CN109369436A - 一种酰胺取代一枝蒿酮酸衍生物及制备方法和用途 - Google Patents
一种酰胺取代一枝蒿酮酸衍生物及制备方法和用途 Download PDFInfo
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- CN109369436A CN109369436A CN201811337991.7A CN201811337991A CN109369436A CN 109369436 A CN109369436 A CN 109369436A CN 201811337991 A CN201811337991 A CN 201811337991A CN 109369436 A CN109369436 A CN 109369436A
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- acid methyl
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- A—HUMAN NECESSITIES
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- C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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Abstract
本发明涉及一种酰胺取代一枝蒿酮酸衍生物及制备方法和用途,该类衍生物以一枝蒿酮酸甲酯为原料,在二异丙基氨基锂(LDA)的存在下,与N‑氯代丁二酰亚胺(NCS)反应得到2‑氯‑一枝蒿酮酸甲酯,再经叠氮取代及PPh3还原后制得2‑氨基‑一枝蒿酮酸甲酯,并与不同的酰氯反应制得酰胺取代的一枝蒿酮酸甲酯。该方法反应条件简单,实验步骤简捷。并对所获得的酰胺取代一枝蒿酮酸衍生物进行了抗流感病毒A(H1N1,H3N2)和抗流感病毒B活性测试,实验结果表明:具备抗流感病毒A中H1N1,H3N2和抗流感病毒B的药物中的用途。
Description
技术领域
本发明涉一种酰胺取代一枝蒿酮酸衍生物及制备方法和用途,该类衍生物经活性检测部分化合物具有抗流感病毒的药物用途。
背景技术
菊科(Compositae)蒿属植物新疆一枝蒿(Artemisia rupestris L.),主要分布于中国新疆、中亚、欧洲等地,全草入药,是哈萨克传统药物,在新疆民间用药历史悠久,有清热解毒,消食健胃,利胆,解蛇毒之功效,用于消化不良,腹胃胀痛,肝炎,荨麻疹,蛇咬伤,感冒发烧等。新疆一枝蒿临床主要用于治疗病毒性感冒,且已有以新疆一枝蒿为主要成分的复方药品上市,如复方一枝蒿颗粒。
一枝蒿酮酸是一种愈创木烷型倍半萜类化合物,是新疆一枝蒿的主要成分之一,赵江瑜等人【有机化学,2012,32(2):333–337;Bioorg.Med.Chem.Lett.2012,22(6):2321–2325】发现一枝蒿酮酸具有抗流感病毒A(H3N2)的活性,并通过对羧酸进行修饰,得到了一系列具有抗流感病毒A(H3N2)酯类和酰胺类衍生物;贺耀武等人【Eur.J.Med.Chem.76(2014)245-255.】利用点击化学在羧基上引入三氮唑,得到了一系列抗流感病毒A(H3N2)的化合物;李根等人【Bioorg.Med.Chem.Lett.27(2017)1484–1487.】在LDA作用下与醛反应,将羟甲基引入到一枝蒿酮酸2位,得到一系列具有较强抗流感病毒A(H3N2)的化合物。
以前一枝蒿酮酸的结构修饰主要集中在羧基的修饰,而其他官能团及结构改变较少。而在其他部位引入取代基及酰胺可以改变药物分子与受体结合的性质。
本发明在国内外有关文献的综合分析和本课题组前期研究工作的基础上,将氨基引入到一枝蒿酮酸的2位亚甲基上,并将烷基、芳基以酰胺键为连接方式引入到一枝蒿酮酸环戊酮的2位亚甲基上,从而合成了一系列酰胺取代一枝蒿酮酸衍生物,并对其进行了抗流感病毒A中(H1N1,H3N2)和抗流感病毒B活性筛选。
发明内容
本发明的目的在于,提供一种酰胺取代一枝蒿酮酸衍生物及制备方法和用途,该类衍生物以一枝蒿酮酸甲酯为原料,在二异丙基氨基锂(LDA)的存在下,与N-氯代丁二酰亚胺(NCS)反应得到2-氯-一枝蒿酮酸甲酯,再经叠氮取代及PPh3还原后制得2-氨基-一枝蒿酮酸甲酯,并与不同的酰氯反应制得酰胺取代的一枝蒿酮酸甲酯。该方法反应条件简单,实验步骤简捷。并对所获得的酰胺取代一枝蒿酮酸衍生物进行了抗流感病毒A(H1N1,H3N2)和抗流感病毒B活性测试,实验结果表明:具备抗流感病毒的药物中的用途。
本发明所述的一种酰胺取代一枝蒿酮酸衍生物,其结构如通式(Ⅰ):
其中,R为乙酰基、苯甲酰基、3-氯-2-甲基丙酰基、N-苯甲酰基-氨基乙酰基、2-氰基乙酰基、N,N-二甲基甲酰基、甲磺酰基、苯甲磺酰基、4-氟苯基磺酰基、4-(硼酸基)苯甲酰基。
所述的一种酰胺取代一枝蒿酮酸衍生物的制备方法,按下列步骤进行:
a、在温度-70℃条件下,将一枝蒿酮酸甲酯溶于干燥的四氢呋喃中,搅拌至全部溶解;加入含二异丙基氨基锂的四氢呋喃溶液,继续在温度-70℃反应1小时;
b、将N-氯代丁二酰亚胺溶于干燥的四氢呋喃中,滴加到步骤a反应体系中,继续在温度-70℃反应半小时后,自然升温至室温,TLC检测反应完全后,再加入乙酸乙酯,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比10:1的石油醚:乙酸乙酯,即得2-氯一枝蒿酮酸甲酯;
c、将步骤b得到的产物溶于二甲基酰胺中,加入NaN3,室温搅拌过夜,TLC检测反应完全后,再加入乙酸乙酯,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比12:1的石油醚:乙酸乙酯,即得2-叠氮一枝蒿酮酸甲酯;
d、将步骤c得到的产物溶于四氢呋喃/水的混合溶剂中,加入三苯基膦加热回流2小时,TLC检测反应完全后,再加入乙酸乙酯,用10%盐酸洗涤3次,水溶液用饱和NaHCO3溶液中和并用乙酸乙酯萃取3次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,即得2-氨基一枝蒿酮酸甲酯;
e、将步骤d得到的产物溶于无水二氯甲烷中,加入三乙胺,冰水浴冷却反应体系至0℃,滴加酰氯,升至室温反应过夜,TLC检测反应完全后,再加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比2-8:1的石油醚:乙酸乙酯,即得酰胺取代一枝蒿酮酸甲酯衍生物。
步骤c中所述产物无需柱层析分离直接用于下步反应。
所述方法获得的酰胺取代一枝蒿酮酸衍生物在制备治疗抗流感病毒A中H1N1,H3N2和抗流感病毒B的药物中的用途。
本发明所述的一种酰胺取代一枝蒿酮酸衍生物,该衍生物中所述的取代甲醛为R为乙酰基、苯甲酰基、3-氯-2-甲基丙酰基、N-苯甲酰基-氨基乙酰基、2-氰基乙酰基、N,N-二甲基甲酰基、甲磺酰基、苯甲磺酰基、4-氟苯基磺酰基、4-(硼酸基)苯甲酰基。
本发明所述的酰胺取代的一枝蒿酮酸衍生物的制备方法,是将氨基引入到一枝蒿酮酸甲酯的2位活泼亚甲基上的同时以此为原料将不同取代的酰胺也引入到一枝蒿酮酸分子中,从而合成一系列酰胺取代的一枝蒿酮酸衍生物,化学反应式为:
其中,R为乙酰基、苯甲酰基、3-氯-2-甲基丙酰基、N-苯甲酰基-氨基乙酰基、2-氰基乙酰基、N,N-二甲基甲酰基、甲磺酰基、苯甲磺酰基、4-氟苯基磺酰基、4-(硼酸基)苯甲酰基。
本发明所述的一种酰胺取代一枝蒿酮酸衍生物及制备方法和用途,以一枝蒿酮酸甲酯为原料,在二异丙基氨基锂(LDA)的存在下,与N-氯代丁二酰亚胺(NCS)反应得到2-氯-一枝蒿酮酸甲酯,再经叠氮取代及PPh3还原后制得2-氨基-一枝蒿酮酸甲酯,并与不同的酰氯反应制得酰胺取代的一枝蒿酮酸甲酯。将所得到的产物进行了抗流感病毒A(H1N1,H3N2)和抗流感病毒B活性测试,实验结果表明:7个衍生物(1a,1b,1d,1g,1h,1i和1j)的抗流感病毒A(H1N1)活性均强于母核一枝蒿酮酸甲酯,其中1i的活性强于阳性对照药物达菲和病毒唑,1h具有比达菲更强并与病毒唑接近的抗流感病毒A(H1N1)活性。同时化合物1b、1g和1i的抗流感病A(H3N2)的活性强于母核一枝蒿酮酸甲酯,其中1i的活性强于阳性对照药物达菲和病毒唑。对抗流感病毒B,化合物1h和1i的活性接近于病毒唑。该方法实验步骤简捷,通过本发明所述方法获得的酰胺取代一枝蒿酮酸衍生物在制备抗流感病毒药物中的用途。
具体实施方式
依据实施例对本发明进一步说明,但本发明不仅限于这些实施例;
试剂:所有试剂均为市售的分析纯;
实施例1
2-(R)-氯-一枝蒿酮酸甲酯的制备:
a、在温度-70℃条件下,将一枝蒿酮酸甲酯5.41g溶于200mL干燥的四氢呋喃中,搅拌至全部溶解;加入含10.66mL浓度为2N的二异丙基氨基锂的四氢呋喃溶液,继续在温度-70℃反应1小时;
b、将10.92g N-氯代丁二酰亚胺溶于200mL干燥的四氢呋喃中,滴加到步骤a反应体系中,继续在温度-70℃反应半小时后,自然升温至室温,TLC检测反应完全后,再加入乙酸乙酯,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比10:1的石油醚:乙酸乙酯,即得2-(R)-氯一枝蒿酮酸甲酯3.94g;
2-(R)-氯-一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ6.23(s,1H),5.63(s,1H),3.96–3.89(m,1H),3.78(s,3H),3.22(s,1H),2.86(dd,J=31.6,15.4Hz,2H),2.52(dd,J=19.2,11.8Hz,1H),2.46–2.36(m,1H),1.94–1.86(m,1H),1.82(ddd,J=13.2,8.3,3.4Hz,2H),1.72(d,J=8.9Hz,3H),1.65(dd,J=13.9,3.7Hz,1H),0.76(d,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ200.44,172.11,167.01,145.74,135.96,123.56,58.93,57.68,52.04,38.21,37.97,36.09,33.24,31.57,12.93,8.47.
2-(S)-叠氮-一枝蒿酮酸甲酯的制备:
c、将步骤b得到的产物3.94g溶于二甲基酰胺中,加入1.80g NaN3,室温搅拌过夜,TLC检测反应完全后,再加入乙酸乙酯,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比12:1的石油醚:乙酸乙酯,即得2-(S)叠氮一枝蒿酮酸甲酯3.47g;
2-(S)-叠氮-一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ6.22(s,1H),5.62(s,1H),3.78(s,3H),3.65(d,J=2.4Hz,1H),2.83(dd,J=29.2,15.2Hz,3H),2.50(dd,J=19.3,11.5Hz,1H),2.33(d,J=3.1Hz,1H),1.91–1.84(m,1H),1.85–1.77(m,2H),1.76–1.65(m,4H),0.78(d,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)δ202.67,172.80,167.01,145.78,135.79,123.53,77.31,77.19,76.99,76.67,64.84,53.23,52.03,38.21,37.94,36.03,33.56,31.64,13.08,8.21.
2-(S)-氨基-一枝蒿酮酸甲酯的制备:
d、将步骤c得到的产物3.47g溶于四氢呋喃/水的混合溶剂中,加入4.68g三苯基膦加热回流2小时,TLC检测反应完全后,再加入乙酸乙酯,用10%盐酸洗涤3次,水溶液用饱和NaHCO3溶液中和,并用乙酸乙酯萃取3次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,即得2-(S)-氨基一枝蒿酮酸甲酯2.95g;
2-(S)-N-乙酰基-一枝蒿酮酸甲酯的制备(1a):
e、将263mg 2-(S)-氨基-一枝蒿酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加106μL乙酰氯,升至室温反应过夜,TLC检测反应完全后,再加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比6:1的石油醚:乙酸乙酯,即得酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-乙酰基-一枝蒿酮酸甲酯(1a)245mg;
2-(S)-乙酰氨基-一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ6.22(s,1H),5.76(d,J=6.4Hz,1H),5.63(s,1H),4.10(dd,J=6.6,2.4Hz,1H),3.77(s,3H),2.93(s,1H),2.87(d,J=19.5Hz,1H),2.83–2.76(m,1H),2.66(s,1H),2.50(dd,J=18.4,12.0Hz,1H),2.04(s,3H),2.01(d,J=5.8Hz,1H),1.91–1.83(m,1H),1.83–1.75(m,2H),1.75–1.69(m,1H),1.68(s,3H),1.63(d,J=7.1Hz,2H),0.83(d,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ204.51,173.37,170.86,146.04,135.64,123.38,58.49,55.39,52.00,38.22,38.20,36.09,32.92,31.88,23.18,12.88,8.28。
实施例2
2-(S)-N-苯甲酰基-一枝蒿酮酸甲酯的制备(1b):
本实施例步骤a-步骤d依据实施例1进行:
e、将263mg 2-(S)-氨基-一枝蒿酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加172μL苯甲酰氯,升至室温反应过夜,TLC检测反应完全后,加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比6:1的石油醚:乙酸乙酯,即得酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-苯甲酰基-一枝蒿酮酸甲酯(1b)240mg;
2-(S)-N-苯甲酰基-一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ7.84–7.77(m,2H),7.50(t,J=7.4Hz,1H),7.42(t,J=7.5Hz,2H),6.58(d,J=6.0Hz,1H),6.22(s,1H),5.64(s,1H),4.30(dd,J=5.8,2.8Hz,1H),3.77(s,3H),3.08(s,1H),2.91(d,J=19.2Hz,1H),2.86–2.76(m,2H),2.54(dd,J=18.8,11.6Hz,1H),1.90(dd,J=8.5,4.7Hz,1H),1.84–1.68(m,6H),0.89(d,J=7.2Hz,3H).13CNMR(101MHz,CDCl3)δ204.63,173.67,168.16,167.12,146.05,135.70,133.69,131.72,128.54,127.07,123.42,58.78,55.50,52.00,38.31,38.27,36.12,33.07,31.88,12.96,8.31。
实施例3
2-(S)-N-(3-氯-2-甲基丙酰基)-一枝蒿酸甲酯的制备(1c):
本实施例步骤a-步骤d依据实施例1进行:
e、将263mg 2-(S)-氨基-一枝蒿酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加197μL3-氯-2-甲基丙酰氯,升至室温反应过夜,TLC检测反应完全后,反应体系中加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比8:1的石油醚:乙酸乙酯,酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-(3-氯-2-甲基丙酰基)-一枝蒿酸甲酯(1c)265mg;
2-(S)-N-(3-氯-2-甲基丙酰基)-一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ6.22(s,1H),6.08(d,J=6.0Hz,1H),5.64(s,1H),4.10–4.03(m,1H),3.78(s,3H),3.66(t,J=10.3Hz,1H),3.58(d,J=10.7Hz,1H),2.95(d,J=9.9Hz,1H),2.91–2.84(m,1H),2.84–2.75(m,1H),2.68(s,1H),2.51(dd,J=18.9,11.9Hz,1H),1.87(s,1H),1.83–1.58(m,8H),1.33(s,6H),1.27(d,J=12.7Hz,1H),0.83(d,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ204.33,175.80,173.44,167.20,146.04,135.71,123.46,58.54,55.33,52.89,52.03,44.29,38.30,38.19,36.13,33.05,31.86,23.60,23.22,12.92,8.31。
实施例4
2-(S)-N-((N-苯甲酰基-氨基乙酰基))-一枝蒿酮酸甲酯的制备(1d):
本实施例步骤a-步骤d依据实施例1进行:
e、将263mg 2-(S)-氨基-一枝蒿酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加210μL N-苯甲酰基-氨基乙酰氯,升至室温反应过夜,TLC检测反应完全后,加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比7:1的石油醚:乙酸乙酯,酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-((N-苯甲酰基-氨基乙酰基))-一枝蒿酮酸甲酯的制备(1d)237mg;
2-(S)-N-((N-苯甲酰基-氨基乙酰基))-一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ7.86–7.80(m,2H),7.45(dq,J=15.1,7.2Hz,4H),7.34(s,1H),6.98(d,J=7.4Hz,1H),6.20(s,1H),5.61(s,1H),4.23(ddd,J=39.0,16.8,5.2Hz,2H),4.12(dd,J=7.3,3.2Hz,1H),3.77(s,3H),3.01(s,1H),2.86(d,J=19.1Hz,1H),2.82–2.74(m,1H),2.53(d,J=19.2Hz,2H),1.85(s,1H),1.77(dd,J=15.3,6.7Hz,3H),1.64(s,3H),0.83(d,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ203.83,173.26,169.62,131.91,128.63,127.16,123.49,58.31,54.80,52.03,43.48,38.41,38.11,36.05,32.96,31.88,12.89,8.33,0.01。
实施例5
2-(S)-N-(2-氰基乙酰基)-一枝蒿酮酸甲酯的制备(1e):
本实施例步骤a-步骤d依据实施例1进行:
e、将263mg 2-(S)-氨基-一枝蒿酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加119μL 2-氰基乙酰氯,升至室温反应过夜,TLC检测反应完全后,加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比6:1的石油醚:乙酸乙酯,酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-(2-氰基乙酰基)-一枝蒿酮酸甲酯的制备(1e)243mg;
2-(S)-N-(2-氰基乙酰基)-一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ6.38(d,J=6.7Hz,1H),6.23(s,1H),5.64(s,1H),4.12(d,J=6.7Hz,1H),3.97(s,1H),3.78(s,3H),3.46(s,2H),3.00(s,1H),2.89(d,J=19.5Hz,1H),2.80(t,J=10.8Hz,1H),2.53(dd,J=19.2,11.8Hz,2H),1.88(s,1H),1.85–1.66(m,7H),0.84(d,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ203.12,173.59,167.10,161.82,145.85,135.87,123.60,114.34,58.70,54.74,52.08,38.30,38.17,36.01,33.06,31.80,28.02,25.93,12.86,8.36。
实施例6
2-(S)-N-(N,N-二甲基甲酰基)-一枝蒿酮酸甲酯的制备(1f):
本实施例步骤a-步骤d依据实施例1进行:
e、将263mg 2-(S)-氨基-一枝蒿酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加108μL N,N-二甲基甲酰氯,升至室温反应过夜,TLC检测反应完全后,加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比2:1的石油醚:乙酸乙酯,酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-(N,N-二甲基甲酰基)-一枝蒿酮酸甲酯(1f)210mg;
2-(S)-N-(N,N-二甲基甲酰基)-一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,DMSO-D6)δ8.60(t,J=6.0Hz,1H),7.96(s,2H),7.67(s,1H),7.65–7.61(m,1H),7.27(s,1H),5.66(s,1H),5.39(s,1H),4.39–4.26(m,2H),3.15(s,1H),2.88(t,J=11.0Hz,1H),2.76–2.68(m,1H),2.55–2.45(m,4H),2.04(d,J=4.2Hz,1H),1.91(d,J=18.3Hz,1H),1.76–1.69(m,2H),1.66(s,1H),1.60–1.48(m,4H),0.57(d,J=7.1Hz,3H)。
实施例7
2-(S)-N-甲磺酰基-一枝蒿酮酸甲酯的制备(1g):
本实施例步骤a-步骤d依据实施例进行:
e、将263mg 2-(S)-氨基-一枝蒿酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加114μL甲磺酰氯,升至室温反应过夜,TLC检测反应完全后,加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比5:1的石油醚:乙酸乙酯,酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-甲磺酰基-一枝蒿酮酸甲酯(1g)200mg;
2-(S)-N-甲磺酰基-酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ6.23(s,1H),5.64(s,1H),4.60(d,J=7.4Hz,1H),3.78(d,J=3.4Hz,3H),3.74(dd,J=7.8,3.2Hz,1H),3.18(s,3H),2.93(d,J=7.4Hz,2H),2.87(s,1H),2.82–2.73(m,1H),2.55(s,2H),1.96–1.90(m,1H),1.85–1.76(m,2H),1.74(d,J=8.5Hz,1H),1.68(s,3H),0.84(d,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ203.70,173.31,145.83,135.15,123.53,61.10,55.22,52.03,41.94,38.36,38.22,36.01,31.75,31.51,12.68,8.27。
实施例8
2-(S)-N-苯甲磺酰基-一枝蒿酮酸甲酯的制备(1h):
本实施例步骤a-步骤d依据实施例1进行:
e、将263mg 2-(S)-氨基-一枝蒿酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加164μL苯甲磺酰氯,升至室温反应过夜,TLC检测反应完全后,加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比5:1的石油醚:乙酸乙酯,酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-苯甲磺酰基-一枝蒿酮酸甲酯(1h)200mg;
2-(S)-N-苯甲磺酰基-一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ7.81(d,J=8.3Hz,2H),7.33(d,J=8.1Hz,2H),6.21(s,1H),5.61(s,1H),4.95(d,J=3.9Hz,1H),3.78(s,3H),3.34(d,J=3.1Hz,1H),3.08(s,1H),2.85(d,J=19.3Hz,1H),2.76(t,J=10.8Hz,1H),2.63(s,1H),2.53–2.45(m,1H),2.43(s,3H),1.87(d,J=13.1Hz,1H),1.84–1.73(m,2H),1.71(d,J=8.0Hz,1H),1.62(s,3H),0.72(d,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ202.73,174.46,167.01,145.90,143.82,136.04,134.96,129.77,127.49,123.49,60.32,55.18,52.00,38.36,38.31,35.95,32.19,31.70,21.57,12.67,8.26。
实施例9
2-(S)-N-(4-氟苯甲磺酰基)一枝蒿酮酸甲酯的制备(1i):
本实施例步骤a-步骤d依据实施例1进行:
e、将263mg 2-(S)-氨基-一枝蒿酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加170μL 4-氟苯甲磺酰氯,升至室温反应过夜,TLC检测反应完全后,加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比7:1的石油醚:乙酸乙酯,酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-(4-氟苯甲磺酰基)一枝蒿酮酸甲酯(1i)220mg;
2-(S)-N-(4-氟苯甲磺酰基)一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.2Hz,2H),7.81(d,J=8.3Hz,2H),6.22(s,1H),5.62(s,1H),5.06(d,J=5.2Hz,1H),3.78(s,3H),3.48–3.43(m,1H),3.05(s,1H),2.87(d,J=19.8Hz,1H),2.80–2.72(m,1H),2.60(s,1H),2.48(dd,J=19.0,12.1Hz,1H),1.91(d,J=9.7Hz,1H),1.84–1.76(m,1H),1.77–1.70(m,2H),1.62(s,3H),0.76(d,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ202.37,174.15,166.96,145.77,135.08,127.93,126.30,126.26,123.55,77.30,77.19,76.99,76.67,60.47,55.22,52.03,38.33,38.30,35.94,32.08,31.65,12.65,8.27。
实施例10
2-(S)-N-(4-(硼酸基)苯甲酰基)一枝蒿酮酸甲酯的制备(1j):
本实施例步骤a-步骤d依据实施例1进行:
e、将263mg 2-(S)-氨基-酮酸甲酯溶于无水二氯甲烷中,加入200μL三乙胺,冰水浴冷却反应体系至0℃,滴加180μL 4-(硼酸基)苯甲酰氯,升至室温反应过夜,TLC检测反应完全后,加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比4:1的石油醚:乙酸乙酯,酰胺取代一枝蒿酮酸甲酯衍生物2-(S)-N-(4-(硼酸基)苯甲酰基)一枝蒿酮酸甲酯(1j)200mg;
2-(S)-N-(4-(硼酸基)苯甲酰基)一枝蒿酮酸甲酯的核磁数据:
1H NMR(400MHz,CDCl3)δ7.71(d,J=7.3Hz,2H),7.64(d,J=7.4Hz,2H),7.52(s,1H),6.21(s,1H),5.63(s,1H),4.38(d,J=5.2Hz,1H),3.76(s,3H),3.12(s,1H),2.83(d,J=13.9Hz,2H),2.51(s,2H),1.76(dd,J=35.3,19.6Hz,4H),1.63(s,3H),0.85(d,J=6.4Hz,3H).13C NMR(101MHz,CDCl3)δ205.86,174.35,168.47,167.30,162.74,145.95,135.62,134.53,134.13,126.19,123.70,58.50,54.92,52.10,38.31,38.23,36.64,35.97,32.73,31.91,31.56,12.92,8.27。
实施例11
本发明的生物活性测试:
将实施例1-10任意一种酰胺取代一枝蒿酮酸衍生物1a-1j进行了抗流感病毒A和B活性测试:
测试原理:以狗肾(MDCK)细胞为病毒宿主,测定样品抑制病毒引起细胞病变程度(CPE);
测试材料和方法:
病毒株:
病毒株:流感病毒A/95-359(H1N1),在鸡胚尿囊腔内培养传代(2013.9),-80℃保存。流感病毒A/汉防/359/95(H3N2),在鸡胚尿囊腔内培养传代(2018.3),-80℃保存。流感病毒B/济防/13/97,在鸡胚尿囊腔内培养传代(2013.9),温度-80℃保存;
样品处理:
样品用稀释液配成适宜初始浓度,再用培养液作3倍稀释,各8个稀释度;
阳性对照药:
病毒唑(RBV),新乡制药股份有限公司(批号20081227);达菲,中国食品药品检定研究院(批号101096-200901);
测试方法:
狗肾(MDCK)细胞接种96孔培养板,置5%CO2,温度37℃培养;24小时后感染流感病毒1/210-5,吸附2小时,弃病毒液,加入含有不同稀释度样品及阳性对照药的维持液,同时设细胞对照孔和病毒对照,5%CO2,温度37℃培养待病毒对照组病变(CPE)达4+时观察各组细胞病变(CPE)(约40小时),计算各样品抗流感病毒半数抑制浓度(IC50);
通过测试本发明的酰胺取代一枝蒿酮酸衍生物1a-1j活性结果如表1所示:
表1衍生物1a-1j抗流感病毒的活性数据
IC50:抗流感病毒半数抑制浓度。
从表中实验结果表明:1i具有比阳性对照药病毒唑和达菲更强的抗流感病毒A(H1N1和H3N2)的活性,1h具有比达菲更强并与病毒唑接近的抗流感病毒A(H1N1)活性,1i和1h的抗流感B病毒活性接近病毒唑。
Claims (3)
1.一种酰胺取代的一枝蒿酮酸衍生物,其特征在于该衍生物的结构如通式(Ⅰ):
其中,R为乙酰基、苯甲酰基、3-氯-2-甲基丙酰基、N-苯甲酰基-氨基乙酰基、2-氰基乙酰基、N,N-二甲基甲酰基、甲磺酰基、苯甲磺酰基、4-氟苯基磺酰基或4-(硼酸基)苯甲酰基。
2.根据权利要求1所述的酰胺取代的一枝蒿酮酸衍生物的制备方法,其特征在于按下列步骤进行:
a、在温度-70℃条件下,将一枝蒿酮酸甲酯溶于干燥的四氢呋喃中,搅拌至全部溶解;加入含二异丙基氨基锂的四氢呋喃溶液,继续在温度-70℃反应1小时;
b、将N-氯代丁二酰亚胺溶于干燥的四氢呋喃中,滴加到步骤a反应体系中,继续在温度-70℃反应半小时后,自然升温至室温,TLC检测反应完全后,再加入乙酸乙酯,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比10:1的石油醚:乙酸乙酯,即得2-氯一枝蒿酮酸甲酯;
c、将步骤b得到的产物溶于二甲基酰胺中,加入NaN3,室温搅拌过夜,TLC检测反应完全后,再加入乙酸乙酯,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比12:1的石油醚:乙酸乙酯,即得2-叠氮一枝蒿酮酸甲酯;
d、将步骤c得到的产物溶于四氢呋喃/水的混合溶剂中,加入三苯基膦加热回流2小时,TLC检测反应完全后,再加入乙酸乙酯,用10%盐酸洗涤3次,水溶液用饱和NaHCO3溶液中和并用乙酸乙酯萃取3次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,即得2-氨基一枝蒿酮酸甲酯;
e、将步骤d得到的产物溶于无水二氯甲烷中,加入三乙胺,冰水浴冷却反应体系至0℃,滴加酰氯,升至室温反应过夜,TLC检测反应完全后,再加入二氯甲烷,用水洗两次,有机相用无水硫酸镁干燥,过滤,真空脱滤液中的溶剂,将残渣采用柱层析梯度洗脱,洗脱剂为体积比2-8:1的石油醚:乙酸乙酯,即得酰胺取代一枝蒿酮酸甲酯衍生物。
3.一种如权利要求1所述方法获得的酰胺取代一枝蒿酮酸衍生物在制备治疗抗流感病毒A中H1N1,H3N2和抗流感病毒B的药物中的用途。
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CN107089913A (zh) * | 2017-05-25 | 2017-08-25 | 中国科学院新疆理化技术研究所 | 一种2‑取代的一枝蒿酮酸甲酯衍生物及其制备方法和用途 |
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CN112876365A (zh) * | 2021-02-20 | 2021-06-01 | 中国科学院新疆理化技术研究所 | 一种含肉桂酰基的一枝蒿酮酸甲酯衍生物及其制备方法和用途 |
CN112961114A (zh) * | 2021-02-20 | 2021-06-15 | 中国科学院新疆理化技术研究所 | 一种2-取代的一枝蒿酮酸异噁唑酰胺衍生物及其制备方法和用途 |
CN112979470A (zh) * | 2021-02-20 | 2021-06-18 | 中国科学院新疆理化技术研究所 | 一种含苯甲酰基的一枝蒿酮酸甲酯衍生物及其制备方法和用途 |
CN112961114B (zh) * | 2021-02-20 | 2023-06-09 | 中国科学院新疆理化技术研究所 | 一种2-取代的一枝蒿酮酸异噁唑酰胺衍生物及其制备方法和用途 |
CN112876365B (zh) * | 2021-02-20 | 2023-09-29 | 中国科学院新疆理化技术研究所 | 一种含肉桂酰基的一枝蒿酮酸甲酯衍生物及其制备方法和用途 |
CN115160160A (zh) * | 2022-02-14 | 2022-10-11 | 厦门稀土材料研究所 | 一枝蒿酮酸麻黄碱衍生物及其制备方法和用途 |
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