JP2903805B2 - Preparation of optically active benzyl glycidyl ether - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing 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 Hitherto, as a production route of optically active benzyl glycidyl ether, a primary hydroxyl group of optically active 3-benzyloxy-1,2-propanediol is monotosylated, followed by base treatment and epoxidation. Methods are known (Takano et al., Heterocycles, 1).
6, 381 (1981)). However, in this method, a small amount of a tosylated compound of a secondary hydroxyl group is generated during monotosylation, which causes a decrease in the optical purity of the optically active benzyl glycidyl ether obtained by subsequent base treatment. .

[0003]

The object of the present invention is to provide a process for producing a high-purity optically active benzyl glycidyl ether without lowering the optical purity as in the prior art.

[0004]

SUMMARY OF THE INVENTION The present invention provides an optically active compound.
A process for producing an optically active benzyl glycidyl ether, comprising reacting benzyloxy-1,2-propanediol with tetrahalogenomethane and triphenylphosphine in an organic solvent to obtain an optically active halogenohydrin derivative, followed by base treatment. It is.

In the method of the present invention, optically active 3-benzyloxy-1,2-propanediol is first converted to an optically active halogenohydrin derivative under mild neutral conditions. At this time, a mixture of two types of optically active halogenohydrin derivatives in which either the primary hydroxyl group or the secondary hydroxyl group is substituted with halogen (optically active 1-benzyloxy-3-
Halogeno-2-propanol and optically active 3-benzyloxy-2-halogeno-1-propanol).
These are converted to optically active benzyl glycidyl ethers having the same steric structure by subsequent base treatment. Accordingly, the optical purity of the benzyl glycidyl ether of extremely high purity can be obtained without lowering the optical purity.

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

[0007]

Embedded image

In the above scheme, first, the optically active 3-
Benzyloxy-1,2-propanediol (I) is reacted with tetrahalogenomethane and triphenylphosphine in an organic solvent to convert into an optically active halogenohydrin derivative mixture (II-1 and II-2). Examples of tetrahalogenomethane include carbon tetrafluoride, carbon tetrachloride, carbon tetrabromide and the like, and particularly preferred are carbon tetrachloride and carbon tetrabromide. In the reaction, the ratio of tetrahalogenomethane and triphenylphosphine is preferably 1 to 1.5 equivalents with respect to the optically active 3-benzyloxy-1,2-propanediol as the raw material, particularly in order to obtain a high yield. Is preferably 1.02 to 1.15 equivalents. As the organic solvent, an aprotic solvent is used, 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.
In particular, it is preferable to perform the reaction at 10 to 40 ° C. because the progress is gentle 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 is added to the mixture of the two. Good to add.

The above-mentioned optically active 3-benzyloxy-1,2-propanediol as a raw material is described as having a high purity by the method of Takano et al.
s, 16, 381 (1981)).

The optically active halogenohydrin derivative obtained by the above-mentioned reaction is a mixture of II-1 and II-2 as shown in the above scheme. This is used as it is, or it is isolated and ring-closed by subsequent base treatment. Provided for reaction. In each case, high-purity optically active benzyl glycidyl ether can be obtained in high yield. As the base used, there are an organic base and an inorganic base, but an inorganic base is preferred in terms of the 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 relative 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. The former is preferred in terms of yield. Organic solvents include ethyl ether, tetrahydrofuran, n
-Hexane, methylene chloride, chloroform and the like. The reaction is carried out at a temperature in the range of 0 to 60 ° C., preferably in the range of 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, optically active (S)-is obtained through a halogenohydrin derivative in an optically active (S) form. When benzyl glycidyl ether is obtained and optically active (S) -3-benzyloxy-1,2-propanediol is used, optically active (R) -benzyl is obtained through a halogenohydrin derivative of an optically active (R) form. Glycidyl ether is obtained in high yield and high purity, respectively.

[0014]

【Example】

Example 1 Optically active (R) -3-benzyloxy-1,2-propanediol 1.00 g (5.49 mmol,> 98%
ee) and 2.01 g (6.06 mmol) of carbon tetrabromide were dissolved in 6 ml of methylene chloride, stirred at 0 ° C., and stirred with 1.59 g (6.06 m) of triphenylphosphine.
mol) in 9 ml of methylene chloride 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, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

4.12 g of a 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, which was washed with water, and further washed with a saturated saline solution.
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.

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

Example 2 2.89 g of triphenylphosphine (11.0 mmo)
l) Dissolved in 25 ml of carbon tetrachloride, refluxed for 37 hours, cooled to room temperature, and distilled off the solvent under reduced pressure. The obtained residue was dissolved in 25 ml of methylene chloride, and 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 at 0 ° C. Add dropwise to the solution and add
Stirred for hours. After the reaction, the reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate 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, and 2.50 g (44.5 mmol) of potassium hydroxide was added thereto.
Stirred for hours. After the reaction, ethyl ether was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

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

Example 3 Optically active (S) -3-benzyloxy-1,2-propanediol (> 98% ee) was used instead of optically active (R) -3-benzyloxy-1,2-propanediol. An 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 Optically active (S) -3-benzyloxy-1,2-propanediol (> 98% ee) was used instead of optically active (R) -3-benzyloxy-1,2-propanediol. An 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 Optically active (R) -3-benzyloxy-1,2-propanediol 1.00 g (5.49 mmol,> 98%
ee) and 2.01 g (6.06 mmol) of carbon tetrabromide were dissolved in 6 ml of methylene chloride, stirred at 0 ° C., and stirred with 1.59 g (6.06 m) of triphenylphosphine.
mol) in 9 ml of methylene chloride 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, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue obtained by the above treatment is separated and purified by silica gel column chromatography (n-hexane: ethyl ether = 8: 1) to obtain an optically active compound (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 (yield 21%) was obtained.

The optically active (S) -3-benzyl obtained above
The properties of ruoxy-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 3438cm^-1  (5)¹H-NMR (CDCl₃) Δ: 2.20 (d
d, J = 6.7, 6.7 Hz, 1H, exchange
able with D₂O), 3.79 (dd, J =
7.3, 10.5 Hz, 1H), 3.83 (dd, J =
5.5, 10.5 Hz, 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%) C₁₀H₁₃O₂ ⁸¹Br calculated value 246.007
8, analysis value 246.0072 C₁₀H₁₃O₂ ⁷⁹Br calculated value 244.009
9, analysis value 244.00075

61 mg of the optically active (S) -3-benzyloxy-2-bromo-1-propanol obtained above.
(0.25 mmol) and 79 mg of potassium hydroxide
(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 saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

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

The optical purity of the optically active (S) -benzyl glycidyl ether obtained above was 98.1% ee as analyzed by high performance liquid chromatography ("Chiral Cell OD" manufactured by Daicel Chemical Industries, Ltd.). Certain optically active (S) -3-benzyloxy-2-bromo-1-
Propanol was found to have very 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, can be easily produced with high yield and high purity.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References Heterocycles, Vol. 16, p. 381 (1981) (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 301/26 C07D 303/22 CA (STN)

Claims (2)

(57) [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, followed by base treatment. 2. The method according to claim 1, wherein the tetrahalogenomethane is carbon tetrabromide or carbon tetrachloride.