CN111303092B - 2,4-二硝基-6-氯苯胺衍生物、合成方法及其应用 - Google Patents

2,4-二硝基-6-氯苯胺衍生物、合成方法及其应用 Download PDF

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CN111303092B
CN111303092B CN202010265735.2A CN202010265735A CN111303092B CN 111303092 B CN111303092 B CN 111303092B CN 202010265735 A CN202010265735 A CN 202010265735A CN 111303092 B CN111303092 B CN 111303092B
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高建伟
徐少华
付忠东
常永恒
姜雯
徐英猛
姚璐
于晓辉
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Shandong Changyi Zaohu Salinization Co ltd
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Abstract

本发明公开了一种新型结构的2,4‑二硝基‑6‑氯苯胺衍生物，
Figure DDA0002441188250000011
其中，R选自
Figure DDA0002441188250000012

Description

2,4-二硝基-6-氯苯胺衍生物、合成方法及其应用
技术领域
本发明属于新药研发领域，涉及一种2,4-二硝基-6-氯苯胺衍生物、合成方法及其应用。
背景技术
2,4-二硝基-6-氯化苯衍生物产业应用主要集中在染料、医药、农药、炸药、化学助剂等领域。随着科技进步，2,4-二硝基-6-氯化苯衍生物在硫化染料和氟喹诺酮类(如：环丙沙星)中得到重要应用。2,4-二硝基-6-氯苯胺作为一个具有多个活性位点的小分子结构，下游产品具有更广阔的结构开发及优化空间，但是除分散染料，其他下游产品规模尚小。2,4-二硝基-6-氯苯胺衍生物作为极具发展潜力的产业链，迫切的需要丰富和发展。
本发明通过化学结构设计并合成一系列2,4-二硝基-6-氯苯胺衍生物，并且通过药理实验确定化合物的生物活性。
发明内容
本发明的目的在于提供一种新型结构的2,4-二硝基-6-氯苯胺衍生物，其结构如式(Ⅰ)所示，
Figure BDA0002441188240000011
其中，R选自
Figure BDA0002441188240000012
Figure BDA0002441188240000013
进一步地，2,4-二硝基-6-氯苯胺衍生物式(Ⅰ)所示的结构如下表：
Figure BDA0002441188240000014
Figure BDA0002441188240000021
本发明的另一目的在于提供一种新型结构的2,4-二硝基-6-氯苯胺衍生物，其结构如式(Ⅱ)所示，
Figure BDA0002441188240000022
其中，R选自
Figure BDA0002441188240000023
Figure BDA0002441188240000024
进一步地，2,4-二硝基-6-氯苯胺衍生物式(Ⅱ)所示的化合物如下表：
Figure BDA0002441188240000025
Figure BDA0002441188240000031
本发明的另一目的在于提供一种新型结构的2,4-二硝基-6-氯苯胺衍生物式(Ⅰ)和/或式(Ⅱ)的合成方法，其合成路线为：
Figure BDA0002441188240000032
其中，R选自
Figure BDA0002441188240000033
具体反应步骤为：
1)在浓硫酸的催化下，邻氯苯胺和浓硝酸发生硝化反应生成2,4-二硝基-6-氯-苯胺；
2)低温下，2,4-二硝基-6-氯-苯胺和相应的取代甲酰胺反应生成对应的2,4-二硝基-6-氯-苯胺衍生物；
3)在钯催化剂的催化下，相应的2,4-二硝基-6-氯-苯胺衍生物和呋喃-3-硼酸发生suzuki偶联反应生成对应的产物。由于苯环上具有两个强吸电子的硝基基团，使得苯环上的氯具有很强的活性，能够在钯催化剂的催化下很容易发生suzuki偶联反应。2,4-二硝基-6-氯-苯胺衍生物的合成设计研究中发现，只有一个或没有硝基基团存在时，氯的活性低，反应难以进行，副产物多，可用溴替代氯，进行相应的反应。
本发明的另一目的在于提供一种2,4-二硝基-6-氯苯胺衍生物式(Ⅰ)和/或式(Ⅱ)及其药学可接受的盐作为抗菌活性药物的应用。在试验例1中以环丙沙星作为阳性对照药测定本发明所述的化合物的最小抑菌浓度(MIC)，根据实验数据可以看出，本发明所示的化合物对枯草芽孢杆菌和铜绿假单胞杆菌均具有一定的杀菌活性，可以预期本发明对革兰氏阳性菌和革兰氏阴性菌中的其他具体菌种可能存在杀菌活性。从最小抑菌浓度(MIC)来看，对于枯草芽孢杆菌除Ⅰb和Ⅰe外，其它化合物均低于阳性对照药环丙沙星(1μg/mL)，其中Ⅱa为62.5ng/mL；对于铜绿假单胞杆菌Ⅰa、Ⅱa和Ⅱb低于阳性对照药环丙沙星(0.5μg/mL)，Ⅰd与环丙沙星相当，其中Ⅰa、Ⅱa为125ng/mL。
本发明的另一目的在于提供一种2,4-二硝基-6-氯苯胺衍生物式(Ⅰ)和/或式(Ⅱ)及其药学可接受的盐在毒杀线虫上的应用。在试验例2中以噻唑膦作为阳性对照对黄瓜根结线虫进行毒力测试，根据实验数据可以看出，本发明所示的化合物对黄瓜根结线虫均具有一定的毒杀能力，从半数致死浓度(LC50)来看，Ⅱa和Ⅱb低于噻唑膦。
具体实施方式
中间体1：2,4-二硝基-6-氯-苯胺的合成
Figure BDA0002441188240000041
将邻氯苯胺(100mmol)加入到200ml浓硫酸中，然后将体系降温至0-5℃，将16.5ml浓硝酸缓慢滴加入体系中，滴加过程中保持体系温度不高于5℃，滴加完毕后升温至40℃搅拌1小时。降温至室温，用25％氢氧化钠溶液调节体系pH至10，向体系中分别加入100ml乙酸乙酯萃取两次，有机相用50ml水洗涤两次，无水硫酸钠干燥，过滤后向体系中滴加两倍体积石油醚，养晶3小时，过滤，得到12.2g红色固体，即2,4-二硝基-6-氯-苯胺，收率56％。1H-NMR(400MHz,CDCl3)δ:7.51(s,2H),8.32(d,1H),8.50(d,1H).13C-NMR(125MHz,CDCl3)δ:121.13,125.66,126.51,137.03,138.20,1448.55.LC-MS(ESI,pos,ion)m/z:218[M+H]。2,4-二硝基-6-氯-苯胺为已知化合物，实际生产过程中也可采用其它合成方法获得，亦可通过购买获得。
实施例1：N-(6-氯-2,4-二硝基苯基)-5-硝基呋喃-2-甲酰胺的合成
Figure BDA0002441188240000051
将200ml水、6g NaOH、2,4-二硝基-6-氯-苯胺(100mmol)加入到反应容器中，搅拌半小时。体系降温至5℃以下，向其中缓慢滴加5-硝基呋喃-2-甲酰氯(105mmol)，滴加过程中保持温度不高于5℃，加毕，保持温度继续搅拌1小时，然后恢复至室温继续搅拌2小时。TLC检测反应完毕后，用浓盐酸调节体系的pH至7-8，用乙酸乙酯萃取体系两遍，有机相减压浓缩至糊状，向其中加入150ml异丙醚，打浆2小时，过滤，得到32.1g亮黄色固体，即N-(6-氯-2,4-二硝基苯基)-5-硝基呋喃-2-甲酰胺，收率：90％。1H-NMR(400MHz,CDCl3)δ:7.80(m,2H),8.62(d,1H),8.80(m,2H).13C-NMR(125MHz,CDCl3)δ:120.64,121.67,122.14,127.22,130.76,138.11,142.88,153.54,158.14.LC-MS(ESI,pos,ion)m/z:357[M+H]。
实施例2：N-(6-氯-2,4-二硝基苯基)-苯并呋喃-2-甲酰胺的合成
Figure BDA0002441188240000052
将200ml水、6g NaOH、2,4-二硝基-6-氯-苯胺(100mmol)加入到反应容器中，搅拌半小时。体系降温至5℃以下，向其中缓慢滴加苯并呋喃-2-甲酰氯(105mmol)，滴加过程中保持温度不高于5℃，加毕，保持温度继续搅拌1小时，然后恢复至室温继续搅拌2小时。TLC检测反应完毕后，用浓盐酸调节体系的pH至7-8，用乙酸乙酯萃取体系两遍，有机相减压浓缩至糊状，向其中加入150ml异丙醚，打浆2小时，过滤，得到33.3g亮黄色固体，即N-(6-氯-2,4-二硝基苯基)-苯并呋喃-2-甲酰胺，收率：92％。1H-NMR(400MHz,CDCl3)δ:7.17(td,1H),7.25(td,1H),7.45(m,2H),7.85(d,1H),8.62(d,1H),8.80(m,2H).13C-NMR(125MHz,CDCl3)δ:110.6,112.41,122.14,123.51,125.73,127.22,130.12,130.76,138.11,142.88,151.88,155.55,158.89.LC-MS(ESI,pos,ion)m/z:362[M+H]。
实施例3：N-(6-氯-2,4-二硝基苯基)-吡啶甲酰胺的合成
Figure BDA0002441188240000061
将200ml水、6gNaOH、2,4-二硝基-6-氯-苯胺(100mmol)加入到反应容器中，搅拌半小时。体系降温至5℃以下，向其中缓慢滴加吡啶甲酰氯(105mmol)，滴加过程中保持温度不高于5℃，加毕，保持温度继续搅拌1小时，然后恢复至室温继续搅拌2小时。TLC检测反应完毕后，用浓盐酸调节体系的pH至7-8，用乙酸乙酯萃取体系两遍，有机相减压浓缩至糊状，向其中加入150ml异丙醚，打浆2小时，过滤，得到30.7g亮黄色固体，即N-(6-氯-2,4-二硝基苯基)-吡啶甲酰胺，收率：95％。1H-NMR(400MHz,CDCl3)δ:7.48(m,1H),8.07(m,2H),8.63(m,2H),8.80(d,1H),9.99(s,1H).13C-NMR(125MHz,CDCl3)δ:122.14,123.99,125.21,127.22,130.76,137.99,138.11,142.88,148.66,151.81,163.47.LC-MS(ESI,pos,ion)m/z:323[M+H]。
实施例4：N-(6-氯-2,4-二硝基苯基)-异恶唑-5-甲酰胺的合成
Figure BDA0002441188240000062
将200ml水、6g NaOH、2,4-二硝基-6-氯-苯胺(100mmol)加入到反应容器中，搅拌半小时。体系降温至5℃以下，向其中缓慢滴加异恶唑-5-甲酰氯(105mmol)，滴加过程中保持温度不高于5℃，加毕，保持温度继续搅拌1小时，然后恢复至室温继续搅拌2小时。TLC检测反应完毕后，用浓盐酸调节体系的pH至7-8，用乙酸乙酯萃取体系两遍，有机相减压浓缩至糊状，向其中加入150ml异丙醚，打浆2小时，过滤，得到27.2g亮黄色固体，即N-(6-氯-2,4-二硝基苯基)-异恶唑-5-甲酰胺，收率：87％。LC-MS(ESI,pos,ion)m/z:313[M+H]。
实施例5：N-(6-氯-2,4-二硝基苯基)-苯甲酰胺的合成
Figure BDA0002441188240000063
将200ml水、6g NaOH、2,4-二硝基-6-氯-苯胺(100mmol)加入到反应容器中，搅拌半小时。体系降温至5℃以下，向其中缓慢滴加苯甲酰氯(105mmol)，滴加过程中保持温度不高于5℃，加毕，保持温度继续搅拌1小时，然后恢复至室温继续搅拌2小时。TLC检测反应完毕后，用浓盐酸调节体系的pH至7-8，用乙酸乙酯萃取体系两遍，有机相减压浓缩至糊状，向其中加入异丙醚，打浆2小时，过滤，得到29.3g亮黄色固体，即N-(6-氯-2,4-二硝基苯基)-苯甲酰胺，收率：91％。LC-MS(ESI,pos,ion)m/z:322[M+H]。
实施例6：N-(2-(呋喃-3-基)-4,6-二硝基苯基)-5-硝基呋喃-2-甲酰胺的合成
由于苯环上具有两个强吸电子的硝基基团，使得苯环上的氯具有很强的活性，能够在钯催化剂的催化下很容易发生suzuki偶联反应。2,4-二硝基-6-氯-苯胺衍生物的合成设计研究中发现，只有一个或没有硝基基团存在时，氯的活性低，反应难以进行，副产物多，可用溴替代氯，进行相应的反应。
Figure BDA0002441188240000071
将Pd(dppf)Cl2(2mmol)加入100ml二氯甲烷溶液中，搅拌5分钟，将悬浊液加入已脱气的N-(6-氯-2,4-二硝基苯基)-5-硝基呋喃-2-甲酰胺(100mmol)的150ml二甲基乙酰胺溶液中，在20℃条件下搅拌1小时，然后混合溶液加热到90℃搅拌1小时。在单独的烧瓶中将呋喃-3-硼酸(105mmol)溶于150ml二甲基乙酰胺中，加入到50ml 5％的碳酸钠水溶液中，然后将此混合溶液一次性加入到之前已升温的体系中，维持温度在90℃以上，搅拌2小时后降温至室温，继续搅拌4小时，然后反应液缓慢倒入1000ml冷水中，将悬浊液继续搅拌1小时，过滤，用100ml水洗涤，得到粗品，真空50℃干燥后用200ml乙酸乙酯40℃打浆2小时，降至室温后过滤，用50ml乙酸乙酯洗涤，真空50℃干燥，得到33.0g淡黄色固体，即N-(2-(呋喃-3-基)-4,6-二硝基苯基)-5-硝基呋喃-2-甲酰胺，收率85％。1H-NMR(400MHz,CDCl3)δ:7.10(t,1H),7.30(d,1H),7.61(t,1H),7.64(d,1H),7.71(t,1H),8.23(d,1H),8.64(d,1H),10.18(s,1H).13C-NMR(125MHz,CDCl3)δ:108.52,114.26,117.55,121.76,123.98,126.86,128,135.59,135.93,138.77,140.58,141.74,150.62,152.15.LC-MS(ESI,pos,ion)m/z:389[M+H]。
实施例7：N-(2-(呋喃-3-基)-4,6二硝基苯基)-异恶唑-5-甲酰胺
Figure BDA0002441188240000081
将Pd(dppf)Cl2(2mmol)的100ml二氯甲烷溶液加入到已脱气的N-(6-氯-2,4-二硝基苯基)-异恶唑-5-甲酰胺(100mmol)的150ml二甲基乙酰胺溶液中，在20℃条件下搅拌1小时，然后混合溶液加热到90℃搅拌1小时。在单独的烧瓶中将呋喃-3-硼酸(105mmol)溶于150ml二甲基乙酰胺中，加入到50ml 5％的碳酸钠水溶液中，然后将此混合溶液一次性加入到之前已升温的体系中，维持温度在90℃以上，搅拌2小时后降温至室温，继续搅拌4小时，然后反应液缓慢倒入1000ml冷水中，将悬浊液继续搅拌1小时，过滤，用100ml水洗涤，得到粗品，真空50℃干燥后用200ml乙酸乙酯40℃打浆2小时，降至室温后过滤，用50ml乙酸乙酯洗涤，真空50℃干燥，得到27.9g淡黄色固体，即N-(2-(呋喃-3-基)-4,6二硝基苯基)-异恶唑-5-甲酰胺，收率81％。1H-NMR(400MHz,CDCl3)δ:7.06(t,1H),7.15(d,1H),7.62(t,1H),7.69(t,1H),8.22(m,2H),8.70(d,1H),10.24(s,1H).13C-NMR(125MHz,CDCl3)δ:108.6,109.76,121.89,123.92,125.95,127.84,135.36,135.64,138.96,140.55,141.91,146.71,159.58,163.72.LC-MS(ESI,pos,ion)m/z:345[M+H]。
试验例1：抗菌活性
环丙沙星为第3代氟喹诺酮类杀菌剂，是以2,4－二氯氟苯为起始原料合成的，同为2,4-二硝基-6-氯化苯产业链的下游产品。氟喹诺酮类抗生素与头孢菌素、大环内酯类抗生素并称全球三大消炎抗菌药物。
本发明以环丙沙星作为阳性对照，采用肉汤稀释法检测各化合物的最小抑菌浓度(MIC)，以评价本发明所述的化合物的抗菌活性。方法如下：
将各待测细菌接种于TSA固体培养基上，置于37℃培养箱中倒置培养。长出菌落后，用接种环挑取各待测细菌的单菌落于TSB液体培养基中，在37℃，180r/min转速的摇床中培养至对数生长期，用TSB液体培养基分别稀释至106CFU/mL。在96孔板采用二倍稀释法得到不同浓度待测样品，具体做法为，在第一个孔中加入180μL TSB液体培养基，其它孔中加入100μL TSB液体培养基，然后在第一个孔中加入20μL一定浓度的待测样品，不同待测样品根据预实验采用不同的浓度，混匀后取100μL加入下一个孔中，混匀后以此类推，最后一个孔中混匀后弃去100μL。阴性对照每孔加入200μL的TSB液体培养基。将96孔板置于37℃培养箱培养24h，用酶标仪在波长600nm处测定吸光度值。
检测结果计算：96孔板中能够完全抑制细菌生长的最低测试样品的浓度作为最小抑菌浓度。MIC测试结果如下表所示：
表 抗菌活性-最小抑菌浓度(MIC)
Figure BDA0002441188240000091
枯草芽孢杆菌为革兰氏阳性菌，铜绿假单胞杆菌为革兰氏阴性菌，根据实验数据可以看出，本发明所示的化合物对枯草芽孢杆菌和铜绿假单胞杆菌均具有一定的杀菌活性，可以预期本发明对革兰氏阳性菌和革兰氏阴性菌中的其他具体菌种可能存在杀菌活性。从最小抑菌浓度(MIC)来看，对于枯草芽孢杆菌除Ⅰb和Ⅰe外，其它化合物均低于阳性对照药环丙沙星(1μg/mL)，其中Ⅱa为62.5ng/mL；对于铜绿假单胞杆菌Ⅰa、Ⅱa和Ⅱb低于阳性对照药环丙沙星(0.5μg/mL)，Ⅰd与环丙沙星相当，其中Ⅰa、Ⅱa为125ng/mL。
试验例2：线虫毒力
噻唑膦为有机磷类杀线虫剂，主要作用方式为抑制根结线虫乙酰胆碱酯酶的合成，可用于防治各类根结线虫。
本发明以噻唑膦作为阳性对照药，采用浸虫法观察各化合物黄瓜根结线虫的死亡情况，以评价本发明所述的化合物的杀线虫活性。方法如下：
人工接种黄瓜根结线虫的黄瓜根部，用组织捣碎机打碎，梯次过筛，过500目筛后，用无菌水冲洗3次，孵化，取2龄幼虫进行测试。不同浓度的待测样品各3ml分别加入试管中，然后加入等量线虫悬浮液3ml，混合均匀。各试管分3次，每次取1ml悬浮液分别加到24孔培养板的不同孔中。将24孔板用封口膜封严后置于25℃培养箱，设无菌水为对照处理。48h后镜检线虫死亡情况，计算校正死亡率，求得毒力回归方程并计算LC50值。毒力测定结果如下表所示：
表 线虫毒力-半数致死浓度(LC50)
化合物 LC<sub>50</sub>(mg/ml)
噻唑膦 4.92
Ⅰa 10.22
Ⅰd 13.08
Ⅱa 1.46
Ⅱb 5.47
根据实验数据可以看出，本发明所示的化合物对黄瓜根结线虫均具有一定的毒杀能力，从半数致死浓度(LC50)来看，Ⅱa和Ⅱb低于噻唑膦。
综上所述，本发明化合物可以作为抗菌药物和/或杀线虫药物在药理、毒理、降解或代谢，以及制剂的开发等方面进行更加深入的研发。

Claims (4)

1.式（Ⅱ）化合物，其结构如下所示，
Figure 837673DEST_PATH_IMAGE001
，其中，R选自
Figure 754814DEST_PATH_IMAGE002
或
Figure 596868DEST_PATH_IMAGE003
。
2.权利要求1所述的式（Ⅱ）化合物在制备作为抗菌活性药物中的应用。
3.如权利要求2所述的应用，其特征是，所述抗菌活性对应的菌为革兰氏阳性菌和/或革兰氏阴性菌。
4.如权利要求1所述的式（Ⅱ）化合物在制备毒杀线虫药物上的应用。
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WO2008130669A1 (en) * 2007-04-20 2008-10-30 The Research Foundation Of State University Of New York Benzimidazoles and pharmaceutical compositions thereof
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