Title of Invention

"PROCESS FOR THE REGIOSELECTIVE PREPARATION OF COMPOUNDS OF 1-R1-2-R2-3- ACETYL-GLYCEROL"

Abstract

A process for the regioselective preparation of compounds of 1-R1-2-R2 -3-acetyl-glycerol of the following Formula 1 comprising the steps of: obtaining 1-R1-3-protecting group-glycerol of Formula 3 by introducing a protecting group to 3-position of 1-R1-glycerol of Formula 2; obtaining 1-R1-2-R2-3-protecting group-glycerol of Formula 4 by introducing R2 group into 2-position of 1-R1-3-protecting group-glycerol of Formula 3; and carrying out the deprotection reaction and the acetylation reaction of 1-R1-2-R2-3-protecting group-glycerol of Formula 4 at the same time, wherein, the compounds of Formula 1 to 4 are racemic compounds or optically active compounds; R1 and R2 are fatty acid groups having 16 to 22 carbon atoms, and are different from each other; and P is trityl group or trialkylsilyl group as the protecting group, and the alkyl in trialkylsilyl group is alkyl group having 1 to 5 carbon atoms.

Full Text

Description PREPARATION OF GLYCEROL DERIVATIVES AND IN¬TERMEDIATES THEREFOR Technical Field [ 1] This invention relates to a preparation of glycerol derivatives and intermediates therefor, and more specifically lo a process for the regioseleclive preparation of glycerol derivatives of the following Formula 1 in a high efficiency and yield. [21 [Formula 11 [31 (Formula Removed) [4] Glycerol derivatives of Formula 1 are racemic compounds or optically active compounds, wherein R and R are fatty acid groups having 16 to 22 carbon atoms, and are different from each other Background Art [5] l-palmitoyl-2-linoleoyl-3-acetylglycerol (PLA), one of the compounds of Formula 1, is separated from the chloroform extracts of a deer antler, and is known as having activities for proliferation of hemalopoietic stem cells and incgakaiyocytcs (Korean Patent No. 10-0283010). As the processes for preparing the compound of Formula I, a method of synthesizing the compound from glycerol and a method of acetolysis of phosphatidyl choline are known (Korean Patent Application No. 10-2000-0045168). However, the method of synthesizing the compound of Formula 1 from glycerol is not a regioselective process, and thus requires separation and purification steps using a column-chromatography after each reaction step. Namely, the target compound (PLA) can be obtained by the steps of separating 1-palmitoylglycerol by using a column chro-matography from the reaction product of glycerol and palmitic acid, arid successively esterifying the separated l-palmitoylglycerol. The method has drawbacks that the yield is very low(about 3.21% from glycerol), and one equivalent of expensive 4-dimulhylamino pyridine (DMAP) should ho used for ihc reaction al low temperature of about 0°C. On the other hand, the acelolysis of phosphatidyl choline has the yield of about 74.5%, but expensive phosphatidyl choline should be used in a large amount for this method. Therefore, the method is not appropriate to produce the largcl compound in a large amount. [ 6 ] [ 7 ] In order to regiosclectively synthesize glyceroi derivative having ester groups'of different fatty acids at i and 2-positions of glyceroi and acetyl group at 3-position of glyceroi, the following process is carried out in a conventional method. First, an ester group is regioselectively introduced into 1-position of glyceroi. Then, hydroxyl group of 3-position of glyceroi is protected and other ester group is introduced into 2-position of glyceroi. The process can regioseleclively introduce ester groups into 1, 2 and 3-positions of glyceroi. However, when the protecting group at 3-position is removed for introducing an ester group into 3-position of giycerol, there is a problem that the ester group of 2-position of glyceroi is migrated to 3-position of glyceroi (.1. Org. Chem., 52(22), 4973 - 4977, 1987). Disclosure of Invention Technical Problem [8] Accordingly, it is an object of this invention to provide a process for the re- gioseleetive preparation of glyceroi derivatives, which has a good efficiency and yield. [9] It is other object of this invention to provide a process for the regioselective preparation of glyceroi derivatives without the problem of migrating of a functional group. [10] It is another object of this invention to provide a simple process for the re- gioselective preparation of glyceroi derivatives and intermediates for preparing glyceroi derivatives. Technical Solution [11] To achieve these and other objects, this invention provides a process for the re- gioselective preparation of 1-R -2-R -3-acetyl-glycerol derivative of the following Formula 1 comprising the steps of: obtaining 1 -R -3-protecting group-glycero! of Formula 3 by introducing a protecting group to 3-position of 1-R -glyceroi of Formula 2; obtaining 1-R -2-R^-3-prolecting group-glycerol of Formula 4 by introducing R^ group into 2-posilion of 1-R -3-prolecting gioup-giyeerol of Formula 3; and carrying out the dcproteclion reaction and the acetylation reaction of 1-R -2-R -3-protecting group-glycerol of Formula 4 at the same lime. [12] [Formula 1] [13] (Formula Removed) [14] [Formula 2] [15] (Formula Removed) [16] [Formula 3] [17] (Formula Removed) [18] [Formula 4] [19] (Formula Removed) [20] The compounds of Formula 1 to 4 are racemic compounds or optically active compounds, wherein R and R are fatty acid groups having 16 to 22 carbon atoms, and are different from each other, and P is trilyl group or trialkylsilyl group as the protec ting group. The alkyl in trialkylsilyl group is alkyl group having 1 to 5 carbon atoms [21] [22] This invention also provides intermediates of Formula 3 or 4 for preparing glycerol derivative of Formula 1. Preferably R is palmitoyl group, R is linoleoyl group and P is trityl group or trialkylsilyl group. Mode for the Invention [23] A more complete appreciation of the invention, and many of the attendant advantages thereof, will be better appreciated by reference to the following detailed de¬scription. [24] In the preparation of 1-R -2-R -3-acetyl-glyccrol derivative of Formula I. this invention prevents a functional group from migrating by simultaneously carrying out the deprotection reaction and the acetylation reaction after introducing a protecting group into a reaction intermediate. The process for the regioselective preparation of 1-R -2-R -3-acctyl-glycerol derivative of Formula 1 according to this invention is shown in the following Reaction 1. [25] [Reaction 11 [26] (Formula Removed) [27] In Reaction 1, R and R are fatty acid groups having 16 to 22 carbon atoms, and are different from each other, and P is trityl group or trialkylsilyl group as a protecting group. The alkyl in trialkylsilyl group is alkyl group having 1 to 5 carbon atoms. The trityl group may be substituted or non-substituted trityl group, and the preferable example of trialkylsilyl group is t-bulyldimethylsilyl group. The compounds shown in Reaction 1 can be racemic compounds or optically active compounds [28] [29] As shown in Reaction 1, in order to obtain 1-R -2-Ri-3-acetyl-glycerol derivative of Formula 1, first, 1-R -3-protecting group-glycerol of Formula 3 is obtained by in¬troducing a protecting group (P) to 3-position of 1-R -glyccrol of Formula 2. 1-K -glycerol of Formula 2, which is a starting material of Reaction 1, may be raccniic 1-R -glycerol or optically active 1-R -glycerol. [30] [31] The compound for introducing the protecting group should selectively protect a primary alcohol and the protecting group should not influence the acelylation reaction during the deprotection reaction thereof. Examples of the compound for introducing the protecting group include trityl chloride or t-bulyldimethylsilyl chloride, and the preferable amount of the compound for introducing the protecting group is 1 to 1.1 equivalents with respect to 1 -R -glycerol of Formula 2. If the amount of the compound for introducing the protecting group is less than 1 equivalent, the protecting reaction may be insufficiently carried out, and if the amount of the compound lor introducing the protecting group is more than 1.1 equivalents, hydroxyl group at 2-posilion of glycerol derivative can be reacted. [32] [33] When the protecting group is trityl group. 1-R -3-protecting group-glycerol of Formula 3 can be preferably obtained in the presence of pyridine solvent or in the presence of nonpolar aprolic organic solvent and organic base. When the pyi idine solvent is used, the pyridine solvent works as a .solvent and a base at the same lime, and the preferable reaction temperature is 40 - 60°C. If the reaction temperature is less than 40°C, the reaction may be insufficiently carried out, and if the reaction temperature is more than 60°C, the trityl group may be introduced into 2-po.Mlion of glycerol. The preferable amount of pyridine solvent is 5 to 10 equivalents with respect to 1-R -glycerol of Formula 2. When the organic solvent and organic base are used, the preferable reaction temperature is from 0°C to room temperature. Examples of the nonpolar aprotic organic solvent include dichloromethane, tctrahydrol'uran, ethyl acetate, and mixtures thereof, and examples of the organic base includes uieihylaniinc, tribulylaminc, l,8-diazabicyclof5, 4, 0]-7-undcecnc (DBU) and rnixiuic.s inoicol. The preferable amount of the organic base is 1 to 2 equivalents with respect to I-K -glycerol of Formula 2, and the preferable amount of the organic solvent is 5 to 10 times by volume with respect to the weight of 1-R -glycerol of Formula 2 (i.e., 5 - 10 ml/g). When the amount of the pyridine solvent or the organic solvent is less than the above-mentioned range, the stirring of the reaction mixture may be difficult, und when the amount of the pyridine solvent or the organic solvent is more than the above-mentioned range, it is economically undesirable without additional advantage. In addition, when the amount of the organic base is less than 1 equivalent with respect lo 1-R -glycerol, the reaction may be insufficiently carried out, and when the amount of the organic base is more than 2 equivalents, it is economically undesirable without additional advantage. [34] [35] When the protecting group is trialkylsilyl group, for example, t-butyldimethylsilyl group, 1-R -3-protecting group-glycerol of Formula 3 can be preferably obtained in the presence of aprotic organic solvent and organic base, and at the temperature of from 0°C to room temperature. Examples of the aprotic organic solvent include dichloromethane, tctrahydrofuran, ethyl acetate, dimcthylformamidc and mixtures thereof, and examples of the organic base include imidazole, triethylamine and the mixtures thereof. The preferable amount of the organic base is 1 to 2 equivalents with respect to 1-R -glycerol of Formula 2, and the preferable amount of the organic solvent is 5 to 10 times by volume with respect to the weight of 1-R -glycerol of Formula 2 (i.e., 5-10 ml/g). When the amount of the organic base is less than 1 equivalent with respect to 1-R -glycerol, the reaction may be insufficiently carried out, and when the amount of the organic base is more than 2 equivalents, it is economically undesirable without additional advantage. In addition, when the amount of the organic solvent is less than the above-mentioned range, the stirring of the reaction mixture may be difficult, and when the amount of the organic solvent is more than the above mentioned range, it is economically undesirable without additional advantage. [36] [37] In 1-R -3-protecting group-glycerol of Formula 3, only the 2-posiiion can participate in an additional eslerificalion reaction. Therefore, R group can he introduced by reacting R^-OH with 1-R -3-proiecling group-glycerol. Preferably, the reaction can be carried out in the presence of an aprolic organic solvent, a caialysl, mid a water remover at the temperature of from 0°C to room temperature.. I'.xumnlcs nf ihu aprotic organic solvent include hexane, heptane, dichloromelhane, ethyl acetate, tetrahydrofuran and mixtures thereof, and example of the catalyst includes dirnethy-laminopyridinc (DMAP). Example of the water remover includes dicyclohexylcar-bodiimide (DCC). Alternatively, an activated compound of R^ fatty acid can be used instead of R -OH, and examples of the activated compound include ester, amide and acid chloride of R fatty acid. [38] [39] When considering reactivity, easy purification, degree of purity and the color of the obtained 1-R -2-R^-3-protecting groap-glycerol of Formula 4, the combination of R -OH and dicyclohexylcarbodiimide (DCC) is more preferable. The preferable amount of DCC is 1 to 1.1 equivalents with respect to 1-R -3-prolecling group-glyceml of Formula 3. When the amount of DCC is less than 1 equivalent, the reaction may be in¬sufficiently carried out, arid when the amount of DCC is more than I. I equivalents, il is economically undesirable without additional advantage. The reaction using dicyclo¬hexylcarbodiimide (DCC) can be carried out in the aprotic organic solvents such as hexane, heptane, ethyl acetate, dichloromethalfe, tetrahydroluran, and so on. However, for easy removal of the by-product of dicyclohexylurea, it is preferable to use hexane or heptane. The preferable amount of the organic solvent is 5 to 10 limes by volume with respect to the weight of 1-R -3-protecting group-glycerol of Formula 3. Also, the preferable amount of dimethylarninopyridine (DMAP) is 0.5 to lmol% with respect to the mole of 1-R -3-protccting group-glycerol. When the amount of dimcthy-laminopyridine (DMAP) is less than ().5mol%, the reaction time may be prolonged, and when the amount of dimethylarninopyridine (DMAP) is more than lrnol%, it is economically undesirable without additional advantage. The preferable amount of R fatty acid or the activated compound of R fatty acid (hereinafter, collectively, R fatty acid) is 1 to 1.1 equivalents with respect to 1-R -3-protecting group-glycerol of Formula 3. When the amount of R fatty acid less than 1 equivalent, the reaction can be insufficiently carried out, and when the amount of R fatty acid is more than 1.1 equivalents, il is economically undesirable without additional advantage. [40] [41] When the deprotection reaction is canned out, R group at 2-posilion of depiotected 1-R -2-R -glyceiol can be easily migrated to 3-position. In such case, a by-product is produced in the following acetyUnion reaction, and the by-product has a Rf (Rate of flow) value similar to that of the target product of Formula I. Thus, the purification of 1-R -2-Ri-3-acetyl-glycerol of Formula I becomes difficult. To solve the above-mentioned problem, the deprotection reaction and the aeelylalinn reaction,arc simul¬taneously carried out in the present invention. In case of using trilyl group or tri-alkylsilyl group as the protecting group, the deprolcction reaction and the acetylation reaction of 1-R -2-R -3-protecling group-glycerol of Formula 4 are carried out at the same time by using both of I^ewis acid and acetic acid anhydride or by using an acetylation agent. Examples of the Lewis acid include Zinc Cniuiide (ZiiCi ). Tin Chloride (SnCl^), boron trifluoride diethyl ether (BF Ht^O) and mixtures thereof, and examples of the acetylation agent include acelylchloride, acetylbromiuc and mixtures thereof. The preferable amount of Lewis acid is 1 to 5 equivalents with respect to 1 -R -2-R -3-protecting gro'up-glycerol of Formula 4. The preferable amount of acetic acid anhydride or the acetylation agent is 1 to 20 equivalents with respect to 1-R -2-R^ -3-protecting group-glycerol. When the amounts of Lewis acid, acetic acid anhydride and acetylation agent are less than the above-mentioned range, the reaction may be in¬sufficiently carried out, arid when the amounts of Ijiwis acid, acetic acid anhydride or the acetylation agent are more than the above-mentioned range, it is economically un¬desirable without additional advantage. The reaction can be carried oui in the presence of an aprotic organic solvent, and the preferable amount of the organic solvent is 5 to 10 times by volume with respect to the weight of I-R -2-R -3-protecting group-glycerol of Formula 4. Examples of the aprotic organic solvent include hexane, heptane, dichloromethane, toluene, ethyl acetate, acelonitrile and mixtures thereof. Al¬ternatively, the reaction can be carried out in the absence of any solvent [42] [43] Also, in case of using trityl group as the protecting group, 1 -R -2;R -3-protecting group-glycerol of Formula 4 can be dcprotcctcd and trialkylsilylatcd, tor example, by using trimethylsilyliodide (TMSI). After the trialkylsilylation, the acetylation reaction can be carried out, for example, by using acetylchloride and Lewis acid which is selected from the group consisting of Zinc Chloride (ZnCl^), Tin Chloride (SnCIJ, boron trifluoride diethyl ether (BF Et^O) and mixtures thereof or by using acetylbromide alone. Namely, 1-R -2-R^-3-acetyI-glycerol of Formula 1 can be obtained by the steps of (a) producing 1-R -2-R^-3-trimethylsilyl-glycerol by using trimethylsilyliodide (TMSI) for deprotecting and trimethylsilylating 1-R -2-R^ -3-protecting group-glycerol of Formula 4, and (b) adding acetylchloride and l^ewis acid or by adding acetylbromide. Trimethylsilyliodide (TMSI) can be used in a reagent form directly, or can be produced by the reactions of sodiumiodide/irimethylsi-lylchloride (Nal/TMSCI) or hcxamcthyldisilazanc/iodme (HMDS/I ) in the reaction solvent. 1-R -2-R -3-acetyl-glycerol of Formula 1 which is produced at the final step can be separated and purified with a column chromalography (hexane or heptane : ethyl acetate = 36 : 1 by volume). The above-mentioned reaction may be carried out in the presence of an aprotic organic solvent which is selected from the group consisting of dichloromethane, ethyl acetate, acelonitrile and mixtures thereof. The preferable amount of the organic solvent is 5 to 10 times by volume with respect to the weight of 1-R -2-R^-3-protecting group-glycerol of Formula 4. The preferable amounts of Lewis acid, trimethylsilyliodidc (TMSI) and both of (namely, sum ot) aceiylchloride and acetylbromide arc 1 to 5 equivalents, I to 5 equivalents and 1 to 20 equivalents with respect to l-Ri-2-Ri-3-protccting group-glyccrol of Formula 4, respectively. When the amounts of Lewis acid, trimethylsilyliodide (TMSI) and both of acety (chloride and acetylbromide are less than the above-mentioned range, the reaction may be insuf¬ficiently carried out, and when the amounts of Lewis acid, trimethylsilyliodide (TMSI) and both of acetylchloride and acetylbromide are more than the above-mentioned range, it is economically undesirable without additional advantage. [44] [45] This invention also provides intermediates of the following Formula 3 and 4 for preparing glycerol derivative of Formula I. [46] [Formula 3] [47] (Formula Removed) [48] [Formula 4] [49] (Formula Removed) [50] [51 ] The compounds of Formula 3 and 4 are racemic compounds or optically active compounds, wherein R and R are fatty acid groups having 16 to 22 carbon atoms, and are different from each other. Preferably R is palmitoyl group, and R^ is linoleoyl group. P is trityl group or trialkylsilyl group as a protecting group, and the alkyl in tri-alkylsilyl group is alkyl group having 1 to 5 carbon atoms. [52] [53] Hereinafter, the preferable examples are provided for better understanding of this invention. However, this invention is not limited by the following examples. [54] [55] [Example 1 ] Preparation of l-pitlmitoyl-3-lritvl-glycerol [56] l-palmitoyl-glycerol(33.0g), pyridine(48ml) and trilyl chloride(3l .3g) were added into 1L reactor. The reaction mixture was healed in 60"C while stirriini., and the reaction was carried out for 3 hours. Alter completion of the reaction, cooled water(240ml) was added slowly into the reaction mixture. The reaction mixture was further stirred for 1 hour, and then filtered. The obtained solid material was washed with cooled water( 120ml), and then dried at 40°C to obtain 57.3g of l-palmitoyl-3-tritlyl-glycerol (yield: 100%) {'H NMR (400MHz, CDCI.): 0.89 -0.93(t, 3H), 1.21 - 1.31 (ni,24H), 1.57 - 1.61(m,2H), 2.31(t,2H), 3.25(cl,2H). 3.97 -4.02(m,lH), 4.16 - 4.27(m,2H), 7.22 - 7.47(m, 15H)} f57] [58] [Example 2] Preparation of l-palmitoyl-3-t-butvldimethylsilyl-glycerol [59] l-palmitoyl-glycerol(33.0g), dichloromethane(330ml) and imidazole(l 3.6g) were added into 1L reactor, and the reaction mixture was cooled to 0°C. Then, t-butyl-dimelhylsilylchloride(18.0g) was added, and the reaction mixture was stirred for 2 hours. After fillering the reaction mixture, the solvent was removed by distillation under reduced pressure, and purified water(165ml) and heptane( 150ml) were added for an extraction. The separated organic layer was extracted with purified waier^80ml) again, and then the organic layer was dehydrated with anhydrous MgSO , and filtered. Then, the solvent was removed by distillation under reduced pressure to obtain l-paImitoyl-3-t-butyldimethylsilyl-glyceroltyield: 100%) {'HNMR (400MHz, CDCI3 ): 0.78 - 0.83(m, 18H), 1.18 - 1.31 (m,24H), 1.50 - 1.56(m,2H), 2.24(t,2H), 3.51 -3.60(m,2H), 3.76 - 3.79(p,lH), 4.01 - 4.10(m,2H)}. [60] [61] [Example 3] Preparation of l-palmitoyl-2-linoleoyl-3-trityl-glycerol [62] l-palmitoyl-3-tritylglycerol (57.3g), which was obtained in Example 1, heptane (300ml), linoleic acid (29.4g) and dimethylaminopyridine (0.122g) were added into 1L reactor. Dicyclohexylcarbodiimide (21.7g) was added into the reactor, and then the reaction mixture was stirred for 3 hours at room temperature. Dicyclohexylurea was filtered to obtain heptane solution of 1 -palmitoyl-2-linolcoyl-3-trityl-glyccrol (expected yield: 100%) {'H NMR (400MHz, CDCl3): 0.92 - 0.95(m, 611), 1.33 - 1.43 (m,36H), 1.60(m,2H), 1.69(m,2H), 2.09 - 2.1 l(m, 4H), 2.26(t,2H), 2.27(1,211), 2.83(t,2H), 3.31(m,2H), 4.24 - 4.42(m,4H), 5.31 - 5.41(m,5H), 7.21 - 7.49 (in, 15H)} [63] [64] [Example 4] Preparation of l-palmitovl-2-linoleovl-3-t-butvl-dimethvlsilvl-(;lvcerol [65] l-paimitoyl-3-t-butyldimethylsilyl-giyccrol (44.4g), which was obtained in Example 2, heptane (225rnl), linoleic acid(29.4g) and dimelhylaniinopyridiiic((). I22g) were added into IL reactor. Dicyclohexylcarbodiimide (21.7g) wa.s added into the reactor, and then the reaction mixture was stirred for 3 hours at room temperature. Oi-cyclohexylurea was filtered to obtain heptane solution of l-palmiloyl-2-linoleoyl-3~t-butyl-dimelliylsilyl-glyi:erol (expected yield: 100%) {III NMR (400MHz, CDCy: 0.76-0.8 l(m. 2111), 1.16- 1.27 (in,36H), 1.50-1.52(m,4H), l.95(q,4H), 2.17 - 2.2l(m, 411), 2.65(1.211), 3.62(d,2ll), 4.02 -4.28(m,4H), 4.96 - 5.27(m,51I)}. [66] [671 [Example 5] Preparation of 1 -palmitoyl-2-linolcoyl-3-acctyl-glycx'rol [68] fPreparation method-1) [691 The solvent of heptane solution of l-palmiloyl-2-linoleoyl-3-trityl-glycerol, which was obtained in Example 3, was removed by distillation under reduced pressure, and then the residue was dissolved with acelonitrile (800ml). Then, tin chloride(22g) and acetic acid anhydride(206ml) were added into the dissolved solution, and the dissolved solution was stirred for 24 hours at room temperature. After concentrating the reaction mixture, purified water(8(K)ml) and heplane(400ml) were added for an extraction. The separated organic layer was washed willi purified walei(40()iiil), and itie washed organic layer was dehydrated with anhydrous MgSO , and filtered. l-palmiloyl-2-linoleoy!-3-acetyl-g!ycerol (36.4g) was obtained with a silica gel(Si-60, 230~400 mesh) column chromalography (heptane : ethyl aeetate= 36 : 1 by volume) (theoretical amounts: 63.5g, yield: 57.4%) {') I NMR (400MH/, CDC.l ): 0.85 -0.91(m,6H), 1.21 - 1.31 (m,38H), 1.62(m,4H), 2.03(m,4H), 2.07(s,3H),' 2.37(m,4H), 2.78(m,2H), 4.14 - 4.29(m, 4H), 5.23 - 5.34(m,5H)). [70] [71] f Preparation method-2] [72] Except for using boron trifluoride diethyl ether (BF EK), 15.2ml) instead of tin chloridc(22g) and stirring for 3 hours, l-palmitoyl-2-linolcoyl-3-acctyl-glycerol(40.1g) was obtained in the same manner as described in Preparation method-1 (theoretical amounts: 63.5g, yield: 63.1%). [73] [74] [Preparation mcthod-31 [75] The solvent of heptane solution of l-palmitoyl-2-linoleoyl-3-lrityl-glycerol. which was obtained in Example 3, was removed by distillation under reduced pressure. Then, acetylbromide(123g) was added into the residue and stirred for 6 hours at room temperature. Heptane (400ml) was added into the reaction mixture, the cooling purified water (400ml) was dropwisely added thereto for extracting the organic layer. The separated organic layer was washed with a solution of saturated sodium bi-carbonalc(l00ml) and purified water(400ml), and then the washed organic layer was dehydrated with anhydrous MgSO , and filtered. 4 l-palmitoyl-2-linolcoyl-3-acelyl-glycerol (46.7g) was obtained with a silica gel(Si-60, 230~400 mesh) column chromatography(heptane : ethyl acelate= 36 : 1 by volume) (theoretical amounts: 63.5g, yield: 73.6%) [76] [77] [Preparation method-4] [78] Except that the solvent of heptane solution of l-palmiloyl-2-linoleoyl- 3-trityl-glyccrol, which was obtained in Example 3, was not removed by distillation under reduced pressure, l-palmiloyl-2-lmoleoyl-3-acetyi-glycerol(43.0g) was obtained in the same manner as described in Preparation method-3 (theoretical amounts: 63.5g, yield: 67.7%). [79] [80] [Preparation method-5] [81] Except for using acetylchloride(157g) instead of acetylbromide( 123g) and stirring for 12 hours, l-palmitoyl-2-linoleoyl-3-acetyl-glycerol (26.3g) was obtained in the same manner as described in Preparation method-3 (theoretical amounts: 63.5g, yield: 41.4%). [82] [83] [Preparation method-6] [84] The solvent of heptane solution of l-palmitoyl-2-linoleoyl-3-trityl-glyceroi, which was obtained in Example 3, was removed by distillation under reduced pressure Then. acetonitrile (800ml), sodium iodide (Nal, 74.9g) and trimethylsilylchloride (TMSCI, 54.3g) were added into the residue and stirred for 2 hours at room temperature. Anhydrous zinc chloride (ZnCl2 , 68.lg) and acetylchloride (157g) were added to the reaction mixture and stirred for 2 hours. The solvent of the reaction mixlure was removed by distillation under reduced pressure, and heptane (400ml) was added into the residue. The cooling purified water (400ml) was dropwiscly added thereto for extracting the organic layer. The separated organic layer was washed with a solution of saturated sodium bicarbonate( 100ml) and purified water(400ml), and then the washed organic layer was dehydrated with anhydrous MgSO , and filtered. 4 l-palmitoyl-2-linolcoyl-3-acetyl- glyccrol(33.3g) was obtained with a silica gcl(Si-60, 230-400 mesh) column chromatography(heptane : ethyl acetate= 36 : 1 by volume) (theoretical amounts: 63.5g, yield: 52.4%) [85] [86] [Preparation method-7] [87] Except for using acetylbromide(!23g) instead of both of anhydrous /.inc chlorideCZnCl^, 68.lg) and acctylchloride(157g) and stirring for 2 hours. l-palmitoyl-2-linoleoyl-3- acetyl-glyceiol(36.yg) was obtained in the same manner as described in Preparation method-6 (theoretical amounts: 63.5g, yield: 58.1%). [88] [89] [Preparation mcthod-8] [90] Acelylbromide (123g) was added into heptane solution of l-palmitoyl-2-linoleoyl-3-t-butyl-dimelhylsilyl-glyeerol, which was obtained in Example 4, and the reaction mixture was stirred for 12 hours at room temperature. Heptane (400ml) was added into the reaction mixture, and the cooling purified water(400ml) was dropwisely added thereto for extracting the organic layer. The separated organic layer was washed with a solution of saturated sodium bi¬carbonate( 100ml) and purified walcr(400rnl), and then the washed organic layer was dehydrated with anhydrous MgSO , and filtered. l-palmitoyl-2-linoleoyl-3-acetyl-glycerol(178g) was obtained with a silica gel(Si-60, 230-400 mesh) column chrornatography(heptane : ethyl acetate= 36 : 1 by volume) (theoretical amounts: 63.5g, yield: 28.0%) - [91] [92] [Preparation method-9] [93] Except for using dichlorornelhane(50ml), acetic aid aiihydride(206ml) :nui boron trifluoride diethyl elher (BF .Etp, 15.2ml) instead of acetylbromide( 123g.), l-palmitoyl-2-linoleoyl-3-acelyl-glycerol(284g) was obtained in the ssiine manner as described in Preparation method-8 (theoretical amounts: 63.5g, yield: 44.7%). [94] [95] [Preparation method-10] [96] By using optically active (R)-l-palmitoyl glycerol and optically active (S)-l-palmitoyl glycerol as the starting materials, and by carrying out Example I and Example 3, respectively, heptane solutions of (R)-l-palmitoyl-2-linoleoyl-3-tritylglycerol and (S)-l -palmitoyl-2-linolcoyl-3-tritylglyccrol were obtained Except for using the optically active compounds instead of racemic l-palmitoyl-2-linoleoyl-3-trityl-glycerol, (S)-l-palmitoyl-2-linoleoyl-3-acetyl-glycerol(45.8g)and (R)-l-palmitoyl-2-linolcoyl-3- acctyl-glycerol(45.8g) were obtained in the same manner as described in Preparation method-3 (theoretical amounls: 63.5g, yield: 72.1%). (R)-enantiomer: {'H NMR (400MHz, CDCI ): 0.85 - 0.92(m, fill). 1.20 -1.33 (m,38H), 1.62(m,4H), 2.03(m,4M), 2.07(s,31I), 2.36(m,4H), 2.77(m,21l). 4.14 -4.31(m, 4H), 5.23 - 5.36(rn,5H)}, (S)-enantiomcr: {'H NMR (400MH7., CDCI,): 0.85 - 0.92(m, 6H), 1.21 - 1.33 (m,38I I), 1.63(in,4I I), 2.02(m,411), 2.07(s,3l I), 2.37(m,4H), 2.78(m,2H), 4.12 - 4.28(m, 4H), 5.21 - 5.35(m,5H)}. Industrial Applicability [97] As described above, Ihe process for the regioseleetive preparation of glycerol derivatives and inlermediales therefor according to this invention can produce glycerol derivative with a high efficiency and yield without the problem of migrating of a functional group. Also, in the process according to this invention, the purification step of using a silica gel column chromatography can be minimized. [98] We Claim: 1. A process for the regioselective preparation of compounds of 1-R1-2-R2 -3-acetyl-glycerol of the following Formula 1 comprising the steps of: obtaining 1-R1-3-protecting group-glycerol of Formula 3 by introducing a protecting group to 3-position of 1-R1-glycerol of Formula 2; obtaining l-R1-2-R2-3-protecting group-glycerol of Formula 4 by introducing R2 group into 2-position of 1-R1-3-protecting group-glycerol of Formula 3; and carrying out the deprotection reaction and the acetylation reaction of 1-R1-2-R2-3-protecting group-glycerol of Formula 4 at the same time, (Formula Removed) wherein, the compounds of Formula 1 to 4 are racemic compounds or optically active compounds; R1 and R2 are fatty acid groups having 16 to 22 carbon atoms, and are different from each other; and P is trityl group or trialkylsilyl group as the protecting group, and the alkyl in trialkylsilyl group is alkyl group having 1 to 5 carbon atoms. 2. The process for the regioselective preparation of glycerol compounds as claimed in claim 1, wherein R1 is palmitoyl group, R2 is linoleoyl group and P is trityl group or t-butyldimethylsilyl group. 3. The process for the regioselective preparation of glycerol compounds as claimed in claim 1, wherein the protecting group is trityl group, 1-R1-3-protecting group-glycerol is obtained in the presence of pyridine solvent at the temperature 40 ~ 60°C or in the presence of nonpolar aprotic organic solvent and organic base at the temperature of 0°C to room temperature, the nonpolar aprotic organic solvent is selected from the group consisting of pyridine, dichloromethane, tetrahydrofuran, ethyl acetate, and mixtures thereof, and the organic base is selected from the group consisting of triethylamine, tributylamine, 1,8-diazabicyclo[5, 4, 0]-7-undecene and mixtures thereof. 4. The process for the regioselective preparation of glycerol compounds as claimed in claim 3, wherein the amounts of pyridine and the organic base are 5 to 10 equivalents and 1 to 2 equivalents with respect to 1-R1-glycerol respectively, the amount of the organic solvent is 5 to 10 times by volume with respect to the weight of 1-Ri-glycerol, and the amount of a compound for introducing the trityl group is 1 to 1.1 equivalents with respect to 1-R1-glycerol. 5. The process for the regioselective preparation of glycerol compounds as claimed in claim 1, wherein the protecting group is trialkylsilyl group, 1-R1-3-protecting group-glycerol is obtained in the presence of aprotic organic solvent and organic base, and at the temperature of from 0°C to room temperature, the aprotic organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide and mixtures thereof, and the organic base is selected from the group consisting of imidazole, triethylamine and the mixtures thereof 6. The process for the regioselective preparation of glycerol compounds as claimed in claim 5, wherein the amount of the organic base is 1 to 2 equivalents with respect to 1-R1-glycerol, the amount of the organic solvent is 5 to 10 times by volume with respect to the weight of 1-R1 -glycerol, and the amount of a compound for introducing the trialkylsilyl group is 1 to 1.1 equivalents with respect to 1-R1 -glycerol. 7. The process for the regioselective preparation of glycerol compounds as claimed in claim 1, wherein the R group is introduced by reacting R2-OH with 1-R1-3-protecting group-glycerol in the presence of an aprotic organic solvent, a catalyst, and a water remover, the aprotic organic solvent is selected from the group consisting of hexane, heptane, dichloromethane, ethyl acetate, tetrahydrofuran and mixtures thereof, and the catalyst is dimethylaminopyridine, and the water remover is dicyclohexylcarbodiimide. 8. The process for the regioselective preparation of glycerol compounds as claimed in claim 1, wherein the deprotection reaction and the acetylation reaction are carried out by using both of Lewis acid and acetic acid anhydride or by using an acetylation agent, the Lewis acid is selected from the group consisting of zinc chloride (ZnCI2), tin chloride (SnCI2), boron trifluoride diethyl ether (BF3Et2O) and mixtures thereof, and the acetylation agent is selected from the group consisting of acetylchloride, acetylbromide and mixtures thereof. 9. The process for the regioselective preparation of glycerol compounds as claimed in claim 8, wherein the deprotection reaction and the acetylation reaction are carried out in the presence or absence of an aprotic organic solvent which is selected from the group consisting of hexane, heptane, dichloromethane, toluene, ethyl acetate, acetonitrile and mixtures thereof. 10. The process for the regioselective preparation of glycerol compounds as claimed in claim 8, wherein the amount of Lewis acid is 1 to 5 equivalents, and the amount of acetic acid anhydride or the acetylation agent is 1 to 20 equivalents with respect to 1-R1-2-R2-3- protecting group-glycerol. 11. The process for the regioselective preparation of glycerol compounds as claimed in claim 1, wherein the protecting group is trityl group, 1-R1-2-R2-3- protecting group-glycerol is deprotected and trialkylsilylated, and then the acetylation reaction is carried out by using acetylchloride and Lewis acid which is selected from the group consisting of zinc chloride (ZnCI2), tin chloride (SnCI2), boron trifluoride diethyl ether (BF3Et2O) and mixtures thereof or by using acetylbromide alone. 12. The process for the regioselective preparation of glycerol compounds as claimed in claim 11, wherein l-R1-2-R2-3- protecting group-glycerol is deprotected and trialkylsilylated in the presence of an aprotic organic solvent which is selected from the group consisting of dichloromethane, ethyl acetate, acetonitrile and mixtures thereof. 13. The process for the regioselective preparation of glycerol compounds as claimed in claim 11, wherein 1-R1-2-R2-3-protecting group-glycerol is deprotected and trialkylsilylated by using trimethylsilyliodide, the amounts of Lewis acid, trimethylsilyliodide and both of acetylchloride and acetylbromide are 1 to 5 equivalents, 1 to 5 equivalents and 1 to 20 equivalents with respect to 1-R1-2-R2-3-protecting group-glycerol, respectively. 14. The process for the regioselective preparation of glycerol compounds as claimed in claim 12, wherein the amount of the organic solvent is 5 to 10 times by volume with respect to the weight of 1-R1-2-R2-3- protecting group-glycerol.

Documents:

2070-DELNP-2003-Assignment-(16-08-2007).pdf

383-DELNP-2008-Abstract-(03-10-2011).pdf

383-delnp-2008-abstract.pdf

383-DELNP-2008-Claims-(03-10-2011).pdf

383-DELNP-2008-Claims-(14-09-2011).pdf

383-delnp-2008-claims.pdf

383-DELNP-2008-Correspondence Others-(03-10-2011).pdf

383-DELNP-2008-Correspondence Others-(08-08-2011).pdf

383-DELNP-2008-Correspondence Others-(14-09-2011).pdf

383-delnp-2008-correspondence-others.pdf

383-delnp-2008-description (complete).pdf

383-DELNP-2008-Form-1-(03-10-2011).pdf

383-DELNP-2008-Form-1-(14-09-2011).pdf

383-delnp-2008-form-1.pdf

383-DELNP-2008-Form-2-(03-10-2011).pdf

383-DELNP-2008-Form-2-(14-09-2011).pdf

383-delnp-2008-form-2.pdf

383-DELNP-2008-Form-3-(08-08-2011).pdf

383-delnp-2008-form-3.pdf

383-delnp-2008-form-5.pdf

383-delnp-2008-gpa.pdf

383-delnp-2008-pct-210.pdf

383-delnp-2008-pct-237.pdf

383-delnp-2008-pct-304.pdf

383-delnp-2008-pct-308.pdf

383-delnp-2008-pct-346.pdf