CN1027065C - 苯酚类或苯甲酸类的四氢化萘酯的制备方法 - Google Patents
苯酚类或苯甲酸类的四氢化萘酯的制备方法 Download PDFInfo
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Abstract
本发明公开了下式所表示的化合物:式中基团R各自为氢或低级烷基;A为-C(O)O,-OC(O)-,-C(O)S-,或-SC(O)-;n为0-5; Z为H,-COB,这里B为-OH或药物上可接受的盐,或者B为R1,这里R1为形成酯的基团。这类化合物显示出维生素A酸样活性。
Description
本发明涉及一类具有维生素A样作用的新颖化合物。更具体地说,本发明涉及包含苯酚酸和对苯二酸四氢化萘酯的化合物。含苯基残基的酸官能团也可转化为醇、醛或酮,或它们的衍生物,或者该基团可以是烷基或H。
在以下的文献中讨论了具有类似性质的化合物,其中A为-C(O)-N(H)-。这些文献包括:Am·Academy of Dermatology,Sporn,M·B·et al·,V·15,№4,p756(1986)上的论文;Kagechika,H·,et al在Chem·pharm·Bull·,32,(10)4209(1984)上的报道;以及Shudo,K·et al在Chem·pharm Bull·,33(1)404-407(1985)上的报道。
本发明包括下式Ⅰ的化合物:
式中基团R各自为氢或低级烷基;A为-C(O)O-,-OC(O)-,-C(O)S-或-SC(O)-;n为0-5;Z为H,-COB,这里B为-CH或药物上可接受的盐,或者B为R1,这里R1为形成酯的基团,或者B为-N(R)2,这里R为氢或低级烷基烷基,或者Z为-OE,这里E为氢或形成醚的基团或-COR2,这里R2为氢、低级烷基、苯基或低级烷基苯基,或者Z为-CHO或其乙缩醇衍生物,或者Z为-COR3,这里R3为-(CH)2mCH3,其中m为0-4,且n与m之和不超过4。
本发明的第二个方面涉及利用式Ⅰ化合物治疗皮肤病,包括治疗粉刺、达里埃氏病、牛皮癣、鳞癣、湿疹、特应性皮炎和上皮癌这些化合物还可用来治疗关节炎和其它免疫性病症(如红斑狼疮);用于促进伤口愈合和治疗干眼综合症(dryeye syndrome),以及治疗或使因受太阳照射引起的皮肤老化和损伤康复。
本发明还涉及药物配方、尤其是具有抗牛皮癣作用的组合物。该配方包含式Ⅰ化合物和与之混合的药物上可接受的赋形剂。
另一方面,本发明涉及式Ⅰ化合物的制备方法,该方法包括:将其中X或Y为酸或酸衍生物的式Ⅱ或式Ⅲ或与相应的其中X或Y为-OH或-SH基团的式Ⅱ或Ⅲ反应。该反应最好在成酯催化剂存在下进行。上述酸或酸衍生物能够形成酯。式Ⅱ和式Ⅲ为:
式中R、n和Z的定义同上。
当欲合成的化合物式中n大于1,且相应式Ⅲ化合物不是市售品时,可以在其中Z为COOH的式Ⅲ的酸官能团中插入理想数量的亚甲基。然后,可将该允许反应产物-酸,还原,形成相应的醛或醇。接着,将这类化合物同相应的式Ⅱ化合物偶合,必要时对官能团Z进行保护。可在温和条件下用适宜的碱处理式Ⅰ酸,将其转化成相应的盐。也可将式Ⅰ的酸转化成酯。
这里所用的术语“酯”是指并包括经典有机化学中所定义的任何化合物。若Z为-COOH,则该术语包括用醇处理该官能团而得到的产物。具体实例包括C1至C6烷基酯(低级烷基)或C1至C6低级烷基苯基酯。若酯是从其中Z为-OH的化合物衍生的,则该术语包括式OC(O)R1的化合物,尤其是具有7至10个碳的化合物,其中R1为任何取代的或未取代的脂族,芳族或脂族-芳族基团。
优选的酯衍生于具有小于等于10个碳原子的饱和脂族醇或酸,或衍生于具有5至10个碳原子的环或饱和脂族环醇和酸。特别优选的脂族为衍生于低级烷基酸和醇的酯。这里,以及在其它场合下,低级烷基意味着具有1-6个碳原子。优选的酯还包括苯基或低级烷基苯基酯。
酰胺的定义与经典有机化学中所给出的定义一致。在本发明中,它包括未取代的酰胺和所有脂族和芳族单取代和双取代的酰胺。优选的酰胺为衍生于具有小于等于10个碳原子的饱和脂族基团,或具有5至10个碳原子的环基或饱和脂族环基单取代和双取代的酰胺,特别优选的酰胺为衍生于低级烷基胺的酰胺。同样优选的酰胺为衍生于苯基或低级烷基苯基胺的单取代或双取代的酰胺,未取代的酰胺也是理想的。
乙缩醇和酮缩醇包括其中K为(-OR1)2的式-CK的基团。这里R1为低级烷基。K也可以是-OR1O-,这里R1是具有2-5个碳原子的直链或支链低级烷基。
可将本发明的任何化合物制成药物上可接受的盐,其条件是:所述化合物须具有能形成这类盐的官能度,例如酸或胺官能度。药物上可接受的盐可以是任何具有如下性质的盐,即:这种盐保留了母体化合物的活性,并且不对施用对象带来有害的或不适宜的影响。
这类盐可以取自任何有机或无机酸或碱,可以是一价或多价离子。就酸官能团而言,特别有价值的是无机离子,钠,钾,钙及镁。可利用胺(尤其是诸如单一,双一和三烷基胺或乙醇胺的铵盐)制备有机胺盐。也可采用咖啡碱,tromethamine和类似的分子形成盐。若所存在的氮的碱性足以形成酸成盐,则可利用任何无机或有机酸或烷化剂(如甲基碘)形成这类盐。优选的酸成盐为无机酸盐,例如盐酸盐、硫酸盐或磷酸盐。可利用具有一个、两个或三个羧酸基团的任何若干普通有机酸制备酸成盐。
本发明可利用按以下位置编号系统。
本发明的优选化合物为:
4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸乙酯,
4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸苄酯,
(1-乙基戊基)4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸酯,
4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸正己酯,
4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸正十四酯,
4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘酰氧基)-3-甲基苯甲酸乙酯,
4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酰胺,
4-甲氧基甲基)苯基)-5,5,8,8-四甲基-5,6,7,8-四氢-2-苯甲酸酯,
4-叔丁基二甲基硅烷氧基甲基)苯基)-5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯,
4-甲酰基苯基)-5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯,
4-二甲氧基甲基苯基)-5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯,
4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸乙酯,
4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酰苄酯,
4-甲氧基甲基苯基-3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酸酯。
4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸,
4-(5,5-二甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸乙酯,
4-(5,5-二甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸苄酯,
4-(5,5-二甲基-5,6,7,8-四氢-2-萘酰氧基)苯甲酸,
(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)对苯二酸苄酯,
(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)对苯二酸乙酯,以及
(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)对苯二酸氢酸酯。
根据待治疗病症,治疗具体部位的要求,药物的施用量以及类似的情况,可系统或局部施用本发明化合物。
就治疗皮肤病而言,一般以局部用药较为理想,虽然在某些情况下(例如治疗严重囊性痤时),口服用药也可能是有效的。
可采用任何常用的局部用药配方,例如溶液、混悬液、凝胶、油膏或软膏等。制备这类局部用药配方的方法已在有关制剂文献中作了充分的介绍,例如参见Remington′s Pharmaceu-tical Science,Edition 17,Mack Publi-shing Company,Easton,Pennsylvania。就局部用药而言,还可将这些化合物制成粉剂或喷雾剂、尤其是以气雾剂形式施用。
可将其它药剂加到这类局部用药配方中,以便起辅助治疗皮肤干燥,抗光照;还可加入其它用于治疗皮肤病、预防感染、减少刺激、减轻炎症等的药剂。
若需要系统用药,则可将药制成粉剂、丸剂、片剂等,或制成糖浆剂或酏剂,供口服使用。就静脉内或腹膜内用药而言,可将化合物制成能通过注射施用的溶液或混悬液。在某些情况下,可将这些化合物制成栓剂或延迟释放的剂型,以便使之沉积在皮下或供肌内注射使用。
通过施用有效剂量的一种本发明的化合物,可以治疗皮肤病或其它任何已知的能用维生素A酸化合物治疗的指征。治疗浓度应保证有效地减轻所治疗的病症或阻滞其加重。在某些情况下,可将本发明化合物用作预防药,防止病发作。具体治疗浓度因具体病症而异,在一定场合下,它随着所治疗疾病的轻重程度及病人对治疗的敏感程度而变化。因此,最好通过常规实验,根据具体情况确定特定的浓度。然而,可以预计的是,在治疗痤疮或其它这类皮肤病时,治疗上有效的浓度为每毫升(局部用药)配方含0.01至0.5毫克化合物。若需要系统用药,则在大多数情况下,治疗或预防剂量为每天每公斤体重用0.01至2mg化合物。
采用传统的方法测定维生素A酸活性,即:根据维生素A酸对鸟氨酸脱羧酶的影响,证实所述化合物是否具维生素A酸样的活性。Verma和Boutwell作了有关维生素A酸与细胞增生减少两者关系的最初研究工作,见:Cancer Research 1977,37,2196-2201。该文献揭示,鸟氨酸脱羧酶(ODC)活性的增加先于聚胺生物合成。另外还证实,可以将聚胺合成的增加同细胞增生相联系。因此,若能抑制ODC活性,那么就能控制细胞的过多增生。虽然ODC活性增加的原因还属未知但已认识到,12-O-十四烷酰佛波醇-13-乙酸盐(TPA)会诱发ODC活性。维生素A酸能够抑制这种由TPA诱发的ODC活性。经(基本上)采用Cancer Res:1662-1670,1975中所述的方法测定证明,本发明的化合物同样可抑制TPA诱发的ODC活性。
可通过多种不同的化学合成途径制得本发明化合物。为说明本发明,现简要叙述一系列步骤。已经证实,当实质上按这些步骤进行所述合成时,可产生式Ⅰ化合物。
其中A为-C(O)O-的式Ⅰ化合物的制备如下:
反应图解1
当四氢化萘环上的3位是烷基(甲基)时,制备过程如下:
这一反应流程图说明了特定化合物,然而,通过改变起始原料或选择适宜的中间体,上述反应图解方法能推广到本发明所公开的包括式中A是C(O)S或SC(O)的全部化合物。
其中A为-C(O)O-、四氢化萘环上的5位或8位是甲基(烷基)的式Ⅰ化合物的制备如反应图解Ⅱ所示。
其中A为-OC(O)-的式Ⅰ化合物的制备如反应图解Ⅲ所示。
下文一般地介绍以上图解中所述化合物的制备方法。
通过用氯化氢气体处理式1的2,5-二羟基-2,5-二甲基己烷,可将该式Ⅰ化合物转化为其相应的式2二氯化物。该反应大约在室温下进行。具体方法是:将氯化氢气体呈气泡形式通入二羟基化合物的含水盐酸混悬液中,直至获得饱和溶液为止。在利用氯化氢气体进行饱和的过程中,二氯化物从溶液中沉淀。收集结晶沉淀物,用水反复洗涤,然后(例如)真空干燥。
在弗瑞德-克莱福特条件下,将2,5-二氯-2,5-二甲基己烷化合物分别同苯和甲苯反应,制得化合物3的四甲基四氢化萘和化合物6(即:五甲基四氢化萘)(见反应图解ⅠA)。例如,将2,5-二氯原料溶解于苯(已冷却到大约-10℃至10℃)。以2,5-二氯原料为基准,加入过量大约50%摩尔的无水氯化铝。之后,在大约10℃至50℃、最好是室温下,将混合物搅拌1至6小时,最好为3小时。然后将溶液回流约30分钟至2小时,最好约1小时。将所得溶液酸化,通过提取和其它方式(例如分馏)收集产品。
在氯化铝的存在下,用乙酰氯处理相应的四氢化萘,可得到图解ⅠA中的式4或7的酮。在惰性气氛及低温(即:-10℃至10℃)下,在极性惰性溶剂中制备氯化铝混悬液。所用惰性气体可以是氩气或氮气,最好为氩气。最好于诸如二氯甲烷一类的溶剂中实施反应。借助于滴液漏斗或类似装置,将四氢化萘和乙酰氯加到氯化铝混悬液中。以四氢
化萘原料为基准,使用大约过量5%摩尔的乙酰氯和过量10%摩尔的氯化铝。搅拌下,于10℃至50℃使反应进行0.5至4小时。最好在室温下、于大约2小时内实施反应。然后加入水和/或冰,使反应骤停,提取产品,并利用蒸馏或其它适宜手段进一步纯化之。
用诸如次氯酸盐的氧化剂或酸式重铬酸盐氧化剂将酮氧化,可制得羧酸官能团(式5和式8)。较理想的是,所用氧化剂为次氯酸盐;利用与水混溶的有机溶剂(如醚),在烯碱存在下进行反应。例如,将乙酰基取代的四氢化萘溶解于二噁烷,加入稀碱(例如2N NaOH)然后将大于等于四倍过量的次氯酸钠水溶液与所得溶液混合。在大约室温至100℃下,将该混合物加热30分钟至4小时,最好大约2小时。在这段时间内,以60℃至70℃的罐温实施氧化。丢弃有机层后,加入还原剂,除去残留氧化剂。然后用强酸(如硫酸)将溶液酸化,并用惯用手段除去四氢萘甲酸。
用适宜的苯酚或苯硫酚除去上述酸后,形成式Ⅰ化合物。采用酯化或硫酯化方法,大多数情况下均能得到所期望的式Ⅰ化合物。就此而言,用1,3-二环己基碳化二亚胺和4-二甲基氨基吡啶处理适当的酸和酚,实现酯化。
若基团Z是醇、醛或酮,那么可先对该基团进行保护,然后用于上述偶合反应。可采用已知方法,以醚或酯的形式保护醇,以乙缩醛或缩酮的形式保护醛和酮,参见:Mcomie,Plenum Publishing press,1973和Protecting Groups,Ed.Greene,John Wiley and Sons,1981。就合成过程的其它情况而言,可采用这些方法制备醚、乙缩醛和缩酮。
按反应图解Ⅱ所示,起始原料1-溴-3-苯基丙烷可方便地从任何精细化学制品商店购得。采用镁、干燥溶剂(例如干燥乙醚和丙酮),通过格氏反应,将伯溴转化成叔醇(式9)。在惰性气氛(如氮)下,先将镁加到含干燥溶剂的无水烧瓶中。然后,在惰性气氛下,加入溴代化合物,同时加热,呈短时回流5至45分钟。然后,在干燥惰性气氛下,加入适宜量的丙酮。之后,加热回流大约10至60分钟。接着,加入水(也可以是冰),通过标准工艺提纯化合物。
低温(如-10℃至10℃)下,用酸,最好用硫酸之类的强酸处理叔醇,以进行闭环反应(式10)。经过短暂反应后,按专业上常用的提取工艺回收反应产物。接着,按反应图解Ⅰ所示的步骤,将所得1,1-二甲基-1,2,3,4-四氢化萘转化为两种酸:8,8-二烷基酸和5,5-二烷基酸。
反应图解Ⅲ说明逆向相关〔即:其中A为-OC(O)-〕的化合物的制备。在氯化铝存在下,将苯酚或相应的2-烷基取代的苯酚同四氢呋喃反应(弗瑞德-克莱福特反应)。采用烷烃或相似类型的溶剂。反应首先在室温下进行5小时左右,最好为约2.5小时,然后回流约相等的时间。之后,加入烯的酸溶液(如3NHCl溶液),使反应骤停。最后,利用标准分离技术回收化合物。
反应图解Ⅲ的酸,即:对苯二酸,可方便从大多数化学制品供应商处购得。可将所述的酸酯化,并选择性地水解成一元酸。就制备最终产物所采用的偶合反应而言,其反应顺序和条件与反应图解Ⅰ给出的一般反应顺序和条件相同,或有显著改变。
醇的制备方法如下:利用亚硫酰氯将式Ⅰ的相应酸转化为酰氯〔见J·March,“Advanced Organic Chemistry”2nd Edition,McGraw-Hill Book Company〕,然后用硼氢化钠将酰氯还原〔March,Ibid,P·1124〕。另外,采用硼氢化钠,可将式Ⅱ醛还原为醇。
利用适度的氧化剂〔例如以重铬酸吡啶鎓为代表的氧化剂〕,于二氯甲烷中,由相应的伯醇制得式Ⅲ化合物的醛(见:Corey,E·J·,Schmidt,G·,Tet·Lett·,399,1979)。在Williamson反应条件下(March,Ibid,P·357),用适宜的烷基卤将上述醇烷化,可得到相应的醚。
采用March,Ibid,P810中所述的方法,可以相应的醛制备乙缩醛。
实施例1
2,5-二氯-2,5-二甲基己烷
将氧化氢气体呈气泡形式通入到含48g(0.33mol)2,5-己二醇(Aldrich)的600ml浓HCl混悬液中,直至将溶液饱和。过滤收集所形成的结晶产物,用水反复洗涤,真空干燥,得到呈白色结晶的标题化合物。PMR(CDCl3):W1.60(12H,S),1.94(4H,S)。
实施例2
1,1,4,4-四甲基-1,2,3,4-四氢化萘剧烈搅拌下,将100g(0.55mol)2,5-二氯
-2,5-二甲基己烷的300ml苯溶液冷却于冰浴中,并分批加入45g(0.34mol)无水氯化铝进行处理。于室温下将该混合物搅拌3小时,回流1小时,冷却,倒在冰和HCl的混合物中。分离有机层,用醚提纯水层。合并有机组分,依次用水、饱和的Na2CO3和NaCl溶液洗涤,然后干燥(MgSO4)。除去溶液之后,将残余物分馏(78℃,0.8mm),得到无色液体状的标题化合物。PMR(CDCl3):W1.3(12H,S),1.7(4H,S),7.1(2H,m),7.5(2H,m)。
实施例3
5,5,8,8-四甲基-2-乙酰基-5,6,7,8-四氢化萘
充氩下,将3.45g(25.9mmol)氯化铝的15ml二氯甲烷混悬液冷却下冰盐浴中,搅拌下,经滴液漏斗,于三十分钟内加入4g(21.2mmol)1,1,4,4-四甲基-1,2,3,4-四氢化萘和1.94g(24.7mmol)乙酰氯的混合物处理之。移去冷却浴,将混合物搅拌2小时,然后加冰,使反应骤停。分离有机层,用2×50ml二氯甲烷提取水层。合并有机提取液,用水和饱和NaHCO3溶液洗涤,然后干燥(MgSO4)。真空除去溶剂,通过kugelrohr法蒸馏残余物(90℃,0.45mm),得到无色油状的标题化合物。PMR(CDCl3):W1.32(6H,S),1.33(6H,S),1.72(4H,S),2.60(3H,S),7.41(1H,d,JN8.9Hz),7.71(1H,dd,JN8.8,2.6Hz)7.96(1H,d,JN2.6Hz)。
实施例4
5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸
将3.8g(16.5mmol)5,5,8,8-四甲基-2-乙酰基-5,6,7,8-四氢化萘(取自上述实施例3)、70ml5.25%次氯酸钠水溶液(49mmol)、25ml2N NaOH水溶液和30ml二噁烷的混合物于60-70℃加热2小时。使混合物冷却,除去含油有机层。然后用醚将水层洗涤两次。用焦亚硫酸钠溶液处理水层,直至溶液对碘化钾/淀粉试验呈阴性。过滤收集白色沉淀物,用水洗涤。用乙醇/水混合物重结晶,进一步提纯该粗制产物,得到呈白色结晶固体的标题化合物PMR(CDCl3):W1.31(6H,S),1.32(6H,S),1.71(4H,S),7.40(1H,d,JN8.8Hz),7.85(1H,dd,JN8.8Hz,1.8Hz),8.08(1H,d,JN1.8Hz)。
实施例5
4-取代酚酯的制备
A.(1-乙基戊基)-4-羟基苯甲酸酯:用备有迪安-斯达克收集器的装置将2,6552g(19.2238mmol)4-羟基苯甲酸、1g(19.1864mmol)1-乙基己醇20ml苯和5滴浓H2SO4的混合物加热回流24小时。除去溶剂,用醚提取残余物。用水,饱和的NaHCO3溶液、饱和的NaCl溶液洗涤,然后干燥。将溶液过滤,真空浓缩。残余物经闪层析纯化(硅胶;15%乙酸乙酯/己烷)得到白色固体状的标题化合物。PMR(CDCl3):6.84(2H,d,JN8.8Hz),7.95(2H,d,JN8.8Hz)。
采用相同的一般方法(除了用正己醇取代外),合成得到4-羟基苯甲酸正己酯(无色的粘性油)。PMR(CDCl3):W0.92(3H,m),1.36(6H,m),1.78(2H,m),4.33(2H,q,JN6.7Hz),6.97(2H,d,JN8.8Hz),7.99(2H,d,JN8.8Hz)。
B.4-羟基苯甲酸正十四烷基酯:将250mg甲基三辛基铵氯化物和4.67g(17mmol)溴代十四烷加到含2.76g(20mmol)4-羟基苯甲酸和800mg(200mmol)氢氧化钠的12ml水溶液中。将混合物加热回流4小时,然后用30ml水稀释。用2×30ml醚提取混合物。合并醚提取液,用水和饱和NaCl溶液洗涤。真空除去溶剂,残留物经闪层析提纯(硅胶:10%乙酸乙酯/己烷),得到白色固体状标题化合物。PMR(CDCl3):W0.88(3H,m),1.26(20H,宽带S),1.42(2H,m),1.75(2H,m),4.29(2H,t,JN6.6Hz),6.90(2H,d,JN8.8Hz),7.96(2H,d,JN8.8Hz)。
C.4-羟基苯甲酸叔丁酯:将过量的异丁烯气体在高压试管中于-78℃下冷凝。所述试管中含13.8g(0.1mol)4-羟基苯甲酸、50ml二噁烷。将1ml浓H2SO4加到上述混合物中。然后将该管封闭,将混合物温热至室温,搅拌2小时。然后将混合物冷却到-78℃,打开该管,缓慢地将其内含物倒入过量的饱和NaHCO3溶液中。利用氮气流除去过量异丁烯,并用醚提取混合物。用1N NaOH溶液提取醚液,丢弃醚层。用烯H2SO4将含水提
取液酸化,接着用醚萃取。醚提取液用NaHCO3溶液洗涤,然后干燥(Na2SO4)。将溶液过滤,真空除去溶剂。残余物经闪层析纯化(硅胶:40%乙酸乙酯/己烷)得到白色固体状标题化合物。PMR(CDCl3):W1.59(9H,S),6.90(2H,d,JN8.5Hz),7.89(2H,d,JN8.5Hz),8.0(1H,宽带S)。
D.4-羟基-3-甲基苯甲酸乙酯:将4-氨基-3-甲基苯甲酸乙酯(3.85g;21.5mmol)溶解于热的35%H2SO4/水溶液中,然后将该混合物冷却到5℃以下。接着,缓慢地将1.91g(22.5mmol)亚硝酸钠的20ml水溶液(冰冷却的溶液)加到上述混合物中,加料速度应使混合物温度不超过5℃。将混合物于5℃下搅拌10分钟,然后用1g尿素处理之,并再搅拌10分钟。将含有50g(207mmol)亚硝酸铜三水合物的750ml水溶液加到反应物中,随后向其中加入2.87g氧化亚铜。将混合物搅拌15分钟,然后用3×300ml醚提取液,用水和饱和的NaCl溶液洗涤,然后干燥(MgSO4)。将溶液过滤,减压除去溶剂,残余物经闪层析纯化(硅胶:13%乙酸乙酯/己烷至20%乙酸乙酯/己烷),得到浅黄色固体状标题化合物。PMR(CDCl3):W1.39(3H,t,JN7.1Hz),2.28(3H,S),4.37(2H,q,JN7.1Hz),6.87(1H,d,JN8.5Hz),7.38(1H,S),7.79(1H,dd,JN8.5Hz,2.0Hz),7.85(1H,d,JH2.0Hz)。
E.4-羟基-3,5-二甲基苯甲酸乙酯:将500mg(3mmol)4-羟基-35-二甲基苯甲酸、20ml无水乙醇和催化量的无水HCl的混合物加热回流2小时。然后将该混合物倒入过量冷却水中,将形成的沉淀物过滤。用水洗涤沉淀物,真空干燥,得到白色固体状标题化合物。PMR(CDCl3):W1.38(3H,t,JN7.0Hz),2.27(6H,S),4.33(2H,9,JN7.0Hz),5.30(1H,宽带S),7.70(2H,S)。
F.4-叔-丁基二甲基甲硅烷氧基甲基酚:于室温充氮下,将1.24g(0.01mol)4-羟基甲基酚、1.8g(0.012mol)叔丁基二甲基甲硅烷基氯、1.7g(0.025mol)咪唑和3ml二甲基甲酰胺的混合物搅拌12小时。将该反应混合物倒入水中,用醚提取三次。合并醚提取液,相继用水和饱和NaCl2溶液洗涤,然后干燥(NaSO4)。减压浓缩醚溶液,所得粗制产物经闪层析提纯(硅胶;10%乙酸乙酯/己烷),得到标题化合物(无色油)。PMR(CDCl3):W0.09(6H,S),0.93(9H,S),4.66(2H,S),5.69(1H,宽带S),6.74(2H,d,JN6.9Hz),7.16(2H,d,JN6.9Hz)。
G.4-二甲氧基甲基酚:将4.88g(40mmol)4-羟基苯甲醛、6.6g(206mmol)甲醇、5.1g(48mmol)三甲基原甲酸酯和28mg对甲苯磺酸的混合物于室温下搅拌12小时。然后加入过量NaHCO3,并将混合物搅拌60小时。接着将混合物过滤,减压除去溶剂,残余物经闪层析提纯(硅胶:20%乙酸乙酯/己烷),得到粘性油状的标题化合物。PMR(CDCl3):W3.26(6H,S),5.38(1H,S),6.82(2H,d,JN8.5Hz),7.31(2H,d,JN8.5Hz),7.36(1H,宽带S)。
实施例6
4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸乙酯
将116mg(0.5mmol)5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸、58mg(0.5mmol)4-羟基苯甲酸乙酯、117mg(0.56mmol)1,3-二环己基碳化二亚胺和30mg(0.25mmol)4-二甲基氨基吡啶的15ml二氯甲烷溶液于室温下搅拌12小时。然后过滤,减压浓缩滤液。残余物经闪层析提纯(硅胶:5%乙酸乙酯/己烷),得到白色结晶状标题化合物。PMR(CDCl3):W1.32(6H,S),1.36(6H,S),1.42(3H,t,JN7.0Hz),1.73(4H,S),4.40(2H,q,JN7.0Hz),7.28(2H,d,JN8.1Hz),7.45(1H,d,JN8.8Hz),7.93(1H,dd,JN8.8Hz,1.8Hz),8.13(2H,d,JN8.1Hz),8.14(1H,S)。
采用相同的通用步骤和原料,但用适宜的酚代替4-羟基苯甲酸乙酯,合成得到以下化合物:
A.4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸苄酯:利用4-羟基苯甲酸苄酯,合成得到白色结晶固体标题化合物。PMR(CDCl3):W1.32(6H,s),1.35(6H,s),1.72(4H,s),5.38(2H,s),7.24-7.48(8H,m),7.92(1H,dd,JN8.8Hz,1.8Hz),8.12-8.20(3H,m)。
B.(1-乙基戊基)4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸酯:利用(1-乙基戊基)4-羟基苯甲酸酯,合成得到标题化合物(无色油)。PMR(CDCl3):W1.33(6H,s),1.36(6H,s),1.73(4H,s),7.30(2H,d,JN8.7Hz),7.46(1H,d,JN8.3Hz),7.96(1H,dd,JN8.3Hz,1.8Hz),8.15(2H,d,JN8.7Hz),8.18(1H,d,JN1.8Hz)。
C.4-(5,5,8,8-四甲基-5,6,7,8-四氢-萘甲酰氧基)苯甲酸正己酯:利用4-羟基苯甲酸正己酯,合成得到标题化合物(无色油)。PMR(CDCl3):W0.92(3H,m),1.33(6H,s),1.35(6H,s),1.42(6H,m),1.74(4H,s),1.77(2H,m),4.34(2H,t,JN6.7Hz),7.30(2H,d,JN8.8Hz),7.46(1H,d,JH8.3Hz),7.95(1H,dd,JN8.3Hz,1.9Hz),8.14(2H,d,JN8.8Hz),8.17(1H,d,JN1.9Hz)。
D.4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸正十四烷酯:采用4-羟基苯甲酸正十四烷酯,合成得到无色油状的标题化合物。PMR(CDCl3):W0.83-0.94(3H,m),1.15-1.50(34H,m)1.70-1.85(6H,m),4.34(2H,t,JN6.7Hz),7.29(2H,d,JN8.7Hz),7.46(1H,d,JN8.4Hz),7.95(1H,dd,JN8.4Hz,1.8Hz),8.14(2H,d,JN8.7Hz),8.16(1H,d,JN1.8Hz)。
E.4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸叔丁酯:利用4-羟基苯甲酸叔丁酯,合成得到白色固体状标题化合物。PMR(CDCl3):W1.33(6H,s),1.35(6H,s),1.62(9H,s),1.73(4H,s),7.25(2H,d,JN8.7Hz),7.45(1H,d,JN8.4Hz),7.93(1H,dd,JN8.4Hz,1.8Hz),8.07(2H,d,JN8.7Hz),8.15(1H,d,JN1.8Hz)。
F.4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)-3-甲基苯甲酸乙酯:利用4-羟基-3-甲基苯甲酸乙酯,合成得到白色固体状标题化合物。PMR(CDCl3):W1.34(6H,s),1.36(6H,s),1.41(3H,t,JN7.2Hz),1.74(4H,s),2.30(3H,s),4.39(2H,t,JN7.2Hz),7.22(1H,d,JN8.4Hz),7.47(1H,d,JN8.3Hz),7.94-8.04(3H,m),8.19(1H,d,JN1.7Hz)。
G.4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)-3,5-二甲基苯甲酸甲酯:利用4-羟基-3,5-二甲基苯甲酸乙酯,合成得到白色固体状标题化合物。PMR(CDCl3):W1.37(6H,s),1.39(6H,s),1.44(3H,t,JN7.0Hz),1.77(4H,s),2.27(6H,s),4.41(2H,q,JN7.0Hz),7.50(1H,d,IN8.4Hz),7.86(2H,s),8.03(1H,dd,JN8.4Hz2.0Hz),8.23(1H,d,JN2.0Hz)。
H.4-(5,5,8,8)-四甲基-5,6,7,8-四氢-2-萘-酰氧基)苯甲酰胺:利用4-羟基苯甲酰胺,合成得到白色固体状标题化合物。PMR(CDCl3):W1.35(6H,s),1,.37(6H,s),1.76(4H,s),7.32(2H,d,JN8.6Hz),7.48(1H,d,JN8.4Hz),7.89-7.98(3H,m),8.17(1H,d,JN1.9Hz)。
I.4-甲氧基甲基苯基5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯:利用4-甲氧基甲基苯酚,合成得到标题化合物(无色油)。PMR(CDCl3):W1.36(6H,s),1.38(6H,s),1.76(4H,s),3.44(3H,s),4.52(2H,s),7.22(2H,d,JN8.4Hz),7.43(2H,d,JN8.4Hz),7.48(1H,d,JN8.4Hz),7.97(1H,dd,JN8.4Hz,1.5Hz),8.19(1H,d,JN1.5Hz)。
J.4-叔丁基二甲基甲硅烷氧基甲基苯基5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯:利用4-叔丁基二甲基甲硅烷氧基甲基苯酚,合成得到白色固体状标题化合物。PMR(CDCl3):W0.14(6H,s),0.98(9H,s),1.34(6H,s),1.37(6H,s),1.75(4H,s),4.79(2H,s),7.18(2H,d,JN9.0Hz),7.40(2H,d,JN9.0Hz),7.46(1H,d,JN8.4Hz),7.88(1H,dd,JN8.4Hz,1.7Hz),8.18(1H,d,JN1.7Hz)。
K.4-甲酰基苯基5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯:利用4-羟基苯甲醛,合成得到白色固体状标题化合物。PMR(CDCl3):W1.32(6H,s)1.34(6H,s),1.73(4H,s),7.39(2H,d,JN9.0Hz),7.45(1H,d,JN8.4Hz),7.92-7.98(3H,m),8.16(1H,d,JN1.8Hz),9.99(1H,s)。
L.4-乙酰基苯基5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯:利用4-乙酰苯酚,合成得到白色固体状标题化合物。PMR(CDCl3):W1.36(6H,s),1.38(6H,s),1.76(4H,s),2.64(3H,s),7.34(2H,d,JN8.4Hz),7.48(1H,d,JN8.4Hz),7.98(1H,dd,JN8.4Hz,2.4Hz),8.07(2H,d,JN8.4Hz),8.19(1H,d,JN2.4Hz)。
M.4-二甲氧基甲基苯基5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯:利用4-二甲氧基甲基苯酚,合成得到无色油状标题化合物。PMR(CDCl3):W1.32(6H,s),1.34(6H,s),1.72(4H,s),3.34(6H,s),5.44(1H,s),7.21(2H,d,JN8.4Hz),7.44(1H,d,JN8.4Hz),7.52(2H,d,JN8.4Hz),7.94(1H,dd,JN8.4Hz,1.8Hz),8.16(1H,d,JN1.8Hz)。
N.4-乙氧基苯基5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯:利用4-乙氧基苯酚,合成得到白色固体状标题化合物。PMR(CDCl3):W1.32(6H,s),1.34(6H,s),1.42(3H,t,JN7.0Hz),1.72(4H,s),4.04(2H,q,JN7.0Hz),6.92(2H,d,JN9.0Hz),7.10(2H,d,JN9.0Hz),7.43(1H,d,JN8.3Hz),7.93(1H,dd,JN8.3Hz,1.9Hz),8.15(1H,d,JN1.9Hz)。
O.4-苄氧基苯基5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯:利用4-苄氧基苯酚,合成得到白色固体状标题化合物。PMR(CDCl3):w1.32(6H,s),1.34(6H,s),1.72(4H,s),5.07(2H,s),7.00(2H,d,JN9.3Hz),7.11(2H,d,JN9.3Hz),7.31-7.47(6H,m),7.92(1H,dd,JN8.4Hz,1.9Hz),8.14(1H,d,JN1.9Hz)。
P.对甲苯基-5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯:利用对甲酚,合成得到白色固体状标题化合物。PMR(CDCl3):w1.34(6H,s),1.36(6H,s),1.74(4H,s),2.39(3H,s),7.09(2H,d,JN8.4Hz),7.23(2H,d,JN8.4Hz),7.45(1H,d,JN8.3Hz),7.95(1H,dd,JN8.3Hz,1.9Hz),8.17(1H,d,JN1.9Hz)。
Q.5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸苯酯:利用苯酚,合成得到白色固体状标题化合物。PMR(CDCl3):w1.35(6H,s),1.38(6H,s),1.76(4H,s),7.21-7.32(3H,m),7.41-7.50(3H,m),7.99(1H,dd,JN8.5Hz,1.8Hz),8.21(1H,d,JN1.8Hz)。
实施例7
4-(5,5,8,8,-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸
在室温、氢气氛下,将150mg(0.3394mmol)4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸苄酯和50mg10%钯-炭在5ml乙酸乙酯中的混合物搅拌4小时。然后将反应混合物过滤,减压浓缩滤液。将残余物溶解于醚中,用NaOH水溶液萃取。然后用冰醋酸将含水提取液酸化,用醚萃取。用饱和NaCl溶液洗涤醚提取液,然后减压浓缩。用乙酸乙酯对所得残余物重结晶,得到白色固体状标题化合物。PMR(CDCl3):w1.34(6H,s),1.36(6H,s),1.76(4H,s),7.33(2H,d,JN8.6Hz),7.46(1H,d,JN7.8Hz),7.94(1H,dd,JN7.8Hz,1.8Hz),8.16(1H,d,JN1.8Hz),8.21(2H,d,JN8.6Hz)。
实施例8
1,1,4,4,6-五甲基-1,2,3,4-四氢化萘搅拌下,将26.6g(0.2mol)无水氯化铝分次加到40g(0.4341mol)甲苯和25g(0.195mol)2,2,5,5-四甲基四氢呋喃的冷却(0℃)混合物中。移去冷却浴,室温下将混合物搅拌20小时,然后加热回流2小时。使混合物冷却至室温,然后将其倒入冰和100ml3NHCl的混合物中,使反应骤停。分离有机层,用3×75ml醚萃取水层。合并有机提取液,依次用3NHCl、饱和的NaHCO3溶液、饱和的NaCl溶液洗涤,用MgSO4干燥。减压除去溶剂,分馏残余物,得到呈无色油状的标题化合物。PMR(CDCl3):w1.30(6H,s),1.32(6H,s),1.70(4H,s),2.33(3H,s),6.98(1H,d,JN7Hz),7.14(1H,s),7.23(1H,d,JN7Hz)。
实施例9
2-乙酰基-3,5,5,8,8-五甲基-5,6,7,8-四氢化萘
将13.72g(102.9mmol)氯化铝的40ml二氯乙烷混悬液在充氮下冷却于冰丙酮浴中,搅拌下,于1小时内,将含有17.11g(84.56mmol)1,1,4,4,6-五甲基-1,2,3,4-四氢化萘的10ml二氯乙烷溶液加到上述混合物中。移去冷却浴,室温下,将混合物搅拌3小时,然后倒在冰上。分离有机层,水层用3×75ml二氯甲烷萃取。合并有机层,依次用水、饱和NaHCO3溶液、饱和NaCl溶液洗涤若干次;然后干燥(MgSO4)。减压除去溶剂,残余物经kugelrohr蒸馏(70℃,0.15mm),得到低熔点的黄色固体,即:标题化合物。PMR(CDCl3):w1.30(6H,s),1.32(6H,s),1.70(4H,s),2.51(3H,s),2.59(3H,s),7.16(1H,s),7.69(1H,s)。
实施例10
3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酸室温下,将8.2g(0.0336mol)2-乙酰基-3,5,5,8,8-五甲基-5,6,7,8-四氢化萘、90ml1.19M(0.107mol)次氯酸钠水溶液和10ml二噁烷的混合物搅拌0.5小时,之后于60℃下搅拌2小时。然后再将70ml1.19M(0.0833mol)次氯酸钠水溶液加到反应混合物中,并于70℃下搅拌混合物1小时。接着,将反应混合物冷却,用亚硫酸氢钠水溶液进行处理,直至该混合物对淀粉/碘纸呈阴性反应。用醚洗涤混合物,然后用H2SO4酸化。用醚分三批萃取混合物,然后合并醚提取液,依次用水、饱和NaCl溶液洗涤,然后干燥(MgSO4)。浓缩醚液,用冷却醚重结晶得到标题化合物(无色结晶体)。PMR(CDCl3):w1.29(6H,s),1.30(6H,s),1.69(4H,s),2.60(3H,s),1.17(1H,s),7.26(1H,s)。
实施例11
4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸乙酯
将399.2mg(1.6204mmol)3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酸、271.8mg(1.6355mmol)4-羟基苯甲酸乙酯、336.6mg(1.6339mmol)1,3-二环己基碳化二亚胺和44.5mg(0.3642mmol)4-二甲基氨基吡啶的混合物溶解于20ml二氯甲烷,室温下,将所得混合物搅拌23小时。将反应混合物过滤,残余物用25ml二氯甲烷洗涤。减压浓缩滤液,所得粗制产物经闪层析纯化(硅胶:10%乙酸乙酯/己烷),得到白色固体状标题化合物。PMR(CDCl3):w1.34(6H,s),1.36(6H,s),1.49(3H,t,JN7.2Hz),1.74(4H,s),2.66(3H,s),4.42(2H,q,JN7.2Hz),7.26(1H,s),7.31(2H,d,JN8.7Hz),8.16(2H,d,JN8.7Hz),8.17(1H,s)。
采用同样的通用方法,并用4-羟基苯甲酸苄酯取代,合成得到呈无色油状的4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸苄酯。PMR(CDCl3):w1.32(6H,s),1.35(6H,s),1.72(4H,s),2.63(3H,s),5.39(2H,s),7.24(1H,s),7.29(2H,d,JN8.4Hz),7.34-7.49(5H,m),8.14(1H,s),8.18(2H,d,JN8.4Hz)。
采用相同的一般方法,但用4-甲氧基甲基苯酚取代,合成得到呈无色油状的4-甲氧基甲基苯基3,5,5,8,8-五甲基,5,6,7,8-四氢-2-萘甲酸酯。PMR(CDCl3):w1.34(6H,s),1.37(6H,s),1.74(4H,s),2.66(3H,s),3.43(3H,s),4.52(2H,s),7.21(1H,s),7.22(2H,d,JN8.3Hz),7.26(1H,s),7.43(2h,d,JN8.3Hz),8.17(1H,s)。
实施例12
4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸
室温、氢气氛下,将430mg(0.94mmol)4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酰氧基)-苯甲酸苄酯、60mg10%钯-炭和6ml乙酸乙酯的混合物搅拌3小时。另外将6ml乙酸乙酯加到反应混合物中并于50℃将所得混合物加热3小时,然后冷却,硅藻土滤过,残余物用5ml热乙酸乙酯洗涤,减压浓缩滤液,所得残余物用乙酸乙酯和己烷混合物重结晶,得到白色结晶固体状标题化合物。PMR(CDCl3):w1.32(6H,s),1.34(6H,s),1.72(4H,s),2.62(3H,s),7.24(1H,s),7.32(2H,d,JN8.2Hz),8.13(1H,s),8.20(2H,d,JN8.2Hz)。
实施例13
2-甲基-5-苯基-2-戊醇
将8.8g(0.37mol)镁屑和150ml无水醚的混
合物置于3颈烧瓶中。所述烧瓶备有氮气进管,回流冷凝器和添加漏斗,并含有73.7g(0.37mol)1-溴-3-苯基丙烷。将少量溴代化合物加到反应混合物中,并将混合物升温,以引发反应。用150ml无水醚处理混合物,然后加入溴代化合物,其添加速率应保证轻度回流。将反应混合物再次加热回流15分钟,然后用21.5g(0.37mol)丙酮慢慢处理。将混合物再加热回流30分钟,冷却,然后缓慢倒入300g碎冰中。加入20%H2SO4,使所得白色沉淀物溶解。分离有机层,水层用醚萃取。合并有机萃取液,用水和饱和NaCl溶液洗涤,然后干燥(MgSO4)。将溶液过滤,减压除去溶剂。将残余物蒸馏(120℃;6mm),得到标题化合物(无色油)。PMR(CDCl3):w1.18(6H,s),1.44-1.53(2H,m),1.62-1.72(2H,m),2.61(2H,t,JN7.6Hz),7.6-7.30(5H,m)。
实施例14
1,1-二甲基-1,2,3,4-四氢化萘
在10分钟内,将17.8g(0.1mol)2-甲基-5-苯基-2-戊醇加到18ml冰冷却的浓H2SO4中。将混合物于0℃下搅拌15分钟,室温下搅拌15分钟。用50ml水处理混合物,然后用醚萃取。合并醚萃取液,用水、饱和NaHCO3溶液洗涤,用MgSO4干燥。将溶液过滤,减压除去溶剂。残余物经蒸馏(93℃;10mm)提纯,得到呈无色油状标题化合物。PMR(CDCl3):w1.19(6H,s),1.45-1.53(2H,m),1.62-1.73(2H,m),2.62(2H,t,JN6.1Hz),7.14-7.30(4H,m)。
实施例15
2-(1羟乙基)-8,8-二甲基-5,6,7,8-四氢化萘和2-(1-羟乙基)-5,5-二甲基-5,6,7,8-四氢化萘
将4.0g(25mmol)1,1-二甲基-1,2,3,4-四氢化萘和2.35g(30mmol)乙酰氯的5ml二氯甲烷溶液慢慢地加到0℃下的4.27g(32mmol)无水氯化铝的15ml二氯甲烷搅拌混悬液中。大约加到一半后,移去冷却浴,在室温下完成加料。然后将反应混合物搅拌1小时,倒入70ml冰-水混合物中。分离有机层,相继用稀HCl,水,饱和NaCl溶液洗涤,然后干燥(MgSO4)。将溶液过滤,减压除去溶剂,残余物经蒸馏(100℃;0.1mm),得到酮,即为2-乙酰基-8,8-二甲基-5,6,7,8-四氢化萘和2-乙酰基-5,5-二甲基-5,6,7,8-四氢化萘的大约2∶1的混合物(无色油)。
将上述制备的4.0g(19.8mmol)酮混合物溶于10ml无水醚中。搅拌下,慢慢地将250mg(6.7mmol)氢化铝锂和30ml无水醚的混合物加到上述溶液中。将反应混合物加热回流0.5小时,冷却,细心地加入乙酸乙酯,破坏过量的氢化铝锂。将水加到混合物中,继之加入足量稀HCl,使沉淀溶解。分离有机层,相继用水饱和NaCl溶液洗涤,然后用MgSO4干燥。将溶液过滤,减压除去溶剂。经蒸馏(115℃;1mm),继之以高压液相层析纯化(Whatman M20 Partisil柱;10%乙酸乙酯-己烷;9.9ml/min),得到纯净的标题化合物(无色粘性油)。
2-(1-羟乙基)-8,8-二甲基-5,6,7,8-四氢化萘的PMR(CDCl3):w1.28(3H,s),1.29(3H,s),1.47(3H,d,JN6.6Hz),1.61-1.70(2H,m),1.72-1.83(2H,m),2.75(2H,t,JN6.3Hz),4.82(1H,q,JN6.6Hz),7.02(1H,d,JN7.8Hz),7.08(1H,dd,JN7.8Hz,1.8Hz),7.32(1H,d,JN1.8Hz)。
2-(1-羟乙基)-5,5-二甲基-5,6,7,8-四氢化萘的PMR(CDCl3):w1.28(6H,s),1.47(3H,d,JN6.6Hz),1.60-1.68(2H,m),1.72-1.83(2H,m),2.74(2H,t,JN6.4Hz),4.78(1H,q,JN6.6Hz),7.03(1H,d,JN1.8Hz),7.11(1H,dd,JN8.1Hz,1.8Hz),7.29(1H,d,JN8.1Hz)。
实施例16
2-乙酰基-8,8-二甲基-5,6,7,8-四氢化萘
将2.44g(11.96mmol)2-(1-羟乙基)-8,8-二甲基-5,6,7,8-四氢-萘溶于35ml二氯甲烷,搅拌下,将6.75(17.9mmol)重铬酸吡啶鎓和330mg(1.68mmol)三氟乙酸吡啶鎓加到上述溶液中。室温下,将混合物搅拌24小时,然后用35ml低沸点的石油醚稀释。使混合物滤过较短的柱(无水MgSO4和硅),然后减压浓缩滤液,得到无色油状的标题化合物。PMR(CDCl3):w1.30(6H,s),1.60-1.70(2H,m),1.72-1.84(2H,m),2.56(3H,s),2.78(2H,t,
JN6.1Hz),7.08(1H,d,JN7.8Hz),7.61(1H,dd,JN7.8Hz,1.9Hz),7.93(1H,d,JN1.9Hz)。
采用相同的一般方法,但用2-(1-羟乙基)-5,5-二甲基-5,6,7,8-四氢-萘代替,合成得到呈无色油状的2-乙酰基-5,5-二甲基-5,6,7,8-四氢化萘。PMR(CDCl3):w1.29(6H,s),1.64-1.70(2H,m),1.76-1.87(2H,m),2.55(3H,s),2.81(2H,t,JN6.1Hz),7.40(1H,d,JN8.4Hz),7.64(1H,d,JN1.8Hz),7.71(1H,dd,JN8.4Hz,1.8Hz)。
实施例17
8,8-二甲基-5,6,7,8-四氢-2-萘甲酸
将1.0g(4.95mmol)2-乙酰基-8,8-二甲基-5,6,7,8-四氢化萘、1.8g氢氧化钠、62ml10%次氯酸钠溶液、10ml水和15ml二噁烷的混合物于65℃下加热,直至薄层色谱分析(硅胶:10%乙酸乙酯/己烷)显示不存在原料酮。将混合物冷却至室温,加入焦亚硫酸钠,直至溶液对淀粉-碘纸呈阴性。然后用稀H2SO4将混合物酸化(pH=4),将沉淀物过滤,用水洗涤,真空干燥,得到白色固体状标题化合物。
PMR(CDCl3):w1.32(6H,s),1.64-1.72(2H,m),1.78-1.88(2H,m),2.82(2H,t,JN6.1Hz),7.14(1H,d,JN8.4Hz),7.80(1H,dd,JN8.4Hz,1.8Hz),8.10(1H,d,JN1.8Hz)。
采用相同的通用方法,但用2-乙酰基-5,5-二甲基-5,6,7,8-四氢化萘取代,合成得到白色固体的5,5-甲基-5,6,7,8-四氢-2-萘甲酸。
PMR(CDCl3):w1.30(6H,s),1.64-1.71(2H,m),1.75-1.84(2H,m),2.81(2H,t,JN6.1Hz),7.40(1H,d,JN8.3Hz),7.81(1H,d,JN1.8Hz),7.85(1H,dd,JN8.3Hz,1.8Hz)。
实施例18
4-(8,8-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)-苯甲酸乙酯
将220.7mg(1.0804mmol)8,8-二甲基-5,6,7,8-四氢-2-萘甲酸、180.6mg(1.0868mmol)4-羟基苯甲酸乙酯、227.3mg(1.1034mmol)1,3-二环己基碳化二亚胺和22.9mg(0.1874mmol)4-二甲基氨基吡啶溶于15ml二氯甲烷中,于室温下,将所得溶液搅拌18小时。将反应混合物过滤,残余物用10ml二氯甲烷洗涤。减压浓缩滤液,所得粗制产物经闪层析提纯(硅胶:5%乙酸乙酯/己烷),得到呈无色油状的标题化合物。
PMR(CDCl3):w1.35(6H,s),1.42(3H,t,JN7.2Hz),1.68-1.76(2H,m),1.80-1.92(2H,m),2.85(2H,t,JN6.1Hz),4.40(2H,q,JN7.2Hz),7.18(1H,d,JN8.0Hz),7.31(2H,d,JN8.7Hz),7.89(1H,dd,JN8.0Hz,1.6Hz),8.11-8.22(3H,m。
采用相同的通用步骤,但用4-羟基苯甲酸苄酯取代,合成得到4-(8,8-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸苄酯(无色油)。
PMR(CDCl3):w1.36(6H,s),1.68-1.77(2H,m),1.80-1.92(2H,m),2.86(2H,t,JN6.3Hz),5.40(2H,s),7.19(1H,d,JN8.0Hz),7.29-7.51(7H,m),7.90(1H,d,JN8.0Hz),8.15-8.23(3H,m)。
采用相同的通用步骤,但用5,5-二甲基-5,6,7,8-四氢-2-萘甲酸和4-羟基苯甲酸乙酯,合成得到4-(5,5-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸乙酯(无色油)。
PMR(CDCl3):w1.33(6H,s),1.41(3H,t,JN7.2Hz),1.68-1.76(2H,m),1.80-1.90(2H,m),2.85(2H,t,JN6.3Hz),4.39(2H,q,JN7.2Hz),7.28(2H,d,JN8.7Hz),7.47(1H,d,JN8.4Hz),7.90(1H,s),7.94(1H,d,JN8.4Hz),8.13(2H,d,JN8.7Hz)。
采用相同的通用步骤,但用5,5-二甲基-5,6,7,8-四氢-2-萘甲酸和4-羟基苯甲酸苄酯,合成得到白色固体化合物:4-(5,5-甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸苄酯。
PMR(CDCl3):w1.37(6H,s),1.71-1.78(2H,m),1.82-1.92(2H,m),2.88(2H,t,JN6.3Hz),5.42(2H,s),7.33(2H,d,
JN8.7Hz),7.37-7.53(5H,m),7.95(1H,s),7.99(1H,d,JN8.4Hz),8.20(2H,d,JN8.7Hz)。
实施例19
4-(8,8-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)-苯甲酸
在室温、氢气氛下,将120mg(0.29mmol)4-(8,8-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸苄酯、50mg10%钯-活性炭和3ml乙酸乙酯的混合物搅拌2小时。然后将混合物离心,滗析上清液。减压除去溶剂,残余物用乙酸乙酯重结晶,得到白色结晶标题化合物。
PMR(CDCl3):w1.34(6H,s),1.67-1.75(2H,m),1.78-1.90(2H,m),2.85(2H,t,JN6.0Hz),7.18(1H,d,JN8.1Hz),7.34(2H,d,JN8.7Hz),7.88(1H,dd,JN8.1Hz,1.8Hz),8.16(1H,d,JN1.8Hz),8.20(2H,d,JN8.7Hz)。
采用相同的通用步骤,但用4-(5,5-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)-苯甲酸苄酯,合成得到白色结晶状4-(5,5-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸。
PMR(CDCl3):w1.33(6H,s),1.67-1.74(2H,m),1.78-1.89(2H,m),2.86(2H,t,JN6.3Hz),7.33(2H,d,JN8.8Hz),7.47(1H,d,JN8.1Hz),7.90(1H,d,JN1.8Hz),7.95(1H,dd,JN8.1Hz,1.8Hz),8.20(2H,d,JN8.8Hz)。
实施例20
5,5,8,8-四甲基-5,6,7,8-四氢-2-萘酚
将13.2g(0.1403mmol)萘酚和12.8g(0.0998mol)2,2,5,5-四甲基四氢呋喃溶于50ml庚烷中,分小批将13.1g(0.0982mol)氯化铝加到上述溶液中。添加完毕后,将混合物于室温下搅拌2.5小时,回流下搅拌2小时,然后室温下再搅拌16小时。之后,用100ml3NHCl处理反应混合物,并搅拌0.5小时。将混合物过滤,用水洗涤残余物,真空干燥,得到粗制产物。从滤液分离有机层,用3×75ml醚萃取水层。合并有机层,用饱和NaCl溶液洗涤,干燥(MgSO4),减压浓缩,得到另外的粗制产物。用己烷对粗制产物重结晶,得到浅棕色晶体状标题化合物。
PMR(CDCl3):w1.26(6H,s),1.28(6H,s),1.67(4H,s),5.08(1H,宽带s),6.68(1H,dd,JN8.7Hz,2.7Hz),6.82(1H,d,JN2.7Hz),7.16(1H,d,JN8.7Hz)。
实施例21
对苯二酸二乙酯
将盐酸气体呈气泡状通入100ml无水乙醇,直至乙醇的量增至大约5g。然后将对苯二酸16.6g(0.1mol)加到酸化乙醇中,并将混合物加热回流31小时。将反应混合物冷却,然后过滤,残余物用乙醇洗涤。减压浓缩滤液,然后倒入水和100ml醚的混合物中。萃取之后,分离醚层,相继用水饱和NaHCO3溶液洗涤,然后干燥(MgSO4)。将醚液过滤,减压下除去溶剂,得到白色固体状标题化合物。
PMR(CDCl3):w1.42(6H,t,JN7.0Hz),4.40(4H,q,JN7.0Hz),8.10(4H,s)。
实施例22
对苯二酸单乙酯
将无水氢氧化钡(3.83g,0.022mol)置于索格利特萃取器中,用热乙醇连续10小时提入10g(0.04mol)对苯二酸二乙酯和100ml无水乙醇的回流混合物中。将沉淀物悬浮于100ml醚中,用过量稀HCl处理。提取后,分离醚层,相继用水和饱和的NaCl溶液洗涤,然后干燥(MgSO4)。将醚液过滤,真空除去溶剂。所得残余物用乙腈重结晶,得到白色固体状标题化合物。
PMR(CDCl3):w1.40(3H,t,JN7.0Hz),4.40(2H,q,JN7.0Hz),8.10(4H,s),9.1(1H,宽带s)。
实施例23
对苯二甲酸二苄酯
在500ml的三颈圆底烧瓶中制备48.5g(0.25mol)对苯二酸二甲酯、108g(1.0mol)苄醇和0.5g叔丁醇钾的混合物。所述烧瓶具备磁性搅拌棒、温度计、氮气进管和空气冷凝器。搅拌下,于140℃,将混合物加热15小时,同时,使氮流迅速通过混合物表面。然后,通过分馏,从混合物中除去大部分过量的苄醇。将残余物溶解于醚和二氯甲烷的混合物中,然后向溶液中加入二氧化硅。
将溶液过滤,减压除去溶剂。用己烷和叔丁甲醚的混合物对残余的粗制产物重结晶,得到无色结晶状标题化合物。
PMR(CDCl3):w5.38(4H,s),7.35-7.50(10H,m),8.13(4H,s)。
实施例24
对苯二酸单苄酯
将9.1g(26mmol)对苯二酸二苄酯、90ml丙酮和30ml水的混合物加热,然后向其中滴加入由1.05g(25mmol)氢氧化锂单水合物,10ml水和10ml丙酮组成的混合物。强烈搅拌下,将所得反应混合物加热回流30分钟,然后使之冷却,用2×10ml醚萃取该水溶液。之后,用冰醋酸将水层酸化,所得白色沉淀物用3×25ml醚萃取。合并醚萃取液,相继用水,饱和NaCl溶液洗涤,然后干燥(MgSO4)。将醚液过滤,减压除去溶剂。所得残余物用丙酮和水的混合物重结晶,得到无色结晶状标题化合物。
PMR(CDCl3):w5.40(2H,s),7.36-7.49(5H,m),8.18(4H,s)。
实施例25
(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)对苯二酸乙酯
将598.8mg(2.9308mmol)5,5,8,8-四甲基-5,6,7,8-四氢-2-萘酚、542mg(2.7912mmol)对苯二酸单乙酯、608mg(2.9515mmol)1,3-二环己基碳化二亚胺和127mg(1.0395mmol)4-二甲基氨基吡啶溶于30ml二氯甲烷,室温下将该溶液搅拌22小时。将反应混合物过滤,残余物用10ml二氯甲烷洗涤。减压减缩滤液,所得粗制产物经闪层析提纯(二氧化硅;6%乙酸乙酯/己烷),得到白色固体状标题化合物。
PMR(CDCl3):w1.32(6H,s),1.33(6H,s),1,46(3H,t,JN7.2Hz),1.73(4H,s,4.46(2H,q,JN7.2Hz),7.02(1H,dd,JN8.5Hz,2.5Hz),7.14(1H,d,JN2.5Hz),7.38(1H,d,JN8.5Hz),8.19(2H,d,JN8.1Hz),8.29(2H,d,JN8.1Hz)。
采用相同的通用方法,但用对苯二酸单乙酯,合成得到呈白色固体状(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-对苯二酸苄酯。
PMR(CDCl3):w1.32(6H,s),1.33(6H,s)1,74(4H,s),5.44(2H,s),7.03(1H,dd,JN8.7Hz,2.4Hz),7.16(1H,d,JN2.4Hz),7.37-7.54(6H,m),8.23(2H,d,JN8.7Hz),8.30(2H,d,JN8.7Hz)。
实施例26
(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)对苯二酸单酯
在室温、氢气氛下,将400mg(0.9mmol)(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-对苯二酸苄酯、60mg10%钯-炭和5ml乙酸乙酯的混合物搅拌3小时。将该反应混合物过滤,将该滤液减压蒸干,得到白色固体状标题化合物。
PMR(CDCl3):w1.30(12H,s),1.71(4H,s),7.05(1H,dd,JN9.0Hz,2.7Hz),7.12(1H,d,JN2.7Hz),7.36(1H,d,JN9.0Hz),8.25(2H,d,JN8.4Hz),8.31(2H,d,JN8.4Hz)。
实施例27
较为理想的是,利用各种处方,以局部用药方式施用上述化合物。这里给出处方两例。
成份 重量/百分比
溶液
维生素A酸 0.1
BHT 0.1
醇(USP) 58.0
聚乙二醇400NF 41.8
凝胶
维生素A酸 0.1
BHT 0.1
醇(USP) 97.8
羟丙基纤维素 2.0
Claims (14)
1、一种制备式Ⅰ化合物的方法,该方法包括,最好在成酯催化剂存在下,由式Ⅱ或式Ⅲ中X或Y是酸或是该酸可成酯衍生物的化合物与相应的式Ⅱ或式Ⅲ中X或Y为-OH或-SH基团的化合物反应,或将式Ⅰ的酸转化为药物上可接受的盐,或将式Ⅰ的酸转化为酯,或将酯转化为酸,或将醇转化为醚,或将醚转化为醇,或将醛转化为缩醛,或将酮转化为缩酮;式Ⅰ为:
式中各基团R独立地为氢或低级烷基;A为-C-(O)O-,-OC(O)-,-C(O)S-,或-SC(O)-;n为0-5;Z为COB,这里B为-OH或药物上可接受的盐,或者B为OR,这里R1为形成酯的基团,或者B为-N(R)2,这里R独立地为氢或低级烷基,或者Z为-OE,这里E为氢或形成醚的基团或-COR2,这里R2为氢、低级烷基、苯基或低级烷基苯基,或者Z为-CHO或其缩醛衍生物,或者Z为-COR3,这里R3为-(CH2)mCH3,其中m为0-4,且n与m之和不超过4;条件是当n为0时,E不是成醚基团;
式中R,n和Z的定义同前。
2、按权利要求1的方法,其中n为0。
3、按权利要求1的方法,其中n为1。
4、按权利要求1的方法,其中n为2。
5、按权利要求2至4之任一方法,其中X为-COOH,Y为-OH,Z为-COB,式中B为-CH,或B为OR1,式中R1为C1至C6烷基,或B为-N(R)2,式中R为C1至C6烷基,或者Z为-OH的酯或醚衍生物,或者Z为-CHO或其缩醛衍生物。
6、按权利要求5的方法,制得了4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸乙酯,或4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸或其药物上可接受的盐。
7、按权利要求5的方法,制得了4-甲氧基甲苯基-5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯,或4-二甲氧基甲苯基-5,5,8,8-四甲基-5,6,7,8-四氢-2-萘甲酸酯。
8、按权利要求5的方法,制得了4-(8,8-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸或其药物上可接受的盐,4-(8,8-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸乙酯,或4-(8,8-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸苄酯。
9、按权利要求5的方法,制得了4-(5,5-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸或其药物上可接受的盐,4-(5,5-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸乙酯,或4-(5,5-二甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸乙酯。
10、按权利要求2至4之任一方法,其中X为-COOH,Y为-OH,式Ⅱ中3位上的基团R为低级烷基;Z为-COB,式中B为-OH,或B为-OR1,式中R1为C1至C6烷基,或者B为-N(R)2,式中R为C1至C6烷基,或者Z为-OH的酯或醚衍生物,或者Z为-CHO或其缩醛衍生物。
11、按权利要求10的方法,制得了4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酰氧基)-苯甲酸或其药物上可接受的盐,4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酰氧基)苯甲酸乙酯或4-(3,5,5,8,8-五甲基-5,6,7,8-四氢-萘甲酰氧基)苯甲酸苄酯。
12、按权利要求10的方法,制得了4-甲氧基甲苯基3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘甲酸酯或4-甲酰苯基3,5,5,8,8-五甲基-5,6,7,8-四氢-萘甲酸酯。
13、按权利要求2至4之任一方法,其中X为-CH,Y为-COOH;Z为-COB,式中B为-OR1,其中R1为C1至C6烷基,或者Z为-OH或其酯或醚,或者Z为-CHO或其缩醛。
14、按权利要求13的方法,制得了4-(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)-对苯二酸乙酯或(5,5,8,8-四甲基-5,6,7,8-四氢-2-萘基)对苯二酸单酯。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US17970088A | 1988-04-11 | 1988-04-11 | |
US179700 | 1988-04-11 | ||
US179,700 | 1988-04-11 |
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CN1038092A CN1038092A (zh) | 1989-12-20 |
CN1027065C true CN1027065C (zh) | 1994-12-21 |
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CN89102318A Expired - Fee Related CN1027065C (zh) | 1988-04-11 | 1989-04-11 | 苯酚类或苯甲酸类的四氢化萘酯的制备方法 |
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US (1) | US5130335A (zh) |
EP (1) | EP0337689B1 (zh) |
JP (1) | JPH0794407B2 (zh) |
KR (1) | KR0139216B1 (zh) |
CN (1) | CN1027065C (zh) |
AT (1) | ATE86601T1 (zh) |
AU (1) | AU618590B2 (zh) |
CA (1) | CA1330567C (zh) |
DE (1) | DE68905215T2 (zh) |
DK (1) | DK171689A (zh) |
ES (1) | ES2053982T3 (zh) |
HU (1) | HU201727B (zh) |
IE (1) | IE63712B1 (zh) |
NO (1) | NO170008C (zh) |
NZ (1) | NZ228682A (zh) |
PT (1) | PT90251B (zh) |
SG (1) | SG32564G (zh) |
ZA (1) | ZA892583B (zh) |
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1989
- 1989-04-07 AU AU32585/89A patent/AU618590B2/en not_active Ceased
- 1989-04-07 KR KR1019890004567A patent/KR0139216B1/ko not_active IP Right Cessation
- 1989-04-10 HU HU891709A patent/HU201727B/hu not_active IP Right Cessation
- 1989-04-10 ES ES89303490T patent/ES2053982T3/es not_active Expired - Lifetime
- 1989-04-10 DE DE8989303490T patent/DE68905215T2/de not_active Expired - Lifetime
- 1989-04-10 NZ NZ228682A patent/NZ228682A/en unknown
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- 1989-04-10 NO NO891466A patent/NO170008C/no unknown
- 1989-04-10 IE IE113589A patent/IE63712B1/en not_active IP Right Cessation
- 1989-04-10 EP EP89303490A patent/EP0337689B1/en not_active Expired - Lifetime
- 1989-04-10 SG SG1995904983A patent/SG32564G/en unknown
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- 1989-04-11 JP JP1092794A patent/JPH0794407B2/ja not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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CN1038092A (zh) | 1989-12-20 |
PT90251B (pt) | 1994-06-30 |
DE68905215T2 (de) | 1993-08-19 |
DK171689A (da) | 1989-10-12 |
AU3258589A (en) | 1989-10-12 |
CA1330567C (en) | 1994-07-05 |
IE891135L (en) | 1989-10-11 |
PT90251A (pt) | 1989-11-10 |
DK171689D0 (da) | 1989-04-10 |
KR0139216B1 (ko) | 1998-05-01 |
ATE86601T1 (de) | 1993-03-15 |
US5130335A (en) | 1992-07-14 |
KR890015988A (ko) | 1989-11-27 |
IE63712B1 (en) | 1995-05-31 |
AU618590B2 (en) | 1992-01-02 |
JPH026437A (ja) | 1990-01-10 |
NO170008C (no) | 1992-09-02 |
HU201727B (en) | 1990-12-28 |
NO891466L (no) | 1989-10-12 |
EP0337689B1 (en) | 1993-03-10 |
ZA892583B (en) | 1989-12-27 |
JPH0794407B2 (ja) | 1995-10-11 |
NZ228682A (en) | 1991-07-26 |
HUT50100A (en) | 1989-12-28 |
ES2053982T3 (es) | 1994-08-01 |
NO170008B (no) | 1992-05-25 |
DE68905215D1 (de) | 1993-04-15 |
SG32564G (en) | 1995-09-01 |
EP0337689A1 (en) | 1989-10-18 |
NO891466D0 (no) | 1989-04-10 |
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