Preparation method of dinucleotide prodrug

A technology of dinucleotides and dinucleosides, which is applied in the field of preparation of dinucleotide prodrugs, can solve the problems of inability to meet the Ribinski standard and the like

Active Publication Date: 2019-11-19
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In fact, dinucleotide prodrugs are compounds with relatively high molecular weight a

Method used

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  • Preparation method of dinucleotide prodrug
  • Preparation method of dinucleotide prodrug
  • Preparation method of dinucleotide prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] The synthetic method of embodiment 1 compound BG001:

[0133]

[0134]

[0135] Step 1: Preparation of intermediate NB-08

[0136] Add SM1 (50g, 0.1284mol), 500mL of dichloromethane, and Molecular sieve 50g. It was then stirred for 1 h under nitrogen protection. Trimethylsilyl trifluoromethanesulfonate (30ml, 0.1658mol) was slowly added dropwise to the reaction solution under an ice-water bath, and the reaction was refluxed for 40h after the dropwise addition was completed. The reaction solution was brown-black. After TLC monitors that the reaction is complete, it is lowered to room temperature, and triethylamine is added dropwise until neutral. After filtering, the filtrate was extracted and washed with ice water (3×300ml), and the aqueous layer was discarded. The organic layer was dried over anhydrous sodium sulfate, stirred for 1 h, and filtered. The filtrate was stirred and dried with anhydrous sodium sulfate for 1-2 hours. Filter to obtain a dichlorom...

Embodiment 2

[0162] Embodiment 2: Compound BG002 synthetic method

[0163]

[0164]

[0165] Step 1: Preparation of intermediate NB-08

[0166] Add SM1 (50g, 0.1284mol), 500mL of dichloromethane, and Molecular sieve 50g. It was then stirred for 1 h under nitrogen protection. Trimethylsilyl trifluoromethanesulfonate (30ml, 0.1658mol) was slowly added dropwise to the reaction solution under an ice-water bath, and the reaction was refluxed for 40h after the dropwise addition was completed. The reaction solution was brown-black. After TLC monitors that the reaction is complete, it is lowered to room temperature, and triethylamine is added dropwise until neutral. After filtering, the filtrate was extracted and washed with ice water (3×300ml), and the aqueous layer was discarded. The organic layer was dried over anhydrous sodium sulfate, stirred for 1 h, and filtered. The filtrate was stirred and dried with anhydrous sodium sulfate for 1-2 hours. Filter to obtain a dichloromethane ...

Embodiment 3

[0186] The preparation of embodiment 3 compound BG003

[0187]

[0188] Step 1: Preparation of intermediate NB-08

[0189] Add SM1 (50g, 0.1284mol), 500mL of dichloromethane, and Molecular sieve 50g. It was then stirred for 1 h under nitrogen protection. Trimethylsilyl trifluoromethanesulfonate (30ml, 0.1658mol) was slowly added dropwise to the reaction solution under an ice-water bath, and the reaction was refluxed for 40h after the dropwise addition was completed. The reaction solution was brown-black. After TLC monitors that the reaction is complete, it is lowered to room temperature, and triethylamine is added dropwise until neutral. After filtering, the filtrate was extracted and washed with ice water (3×300ml), and the aqueous layer was discarded. The organic layer was dried over anhydrous sodium sulfate, stirred for 1 h, and filtered. The filtrate was stirred and dried with anhydrous sodium sulfate for 1-2 hours. Filter to obtain a dichloromethane solution of...

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Abstract

The present invention provides a preparation method of a dinucleotide prodrug with a novel structure, and an application of the dinucleotide prodrug in preparing medicines for treating viral infection, particularly hepatitis B virus (HBV) infection and liver diseases associated with the HBV. With the dinucleoside precursor compounds, the targeting ability in the liver is significantly improved, the accumulation ability in the liver part is improved also, further the pharmacological activity is effectively improved, the use dosage is also reduced, and thus the toxic and side effects are reduced. The dinucleotide prodrug is high in oral bioavailability, and has good stability in the stomach and long half-life period in body. The provided preparation method of the dinucleotide prodrug is simple, purification is not needed after completion of reactions in multiple steps, a next reaction can be directly conducted, and operation steps are simplified.

Description

technical field [0001] The invention relates to a preparation method of a novel dinucleotide prodrug and its application in the preparation of a medicine for treating viral infection, especially hepatitis B virus (HBV) infection and liver disease related to HBV. Background technique [0002] Hepatitis B is one of the diseases with the greatest social burden in our country. At present, about 100 million people in my country are hepatitis B virus carriers, accounting for about 8%-10% of the total population in my country, and there are about 20 million people with chronic hepatitis B (inflammatory lesions have appeared in the liver). It is estimated that there are 350 million chronic HBV carriers worldwide. According to the Centers for Disease Control, approximately 3 to 7 million people die each year from infection-related complications such as cirrhosis and hepatocellular carcinoma. A large number of patients undergoing liver transplantation also continue to require anti-H...

Claims

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Application Information

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IPC IPC(8): C07H21/04C07H1/00A61P31/20A61K31/7084
CPCC07H21/04C07H1/00A61P31/20Y02P20/55
Inventor 袁建栋刘平林祥义孙占莉丁海峰王叶亭
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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