CN114057721A - 系列氮杂[n.2.1](n=3,4)桥环骨架化合物及其合成方法与应用 - Google Patents
系列氮杂[n.2.1](n=3,4)桥环骨架化合物及其合成方法与应用 Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 title abstract description 12
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 21
- 150000001336 alkenes Chemical class 0.000 claims abstract description 18
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims abstract description 17
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000002950 deficient Effects 0.000 claims abstract description 12
- 239000000543 intermediate Substances 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 120
- 238000006243 chemical reaction Methods 0.000 claims description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 22
- 239000003480 eluent Substances 0.000 claims description 20
- 239000003208 petroleum Substances 0.000 claims description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000741 silica gel Substances 0.000 claims description 18
- 229910002027 silica gel Inorganic materials 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 14
- 239000012267 brine Substances 0.000 claims description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 13
- 238000002390 rotary evaporation Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000011261 inert gas Substances 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 abstract description 5
- 238000007142 ring opening reaction Methods 0.000 abstract description 3
- 238000006845 Michael addition reaction Methods 0.000 abstract 1
- 150000001541 aziridines Chemical class 0.000 abstract 1
- 238000007306 functionalization reaction Methods 0.000 abstract 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 238000006352 cycloaddition reaction Methods 0.000 description 4
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000605 extraction Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- FZTDYEUXQXNEER-UHFFFAOYSA-N 2-prop-2-enylbenzaldehyde Chemical compound C=CCC1=CC=CC=C1C=O FZTDYEUXQXNEER-UHFFFAOYSA-N 0.000 description 1
- WWQQPHUHTAZWDH-UHFFFAOYSA-N 4-ethylbenzenethiol Chemical compound CCC1=CC=C(S)C=C1 WWQQPHUHTAZWDH-UHFFFAOYSA-N 0.000 description 1
- DGHJKOUXAHNRAP-UHFFFAOYSA-N 4-methyloxadiazole Chemical compound CC1=CON=N1 DGHJKOUXAHNRAP-UHFFFAOYSA-N 0.000 description 1
- USLRUYZDOLMIRJ-UHFFFAOYSA-N 5-Hexenal Chemical compound C=CCCCC=O USLRUYZDOLMIRJ-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044727 chloramine-t trihydrate Drugs 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 238000006142 intramolecular cycloaddition reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- NZYOAGBNMCVQIV-UHFFFAOYSA-N sodium;chloro-(4-methylphenyl)sulfonylazanide;trihydrate Chemical compound O.O.O.[Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 NZYOAGBNMCVQIV-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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Abstract
本发明公开了系列氮杂[n.2.1](n=3,4)桥环骨架化合物及其合成方法与应用。它是在碘化锂的促进下,首先进行碘化锂对氮丙啶的开环反应,继而发生氮丙啶与缺电子烯烃的分子内[3+2]环加成反应,从而有效地构建氮杂[n.2.1](n=3,4)桥环骨架化合物。这一方法涉及氮丙啶的顺序开环、迈克尔加成和亲核取代。该方法的优点包括原子经济性好,成键效率高,条件温和、产率高,对各类取代基具有较好的普适性以及环的通用性好。所开发出的系列氮杂[n.2.1](n=3,4)桥环骨架化合物官能团化程度高,具有良好的应用前景,特别是在用于合成homoepiboxidine的重要中间体方面有很好的应用价值。
Description
本发明得到天津市自然科学基金(18JCQNJC06700),天津师范大学优秀青年创新团队培养计划,天津大学创新研究团队计划(TD13-5074)的资助。
技术领域
本发明属于有机化学合成技术领域,特别是涉及一种氮杂[n.2.1](n=3,4)桥环骨架化合物及其合成方法与应用。
背景技术
氮杂[n.2.1](n=3,4)桥环骨架广泛存在于许多天然产物和具有生物活性的化合物中。此外,这些氮杂[n.2.1](n=3,4)桥环骨架也可用于合成七元和八元的环。
目前氮杂[n.2.1](n=3,4)桥环骨架的合成方法主要是分子间的环加成反应,如甲亚胺叶立德的[3+2]环加成反应、和[6+2]氮杂吡啶的环加成反应。(a)Padwa, A. Chem. Soc. Rev. 2009, 38, 3072; (b) Nair, V.; Suja, T. D. Tetrahedron2007, 63,12247; (c) Padwa, A. Helv. Chim. Acta2005, 88, 1357; (d) Mehta, G.;Muthusamy, S. Tetrahedron2002, 58, 9477; (e) Hodgson, D. M.; Pierard, F. Y.T. M.; Stupple, P. A. Chem. Soc. Rev.2001, 30, 50; (f) Padwa, A.; Weingarten,M. D. Chem. Rev. 1996, 96, 223; (g) Padwa, A. Acc. Chem. Res. 1991, 24, 22;selected recent examples: (h) Zhang, C.; Wang, G.; Zhan, L.; Yang, X.; Wang,J.; Wei, Y.; Xu, S.; Shi, M.; Zhang, J. ACS Catal. 2020, 10, 6682; (i) Suga,H.; Yoshiwara, M.; Yamaguchi, T.; Bando, T.; Taguchi, M.; Inaba, A.; Goto,Y.; Kikuchi, A.; Itoh, K.; Toda, Y. Chem. Commun. 2019, 1552.(j) Rigby, J.H.; Pigge, F. C. J. Org. Chem. 1996, 60, 7392; (k) Kreiter, C. G.; Özkar, S.Z. Naturforsch.1977, 32B, 408; (l) Paquette, L. A.; Kuhla, D. E.; Barrett, J.H.; Halueka, R. J. J. Org. Chem.1969, 34, 2866.近年来也对分子内环加成反应进行了研究。(a) He, J.; Chen, Z.; Li, W.; Low, K. -H.; Chiu, P. Angew. Chem., Int. Ed. 2018, 57, 5253; (b) Chung, W. K.; Lam, S. K.; Lo, B.; Liu, L. L.; Wong,W. -T.; Chiu, P. J. Am. Chem. Soc.2009, 131, 4556.(c) Xing S.; Pan W.; LiuC.; Ren, J.; Wang Z. Angew. Chem. Int. Ed.2010, 49, 3215; (d) Xing S.; Li Y.;Li Z.; Liu C.; Ren, J. Wang Z. Angew. Chem. Int. Ed.2011, 50, 12605; (e)Zhang J.; Xing S.; Ren J.; Jiang S. Wang Z. Org. Lett. 2015, 17, 218; (f) LiuP.; Cui Y.; Chen K.; Zhou X.; Pan W.; Ren J.; Wang Z. Org. Lett. 2018, 20,2517.尽管这些策略能够提供有效的氮杂[n.2.1](n=3,4)桥环骨架的合成方法,但很少有环加成反应能够为所有氮杂[n.2.1](n=3,4)桥环骨架的构建提供一种通用而有效的方法。考虑到氮杂[n.2.1](n=3,4)桥环骨架的重要性,发展高效的,绿色的,条件温和的氮杂[n.2.1](n=3,4)桥环骨架的合成方法仍然是一个值得深入研究的课题。
从含缺电子烯烃氮丙啶出发,我们选用合适的催化剂,乙酸乙酯为溶剂,首先发生碘化锂对氮丙啶的开环反应,继而发生氮丙啶与缺电子烯烃的分子内[3+2]环加成反应,高效的合成出了一系列氮杂[n.2.1](n=3,4)桥环骨架。这一方法成键效率高,原子经济性好,反应条件温和,产率高、产物中环尺寸的通用性好,具有很好的工业化前景。
发明内容
为了解决上述问题,本发明提供一种碘化锂促进的氮丙啶与缺电子烯烃的分子内[3+2]环加成反应,即通过这一新方法可进一步高效,高原子经济性合成氮杂[n.2.1](n=3,4)桥环骨架化合物,反应条件温和,产率高、产物环尺寸的通用性好,具备潜在的工业开发前景。
为实现上述目的,本发明公开了如下技术内容:
一种如式(II)所示的系列氮杂[n.2.1](n=3 ,4)桥环骨架,其结构如下:
式(II)中R1取代基为烷基;
R2取代基为对甲苯磺酰基,对溴苯磺酰基,对硝基苯磺酰基或苯基磺酰基;
R3为氢,C1-C5的烷基或卤素,所述卤素是F或Cl;其系列氮杂[n.2.1](n=3,4)桥环骨架指的是:
(1) 10-对甲苯磺酰基-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二甲酯;
(2) 10-(4-溴苯磺酰基)-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二乙酯;
(3) 2-氟-10-对甲苯磺酰基-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二乙酯;
(4) 11-对甲苯磺酰基-7,8,9,10-四氢-5,8-氨基苯并[8]环烯-6,6(5H)-二甲酸二乙酯;
(5) 2-氟-11-对甲苯磺酰基-7,8,9,10-四氢-5,8-氨基苯并[8]环烯-6,6(5H)-二甲酸二乙酯;
(6) 8-(4-硝基苯磺酰基)-8-氮杂双环[3.2.1]辛烷-6,6-二甲酸二甲酯。
本发明进一步公开了如式(II)所示的系列氮杂[n.2.1](n=3,4)桥环骨架的合成方法,其特征在于:
在无需惰性气体保护的室温条件下,反应体系中加入含缺电子烯烃氮丙啶(I),乙酸乙酯,催化剂,室温至60℃反应3个小时,TLC跟踪监测反应结束后,后处理得到氮杂[n.2.1](n=3,4)桥环骨架;所述的后处理指的是:反应结束后提纯,冷却至室温,加入适量的水搅拌,用乙酸乙酯多次萃取,合并有机相,有机相用卤水洗,无水硫酸钠干燥,然后水泵减压,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,洗脱液除去溶剂所得即为式(II)所示的系列氮杂[n.2.1](n=3,4)桥环骨架。
式(I)(II)中R1取代基为烷基;
R2取代基为对甲苯磺酰基,对溴苯磺酰基,对硝基苯磺酰基或苯基磺酰基;
R3为氢,C1-C5的烷基或卤素,所述卤素是F或Cl;
反应体系中催化剂的用量以含缺电子烯烃氮丙啶(I)的量计算为20%-200%。
反应体系中溶剂的用量以含缺电子烯烃氮丙啶(I)的量计算为1mL/mmol。
所述催化剂为碘化锂,碘化钠,碘化钾,溴化锂和氯化锂;优先的催化剂是碘化锂。
本发明合成的典型化合物如下:
(1) 10-对甲苯磺酰基-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二甲酯
(2) 10-(4-溴苯磺酰基)-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二乙酯
(3) 2-氟-10-对甲苯磺酰基-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二乙酯
(4) 11-对甲苯磺酰基-7,8,9,10-四氢-5,8-氨基苯并[8]环烯-6,6(5H)-二甲酸二乙酯
(5) 2-氟-11-对甲苯磺酰基-7,8,9,10-四氢-5,8-氨基苯并[8]环烯-6,6(5H)-二甲酸二乙酯
(6) 8-(4-硝基苯磺酰基)-8-氮杂双环[3.2.1]辛烷-6,6-二甲酸二甲酯
本发明开发了一种碘化锂促进的氮丙啶与缺电子烯烃的分子内[3+2]环加成反应,用于制备系列氮杂[n.2.1](n=3,4)桥环骨架,其反应方程式如下:
本发明以TLC监测反应进程,TLC的展开剂配比为乙酸乙酯:石油醚=1:5的混合溶剂。通常反应时间为3到6小时。
本发明推荐实践步骤:在无需惰性气体保护的室温条件下,反应体系中加入含缺电子烯烃氮丙啶(I),乙酸乙酯,20%-200%催化剂,室温至60℃反应3个小时,TLC跟踪监测反应结束。
本发明所述反应后处理方法为:反应结束后,冷却至室温,加入适量的水搅拌,用乙酸乙酯多次萃取,合并有机相,有机相用卤水洗,无水硫酸钠干燥,然后水泵减压,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,洗脱液除去溶剂所得即为式(II)所示的系列氮杂[n.2.1](n=3,4)桥环骨架。
本发明进一步公开了系列氮杂[n.2.1](n=3,4)桥环骨架在作为缓解疼痛药物中间体方面的应用,实验结果显示,本发明公开的(6)典型化合物能够有效地合成homoepiboxidine重要中间体。
本发明提供了一种高效制备系列氮杂[n.2.1](n=3,4)桥环骨架的方法,以式(I)氮丙啶为原料,在碘化锂催化下通过分子内[3+2]环加成反应,合成出了一系列氮杂[n.2.1](n=3,4)桥环骨架化合物。
本发明公开的系列氮杂[n.2.1](n=3,4)桥环骨架的合成新方法与现有技术相比所具有的积极效果在于:
(1)原料易得,成本低,绿色环保,催化剂廉价易得,仅催化量的催化剂被使用;
(2)方法简单,操作简便,一部反映高效的形成两个单键;成键效率高,原子利用率好;
(3)反应条件温和,反应温度为rt~60℃,反应时间为3到6小时之间,无需惰性气体保护;
(4)该方法普适性好,不同取代效应的底物均可通过该方法合成氮杂[n.2.1](n=3,4)桥环骨架。
具体实施方式
下面通过具体的实施方案叙述本发明。除非特别说明,本发明中所用的技术手段均为本领域技术人员所公知的方法。另外,实施方案应理解为说明性的,而非限制本发明的范围,本发明的实质和范围仅由权利要求书所限定。对于本领域技术人员而言,在不背离本发明实质和范围的前提下,对这些实施方案中的物料成分和用量进行的各种改变或改动也属于本发明的保护范围。本发明所用原料及试剂均有市售;另外:
2-(2-((1-对甲苯磺酰基氮丙啶-2-基)甲基)亚苄基)丙二酸二甲酯,2-(2-((1-((4-溴苯基)磺酰基)氮丙啶-2-基)甲基)亚苄基)丙二酸二乙酯和2-(4-氟-2-((1-对甲苯磺酰基氮丙啶-2-基)甲基)亚苄基)丙二酸二乙酯的合成方法如下:
在室温下,向乙腈(25mL)中加入氯胺-T三水合物(1.2g,4.24mmol,1.1eq)和烯烃(1g,3.85mmol,1eq),然后加苯基三甲基三溴化铵(14.5mg,0.385mmol)在室温下剧烈搅拌15小时后抽滤,旋转蒸发除去溶剂,残余物湿法上样,并通过短柱(硅胶,3x4cm)快速分离,淋洗剂选取乙酸乙酯:石油醚=1:10,得到中间体。然后将所得中间体溶解在乙腈(10mL)中,加碳酸钾(2.12g,15.4mmol,4eq)在45℃下剧烈搅拌2小时。然后将反应冷却至室温,过滤并浓缩。经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:3,得到产物。(所述烯烃分别是:2-(2-烯丙基亚苄基)丙二酸二甲酯,2-(2-烯丙基亚苄基)丙二酸二乙酯和2-(2-烯丙基-4-氟苄基)丙二酸二乙酯)。
烯烃的合成方法如下:
在室温下,将相应醛(20mmol)和丙二酸酯(26mmol)溶于甲苯,然后加入哌啶(1mL)和4Å分子筛(8g),混合物在65℃下搅拌8小时。反应冷却至室温,过滤后萃取浓缩。经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:25,得到产物。(所述醛分别为2-烯丙基苯甲醛;合成方法参照: K. Sravan, Thummanapelli, H. Seyedmorteza, Y. J. Su, G. Novruz,Akhmedov, X. D. Shi, J. Name. 2012, 00, 1 – 3。2-烯丙基-4-氟苯甲醛;合成方法参照: M. Zhang, S. Liu, H. Li, Y. Guo, N, Li. M. Guan, H. Mehfooz, J. Zhao, Q.Zhang, Chemistry - A European Journal. 2019, 25, 12620 - 12627.)。
2-(2-(2-(1-对甲苯磺酰基氮丙啶-2-基)乙基)亚苄基)丙二酸二乙酯和2-(4-氟-2-(2-(1-对甲苯磺酰基氮丙啶-2-基)乙基)亚苄基)丙二酸二乙酯的合成方法如下:
在氩气下,将烯烃(3mmol,1eq)和碘代亚胺(4.5mmol,1.5eq)溶于乙腈(30mL)中,最后加入六氟磷酸四乙腈铜(0.45mmol,0.15eq),室温反应过夜,然后将反应用乙酸乙酯(300mL)稀释,并用盐水(100mL)洗涤,无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,得到产物。(所述烯烃分别是:2-(2-(3-烯-1-基)亚苄基)丙二酸二乙酯和2-(2-(3-烯-1-基)-4-氟苄基)丙二酸二乙酯)。
烯烃的合成方法如下:
在室温下,将相应醛(20mmol)和丙二酸酯(26mmol)溶于甲苯,然后加入哌啶(1mL)和4Å分子筛(8g),混合物在65℃下搅拌8小时。反应冷却至室温,过滤后萃取浓缩。经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:25,得到产物。(所述醛分别为2-(3-烯-1-基)苯甲醛和2-(3-烯-1-基)-4-氟苯甲醛,合成方法参照:S. Xing, W. Pan, C. Liu, J. Ren, Z.Wang, Angew. Chem. Int. Ed. 2010, 49, 3215 - 3218.)。
2-(4-(1-(4-硝基苯磺酰基)氮丙啶-2-基)亚丁基)丙二酸二甲酯的合成方法如下:
在氩气下,将氯化亚铜(0.45mmol,0.15eq)溶于乙腈(30mL)中,然后加入2-(5-烯-1-亚基)丙二酸二甲酯(3mmol,1eq)和碘代亚胺(4.5mmol,1.5eq),室温反应过夜,然后将反应用乙酸乙酯(300mL)稀释,并用盐水(100mL)洗涤,无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,得到产物。
2-(5-烯-1-亚基)丙二酸二甲酯的合成方法如下:室温下,5-己烯-1-醛和丙二酸二甲酯(76.5mmol)溶于二氯甲烷(25mL),加入哌啶(10.2mmol)和乙酸(10.2mmol),室温搅拌45分钟后,添加等量的乙酸和哌啶,再搅拌15分钟,然后将反应用二氯甲烷(30mL)稀释,并用盐水(10mL)洗涤,无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:25,得到产物。
实施例1
反应无需惰性气体保护,室温条件下,将2-(2-((1-对甲苯磺酰基氮丙啶-2-基)甲基)亚苄基)丙二酸二甲酯(200mg,0.465mmol)溶于乙酸乙酯(4.65mL),继而加入碘化锂(12.45mg,0.093mmol,0.2eq),室温反应3小时后将反应倒入20mL水中,用10mL乙酸乙酯萃取3次,合并有机相,有机相用20mL卤水洗一次,无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,得到产物(176mg,产率88%)。
产物名称:10-对甲苯磺酰基-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二甲酯;白色固体;熔点:113 ~ 116℃;1H NMR (400 MHz, CDCl3) δ 7.56 – 7.51 (m,2H), 7.01 – 6.96 (m, 5H), 6.78 – 6.74 (m, 1H), 5.55 (s, 1H), 4.44 (ddd, J =7.4, 6.2, 1.2 Hz, 1H), 3.74 (s, 3H), 3.42 (s, 3H), 3.09 (dd, J = 17.2, 5.6Hz, 1H), 2.77 (ddd, J = 13.2, 8.8, 1.6 Hz, 1H), 2.65 – 2.52 (m, 2H), 2.31 (s,3H); 13C NMR (100 MHz, CDCl3) δ 169.81, 167.48, 143.10, 136.84, 133.16,132.42, 129.33, 128.90, 128.23, 127.52, 126.93, 125.65, 68.83, 63.19, 55.15,53.15, 52.78, 38.77, 34.49, 21.38; HRMS (ESI) Calcd for C22H24NO6S (M+H)+:430.1319; Found: 430.1321; IR (neat): v = 536, 619, 673, 1094, 1637, 1739,3430 cm-1。
实施例2
反应无需惰性气体保护,室温条件下,将2-(2-((1-((4-溴苯基)磺酰基)氮丙啶-2-基)甲基)亚苄基)丙二酸二乙酯(200mg,0.383mmol)溶于乙酸乙酯(3.83mL),继而加入碘化锂(10.26mg,0.077mmol,0.2eq),室温反应3小时后将反应倒入20mL水中,用10mL乙酸乙酯萃取3次,合并有机相,有机相用20mL卤水洗一次,无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,得到产物(190mg,产率95%)。
产物名称:10-(4-溴苯磺酰基)-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二乙酯;白色固体;熔点:139 ~ 142℃; 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.40(m, 2H), 7.30 – 7.25 (m, 2H), 7.04 – 6.91 (m, 3H), 6.69 – 6.66 (m, 1H), 5.49(s, 1H), 4.37 (t, J = 6.4 Hz, 1H), 4.20 – 4.08 (m, 2H), 3.88 – 3.80 (m, 1H),3.74 – 3.65 (m, 1H), 2.96 (dd, J = 17.2, 5.2 Hz, 1H), 2.69 – 2.63 (m, 1H),2.59 – 2.48 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H); 13CNMR (100 MHz, CDCl3) δ 169.20, 166.89, 138.77, 132.85, 132.09, 131.36,129.27, 128.85, 128.38, 127.18, 125.64, 68.48, 63.12, 62.07 (d, J = 11.9 Hz),55.21, 38.84, 34.27, 13.83 (d, J = 16.3 Hz); HRMS (ESI) Calcd for C23H25BrNO6S(M+H)+: 522.0580; Found: 522.0584; IR (neat): v = 533, 621, 737, 995, 1094,1256, 1638, 1749, 3433 cm-1。
实施例3
反应无需惰性气体保护,室温条件下,将2-(4-氟-2-((1-对甲苯磺酰基氮丙啶-2-基)甲基)亚苄基)丙二酸二乙酯(200mg,0.42mmol)溶于乙酸乙酯(4.2mL),继而加入碘化锂(11.24mg,0.084mmol,0.2equiv),室温反应3小时后将反应倒入20mL水中,用10mL乙酸乙酯萃取3次,合并有机相,有机相用20mL卤水洗一次,无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,得到产物(162mg,产率81%)。
产物名称:2-氟-10-对甲苯磺酰基-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二乙酯;白色固体;熔点:92 ~ 95℃ ;1H NMR (400 MHz, CDCl3) δ 7.45 (d, J =8.4 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.92 (dd, J = 8.4, 5.6 Hz, 1H), 6.68(td, J = 8.4, 2.8 Hz, 1H), 6.39 (dd, J = 9.6, 2.8 Hz, 1H), 5.48 (s, 1H), 4.34(t, J = 6.4 Hz, 1H), 4.17 – 4.10 (m, 2H), 3.91 – 3.82 (m, 1H), 3.76 – 3.67(m, 1H), 3.01 (dd, J = 17.2, 5.2 Hz, 1H), 2.67 (ddd, J = 13.4, 8.6, 1.2 Hz,1H), 2.55 – 2.44 (m, 2H), 2.25 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H), 1.03 (t, J= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.12, 166.98, 163.55, 161.10,143.27, 136.62, 134.99, 134.91, 129.15, 128.87, 128.65, 127.43, 115.95,112.60 (d, J = 21.6 Hz), 68.51, 62.40, 62.07, 54.51, 38.72, 34.43, 21.36,13.84 (d, J = 11.7 Hz); HRMS (ESI) Calcd for C24H27FNO6S (M+H)+: 476.1538;Found: 476.1540; IR (neat): v = 534, 589, 670, 993, 1112, 1248, 1638, 1734,3432 cm-1。
实施例4
反应无需惰性气体保护,室温条件下,将2-(2-(2-(1-对甲苯磺酰基氮丙啶-2-基)乙基)亚苄基)丙二酸二乙酯(200mg,0.424mmol)溶于乙酸乙酯(4.24mL),继而加入碘化锂(113.4mg,0.85mmol,2eq),反应用油浴加热到60℃反应6小时。然后将反应混合物冷却至室温,倒入20mL水中,用10mL乙酸乙酯萃取3次,合并有机相,有机相用20mL卤水洗一次,无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,得到产物(126mg,产率63%)。
产物名称:11-对甲苯磺酰基-7,8,9,10-四氢-5,8-氨基苯并[8]环烯-6,6(5H)-二甲酸二乙酯;黄色固体;熔点:82 ~ 85℃; 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.4Hz, 2H), 7.33 – 7.29 (m, 1H), 7.12 – 7.09 (m, 2H), 7.06 (d, J = 8.0 Hz, 2H),6.97 – 6.94 (m, 1H), 5.90 (s, 1H), 4.53 – 4.50 (m, 1H), 4.26 – 4.11 (m, 2H),3.77 – 3.68 (m, 1H), 3.66 – 3.57 (m, 1H), 3.38 – 3.28 (m, 1H), 2.96 (d, J =14.8 Hz, 1H), 2.59 – 2.47 (m, 2H), 2.32 (s, 3H), 1.84 – 1.75 (m, 1H), 1.71 –1.65 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 0.75 (t, J = 7.2 Hz, 3H); 13C NMR (100MHz, CDCl3) δ 170.43, 167.58, 142.64, 139.48, 138.87, 137.98, 131.46, 131.22,129.03, 127.99, 127.33, 125.75, 68.74, 66.40, 61.98 (d, J = 45.2 Hz), 58.99,36.85, 31.15, 30.53, 21.37, 13.58 (d, J = 7.5 Hz); HRMS (ESI) Calcd forC25H30NO6S (M+H)+: 472.1788; Found: 472.1791; IR (neat): v = 534, 619, 850,991, 1096, 1638, 3433 cm-1。
实施例5
反应无需惰性气体保护,室温条件下,将2-(4-氟-2-(2-(1-对甲苯磺酰基氮丙啶-2-基)乙基)亚苄基)丙二酸二乙酯(200mg,0.408mmol)溶于乙酸乙酯(4.08Ml),继而加入碘化锂(109.2mg,0.82mmol,2eq),反应用油浴加热到60℃反应6小时。然后将反应混合物冷却至室温,倒入20mL水中,用10mL乙酸乙酯萃取3次,合并有机相,有机相用20mL卤水洗一次,无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,得到产物(136mg,产率68%)。
产物名称:2-氟-11-对甲苯磺酰基-7,8,9,10-四氢-5,8-氨基苯并[8]环烯-6,6(5H)-二甲酸二乙酯;白色固体;熔点:112 ~ 116℃; 1H NMR (400 MHz, CDCl3) δ 7.50 –7.47 (m, 2H), 7.31 – 7.26 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.81 (td, J =8.0, 2.8 Hz, 1H), 6.70 (dd, J = 9.6, 2.8 Hz, 1H), 5.89 (s, 1H), 4.52 – 4.49(m, 1H), 4.26 – 4.10 (m, 2H), 3.82 – 3.73 (m, 1H), 3.70 – 3.62 (m, 1H), 3.40– 3.30 (m, 1H), 2.95 (d, J = 14.8 Hz, 1H), 2.57 – 2.46 (m, 2H), 2.35 (s, 3H),1.92 – 1.83 (m, 1H), 1.74 – 1.68 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 0.81 (t,J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.23, 167.46, 163.26, 160.80,142.86, 142.27, 137.80, 135.13, 133.03, 129.08, 127.31, 117.91, 112.21,67.94, 66.31, 62.01 (d, J = 42.6 Hz), 58.80, 36.74, 31.18, 30.56, 21.34,13.62 (d, J = 49.1 Hz); HRMS (ESI) Calcd for C25H29FNO6S (M+H)+: 490.1694;Found: 490.1697; IR (neat): v = 533, 845, 991, 1092, 1637, 1735, 3378 cm-1。
实施例6
反应无需惰性气体保护,室温条件下,将2-(4-(1-(4-硝基苯磺酰基)氮丙啶-2-基)亚丁基)丙二酸二甲酯(200mg,0.485mmol)溶于乙酸乙酯(4.85mL),继而加入碘化锂(12.99mg,0.097mmol,0.2eq),室温反应3小时后将反应倒入20mL水中,用10mL乙酸乙酯萃取3次,合并有机相,有机相用20mL卤水洗一次,无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,得到产物(166mg,产率83%)。
产物名称:8-(4-硝基苯磺酰基)-8-氮杂双环[3.2.1]辛烷-6,6-二甲酸二甲酯;黄色固体;熔点:124 ~ 127℃; 1H NMR (400 MHz, CDCl3) δ 8.27 – 8.23 (m, 2H), 8.00 –7.96 (m, 2H), 4.66 (s, 1H), 4.14 (d, J = 7.6 Hz, 1H), 3.68 (s, 3H), 3.48 (s,3H), 2.63 (d, J = 14.0 Hz, 1H), 2.44 (dd, J = 14.0, 7.6 Hz, 1H), 2.03 – 1.90(m, 2H), 1.76 – 1.62 (m, 2H), 1.58 – 1.50 (m, 2H); 13C NMR (100 MHz, CDCl3) δ170.21, 168.19, 149.74, 146.85, 128.37, 123.94, 63.22, 61.24, 56.59, 53.13(d, J = 1.4 Hz), 36.13, 30.34, 27.36, 16.08; HRMS (ESI) Calcd for C17H21N2O8S(M+H)+: 413.1013; Found: 413.1017; IR (neat): v = 534, 626, 853, 984, 1152,1349, 1385, 1531, 1634, 1733, 3461 cm-1。
实施例7
应用实例:
本发明所合成的典型化合物8-(4-硝基苯磺酰基)-8-氮杂双环[3.2.1]辛烷-6,6-二甲酸二甲酯可以转化为homoepiboxidine重要中间体。
homoepiboxidine的合成:
Homoepiboxidine是一种缓解疼痛的药物,选取小鼠进行生理学实验,给小鼠分别注射100mg/kg的homoepiboxidine;100mg/kg的N-methylhomoepiboxidine;100mg/kg的methyloxadiazole,30分钟后注射homoepiboxidine的小鼠仍有明显镇痛作用,同时比较培养细胞的神经节α3受体,神经元α4β2受体,homoepiboxidine也都表现出亲和力和功能活性,详细信息请参照W. Fitch, X. Pei, Y. Kaneko, T. Gupta, D. Shi, I. Federova,W. Daly, Bioorganic & Medicinal Chemistry. 2004, 12, 179 – 190。
Homoepiboxidine重要中间体合成的反应步骤如下:
在室温下,向DMF(57mL)中加入8-(4-硝基苯磺酰基)-8-氮杂双环[3.2.1]辛烷-6,6-二甲酸二甲酯(4mmol,1eq)和LiCl(16mmol,4eq),然后加H2O(11mL)。体系放入120℃的油浴中反应5小时,通过TLC监测反应完成。然后将所得混合物冷却至室温,用Et2O(100mL)稀释,盐水(50mLx3)洗涤。合并有机层用无水硫酸钠干燥,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:3,得到8-((4-硝基苯基)磺酰基)-8-氮杂双环[3.2.1]辛烷-6-羧酸甲酯(产率56%)。
在氮气气氛下,将碳酸钾(6.4mmol)和4-乙基苯硫酚(4.8mmol)溶于乙腈(30.4mL)中。然后向其中滴加8-((4-硝基苯基)磺酰基)-8-氮杂双环[3.2.1]辛烷-6-羧酸甲酯(1.6mmol)溶于乙腈(16mL)的溶液,最后加二甲基亚砜,将所得混合物升温至50℃搅拌2小时。用盐水(20 mLx3)洗涤混合物,无水硫酸钠干燥,过滤并减压浓缩。然后将所得混合物溶于THF(1mL)和H2O(3mL)中,并加入二碳酸二叔丁酯(119mg,0.55mmol)和NaHCO3(100mg,1.2mmol)搅拌过夜,然后用乙醚(5mLx2)萃取。旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,得到无色油状的homoepiboxidine重要中间体8-叔丁基6-甲基8-氮杂双环[3.2.1]辛烷-6,8-羧酸甲酯(产率50%)。该中间体可经两步反应得到homoepiboxidine,具体合成方法请参照W. Fitch, X. Pei, Y. Kaneko, T.Gupta, D. Shi, I. Federova, W. Daly, Bioorganic & Medicinal Chemistry. 2004,12, 179 – 190。
在详细说明的较佳实施例之后,熟悉该项技术人士可清楚地了解,在不脱离上述申请专利范围与精神下可进行各种变化与修改,凡依据本发明的技术实质对以上实施例所作任何简单修改、等同变化与修饰,均属于本发明技术方案的范围。且本发明亦不受说明书中所举实例实施方式的限制。
Claims (7)
1.一种如式(II)所示的系列氮杂[n.2.1](n=3,4)桥环骨架,其结构如下:
式(II)中R1取代基为烷基;
R2取代基为对甲苯磺酰基,对溴苯磺酰基,对硝基苯磺酰基或苯基磺酰基;
R3为氢,C1-C5的烷基或卤素,所述卤素是F或Cl;其系列氮杂[n.2.1] (n=3,4)桥环骨架指的是:
10-对甲苯磺酰基-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二甲酯;
10-(4-溴苯磺酰基)-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二乙酯;
2-氟-10-对甲苯磺酰基-5,7,8,9-四氢-6H-5,8-氨基苯并[7]环烯-6,6-二甲酸二乙酯;
11-对甲苯磺酰基-7,8,9,10-四氢-5,8-氨基苯并[8]环烯-6,6(5H)-二甲酸二乙酯;
2-氟-11-对甲苯磺酰基-7,8,9,10-四氢-5,8-氨基苯并[8]环烯-6,6(5H)-二甲酸二乙酯;
8-(4-硝基苯磺酰基)-8-氮杂双环[3.2.1]辛烷-6,6-二甲酸二甲酯。
2.一种如式(II)所示的系列氮杂[n.2.1](n=3,4)桥环骨架的合成方法,其特征在于:在无需惰性气体保护的室温条件下,反应体系中加入含缺电子烯烃氮丙啶(I),乙酸乙酯,催化剂,室温至60oC反应3个小时,TLC跟踪监测反应结束后,后处理得到多官能团化氮杂[n.2.1](n=3,4)桥环骨架;
式(I) (II)中R1取代基为烷基;
R2取代基为对甲苯磺酰基,对溴苯磺酰基,对硝基苯磺酰基或苯基磺酰基;
R3为氢,C1-C5的烷基或卤素,所述卤素是F或Cl;
反应体系中催化剂的用量以含缺电子烯烃氮丙啶(I)的量计算为20%-250%;
反应体系中溶剂的用量以含缺电子烯烃氮丙啶(I)的量计算为1-2mL/mmol;
所述催化剂为碘化锂,碘化钠,碘化钾,溴化锂或氯化锂。
3.权利要求2所述的合成方法,其特征在于所述溶剂的用量以含氮丙啶(I)的量计算为1mL/mmol。
4.权利要求2所述的合成方法,其特征在于所述催化剂为碘化锂。
5.权利要求2所述的合成方法,其特征在于反应体系中催化剂的用量以含氮丙啶(I)的量计算为20%-200%。
6.权利要求2所述的合成方法,其特征在于后处理指的是:反应结束后提纯,冷却至室温,加入适量的水搅拌,用乙酸乙酯多次萃取,合并有机相,有机相用卤水洗,无水硫酸钠干燥,然后水泵减压,旋转蒸发除去溶剂,残余物湿法上样,经硅胶柱分离,淋洗剂选取乙酸乙酯:石油醚=1:5,洗脱液除去溶剂所得即为式(II)所示的系列氮杂[n.2.1](n=3,4)桥环骨架。
7.权利要求1所述系列氮杂[n.2.1](n=3,4)桥环骨架在制备作为缓解疼痛药物中间体方面的应用;所述的缓解疼痛药物中间体指的是homoepiboxidine重要中间体。
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Non-Patent Citations (4)
Title |
---|
MIAO-MIAO XIA ET AL: "Synthesis of Chiral Aza-[n.2.1] Skeletons by Separable Epimers of Intramolecular [3+2] Cross Cycloaddition of Cyclopropane 1,1-Diesters with Chiral Sulfinylimines", ADV. SYNTH. CATAL., vol. 362, pages 1112, XP072362104, DOI: 10.1002/adsc.201901543 * |
RICHARD W. FITCH ET AL: "Homoepiboxidines: further potent agonists for nicotinic receptors", BIOORGANIC & MEDICINAL CHEMISTRY, no. 12, pages 180 * |
SIYANG XING ET AL: "Construction of Bridged Aza- and Oxa‑[n.2.1] Skeletons via an Intramolecular Formal [3+2] Cycloaddition of Aziridines and Epoxides with Electron-Deficient Alkenes", J. ORG. CHEM., vol. 87, pages 6426 - 6431 * |
YUYA NAKAGAWA ET AL: "Iodide-Mediated [3 + 2]-Cycloaddition Reaction with N‑Tosylaziridines and α,β-Unsaturated Ketones", J. ORG. CHEM., no. 86, pages 7789 * |
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