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Preparation method of 2'-O-substituted uridine

A technology of epoxyuridine and compound, applied in the new synthesis field of uridine nucleoside, can solve the problems of difficult industrialization promotion, harsh reaction conditions, difficult commercialization and the like

Inactive Publication Date: 2019-11-05
SHANGHAI ZHAOWEI TECH DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the methods for synthesizing 2'-O-alkylated uridine derivatives by ring-opening of 2,2'-anhydrouridine (CYU) generally have problems such as harsh reaction conditions, difficult product purification, low yield, or even no reaction at all. , making industrialization difficult
Al(OCH 2 CH 2 OCH 3 ) 3 The method of introducing methoxyethoxy to the 2'-position (Legorburu, U.; Reese, C.B.; Song, Q. Tetrahedron 1999, 55, 5635-5640.) also has harsh reaction conditions, post-reaction treatment and product purification Difficulty, low yield, etc.
Due to the above difficulties and defects, it is very difficult to commercialize

Method used

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  • Preparation method of 2'-O-substituted uridine
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  • Preparation method of 2'-O-substituted uridine

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preparation example Construction

[0032] The reaction solvent in the preparation method of compound 1 provided by the present invention is a mixed solution, and the mixed solution is composed of the above-mentioned organic solvent 1 and organic solvent 2, and the organic solvent 2 is N,N-dimethylformamide ( DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP).

[0033] In one embodiment of the present invention, the volume ratio of organic solvent 2 and organic solvent 1 in the mixed liquid is 99:1-10:90, such as but not limited to, 90:10, 80:20, 95:5 , 70:30, 83:17, 60:40, 65:35, 50:50, 51:49, 45:55, 30:70, 25:75, 50:10, 30:10, 20:10, 45 :10, 25:10, etc.

[0034] In one embodiment of the present invention, the preparation method of 2'-O-substituted uracil (compound 1) provided comprises the steps of: combining 2,2'-epoxyuridine (CYU), silicon ether, BF 3The tetrahydrofuran solution and the 6:4 DMF / Diglyme mixture are mixed to form a reaction system, and the reaction is ca...

Embodiment 1

[0056] Myristyl alcohol tert-butyl dimethyl silyl ether (C 14 h 29 OTBDMS) synthesis

[0057]

[0058] Add 1.65kg of myristyl alcohol, 577g of imidazole, and 16.5L of DMF into the reaction kettle, stir and dissolve and add 1.28kg of tert-butyldimethylsilyl chloride dropwise. Stir the reaction at 25°C for 2 hours, UPLC analysis shows that the reaction is complete, pour the reaction solution into 50L of ice water, extract once with 16.0L of ethyl acetate, wash the organic phase with saturated brine, Na 2 SO 4 Dried and spin-dried to obtain 2.54kg of pale yellow C 14 h 29 The crude product of OTBDMS was directly used in the next reaction.

[0059] Synthesis of 2'-O-tetradecyluridine (compound 1A)

[0060]

[0061] Add 560g CYU, 2.21kg C 14 h 29 OTBDMS, 2.70L DMF and 1.80L Diglyme, add 690g BF dropwise with stirring 3 / THF solution. Raise the temperature to 140°C for 16 hours, UPLC analysis showed that the reaction was complete, cooled to room temperature, poured t...

Embodiment 2

[0064] Myristyl alcohol tert-butyl diphenylsilane (C 14 h 29 OTBDPS) synthesis

[0065]

[0066] In reactor, add 1.65kg myristyl alcohol, 577g imidazoles, 16.5L DMF, after stirring and dissolving, add dropwise 2. 40 kg tert-butyldiphenylchlorosilane (TBDPSCl). Stir and react at 25°C for 2 hours, UPLC analysis shows that the reaction is complete, pour the reaction solution into 50L water, extract once with 16.0L petroleum ether, wash the organic phase with saturated brine, Na 2 SO 4 Dried and spin-dried to obtain 3.55kg of light yellow C 14 h 29 The crude product of OTBDPS was directly used in the next reaction.

[0067] Synthesis of 2'-O-tetradecyluridine (compound 1A)

[0068]

[0069] Add 560g CYU, 3.10kg C to the reactor 14 h 29 OTBDPS, 2.70L DMAc and 1.80L Diglyme, add 690g BF dropwise with stirring 3 / THF solution. Raise the temperature to 140°C for 18 hours, UPLC analysis showed that the reaction was complete, cooled to room temperature, poured the react...

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Abstract

The invention discloses a preparation method of 2'-O-substituted uridine. The method comprises the steps of: mixing 2,2'-epoxyuridine, silyl ether, a Lewis acid catalyst and a solvent and reacting toobtain a compound having a structure as shown in Formula 1.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a novel synthesis method of 2'-O-substituted uridine nucleoside. Background technique [0002] Chemically modified nucleic acids are tools for various researches related to molecular biology, gene detection, gene therapy and bioindustry, among them, oligonucleotides containing 2'-O-alkyl substitutions are key intermediates of gene medicines , has very good application prospects, for example, 2′-O-alkyl nucleoside phosphoramidites are important raw materials for the synthesis of 2′-O-alkyl substituted oligonucleotides, and the market demand is very extensive. Therefore, it must be considered Cost and product purity of synthetic phosphoramidites. [0003] At present, the methods for synthesizing 2'-O-alkylated uridine derivatives by ring-opening of 2,2'-anhydrouridine (CYU) generally have problems such as harsh reaction conditions, difficult product purification, low yield, or even n...

Claims

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Application Information

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IPC IPC(8): C07H19/09C07H1/00
CPCC07H19/09C07H1/00
Inventor 于高辉杨阳阮洋庭姚峰刘洋
Owner SHANGHAI ZHAOWEI TECH DEV
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