KR100976749B1 - Process for producing glycidyl ether - Google Patents

Abstract

In the case of preparing glycidyl ethers by reacting alcohols with epihalohydrin in the presence of a base, glycidyl ether and the reaction thereof are carried out in a bilayer system of a non-aqueous organic solvent and an aqueous solution. Process for preparing optically active compound in high yield and high optical purity.

Description

Production method of glycidyl ether {PROCESS FOR PRODUCING GLYCIDYL ETHER}

The present invention relates to glycidyl ethers, which are important as synthetic intermediates of pharmaceuticals, pesticides, and bioactive substances, and methods of preparing the optically active substances thereof.

Glycidyl ethers are important as synthetic intermediates of various pharmaceuticals, and in particular, optically active glycidyl ethers have recently been used in pharmaceutical development.

Generally optically active pharmaceuticals or their intermediates are required to be at least 98% pure. Therefore, establishing a high purity optically active glycidyl ether production method is an important task.

As a general method for preparing racemic glycidyl ethers used to prepare epoxide resin monomers, 1 mole of phenol in an aqueous sodium hydroxide solution and 3 to 7 moles of epichlorohydrin at 45 to 90 ° C. Methods have been developed that include reacting for time.

In addition, the optically active glycidyl ether, an intermediate for preparing athenol represented by the following chemical formula, is reacted in the presence of alkali hydroxide and tetravalent ammonium salt in a solvent containing 4-carbamoylmethylphenol and optically active epichlorohydrin. A manufacturing method is disclosed (Japanese Patent Laid-Open No. 6-37482);

However, the glycidyl ether yield and the optical purity of the optically active compound thereof were not satisfactory.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve the said subject, when the inventors produce glycidyl ether by making alcohol react with epihalohydrin in presence of a base, in the bilayer system of a non-aqueous organic solvent and a water solvent. The present invention has been completed by the discovery that by carrying out the reaction, glycidyl ethers can be obtained in high yield and optically active compounds thereof in high purity.

That is, the present invention is represented by the following formula (1);

ArOH (1)

(Wherein Ar is a substituted or unsubstituted aromatic group) in the presence of 1 mole or 1 mole or more of bases of the following formula (2);

Wherein 1 to 3 moles of epihalohydrin represented by (wherein X is a halogen atom) is reacted in a two-layer system of a non-aqueous organic solvent and a solvent.

(Wherein Ar is as defined above).

The present invention also relates to a method for preparing glycidyl ether, which comprises carrying out the above reaction by adding a tetravalent ammonium salt represented by the following formula (4);

^{R 1 R 2 R 3 R 4} N + X - (4)

(Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and represent an alkyl group, an alkenyl group, an aralkyl group or an aryl group, and X ⁻ represents a chloride ion, bromide ion, iodide ion, hydrogen sulfate ion or hydroxide ion).

According to the present invention, when epihalohydrin is used in the optically active form, it is possible to obtain optically active glycidyl ether in high optical purity almost without racemate.

The reaction principle of the present invention is that when reacting alcohols present in non-aqueous epihalohydrin and basic aqueous solution, the concentration of epihalohydrin and the resulting glycidyl ether that is non-aqueous is added by adding a non-aqueous organic solvent. It is lowered. As a result, side reactions are suppressed by epihalohydrin, glycidyl ethers and alcohols in basic aqueous solution in the non-aqueous organic solvent, thereby obtaining glycidyl ether in high yield and high purity. This reaction principle regarding the preparation of glycidyl ethers starting with epihalohydrin has not been reported and is novel.

Preferred Embodiments of the Invention

Alcohols (1) used in this reaction include an aromatic compound substituted with a hydroxyl group such as unsubstituted phenol or phenol having substituent (s).

Substituents are not limited as long as they affect the reaction, but are not limited to saturated or unsaturated alkyl groups such as methyl, ethyl, allyl, etc., methoxymethyl, 2-methoxyethyl, allyloxymethyl, (2-methoxyethoxy) methyl, ( Alkyl groups having ether bonds such as 2-isopropoxyoxy) methyl, halogen atoms such as fluoro, chloro, bromo or iodine atoms, halogenated alkyl groups such as trifluoromethyl, chloromethyl, methoxy, allyloxy, Alkoxy groups such as methoxymethoxy, amido groups such as acetylamide, carbamoylamide groups, acyl groups such as aldehyde groups, acetyl, benzoyl and the like, nitro groups and the like, or substituents such as tetramethylene, methylenedioxy and the like Can be formed. In addition, a plurality of substituents may be present.

The aromatic compound substituted with a hydroxyl group also includes a polycyclic aromatic compound substituted with a hydroxyl group such as α-naphthol, β-naphthol, 7-hydroxyindene and the like, and further includes 2-pyridyl alcohol, 3-hydroxyfuran Heterocyclic aromatic compounds such as 4-hydroxyindole, 5-hydroxykinolin, and the like.

Among the alcohols (1), phenol is preferable, and unsubstituted phenol, 4-fluorophenol, 4-methylphenol, 4-methoxyphenol and 2-allyloxyphenol are particularly preferable.

Bases used in the reaction include alkali hydroxides such as lithium hydroxide, sodium hydroxide or calcium hydroxide, alkali bases such as sodium carbonate or potassium carbonate, aqueous bases such as tert-butoxide potassium and the like, but alkali hydroxides are preferred, in particular Sodium hydroxide and potassium hydroxide are preferred.

The content of the base used in this reaction is preferably 1 mol or 1 mol or more, more preferably 1-2 mol, with respect to alcohols (1).

Epihalohydrin (2) used in this reaction includes epichlorohydrin, epibromohydrin and epiiodhydrin, preferably epichlorohydrin and epibromohydrin. The content of epihalohydrin is 1 to 3 moles, preferably 1.5-2 moles, relative to alcohols (1). The content may exceed 3 moles, but the yield does not increase significantly. If the content is less than 1 mole, the unreacted alcohols (1) and the reacted glycidyl ether (3) further react, causing a decrease in purity and yield.

The non-aqueous organic solvent used in this reaction is not mixed and reacted with the basic aqueous solution, and is not limited as long as it is a non-aqueous organic solvent in which epihalohydrin (2) and glycidyl ethers (3) are dissolved. It is halogenated such as alkane such as hexane, heptane, diethyl ether, dibutyl ether, ether such as tert-butylmethyl ether, aromatic hydrocarbon such as benzene, toluene, xylene, chloroform, dichloromethane, 1,2-dichloroethane, etc. Compounds, and preferably toluene, tert-butylmethyl ether and 1,2-dichloroethane.

The suitable content of water used in this reaction is 1 to 20 times (w / w) with respect to the content of alcohols. The content of the non-aqueous organic solvent is 0.5 to 3 times (v / v) with respect to the content of water.                 

This reaction is accelerated by the addition of a tetravalent ammonium salt to obtain the desired glycidyl ether (1) in high yield.

The tetravalent ammonium salt (4) is, for example, benzyltrimethylammonium chloride, diallyldimethylammonium chloride, benzyltrimethylammonium bromide, n-octyltrimethylammonium bromide, stearyltrimethylammonium bromide, cetyldimethylethylammonium bromide, tetra n-butyl Ammonium iodide, β-methylcholine iodide, hydrogen sulfate tetra-n-butylammonium, phenyltrimethylammonium hydroxide without limitation.

The content of the tetravalent ammonium salt (4) used in this reaction is a catalytic amount, preferably 0.005 to 0.1 mol, relative to the alcohols (1).

The reaction temperature is preferably 0-50 ° C, more preferably 0-40 ° C. Below 0 ° C., the reaction is inhibited and water is likely to freeze in the reaction medium, which is undesirable. In addition, if the reaction temperature exceeds 50 ° C, side reactions proceed to cause a decrease in yield, which is undesirable, and when the optically active epihalohydrin (2) is used, racemization proceeds and the optically active glycidyl ether ( The optical purity of 1) is reduced.

The advantage of this reaction is the desired glycidyl ether in high yield and high purity by a very simple process of removing the organic solvent after the completion of the reaction, neutralizing with a dilute mineral acid such as hydrochloric acid and then evaporating the solvent. It is in obtaining. In addition, when the optically active epihalohydrin (2) is used, the optically active glycidyl ether (3) can be obtained in a state almost maintaining optical purity. In particular, when the glycidyl ether as the reaction product is a liquid, the crystal method cannot be used, and it is possible to obtain the glycidyl ether at once with high optical purity by carrying out the method of the present invention.

If the yield is lowered, after the reaction, sodium chloride, potassium chloride, sodium carbonate, potassium carbonate, magnesium sulfate or sodium sulfate is added in an appropriate amount, and then it is preferable to remove the organic layer, and if necessary, purification by distillation, crystallization or column chromatography may be carried out. It can be carried out after evaporation of the solvent.

The present invention is illustrated by the following examples, but the present invention is not limited by the examples.

Example 1

(R) -Epichlorohydrin (99% ee, 60.Og, 0.64 mol), benzyltrimethylammonium chloride (0.80 g), toluene (140 ml) and water (140 ml) were added to the reactor and the reaction mixture was iced. Cooled. After addition of 4-fluorophenol (48.5 g, 0.43 mol), a 24% aqueous NaOH solution (94.Og, 0.56 mol) was added dropwise with stirring for 1 hour. The mixture was stirred for 30 minutes under ice-cooling and then for 48 hours at room temperature. After the reaction, the aqueous layer was removed and the organic layer was washed with 5% aqueous HCl solution (140 ml), followed by water (70 ml). After removal of toluene, the residue was distilled to give the desired (S) -glycidyl-4-fluorophenyl ether (61.5 g, yield 85%, optical purity 99% ee) as a colorless liquid.

bp 73-75 ℃ / 0.6-0.7 Torr                 

NMR (270 MHz, CDCl ₃ ) sigma 2.75 (1H, dd), 2.92 (1H, dd), 3.34 (1H, dddd), 3.90 (1H, dd), 4.20 (1H, dd), 6.77-7.02 (4H, m)

Example 2

(S) -Epichlorohydrin (99% ee, 30.Og, 0.32 mol), benzyltrimethylammonium chloride (0.80 g), toluene (70 ml) and water (70 ml) were added to the reactor and the reaction mixture was iced. Cooled. After addition of phenol (20.3 g, 0.22 mol), 24% aqueous NaOH solution (54.Og, 0.33 mol) was added dropwise thereto while stirring for 1 hour. The mixture was stirred for 30 minutes under ice-cooling and then for 39 hours at room temperature. After the reaction, the aqueous layer was removed and the organic layer was neutralized with 5% aqueous HCl solution (70 ml) and washed with water (40 ml). After toluene was removed, the residue was distilled off to give the desired (R) -glycidylphenyl ether (27.Og, yield 83%, optical purity 98% ee) as a colorless liquid.

bp 85-86 ℃ / 0.8 Torr

NMR (270 MHz, CDCl ₃ ) sigma 2.76 (1H, dd), 2.91 (1H, dd), 3.36 (1H, dddd), 3.97 (1H, dd), 4.21 (1H, dd), 6.91-6.99 (3H, m), 7.25-7.32 (2H, m)

Example 3

(S) -Epichlorohydrin (99% ee, 2.64 g, 29 mmol), toluene (6 ml) and water (6 ml) were added to the reactor and the mixture was cooled with ice. After addition of phenol (1.78 g, 19 mmol), a 24% aqueous NaOH solution (4.75 g, 29 mmol) was added dropwise thereto while stirring for 10 minutes. The mixture was stirred under ice cooling for 30 minutes and then stirred at room temperature for 50 hours. The aqueous layer was removed and the organic layer was neutralized with 5% HCl and washed twice with water. Removal of solvent gave the desired crude (R) -glycidylphenyl ether (1.96 g, yield 69%, optical purity 98% ee) as an oil.

Example 4

(S) -Epichlorohydrin (99% ee, 2.64 g, 29 mmol), benzyltrimethylammonium chloride (36 mg), 1,2-dichloroethane (6 ml) and water (6 ml) were added to the reactor and the mixture was iced. Cooled to. After addition of phenol (1.78 g, 19 mmol), 24% aqueous NaOH solution (4.1Og, 25 mmol) was added dropwise thereto while stirring for 10 minutes. The mixture was stirred for 30 minutes under ice-cooling and then for 42 hours at room temperature. The aqueous layer was removed and the organic layer was neutralized with 5% HCl and washed twice with water. Removal of the solvent gave the desired crude (R) -glycidylphenyl ether (2.27 g, yield 80%, optical purity 98% ee) as an oil.

Example 5

(S) -Epichlorohydrin (99% ee, 2.64 g, 29 mmol), benzyltrimethylammonium chloride (72 mg), tert-butylmethyl ether (6 ml) and water (6 ml) were added to the reactor and the mixture was iced. Cooled. After addition of phenol (1.78 g, 19 mmol), a 24% aqueous NaOH solution (4.75 g, 29 mmol) was added dropwise thereto while stirring for 10 minutes. The mixture was stirred under ice cooling for 30 minutes and then at room temperature for 37 hours. The aqueous layer was removed and the organic layer was neutralized with 5% HCl and washed twice with water. Removal of the solvent gave the desired crude (R) -glycidylphenyl ether (2.13 g, yield 75%, optical purity 98% ee) as an oil.

Example 6

(R) -Epichlorohydrin (99% ee, 5.00 g, 54 mmol), benzyltrimethylammonium chloride (50 mg), toluene (45 ml) and water (45 ml) were added to the reactor and the mixture was cooled with ice. After the addition of p-cresol (2.92 g, 27 mmol), an aqueous 24% NaOH solution (6.75 g, 40 mmol) was added dropwise with stirring for 10 minutes. The mixture was stirred under ice cooling for 30 minutes and then at 45 ° C. for 30 hours. After cooling the reaction mixture at room temperature, the organic layer was removed, washed with 5% aqueous HCl solution (30 ml) and then twice with water (30 ml). Toluene was removed to afford the desired crude (S) -glycidyl-4-methylphenyl ether (3.58 g, yield 81%, optical purity 98% ee) as an oil.

NMR (270 MHz, CDCl ₃ ) σ 2.45 (3H, S), 2.76 (1H, dd), 2.91 (1H, dd), 3.37 (1H, dddd), 3.83 (1H, dd), 4.17 (lH, dd), 6.57-7.12 (4H, m)

Example 7

(R) -Epichlorohydrin (98% ee, 7.40 g, 54 mmol), benzyltrimethylammonium chloride (0.54 g), toluene (15 ml) and water (l 5 ml) were added to the reactor and the mixture was cooled with ice. After adding 4-methoxyphenol (6.70 g, 27 mmol), a 24% NaOH aqueous solution (6.75 g, 40 mmol) was added dropwise thereto while stirring for 10 minutes. The mixture was stirred for 30 minutes under ice-cooling and then for 35 hours at room temperature. The aqueous layer was removed and the organic layer was washed with 5% aqueous HCl solution (15 ml) and then twice with water (15 ml). Toluene was removed to afford the desired crude (S) -glycidyl-4-methoxyphenyl ether (4.33 g, yield 89%, optical purity 98% ee) as an oil.

NMR (270 MHz, CDCl ₃ ) sigma 2.75 (1H, dd), 2.90 (1H, dd), 3.37 (1H, dddd), 3.84 (1H, dd), 3.95 (3H, S), 4.19 (1H, dd) , 6.61-6.93 (4H, m)

Example 8

(R) -Epichlorohydrin (99% ee, 3.OOg, 32 mmol), benzyltrimethylammonium chloride (40 mg), 2-allyloxyphenol (3.24 g), toluene (7.2 ml) and water (7.2 ml) ) Was added and the mixture was cooled with ice. A 24% NaOH aqueous solution (5.40 g, 32 mmol) was added dropwise thereto while stirring for 15 minutes. The mixture was stirred for 30 minutes under ice-cooling and then for 48 hours at room temperature. After the reaction, the aqueous layer was removed, the organic layer was removed, washed with 5% aqueous HCl solution (10 ml), and then washed with water (10 ml). Toluene was removed to afford the desired crude (S) -allylglycidyl ether (3.79 g, yield 86%, optical purity 98% ee) as an oil.

NMR (270 MHz, CDCl ₃ ) sigma 2.76 (1H, dd), 2.89 (1H, dd), 3.36-3.40 (1H, m), 4.04 (1H, dd), 4.25 (1H, dd), 4.57-4.6 1 (2H, m), 5.25-5.30 (1H, m), 5.37-5.45 (1H, m), 6.01-6. 13 (1H, m), 6.88-96 (4H, m)

Comparative Example 1

(R) -Epichlorohydrin (99% ee, 1.OOg, 11 mmol), 4-fluorophenol (1.21 g, 11 mmol), benzyltrimethylammonium chloride (10 mg) and water (3.6 ml) were added to the reactor. And the mixture was cooled with ice. A 24% NaOH aqueous solution (2.16 g, 13 mmol) was added dropwise thereto while stirring for 10 minutes. The mixture was stirred under ice cooling for 1 hour and then at room temperature for 28 hours. After the reaction, the reaction mixture was extracted with toluene (3.6 ml) and the extracts were separated using a separatory funnel. The organic layer was washed with 5% aqueous HCl solution and then twice with water. Removal of solvent gave the desired crude (S) -glycidyl-4-fluorophenyl ether (0.98 g, yield 54%, optical purity 95% ee) as an oil.

Comparative Example 2

(S) -Epichlorohydrin (99% ee, 2.64 g, 29 mmol), methanol (9 ml) and water (6 ml) were added to the reactor and the mixture was cooled with ice. After addition of phenol (1.79 g, 19 mmol), a 24% NaOH aqueous solution (4.10 g, 25 mmol) was added dropwise thereto while stirring for 10 minutes. The mixture was stirred under ice cooling for 30 minutes and then at room temperature for 37 hours. After the methanol was removed, the reaction mixture was extracted with toluene (3.6 ml). The organic layer was neutralized with 5% HCl and washed twice with water. Removal of solvent gave crude (R) -glycidylphenyl ether (1.49 g, yield 52%, optical purity 92% ee) as an oil.

Comparative Example 3

(S) -Epichlorohydrin (99% ee, 2.64 g, 29 mmol), tetrahydrofuran (9 ml), benzyltrimethylammonium chloride (36 mg) and water (6 ml) were added to the reactor and the mixture was cooled with ice. . After addition of phenol (1.79 g, 19 mmol), a 24% NaOH aqueous solution (4.75 g, 29 mmol) was added dropwise with stirring for 10 minutes. The mixture was stirred for 30 minutes under ice-cooling and then for 41 hours at room temperature. After the tetrahydrofuran was removed, the reaction mixture was extracted with toluene. The organic layer was neutralized with 5% HCl and washed twice with water. Removal of solvent gave crude (R) -glycidylphenyl ether (1.08 g, yield 38%, optical purity 92% ee) as an oil.

According to the method of the present invention, after completion of the reaction, the glycine represented by the formula (3) is removed by a very simple process of removing the organic solvent, neutralizing with a dilute mineral acid such as dilute hydrochloric acid, and then removing the organic solvent. Dill ethers can be obtained in high yield and high purity and their optically active compounds can be obtained in high optical purity.

Claims (11)

Formula (1) ArOH (1) Wherein Ar is a phenyl group substituted with an unsubstituted phenyl or a saturated or unsaturated alkyl group, a phenyl group substituted with an alkyl group having an ether bond, a phenyl group substituted with a halogen atom, a phenyl group substituted with a halogenated alkyl group, a phenyl group substituted with an alkoxy group, an amido group Substituted phenyl group, phenyl group substituted with carbamoyl group, phenyl group substituted with aldehyde group, phenyl group substituted with acyl group, phenyl group substituted with nitro group, phenyl group forming bridge such as tetramethylene group or methylenedioxy group, 1-naphthyl group Or 2-naphthyl group.)    In the presence of 1 mole or 1 mole or more of bases of alcohol represented by

Formula (3) comprising reacting with 1-3 moles of epihalohydrin represented by formula (wherein X is a halogen atom)

(Wherein Ar is as defined above) a method for producing glycidyl ether. The method for producing glycidyl ether according to claim 1, comprising adding a tetravalent ammonium salt represented by the following formula (4) to the reaction system. ^{R 1 R 2 R 3 R 4} N + X - (4) (Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and represent an alkyl group, an alkenyl group, an aralkyl group or an aryl group, and X ⁻ represents a chloride ion, bromide ion, iodide ion, hydrogen sulfate ion or hydroxyl ion) delete The process for producing glycidyl ether according to claim 1 or 2, wherein the base is alkali hydroxide. delete The method for producing glycidyl ether according to claim 1 or 2, wherein the alcohols are phenol, 4-fluorophenol, 4-methylphenol, 4-methoxyphenol or 2-allyloxyphenol. The process for producing glycidyl ether according to claim 1 or 2, wherein the non-aqueous organic solvent is toluene, tert-butylmethyl ether or 1,2-dichloroethane. The process for producing optically active glycidyl ethers according to claim 1 or 2, wherein epihalohydrin is an optically active compound. The alcohol according to claim 1, wherein the alcohols are represented by the following general formula (1). ArOH (1) (Wherein Ar is a phenyl group substituted with an unsubstituted phenyl or a saturated or unsaturated alkyl group, a phenyl group substituted with an alkyl group having an ether bond, a phenyl group substituted with a halogen atom, a phenyl group substituted with a halogenated alkyl group, a phenyl group substituted with an alkoxy group, 1- Naphthyl group or 2-naphthyl group.) It is represented by, Method for producing glycidyl ether. The alcohol according to claim 1, wherein the alcohols are represented by the following general formula (1). ArOH (1) (Wherein Ar represents an unsubstituted phenyl or a phenyl group substituted with a saturated or unsaturated alkyl group, a phenyl group substituted with a halogen atom, a phenyl group substituted with an alkoxy group, 1-naphthyl group or 2-naphthyl group.) It is represented by, Method for producing glycidyl ether. The method for producing glycidyl ether according to claim 1 or 2, wherein the halogen atom of epihalohydrin is chlorine or bromine.