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Synthetic method for capecitabine key intermediate

A capecitabine and synthesis method technology, applied in the field of medicinal chemistry, can solve problems such as increased route cost, and achieve the effects of improved product purity, good quality and high finished product yield

Active Publication Date: 2015-09-23
广安凯特制药有限公司
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0011] This route also uses 5-fluorocytosine as the starting material, first condenses with n-pentyl chloroformate, and then reacts with 1,2,3-O-triacetyl-5-deoxy-6-ribofuranose to obtain 2', 3'-O-Diacetyl-5'-deoxy-5-fluoro-N 4 -[(pentyloxy)carbonyl]cytidine, this route still requires silylating reagents, resulting in higher cost of the route

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  • Synthetic method for capecitabine key intermediate
  • Synthetic method for capecitabine key intermediate
  • Synthetic method for capecitabine key intermediate

Examples

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Effect test

Embodiment 1

[0034] (1) Mix 100g of 5-fluorocytosine, 600g of chloroform, 123g of sodium carbonate, 200g of water, and 2g of tetrabutylammonium bromide, and add 175g of n-pentyl chloroformate dropwise at 5°C-10°C. After completion, keep warm for the reaction After 1.0 hour, the layers were allowed to stand, and the organic layer was washed with 200 g of water and dried to obtain a chloroform solution ① of pentyl (5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate.

[0035](2) Add 201.6g of 1,2,3-tri-O-acetyl-5-deoxy-6-ribofuranose to step ① of step (1), and add 184g of trifluoride dropwise at a temperature of 5°C-10°C After the addition of boroethyl ether, heat up to 35°C-40°C and keep it warm for 3 hours, then drop it back into 413.3g of sodium bicarbonate and 153.3g of water mixture, stir and react for 2h, and filter the organic layer to dry and concentrate it. The concentrated solution was crystallized with 50g methanol and 200g water mixed liquid for 2h, suction filtered and dried to o...

Embodiment 2

[0037] (1) Mix 100g of 5-fluorocytosine, 800g of chloroform, 117.6g of triethylamine, 2.1g of tetrabutylammonium bisulfate, and 200g of water, add 175g of n-pentyl chloroformate dropwise at 5°C-10°C, add Complete, after 1.0 hours of heat preservation reaction, add dropwise 300g of water to wash, separate layers, and dry to obtain a chloroform solution of (5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)amyl carbamate ① .

[0038] (2) Add 201.6g of 1,2,3-tri-O-acetyl-5-deoxy-6-ribofuranose to step ① of step (1), and add 184g of trifluoride dropwise at a temperature of 5°C-10°C Boroethyl ether, after completion, heat up to 35°C-40°C and keep it warm for 3 hours, then drop it back into 413.3g of sodium bicarbonate and 153.3g of water mixture, stir and react for 2h, filter the organic layer and dry it, then concentrate it, and then concentrate Mix 50g of methanol and 200g of water for liquid crystallization for 2h, filter with suction and dry to obtain capecitabine intermediate 2',3'-O-...

Embodiment 3

[0040] (1) Mix 100g of 5-fluorocytosine, 600g of chloroform, 123g of sodium carbonate, 200g of water, and 2g of tetrabutylammonium bromide, and add 175g of n-pentyl chloroformate dropwise at 5°C-10°C. After completion, keep warm for the reaction After 1.0 hour, the layers were allowed to stand, and the organic layer was washed with 200 g of water and dried to obtain a chloroform solution ① of pentyl (5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate.

[0041] (2) Add 201.6g of 1,2,3-tri-O-acetyl-5-deoxy-6-ribofuranose to step ① of step (1), and add 185.9g of trichloride at 5°C-10°C Aluminum, complete, heat up to 35°C-40°C and keep it warm for 3 hours, then drop it back into 413.3g of sodium bicarbonate and 153.3g of water mixture, stir for 2 hours, filter the organic layer and dry it, concentrate it, and dilute the concentrated solution Mixed liquid crystallization with 50g methanol and 200g water for 2h, suction filtration and drying to obtain capecitabine intermediate 2',3'...

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Abstract

The invention discloses a synthetic method for capecitabine key intermediate 2`,3`-O-diacetylpyridine-5`-deoxygenation-5-fluorine-N4-[(pentyloxy) carbonyl] cytidine. The synthetic method for the capecitabine key intermediate comprises the following steps that 1, 5- fluorocytosine, an acid-binding agent, chloroform, water and phase transfer catalyst are mixed, pentyl chloroformate is added dropwise under stirring, and the chloroform solution of (5-fluorine-2-oxo-1,2-dihydropyrimidine-4-base) amylcarbamate is obtained; 2, 1,2,3-three-O-acetyl-5-deoxygenation-6- ribofuranose is added into the chloroform solution obtained in the step 1, lewis acid is added dropwise, the reaction is performed for 2-10 hours after adding, and the capecitabine key intermediate is obtained after post-processing. The synthetic method is simple and convenient in operation, a silicane protective agent and intermediate product purification are not needed, the high yield of finished products is achieved, the proportion of alpha isomer in the products is effectively controlled, and compared with literature data, the purity of the obtained products is greatly improved.

Description

Technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a key intermediate of capecitabine-2',3'-O-diacetyl-5'-deoxy-5-fluoro-N 4 -Synthetic method of [(pentyloxy)carbonyl]cytidine. Background technique [0002] Capecitabine, whose chemical name is 5’-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, was developed by the Swiss company Hoffman-La Roche and was first launched in Switzerland in 1998. This product is a new type of oral flucytosine nucleoside analogue. It is non-toxic to cells. It is metabolized into 5-fluorouracil under the action of enzymes in the body, and then exerts anti-tumor effects. It is clinically used for advanced breast cancer, node / Rectal cancer and other solid tumors. [0003] 2’,3’-O-diacetyl-5’-deoxy-5-fluoro-N 4 -[(Pentyloxy)carbonyl]cytidine (structural formula shown below) is a key intermediate in the synthesis of capecitabine, from which capecitabine can be obtained by removing ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H1/00
Inventor 谭超周旭东王廷圣邹鑫王喜
Owner 广安凯特制药有限公司
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