CN102471238B - 千日菊素的制造方法及其制造中间体 - Google Patents
千日菊素的制造方法及其制造中间体 Download PDFInfo
- Publication number
- CN102471238B CN102471238B CN201080026898.XA CN201080026898A CN102471238B CN 102471238 B CN102471238 B CN 102471238B CN 201080026898 A CN201080026898 A CN 201080026898A CN 102471238 B CN102471238 B CN 102471238B
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- CN
- China
- Prior art keywords
- spilanthol
- isobutyl
- carbon number
- alkyl
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims description 18
- BXOCHUWSGYYSFW-HVWOQQCMSA-N spilanthol Chemical compound C\C=C\C=C/CC\C=C\C(=O)NCC(C)C BXOCHUWSGYYSFW-HVWOQQCMSA-N 0.000 title abstract description 48
- BXOCHUWSGYYSFW-UHFFFAOYSA-N all-trans spilanthol Natural products CC=CC=CCCC=CC(=O)NCC(C)C BXOCHUWSGYYSFW-UHFFFAOYSA-N 0.000 title abstract description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 150000001408 amides Chemical class 0.000 claims description 25
- 150000002148 esters Chemical class 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 3
- -1 amide ester Chemical class 0.000 abstract description 17
- 239000000203 mixture Substances 0.000 abstract description 5
- 239000000796 flavoring agent Substances 0.000 abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 150000007514 bases Chemical class 0.000 abstract 1
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 235000018927 edible plant Nutrition 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000004821 distillation Methods 0.000 description 11
- 239000002537 cosmetic Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 229910001873 dinitrogen Inorganic materials 0.000 description 8
- 210000004209 hair Anatomy 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 235000005911 diet Nutrition 0.000 description 7
- 230000037213 diet Effects 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000003205 fragrance Substances 0.000 description 6
- 230000001953 sensory effect Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- ZENOXNGFMSCLLL-UHFFFAOYSA-N vanillyl alcohol Chemical compound COC1=CC(CO)=CC=C1O ZENOXNGFMSCLLL-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 235000013361 beverage Nutrition 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000006210 lotion Substances 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- GVKGXDFZFAFBIW-MQQKCMAXSA-N (4e,6e)-octa-4,6-dienoic acid Chemical compound C\C=C\C=C\CCC(O)=O GVKGXDFZFAFBIW-MQQKCMAXSA-N 0.000 description 4
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- CBRLROMGPLCADD-UHFFFAOYSA-N methyl 3-hydroxydeca-6,8-dienoate Chemical class COC(=O)CC(O)CCC=CC=CC CBRLROMGPLCADD-UHFFFAOYSA-N 0.000 description 4
- JQCJBTMFIAOANG-UHFFFAOYSA-N methyl 3-oxodeca-6,8-dienoate Chemical class COC(=O)CC(=O)CCC=CC=CC JQCJBTMFIAOANG-UHFFFAOYSA-N 0.000 description 4
- 239000002304 perfume Substances 0.000 description 4
- 239000002453 shampoo Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 235000014347 soups Nutrition 0.000 description 4
- 235000013599 spices Nutrition 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010033799 Paralysis Diseases 0.000 description 3
- 244000089698 Zanthoxylum simulans Species 0.000 description 3
- 235000009932 Zanthoxylum simulans Nutrition 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 235000012970 cakes Nutrition 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 3
- 235000015110 jellies Nutrition 0.000 description 3
- 239000008274 jelly Substances 0.000 description 3
- 239000008267 milk Substances 0.000 description 3
- 235000013336 milk Nutrition 0.000 description 3
- 210000004080 milk Anatomy 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000344 soap Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 244000301850 Cupressus sempervirens Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 244000246386 Mentha pulegium Species 0.000 description 2
- 235000016257 Mentha pulegium Nutrition 0.000 description 2
- 235000004357 Mentha x piperita Nutrition 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 244000269722 Thea sinensis Species 0.000 description 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001336 alkenes Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- NBDKAHGXLWPFNI-UHFFFAOYSA-N ethyl octa-4,6-dienoate Chemical compound CCOC(=O)CCC=CC=CC NBDKAHGXLWPFNI-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- DCAYPVUWAIABOU-UHFFFAOYSA-N hexadecane Chemical compound CCCCCCCCCCCCCCCC DCAYPVUWAIABOU-UHFFFAOYSA-N 0.000 description 2
- 235000001050 hortel pimenta Nutrition 0.000 description 2
- 239000010422 internal standard material Substances 0.000 description 2
- ZYTMANIQRDEHIO-KXUCPTDWSA-N isopulegol Chemical compound C[C@@H]1CC[C@@H](C(C)=C)[C@H](O)C1 ZYTMANIQRDEHIO-KXUCPTDWSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000001683 mentha spicata herb oil Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000008601 oleoresin Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 235000019633 pungent taste Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 235000011888 snacks Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019721 spearmint oil Nutrition 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-N 0.000 description 1
- JWNQZUYANXGJGX-UHFFFAOYSA-N (1-methyl-4-propan-2-ylcyclohexyl) 2-hydroxypropanoate Chemical compound CC(C)C1CCC(C)(OC(=O)C(C)O)CC1 JWNQZUYANXGJGX-UHFFFAOYSA-N 0.000 description 1
- 239000001871 (1R,2R,5S)-5-methyl-2-prop-1-en-2-ylcyclohexan-1-ol Substances 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- RFGCVZIIIHRESZ-UHFFFAOYSA-N 2-Methoxy-4-(4-methyl-1,3-dioxolan-2-yl)phenol Chemical compound C1=C(O)C(OC)=CC(C2OC(C)CO2)=C1 RFGCVZIIIHRESZ-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- YSTPAHQEHQSRJD-UHFFFAOYSA-N 3-Carvomenthenone Chemical compound CC(C)C1CCC(C)=CC1=O YSTPAHQEHQSRJD-UHFFFAOYSA-N 0.000 description 1
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- CTMTYSVTTGVYAW-FRRDWIJNSA-N 5-[(1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl]oxy-5-oxopentanoic acid Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)CCCC(O)=O CTMTYSVTTGVYAW-FRRDWIJNSA-N 0.000 description 1
- JGVWYJDASSSGEK-UHFFFAOYSA-N 5-methyl-2-propan-2-ylidenecyclohexan-1-ol Chemical compound CC1CCC(=C(C)C)C(O)C1 JGVWYJDASSSGEK-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- NFLGAXVYCFJBMK-UHFFFAOYSA-N Menthone Chemical compound CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供一种作为千日菊素等香料化合物等的制造中间体有用的酰胺酯及使用其的千日菊素的制造方法。通过使下述通式(1)(式中，R1表示碳数1～6的烷基，及可以用碳数1～4的烷基、碳数1～4的烷氧基或卤原子取代的苯基，R2表示碳数1～8的烃基，波浪线表示顺式构型、反式构型或两种构型的混合。)表示的酰胺酯与碱性化合物反应，可以制造高纯度的千日菊素。
Description
技术领域
本发明涉及一种作为香料可以在香味方面以良好的方式制造有用的千日菊素的制造方法及其中使用的新型的中间体。
背景技术
已知有千日菊素(N-异丁基-2，6，8-癸三烯酰胺)产生渗透的、麻痹的刺激和/或刺痛的刺激感，作为香料和/或草本植物香辣料灵活运用于饮食品。特别是(2E，6Z，8E)体为黄柏印度金纽扣的主要成分，作为具有强的麻痹、收敛性作用的有效成分众所周知，作为感觉刺激成分，具有对饮食品或香妆品等广泛的制品的利用价值。另一方面，作为千日菊素的获得方法，已知有例如从黄柏印度金纽扣的提取等来自天然物的方法。另外，在非专利文献1、2或3等中公开有千日菊素的合成法，但不能说是工业的制造方法。另外，在专利文献1中公开有几种工业的制造方法。
现有技术文献
专利文献
专利文献1：WO2009/091040 A1
非专利文献
非专利文献1：J.Am.Chem.Soc.，2461-2463，(1955)
非专利文献2：Naturally Occurring Insecticides，149-156(1971)
非专利文献3：Tetrahedron，731-741(1987)
发明内容
本发明要解决的问题
本发明的目的在于，提供一种以高收率制造在香味方面良好的千日菊素的方法及其中使用的新型中间体。
解决问题的手段
本发明人等为了解决上述课题，进行了潜心研究，结果发现，通过将新型的酰胺酯用作中间体，以高收率及高纯度可得到在香味方面良好的千日菊素。
即，本发明包含以下的内容。
[1]一种酰胺酯，其用下述通式(1)表示。
[化1]
(式中，R1表示碳数1～6的烷基及碳数1～4的烷基、碳数1～4的烷氧基或可以用卤原子取代的苯基，R2表示碳数1～8的烃基，波浪线表示顺式构型、反式构型或两种构型的混合。)
[2]如上述[1]所述的酰胺酯，其中，R1为碳数1～4的烷基。
[3]如上述[2]所述的酰胺酯，其中，R1为甲基。
[4]如上述[1]～[3]中任一项所述的酰胺酯，其中，R2为异丁基或仲丁基。
[5]一种2，6，8-癸三烯酰胺的制造方法，其中，使上述[1]～[4]中任一项所述的酰胺酯与碱性化合物反应。
[6]一种饮食品、香妆品或医药品，其含有利用上述[5]所述的方法合成、化学纯度为80％以上且2E，6Z，8E-异构体含量为65％以上的2，6，8-癸三烯酰胺。
发明效果
根据本发明，提供一种在作为香料有用的N-异丁基-2，6，8-癸三烯酰胺 (千日菊素)的制造中有用的新型的中间体，通过使用该中间体，可以以高收率及高纯度制造在香味方面也良好的千日菊素。
具体实施方式
下面，对本发明进一步进行详细说明。
通式(1)表示的本发明化合物的酰胺酯可以用以下的方法得到。
[化2]
作为R1表示的碳数1～6的烷基，可列举例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
另外，在R1表示的可以用碳数1～4的烷基、碳数1～4的烷氧基或卤原子取代的苯基中，烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基及叔丁基，碳数1～4的烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基及叔丁氧基，卤原子为氟原子、氯原子及溴原子。作为优选的R1，为碳数1～4的烷基，其中，更优选甲基。
作为R2表示的碳数1～8的烃基，可列举例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、2-甲基丁基、己基等直链或支链的烷基、苯基、甲苯基、二甲苯基等烷基取代苯基、苄基、苯乙基等芳烷基，优选的R2为异丁基或仲丁基。
作为在此所使用的酰化剂，可列举酸酐(R1COOCOR1)、酰氯(R1COCl)等，作为R1的例示，可列举上述的基团。作为具体的酸酐，可列举：醋酸酐、丙酸酐、丁酸酐等。作为酰氯，可列举：乙酰氯、丙酰氯、新戊酰氯、苯甲酰氯等。
另外，在进行化合物(h)的酰化反应时，优选使碱性化合物共存，作为所使用的碱性化合物，可列举：三乙基胺、三丁基胺、吡啶、碳酸钠、氢 氧化钠、氢氧化钾等，其中，优选三乙基胺。
化合物(h)的酰化反应可以在约-5℃～100℃、优选10℃～30℃的温度下进行，反应时间在约1小时～6小时左右为充分。作为可以用于反应的溶剂，例如为甲苯、己烷、庚烷、二乙基醚、四氢呋喃，其中，优选甲苯。酰化剂的使用量相对化合物(h)为1倍摩尔～2倍摩尔，优选1.05倍摩尔～1.2倍摩尔。
反应结束后，可以用萃取、蒸馏、各种色谱法等进行精制。
另外，作为本发明的酰胺酯的原料的化合物(h)可以用例如以下的方法制造。
[化3]
(式中，波浪线表示顺式构型、反式构型或两种构型的混合。)
而且，对使用在通式(1)表示的本发明的酰胺酯中R2为异丁基的化合物(1)-i-Bu的N-异丁基-2，6，8-癸三烯酰胺(千日菊素)的制造方法进行说明。该制造方法利用以下的方案(scheme)表示。
[化4]
作为在此所使用的碱性化合物，可列举：胺、烷基锂、格氏试剂、金 属氢化物、金属酰胺、金属醇盐等。作为具体的碱性化合物，可列举：三乙基胺、吡啶、1，8-二氮杂双环[5，4，0]-7-十一碳烯、正丁基锂、叔丁基氯化镁、氢氧化钠、锂酰胺、二异丙基氨基锂、甲醇钠、叔丁醇钠、叔丁醇钾等。作为优选的碱性化合物，可列举叔丁醇钠、叔丁醇钾。
作为反应温度，可以在约-20℃～50℃、优选-5℃～10℃的温度下进行，反应时间在约1小时～5小时左右为充分。作为可以用于反应的溶剂，例如为甲苯、庚烷、四氢呋喃，其中，优选甲苯。碱性化合物的使用量相对化合物(1)-i-Bu为1倍摩尔～2倍摩尔，优选1.05倍摩尔～1.2倍摩尔。反应结束后，可以用萃取、蒸馏、各种色谱法等进行精制。
通过这样得到的千日菊素单独或与现有的冷感剂或热感剂等感觉(味觉、皮肤感觉等)刺激剂组合，作为饮食品、香妆品、医药品等香味添加剂，更具体而言，作为赋予并增强冷感或热感或者酒精感、碳酸感、唾液分泌效果等的有效成分是有用的。
作为上述现有的冷感剂，可以列举例如：薄荷醇、薄荷酮、樟脑、胡薄荷醇、异胡薄荷醇、桉树醇、薄荷精油、薄荷油、留兰香油、桉叶油、1-薄荷氧基丙烷-1，2-二醇、N-烷基-对薄荷烷-3-甲酰胺、N-[(4-氰基甲基)苯基]-对薄荷烷甲酰胺、3-1-薄荷氧基-2-甲基丙烷-1，2-二醇、对薄荷烷-3，8-二醇、2-1-薄荷氧基乙烷-1-醇、3-1-薄荷氧基丙烷-1-醇、乳酸1-薄荷酯、薄荷酮甘油缩酮、N-甲基-2，2-异丙基甲基-3-甲基丁烷酰胺、乙醛酸薄荷酯、戊二酸单薄荷酯、琥珀酸单薄荷酯、戊二酸二薄荷酯、琥珀酸二薄荷酯、薄荷精油、薄荷油或留兰香等，这些物质可以使用1种或适当配合使用2种以上。
另外，作为热感(辣味)剂，可列举例如：香草醇乙醚、香草醇丙醚、香草醇丁醚、香兰素丙二醇缩醛、乙基香兰素丙二醇缩醛、辣椒素、姜酮醇、辣椒油、辣椒油树脂、姜油树脂、壬酸香草酰胺、千日菊油树脂、山椒提取物、山椒油-I、山椒油-Ⅱ、山椒酰胺、黑胡椒提取物、胡椒脂碱、胡椒碱等，这些物质可以使用1种或适当配合使用2种以上。
另外，千日菊素可以直接调配于饮食品、香妆品、医药品等各种制品，也可以特别与上述感觉刺激剂一起首先调配于香料组合物中，将该香料组 合物调配于制品中。
作为饮食品，可列举例如：果汁饮料类、果酒类、牛奶饮料类、碳酸饮料、清凉饮料、能量饮料之类的饮料类；冰淇淋类、冰冻果子露类、冰棒之类的冰制食品类；果冻、布丁等甜点心类；蛋糕、饼干、巧克力、口香糖等西式糕点类；豆沙包、羊羹、米粉糕等日本点心类；果酱类、糖果类、面包类；绿茶、乌龙荼、红茶、柿子叶荼、洋甘菊荼、山白竹荼、桑荼、鱼腥草荼、普洱荼、马黛荼、路易波士荼、武靴藤荼、番石榴荼、咖啡、可可荼之类的荼饮料或嗜好饮料类；日本式汤、西式汤、中华汤之类的汤类；风味调味料；各种即食饮料或食品类；各种零食类等。
作为香妆品，可列举例如：淡香精、淡香水、科隆香水之类的香水制品；洁面奶、洗面奶、冷霜、按摩霜、乳液、化妆水、美容液、润肤膏、卸妆乳之类的基础化妆品类；粉底霜、香粉、固体香粉、爽身粉、口红、润唇膏、胭脂、眼线笔、睫毛膏、眼影、眼贴膜之类的精加工化妆品类；润发油、卷发剂、发油、护发素、发乳、整发露、生发水、发胶、生发剂、染发剂之类的头发化妆品；晒黑用化妆品、抑汗剂、剃须后美容水及凝胶、烫发剂、药用皂、药用洗发剂、药用皮肤化妆料之类的药用化妆品；洗发剂、润丝含润丝洗发剂、护发素、修复剂、发膜之类的修整头发制品；肥皂、沐浴露、香体露、洗手液之类的身体清洗剂；沐浴剂(浴盐、方块浴盐、沐浴液等)、泡泡浴露(泡沫浴等)、沐浴油(沐浴香水、沐浴胶囊等)、牛奶浴、沐浴冻、洗浴香精块之类的浴用剂；洗剂；柔顺剂；消臭、芳香剂；驱虫剂；牙膏、口腔清洗料、漱口水之类的口腔用制剂；其它杂货类等。
作为医药品，可列举例如敷剂、软膏剂之类的皮肤外用剂、锭剂、内服剂等。
添加配合于本发明的千日菊素的各种饮食品、香妆品、医药品的量因对象物等而大幅度地不同，通常相对对象物优选为0.00001～30质量％，更优选为0.0001～10质量％。
实施例
下面，利用参考例、实施例及比较例对本发明进行具体说明，但本发明并不受这些实例限定。
(参考例1)N-异丁基-3-羟基-6，8-癸二烯酰胺的制造
(1)Wittig反应工序
[化5]
在氮气流下，在1L烧瓶中加入4-溴丁酸乙酯(a)(195g、1.0mol)、三苯基膦(288g、1.1mol)、乙腈(195ml)，在90℃下搅拌40小时。将反应溶液滴加于甲苯(800ml)，冷却至20℃。过滤析出的白色固体，进行减压干燥(50℃/1托)，得到鏻盐(b)(420g、收率92％)。
接着，在氮气流下，在5L烧瓶中加入鏻盐(b)(420g、0.92mol)、甲苯(1600ml)、碳酸钾(506.2g、3.66mol)、丁烯醛(256.7g、3.66mol)，在65℃下搅拌7小时。将反应溶液冷却至室温，加入水(840g)并搅拌30分钟后，进行分液。在减压下从有机层蒸馏除去溶剂，过滤析出的固体并除去。将此溶液进行减压蒸馏(65～70℃/1.5托)，得到4，6-辛二烯酸乙酯(c)(114.4g、收率74％)。
(2)水解工序
[化6]
在四口烧瓶中加入20％氢氧化钾水溶液(477g、1.7mol)、4，6-辛二烯酸乙酯(c)(114.4g、0.68mol)，在45℃下搅拌3小时。将反应溶液冷却至室温，加入庚烷(230mL)，滴加35％盐酸(177g)。分液后，将有机层进行水洗(230mL)，在减压下蒸馏除去溶剂，得到4，6-辛二烯酸(d)(90.6g、收率95％)。
(3)混合酸酐合成工序
[化7]
在氮气流下，在2L反应烧瓶中加入4，6-辛二烯酸(d)(90.6g、0.65mol)、甲苯(720ml)、新戊酰氯(85.7g、0.71mol)，冷却至5℃。用1小时滴加三乙基胺(71.9g、0.71mol)，其后缓慢地提高温度至室温，搅拌2小时。进行3次水洗(270mL)并浓缩后，得到粗制的4，6-辛二烯酸新戊酰酸酐(e)139.8g。
(4)增碳反应工序
[化8]
在500ml烧瓶中加入由上述(3)得到的粗制的4，6-辛二烯酸新戊酰酸酐(e)(139.8g)、THF(140ml)、三乙基胺(69.3g、0.685mol)，冷却至5℃，加入咪唑(45.2g、0.72mol)并搅拌1小时。
在氮气流下，在另外准备好的2L烧瓶中加入氯化镁(75.3g、0.79mol)、THF(560ml)、丙二酸单甲酯钾盐(155g、0.996mol)，用1小时滴加上述的反应溶液，进一步搅拌5小时。滴加35％盐酸水溶液(265g、2.55mol)后，进行分液，将有机层用10％碳酸钠水溶液(660mL)清洗2次。减压蒸馏除去溶剂，进行减压蒸馏(90℃/0.5托)，得到3-氧代-6，8-癸二烯酸甲酯(f)(88.8g、收率70％)。
(5)还原工序
[化9]
在氮气流下，在1L烧瓶中加入硼氢化钠(5.1g、0.14mol)、THF(360ml)，冷却至0℃，用1小时滴加3-氧代-6.8-癸二烯酸甲酯(f)(88.8g、0.45mol)。 滴加结束后，滴加35％盐酸水溶液(47g)，用醋酸乙酯(180ml)萃取2次。将有机层进行水洗(178mL)后，减压除去溶剂，得到3-羟基-6，8-癸二烯酸甲酯(g)(86.1g、0.43mol、收率96％)。
(6)酰胺化工序
[化10]
在500ml烧瓶中加入3-羟基-6，8-癸二烯酸甲酯(g)(86.1g、0.43mol)、异丁胺(95.3g、1.3mol)，在90℃下搅拌24小时。减压下回收异丁基胺后，加入庚烷(700ml)，冷却至0℃。过滤析出的白色固体，减压下进行干燥，得到N-异丁基-3-羟基-6，8-癸二烯酰胺(h)(85.2g、0.35mol、收率82％)。
(实施例1)N-异丁基-3-乙酸基-6，8-癸三烯酰胺的制造
[化11]
在氮气流下，在500ml烧瓶中加入N-异丁基-3-羟基-6，8-癸二烯酰胺(h)(80.0g、0.336mol)、甲苯(240ml)、三乙基胺(39.65g、0.403mol)、DMAP(0.21g、0.0017mol)，一边将反应温度调节为20℃，一边用1小时滴加醋酸酐(37.7g、0.370mol)。搅拌3小时后，加入水(160ml)，将有机层进行分液。将所得的有机层用0.5％盐酸水溶液(100ml)清洗，用水(200ml)清洗4次。减压除去溶剂，得到N-异丁基-3-乙酸基-6，8-癸三烯酰胺(93.0g、0.331mol、收率98.6％)。
GC/MS(m/e)；281(M+，10％)，238(4)，221(95)，206(12)，192(7)，178(5)，155(4)，149(13)，128(4)，115(73)，107(53)，93(60)，79(68)，57(100)，43(68)，30(21)
1H-NMR(CDCl3)：δ0.88(d，6H，J＝6.7Hz)，1.69～1.72(m，4H)，1.74(d， 3H，J＝7.2Hz)，2.03(s，3H)，2.17～2.22(m，2H)，2.41～2.51(m，2H)，3.04～3.07(m，2H)，5.10～5.16(m，1H)，5.18～5.24(m，1H)，5.64～5.70(m，1H)，5.85(br，1H)，5.91～5.99(m，1H)，6.21～6.27(m，1H)
13C-NMR(CDCl3)：δ18.23，20.00，21.11，23.44，28.41，33.87，41.71，46.83，71.25，126.54，127.50，129.43，129.83，131.10，169.30，170.56
(实施例2)N-异丁基-2，6，8-癸三烯酰胺的制造
[化12]
在1000ml烧瓶中加入t-BuONa(35.03g、0.361mol)、甲苯(600ml)，冷却至-5℃。此时用2小时滴加N-异丁基-3-乙酸基-6，8-癸三烯酰胺(93.0g、0.331mol)，进行1小时搅拌，加入水(200ml)，将有机层进行分液。其后，进行4次水洗(186mL)，减压除去溶剂，将其残渣进行减压蒸馏(130～135℃/0.1托)，以收率84.0％得到N-异丁基-2，6，8-癸三烯酰胺(千日菊素)(67.0g)。
此时，N-异丁基-2，6，8-癸三烯酰胺的纯度为96.8％，链烯部位的异构体比为：(2E，6Z，8E)为79.0％、(2E，6E，8E)为17.5％、(2E，6Z，8Z)为3.5％。
GC/MS(m/e)；221(M+，10％)，206(3)，192(4)，178(2)，167(2)，141(70)，126(44)，98(30)，81(100)，69(15)，53(17)，41(24)
1H-NMR(CDCl3)；δ6.82(dt，1H，J＝15.3，6.7Hz)，6.28(dd，1H，J＝10.7，15.0Hz)，5.97(dd，1H，J＝10.7，10.7Hz)，5.87(bs，1H)，5.85(d，1H，J＝15.3Hz)，5.69(dq，1H，J＝15.0，6.7Hz)，5.26(dt，1H，J＝10.7，6.8Hz)，3.14(dd，2H，J＝6.8，6.8Hz)，2.31(dt，2H，J＝6.8，6.8Hz)，2.26(dt，2H，J＝6.7，6.8Hz)，1.81(dq，1H，J＝6.8，6.8Hz)，1.77(d，3H，J＝6.7Hz)，0.92(d，6H，J＝6.7Hz)
13C-NMR(CDCl3)；δ166.45，143.74，130.29，129.83，128.03，127.09，124.65，47.26，32.50，28.97，26.79，20.53，18.67
(比较例1)
如下述所示，将3-羟基-6，8-癸二烯酰胺(h)转化为甲磺酸酯(i)后，利用脱甲磺酸合成N-异丁基-2，6，8-癸三烯酰胺(千日菊素)，关于稳定性及感官评价，与由上述实施例2得到的N-异丁基-2，6，8-癸三烯酰胺(千日菊素)进行比较。
[化13]
在带有搅拌装置、温度计、滴加漏斗的1L烧瓶中，在氮气流下加入N-异丁基-3-羟基-6，8-癸二烯酰胺(h)(85.2g、0.35mol)、醋酸乙酯(680ml)、三乙基胺(72.1g、0.70mol)，冷却至5℃，其后，用1小时滴加甲磺酰氯(44.7g、0.392mol)。滴加结束后，加入水(170ml)并进行分液。进一步进行3次水洗(170mL)，减压下除去溶剂，得到N-异丁基-3-磺酰氧基-6，8-癸二烯酰胺(i)(108.9g、收率98％)。
N-异丁基-3-磺酰氧基-6，8-癸二烯酰胺(i)
GC/MS(m/e)；317(M+，3％)，301(18)，288(2)，260(3)，243(1)，222(48)，206(12)，192(7)，178(5)，155(4)，141(18)，128(40)，115(50)，107(53)，93(63)，79(80)，57(100)，41(68)
在使N-异丁基-3-磺酰氧基-6，8-癸二烯酰胺(i)(108.9g)溶解于THF(425ml)并冷却至0℃的溶液中，用1小时滴加28％甲醇钠-甲醇溶液(75.5g、0.39mol)，滴加结束后，进一步搅拌2小时。加入水(170g)并进行分液后，进行2次水洗(170mL)，减压除去溶剂，得到粗生成物。将该粗生成物进行减压蒸馏(140℃/0.3托)，以收率76％(由N-异丁基-3-羟基-6，8-癸二烯酰胺(h))得到N-异丁基-2，6，8-癸三烯酰胺(千日菊素)(58.8g)。
此时，N-异丁基-2，6，8-癸三烯酰胺的纯度为97.2％，链烯部位的异构体比为：(2E，6Z，8E)为78.2％、(2E，6E，8E)为18.0％、(2E，6Z，8Z)为3.8％。
(稳定性评价)
关于由实施例2得到的N-异丁基-2，6，8-癸三烯酰胺的蒸馏前的粗生成物和由比较例1得到的粗生成物，假设高温下的蒸馏，将180℃下的热稳定性如下所述进行比较。
在氮气流下，在烧瓶中分别加入粗生成物1g、作为内部标准物质的十六烷0.1g，在180℃下搅拌6小时。利用气相色谱法比较相对于内部标准物质的面积比的N-异丁基-2，6，8-癸三烯酰胺的面积比，由此测定N-异丁基-2，6，8-癸三烯酰胺的残存率。
就3小时后的残存率而言，实施例2为98％，比较例1为89％，确认为利用本发明的制造方法制成的N-异丁基-2，6，8-癸三烯酰胺的明显的热稳定性的提高。
(感官评价)
将由实施例2及比较例1得到的N-异丁基-2，6，8-癸三烯酰胺分别设定为10ppm的水溶液，进行感官评价。表1表示其结果。
[表1]
| 香味 | 感官评价(麻痹、收敛性作用) | |
| 实施例2 | 几乎没有气味 | 清晰且强 |
| 比较例1 | 感觉到不愉快的鱼臭、胺那样的异臭 | 强，但稍微伴有异味 |
已确认为由实施例2得到的N-异丁基-2，6，8-癸三烯酰胺与由比较例1得到的N-异丁基-2，6，8-癸三烯酰胺相比，几乎没有异臭，且显示优异的麻痹、收敛性作用。
工业上应用的可能性
根据本发明，提供一种在作为香料有用的N-异丁基-2，6，8-癸三烯酰胺(千日菊素)的制造中有用的新型的中间体，通过使用该中间体，可以制造为高收率及高纯度且在热稳定性、香味、功效方面均良好的千日菊素。
Claims (5)
1.一种酰胺酯，其用下述通式(1)表示，
式中，R1表示碳数1～6的烷基及碳数1～4的烷基、碳数1～4的烷氧基或可以用卤原子取代的苯基，R2表示碳数1～8的烃基，波浪线表示顺式构型、反式构型或两种构型的混合。
2.如权利要求1所述的酰胺酯，其中，R1为碳数1～4的烷基。
3.如权利要求2所述的酰胺酯，其中，R1为甲基。
4.如权利要求1～3中任一项所述的酰胺酯，其中，R2为异丁基或仲丁基。
5.一种2,6,8-癸三烯酰胺的制造方法，其中，使权利要求1～4中任一项所述的酰胺酯与碱性化合物反应。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2009165530 | 2009-07-14 | ||
| JP2009-165530 | 2009-07-14 | ||
| PCT/JP2010/061912 WO2011007807A1 (ja) | 2009-07-14 | 2010-07-14 | スピラントールの製造法及びその製造中間体 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102471238A CN102471238A (zh) | 2012-05-23 |
| CN102471238B true CN102471238B (zh) | 2014-04-02 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201080026898.XA Active CN102471238B (zh) | 2009-07-14 | 2010-07-14 | 千日菊素的制造方法及其制造中间体 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US9029593B2 (zh) |
| EP (1) | EP2455363B1 (zh) |
| JP (1) | JP5587313B2 (zh) |
| CN (1) | CN102471238B (zh) |
| ES (1) | ES2512240T3 (zh) |
| IN (1) | IN2012DN00361A (zh) |
| WO (1) | WO2011007807A1 (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2986001B1 (fr) | 2012-01-24 | 2014-08-15 | Robertet Sa | Nouveau procede de concentration de spilanthol et/ou de ses isomeres et/ou homologues |
| WO2013140973A1 (ja) * | 2012-03-23 | 2013-09-26 | 大正製薬株式会社 | 飲料 |
| TW201625140A (zh) * | 2014-08-29 | 2016-07-16 | San Ei Gen Ffi Inc | 經口組成物用添加劑 |
| BR102016017871B1 (pt) * | 2016-07-29 | 2023-03-21 | Universidade Estadual De Campinas - Unicamp | Processo de obtenção do espilantol e análogos, espilantol e análogos obtidos |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080050500A1 (en) * | 2004-12-20 | 2008-02-28 | Ogawa & Co., Ltd. | Additive for Carbonated Beverage |
| US20080069912A1 (en) * | 2004-01-15 | 2008-03-20 | Gattefosse Sas | Use of an Acmella Oleracea Extract for the Botox-Like Effect Thereof in an Anti-Wrinkle Cosmetic Composition |
| US20090124701A1 (en) * | 2007-11-08 | 2009-05-14 | Symrise Gmbh & Co. Kg | Use of alkamides for masking an unpleasant flavor |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0790294A (ja) * | 1993-09-20 | 1995-04-04 | Lion Corp | スピラントール高含有精油及びその製造方法並びにスピラントール高含有精油配合口腔用組成物 |
| DE602004003056D1 (de) * | 2003-06-13 | 2006-12-14 | Ecopia Biosciences Inc | Polyenoxazole mit antitumorwirkung und verfahren zu deren herstellung mittels eines streptomyces-stamms |
| JP4688517B2 (ja) * | 2005-02-15 | 2011-05-25 | 小川香料株式会社 | 高甘味度甘味料の呈味改善剤 |
| JP4508932B2 (ja) * | 2005-04-25 | 2010-07-21 | 小川香料株式会社 | 呈味増強剤及び該呈味増強剤を含有する香味料並びに該香味料を含有する飲食物 |
| JP4530906B2 (ja) * | 2005-04-25 | 2010-08-25 | 小川香料株式会社 | 飲食品の香味増強剤 |
| US8217192B2 (en) * | 2008-01-18 | 2012-07-10 | Takasago International Corporation | Production method of (2E,6Z,8E)-N-isobutyl-2,6,8-decatrienamide (spilanthol), and food or drink, fragrance or cosmetic, or pharmaceutical comprising the same |
-
2010
- 2010-07-14 US US13/383,547 patent/US9029593B2/en not_active Expired - Fee Related
- 2010-07-14 WO PCT/JP2010/061912 patent/WO2011007807A1/ja active Application Filing
- 2010-07-14 IN IN361DEN2012 patent/IN2012DN00361A/en unknown
- 2010-07-14 CN CN201080026898.XA patent/CN102471238B/zh active Active
- 2010-07-14 EP EP10799865.0A patent/EP2455363B1/en not_active Not-in-force
- 2010-07-14 ES ES10799865.0T patent/ES2512240T3/es active Active
- 2010-07-14 JP JP2011522838A patent/JP5587313B2/ja not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080069912A1 (en) * | 2004-01-15 | 2008-03-20 | Gattefosse Sas | Use of an Acmella Oleracea Extract for the Botox-Like Effect Thereof in an Anti-Wrinkle Cosmetic Composition |
| US20080050500A1 (en) * | 2004-12-20 | 2008-02-28 | Ogawa & Co., Ltd. | Additive for Carbonated Beverage |
| US20090124701A1 (en) * | 2007-11-08 | 2009-05-14 | Symrise Gmbh & Co. Kg | Use of alkamides for masking an unpleasant flavor |
Non-Patent Citations (2)
| Title |
|---|
| Constituents of Heliopsis Species. IV. The Total Synthesis of trans-Afhin;MARTINJ ACOBSON;《J.Am.Chem.Soc.》;19550505;第77卷;第2461-2463页 * |
| MARTINJ ACOBSON.Constituents of Heliopsis Species. IV. The Total Synthesis of trans-Afhin.《J.Am.Chem.Soc.》.1955,第77卷第2461-2463页. |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2455363B1 (en) | 2014-10-01 |
| CN102471238A (zh) | 2012-05-23 |
| EP2455363A4 (en) | 2012-12-26 |
| JPWO2011007807A1 (ja) | 2012-12-27 |
| WO2011007807A1 (ja) | 2011-01-20 |
| ES2512240T3 (es) | 2014-10-23 |
| IN2012DN00361A (zh) | 2015-05-22 |
| JP5587313B2 (ja) | 2014-09-10 |
| US20120116116A1 (en) | 2012-05-10 |
| EP2455363A1 (en) | 2012-05-23 |
| US9029593B2 (en) | 2015-05-12 |
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Effective date of registration: 20220225 Address after: 456 KANGYI Road, Kangqiao Industrial Zone, Pudong New Area, Shanghai Patentee after: Shanghai Takasago-Union Fragrances & Flavors Co.,Ltd. Address before: Tokyo, Japan Patentee before: TAKASAGO INTERNATIONAL Corp. |
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