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A kind of preparation method of telbivudine

A telbivudine and weighing technology is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc. The effect of stable physical and chemical properties, easy operation and high yield

Active Publication Date: 2019-10-25
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As we all know, pyridine is very toxic to the human body and is easy to pollute the environment, which is easy to cause health problems and pollution incidents. However, when using toluenesulfonyl chloride as a raw material, the production operation is complicated and difficult, and it is easy to degrade and deteriorate, which affects the quality of the product

Method used

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  • A kind of preparation method of telbivudine
  • A kind of preparation method of telbivudine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1): Weigh 10g thymine, add 50ml dimethyl sulfoxide at room temperature, add 15g hexamethyldisilazane (HMDS), heat to 60-70°C for 28 hours, cool to 0-5°C and store in in the reaction vessel for use.

[0044] 2): Weigh 24g (2S,3R)-5-chloro-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl)4-methylbenzoate, Divide into four portions, namely 6g each. Add a portion of the weighed material every 10 minutes, and keep warm at 20-25°C for 12 hours after adding. At the end of the timing, slowly add 200g of saturated NaHCO 3 solution, stirred until the solution was a milky white suspension, and then filtered. The filtrate was concentrated under reduced pressure at 70°C to obtain a viscous mixture containing a large amount of compound B.

[0045]3): Take 120ml of methanol and add it to the concentration container in the previous step, take 1.6g of sodium ethoxide and add it, stir and heat up to 50-60°C for 18 hours, add 40g of cation exchange resin, and keep stirring for 30 ...

experiment example 2

[0048] 1): Weigh 10g thymine, add 70ml dimethylformamide at room temperature, add 18g hexamethyldisilazane (HMDS), heat to 80-90°C for 26 hours, cool to 0-5°C and store in in the reaction vessel for use.

[0049] 2): Weigh 24g (2S,3R)-5-chloro-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl)-4-methylbenzoate , are equally divided into four portions, that is, each portion is 6g. Add a portion of the weighed material every 10 minutes, and keep warm at 25-35°C for 10 hours after adding. Slowly add 220g of saturated NaHCO at the end of the timer 3 solution, stirred until the solution was a milky white suspension, and then filtered. The filtrate was concentrated under reduced pressure at 70°C to obtain a viscous mixture containing a large amount of compound B.

[0050] 3): Take 130ml of absolute ethanol and add it to the concentration container in the previous step, take 1.7g of sodium ethoxide and add it, stir and heat up to 65-75°C for 16 hours, add 42g of cation exchang...

experiment example 3

[0053] 1): Weigh 10g thymine, add 80ml N'N-diethylformamide at room temperature, add 19g hexamethyldisilazane (HMDS), heat to 90-100°C for 26 hours, reduce to 0-5 °C and stored in a reaction vessel until use.

[0054] 2): Weigh 24g (2S,3R)-5-chloro-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-methylbenzoate, Divide into four portions, ie 6g each. Add one portion of the weighed material every 10 minutes, and keep warm at 35-40°C for 8 hours after adding. Add 230g saturated NaHCO at the end of timing 3 solution, stirred until the solution was a milky white suspension, and then filtered. The filtrate was concentrated under reduced pressure at 70°C to obtain a viscous mixture containing a large amount of compound B.

[0055] 3): Take 140ml of isopropanol and add it to the concentration container in the previous step, take 1.7g of sodium ethoxide and add it, stir and heat up to 75-85°C for 14 hours, add 45g of cation exchange resin, and keep stirring for 50 minutes. ...

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Abstract

The invention provides a preparation method of telbivudine, wherein the method comprises the following steps: 1) adding thymine and hexamethyl disilylamine to an organic solvent, and carrying out a reaction, wherein the organic solvent comprises one of dimethyl sulfoxide, N,N-dimethylformamide, and N,N-diethyl formamide; 2) adding (2S,3R)-5-chloro-2-(((4-methyl benzoyl)oxo)methyl)tetrahydrofuran)-3-yl)-4-methyl benzoate, carrying out a reaction, adding an NaHCO3 solution, stirring and filtering, and carrying out reduced pressure concentration on the filtrate; and 3) adding an alcohol solvent, then adding sodium ethoxide, carrying out a reaction, adding cation exchange resin, and carrying out heat preservation stirring; and cooling and filtering, concentrating the filtrate until a solid is precipitated, and crystallizing, to obtain a telbivudine crude product. The adopted reagents and raw materials both have low toxicity; the method has the advantages of simple preparation process, mild reaction conditions, easy operation, stable physical and chemical properties of the raw materials, fewer by-products and high yield.

Description

technical field [0001] The invention belongs to the field of preparation of telbivudine, and in particular relates to a preparation method of telbivudine with low reagent toxicity, easy process operation and high yield. Background technique [0002] Telbivudine is a hepatitis B treatment drug developed by Novartis for the treatment of chronic hepatitis B with evidence of viral replication and persistently elevated serum transaminases (ALT or AST) or evidence of active liver tissue lesions. [0003] Traditional preparation methods, such as US6395716 and WO2001034618, not only have many steps in the preparation process and expensive reagents, but also have unsatisfactory yields. [0004] In the prior art, although a process with shorter steps and better yield has been produced, it is often necessary to use pyridine as a reaction solvent and p-toluenesulfonyl chloride as a raw material in the preparation process, such as CN200810121107. As we all know, pyridine is very toxic t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H1/00C07H1/06
Inventor 庹世川冷盛东黄耀宗王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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