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Preparation of capecitabine intermediate

A capecitabine and intermediate technology, applied in the field of pharmaceutical synthesis, can solve problems such as low purity, achieve high yield and purity, save a lot of solvent extraction, and simplify post-processing operations.

Pending Publication Date: 2021-08-31
LIANYUNGANG RUNZHONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the currently disclosed method, the general post-processing method is that the reaction liquid is extracted and washed multiple times, dried, filtered and concentrated to obtain an oily substance with low purity, and a solvent needs to be added to precipitate a solid later.

Method used

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  • Preparation of capecitabine intermediate
  • Preparation of capecitabine intermediate
  • Preparation of capecitabine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] The preparation of formula II compound

[0023]

[0024] In the reaction flask, add 320 g of acetone, 200 g of the compound of formula I, and 132 g of pyridine, stir for 30 min, and cool down to -10~-5°C. 132 g of n-pentyl chloroformate was added dropwise, and the temperature was controlled at -10 to 0°C during the dropwise addition. After dropping, react at -5~5°C for 2 hours, and monitor by TLC until the reaction is completed. The reaction solution was added to the sodium chloride / purified water system (600g / 2200g) pre-cooled to below -5°C, then added dropwise with pre-cooled hydrochloric acid solution to adjust to neutrality, stirred below -5°C until solids were precipitated, and then -10 Stir at ~0°C for more than 4h. The filter cake was rinsed with 600 g of purified water at 0-5° C. to rinse and filter the filter cake to obtain 338 g of the wet product of the compound of formula II (equivalent to 267.0 g of dry product), and the purity was 99.7% as determined ...

Embodiment 2

[0026] Preparation of formula Ⅲ compound capecitabine

[0027]

[0028] Throw about 338g of the wet product of the compound of the above formula II, 460g of purified water, stir, cool down to below -5°C, add dropwise an aqueous solution of sodium hydroxide (79g of sodium hydroxide is added to 673g of water), and control the temperature during the dropwise addition at -5 to 5°C. ℃. After dropping, keep the temperature at -5-5°C for 1 hour, and then track and monitor the mixture until the end of the reaction by TLC. Add hydrochloric acid water (hydrochloric acid / water: 76g / 76g) solution dropwise, adjust the pH to 6-7, after dropping, add 1200g of dichloromethane and stir for 10min, then add 200g of sodium chloride and stir for 10min, extract and separate. The organic phase was washed 3 times with purified water, each time using 480 g. The organic phase was concentrated to dryness under reduced pressure by controlling the temperature of the water bath at 35-40°C, adding 230 ...

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Abstract

The invention belongs to the field of drug synthesis, and provides a preparation method of a capecitabine intermediate. Specifically, a compound shown in a formula I reacts with n-amyl haloformate in the presence of a ketone solvent and organic base to obtain a compound shown in a formula II. A large amount of solvent extraction is omitted in post-treatment, the operation is more environmentally friendly, the steps are simple, and the preparation method is very suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of a capecitabine intermediate. Background technique [0002] Capecitabine (capecitabine), the chemical name is 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, and its structural formula is shown in formula III: [0003] [0004] Capecitabine is a new type of 5-fluorocytosine prodrug developed by Roche. It is an oral cytotoxic preparation with selective activity on tumor cells. It was launched in the United States in 1998 and is used for the treatment of metastatic breast cancer, Malignant tumors such as colon cancer, gastric cancer, and rectal cancer. In 2001, FDA approved this product for the treatment of metastatic colorectal cancer. [0005] The compound shown in formula II is an important intermediate for the preparation of capecitabine, which is deacetylated by hydrolysis to obtain capecitabine, [0006] [0007] CN103059085A discloses a prepar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H19/067
CPCC07H1/00C07H19/067
Inventor 仲兆柏程进荣贺绍杰苏旭
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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