JP2018070509A - Novel tocopheryl ascorbic acid derivative and process for producing the same - Google Patents
Novel tocopheryl ascorbic acid derivative and process for producing the same Download PDFInfo
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- JP2018070509A JP2018070509A JP2016212132A JP2016212132A JP2018070509A JP 2018070509 A JP2018070509 A JP 2018070509A JP 2016212132 A JP2016212132 A JP 2016212132A JP 2016212132 A JP2016212132 A JP 2016212132A JP 2018070509 A JP2018070509 A JP 2018070509A
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- Prior art keywords
- ascorbic acid
- chemical formula
- substance
- salt
- synthesizing
- Prior art date
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- -1 tocopheryl ascorbic acid derivative Chemical class 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims description 17
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 142
- 239000000126 substance Substances 0.000 claims abstract description 76
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 63
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 52
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 49
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 48
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims abstract description 22
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 claims abstract description 17
- ZAKOWWREFLAJOT-ADUHFSDSSA-N [2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] acetate Chemical group CC(=O)OC1=C(C)C(C)=C2OC(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-ADUHFSDSSA-N 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 229930003799 tocopherol Natural products 0.000 claims abstract description 11
- 239000011732 tocopherol Substances 0.000 claims abstract description 11
- 235000010384 tocopherol Nutrition 0.000 claims abstract description 10
- 229960001295 tocopherol Drugs 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 239000007858 starting material Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 27
- 230000002194 synthesizing effect Effects 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 150000003863 ammonium salts Chemical class 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
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- 229910052700 potassium Inorganic materials 0.000 claims description 3
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- 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 150000001879 copper Chemical class 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 125000004185 ester group Chemical group 0.000 claims 2
- 125000001033 ether group Chemical group 0.000 claims 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
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- 125000005647 linker group Chemical group 0.000 claims 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 12
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 27
- 239000011718 vitamin C Substances 0.000 description 27
- 229940046009 vitamin E Drugs 0.000 description 27
- 235000019154 vitamin C Nutrition 0.000 description 26
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 24
- 229930003268 Vitamin C Natural products 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 9
- 229940087168 alpha tocopherol Drugs 0.000 description 8
- 229960000984 tocofersolan Drugs 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000002076 α-tocopherol Substances 0.000 description 8
- 229940088594 vitamin Drugs 0.000 description 7
- 239000011782 vitamin Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 230000003078 antioxidant effect Effects 0.000 description 6
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- 239000012044 organic layer Substances 0.000 description 6
- 235000004835 α-tocopherol Nutrition 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000003712 vitamin E derivatives Chemical class 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000002211 L-ascorbic acid Substances 0.000 description 4
- 235000000069 L-ascorbic acid Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 150000003700 vitamin C derivatives Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000001793 charged compounds Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012156 elution solvent Substances 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
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- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 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
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
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- GJJVAFUKOBZPCB-ZGRPYONQSA-N (r)-3,4-dihydro-2-methyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2h-1-benzopyran-6-ol Chemical class OC1=CC=C2OC(CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-ZGRPYONQSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 description 1
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 1
- SCLDYIHKBCFVTE-UHFFFAOYSA-N CC(C)CCCC(C)CCCC(C)CCCC(C)(CCc1c2C)Oc1c(C)c(C)c2OC Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)(CCc1c2C)Oc1c(C)c(C)c2OC SCLDYIHKBCFVTE-UHFFFAOYSA-N 0.000 description 1
- JCRKSXXNCDPKJF-UHFFFAOYSA-N COC(C(C1OCOC1)OC1=O)=C1O Chemical compound COC(C(C1OCOC1)OC1=O)=C1O JCRKSXXNCDPKJF-UHFFFAOYSA-N 0.000 description 1
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- CIWBSHSKHKDKBQ-MVHIGOERSA-N D-ascorbic acid Chemical compound OC[C@@H](O)[C@@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-MVHIGOERSA-N 0.000 description 1
- GZIFEOYASATJEH-UHFFFAOYSA-N D-delta tocopherol Natural products OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
【課題】新規トコフェリルアスコルビン酸誘導体とその製造方法の提供。【解決手段】グリセリルアスコルビン酸を出発原料とする。グリセリルアスコルビン酸の、グリセリル基の２つの水酸基及びアスコルビン酸の５、６位の水酸基を保護し、前記物質をブロモアセチル化されたトコフェロールと反応させる。最後に脱保護して下記式で表されるトコフェリルグリセリルアスコルビン酸を得る。前記製造方法により高い反応収率で目的のトコフェリルグリセリルアスコルビン酸を得られる。【選択図】なしA novel tocopheryl ascorbic acid derivative and a method for producing the same are provided. The starting material is glyceryl ascorbic acid. Protecting the two hydroxyl groups of glyceryl group and the 5- and 6-position hydroxyl groups of ascorbic acid of glyceryl ascorbic acid, the substance is reacted with bromoacetylated tocopherol. Finally, deprotection is performed to obtain tocopheryl glyceryl ascorbic acid represented by the following formula. By the above production method, the desired tocopheryl glyceryl ascorbic acid can be obtained with a high reaction yield. [Selection figure] None
Description
本発明は、生物に必要とされる栄養素であるビタミンCとビタミンEを同一分子内に持つ新規のトコフェリルアスコルビン酸誘導体とその製造方法に関する。 The present invention relates to a novel tocopheryl ascorbic acid derivative having vitamin C and vitamin E, which are nutrients required for living organisms, in the same molecule and a method for producing the same.
ビタミンＣ（Ｌ−アスコルビン酸）は、ヒトを含む多くの生物において重要な生体内酸化還元反応を媒介する栄養素として知られている水溶性の化合物である。アスコルビン酸（アスコルビンさん、英: ascorbic acid）は、栄養素ビタミンC としてはたらく、ラクトン構造を持つ有機化合物の1種である。分子量は176.13 g/mol。光学活性化合物であり、ビタミンCとして知られるのはL体の方である。そのCAS登録番号は、50-81-7である。 Vitamin C (L-ascorbic acid) is a water-soluble compound known as a nutrient that mediates important in vivo redox reactions in many organisms, including humans. Ascorbic acid (ascorbic acid) is a kind of organic compound with a lactone structure that acts as a nutrient vitamin C. The molecular weight is 176.13 g / mol. The L-form is an optically active compound and is known as vitamin C. Its CAS registration number is 50-81-7.
ビタミンＥ（α，β，γ，δ−トコフェロール及びトコトリエノール及びその光学異性体であるＤ及びＬ体）は、ビタミンCと同様にヒトを含む多くの生物において重要な生体内酸化還元反応を媒介する栄養素として知られている脂溶性の化合物である。ビタミンＥとして代表的なα-トコフェロールは、分子量は430.79g/molでありそのCAS登録番号は，59-02-9である。ビタミンC，ビタミンEの両者は、食品添加物の酸化防止剤として、広く使用される。 Vitamin E (α, β, γ, δ-tocopherol and tocotrienol and its optical isomers D and L) mediate important in vivo redox reactions in many organisms, including humans, as well as vitamin C. It is a fat-soluble compound known as a nutrient. The typical α-tocopherol as vitamin E has a molecular weight of 430.79 g / mol and its CAS registry number is 59-02-9. Both vitamin C and vitamin E are widely used as antioxidants in food additives.
ビタミンEはトコフェロール類とトコトリエノール類の共同名で、抗酸化機能を持つ脂溶性ビタミンである（非特許文献１及び２）。ビタミンE のうち、α-トコフェロールのバイオアベイラビリティが選択的吸収および代謝とともに最も研究がなされている（非特許文献３）。
α-トコフェロールは、脂質過酸化連鎖反応で生成する脂質ラジカルによる酸化から細胞膜を保護するため、最も重要な脂溶性抗酸化物質である（非特許文献１，４、５、６）。
つまりはフリーラジカル中間体の除去により、それによる成長反応を抑制している。この反応では酸化型である α-トコフェロキシルラジカルが生成するが、アスコルビン酸などにより、元の還元型にリサイクルされる（非特許文献７）。
Vitamin E is a joint name of tocopherols and tocotrienols, and is a fat-soluble vitamin having an antioxidant function (Non-patent Documents 1 and 2). Among vitamin E, α-tocopherol bioavailability has been studied most together with selective absorption and metabolism (Non-patent Document 3).
α-Tocopherol is the most important fat-soluble antioxidant because it protects cell membranes from oxidation by lipid radicals generated by lipid peroxidation chain reaction (Non-patent Documents 1, 4, 5, and 6).
In other words, the growth reaction caused by the removal of the free radical intermediate is suppressed. In this reaction, an oxidized α-tocopheroxyl radical is generated, but is recycled to the original reduced form by ascorbic acid or the like (Non-patent Document 7).
このため、アスコルビン酸とビタミンEは、その併用により相乗的な効果を発揮する報告が複数存在するため、ビタミンEとビタミンCを同時に併用する試みがなされてきた（非特許文献８、９、１０）。 For this reason, ascorbic acid and vitamin E have a plurality of reports that exhibit a synergistic effect by the combined use thereof, attempts have been made to use vitamin E and vitamin C in combination (Non-Patent Documents 8, 9, 10). ).
しかし、ビタミンＣは水溶性であり、ビタミンＥは粘性の高い水飴状の脂溶性である為に、併用使用することは困難であり、ビタミンＥを脂に混ぜて粘度を低下させ乳化などの方法で水に溶かしてビタミンＣと併用する方法が取られたが、両者は強力な還元剤である為に酸化分解されやすく、褐変や異臭の発生、プロオキシダントによる細胞毒性や刺激の問題が発生するという問題があった。安定化させたビタミンＣ誘導体とビタミンＥ誘導体を併用するという方法もあるが、２つの誘導体を同時に添加するにはコスト高になると言う問題と、それぞれの誘導体に側鎖が修飾されている為に一定のビタミン量を確保する為には多くの量を添加しなければならないという問題もあり、異なる２誘導体の安定なｐＨや水に対する溶解性、疎水性がそれぞれ異なるという問題などから混合した製剤に沈殿や分離、力価低下が見られるという問題が発生した。 However, since vitamin C is water-soluble and vitamin E is highly soluble in a varicella-like fat, it is difficult to use in combination. Vitamin E is mixed with fat to reduce viscosity and emulsify. However, both of them are strong reducing agents, so they are prone to oxidative degradation, causing browning and off-flavors, and problems with cytotoxicity and irritation caused by prooxidants. There was a problem. There is also a method of using a stabilized vitamin C derivative and a vitamin E derivative together, but the problem is that it is expensive to add two derivatives at the same time, and the side chain is modified to each derivative. In order to ensure a certain amount of vitamins, there is a problem that a large amount must be added. Due to problems such as stable pH, solubility in water and hydrophobicity of two different derivatives, There was a problem that precipitation, separation, and titer reduction were observed.
そこで、ビタミンＣとビタミンＥを一つの誘導体にまとめてしまおうという試みがなされた。ビタミンＣとビタミンＥを結合させた誘導体として、既にビタミンＥとビタミンＣとの水溶性リン酸ジエステル化合物が知られている（特許文献１、２）。 Therefore, an attempt was made to combine vitamin C and vitamin E into one derivative. As a derivative obtained by binding vitamin C and vitamin E, a water-soluble phosphodiester compound of vitamin E and vitamin C is already known (Patent Documents 1 and 2).
また、ビタミンＣ，Ｅの溶解性を互いに補うものとして、トコフェロール／トコトリフェノール−Ｌ−ビタミンＣ−６−ジカルボン酸ジエステルが報告されている（特許文献３）。また、ビタミンＣとビタミンＥ誘導体として、α−トコフェリールグリセリルビタミンＣが知られている（特許文献４）。さらに、Ｌ−ビタミンＣ−２−Ｏ−マレイン酸−α−トコフェロールジエステルが（特許文献５）により開示されている。 Moreover, tocopherol / tocotriphenol-L-vitamin C-6-dicarboxylic acid diester has been reported as a supplement to the solubility of vitamins C and E (Patent Document 3). As vitamin C and vitamin E derivatives, α-tocopheryl glyceryl vitamin C is known (Patent Document 4). Furthermore, L-vitamin C-2-O-maleic acid-α-tocopherol diester is disclosed by (Patent Document 5).
しかし、前述のように、ビタミンＥとビタミンＣとの水溶性リン酸ジエステル化合物（特許文献６，７）、及びトコフェロール／トコトリフェノール−Ｌ−ビタミンＣ−６−ジカルボン酸ジエステル（特許文献８）及び、ビタミンＣとビタミンＥ誘導体として、α−トコフェリールグリセリルビタミンＣ（特許文献９）は、エステル結合が強すぎて酵素的に加水分解されにくいためターゲット組織中でビタミンＣを効率的に放出できない。 However, as described above, water-soluble phosphate diester compounds of vitamin E and vitamin C (Patent Documents 6 and 7), and tocopherol / tocotriphenol-L-vitamin C-6-dicarboxylic acid diester (Patent Document 8) And, as vitamin C and vitamin E derivatives, α-tocopheryl glyceryl vitamin C (Patent Document 9) efficiently releases vitamin C in the target tissue because the ester bond is too strong to be enzymatically hydrolyzed. Can not.
一方で、Ｌ−ビタミンＣ−２−Ｏ−マレイン酸−α−トコフェロールジエステル（特許文献１０）は、エステル結合が弱すぎて、酵素が全く存在しない水中でも速やかに分解される為に誘導体としての効果が十分に発揮できないという問題があった。 On the other hand, L-vitamin C-2-O-maleic acid-α-tocopherol diester (Patent Document 10) is a derivative because it has a weak ester bond and is rapidly decomposed even in water in which no enzyme is present. There was a problem that the effect could not be fully exhibited.
即ち、これらの問題は、ビタミンＣ又はビタミンＥ誘導体のエステル構造の酵素的結合力の問題に起因するものであり、ここではリン酸エステルに対する生体酵素分解力に起因する。即ち、生体酵素に対して理想的な安定性と分解性をコントロールできるエステル構造分子が見いだせればこの問題を解決できる。 That is, these problems are caused by the problem of the enzymatic binding force of the ester structure of vitamin C or vitamin E derivative, and here, due to the ability of bioenzymatic degradation to phosphate esters. That is, this problem can be solved if an ester structure molecule capable of controlling ideal stability and degradability for a biological enzyme is found.
本発明者等はこの問題を解決する為に、ビタミンＣとの化学結合が弱すぎず、又は強すぎないエステル構造をもつ分子の探索を行い、その結果、アセチルジエステル結合型ビタミンＣ誘導体を最近発明した（特許文献１１）。 In order to solve this problem, the present inventors have searched for a molecule having an ester structure whose chemical bond with vitamin C is not too weak or too strong. Invented (Patent Document 11).
本発明者らが近年発明したアセチルジエステル結合型ビタミンＣ誘導体（特許文献１１）は、効果の点では従来の誘導体を遥かに凌駕する優れた結果が得られた。しかし、アセチルジエステル結合型ビタミンＣ誘導体（特許文献１１）の製造法において、５，６−イソピリデン−ビタミンＣと、ハロゲン化アセチルビタミンE化合物をＤＭＦの溶媒に溶解し、塩基として炭酸水素カリウムの存在下で反応させるた場合、ビタミンＥは、アスコルビン酸の主に３位に結合し、一方、主に２位にビタミンＥを結合させる場合は、ＤＭＳＯ、ＴＨＦ、ＣＨ２Ｃｌ２、ＤＭＦから選択される一種以上の単独叉は混合溶媒に溶解し、塩基としてｔ−ＢｕＯＫの存在下で反応させるものであるが、アスコルビン酸の２位と３位の一方が保護されていない為に合成物の２位及び３位の結合選択性が低く、不純物として、同分子量の異性体が同時に混在してしまうという問題があった。 The acetyl diester-bonded vitamin C derivative invented in recent years by the present inventors (Patent Document 11) has an excellent result far surpassing that of conventional derivatives in terms of effects. However, in the method for producing an acetyl diester-linked vitamin C derivative (Patent Document 11), 5,6-isopyridene-vitamin C and a halogenated acetyl vitamin E compound are dissolved in a DMF solvent, and the presence of potassium hydrogen carbonate as a base When reacted below, vitamin E binds primarily to the 3rd position of ascorbic acid, while when vitamin E is primarily bonded to the 2nd position, it is selected from DMSO, THF, CH 2 Cl 2 , DMF In the presence of t-BuOK as a base, one or more of the ascorbic acid is not protected and one of the 2nd and 3rd positions of ascorbic acid is not protected. The bond selectivity at the position 3 and the position 3 was low, and there was a problem that isomers of the same molecular weight were mixed at the same time as impurities.
つまり、アセチルジエステル結合型ビタミンＣ誘導体（特許文献１１）においては、単一物質の純度が工業的生産スケールにおいて充分に高まらないという問題があった。この為、純度を高める為には、多段階の精製行程を実施する必要があり、コストの上昇を招くという問題があった。 That is, the acetyl diester-linked vitamin C derivative (Patent Document 11) has a problem that the purity of a single substance is not sufficiently increased on an industrial production scale. For this reason, in order to raise purity, it was necessary to carry out a multi-step purification process, and there was a problem that the cost was increased.
即ち、２位及び３位の選択性を高めるため、アスコルビン酸の保護基の代わりとなる出発物質の検討を行なったところ、グリセリルアスコルビン酸を出発原料とし、以下の方法で合成することにより、この問題が解決できる事を見いだした。 That is, in order to enhance the selectivity at the 2nd and 3rd positions, a starting material that can be used as a substitute for the protecting group of ascorbic acid was examined. As a result, glyceryl ascorbic acid was used as a starting material and synthesized by the following method. I found that the problem could be solved.
グリセリルアスコルビン酸を出発原料とし、グリセリルアスコルビン酸の、グリセリル基とアスコルビン酸の5,6位を保護した物質Aを合成し、これにブロモアセチル化されたトコフェロールと反応させた物質Bを合成し、物質Aと物質Bを結合させた物質Cを合成した後、物質Cの保護基を解放することにより、高い反応収率で同分子量の異性体を含まないトコフェリルグリセリルアスコルビン酸の合成方法を確立することが可能となった。 Using glyceryl ascorbic acid as a starting material, synthesize glyceryl ascorbic acid, substance A in which glyceryl group and ascorbic acid are protected at positions 5 and 6, and then synthesize substance B reacted with bromoacetylated tocopherol, After synthesizing substance C in which substance A and substance B are combined, the protective group of substance C is released to establish a method for synthesizing tocopherylglyceryl ascorbic acid that does not contain isomers of the same molecular weight with a high reaction yield. It became possible to do.
本発明は、以下の項目から構成される。
（１）下記の一般式［化１］で表されることを特徴とするトコフェリルグリセリルアスコルビン酸又はその塩。
The present invention includes the following items.
(1) Tocopheryl glyceryl ascorbic acid or a salt thereof represented by the following general formula [Chemical Formula 1]
（２）下記の一般式［化２］で表されることを特徴とする［化１］のトコフェリルグリセリルアスコルビン酸又はその塩。 (2) Tocopherylglyceryl ascorbic acid of [Chemical Formula 1] or a salt thereof represented by the following general formula [Chemical Formula 2]:
（３）グリセリルアスコルビン酸を出発原料とし、グリセリルアスコルビン酸の、グリセリル基の２つの水酸基が保護され、同時にアスコルビン酸の5,6位の２つの水酸基が保護された物質Aを合成し、別にブロモアセチル化されたトコフェロールと反応させた物質Bを合成し、物質Aと物質Bを結合させた物質Cを合成した後、物質Cの保護基を解除して４つの水酸基に戻すことを特徴とする、［化１］のトコフェリルグリセリルアスコルビン酸の合成方法。
（４）物質Aと、物質BをＤＭＳＯ、ＴＨＦ、ＣＨ２Ｃｌ２、ＤＭＦから選択される一種以上の単独叉は混合溶媒に溶解し、塩基としてｔ−ＢｕＯＫの存在下で反応させて物質Cを合成する製造工程を含む、（３）のトコフェリルグリセリルアスコルビン酸の合成方法。
（５）下記の一般式［化３］で表される物質Aと、下記の一般式［化４］で表される物質Bを反応させ、下記の一般式［化５］で表される物質Cを合成する製造工程を含むことを特徴とする、［化１］のトコフェリルグリセリルアスコルビン酸の合成方法。
(3) Using glyceryl ascorbic acid as a starting material, synthesizes substance A in which the two hydroxyl groups of glyceryl group of glyceryl ascorbic acid are protected and at the same time the two hydroxyl groups at 5,6 position of ascorbic acid are protected, and bromo It is characterized by synthesizing substance B reacted with acetylated tocopherol, synthesizing substance C in which substance A and substance B are combined, and then releasing the protective group of substance C to return it to four hydroxyl groups. , [Chemical Formula 1] tocopherylglyceryl ascorbic acid synthesis method.
(4) Substance A and substance B are dissolved in one or more single or mixed solvents selected from DMSO, THF, CH 2 Cl 2 , and DMF, and reacted in the presence of t-BuOK as a base. A method for synthesizing tocopheryl glyceryl ascorbic acid according to (3), which comprises a production step of synthesizing.
(5) A substance represented by the following general formula [Chemical Formula 5] is reacted with a substance B represented by the following general formula [Chemical Formula 4]. A method for synthesizing tocopherylglyceryl ascorbic acid of [Chemical Formula 1], which comprises a production step of synthesizing C.
（６）［化３］が一般式［化６］で表されることを特徴とする［化１］のトコフェリルグリセリルアスコルビン酸の合成方法。 (6) A method for synthesizing tocopherylglyceryl ascorbic acid of [Chemical Formula 1], wherein [Chemical Formula 3] is represented by the general formula [Chemical Formula 6].
（７）［化４］が一般式［化７］で表されることを特徴とする［化１］のトコフェリルグリセリルアスコルビン酸の合成方法。 (7) A method for synthesizing tocopherylglyceryl ascorbic acid of [Chemical Formula 1], wherein [Chemical Formula 4] is represented by the general formula [Chemical Formula 7].
（８）［化５］が一般式［化８］で表されることを特徴とする［化１］のトコフェリルグリセリルアスコルビン酸の合成方法。 (8) A method for synthesizing tocopherylglyceryl ascorbic acid of [Chemical Formula 1], wherein [Chemical Formula 5] is represented by the general formula [Chemical Formula 8].
（９）薬理学的に許容される塩がNナトリウム、カリウム、アルミニウム、マグネシウム、カルシウム、亜鉛、鉄、銅の塩、及びアンモニウム塩から選択される単体、又は２つ以上の混合塩から選択される塩である［化１］のトコフェリルグリセリルアスコルビン酸の塩。 (9) The pharmacologically acceptable salt is selected from a simple substance selected from N sodium, potassium, aluminum, magnesium, calcium, zinc, iron, copper salt, and ammonium salt, or a mixed salt of two or more. A salt of tocopheryl glyceryl ascorbic acid of [Chemical Formula 1].
本発明の溶媒可溶性炭化水素の溶媒とは、塩化メチレン、ＤＭＳＯ、ＴＨＦ、ＣＨ２Ｃｌ２、ＤＭＦなどの単独溶媒叉は混合溶媒を４０℃に加熱するとき、トコフェロールを１重量％以上溶解可能な溶媒である。従って、本発明の溶媒可溶性炭化水素とは、この溶媒に４０℃で１％重量以上溶解可能な炭化水素化合物である。 The solvent of the solvent-soluble hydrocarbon of the present invention can dissolve 1% by weight or more of tocopherol when a single solvent such as methylene chloride, DMSO, THF, CH 2 Cl 2 , DMF, or a mixed solvent is heated to 40 ° C. It is a solvent. Therefore, the solvent-soluble hydrocarbon of the present invention is a hydrocarbon compound that can be dissolved in this solvent at 40 ° C. by 1% by weight or more.
ちなみにトコフェロールは、炭化水素、溶媒可溶性炭化水素、ベンゼン環、クロマン環、ベンゾピランのいずれにも該当する。本発明の溶媒可溶性炭化水素が、溶媒に４０℃で１％重量以上溶解しない場合でも、本発明に使用可能であるが、反応効率が低下し製造コストが高騰するため使用が困難となる。 Incidentally, tocopherol corresponds to any of hydrocarbon, solvent-soluble hydrocarbon, benzene ring, chroman ring, and benzopyran. The solvent-soluble hydrocarbon of the present invention can be used in the present invention even when it is not dissolved in the solvent at 40 ° C. at 1% by weight or more, but it is difficult to use because the reaction efficiency is lowered and the production cost is increased.
本発明の合成に使用されるビタミンＣとしては、Ｌ−アスコルビン酸叉はその塩がある。本発明の請求項１の薬理学的に許容できる塩とはナトリウム塩やカリウム塩などのアルカリ金属塩およびカルシウム塩やマグネシウム塩などのアルカリ土類金属塩が挙げられるが、これら以外のアンモニウム塩などの薬理学的に許容できる塩であればいずれのものであってもよい。また、これらの中から選択される１種叉は２種以上の混合物でもよい。具体的には、Na、K、Al、Mg、Ca、Zn、Fe、Cuなどの金属塩、及びアンモニウム塩が例示される。 Vitamin C used in the synthesis of the present invention includes L-ascorbic acid or a salt thereof. Examples of the pharmacologically acceptable salt of claim 1 of the present invention include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt, and ammonium salts other than these. Any pharmacologically acceptable salt may be used. Moreover, 1 type selected from these, or 2 or more types of mixtures may be sufficient. Specifically, metal salts such as Na, K, Al, Mg, Ca, Zn, Fe, and Cu, and ammonium salts are exemplified.
ビタミンＥには、複数の種類が存在することが知られているが、本発明に使用できるトコフェロールは、α−トコフェロールであり、これには、旋光性が異なるD型（ｄｅｘｔｒｏ-ｒｏｔａｔｏｒｙ＝右旋性（＋））、及びL型（ｌｅｖｏ-ｒｏｔａｔｏｒｙ＝左旋性（−））のどちらも使用でき、本発明にはどちらの型も使用でき、更にそれらの混合物であるラセミ混合物（ｒａｃ−として表記）やＤＬ型（ＤＬ−として表記）も本発明のトコフェロールとして使用することができる。また、これらの中から選択される１種叉は２種以上の混合物でもよい。 It is known that there are a plurality of types of vitamin E, but the tocopherol that can be used in the present invention is α-tocopherol, which includes D-type (dextro-rotatory = right-handed rotation) having different optical activity. (+)) And L-type (levo-rotary = Left-rotation (-)) can be used, and both types can be used in the present invention, and a mixture thereof, which is expressed as a racemic mixture (rac-) ) And DL type (denoted as DL-) can also be used as the tocopherol of the present invention. Moreover, 1 type selected from these, or 2 or more types of mixtures may be sufficient.
本発明に使用可能なビタミンＥの塩とは、ビタミンＥの持つＨＯ−のＨがナトリウム塩やカリウム塩などのアルカリ金属塩およびカルシウム塩やマグネシウム塩などのアルカリ土類金属塩に置き換わったものであり、上記以外のアンモニウム塩などの塩であっても薬理学的に許容できる塩であればいずれのものであってもよい。また、これらの中から選択される１種叉は２種以上の混合物でもよい。 Vitamin E salt usable in the present invention is obtained by replacing HO-H of vitamin E with alkali metal salts such as sodium salt and potassium salt and alkaline earth metal salts such as calcium salt and magnesium salt. Yes, any salt other than those described above may be used as long as it is a pharmacologically acceptable salt. Moreover, 1 type selected from these, or 2 or more types of mixtures may be sufficient.
本名発明のビタミンＣとは、Ｌ−アスコルビン酸とＤ−アスコルビン酸であるが、生物活性の問題からＬ−アスコルビン酸が望ましい。また、これらの中から選択される１種叉は２種以上の混合物でもよい。 Vitamin C of the present invention is L-ascorbic acid and D-ascorbic acid, but L-ascorbic acid is desirable from the viewpoint of biological activity. Moreover, 1 type selected from these, or 2 or more types of mixtures may be sufficient.
本発明のアセチルジエステル構造を持つ化合物は、例えば次の合成法により、またはこれに準じて適宜合成することができる。 The compound having an acetyl diester structure of the present invention can be appropriately synthesized by, for example, the following synthesis method or a similar manner.
ビタミンＣの５，６位の水酸基の保護基としては、以下のイソプロピリデン基に限定されず、例えばベンジリデン基などのアシル基でも可能であるが、イソプロピリデン基が一般的である。これらの保護基は、反応液を酸性とすることにより容易に離脱させることができる。酸性とするにあたっては、例えば塩酸、リン酸、硫酸などの無機酸または酢酸、クエン酸などの有機酸などの一般的な酸性化合物を用いることができる。 The protecting group for the hydroxyl groups at the 5- and 6-positions of vitamin C is not limited to the following isopropylidene group, and may be an acyl group such as a benzylidene group, but an isopropylidene group is common. These protecting groups can be easily removed by acidifying the reaction solution. For acidification, a general acidic compound such as an inorganic acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or an organic acid such as acetic acid or citric acid can be used.
成和化成社製造グリセリル-2-アスコルビン酸（製品名：アミトースA2G）をN、N-ジメチルホルムアミドに溶解し、この溶液に、p-トルエンスルホン酸及び、又は2,2-ジメトキシプロパンを添加し、この混合物をおよそ3時間撹拌しながら反応させる。 Glyceryl-2-ascorbic acid (product name: Amitose A2G) manufactured by Seiwa Kasei Co., Ltd. is dissolved in N, N-dimethylformamide, and p-toluenesulfonic acid and / or 2,2-dimethoxypropane are added to this solution. The mixture is allowed to react with stirring for approximately 3 hours.
この液を、重炭酸ナトリウムなどの中性からアルカリ性の水溶液で中和し、その後酢酸エチルなどの、物質Aの固形物の溶解度が１％以下の溶媒で抽出し、有機層を水などで洗浄し、無水Na2SO4などを加えて、及び又は、真空乾燥機で乾燥させることにより、本発明の請求項記載の請求項５の一般式化３及び請求項６の一般式化６に記載の物質Aの固形物を得る。 This solution is neutralized with a neutral to alkaline aqueous solution such as sodium bicarbonate, and then extracted with a solvent such as ethyl acetate that has a solid solubility of 1% or less, and the organic layer is washed with water or the like. Then, by adding anhydrous Na 2 SO 4 or the like and / or drying with a vacuum dryer, the general formula 3 of claim 5 and the general formula 6 of claim 6 of the present invention are described. A solid of substance A is obtained.
窒素雰囲気などの無酸素状態下で、ビタミンＥを塩化メチレン、DMSO，THFの単体又はその混合物など５％重量以上溶解できる溶解溶媒に溶解し、ピリジンなどのアルカリ触媒、酸触媒及び相間移動触媒を必要応じて加え、ブロモアセチルブロミド、tert-ブトキシドカリウムなどのハロゲン化アセチルを加えて撹拌し、本発明の請求項記載の請求項５の一般式化４及び請求項か７の一般式化７で表される物質Bを得る。 Under anaerobic conditions such as nitrogen atmosphere, vitamin E is dissolved in a dissolving solvent that can dissolve 5% by weight or more of methylene chloride, DMSO, THF alone or a mixture thereof, and an alkali catalyst such as pyridine, an acid catalyst, and a phase transfer catalyst. If necessary, acetyl halide such as bromoacetyl bromide, potassium tert-butoxide and the like are added and stirred, and in general formula 4 of claim 5 and general formula 7 of claim 7 of the present invention, Obtain the substance B represented.
これに前記溶解溶媒などを加えて薄め撹拌し、その後室温で3時間撹拌反応した。これに塩化アンモニウム溶液を加えて中和し、その後酢酸エチルで抽出し、有機層を水で洗浄し、無水硫酸ナトリウムで乾燥させ、硫酸ナトリウムを必要に応じてこれを濾過等で除去し、真空乾燥させ、本発明の請求項記載の請求項５の一般式化５及び請求項８の一般式化８の物質Cを得る。 The dissolution solvent and the like were added thereto, and the mixture was diluted and stirred, and then stirred at room temperature for 3 hours. This was neutralized by adding an ammonium chloride solution, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and sodium sulfate was removed by filtration or the like as necessary. Drying yields substance C of general formula 5 of claim 5 and general formula 8 of claim 8 of the present invention.
この物質Cを、室温下でメタノール，THF，１−プロパノール、ｎ−ヘキサン、シクロヘキサン、石油エーテルなどの単体又はその混合物に溶かし、塩酸を加えた後、1時間、50℃ 付近で反応した。これに重炭酸ナトリウム溶液などで中和し、その後酢酸エチルなどで抽出し、有機層を水で洗浄し、無水Na2SO4などで乾燥させ、真空乾燥させ、本発明の請求項記載の請求項１の一般式化１及び請求項２の一般式化２記載の本発明のトコフェリルグリセリルアスコルビン酸を得ることができる。 This substance C was dissolved in a simple substance such as methanol, THF, 1-propanol, n-hexane, cyclohexane, petroleum ether or a mixture thereof at room temperature, and hydrochloric acid was added, followed by reaction at around 50 ° C. for 1 hour. This is neutralized with a sodium bicarbonate solution or the like, and then extracted with ethyl acetate or the like, and the organic layer is washed with water, dried over anhydrous Na 2 SO 4 or the like, and vacuum-dried. The tocopheryl glyceryl ascorbic acid of the present invention according to general formula 1 of claim 1 and general formula 2 of claim 2 can be obtained.
このようにして得られた本化合物は、公知の方法により、薬理学的に許容できる塩として得てもよい。塩への変換は、一旦反応液から単離した後に行ってもよく、反応液から単離することなく行ってもよい。 The present compound thus obtained may be obtained as a pharmacologically acceptable salt by a known method. Conversion to a salt may be performed after isolation from the reaction solution, or may be performed without isolation from the reaction solution.
本化合物は、食品や医薬品などビタミンEやビタミンCが効果があるとされる全ての製品に適宜添加することができる。 This compound can be added as appropriate to all products such as foods and pharmaceuticals where vitamin E and vitamin C are considered effective.
本製造方法により、本発明の本発明のトコフェリルグリセリルアスコルビン酸は、異性体の存在しない単一物質が高収率で得る事が可能となり、工業生産に置いてコストダウンが可能となり、より広範囲の用途に使用できるようになった。 By this production method, the tocopheryl glyceryl ascorbic acid of the present invention of the present invention can obtain a single substance having no isomer in a high yield, can be reduced in cost for industrial production, and more widely. Can be used for
次に、製造例、実施例（処方例）及び試験例を掲げ、本発明をさらに具体的に説明するが、これらは単に本発明の説明のため、その具体的な態様の参考のために提供されているものである。これらは本発明の特定の具体的な態様を説明するためのものであるが、本願で開示する発明の範囲を限定したり、あるいは制限することを表すものではない。本発明では、本明細書の思想に基づく様々な実施形態が可能であることは理解されるべきである。全ての製造例、実施例（処方例）及び試験例は、他に詳細に記載するもの以外は、標準的な技術を用いて実施したもの、又は実施することのできるものであり、これは当業者にとり周知で慣用的なものである。なお、以下に於いて、部はすべて重量部を、また％はすべて重量％を意味する。 Next, the present invention will be described more specifically with reference to production examples, examples (formulation examples), and test examples, which are provided merely for the description of the present invention and for reference of specific embodiments thereof. It is what has been. These are for the purpose of describing specific specific embodiments of the present invention, but are not intended to limit or limit the scope of the invention disclosed in the present application. In the present invention, it should be understood that various embodiments based on the idea of the present specification are possible. All production examples, examples (formulation examples), and test examples, except those described in detail elsewhere, have been performed or can be performed using standard techniques. It is well-known and customary for traders. In the following, all parts are by weight, and all% are by weight.
成和化成社製、製品名：アミトースA2Gであるグリセリルアスコルビン酸（0.4 g、1.6ミリモル）をN、N-ジメチルホルムアミド（2ml）に溶解し、この溶液に、p-トルエンスルホン酸（0.016 g、0.08ミリモル）および2,2-ジメトキシプロパン（2ml）を添加し、この混合物を室温で12時間撹拌しながら反応させた。 Product name: Amitose A2G glyceryl ascorbic acid (0.4 g, 1.6 mmol) was dissolved in N, N-dimethylformamide (2 ml), and p-toluenesulfonic acid (0.016 g, 0.08 mmol) and 2,2-dimethoxypropane (2 ml) were added and the mixture was allowed to react with stirring at room temperature for 12 hours.
この液を、重炭酸ナトリウム溶液（pH約7）で中和し、その後酢酸エチルで抽出し、有機層を水で洗浄し、無水Na2SO4で乾燥させ、真空乾燥させた。この残留物をシリカゲルカラムクロマトグラフ （溶出溶媒；ジクロロメタン:メタノール= 90：8）により精製分離し、ジアステレオマー混合物である無色の液体（0.37 g、1.12ミリモル、70％）を物質Aとして得た。 This solution was neutralized with sodium bicarbonate solution (pH about 7) and then extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous Na 2 SO 4 and dried in vacuo. The residue was purified and separated by silica gel column chromatography (elution solvent: dichloromethane: methanol = 90: 8) to obtain a colorless liquid (0.37 g, 1.12 mmol, 70%) as a diastereomer mixture as substance A. .
この物質Aを1H NMR で分析したところ以下の結果を得た。
1H NMR (400 MHz, CDCl3) : δ 4.62 (2H, t, J = 4.0 Hz), 4.46-4.39 (2H, m), 4.38-4.31 (2H, m), 4.27- 3.89 (12H, m), 1.51 (6H, s), 1.46 (6H, s), 1.40 (3H, s, major), 1.39 (3H, s, minor), 1.37 (3H, s, major), 1.35 (3H, s, minor)
This substance A was analyzed by 1H NMR, and the following results were obtained.
1 H NMR (400 MHz, CDCl 3 ): δ 4.62 (2H, t, J = 4.0 Hz), 4.46-4.39 (2H, m), 4.38-4.31 (2H, m), 4.27- 3.89 (12H, m), 1.51 (6H, s), 1.46 (6H, s), 1.40 (3H, s, major), 1.39 (3H, s, minor), 1.37 (3H, s, major), 1.35 (3H, s, minor)
この物質Aを13C NMRで分析したところ以下の結果を得た。
13C NMR (125 MHz, CDCl3): δ169.4 (split), 157.9 (split), 122.1 (split), 110.6 (split), 110.3 (split), 74.9, 74.8, 74.0, 72.9 (split), 65.4 (split), 65.2, 26.0 (split), 25.9, 25.5, 25.3 (split)
This substance A was analyzed by 13 C NMR, and the following results were obtained.
13 C NMR (125 MHz, CDCl 3 ): δ169.4 (split), 157.9 (split), 122.1 (split), 110.6 (split), 110.3 (split), 74.9, 74.8, 74.0, 72.9 (split), 65.4 (split) , 65.2, 26.0 (split), 25.9, 25.5, 25.3 (split)
質量分析装置にて物質Aの分子イオンピークの質量電荷比を求めたところ 分子式C15H21O8 (M-1) としてESI m/z は、329.10であり、モル質量(M-1) の理論値329.13 g/molと極めて一致し、上記の1H NMR及び13C NMRの結果を合わせると、物質Aは以下の本発明の請求項６の［化６］の構造式をもつ化合物であることが確認された。 When the mass-to-charge ratio of the molecular ion peak of substance A was determined using a mass spectrometer, the ESI m / z was 329.10 as the molecular formula C 15 H 21 O 8 (M-1), and the molar mass (M-1) The substance A is a compound having the structural formula of [Chemical Formula 6] of claim 6 of the present invention, which is in very agreement with the theoretical value of 329.13 g / mol and the above 1 H NMR and 13 C NMR results are combined. It was confirmed.
次に、一般式［化６］で表される物質A(0.2 g, 0.6 mmol) を氷冷したDMSO:THF＝3:2, 2mlに窒素雰囲気下でtert-ブトキシドカリウム (0.068 g, 0.62 mmol)と5分間撹拌し反応させた後、一般式［化９］で表されるトコフェリル誘導体である物質B (0.32 g, 0.6 mmol) を溶解添加し、その後室温で3時間撹拌反応した。 Next, substance A (0.2 g, 0.6 mmol) represented by the general formula [Chemical Formula 6] was cooled with ice-cooled DMSO: THF = 3: 2, 2 ml in a nitrogen atmosphere under potassium tert-butoxide (0.068 g, 0.62 mmol). ) And a reaction with stirring for 5 minutes, and then the substance B (0.32 g, 0.6 mmol), which is a tocopheryl derivative represented by the general formula [Chemical Formula 9], was dissolved and added, followed by stirring at room temperature for 3 hours.
これに塩化アンモニウム溶液を加えて中和し、その後酢酸エチルで抽出し、有機層を水で洗浄し、無水Na2SO4で乾燥させ、必要に応じてこれを濾過等で除去し、真空乾燥させた。これをシリカゲルカラムクロマトグラフ (溶出溶媒：dichloromethane:methanol = 90:4)の条件で精製し、物質Cとして（0.23 g、0.3ミリモル、48％）と構造が未知の化合物を得た。 This was neutralized by adding an ammonium chloride solution, and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous Na 2 SO 4. If necessary, this was removed by filtration, etc., and vacuum dried. I let you. This was purified under the conditions of silica gel column chromatography (elution solvent: dichloromethane: methanol = 90: 4) to obtain a compound with unknown structure as substance C (0.23 g, 0.3 mmol, 48%).
この物質Cを1H NMR で分析したところ以下の結果を得た。
1H NMR (400 MHz, CDCl3) : δ5.46 (1H, dd, J = 16.0, 4.0 Hz), 5.35 (1H, dd, J = 16.0, 4.0 Hz), 4.67 (1H, d, J = 4.0 Hz), 4.48 - 4.31 (3H, m), 4.19 - 4.04 (4H, m), 3.81 - 3.71 (1H, m), 2.62 - 2.55 (2H, m), 2.09 (3H, s), 2.03 (3H, s), 1.98 (3H, s), 1.87 - 1.70 (2H, m), 1.58 - 1.48 (4H, m), 1.47 - 1.17 (26H, m), 1.16 - 1.10 (6H, m), 0.88 - 0.82 (12H, m)
This material C was analyzed by 1H NMR, and the following results were obtained.
1 H NMR (400 MHz, CDCl 3 ): δ5.46 (1H, dd, J = 16.0, 4.0 Hz), 5.35 (1H, dd, J = 16.0, 4.0 Hz), 4.67 (1H, d, J = 4.0 Hz), 4.48-4.31 (3H, m), 4.19-4.04 (4H, m), 3.81-3.71 (1H, m), 2.62-2.55 (2H, m), 2.09 (3H, s), 2.03 (3H, s), 1.98 (3H, s), 1.87-1.70 (2H, m), 1.58- 1.48 (4H, m), 1.47-1.17 (26H, m), 1.16-1.10 (6H, m), 0.88-0.82 (12H, m)
この物質Cを13C NMRで分析したところ以下の結果を得た。
13C NMR (125 MHz, CDCl3) : δ168.2, 166.4, 154.9 (split), 150.0, 139.9, 126.6, 124.9, 123.5, 122.8 (split), 117.8, 110.5, 110.0, 75.4, 75.1, 74.5 (split), 74.1 (split), 72.5, 67.5, 65.9 (split), 65.5, 39.5, 37.6, 37.4, 32.9, 32.8, 31.2, 28.1, 27.0, 26.1, 25.6, 25.4, 24.9, 24.6, 22.8, 22.7, 20.9 (split), 19.9, 19.8, 13.1, 12.3, 11.9
This material C was analyzed by 13 C NMR, and the following results were obtained.
13 C NMR (125 MHz, CDCl 3 ): δ168.2, 166.4, 154.9 (split), 150.0, 139.9, 126.6, 124.9, 123.5, 122.8 (split), 117.8, 110.5, 110.0, 75.4, 75.1, 74.5 (split), 74.1 (split), 72.5, 67.5, 65.9 (split), 65.5, 39.5, 37.6, 37.4, 32.9, 32.8, 31.2, 28.1, 27.0, 26.1, 25.6, 25.4, 24.9, 24.6, 22.8, 22.7, 20.9 (split), 19.9, 19.8, 13.1, 12.3, 11.9
質量分析装置にて本化合物の物質Cの分子イオンピークの質量電荷比を測定したところC46H72O11Na(M+Na)の質量電荷比は、m/z 823.60であり、分子量理論値824.0470 g/molと極めて一致した。上記の1H NMR及び13C NMRの結果を合わせると、本化合物の物質Cは、以下の本発明請求項８の［化８］の構造式をもつ化合物であることが確認された。 When the mass-to-charge ratio of the molecular ion peak of the substance C of this compound was measured with a mass spectrometer, the mass-to-charge ratio of C46H72O11Na (M + Na) was m / z 823.60, which is an extremely theoretical molecular weight of 824.0470 g / mol. Matched. Combining the results of the above 1 H NMR and 13 C NMR, it was confirmed that the substance C of the present compound was a compound having the structural formula of [Chemical Formula 8] of the following claim 8 of the present invention.
この化合物４(0.09 g, 0.11 mmol)を、室温下でMeOH:THF＝5:2, 2 mlに溶かし、2N HCl (0.1 ml)を加えて1時間、50℃ で反応した。これに重炭酸ナトリウム溶液（pH約７）を加えて中和し、その後酢酸エチルで抽出し、有機層を水で洗浄し、無水Na 2 SO 4で乾燥させ、真空乾燥させた。この残留物をシリカゲルカラムクロマトグラフ (溶出溶媒： dichloromethane:methanol = 90:5)の条件で精製したところ、無色の液体として請求項１の一般式化１で表される本発明のトコフェリルグリセリルアスコルビン酸である化合物 (0.062 g, 0.086 mmol, 78%)を得た。 This compound 4 (0.09 g, 0.11 mmol) was dissolved in MeOH: THF = 5: 2, 2 ml at room temperature, and 2N HCl (0.1 ml) was added and reacted at 50 ° C. for 1 hour. This was neutralized by adding sodium bicarbonate solution (pH about 7), and then extracted with ethyl acetate, and the organic layer was washed with water, dried over anhydrous Na 2 SO 4 and vacuum dried. The residue was purified under the conditions of silica gel column chromatography (elution solvent: dichloromethane: methanol = 90: 5), and as a colorless liquid, the tocopheryl glyceryl ascorbine of the present invention represented by the general formula 1 of claim 1 was obtained. The acid compound (0.062 g, 0.086 mmol, 78%) was obtained.
以下に1H NMRの測定結果を示す。
1H NMR (500 MHz, CDCl3) : δ5.64 (1H, dd, J = 15.0, 5.0 Hz), 5.15 (1H, dd, J = 15.0, 5.0 Hz), 4.82 (1H, s), 4.26-4.19 (1H, m), 4.15-4.09 (1H, m), 4.08-4.02 (1H, m), 4.01-3.93 (1H, m), 3.90-3.83 (1H, m), 3.79-3.65 (3H, m), 3.42 (bs, 1H), 3.18 (bd, 1H), 2.61-2.56 (2H, m), 2.55 (bd, 1H), 2.18 (bs, 1H), 2.09 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H), 1.85-1.72 (2H, m), 1.57-1.48 (4H, m), 1.47-1.00 (20H, m), 0.88-0.82 (12H, m)
The measurement result of 1 H NMR is shown below.
1 H NMR (500 MHz, CDCl 3 ): δ5.64 (1H, dd, J = 15.0, 5.0 Hz), 5.15 (1H, dd, J = 15.0, 5.0 Hz), 4.82 (1H, s), 4.26-4.19 (1H , m), 4.15-4.09 (1H, m), 4.08-4.02 (1H, m), 4.01-3.93 (1H, m), 3.90-3.83 (1H, m), 3.79-3.65 (3H, m), 3.42 (bs, 1H), 3.18 (bd, 1H), 2.61-2.56 (2H, m), 2.55 (bd, 1H), 2.18 (bs, 1H), 2.09 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H), 1.85-1.72 (2H, m), 1.57-1.48 (4H, m), 1.47-1.00 (20H, m), 0.88-0.82 (12H, m)
以下に13C NMRの測定結果を示す。
13C NMR (125 MHz, CDCl3) : δ170.2, 167.5, 156.2 (split), 149.9, 139.7, 126.4, 124.8, 123.4, 122.8 (split), 117.7, 76.0 (split), 75.3, 73.5 (split), 70.5 (split), 69.6, 67.1, 63.2, 63.0 (split), 39.4, 37.5, 37.3, 32.8, 32.7, 31.0, 28.0, 24.8, 24.5, 22.7, 22.6, 20.8 (split), 19.9, 19.8, 13.1, 12.2, 11.9
The measurement results of 13 C NMR are shown below.
13 C NMR (125 MHz, CDCl 3 ): δ170.2, 167.5, 156.2 (split), 149.9, 139.7, 126.4, 124.8, 123.4, 122.8 (split), 117.7, 76.0 (split), 75.3, 73.5 (split), 70.5 ( split), 69.6, 67.1, 63.2, 63.0 (split), 39.4, 37.5, 37.3, 32.8, 32.7, 31.0, 28.0, 24.8, 24.5, 22.7, 22.6, 20.8 (split), 19.9, 19.8, 13.1, 12.2, 11.9
質量分析装置にて本化合物の分子イオンピークの質量電荷比を求めたところC46H72O11Na (M+Na) としてESI m/z は、 743.39であり、モル質量C40H64O11Naの理論値 743.9193 g/molと極めて一致した。上記の1H NMR及び13C NMRの結果を合わせると、以下の本発明請求項２の［化２］の構造式をもつ化合物であることが確認された。 When the mass-to-charge ratio of the molecular ion peak of this compound was determined using a mass spectrometer, the ESI m / z was 743.39 as C46H72O11Na (M + Na), which was very consistent with the theoretical value of 743.9193 g / mol for the molar mass C40H64O11Na. . Combining the results of the above 1 H NMR and 13 C NMR, it was confirmed that the compound had the following structural formula of [Chemical Formula 2] of claim 2 of the present invention.
本発明の化合物であるトコフェリルグリセリルアスコルビン酸は、食品、医薬品など、ビタミンE及びビタミンCが有効であるとして使用される全ての製品に使用することができる。 Tocopheryl glyceryl ascorbic acid, which is a compound of the present invention, can be used in all products such as foods and pharmaceuticals where vitamin E and vitamin C are effective.
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