CN114940665B - 一种用作杀菌剂的苯并异噻唑啉酮类化合物及其制备方法 - Google Patents
一种用作杀菌剂的苯并异噻唑啉酮类化合物及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种用作杀菌剂的苯并异噻唑啉酮类化合物,其结构通式如下所示:其中,R1为氢原子、甲基、乙基、丙基,R为C1‑C8的烷基(包括甲基、乙基、丙基、异丙基、正丁基、正戊基、正辛基、2‑乙基己基等)。本发明以苯并异噻唑啉酮(BIT)为原料,与脂肪醛和脂肪醇反应得到的目标化合物。并对合成的BIT衍生物进行了抑菌活性测定,结果表明对金黄色葡萄球菌和白色念珠菌具有良好的抑制活性。
Description
技术领域
本发明属于杀菌剂合成技术领域,具体涉及一种用作杀菌剂的苯并异噻唑啉酮类化合物及其制备方法。
背景技术
苯并异噻唑啉酮(BIT)性质稳定且具有良好的杀菌、防霉功能,对细菌、真菌均具有抑制作用,且毒性较小(LD50 1400mg/kg),被广泛使用。BIT衍生物及其活性有较多报道。Dou D F,et al(Bioorg Med Chem.2011.19:5782-5787)报道合成了一类BIT衍生物,不同酰胺取代基的衍生物,其中甲基和苯基同时取代的化合物的抑菌活性最高,对白色念珠菌等的MIC50达到1.6μg/ml。Gopinath P,et al(Bioorg Med Chem lett2017 27(5):1291-1295)报道了芳基、烷基、酯,肽等取代的衍生物以及苯并异噻唑啉酮二聚体类衍射物,并对它们的抑菌和防霉活性进行了测试,其中2-乙烷基二苯并异噻唑啉酮对金黄色葡萄球菌的MIC50达到了0.4μg/ml,苄基苯并异噻唑啉酮对黄曲霉素抑制IC50=0.1μg/ml。虽然现有研究合成了较多的苯并异噻唑啉酮类化合物,但大多合成步骤复杂,不利于进一步的推广应用。
本发明设计、制备了系列烷氧基甲基苯并异噻唑啉酮类化合物,采用一锅煮的方法,合成方法简便,收率高,所得到的化合物具有较高的抑菌活性。
发明内容
本发明的目的在于克服现有技术缺陷,提供一类具有杀菌效果的苯并异噻唑啉酮类化合物,该类化合物具有较高的抑菌活性。
本发明还提供了上述用作杀菌剂的苯并异噻唑啉酮类化合物的制备方法。
为实现上述目的,本发明采用如下技术方案:
一种用作杀菌剂的苯并异噻唑啉酮类化合物,其结构通式如下所示:
其中,R1为氢原子、甲基、乙基或丙基等,R为C1-C8的烷基。
具体的,R可以包括甲基、乙基、丙基、异丙基、正丁基,正戊基、正辛基或2-乙基己基等。
本发明提供了一种上述苯并异噻唑啉酮类化合物的制备方法,其合成路线如下所示:
具体包括如下步骤:在对甲苯磺酸作用下,将苯并异噻唑啉酮(化合物1)与脂肪醛、脂肪醇于70-95℃反应3-8h,即得目标化合物。
具体的,上述苯并异噻唑啉酮类化合物的制备方法中,所述苯并异噻唑啉酮与脂肪醛的摩尔比为1:1-5,优选1:1.2;苯并异噻唑啉酮与脂肪醇的摩尔比为1:1-40,优选1:10-25。
具体的,上述苯并异噻唑啉酮类化合物的制备方法中,所述对甲苯磺酸与苯并异噻唑啉酮的摩尔比为1:10-40,优选1:10-25。
具体的,上述苯并异噻唑啉酮类化合物的制备方法中,所述脂肪醛包括甲醛、乙醛、丙醛或丁醛等,优选甲醛和丁醛;所述脂肪醇包括C1-C8的直连及支链醇,优选乙醇、丙醇、丁醇。
进一步的,所述甲醛可以是多聚甲醛或甲醛水溶液。
本发明还提供了上述苯并异噻唑啉酮类化合物作为杀菌剂的应用。
本发明采用一锅煮的方法合成了苯并异噻唑啉酮类化合物,并对化合物进行了抑菌活性测定。和现有技术相比,本发明具有如下优点:
1)本发明采用简洁的一锅煮方法,得到了新的BIT类衍生物,具有合成方法简单,收率高等优点,易于后续的进一步应用;
2)经试验验证:本发明系列烷氧基甲基苯并异噻唑啉酮类化合物具有较高的抑菌活性,尤其是对金黄色葡萄球菌和白色念珠菌抑菌效果良好,可用作杀菌剂。
具体实施方式
以下结合实施例对本发明的技术方案作进一步地详细介绍,但本发明的保护范围并不局限于此。
下述实施例中,所用原料均为普通市售产品:多聚甲醛、碳酸氢钠、无水硫酸钠,分析纯,天津科密欧试剂有限公司;二氯甲烷、石油醚、乙酸乙酯、乙醇、正丁醇、正戊醇、甲醇、正丙醇,分析纯,烟台双双化工有限公司;对甲苯磺酸,分析纯,上海麦克林生化科技有限公司。
实施例1:化合物2-乙氧甲基苯并异噻唑啉酮(2a)的合成
在25mL反应瓶中,加入苯并异噻唑啉酮BIT(1.0,6.6mmol),多聚甲醛(0.24g,7.9mmol),对甲苯磺酸(0.1g,0.58mmol),乙醇(5g,108.5mmol),加热到80℃回流反应4.5h,反应结束后蒸馏除去过量的乙醇。然后加入5%碳酸氢钠水溶液15mL,用二氯甲烷萃取2次(2*20ml),无水硫酸钠干燥二氯甲烷层,旋转蒸发浓缩后,经柱层析(石油醚:乙酸乙酯=4:1,体积比,下同)分离得到产物0.9g,无色粘稠液体,收率65.2%;1H NMR(400MHz,CDCl3),δ:8.06(d,J=8.0Hz,1H),7.66-7.64(t,J=8.4Hz,1H),7.58(d,J=8.0Hz,1H),7.43-7.39(t,J=8.0Hz,1H),5.35(s,2H),3.64-3.59(t,J=14.4Hz,2H),1.23-1.20(t,J=12Hz,3H)。
实施例2:化合物2-丙氧甲基苯并异噻唑啉酮(2b)的合成
在25mL反应瓶中,加入BIT(1g,6.6mmol),多聚甲醛(0.24g,7.9mmol),对甲苯磺酸(0.1g,0.58mmol),正丙醇(8g,133.3mmol),加热到85℃反应4.5h,反应结束后蒸馏除去过量的正丙醇。然后加入5%碳酸氢钠水溶液15mL,用二氯甲烷萃取2次(2*20ml),无水硫酸钠干燥有机层,旋转蒸发浓缩后,经柱层析(石油醚:乙酸乙酯=4:1)分离得到产物1.2g,白色固体,收率81.6%;1H NMR(400MHz,CDCl3),δ:8.06(d,J=8.0Hz,1H),7.65-7.62(t,J=7.6Hz,1H),7.59(d,J=8.0Hz,1H),7.43-7.39(t,J=7.6Hz,1H),5.35(s,2H),3.52-3.49(t,2H),1.64-1.55(m,2H),0.90-0.88(t,3H)。
实施例3:化合物2-丁氧甲基苯并异噻唑啉酮(2c)的合成
在25mL反应瓶中,加入BIT(1g,6.6mmol),多聚甲醛(0.24g,7.9mmol),对甲苯磺酸(0.1g,0.58mmol),正丁醇(10g,135.1mmol),加热到95℃反应4h,反应结束后蒸馏除去过量的正丁醇。然后加入5%碳酸氢钠水溶液25mL,用二氯甲烷萃取2次(2*20ml),无水硫酸钠干燥有机层,旋转蒸发浓缩,经柱层析(石油醚:乙酸乙酯=4:1)分离得到产物1.25g,淡黄色粘稠液体,收率80.1%;1H NMR(400MHz,CDCl3),δ:8.06(d,J=8.0Hz,1H),7.66-7.64(t,J=8.4Hz,1H),7.58(d,J=7.6Hz,1H),7.43-7.41(d,J=8.0Hz,1H),5.34(s,2H),3.56-3.53(t,J=13.2Hz,2H),1.59-1.54(m,2H),1.38-1.32(m,2H),0.90-0.87(t,J=14.8Hz,3H).
实施例4:化合物2-戊氧甲基苯并异噻唑啉酮(2d)的合成
在25mL反应瓶中,加入BIT(1g,6.6mmol),多聚甲醛(0.24g,7.9mmol),对甲苯磺酸(0.1g,0.58mmol),正戊醇(10g,113.6mmol),加热到95℃反应4.5h,反应结束后蒸馏除去过量的正戊醇。然后加入5%碳酸氢钠水溶液15mL,用二氯甲烷萃取2次(2*20ml),无水硫酸钠干燥有机层,旋转蒸发浓缩,经柱层析(石油醚:乙酸乙酯=4:1)分离得到产物1.30g,无色粘稠液体,收率78.3%;1H NMR(400MHz,CDCl3),δ:8.06(d,J=7.6Hz,1H),7.66-7.64(t,J=7.6Hz,1H),7.58(d,J=8.0Hz,1H),7.43-7.39(t,J=8.0Hz,1H),5.35(s,2H),3.55-3.52(t,2H),1.71-1.56(m,2H),1.31-1.28(m,4H),0.88-0.84(t,3H)。
实施例5:化合物2-甲氧丁基苯并异噻唑啉酮(2e)的合成
在25mL反应瓶中,加入BIT(1g,6.6mmol),丁醛(0.57g,7.9mmol),对甲苯磺酸(0.1g,0.58mmol),甲醇(5g,156mmol),加热到70℃反应4.5h,反应结束后蒸馏除去过量的甲醇。然后加入5%碳酸氢钠水溶液15mL,用二氯甲烷萃取2次(2*20ml),无水硫酸钠干燥有机层,旋转蒸发浓缩,经柱层析(石油醚:乙酸乙酯=4:1)分离得到产物0.9g,淡色粘稠液体,收率57.3%;1H NMR(400MHz,CDCl3),δ:8.06(d,J=8.0Hz,1H),7.65-7.63(t,J=8.0Hz,1H),7.59(d,J=7.8Hz,1H),7.43-7.39(t,J=8.0Hz,1H),5.83-5.80(t,2H),3.33(s,3H),1.92-1.76(m,2H),1.48-1.38(m,2H),0.98-0.94(t,3H)。
实施例6:化合物2-丙氧丁基苯并异噻唑啉酮(2f)的合成
在25mL反应瓶中,加入BIT(1g,6.6mmol),丁醛(0.57g,7.9mmol),对甲苯磺酸(0.1g,0.58mmol),正丙醇(8g,133.3mmol),加热到85℃反应4h,反应结束后蒸馏除去过量的正丙醇。然后加入5%碳酸氢钠水溶液15mL,用二氯甲烷萃取2次(2*20ml),无水硫酸钠干燥有机层,旋转蒸发浓缩,经柱层析(石油醚:乙酸乙酯=4:1)分离得到产物1.5g,无色粘稠液体,收率85.4%;1H NMR(400MHz,CDCl3),δ:8.05(d,J=7.6Hz,1H),7.64-7.60(t,J=7.6Hz,1H),7.58(d,J=8.0Hz,1H),7.42-7.38(t,J=8.0Hz,1H),5.90(s,1H),3.44-3.41(t,2H),1.93-1.76(m,2H),1.63-1.54(m,2H),1.50-1.33(m,2H),0.97-0.94(t,3H),0.92-0.88(t,3H)。
抑菌活性测定:
采用微量肉汤稀释法测定实施例1至6合成所得化合物对常见微生物的最低抑制浓度。
受试菌株包括金黄色葡萄球菌(CICC 21600)、大肠杆菌(CICC 10389)、铜绿假单胞菌(CICC 21636)和白色念珠菌(CICC 1965),所有菌种均购自中国工业微生物菌种保藏管理中心(CICC)。
实验方法:
1、抗菌制剂的配置:
准确称量实施例化合物、乳化剂Span80和助溶剂二丙二醇甲醚,按照重量比5:15:80混合均匀,得到质量分数为5%的抗菌制剂。然后将其作为起始浓度,用培养液依次进行稀释(金黄色葡萄球菌、大肠杆菌和铜绿假单胞菌实验用营养肉汤(NB)培养液,白色念珠菌实验用马铃薯葡萄糖(PDB)培养液,下同),从而得到一系列不同浓度的样品溶液。选用杀菌效果较好的左氧氟沙星作为对照例。
2、菌悬液的配制:
分别取固体培养基斜面上新鲜菌种培养物,用吸管吸取5.0ml培养液加入斜面试管内,反复吹吸,洗下菌苔。随后,用吸管将洗液移至另一无菌试管中,用电动混合器混合(振荡)20s,以使菌体悬浮均匀。以培养液稀释为0.5麦氏比浊标准,再用培养液进行1:1000稀释后备用,测试菌浓度约为1.5×105CFU/ml。
3、96孔培养板的准备:
将不同浓度的样品溶液分别加到灭菌的培养板中,每孔100μl。另取100μl菌悬液接种于含样品溶液的孔中,作为试验组;另外以同样方法接种200μl菌悬液至培养孔中,作为阳性对照组;取200μl培养液加入培养孔中,作为阴性对照组。
将金黄色葡萄球菌、大肠杆菌和铜绿假单胞菌培养板放置37℃培养箱中培养24h,白色念珠菌培养板放置25℃培养箱中培养48h。
4、最低抑制浓度(MIC)的确定:
当阳性对照孔内测试菌明显生长,阴性对照孔无测试菌生长时,观察在某样品浓度的培养孔内测试菌不生长,而相邻较低浓度样品的培养孔内测试菌明显生长,则该浓度即为该样品对该测试菌的最低抑制浓度。结果如下表所示。
上表的活性测定结果表明:本发明苯并异噻唑啉酮类化合物对金黄色葡萄球菌和白色念珠菌具有良好的抑菌效果,可用作杀菌剂。
Claims (5)
1.一种用作杀菌剂的苯并异噻唑啉酮类化合物,其特征在于,结构通式如下所示:
;其中,化合物选自如下结构:
、/>、/>、、/>。
2.一种权利要求1所述苯并异噻唑啉酮类化合物的制备方法,其特征在于,合成路线如下所示:
具体包括如下步骤:在对甲苯磺酸作用下,将苯并异噻唑啉酮与脂肪醛、脂肪醇于70-95℃反应3-8 h,即得。
3.如权利要求2所述苯并异噻唑啉酮类化合物的制备方法,其特征在于,所述苯并异噻唑啉酮与脂肪醛的摩尔比为1:1-5,苯并异噻唑啉酮与脂肪醇的摩尔比为1:1-40。
4.如权利要求2所述苯并异噻唑啉酮类化合物的制备方法,其特征在于,所述对甲苯磺酸与苯并异噻唑啉酮的摩尔比为1:10-40。
5.权利要求1所述苯并异噻唑啉酮类化合物在制备杀菌剂药物中的应用,其特征在于,所述菌为金黄色葡萄球菌和白色念珠菌。
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