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Synthetic method of capecitabine

A synthetic method and capecitabine technology, applied in the field of drug preparation, can solve problems such as increased pollution, health hazards of workers, and increased costs, and achieve the effects of ensuring health, facilitating industrial production, and increasing productivity

Active Publication Date: 2015-07-01
SHANDONG INOMIC INST OF PHARM RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] There are many synthetic methods for capecitabine in the existing synthetic technology, usually two fragments are docked, wherein 5-deoxy-triacetyl ribose and 5-fluorocytosine are used as raw materials to synthesize N-pentoxycarbonyl-2' ,In the process of 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, a large amount of organic bases are used, resulting in increased costs, increased pollution, and harm to the health of workers

Method used

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  • Synthetic method of capecitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Under ice bath, control the temperature at 5°C, slowly drop n-amyl chloroformate (21.5mmol) into K 2 CO 3 (21.7mmol), dimethylaminopyridine (2.46mmol) and 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (14.5mmol) in dichloromethane (30mL) , keep warm for 45 minutes. After filtration, the filtrate was washed successively with 0.2M hydrochloric acid (10 mL), water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a white solid (6.1 g, yield 90.6%).

[0020] Add N-pentyloxycarbonyl-2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (5 g) and methanol (40 mL) into a 100 mL three-necked flask. After cooling to 0°C, 10 mL of 2M sodium hydroxide was added dropwise, and the temperature was maintained at 5 to 15°C. After reacting for 1 hour, 2M hydrochloric acid was added dropwise to adjust the pH value to about 6. After three extractions with dichloromethane (150 mL), the combined organic phases were ...

Embodiment 2

[0022] Under ice bath, the temperature was controlled to be 15°C, and n-amyl chloroformate (20.4 mmol) was slowly dropped into Na 2 CO 3 (20.3mmol), dimethylaminopyridine (2.67mmol) and 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (14.5mmol) in chlorothane (30mL) solution, Insulation reaction 45min. After filtration, the filtrate was washed successively with 0.2M hydrochloric acid (10 mL), water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a white solid (5.9 g, yield 87.6%).

[0023] Add N-pentyloxycarbonyl-2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (5 g) and methanol (40 mL) into a 100 mL three-necked flask. After cooling to 0°C, 11 mL of 2M potassium hydroxide was added dropwise, and the temperature was maintained at 5 to 15°C. After reacting for 1 hour, 2M hydrochloric acid was added dropwise to adjust the pH to about 6. After three extractions with dichloromethane (150 mL), the com...

Embodiment 3

[0025] Under ice bath, the temperature was controlled to be 1°C, and n-amyl chloroformate (23.1 mmol) was slowly dropped into K 2 CO 3 (22.6mmol), dimethylaminopyridine (2.65mmol) and 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (14.5mmol) in toluene (30mL) solution, incubated React for 45 minutes. After filtration, the filtrate was washed successively with 0.2M hydrochloric acid (10 mL), water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a white solid (5.7 g, yield 84.7%).

[0026] Add N-pentyloxycarbonyl-2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (5 g) and methanol (40 mL) into a 100 mL three-necked flask. After cooling to 0°C, 12 mL of 2M sodium methoxide was added dropwise, and the temperature was maintained at 5 to 15°C. After reacting for 1 hour, 2M hydrochloric acid was added dropwise to adjust the pH value to about 6. After three extractions with dichloromethane (150 mL), the c...

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Abstract

The invention belongs to the technical field of medicine preparation and relates to a synthetic method of capecitabine. The method comprises the following steps: 1) condensation reaction: reacting 2', 3'-bi-O-acetyl-5'-deoxy-5-fluoro-cytidine with halo n-amyl formate in the presence of an acid applying agent and a dimethylamino-pyridine catalyst to prepare N-pentyloxy carbonyl-2' 3'-bi-O-actyl-5'-deoxy-5-fluoro-cytidine; and 2) hydrolysis reaction: carrying out hydrolysis reaction on N-pentyloxy carbonyl-2' 3'-bi-O-actyl-5'-deoxy-5-fluoro-cytidine in the presence of an inorganic base to prepare the final product capecitabine. Compared with the prior art, the method provided by the invention has the advantages that by taking the inorganic base as the acid applying agent, use of a lot of organic bases is avoided and therefore the yield is improved, the production cost lowered, the environmental pollution is reduced, the physical health of the worker is ensured, and industrial production is facilitated.

Description

Technical field [0001] The invention belongs to the technical field of drug preparation, and specifically relates to a method for synthesizing capecitabine. Background technique [0002] The structure of capecitabine is shown in the following formula. The trade name is Xeloda. It is a 5-fluorouracil (5-FU) precursor anti-cancer drug first developed by Haofme Roche Co., Ltd. in Basel, Switzerland. It itself does not It is non-cytotoxic, but can be converted into cytotoxic 5-fluorouracil in three steps under the action of enzymes in the body. The concentration of enzymes related to the metabolism of capecitabine is higher in tumor tissues than in normal tissues, so high selectivity can be achieved. [0003] [0004] There are many synthesis methods for capecitabine in the existing synthesis technology, usually two-fragment docking, in which 5-deoxy-triacetylribose and 5-fluorocytosine are used as raw materials to synthesize N-pentyloxycarbonyl-2' ,3'-Di-O-acetyl-5'-deoxy-...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
CPCC07H1/00C07H19/06
Inventor 李明丽张娜
Owner SHANDONG INOMIC INST OF PHARM RES CO LTD
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