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Novel synthesis method of capecitabine key intermediate 1,2,3-O-triacetyl-5-deoxy-D-ribose

A technology of triacetyl and a new method, which is applied in the fields of chemical industry and medicinal chemistry, can solve the problems of high acetylation temperature, difficulty in crystallization, and many by-products, and achieve the effect of high product purity, fast reaction speed, and few by-products

Inactive Publication Date: 2015-05-27
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this method are: the cost of iodine / imidazole / triphenylphosphine system is high, and the acetylation temperature is high, there are many by-products, and it is difficult to crystallize

Method used

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  • Novel synthesis method of capecitabine key intermediate 1,2,3-O-triacetyl-5-deoxy-D-ribose

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]During the preparation of 1-methyl-2,3-O-methoxymethylene-D-ribofuranose, D-ribose (10.0 g, 66.7 mmol ), methyl orthoformate (2.5ml, 22.23mmol), p-toluenesulfonic acid (0.2g), stirred at 26-30°C for 4 h, tracked by TLC and liquid chromatography. After the reaction, the pH was adjusted to 8-9 with sodium carbonate, filtered, washed with dichloromethane and water, and the organic phase was rotary evaporated to obtain an oily substance, which was dried to obtain 19.7 g of white crystals with a yield of 85%. The purity by liquid chromatography test was 99.8%.

Embodiment 2

[0034] During the preparation of 1-methyl-2,3-O-methoxymethylene-D-ribofuranose, D-ribose (10.0 g, 66.7 mmoL ), methanol (50 ml), acetone (75 ml), concentrated hydrochloric acid (2.5 ml), stirred at room temperature for 19 h, followed by TLC and liquid chromatography. After the reaction, the pH was adjusted to 8-9 with sodium carbonate, filtered, washed with dichloromethane and water, and the organic phase was rotary evaporated to obtain an oily substance, which was dried to obtain 10.3 g of white crystals with a yield of 43.09%. The purity by liquid chromatography was 95%.

Embodiment 3

[0036] During the preparation of 1-methyl-2,3-O-methoxymethylene-5-O-tosyl-D-ribofuranose, add In the first step, protect the intermediate product of the reaction, then add 11.5 ml triethylamine, 0.5 g DMAP, weigh 75 ml dichloromethane, 12.5 g p-toluenesulfonyl chloride, dissolve p-toluenesulfonyl chloride with dichloromethane and drop into the reaction solution Add, ice-salt bath treatment, keep the temperature at about 5°C, and finish adding dropwise in 1 hour. An appropriate amount of triethylamine was added to keep the reaction conditions alkaline. After reacting for 12 h, wash with water and refine with isopropanol. The yield is 83%.

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Abstract

The invention discloses a novel synthesis method of a capecitabine key intermediate 1,2,3-O-triacetyl-5-deoxy-D-ribose. The synthesis method is characterized by comprising the following steps: reacting D-ribose which serves as an initial raw material with triethyl orthoformate under the catalytic action of acid, and realizing 2nd-site, 3rd-site and 4th-site hydroxyl protection in one step so as to obtain an intermediate product, namely 1-methyl-2,3-O-methoxymethylene-D-ribofuranose, and carrying out such steps as p-tosylation, hydrogenation reduction, deprotection and acylation so as to realize a new synthesis route of a target compound, namely 1,2,3-O-triacetyl-5-deoxy-D-ribose. The total yield of the route is 60% and product purity is 99.5%. The method disclosed by the invention has the advantages of original route design, high yield, good product purity, low production cost, safe and convenient operation, easy industrial production in a large scale and the like.

Description

technical field [0001] The invention belongs to the fields of chemical industry and pharmaceutical chemistry, and in particular relates to a new method for synthesizing 1,2,3-O-triacetyl-5-deoxy-D-ribose, a key intermediate of capecitabine. Background technique [0002] Capecitabine (Capecitabine) is an oral 5-fluorouracil (5-Fluorouracil, 5-FU) anti-tumor prodrug developed by Roche Pharmaceutical Company in Switzerland. It has achieved good results in the treatment of patients with recurrent and metastatic breast cancer and advanced colon cancer. There are many reports on the process route of capecitabine in early patents and literature, and the representative patent 102009071726.1 once disclosed the synthesis method of capecitabine, which uses flucytosine as the starting material, by making the The amino group is acylated to introduce a non-polar side chain, and then coupled with 1,2,3-O-triacetyl-5-deoxy-D-ribose, and finally the diacetyl group on the sugar group is remo...

Claims

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Application Information

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IPC IPC(8): C07H13/06C07H1/00
Inventor 郑庚修杨柳马志佳付凯刘庆东杨倩
Owner UNIV OF JINAN
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