(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization International Bureau

(43) International Publication Date (10) International Publication Number 22 November 2007 (22.11.2007) PCT WO 2007/132990 Al

(51) International Patent Classification: (74) Agents: KIM, Jin-Hak et al; # 1106, Kumsan Bldg., 17-1 C07D 405/06 (2006.01) Youido-dong, Youngdeungpo-ku, Seoul 150-727 (KR).

(21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/KR2007/002154 kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (22) International Filing Date: 2 May 2007 (02.05.2007) CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, (25) Filing Language: English IS, JP, KE, KG, KM, KN, KP, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, (26) Publication Language: English NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, (30) Priority Data: TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW 10-2006-0042433 11 May 2006 (11.05.2006) KR

(71) Applicant (for all designated States except US): RSTECH (84) Designated States (unless otherwise indicated, for every CORPORATION [KR/KR]; #306, Venture Town Jangy- kind of regional protection available): ARIPO (BW, GH, oungsilgwan, 1688-5 Sinil-dong, Daeduk-gu, Daejeon GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 306-230 (KR). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (75) Inventors/Applicants (for US only): KANG, Hyun PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, Bin [KR/KR]; #102-201 Daeju Apt., Sipjeong-dong, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Bupyeong-gu, Incheon 403-130 (KR). QUAN, Long Guo [CN/KR]; #304, Venture Town Jangyoungsilgwan, Published: 1688-5 Sinil-dong, Daeduk-ku, Daejeon 306-230 (KR). — with international search report LEE, Jae Kwan [KR/KR]; #6-706 Samsung Apt., 924-3 Dongchun-dong, Yeonsu-ku, Incheon 406-130 (KR). For two-letter codes and other abbreviations, refer to the "G uid KIM, Seong-Jin [KR/KR]; #502, Keangnamhonorsville, ance Notes on Codes and Abbreviations" appearing at the beg in lijok-dong, Yuseong-gu, Deajeon 305-330 (KR). ning of each regular issue of the PCT Gazette.

(54) Title: PROCESS FOR THE PREPARATION OF CHIRAL GLYCIDYLPHTHALIMIDE IN HIGHLY OPTICAL PURITY

(57) Abstract: The present invention relates to a process for the preparation of highly optical pure glycidylphthalimide. More particularly, the present invention relates to a process for the preparation of chiral glycidylphthalimide, which comprises the steps of reacting an optically active 3-susbstituted l-amino-2-propanol acid addition salt with phthalic anhydride in a presence of a base to obtain yV-(3-substituted-2-hydroxypropyl)phthalimide and subjecting the obtained compound to an epoxide cyclization reaction to prepare the targeted glycidylphthalimide. According to the process, the chirality of the starting material is substantially retained throughout overall procedures. Therefore, the process can prepare the targeted glycidylphthalimide in an optically pure form having 99%ee or higher. And, the reactions are carried out under mild conditions through overall procedures and in a single reaction vessel without any special purification. This increases the yield of the target compound. Description PROCESS FOR THE PREPARATION OF CHIRAL GLY- CIDYLPHTHALIMIDE IN HIGHLY OPTICAL PURITY Technical Field [1] The present invention relates to a process for the preparation of glycidylphthalimide. More particularly, the present invention relates to a process for the preparation of chiral glycidylphthalimide with high optical purity without decrease of the optical purity of the starting material. Background Art [2] Most of recently developed or commercially available medicines are optically active substances. This is attributed to the fact that conventional racemic medicines often cause side effects or exhibit low therapeutic effects. Various efforts are made to develop medicines with high optical purity in a pure stereo-isomeric form in order to increase stability and therapeutic efficacy of the medicines. In order to synthesize the medicines having high optical purity, the optical purity of the corresponding in termediates should be high. As the optical purity is higher, the price of the compound is even more expensive. Thus, compounds having high optical purity of 99%ee or higher are of great value. [3] Glycidylphthalimide is widely used as an intermediate of medicines, agrochemicals or physiologically active materials. Conventional methods for preparing glycidylph thalimide known in the art are as follows. [4] There was disclosed a method for preparing glycidylphthalimide, comprising reacting phthalimide with epichlorohydrin in a presence of tetra-n-butylammonium iodide and potassium carbonate inside a microwave oven (Synlett, 1996, p873-874). However, the method fails to produce the target compound in a satisfactory yield. [5] There was disclosed another method for preparing glycidylphthalimide by refluxing potassium phthalimide under an epichlorohydrin solvent (J. Org. Chem. 1963, vol. 28, pl589-1593; J. Am. Chem. Soc. 1995, vol. 117, p i 1220-1 1229). However, the method suffers from the disadvantages that optical purity of the glycidylphthalimide decreases due to racemization that takes place during refluxing epihalohydrin in the presence of potassium phthalimide. Further, excessive use of the expensive optically active epi halohydrin as a solvent deteriorates the price competitiveness. [6] There was disclosed a method for preparingglycidylphthalimide by reacting epichlorohydrin with potassium phthalimide in a , -dimethylformaldehyde solvent ( HeIv. Chim. Acta 1990, vol. 73, p912-915). The method reduces the amount of epichlorohydrin to be used. However, when optically active epichlorohydrin (99%ee) reacts with potassium phthalimide in a polar aprotic solvent such as N,N- dimethylamide, selectivity decreases and racemization takes place. Consequently, the resultant glycidylphthalimide has poor optical purity (63%ee), which is not adequate for medicines. [7] As an alterative, there was disclosed a method for preparing optically active gly cidylphthalimide by coupling optically active glycidol with phthalimide in a presence of diethylazodicarboxylate and triphenylphosphine that are Mitsunobu reagents ( TetrahedronAsymmetry, 1996, vol. 7, pl641-1648 and Tetrahedron, 2004, vol. 60, p7679-7692). However, the method has a problem that purification of the resultant optically active glycidylphthalimide is not easy due to the byproducts of the Mitsunobu reactions. Therefore, the method is not applicable to industrial-scale production. [8] Recently, U.S. Patent No. 6,875,875 disclosed a method for preparing glycidylph thalimide by reacting optically active epichlorohydrin with an alkali metal salt of ph thalimide in an alcohol solvent, or by reacting optically active epihalohydrin with ph thalimide in the presence of an inorganic salt (e.g., alkali metal carbonate or alkali metal hydrogencarbonate) or a quaternary ammonium salt to obtain N - (3-halo-2-hydroxypropyl)phthalimide, and then by cyclizing the obtained product with alkali metal alkoxide. According to the method, chiral glycidylphthalimide is obtained in high optical purity of 98%ee. However, the method requires excessive use of the expensive optically active epichlorohydrin in an amount of 3 times or 2 times of the alkali metal phthalimide or phthalimide. Further, in the synthesis of the glycidylph thalimide from -(3-halo-2-hydroxypropyl)phthalimide, some of glycidylphthalimide synthesized undergoes decomposition by the addition of water after completion of the cyclization reaction. In addition, the optical purity of the starting material is somewhat reduced because selectivity is not distinguishable. Accordingly, the resultant gly cidylphthalimide has an optical purity of 98%ee or less. For these reasons, the industrial-scale synthesis of glycidylphthalimide having high optical purity of 98%ee or higher, preferably 99%ee or higher is being demanded. Disclosure of Invention Technical Problem [9] An object of the present invention is to provide a process for the efficient preparation of chiral glycidylphthalimide with high optical purity of 99%ee or higher. The process of the present invention makes it possible to prepare the targeted glycidylphthalimide with an optical purity of 99%ee or higher, while chirality of the starting material is retained. Technical Solution [10] According to a preferred embodiment of the present invention, there is provided a process for the preparation of chiral glycidylphthalimide, which comprises the steps of a) reacting an optically active 3-substituted l-amino-2-propanol acid addition salt with phthalic anhydride in a presence of a base to obtain N - (3-sustituted-2-hydroxypropyl)phthalimide and b) subjecting the obtained compound to an epoxide cyclization reaction to prepare the chiral glycidylphthalimide. [11] According to more preferred embodiment of the present invention, there is provided a process for the preparation of glycidylphthalimide, wherein 3-substituted l-amino-2-propanol acid addition salt is l-amino-3-halo-propanol acid addition salt including l-amino-3-halo-2-propanol hydrochloride salt, l-amino-3-halo-2-propanol hydrobromide salt, l-amino-3-halo-2-propanol hydroiodide salt or l-amino-3-halo-2-propanol methanesulfonic acid salt. [12] According to even more preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the l-amino-3-halo-2-propanol acid addition salt is l-amino-3-halo-2-propanol methanesulfonic acid salt. [13] According to another preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the base in the step a) is an organic base. [14] According to yet another preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the base in the step a) is a tertiary amine. [15] According to further another preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the epoxide cyclization of the step b) is carried out in a presence of a base. [16] According to further yet another preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the epoxide cyclization of the step b) is carried out in a presence of an inorganic base. Advantageous Effects [17] According to the process of the present invention, glycidylphthalimide can be prepared with high optical purity, while the optical purity of the starting material is substantially retained. Particularly, the resultant target compound can be prepared with high optical purity, while the chirality of the chiral compound represented by Formula 2, which is used as the starting material, is not reduced. Consequently, glycidylph thalimide can be prepared with the optical purity of 99%ee or higher in high yield, while the optical purity of the starting material is retained. And, the compound of formula 4 obtained from the condensation of the optically active 3-substiuted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3 is applicable to the subsequent cyclization reaction, without any special purification. The subsequent cyclization reaction is performed under mild condition. Therefore, the process for the preparation of glycidylphthalimide in accordance with the present invention is carried out under the mild condition and proceeds as one-pot reaction, throughout overall processes. This means that the process in accordance with the present invention is useful for industrial-scale production of glycidylphthalimide with high optical purity. Mode for the Invention [18] The present invention relates to a process for the preparation of glycidylphthalimide, which comprises the steps of a) reacting an optically active 3-substituted l-amino-2-propanol acid addition salt (or acid salt) with phthalic anhydride in a presence of a base to obtain -(3-sustituted-2-hydroxypropyl)phthalimide and b) subjecting the obtained compound to an epoxide cyclization reaction to prepare the glycidylphthalimide in an optically pure form. [19] More particularly, the present invention relates to a process for the preparation of chiral glycidylphthalimide having formula 1, which comprises the steps of a) reacting an optically active 3-substituted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3 in a presence of a base to obtain N - (3-sustituted-2-hydroxypropyl)phthalimide of formula 4 and b) subjecting the obtained compound of formula 4 to an epoxide cyclization reaction to prepare the targeted chiral glycidylphthalimide having formula 1. The glycidylphthalimide of formula 1 is easily isolated through recrystallization and has optical purity of 99%ee or higher while the optical purity of the starting material is retained. [20] Formula 1

[22] Formula 2

[24] Formula 3

[26] Formula 4 [28] In the formula 1 to 4, * represents a chiral center, X represents a leaving group and Y represents sulfonyl, halogen or carboxyl group. [29] The process for the preparation of chiral glycidylphthalimide in the accordance with the present invention can be summarized in the following scheme 1: [30] Scheme 1

Cychzation

[32] As shown in the scheme 1, -(3-substituted-2-hydroxypropyl)phthalimide of formula 4 is obtained from the condensation of an optically active 3-substituted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3. The 3-substituted l-amino-2-propanol acid addition salt of formula 2 is firstly converted, with aid of a base, to a free basic form and then takes part in the con densation with phthalic anhydride of formula 3. The phthalic anhydride of formula 3 is added in an amount of 0.9-1.5 equivalents, preferably in an amount of 1-1.2 equivalents, based on the 3-substituted l-amino-2-propanol acid addition salt of formula 2. In order to convert the 3-substiuted l-amino-2-propanol acid addition salt of formula 2 into a free basic form, the condensation reaction is carried out in the presence of a base. As a based to be used in the condensation reaction, an organic base or an inorganic base may be used. Preferred examples of the organic base include a tertiary amine represented by R R R N, wherein R , R and R represent each inde- pendently C -C alkyl, C -C alkenyl, C -C arylalkyl or C -C alkylaryl. Specific 1 16 2 16 7 16 7 16 examples of the tertiary amine include trimethylamine, triethylamine, tributylamine, triphenylamine and diisopropylethylamine. As an inorganic base, an alkali metal salt may be used. For example, alkali metal carbonate, alkali metal bicarbonate or alkali metal phosphate may be used. Specifically, lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and cesium bicarbonate; and lithium phosphate, sodium phosphate, potassium phosphate and cesium phosphate may be used. Most preferable is trialkylamine. The base is added in an amount of 1-10 equivalents, preferably in an amount of 1-5 equivalents, most preferably in an amount of 1.1-2 equivalents, based on the 3-substituted l-amino-2-propanol acid addition salt of formula 2. [33] The condensation reaction is carried out in an organic solvent system. An organic solvent well known in the art may be widely used in the condensation reaction. Polar organic solvents such as alcohol, tetrahydrofuran, dioxane, acetone, N,N - dimethylformaldehyde and dimethylsulfoxide, or low polar organic solvents such as aromatic hydrocarbon, ether and C -C halogenated hydrocarbon may be used as an organic solvent. Preferable is an aprotic organic solvent. More preferable is an aromatic hydrocarbon such as toluene. The organic solvent is preferably used in an amount of 3 to 15 times (w/w) of the 3-substituted l-amino-2-propanol acid addition salt of formula 2. [34] Various leaving groups may be substituted at the C3 position of the 3-substiuted l-amino-2-propanol acid addition salt having formula 2. For example, the leaving group may be a halogen group or a sulfonyl group represented by

(wherein R is C -C alkyl; C -C aryl; or C -C aryl substituted with nitro, methyl, V 4 1 10 J 6 10 J 6 10 J J ethyl, fluoro or chloro). Preferred examples of the sulfonyl group include methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl or n itrobenzenesulfonyl. l-Amino-3-halo-2-proanol acid addition salt is preferred. For example, l-amino-3-chloro-2-propanol acid addition salt, l-amino-3-bromo-2-propanol acid addition salt or l-amino-3-iodo-2-propanol acid addition salt may be used. Most preferable is l-amino-3-chloro-2-propanol acid addition salt. For the formation of the acid addition salt, hydrochloric acid, hy- drobromic acid, hydroiodic acid, C -C alkyl sulfonic acid, C -C aryl sulfonic acid, C J 1 10 J 6 10 J -C alkylaryl sulfonic acid, C -C arylalkyl sulfonic acid or C -C carboxylic acid may be used. Preferable is C -C alkyl sulfonic acid, C -C aryl sulfonic acid, C -C 1 10 6 10 7 11 alkylaryl sulfonic acid or C -C arylalkyl sulfonic acid. l-Amino-3-halo-2-propanol methanesulfonate is most preferable. [35] The compound of formula 4 produced from the condensation reaction may be directly subjected to a cyclization reaction after evaporation of the solvent under reduced pressure, without any further special purification. Therefore, the condensation and the subsequent cyclization may be carried out as a one-pot reaction. This simplifies the reaction procedure and improves the production yield. [36] The cyclization reaction is also carried out in the presence of a base. For an organic base, the tertiary amine mentioned in the above may be used. An inorganic base is more preferable. Examples of the inorganic base include an alkali metal salt and an alkaline earth metal salt. Preferably, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal phosphate or alkaline earth metal phosphate may be used. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bi carbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, magnesium phosphate and calcium phosphate may be used. Potassium phosphate is most preferable. The base is added in an amount of 1-10 equivalents, preferably in an amount of 1-5 equivalents, most preferably in an amount of 1.5-3 equivalents, based on the 3-substituted l-amino-2-propanol acid addition salt of formula 2. [37] The cyclization reaction is also carried out in an organic solvent system. Polar organic solvents such as acetonitrile, tetrahydrofuran, acetone, N,N- dimethylformaldehyde and dimethylsulfoxide, or low polar organic solvents such as aromatic hydrocarbon, ether and C -C halogenated hydrocarbon may be used. An 1 4 aprotic organic solvent is preferable. Aromatic hydrocarbon or C -C halogenated hy- 1 4 drocarbon is more preferable. Most preferable is 1,2-Dichloroethane. Preferably, the organic solvent is used in an amount of 3 to 15 times (w/w) of the 3-substituted l-amino-2-propnaol acid addition salt of formula 2. [38] The glycidylphthalimide of formula 1 obtained from the cyclization reaction may be purified throughout common workup processes (extraction, drying and solvent evaporation) and recrystallization. As a solvent to be used in the recrystallization, a single solvent system or a mixed solvent system may be used. According to the method disclosed in U.S. Patent No. 6,875,875, the recrystallization was carried out using a mixed solvent of ethyl acetate/hexane. In addition to the mixed solvent system, C -C alcohol such as methanol, ethanol, propanol, isopropanol or butanol may be used in the recrystallization. According to a specific example of the invention, recrystallization under ethanol gave highly optical pure glycidylphthalimide of formula 1. [39] The most important advantage of the process for preparation of glycidylphthalimide in accordance with the present invention is that the optical purity of the starting material is substantially completely retained. That is, the resultant target compound is prepared in an optically pure form, without any decrease of the chirality of the chiral compound of formula 2. Consequently, glycidylphthalimide with high optical purity of 99%ee or higher is prepared in high yield, while the optical purity of the starting material is retained. Further, overall reactions are carried out under mild conditions and in a single reaction vessel without any special purification. This increases the yield of the target compound. [40] EXAMPLES [41] Example 1 [42] 25.00 g of (S)-l-amino-3-chloro-2-propanol methanesulfonic acid salt (0.123 mol), 25.34 g of phthalic anhydride (0.123 mol), 18.63 ml of triethylamine (0.134 mol) and 121 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 64.51 g of potassium phosphate (0.304 mol) and 121 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 17.91 g of the targeted (S)-glycidylphthalimide (yield: 72%, optical purity: 99.5%ee) as a white crystal. [43] Melting point: 100-102°C 1 δ [44] H NMR (CDCl3, 300 MHz): 7.70-8.00 (m, 4H), 3.95 (dd, IH, J=14.4Hz, 5.1Hz), 3.79 (dd, IH), 3.22-3.26 (m, 1 H), 2.80 (dd, IH), 2.67 (dd, IH, J=7.8Hz, 2.4Hz) [45] The optical purity (%ee) of glycidylphthalimide was confirmed from high speed liquid chromatography (HPLC). CHRALPAC AD™ Column (0.46 cm x 25 cm, available from Daicel Co., Ltd) was used. The mobile phase was a mixed solvent of n - hexane/isopropanol (90/10 (Wv)) and was flown at a velocity of 1 ml/min. Detection was performed at 254 nm. The (S) isomer was detected at 14.2 minutes and the (R) isomer was detected at 19.2 minutes. [46] Example 2 [47] 25.00 g of (S)-l-amino-3-chloro-2-propanol methanesulfonic acid salt (0.123 mol), 25.34 g of phthalic anhydride (0.123 mol), 18.63 ml of triethylamine (0.134 mol) and 121 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the organic layer was washed with water at room temperature. After drying with anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Subsequently, 64.51 g of potassium phosphate (0.304 mol) and 121 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 18.12 g of the targeted (S)-glycidylphthalimide (yield: 73%, optical purity: 99.5%ee) as a white crystal. [48] Example 3 [49] 25.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.171 mol), 25.34 g of phthalic anhydride (0.171 mol), 28.64 ml of triethylamine (0.206 mol) and 171 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 90.86 g of potassium phosphate (0.342 mol) and 171 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 24.01 g of the targeted (S)-glycidylphthalimide (yield: 69%, optical purity: 99.5%ee) as a white crystal. [50] Example 4 [51] 25.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.171 mol), 25.34 g of phthalic anhydride (0.171 mol), 28.64 ml of triethylamine (0.206 mol) and 171 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 90.86 g of potassium phosphate (0.342 mol) and 171 ml of acetonitrile were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 22.34 g of the targeted (S)-glycidylphthalimide (yield: 64%, optical purity: 99.5%ee) as a white crystal. [52] Example 5 [53] 5.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.034 mol), 5.069 g of phthalic anhydride (0.034 mol), 5.73 ml of triethylamine (0.041 mol) and 34 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, 30 ml of water was added into the reaction vessel. An organic layer was obtained by extracting with toluene. Then, the obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Sub sequently, 18.17 g of potassium phosphate (0.069 mol) and 34 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 4.68 g of the targeted (S)-glycidylphthalimide (yield: 67%, optical purity: 99.5%ee) as a white crystal. [54] Example 6 [55] 5.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.034 mol), 5.069 g of phthalic anhydride (0.034 mol), 5.73 ml of triethylamine (0.041 mol) and 34 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 18.17 g of potassium phosphate (0.069 mol) and 34 ml of Λ -dimethylformamide were sequentially added to the reaction vessel. The mixture was stirred for 3.5 hours at 40°C. After cooling to 0°C, potassium phosphate was filtered and pH of the resultant precipitate was adjusted to 5-6 by addition of sulfuric acid. Then, an organic layer was obtained by extracting with ethyl acetate. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 4.07 g of the targeted (S)-glycidylphthalimide (yield: 59%, optical purity: 99.5%ee) as white crystals. Claims

[1] A process for the preparation of glycidylphthalimide represented by formula 1, which comprises the steps of: a) reacting 3-substituted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3 in a presence of a base to obtain N - (3-substituted-2-hydroxypropyl)phthalimide of formula 4; and b) subjecting the obtained compound (4) to an epoxide cyclization reaction to prepare the targeted glycidylphthalimide of formula 1: Formula 1

wherein * represents a chiral center, X is a leaving group and Y is a sulfonyl, halogen or carboxyl group. [2] The process as set forth in claim 1, wherein the 3-substituted l-amino-2-propanol acid addition salt of formula 2 is an optically active compound. [3] The process as set forth in claim 1, wherein X is a halogen group or a sulfonyl group represented by , wherein R is C -C alkyl; C -C aryl; or C -C aryl substituted with nitro, 4 1 10 J 6 10 J 6 10 J methyl, ethyl, fluoro or chloro. [4] The process as set forth in claim 3, wherein X is a halogen group selected from the group consisting of chloride, bromide and iodide. [5] The process for the preparation of glycidylphthalimide as set forth in claim 4, wherein X is chloride. [6] The process as set forth in claim 1, wherein HY is hydrochloric acid, hy- drobromide acid, hydroiodide acid, C -C alkyl sulfonic acid, C -C aryl sulfonic acid, C -C alkylaryl sulfonic acid, C -C aiylalkyl sulfonic acid or C - 7 11 7 11 1 C carboxylic acid. [7] The process as set forth in claim 6, wherein HY is methanesulfonic acid. [8] The process as set forth in claim 1, wherein the 3-substituted l-amino-2-propanol acid addition salt is l-amino-3-chloro-2-propanol methanesulfonic acid salt. [9] The process as set forth in claim 1, wherein the step a) is carried out in a presence of a tertiary amine represented by R R R N (wherein R , R and R are each independently C -C alkyl, C -C alkenyl, C -C arylalkyl or C -C J 1 16 J 2 16 J 7 16 J J 7 16 alkylaryl). [10] The process as set forth in claim 1, wherein the step b) is carried out in a presence of an inorganic base selected from the group consisting of an alkali metal salt and an alkaline earth metal salt. A. CLASSIFICATION OF SUBJECT MATTER

C07D 405/06(2006.01)1

According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols)

IPC 8 as above Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

PUB MED

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category' Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No

US 6875875 B2 (YOSHIRO FURUKAWA) 05 Apr 2005 1-10 See abstract, examples 1-5, claims 1-20

Further documents are listed in the continuation of Box C See patent family annex

* Special categories of cited documents "T" later document published after the international filing date or priority "A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention "E" earlier application or patent but published on or after the international "X" document of particular relevance, the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of citation or other "Y" document of particular relevance, the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents,such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later "&" document member of the same patent family than the priority date claimed Date of the actual completion of the international search Date of mailing of the international search report 16 AUGUST 2007 (16 08 2007) 16 AUGUST 2007 (16.08.2007) Name and mailing address of the ISA/KR Authorized officer Korean Intellectual Property Office 920 Dunsan-dong, Seo-gu, Daejeon 302-701, CHOI, Won Chul Republic of Korea Facsimile No 82-42-472-7140 Telephone No 82-42-481-5608 Form PCT/ISA/210 (second sheet) (April 2007) Patent document Publication Patent family Publication cited in search report date member(s) date

US 6875875 B2 05.04.2005 EP 1403267 B 1 11.01.2006 JP 2004292425 A2 21.10.2004

Form PCT/ISA/210 (patent family annex) (April 2007)