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Method for preparing capecitabine and hydroxyl derivative intermediate thereof

A technology of hydroxy derivatives and capecitabine, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of uneconomical total cost, poor process controllability, and high toxicity, and achieve Avoid the use of toxic or expensive raw materials, good process controllability, and easy industrial production

Inactive Publication Date: 2011-11-16
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the above-mentioned methods for preparing capecitabine mainly have two problems: (1) harsh methods such as strong acid or strong base are commonly used to remove the hydroxyl protecting group, which often causes side reactions to occur, and then causes the controllable process. Poor property, low purity of crude product, difficult to purify and low yield, pollution is also great; (2) usually use more expensive or toxic raw materials or reagents, such as: hexamethyldisilazane, tin tetrachloride, trichloride Methyl chlorosilane, Raney Ni catalyst or sodium iodide, etc. lead to troublesome and complicated operation and post-treatment, and the total cost is uneconomical, so it is not suitable for industrial production

Method used

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  • Method for preparing capecitabine and hydroxyl derivative intermediate thereof
  • Method for preparing capecitabine and hydroxyl derivative intermediate thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0020] Example 1: Preparation of 2′, 3′, 5′-tri-O-benzoyl-N-[(n-pentyloxy)carbonyl]-5-fluorocytidine nucleoside (I)

[0021] 25.00g (0.10mol) of N-[(n-pentyloxy)carbonyl]-5-fluorocytosine was dissolved in 1,2-dichloroethane (150mL), and benzoyl chloride (12.52mL, 0.11mol ), stirred and heated to reflux for 1h, slowly added triethylamine (14.0mL, 0.11mol) dropwise, continued to reflux and stir for 5h, cooled to room temperature and filtered, the filter cake was washed with a small amount of 1,2-dichloroethane, and the filtrate and washings were combined , to obtain light brown transparent liquid. Dissolve 55.0g (0.11mol) of 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribose in the above solution, and add titanium tetrachloride (4.0ml, 0.10 mol) solution was stirred overnight at room temperature. The reaction mixture was poured into ice water (200ml), chloroform (10ml) was added, and the layers were allowed to stand. The organic phase was washed with water, dried over anhydrous magnesium...

Embodiment 2

[0022] Example 2: Preparation of N-[(n-pentyloxy)carbonyl]-5-fluorocytosine nucleoside (II)

[0023] 35.73g (51.96mmol) of 2′, 3′, 5′-tri-O-benzoyl-N-[(n-pentyloxy)carbonyl]-5-fluorocytosine nucleoside was dissolved in 300mL of methanol and added dropwise 320mL (0.5M) methanol solution of sodium methoxide, stirred at room temperature for 24h. Neutralize with 1.0mol / L hydrogen chloride methanol solution to about pH 6.5, filter to remove sodium chloride, and concentrate to dryness under reduced pressure. Dissolve in 20 mL of methanol, filter, and evaporate to dryness. The residue was dissolved in 100 mL of water, benzoic acid was extracted with chloroform, and the aqueous phase was evaporated to dryness under reduced pressure to obtain 18.53 g of white solid N-[(n-pentyloxy)carbonyl]-5-fluorocytosine nucleoside with a yield of 95%. processed for the next reaction.

Embodiment 3

[0024] Example 3: Preparation of 2', 3'-O-(methoxy)methine-N-[(n-pentyloxy)carbonyl]-5-fluorocytosine nucleoside (III)

[0025] Under nitrogen atmosphere, dissolve 13.54g (36.08mmol) N-[(n-pentyloxy)carbonyl]-5-fluorocytidine nucleoside and 75mg (0.40mmol) p-toluenesulfonic acid in 100ml acetocyanide, stir After uniformity, add 5.74g (54.12mmol) trimethyl orthoformate, react at room temperature for 4 hours, evaporate the volatile reagents under reduced pressure, dissolve the crude product in ethyl acetate, wash with 10% aqueous sodium carbonate solution and saturated brine , dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 13.40 g of white solid 2', 3'-O-(methoxy)methine-N-[(n-pentyloxy)carbonyl]-5-fluorocytosine nucleus Glycosides, the yield was 89%, and were used in the next step without treatment.

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Abstract

The invention discloses a method for preparing an anticancer medicine capecitabine and a hydroxyl derivative key intermediate thereof, and belongs to the technical field of pharmaceutical chemistry. The method is characterized in that: N-[(p-pentyloxy)carbonyl]-5-flurocytosin is taken as an initial raw material, and is subjected to five steps of chemical reactions to form the capecitabine. The preparation method has the advantages of reasonable sequence, readily available raw materials, mild reaction conditions, high process controllability, high yield and low cost. The crude intermediate has high purity, complicated purification treatment is avoided, the capecitabine obtained in a later stage can reach the standard of United States Pharmacopeia, and the method is more suitable for industrial production.

Description

technical field [0001] The invention discloses a preparation method of a key intermediate of an anticancer drug capecitabine and a hydroxyl derivative thereof, belonging to the technical field of medicinal chemistry. Background technique [0002] Capecitabine is the first oral fluoropyrimidine carbamate antineoplastic drug that has been marketed, and it can be used as a new targeted drug for the treatment of breast cancer and colorectal cancer. As an oral cytotoxic drug activated in tumors, capecitabine is completely absorbed through the gastrointestinal tract after oral administration, and is catalyzed by liver carboxylesterase to 5′-deoxy-5-fluorocytosine nucleoside, and then passed through the liver And cytidine deaminase in tumor cells catalyzes the conversion into 5'-deoxy-5-fluorouracil, and finally catalyzes the conversion into 5-FU by thymidine phosphorylase. Capecitabine and its metabolites do not have the ability to kill cells, and finally transform into 5-FU to p...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
CPCY02P20/55
Inventor 唐汝培
Owner JIANGNAN UNIV
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