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A method for the synthesis of chiral three-membered carbocyclic nucleosides by asymmetric cyclopropanation initiated by Michael addition

A three-membered carbocyclic, chemical synthesis technology, applied in organic chemistry and other directions, can solve the problems of high synthesis cost and cumbersome cyclopropane nucleoside derivative methods, and achieve an efficient synthesis method, rich product structure, and high product stereoselectivity. Effect

Active Publication Date: 2019-10-18
HENAN NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the methods for constructing cyclopropane nucleoside derivatives by these two methods are too cumbersome and the synthesis cost is relatively high.

Method used

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  • A method for the synthesis of chiral three-membered carbocyclic nucleosides by asymmetric cyclopropanation initiated by Michael addition
  • A method for the synthesis of chiral three-membered carbocyclic nucleosides by asymmetric cyclopropanation initiated by Michael addition
  • A method for the synthesis of chiral three-membered carbocyclic nucleosides by asymmetric cyclopropanation initiated by Michael addition

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020]

[0021]

[0022]

[0023] a Unless otherwise stated, the reaction conditions were as follows: α-purine-substituted acrylate 1a (0.1 mmol), tert-butyl bromoacetate 2c (0.11 mmol), quinine-based catalyst (10 mol%) and base (1.1 equivalents) in 1 mL of solvent in 0°C reaction. b Separation yield. c Determined by chiral HPLC analysis. d React at room temperature. e Increasing the amount of base to 2 equivalents increased the yield to 52%, ee=92%. f The amount of catalyst used is 5 mol%. g at -10°C. h at -20°C.

[0024] In the process of screening the reaction conditions, the influence of amine catalysts on the reaction was firstly investigated (markers 1-6). At the same time, by comparing the effects of different catalysts on the reaction, the best catalyst for catalyst 4f was determined.

[0025] Investigation of reaction conditions: In a 10mL vacuum tube, add α-purine substituted 6-Cl ethyl acrylate 1a (25.2mg, 0.1mmol), (DHQD) 2 AQN (8.6 mg, 10 mol%), ...

Embodiment 2

[0038] In a 10 mL vacuum tube, α-purine substituted 6-dimethylaminoacrylate (26.1 mg, 0.1 mmol), (DHQD) 2 AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was tracked by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3fc was obtained by column chromatography with a yield of 84%, 97% ee.

Embodiment 3

[0040] In a 10 mL vacuum tube, α-purine substituted 6-diethylaminoacrylate (28.9 mg, 0.1 mmol), (DHQD) 2 AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was followed by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3gc was obtained by column chromatography with a yield of 87%, 94% ee.

[0041] Representative compound characterization data are as follows:

[0042]3gc colorless oily liquid, 87% yield, 94% ee.[α] 25 D =-80.1 (c=1.2, CH 2 Cl 2 ); Ee value is detected by chiral HPLC (mobile phase, n-hexane / 2-propanol=80 / 20, flow rate: 0.6mL / min, detection wavelength: 250nm, retention time: 13.924min, 18.512min.); 1 H NMR (600MHz, CDCl 3 ):8.30(s,1H),7.66(s,1H),4.13-4.16(m,2H),3.96(br,4H),2.98(br,1H),2.05-2.45(m,2H)...

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Abstract

The invention discloses a method for synthesizing chiral ternary carbocyclic nucleoside through asymmetric cyclopropanation triggered by Michael addition and belongs to the field of asymmetric synthesis in organic chemistry. Chiral cyclopropane carbocycle purine nucleoside is prepared from alpha-purine substituted acrylate and bromo-tert-butyl acetate as raw materials after a chiral amine catalysis reaction derived by quinine, the reaction enantioselectivity is good, and the yield is medium to excellent.

Description

technical field [0001] The invention relates to a synthesis method of chiral carbocyclic purine nucleosides, in particular to a method for synthesizing chiral three-membered carbocyclic nucleosides through asymmetric cyclopropanization triggered by Michael addition, which belongs to the field of asymmetric synthesis in organic chemistry . Background technique [0002] Chiral cyclopropane carbocyclic purine nucleoside compounds have a wide range of physiological activities, such as Besifovir, MBX1616 and A5021 have shown high drug activity (reference: Boutureira, O.; Matheu, M.I.; Díaz, Y.; Castillón, S. Chem. Soc. Rev. 2013, 42, 5056). For example, the currently known LB80317, LB80380 and A-5021 all pass a cyclopropane and a cyclopropane. They are linked to bases and exhibit good antiviral activity. They have been used in Phase II clinical trials to treat hepatitis B virus and herpes simplex virus. At the same time, compounds with different configurations will also produce...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/40C07D473/34C07D473/30C07D473/38C07D473/00
Inventor 谢明胜郭海明赵国锋李建平王东超王海霞
Owner HENAN NORMAL UNIV
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