KR20160125115A

KR20160125115A - Preparation Method for 3-Hydroxytetrahydrofuran

Info

Publication number: KR20160125115A
Application number: KR1020150055864A
Authority: KR
Inventors: 엄기남
Original assignee: 주식회사 비앤팜
Priority date: 2015-04-21
Filing date: 2015-04-21
Publication date: 2016-10-31

Abstract

The present invention relates to a process for preparing 3-hydroxytetrahydrofuran, and more particularly to a process for producing 3-hydroxytetrahydrofuran from 4-halo-3-hydroxybutyrate ester (1) (3), 4-halo-1,3-butanediol is reacted with an inorganic base in an alcohol of C1-C4, and the resulting salt is removed by filtration and vacuum distillation is carried out to obtain 3-hydroxytetrahydro Hydroxytetrahydrofuran, which comprises purifying furan. The present invention also relates to a process for producing 3-hydroxytetrahydrofuran.
[Reaction Scheme 1]

Wherein X = Cl, Br or I, and R = C1-C4 alkyl or aryl.

Description

Preparation Method for 3-Hydroxytetrahydrofuran < RTI ID = 0.0 >

The present invention relates to a process for preparing 3-hydroxytetrahydrofuran.

3-hydroxytetrahydrofuran is an important intermediate used in the manufacture of medicines and pesticides, particularly as a key intermediate in the synthesis of Amprenavir, which is used as an HIV protease inhibitor for the treatment of AIDS have.

(1,2,4-butanetriol) is catalytically dehydrated in the presence of para-toluenesulfonic acid or a strongly acidic cation exchange resin having a sulfuric acid group as an exchange group as a method for producing 3-hydroxytetrahydrofuran. (Japanese Patent Application Laid-Open No. 10-2006-0067620). However, in this case, a method for producing 1,2,5-butanetriol Is not easy and expensive, and thus is not suitable for use as an economical production method of 3-hydroxytetrahydrofuran.

Other methods are disclosed in Japanese Laid-Open Patent Application No. 09-77759 (1997), US Patent No. 5,780,649 and Liebigs Ann./Recl, page 1877 (1997) disclose 4-halo- 3-hydroxybutyric acid ester) by a two-step method. More specifically, 4-halo-3-hydroxybutyric acid ester is dissolved in sodium borohydride in an organic solvent which is miscible with water, such as tetrahydrofuran, To produce 4-halo-1,3-butanediol, which is then cyclized in aqueous hydrochloric acid to produce 3-hydroxytetrahydrofuran.

However, in the above method, 3,4-epoxy-1-butanol is generated in the reduction reaction and 2,5-dihydrofuran is produced as a by-product in the cyclization reaction, resulting in a very low total yield of 58 to 68% there is a problem. In order to solve this problem, by-products are greatly reduced by using a solvent which is not miscible with water in the reduction reaction step. However, the reaction time is about 40 hours and a severe condition such as continuous extraction at 70 ° C. is required in the extraction step It was also difficult to apply it to mass production. Further, since the cyclization reaction proceeds in an aqueous solution, it is difficult to separate the target compound which is water-soluble after completion of the reaction.

As described above, the process for producing 3-hydroxytetrahydrofuran according to the prior art is not suitable for mass production and has a high production cost. Therefore, a low-priced starting material and a reaction material are used, and a high- There is a need for development of a process for preparing 3-hydroxytetrahydrofuran.

Published Patent No. 10-2006-0067620 Japanese Laid-Open Patent Application No. 09-77759 U.S. Patent No. 5,780,649

Liebigs Ann./Recl, 1877 (1997).

In order to solve the problems of the prior art, the present invention provides a process for mass-producing high-quality 3-hydroxytetrahydrofuran in a high yield by a simple process while using a low-cost 4-halo-3-hydroxybutyric acid seed ester as a starting material And to provide a method that can be used.

In order to achieve the above object, the present invention provides a process for producing 3-hydroxytetrahydrofuran (3) from a 4-halo-3-hydroxybutyric acid ester (1) -Halo-1,3-butanediol is reacted with an inorganic base in an alcohol, and the resulting salt is removed by filtration and vacuum distillation is carried out to purify 3-hydroxytetrahydrofuran And a method for producing the same.

[Reaction Scheme 1]

Wherein X = Cl, Br or I, and R = C1-C4 alkyl or aryl.

In the present invention, the cyclization reaction is carried out using an inorganic base in an alcohol of C1 to C3 without using water in the cyclization reaction, and the resulting salt is removed by filtration to concentrate the volatile alcohol, followed by vacuum distillation The target compound is obtained. Therefore, not only the time required for mass production is long, but also the water condensing agent which generates by-products resulting from the temperature elevation to a high temperature during the condensation is not included, so that the target compound can be obtained in a short time in a high yield. In addition, since 3-hydroxytetrahydrofuran is purified by vacuum distillation in the state where there are few by-products, it is possible to produce a compound of high purity. It is preferable that the solvent is C1-C4 alcohol. In the case of butanol, since the solubility of the inorganic base is low and the boiling point is high, it is more preferable to use C1-C3 alcohol.

As the inorganic base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate can be used. The reaction temperature may be in the range of 5 to 80 ° C. If the reaction temperature is too low, the reaction rate is slow. However, the reaction rate is increased as the reaction temperature is increased. When the inorganic base is added, the temperature may rise due to heat generation, and therefore it is preferable to add slowly so that the temperature can be maintained at 40 ° C or lower. The salt formed by the reaction can be easily removed by filtration.

In addition, in the present invention, 4-halo-1,3-butanediol is more preferable to reduce 4-halo-3-hydroxybutyric acid ester to sodium borohydride using C1-C4 lower alcohol as a solvent Do. The temperature for the reduction reaction is preferably 5 to 60 ° C, more preferably 20 to 40 ° C.

Further, when 4-halo-3-hydroxybutyric acid ester having optical activity is used as a starting material in the production method of the present invention, 4-halo-1,3-butanediol (2) 3-hydroxytetrahydrofuran can be prepared.

As described above, according to the present invention, by using a low-cost 4-halo-3-hydroxybutyric acid seed ester which is easy to supply and demand as a starting material, a high quality 3-hydroxytetrahydro Furan can be mass produced. Furthermore, since the desired compound can be prepared in a state in which optical activity is maintained, when optically active 4-halo-3-hydroxybutyric acid seed ester is used as the starting material, 3-hydroxy tetrahydrofuran Can be produced.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the drawings and the embodiments are only illustrative of the contents and scope of the technical idea of the present invention, and the technical scope of the present invention is not limited or changed. It will be apparent to those skilled in the art that various changes and modifications can be made within the scope of the technical idea of the present invention based on these examples.

Example

Example 1: Preparation of S-3-hydroxytetrahydrofuran by stepwise reaction

1) Preparation of S-4-chloro-1,3-butanediol

34 g (99.5% ee) of ethyl 4-chloro-3-hydroxybutyrate was dissolved in 60 ml of ethanol, and 22.6 g of sodium borohydride was added slowly while keeping the temperature below 20 ° C, followed by stirring at 30 ° C for 6 hours. After completion of the reaction, 2N hydrochloric acid was added to maintain the pH at 4 while maintaining the temperature at 10 ° C. The mixture was extracted three times with 60 ml of ethyl acetate each time, and the organic layers were combined and concentrated under reduced pressure. The concentrated residue was purified by column chromatography to give 22.8 g of S-4-chloro-1,3-butanediol (yield 92%, 99.5% ee).

2) Preparation of S-3-hydroxytetrahydrofuran

(1) Production Example 1

12.4 g (99.5% ee) of S-4-chloro-1,3-butanediol was dissolved in 150 ml of methanol. Sodium hydroxide (4.8 g) was slowly added thereto and stirred at 40 ° C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solid was filtered. The solvent was concentrated under reduced pressure to obtain 8.45 g of S-3-hydroxytetrahydrofuran (yield: 96%, 99.5% ee).

(2) Production example 2

12.4 g (99.5% ee) of S-4-chloro-1,3-butanediol was dissolved in 150 ml of methanol. 6.2 g of potassium hydroxide was slowly added thereto and stirred at 40 ° C for 4 hours. After cooling to room temperature, the solid was filtered and the solvent was concentrated under reduced pressure to obtain 8.54 g of S-3-hydroxytetrahydrofuran (yield 97%, 99.5% ee).

Example 2: Preparation of S-3-hydroxytetrahydrofuran omitting the purification process

333.8 g (99.5% ee) of ethyl 4-chloro-3-hydroxybutyrate was dissolved in 510 ml of ethanol and 226.8 g of sodium borohydride was slowly added while the temperature was kept below 20 ° C. When the addition was completed, the temperature was raised to 30 占 폚 and further stirred for 6 hours while maintaining the temperature. When the reaction was completed, the pH was adjusted to 4 using 2N hydrochloric acid at 10 캜 or lower. After repeating extraction three times with 600 ml of ethyl acetate, the organic layers were combined and concentrated under reduced pressure.

Methanol (100 ml) was added to the concentrated residue, and the mixture was concentrated under reduced pressure once again to obtain 228 g of crude S-4-chloro-1,3-butanediol. The concentrated residue was dissolved in 1 liter of methanol, and 99.3 g of potassium hydroxide was slowly added thereto, followed by stirring at 40 ° C for 4 hours. When the reaction was completed, the reaction solution was cooled to room temperature and the solid was filtered and washed. The filtrate and washing solution were combined, concentrated under reduced pressure, and distilled under reduced pressure to give 154.8 g (total yield 87%, 99.5% ee) of S-3-hydroxytetrahydrofuran.

Claims

A process for producing 3-hydroxytetrahydrofuran (3) from 4-halo-3-hydroxybutyric acid ester (1) by the following Reaction Scheme 1,
3-hydroxytetrahydrofuran is purified by reacting 4-halo-1,3-butanediol with an inorganic base in an alcohol of C1-C4 and removing the resulting salt by filtration and vacuum distillation. / RTI > hydroxytetrahydrofuran.
[Reaction Scheme 1]

Wherein X = Cl, Br or I, and R = C1-C4 alkyl or aryl.

The method according to claim 1,
Wherein the inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate.

3. The method according to claim 1 or 2,
4-halo-1,3-butanediol is a product obtained by reducing a 4-halo-3-hydroxybutyric acid ester with sodium borohydride using a C1-C4 alcohol as a solvent. &Lt; / RTI >