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Synthesis method of 2'-deoxy-beta-uridine

A synthesis method and technology of uridine, applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve problems affecting product quality, low selectivity, high impurity content, etc., to improve industrial application prospects, reaction The effect of simple conditions and high product yield

Inactive Publication Date: 2018-07-20
王成宇
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The previous mainstream route used uridine as the main raw material for structural modification, which had problems such as cumbersome operation, low selectivity, poor yield, poor safety, high impurity content, and high energy consumption.
For example, uridine is obtained by protecting the 3 and 5 positions with alkylacyl bromide, and simultaneously brominating the 2 positions, followed by debromination and saponification. The debromination is mainly debrominated by catalytic hydrogenation of Pd / C and Raney-Ni. This process route The cost is high, and the most prominent disadvantage is that the unremoved brominated impurities will be brought into the product and affect the quality of the product

Method used

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  • Synthesis method of 2'-deoxy-beta-uridine
  • Synthesis method of 2'-deoxy-beta-uridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: Add 2'-deoxyribose (6.00 g, 44.7 mmol) and anhydrous methanol (30 mL) to the reaction flask in sequence, add acetyl chloride (0.17 g, 2.2 mmol) in an ice-water bath and stir for 2 h, then add triethyl The amine (0.33 g, 3.3 mmol) was stirred for 10 min. Distill methanol off under reduced pressure, add 1,4-dioxane (40 mL), DMAP (0.18 mg, 1.5 mmol), triethylamine (9.95 g, 98.3 mmol), add p-chlorobenzyl dropwise under ice-water bath A solution of acid chloride (16.43 g, 93.9 mmol) in 1,4-dioxane (20 mL) was moved to room temperature and stirred for 13 h. Filter, evaporate the solvent under reduced pressure, add 1,4-dioxane (20 mL), acetyl chloride (0.64 g, 8.2 mmol), glacial acetic acid (35 mL), and pass through dry hydrogen chloride gas until TLC shows that the raw material point disappears , filtered, slurried with methyl tert-butyl ether (60 mL×2), and dried to obtain a white solid (14.5 g, yield 75.4%), HPLC purity 89.5%.

Embodiment 2

[0022] Example 2: In the reaction flask, chloroform (30 mL), the white solid obtained in Example 1 (3.0 g, 7.0 mmol), 2,4-bis(trimethylsiloxy)pyrimidine (2.51 g, 9.8 mmol), lithium triflate (0.11 g, 0.7 mmol). Under nitrogen protection, stir for 2 h. Evaporate the solvent under reduced pressure, beat with ethanol (20 mL×2), filter, add methanol (30 mL) to reflux, cool down to crystallize, filter, and dry to obtain a white solid (2.50 g, yield 74.8%), HPLC purity 98.4%.

Embodiment 3

[0023] Example 3: In the reaction flask, chloroform (30 mL), the white solid obtained in Example 1 (3.0 g, 7.0 mmol), 2,4-bis(trimethylsiloxy)pyrimidine (2.51 g, 9.8 mmol), ytterbium triflate (0.44 g, 0.7 mmol). Under nitrogen protection, stir for 2 h. Evaporate the solvent under reduced pressure, beat with ethanol (20 mL×2), filter, add methanol (30 mL) to reflux, cool down to crystallize, filter, and dry to obtain a white solid (2.45 g, yield 73.3%), HPLC purity 98.2%.

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Abstract

The invention discloses a synthesis method of 2'-deoxy-beta-uridine, and belongs to the technical field of medicinal chemistry. The synthesis method comprises the following steps: preparing 1-chloro-2-deoxy-3, 5-O-bis(4-chlorobenzoyl)-alpha-D- red-furanose from 2'-deoxyribose by a one-pot methylation, acylation and chlorine substitution method, then coupling with 2, 4-bis(trimethylsilyloxy)pyrimidine, and finally deacylating and recrystallizing to obtain the 2'-deoxy-beta-uridine. By the synthesis method, the defects that when uridylic acid is used as a raw material, stereoisomers are difficult to control and the quality is relatively poor are overcome, the reaction condition is simple, the raw materials are easy to obtain, the product is high in yield and purity and the energy consumptionis reduced, so that the industrial application prospect is greatly improved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacy, and in particular relates to a method for synthesizing a pharmaceutical intermediate 2'-deoxy-β-uridine. Background technique [0002] The pharmaceutical intermediate 2'-deoxy-β-uridine is a widely used nucleoside, especially in the synthesis of enzyme inhibitors, antitumor and antiviral drugs, and is mainly used in the production of The demand for raw materials of antineoplastic drug FUDR, antiviral drug IDUR and BrDUR is increasing day by day. The previous mainstream route used uridine as the main raw material for structural modification, which had problems such as cumbersome operation, low selectivity, poor yield, poor safety, high impurity content, and high energy consumption. For example, uridine is obtained by protecting the 3 and 5 positions with alkylacyl bromide, and simultaneously brominating the 2 positions, followed by debromination and saponification. The debrominatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H19/073
CPCC07H1/00C07H19/073
Inventor 王成宇
Owner 王成宇
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