CN105541702B - 类卢扎朵仑结构的芳胺基烷基硫类化合物及其制备方法 - Google Patents

类卢扎朵仑结构的芳胺基烷基硫类化合物及其制备方法 Download PDF

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CN105541702B
CN105541702B CN201610055025.0A CN201610055025A CN105541702B CN 105541702 B CN105541702 B CN 105541702B CN 201610055025 A CN201610055025 A CN 201610055025A CN 105541702 B CN105541702 B CN 105541702B
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朱其明
原庆贺
陈烨
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Abstract

一种类卢扎朵仑结构的芳胺基烷基硫类化合物及其制备方法，该化合物是将Ar1‑X1、通式Ⅲ所表示的化合物、Ar2‑X2及硫源加入到溶剂中，按反应式(1)加热反应完全后得到；或者是将Ar1‑X1、通式Ⅲ所表示的化合物及Ar2‑S‑M+加入到溶剂中，按反应式(2)加热反应完全后得到。本方法操作简单高效，反应条件温和，所用到的试剂廉价易得，安全性强，适于工业化大生产。

Description

类卢扎朵仑结构的芳胺基烷基硫类化合物及其制备方法
技术领域
本发明属于医药化学技术领域，具体涉及一类与卢扎朵仑结构类似的芳胺基烷基硫化合物及其制备方法。
背景技术
芳胺基烷基硫类衍生物是一类重要的化合物，许多该结构的衍生物具有药效活性。6-(4-(2-苯基硫乙基)-1-哌嗪基)-3-(2H)-哒嗪酮及其芳胺基烷基硫类衍生物具有α1-肾上腺素受体拮抗作用的(Bioorg Med Chem Lett.1999,7,2615-2620)；1-(2-甲氧基苯基)-4-(2-(5-甲氧基-1,2,3,4-四氢萘酚-1-基)硫)乙基)哌嗪及其芳胺基烷基硫类衍生物具有低IC50值，高5-HT(A1)选择性抗抑郁作用(J.Med.Chem.1995,38,942-949)；2-(4-(4-(2-嘧啶基)-l-哌嗪基)丁酰胺基)-4,5-二甲基-3-噻吩及其芳胺基烷基硫类衍生物具有选择性5-HT4受体拮抗作用的芳胺基烷基硫类衍生物(Eur J Med Chem.2001,36,287-301)。
芳胺基烷基硫类衍生物具有广阔的应用前景。此类化合物传统的合成工艺涉及多步合成与转化，包括胺基的保护与脱保护(J.Org.Chem.1980,45,4519)；芳基卤的胺化；羟基的卤代(Chem.Pharm.Bull.,1991,39,1753-1759)；芳基烷基硫醚的合成等过程。芳基烷基硫醚类化合物的合成通常采用过渡金属催化的芳基卤化物与烷基硫醇(Org.Lett.2002,4,2803-2806)或芳基卤化物与过硫化物(J.Org.Chem.2007,72,1241-1245)的偶联反应；其中还包括硫脲或硫代乙酸盐作为硫源，过渡金属催化芳基卤化物反应与烷基卤化物(Adv.Synth.Catal.2010,352,119-124；J.Org.Chem.2011,76,4371-4378)的偶联反应。
传统的合成工艺使用保护基策略，增加了合成步骤，不仅导致合成效率低下，而且造成了资源的浪费；芳基烷基硫醚的合成步骤通常需要使用过渡金属做催化剂，反应条件苛刻，这就造成了工艺成本高，操作繁琐，而且过渡金属的使用，可能会导致合成的产物中重金属残留。
发明内容
本发明的目的是提供一种类卢扎朵仑结构的芳胺基烷基硫类化合物及其制备方法，该方法工艺路线简短，不需过渡金属催化剂，操作简单高效，所用试剂廉价易得，成本低，适合工业化生产。
为达上述目的，本发明采用的技术方案是：具有下述通式的化合物
其中，表示为一根化学键或者没有化学键；
Ar1为通式A所表示的基团或者通式B所表示的基团，
通式A中：
当Z、Q、M皆为C时，R1为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基或卤素，位于X1的邻位或对位；R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z为N，Q、M为C时，R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z、Q为N，M为C时，R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z为C，Q、M为N时，R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z、M为N，Q为C时，R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
通式B中：
当Z、Q、M皆为C时，R1为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基或卤素，位于X1的邻位或对位；R2、R'、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z为N，Q、M为C时，R1、R2、R'分别为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R3不存在；
当Z、Q为N，M为C时，R1、R'分别为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R2和R3不存在；
当Z为C，Q、M为N时，R1、R'分别为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R2和R3不存在；
当Z、M为N，Q为C时，R1、R'分别为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R2和R3不存在；
n为0～5的正整数；
Y选自碳、氮、氧或硫原子；
R选自C1～C10的烷烃基或C1～C20芳基取代的烷基；
Ar2为通式C或者通式D或者通式E所表示的基团，
通式C中：Z、Q、M选自碳或氮；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
通式D中：Z、Q、M选自碳或氮；R1、R2、R3、R'为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
通式E中：R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基。
上述化合物是将Ar1-X1、通式Ⅲ的化合物、Ar2-X2、及硫源加入到溶剂中，按反应式(1)加热反应完全后得到；或者是将Ar1-X1、通式Ⅲ的化合物、及Ar2-S- M +加入到溶剂中，按反应式(2)加热反应完全后得到；
其中，Ar1-X1为通式Ⅰ的单环芳香化合物、或者为通式Ⅱ所表示的二环芳香化合物，
通式Ⅰ中：
当Z、Q、M皆为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基或卤素，位于X1的邻位或对位；R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z为N，Q、M为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基，位于Z的邻位或对位；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z、Q为N，M为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z为C，Q、M为N时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z、M为N，Q为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
通式Ⅱ中：
当Z、Q、M皆为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基或卤素，位于X1的邻位或对位；R2、R'、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z为N，Q、M为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基，位于Z的邻位或对位；R1、R2、R'分别为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R3不存在；
当Z、Q为N，M为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R'分别为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R2和R3不存在；
当Z为C，Q、M为N时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R'分别为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R2和R3不存在；
当Z、M为N，Q为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R'分别为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R2和R3不存在；
反应式中的通式Ⅲ所示的化合物，其中，n为0～5的正整数，Y选自碳、氮、氧或硫原子，R选自C1～C10的烷烃基或C1～C20芳基取代的烷基；
反应式(1)中的Ar2-X2为通式Ⅳ的单环芳香化合物、或者为通式Ⅴ的二环芳香化合物、或者为通式Ⅵ所表示的三唑类化合物，
通式Ⅳ中：Z、Q、M选自碳或氮；X2为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
通式Ⅴ中：Z、Q、M选自碳或氮；X2为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3、R'为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
通式Ⅵ中：X2为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
反应式(2)中的Ar2-S- M +为通式Ⅶ的单环芳香化合物、或者为通式Ⅷ的二环芳香化合物、或者为通式Ⅸ所表示的三唑类化合物；
通式Ⅶ中：Z、Q、M选自碳或氮；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；M选自氢、锂、钠或钾；
通式Ⅷ中：Z、Q、M选自碳或氮；R1、R2、R3、R'为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；M选自氢、锂、钠或钾；
通式Ⅸ中：R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、醛基、乙酰基、硝基、氰基、酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；M选自氢、锂、钠或钾。
上述反应式(1)中的硫源选自单质硫、MS、MSCN或MSCSOR，其中，单质硫选自S2、S4、S6、S8或无定形硫中的一种；M选自锂、钠、钾或铯；R选自甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
上述反应式(1)和(2)中的溶剂选自甲苯、二氯甲烷、四氢呋喃、1，4-二氧六环、甲醇、乙醚、二甲基亚砜、N,N-二甲基甲酰亚胺或乙腈。
上述反应式(1)和(2)可在无碱的条件下进行，或者在有碱的条件下进行。在有碱的条件下，碱的通式为MOH、MOR或MY，其中，M选自锂、钠、钾或铯；R选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基或羰基；Y选自碳酸根、磷酸根、乙酸根、丙酸根、正丁酸根、异丁酸根、正戊酸根、异戊酸根或新戊酸根。
如无特别说明，本文中的S为硫原子，C为碳原子，N为氮原子，O为氧原子，H为氢原子。
操作时，所述反应式(1)中Ar1-X1与通式Ⅲ的化合物的摩尔比为1：10到10:1，Ar1-X1与Ar2-X2的摩尔比1：10到10:1，Ar1-X1与硫源的摩尔比为1：10到10:1；有碱时，Ar1-X1与碱的摩尔比为1：10到10:1。
所述反应式(2)中Ar1-X1与通式Ⅲ的化合物的摩尔比为1：10到10:1，Ar1-X1与Ar2-S- M +的摩尔比为1：10到10:1，有碱时，Ar1-X1与碱的摩尔比为1：10到10:1。
具体操作过程为：按上述摩尔比取各物料加入到干燥的反应器中；溶剂按1mmolAr1-X1原料取1-10ml溶剂的量取，并加入到反应器中，将反应器置于0-200℃油浴中加热反应。待反应完全后，将反应器冷却至室温，于反应器中的反应体系中加入水，水相用乙酸乙酯萃取3次，合并有机相，减压蒸干溶剂，柱层析分离得目标产物。
本发明同时提供类卢扎朵仑结构的芳胺基烷基硫类化合物在制备镇痛药物中的应用。
本发明具有如下优点：
1、工艺路线短，仅用一步合成芳基氨基烷基硫醚结构，降低了合成工艺的成本。
2、不需要使用催化剂，降低了合成工艺的成本，且避免了药物合成中重金属残留等问题。
3、反应中所用到的硫化钠、单质硫、硫氰化钾等硫源廉价易得，且原子利用率高。
4、反应中所用到的碱是一些廉价易得的碱。
5、操作简单高效，反应条件温和，所用的试剂廉价易得，成本低、安全性强，适合工业化生产。
具体实施方式
现通过以下实施例进一步说明本发明，但并非限定本发明的范围。
实施例1：1-(2-吡啶基)-4-(2-(吡啶-2-硫基)乙基)哌嗪的合成
将2-溴吡啶(158mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫化钠(39mg,0.5mmol)、碳酸钾(138mg,1mol)、N,N-二甲基甲酰胺(2ml)加入到干燥的反应管中，悬置于120℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到123mg黄色油状液体即1-(2-吡啶基)-4-(2-(吡啶-2-硫基)乙基)哌嗪，收率为82％。
将2-溴吡啶(158mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫化钠(39mg,0.5mmol)、N,N-二甲基甲酰胺(2ml)加入到干燥的反应管中，悬置于120℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到105mg黄色油状液体即1-(2-吡啶基)-4-(2-(吡啶-2-硫基)乙基)哌嗪，收率为70％。
实施例2：1-(2-吡啶基)-4-(2-(吡啶-2-硫基)乙基)哌嗪的合成
将2-溴吡啶(158mg,1mmol)、三乙烯二胺(224mg,2mmol)、乙基黄原酸钾(80mg,0.5mmol)、碳酸钾(138mg,1mol)、N,N-二甲酰胺(2ml)加入到干燥的反应管中，悬置于120℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到111mg黄色油状液体即1-(2-吡啶基)-4-(2-(吡啶-2-硫基)乙基)哌嗪，收率为74％。
实施例3：1-(2-((4-硝基苯基)硫基)乙基)-4-(吡啶基-2-基)哌嗪的合成
将2-碘吡啶(102mg,0.5mmol)、三乙烯二胺(224mg,2mmol)、硫粉(16mg,0.5mmol)、对硝基氯苯(79mg,0.5mmol)、磷酸钾(217mg,1mmol)、二甲基亚砜(2ml)加入到干燥的反应管中，悬置于140℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到146mg黄色固体即1-(2-((4-硝基苯基)硫基)乙基)-4-(2-吡啶基)哌嗪，收率为85％。
实施例4：2-((2-(4-(2-嘧啶基)-1-哌嗪基)乙基)硫)嘧啶的合成
将2-氯嘧啶(114mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫化钠(39mg,0.5mmol)、磷酸钾(217mg,1mmol)、甲苯(2ml)加入到干燥的反应管中，悬置于40℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到117mg无色固体即2-((2-(4-(2-嘧啶基)-1-哌嗪基)乙基)硫)嘧啶，收率为78％。
将2-氯嘧啶(114mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫化钠(39mg,0.5mmol)、甲苯(2ml)加入到干燥的反应管中，悬置于40℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到103mg无色固体即2-((2-(4-(2-嘧啶基)-1-哌嗪基)乙基)硫)嘧啶，收率为68％。
实施例5：5-甲基-2-((2-(4-(2-(5-甲基嘧啶基))-1-哌嗪基)乙基)硫)嘧啶的合成
将2-氯-5-甲基嘧啶(128mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫化钠(39mg,0.5mmol)、磷酸钾(217mg,1mmol)、甲苯(2ml)加入到干燥的反应管中，悬置于40℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到130mg无色固体即2-((2-(4-(2-嘧啶基)-1-哌嗪基)乙基)硫)嘧啶，收率为79％。
将2-氯-5-甲基嘧啶(128mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫化钠(39mg,0.5mmol)、甲苯(2ml)加入到干燥的反应管中，悬置于40℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到115mg无色固体即2-((2-(4-(2-嘧啶基)-1-哌嗪基)乙基)硫)嘧啶，收率为70％。
实施例6：5-氯-2-((2-(4-(2-(5-氯嘧啶基))-1-哌嗪基)乙基)硫)嘧啶的合成
将2,5-二氯嘧啶(128mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫化钠(39mg,0.5mmol)、磷酸钾(217mg,1mmol)、甲苯(2ml)加入到干燥的反应管中，悬置于40℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到148mg无色固体即2-((2-(4-(2-嘧啶基)-1-哌嗪基)乙基)硫)嘧啶，收率为80％。
将2,5-二氯嘧啶(128mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫化钠(39mg,0.5mmol)、甲苯(2ml)加入到干燥的反应管中，悬置于40℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到129mg无色固体即2-((2-(4-(2-嘧啶基)-1-哌嗪基)乙基)硫)嘧啶，收率为70％。
实施例7：2-(4-(2-((4-(三氟甲基)苯基)硫基)乙基)1-哌嗪基)嘧啶的合成
将2-氯嘧啶(57mg,0.5mmol)、三乙烯二胺(224mg,2mmol)、硫脲(38mg,0.5mmol)、4-三氟甲基碘苯(186mg,0.5mmol)、氢氧化钠(40mg,1mmol)、甲苯(2ml)加入到干燥的反应管中，悬置于100℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到119mg黄色固体即2-(4-(2-((4-(三氟甲基)苯基)硫基)乙基)1-哌嗪基)嘧啶，收率为65％。
实施例8：2-((2-(4-(2-喹啉基)1-哌啶基)乙基)硫)喹啉的合成
将2-氟喹啉(147mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫氰化钾(49mg,0.5mmol)、甲醇钠(54mg,1mmol)、乙腈(2ml)加入到干燥的反应管中，悬置于80℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到144mg黄色固体即2-((2-(4-(2-喹啉基)1-哌啶基)乙基)硫)喹啉，收率为72％。
实施例9：2-((2-(4-(2-喹喔啉基)1-哌啶基)乙基)硫)喹喔啉的合成
将2-溴喹喔啉(207mg,1mmol)、三乙烯二胺(224mg,2mmol)、硫化钠(39mg,0.5mmol)、磷酸钾(217mg,1mmol)、N,N-二甲基甲酰胺(2ml)加入到干燥的反应管中，悬置于80℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到151mg黄色固体即N-甲基-N-(4-(2-硫基喹啉基)丁基)喹啉-2-胺，收率为75％。
实施例10：N-乙基-N-(2-(2-(嘧啶基-2-硫)乙氧基)乙基)嘧啶基-2-胺的合成
将2-氯嘧啶(114mg,1mmol)、N-乙基吗啉(228mg,2mmol)、硫化钠(39mg,0.5mmol)、乙酸钾(112mg,1mmol)、二甲基亚砜(2ml)加入到干燥的反应管中，悬置于60℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到无色固体即N-乙基-N-(2-(2-(嘧啶基-2-硫)乙氧基)乙基)嘧啶基-2-胺114mg，收率为75％。
实施例11：1-(4-((2-(2-((4-苯乙酰基)(甲基)胺)乙氧基)乙基)硫基)苯基)酮的合成
将4-氟苯乙酮(147mg,1mmol)、N-甲基吗啉(228mg,2mmol)、硫化钠(39mg,0.5mmol)、乙酸钾(112mg,1mmol)、四氢呋喃(2ml)加入到干燥的反应管中，悬置于60℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即1-(4-((2-(2-((4-苯乙酰基)(甲基)胺)乙氧基)乙基)硫基)苯基)酮121mg，收率为65％。
实施例12：3-((2-(4-(2,4-二氟苯基)-哌嗪基-1-基)乙基)硫基)-[1,2,4]三唑[4,3-a]吡啶的合成
将1，2，4-三氟苯(66mg,0.5mmol)、三乙烯二胺(224mg,2mmol)、[1,2,4]三唑并[4,3-A]吡啶-3-硫酚(76mg,0.5mmol)、氢氧化锂(24mg,1mmol)、1，4-二氧六环(2ml)加入到干燥的反应管中，悬置于90℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色油状液体即3-((2-(4-(2,4-二氟苯基)-1-哌嗪基)乙基)硫基)-[1,2,4]三唑[4,3-a]吡啶178mg，收率为95％。
实施例13：1-(4-硝基苯基)-4-(2-(苯硫基)乙基)哌嗪的合成
将4-三氟甲磺酸酯基硝基苯(135mg,0.5mmol)、三乙烯二胺(224mg,2mmol)、苯硫酚钠(66mg,0.5mmol)、碳酸铯(325mg,1mmol)、乙醚(2ml)加入到干燥的反应管中，悬置于90℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即1-(4-硝基苯基)-4-(2-(苯硫基)乙基)哌嗪(154mg，收率为90％)。
实施例14：4-(异丙基(4-(4’-甲基苯硫基)丁基)胺基)苯甲醛的合成
将4-氯苯甲醛(70mg,0.5mmol)、N-异丙基吡咯(226mg,2mmol)、4-甲基苯硫酚钾(81mg,0.5mmol)、叔丁醇钾(112mg,1mmol)、二甲基亚砜(2ml)加入到干燥的反应管中，悬置于90℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即4-(异丙基(4-(p-甲基苯硫基)丁基)胺基)苯甲醛(129mg，收率为76％)。
实施例15：4-((4-((2-氰基苯基)(甲基)胺基)丁基)硫基)苯甲酸甲酯的合成
将2-氟苯腈(61mg,0.5mmol)、N-甲基基吡咯(226mg,2mmol)、4-巯基苯甲酸(84mg,0.5mmol)、硫化钠(39mg,0.5mmol)、叔丁醇钾(112mg,1mmol)、甲苯(2ml)加入到干燥的反应管中，悬置于110℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即4-((4-((2-氰基苯基)(甲基)胺基)丁基)硫基)苯甲酸甲酯(126mg，收率为71％)。
实施例16：2-((2-(4-(4-溴苯基)-哌啶基-1-基)乙基)硫基)嘧啶的合成
将4-氟溴苯(87mg,0.5mmol)、三乙烯二胺(224mg,2mmol)、2-溴嘧啶(57mg,0.5mmol)、硫脲(38mg,0.5mmol)、碳酸钾(138mg,1mmol)乙醇(2ml)加入到干燥的反应管中，悬置于180℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即2-((2-(4-(4-溴苯基)-1-对二氮环己基)乙基)硫基)嘧啶(130mg，收率为69％)。
实施例17：N,5-二甲基-N-(4-((5-甲基嘧啶-2-基)硫)丁基)嘧啶2-胺的合成
将2-氟-5-甲基嘧啶(112mg,1mmol)、N-甲基吡咯(228mg,2mmol)、硫化钠(39mg,0.5mmol)、磷酸钾(217mg,1mmol)、二甲基亚砜(2ml)加入到干燥的反应管中，悬置于50℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即N,5-二甲基-N-(4-((5-甲基嘧啶-2-基)硫)丁基)嘧啶2-胺(118mg，收率为78％)。
实施例18：N,6-二甲基-N-(4-((6-甲基喹啉-2-基)硫)丁基)喹啉-2-胺的合成
将2-溴-6-甲基喹啉(220mg,1mmol)、N-甲基吡咯(170mg,2mmol)、硫化钠(39mg,0.5mmol)、碳酸钾(138mg,1mmol)、二甲基亚砜(2ml)加入到干燥的反应管中，悬置于50℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即N,6-二甲基-N-(4-((6-甲基喹啉-2-基)硫)丁基)喹啉-2-胺(150mg，收率为75％)。
实施例19：6-((2-(4-(6-(甲氧羰基)吡啶基-2-基)哌嗪基-1-基)乙基)硫基)吡啶甲酸甲酯的合成
将2-氯-6-甲酸甲酯吡啶(171mg,1mmol)、三乙烯二胺(224mg,2mmol)、九水合硫化钠(120,0.5mmol)、乙酸钠(82mg,1mmol)、N,N-二甲基甲酰胺(2ml)加入到干燥的反应管中，悬置于70℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即甲基6-((2-(4-(6-(甲氧羰基)吡啶基-2-基)哌嗪基-1-基)乙基)硫基)吡啶甲酸甲酯(162mg，收率为78％)。
实施例20：5-溴-N-(4-((5-溴吡啶-2-基)硫)丁基)-N-甲基吡啶-2-胺的合成
将2-氟-5-溴吡啶(176mg,1mmol)、N-甲基吡咯烷(170mg,2mmol)、硫氰化钾(49mg,0.5mmol)、氢氧化锂(24mg,1mmol)、乙腈(2ml)加入到干燥的反应管中，悬置于70℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色油状液体即5-溴-N-(4-((5-溴吡啶-2-基)硫)丁基)-N-甲基吡啶-2-胺(154mg，收率为72％)。
实施例21：6-((4-((5-(乙氧羰基)吡啶-2-基)(甲基)胺)丁基)硫)烟酸乙酯的合成
将(6-氟吡啶-3-基)甲酸乙酯(169mg,1mmol)、N-甲基吡咯烷(170mg,2mmol)、硫脲(38mg,0.5mmol)、碳酸铯(325mg,1mmol)、乙腈(2ml)加入到干燥的反应管中，悬置于70℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即6-((4-((5-(乙氧羰基)吡啶-2-基)(甲基)胺)丁基)硫)烟酸乙酯(144mg，收率为69％)。
实施例22：N-苄基-N-(4-(嘧啶-2-硫)丁基)嘧啶-2-胺的合成
将2-氯嘧啶(114mg,1mmol)、N-苄基吡咯烷(322mg,2mmol)、硫化钠(39mg,0.5mmol)、碳酸钾(138mg,1mmol)、二甲基亚砜(2ml)加入到干燥的反应管中，悬置于70℃油浴中反应12h。将反应体系冷却后，加入15ml水，水相用乙酸乙酯30ml萃取3次，合并有机相，减压蒸干溶剂，柱层析得到黄色固体即N-苄基-N-(4-(嘧啶-2-硫)丁基)嘧啶-2-胺(137mg，收率为78％)。
上述各实施例中所对应合成化合物的结构式如下表1。
表1各实施例中所对应化合物的结构式
实施例23：胺烷基硫类化合物的镇痛活性实验，热板实验
实验过程：将恒温控制热力板上的温度设定56℃，温度稳定后将老鼠放置于该热力板上，测量老鼠添后爪反应的时间即为老鼠的反应时间，老鼠置于热力板上持续时间不能超过30秒。
进度管理：以10只老鼠为一组，将上述实施例中合成的化合物对各组老鼠进行口服给药(0.2ml/20g)；给药后30分钟，将老鼠置于热板上进行实验。上述实施例中所合成化合物分别按如下剂量给药：0,3,30,100mg/Kg。
结果表示：计算最大反应时间(30秒)和每一被治疗组的平均反应时间的差别。
数据统计：对实验数据进行数理统计，通过线性回归，确定50％有效剂量和置信限。
实验结果：实验结果如表2所示，并确定AD50。实验结果表明，各实施例所合成化合物具有镇痛活性。
表2各实施例中所合成化合物的镇痛活性
实施例所对应化合物 每一组老鼠数量 AD<sub>50</sub>置信限(mg/kg)
实施例1 10 3.23(1.45-7.48)
实施例3 10 8.43(5.12-16.23)
实施例4 10 1.82(1.03-3.05)
实施例5 10 4.35(2.43-7.82)
实施例6 10 11.32(7.58-16.92)
实施例7 10 16.14(9.51-25.36)
实施例8 10 23.25(16.98-32.21)
实施例9 10 2.35(1.39-3.79)
实施例10 10 17.45(13.88-22.36)
实施例11 10 14.18(6.15-32.66)
实施例13 10 2.38(1.36-3.74)
实施例14 10 25.63(19.31-34.25)
实施例15 10 13.25(9.87-18.02)
实施例16 10 12.55(9.02-16.87)
实施例17 10 15.63(9.51-25.89)
实施例18 10 9.78(4.01-25.87)
实施例19 10 5.56(3.65-8.85)
实施例20 10 10.45(6.93-16.65)
实施例21 10 16.38(10.03-26.12)
实施例22 10 14.56(5.98-33.89)

Claims (8)

1.一种具有类卢扎朵结构的芳胺基烷基硫类化合物的制备方法：
(1)
(2)
其中，“---”表示为一根化学键或者没有化学键；所述的方法包括：
将Ar1-X1、通式III的化合物、Ar2-X2及硫源加入到溶剂中，按反应式(1)加热反应完全；
或，将Ar1-X1、通式III的化合物、及Ar2-S-M+加入到溶剂中，按照反应式(2)加热反应完全；
其中，反应式(1)和反应式(2)中的Ar1-X1为通式I的单环芳香化合物、或者为通式II的稠环芳香化合物，
其中，通式Ⅰ中：
当Z、Q、M皆为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基或卤素，位于X1的邻位或对位；R2、R3为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z为N，Q、M为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基，位于Z的邻位或对位；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z、Q为N，M为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、甲氧羰基、乙氧羰基、磺酸酯基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z为C，Q、M为N时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z、M为N，Q为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
通式Ⅱ中：
当Z、Q、M皆为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基或卤素，位于X1的邻位或对位；R2、R'、R3为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
当Z为N，Q、M为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基，位于Z的邻位或对位；R1、R2、R'分别为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R3不存在；
当Z、Q为N，M为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R'分别为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R2和R3不存在；
当Z为C，Q、M为N时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R'分别为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R2和R3不存在；
当Z、M为N，Q为C时，X1为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R'分别为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、氢、羟基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；R2和R3不存在；
反应式(1)和(2)中的通式Ⅲ所示化合物，其中，n为0～5的正整数，Y选自碳、氮、氧或硫原子，R选自C1～C10的烷烃基或C6～C20芳基取代的烷基；
反应式(1)中的Ar2-X2为通式Ⅳ的单环芳香化合物、或者为通式Ⅴ的二环芳香化合物，
通式Ⅳ中：Z、Q、M选自碳或氮；X2为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
通式Ⅴ中：Z、Q、M选自碳或氮；X2为卤素、三氟甲磺酸酯基或对甲基苯磺酸酯基；R1、R2、R3、R'为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、羟基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；
反应式(2)中的Ar2-S- M +为通式Ⅶ的单环芳香化合物、或者为通式Ⅷ的二环芳香化合物；
通式Ⅶ中：Z、Q、M选自碳或氮；R1、R2、R3为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、卤素、甲氧基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；M自氢、锂、钠或钾；
通式Ⅷ中：Z、Q、M选自碳或氮；R1、R2、R3、R'为三氟甲基、三氯甲基、三溴甲基、甲酰基、乙酰基、硝基、氰基、磺酸酯基、氯元素、溴元素、碘元素、甲氧基、氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基；M选自氢、锂、钠或钾。
2.如权利要求1所述的方法，其特征在于，所述反应式(1)和(2)是在有碱的条件下进行的，碱的通式为M1OH或M1Y1，碱的通式中M1选自锂、钠、钾或铯；Y1选自乙酸根、丙酸根、正丁酸根、异丁酸根、正戊酸根、异戊酸根或新戊酸根。
3.如权利要求1所述的方法，其特征在于，所述反应式(1)中的硫源选自单质硫、M2 1S、M1SCN或M1SCSORA，其中，单质硫选自S2、S4、S6、S8或无定形硫中的一种；M1S、M1SCN或M1SCSORA中的M1选自锂、钠、钾或铯；M1SCSORA中的RA选自甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
4.如权利要求1或2所述的方法，其特征在于，所述反应式(1)和(2)中的溶剂选自甲苯、二甲苯、三甲苯、二氯甲烷、三氯甲烷、四氢呋喃、1，4-二氧六环、甲醇、乙醇、正丙醇、异丙醇、乙醚、甲乙醚、甲基叔丁基醚、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或乙腈。
5.如权利要求2所述的方法，其特征在于，所述反应式(1)中Ar1-X1与通式Ⅲ所表示化合物的摩尔比为1：10～10:1，Ar1-X1与Ar2-X2的摩尔比1：10～10:1，Ar1-X1与硫源的摩尔比为1：10～10:1。
6.如权利要求2所述的方法，其特征在于，所述反应式(2)中Ar1-X1与通式Ⅲ所表示化合物的摩尔比为1：10～10:1，Ar1-X1与Ar2-S-M+的摩尔比为1：10～10:1。
7.如权利要求3所述的方法，其特征在于，所述反应式(1)和(2)中，在有碱条件下Ar1-X1与碱的摩尔比为1：10～10:1。
8.如权利要求2所述的方法，其特征在于，所述反应式(1)和(2)中的加热反应温度为0-200℃。
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