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Preparation methods of capecitabine and intermediate thereof

A technology of capecitabine and methyl, which is applied in the field of preparation of capecitabine and its intermediates, can solve the problems affecting the yield of products, and achieve the effects of avoiding by-products, reducing pollution and high yield

Active Publication Date: 2011-10-12
CHIA TAI TIANQING PHARMA GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Secondly, because the reduction of sugar sulfonate compounds is often accompanied by the breakage of O-S bonds, there are hydrolysis by-products in the product, which need to be separated by column chromatography, which affects the yield of the product

Method used

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  • Preparation methods of capecitabine and intermediate thereof
  • Preparation methods of capecitabine and intermediate thereof

Examples

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Effect test

Embodiment 1

[0036] Preparation of 1-O-methyl-2,3-O-isopropylidene-D-ribofuranose (4):

[0037] D-ribose (3) (20g, 133mmol) was dissolved in methanol (80ml) and acetone (120ml), concentrated hydrochloric acid (2ml) was added, the mixture was refluxed for 3h, allowed to cool, neutralized with solid sodium bicarbonate The pH of the solution was 6-7, the solvent was evaporated under reduced pressure, water (60ml) and ethyl acetate (100ml) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phase was washed and dried, filtered, and evaporated to dryness to obtain an oily Material 4 (23.6g, 86.8%) can be directly used in the next reaction.

Embodiment 2

[0039] Preparation of 1-O-methyl-2,3-O-isopropylidene-5-O-p-methylbenzenesulfonyl-D-ribofuranose (5):

[0040] Dissolve the oil 4 (47g, 0.23mol) in dichloromethane (200ml), add triethylamine (56ml), cool to 0-5°C, add p-toluenesulfonyl chloride (62.4g) six times, Each interval is about 10min. After the addition is completed, continue to keep at 5°C, stir for 3h, wash with water (50ml), 1mol / L hydrochloric acid (25ml), saturated aqueous sodium bicarbonate solution (25ml) and water (50ml) successively, evaporate to dryness, and add Ice water, stirred, filtered, washed with water, and dried to obtain solid 5 (60g, 72.7%), mp 80-81°C.

Embodiment 3

[0042] Preparation of 1-O-methyl-2,3-O-isopropylidene-5-deoxy-5-iodo-D-ribofuranose (1):

[0043] Compound 5 (10g, 31.8mmol) was dissolved in acetonitrile (104ml), sodium iodide (12.5g) was added, and the reaction was refluxed for 12h. Let cool, filter, distill off the solvent, add isopropyl ether to stir, filter, wash with isopropyl ether, and evaporate the filtrate to dryness under reduced pressure to give yellow oil 1 (8.5 g, 100%). No need to deal with, directly put into the next reaction.

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Abstract

The invention discloses a preparation method of capecitabine. The method comprises the following steps: based on D-ribose serving as a starting raw material, carrying out hydroxyl protection, 5-site tosylation, iodine substitution, hypophosphorous acid deiodination and acetylation so as to obtain the key intermediate 12,3-tri-O-acetyl-5-deoxy-beta-D-ribofuranose; carrying out glycosylation on the key intermediate and 5-fluorocytosine; and finally, carrying out N-4 site acylation and deprotection so as to obtain the capecitabine. In the method, a metal catalyst dose not need to be used for participating in reaction, the reaction condition is mild, and the yield is high, thus the method is economical and effective as well as suitable for industrial production on a large scale.

Description

technical field [0001] The invention relates to the technical field of preparation methods of capecitabine and its intermediates. Background technique [0002] Capecitabine is a nucleoside anticancer drug developed by Roche, Switzerland. It was approved by the U.S. Food and Drug Safety Administration in 1998 for the treatment of metastatic colorectal cancer and docetaxel (trade name). : Taisudi, ) combination therapy for the treatment of metastatic breast cancer, which went on the market in my country in 2001. In August 2008, China Food and Drug Administration approved its treatment for advanced gastric cancer. More than 100 countries are currently using capecitabine to treat the above-mentioned cancers. [0003] The chemical name of capecitabine is 5′-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, and the structure is as follows: [0004] [0005] The synthesis of capecitabine is divided into two parts: [0006] 1. Preparation of 1,2,3-tri-O-acetyl-5-deoxy-β-D-rib...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H15/04C07H1/00
Inventor 陈莉莉岑均达
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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