WO2022260401A1 - Novel glyceride compound, and method for preparing same - Google Patents
Novel glyceride compound, and method for preparing same Download PDFInfo
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- WO2022260401A1 WO2022260401A1 PCT/KR2022/008012 KR2022008012W WO2022260401A1 WO 2022260401 A1 WO2022260401 A1 WO 2022260401A1 KR 2022008012 W KR2022008012 W KR 2022008012W WO 2022260401 A1 WO2022260401 A1 WO 2022260401A1
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- -1 glyceride compound Chemical class 0.000 title claims abstract description 128
- 238000000034 method Methods 0.000 title description 10
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims abstract description 60
- 150000007524 organic acids Chemical class 0.000 claims abstract description 55
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims abstract description 44
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229960004889 salicylic acid Drugs 0.000 claims abstract description 30
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims abstract description 29
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims abstract description 29
- 229940114124 ferulic acid Drugs 0.000 claims abstract description 29
- 235000001785 ferulic acid Nutrition 0.000 claims abstract description 29
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 claims abstract description 29
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims abstract description 29
- 235000019136 lipoic acid Nutrition 0.000 claims abstract description 22
- 229960002663 thioctic acid Drugs 0.000 claims abstract description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 19
- 125000001424 substituent group Chemical group 0.000 claims abstract description 17
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims abstract description 14
- 229930002330 retinoic acid Natural products 0.000 claims abstract description 14
- 229960001727 tretinoin Drugs 0.000 claims abstract description 14
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960004705 kojic acid Drugs 0.000 claims abstract description 13
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 73
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 71
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 16
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 11
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- 235000020944 retinol Nutrition 0.000 claims description 10
- 239000011607 retinol Substances 0.000 claims description 10
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- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 8
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
- 235000019439 ethyl acetate Nutrition 0.000 description 51
- 238000002360 preparation method Methods 0.000 description 37
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 31
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- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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- 238000010992 reflux Methods 0.000 description 15
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 14
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- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 5
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- 231100000274 skin absorption Toxicity 0.000 description 1
- 230000037370 skin discoloration Effects 0.000 description 1
- 230000036560 skin regeneration Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000004382 visual function Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/24—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran
- C07C67/26—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran with an oxirane ring
-
- 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
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the present invention relates to a novel glyceride compound and a method for producing the same, and more specifically, to a functional alcohol compound widely used as a raw material for cosmetics, health supplements, or pharmaceuticals, and a physiologically active organic acid compound are linked through glycerol having excellent moisturizing properties.
- a novel glyceride compound that eliminates skin toxicity of physiologically active organic acid compounds, has a synergistic effect on physiological activity, and is more effective in skin penetration and a method for preparing the same.
- Functional alcohol compounds and physiologically active organic acid compounds are widely used as raw materials for cosmetics, health supplements, or pharmaceuticals due to their effects such as antioxidant, antibacterial, skin damage treatment, skin aging prevention and whitening.
- functional alcohol compounds are hydrophobic and do not have a good skin penetration effect, and in particular, physiologically active organic acid compounds have a problem of skin toxicity due to acidic carboxyl groups.
- Korean Patent Registration Publication KR10-1261270B1 published by the present inventor, is a new functional cosmetic raw material that contains retinol acid with excellent skin regeneration and wrinkle removal effects and vitamin E (alpha-tocopherol) with excellent antioxidant function in glycerol with excellent skin absorption and moisturizing effect.
- a glyceride compound synthesized by attachment is disclosed.
- carboxylic acid is limited to retinol acid
- functional alcohol compounds are limited to vitamin E (or alpha-tocopherol), so that physiologically active organic acid compounds and functional alcohol compounds having various physiologically active functions
- physiologically active organic acid compounds and functional alcohol compounds having various physiologically active functions There was a limit that could not expand the scope of
- US Patent Registration Publication US 8,318,795 B2 is an invention related to a polymer compound containing a 1,2-dithiolane group that acts as a free radical scavenger, and specifically, the identification number of the US Patent Registration Publication.
- [0046] and [0047] disclose that the 1,2-dithiolane compound was synthesized as a preparation example for preparing an antioxidant acetal compound and an ester compound.
- the US patent registration publication only discloses that alpha-lipoic acid and glycerol react to produce a glyceride compound, and 1,2-diglyceride compounds and 1,3-diglyceride compounds according to the present invention and monoglyceride compounds are not specifically disclosed.
- an object of the present invention is to link a physiologically active organic acid compound and a functional alcohol compound widely used in cosmetics, health supplements, or pharmaceuticals through glycerol having excellent moisturizing properties, so that the bioactive organic acid compound It is to provide a novel glyceride compound that can remove skin toxicity, obtain a synergistic effect of physiological activity, and secure intramolecular structural flexibility so that skin enzymes can easily recognize it.
- Another object of the present invention is to provide a novel glyceride compound capable of selectively undergoing an esterification reaction at a hydroxy group bonded to carbon number 2 of the glycerol by reacting a physiologically active organic acid compound with a protecting group attached to glycerol.
- Another object of the present invention is to provide a novel glyceride compound prepared by reacting the novel glyceride compound synthesized using a protecting group with another physiologically active organic acid compound.
- Another object of the present invention is to provide a method for preparing the novel glyceride compound.
- the present inventor selects a physiologically active organic acid compound and a functional alcohol compound as follows to maintain the hydrophilicity of glycerol having a moisturizing effect while maintaining the physiological activity of the physiologically active organic acid compound and functional alcohol compound
- a physiologically active organic acid compound and a functional alcohol compound as follows to maintain the hydrophilicity of glycerol having a moisturizing effect while maintaining the physiological activity of the physiologically active organic acid compound and functional alcohol compound
- the skin toxicity of the bioactive organic acid compound was eliminated, and a new material was synthesized with structural fluidity in the molecule.
- the physiologically active organic acid compound according to the present invention is any one selected from the group consisting of salicylic acid, ferulic acid, kojic acid, alpha-lipoic acid and retinoic acid.
- Salicylic acid according to the present invention is a compound represented by the following Chemical Formula A-1, and can improve tissue and skin color of skin damaged by exposure to ultraviolet rays, and can be particularly effective in treating acne.
- Ferulic acid according to the present invention is a compound represented by the following Chemical Formula A-2, which is widely found in plant cell walls and is a main component of ligno-cellulose that binds lignin and cellulose to make cell walls strong. Specifically, the ferulic acid is widely used as an antioxidant or cancer prevention and treatment agent.
- Kojic acid according to the present invention is a compound represented by the following formula A-3, and can cure melasma-related skin discoloration problems, and specifically, has a similar action to hydroquinone and is used as a melanogenesis inhibitor, reducing or removing melasma can do.
- Alpha-lipoic acid according to the present invention is a compound represented by Formula A-4 below, has an excellent effect on preventing skin aging, and can be used as a powerful antioxidant to treat and prevent skin damage.
- alpha-lipoic acid dissolves well in both water and oil and is easily delivered to all cell tissues, so it has a very wide range of action.
- Retinol acid according to the present invention is a compound represented by the following Chemical Formula A-5, and as vitamin A, it may be involved in visual function and act as a growth factor.
- retinoic acid can play an important role in the growth and differentiation of cell tissues and can suppress skin wrinkles.
- retinoic acid can not only block ultraviolet rays, but also inhibit the darkening of the skin due to pigmentation.
- the functional alcohol compound according to the present invention is any one selected from the group consisting of carvacrol, sesamol and alpha-tocopherol.
- Carvacrol according to the present invention is a compound represented by the following formula B-1, which is added to essential oils such as herbs, can inhibit the growth of bacteria, has low toxicity and has good taste and aroma, and is used as a food additive. It has the advantage of being widely used.
- Sesamol according to the present invention is a compound represented by the following Chemical Formula B-2, and is a white solid as a main component of sesame seeds.
- sesamol is widely used as an antioxidant and can protect the body from free radicals, carcinogens.
- Alpha-tocopherol according to the present invention is a compound represented by the following formula B-3, and is vitamin E or fat-soluble vitamin.
- Alpha-tocopherol is a natural antioxidant isolated from vegetable oil that can remove free radicals and inhibit the oxidation of unsaturated fatty acids constituting cell membranes. Also, alpha-tocopherol can prevent skin aging.
- the novel glyceride compound may have a synergistic effect on the physiological activity of the above-mentioned physiologically active organic acid compound and functional alcohol compound, and has a moisturizing effect due to the molecular structure derived from glycerol, so that it can be used in cosmetics, health supplements, or pharmaceuticals. can be widely used in
- One embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 1.
- R 1 is an organic acid-derived substituent
- R 1 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid
- H of R 1 -OH is It is a hydrogen atom with the lowest pKa in the molecular structure of the organic acid.
- the R 1 is , , and It is any one selected from the group consisting of.
- Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 2.
- R 2 is a substituent derived from an organic acid
- R 2 -OH is any one organic acid selected from the group consisting of ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid
- H of R 2 -OH is the organic acid is the hydrogen atom with the lowest pKa in the molecular structure of
- the R 2 is , and It is any one selected from the group consisting of.
- Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 3.
- R 3 is an organic acid-derived substituent
- R 3 -OH is any one organic acid selected from the group consisting of retinol acid, ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid
- H of R 3 -OH is a hydrogen atom with the lowest pKa in the molecular structure of the organic acid.
- the R 3 is , and It is any one selected from the group consisting of.
- 1,3-diglyceride compound according to the present invention is any one selected from the group consisting of compounds represented by Formulas 1 to 14 below.
- Another embodiment of the present invention is a method for preparing the 1,3-diglyceride compound described above.
- a method for preparing a 1,3-diglyceride compound according to an embodiment of the present invention is epichlorohydrin, a physiologically active phenol compound, tetrabutylammonium hydrogen sulfate (TBAHS) and A step of preparing an epoxy compound to which a physiologically active phenol group is bound by mixing a basic solution may be included.
- the basic solution may be an aqueous solution of potassium hydroxide or an aqueous solution of sodium hydroxide, and may undergo an acid-base reaction with acidic hydrogen atoms of the physiologically active phenolic compound.
- the technical idea of the present invention is not limited to the type of basic solution, and any basic surface capable of removing acidic hydrogen atoms of the physiologically active phenolic compound can be applied.
- the physiologically active phenolic compound from which hydrogen is removed by the basic solution may attack the carbon of the C-Cl bond of the epichlorohydrin to proceed with the SN 2 reaction.
- the catalyst, Bu 4 NBr undergoes a proton transfer reaction with the carboxylic acid compound, so that the carboxylic acid compound from which hydrogen is removed can easily attack the epoxy compound to which the phenol group is bonded, so that the reactivity can be improved. have. That is, the carboxylic acid compound from which hydrogen is removed may attack carbon having a small steric hindrance in the epoxy compound to which the phenol group is bonded, thereby proceeding with a ring opening reaction. As a result, a 1,3-diglyceride compound can be produced.
- the phenol compound in which R a is substituted is any one selected from the group consisting of carvacrol, alpha-tocopherol and sesamol
- the carboxylic acid compound to which R b is bonded is retinol acid, ferulic acid, salicylic acid and It is any one selected from the group consisting of alpha-lipoic acid.
- the carboxylic acid compound to which R b is bonded may be replaced with kojic acid.
- Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 4.
- R 4 is an organic acid-derived substituent
- R 4 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid-derived acetate derivatives, and salicylic acid-derived acetate derivatives
- the H of R 4 -OH is a hydrogen atom with the lowest pKa in the molecular structure of the organic acid.
- the acetate derivative derived from ferulic acid is defined to mean a derivative in which the phenol group of ferulic acid is substituted with acetate.
- an acetate derivative derived from salicylic acid is defined to mean a derivative in which the phenol group of salicylic acid is substituted with acetate.
- the R 4 is, , and It is any one selected from the group consisting of.
- the monoglyceride compound according to the present invention is any one selected from the group consisting of compounds represented by Formulas 15 to 17 below.
- Another embodiment of the present invention (a) mixing glycerol and a benzaldehyde-based compound as shown in Scheme 2-1 below and attaching a protecting group to the glycerol, as shown in Scheme 2-2 below, (b) the protecting group It may include preparing an ester compound by mixing glycerol to which is attached and a first carboxylic acid compound, and (c) preparing a novel monoglyceride compound by deprotecting the ester compound under acidic conditions.
- Step (a) is a step in which the hydroxyl group bonded to the 1st and 3rd carbons of glycerol reacts with benzaldehyde to form an acetal structure. This is a step that allows
- Step (b) is an esterification reaction in which an ester compound is generated by reacting the first carboxylic acid compound with a hydroxyl group bonded to carbon 2 of glycerol to which a protecting group is attached.
- the esterification reaction may be carried out under mild conditions using, for example, N,N'-Dicyclohexylcarbodiimide (DCC).
- DCC N,N'-Dicyclohexylcarbodiimide
- the technical idea of the present invention is not limited thereto, and a reaction in which an esterification reaction proceeds may be possible by introducing a good leaving group into the first carboxylic acid compound.
- the step (c) is a step of deprotecting the acetal functional group of the ester compound, and may be a step of deprotecting the acetal functional group of the ester compound with an acidic solution in which para -toluenesulfonic acid, which is a weakly acidic condition, and methanol are mixed.
- the benzaldehyde-based compound may correspond to benzaldehyde or a compound in which a sulfonyl substituent is introduced at the para position based on the aldehyde functional group of benzaldehyde.
- the sulfonyl substituent may correspond to a benzenesulfonyl group.
- the carboxylic acid compound to which the Rc group is bonded is any one selected from the group consisting of retinoic acid, ferulic acid-derived acetate derivatives, and salicylic acid-derived acetate derivatives.
- Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 5.
- R 5 is a substituent derived from an organic acid
- R 5 -OH is any organic acid selected from the group consisting of ferulic acid, alpha-lipoic acid, and salicylic acid
- H of R 5 -OH is a molecule of the organic acid. It is the hydrogen atom with the lowest pKa in the structure.
- the R 5 is, , and It is any one selected from the group consisting of.
- Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 6.
- R 6 is an organic acid-derived substituent
- R 6 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid, and salicylic acid
- H of R 6 -OH is a molecular structure of the organic acid. is the hydrogen atom with the lowest pKa in
- the R 6 is , and It is any one selected from the group consisting of.
- the 1,2-diglyceride compound according to the present invention is any one selected from the group consisting of compounds represented by Formulas 18 to 23 below.
- Another embodiment of the present invention is (S1) mixing glycerol and a benzaldehyde-based compound and attaching a protecting group to the glycerol, (S2) mixing the glycerol to which the protecting group is attached and a second carboxylic acid compound to form an ester preparing a compound and (S3) deprotecting the ester compound and then mixing the deprotected ester compound with a third carboxylic acid compound to prepare a 1,2-diglyceride compound;
- the second and third carboxylic acid compounds are each independently selected from the group consisting of retinoic acid, ferulic acid, alpha-lipoic acid, and salicylic acid, and the second and third carboxylic acid compounds are different from each other. It is a method for preparing a glyceride compound. Descriptions overlapping with the foregoing will be briefly described or omitted.
- the second carboxylic acid compound may be the same as the first carboxylic acid compound described above. Accordingly, the step (S1) may correspond to the step (a), and the step (S2) may correspond to the step (b).
- the step (S3) may be a step of preparing a 1,2-diglyceride compound by reacting the deprotected ester compound with the carboxylic acid compound to which R d is bonded, as shown in Scheme 2-3 below.
- the 1,2-diglyceride compound is represented by the following general formula (5).
- R 5 is a substituent derived from an organic acid
- R 5 -OH is any organic acid selected from the group consisting of ferulic acid, alpha-lipoic acid, and salicylic acid
- H of R 5 -OH is a molecule of the organic acid. It is the hydrogen atom with the lowest pKa in the structure.
- the 1,2-diglyceride compound is represented by the following general formula (6).
- R 6 is an organic acid-derived substituent
- R 6 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid, and salicylic acid
- H of R 6 -OH is a molecular structure of the organic acid. is the hydrogen atom with the lowest pKa in
- glycerol by combining glycerol with a physiologically active organic acid and a functional alcohol compound, skin toxicity of the physiologically active organic acid can be removed and a synergistic effect on the physiological activity of the physiologically active organic acid and functional alcohol compound can be expected.
- a skin moisturizing effect through the hydroxyl group of glycerol it is possible to provide a novel glyceride compound improved in terms of physiological activity, moisturizing effect and skin penetration effect compared to existing cosmetic raw materials. Additionally, these novel glyceride compounds can be extended not only to the cosmetic field but also to the health supplement or pharmaceutical field.
- One embodiment of the present invention is a novel 1,3-glyceride compound and a method for preparing the same.
- Preparation Example 1 is a compound represented by Formula 1a below.
- Preparation Example 1 was synthesized as a first epoxide compound in the following manner.
- Example 1 is a compound represented by Formula 1 below.
- Example 1 (541 mg, 2.62 mmol), retinol acid (787 mg, 2.62 mmol) and tetrabutylammonium bromide (85 mg, 0.26 mmol) in a 100 mL round flask, dissolve in THF (20 mL), and then 24 Heat at reflux for an hour. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 1 (822 mg, 1.62 mmol) as a yellow liquid in a yield of 62%.
- Example 2 is a compound represented by Formula 2 below.
- Example 1 (1.30 g, 6.30 mmol), ferulic acid (1.35 mg, 6.93 mmol) and tetrabutylammonium bromide (203 mg, 0.63 mmol) were dissolved in THF (20 mL) and then 24 Heat at reflux for an hour. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 2 (1.00 g, 2.50 mmol) as a pale yellow liquid in a yield of 40%.
- Example 3 is a compound represented by Formula 3 below.
- Example 1 (980 mg, 4.75 mmol), alpha-lipoic acid (980 mg, 4.75 mmol) and tetrabutylammonium bromide (306 mg, 0.95 mmol) in a 250 mL round flask and dissolve in THF (10 mL). Heat at reflux for 10 hours. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 3 (530 mg, 1.28 mmol) as a pale yellow liquid in a yield of 27%.
- Example 4 is a compound represented by Formula 4 below.
- Example 1 Into a 100 mL round flask, Example 1 (500 mg, 2.42 mmol), kojic acid (344 mg, 2.42 mmol) and tetrabutylammonium bromide (234 mg, 0.73 mmol) were dissolved in THF (7 mL) and then stirred for 4 hours. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 4 (77 mg, 0.22 mmol) as a pale yellow liquid in a yield of 9%.
- Example 5 is a compound represented by Formula 5 below.
- Example 1 Into a 250 mL round flask, Example 1 (1.64 g, 7.95 mmol), salicylic acid (157 mg, 5.68 mmol) and tetrabutylammonium bromide (367 mg, 1.14 mmol) were added and dissolved in THF (5 mL) for one day. Heat to reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 5 (1.53 g, 4.45 mmol) as a clear liquid in a yield of 56%.
- Preparation Example 2 is a compound represented by Formula 2a below.
- Preparation Example 2 was synthesized as a second epoxide compound in the following manner.
- Example 6 is a compound represented by Formula 6 below.
- Example 2 Into a 250 mL round flask, Example 2 (1.10 g, 2.27 mmol), perolic acid (441 mg, 2.27 mmol) and tetrabutylammonium bromide (73 mg, 0.23 mmol) were dissolved in THF (5 mL) and then dissolved in 20 mL. Heat at reflux for an hour. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 6 (200 mg, 0.30 mmol) in a yield of 13%.
- Example 7 is a compound represented by Formula 7 below.
- Example 2 (780 mg, 1.58 mmol), alpha-lipoic acid (300 mg, 1.44 mmol) and tetrabutylammonium bromide (45 mg, 0.14 mmol) in a 100 mL round flask and dissolve in dioxane (40 mL). Heat to reflux for 24 hours. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 7 (410 mg, 0.60 mmol) as a yellow oil in a yield of 42%.
- Example 8 is a compound represented by Formula 8 below.
- Example 2 Into a 100 mL round flask, Example 2 (1.00 g, 2.00 mmol), kojic acid (0.30 g, 2.20 mmol) and tetrabutylammonium bromide (60 mg, 0.19 mmol) were added and dissolved in THF (8 mL) for 24 hours. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 8 (40 mg, 0.063 mmol) in a yield of 3%.
- Example 9 is a compound represented by Formula 9 below.
- Example 2 Into a 100 mL round flask, Example 2 (380 mg, 0.78 mmol), salicylic acid (119 mg, 0.86 mmol) and tetrabutylammonium bromide (25 mg, 0.08 mmol) were added and dissolved in THF (20 mL) for 6 hours. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 9 (93 mg, 0.15 mmol) as a transparent liquid in a yield of 19%.
- Preparation Example 3 is a compound represented by Formula 3a below.
- Example 10 is a compound represented by Formula 10 below.
- Example 3 Into a 100 mL round flask, Example 3 (610 mg, 3.14 mmol), retinoic acid (1.04 mg, 3.45 mmol) and tetrabutylammonium bromide (152 mg, 0.47 mmol) were dissolved in THF (20 mL) and then 13 Heat at reflux for an hour. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 10 (1.05 g, 2.13 mmol) as a yellow liquid in a yield of 68%.
- Example 11 is a compound represented by Formula 11 below.
- Example 3 Into a 100 mL round flask, Example 3 (467 mg, 2.41 mmol), perolic acid (514 mg, 2.65 mmol) and tetrabutylammonium bromide (78 mg, 0.24 mmol) were added and dissolved in dioxane (10 mL) for one day. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 11 (303 mg, 0.78 mmol) as a clear liquid in a yield of 32%.
- Example 12 is a compound represented by Formula 12 below.
- Example 3 500 mg, 2.57 mmol
- alpha-lipoic acid 530 mg, 2.57 mmol
- tetrabutylammonium bromide 80 mg, 0.25 mmol
- THF 40 mL
- H 2 O was added to terminate the reaction
- the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure.
- the concentrated product was purified by silica gel column chromatography to obtain Example 12 (110 mg, 0.27 mmol) as a white solid in a yield of 11%.
- Example 13 is a compound represented by Formula 13 below.
- Example 3 Into a 100 mL round flask, Example 3 (450 mg, 2.32 mmol), kojic acid (330 mg, 2.32 mmol) and tetrabutylammonium bromide (74 mg, 0.23 mmol) were added and dissolved in THF (30 mL) for 24 hours. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 13 (47 mg, 0.139 mmol) as a white solid in a yield of 6%.
- Example 14 is a compound represented by Formula 14 below.
- Example 3 Into a 100 mL round flask, Example 3 (197 mg, 1.01 mmol), salicylic acid (157 mg, 1.13 mmol) and tetrabutylammonium bromide (33 mg, 0.10 mmol) were added and dissolved in THF (5 mL) for one day. Heat to reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 14 (1.05 g, 0.52 mmol) as a clear liquid in a yield of 51%.
- Another embodiment of the present invention is a novel monoglyceride compound and method for its preparation.
- Preparation Example 4 is a preparation example necessary for synthesizing Example 15 below, and is a compound represented by Formula 4a below.
- Preparation Example 4 is an ester compound to which a protecting group is attached, and is synthesized in the following manner.
- Example 4 (0.55 g 1.20 mmol) in a yield of 36%.
- Preparation Example 5 is a compound represented by Formula 5a as a preparation example necessary for synthesizing Preparation Examples 6 and 7 below.
- Preparation Example 5 is a novel glycerol compound having a protecting group containing a benzenesulfonyl group attached to the para-position of benzaldehyde instead of 2-phenyl-1,3-dioxan-5-ol of Preparation Example 4. , It has an excellent crystalline phase and can be easily purified by recrystallization, and is synthesized in the following way similar to the synthesis of 2-phenyl-1,3-dioxan-5-ol.
- Preparation Example 6 is a compound represented by Formula 6a as a preparation example necessary for synthesizing Example 16 below.
- Preparation Example 6 is an ester compound to which a protecting group is attached, and is synthesized in the following manner.
- Example 5 In a 100 mL round flask, Example 5 (100 mg, 0.30 mmol) and 3-(4-acetoxy-3-methoxyphenyl)acrylic acid (85 mg, 0.36 mmol), dimethylaminopyridine methanesulfonate (DPMS) (144 mg, 0.66 mmol) ) was dissolved in CH 2 Cl 2 (20 mL), dicyclohexyl carbodiimide (DCC) (74 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 22 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 6 (160 mg, 0.289 mmol) in a yield of 96%.
- DPMS dimethylaminopyridine methanesulfonate
- DCC dicycl
- Preparation Example 7 is a compound represented by Formula 7a as a preparation example necessary for synthesizing Example 17 below.
- Preparation Example 7 is an ester compound to which a protecting group is attached, and is synthesized in the following manner.
- Example 5 In a 100 mL round flask, Example 5 (1.30 g, 3.89 mmol), 2-acetoxybenzoic acid (0.70 g, 3.89 mmol), and dimethylaminopyridine methanesulfonate (DPMS) (2.12 g, 9.71 mmol) were added to CH 2 Cl 2 (40 mL). ), then DCC (0.074 g, 0.36 mmol) was added and stirred at room temperature for 22 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 7 (0.17 g, 0.34 mmol) in a yield of 9%.
- DPMS dimethylaminopyridine methanesulfonate
- Preparation Example 8-1 is a compound represented by Formula 8a as a preparation example required for synthesizing Example 21 below.
- Example 8-1 (3.40 g, 9.23 mmol) as a yellow solid in a yield of 79%.
- Preparation Example 8-2 is a compound represented by Formula 8b as a preparation example required for synthesizing Example 21 below.
- the Preparation Example 8-2 was synthesized in the following manner.
- Example 8-1 (2.45 g, 6.65 mmol) was dissolved in CH 2 Cl 2 (10 mL), methanol (50 mL) and p -TsOH (0.11 g, 0.66 mmol) were added, and room temperature stirred for 4 hours. Most of the solvent was removed under reduced pressure, H 2 O was added, the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 8-2 (1.23 g, 4.40 mmol) as a pale yellow liquid in a yield of 66%.
- Example 15 is a compound represented by Formula 15 below.
- Example 4 In a 100 mL round flask, the above Example 4 (2.70 g, 5.8- mmol) was dissolved in CH 2 Cl 2 (10 mL), methanol (50 mL) and p -TsOH (0.10 g, 0.58 mmol) were added, and the mixture was stirred at room temperature. Stir for 3 hours. Most of the solvent was removed under reduced pressure, H 2 O was added, the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 15 (1.99 g, 5.30 mmol) as a dark yellow liquid in a yield of 92%.
- Example 16 is a compound represented by Formula 16 below.
- Example 6 Dissolve Example 6 (0.16 g, 0.29 mmol) in MeOH (20 mL) in a 100 mL round flask, add p -TsOH (0.01 g, 0.06 mmol), and stir at room temperature for 12 hours.
- the reaction mixture was concentrated under reduced pressure to remove most of the solvent, water was added, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure.
- the concentrated product was purified by silica gel column chromatography to obtain Example 16 (0.05 g 0.16 mmol) in a yield of 56%.
- Example 17 is a compound represented by Formula 17 below.
- Example 7 Dissolve Example 7 (0.17 g, 0.34 mmol) in MeOH (25 mL) in a 100 mL round flask, add p-TsOH (17 mg, 0.10 mmol), and stir at room temperature for 4 hours.
- the product concentrated under reduced pressure was purified by silica gel column chromatography to obtain Example 17 (1.3 mg, 0.005 mmol) in a yield of 2%.
- Another embodiment of the present invention is a novel 1,2-diglyceride compound and method for its preparation.
- Example 18 is a compound represented by Formula 18 below.
- Example 15 (0.48 g, 1.30 mmol), ferulic acid (0.25 g, 1.30 mmol), and DPMS (0.7 g, 3.25 mmol) were dissolved in CH 2 Cl 2 (15 mL), DCC (0.32 g, 1.56 mmol) was added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 18 (0.26 g, 0.47 mmol) as a yellow liquid in a yield of 36%.
- Example 19 is a compound represented by Formula 19 below.
- Example 15 (0.38 g, 1.00 mmol), alpha-lipoic acid (0.21 g, 1.00 mmol), and DPMS (0.55 g, 2.50 mmol) were dissolved in CH 2 Cl 2 (10 mL), DCC (0.25 g, 1.20 mmol) is added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 19 (0.30 g, 0.53 mmol) as a viscous yellow liquid in a yield of 53%.
- Example 20 is a compound represented by Formula 20 below.
- Example 15 (0.25 g, 0.67 mmol), salicylic acid (90 mg, 0.67 mmol), and DPMS (0.36 g, 1.67 mmol) were dissolved in CH 2 Cl 2 (20 mL) in a 100 mL round flask, then DCC ( 0.16 g, 0.80 mmol) was added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 20 (45 mg, 0.90 mmol) in a yield of 14%.
- Example 21 is a compound represented by Formula 21 below.
- Example 8-2 (62 mg, 0.22 mmol), retinol acid (67 mg, 0.22 mmol), and DPMS (100 mg, 2.20 mmol) were dissolved in CH 2 Cl 2 (20 mL).
- DCC 45 mg, 0.22 mmol was added and stirred at room temperature for 24 hours.
- the reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure.
- the concentrated product was purified by silica gel column chromatography to obtain Example 21 (17 mg, 0.03 mmol) in a yield of 13%.
- Example 22 is a compound represented by Formula 22 below.
- Example 8-2 130 mg, 0.46 mmol
- ferulic acid 90 mg, 0.46 mmol
- DPMS DPMS
- CH 2 Cl 2 30 mL
- DCC 90 mg, 0.46 mmol
- the reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure.
- the concentrated product was purified by silica gel column chromatography to obtain Example 22 (85 mg, 0.19 mmol) in a yield of 40%.
- Example 23 is a compound represented by Formula 23 below.
- Example 8-2 Dissolve Example 8-2 (46 mg, 0.16 mmol), salicylic acid (34 mg, 0.25 mmol) and DPMS (90 mg, 0.41 mmol) in CH 2 Cl 2 (10 mL) in a 100 mL round flask, DCC (40 mg, 0.20 mmol) is added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 23 (85 mg, 0.19 mmol) in a yield of 31%.
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Abstract
Provided is a novel glyceride compound. An embodiment of the present invention is a novel glyceride compound represented by general formula (1). [General formula 1] In general formula 1, R1 is a substituent derived from an organic acid, R1-OH is an organic acid selected from the group consisting of retinoic acid, ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid, and H in the R1-OH is the hydrogen atom having the lowest pKa in the molecular structure of the organic acid.
Description
본 발명은 신규한 글리세라이드 화합물 및 그의 제조방법에 관한 것으로, 보다 구체적으로 화장품, 건강보조식품 또는 의약품 원료로 널리 사용되는 기능성 알코올류 화합물 및 생리활성 유기산 화합물을 보습성이 뛰어난 글리세롤을 통해 연결하여, 생리활성 유기산 화합물의 피부 독성을 제거하고 생리활성에 대한 시너지 효과를 가짐과 동시에, 피부 침투에 더욱 효과적인 신규한 글리세라이드 화합물 및 그의 제조방법에 관한 것이다. The present invention relates to a novel glyceride compound and a method for producing the same, and more specifically, to a functional alcohol compound widely used as a raw material for cosmetics, health supplements, or pharmaceuticals, and a physiologically active organic acid compound are linked through glycerol having excellent moisturizing properties. , It relates to a novel glyceride compound that eliminates skin toxicity of physiologically active organic acid compounds, has a synergistic effect on physiological activity, and is more effective in skin penetration and a method for preparing the same.
기능성 알코올류 화합물 및 생리활성 유기산 화합물들은 항산화, 항균, 피부손상 치료, 피부노화 방지 및 미백 등의 효과로 인해 화장품, 건강보조식품 또는 의약품의 원료로 널리 사용되고 있다. 하지만 기능성 알코올류 화합물은 소수성으로 피부 침투 효과가 좋지 않으며, 특히 생리활성 유기산 화합물은 산성을 나타내는 카르복실기로 인해 피부독성의 문제점이 있었다. Functional alcohol compounds and physiologically active organic acid compounds are widely used as raw materials for cosmetics, health supplements, or pharmaceuticals due to their effects such as antioxidant, antibacterial, skin damage treatment, skin aging prevention and whitening. However, functional alcohol compounds are hydrophobic and do not have a good skin penetration effect, and in particular, physiologically active organic acid compounds have a problem of skin toxicity due to acidic carboxyl groups.
이러한 생리활성 유기산 화합물의 피부 독성 문제점을 해결하기 위해 기능성 알코올류 화합물과의 에스테르 유도체를 제조하여 사용하는 방법이 일반적으로 이용되고 있다. 이는 생리활성 유기산 화합물의 독성 문제를 해결하고 생리활성 유기산과 기능성 알코올류 화합물의 생리활성의 시너지 효과를 보기 위한 시도이지만, 화합물의 물성이 변화하고 소수성이 더 심화되어 피부세포 내로 생리활성 유기산 화합물 및 기능성 알코올류 화합물을 효과적으로 전달하지 못하는 문제점을 갖고 있었다.In order to solve the skin toxicity problem of these physiologically active organic acid compounds, a method of preparing and using an ester derivative with a functional alcohol compound is generally used. This is an attempt to solve the toxicity problem of the bioactive organic acid compound and to see the synergistic effect of the physiological activity of the bioactive organic acid and functional alcohol compound, but the physical properties of the compound change and the hydrophobicity becomes more intense, so that the bioactive organic acid compound and It had a problem of not effectively delivering functional alcohol compounds.
본 발명자에 의해 공개된 대한민국 특허등록공보 KR10-1261270B1는 신기능성 화장품 원료로서 피부재생 및 주름살 제거 효과가 뛰어난 레티놀산과 항산화 기능이 탁월한 비타민 E(알파-토코페롤)를 피부 흡수 및 보습 효과가 뛰어난 글리세롤에 부착시켜 합성된 글리세라이드 화합물을 개시하고 있다. 하지만, 상기 특허등록공보는 카르복실산이 레티놀산으로 한정되어 있고, 기능성 알코올류 화합물도 비타민 E(또는 알파-토코페롤)로 한정되어 있어, 다양한 생리활성 기능을 갖는 생리활성 유기산 화합물과 기능성 알코올류 화합물의 범위를 넓히지 못한 한계점이 있었다.Korean Patent Registration Publication KR10-1261270B1, published by the present inventor, is a new functional cosmetic raw material that contains retinol acid with excellent skin regeneration and wrinkle removal effects and vitamin E (alpha-tocopherol) with excellent antioxidant function in glycerol with excellent skin absorption and moisturizing effect. A glyceride compound synthesized by attachment is disclosed. However, in the Patent Registration Publication, carboxylic acid is limited to retinol acid, and functional alcohol compounds are limited to vitamin E (or alpha-tocopherol), so that physiologically active organic acid compounds and functional alcohol compounds having various physiologically active functions There was a limit that could not expand the scope of
또 다른 선행기술문헌인 미국 특허등록공보 US 8,318,795 B2는 자유라디칼의 스캐빈저로 작용하는 1,2-디싸이올란기를 함유하는 고분자 화합물에 관한 발명으로, 구체적으로 상기 미국 특허등록공보의 식별번호 [0046] 및 [0047]에서 1,2-디싸이올란 화합물을 항산화제 아세탈 화합물 및 에스터 화합물을 제조하기 위한 준비예로 합성하였음을 개시하고 있다. 하지만, 상기 미국 특허등록공보는, 알파-리포산과 글리세롤이 반응하여 글리세라이드 화합물이 생성되는 점만을 개시할 뿐, 본 발명에 따른 1,2-디글리세라이드 화합물, 1,3-디글리세라이드 화합물 및 모노글리세라이드 화합물을 구체적으로 개시하지 못하고 있다. Another prior art document, US Patent Registration Publication US 8,318,795 B2, is an invention related to a polymer compound containing a 1,2-dithiolane group that acts as a free radical scavenger, and specifically, the identification number of the US Patent Registration Publication. [0046] and [0047] disclose that the 1,2-dithiolane compound was synthesized as a preparation example for preparing an antioxidant acetal compound and an ester compound. However, the US patent registration publication only discloses that alpha-lipoic acid and glycerol react to produce a glyceride compound, and 1,2-diglyceride compounds and 1,3-diglyceride compounds according to the present invention and monoglyceride compounds are not specifically disclosed.
본 발명의 목적은, 상기 문제점을 해결하기 위해, 화장품, 건강보조식품 또는 의약품 분야에서 널리 사용되는 생리활성 유기산 화합물과 기능성 알코올류 화합물을 보습성이 뛰어난 글리세롤을 통해 연결하여, 생리활성 유기산 화합물의 피부 독성을 제거하고, 생리활성의 시너지 효과를 얻을 수 있을 뿐만 아니라, 분자 내 구조적 유동성(flexibility)이 확보되어 피부의 효소가 쉽게 인식할 수 있는 신규한 글리세라이드 화합물을 제공하는 것이다.In order to solve the above problems, an object of the present invention is to link a physiologically active organic acid compound and a functional alcohol compound widely used in cosmetics, health supplements, or pharmaceuticals through glycerol having excellent moisturizing properties, so that the bioactive organic acid compound It is to provide a novel glyceride compound that can remove skin toxicity, obtain a synergistic effect of physiological activity, and secure intramolecular structural flexibility so that skin enzymes can easily recognize it.
본 발명의 다른 목적은, 생리활성 유기산 화합물과 보호기가 부착된 글리세롤을 반응시켜 상기 글리세롤의 2번 탄소에 결합된 히드록시기에서 선택적으로 에스터화 반응이 가능해진 신규한 글리세라이드 화합물을 제공하는 것이다.Another object of the present invention is to provide a novel glyceride compound capable of selectively undergoing an esterification reaction at a hydroxy group bonded to carbon number 2 of the glycerol by reacting a physiologically active organic acid compound with a protecting group attached to glycerol.
본 발명의 또 다른 목적은, 보호기를 이용하여 합성된 상기 신규한 글리세라이드 화합물과 다른 생리활성 유기산 화합물을 반응시켜 제조된 신규한 글리세라이드 화합물을 제공하는 것이다.Another object of the present invention is to provide a novel glyceride compound prepared by reacting the novel glyceride compound synthesized using a protecting group with another physiologically active organic acid compound.
본 발명의 또 다른 목적은, 상기 신규한 글리세라이드 화합물을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the novel glyceride compound.
본 발명의 목적들은 이상에서 언급한 목적으로 제한되지 않으며, 언급되지 않은 본 발명의 다른 목적 및 장점들은 하기의 설명에 의해서 이해될 수 있고, 본 발명의 실시예에 의해 보다 분명하게 이해될 것이다. 또한, 본 발명의 목적 및 장점들은 청구범위에 나타낸 수단 및 그 조합에 의해 실현될 수 있음을 쉽게 알 수 있을 것이다.The objects of the present invention are not limited to the above-mentioned objects, and other objects and advantages of the present invention not mentioned above can be understood by the following description and will be more clearly understood by the examples of the present invention. It will also be readily apparent that the objects and advantages of the present invention may be realized by means of the instrumentalities and combinations indicated in the claims.
1. 선정된 생리활성 유기산 화합물 및 기능성 알코올류 화합물1. Selected physiologically active organic acid compounds and functional alcohol compounds
상기 목적을 달성하기 위해, 본 발명자는 생리활성 유기산 화합물과 기능성 알코올류 화합물을 하기와 같이 선정하여 보습 효과를 갖는 글리세롤의 친수성을 유지하면서 상기 생리활성 유기산 화합물 및 기능성 알코올류 화합물의 생리활성에 대한 시너지 효과를 달성할 있을 뿐만 아니라, 상기 생리활성 유기산 화합물의 피부 독성을 제거하고, 분자 내 구조적 유동성이 확보된 새로운 물질을 합성하였다.In order to achieve the above object, the present inventor selects a physiologically active organic acid compound and a functional alcohol compound as follows to maintain the hydrophilicity of glycerol having a moisturizing effect while maintaining the physiological activity of the physiologically active organic acid compound and functional alcohol compound In addition to achieving a synergistic effect, the skin toxicity of the bioactive organic acid compound was eliminated, and a new material was synthesized with structural fluidity in the molecule.
본 발명에 따른 생리활성 유기산 화합물은, 살리실산, 퍼룰릭산, 코직산, 알파-리포산 및 레티놀산으로 이루어진 군에서 선택된 어느 하나이다.The physiologically active organic acid compound according to the present invention is any one selected from the group consisting of salicylic acid, ferulic acid, kojic acid, alpha-lipoic acid and retinoic acid.
본 발명에 따른 살리실산은 하기 화학식 A-1로 표시되는 화합물이며, 자외선에 노출되어 손상된 피부의 조직과 피부색을 개선할 수 있고 특히, 여드름 치료에 효과적일 수 있다. Salicylic acid according to the present invention is a compound represented by the following Chemical Formula A-1, and can improve tissue and skin color of skin damaged by exposure to ultraviolet rays, and can be particularly effective in treating acne.
[화학식 A-1][Formula A-1]
본 발명에 따른 퍼룰릭산은, 하기 화학식 A-2로 표시되는 화합물이며, 식물의 세포벽에서 널리 발견되며 세포벽을 견고하게 하기 위해 리그닌과 셀룰로오스를 묶는 리그노-셀룰로오스(ligno-cellulose)의 주성분이다. 구체적으로, 상기 퍼룰릭산은 항산화제 또는 암 예방 및 치료제로 널리 사용된다.Ferulic acid according to the present invention is a compound represented by the following Chemical Formula A-2, which is widely found in plant cell walls and is a main component of ligno-cellulose that binds lignin and cellulose to make cell walls strong. Specifically, the ferulic acid is widely used as an antioxidant or cancer prevention and treatment agent.
[화학식 A-2][Formula A-2]
본 발명에 따른 코직산은, 하기 화학식 A-3로 표시되는 화합물이며, 기미 관련 피부 착색 문제를 치유할 수 있고, 구체적으로 하이드로퀴논과 유사한 작용을 하여 멜라닌 생성 억제제로 사용되거나, 기미를 줄이거나 제거할 수 있다.Kojic acid according to the present invention is a compound represented by the following formula A-3, and can cure melasma-related skin discoloration problems, and specifically, has a similar action to hydroquinone and is used as a melanogenesis inhibitor, reducing or removing melasma can do.
[화학식 A-3][Formula A-3]
본 발명에 따른 알파-리포산은, 하기 화학식 A-4로 표시되는 화합물이며, 피부 노화 방지에 탁월한 효과를 가지며 강력한 항산화제로 사용되어 피부 손상을 치료 및 예방할 수 있다. 또한, 알파-리포산은 물과 기름에 모두 잘 녹아 모든 세포 조직에 전달이 쉽게 되어 작용 범위가 매우 넓은 장점을 가지고 있다.Alpha-lipoic acid according to the present invention is a compound represented by Formula A-4 below, has an excellent effect on preventing skin aging, and can be used as a powerful antioxidant to treat and prevent skin damage. In addition, alpha-lipoic acid dissolves well in both water and oil and is easily delivered to all cell tissues, so it has a very wide range of action.
[화학식 A-4][Formula A-4]
본 발명에 따른 레티놀산은, 하기 화학식 A-5로 표시되는 화합물이며, 비타민 A로 시각 기능에 관여하고 성장 인자로 작용할 수 있다. 또한, 레티놀산은 세포 조직의 생장 및 분화에 중요한 역할을 담당할 수 있고 피부의 주름살을 억제할 수 있다. 추가적으로, 레티놀산은 자외선을 차단할 수 있을 뿐만 아니라 색소 침착으로 피부가 어두워지는 현상을 억제할 수 있다.Retinol acid according to the present invention is a compound represented by the following Chemical Formula A-5, and as vitamin A, it may be involved in visual function and act as a growth factor. In addition, retinoic acid can play an important role in the growth and differentiation of cell tissues and can suppress skin wrinkles. In addition, retinoic acid can not only block ultraviolet rays, but also inhibit the darkening of the skin due to pigmentation.
[화학식 A-5][Formula A-5]
본 발명에 따른 기능성 알코올류 화합물은, 카바크롤, 세사몰 및 알파-토코페롤로 이루어진 군에서 선택된 어느 하나이다.The functional alcohol compound according to the present invention is any one selected from the group consisting of carvacrol, sesamol and alpha-tocopherol.
본 발명에 따른 카바크롤은, 하기 화학식 B-1로 표시되는 화합물이며, 허브 등의 에센스 오일에 첨가되고, 박테리아의 생장을 방해할 수 있을 뿐만 아니라, 독성이 낮고 맛과 향기가 좋아 음식물 첨가제로 널리 사용되는 이점을 가지고 있다.Carvacrol according to the present invention is a compound represented by the following formula B-1, which is added to essential oils such as herbs, can inhibit the growth of bacteria, has low toxicity and has good taste and aroma, and is used as a food additive. It has the advantage of being widely used.
[화학식 B-1][Formula B-1]
본 발명에 따른 세사몰은 하기 화학식 B-2로 표시되는 화합물이며, 참깨의 주성분으로 흰색 고체이다. 또한 세사몰은 항산화제로 널리 사용되며 발암물질인 자유 라디칼(free radical)로부터 인체를 보호할 수 있다.Sesamol according to the present invention is a compound represented by the following Chemical Formula B-2, and is a white solid as a main component of sesame seeds. In addition, sesamol is widely used as an antioxidant and can protect the body from free radicals, carcinogens.
[화학식 B-2][Formula B-2]
본 발명에 따른 알파-토코페롤은, 하기 화학식 B-3으로 표시되는 화합물이며, 비타민 E 또는 지용성 비타민이다. 알파-토코페롤은 식물성 기름에서 분리되는 천연 산화 방지제로 자유 라디칼(free radical)을 제거할 수 있고 세포막을 구성하는 불포화 지방산의 산화를 억제할 수 있다. 또한, 알파-토코페롤은 피부 노화를 예방할 수 있다.Alpha-tocopherol according to the present invention is a compound represented by the following formula B-3, and is vitamin E or fat-soluble vitamin. Alpha-tocopherol is a natural antioxidant isolated from vegetable oil that can remove free radicals and inhibit the oxidation of unsaturated fatty acids constituting cell membranes. Also, alpha-tocopherol can prevent skin aging.
[화학식 B-3][Formula B-3]
이하, 신규한 글리세라이드 화합물은 전술한 생리활성 유기산 화합물 및 기능성 알코올류 화합물의 생리활성에 대한 시너지 효과를 가질 수 있고, 글리세롤에서 유래된 분자 구조로 인해 보습 효과를 가져 화장품, 건강보조식품 또는 의약품에 널리 사용될 수 있다.Hereinafter, the novel glyceride compound may have a synergistic effect on the physiological activity of the above-mentioned physiologically active organic acid compound and functional alcohol compound, and has a moisturizing effect due to the molecular structure derived from glycerol, so that it can be used in cosmetics, health supplements, or pharmaceuticals. can be widely used in
2. 신규한 1,3-디글리세라이드 화합물 및 그의 제조방법2. Novel 1,3-diglyceride compound and its preparation method
상기 목적을 달성하기 위한 본 발명의 일 실시예는, 하기 일반식 1로 표시되는 신규한 글리세라이드 화합물이다.One embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 1.
[일반식 1][Formula 1]
상기 일반식 1에서 R1은 유기산 유래 치환기이고, R1-OH는 레티놀산, 퍼룰릭산, 알파-리포산, 코직산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R1-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다. In Formula 1, R 1 is an organic acid-derived substituent, R 1 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid, and H of R 1 -OH is It is a hydrogen atom with the lowest pKa in the molecular structure of the organic acid.
구체적으로, 상기 R1은 
, 
, 
, 
및 
로 이루어진 군에서 선택된 어느 하나이다.Specifically, the R 1 is , , , and It is any one selected from the group consisting of.
상기 목적을 달성하기 위한 본 발명의 다른 실시예는, 하기 일반식 2로 표시되는 신규한 글리세라이드 화합물이다.Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 2.
[일반식 2][Formula 2]
상기 일반식 2에서 R2는, 유기산 유래 치환기이고, R2-OH는 퍼룰릭산, 알파-리포산, 코직산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R2-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.In Formula 2, R 2 is a substituent derived from an organic acid, R 2 -OH is any one organic acid selected from the group consisting of ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid, and H of R 2 -OH is the organic acid is the hydrogen atom with the lowest pKa in the molecular structure of
구체적으로, 상기 R2는 
, 
, 
및 
로 이루어진 군에서 선택된 어느 하나이다.Specifically, the R 2 is , , and It is any one selected from the group consisting of.
상기 목적을 달성하기 위한 본 발명의 또 다른 실시예는, 하기 일반식 3으로 표시되는 신규한 글리세라이드 화합물이다.Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 3.
[일반식 3][Formula 3]
상기 일반식 3에서 R3은, 유기산 유래 치환기이고, R3-OH는 레티놀산, 퍼룰릭산, 알파-리포산, 코직산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R3-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.In Formula 3, R 3 is an organic acid-derived substituent, R 3 -OH is any one organic acid selected from the group consisting of retinol acid, ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid, and H of R 3 -OH is a hydrogen atom with the lowest pKa in the molecular structure of the organic acid.
구체적으로, 상기 R3은 
, 
, 
및 
로 이루어진 군에서 선택된 어느 하나이다.Specifically, the R 3 is , , and It is any one selected from the group consisting of.
즉, 본 발명에 따른 1,3-디글리세라이드 화합물은 하기 화학식 1 내지 14로 표시되는 화합물로 이루어진 군에서 선택된 어느 하나이다.That is, the 1,3-diglyceride compound according to the present invention is any one selected from the group consisting of compounds represented by Formulas 1 to 14 below.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
[화학식 8][Formula 8]
[화학식 9][Formula 9]
[화학식 10][Formula 10]
[화학식 11][Formula 11]
[화학식 12][Formula 12]
[화학식 13][Formula 13]
[화학식 14][Formula 14]
본 발명의 또 다른 실시예는 전술한 1,3-디글리세라이드 화합물의 제조방법이다.Another embodiment of the present invention is a method for preparing the 1,3-diglyceride compound described above.
본 발명의 일 실시예에 따른 1,3-디글리세라이드 화합물의 제조방법은, 하기 반응식 1과 같이 에피클로로하이드린, 생리활성 페놀 화합물, 테트라부틸암모늄 하이드로겐설페이트(Tetrabutylammonium Hydrogen Sulfate; TBAHS) 및 염기성 용액을 혼합하여 생리활성 페놀기가 결합된 에폭시 화합물을 제조하는 단계를 포함할 수 있다. A method for preparing a 1,3-diglyceride compound according to an embodiment of the present invention is epichlorohydrin, a physiologically active phenol compound, tetrabutylammonium hydrogen sulfate (TBAHS) and A step of preparing an epoxy compound to which a physiologically active phenol group is bound by mixing a basic solution may be included.
구체적으로, 상기 염기성 용액은 수산화칼륨 수용액 또는 수산화나트륨 수용액일 수 있고, 상기 생리활성 페놀 화합물의 산성인 수소 원자와 산-염기 반응을 진행할 수 있다. 다만 본 발명의 기술사상이 염기성 용액의 종류에 제한되는 것은 아니고, 상기 생리활성 페놀 화합물의 산성인 수소 원자를 제거할 수 있는 염기면 모두 적용될 수 있다.Specifically, the basic solution may be an aqueous solution of potassium hydroxide or an aqueous solution of sodium hydroxide, and may undergo an acid-base reaction with acidic hydrogen atoms of the physiologically active phenolic compound. However, the technical idea of the present invention is not limited to the type of basic solution, and any basic surface capable of removing acidic hydrogen atoms of the physiologically active phenolic compound can be applied.
상기 염기성 용액으로 수소가 제거된 상기 생리활성 페놀 화합물은 상기 에피클로로하이드린의 C-Cl 결합의 탄소를 공격하여 SN2 반응을 진행시킬 수 있다. 이후, 촉매인 Bu4NBr는 카르복실산 화합물과 양성자 교환(proton transfer) 반응을 함으로써, 수소가 제거된 카르복실산 화합물이 상기 페놀기가 결합된 에폭시 화합물을 쉽게 공격할 수 있도록 반응성을 향상시킬 수 있다. 즉, 상기 수소가 제거된 카르복실산 화합물은 상기 페놀기가 결합된 에폭시 화합물의 입체 장애가 작은 탄소를 공격하여 고리 열림(ring opening) 반응을 진행시킬 수 있다. 그 결과 1,3-디글리세라이드 화합물이 제조될 수 있다.The physiologically active phenolic compound from which hydrogen is removed by the basic solution may attack the carbon of the C-Cl bond of the epichlorohydrin to proceed with the SN 2 reaction. Thereafter, the catalyst, Bu 4 NBr, undergoes a proton transfer reaction with the carboxylic acid compound, so that the carboxylic acid compound from which hydrogen is removed can easily attack the epoxy compound to which the phenol group is bonded, so that the reactivity can be improved. have. That is, the carboxylic acid compound from which hydrogen is removed may attack carbon having a small steric hindrance in the epoxy compound to which the phenol group is bonded, thereby proceeding with a ring opening reaction. As a result, a 1,3-diglyceride compound can be produced.
[반응식 1][Scheme 1]
상기 반응식 1에서 Ra가 치환된 페놀 화합물은, 카바크롤, 알파-토코페롤 및 세사몰로 이루어진 군에서 선택된 어느 하나이고, Rb가 결합된 카르복실산 화합물은, 레티놀산, 퍼룰릭산, 살리실산 및 알파-리포산로 이루어진 군에서 선택된 어느 하나이다. 또한, 상기 반응식 1에 도시된 것과 달리, Rb가 결합된 카르복실산 화합물은 코직산으로 대체될 수 있다.In Scheme 1, the phenol compound in which R a is substituted is any one selected from the group consisting of carvacrol, alpha-tocopherol and sesamol, and the carboxylic acid compound to which R b is bonded is retinol acid, ferulic acid, salicylic acid and It is any one selected from the group consisting of alpha-lipoic acid. Also, unlike shown in Reaction Scheme 1, the carboxylic acid compound to which R b is bonded may be replaced with kojic acid.
3. 신규한 모노글리세라이드 화합물 및 그의 제조방법3. Novel monoglyceride compound and its preparation method
상기 목적을 달성하기 위한 본 발명의 또 다른 실시예는, 하기 일반식 4로 표시되는 신규한 글리세라이드 화합물이다.Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 4.
[일반식 4][Formula 4]
상기 일반식 4에서 R4는, 유기산 유래 치환기이고, R4-OH는 레티놀산, 퍼룰릭산 유래 아세테이트 유도체 및 살리실산 유래 아세테이트 유도체로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R4-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.In Formula 4, R 4 is an organic acid-derived substituent, R 4 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid-derived acetate derivatives, and salicylic acid-derived acetate derivatives, and the H of R 4 -OH is a hydrogen atom with the lowest pKa in the molecular structure of the organic acid.
본 명세서에서, 퍼룰릭산 유래 아세테이트 유도체는, 퍼룰릭산의 페놀기가 아세테이트로 치환된 유도체를 의미하는 것으로 정의된다.In the present specification, the acetate derivative derived from ferulic acid is defined to mean a derivative in which the phenol group of ferulic acid is substituted with acetate.
본 명세서에서, 살리실산 유래 아세테이트 유도체는, 살리실산의 페놀기가 아세테이트로 치환된 유도체를 의미하는 것으로 정의된다.In the present specification, an acetate derivative derived from salicylic acid is defined to mean a derivative in which the phenol group of salicylic acid is substituted with acetate.
상기 R4는, 
, 
및 
로 이루어진 군에서 선택된 어느 하나이다.The R 4 is, , and It is any one selected from the group consisting of.
즉, 본 발명에 따른 모노글리세라이드 화합물은, 하기 화학식 15 내지 17로 표시되는 화합물로 이루어진 군에서 선택된 어느 하나이다.That is, the monoglyceride compound according to the present invention is any one selected from the group consisting of compounds represented by Formulas 15 to 17 below.
[화학식 15][Formula 15]
[화학식 16][Formula 16]
[화학식 17][Formula 17]
본 발명의 또 다른 실시예는, (a) 하기 반응식 2-1과 같이 글리세롤과 벤즈알데하이드계 화합물을 혼합하여 상기 글리세롤에 보호기를 부착하는 단계, 하기 반응식 2-2와 같이, (b) 상기 보호기가 부착된 글리세롤과 제1 카르복실산 화합물을 혼합하여 에스테르 화합물을 제조하는 단계 및 (c) 상기 에스테르 화합물을 산성 조건에서 탈보호시켜 신규한 모노글리세라이드 화합물을 제조하는 단계를 포함할 수 있다. Another embodiment of the present invention, (a) mixing glycerol and a benzaldehyde-based compound as shown in Scheme 2-1 below and attaching a protecting group to the glycerol, as shown in Scheme 2-2 below, (b) the protecting group It may include preparing an ester compound by mixing glycerol to which is attached and a first carboxylic acid compound, and (c) preparing a novel monoglyceride compound by deprotecting the ester compound under acidic conditions.
상기 (a) 단계는, 글리세롤의 1번과 3번 탄소에 결합된 히드록시기가 벤즈알데하이드와 반응하여 아세탈 구조를 형성하는 단계로, 글리세롤의 2번 탄소에 결합된 히드록시기에서 후술할 에스터화 반응이 진행될 수 있도록 하는 단계이다.Step (a) is a step in which the hydroxyl group bonded to the 1st and 3rd carbons of glycerol reacts with benzaldehyde to form an acetal structure. This is a step that allows
상기 (b) 단계는 보호기가 부착된 글리세롤의 2번 탄소에 결합된 히드록시기와 제1 카르복실산 화합물이 반응하여 에스터 화합물이 생성되는 에스터화 반응이다. 상기 에스터화 반응은 예를 들어, DCC(N,N'-Dicyclohexylcarbodiimide)를 이용하여 온화한 조건에서 진행될 수 있다. 다만 본 발명의 기술사상이 이에 제한되는 것은 아니고 좋은 이탈기(good leaving group)를 상기 제1 카르복실산 화합물에 도입하여 에스터화 반응이 진행되는 반응이 가능할 수 있다.Step (b) is an esterification reaction in which an ester compound is generated by reacting the first carboxylic acid compound with a hydroxyl group bonded to carbon 2 of glycerol to which a protecting group is attached. The esterification reaction may be carried out under mild conditions using, for example, N,N'-Dicyclohexylcarbodiimide (DCC). However, the technical idea of the present invention is not limited thereto, and a reaction in which an esterification reaction proceeds may be possible by introducing a good leaving group into the first carboxylic acid compound.
상기 (c) 단계는 상기 에스터 화합물의 아세탈 작용기를 탈보호시키는 단계로 약한 산성 조건인 para-toluenesulfonic acid와 메탄올이 혼합된 산성 용액으로 탈보호시키는 단계일 수 있다. The step (c) is a step of deprotecting the acetal functional group of the ester compound, and may be a step of deprotecting the acetal functional group of the ester compound with an acidic solution in which para -toluenesulfonic acid, which is a weakly acidic condition, and methanol are mixed.
상기 벤즈알데하이드계 화합물은, 벤즈알데하이드 또는 벤즈알데하이드의알데하이드 작용기를 기준으로 파라 위치에 설포닐 치환기가 도입된 화합물에 해당할 수 있다. 구체적으로, 상기 설포닐 치환기는 벤젠설포닐기에 해당할 수 있다.The benzaldehyde-based compound may correspond to benzaldehyde or a compound in which a sulfonyl substituent is introduced at the para position based on the aldehyde functional group of benzaldehyde. Specifically, the sulfonyl substituent may correspond to a benzenesulfonyl group.
[반응식 2-1][Scheme 2-1]
[반응식 2-2][Scheme 2-2]
상기 반응식 2-2에서 Rc기가 결합된 카르복실산 화합물은 레티놀산, 퍼룰릭산 유래 아세테이트 유도체 및 살리실산 유래 아세테이트 유도체로 이루어진 군에서 선택된 어느 하나이다.In Scheme 2-2, the carboxylic acid compound to which the Rc group is bonded is any one selected from the group consisting of retinoic acid, ferulic acid-derived acetate derivatives, and salicylic acid-derived acetate derivatives.
4. 신규한 1,2-디글리세라이드 화합물 및 그의 제조방법4. Novel 1,2-diglyceride compound and its preparation method
상기 목적을 달성하기 위한 본 발명의 또 다른 실시예는, 하기 일반식 5로 표시되는 신규한 글리세라이드 화합물이다.Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 5.
[일반식 5][Formula 5]
상기 일반식 5에서 R5는, 유기산 유래 치환기이고, R5-OH는 퍼룰릭산, 알파-리포산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R5-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.In Formula 5, R 5 is a substituent derived from an organic acid, R 5 -OH is any organic acid selected from the group consisting of ferulic acid, alpha-lipoic acid, and salicylic acid, and H of R 5 -OH is a molecule of the organic acid. It is the hydrogen atom with the lowest pKa in the structure.
상기 R5는, 
, 
및 
로 이루어진 군에서 선택된 어느 하나이다.The R 5 is, , and It is any one selected from the group consisting of.
상기 목적을 달성하기 위한 본 발명의 또 다른 실시예는 하기 일반식 6으로 표시되는 신규한 글리세라이드 화합물이다.Another embodiment of the present invention for achieving the above object is a novel glyceride compound represented by the following general formula 6.
[일반식 6][Formula 6]
상기 일반식 6에서, R6은 유기산 유래 치환기이고, R6-OH는 레티놀산, 퍼룰릭산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R6-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.In Formula 6, R 6 is an organic acid-derived substituent, R 6 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid, and salicylic acid, and H of R 6 -OH is a molecular structure of the organic acid. is the hydrogen atom with the lowest pKa in
상기 R6은 
, 
및 
로 이루어진 군에서 선택된 어느 하나이다.The R 6 is , and It is any one selected from the group consisting of.
즉, 본 발명에 따른 1,2-디글리세라이드 화합물은 하기 화학식 18 내지 23으로 표시되는 화합물로 이루어진 군에서 선택된 어느 하나이다.That is, the 1,2-diglyceride compound according to the present invention is any one selected from the group consisting of compounds represented by Formulas 18 to 23 below.
[화학식 18][Formula 18]
[화학식 19][Formula 19]
[화학식 20][Formula 20]
[화학식 21][Formula 21]
[화학식 22][Formula 22]
[화학식 23][Formula 23]
본 발명의 또 다른 실시예는 (S1) 글리세롤과 벤즈알데하이드계 화합물을 혼합하여 상기 글리세롤에 보호기를 부착하는 단계, (S2) 상기 보호기가 부착된 글리세롤과, 제2 카르복실산 화합물을 혼합하여 에스테르 화합물을 제조하는 단계 및 (S3) 상기 에스테르 화합물을 탈보호시킨 뒤, 상기 탈보호된 에스테르 화합물을 제3 카르복실산 화합물과 혼합하여 1,2-디글리세라이드 화합물을 제조하는 단계를 포함하고, 상기 제2 및 제3 카르복실산 화합물은 각각 독립적으로, 레티놀산, 퍼룰릭산, 알파-리포산 및 살리실산으로 이루어진 군에서 선택된 어느 하나이고, 상기 제2 및 제3 카르복실산 화합물은 서로 상이한, 신규한 글리세라이드 화합물의 제조방법이다. 전술한 사항과 중복된 설명은 간략히 설명하거나 생략한다.Another embodiment of the present invention is (S1) mixing glycerol and a benzaldehyde-based compound and attaching a protecting group to the glycerol, (S2) mixing the glycerol to which the protecting group is attached and a second carboxylic acid compound to form an ester preparing a compound and (S3) deprotecting the ester compound and then mixing the deprotected ester compound with a third carboxylic acid compound to prepare a 1,2-diglyceride compound; The second and third carboxylic acid compounds are each independently selected from the group consisting of retinoic acid, ferulic acid, alpha-lipoic acid, and salicylic acid, and the second and third carboxylic acid compounds are different from each other. It is a method for preparing a glyceride compound. Descriptions overlapping with the foregoing will be briefly described or omitted.
상기 제2 카르복실산 화합물은 전술한 상기 제1 카르복실산 화합물과 서로 동일할 수 있다. 따라서, 상기 (S1) 단계는 상기 (a) 단계와 대응될 수 있고, 상기 (S2) 단계는 상기 (b) 단계와 대응될 수 있다.The second carboxylic acid compound may be the same as the first carboxylic acid compound described above. Accordingly, the step (S1) may correspond to the step (a), and the step (S2) may correspond to the step (b).
상기 (S3) 단계는 하기 반응식 2-3과 같이 탈보호된 에스테르 화합물이 Rd가 결합된 카르복실산 화합물과 반응하여 1,2-디글리세라이드 화합물을 제조하는 단계일 수 있다.The step (S3) may be a step of preparing a 1,2-diglyceride compound by reacting the deprotected ester compound with the carboxylic acid compound to which R d is bonded, as shown in Scheme 2-3 below.
[반응식 2-3][Scheme 2-3]
상기 1,2-디글리세라이드 화합물은, 하기 일반식 5로 표시되는 것이다.The 1,2-diglyceride compound is represented by the following general formula (5).
[일반식 5][Formula 5]
상기 일반식 5에서 R5는, 유기산 유래 치환기이고, R5-OH는 퍼룰릭산, 알파-리포산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R5-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.In Formula 5, R 5 is a substituent derived from an organic acid, R 5 -OH is any organic acid selected from the group consisting of ferulic acid, alpha-lipoic acid, and salicylic acid, and H of R 5 -OH is a molecule of the organic acid. It is the hydrogen atom with the lowest pKa in the structure.
상기 1,2-디글리세라이드 화합물은, 하기 일반식 6으로 표시되는 것이다.The 1,2-diglyceride compound is represented by the following general formula (6).
[일반식 6][Formula 6]
상기 일반식 6에서, R6은 유기산 유래 치환기이고, R6-OH는 레티놀산, 퍼룰릭산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R6-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.In Formula 6, R 6 is an organic acid-derived substituent, R 6 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid, and salicylic acid, and H of R 6 -OH is a molecular structure of the organic acid. is the hydrogen atom with the lowest pKa in
본 발명에 따르면, 글리세롤과 생리활성 유기산 및 기능성 알코올류 화합물의 조합에 의해 상기 생리활성 유기산의 피부 독성을 제거하고 생리활성 유기산 및 기능성 알코올류 화합물의 생리활성에 대한 시너지 효과를 기대할 수 있다. 또한, 본 발명에 따르면 글리세롤의 히드록시기를 통한 피부 보습 효과를 가짐으로써, 기존의 화장품 원료보다 생리활성, 보습 및 피부 침투 효과 부분에서 개선된 신규한 글리세라이드 화합물을 제공할 수 있다. 추가적으로, 이러한 신규한 글리세라이드 화합물을 화장품 분야뿐만 아니라 건강보조식품 또는 의약품 분야로 확장시킬 수 있다.According to the present invention, by combining glycerol with a physiologically active organic acid and a functional alcohol compound, skin toxicity of the physiologically active organic acid can be removed and a synergistic effect on the physiological activity of the physiologically active organic acid and functional alcohol compound can be expected. In addition, according to the present invention, by having a skin moisturizing effect through the hydroxyl group of glycerol, it is possible to provide a novel glyceride compound improved in terms of physiological activity, moisturizing effect and skin penetration effect compared to existing cosmetic raw materials. Additionally, these novel glyceride compounds can be extended not only to the cosmetic field but also to the health supplement or pharmaceutical field.
상술한 효과와 더불어 본 발명의 구체적인 효과는 이하 발명을 실시하기 위한 구체적인 내용을 설명하면서 함께 기술한다.In addition to the above effects, specific effects of the present invention will be described together while explaining specific details for carrying out the present invention.
이하, 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본 발명의 각 구성을 보다 상세히 설명하나, 이는 하나의 예시에 불과할 뿐, 본 발명의 권리범위가 다음 내용에 의해 제한되지 아니한다.Hereinafter, each configuration of the present invention will be described in more detail so that those skilled in the art can easily practice it, but this is only one example, and the scope of the present invention is Not limited.
1. 신규한 1,3-디글리세라이드 화합물 및 그의 제조방법1. Novel 1,3-diglyceride compound and its preparation method
본 발명의 일 실시예는 신규한 1,3-글리세라이드 화합물 및 그의 제조방법이다.One embodiment of the present invention is a novel 1,3-glyceride compound and a method for preparing the same.
[실시준비예 1: 제1 에폭사이드 화합물의 합성][Example 1: Synthesis of the first epoxide compound]
실시준비예 1은 하기 화학식 1a로 표시되는 화합물이다. Preparation Example 1 is a compound represented by Formula 1a below.
[화학식 1a][Formula 1a]
상기 실시준비예 1은, 제1 에폭사이드 화합물로 다음과 같은 방법으로 합성된다.Preparation Example 1 was synthesized as a first epoxide compound in the following manner.
100 mL 둥근 플라스크에 에피클로로하이드린 (1.39 g, 15.0 mmol), 카바크롤 (1.50 g, 9.99 mmol), 테트라부틸암모늄 하이드로겐설페이트 (340 mg, 1.00 mmol)를 순차적으로 넣는다. 용기를 0℃의 얼음 물에 담근 뒤 50% KOH 수용액 (2.6 mL)을 가한 다음 bath를 제거하고 실온에서 4시간 동안 교반한다. 반응 혼합물에 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 투명한 액체의 상기 실시준비예 1(1.24 mg, 6.00 mmol)을 60%의 수율로 얻을 수 있었다.Into a 100 mL round flask, put epichlorohydrin (1.39 g, 15.0 mmol), carvacrol (1.50 g, 9.99 mmol), and tetrabutylammonium hydrogen sulfate (340 mg, 1.00 mmol) sequentially. After immersing the container in ice water at 0 ° C, 50% KOH aqueous solution (2.6 mL) was added, the bath was removed, and the mixture was stirred at room temperature for 4 hours. The reaction was terminated by adding H 2 O to the reaction mixture, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Preparation Example 1 (1.24 mg, 6.00 mmol) as a clear liquid in a yield of 60%.
[Data] [Data]
Rf = 0.70 (4:1 hexane/EtOAc). 1H-NMR δ = 1.23 (d, J = 6.8 Hz, 6H), 2.21 (s, 3H), 2.79 (dd, J = 4.8, 2.8 Hz, 1H), 2.85 (heptet, J = 6.8 Hz, 1H), 2.91 (dd, J = 4.8, 4.0 Hz, 1H), 3.37 (dddd, J = 5.2, 4.0, 3.6, 2.8 Hz, 1H), 4.00 (dd, J = 10.8, 5.2 Hz, 1H), 4.21 (dd, J = 10.8, 3.6 Hz, 1H), 6.69 (d, J = 1.6 Hz, 1H), 6.76 (dd, J = 7.2, 1.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H) ppm.R f = 0.70 (4:1 hexane/EtOAc). 1H - NMR δ = 1.23 (d, J = 6.8 Hz, 6H), 2.21 (s, 3H), 2.79 (dd, J = 4.8, 2.8 Hz, 1H), 2.85 (heptet, J = 6.8 Hz, 1H) , 2.91 (dd, J = 4.8, 4.0 Hz, 1H), 3.37 (dddd, J = 5.2, 4.0, 3.6, 2.8 Hz, 1H), 4.00 (dd, J = 10.8, 5.2 Hz, 1H), 4.21 (dd , J = 10.8, 3.6 Hz, 1H), 6.69 (d, J = 1.6 Hz, 1H), 6.76 (dd, J = 7.2, 1.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H) ppm.
(1) 실시예 1(1) Example 1
2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propyl (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propyl (2 E ,4 E ,6 E ,8 E )-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en -1-yl)nona-2,4,6,8-tetraenoate
실시예 1은 하기 화학식 1로 표시되는 화합물이다.Example 1 is a compound represented by Formula 1 below.
[화학식 1][Formula 1]
[합성예 1][Synthesis Example 1]
100 mL 둥근 플라스크에 상기 실시준비예 1 (541 mg, 2.62 mmol), 레티놀산 (787 mg, 2.62 mmol)과 테트라부틸암모늄 브로마이드 (85 mg, 0.26 mmol)를 넣고 THF (20 mL)에 녹인 다음 24시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 노란색 액체의 실시예 1(822 mg, 1.62 mmol)을 62%의 수율로 얻을 수 있었다.Put Example 1 (541 mg, 2.62 mmol), retinol acid (787 mg, 2.62 mmol) and tetrabutylammonium bromide (85 mg, 0.26 mmol) in a 100 mL round flask, dissolve in THF (20 mL), and then 24 Heat at reflux for an hour. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 1 (822 mg, 1.62 mmol) as a yellow liquid in a yield of 62%.
[Data][Data]
Rf
= 0.38 (4:1 hexane/EtOAc) 1H-NMR δ = 1.03 (s, 6H), 1.24 (d, J = 7.2 Hz, 6H), 1.44-1.50 (m, 2H), 1.57-1.66 (m, 2H), 1.71 (s, 3H), 1.99-2.06 (m, 2H), 2.01 (s, 3H), 2.20 (s, 3H), 2.37 (s, 3H), 2.66 (br s, 1H), 2.86 (septet, J = 7.2 Hz, 1H), 4.03-4.09 (m, 2H), 4.25-4.33 (m, 1H), 4.34 (d of A of ABq, JAB = 11.6, Jd = 5.6 Hz, 1H), 4.39 (d of B of ABq, JAB = 11.6, Jd = 4.0 Hz, 1H), 5.83 (s, 1H), 6.14 (d, J = 15.2 Hz, 1H), 6.15 (d, J = 11.2 Hz, 1H), 6.29 (d, J = 15.2 Hz, 2H), 6.70 (d, J = 1.6 Hz, 1H), 6.77 (dd, J = 7.6, 1.6 Hz, 1H), 7.03 (dd, J = 15.2, 11.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H) ppm. 13C-NMR δ = 12.8, 13.9, 15.7, 19.1, 21.6, 24.0, 24.0, 28.9, 33.0, 34.0, 34.1, 39.5, 64.8, 68.6, 68.8, 109.6, 117.4, 118.6, 124.0, 128.8, 129.3, 130.0, 130.5, 131.4, 134.7, 137.1, 137.6, 139.9, 147.9, 154.0, 156.2, 167.2 ppm. IR 3477, 2959, 2926, 2870, 1707, 1615, 1588, 1518, 1459, 1426, 1396, 1362, 1248, 1147, 1055, 966, 881, 855, 822, 763, 741, 674, 647 cm-1. HRMS (ESI) calcd for C33H46O4+Na 529.3288, found 529.3293.R f = 0.38 (4: 1 hexane/EtOAc) 1H-NMR δ = 1.03 (s, 6H), 1.24 (d, J = 7.2 Hz, 6H), 1.44-1.50 (m, 2H), 1.57-1.66 (m, 2H), 1.71 (s, 3H), 1.99-2.06 (m, 2H), 2.01 (s, 3H), 2.20 (s, 3H), 2.37 (s, 3H), 2.66 (br s, 1H), 2.86 ( septet, J = 7.2 Hz, 1H), 4.03–4.09 (m, 2H), 4.25–4.33 (m, 1H), 4.34 (d of A of ABq, JAB = 11.6, Jd = 5.6 Hz, 1H), 4.39 ( d of B of ABq, JAB = 11.6, Jd = 4.0 Hz, 1H), 5.83 (s, 1H), 6.14 (d, J = 15.2 Hz, 1H), 6.15 (d, J = 11.2 Hz, 1H), 6.29 (d, J = 15.2 Hz, 2H), 6.70 (d, J = 1.6 Hz, 1H), 6.77 (dd, J = 7.6, 1.6 Hz, 1H), 7.03 (dd, J = 15.2, 11.2 Hz, 1H) , 7.06 (d, J = 7.6 Hz, 1 H) ppm. 13 C-NMR Δ = 12.8, 13.9, 15.7, 19.1, 21.6, 24.0, 24.0, 28.9, 33.0, 34.0, 34.1, 39.5, 64.8, 68.6, 68.8, 109.6, 117.4, 118.6, 124.8, 128.8, 129.3, 129.3, 129.3 130.5, 131.4, 134.7, 137.1, 137.6, 139.9, 147.9, 154.0, 156.2, 167.2 ppm. IR 3477, 2959, 2926, 2870, 1707, 1615, 1588, 1518, 1459, 1426, 1396, 1362, 1248, 1147, 1055, 966, 881, 855, 822, 763, 741, 47 cm -1 6.674, HRMS (ESI) calcd for C 33 H 46 O 4 +Na 529.3288, found 529.3293.
(2) 실시예 2(2) Example 2
2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propyl ( E )-3-(4-hydroxy-3-methoxyphenyl)acrylate
실시예 2는 하기 화학식 2로 표시되는 화합물이다.Example 2 is a compound represented by Formula 2 below.
[화학식 2][Formula 2]
[합성예 2][Synthesis Example 2]
50 mL 둥근 플라스크에 상기 실시준비예 1(1.30 g, 6.30 mmol), 퍼룰릭산 (1.35 mg, 6.93 mmol)과 테트라부틸암모늄 브로마이드 (203 mg, 0.63 mmol)를 넣고 THF (20 mL)에 녹인 다음 24시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 연한 노란색 액체의 실시예 2(1.00 g, 2.50 mmol)를 40%의 수율로 얻을 수 있었다.Into a 50 mL round flask, Example 1 (1.30 g, 6.30 mmol), ferulic acid (1.35 mg, 6.93 mmol) and tetrabutylammonium bromide (203 mg, 0.63 mmol) were dissolved in THF (20 mL) and then 24 Heat at reflux for an hour. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 2 (1.00 g, 2.50 mmol) as a pale yellow liquid in a yield of 40%.
[Data][Data]
Rf = 0.43 (3:2 hexane/EtOAc). 1H-NMR δ = 1.24 (d, J = 7.2 Hz, 6H), 2.21 (s, 3H), 2.85 (d, J = 5.2 Hz, 1H), 2.86 (heptet, J = 7.2 Hz, 1H), 3.91 (s, 3H), 4.10 (dd, J = 5.6, 1.2 Hz, 2H), 4.30-4.37 (m, 1H), 4.42 (d of A of ABq, JAB = 11.2, Jd = 5.6 Hz, 1H), 4.48 (d of B of ABq, JAB = 11.2, Jd = 4.4 Hz, 1H), 6.05 (s, 1H), 6.33 (d, J = 16.0 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.77 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0, 1.6 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H) ppm. 13C-NMR δ = 15.8, 24.1, 24.1, 34.0, 55.9, 65.5, 68.6, 68.9, 109.4, 109.7, 114.6, 114.8, 118.8, 123.2, 124.0, 126.7, 130.6, 145.7, 146.8, 148.1, 148.2, 156.2, 167.5 ppm. IR 3432, 3022, 2965, 2867, 1703, 1631, 1591, 1517, 1461, 1429, 1384, 1253, 1160, 1133, 1030, 981, 950, 853, 824, 752, 670, 648 cm-1. HRMS(ESI) calcd for C23H28O6+Na 423.1778, found 423.1783.R f = 0.43 (3:2 hexane/EtOAc). 1H - NMR δ = 1.24 (d, J = 7.2 Hz, 6H), 2.21 (s, 3H), 2.85 (d, J = 5.2 Hz, 1H), 2.86 (heptet, J = 7.2 Hz, 1H), 3.91 (s, 3H), 4.10 (dd, J = 5.6, 1.2 Hz, 2H), 4.30–4.37 (m, 1H), 4.42 (d of A of ABq, JAB = 11.2, Jd = 5.6 Hz, 1H), 4.48 (d of B of ABq, JAB = 11.2, Jd = 4.4 Hz, 1H), 6.05 (s, 1H), 6.33 (d, J = 16.0 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.77 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0, 1.6 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H) ppm. 13 C-NMR Δ = 15.8, 24.1, 24.1, 34.0, 55.9, 65.5, 68.6, 68.9, 109.4, 109.7, 114.6, 114.8, 118.8, 123.2, 124.0, 126.7, 130.6, 145.7, 146.8, 148.1, 148.2, 146.2 167.5 ppm. IR 3432, 3022, 2965, 2867, 1703, 1631, 1591, 1517, 1461, 1429, 1384, 1253, 1160, 1133, 1030, 981, 950, 853, 824, 752, 670, 648 cm -1 . HRMS (ESI) calcd for C 23 H 28 O 6 +Na 423.1778, found 423.1783.
(3) 실시예 3(3) Example 3
2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propyl 5-((R)-1,2-dithiolan-3-yl)pentanoate2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propyl 5-(( R )-1,2-dithiolan-3-yl)pentanoate
실시예 3은 하기 화학식 3으로 표시되는 화합물이다.Example 3 is a compound represented by Formula 3 below.
[화학식 3][Formula 3]
[합성예 3][Synthesis Example 3]
250 mL 둥근 플라스크에 상기 실시준비예 1(980 mg, 4.75 mmol), 알파-리포산 (980 mg, 4.75 mmol)과 테트라부틸암모늄 브로마이드 (306 mg, 0.95 mmol)를 넣고 THF (10 mL)에 녹인 다음 10시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 연한 노란색 액체의 실시예 3(530 mg, 1.28 mmol)을 27%의 수율로 얻을 수 있었다.Put Example 1 (980 mg, 4.75 mmol), alpha-lipoic acid (980 mg, 4.75 mmol) and tetrabutylammonium bromide (306 mg, 0.95 mmol) in a 250 mL round flask and dissolve in THF (10 mL). Heat at reflux for 10 hours. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 3 (530 mg, 1.28 mmol) as a pale yellow liquid in a yield of 27%.
[Data][Data]
Rf = 0.19 (4:1 hexane/EtOAc) 1H-NMR δ = 1.24 (d, J = 7.2 Hz, 6H), 1.40-1.56 (m, 2H), 1.62-1.75 (m, 4H), 1.85-1.95 (m, 1H), 2.19 (s, 3H), 2.39 (dd, J = 7.6, 7.2 Hz, 2H), 2.37-2.49 (m, 1H), 2.52 (d, J = 4.8 Hz, 1H), 2.87 (heptet, J = 7.2 Hz, 1H), 3.07-3.21 (m, 2H), 3.50-3.60 (m, 1H), 4.01-4.08 (m, 2H), 4.10-4.18 (m, 1H), 4.22-4.38 (m, 2H), 6.69 (d, J = 1,6 Hz, 1H), 6.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H) ppm. 13C-NMR δ = 15.3, 23.7, 23.7, 24.1, 28.1, 33.4, 33.5, 34.0, 37.9, 39.7, 55.7, 64.9, 68.0, 68.2, 109.1, 118.1, 123.4, 130.0, 147.4, 155.9, 173.1 ppm. IR 3496, 2963, 2929, 2873, 1738, 1615, 1585, 1515, 1456, 1423, 1257, 1181, 1129, 1049, 1000, 949, 913, 852, 816, 760, 734, 647 cm-1.HRMS (ESI): calcd for C21H32O4S2+Na 435.1634, found 435.1639.R f = 0.19 (4:1 hexane/EtOAc) 1 H-NMR δ = 1.24 (d, J = 7.2 Hz, 6H), 1.40-1.56 (m, 2H), 1.62-1.75 (m, 4H), 1.85- 1.95 (m, 1H), 2.19 (s, 3H), 2.39 (dd, J = 7.6, 7.2 Hz, 2H), 2.37-2.49 (m, 1H), 2.52 (d, J = 4.8 Hz, 1H), 2.87 (heptet, J = 7.2 Hz, 1H), 3.07-3.21 (m, 2H), 3.50-3.60 (m, 1H), 4.01-4.08 (m, 2H), 4.10-4.18 (m, 1H), 4.22-4.38 (m, 2H), 6.69 (d, J = 1,6 Hz, 1H), 6.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H) ppm. 13 C-NMR δ = 15.3, 23.7, 23.7, 24.1, 28.1, 33.4, 33.5, 34.0, 37.9, 39.7, 55.7, 64.9, 68.0, 68.2, 109.1, 118.1, 123.4, 130.4, 1.57.0, 147 ppm IR 3496, 2963, 2929, 2873, 1738, 1615, 1585, 1515, 1456, 1423, 1257, 1181, 1129, 1049, 1000, 949, 913, 852, 816, 760, 734, 647 cm ESI): calcd for C 21 H 32 O 4 S 2 +Na 435.1634, found 435.1639.
(4) 실시예 4(4) Example 4
5-(2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propoxy)-2-(hydroxymethyl)-4H-pyran-4-one5-(2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propoxy)-2-(hydroxymethyl) -4H -pyran-4-one
실시예 4는 하기 화학식 4로 표시되는 화합물이다.Example 4 is a compound represented by Formula 4 below.
[화학식 4][Formula 4]
[합성예 4][Synthesis Example 4]
100 mL 둥근 플라스크에 상기 실시준비예 1(500 mg, 2.42 mmol), 코직산 (344 mg, 2.42 mmol)과 테트라부틸암모늄 브로마이드 (234 mg, 0.73 mmol)를 넣고 THF (7 mL)에 녹인 다음 4시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 연노랑색 액체의 실시예 4(77 mg, 0.22 mmol)를 9%의 수율로 얻을 수 있었다.Into a 100 mL round flask, Example 1 (500 mg, 2.42 mmol), kojic acid (344 mg, 2.42 mmol) and tetrabutylammonium bromide (234 mg, 0.73 mmol) were dissolved in THF (7 mL) and then stirred for 4 hours. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 4 (77 mg, 0.22 mmol) as a pale yellow liquid in a yield of 9%.
[Data][Data]
Rf = 0.2 (3:2 EtOAc/Acetone). 1H-NMR δ = 1.23 (d, J = 6.8 Hz, 6H), 2.17 (s, 3H), 2.85 (heptet, J = 6.8 Hz, 1H), 4.03 (d of A of ABq, JAB= 9.6, Jd = 6.4 Hz, 1H), 4.07 (d of B of ABq, JAB= 9.6, Jd = 7.2 Hz, 1H), 4.12-4.18 (m, 2H), 4.32-4.39 (m, 1H), 4.47 (s, 2H), 5.15 (br s, 1H), 6.56 (s, 1H), 6.72 (d, J = 1,6 Hz), 6.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H) ppm. 13C-NMR δ = 15.8, 24.0, 24.0, 34.0, 60.4, 67.9, 68.4, 72.4, 109.5, 111.7, 118.5, 123.8, 130.4, 141.1, 147.5, 148.0, 156.3, 168.6, 175.4 ppm. IR 3355, 3092, 3018, 2959, 2870, 1647, 1614, 1514, 1459, 1422, 1340, 1266, 1214, 1181, 1137, 1048, 948, 918, 874, 825, 766, 740, 677, 644 cm-1. HRMS (ESI): calcd for C19H24O6+Na 371.1465, found 371.1469.R f = 0.2 (3:2 EtOAc/Acetone). 1H - NMR δ = 1.23 (d, J = 6.8 Hz, 6H), 2.17 (s, 3H), 2.85 (heptet, J = 6.8 Hz, 1H), 4.03 (d of A of ABq, J AB = 9.6, Jd = 6.4 Hz, 1H), 4.07 (d of B of ABq, J AB = 9.6, Jd = 7.2 Hz, 1H), 4.12-4.18 (m, 2H), 4.32-4.39 (m, 1H), 4.47 (s) , 2H), 5.15 (br s, 1H), 6.56 (s, 1H), 6.72 (d, J = 1,6 Hz), 6.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H) ppm. 13 C-NMR δ = 15.8, 24.0, 24.0, 34.0, 60.4, 67.9, 68.4, 72.4, 109.5, 111.7, 118.5, 123.8, 130.4, 141.1, 147.5, 148.0, 156.3, 168.6 ppm IR 3355, 3092, 3018, 2959, 2870, 1647, 1614, 1514, 1459, 1422, 1340, 1266, 1214, 1181, 1137, 1048, 948, 918, 874, 825, 766, 6 cm -770 , 6 cm 1 . HRMS (ESI): calcd for C 19 H 24 O 6 +Na 371.1465, found 371.1469.
(5) 실시예 5(5) Example 5
2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propyl 2-hydroxybenzoate2-Hydroxy-3-(5-isopropyl-2-methylphenoxy)propyl 2-hydroxybenzoate
실시예 5는 하기 화학식 5로 표시되는 화합물이다.Example 5 is a compound represented by Formula 5 below.
[화학식 5][Formula 5]
[합성예 5][Synthesis Example 5]
250 mL 둥근 플라스크에 상기 실시준비예 1(1.64 g, 7.95 mmol), 살리실산 (157 mg, 5.68 mmol)과 테트라부틸암모늄 브로마이드 (367 mg, 1.14 mmol)를 넣고 THF (5 mL)에 녹인 다음 하루 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 투명한 액체의 실시예 5(1.53 g, 4.45 mmol)를 56%의 수율로 얻을 수 있었다.Into a 250 mL round flask, Example 1 (1.64 g, 7.95 mmol), salicylic acid (157 mg, 5.68 mmol) and tetrabutylammonium bromide (367 mg, 1.14 mmol) were added and dissolved in THF (5 mL) for one day. Heat to reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 5 (1.53 g, 4.45 mmol) as a clear liquid in a yield of 56%.
[Data][Data]
Rf = 0.3 (4:1 hexane/EtOAc). 1H-NMR δ = 1.24 (d, J = 7.2 Hz, 6H), 2.21 (s, 3H), 2.56 (d, J = 5.2 Hz, 1H), 2.87 (heptet, J = 7.2 Hz, 1H), 4.12 (d of A of ABq, JAB = 9.2, Jd = 6.0 Hz, 1H), 4.16 (d of B of ABq, JAB = 9.2, Jd = 4.8 Hz, 1H), 4.42 (sextet, J = 5.2 Hz, 1H), 4.57 (d of A of ABq, JAB = 11.6, Jd = 6.0 Hz, 1H), 4.61 (d of B of ABq, JAB= 11.6, Jd= 4.8 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 6.79 (dd, J = 7.4, 1.6 Hz, 1H), 6.89 (ddd, J = 8.0, 7.4, 1.6 Hz, 1H), 7.00 (dd, J = 8.0, 0.8 Hz, 1H), 7.08 (dd, J = 8.0, 0.8 Hz, 1H), 7.48 (ddd, J = 8.0, 7.4, 1.6 Hz, 1H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 10.64 (s, 1H) ppm. 13C-NMR δ = 15.9, 24.1, 24.1, 34.1, 66.1, 68.6, 68.6, 109.7, 112.1, 117.7, 119.0, 119.3, 124.1, 130.0, 130.7, 136.0, 148.2, 156.2, 161.7, 170.1 ppm. IR 3457, 3212. 3055, 3020, 2964, 2929, 2873, 1680, 1619, 1586, 1461, 1423, 1333, 1295, 1255, 1215, 1186, 1165, 1135, 1087, 1050, 997, 938, 911, 847, 818, 762, 706, 669, 647 cm-1.R f = 0.3 (4:1 hexane/EtOAc). 1H - NMR δ = 1.24 (d, J = 7.2 Hz, 6H), 2.21 (s, 3H), 2.56 (d, J = 5.2 Hz, 1H), 2.87 (heptet, J = 7.2 Hz, 1H), 4.12 (d of A of ABq, J AB = 9.2, Jd = 6.0 Hz, 1H), 4.16 (d of B of ABq, J AB = 9.2, J d = 4.8 Hz, 1H), 4.42 (sextet, J = 5.2 Hz) , 1H), 4.57 (d of A of ABq, J AB = 11.6, Jd = 6.0 Hz, 1H), 4.61 (d of B of ABq, J AB = 11.6, J d = 4.8 Hz, 1H), 6.71 (d , J = 1.6 Hz, 1H), 6.79 (dd, J = 7.4, 1.6 Hz, 1H), 6.89 (ddd, J = 8.0, 7.4, 1.6 Hz, 1H), 7.00 (dd, J = 8.0, 0.8 Hz, 1H), 7.08 (dd, J = 8.0, 0.8 Hz, 1H), 7.48 (ddd, J = 8.0, 7.4, 1.6 Hz, 1H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 10.64 (s , 1H) ppm. 13 C-NMR δ = 15.9, 24.1, 24.1, 34.1, 66.1, 68.6, 68.6, 109.7, 112.1, 117.7, 119.0, 119.3, 124.1, 130.0, 130.7, 136.0, 148.2, 116.2, 156.2, ppm IR 3457, 3212. 3055, 3020, 2964, 2929, 2873, 1680, 1619, 1586, 1461, 1423, 1333, 1295, 1255, 1215, 1186, 1165, 1135, 1087, 9, 9070, , 818, 762, 706, 669, 647 cm -1 .
[실시준비예 2: 제2 에폭사이드 화합물의 합성][Example 2: Synthesis of second epoxide compound]
실시준비예 2는 하기 화학식 2a로 표시되는 화합물이다.Preparation Example 2 is a compound represented by Formula 2a below.
[화학식 2a][Formula 2a]
상기 실시준비예 2는, 제2 에폭사이드 화합물로 다음과 같은 방법으로 합성된다.Preparation Example 2 was synthesized as a second epoxide compound in the following manner.
50 mL 둥근 플라스크에 에피클로로하이드린 (870 mg, 9.44 mmol), 알파-토코페롤 (2.71 mg, 6.29 mmol), 테트라부틸암모늄 하이드로겐설페이트 (215 mg, 0.57 mmol)를 순차적으로 넣는다. 용기를 0℃ 얼음 물에 담근 뒤 50% KOH 수용액 (3.5 mL)을 가한 다음 bath를 제거하고 실온에서 7시간 동안 교반한다. 반응 혼합물에 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 연한 주황색 액체의 실시준비예 2(2.67 g, 5.49 mmol)를 87%의 수율로 얻을 수 있었다.In a 50 mL round flask, epichlorohydrin (870 mg, 9.44 mmol), alpha-tocopherol (2.71 mg, 6.29 mmol), and tetrabutylammonium hydrogen sulfate (215 mg, 0.57 mmol) are sequentially put. After immersing the container in ice water at 0 ° C, 50% KOH aqueous solution (3.5 mL) was added, the bath was removed, and the mixture was stirred at room temperature for 7 hours. The reaction was terminated by adding H 2 O to the reaction mixture, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Preparation Example 2 (2.67 g, 5.49 mmol) as a pale orange liquid in a yield of 87%.
[Data][Data]
Rf = 0.7 (4:1 hexane/EtOAc); 1H NMR d 0.84 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 6H), 1.00-1.60 (m, 21 H), 1.23 (s, 3H), 1.71-1.85 (m, 2H), 2.08 (s, 3H), 2.14 (s, 3H), 2.18 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.70 (dd, J = 5.0, 2.6 Hz, 1H), 2.87 (dd, J = 5.0, 4.0 Hz, 1H), 3.35 (dddd, J = 5.8, 4.0, 3.2, 2.6 Hz, 1H), 3.66 (ddd, J = 11.0, 5.8, 1.8 Hz, 1H), 3.90 (ddd, J = 11.0, 3.2, 1.6 Hz, 1H) ppm; 13C NMR d 14.2, 14.2, 15.1, 22.1, 22.1, 23.0, 23.4, 25.0, 25.1, 26.3, 26.8, 27.2, 30.4, 33.6, 35.1, 35.2, 39.7, 39.8, 39.9, 40.0, 41.8, 42.4, 47.0, 52.9, 76.1, 77.2, 120.0, 125.3, 128.1, 130.1, 150.2, 150.4 ppm; IR (KBr) 2924, 2866, 1458, 1404, 1377, 1253, 1157, 1088, 1018, 910, 852, 737 cm-1; HRMS (FAB+) calcd for C32H54O3 486.4073, found 486.4070.R f = 0.7 (4:1 hexane/EtOAc); 1H NMR d 0.84 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 6H), 1.00-1.60 (m, 21 H), 1.23 (s, 3H), 1.71-1.85 (m, 2H), 2.08 (s, 3H), 2.14 (s, 3H), 2.18 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.70 (dd, J = 5.0, 2.6 Hz, 1H), 2.87 (dd, J = 5.0, 4.0 Hz, 1H), 3.35 (dddd, J = 5.8, 4.0, 3.2, 2.6 Hz, 1H), 3.66 (ddd, J = 11.0, 5.8, 1.8 Hz, 1H), 3.90 (ddd, J = 11.0, 3.2, 1.6 Hz, 1H) ppm; 13 C NMR d 14.2, 14.2, 15.1, 22.1, 22.1, 23.0, 23.4, 25.0, 25.1, 26.3, 26.8, 27.2, 30.4, 33.6, 35.1, 35.2, 39.7, 39.8, 39.9, 4 7.0.9, 4 40.0 52.9, 76.1, 77.2, 120.0, 125.3, 128.1, 130.1, 150.2, 150.4 ppm; IR (KBr) 2924, 2866, 1458, 1404, 1377, 1253, 1157, 1088, 1018, 910, 852, 737 cm -1 ; HRMS (FAB+) calcd for C 32 H 54 O 3 486.4073, found 486.4070.
(6) 실시예 6(6) Example 6
2-Hydroxy-3-((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxy)propyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate2-Hydroxy-3-((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxy)propyl ( E )-3-(4-hydroxy-3 -methoxyphenyl)acrylate
실시예 6은 하기 화학식 6으로 표시되는 화합물이다.Example 6 is a compound represented by Formula 6 below.
[화학식 6][Formula 6]
[합성예 6][Synthesis Example 6]
250 mL 둥근 플라스크에 상기 실시준비예 2(1.10 g, 2.27 mmol), 퍼롤릭산 (441 mg, 2.27 mmol)과 테트라부틸암모늄 브로마이드 (73 mg, 0.23 mmol)를 넣고 THF (5 mL)에 녹인 다음 20시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시예 6(200 mg, 0.30 mmol)을 13%의 수율로 얻을 수 있었다.Into a 250 mL round flask, Example 2 (1.10 g, 2.27 mmol), perolic acid (441 mg, 2.27 mmol) and tetrabutylammonium bromide (73 mg, 0.23 mmol) were dissolved in THF (5 mL) and then dissolved in 20 mL. Heat at reflux for an hour. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 6 (200 mg, 0.30 mmol) in a yield of 13%.
[Data][Data]
Rf = 0.67 (3:2 hexane/EtOAc). 1H-NMR δ = 0.84 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.4 Hz, 6H), 1.00-1.56 (m, 21H), 1.23 (s, 3H), 1.71-1.86 (m, 2H), 2.08 (s, 3H), 2.14 (s, 3H), 2.18 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.75 (d, J = 5.2 Hz, 1H), 3.74-3.81 (m, 2H), 3.94 (s, 3H), 4.31 (sextet, J = 5.0 Hz, 1H), 4.42 (d of A of ABq, JAB = 11.6, Jd = 6.0 Hz, 1H), 4.47 (d of B of ABq, JAB= 11.6, Jd = 4.8 Hz, 1H), 5.86 (s, 1H), 6.34 (d, J = 16.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 7.66 (d, J = 16.0 Hz, 1H) ppm. 13C-NMR δ = 11.6, 11.6, 12.5, 19.5, 20.4, 20.8, 22.5, 22.6, 23.6, 24.2, 24.6, 27.8, 31.0, 31.1, 32.5, 32.6, 37.1, 37.2, 37.3, 39.2, 39.8, 39.9, 55.6, 65.3, 69.2, 73.0, 74.6, 109.5, 114.4, 114.8, 117.4, 122.8, 122.9, 125.4, 126.5, 127.4, 145.5, 146.8, 147.2, 147.8, 148.2, 167.3 ppm. IR 3538, 3419, 2928, 2872, 1704, 1638, 1599, 1519, 1463, 1435, 1383, 1262, 1218, 1167, 1118, 1087, 1038, 982, 912, 851, 820, 758, 740, 673, 648 cm-1. HRMS (ESI) calcd for C42H64O7+Na 703.4544, found 703.4549.R f = 0.67 (3:2 hexane/EtOAc). 1H - NMR δ = 0.84 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.4 Hz, 6H), 1.00-1.56 (m, 21H) , 1.23 (s, 3H), 1.71–1.86 (m, 2H), 2.08 (s, 3H), 2.14 (s, 3H), 2.18 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.75 (d, J = 5.2 Hz, 1H), 3.74-3.81 (m, 2H), 3.94 (s, 3H), 4.31 (sextet, J = 5.0 Hz, 1H), 4.42 (d of A of ABq, J AB = 11.6, Jd = 6.0 Hz, 1H), 4.47 (d of B of ABq, J AB = 11.6, Jd = 4.8 Hz, 1H), 5.86 (s, 1H), 6.34 (d, J = 16.0 Hz, 1H) , 6.93 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 7.66 (d, J = 16.0 Hz, 1H) ppm. 13 C-NMR δ = 11.6, 11.6, 12.5, 19.5, 20.4, 20.8, 22.5, 22.6, 23.6, 24.2, 24.6, 27.8, 31.0, 31.1, 32.5, 32.6, 37.1, 37.2, 39.8,2, 39.8,3, 39.8,3 55.6, 65.3, 69.2, 73.0, 74.6, 109.5, 114.4, 114.8, 117.4, 122.8, 122.9, 125.4, 126.5, 127.4, 145.5, 146.8, 147.2, 147.8, .148.2 ppm IR 3538, 3419, 2928, 2872, 1704, 1638, 1599, 1519, 1463, 1435, 1383, 1262, 1218, 1167, 1118, 1087, 1038, 982, 912, 851, 80, 640, 7 75 cm -1 . HRMS (ESI) calcd for C 42 H 64 O 7 +Na 703.4544, found 703.4549.
(7) 실시예 7(7) Example 7
2-Hydroxy-3-((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxy)propyl 5-((R)-1,2-dithiolan-3-yl)pentanoate2-Hydroxy-3-((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxy)propyl 5-(( R )-1,2-dithiolan -3-yl)pentanoate
실시예 7은 하기 화학식 7로 표시되는 화합물이다.Example 7 is a compound represented by Formula 7 below.
[화학식 7][Formula 7]
[합성예 7][Synthesis Example 7]
100 mL 둥근 플라스크에 상기 실시준비예 2(780 mg, 1.58 mmol), 알파-리포산 (300 mg, 1.44 mmol)과 테트라부틸암모늄 브로마이드(45 mg, 0.14 mmol)를 넣고 dioxane (40 mL)에 녹인 다음 24시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 노란색 오일의 실시예 7(410 mg, 0.60 mmol)을 42%의 수율로 얻을 수 있었다.Put Example 2 (780 mg, 1.58 mmol), alpha-lipoic acid (300 mg, 1.44 mmol) and tetrabutylammonium bromide (45 mg, 0.14 mmol) in a 100 mL round flask and dissolve in dioxane (40 mL). Heat to reflux for 24 hours. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 7 (410 mg, 0.60 mmol) as a yellow oil in a yield of 42%.
[Data][Data]
Rf = 0.12 (4:1 hexane/EtOAc). 1H-NMR δ = 0.84 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.4 Hz, 6H), 1.00-1.96 (m, 30H), 1.22 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 2.39 (dd, J = 7.6, 7.2 Hz, 2H), 2.41-2.50 (m, 1H), 2.57 (t, J = 6.8 Hz, 2H), 3.07-3.22 (m, 2H), 3.33 (d, J = 6.4 Hz, 1H), 3.52-3.61 (m, 1H), 3.68-3.76 (m, 2H), 4.20-4.25 (m, 1H), 4.30 (d of A of ABq, JAB = 11.2, Jd = 6.0 Hz, 1H), 4.34 (d of B of ABq, JAB = 11.2, Jd = 4.8 Hz, 1H) ppm. 13C-NMR δ = 11.8, 12.7, 19.6, 19.7, 19.7, 20.6, 21.0, 22.6, 22.7, 23.8, 24.4, 24.6, 24.8, 28.0, 28.7, 31.1, 32.7, 32.8, 33.9, 34.6, 37.3, 37.4, 37.5, 37.6, 38.5, 39.3, 40.1, 40.2, 56.3, 65.3, 69.2, 72.9, 74.9, 117.7, 123.1, 125.6, 127.5, 147.2, 148.1, 173.6 ppm. IR 3482, 2926, 2865, 1737, 1465, 1416, 1375, 1336, 1255, 1172, 1089, 1024, 943, 862, 761, 670 cm-1. HRMS (ESI): calcd for C40H68O5S2+Na 715.4400, found 715.4403.R f = 0.12 (4:1 hexane/EtOAc). 1H - NMR δ = 0.84 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.4 Hz, 6H), 1.00-1.96 (m, 30H) , 1.22 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 2.39 (dd, J = 7.6, 7.2 Hz, 2H), 2.41–2.50 (m, 1H) ), 2.57 (t, J = 6.8 Hz, 2H), 3.07–3.22 (m, 2H), 3.33 (d, J = 6.4 Hz, 1H), 3.52–3.61 (m, 1H), 3.68–3.76 (m, 2H), 4.20-4.25 (m, 1H), 4.30 (d of A of ABq, J AB = 11.2, Jd = 6.0 Hz, 1H), 4.34 (d of B of ABq, J AB = 11.2, J d = 4.8 Hz, 1H) ppm. 13 C-NMR δ = 11.8, 12.7, 19.6, 19.7, 19.7, 20.6, 21.0, 22.6, 22.7, 23.8, 24.4, 24.6, 24.8, 28.0, 28.7, 31.1, 32.7, 32.8, 37.3, 6, 37.3, 9, 37.3, 9 37.5, 37.6, 38.5, 39.3, 40.1, 40.2, 56.3, 65.3, 69.2, 72.9, 74.9, 117.7, 123.1, 125.6, 127.5, 147.2, 148.1, 173.6 ppm. IR 3482, 2926, 2865, 1737, 1465, 1416, 1375, 1336, 1255, 1172, 1089, 1024, 943, 862, 761, 670 cm -1 . HRMS (ESI): calcd for C 40 H 68 O 5 S 2 +Na 715.4400, found 715.4403.
(8) 실시예 8(8) Example 8
5-(2-Hydroxy-3-((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxy)propoxy)-2-(hydroxymethyl)-4H-pyran-4-one5-(2-Hydroxy-3-((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxy)propoxy)-2-(hydroxymethyl)-4H -pyran-4-one
실시예 8은 하기 화학식 8로 표시되는 화합물이다.Example 8 is a compound represented by Formula 8 below.
[화학식 8][Formula 8]
[합성예 8][Synthesis Example 8]
100 mL 둥근 플라스크에 상기 실시준비예 2(1.00 g, 2.00 mmol), 코직산 (0.30 g, 2.20 mmol)과 테트라부틸암모늄 브로마이드 (60 mg, 0.19 mmol)를 넣고 THF (8 mL)에 녹인 다음 24시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시예 8(40 mg, 0.063 mmol)을 3%의 수율로 얻을 수 있었다.Into a 100 mL round flask, Example 2 (1.00 g, 2.00 mmol), kojic acid (0.30 g, 2.20 mmol) and tetrabutylammonium bromide (60 mg, 0.19 mmol) were added and dissolved in THF (8 mL) for 24 hours. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 8 (40 mg, 0.063 mmol) in a yield of 3%.
[Data][Data]
Rf = 0.37 (5.5:1 EtOAc /Acetone). 1H-NMR δ = 0.84 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.4 Hz, 6H), 1.00-1.60 (m, 21H), 1.22 (s, 3H), 1.70-1.85 (m, 2H), 2.07 (s, 3H), 2.11 (s, 3H), 2.15 (s, 3H), 2.56 (t, J = 6.8 Hz, 2H), 3.45 (br s, 1H), 3.80 (d, J = 6.0 Hz, 2H), 4.12 (d of A of ABq, JAB = 9.6, Jd = 6.4 Hz, 1H), 4.20 (d of B of ABq, JAB= 9.6, Jd= 2.8 Hz, 1H), 4.30-4.37 (m, 1H), 4.49 (br s, 1H), 4.52 (br s, 2H), 6.55 (s, 1H), 7.75 (s, 1H) ppm. IR 3393, 2930, 2859, 1658, 1618, 1466, 1381, 1259, 1222, 1159, 1096, 1026, 948, 874, 766, 726, 677 cm-1. HRMS (ESI): calcd for C38H60O7+Na 651.4231, found 651.4237.R f = 0.37 (5.5:1 EtOAc/Acetone). 1H - NMR δ = 0.84 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.4 Hz, 6H), 1.00-1.60 (m, 21H) , 1.22 (s, 3H), 1.70–1.85 (m, 2H), 2.07 (s, 3H), 2.11 (s, 3H), 2.15 (s, 3H), 2.56 (t, J = 6.8 Hz, 2H), 3.45 (br s, 1H), 3.80 (d, J = 6.0 Hz, 2H), 4.12 (d of A of ABq, J AB = 9.6, Jd = 6.4 Hz, 1H), 4.20 (d of B of ABq, J AB = 9.6, Jd = 2.8 Hz, 1H), 4.30–4.37 (m, 1H), 4.49 (br s, 1H), 4.52 (br s, 2H), 6.55 (s, 1H), 7.75 (s, 1H) ) ppm. IR 3393, 2930, 2859, 1658, 1618, 1466, 1381, 1259, 1222, 1159, 1096, 1026, 948, 874, 766, 726, 677 cm -1 . HRMS (ESI): calcd for C 38 H 60 O 7 +Na 651.4231, found 651.4237.
(9) 실시예 9(9) Example 9
2-Hydroxy-3-((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxy)propyl 2-hydroxybenzoate2-Hydroxy-3-((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl)oxy)propyl 2-hydroxybenzoate
실시예 9는 하기 화학식 9로 표시되는 화합물이다.Example 9 is a compound represented by Formula 9 below.
[화학식 9][Formula 9]
[합성예 9][Synthesis Example 9]
100 mL 둥근 플라스크에 상기 실시준비예 2(380 mg, 0.78 mmol), 살리실산 (119 mg, 0.86 mmol)과 테트라부틸암모늄 브로마이드 (25 mg, 0.08 mmol)를 넣고 THF (20 mL)에 녹인 다음 6시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 투명색 액체의 실시예 9(93 mg, 0.15 mmol)를 19%의 수율로 얻을 수 있었다.Into a 100 mL round flask, Example 2 (380 mg, 0.78 mmol), salicylic acid (119 mg, 0.86 mmol) and tetrabutylammonium bromide (25 mg, 0.08 mmol) were added and dissolved in THF (20 mL) for 6 hours. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 9 (93 mg, 0.15 mmol) as a transparent liquid in a yield of 19%.
[Data][Data]
Rf = 0.4 (4:1 hexane/EtOAc). 1H-NMR δ = 0.84 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.0 Hz, 6H), 1.00-1.60 (m, 21H), 1.23 (s, 3H), 1.71-1.86 (m, 2H), 2.08 (s, 3H), 2.14 (s, 3H), 2.18 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.71 (br s, 1H), 3.79-3.86 (m, 2H), 4.38 (quintet, J = 5.6 Hz, 1H), 4.56 (d of A of ABq, JAB = 11.2, Jd = 5.6 Hz, 1H), 4.61 (d of B of ABq, JAB= 11.2, Jd = 5.6 Hz, 1H), 6.89 (dt, Jd = 1.6, Jt = 7.6 Hz, 1H), 7.00 (dd, J = 7.6, 1.6 Hz, 1H), 7.48 (dt, Jd = 1.6, Jt = 7.6 Hz, 1H), 7.87 (dd, J = 7.6, 1.6 Hz, 1H) ppm. 13C-NMR δ = 11.8, 11.8, 12.7, 19.7, 20.6, 21.0, 22.6, 22.7, 23.8, 24.4, 24.8, 28.0, 31.2, 31.2, 32.7, 32.8, 37.3, 37.4, 37.4, 39.4, 40.0, 40.1, 65.9, 69.1, 72.7, 74.9, 112.1, 117.7, 117.8, 119.2, 123.2, 125.6, 127.5, 129.9, 136.0, 147.2, 148.2, 161.8, 170.0 ppm. IR 3474, 3211, 2955, 2930, 2870, 1685, 1622, 1588, 1466, 1422, 1389, 1308, 1255, 1207, 1170, 1096, 1025, 996, 914, 870, 803, 766, 736, 711, 677 cm-1. HRMS (ESI) calcd for C39H60O6+Na 647.4282, found 647.4285.R f = 0.4 (4:1 hexane/EtOAc). 1H - NMR δ = 0.84 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.0 Hz, 6H), 1.00-1.60 (m, 21H) , 1.23 (s, 3H), 1.71–1.86 (m, 2H), 2.08 (s, 3H), 2.14 (s, 3H), 2.18 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.71 (br s, 1H), 3.79–3.86 (m, 2H), 4.38 (quintet, J = 5.6 Hz, 1H), 4.56 (d of A of ABq, J AB = 11.2, Jd = 5.6 Hz, 1H), 4.61 (d of B of ABq, J AB = 11.2, J d = 5.6 Hz, 1H), 6.89 (dt, J d = 1.6, J t = 7.6 Hz, 1H), 7.00 (dd, J = 7.6, 1.6 Hz) , 1H), 7.48 (dt, J = 1.6, Jt = 7.6 Hz, 1H), 7.87 (dd, J = 7.6, 1.6 Hz, 1H) ppm. 13 C-NMR δ = 11.8, 11.8, 12.7, 19.7, 20.6, 21.0, 22.6, 22.7, 23.8, 24.4, 24.8, 28.0, 31.2, 31.2, 32.7, 32.8, 37.3, 37.4, 37.0,4, 40.1,4, 3 65.9, 69.1, 72.7, 74.9, 112.1, 117.7, 117.8, 119.2, 123.2, 125.6, 127.5, 129.9, 136.0, 147.2, 148.2, 161.8, 170.0 ppm. IR 3474, 3211, 2955, 2930, 2870, 1685, 1622, 1588, 1466, 1422, 1389, 1308, 1255, 1207, 1170, 1096, 1025, 996, 914, 870, 6,713, 776 cm -1 . HRMS (ESI) calcd for C 39 H 6 O 6 +Na 647.4282, found 647.4285.
[실시준비예 3: 제3 에폭사이드 화합물의 합성][Example 3: Synthesis of the third epoxide compound]
실시준비예 3은 하기 화학식 3a로 표시되는 화합물이다.Preparation Example 3 is a compound represented by Formula 3a below.
[화학식 3a][Formula 3a]
상기 실시준비예 3은, 제3 에폭사이드 화합물로 다음과 같은 방법으로 합성된다.Preparation Example 3 was synthesized as a third epoxide compound in the following manner.
100 mL 둥근 플라스크에 에피클로로하이드린 (306 mg, 3.31 mmol), 세사몰 (300 mg, 2.21 mmol), 테트라부틸암모늄 하이드로겐설페이트 (150 mg, 0.44 mmol)를 순차적으로 넣는다. 용기를 0℃의 얼음 물에 담근 뒤 50% KOH 수용액 (5 mL)을 가한 bath를 제거하고 실온에서 7시간 동안 교반한다. 반응 혼합물에 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 투명한 액체의 실시준비예 3(260 mg, 1.34 mmol)을 61%의 수율로 얻을 수 있었다.In a 100 mL round flask, epichlorohydrin (306 mg, 3.31 mmol), sesamol (300 mg, 2.21 mmol), and tetrabutylammonium hydrogen sulfate (150 mg, 0.44 mmol) are sequentially put. After immersing the container in ice water at 0 ° C, remove the bath to which 50% KOH aqueous solution (5 mL) was added, and stir at room temperature for 7 hours. The reaction was terminated by adding H 2 O to the reaction mixture, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 3 (260 mg, 1.34 mmol) as a clear liquid in a yield of 61%.
[Data] [Data]
Rf = 0.48 (4:1 hexane/EtOAc). 1H-NMR δ = 2.72 (dd, J = 4.8, 2.4 Hz, 1H), 2.88 (dd, J = 4.8, 4.4 Hz, 1H), 3.31 (dddd, J = 5.6, 4.4, 3.2, 2.4 Hz, 1H), 3.86 (dd, J = 11.2, 5.6 Hz, 1H), 4.13 (dd, J = 11.2, 3.2 Hz, 1H), 5.90 (s, 2H), 6.32 (dd, J = 8.4, 2.4 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H) ppm.R f = 0.48 (4:1 hexane/EtOAc). 1H - NMR δ = 2.72 (dd, J = 4.8, 2.4 Hz, 1H), 2.88 (dd, J = 4.8, 4.4 Hz, 1H), 3.31 (dddd, J = 5.6, 4.4, 3.2, 2.4 Hz, 1H) ), 3.86 (dd, J = 11.2, 5.6 Hz, 1H), 4.13 (dd, J = 11.2, 3.2 Hz, 1H), 5.90 (s, 2H), 6.32 (dd, J = 8.4, 2.4 Hz, 1H) , 6.50 (d, J = 2.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H) ppm.
(10) 실시예 10(10) Example 10
3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropyl (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropyl (2 E ,4 E ,6 E ,8 E )-3,7-dimethyl-9-(2,6,6 -trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate
실시예 10은 하기 화학식 10으로 표시되는 화합물이다.Example 10 is a compound represented by Formula 10 below.
[화학식 10][Formula 10]
[합성예 10][Synthesis Example 10]
100 mL 둥근 플라스크에 상기 실시준비예 3(610 mg, 3.14 mmol), 레티노산 (1.04 mg, 3.45 mmol)과 테트라부틸암모늄 브로마이드 (152 mg, 0.47 mmol)를 넣고 THF (20 mL)에 녹인 다음 13시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 노란색 액체의 실시예 10(1.05 g, 2.13 mmol)을 68%의 수율로 얻을 수 있었다Into a 100 mL round flask, Example 3 (610 mg, 3.14 mmol), retinoic acid (1.04 mg, 3.45 mmol) and tetrabutylammonium bromide (152 mg, 0.47 mmol) were dissolved in THF (20 mL) and then 13 Heat at reflux for an hour. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 10 (1.05 g, 2.13 mmol) as a yellow liquid in a yield of 68%.
[Data][Data]
Rf = 0.73 (3:2 hexane/EtOAc). 1H-NMR δ = 1.03 (s, 6H), 1.44-1.51 (m, 2H), 1.47-1.57 (m, 2H), 1.72 (s, 3H), 1.99-2.06 (m, 2H), 2.05 (s, 3H), 2.37 (s, 3H), 2.63 (d, J = 4.8 Hz, 1H), 3.95 (d of A of ABq, JAB = 11.6, Jd = 5.6 Hz, 1H), 3.99 (d of B of ABq, JAB = 11.6, Jd = 4.8 Hz, 1H), 4.19-4.28 (m, 1H), 4.28-4.37 (m, 2H), 5.82 (s, 1H), 5.92 (s, 2H), 6.14 (d, J = 16.0 Hz, 1H), 6.15 (d, J = 11.2 Hz, 1H), 6.29 (d, J = 14.8 Hz, 2H), 6.29 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 8.4, 2.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 14.8, 11.2 Hz, 1H) ppm. 13C-NMR δ = 12.9, 14.0, 19.2, 21.7, 28.9, 28.9, 33.1, 34.2, 39.6, 64.7, 68.7, 69.8, 98.2, 101.2, 105.8, 107.9, 117.5, 128.9, 129.4, 130.1, 131.5, 134.8, 137.2, 137.6, 140.0, 142.0, 148.3, 153.9, 154.1, 167.2 ppm. IR 3471, 2932, 1710, 1618, 1583, 1485, 1458, 1402, 1361, 1266, 1241, 1190, 1152, 1041, 973, 938, 884, 843, 814, 732, 651, 616 cm-1.R f = 0.73 (3:2 hexane/EtOAc). 1H - NMR δ = 1.03 (s, 6H), 1.44-1.51 (m, 2H), 1.47-1.57 (m, 2H), 1.72 (s, 3H), 1.99-2.06 (m, 2H), 2.05 (s , 3H), 2.37 (s, 3H), 2.63 (d, J = 4.8 Hz, 1H), 3.95 (d of A of ABq, J AB = 11.6, Jd = 5.6 Hz, 1H), 3.99 (d of B of ABq, J AB = 11.6, J d = 4.8 Hz, 1H), 4.19–4.28 (m, 1H), 4.28–4.37 (m, 2H), 5.82 (s, 1H), 5.92 (s, 2H), 6.14 ( d, J = 16.0 Hz, 1H), 6.15 (d, J = 11.2 Hz, 1H), 6.29 (d, J = 14.8 Hz, 2H), 6.29 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 8.4, 2.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 14.8, 11.2 Hz, 1H) ppm. 13 C-NMR Δ = 12.9, 14.0, 19.2, 21.7, 28.9, 28.9, 33.1, 34.2, 39.6, 64.7, 68.7, 69.8, 98.2, 101.2, 105.8, 107.9, 117.5, 128.9, 129.4, 130.1, 131.5, 134.8 137.2, 137.6, 140.0, 142.0, 148.3, 153.9, 154.1, 167.2 ppm. IR 3471, 2932, 1710, 1618, 1583, 1485, 1458, 1402, 1361, 1266, 1241, 1190, 1152, 1041, 973, 938, 884, 843, 814, 732, 651, 616 cm -1
(11) 실시예 11(11) Example 11
3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropyl ( E )-3-(4-hydroxy-3-methoxyphenyl)acrylate
실시예 11은 하기 화학식 11로 표시되는 화합물이다.Example 11 is a compound represented by Formula 11 below.
[화학식 11][Formula 11]
[합성예 11][Synthesis Example 11]
100 mL 둥근 플라스크에 상기 실시준비예 3(467 mg, 2.41 mmol), 퍼롤릭산 (514 mg, 2.65 mmol)과 테트라부틸암모늄 브로마이드(78 mg, 0.24 mmol)를 넣고 dioxane (10 mL)에 녹인 다음 하루 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 투명한 액체의 실시예 11(303 mg, 0.78 mmol)을 32%의 수율로 얻을 수 있었다.Into a 100 mL round flask, Example 3 (467 mg, 2.41 mmol), perolic acid (514 mg, 2.65 mmol) and tetrabutylammonium bromide (78 mg, 0.24 mmol) were added and dissolved in dioxane (10 mL) for one day. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 11 (303 mg, 0.78 mmol) as a clear liquid in a yield of 32%.
[Data][Data]
Rf = 0.2 (3:2 hexane/EtOAc). 1H-NMR δ = 2.66 (d, J = 4.8 Hz, 1H), 3.93 (s, 3H), 3.98 (d of A of ABq, JAB = 9.2, Jd = 5.6 Hz, 1H), 4.02 (d of B of ABq, JAB = 9.2, Jd = 4.8 Hz, 1H), 4.28 (sextet, J = 4.8 Hz, 1H), 4.37 (d of A of ABq, JAB = 12.0, Jd = 5.2 Hz, 1H), 4.42 (d of B of ABq, JAB = 12.0, Jd = 4.8 Hz, 1H), 5.88 (s, 1H), 5.92 (s, 2H), 6.33 (d, J = 15.6 Hz, 1H), 6.35 (dd, J = 8.4, 2.4 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 7.66 (d, J = 15.6 Hz, 1H) ppm. 13C-NMR δ = 55.9, 65.3, 68.8, 69.8, 98.2, 101.2, 105.8, 108.0, 109.4, 114.6, 114.7, 123.3, 126.8, 142.1, 145.8, 146.8, 148.2, 148.3, 153.8, 167.4 ppm. IR 3449, 3025, 2895, 2780, 1708, 1643, 1605, 1518, 1490, 1469, 1441, 1396, 1278, 1186, 1137, 1039, 990, 947, 854, 827, 762, 675, 609, 577 cm-1. HRMS (ESI) calcd for C20H20O8+Na 411.1050, found 411.1054.R f = 0.2 (3:2 hexane/EtOAc). 1H - NMR δ = 2.66 (d, J = 4.8 Hz, 1H), 3.93 (s, 3H), 3.98 (d of A of ABq, J AB = 9.2, J d = 5.6 Hz, 1H), 4.02 (d of B of ABq, J AB = 9.2, J d = 4.8 Hz, 1H), 4.28 (sextet, J = 4.8 Hz, 1H), 4.37 (d of A of ABq, J AB = 12.0, Jd = 5.2 Hz, 1H) ), 4.42 (d of B of ABq, J AB = 12.0, J d = 4.8 Hz, 1H), 5.88 (s, 1H), 5.92 (s, 2H), 6.33 (d, J = 15.6 Hz, 1H), 6.35 (dd, J = 8.4, 2.4 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 7.66 (d, J = 15.6 Hz, 1H) ppm. 13 C-NMR δ = 55.9, 65.3, 68.8, 69.8, 98.2, 101.2, 105.8, 108.0, 109.4, 114.6, 114.7, 123.3, 126.8, 142.1, 145.8, 146.8, 148.3, 148.3, 148.3 ppm IR 3449, 3025, 2895, 2780, 1708, 1643, 1605, 1518, 1490, 1469, 1441, 1396, 1278, 1186, 1137, 1039, 990, 947, 854, 827, 762, 7 cm -675 , 6 cm 1 . HRMS (ESI) calcd for C 20 H 20 O 8 +Na 411.1050, found 411.1054.
(12) 실시예 12(12) Example 12
3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropyl 5-((R)-1,2-dithiolan-3-yl)pentanoate3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropyl 5-(( R )-1,2-dithiolan-3-yl)pentanoate
실시예 12는 하기 화학식 12로 표시되는 화합물이다.Example 12 is a compound represented by Formula 12 below.
[화학식 12][Formula 12]
[합성예 12][Synthesis Example 12]
100 mL 둥근 플라스크에 상기 실시준비예 3(500 mg, 2.57 mmol), 알파-리포산 (530 mg, 2.57 mmol)과 테트라부틸암모늄 브로마이드 (80 mg, 0.25 mmol)를 넣고 THF (40 mL)에 녹인 다음 24시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 하얀색 고체의 실시예 12(110 mg, 0.27 mmol)를 11%의 수율로 얻을 수 있었다.Put Example 3 (500 mg, 2.57 mmol), alpha-lipoic acid (530 mg, 2.57 mmol) and tetrabutylammonium bromide (80 mg, 0.25 mmol) in a 100 mL round flask and dissolve in THF (40 mL). Heat to reflux for 24 hours. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 12 (110 mg, 0.27 mmol) as a white solid in a yield of 11%.
[Data][Data]
Rf = 0.33 (3:2 hexane/EtOAc). 1H-NMR δ = 1.38-1.56 (m, 2H), 1.59-1.76 (m, 4H), 1.90 (ddt, Jd = 13.2, 6.8, Jt = 6.8 Hz, 1H), 2.38 (t, J = 6.8 Hz, 2H), 2.45 (ddt, Jd = 13.2, 5.6, Jt = 6.8 Hz, 1H), 2.59 (br s, 1H), 3.01 (t of A of ABq, JAB = 11.2, Jt = 7.2 Hz, 1H), 3.18 (dd of B of ABq, JAB = 11.2, Jd = 7.2, 5.6 Hz, 1H), 3.55 (ddt, Jd = 8.0, 6.4, Jt = 6.4 Hz, 1H), 3.93 (d of A of ABq, JAB = 9.6, Jd = 5.6 Hz, 1H), 3.97 (d of B of ABq, JAB = 9.6, Jd = 4.4 Hz, 1H), 4.20 (quintet, J = 4.8 Hz, 1H), 4.25 (d of A of ABq, JAB = 11.6, Jd = 5.6 Hz, 1H), 4.30 (d of B of ABq, JAB = 11.6, Jd = 4.8 Hz, 1H), 5.92 (s, 2H), 6.33 (dd, J = 8.4, 2.8 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H) ppm. 13C-NMR δ = 24.6, 28.7, 33.9, 34.5, 38.5, 40.2, 56.3, 65.2, 68.6, 69.7, 98.2, 101.2, 105.7, 107.9, 142.1, 148.3, 153.8, 173.6 ppm. IR (KBr) 3483, 2937, 1737, 1633, 1490, 1459, 1246, 1186, 1135, 1105, 1040, 940, 929, 838, 817, 790, 616 cm-1.R f = 0.33 (3:2 hexane/EtOAc). 1 H-NMR δ = 1.38-1.56 (m, 2H), 1.59-1.76 (m, 4H), 1.90 (ddt, J d = 13.2, 6.8, J t = 6.8 Hz, 1H), 2.38 (t, J = 6.8 Hz, 2H), 2.45 (ddt, J d = 13.2, 5.6, J t = 6.8 Hz, 1H), 2.59 (br s, 1H), 3.01 (t of A of ABq, J AB = 11.2, J t = 7.2 Hz, 1H), 3.18 (dd of B of ABq, J AB = 11.2, Jd = 7.2, 5.6 Hz, 1H), 3.55 (ddt, J d = 8.0, 6.4, J t = 6.4 Hz, 1H), 3.93 (d of A of ABq, J AB = 9.6, J d = 5.6 Hz, 1H), 3.97 (d of B of ABq, J AB = 9.6, J d = 4.4 Hz, 1H), 4.20 (quintet, J = 4.8 Hz, 1H), 4.25 (d of A of ABq, J AB = 11.6, J d = 5.6 Hz, 1H), 4.30 (d of B of ABq, J AB = 11.6, J d = 4.8 Hz, 1H), 5.92 (s, 2H), 6.33 (dd, J = 8.4, 2.8 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H) ppm. 13 C-NMR δ = 24.6, 28.7, 33.9, 34.5, 38.5, 40.2, 56.3, 65.2, 68.6, 69.7, 98.2, 101.2, 105.7, 107.9, 142.1, 148.3, 153.8, 173.6 ppm. IR (KBr) 3483, 2937, 1737, 1633, 1490, 1459, 1246, 1186, 1135, 1105, 1040, 940, 929, 838, 817, 790, 616 cm -1 .
(13) 실시예 13(13) Example 13
5-(3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropoxy)-2-(hydroxymethyl)-4H-pyran-4-one5-(3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropoxy)-2-(hydroxymethyl) -4H -pyran-4-one
실시예 13은 하기 화학식 13으로 표시되는 화합물이다.Example 13 is a compound represented by Formula 13 below.
[화학식 13][Formula 13]
[합성예 13][Synthesis Example 13]
100 mL 둥근 플라스크에 상기 실시준비예 3(450 mg, 2.32 mmol), 코직산 (330 mg, 2.32 mmol)과 테트라부틸암모늄 브로마이드 (74 mg, 0.23 mmol)를 넣고 THF (30 mL)에 녹인 다음 24시간 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 흰색 고체의 실시예 13(47 mg, 0.139 mmol)을 6%의 수율로 얻을 수 있었다.Into a 100 mL round flask, Example 3 (450 mg, 2.32 mmol), kojic acid (330 mg, 2.32 mmol) and tetrabutylammonium bromide (74 mg, 0.23 mmol) were added and dissolved in THF (30 mL) for 24 hours. while heating under reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 13 (47 mg, 0.139 mmol) as a white solid in a yield of 6%.
[Data][Data]
Rf = 0.08 (5.5:1 EtOAc /Acetone). 1H-NMR δ = 3.95-4.10 (m, 4H), 4.25-4.33 (m, 1H), 4.50 (s, 2H), 4.59 (br s, 1H), 5.01 (br s, 1H), 5.90 (s, 2H), 6.33 (dd, J = 8.4, 2.8 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.54 (s, 1H), 6.68 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H) ppm.13C-NMR δ = 60.8, 68.4, 69.0, 72.6, 98.1, 101.2, 105.7, 107.9, 109.2, 112.1, 137.6, 141.7, 148.3, 153.9, 167.8, 175.4 ppm. IR (KBr) 3327, 2930, 2858, 1652, 1615, 1493, 1468, 1383, 1346, 1268, 1239, 1196, 1149, 1109, 1076, 1039, 949, 872, 822, 797, 670 cm-1.R f =0.08 (5.5:1 EtOAc/Acetone). 1 H-NMR δ = 3.95-4.10 (m, 4H), 4.25-4.33 (m, 1H), 4.50 (s, 2H), 4.59 (br s, 1H), 5.01 (br s, 1H), 5.90 (s , 2H), 6.33 (dd, J = 8.4, 2.8 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.54 (s, 1H), 6.68 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H) ppm. 13 C-NMR δ = 60.8, 68.4, 69.0, 72.6, 98.1, 101.2, 105.7, 107.9, 109.2, 112.1, 137.6, 141.7, 148.3, 153.9, 167.8, 175.4 ppm. IR (KBr) 3327, 2930, 2858, 1652, 1615, 1493, 1468, 1383, 1346, 1268, 1239, 1196, 1149, 1109, 1076, 1039, 949, 872, 822, 797, 670 cm -1
(14) 실시예 14(14) Example 14
3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropyl 2-hydroxybenzoate3-(Benzo[d][1,3]dioxol-5-yloxy)-2-hydroxypropyl 2-hydroxybenzoate
실시예 14는 하기 화학식 14로 표시되는 화합물이다.Example 14 is a compound represented by Formula 14 below.
[화학식 14][Formula 14]
[합성예 14][Synthesis Example 14]
100 mL 둥근 플라스크에 상기 실시준비예 3(197 mg, 1.01 mmol), 살리실산 (157 mg, 1.13 mmol)과 테트라부틸암모늄 브로마이드 (33 mg, 0.10 mmol)를 넣고 THF (5 mL)에 녹인 다음 하루 동안 환류 가열한다. 실온으로 식힌 뒤 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 투명한 액체의 실시예 14(1.05 g, 0.52 mmol)를 51%의 수율로 얻을 수 있었다.Into a 100 mL round flask, Example 3 (197 mg, 1.01 mmol), salicylic acid (157 mg, 1.13 mmol) and tetrabutylammonium bromide (33 mg, 0.10 mmol) were added and dissolved in THF (5 mL) for one day. Heat to reflux. After cooling to room temperature, H 2 O was added to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 14 (1.05 g, 0.52 mmol) as a clear liquid in a yield of 51%.
[Data][Data]
Rf = 0.6 (3:2 hexane/EtOAc). 1H-NMR δ = 3.42 (br s, 1H), 4.01 (d of A of ABq, JAB = 9.6, Jd = 5.6 Hz, 1H), 4.05 (d of B of ABq, JAB = 9.6, Jd = 4.8 Hz, 1H), 4.35 (quintet, J = 5.2 Hz, 1H), 4.50 (d of A of ABq, JAB = 11.6, Jd = 5.2 Hz, 1H), 4.54 (d of B of ABq, JAB = 11.6, Jd = 4.8 Hz, 1H), 5.89 (s, 2H), 6.33 (dd, J = 8.4, 2.4 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.86 (dt, Jd = 0.8, Jt = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 0.8 Hz, 1H), 7.44 (dt, Jd = 1.6, Jt = 8.4 Hz, 1H), 7.85 (dd, J = 8.4, 1.6 Hz, 1H), 10.63 (br s, 1H) ppm.13C-NMR δ = 65.9, 68.5, 69.7, 98.2, 101.3, 105.8, 108.0, 112.0, 117.7, 119.3, 129.9, 136.1, 142.3, 148.4, 153.7, 161.7, 170.0 ppm. HRMS (ESI) calcd for C17H16O7+Na 355.0788, found 355.0790.R f = 0.6 (3:2 hexane/EtOAc). 1H - NMR δ = 3.42 (br s, 1H), 4.01 (d of A of ABq, J AB = 9.6, J d = 5.6 Hz, 1H), 4.05 (d of B of ABq, J AB = 9.6, J d = 4.8 Hz, 1H), 4.35 (quintet, J = 5.2 Hz, 1H), 4.50 (d of A of ABq, J AB = 11.6, J d = 5.2 Hz, 1H), 4.54 (d of B of ABq, J AB = 11.6, J = 4.8 Hz, 1H), 5.89 ( s , 2H), 6.33 (dd, J = 8.4, 2.4 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 6.68 (d , J = 8.4 Hz, 1H), 6.86 (dt, J = 0.8, Jt = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 0.8 Hz, 1H), 7.44 (dt, J = 1.6, J t = 8.4 Hz, 1H), 7.85 (dd, J = 8.4, 1.6 Hz, 1H), 10.63 (br s, 1H) ppm. 13 C-NMR δ = 65.9, 68.5, 69.7, 98.2, 101.3, 105.8, 108.0, 112.0, 117.7, 119.3, 129.9, 136.1, 142.3, 148.4, 153.7, 161.7, 170.0 ppm. HRMS (ESI) calcd for C 17 H 16 O 7 +Na 355.0788, found 355.0790.
2. 신규한 모노글리세라이드 화합물 및 그의 제조방법2. Novel monoglyceride compound and its preparation method
본 발명의 다른 실시예는 신규한 모노글리세라이드 화합물 및 그의 제조방법이다.Another embodiment of the present invention is a novel monoglyceride compound and method for its preparation.
[실시준비예 4: 보호기가 부착된 에스테르 화합물의 합성][Example 4: Synthesis of ester compound with protecting group attached]
실시준비예 4는 하기 실시예 15를 합성하는데 필요한 준비예로, 하기 화학식 4a로 표시되는 화합물이다.Preparation Example 4 is a preparation example necessary for synthesizing Example 15 below, and is a compound represented by Formula 4a below.
[화학식 4a][Formula 4a]
상기 실시준비예 4는, 보호기가 부착된 에스테르 화합물로, 다음과 같은 방법으로 합성된다.Preparation Example 4 is an ester compound to which a protecting group is attached, and is synthesized in the following manner.
250 mL 둥근 플라스크에 2-phenyl-1,3-dioxan-5-ol (0.60 g, 3.33 mmol), 레티놀산 (1.10 g, 3.66 mmol), dimethylaminopyridine methanesulfonate (DPMS) (2.33 g, 10.66 mmol)을 CH2Cl2 (80 mL)에 녹인 다음 dicyclohexyl carbodiimide (DCC) (0.69 g, 3.33 mmol)를 가하고 실온에서 24시간 동안 교반한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시준비예 4(0.55 g 1.20 mmol)를 36%의 수율로 얻을 수 있었다.In a 250 mL round flask, 2-phenyl-1,3-dioxan-5-ol (0.60 g, 3.33 mmol), retinolic acid (1.10 g, 3.66 mmol), and dimethylaminopyridine methanesulfonate (DPMS) (2.33 g, 10.66 mmol) were added to CH After dissolving in 2 Cl 2 (80 mL), dicyclohexyl carbodiimide (DCC) (0.69 g, 3.33 mmol) was added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 4 (0.55 g 1.20 mmol) in a yield of 36%.
[Data][Data]
Rf = 0.45 (4:1 hexane/EtOAc). 1H-NMR δ = 1.01 (s, 6H), 1.41-1.49 (m, 2H), 1.55-1.64 (m, 2H), 1.70 (s, 3H), 1.98-2.04 (m, 2H), 1.99 (s, 3H), 2.36 (s, 3H), 4,18 (br d, J = 13.0 Hz, 2H), 4.31 (br d, J = 13.0 Hz, 2H), 4.77 (quintet, J = 1.6 Hz, 1H), 5.57 (s, 1H), 5.93 (s, 1H), 6.11 (d, J = 11.6 Hz, 1H), 6.13 (d, J = 16.0 Hz, 1H), 6.27 (d, J = 16.0 Hz, 1H), 6.28 (d, J = 15.2 Hz, 1H), 7.01 (dd, J = 15.2, 11.6 Hz, 1H), 7.30-7.38 (m, 3H), 7.47-7.52 (m, 2H) ppm.R f = 0.45 (4:1 hexane/EtOAc). 1H - NMR δ = 1.01 (s, 6H), 1.41-1.49 (m, 2H), 1.55-1.64 (m, 2H), 1.70 (s, 3H), 1.98-2.04 (m, 2H), 1.99 (s , 3H), 2.36 (s, 3H), 4,18 (br d, J = 13.0 Hz, 2H), 4.31 (br d, J = 13.0 Hz, 2H), 4.77 (quintet, J = 1.6 Hz, 1H) , 5.57 (s, 1H), 5.93 (s, 1H), 6.11 (d, J = 11.6 Hz, 1H), 6.13 (d, J = 16.0 Hz, 1H), 6.27 (d, J = 16.0 Hz, 1H) , 6.28 (d, J = 15.2 Hz, 1H), 7.01 (dd, J = 15.2, 11.6 Hz, 1H), 7.30–7.38 (m, 3H), 7.47–7.52 (m, 2H) ppm.
[실시준비예 5: 아세탈 보호기가 부착된 글리세롤 화합물의 합성][Example 5: Synthesis of glycerol compound with an acetal protecting group attached]
실시준비예 5는 하기 실시준비예 6과 7을 합성하는데 필요한 준비예로 하기 화학식 5a로 표시되는 화합물이다.Preparation Example 5 is a compound represented by Formula 5a as a preparation example necessary for synthesizing Preparation Examples 6 and 7 below.
[화학식 5a][Formula 5a]
상기 실시준비예 5는, 실시준비예 4의 2-phenyl-1,3-dioxan-5-ol을 대신하여 벤즈알데하이드의 파라-위치에 벤젠설포닐기를 함유하는 보호기가 부착된 신규의 글리세롤 화합물로, 결정성상이 우수하여 재결정의 방법으로 쉽게 정제될 수 있으며, 2-phenyl-1,3-dioxan-5-ol의 합성과 유사하게 다음과 같은 방법으로 합성된다.Preparation Example 5 is a novel glycerol compound having a protecting group containing a benzenesulfonyl group attached to the para-position of benzaldehyde instead of 2-phenyl-1,3-dioxan-5-ol of Preparation Example 4. , It has an excellent crystalline phase and can be easily purified by recrystallization, and is synthesized in the following way similar to the synthesis of 2-phenyl-1,3-dioxan-5-ol.
250 mL 둥근 플라스크에 4-formylphenyl benzenesulfonate (7.00 g, 26.69 mmol)을 벤젠 (60 mL)에 녹인 다음, 글리세롤(3.69 g, 40.04 mmol)과 진한 황산 2 drops을 넣고 Dean-Stark 컬럼을 설치하여 7시간 동안 환류 가열한다. 실온으로 식힌 뒤 반응 혼합물에 H2O를 가하여 반응을 종결하고, 에틸 아세테이트로 유기 층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 Diethyl ether를 이용하여 재결정 방법으로 정제하여 실시준비예 5(3.59 g, 10.68 mmol)를 40%의 수율로 얻을 수 있었다.After dissolving 4-formylphenyl benzenesulfonate (7.00 g, 26.69 mmol) in benzene (60 mL) in a 250 mL round flask, glycerol (3.69 g, 40.04 mmol) and 2 drops of concentrated sulfuric acid were added, and a Dean-Stark column was installed for 7 hours. while heating under reflux. After cooling to room temperature, H 2 O was added to the reaction mixture to terminate the reaction, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by recrystallization using diethyl ether to obtain Example 5 (3.59 g, 10.68 mmol) in a yield of 40%.
[Data] [Data]
Rf = 0.17 (3:2 hexane/EtOAc). 1H-NMR δ = 2.92 (d, J = 10.8 Hz, 1H), 3.64 (dt, Jd = 10.8. Jt = 1.6 Hz, 1H), 4.11 (d of A of ABq, JAB = 12.0, Jd = 1.6 Hz, 2H), 4.17 (d of B of ABq, JAB = 12.0, Jd = 1.6 Hz, 2H), 5.51 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.49-7.56 (m, 2H), 7.64-7.70 (m, 1H), 7.80-7.86 (m, 2H) ppm.R f = 0.17 (3:2 hexane/EtOAc). 1 H-NMR δ = 2.92 (d, J = 10.8 Hz, 1H), 3.64 (dt, J d = 10.8. J t = 1.6 Hz, 1H), 4.11 (d of A of ABq, J AB = 12.0, J d = 1.6 Hz, 2H), 4.17 (d of B of ABq, J AB = 12.0, J d = 1.6 Hz, 2H), 5.51 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.49–7.56 (m, 2H), 7.64–7.70 (m, 1H), 7.80–7.86 (m, 2H) ppm.
[실시준비예 6: 보호기가 부착된 에스테르 화합물의 합성][Example 6: Synthesis of ester compound with protecting group attached]
실시준비예 6은 하기 실시예 16을 합성하는데 필요한 준비예로 화학식 6a로 표시되는 화합물이다.Preparation Example 6 is a compound represented by Formula 6a as a preparation example necessary for synthesizing Example 16 below.
[화학식 6a][Formula 6a]
상기 실시준비예 6은, 보호기가 부착된 에스테르 화합물로, 다음과 같은 방법으로 합성된다.Preparation Example 6 is an ester compound to which a protecting group is attached, and is synthesized in the following manner.
100 mL 둥근 플라스크에 상기 실시준비예 5(100 mg, 0.30 mmol)와 3-(4-acetoxy-3-methoxyphenyl)acrylic acid (85 mg, 0.36 mmol), dimethylaminopyridine methanesulfonate (DPMS) (144 mg, 0.66 mmol)를 CH2Cl2 (20 mL)에 녹인 다음 dicyclohexyl carbodiimide (DCC) (74 mg, 0.36 mmol)을 가하고 실온에서 22시간 동안 교반 한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시준비예 6(160 mg, 0.289 mmol)을 96%의 수율로 얻을 수 있었다.In a 100 mL round flask, Example 5 (100 mg, 0.30 mmol) and 3-(4-acetoxy-3-methoxyphenyl)acrylic acid (85 mg, 0.36 mmol), dimethylaminopyridine methanesulfonate (DPMS) (144 mg, 0.66 mmol) ) was dissolved in CH 2 Cl 2 (20 mL), dicyclohexyl carbodiimide (DCC) (74 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 22 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 6 (160 mg, 0.289 mmol) in a yield of 96%.
[Data][Data]
Rf = 0.33 (3:2 hexane/EtOAc). 1H-NMR δ = 2.33 (s, 3H), 3.85 (dd, J = 8.4, 6.8 Hz, 1H), 3.87 (s, 3H), 4.29 (dd, J = 8.4, 6.8 Hz, 1H), 4.35 (d of A of Abq, JAB = 12.0, Jd = 6.0 Hz, 1H), 4.38 (d of B of Abq, JAB = 12.0, Jd = 4.4 Hz, 1H), 4.52-4.59 (m, 1H), 5.93 (s, 1H), 6.43 (d, J = 16.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 7.10-7.15 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.50-7.55 (m, 2H), 7.64-7.69 (m, 1H), 7.69 (d, J = 16.0 Hz, 1H), 7.81-7.85 (m, 2H) ppm.R f = 0.33 (3:2 hexane/EtOAc). 1H - NMR δ = 2.33 (s, 3H), 3.85 (dd, J = 8.4, 6.8 Hz, 1H), 3.87 (s, 3H), 4.29 (dd, J = 8.4, 6.8 Hz, 1H), 4.35 ( d of A of Abq, J AB = 12.0, Jd = 6.0 Hz, 1H), 4.38 (d of B of Abq, J AB = 12.0, J d = 4.4 Hz, 1H), 4.52-4.59 (m, 1H), 5.93 (s, 1H), 6.43 (d, J = 16.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 7.10-7.15 (m, 2H) ), 7.42 (d, J = 8.4 Hz, 2H), 7.50–7.55 (m, 2H), 7.64–7.69 (m, 1H), 7.69 (d, J = 16.0 Hz, 1H), 7.81–7.85 (m, 2H) ppm.
[실시준비예 7: 보호기가 부착된 에스테르 화합물의 합성][Example 7: Synthesis of ester compound with protecting group attached]
실시준비예 7은 하기 실시예 17을 합성하는데 필요한 준비예로 화학식 7a로 표시되는 화합물이다.Preparation Example 7 is a compound represented by Formula 7a as a preparation example necessary for synthesizing Example 17 below.
[화학식 7a][Formula 7a]
상기 실시준비예 7은, 보호기가 부착된 에스테르 화합물로, 다음과 같은 방법으로 합성된다. Preparation Example 7 is an ester compound to which a protecting group is attached, and is synthesized in the following manner.
100 mL 둥근 플라스크에 상기 실시준비예 5(1.30 g, 3.89 mmol), 2-acetoxybenzoic acid (0.70 g, 3.89 mmol), dimethylaminopyridine methanesulfonate (DPMS) (2.12 g, 9.71 mmol)을 CH2Cl2 (40 mL)에 녹인 다음 DCC(0.074 g, 0.36 mmol)를 가하고 실온에서 22시간 동안 교반한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시준비예 7(0.17 g, 0.34 mmol)을 9%의 수율로 얻을 수 있었다.In a 100 mL round flask, Example 5 (1.30 g, 3.89 mmol), 2-acetoxybenzoic acid (0.70 g, 3.89 mmol), and dimethylaminopyridine methanesulfonate (DPMS) (2.12 g, 9.71 mmol) were added to CH 2 Cl 2 (40 mL). ), then DCC (0.074 g, 0.36 mmol) was added and stirred at room temperature for 22 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 7 (0.17 g, 0.34 mmol) in a yield of 9%.
[Data][Data]
Rf = 0.57 (3:2 hexane/EtOAc). 1H-NMR δ = 2.08 (s, 3H), 3.92 (dd, J = 8.8, 6.4 Hz, 1H), 4.31 (dd, J = 8.8, 6.4 Hz, 1H), 4.51 (d, J = 5.2 Hz, 2H), 4.57-4.66 (m, 1H), 5.96 (s, 1H), 6.87-6.92 (m, 1H), 6.96-7.02 (m, 3H), 7.38-7.44 (m, 2H), 7.45-7.56 (m, 3H), 7.64-7.69 (m, 1H), 7.80-7.88 (m, 3H) ppm.R f = 0.57 (3:2 hexane/EtOAc). 1H - NMR δ = 2.08 (s, 3H), 3.92 (dd, J = 8.8, 6.4 Hz, 1H), 4.31 (dd, J = 8.8, 6.4 Hz, 1H), 4.51 (d, J = 5.2 Hz, 2H), 4.57-4.66 (m, 1H), 5.96 (s, 1H), 6.87-6.92 (m, 1H), 6.96-7.02 (m, 3H), 7.38-7.44 (m, 2H), 7.45-7.56 ( m, 3H), 7.64-7.69 (m, 1H), 7.80-7.88 (m, 3H) ppm.
[실시준비예 8-1: 보호기가 부착된 에스테르 화합물의 합성][Example 8-1: Synthesis of ester compound with protecting group attached]
2-Phenyl-1,3-dioxan-5-yl (R)-5-(1,2-dithiolan-3-yl)pentanoate2-Phenyl-1,3-dioxan-5-yl ( R )-5-(1,2-dithiolan-3-yl)pentanoate
실시준비예 8-1은 하기 실시예 21을 합성하는데 필요한 준비예로 하기 화학식 8a로 표시되는 화합물이다. Preparation Example 8-1 is a compound represented by Formula 8a as a preparation example required for synthesizing Example 21 below.
[화학식 8a][Formula 8a]
상기 실시준비예 8-1은 다음과 같은 방법으로 합성된다.Preparation Example 8-1 was synthesized in the following manner.
250 mL 둥근 플라스크에 2-phenyl-1,3-dioxan-5-ol (2.10 g, 11.65 mmol), 알파-리포산 (2.40 g, 11.65 mmol), DPMS (6.36 g, 29.12 mmol)을 CH2Cl2 (100 mL)에 녹인 다음 DCC (2.90 g, 14 mmol)를 가하고 실온에서 24시간 동안 교반한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 노란색 고체의 실시준비예 8-1(3.40 g, 9.23 mmol)을 79%의 수율로 얻을 수 있었다.CH 2 Cl 2 (100 mL), DCC (2.90 g, 14 mmol) was added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 8-1 (3.40 g, 9.23 mmol) as a yellow solid in a yield of 79%.
[Data][Data]
Rf =0.57 (3:2 hexane/EtOAc). 1H-NMR δ = 1.42-1.56 (m, 2H), 1.64-1.78 (m, 4H), 1.85-1.95 (m, 1H), 2.39-2.48 (m, 1H), 2.46 (dd, J = 7.6, 7.2 Hz, 2H), 3.05-3.20 (m, 2H), 3.52-3.60 (m, 1H), 4.18 (d of A of ABq, JAB = 13.6, Jd = 1.6 Hz, 2H), 4.29 (d of B of ABq, JAB = 13.6, Jd = 1.6 Hz, 2H), 4.73 (quintet, J = 1.6 Hz, 1H), 5.57 (s, 1H), 7.34-7.41 (m, 3H), 7.49-7.53 (m, 2H) ppm.R f =0.57 (3:2 hexane/EtOAc). 1H - NMR δ = 1.42-1.56 (m, 2H), 1.64-1.78 (m, 4H), 1.85-1.95 (m, 1H), 2.39-2.48 (m, 1H), 2.46 (dd, J = 7.6, 7.2 Hz, 2H), 3.05-3.20 (m, 2H), 3.52-3.60 (m, 1H), 4.18 (d of A of ABq, J AB = 13.6, J d = 1.6 Hz, 2H), 4.29 (d of B of ABq, J AB = 13.6, J d = 1.6 Hz, 2H), 4.73 (quintet, J = 1.6 Hz, 1H), 5.57 (s, 1H), 7.34–7.41 (m, 3H), 7.49–7.53 ( m, 2H) ppm.
[실시준비예 8-2: 글리세롤 보호기가 부착된 에스테르 화합물의 합성][Example 8-2: Synthesis of ester compound with glycerol protecting group attached]
1,3-Dihydroxypropan-2-yl (R)-5-(1,2-dithiolan-3-yl)pentanoate1,3-Dihydroxypropan-2-yl ( R )-5-(1,2-dithiolan-3-yl)pentanoate
실시준비예 8-2는 하기 실시예 21을 합성하는데 필요한 준비예로 하기 화학식 8b로 표시되는 화합물이다.Preparation Example 8-2 is a compound represented by Formula 8b as a preparation example required for synthesizing Example 21 below.
[화학식 8b][Formula 8b]
상기 실시준비예 8-2는 다음과 같은 방법으로 합성된다.The Preparation Example 8-2 was synthesized in the following manner.
100 mL 둥근 플라스크에서 상기 실시준비예 8-1(2.45 g, 6.65 mmol)을 CH2Cl2 (10 mL)에 녹이고 메탄올 (50 mL)과 p-TsOH (0.11 g, 0.66 mmol)을 더한 뒤 상온에서 4시간 동안 교반한다. 대부분의 용매를 감압 하에 제거하고 H2O를 첨가한 다음 CH2Cl2로 유기층을 추출하고, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 연노랑색 액체인 실시준비예 8-2(1.23 g, 4.40 mmol)를 66%의 수율로 얻을 수 있었다.In a 100 mL round flask, the above Example 8-1 (2.45 g, 6.65 mmol) was dissolved in CH 2 Cl 2 (10 mL), methanol (50 mL) and p -TsOH (0.11 g, 0.66 mmol) were added, and room temperature stirred for 4 hours. Most of the solvent was removed under reduced pressure, H 2 O was added, the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 8-2 (1.23 g, 4.40 mmol) as a pale yellow liquid in a yield of 66%.
[Data][Data]
Rf =0.48 (5.5:1 EtOAc /Acetone). 1H-NMR δ = 1.40-1.56 (m, 2H), 1.61-1.76 (m, 4H), 1.87-1.98 (m, 1H), 2.38 (dd, J = 7.6, 7.2 Hz, 2H), 2.41-2.51 (m, 1H), 3.12 (dd of A of ABq, JAB = 11.2, Jd = 7.2, 6.8 Hz, 1H), 3.19 (dd of B of ABq, JAB = 11.2, Jd = 7.2, 5.6 Hz, 1H), 3.54-3.62 (m, 1H), 3.59 (d of A of ABq, JAB = 11.6, Jd = 6.0 Hz, 1H), 3.70 (d of B of ABq, JAB = 11.6, Jd = 4.0 Hz, 1H), 3.82 (d, J = 5.6 Hz, 1H), 3.90-3.97 (m, 1H), 4.15 (dd of A of ABq, JAB = 12.0, Jd = 6.0, 1.2 Hz, 1H), 4.20 (dd of B of ABq, JAB = 12.0, Jd = 4.8, 0.8 Hz, 1H) ppm.R f =0.48 (5.5:1 EtOAc/Acetone). 1H - NMR δ = 1.40-1.56 (m, 2H), 1.61-1.76 (m, 4H), 1.87-1.98 (m, 1H), 2.38 (dd, J = 7.6, 7.2 Hz, 2H), 2.41-2.51 (m, 1H), 3.12 (dd of A of ABq, J AB = 11.2, J d = 7.2, 6.8 Hz, 1H), 3.19 (dd of B of ABq, J AB = 11.2, J d = 7.2, 5.6 Hz , 1H), 3.54–3.62 (m, 1H), 3.59 (d of A of ABq, J AB = 11.6, J d = 6.0 Hz, 1H), 3.70 (d of B of ABq, J AB = 11.6, J d = 4.0 Hz, 1H), 3.82 (d, J = 5.6 Hz, 1H), 3.90-3.97 (m, 1H), 4.15 (dd of A of ABq, J AB = 12.0, J d = 6.0, 1.2 Hz, 1H ), 4.20 (dd of B of ABq, J AB = 12.0, J d = 4.8, 0.8 Hz, 1H) ppm.
(1) 실시예 15(1) Example 15
1,3-Dihydroxypropan-2-yl (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate1,3-Dihydroxypropan-2-yl (2 E ,4 E ,6 E ,8 E )-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona- 2,4,6,8-tetraenoate
실시예 15는 하기 화학식 15로 표시되는 화합물이다.Example 15 is a compound represented by Formula 15 below.
[화학식 15][Formula 15]
[합성예 15][Synthesis Example 15]
100 mL 둥근 플라스크에서 상기 실시준비예 4(2.70 g, 5.8- mmol)을 CH2Cl2 (10 mL)에 녹이고 메탄올 (50 mL)과 p-TsOH (0.10 g, 0.58 mmol)을 더한 뒤 상온에서 3시간 동안 교반한다. 대부분의 용매를 감압 하에 제거하고 H2O를 첨가한 다음 CH2Cl2로 유기층을 추출하고, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 진한 노랑색 액체인 실시예 15(1.99 g, 5.30 mmol)를 92%의 수율로 얻을 수 있었다.In a 100 mL round flask, the above Example 4 (2.70 g, 5.8- mmol) was dissolved in CH 2 Cl 2 (10 mL), methanol (50 mL) and p -TsOH (0.10 g, 0.58 mmol) were added, and the mixture was stirred at room temperature. Stir for 3 hours. Most of the solvent was removed under reduced pressure, H 2 O was added, the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 15 (1.99 g, 5.30 mmol) as a dark yellow liquid in a yield of 92%.
[Data][Data]
Rf = 0.17 (3:2 hexane/EtOAc). 1H-NMR δ = 1.04 (s, 6H), 1.42-1.51 (m, 2H), 1.58-1.66 (m, 2H), 1.72 (s, 3H), 1.99-2.06 (m, 2H), 2.01 (s, 3H), 2.36 (s, 3H), 2.56 (br s, 1H), 3.84 (d, J = 13.2 Hz, 2H), 4.93-5.00 (m, 1H), 5.83 (s, 1H), 6.14 (d, J = 15.6 Hz, 1H), 6.16 (d, J = 15.2 Hz, 1H), 6.25 (d, J = 11.2 Hz, 1H), 6.28 (d, J = 15.6 Hz, 1H), 7.03 (dd, J = 15.2, 11.2 Hz, 1H) ppm. HRMS (ESI) calcd for C23H34O4+Na 397.2349, found 397.2359.R f = 0.17 (3:2 hexane/EtOAc). 1H - NMR δ = 1.04 (s, 6H), 1.42-1.51 (m, 2H), 1.58-1.66 (m, 2H), 1.72 (s, 3H), 1.99-2.06 (m, 2H), 2.01 (s , 3H), 2.36 (s, 3H), 2.56 (br s, 1H), 3.84 (d, J = 13.2 Hz, 2H), 4.93–5.00 (m, 1H), 5.83 (s, 1H), 6.14 (d , J = 15.6 Hz, 1H), 6.16 (d, J = 15.2 Hz, 1H), 6.25 (d, J = 11.2 Hz, 1H), 6.28 (d, J = 15.6 Hz, 1H), 7.03 (dd, J = 15.2, 11.2 Hz, 1H) ppm. HRMS (ESI) calcd for C 23 H 34 O 4 +Na 397.2349, found 397.2359.
(2) 실시예 16(2) Example 16
1,3-Dihydroxypropan-2-yl (E)-3-(4-acetoxy-3-methoxyphenyl)acrylate1,3-Dihydroxypropan-2-yl ( E )-3-(4-acetoxy-3-methoxyphenyl)acrylate
실시예 16은 하기 화학식 16으로 표시되는 화합물이다.Example 16 is a compound represented by Formula 16 below.
[화학식 16][Formula 16]
[합성예 16][Synthesis Example 16]
100 mL 둥근 플라스크에 상기 실시준비예 6(0.16 g, 0.29 mmol)을 MeOH (20 mL)에 녹인 다음 p-TsOH (0.01 g, 0.06 mmol)을 가하고 실온에서 12시간 동안 교반 한다. 반응 혼합물을 감압 농축하여 대부분의 용매를 제거하고, 물을 더한 뒤, ethyl acetate로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시예 16(0.05 g 0.16 mmol)을 56%의 수율로 얻을 수 있었다.Dissolve Example 6 (0.16 g, 0.29 mmol) in MeOH (20 mL) in a 100 mL round flask, add p -TsOH (0.01 g, 0.06 mmol), and stir at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to remove most of the solvent, water was added, and the organic layer was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 16 (0.05 g 0.16 mmol) in a yield of 56%.
[Data][Data]
Rf = 0.10 (2:3 hexane/EtOAc). 1H-NMR δ = 2.33 (s, 3H), 3.66 (d of A of ABq, JAB = 11.6, Jd = 6.0 Hz, 1H), 3.74 (d of B of ABq, JAB = 11.6, Jd = 4.4 Hz, 1H), 3.93 (s, 3H), 3.98-4.06 (m, 1H), 4.26-4.38 (m, 2H), 6.32 (d, J = 16.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 7.66 (d, J = 16.0 Hz, 1H) ppm.R f = 0.10 (2:3 hexane/EtOAc). 1H - NMR δ = 2.33 (s, 3H), 3.66 (d of A of ABq, J AB = 11.6, J d = 6.0 Hz, 1H), 3.74 (d of B of ABq, J AB = 11.6, J d = 4.4 Hz, 1H), 3.93 (s, 3H), 3.98-4.06 (m, 1H), 4.26-4.38 (m, 2H), 6.32 (d, J = 16.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 7.66 (d, J = 16.0 Hz, 1H) ppm.
(3) 실시예 17(3) Example 17
1,3-Dihydroxypropan-2-yl 2-acetoxybenzoate1,3-Dihydroxypropan-2-yl 2-acetoxybenzoate
실시예 17은 하기 화학식 17로 표시되는 화합물이다.Example 17 is a compound represented by Formula 17 below.
[화학식 17][Formula 17]
[합성예 17][Synthesis Example 17]
100mL 둥근 플라스크에 상기 실시준비예 7(0.17 g, 0.34 mmol)을 MeOH (25 mL)에 녹인 다음 p-TsOH (17 mg, 0.10 mmol)을 가하고 실온에서 4시간 동안 교반 한다. 감압 농축한 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시예 17(1.3 mg, 0.005 mmol)을 2%의 수율로 얻을 수 있었다.Dissolve Example 7 (0.17 g, 0.34 mmol) in MeOH (25 mL) in a 100 mL round flask, add p-TsOH (17 mg, 0.10 mmol), and stir at room temperature for 4 hours. The product concentrated under reduced pressure was purified by silica gel column chromatography to obtain Example 17 (1.3 mg, 0.005 mmol) in a yield of 2%.
[Data][Data]
Rf = 0.3 (2:3 hexane/EtOAc). 1H-NMR δ = 2.11 (s, 3H), 3.72 (d of A of ABq, JAB = 11.2, Jd = 6.0 Hz, 1H), 3.82 (d of B of ABq, JAB = 11.2, Jd = 3.6 Hz, 1H), 4.00 (d, J = 4.8 Hz, 1H), 4.06-4.16 (m, 1H), 4.44 (d of A of ABq, JAB = 11.6, Jd = 6.0 Hz, 1H), 4.48 (d of B of ABq, JAB = 11.6, Jd = 5.2 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 7.48 (dt, Jd = 1.6, Jt = 8.0 Hz, 1H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), ppm.R f = 0.3 (2:3 hexane/EtOAc). 1H - NMR δ = 2.11 (s, 3H), 3.72 (d of A of ABq, J AB = 11.2, J d = 6.0 Hz, 1H), 3.82 (d of B of ABq, J AB = 11.2, J d = 3.6 Hz, 1H), 4.00 (d, J = 4.8 Hz, 1H), 4.06-4.16 (m, 1H), 4.44 ( d of A of ABq, J AB = 11.6, J = 6.0 Hz, 1H), 4.48 (d of B of ABq, J AB = 11.6, J d = 5.2 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 7.48 (dt, Jd = 1.6, J t = 8.0 Hz, 1H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), ppm.
3. 신규한 1,2-디글리세라이드 화합물 및 그의 제조방법3. Novel 1,2-diglyceride compound and its preparation method
본 발명의 또 다른 실시예는 신규한 1,2-디글리세라이드 화합물 및 그의 제조방법이다.Another embodiment of the present invention is a novel 1,2-diglyceride compound and method for its preparation.
(1) 실시예 18(1) Example 18
1-Hydroxy-3-(((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)propan-2-yl (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate1-Hydroxy-3-((( E )-3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)propan-2-yl (2 E ,4 E ,6 E ,8 E )-3,7- dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate
실시예 18은 하기 화학식 18로 표시되는 화합물이다.Example 18 is a compound represented by Formula 18 below.
[화학식 18][Formula 18]
[합성예 18][Synthesis Example 18]
100 mL 둥근 플라스크에 상기 실시예 15(0.48 g, 1.30 mmol)와 퍼룰릭산 (0.25 g, 1.30 mmol), 및 DPMS (0.7 g, 3.25 mmol)를 CH2Cl2 (15 mL)에 녹인 다음, DCC (0.32 g, 1.56 mmol)를 가하고 실온에서 24시간 동안 교반한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 노란색 액체인 실시예 18(0.26 g, 0.47 mmol)을 36%의 수율로 얻을 수 있었다.In a 100 mL round flask, Example 15 (0.48 g, 1.30 mmol), ferulic acid (0.25 g, 1.30 mmol), and DPMS (0.7 g, 3.25 mmol) were dissolved in CH 2 Cl 2 (15 mL), DCC (0.32 g, 1.56 mmol) was added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 18 (0.26 g, 0.47 mmol) as a yellow liquid in a yield of 36%.
[Data][Data]
Rf =0.37 (3:2 hexane/EtOAc). 1H-NMR δ = 1.03 (s, 6H), 1.43-1.51 (m, 2H), 1.57-1.65 (m, 2H), 1.71 (s, 3H), 1.98-2.06 (m, 2H), 2.00 (s, 3H), 2.36 (s, 3H), 2.57 (br t, J = 4.8 Hz, 1H), 3.82 (br dd, J = 6.0, 4.8 Hz, 2H), 3.92 (s, 3H), 4.44 (d, J = 4.8 Hz, 2H), 5.20 (tt, J = 6.0, 4.8 Hz, 1H), 5.83 (s, 1H), 6.12 (d, J = 15.6 Hz, 1H), 6.14 (d, J = 12.0 Hz, 1H), 6.28 (d, J = 15.6 Hz, 1H), 6.29 (d, J = 16.0 Hz, 1H), 6.29 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 7.00-7.08 (m, 1H), 7.02 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.0, 2.0 Hz, 1H), 7.63 (d, J = 16.0 Hz, 1H) ppm. IR 3524, 3396, 2935, 2860, 1709, 1629, 1594, 1518, 1455, 1428, 1380, 1355, 1272, 1231, 1145, 1038, 977, 911, 850, 823, 735, 652 cm-1.R f =0.37 (3:2 hexane/EtOAc). 1H - NMR δ = 1.03 (s, 6H), 1.43-1.51 (m, 2H), 1.57-1.65 (m, 2H), 1.71 (s, 3H), 1.98-2.06 (m, 2H), 2.00 (s , 3H), 2.36 (s, 3H), 2.57 (br t, J = 4.8 Hz, 1H), 3.82 (br dd, J = 6.0, 4.8 Hz, 2H), 3.92 (s, 3H), 4.44 (d, J = 4.8 Hz, 2H), 5.20 (tt, J = 6.0, 4.8 Hz, 1H), 5.83 (s, 1H), 6.12 (d, J = 15.6 Hz, 1H), 6.14 (d, J = 12.0 Hz, 1H), 6.28 (d, J = 15.6 Hz, 1H), 6.29 (d, J = 16.0 Hz, 1H), 6.29 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H) , 7.00–7.08 (m, 1H), 7.02 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.0, 2.0 Hz, 1H), 7.63 (d, J = 16.0 Hz, 1H) ppm. IR 3524, 3396, 2935, 2860, 1709, 1629, 1594, 1518, 1455, 1428, 1380, 1355, 1272, 1231, 1145, 1038, 977, 911, 850, 823, 735, 652 cm -1 .652 cm
(2) 실시예 19(2) Example 19
1-((5-((R)-1,2-Dithiolan-3-yl)pentanoyl)oxy)-3-hydroxypropan-2-yl (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate1-((5-(( R )-1,2-Dithiolan-3-yl)pentanoyl)oxy)-3-hydroxypropan-2-yl (2 E ,4 E ,6 E ,8 E )-3,7 -dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate
실시예 19는 하기 화학식 19로 표시되는 화합물이다.Example 19 is a compound represented by Formula 19 below.
[화학식 19][Formula 19]
[합성예 19][Synthesis Example 19]
100 mL 둥근 플라스크에 상기 실시예 15(0.38 g, 1.00 mmol)와 알파-리포산 (0.21 g, 1.00 mmol), 및 DPMS (0.55 g, 2.50 mmol)를 CH2Cl2 (10 mL)에 녹인 다음, DCC (0.25 g, 1.20 mmol)를 가하고 실온에서 24시간 동안 교반한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 점성 있는 노란색 액체인 실시예 19(0.30 g, 0.53 mmol)를 53%의 수율로 얻을 수 있었다.In a 100 mL round flask, Example 15 (0.38 g, 1.00 mmol), alpha-lipoic acid (0.21 g, 1.00 mmol), and DPMS (0.55 g, 2.50 mmol) were dissolved in CH 2 Cl 2 (10 mL), DCC (0.25 g, 1.20 mmol) is added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 19 (0.30 g, 0.53 mmol) as a viscous yellow liquid in a yield of 53%.
[Data][Data]
Rf =0.52 (3:2 hexane/EtOAc). 1H-NMR δ = 1.03 (s, 6H), 1.42-1.52 (m, 4H), 1.58-1.73 (m, 6H), 1.72 (s, 3H), 1.85-1.96 (m, 1H), 1.99-2.06 (m, 2H), 2.01 (s, 3H), 2.36 (t, J = 7.6 Hz), 2.36 (s, 3H), 2.41-2.50 (m, 1H), 3.06-3.22 (m, 2H), 3.56 (quintet, J = 6.8 Hz, 1H), 3.77 (br s, 2H), 4.26-4.36 (m, 2H), 5.07-5.16 (m, 1H), 5.80 (s, 1H), 6.14 (d, J = 16.0 Hz, 1H), 6.15 (d, J = 11.2 Hz, 1H), 6.29 (d, J = 15.2 Hz, 1H), 6.29 (d, J = 16.0 Hz, 1H), 7.04 (dd, J = 15.2, 11.2 Hz, 1H) ppm. IR 3493, 2930, 2865, 1738, 1712, 1605, 1584, 1447, 1384, 1361, 1239, 1150, 1057, 973, 760 cm-1.R f =0.52 (3:2 hexane/EtOAc). 1H - NMR δ = 1.03 (s, 6H), 1.42-1.52 (m, 4H), 1.58-1.73 (m, 6H), 1.72 (s, 3H), 1.85-1.96 (m, 1H), 1.99-2.06 (m, 2H), 2.01 (s, 3H), 2.36 (t, J = 7.6 Hz), 2.36 (s, 3H), 2.41–2.50 (m, 1H), 3.06–3.22 (m, 2H), 3.56 ( quintet, J = 6.8 Hz, 1H), 3.77 (br s, 2H), 4.26–4.36 (m, 2H), 5.07–5.16 (m, 1H), 5.80 (s, 1H), 6.14 (d, J = 16.0 Hz, 1H), 6.15 (d, J = 11.2 Hz, 1H), 6.29 (d, J = 15.2 Hz, 1H), 6.29 (d, J = 16.0 Hz, 1H), 7.04 (dd, J = 15.2, 11.2 Hz, 1H) ppm. IR 3493, 2930, 2865, 1738, 1712, 1605, 1584, 1447, 1384, 1361, 1239, 1150, 1057, 973, 760 cm -1 .
(3) 실시예 20(3) Example 20
2-(((2E,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoyl)oxy)-3-hydroxypropyl 2-hydroxybenzoate2-(((2 E ,4 E ,6 E ,8 E )-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6 ,8-tetraenoyl)oxy)-3-hydroxypropyl 2-hydroxybenzoate
실시예 20은 하기 화학식 20으로 표시되는 화합물이다.Example 20 is a compound represented by Formula 20 below.
[화학식 20][Formula 20]
[합성예 20][Synthesis Example 20]
100 mL 둥근 플라스크에 상기 실시예 15(0.25 g, 0.67 mmol)와 살리실산 (90 mg, 0.67 mmol), 및 DPMS (0.36 g, 1.67 mmol)를 CH2Cl2 (20 mL)에 녹인 다음, DCC (0.16 g, 0.80 mmol)를 가하고 실온에서 24시간 동안 교반한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시예 20(45 mg, 0.90 mmol)을 14%의 수율로 얻을 수 있었다.Example 15 (0.25 g, 0.67 mmol), salicylic acid (90 mg, 0.67 mmol), and DPMS (0.36 g, 1.67 mmol) were dissolved in CH 2 Cl 2 (20 mL) in a 100 mL round flask, then DCC ( 0.16 g, 0.80 mmol) was added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 20 (45 mg, 0.90 mmol) in a yield of 14%.
[Data][Data]
Rf =0.67 (3:2 hexane/EtOAc). 1H-NMR δ = 1.03 (s, 6H), 1.44-1.52 (m, 2H), 1.57-1.66 (m, 2H), 1.71 (s, 3H), 1.99-2.06 (m, 2H), 2.01 (s, 3H), 2.36 (s, 3H), 3.88 (br d, J = 4.4 Hz, 2H), 3.92 (s, 3H), 4.55 (d of A of ABq, JAB = 12.0, Jd = 6.0 Hz, 1H), 4.60 (d of B of ABq, JAB = 12.0, Jd = 4.8 Hz, 1H),5.29 (tt, J = 6.0, 4.8 Hz, 1H), 5.81 (s, 1H), 6.14 (d, J = 16.0 Hz, 1H), 6.14 (d, J = 11.2 Hz, 1H), 6.28 (d, J = 16.0 Hz, 1H), 6.28 (d, J = 15.2 Hz, 1H), 6.88 (dt, Jd = 1.6, Jt = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 7.03 (dd, J = 15.2, 11.2 Hz, 1H), 7.46 (dt, Jd = 1.6, Jt = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 10.59 (s, 1H) ppm. IR 3463, 3217, 2951, 2912, 2870, 1679, 1619, 1589, 1486, 1448, 1394, 1360, 1303, 1252, 1215, 1153, 1086, 1055, 973, 760 cm-1.R f =0.67 (3:2 hexane/EtOAc). 1 H-NMR δ = 1.03 (s, 6H), 1.44-1.52 (m, 2H), 1.57-1.66 (m, 2H), 1.71 (s, 3H), 1.99-2.06 (m, 2H), 2.01 (s , 3H), 2.36 (s, 3H), 3.88 (br d, J = 4.4 Hz, 2H), 3.92 (s, 3H), 4.55 (d of A of ABq, J AB = 12.0, J d = 6.0 Hz, 1H), 4.60 (d of B of ABq, J AB = 12.0, J d = 4.8 Hz, 1H), 5.29 (tt, J = 6.0, 4.8 Hz, 1H), 5.81 (s, 1H), 6.14 (d, J = 16.0 Hz, 1H), 6.14 (d, J = 11.2 Hz, 1H), 6.28 (d, J = 16.0 Hz, 1H), 6.28 ( d , J = 15.2 Hz, 1H), 6.88 (dt, J = 1H) = 1.6, J t = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 7.03 (dd, J = 15.2, 11.2 Hz, 1H), 7.46 (dt, J = 1.6, J t = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 10.59 (s, 1H) ppm. IR 3463, 3217, 2951, 2912, 2870, 1679, 1619, 1589, 1486, 1448, 1394, 1360, 1303, 1252, 1215, 1153, 1086, 1055, 973, 760 cm -1 .
(4) 실시예 21(4) Example 21
2-((5-((R)-1,2-Dithiolan-3-yl)pentanoyl)oxy)-3-hydroxypropyl (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate2-((5-(( R )-1,2-Dithiolan-3-yl)pentanoyl)oxy)-3-hydroxypropyl (2 E ,4 E ,6 E ,8 E )-3,7-dimethyl-9 -(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate
실시예 21은 하기 화학식 21로 표시되는 화합물이다.Example 21 is a compound represented by Formula 21 below.
[화학식 21][Formula 21]
[합성예 21][Synthesis Example 21]
100 mL 둥근 플라스크에 상기 실시준비예 8-2(62 mg, 0.22 mmol)와 레티놀산 (67 mg, 0.22 mmol), 및 DPMS (100 mg, 2.20 mmol)를 CH2Cl2 (20 mL)에 녹인 다음, DCC (45 mg, 0.22 mmol)를 가하고 실온에서 24시간 동안 교반한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시예 21(17 mg, 0.03 mmol)을 13%의 수율로 얻을 수 있었다.In a 100 mL round flask, Example 8-2 (62 mg, 0.22 mmol), retinol acid (67 mg, 0.22 mmol), and DPMS (100 mg, 2.20 mmol) were dissolved in CH 2 Cl 2 (20 mL). Next, DCC (45 mg, 0.22 mmol) was added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 21 (17 mg, 0.03 mmol) in a yield of 13%.
[Data][Data]
Rf = 0.44 (3:2 hexane/EtOAc). 1H-NMR δ = 1.03 (s, 6H), 1.40-1.53 (m, 4H), 1.58-1.76 (m, 6H), 1.72 (s, 3H), 1.84-1.98 (m, 1H), 2.01 (s, 3H), 2.03 (t, J = 6.4 Hz, 2H), 2.36 (s, 3H), 2.38 (t, J = 7.2 Hz), 2.41-2.51 (m, 1H), 3.06-3.22 (m, 2H), 3.57 (quintet, J = 6.4 Hz, 1H), 3.76 (br t, J = 5.2 Hz, 1H), 4.08-4.26 (m, 4H), 4.26-4.38 (m, 1H), 5.80 (s, 1H), 6.15 (d, J = 16.0 Hz, 1H), 6.15 (d, J = 11.2 Hz, 1H), 6.29 (d, J = 14.8 Hz, 1H), 6.29 (d, J = 16.0 Hz, 1H), 7.03 (dd, J = 14.8, 11.2 Hz, 1H) ppm. 13C-NMR δ = 12.9, 14.0, 19.2, 21.8, 24.6, 28.7, 29.0, 29.0, 33.1, 33.9, 34.3, 34.6, 38.5, 39.6, 40.2, 56.3, 64.6, 65.2, 68.4, 117.3, 129.0, 129.4, 130.2, 131.7, 134.7, 137.2, 137.7, 140.2, 154.4, 167.1, 173.5 ppm. IR 3476, 2936, 2873, 1745, 1720, 1611, 1577, 1450, 1385, 1356, 1239, 1151, 1046, 970, 760 cm-1.R f = 0.44 (3:2 hexane/EtOAc). 1H - NMR δ = 1.03 (s, 6H), 1.40-1.53 (m, 4H), 1.58-1.76 (m, 6H), 1.72 (s, 3H), 1.84-1.98 (m, 1H), 2.01 (s , 3H), 2.03 (t, J = 6.4 Hz, 2H), 2.36 (s, 3H), 2.38 (t, J = 7.2 Hz), 2.41–2.51 (m, 1H), 3.06–3.22 (m, 2H) , 3.57 (quintet, J = 6.4 Hz, 1H), 3.76 (br t, J = 5.2 Hz, 1H), 4.08–4.26 (m, 4H), 4.26–4.38 (m, 1H), 5.80 (s, 1H) , 6.15 (d, J = 16.0 Hz, 1H), 6.15 (d, J = 11.2 Hz, 1H), 6.29 (d, J = 14.8 Hz, 1H), 6.29 (d, J = 16.0 Hz, 1H), 7.03 (dd, J = 14.8, 11.2 Hz, 1H) ppm. 13 C-NMR δ = 12.9, 14.0, 19.2, 21.8, 24.6, 28.7, 29.0, 29.0, 33.1, 33.9, 34.3, 34.6, 38.5, 39.6, 40.2, 56.3, 64.6, 65.2, 68.4, 117.3, 129.4, 130.2, 131.7 134.7, 137.2, 137.7, 140.2, 154.4, 167.1, 173.5 ppm. IR 3476, 2936, 2873, 1745, 1720, 1611, 1577, 1450, 1385, 1356, 1239, 1151, 1046, 970, 760 cm -1 .
(5) 실시예 22(5) Example 22
1-Hydroxy-3-(((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)propan-2-yl 5-((R)-1,2-dithiolan-3-yl)pentanoate1-Hydroxy-3-((( E )-3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)propan-2-yl 5-(( R )-1,2-dithiolan-3-yl)pentanoate
실시예 22는 하기 화학식 22로 표시되는 화합물이다.Example 22 is a compound represented by Formula 22 below.
[화학식 22][Formula 22]
[합성예 22][Synthesis Example 22]
100 mL 둥근 플라스크에 상기 실시준비예 8-2(130 mg, 0.46 mmol)와 퍼룰릭산 (90 mg, 0.46 mmol), 및 DPMS (220 mg, 2.20 mmol)를 CH2Cl2 (30 mL)에 녹인 다음, DCC (90 mg, 0.46 mmol)을 가하고 실온에서 24시간 동안 교반한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시예 22(85 mg, 0.19 mmol)를 40%의 수율로 얻을 수 있었다.In a 100 mL round flask, Example 8-2 (130 mg, 0.46 mmol), ferulic acid (90 mg, 0.46 mmol), and DPMS (220 mg, 2.20 mmol) were dissolved in CH 2 Cl 2 (30 mL). Next, DCC (90 mg, 0.46 mmol) was added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 22 (85 mg, 0.19 mmol) in a yield of 40%.
[Data][Data]
Rf = 0.12 (3:2 hexane/EtOAc). 1H-NMR δ = 1.40-1.57 (m, 2H), 1.60-1.77 (m, 4H), 1.83-1.96 (m, 1H), 2.39 (dd, J = 7.6, 7.2 Hz, 2H), 2.40-2.50 (m, 1H), 3.04-3.22 (m, 2H), 3.50-3.61 (m, 1H), 3.80 (dd, J = 11.2, 4.8 Hz, 1H), 3.93 (s, 3H), 4.14-4.43 (m, 5H), 5.96 (br s, 1H), 6.32 (d, J = 15.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 7.08 (dd, J = 8.0, 1.6 Hz, 1H), 7.65 (d, J = 15.6 Hz, 1H) ppm. 13C-NMR δ = 24.6, 28.7, 33.8, 34.5, 38.4, 40.2, 55.9, 56.3, 65.2, 68.4, 72.3, 109.4, 114.4, 114.8, 123.3, 126.7, 145.9, 146.8, 148.2, 167.3, 173.5 ppm. HRMS (ESI): calcd for C21H28O7S2+Na 479.1169, found 479.1172.R f = 0.12 (3:2 hexane/EtOAc). 1H - NMR δ = 1.40-1.57 (m, 2H), 1.60-1.77 (m, 4H), 1.83-1.96 (m, 1H), 2.39 (dd, J = 7.6, 7.2 Hz, 2H), 2.40-2.50 (m, 1H), 3.04–3.22 (m, 2H), 3.50–3.61 (m, 1H), 3.80 (dd, J = 11.2, 4.8 Hz, 1H), 3.93 (s, 3H), 4.14–4.43 (m) , 5H), 5.96 (br s, 1H), 6.32 (d, J = 15.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 7.08 ( dd, J = 8.0, 1.6 Hz, 1H), 7.65 (d, J = 15.6 Hz, 1H) ppm. 13 C-NMR δ = 24.6, 28.7, 33.8, 34.5, 38.4, 40.2, 55.9, 56.3, 65.2, 68.4, 72.3, 109.4, 114.4, 114.8, 123.3, 126.7, 145.9, 5, 146.3.8 ppm HRMS (ESI): calcd for C 21 H 28 O 7 S 2 +Na 479.1169, found 479.1172.
(6) 실시예 23(6) Example 23
2-((5-((R)-1,2-Dithiolan-3-yl)pentanoyl)oxy)-3-hydroxypropyl 2-hydroxybenzoate2-((5-(( R )-1,2-Dithiolan-3-yl)pentanoyl)oxy)-3-hydroxypropyl 2-hydroxybenzoate
실시예 23은 하기 화학식 23으로 표시되는 화합물이다.Example 23 is a compound represented by Formula 23 below.
[화학식 23][Formula 23]
[합성예 23][Synthesis Example 23]
100 mL 둥근 플라스크에 상기 실시준비예 8-2(46 mg, 0.16 mmol)와 살리실산 (34 mg, 0.25 mmol) 및 DPMS (90 mg, 0.41 mmol)를 CH2Cl2 (10 mL)에 녹인 다음, DCC (40 mg, 0.20 mmol)를 가하고 실온에서 24시간 동안 교반한다. H2O를 가하여 반응을 종결하고, CH2Cl2로 유기층을 추출한 다음, 무수 황산 나트륨으로 수분을 제거하고 거름 종이로 거르고 감압 농축한다. 농축된 결과물을 실리카겔 컬럼 크로마토그래피의 방법으로 정제하여 실시예 23(85 mg, 0.19 mmol)을 31%의 수율로 얻을 수 있었다.Dissolve Example 8-2 (46 mg, 0.16 mmol), salicylic acid (34 mg, 0.25 mmol) and DPMS (90 mg, 0.41 mmol) in CH 2 Cl 2 (10 mL) in a 100 mL round flask, DCC (40 mg, 0.20 mmol) is added and stirred at room temperature for 24 hours. The reaction was terminated by adding H 2 O, and the organic layer was extracted with CH 2 Cl 2 , dried with anhydrous sodium sulfate, filtered through filter paper, and concentrated under reduced pressure. The concentrated product was purified by silica gel column chromatography to obtain Example 23 (85 mg, 0.19 mmol) in a yield of 31%.
[Data][Data]
Rf = 0.37 (3:2 hexane/EtOAc). 1H-NMR δ = 1.40-1.56 (m, 2H), 1.60-1.76 (m, 4H), 1.91 (ddt, Jd = 12.4, 6.8, Jt = 6.8 Hz, 1H), 2.38 (t, J = 7.2 Hz, 2H), 2.46 (ddt, Jd = 12.4, 6.0, Jt = 6.4 Hz, 1H), 2.58 (br s, 1H), 3.11 (t of A of ABq, JAB = 11.2, Jt = 6.8 Hz, 1H), 3.18 (dd of B of ABq, JAB = 11.2, Jd = 7.2, 5.6 Hz, 1H), 3.57 (ddt, Jd
= 8.4, 6.4, Jt = 6.0 Hz, 1H), 4.20-4.34 (m, 3H), 4.42 (d of A of ABq, JAB = 11.6, Jd = 5.2 Hz, 1H), 4.46 (d of B of ABq, JAB = 11.6, Jd = 4.4 Hz, 1H), 6.90 (dt, Jd = 0.8, Jt = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 7.48 (dt, Jd = 1.6, Jt = 8.0 Hz, 1H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 10.58 (br s, 1H) ppm. 13C-NMR δ = 24.7, 28.7, 33.8, 34.5, 38.5, 40.2, 56.3, 65.2, 65.7, 68.2, 111.9, 117.7, 119.3, 129.9, 136.2, 161.7, 169.3, 173.6 ppm. IR 3480, 3208, 2936, 2853, 1736, 1685, 1617, 1585, 1491, 1459, 1385, 1303, 1254, 1208, 1152, 1136, 1081, 1030, 985, 756, 702, 670 cm-1. HRMS (ESI): calcd for C18H24O6S2+Na 423.0907, found 423.0910.R f = 0.37 (3:2 hexane/EtOAc). 1 H-NMR δ = 1.40-1.56 (m, 2H), 1.60-1.76 (m, 4H), 1.91 (ddt, J d = 12.4, 6.8, J t = 6.8 Hz, 1H), 2.38 (t, J = 7.2 Hz, 2H), 2.46 (ddt, J d = 12.4, 6.0, J t = 6.4 Hz, 1H), 2.58 (br s, 1H), 3.11 (t of A of ABq, J AB = 11.2, J t = 6.8 Hz, 1H), 3.18 (dd of B of ABq, J AB = 11.2, J d = 7.2, 5.6 Hz, 1H), 3.57 (ddt, J d = 8.4, 6.4, J t = 6.0 Hz, 1H), 4.20–4.34 (m, 3H), 4.42 (d of A of ABq, J AB = 11.6, J d = 5.2 Hz, 1H), 4.46 (d of B of ABq, J AB = 11.6, J d = 4.4 Hz, 1H), 6.90 (dt, J d = 0.8, J t = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 7.48 (dt , Jd = 1.6, Jt = 8.0 Hz, 1H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 10.58 (br s , 1H) ppm. 13 C-NMR δ = 24.7, 28.7, 33.8, 34.5, 38.5, 40.2, 56.3, 65.2, 65.7, 68.2, 111.9, 117.7, 119.3, 129.9, 136.2, 161.7, 169.3, 173.6 ppm. IR 3480, 3208, 2936, 2853, 1736, 1685, 1617, 1585, 1491, 1459, 1385, 1303, 1254, 1208, 1152, 1136, 1081, 1030, 985, 756, 702 cm -1 6 7 . HRMS (ESI): calcd for C 18 H 24 O 6 S 2 +Na 423.0907, found 423.0910.
이상에서 본 발명의 바람직한 실시예들에 대하여 상세하게 설명하였지만 본 발명의 권리 범위는 이에 한정되는 것은 아니고 다음의 청구범위에서 정의하고 있는 본 발명의 기본 개념을 이용한 당업자의 여러 변형 및 개량 형태 또한 본 발명의 권리범위에 속하는 것이다.Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements of those skilled in the art using the basic concept of the present invention defined in the following claims are also present. fall within the scope of the invention.
Claims (9)
- 하기 일반식 1로 표시되는 신규한 글리세라이드 화합물.A novel glyceride compound represented by the following general formula 1.[일반식 1][Formula 1]
(상기 일반식 1에서 R1은 유기산 유래 치환기이고, R1-OH는 레티놀산, 퍼룰릭산, 알파-리포산, 코직산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R1-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.)(In Formula 1, R 1 is an organic acid-derived substituent, R 1 -OH is any one organic acid selected from the group consisting of retinol acid, ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid, and the H of R 1 -OH is a hydrogen atom with the lowest pKa in the molecular structure of the organic acid.) - 하기 일반식 2로 표시되는 신규한 글리세라이드 화합물.A novel glyceride compound represented by the following general formula 2.[일반식 2][Formula 2]
(상기 일반식 2에서 R2는, 유기산 유래 치환기이고, R2-OH는 퍼룰릭산, 알파-리포산, 코직산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R2-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.)(In Formula 2, R 2 is an organic acid-derived substituent, R 2 -OH is any one organic acid selected from the group consisting of ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid, and H of R 2 -OH is It is the hydrogen atom with the lowest pKa in the molecular structure of an organic acid.) - 하기 일반식 3으로 표시되는 신규한 글리세라이드 화합물.A novel glyceride compound represented by the following general formula 3.[일반식 3][Formula 3]
(상기 일반식 3에서 R3은, 유기산 유래 치환기이고, R3-OH는 레티놀산, 퍼룰릭산, 알파-리포산, 코직산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R3-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다)(In Formula 3, R 3 is an organic acid-derived substituent, R 3 -OH is any organic acid selected from the group consisting of retinol acid, ferulic acid, alpha-lipoic acid, kojic acid, and salicylic acid, and R 3 -OH H is a hydrogen atom with the lowest pKa in the molecular structure of the organic acid) - 하기 일반식 4로 표시되는 신규한 글리세라이드 화합물.A novel glyceride compound represented by the following general formula 4.[일반식 4][Formula 4]
(상기 일반식 4에서 R4는, 유기산 유래 치환기이고, R4-OH는 레티놀산, 퍼룰릭산 유래 아세테이트 유도체 및 살리실산 유래 아세테이트 유도체로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R4-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.)(In Formula 4, R 4 is an organic acid-derived substituent, R 4 -OH is any organic acid selected from the group consisting of retinoic acid, ferulic acid-derived acetate derivatives and salicylic acid-derived acetate derivatives, and R 4 -OH H is a hydrogen atom with the lowest pKa in the molecular structure of the organic acid.) - 하기 일반식 5로 표시되는 신규한 글리세라이드 화합물.A novel glyceride compound represented by the following general formula 5.[일반식 5][Formula 5]
(상기 일반식 5에서 R5는, 유기산 유래 치환기이고, R5-OH는 퍼룰릭산, 알파-리포산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R5-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.)(In Formula 5, R 5 is a substituent derived from an organic acid, R 5 -OH is any one organic acid selected from the group consisting of ferulic acid, alpha-lipoic acid, and salicylic acid, and H of R 5 -OH is the organic acid It is the hydrogen atom with the lowest pKa in its molecular structure.) - 하기 일반식 6으로 표시되는 신규한 글리세라이드 화합물.A novel glyceride compound represented by the following general formula 6.[일반식 6][Formula 6]
(상기 일반식 6에서, R6은 유기산 유래 치환기이고, R6-OH는 레티놀산, 퍼룰릭산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R6-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.)(In Formula 6, R 6 is an organic acid-derived substituent, R 6 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid, and salicylic acid, and H of R 6 -OH is a molecule of the organic acid It is the hydrogen atom with the lowest pKa in the structure.) - (S1) 글리세롤과 벤즈알데하이드계 화합물을 혼합하여 상기 글리세롤에 보호기를 부착하는 단계;(S1) attaching a protecting group to the glycerol by mixing glycerol and a benzaldehyde-based compound;(S2) 상기 보호기가 부착된 글리세롤과, 제1 카르복실산 화합물을 혼합하여 에스테르 화합물을 제조하는 단계; 및(S2) preparing an ester compound by mixing the protecting group-attached glycerol and the first carboxylic acid compound; and(S3) 상기 에스테르 화합물을 탈보호시킨 뒤, 상기 탈보호된 에스테르 화합물을 제2 카르복실산 화합물과 혼합하여 1,2-디글리세라이드 화합물을 제조하는 단계;를 포함하고,(S3) preparing a 1,2-diglyceride compound by deprotecting the ester compound and then mixing the deprotected ester compound with a second carboxylic acid compound;상기 제1 및 제2 카르복실산 화합물은 각각 독립적으로, The first and second carboxylic acid compounds are each independently,레티놀산, 퍼룰릭산, 알파-리포산 및 살리실산으로 이루어진 군에서 선택된 어느 하나이고,any one selected from the group consisting of retinol acid, ferulic acid, alpha-lipoic acid and salicylic acid;상기 제1 및 제2 카르복실산 화합물은 서로 상이한The first and second carboxylic acid compounds are different from each other신규한 글리세라이드 화합물의 제조방법.A method for producing a novel glyceride compound.
- 제7항에 있어서,According to claim 7,상기 1,2-디글리세라이드 화합물은,The 1,2-diglyceride compound,하기 일반식 5로 표시되는 것인Which is represented by the following general formula 5신규한 글리세라이드 화합물의 제조방법.A method for producing a novel glyceride compound.[일반식 5][Formula 5]
(상기 일반식 5에서 R5는, 유기산 유래 치환기이고, R5-OH는 퍼룰릭산, 알파-리포산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R5-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.)(In Formula 5, R 5 is a substituent derived from an organic acid, R 5 -OH is any one organic acid selected from the group consisting of ferulic acid, alpha-lipoic acid, and salicylic acid, and H of R 5 -OH is the organic acid It is the hydrogen atom with the lowest pKa in its molecular structure.) - 제7항에 있어서,According to claim 7,상기 1,2-디글리세라이드 화합물은,The 1,2-diglyceride compound,하기 일반식 6으로 표시되는 것인Which is represented by the following general formula 6신규한 글리세라이드 화합물의 제조방법.A method for producing a novel glyceride compound.[일반식 6][Formula 6]
(상기 일반식 6에서, R6은 유기산 유래 치환기이고, R6-OH는 레티놀산, 퍼룰릭산 및 살리실산으로 이루어진 군에서 선택된 어느 하나의 유기산이고, 상기 R6-OH의 H는 상기 유기산의 분자 구조 내에서 pKa가 가장 낮은 수소 원자이다.)(In Formula 6, R 6 is an organic acid-derived substituent, R 6 -OH is any one organic acid selected from the group consisting of retinoic acid, ferulic acid, and salicylic acid, and H of R 6 -OH is a molecule of the organic acid It is the hydrogen atom with the lowest pKa in the structure.)
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| KR20130001451A (en) * | 2011-06-27 | 2013-01-04 | 명지대학교 산학협력단 | New functional glycerol derivatives of vitamin e and retinoic acid, and synthetic method of the same |
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| KR20090018828A (en) * | 2006-05-19 | 2009-02-23 | 마리 케이 인코포레이티드 | Glyceryl and glycol acid compounds |
| KR20130001451A (en) * | 2011-06-27 | 2013-01-04 | 명지대학교 산학협력단 | New functional glycerol derivatives of vitamin e and retinoic acid, and synthetic method of the same |
| CN104230709A (en) * | 2014-09-24 | 2014-12-24 | 上海大学 | Preparation method of beta-glycol monoacetate |
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| BÓDAI VIKTÓRIA, NOVÁK LAJOS, POPPE LÁSZLÓ: "Synthesis and Lipase-Catalyzed Enantiotope Selective Acetylation of 2-Benzoyloxy-1,3-propanediol", SYNLETT, vol. 1999, no. 6, 1 June 1999 (1999-06-01), DE , pages 759 - 761, XP093012736, ISSN: 0936-5214, DOI: 10.1055/s-1999-2720 * |
| CHOI BO SEUL, CHOI JEONGAE, BAK SEONYOUNG, KOO SANGHO: "Regioselective Synthesis of 1,3- and 1,2-Tocopheryl Glyceride Ethers of Carboxylic Acids : 1,3- and 1,2-Tocopheryl Glyceride Ethers of Carboxylic Acids", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2015, no. 3, 1 January 2015 (2015-01-01), DE , pages 514 - 524, XP093012741, ISSN: 1434-193X, DOI: 10.1002/ejoc.201403267 * |
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