US20140243548A1 - Preparation method of 1-palmitoyl-3-acetylglycerol, and preparation method of 1-palmitoyl-2-linoleoyl-3-acetylglycerol using same - Google Patents

Preparation method of 1-palmitoyl-3-acetylglycerol, and preparation method of 1-palmitoyl-2-linoleoyl-3-acetylglycerol using same Download PDF

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US20140243548A1
US20140243548A1 US14/346,783 US201214346783A US2014243548A1 US 20140243548 A1 US20140243548 A1 US 20140243548A1 US 201214346783 A US201214346783 A US 201214346783A US 2014243548 A1 US2014243548 A1 US 2014243548A1
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palmitoyl
acetylglycerol
preparing
amount
linoleoyl
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Tae-Suk Lee
Jin-Soo Yook
Chang-Hyun Yoo
Cheol-Min Lee
Eun-kyung Kim
Ju-Cheol Lee
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Enzychem Lifesciences Corp
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Enzychem Lifesciences Corp
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Assigned to ENZYCHEM LIFESCIENCES CORPORATION reassignment ENZYCHEM LIFESCIENCES CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KIM, EUN-KYUNG, LEE, CHEOL-MIN, LEE, JU-CHEOL, LEE, TAE-SUK, YOO, CHANG-HYUN, YOOK, JIN-SOO
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/30—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with trihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • This invention relates to a method for preparing 1-palmitoyl-3-acetylglycerol and a method for preparing 1-palmitoyl-2-linoleoyl-3-acetylglycerol using the same, and more specifically, to a method for preparing 1-palmitoyl-3-acetylglycerol in high purity and high yield without a purification process using a column chromatography, and a method for preparing 1-palmitoyl-2-linoleoyl-3-acetylglycerol in high purity and high yield using the 1-palmitoyl-3-acetylglycerol as a key intermediate.
  • Rho-1-palmitoyl-2-linoleoyl-3-acetylglycerol is one of components of deer antler, and is known as one of the most active components having the growth-stimulating effects of hematopoietic stem cells and megakaryocytes which can be obtained from chloroform extracts of the deer antler (Korean Patent No. 10-0283010).
  • Korean Patent No. 10-0291743 two methods for preparing the rac-1-palmitoyl-2-linoleoyl-3-acetyl glycerol, (a) a method of synthesizing the compound from glycerol and (b) a method of using acetolysis of phosphatidylcholine are disclosed.
  • reaction of method (a) has no regioselectivity.
  • 1-palmitoylglycerol should be separated by using a column chromatography.
  • the separated 1-palmitoylglycerol is acetylated and separated again by using a column chromatography.
  • a linoleoylation reaction is carried out for the above reaction product and a separation step using a column chromatography is again carried out to produce the target compound of rac-1-palmitoyl-2-linoleoyl-3-acetylglycerol.
  • the reaction of method (a) Since the reaction of method (a) has no regioselectivity, the reaction product of each reaction step should be separated and purified by using a column chromatography, and the overall yield of the target compound is very low (about 3.21% from glycerol). Furthermore, the reaction of method (a) utilizes Steglich esterification using N,N′-dicyclohexyl carbodiimide (DCC), and a side reaction, in which an acyl group is migrated in an adduct of DCC and carboxylic acid, may occur. To reduce the side reaction, the expensive catalyst 4-dimethylaminopyridine (DMAP) should be used in the amount of more than one equivalent. However, the side reaction cannot be completely suppressed, dicyclohexylurea is formed as a by-product, and it is difficult to completely remove the by-product by a filtration and an extraction.
  • DCC N,N′-dicyclohexyl carbodiimide
  • DMAP 4-d
  • an ester group is regioselectively introduced into 1-position of glycerol.
  • ester group should be introduced into 2-position of glycerol.
  • the process can regioselectively introduce ester groups into 1, 2 and 3-positions of glycerol.
  • 1-palmitoyl-3-acetyl glycerol represented by the following Formula 1 is used to synthesis 1-palmitoyl-2-linoleoyl-3-acetylglycerol, the above-mentioned drawbacks can be eliminated. Therefore, there are demands for preparing racemic or optically active and pure 1-palmitoyl-3-acetylglycerol.
  • this invention provides a method for preparing 1-palmitoyl-3-acetylglycerol comprising the steps of: forming a reaction mixture including 1-palmitoyl-3-acetylglycerol represented by the following Formula 1 by reacting 1-palmitoylglycerol represented by the following Formula 2 and an acetylating agent; and separating optically active 1-palmitoyl-3-acetylglycerol by crystallizing the reaction mixture in a saturated hydrocarbon solvent having 5 to 7 carbon atoms.
  • the compounds of the above formula 1 and 2 are racemic or optically active compounds.
  • This invention also provides a method for preparing 1-palmitoyl-2-linoleoyl-3-acetylglycerol comprising the steps of: preparing a mixed anhydride by reacting linoleic acid and pivaloyl chloride in a non-polar organic solvent in the presence of an organic base; and preparing 1-palmitoyl-2-linoleoyl-3-acetylglycerol represented by the following Formula 3 by reacting 1-palmitoyl-3-acetylglycerol and the mixed anhydride in the presence of 4-dimethylaminopyridine.
  • the compound of the above formula 3 is racemic or optically active compound.
  • 1-palmitoyl-3-acetylglycerol (racemic or optically active compound) can be prepared in high purity and high yield by simple steps (an acetylation step and a crystallization step) without the separation and purification process using a column chromatography.
  • 1-palmitoyl-2-linoleoyl-3-acetylglycerol (racemic or optically active compound) can be prepared in high purity and high yield (more than 98%) by using 1-palmitoyl-3-acetylglycerol as an intermediate, and using pivaloyl chloride as a coupling reagent without the separation and purification process using a column chromatography. Accordingly, the methods of the present invention are suitable for a mass production.
  • 1-palmitoyl-2-linoleoyl-3-acetylglycerol (racemic or optically active compound) and its intermediate 1-palmitoyl-3-acetylglycerol (racemic or optically active compound) are prepared in high purity and high yield without a separation and purification process using a column chromatography.
  • a reaction mixture including the 1-palmitoyl-3-acetylglycerol is formed by reacting 1-palmitoylglycerol of the following Formula 2 and an acetylating agent as starting materials (acetylation reaction).
  • the compounds of the above formula 1 and 2 are racemic or optically active compounds.
  • 1-palmitoyl-2-acetylglycerol is produced by competition reactions of hydroxyl groups at 2- and 3-positions of 1-palmitoylglycerol during the initial stage of the acetylation reaction, and the hydroxyl group at 3-position of the produced byproduct, 1-palmitoyl-2-acetylglycerol, is also acetylated in a competition reaction with the hydroxyl group at 3-position of the starting material, 1-palmitoylglycerol, to produce 1-palmitoyl-2,3-diacetylglycerol as the by-product.
  • the inventors of the present invention have tried to reduce the kind of compounds present in the reaction mixture after completion of the reaction by using the reaction mechanism. Specifically, the inventors has controlled the amount of the acetylating agent used in the acetylation reaction so that the by-product, 1-palmitoyl-2-acetylglycerol is completely converted to 1-palmitoyl-2,3-diacetylglycerol, and the starting material (1-palmitoylglycerol) does not exist, and thereby the reaction mixture includes only two compounds of 1-palmitoyl-3-acetylglycerol and the by-product of 1-palmitoyl-2,3-diacetylglycerol.
  • the reaction mixture includes 4 kind of compounds (1-palmitoyl-3-acetylglycerol, 1-palmitoyl-2-acetylglycerol, 1-palmitoyl-2,3-diacetylglycerol and unreacted 1-palmitoylglycerol).
  • it is very important to reduce the amounts of the starting material and the by-product of 1-palmitoyl-2-acetylglycerol. If they are remained in the reaction mixture, they are not removed during a purification process (a crystallization step) for purifying and obtaining pure 1-palmitoyl-3-acetylglycerol.
  • acetylating agent used in the present invention examples include acetylchloride, acetylbromide, the mixtures thereof and so on.
  • the amount of the acetylating agent is 1.3 to 1.4 equivalents, preferably 1.31 to 1.35 equivalents with respect to the 1-palmitoylglycerol.
  • the amount of the acetylating agent is less than 1.3 equivalents with respect to the 1-palmitoylglycerol, the unreacted 1-palmitoylglycerol and 1-palmitoyl-2-acetylglycerol may be present in the reaction mixture.
  • the amount of the acetylating agent is more than 1.4 equivalents with respect to the 1-palmitoylglycerol
  • the produced 1-palmitoyl-3-acetylglycerol is further acetylated to produce 1-palmitoyl-2,3-acetylglycerol, which may reduce the yield of the 1-palmitoyl-3-acetylglycerol.
  • the acetylation reaction can be carried out in a solvent and in the presence of an organic base.
  • the organic base include pyridine and so on.
  • the amount of the organic base is 1.3 to 5 equivalents, preferably 2 to 4.5 equivalents, more preferably 3 to 4 equivalents with respect to 1-palmitoylglycerol.
  • acids produced during the acetylation reaction may not be fully neutralized.
  • the amount of the organic base is more than 5 equivalents with respect to 1-palmitoylglycerol, there is no additional advantage.
  • the solvent examples include a non-polar and aprotic solvent such as dichloromethane, acetone, ethyl acetate, the mixtures thereof, and so on, and preferably include dichloromethane.
  • the amount of the solvent is 5 to 10 times, preferably 8 to 10 times in volume ratio with respect to the weight of 1-palmitoylglycerol (volume/weight).
  • the amount of the solvent is too small, the reaction mixture may not be smoothly stirred due to the salt precipitated during the reaction.
  • the amount of the solvent is too much, there is no additional advantage.
  • the reaction mixture is crystallized in a saturated hydrocarbon solvent having 5 to 7 carbon atoms to separate 1-palmitoyl-3-acetylglycerol.
  • the saturated hydrocarbon solvent having 5 to 7 carbon atoms for example, pentane, hexane, heptane, and so on, preferably, hexane
  • 1-palmitoyl-2,3-diacetylglycerol having a high solubility to the solvent is remained dissolved, but 1-palmitoyl-3-acetylglycerol is crystallized out in pure form.
  • the crystallized 1-palmitoyl-3-acetylglycerol is filtered to obtain 1-palmitoyl-3-acetylglycerol which is in a solid form at the room temperature with a relatively high yield (for example, 60 to 65%) and a high purity in a simple process.
  • the obtained 1-palmitoyl-3-acetylglycerol does not includes impurities which produce by-products in the synthesis of 1-palmitoyl-2-linoleoyl-3-acetylglycerol.
  • the amount of the saturated hydrocarbon solvent is 2.5 to 5 times, preferably 3 to 4 times in volume ratio with respect to the weight of the reaction mixture (volume/weight).
  • the reaction mixture may not be easily stirred in the crystallization process.
  • the amount of the saturated hydrocarbon solvent is too much, the yield of crystallized 1-palmitoyl-3-acetylglycerol may be decreased.
  • 1-palmitoyl-2-linoleoyl-3-acetylglycerol of the following Formula 3 is prepared by the above-mentioned method for preparing 1-palmitoyl-3-acetylglycerol.
  • the compound of the above formula 3 is racemic or optically active compound.
  • the step of reacting linoleic acid and pivaloyl chloride (step (b)) can be easily carried out in a conventional non-polar organic solvent, but is preferably carried out in a saturated hydrocarbon solvent having 5 to 7 carbon atoms such as pentane, hexane, heptane, the mixtures thereof and so on in consideration of easy feasibility of product purification and possible residue of solvent in the product.
  • the organic base is used to neutralize hydrochloric acid (HCl) produced in the reaction of linoleic acid and pivaloyl chloride and to neutralize pivalic acid produced in the reaction of the mixed anhydride and 1-palmitoyl-3-acetylglycerol. Examples of the organic base include triethylamine and so on.
  • the amount of linoleic acid is 1 to 1.05 equivalents, preferably 1.01 to 1.04 equivalents with respect to 1-palmitoyl-3-acetylglycerol.
  • the amount of pivaloyl chloride is less than or equal to the amount of linoleic acid.
  • the amount of pivaloyl chloride is 0.97 to 1 equivalents, preferably 0.98 to 0.99 equivalents with respect to linoleic acid.
  • pivaloyl chloride reacts with 1-palmitoyl-3-acetylglycerol to produce by-products or it may be difficult to remove the unreacted linoleic acid.
  • the amount of the organic base is 2 to 3 equivalents, preferably 2.1 to 2.3 equivalents with respect to 1-palmitoylglycerol.
  • the amount of the non-polar organic solvent is 10 to 15 times, preferably 11 to 12 times in volume ratio with respect to the weight of 1-palmitoyl-3-acetylglycerol (volume/weight).
  • amount of the non-polar organic solvent is less than 10 times in volume ratio with respect to the weight of 1-palmitoyl-3-acetylglycerol, it may be difficult to stir the reaction mixture.
  • amount of the non-polar organic solvent is more than 15 times in volume ratio with respect to the weight of 1-palmitoyl-3-acetylglycerol, there is no additional advantage.
  • step (b)) The reaction of linoleic acid and pivaloyl chloride (step (b)) is carried out at the temperature of 15 to 25° C., preferably at the temperature of 20 to 24° C., and the reaction time is 30 to 60 minutes, preferably 40 to 50 minutes.
  • the reaction temperature and the reaction time are out of the above-mentioned ranges, the reaction may be slowly carried out or unreacted compounds may remain, and there is no additional advantage.
  • step (c) The step of reacting the mixed anhydride and 1-palmitoyl-3-acetylglycerol (step (c)) is carried out by: adding 1-palmitoyl-3-acetylglycerol and the catalyst 4-dimethyl aminopyridine (DMAP) to the reaction mixture including the mixed anhydride, and reacting the mixed anhydride and 1-palmitoyl-3-acetylglycerol at the temperature of 20 to 40° C., preferably 25 to 35° C. for 4 to 10 hours, preferably 5 to 6 hours.
  • DMAP 4-dimethyl aminopyridine
  • 1-palmitoyl-2-linoleoyl-3-acetylglycerol of Formula 3 prepared from the above-mentioned step can be obtained in high purity of more than 98% and in high yield of more than 70% by conducting simple purification process, for example, a conventional extraction process and adsorption process without conducting a purification process using a column chromatography.
  • the amount of 4-dimethylaminopyridine is 1 to 10 parts by mole, preferably 1.1 to 5 parts by mole with respect to 100 parts by mole of 1-palmitoyl-3-acetylglycerol.
  • the reaction may not be carried out or may be slowly carried out.
  • the amount of 4-dimethylamino pyridine is more than 10 parts by mole, there is no additional advantage.
  • the reaction temperature is less than 20° C., the reaction may be slowly carried out.
  • reaction temperature is more than 40° C., by-products may be produced and there is no advantage.
  • the reaction time is less than 4 hours, the reaction may be incompletely carried out and unreacted compounds may remain.
  • the reaction time is more than 10 hours, there is no advantage.
  • Linoleic acid (99%, 2.89 g) and pivaloyl chloride (1.262 ml) were added to hexane (28.9 ml), and triethylamine (2.857 ml) was slowly added thereto at the solution temperature of 20 to 25° C. The reaction mixture was stirred for 30 minutes to produce a mixed anhydride.

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  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US14/346,783 2011-09-23 2012-09-24 Preparation method of 1-palmitoyl-3-acetylglycerol, and preparation method of 1-palmitoyl-2-linoleoyl-3-acetylglycerol using same Abandoned US20140243548A1 (en)

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KR1020110096341A KR101278874B1 (ko) 2011-09-23 2011-09-23 1-팔미토일-3-아세틸글리세롤의 제조방법 및 이를 이용한 1-팔미토일-2-리놀레오일-3-아세틸글리세롤의 제조방법
PCT/KR2012/007644 WO2013043009A2 (ko) 2011-09-23 2012-09-24 1-팔미토일-3-아세틸글리세롤의 제조방법 및 이를 이용한 1-팔미토일-2-리놀레오일-3-아세틸글리세롤의 제조방법

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US14/958,734 Active 2032-10-25 US9701613B2 (en) 2011-09-23 2015-12-03 Preparation method of 1-palmitoyl-3-acetylglycerol, and preparation method of 1-palmitoyl-2-linoleoyl-3-acetylglycerol using same
US15/448,728 Abandoned US20170183287A1 (en) 2011-09-23 2017-03-03 Preparation method of 1-palmitoyl-3-acetylglycerol, and preparation method of 1-palmitoyl-2-linoleoyl-3-acetylglycerol using same

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US15/448,728 Abandoned US20170183287A1 (en) 2011-09-23 2017-03-03 Preparation method of 1-palmitoyl-3-acetylglycerol, and preparation method of 1-palmitoyl-2-linoleoyl-3-acetylglycerol using same

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KR (1) KR101278874B1 (enrdf_load_stackoverflow)
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KR101278874B1 (ko) 2011-09-23 2013-06-26 주식회사 엔지켐생명과학 1-팔미토일-3-아세틸글리세롤의 제조방법 및 이를 이용한 1-팔미토일-2-리놀레오일-3-아세틸글리세롤의 제조방법
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