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Preparation method of 5-deoxy-D-ribofuranose oxygen glycosides compound

A technology of ribofuranosides and compounds, which is applied to the preparation of sugar derivatives, chemical instruments and methods, and sugar derivatives, and can solve problems such as unstable quality control and difficult implementation

Active Publication Date: 2013-07-03
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the production process of this drug, multiple double glycosidation impurities will be produced. At present, the impurity compounds can only be obtained by separating the reaction solution, which is difficult to implement, and the quality control is unstable, and there is no public information about the double glycosidation of capecitabine. Synthesis of substances

Method used

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  • Preparation method of 5-deoxy-D-ribofuranose oxygen glycosides compound
  • Preparation method of 5-deoxy-D-ribofuranose oxygen glycosides compound
  • Preparation method of 5-deoxy-D-ribofuranose oxygen glycosides compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 2,3-two- O -Synthesis of tert-butyldimethylsilyl-5-deoxy-β-D-ribofuranose glucosinolate sugar donor

[0031] Dissolve 16g of tetraacetyl ribose and 6g of thiophenol in 100mL of dichloromethane, add BF dropwise under ice bath 3 -Et 2 O 2mL, after the addition was completed, the ice bath was removed to react for 4 hours, the reaction solution was washed with saturated sodium bicarbonate until neutral, the organic layer was separated and concentrated to obtain a yellowish oil. Disperse the oily substance in 250 mL of methanol, pass ammonia gas to saturation, react for 12 hours, evaporate the solvent under reduced pressure, and obtain a light yellow oily substance. Disperse the oil in 200mL of acetone, slowly add 1mL of concentrated sulfuric acid dropwise, and react at room temperature for 12 hours, add 10g of sodium bicarbonate, stir until the reaction solution is weakly alkaline, concentrate under reduced pressure, and dissolve the obtained residue in 200m...

Embodiment 2

[0033] Example 2 2'- O -Synthesis of tert-butyldimethylsilyl capecitabine

[0034] Take 3.6 g of capecitabine, dissolve it in 100 mL of anhydrous dichloromethane, add 1 g of imidazole and 2 g of tert-butyldimethylchlorosilane, stir for 1 hour, add water to terminate the reaction, separate the organic layer, and obtain 2'- O - tert-butyldimethylsilyl capecitabine 2.5g, yield 52.7%.

Embodiment 3

[0035] Example 3 3'-(5''-deoxy-2'',3''-di- O -tert-butyldimethylsilyl-β-D-ribose)-2'- O -tert-butyldimethylsilyl capecitabine and 3'-(5''-deoxy-2,3-di- O -tert-butyldimethylsilyl-α-D-ribose)-3'- O -Synthesis of tert-butyldimethylsilyl capecitabine

[0036] Take 2'- O - tert-Butyldimethylsilyl capecitabine 473 mg, 2,3-di- O - tert-butyldimethylsilyl-5-deoxy-β-D-ribofuranose glucosinolate sugar donor 680mg, N - Dissolve 520 mg of iodosuccinimide in anhydrous dichloromethane, add molecular sieves, stir for 2 hours under argon protection, add 100 mg of silver trifluoromethanesulfonate, continue stirring for 2 hours, add saturated sodium thiosulfate solution, Stir for 10 minutes, separate the layers, and perform column chromatography to obtain 3'-(5''-deoxy-2'',3''-di- O -tert-butyldimethylsilyl-β-D-ribose)-2'- O - tert-butyldimethylsilyl capecitabine 460mg, yield 56.3%; 3'-(5''-deoxy-2,3-di- O -tert-butyldimethylsilyl-α-D-ribose)-3'- O - tert-butyldimethylsilyl capec...

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Abstract

The invention relates to a preparation method of substances 3'-O-(5''-deoxy-beta-D-ribose) capecitabine and 3'-O-(5''-deoxy-alpha-D-ribose) capecitabine relative to capecitabine medicines used for antineoplastic effect, which solves the problem that the impurity generated during a capecitabine production process can be separated from a reaction solution. The method is characterized in that a 5-deoxy-D-ribose donor is prepared, and is subjected to a glycosylation reaction with capecitabine protected by silane, and a protective group is removed to prepare the target product. A double glycosylation related substance can be generated during the production process of capecitabine prepared by a chemical method, and the method provides a qualified reference substance for controlling the quality of capecitabine.

Description

technical field [0001] The invention relates to the fields of chemical industry and medicinal chemistry, and relates to a preparation method of 5-deoxy-D-ribofuranoside compounds, which can be applied to the synthesis of two related substances of double glycosidation produced in the production process of antineoplastic drug capecitabine . Background technique [0002] Capecitabine, trade name Xeloda, developed by Roche, Switzerland, is clinically used for the further treatment of paclitaxel and chemotherapy regimens including anthracyclines ineffective for advanced primary or metastatic breast cancer. During the production process of this drug, multiple double glycosidation impurities will be produced. At present, the impurity compounds can only be obtained by separating the reaction solution, which is difficult to implement, and the quality control is unstable, and there is no public information about the double glycosidation of capecitabine. Methods of synthesis of substa...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
CPCY02P20/55
Inventor 刘洋程卯生王博王晶晶
Owner SHENYANG PHARMA UNIVERSITY
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