Method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction

An asymmetric and isonucleoside technology, which is applied in the field of asymmetric cycloaddition synthesis of chiral isonucleosides and chiral isonucleosides, can solve the problem of low yield, high cost, and difficult preparation of chiral substrates and other problems, to achieve the effect of efficient synthesis method, easy access to reaction raw materials, and rich product structure

Active Publication Date: 2019-12-20
HENAN NORMAL UNIV
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Problems solved by technology

The yield of this method is very low, and the chiral

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  • Method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction
  • Method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction
  • Method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction

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[0025] Example 1

[0026]

[0027]

[0028]

[0029] a Unless otherwise specified, the reaction steps are as follows: under nitrogen atmosphere, metal (10mol%), ligand (12mol%), 1a (0.1mmol), 2 (0.12mmol) in the solvent for 1 day. b Separation yield. c The dr value passed the nuclear magnetic test of the crude product. d The ee value is separated by high performance liquid chromatography.

[0030] In the process of screening reaction conditions, the influence of ligands on the reaction (numbers 1-14), the influence of reaction solvents on the reaction (numbers 15-18), and the influence of temperature on the reaction (numbers 19-21) were investigated. Finally determined Pd(PPh 3 ) 4 As the best metal, ligand L6 is the best ligand, and toluene is the best solvent.

[0031] Investigation of reaction conditions: In a 10mL vacuum tube, add α-5-methyluracil substituted methyl acrylate 1a (31.4mg, 0.1mmol), Pd(PPh 3 ) 4 (5.8mg, 5mol%) and L6 (3.6mg, 6mol%). Replace with nitrogen for 3 time...

Example Embodiment

[0035] Example 2:

[0036] In a 10mL vacuum tube, add α-5-ethyluracil substituted methyl acrylate 1b (32.8mg, 0.1mmol), Pd(PPh 3 ) 4 (5.7mg, 5mol%) and L6 (3.7mg, 6mol%). Replace with nitrogen for 3 times, then add 0.5 mL of toluene, stir for half an hour, and then dissolve epoxybutene 2 (9.0 mg, 0.12 mmol) in 0.5 mL of toluene and add it to the reaction tube. The reaction tube was placed at room temperature for 1 day. The reaction was followed by TLC. After the reaction was terminated, dichloromethane / water was added for extraction, the organic phase was dried with anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then the target compound 3b was obtained by column chromatography with a yield of 90%, 6:1 dr and 92%ee.

Example Embodiment

[0037] Example 3:

[0038] In a 10mL vacuum tube, add α-5-fluorouracil substituted methyl acrylate 1c (32.8mg, 0.1mmol), Pd(PPh 3 ) 4 (11.4mg, 10mol%) and L6 (7.4mg, 12mol%). Replace with nitrogen for 3 times, then add 0.5 mL of toluene, stir for half an hour, and then dissolve epoxybutene 2 (9.0 mg, 0.12 mmol) in 0.5 mL of toluene and add it to the reaction tube. The reaction tube was placed at room temperature for 1 day. The reaction was followed by TLC. After the reaction was terminated, dichloromethane / water was added for extraction, the organic phase was dried with anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then the target compound 3c was obtained by column chromatography with a yield of 81%, 6:1 dr and 91%ee. HPLC CHIRALCEL IA, n-hexane / isopropanol=90 / 10, flow rate 0.8mL / min, column temperature 25℃, wavelength 250nm, retention time: 34.007min (major), 37.667min (minor). 1 H NMR(600MHz, CDCl 3 ): δ7.90(d,J=7.8Hz,2H), 7.73(d,J=6.6Hz,1H), 7.69...

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Abstract

The invention discloses a method for synthesizing chiral isonucleoside analogues through asymmetric cycloaddition reaction, and belongs to the field of asymmetric synthesis in organic chemistry. Purine substituted olefin 1 and epoxy butene 2 are used as raw materials; in the presence of a palladium catalyst and a chiral diphosphine ligand SegPHOS or MeOBIPHEP, asymmetric cycloaddition reaction iscarried out to obtain a chiral isonucleoside analogue 3, dr is 1/1-7/1, the maximum enantiomeric excess ee reaches 95%, and a variety of functional group substituted chiral isonucleosides 7-11 are obtained after derivation. The method provides a simple, convenient, cheap and efficient way for synthesizing the chiral isonucleoside compound series.

Description

technical field [0001] The invention relates to a synthesis method of chiral isonucleosides, in particular to a method for synthesizing chiral isonucleosides through an asymmetric cycloaddition reaction, and belongs to the field of asymmetric synthesis in organic chemistry. Background technique [0002] Natural nucleoside drugs are easily hydrolyzed and enzymatically hydrolyzed due to the aminal structure. In order to increase the stability, the bases were shifted to construct a new class of nucleoside compounds called isonucleosides. Chiral isonucleoside compounds play an important role in biology and medicinal chemistry. For example, the anti-HIV activity and selectivity of the isonucleoside compound Iso-ddA are equivalent to those of the nucleoside compound ddA. However, very few types of isonucleoside structures have been discovered and applied so far, and it is of great significance to further modify their structures in order to change or enhance their antiviral or ant...

Claims

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Application Information

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IPC IPC(8): C07B53/00C07D405/04C07D473/40C07D473/30C07D473/34
CPCC07B53/00C07D405/04C07D473/40C07D473/30C07D473/34C07B2200/07Y02P20/55
Inventor 郭海明黄可心王东超谢明胜王海霞渠桂荣
Owner HENAN NORMAL UNIV
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