KR100230653B1 - Water stable L-ascorbic acid derivatives and a method for preparation thereof - Google Patents
Water stable L-ascorbic acid derivatives and a method for preparation thereof Download PDFInfo
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- KR100230653B1 KR100230653B1 KR1019970023005A KR19970023005A KR100230653B1 KR 100230653 B1 KR100230653 B1 KR 100230653B1 KR 1019970023005 A KR1019970023005 A KR 1019970023005A KR 19970023005 A KR19970023005 A KR 19970023005A KR 100230653 B1 KR100230653 B1 KR 100230653B1
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- Prior art keywords
- ascorbic acid
- organic solvent
- derivative
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- 150000000996 L-ascorbic acids Chemical class 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims description 18
- 238000002360 preparation method Methods 0.000 title description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 105
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 53
- 239000002211 L-ascorbic acid Substances 0.000 claims abstract description 49
- 235000000069 L-ascorbic acid Nutrition 0.000 claims abstract description 49
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 28
- KTJQXXIVWRXBCC-UHFFFAOYSA-N 2-chloro-1,3,2$l^{5}-oxazaphosphinane 2-oxide Chemical compound ClP1(=O)NCCCO1 KTJQXXIVWRXBCC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000007530 organic bases Chemical class 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000003495 polar organic solvent Substances 0.000 claims abstract description 7
- -1 phenylethylidene group Chemical group 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000008213 purified water Substances 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- JYCULSYEFRCGNR-UHFFFAOYSA-N O=P1OC=CC=N1 Chemical compound O=P1OC=CC=N1 JYCULSYEFRCGNR-UHFFFAOYSA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001412 amines Chemical group 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 230000001012 protector Effects 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 239000000243 solution Substances 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 239000002537 cosmetic Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004040 coloring Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000013049 sediment Substances 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KUQZVISZELWDNZ-UHFFFAOYSA-N 3-aminopropyl dihydrogen phosphate Chemical compound NCCCOP(O)(O)=O KUQZVISZELWDNZ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ACFGRWJEQJVZTM-LEJBHHMKSA-L Magnesium L-ascorbic acid-2-phosphate Chemical compound [Mg+2].OC[C@H](O)[C@H]1OC(=O)C(OP([O-])([O-])=O)=C1O ACFGRWJEQJVZTM-LEJBHHMKSA-L 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 0 O=P1(**CCC*1)Cl Chemical compound O=P1(**CCC*1)Cl 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000003712 anti-aging effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002087 whitening effect Effects 0.000 description 2
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- BKMMTJMQCTUHRP-UHFFFAOYSA-N 2-aminopropan-1-ol Chemical compound CC(N)CO BKMMTJMQCTUHRP-UHFFFAOYSA-N 0.000 description 1
- 206010014970 Ephelides Diseases 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- 208000003351 Melanosis Diseases 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 206010047623 Vitamin C deficiency Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008099 melanin synthesis Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- QMOLOYHRWXFQRZ-UHFFFAOYSA-N phosphoric acid;propan-1-amine Chemical compound CCCN.OP(O)(O)=O QMOLOYHRWXFQRZ-UHFFFAOYSA-N 0.000 description 1
- YOPKGUUNMWGPCZ-UHFFFAOYSA-N phosphoric acid;propane Chemical compound CCC.OP(O)(O)=O YOPKGUUNMWGPCZ-UHFFFAOYSA-N 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 208000010233 scurvy Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000012607 strong cation exchange resin Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
본 발명은 하기 구조식 (I)로 표시되는 수안정형 L-아스코르빈산 유도체 및 그의 제조방법에 관한 것으로, 3-아미노-1-프로판올과 옥시염화인을 1 : 1~1.3의 당량비로 유기염기 존재하에 유기용매하에서 반응시켜서 생성된 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드와 5,6-수산기가 보호된 L-아스코르빈산을 유기염기 존재하에 유기용매에서 반응시킨 후, 가수분해하고 극성 유기용매로 결정화함을 특징으로 한다.The present invention relates to a water-stable L-ascorbic acid derivative represented by the following structural formula (I) and a method for preparing the same, wherein 3-amino-1-propanol and phosphorus oxychloride are present in an organic base in an equivalent ratio of 1: 1 to 1.3. 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide and L-ascorbic acid protected by 5,6-hydroxy group formed by reaction under an organic solvent in the presence of organic base After reacting at, it is hydrolyzed and crystallized with a polar organic solvent.
(Ⅰ)(Ⅰ)
Description
본 발명은 하기 구조식(Ⅰ)로 표시되는 수안정형 L-아스코르빈산 유도체 및 그의 제조방법에 관한 것이다. 더욱 상세하게는 수안정성이 매우 우수하고, 3-아미노프로판인산과 L-아스코르빈산이 인산 디에스테르 형태로 연결되어 있기 때문에 생체내의 효소에 의해 분해되어 3-아미노프로판인산과 L-아스코르빈산의 생리활성도 나타낼 수 있는 L-아스코르빈산의 유도체 및 그의 제조방법에 관한 것이다.The present invention relates to a water-stable L-ascorbic acid derivative represented by the following structural formula (I) and a preparation method thereof. More specifically, the water stability is very excellent, and since 3-aminopropanoic acid and L-ascorbic acid are linked in the form of phosphate diester, it is decomposed by enzymes in vivo and 3-aminopropaneic acid and L-ascorbic acid. It relates to a derivative of L-ascorbic acid which can also exhibit the physiological activity of and a preparation method thereof.
(I)(I)
L-아스코르빈산은 강한 항산화 작용을 가진 생체 활성물질로서 괴혈병 치료에 사용되며, 기미나 주근깨 등의 원인인 멜라닌 색소의 축적을 억제하는 등의 다양한 생리활성 및 약리 효과 때문에 의약품, 화장품, 식품 등 여러 분야에 응용되고 있다. 그러나, L-아스코르빈산은 수상에서 쉽게 산화되어 분해되기 때문에 의약품, 화장품, 식품등에 응용시 장기간 보관하는 경우나 제조 공정에서 역가의 감소를 가져올 뿐만 아니라, 색상을 변색시키는 등 많은 문제점이 있다.L-ascorbic acid is a bioactive substance with strong antioxidant activity and is used for the treatment of scurvy, and because of various physiological and pharmacological effects such as inhibiting the accumulation of melanin pigment, which causes blemishes and freckles, medicines, cosmetics, food, etc. It is applied to various fields. However, since L-ascorbic acid is easily oxidized and decomposed in an aqueous phase, there are many problems such as color change in color as well as a decrease in the titer in the case of long-term storage or manufacturing process when applied to medicines, cosmetics, and food.
따라서, L-아스코르빈산의 수상에서의 불안정성을 개선하기 위해서 많은 유도체들이 개발되어 왔고, 그 예로는 L-아스코르빈산의 2-포스페이트 마그네슘염, 폴리포스페이트 무기염, 2-설페이트 무기염, 2-글루코스등이 있다. 특히, 상기한 유도체들 중에서 L-아스코르빈산의 안정화가 뛰어난 L-아스코르빈산-2-포스페이트 마그네슘염의 경우에는 이를 유효성분으로 하는 미백화장료의 제조가 공지(일본공개특허공보 평 1-283208호, 일본공개특허공보 평 3-227907호)되어 있으나, 이 유도체 또한 수상 제품에 적용하는 경우 변색현상과 자체적으로 불용성 결정이 생성되어 침전현상이 생기는 등 많은 문제점을 야기시켰다. 따라서, 착색 방지를 위한 고순도 화합물을 얻기 위한 정제방법과 침전현상을 개선하는 방법들도 공지되어 있으나(일본공개특허공소 소 62-30791호 및 일본 공개특허공보 평 4-275206호), 효과적이지 못하다.Therefore, many derivatives have been developed to improve the instability of the L-ascorbic acid in the water phase, for example, 2-phosphate magnesium salt, polyphosphate inorganic salt, 2-sulfate inorganic salt, 2 of L-ascorbic acid. -Glucose, etc. Particularly, in the case of L-ascorbic acid-2-phosphate magnesium salt having excellent stabilization of L-ascorbic acid among the above-mentioned derivatives, the production of a whitening cosmetic using the same as an active ingredient is known (Japanese Patent Laid-Open No. 1-283208). , Japanese Patent Application Laid-Open No. 3-227907), but this derivative also causes a number of problems such as discoloration and insoluble crystals generated by itself when applied to an aqueous product. Therefore, purification methods for obtaining high purity compounds for preventing coloration and methods for improving precipitation phenomenon are also known (Japanese Patent Laid-Open No. 62-30791 and Japanese Patent Laid-Open No. 4-275206), but are not effective. .
이에, 본 발명자들은 L-아스코르빈산 유도체의 상기한 문제점을 해결할 목적으로, 수안정형 L-아스코르빈산의 유도체를 개발하고자 예의 연구하였다. 그 결과, 섬유아세포의 증식 및 콜라겐 합성에 관한 효과와 피부에 대한 안정성이 매우 우수하여 노화방지용 화장료 조성물의 유효성분으로 널리 사용되고 있음이 공지된 3-아미노프로판인산을 L-아스코르빈산의 2-위치에 인산디에스테르 형태로 연결시키는 경우, 상기한 목적을 달성할 수 있음을 발견하고 본 발명을 완성하게 되었다.Accordingly, the present inventors earnestly studied to develop derivatives of water-stable L-ascorbic acid in order to solve the above problems of L-ascorbic acid derivatives. As a result, 3-aminopropane phosphoric acid, which is known to be widely used as an active ingredient of anti-aging cosmetic composition because of its excellent effect on the proliferation and collagen synthesis of fibroblasts and the stability to the skin, was selected from 2- of L-ascorbic acid. When linked to the position in the diester phosphate form, it was found that the above object can be achieved and the present invention has been completed.
따라서, 본 발명의 목적은 하기 구조식(Ⅰ)로 표시되는 수안정형 L-아스코르빈산의 유도체를 제공하는 것이다.Accordingly, an object of the present invention is to provide a derivative of water-stable L-ascorbic acid represented by the following structural formula (I).
(Ⅰ)(Ⅰ)
나아가, 본 발명의 다른 목적은, 상기한 L-아스코르빈산의 제조방법을 제공하는 것이다.Furthermore, another object of the present invention is to provide a method for producing L-ascorbic acid described above.
상기한 목적은, 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드와 5,6-수산기가 보호된 L-아스코르빈산을 반응시킴으로써 달성될 수 있으며, 보다 구체적으로 본 발명에 따른 L-아스코르빈산 유도체의 제조방법은, 우선, 3-아미노-1-프로판올과 옥시염화인을 1 : 1~1.3의 당량비로 유기염기 존재하에 유기용매하에서 0∼5℃의 온도로 1∼2시간 동안 반응시켜서 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드를 제조한 후, 이를 유기용매 존재하에 5,6-수산기가 보호된 L-아스코르빈산과 반응시키고, 가수분해한 후, 극성 유기용매로 결정화시킴을 특징으로 한다.The above object can be achieved by reacting 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide with L-ascorbic acid in which a 5,6-hydroxy group is protected, more specifically As a method for producing an L-ascorbic acid derivative according to the present invention, first, 3-amino-1-propanol and phosphorus oxychloride are in an organic solvent in the presence of an organic base at an equivalent ratio of 1: 1 to 1.3, at 0 to 5 ° C. The reaction was carried out at a temperature of 1 to 2 hours to prepare 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide, which was then protected by L- with 5,6-hydroxyl group protected in the presence of an organic solvent. It is characterized by reacting with ascorbic acid, hydrolyzing and crystallizing with a polar organic solvent.
이하 본 발명을 보다 구체적으로 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명에 따른 L-아스코르빈산 유도체의 제조방법은,Method for producing L-ascorbic acid derivatives according to the present invention,
(A) 3-아미노-1-프로판올과 옥시염화인을 1 : 1~1.3의 당량비로 유기염기 존재하에 유기용매하에서 0∼5℃의 온도로 1∼2시간 동안 반응시켜 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드를 생성시키는 단계 ;(A) 3-amino-1-propanol and phosphorus oxychloride were reacted for 1 to 2 hours at an temperature of 0 to 5 DEG C in an organic solvent in the presence of an organic base in an equivalent ratio of 1: 1 to 1.3. Producing 2H-1,3,2-oxazaphosphorine P-oxide;
(B) L-아스코르빈산의 5,6-수산기를 보호기(protective group)와 반응시켜 5,6-수산기가 보호된 L-아스코르빈산을 생성시키는 단계 ;(B) reacting the 5,6-hydroxyl group of L-ascorbic acid with a protective group to produce L-ascorbic acid in which the 5,6-hydroxyl group is protected;
(C) 상기 (A)단계에서 생성된 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드와 상기 (B)단계에서 생성된 5,6-수산기가 보호된 L-아스코르빈산을 유기염기 존재하에 유기용매에서 반응시키는 단계;(C) L protected with 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide produced in step (A) and 5,6-hydroxyl group produced in step (B) Reacting ascorbic acid in an organic solvent in the presence of an organic base;
(D) 반응액을 여과하여 얻은 여액을 감압, 농축한 후 얻어진 잔사에 정제수를 부가하여 5∼100℃의 온도에서 약 3시간 동안 반응하여 가수분해시키는 단계; 및(D) depressurizing and concentrating the filtrate obtained by filtration of the reaction solution, and adding purified water to the obtained residue to react and hydrolyze at a temperature of 5 to 100 ° C. for about 3 hours; And
(E) 극성 유기용매로 결정화하는 단계;(E) crystallizing with polar organic solvent;
를 포함하는 것을 특징으로 한다.Characterized in that it comprises a.
본 발명에 따른 제조방법은 다음의 반응식 1로 도식화될 수 있다 :The preparation method according to the invention can be represented by the following scheme 1:
(II)(II)
(B)(B)
+ 보호기 ------> + Protector ------>
(III)(III)
(C)(C)
+-------> + ------- >
(III) (II) (IV)(III) (II) (IV)
(D)(D)
--------> -------- >
(IV) (I)(IV) (I)
본 발명에 따른 L-아스코르빈산 유도체의 제조방법을 상기한 반응식 1에서 알 수 있는 바와 같이, 구체적으로 설명하면 다음과 같다.As can be seen in Scheme 1, a method for preparing an L-ascorbic acid derivative according to the present invention is described in detail as follows.
(A) 유기염기 존재하에 유기용매에서 3-아미노-1-프로판올과 옥시염화인을 0∼5℃의 온도에서 1∼2시간동안 교반하여 상기 구조식 (II)로 표시되는 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린P-옥시드(2-Chlorotetrahydro-2H-1,3,2-oxaza phosphorin P-oxide)를 생성시키는 단계;(A) 2-chlorotetrahydro- represented by the above formula (II) by stirring 3-amino-1-propanol and phosphorus oxychloride in an organic solvent for 1 to 2 hours at a temperature of 0 to 5 ° C. in the presence of an organic base. Producing 2H-1,3,2-oxazaphosphorin P-oxide; 2-Chlorotetrahydro-2H-1,3,2-oxaza phosphorin P-oxide;
상기한 단계에서 3-아미노-1-프로판올과 옥시염화인은 1:1∼1.3의 당량비로 반응시키는 것이 바람직하다. 당량비가 1:1 미만이면 목적하는 생성물을 얻을 수 없고, 1: 1.3이상이면 목적하는 생성물 이외에 과량의 부산물이 생성된다. 따라서, 상기한 방법으로 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드를 제조하는 경우, 3-아미노-1-프로판올과 옥시염화인이 1:1로 결합한 중간체가 95% 이상 생성되고, 3-아미노-1-프로판올과 옥시염화인이 2:1로 결합한 부산물이 1∼2% 이하로 생성된다. 그러나, 상기한 부산물은 크로마토그래피를 이용하여 분리하거나, 톨루엔에 대한 용해도 차이를 이용하여 용이하게 제거할 수 있다. 특히, 옥시염화인 분자내의 3개의 염소원자중 두개의 염소원자가 3-아미노-1-프로판올의 두 관능기, 즉 수산기와 아민기에 의해 치환되어 고리화된 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드가 생성되며, 나머지 하나의 염소원자는 5℃이하의 저온에서는 반응성이 감소되어 치환되지 않고 그대로 남아 있게 된다. 이는 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드의 염소원자가 저온의 무수 비활성 용매중에서 안정하여 3-아미노-1-프로판올과 쉽게 치환되지 않기 때문이다. 따라서, 본 발명의 제조방법은 3-아미노-1-프로판올과 옥시염화인을 1:1.0∼1.3의 당량비로하여 0∼5℃의 온도에서 1∼2시간 동안 반응시키므로, 3-아미노-1-프로판올과 옥시염화인이 2:1 이상으로 반응한 부산물의 생성을 방지할 수 있으며, 특히 옥시염화인 중 하나의 염소원자를 보호하기 위해 에스테르기나, 아미드기를 도입하는 공정이 필요하지 않으므로, 반응공정을 줄일 수 있는 장점이 있다.In the above step, 3-amino-1-propanol and phosphorus oxychloride are preferably reacted in an equivalent ratio of 1: 1 to 1.3. If the equivalent ratio is less than 1: 1, the desired product cannot be obtained, and if it is 1: 1.3 or more, an excess of by-products are produced in addition to the desired product. Therefore, when 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide is prepared by the above-described method, an intermediate in which 3-amino-1-propanol and phosphorus oxychloride are 1: 1 bound 95% or more is produced, and by-products in which 2-amino-1-propanol and phosphorus oxychloride are 2: 1 bonded are produced in 1 to 2% or less. However, the by-products can be separated using chromatography, or easily removed by using a difference in solubility in toluene. In particular, two chlorine atoms of the three chlorine atoms in the phosphorus oxychloride molecule are substituted by two functional groups of 3-amino-1-propanol, ie, hydroxyl and amine groups, and cyclized 2-chlorotetrahydro-2H-1,3, The 2-oxaphosphorine P-oxide is produced, and the other chlorine atom is reduced in reactivity at 5 ° C or lower and remains unsubstituted. This is because the chlorine atom of 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorin P-oxide is stable in a low temperature anhydrous inert solvent and is not easily substituted with 3-amino-1-propanol. Therefore, in the preparation method of the present invention, 3-amino-1-propanol and phosphorus oxychloride are reacted at a temperature of 0 to 5 ° C. for 1 to 2 hours at an equivalent ratio of 1: 1.0 to 1.3. Propanol and phosphorus oxychloride can prevent the formation of by-products reacted at 2: 1 or more, and in particular, it is not necessary to introduce ester groups or amide groups in order to protect chlorine atoms of phosphorus oxychloride. There is an advantage to reduce.
본 발명의 제조방법중 (A) 단계에서 유기염기로는 피리딘, 트리에틸아민등을 사용할 수 있으나, 트리에틸아민을 사용하는 것이 바람직하다.As the organic base in step (A) of the production method of the present invention, pyridine, triethylamine, and the like may be used, but triethylamine is preferably used.
본 발명의 제조방법중 (A) 단계에서 유기용매로는 디클로로메탄, 테트라히드로퓨란, 초산에틸, 아세토니트릴, 클로로포름, 에틸에테르 등과 같은 비활성 용매를 사용할 수 있으나, 디클로로메탄을 사용하는 것이 바람직하다.In the method (A) of the present invention, an organic solvent may be an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether, etc., but dichloromethane is preferably used.
한편, 반응온도는 5℃이상에서는 2당량 이상의 3-아미노-1-프로판올이 옥시염화인에 치환되어 부산물의 생성이 증가되고, 0℃미만의 온도에서는 반응물의 용해도가 감소되어 반응의 진행이 어려우며, 미반응물의 함량이 증가되어 반응 수율이 낮아지므로 0∼5℃ 범위의 온도가 바람직하다.On the other hand, the reaction temperature is more than 2 equivalents of 3-amino-1-propanol is substituted with phosphorus oxychloride to increase the production of by-products, and the temperature of less than 0 ℃ to reduce the solubility of the reactants difficult to proceed the reaction. In this case, a temperature in the range of 0 to 5 ° C. is preferable because the content of unreacted material is increased to lower the reaction yield.
(B) L-아스코르빈산의 5,6-수산기를 보호기(protective group)와 반응시켜 5,6-수산기가 보호된 L-아스코르빈산을 생성시키는 단계;(B) reacting the 5,6-hydroxyl group of L-ascorbic acid with a protective group to produce L-ascorbic acid in which the 5,6-hydroxyl group is protected;
본 발명의 제조방법중 5,6-수산기가 보호된 L-아스코르빈산을 생성시키는 단계에서 보호기로는 벤질리덴기, 페닐에틸리덴기, 이소프로필리덴기등을 사용할 수 있으나, 이소프로필리덴기를 사용하는 것이 바람직하다.Benzilidene group, phenylethylidene group, isopropylidene group and the like may be used as the protecting group in the step of producing L-ascorbic acid protected with 5,6-hydroxyl group in the production method of the present invention, isopropylidene group It is preferable to use.
(C) 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드와 5,6-수산기가 보호된 L-아스코르빈산을 유기 염기존재하에 유기용매에서 반응시키는 단계;(C) reacting 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide with L-ascorbic acid protected with 5,6-hydroxy group in an organic solvent in the presence of an organic base;
본 발명의 제조방법중 (C)단계에서 유기염기로는 상기 공정(A)에서 설명한 바와 같이 피리딘, 트리에틸아민등을 사용할 수 있으나, 트리에틸아민을 사용하는 것이 바람직하다.As the organic base in step (C) of the production method of the present invention, pyridine, triethylamine, and the like may be used as described in step (A), but it is preferable to use triethylamine.
본 발명의 제조방법중 (C)단계에서 유기용매로는 디클로로메탄, 테트라히드로퓨란, 초산에틸, 아세토니트릴, 클로로포름, 에틸에테르 등과 같은 비활성 용매를 사용할 수 있으나, 클로로포름을 사용하는 것이 바람직하다.In step (C) of the production method of the present invention, an organic solvent may be an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether, etc., but chloroform is preferably used.
(E) 반응액을 여과하여 얻은 여액을 감압 농축한 후 얻어진 잔사에 정제수를 부가하여 약 5∼100℃의 온도에서 약 3시간 동안 반응시켜 가수분해시키는 단계 ;(E) concentrating the filtrate obtained by filtration of the reaction solution under reduced pressure, and then adding purified water to the obtained residue to react for about 3 hours at a temperature of about 5 to 100 ° C. for hydrolysis;
본 발명에 따른 제조방법에서 반응액을 여과하여 얻은 여액을 감압 농축하여 얻은 잔사의 가수분해는 일반적인 가수분해 조건인 강 양이온 교환수지(Amberlyst 15), 염산 또는 황산 등의 산촉매를 사용하여 가수분해할 수 있으나, 상기 구조식 (IV)의 화합물의 수용액이 강한 산성(1% 수용액 pH=2)을 나타내므로, 잔사에 정제수를 부가한 후 5∼100℃온도로 승온하여 교반하는 경우 탈보호 및 P-N결합이 가수분해될 수 있다. 따라서, 반응액을 여과하여 얻은 여액을 농축한 후 얻은 잔사에 정제수를 부가하여 약 5∼100℃온도, 바람직하게는 50℃ 온도에서 약 3시간동안 반응시켜서 가수분해시키는 것이 바람직하다.Hydrolysis of the residue obtained by concentrating the filtrate obtained by filtration of the reaction solution under reduced pressure in the production method according to the present invention can be hydrolyzed using an acid catalyst such as strong cation exchange resin (Amberlyst 15), hydrochloric acid or sulfuric acid, which are general hydrolysis conditions. However, since the aqueous solution of the compound of formula (IV) shows strong acidity (1% aqueous solution pH = 2), when purified water is added to the residue and then stirred at a temperature of 5 to 100 ° C. for deprotection and PN bonding This can be hydrolyzed. Therefore, it is preferable to add the purified water to the residue obtained by concentrating the filtrate obtained by filtration of the reaction solution, and to react it for about 3 hours at a temperature of about 5 to 100 ° C, preferably 50 ° C for hydrolysis.
(E) 극성 유기용매를 서서히 적가하여 L-아스코르빈산의 유도체인 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르를 결정화하는 단계 ;(E) gradually dropping a polar organic solvent to crystallize L-ascorbic acid and 3-aminopropanol phosphate diester, which are derivatives of L-ascorbic acid;
본 발명에서 사용되는 석출 용매인 극성 유기용매는 특별히 한정되지는 않지만, 예를 들면, 메탄올, 에탄올, 이소프로판올, 아세톤, 테트라히드로퓨란, 아세토니트릴 또는 디옥산을 사용할 수 있다.Although the polar organic solvent which is a precipitation solvent used by this invention is not specifically limited, For example, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, or dioxane can be used.
상기한 제조방법에 의해 제공되는 L-아스코르빈산의 유도체는 이를 중화하여 염의 형태로도 사용할 수 있는데, 구체적인 예로는 나트륨, 칼륨 등의 알칼리금속류염; 칼슘, 마그네슘 등의 알칼리토금속류염; 트리에탄올아민 등의 아민 또는 암모니아에 의한 염의 형태로 사용될 수 있다.Derivatives of L-ascorbic acid provided by the above production method may be used in the form of salts by neutralizing them, and specific examples thereof include alkali metal salts such as sodium and potassium; Alkaline earth metal salts such as calcium and magnesium; Amines such as triethanolamine or salts with ammonia.
이하 실시예를 통하여 본 발명에 따른 L-아스코르빈산 유도체의 제조방법을 보다 구체적으로 설명한다. 그러나, 이들 실시예에 본 발명이 한정되는 것은 아니다.Hereinafter, the preparation method of the L-ascorbic acid derivative according to the present invention will be described in more detail. However, the present invention is not limited to these examples.
[제조예] 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린P-옥시드(2-Chlorotetrahydro-2H-1,3,2-oxaza phosphorin P-oxide)[Production Example] 2-Chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide (2-Chlorotetrahydro-2H-1,3,2-oxaza phosphorin P-oxide)
옥시염화인 34.1㎖(0.36mol)을 디클로로메탄 400㎖에 녹인 다음 얼음물 중탕에서 용액을 0∼5℃로 냉각시켰다. 다른 용기에 3-아미노-1-프로판올 30㎖(0.39mol)와 트리에틸아민 102㎖(0.73mol)용액을 디클로로메탄 200㎖로 희석한 후, 앞에서 제조한 반응용액을 2시간 동안 적가하였다. 적가가 끝난 후 생성된 트리에틸암모늄클로라이드를 제거하였다. 여액은 100㎖ 정제수를 사용하여 세척하고, 무수황산나트륨으로 건조시킨 다음, 여과하고, 감압하여 농축하였다. 농축한 후, 얻어진 잔사에 톨루엔을 가하여 결정을 얻었다. 얻어진 결정은 진공건조하여 반응생성물인 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드를 53g의 백색고체로서 얻었다.34.1 mL (0.36 mol) of phosphorus oxychloride was dissolved in 400 mL of dichloromethane, and the solution was cooled to 0-5 ° C. in an ice water bath. In another vessel, 30 mL (0.39 mol) of 3-amino-1-propanol and 102 mL (0.73 mol) of triethylamine were diluted with 200 mL of dichloromethane, and the reaction solution prepared above was added dropwise for 2 hours. After the addition, the triethylammonium chloride produced was removed. The filtrate was washed with 100 ml purified water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After concentration, toluene was added to the obtained residue to obtain a crystal. The obtained crystals were dried in vacuo to give 53 g of white solid as a reaction product, 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide.
녹는점 : 79∼82℃Melting Point: 79 ~ 82 ℃
IR(CHCl3, ㎝-1) : 3254, 1477, 1274, 1092, 1036, 996IR (CHCl 3 , cm −1 ): 3254, 1477, 1274, 1092, 1036, 996
1H-NMR(CDCl3) : δ(ppm) = 1.7(m, 1H), 1.1(m, 1H), 3.3(m, 2H), 4.4(m, 2H), 4.9(br, 1H) 1 H-NMR (CDCl 3 ): δ (ppm) = 1.7 (m, 1H), 1.1 (m, 1H), 3.3 (m, 2H), 4.4 (m, 2H), 4.9 (br, 1H)
13C-NMR(CDCl3) : δ(ppm) = 25.78, 25.85, 42.05, 42.11, 71.69, 71.81 13 C-NMR (CDCl 3 ): δ (ppm) = 25.78, 25.85, 42.05, 42.11, 71.69, 71.81
[실시예 1] L-아스코르빈산, 3-아미노프로판올 인산 디에스테르Example 1 L-ascorbic acid and 3-aminopropanol phosphate diester
이소프로필리덴기를 사용하여 L-아스코르빈산의 5,6-수산기를 보호한 5,6-이소프로필리덴아스코르빈산 10g(0.046mol)을 클로로포름 100㎖에 녹인 다음, 5℃의 얼음물 중탕에서 트리에틸아민 12.9㎖(0.093mol)을 적가하였다. 등온도에서 클로로포름 20㎖에 녹인 2-클로로테트라히드로-2H-1,3,2-옥사자포스포린 P-옥시드 8.6g(0.055mol)을 적가하였다. 적가가 끝난 후 하룻밤동안 상온에서 교반한 후, 인산 수용액으로 유기층을 세척하고, 무수황산나트륨과 활성탄을 가하여 건조, 탈색하였다. 반응액을 여과하고 얻은 여액을 감압 농축한 후 얻어진 잔사를 정제수 30㎖에 녹이고, 50℃ 항온조에서 3시간 동안 교반하였다. 교반이 끝난 반응액에 이소프로판올 150㎖를 가하여 결정을 얻고, 얻어진 결정을 진공건조하여 생성물인 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르를 6g의 백색고체로서 얻었다.10 g (0.046 mol) of 5,6-isopropylidene ascorbic acid, which protected the 5,6-hydroxyl group of L-ascorbic acid using an isopropylidene group, was dissolved in 100 ml of chloroform, and then, 12.9 mL (0.093 mol) of ethylamine was added dropwise. 8.6 g (0.055 mol) of 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide dissolved in 20 ml of chloroform at the same temperature was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature overnight, the organic layer was washed with an aqueous solution of phosphoric acid, dried over anhydrous sodium sulfate and activated carbon, and decolorized. The reaction solution was filtered and the filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in 30 ml of purified water and stirred for 3 hours at 50 ° C in a thermostat. 150 ml of isopropanol was added to the stirred reaction solution to obtain crystals, and the obtained crystals were dried in vacuo to obtain L-ascorbic acid and 3-aminopropanol phosphate diester as 6 g of a white solid.
녹는점 : 176∼180℃Melting Point: 176 ~ 180 ℃
IR(KBr, ㎝-1) : 3407, 3322, 3101, 2914, 1747, 1673, 1664, 1533, 1364, 1218, 1072IR (KBr, cm −1 ): 3407, 3322, 3101, 2914, 1747, 1673, 1664, 1533, 1364, 1218, 1072
1H-NMR(D2O) : δ(ppm) = 1.9(m, 2H), 3.05(t, 2H), 3.62(m, 2H), 3.98(m, 3H), 4.90(s, 1H) 1 H-NMR (D 2 O): δ (ppm) = 1.9 (m, 2H), 3.05 (t, 2H), 3.62 (m, 2H), 3.98 (m, 3H), 4.90 (s, 1H)
13C-NMR(D2O) : δ(ppm) = 26.76, 22.86, 32.35, 57.30, 59.77, 59.84, 64.15, 71.55, 71.72, 109.79, 109.88, 156.58, 156.63, 167.32, 167.38 13 C-NMR (D 2 O): δ (ppm) = 26.76, 22.86, 32.35, 57.30, 59.77, 59.84, 64.15, 71.55, 71.72, 109.79, 109.88, 156.58, 156.63, 167.32, 167.38
[실시예 2] L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 나트륨염Example 2 L-ascorbic acid and 3-aminopropanol phosphate diester sodium salt
실시예 1에서 얻은 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 1g을 정제수 30㎖에 녹인 후, 여기에 5% 탄산나트륨 수용액을 부가하여 pH 7로 만들었다. 상기 용액을 동결 건조하여 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 나트륨염을 백색고체로서 얻었다.After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, 5% aqueous sodium carbonate solution was added thereto to pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester sodium salt as a white solid.
[실시예 3] L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 칼륨염Example 3 L-ascorbic acid and 3-aminopropanol phosphate diester potassium salt
실시예 1에서 얻은 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 1g을 정제수 30㎖에 녹인 후, 여기에 5% 탄산칼륨 수용액을 부가하여 pH 7로 만들었다. 상기 용액을 동결 건조하여 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 칼륨염을 백색고체로서 얻었다.After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, 5% aqueous potassium carbonate solution was added thereto to pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester potassium salt as a white solid.
[실시예 4] L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 칼슘염Example 4 L-ascorbic acid and 3-aminopropanol phosphate diester calcium salt
실시예 1에서 얻은 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 1g을 정제수 30㎖에 녹인 후, 여기에 수산화칼륨을 부가하여 pH 7로 만들었다. 상기 용액을 동결 건조하여 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 칼슘염을 백색고체로서 얻었다.After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, potassium hydroxide was added thereto to pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester calcium salt as a white solid.
[실시예 5] L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 마그네슘염Example 5 L-ascorbic acid and 3-aminopropanol phosphate diester magnesium salt
실시예 1에서 얻은 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 1g을 정제수 30㎖에 녹인 후, 여기에 산화마그네슘을 부가하여 pH 7로 만들었다. 상기 용액을 동결 건조하여 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 마그네슘염을 백색고체로서 얻었다.After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, magnesium oxide was added thereto to make pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester magnesium salt as a white solid.
[실시예 6] L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 트리에탄올아민염Example 6 L-ascorbic acid and 3-aminopropanol phosphate diester triethanolamine salt
실시예 1에서 얻은 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 1g을 정제수 30㎖에 녹인 후, 여기에 5% 트리에탄올아민 수용액을 부가하여 pH 7로 만들었다. 상기 용액을 동결 건조하여 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 트리에탄올아민염을 백색고체로서 얻었다.After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, 5% triethanolamine aqueous solution was added thereto to pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester triethanolamine salt as a white solid.
[시험예 1][Test Example 1]
실시예 2의 화합물인 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 나트륨염과 L-아스코르빈산 2-포스페이트 마그네슘염 각각 3g을 정제수 100㎖에 녹인다음, 50℃ 항온조에서 30일 동안 보관한 후 침전생성과 착색 유무등의 경시변화를 하기 평가기준에 따라 관찰하고, 그 결과를 표 1과 표 2에 나타내었다.3 g of L-ascorbic acid, 3-aminopropanol phosphate diester sodium salt and L-ascorbic acid 2-phosphate magnesium salt, which are the compounds of Example 2, were dissolved in 100 ml of purified water, and then stored in a 50 ° C. thermostat for 30 days. After the change of sedimentation and the presence or absence of coloration was observed according to the following evaluation criteria, the results are shown in Table 1 and Table 2.
<평가기준><Evaluation Criteria>
- : 침전물이 없슴 + : 침전물 생성이 소-: No sedimentation +: Less sediment formation
++ : 침전물 생성이 중 +++ : 침전물 생성이 대++: Sediment generation is large +++: Sediment generation is large
<평가기준><Evaluation Criteria>
- : 무색 또는 미황색 + : 착색 소-: Colorless or light yellow +: coloring pigment
++ : 착색 중 +++ : 착색 대++: during coloring +++: coloring
상기 표 1∼2에서 알 수 있는 바와 같이, 본 발명의 화합물은 수상에서 매우 안정하고 고순도이기 때문에 변색이 일어나지 않고, 침전이 생성되지 않는다.As can be seen from Tables 1 and 2, since the compound of the present invention is very stable and high purity in the aqueous phase, discoloration does not occur and precipitation does not occur.
[시험예 2][Test Example 2]
실시예 1의 화합물인 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르와 L-아스코르빈산을 각각 50μM의 농도로 hydrion pH 7 완충 용액에 녹인 다음, 50℃ 항온조에서 보관한 후 일정 시간마다, 실시예의 시료는 259㎚에서, L-아스코르빈산은 266㎚에서 UV 흡수도를 측정하였다. 시료 용액중의 시료 잔존율(%)을 표 3에 나타내었다.L-ascorbic acid, 3-aminopropanol phosphate diester and L-ascorbic acid, which are the compounds of Example 1, were dissolved in hydrion pH 7 buffer solution at a concentration of 50 μM, respectively, and then stored in a constant temperature bath at 50 ° C. for a predetermined time. The sample of Example was measured for UV absorption at 259 nm and L-ascorbic acid at 266 nm. Table 3 shows the sample residual ratio (%) in the sample solution.
일반적으로 희석농도에서 시료의 안정성은 크게 저하된다. 그러나, 표 3에서 알 수 있는 바와 같이, 실시예 1의 화합물은 중성의 수용액에서 안정한 상태로 존재하나 L-아스코르빈산 수용액은 1시간 이내에 거의 분해된다.In general, the stability of the sample at dilution concentration is greatly reduced. However, as can be seen from Table 3, the compound of Example 1 is present in a stable state in a neutral aqueous solution, but the L-ascorbic acid aqueous solution almost decomposes within 1 hour.
본 발명의 방법에 의해 제공된 L-아스코르빈산의 유도체인 L-아스코르빈산, 3-아미노프로판올 인산 디에스테르 또는 그의 염은 수상에서 안정하고 고순도이기 때문에 수상제품에 응용이 용이하고, 또한, 생체내의 효소(포스파타아제 등)작용에 의해 멜라닌 생성 억제능을 가진 L-아스코르빈산과, 인체섬유아세포를 증식시키며, 교원질섬유(콜라젠)의 합성을 촉진하고, 더구나 인체 피부 안정성이 우수한 3-아미노프로판인산으로 분해될 수 있기 때문에, 특히 미백 및 노화방지용 화장료 조성물의 원료로서 유용하게 사용될 수 있을 것이다.L-ascorbic acid, 3-aminopropanol phosphate diester or a salt thereof, which is a derivative of L-ascorbic acid provided by the method of the present invention, is easy to be applied to a water-based product because it is stable and high-purity in the water phase, L-ascorbic acid with melanin production and human fibroblasts are promoted by the action of enzymes (phosphatase, etc.) in the body, promote the synthesis of collagen fibers (collagen), and furthermore, 3-amino having excellent human skin stability. Since it can be decomposed into propane phosphoric acid, it may be particularly useful as a raw material of the whitening and anti-aging cosmetic composition.
Claims (7)
Priority Applications (6)
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KR1019970023005A KR100230653B1 (en) | 1997-06-04 | 1997-06-04 | Water stable L-ascorbic acid derivatives and a method for preparation thereof |
FR9807041A FR2764891B1 (en) | 1997-06-04 | 1998-06-04 | DERIVED FROM L-ASCORBIC ACID STABLE IN WATER, PROCESS FOR ITS PREPARATION AND COSMETIC COMPOSITION OF BLEACHING THE SKIN CONTAINING IT |
US09/090,226 US5916915A (en) | 1997-06-04 | 1998-06-04 | Water-in-stable L-ascorbic acid derivative and a method for preparation thereof, and a skin-whitening cosmetic composition containing the same |
CN98101499A CN1069904C (en) | 1997-06-04 | 1998-06-04 | Water stable L-ascorbic acid derivative and its preparation method, and beauty composition containing same for making face white-skinned |
JP10156461A JP2926046B2 (en) | 1997-06-04 | 1998-06-04 | Water-stable L-ascorbic acid derivative, method for producing the same, and whitening cosmetic composition containing the same |
DE19824983A DE19824983C2 (en) | 1997-06-04 | 1998-06-04 | 2- (3-aminopropylphosphoric acid) -L-ascorbate, process for its preparation and cosmetic preparation containing it for lightening the skin |
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