CN108484617B - 新型苯并呋喃氮杂萘二酮衍生物及其制备方法 - Google Patents
新型苯并呋喃氮杂萘二酮衍生物及其制备方法 Download PDFInfo
- Publication number
- CN108484617B CN108484617B CN201810205397.6A CN201810205397A CN108484617B CN 108484617 B CN108484617 B CN 108484617B CN 201810205397 A CN201810205397 A CN 201810205397A CN 108484617 B CN108484617 B CN 108484617B
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- Prior art keywords
- dione
- quinoline
- solvent
- solution
- benzofuran
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- -1 benzofuran azanaphthalene dione derivative Chemical class 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 65
- YYFLDZZDOUDZQM-UHFFFAOYSA-N 3-[1-[[4-(3-phenylquinolin-2-yl)phenyl]methyl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C(CC1)CCN1CC(C=C1)=CC=C1C1=NC2=CC=CC=C2C=C1C1=CC=CC=C1 YYFLDZZDOUDZQM-UHFFFAOYSA-N 0.000 claims description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 239000012047 saturated solution Substances 0.000 claims description 13
- 238000000926 separation method Methods 0.000 claims description 13
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 12
- 230000002829 reductive effect Effects 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 239000008367 deionised water Substances 0.000 claims description 7
- 229910021641 deionized water Inorganic materials 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- RAGSWDIQBBZLLL-UHFFFAOYSA-N 2-chloroethyl(diethyl)azanium;chloride Chemical compound Cl.CCN(CC)CCCl RAGSWDIQBBZLLL-UHFFFAOYSA-N 0.000 claims description 5
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 5
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Substances BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 claims description 5
- 239000004304 potassium nitrite Substances 0.000 claims description 5
- 235000010289 potassium nitrite Nutrition 0.000 claims description 5
- 229910015845 BBr3 Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 17
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 abstract description 14
- 125000001624 naphthyl group Chemical group 0.000 abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- 239000004698 Polyethylene Substances 0.000 description 12
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- 239000000203 mixture Substances 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000012467 final product Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 229910019142 PO4 Inorganic materials 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 235000001727 glucose Nutrition 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 239000002250 absorbent Substances 0.000 description 3
- 230000002745 absorbent Effects 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
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- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
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- 239000005995 Aluminium silicate Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
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- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Abstract
本发明公开了一种新型苯并呋喃氮杂萘二酮衍生物及其制备方法，本发明针对一类抗肿瘤候选化合物在应用方面存在的不足，对其母核结构进行优化，采用在萘环上引入氮原子的方法，设计并合成了具有全新母核架构的新型苯并呋喃氮杂萘二酮系列衍生物，该类化合物的水溶性、脂水分布性质具有显著的改善，表现出良好的生物利用度，其结构更加多样化，在化工生产、临床医药中将表现出更加广泛的应用和广阔的前景。
Description
技术领域
本发明属于化学合成领域，尤其涉及新型苯并呋喃氮杂萘二酮衍生物及其制备方法。
背景技术
胞细毒类药物通过干扰细胞DNA的合成、复制等优先杀死分裂期的细胞，这些药物在杀死大数量且不断生成的肿瘤细胞方面表现出明显优势。例如，抗癌药喜树碱(Camptothecin，CPT)、11-羟基喜树碱(Camptothecin-11，CPT-11，伊立替康)是临床常用的细胞毒类抗肿瘤药物。郑家骏(C.C.Cheng)在上世纪的八十年代通过研究分析大量的天然和合成的化合物的构效关系，提出了包含“2-苯基取代奈”的结构可能是干扰肿瘤DNA合成的药效基团。该研究室设计、合成若干类似化合物并发现的一些有较好细胞毒的抗肿瘤候选化合物，在文献“Design of antineoplastic agents on the basis of the"2-phenylnaphthalene-type"structural pattern.2.Synthesis and biological activitystudies of benzo[b]naphtho[2,3-d]furan-6,11-dione derivatives”中报道了DQ-93及类似化合物表现出对白血病(HL-60)和小细胞肺癌(SCLC)等显著的抑制作用。但这类化合物在水溶液中的溶解度都比较小，生物利用度不高。
目前仍需要通过结构优化，合成新的衍生物，以提高其水溶液中的溶解度、提高其生物利用度。
发明内容
本发明的发明目的在于：针对上述存在的问题，本发明提供新型苯并呋喃氮杂萘二酮衍生物及其制备方法，来克服传统DQ-93类化合物水溶性差，生物利用度低的问题，对其母核结构进行优化，采用在萘环上引入氮原子的方法，设计并合成具有全新母核结构的新型苯并呋喃氮杂萘二酮系列衍生物。此衍生物的水溶性、脂水分布等性质相较于母核而言得到显著改善，具有良好的生物利用度。
本发明采用的技术方案如下：一种新型苯并呋喃氮杂萘二酮衍生物，所述衍生物的结构通式为：
其中，X1可为CH、C-CR3或N；
X2可为CH、C-CR3或N；
X3可为CH、C-CR3或N；
X4可为CH、C-CR3或N；
当X1＝N,X2、X3、X4优选为CH；
当X2＝N,X1、X3、X4优选为CH；
当X3＝N,X1、X2、X4优选为CH；
当X4＝N,X1、X2、X3优选为CH；
当X1＝X4＝N,X2、X3优选为CH；
当X2＝X3＝N,X1、X4优选为CH；
当X1＝X3＝N,X2、X4优选为CH；
当X1＝X2＝N,X3、X4优选为CH；
当X2＝X4＝N,X1、X3优选为CH；
当X3＝X4＝N,X1、X2优选为CH；
R＝(CH2CHR1)nN[(CH2)mR3]2，其中n、m互相独立，为1-4的整数；R1、R3优选氢、氟、氯、溴、甲基、乙基、甲氧基、乙氧基、羟基或三氟甲基中的一种。
所述衍生物可以与酸或碱形成药用盐，所述酸为无机酸或有机酸；所述的碱为碱金属、碱土金属或有机碱。
所述的无机酸包括：盐酸、硫酸、磷酸和氢溴酸中的至少一种；所述有机酸包括：乙酸、草酸、柠檬酸、葡萄糖酸、琥珀酸、酒石酸、对甲苯磺酸、甲磺酸、苯甲酸、乳酸和马来酸中的至少一种；所述碱金属包括：锂、钠和钾中的至少一种；所述碱土金属包括：钙和镁中的至少一种；所述有机碱包括：二乙醇胺和胆碱中的至少一种。
所述新型苯并呋喃氮杂萘二酮衍生物可以通过一系列工艺制成不同剂型的药物，所述剂型包括：片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含剂、检剂、膏剂、贴剂、注射剂和冻干粉针剂中的至少一种。
所述不同剂型的制作载体包括：稀释剂和吸收剂、湿润剂和粘合剂、崩解剂、崩解抑制剂、吸收促进剂和润滑剂中的至少一类。
所述片剂的稀释剂和吸收剂包括：淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素和硅酸铝中的至少一种；所述片剂的湿润剂和粘合剂包括：水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾和聚乙烯吡咯烷酮中的至少一种；所述片剂的崩解剂包括：干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素和乙基纤维素中的至少一种；所述片剂的崩解抑制剂包括：蔗糖、三硬脂酸甘油酯、可可脂和氢化油中的至少一种；所述片剂的吸收促进剂包括：季铵盐和十二烷基硫酸钠中的至少一种；所述片剂的润滑剂包括：滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡和聚乙二醇中的至少一种。
所述的片剂还可以进一步制作为包衣片，所述包衣片包括：糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片中的至少一种。
所述的丸剂的稀释剂与吸收剂载体包括：葡萄糖、乳糖、淀粉、可可脂、氮化植物油、聚乙烯吡咯烷酮、高岭土和滑石粉中的至少一种；所述粘合剂包括：阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊和面糊中的至少一种；所述崩解剂包括：琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素和乙基纤维素中的至少一种。
所述的检剂载体包括：聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶和半合成甘油酯中的至少一种。
所述的注射剂还可以制备成等渗注射液，所述添加剂包括氯化钠、葡萄糖、甘油中的至少一种；此外，还可根据需要添加包括助溶剂、缓冲剂、pH调节剂、着色剂、防腐剂、香料、矮味剂、甜味剂中的至少一种。
具体地，本发明涉及的作为活性成分的有效剂量的至少一种化合物I，或者其药用盐、立体异构体与常规药物载体、辅剂可以以任意比例进行任意搭配，来制备不同剂型的药物。
一种新型苯并呋喃氮杂萘二酮衍生物的制备方法，所述制备方法包括以下步骤：
(1)化合物I的氧化：
将化合物I溶于DMF/甲醇溶剂中，室温下滴入饱和KH2PO4溶液，保持pH＝6，分批加入氧化剂，充分搅拌均匀，升温至反应0.5-3.0h。加碳酸氢钠饱和溶液调节至中性，用乙酸乙酯进行萃取，干燥，再用无水硫酸钠干燥过夜，回收溶剂，进行柱分离(PE:EA＝1：1)纯化，回收溶剂，得萘醌型Ia化合物。
(2)化合物Ia脱甲醚：
将化合物Ia溶于有机溶剂中，冰盐浴冷却下，滴加酸溶液，自然升温至室温，反应1-4h，加碳酸氢钠饱和溶液稀释，进行猝灭反应，减压除去二氯甲烷，用乙酸乙酯萃取，干燥，加无水硫酸钠干燥过夜，回收溶剂，进行柱分离(PE:EA＝1：1)纯化，回收溶剂，即得Ib化合物。
(3)化合物Ib烃基化：
在适宜的碱存在条件下，将化合物Ib加入氯仿中,随后加入
加热回流1-4h。反应完全后降温，加入去离子水洗涤，水相DCM萃取1-3次，合并有机相，用饱和食盐水洗涤1-3次，有机相用无水硫酸钠干燥，浓缩至干，柱层析进行分离，得新型苯并呋喃氮杂萘二酮衍生物。
所述步骤(1)中所述DMF/甲醇的体积比为1:2-1:5，优选1:3；所述的升温温度为30-60℃，优选45-50摄氏度；所述反应时间优选1.0h。
所述步骤(1)中所述氧化剂包括亚硝基过硫酸钾、氧化汞、三氟甲基乙酸汞、溴、二氯二氰基苯醌、溴化银、重铬酸钠、氧化铅中的至少一种，优选亚硝基过硫酸钾。
所述步骤(2)所述的有机溶剂包括二氯甲烷、甲醇、乙醚、苯，二甲基亚砜中的至少一种，优选二氯甲烷。
所述步骤(2)所述的酸包括质子酸、路易斯酸中的至少一种；所述质子酸包括盐酸、硫酸、磷酸、乙酸、HCO3 -、NH4 +中的至少一种；所述路易斯酸包括AlCl3、SnCl、FeCl3、BF3、BBr3中的至少一种，优选BBr3。
所述步骤(3)所述的适宜碱条件是指溶液呈碱性的化合物，所述化合物包括：碳酸钠、碳酸钾、碳酸氢钠中的至少一种，优选碳酸钠。
所述步骤(3)所述
中，X为Cl、Br、I、OMs离去基团中的一种；n、m互相独立，为1-4的整数；R1、R3优选氢、氟、氯、溴、甲基、乙基、甲氧基、乙氧基、羟基或三氟甲基中的一种。
综上所述，由于采用了上述技术方案，本发明的有益效果是：本发明提供新型苯并呋喃氮杂萘二酮衍生物及其制备方法，来克服传统DQ-93类化合物水溶性差，生物利用度低的问题，对其母核结构进行优化，采用在萘环上引入氮原子的方法，设计并合成具有全新母核结构的新型苯并呋喃氮杂萘二酮系列衍生物。此衍生物的水溶性、脂水分布等性质相较于母核而言得到显著改善，具有良好的生物利用度。其结构更加多样化，在化工生产、临床医药中将表现出更加广泛的应用和广阔的前景。
附图说明
本发明将通过例子并参照附图的方式说明，其中：
图1为新型苯并呋喃氮杂萘二酮衍生物的结构通式。
具体实施方式
本发明可通过下列实施例得到进一步说明，但这些实施例并不限制本发明的摘要、摘要附图、权利要求及说明书中所阐述的本发明。
实施例1：
衍生物1：8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
(1)6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取5-羟基-6,8-二甲氧基苯并呋喃[3,2-g]喹啉中间体0.46g(1.8mmol)溶于DMF/甲醇(1:3)5ml，室温下滴入饱和KH2PO4溶液2ml，保持pH＝6，分批加入亚硝酸过硫酸钾1.16g(4.4mmol)充分搅拌均匀，升温至45-50℃，反应1h。加碳酸氢钠饱和溶液调节至中性，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为78％。
Mp：187-189℃；
1H NMR(CDCl3):δ＝9.05(d,J＝7.6Hz,1H),8.54(dd,J1＝6.7Hz,J2＝7.6Hz,1H),7.68(dd,J1＝7.1Hz,J2＝7.2Hz,1H),6.75(s,1H),6.48(s,1H),4.04(s,3H),3.91(s,3H)；
LC-MS(ESI)：310.2[M+H]+。
(2)6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取上述6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮中间体0.31g(1.01mmol)溶于2ml二氯甲烷，冰盐浴冷却下，滴入1mol/L的BBr3溶液2ml，自然升温至室温反应2h。加碳酸氢钠饱和溶液稀释淬灭反应，减压除去二氯甲烷，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为92％。
Mp:210-213℃；
1H NMR(DMSO－d6):δ＝9.01(d,J＝7.6Hz,1H),8.58(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.26(d,J＝7.8Hz,1H),7.75(dd,J1＝7.1Hz,J2＝7.2Hz,1H),7.26(m,1H)；
LC-MS(ESI):282.3[M+H]+。
(3)8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮0.22g(0.80mmol)加入氯仿(2.0mL),将碳酸钠30.15mg(4eq)溶于水中，加入反应液中，加入2-二乙氨基氯乙烷盐酸盐(1.5eq)，加热至回流反应2h。反应完全后降温，加入去离子水洗涤，水相用二氯甲烷萃取一次，合并有机相，饱和食盐水洗涤一次。有机相用无水硫酸钠干燥，浓缩至干，柱层析分离得衍生物1，收率为61％。
Mp:231-233℃；
1H NMR(CDCl3):δ＝9.50(d,J＝9.6Hz,1H),δ＝9.06(d,J＝7.6Hz,1H),8.71(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.02(d,J＝7.8Hz,1H),7.75(dd,J1＝7.1Hz,J2＝7.2Hz,1·H),5.34(t,J＝7.2Hz,2H),2.17(t,J＝7.2Hz,2H),2.01(m,4H),1.26(m,6H)；
LC-MS(ESI):381.1[M+H]+。
实施例2：
化合物1：8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
(1)6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取5-羟基-6,8-二甲氧基苯并呋喃[3,2-g]喹啉中间体0.46g(1.8mmol)溶于DMF/甲醇(1:3)5ml，室温下滴入饱和KH2PO4溶液2ml，保持pH＝6，分批加入溴化银0.826g(4.4mmol)充分搅拌均匀，升温至45-50℃，反应1h。加碳酸氢钠饱和溶液调节至中性，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为76％。
Mp:185-187℃；
1H NMR(CDCl3):δ＝9.05(d,J＝7.6Hz,1H),8.52(dd,J1＝6.7Hz,J2＝7.6Hz,1H),7.67(dd,J1＝7.1Hz,J2＝7.2Hz,1H),6.65(s,1H),6.48(s,1H),4.04(s,3H),3.91(s,3H)；
LC-MS(ESI)：310.1[M+H]+。
(2)6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取上述6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮中间体0.31g(1.01mmol)溶于2ml二氯甲烷，冰盐浴冷却下，滴入1mol/L的BBr3溶液2ml，自然升温至室温反应2h。加碳酸氢钠饱和溶液稀释淬灭反应，减压除去二氯甲烷，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为90％。
Mp:208-210℃；
1H NMR(DMSO－d6):δ＝9.01(d,J＝7.6Hz,1H),8.57(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.25(d,J＝7.8Hz,1H),7.75(dd,J1＝7.1Hz,J2＝7.2Hz,1H),7.25(m,H)；
LC-MS(ESI):282.1[M+H]+。
(3)8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮0.22g(0.80mmol)加入氯仿(2.0mL),将碳酸钠30.15mg(4eq)溶于水中，加入反应液中，加入2-二乙氨基氯乙烷盐酸盐(1.5eq)，加热至回流反应2h。反应完全后降温，加入去离子水洗涤，水相用二氯甲烷萃取一次，合并有机相，饱和食盐水洗涤一次。有机相用无水硫酸钠干燥，浓缩至干，柱层析分离得衍生物1，收率为60％。
Mp:228-231℃；
1H NMR(CDCl3):δ＝9.50(d,J＝9.6Hz,1H),δ＝9.05(d,J＝7.6Hz,1H),8.71(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.01(d,J＝7.8Hz,1H),7.75(dd,J1＝7.1Hz,J2＝7.2Hz,1H),5.34(t,J＝7.2Hz,2H),2.17(t,J＝7.2Hz,2H),2.01(m,4H),1.25(m,6H)；
LC-MS(ESI):381.0[M+H]+。
通过1,2实施例的比对发现，步骤(1)中氧化剂的选择会直接影响最终产物的产率，当氧化剂为亚硝基过硫酸钾时，所得终产物的产率相应提高。
实施例3：
化合物1：8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
(1)6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取5-羟基-6,8-二甲氧基苯并呋喃[3,2-g]喹啉中间体0.46g(1.8mmol)溶于DMF/甲醇(1:3)5ml，室温下滴入饱和KH2PO4溶液2ml，保持pH＝6，分批加入亚硝酸过硫酸钾1.16g(4.4mmol)充分搅拌均匀，升温至45-50℃，反应1h。加碳酸氢钠饱和溶液调节至中性，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为78％。
Mp：187-189℃；
1H NMR(CDCl3):δ＝9.05(d,J＝7.6Hz,1H),8.54(dd,J1＝6.7Hz,J2＝7.6Hz,1H),7.68(dd,J1＝7.1Hz,J2＝7.2Hz,1H),6.75(s,1H),6.48(s,1H),4.04(s,3H),3.91(s,3H)；
LC-MS(ESI)：310.2[M+H]+。
(2)6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取上述6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮中间体0.31g(1.01mmol)溶于2ml二氯甲烷，冰盐浴冷却下，滴入1mol/L的乙酸溶液2ml，自然升温至室温反应2h。加碳酸氢钠饱和溶液稀释淬灭反应，减压除去二氯甲烷，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为90.5％。
Mp:209-210℃；
1H NMR(DMSO－d6):δ＝9.01(d,J＝7.6Hz,1H),8.57(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.25(d,J＝7.8Hz,1H),7.75(dd,J1＝7.1Hz,J2＝7.2Hz,1H),7.26(m,1H)；
LC-MS(ESI):282.2[M+H]+。
(3)8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮0.22g(0.80mmol)加入氯仿(2.0mL),将碳酸钠30.15mg(4eq)溶于水中，加入反应液中，加入2-二乙氨基氯乙烷盐酸盐(1.5eq)，加热至回流反应2h。反应完全后降温，加入去离子水洗涤，水相用二氯甲烷萃取一次，合并有机相，饱和食盐水洗涤一次。有机相用无水硫酸钠干燥，浓缩至干，柱层析分离得衍生物1，收率为61％。
Mp:229-231℃；
1H NMR(CDCl3):δ＝9.50(d,J＝9.6Hz,1H),δ＝9.05(d,J＝7.6Hz,1H),8.71(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.02(d,J＝7.8Hz,1H),7.74(dd,J1＝7.1Hz,J2＝7.2Hz,1H),5.33(t,J＝7.2Hz,2H),2.17(t,J＝7.2Hz,2H),2.01(m,4H),1.26(m,6H)；
LC-MS(ESI):380.9[M+H]+。
通过1,3实施例的比对发现，步骤(2)中脱甲醚保护所用酸的选择会直接影响最终产物的产率，当所用酸为路易斯酸BBr3时，所得终产物的产率相应提高。
实施例4：
化合物1：8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
(1)6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取5-羟基-6,8-二甲氧基苯并呋喃[3,2-g]喹啉中间体0.46g(1.8mmol)溶于DMF/甲醇(1:3)5ml，室温下滴入饱和KH2PO4溶液2ml，保持pH＝6，分批加入亚硝酸过硫酸钾1.16g(4.4mmol)充分搅拌均匀，升温至45-50℃，反应1h。加碳酸氢钠饱和溶液调节至中性，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为78％。
Mp：187-189℃；
1H NMR(CDCl3):δ＝9.05(d,J＝7.6Hz,1H),8.54(dd,J1＝6.7Hz,J2＝7.6Hz,1H),7.68(dd,J1＝7.1Hz,J2＝7.2Hz,1H),6.75(s,1H),6.48(s,1H),4.04(s,3H),3.91(s,3H)；
LC-MS(ESI)：310.2[M+H]+。
(2)6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取上述6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮中间体0.31g(1.01mmol)溶于2ml二氯甲烷，冰盐浴冷却下，滴入1mol/L的BBr3溶液2ml，自然升温至室温反应2h。加碳酸氢钠饱和溶液稀释淬灭反应，减压除去二氯甲烷，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为92％。
Mp:210-213℃；
1H NMR(DMSO－d6):δ＝9.01(d,J＝7.6Hz,1H),8.58(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.26(d,J＝7.8Hz,1H),7.75(dd,J1＝7.1Hz,J2＝7.2Hz,1H),7.26(m,1H)；
LC-MS(ESI):282.3[M+H]+。
(3)8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮0.22g(0.80mmol)加入氯仿(2.0mL),将碳酸氢钠23.89mg(4eq)溶于水中，加入反应液中，加入2-二乙氨基氯乙烷盐酸盐(1.5eq)，加热至回流反应2h。反应完全后降温，加入去离子水洗涤，水相用二氯甲烷萃取一次，合并有机相，饱和食盐水洗涤一次。有机相用无水硫酸钠干燥，浓缩至干，柱层析分离得衍生物1，收率为59％。
Mp:231-232℃；
1H NMR(CDCl3):δ＝9.50(d,J＝9.6Hz,1H),δ＝9.06(d,J＝7.6Hz,1H),8.71(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.01(d,J＝7.8Hz,1H),7.75(dd,J1＝7.1Hz,J2＝7.2Hz,1H),5.34(t,J＝7.2Hz,2H),2.16(t,J＝7.2Hz,2H),2.01(m,4H),1.26(m,6H)；
LC-MS(ESI):381.1[M+H]+。
通过1,4实施例的比对发现，步骤(3)中碱环境用碱的选择会直接影响最终产物的产率，当所用碱为碳酸钠时，所得终产物的产率相应提高。
实施例5：
衍生物2：8-(2-甲胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
(1)6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取5-羟基-6,8-二甲氧基苯并呋喃[3,2-g]喹啉中间体0.46g(1.8mmol)溶于DMF/甲醇(1:3)5ml，室温下滴入饱和KH2PO4溶液2ml，保持pH＝6，分批加入亚硝酸过硫酸钾1.16g(4.4mmol)充分搅拌均匀，升温至45-50℃，反应1h。加碳酸氢钠饱和溶液调节至中性，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为78％。
Mp：187-189℃；
1H NMR(CDCl3):δ＝9.05(d,J＝7.6Hz,1H),8.54(dd,J1＝6.7Hz,J2＝7.6Hz,1H),7.68(dd,J1＝7.1Hz,J2＝7.2Hz,1H),6.75(s,1H),6.48(s,1H),4.04(s,3H),3.91(s,3H)；
LC-MS(ESI)：310.2[M+H]+。
(2)6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
取上述6,8-二甲氧基苯并呋喃[3,2-g]喹啉-5,11-二酮中间体0.31g(1.01mmol)溶于2ml二氯甲烷，冰盐浴冷却下，滴入1mol/L的BBr3溶液2ml，自然升温至室温反应2h。加碳酸氢钠饱和溶液稀释淬灭反应，减压除去二氯甲烷，用乙酸乙酯萃取，干燥，无水硫酸钠干燥过夜，回收溶剂，柱分离(PE:EA＝1：1)纯化、回收溶剂，即得6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮，收率为92％。
Mp:210-213℃；
1H NMR(DMSO－d6):δ＝9.01(d,J＝7.6Hz,1H),8.58(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.26(d,J＝7.8Hz,1H),7.75(dd,J1＝7.1Hz,J2＝7.2Hz,1H),7.26(m,2H)；
LC-MS(ESI):282.3[M+H]+。
(3)8-(2-甲胺基乙氧基)-6-羟基苯并呋喃[3,2-g]喹啉-5,11-二酮的制备：
6,8-二羟基苯并呋喃[3,2-g]喹啉-5,11-二酮0.22g(0.80mmol)加入氯仿(2.0mL),将碳酸钠30.15mg(4eq)溶于水中，加入反应液中，加入2-甲胺基溴乙烷盐酸盐(1.5eq)，加热至回流反应2h。反应完全后降温，加入去离子水洗涤，水相用二氯甲烷萃取一次，合并有机相，饱和食盐水洗涤一次。有机相用无水硫酸钠干燥，浓缩至干，柱层析分离得衍生物2，收率为62％。
Mp:220-225℃；
1H NMR(CDCl3):δ＝9.50(d,J＝9.6Hz,1H),δ＝9.03(d,J＝7.7Hz,1H),8.70(dd,J1＝6.7Hz,J2＝7.6Hz,1H),8.00(d,J＝7.9Hz,1H),7.76(dd,J1＝7.1Hz,J2＝7.1Hz,1H),5.33(t,J＝7.2Hz,2H),2.18(t,J＝7.2Hz,2H),2.03(s,6H)；
LC-MS(ESI):353.0[M+H]+。
通过1,5实施例的比对发现，步骤(3)中
的选择会直接影响最终产物的种类，所得最终产物受n、m整数的影响，同时亦受R1和R3种类的影响；X的选择不影响终产物的种类。
以上实施例仅为举例说明，并不限定本发明所述的所有内容，凡是依照本发明所做的一系列衍生物，或者采用本领域的惯用替换手段，都属本发明保护范围。
Claims (2)
1.一种苯并呋喃氮杂萘二酮衍生物的制备方法，其特征在于，所述苯并呋喃氮杂萘二酮衍生物为8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3，2-g]喹啉-5，11-二酮，所述制备方法包括以下步骤：
(1)将5-羟基-6，8-二甲氧基苯并呋喃[3，2-g]喹啉中间体溶于DMF/甲醇溶剂中，室温下滴入饱和KH2PO4溶液，保持pH＝6，分批加入氧化剂亚硝酸过硫酸钾，充分搅拌均匀，升温反应0.5～3.0h，加碳酸氢钠饱和溶液调节至中性，用乙酸乙酯进行萃取，干燥，再用无水硫酸钠干燥过夜，回收溶剂，进行柱分离纯化，回收溶剂，即得6，8-二甲氧基苯并呋喃[3，2-g]喹啉-5，11-二酮；
(2)将6，8-二甲氧基苯并呋喃[3，2-g]喹啉-5，11-二酮溶于有机溶剂二氯甲烷中，冰盐浴冷却下，滴加BBr3溶液，自然升温至室温，反应1-4h，加碳酸氢钠饱和溶液稀释，进行猝灭反应，减压除去二氯甲烷，用乙酸乙酯萃取，干燥，加无水硫酸钠干燥过夜，回收溶剂，进行柱分离纯化，回收溶剂，即得6，8-二羟基苯并呋喃[3，2-g]喹啉-5，11-二酮；
(3)在碳酸钠存在条件下，将6，8-二羟基苯并呋喃[3，2-g]喹啉-5，11-二酮加入氯仿中，随后加入2-二乙氨基氯乙烷盐酸盐，加热回流1～4h，反应完全后降温，加入去离子水洗涤，水相用二氯甲烷萃取1～3次，合并有机相，用饱和食盐水洗涤1～3次，有机相用无水硫酸钠干燥，浓缩至干，柱层析进行分离，得8-(2-二乙胺基乙氧基)-6-羟基苯并呋喃[3，2-g]喹啉-5，11-二酮。
2.如权利要求1所述的一种苯并呋喃氮杂萘二酮衍生物的制备方法，其特征在于，所述步骤(1)中所述DMF/甲醇的体积比为1∶2～1∶5；所述的升温温度为30～60℃。
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Denomination of invention: New benzofuran azonaphthalene ketone derivatives and their preparation methods Granted publication date: 20210831 Pledgee: Chengdu Rural Commercial Bank Co.,Ltd. Xipu Branch Pledgor: ASTATECH (CHENGDU) BIOPHARMACEUTICAL Corp. Registration number: Y2024980014308 |