Method used for synthesis of chiral cis-carbocycle N3-purine nucleoside

A purine nucleoside and chirality technology, which is applied in the field of synthesizing chiral cis-carbocyclic N3-purine nucleosides, can solve the problems of cumbersome process and high cost, and achieves high reaction yield, high-efficiency synthesis method, and easy-to-obtain reaction raw materials. Effect

Inactive Publication Date: 2019-09-17
HENAN NORMAL UNIV
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional method of constructing N 3 -Purine nucleosides usually start from pyrimidine nucleosides and undergo multi-step synthesis, the process is cumbersome and the cost is high

Method used

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  • Method used for synthesis of chiral cis-carbocycle N3-purine nucleoside
  • Method used for synthesis of chiral cis-carbocycle N3-purine nucleoside
  • Method used for synthesis of chiral cis-carbocycle N3-purine nucleoside

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022]

[0023]

[0024]

[0025] [a] Unless otherwise specified, the reaction steps are as follows: 1a (0.1mmol), 0.5-2% catalyst, 1mL solvent, HCO 2 H / TEA (molar ratio 1:1) was reacted at 27°C for 1 day [b] dr>20:1, judged by NMR detection of crude product [c] separation yield [d] ee value was analyzed by chiral column [ e] HCO 2 H / TEA=2.5:1[f]HCO 2 H / TEA=0.2:1.

[0026] In the screening process of reaction conditions, the influence of metal catalysts on the reaction was firstly investigated (markers 1-4). At the same time, by comparing the effects of different ligands on the reaction and considering the price factor, the catalyst (R,R)-D was finally determined to be the best catalyst. Afterwards the best solvent dioxane, HCO was selected 2 H / TEA=1:1.

[0027] The investigation of reaction condition: (taking label 13 as example)

[0028] In a 10mL reaction flask, add α-(6-diethylamino-3H-purinyl)cyclopentanone 1a (27.5mg, 0.1mmol), catalyst (R,R)-D (0.7mg, 1mo...

Embodiment 2

[0030]

[0031] In a 10mL reaction flask, add α-(6-dimethylamino-3H-purinyl)cyclopentanone 1b (24.5mg, 0.1mmol), catalyst (R,R)-D (0.7mg, 1mol%) and 1 mL of dioxane. Then add HCO 2 H / TEA=1:1 mixed solvent 70 μL, put the reaction tube at 27°C for 24 hours. Track the reaction with TLC. After the reaction is terminated, the organic phase is concentrated in vacuo, and column chromatography obtains a white solid 2b (single crystal X-ray diffraction is figure 1 ), yield 95%, 99.9%ee, dr>20:1, melting point: 230.5-234.9°C. [α] D 20 =-72.89 (c=0.584, CH 2 Cl 2 ); 1 H NMR (600MHz, CDCl 3 )δ8.14(s,1H),7.59(s,1H),4.86(dt,J=11.4,5.4Hz,1H),4.70(d,J=5.4Hz,1H),3.54(s,3H), 3.26(s,3H),2.39-2.31(m,1H),2.27-2.21(m,1H),2.09-2.02(mm,2H),1.95-1.90(m,1H),1.72-1.64(m,1H ); 13 C NMR (150MHz, CDCl 3 )δ152.5, 152.1, 150.4, 140.3, 119.7, 70.1, 63.7, 39.7, 38.0, 32.8, 26.6, 20.5; HRMS (ESI-TOF): exact mass calcd for C 12 h 18 N 5 O(M+H) + requires m / z 248.1506, found m / z 248.1507.

Embodiment 3

[0033]

[0034] In a 10mL reaction flask, add α-(6-ethoxy-3H-purinyl)cyclopentanone 1c (24.8mg, 0.1mmol), catalyst (R,R)-D (0.7mg, 1mol%) and 1mL Dioxane. Then add HCO 2H / TEA=1:1 mixed solvent 70 μL, put the reaction tube at 27°C for 24 hours. The reaction was tracked by TLC. After the reaction was terminated, the organic phase was concentrated in vacuo, and column chromatography obtained a white solid 2c with a yield of 94%, 95% ee, dr>20:1, melting point: 215.0-218.9°C. [α] D 20 =-133.66 (c=0.153, CH 2 Cl 2 ); 1 H NMR (600MHz, CD 3 OD):8.75(s,1H),8.08(s,1H),5.24-5.20(m,1H),4.79-4.75(m,2H),4.47-4.46(m,1H),2.56-2.49(m, 1H),2.30-2.25(m,1H),2.23-2.17(m,1H),2.15-2.09(m,1H),1.93-1.80(m,2H),1.52(t,J=7.2Hz,3H) ; 13 C NMR (150MHz, CD 3 OD):161.2,155.7,155.4,143.9,123.8,71.5,65.7,65.6,33.7,27.5,21.1,14.9; HRMS(ESI-TOF):exact mass calcd for C 12 h 17 N 4 o 2 (M+H) + requires m / z 249.1346, found m / z 249.1345.

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Abstract

The invention discloses a method used for synthesis of chiral cis-carbocycle N3-purine nucleoside, and belongs to the field of asymmetric synthesis in organic chemistry. According to the method, in the presence of a chiral ruthenium catalyst, formic acid, and triethylamine, asymmetric hydrogen transfer reaction induced dynamic kinetic resolution is carried out so as to obtain cis-carbocycle N3-purine nucleoside2 with two chiral centers. The method can be used for preparing the chiral cis-carbocycle N3-purine nucleoside compounds; reaction yield and stereoselective selectivity are high; only cis products are obtained; the highest enantioselectivity is larger than 99.9%; and gram grade scale preparation can be realized.

Description

technical field [0001] The present invention specifically relates to a kind of synthetic chiral cis carbocyclic N 3 - A method of purine nucleosides, belonging to the field of asymmetric synthesis in organic chemistry. Background technique [0002] Dual-target antiviral drugs can not only improve the therapeutic effect of antiviral drugs, but also reduce drug resistance. Among them, because the structure of the receptor active site is similar, designing a structural unit so that it can act on these two receptors at the same time is an important design pattern for dual-target drugs. Since 3H-purine possesses key structural features of both purine and pyrimidine, N 3 - Purine nucleosides have the potential to be recognized by both purine and pyrimidine metabolizing enzymes. In view of this, N 3 -Purine nucleosides are expected to be used as potential dual-target drugs in antiviral therapy. [0003] At present, due to the difficulty of constructing 3H-purine, the synthesis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34C07D473/30C07D473/38
CPCC07D473/30C07D473/34C07D473/38
Inventor 张齐英白娟郭海明张一铭渠桂荣
Owner HENAN NORMAL UNIV
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