CN112409420B - Purification method of 2 '-fluoro-2' -deoxyuridine - Google Patents
Purification method of 2 '-fluoro-2' -deoxyuridine Download PDFInfo
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- CN112409420B CN112409420B CN202011443647.3A CN202011443647A CN112409420B CN 112409420 B CN112409420 B CN 112409420B CN 202011443647 A CN202011443647 A CN 202011443647A CN 112409420 B CN112409420 B CN 112409420B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
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Abstract
The application discloses a method for purifying 2 '-fluoro-2' -deoxyuridine, which comprises the following steps: 1) Dissolving the crude product of 2 '-fluoro-2' -deoxyuridine in ethyl acetate, adding triethylamine, and dropwise adding an acylation reagent for reaction under the controlled temperature; 2) Adding methanol after the reaction is finished, stirring, cooling, crystallizing, filtering, washing a filter cake with ethyl acetate, and drying the filter cake to obtain a compound 2; 3) And dissolving the compound 2 in methanol, adding sodium hydroxide, filtering after complete reaction, and drying a filter cake to obtain the 2 '-fluoro-2' -deoxyuridine. The method has the advantages of high purification efficiency, high product purity of more than 98.5 percent, simple operation and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a purification method of 2 '-fluoro-2' -deoxyuridine.
Background
2 '-fluoro-2' -deoxyuridine is an important pharmaceutical and chemical intermediate, and is generally synthesized by taking uridine as a raw material, wherein the reaction steps comprise dehydrating and condensing the 2 '-position and the 1-position keto group of uridine, and then introducing a fluoro group into the 2' -position by using a fluorinating reagent to generate 2 '-fluoro-2' -deoxyuridine (compound 1), and the simple reaction formula is as follows. Because the nucleoside compounds are extremely sticky and difficult to form solids, and other impurities are generated in the reaction process, the 2 '-fluoro-2' -deoxyuridine is difficult to be directly refined by the traditional method, and a pure product can hardly be obtained.
Disclosure of Invention
The main object of the present application is to provide a method for purifying 2 '-fluoro-2' -deoxyuridine.
The technical scheme is as follows:
a method of purifying 2 '-fluoro-2' -deoxyuridine, comprising the steps of:
1) Dissolving the crude product of 2 '-fluoro-2' -deoxyuridine in ethyl acetate, adding triethylamine, and dropwise adding an acylation reagent for reaction under controlled temperature;
2) After the reaction is finished, adding methanol, stirring, cooling, crystallizing, filtering, washing a filter cake with ethyl acetate, and drying the filter cake to obtain a compound 2;
3) And dissolving the compound 2 in methanol, adding sodium hydroxide, filtering after complete reaction, and drying a filter cake to obtain the 2 '-fluoro-2' -deoxyuridine.
Further, the acylating agent is one of acetic anhydride or benzoyl chloride.
Further, when the acylating agent added in the step 1) is acetic anhydride, a catalyst is required to be added, and the catalyst is 4-dimethylaminopyridine.
Further, 2 '-fluoro-2' -deoxyuridine in step 1): triethylamine: the weight ratio of the acylating agent is 1.
Further, the reaction temperature in the step 1) is controlled between 0 and 20 ℃.
Further, the temperature of the temperature reduction in the step 2) is-20 to 10 ℃.
Further, the molar ratio of the compound 2 to the sodium hydroxide in the step 2) is 1.
The method comprises the steps of introducing esterification protecting groups such as acetyl, benzoyl and the like into two positions of 3 'and 4' of a crude product of 2 '-fluoro-2' -deoxyuridine (compound 1) to obtain a compound 2, refining the compound 2 in a solvent such as ethyl acetate and the like to more than 98.5%, and then hydrolyzing to remove the protecting groups to obtain the 2 '-fluoro-2' -deoxyuridine, wherein the reaction formula is as shown in the following formula.
The method for purifying the 2 '-fluoro-2' -deoxyuridine has the advantages of simple operation and high purification efficiency, and is suitable for industrial production.
Detailed Description
In order to make those skilled in the art better understand the technical solutions in the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Example 1
Adding 25g of crude 2 '-fluoro-2' -deoxyuridine into a reaction bottle, adding 100g of ethyl acetate, 0.05g of 4-dimethylaminopyridine and 41.0g of triethylamine, dropwise adding 31.1g of acetic anhydride at the temperature of 0-20 ℃, adding 10ml of methanol into reaction liquid after the reaction is finished, stirring for 0.5 hour, cooling to-20-10 ℃, precipitating a large amount of solid, filtering, washing filter cakes with cold ethyl acetate, and drying the filter cakes to obtain 23.9g of compound 2, wherein the yield is 76.8% and the purity is 99.1%.
20g of the compound 2 is added into a reaction bottle, 110ml of methanol is added, 4g of sodium hydroxide is added, after the reaction is completed, the mixture is filtered, and a filter cake is dried to obtain 15.0g of 2 '-fluoro-2' -deoxyuridine, wherein the yield is 93.5 percent and the purity is 98.8 percent.
Example 2
Adding 20g of crude 2 '-fluoro-2' -deoxyuridine into a reaction bottle, adding 80g of ethyl acetate and 40.0g of triethylamine, controlling the temperature to be 0-20 ℃, dropwise adding 22.8g of benzoyl chloride, adding 10ml of methanol into reaction liquid after the reaction is finished, stirring for 0.5 hour, cooling to-20-10 ℃, precipitating a large amount of solid, filtering, washing a filter cake with cold ethyl acetate, and drying the filter cake to obtain 28.9g of compound 2, wherein the yield is 78.4% and the purity is 98.7%.
50g of the compound 2, 310ml of methanol and 9g of sodium hydroxide are added into a reaction flask, after the reaction is completed, the mixture is filtered, and a filter cake is dried to obtain 26.1g of 2 '-fluoro-2' -deoxyuridine, wherein the yield is 96.5 percent and the purity is 99.4 percent.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (1)
1. A method for purifying 2 '-fluoro-2' -deoxyuridine, comprising the steps of:
1) Dissolving the crude product of 2 '-fluoro-2' -deoxyuridine in ethyl acetate, adding triethylamine, dropwise adding an acylation reagent under controlled temperature for reaction, and controlling the reaction temperature to be 0-20 ℃;
2) After the reaction is finished, adding methanol, stirring, cooling, crystallizing, filtering, washing a filter cake with ethyl acetate, and drying the filter cake to obtain a compound 2, wherein the cooling temperature is-20-10 ℃;
3) Dissolving the compound 2 in methanol, adding sodium hydroxide, filtering after complete reaction, and drying a filter cake to obtain 2 '-fluoro-2' -deoxyuridine, wherein the molar ratio of the compound 2 to the sodium hydroxide is 1;
the acylating reagent is acetic anhydride, and a catalyst 4-dimethylamino pyridine is added;
2 '-fluoro-2' -deoxyuridine: triethylamine: the weight ratio of the acylating agent is 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011443647.3A CN112409420B (en) | 2020-12-11 | 2020-12-11 | Purification method of 2 '-fluoro-2' -deoxyuridine |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202011443647.3A CN112409420B (en) | 2020-12-11 | 2020-12-11 | Purification method of 2 '-fluoro-2' -deoxyuridine |
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| CN112409420A CN112409420A (en) | 2021-02-26 |
| CN112409420B true CN112409420B (en) | 2022-12-27 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US7388094B2 (en) * | 2003-04-10 | 2008-06-17 | Central Glass Company Limited | Processing for producing 2′-deoxy-2′-fluorouridine |
| CN103570660B (en) * | 2012-07-23 | 2015-09-09 | 昆明制药集团股份有限公司 | A kind of method preparing breviscapine B aglycone |
| CN103897007B (en) * | 2012-12-28 | 2017-03-29 | 上海兆维科技发展有限公司 | The preparation method of 5 fluorodeoxyuridine of high-purity |
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