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Preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside

A ribofuranoside and isopropylidene technology is applied in the field of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside preparation, and can solve the problem of complicated operation, difficulty in recycling and recovery Difficulties and other problems, to achieve the effect of mild conditions and low production costs

Inactive Publication Date: 2015-11-11
启东东岳药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The methyl-2,3-O-isopropylidene-5-O-p-toluenesulfonyl-D-ribofuranoside obtained in this patent needs a large amount of isopropanol as a crystallization solvent, and also needs to go through processes such as filtration and drying. Complicated; and using dimethyl sulfoxide as a reducing solvent, there will be a foul smell during post-treatment and it will be difficult to recover and recycle

Method used

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  • Preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside
  • Preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside

Examples

Experimental program
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Effect test

Embodiment 1

[0020] Add 50g of D-ribose, 400ml of methanol, 400ml of acetone, and 4g of methanesulfonic acid into a 1000ml three-necked flask, stir to dissolve, heat up to reflux for 2.5 hours, cool to room temperature, add triethylamine to adjust the pH to 7-8, and concentrate under reduced pressure to remove Methanol and acetone, cooled to 15-20°C, diluted with 50ml of water, extracted with 300ml+200ml of toluene. Combine the toluene phases, cool to 5-10°C, add 57.5g of p-toluenesulfonyl chloride, 1g of triethylbenzyl ammonium chloride, dropwise add 54g of 50% sodium hydroxide solution, keep the reaction for 4 hours after dropping, add 5ml of methanol, continue React for 1 hour, add 100ml×2 water to wash the salt, add 200ml saturated aqueous sodium bicarbonate solution to the toluene phase, heat up and reflux for 1 hour, cool to room temperature, and separate the phases to obtain methyl-2,3-O-isopropylidene-5- O-toluenesulfonyl-D-ribofuranoside toluene is about 550ml.

Embodiment 2

[0022] The methyl-2,3-O-isopropylidene-5-O-p-toluenesulfonyl-D-ribofuranoside toluene obtained in Example 1 was mixed with about 550ml of toluene, concentrated under reduced pressure to remove the toluene, added 200ml of HMPA, and heated to 90-95 ℃, slowly add 16.2g of potassium borohydride in batches, keep warm for 4 hours after addition, cool to 15-20℃, add 200ml of water dropwise to quench the reaction. Extract with 150ml×3 petroleum ether, combine the petroleum ether phases, wash with 20ml of water, concentrate to remove the petroleum ether, and obtain 50g of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside, The total yield is 80%, and the GC content is 96.9%.

Embodiment 3

[0024] The methyl-2,3-O-isopropylidene-5-O-p-toluenesulfonyl-D-ribofuranoside toluene obtained in Example 1 contained about 550ml of toluene, concentrated under reduced pressure to remove the toluene, added 200ml of DMI, and raised the temperature to 90-95 ℃, slowly add 16.2g of potassium borohydride in batches, keep warm for 4 hours after addition, cool to 15-20℃, add 200ml of water dropwise to quench the reaction. Extract with 150ml×3 petroleum ether, combine the petroleum ether phases, wash with 20ml of water, concentrate to remove the petroleum ether, and obtain 51g of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside, The total yield is 81%, and the GC content is 97.5%.

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Abstract

The invention discloses a preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside. The method comprises: taking D-ribose as an initial material to obtain methyl-2,3-O-isopropylidene-D-ribofuranoside under the protection of methanol / acetone; reacting methyl-2,3-O-isopropylidene-D-ribofuranoside with paratoluensulfonyl chloride to obtain methyl-2,3-O-isopropylidene-5-O-paratoluenesulfonyl-D-ribofuranoside in alkaline condition, wherein the reaction is subjected to proper treatment and needs no purification; taking hexamethylphosphoric triamide or N,N-dimethyl-2-imidazolidinone as a reducing solvent; and using hydroboron for reduction to obtain methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside. The reducing reaction agent can be recycled; the reaction intermediates are subjected to proper treatment and need no purification; and the preparation method is simple to operate, wild in condition, and low in production cost.

Description

technical field [0001] The invention relates to a method for preparing methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside. Background technique [0002] Methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside is a key intermediate in the synthesis of antiviral drug capecitabine. The structure is as follows: [0003] [0004] The preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside has been reported in the literature and patents, generally using D-ribose as raw material, protected by methanol and acetone, p-toluene Esterification of sulfonyl chloride and reduction of borohydride, the reaction principle is as follows: [0005] [0006] The world patent WO2010065586A2 reports that D-ribose is protected by methanol and acetone, and triethylamine is used as an acid-binding agent to esterify p-toluenesulfonyl chloride to obtain methyl-2,3-O-isopropylidene-5-O-p- Tosyl-D-ribofuranoside, this intermediate was purified by crystallization in isopropanol a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04C07H1/00
Inventor 李林旺龙中柱郭忠武张文文蔡水洪
Owner 启东东岳药业有限公司
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