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Novel method for synthesizing 5-carboxyl-2'-deoxycytidine

A deoxycytidine and carboxyl technology, applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve the problems of expensive raw materials, etc., and achieve simple synthesis methods, high product yields, and cheap and easy-to-obtain raw materials Effect

Inactive Publication Date: 2015-05-06
JIANGXI SCI & TECH NORMAL UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

In this method, the raw material of 5-iodo-2'-deoxycytidine is expensive, and the gas carbon monoxide in the carboxylation reaction requires special pressurized reaction equipment, thus limiting the application of this method

Method used

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  • Novel method for synthesizing 5-carboxyl-2'-deoxycytidine

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Experimental program
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Effect test

Embodiment 1

[0011] 1) 3',5'-di-tert-butyldimethylsilyl-5-acetylmethyl-2'-deoxyuridine ( 3 ) synthesis: under argon protection, the 2 (12 g, 25.4 mmol) was dissolved in dry carbon tetrachloride (200 mL), and recrystallized NBS (5.42 g, 30.4 mmol) and AIBN (100 mg, 0.61 mmol) were added at 60 °C, and the temperature was raised to 80 °C for 0.5 h, then added a second batch of recrystallized NBS (5.42 g, 30.4 mmol) and AIBN (100 mg, 0.61 mmol) into the reaction flask, and continued to stir for 1 h. Cool to room temperature, add chloroform (100 mL) to dilute the reaction solution, then wash with saturated brine (200 mL × 2), collect the organic phase, wash with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain crude 5-bromomethyl-2'-deoxyuridine. Subsequently, under the protection of argon, dry N , N - Dimethylformamide (20 mL) and potassium acetate (6.2 g, 63.5 mmol), heated to 40 °C for 0.5 hours. Cool to room temperature, add ethyl acetate (200 mL) to dilute the...

Embodiment 2

[0016] 1) 3',5'-di-tert-butyldimethylsilyl-5-acetylmethyl-2'-deoxycytidine ( 4 ) synthesis: under argon protection, the 3 (4.22 g, 8 mmol) dissolved in dry tetrahydrofuran (80 mL), added at 0 °C N - Methylpiperidine (960 mg, 9.6 mmol) triethylamine (2.44 mL, 17.6 mmol) and p-toluenesulfonyl chloride (3.8 g, 20 mmol). After reacting for 4 hours, 28% concentrated ammonia water (20 mL) was added at 0 °C, and the temperature was raised to 20 °C for 0.5 hour. Add ethyl acetate (400 mL) to dilute the reaction solution, then wash with saturated brine (400 mL×2), collect the organic phase, wash with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. Column chromatography separation (dichloromethane: methanol = 40: 1) to obtain a white solid ( 4 ) 3.03 g, yield 72%;

[0017] 2) 5-Carboxy-2′-deoxycytidine 1 The synthesis of 5 (2.91 g, 6 mmol) was dissolved in acetonitrile (30 mL), water (15 mL) was added, followed by TEMPO (94 mg, 0.6 mmol) and BAIB (3.86 g, 12 mmol...

Embodiment 3

[0019] 1) 3',5'-di-tert-butyldimethylsilyl-5-acetylmethyl-2'-deoxycytidine ( 4 ) synthesis: under argon protection, the 3 (4.22 g, 8 mmol) dissolved in dry dichloromethane (80 mL), added at 0 °C N - Methylpiperidine (960 mg, 9.6 mmol) triethylamine (2.44 mL, 17.6 mmol) and p-toluenesulfonyl chloride (4.56 g, 24 mmol). After reacting for 2 hours, 20% concentrated ammonia water (20 mL) was added at 0 °C, and the temperature was raised to 20 °C for 1 hour. Add ethyl acetate (400 mL) to dilute the reaction solution, then wash with saturated brine (400 mL × 2), collect the organic phase, wash with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. Column chromatography separation (dichloromethane: methanol = 40: 1) to obtain a white solid ( 5 ) 2.94 g, yield 70%;

[0020] 2) 5-carboxy-2′-deoxycytidine ( 1 ) synthesis: the 5 (2.91 g, 6 mmol) was dissolved in acetonitrile (30 mL), then TEMPO (282 mg, 1.8 mmol) and BAIB (5.76 g, 18 mmol) were added and reacted at ...

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Abstract

The invention relates to a method for synthesizing 5-carboxyl-2'-deoxycytidine. The method comprises the following steps: 1) brominating 3', 5'-biTBS deoxythymidine by using an N-bromo-succinimide NBS/azodiisobutyronitrile (AIBN) system to obtain a bromo intermediate and carrying out in-situ acetate substitution to obtain an acetyl protective intermediate (3); 2) aminating a nucleoside base by using a paratoluensulfonyl chloride/N-methylpiperidine/triethylamine and ammonia water system to obtain an acetyl protected hydroxymethyl deoxycytidine precursor (4); 3) removing acetyl under an alkaline condition by using potassium carbonate to obtain a hydroxymethyl precursor (5); and 4) oxidizing the hydroxymethyl precursor (5) by using a 2, 2, 6, 6-tetramethyl piperidine-nitro-oxide (TEMPO)/iodobenzene diacetate (BAIB) oxidizing system and removing the TBS protective group under the TFA condition to obtain a target object. The method provided by the invention has the advantages of simple method and high yield.

Description

technical field [0001] The invention belongs to the field of chemical synthesis and relates to a novel synthesis method for synthesizing 5-carboxy-2'-deoxycytidine by protecting deoxythymidine raw materials with double TBS. technical background [0002] In mammalian genes, 5-methyl-2'-deoxycytidine is a low-content nucleoside, accounting for only about 1% of the total DNA nucleosides. The latest research shows that 5-methyl-2'-deoxycytidine can be oxidized to 5-hydroxymethyl-2'-deoxycytidine, 5-formyl-2'-deoxycytidine and 5-formyl-2'-deoxycytidine under the action of special oxidase -Carboxy-2'-deoxycytidine. These three nucleoside oxides are thought to be involved in the regulation of cellular epigenetic programs. Therefore, the synthesis of oligonucleotides and triphosphates from 5-carboxy-2'-deoxycytidine and other 5-methyl-2'-deoxycytidine oxides as raw materials and molecular biological research on the regulation of epigenetic programs has important meaning. However...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00
CPCY02P20/55C07H19/073C07H1/00
Inventor 龚珊珊孙麒孙剑马茶
Owner JIANGXI SCI & TECH NORMAL UNIV
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