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Fluoropyrimidine compound carbalkoxylation method

A compound and acetyl technology, applied in the field of synthesizing antitumor drug-capecitabine, can solve the problem of high device requirements, and achieve the effects of simple equipment, easy control and mild reaction conditions

Active Publication Date: 2007-03-28
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In this method, trimerized phosgene is used as an acylating reagent. In actual operation, highly toxic phosgene is generated, and the requirements for the device are relatively high.

Method used

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  • Fluoropyrimidine compound carbalkoxylation method
  • Fluoropyrimidine compound carbalkoxylation method
  • Fluoropyrimidine compound carbalkoxylation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: 2', 3'-di-O-acetyl-5'-deoxy-5-fluoro-N 4 Preparation of -[(pentyloxy)carbonyl]cytidine nucleoside (1-1a)

[0065]

[0066] In a 100ml three-necked flask equipped with a thermometer, a reflux condenser, and mechanical stirring, add 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-cytidine (8a) (3.29g, 10mmol ), a dry mixture of DMF and chloroform (50 mL, DMF:CHCl 3 =1:2, volume ratio) after stirring and dissolving, add pre-grinded potassium carbonate powder (4.83g, 35mmol), and n-pentoxyformyl p-nitrophenolate (9-1) (3.54g, 14mmol) , under stirring, heated to reflux for about 20 hours. After the reaction was completed, it was filtered, and the filter residue was washed with chloroform, and the organic phases were combined and concentrated under reduced pressure at 50° C. to obtain an oily substance. The oil was dissolved in ethyl acetate, washed with saturated brine, dried and desolvated, and the residue was purified by silica gel column chromatography to obtain 3.61...

Embodiment 2

[0068] Example 2: 2', 3'-di-O-acetyl-5'-deoxy-5-fluoro-N 4 - Preparation of [(butoxy)carbonyl]cytidine nucleoside (1-2a)

[0069]

[0070] According to the method of embodiment 1, replace n-pentoxyformyl p-nitrophenol ester (9-2) (40.8g, 0.24mol) in reference example 1 with p-nitrophenol n-butoxyformate 1), the other conditions were the same, and an oily substance was obtained. Purified by silica gel column chromatography to obtain 3.23 g of the title compound (1-2a) as an oil, with a yield of 75.3%.

[0071] 1 H NMR (400 MHz, DMSO-d6) δ10.61 (brs, 1H), 8.35 (brs, 1H), 5.84 (d, J=4.2Hz, 1H), 5.47 (br.t, 1H), 5.11 (br .t, 1H), 4.12(m, 3H), 2.08(s, 3H), 2.04(s, 3H), 1.59(m, 2H), 1.36(m, 5H), 0.86(t, J=7.2Hz, 3H) ppm.

Embodiment 3

[0072] Example 3: 2', 3'-isopropylidene-5'-deoxy-5-fluoro-N 4 - Preparation of [(pentyloxy)carbonyl]cytidine nucleoside (1-1b)

[0073]

[0074] In a 100ml three-neck flask equipped with a thermometer, a reflux condenser, and a magnetic stirrer, add 2',3'-isopropylidene-5'-deoxy-5-fluoro-cytidine (8b) (4.29g, 15mmol), n-pentyloxyformyl p-nitrophenolate (9-1) (4.30g, 17mmol), dried DMF (50mL) was stirred and dissolved, then added pre-ground potassium carbonate powder (4.83g, 35mmol) and stirred, React at 35°C for about 25 hours. After the reaction was completed, it was filtered, and the filter residue was washed with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure at 50° C. to obtain an oily substance. The oil was dissolved in ethyl acetate, washed with saturated brine, dried, and desolvated. The residue was purified by silica gel column chromatography to obtain 5.11 g of the title compound (1-1b) as a foam, with a yield of 85.3%...

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Abstract

The invention relates to fluorine contained miazines compound N-4 position alkyl oxygen carbonyl acidylating method, and its use in composing antineoplastic medicine-capecitabine. The invention has the advantages of avoiding using severe toxicity reagent such as, chloro formate, or phosgene etc, stable and easily gaining raw material, easy industrialization operation etc.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and organic chemistry. Specifically, the present invention relates to a preparation method of a compound having a general structural formula as shown in formula (1), and the method is used in synthesizing antineoplastic drug---capecitabine ( 2) Use in. [0002] Background technique [0003] Capecitabine (Capecitabine, 2) is an oral cytotoxic agent with selective activity on tumor cells, chemical name: 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytotoxicity pyrimidine nucleosides. [0004] The known synthetic method of capecitabine is as described in U.S. Patent No. 5,476,932A, using 5'-deoxy-5-fluorocytidine (3) as a starting material, and reacting with excess n-pentyl chloroformate to obtain an intermediate ( 4), the latter obtains capecitabine (2) through selective deprotection reaction, as shown in reaction formula (1): [0005] Reaction formula (1) [0006] [0007] In this method, ...

Claims

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Application Information

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IPC IPC(8): C07H19/073
Inventor 陶国建陈云华
Owner ZHEJIANG HISUN PHARMA CO LTD
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