CN108440389B - 3,4,5-三羟基苯甲酸衍生物及其制备方法与应用 - Google Patents
3,4,5-三羟基苯甲酸衍生物及其制备方法与应用 Download PDFInfo
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- CN108440389B CN108440389B CN201810426499.0A CN201810426499A CN108440389B CN 108440389 B CN108440389 B CN 108440389B CN 201810426499 A CN201810426499 A CN 201810426499A CN 108440389 B CN108440389 B CN 108440389B
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- chloride
- dmso
- methoxybenzoyl
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- 150000005432 3,4,5-trihydroxybenzoic acid derivatives Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 239000003112 inhibitor Substances 0.000 claims abstract description 14
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 183
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 177
- -1 acetyl Chemical group 0.000 claims description 129
- 238000006243 chemical reaction Methods 0.000 claims description 90
- 239000000543 intermediate Substances 0.000 claims description 80
- 239000000243 solution Substances 0.000 claims description 78
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 150000001263 acyl chlorides Chemical class 0.000 claims description 11
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 5
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 claims description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 claims description 5
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims description 5
- PVJZBZSCGJAWNG-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonyl chloride Chemical compound CC1=CC(C)=C(S(Cl)(=O)=O)C(C)=C1 PVJZBZSCGJAWNG-UHFFFAOYSA-N 0.000 claims description 4
- RZNHSEZOLFEFGB-UHFFFAOYSA-N 2-methoxybenzoyl chloride Chemical compound COC1=CC=CC=C1C(Cl)=O RZNHSEZOLFEFGB-UHFFFAOYSA-N 0.000 claims description 4
- NRCGMEJBEDWPMG-UHFFFAOYSA-N 3,4,5-tris(phenylmethoxy)benzoic acid Chemical compound C=1C=CC=CC=1COC=1C(OCC=2C=CC=CC=2)=CC(C(=O)O)=CC=1OCC1=CC=CC=C1 NRCGMEJBEDWPMG-UHFFFAOYSA-N 0.000 claims description 4
- LSAGRAXLOLZVKO-UHFFFAOYSA-N 3,5-dimethylbenzenesulfonyl chloride Chemical compound CC1=CC(C)=CC(S(Cl)(=O)=O)=C1 LSAGRAXLOLZVKO-UHFFFAOYSA-N 0.000 claims description 4
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 claims description 4
- DTJVECUKADWGMO-UHFFFAOYSA-N 4-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1 DTJVECUKADWGMO-UHFFFAOYSA-N 0.000 claims description 4
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 claims description 4
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 claims description 4
- YEZADZMMVHWFIY-UHFFFAOYSA-N 4-tert-butylbenzenesulfonyl chloride Chemical compound CC(C)(C)C1=CC=C(S(Cl)(=O)=O)C=C1 YEZADZMMVHWFIY-UHFFFAOYSA-N 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 4
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 claims description 4
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- CVXXHXPNTZBZEL-UHFFFAOYSA-N methyl 4-carbonochloridoylbenzoate Chemical compound COC(=O)C1=CC=C(C(Cl)=O)C=C1 CVXXHXPNTZBZEL-UHFFFAOYSA-N 0.000 claims description 4
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- JAPYIBBSTJFDAK-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC(C(C)C)=C(S(Cl)(=O)=O)C(C(C)C)=C1 JAPYIBBSTJFDAK-UHFFFAOYSA-N 0.000 claims description 2
- TWAOVIVEUFBAHK-UHFFFAOYSA-N 2-(dimethylamino)benzoyl chloride Chemical compound CN(C)C1=CC=CC=C1C(Cl)=O TWAOVIVEUFBAHK-UHFFFAOYSA-N 0.000 claims description 2
- NXGKPRKPUCSEIL-UHFFFAOYSA-N 2-acetamido-4-methyl-1,3-thiazole-5-sulfonyl chloride Chemical compound CC(=O)NC1=NC(C)=C(S(Cl)(=O)=O)S1 NXGKPRKPUCSEIL-UHFFFAOYSA-N 0.000 claims description 2
- KFPMLWUKHQMEBU-UHFFFAOYSA-N 3-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC(S(Cl)(=O)=O)=C1 KFPMLWUKHQMEBU-UHFFFAOYSA-N 0.000 claims description 2
- ZIFLQZGEARCNEY-UHFFFAOYSA-N 4-(4-methylbenzoyl)oxycarbonylbenzoic acid Chemical compound C1=CC(C)=CC=C1C(=O)OC(=O)C1=CC=C(C(O)=O)C=C1 ZIFLQZGEARCNEY-UHFFFAOYSA-N 0.000 claims description 2
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 claims description 2
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 claims description 2
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 claims description 2
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 claims description 2
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- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical class NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 claims description 2
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
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- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
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Abstract
本发明提供了一种3,4,5‑三羟基苯甲酸衍生物及其制备方法与应用,所述化合物具有如下通式I或II所示的结构。本发明还涉及该类衍生物的制备方法。活性测试结果表明,本发明大部分3,4,5‑三羟基苯甲酸衍生物表现出显著的HIV‑1 RNase H抑制活性,说明该类化合物作为一系列结构新颖的HIV‑1 RNase H制剂,具有进一步的研究价值。因此,本发明还涉及该类衍生物作为HIV抑制剂在制备抗艾滋病药物中的应用。
Description
技术领域
本发明涉及一种衍生物及其制备方法,具体涉及3,4,5-三羟基苯甲酸衍生物及其制备方法以及其在抗HIV药物领域的应用,属于有机合成与医药应用技术领域。
背景技术
艾滋病,即获得性免疫缺陷综合征(Acquired Immunodeficiency Syndrome,AIDS),是主要由I型人类免疫缺陷病毒(Human Immunodeficiency VirusType 1,HIV-1)引起的危害人类健康的严重传染性疾病。目前,高效抗逆转录病毒疗法(Highly ActiveAntiretroviral Therapy, HAART)是治疗艾滋病的最有效方法,然而,HIV-1耐药突变株的出现影响了HAART的功效。因此,迫切需要开发具有新机制、新结构的靶向HIV-1复制关键环节的抗艾滋病药物。
HIV-1逆转录酶(Reverse Transcriptase,RT)在HIV-1复制过程中发挥着关键作用。RT 通过两种不同的酶功能将病毒单链RNA转化成双链DNA,即合成前病毒DNA的DNA聚合酶活性和选择性降解DNA/RNA异源双链中RNA链的核糖核酸酶H(Ribonuclease H,RNase H)活性。目前批准上市的逆转录酶抑制剂分为两类:核苷(酸)类逆转录酶抑制剂(N(t)RTIs)和非核苷类逆转录酶抑制剂(NNRTIs),它们均靶向于DNA聚合酶活性。尚无RNase H抑制剂上市,鉴于RNase H在病毒复制中的关键作用及其活性位点高度保守的氨基酸残基 (D443/E478/D498/D549),以RNase H为靶标进行抗艾滋病创新药物研究有望克服现有药物的耐药性,具有重要的科学意义。现有技术中关于3,4,5-三羟基苯甲酸类HIV-1RNase H抑制剂未见报道。
发明内容
本发明提供了3,4,5-三羟基苯甲酸衍生物及其制备方法,本发明还提供了上述化合物的部分活性筛选结果及其用途。
本发明的技术方案如下:
一、3,4,5-三羟基苯甲酸衍生物
本发明的3,4,5-三羟基苯甲酸衍生物,具有如下通式I或II所示的结构:
其中,
R1为叔丁氧羰基、H、乙酰基、甲基磺酰基、乙基磺酰基、N,N-二甲基甲酰基、N, N-二甲基甲磺酰基、丙二酸单乙酯酰基、苯甲酰基、对氟苯甲酰基、对甲基苯甲酰基、对氨基苯甲酰基、对苯二甲酸单甲酯酰基、对甲氧基苯甲酰基、间甲氧基苯甲酰基、邻甲氧基苯甲酰基、苯磺酰基、对氟苯磺酰基、对甲苯磺酰基、对叔丁基苯磺酰基、3,5-二甲基苯磺酰基、2,4,6-三甲基苯磺酰基、对甲氧基苯磺酰基、2-乙酰胺基-4-甲基噻唑-5-磺酰基。
R2为叔丁氧羰基、H、乙酰基、N,N-二甲基甲酰基、甲基磺酰基、乙基磺酰基、丙基磺酰基、N,N-二甲基甲磺酰基、苯甲酰基、对氟苯甲酰基、对甲基苯甲酰基、对氨基苯甲酰基、对苯二甲酸单甲酯酰基、对甲氧基苯甲酰基、间甲氧基苯甲酰基、邻甲氧基苯甲酰基、苯磺酰基、对氟苯磺酰基、对甲苯磺酰基、间甲苯磺酰基、对叔丁基苯磺酰基、3,5-二甲基苯磺酰基、2,4,6-三甲基苯磺酰基、2,4,6-三异丙基苯磺酰基、对氨基苯磺酰基、对乙酰氨基苯磺酰基、对甲氧基苯磺酰基。
根据本发明优选的,3,4,5-三羟基苯甲酸衍生物,是下列之一:
二、3,4,5-三羟基苯甲酸衍生物的制备方法
本发明3,4,5-三羟基苯甲酸衍生物的制备方法,步骤包括:以3,4,5-三苄氧基苯甲酸 (I-a/II-a)为原料,与1-Boc-4-氨基哌啶/1-Boc-哌嗪经酰化反应制得中间体(I-b/II-b),利用盐酸/乙酸乙酯溶液将Boc脱去得到中间体(I-c/II-c),相应的酰氯或磺酰氯对I-c/II-c进行亲核取代反应得到关键中间体哌啶胺/哌嗪衍生物I-d(1-24)/II-d(1-27),最后在氢气/钯碳条件下脱去三个苄基制得目标化合物I-e(1-24)/II-e(1-27)。
合成路线为如下之一:
路线1:
反应试剂与反应条件:i)1-Boc-4-氨基哌啶,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐, 1-羟基苯并***,三乙胺,N,N-二甲基甲酰胺,室温,12h;ii)盐酸/乙酸乙酯,室温,2h; iii)相应的酰氯或磺酰氯1,三乙胺,二氯甲烷,室温,12h;iv)氢气/钯碳,二氯甲烷/甲醇,室温,24h。
其中,R1如上述通式I中所述。
所述的相应酰氯或磺酰氯1选自:乙酰氯、甲磺酰氯、乙磺酰氯、二甲氨基甲酰氯、二甲胺基磺酰氯、氯甲酰乙酸乙酯、苯甲酰氯、对氟苯甲酰氯、对甲基苯甲酰氯、对硝基苯甲酰氯、4-氯甲酰基苯甲酸甲酯、对甲氧基苯甲酰氯、间甲氧基苯甲酰氯、邻甲氧基苯甲酰氯、苯磺酰氯、对氟苯磺酰氯、对甲苯磺酰氯、对叔丁基苯磺酰氯、3,5-二甲基苯磺酰氯、2,4,6-三甲基苯磺酰氯、对甲氧基苯磺酰氯、2-乙酰胺基-4-甲基噻唑-5-磺酰氯。
路线2:
反应试剂与反应条件:i)1-Boc-哌嗪,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,1-羟基苯并***,三乙胺,N,N-二甲基甲酰胺,室温,12h;ii)盐酸/乙酸乙酯,室温,6h;iii)相应的酰氯或磺酰氯2,三乙胺,二氯甲烷,室温,12h;iv)氢气/钯碳,二氯甲烷/甲醇,室温,24h。
其中,R2如上述通式II中所述。
所述的相应酰氯或磺酰氯2选自:乙酰氯、二甲氨基甲酰氯、甲磺酰氯、乙磺酰氯、丙磺酰氯、二甲胺基磺酰氯、苯甲酰氯、对氟苯甲酰氯、对甲基苯甲酰氯、对硝基苯甲酰氯、4-氯甲酰基苯甲酸甲酯、对甲氧基苯甲酰氯、间甲氧基苯甲酰氯、邻甲氧基苯甲酰氯、苯磺酰氯、对氟苯磺酰氯、对甲苯磺酰氯、间甲苯磺酰氯、对叔丁基苯磺酰氯、3,5-二甲基苯磺酰氯、2,4,6-三甲基苯磺酰氯、2,4,6-三异丙基苯磺酰氯、对硝基苯磺酰氯、对乙酰氨基苯磺酰氯、对甲氧基苯磺酰氯。
三、3,4,5-三羟基苯甲酸衍生物的应用
活性测试结果表明,本发明大部分3,4,5-三羟基苯甲酸衍生物表现出显著的HIV-1RNase H抑制活性,其中化合物II-25活性最高(IC50=0.72±0.07μM),约为阳性对照β-thujaplicinol (IC50=1.98±0.22μM)的2.8倍,说明该类化合物作为一系列结构新颖的HIV-1RNase H 制剂,具有进一步的研究价值。
因此,本发明所提供的3,4,5-三羟基苯甲酸衍生物可作为HIV-1RNase H抑制剂用于制备抗艾滋病药物。
一种抗HIV-1的药物组合物,含有上述的3,4,5-三羟基苯甲酸衍生物及其药学上可接受的盐和一种或多种药学上可接受载体或赋形剂。
具体实施方式
下面结合实施例对本发明做进一步说明,所有目标化合物的编号与发明内容部分优选的化合物相同,所述百分比数均为质量百分比。
实施例1:中间体4-(3,4,5-三(苄氧基)苯甲酰氨基)哌啶-1-甲酸叔丁酯(I-b)的制备
称取3,4,5-三苄氧基苯甲酸(2.0g,4.5mmol)置于250mL烧瓶中,加入50mL N,N-二甲基甲酰胺(DMF)溶解,冰浴搅拌条件下加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,0.96g,5.0mmol),1-羟基苯并***(HOBT,0.67g,5.0mmol),三乙胺(1.3mL,10mmol),搅拌15分钟后,撤去冰浴,室温搅拌1小时。最后向烧瓶中加入1-Boc-4-氨基哌啶(1.1g,5.4mmol),反应12小时。反应结束后,加入100mL水,乙酸乙酯萃取三次(3×50 mL),合并有机相,依次用稀盐酸水溶液和饱和碳酸氢钠溶液分别洗涤2-3次,最后饱和氯化钠溶液洗涤。取有机相,加入适量的无水硫酸钠,干燥、过滤、浓缩得粗品。硅胶干法拌样,湿法装柱进行柱层析,乙酸乙酯:石油醚=1:3进行洗脱,分得白色固体I-b。收率:80.3%, mp:209-210℃。
波谱数据:1HNMR(400MHz,DMSO-d6,ppm)δ:8.19(d,J=7.9Hz,1H,NH),7.51-7.45(m, 4H,Ph-H),7.44-7.38(m,4H,Ph-H),7.38-7.33(m,4H,Ph-H),7.32(s,2H,Ph-H),7.30-7.23(m, 3H,Ph-H),5.16(s,4H,2×CH2),4.99(s,2H,CH2),3.98(dt,J=7.8,4.0Hz,1H,CH),2.87(d,J= 18.9Hz,2H,CH2),1.79(d,J=11.8Hz,2H,CH2),1.41(s,9H,3×CH3).13C NMR(100MHz, DMSO-d6,ppm)δ:165.13(C=O),154.31(C=O),152.39(2×C),139.96,137.90,137.33(3×C), 130.24,128.90(6×C),128.64(2×C),128.51(2×C),128.39,128.31,128.16(6×C),106.98,79.10, 74.65,70.87,47.10,28.57(3×C).ESI-MS:m/z623.4(M+1),645.4(M+23).C38H42N2O6[622.30]
实施例2:中间体3,4,5-三(苄氧基)-N-(哌啶-4-基)苯甲酰胺(I-c)的制备
将中间体I-b置于250mL烧瓶中,搅拌下逐渐加入4mol/L的盐酸/乙酸乙酯溶液至溶液变澄清,室温反应2小时。将反应液蒸干,得白色固体,加1mol/L的NaOH溶液调节pH 至近中性,然后过滤,得白色固体I-c。收率:89.8%,mp:169-170℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:8.18(d,J=7.8Hz,1H,NH),7.51-7.45(m,4H,Ph-H),7.44-7.38(m,4H,Ph-H),7.38-7.31(m,6H,Ph-H),7.30-7.23(m,3H,Ph-H),5.17 (s,4H,2×CH2),4.99(s,2H,CH2),3.81(dt,J=7.8,4.0Hz,1H,CH),2.96(dt,J=12.6,3.3Hz,2H, CH2),2.53(d,J=2.2Hz,1H,CH),2.47(d,J=2.4Hz,1H,CH),2.16(s,1H,NH),1.78-1.67(m, 2H,CH2),1.42(qd,J=12.0,4.1Hz,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ: 164.92(C=O),152.34(2×C),139.80,137.92,137.36(3×C),130.43,128.90(6×C),128.65(2×C), 128.52(2×C),128.39,128.31,128.16(6×C),106.93,74.64,70.82,48.06,45.89,33.60.ESI-MS: m/z523.4(M+1),545.3(M+23).C33H34N2O4[522.25].
实施例3:制备中间体I-d的通法
称取中间体I-c(0.10g,0.19mmol,1eq.)加入到25mL烧瓶中,加入4mL二氯甲烷溶解,冰浴下向反应瓶中加入三乙胺(2eq.)和相应的酰氯取代基(1.2-1.5eq.),室温搅拌12个小时。反应完成后,将反应液蒸干,加乙酸乙酯超声过滤得中间体粗品直接或柱层析纯化后投下一步反应。以I-5中间体3,4,5-三(苄氧基)-N-(1-(乙基磺酰基)哌啶-4-基)苯甲酰胺(I-d-5)为例。
称取中间体I-c(0.10g,0.19mmol)加入到25mL烧瓶中,加入6mL二氯甲烷溶解,冰浴下向反应瓶中加入三乙胺(53μL,0.38mmol)和乙基磺酰氯(30mg,0.23mmol),室温搅拌12个小时。反应结束后,蒸干反应液,得白色固体,乙酸乙酯超声后过滤得中间体I-d-5。收率:75.3%,mp:212-213℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:8.26(d,J=7.8Hz,1H,NH),7.51-7.45(m,4H,Ph-H),7.41(tt,J=6.3,1.0Hz,4H,Ph-H),7.36(ddd,J=7.7,4.7,2.1Hz,4H,Ph-H),7.32 (s,2H,Ph-H),7.27(tdd,J=4.1,3.2,1.2Hz,3H,Ph-H),5.17(s,4H,2×CH2),4.99(s,2H,CH2), 4.03-3.85(m,1H,CH),3.65(d,J=12.0Hz,2H,CH2),3.07(q,J=7.4Hz,2H,CH2),2.95(td,J= 12.4,2.5Hz,2H,CH2),1.90(d,J=12.4Hz,2H,CH2),1.58(qd,J=12.2,4.2Hz,2H,CH2),1.22 (t,J=7.4Hz,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:165.33(C=O),152.40(2×C), 140.00,137.89,137.33(3×C),130.21,128.90(6×C),128.65(2×C),128.52(2×C),128.40,128.32, 128.16(6×C),107.03,74.66,70.88,46.68,45.07,43.50,31.87,8.10(CH3).ESI-MS:m/z615.3 (M+1),637.3(M+23).C35H38N2O6S[614.25].
实施例4:3,4,5-三羟基苯甲酸衍生物I-(1-24)的制备
称取相应的中间体I-d约0.10g至烧瓶中,加入适量二氯甲烷/甲醇(1:1)溶解,加两倍量的10%钯碳。反应体系通氢气,室温反应24小时。反应液经硅藻土过滤,滤液蒸干,用二氯甲烷或乙酸乙酯洗涤所得固体或进行重结晶,得到目标产物。
中间体I-d选用I-d-1即4-(3,4,5-三(苄氧基)苯甲酰氨基)哌啶-1-甲酸叔丁酯(I-b) 反应制得4-(3,4,5-三羟基苯甲酰氨基)哌啶-1-甲酸叔丁酯(I-1)。反应液经硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰色固体。收率:57.2%,mp:152-153℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.00(s,2H,2×OH),8.69(s,1H,OH),7.89(s,1H,NH),6.82(s,2H,Ph-H),4.05-3.78(m,3H,CH2,CH),2.79(s,2H,CH2),1.81-1.63(m, 2H,CH2),1.40(s,11H,3×CH3,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:166.15(C=O),154.37(C=O),145.81(2×C),136.55,125.44,107.29(2×C),79.05(2×C),55.39,46.77(2×C),31.83, 28.56(3×CH3).ESI-MS:m/z 353.3(M+1),375.4(M+23).C17H24N2O6[352.16].
中间体I-d选用I-d-2即中间体3,4,5-三(苄氧基)-N-(哌啶-4-基)苯甲酰胺(I-c)反应制得3,4,5-三羟基-N-(哌啶-4-基)苯甲酰胺(I-2)。反应液经硅藻土过滤,滤液蒸干,二氯甲烷洗涤,滤饼甲醇/乙酸乙酯重结晶,得灰色固体。收率:59.5%,mp:109-110℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,3H,3×OH),8.13(d,J=7.2Hz,1H,NH),6.85(s,2H,Ph-H),3.97(d,J=9.4Hz,1H,CH),3.28(s,2H,CH2),2.96(s,2H,CH2),1.91(d,J=13.0Hz,2H,CH2),1.75(d,J=12.0Hz,2H,CH2).13C NMR(100MHz,DMSO-d6, ppm)δ:166.52(C=O),145.84(2×C),136.68,125.19,107.48(2×C),44.65,42.62(2×C),28.62(2×C).ESI-MS:m/z 253.2(M+1),275.3(M+23).C12H16N2O4[252.11].
中间体I-d选用N-(1-乙酰基哌啶-4-基)-3,4,5-三(苄氧基)苯甲酰胺(I-d-3)反应制得N-(1-乙酰基哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-3)。反应液经硅藻土过滤,滤液蒸干,二氯甲烷、乙酸乙酯洗涤,得灰色固体。收率:50.0%,mp:222-223℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.02(s,2H,2×OH),8.65(s,1H,OH),7.92(d,J=7.8Hz,1H,NH),6.82(s,2H,Ph-H),4.32(d,J=13.4Hz,1H,CH),3.92(ddd,J=11.1,7.4,3.9Hz,1H,CH),3.81(d,J=13.8Hz,1H,CH),3.10(td,J=13.7,13.0,2.8Hz,1H,CH), 2.63(td,J=12.8,2.9Hz,1H,CH),2.00(s,3H,CH3),1.76(dd,J=25.2,12.8Hz,2H,CH2),1.45 (td,J=12.0,4.1Hz,1H,CH),1.34(qd,J=12.0,4.0Hz,1H,CH).13C NMR(100MHz,DMSO-d6, ppm)δ:168.44(C=O),166.26(C=O),145.80(2×C),136.57,125.44,107.28(2×C),46.86(2×C), 45.35,32.47,31.63,21.76.ESI-MS:m/z295.4(M+1),317.3(M+23).C14H18N2O5[294.12].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(甲基磺酰基)哌啶-4-基)苯甲酰胺(I-d-4) 反应制得3,4,5-三羟基-N-(1-(甲基磺酰基)哌啶-4-基)苯甲酰胺(I-4)。反应液经硅藻土过滤,滤液蒸干,二氯甲烷、乙酸乙酯洗涤,得灰色固体。收率:61.1%,mp:249-250℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,2H,2×OH),8.64(s,1H,OH),7.96(d,J=7.8Hz,1H,NH),6.82(s,2H,Ph-H),3.83(dt,J=7.8,4.0Hz,1H,CH),3.54(d,J=12.0Hz,2H,CH2),2.87(s,3H,CH3),2.80(dd,J=12.0,2.6Hz,2H,CH2),1.84(d,J=12.7Hz,2H,CH2),1.57(qd,J=12.1,4.1Hz,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ: 166.38(C=O),145.83(2×C),136.61,125.37,107.30(2×C),46.15,45.27(2×C),34.67(2×C),31.26.ESI-MS:m/z 331.3(M+1),353.3(M+23).C13H18N2O6S[330.09].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(乙基磺酰基)哌啶-4-基)苯甲酰胺(I-d-5) 反应制得N-(1-(乙基磺酰基)哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-5)。反应液经硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰色固体。收率:59.9%,mp:235-236℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,2H,2×OH),8.67(s,1H,OH),7.96(d,J=7.8Hz,1H,NH),6.82(s,2H,Ph-H),3.85(dt,J=7.6,3.9Hz,1H,CH),3.59(dt,J= 12.8,3.7Hz,2H,CH2),3.05(q,J=7.4Hz,2H,CH2),2.91(td,J=12.2,2.6Hz,2H,CH2),1.87- 1.76(m,2H,CH2),1.54(tt,J=11.7,6.0Hz,2H,CH2),1.22(t,J=7.4Hz,3H,CH3).13CNMR (100MHz,DMSO-d6,ppm)δ:166.32(C=O),145.83(2×C),136.60,125.39,107.31(2×C),46.22, 45.04(2×C),43.25(2×C),31.68,8.04.ESI-MS:m/z 345.3(M+1),367.2(M+23).C14H20N2O6S [344.10].
中间体I-d选用N,N-二甲基-4-(3,4,5-三(苄氧基)苯甲酰氨基)哌啶-1-甲酰胺(I-d-6) 反应制得N,N-二甲基-4-(3,4,5-三羟基苯甲酰氨基)哌啶-1-甲酰胺(I-6)。反应液经硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰黑色固体,再用乙酸乙酯超声,过滤,滤液蒸干得浅灰色固体。收率:54.6%,mp:202-203℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.00(s,2H,2×OH),8.64(s,1H,OH),7.92(d,J=7.8Hz,1H,NH),6.83(s,2H,Ph-H),3.86(dtd,J=11.2,7.3,4.0Hz,1H,CH),3.55(d, J=13.0Hz,2H,CH2),2.77(d,J=11.9Hz,2H,CH2),2.73(s,6H,2×CH3),1.99(s,1H,CH),1.71 (s,1H,CH),1.48(dd,J=11.8,3.8Hz,2H,CH2).13CNMR(100MHz,DMSO-d6,ppm)δ:166.14(C=O),164.32(C=O),145.78(2×C),136.54,125.45,107.27(2×C),60.23,47.08,46.07(2×C), 31.80,21.24,14.56.ESI-MS:m/z 324.4(M+1),346.3(M+23).C15H21N3O5[323.15].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(N,N-二甲基氨基)哌啶-4-基)苯甲酰胺(I-d-7)反应制得N-(1-(N,N-二甲基氨磺酰基)哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-7)。反应液经硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰色固体,再用乙酸乙酯洗涤,过滤,滤液蒸干得浅灰色固体。收率:49.8%,mp:211-212℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:8.99(s,2H,2×OH),8.63(s,1H,OH),7.94(d,J=7.8Hz,1H,NH),6.82(s,2H,Ph-H),3.85(ddd,J=11.2,7.7,4.1Hz,1H,CH),3.57(d, J=12.3Hz,2H,CH2),2.94(td,J=12.4,2.5Hz,2H,CH2),2.75(s,6H,2×CH3),1.91-1.69(m,2H, CH2),1.64-1.44(m,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:166.28(C=O),145.81(2×C),136.59,125.37,107.29(2×C),46.21,46.09,45.84(2×C),38.33,31.62,9.04.ESI-MS: m/z 360.3(M+1),382.3(M+23).C15H25N3O6S[359.12].
中间体I-d选用乙基3-氧代-3-(4-(3,4,5-三(苄氧基)苯甲酰氨基)哌啶-1-基)丙酸乙酯(I-d-8)反应制得3-氧代-3-(4-(3,4,5-三羟基苯甲酰氨基)哌啶-1-基)丙酸乙酯(I-8)。反应液经硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,滤饼再用乙酸乙酯洗涤,过滤,滤液蒸干得白色固体。收率:56.7%,mp:213-215℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.02(s,2H,2×OH),8.66(s,1H,OH),7.96(d,J=7.8Hz,1H,NH),6.83(s,2H,Ph-H),4.31(d,J=13.2Hz,1H,CH),4.10(q,J=7.1Hz, 2H,CH2),3.95(dtd,J=11.3,7.4,3.3Hz,1H,CH),3.76(d,J=13.6Hz,1H,CH),3.60-3.47(m, 2H,CH2),3.19-3.01(m,1H,CH),2.70(td,J=12.9,2.8Hz,1H,CH),1.85-1.68(m,2H,CH2), 1.42(dqd,J=44.3,12.2,4.1Hz,2H,CH2),1.20(t,J=7.1Hz,3H,CH3).13CNMR(100MHz, DMSO-d6,ppm)δ:168.30(C=O),166.28(C=O),164.59(C=O),145.79(2×C),136.57,125.40, 107.29(2×C),60.97,46.72,45.27,41.25,40.88,32.25,31.53,14.51.ESI-MS:m/z 367.2(M+1), 389.3(M+23).C17H22N2O7[366.14].
中间体I-d选用N-(1-苯甲酰哌啶-4-基)-3,4,5-三(苄氧基)苯甲酰胺(I-d-9)反应制得N-(1-苯甲酰基哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-9)。反应液经硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,乙酸乙酯洗涤,得灰色固体。收率:47.7%,mp:256-257℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,2H,2×OH),8.69(s,1H,OH),7.94(d,J=7.8Hz,1H,NH),7.50-7.42(m,3H,Ph-H),7.41-7.32(m,2H,Ph-H),6.83(s,2H,Ph-H),4.44(s,1H,CH),4.11-3.86(m,1H,CH),3.57(s,1H,CH),2.91(s,1H,CH),1.78(d,J=41.1Hz,3H,CH2,CH),1.47(s,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:169.45(C=O),166.21(C=O),145.82,136.75,136.60,129.86,128.93,127.02,125.37,107.30,46.75.ESI-MS:m/z 357.3(M+1),379.3(M+23).C19H20N2O5[356.14].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(4-氟苯甲酰基)哌啶-4-基)苯甲酰胺(I-d-10) 反应制得N-(1-(4-氟苯甲酰基)哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-10)。反应液经硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰色固体,再用乙酸乙酯超声,过滤,滤液蒸干得白色固体。收率:52.2%,mp:278-279℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,2H,2×OH),8.67(s,1H,OH),7.94(d,J=7.8Hz,1H,NH),7.50-7.39(m,2H,Ph-H),7.29(t,J=8.8Hz,2H,Ph-H),6.82(s,2H, Ph-H),4.41(s,1H,CH),4.01(dp,J=11.3,7.1Hz,1H,CH),3.57(s,1H,CH),3.08(d,J=7.3Hz, 1H,CH),2.92(s,1H,CH),1.78(d,J=29.0Hz,2H,CH2),1.47(s,2H,CH2).13C NMR(100MHz, DMSO-d6)168.56(C=O),166.21(C=O),162.91(d,J=246.5Hz),145.82(2×C),136.60,133.09 (d,J=3.6Hz),129.66(d,J=8.6Hz,2×C),125.38,115.91(d,J=21.7Hz,2×C),107.29(2×C), 60.22,46.74(2×C),46.06(2×C).ESI-MS:m/z 375.4(M+1),397.3(M+23).C19H19FN2O5[374.13].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(4-甲基苯甲酰基)哌啶-4-基)苯甲酰胺(I-d-11) 反应制得3,4,5-三羟基-N-(1-(4-甲基苯甲酰基)哌啶-4-基)苯甲酰胺(I-11)。反应液经硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰色固体,再用乙酸乙酯超声,过滤,滤液蒸干得浅灰色固体。收率:55.7%,mp:252-253℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:8.98(s,2H,2×OH),8.62(s,1H,OH),7.91(d,J=7.9Hz,1H,NH),7.26(s,4H,Ph-H),6.83(s,2H,Ph-H),4.41(s,1H,CH),4.00(tdd,J =11.3,7.5,4.8Hz,1H,CH),3.61(s,1H,CH),3.01(d,J=76.9Hz,2H,CH2),2.34(s,3H,CH3), 1.77(s,2H,CH2),1.47(s,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:169.58(C=O), 166.20(C=O),145.81(2×C),139.51,136.60,133.82,129.38(2×C),127.17(2×C),125.40, 107.28(2×C),46.79,21.36(CH3).ESI-MS:m/z 371.4(M+1),393.2(M+23).C20H22N2O5[370.15].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(4-硝基苯甲酰基)哌啶-4-基)苯甲酰胺(I-d-12) 反应制得N-(1-(4-氨基苯甲酰基)哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-12)。反应液硅藻土过滤,滤液蒸干,二氯甲烷洗涤,过滤,得灰色固体。收率:53.5%,mp:189-190℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,2H,2×OH),8.72(d,J=12.4Hz, 1H,OH),7.92(d,J=7.8Hz,1H,NH),7.11(d,J=8.2Hz,2H,Ph-H),6.82(s,2H,Ph-H),6.57(d, J=8.2Hz,2H,Ph-H),5.63(s,2H,NH2),4.21-3.82(m,2H,CH2),2.99(d,J=12.9Hz,2H,CH2), 1.88-1.60(m,3H,CH,CH2),1.45(dd,J=12.0,4.1Hz,1H,CH),1.17(t,J=7.1Hz,1H,CH).13C NMR(100MHz,DMSO-d6,ppm)δ:170.34(C=O),166.18(C=O),145.82,136.57,129.37,125.43, 113.33,107.32,60.23,46.97,32.18,21.24,14.56.ESI-MS:m/z372.3(M+1),394.2(M+23). C19H21N3O5[371.15].
中间体I-d选用4-(4-(3,4,5-三(苄氧基)苯甲酰氨基)哌啶-1-羰基)苯甲酸甲酯(I-d-13) 反应制得4-(4-(3,4,5-三羟基苯甲酰氨基)哌啶-1-羰基)苯甲酸甲酯(I-13)。反应液硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰黑色固体,再用乙酸乙酯超声,过滤,滤液蒸干得白色固体。收率:59.2%,mp:160-161℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:8.98(s,2H,2×OH),8.63(s,1H,OH),8.03(d,J=7.8Hz,2H,Ph-H),7.93(d,J=7.8Hz,1H,NH),7.51(d,J=7.9Hz,2H,Ph-H),6.83(s,2H,Ph-H),4.44(s,1H,CH),4.03(dd,J=15.3,8.0Hz,2H,CH2),3.88(s,3H,CH3),3.48(s,1H,CH),3.05(d,J=84.3Hz,2H,CH2),1.79(d,J=54.2Hz,2H,CH2),1.49(d,J=31.8Hz,1H,CH).13C NMR(100MHz,DMSO-d6,ppm)δ:168.44(C=O),166.23(C=O),166.15(C=O),145.82(2×C),141.26,136.62,130.70,129.87(2×C),127.35(2×C),125.38,107.29(2×C),52.80, 46.68(2×C),32.39(2×C),14.56(CH3).ESI-MS:m/z 415.4(M+1),437.4(M+23).C21H22N2O7 [414.14].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(4-甲氧基苯甲酰基)哌啶-4-基)苯甲酰胺 (I-d-14)反应制得3,4,5-三羟基-N-(1-(4-甲氧基苯甲酰基)哌啶-4-基)苯甲酰胺(I-14)。反应液硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰色固体。收率:43.3%,mp:154-156℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,2H,2×OH),8.73(s,1H,OH),7.94(d,J=7.8Hz,1H,NH),7.41-7.25(m,2H,Ph-H),7.04-6.92(m,2H,Ph-H),6.83(s,2H,Ph-H),4.36(s,1H,CH),3.99(d,J=7.7Hz,1H,CH),3.80(s,3H,CH3),3.05(q,J=7.2Hz,1H,CH),1.77(s,2H,CH2),1.47(s,2H,CH2),1.19(t,J=7.2Hz,2H,CH2).13C NMR(100MHz, DMSO-d6,ppm)δ:169.42(C=O),166.19(C=O),160.55,145.86(2×C),136.59,129.16(2×C),128.62,125.43,114.14(2×C),107.37(2×C),55.71,46.83,45.77.ESI-MS:m/z 387.3(M+1),409.4 (M+23).C20H22N2O6[386.15].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(3-甲氧基苯甲酰基)哌啶-4-基)苯甲酰胺 (I-d-15)反应制得3,4,5-三羟基-N-(1-(3-甲氧基苯甲酰基)哌啶-4-基)苯甲酰胺(I-15)。反应液硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰色固体。收率:45.5%,mp:218-219℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.02(s,2H,2×OH),8.72(s,1H,OH),7.94(d,J=7.8Hz,1H,NH),7.37(t,J=7.9Hz,1H,Ph-H),7.02(dd,J=8.2,2.6Hz,1H,Ph-H), 6.95-6.86(m,2H,Ph-H),6.83(s,2H,Ph-H),4.42(s,1H,CH),4.11-3.89(m,1H,CH),3.79(s,3H, CH3),3.58(d,J=13.9Hz,1H,CH),3.13(s,1H,CH),2.90(s,1H,CH),1.78(d,J=46.2Hz,2H, CH2),1.48(s,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:169.09(C=O),166.17(C=O), 159.57,145.83(2×C),138.15,136.59,130.19,125.37,118.96,115.43,112.37,107.29(2×C),55.67, 46.74.ESI-MS:m/z 387.3(M+1),409.4(M+23).C20H22N2O6[386.15].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(2-甲氧基苯甲酰基)哌啶-4-基)苯甲酰胺 (I-d-16)反应制得3,4,5-三羟基-N-(1-(2-甲氧基苯甲酰基)哌啶-4-基)苯甲酰胺(I-16)。反应液硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰色固体。收率:40.9%,mp:180-181℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.02(d,J=2.8Hz,2H,2×OH),8.78(s,1H,OH),7.95(dd,J=27.9,7.8Hz,1H,NH),7.39(q,J=7.3Hz,1H,Ph-H),7.15(t,J=7.2Hz,1H,Ph-H),7.08(d,J=8.3Hz,1H,Ph-H),7.00(dt,J=10.9,7.2Hz,1H,Ph-H),6.83(d,J=8.2 Hz,2H,Ph-H),4.46(d,J=9.6Hz,1H,CH),4.08-3.89(m,1H,CH),3.81(d,J=14.4Hz,3H, CH3),3.00(dd,J=34.6,11.3Hz,2H,CH2),2.84(t,J=12.4Hz,1H,CH),1.90-1.75(m,1H,CH), 1.65(d,J=12.2Hz,1H,CH),1.59-1.26(m,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ: 166.59(C=O),166.16(C=O),155.37,145.85,136.57,130.73,125.49,121.07,111.72,107.41,55.90, 46.76,45.76,32.25,31.75.ESI-MS:m/z 387.3(M+1),409.4(M+23).C20H22N2O6[386.15].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(苯基磺酰基)哌啶-4-基)苯甲酰胺(I-d-17) 反应制得3,4,5-三羟基-N-(1-(苯基磺酰基)哌啶-4-基)苯甲酰胺(I-17)。反应液硅藻土过滤,滤液蒸干,加二氯甲烷超声,过滤,得灰色固体。收率:51.1%,mp:264-265℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,2H,2×OH),8.66(s,1H,OH),7.93(d,J=7.7Hz,1H,NH),7.79-7.71(m,3H,Ph-H),7.67(d,J=7.4Hz,2H,Ph-H),6.78(s,2H, Ph-H),3.64(dd,J=9.4,5.6Hz,3H,CH,CH2),3.09(d,J=8.1Hz,1H,CH),2.36(d,J=2.7Hz, 1H,CH),1.80(s,1H,CH),1.56(d,J=8.2Hz,1H,CH),1.24(s,2H,CH2).13C NMR(100MHz, DMSO-d6,ppm)δ:166.33(C=O),145.78(2×C),136.59,136.08,133.58,129.87(2×C), 127.82(2×C),125.31,107.24(2×C),45.98,45.76(2×C),31.10(2×C).ESI-MS:m/z 393.2(M+1), 415.3(M+23).C18H20N2O6S[392.10].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-((4-氟苯基)磺酰基)哌啶-4-基)苯甲酰胺 (I-d-18)反应制得N-(1-((4-氟苯基)磺酰基)哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-18)。反应液硅藻土过滤,滤液蒸干,加乙酸乙酯超声,过滤,二氯甲烷洗涤,得灰色固体。收率: 50.6%,mp:275-276℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.03(s,2H,2×OH),8.78(s,1H,OH),7.94(d,J=7.8Hz,1H,NH),7.83(dd,J=8.5,5.1Hz,2H,Ph-H),7.50(t,J=8.6Hz,2H,Ph-H), 6.79(s,2H,Ph-H),3.62(d,J=11.8Hz,2H,CH2),2.46-2.32(m,2H,CH2),1.80(t,J=6.5Hz,2H, CH2),1.56(dd,J=12.0,3.9Hz,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ166.35(C=O), 162.92(d,J=174.2Hz),145.83(2×C),136.58,132.55,130.91(d,J=9.3Hz,2×C),125.34,117.08 (d,J=22.6Hz,2×C),107.34(2×C),45.90,45.71(2×C).,31.05(2×C).ESI-MS:m/z 411.3(M+1), 433.4(M+23).C18H19FN2O6S[410.09].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-甲苯磺酰基哌啶-4-基)苯甲酰胺(I-d-19)反应制得3,4,5-三羟基-N-(1-甲苯磺酰基哌啶-4-基)苯甲酰胺(I-19)。反应液硅藻土过滤,滤液蒸干,依次二氯甲烷、乙酸乙酯超声,过滤,得灰色固体。收率:57.7%,mp:240-243℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.03(s,2H,2×OH),8.74(s,1H,OH),8.10(d,J=7.4Hz,1H,NH),7.49(d,J=7.8Hz,2H,Ph-H),7.12(d,J=7.7Hz,2H,Ph-H),6.85(s,2H,Ph-H),4.03(q,J=7.1Hz,1H,CH),2.97(d,J=9.8Hz,3H,CH3),2.89(s,1H,CH),2.73(s,1H,CH),2.29(s,2H,CH2),1.91(dd,J=14.1,3.8Hz,2H,CH2),1.72(d,J=12.1Hz,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:166.52(C=O),146.06,145.83(2×C),138.15,136.69, 128.54(2×C),125.95(2×C),125.15,107.42(2×C),60.23,56.48,44.61,42.75(2×C),31.24(2×C), 21.25.ESI-MS:m/z 405.5(M-1).C19H22N2O6S[406.12].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-((4-(叔丁基)苯基)磺酰基)哌啶-4-基)苯甲酰胺(I-d-20)反应制得N-(1-((4-(叔丁基)苯基)磺酰基)哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-20)。反应液硅藻土过滤,滤液蒸干,依次二氯甲烷、乙酸乙酯超声,过滤,得灰色固体。收率:60.6%,mp:154-155℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.02(s,2H,2×OH),8.68(s,1H,OH),7.94(d,J=7.8Hz,1H,NH),7.67(s,4H,Ph-H),6.79(s,2H,Ph-H),3.77-3.52(m,3H,CH,CH2), 2.34(td,J=12.1,2.5Hz,2H,CH2),1.88-1.74(m,2H,CH2),1.58(qd,J=12.1,4.1Hz,2H,CH2), 1.33(s,9H,3×CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:166.33(C=O),156.49,145.80(2×C), 136.59,133.17,127.81(2×C),126.66(2×C),125.32,107.26(2×C),45.97,45.77(2×C),35.39(2×C), 31.26,31.14(3×C).ESI-MS:m/z 449.4(M+1),471.3(M+23).C22H28N2O6S[448.17].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-((3,5-二甲基苯基)磺酰基)哌啶-4-基)苯甲酰胺(I-d-21)反应制得N-(1-((3,5-二甲基苯基)磺酰基)哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-21)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,滤液蒸干得白色固体。收率:55.6%,mp:276-278℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,2H,2×OH),8.66(s,1H,OH),7.93(d,J=7.7Hz,1H,NH),7.35(s,3H,Ph-H),6.79(s,2H,Ph-H),3.63(t,J=16.2Hz,4H, 2×CH2),2.38(s,6H,2×CH3),2.36-2.34(m,1H,CH),1.82(dd,J=13.2,3.8Hz,2H,CH2),1.57(dd,J=11.9,3.8Hz,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:166.34(C=O), 145.79(2×C),139.40(2×C),136.59,135.86,134.91,125.32(2×C),125.26(2×C),107.26,46.03, 45.80(2×C),31.12(2×C),21.23(2×C).ESI-MS:m/z 421.3(M+1),443.4(M+23).C20H24N2O6S [420.14].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-(2,4,6-三甲基苯磺酰基)哌啶-4-基)苯甲酰胺(I-d-22)反应制得3,4,5-三羟基-N-(1-(2,4,6-三甲基苯磺酰基)哌啶-4-基)苯甲酰胺(I-22)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,得灰黑色固体,乙酸乙酯洗涤,乙酸乙酯相蒸干得白色固体。收率:50.7%,mp:186-187℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:8.99(s,2H,2×OH),8.64(s,1H,OH),7.94(d,J=7.8Hz,1H,NH),7.09(s,2H,Ph-H),6.82(s,2H,Ph-H),3.86(dt,J=7.5,3.9Hz,1H, CH),3.46(d,J=12.2Hz,2H,CH2),2.81(td,J=12.3,2.6Hz,2H,CH2),2.56(s,6H,2×CH3), 2.29(s,3H,CH3),1.85-1.71(m,2H,CH2),1.51(qd,J=11.9,4.1Hz,2H,CH2).13C NMR(100 MHz,DMSO-d6,ppm)δ:166.19(C=O),145.79(2×C),142.81,140.01(2×C),136.61,132.39(2×C), 132.30,125.30,107.28(2×C),46.27,43.58(2×C),31.18(2×C),22.75(2×C),20.92.ESI-MS:m/z 435.4(M+1),457.3(M+23).C21H26N2O6S[434.15].
中间体I-d选用3,4,5-三(苄氧基)-N-(1-((4-甲氧基苯基)磺酰基)哌啶-4-基)苯甲酰胺(I-d-23)反应制得3,4,5-三羟基-N-(1-((4-甲氧基苯基)磺酰基)哌啶-4-基)苯甲酰胺(I-23)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,得灰色固体。收率:56.6%, mp:245-247℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.01(s,2H,2×OH),8.72(s,1H,OH),7.92(d,J=7.7Hz,1H,NH),7.68(d,J=8.4Hz,2H,Ph-H),7.16(d,J=8.4Hz,2H,Ph-H),6.78(s,2H,Ph-H),3.86(s,3H,CH,CH2),3.59(d,J=12.1Hz,3H,CH3),3.17(d,J=3.6Hz,2H,CH2), 2.31(t,J=11.5Hz,2H,CH2),1.86-1.74(m,2H,CH2),1.56(d,J=11.1Hz,1H,CH).13CNMR (100MHz,DMSO-d6,ppm)δ:166.35(C=O),163.11,145.82(2×C),136.59,130.06(2×C),127.58, 125.38,114.99(2×C),107.34(2×C),56.17,49.05,45.76(2×C),31.07(2×C).ESI-MS:m/z 423.3 (M+1),445.4(M+23).C19H22N2O7S[422.11].
中间体I-d选用N-(1-((2-乙酰氨基-4-甲基噻唑-5-基)磺酰基)哌啶-4-基)-3,4,5- 三(苄氧基)苯甲酰胺(I-d-24)反应制得N-(1-((2-乙酰氨基-4-甲基噻唑-5-基)磺酰基) 哌啶-4-基)-3,4,5-三羟基苯甲酰胺(I-24)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,得灰色固体,再用乙酸乙酯超声,过滤,滤液蒸干,得浅灰色固体。收率:45.3%,mp: 267-268℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:12.62(s,1H,NH),9.00(s,2H,2×OH),8.64(s,1H,OH),7.94(d,J=7.8Hz,1H,NH),6.80(s,2H,Ph-H),3.75(d,J=9.9Hz,1H,CH),3.63(d,J=11.3Hz,2H,CH2),2.69-2.58(m,2H,CH2),2.53-2.50(m,3H,CH3),2.18(s,3H,CH3), 1.85(d,J=12.6Hz,2H,CH2),1.57(d,J=12.6Hz,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:169.98(C=O),166.37(C=O),159.79,152.97,145.80(2×C),136.59,125.34,107.27(2×C), 45.85,45.67(2×C),31.09(2×C),22.85,16.97.ESI-MS:m/z 471.4(M+1),493.4(M+23). C18H22N4O7S2[470.09].
实施例5:中间体4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-1-甲酸叔丁酯(II-b)的制备
称取3,4,5-三苄氧基苯甲酸(2.0g,4.5mmol)置于250mL烧瓶中,加入50mL DMF溶解,冰浴搅拌条件下加入EDCI(0.96g,5.0mmol),HOBT(0.67g,5.0mmol),三乙胺(1.3 mL,10mmol),搅拌15分钟后撤走冰浴,室温搅拌1小时。最后向烧瓶中加入1-Boc-哌嗪(1.015g,5.4mmol),反应12小时。加入100mL水,乙酸乙酯萃取三次(3×50mL),合并有机相,依次用稀盐酸水溶液和饱和碳酸氢钠溶液分别洗涤2-3次,最后饱和氯化钠溶液洗涤。有机相置于锥形瓶中,加入适量的无水硫酸钠,搅拌干燥数小时后,过滤,滤液减压浓缩后,加入适量硅胶,蒸干。湿法装柱,干法上样,乙酸乙酯:石油醚=1:3进行洗脱,得白色固体II-b。收率:83.5%,mp:132-133℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:7.45(d,J=6.9Hz,4H,Ph-H),7.43-7.37 (m,6H,Ph-H),7.37-7.31(m,2H,Ph-H),7.28(dd,J=5.2,1.9Hz,3H,Ph-H),6.80(s,2H,Ph-H), 5.17(s,4H,2×CH2),5.00(s,2H,CH2),1.42(s,9H,3×CH3).13C NMR(100MHz,DMSO-d6,ppm) δ:169.12(C=O),154.26(C=O),152.43,138.53,138.03,137.36,131.36,128.88,128.64,128.53, 128.30,128.02,106.69,79.66,74.76,70.58,28.50(CH3).ESI-MS:m/z609.3(M+1). C37H40N2O6[608.29].
实施例6:哌嗪-1-基(3,4,5-三(苄氧基)苯基)甲酮(II-c)的制备
将中间体II-b置于烧瓶中,搅拌下逐渐加入4mol/L的盐酸/乙酸乙酯溶液至溶液变澄清,室温反应6个小时。反应液减压浓缩,加水50mL,搅拌下滴加饱和碳酸氢钠溶液,调节pH 至近中性,加二氯甲烷萃取(3×50mL),合并有机相,蒸干得浅黄色黏性固体II-c粗品,不经纯化,直接投下步反应。收率:88.1%,mp:85-87℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:7.45(d,J=6.9Hz,5H,Ph-H),7.42-7.36 (m,5H,Ph-H),7.36-7.23(m,5H,Ph-H),6.74(s,2H,Ph-H),5.16(s,4H,2×CH2),4.99(s,2H, CH2).ESI-MS:m/z509.4(M+1),531.3(M+23).C32H32N2O4[508.24].
实施例7:制备中间体II-d的通法
称取中间体II-c(0.20g,0.39mmol,1eq.)加入到25mL烧瓶中,加入8mL二氯甲烷溶解,冰浴搅拌下向反应瓶中加入三乙胺(2eq.)和相应的酰氯取代基(1.2-1.5eq.),冰浴下搅拌15分钟,室温反应12个小时。
反应完成后,将反应液蒸干,乙酸乙酯/石油醚柱层析或用乙酸乙酯超声洗涤后投下一步反应。以II-5中间体(4-(甲基磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮II-d-5 为例。
称取中间体II-c(0.21g,0.42mmol)加入到25mL烧瓶中,加入8mL二氯甲烷溶解,冰浴下向反应瓶中加入三乙胺(117μL,0.84mmol)和甲基磺酰氯(72mg,0.63mmol),室温搅拌12个小时。反应完成后,将反应液蒸干,得油状物,二氯甲烷溶解,干法上样,乙酸乙酯:石油醚=1:1进行洗脱,分得白色固体II-d-5。收率:77.2%,mp:134-135℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:7.49-7.43(m,4H,Ph-H),7.43-7.37(m,6H,Ph-H),7.37-7.31(m,2H,Ph-H),7.28(dd,J=5.2,1.9Hz,3H,Ph-H),6.81(s,2H,Ph-H),5.17 (s,4H,2×CH2),5.00(s,2H,CH2),2.91(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:169.10(C=O),152.51,138.65,138.00,137.31,131.10,128.90,128.65,128.54,128.34,128.32, 128.04,106.73,74.76,70.66,45.75,34.64.ESI-MS:m/z587.3(M+1),609.2(M+23).C33H34N2O6S [586.21].
实施例8:3,4,5-三羟基苯甲酸衍生物II-(1-27)的制备
称取不同的中间体II-d约0.1g至烧瓶中,加入适量二氯甲烷/甲醇(1:1)溶解,加两倍量的10%钯碳。反应体系通氢气,室温反应24小时。将反应液用硅藻土过滤,滤液蒸干,用二氯甲烷或乙酸乙酯洗涤所得固体或进行重结晶,得到目标产物。
中间体II-d选用II-d-1即4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-1-甲酸叔丁酯(II-b) 反应制得4-(3,4,5-三羟基苯甲酰基)哌嗪-1-甲酸叔丁酯(II-1)。反应液硅藻土过滤,滤液蒸干,得油状物,用二氯甲烷和正己烷重结晶,得灰色粉末状固体。收率:58.2%,mp: 181-182℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.11(s,2H,2×OH),8.52(s,1H,OH),6.33(s,2H,Ph-H),1.41(s,9H,3×CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:170.05(C=O),154.29(C=O),146.10(2×C),135.24,125.76,107.03(2×C),79.61,28.50(3×CH3).ESI-MS: m/z339.4(M+1),361.3(M+23).C16H22N2O6[338.15].
中间体II-d选用II-d-2即哌嗪-1-基(3,4,5-三(苄氧基)苯基)甲酮(II-c)反应制得哌嗪-1-基(3,4,5-三羟基苯基)甲酮(II-2)。反应液硅藻土过滤,滤液蒸干,依次用二氯甲烷和乙酸乙酯超声洗涤,过滤,得灰色固体。收率:61.0%,mp:75-77℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.23(s,2H,2×OH),8.69(s,1H,OH),6.42(s,2H,Ph-H),3.70(d,J=5.1Hz,4H,2×CH2),3.09(t,J=5.2Hz,4H,2×CH2),1.99(s,1H, NH).13C NMR(100MHz,DMSO-d6,ppm)δ:170.18(C=O),146.21(2×C),135.55,124.86,107.26 (2×C),60.23,43.00,21.24,14.56.ESI-MS:m/z239.3(M+1),261.2(M+23).C11H14N2O4[238.10].
中间体II-d选用1-(4-(3,4,5-三(苯甲氧基)苯甲酰基)哌嗪-1-基)乙酮(II-d-3)反应制得1-(4-(3,4,5-三羟基苯甲酰基)哌嗪-1-基)乙酮(II-3)。反应液硅藻土过滤,滤液蒸干,用二氯甲烷超声,过滤,乙酸乙酯洗涤,乙酸乙酯相蒸干,得灰色固体。收率:40.7%,mp:178-179℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.13(s,2H,2×OH),8.53(s,1H,OH),6.36(d,J=12.8Hz,2H,Ph-H),2.01(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm)δ: 170.09(C=O),168.94(C=O),150.59,146.11,135.25,125.74,107.02,106.35,46.12(4×C),21.74.ESI-MS:m/z281.3(M+1),303.4(M+23).C13H16N2O5[280.11].
中间体II-d选用N,N-二甲基-4-(3,4,5-三(苯甲氧基)苯甲酰基)哌嗪-1-甲酰胺(II-d-4) 反应制得N,N-二甲基-4-(3,4,5-三羟基苯甲酰基)哌嗪-1-甲酰胺(II-4)。反应液硅藻土过滤,滤液蒸干,用二氯甲烷超声,过滤,得灰色固体。收率:56.6%,mp:122-123℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.13(s,2H,2×OH),8.55(s,1H,OH),6.34(s,2H,Ph-H),3.47(s,4H,2×CH2),3.11(d,J=5.2Hz,4H,2×CH2),2.75(s,6H,2×CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:170.01(C=O),164.05(C=O),146.13(2×C),135.16,125.89, 107.04(2×C),55.39(2×C),47.00(2×C),38.46(2×C).ESI-MS:m/z310.4(M+1),332.3(M+23). C14H19N3O5[309.13].
中间体II-d选用(4-(甲基磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-5) 反应制得(4-(甲基磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-5)。反应液硅藻土过滤,滤液蒸干,依次用二氯甲烷和乙酸乙酯超声洗涤,过滤,得灰色固体。收率:52.3%,mp: 238-239℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.15(s,2H,2×OH),8.59(s,1H,OH),6.35(s,2H,Ph-H),3.57(s,4H,2×CH2),3.11(s,4H,2×CH2),2.90(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:170.05(C=O),146.16(2×C),135.34,125.50,107.06(2×C),45.93(2×C), 34.45(2×C).ESI-MS:m/z317.3(M+1),339.3(M+23).C12H16N2O6S[316.07].
中间体II-d选用(4-(乙基磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-6) 反应制得(4-(乙基磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-6)。反应液硅藻土过滤,滤液蒸干,用乙酸乙酯超声洗涤,过滤,得灰色固体。收率:49.9%,mp:205-206℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.16(s,2H,2×OH),8.60(s,1H,OH),6.35(s,2H,Ph-H),3.54(s,4H,2×CH2),3.18(t,J=5.0Hz,4H,2×CH2),3.08(q,J=7.2Hz,2H, CH2),1.21(t,J=7.3Hz,3H,CH3).ESI-MS:m/z331.3(M+1),353.3(M+23).C13H18N2O6S[330.09].
中间体II-d选用(4-(丙基磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-7) 反应制得(4-(丙基磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-7)。反应液硅藻土过滤,滤液蒸干,用乙酸乙酯和正己烷重结晶,得灰色固体。收率:43.4%,mp:112-113℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.14(s,2H,2×OH),8.63(s,1H,OH),6.35(s,2H,Ph-H),3.54(s,4H,2×CH2),3.17(t,J=4.8Hz,4H,2×CH2),3.03(t,J=7.7Hz,2H, CH2),1.69(q,J=7.5Hz,2H,CH2),0.98(t,J=7.4Hz,3H,CH3).13C NMR(100MHz,DMSO-d6) δ:170.06(C=O),146.15(2×C),135.31,125.55,107.06(2×C),49.66(2×C),45.75,16.79,13.31. ESI-MS:m/z345.3(M+1),367.2(M+23).C14H20N2O6S[344.10].
中间体II-d选用N,N-二甲基-4-(3,4,5-三(苯甲氧基)苯甲酰基)哌嗪-1-磺酰胺(II-d-8) 反应制得N,N-二甲基-4-(3,4,5-三羟基苯甲酰基)哌嗪-1-磺酰胺(II-8)。反应液硅藻土过滤,滤液蒸干,用乙酸乙酯超声洗涤,过滤,得灰色固体。收率:63.7%,mp:232-233℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.15(s,2H,2×OH),8.58(s,1H,OH),6.35 (s,2H,Ph-H),3.52(s,4H,2×CH2),3.17(t,J=4.7Hz,4H,2×CH2),2.78(s,6H,2×CH3).13C NMR (100MHz,DMSO-d6,ppm)δ:170.06(C=O),146.15(2×C),135.29,125.52,107.09(2×C),46.60 (4×C),38.34(2×C).ESI-MS:m/z346.2(M+1),368.2(M+23).C13H19N3O6S[345.10].
中间体II-d选用(4-苯甲酰基哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-9)反应制得(4-苯甲酰基哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-9)。反应液硅藻土过滤,滤液蒸干,二氯甲烷、乙酸乙酯依次超声过滤,得灰色固体。收率:53.3%,mp:253-256℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.16(s,2H,2×OH),8.60(s,1H,OH),7.45(tt,J=9.2,5.7Hz,5H,Ph-H),6.37(s,2H,Ph-H),3.53(s,8H,4×CH2).13C NMR(100MHz, DMSO-d6,ppm)δ:170.12(C=O),169.66(C=O),146.15(2×C),136.13,135.30,130.10,128.90 (2×C),127.48(2×C),125.64,107.14(2×C).ESI-MS:m/z343.4(M+1),365.3(M+23).C18H18N2O5 [342.12].
中间体II-d选用(4-(4-氟苯甲酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-10) 反应制得(4-(4-氟苯甲酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-10)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声过滤,得灰色固体。收率:50.9%,mp:256-257℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.15(s,2H,2×OH),8.59(s,1H,OH),7.50(dd,J=8.4,5.4Hz,2H,Ph-H),7.28(t,J=8.7Hz,2H,Ph-H),6.36(s,2H,Ph-H),3.43(d,J =72.6Hz,10H,4×CH2,H2O).13C NMR(100MHz,DMSO-d6,ppm)δ170.15(C=O),168.78(C=O), 163.05(d,J=246.7Hz),146.17(2×C),135.29,132.51,130.14(2×C,d,J=8Hz),125.64,115.87 (2×C,d,J=21Hz),107.18(2×C).ESI-MS:m/z361.3(M+1),383.3(M+23).C18H17FN2O5 [360.11].
中间体II-d选用(4-(4-甲基苯甲酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-11) 反应制得(4-(4-甲基苯甲酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-11)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,得灰色固体。收率:55.1%,mp:235-236℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.11(s,2H,2×OH),8.52(s,1H,OH),7.32(d,J=7.8Hz,2H,Ph-H),7.25(d,J=7.8Hz,2H,Ph-H),6.35(s,2H,Ph-H),3.51(s,8H,4×CH2),2.34(s,3H,CH3).ESI-MS:m/z357.3(M+1),379.3(M+23).C19H20N2O5[356.14].
中间体II-d选用(4-(4-硝基苯甲酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-12) 反应制得(4-(4-氨基苯甲酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-12)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,得灰色固体。收率:47.2%,mp:150-152℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.11(s,2H,2×OH),8.51(s,1H,OH),7.15(d,J=8.1Hz,2H,Ph-H),6.58–6.50(m,2H,Ph-H),6.35(s,2H,Ph-H),5.54(s,2H,NH2),3.50(s,8H,4×CH2).13C NMR(100MHz,DMSO-d6)δ:170.52(C=O),170.08(C=O),150.98,146.14(2×C),135.23,129.85(2×C),125.74,122.00,113.20(2×C),107.13(2×C).ESI-MS: m/z358.3(M+1),380.4(M+23).C18H19N3O5[357.13].
中间体II-d选用4-(4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-1-羰基)苯甲酸甲酯(II-d-13) 反应制得4-(4-(3,4,5-三羟基苯甲酰基)哌嗪-1-羰基)苯甲酸甲酯(II-13)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,得灰色固体。收率:49.7%,mp:140-141℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.14(s,2H,2×OH),8.66(s,1H,OH),8.02(d,J=7.9Hz,2H,Ph-H),7.57(d,J=7.9Hz,2H,Ph-H),6.36(s,2H,Ph-H),3.88(s,3H,CH3),3.74-3.41(m,8H,4×CH2).ESI-MS:m/z401.4(M+1),423.3(M+23).C20H20N2O7[400.13].
中间体II-d选用(4-(4-甲氧基苯甲酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-14)反应制得(4-(4-甲氧基苯甲酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-14)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,滤液蒸干,正己烷洗涤,得浅灰色固体。收率:50.9%,mp:127-128℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.13(s,2H,2×OH),8.54(s,1H,OH),7.40(d,J=8.3Hz,2H,Ph-H),6.99(d,J=8.4Hz,2H,Ph-H),6.35(s,2H,Ph-H),3.79(s,3H,CH3),3.52(s,8H,4×CH2).ESI-MS:m/z373.2(M+1),395.2(M+23).C19H20N2O6[372.13].
中间体II-d选用(4-(3-甲氧基苯甲酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮 (II-d-15)反应制得(4-(3-甲氧基苯甲酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-15)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,滤液蒸干,正己烷洗涤,得白色固体。收率:46.9%,mp:82-83℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.14(s,2H,2×OH),8.56(s,1H,OH),7.36(s,1H,Ph-H),7.12-6.87(m,3H,Ph-H),6.36(s,2H,Ph-H),3.78(s,3H,CH3),3.53(s,8H, 4×CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:170.12(C=O),169.34(C=O),159.55,146.13 (2×C),137.53,135.30,130.14,125.63,119.40,115.77,112.74,107.11(2×C),55.70,45.86(4×C). ESI-MS:m/z373.2(M+1),395.2(M+23).C19H20N2O6[372.13].
中间体II-d选用(4-(2-甲氧基苯甲酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮 (II-d-16)反应制得(4-(2-甲氧基苯甲酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-16)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,滤液蒸干,二氯甲烷洗涤,得白色固体。收率:51.5%,mp:133-134℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppmδ:9.10(s,2H,2×OH),8.51(s,1H,OH),7.40 (td,J=8.0,7.5,1.8Hz,1H,Ph-H),7.20(dd,J=7.4,1.8Hz,1H,Ph-H),7.08(d,J=8.4Hz,1H, Ph-H),7.00(t,J=7.4Hz,1H,Ph-H),6.35(s,2H,Ph-H),3.80(s,3H,CH3),3.73-3.38(m,6H, 3×CH2),3.15(m,2H,CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:170.09(C=O),167.09(C=O), 155.34,146.11(2×C),135.29,130.96,128.30,125.78,125.66,121.12,111.83,107.09(2×C), 60.22,55.91,46.78(2×C).ESI-MS:m/z373.2(M+1),395.2(M+23).C19H20N2O6[372.13].
中间体II-d选用(4-(苯基磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-17) 反应制得(4-(苯基磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-17)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,滤液蒸干,乙酸乙酯洗涤,乙酸乙酯相蒸干,乙酸乙酯和正己烷重结晶,得白色固体。收率:56.4%,mp:60-62℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.10(s,2H,2×OH),8.55(s,1H,OH),7.79-7.72(m,3H,Ph-H),7.71-7.64(m,2H,Ph-H),6.24(s,2H,Ph-H),3.54(t,J=4.8Hz,4H,2×CH2),2.91(d,J=4.9Hz,4H,2×CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:170.14(C=O),146.10(2×C),135.38,135.26,133.91,130.01(2×C),127.99(2×C),125.21,107.01(2×C),46.40 (2×C),45.89(2×C).ESI-MS:m/z379.3(M+1),401.4(M+23).C17H18N2O6S[378.09].
中间体II-d选用(4-((4-氟苯基)磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-18)反应制得(4-((4-氟苯基)磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-18)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,滤液蒸干,得浅灰色固体。收率:50.0%, mp:130-131℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.12(s,2H,2×OH),8.56(s,1H,OH),7.82(dd,J=8.6,5.1Hz,2H,Ph-H),7.51(t,J=8.6Hz,2H,Ph-H),6.26(s,2H,Ph-H),3.55(t,J= 4.9Hz,4H,2×CH2),2.93(d,J=5.0Hz,4H,2×CH2).13C NMR(100MHz,DMSO-d6,ppm)δ: 170.10(C=O),165.21(d,J=250Hz),146.10(2×C),135.36,131.75,131.11(2×C,d,J=10Hz), 125.27,117.24(2×C,d,J=23Hz),107.03(2×C),46.33(2×C),45.94(2×C).ESI-MS:m/z397.3 (M+1),419.3(M+23).C17H17FN2O6S[396.08].
中间体II-d选用((4-甲苯磺酰基哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-19) 反应制得(4-甲苯磺酰基哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-19)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,滤液蒸干,乙酸乙酯洗涤,乙酸乙酯相蒸干,得白色固体。收率:58.7%,mp:69-71℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.15(s,2H,2×OH),8.58(s,1H,OH),7.62(d,J=7.7Hz,2H,Ph-H),7.47(d,J=7.9Hz,2H,Ph-H),6.25(s,2H,Ph-H),3.06(q,J=7.3 Hz,4H,2×CH2),2.96-2.76(m,4H,2×CH2),2.42(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:170.13(C=O),146.10(2×C),144.35,135.38,132.27,130.45(2×C),128.05(2×C), 125.19,107.02(2×C),46.40(2×C),45.88(2×C),21.52.ESI-MS:m/z393.2(M+1),415.3(M+23). C18H20N2O6S[392.10].
中间体II-d选用(4-(间甲苯基磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-20) 反应制得(4-(M-甲苯基磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-20)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,滤液蒸干,乙酸乙酯超声,过滤,得灰色固体。收率:60.3%,mp:193-194℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.11(s,2H,2×OH),8.54(s,1H,OH),7.55(s,4H,Ph-H),6.25(s,2H,Ph-H),3.55(s,4H,2×CH2),2.90(s,4H,2×CH2),2.43(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:170.10(C=O),146.08(2×C),139.85,135.39,135.17,134.53,129.81,128.13,125.20,125.17,107.01(2×C),46.41(4×C),21.32.ESI-MS: m/z393.2(M+1),415.3(M+23).C18H20N2O6S[392.10].
中间体II-d选用(4-((4-(叔丁基)苯基)磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-21)反应制得(4-((4-(叔丁基)苯基)磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-21)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,滤液蒸干,正己烷洗涤,得灰色固体。收率:61.5%,mp:87-88℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.11(s,2H,2×OH),8.55(s,1H,OH),7.67(s,4H,Ph-H),6.26(s,2H,Ph-H),3.55(t,J=4.9Hz,4H,2×CH2),2.91(t,J=4.9Hz,4H, 2×CH2),1.32(s,9H,3×CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:170.10(C=O),156.84,146.09(2×C),135.40,132.58,127.95(2×C),126.82(2×C),125.20,107.06(2×C),46.36(2×C), 45.98(2×C),35.43,31.23(3×C).ESI-MS:m/z435.4(M+1),457.3(M+23).C21H26N2O6S[434.15].
中间体II-d选用(4-((3,5-二甲基苯基)磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-22)反应制得(4-((3,5-二甲基苯基)磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-22)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,滤液蒸干,二氯甲烷和正己烷重结晶,得灰色固体。收率:59.9%,mp:78-79℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.12(s,2H,2×OH),8.57(s,1H,OH),7.37(s,1H,Ph-H),7.34(s,2H,Ph-H),6.26(s,2H,Ph-H),3.55(t,J=4.9Hz,4H,2×CH2),2.89(t, J=4.9Hz,4H,2×CH2),2.38(s,6H,2×CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:170.09(C=O),146.09(2×C),139.58(2×C),135.40,135.24,135.09,125.40(2×C),125.19,107.07 (2×C),46.42(2×C),45.93(2×C),21.22(2×C).ESI-MS:m/z407.4(M+1),429.4(M+23). C19H22N2O6S[406.12].
中间体II-d选用(4-(2,4,6-三甲基苯磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-23)反应制得(4-(2,4,6-三甲基苯磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-23)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,滤液蒸干,二氯甲烷洗涤,得白色固体。收率:57.7%,mp:127-128℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.13(s,2H,2×OH),8.54(s,1H,OH),7.10(s,2H,Ph-H),6.32(s,2H,Ph-H),3.58-3.43(m,4H,2×CH2),3.05(t,J=5.0Hz,4H,2×CH2), 2.55(s,6H,2×CH3),2.28(s,3H,CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:170.09(C=O), 146.13(2×C),143.20,140.26(2×C),135.36,132.43(2×C),131.45,125.40,107.07(2×C),44.61 (4×C),22.91(2×C),20.93.ESI-MS:m/z421.3(M+1),443.4(M+23).C20H24N2O6S[420.14].
中间体II-d选用(4-((2,4,6-三异丙基)磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-24)反应制得(3,4,5-三羟基苯基)(4-((2,4,6-三异丙基)磺酰基)哌嗪-1- 基)甲酮(II-24)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,得灰色固体。收率:52.1%,mp:272-273℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.14(s,2H,2×OH),8.57(s,1H,OH),7.30(s,2H,Ph-H),6.35(s,2H,Ph-H),4.15-3.99(m,2H,2×CH),3.50(d,J=6.1Hz,4H,2×CH2), 3.07(t,J=4.9Hz,4H,2×CH2),3.00-2.86(m,1H,CH),1.21(dd,J=6.9,2.8Hz,18H,6×CH3).13C NMR(100MHz,DMSO-d6,ppm)δ:170.17(C=O),153.80,151.67(2×C),146.15(2×C),135.38, 129.83,125.37,124.45(2×C),107.12(4×C),44.37(2×C),33.85,29.29(2×C),25.04(2×C),23.82 (4×C).ESI-MS:m/z505.4(M+1),527.4(M+23).C26H36N2O6S[504.23].
中间体II-d选用(4-((4-硝基苯基)磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基)甲酮(II-d-25)反应制得(4-((4-氨基苯基)磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基)甲酮(II-25)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,得灰色固体。收率:50.9%,mp:156-157℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.12(s,2H,2×OH),8.56(s,1H,OH),7.35(d,J=8.2Hz,2H,Ph-H),6.66(d,J=8.3Hz,2H,Ph-H),6.26(s,2H,Ph-H),6.15(s,2H,NH2),3.53(d,J=5.9Hz,4H,2×CH2),2.80(t,J=5.0Hz,4H,2×CH2).13C NMR(100MHz,DMSO-d6)δ:170.14(C=O),153.84,146.12(2×C),135.34,130.06(2×C),125.30,119.38,113.22 (2×C),106.99(2×C),55.41(2×C),46.45(2×C).ESI-MS:m/z394.2(M+1),416.3(M+23). C17H19N3O6S[393.10].
中间体II-d选用N-(4-((4-(3,4,5-三(苯甲氧基)苯甲酰基)哌嗪-1-基)磺酰基)苯基)乙酰胺(II-d-26)反应制得N-(4-((4-(3,4,5-三羟基苯甲酰基)哌嗪-1-基)磺酰基)苯基)乙酰胺(II-26)。反应液硅藻土过滤,滤液蒸干,二氯甲烷超声,过滤,滤饼再经乙酸乙酯超声,乙酸乙酯相蒸干,得白色固体。收率:51.6%,mp:160-161℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:10.41(s,1H,NH),9.08(s,2H,2×OH),8.50(s,1H,OH),7.84(d,J=8.4Hz,2H,Ph-H),7.68(d,J=8.4Hz,2H,Ph-H),6.25(s,2H,Ph-H),3.54(t,J=4.8Hz,4H,2×CH2),2.88(t,J=4.8Hz,4H,2×CH2),2.10(s,3H,CH3).13CNMR(100MHz,DMSO-d6,ppm)δ:170.12(C=O),169.61(C=O),146.09(2×C),144.10,135.37, 129.29(2×C),128.62,125.25,119.16(2×C),106.99(2×C),46.39(4×C),24.64.ESI-MS:m/z436.3 (M+1),458.3(M+23).C19H21N3O7S[435.11].
中间体II-d选用(4-((4-甲氧基苯基)磺酰基)哌嗪-1-基)(3,4,5-三(苄氧基)苯基) 甲酮(II-d-27)反应制得(4-((4-甲氧基苯基)磺酰基)哌嗪-1-基)(3,4,5-三羟基苯基) 甲酮(II-27)。反应液硅藻土过滤,滤液蒸干,乙酸乙酯超声,过滤,滤液蒸干,少量甲醇洗涤,得白色固体。收率:47.7%,mp:217-218℃。
波谱数据:1H NMR(400MHz,DMSO-d6,ppm)δ:9.11(s,2H,2×OH),8.54(s,1H,OH),7.76-7.58(m,2H,Ph-H),7.26-7.05(m,2H,Ph-H),6.24(s,2H,Ph-H),3.87(s,3H,CH3),3.61-3.46(m,4H,2×CH2),2.87(d,J=4.9Hz,4H,2×CH2).13C NMR(100MHz,DMSO-d6,ppm)δ:170.10(C=O),163.33,146.09(2×C),135.37,130.26(2×C),126.66,125.23,115.12(2×C), 106.99(2×C),56.20,46.40(4×C).ESI-MS:m/z409.3(M+1),431.2(M+23).C18H20N2O7S [408.10].
实施例9:核糖核酸酶H(RNase H)抑制活性测试
实验原理
采用变性聚丙烯酰胺凝胶电泳法测试RNase H靶点抑制活性,通过检测32P标记的RNA 链的裂解情况反映化合物抑制活性。标记方法是利用[γ-32P]ATP在T4多聚核苷酸激酶催化下标记RNA5’末端。31T-RNA为模板RNA,21P为引物DNA,前者被32P标记,逆转录酶催化杂合链的水解,抑制剂(需提前与逆转录酶孵育)存在下水解作用则被抑制。变性聚丙烯酰胺凝胶电泳检测相应的裂解产物,其斑点越淡,可认为抑制效果越强。
实验材料:
由大肠杆菌表达并经纯化的野生型HIV-1BH10逆转录酶;合成寡核苷酸31-nt RNA(31T-RNA;5′-UUUUUUUUUAGGAUACAUAUGGUUAAAGUAU-3′)和21-nt DNA primer (21P;5′-ATACTTTAACCATATGTATCC-3′)购自Sigma;阳性对照β-thujaplicinol购自上海毕得医药科技有限公司。
实验步骤:
使用模板-引物31T-RNA/21P测定RNase H活性。模板RNA在其5'末端用[γ-32P]ATP(Perkin Elmer)和T4多聚核苷酸激酶(New England Biolabs)标记,然后使用小型快速旋转柱(Roche)进行纯化。将标记好的模板在含有50mM NaCl的50mM Tris-HCl(pH8.0) 中退火到21个核苷酸的引物(21P)。其中,引物较模板来说是过量的,最终制得浓度为500 nM的模板-引物。将样品在95℃孵育4分钟,然后缓慢冷却至室温。RNase H裂解试验利用20-40nMHIV-1RT(活性位点浓度)在30μL含50mM Tris-HCl(pH8.0)、50mM NaCl、 5mM MgCl2、25nM32P标记的模板-引物(31T-RNA/21P)和5%二甲基亚砜(DMSO)的培养液中孵育0-4分钟(37℃)。待测的潜在RNase H抑制剂用50%DMSO溶解,适当稀释配成一定的浓度梯度。将这些待测样品在试验缓冲液中与RT预孵育5分钟(37℃),然后通过加入标记的模板-引物开始反应。在适当的时间(反应时间点分别为0、0.25、0.5、1、2、3 和4分钟)取出等分试样并用等体积的上样缓冲液[10mM EDTA的90%甲酰胺,含有二甲苯蓝FF(3mg/mL)和溴酚蓝(3mg/mL)]淬火,并通过变性聚丙烯酰胺凝胶电泳进行分析。空白及阳性对照组实验,同样操作,在0、1、2和4分钟时取出等分试样测试。
实验结果:
对本发明的51个化合物(系列I和II)分别进行抗HIV-1RNase H活性筛选,其HIV-1RNase H抑制活性数据分别见表1和表2。阳性对照药为β-thujaplicinol。
表1系列I目标化合物对野生型HIV-1RNase H的抑制活性
表2系列II目标化合物对野生型HIV-1RNase H的抑制活性
如表1所示,系列I目标化合物中有6个化合物对野生型HIV-1RNase H表现出较弱的抑制活性。表2中系列II目标化合物与系列I相比,HIV-1RNase H抑制活性有了大幅度的提高(约10倍),而且绝大多数的化合物活性均优于阳性对照。其中,14个化合物的IC50值达到亚微摩尔水平,尤其以化合物II-25的活性最高(IC50=0.72±0.07μM),约为阳性对照的2.8倍。
实施例10:逆转录酶(RT)活性测试
实验原理:实验中RT以poly(A)作为模板,以oligo(dT)15为引物,以生物素(Biotin) 及地高辛(Digoxin,DIG)标记的dNTPs为底物,逆转录合成DNA。将新生的DNA/RNA杂合链结合到链霉素亲和素包被的微孔板(Streptavidin-coated MTP)表面,再与过氧化物酶 (Peroxidase,POD)偶联的地高辛抗体(Anti-DIG)结合。然后,加入POD底物ABTS (2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate)),ABTS即在POD作用下产生颜色反应,最后用酶标仪在特定波长下测定其吸光值(一定浓度范围内,吸光值与RT活性呈线性相关),计算即可得出相应的RT半数抑制浓度(IC50值)。
实验材料:
逆转录酶试剂盒(Recombinant HIV-1RT kit,Roche),微量加样枪,EP管,待测化合物,阳性对照药物依法韦仑(Efavirenz,EFV)和奈韦拉平(Nevirapine,NVP),双蒸水,DMSO。
实验方法:
实验操作操作流程大致如下:将待测样品和阳性对照用DMSO溶解,再用裂解缓冲液 (lysis buffer)分别稀释至5个浓度梯度。冷冻干燥的重组逆转录酶用微量三蒸水复溶,再用lysis buffer稀释至0.2ng/μL溶液并冰盒保存。冷冻干燥的模板用三蒸水稀释,核苷底物用孵育缓冲液溶解,再将二者按说明制成一定浓度的模板底物混合反应液。三蒸水将抗地高辛超氧化物酶(anti-DIG-POD)溶解并稀释制成anti-DIG-POD工作溶液。ABTS用底物缓冲液(substrate buffer)溶解,临用前恢复至室温。样品溶液,酶溶液和模板底物的混合反应液各取20μL混合,37℃孵育1小时后,转移到特制微孔板上,孵育一小时。将反应混合液弃掉并洗涤,再加入anti-DIG-POD工作溶液37℃孵育1小时。弃掉反应液并洗涤后,加入ABTS 溶液室温反应至呈显淡绿色,立即用酶标仪在405nm(参比波长为490nm)波长下每隔5分钟记录每个孔的吸光度。
抑制率计算:据公式抑制率%=[阴性对照孔O.D.值(有RT无抑制剂)-抑制剂孔O.D.值 (有RT和抑制剂)]/[阴性对照孔O.D.值(有RT无抑制剂)-空白孔O.D.值[无抑制剂,无 RT])×100%。计算出在不同浓度下样品对逆转录酶的抑制率,并将浓度和相应的抑制率做线性回归,根据回归方程算出抑制率为50%下对应的样品(化合物或阳性药)浓度,即IC50值。
实验结果:
对本发明的部分化合物(25个)进行抗HIV-1逆转录酶(聚合酶)活性筛选,其HIV-1逆转录酶抑制活性数据见表3。阳性对照药为依法韦仑(Efavirenz,EFV)和奈韦拉平(Nevirapine,NVP)。
表3目标化合物对野生型HIV-1R(聚合酶)T的抑制活性
如表3所示,在测试化合物中,只有4个化合物对HIV-1RT(聚合酶)表现出较弱的抑制活性(<100μM)。系列I中RNase H抑制活性最好的化合物I-5(RNase H IC50=10.6± 1.4μM),相对于RT表现出较高的选择性(IC50≥293.3μM);化合物I-16对RT(聚合酶) 抑制活性最高(IC50=39.9±2.3μM),但仍远低于其RNase H抑制活性(IC50=13.1±3.2μM)。系列II的化合物II-1同样表现出较高的选择性,对RNase H和RT(聚合酶)的IC50值分别为1.11±0.35μM和>354.7μM。由此可以推断,本文所设计的多酚类化合物属于结构新颖的选择性RNase H抑制剂。
Claims (5)
1.3,4,5-三羟基苯甲酸衍生物,其特征在于,具有如下通式I或II所示的结构:
其中,
R1为乙酰基、甲基磺酰基、乙基磺酰基、N,N-二甲胺基甲酰基、N,N-二甲胺基磺酰基、丙二酸单乙酯酰基、苯甲酰基、对氟苯甲酰基、对甲基苯甲酰基、对氨基苯甲酰基、对苯二甲酸单甲酯酰基、对甲氧基苯甲酰基、间甲氧基苯甲酰基、邻甲氧基苯甲酰基、苯磺酰基、对氟苯磺酰基、对甲苯磺酰基、对叔丁基苯磺酰基、3,5-二甲基苯磺酰基、2,4,6-三甲基苯磺酰基、对甲氧基苯磺酰基、2-乙酰胺基-4-甲基噻唑-5-磺酰基;
R2为乙酰基、N,N-二甲胺基甲酰基、甲基磺酰基、乙基磺酰基、丙基磺酰基、N,N-二甲胺基甲磺酰基、苯甲酰基、对氟苯甲酰基、对甲基苯甲酰基、对氨基苯甲酰基、对苯二甲酸单甲酯酰基、对甲氧基苯甲酰基、间甲氧基苯甲酰基、邻甲氧基苯甲酰基、苯磺酰基、对氟苯磺酰基、对甲苯磺酰基、间甲苯磺酰基、对叔丁基苯磺酰基、3,5-二甲基苯磺酰基、2,4,6-三甲基苯磺酰基、2,4,6-三异丙基苯磺酰基、对氨基苯磺酰基、对乙酰氨基苯磺酰基、对甲氧基苯磺酰基。
2.3,4,5-三羟基苯甲酸衍生物的制备方法,其特征在于,步骤包括:
以3,4,5-三苄氧基苯甲酸为原料,与1-Boc-4-氨基哌啶或1-Boc-哌嗪经酰化反应制得中间体I-b或II-b,利用盐酸的乙酸乙酯溶液将Boc脱去得到中间体I-c或II-c,相应的酰氯或磺酰氯对I-c或II-c进行亲核取代反应得到关键中间体哌啶胺衍生物I-d(3-24)或哌嗪衍生物II-d(3-27),最后在氢气,钯碳条件下脱去三个苄基制得目标化合物I-e(3-24)或II-e(3-27);
中间体I-b、II-b、I-c、II-c及目标化合物I-e(3-24)、II-e(3-27)的结构式如下:
所述的I-d(3-24)是相应目标化合物I-e(3-24)结构中的三个酚羟基被苄基保护的中间体化合物;II-d(3-27)是相应目标目标II-e(3-27)结构中的三个酚羟基被苄基保护的中间体化合物。
3.如权利要求2所述的3,4,5-三羟基苯甲酸衍生物的制备方法,其特征在于,合成路线为如下之一:
路线1:
反应试剂与反应条件:i)1-Boc-4-氨基哌啶,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,1-羟基苯并***,三乙胺,N,N-二甲基甲酰胺,室温,12h;ii)盐酸,乙酸乙酯,室温,2h,氢氧化钠水溶液;iii)相应的酰氯或磺酰氯1,三乙胺,二氯甲烷,室温,12h;iv)氢气,钯碳,二氯甲烷与甲醇混合溶液,室温,24h;
其中,R1如权利要求1的通式I中所述;
所述的相应酰氯或磺酰氯1选自:乙酰氯、甲磺酰氯、乙磺酰氯、二甲氨基甲酰氯、二甲胺基磺酰氯、氯甲酰乙酸乙酯、苯甲酰氯、对氟苯甲酰氯、对甲基苯甲酰氯、对硝基苯甲酰氯、4-氯甲酰基苯甲酸甲酯、对甲氧基苯甲酰氯、间甲氧基苯甲酰氯、邻甲氧基苯甲酰氯、苯磺酰氯、对氟苯磺酰氯、对甲苯磺酰氯、对叔丁基苯磺酰氯、3,5-二甲基苯磺酰氯、2,4,6-三甲基苯磺酰氯、对甲氧基苯磺酰氯、2-乙酰胺基-4-甲基噻唑-5-磺酰氯;
路线2:
反应试剂与反应条件:i)1-Boc-哌嗪,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,1-羟基苯并***,三乙胺,N,N-二甲基甲酰胺,室温,12h;ii)盐酸的乙酸乙酯溶液,室温,6h,;iii)相应的酰氯或磺酰氯2,三乙胺,二氯甲烷,室温,12h;iv)氢气,钯碳,二氯甲烷与甲醇混合溶液,室温,24h;
其中,R2如权利要求1的通式II中所述;
所述的相应酰氯或磺酰氯2选自:乙酰氯、二甲氨基甲酰氯、甲磺酰氯、乙磺酰氯、丙磺酰氯、二甲胺基磺酰氯、苯甲酰氯、对氟苯甲酰氯、对甲基苯甲酰氯、对硝基苯甲酰氯、4-氯甲酰基苯甲酸甲酯、对甲氧基苯甲酰氯、间甲氧基苯甲酰氯、邻甲氧基苯甲酰氯、苯磺酰氯、对氟苯磺酰氯、对甲苯磺酰氯、间甲苯磺酰氯、对叔丁基苯磺酰氯、3,5-二甲基苯磺酰氯、2,4,6-三甲基苯磺酰氯、2,4,6-三异丙基苯磺酰氯、对硝基苯磺酰氯、对乙酰氨基苯磺酰氯、对甲氧基苯磺酰氯。
4.如权利要求1所述的3,4,5-三羟基苯甲酸衍生物作为HIV-1RNase H抑制剂在制备抗艾滋病药物中的应用。
5.一种抗HIV药物组合物,其特征在于,含有权利要求1所述的3,4,5-三羟基苯甲酸衍生物或其药学上可接受的盐和一种或多种药学上可接受载体或赋形剂。
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