Preparation method of beta-thymidine

A technology of thymidine and equation, applied in the field of preparation of β-thymidine, can solve the problems of lack of stereospecificity of β-thymidine reaction, low utilization rate of raw materials, complicated separation process, etc., and achieve low cost, high cost and high product quality The effect of high purity

Active Publication Date: 2011-06-08
ZHEJIANG XIANFENG TECH
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Problems solved by technology

[0003] The early chemical method of synthesizing β-thymidine lacked stereospecificity, and a certain amount of α-isomer was generated while generating β-thymidine, which made the utilization rate of raw materials low, the separation process was complicated, and the cost was greatly increased.
In 1998, someone proposed a relatively complete method for preparing β-thymidine: using 5-methyluridine to synthesize β-thymidine through halogenation-acylation, catalytic hydrogenation and alcoholysis (CN1055293), although the reaction has stereospecificity Uniformity, but the yield is not very high

Method used

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  • Preparation method of beta-thymidine
  • Preparation method of beta-thymidine

Examples

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Effect test

Embodiment 1

[0026] Example 1 Add 25.8g of 5-methyluridine (0.1mol) and 25.7g of diphenyl carbonate (0.12mol) into 60ml of MDAC, start stirring and raise the temperature to 90°C, after the solid dissolves, add 1g of NaOH to reflux After keeping for 1 hour, after using TCL to measure the absence of raw materials, the solvent was distilled off under reduced pressure under cooling. After the distillation, cooling crystallized and filtered to obtain 21.9 g of intermediate (II) in the form of colorless crystal powder, with a yield of 94%.

[0027] In this embodiment, diphenyl carbonate is replaced with dimethyl carbonate, diethyl carbonate, dipropyl carbonate or dibutyl carbonate; the solvent is replaced with one or more mixed solvents in DMF, MDAC or acetonitrile MDAC, using KOH instead of NaOH, can achieve the above effects.

Embodiment 2

[0028] Example 2 Add 25.8g of 5-methyluridine (0.1mol) and 32.1g of diphenyl carbonate (0.15mol) into 60ml of DMF, start stirring and raise the temperature to 90°C, after the solid dissolves, add 1.5g of KOH to reflux After heat preservation for 2 hours, after no raw material was determined by TCL, the solvent was distilled off under reduced pressure under cooling, crystallized by cooling after distillation, and filtered to obtain 22.1 g of intermediate (II) in the form of colorless crystal powder, with a yield of 95%.

Embodiment 3

[0029] Example 3 Add 25.8g of 5-methyluridine (0.1mol) and 10.8g of dimethyl carbonate (0.12mol) into 50ml of DMF, start stirring and raise the temperature to 120°C, after the solid dissolves, add 1g of KOH to keep it under reflux After 3 hours, after no raw materials were measured with TCL, the solvent was distilled off under reduced pressure under cooling. After the distillation, cooling crystallized and filtered to obtain 22.1 g of colorless crystal powdery intermediate (II), with a yield of 95%.

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Abstract

The invention provides a preparation method of beta-thymidine, belonging to the technical field of fine chemical industry. The preparation method is as follows: reacting 5-methyl uridine used as a raw material with dialkyl carbonate (RO)2CO for dehydration; generating halogenation reaction with a halogenation reagent; and finally, carrying out catalytic hydrogenation by reducing metal so as to prepare the beta-thymidine. The synthesis process is simple, and the cost is low; and only twice separations and purifications are carried out, thereby greatly reducing labor intensity and avoiding the defects that propionyl bromide is used, cost is high, yield is low, and equipment corrosion is severe in the original halogenation reaction process. By using a novel halogenation reaction system, raw material cost is reduced, conversion rate is high, yield is up to above 85%, the purity of the product is high, and high-performance liquid chromatography (HPLC) is larger than 99.8%.

Description

technical field [0001] The invention belongs to fine chemical technology, and in particular relates to a method for preparing β-thymidine with 5-methyluridine as a starting material. Background technique [0002] β-Thymidine, also known as Deoxythymidine, is the key intermediate of Zidovudine and Stavudine, which are used to treat AIDS, and there is no natural product. At present, artificial preparation methods include biosynthesis and chemical synthesis. Biosynthesis methods (including DNA enzymatic hydrolysis, fermentation, and enzymatic methods) require high production conditions and equipment, and are expensive. At present, the preparation of β-thymidine is mainly based on chemical synthesis. [0003] The early chemical methods for synthesizing β-thymidine lacked stereospecificity, and a certain amount of α-isomer was generated while generating β-thymidine, which made the utilization rate of raw materials low, the separation process was complicated, and the cost was gr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00
Inventor 高飞飞赫英志李凤林戴晓楠
Owner ZHEJIANG XIANFENG TECH
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