The invention relates to 2apos; -fluoro-2apos,-fluoro-2apos; method for purifying-deoxyuridine

Abstract

The present invention relates to the field of organic chemistry, and discloses a 2 '-fluoro-2'-deoxyuridine purification method, which comprises: dissolving dehydrated uridine in dioxane, dropwise adding hydrofluoric acid pyridine at a controlled temperature, and carrying out a heating reaction until the reaction is complete to obtain an FdU crude product; diluting the FdU crude product with methanol, controlling the temperature, adding calcium carbonate to neutralize acid and convert F ions into insoluble calcium fluoride, stirring, filtering to remove inorganic salt to obtain diluted reaction liquid, adding activated carbon, stirring, decolorizing, and filtering; desolventizing the filtrate, eluting through column chromatography to obtain an eluent, collecting the eluent, desolventizing and drying to obtain a primarily purified crude product; and dispersing the preliminarily purified crude product in an alcohol solvent, heating, dissolving, cooling until solids are separated out, dropwise adding a poor solvent, cooling to room temperature, and filtering to obtain a filter cake which is a qualified product. According to the method, the reaction steps are reduced, and the time cost and the production cost are effectively reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemistry, in particular to a purification method of 2'-fluoro-2'-deoxyuridine. BACKGROUND

[0002] 2'-Fluoro-2'-deoxyuridine (FdU or 2'-F-2'-dU for short) is an important pharmaceutical intermediate, which has a wide range of applications in organic synthesis and biochemistry. Due to its special structure (2' hydroxyl group is replaced by fluorine), it has many potential applications in biomedical and chemical research, mainly in the fields of antiviral, anticancer, nucleic acid research and radio labeling. And it plays a key role in the synthesis route of complex organic molecules, especially in drug synthesis. By modifying the structure of 2'-fluoro-2'-deoxyuridine, new drug molecules or small organic molecule inhibitors can be generated for the treatment of influenza virus and other related diseases. At present, the chemical synthesis method of 2'-fluoro-2'-deoxyuridine is as follows: ; The crude product is obtained by ring opening of dehydrated uridine with hydrogen fluoride reagent, and then the crude product is esterified by derivatization reaction, and finally hydrolysis is carried out to obtain the product. The purpose of multi-stage purification is achieved by derivatization.

[0003] The existing synthesis method has three reaction steps through derivatization purification. Although qualified products can be obtained, it is time-consuming, high in cost, and large in three waste production, which is not conducive to scale-up production. SUMMARY

[0004] In view of the above technical deficiencies, the technical problem to be solved by the present application is to provide a purification method of 2'-fluoro-2'-deoxyuridine, which aims to solve the problems of long time consumption, high cost, large three waste production and not conducive to scale-up production in the synthesis of 2'-fluoro-2'-deoxyuridine.

[0005] To solve the above technical problems, the technical scheme adopted by the present application is as follows: the present application provides a purification method of 2'-fluoro-2'-deoxyuridine, comprising the following steps: ; S1, dehydrated uridine as shown in formula I is dissolved in dioxane, hydrogen fluoride acid pyridine is added dropwise under temperature control, and heating reaction is carried out until the reaction is complete to obtain a crude product as shown in formula II; S2, the crude product as shown in formula II is diluted with methanol, calcium carbonate is added under temperature control to neutralize the acid and convert F ion into insoluble calcium fluoride, after stirring, the inorganic salt is removed by filtration, the obtained diluted reaction liquid is added with activated carbon and stirred to decolorize, and then filtered; S3, after the filtrate is desolventized, elution is carried out through column chromatography to obtain an eluate, the eluate is collected and desolventized and dried to obtain a crude product of primary purification; S4, the crude product of primary purification is dispersed in an alcohol solvent, is dissolved and clarified by heating, is cooled to solid precipitation, then a poor solvent is added dropwise, is cooled to room temperature, is filtered, and the obtained filter cake is the qualified product.

[0006] Further, in the step S1, the 70% hydrofluoric acid pyridine is added dropwise at a temperature of 5-10 DEG C.

[0007] Further, the equivalent of the hydrofluoric acid pyridine is 2.0 eq.

[0008] Further, in the step S2, the amount of the methanol is 5-10 v.

[0009] Further, in the step S2, the amount of the activated carbon is 2-20 wt% based on the total mass of the diluted reaction liquid as 100 wt%.

[0010] Further, in the step S3, 100-200 mesh silica gel is used as the filler, and the amount of the silica gel is 1.0-3.0 times the mass of the dehydrated uridine raw material.

[0011] Further, the height-diameter ratio of the chromatography column is 3.0.

[0012] Further, in the step S3, gradient elution is used, and the following three sections of mixed solvents are used in sequence: The volume ratio of dichloromethane to methanol is 30:1, and the amount is 5-10 times the column volume; The volume ratio of dichloromethane to methanol is 20:1, and the amount is 5-8 times the column volume; The volume ratio of dichloromethane to methanol is 10:1, and the amount is 6-10 times the column volume.

[0013] Further, the alcohol solvent in the step S4 is methanol, ethanol or isopropyl alcohol.

[0014] Further, the poor solvent in the step S4 is petroleum ether, n-heptane, n-hexane or methyl tert-butyl ether.

[0015] The present application has the following beneficial effects: 1. The present application reduces the number of reaction steps, effectively reduces the time cost and production cost.

[0016] 2. The present application uses the physical properties of the product and impurities, and combines simple acid-base neutralization, rapid column chromatography and crystallization to form a set of purification schemes that can be scaled up for production, and obtain high-quality and high-yield products. BRIEF DESCRIPTION OF DRAWINGS

[0017] In order to describe the technical solutions in the embodiments of the present application or the prior art more clearly, the accompanying drawings needed in the description of the embodiments or the prior art will be briefly introduced. Obviously, the accompanying drawings in the following description are only some embodiments of the present application, and all other drawings obtained by those of ordinary skill in the art without creative work based on these drawings are within the protection scope of the present application.

[0018] Figure 1 Chromatogram of 2'-fluoro-2'-deoxyuridine prepared for the present application embodiment 1.

[0019] Figure 2 Chromatogram of 2'-fluoro-2'-deoxyuridine prepared for the present application embodiment 2. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are only some embodiments of the present application, not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work are within the protection scope of the present application. EMBODIMENT

[0021] The present embodiment provides a purification method of 2'-fluoro-2'-deoxyuridine, comprising: After the ring-opening reaction of 100 g of anhydrous uridine is completed, the reaction solution is cooled to about 5-10°C, and then 5.0 v of methanol is added for dilution. Then, calcium carbonate is added in batches to adjust the pH to about 7 while controlling the temperature at 5-10°C. After stirring for 1 h, the inorganic salt is removed by filtration. The obtained brown clear liquid is stirred with 2 wt% of activated carbon for 1 h for decolorization, and then filtered. The filtrate is dissolved at 50°C for sand preparation. The sand preparation crude product is subjected to column chromatography for rapid elution: 1.0 M 100-200 mesh silica gel, eluent is a mixed solution of dichloromethane and methanol, gradient elution is performed, the initial volume ratio of dichloromethane to methanol is 30:1, the amount is 5 times the column volume, then the volume ratio of dichloromethane to methanol is 20:1, the amount is 5 times the column volume, and finally the volume ratio of dichloromethane to methanol is 10:1, the amount is 6 times the column volume. The eluent is dried. The crude product is dispersed in 6 v of methanol, heated to 40°C to dissolve, cooled to a small amount of solid precipitates, 5.0 v of petroleum ether is added dropwise, cooled to 20°C, stirred for 1.5 h, filtered, and the obtained filter cake is dried at 50°C for 10 h to obtain 78.1 g of light yellow solid powder, HPLC: 97.98%, yield: 72.39%, see Figure 1 . EMBODIMENT

[0022] The present embodiment provides a purification method of 2'-fluoro-2'-deoxyuridine, comprising: 100g dehydrated uridine open loop reaction is completed, the reaction solution is cooled to about 5~10℃, 8.0v of methanol is added for dilution, then calcium carbonate is added in batches to adjust the pH to about 7 under the temperature control of 5~10℃, stirred for 1h, then the inorganic salt is removed by filtration; the obtained brown clear liquid is added with 10wt% activated carbon for stirring for 1h for decolorization, then filtered, and the filtrate is dissolved at 50℃ for sand preparation; sand preparation crude product column chromatography rapid elution: 2.0M 100~200 mesh silica gel, eluent is a mixture of dichloromethane and methanol, gradient elution is carried out, the initial volume ratio of dichloromethane to methanol is 30:1, the amount is 8 times the column volume, then the volume ratio of dichloromethane to methanol is 20:1, the amount is 6 times the column volume, finally the volume ratio of dichloromethane to methanol is 10:1, the amount is 8 times the column volume; the eluent is dried; the crude product is dispersed in 6v of ethanol, heated to 55℃ to dissolve, cooled to a small amount of solid precipitates, then 5.0v of n-heptane is added dropwise, cooled to 20℃, stirred for 1.5h, filtered, and the obtained filter cake is dried at 50℃ for 10h to obtain 88.2g of white solid powder, HPLC: 99.68%, yield: 81.75%, see Figure 2 . Embodiment

[0023] The embodiment provides a purification method of 2'-fluoro-2'-deoxyuridine, which comprises the following steps: 100g dehydrated uridine open loop reaction is completed, the reaction solution is cooled to about 5~10℃, 8.0v of methanol is added for dilution, then calcium carbonate is added in batches to adjust the pH to about 7 under the temperature control of 5~10℃, stirred for 1h, then the inorganic salt is removed by filtration; the obtained brown clear liquid is added with 10wt% activated carbon for stirring for 1h for decolorization, then filtered, and the filtrate is dissolved at 50℃ for sand preparation; sand preparation crude product column chromatography rapid elution: 2.0M 100~200 mesh silica gel, eluent is a mixture of dichloromethane and methanol, gradient elution is carried out, the initial volume ratio of dichloromethane to methanol is 30:1, the amount is 8 times the column volume, then the volume ratio of dichloromethane to methanol is 20:1, the amount is 6 times the column volume, finally the volume ratio of dichloromethane to methanol is 10:1, the amount is 8 times the column volume; the eluent is dried; the crude product is dispersed in 6v of ethanol, heated to 55℃ to dissolve, cooled to a small amount of solid precipitates, then 5.0v of n-heptane is added dropwise, cooled to 20℃, stirred for 1.5h, filtered, and the obtained filter cake is dried at 50℃ for 10h to obtain 88.2g of white solid powder, HPLC: 99.68%, yield: 81.75%, see Embodiment

[0024] The embodiment provides a purification method of 2'-fluoro-2'-deoxyuridine, which comprises the following steps: After the ring-opening reaction of 100g dehydrated uridine is completed, the reaction solution is cooled to about 5-10℃, diluted with 8.0v methanol, and the temperature is controlled at 5-10℃. Calcium carbonate is added in batches to adjust the pH to about 7, stirred for 1h, and filtered to remove inorganic salts; the obtained brown clear liquid is added with 10wt% activated carbon and stirred for 1h for decolorization, filtered, and the filtrate is desolvated at 50℃ for sand making; the crude sand product is quickly eluted by column chromatography: 2.0M 100-200 mesh silica gel, eluent: a mixed solution of dichloromethane and methanol, gradient elution, the initial volume ratio of dichloromethane to methanol was 30:1, the amount used was 8 column volumes, followed by a volume ratio of dichloromethane to methanol of 20:1, the amount used was 6 column volumes, and finally a volume ratio of dichloromethane to methanol of 10:1, the amount used was 8 column volumes; the eluent was desolventized to dryness; the crude product was dispersed in 6 v ethanol, heated to 55°C to dissolve, cooled until a small amount of solid precipitated, 5.0 v methyl tert-butyl ether was added dropwise, the temperature was cooled to 20°C, stirred for 1.5 h, filtered, and the filter cake was dried at 50°C for 10 h to obtain 86.3 g of white solid powder, HPLC: 99.21%, yield: 80.00%.

[0025] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art will be able to modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A method for purifying 2'-fluoro-2'-deoxyuridine, characterized in that: The following steps are involved: ； S1. Dissolve dehydrated uridine as shown in Formula I in dioxane, add pyridine hydrofluoride dropwise under temperature control, and heat to react until the reaction is complete to obtain a crude product as shown in Formula II; S2. diluting the crude product of Formula II with methanol, adding calcium carbonate at a controlled temperature to neutralize the acid and convert the F ions into insoluble calcium fluoride, stirring, and filtering to remove inorganic salts. Adding activated carbon to the obtained diluted reaction solution, stirring, decolorizing, and filtering; S3, after desolventizing the filtrate, eluting it through column chromatography to obtain an eluate, collecting the eluate, desolventizing and drying it to obtain a preliminarily purified crude product; S4. The crude product after preliminary purification is dispersed in an alcohol solvent, heated to dissolve, cooled until solid precipitates, then a poor solvent is added dropwise, cooled to room temperature, and filtered. The filter cake obtained is the qualified product.

2. The method for purifying 2'-fluoro-2'-deoxyuridine according to claim 1, wherein In step S1, the temperature is controlled at 5-10° C. and 70% pyridine hydrofluoride is added dropwise.

3. The method for purifying 2'-fluoro-2'-deoxyuridine according to claim 2, wherein: The pyridine hydrofluoric acid equivalent is 2.0eq.

4. The method for purifying 2'-fluoro-2'-deoxyuridine according to claim 1, wherein The amount of methanol used in step S2 is 5-10v.

5. The method for purifying 2'-fluoro-2'-deoxyuridine according to claim 1, wherein In step S2, based on the total mass of the diluted reaction solution being 100 wt %, the amount of activated carbon used is 2-20 wt %.

6. The method for purifying 2'-fluoro-2'-deoxyuridine according to claim 1, wherein In step S3, 100-200 mesh silica gel is used as filler, and the amount of silica gel used is 1.0-3.0 times the mass of the dehydrated uridine raw material.

7. The method for purifying 2'-fluoro-2'-deoxyuridine according to claim 1, wherein The height-to-diameter ratio of the chromatography column is 3.

0.

8. The method for purifying 2'-fluoro-2'-deoxyuridine according to claim 1, wherein In step S3, gradient elution is performed using the following three mixed solvents in sequence: The volume ratio of dichloromethane to methanol was 30:1, and the amount used was 5 to 10 column volumes; The volume ratio of dichloromethane to methanol was 20:1, and the amount used was 5 to 8 column volumes; The volume ratio of dichloromethane to methanol is 10:1, and the amount used is 6 to 10 times the column volume.

9. The method for purifying 2'-fluoro-2'-deoxyuridine according to claim 1, wherein The alcohol solvent in step S4 is methanol, ethanol or isopropanol.

10. The method for purifying 2'-fluoro-2'-deoxyuridine according to claim 1, wherein The poor solvent in step S4 is petroleum ether, n-heptane, n-hexane or methyl tert-butyl ether.

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