KR890000290B1 - Process for preparing oxlane derivatives - Google Patents

Abstract

Title compds. (I)[Ar=unsubstituted aryl, aryl substituted by C1-5 alkyl, alkenyl, alkoxy are prepd.. Thus, a material obtained from 100ml acetonitrile soln. contg. 18.8g phenol and 8.0g NaOH is treated with n-hexane and a mixt. contg. 3 parts H2O, 2 parts methanol and 1 part isopropyl alcohol to give 25.6g 1phenoxy-2,3-epoxy propane (yield-85.3%).

Description

Process for preparing oxirane derivative

The present invention relates to a method for producing the oxirane derivative of the following structural formula (1), namely 1-aryloxy-2, 3-ethoxypropane.

In the above formula, Ar represents an unsubstituted aryl group or an aryl group substituted with an alkyl group, alkenyl group or alkoxy having 1 to 5 carbon atoms.

Compounds of formula (1) are generally widely used as useful synthetic intermediates of β-blockers.

General methods for the preparation of this compound are described in US Pat. No. 3,466,376 (Examples 1-4), UK Patent No. 1,307,405 (Example 1, Method-b) and Japanese Patent Application Publication No. 42-9, 954 ( Examples 1 and 2). Comprehensive description of these prior arts, the compound of formula (1) is added to the alkali, such as hydroxyaryl derivatives, Ar-OH and sodium hydroxide, potassium hydroxide in the presence of a water solvent, to the epihalo of the following structural formula Hydrin,

In particular, epichlorohydrin is added to the hydroxyaryl derivative at about 1: 1 to 1: 2 molar ratio, followed by stirring and reaction. The reaction product is extracted with ether, chloroform and the like, and the solution is subjected to high temperature and high vacuum (usually, Distillation under 100-150 ° C./1 mmHg or less) to obtain the desired product. This reaction can be summarized as follows.

However, in the method proposed in the above-mentioned prior art, since a large amount of unnecessary by-products are generated, and the removal of such by-products is difficult and difficult, not only a high temperature and high vacuum distillation process requiring an industrially complicated facility is required, Poor yields are known. According to the experiments performed by the inventors according to the contents of the prior art described above, two or more by-products are usually produced at a ratio of 45-55%, and the target product (1-aryloxy-2, The final yield of 3-epoxypropane) was only 30-40% (see Comparative Examples 1 and 2 below). An important example of such by-products is 1, 3-diaryloxy-2-propanol, which is produced in the highest amounts, and another by-product is 1-aryloxy-2, 3-propanediol resulting from the use of water as the reaction solvent. Even when lower alcohols are used as solvents, by-products similar to those when water is used as solvents are produced. In addition, two different levels of by-products are found in thin layer chromatography (TLC). In addition, in the reaction solution of the reaction, in addition to the above by-products, unreacted aryl derivatives, epihalohydrin, and 1-aryloxy-2 and 3-epoxypropane as target products are mixed together, and thus the desired product is contained. The concentrated solution in vacuo results in a syrupy, viscous solution, which not only requires high temperature, especially high vacuum, demanding conditions for the distillation process (it is not easy to industrially use a vacuum of 1 mmHg or less), but also distillation yield. Is lowered. Furthermore, in the high temperature state where various impurities are mixed, the epoxy group of 1-aryloxy-2, 3-epoxypropane, that is,

There is a problem that the structure is easy to decompose.

Therefore, the present inventors have been able to reach the present invention by improving the reaction conditions of the conventional method, more specifically, the reaction solvent, the purification method, etc., as a result of long-term research to solve the above-mentioned drawbacks of the previous method. there was.

Accordingly, the present invention aims to obtain high-purity 1-aryloxy-2, 3-epoxypropane in high yield without generation of by-products that are problematic in the conventional methods.

The object of the present invention is to react 1-aryloxy-2, 3 of the following structural formula (1) by reacting hydroxyaryl derivative of the following structural formula (2) and epihalohydrin of the following structural formula (3) in the presence of an alkalizing agent. In preparing the epoxy propane, the reaction solution containing the desired product can be extracted with a nonpolar organic solvent, and then the extract is further extracted with a mixed solvent.

In each formula, Ar is an unsubstituted aryl group or an aryl group substituted with an alkyl group, alkenyl group or alkoxy group having 1 to 5 carbon atoms.

In the present invention, the unsubstituted aryl group is a phenyl group or a naphthyl group, and the substituents that may be substituted with the aryl group include alkyl groups such as methyl, ethyl, propyl, butyl, or pentyl, 2-propenyl, or methoxy, Alkoxy groups such as ethoxy, propoxy and butoxy. Methyl, methoxy and the like are preferred.

For the purposes of the present invention, as the reaction solvent used for the reaction of the compounds of the above formulas (2) and (3), lower ketones such as acetone and methyl ethyl ketone, acetonitrile, N, N-dimethylformamide, pyridine, chloroform, Ethyl acetate and the like. In the above reaction, the addition ratio of the structural formula (3) to the structural formula (2) is 2 to 10 times, preferably 3 to 6 times in molar ratio. As the alkalizing agent, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like are used. Sodium hydroxide and potassium hydroxide are preferred.

Reaction progress temperature is 10-40 degreeC, Preferably it is 20-30 degreeC. The reaction progress time is 10 to 30 hours, preferably 12 to 24 hours.

The reaction proceeds almost quantitatively under the above reaction conditions (this can be easily done by dry weighing the produced NaCl or KCl), with little byproducts produced, but only chloroform, ethyl acetate, benzene (4 When only 1: 2) was used as a developing solvent and confirmed by silica gel thin layer chromatography, trace amounts of 1,3-diaryloxy-2-propanol were only observed.

As a purification method after the reaction, in consideration of the fact that the desired 1-aryloxy-2, 3-epoxypropane is a viscous liquid, it is difficult to operate and is limited to the column chromatography method or the high temperature and high vacuum distillation method limited to the laboratory method, By using the solvent extraction method, the process was simple and the working time was shortened. That is, high temperature, high vacuum distillation and column chromatography are very limited methods on a laboratory scale, while solvent extraction is an advantageous method for industrial mass production.

The extraction process is divided into two steps, firstly, extraction with a nonpolar organic solvent, and secondly, extraction of a mixed solvent with respect to the organic solvent extract. At this time, as the non-polar organic solvent, n-hexane, cyclohexane, toluene, xylene, petroleum ether, carbon tetrachloride or the like is used alone or in combination of two or more thereof.Acetonitrile and lower alcohols (methanol, ethanol, n- Propanol, isopropanol, etc.) is used alone or in a mixture of two or more water mixed with water, the mixing ratio is in the range of 1: 5 to 5: 1 (volume ratio) of alcohol and acetonitrile based on water . Preferably, 3: 2 to 2: 3 is good, but the composition and ratio of the mixed solvent slightly vary depending on the amount of unreacted substances and by-products present in the reaction solution.

The extraction process by the above extraction solvent is as follows. That is, after completion of the reaction, the reaction solution is concentrated under reduced pressure, leaving a viscous liquid. When the concentrate is extracted 2-3 times with a nonpolar organic solvent of 1: 5 to 1: 10 (volume ratio), the color in the concentrate is concentrated. Impurities such as unreacted polar substances and residual alkalis are removed, and 1-aryloxy-2, 3-epoxypropane, trace by-products and epihalohydrin remain in the solvent layer. When the extract is extracted 1-2 times with a mixed solvent of 1: 3 to 1: 6 times (volume ratio) of the excess epihalohydrin remaining in the excess, the epihalohydrin and an extremely small amount of by-products are transferred to the mixed solvent. The organic solvent layer is left in pure-1-aryloxy-2 and 3-epoxypropane, which appear as single spots on silica gel thin layer chromatography, and when the organic solvent is concentrated under reduced pressure, 1-aryloxy-2, 3-epoxypropane could usually be obtained in a yield of 85-90%. In addition, when the mixed solvent from which epihalohydrin is extracted is concentrated by evaporation, epihalohydrin can be easily recovered.

The advantage of the present invention is to suppress the production of by-products as much as possible, without the high temperature, high vacuum distillation process, using a solvent extraction method of high purity, high yield of 1-aryloxy-2, 3-epoxypropane industrially Can be mass produced. Hereinafter, an Example demonstrates this invention concretely.

Example 1

Add 28.8 g of alpha-naphthol and 8.0 g of sodium hydroxide to 100 milliliters of acetone, stir until the sodium hydroxide is completely dissolved, then add 11 g of calcium oxide, stir again, and filter. The filtrate is kept at 15 ° C, and 75 g of epichlorohydrin is slowly added thereto, and the temperature is raised, and the reaction mixture is stirred under nitrogen stream at 30 ° C for 24 hours. The resulting sodium chloride is filtered off and the acetone is distilled off under reduced pressure. The residue was stirred and extracted three times with 200, 100 and 100 milliliters of each of petroleum ether: cyclohexane (1: 1) mixed solvent, and the mixed solvent extract was extracted again with water: methanol: ethanol (3: 2: 1). Extract twice with 100 and 50 milliliters. The upper layer was taken, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 34.8 g of 1-naphthoxy-2 and 3-epoxypropane in a yield of 87.0%.

Silica Gel Thin Layer Chromatography: Single Spot

Developing solvent: Chloroform: Ethyl acetate: Benzene (4: 1: 2)

Rf value: 0.50-0.52

Example 2

To 100 milliliters of acetonitrile, 18.8 g of phenol and 8.0 g of sodium hydroxide were added, stirred until the sodium hydroxide was completely dissolved, and then dehydrated with 10 g of anhydrous sodium sulfate. The mixture was extracted three times with 100 and 100 milliliters, and the n-hexane extract was extracted twice with 100 and 50 milliliters of each solvent: water: methanol: isopropyl alcohol (3: 2: 1). The n-hexane layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give 25.6 g of 1-phenoxy-2 and 3-epoxypropane in a yield of 85.3%.

Silica Gel Thin Layer Chromatography: Single Spot

Development solvent: same as Example 1

Rf: 0.48-0.50

Example 3

21.6 g of meta-cresol and 8.0 g of sodium hydroxide were added to 100 milliliters of N and N-dimethylformamide, and stirred until the sodium hydroxide was completely dissolved. The residue was extracted twice with 200 and 150 milliliters of cyclonucleic acid: xylene (1: 1), and the extract was extracted again with water: methanol: n-propanol (6: 4: 1:). Extract times. The upper layer was taken, dehydrated and concentrated under reduced pressure to yield 29.0 g of 1- (3-methyl) phenoxy-2,3-epoxypropane in a yield of 89.1%.

Silica Gel Thin Layer Chromatography: Single Spot

Development solvent: same as Example 1

Rf: 0.54-0.56

Example 4

To 100 milliliters of acetone, 24.8 g of guai alcohol and 8.Og of sodium hydroxide were added, and it proceeds as in Example 1 below. The residue was extracted three times with 150, 100 and 100 milliliters of petroleum ether: toluene (4: 1) mixed solvent, and the extract was extracted twice with 100 and 50 milliliters of water (methanol (1: 1) mixed solvent). do. The upper layer is taken, dehydrated and concentrated under reduced pressure to yield 30.5 g of 1- (2-methoxy) phenoxy-2 and 3-epoxypropane in a yield of 85.2%.

Silica Gel Thin Layer Chromatography: Single Spot

Development solvent: same as Example 1

Rf: 0.43-0.45

Example 5

50 milliliters of petroleum ether and 9.75 g of sodium hydride (dispersed in 50% share) are added to the reactor, followed by stirring to pour out the solvent, followed by treatment with 50 milliliters of petroleum ether. 70 milliliters of N and N-dimethylformamide were immediately added thereto, and the temperature was cooled to 15 ° C. A solution of 26.8 g of 2- (2-propenyl) phenol in 30 milliliters of N, N-dimethylformamide was added dropwise over 30 minutes. After the dropwise addition, the reaction was stirred at room temperature for 1 hour, while 92 g of epichlorohydrin was gradually added while maintaining the temperature at 15 ° C, and the temperature was raised, and the reaction was stirred at 35 ° C under a stream of nitrogen for 30 hours. The residue obtained by treating in the same manner as in Example 1 was then stirred and extracted three times with 200, 100 and 100 milliliters of cyclohexane each, and the cyclohexane extract was extracted with water: methanol: ethanol (4: 2: 1) and mixed solvent for each 100. And 50 milliliters twice. The upper layer was taken up, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 32.2 g of 1- [2- (2-propenyl) phenoxy] -2 and 3-epoxypropane in a yield of 84.7%.

Silica Gel Thin Layer Chromatography: Single Spot

Development solvent: same as Example 1

Rf: 0.54-0.56

Comparative Example 1

Dissolve 8.0 g of sodium hydroxide in 100 milliliters of water, add 18.8 g of phenol, and stir. 40 g of epichlorohydrin is slowly added thereto, followed by stirring at room temperature for 24 hours. After the reaction, 100 ml of chloroform was extracted twice, dehydrated with anhydrous sodium sulfate, and the chloroform was distilled under reduced pressure. The residue is distilled off at 60-80 ° C. or below 40 mm Hg to remove epichlorohydrin. Distillation at 100-105 ° C. or less at 1 mmHg yields 11.6 g of 1-phenoxy-2, 3-epoxypropane in a yield of 38.7%.

Silica Gel Thin Layer Chromatography: Single Spot

Development solvent: same as Example 1

Rf: 0.48-0.50

Comparative Example 2

Dissolve 8.0 g of sodium hydroxide in 150 milliliters of water and add 28.8 g of alpha-naphthol. It proceeds as in Comparative Example 1 below. Epichlorohydrin is distilled at 60-80 ° C. and 40 mmHg or less, and again distilled at 125-130 ° C. and below 1 mmHg to obtain 12.9 g of 1-naphthoxy-2 and 3-epoxypropane in a yield of 32.3%.

Execution gel thin layer chromatography: single spot

Development solvent: same as Example 1

Rf: 0.50-0.52

Claims (8)

In the preparation of 1-aryloxy-2, 3-epoxypropane of the following formula (1) by reacting the hydroxyaryl derivative of the following formula (2) and epihalohydrin of the following formula (3) in the presence of an alkalizing agent And extracting the reaction solution containing the desired product with a non-polar organic solvent, and then extracting the extract further with a mixed solvent.

In each of the above formulas, Ar is an unsubstituted aryl group or an aryl group substituted with an alkyl group, alkenyl group or alkoxy group having 1 to 5 carbon atoms. The method of claim 1 wherein the reaction temperature is 10 to 40 ° C. The method of claim 1 wherein the reaction time is 10 to 30 hours. The method of claim 1, wherein the ratio of epihalohydrin to the hydroxyaryl derivative is 2 to 10 molar ratio. The method of claim 1, wherein the nonpolar organic solvent is n-hexane, cyclohexane, toluene, xylene, petroleum ether, carbon tetrachloride alone or a mixture of two or more thereof. The method according to claim 1, wherein the mixed solvent is water mixed with acetonitrile and lower alcohol alone or with a mixture thereof. The method according to claim 6, wherein the mixing ratio of the mixed solvent is 1: 5 to 5: 1 by volume of acetonitrile and lower alcohol with respect to water. 8. The process of claim 7, wherein the lower alcohol is methanol, ethanol, n-propane or isopropanol.