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Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent

A technology of alkoxycarbonylation and alkoxycarbonyl, which is applied in the application field of alkoxycarbonylation of fluorinated pyrimidine compounds and the synthesis of capecitabine, which can solve the problems of unfavorable industrial production and achieve easy control and process Simple process and equipment, high yield effect

Inactive Publication Date: 2011-10-19
连云港杰瑞药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Said method adopts pentyloxyformyl p-nitrophenol ester as an acylating agent, and aftertreatment needs silica gel column chromatography purification, which is unfavorable for suitability for industrialized production

Method used

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  • Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent
  • Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent
  • Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058]

[0059] At room temperature, dissolve 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (8a) (10g, 30mmol) with 400ml of dichloromethane and add 1,1' -Carbonyldiimidazole (1-1) (9.7g, 60mmol), TLC until the reaction is complete (developing solvent: dichloromethane / methanol=12:1), add n-pentanol (6.6ml, 60mmol), TLC until the reaction is complete (Developer: dichloromethane / methanol=12:1), washed with 50ml×3 water, dried the organic phase with anhydrous sodium sulfate, filtered, and concentrated the filtrate to dryness to obtain a yellow oil, namely compound (2-1a) 10.7 g, yield 80.5%.

Embodiment 2

[0060] Example 2: Preparation of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine nucleoside (2-1a).

[0061] At room temperature, dissolve 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (8a) (10g, 30mmol) with 400ml of dichloromethane and add 1,1' -Carbonyldiimidazole (1-1) (13.2g, 80mmol), TLC until the reaction is complete (developing solvent: dichloromethane / methanol=12:1), add n-pentanol (8.7ml, 80mmol), TLC until the reaction is complete (Developer: dichloromethane / methanol=12:1), washed with 50ml×3 water, dried the organic phase with anhydrous sodium sulfate, filtered, and concentrated the filtrate to dryness to obtain a yellow oil, namely compound (2-1a) 10.8 g, yield 81.5%.

Embodiment 3

[0062] Example 3: Preparation of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine nucleoside (2-1a).

[0063] At room temperature, the compound of formula (8a) (10g, 30mmol) was stirred and dissolved in 400ml of dichloromethane, and N,N'-disuccinimidyl carbonate (DSC) (15.4g, 60mmol) was added, TLC until the reaction was complete (Developer: dichloromethane / methanol=12:1), filter off the white solid, add n-pentanol (6.6ml, 60mmol) to the filtrate, TLC until the reaction is complete (developer: dichloromethane / methanol=12: 1), washed with 50ml×3 water, dried the organic phase with anhydrous sodium sulfate, filtered, and concentrated the filtrate to dryness to obtain 9.2g of compound (2-1a) as a yellow oil, with a yield of 68.7%.

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Abstract

The invention discloses a method for carrying out carbalkoxylation acylation on fluorouracil compound with an active coupling agent, and applications thereof in synthesizing capecitabine. The method comprises the steps of carrying out N-4 site acylation reaction of coupling agent shown as the formula (1) and fluorouracil complex shown as the formula (8), introducing active carbonyl at N-4 site to obtain acylate, directly reacting the acylate with alcohol or phenol without separation, and carrying out N-4 site carbalkoxylation acylation reaction, thus obtaining carbalkoxylation acylate of fluorouracil compound. The carbalkoxylation acylation method can be used for preparing capecitabine. The method conducts acylation and carbalkoxylation acylation on cytidine by adopting coupling agent and alcohol or phenol, thus avoiding use of chlorocarbonic ester or phosgene acylating agent, being used for preparing capecitabine, and being stable and easy to obtain raw materials, high in product purity, safe and environment-friendly for operation environment, and easy for industrial operation.

Description

technical field [0001] The invention belongs to the fields of organic chemistry and medicinal chemistry, and relates to a method for alkoxycarbonylation of fluorinated pyrimidine compounds, in particular to N-4 acylation and further alkoxycarbonylation of fluorinated pyrimidine compounds using an active coupling agent The method, and the application of this method in the synthesis of capecitabine. Background technique [0002] Fluorinated pyrimidines are currently the first-line anti-tumor drugs commonly used in clinical practice, and play an extremely important role in the treatment of malignant tumors such as breast cancer, non-small cell lung cancer, gastric cancer, and colorectal cancer. Capecitabine (Capecitabine, 3) is the latest fluorinated pyrimidine carbamate drug. It is an oral cytotoxic agent with selective activity on tumor cells. Its chemical name is: 5'-deoxy-5-fluoro- N 4 -[(pentyloxy)carbonyl]cytidine nucleoside, which has the structure shown in the followi...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
CPCY02P20/55
Inventor 张兰平温树启季锡平王寅吴书勇董玉萍
Owner 连云港杰瑞药业有限公司
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