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A manufacturing process of 2',2'-difluoronucleoside and intermediate

An enantiomer, NO2 technology, applied in the 2' field, can solve the problems of affecting the purity and cumbersome processing

Inactive Publication Date: 2007-06-20
DONG A PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, it is not necessary to perform glycosylation after isolation of the α-anomer in low yields below 68%
In addition, the reaction solvent uses toxic anisole with a boiling point of 154 ° C, so the post-reaction treatment is very cumbersome
Therefore, the final product, 2'-deoxy-2',2'-difluoronucleoside, has residual solvent which affects the purity

Method used

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  • A manufacturing process of 2',2'-difluoronucleoside and intermediate
  • A manufacturing process of 2',2'-difluoronucleoside and intermediate
  • A manufacturing process of 2',2'-difluoronucleoside and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Preparation of 2-deoxy-2,2-difluoro-1-oxo-ribose

[0054] (3R, S)-2,2-difluoro-3-hydroxyl-3-(2,2-dimethyldioxolan-4-yl)propanoic acid ethyl ester (30 g, 0.118 mol) After adding acetonitrile (165 ml), acetic acid (67.6 ml) and water (11.7 ml) to dissolve, the mixture was stirred and refluxed for 4 hours. After the reaction liquid was concentrated under reduced pressure, toluene (165 ml) was added to carry out concentration under reduced pressure. Acetonitrile (165 ml) was added to the concentrate, and toluene (300 ml) was added thereto, followed by distillation and concentration under reduced pressure. Ethyl acetate (200 ml) was added to the concentrate for dilution, and activated carbon (3 g) was added thereto and stirred for 10 minutes. After the mixture was treated with anhydrous sodium sulfate, it was filtered through celite, and the obtained filtrate was concentrated under reduced pressure to obtain 2-deoxy-2,2-difluoro-1-oxoribose (20 g, 100%).

[0055] 1 H NMR...

Embodiment 2

[0057] Preparation of 2-deoxy-2,2-difluoro-D-erythro-3,5-bis(3-fluorobenzoate)pentofurano-1-side

[0058] 2-deoxy-2,2-difluoro-1-oxo-ribose (20 g, 0.119 mol) was dissolved in ethyl acetate (200 ml), then 4-dimethylaminopyridine (29 g) was added, and After adding pyridine (28 g), 3-fluorobenzoyl chloride (2.5 g) was added. The reaction solution was stirred day and night at 60°C. After the reaction, it was washed with dilute hydrochloric acid aqueous solution and saturated brine, respectively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (23 ml) was added to the concentrate to dissolve it, and hexane (68 ml) was added thereto, followed by cooling to 0°C. After the resulting crystals were filtered, washed with a cooled mixture of ethyl acetate:hexane=1:3 (volume ratio), and dried to obtain 2-deoxy-2,2-difluoro-D-erythro-3, 5-bis(3-fluorobenzoate)pentofurano-1-side (26.7 g, 46%).

[0059] 1 H NMR (...

Embodiment 3

[0061] Preparation of 2-deoxy-2,2-difluoro-3,5-bis(3-fluorobenzoate)-D-ribofuranose

[0062] Add tetrahydrofuran (240 ml ) was dissolved, lithium tri-tert-butoxyaluminum hydride (22.2 g, 0.087 mol) was added, and stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction solution was diluted with ethyl acetate (960 ml), and washed with dilute aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water, and saturated brine, respectively. After drying with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain 2-deoxy-2,2-difluoro-3,5-bis(3-fluorobenzoyl)-D-ribofuranose (24 g, 100% ).

[0063] 1 H NMR (CDCl 3 ); δ=4.4~4.75(m, 3H), 5.55(d, 1H), 5.4~5.7(m, 1H), 7.23~7.45(m, 4H), 7.70~7.89(m, 4H)

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Abstract

The present invention relates to more improved process for preparing 2'-deoxy-2',2'-difluoronucleoside and its intermediate. The present invention provide a process for preparing an erythro enantiomer in greater than 98% purity, comprising forming a lactone ring by hydrolyzing ethyl (3RS )-2,2-difluoro-3-hydroxy-3-(2,2-dimethyloxolan-4-yl)propionate is hydrolyzed in the presence of hydrolysis reagents selected from acetic acid or chloroacetic acid, water and a mixture of organic solvents selected from the group comprising acetonitrile, dioxane, tetrahydrofuran or toluene, in not troducing a substituted benzoyl protecting group at the 3-position and 5-position, and recrys- tallizing said erythro enantiomer. Further, the present invention provides a process for selectively preparing, in greater than 99% purity, a beta-anomer 2'-deoxy-2',2'-difluoronucleoside at the 3'-position and 5'-position that are protected by a substituted benzoyl in a 2:3 alpha / beta anomeric ratio.

Description

technical field [0001] The present invention relates to a method for preparing 2',2'-difluoronucleosides represented by the following chemical formula 1 and intermediates thereof having good antitumor activity. [0002] chemical formula 1 [0003] Background technique [0004] European Patent EP184365 describes the use of 2'-deoxy-2', 2'-difluoronucleoside represented by the above chemical formula 1 as an elimination compound for tumor cells, the 2'-deoxy-2', 2'-difluoronucleoside Fluorinucleosides are currently widely used as therapeutic agents for non-small cell lung cancer, pancreatic cancer, bladder cancer, and metastatic breast cancer. [0005] The preparation method of the above-mentioned 2'-deoxy-2', 2'-difluoronucleoside has been disclosed in US4526988 and US4808614. Its reaction formula is as following reaction formula 1. [0006] [Reaction 1] [0007] [0008] In the above reaction formula 1, R 4 and R 5 independently represent C 1 -C 3 An alkyl group...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33C07H19/067
CPCC07D307/33C07D307/20C07D405/04C07H19/06Y02P20/55C07D307/32
Inventor 金文成金容稙崔俊浩林弘珪车大元
Owner DONG A PHARMA
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