CN1040062C - 新的药理活性儿茶酚衍生物的制备方法 - Google Patents

新的药理活性儿茶酚衍生物的制备方法 Download PDF

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CN1040062C
CN1040062C CN87108011A CN87108011A CN1040062C CN 1040062 C CN1040062 C CN 1040062C CN 87108011 A CN87108011 A CN 87108011A CN 87108011 A CN87108011 A CN 87108011A CN 1040062 C CN1040062 C CN 1040062C
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gram
dihydroxy
milliliters
product
obtains
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CN87108011A (zh
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巴克斯特罗姆·里约·约翰尼斯
海诺拉·卡莱维·埃沃特
霍恩卡南·埃基·朱哈尼
卡科拉·塞波·卡莱维
卡里萨洛·彼卡·朱哈尼
林登·英格·布里特·沃恩
曼尼斯托·彼卡·托彼亚斯
尼希南·埃基·阿恩·奥拉维
波托·盘蒂
彼普里·阿诺·基利基
彼蒂南·扎莫·约翰
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Abstract

结构式为Ⅰ的有药理活性的儿茶酚衍生物
式中各取代基定义见说明书。

Description

新的药理活性儿茶酚衍生物的制备方法
本发明涉及儿茶酚衍生物及其制备方法。更具体地，本发明涉及具有下列结构式I的儿茶酚衍生物：
Figure C8710801100041
其中：R1和R2分别代表氢、烷基、任意取代的酰基或芳酰基、短链的烷基磺酰或烷基氨基甲酰基或R1和R2共同形成一个低级次烷基或环次烷基；X代表负电性的取代基例如卤素、硝基、氰基、较低分子的烷基磺酰基、磺酰胺撑、醛、羧基或三氟甲基；R3代表氢、卤素、可取代的烷基，羟基烷基、硝基、任意取代的氨基、三氟甲基、较低分子的烷基磺酰基、氨磺酰基、醛基、烷基或亚烷芳基或羧基，或选自下列基团的一个基团，
Figure C8710801100042
或
Figure C8710801100043
其中R4代表氢、烷基、氨基、氰基、羧基或酰基；R5代表氢、氨基、氰基、羧基、烷氧羰基、羧化链烯基、硝基、酰基、羟烷基、羧烷基或一个任意取代的基团；羧基酰氨基、氨基甲酰基、芳酰基或杂芳酰基，或R4和R5组成一个五到七元的基团，优选的为可取代的环烷酮。羧烷基为：
-(CO)n(CH2)m-COR
其中n是0-1，m是0-7，R代表烷基、羟基、羧烷基、可随意被替换的链烯基、烷氧基或可被取代的氨基。该氨基为：
Figure C8710801100051
其中R8和R9分别代表氢或下述中任一个可随意被取代的基团：烷基、链烯基、炔基、环烷基、芳烷基或R8和R9相联的一个可随意被取代的哌啶基。
氨基亦可被如下基团取代
-NH-CO-R10
其中R10代表一个被取代的烷基。
这里所用术语“烷基”指最多为18个碳原子的直链和支链烷基，较好的为1-8个碳原子的，最好为1-4个碳原子的。所用术语“短链烷基”或“低级烷基”是指1-7碳原子的直链和支链烷基，较好的为1-4碳原子，最好的为1或2个碳原子的。作为烷基和低碳烷基的例子如：甲基、乙基、丙基、异丙基、丁基、叔丁基、戊烷基、己烷基、辛基、癸基和十二烷基及它们的支链异构体。
术语“烯基”和“炔基”是如上烷基所定义的碳原子的碳氢基团包含至少一个碳碳间双键或叁键的基团。烯基和炔基含碳原子最多为12个，较好的为1-8个，最好为1-4个。
术语“酰基”除其本身意义外，还包括烷基羰基或烯基羰基，其烷基和烯基如上定义。
术语“芳酰基”除其本身外还包括芳基羰基。其芳基可是单环或双环的，每个环由6-10碳组成，例如：苯基，萘基及类似物。
术语“低级次烷基”是指含2-8碳原子的链，优选的为2-4个碳原子的。同样术语“环次烷基”是指含3-8碳原子的环状碳氢基团，优选的是5-7个碳。
术语“烷氧基”包括上述定义的烷基连结一个氧原子。
术语“环烷基”包括含3-8碳原子的饱和碳氢基团，优选的是5-7碳原子。例如：环戊基、环己基、环庚基和金刚烷基。
术语“芳烷基”是指上述定义的烷基具有一个芳基取代基，例如：苄基。
术语“卤素”是指氯、溴、氟或碘，优选的为氯和溴。
术语“任意取代基”是指诸如氟、氯、溴、碘的卤素或三氟甲基，烷氧基，芳基，烷芳基，卤芳基，环烷基，烷基环烷基，羟基，烷基氨基，链烷酰基氨基，芳羰基氨基，硝基，氰基，硫羟基或烷基硫羟基等取代基。“任意取代基”可含1-3碳原子，较好的为1或2个碳原子，最好的为1个碳原子。
术语“杂芳酰基”或“杂芳基”是指1-3个杂N和/或杂O和/或杂S原子的单环或双环，优选的是含1或2个杂原子。例如：吗啉基，哌啶基，piperidinyl，哌嗪基，吡啶基，吡咯基，喹啉基和quinolinyl。
本发明还涉及本发明化合物的药理上可接受的盐。
现在的发明同样涉及制备结构式为I的这类化合物的方法。根据现在的发明，结构式为I的化合物可以被制取。例如，结构式为II的醛在碱或酸催化反应中和结构式为III的一个化合物缩合，得到结构式为Ia的一类化合物。
Figure C8710801100071
Figure C8710801100072
Figure C8710801100073
其中R1、R2和X的组成如上所述。结构式为III的化合物具有一个活性的甲基或亚甲基，其中的R4和R5的组成仍如上述。在结构式为Ia的化合物中双键可随意被还原成单键。
根据这个发明，结构式为II的这类化合物除了成为有价值的药物外，还可以作为新的有价值的中间体去制备其他有用的产物。
结构式为II并X是一个氯基的化合物能够由相应的化合物、X为囟素，最好是溴在高温下(100-200℃)在一种极性、非质子溶剂例如吡啶、N-甲基吡咯烷酮或N，N-二烃甲酰胺溶液中和氰化亚铜反应制得。
或者结构式为II并X是一个5-氰基的化合物可从由2，3-二羟苄腈和六亚甲基四胺甲酰化制得。
结构式为II并X是一个5-三氟甲基的化合物可以开始从结构式为XIV的3-甲氧基三氟甲基苯制取。
Figure C8710801100081
结构式为XIV的3-甲氧基三氟甲基苯首先用丁基锂处理。然后用硼酸三甲酯，进一步用过甲酸处理，得到结构式为XV的化合物。
结构式为XV的化合物在三氟醋酸中用六甲基四胺进行甲酰化得到结构式为XVI的化合物。
Figure C8710801100083
结构式为XVI的化合物如果理想的话，可用三溴化硼去甲基得到结构式为XVII的化合物。
Figure C8710801100084
结构式为II并X是由一个5-甲磺酰基组成的化合物，可由结构式XVIII的2，3-二甲氧苯硫基甲烷制取。例如结构式为XVIII的化合物首先用过氧醋酸处理得到相应的结构式为XIX的砜。
然后在三氟醋酸中和六亚甲基四胺进行甲酰化得到结构式XX的化合物。该化合物如果理想的话可以被去甲基(HBr或BBr)得到结构式为XXI的化合物。
Figure C8710801100092
结构式为II并X由亚磺酰氨基组成的化合物可以由结构式为XXII的2，3-二羟基苯磺酰氨甲酰化制取，得到结构式为XXIII的化合物。
Figure C8710801100094
其中R11意味着氢或烷基。
或者结构式为I的化合物，根据现在的发明可以从结构式为IV的一个酮和结构式为V的一个醛缩合而制得结构式为Ib的化合物。
Figure C8710801100101
Figure C8710801100102
Figure C8710801100103
其中R1、R2和X的组成如上所述。R6由氢或烷基组成。R7由氢、烷基、烷氧基或二烷氨基组成。
或者结构式为I并R3由一个被取代的烷基组成的化合物可由结构式为VI的化合物借助弗瑞德-克来福特反应制取。
Figure C8710801100104
其中R1和R2的组成如上述。使结构式为VI的化合物在氯化铝存在的条件下和结构式为VII的一个环酸酐，或者和一个结构式为VIII的氯化二羧酸酯起反应，得到结构式为IX的化合物。
Figure C8710801100111
其中m为1-7。
Hal-(CO)n-(CH2)m-COR    VIII其中m为0-7，n为0-1，R的组成如上述，Hal是一个囟素原子。其中芳香环将被X基团取代得到结构式为Ic的化合物。
Figure C8710801100113
其中R、R1、R2和X的组成如上述。
在结构式为Ic的化合物中羰基能用常规的方法(克来门逊和沃尔夫-基斯切那还原)还原成一个亚甲基，得到结构式为Id的化合物。
根据现在的发明，R3由一个被取代的脲基组成的化合物能够由一个被活化的结构式为X的苯甲酸衍生物和一个结构式为XI的胺起反应，得到结构式为Ie的化合物而制得。其中R1、R2和X的组成如上述。Y由囟素或某些其他活化基团组成。其中R8和R7的组成如上述。其中R1、R2、X、R8和R9的组成如上所述。
结构式为I并R3是一个酰化氨基同时具有结构式为If的化合物可以由结构式为XII的一个苯胺衍生物和结构式为XIII的一个活化的羧酸衍生物制得。
Figure C8710801100132
其中R1、R2、X和R10的组成如上所述。其中R1、R2和X的组成如上述。
Y-CO-R10    XIII其中Y和R10的组成如上述。
这个发明同样涉及到这类新的化合物和左旋多巴结合而成的物质。这些物质同样可能包括外周多巴脱羧酶(DDC)抑制剂例如碳化多巴或羟苄丝肼，但并不总是必须有这些抑制剂存在。
儿茶酚-O-甲基移位酶(COMT)催化甲基从S-腺苷-L-蛋氨酸转移到许多具有儿茶酚结构的化合物上。这个酶对于儿茶酚胺和具有儿茶酚结构的药物在神经元失活是主要的。COMT是涉及儿茶酚胺代谢的最重要的酶中的一种。它存在在外周和中枢神经系统中的大多数组织中。在肝、肠和肾中其活性最高。COMT可能是以溶解型和膜结合型存在。这两种形式的精确特性还没有被确定。
在帕金森氏病中，多巴胺能神经元，主要是黑质纹状体神经元受损引起大脑基底节中多巴胺缺乏。这种多巴胺缺乏可以被左旋多巴所代偿，因为左旋多巴在DDC的作用下可以在中枢神经系统中转换成多巴胺。
今天，左旋多巴治疗时几乎是不可避免地同时使用一种外周DDC抑制剂以抑制多巴胺过早的形成，从而增加脑中左旋多巴的浓度并减少多巴胺的外周付作用。
除了DDC外，COMT使得左旋多巴转变成3-O-甲基多巴(3-OMD)。3-OMD容易经过主动转运系统透过血脑屏障。它和左旋多巴竞争，就其治疗而言，它是无效的并且是有害的。因为3-OMD的半寿期(计算值：15小时)和左旋多巴(计算值：1小时)相比较长，它被蓄积在组织中。尽管存在有外周DDC抑制剂，但COMT的活性高时，明显的左旋多巴的效能差。
除了单胺氧化酶(MAO)外，COMT是一个参与胺代谢的最主要的酶。借助抑制内源性儿茶酚胺(多巴胺、去甲肾上腺素、肾上腺素)在脑中的代谢，COMT抑制剂减低了这些内源性儿茶酚胺的分解。这样，COMT抑制剂对治疗抑郁症可能是有用的。
借助有效地抑制外周COMT，COMT抑制剂使左旋多巴的代谢途径导向脱羧，从而形成更多的多巴胺。而多巴胺在治疗高血压和心力衰竭中是重要的。
意外地观察到，现在发现的这些化合物是非常有效的COMT抑制剂。它们揭示了在治疗帕金森氏病方面一些新的，以前不清楚的可能性。除此之外，这些新的化合物同样在治疗抑郁症、心力衰竭和高血压中可能是有用的。
这些新的COMT抑制剂抑制3-OMD的形成可能减少长期使用左旋多巴的付作用。而且左旋多巴的剂量能被减少。已经表明使用COMT抑制剂和不使用COMT抑制剂相比，左旋多巴的剂量能减少二分之一到三之一。因为左旋多巴的剂量有个体差异，难于给予任何绝对的剂量，但开始每天给予25-50毫克认为是足够的。
关于n-丁基棓酸盐——一种已知的COMT抑制一初步临床试验显示，帕金森氏病患者明显地从n-丁基棓酸盐中得到好处。不过这个研究被中断了，因为n-丁基棓酸盐的毒性太高。
使用如下实验过程检验了现在发明的这类COMT抑制剂的效能。
离体COMT活性的测定：
-------------------
离体COMT的活性是在体重100克的雌性Han：Wist种鼠的脑和肝分离的酶标本中测定的。鼠用二氧化碳处死，取出组织并储存在-80℃直到测定酶的活性。
所用组织在pH7.4含有0.5mM二硫苏糖醇的10mM的磷酸盐缓冲液(1∶10组织重g/ml)中搅匀制取酶的标本。匀浆15000×G离心20分钟。上清液用100,000×G再离心60分钟。所有操作均在4℃完成。最后将在100,000×G离心的上清液用于测定溶解型COMT酶的活性。(G为平均离心力场)。
IC50的测定：
-------------
IC50值是酶抑制引起COMT活性减少50％的浓度。IC50的测定是通过测定在含有酶制备液、0.4mM二羟基苯甲酸(底物)、5mM氯化镁、0.2mM S-腺苷-L-蛋氨酸和酶抑制剂并含有几种不同浓度的药物的pH7.4，0.1M磷酸盐缓冲液中COMT的活性而得到。对照样品中不加入COMT抑制剂。混合液在37℃下恒温30分钟，然后加入高氯酸使反应停止并离心(4000×G)10分钟将所沉淀的蛋白质移除。酶的活性是通过使用高压液相的一个电化学检测器测定从COMT的底物(二羟苯甲酸)形成的3-甲氧-4-羟基苯甲酸的浓度而得到的。注入20微升的样品进入一个4.6mm×150mm的Spherisorb ODS柱(颗粒大小为5微米)而完成层析。反应产物用20％甲醇并含有0.1M磷酸盐、20mM柠檬酸和0.15mM乙二胺四乙酸、pH3.2并以1.5毫升/分的流速从柱子中洗脱出来。这个电化学检测器定为与银/氯化银电极相比0.9伏。比较对照样品和含有COMT抑制剂的样品中反应产物3-甲氧-4-羟基苯甲酸的浓度。
体内COMT抑制剂的作用：
本实验使用雄性Han：Wist鼠重200-250克。对照组在给予左旋多巴(50毫克/公斤)前30分钟给予50毫克/公斤碳化多巴。试验组在给予左旋多巴和COMT抑制剂前30分钟同样给予50毫克/公斤碳化多巴。所有药物均经口给予。
取样：
---
从尾动脉抽取大约0.5毫升的血液。样品在冰中凝血，然后离心，分离出血清。血清一直保存在-80℃，直到进行左旋多巴和它的代谢物3-OMD的测定。
血清左旋多巴和3-OMD浓度的测定：
一个与血清同等容易并含有二羟基苄胺作为内标的0.4M高氯酸、0.1％硫酸钠、0.01％乙二胺四乙酸液加到血清(100微升)中。样品混匀后在冰中保存。离心(4000×G10分钟)后去除蛋白质。使用高压液相中的电化学检测器测定左旋多巴和3-OMD的浓度。混合液经4.6毫米×150毫米的Utrasphere ODS柱分离，用含有4％乙腈、0.1M磷酸盐缓冲液、20mM柠檬酸、0.15mM乙二胺四乙酸、2mM辛基磺酸和0.2％tetrahydropholan，pH为2.8的洗脱液洗提。流速为2毫升/分。电化学检测器定为与银/氯化银电极相比+0.8伏。左旋多巴和3-OMD的浓度是通过其峰高度和内标的峰高度相比而决定的。并计算对照鼠和给予COMT抑制剂鼠的左旋多巴和3-OMD血清浓度的比值。
结果：
现在发明的最好的COMT抑制剂在离体与已知的最强的COMT抑制剂U-0521相比其作用要强1000倍(见表I)。同样口服使用现在发明的COMT抑制剂和U-0521相比是更加显著地抑制了血清中3-OMD的形成。这个参照物U-0521进一步能通过血脑屏障并抑制酪氨酸羟化酶，从而阻断了最重要的儿茶酚胺的生物合成。与此相反，现在发明的这些化合物是特殊性抑制COMT并没有显著地通过血脑屏障。
表1
Figure C8710801100191
实施例  R1 R2                X             R3                                      脑组织中化合物                                                                                COMT抑制
                                                                                  (IC50(nM)79    H    H                  5-NO2     
Figure C8710801100192
                     311    H    H                  5-NO2                          5
  R1 R2                 X            R38     H    H                  5-NO2     
Figure C8710801100194
                           66     H    H                  5-NO2     
Figure C8710801100195
                             12110   H    H                  5-NO2       NO2                                         12109   H    H                  5-NO2                                             16130 
Figure C8710801100197
       5-NO2       NO2                                         185              H            H         5-NO2    
Figure C8710801100201
                                 2027             H            H         5-NO2    
Figure C8710801100202
              2016             H            H         5-NO2                               23111            H            H         5-NO2    
Figure C8710801100204
                                          24113            H            H         5-NO2       Cl                                           25112            H            H         5-NO2       CN                                           30
           R1          R2       X            R328             H            H         5-NO2                    2726             H            H         5-NO2    
Figure C8710801100206
             333              H            H         5-NO2      CH＝CH-COOH      37128  
Figure C8710801100207
  NO2                                                       60127           NO2                                                       7524     H        H     5-NO2    CH2CH2CH2CH2COOH               90109    H        H     5-NO2    H                                  140131
Figure C8710801100211
H    5-NO2   NO2                                22041     H        H     6-NO2   CH2CH2CH2CH2COOH               38054     H        H     5-Cl   
Figure C8710801100212
                      40067    CH3CO    CH3CO6-NO2 
Figure C8710801100213
          750U-0521 H        H     5-H                             6000表2体内实验结果：
                     3-OMD的对照百分浓度口服剂量       化合物    1小时    5小时3毫克/公斤      10       -97      -804.3毫克/公斤    127      -67      -764.7毫克/公斤    128      -70      -774.3毫克/公斤    131       92      -834.1毫克/公斤    130      -98      -9230毫克/公斤     19       -99      -7630毫克/公斤     111      -100     -6530毫克/公斤     5        -96      -8930毫克/公斤     6        -84      -4930毫克/公斤     11       -63      -2630毫克/公斤     8        -58      -34100毫克/公斤    24       -86      -41100毫克/公斤    U-0521   -34      -14
这些结果表明，现在发明的这类化合物在离体实验中和参照物(U-0521)相比作用强1000多倍(表1)。以血清3-OMD浓度减少为指征同样显示口服这类新化合物在体内的作用明显比参照物好(表2)。况且参照物U-0521能透过血脑屏障，非特异地抑制酪氨酸羧化酶，而酪氨酸羧化酶在儿茶酚胺的生物合成中是重要。
图1显示了新的化合物(例5)和不含COMT抑制剂的对照物中3-OMD血清浓度。实验设计是和上述体内实验相同。图2显示相同处理后血清中左旋多巴的浓度。这些数字表明现在发明的这些化合物增加左旋多巴的生物有效度并减低有害代谢产物3-OMD的水平。血清中3-OMD和左旋多巴浓度的变化反映着脑中3-OMD和左旋多巴的改变。
特异性COMT抑制：
--------------
这一类新的化合物是特异的COMT抑制剂并不是其他必须酶的抑制剂。这一点已在上述离体实验结果中表明了。
IC50(nM)化合物 COMT   TH   DBH    DDC     MAO-A  MAO-B----------------------------------------------例87    3    38.000＞50.000＞50.000＞50.000＞50.000例11    5    18.000＞50.000＞50.000＞50.000＞50.000例8     6    21.000＞50.000＞50.000＞50.000＞50.000例6     12   50.000＞50.000＞50.000＞50.000＞50.000例110   12   14.000＞50.000＞50.000＞50.000＞50.000例19    16   17.500＞50 000＞50.000＞50.000＞50.000例5     20   21.000＞50.000＞50.000＞50.000＞50.000例111   24   50.000＞50.000＞50.000＞50.000＞50.000U-0521  6000 24.000＞50.000＞50.000＞50.000＞50.000
TH为酪氨酸羟化酶，DBH为多巴胺-β-羟化酶，MAO-A和-B是单胺氧化酶A和B。
现在发现的这些COMT抑制剂是极端特异的酶抑制剂。它们在低浓度时有效地抑制COMT，而有关儿茶酚胺代谢的其他酶被抑制却需要比这高1000-10000倍的浓度。参照物U-0521对COMT和TH的抑制的浓度差仅4倍。
IC是酶的活性被抑制50％识所需化合物的浓度。
毒性：
这些新的COMT抑制剂是无毒的。例如3-(3，4-二羟基-5-硝基苯基)-1-(3，4，5-三甲氧苯基)丙-2-烯-1酮(例11)给鼠口服悬液的LD(半数致死量)是大于2500毫克/公斤。
例1
--
3-硝基-5-[2-(4-吡啶基)乙烯基]儿茶酚。
9.0毫升乙酐中含有2.0克(0.011克分子)的3，4-二羟-5-硝基苯甲醛和2.23克(0.024克分子)的4-甲基吡啶溶液回馏1小时。然后加入大约15毫升异丙醇并使溶液冷却到0℃直到期望的二乙酰衍生物被结晶出来。过滤后结晶产物悬浮于100毫升0.5N盐酸中并回馏1.5小时。冷却后将沉淀过滤，用水和丙酮洗涤并干燥，得到该化合物1.89克(67％)，熔点在350℃以上。
例2
--
3-硝基-5-[2-(4-喹啉基)乙烯基]儿茶酚
使用2.0克(0.011克分子)的3，4-二羟-5-硝基苯甲醛和3.44克(0.024克分子)的4-喹哪啶重复例1的操作，得到1.7克(50％)，熔点250℃(分解)。
例3
--
4-羟-3-甲氧-5-硝基肉桂酸
10毫升吡啶中含1.0克的5-硝基香草醛和4.0克的丙二酸溶液在80℃加热50小时。这个反应混合物用水稀释，用盐酸酸化，用水洗涤并干燥。得到0.44克(36％)。H-核磁共振谱是和所述的结构一致的。
例4
--
3，4-二羟基-5，ω-二硝基苯乙烯
10毫升无水乙醇含有3.66克(0.02摩尔)的3，4-二羟基-5-硝基苯甲醛3.66克(0.06摩尔)的硝基甲烷和3.31克乙酸铵的溶液回馏6小时。然后加水到这个反应混合物中。这个反应混合物用盐酸酸化并用亚甲基氯提取。亚甲基氯提取物用水洗涤并在真空中蒸发溶剂。剩余物从异丙醇中结晶，得到1.9克(40％)，熔点258～260℃。
例5
--
3，4-二羟基-5-硝基-ω，ω-二氰基苯乙烯
使用3.0克的3，4-二羟基-5-硝基苯甲醛和3.0克的丙二腈重复例4的操作。反应产物从甲醇-水中结晶，产生1.9克(50％)，熔点205-209℃。
例6
--
4-(3，4-二羟-5-硝基苯基-3-甲基丁-3-烯-2-酮
含有0.5克的3，4-二羟基-5-硝基苯甲醛的2.0毫升丁酮溶液用气态氯化氢饱和。静置过夜后加入乙醚并过滤。滤液后产物从异丙醇中结晶，得到0.2克(30％)，熔点139-141℃。
例7
--
3-(3，4-二羟基-5-硝基苄叉基)-2，4-戊二酮
10毫升四氢呋喃溶液中含有1.83克3，4-二羟基-5-硝基苯甲醛和1.00克2，4-戊二酮，用气体氯化氢加以饱和。在5℃静置过夜后，该产物被过滤并用乙醚洗涤，得到1.2克(50％)，熔点为175-178℃。
例8
--
3-(3，4-二羟基-5-硝基苯基)-1-苯基丙-2-烯-1-酮
10毫升含有0.55克3，4-二羟基-5-硝基苯甲醛和0.36克乙酰苯的甲醇溶液用气态氯化氢饱和。在5℃静置一夜后，该产物滤过后用甲醇洗涤，得到0.55克(68％)，熔点192-195℃。
例9
--
3-(3，4-二羟基-5-硝基苯基)-1-(4-甲氧苯基)-丙-2-烯-1-酮
使用20毫升含1.8克3，4-二羟基-5-硝基苯甲醛和1.5克4′-甲氧基乙酰苯的四氢呋喃溶液重复例8的操作，得到1.88克(60％)，熔点222-228℃。
例10
--
3-(3，4-二羟基-5-硝基苯基)-1-(3，4-二甲氧苯基)丙-2-烯-1-酮
使用20毫升含1.8克3，4-二羟-5-硝基苯甲醛和1.8克3′，4′-二甲氧乙酰苯的甲醇溶液重复例8的操作，得到1.7克(50％)，熔点206-208℃。
例11
--
3-(3，4-二羟基-5-硝基苯基)-1-(3，4，5-三甲氧苯基)丙-2-烯-1-酮
使用0.55克3，4-二羟基-5-硝基苯甲醛和0.63克3′，4′，5′-三甲氧乙酰苯，重复例8的操作，得到0.50克(44％)，熔点213-216℃。
例12
--
3-(3，4-二羟基-5-硝基苯基)-1-(2-羟基苯基)丙-2-烯-1-酮
使用1.0克3，4-二羟-5-硝基苯甲醛和0.74克2′-羟乙酰苯重复例8的操作，得到2.0克(12％)，熔点231-234℃。
例13
--
3-(3，4-二乙酸基-5-硝基苯基)-1-苯丙-2-烯-1-酮
5.0毫升含有在例8中得到的产物1.0克的乙酐溶液回馏2小时。冷却后反应产物被滤过并用乙醚洗涤，得到0.73克(68％)，熔点183-185℃。
例14
--
3-(3，4-二苯甲酸基-5-硝基苯基)-1-苯丙-2-烯-1-酮
1.0克从例8中得到的产物和2.0毫升苯甲酰氯溶于5毫升四氢呋喃中，然后最大限度地将四氢呋喃蒸馏掉。剩余物回馏2小时，冷却后将乙醚加入到这个混合物中，反应产物被滤过并和乙基甲基酮研制，得到0.50克(29％)，熔点206-210℃。
例15
--
3-(3-三甲基乙酰氧基-4-羟基-5-硝基苯基)-1-苯丙-2烯-1-酮
1.0克从例8中得到的反应产物溶于5毫升四氢呋喃中，加入4.7毫升三甲基乙酰氯。该混合物回馏16小时。在真空中蒸发溶剂，剩余物在硅胶柱中使用甲苯-醋酸-二噁烷(18∶1∶1)混合物作为洗脱剂纯化。该产物从乙醚中结晶出来，熔点为148-150℃。
例16
--
4-(3，4-二羟基-5-硝基苯基)-3-甲基丁-3-烯-2-醇
1.8克从例6中获得的反应产物溶于20毫升1N氢氧化钠溶液并加入溶于少量水的4.0克氢硼化钠。该混合物在室温下搅拌一夜，然后用盐酸酸化并用乙醚提取。溶剂在真空中蒸发。剩余物在硅胶柱中使用甲苯-醋酸-二噁烷(18∶1∶1)纯化。产物从二氯代甲烷石油醚中结晶，得到0.80克(44％)，熔点102-104℃。
例17
7-(3，4-二羟基-5-硝基苄叉基)-8-酮壬酸
使用1.83克3，4-二羟基-5-硝基苯甲醛和1.72克8-酮壬酸重复例9所述的操作，得到1.85克(55％)，黄色粘性油。
例18
--
4′-羟基-3′-甲氧基-5-硝基苯乙酮
边冷却(低于7℃)边搅拌将25.0克4′-羟基-3′-甲氧乙酰苯逐渐加入到含有40毫升硝酸(d＝1.41)和46毫升水的溶液中。在0℃搅拌半小时后，反应产物被滤过，首先用稀释硝酸(1∶1)，然后用水洗涤，得到24.0克(75％)。该产物的H-核磁共振谱与所述的结构相一致。
例19
--
3′4′-二羟基-5′-硝基乙酰苯
含有19.9克从例18中得到的反应产物的200毫升醋酸和200毫升48％氢溴酸溶液回馏5小时。500毫升饱和硫酸钠溶液加入该反应混合物中，并在5℃静置一夜。该溶液用乙醚提取。乙醚相用200毫升水洗涤，干燥并且溶剂在真空中蒸发。剩余物从异丙醇中结晶，得到10.2克(55％)，熔点155-159℃。
例20
--
1-(3，4-二羟基-5-硝基苯基)-3-(4-二甲基氯基-苯基)-丙-2-烯-1-酮
5毫升含有0.5克从例19中得到产物和0.38克4-二甲基氨基苯甲醛的甲醇溶液用气态氯化氢饱和。溶液被回馏1小时。冷却后反应产物被过滤并用甲醇洗涤，得到0.26克(70％)，加热时分解。
例21
--
5-(4-苄氧基-3-甲氧基苯基)-2，4-戊二烯酸
149.6克的叔丁醇钾逐渐加入到1200毫升含有260克4-苄氧基-3-甲氧苯甲醛和200毫升巴豆酸乙酯的N-甲基吡啶烷酮中并同时搅拌及在0℃冷却。该溶液充分搅拌半小时，然后加入200毫升10N氢氧化钠溶液并在0℃搅拌半个多小时。该反应混合物加到盐酸和冰的混合物中。未纯化的半固态产物分离出来并用于下一步。
例22
--
5-(4-羟基-3-甲氧苯基)戊酸
例21得到的粗产物溶于500毫升N，N-二甲基甲酰胺中并且加入22克10％有钯及活性碳催化剂。该混合物在60℃和正常压力下被氢化直到理论剂量(3摩尔)的氢被消耗。滤过后，溶剂在真空中最大程度的被蒸发，剩余物溶于1升二氯甲烷中，并用2升水洗涤。该产物用1.5升饱和碳酸氢钠溶液提取。用盐酸对水相酸化后，反应产物用1升二氯代甲烷提取。该溶剂在真空中蒸馏，所得到的半固态剩余物(180克)用于下一步。
例23
--
5-(4-羟基-3-甲氧基-5-硝基苯基)戊酸
上述反应产物180克溶于1升二氯甲烷中并且820毫升1摩尔的硝酸-二氯甲烷溶液逐渐加入其中同时搅拌并在0-5℃冷却。该溶液在0℃搅拌10多分钟，然后加入水。有机相分离出来并用水洗涤。该溶剂在真空中蒸发，半固态剩余物用于下一步。
例24
--
5-(3，4-二羟基-5-硝基苯基)-戊酸
从例23中得到的上述产物溶于含有500毫升醋酸和500毫升48％氢溴酸混合液中并回馏4小时。加入1升饱和硫酸钠溶液到上述反应混合物中，然后在5℃静置一夜。结晶产物被滤过并用50％醋酸洗涤。该产物从乙酯中重结晶得到产物32克(16％)，熔点135-138℃。
例25
----
1-苯甲基-4--5-(3，4-二羟基-5-硝基苯基-戊酰-盐酸哌嗪
18毫升含有从例24得到的产物3.0克的亚硫酰氯溶液回馏10分钟。在真空中过多的亚硫酰氯蒸发掉。所形成的酸氯溶于20毫升二氯代甲烷中。加入该溶液中20毫升含有2.1克1-苯甲基哌嗪的二氯代甲烷，边搅拌边加入并搅拌半个多小时。乙醚加入该反应混合物中，结晶被过滤，得到3.55克(73％)，熔点85～89℃。
例26
----
N-异丙基-5-(3，4-二羟基-5-硝基苯基)戊酰胺
2.5毫升含有0.5克从例24得到的产物的亚硫酰氯回馏10分钟。过多的亚硫酰氯在真空中被蒸发掉，剩余物溶于25毫升二氯代甲烷中。0.47克异丙胺加入到该溶液中并在20℃搅拌1小时。二氯代甲烷相用1N盐酸洗涤并在真空中蒸发。剩余物从甲苯中结晶出来，得到0.44克(75％)，熔点113～115℃。
例27
----
N-甲基(-N-炔丙基-5-(3，4-二羟基-5-硝基苯基)-戊酰胺
使用0.5克甲基炔丙基胺代替异丙基胺重复例26所述的操作，得到0.5克(83％)产物，熔点为133～135℃。
例28
----
N-(1-金刚烷基)-5-(3，4-二羟基-5-硝基苯基)-戊酰胺
使用1.5克1-氨基金刚烷代替异丙基胺重复例26所述的操作，得到0.16克(80％)的产物，熔点为157～160℃。
例29
十四烷基-5-(3，4-二羟基-5-硝基苯基)戊酸酯
使用1.26克1-十四烷醇代替异丙基胺重复例26所述的操作。反应混合物用水洗涤，溶剂在真空中蒸发，得到0.44克(50％)产物，熔点46～47℃。
例30
----
十四烷基-5-(3，4-二乙酰基-5-硝基苯基)戊酸酯
2毫升含有0.1克从例29中得到的产物的乙酐溶液回馏20分钟。溶剂在真空中蒸发，剩余物从石油醚中结晶，石油醚熔点40℃，结晶物熔点52～54℃。
例31
----
十四烷基-5-(4-羟基-3-三甲基乙酰氯-5-硝基苯基)-戊酸酯
使用2毫升三甲基乙酰氯代替乙酐重复例30所述的操作。反应产物是粘性油。
例32
----
5-(3，4-二甲氧基-5-氯苯基)-2，4-戊二烯酸
边搅拌边将6.7克叔丁醇钾加入65毫升含有10.0克二氧基-5-氯苯甲醛和8.3毫升巴豆酸乙酯的N-甲基吡咯烷酮溶液中。溶液在20℃搅拌半个多小时，然后倒入冰和盐酸混合物中，并用乙醚提取。乙醚提取物用水洗涤，然后用碳酸氢钠溶液提取。水相用盐酸酸化。半固态产物被分离出来并用水洗涤，得到7.3克(55％)产物。
例33
----
5-(3，5-二甲氧基-5-氯苯基)戊酸
6.2克从例32得到的产物溶于30毫升醋酸和3毫升浓盐酸的混合液中。加入含有活性碳催化剂的钯(10％钯)，混合物在正常压力和室温下氢化。滤过后溶剂在真空中蒸发，得到3.2克(55％)粘性油。
例34
----
5-(3，4-二羟基-5-氯苯基)戊酸
含有上述产物3.2克的8毫升醋酸和10毫升48％氢溴酸溶液回馏3小时。饱和硫酸钠水溶液加入该反应混合物中。结晶产物被滤过，并用水洗涤，然后从甲苯中重结晶，得到结晶物熔点99～101℃。
例35
----
5-(3，4-二甲氧基-6-氯苯基)-2，4-戊二烯酸
边搅拌边将6.0克叔丁醇钾加入60毫升含有10.0克3，4-二甲氧基-6-氯苯甲醛和8毫升巴豆酸乙酯的N-甲基吡咯烷酮。该溶液搅拌在20℃温度下半个多小时，然后倒入冰和盐酸的混合物中。该溶液用乙醚提取。乙醚溶液用水洗涤并用2.5N的氢氧化钠溶液提取，水相用盐酸酸化，并将半固态产物分离出来，得到10.8克(81％)的产物。
例36
----
5-(3，4-二羟基-6-氯苯基-2，4-戊二烯酸
6毫升1摩尔三溴化硼-二氯代甲烷溶液加入到6毫升含有0.54克从例35得到的产物的二氯代甲烷并搅拌在20℃温度下24小时。溶剂在真空中蒸发，2N的盐酸加入到剩余物中。反应产物被滤过并用水洗涤，然后从异丙醇一水中重结晶，得到0.22克期待的产物(46％)，熔点为203～206℃。
例37
----
3-(3，4-二羟基-5-硝基苯基)-1-(4-甲基苯基)-丙-2-烯-1-酮
催化剂量的气态氯化氢加入到50毫升含有5.49克3，4-二羟基-5-硝基苯甲醛和5.37克4′-甲基苯乙酮的四氢呋喃中，并回馏4.5小时。溶剂在真空中蒸发，剩余物从乙醚—石油醚中结晶，得到产物1.85克(21％)，熔点184～186℃。
例38
----
5-(3，4-二甲氧苯基)-5-酮戊酸
120毫升含有36克邻二甲氧基苯和30克戊二醛的硝基苯溶液在搅拌和冷却下逐渐加入到72克无水氯化铝和240毫升硝基苯混合物中，在0℃搅拌冷却1小时，然后在20℃搅拌18小时。冰和盐酸加入该反应混合物中。硝基苯层被分离出来并加入乙酸乙酯，直到形成结晶。滤过后结晶物用乙酸乙酯洗涤，得到42.3克(64％)产物。
例39
----
5-(3，4-二甲氧苯基)戊酸
含有37.6克从例38得到的产物64克锌屑(用氯化汞溶液处理)、55毫升甲苯和220毫升浓盐酸的混合物回馏1小时。甲苯相被分离并在真空中蒸发，剩余物从甲苯-石油醚中结晶，得到11.5克(32％)产物。
例40
----
5-(3，4-二甲氧-6-硝基苯基)戊酸
15克从例39中得到的产物在20℃逐渐地加入到75毫升的硝酸(d＝1.41)中。该混合物搅拌20多分钟。冰水加入其中，该溶液用二氯代甲烷提取。溶剂在真空中蒸发，得到14.0克(79％)期待的产物。
例41
----
5-(3，4-二羟基-6-硝基苯基)戊酸
含有42.0克例40中获得的产物的100毫升醋酸和150毫升48％氢溴酸溶液回馏10小时。1升饱和硫酸钠溶液加入该反应混合物中并用乙醚提取。溶剂在真空中蒸发，剩余物从乙酸乙酯-石油醚中结晶，得到7.9克(19％)产物，熔点为111～114℃。
例42
----
3-(3，4-二甲磺酰氧基-5-硝基苯基-1-苯基丙-2-烯-1-酮
20毫升含有2.0克例2中得到的产物和5毫升甲磺酰氯的N-甲基吡咯烷酮在100℃加热1个半小时。冷却后加入水并用乙醚提取。溶剂在真空中蒸发，剩余物从1-丙醇中结晶，得到0.14克产物，熔点为181～184℃。
例43
----
N-(1-金刚烷基)-3，4-二乙酸基-5-硝基苯甲酰胺
10毫升含有0.85克3，4-二乙酸基-5-硝基苯甲酸和0.32毫升亚硫酰氯和催化剂量的N，N-二甲基甲酰胺的甲苯溶液在80℃加热1小时。溶剂在真空中蒸发，剩余物溶于5毫升二氯代甲烷，然后加入到10毫升含有0.56克1-盐酸氨基金刚烷和0.94毫升三乙胺的二氯代甲烷中并在0℃温度下搅拌15分钟，在20℃15分钟。水加入到该反应混合物中并二氯代甲烷相被分离。溶剂在真空中蒸发，得到黄色粘性油1.2克(100％)。
例44
----
N-(1-金刚烷基)-3，4-二羟基-5-硝基苯甲酰胺
10毫升含有1.2克从例43中得到的产物和催化剂量的硫酸的甲醇溶液回馏3小时。加入20毫升的水冷却，结晶出0.85克(89.5％)期待的产物，熔点207～208℃。
例45
----
4-环己基羰基-1-(3，4-二乙酸基-5-硝基苯甲酰基)-哌啶
使用0.58克环己基羰基哌啶和0.38毫升2，6-二甲基吡啶分别代替1-氨基金刚烷盐酸盐和三乙胺重复例43所述的操作，得到1.2克(87％)黄色粘性油。
例46
----
4-环己基羰基-1-(3，4-二羟基-5-硝基苯甲酰基-哌啶
使用1.2克从例45得到的产物重复例44所述的操作，得到0.5克(50％)产物，熔点为155～165℃。
例47
----
N-苯甲基-3，4-二乙酸基-5-硝基苯甲酰胺
0.75克3，4-二乙酸基-5-硝基苯甲酸正象例43中所述那样转换成相应的酰氯，然后溶于5毫升二氯代甲烷并加入到7毫升含有0.27毫升苄胺和0.5毫升2，6-二甲基吡啶的二氯代甲烷溶液中，得到0.95克(96％)的产物，为粘性油。
例48
----
N-苯甲基-3，4-二羟基-5-硝基苯甲酰胺
使用0.95克从例47中得到的产物重复例44所述的操作，得到0.5克(68％)的产物，熔点为185～189℃。
例49
----
N-(1-金刚烷基)-3，4-亚环己基二氧-6-硝基苯甲酰胺
按例43所述将2克3，4-亚环己基二氧-6-硝基苯甲酸转换成相应的酸氯，然后加入到15毫升含有1.1克1-氨基金刚烷和1.1毫升三乙胺的二氯代甲烷溶液中，得到2.9克(98％)粘性油。
例50
----
N-(1-金刚烷基)-3，4-二羟基-6-硝基苯甲酰胺
8毫升含有0.5克从例49中得到的产物和0.09毫升甲磺酸的98％甲酸溶液在60℃加热15分钟。溶剂在真空中蒸发并将水加到剩余物中，得到0.35克(88％)的产物，熔点为250～255℃。
例51
----
N-(4-吗啉代乙基)-3，4-亚环己基二氧-6-硝基苯甲酰胺
按例43所述将2.0克3，4-亚环己基二氧-6-硝基苯甲酸转换成相应的酸氯，然后加入到15毫升含有0.9毫升4-(2-氨基乙基)吗啉和1.1毫升三乙胺的二氯代甲烷溶液中，得到2.5克(89％)粘性油。
例52
----
N-(4-吗啉代乙基)-3，4-二羟基-6-硝基苯甲酰胺甲磺酸盐
使用1.95克从例51中获得的成为重复例50所述的操作，得到0.8克(40％)的粘性油。H-核磁共振谱和所述的结构是一致的。
例53
----
N-(1-金刚烷基)-3，4-二乙酸基-5-氯苯甲酰胺
按例43将0.7克3，4-二乙酸基-5-氯苯甲酸转换成相应的酸氯并重复例43所述的操作，得到1.0克(95％)粘性油。
例54
----
N-(1-金刚烷基)-3，4-二羟基-5-氯苯甲酰胺
按例44将例53的产物去乙酰基，得到0.6克(78％)的产物，熔点为244～247℃。
例55
----
N-(1-金刚烷基)-3，4-亚环己基二氧-6-氯苯甲酰胺
0.8克3，4-亚环己基二氧-6-氯苯甲酸被转换成相应的酸氯并重复例43的操作，得到1.0克(83％)粘性油。
例56
----
N-(1-金刚烷基)-3，4-二羟基-6-氯苯甲酰胺
按例50所述将1.0克从例55中得到的产物用甲磺酸在甲酸液中处理，得到0.65克(81％)产物，熔点225～230℃。
例57
----
N-(1-金刚烷基)-3，4-二乙酸基-5-氰基苯甲酰胺
将0.6克3，4-二乙酸基-5-氰基苯甲酸转换成相应的酸氯并重复例43的操作，得到0.75克(88％)粘性油。
例58
----
N-(1-金刚烷基)-3，4-二羟基-5-氰基苯甲酰胺
0.75克上述产物按例44所述去乙酰基，得到0.5克(89％)产物，熔点为253～255℃。
例59
----
1-丁基-3，4-二羟基-5-氰基苯甲酸酯
10毫升含有0.5克3，4-二羟基-5-氰基苯甲酸的丁醇溶液在0℃用气态氯化氢饱和，然后该溶液在100℃加热3小时。溶剂在真空中蒸发并将二氯代甲烷加入剩余物中。滤过所形成的结晶，得到0.19克(30％)产物，熔点为135～140℃。
例60
----
ω-(2-甲哌啶基)-3，4-二甲氧基-6-氰基丙酰苯胺
15毫升含有2.68克ω-氯-3，4-二甲氧基-6-氰基丙酰苯胺，1.5克2-甲基哌啶，1.4克氧化钙和催化剂量的碘化钾的甲苯混合物在100℃加热18小时。该溶液被过滤，用水洗涤并在真空中蒸发，剩余物用石油醚处理后过滤，得到2.79克(84％)的产物，熔点为126～127℃。
例61
----
ω-(1-金刚烷基氨基)-3，4-二甲氧基-6-氰基丙酰苯胺
将3.0克ω-氯-3，4-二甲氧基-6-氰基丙酰苯胺，2.3克的1-氨基金刚烷盐酸盐，4.6克碳酸钾和催化量的碘化钾溶液混溶在15毫升的甲苯中，将混液在100℃下搅拌并加热。过滤溶液，真空蒸出溶剂。将水加入剩余物，过滤产物，得到3.4克(74％)产物，其熔点为137～140℃。
例62
----
1-(3，4-亚环己基二氧基-6-硝基苯甲酰基)-4-环己基-羰基哌啶
如例43所述将0.5克3，4-亚环己基二氧基-6-硝基苯甲酸转换成相应的酰氯。将其加入一个在30毫升二氯甲烷中含0.35克4-环己基羰基哌啶和0.2克三乙胺的溶液中，得到0.7克(85％)产物，其熔点为270℃。
例63
----
1-(3，4-二羟基-6-硝基苄基)-4-环己基羰基哌啶
如例50所述，将0.48克上述产物用混在甲酸中的甲磺酸处理，得到0.3克产物(75％)，其熔点为240℃。
例64
----
1-(3，4-亚环己基二氧基-6-硝基苯甲酰基)-4-(1-哌啶基)-哌啶
用0.3克4-(1-哌啶基)哌啶代替4-环己基-羰基哌啶重复例62所述操作，得到0.57克(74％)产物，其熔点为200℃
例65
----
环己基-4-〔1-(3，4-亚环己基二氧基-6-硝基苯甲酰基)哌啶基〕甲醇
将0.1克硼氢化钠在室温下加入20毫升含有0.5克从例62所得到的产物和1.1毫升1当量浓度氢氧化钠溶液的甲醇溶液。用醋酸酸化该溶液，再用二氯甲烷提取。减压除去溶剂，再用石油醚处理剩余物，得到0.45克产物(90％)，其熔点为155℃。
例66
----
1-(3，4-二羟基-6-硝基苯甲酰基)-4-(1-哌啶基)哌啶氢甲磺酸酯
如例50所述将0.3克例64得到的产物用溶在甲酸中的甲磺酸处理，得到0.26克(84％)产物，其熔点为290℃。
例67
----
1-(3，4-二醋酸基-6-硝基苯甲酰基)-4-环己基羰基-哌啶
将0.5克例63中得到的产物加入10毫升的醋酸酐并在40℃下加热1小时。加入冰水，过滤产物，得到0.5克(87％)产物，其熔点为160～165℃。
例68
----
N-甲基-N-炔丙基-3，4-亚环己基二氧基-6-硝基苯甲酰胺
将0.5克3，4-亚环己基二氧基-6-硝基苯甲酸转换成相应的酰氯，加入到20毫升含有0.12克甲基炔丙基胺和0.18克三乙胺的二氯甲烷溶液中，得到0.3克(50％)产物，其熔点为50～55℃。
例69
----
1-(3，4-二甲氧基-6-硝基苯甲酰基)-4-环己基羰基哌啶
如例43所述步骤将10.3克3，4-二甲氧基-6-硝基苯甲酸转换为相应的酰氯。加入一个在300毫升含有8.83克4-环己基羰基哌啶和4.58克三乙胺的二氯己烷溶液中，得到16.4克(90％)产物，其熔点为120～125℃。
例70
----
1-(3，4-二羟基-6-硝基苯甲酰基)-4-环己基羰基-哌啶
将一个12毫升含有0.81克上述化合物的1摩尔的BBr-CHCl溶液在20℃下搅拌过液。加水，过滤，得到0.5克(67％)产品，其熔点为240℃。
例71
----
环己基-4-〔1-(3，4-二甲氧基-6-硝基苯甲酰基)哌啶基〕甲醇
如例65所述操作将2.03克例69中得到产物用硼氢化钠还原，得到1.89克(93％)产物，其熔点为145～150℃。
例72
----
3-(3-乙氧基羰基甲基氨基甲酰氧基-4-羟基-5-硝基苯基)-1-苯基丙-2-烯-1-酮
将1.5克异氰基乙酸乙酯加入到10毫升含有0.54克例8所得产品的四氢呋喃溶液中。将该混合液于20℃下搅拌3天。减压除去溶剂，在硅胶柱中纯化粗产品，用甲苯-二噁烷-乙酸(8∶1∶1)作为洗脱剂。从丙酮-石油醚中结晶产物，得到0.13克(17％)所需产物，其熔点为155℃～158℃。
例73
----
3-(3，4-甲叉二氧基-6-硝基苯基)-1-苯基丙-2-烯-1-酮
用溶在30毫升甲醇的1.95克6-硝基胡椒醛和2.10克3′，4′，4′-三甲氧基-苯乙酮重复8所述步骤，得到0.88克(24％)产物，其熔点为157～159℃。
例74
----
3-(4-羟基-3-甲氧基-5-硝基苯基)-1-(3，4，5-三甲氧基-苯基)丙-2-烯-1-酮
用2.0克4-羟基-3-甲氧基-5-硝基苯甲醛和2.1克3′，4′，5′-三甲氧基苯乙酮重复例8所述操作，得到2.2克(57％)产物，其熔点为123～125℃。
例75
----
3-(3，4-二羟基-5-硝基苯基)-1-(2-羟基苯基)丙-2-烯-1-酮
用1.83克3，4-二羟基-5-硝基苯甲醛和1.64克2′-羧基苯乙酮重复例8所述操作，得到0.36克(11％)产物，其熔点为178～180℃。
例76
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3-(3，4-二羟基-5-硝基苯基)-1-(4-硝基苯基)-丙-2-烯-1-酮
用1.83克3，4-二羟基-5-硝基苯甲醛和1.65克4′-硝基苯乙酮重复例8所述操作，得到1.25克(38％)产物，其熔点为255～256℃。
例77
----
3-(3-甲氧基-4-羟基-5-三氟甲基苯基)-1-(3，4，5-三甲氧基苯基)丙-2-烯-1-酮
用2.2克3-甲氧基-4-羟基-5-三氟甲基苯甲醛和2.1克3′，4′，5′-三甲氧基苯乙酮重复例8所述操作，得到2.6克(61％)产物，其熔点为190～192℃。
例78
----
4-(3，4-二甲氧基-5-甲基磺酰苯基)-3-甲基-丁-3-烯-2-酮
用2.44克3，4-二甲氧基-5-甲基磺酰苯甲醛和1.0克2-丁酮重复例8所述操作，得到2.0克(63％)粘性油状产物。
例79
----
2，5-双-(3，4-二羟基-5-硝基苯亚甲基)环戊酮
用5.0克3，4-二羟基-5-硝基苯甲醛和2.0克环戊酮重复例8所述操作，得到4.4克(78％)产品，其熔点为300℃(分解)。
例80
----
1-苯基-3-(3-硬脂酰氧基-4-羟基-5-硝基苯基)-丙-2-烯-1-酮
将2.0克例8中所得产物和10.0克硬脂酰氯加入10毫升二噁烷中，搅拌并在90℃加热18小时。冷却后加入石油醚，过滤产物，从二氯甲烷一石油醚中重结晶，得到0.64克(17％)所需产物，其熔点为112～118℃。
例81
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2-氰基-3-(3，4-二羟基-5-硝基苯基)丙烯酸乙酯
用10毫升含有1.0克3.4-二羟基-5-硝基苯甲醛，0.9克氰基乙酸乙酯和0.15克醋酸铵的乙醇溶液重复例4所述操作，得到0.87克(57％)产品，其熔点为205～210℃。
例82
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3-(3，4-二羟基-5-硝基苯亚甲基)-4-酮基戊酸甲酯
将10毫升含有1.83克3，4-二羟基-5-硝基苯甲醛和1.1克乙酰丙酸的甲醇溶液用气态氯化氢饱和。将该溶液回馏20小时，然后加入水，再用乙醚提取。减压蒸出溶剂，从乙醚-石油醚中结晶剩余物，得到0.54克(20％)产物，其熔点为142～150℃。
例83
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3，4-二羟基-5-硝基苄基丙二腈
室温下将1.5克硼氢化钠加入10毫升含有3.7克从例5中得到的产物的水中，并搅拌2个多小时，用盐酸酸化，再用乙醚提取。真空蒸出溶剂，从甲醇-异丙醇中结晶剩余物，得到1.1克(30％)产物，其熔点为211～215℃。
例84
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3，4-二羟基-5-硝基苄基氰基乙酸乙酯
用2.78克例81中得到的产物重复例83所述操作，得到0.98克(35％)产物，为黄色粘性油状。
例85
1-苯基-3-(3-甲氧基-4-羟基-5-三氟甲基苯基)丙-2-烯-1-酮
用1.7克3-甲氧基-4-羟基-5-三氟甲基苯甲醛和1.0克苯乙酮重复例8所述操作，得到1.1克(45％)产物，其熔点为166～168℃。
例86
1-苯基-3-(3，4-二羟基-5-三氟甲基苯基)-丙-2-烯-1-酮
将10毫升含有0.32克从例85中得到的产物的二氯甲烷溶液加入3毫升1摩尔的BBr3-CH2Cl2。将该混液在室温下搅拌20分钟，用10毫升2N盐酸酸化，再用二氯甲烷提取。减压蒸出溶剂，从丙酮-二氯甲烷中结晶剩余物，得到0.07克(23％)产品，其熔点为196～201℃。
例87
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3，4-二羟基-5-磺酰氨撑苯甲醛
将20毫升含1.89克2，3-二羟基苯-磺酰胺和1.4克六甲撑四胺的三氟乙酸溶液分馏2小时，真空蒸出溶剂，加水过滤产物，得到0.78克(35％)所需的产物。
例88
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2-甲氧基-6-三氟甲基酚
将160毫升溶在己烷中1.6摩尔的丁基锂溶液，300毫升四氢呋喃和40毫升N，N，N′，N′-四甲基二胺混合。将混液冷却到-78℃，在氮气下搅拌加入43.3克3-三氟甲基苯甲醚。将混液加热到室温再冷却至-78℃，然后加入35毫升三甲基硼酸酯。将混液加热至20℃，加入50毫升浓氨水。减压除去溶剂，向剩余物中加入60毫升98～100％甲酸，再加入25毫升35％过氧化氢。用醚—石油醚(1∶1)提取。分离出有机相，再用2.5当量氢氧化钠溶液提取。用盐酸酸化水相，再用二氯甲烷提取产物，真空除去大部分溶剂，然后加入石油醚。将结晶过滤，得到8.5克(18％)产品，其熔点51～53℃。
例89
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4-羟基-3-甲氧基-5-三氟甲基苯甲醛
将20毫升含1.9克2-甲氧基-6-三氟甲基酚和1.4克六撑四胺的四氟乙酸回馏1小时。减压除去溶剂，将50毫升1当量盐酸加入剩余物。用二氯甲烷提取该混合液。在真空中蒸出大部分溶剂，然后再加入石油醚，从而结晶出0.7克(32％)产品，其熔点151～152℃。
例90
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3，4-二甲氧基-5-氰基苯甲醛
将含2.5克3，4-二甲氧基-5-溴苯甲醛和1.0克氰化亚铜的N-甲基吡咯烷酮溶液回馏2小时，加水，再用二氯甲烷提取混合液。真空蒸出溶剂，得到1.55克(81％)产品，其熔点为109～112℃。
例91
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3，4-二羟基-5-氰基苯甲醛
将含0.96克上述产物的15毫升1摩尔的BBr3-CH2Cl2溶液在室温、氮气下搅拌4小时。加入15毫升1当量的盐酸。分出二氯甲烷相。真空蒸出溶剂，得到0.61克(75％)产品，其熔点为210～215℃。
例92
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2，3-二甲氧基-3-甲基磺酰基苯
边搅拌边向50毫升含有3.68克2，3-二甲氧基硫苯甲醚的二氯甲烷中加入3.6克3-氯过氧苯甲酸。在室温下连续搅拌18小时。再加入30毫升1当量的氢氧化钠溶液，分离出二氯甲烷相。真空蒸出溶剂，得到4.51克(91％)产品，为一种稠油状物。
例93
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3，4-二甲氧基-5-甲基磺酰基苯甲醛
用2.16克2，3-二甲氧基-3-甲基磺酰基苯和1.4克六亚甲基四胺，按例80步骤操作。得0.97g(45％)粘油。
例94
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3，4-二羟基-5-甲基磺酰基苯甲醛
将0.5克上述产物、5毫升48％氢溴酸和5毫升乙酸混合分馏8小时，加水。用二氯甲烷提取该混合液，真空蒸出溶剂，得到0.3克(68％)产品，为一种稠油状物。
例95
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3，4-二羟基-5-氰基苯甲醛
将20毫升含1.35克2，3-二羟基苯基氰和1.4克六甲撑四胺的三氟乙酸回馏1个半小时，加水，过滤所得产物，得到0.9克(55％)产品，其熔点为211～215℃。
例96
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3-(3，4-二羟基-5-三氟甲基苯基)-1-苯基丙-2-烯-1-酮
用2.06克3，4-二羟基-5-三氟甲基苯甲醛和1.20克苯乙酮重复例8所述的操作，得到2.19克(71％)产品，其熔点为196～210℃。
例97
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3，4-二羟基-5-三氟甲基苯甲醛
将含2.2克4-羟基-3-甲氧基-5-三氟甲基苯甲醛溶于65毫升1摩尔BBr3的二氯甲烷溶液中并在室温下搅拌2小时。加入盐酸，分离出有机相。真空蒸出溶剂，得到1.4克(68％)产品，其熔点为188～192℃。
例98
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2-氰基-3-(3，4-二羟基-5-硝基苯基)丙烯酰胺
将40毫升含1.3克3，4-二羟基-5-硝基-苯甲醛，0.73克氰基乙酰胺和催化量哌啶乙酸酯的无水乙醇回馏一夜，真空蒸出溶剂，从水-二甲胺甲苯酚(water-DMP)结晶出剩余物，得到产物0.84克(48％)，其熔点为296～298℃。
例99
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N，N-二甲基-2-氰基-3-(3，4-二羟基-5-硝基苯基)丙烯酰胺
将40毫升含有1.83克3，4-二羟基-5-硝基苯甲醛，1.2克N，N-二甲基氰基乙酰胺及催化量哌啶乙酸酯的无水乙醇回馏一夜，得到1.1克(40％)产物，其熔点为183～185℃。
例100
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N，N-二乙基-2-氰基-3-(3，4-二羟基-5-硝基苯基)-丙烯酰胺
用1.83克3，4-二羟基-5-硝基苯甲醛和1.5克N，N-二乙基氰基乙酰胺重复例99所述的操作，得到2.23克(73％)产品，其熔点为153～156℃。
例101
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N-异丙基-2-氰基-3-(3，4-二羟基-5-硝基苯基)-丙烯酰胺
用1.83克3，4-二羟基-5-硝基苯甲醛和1.3克N-异丙基氰基乙酰胺重复例99所述操作，得到产物1.46克(50％)，其熔点为243～245℃。
例102
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N′-甲基-N″-〔2-氰基-3-(3，4-二羟基-5-硝基苯基)-丙烯酰〕哌嗪
用1.83克3，4-二羟基-5-硝基苯甲醛和1.7克N′-甲基-N″-氰基乙酰基哌嗪重复例99所述的操作，得到2.16克(65％)产品，其熔点为265℃(分解)。
例103
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3-(3，4-二羟基-5-三氟甲基苯亚甲基)-2，4-戊二酮
用2.06克3，4-二羟基-5-三氟甲基-苯甲醛和1.00克2，4-戊二酮重复例7所述的操作，得到1.39克(45％)产品，其熔点为198～205℃。
例104
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3，4-二羟基-5-硝基苯甲醇
向50毫升含6.0克硼氢化钠水溶液在室温下搅拌加入9.15克3，4-二羟基-5-硝基苯甲醛。将混液搅拌1个多小时，然后用盐酸酸化。过滤除去残留杂质，再用乙醚提取4次。用无水硫酸钠干燥乙醚提取物，过滤，浓缩，得到约100毫升，滤出晶状固体，得到6.0克(65％)产品，其熔点为100℃(分解)。
例105
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3，4-二羟基-5-硝基苄基-2-甲氧基乙醚
将含1.0克3，4-二羟基-5-硝基甲醇的5.0毫升2-甲氧基乙醇回馏1小时，真空蒸出溶剂，用异丙醇粉化剩余物，得到0.4克(30％)产品，其熔点为154～157℃。
例106
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3，4-二羟基-5-硝基苄基硫代醋酸
将含1.0克3，4-二羟基-5-硝基苯甲醇的5克硫基醋酸在120℃下搅拌1个半小时，加入25毫升水，过滤，用水洗涤，得到0.25克(19％)产品，其熔点为91～93℃。
例107
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2，(3，4-二羟基-5-硝基苄基)吡咯
将含1.0克的3，4-二羟基-5-硝基苯甲醇加入5.0毫升吡咯中，再将混液加入3.0毫升的二噁烷中，在100℃加热上述混液5小时，加水，用氯甲烷提取，蒸出溶剂。在硅胶柱中纯化，用甲苯-乙酸-二噁烷(18∶1∶1)混合剂洗脱，得到0.42克(33％)产品，其熔点115～118℃。
例108
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2-氰基-3-(3，4-二羟基-5-硝基苯基)丙醇
向70毫升含0.85克2-氰基-3-(3，4-二羟基-5-硝基苯基丙烯酸乙酯(例81)的无水乙醇中缓缓加入0.3克硼氢化钠。室温下将混液搅拌半个小时，用盐酸酸化，再用乙酸乙酯提取，蒸出溶剂，得到0.55克(75％)黄色晶状产物，其熔点为149～152℃。
例109
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3-硝基儿茶酚
向含2.5克儿茶酚的125毫升的乙醚中缓缓加入10毫升浓硝酸(d＝1.52)。室温下搅拌过夜，用水洗涤，蒸出溶剂，用沸石油醚(沸点为60～80℃)处理剩余物，过滤去掉不溶的4-硝基儿茶酚，真空浓缩滤物，冷却后，将3-硝基儿茶酚过滤，得到0.85克(24％)，熔点82～85℃。
例110
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3，5-二硝基儿茶酚
向含50.0克儿茶酚二醋酸酯的250毫升醋酸缓缓加入125毫升硝酸(d＝1.42)。50℃下搅拌混液1个半小时以上，然后倾入碎冰中，过滤，用水洗涤，再将其溶在含1.0毫升浓硫酸的500毫升甲醇中。将混液回馏2.5小时。最大限度蒸出甲醇，加入100毫升水。真空蒸出残留甲醇，将剩下产物结晶，得到20.9克(40.4％)产品，其熔点为168～170℃。
例111
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3，4-二羟基-5-硝基苯甲醛
将含8.0千克5-硝基香草醛，8.7千克乙酸的35千克浓氢硼酸回馏20小时，加入0.6千克儿茶酚，过滤混液，边搅拌边加入32千克水。将溶液冷却到-10℃，连续搅拌2小时以上。过滤结晶，用水洗涤之，得到5.66千克(80％)产品，其熔点为135～137℃。
例112
3，4-二羟基-5-硝基苄腈
将含0.92克3，4-二羟基-5-硝基苯甲醛，0.49克盐酸羟胺的5.0毫升的甲酸回馏1小时，加入50毫升水，过滤产物，用水洗涤，得到0.3克(33％)所需产品，其熔点为175～178℃。
例113
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4-氯-6-硝基儿茶酚
将含1.0克4-氯-3-甲氧基-6-硝基苯酚的20毫升浓氢硼酸回馏2小时，冷却后，过滤，再用水洗涤，得到产品0.6克(65％)，其熔点108～111℃。
例114
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4，5-二羟基异苯二醛
将含1.8克4-羟基-5-甲氧基-异苯二醛的20毫升二氯甲烷加入35毫升溶于二氯甲烷的一摩尔的PBr液中。将混液于室温下放置过夜，倾入冰水中。真空蒸出二氯甲烷，冷却后，过滤产物，用水洗涤，得到0.94克(57％)产品，其熔点为192～195℃。
例115
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3，4-二羟基-5-氰基苯甲酸
向10毫升含2.3克4-乙酰氧基-3-氰基-5-甲氧基苯甲酸的二氯甲烷中加入40毫升1摩尔的PBr和二氯甲烷混合液，室温下将混合液搅拌过夜。真空除去溶剂。向剩余物中加入冰水，过滤产物，用水洗涤，得到1.25克(74％)产物，其熔点为269～271℃。
例116
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3，4-二羟基-5-硝基苯丙氨酸氢溴酸盐
将10毫升含1.2克4-羟基-3-甲氧基-5-硝基苯丙氨酸硫酸氢盐的浓氢溴酸回馏2小时，真空浓缩，在冰箱中静置过夜。过滤，用氢溴酸洗涤，干燥，得到0.25克产品，其熔点为170℃(分解)。
例117
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3，5-二氰基儿茶酚
将30毫升含0.83克3，5-二甲酰儿茶酚和0.90克盐酸羟胺的甲酸回馏16小时。真空除去甲酸，向剩余物中加入水，用乙醚提取。蒸出溶剂，从乙醇-水中结晶剩余物，得到0.28克(43％)产物，其熔点为300℃(分解)
例118
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N，N-二乙基-5-氯-2，3-二羟基苯磺酰胺
将10毫升含0.7克N，N-二乙基-5-氯-3，4-二乙基苯磺酰胺的二氯甲烷加入9.0毫升含1摩尔BBr的二氯甲烷中。混液在室温下搅拌过夜。加水和盐酸，用二氯甲烷提取混液，蒸出溶剂，得到0.3克(47％)产物，其熔点为62～64℃。
例119
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4-氯-6-甲基磺酰基儿茶酚
用4-氯-2甲氧基-6-甲基磺酰基苯酚重复例118所述的操作，得到50％产品，其熔点142～145℃。
例120
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4-硝基-6-甲基磺酰基儿茶酚
用2-甲氧基-4-硝基-6-甲基磺酰苯酚重复例118所述的操作，得到21％产品，其熔点为221～224℃。
例121
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3，4-二羟基-5-甲基磺酰基苯甲醛
用4-羟基-3-甲氧基-5-甲基磺酰苯甲醛重复例118所述操作，得到17％产物，其熔点为169～171℃。
例122
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N-(3-羟基丙基)-3，4-二羟基-5-硝基苯酰胺
用3，4-二乙酰氧基-5-硝基苯甲酸和3-氨基丙烷-1-醇重复例43和44所述操作，得到85％产物，其熔点为160～163℃。
例123
----
2-氰基-3-(3，4-二羟基-5-硝基苯基)-丙烯酸新戊酯
用3，4-二羟基-5-硝基苯甲醛和氰基乙酸新戊酯重复例4所述操作，得到67％产物，其熔点为173～179℃。
例124
----
N-(3-羟基丙基)-2-氰基-3-(3，4-二羟基-5-硝基苯基)丙烯酰胺
用N-(3-羟基丙基)氰基乙酰胺和3，4-二羟基与一硝基苯甲醛重复例99所述操作，得到52％的产物，其熔点为223～228℃。
例125
----
2，3-二羟基-5-硝基苄腈
用2-羟基-3-甲氧基-5-硝基苄腈重复例118所述的操作，得到45％的产物。
例126
----
3，5-二氰基儿茶酚
向含2，4-二氰基-6-甲氧基苯酚的20毫升二氯甲烷溶液中加入20毫升含1摩尔BBr溶液的二氯甲烷。将混合液在室温下搅拌过夜，加入水和盐酸，再用二氯甲烷提取该混合液，蒸出溶剂，得到0.8克(50％)产物，其熔点为300℃(分解)。
例127
----
1，2-二乙酰氧基-3，5-二硝基苯
将催化量的浓硫酸加入15毫升含2.0克3，5-二硝基儿茶酚的醋酸酐溶液，混合液在50～60℃下混合半小时，加入冰水，使其在0℃下结晶，过滤产物，用水洗涤，再干燥，得到2.75克(97％)产物，其熔点为115～117℃。
例128
----
1，2-二丙酰氧基-3，5-二硝基苯
用丙酸酐代替醋酸酐重复127所述的操作，得到2.8克(90％)产物，其熔点为72～73℃。
例129
----
1，2-二丁酰氧基-3，5-二硝基苯
用丁酸酐代替醋酸酐重复例127所述的操作，得到70％产物，其熔点为55～60℃。
例130
----
2-丁酰氧基-4，6-二硝基苯酚
将8.7毫升硝酸(d＝1.42)边搅拌边冷却加入25毫升含2.4克儿茶酚二丁酸酯的醋酸中，将混合液继续搅拌半小时，加入冰水，过滤，用水洗涤之，得到1.85克(53％)的产物，其熔点为65～70℃。
例131
----
2-三甲基乙酰氧基-4，6-二硝基苯酚
将6.7毫升硝酸(d＝1.42)边搅拌边冷却(20～25℃)加入20毫升含有1.94克儿茶酚单三甲基乙酸酯的醋酸中，将混合液在50℃搅拌半小时，加入冰水，过滤，再用水洗涤，得到1.75克(62.5％)产物，其熔点为132～135℃。
例132
----
2-苯甲酰氧基-4，6-二硝基苯酚
将5毫升含有2.0克3，5-二硝基儿茶酚的苯甲酰氯在100℃煮4小时，加入冷石油醚(沸点为40℃)，过滤产品，再用石油醚洗涤，从乙醇中结晶粗产品，得到2.5克(82％)产物，熔点150～152℃。
例133
----
3-(4-羟基-5-硝基-3-三甲基乙酰氧基苯亚甲基)-2，4-戊烷二酮
将5毫升含2.0克从例7中所得产物的三甲基乙酰氯溶液在100℃加热4小时，减压蒸出多余的三甲基乙酰氯，加入乙醚，过滤，用乙醚洗涤，得到1.41克(58％)产物，其熔点为143～145℃。
例134
----
2-(2，6-二甲基苯甲酰氧基)4，6-二硝基苯酚
将5毫升含2.0克3，5-二硝基儿茶酚的2，6-二甲基苯甲酰氯在100℃加热20小时，高真空下除去过剩的2，6-二甲基苯甲酰氯。将剩余物在硅胶柱中纯化，得到1.5克(4.5％)黄稠油状物，再用石油醚结晶，其熔点为163～165℃。
例135
----
2-(2，6-二甲氧基苯甲酰氧基)-4，6-二硝基苯酚
用2，6-二甲氧基苯甲酰氯重复例134所述的操作，得到1.3克(36％)产物，其熔点217～218℃。
例136
----
2-(1-甲基环己基羰基氧基)-4，6-二硝基苯酚
用1-甲基环己酰氯重复例134所述的操作，得到1.6克(49％)黄色稠油状物。
例137
----
1，2-双(2，6-二甲基苯甲酰氧基)-3，5-二硝基苯
用134℃重复例134所述的操作，得到产品用50％乙醇结晶，得60％产物，其熔点175～178℃。
例138
----
1，2-双(3-乙氧基羰基丙酰氧基)-3，5-二硝基苯
将2.5毫升含1克3，5-二硝基儿茶酚的丁二酸单乙酯单酰氯在100℃加入3小时，将产物在硅胶柱中纯化，其产物熔点为60～63℃。

Claims (6)

1.制备如下结构式I所示的新的药理活性儿茶酚衍生物的方法，
Figure C8710801100021
其中R1和R2分别代表氢、C1-8烷基氨基甲酰基、C1-8烷基羰基或苯甲酰基，
X代表卤素、硝基或氰基，
R3代表
-CH＝CR4R5
其中R4代表氢、C1-4烷基、氰基或C1-4烷基羰基，R5代表氰基、C1-4烷氧羰基、硝基、C1-4烷基羰基、C1-4羟烷基或COZ，其中Z为可被C1-8烷基或C1-8羟烷基取代的氨基甲酰基；被C1-8烷基取代的哌啶基或可被C1-3烷氧基、羟基、羧基或硝基取代的苯基；
该方法包括将一个结构式为II的化合物和结构式为III的化合物在碱或酸催化反应中缩合得到结构式为Ia的化合物，
Figure C8710801100022
其中R1、R2和X的定义同上，
结构式为III的化合物具有一个活性甲基或亚甲基，且其中R4和R5的定义同上，
结构式Ia化合物中各取代基的定义同前。
2.根据权利要求1所述的方法，其中所制备的化合物为3-(3，4-二羟基-5-硝基-亚苄基)-2，4-戊二酮。
3.根据权利要求1所述的方法，其中所制备的化合物为2-氰基-3-(3，4-二羟基-5-硝基苯基)丙烯酰胺。
4.根据权利要求1所述的方法，其中所制备的化合物为N，N
二甲基-2-氰基-3-(3，4-二羟基-5-硝基苯基)-丙烯酰胺。
5.根据权利要求1所述的方法，其中所制备的化合物为N，N-二乙基-2-氰基-3-(3，4-二羟基-5-硝基苯基)丙烯酰胺。
6.根据权利要求1所述的方法，其中所制备的化合物为N-异丙基-2-氰基-3-(3，4-二羟基-5-硝基苯基)丙烯酰胺。
CN87108011A 1986-11-28 1987-11-26 新的药理活性儿茶酚衍生物的制备方法 Expired - Lifetime CN1040062C (zh)

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