CN117186089A - 一种四氢咔啉衍生物的制备方法 - Google Patents
一种四氢咔啉衍生物的制备方法 Download PDFInfo
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- CN117186089A CN117186089A CN202310829905.9A CN202310829905A CN117186089A CN 117186089 A CN117186089 A CN 117186089A CN 202310829905 A CN202310829905 A CN 202310829905A CN 117186089 A CN117186089 A CN 117186089A
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- Prior art keywords
- substituted
- alkyl
- unsubstituted
- mmol
- tetrahydrocarboline
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- 238000002360 preparation method Methods 0.000 title abstract description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 98
- -1 primary amine compounds Chemical class 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000006683 Mannich reaction Methods 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 2
- 125000005201 cycloalkylcarbonyloxy group Chemical group 0.000 claims description 2
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 2
- 239000002207 metabolite Substances 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 150000003254 radicals Chemical group 0.000 claims 1
- 125000005504 styryl group Chemical group 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 31
- 230000015572 biosynthetic process Effects 0.000 abstract description 28
- 239000000047 product Substances 0.000 description 35
- 239000007858 starting material Substances 0.000 description 12
- DPNOTFHCABPNQH-UHFFFAOYSA-N 1-benzyl-2-methylindole Chemical compound CC1=CC2=CC=CC=C2N1CC1=CC=CC=C1 DPNOTFHCABPNQH-UHFFFAOYSA-N 0.000 description 11
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- ONJGNGCOSIZSAO-UHFFFAOYSA-N tert-butyl 6-methoxy-3-methylindole-1-carboxylate Chemical compound COC1=CC=C2C(C)=CN(C(=O)OC(C)(C)C)C2=C1 ONJGNGCOSIZSAO-UHFFFAOYSA-N 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 2
- RDMFHRSPDKWERA-UHFFFAOYSA-N 5H-Pyrido[4,3-b]indole Chemical class C1=NC=C2C3=CC=CC=C3NC2=C1 RDMFHRSPDKWERA-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
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- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
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- 239000007864 aqueous solution Substances 0.000 description 2
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- 150000001555 benzenes Chemical group 0.000 description 2
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 2
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
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- 230000002194 synthesizing effect Effects 0.000 description 2
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- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 2
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- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 2
- QXMRXPZMEBBMNW-WCCKRBBISA-N (4s)-4-amino-5-methoxy-5-oxopentanoic acid;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CCC(O)=O QXMRXPZMEBBMNW-WCCKRBBISA-N 0.000 description 1
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- FDEWRHAISTXBET-UHFFFAOYSA-N 1-benzyl-2-methylpyrrolo[2,3-b]pyridine Chemical compound CC1=CC2=CC=CN=C2N1CC1=CC=CC=C1 FDEWRHAISTXBET-UHFFFAOYSA-N 0.000 description 1
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- CJDRUOGAGYHKKD-RQBLFBSQSA-N 1pon08459r Chemical compound CN([C@H]1[C@@]2(C[C@@]3([H])[C@@H]([C@@H](O)N42)CC)[H])C2=CC=CC=C2[C@]11C[C@@]4([H])[C@H]3[C@H]1O CJDRUOGAGYHKKD-RQBLFBSQSA-N 0.000 description 1
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Abstract
本发明涉及四氢咔啉衍生物的制备方法,其包括如下步骤:烷基吲哚,甲醛和伯胺类化合物或其盐在溶剂中发生三组分Mannich反应。反应完成后,经后处理得到所述的四氢咔啉衍生物;该制备方法通过两次Mannich反应,在温和的条件下实现了四氢咔啉的快速合成,反应高效简洁快速,收率较高,对于有机合成和药物化学具有深远意义。
Description
技术领域
本发明属于有机合成领域,具体涉及一种四氢咔啉衍生物的制备方法。
背景技术
吲哚是天然化合物中一类重要的杂环骨架,存在于众多天然产物、药物分子、农药分子、染料香料和功能材料的核心结构中。β-咔啉类化合物广泛的存在于自然界中,包括植物、动物、细菌、真菌和食品,并且由于其拥有广泛的药理和生理活性而被大量人工合成。β-咔啉类化合物有广泛的药理和生理活性,包括抗癌、抗病毒、抗高血压、抗氧化、抗炎、抗菌、抗血栓、抗疟原虫、抗利什曼虫、抗溃疡、抗烟花草叶病毒和中枢神经兴奋等。其中有些己经被开发为药物,并得到广泛的应用。例如从Reuwolfia serpentina分离得到的利血平(Reserpine),被用做降压药和镇静药。从Pausinystalia yohimbe中分离得到的育亨宾碱(Yohimbine),临床用于治疗男性各型阳痿以及性功能减退。从Catharanthus roseus中分离得到的阿吗碱(Ajmalicine),被用于治疗高血压。化学合成四氢咔啉最常用的方法是由吲哚胺类(如色胺和色氨酸及其衍生物)和羰基化合物(例如醛和酮)通过Pictet-Spengler反应得到。反应通常在酸(盐酸、硫酸、三氟乙酸、甲磺酸等),Lewis酸(三氟化硼乙醚、三氟甲磺酸银、三氟甲磺酸镱等)或者酶的催化下进行,溶剂使用质子溶剂和非质子溶剂均可。γ-咔啉类生物碱具有众多重要的药理活性,比如抗菌活性,抗病毒活性,抗寄生虫活性,抗癌活性和抗氧化活性以及其它活性。如Lumateperone,被用于治疗抑郁和精神分裂的药物,于2019年在美国批准上市;Dimebolin,作为一种AChE抑制剂和NMDAR拮抗剂,被用于治疗过敏性鼻炎,于1983年在美国批准上市。合成γ-咔啉的方法是格雷贝-乌尔曼法,该方法涉及到相应苯并三唑的热裂解,并被用来合成各种咔唑。Wang et al.(2014)通过Fisher法以哌啶酮盐酸盐和邻位苯肼为起始原料合成了四氢γ-咔啉。本文通过易得的烷基吲哚经过两次Mannich反应环化得到四氢咔啉,并保持天然氨基酸的手性,这在之前是未报道过的。
发明内容
本发明提供了一种四氢咔啉衍生物的制备方法,该制备方法能够将3-烷基吲哚,甲醛和伯胺类化合物或其盐通过一锅法高效快速地合成四氢咔啉衍生物。
一种四氢咔啉衍生物的制备方法包括如下步骤:烷基吲哚化合物,甲醛和伯胺类化合物或其盐在溶剂中发生三组分Mannich反应,反应完成后,经后处理得到所述的四氢咔啉衍生物
所述的四氢咔啉的结构如式(Ⅰ)所示:
本发明的反应式如下:
其中,
X为-CH2-或-CHR2-;
Y为-CH2-或-CHR2-;
M为-CH2-或-NR4-;
Q为-CH2-或-NR4-;
R1为H,取代或未取代的C1-C8烷基,取代或未取代的C2-C8烯基,取代或未取代的C2-C8炔基,取代或未取代的C1-C8羰基,取代或未取代的C3-C8环烷基,取代或未取代的C3-C8环烯基,取代或未取代的C6-C10芳基,取代或未取代的C5-C10杂环基,取代或未取代的C5-C10杂芳基,C1~C6烷硫基,羟基,烷氧基,卤素,酯基,硼酸酯基各种取代的苯环中的一个或者多个;
R2为氢、各种取代的苯环、酯基、酰胺、卤素或取代或者未取代的烷基;R3为C1~C8烷基、C1~C8烃氧基、C1~C8烷硫基、羟基、卤素、酯基、硼酸酯基、烯基;
R4为取代或者未取代的烷基;
其中,C1-C8烷基、C2-C8烯基、C2-C8炔基、C1-C8羰基、C3-C8环烷基、C3-C8环烯基、C6-C10芳基、C5-C10杂环基、C5-C10杂芳基、苯环、烷基上的取代基选自卤素,硝基,氰基,氨基,羟基,羟甲基,羟乙基,巯基,羧基,酯基,C1-C6烷基单取代胺基,C1-C6烷基双取代胺基,C1-C6烷氧基,C1-C6烷基羰氧基,C1-C6环烷基羰氧基,杂环基羰氧基,C1-C6烷氧基羰基,C1-C6环烷氧基羰基,杂环氧基羰基,C1-C6烷基羰胺基,C1-C6环烷基羰胺基,杂环基羰胺基,胺基羰基,C1-C6烷氧甲酰胺基,C1-C6烷巯基,或者水溶性官能基中的一个或多个。
本发明所使用术语中“C1-C8烷基”是指含有1-8个碳原子的直链或支链烷烃基,包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基等。
“C2-C8烯基”是指含有2-8个碳原子的直链或支链烯烃基,包括但不限于乙烯基、烯丙基等。
“C3-C8环烷基或环烯基”是指具有饱和或不饱和环的3-8个碳原子单环系统的烃基,包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环丙烯基、环己烯基等。
“C1-C8羰基”是指含有1-8个碳原子的酮或醛失去一个氢原子形成的取代基。
“芳基”是指含有6-14个碳原子的单碳环芳香基或稠合或非稠合的多碳环芳香基,在多碳环的情况下,只要一个碳环是芳香环的即可。
“杂芳基”是指在环中含有1-4个杂原子作为环成员的芳香环基团。杂原子是指氮、氧或硫。杂芳基可以是具有5-7个环原子的单环杂芳基,或者具有7-11个环原子的双环杂芳基。所述双环杂芳基中只要一个环是杂芳环即可,另一个可以是芳香环或非芳香环的,含杂原子的或不含杂原子的。此外,所述双环杂芳基既可以是并环结构,也可以是螺环结构,也可以是两个杂环直接相连。杂芳基的例子包括但不限于吡咯基、吡唑基、咪唑基、噁唑基、吡啶基、嘧啶基、呋喃基、噻吩基、吲哚基等。
“杂环基”是指在环中含有1-4个杂原子作为环成员的非芳香环基团。杂原子是指氮、氧或硫。杂环基可以是具有4-8个环原子的单环杂环基,或者具有7-11个环原子的双环杂环基。所述双环杂环基中只要一个环是杂环即可,另一个可以是芳香环或非芳香环的,含杂原子的或不含杂原子的。此外,所述双环杂环基既可以是并环结构,也可以是螺环结构,也可以是两个杂环直接相连。杂环基的例子包括但不局限于氮杂环丁基、吡咯烷基、吡咯啉基、四氢呋喃基、二氢呋喃基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢噻吩基等。
“卤素”是指氟、氯、溴或碘。
所述的“水溶性官能基”选自羟基,多羟基烷氧基,糖残基,羧基,磺酸基,磷酸基,多羟基C1-C6烷氧基羰基,羧基C1-C6烷氧基,羧基C1-C6烷基甲酰氧基。
本反应条件温和,收率优良。将3-烷基吲哚和Mannich反应很好的结合,快速高效地合成四氢咔啉衍生物。
作为优选,所述的3-烷基吲哚、甲醛及胺类化合物的摩尔比为1:2~8:1~4,后面两种组分过量保证反应比较彻底。
作为优选,所述的溶剂为乙腈、乙酸、乙醇、甲醇、丙酮、二氧六环、四氢呋喃、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或混合溶剂。
作为优选,所述的反应温度为20-90℃,温度过高会导致产物分解,温度过低会导致反应转化率过低。
本发明中,反应的时间可以通过薄层层析(TLC)进行监测,一般进行0.5-24小时后,反应比较彻底。
本发明中,所述的伯胺类化合物为单体及其盐酸盐、硫酸盐、或氢溴酸盐。
本发明中,根据上述要求,其为式(II)及式(III)所示的结构或式(II)及式(III)所示结构的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药,
本发明一个优选的实施方案,发明通式(I)所示的四氢咔啉衍生物包括,但不限于以下化合物:
附图说明
代表性核磁谱图如下所示:
图1为实施例1所制得的产物的1H NMR谱图。
图2为实施例1所制得的产物的13C NMR谱图。
图3为实施例8所制得的产物的1H NMR谱图。
图4为实施例8所制得的产物的13C NMR谱图。
图5为实施例13所制得的产物的1H NMR谱图。
图6为实施例13所制得的产物的13C NMR谱图。
具体实施方式
本发明中所用的反应物3-烷基吲哚化合物均可以采用已知方法制备或商业获得。
实施例1:合成化合物(S1)
在干燥的反应管中称入N-Boc-5,6-二甲氧基-3-甲基吲哚(0.2mmol)和甘氨酸甲酯盐酸盐(0.4mmol),加入1mL乙腈,加入甲醛水溶液(0.8mmol),60℃反应3小时,TLC检测反应转化完全。加入碳酸氢钠饱和水溶液中和,乙酸乙酯萃取三次,合并有机相,饱和食盐水洗一次,有机相用无水硫酸钠干燥。减压浓缩。粗品用硅胶柱层析得到产物65mg,收率80%。
1H NMR(400MHz,CDCl3)δ7.75(s,1H),6.83(s,1H),4.06(s,2H),3.93(m,6H),3.75(s,3H),3.52(s,2H),2.98(t,J=5.6Hz,2H),2.74(t,J=5.6Hz,2H),1.64(s,9H).13C NMR(101MHz,CDCl3)δ171.1,150.3,147.0,146.2,130.8,129.7,121.9,114.4,99.8,99.7,83.5,58.0,56.2,56.1,52.2,51.9,49.4,28.3,21.1.HRMS(ESI-TOF)calcd for C21H28N2O6(M+H+):405.2020;Found:405.2017.
实施例2:化合物S2的合成
以N-Boc-5,6-二甲氧基-3-甲基吲哚(0.2mmol),丙氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S2,得到产物64mg,合计收率77%。
1H NMR(400MHz,CDCl3)δ7.81(s,1H),6.86(s,1H),4.10(s,2H),3.96(d,J=5.2Hz,6H),3.77(s,3H),3.67(q,J=7.2Hz,1H),3.04(dd,J1=11.6Hz,J2=5.6Hz,1H),2.92(dd,J1=11.6Hz,J2=6.0Hz,1H),2.74(d,J=3.2Hz,2H),1.69(s,9H),1.48(d,J=7.2Hz,3H).13CNMR(101MHz,CDCl3)δ173.7,150.3,146.9,146.2,131.3,129.9,122.0,114.9,99.7,99.7,83.4,61.9,56.2,56.1,51.6,49.3,46.3,28.3,22.2,15.2.HRMS(ESI-TOF)calcd forC22H30N2O6(M+H+):419.2177;Found:419.2175.
实施例3:化合物S3的合成
以N-Boc-5,6-二甲氧基-3-甲基吲哚(0.2mmol),苯丙氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S3,得到产物62mg,合计收率63%。
1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.36–7.19(m,5H),6.87(s,1H),4.15(t,J=7.2Hz,2H),3.98(d,J=5.2Hz,6H),3.78(dd,J1=9.2Hz,J2=5.6Hz,1H),3.66(s,3H),3.34–3.21(m,1H),3.21–3.06(m,2H),2.93(m,1H),2.74(d,J=4.8Hz,2H),1.70(s,9H).13C NMR(101MHz,CDCl3)δ172.0,150.2,147.0,146.2,138.0,131.2,129.9,129.2,128.5,126.6,121.9,114.8,99.7,99.7,83.4,69.1,56.2,56.2,51.3,49.9,46.3,36.1,28.3,22.4.HRMS(ESI-TOF)calcd for C28H34N2O6(M+H+):495.2490;Found:495.2483.
实施例4:化合物S4的合成
以N-Boc-5,6-二甲氧基-3-甲基吲哚(0.2mmol),谷氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S4,得到产物52mg,合计收率53%。
1H NMR(400MHz,CDCl3)δ7.78(s,1H),6.82(s,1H),4.10(d,J=16.0Hz,1H),3.94(m,7H),3.72(s,3H),3.60(s,3H),3.52(m,1H),3.13–2.99(m,1H),2.79(m,1H),2.66(d,J=2.0Hz,2H),2.44(t,J=7.2Hz,2H),2.14(m,2H),1.66(s,9H).13C NMR(101MHz,CDCl3)δ173.7,172.4,150.2,146.9,146.2,131.5,129.8,121.9,114.9,99.7,99.7,83.5,66.0,56.2,56.2,51.6,51.4,49.5,46.1,30.7,28.3,24.4,22.4.HRMS(ESI-TOF)calcd forC25H34N2O8(M+H+):491.2388;Found:491.2387.
实施例5:化合物S5的合成
以N-Boc-6-甲氧基-3-甲基吲哚(0.2mmol),环丁胺盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S5,得到产物62mg,合计收率80%。
1H NMR(400MHz,CDCl3)δ7.76(s,1H),6.82(s,1H),3.92(m,8H),3.27–3.07(m,1H),2.80(s,4H),2.17(m,4H),1.90–1.72(m,2H),1.65(s,9H).13C NMR(101MHz,CDCl3)δ150.2,147.2,146.3,136.0,129.9,121.7,114.6,99.8,99.7,83.6,59.3,56.2,56.1,49.0,45.7,28.3,27.3,20.6,14.4.HRMS(ESI-TOF)calcd for C22H30N2O4(M+H+):387.2278;Found:387.2274.
实施例6:化合物S6的合成
以N-Boc-6-甲氧基-3-甲基吲哚(0.2mmol),丙氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S6,得到产物33mg,合计收率43%。
1H NMR(400MHz,CDCl3)δ7.75(d,J=1.6Hz,1H),7.25(d,J=8.0Hz,1H),6.85(dd,J1=8.4Hz,J2=2.4Hz,1H),4.07(s,2H),3.86(s,3H),3.74(s,3H),3.64(q,J=7.2Hz,1H),2.93(m,2H),2.71(m,2H),1.66(s,9H),1.44(d,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ173.7,157.3,150.3,136.8,131.6,123.2,118.1,114.9,111.4,100.3,83.5,62.0,55.7,51.5,49.3,46.3,28.3,22.1,15.2.HRMS(ESI-TOF)calcd for C21H28N2O5(M+H+):389.2071;Found:389.2073.
实施例7:化合物S7的合成
以N-Boc-6-甲氧基-3-甲基吲哚(0.2mmol),苯丙氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S7,得到产物42mg,合计收率45%。
1H NMR(400MHz,CDCl3)δ7.81(s,1H),7.29(m,6H),6.90(dd,J1=8.4Hz,J2=2.0Hz,1H),4.29–4.06(m,2H),3.91(s,3H),3.79(dd,J1=9.2Hz,J2=5.6Hz,1H),3.66(d,J=4.4Hz,3H),3.27(m,1H),3.21–3.07(m,2H),2.93(m,1H),2.84–2.66(m,2H),1.71(s,9H).13C NMR(101MHz,CDCl3)δ172.0,157.4,150.3,138.1,136.8,131.5,129.2,128.5,126.6,123.2,118.1,114.9,111.5,100.2,83.6,69.1,55.7,51.3,49.9,46.3,36.1,28.3,22.3.HRMS(ESI-TOF)calcd for C27H32N2O5(M+H+):465.2384;Found:465.2389.
实施例8:化合物S8的合成
以N-Boc-6-甲氧基-3-甲基吲哚(0.2mmol),缬氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S8,得到产物29mg,合计收率35%。
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.25(d,J=8.4Hz,1H),6.85(dd,J1=8.4Hz,J2=2.0Hz,1H),4.07–3.79(m,5H),3.72(d,J=9.2Hz,3H),3.04(t,J=10.4Hz,2H),2.68(d,J=7.6Hz,3H),2.28–2.15(m,1H),1.66(s,9H),1.02(d,J=6.4Hz,3H),0.93(d,J=6.4Hz,3H).13C NMR(101MHz,CDCl3)δ172.4,157.3,150.3,136.8,131.9,123.2,118.0,115.0,111.5,100.2,83.5,74.0,55.7,50.8,50.2,45.5,28.3,27.4,22.4,19.9,19.4.HRMS(ESI-TOF)calcd for C23H32N2O5(M+H+):417.2384;Found:417.2386.
实施例9:化合物S9的合成
以N-Boc-6-苄氧基-3-甲基吲哚(0.2mmol),甘氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S9,得到产物23mg,合计收率25%。
1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.46(m,J=7.4Hz,2H),7.38(m,2H),7.30(m,2H),6.94(m,1H),5.12(s,2H),4.08(s,2H),3.76(s,3H),3.52(s,2H),2.98(t,J=5.6Hz,2H),2.76(t,J=5.6Hz,2H),1.64(s,9H).13C NMR(101MHz,CDCl3)δ171.1,156.6,150.3,137.3,136.7,131.2,128.5,127.9,127.6,123.5,118.1,114.5,112.2,101.7,83.7,70.6,58.1,52.1,51.8,49.4,28.3,21.0.HRMS(ESI-TOF)calcd for C26H30N2O5(M+H+):451.2227;Found:451.2225.
实施例10:化合物S10的合成
以N-Boc-6-羟基-3-甲基吲哚(0.2mmol),甘氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S10,得到产物14mg,合计收率20%。
1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.19(d,J=8.0Hz,1H),6.76(d,J=8.0Hz,1H),4.07(s,2H),3.76(s,3H),3.53(s,2H),2.99(m,2H),2.75(m 2H),1.64(s,9H).13CNMR(101MHz,CDCl3)δ171.0,153.2,150.3,136.7,130.9,123.3,118.2,114.5,111.5,102.8,83.8,58.0,52.0,51.9,49.4,28.3,20.9.HRMS(ESI-TOF)calcd for C19H24N2O5(M+H+):361.1758;Found:361.1762.
实施例11:化合物S11的合成
以N-Cbz-5,6-二甲氧基-3-甲基吲哚(0.2mmol),甘氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S11,得到产物63mg,合计收率72%。
1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.47(m,2H),7.44–7.31(m,3H),6.82(s,1H),5.39(s,2H),4.06(s,2H),3.91(s,3H),3.75(m,6H),3.49(s,2H),2.98(t,J=5.6Hz,2H),2.74(t,J=5.6Hz,2H).13C NMR(101MHz,CDCl3)δ171.0,151.4,147.2,146.5,134.9,130.8,129.7,128.8,128.7,122.1,115.3,99.9,68.8,57.9,56.2,56.0,51.8,51.8,49.3,21.1.HRMS(ESI-TOF)calcd for C24H26N2O6(M+H+):439.1864;Found:439.1862.
实施例12:化合物S12的合成
以N-Cbz-5,6-二甲氧基-3-甲基吲哚(0.2mmol),甘氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S1的方法制备S12,得到产物20mg,合计收率27%。
1H NMR(400MHz,CDCl3)δ6.88(s,1H),6.82(s,1H),3.91(m,8H),3.75(s,3H),3.50(s,2H),3.19–2.93(m,8H),2.80(d,J=5.2Hz,2H).13C NMR(101MHz,CDCl3)δ171.0,154.6,147.0,145.9,131.0,129.1,121.1,112.0,100.5,96.7,58.3,56.6,56.3,51.9,50.4,50.3,38.4,21.3.HRMS(ESI-TOF)calcd for C19H25N3O5(M+H+):376.1867;Found:376.1868.
实施例13:化合物S13的合成
在干燥的反应管中称入N-苄基-2-甲基吲哚(0.2mmol)和甘氨酸甲酯盐酸盐(0.4mmol),加入1mL N,N-二甲基甲酰胺,加入甲醛水溶液(0.8mmol),60℃反应3小时,TLC检测反应转化完全。加入碳酸氢钠饱和水溶液中和,乙酸乙酯萃取三次,合并有机相,饱和食盐水洗一次,有机相用无水硫酸钠干燥。减压浓缩。粗品用硅胶柱层析得到产物62mg,收率92%。
1H NMR(400MHz,CDCl3)δ7.48(d,J=7.2Hz,1H),7.36–7.22(m,4H),7.21–7.09(m,2H),7.05(d,J=6.8Hz,2H),5.29(s,2H),3.98(s,2H),3.81(s,3H),3.58(s,2H),3.08(t,J=5.6Hz,2H),2.84(t,J=5.6Hz,2H).13C NMR(101MHz,CDCl3)δ171.2,137.9,136.8,133.3,128.8,127.4,126.2,125.8,121.1,119.2,117.7,109.3,107.9,58.6,51.8,50.3,49.5,46.4,22.6.HRMS(ESI-TOF)calcd for C21H22N2O2(M+H+):335.1754;Found:335.1757.
实施例14:化合物S14的合成
以N-苄基-2-甲基吲哚(0.2mmol),异亮氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S14,得到产物60mg,合计收率77%。
1H NMR(400MHz,CDCl3)δ7.51(d,J=7.6Hz,1H),7.29(m,4H),7.20–7.10(m,2H),7.07(d,J=7.2Hz,2H),5.29(s,2H),3.99–3.86(m,2H),3.78(s,3H),3.24(d,J=10.4Hz,1H),3.21–3.11(m,1H),2.90–2.82(m,1H),2.78(t,J=4.8Hz,2H),2.12(m,1H),1.81(m,1H),1.22(m,1H),0.95(m,6H).13C NMR(101MHz,CDCl3)δ172.5,138.0,136.8,134.1,128.8,127.3,126.2,125.8,121.0,119.2,117.6,109.3,108.8,72.5,50.8,46.6,46.6,46.5,33.1,25.1,23.8,16.1,10.6.HRMS(ESI-TOF)calcd for C25H30N2O2(M+H+):391.2380;Found:391.2377.
实施例15:化合物S15的合成
以N-苄基-2-甲基吲哚(0.2mmol),苯丙氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S15,得到产物84mg,合计收率99%。
1H NMR(400MHz,CDCl3)δ7.45(d,J=7.2Hz,1H),7.32–7.15(m,9H),7.14–7.04(m,2H),7.00(d,J=7.2Hz,2H),5.22(s,2H),3.99(q,J=13.2Hz,2H),3.76(dd,J1=9.6Hz,J1=5.6Hz,1H),3.61(s,3H),3.31–3.04(m,3H),2.96(m,1H),2.75(d,J=5.2Hz,2H).13C NMR(101MHz,CDCl3)δ172.1,138.2,137.9,136.9,133.7,129.3,128.8,128.5,127.4,126.6,126.3,125.8,121.1,119.2,117.7,109.3,108.4,69.5,51.3,47.2,46.6,46.5,36.2,23.8.HRMS(ESI-TOF)calcd for C28H28N2O2(M+H+):425.2224;Found:425.2224.
实施例16:化合物S16的合成
以N-苄基-2-甲基吲哚(0.2mmol),乙胺盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S16,得到产物47mg,合计收率81%。
1H NMR(400MHz,CDCl3)δ7.51(d,J=7.6Hz,1H),7.35–7.21(m,4H),7.15(dd,J1=13.6Hz,J2=7.2Hz,2H),7.07(d,J=7.6Hz,2H),5.29(s,2H),3.83(s,2H),2.94(t,J=5.6Hz,2H),2.84(t,J=5.2Hz,2H),2.77(q,J=7.2Hz,2H),1.29(t,J=7.2Hz,3H).13CNMR(101MHz,CDCl3)δ137.9,136.9,133.8,128.8,127.3,126.3,125.9,121.0,119.1,117.7,109.3,108.2,51.9,50.4,49.3,46.5,22.9,12.7.HRMS(ESI-TOF)calcd for C20H22N2(M+H+):291.1856;Found:291.1853.
实施例17:化合物S17的合成
以N-苄基-2-甲基吲哚(0.2mmol),烯丙胺盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S17,得到产物56mg,合计收率93%。
1H NMR(400MHz,CDCl3)δ7.51(d,J=7.2Hz,1H),7.36–7.23(m,4H),7.22–7.10(m,2H),7.07(d,J=6.8Hz,2H),6.07(m,1H),5.39–5.21(m,4H),3.83(s,2H),3.35(d,J=6.0Hz,2H),2.94(t,J=5.6Hz,2H),2.83(t,J=5.6Hz,2H).13C NMR(101MHz,CDCl3)δ137.9,136.9,135.6,133.8,128.8,127.3,126.3,125.9,121.0,119.1,118.0,117.7,109.3,108.4,61.2,50.2,49.8,46.5,22.9.HRMS(ESI-TOF)calcd for C21H22N2(M+H+):303.1856;Found:303.1853.
实施例18:化合物S18的合成
以N-苄基-2-甲基吲哚(0.2mmol),炔丙胺盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S18,得到产物53mg,合计收率89%。
1H NMR(400MHz,CDCl3)δ7.56–7.48(m,1H),7.36–7.23(m,4H),7.21–7.12(m,2H),7.06(d,J=7.2Hz,2H),5.30(s,2H),3.97(s,2H),3.67(d,J=2.4Hz,2H),3.04(t,J=5.6Hz,2H),2.86(t,J=5.6Hz,2H),2.36(t,J=2.4Hz,1H).13C NMR(101MHz,CDCl3)δ137.9,136.9,133.3,128.8,127.4,126.2,125.8,121.1,119.2,117.7,109.3,108.2,79.1,73.4,49.5,48.5,46.6,46.4,23.0.HRMS(ESI-TOF)calcd for C21H20N2(M+H+):301.1699;Found:301.1699.
实施例19:化合物S19的合成
以N-苄基-2-甲基吲哚(0.2mmol),氯乙胺盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S19,得到产物56mg,合计收率86%。
1H NMR(400MHz,CDCl3)δ7.51(d,J=7.6Hz,1H),7.37–7.24(m,4H),7.23–7.12(m,2H),7.08(d,J=6.8Hz,2H),5.29(s,2H),3.93(s,2H),3.78(t,J=7.2Hz,2H),3.07(t,J=7.2Hz,2H),3.03(t,J=5.6Hz,2H),2.83(t,J=5.6Hz,2H).13C NMR(101MHz,CDCl3)δ137.9,136.9,133.5,128.8,127.4,126.3,125.8,121.2,119.3,117.7,109.4,107.9,59.1,50.7,49.7,46.5,41.6,22.7.HRMS(ESI-TOF)calcd for C20H21N2Cl(M+H+):325.1466;Found:325.1463.
实施例20:化合物S20的合成
以N-苄基-2-甲基吲哚(0.2mmol),3-氨基丙腈盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S20,得到产物60.0mg,合计收率95%。
1H NMR(400MHz,CDCl3)δ7.49(d,J=7.2Hz,1H),7.36–7.24(m,4H),7.22–7.11(m,2H),7.06(d,J=6.8Hz,2H),5.29(s,2H),3.89(s,2H),3.10–2.95(m,4H),2.82(t,J=5.6Hz,2H),2.68(t,J=7.2Hz,2H).13C NMR(101MHz,CDCl3)δ137.8,136.9,133.4,128.8,127.4,126.2,125.7,121.3,119.3,118.9,117.6,109.4,107.6,52.9,50.4,49.3,46.5,22.7,16.6.HRMS(ESI-TOF)calcd for C21H21N3(M+H+):316.1808;Found:316.1807.
实施例21:化合物S21的合成
以N-苄基-2-甲基吲哚(0.2mmol),环丙胺盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S21,得到产物55mg,合计收率91%。
1H NMR(400MHz,CDCl3)δ7.56–7.48(m,1H),7.35–7.25(m,4H),7.21–7.12(m,2H),7.09(d,J=6.8Hz,2H),5.28(s,2H),3.99(s,2H),3.12(t,J=5.6Hz,2H),2.82(t,J=5.6Hz,2H),2.05–1.99(m,1H),0.63(d,J=4.0Hz,4H).13C NMR(101MHz,CDCl3)δ138.0,136.9,133.7,128.8,127.3,126.4,125.9,121.0,119.1,117.7,109.2,108.5,50.8,49.8,46.5,37.9,22.8,6.5.HRMS(ESI-TOF)calcd for C21H22N2(M+H+):303.1856;Found:303.1855.
实施例22:化合物S22的合成
以N-苄基-2-甲基吲哚(0.2mmol),4-氨基四氢吡喃盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S22,得到产物54mg,合计收率79%。
1H NMR(400MHz,CDCl3)δ7.52–7.46(m,1H),7.28(m,4H),7.20–7.02(m,4H),5.28(s,2H),4.12(dd,J1=11.2Hz,J2=4.0Hz,2H),3.95(s,2H),3.48(t,J=11.2Hz,2H),3.02(t,J=5.6Hz,2H),2.88–2.73(m,3H),1.99–1.91(m,2H),1.87–1.74(m,2H).13CNMR(101MHz,CDCl3)δ137.9,136.9,133.9,128.8,127.3,126.3,126.0,121.0,119.1,117.6,109.3,108.4,67.7,60.4,46.5,46.4,45.5,29.9,23.4.HRMS(ESI-TOF)calcd for C23H26N2O(M+H+):347.2118;Found:347.2119.
实施例23:化合物S23的合成
以N-苄基-2-甲基吲哚(0.2mmol),苯甲胺盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S23,得到产物66.0mg,合计收率93%。
1H NMR(400MHz,CDCl3)δ7.48(d,J=7.6Hz,3H),7.40(t,J=7.2Hz,2H),7.37–7.27(m,5H),7.20–7.02(m,4H),5.29(s,2H),3.86(d,J=6.8Hz,4H),2.94(t,J=5.6Hz,2H),2.81(t,J=5.6Hz,2H).13C NMR(101MHz,CDCl3)δ138.7,138.0,136.9,133.9,129.2,128.8,128.4,127.3,127.2,126.3,125.9,121.0,119.1,117.7,109.2,108.5,62.4,50.2,50.0,46.5,22.9.HRMS(ESI-TOF)calcd for C25H24N2(M+H+):353.2012;Found:353.2009.
实施例24:化合物S24的合成
以N-苄基-6-氯-2-甲基吲哚(0.2mmol),甘氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S24,得到产物33mg,合计收率45%。
1H NMR(400MHz,CDCl3)δ7.32(m,4H),7.23(s,1H),7.08(dd,J1=8.4Hz,J2=1.6Hz,1H),7.02(d,J=7.2Hz,2H),5.23(s,2H),3.93(s,2H),3.80(s,3H),3.57(s,2H),3.06(t,J=5.6Hz,2H),2.82(t,J=5.6Hz,2H).13C NMR(101MHz,CDCl3)δ171.1,137.3,134.2,128.9,127.6,127.0,126.1,124.4,119.8,118.5,109.4,108.1,58.5,51.9,50.1,49.2,46.5,22.7.HRMS(ESI-TOF)calcd for C21H21N2O2Cl(M+H+):369.1364;Found:369.1359.
实施例25:化合物S25的合成
以N-苄基-2-甲基-7-氮杂吲哚(0.2mmol),甘氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S25,得到产物50mg,合计收率75%。
1H NMR(400MHz,CDCl3)δ8.29(d,J=4.4Hz,1H),7.74(d,J=7.6Hz,1H),7.27(m,3H),7.17–6.96(m,3H),5.49(s,2H),3.91(s,2H),3.79(s,3H),3.54(s,2H),3.03(t,J=5.6Hz,2H),2.81(t,J=5.2Hz,2H).13C NMR(101MHz,CDCl3)δ171.1,148.3,142.0,138.0,134.0,128.7,127.3,126.8,125.4,118.2,115.5,106.2,58.7,51.9,50.1,49.0,44.8,22.9.HRMS(ESI-TOF)calcd for C20H21N3O2(M+H+):336.1707;Found:336.1708.
实施例26:化合物S26的合成
以N-苄基-3,5-二甲基吡咯-2-甲酸乙酯(0.2mmol),甘氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S26,得到产物60.0mg,合计收率77%。
实施例27:化合物S27的合成
以N-甲基-2-甲基吲哚(0.2mmol),甘氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S27,得到产物45mg,合计收率87%。
1H NMR(400MHz,CDCl3)δ7.44(d,J=7.6Hz,1H),7.30(d,J=8.0Hz,1H),7.21(t,J=7.6Hz,1H),7.11(t,J=7.6Hz,1H),3.94(s,2H),3.81(s,3H),3.66(s,3H),3.58(s,2H),3.11(t,J=5.6Hz,2H),2.92(t,J=5.6Hz,2H).13C NMR(101MHz,CDCl3)δ171.3,137.1,133.4,125.6,120.8,118.9,117.6,108.7,107.2,58.5,51.8,50.3,49.5,29.1,22.5.HRMS(ESI-TOF)calcd for C15H18N2O2(M+H+):259.1441;Found:259.1439.
实施例28:化合物S28的合成
以N-苯乙烯基-2-甲基吲哚(0.2mmol),甘氨酸甲酯盐酸盐(0.4mmol),甲醛水溶液(0.8mmol)为原料,参考S13的方法制备S28,得到产物55mg,合计收率79%。
1H NMR(400MHz,CDCl3)δ7.44–7.38(m,1H),7.15(m,3H),7.12–7.05(m,3H),7.02–6.94(m,2H),6.73(d,J=8.8Hz,1H),6.52(d,J=8.8Hz,1H),3.93(s,2H),3.75(s,3H),3.48(s,2H),2.92(t,J=5.6Hz,2H),2.58(t,J=5.6Hz,2H).13C NMR(101MHz,CDCl3)δ171.3,135.6,134.7,133.0,128.6,128.5,128.0,127.1,126.5,122.3,121.5,120.0,117.5,110.9,109.8,58.1,51.8,50.2,49.2,22.8.HRMS(ESI-TOF)calcd for C22H22N2O2(M+H+):347.1754;Found:347.1748。
Claims (9)
1.一种四氢咔啉衍生物的制备方法,其特征在于,包括如下步骤:烷基吲哚化合物,甲醛和伯胺类化合物或其盐在溶剂中发生三组分Mannich反应,反应完成后,经后处理得到所述的四氢咔啉衍生物:
所述的四氢咔啉衍生物的结构如式(Ⅰ)所示:
反应式如下:
其中,
X为-CH2-或-CHR2-;
Y为-CH2-或-CHR2-;
M为-CH2-或-NR4-;
Q为-CH2-或-NR4-;
R1为H,取代或未取代的C1-C8烷基,取代或未取代的C2-C8烯基,取代或未取代的C2-C8炔基,取代或未取代的C1-C8羰基,取代或未取代的C3-C8环烷基,取代或未取代的C3-C8环烯基,取代或未取代的C6-C10芳基,取代或未取代的C5-C10杂环基,取代或未取代的C5-C10杂芳基,C1~C6烷硫基,羟基,烷氧基,卤素,酯基,硼酸酯基中的一个或者多个;
R2为氢、各种取代的苯环、酯基、酰胺、卤素或取代或者未取代的烷基;R3为C1~C8烷基、C1~C8烃氧基、C1~C8烷硫基、羟基、卤素、酯基、硼酸酯基、烯基;
R4为取代或者未取代的烷基;
其中,C1-C8烷基、C2-C8烯基、C2-C8炔基、C1-C8羰基、C3-C8环烷基、C3-C8环烯基、C6-C10芳基、C5-C10杂环基、C5-C10杂芳基、苯环、烷基上的取代基选自卤素,硝基,氰基,氨基,羟基,羟甲基,羟乙基,巯基,羧基,酯基,C1-C6烷基单取代胺基,C1-C6烷基双取代胺基,C1-C6烷氧基,C1-C6烷基羰氧基,C1-C6环烷基羰氧基,杂环基羰氧基,C1-C6烷氧基羰基,C1-C6环烷氧基羰基,杂环氧基羰基,C1-C6烷基羰胺基,C1-C6环烷基羰胺基,杂环基羰胺基,胺基羰基,C1-C6烷氧甲酰胺基,C1-C6烷巯基,或者水溶性官能基中的一个或多个。
2.根据权利要求1所述的四氢咔啉衍生物的制备方法,其特征在于,所述R1为甲氧基、羟基、酯基、羧基、甲硫基、苄氧基、氰基、卤素、各种取代的烷基、各种取代的苯基、中的一个或者多个;R2为氢、各种取代的苯基、酯基、酰胺、卤素或取代或者未取代的烷基;R3为C1~C8烷基、C1~C8烃氧基、C1~C8烷硫基、羟基、卤素、酯基、硼酸酯基、烯基;R4为取代或者未取代的甲基、乙基、丁基或者环丙基,所述甲基、乙基、丁基或者环丙基上的取代基选自C1~C4烷氧羰基、炔基、烯基、卤素、酯基、酰胺基、烷基或各种取代的苯基。
3.根据权利要求1所述的四氢咔啉衍生物的制备方法,其特征在于,R1为H、C1~C4烷基、C1~C4烷氧基、苄氧基、羟基、C1~C4烷氧羰基中的一个或者多个;
R3为叔丁氧羰基、苄氧羰基、二甲胺羰基、苄基、C1~C4烷基或苯乙烯基;
X为-CH2-,Y为-CHR2-,或者X为-CHR2-,Y为-CH2-;
R2为C3~C6环烷基、C1~C4烷基、烯丙基、炔丙基、卤素取代的C1~C4烷基或氰基取代的C1~C4烷基;
R5为H、C1~C4烷基、苄基、C1~C4烷氧羰基取代的C1~C4亚烷基。
4.根据权利要求1所述的四氢咔啉衍生物的制备方法,其特征在于,所述的烷基吲哚化合物,甲醛和伯胺类化合物的摩尔比为1:2~8:1~4。
5.根据权利要求1所述的四氢咔啉衍生物的制备方法,其特征在于,所述的溶剂为乙腈、乙酸、乙醇、甲醇、丙酮、二氧六环、四氢呋喃、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或混合溶剂。
6.根据权利要求1所述的四氢咔啉的制备方法,其特征在于,反应的温度为20~90℃。
7.根据权利要求1所述的四氢咔啉衍生物的制备方法,其特征在于,所述的伯胺类化合物或其盐为单体及其盐酸盐、硫酸盐、或氢溴酸盐。
8.根据权利要求1-7任一项所述的四氢咔啉衍生物的制备方法,其特征在于,所述的四氢咔啉衍生物为式(II)及式(III)所示的结构或式(II)及式(III)所示结构的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药,
9.根据权利要求1所述的四氢咔啉衍生物的制备方法,其特征在于,所述的四氢咔啉衍生物包括,但不限于以下化合物:
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