JP3250350B2 - Production method of optically active glycidyl tosylate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing optically active glycidyl silicate. Optically active glycidyl tosylate is a substance useful as a synthetic intermediate for synthesizing various drugs, agricultural chemicals, physiologically active substances, and the like, and its application is described in, for example, Chemical Reviews, 91 , 437.
(1991).

[0002]

2. Description of the Related Art Generally, as a method for obtaining optically active glycidyl tosylate, allyl alcohol is asymmetrically oxidized to optically active glycidol (J. Am. Chem. S.
oc., 102 , 5974 (1980)), and a method for p-toluenesulfonylation of this product. In this case, it is known that the optically active glycidol, which is an intermediate, itself is thermally unstable, and a part thereof is polymerized into an oligomer or a polymer when a distillation operation is performed to isolate the glycidol. Furthermore, the optically active glycidol obtained by this method has a yield of 65% and an optical purity of about 88 to 91% ee (Chemical Rev.).
iews, 91 , 437 (1991)), therefore, the overall yield (40%) and optical purity (94% ee) of optically active glycidyl tosylate derived from this optically active glycidol are not good (J. Org. Chem., 51 , 3712 (1986)). In order to improve the optical purity of the optically active glycidyl tosylate obtained by the above-mentioned method, several recrystallization operations are required, and if this is performed, it is unavoidable that the yield will be further reduced. Thus, for example, an optical purity of 98
It is not satisfactory as a method for obtaining a high-purity optically active glycidyl tosylate of not less than% ee in a high yield.

Further, as a method for obtaining an optically active glycidol having a high optical purity for deriving optically active glycidyl tosylate having an optical purity of about 98% ee, the methods described in Japanese Patent Publication Nos. 4-73998 and 4-73999 are disclosed. A method is conceivable in which the obtained optically active 3-chloro-1,2-propanediol is intramolecularly cyclized under basic conditions. In this case, when the reaction is carried out in an aqueous solution using, for example, potassium hydroxide as the base, the isolation yield is low due to the high water solubility of optically active glycidol, which is economically disadvantageous. Also, for example, when potassium carbonate is used as a base and a heterogeneous reaction is performed in an organic solvent, when separating generated salts,
Filtration is extremely difficult even under reduced or increased pressure due to the fineness of the solid.Not only does the filtration process take a long time, but also a large amount of washing solvent is required to sufficiently separate and purify optically active glycidol. It is very difficult to do. Further, as described above, when the optically active glycidol is purified by distillation, the yield is reduced due to its thermal instability.

In order to obtain high-purity optically active glycidyl tosylate in high yield, the present inventors have obtained optically active glycidol, which is a production intermediate, with high optical purity and high yield. Without isolation, under mild conditions
It was considered necessary to perform p-toluenesulfonylation.
That is, 3-chloro-1,2- having high optical purity
Using propanediol as a raw material, this is reacted with a base to obtain optically active glycidol, and without isolating it, it is subsequently p-toluenesulfonylated under mild conditions to minimize side reactions as much as possible.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have found that optically active 3-chloro-1,2-propanediol can be converted into a basic compound in an organic solvent. Under the conditions, without isolating the glycidol obtained as intermediate, followed by tertiary amines,
The present inventors have found that high-purity optically active glycidyl tosylate can be easily obtained by reacting p-toluenesulfonyl chloride in the presence of 4-dimethylaminopyridine, and the present invention has been completed.

The present invention provides an optically active 3-chloropropane-1,2-diol in an organic solvent at least one selected from the group consisting of alkali metal carbonates, bicarbonates and alkaline earth metal carbonates. With p-
Toluenesulfonyl chloride, tertiary amine and 4-
This is a process for producing optically active glycidyl silicate, which is characterized by reacting with dimethylaminopyridine.

The present invention is achieved by a two-step reaction represented by the following formula.

[0008]

Embedded image

That is, first, optically active 3-chloro-1,2
-An optically active glycidyl silicate is obtained by introducing an intermediate to an optically active glycidol by a cyclization reaction of propanediol, and then substituting a hydroxyl group with a p-toluenesulfonyl group.

Optically active 3-chloro- used as a raw material
It is preferable to use 1,2-propanediol having a high optical purity. Optically active 3-chloro-1,
As 2-propanediol, the applicant of the present invention
Those obtained by the methods described in JP-A-4-73998 and JP-B-4-73999 are preferred because of their high optical purity (98% ee or more).
According to the method of the present invention, R-3-chloro-1,2-
S-glycidyl tosylate from propanediol
From S-3-chloro-1,2-propanediol, R-
Glycidyl silicate is obtained.

The cyclization of the optically active 3-chloro-1,2-propanediol is carried out in an organic solvent under basic conditions.
In this case, as the base to be used, carbonates of alkali metals, hydrogen carbonates, or carbonates of alkaline earth metals can be used alone or in combination. For example, lithium carbonate, sodium carbonate, potassium carbonate ,
Preferred are lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and calcium carbonate.

The amount of the base used is 1.0 to 3.0 mol, more preferably 1.2 to 2.5 mol, based on the optically active 3-chloro-1,2-propanediol as a raw material. Examples of the organic solvent to be used include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, 1,1-dichloroethane and chloroform, and ethers such as tetrahydrofuran, diethyl ether, t-butylmethyl ether and isopropyl ether. , Acetone, methyl isobutyl ketone and the like, or aromatic hydrocarbons such as benzene, toluene and xylene are preferably used alone or in combination. The reaction temperature of the cyclization reaction is 10 to
40 ° C, preferably 20-30 ° C, more preferably 25-28 ° C
It is. If it is less than this range, the progress of the reaction is slow, and the viscosity of the reaction solution also increases.

The reaction is carried out by adding an optically active 3-chloro-diluted solution of a base and an organic solvent to a slurry solution of the organic solvent.
It is carried out by dropping 1,2-propanediol or by dropping without dilution and stirring. The reaction is usually completed in 5 to 24 hours, and an optically active glycidol as an intermediate is obtained, followed by the next substitution reaction.

The reaction for obtaining optically active glycidyl tosylate from optically active glycidol is achieved as follows. That is, according to the above method, a tertiary amine, 4-dimethylaminopyridine, and p-toluenesulfonyl chloride are reacted with the obtained reaction mixture containing the optically active glycidol to obtain an optically active glycidyl silicate. .

As the reaction solvent, the same solvent as used in the above-mentioned cyclization reaction can be used as it is. p
The amount of -toluenesulfonyl chloride to be used is 1 to 2 moles, preferably 1 to 1.5 moles, relative to 3-chloro-1,2-propanediol. p-Toluenesulfonyl chloride may be dissolved in the reaction solvent to be used and added dropwise, or may be added to the reaction solution as crystals. As the tertiary amines, it is preferable to use triethylamine or pyridine.
It is 1 to 3 moles, preferably 1 to 2 moles, based on chloro-1,2-propanediol. Further, the reaction temperature of the tosylation reaction is preferably from -15 to 40C, more preferably from -10 to 30C. The amount of 4-dimethylaminopyridine used may be optically active 3-chloro-1,2-
It is 0.001 to 0.2 mol%, preferably 0.005 to 0.05 mol%, based on propanediol. Under the above conditions, the reaction is completed in 0.5 to 10 hours. When 4-dimethylaminopyridine is not added, it takes 10 hours or more to complete the reaction at the same temperature. In addition, HPLC
In the analysis of the reaction solution, it was observed that when 4-dimethylaminopyridine was added, the generation of by-products was suppressed as compared with the case where 4-dimethylaminopyridine was not added.

After completion of the reaction, as a post-treatment of the reaction solution, the desired optically active glycidyl tosylate can be easily separated into an organic layer by a liquid separation operation with hydrochloric acid. That is, the reaction solution is neutralized with hydrochloric acid, subjected to a liquid separation treatment, and then the product obtained by distilling off the solvent is recrystallized.
(Chemical purity of 98% or more, optical purity of 98% or more) can be obtained.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

[0018]

【Example】

Example 1 A stirred solution of potassium carbonate (224.25 g, 1.623 mol) and 1,2-dichloroethane (1500 ml) was stirred at 24-28 ° C. while stirring (R) -3-chloro-1,2-propanedioxide. (1
20.03 g, 1.085 mol, 99.74% ee) was added dropwise over 30 minutes.
After stirring for 21 hours after the completion of dropping, the reaction solution was cooled, and
While stirring at 0 ° C, triethylamine (120.73g, 1.193mo
l) was added dropwise over 15 minutes, then 4-dimethylaminopyridine (1.99 g, 0.016 mol) and p-toluenesulfonyl chloride (206.97 g, 1.086 mol) were added over 30 minutes. After completion of the addition, the mixture was stirred for 2 hours, and 3% hydrochloric acid (900 ml) was added to dissolve the salt. The organic layer was washed with 3% hydrochloric acid (600 ml) and then with water (900 ml), and the excess solvent was distilled off under reduced pressure. The residue after distillation (2
11.73 g) with isopropyl alcohol (424 ml) and hexane (4
(S) -glycidyl tosylate 170.3
2 g were obtained. The chemical purity determined by HPLC was 96.53%, and the optical purity was 96.67% ee. The product was recrystallized from isopropyl alcohol (340 ml) and hexane (340 ml) to give (S)-having a chemical purity of 99.85% and an optical purity of 98.01% ee.
147.38 g of glycidyl sylate was obtained. (Isolation yield 59.51
%)

EXAMPLE 2 A suspension of potassium carbonate (35.14 g, 0.254 mol) and 1,2-dichloroethane (120 ml) was stirred at 24-28 ° C.
(S) -3-Chloro-1,2-propanediol was converted to (13.
(10 g, 0.118 mol, 99.74% ee) was added dropwise over 10 minutes. After stirring for 22 hours after the completion of the dropwise addition, 1,2-dichloroethane (55 m
l) was added, the reaction solution was cooled, and triethylamine (14.36 g, 0.142 mol) was added dropwise with stirring at 5 to 10 ° C, and then 4-dimethylaminopyridine (0.24 g, 0.002 mol), p-toluenesulfonyl chloride (22.59 g) was added. g, 0.118 mol) was added over 10 minutes. Stir for 3 hours after completion of the addition, and add 6% hydrochloric acid (125 ml).
Was added to dissolve the salt. The organic layer was washed with 3% hydrochloric acid (30 ml) and then with water (100 ml × 2), and the excess solvent was distilled off under reduced pressure.
Further, isopropyl alcohol (30 ml) was added to the residue (30.02 g) after the distillation and mixed well, and then the isopropyl alcohol was distilled off under reduced pressure. The oily residue (24.50 g) was recrystallized from isopropyl alcohol (50 ml) and hexane (50 ml) to give (R) -glycidyl tosylate (20.69 g). HPLC
Is 99.31%, optical purity is 96.91% ee
Met. This product was further treated with isopropyl alcohol (4
(R) -glycidyl silicate having a chemical purity of 99.87% and an optical purity of 98.23% ee was obtained by recrystallization from hexane (40 ml) and hexane (40 ml). (Isolation yield 70.94%)

Comparative Example No use of 4-dimethylaminopyridine,
The reaction was carried out in the same manner as in Example 1 except that stirring was carried out for 24 hours after the completion of the addition of p-toluenesulfonyl chloride. (S) -Glycidyl tosylate (chemical purity)
The isolation yield of 98.4%, optical purity 98.0% ee) was 43.3%.

[0021]

According to the present invention, high optical purity (98% ee
Simple operation without isolating the optically active glycidol as an intermediate, and
It can be obtained in good yield.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-6-179663 (JP, A) JP-A-6-184129 (JP, A) JP-A-6-306067 (JP, A) JP-A-4- 228094 (JP, A) WO 97/26254 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 303/12 C07D 301/26 CA (STN)

Claims (1)

(57) [Claims] An optically active 3-chloropropane-1,2-
The diol is reacted with at least one selected from alkali metal carbonates, bicarbonates, and alkaline earth metal carbonates in an organic solvent, followed by p-toluenesulfonyl chloride, tertiary amine and quaternary amine. -A process for producing optically active glycidyl silicate, characterized by reacting with dimethylaminopyridine.