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A kind of synthetic method of 3-hydroxymethyl tetrahydrofuran

A technology of hydroxymethyltetrahydrofuran and synthesis method, applied in the direction of organic chemistry, etc., can solve the problems of low total yield, high cost of reaction raw materials, large amount of metal borohydride used, etc., to reduce the production of by-products and the cost of preparation Reduction, the effect of usage reduction

Inactive Publication Date: 2016-05-25
XIAN MODERN CHEM RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There is a large amount of metal borohydride used in this technology, the mol ratio of metal borohydride used and 2-ethoxyl-diethyl succinate is 3:1, the reaction raw material cost is higher, and the total yield is lower. 53.5%

Method used

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  • A kind of synthetic method of 3-hydroxymethyl tetrahydrofuran
  • A kind of synthetic method of 3-hydroxymethyl tetrahydrofuran
  • A kind of synthetic method of 3-hydroxymethyl tetrahydrofuran

Examples

Experimental program
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Effect test

Embodiment 1

[0018] (1) In a 500ml reaction flask, after adding 80g of diethyl malonate, add dropwise 200ml of ethanol solution of 56g of potassium tert-butoxide, and slowly heat to 80°C to react. After dropping, drop slowly Add 40.3 grams of 2-chloroethanol, drop it, and react at a temperature of 80°C for 7 hours, evaporate the ethanol solvent, and filter to obtain 96 grams of intermediate 2-hydroxyethyl-diethyl succinate, with a yield of 95%. Purity 96% (HPLC).

[0019] IR :3638,3462,2984,1736,1174,859cm -1 .

[0020] (2) 96 grams of 2-hydroxyethyl-diethyl succinate prepared in step (1) are dropped into a 500 milliliter reaction flask, add 200 milliliters of methanol as a solvent, then add 36 grams of boron in batches Sodium hydride, temperature controlled at 70°C, reacted for 2 hours, and reduced to obtain 43 g of crude 2-hydroxymethyl-1,4-butanediol with a yield of 80% and a purity of 98% (HPLC).

[0021] 1 HNMR (D 2 O,δ:ppm):δ1.53(2H,q,J=6Hz,CH CH 2 ),1.75(1H,m, CHCH 2 ),3...

Embodiment 2

[0028] (1) In a 1000 ml reaction flask, after adding 261 grams of diethyl malonate, 200 ml of ethanol solution of 62 grams of sodium methoxide was added dropwise, and slowly heated to 75°C to react. After dropping, slowly add 132 grams of 2-Chloroethanol, after dripping, reacted at 75°C for 6 hours, evaporated the ethanol solvent, cooled and filtered, and removed sodium chloride to obtain 312.5 grams of 2-hydroxyethyl-diethyl succinate with a yield of 95 %, purity 96% (HPLC).

[0029] (2) 96 grams of intermediate 2-hydroxyethyl-diethyl succinate obtained in step (1) are dropped into a 500-ml reaction flask, and 200 ml of methyl alcohol is added as a solvent, and then 36 1 g of sodium borohydride was reacted at a temperature of 70° C. for 2 hours, and then reduced to obtain 41.9 g of crude 2-hydroxymethyl-1,4-butanediol with a yield of 80% and a purity of 98% (HPLC).

[0030] (3) get the 2-hydroxymethyl-1,4-butanediol that makes in step (2) and can add in the 500 milliliters t...

Embodiment 3

[0032] (1) In a 1000 ml reaction flask, after adding 160 grams of diethyl malonate, dropwise add 52 grams of ethanol solution of sodium ethylate, and slowly heat to 60°C for reaction, after dropping, slowly add 89 grams of 2- Chlorohydrin, dropwise, reacted at 60°C for 10 hours at a temperature of 60°C, evaporated the ethanol solvent, and filtered to obtain 194 g of 2-hydroxyethyl-diethyl succinate with a yield of 96% and a purity of 97% (HPLC).

[0033] (2) Get 96 grams of 2-hydroxyethyl-diethyl succinate prepared in step (1) and drop into a 500-ml reaction flask, add 200 ml of methanol as a solvent, then add 52 grams of boron in batches Potassium hydride was reacted at a temperature of 60°C for 2 hours, and 41 g of crude 2-hydroxymethyl-1,4-butanediol was obtained by reduction, with a yield of 80% and a purity of 97% (HPLC).

[0034] (3) 2-hydroxymethyl-1,4-butanediol prepared in step (2) can be added in the 500 milliliter three-neck reaction flask that water trap and reflux...

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Abstract

The invention discloses a synthetic method for 3-hydroxylmethal tetrahydrofuran. The synthetic method comprises the following steps: with 2-chloroethanol and diethyl malonate as raw materials, reacting under the action of alkaline in the presence of an organic solvent or in absence of a solvent to obtain an intermediate 2-ethoxy-diethyl succinate; then, reducing the intermediate 2-ethoxy-diethyl succinate by virtue of metal borohydride to obtain 2-hydroxymethyl-1,4-butanediol; and finally, producing 3-hydroxylmethal tetrahydrofuran under the action of a dehydrating agent. According to the synthetic method, the usage amount of the reducing agent metal borohydride is remarkably lowered, and yield of a byproduct sodium metaborate is reduced at the same time. The invention provides the synthetic method for the drug intermediate 3-hydroxylmethal tetrahydrofuran.

Description

technical field [0001] The invention relates to a method for synthesizing a pharmaceutical intermediate, in particular to a method for synthesizing 3-hydroxymethyltetrahydrofuran. Background technique [0002] 3-Hydroxymethyltetrahydrofuran compound is a key intermediate for the preparation of the third-generation nicotinic insecticide dinotefuran and medicine penciclovir, and its structural formula is as follows: [0003] [0004] At present, there are few documents on the method of synthesizing 3-hydroxymethyltetrahydrofuran at home and abroad. The traditional synthesis process (WO2005065689) is to use 2-ethoxyl-diethyl succinate as raw material, and generate 2 after sodium borohydride reduction. -Hydroxymethyl-1,4-butanediol, followed by acidic dehydration to obtain 3-hydroxymethyltetrahydrofuran. Its synthetic route is as follows: [0005] [0006] There is a large amount of metal borohydride used in this technology, and the mol ratio of metal borohydride used an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/12
CPCC07D307/12
Inventor 王威何琦文王月梅张媛媛王安勇张晓光王列平林双政宁斌科薛超
Owner XIAN MODERN CHEM RES INST
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