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Process for the preparation of β-thymidine

A thymidine and buffer system technology, applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of low yield of β-thymidine, easy breakage of glycosidic bonds, poor purity, etc.

Active Publication Date: 2016-09-21
SHANGHAI DESANO PHARMA INVESTMENT +1
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0011] The above two processes have the same disadvantages: in the reaction, it is found that the glycosidic bonds of the reaction substrate and the reaction product are easily broken, and there are 10-15% of the by-product thymine in the reaction product.
Therefore, the obtained β-thymidine yield is not high, and the purity is not good

Method used

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  • Process for the preparation of β-thymidine
  • Process for the preparation of β-thymidine
  • Process for the preparation of β-thymidine

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preparation example Construction

[0065] Preparation method of β-thymidine

[0066] The preparation method of β-thymidine according to the present invention comprises the steps of: in a hydrogen atmosphere, in the presence of a catalyst, at a certain temperature (20-60°C, preferably 20-40°C), at a pH of 6.5- In the buffer system of 8.0, the compound represented by formula II is dehalogenated for a period of time (such as 2-20 hours, preferably 5-10 hours), so as to obtain β-thymidine represented by formula I;

[0067]

[0068] Wherein, X is Cl or Br.

[0069] In another preferred example, the dehalogenation reaction is carried out under normal pressure, that is to say, the pressure of the hydrogen atmosphere is the gas pressure produced by the atmosphere we usually live in, which is about a standard atmospheric pressure (101.325KPa) .

[0070] In another preferred example, the pH of the buffer system is 7.0-8; more preferably 7.0-7.6.

[0071] In another preferred embodiment, when the dehalogenation reac...

Embodiment 1

[0097] Preparation of 2,2'-anhydrothymidine:

[0098] Add DMF 100mL, 5-methyluridine (50.0g, 0.19mol), sodium hydroxide (0.18g, 4.4mmol) and diethyl carbonate (46mL, 0.38mol) into the reaction flask, heat up to 120°C, keep warm The reaction was stirred for 8 hours. It was detected by TLC that the reaction of the raw materials was complete, and the temperature was lowered to room temperature, and the pH value was adjusted to neutrality (about 7.0) with 30% ethanol hydrochloric acid solution, and concentrated to dryness. Add 50 mL of ethyl acetate to the concentrate and reflux for beating for 1 hour, cool down to room temperature, filter, collect the solid, and dry the solid under vacuum at 60°C to obtain the title compound (white solid, 44.5 g), with a molar yield of 95.6% and an HPLC purity of 98.2%. MS (ESI) m / z: (M+H) 241.2, (M+Na) 263.2.

Embodiment 2

[0100] Preparation of 2'-bromothymidine:

[0101] Add 16% hydrogen bromide DMF solution (119.3g, 0.24mol) into the reaction flask, add 2,2'-dehydrothymidine (44.5g, 0.18mol) under stirring, and heat up to 40°C for 2 hours. Add 16% hydrogen bromide DMF solution (27.5 g, 0.054 mol) and continue to keep warm for 2 hours. TLC detected that the reaction of the raw materials was complete, and the DMF was distilled off under reduced pressure to obtain a viscous oily bromide, which was directly put into the next reaction. MS (ESI) m / z: (M+H) 322.2, (M+Na) 344.2.

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Abstract

The invention relates to a preparation method of beta-thymidine, and specifically discloses a method of preparing beta-thymidine from the formula II compound. The method comprises following steps: subjecting the compound represented as the formula II to carry out dehalogenation reactions, in a hydrogen atmosphere, in the presence of a catalyst, and in a buffer system with a pH value of 6.5 to 8.0, so as to obtain beta-thymidine represented as the formula I, wherein X represents Cl or Br. The dehalogenation reactions are carried out under atmospheric pressure, and the preparation method has the advantages of environment-friendliness, economy, high product yield, good product purity, and suitability for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a method for preparing β-thymidine. Background technique [0002] Zidovudine is the world's first anti-AIDS drug approved by the US FDA. Because of its definite curative effect, it has become the most basic component of the "cocktail" therapy. The chemical name of Zidovudine (AZT) is 3'-Azide-3'-deoxythymidine, and its structural formula is shown below. [0003] [0004] β-thymidine is a key intermediate in the preparation of zidovudine. At present, the synthesis process of β-thymidine mostly adopts chemical synthesis method. Among them, the following synthetic route reported in CN1055293C and "Pharmaceutical Progress" (2005, 29(7), 327-331) has been applied in production. [0005] [0006] This route requires repeated protection and deprotection steps for hydroxyl groups, high raw material costs, uneconomical industrial production, and more waste ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H1/00
Inventor 李金亮赵楠吴俊
Owner SHANGHAI DESANO PHARMA INVESTMENT
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