CN1106376C - 肉桂叉樟脑衍生物和它们作为uv－a－光防护剂的应用 - Google Patents

肉桂叉樟脑衍生物和它们作为uv－a－光防护剂的应用 Download PDF

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CN1106376C
CN1106376C CN97193057A CN97193057A CN1106376C CN 1106376 C CN1106376 C CN 1106376C CN 97193057 A CN97193057 A CN 97193057A CN 97193057 A CN97193057 A CN 97193057A CN 1106376 C CN1106376 C CN 1106376C
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C·坎德兹尔
H·维斯藤菲尔德
V·谢尔曼
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Abstract

本发明涉及式(1)的肉桂叉樟脑衍生物，其中二烯体系是以Z，Z，Z，E，E，Z或E，E构型存在，和R1＝H，CH3，R2＝C1-6-烷基，C1-6-烷氧基、卤素、NR3H，NR3 2，R3＝C1-4-烷基，R4＝H，C1-6-烷基；n＝1，2；和它们作为UV-A-光防护剂，特别是在化妆品和药物制剂中应用。

Description

肉桂叉樟脑衍生物和它们作为 UV-A-光防护剂的应用
本发明涉及式(1)的肉桂叉樟脑衍生物及其在化妆品和药物制剂中的应用，
以樟脑衍生物为基础的滤光剂是已知的。在DE-23 36 219中曾描述磺化的苄叉-和肉桂叉-樟脑衍生物，它们在苯环上的第4位置上是未取代的或被甲基，甲氧基或氯取代的。
在DE34 45 712中描述了一系列不饱和的樟脑衍生物，优选苄叉樟脑衍生物，它们作为药物适用于治疗皮肤病。
在DE44 26 216中描述了苄叉降樟脑衍生物，它们作为太阳滤光剂和可用于预防炎症与皮肤病。
在DE 44 24 489中描述了取代的4-甲叉肉桂酸衍生物的制备方法。
对用作UV-A滤光剂的光防护剂所提出的要求是很多的(Suncreens，ed.N.J.Lowe，N.A.Shaath，Marcel Dekker Inc.，NewYork 1990，S.230-231)。最重要的是：
1)在UV-A区域320至360nm的范围有它的最大吸收值；
2)在此范围有一高的比吸收值；
3)它是无色的，亦即在400nm以上的吸收是非常小的，以使护肤制剂不着色或在使用后衣服不着色；
4)它是光和热稳定的；
5)它与皮肤是相容的，对皮肤无刺激或无毒性作用；
6)它与皮肤有很好附着性；
7)它与化妆品是相容的和在化妆品的溶剂和制剂中有好的溶解性；
8)它是异构纯的。
已知的肉桂叉樟脑衍生物是宽谱带UV滤光剂，它在UV-A范围的保护作用不足够。此外它对于某些用途特别在油相中的溶解度是不能令人满意的。
本发明的目的是提供适于作为UV-A滤光剂的、具有特别是好的对光稳定性、好的油相中的溶解性和在UV-A区域显著的最大吸收的化合物。
已发现，式(1)的肉桂叉樟脑衍生物实现了该目的，式(1)中，二烯体系是以Z，Z；Z，E；E，Z或E，E构型存在，和其中
R1＝H，CH3；
R2＝C1-6-烷基，C1-6-烷氧基，卤素，NR3H，NR3 2；
R3＝C1-4-烷基；
R4＝H，C1-6-烷基；
n＝1，2。
(1)的制备是在碱的存在下在有或没有添加一种或多种溶剂的条件下使樟脑(2a)或降樟脑(2b)与如可按EP 392 579或DE 3831713公开的那样获得的肉桂醛(3)在0-200℃之间的温度进行反应，在其中樟脑(2a)可以外消旋或光学活性形式，亦即作为所阐明的对映异构体或对映异构体的任意混合物存在。肉桂醛(3)可作为双键的Z或E异构体或作为几何异构体的任意混合物使用。
内桂醛(3)可通过在苯甲醛缩醛中嵌入烯醇醚来制备。在此苯甲醛缩醛(4)与烯醇醚(5)在路易斯酸催化剂作用下转化成(6)，由(6)通过水解得到肉桂醛(3)。
Figure C9719305700051
为此反应，将苯甲醛缩醛(4)与烯醇醚以等摩尔的量进行反应。优选三氟化硼醚合物作催化剂，每摩尔缩醛(4)加入0.001-0.01摩尔的催化剂。反应在0到60℃，优选在20到40℃之间进行。
得到的嵌入产物(6)通过水解，优选用盐酸水溶液转化成肉桂醛(3)。
本发明的化合物(1)原则上可以其不同的几何异构体，亦即Z.Z；Z，E；E，Z或E，E-构型的二烯体系存在。全E异构体特别优选作为化妆品的光防护剂。
(2)和(3)转化成(1)的反应，这在文献中以通用概念“醛醇缩合”而著称(有机反应1968，16卷)和可用常规的方法进行。
为制备本发明化合物，将(2)和(3)以摩尔比为0.1∶1至1∶10进行反应。
Figure C9719305700052
摩尔比可在宽的界限变化：其中(3)比(2)过量是有利的，因肉桂醛由于它的氧化敏感性早在副反应中被消耗。特别有利的是采用(3)对(2)过量1.01-1.2倍的摩尔比，但是采用明显高的过量也无害处。
(2)和(3)引入反应的次序是任意的。可预加入碱或也可计量加入。反应也可作为一釜反应进行。同样(2)也可与碱一起加入而将(3)计量加入，也可以反过来。可以想像，碱与(3)一起加入而将(2)计量加入。然而，优选的是(2)与碱混合而(3)计量加入。
所用的碱量相对于(2)可在宽的范围变化。碱对(2)的摩尔比为0.1∶1至1∶20。但优选采用摩尔过量的碱。特别优选相对于(2)碱摩尔量为110摩尔％。
作为碱可用任何一般在醛醇反应中所采用的有机或无机碱。碱可在反应混合物中均化或也可以不均匀状态存在。也可利用两种或多种碱的混合物。无机碱可采用碱金属-或碱土金属氢氧化物，例如氢氧化钠、氢氧化钾、氢氧化钙，碱金属-或碱土金属碳酸盐，如碳酸钠、碳酸钾、碳酸钙，或碱金属-或碱土金属氢化物，例如氢化钠或氢化钙。合适的有机碱是碱金属或碱土金属的烷氧基盐或羧酸盐，例如甲醇钠，乙醇钠或醋酸钠。但也可用胺，例如三甲胺，二乙胺，三异丙基胺、哌啶、吡啶、DBU、Dabco或碱性离子交换剂。优选的是碱金属的氢氧化物和碱金属的烷氧基盐。特别优选是氢氧化钾和甲醇钠。
反应通常在脂肪族溶剂例如甲苯、二甲苯、己烷、二丁基醚或C1至C20的石蜡烃混合物中进行。反应同样可在质子溶剂例如乙醇中进行。然而，反应也可以不用  溶剂而在混合物的熔点温度以上进行。优选使用甲苯或石蜡烃混合物(C5至C15)。为取得良好的时空收率，使用能在反应温度下生成可搅拌的混合物的最少量的溶剂。但是较大量的溶剂也非缺点。
反应可在0℃至200℃的宽的温度范围进行。优选温度范围是20℃至110℃。特别优选的温度范围是60-90℃。
反应时间直接与反应温度有关。通常，反应在特别优选的温度范围在1至5小时后可结束。在较低的温度或低稳态浓度时反应时间明显的延长和需延长至最多48小时。
在温度范围为-20℃和40℃之间通过用水，冰或冰-水水解进行后处理。优选的温度范围在-5℃和+10℃之间。为中和过量的碱可以采用任何质子酸，例如H2SO4，HCl，HCOOH，CH3COOH。优选采用含有5-20％(重量)酸的稀的水溶液，例如10％的盐酸。
所要的产物(1)的分离可采用普通技术，如沉降，过滤、离心、相分离和用溶剂萃取，这些溶剂至少在盐的存在下与水不混溶，或有有限的水溶性。优选在水解加工后采用相分离的分离方法。在此情况下，有利的是，在混合物中加入较多的在反应中用的溶剂，例如甲苯，以改进相分离或防止产物从有机相中析出。作为这类溶液的增溶剂也可用其它任何的有机溶剂，在其中所要的产物具有足够的溶解度和它与水不可混溶的，或仅有有限的水溶性。
所要的产物(1)的提纯可用从有机溶剂和它们的混合物和/或水中重结晶进行。优选的是含醇的混合物。
也可用区域熔化和色谱方法或用蒸馏方法进行提纯。
本发明的化合物(1)可在苯环上带有一个或两个取代基R2，在两个取代基的情况下它们可相同或不同。取代基优选在2-、4-或2-和4-位置。优选的化合物(1)是由R2在第4-位上单取代的化合物。
本发明的化合物(1)可由樟脑部分(R1＝CH3)或由降樟脑部分(R1＝H)组成。
R2基具有下列意义：
C16-烷基，优选为C3-4-烷基如正丙基，异丙基、正丁基，异丁基，叔丁基；C1-6-烷氧基，优选为甲氧基；卤素，优选为氯；一或二烷基氨基NR3H或NR3 2，其中R3是C1-4-烷基和n＝1或2。
R4基是H，C1-6-烷基，优选为甲基、乙基、正丙基、异丙基、正丁基，异丁基、叔丁基，特别优选的是H，甲基和乙基。
本发明的化合物(1)特别适于作为光防护剂，尤其是作为UV-A滤光剂，用于化妆品和药物用途。然而，UV滤光剂的作用也可用于稳定塑料，染料配方或油漆。
化妆产品或制备物含化合物(1)一般为0.1至15％(重量)，优选为5-10％(重量)(以配方为基础)，除此之外在化妆品中含有化妆品中常用的赋形剂或稀释剂和必要时含常规的化妆品助剂。
最终的含光防护剂产品是溶液，油、霜剂、软膏、洗液、凝胶或粉末与否，取决于载体、助剂或稀释剂的性质。这样的制备物例如可在“肥皂、油、油脂、蜡”杂志1955，第147页中找到。
通常应用的并且是合适的添加剂的化妆品助剂是例如乳化剂，如脂肪醇乙氧基化物，脱水山梨醇脂肪酸酯或羊毛脂衍生物，增稠剂如羧甲基纤维素或交联的聚丙烯酸，防腐剂和香料。
防晒油基质的实例是植物油，如花生油、橄榄油、芝麻油、棉子油、椰子油、葡萄子油、蓖麻子油或矿物油如液体凡士林，或特别是液体石蜡、合成的脂肪酸酯和甘油酯。软膏基质的实例是凡士林、羊毛脂、优塞林或聚乙二醇类。
霜剂基质的实例是富脂的乳脂，甘油，多糖，纤基醋酸钠乳脂、对脂肪和蜡为基础的乳脂是鲸蜡基醇，羊毛脂乳脂，可可脂、蜂蜡、硬脂酸、硬脂醇，甘油单硬脂酸酯，天然的或矿物油和脂。
乳剂的基质的实例是由硬脂基二醇，植物油和/或矿物油，如杏仁油，液体石蜡和凡士林，和水组成的混合物或由乙醇，水，羊毛脂和黄蓍组成的混合物，或由乙醇，硬脂精，水、黄蓍和甘油组成的混合物或由硬脂酸，液体石蜡，丙醇或异丙醇和水组成的。
本发明的化合物可作为唯一的UV吸收剂加入适当的制备物中；但也可以将其与其它的UV吸收剂特别是UV-B吸收剂联合使用。
这样的化合物的例子是乙氧基化的对-氨基苯甲酸乙酯(25摩尔)，对-甲氧基肉桂酸-2-乙基己基酯，2-氰基-3，3-二苯基丙烯酸2-乙基己基酯，2-苯基苯并咪唑磺酸和盐，2-羟基-4-甲氧基二苯甲酮、2-羟基-4-甲氧基二苯甲酮-5-磺酸、3-(4′-甲基苄叉)-d，1-樟脑，2，4，6-三苯胺基-(对-羰基-2′-乙基己基-1′-氧基)-1，3，5-三嗪。
实施例1
4-叔丁基肉桂叉樟脑(1)的制备
在一带有温度计，回流冷凝器和搅拌器的500ml四颈烧瓶中在氮气下将31.7g(0.2摩尔)的D，L-樟脑(96％)溶解在40g的甲苯中。在加入12.1g(0.22摩尔)的甲醇钠和加热到70℃后生成黄色悬浮液。将其在70℃再搅拌半小时。
随后在3.25小时内滴加入42.2g(0.21摩尔)的4-叔丁基肉桂醛溶于120g甲苯的溶液。悬浮液的颜色变深至橙色调。在室温下再搅拌半小时。
为后处理，将200g蒸馏水加入混合物中，搅拌和进行相分离。上面的有机相再加入100g水和在50℃用3％硫酸水溶液将pH值调至5。再重新进行相分离，随后在真空中蒸出溶剂。
蒸馏残渣在甲醇中重结晶。带黄色的晶体用130ml的甲醇/水1∶1洗涤和在50℃干燥。这样可得到22.3g分析纯的晶体。
熔点：98℃
UV光谱(甲醇)：λ最大：338.1nm
元素分析：        C   85.8％    (理论值85.7％)
                  H   9.0％     (理论值9.4％)
                  O   5.0％     (理论值5.0％)
1H-NMR(CDCl3)：
                  7.4ppm        (四重峰，4H)
                  6.95ppm       (多重峰，3H)
                  2.95ppm       (双重峰，1H)
                  1.40-2.10ppm  (多重峰，4H)
                  1.3ppm        (单重峰，9H)
                  1.00ppm       (两个单重峰，6H)
                  0.85ppm       (单重峰，3H)
实施例2
4-正丁氧基肉桂叉樟脑的制备
在一带有温度计，回流冷凝器和搅拌器的500ml四颈烧瓶中在氮气下将31.7g(0.2摩尔)D，L-樟脑(96％)溶于30g甲苯中。在加入12.1g(0.22摩尔)甲醇钠和加热至70℃后生成黄色悬浮液。在70℃再搅拌半小时。
随后在3小时内滴加入溶解在40g甲苯的44.5g(0.21摩尔)4-正丁氧基肉桂醛和在70℃再搅拌半小时。
为后处理，向混合物中加入200g蒸馏水，进行搅拌和相分离。上层有机相重新加入100g水和在50℃用3％硫酸水溶液将pH值调至3。重新再进行相分离和随后在110℃和1毫巴进行蒸馏除去溶剂。红色残渣在140ml乙醇中重结晶。晶体用冷的乙醇洗涤和在50℃进行干燥。
得到35g分析纯的结晶
熔点：108-109℃
UV光谱：λ最大：353nm
元素分析：    C  81.5％    (理论值81.61％)
              H  8.9％     (理论值8.93％)
              O  9.3％     (理论值9.45％)
实施例3
类似实例1和2制备下表1列出的化合物1.1-1.15
Figure C9719305700101
                    表1
化合物  R1     R2     R4
 1.1  CH3  2-OCH3     H
 1.2  CH3  2-CH3     H
 1.3  CH3  4-N(CH3)2     H
 1.4  CH3  4-叔丁氧基     H
 1.5  CH3  4-OCH3     H
 1.6  CH3  4-CH3     H
 1.7  CH3  4-正丁基     H
 1.8  CH3  4-异丙基     H
 1.9  H  4-叔丁基     H
 1.10  CH3  4-OCH3     CH3
 1.11  CH3  4-CH3     CH3
 1.12  CH3  4-叔丁基     CH3
 1.13  CH3  4-CH3   CH2-CH3
 1.14  CH3  4-OCH3   CH2-CH3
 1.15  CH3  4-叔丁基   CH2-CH3

Claims (5)

1.式(1)的肉桂叉樟脑衍生物，其中二烯体系以Z，Z；Z，E；E，Z或E，E构型存在和R1＝H，CH3；R2＝C4-6-烷基，C4-6-烷氧基，NR3H，NR3 2；R3＝C1-4-烷基；R4＝H，C1-6-烷基；n＝1，2。
2.根据权利要求1的化合物，其特征是，二烯体系以E，E构型存在。
3.根据权利要求1的化合物，其特征是，R1＝CH3，R2＝叔丁基，n＝1和R2在第4-位。
4.权利要求1-3之一所要求的化合物在制备光防护剂中的应用。
5.根据权利要求4的应用，其中所述化合物用在制备化妆品或药物制剂中。
CN97193057A 1996-03-13 1997-03-06 肉桂叉樟脑衍生物和它们作为uv－a－光防护剂的应用 Expired - Fee Related CN1106376C (zh)

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