved in 0.5 mL DCM into ultrasound at -20°C, and reacted for 6 h, and the reaction was complete as detected by TLC. Post-processing method: After the reaction is complete, extract with CH2Cl2 (3×10mL), dry over anhydrous Na2SO4, spin dry, and pass through the column to obtain a colorless oil. 88% yield, 50:50B / L, N9 / N7>95:5, 98% ee. 1H NMR (400MHz, CDCl3) δ (ppm) 8.32 (s, 1H), 7.85 (s, 1H), 6.48 (s, 1H), 5.91 (s, 1H), 5.81-5.69 (m, 1H), 5.56 ( dd,J=9.6,5.6Hz,1H),4.99-4.95(m,3H),4.24(br,4H),2.48-2.37(m,1H),2.33-2.25(m,1H),2.07-1.92( m,5H),1.89-1.81(m,4H),1.79-1.67(m,9H),1.65-1.48(m,4H).13C NMR(100MHz,CDCl3)δ(ppm)164.8,154.0,152.5,151.0 ,139.3,137.5,136.6,127.8,120.1,116.2,78.3,54.7,...

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Abstract

The invention discloses a method for synthesizing chiral non-cyclic and carbocyclic nucleoside analogues through asymmetric allyl ammoniation and belongs to the technical field of organic synthesis. The method comprises the steps as follows: a reaction solvent, a purine compound 1, an additive, an SKP diphosphine ligand and metal palladium are mixed, an MBH adduct 2 is added, a mixture is subjected to a thermal insulation reaction, an N-allyl olefination product 3 is obtained, and non-cyclic nucleoside 7 is obtained through DIBAL-H reduction or carbocyclic nucleoside 9 is obtained through Grubb olefin metathesis and DIBAL-H reduction in sequence. The method has the advantages of adopting available raw materials and mild reaction conditions and being simple to operate and high in selectivity, and has potential actual application value.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing chiral acyclic and carbocyclic nucleoside analogs. Background technique [0002] Nucleoside compounds are favored by researchers because of their potential excellent antiviral activity and anticancer activity. Nucleoside compounds can be divided into acyclic nucleoside compounds and cyclic nucleoside compounds, among which cyclic nucleoside drugs represent Non-cyclic nucleoside drugs include Acyclovir, (S)-DHPA, (S)-HPMFA, Tenofovir, etc. [0003] At present, the traditional synthesis steps are too complicated, and most of them use chiral auxiliary agents to induce and chiral sources to synthesize chiral nucleoside analogs. Potential antithrombotic uridine acid ketose analogs may have the effect of treating diabetes or antithrombotic, which greatly limits their development. Finding convenient and quick synthetic chiral drugs requires the conti...

Claims

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Application Information

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IPC IPC(8): C07D473/40C07D473/38C07D473/34C07D473/18C07D473/30C07D473/00
CPCC07D473/00C07D473/18C07D473/30C07D473/34C07D473/38C07D473/40
Inventor 郭海明王海霞谢明胜于露露渠桂荣
Owner HENAN NORMAL UNIV
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