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Heterocyclic compound as well as preparation method and application thereof

A technology for heterocyclic compounds and compounds, applied in the field of compounds, can solve the problems of influence, low yield, long route and the like

Pending Publication Date: 2022-03-08
安徽诺全药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above synthetic methods of purine nucleoside analogs based on purine analog formula 2 all have problems such as a yield lower than 60% or a long route.
Seriously affected industrialized mass production

Method used

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  • Heterocyclic compound as well as preparation method and application thereof
  • Heterocyclic compound as well as preparation method and application thereof
  • Heterocyclic compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060]

[0061] (1) Suspend the compound of formula 2a (1.0mmol) in the solvent THF (tetrahydrofuran) (5mL), add TMSCl (trimethylchlorosilane) (1.1mmol) at room temperature, then cool down to -60°C, and dropwise add excess n-Butyllithium (2.5M hexane solution, 3.2mmol), kept stirring at -60°C for 2h after dropping; while preparing the compound of formula 2b, the H on the 7-position of the compound of formula 2b was removed;

[0062] (2) Prepare another reaction bottle, add electrophile ethylene oxide (2.0mmol) and THF (10mL), and stir at room temperature to obtain an electrophile solution;

[0063] (3) Pre-cool the electrophile solution prepared in step (2) to -60°C and add it to step (1), continue to stir at -60°C for 3h; then gradually heat to -20°C, add acetic acid (3mmol) quenching reaction,

[0064] (4) The reaction solution was washed successively with water, saturated aqueous sodium bicarbonate solution, and saturated brine. Finally, the obtained organic phase is c...

Embodiment 2

[0066]

[0067] (1) Suspend the compound of formula 2a (1.0mmol) in THF (5mL), add TMSCl (1.1mmol) at room temperature, then cool down to 0°C, add NaH (60% suspended in mineral oil, 1.1mmol), then Stir at 0°C for 30 min to obtain the compound of formula 2b;

[0068] (2) Cool down to -60°C, add n-butyllithium (2.5M hexane solution, 2.2mmol) dropwise, and stir at -60°C for 2 hours after dropping, to remove the H on the 7-position of the compound of formula 2b.

[0069] (3) Prepare another reaction bottle, add ethylene oxide (2.0mmol) and THF (10mL), and stir to obtain an electrophilic reagent solution;

[0070] (4) Precool the electrophile solution obtained by stirring evenly to -60° C., and add it to the lithiated mixture in step (2). The mixture was continued to be stirred at -60°C for 3 h, gradually heated to -20°C, acetic acid (3 mmol) was added to quench the reaction, and the reaction solution was washed successively with water, saturated aqueous sodium bicarbonate solu...

Embodiment 3

[0072]

[0073] Suspend the compound of formula 2a (1.0mmol) in THF (5mL), add TMSCl (1.1mmol) at room temperature, then cool down to 0°C, add N,N-diisopropylethylamine (2.0mmol), and then Stir at ℃ for 30 min, then cool down to -60°C, add n-butyllithium (2.5M hexane solution, 2.2mmol) dropwise, and stir at -60°C for 2h after dropping.

[0074] Prepare another reaction vial, add ethylene oxide (2.0 mmol) and THF (10 mL), and pre-cool the solution to -60°C, add to the above lithiated mixture. The mixture was continued to be stirred at -60°C for 3 h, gradually heated to -20°C, acetic acid (3 mmol) was added to quench the reaction, and the reaction solution was washed successively with water, saturated aqueous sodium bicarbonate solution, and saturated brine. Finally, the obtained organic phase was concentrated and then column chromatographed to obtain the compound of formula 3a with a yield of 71%, and the analytical data was the same as that of the standard sample of compoun...

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Abstract

The invention discloses a heterocyclic compound and a preparation method and application thereof, and the heterocyclic compound has a structure of a compound as shown in a formula 3: starting from a 4-amino heterocyclic compound as shown in a formula 2a which is lower in cost, the 7-site of the compound as shown in the formula 2a can be directly metallized to synthesize the compound as shown in the formula 3 through 4-NH2 temporary silicon protection without using a 7-halogen substitution step, and the compound as shown in the formula 3 can be used for preparing the compound as shown in the formula 2a. The method has the remarkable advantages of high yield, good regioselectivity, easiness in industrial production and the like, and the total yield of the method is remarkably higher than that of a currently known 7-halogenation scheme.

Description

technical field [0001] The invention belongs to the field of compounds, and in particular relates to a direct metallation reaction of a silicon-protected 4-amino heterocyclic compound 2 and its reaction with different electrophilic reagents R4Lg, a method for preparing purine nucleoside analog formula 3 and its application . Background technique [0002] Purine nucleoside analogs are important biologically active compounds, which are of great significance in the development of antitumor and antiviral drugs. A large number of purine nucleoside analogs have shown anti-tumor, anti-virus, anti-coagulation and other biological activities, among which purine nucleoside analogs such as remdesivir, acyclovir, entecavir, and ticagrelor have been marketed. [0003] It is difficult to modify the 7-position of the purine analog formula 2, so the corresponding purine nucleoside analogs are also difficult to obtain. It is usually necessary to replace the 7-position halogen on the 4-amin...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07H7/06C07H1/00
CPCC07D487/04C07H7/06C07H1/00
Inventor 陈越磊何勇胡志刚何大荣杜小鹏钱祝进许良志江雨生产祝朋周玮婷
Owner 安徽诺全药业有限公司
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