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Preparation method of capectabine

A technology of capecitabine and cytidine, which is applied in the field of preparation of capecitabine and fluoropyrimidine drug compounds, can solve problems such as unfavorable industrial production, and achieve easy control, easy purification, and mild reaction conditions Effect

Active Publication Date: 2014-07-09
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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  • Preparation method of capectabine
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  • Preparation method of capectabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Preparation of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine nucleoside (10a).

[0032]

[0033] At room temperature, dissolve 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (7a) (10g, 30mmol) with 400ml of dichloromethane and add 1,1' -Carbonyl bis(1,2,4-triazole) (9.8g, 60mmol), TLC monitoring until the reaction is complete (developing solvent: dichloromethane / methanol=12:1), add n-pentanol (6.6ml, 60mmol ), TLC monitored until the reaction was complete (developing solvent: dichloromethane / methanol=12:1), washed the reaction mixture with 150ml×3 water, dried the organic phase with anhydrous sodium sulfate, filtered, and concentrated the filtrate to dryness to obtain a yellow oil , that is, compound (10a) 10.7g, yield 80.5%, directly used in the next step without purification.

Embodiment 2

[0034] Example 2: Preparation of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine nucleoside (10a).

[0035] At room temperature, dissolve 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (7a) (10g, 30mmol) with 400ml of dichloromethane and add 1,1' -Carbonyl bis(1,2,4-triazole) (13.1g, 80mmol), TLC monitoring until the reaction is complete (developing solvent: dichloromethane / methanol=12:1), add n-pentanol (6.6ml, 60mmol ), TLC monitored until the reaction was complete (developing solvent: dichloromethane / methanol=12:1), washed the reaction mixture 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 (10a) 11.0g, yield 82.7%, directly used in the next step without purification.

Embodiment 3

[0036] Example 3: 5'-deoxy-5-fluoro-N 4 -[(pentyloxy)carbonyl]cytidine (capecitabine, 1) preparation.

[0037]

[0038]The 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine (10a) obtained in Example 1 (8.9g, 20mmol), 150ml of methanol was stirred and dissolved, at -25℃~-20℃, 50ml of 2mol / L sodium hydroxide solution was added dropwise, and TLC monitored until the reaction was complete ((developing solvent: dichloromethane / methanol=9:1), Adjust the pH to 5.0-6.0 with concentrated hydrochloric acid, extract with 200ml×3 dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and recrystallize from ethyl acetate to obtain a white solid, the target compound card Betabine (1) 6.2g, yield 86.1%, HPLC: 99.97%, melting point: 113-116°C, specific rotation: 98.10°.

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Abstract

The invention discloses a preparation method of capectabine, which comprises the following steps of: reacting 1, 1'- dicarbonyl (1, 2, 4-triazole) and 5'-deoxygenation-5-fluorocytidine protected by hydroxy at a N-4 site, directly reacting an obtained product with n-amyl alcohol so as to obtain a N-4 amyl formate compound of cytidine, and then removing a protective group so as to obtain the capectabine. In the preparation method, chloro-carbonic ester or phosgene acylating agent with great toxicity are not used, raw materials are easily obtained, the after-treatment is simple and convenient, the product yield and the purity are high, operation environments are safe and environmental-friendly and are suitable for industrial production.

Description

technical field [0001] The invention belongs to the fields of organic chemistry and medicinal chemistry, and relates to a preparation method of fluoropyrimidine drug compounds, in particular to a preparation method of capecitabine. Background technique [0002] Capecitabine (1), chemical name 5'-deoxy-5-fluoro-N 4 -[(pentyloxy)carbonyl]cytidine, which has the structure shown in the following formula: [0003] [0004] It is an oral cytotoxic preparation with selective activity on tumor cells, and it is a new targeted drug for the treatment of breast cancer and colorectal cancer. [0005] The known synthetic method of capecitabine, as disclosed in U.S. Pat. No. 5,476,932 and U.S. Pat. No. 5,472,949A, uses 5'-deoxy-5-fluoro-cytidine (3) as a starting material, and N-pentyl chloroformate for N Carbamate reaction at the -4 position, and capecitabine is obtained after removal of the protecting group, as shown in the reaction formula (I): [0006] (I) [0007] The method...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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