PFP结构类似物的化学合成和催眠活性研究
摘要
E)-dimethyl 5,5'-(but-1-ene-1,3-diyl)bis(4-methylnicotinate)(PFP)，是本课题组从茉莉根中分离得到的一个新吡啶类生物碱。初步的催眠活性评价显示，该化合物能够显著延长戊巴比妥钠诱导的小鼠睡眠时间。但该化合物在茉莉根中含量很低，难于大量制备。为了进一步研究PFP结构类似物的生物活性，需要研究该化合物及其结构类似物的化学合成方法，以寻找有开发前景的先导化合物。
对PFP进行全合成主要面临两个问题，其一是如何构建PFP分子中的3,4,5-三取代吡啶环。吡啶环上发生芳香亲电取代反应时，通常需要苛刻的反应条件且产率很低，并且吡啶环上不能发生傅克反应。吡啶环虽然较容易发生亲核取代反应，但反应主要发生在吡啶环的α或γ碳上。因而吡啶环形成后很难通过取代反应在适当的位置引入取代基。为此我们考虑先将不同的取代基引入到构建吡啶环所需的前体化合物中，然后再关环得到不同取代的吡啶环。以往报道的吡啶环合成方法中，一个较好的方法是以适当取代的乙酰乙酸乙酯衍生物与氰基乙酰胺缩合得到一个3,4,5位三取代的吡啶环，然后通过官能团转换，将3,4,5位的取代基转化成PFP分子中的取代基团。PFP合成中的另一个问题是，两个吡啶环之间有一个反式碳碳双键，需要考虑到合成方法对双键几何构型和位置的选择性。由于双键邻位有一个叔碳原子，如果采用卤代烃或醇的消除反应来制备该双键，反应将主要生成热力学更稳定的产物，双键会连接在叔碳上。所以我们选择Wittig-Horner反应来制备碳碳双键。一般认为Wittig-Horner试剂的位置选择性较好，且产物主要为E-构型。
逆合成分析显示，PFP可拆分为Wittig-Horner反应的两个前体化合物，一部分为醛，即4-甲基-5-（1-甲酰基乙基）尼古丁腈（08）；另一部分为膦酸酯，即4-甲基-5-氰基吡啶-3-甲基膦酸二乙酯（16）。为合成化合物08，我们进行了以下尝试：
（1）将2-溴乙基甲基醚与乙酰乙酸乙酯缩合，得到α-(β-甲氧基乙基)-乙酰乙酸乙酯，再与氰基乙酰胺缩合得到了2,6-二羟基-3-氰基-5-（2-甲氧基乙基）-4-甲基吡啶（01）。原计划将化合物01经过酚羟基的氯代、还原脱氯、断裂醚键再经氧化反应转化为一个醛类化合物4-甲基-5-乙醛基尼古丁腈（07），化合物07的亚胺衍生物经甲基化即可得到关键中间体08。但实验中化合物01酚羟基的氯代反应在多种反应条件下均未能实现。
（2）将α-乙酰-γ-丁内酯与氰基乙酰胺缩合得到4-甲基-5-（2-羟乙基）-2,6-二羟基尼古丁腈（03），氯代后得到4-甲基-5-（2-氯乙基）-2,6-二氯尼古丁腈（04），选择性脱去吡啶环上的氯原子得到4-甲基-5（- 2-氯乙基）尼古丁腈（05），将05与KI在丙酮中反应希望得到碘代产物4-甲基-5-（2-碘乙基）尼古丁腈（06），然后利用DMSO将06氧化为07并进一步转化为08。但化合物05的碘代反应未生成化合物06，而是定量地转变为4-甲基-5-乙烯基尼古丁腈（09）。
（3）尝试将化合物05和甲酸钠反应成酯，再经水解、氧化得到化合物07，但是在与甲酸钠的反应中，化合物05同样定量的转变为化合物09。
（4）化合物09经羟汞化-还原反应得到了4-甲基-5-（1-羟乙基）尼古丁腈（10），氧化得到4-甲基-5-乙酰基尼古丁腈（11），通过Wittig反应制成烯醇醚4-甲基-5-（1-甲基-2-甲氧基乙烯基）尼古丁腈（12），12经酸水解有可能得到中间体08。但是其中的羟汞化-还原反应在多种反应条件下产率都较低，仅少数时候能达到40%，并且该反应的重复性很差。
（5）通过臭氧化反应将化合物09转化为4-甲基-5-甲酰基尼古丁腈（13），化合物13与甲基溴化镁反应制得化合物10，氧化得到化合物11，通过Wittig反应制成烯醇醚12，12经酸水解得到关键中间体08。
在此基础上，以化合物13为原料，经过还原、氯代、膦酸酯化三步反应，成功制得了另一个关键中间体16。
化合物08和16通过Wittig-Horner反应进行连接时，在各种常用的反应条件下，烯烃产物的产率均低于5%。当在反应体系中加入DMPU作为共溶剂时，反应产率提高到60%。在把产物中的氰基转化为酯基时，亦曾尝试了各种可能的途径，但是无论在酸性条件下还是碱性条件下，双键都会发生移位，主要得到热力学上更稳定的三取代双键产物，只有在碱性条件下才会生成极少量的目标产物PFP。上述结果显示，PFP的稳定性较差，由于其分子中与吡啶环相连的次甲基质子较活泼，其双键极易转移到叔碳上。
采用增加小鼠戊巴比妥钠睡眠时间的方法对所得的六个PFP类似物进行活性评价，评价结果显示：5,5′- [(Z)-1-丁烯-1,3-二取代]双(4-甲基尼古丁腈)（18）和5,5′- [(E)-2-丁烯-1,3-二取代]双(4-甲基尼古丁腈)（19）具有明显的催眠活性。
(E)-dimethyl 5,5'-(but-1-ene-1,3-diyl)bis(4-methylnicotinate)(PFP) is a newpyridine alkaloid isolated from the root of Jasminum sambac (L.) Aiton by our group.Preliminary hypnotic evaluation showed that PFP significantly prolonged thepentobarbital sodium induced sleeping time in mice. However, preparation of thiscompound is difficult because of its low content in the original plant. Thus, it isnecessary to develop a synthetic method for preparation of PFP and its structuralanalogues in order to find potential lead compound.
There are two major issues in the total synthesis of PFP. The first is how to formthe 3,4,5-trisubstituted pyridine ring. Pyridine ring occur aromatic electrophilicsubstitution on very harsh reaction conditions and with low yields. Furthermore,pyridine ring can’t occur Friedel-Crafts reaction. Pyridine ring is prone to occurnucleophilic substitution but mainly at theα- orγ-C of pyridine ring. So it is verydifficult to add substituting groups at proper site of the pyridine moiety by substitutionreactions. For this reason, it is better to prepare precursors which carry appropriatesubstituting groups and then create the pyridine ring by cyclization reaction. Accordingto the known synthetic methods for pyridine derivatives, a feasible approach is tocondense an appropriate substituted acetylacetic ester with cyanoacetamide to afford amultiple substituted pyridine derivative, which can be converted into the3,4,5-trisubstituted pyridine moiety in PFP by modifying the functional groups. Theother issue in the synthesis of PFP is that there is a trans carbon-carbon double bond inthe molecule, and adjacent to the double bond is a tertiary carbon. The double bond cannot be established by elimination reactions since it will shift to the tertiary carbon toform the thermodynamically more stable product. Therefore, Wittig-Horner reaction ischosen for creation of the double bond, since it is known to have relatively higher position and stereo selectivities, the products have the tendency to form E-configuration.
Retrosynthetic analysis show that the structure of PFP can be divided into twoprecursors of Wittig-Horner reaction, one is an aldehyde, that is, 4-methy-5-(1-oxopropan-2-yl)-nicotinonitrile (08), and the other is a phosphonate ester, that is,diethyl- (5-cyano-4-methylpyridin-3-yl)-methylphosphonate (16). For the synthesis of08, following steps were carried out:
(1) Reaction of 1-bromo-2-methoxyethane with ethyl acetoacetate to give ethylα-(β-methoxyethyl)-acetoacetate, then condense with cyanoacetamide to afford2,6-dihydroxy-3-cyano-5-(2-methoxyethyl)-4-methylpyriding (01). Chlorination of thephenolic hydroxyls of 01 followed by selective dechlorination, cleavage of the etherbond and oxidation of the aliphatic hydroxyl can afford 4-methy-5-(1-oxoethyl)nicotinonitrile (07). Methylation of an imine derivative of 07 would givethe key intermediate 08. However, chlorination of the phenol groups of 01 was failedeven if most of the common chlorination conditions have been tried.
(2)α-Acetyl-γ-butyrolactone was reacted with cyanoacetamide to give2,6-dihydroxy-5-(2-hydroxyethyl)-4-methylnicotinonitrile (03). Chlorination of 03 give2,6-dichloro-5-(2-chloroethyl)-4-methylnicotinonitrile (04). Selective removal thechlorines on the pyridine ring afforded 5-(2-chloroethyl)-4-methylnicotinonitrile (05)which is subjected to KI in acetone in order to get5-(2-iodoethyl)-4-methylnicotinonitrile (06). It was planed to oxidize 06 with DMSO toform 07, and then transform it into 08. But the iodination of 05 have not given theaimed compound 06 but 4-methyl-5-vinylnicotinonitrile (09) in nearly quantitativeyield.
(3) Compound 05 was let to react with sodium formate to form a formate ester,which would be transformed into compound 07 by hydrolyzation and oxydation. But thereaction of 05 with sodium formate also led to compound 09 quantitatively.
(4) Compound 09 was converted into 5-(1-hydroxyethyl)-4-methylnicotinonitrile(10) by hydroxy mercury-reduction reaction and then oxidized to 5-acetyl-4-methylnicotinonitrile (11). Compound 11 was converted to the enol ether(E)-5-(1-methoxyprop-1-en-2-yl)-4-methylnicotinonitrile (12) by wittig reaction.Compound 12 was hydrolyzed to the key intermediate 08. In this course, the yield of thehydroxyl mercury-reduction reaction was very low and hard to reduplicate even if thereaction condition was carefully controlled.
(5) Compound 09 was converted to 5-formyl-4-methylnicotinonitrile (13) throughozonation. The reaction of 13 with methylmagnesium bromide gave 10 which was thenoxidized to 11. Compound 11 was converted to the enol ether 12 by Wittig reaction andthen hydrolyzed to the key intermediate 08 in excellent yield.
Started from compound 13, the other key intermediate 16 was obtained viareduction, chlorination and Arbuzov rearrangement reaction.
To connect the key intermediates 08 and 16 by Wittig-Horner reaction, most of thecommon conditions of Wittig-Horner reaction have been tested, but the yield of olefinproducts was less than 5%. The yield of olefin products increased to 60% only whenDMPU was added to the reaction system as a co-solvent. In the process of transformingthe cyano group into an ester group, the olefin bond translocated to the tertiary carbon,forming predominant products with a thermodynamicly more stable trisubstituteddouble bond, whether under acidic or alkaline conditions. Only alkaline conditionsafforded a very small amount of target product PFP. This result revealed that PFP isquite unstable. Because the proton of the methine group connecting with the pyridinering is relatively active, the double bond is very easy to shift to the tertiary carbon.
The hypnotic activity of six PFP analogues have been evaluated by thepentobarbital sodium induced sleeping time test in mice. Compound 18 and 19 showedsignificant hypnotic activity, comparable to that of PFP.
对PFP进行全合成主要面临两个问题，其一是如何构建PFP分子中的3,4,5-三取代吡啶环。吡啶环上发生芳香亲电取代反应时，通常需要苛刻的反应条件且产率很低，并且吡啶环上不能发生傅克反应。吡啶环虽然较容易发生亲核取代反应，但反应主要发生在吡啶环的α或γ碳上。因而吡啶环形成后很难通过取代反应在适当的位置引入取代基。为此我们考虑先将不同的取代基引入到构建吡啶环所需的前体化合物中，然后再关环得到不同取代的吡啶环。以往报道的吡啶环合成方法中，一个较好的方法是以适当取代的乙酰乙酸乙酯衍生物与氰基乙酰胺缩合得到一个3,4,5位三取代的吡啶环，然后通过官能团转换，将3,4,5位的取代基转化成PFP分子中的取代基团。PFP合成中的另一个问题是，两个吡啶环之间有一个反式碳碳双键，需要考虑到合成方法对双键几何构型和位置的选择性。由于双键邻位有一个叔碳原子，如果采用卤代烃或醇的消除反应来制备该双键，反应将主要生成热力学更稳定的产物，双键会连接在叔碳上。所以我们选择Wittig-Horner反应来制备碳碳双键。一般认为Wittig-Horner试剂的位置选择性较好，且产物主要为E-构型。
逆合成分析显示，PFP可拆分为Wittig-Horner反应的两个前体化合物，一部分为醛，即4-甲基-5-（1-甲酰基乙基）尼古丁腈（08）；另一部分为膦酸酯，即4-甲基-5-氰基吡啶-3-甲基膦酸二乙酯（16）。为合成化合物08，我们进行了以下尝试：
（1）将2-溴乙基甲基醚与乙酰乙酸乙酯缩合，得到α-(β-甲氧基乙基)-乙酰乙酸乙酯，再与氰基乙酰胺缩合得到了2,6-二羟基-3-氰基-5-（2-甲氧基乙基）-4-甲基吡啶（01）。原计划将化合物01经过酚羟基的氯代、还原脱氯、断裂醚键再经氧化反应转化为一个醛类化合物4-甲基-5-乙醛基尼古丁腈（07），化合物07的亚胺衍生物经甲基化即可得到关键中间体08。但实验中化合物01酚羟基的氯代反应在多种反应条件下均未能实现。
（2）将α-乙酰-γ-丁内酯与氰基乙酰胺缩合得到4-甲基-5-（2-羟乙基）-2,6-二羟基尼古丁腈（03），氯代后得到4-甲基-5-（2-氯乙基）-2,6-二氯尼古丁腈（04），选择性脱去吡啶环上的氯原子得到4-甲基-5（- 2-氯乙基）尼古丁腈（05），将05与KI在丙酮中反应希望得到碘代产物4-甲基-5-（2-碘乙基）尼古丁腈（06），然后利用DMSO将06氧化为07并进一步转化为08。但化合物05的碘代反应未生成化合物06，而是定量地转变为4-甲基-5-乙烯基尼古丁腈（09）。
（3）尝试将化合物05和甲酸钠反应成酯，再经水解、氧化得到化合物07，但是在与甲酸钠的反应中，化合物05同样定量的转变为化合物09。
（4）化合物09经羟汞化-还原反应得到了4-甲基-5-（1-羟乙基）尼古丁腈（10），氧化得到4-甲基-5-乙酰基尼古丁腈（11），通过Wittig反应制成烯醇醚4-甲基-5-（1-甲基-2-甲氧基乙烯基）尼古丁腈（12），12经酸水解有可能得到中间体08。但是其中的羟汞化-还原反应在多种反应条件下产率都较低，仅少数时候能达到40%，并且该反应的重复性很差。
（5）通过臭氧化反应将化合物09转化为4-甲基-5-甲酰基尼古丁腈（13），化合物13与甲基溴化镁反应制得化合物10，氧化得到化合物11，通过Wittig反应制成烯醇醚12，12经酸水解得到关键中间体08。
在此基础上，以化合物13为原料，经过还原、氯代、膦酸酯化三步反应，成功制得了另一个关键中间体16。
化合物08和16通过Wittig-Horner反应进行连接时，在各种常用的反应条件下，烯烃产物的产率均低于5%。当在反应体系中加入DMPU作为共溶剂时，反应产率提高到60%。在把产物中的氰基转化为酯基时，亦曾尝试了各种可能的途径，但是无论在酸性条件下还是碱性条件下，双键都会发生移位，主要得到热力学上更稳定的三取代双键产物，只有在碱性条件下才会生成极少量的目标产物PFP。上述结果显示，PFP的稳定性较差，由于其分子中与吡啶环相连的次甲基质子较活泼，其双键极易转移到叔碳上。
采用增加小鼠戊巴比妥钠睡眠时间的方法对所得的六个PFP类似物进行活性评价，评价结果显示：5,5′- [(Z)-1-丁烯-1,3-二取代]双(4-甲基尼古丁腈)（18）和5,5′- [(E)-2-丁烯-1,3-二取代]双(4-甲基尼古丁腈)（19）具有明显的催眠活性。
(E)-dimethyl 5,5'-(but-1-ene-1,3-diyl)bis(4-methylnicotinate)(PFP) is a newpyridine alkaloid isolated from the root of Jasminum sambac (L.) Aiton by our group.Preliminary hypnotic evaluation showed that PFP significantly prolonged thepentobarbital sodium induced sleeping time in mice. However, preparation of thiscompound is difficult because of its low content in the original plant. Thus, it isnecessary to develop a synthetic method for preparation of PFP and its structuralanalogues in order to find potential lead compound.
There are two major issues in the total synthesis of PFP. The first is how to formthe 3,4,5-trisubstituted pyridine ring. Pyridine ring occur aromatic electrophilicsubstitution on very harsh reaction conditions and with low yields. Furthermore,pyridine ring can’t occur Friedel-Crafts reaction. Pyridine ring is prone to occurnucleophilic substitution but mainly at theα- orγ-C of pyridine ring. So it is verydifficult to add substituting groups at proper site of the pyridine moiety by substitutionreactions. For this reason, it is better to prepare precursors which carry appropriatesubstituting groups and then create the pyridine ring by cyclization reaction. Accordingto the known synthetic methods for pyridine derivatives, a feasible approach is tocondense an appropriate substituted acetylacetic ester with cyanoacetamide to afford amultiple substituted pyridine derivative, which can be converted into the3,4,5-trisubstituted pyridine moiety in PFP by modifying the functional groups. Theother issue in the synthesis of PFP is that there is a trans carbon-carbon double bond inthe molecule, and adjacent to the double bond is a tertiary carbon. The double bond cannot be established by elimination reactions since it will shift to the tertiary carbon toform the thermodynamically more stable product. Therefore, Wittig-Horner reaction ischosen for creation of the double bond, since it is known to have relatively higher position and stereo selectivities, the products have the tendency to form E-configuration.
Retrosynthetic analysis show that the structure of PFP can be divided into twoprecursors of Wittig-Horner reaction, one is an aldehyde, that is, 4-methy-5-(1-oxopropan-2-yl)-nicotinonitrile (08), and the other is a phosphonate ester, that is,diethyl- (5-cyano-4-methylpyridin-3-yl)-methylphosphonate (16). For the synthesis of08, following steps were carried out:
(1) Reaction of 1-bromo-2-methoxyethane with ethyl acetoacetate to give ethylα-(β-methoxyethyl)-acetoacetate, then condense with cyanoacetamide to afford2,6-dihydroxy-3-cyano-5-(2-methoxyethyl)-4-methylpyriding (01). Chlorination of thephenolic hydroxyls of 01 followed by selective dechlorination, cleavage of the etherbond and oxidation of the aliphatic hydroxyl can afford 4-methy-5-(1-oxoethyl)nicotinonitrile (07). Methylation of an imine derivative of 07 would givethe key intermediate 08. However, chlorination of the phenol groups of 01 was failedeven if most of the common chlorination conditions have been tried.
(2)α-Acetyl-γ-butyrolactone was reacted with cyanoacetamide to give2,6-dihydroxy-5-(2-hydroxyethyl)-4-methylnicotinonitrile (03). Chlorination of 03 give2,6-dichloro-5-(2-chloroethyl)-4-methylnicotinonitrile (04). Selective removal thechlorines on the pyridine ring afforded 5-(2-chloroethyl)-4-methylnicotinonitrile (05)which is subjected to KI in acetone in order to get5-(2-iodoethyl)-4-methylnicotinonitrile (06). It was planed to oxidize 06 with DMSO toform 07, and then transform it into 08. But the iodination of 05 have not given theaimed compound 06 but 4-methyl-5-vinylnicotinonitrile (09) in nearly quantitativeyield.
(3) Compound 05 was let to react with sodium formate to form a formate ester,which would be transformed into compound 07 by hydrolyzation and oxydation. But thereaction of 05 with sodium formate also led to compound 09 quantitatively.
(4) Compound 09 was converted into 5-(1-hydroxyethyl)-4-methylnicotinonitrile(10) by hydroxy mercury-reduction reaction and then oxidized to 5-acetyl-4-methylnicotinonitrile (11). Compound 11 was converted to the enol ether(E)-5-(1-methoxyprop-1-en-2-yl)-4-methylnicotinonitrile (12) by wittig reaction.Compound 12 was hydrolyzed to the key intermediate 08. In this course, the yield of thehydroxyl mercury-reduction reaction was very low and hard to reduplicate even if thereaction condition was carefully controlled.
(5) Compound 09 was converted to 5-formyl-4-methylnicotinonitrile (13) throughozonation. The reaction of 13 with methylmagnesium bromide gave 10 which was thenoxidized to 11. Compound 11 was converted to the enol ether 12 by Wittig reaction andthen hydrolyzed to the key intermediate 08 in excellent yield.
Started from compound 13, the other key intermediate 16 was obtained viareduction, chlorination and Arbuzov rearrangement reaction.
To connect the key intermediates 08 and 16 by Wittig-Horner reaction, most of thecommon conditions of Wittig-Horner reaction have been tested, but the yield of olefinproducts was less than 5%. The yield of olefin products increased to 60% only whenDMPU was added to the reaction system as a co-solvent. In the process of transformingthe cyano group into an ester group, the olefin bond translocated to the tertiary carbon,forming predominant products with a thermodynamicly more stable trisubstituteddouble bond, whether under acidic or alkaline conditions. Only alkaline conditionsafforded a very small amount of target product PFP. This result revealed that PFP isquite unstable. Because the proton of the methine group connecting with the pyridinering is relatively active, the double bond is very easy to shift to the tertiary carbon.
The hypnotic activity of six PFP analogues have been evaluated by thepentobarbital sodium induced sleeping time test in mice. Compound 18 and 19 showedsignificant hypnotic activity, comparable to that of PFP.
引文
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