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A kind of method for synthesizing chiral acyclic nucleoside analogs by asymmetric allyl amination reaction

A technology for nucleoside analogs and allylamine, which is applied in the field of asymmetric allyl amination reaction to synthesize chiral acyclic nucleoside analogs, can solve problems such as complex process control, and achieves easy availability of raw materials and reaction conditions. Mild, high-yield effects

Active Publication Date: 2019-07-09
HENAN NORMAL UNIV
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  • 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 nucleoside analogs were synthesized through a simple, green and efficient asymmetric allyl amination reaction, based on solving the synthesis of such compounds Problems such as complex process control in the process provide reference value for the synthesis and application of nucleoside drugs, and provide raw materials for the research of new antiviral and anticancer active drugs

Method used

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  • A kind of method for synthesizing chiral acyclic nucleoside analogs by asymmetric allyl amination reaction
  • A kind of method for synthesizing chiral acyclic nucleoside analogs by asymmetric allyl amination reaction
  • A kind of method for synthesizing chiral acyclic nucleoside analogs by asymmetric allyl amination reaction

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Experimental program
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Effect test

Embodiment 1

[0036]

[0037] 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, and the reaction was complete by TLC detection. Post-processing method: After the reaction is complete, extract with CH2Cl2 (3×10mL), dry with anhydrous Na2SO4, spin dry, and pass through the column to obtain a colorless oil for 3 hn. 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

[0039]

[0040]Take a Shurank reaction tube, add 1j (49.2mg, 0.3mmol), SKP (3.6mg, 5mol%) and Pd2(dba)3 (1.8mg, 2.5mol%), K2CO3 (41.4mg, 0.3mmol), cover Put on the rubber stopper, react with nitrogen replacement several times, add 0.5mL DCM, react at room temperature for 30min, put it into a low-temperature reaction instrument at -10°C, add 2n (34.6mg, 0.1mmol) dissolved in 0.5mL DCM, react, and detect by TLC The response is complete. 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 oily substance 3jn. 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 ...

Embodiment 3

[0042]

[0043] Take a Shurank reaction tube, add 1l (60.9mg, 0.3mmol), SKP (3.6mg, 5mol%) and Pd2(dba)3 (1.8mg, 2.5mol%), K2CO3 (13.68mg, 0.1mmol), cover Put on the rubber stopper, after several times of reaction to replace nitrogen, add 0.5mL toluene, react at room temperature for a while, then put it into a low-temperature reaction instrument at -10°C, add 2n (34.6mg, 0.1mmol) dissolved in 0.5mL toluene to react, TCL The detection response is complete. Post-processing method: After the reaction is complete, extract with CH2Cl2 (3×10 mL), dry over anhydrous Na2SO4, spin dry, and pass through the column to obtain a colorless oily substance 3ln. 88% yield, 50:50B / L, N9 / N7>95:5, 91% 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,...

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Abstract

The invention discloses a method for synthesizing a chiral noncyclic nucleoside analog through an asymmetric allyl amination reaction and belongs to the technical field of organic synthesis. A reaction solvent, a purine compound 1, an additive, an SKP diphosphine ligand and metal palladium are mixed, then, an MBH (Morita-Baylis-Hillman) adduct 2 is added, the mixture is subjected to a thermal reaction, and noncyclic nucleoside 3 is obtained. The method has the advantages that raw materials are easy to obtain, the method is simple to operate and adopts mild reaction conditions, and a chiral branched chain N-allylation product with medium to excellent regioselectivity (up to 99% B / L) and excellent enanioselectivity (up to 99% ee) can be obtained through the reaction.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing chiral acyclic nucleoside analogs by asymmetric allyl amination reaction. 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 synthe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/40C07D473/38C07D473/34C07D473/18C07D473/30C07D473/00
CPCC07B2200/07C07D473/00C07D473/18C07D473/30C07D473/34C07D473/38C07D473/40
Inventor 谢明胜于露露王海霞郭海明渠桂荣
Owner HENAN NORMAL UNIV