Method for synthesizing 5-((E)-2-bromovinyl)-2'-deoxyuridine (brivudine)

Abstract

The invention discloses a method for synthesizing 5-((E)-2-bromovinyl)-2'-deoxyuridine (brivudine). The method comprises the following steps of: performing condensation reaction on 5-formoxyl-3',5'-diacetoxy-2'-deoxyuridine which is taken as a raw material and carbon tetrabromide to obtain 5-(2,2-dibromovinyl)-3',5'-diacetoxy-2'-deoxyuridine, and stereoselectively removing one bromine atom and an acetyl protective group under alkaline conditions; and after the reaction is finished, extracting, concentrating and performing column chromatography to obtain the 5-((E)-2-bromovinyl)-2'-deoxyuridine (brivudine). The synthetic route is short, the selectivity and the reaction efficiency are high, and the method is convenient to operate. Required raw materials are readily available, a used reagent is safe, the reaction process is simple and practicable, and the method is favorable for industrialized production.

Description

technical field

[0001] The present invention relates to the fields of synthetic chemistry and medicine, and mainly relates to a synthetic antiviral drug——5-((E)-2-bromovinyl)-2′-deoxyuridine (BVDU, bromofuridine) method Background technique

[0002] 5-((E)-2-bromovinyl)-2′-deoxyuridine (sniffuridine), can effectively inhibit the herpes simplex virus (HSV-1) and varicella-zoster virus (VZV) Replication, clinically used for skin and mucous membrane infection caused by HSV-1 and VZV, it is currently the most active pyrimidine nucleoside derivative against HSV-1. Bromfuridine can undergo a series of phosphorylation under the catalysis of viral thymidine kinase, and finally form bromfuridine triphosphate. Bromfuridine triphosphate can inhibit virus replication by interacting with viral DNA polymerase. Since the phosphorylation process of bromfuridine is only carried out in virus-infected cells, its antiviral effect is highly selective.

[0003] At present, there are three ma...

Examples

Embodiment Construction

[0014] In a 50 mL reaction flask, add triphenylphosphine (0.262 g, 1 mmol), zinc powder (0.065 g, 1 mmol) and dichloromethane in sequence, and stir at room temperature to dissolve triphenylphosphine. A dichloromethane solution of carbon tetrabromide (0.332 g, 1 mmol) was then added dropwise to the above system. After stirring at room temperature for 2 h, the reaction flask was placed in an ice-water bath, and 5-formyl-3′,5′-diacetoxy-2′-deoxyuridine (0.1711 g, 0.5 mmol) in dichloromethane solution, and then stirred at room temperature for about 1.5h. Suction filtration to remove solid impurities. The filtrate was washed with water, dried and concentrated under reduced pressure, the residue was dissolved in DMF, and then diethyl phosphite (0.276g, 2mmol) and triethylamine (0.228g, 2.25mmol) were added successively to the system; Stir the reaction in an oil bath at 70°C for about 12 hours, and TLC detects that the reaction is complete. Add an appropriate amount of water to di...

technical field

[0001] The present invention relates to the fields of synthetic chemistry and medicine, and mainly relates to a synthetic antiviral drug——5-((E)-2-bromovinyl)-2′-deoxyuridine (BVDU, bromofuridine) method Background technique

[0002] 5-((E)-2-bromovinyl)-2′-deoxyuridine (sniffuridine), can effectively inhibit the herpes simplex virus (HSV-1) and varicella-zoster virus (VZV) Replication, clinically used for skin and mucous membrane infection caused by HSV-1 and VZV, it is currently the most active pyrimidine nucleoside derivative against HSV-1. Bromfuridine can undergo a series of phosphorylation under the catalysis of viral thymidine kinase, and finally form bromfuridine triphosphate. Bromfuridine triphosphate can inhibit virus replication by interacting with viral DNA polymerase. Since the phosphorylation process of bromfuridine is only carried out in virus-infected cells, its antiviral effect is highly selective.

[0003] At present, there are three ma...

Examples

Embodiment Construction

[0014] In a 50 mL reaction flask, add triphenylphosphine (0.262 g, 1 mmol), zinc powder (0.065 g, 1 mmol) and dichloromethane in sequence, and stir at room temperature to dissolve triphenylphosphine. A dichloromethane solution of carbon tetrabromide (0.332 g, 1 mmol) was then added dropwise to the above system. After stirring at room temperature for 2 h, the reaction flask was placed in an ice-water bath, and 5-formyl-3′,5′-diacetoxy-2′-deoxyuridine (0.1711 g, 0.5 mmol) in dichloromethane solution, and then stirred at room temperature for about 1.5h. Suction filtration to remove solid impurities. The filtrate was washed with water, dried and concentrated under reduced pressure, the residue was dissolved in DMF, and then diethyl phosphite (0.276g, 2mmol) and triethylamine (0.228g, 2.25mmol) were added successively to the system; Stir the reaction in an oil bath at 70°C for about 12 hours, and TLC detects that the reaction is complete. Add an appropriate amount of water to di...

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