CN103755541A - 一类查尔酮衍生物及其制备方法和用途 - Google Patents
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- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 title claims abstract description 14
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- 235000005513 chalcones Nutrition 0.000 claims abstract description 13
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical class C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 claims abstract description 10
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
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- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 5
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- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 238000005618 Fries rearrangement reaction Methods 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
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- 238000005882 aldol condensation reaction Methods 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
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- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 2
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- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 150000001789 chalcones Chemical class 0.000 description 5
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- ABXFXDSGHDZAEV-UHFFFAOYSA-N OC1=C(C(=O)C=NO)C=C(C=C1)C Chemical compound OC1=C(C(=O)C=NO)C=C(C=C1)C ABXFXDSGHDZAEV-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
- C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Abstract
一类查尔酮衍生物及其制备方法和用途,涉及一类查尔酮衍生物。1.中间体邻羟基苯乙酮及其衍生物的制备;2.中间体金刚烷基苯甲醛的制备:2.1化合物2,4-二羟基-5-金刚烷基苯甲醛的合成;2.2化合物2,4-醚基-5-金刚烷基苯甲醛的合成;3.查尔酮衍生物—3-(5-金刚烷基-2,4-二取代基苯基)-1-(2-羟基-5-取代基苯基)-丙烯酮的合成。查尔酮衍生物—3-(5-金刚烷基-2,4-二取代苯基)-1-(2-羟基-5-取代苯基)-丙烯酮可在制备抗艾滋病药物中应用。
Description
技术领域
本发明涉及一类查尔酮衍生物,尤其是涉及一类查尔酮衍生物及其制备方法和用途。
背景技术
查尔酮类化合物的基本结构为1,3-二苯基丙烯酮,是合成黄酮类化合物的重要中间体,由于其分子结构具有较大柔性,能与多种受体结合,呈现出广泛的生物活性,如抗肿瘤、抗炎、抗菌、抗寄生虫、抗氧化和抗病毒作用等(Go,M.L.;Wu,X.;Liu,X.L.;Chalcones∶an update on cytotoxic and chemoprotective properties[J].Curr Med Chem,2005,12(4)∶481;Ducki,S.;The development of chalcones as promising anticancer agents[J].Drugs,2007,10(1)∶42)。近年来,随着查尔酮类衍生物在抗病毒方面活性研究的展开,人们发现查尔酮类化合物可激活潜伏期HIV病毒,是一类很有发展前景的治疗艾滋病的药物。
发明内容
本发明的第一目的在于提供一类查尔酮衍生物。
本发明的第二目的在于提供一类查尔酮衍生物的制备方法。
本发明的第三目的在于提供一类查尔酮衍生物在制备抗艾滋病药物中的应用。
所述查尔酮衍生物的结构式为:
其中,R1是氢,烷基,卤素,烷氧基,羧基或羧酸衍生物;R2和R3相同,是氢,烷基或甲氧甲基;Ad是金刚烷基。
所述一类查尔酮衍生物的制备方法包括以下步骤:
1.中间体邻羟基苯乙酮及其衍生物的制备
中间体邻羟基苯乙酮衍生物可用Fries重排方法(参见文献:杜秀丽.黄酮-6-羧酸类化合 物的合成及生物活性研究[M].南昌大学,2008)进行制备。邻羟基苯乙酮衍生物的制备方法,以各取代苯酚为原料,先和醋酐反应成酯,再经Fries重排得到粗产物,最后进行重结晶得到对应取代的苯乙酮的纯品;具体步骤如下:
a)氮气保护下,在反应瓶中先分别加入苯酚类化合物、乙酸酐,再在磁力搅拌下加入80~200μL硫酸,固体迅速溶解并变成无色透明溶液,继续反应20~60min后,停止反应,得到的反应液备用,其中苯酚类化合物和乙酸酐摩尔配比为1∶(1~1.5);所述苯酚类化合物为苯酚、对烷基苯酚、对卤素苯酚、对烷氧基苯酚、对羧基苯酚、对酯基苯酚等中的一种;
b)将步骤a)的反应液倒入冰水中,立即析出大量白色固体,过滤,滤饼先用饱和碳酸钠溶液洗两次,再用双蒸水洗涤后,自然干燥,得到对位取代的乙酰氧基苯类衍生物;
c)Fries重排:在反应瓶中加入步骤b)中得到的对位取代的乙酰氧基苯类衍生物和无水三氯化铝,油浴加热至160~180℃,继续搅拌反应4~6h,停止反应后,冷却;在冰浴下向反应体系中加入2mol/L的盐酸溶液后,先用第一有机溶剂萃取三次,再用饱和食盐水洗三次,合并有机相,用无水硫酸钠干燥过夜,过滤,有机相减压浓缩后得到各相应的邻羟基苯乙酮衍生物粗产品,最后用第二有机溶剂重结晶得邻羟基苯乙酮衍生物的纯品,收率40%~65%;其中对取代乙酰氧基甲苯、无水三氯化铝和盐酸的摩尔配比为1∶(2~4)∶(6~10);邻羟基苯乙酮衍生物包括邻羟基苯乙酮、2-羟基-5-烷基苯乙酮、2-羟基-5-卤素苯乙酮、2-羟基-5-烷氧基苯乙酮、2-羟基-5-羧基苯乙酮和2-羟基-5-酯基苯乙酮;第一有机溶剂为乙酸乙酯、氯仿或乙醚等;第二有机溶剂为乙醇、异丙醇或四氢呋喃等;
2.中间体金刚烷基苯甲醛的制备
2.1化合物2,4-二羟基-5-金刚烷基苯甲醛的合成
2,4-二羟基-5-金刚烷基苯甲醛的具体合成步骤如下:
a)氮气保护下,在干燥的反应瓶中加入2,4-二羟基苯甲醛、1-金刚烷醇和适量干燥的第一有机溶剂,搅拌使其充分溶解,于冰浴下向反应体系中缓慢滴加浓硫酸,滴加完毕后,继续搅拌反应30~60min,撤掉冰浴,再升温至40~60℃,搅拌回流20~28h后,结束反应,得到的反应液备用;其中所述2,4-二羟基苯甲醛、1-金刚烷醇和浓硫酸的摩尔配比为1∶(1~1.5)∶(1~2);第一有机溶剂为二氯甲烷、氯仿或四氢呋喃等;
b)将步骤a)得到的反应液冷却至室温,先用饱和碳酸氢钠溶液调pH至7~8,再用第一有机溶剂萃取3次,合并有机相,无水硫酸钠干燥过夜,过滤,有机相减压浓缩得到的残留物通过硅胶柱层析分离(洗脱剂为石油醚和乙酸乙酯的混合溶剂),得2,4-二羟基-5-金刚烷基苯甲醛的白色固体,收率70%~90%;其中所述第一有机溶剂为二氯甲烷或乙酸乙酯等;
2.2化合物2,4-醚基-5-金刚烷基苯甲醛的合成
2,4-醚基-5-金刚烷基苯甲醛的具体合成步骤如下:
a)氮气保护下,在反应瓶中加入2,4-二羟基-5-金刚烷基苯甲醛、钠氢和第一有机溶剂,搅拌使其溶解;于0~5℃冰浴下向反应体系中加入卤化物,继续搅拌反应30min,撤掉冰浴,室温搅拌2~4h,结束反应,得到的反应液备用;其中所述2,4-二羟基-5-金刚烷基苯甲醛、钠氢和卤化物的摩尔配比为1∶(1.5~3)∶(1.5~3);卤化物为氯化物、碘化物、溴化物等中的一种;第一有机溶剂为二氯甲烷、氯仿、乙腈、二甲基甲酰胺(DMF)等中的一种;
b)将步骤a)得到的反应液倒入2~4倍体积的冰水中,用等体积的第一有机溶剂萃取,合并有机相,无水硫酸镁干燥过夜,过滤,有机相减压浓缩后得到的残留物通过硅胶柱层析分离(洗脱剂为石油醚和乙酸乙酯的混合溶剂),得2,4-醚基-3-金刚烷基苯甲醛,收率60%~85%;
3.查尔酮衍生物—3-(5-金刚烷基-2,4-二取代基苯基)-1-(2-羟基-5-取代基苯基)-丙烯酮的合成
采用经典的碱性条件下的Claisen—Schmidt反应(参见文献:Kohler,E.P.;Chadwell,H.M.;Synthesis of Chalcone[J].Org.Syn.1956,1(1)∶78),以步骤1得到的中间体邻羟基苯乙酮、步骤2得到的中间体金刚烷基苯甲醛以及取代的苯甲醛和取代的苯乙酮为原料合成查尔酮,具体的合成步骤如下:
a)氮气保护下,在反应瓶中加入中间体金刚烷基苯甲醛、中间体取代苯乙酮和第一有机溶剂,搅拌使其溶解,于冰浴下向反应体系中加入2mol/L氢氧化钾的第一有机溶剂的溶液(体积分数为50%),室温反应20~28h后,得到的反应液备用;其中所述中间体金刚烷基苯甲醛、中间体取代苯乙酮和氢氧化钾的摩尔比为1∶(1~1.5)∶(3~6);第一有机溶剂为甲醇或乙醇等;
b)减压浓缩除去步骤a)反应后反应液中的溶剂,冰浴条件下向残渣中加入蒸馏水溶解,用1mol/L的盐酸调pH值至5~7,此过程中即产生大量沉淀,将沉淀过滤,滤饼用蒸馏水洗涤3次后干燥得粗产物,最后用硅胶柱层析(洗脱剂为石油醚和乙酸乙酯的混合溶剂或二氯甲烷和甲醇的混合溶剂)分离,得查尔酮衍生物—3-(5-金刚烷基-2,4-二取代基苯基)-1-(2-羟基-5-取代基苯基)-丙烯酮,收率10%~70%。
通过流式细胞仪药物筛选实验和Luciferase转录活性实验发现具有上述结构式的查尔酮衍生物对细胞潜在的HIV基因可能具有激活作用,它们对潜伏期HIV的激活率为0~45%。如,流式检测结果(图1)显示随着化合物WA-28浓度由50μg/mL提高到100μg/mL时, 药物对GFP的激活明显增强,在浓度为100ug/mL时对潜伏期HIV的激活率可达27.7%,但是由于药物毒性较大,当浓度增大到200μg/mL时,大量细胞死亡;Luciferase转录活性实验结果(图2)显示随着WA-28浓度从50μg/mL到200μg/mL的增加,Luciferase催化的底物发光强度逐渐增加,即WA-28对于潜伏期HIV有着激活作用,但当浓度增大到300μg/mL时显微镜下细胞死亡较多,因此光强度降低。由此可见,查尔酮衍生物—3-(5-金刚烷基-2,4-二取代苯基)-1-(2-羟基-5-取代苯基)-丙烯酮可在制备抗艾滋病药物中应用。
附图说明
图1为WA-28流式筛选结果图。在图1中,横坐标为样品浓度(nmol·L-1);纵坐标为HIV的激活率(%);Con为空白对照,DMSO为阴性对照,Prostrain为阳性对照。
图2为WA-28的Luciferase转录活性实验结果图。在图2中,横坐标为样品浓度(nmol·L-1);纵坐标为光强度;Con为空白对照,DMSO为阴性对照(不同DMSO浓度处理细胞是因为加入的WA-28药物的量不同),HMBA为阳性对照。
具体实施方式
为了便于理解本发明,现结合具体实施方式对本发明作进一步说明,以进一步诠释本发明,但不构成对本发明的任何方式的限制。
实施例1
氮气保护下,在250mL干燥的反应瓶中加入2,4-二羟基苯甲醛(5.0g,36mmol)、1-金刚烷醇(5.8g,38mmol)和干燥的二氯甲烷50mL,搅拌使其充分溶解。于0℃冰浴下向反应体系中缓慢滴加浓硫酸(3.11mL,56mmol),滴加完毕后,继续搅拌反应30min,撤掉冰浴。再升温至45℃,搅拌回流24h后,结束反应。反应液冷却至室温,用饱和碳酸氢钠溶液调pH至7~8,再用CH2Cl2(20mL×3)萃取,合并有机相,无水硫酸钠干燥过夜,过滤,有机相减压浓缩得到的残留物通过硅胶柱层析分离(洗脱剂为石油醚∶乙酸乙酯=20∶1,v/v),得2,4-二羟基-5-金刚烷基苯甲醛白色固体7.88克,收率72.9%。
波谱数据,1H-NMR(400MHz,CDCl3)∶δ11.24(s,1H),9.73(s,1H),7.36(s,1H),6.26(s,1H),2.11-2.08(m,9H),1.83-1.78(m,6H);13C-NMR(100MHz,CDCl3)∶δ194.9,162.7,162.0,133.1,130.0,115.1,104.3,40.7,36.9,36.2,28.9;ESI-MS(-)∶m/z270.2[M-H]-.
实施例2
氮气保护下,在100mL的干燥双颈瓶中加入2,4-二羟基-5-金刚烷基苯甲醛(1.5g,5.5 mmol)、钠氢(0.48g,12mmol)和DMF(30mL),搅拌使其充分溶解。于0℃冰浴下向反应体系中缓慢滴加甲氧基甲基氯(0.911mL,12mmol),滴加完毕后,继续搅拌反应30min,撤掉冰浴。室温搅拌2h,薄层色谱检测反应完全,结束反应。将反应液倒入100mL冰水中,用乙酸乙酯(20mL×3)萃取,合并有机相,无水硫酸镁干燥过夜,过滤,有机相减压浓缩后得到的残留物通过硅胶柱层析分离(洗脱剂为石油醚∶乙酸乙酯=50∶1,v/v),得2,4-二甲氧甲氧基-3-金刚烷基苯甲醛白色固体2.96克,收率82.3%。
波谱数据,1H-NMR(400MHz,CDCl3)∶δ10.34(s,1H),7.74(s,1H),6.90(s,1H),5.29(d,4H,J=8.8Hz),3.53(d,6H,J=5.0Hz),2.10-2.07(m,9H),1.78-1.75(m,6H);13C-NMR(100MHz,CDCl3)∶δ188.5,162.5,159.7,132.9,126.8,119.1,101.0,94.8,94.1,56.7,56.5,40.7,37.0,36.7,29.0;ESI-MS(+)∶m/z361.2[M+H]+,383.2[M+Na]+.
实施例3
氮气保护下,在50mL的干燥双颈瓶中加入邻羟基苯乙酮(0.144mL,1.2mmol)、5-金刚烷基-2,4-二甲氧甲氧基苯甲醛(0.360g,1mmol)和无水乙醇15mL,搅拌使其充分溶解,常温下向反应体系中慢慢滴加50%的氢氧化钾—乙醇溶液2mL,滴加完毕后,室温反应24h,薄层色谱检测反应已达到平衡,反应液变为血红色,结束反应。减压浓缩除去反应液中的溶剂,在冰浴条件下向残渣中加入适量蒸馏水溶解,用1mol/L的盐酸调pH值至6-7,溶液中即产生大量黄色沉淀。将沉淀过滤,滤饼用蒸馏水洗涤3次后干燥得粗产物。最后用硅胶柱层析(洗脱剂为石油醚∶乙酸乙酯=30∶1,v/v)分离,得淡黄色固体3-(5-金刚烷基-2,4-二甲氧甲氧基苯基)-1-(2-羟基苯基)-丙烯酮305mg,收率60.5%。
波谱数据,1H-NMR(400MHz,CDCl3)∶δ13.08(s,1H),8.26(d,1H,J=15.6Hz),7.95(dd,1H,J=8.0Hz,J=1.3Hz),7.68(d,1H,J=15.3Hz),7.52(s,1H),7.50(dt,1H,J=15.6Hz),7.03(dd,1H,J=8.3Hz,J=1.0Hz),6.97(dt,2H,J=15.3Hz),5.28(d,4H,J=4.3Hz),3.54(d,6H,J=2.0Hz),2.14-2.10(m,9H),1.80-1.78(m,6H);13C-NMR(100MHz,CDCl3)∶δ194.2,163.6,159.8,156.4,141.6,135.9,132.8,129.6,127.6,120.4,118.7,118.5,117.9,117.1,101.8,94.9,94.3,56.6,56.5,40.8,37.0,36.7,29.0;HRMS(-)∶m/z477.2282([M-H]-,C29H33O6 -calcd∶477.2277).
实施例4
氮气保护下,在50mL的干燥双颈瓶中加入2-羟基-5-甲基苯乙酮(0.170g,1.2mmol)、5-金刚烷基-2,4-二甲氧甲氧基苯甲醛(0.360g,1mmol)和无水乙醇15mL,搅拌使其充分溶解,常温下向反应体系中慢慢滴加50%的氢氧化钾—乙醇溶液2mL,滴加完毕后,室温反 应24h,薄层色谱检测反应已达到平衡,反应液变为血红色,结束反应。减压浓缩除去反应液中的溶剂,在冰浴条件下向残渣中加入适量蒸馏水溶解,用1mol/L的盐酸调pH值至7,溶液中即产生大量红色沉淀。将沉淀过滤,滤饼用蒸馏水洗涤3次后干燥得粗产物。最后用乙醇重结晶,得红色固体-(5-金刚烷基-2,4-二甲氧甲氧基苯基)-1-(2-羟基-5-甲基苯基)-丙烯酮346mg,收率65.4%。
波谱数据,1H-NMR(400MHz,DMSO-d6)∶δ12.88(s,1H),8.23(d,1H,J=15.6Hz),7.69(d,1H,J=1.4Hz),7.67(d,1H,J=15.6Hz),7.51(s,1H),7.29(dd,1H,J=8.4Hz,J=1.9Hz),6.93(s,1H),6.91(d,1H,J=8.5Hz),5.28(d,4H,J=4.5Hz),3.53(s,6H),2.35(s,3H),2.12-2.10(m,9H),1.82-1.78(m,6H);13C-NMR(100MHz,DMSO-d6)∶δ193.2,160.4,158.7,155.3,140.4,135.9,131.7,128.3,126.7,126.6,119.0,117.2,116.2,100.8,93.9,93.2,55.5,55.5,39.8,36.0,35.7,28.0,19.7;HRMS(-)∶m/z491.2430([M-H]-,C30H35O6 -calcd∶491.2434).
实施例5
氮气保护下,在50mL的干燥双颈瓶中加入2-羟基-5-氯基苯乙酮(0.200g,1.2mmol)、5-金刚烷基-2,4-二甲氧甲氧基苯甲醛(0.360g,1mmol)和无水乙醇15mL,搅拌使其充分溶解,常温下向反应体系中慢慢滴加50%的氢氧化钾—乙醇溶液2mL,滴加完毕后,室温反应24h,薄层色谱检测反应已达到平衡,反应液变为血红色,结束反应。减压浓缩除去反应液中的溶剂,在冰浴条件下向残渣中加入适量蒸馏水溶解,用1mol/L的盐酸调pH值至7,溶液中即产生大量黄色沉淀。将沉淀过滤,滤饼用蒸馏水洗涤3次后干燥得粗产物。最后用乙醇重结晶,得黄色固体3-(5-金刚烷基-2,4-二甲氧甲氧基苯基)-1-(2-羟基-5-氯基苯基)-丙烯酮355mg,收率63.4%。
波谱数据,1H-NMR(400MHz,CDCl3)∶δ13.00(s,1H),8.26(d,1H,J=15.6Hz),7.87(d,1H,J=2.5Hz),7.59(d,1H,J=15.6Hz),7.50(s,1H),7.43(dd,1H,J=8.8Hz,J=2.5Hz),6.98(d,1H,J=9.0Hz),6.94(s,1H),5.29(d,4H,J=6.3Hz),3.55(d,6H,J=3.0Hz),2.13-2.10(m,9H),1.82-1.78(m,6H);13C-NMR(100MHz,CDCl3)∶δ192.3,161.0,159.1,155.6,141.8,134.6,131.9,127.8,127.0,122.2,120.0,119.1,116.3,115.8,100.7,93.9,93.2,56.6,56.6,39.8,36.0,35.7,28.0;HRMS(-)∶m/z511.1880([M-H]-,C29H32ClO6 -calcd∶511.1887).
实施例6
氮气保护下,在50mL的干燥双颈瓶中加入2-羟基-5-甲氧基苯乙酮(0.200g,1.2mmol)、5-金刚烷基-2,4-二甲氧甲氧基苯甲醛(0.360g,1mmol)和无水乙醇15mL,搅拌使其充分溶解,常温下向反应体系中慢慢滴加50%的氢氧化钾—乙醇溶液2mL,滴加完毕后,室温反 应24h,薄层色谱检测反应已达到平衡,反应液变为血红色,结束反应。减压浓缩除去反应液中的溶剂,在冰浴条件下向残渣中加入适量蒸馏水溶解,用1mol/L的盐酸调pH值至7,溶液中即产生大量红色沉淀。将沉淀过滤,滤饼用蒸馏水洗涤3次后干燥得粗产物。最后用硅胶柱层析(洗脱剂为石油醚∶乙酸乙酯=30∶1,v/v)分离,得红色固体3-(5-金刚烷基-2,4-二甲氧甲氧基苯基)-1-(2-羟基-5-甲氧基苯基)-丙烯酮296mg,收率53.2%。
波谱数据,1H-NMR(400MHz,CDCl3)∶δ12.59(s,1H),8.23(d,1H,J=15.6Hz),7.64(d,1H,J=15.6Hz),7.50(s,1H),7.40(d,1H,J=3.0Hz),7.13(dd,1H,J=9.0Hz,J=3.0Hz),6.97(d,1H,J=9.0Hz),6.94(s,1H),5.28(d,4H,J=4.3Hz),3.83(s,3H),3.53(d,6H,J=2.0Hz),2.13-2.10(m,9H),1.81-1.77(m,6H);13C-NMR(100MHz,CDCl3)∶δ192.9,158.8,156.8,155.4,150.5,140.8,131.8,126.9,121.9,119.0,118.1,117.2,116.1,112.4,100.7,93.9,93.2,55.6,55.5,55.0,39.8,36.0,35.7,28.0;HRMS(-)∶m/z507.2382([M-H]-,C30H35O7 -calcd∶507.2383).
实施例7
氮气保护下,在50mL的干燥双颈瓶中加入3-乙酰基-4-羟基苯甲酸(0.180g,1mmol)、5-金刚烷基-2,4-二甲氧甲氧基苯甲醛(0.360g,1mmol)和无水乙醇15mL,搅拌使其充分溶解,常温下向反应体系中慢慢滴加50%的氢氧化钾—乙醇溶液2.5mL,滴加完毕后,室温反应24h,薄层色谱检测反应已达到平衡,反应液变为血红色,结束反应。减压浓缩除去反应液中的溶剂,在冰浴条件下向残渣中加入适量蒸馏水溶解,用1mol/L的盐酸调pH值至6,溶液中即产生大量红色沉淀。将沉淀过滤,滤饼用蒸馏水洗涤3次后干燥得粗产物。最后用硅胶柱层析(洗脱剂为二氯甲烷∶甲醇=150∶1,v/v)分离,得红色固体3-(5-金刚烷基-2,4-二甲氧甲氧基苯基)-1-(2-羟基-5-羧基苯基)-丙烯酮164mg,收率30.3%。
波谱数据,1H-NMR(400MHz,CDCl3)∶δ13.70(s,1H),8.71(d,1H,J=2.0Hz),8.20(dd,1H,J=8.8Hz,J=2.0Hz),7.85(dd,1H,J=14.6Hz,J=11.5Hz),7.49(s,1H),7.45(d,1H,J=3.3Hz),7.09(d,1H,J=8.5Hz),6.94(s,1H),5.28(s,4H),3.56(s,6H),2.15-2.13(m,9H),1.83-1.81(m,6H);13C-NMR(100MHz,CDCl3)∶δ193.4,163.8,159.8,158.4,153.6,146.8,142.3,132.8,131.4,125.4,124.9,123.5,119.5,119.0,118.7,116.3,94.9,94.3,56.6,56.5,40.8,37.0,36.7,29.0;HRMS(-)∶m/z521.2168([M-H]-,C30H33O8 -calcd∶521.2175)。
Claims (3)
1.一类查尔酮衍生物,其特征在于其结构式为:
其中,R1是氢,烷基,卤素,烷氧基,羧基或羧酸衍生物;R2和R3相同,是氢,烷基或甲氧甲基;Ad是金刚烷基。
2.如权利要求1所述一类查尔酮衍生物的制备方法,其特征在于包括以下步骤:
(1)中间体邻羟基苯乙酮及其衍生物的制备
中间体邻羟基苯乙酮衍生物可用Fries重排方法进行制备;邻羟基苯乙酮衍生物的制备方法,以各取代苯酚为原料,先和醋酐反应成酯,再经Fries重排得到粗产物,最后进行重结晶得到对应取代的苯乙酮的纯品;具体步骤如下:
a)氮气保护下,在反应瓶中先分别加入苯酚类化合物、乙酸酐,再在磁力搅拌下加入80~200μL硫酸,固体迅速溶解并变成无色透明溶液,继续反应20~60min后,停止反应,得到的反应液备用,其中苯酚类化合物和乙酸酐摩尔配比为1∶1~1.5;所述苯酚类化合物为苯酚、对烷基苯酚、对卤素苯酚、对烷氧基苯酚、对羧基苯酚、对酯基苯酚中的一种;
b)将步骤a)的反应液倒入冰水中,立即析出大量白色固体,过滤,滤饼先用饱和碳酸钠溶液洗两次,再用双蒸水洗涤后,自然干燥,得到对位取代的乙酰氧基苯类衍生物;
c)Fries重排:在反应瓶中加入步骤b)中得到的对位取代的乙酰氧基苯类衍生物和无水三氯化铝,油浴加热至160~180℃,继续搅拌反应4~6h,停止反应后,冷却;在冰浴下向反应体系中加入2mol/L的盐酸溶液后,先用第一有机溶剂萃取三次,再用饱和食盐水洗三次,合并有机相,用无水硫酸钠干燥过夜,过滤,有机相减压浓缩后得到各相应的邻羟基苯乙酮衍生物粗产品,最后用第二有机溶剂重结晶得邻羟基苯乙酮衍生物的纯品,其中对取代乙酰氧基甲苯、无水三氯化铝和盐酸的摩尔配比为1∶(2~4)∶(6~10);邻羟基苯乙酮衍生物包括邻羟基苯乙酮、2-羟基-5-烷基苯乙酮、2-羟基-5-卤素苯乙酮、2-羟基-5-烷氧基苯乙酮、2-羟基-5-羧基苯乙酮和2-羟基-5-酯基苯乙酮;第一有机溶剂为乙酸乙酯、氯仿或乙醚;第二有机溶剂为乙醇、异丙醇或四氢呋喃;
(2)中间体金刚烷基苯甲醛的制备
2.1化合物2,4-二羟基-5-金刚烷基苯甲醛的合成
2,4-二羟基-5-金刚烷基苯甲醛的具体合成步骤如下:
a)氮气保护下,在干燥的反应瓶中加入2,4-二羟基苯甲醛、1-金刚烷醇和适量干燥的第一有机溶剂,搅拌使其充分溶解,于冰浴下向反应体系中缓慢滴加浓硫酸,滴加完毕后,继续搅拌反应30~60min,撤掉冰浴,再升温至40~60℃,搅拌回流20~28h后,结束反应,得到的反应液备用;其中所述2,4-二羟基苯甲醛、1-金刚烷醇和浓硫酸的摩尔配比为1∶(1~1.5)∶(1~2);第一有机溶剂为二氯甲烷、氯仿或四氢呋喃;
b)将步骤a)得到的反应液冷却至室温,先用饱和碳酸氢钠溶液调pH至7~8,再用第一有机溶剂萃取3次,合并有机相,无水硫酸钠干燥过夜,过滤,有机相减压浓缩得到的残留物通过硅胶柱层析分离,洗脱剂为石油醚和乙酸乙酯的混合溶剂,得2,4-二羟基-5-金刚烷基苯甲醛的白色固体,其中所述第一有机溶剂为二氯甲烷或乙酸乙酯;
2.2化合物2,4-醚基-5-金刚烷基苯甲醛的合成
2,4-醚基-5-金刚烷基苯甲醛的具体合成步骤如下:
a)氮气保护下,在反应瓶中加入2,4-二羟基-5-金刚烷基苯甲醛、钠氢和第一有机溶剂,搅拌使其溶解;于0~5℃冰浴下向反应体系中加入卤化物,继续搅拌反应30min,撤掉冰浴,室温搅拌2~4h,结束反应,得到的反应液备用;其中所述2,4-二羟基-5-金刚烷基苯甲醛、钠氢和卤化物的摩尔配比为1∶(1.5~3)∶(1.5~3);卤化物为氯化物、碘化物、溴化物中的一种;第一有机溶剂为二氯甲烷、氯仿、乙腈、二甲基甲酰胺中的一种;
b)将步骤a)得到的反应液倒入2~4倍体积的冰水中,用等体积的第一有机溶剂萃取,合并有机相,无水硫酸镁干燥过夜,过滤,有机相减压浓缩后得到的残留物通过硅胶柱层析分离,洗脱剂为石油醚和乙酸乙酯的混合溶剂,得2,4-醚基-3-金刚烷基苯甲醛;
(3)查尔酮衍生物—3-(5-金刚烷基-2,4-二取代基苯基)-1-(2-羟基-5-取代基苯基)-丙烯酮的合成
采用经典的碱性条件下的Claisen—Schmidt反应,以步骤1得到的中间体邻羟基苯乙酮、步骤2得到的中间体金刚烷基苯甲醛以及取代的苯甲醛和取代的苯乙酮为原料合成查尔酮,具体的合成步骤如下:
a)氮气保护下,在反应瓶中加入中间体金刚烷基苯甲醛、中间体取代苯乙酮和第一有机溶剂,搅拌使其溶解,于冰浴下向反应体系中加入2mol/L氢氧化钾的第一有机溶剂的溶液,体积分数为50%,室温反应20~28h后,得到的反应液备用;其中所述中间体金刚烷基苯甲醛、中间体取代苯乙酮和氢氧化钾的摩尔比为1∶(1~1.5)∶(3~6);第一有机溶剂为甲醇或乙醇;
b)减压浓缩除去步骤a)反应后反应液中的溶剂,冰浴条件下向残渣中加入蒸馏水溶解,用1mol/L的盐酸调pH值至5~7,此过程中即产生大量沉淀,将沉淀过滤,滤饼用蒸馏水洗涤3次后干燥得粗产物,最后用硅胶柱层析分离,洗脱剂为石油醚和乙酸乙酯的混合溶剂或二氯甲烷和甲醇的混合溶剂,得查尔酮衍生物—3-(5-金刚烷基-2,4-二取代基苯基)-1-(2-羟基-5-取代基苯基)-丙烯酮。
3.如权利要求1所述一类查尔酮衍生物在制备抗艾滋病药物中应用。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106543155A (zh) * | 2016-09-26 | 2017-03-29 | 赵庆春 | 作为极光激酶抑制剂的查尔酮及黄酮类衍生物 |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060189549A1 (en) * | 2001-12-19 | 2006-08-24 | Liming Ni | Chalcone derivatives and their use to treat diseases |
CN101448551A (zh) * | 2005-05-24 | 2009-06-03 | 强生消费者公司 | 查耳酮在治疗病毒性疾病中的应用 |
-
2014
- 2014-02-19 CN CN201410056278.0A patent/CN103755541B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060189549A1 (en) * | 2001-12-19 | 2006-08-24 | Liming Ni | Chalcone derivatives and their use to treat diseases |
CN101448551A (zh) * | 2005-05-24 | 2009-06-03 | 强生消费者公司 | 查耳酮在治疗病毒性疾病中的应用 |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106543155A (zh) * | 2016-09-26 | 2017-03-29 | 赵庆春 | 作为极光激酶抑制剂的查尔酮及黄酮类衍生物 |
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CN110655464B (zh) * | 2019-10-22 | 2022-10-21 | 肇庆学院 | 一种含氧乙酸结构的查尔酮类化合物及其用途 |
CN113215827A (zh) * | 2021-05-28 | 2021-08-06 | 安徽弋尚纺织科技有限公司 | 一种抗菌耐污的西服面料及其生产工艺 |
CN115572255A (zh) * | 2022-04-29 | 2023-01-06 | 无锡捷化医药科技有限公司 | 一种查尔酮类化合物的制备方法 |
CN116102528A (zh) * | 2023-02-03 | 2023-05-12 | 三峡大学 | 一类泽兰素查尔酮类化合物,制备方法及其应用 |
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