JPH0532649A - Production of optically active benzyl glycidyl ether - Google Patents

Abstract

PURPOSE:To obtain an optically active benzyl glycidyl ether useful as an intermediate for optically active natural substance, etc., in high purity, simply. CONSTITUTION:(A) An optically active 3-benzyloxy-1,2-propanediol shown by formula I (Ph is phenyl; *shows that carbon atom thereof is asymmetric carbon atom) is reacted with (B) a tetrahalogenomethane, especially carbon tetrachloride or carbon tetrabromide and (C) triphenylphosphine in an organic solvent (preferably aprotic solvent such as methylene chloride) preferably at 0-50 deg.C, especially 10-40 deg.C to give an optically active halogenohydrin derivatives shown by formula II-1 and formula II-2 (X is halogen). Then these derivatives are treated with a base, preferably an inorganic base such as KOH to suppress reduction in optical purity and to give optically active glycidyl ether shown by formula III in high purity and in high yield. The ratio of the components B and C based on the raw material A are preferably 1-5 equivalent, especially 1.02-1.15 equivalents, respectively.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an optically active benzyl glycidyl ether. This compound is known as a useful intermediate for the synthesis of, for example, optically active natural products (Takano et al., J. Syn. Org. Chem. Jp.
n. , 47, 813 (1989)).

[0002]

2. Description of the Related Art Conventionally, as a production route of optically active benzyl glycidyl ether, the primary hydroxyl group of optically active 3-benzyloxy-1,2-propanediol is monotosylated and then treated with base to be epoxidized. Methods are known (Takano et al., Heterocycles, 1
6, 381 (1981)). However, in this method, a small amount of a compound tosylated with a secondary hydroxyl group is produced during monotosylation, which causes a decrease in the optical purity of the optically active benzyl glycidyl ether obtained by the subsequent base treatment. .

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a method for producing a highly pure optically active benzyl glycidyl ether, which is free from deterioration of optical purity as in the prior art.

[0004]

The present invention provides an optically active 3-
Process for producing an optically active benzyl glycidyl ether, characterized in that benzyloxy-1,2-propanediol is reacted with tetrahalogenomethane and triphenylphosphine in an organic solvent to obtain an optically active halogenohydrin derivative, which is then treated with a base. Is.

In the process of the present invention, the optically active 3-benzyloxy-1,2-propanediol is first converted into the optically active halogenohydrin derivative under mild neutral conditions. At this time, either the primary hydroxyl group or the secondary hydroxyl group is substituted with halogen, and a mixture of two kinds of optically active halogenohydrin derivatives (optically active 1-benzyloxy-3-
Halogeno-2-propanol and optically active 3-benzyloxy-2-halogeno-1-propanol),
By the subsequent base treatment, these are converted into optically active benzyl glycidyl ether having the same three-dimensional structure. Therefore, the optical purity does not decrease, and an extremely high-purity optically active benzyl glycidyl ether can be obtained.

The present invention proceeds according to the following scheme. In the scheme below, Ph represents a phenyl group, X represents a halogen atom, and the symbol * indicates that the carbon atom is an asymmetric carbon atom.

[0007]

[Chemical 1]

In the above scheme, the optically active 3-
Benzyloxy-1,2-propanediol (I) is converted to an optically active halogenohydrin derivative mixture (II-1 and II-2) by reacting with tetrahalogenomethane and triphenylphosphine in an organic solvent. Examples of the tetrahalogenomethane include carbon tetrafluoride, carbon tetrachloride and carbon tetrabromide, with carbon tetrachloride and carbon tetrabromide being particularly preferred. In the reaction, the ratio of tetrahalogenomethane and triphenylphosphine is preferably 1 to 1.5 equivalents, respectively, with respect to the optically active 3-benzyloxy-1,2-propanediol as a raw material, in order to obtain a particularly high yield. Is preferably 1.02 to 1.15 equivalents. An aprotic solvent is used as the organic solvent, and for example, chloroform, methylene chloride, tetrahydrofuran, ethyl ether and the like are preferable.

In the above reaction, the reaction temperature is 0 to 50 ° C.
However, it is preferable to carry out the heating at 10 to 40 ° C. since the progress is mild and the yield is good. In this temperature range,
The reaction is completed in 5 to 80 hours. In the reaction, the optically active 3-benzyloxy-1,2-propanediol, tetrahalogenomethane and triphenylphosphine may be added in any order, but triphenylphosphine may be added to the mixture of the former two. Good to add.

The optically active 3-benzyloxy-1,2-propanediol, which is the above-mentioned raw material, is a highly pure product of the method of Takano et al. (Heterocycle).
s, 16, 381 (1981)).

The optically active halogenohydrin derivative obtained by the above reaction is a mixture of II-1 and II-2 as shown in the above scheme, which is used as it is or is isolated from each of them and subjected to the ring closure by the subsequent base treatment. It is subjected to the reaction. In any case, a high-yield and highly pure optically active benzyl glycidyl ether can be obtained. The base used includes an organic base and an inorganic base, but the inorganic base is preferable in terms of yield. As the inorganic base, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate and the like are preferably used. The amount used is preferably in the range of 4 to 20 equivalents with respect to the optically active halogenohydrin derivative in terms of yield and reaction time.

The reaction is carried out in an organic solvent or a mixed solvent of an organic solvent and water, and the former is preferred in terms of yield. As the organic solvent, ethyl ether, tetrahydrofuran, n
-Hexane, methylene chloride, chloroform and the like. The reaction is carried out in the range of 0 to 60 ° C, preferably 5 to 40 ° C in terms of yield. In this temperature range, the reaction is completed in 30 minutes to 10 hours.

In the present invention, when optically active (R) -3-benzyloxy-1,2-propanediol is used as a raw material, the optically active (S) -form is passed through the optically active (S) form of the halogenohydrin derivative. When benzyl glycidyl ether is obtained and optically active (S) -3-benzyloxy-1,2-propanediol is used, the optically active (R) -isomer is passed through the optically active (R) -form halogenohydrin derivative. Glycidyl ether is obtained in high yield and high purity, respectively.

[0014]

【Example】

Example 1 1.00 g (5.49 mmol,> 98%) of optically active (R) -3-benzyloxy-1,2-propanediol.
ee) and 2.01 g (6.06 mmol) of carbon tetrabromide were dissolved in 6 ml of methylene chloride and stirred at 0 ° C., and 1.59 g (6.06 m of triphenylphosphine) was stirred therein.
(9 mol) methylene chloride solution was added dropwise, and the mixture was further stirred at room temperature for 53 hours. After the reaction, the reaction mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

4.12 g of the residue obtained by the above treatment
Was dissolved in 30 ml of tetrahydrofuran, 2.42 g (43.1 mmol) of potassium hydroxide was added at 0 ° C., and the mixture was stirred at room temperature for 6 hours. After the reaction, ethyl ether was added to the reaction mixture and the mixture was washed with water and further washed with saturated saline,
It was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.

The residue obtained by the above treatment was purified by silica gel column chromatography (n-hexane: ethyl ether = 8: 1) to obtain 748 mg of optically active (S) -benzyl glycidyl ether as an oil (yield 83%,> 98% ee) was obtained. [Α] _D (31 ° C.)-10.61 ° (c = 5.36, methanol) All spectral data are literature values (Takano et al., Heter.
Cycles, 31, 1715 (1990)).

Example 2 2.89 g (11.0 m mo) of triphenylphosphine
l) It was dissolved in 25 ml of carbon tetrachloride, refluxed for 37 hours, cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 25 ml of methylene chloride, and at 0 ° C., 1.00 g (5.49 mmol,> 98% ee) of optically active (R) -3-benzyloxy-1,2-propanediol was added to 5 ml of methylene chloride. Add it dropwise to the solution and add it at room temperature for 11
Stir for hours. After the reaction, the reaction mixture was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

4.45 g of the residue obtained by the above treatment
Was dissolved in 20 ml of tetrahydrofuran, 2.50 g (44.5 mmol) of potassium hydroxide was added, and the mixture was stirred at room temperature for 2 hours.
Stir for hours. After the reaction, ethyl ether was added to the reaction mixture, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The residue obtained by the above treatment was purified by silica gel column chromatography (n-hexane: ethyl ether = 8: 1), and 794 mg of optically active (S) -benzyl glycidyl ether was obtained as oil (yield 88%,> 98% ee) was obtained. [Α] _D (30 ° C.) -10.28 ° (c = 5.23, methanol) All the spectral data were in agreement with the optically active (S) -benzyl glycidyl ether obtained according to Example 1.

Example 3 Instead of optically active (R) -3-benzyloxy-1,2-propanediol, optically active (S) -3-benzyloxy-1,2-propanediol (> 98% ee) was used. Optically active (R) -benzyl glycidyl ether was obtained in the same manner as in Example 1 except that it was used (yield: 82%,> 98%).
ee). [Α] _D (31 ° C) + 10.40 ° (c = 5.06, methanol)

Example 4 Instead of optically active (R) -3-benzyloxy-1,2-propanediol, optically active (S) -3-benzyloxy-1,2-propanediol (> 98% ee) was used. Optically active (R) -benzyl glycidyl ether was obtained in the same manner as in Example 2 except that it was used (yield 87%,> 98%).
ee). [Α] _D (30 ° C.) + 10.33 ° (c = 5.50, methanol)

Example 5 1.00 g (5.49 mmol,> 98%) of optically active (R) -3-benzyloxy-1,2-propanediol
ee) and 2.01 g (6.06 mmol) of carbon tetrabromide were dissolved in 6 ml of methylene chloride and stirred at 0 ° C., and 1.59 g (6.06 m of triphenylphosphine) was stirred therein.
(9 mol) methylene chloride solution was added dropwise, and the mixture was further stirred at room temperature for 53 hours. After the reaction, the reaction mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue obtained by the above treatment was separated and purified by silica gel column chromatography (n-hexane: ethyl ether = 8: 1) to obtain an optical activity (S).
951 mg (71% yield) of -1-benzyloxy-3-bromo-2-propanol and 279 m of optically active (S) -3-benzyloxy-2-bromo-1-propanol.
g (21% yield) was obtained.

The optically active (S) -3-benzi obtained above.
The properties of luoxy-2-bromo-1-propanol are as follows.
Shown in. (1) colorless oil (2) [α]_D(31 ° C) -3.48 ° (c = 1.0
6, chloroform) (4) IR (neat) νmax 3438 cm^-1 (5)¹H-NMR (CDCl_Three) Δ: 2.20 (d
d, J = 6.7, 6.7 Hz, 1H, exchange
available with D_TwoO), 3.79 (dd, J =
7.3, 10.5 Hz, 1H, 3.83 (dd, J =
5.5, 10.5Hz, 1H), 3.91 (ddd, J
= 5.5, 6.7, 12.2 Hz, 1H), 3.95
(Ddd, J = 5.5, 6.7, 12.2 Hz, 1
H), 4.22 (m, 1H), 4.59 (s, 2H),
7.35 (m, 5H) (6) MS (m / z) 246, 244 (M⁺), 91
(100%) C₁₀H_ThirteenO_Two  ⁸¹Br calculated value 246.007
8, analytical value 246.0072 C₁₀H_ThirteenO_Two  ⁷⁹Calculated Br value 244.009
9, analytical value 244.0075

61 mg of the optically active (S) -3-benzyloxy-2-bromo-1-propanol obtained above.
(0.25 mmol) and potassium hydroxide 79 mg
(1.41 mmol) was stirred in 1 ml of tetrahydrofuran at room temperature for 6.5 hours. After the reaction, ethyl ether was added and the mixture was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The residue obtained above was subjected to silica gel column chromatography (n-hexane: ethyl ether = 8:
Purification in 1) gave 36 mg of oily optically active (S) -benzyl glycidyl ether (yield 88%). [Α] _D (30 ° C.)-10.95 ° (c = 1.10, methanol) All spectral data are literature values (Takano et al., Hetero).
Cycles, 31, 1715 (1990)).

The optical purity of the above-obtained optically active (S) -benzyl glycidyl ether was 98.1% ee as analyzed by high performance liquid chromatography (“Chiralcel OD” manufactured by Daicel Chemical Industries, Ltd.), which was an intermediate. Some optically active (S) -3-benzyloxy-2-bromo-1-
It was found that propanol has an extremely high optical purity.

[0028]

According to the method of the present invention, an optically active benzyl glycidyl ether, which is an intermediate useful for the production of optically active natural products and the like, can be easily produced with high yield and high purity.

Claims (2)

[Claims] 1. Optically active 3-benzyloxy-1,2-
A process for producing an optically active benzyl glycidyl ether, which comprises reacting propanediol with tetrahalogenomethane and triphenylphosphine in an organic solvent to obtain an optically active halogenohydrin derivative, which is then treated with a base. 2. The method according to claim 1, wherein the tetrahalogenomethane is carbon tetrabromide or carbon tetrachloride.