KR100612779B1 - New process for the preparation of chiral glycidylphthalimide in highly optical purity - Google Patents

Abstract

The present invention relates to a process for preparing chiral glycidylphthalimide with high optical purity. More specifically, the present invention reacts the N- (3-substituted-2-hydroxypropyl by reacting an optically active substance of 3-substituted-1-amino-2-propanol acid addition salt with phthalic anhydride in the presence of a base. A method for preparing chiral glycidylphthalimide comprising the steps of obtaining phthalimide and subjecting the obtained compound to an epoxide cyclization reaction to produce the desired glycidylphthalimide. According to this method, throughout the entire process, the chirality of the starting material is maintained completely, with the result that glycidylphthalimide having a high optical purity of 99% ee or more is easily obtained in high yield. The reaction is then achieved under mild conditions throughout the entire process, and chiral glycidylphthalimide is prepared in high optical purity in one reactor without special purification processes.

Description

Process for producing chiral glycidyl phthalimide with high optical purity {NEW PROCESS FOR THE PREPARATION OF CHIRAL GLYCIDYLPHTHALIMIDE IN HIGHLY OPTICAL PURITY}

The present invention relates to a method for preparing chiral glycidylphthalimide. More specifically, the present invention relates to a method for preparing chiral glycidylphthalimide in high optical purity without lowering the optical purity of the starting material.

Most recently developed or marketed drugs are optically active drugs. This is because conventional racemic drugs sometimes cause side effects or exhibit reduced efficacy. Therefore, modern medicines are trying to develop high optical purity medicines composed of pure stereoisomers to increase the safety and efficacy of drugs. In order to synthesize drugs having high optical purity, the optical purity of the intermediates used in the synthesis thereof must be high. At present, the price of the optically active compound which is commercially available increases rapidly as optical purity increases. Thus, compounds with high optical purity of 99% ee or higher have very high value.

Glycidyl phthalimide is widely used as an intermediate of medicines, pesticides or bioactive substances. The conventional manufacturing method of the conventional glycidyl phthalimide so far is as follows.

First, a preparation method (Synlett, 1996, p873-874) is known in which a phthalimide and epichlorohydrin are reacted in the presence of tetra-n-butylammonium iodide and potassium carbonate in a microwave oven. However, this method does not provide the desired compound in a satisfactory yield.

Epichlorohydrin is used as a solvent and refluxed with potassium phthalimide (J. Org. Chem. 1963, vol. 28, p1589-1593; J. Am. Chem. Soc. 1995, vol. 117, p11220) -11229) is known. The above method has a problem that racemic reaction proceeds when reflux of epihalohydrin in the presence of potassium phthalimide potassium, resulting in a decrease in optical purity of the synthesized glycidyl phthalimide. In addition, the use of expensive epihalohydrin optically active as a solvent in excess of the production price is less competitive.

The method of reacting epichlorohydrin and potassium phthalimide in N, N-dimethylformaldehyde solvent (Helv. Chim. Acta 1990, vol. 73, p912-915 and U.S. Pat.No. 6,875,875) is known as epichlorohydrin. Although the amount of use can be reduced, the optically active substance (99% ee) of epichlorohydrin is less selective and racemized when reacted with potassium phthalimide in the presence of N, N-dimethylamide, a polar aprotic solvent. Proceeds. As a result, the optical purity (63% ee) of the optically active substance of the desired glycidylphthalimide is insufficient for use in medicine.

As another alternative, in the presence of Mitsunobu reagent diethylazodicarboxylate and triphenylphosphine, the optically active agent of glycidyl phthalimide is formed by coupling the optically active agent of glycidol and phthalimide. A method of obtaining (Tetrahedron Asymmetry, 1996, vol. 7, p1641-1648; Tetrahedron, 2004, vol. 60, p7679-7692) has been reported. However, this method has a problem that it is difficult to purify the glycidyl phthalimide optical active material by the by-product of the Mitsunobu reaction. Thus, the method is not applicable to commercial mass production.

Recently, US Pat. No. 6,875,875 discloses the reaction of an optically active compound of epichlorohydrin with an alkali metal salt of phthalimide in the presence of an alcoholic solvent, or a phthalimide and an optically active epihalohydrin as an inorganic base (e. : Reacted in the presence of an alkali metal carbonate or an alkali metal carbonate) or a quaternary ammonium salt, and the obtained N- (3-halo-2-hydroxypropyl) phthalimide is cyclized using an alkali metal alkoxide to give glyc A method for producing cydyl phthalimide is proposed. By this method, chiral glycidylphthalimide was obtained with a high optical purity of 98% ee. However, the method uses an excess amount of the optically active substance of epichlorohydrin which is expensive in the ratio of 3: 1 or 2: 1 than phthalimide alkali metal or phthalimide. In addition, in the step of synthesizing glycidyl phthalimide from N- (3-halo-2-hydroxypropyl) phthalimide, the glycidyl synthesized by cyclization using an alkali metal alkoxide and then water Some of the phthalimide is decomposed. In addition, even if the reaction proceeds using an optical activator of epichlorohydrin having an optical purity of 99% ee, since the difference in selectivity is not very large, the optical purity of the starting material is partially reduced. Thus, glycidylphthalimide having an optical purity of 98% ee or less is obtained. From these results, it is believed that it is difficult to synthesize glycidylphthalimide with high optical purity of at least 98% ee, more preferably at least 99% ee, in commercial mass production.

It is an object of the present invention to provide a method for efficiently preparing an optically active substance of glycidylphthalimide with high optical purity of 99% ee or more. According to the present invention, there is provided a method for preparing the desired glycidylphthalimide with high optical purity of 99% ee or higher while maintaining the chirality of the starting material.

According to a preferred embodiment of the invention, a) an N- (3-substituted-2-hydride is reacted by reacting an optically active compound of 3-substituted 1-amino-2-propanol acid addition salt with phthalic anhydride in the presence of a base. Obtaining oxypropyl) phthalimide, and b) applying the obtained compound to an epoxide cyclization reaction to produce chiral glycidylphthalimide. This is provided.

According to a more preferred embodiment of the invention, the 1-amino-3-halo-2-propanol acid addition salt is 1-amino-3-halo-2-propanol hydrochloride, 1-amino-3-halo-2-propanol bromate , 1-amino-3-halo-2-propanol bromate, 1-amino-3-halo-2-propanol iodide or 1-amino-3-halo-2-propanol methanesulfonate Provided is a method for preparing phthalimide.

According to a further preferred embodiment of the invention, the glycidyl phthalimide, characterized in that the 1-amino-3-halo-2-propanol acid addition salt is 1-amino-3-halo-2-propanol methanesulfonate Provided is a method for preparing.

According to another preferred embodiment of the present invention, there is provided a method for preparing glycidylphthalimide, wherein the base of step a) is an organic base.

According to another preferred embodiment of the present invention, there is provided a method for preparing glycidylphthalimide, wherein the base of step a) is a tertiary amine.

According to another preferred embodiment of the present invention, there is provided a method for preparing glycidylphthalimide, characterized in that the epoxide cyclization of step b) is carried out in the presence of an inorganic base.

According to another preferred embodiment of the present invention, there is provided a method for preparing glycidylphthalimide, characterized in that the epoxide cyclization of step b) is carried out in the presence of an inorganic base.

The present invention relates to a method for preparing glycidylphthalimide, which method comprises a) an optically active substance of 3-substituted 1-amino-2-propanol acid addition salt (or acid salt) in the presence of a base, Reacting with phthalic acid to obtain N- (3-substituted-2-hydroxypropyl) phthalimide, and b) applying the obtained compound to epoxide cyclization to obtain a high optical purity of glycidylphthalimide. It comprises the step of obtaining an optically active material.

More specifically, the present invention relates to a method for preparing glycidylphthalimide represented by the formula (1), wherein a) 3-substituted 1-amino-2-propanol acid addition salt having the formula (2) in the presence of a base Reacting with phthalic anhydride having formula (3) to obtain N- (3-substituted-2-hydroxypropyl) phthalimide represented by formula (4), and b) cyclizing the obtained compound of formula (4). Applying to the reaction comprises the step of preparing the glycidyl phthalimide of the formula (1). At this time, the glycidyl phthalimide of the formula (1) is easily obtained through recrystallization, it is obtained with an optical purity of 99% ee or more while maintaining the optical purity of the starting material.

In Chemical Formulas 1 to 4, * denotes a chiral center, X denotes a leaving group, and Y denotes a sulfone group, a halogen group or a carboxyl group.

The method for preparing chiral glycidylphthalimide according to the present invention can be summarized by the following scheme 1.

As shown in Scheme 1, N- having a formula (4) by a condensation reaction between the optically active agent of the 3-substituted 1-amino-2-propanol acid addition salt having the formula (2) and the phthalic anhydride having the formula (3) 3-Substituted-2-hydroxypropyl) phthalimide is obtained. The 3-substituted 1-amino-2-propanol acid addition salts having the formula (2), with the aid of a base, are converted to a free base and participate in the condensation reaction with phthalic anhydride. In this case, the phthalic anhydride of the formula (3) is used in 0.9-1.5 equivalents, preferably 1-1.2 equivalents, based on the 3-substituted 1-amino-2-propanol acid addition salt having the formula (2). In order to convert the 3-substituted 1-amino-2-propanol acid addition salt having the formula (2) into the form of a free base, the condensation reaction is carried out in the presence of a base. As the base that can be used for the condensation reaction, an organic base or an inorganic base can be used. Preferred examples of the organic base are tertiary amines represented by R ₁ R ₂ R ₃ N. R ₁ , R ₂ and R ₃ here independently represent a C ₁ -C ₁₆ alkyl group, a C ₂ -C ₁₆ alkenyl group, a C ₇ -C ₁₆ arylalkyl group or a C ₇ -C ₁₆ alkylaryl group. Specific examples of tertiary amines include trimethylamine, triethylamine, tributylamine, triphenylamine, and diisopropylethylamine. Examples of the inorganic bases include alkali metal salts. For example, alkali carbonates, alkali bicarbonates or alkali phosphates can be used. Specifically, lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate and the like can be used. Most preferably trialkylamine. The base is used in the range of 1-10 equivalents, preferably 1-5 equivalents, and most preferably 1.1-2 equivalents, based on the 3-substituted 1-amino-2-propanol acid addition salt of the formula (2). .

The condensation reaction is carried out in an organic solvent system. Organic solvents that can be used in the condensation reaction are well known in the art. Polar organic solvents such as alcohols, tetrahydrofuran, dioxane, acetone, N, N-dimethylformaldehyde, dimethyl sulfoxide and the like or low polar organic solvents such as aromatic hydrocarbons, ethers, C ₁ -C ₄ halogenated hydrocarbons and the like are widely employed. Can be. Preferably it is an aprotic organic solvent. Among them, an aromatic hydrocarbon such as toluene is more preferable. The organic solvent is preferably used in an amount of 3 to 15 times based on the weight of the 3-substituted 1-amino-2-propanol acid addition salt of the formula (2).

(R₄는 C₁-C₁₀ 알킬기; C₆-C₁₀ 아릴기; 또는 니트로기, 메틸기, 에틸기, 플루오로기 또는 클로로기로 치환된 C₆-C₁₀ 아릴기)로 표시되는 술폰기가 이탈기로서 사용될 수 있다. 술폰기의 바람직한 예로는 메탄술폰기, p-톨루엔술폰기, 벤젠술폰기, 트리플루오로메탄술폰기 또는 니트로벤젠술폰기를 들 수 있다. 바람직하게는, 1-아미노-3-할로-2-프로판올 산부가염이다. 1-아미노-3-클로로-2-프로판올 산부가염, 1-아미노-3-브로모-2-프로판올 산부가염, 1-아미노-3-요오드-2-프로판올 산부가염이 사용될 수 있다. 1-아미노-3-클로로-2-프로판올 산부가염이 가장 바람직하다. 산부가염을 형성하기 위해, 염산, 브롬산, 요오드산, C₁-C₁₀ 알킬설폰산, C₆-C₁₀ 아릴설폰산, C₇-C₁₁ 알킬아릴설폰산, C₇-C₁₁ 아릴알킬설폰산 또는 C₁-C₁₀의 카르복실산이 사용될 수 있다. 바람직하게는, C₁-C₁₀ 알킬설폰산, C₆-C₁₀ 아릴설폰산, C₇-C₁₁ 알킬아릴설폰산 또는 C₇-C₁₁ 아릴알킬설폰산이다. 가장 바람직하게는, 1-아미노-3-할로-2-프로판올 메탄설폰산염이다.As the 3-substituted 1-amino-2-propanol acid addition salt represented by the formula (2), various leaving groups may be introduced to carbon 3. For example, a halogen group, or

The sulfone group represented by (R ₄ is a C ₁ -C ₁₀ alkyl group; C ₆ -C ₁₀ aryl group; or a C ₆ -C ₁₀ aryl group substituted with a nitro group, methyl group, ethyl group, fluoro group or chloro group) Can be used as. Preferable examples of the sulfone group include methane sulfone group, p-toluene sulfone group, benzene sulfone group, trifluoromethane sulfone group or nitrobenzene sulfone group. Preferably, it is 1-amino-3-halo-2-propanol acid addition salt. 1-amino-3-chloro-2-propanol acid addition salt, 1-amino-3-bromo-2-propanol acid addition salt, 1-amino-3-iodine-2-propanol acid addition salt may be used. Most preferred is 1-amino-3-chloro-2-propanol acid addition salt. To form an acid addition salt, hydrochloric acid, bromic acid, iodic acid, C ₁ -C ₁₀ alkylsulfonic acid, C ₆ -C ₁₀ arylsulfonic acid, C ₇ -C ₁₁ alkylarylsulfonic acid, C ₇ -C ₁₁ arylalkyl Sulphonic acid or C ₁ -C ₁₀ carboxylic acids can be used. Preferably, it is C ₁ -C ₁₀ alkylsulfonic acid, C ₆ -C ₁₀ arylsulfonic acid, C ₇ -C ₁₁ alkylarylsulfonic acid or C ₇ -C ₁₁ arylalkylsulfonic acid. Most preferably, it is 1-amino-3-halo-2-propanol methanesulfonate.

The compound of formula 4 produced by the condensation reaction can be applied to the cyclization immediately after evaporation of the solvent under reduced pressure without purification. Therefore, the condensation reaction and the cyclization reaction proceed to a one-pot reaction. This simplifies the reaction process and provides an improved yield of the product.

The cyclization reaction is also carried out in the presence of a base. As the organic base, the above-mentioned tertiary amines can be mentioned. More preferably, it is an inorganic base. Examples of inorganic bases that can be used include alkali metal salts or alkaline earth metal salts. Preferably, they are alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal phosphate and alkaline earth metal phosphate. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, magnesium phosphate, calcium phosphate, etc. This can be used. Most preferably potassium phosphate. The base is used in the range of 1-10 equivalents, preferably 1-5 equivalents, and most preferably 1.5-3 equivalents, based on the 3-substituted 1-amino-2-propanol acid addition salt of the formula (2). .

The cyclization is also carried out in an organic solvent system. Polar organic solvents such as acetonitrile, tetrahydrofuran, acetone, N, N-dimethylformaldehyde, dimethyl sulfoxide and the like or low polar organic solvents such as aromatic hydrocarbons, ethers, C ₁ -C ₄ halogenated hydrocarbons can be widely employed. have. Preferably it is an aprotic organic solvent. Aromatic hydrocarbons or C ₁ -C ₄ halogenated hydrocarbons are more preferred. Most preferably, 1,2-dichloroethane. The organic solvent is preferably used in an amount of 3 to 15 times based on the weight of the 3-substituted 1-amino-2-propanol acid addition salt of the formula (2).

Glycidyl phthalimide of Formula 1 obtained as a product of the cyclization reaction can be purified purely by recrystallization after a normal work-up process (extraction, drying and solvent evaporation). As the solvent used for recrystallization, a single solvent or mixed solvent system may be employed. U.S. Patent No. 6,875,875 performed recrystallization using a mixed solvent of ethyl acetate-hexane. In addition to the mixed solvent system, C ₁ -C ₄ alcohols such as methanol, ethanol, propanol, isopropanol, butanol and the like may be used for recrystallization. In a preferred embodiment of the present invention, the glycidylphthalimide of the formula (1) is purified to high optical purity through recrystallization with ethanol.

The greatest advantage of the method for preparing glycidylphthalimide according to the present invention is that the optical purity of the starting material is maintained substantially completely. In other words, the chiral compound of formula (2) is prepared in high optical purity without any reduction in chirality. As a result, glycidylphthalimide having a high optical purity of 99% ee or more is prepared in high yield while maintaining the optical purity of the starting material.

Example 1

(S) -1-amino-3-chloro-2-propanol methanesulfonate 25.00 g (0.123 mol), 25.34 g (0.123 mol) phthalic anhydride, 18.63 ml (0.134 mol) triethylamine, 121 ml of toluene After stirring at ˜120 ° C. for 2 hours, the solvent was removed under reduced pressure. Subsequently, 64.51 g (0.304 mol) of potassium phosphate and 121 ml of 1,2-dichloroethane were added thereto, followed by stirring at 80 ° C. for 14 hours. After cooling to 0 ° C., 100 ml of water was added to dissolve potassium phosphate, and extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 17.91 g (yield 72%, optical purity 99.5% ee) of the target compound (S) -glycidylphthalimide as white crystals.

Melting point: 100-102 ℃

¹ H NMR (CDCl ₃ , 300 MHz): δ 7.70-8.00 (m, 4H), 3.95 (dd, 1H, J = 14.4 Hz, 5.1 Hz), 3.79 (dd, 1H), 3.22-3.26 (m, 1 H), 2.80 (dd, 1H), 2.67 (dd, 1H, J = 7.8 Hz, 2.4 Hz)

The optical purity (% ee) of glycidyl phthalimide was calculated from the area ratio by using a high performance liquid chromatography method. As a column, CHIRALPAC AD ^™ (0.46 cm × 25 cm) manufactured by Daicel Chemical Industry Co., Ltd. was flowed with a mixed solvent of 90:10 (v / v) of n-hexane and isopropanol at 1 ml / min. Spectra were obtained at 254 nm and (S) was detected at 14.2 min and (R) at 19.2 min.

Example 2

(S) -1-amino-3-chloro-2-propanol methanesulfonate 25.00 g (0.123 mol), 25.34 g (0.123 mol) phthalic anhydride, 18.63 ml (0.134 mol) triethylamine, 121 ml of toluene After stirring at ˜120 ° C. for 2 hours, the organic layer is washed with water at room temperature. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. Subsequently, 64.51 g (0.304 mol) of potassium phosphate and 121 ml of 1,2-dichloroethane were added thereto, followed by stirring at 80 ° C. for 14 hours. After cooling to 0 ° C., 100 ml was added to dissolve potassium phosphate, and extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 18.12 g (yield 73%, optical purity 99.5% ee) of the target compound (S) -glycidylphthalimide as white crystals.

Example 3

Add 25.00 g (0.171 mol) of (S) -1-amino-3-chloro-2-propanol hydrochloride, 25.34 g (0.171 mol) of phthalic anhydride, 28.64 ml (0.206 mol) of triethylamine, and 171 ml of toluene. After stirring for 2 h at 占 폚, the solvent was removed under reduced pressure. Subsequently, 90.86 g (0.342 mol) of potassium phosphate and 171 ml of 1,2-dichloroethane were added thereto, followed by stirring at 80 ° C. for 14 hours. After cooling to 0 ° C., 100 ml of water was added to dissolve potassium phosphate, and extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 24.01 g (yield 69%, optical purity 99.5% ee) of the target compound (S) -glycidylphthalimide as white crystals.

Example 4

Add 25.00 g (0.171 mol) of (S) -1-amino-3-chloro-2-propanol hydrochloride, 25.34 g (0.171 mol) of phthalic anhydride, 28.64 ml (0.206 mol) of triethylamine, and 171 ml of toluene. After stirring for 2 h at rt, the solvent was removed under reduced pressure. Subsequently, 90.86 g of potassium phosphate (0.342 mol) and 171 ml of acetonitrile were added thereto, and the mixture was stirred at 80 ° C. for 14 hours. After cooling to 0 ° C., 100 ml of water was added to dissolve potassium phosphate, and extracted with ethyl acetate to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 22.34 g (yield 64%, optical purity 99.5% ee) of the target compound (S) -glycidylphthalimide as white crystals.

Example 5

(S) -1-amino-3-chloro-2-propanol hydrochloride 5.00 g (0.034 mol), 5.069 g (0.034 mol) of phthalic anhydride, 5.73 ml (0.041 mol) of triethylamine, and 34 ml of toluene After stirring at 2 ° C. for 2 hours, 30 ml of water was added thereto, extracted with toluene to obtain an organic layer, and the obtained organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Then 18.17 g (0.069 mol) of potassium phosphate and 34 ml of 1,2-dichloroethane were added thereto and stirred at 80 ° C. for 14 hours. After cooling to 0 ° C., 100 ml of water was added to dissolve potassium phosphate, and extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 4.68 g (yield 67%, optical purity 99.5% ee) of the target compound (S) -glycidyl phthalimide as white crystals.

Example 6

5.00 g (0.034 mol) of (S) -1-amino-3-chloro-2-propanol hydrochloride, 5.069 g (0.034 mol) of phthalic anhydride, 5.73 ml (0.041 mol) of triethylamine, and 34 ml of toluene After stirring for 2 h at rt, the solvent was removed under reduced pressure. Then 18.17 g (0.069 mol) of potassium phosphate and 34 ml of N, N-dimethylformamide were sequentially added and stirred at 40 ° C. for 3.5 hours. After cooling the temperature to room temperature, potassium phosphate was filtered and the obtained mother liquor was added with sulfuric acid to adjust the pH to 5 to 6, and then extracted with ethyl acetate to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 4.07 g (yield 59%, optical purity 99.5% ee) of the target compound (S) -glycidylphthalimide as white crystals.

According to the method for preparing glycidyl phthalimide according to the present invention, glycidyl phthalimide can be prepared in high optical purity while maintaining the optical purity of the starting material substantially completely. Specifically, the chiral compound of formula (2) used as starting material can be prepared in high optical purity without any reduction in chirality. As a result, glycidylphthalimide having a high optical purity of 99% ee or more can be prepared in high yield while maintaining the optical purity of the starting material. The compound of formula (4) obtained by condensation reaction between an optically active agent of 3-substituted 1-amino-2-propanol acid addition salt having formula (2) and phthalic anhydride having formula (3), without undergoing purification, It can be applied to the next cyclization reaction. And the next cyclization reaction is carried out under mild conditions. Therefore, the method for producing glycidylphthalimide according to the present invention is carried out under mild conditions throughout the whole process, and proceeds as a one-pot reaction. This means that the method according to the invention can be usefully applied for commercial mass production of glycidylphthalimide with high optical purity.

Claims (10)

a) N- (3-substituted-2 represented by the following formula (4) by reacting a 3-substituted 1-amino-2-propanol acid addition salt having the formula (2) with phthalic anhydride having the formula (3) in the presence of a base; -Obtaining hydroxypropyl) phthalimide, and b) applying the obtained compound of formula 4 to an epoxide cyclization reaction to prepare the glycidylphthalimide of formula 1, Method for preparing glycidylphthalimide represented by Formula 1: Formula 1

Formula 2

Formula 3

Formula 4

In Chemical Formulas 1 to 4, * means chiral center, X means leaving group, and Y means sulfone group, halogen group or carboxyl group. The method for preparing glycidylphthalimide according to claim 1, wherein the 3-substituted 1-amino-2-propanol acid addition salt having the formula (2) is an optically active agent. The method of claim 1, wherein X is a halogen group, or

A sulfone group represented by: wherein R ₄ is a C ₁ -C ₁₀ alkyl group; C ₆ -C ₁₀ aryl group; Or a C ₆ -C ₁₀ aryl group substituted with a nitro group, a methyl group, an ethyl group, a fluoro group or a chloro group. The method for producing glycidylphthalimide according to claim 3, wherein X is a halogen group selected from the group consisting of chloro group, bromo group and iodo group. The method for producing glycidylphthalimide according to claim 4, wherein X is a chloro group. The method of claim 1, wherein the HY is hydrochloric acid, bromic acid, iodic acid, C ₁ -C ₁₀ alkylsulfonic acid, C ₆ -C ₁₀ arylsulfonic acid, C ₇ -C ₁₁ alkylarylsulfonic acid, C ₇ -C ₁₁ A method for producing glycidylphthalimide, characterized in that it is arylalkylsulfonic acid or C ₁ -C ₁₀ carboxylic acid. The method of claim 6, wherein the HY is methanesulfonic acid. The chiral glycidylphthalimide of claim 1, wherein the 3-substituted 1-amino-2-propanol acid addition salt is 1-amino-3-chloro-2-propanol methanesulfonate. Way. The method of claim 1, wherein step a) is R ₁ R ₂ R ₃ N wherein R ₁ , R ₂ and R ₃ are independently of each other a C ₁ -C ₁₆ alkyl group, C ₂ -C ₁₆ alkenyl group, C ₇ A method for producing glycidylphthalimide, which is carried out in the presence of a tertiary amine represented by -C ₁₆ arylalkyl group or C ₇ -C ₁₆ alkylaryl group. The method of claim 1, wherein step b) is performed in the presence of an inorganic base selected from the group consisting of alkali metal salts and alkaline earth metal salts.