CN103380111A - 羟基羧酸和羟基羧酸低聚物的视黄基酯 - Google Patents
羟基羧酸和羟基羧酸低聚物的视黄基酯 Download PDFInfo
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- CN103380111A CN103380111A CN2012800097646A CN201280009764A CN103380111A CN 103380111 A CN103380111 A CN 103380111A CN 2012800097646 A CN2012800097646 A CN 2012800097646A CN 201280009764 A CN201280009764 A CN 201280009764A CN 103380111 A CN103380111 A CN 103380111A
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- acid
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- unsubstituted
- retinyl ester
- ester
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical group [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
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- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 3
- ZDHCZVWCTKTBRY-UHFFFAOYSA-N 12-hydroxylauric acid Chemical compound OCCCCCCCCCCCC(O)=O ZDHCZVWCTKTBRY-UHFFFAOYSA-N 0.000 claims description 3
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- AYOLELPCNDVZKZ-UHFFFAOYSA-N 3-hydroxy-3-phenylpropionic acid Chemical compound OC(=O)CC(O)C1=CC=CC=C1 AYOLELPCNDVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
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- LDLDJEAVRNAEBW-UHFFFAOYSA-N Methyl 3-hydroxybutyrate Chemical class COC(=O)CC(C)O LDLDJEAVRNAEBW-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
羟基羧酸视黄基酯和羟基羧酸低聚物的视黄基酯使用化学酶来制备，通过视黄醇与短链羟基羧酸酯或短链羟基羧酸酯获得。酸中羟基官能团的存在可以导致酯是来自多种羟基-取代羧酸低聚物的混合物。视黄基酯产物容易在体外酶促进水解，它应用在皮肤上可以释放抗衰老成分视黄基酯（无内在不稳定和刺激性）和酸，如果选择合适，酸也具有很好的生物效果。这种结合物可以成为效果较好的抗衰老护肤成分。
Description
技术领域
本发明涉及视黄基酯及其制备方法
背景技术
视黄醇（维生素A）及其衍生物作为活性成分应用在化妆品中的历史悠久，它们能提高皮肤的整体面貌。视黄醇本身不稳定，且过量应用具有刺激性。长链的视黄醇酯由于其较为稳定且对皮肤刺激性小，因此有时更容易被人们选择。人们希望这些酯容易在皮肤上分解成视黄醇用于新陈代谢而发挥功效。由于视黄醇酯中含有脂肪酸成分，脂肪酸的水解成分可以提供更多益处。除了脂肪酸，具有各种生物特性的其它物质，也希望被用于视黄基轭合物中来提高或扩大生物收益。
制备视黄基酯的化学手段一种是视黄醇与长链酸或氯化酰基或酯进行反应，一种是用短链视黄醇酯与长链脂肪酸酯进行酯交换反应。这些过程使用烈性试剂或高温，这类反应条件，致使不稳定的视黄醇或视黄基酯产生降解。另外，这些方法不适合那些具有活性基团的部分，如醇类，除非醇被保护。羟基的保护和去保护增加合成这类分子的成本、时间和废物。
一些用视黄醇合成视黄醇酯的生物手段已被报道（O'Connor et.al.Aust.J.Chem.1992,45,641;Maugard,et.al.J.Mol.Catal.B:Enzymatic2000,8,275;Maugard et.al.,Biotechnol.Prog.2000,16,358;Maugard et.al.Biotechnol.Prog.2002,18,424.）。这些方法通常使用易于酯形成且较少复杂活性基团的长链酸。乳酸视黄基酯是个例外，它可以用视黄醇与乳酸甲酯通过酶的酯化反应制得（Maugard,et.al.J.Mol.Catal.B:Enzymatic2000,8,275;Maugard et.al.Biotechnol.Prog.2000,16,358;Maugard et.al.Biotechnol.Prog.2002,18,424.）。这是个不寻常案例，由于乳酸中的羟基周围位阻使其在酶酯化反应中较为稳定。
视黄基酯比视黄醇本身更加趋于稳定且无毒。酸部分的选择出于这些目的，或受其它生物学考虑的影响。例如3-羟基丁酸和它的酯，包括其低聚物，作为细胞能量来源广泛为人所知，被Stryer记载在《生物化学》第四版（1995）第613页，其中他提到“乙酰乙酸和β-羟基丁酸是呼吸作用的常见燃料，其在数量上跟能源同样重要”。β-羟基丁酸或其低聚物与视黄基酯的偶合物，在细胞中被水解成相应的酸和醇，可以具有双重功效-视黄醇提升变异而羟基丁酸提供能量。
因此3-羟基丁酸和3-羟基丁酸低聚物以及其他羟基直链酸形成的视黄基酯可以作为具有优势的新物质被应用于抗衰老化妆品中。
发明概述
一方面，本发明涉及如下通式1中所示的视黄基酯：
其中R选自取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的二价C1-C22烷基，取代和未取代的二价C3-C8环烷基，取代和未取代的二价C6-C20碳环芳基，和取代和未取代的二价C4-C20杂环基，其中杂原子选自硫、氮、和氧原子；R1选自氢，取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的C1-C22烷基，取代和未取代的C3-C8环烷基，取代和未取代的C6-C20碳环芳基，和取代和未取代的C4-C20杂环基，其中杂原子选自硫、氮、和氧原子；并且n代表0-10；以及上述酯的混合物。
再一方面，R是取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的二价C1-C18烷基，或饱和或单不饱和的直链C1-C10烷基；R1是氢，取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的C1-C18烷基，n代表0-10。
再一方面，R是取代和未取代的、支链和直链的、饱和、不饱和、或多不饱和的二价C1-C10烷基，或饱和或单不饱和的直链C1-C10烷基；或饱和或单不饱和的直链C1-C4烷基；R1是氢，取代和未取代的、支链和直链的、饱和、不饱和、或多不饱和的C1-C18烷基、或C1-C12烷基、或C1-C4烷基；并且n是0-6，或其混合物。
在再一方面，R是甲基、乙基或丙基；R1是甲基、乙基或丙基；并且n是从0到6，或其混合物。在进一方面，R是亚甲基；R1是甲基，并且n=1、2、3和4。即，该视黄基酯可以是不同长度和包括重复单元的酯的混合物。
再一方面，该视黄基酯可以源自视黄醇和一种或多种羟基-取代的羧酸制得，如一种或多种3-羟基丁酸，3-羟基-3-甲基丁酸，3-羟基辛酸，羟基丁二酸，3-苯基-3-羟基丙酸，10-羟基癸酸，12-羟基十二烷酸，16-羟基十六烷酸，或蓖麻油酸。
再一方面，所述酯包括含有多于一个重复单元的低聚物（或由多于一个重复单元构成的低聚物），重复单元源自一种或多种羟基-取代的羧酸。
在进一方面，本发明涉及上述视黄基酯的制备方法，该方法包括在酶的存在下，视黄醇与酸或如式2所示羟基链烷酸酯的短链酯反应。
其中，R和R1如前述定义，并且R5选自氢或直链或支链C1-C5烷烃或烯烃。
该方法在溶剂中进行，其中溶剂选自乙醚、二异丙醚、叔丁基甲醚、四氢呋喃、苯、甲苯、二甲苯、己烷、庚烷、环己烷、苧烯、二氯甲烷、二氯乙烷、二溴乙烷、四氯乙烯、氯苯、乙腈、二甲基甲酰胺，或二甲基亚砜，或其混合物。
再一方面，该方法可以在甲苯、苧烯、庚烷或乙腈中一种或多种溶剂中进行。可选择地，该方法可以在无溶剂条件下进行。本发明的方法中所应用的酶包括脂酶、酯酶、或蛋白酶中的一种或多种，尤其是脂酶。
再一方面，酸或如式2所示羟基链烷酸酯的短链酯可能包含3-羟基丁酸乙酯或3-羟基丁酸甲酯中的一种或多种。
在再一方面，本发明涉及包含本发明的视黄基酯的化妆品组合物。
本发明的进一步方面在说明书中被公开并被要求保护。
发明详述
其中使用的短语“烷基”和“烷基官能团”，是为了适用于无论是以一价、二价甚至是三价相连的碳原子，只要基团包含碳原子链和氢原子。有机化学领域众所周知，其中一些氢原子可以被其它原子或基团取代。
因此，在一方面，本发明涉及如通式1所示的视黄基酯。
其中R选自取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的二价C1-C22烷基，取代和未取代的二价C3-C8环烷基，取代和未取代的二价C6-C20碳环芳基，和取代和未取代的二价C4-C20杂环（其中杂原子选自硫、氮、和氧原子），并且R1选自氢、取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的C1-C22烷基，取代和未取代的C3-C8环烷基，取代和未取代的C6-C20碳环芳基，取代和未取代的C4-C20杂环（其中杂原子选自硫、氮、和氧原子），并且n是0-10或其混合物。
本发明的化合物为可以是外消旋体，富含对映异构体（enantiomerically enriched），富含非对映异构体（diasteroemericallyenriched），基本纯的非对映异构体，基本纯的对映异构体。
再一方面，本发明涉及式1所示物质，其中R选自取代和未取代的、支链和直链的饱和二价C1-C18烷基，取代和未取代的、直链和支链的二价C2-C18烯基，取代和未取代的、直链和支链的二价C4-C18二烯基，取代和未取代的二价C3-C8环烷基，取代和未取代的二价C6-C12碳环芳基，取代和未取代的二价C4-C12杂环，R1选自氢，取代和未取代的、支链和直链的饱和C1-C18烷基，取代和未取代的、支链和直链的C2-C18烯基，取代和未取代的、支链和直链的C4-C18二烯基，取代和未取代的C3-C8环烷基，取代和未取代的C6-C12碳环芳基，取代和未取代的C4-C12杂环基，n是0-6，或其混合物。
R所代表的饱和、不饱和、和多不饱和的烷基和环烷基团可以代表包含高至约22个碳原子的直链或支链的二价烃基，并且该烃基可以被取代，例如，一到五个如下取代基取代：C1-C6烷氧基、羧基、氨基，C1-C15氨基羰基，C1-C15酰氨基，氰基，C2-C6烷氧羰基，C2-C6烷酰基氧基，羟基，芳基、杂芳基，硫醇，硫醚，C2-C10二烷基氨基，C3-C15三烷基铵和卤素。其中术语“C1-C6烷氧基”、“C2-C6烷氧羰基”、“C2-C6烷酰基氧基”分别表示基团-OR2、-CO2R2、和-OCOR2的结构，其中R2是指C1-C6烷基或取代C1-C6烷基。术语“C1-C15氨基羰基”、“C1-C15酰氨基”分别表示基团-NHCOR3,-CONHR3，其中R3是C1-C15烷基或取代C1-C15烷基。术语“C3-C8环烷基”用来表示碳原子数为3-8的饱和碳环烃基。术语“卤素”通常包括氟、氯、溴、碘。
R1所代表的饱和、不饱和、和多不饱和的烷基基团可以是包含高至约22个碳原子的直链或支链的烃基，并且该烃基可以被取代，例如，被一到五个如下取代基取代：C1-C6烷氧基、羧基、氨基，C1-C15氨基羰基，C1-C15酰氨基，氰基，C2-C6烷氧羰基，C2-C6烷酰基氧基，羟基，芳基、杂芳基，硫醇，硫醚，C2-C10二烷基氨基，C3-C15三烷基铵和卤素。其中术语“C1-C6烷氧基”、“C2-C6烷氧羰基”、“C2-C6烷酰基氧基”分别表示基团-OR2、-CO2R2、和-OCOR2的结构，其中R2是指C1-C6烷基或取代C1-C6烷基。术语“C1-C15氨基羰基”、“C1-C15酰氨基”分别表示基团-NHCOR3,-CONHR3，其中R3是C1-C15烷基或取代C1-C15烷基。术语“C3-C8环烷基”用来表示碳原子数为3-8的饱和碳环烃基。术语“卤素”通常包括氟、氯、溴、碘。
支链的和/或取代的R和R1可以连接形成环形。
R所代表的芳基可以包括：二价苯基、萘基、或蒽基和被一到五个如下取代基取代的二价苯基、萘基、或蒽基：C1-C6烷基、取代C1-C6烷基、C6-C10芳基、取代C6-C10芳基、C1-C6烷氧基、卤素、羧基、氰基、C1-C6烷酰基氧基、C1-C6烷硫基、C1-C6烷基磺酰基、三氟甲基、羟基、C2-C6烷氧羰基，C2-C6烷酰氨基和–OR4,-S-R4,-SO2-R4,-NHSO2R4和-NHCO2R4，其中R4为苯基、萘基或被C1-C6烷基、C6-C10芳基、C1-C6烷氧基和卤素中的一到三种取代基取代的苯基或萘基。术语“卤素”包括氟、氯、溴、碘。
R1所代表的芳基（或任何芳基取代基）可以包括：苯基、萘基、或蒽基和被一到五个如下取代基取代的苯基、萘基、或蒽基：C1-C6烷基、取代C1-C6烷基、C6-C10芳基、取代C6-C10芳基、C1-C6烷氧基、卤素、羧基、氰基、C1-C6烷酰基氧基、C1-C6烷硫基、C1-C6烷基磺酰基、三氟甲基、羟基、C2-C6烷氧羰基，C2-C6烷酰氨基和–OR4,-S-R4,-SO2-R4,-NHSO2R4和-NHCO2R4，其中R4为苯基、萘基或被C1-C6烷基、C6-C10芳基、C1-C6烷氧基和卤素中的一到三种取代基取代的苯基或萘基。术语“卤素”通常包括氟、氯、溴、碘。
R代表的二价杂环基包括含有选自氧、硫、氮中一到三种杂原子的5或6元环。此杂环基团可以是：吡喃基、含氧吡喃基、二氢吡喃基、含氧二氢吡喃基、四氢吡喃基、噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、四唑基、吡啶基、嘧啶基、苯并噁唑基、苯并噻唑基，苯并咪唑基，吲哚基等。杂环基团可以被取代，例如被高至三个基团取代，如C1-C6烷基、C1-C6烷氧基、取代C1-C6烷基、卤素、C1-C6烷硫基、芳基、芳硫基、芳氧基、C2-C6烷氧羰基、C2-C6烷酰氨基。杂环基团也可以被稠环系统取代，如：可以被如上述取代基中的最多三种基团取代或未取代的苯并或萘并残基。术语“卤素”通常包括氟、氯、溴、碘。
R1（或任意杂芳取代基）所代表的杂环基团是包括含有选自氧、硫、氮中一到三种杂原子的5或6元环。此杂环基团可以是：吡喃基、含氧吡喃基、二氢吡喃基、含氧二氢吡喃基、四氢吡喃基、噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、四唑基、吡啶基、嘧啶基、苯并噁唑基、苯并噻唑基，苯并咪唑基，吲哚基等。杂环基团可以被取代，例如被高至三个基团取代，如C1-C6烷基、C1-C6烷氧基、取代C1-C6烷基、卤素、C1-C6烷硫基、芳基、芳硫基、芳氧基、C2-C6烷氧羰基、C2-C6烷酰氨基。杂环基团也可以被稠环系统取代，如：可以被如上述取代基中的最多三种基团取代或未取代的苯并或萘并残基。术语“卤素”通常包括氟、氯、溴、碘。
本发明所述化合物的例子包括如式1所代表的化合物，其中R为亚甲基，R1为甲基并且n是0到6，以及上述混合物。
再一方面，本发明所涉及的视黄基酯通式如式1所示：
其中R选自取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的二价C1-C18烷基，或C1-C12烷基，或C1-C10烷基，或饱和或单不饱和直链C1-C10烷基，或C1-C4烷基；并且R1选自氢、取代和未取代的、支链和支链的、饱和、不饱和、和多不饱和的C1-C18烷基，或C1-C12烷基、或C1-C4烷基；并且n为0-10或1-6或1-4，或其混合物。
在多个其他方面，本发明所述化合物的例子包括如式1所代表的化合物，其中R为甲基、乙基、或丙基，R1为甲基、乙基、丙基，并且n为从0到6，和其混合物。我们发现根据本发明制备方法中使用不同的羟基-取代的羧酸，每一个R和R1基团可以相互独立存在，但是如果使用单一羟基-取代的羧酸，每一个R和R1基团将会相同，并且制得的视黄基酯将含有具有不同长度的低聚物，此类视黄基酯是其中n=0,n=1,n=2,n=3等的化合物的混合物。然而，如n定义为0-6，不意味着因此排除含有n=7,n=8等的化合物的混合物，虽然即使它们存在，通常也将为少量。
本发明所述化合物的其他例子包括如式1所代表的化合物，其中R为亚甲基，R1为甲基，n为0-6，并且包含所述其中n=0,n=1,n=2,n=3,和n=4的化合物的混合物。
本发明的另一方面，符合通式1所示的视黄基酯：
其中R选自取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的二价C1-C22烷基，或C1-C18烷基，或C1-C12烷基，或不饱和、单一不饱和、或多不饱和的直链C2-C22烷基，或C4-C18烷基；并且R1选自氢、取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的C1-C18烷基、或C1-C12基、或C1-C4烷基；并且n为0-10或1-6或1-4，或其混合物。在这一方面，视黄基酯可以源自视黄醇和以下一种或多种的羟基-取代羧酸，如3-羟基丁酸，3-羟基-3-甲基丁酸，3-羟基辛酸，羟基丁二酸，3-羟基-3-甲基戊二酸、3-苯基-3-羟基丙酸，10-羟基癸酸，12-羟基十二烷酸，16-羟基十六烷酸，或蓖麻油酸。
由羟基-取代羧酸制得的视黄基酯可能含有低聚物，该低聚物包含多于一种脂肪酸重复结构单元，其取决于酸的羟基取代部分的活性。
本发明中另一实施方式是新酶化方法，用于制备如通式1所示的视黄基酯化合物：
其中，R选自取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的二价C1-C22烷基，取代和未取代的二价C3-C8环烷基，取代和未取代的二价C6-C20碳环芳基，取代和未取代的二价C4-C20杂环（其中杂原子选自硫、氮、和氧原子），并且R1选自氢、取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的C1-C22烷基，取代和未取代的C3-C8环烷基，取代和未取代的C6-C20碳环芳基，取代和未取代的C4-C20杂环基（其中杂原子选自硫、氮、和氧原子），如通式1所示的化合物可以为外消旋体，富含对映异构体（enantiomerically enriched），富含非对映异构体（diasteroemerically enriched），基本纯的非对映异构体，基本纯的对映异构体，并且n是0-10或由视黄醇与酸或如式2所示羟基链烷酸酯的短链酯反应制得的上述化合物的混合物：
其中，R和R1已定义，并且R5选自氢或C1-C5直链或支链烷烃或烯烃，在脂酶、酯酶或蛋白酶的存在下。
该方法在无溶剂或惰性溶剂下进行，其中惰性溶剂选自环-或非环的醚溶剂，如乙醚、异丙醚、叔丁基甲醚，或四氢呋喃、芳香烃如苯、甲苯、或二甲苯，饱和或不饱和脂肪族或脂肪环的烃基如己烷、庚烷、环己烷，或苧烯或卤代烃如二氯甲烷、二氯乙烷、二溴乙烷、四氟乙烯或氯苯，极性、质子惰性的溶剂如乙腈、二甲基甲酰胺或二甲基亚砜，或它们的混合物。
优选的溶剂是无溶剂，甲苯、苧烯、庚烷和乙腈。该方法在温度约-100℃和溶剂沸点之间进行，优选0-60℃，最优选为20-50℃。酸或短链酯2的用量可以为视黄醇的0.85-20当量，优选为1-10当量，最优选的为1-4当量。
该方法使用的酶选自多种水解酶，如蛋白酶、脂酶、或酯酶。优选脂酶。这些脂酶可以是以整个细胞，或分离的原生酶，或支持物固定的形式。
适宜的脂酶例子包括但不限于以下几种：脂酶PS（来自假单胞菌属）（Lipase PS）（from Pseudomonas sp），脂酶PS-C（来自假单胞菌属固定在陶瓷材料上）（Lipase PS-C）（from Pseudomonas sp immobilized onceramic），脂酶PS-D（来自假单胞菌属固定在硅藻土）（Lipase PS-D）（from Pseudomonas sp immobilized on diatomaceous earth），Lipoprime50T、Lipozyme TL IM或Novozym435（南极假丝酵母脂酶B固定在丙烯酸树脂）（Candida antarctica lipase B immobilized on acrylic resin）。如果需要除去水或醇副产物，根据需要，可以通过水或醇吸收剂（如分子筛）的化学手段或物理手段除去水或醇。副产物的去除手段优选使用蒸馏，或者用如氮、氩、氦的惰性气体吹扫反应混合物，或者减压下进行反应，或二者同时使用，在此条件下，式1的视黄醇的转化率可以达到>95%。优选的反应压力为1托到环境压力，更优选的为50托到环境压力。在制备方法中包含的任何有机溶剂可以或可以不必与水或醇一同除去。式2的例子中包括3-羟基丁酸乙酯和3-羟基丁酸甲酯。
该反应产物1使用该领域技术人员熟知的手段进行分离，如通过萃取、过滤或结晶。
本发明所得到视黄基酯可用于组合物，如化妆品组合物、护肤品组合物成分和类似物。该组合物非常有用，如降低肌肤粗糙度、细线和皱纹，改善晒伤肌肤，再生肌肤，减少肌肤过多色素沉淀、降低肌肤的刺激或炎症反应。
本发明化妆品和/或护肤品组合物包含至少0.001wt%根据本发明碳酸盐（或酯）。如，所述组合物可以含有大约0.001wt%到大约20.0wt%或大约0.01wt%到大约10.0wt%的本发明视黄基酯。较低浓度则效果不明显，较高浓度可以表现更明显效果。建议范围取决于该组合物所使用的辅助材料。
本发明的化妆品或护肤品组合物除视黄基酯外也可含有其他皮肤调节成分。这些成分包括但不限于，护肤成分如视黄醇、视黄基脂肪酸酯、特窗酸（tetronic acid）、特窗酸衍生物、对苯二酚、曲酸、五倍子酸、熊果苷、α-羟基酸、抗坏血酸和抗坏血酸的脂肪酸酯。这些其他成分是被本领域技术人员已知的那些。
通常，局部应用在皮肤上需要载体进行辅助。应用的载体理想的为惰性的，不会使活性或辅助成分失活或氧化，不会为应用的皮肤区域带来任何明显副作用。比如，根据本发明的化合物可以与皮肤病理上可以接受的载体或材料（如洗剂（lotion）、霜、药膏（ointment）、皂（soap）、棒（stick）等）进行混合使用，以便适于局部使用，有时候还会产生额外的有益效果，如湿润使用皮肤区域。
适当的制剂包括含有油和/或醇的洗剂以及如以下所示润肤剂（emollients）：如，橄榄油、烃油和石蜡、硅油、其它植物油、动物油或海洋动物脂肪或油、甘油酯衍生物、脂肪酸或脂肪酸酯或醇类或醇醚、卵磷脂、羊毛脂和其衍生物、多元醇或其酯、蜡酯、甾醇、磷脂等，通常还有乳化剂（非离子，阳离子或阴离子），虽然一些润肤剂本身具有乳化性能。这些相同的常规材料可以按配方制成面霜而不是洗剂，或制成凝胶剂或固体棒剂（solid sticks），通过利用材料的不同比例和/或加入粘稠剂，如树胶或其他类型亲水胶体。
本发明提供的新制备方法通过以下实施例进一步说明。
具体实施方式
实施例1
制备视黄基-3-羟基丁酸酯的低聚物（1a）（n=0-4）
庚烷中，向小瓶中依次加入视黄醇（58%的视黄醇25.9g，15.0g视黄醇；52.4mmol），3-羟基丁酸乙酯（20.76g；157mmol；3倍当量），和Novozym435（1.5g）。混合物在室温下通入氮气吹扫搅拌48h，得到视黄醇转化率为96.7%的视黄基-3-羟基丁酸酯的低聚物的混合物。该混合物用甲苯（30ml）进行稀释，过滤，得到固体用甲苯（30ml）进行洗涤。甲苯溶液用水：甲醇为1:1（60ml）进行洗涤，倒出水相用庚烷（25ml）反向萃取，合并有机层，用水：甲醇为1:1（60ml）进行洗涤，用无水硫酸钠进行干燥，浓缩得到深黄色油状物17.79g1a(R=CH2,R1=CH3)。HPLC（高效液相色谱法）分析得3.7%的视黄醇和95.5%的1a低聚物。HPLC测得1a,n=0(53.7%),1a,n=1(32.9%),1a,n=2(7.1%),1a,n=3(1.4%),和1a,n=4(0.3%)。
HPLC和HPLC-MS(4.6x150mm Zorbax SB-C8色谱柱[安捷伦],3.5μ厚度,80:20甲醇:水(包含0.1%三氟乙酸)检测时间20min，检测波长325nm):tR6.6min(视黄醇);tR8.0min(1a,n=0,M+=372);tR8.8min(1a,n=1,M+=458);tR9.7min(1a,n=2,M+=544);tR10.6min(1a,n=3,M+=630);tR11.8min(1a,n=4,M+=716)。
实施例2
制备视黄基蓖麻油酸酯（1b）
于甲苯中，向小瓶中依次加入视黄醇（54%的视黄醇1.852g，1.0g；视黄醇，3.49mmol），蓖麻油酸（80%含量；1.250g；4.19mmol；1.2倍当量），和Novozym435（1g）。混合物密闭在室温下搅拌21h，视黄醇转化率为83%得到1b。
HPLC(4.6x150mm Zorbax SB-C8色谱柱[安捷伦],3.5μ厚度,90:10甲醇:水(包含0.1%三氟乙酸)检测时间7min，在1min内梯度转成95:5甲醇:水(包含0.1%三氟乙酸)，维持浓度检测时间12min，在1min内梯度转成100%甲醇，维持100%甲醇，检测波长325nm):tR3.9min(视黄醇);tR14.2min(1b)。
实施例3
酶法水解视黄基-3-羟基丁酸酯的低聚物（1a）（n=0-4）
将视黄基-3-羟基丁酸酯的低聚物（1a；100mg）溶解于2ml甲苯中，加入pH值为7的缓冲溶液（2ml），加入Novozym435(100mg)，混合物在室温下剧烈搅拌，在1、24、48h抽取上层液通过HPLC进行分析，所得结果如表1所示，并且显示在48h有大量水解。没有酶的对照试验显示48小时后无水解。
表1酶法水解视黄基-3-羟基丁酸酯的低聚物
| 时间(h) | %转化率 | %1a,n=0%1a,n=1 | %1a,n=2 | %1a,n=3 | %1a,n=4 |
| 0 | 3.7 | 54.233.2 | 7.2 | 1.4 | 0.3 |
| 1 | 25.1 | 37.030.0 | 6.5 | 1.3 | 0.3 |
| 24 | 81.4 | 6.67.7 | 3.0 | 1.1 | 0.2 |
| 48 | 84.8 | 5.34.2 | 2.7 | 2.4 | 0.6 |
Claims (15)
1.如通式1所示视黄基酯:
其中，
R选自取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的二价C1-C22烷基，取代和未取代的二价C3-C8环烷基，取代和未取代的二价C6-C20碳环芳基，和取代和未取代的二价C4-C20杂环基，其中杂原子选自硫、氮和氧；
R1选自氢，取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的C1-C22烷基，取代和未取代的C3-C8环烷基，取代和未取代的C6-C20碳环芳基，和取代和未取代的C4-C20杂环基，其中杂原子选自硫、氮和氧；并且
n是0-10，
或其混合物。
2.权利要求1所述视黄基酯，其中R是取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的二价C1-C10烷基，或饱和或单不饱和的直链C1-C4烷基；R1是氢，取代和未取代的、支链和直链的、饱和、不饱和、和多不饱和的C1-C18烷基，或C1-C12烷基，或C1-C4烷基；并且n是0-6，或其混合物。
3.权利要求1所述视黄基酯，其中R是亚甲基、亚乙基或亚丙基；R1是甲基、乙基或丙基；并且n是从0到6，或其混合物。
4.权利要求1所述视黄基酯，其中R是亚甲基；R1是甲基，并且n=0,1,2,3和4。
5.权利要求1所述视黄基酯，其中视黄基酯由视黄醇和一种或多种羟基-取代羧酸制备。
6.权利要求5所述视黄基酯，其中一种或多种的羟基-取代羧酸包括一种或多种3-羟基丁酸，3-羟基-3-甲基丁酸，3-羟基辛酸，羟基丁二酸，3-羟基-3-甲基戊二酸、3-苯基-3-羟基丙酸，10-羟基癸酸，12-羟基十二烷酸，16-羟基十六烷酸，或蓖麻油酸。
7.权利要求5所述视黄基酯，其中所述酯包括含有多于一个重复单元的低聚物，重复单元源自一种或多种羟基-取代的羧酸。
8.权利要求1所述视黄基酯的制备方法，包括在酶的存在下，视黄醇与酸或如式2所示羟基链烷酸酯的短链酯反应
其中，R和R1在权利要求1中已定义，并且R5选自氢，或直链或支链的C1-C5烷基或烯基。
9.根据权利要求8所述视黄基酯的制备方法，其中方法在选自以下的溶剂中进行：乙醚、二异丙醚、叔丁基甲醚、四氢呋喃、苯、甲苯、二甲苯、己烷、庚烷、环己烷、苧烯、二氯甲烷、二氯乙烷、二溴乙烷、四氯乙烯，氯苯、乙腈、二甲基甲酰胺或二甲基亚砜，或它们的混合物。
10.根据权利要求9所述视黄基酯的制备方法，其中溶剂选自甲苯、苧烯、庚烷或乙腈中的一种或多种。
11.根据权利要求8所述视黄基酯的制备方法，其中方法在无溶剂下进行。
12.根据权利要求8所述视黄基酯的制备方法，其中酶包含脂酶、酯酶或蛋白酶中的一种或多种。
13.根据权利要求8所述视黄基酯的制备方法，其中酶为脂酶。
14.根据权利要求8所述视黄基酯的制备方法，其中酸或如式2所示羟基链烷酸酯的短链酯包含3-羟基丁酸乙酯、3-羟基丁酸甲酯或蓖麻油酸中的一种或多种。
15.化妆品组合物，其包含权利要求1的视黄基酯。
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| WO2012154243A1 (en) | 2012-11-15 |
| EP2678314B1 (en) | 2016-01-06 |
| BR112013019559A2 (pt) | 2018-07-10 |
| JP2014514249A (ja) | 2014-06-19 |
| KR20140015358A (ko) | 2014-02-06 |
| EP2678314A1 (en) | 2014-01-01 |
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| US20120215024A1 (en) | 2012-08-23 |
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