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Preparation method of high-purity capecitabine key intermediate

A technology of Chinese formula and compound, which is applied in the field of medicine and drug synthesis, can solve the problems of high cost of raw materials, difficulty in recycling, and expensive pyridine, etc., and achieve the effects of small α-isomer content, mild reaction conditions, and high chiral selectivity

Active Publication Date: 2019-02-22
广安凯特制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the second step of the method, pyridine is used as a base for tosylation. Pyridine is expensive, has a strong taste, is not easy to recycle, and has high raw material costs, so it is not suitable for industrialized economical production.
Moreover, in the reaction of the acetyl group in the fourth step, the literature uses pyridine as a solvent and also as a base. This method involves distilled water, and its energy consumption is large, and the amount of pyridine is large, and the cost is high; the yield is low, and the last two steps of the literature report The reaction crude yield is 81%, the refined yield is 60%, and the total yield is only 48.6%

Method used

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  • Preparation method of high-purity capecitabine key intermediate
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  • Preparation method of high-purity capecitabine key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: Preparation of compound of formula 1

[0044]

[0045] Add anhydrous methanol (2.4kg), acetone (0.8kg) to the dry three-necked flask, add concentrated sulfuric acid (164g) dropwise in an ice bath, add D-ribose (500g), control the temperature at 10-20℃, keep warm and stir for 20~ 30 hours. After the completion of the reaction monitored by TLC, the reaction liquid was added dropwise to a solution of sodium hydroxide (133 g) in methanol (666 g), and the methanol and acetone were removed by concentration. Add water (2.5kg) and toluene (2.5kg) to the concentrate, stir and extract, separate liquids, extract the aqueous phase toluene (500g) twice, combine the organic phases, wash once with saturated brine (1.5kg), and use the organic phase directly Next reaction.

Embodiment 2

[0046] Example 2: Preparation of the compound of formula 2

[0047]

[0048] The toluene solution of the compound of formula 1 obtained in Example 1, 4-dimethylaminopyridine (0.3g), and sodium hydroxide (195.0g) were sequentially added to the four-neck flask, the temperature was controlled at 5-15°C, and p-toluenesulfonate was added dropwise A solution of acid chloride (560.0g) in toluene (600g). After the dripping is completed, the temperature is controlled and reacted for 1 to 5 hours. After the completion of the reaction is monitored by TLC, water (2kg) is added and the liquids are separated. The water phase is extracted once with toluene (1.0kg). The organic phases were combined, washed once with saturated brine (2kg), the organic layer was concentrated and ethanol (2.5kg) was added to raise the temperature to 60-75°C, and after dissolution, the temperature was lowered to 0-10°C. After filtration, the filter cake was rinsed once with ethanol, and dried by blowing to obtain 95...

Embodiment 3

[0049] Example 3: Preparation of compound of formula 3

[0050]

[0051] The compound of formula 2 (317g), N,N-dimethylacetamide (915g), potassium borohydride (57.1g) were added to the reaction flask in sequence, the temperature was raised to 75~90℃, and the reaction was carried out at this temperature for 15~ After 25 hours, TLC monitors the completion of the reaction, cool to room temperature, add water (2.3kg) to quench the reaction, add n-hexane (1.2kg) for extraction three times, combine the organic layers, and concentrate to dryness to obtain 161.0g of a colorless liquid compound of formula 3. The yield was 96.7%.

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Abstract

The invention discloses a preparation method of a high-purity capecitabine key intermediate. The preparation method comprises the following steps: taking D-ribose as an initial raw material, performing hydroxyl protection, 5-site tosylation, reduction, deprotection and acetylation to obtain high-purity 1,2,3-O-triacetyl-5-deoxo-D-ribose, wherein the 5-site tosylation reaction is carried out in anorganic solvent 1 by adopting inorganic base 1. Meanwhile, the acetylation reaction is carried in the presence of alkali 2 by taking water as a reaction solvent and taking 4-dimethylamiopryidine as acatalyst. The preparation method disclosed by the invention is mild in reaction conditions, high in yield, economic and effective, the purity of the prepared 1,2,3-O-triacetyl-5-deoxo-D-ribose can reach 99.0%, the alpha-isomer is small in content even is not detected, and the preparation method is applicable to large-scale industrial production.

Description

Technical field [0001] The invention belongs to the technical field of medical drug synthesis, and specifically relates to a preparation method of 1,2,3-O-triacetyl-5-deoxy-D-ribose, a key intermediate of the antitumor drug capecitabine. Background technique [0002] Capecitabine (Capecitabine) is a nucleoside anti-cancer drug developed by Roche in Switzerland. It was first launched in Switzerland in 1998. In September 1998, it was approved by the US FDA for listing in the United States for the treatment of metastatic colorectal cancer, and combined with docetaxel for the treatment of metastatic breast cancer. It was launched in Japan with the same adaptability in April 2003. In August 2008, the China Food and Drug Administration approved its treatment for advanced gastric cancer. Capecitabine is currently being used in more than 100 countries. According to statistics, in 2016, the global capecitabine bulk drug market demand was about 200 tons, and the domestic market alone was...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H13/04C07H1/00
CPCC07H1/00C07H13/04
Inventor 左小勇张耀春罗绪时俊鹏周福委周旭东邹鑫
Owner 广安凯特制药有限公司
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