(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,