CN109384697B - 含硫紫草素肟衍生物及其用途 - Google Patents

含硫紫草素肟衍生物及其用途 Download PDF

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CN109384697B
CN109384697B CN201710662316.0A CN201710662316A CN109384697B CN 109384697 B CN109384697 B CN 109384697B CN 201710662316 A CN201710662316 A CN 201710662316A CN 109384697 B CN109384697 B CN 109384697B
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李绍顺
黄广
孟青青
赵会然
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Abstract

本发明提供了一种含硫紫草素肟衍生物及其用途，结构通式如式(I)所示：
Figure DDA0001370883200000011
其中
Figure DDA0001370883200000012
为—，
Figure DDA0001370883200000013
或
Figure DDA0001370883200000014
R为R1或COR2；所述R1为碳原子长度为1～16的烷烃、烯烃、芳香烃或取代芳香烃，R2为碳原子长度为1～6的烷烃、烯烃、芳香烃或取代芳香烃。本发明的含硫紫草素肟衍生物的制备方法简便，产率较高；体外抗肿瘤结果显示，该类化合物具有均显示较好的抗肿瘤活性和抗肿瘤耐药活性，硫原子的引入具有更好的生物相容性，能提高抗肿瘤活性。

Description

含硫紫草素肟衍生物及其用途
技术领域
本发明属于医药领域，具体涉及一类含硫紫草素肟衍生物，根据结构中所含手性碳原子的构型不同，衍生为外消旋体含硫紫草素肟、光学纯含硫紫草素肟、光学纯含硫阿卡宁肟衍生物及其用途。
背景技术
紫草为《中华人民共和国药典》收载的中药。紫草可分为硬紫草(又名东北紫草，Lithospermum erythrohizon)和软紫草(又名新疆紫草，A.euchroma Johnst)。硬紫草中的主要有效成分为紫草素及其衍生物，软紫草中含有阿卡宁及其衍生物。紫草素和阿卡宁互为对映异构体，紫草素为R构型，阿卡宁为S构型。两者均具有抗菌、抗病毒、抗炎、促进伤口愈合、抗血栓、降血糖、抗免疫低下、抗甲状腺功能亢进及保肝护肝等多种生物活性。近年来，紫草素、阿卡宁及其消旋体衍生物的抗肿瘤活性研究引人关注，以天然产物紫草素和阿卡宁为先导化合物开发抗肿瘤新药的研究具有重要意义。
目前文献所报道的紫草素衍生物的抗肿瘤研究，大多在保留紫草素萘茜母核(5,8-二羟基-1,4-萘醌)结构的基础上，对其侧链羟基进行结构修饰(中国发明专利，公开号：CN1420111，CN1112363，CN101239936)。我们之前通过萘茜母核羟基及醌羰基进行结构修饰，发明了萘茜母核氧烷基化、酰基化、羰基肟化的紫草素衍生物(中国专利，ZL201010046435.2，ZL201010209926.3，ZL201210021929.3，ZL201210065488.7，ZL201310044877.6)。许多研究结果显示，含硫化合物较其相应的含氧化合物具有更强的生物活性(Qian et al,J.Chem.Soc.,Perkin Trans.2 2000,715-718.)。但现有技术中，均未见有同时对萘茜母核羟基甲基化、羰基肟化和侧链进行硫取代修饰的任何报道。本发明在对其侧链羟基的氧用生物电子等排体硫取代进行修饰的同时，对萘茜母核羟基甲基化和羰基肟化，得到一类含硫紫草素肟衍生物，包括外消旋体含硫紫草素肟衍生物、光学纯含硫紫草素肟衍生物及光学纯含硫阿卡宁肟衍生物。体外抗肿瘤结果显示，该类化合物具有均显示较好的抗肿瘤活性和抗肿瘤耐药活性，硫原子的引入具有更好的生物相容性，能提高抗肿瘤活性。
发明内容
本发明要解决的技术问题是，针对现有技术不足，提出一种含硫紫草素肟衍生物及其制备方法和用途。本发明通过对其侧链羟基的氧用生物电子等排体硫取代进行修饰的同时，对萘茜母核羟基甲基化和羰基肟化，得到一类含硫紫草素肟衍生物，包括外消旋体含硫紫草素肟衍生物、光学纯含硫紫草素肟衍生物及光学纯含硫阿卡宁肟衍生物。体外抗肿瘤结果显示，该类化合物具有均显示较好的抗肿瘤活性和抗肿瘤耐药活性，硫原子的引入具有更好的生物相容性，能提高抗肿瘤活性。
发明的目的是通过以下技术方案实现的：
第一方面，本发明提供了一种含硫紫草素肟衍生物，结构通式如式(I)所示：
Figure BDA0001370883180000021
其中
Figure BDA0001370883180000022
为-，
Figure BDA0001370883180000023
或
Figure BDA0001370883180000024
R为R1或COR2；
所述R1为碳原子长度为1～16的烷烃、烯烃、芳香烃或取代芳香烃，R2为碳原子长度为1～6的烷烃、烯烃、芳香烃或取代芳香烃。
优选地，当通式(I)中波浪线
Figure BDA0001370883180000025
为实线(-)时，为结构式(II)所代表的含硫外消旋体紫草素肟衍生物，所述结构式(II)如下所示：
Figure BDA0001370883180000026
其中R为R1或COR2；
所述R1为碳原子长度为1～16的烷烃、烯烃、芳香烃或取代芳香烃，R2为碳原子长度为1～6的烷烃、烯烃、芳香烃或取代芳香烃。
更优选地，所述结构式(II)中R＝R1时，为结构式(III)所代表的硫醚类外消旋体紫草素肟衍生物；所述结构式(II)中R＝COR2时，为结构式(IV)所代表的硫酯类外消旋体紫草素肟衍生物；
Figure BDA0001370883180000027
其中，所述结构式(III)中，所述R1为乙基、丁基、异戊基、异戊烯基、己基、庚基、辛基、壬基、癸基、十二烷基、十六烷基、苄基、法尼基；
所述结构式(IV)中，R2为甲基、乙基、异丙基、异丁基、异丁烯基、2-羟基-2-甲基丙基、戊基、苯基、对甲苯基、4-硝基苯基、4-叔丁氧甲酰氨基苯基、对氨基苯基、4-三氟甲基苯基、3-三氟甲基苯基、肉桂基、3,4-二甲氧基苯基、3,4,5-三甲氧基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-呋喃基、2-噻吩基、3-吡啶基和4-吡啶基。
优选地，当通式(I)中的波浪线
Figure BDA0001370883180000031
为粗实线
Figure BDA0001370883180000032
时，为结构式(V)所代表的含硫光学纯紫草素肟衍生物，所述结构式(V)如下所示：
Figure BDA0001370883180000033
其中R为R1或COR2；
所述R1为碳原子长度为1～8的烷烃、烯烃、芳香烃或取代芳香烃；R2为碳原子长度为1～6的烷烃、烯烃、芳香烃或取代芳香烃。
更优选地，所述结构式(V)中R＝R1时，为结构式(VI)所代表的硫醚类光学纯紫草素肟衍生物；所述结构式(V)中R＝COR2时，为结构式(VII)所代表的硫酯类光学纯紫草素肟衍生物；
Figure BDA0001370883180000034
其中，所述结构式(VI)中，所述R1为异戊基、异戊烯基、辛基、苄基；结构式(VII)中，R2为异丁基、异丁烯基、苯基、对甲苯基、肉桂基、4-氟苯基、4-甲氧基苯基、3,4-二甲氧基苯基、3,4,5-三甲氧基苯基、2-呋喃基、2-噻吩基、3-吡啶基。
优选地，当通式(I)中波浪线
Figure BDA0001370883180000035
为粗虚线
Figure BDA0001370883180000036
时，为结构式(VIII)所代表的含硫光学纯阿卡宁肟衍生物，所述结构式(VIII)如下所示：
Figure BDA0001370883180000037
其中R为R1或COR2；
所述R1为碳原子长度为1～8的烷烃、烯烃、芳香烃或取代芳香烃；R2为碳原子长度为1～6的烷烃、烯烃、芳香烃或取代芳香烃。
更优选地，所述结构式(VIII)中R＝R1时，为结构式(IX)所代表的硫醚类光学纯阿卡宁肟衍生物；所述结构式(VIII)中R＝COR2时，为结构式(X)所代表的硫酯类光学纯阿卡宁肟衍生物；
Figure BDA0001370883180000041
其中，所述结构式(IX)中，所述R1为异戊基、异戊烯基、辛基、苄基；结构式(X)中，R2为异丁基、异丁烯基、苯基、对甲苯基、肉桂基、4-氟苯基、4-甲氧基苯基、3,4-二甲氧基苯基、3,4,5-三甲氧基苯基、2-呋喃基、2-噻吩基、3-吡啶基。
第二方面，本发明提供了一种含硫紫草素肟衍生物的制备方法，包括以下步骤：
S1、将制备的巯基化合物溶于乙醇中，以碘化钾为催化剂，与卤代烃R1X发生醚化反应，得硫醚衍生物；所述R1X中，R1为碳原子长度为1～16的烷烃、烯烃、芳香烃或取代芳香烃，X为卤元素；
或以4-二甲基吡啶为催化剂，在N,N'-二环己基碳二亚胺存在条件下，羧酸R2COOH与制备的巯基化合物发生反应，得硫酯衍生物；所述R2COOH中，R2为碳原子长度为1～6的烷烃、烯烃、芳香烃或取代芳香烃；
S2、将步骤S1中所述的硫醚衍生物或硫酯衍生物溶于溶剂中，在冰浴条件下，与硝酸铈铵发生氧化脱甲基反应，得6位侧链取代的5,8-二甲氧基1,4-萘醌硫醚或硫酯衍生物；
S3、将步骤S2中的6位侧链取代的5,8-二甲氧基1,4-萘醌硫醚或硫酯衍生物溶于乙醇中与盐酸羟胺发生缩合反应，即得所述含硫紫草素肟衍生物。
优选地，步骤S1中，所述巯基化合物包括2-(1-巯基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘、R构型的1,4,5,8-O-四甲基-1’-巯基紫草素衍生物、S构型的1,4,5,8-O-四甲基-1’-巯基阿卡宁衍生物。
优选地，所述2-(1-巯基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘的制备方法如下：
A1、将1,4,5,8-四甲氧基-2-萘甲醛溶于干燥四氢呋喃中，与异戊烯溴化锌试剂室温反应后，加入六甲基磷酰三胺，高温条件下发生重排反应，得外消旋体1,4,5,8-O-四甲基紫草素，所述重排反应在惰性气体氮气或氩气保护下进行，反应温度为130～180℃。
A2、将所述外消旋体1,4,5,8-O-四甲基紫草素溶于乙醇中，加入氢溴酸和硫脲，加热回流，冷却后加入乙醚和水，分离出水层，然后加入氢氧化钠或氢氧化钾，加热回流发生水解反应，即得巯基化合物2-(1-巯基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘；所述水解反应在惰性气体氮气或氩气保护下进行。
优选地，所述R构型的1,4,5,8-O-四甲基-1’-巯基紫草素衍生物和S构型的1,4,5,8-O-四甲基-1’-巯基阿卡宁衍生物的制备方法如下：
将光学纯(R)-2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘或者(S)-2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘在甲苯中与劳森试剂加热反应，即得。
优选地，步骤S1中，所述巯基化合物为2-(1-巯基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘时，所述醚化反应碳酸钾或碱性条件下、且在惰性气体氮气或氩气保护下进行，反应温度为80℃。
优选地，步骤S2中，所述溶剂包括乙酸乙酯或乙酸乙酯与水的混合物。
第三方面，本发明提供了一种含硫紫草素肟衍生物在制备抗肿瘤药物中的用途。
与现有技术相比，本发明具有如下的有益效果：
本发明的含硫外消旋体紫草素肟衍生物、光学纯含硫紫草素肟和阿卡宁肟衍生物的制备方法简便，产率较高；此外，所使用的原料(R)或(S)-2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘采用发明人已授权的发明专利(中国专利，ZL201110209290.7)的制备方法，产物的光学纯度高(ee值大于99％)；体外抗肿瘤活性实验表明，所制备的含硫外消旋体紫草素肟衍生物、光学纯含硫紫草素和阿卡宁肟衍生物具有较好的抗肿瘤活性，其中部分化合物的抗肿瘤活性强于先导化合物紫草素和阿卡宁。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1为硫醚类外消旋体紫草素肟衍生物(结构式III)和硫酯类外消旋体紫草素肟衍生物(结构式IV)的制备过程示意图；
图2为光学纯硫醚类紫草素肟衍生物(结构式VI)和光学纯硫酯类紫草素肟衍生物(结构式VII)的制备过程示意图；
图3为光学纯硫醚类阿卡宁肟衍生物(结构式IX)和光学纯硫酯类阿卡宁肟衍生物(结构式X)的制备过程示意图；
图4为光学纯(R)-2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘的制备过程示意图；
图5为光学纯(S)-2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘的制备过程示意图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变化和改进。这些都属于本发明的保护范围。下列实施列中未注明具体条件的实验方法，通常按照常规条件，或制造厂商所建议的条件。
实施例1
本实施例涉及一种具有结构式(III)的硫醚类外消旋体紫草素肟衍生物制备方法，如图1所示，包括如下步骤：
步骤一，将已活化的锌粉(30.0g,0.46mol)混悬于无水四氢呋喃(120mL)，氮气保护下，缓慢滴加溴代异戊烯(24.0mL,0.21mol)，滴加结束后室温下搅拌，2h后，迅速将反应液分装至50mL离心管中，4000rpm离心10min，取上清液(彻底除去锌粉)备用。取1,4,5,8-四甲氧基-2-萘甲醛(8.0g,29.0mmol)溶于无水四氢呋喃(60mL)中，氮气保护下，将已制备好的金属溴代物(上清液)缓慢加入反应瓶中，反应液由黄色变成白色泡沫状，室温下继续搅拌反应2h，待反应结束后，加入六甲基磷酰三胺(60.0mL)，150℃时减压蒸除四氢呋喃后，该温度下继续反应2h，TLC检测反应完全，待反应液冷却后，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥有机相，蒸除有机溶剂，柱层析分离得2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘，黄色油状物8.7g，收率87％。1H NMR(400MHz,CDCl3):δ7.03(s,1H,ArH),6.85–6.80(m,2H,ArH),5.23-5.28(m,2H,ArCHOH+CH2CH＝C),3.96(s,3H,OCH3),3.94(s,3H,OCH3),3.90(s,3H,OCH3),3.77(s,3H,OCH3),2.53(t,J＝6.8Hz,2H,CHCH 2CH＝C),1.73(s,3H,CH3),1.66(s,3H,CH3)。
步骤二，将步骤一所得产物(1.73g,5.0mmol)、硫脲(0.76g,10.0mmol)和48％氢溴酸(1.2mL)溶于乙醇(60mL)中，回流反应2h，冷却，蒸除溶剂后加入乙醚(50mL)和水(25mL)，分离出水层并于氮气保护下向其缓慢滴入40％氢氧化钠的水溶液(20mL)，继续回流反应2h后，冷却至室温，6M盐酸调节反应液pH值至弱酸性，二氯甲烷萃取，无水硫酸钠干燥有机相，蒸除有机溶剂，柱层析分离得2-(1-巯基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘，黄色油状物1.27g，收率70％。1H NMR(400MHz,CDCl3):δ6.89(s,1H,ArH),6.74(s,2H,ArH),5.03(t,J＝7.2Hz,1H,CH2CH＝C),4.73(dd,J1＝12.4,J2＝7.2Hz,1H,ArCHS),3.88(s,3H,OCH3),3.85(s,3H,OCH3),3.81(s,3H,OCH3),3.68(s,3H,OCH3),2.63–2.50(m,2H,CH 2CH＝C),1.97(d,J＝4.0Hz,1H,SH),1.56(s,3H,CH3),1.55(s,3H,CH3)。
步骤三合成通法，将步骤二所得产物(0.5mmol)、碘化钾(0.05mmol)和溴代烷烃R1Br(0.5mmol)溶于10mL乙醇中，氮气保护下，迅速滴加40％氢氧化钠溶液(0.5mL)，滴加结束后回流反应4h，TLC检测原料点消失，蒸去乙醇，二氯甲烷萃取，依次用饱和氯化钠溶液和水洗涤有机层，无水硫酸钠干燥，蒸除有机溶剂，柱层析分离得2-(1-烷硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘衍生物，无色油状物。
采用上述方法，当溴代烷烃中，R1为乙基时，所得2-(1-乙硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率80％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.76(q,J＝8.6Hz,2H,ArH),5.06(t,J＝7.6Hz,1H,CH2CH＝C),4.59(t,J＝7.6Hz,1H,ArCHS),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.59–2.47(m,2H,CH 2CH＝C),2.38–2.31(m,1H,1/2×(SCH 2CH3)),2.24–2.16(m,1H,1/2×(SCH 2CH3)),1.55(s,3H,CH＝C-CH 3),1.50(s,3H,CH＝C-CH 3),1.06(t,J＝7.4Hz,3H,SCH2CH 3)。
采用上述方法，当溴代烷烃中，R1为丁基时，所得2-(1-丁硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率78％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.76(q,J＝8.6Hz,2H,ArH),5.07(t,J＝7.0Hz,1H,CH2CH＝C),4.56(t,J＝7.4Hz,1H,ArCHS),3.87(s,3H),3.85(s,3H,OCH3),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.58–2.46(m,2H,CH 2CH＝C),2.41–2.34(m,1H,1/2×(SCH 2CH2)),2.22–2.14(m,1H,1/2×(SCH 2CH2)),1.54(s,3H,CH＝C-CH 3),1.48(s,3H,CH＝C-CH 3),1.42–1.34(m,2H,CH 2CH2CH3),1.24–1.18(m,2H,CH2CH 2CH3),0.72(t,J＝7.4Hz,3H,CH2CH2CH 3)。
采用上述方法，当溴代烷烃中，R1为异戊基时，所得2-(1-异戊硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率84％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.75(q,J＝8.6Hz,2H,ArH),5.07(t,J＝6.8Hz,1H,CH2CH＝C),4.56(t,J＝7.4Hz,1H,ArCHS),3.88(s,3H,OCH3),3.85(s,3H,OCH3),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.58–2.46(m,2H,CH 2CH＝C),2.42–2.35(m,1H,1/2×(SCH 2CH2)),2.23–2.15(m,1H,1/2×(SCH 2CH2)),1.54(s,3H,CH＝C-CH 3),1.49(s,3H,CH＝C-CH 3),1.32–1.26(m,2H,SCH2CH 2CH),1.21–1.15(m,1H,SCH2CH2CH),0.69(dd,J＝14.8,6.6Hz,6H,CH(CH 3)2)。
采用上述方法，当溴代烷烃中，R1为异戊烯基时，所得2-(1-异戊烯硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率82％。1H NMR(400MHz,CDCl3):δ7.01(s,1H,ArH),6.79–6.73(m,2H,ArH),5.13–5.04(m,2H,CH2CH＝C+CH＝C(CH3)2),4.57(t,J＝7.4Hz,1H,ArCHS),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.83(s,3H,OCH3),3.65(s,3H,OCH3),3.04–2.99(m,1H,CH 2CH＝C),2.87–2.82(m,1H,1/2×(SCH 2CH2)),2.59–2.46(m,2H,1/2×(SCH 2CH2)),1.58(s,3H,CH＝C-CH 3),1.53(s,3H,CH＝C-CH 3),1.48(s,3H,CH＝C-CH 3),1.45(s,3H,CH＝C-CH 3)。
采用上述方法，当溴代烷烃中，R1为己基时，所得2-(1-己硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率81％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.76(q,J＝8.6Hz,2H,ArH),5.07(t,J＝7.2Hz,1H,CH2CH＝C),4.56(t,J＝7.6Hz,1H,ArCHS),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.84(s,3H,OCH3),3.65(s,3H,OCH3),2.59–2.44(m,2H,CH 2CH＝C),2.40–2.34(m,1H,1/2×(SCH 2CH2)),2.21–2.13(m,1H,1/2×(SCH 2CH2)),1.54(s,3H,CH＝C-CH 3),1.49(s,3H,CH＝C-CH 3),1.43–1.33(m,2H,SCH2CH 2),1.20–1.05(m,6H,3×CH2),0.73(t,J＝7.0Hz,3H,CH2CH 3)。
采用上述方法，当溴代烷烃中，R1为庚基时，所得2-(1-庚硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率85％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.76(q,J＝8.6Hz,2H,ArH),5.07(t,J＝7.0Hz,1H,CH2CH＝C),4.56(t,J＝7.4Hz,1H,ArCHS),3.88(s,3H,OCH3),3.85(s,3H,OCH3),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.58–2.44(m,2H,CH 2CH＝C),2.41–2.33(m,1H,1/2×(SCH 2CH2)),2.22–2.13(m,1H,1/2×(SCH 2CH2)),1.54(s,3H,CH＝C-CH 3),1.49(s,3H,CH＝C-CH 3),1.41–1.32(m,2H,SCH2CH 2),1.19–1.07(m,8H,4×CH2),0.75(t,J＝6.8Hz,3H,CH2CH 3)。
采用上述方法，当溴代烷烃中，R1为辛基时，所得2-(1-辛硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率82％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.76(q,J＝8.6Hz,2H,ArH),5.07(t,J＝7.2Hz,1H,CH2CH＝C),4.56(t,J＝7.6Hz,1H,ArCHS),3.88(s,3H,OCH3),3.85(s,3H,OCH3),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.59–2.44(m,2H,CH 2CH＝C),2.40–2.33(m,1H,1/2×(SCH 2CH2)),2.20–2.13(m,1H,1/2×(SCH 2CH2)),1.54(s,3H,CH＝C-CH 3),1.48(s,3H,CH＝C-CH 3),1.41–1.32(m,2H,SCH2CH 2),1.19–1.06(m,10H,5×CH2),0.76(t,J＝7.0Hz,3H,CH2CH 3)。
采用上述方法，当溴代烷烃中，R1为壬基时，所得2-(1-壬硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率83％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.76(q,J＝8.6Hz,2H,ArH),5.07(t,J＝7.2Hz,1H,CH2CH＝C),4.56(t,J＝7.6Hz,1H,ArCHS),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.84(s,3H,OCH3),3.65(s,3H,OCH3),2.58–2.44(m,2H,CH 2CH＝C),2.41–2.33(m,1H,1/2×(SCH 2CH2)),2.21–2.13(m,1H,1/2×(SCH 2CH2)),1.54(s,3H,CH＝C-CH 3),1.49(s,3H,CH＝C-CH 3),1.43–1.34(m,2H,SCH2CH 2),1.19–1.06(m,12H,6×CH2),0.78(t,J＝7.0Hz,3H,CH2CH 3)。
采用上述方法，当溴代烷烃中，R1为癸基时，所得2-(1-癸硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率79％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.76(q,J＝8.6Hz,2H,ArH),5.07(t,J＝7.0Hz,1H,CH2CH＝C),4.56(t,J＝7.6Hz,1H,ArCHS),3.88(s,3H,OCH3),3.85(s,3H,OCH3),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.58–2.44(m,2H,CH 2CH＝C),2.40–2.33(m,1H,1/2×(SCH 2CH2)),2.21–2.13(m,1H,1/2×(SCH 2CH2)),1.54(s,3H,CH＝C-CH 3),1.49(s,3H,CH＝C-CH 3),1.43–1.34(m,2H,SCH2CH 2),1.20–1.08(m,14H,7×CH2),0.79(t,J＝6.8Hz,3H,CH2CH 3)。
采用上述方法，当溴代烷烃中，R1为十二烷基时，所得2-(1-十二烷硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率77％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.77(q,J＝8.6Hz,2H,ArH),5.07(t,J＝7.2Hz,1H,CH2CH＝C),4.56(t,J＝7.6Hz,1H,ArCHS),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.84(s,3H,OCH3),3.65(s,3H,OCH3),2.59–2.44(m,2H,CH 2CH＝C),2.40–2.33(m,1H,1/2×(SCH 2CH2)),2.21–2.14(m,1H,1/2×(SCH 2CH2)),1.55(s,3H,CH＝C-CH 3),1.49(s,3H,CH＝C-CH 3),1.43–1.33(m,2H,SCH2CH 2),1.20–1.10(m,18H,9×CH2),0.80(t,J＝7.0Hz,3H,CH2CH 3)。
采用上述方法，当溴代烷烃中，R1为十六烷基时，所得2-(1-十六烷硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率78％。1H NMR(400MHz,CDCl3):δ7.00(s,1H,ArH),6.76(q,J＝8.6Hz,2H,ArH),5.07(t,J＝7.2Hz,1H,CH2CH＝C),4.56(t,J＝7.6Hz,1H,ArCHS),3.88(s,3H,OCH3),3.85(s,3H,OCH3),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.58–2.45(m,2H,CH 2CH＝C),2.40–2.33(m,1H,1/2×(SCH 2CH2)),2.21–2.14(m,1H,1/2×(SCH 2CH2)),1.54(s,3H,CH＝C-CH 3),1.49(s,3H,CH＝C-CH 3),1.42–1.34(m,2H,SCH2CH 2),1.19–1.09(m,26H,13×CH2),0.80(t,J＝6.8Hz,3H,CH2CH 3)。
采用上述方法，当溴代烷烃中，R1为苯甲基时，所得2-(1-苯甲硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率74％。1H NMR(400MHz,CDCl3):δ7.19(s,2H,ArH),7.15(d,J＝1.4Hz,1H,ArH),7.14(s,2H,ArH),7.09(dd,J＝9.4,4.4Hz,1H,ArH),7.01(s,1H,ArH),6.77(s,1H,ArH),5.04(t,J＝7.2Hz,1H,CH2CH＝C),4.58(t,J＝7.4Hz,1H,ArCHS),3.87(s,3H,OCH3),3.86(s,3H,OCH3),3.84(s,3H,OCH3),3.68–3.61(m,2H,SCH 2Ar),3.55(s,3H,OCH3),2.60–2.46(m,2H,CH 2CH＝C),1.53(s,3H,CH＝C-CH 3),1.49(s,3H,CH＝C-CH 3)。
采用上述方法，当溴代烷烃中，R1为法尼基时，所得2-(1-法尼硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率75％。1H NMR(400MHz,CDCl3):δ7.02(s,1H,ArH),6.79–6.73(m,2H,ArH),5.13(t,J＝7.8Hz,1H,CH2CH＝C),5.06(t,J＝7.2Hz,1H,CH2CH＝C),5.00(dd,J＝12.0,5.6Hz,2H,2×(CH2CH＝C)),4.57(t,J＝7.2Hz,1H,ArCHS),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.83(s,3H,OCH3),3.65(s,3H,OCH3),3.07–3.01(m,1H,1/2×(SCH 2CH＝C)),2.89–2.82(m,1H,1/2×(SCH 2CH＝C)),2.58–2.48(m,2H,CH 2CH＝C),1.98–1.93(m,4H,2×CH2),1.90–1.85(m,4H,2×CH2),1.59(s,3H,CH＝C-CH 3),1.54(s,3H,CH＝C-CH 3),1.52(s,3H,CH＝C-CH 3),1.49(s,3H,CH＝C-CH 3),1.48(s,3H,CH＝C-CH 3),1.46(s,3H,CH＝C-CH 3)。
步骤四合成通法，将步骤三中所得硫醚衍生物(1.0mmol)溶于乙酸乙酯中，在冰浴条件下，缓慢滴入2.5mL硝酸铈铵的水溶液(2.6mmol)，8min后反应结束，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，蒸除溶剂，柱层析分离得6-侧链取代5,,8-二甲氧基-1,4-萘醌衍生物，黄色油状物。具体产物如下：
6-(1-乙硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率27％。1H NMR(400MHz,CDCl3):δ7.48(s,1H,ArH),6.72(s,2H,QuinH),5.03(t,J＝7.6Hz,1H,CH2CH＝C),4.45(t,J＝7.6Hz,1H,ArCHS),3.92(s,3H,OCH3),3.75(s,3H,OCH3),2.52–2.46(m,2H,CH 2CH＝C),2.37–2.29(m,2H,SCH 2CH3),1.58(s,3H,CH＝C-CH 3),1.48(s,3H,CH＝C-CH 3),1.13(t,J＝7.4Hz,3H,SCH2CH 3)。
6-(1-丁硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率29％。1H NMR(400MHz,CDCl3):δ7.49(s,1H,ArH),6.72(d,J＝2.4Hz,2H,QuinH),5.03(t,J＝7.2Hz,1H,CH2CH＝C),4.41(t,J＝7.4Hz,1H,ArCHS),3.92(s,3H,OCH3),3.74(s,3H,OCH3),2.53–2.45(m,2H,CH 2CH＝C),2.40–2.34(m,1H,1/2×(SCH 2CH2)),2.30–2.21(m,1H,1/2×(SCH 2CH2)),1.57(s,3H,CH＝C-CH 3),1.47(s,3H,CH＝C-CH 3),1.44–1.38(m,2H,SCH2CH 2),1.26–1.20(m,2H,CH2CH 2CH3),0.77(t,J＝7.2Hz,3H,CH2CH 3)。
6-(1-异戊硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率32％。1H NMR(400MHz,CDCl3):δ7.53(s,1H,ArH),6.76(d,J＝3.4Hz,2H,QuinH),5.08(t,J＝7.6Hz,1H,CH2CH＝C),4.46(t,J＝7.4Hz,1H,ArCHS),3.97(s,3H,OCH3),3.79(s,3H,OCH3),2.56–2.50(m,2H,CH 2CH＝C),2.45–2.40(m,1H,1/2×(SCH 2CH2)),2.35–2.28(m,1H,1/2×(SCH 2CH2)),1.62(s,3H,CH＝C-CH 3),1.52(s,3H,CH＝C-CH 3),1.39–1.35(m,2H,SCH2CH 2),1.27–1.24(m,1H,CH2CH(CH3)2),0.81(d,J＝6.8Hz,3H,CH2CHCH 3),0.78(d,J＝6.8Hz,3H,CH2CHCH 3)。
6-(1-异戊烯硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率29％。1HNMR(400MHz,CDCl3):δ7.48(s,1H,ArH),6.75–6.68(m,2H,QuinH),5.10(t,J＝7.6Hz,1H,CH2CH＝C),5.01(t,J＝7.2Hz,1H,CH2CH＝C),4.41(t,J＝7.2Hz,1H,ArCHS),3.93(s,3H,OCH3),3.74(s,3H,OCH3),3.05–2.93(m,2H,SCH 2CH＝C),2.55–2.45(m,2H,CH 2CH＝C),1.61(s,3H,CH＝C-CH 3),1.57(s,3H,CH＝C-CH 3),1.48(s,3H,CH＝C-CH 3),1.46(s,3H,CH＝C-CH 3)。
6-(1-己硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率27％。1H NMR(400MHz,CDCl3):δ7.49(s,1H,ArH),6.75–6.69(m,2H,QuinH),5.02(t,J＝7.2Hz,1H,CH2CH＝C),4.41(t,J＝7.2Hz,1H,ArCHS),3.92(s,3H,OCH3),3.74(s,3H,OCH3),2.55–2.43(m,2H,CH 2CH＝C),2.41–2.34(m,1H,1/2×(SCH 2CH2)),2.29–2.21(m,1H,1/2×(SCH 2CH2)),1.57(s,3H,CH＝C-CH 3),1.47(s,3H,CH＝C-CH 3),1.44–1.38(m,2H,SCH2CH 2),1.25–1.12(m,6H,3×CH2),0.77(t,J＝7.0Hz,3H,CH2CH 3)。
6-(1-庚硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率24％。1H NMR(400MHz,CDCl3):δ7.49(s,1H,ArH),6.76–6.67(m,2H,QuinH),5.03(t,J＝7.0Hz,1H,CH2CH＝C),4.41(t,J＝7.2Hz,1H,ArCHS),3.92(s,3H,OCH3),3.74(s,3H,OCH3),2.55–2.43(m,2H,CH 2CH＝C),2.42–2.33(m,1H,1/2×(SCH 2CH2)),2.41–2.33(m,1H,1/2×(SCH 2CH2)),1.57(s,3H,CH＝C-CH 3),1.47(s,3H,CH＝C-CH 3),1.44–1.39(m,2H,SCH2CH 2),1.19–1.13(m,8H,4×CH2),0.78(t,J＝6.8Hz,3H,CH2CH 3)。
6-(1-辛硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率26％。1H NMR(400MHz,CDCl3):δ7.49(s,1H,ArH),6.76–6.68(m,2H,QuinH),5.02(t,J＝7.2Hz,1H,CH2CH＝C),4.41(t,J＝7.2Hz,1H,ArCHS),3.92(s,3H,OCH3),3.74(s,3H,OCH3),2.55–2.43(m,2H,CH 2CH＝C),2.42–2.34(m,1H,1/2×(SCH 2CH2)),2.29–2.21(m,1H,1/2×(SCH 2CH2)),1.57(s,3H,CH＝C-CH 3),1.47(s,3H,CH＝C-CH 3),1.44–1.37(m,2H,SCH2CH 2),1.24–1.18(m,4H,2×CH2),1.16–1.12(m,6H,3×CH2),0.78(t,J＝7.0Hz,3H,CH2CH 3)。
6-(1-壬硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率22％。1H NMR(400MHz,CDCl3):δ7.49(s,1H,ArH),6.71(t,J＝7.0Hz,2H,QuinH),5.02(t,J＝7.2Hz,1H,CH2CH＝C),4.41(t,J＝7.6Hz,1H,ArCHS),3.92(s,3H,OCH3),3.74(s,3H,OCH3),2.55–2.42(m,2H,CH 2CH＝C),2.41–2.34(m,1H,1/2×(SCH 2CH2)),2.29–2.21(m,1H,1/2×(SCH 2CH2)),1.57(s,3H,CH＝C-CH 3),1.47(s,3H,CH＝C-CH 3),1.44–1.38(m,2H,SCH2CH 2),1.21–1.12(m,12H,6×CH2),0.79(t,J＝7.0Hz,3H,CH2CH 3)。
6-(1-癸硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率21％。1H NMR(400MHz,CDCl3):δ7.49(s,1H,ArH),6.76–6.68(m,2H,QuinH),5.03(t,J＝7.2Hz,1H,CH2CH＝C),4.41(t,J＝7.2Hz,1H,ArCHS),3.92(s,3H,OCH3),3.74(s,3H,OCH3),2.56–2.42(m,2H,CH 2CH＝C),2.40–2.33(m,1H,1/2×(SCH 2CH2)),2.28–2.22(m,1H,1/2×(SCH 2CH2)),1.57(s,3H,CH＝C-CH 3),1.47(s,3H,CH＝C-CH 3),1.44–1.39(m,2H,SCH2CH 2),1.20–1.15(m,14H,7×CH2),0.80(t,J＝7.0Hz,3H,CH2CH 3)。
6-(1-十二烷硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率24％。1HNMR(400MHz,CDCl3):δ7.49(s,1H,ArH),6.71(t,J＝6.8Hz,2H,QuinH),5.03(t,J＝7.2Hz,1H,CH2CH＝C),4.41(t,J＝7.2Hz,1H,ArCHS),3.92(s,3H,OCH3),3.74(s,3H,OCH3),2.54–2.43(m,2H,CH 2CH＝C),2.40–2.34(m,1H,1/2×(SCH 2CH2)),2.29–2.22(m,1H,1/2×(SCH 2CH2)),1.57(s,3H,CH＝C-CH 3),1.47(s,3H,CH＝C-CH 3),1.45–1.39(m,2H,SCH2CH 2),1.20–1.10(m,18H,9×CH2),0.81(t,J＝6.8Hz,3H,CH2CH 3)。
6-(1-十六烷硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率27％。1HNMR(400MHz,CDCl3):δ7.49(s,1H,ArH),6.70(t,J＝6.8Hz,2H,QuinH),5.03(t,J＝7.0Hz,1H,CH2CH＝C),4.41(t,J＝7.2Hz,1H,ArCHS),3.92(s,3H,OCH3),3.74(s,3H,OCH3),2.53–2.43(m,2H,CH 2CH＝C),2.41–2.34(m,1H,1/2×(SCH 2CH2)),2.29–2.22(m,1H,1/2×(SCH 2CH2)),1.57(s,3H,CH＝C-CH 3),1.47(s,3H,CH＝C-CH 3),1.45–1.39(m,2H,SCH2CH 2),1.19–1.13(m,26H,13×CH2),0.80(t,J＝7.0Hz,3H,CH2CH 3)。
6-(1-苯甲硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率27％。1H NMR(400MHz,CDCl3):δ7.42(s,1H,ArH),7.17–7.11(m,5H,QuinH+ArH),6.71(d,J＝4.0Hz,2H,ArH),4.98(t,J＝7.2Hz,1H,CH2CH＝C),4.35(t,J＝7.2Hz,1H,ArCHS),3.88(s,3H,OCH3),3.64–3.60(m,1H,1/2×(SCH 2Ar)),3.59(s,3H,OCH3),3.56–3.52(m,1H,1/2×(SCH 2Ar)),2.52–2.46(m,2H,CH 2CH＝C),1.56(s,3H,CH＝C-CH 3),1.43(s,3H,CH＝C-CH 3)。
6-(1-法尼硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率32％。1H NMR(400MHz,CDCl3):δ7.54(s,1H,ArH),6.76(d,2H,QuinH),5.08–5.04(m,4H,4×(CH＝C)),4.47(t,J＝7.6Hz,1H,ArCHS),3.97(s,3H,OCH3),3.79(s,3H,OCH3),3.10–3.03(m,2H,SCH 2CH＝C),2.57–2.52(m,2H,CH2CH＝C),2.02–1.96(m,8H,4×CH2),1.66(s,6H,2×(CH＝C-CH 3)),1.62(s,3H,CH＝C-CH 3),1.57(s,3H,CH＝C-CH 3),1.53(s,3H,CH＝C-CH 3),1.51(s,3H,CH＝C-CH 3)。
步骤五合成通法，将步骤四中所得6位氧化产物(1.0mmol)溶于无水乙醇(12.0mL)，加入吡啶(3.5mmol)和盐酸羟胺(3.5mmol)，50℃加热反应过夜，TLC检测反应结束后，蒸除溶剂得到黄色固体，无水乙醇重结晶，得到目标产物。分别如下：
(E,E)-6-(1-乙硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-1)：淡黄色固体，收率78％。1H NMR(400MHz,DMSO-d6):δ12.07(s,2H,2×(N＝OH)),7.40(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝7.0Hz,1H,CH2CH＝C),4.41(t,J＝7.0Hz,1H,ArCH(CH2)S),3.80(s,3H,OCH3),3.59(s,3H,OCH3),2.58(t,2H,J＝7.0Hz,CHCH 2CH＝C),2.38(q,J＝7.2Hz,2H,SCH 2CH3),1.61(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.13(t,J＝7.4Hz,3H,CH2CH 3)。
(E,E)-6-(1-丁硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-2)：淡黄色固体，收率80％。1H NMR(400MHz,DMSO-d6):δ12.07(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝6.8Hz,1H,CH2CH＝C),4.37(t,J＝7.4Hz,1H,ArCH(CH2)S),3.80(s,3H,OCH3),3.59(s,3H,OCH3),2.58(t,J＝7.0Hz,2H,CHCH 2CH＝C),2.43–2.34(m,2H,SCH 2CH2),1.61(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.47–1.39(m,2H,CH2),1.34–1.25(m,2H,CH2),0.79(t,J＝7.2Hz,3H,CH2CH 3)。
(E,E)-6-(1-异戊硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-3)：淡黄色固体，收率75％。1H NMR(400MHz,DMSO-d6):δ12.02(s,2H,2×(N＝OH)),7.35(s,2H,QuinH),7.17(s,1H,ArH),5.07(t,J＝7.2Hz,1H,CH2CH＝C),4.33(t,J＝7.6Hz,1H,ArCH(CH2)S),3.75(s,3H,OCH3),3.55(s,3H,OCH3),2.54(t,J＝7.2Hz,2H,CHCH 2CH＝C),2.39–2.28(m,2H,SCH 2CH2),1.56(s,3H,C＝CH3),1.54–1.48(m,4H,C＝CH3and CH(CH3)2),1.31–1.25(m,2H,CH2),0.75(d,J＝6.6Hz,3H,CHCH 3),0.71(d,J＝6.6Hz,3H,CHCH 3)。
(E,E)-6-(1-异戊烯硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-4)：淡黄色固体，收率81％。1H NMR(400MHz,DMSO-d6):δ12.02(s,2H,2×(N＝OH)),7.35(s,2H,QuinH),7.16(s,1H,ArH),5.12(t,J＝6.6Hz,1H,CH2CH＝C),5.03(t,J＝6.6Hz,1H,SCH2CH＝C),4.31(t,J＝7.0Hz,1H,ArCH(CH2)S),3.76(s,3H,OCH3),3.55(s,3H,OCH3),3.04(d,J＝7.2Hz,2H,SCH 2CH＝C),2.56(t,2H,CHCH 2CH＝C),1.60(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.51(s,3H,C＝CH3),1.49(s,3H,C＝CH3)。
(E,E)-6-(1-己硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-5)：淡黄色固体，收率68％。1H NMR(400MHz,DMSO-d6):δ12.07(s,2H,2×(N＝OH)),7.40(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝7.2Hz,1H,CH2CH＝C),4.37(t,J＝7.2Hz,1H,ArCH(CH2)S),3.80(s,3H,OCH3),3.59(s,3H,OCH3),2.63–2.55(m,2H,CHCH 2CH＝C),2.44–2.38(m,2H,SCH 2CH2),1.61(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.47–1.37(m,2H,SCH2CH 2),1.26–1.11(m,6H,3×CH2),0.79(t,J＝7.0Hz,3H,CH2CH 3)。
(E,E)-6-(1-庚硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-6)：淡黄色固体，收率75％。1H NMR(400MHz,DMSO-d6):δ12.03(s,2H,2×(N＝OH)),7.40(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝6.6Hz,1H,CH2CH＝C),4.37(t,J＝7.4Hz,1H,ArCH(CH2)S),3.80(s,3H,OCH3),3.59(s,3H,OCH3),2.57(t,J＝6.8Hz,2H,CHCH 2CH＝C),2.44–2.32(m,2H,SCH 2CH2),1.61(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.46–1.39(m,2H,SCH2CH 2),1.25–1.12(m,8H,4×CH2),0.81(t,J＝6.8Hz,3H,CH2CH 3)。
(E,E)-6-(1-辛硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-7)：淡黄色固体，收率83％。1H NMR(400MHz,DMSO-d6):δ12.06(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝6.6Hz,1H,CH2CH＝C),4.36(t,J＝7.6Hz,1H,ArCH(CH2)S),3.79(s,3H,OCH3),3.58(s,3H,OCH3),2.57(t,J＝7.0Hz,2H,CHCH 2CH＝C),2.44–2.31(m,2H,SCH 2CH2),1.60(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.45–1.38(m,2H,SCH2CH 2),1.25–1.12(m,10H,5×CH2),0.82(t,J＝6.8Hz,3H,CH2CH 3)。
(E,E)-6-(1-壬硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-8)：淡黄色固体，收率79％。1H NMR(400MHz,DMSO-d6):δ12.03(s,2H,2×(N＝OH)),7.40(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝6.6Hz,1H,CH2CH＝C),4.37(t,J＝7.4Hz,1H,ArCH(CH2)S),3.80(s,3H,OCH3),3.59(s,3H,OCH3),2.57(t,J＝7.0Hz,2H,CHCH 2CH＝C),2.45–2.32(m,2H,SCH 2CH2),1.61(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.46–1.38(m,2H,SCH2CH 2),1.25–1.12(m,12H,6×CH2),0.83(t,J＝6.8Hz,3H,CH2CH 3)。
(E,E)-6-(1-癸硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-9)：淡黄色固体，收率86％。1H NMR(400MHz,DMSO-d6):δ12.02(s,2H,2×(N＝OH)),7.40(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝7.2Hz,1H,CH2CH＝C),4.37(t,J＝7.2Hz,1H,ArCH(CH2)S),3.80(s,3H,OCH3),3.59(s,3H,OCH3),2.60–2.53(m,2H,CHCH 2CH＝C),2.43–2.32(m,2H,SCH 2CH2),1.61(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.45–1.38(m,2H,SCH2CH 2),1.24–1.13(m,14H,7×CH2),0.84(t,J＝6.8Hz,3H,CH2CH 3)。
(E,E)-6-(1-十二烷硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-10)：淡黄色固体，收率82％。1H NMR(400MHz,DMSO-d6):δ12.03(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝6.8Hz,1H,CH2CH＝C),4.37(t,J＝7.4Hz,1H,ArCH(CH2)S),3.79(s,3H,OCH3),3.59(s,3H,OCH3),2.60–2.53(m,2H,CHCH 2CH＝C),2.43–2.33(m,2H,SCH 2CH2),1.61(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.46–1.39(m,2H,SCH2CH 2),1.26–1.12(m,18H,9×CH2),0.85(t,J＝6.8Hz,3H,CH2CH 3)。
(E,E)-6-(1-十六烷硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-11)：淡黄色固体，收率79％。1H NMR(400MHz,DMSO-d6):δ12.04(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.20(s,1H,ArH),5.11(t,J＝6.8Hz,1H,CH2CH＝C),4.36(t,J＝7.4Hz,1H,ArCH(CH2)S),3.79(s,3H,OCH3),3.59(s,3H,OCH3),2.60–2.50(m,2H,CHCH 2CH＝C),2.45–2.30(m,2H,SCH 2CH2),1.60(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.45–1.39(m,2H,SCH2CH 2),1.27–1.11(m,26H,13×CH2),0.84(t,J＝6.8Hz,3H,CH2CH 3)。
(E,E)-6-(1-苯甲硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-12)：淡黄色固体，收率71％。1H NMR(400MHz,DMSO-d6):δ12.04(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.30–7.25(m,4H,ArH),7.23–7.18(m,2H,ArH),5.02(t,J＝6.2Hz,1H,CH2CH＝C),4.31(t,J＝7.4Hz,1H,ArCH(CH2)S),3.79(s,3H,OCH3),3.70(s,2H,ArCH 2S),3.45(s,3H,OCH3),2.60(t,J＝6.8Hz,2H,CHCH 2CH＝C),1.58(s,3H,C＝CH3),1.52(s,3H,C＝CH3)。
(E,E)-6-(1-法尼硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(III-13)：淡黄色固体，收率67％。1H NMR(400MHz,DMSO-d6):δ11.99(s,2H,2×(N＝OH)),7.35(s,2H,QuinH),7.15(s,1H,ArH),5.11(t,J＝7.8Hz,1H,CH2CH＝C),5.05–4.96(m,3H,3×(CH2CH＝C)),4.31(t,J＝7.2Hz,1H,ArCH(CH2)S),3.74(s,3H,OCH3),3.54(s,3H,OCH3),3.08–2.99(m,2H,CHCH 2CH＝C)),2.57–2.50(m,2H,SCH 2CH2),2.02–1.79(m,10H,5×CH2),1.61–1.53(m,9H,3×CH3),1.51–1.46(m,9H,3×CH3)。
实施例2
本实施例涉及一种具有结构式(IV)的硫酯类外消旋体紫草素肟衍生物制备方法，如图1所示，包括如下步骤：
本实施例步骤一、二与实施例一中步骤一、二相同。
步骤三合成通法，将步骤二中所得产物(0.5mmol)、4-二甲氨基吡啶(0.25mmol)和羧酸R2COOH(0.6mmol)混悬于无水二氯甲烷中，冰浴条件下，分批次加入N,N-二环己基碳二亚胺(0.6mmol)，添加结束后，室温搅拌过夜，此时析出白色固体，加入石油醚后白色固体增多，4℃静置1h后过滤，蒸除溶剂，柱层析分离得2-(1-酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘衍生物，无色油状物。
采用上述方法，当羧酸R2COOH中，R2为甲基时，所得2-(1-乙酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率93％。1H NMR(400MHz,CDCl3):δ6.75(s,2H,ArH),6.73(s,1H,ArH),5.22(t,J＝7.6Hz,1H,CH2CH＝C),4.98(t,J＝6.8Hz,1H,ArCH(CH2)S),3.86(s,6H,2×OCH3),3.82(s,3H,OCH3),3.71(s,3H,OCH3),2.68–2.53(m,2H,CH 2CH＝C),2.24(s,3H,COCH3),1.52(s,6H,2×(＝C-CH3))。
采用上述方法，当羧酸R2COOH中，R2为乙基时，所得2-(1-丙酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率91％。1H NMR(400MHz,CDCl3):δ6.75(s,2H,ArH),6.74(s,1H,ArH),5.24(t,t,J＝7.6Hz,1H,CH2CH＝C),4.98(t,J＝7.2Hz,1H,ArCH(CH2)S),3.86(s,6H,2×OCH3),3.83(s,3H,OCH3),3.72(s,3H,OCH3),2.69–2.56(m,2H,CH 2CH＝C),2.49(q,J＝7.6Hz,2H,COCH 2CH3),1.52(s,6H,2×(＝C-CH3)),1.09(t,J＝7.6Hz,3H,CH2CH 3)。
采用上述方法，当羧酸R2COOH中，R2为异丙基时，所得2-(1-异丁酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率89％。1H NMR(400MHz,CDCl3):δ6.75(s,1H,ArH),6.74(s,2H,ArH),5.22(t,J＝7.6Hz,1H,CH2CH＝C),4.99(t,J＝7.6Hz,1H,ArCH(CH2)S),3.86(s,6H,2×OCH3),3.82(s,3H,OCH3),3.71(s,3H,OCH3),2.68–2.61(m,2H,CH 2CH＝C),2.59–2.53(m,1H,COCH(CH3)2),1.52(s,6H,2×(＝C-CH3)),1.12(d,J＝7.0Hz,3H,CHCH 3),1.08(d,J＝7.0Hz,3H,CHCH 3)。
采用上述方法，当羧酸R2COOH中，R2为异丁基时，所得2-(1-异戊酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率87％。1H NMR(400MHz,CDCl3):δ6.79(s,3H,ArH),5.30(t,J＝7.4Hz,1H,CH2CH＝C),5.05(t,J＝7.2Hz,1H,ArCH(CH2)S),3.90(s,6H,2×OCH3),3.87(s,3H,OCH3),3.77(s,3H,OCH3),2.72–2.60(m,2H,CH 2CH＝C),2.38(d,J＝7.4Hz,2H,COCH 2CH),2.12–2.07(m,1H,COCH2CH),1.57(s,6H,2×(＝C-CH3)),0.96(d,J＝6.8Hz,6H,CH(CH 3)2)。
采用上述方法，当羧酸R2COOH中，R2为异丁烯基时，所得2-(1-异戊烯酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率87％。1H NMR(400MHz,CDCl3):δ6.76(s,1H,ArH),6.74(s,2H,ArH),5.87(s,1H,COCH＝C),5.25(t,J＝7.6Hz,1H,CH2CH＝C),5.01(t,J＝7.2Hz,1H,ArCH(CH2)S),3.85(s,6H,2×OCH3),3.82(s,3H,OCH3),3.73(s,3H,OCH3),2.70–2.56(m,2H,CH 2CH＝C),2.08(s,3H,＝C-CH3),1.78(s,3H,＝C-CH3),1.51(s,6H,2×(＝C-CH3))。
采用上述方法，当羧酸R2COOH中，R2为2-羟基-2-甲基丙基时，所得2-[1-(β-羟基异戊酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率79％。1H NMR(400MHz,CDCl3):δ6.76(s,2H,ArH),6.72(s,1H,ArH),5.29(t,J＝7.6Hz,1H,CH2CH＝C),5.01(t,J＝7.6Hz,1H,ArCH(CH2)S),3.87(s,3H,OCH3),3.85(s,3H,OCH3),3.83(s,3H,OCH3),3.72(s,3H,OCH3),2.69–2.62(m,3H,CH 2CH＝C+1/2×(COCH2)),2.62–2.56(m,1H,1/2×(COCH2)),1.54(d,J＝4.2Hz,6H,2×(＝C-CH3)),1.21(s,3H,CH3),1.17(s,3H,CH3).
采用上述方法，当羧酸R2COOH中，R2为戊基时，所得2-(1-己酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率82％。1H NMR(400MHz,CDCl3):δ6.74(s,3H,3ArH),5.24(t,J＝7.4Hz,1H,CH2CH＝C),4.99(t,J＝7.0Hz,1H,ArCH(CH2)S),3.85(s,6H,2×OCH3),3.81(s,3H,OCH3),3.71(s,3H,OCH3),2.68–2.53(m,2H,CH 2CH＝C),2.44(t,J＝7.6Hz,2H,COCH 2CH2),1.62–1.54(m,2H,COCH2CH 2),1.52(s,6H,2×(＝C-CH3)),1.25–1.18(m,4H,CH2CH2),0.79(t,J＝6.2Hz,3H,CH2CH 3)。
采用上述方法，当羧酸R2COOH中，R2为苯基时，所得2-(1-苯甲酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率84％。1H NMR(400MHz,CDCl3):δ7.89(d,J＝7.8Hz,2H,ArH),7.46(t,J＝7.4Hz,1H,ArH),7.35(t,J＝7.6Hz,2H,ArH),6.84(s,1H,ArH),6.75(s,2H,ArH),5.47(t,J＝7.6Hz,1H,CH2CH＝C),5.04(t,J＝7.2Hz,1H,ArCH(CH2)S),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.82(s,3H,OCH3),3.76(s,3H,OCH3),2.81–2.74(m,1H,1/2×(CH 2CH＝C)),2.72–2.64(m,1H,1/2×(CH 2CH＝C)),1.55(s,3H,＝C-CH3),1.52(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为对苯基时，所得2-[1-(对甲基苯甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率87％。1H NMR(400MHz,CDCl3):δ7.84(d,J＝7.6Hz,2H,ArH),7.20(d,J＝7.8Hz,2H,ArH),6.90(s,1H,ArH),6.81(s,2H,ArH),5.51(t,J＝7.6Hz,1H,CH2CH＝C),5.10(t,J＝7.2Hz,1H,ArCH(CH2)S),3.93(s,3H,OCH3),3.92(s,3H,OCH3),3.88(s,3H,OCH3),3.81(s,3H,OCH3),2.86–2.79(m,1H,1/2×(CHCH 2CH＝C)),2.77–2.69(m,1H,1/2×(CHCH 2CH＝C)),2.37(s,3H,ArCH 3),1.61(s,3H,＝C-CH3),1.58(s,3H,＝C-CH3).
采用上述方法，当羧酸R2COOH中，R2为对硝基苯基时，所得2-[1-(对硝基苯甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率85％。1H NMR(400MHz,CDCl3):δ8.19(d,J＝9.0Hz,2H,ArH),8.02(d,J＝9.0Hz,2H,ArH),6.81(s,1H,ArH),6.76(s,2H,ArH),5.48(t,J＝7.6Hz,1H,CH2CH＝C),5.04(t,J＝7.4Hz,1H,ArCH(CH2)S),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.82(s,3H,OCH3),3.75(s,3H,OCH3),2.83–2.66(m,2H,CHCH 2CH＝C),1.57(s,3H,＝C-CH3),1.54(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为4-叔丁氧酰氨基苯基时，所得2-[1-(4-叔丁氧酰氨基)苯甲酰硫基-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率85％。1H NMR(400MHz,CDCl3):δ8.19(d,J＝9.0Hz,2H,ArH),8.02(d,J＝9.0Hz,2H,ArH),6.81(s,1H,ArH),6.76(s,2H,ArH),5.48(t,J＝7.6Hz,1H,CH2CH＝C),5.04(t,J＝7.4Hz,1H,ArCH(CH2)S),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.82(s,3H,OCH3),3.75(s,3H,OCH3),2.83–2.66(m,2H,CHCH 2CH＝C),1.57(s,3H,＝C-CH3),1.54(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为对三氟甲基苯基时，所得2-[1-(对三氟甲基苯甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率84％。1H NMR(400MHz,CDCl3):δ7.96(d,J＝8.2Hz,2H,ArH),7.58(d,J＝8.2Hz,2H,ArH),6.81(s,1H,ArH),6.73(s,2H,ArH),5.47(t,J＝7.6Hz,1H,CH2CH＝C),5.03(t,J＝7.2Hz,1H,ArCH(CH2)S),3.86(s,3H,OCH3),3.83(s,3H,OCH3),3.79(s,3H,OCH3),3.74(s,3H,OCH3),2.82–2.64(m,2H,CHCH 2CH＝C),1.55(s,3H,＝C-CH3),1.51(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为间三氟甲基苯基时，所得2-[1-(间三氟甲基苯甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率86％。1H NMR(400MHz,CDCl3):δ8.14(s,1H,ArH),8.06(d,J＝7.8Hz,1H,ArH),7.72(d,J＝7.8Hz,1H,ArH),7.49(t,J＝7.8Hz,1H,ArH),6.83(s,1H,ArH),6.76(s,2H,ArH),5.49(t,J＝7.6Hz,1H,CH2CH＝C),5.04(t,J＝7.0Hz,1H,ArCH(CH2)S),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.82(s,3H,OCH3),3.75(s,3H,OCH3),2.88–2.75(m,1H,1/2×(CHCH 2CH＝C)),2.74–2.66(m,1H,1/2×(CHCH 2CH＝C)),1.57(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为肉桂基时，所得2-(1-肉桂酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率85％。1H NMR(400MHz,CDCl3):δ7.53(d,J＝15.8Hz,1H,ArH),7.43(d,J＝4.8Hz,2H,ArH),7.29(d,J＝4.8Hz,3H,ArH and COCH＝CHAr),6.80(s,1H,ArH),6.75(s,2H,ArH),6.62(d,J＝15.8Hz,1H,COCH＝CHAr),5.39(t,J＝7.6Hz,1H,CH2CH＝C),5.03(t,J＝7.0Hz,1H,ArCH(CH2)S),3.87(s,3H,OCH3),3.86(s,3H,OCH3),3.82(s,3H,OCH3),3.75(s,3H,OCH3),2.77–2.61(m,2H,CHCH 2CH＝C),1.55(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3,4-二甲氧基苯基时，所得2-[1-(3,4-二甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率89％。1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.6Hz,1H,ArH),7.40(s,1H,ArH),6.85(s,1H,ArH),6.79(d,J＝8.6Hz,1H,ArH),6.76(s,2H,ArH),5.45(t,J＝7.0Hz,1H,CH2CH＝C),5.04(t,J＝7.0Hz,1H,ArCH(CH2)S),3.88(s,3H,OCH3),3.87(s,3H,OCH3),3.86(s,3H,OCH3),3.85(s,3H,OCH3),3.83(s,3H,OCH3),3.76(s,3H,OCH3),2.83–2.74(m,1H,1/2×(CHCH 2CH＝C)),2.72–2.64(m,1H,1/2×(CHCH 2CH＝C)),1.56(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3,4,5-三甲氧基苯基时，所得2-[1-(3,4,5-三甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率92％。1H NMR(400MHz,CDCl3):δ7.15(s,2H,ArH),6.85(s,1H,ArH),6.76(s,2H,ArH),5.45(t,J＝7.0Hz,1H,CH2CH＝C),5.03(t,J＝7.2Hz,1H,ArCH(CH2)S),3.89(s,3H,OCH3),3.87(s,3H,OCH3),3.83(s,12H,4×OCH3),3.75(s,3H,OCH3),2.75–2.83(m,1H,1/2×(CHCH 2CH＝C)),2.64–2.73(m,1H,1/2×(CHCH 2CH＝C)),1.57(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为邻氟苯基时，所得2-(1-邻氟苯甲酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率83％。1H NMR(400MHz,CDCl3):δ7.82(t,J＝7.6Hz,1H,ArH),7.45(dd,J＝13.6,7.0Hz,1H,ArH),7.16(t,J＝7.6Hz,1H,ArH),7.10(t,J＝7.6Hz,1H,ArH),6.88(s,1H,ArH),6.80(d,J＝7.6Hz,2H,ArH),5.54(t,J＝7.0Hz,1H,CH2CH＝C),5.10(t,J＝7.2Hz,1H,ArCH(CH2)S),3.93(s,3H,OCH3),3.92(s,3H,OCH3),3.88(s,3H,OCH3),3.82(s,3H,OCH3),2.88–2.82(m,1H,1/2×(CHCH 2CH＝C)),2.78–2.71(m,1H,1/2×(CHCH 2CH＝C)),1.61(s,3H,＝C-CH3),1.58(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为间氟苯基时，所得2-(1-间氟苯甲酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率85％。1H NMR(400MHz,CDCl3):δ7.73(d,J＝7.8Hz,1H,ArH),7.63(d,J＝10.4Hz,1H,ArH),7.38(dd,J＝14.4,7.2Hz,1H,ArH),7.23(d,J＝8.2Hz,1H,ArH),6.88(s,1H,ArH),6.81(s,2H,ArH),5.52(t,J＝7.4Hz,1H,CH2CH＝C),5.10(t,J＝7.0Hz,1H,ArCH(CH2)S),3.93(s,3H,OCH3),3.92(s,3H,OCH3),3.88(s,3H,OCH3),3.81(s,3H,OCH3),2.87–2.69(m,2H,CHCH 2CH＝C),1.61(s,3H,＝C-CH3),1.59(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为对氟苯基时，所得2-(1-对氟苯甲酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率81％。1H NMR(400MHz,CDCl3):δ7.95(dd,J＝9.0,5.4Hz,2H,ArH),7.06(t,J＝8.6Hz,2H,ArH),6.87(s,1H,ArH),6.80(s,2H,ArH),5.49(t,J＝7.4Hz,1H,CH2CH＝C),5.08(t,J＝7.4Hz,1H,ArCH(CH2)S),3.92(s,3H,OCH3),3.90(s,3H,OCH3),3.86(s,3H,OCH3),3.79(s,3H,OCH3),2.85–2.68(m,2H,CHCH 2CH＝C),1.59(s,3H,＝C-CH3),1.57(s,3H,＝C-CH3).
采用上述方法，当羧酸R2COOH中，R2为邻氯苯基时，所得2-(1-邻氯苯甲酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率86％。1H NMR(400MHz,CDCl3):δ7.57(dd,J＝7.8,1.6Hz,1H,ArH),7.42–7.32(m,2H,ArH),7.26(dd,J＝7.8,1.6Hz,1H,ArH),6.86(s,1H,ArH),6.82(s,2H,ArH),5.53(t,J＝8.6Hz,1H,CH2CH＝C),5.13(t,J＝8.6Hz,1H,ArCH(CH2)S),3.93(s,3H,OCH3),3.92(s,3H,OCH3),3.88(s,3H,OCH3),3.83(s,3H,OCH3),2.88–2.81(m,1H,1/2×(CHCH 2CH＝C)),2.79–2.72(m,1H,1/2×(CHCH 2CH＝C)),1.62(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为间氯苯基时，所得2-(1-间氯苯甲酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率81％。1H NMR(400MHz,CDCl3):δ7.91(s,1H,ArH),7.80(d,J＝7.8Hz,1H,ArH),7.48(d,J＝10.0Hz,1H,ArH),7.33(t,J＝7.8Hz,1H,ArH),6.87(s,1H,ArH),6.80(s,2H,ArH),5.50(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.2Hz,1H,ArCH(CH2)S),3.92(s,3H,OCH3),3.91(s,3H,OCH3),3.87(s,3H,OCH3),3.80(s,3H,OCH3),2.85–2.68(m,2H,CHCH 2CH＝C),1.60(s,3H,＝C-CH3),1.58(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为对氯苯基时，所得2-(1-对氯苯甲酰硫基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘：收率87％。1H NMR(400MHz,CDCl3):δ7.87(d,J＝8.6Hz,2H,ArH),7.37(d,J＝8.6Hz,2H,ArH),6.87(s,1H,ArH),6.80(s,2H,ArH),5.49(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.2Hz,1H,ArCH(CH2)S),3.92(s,3H,OCH3),3.91(s,3H,OCH3),3.87(s,3H,OCH3),3.79(s,3H,OCH3),2.86–2.77(m,1H,1/2×(CHCH 2CH＝C)),2.76–2.68(m,1H,1/2×(CHCH 2CH＝C)),1.60(s,3H,＝C-CH3),1.57(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为2-甲氧基苯基时，所得2-[1-(2-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率87％。1H NMR(400MHz,CDCl3):δ7.87(d,J＝8.6Hz,2H,ArH),7.37(d,J＝8.6Hz,2H,ArH),6.87(s,1H,ArH),6.80(s,2H,ArH),5.49(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.2Hz,1H,ArCH(CH2)S),3.92(s,3H,OCH3),3.91(s,3H,OCH3),3.87(s,3H,OCH3),3.79(s,3H,OCH3),2.86–2.77(m,1H,1/2×(CHCH 2CH＝C)),2.76–2.68(m,1H,1/2×(CHCH 2CH＝C)),1.60(s,3H,＝C-CH3),1.57(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3-甲氧基苯基时，所得2-[1-(3-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率88％。1H NMR(400MHz,CDCl3):δ7.54(d,J＝8.0Hz,1H,ArH),7.43(s,1H,ArH),7.29(t,J＝8.0Hz,1H,ArH),7.06(dd,J＝8.2,2.6Hz,1H,ArH),6.89(s,1H,ArH),6.80(s,2H,ArH),5.20(t,J＝7.6Hz,1H,CH2CH＝C),5.09(t,J＝7.6Hz,1H,ArCH(CH2)S),3.92(s,3H,OCH3),3.91(s,3H,OCH3),3.87(s,3H,OCH3),3.80(s,6H,2×OCH3),2.86–2.68(m,2H,CHCH 2CH＝C),1.60(s,3H,＝C-CH3),1.57(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为4-甲氧基苯基时，所得2-[1-(4-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率90％。1H NMR(400MHz,CDCl3):δ7.86(d,J＝8.8Hz,2H,ArH),6.82(t,J＝8.0Hz,3H),6.74(s,2H),5.44(t,J＝7.2Hz,1H,CH2CH＝C),5.03(t,J＝7.0Hz,1H,ArCH(CH2)S),3.87(s,3H,OCH3),3.85(s,3H,OCH3),3.81(s,3H,OCH3),3.75(s,6H,2×OCH3),2.80–2.63(m,2H,CHCH 2CH＝C),1.54(s,3H,＝C-CH3),1.51(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为2-呋喃基时，所得2-[1-(2-呋喃甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率87％。1H NMR(400MHz,CDCl3):δ7.47(s,1H,OCH＝CH),7.09(d,J＝3.6Hz,1H,C＝CH),6.82(s,1H,ArH),6.75(s,2H,ArH),6.43(t,J＝7.4Hz,1H,CH＝CH＝CH),5.46(t,J＝7.4Hz,1H,CH2CH＝C),5.03(t,J＝7.4Hz,1H,ArCH(CH2)S),3.87(s,3H,OCH3),3.86(s,3H,OCH3),3.82(s,3H,OCH3),3.75(s,3H,OCH3),2.80–2.63(m,2H,CHCH 2CH＝C),1.54(s,3H,＝C-CH3),1.52(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为2-噻吩基时，所得2-[1-(2-噻吩甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率83％。1H NMR(400MHz,CDCl3):δ7.70(d,J＝3.8Hz,1H,SCH＝CH),7.51(d,J＝4.8Hz,1H,C＝CH),7.01(t,J＝4.2Hz,1H,CH＝CH＝CH),6.83(s,1H,ArH),6.76(s,2H,ArH),5.45(t,J＝7.6Hz,1H,CH2CH＝C),5.03(t,J＝7.2Hz,1H,ArCH(CH2)S),3.88(s,3H,OCH3),3.86(s,3H,OCH3),3.82(s,3H,OCH3),3.75(s,3H,OCH3),2.79–2.75(m,1H,1/2×(CHCH 2CH＝C)),2.73–2.64(m,1H,1/2×(CHCH 2CH＝C)),1.55(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为2-吡啶基时，所得2-[1-(3-吡啶甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率81％。1H NMR(400MHz,CDCl3):δ9.10(s,1H,C＝CH-N),8.69(d,J＝4.0Hz,1H,N＝CH＝CH),8.12(d,J＝8.0Hz,1H,C＝CH＝CH),7.30(dd,J＝8.0,5.0Hz,1H,C＝CH＝CH),6.82(s,1H,ArH),6.76(s,2H,ArH),5.50(t,J＝7.4Hz,1H,CH2CH＝C),5.04(t,J＝7.4Hz,1H,ArCH(CH2)S),3.88(s,3H,OCH3),3.87(s,3H,OCH3),3.83(s,3H,OCH3),3.76(s,3H,OCH3),2.83–2.65(m,2H,CHCH 2CH＝C),1.57(s,3H,＝C-CH3),1.54(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为4-吡啶基时，所得2-[1-(4-吡啶甲酰硫基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘：收率86％。1H NMR(400MHz,CDCl3):δ8.69(s,2H,2×(CH＝N)),7.68(d,J＝4.4Hz,2H,2×(CH＝CH＝N)),6.80(s,1H,ArH),6.76(s,2H,ArH),5.47(t,J＝7.6Hz,1H,CH2CH＝C),5.03(t,J＝7.0Hz,1H,ArCH(CH2)S),3.87(s,3H,OCH3),3.86(s,3H,OCH3),3.82(s,3H,OCH3),3.75(s,3H,OCH3),2.81–2.65(m,2H,CHCH 2CH＝C),1.57(s,3H,＝C-CH3),1.54(s,3H,＝C-CH3)。
步骤四合成通法，与实施例1中步骤四相同，硫酯衍生物替换硫醚衍生物，经硝酸铈铵氧化脱甲基化后，得6-侧链取代-5,8-二甲氧基-1,4-萘醌衍生物，黄色油状物。所得产物具体如下：
6-(1-乙酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率41％。1H NMR(400MHz,CDCl3):δ7.28(s,1H,ArH),6.76(s,2H,QuinH),5.03(q,J＝6.6Hz,2H,CH2CH＝C+ArCH(CH2)S),3.94(s,3H,OCH3),3.88(s,3H,OCH3),2.60(t,J＝7.2Hz,2H,CH 2CH＝C),2.30(s,3H,COCH3),1.62(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3).
6-(1-丙酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率45％。1H NMR(400MHz,CDCl3):δ7.25(s,1H,ArH),6.72(s,2H,QuinH),5.03–4.94(m,2H,CH2CH＝C+ArCH(CH2)S),3.90(s,3H,OCH3),3.85(s,3H,OCH3),2.55(t,J＝7.2Hz,2H,CH 2CH＝C),2.48(q,J＝7.6Hz,2H,COCH 2CH3),1.57(s,3H,＝C-CH3),1.48(s,3H,＝C-CH3),1.09(t,J＝7.6Hz,3H,CH2CH 3).
6-(1-异丁酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率51％。1HNMR(400MHz,CDCl3):δ7.26(s,1H,CDCl3),6.72(s,2H,QuinH),5.01–4.93(m,2H,CH2CH＝C+ArCH(CH2)S),3.90(s,3H,OCH3),3.85(s,3H,OCH3),2.69–2.60(m,1H,1/2×(CH 2CH＝C)),2.54(t,J＝7.4Hz,2H,1/2×(CH 2CH＝C)+COCH(CH3)2),1.57(s,3H,＝C-CH3),1.48(s,3H,＝C-CH3),1.12(d,J＝7.0Hz,3H,CHCH 3),1.09(d,J＝7.0Hz,3H,CHCH 3)。
6-(1-异戊酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率53％。1HNMR(400MHz,CDCl3):δ7.30(s,1H,ArH),6.76(s,2H,QuinH),5.07–5.00(m,2H,CH2CH＝C+ArCH(CH2)S),3.94(s,3H,OCH3),3.89(s,3H,OCH3),2.58(t,J＝7.4Hz,2H,CH 2CH＝C),2.39(d,J＝7.2Hz,2H,COCH 2CH),2.16–2.08(m,1H,CH2CH(CH3)2),1.62(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3),0.91(d,J＝6.8Hz,6H,CH(CH 3)2)。
6-(1-异戊烯酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率48％。1HNMR(400MHz,CDCl3):δ7.32(s,1H,ArH),6.75(s,2H,QuinH),5.91(s,1H,COCH＝C),5.09–5.00(m,2H,CH2CH＝C+ArCH(CH2)S),3.94(s,3H,OCH3),3.90(s,3H,OCH3),2.60(t,J＝8.0Hz,2H,CH 2CH＝C),2.11(s,3H,＝C-CH3),1.84(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3),1.52(s,3H,＝C-CH3)。
6-[1-(β-羟基异戊酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率49％。1HNMR(400MHz,CDCl3):δ7.20(s,1H,ArH),6.72(s,2H,QuinH),5.04(t,J＝7.6Hz,1H,CH2CH＝C),4.98(t,J＝7.6Hz,1H,ArCH(CH2)S),3.89(s,3H,OCH3),3.84(s,3H,OCH3),2.66(d,2H,CH 2CH＝C),2.55(s,2H,COCH2),1.58(s,3H,＝C-CH3),1.50(s,3H,＝C-CH3),1.20(s,3H,CH3),1.17(s,3H,CH3)。
6-(1-己酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率46％。1H NMR(400MHz,CDCl3):δ7.27(s,1H,ArH),6.73(s,2H,QuinH),5.05–4.97(m,2H,CH2CH＝C+ArCH(CH2)S),3.92(s,3H,OCH3),3.87(s,3H,OCH3),2.57(t,J＝7.2Hz,2H,CH 2CH＝C),2.48(t,J＝7.6Hz,2H,COCH 2CH2),1.62–1.56(m,5H,＝C-CH3+COCH2CH 2),1.51(s,3H,＝C-CH3),1.27–1.20(m,4H,CH2CH2),0.82(t,J＝6.8Hz,3H,CH2CH 3)。
6-(1-苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率49％。1HNMR(400MHz,CDCl3):δ7.87(d,J＝8.0Hz,2H,ArH),7.51(t,J＝7.4Hz,1H,ArH),7.40–7.35(m,3H,ArH),6.72(s,2H,QuinH),5.22(t,J＝7.6Hz,1H,CH2CH＝C),5.04(t,J＝7.0Hz,1H,ArCH(CH2)S),3.91(s,6H,2×OCH3),2.66(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.59(s,3H,＝C-CH3),1.52(s,3H,＝C-CH3)。
6-[1-(对甲基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率50％。1H NMR(400MHz,CDCl3):δ7.77(d,J＝7.6Hz,2H,ArH),7.18(d,J＝4.0Hz,2H,ArH),7.16(s,1H,ArH),6.71(s,2H,QuinH),5.21(t,J＝7.6Hz,1H,CH2CH＝C),5.04(t,J＝7.6Hz,1H,ArCH(CH2)S),3.90(s,6H,2×OCH3),2.65(t,J＝7.3Hz,2H,CHCH 2CH＝C),2.33(s,3H,ArCH3),1.58(s,3H,＝C-CH3),1.51(s,3H,＝C-CH3)。
6-[1-(4-硝基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率50％。1H NMR(400MHz,CDCl3):δ7.77(d,J＝7.6Hz,2H,ArH),7.18(d,J＝4.0Hz,2H,ArH),7.16(s,1H,ArH),6.71(s,2H,QuinH),5.21(t,J＝7.6Hz,1H,CH2CH＝C),5.04(t,J＝7.6Hz,1H,ArCH(CH2)S),3.90(s,6H,2×OCH3),2.65(t,J＝7.3Hz,2H,CHCH 2CH＝C),2.33(s,3H,ArCH3),1.58(s,3H,＝C-CH3),1.51(s,3H,＝C-CH3)。
6-[1-(4-叔丁氧酰氨基)苯甲酰硫基-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率69％。1H NMR(400MHz,CDCl3):δ7.81(d,J＝8.8Hz,2H,ArH),7.40(d,J＝8.8Hz,2H,ArH),7.35(s,1H,ArH),6.71(s,2H,QuinH),5.20(t,J＝7.2Hz,1H,CH2CH＝C),5.03(t,J＝7.2Hz,1H,ArCH(CH2)S),3.89(s,6H,2×OCH3),2.64(t,J＝8.0Hz,2H,CHCH 2CH＝C),1.57(s,3H,＝C-CH3),1.50(s,3H,＝C-CH3),1.42(s,9H,OCOC(CH 3)3)。
6-[1-(对三氟甲基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率69％。1H NMR(400MHz,CDCl3):δ7.81(d,J＝8.8Hz,2H,ArH),7.40(d,J＝8.8Hz,2H,ArH),7.35(s,1H,ArH),6.71(s,2H,QuinH),5.20(t,J＝7.2Hz,1H,CH2CH＝C),5.03(t,J＝7.2Hz,1H,ArCH(CH2)S),3.89(s,6H,2×OCH3),2.64(t,J＝8.0Hz,2H,CHCH 2CH＝C),1.57(s,3H,＝C-CH3),1.50(s,3H,＝C-CH3),1.42(s,9H,OCOC(CH 3)3)。
6-[1-(间三氟甲基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率49％。1H NMR(400MHz,CDCl3):δ8.12(s,1H,ArH),8.05(d,J＝7.8Hz,1H,ArH),7.76(d,J＝7.8Hz,1H,ArH),7.53(t,J＝7.8Hz,1H,ArH),7.34(s,1H,ArH),6.72(s,2H,QuinH),5.24(t,J＝7.6Hz,1H,CH2CH＝C),5.04(t,J＝7.0Hz,1H,ArCH(CH2)S),3.91(s,3H,OCH3),3.90(s,3H,OCH3),2.67(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.59(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
6-(1-肉桂酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率50％。1HNMR(400MHz,CDCl3):δ7.53(d,J＝15.8Hz,1H,ArH),7.44(d,J＝4.8Hz,2H,ArH),7.29(d,J＝4.5Hz,3H,ArH),6.80(s,1H,ArCH＝CHCO),6.75(s,2H,QuinH),6.62(d,J＝15.8Hz,1H,ArCH＝CHCO),5.39(t,J＝7.6Hz,1H,CH2CH＝C),5.03(t,J＝7.0Hz,1H,ArCH(CH2)S),3.87(s,3H,OCH3),3.86(s,3H,OCH3),3.82(s,3H,OCH3),3.75(s,3H,OCH3),2.75–2.61(m,2H,CHCH 2CH＝C),1.55(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
6-[1-(3,4-二甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率53％。1H NMR(400MHz,CDCl3):δ7.57(d,J＝8.6Hz,1H,ArH),7.36(s,2H,QuinH),6.81(d,J＝8.6Hz,1H,ArH),6.71(s,2H,ArH),5.21(t,J＝7.2Hz,1H,CH2CH＝C),5.04(t,J＝7.0Hz,1H,ArCH(CH2)S),3.90(s,6H,2×OCH3),3.87(s,3H,OCH3),3.84(s,3H,OCH3),2.65(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.58(s,3H,＝C-CH3),1.52(s,3H,＝C-CH3)。
6-[1-(3,4,5-三甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率56％。1H NMR(400MHz,CDCl3):δ7.34(s,1H,ArH),7.12(s,2H,ArH),6.72(s,2H,QuinH),5.21(t,J＝7.2Hz,1H,CH2CH＝C),5.04(t,J＝7.2Hz,1H,ArCH(CH2)S),3.91(s,3H,OCH3),3.90(s,3H,OCH3),3.83(s,9H,3×OCH3),2.66(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.59(s,3H,OCH3),1.52(s,3H,OCH3)。
6-(1-邻氟苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率46％。1H NMR(400MHz,CDCl3):δ7.80(t,J＝7.6Hz,1H,ArH),7.50(dd,J＝13.6,7.0Hz,1H,ArH),7.40(s,1H,ArH),7.19(t,J＝7.6Hz,1H,ArH),7.13(t,J＝7.6Hz,1H,ArH),6.77(s,2H,QuinH),5.26(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.2Hz,1H,ArCH(CH2)S),3.95(s,6H,2×OCH3),2.69(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.63(s,3H,＝C-CH3),1.56(s,3H,＝C-CH3)。
6-(1-间氟苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率42％。1H NMR(400MHz,CDCl3):δ7.73(d,J＝7.8Hz,1H,ArH),7.63(d,J＝10.4Hz,1H,ArH),7.38(dd,J＝14.4,7.2Hz,1H,ArH),7.23(d,J＝8.2Hz,1H,ArH),6.88(s,1H,ArH),6.81(s,2H,QuinH),5.52(t,J＝7.4Hz,1H,CH2CH＝C),5.10(t,J＝7.0Hz,1H,ArCH(CH2)S),3.93(s,3H,OCH3),3.92(s,3H,OCH3),3.88(s,3H,OCH3),3.81(s,3H,OCH3),2.87–2.69(m,2H,CHCH 2CH＝C),1.61(s,3H,＝C-CH3),1.59(s,3H,＝C-CH3)。
6-(1-对氟苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率44％。1H NMR(400MHz,CDCl3):δ7.94(dd,J＝9.0,5.4Hz,2H,ArH),7.37(s,1H,ArH),7.09(t,J＝8.6Hz,2H,ArH),6.75(s,2H,QuinH),5.24(t,J＝7.4Hz,1H,CH2CH＝C),5.07(t,J＝7.4Hz,1H,ArCH(CH2)S),3.94(s,3H,OCH3),3.93(s,3H,OCH3),2.69(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.62(s,3H,＝C-CH3),1.56(s,3H,＝C-CH3)。
6-(1-邻氯苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率45％。1H NMR(400MHz,CDCl3):δ7.57(d,J＝8.0Hz,1H,ArH),7.43–7.36(m,3H,ArH),7.31–7.27(m,1H,ArH),6.78(s,2H,QuinH),5.25(t,J＝7.4Hz,1H,CH2CH＝C),5.09(t,J＝7.0Hz,1H,ArCH(CH2)S),3.96(s,3H,OCH3),3.95(s,3H,OCH3),2.71(t,J＝7.4Hz,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.57(s,3H,＝C-CH3)。
6-(1-间氯苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率47％。1H NMR(400MHz,CDCl3):δ7.87(s,1H,ArH),7.78(d,J＝7.8Hz,1H,ArH),7.51(d,J＝10.0Hz,1H,ArH),7.38–7.33(m,2H,ArH),6.76(s,2H,QuinH),5.25(t,J＝7.4Hz,1H,CH2CH＝C),5.06(t,J＝7.4Hz,1H,ArCH(CH2)S),3.94(s,3H,OCH3),3.93(s,3H,OCH3),2.69(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.62(s,3H,＝C-CH3),1.56(s,3H,＝C-CH3)。
6-(1-对氯苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘醌：收率43％。1H NMR(400MHz,CDCl3):δ7.81(s,1H,ArH),7.79(s,1H,ArH),7.35(s,1H,ArH),7.33(d,J＝1.9Hz,2H,ArH),6.71(s,2H,QuinH),5.21(t,J＝7.2Hz,1H,CH2CH＝C),5.03(t,J＝7.2Hz,1H,ArCH(CH2)S),3.90(s,3H,OCH3),3.89(s,3H,OCH3),2.65(t,J＝7.4Hz,2H,CHCH 2CH＝C),1.58(s,3H,＝C-CH3),1.52(s,3H,＝C-CH3)。
6-[1-(2-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率46％。1H NMR(400MHz,CDCl3):δ7.70(d,J＝8.0Hz,1H,ArH),7.38(s,1H),7.35(d,J＝8.0Hz,1H,ArH),7.20(dd,J＝7.4,3.6Hz,2H,ArH),6.76(s,2H,QuinH),5.23(t,J＝7.2Hz,1H,CH2CH＝C),5.09(t,J＝7.4Hz,1H,ArCH(CH2)S),3.95(s,3H,OCH3),3.94(s,3H,OCH3),2.69(t,J＝7.2Hz,2H,CHCH 2CH＝C),2.41(s,3H,OCH3),1.63(s,3H,＝C-CH3),1.56(s,3H,＝C-CH3)。
6-[1-(3-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率48％。1H NMR(400MHz,CDCl3):δ7.52(d,J＝8.0Hz,1H,ArH),7.39(s,2H,ArH),7.32(t,J＝7.0Hz,1H,ArH),7.08(dd,J＝8.2,2.6Hz,1H,ArH),6.76(s,2H,QuinH),5.25(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.6Hz,1H,ArCH(CH2)S),3.94(s,6H,2×OCH3),3.81(s,3H,OCH3),2.69(t,J＝7.4Hz,2H,CHCH 2CH＝C),1.63(s,3H,＝C-CH3),1.56(s,3H,＝C-CH3)。
6-[1-(4-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率47％。1H NMR(400MHz,CDCl3):δ7.90(d,J＝8.8Hz,2H,ArH),7.40(s,1H,ArH),7.24(s,1H,ArH),6.88(s,1H,ArH),6.77(s,2H,ArH),5.25(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.6Hz,1H,ArCH(CH2)S),3.95(s,6H,2×OCH3),3.84(s,3H,OCH3),2.69(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.63(s,3H,＝C-CH3),1.56(s,3H,＝C-CH3)。
6-[1-(2-呋喃甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率48％。1H NMR(400MHz,CDCl3):δ7.55(s,1H,OCH＝CH),7.38(s,1H,ArH),7.16(d,J＝3.6Hz,1H,C＝CH),6.76(s,2H,QuinH),6.51(t,J＝7.4Hz,1H,CH＝CH＝CH),5.25(t,J＝7.4Hz,1H,CH2CH＝C),5.07(t,J＝7.4Hz,1H,ArCH(CH2)S),3.94(s,6H,2×OCH3),2.68(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.63(s,3H,＝C-CH3),1.55(s,3H,＝C-CH3)。
6-[1-(2-噻吩甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率51％。1H NMR(400MHz,CDCl3):δ7.71(d,J＝3.0Hz,1H,SCH＝CH),7.55(d,J＝4.8Hz,1H,C＝CH-CH),7.34(s,1H,ArH),7.03(t,J＝4.2Hz,1H,CH＝CH＝CH),6.70(s,2H,QuinH),5.20(t,J＝7.2Hz,1H,CH2CH＝C),5.02(t,J＝7.2Hz,1H,ArCH(CH2)S),3.90(s,3H,OCH3),3.89(s,3H,OCH3),2.65(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.57(s,3H,＝C-CH3),1.51(s,3H,＝C-CH3)。
6-[1-(3-吡啶甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率41％。1H NMR(400MHz,CDCl3):δ9.08(s,1H,C＝CH-N),8.72(d,J＝4.0Hz,1H,N＝CH＝CH),8.12(d,J＝8.0Hz,1H,C＝CH＝CH),7.35(t,J＝4.0Hz,1H,C＝CH＝CH),7.34(s,1H,ArH),6.73(s,2H,QuinH),5.25(t,J＝7.4Hz,1H,CH2CH＝C),5.03(t,J＝7.2Hz,1H,ArCH(CH2)S),3.91(s,3H,OCH3),3.90(s,3H,OCH3),2.67(t,J＝7.4Hz,2H,CHCH 2CH＝C),1.59(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
6-[1-(4-吡啶甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌：收率44％。1H NMR(400MHz,CDCl3):δ8.72(s,2H,2×(CH＝N)),7.66(d,J＝4.6Hz,2H,2×(CH＝CH＝N)),7.31(s,1H,ArH),6.72(s,2H,QuinH),5.22(t,J＝7.2Hz,1H,CH2CH＝C),5.02(t,J＝7.2Hz,1H,ArCH(CH2)S),3.91(s,3H,OCH3),3.89(s,3H,OCH3),2.67(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.59(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
步骤五的合成通法，与实施例一中步骤五相同，硫酯衍生物替换硫醚衍生物，与盐酸羟胺发生缩合反应，得目标化合物(IV)。具体如下：
(E,E)-6-(1-乙酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-1)：淡黄色固体，收率70％。1H NMR(400MHz,DMSO-d6):δ12.09(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.10(s,1H,ArH),5.02(t,J＝7.6Hz,2H,CH2CH＝C+ArCH(CH2)S),3.80(s,3H,OCH3),3.61(s,3H,OCH3),2.74–2.67(m,1H,1/2×(CH 2CH＝C)),2.64–2.57(m,1H,1/2×(CH 2CH＝C)),2.34(s,3H,COCH3),1.59(s,6H,2×(＝C-CH3))。
(E,E)-6-(1-丙酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-2)：淡黄色固体，收率63％。1H NMR(400MHz,DMSO-d6):δ12.07(s,2H,2×(N＝OH)),7.33(s,2H,QuinH),7.05(s,1H,ArH),5.00–4.95(m,2H,CH2CH＝C+ArCH(CH2)S),3.74(s,3H,OCH3),3.55(s,3H,OCH3),2.66–2.61(m,1H,1/2×(CH 2CH＝C)),2.57–2.51(m,3H,1/2×(CH 2CH＝C)+COCH 2CH3),1.54(s,6H,2×(＝C-CH3)),1.01(t,J＝7.4Hz,3H,CH2CH 3)。
(E,E)-6-(1-异丁酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-3)：淡黄色固体，收率69％。1H NMR(400MHz,DMSO-d6):δ12.11(s,2H,2×(N＝OH)),7.40(s,2H,QuinH),7.13(s,1H,ArH),5.06–4.99(m,2H,CH2CH＝C+ArCH(CH2)S),3.81(s,3H,OCH3),3.61(s,3H,OCH3),2.78–2.66(m,2H,CH 2CH＝C),2.64–2.57(m,1H,COCH(CH3)2),1.60(s,6H,2×(＝C-CH3)),1.11(dd,J＝10.6,7.0Hz,6H)。
(E,E)-6-(1-异戊酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-4)：淡黄色固体，收率76％。1H NMR(400MHz,DMSO-d6):δ12.05(s,2H,2×(N＝OH)),7.34(s,2H,QuinH),7.06(s,1H,ArH),5.04–4.96(m,2H,CH2CH＝C+ArCH(CH2)S),3.75(s,3H,OCH3),3.56(s,3H,OCH3),2.68–2.53(m,2H,CH 2CH＝C),2.41(d,J＝7.1Hz,2H,COCH 2CH),2.04–1.97(m,1H,CH2CH(CH3)2),1.55(s,6H,2×(C＝CH3)),0.85(d,J＝6.4Hz,6H,CH(CH 3)2)。
(E,E)-6-(1-异戊烯酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-5)：淡黄色固体，收率84％。1H NMR(400MHz,DMSO-d6):δ12.10(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.12(s,1H,ArH),6.05(s,1H,COCH＝C),5.10–5.00(m,2H,CH2CH＝C+ArCH(CH2)S),3.80(s,3H,OCH3),3.62(s,3H,OCH3),2.76–2.69(m,1H,1/2×(CH 2CH＝C)),2.66–2.57(m,1H,1/2×(CH 2CH＝C)),2.12(s,3H,＝C-CH3),1.87(s,3H,＝C-CH3),1.60(s,6H,2×(＝C-CH3))。
(E,E)-6-[1-(β-羟基异戊酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-6)：淡黄色固体，收率82％。1H NMR(400MHz,DMSO-d6):δ12.08(s,2H,2×(N＝OH)),7.38(s,2H,QuinH),7.10(s,1H,ArH),5.02(t,J＝7.6Hz,2H,CH2CH＝C+ArCH(CH2)S),4.66(s,1H,OH),3.79(s,3H,OCH3),3.60(s,3H,OCH3),2.66(s,2H,COCH2),1.59(s,6H,2×(＝C-CH3)),1.19(s,3H,CH3),1.17(s,3H,CH3)。
(E,E)-6-(1-己酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-7)：淡黄色固体，收率81％。1H NMR(400MHz,DMSO-d6):δ12.07(s,2H,2×(N＝OH)),7.34(s,2H,QuinH),7.06(s,1H,ArH),5.02–4.95(m,2H,CH2CH＝C+ArCH(CH2)S),3.75(s,3H,OCH3),3.56(s,3H,OCH3),2.55–2.51(m,2H,CH 2CH＝C),2.49–2.45(m,2H,COCH 2CH2),1.58–1.52(m,8H,2×(＝C-CH3)+COCH2CH 2),1.23–1.18(m,4H,CH2CH2),0.80(t,J＝7.4Hz,3H,CH2CH 3)。
(E,E)-6-(1-苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-8)：淡黄色固体，收率87％。1H NMR(400MHz,DMSO-d6):δ12.14(s,2H,2×(N＝OH)),7.96(d,J＝7.4Hz,2H,ArH),7.69(t,J＝6.8Hz,1H,ArH),7.56(t,J＝7.1Hz,2H,ArH),7.44(s,2H,QuinH),7.25(s,1H,ArH),5.31(t,J＝7.2Hz,1H,CH2CH＝C),5.11(t,J＝7.0Hz,1H,ArCH(CH2)S),3.86(s,3H,OCH3),3.69(s,3H,OCH3),2.89–2.71(m,2H,CHCH 2CH＝C),1.66(s,3H,＝C-CH3),1.62(s,3H,＝C-CH3)。
(E,E)-6-(1-对甲基苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-9)：淡黄色固体，收率89％。1H NMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),7.83(d,J＝7.6Hz,2H,ArH),7.40(s,2H,ArH),7.35(d,J＝7.4Hz,2H,QuinH),7.22(s,1H,ArH),5.26(t,J＝7.0Hz,1H,CH2CH＝C),5.08(t,J＝7.0Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.86–2.68(m,2H,CHCH 2CH＝C),2.38(s,3H,ArCH3),1.64(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
(E,E)-6-[1-(对硝基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-10)：黄色固体，收率83％。1H NMR(400MHz,DMSO-d6):δ12.11(s,2H,2×(N＝OH)),8.36(d,J＝7.6Hz,2H,ArH),8.16(d,J＝7.0Hz,2H,ArH),7.41(s,2H,QuinH),7.25(s,1H,ArH),5.32(t,J＝7.4Hz,1H,CH2CH＝C),5.11(t,J＝7.4Hz,1H,ArCH(CH2)S),3.84(s,3H,OCH3),3.67(s,3H,OCH3),2.90–2.74(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.62(s,3H,＝C-CH3)。
(E,E)-6-[1-(4-叔丁氧酰氨基)苯甲酰硫基-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-11)：淡黄色固体，收率85％。1H NMR(400MHz,DMSO-d6):δ12.02(s,1H,2×(N＝OH)),9.80(s,1H,NH),7.79(d,J＝8.6Hz,2H,ArH),7.54(d,J＝8.6Hz,2H,ArH),7.32(s,2H,QuinH),7.14(s,1H,ArH),5.17(t,J＝7.6Hz,1H,CH2CH＝C),5.00(t,J＝6.8Hz,1H,ArCH(CH2)S),3.75(s,3H,OCH3),3.57(s,3H,OCH3),2.78–2.70(m,1H,1/2×(CHCH 2CH＝C)),2.68–2.61(m,1H,1/2×(CHCH 2CH＝C)),1.56(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3),1.42(s,9H,3×CH3)。
(E,E)-6-[1-(对氨基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟盐酸盐(IV-12)：取化合物IV-11(0.135mmol)混悬于乙酸乙酯中，室温下缓慢滴入3M乙酸乙酯盐酸溶液(0.45mL)，室温搅拌，析出大量红棕色固体，乙酸乙酯－乙醇混合溶剂重结晶，得淡红色固体，收率49％。1H NMR(400MHz,DMSO-d6):δ7.73(d,J＝8.6Hz,2H,ArH),7.39(s,2H,QuinH),7.19(s,1H,ArH),6.79(d,J＝8.6Hz,2H,ArH),6.18(s,4H,2×(N＝OH)+NH2),5.21(t,J＝7.6Hz,1H,CH2CH＝C),5.06(t,J＝7.0Hz,1H,ArCH(CH2)S),3.81(s,3H,OCH3),3.63(s,3H,OCH3),2.82–2.65(m,2H,CHCH 2CH＝C),1.62(s,3H,＝C-CH3),1.59(s,3H,＝C-CH3)。
(E,E)-6-[1-(对三氟甲基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-13)：淡黄色固体，收率85％。1H NMR(400MHz,DMSO-d6):δ12.14(s,2H,2×(N＝OH)),8.12(d,J＝8.2Hz,2H,ArH),7.93(d,J＝8.0Hz,2H,ArH),7.39(s,2H,QuinH),7.24(s,1H,ArH),5.30(t,J＝7.6Hz,1H,CH2CH＝C),5.09(t,J＝7.2Hz,1H,ArCH(CH2)S),3.82(s,3H,OCH3),3.65(s,3H,OCH3),2.88–2.82(m,1H,1/2×(CHCH 2CH＝C)),2.79–2.71(m,1H,1/2×(CHCH 2CH＝C)),1.64(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
(E,E)-6-[1-(间三氟甲基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-14)：淡黄色固体，收率85％。1H NMR(400MHz,DMSO-d6):δ12.10(s,2H,2×(N＝OH)),8.24(d,J＝7.8Hz,1H,ArH),8.13(s,1H,ArH),8.09(d,J＝8.2Hz,1H,ArH),7.82(t,J＝7.8Hz,1H,ArH),7.38(s,2H,QuinH),7.24(s,1H,ArH),5.31(t,J＝7.6Hz,1H,CH2CH＝C),5.08(d,J＝7.0Hz,1H,ArCH(CH2)S),3.82(s,3H,OCH3),3.64(s,3H,OCH3),2.86–2.70(m,2H,CHCH 2CH＝C),1.64(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
(E,E)-6-(1-肉桂酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-15)：淡黄色固体，收率82％。1H NMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),7.76(d,J＝4.8Hz,2H,ArH),7.64(d,J＝15.8Hz,1H,ArH),7.43(d,J＝15.8Hz,5H,ArH+QuinH),7.19(s,1H,ArH),7.02(d,J＝15.8Hz,1H,COCH＝CHAr),5.20(t,J＝7.4Hz,1H,1H,CH2CH＝C),5.07(t,J＝4.6Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.84–2.67(m,2H,CHCH 2CH＝C),1.63(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
(E,E)-6-[1-(3,4-二甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-16)：淡黄色固体，收率83％。1H NMR(400MHz,DMSO-d6):δ12.09(s,2H,2×(N＝OH)),7.58(d,J＝8.6Hz,1H,ArH),7.37(s,3H,QuinH+ArH),7.20(s,1H,ArH),7.05(s,1H,ArH),5.22(t,J＝7.2Hz,1H,CH2CH＝C),5.05(t,J＝7.0Hz,1H,ArCH(CH2)S),3.80(s,9H,3×OCH3),3.62(s,3H,OCH3),2.75(t,J＝7.2Hz,2H,CHCH 2CH＝C),1.61(s,3H,＝C-CH3),1.57(s,3H,＝C-CH3)。
(E,E)-6-[1-(3,4,5-三甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-17)：淡黄色固体，收率79％。1H NMR(400MHz,DMSO-d6):δ12.11(s,2H,2×(N＝OH)),7.40(s,2H,QuinH),7.24(s,1H,ArH),7.20(s,2H,ArH),5.26(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.2Hz,1H,ArCH(CH2)S),3.85(s,6H,2×OCH3),3.83(s,3H,OCH3),3.75(s,3H,OCH3),3.64(s,3H,OCH3),2.88–2.81((m,1H,1/2×(CHCH 2CH＝C)),2.79–2.70(m,1H,1/2×(CHCH 2CH＝C)),1.66(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
(E,E)-6-(1-邻氟苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-18)：淡黄色固体，收率74％。1H NMR(400MHz,DMSO-d6):δ12.18(s,2H,2×(N＝OH)),7.85(t,J＝7.6Hz,1H,ArH),7.69(dd,J＝13.6,7.6Hz,1H,ArH),7.40(s,2H,QuinH),7.37(t,J＝7.6Hz,1H,ArH),7.22(s,1H,ArH),5.28(t,J＝7.6Hz,1H,CH2CH＝C),5.10(t,J＝6.8Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.66(s,3H,OCH3),2.84–2.73(m,2H,CHCH 2CH＝C),1.64(s,3H,＝C-CH3),1.62(s,3H,＝C-CH3)。
(E,E)-6-(1-间氟苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-19)：淡黄色固体，收率78％。1H NMR(400MHz,DMSO-d6):δ12.11(s,2H,2×(N＝OH)),7.80(d,J＝7.0Hz,1H,ArH),7.67(d,J＝10.0Hz,1H,ArH),7.60(dd,J＝16.4,7.8Hz,2H,ArH),7.39(s,2H,QuinH),7.22(s,1H,ArH),5.27(t,J＝7.4Hz,1H,CH2CH＝C),5.08(t,J＝7.4Hz,1H,ArCH(CH2)S),3.82(s,3H,OCH3),3.65(s,3H,OCH3),2.85–2.79(m,1H,1/2×(CHCH 2CH＝C)),2.77–2.72(m,1H,1/2×(CHCH 2CH＝C)),1.64(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
(E,E)-6-(1-对氟苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-20)：淡黄色固体，收率85％。1H NMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),8.02(dd,J＝9.0,5.4Hz,2H,ArH),7.41(s,2H,QuinH),7.38(d,J＝8.0Hz,2H,ArH),7.24(s,1H,ArH),5.28(t,J＝7.6Hz,1H,CH2CH＝C),5.09(t,J＝7.0Hz,1H,ArCH(CH2)S),3.84(s,3H,OCH3),3.67(s,3H,OCH3),2.88–2.71(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
(E,E)-6-(1-邻氯苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-21)：淡黄色固体，收率81％。1H NMR(400MHz,DMSO-d6):δ12.13(s,2H,2×(N＝OH)),7.67(d,J＝7.4Hz,1H,ArH),7.59(d,J＝6.4Hz,2H,ArH),7.48(t,J＝7.0Hz,1H),7.41(s,2H,QuinH),7.21(s,1H,ArH),5.28(t,J＝7.6Hz,1H,CH2CH＝C),5.12(t,J＝6.4Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.68(s,3H,OCH3),2.88–2.74(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.63(s,3H,＝C-CH3)。
(E,E)-6-(1-间氯苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-22)：淡黄色固体，收率74％。1H NMR(400MHz,DMSO-d6):δ12.03(s,2H,2×(N＝OH)),7.82(d,J＝8.6Hz,2H,ArH),7.68(d,J＝8.0Hz,1H,ArH),7.50(t,J＝7.8Hz,1H,ArH),7.32(s,2H,QuinH),7.15(s,1H,ArH),5.20(t,J＝7.6Hz,1H,CH2CH＝C),5.01(t,J＝7.0Hz,1H,ArCH(CH2)S),3.76(s,3H,OCH3),3.58(s,3H,OCH3),2.79–2.63(m,2H,CHCH 2CH＝C),1.56(s,3H,＝C-CH3),1.52(s,3H,＝C-CH3)。
(E,E)-6-(1-对氯苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IV-23)：淡黄色固体，收率79％。1H NMR(400MHz,DMSO-d6):δ12.13(s,2H,2×(N＝OH)),7.95(d,J＝8.0Hz,2H,ArH),7.62(d,J＝7.8Hz,2H,ArH),7.41(s,2H,QuinH),7.23(s,1H,ArH),5.28(t,J＝7.0Hz,1H,CH2CH＝C),5.09(t,J＝7.0Hz,1H,ArCH(CH2)S),3.84(s,3H,OCH3),3.67(s,3H,OCH3),2.87–2.70(m,2H,CHCH 2CH＝C),1.64(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
(E,E)-6-[1-(2-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-24)：黄色固体，收率84％。1H NMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),7.68(d,J＝4.0Hz,1H,ArH),7.48(t,J＝7.4Hz,1H,ArH),7.41(s,2H,ArH),7.35(s,2H,QuinH),7.21(s,1H,ArH),5.25(t,J＝7.2Hz,1H,CH2CH＝C),5.09(t,J＝7.4Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.67(s,3H,OCH3),2.78(t,J＝4.0Hz,2H,CHCH 2CH＝C),2.40(s,3H,OCH3),1.65(s,3H,＝C-CH3),1.63(s,3H,＝C-CH3)。
(E,E)-6-[1-(3-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-25)：黄色固体，收率81％。1H NMR(400MHz,DMSO-d6):δ12.04(s,2H,2×(N＝OH)),7.46(d,J＝7.6Hz,1H,ArH),7.39(t,J＝8.0Hz,1H,ArH),7.33(s,2H,ArH,QuinH),7.31(s,1H,ArH),7.19(d,J＝7.6Hz,1H,ArH),7.16(s,1H,ArH),5.19(t,J＝7.6Hz,1H,CH2CH＝C),5.01(t,J＝6.6Hz,1H,ArCH(CH2)S),3.76(s,3H,OCH3),3.75(s,3H,OCH3),3.58(s,3H,OCH3),2.79–2.72(m,1H,1/2×(CHCH 2CH＝C)),2.69–2.64(m,1H,1/2×(CHCH 2CH＝C)),1.57(s,3H,＝C-CH3),1.53(s,3H,＝C-CH3)。
(E,E)-6-[1-(4-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(IV-26)：黄色固体，收率83％。1H NMR(400MHz,DMSO-d6):δ12.03(s,2H,2×(N＝OH)),7.83(d,J＝7.2Hz,2H,ArH),7.33(s,2H,QuinH),7.14(s,1H,ArH),6.98(d,J＝6.4Hz,2H,ArH),5.18(t,J＝7.2Hz,1H,CH2CH＝C),5.00(t,J＝7.4Hz,1H,ArCH(CH2)S),3.75(s,6H,2×OCH3),3.58(s,3H,OCH3),2.77–2.62(m,2H,CHCH 2CH＝C),1.55(s,3H,＝C-CH3),1.51(s,3H,＝C-CH3)。
(E,E)-6-[1-(2-呋喃甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌(IV-27)：淡黄色固体，收率81％。1H NMR(400MHz,DMSO-d6):δ12.04(s,2H,2×(N＝OH)),7.98(s,1H,OCH＝CH),7.38–7.32(m,3H,QuinH and ArH),7.15(s,1H,C＝CH),6.70(s,1H,CH＝CH＝CH),5.19(t,J＝7.6Hz,1H,CH2CH＝C),5.01(t,J＝6.8Hz,1H,ArCH(CH2)S),3.77(s,3H,OCH3),3.58(s,3H,OCH3),2.79–2.71(m,1H,1/2×(CHCH 2CH＝C)),2.70–2.62(m,1H,1/2×(CHCH 2CH＝C)),1.57(s,3H,＝C-CH3),1.55(s,3H,＝C-CH3)。
(E,E)-6-[1-(2-噻吩甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌(IV-28)：黄色固体，收率67％。1H NMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),8.06(d,J＝4.8Hz,1H,SCH＝CH),7.90(d,J＝3.6Hz,1H,C＝CH-CH),7.41(s,2H,QuinH),7.25(t,J＝4.2Hz,1H,CH＝CH＝CH),7.23(s,1H,ArH),5.26(t,J＝7.4Hz,1H,CH2CH＝C),5.08(t,J＝6.6Hz,1H,ArCH(CH2)S),3.84(s,3H,OCH3),3.65(s,3H,OCH3),2.87–2.71(m,2H,CHCH 2CH＝C),1.64(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
(E,E)-6-[1-(3-吡啶甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌(IV-29)：黄色固体，收率69％。1H NMR(400MHz,DMSO-d6):δ12.14(s,2H,2×(N＝OH)),9.06(s,1H,C＝CH-N),8.85(d,J＝4.6Hz,1H,N＝CH＝CH),8.28(d,J＝8.0Hz,1H,C＝CH＝CH),7.60(dd,J＝8.0,5.0Hz,1H,C＝CH＝CH),7.39(s,2H,QuinH),7.23(s,1H,ArH),5.30(t,J＝7.6Hz,1H,CH2CH＝C),5.09(t,J＝7.0Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.85–2.81(m,1H,1/2×(CHCH 2CH＝C)),2.79–2.72(m,1H,1/2×(CHCH 2CH＝C)),1.64(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
(E,E)-6-[1-(4-吡啶甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌(IV-30)：黄色固体，收率74％。1H NMR(400MHz,DMSO-d6):δ12.17(s,2H,2×(N＝OH)),8.83(d,J＝4.0Hz,2H,2×(CH＝N)),7.81(d,J＝4.0Hz,2H,2×(CH＝CH＝N)),7.41(s,2H,QuinH),7.25(s,1H,ArH),5.31(t,J＝7.2Hz,1H,CH＝C),5.11(t,J＝7.2Hz,1H,ArCH(CH2)S),3.85(s,3H,OCH3),3.67(s,3H,OCH3),2.89–2.89(m,1H,1/2×(CHCH 2CH＝C)),2.80–2.73(m,1H,1/2×(CHCH 2CH＝C)),1.65(s,3H,＝C-CH3),1.62(s,3H,＝C-CH3)。
实施例3
本实施例涉及一种具有结构式(VI)的硫醚类光学纯紫草素肟衍生物制备方法，如图2所示，包括如下步骤：
步骤一，将光学纯(R)-2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘(制备方法如图4)溶于甲苯中，加入0.52当量劳森试剂，氮气保护下，90℃反应8min，TLC检测原料点消失，向反应液中加入适量的水，冷却，分离出有机层，蒸除溶剂，硅胶柱层析分离得到光学纯(R)-2-(1-巯基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘，棕黄色油状物，收率75％。1H NMR(400MHz,CDCl3):δ6.89(s,1H,Ar-H),6.75(s,2H,ArH),5.02(t,J＝7.2Hz,1H,CH＝C),4.73(dd,J1＝12.4,J2＝7.2Hz,1H,ArCHOH),3.88(s,3H,OCH3),3.85(s,3H,OCH3),3.81(s,3H,OCH3),3.68(s,3H,OCH3),2.63–2.50(m,2H,CH2),1.97(d,J＝4.0Hz,1H,SH),1.57(s,3H,CH3),1.55(s,3H,CH3)。
步骤二合成通法：将上述产物干燥后溶于无水乙醇中，加入0.05当量碘化钾及0.5当量溴代烷烃R1Br，氮气保护下，加入10当量40％氢氧化钠溶液，回流反应4h后，蒸去乙醇，二氯甲烷萃取，依次用饱和氯化钠溶液和水洗涤有机层，无水硫酸钠干燥，蒸除有机溶剂，硅胶柱层析分离得到无色油状物。将步骤二收集的产物溶于乙酸乙酯中，在冰浴条件下，缓慢滴入2.6当量的硝酸铈铵水溶液，反应完全后，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，蒸除溶剂，柱层析分离得到黄色油状物。将步骤三所得产物干燥后溶于无水乙醇中，加入7当量盐酸羟胺和7当量吡啶，50℃加热反应过夜，TLC检测反应结束后停止搅拌，蒸除溶剂得到黄色固体，无水乙醇重结晶，得到光学纯硫醚类紫草素肟衍生物。
采用上述方法，当溴代烷烃R1Br中，R1为异戊基时，所得(E,E)-(R)-6-(1-异戊硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(VI-1)：淡黄色固体，收率85％，1HNMR(400MHz,DMSO-d6):δ12.09(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝6.4Hz,1H,CH2CH＝C),4.37(t,J＝7.4Hz,1H,ArCH(CH2)S),3.80(s,3H,OCH3),3.59(s,3H,OCH3),2.58(t,J＝6.8Hz,2H,CHCH 2CH＝C),2.44–2.34(m,2H,SCH 2CH2),1.61(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.55–1.50(m,1H,CH(CH3)2),1.33(dd,J＝13.6,7.0Hz,2H,CH2CH 2CH),0.79(d,J＝6.6Hz,3H,CHCH 3),0.75(d,J＝6.6Hz,3H,CHCH 3)。
采用上述方法，当溴代烷烃R1Br中，R1为异戊烯基时，所得(E,E)-(R)-6-(1-异戊烯硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(VI-2)：淡黄色固体，收率87％，1H NMR(400MHz,DMSO-d6):δ12.04(s,2H,2×(N＝OH)),7.37(s,2H,QuinH),7.17(s,1H,ArH),5.13(t,J＝6.6Hz,1H,CH2CH＝C),5.04(t,J＝6.6Hz,1H,SCH2CH＝C),4.32(t,J＝7.0Hz,1H,ArCH(CH2)S),3.77(s,3H,OCH3),3.56(s,3H,OCH3),3.05(d,J＝7.2Hz,2H,SCH 2CH＝C),2.57(t,2H,CHCH 2CH＝C),1.61(s,3H,C＝CH3),1.57(s,3H,C＝CH3),1.52(s,3H,C＝CH3),1.50(s,3H,C＝CH3)。
采用上述方法，当溴代烷烃R1Br中，R1为正辛基时，所得(E,E)-(R)-6-(1-正辛硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(VI-3)：淡黄色固体，收率85％。1HNMR(400MHz,DMSO-d6):δ12.07(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝6.6Hz,1H,CH2CH＝C),4.36(t,J＝7.6Hz,1H,ArCH(CH2)S),3.79(s,3H,OCH3),3.58(s,3H,OCH3),2.57(t,J＝7.0Hz,2H,CHCH 2CH＝C),2.44–2.31(m,2H,SCH 2CH2),1.60(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.45–1.38(m,2H,SCH2CH 2),1.25–1.12(m,10H,5×CH2),0.82(t,J＝6.8Hz,3H,CH2CH 3)。
采用上述方法，当溴代烷烃R1Br中，R1为苄基时，所得(E,E)-(R)-6-(1-苯甲硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(VI-4)：淡黄色固体，收率78％。1H NMR(400MHz,DMSO-d6):δ12.06(s,2H,2×(N＝OH)),7.41(s,2H,QuinH),7.31–7.26(m,4H,ArH),7.24–7.19(m,2H,ArH),5.03(t,J＝6.2Hz,1H,CH2CH＝C),4.32(t,J＝7.4Hz,1H,ArCH(CH2)S),3.80(s,3H,OCH3),3.71(s,2H,ArCH 2S),3.46(s,3H,OCH3),2.61(t,J＝6.8Hz,2H,CHCH 2CH＝C),1.59(s,3H,C＝CH3),1.53(s,3H,C＝CH3)。
实施例4
本实施例涉及一种具有结构式(VII)的硫酯类光学纯紫草素肟衍生物制备方法，如图2所示，包括如下步骤：
本实施例步骤一与实施例3步骤一相同；
步骤二合成通法：将上述产物干燥后溶于无水二氯甲烷中，加入0.5当量4-二甲氨基吡啶、1.2当量羧酸R2COOH和1.2当量N,N-二环己基碳二亚胺，室温搅拌过夜，抽滤除去反应过程中生成的白色沉淀，滤液冷却至0℃左右，搅拌下滴入2.6当量的硝酸铈铵水溶液，反应完全后，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，蒸除溶剂，柱层析分离得到黄色油状物。将步骤二所得产物干燥后溶于无水乙醇中，加入7当量盐酸羟胺和7当量吡啶，50℃加热反应过夜，TLC检测反应结束后停止搅拌，蒸除溶剂得到黄色固体，无水乙醇重结晶，得到光学纯硫酯类紫草素肟衍生物。
采用上述方法，当羧酸R2COOH中，R2为异丁基时，所得(E,E)-(R)-6-(1-异戊酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(VII-1)：淡黄色固体，收率76％。1HNMR(400MHz,DMSO-d6):δ12.07(s,2H,2×(N＝OH)),7.35(s,2H,QuinH),7.07(s,1H,ArH),5.05–4.97(m,2H,CH2CH＝C+ArCH(CH2)S),3.76(s,3H,OCH3),3.57(s,3H,OCH3),2.69–2.54(m,2H,CH 2CH＝C),2.41(d,J＝7.1Hz,2H,COCH 2CH),2.04–1.97(m,1H,CH2CH(CH3)2),1.55(s,6H,2×(C＝CH3)),0.85(d,J＝6.4Hz,6H,CH(CH 3)2)。
采用上述方法，当羧酸R2COOH中，R2为异丁烯基时，所得(E,E)-(R)-6-(1-异戊烯酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(VII-2)：淡黄色固体，收率80％。1H NMR(400MHz,DMSO-d6):δ12.13(s,2H,2×(N＝OH)),7.41(s,2H,QuinH),7.14(s,1H,ArH),6.07(s,1H,COCH＝C),5.12–5.02(m,2H,CH2CH＝C+ArCH(CH2)S),3.81(s,3H,OCH3),3.63(s,3H,OCH3),2.78–2.71(m,1H,1/2×(CH 2CH＝C)),2.68–2.59(m,1H,1/2×(CH 2CH＝C)),2.14(s,3H,＝C-CH3),1.89(s,3H,＝C-CH3),1.62(s,6H,2×(＝C-CH3))。
采用上述方法，当羧酸R2COOH中，R2为苯基时，所得(E,E)-(R)-6-(1-苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(VII-3)：淡黄色固体，收率85％。1HNMR(400MHz,DMSO-d6):δ12.14(s,2H,2×(N＝OH)),7.95(d,J＝7.6Hz,2H,ArH),7.70(t,J＝7.4Hz,1H,ArH),7.56(t,J＝7.4Hz,2H,ArH),7.41(s,2H,QuinH),7.24(s,1H,ArH),5.29(t,J＝7.6Hz,1H,CH2CH＝C),5.10(t,J＝7.0Hz,1H,ArCH(CH2)S),3.84(s,3H,OCH3),3.67(s,3H,OCH3),2.88–2.71(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为4-甲基苯基时，所得(E,E)-(R)-6-[1-(4-甲基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(VII-4)：淡黄色固体，收率84％。1H NMR(400MHz,DMSO-d6):δ12.13(s,2H,2×(N＝OH)),7.84(d,J＝7.2Hz,2H,ArH),7.40(s,2H,ArH),7.35(d,J＝7.8Hz,2H,QuinH),7.23(s,1H,ArH),5.26(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.0Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.87–2.79(m,1H,1/2×(CHCH 2CH＝C)),2.76–2.69(m,1H,1/2×(CHCH 2CH＝C)),2.38(s,3H,ArCH3),1.64(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为4-氟苯基时，所得(E,E)-(R)-6-[1-(4-氟苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(VII-5)：淡黄色固体，收率80％。1H NMR(400MHz,DMSO-d6):δ12.15(s,2H,2×(N＝OH)),8.03(dd,J＝8.2,6.0Hz,2H,ArH),7.41(s,2H,QuinH),7.38(d,J＝8.0Hz,2H,ArH),7.24(s,1H,ArH),5.28(t,J＝7.6Hz,1H,CH2CH＝C),5.09(t,J＝7.0Hz,1H,ArCH(CH2)S),3.85(s,3H,OCH3),3.67(s,3H,OCH3),2.88–2.71(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为4-甲氧基苯基时，所得(E,E)-(R)-6-[1-(4-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(VII-6)：黄色固体，收率80％。1H NMR(400MHz,DMSO-d6):δ12.13(s,2H,2×(N＝OH)),7.92(d,J＝7.6Hz,2H,ArH),7.41(s,2H,QuinH),7.23(s,1H,ArH),7.07(d,J＝7.6Hz,2H,ArH),5.25(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.4Hz,1H,ArCH(CH2)S),3.85(s,3H,OCH3),3.84(s,3H,OCH3),3.65(s,3H,OCH3),2.86–2.70(m,2H,ArCH(CH2)S),1.64(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3,4-二甲氧基苯基时，所得(E,E)-(R)-6-[1-(3,4-二甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(VII-7)：淡黄色固体，收率79％。1H NMR(400MHz,DMSO-d6):δ12.11(s,2H,2×(N＝OH)),7.62(d,J＝9.8Hz,1H,ArH),7.40(s,3H,QuinH and ArH),7.23(s,1H,ArH),7.09(d,J＝8.6Hz,1H,ArH),5.25(t,J＝7.6Hz,1H,CH2CH＝C),5.08(t,J＝7.0Hz,1H,ArCH(CH2)S),3.85(s,3H,OCH3),3.82(s,6H,2×OCH3),3.64(s,3H,OCH3),2.87–2.70(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3,4,5-三甲氧基苯基时，所得(E,E)-(R)-6-[1-(3,4,5-三甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(VII-8)：淡黄色固体，收率76％。1H NMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),7.40(s,2H,QuinH),7.25(s,1H,ArH),7.20(s,2H,ArH),5.26(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.2Hz,1H,ArCH(CH2)S),3.85(s,6H,2×OCH3),3.84(s,3H,OCH3),3.75(s,3H,OCH3),3.64(s,3H,OCH3),2.90–2.82((m,1H,1/2×(CHCH 2CH＝C)),2.80–2.71(m,1H,1/2×(CHCH 2CH＝C)),1.66(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为肉桂基时，所得(E,E)-(R)-6-(1-肉桂酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(VII-9)：淡黄色固体，收率74％。1HNMR(400MHz,DMSO-d6):δ12.13(s,2H,2×(N＝OH)),7.77(d,J＝5.2Hz,2H,ArH),7.64(d,J＝15.8Hz,1H,ArH),7.46–7.42(m,3H,ArH),7.40(s,2H,QuinH),7.19(s,1H,ArH),7.02(d,J＝15.8Hz,1H,COCH＝CHAr),5.20(t,J＝7.4Hz,1H,1H,CH2CH＝C),5.07(t,J＝4.6Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.83–2.66(m,2H,CHCH 2CH＝C),1.64(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为2-呋喃基时，所得(E,E)-(R)-6-[1-(2-呋喃甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(VII-10)：淡黄色固体，收率84％。1H NMR(400MHz,DMSO-d6):δ12.06(s,2H,2×(N＝OH)),8.00(s,1H,OCH＝CH),7.40–7.34(m,3H,QuinH and ArH),7.17(s,1H,C＝CH),6.72(s,1H,CH＝CH＝CH),5.21(t,J＝7.6Hz,1H,CH2CH＝C),5.03(t,J＝6.8Hz,1H,ArCH(CH2)S),3.79(s,3H,OCH3),3.60(s,3H,OCH3),2.81–2.73(m,1H,1/2×(CHCH 2CH＝C)),2.72–2.64(m,1H,1/2×(CHCH 2CH＝C)),1.59(s,3H,＝C-CH3),1.57(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为2-噻吩基时，所得(E,E)-(R)-6-[1-(2-噻吩甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(VII-11)：淡黄色固体，收率67％。1H NMR(400MHz,DMSO-d6):δ12.14(s,2H,2×(N＝OH)),8.07(d,J＝4.8Hz,1H,SCH＝CH),7.92(d,J＝3.6Hz,1H,C＝CH-CH),7.42(s,2H,QuinH),7.26(t,J＝4.2Hz,1H,CH＝CH＝CH),7.24(s,1H,ArH),5.28(t,J＝7.4Hz,1H,CH2CH＝C),5.10(t,J＝6.6Hz,1H,ArCH(CH2)S),3.86(s,3H,OCH3),3.67(s,3H,OCH3),2.89–2.73(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.62(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3-吡啶基时，所得(E,E)-(R)-6-[1-(3-吡啶甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(VII-12)：淡黄色固体，收率69％。1H NMR(400MHz,DMSO-d6):δ12.16(s,2H,2×(N＝OH)),9.08(s,1H,C＝CH-N),8.87(d,J＝4.6Hz,1H,N＝CH＝CH),8.29(d,J＝8.0Hz,1H,C＝CH＝CH),7.62(dd,J＝8.0,5.0Hz,1H,C＝CH＝CH),7.40(s,2H,QuinH),7.24(s,1H,ArH),5.32(t,J＝7.6Hz,1H,CH2CH＝C),5.11(t,J＝7.0Hz,1H,ArCH(CH2)S),3.84(s,3H,OCH3),3.67(s,3H,OCH3),2.86–2.82(m,1H,1/2×(CHCH 2CH＝C)),2.79–2.72(m,1H,1/2×(CHCH 2CH＝C)),1.66(s,3H,＝C-CH3),1.63(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3-吡啶基时，所得(E,E)-(S)-6-[1-(3-吡啶甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌(X-12)：淡黄色固体，收率69％。1HNMR(400MHz,DMSO-d6):δ12.14(s,2H,2×(N＝OH)),9.06(s,1H,C＝CH-N),8.85(d,J＝4.6Hz,1H,N＝CH＝CH),8.28(d,J＝8.0Hz,1H,C＝CH＝CH),7.60(dd,J＝7.8,5.0Hz,1H,C＝CH＝CH),7.39(s,2H,QuinH),7.23(s,1H,ArH),5.30(t,J＝7.6Hz,1H,CH2CH＝C),5.09(t,J＝6.8Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.86–2.82(m,1H,1/2×(CHCH 2CH＝C)),2.80–2.73(m,1H,1/2×(CHCH 2CH＝C)),1.65(s,3H,＝C-CH3),1.63(s,3H,＝C-CH3)。
实施例5
本实施例涉及一种具有结构式(IX)的硫醚类光学纯阿卡宁肟衍生物制备方法，如图3所示，包括如下步骤：
步骤一，将光学纯(S)-2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘(制备方法如图5)萘溶于甲苯中，加入0.52当量劳森试剂，氮气保护下，90℃反应8min，TLC检测原料点消失，向反应液中加入适量的水，冷却，分离出有机层，蒸除溶剂，硅胶柱层析分离得到光学纯(S)-2-(1-巯基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘，棕色油状物，收率76％。1H NMR(400MHz,CDCl3):δ6.89(s,1H),6.74(s,2H),5.03(t,J＝7.2Hz,1H),4.73(dd,J＝12.6,7.6Hz,1H),3.88(s,3H),3.85(s,3H),3.81(s,3H),3.69(s,3H),2.60–2.54(m,2H),1.97(d,J＝4.0Hz,1H),1.57(s,3H),1.55(s,3H)。
步骤二，合成方法与实施例3的步骤二的合成通法相同。
采用上述方法，当溴代烷烃R1Br中，R1为异戊基时，所得(E,E)-(S)-6-(1-异戊硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IX-1)：淡黄色固体，收率82％；1HNMR(400MHz,DMSO-d6):δ12.08(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝6.8Hz,1H,CH2CH＝C),4.37(t,J＝6.4Hz,1H),3.80(s,3H,OCH3),3.59(s,3H,OCH3),2.58(t,J＝6.8Hz,2H,CHCH 2CH＝C),2.44–2.34(m,2H,SCH 2CH2),1.61(s,3H,C＝CH3),1.59–1.53(m,4H,C＝CH3+CH(CH3)2),1.33(d,J＝5.4Hz,2H),0.79(d,J＝6.2Hz,3H,CHCH 3),0.76(d,J＝6.2Hz,3H,CHCH 3)。
采用上述方法，当溴代烷烃R1Br中，R1为异戊烯基时，所得(E,E)-(S)-6-(1-异戊烯硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IX-2)：淡黄色固体，收率85％，1H NMR(400MHz,DMSO-d6):δ12.03(s,2H,2×(N＝OH)),7.35(s,2H,QuinH),7.16(s,1H,ArH),5.12(t,J＝6.6Hz,1H,CH2CH＝C),5.03(t,J＝6.6Hz,1H,SCH2CH＝C),4.32(t,J＝7.0Hz,1H,ArCH(CH2)S),3.76(s,3H,OCH3),3.55(s,3H,OCH3),3.05(d,J＝7.2Hz,2H,SCH 2CH＝C),2.56(t,2H,CHCH 2CH＝C),1.61(s,3H,C＝CH3),1.57(s,3H,C＝CH3),1.52(s,3H,C＝CH3),1.50(s,3H,C＝CH3)。
采用上述方法，当溴代烷烃R1Br中，R1为正辛基时，所得(E,E)-(S)-6-(1-正辛硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IX-3)：淡黄色固体，收率82％。1HNMR(400MHz,DMSO-d6):δ12.08(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.21(s,1H,ArH),5.11(t,J＝6.6Hz,1H,CH2CH＝C),4.36(t,J＝7.6Hz,1H,ArCH(CH2)S),3.79(s,3H,OCH3),3.58(s,3H,OCH3),2.57(t,J＝7.0Hz,2H,CHCH 2CH＝C),2.44–2.31(m,2H,SCH 2CH2),1.60(s,3H,C＝CH3),1.56(s,3H,C＝CH3),1.46–1.39(m,2H,SCH2CH 2),1.26–1.13(m,10H,5×CH2),0.83(t,J＝6.8Hz,3H,CH2CH 3)。
采用上述方法，当溴代烷烃R1Br中，R1为苄基时，所得(E,E)-(S)-6-(1-苯甲硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(IX-4)：淡黄色固体，收率75％。1H NMR(400MHz,DMSO-d6):δ12.05(s,2H,2×(N＝OH)),7.41(s,2H,QuinH),7.31–7.26(m,4H,ArH),7.23–7.18(m,2H,ArH),5.03(t,J＝6.2Hz,1H,CH2CH＝C),4.32(t,J＝7.4Hz,1H,ArCH(CH2)S),3.79(s,3H,OCH3),3.70(s,2H,ArCH 2S),3.46(s,3H,OCH3),2.61(t,J＝6.8Hz,2H,CHCH 2CH＝C),1.59(s,3H,C＝CH3),1.52(s,3H,C＝CH3)。
实施例6
本实施例涉及一种具有结构式(X)的硫酯类光学纯阿卡宁肟衍生物制备方法，如图3所示，包括如下步骤：
步骤一，合成方法与实施例5步骤一相同；
步骤二，合成方法与案施例4步骤二相同。
采用上述方法，当羧酸R2COOH中，R2为异丁基时，所得(E,E)-(S)-6-(1-异戊酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(X-1)：淡黄色固体，收率76％。1HNMR(400MHz,DMSO-d6):δ12.06(s,2H,2×(N＝OH)),7.35(s,2H,QuinH),7.07(s,1H,ArH),5.04–4.96(m,2H,CH2CH＝C+ArCH(CH2)S),3.75(s,3H,OCH3),3.56(s,3H,OCH3),2.68–2.53(m,2H,CH 2CH＝C),2.41(d,J＝7.1Hz,2H,COCH 2CH),2.04–1.97(m,1H,CH2CH(CH3)2),1.54(s,6H,2×(C＝CH3)),0.84(d,J＝6.4Hz,6H,CH(CH 3)2)。
采用上述方法，当羧酸R2COOH中，R2为异丁烯基时，所得(E,E)-(S)-6-(1-异戊烯酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(X-2)：淡黄色固体，收率81％。1HNMR(400MHz,DMSO-d6):δ12.11(s,2H,2×(N＝OH)),7.40(s,2H,QuinH),7.13(s,1H,ArH),6.06(s,1H,COCH＝C),5.11–5.01(m,2H,CH2CH＝C+ArCH(CH2)S),3.81(s,3H,OCH3),3.63(s,3H,OCH3),2.78–2.71(m,1H,1/2×(CH 2CH＝C)),2.67–2.58(m,1H,1/2×(CH 2CH＝C)),2.14(s,3H,＝C-CH3),1.88(s,3H,＝C-CH3),1.61(s,6H,2×(＝C-CH3))。
采用上述方法，当羧酸R2COOH中，R2为苯基时，所得(E,E)-(S)-6-(1-苯甲酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(X-3)：淡黄色固体，收率79％。1H NMR(400MHz,DMSO-d6):δ12.15(s,2H,2×(N＝OH)),7.95(d,J＝7.6Hz,2H,ArH),7.70(t,J＝7.2Hz,1H,ArH),7.56(t,J＝7.2Hz,2H,ArH),7.41(s,2H,QuinH),7.24(s,1H,ArH),5.29(t,J＝7.4Hz,1H,CH2CH＝C),5.10(t,J＝7.0Hz,1H,ArCH(CH2)S),3.84(s,3H,OCH3),3.66(s,3H,OCH3),2.88–2.71(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为4-甲基苯基时，所得(E,E)-(S)-6-[1-(4-甲基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(X-4)：淡黄色固体，收率78％。1H NMR(400MHz,DMSO-d6):δ12.13(s,2H,2×(N＝OH)),7.84(d,J＝7.2Hz,2H,ArH),7.40(s,2H,ArH),7.35(d,J＝7.0Hz,2H,QuinH),7.22(s,1H,ArH),5.26(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.0Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.88–2.79(m,1H,CHCH 2CH＝C),2.77–2.70(m,1H,1/2×(CHCH 2CH＝C)),2.38(s,3H,ArCH3),1.64(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为4-氟苯基时，所得(E,E)-(S)-6-[1-(4-氟苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(X-5)：淡黄色固体，收率82％。1H NMR(400MHz,DMSO-d6):δ12.14(s,2H,2×(N＝OH)),8.03(dd,J＝9.0,5.4Hz,2H,ArH),7.40(s,2H,QuinH),7.36(d,J＝4.0Hz,2H,ArH),5.28(t,J＝7.6Hz,1H,CH2CH＝C),5.09(t,J＝7.0Hz,1H,ArCH(CH2)S),3.84(s,3H,OCH3),3.66(s,3H,OCH3),2.88–2.71(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为4-甲氧基苯基时，所得(E,E)-(S)-6-[1-(4-甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(X-6)：黄色固体，收率80％。1H NMR(400MHz,DMSO-d6):δ12.13(s,2H,2×(N＝OH)),7.92(d,J＝7.2Hz,2H,ArH),7.40(s,2H,QuinH),7.22(s,1H,ArH),7.08(d,J＝6.4Hz,2H,ArH),5.25(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.4Hz,1H,ArCH(CH2)S),3.84(s,6H,2×OCH3),3.65(s,3H,OCH3),2.87–2.79(m,1H,1/2×(CHCH 2CH＝C)),2.76–2.69(m,1H,ArCH(CH2)S),1.64(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3,4-二甲氧基苯基时，所得(E,E)-(S)-6-[1-(3,4-二甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(X-7)：淡黄色固体，收率83％。1H NMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),7.62(d,J＝8.6Hz,1H,ArH),7.39(s,3H,QuinH+ArH),7.23(s,1H,ArH),7.09(s,1H,ArH),5.25(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.0Hz,1H,ArCH(CH2)S),3.85(s,3H,OCH3),3.83(s,6H,2×OCH3),3.64(s,3H,OCH3),2.87–2.79(m,1H,1/2×(CHCH 2CH＝C)),2.76–2.69(m,1H,1/2×(CHCH 2CH＝C)),1.65(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3,4,5-三甲氧基苯基时，所得(E,E)-(S)-6-[1-(3,4,5-三甲氧基苯甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟(X-8)：淡黄色固体，收率79％。1H NMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),7.39(s,2H,QuinH),7.25(s,1H,ArH),7.20(s,2H,ArH),5.26(t,J＝7.2Hz,1H,CH2CH＝C),5.08(t,J＝7.2Hz,1H,ArCH(CH2)S),3.85(s,6H,2×OCH3),3.84(s,3H,OCH3),3.75(s,3H,OCH3),3.64(s,3H,OCH3),2.89–2.81((m,1H,1/2×(CHCH 2CH＝C)),2.79–2.71(m,1H,1/2×(CHCH 2CH＝C)),1.65(s,3H,＝C-CH3),1.60(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为肉桂基时，所得(E,E)-(S)-6-(1-肉桂酰硫基-4-甲基-3-戊烯基)-5,8-二甲氧基-1,4-萘二酮二肟(X-9)：淡黄色固体，收率82％。1HNMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),7.76(d,J＝4.8Hz,2H,ArH),7.64(d,J＝15.8Hz,1H,ArH),7.46–7.42(m,3H,ArH),7.40(s,2H,QuinH),7.19(s,1H,ArH),7.02(d,J＝15.8Hz,1H,COCH＝CHAr),5.19(t,J＝7.4Hz,1H,1H,CH2CH＝C),5.07(t,J＝4.6Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.83–2.75(m,1H,1/2×(CHCH 2CH＝C)),2.73–2.66(m,1H,1/2×(CHCH 2CH＝C)),1.65(s,3H,＝C-CH3),1.61(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为2-呋喃基时，所得(E,E)-(S)-6-[1-(2-呋喃甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌(X-10)：淡黄色固体，收率82％。1HNMR(400MHz,DMSO-d6):δ12.05(s,2H,2×(N＝OH)),7.99(s,1H,OCH＝CH),7.40–7.34(m,3H,QuinH and ArH),7.17(s,1H,C＝CH),6.71(s,1H,CH＝CH＝CH),5.20(t,J＝7.6Hz,1H,CH2CH＝C),5.02(t,J＝6.8Hz,1H,ArCH(CH2)S),3.78(s,3H,OCH3),3.59(s,3H,OCH3),2.80–2.72(m,1H,1/2×(CHCH 2CH＝C)),2.71–2.63(m,1H,1/2×(CHCH 2CH＝C)),1.58(s,3H,＝C-CH3),1.57(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为2-噻吩基时，所得(E,E)-(S)-6-[1-(2-噻吩甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌(X-11)：淡黄色固体，收率67％。1HNMR(400MHz,DMSO-d6):δ12.12(s,2H,2×(N＝OH)),8.06(d,J＝4.8Hz,1H,SCH＝CH),7.91(d,J＝3.6Hz,1H,C＝CH-CH),7.41(s,2H,QuinH),7.26(t,J＝4.2Hz,1H,CH＝CH＝CH),7.24(s,1H,ArH),5.27(t,J＝7.4Hz,1H,CH2CH＝C),5.09(t,J＝6.6Hz,1H,ArCH(CH2)S),3.85(s,3H,OCH3),3.66(s,3H,OCH3),2.88–2.72(m,2H,CHCH 2CH＝C),1.65(s,3H,＝C-CH3),1.62(s,3H,＝C-CH3)。
采用上述方法，当羧酸R2COOH中，R2为3-吡啶基时，所得(E,E)-(S)-6-[1-(3-吡啶甲酰硫基)-4-甲基-3-戊烯基]-5,8-二甲氧基-1,4-萘醌(X-12)：淡黄色固体，收率69％。1HNMR(400MHz,DMSO-d6):δ12.14(s,2H,2×(N＝OH)),9.06(s,1H,C＝CH-N),8.85(d,J＝4.6Hz,1H,N＝CH＝CH),8.28(d,J＝8.0Hz,1H,C＝CH＝CH),7.60(dd,J＝7.8,5.0Hz,1H,C＝CH＝CH),7.39(s,2H,QuinH),7.23(s,1H,ArH),5.30(t,J＝7.6Hz,1H,CH2CH＝C),5.09(t,J＝6.8Hz,1H,ArCH(CH2)S),3.83(s,3H,OCH3),3.65(s,3H,OCH3),2.86–2.82(m,1H,1/2×(CHCH 2CH＝C)),2.80–2.73(m,1H,1/2×(CHCH 2CH＝C)),1.65(s,3H,＝C-CH3),1.63(s,3H,＝C-CH3)。
实施例7
对实施例1～6制得的一系列含硫外消旋体紫草素肟衍生物、光学纯含硫紫草素肟衍生物和阿卡宁肟肟衍生物分别进行体外肿瘤细胞抑制实验，选用人结肠癌细胞株(HCT-15)、人肝癌细胞株(Bel7402)和人胃癌细胞株(MGC-803)进行生长抑制实验；以紫草素为阳性对照化合物，根据公式：抑制率＝(对照组平均OD值–给药组平均OD值)/给药组平均OD值，计算了各化合物对不同肿瘤细胞的IC50值，结果见表1。
表1化合物对四种肿瘤细胞的IC50值
Figure BDA0001370883180000411
Figure BDA0001370883180000421
Figure BDA0001370883180000431
Figure BDA0001370883180000441
由表1可知，本发明制备的含硫紫草素肟衍生物对人结肠癌细胞株(HCT-15)、人肝癌细胞株(Bel7402)和人胃癌细胞株(MGC-803)均具有生长抑制作用，且部分化合物的抑制活性强于先导化合物紫草素，尤其是化合物IV-9，IV-15，IV-16，IV-17，IV-20，VII-7，VII-8，VII-9，X-7，X-8和X-9的抑制活性明显强于紫草素和阿卡宁，能够用于制备抗肿瘤药物。
实施例8
对实施案例5和6的中光学纯化合物IX-1和X-8分别进行体外肿瘤细胞生长抑制实验。选用人乳腺癌细胞株(MCF-7)、耐阿霉素的人乳腺癌细胞株(MCF-7/ADR)、人肺癌细胞株(A549)和耐紫杉醇的人肺癌细胞株(A549/TAX)进行生长抑制实验；以阿霉素(ADR)和紫杉醇(TAX)为阳性对照，根据公式：抑制率＝(对照组平均OD值–给药组平均OD值)/给药组平均OD值，计算了化合物对不同肿瘤细胞的IC50值，结果见表2。
表2化合物对两组肿瘤细胞和耐药肿瘤细胞的IC50值
Figure BDA0001370883180000451
由表2可知，本发明的含硫紫草素肟衍生物对人乳腺癌细胞株(MCF-7)、耐阿霉素的人乳腺癌细胞株(MCF-7/ADR)、人肺癌细胞株(A549)和耐紫杉醇的人肺癌细胞株(A549/TAX)均具有较强的生长抑制作用，能够用于制备抗肿瘤耐药药物。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变化或修改，这并不影响本发明的实质内容。在不冲突的情况下，本申请的实施例和实施例中的特征可以任意相互组合。

Claims (8)

1.一种含硫紫草素肟衍生物，其特征在于，结构通式如式(I)所示：
Figure FDA0002566954200000011
其中
Figure FDA0002566954200000018
为-，
Figure FDA0002566954200000019
R为R1或COR2；
所述R1或者R2为
Figure FDA0002566954200000012
2.根据权利要求1所述的含硫紫草素肟衍生物，其特征在于，当通式(I)中
Figure FDA00025669542000000110
为-时，为结构式(II)所代表的含硫外消旋体紫草素肟衍生物，所述结构式(II)如下所示：
Figure FDA0002566954200000013
其中R为R1或COR2；
所述R1或者R2为
Figure FDA0002566954200000014
3.根据权利要求2所述的含硫紫草素肟衍生物，其特征在于，所述结构式(II)中R＝R1时，为结构式(III)所代表的硫醚类外消旋体紫草素肟衍生物；所述结构(II)中R＝COR2时，为结构式(IV)所代表的硫酯类外消旋体紫草素肟衍生物；
Figure FDA0002566954200000015
其中，所述结构式(III)中，R1为
Figure FDA0002566954200000016
所述结构式(IV)中，R2为
Figure FDA0002566954200000017
4.根据权利要求1所述的含硫紫草素肟衍生物，其特征在于，当通式(I)中的
Figure FDA00025669542000000111
为
Figure FDA0002566954200000028
时，为结构式(V)的含硫光学纯紫草素肟衍生物，所述结构式(V)如下所示：
Figure FDA0002566954200000021
其中R为R1或COR2；
所述R1或者R2为
Figure FDA0002566954200000022
5.根据权利要求4所述的含硫紫草素肟衍生物，其特征在于，所述结构式(V)中R＝R1时，为结构式(VI)所代表的硫醚类光学纯紫草素肟衍生物；所述结构式(V)中R＝COR2时，为结构式(VII)所代表的硫酯类光学纯紫草素肟衍生物；
Figure FDA0002566954200000023
其中，所述结构式(VI)中，R1为
Figure FDA0002566954200000024
结构式(VII)中，R2为
Figure FDA0002566954200000025
6.根据权利要求1所述的含硫紫草素肟衍生物，其特征在于，当通式(I)中的
Figure FDA0002566954200000029
为
Figure FDA00025669542000000210
时，为结构式(VIII)所代表的含硫光学纯阿卡宁肟衍生物，所述结构式(VIII)如下所示：
Figure FDA0002566954200000026
其中R为R1或COR2；
所述R1或者R2为
Figure FDA0002566954200000027
7.根据权利要求6所述的含硫紫草素肟衍生物，其特征在于，所述结构式(V)中R＝R1时，为结构式(IX)所代表的硫醚类光学纯阿卡宁肟衍生物；所述结构式(V)中R＝COR2时，为结构式(X)所代表的硫酯类光学纯阿卡宁肟衍生物；
Figure FDA0002566954200000031
其中，所述结构式(IX)中，R1为
Figure FDA0002566954200000032
结构式(X)中，R2为
Figure FDA0002566954200000033
8.一种根据权利要求1所述的含硫紫草素肟衍生物在制备抗耐药性肿瘤药物中的用途。
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