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Preparation method of cytidine and cytidine derivatives

A technology of cytidine nucleosides and derivatives, which is applied in the field of compound preparation, can solve the problems of product purity, incomplete matching of acidity, etc., and achieve the effects of environmental friendliness, simple operation, and simple post-treatment

Inactive Publication Date: 2013-09-11
上海新浦特种助剂有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

When a single Lewis acid is used, due to the special requirement for acidity in the synthesis of cytidine, a single tin tetrachloride, trimethylsilyl trifluoromethanesulfonate, and trimethylsilyl perfluorobutanesulfonate all have acidic The problem of incomplete matching will lead to the generation of isomeric intermediate σ-complex, which will lead to the generation of isomeric product N(3)-nucleoside, which will affect the purity of the product

Method used

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  • Preparation method of cytidine and cytidine derivatives
  • Preparation method of cytidine and cytidine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Preparation of Compound III

[0028] Under the protection of nitrogen, add 11g of cytosine to 65ml of hexamethyldisilazane, and add 0.01g of ammonium sulfate, heat up and reflux until the solution is clear, continue to keep warm for 4 hours, cool down to room temperature, and concentrate under reduced pressure to remove excess hexamethyldisilazane. Methyldisilazane to give compound Ⅲ as a white solid.

Embodiment 2

[0029] Example 2 Preparation of Compound I

[0030] N 2 Under protection, add 100ml 1,2-dichloroethane to compound III, make it dissolve completely, add fluorine-containing composite catalyst (TMSOTf:Sncl 4 =5:1) 1.28g, add dropwise 5.3g (0.0125mol) 2-deoxy-D-ribofuran-3,5-di-O-benzoyl-methanesulfonate compound (compound Ⅱ) in 20ml 1, 2-dichloroethane solution, after the dropwise reaction, raise the temperature and reflux until the raw material disappears (about 7h). Cool down to room temperature, add 100ml of ice water dropwise, continue stirring for 30 minutes after the dropwise addition, filter with suction, and wash the filter cake twice with 1,2-dichloroethane. The organic phase was concentrated to obtain 4.9 g of the target compound I with a HPLC purity of 96.5% (α:β=1:1.5).

Embodiment 3

[0031] Example 3 Preparation of Compound I

[0032] N 2 protection, add 100ml xylene to compound III obtained in Example 1, make it dissolve completely, add fluorine-containing composite catalyst (TMSOTf: trimethylsilyl perfluorobutanesulfonate: Sncl 4 =0.5:0.5:2) 3.8g, add dropwise 4.86g 2-deoxy-3,5-di-oxo-p-toluoyl-D-ribofuran-1-chloride (compound Ⅱ) (α:β=1:1 ) of 20ml xylene solution, after the drop, the temperature was raised to reflux until the raw material disappeared (about 5h). Cool down to room temperature, add 65ml of ice water dropwise, continue stirring for 30 minutes after the dropwise addition, filter with suction, and wash the filter cake twice with 1,2-dichloroethane. The organic phase was concentrated and dried to obtain 4.9 g of the target compound I with a HPLC purity of 96.6% (α:β=1.4:1).

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Abstract

The invention discloses a preparation method of cytidine and cytidine derivatives. The preparation method is characterized in that compounds II and compounds III are utilized as raw materials; fluoride compound catalysts are utilized to perform catalysis in organic solvent; and reaction is performed for 5 to 48 hours under 50 to 200 DEG C to obtain the cytidine namely compounds I. The preparation route includes that L is selected from any of halogens, C1 - C4 alkane acyl, C1 - C4 alkane sulfonyl oxygen radicals, aryl sulfonyl oxygen radicals, substitutional alkyl sulfonyl oxygen radicals or substitutional aryl sulfonyl oxygen radicals; P is H or - OR1; R1, R2 and R3 which are hydroxyl protection radicals are selected from any of C1 - C4 alkane acyl radicals, aryl formyl radicals or substitutional aryl formyl radicals respectively; and R4 which is silicon protection radicals is selected from any of C1 - C7 trialkyl silicon radicals. The preparation method of the cytidine and the cytidine derivatives has the advantages of enabling expensive catalysts to be abandoned, reducing the costs, being mild in reaction condition and simple in post-processing, enabling reagents to be conveniently recycled and being environmentally friendly, simple and convenient to operate and suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation process of a compound, in particular to a method for chemically preparing cytidine (abbreviated as cytidine) and its derivatives. Background technique [0002] Cytidine nucleoside and its analogs are mainly used in the production of intermediates of anti-tumor and anti-viral drugs, and are used for the manufacture of cytarabine (Ara-CR), cyclocytidine (Cyclo C), cytidine triphosphate (CTP), The main raw material of drugs such as citicoline (CDP-Choline). The development of cytidine products can provide sufficient raw materials for a series of cytidine drugs and biochemical reagents, and play a certain role in promoting the development of genetic engineering and pharmaceutical industry. [0003] In the chemical synthesis of cytidine and its analogues, glycosylation is an important step in the synthesis process. [0004] European patent EP 0136693 reports the preparation of cytidine and its derivatives by ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00
CPCY02P20/55
Inventor 苏莹赵敏盛荣杰
Owner 上海新浦特种助剂有限公司
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