Preparation of Capecitabine Intermediate

Abstract

The present invention belongs to the field of pharmaceutical synthesis and provides a preparation method of a capecitabine intermediate. Specifically, in the presence of a ketone solvent and an organic base, the compound of formula I reacts with n-pentyl chloroformate to obtain the compound of formula II. The post-treatment omits a large amount of solvent extraction, is more environmentally friendly in operation, has simple steps, and is very suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing a capecitabine intermediate. Background Art

[0002] Capecitabine, chemically named 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, has a structural formula as shown in Formula III:

[0003]

[0004] Capecitabine is a new 5-fluorocytosine prodrug developed by Roche. It is an oral cytotoxic agent that is selectively active against tumor cells. It was launched in the United States in 1998 for the treatment of malignant tumors such as metastatic breast cancer, colon cancer, gastric cancer, and rectal cancer. In 2001, the FDA approved this product for the treatment of metastatic colorectal cancer.

[0005] The compound shown in formula II is an important intermediate for preparing capecitabine. It can be obtained by removing the acetyl group through hydrolysis reaction.

[0006]

[0007] CN103059085A discloses a preparation method of formula II: the compound of formula I reacts with n-pentyl chloroformate in dichloromethane and pyridine, and then is extracted, concentrated, and recrystallized to obtain the compound of formula II.

[0008]

[0009] In addition, domestic applications CN101845070A, CN102212095A, CN101768196A, and CN103601777 disclose similar preparation methods. In the currently disclosed methods, the general post-treatment method is to extract and wash the reaction solution multiple times, dry, filter, and concentrate to obtain an oily substance with low purity, and then add a solvent to precipitate the solid. Summary of the invention

[0010] The present invention provides a method for preparing a capecitabine intermediate, comprising:

[0011] (1) reacting the compound of formula I with n-pentyl haloformate in the presence of a ketone solvent and an organic base to obtain a mixture containing the compound of formula II;

[0012]

[0013] (2) The mixture of step (1) is mixed with a sodium chloride aqueous solution, the pH value is adjusted to neutral, and then cooled to precipitate a solid, and the solid compound of formula II is separated.

[0014] The compound of Formula II in step (2) can be hydrolyzed in the presence of an inorganic base to obtain capecitabine.

[0015] In step (1), in some embodiments, the reaction temperature of step (1) is -10°C to 5°C; preferably -5°C to 5°C.

[0016] In some embodiments of step (1), the molar ratio of the compound of Formula I to n-pentyl chloroformate is 1:1 to 2, preferably 1:1.4; in some embodiments, the molar ratio of the compound of Formula I to the organic base is 1:1 to 4, preferably 1:2 to 3, more preferably 1:2.7.

[0017] In some embodiments of step (1), the ketone solvents include but are not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, isophorone, diacetone alcohol; in some embodiments of step (1), the ketone solvent is acetone; in some embodiments, the organic bases include but are not limited to N,N-diisopropylethylamine, pyridine or dimethylaminopyridine, triethylamine, trimethylamine; in some embodiments, the organic base is pyridine; in some embodiments, the n-pentyl chloroformate is selected from n-pentyl chloroformate.

[0018] In step (2), the aqueous sodium chloride solution can be either an unsaturated aqueous solution or a saturated aqueous solution; in some embodiments, calculated by mass fraction, the concentration of the aqueous sodium chloride solution is 5% to the concentration of the saturated aqueous sodium chloride solution; in some embodiments, the concentration of the aqueous sodium chloride solution is 10% to the concentration of the saturated aqueous sodium chloride solution; in some embodiments, the concentration of the aqueous sodium chloride solution is 15 - 26.5%; in some embodiments, the volume ratio of the aqueous sodium chloride solution to the ketone solvent in step (1) is 4 - 15:1; in some embodiments, the volume ratio of the aqueous sodium chloride solution to the ketone solvent in step (1) is 5 - 10:1.

[0019] In step (2), in some embodiments, the aqueous sodium chloride solution is pre-cooled to -10°C to 5°C; preferably -5°C to 0°C. In some embodiments, an aqueous hydrochloric acid solution is used to adjust the pH value to neutral; in some embodiments, the aqueous hydrochloric acid solution is pre-cooled to -10°C to 5°C; preferably -5°C to 0°C. In some embodiments, a solid is precipitated at -10°C to 5°C; in some embodiments, a solid is precipitated at -5°C to 0°C.

[0020] The preparation method of the capecitabine intermediate described in this application has the following advantages: It provides a preparation method suitable for large-scale industrial production, which avoids the need for multiple extractions, washings, and concentration in the prior art to obtain the crude product; By selecting a ketone solvent, adding an aqueous sodium chloride solution during post-treatment, and then adjusting the pH value to neutral, solids can be precipitated, simplifying the post-treatment operation, eliminating a large amount of solvent extraction, making the operation simpler and more environmentally friendly, and obtaining a high yield and purity of the intermediate. The yield can reach over 95%, and its purity reaches over 99%; If the solvent is dichloromethane or chloroform, adding an aqueous sodium chloride solution during post-treatment will result in layering and no solid precipitation. Detailed implementation mode

[0021] Example 1

[0022] Preparation of the compound of formula II

[0023]

[0024] In a 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 to -5 °C. Dropwise add 132 g of n-pentyl chloroformate, and control the temperature at -10 to 0 °C during the dropping process. After the addition is complete, react at -5 to 5 °C for 2 h, and monitor by TLC until the reaction ends. Add the reaction solution to a sodium chloride / purified water system (600 g / 2200 g) pre-cooled to below -5 °C, then dropwise add a pre-cooled hydrochloric acid solution to adjust to neutral, stir at below -5 °C until solids precipitate, and then stir at -10 to 0 °C for more than 4 h. Filter by centrifugation, and wash the filter cake with 600 g of purified water at 0 to 5 °C and filter by centrifugation 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 measured by area normalization method is 99.7%.

[0025] Example 2

[0026] Preparation of the capecitabine of the compound of formula III

[0027]

[0028] Add about 338 g of the wet product of the compound of Formula II and 460 g of purified water, stir, cool down to below -5°C, and dropwise add an aqueous sodium hydroxide solution (79 g of sodium hydroxide added to 673 g of water). Control the temperature at -5 to 5°C during the dropping process. After the dropping is complete, maintain the temperature at -5 to 5°C and react for 1 hour, then monitor by TLC until the reaction reaches the end point. Dropwise add a hydrochloric acid solution (hydrochloric acid / water: 76 g / 76 g) to adjust the pH to 6 - 7. After the dropping is complete, add 1200 g of dichloromethane and stir for 10 min, then add 200 g of sodium chloride and stir for 10 min, and perform extraction and liquid separation. Wash the organic phase with purified water 3 times, with a dosage of 480 g each time. Control the water bath temperature of the organic phase at 35 to 40°C and concentrate it under reduced pressure to dryness. Add 230 g of ethyl acetate, control the water bath temperature at 35 to 40°C and concentrate it under reduced pressure to dryness. Add 230 g of ethyl acetate and stir for 1 hour. Dropwise add 230 g of n-hexane. After the addition is complete, control the temperature at 15 to 20°C and stir for crystallization for more than 8 hours, then perform suction filtration and drying to obtain 180 g of the product.

Claims

1. A preparation method of capecitabine intermediate, comprising: (1) Reacting the compound of formula I with n-pentyl chloroformate in the presence of a ketone solvent and an organic base to obtain a mixture containing the compound of formula II, wherein the ketone solvent is acetone and the organic base is pyridine, (2) Mixing the mixture obtained in step (1) with an aqueous sodium chloride solution, adjusting the pH value to neutral, then cooling to precipitate a solid, and separating to obtain the solid of the compound of formula II.

2. The preparation method according to claim 1, characterized in that, in step (1), the reaction temperature is -10°C to 5°C.

3. The preparation method according to claim 1 or 2, characterized in that, in step (1), the molar ratio of the compound of formula I to n-pentyl chloroformate is 1:1 to 2.

4. The preparation method according to claim 1, characterized in that, in step (1), the n-pentyl chloroformate is selected from n-pentyl chloroformate.

5. The preparation method according to any one of claims 1, 2 or 4, characterized in that, in step (2), the mass fraction of the aqueous sodium chloride solution is 5% to the saturated concentration.

6. The preparation method according to claim 1, characterized in that, in step (2), the cooling temperature is -10 to 5°C.

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