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Synthetic method of entecavir intermediate

A synthesis method and compound technology, applied in the field of medicine, can solve the problems of serious environmental pollution, low yield, large dosage, etc., and achieve the effects of good atom economy, high product yield and less solid waste.

Active Publication Date: 2020-01-21
LUOXIN PHARM SHANGHAI CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

TiCl 4 The yield as Lewis acid is low, and TiCl 4 The amount of the waste is relatively large, resulting in a large amount of waste solids in the post-processing, the post-processing operation is cumbersome, the utilization rate of atoms is low, the environmental pollution is serious, and it is not suitable for industrial production

Method used

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  • Synthetic method of entecavir intermediate
  • Synthetic method of entecavir intermediate
  • Synthetic method of entecavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Ti(OiPr) at room temperature 4 (0.2eq) Slowly add TiCl dropwise 4 (0.2eq) in dichloromethane solution (2V), add and stir at room temperature for 1h (standby); add Nysted (4.0eq) tetrahydrofuran solution into the reaction flask (nitrogen protection), cool to -75°C, Slowly add the above-mentioned Ti ligand mixed solution to the system dropwise, keep the temperature of the system not higher than -65°C, after the addition is completed, keep the reaction for 4 hours, and at the same time dissolve N6 (1.0eq) in tetrahydrofuran (2V), Slowly add it dropwise to the system, keep the system temperature at -65°C, after the addition is complete, return to room temperature under nitrogen protection until the end of the reaction, filter with diatomaceous earth, extract, combine the filtrates, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the target product N7 (HPLC: greater than 98.5%, yield: 67%).

[0030] 1HNMR (400MHz, CDCl 3 ):7.86...

Embodiment 2

[0033] Ti(OiPr) at room temperature 4 (0.2eq) Slowly add TiCl dropwise 4 (0.8eq) in dichloromethane solution (6V), add and stir at room temperature for 2h (standby); add Nysted (4.0eq) tetrahydrofuran solution into the reaction flask (nitrogen protection), cool to -70°C, Slowly add the above-mentioned Ti ligand mixed solution to the system dropwise, keep the system temperature at -60°C, after the addition is complete, keep it warm for 1 hour, and at the same time dissolve N6 (1.0eq) in tetrahydrofuran (4V), and slowly add it dropwise In the system, keep the temperature of the system at -60°C. After the addition is complete, return to room temperature under nitrogen protection until the end of the reaction, filter with diatomaceous earth, extract, combine the filtrates, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the target product N7 (HPLC: Greater than 98.5%, yield: 90%).

[0034] 1HNMR (400MHz, CDCl 3 ):7.86(s,1H),7.41-7.31...

Embodiment 3

[0037] Ti(OiPr) at room temperature 4 (0.2eq) Slowly add TiCl dropwise 4 (1.2eq) in dichloromethane solution (10V), add and stir at room temperature for 4h (standby); add Nysted (4.0eq) tetrahydrofuran solution into the reaction flask (nitrogen protection), cool to -70°C, Slowly add the above-mentioned Ti ligand mixed solution to the system dropwise, keep the system temperature at -70°C, after the addition is complete, keep it warm for 2 hours, and at the same time dissolve N6 (1.0eq) in tetrahydrofuran (8V), and slowly add it dropwise In the system, keep the temperature of the system at -70°C, after the addition is complete, return to room temperature under nitrogen protection until the reaction is complete, filter with diatomaceous earth, extract, combine the filtrates, concentrate under reduced pressure to dryness, and purify by column chromatography to obtain the target product N7 (HPLC: Greater than 98.5%, yield: 75%).

[0038] 1HNMR (400MHz, CDCl 3):7.86(s,1H),7.41-7....

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Abstract

The invention relates to a synthetic method of an entecavir intermediate. In particular, the present invention relates to the synthesis of compounds represented in the formula N7 by using TiCl4 and Ti(OiPr)4 as Lewis acids.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for synthesizing an entecavir intermediate. Background technique [0002] As an important class of compounds, nucleotide analogues have received extensive attention in the field of medicinal chemistry. Research related to it has produced a large number of important drugs, especially in the field of antiviral drugs. A considerable number of anti-AIDS drugs and anti-hepatitis B drugs have benefited from in-depth research in this field. [0003] There are 350 million to 400 million hepatitis B virus (HBV) infected people in the world, and nearly 1 million patients die of liver cirrhosis and liver cancer caused by HBV infection every year. There are more than 120 million HBV infections in my country, accounting for more than 1 / 3 of the world's total, ranking first in the world, and 30 million patients with chronic hepatitis B (hepatitis B), and this number is currently on...

Claims

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Application Information

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IPC IPC(8): C07D473/18
CPCC07D473/18
Inventor 唐伟高风明王振宇杨文谦王铁林
Owner LUOXIN PHARM SHANGHAI CO LTD