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Preparation method of capecitabine impurity F

A capecitabine and impurity technology, applied in the field of organic synthesis, can solve problems such as unpublished synthetic routes, and achieve the effects of promoting acylation and simplifying process steps

Inactive Publication Date: 2019-03-19
南京聚科生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The capecitabine impurity is of great significance to the in-depth study of capecitabine, and the synthetic method of capecitabine impurity A, impurity B, impurity C etc. and described impurity has been disclosed in the prior art, and capecitabine The synthetic routes of other impurities have not been disclosed

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  • Preparation method of capecitabine impurity F
  • Preparation method of capecitabine impurity F

Examples

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preparation example Construction

[0016] The preparation method of the capecitabine impurity F of the present invention comprises the following steps: (a) adding 2-methyl-1-butanol, tetrahydrofuran, triethylamine, nano-titanium dioxide and nano-ferric oxide into a reaction vessel, After nitrogen replacement, the temperature is lowered to ≤0°C, a tetrahydrofuran solution of triphosgene is added dropwise, and the reaction is carried out under the irradiation of ultraviolet light; the filtrate is filtered and spin-dried to obtain the first mixture; the nano-titanium dioxide, nano-ferric oxide and triphosgene The mass ratio is 5~10:5~10:100; (b) Add potassium carbonate, 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine to another reaction vessel After replacing with acetone and nitrogen, drop the acetone solution of the first mixture to react, and filter to obtain the reaction solution of the second mixture; (c) cool the reaction solution of the second mixture to ≤-10°C, adjust the pH to alkaline to Carry out the reacti...

Embodiment 1

[0020] The present embodiment provides a kind of preparation method of capecitabine impurity F, such as figure 1 As shown, it includes the following steps:

[0021] (a) Add 2-methyl-1-butanol (CAS: 137-32-6) (7.5g, 1.0eq), tetrahydrofuran (40 mL), triethylamine (8.6g, 1.0 eq), nano-titanium dioxide (anatase type, 2.5g) and nano-ferric oxide (2.5g), nitrogen replacement 3 times, cooling to 0 ° C, dropwise adding triphosgene (25.3g, 1.0eq) in tetrahydrofuran (40 mL), after the dropwise addition was completed, it was raised to room temperature and reacted for 0.5 hours; the reaction solution was filtered, the filter cake was washed twice with tetrahydrofuran, and the filtrate was spin-dried to obtain the first mixture (directly dropped into the first step reaction, that is, compound 2);

[0022] (b) Add potassium carbonate (23.5g, 2.0eq), 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (CAS: 161599-46- 8, 22g, 0.8eq) and acetone (100ml), replace with nitrogen for 3 times, and slowl...

Embodiment 2

[0025] This example provides a method for preparing capecitabine impurity F, which is basically the same as that in Example 1, except that in step (a), anatase-type nano-titanium dioxide (anatase-type, 1.3 g) and nanometer ferric oxide (2.6g), then warmed up to room temperature and reacted for 1 hour; finally, 11.5g of compound 1 was obtained by column chromatography.

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Abstract

The invention relates to a preparation method of a capecitabine impurity F. The preparation method comprises the following steps: (a) adding 2-methyl-1-butanol, tetrahydrofuran, triethylamine, nanometer titania and nano-iron oxide into a reaction container, performing nitrogen displacement, cooling to a temperature of less than or equal to 0 DEG C, dropwise adding a tetrahydrofuran solution of triphosgene, reacting under UV-irradiation, filtering to obtain filtrate, and performing spin drying so as to obtain a first mixture; (b) adding potassium carbonate, 2', 3'-bi-O-acetyl-5'-deoxo-5-fluorocytidine and acetone into another reaction container, dropwise adding an acetone solution of the first mixture to react after nitrogen displacement, and filtering to obtain a reaction solution of a second mixture; and (c) cooling the reaction solution of the second mixture to a temperature of less than or equal to 10 DEG C below zero, regulating the pH value to be alkaline, and reacting. Therefore,the product purity is improved on the premise of shortening the reaction time, and the process steps are simplified.

Description

technical field [0001] The invention belongs to the field of organic synthesis and relates to a capecitabine impurity, in particular to a preparation method of capecitabine impurity F. Background technique [0002] The chemical name of capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine (nucleoside) Cytotoxic, metabolized under the action of enzymes in the body to exert anti-tumor effects, and is mainly used clinically for the treatment of advanced breast cancer, colorectal cancer, etc. [0003] It needs to control the content of process impurities to be less than 0.15% (weight ratio) during the synthesis process. Process impurities include unreacted raw materials, impurities contained in raw materials and their chemical derivatives, synthesis by-products and degradation products. Capecitabine not only contains the 10 impurities mentioned in the USP 40th edition capecitabine quality standards, but also other impurities. [0004] The capecitabine impurity is...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
CPCC07H1/00C07H19/06
Inventor 张红美
Owner 南京聚科生物科技有限公司
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