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CN-117447532-B - Purification method of 2 '-fluoro-2' -deoxyadenosine

CN117447532BCN 117447532 BCN117447532 BCN 117447532BCN-117447532-B

Abstract

The application relates to the technical field of biological medicaments, in particular to a purification method of 2 '-fluoro-2' -deoxyadenosine, which comprises the steps of (1) reacting a2 '-fluoro-2' -deoxyadenosine crude product containing adenine shown in a formula I with an acetylating reagent under alkaline condition to obtain diacetylated 2 '-fluoro-2' -deoxyadenosine shown in a formula II after purification, removing adenine, (2) deacetylating the diacetylated 2 '-fluoro-2' -deoxyadenosine shown in a formula II under the action of ammonia to obtain a crude product of the formula III, and pulping to obtain a pure product of the 2 '-fluoro-2' -deoxyadenosine.

Inventors

  • TONG KUN
  • ZHAO DAN

Assignees

  • 江苏申基生物科技有限公司

Dates

Publication Date
20260512
Application Date
20231025

Claims (9)

  1. 1. A method for purifying 2 '-fluoro-2' -deoxyadenosine, which is characterized by comprising the following steps: ; ; The purification steps are specifically as follows: (1) Dissolving a coarse product of 2 '-fluoro-2' -deoxyadenosine containing adenine shown in the formula I in a solvent, and reacting with an acetylating reagent in the presence of alkali to obtain diacetylated 2 '-fluoro-2' -deoxyadenosine shown in the formula II; (2) The diacetylated 2 '-fluoro-2' -deoxyadenosine shown in the formula II reacts with ammonia to obtain a compound shown in the formula III, and the compound shown in the formula III is pulped to obtain a pure 2 '-fluoro-2' -deoxyadenosine product.
  2. 2. The method for purifying 2 '-fluoro-2' -deoxyadenosine according to claim 1, wherein the base in the step (1) is at least one of triethylamine, N-diisopropylethylamine and pyridine.
  3. 3. The method for purifying 2 '-fluoro-2' -deoxyadenosine according to claim 1, wherein the acetylating reagent in the step (1) is one or both of acetic anhydride and acetyl chloride.
  4. 4. The method for purifying 2 '-fluoro-2' -deoxyadenosine according to claim 1, wherein the ammonia in the step (2) is at least one of aqueous ammonia, a methanol solution of ammonia, and an ethanol solution of ammonia.
  5. 5. The method for purifying 2 '-fluoro-2' -deoxyadenosine according to claim 1, wherein the solvent used for beating in the step (2) is one or both of ethanol and isopropanol.
  6. 6. The method for purifying 2 '-fluoro-2' -deoxyadenosine according to claim 1, wherein in the step (1), the molar ratio of the base to the acetylating agent in the crude 2 '-fluoro-2' -deoxyadenosine containing adenine is 1 (2-4): 1.8-3; The solvent used in the step (1) is N, N-dimethylformamide, and the mass-volume ratio of the content of 2 '-fluoro-2' -deoxyadenosine in the adenine-containing 2 '-fluoro-2' -deoxyadenosine crude product to the N, N-dimethylformamide is 1 (3-6).
  7. 7. The method for purifying 2 '-fluoro-2' -deoxyadenosine according to claim 1, wherein the reaction temperature in the step (1) is 10-30 ℃ and the reaction time is 3-8 hours.
  8. 8. The method for purifying 2 '-fluoro-2' -deoxyadenosine according to claim 1, wherein the mass/volume ratio of the 2 '-fluoro-2' -deoxyadenosine in the crude 2 '-fluoro-2' -deoxyadenosine containing adenine in the step (1) to ammonia in the step (2) is 1 (2-5).
  9. 9. The method for purifying 2 '-fluoro-2' -deoxyadenosine according to claim 1, wherein in the step (2), the diacetylated 2 '-fluoro-2' -deoxyadenosine is reacted with ammonia at a temperature of 40-50 ℃ for a reaction time of 12-16 hours.

Description

Purification method of 2 '-fluoro-2' -deoxyadenosine Technical Field The application relates to the technical field of biological medicines, in particular to a method for purifying 2 '-fluoro-2' -deoxyadenosine. Background The small nucleic acid structure in natural state is easy to be degraded by nuclease in vivo, and in order to ensure the patentability of nucleic acid medicine, improve the enzymolysis resistance and the like, the nucleoside needs to be subjected to multi-site chemical modification. Compared with unmodified 2'-OH, the 2' -fluoro modification has better nuclease resistance, improves the stability of the drug in blood plasma, increases the half-life period in tissues and can prolong the drug effect time. The 2 '-fluoro-2' -deoxyadenosine of the prior art can be prepared by chemical synthesis, but generally requires redundant steps of protection and deprotection, and the control of the region and stereoselectivity of glycosylation reaction is required. In contrast, the enzymatic synthesis of 2 '-fluoro-2' -deoxyadenosine is mild in condition and environment-friendly, and is an attractive alternative. The prior art discloses a method for generating 2 '-fluoro-2' -deoxyadenosine by performing transglycosylation reaction on 2 '-fluoro-2' -deoxyuridine and adenine under the catalysis of nucleoside phosphorylase, wherein excessive adenine is remained in the product, and the 2 '-fluoro-2' -deoxyadenosine is difficult to wash out by water due to similar solubility of adenine and 2 '-fluoro-2' -deoxyadenosine, so that high-purity 2 '-fluoro-2' -deoxyadenosine cannot be obtained. In the prior art, in order to obtain high-purity 2 '-fluoro-2' -deoxyadenosine, purification is performed by column chromatography, so that the purity is improved. The method can purify the 2 '-fluoro-2' -deoxyadenosine, but has complex process and lower purity, and cannot meet the requirement of industrial production. Therefore, it is necessary to develop a purification method which is simple in synthesis process and can obtain high purity. Disclosure of Invention Aiming at the defects existing in the prior art, the application provides a method for purifying 2 '-fluoro-2' -deoxyadenosine. The application provides a purification method of 2 '-fluoro-2' -deoxyadenosine, which adopts the following technical scheme: A method for purifying 2 '-fluoro-2' -deoxyadenosine comprises the following steps: preferably, the purification steps are specifically as follows: (1) Dissolving a coarse product of 2 '-fluoro-2' -deoxyadenosine containing adenine shown in a formula I in a solvent, reacting with an acetylating reagent in the presence of alkali, and purifying to obtain diacetylated 2 '-fluoro-2' -deoxyadenosine shown in a formula II; (2) The diacetylated 2 '-fluoro-2' -deoxyadenosine shown in the formula II reacts with ammonia to obtain a compound shown in the formula III, and the compound shown in the formula III is pulped to obtain a pure 2 '-fluoro-2' -deoxyadenosine product. Preferably, the base in the step (1) is at least one of triethylamine, N-diisopropylethylamine and pyridine. Preferably, the acetylating agent in the step (1) is one or both of acetic anhydride and acetyl chloride. Preferably, the ammonia in the step (2) is at least one of ammonia water, methanol solution of ammonia and ethanol solution of ammonia. Preferably, the solvent used for pulping in the step (2) is one or two of ethanol and isopropanol. Preferably, in the step (1), the molar ratio of the alkali to the acetylating agent in the 2 '-fluoro-2' -deoxyadenosine crude product containing adenine is 1 (2-4): 1.8-3. Preferably, the solvent used in the step (1) is N, N-Dimethylformamide (DMF), and the mass-volume ratio of the 2 '-fluoro-2' -deoxyadenosine content in the adenine-containing 2 '-fluoro-2' -deoxyadenosine crude product to DMF is 1 (3-6). Preferably, the reaction temperature in the step (1) is 10-30 ℃ and the reaction time is 3-8h. Preferably, the mass-volume ratio of the 2 '-fluoro-2' -deoxyadenosine content in the adenine-containing 2 '-fluoro-2' -deoxyadenosine crude product in the step (1) to the ammonia in the step (2) is 1 (2-5). Preferably, in the step (2), diacetylated 2 '-fluoro-2' -deoxyadenosine is reacted with ammonia at a temperature of 40-50 ℃ for a reaction time of 12-16 hours. The application discloses a purification method of 2 '-fluoro-2' -deoxyadenosine, which comprises the steps of firstly, derivatizing by a chemical method to obtain diacetylated 2 '-fluoro-2' -deoxyadenosine, removing main impurity adenine which does not participate in the reaction by a filtering mode, and then ammonolyzing the diacetylated 2 '-fluoro-2' -deoxyadenosine, and obtaining pure 2 '-fluoro-2' -deoxyadenosine by thermal pulping. In a specific embodiment, a method for purifying 2 '-fluoro-2' -deoxyadenosine comprises the steps of: (1) Dispersing a coarse product of 2 '-fluoro-2' -deoxyadenosine containing adenine shown in formula I in a solvent (DMF),