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CN112028903A - Tetrahydronaphthofuranone spiropyrrolidone compound and preparation method thereof - Google Patents

Tetrahydronaphthofuranone spiropyrrolidone compound and preparation method thereof Download PDF

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CN112028903A
CN112028903A CN202010050184.8A CN202010050184A CN112028903A CN 112028903 A CN112028903 A CN 112028903A CN 202010050184 A CN202010050184 A CN 202010050184A CN 112028903 A CN112028903 A CN 112028903A
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刘丹丹
廖秉华
周宜荣
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Jiangxi Normal University
Pingdingshan University
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Pingdingshan University
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The invention provides a tetralone furanone spiropyrrolidinone compound and a preparation method thereof. The method adopts metal-free organic catalysis series reaction, and takes various ortho-pyrrolidone substituted benzaldehyde and 2(5H) -furanone as reaction substrates. The reaction yield can reach medium to excellent, and the method has excellent chemical selectivity and diastereoselectivity, high reaction atom economy, mild reaction conditions and wide substrate application range; the method has the advantages of simple operation, low cost, less side reaction, high product purity, convenient separation and purification and suitability for large-scale preparation. Moreover, the obtained product has very good application prospect in the field of biological medicines.

Description

四氢萘并呋喃酮螺吡咯烷酮化合物及其制备方法Tetrahydronaphthofuranone spiropyrrolidone compound and preparation method thereof

技术领域technical field

本发明涉及有机化学领域，尤其涉及包含氢化萘并呋喃结构的化合物及其制备方法。The invention relates to the field of organic chemistry, in particular to a compound comprising a hydronaphthofuran structure and a preparation method thereof.

背景技术Background technique

四氢萘并呋喃酮结构广泛存在于天然产物和药物分子当中，具有一系列的重要生理药物活性，例如具有重要的抗肿瘤活性的天然产物依托泊苷(etoposide)、可以作为纯天然植物来源的有效抗生素的花果酚A(hanagokenol A)；具有重要的抗疟活性的异戊醌(xestoquinone)((a)Yoshikawa,K.；Kokudo,N.；Tanaka,M.；Nakano,T.；Shibata,H.；Aragaki,N.；Higuchi,T.；Hashimoto,T.Chem.Pharm.Bull.2008,56,89–92.(b)Yao,S.；Tang,C.P.；Ke,C.Q.；Ye,Y.J.Nat.Prod.2008,71,1242–1246.(c)Cao,S.；Foster,C.；Brisson,M.；Lazo,J.S.；Kingston,D.G.I.Bioorg.Med.Chem.2005,13,999–1003.(d)Laurent,D.；Jullian,V.；Parenty,A.；Knibiehler,M.；Dorin,D.；Schmitt,S.；Lozach,O.；Lebouvier,N.；Frostin,M.；Alby,F.；Maurel,S.；Doerig,C.；Meijerf,L.；Sauvain,M.Bioorg.Med.Chem.2006,14,4477–4482.(e)Du,L.；Mahdi,F.；Datta,S.；Jekabsons,M.B.；Zhou,Y.；Nagle,D.G.J.Nat.Prod.2012,75,1553–1559.(f)Sergio R.Peraza-Sánchez,Daniel Chávez,Hee-Byung Chai,Young Geun Shin,Ricardo García,MiliciadesMejía,Craig R.Fairchild,Kate E.Lane,Ana T.Menendez,Norman R.Farnsworth,Geoffrey A.Cordell,John M.Pezzuto,and A.Douglas Kinghorn,J.Nat.Prod.2000,63,492–495.(g)Sugimoto,K.；Tamura,K.；Tohda,C.；Toyooka,N.；Nemoto,H.；Matsuy,Y.Bioorg.Med.Chem.2013,21,4459–4471.(h)Zhao,M.；Onakpa,M.M.；Santarsiero,B.D.；Huang,X.；Zhang,X.；Chen,J.；Cheng,J.；Longnecker,R.；Che,C.Org.Lett.2015,17,3834–3837.(i)Zhao,M.；Onakpa,M.M.；Santarsiero,B.D.；Chen,W.；Szymulanska-Ramamurthy,K.M.；Swanson,S.M.；Burdette,J.E.；Che,C.J.Nat.Prod.2015,78,2731–2737.(j)Guo,B.；Onakpa,M.M.；Huang,X.；Santarsiero,B.D.；Chen,W.；Zhao,M.；Zhang,X.；Swanson,S.M.；Burdette,J.E.；Che,C.J.Nat.Prod.2016,79,1815–1821.)。The tetrahydronaphthofuranone structure exists widely in natural products and drug molecules, and has a series of important physiological and pharmaceutical activities, such as the natural product etoposide with important antitumor activity, which can be used as a pure natural plant source. Effective antibiotic hanagokenol A; xestoquinone with important antimalarial activity ((a) Yoshikawa, K.; Kokudo, N.; Tanaka, M.; Nakano, T.; Shibata Aragaki, N.; Higuchi, T.; Hashimoto, T.Chem.Pharm.Bull.2008,56,89–92.(b)Yao,S.;Tang,C.P.;Ke,C.Q.;Ye, 2008, 71, 1242–1246. (c) Cao, S.; Foster, C.; Brisson, M.; Lazo, J.S.; Kingston, D.G.I. (d) Laurent, D.; Jullian, V.; Parenty, A.; Knibiehler, M.; Dorin, D.; Schmitt, S.; Lozach, O.; Lebouvier, N.; Frostin, M.; Alby, F.; Maurel, S.; Doerig, C.; Meijerf, L.; Sauvain, M. Bioorg. Med. Chem. 2006, 14, 4477–4482. , S.; Jekabsons, M.B.; Zhou, Y.; Nagle, D.G.J.Nat.Prod. 2012, 75, 1553–1559. (f) Sergio R. Ricardo García,MiliciadesMejía,Craig R.Fairchild,Kate E.Lane,Ana T.Menendez,Norman R.Farnsworth,Geoffrey A.Cordell,John M.Pezzuto,and A.Douglas Kinghorn,J.Nat.Prod.2000,63,492 –495. (g) Sugimoto, K.; Tamura, K.; Tohda, C.; Toyooka, N.; Nemoto, H.; Matsu y, Y. Bioorg. Med. Chem. 2013, 21, 4459–4471. (h) Zhao, M.; Onakpa, M.M.; Santarsiero, B.D.; Huang, X.; Zhang, X.; Chen, J.; Cheng , J.; Longnecker, R.; Che, C. Org. Lett. 2015, 17, 3834–3837. (i) Zhao, M.; Onakpa, M.M.; Santarsiero, B.D.; Chen, W.; K.M.; Swanson, S.M.; Burdette, J.E.; Che, C.J. Nat. Prod. 2015, 78, 2731–2737. ; Zhao, M.; Zhang, X.; Swanson, S.M.; Burdette, J.E.; Che, C.J. Nat. Prod. 2016, 79, 1815–1821.).

螺吡咯烷酮作为优势结构也广泛存在各种人工合成的药物分子当中，可以作为镉肝毒性改善剂、醛糖还原酶抑制剂等((a)Zheng,Y.；Tice,C.M.；Singh,S.B.Bioorg.Med.Chem.Lett.2014,24,3673–3682.(b)Sk,U.H.；Sharma,K.A.；Ghosh,S.；Bhattacharya,S.Eur.J.Med.Chem.2010,45,3265–3273.(c)Malamas,M.S.；Hohman,T.C.；Millen,J.J.Med.Chem.1994,37,2043–2058.(d)Wrobel,J.；Dietrich,A.；Woolson,S.A.；Millen,J.；McCaleb,M.；Harrison,M.C.；Hohman,T.C.；Sredy,J.；Sullivan,D.J.Med.Chem.1992,35,4613–4627.(e)Crooks,P.A.；Szyndler,R.J.Med.Chem.1980,23,679–682.)。As a dominant structure, spiropyrrolidone also widely exists in various synthetic drug molecules, and can be used as cadmium hepatotoxicity improver, aldose reductase inhibitor, etc. ((a) Zheng, Y.; Tice, C.M.; Singh, S.B. Bioorg. 2014, 24, 3673–3682. (b) Sk, U.H.; Sharma, K.A.; Ghosh, S.; (c) Malamas, M.S.; Hohman, T.C.; Millen, J.J. Med.Chem. 1994, 37, 2043–2058. (d) Wrobel, J.; Dietrich, A.; Woolson, S.A.; Millen, J.; McCaleb, M.; Harrison, M.C.; Hohman, T.C.; Sredy, J.; Sullivan, D.J. Med.Chem. .).)

为了获得具有四氢萘并呋喃酮结构的化合物，采用传统的合成方法所需要的步骤较长，原料不易得，原子经济性和步骤经济性低，需要用到昂贵的金属催化剂和手性配体，因此迫切需要开发简洁高效的新型合成路线((a)Alvarez-Manzaneda,E.；Chahboun,R.；Alvarez,E.；Ramos,J.M.；Guardia,J.J.；Messouri,I.；Chayboun,I.；Mansour,A.I.；Dahdouh,A.Synthesis2010,20,3493–3503.(b)Lang,Y.；Souza,F.E.S.；Xu,X.；Taylor,N.J.；Assoud,A.；Rodrigo,R.J.Org.Chem.2009,74,5429–5439.(c)Shen,R.；Huang,X.Org.Lett.2008,10,3283–3286.(d)Wang,Y.；Cui,S.；Lin,X.Org.Lett.2006,8,1241–1244.(e)Matsuya,Y.；Sasaki,K.；Nagaoka,M.；Kakuda,H.；Toyooka,N.；Imanishi,N.；Ochiai,H.；Nemoto,H.J.Org.Chem.2004,69,7989–7993.(f)Hanessian,S.；Ma,J.Tetrahedron Lett.2001,42,8785–8788.(g)Kablaoui,N.M.；Hicks,F.A.；Buchwald,S.L.J.Am.Chem.Soc.1997,119,4424–4431.(h)Carlini,R.；Higgs,K.；Older,C.；Randhawa,S.J.Org.Chem.1997,62,2330–2331.(i)Sutherland,H.S.；Higgs,K.C.；Taylor,N.J.；Rodrigo,R.Tetrahedron 2001,57,309–317.(j)Harada,N.；Sugioka,T.；Uda,H.；Kuriki,T.；Kobayashi,M.；Kitagawa,I.J.Org.Chem.1994,59,6606–6613.(k)Harada,N.；Sugioka,T.；Uda,H.；Kuriki,T.J.Org.Chem.1990,55,3158–3163.(l)Miyazaki,F.；Uotsu,K.；Shibasaki,M.Tetrahedron 1998,54,13073–13078.(m)Jeffs,P.W.；Molina,G.；Cass,M.W.；Cortese,N.A.J.Org.Chem.1982,47,3871–3875.)。Stephenson和Chemler小组分别独立发展了钯催化和铜催化氧化串联反应序列构建四氢萘并呋喃酮三环骨架((a)Matsuura,B.S.；Condie,A.G.；Buff,R.C.；Karahalis,G.J.；Stephenson,C.R.J.Org.Lett.2011,13,6320–6323.(b)Miller,Y.；Miao,L.；Hosseini,A.S.；Chemler,S.R.J.Am.Chem.Soc.2012,134,12149–12156.(c)Bovino,M.T.；Liwosz,T.W.；Kendel,N.E.；Miller,Y.；Tyminska,N.；Zurek,E.；Chemler,S.R.Angew.Chem.,Int.Ed.2014,53,6383–6387.)。最近Peng小组报道了镍催化还原串联反应序列合成四氢萘并呋喃酮化合物(Peng,Y.；Xiao,J.；Xu,X.；Duan,S.；Ren,L.；Shao,Y.；Wang,Y.Org.Lett.2016,18,5170-5173.)。以上三个小组均实现了一锅多步的串联反应制备复杂四氢萘并呋喃酮化合物，大大提高了步骤经济性。但他们的反应底物非常复杂，需预留出多个双键或卤素反应位点，原料并非简单易得，最重要的是他们均使用了金属催化剂和过量的氧化剂和还原剂。过量的添加剂不可避免产生化学计量的副产物，大大降低了串联反应的原子经济性。而金属催化剂的使用则极大的限制了其方法在药物合成工业中的应用前景，因为金属催化剂可能造成金属残留问题，非常不利于后期分离纯化。In order to obtain a compound with a tetrahydronaphthofuranone structure, the traditional synthesis method requires long steps, the raw materials are not readily available, the atom economy and step economy are low, and expensive metal catalysts and chiral ligands are required. , so there is an urgent need to develop concise and efficient new synthetic routes ((a) Alvarez-Manzaneda, E.; Chahboun, R.; Alvarez, E.; Ramos, J.M.; Guardia, J.J.; Messiouri, I.; Chayboun, I.; Mansour, A.I.; Dahdouh, A. Synthesis 2010, 20, 3493–3503. (b) Lang, Y.; Souza, F.E.S.; Xu, X.; Taylor, N.J.; Assoud, A.; , 74, 5429–5439. (c) Shen, R.; Huang, X. Org. Lett. 2008, 10, 3283–3286. (d) Wang, Y.; Cui, S.; Lin, X. Org. Lett. 2006, 8, 1241–1244. (e) Matsuya, Y.; Sasaki, K.; Nagaoka, M.; Kakuda, H.; Toyooka, N.; Imanishi, N.; Ochiai, H.; Nemoto, 2004, 69, 7989–7993. (f) Hanessian, S.; Ma, J. Tetrahedron Lett. 2001, 42, 8785–8788. (g) Kablaoui, N.M.; Hicks, F.A.; Am. Chem. Soc. 1997, 119, 4424–4431. (h) Carlini, R.; Higgs, K.; Older, C.; Randhawa, S. J. Org. Chem. Sutherland, H.S.; Higgs, K.C.; Taylor, N.J.; Rodrigo, R. Tetrahedron 2001, 57, 309–317. (j) Harada, N.; Sugioka, T.; Uda, H.; Kuriki, T.; Kobayashi, M. ; Kitagawa, I.J.Org.Chem.1994,59,6606–6613.(k)Harada,N.;Sugioka,T.;Uda,H.; l) Miyazaki, F.; Uotsu, K.; Shibasaki, M. Tetrahedron 1998, 54, 13073–13078. (m) Jeffs, P.W.; Molina, G.; Cass, M.W.; Cortese, N.A.J.Org.Chem. 3875.). Stephenson and Chemler's groups independently developed palladium-catalyzed and copper-catalyzed oxidation tandem reaction sequences to construct tetrahydronaphthofuranone tricyclic skeletons ((a) Matsuura, B.S.; Condie, A.G.; Buff, R.C.; Karahalis, G.J.; Stephenson, C.R.J. Org. Lett. 2011, 13, 6320–6323. (b) Miller, Y.; Miao, L.; Hosseini, A.S.; Chemler, S.R.J.Am.Chem.Soc. , M.T.; Liwosz, T.W.; Kendel, N.E.; Miller, Y.; Tyminska, N.; Zurek, E.; Chemler, S.R. Angew. Chem., Int. Ed. 2014, 53, 6383–6387.). Recently, Peng's group reported the synthesis of tetrahydronaphthofuranone compounds by a series of nickel-catalyzed reduction reactions (Peng, Y.; Xiao, J.; Xu, X.; Duan, S.; Ren, L.; Shao, Y.; Wang, Y. Org. Lett. 2016, 18, 5170-5173.). The above three groups have realized the preparation of complex tetrahydronaphthofuranone compounds by one-pot multi-step series reaction, which greatly improves the step economy. However, their reaction substrates are very complex, and multiple double bonds or halogen reaction sites need to be reserved. The raw materials are not simple and easy to obtain. The most important thing is that they all use metal catalysts and excess oxidants and reductants. Excessive additives inevitably produce stoichiometric by-products, which greatly reduces the atom economy of tandem reactions. The use of metal catalysts greatly limits the application prospects of the method in the pharmaceutical synthesis industry, because metal catalysts may cause metal residues, which are very unfavorable for later separation and purification.

近十年兴起的有机催化则可以从根本上解决医药合成工业中金属残留的问题，因为有机催化采用的催化剂是有机小分子，避免使用金属，所以有机催化从一出现就受到有机化学家和药物学家的广泛关注((a)Sahoo,B.M.；Banik,B.K.Curr.Organocatalysis,2019,6,92-105.(b)Hughes,D.L.Org.Process Res.Dev.2018,22,574-584.(c)Y.；Qin,Zhu,L.；Luo,S.Chem.Rev.2017,117,9433-9520.(d)Vogel,P.；Lam,Y.；Simon,A.；Houk,K.N.Catalysts 2016,6,128.(e)Alemán,J.；Cabrera,S.Chem.Soc.Rev.2013,42,774-793.)。有机催化串联反应策略的出现，进一步大大增强了有机催化的实用性((a)Vetica,F.；Chauhan,P.；Dochain,S.；Enders,D.Chem.Soc.Rev.2017,46,1661–1674.(b)Wang,Y.；Lu,H.；Xu,P.Acc.Chem.Res.2015,48,1832–1844.(c)Volla,C.M.R.；Atodiresei,I.；Rueping,M.Chem.Rev.2014,114,2390–2431.(d)Pellissier,H.Adv.Synth.Catal.2012,354,237–294.(e)Marson,C.M.Chem.Soc.Rev.2012,41,7712–7722.(f)Moyano,A.；Rios,R.Chem.Rev.2011,111,4703–4832.(g)Xu,P.；Wang,W.Catalytic Cascade Reactions；Wiley,Hoboken,2013.(h)Pellissier,H.Asymmetric Domino Reactions；RSCPublishing:Cambridge,U.K.,2013.(i)Bonne,D.；Rodriguez,J.StereoselectiveMultiple Bondforming Transformations in Organic Synthesis；Wiley,Hoboken,2015.)。发明人的课题组也发展了几类有机催化串联反应，构筑手性杂环化合物((a)Zhou,Y.；Wei,Y.；Rodriguez,J.；Coquerel,Y.Angew.Chem.Int.Ed.2019,58,456–460.(b)Zhou,Y.；Yang,Q.；Shen,J.；Chen,X.；Peng,Y.；Gong,Y.J.Org.Chem.2015,80,1446–1456.(c)Zhang,F.；Wei,M.；Dong,J.；Zhou,Y.；Lu,D.；Gong,Y.；Yang,X.Adv.Synth.Catal.2010,352,2875–2880.(d)Wei,M.；Zhou,Y.；Gu,L.；Luo,F.；Zhang,F.Tetrahedron Lett.2013,54,2546–2548.)。此外发明人还发展了邻位吡咯烷酮取代的苯甲醛作为双官能平台分子，可以发生一系列串联反应合成杂环化合物(10.(a)Li,F.；Zhou,Y.；Yang,H.；Liu,D.；Sun,B.；Zhang,F.Org.Lett.2018,20,146–149.(b)Liu,W.；Yang,H.；Sun,B.；Zhang,F.；Liu,D.；Zheng,H.Tetrahedron Lett.2018,59,3554–3557.(c)Yang,H.；Liu,D.；Yu,Q.；Xia,S.；Yu,D.；Zhang,M.；Sun,B.；Zhang,F.Eur.J.Org.Chem.2019,852–856.)。但之前的反应模式较为单一，均是从苄位的加成开始，然后以分子内另一组分对醛基的亲核进攻结束。从多样性导向合成角度出发，迫切需要开发更多的新型串联反应模式，实现复杂螺环化合物的合成(11.(a)Garcia-Castro,M.；Zimmermann,S.；Sankar,M.G.；Kumar,K.Angew.Chem.Int.Ed.2016,55,7586–7605.(b)O’Connor,C.J.；Beckmann,H.S.G.；Spring,D.R.Chem.Soc.Rev.2012,41,4444–4456.(c)Schreiber,S.L.Science 2000,287,1964–1969.)。Organocatalysis, which has emerged in the past decade, can fundamentally solve the problem of metal residues in the pharmaceutical synthesis industry. Because the catalysts used in organic catalysis are small organic molecules and avoid the use of metals, organic catalysis has been favored by organic chemists and drugs since its emergence. ((a) Sahoo, B.M.; Banik, B.K.Curr.Organocatalysis, 2019,6,92-105.(b) Hughes, D.L.Org.Process Res.Dev.2018,22,574-584.(c) Y.; Qin, Zhu, L.; Luo, S. Chem. Rev. 2017, 117, 9433-9520. (d) Vogel, P.; Lam, Y.; Simon, A.; Houk, K.N. Catalysts 2016, 6, 128. (e) Alemán, J.; Cabrera, S. Chem. Soc. Rev. 2013, 42, 774-793.). The emergence of organocatalytic tandem reaction strategies has further greatly enhanced the practicality of organocatalysis ((a) Vetica, F.; Chauhan, P.; Dochain, S.; Enders, D.Chem.Soc.Rev.2017,46, 1661–1674. (b) Wang, Y.; Lu, H.; Xu, P. Acc. Chem. Res. 2015, 48, 1832–1844. (c) Volla, C.M.R.; Atodiresei, I.; Rueping, M .Chem.Rev.2014,114,2390–2431.(d)Pellissier,H.Adv.Synth.Catal.2012,354,237–294.(e)Marson,C.M.Chem.Soc.Rev.2012,41,7712– 7722. (f) Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703–4832. (g) Xu, P.; Wang, W. Catalytic Cascade Reactions; Wiley, Hoboken, 2013. (h ) Pellissier, H. Asymmetric Domino Reactions; RSC Publishing: Cambridge, U.K., 2013. (i) Bonne, D.; Rodriguez, J. Stereoselective Multiple Bondforming Transformations in Organic Synthesis; Wiley, Hoboken, 2015.). The inventor's research group has also developed several types of organocatalytic tandem reactions to construct chiral heterocyclic compounds ((a) Zhou, Y.; Wei, Y.; Rodriguez, J.; Coquerel, Y. Angew. Chem. Int. Ed. 2019, 58, 456–460. (b) Zhou, Y.; Yang, Q.; Shen, J.; Chen, X.; Peng, Y.; .(c) Zhang, F.; Wei, M.; Dong, J.; Zhou, Y.; Lu, D.; Gong, Y.; Yang, X. Adv. Synth. Catal. 2010, 352, 2875– 2880. (d) Wei, M.; Zhou, Y.; Gu, L.; Luo, F.; Zhang, F. Tetrahedron Lett. 2013, 54, 2546–2548.). In addition, the inventors have also developed ortho-pyrrolidone-substituted benzaldehyde as a bifunctional platform molecule, which can undergo a series of tandem reactions to synthesize heterocyclic compounds (10.(a)Li,F.; Zhou, Y.; Yang, H.; Liu, D.; Sun, B.; Zhang, F. Org. Lett. 2018, 20, 146–149. (b) Liu, W.; Yang, H.; Sun, B.; Zhang, F.; Liu, D. .; Zheng, H. Tetrahedron Lett. 2018, 59, 3554–3557. (c) Yang, H.; Liu, D.; Yu, Q.; Xia, S.; Yu, D.; Zhang, M.; Sun, B.; Zhang, F. Eur. J. Org. Chem. 2019, 852–856.). However, the previous reaction modes were relatively simple, starting from the addition of the benzylic position, and then ended with the nucleophilic attack of the aldehyde group by another component in the molecule. From the perspective of diversity-oriented synthesis, it is urgent to develop more novel tandem reaction modes to realize the synthesis of complex spiro compounds (11.(a) Garcia-Castro, M.; Zimmermann, S.; Sankar, M.G.; Kumar, K.Angew.Chem.Int.Ed.2016,55,7586–7605.(b)O'Connor,C.J.;Beckmann,H.S.G.;Spring,D.R.Chem.Soc.Rev.2012,41,4444–4456.(c ) Schreiber, S.L. Science 2000, 287, 1964–1969.).

另外，发明人发现2(5H)-呋喃酮作为一个有用的合成子，可以参与一系列有机化学反应，包括羟醛缩合反应((a)Yang,Y.；Zheng,K.；Zhao,J.；Shi,J.；Lin,L.；Liu,X.；Feng,X.J.Org.Chem.2010,75,5382–5384.(b)Pansare,S.V.；Paul,E.K.Chem.Commun.2011,47,1027–1029.(c)Pansare,S.V.；Paul,E.K.Org.Biomol.Chem.2012,10,2119–2125.(d)Claraz,A.；Oudeyer,S.；Levacher,V.Adv.Synth.Catal.2013,841–846.(e)Sakai,T.；Hirashima,S.；Yamashita,Y.；Arai,R.；Nakashima,K.；Yoshida,A.；Koseki,Y.；Miura,T.J.Org.Chem.2017,82,4661–4667.)；迈克尔加成反应((a)Trost,B.M.；Hitce,J.J.Am.Chem.Soc.2009,131,4572–4573.(b)Zhang,Y.；Yu,C.；Ji,Y.；Wang,W.Chem.Asian J.2010,5,1303–1306.(c)Huang,H.；Yu,F.；Jin,Z.；Li,W.；Wu,W.；Liang,X.；Ye,J.Chem.Commun.2010,46,5957–5959.(d)Luo,X.；Zhou,Z.；Yu,F.；Li,X.；Liang,X.；Ye,J.Chem.Lett.2011,40,518–520.(e)Yin,L.；Takada,H.；Lin,S.；Kumagai,N.；Shibasaki,M.Angew.Chem.Int.Ed.2014,53,5327–5331.(f)Zhang,M.；Kumagai,N.；Shibasaki,M.Chem.Eur.J.2016,22,5525–5529.)；曼尼希反应((a)Yamaguchi,A.；Matsunaga,S.；Shibasaki,M.Org.Lett.2008,10,2319–2322.(b)Yin,L.；Takada,H.；Kumagai,N.；Shibasaki,M.Angew.Chem.Int.Ed.2013,52,7310–7313.(c)Nakamura,S.；Yamaji,R.；Hayashi,M.Chem.Eur.J.2015,21,9615–9618.(d)Trost,B.M.；Gnanamani,E.；Tracy,J.S.；Kalnmals,C.A.J.Am.Chem.Soc.2017,139,18198–18201.)等等。但是基于2(5H)-呋喃酮的串联反应则非常罕见，到目前只有一例(Yang,J.；Huang,H.；Jin,Z.；Wu,W.；Ye,J.Synthesis 2011,12,1984–1987.)，因此开发基于2(5H)-呋喃酮合成子的多样性导向串联反应，来高效制备复杂多环环化合物具有重要的意义和研究价值。In addition, the inventors found that 2(5H)-furanone, as a useful synthon, can participate in a series of organic chemical reactions, including aldol condensation reactions ((a) Yang, Y.; Zheng, K.; Zhao, J. ; Shi, J.; Lin, L.; Liu, X.; Feng, X. J. Org. Chem. 2010, 75, 5382–5384. (b) Pansare, S. V.; -1029. (c) Pansare, S.V.; Paul, E.K.Org.Biomol.Chem. 2012, 10, 2119–2125. 2013, 841–846. (e) Sakai, T.; Hirashima, S.; Yamashita, Y.; Arai, R.; Nakashima, K.; Yoshida, A.; Koseki, Y.; Miura, T.J. . 2017, 82, 4661–4667.); Michael addition reactions ((a) Trost, B.M.; Hitce, J.J. Am. Chem. Soc. 2009, 131, 4572–4573. (b) Zhang, Y.; Yu, C.; Ji, Y.; Wang, W. Chem. Asian J. 2010, 5, 1303–1306. (c) Huang, H.; Yu, F.; Jin, Z.; Li, W.; Wu, W.; Liang, X.; Ye, J. Chem. Commun. 2010, 46, 5957–5959. (d) Luo, X.; Zhou, Z.; Yu, F.; Li, X.; Liang, X. .; Ye, J. Chem. Lett. 2011, 40, 518–520. (e) Yin, L.; Takada, H.; Lin, S.; Kumagai, N.; 2014, 53, 5327–5331. (f) Zhang, M.; Kumagai, N.; Shibasaki, M. Chem. Eur. J. 2016, 22, 5525–5529.); Mannich reaction ((a) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 2319–2322. (b) Yin, L.; Takada, H.; Kumagai, N.; Shibasaki, M. Angew. Chem.Int.Ed.2013, 52, 7310–7313. (c) Nakamura, S.; Yamaji, R.; Hayashi, M. Chem. Eur. J. 2015, 21, 9615–9618. (d) Trost, B. M.; Gnanamani, E.; Tracy , J.S.; Kalnmals, C.A.J.Am.Chem.Soc. 2017, 139, 18198–18201.) et al. However, the tandem reaction based on 2(5H)-furanone is very rare, and there is only one case so far (Yang, J.; Huang, H.; Jin, Z.; Wu, W.; Ye, J. Synthesis 2011, 12, 1984–1987.), it is of great significance and research value to develop a diversity-directed tandem reaction based on the 2(5H)-furanone synthon to efficiently prepare complex polycyclic compounds.

发明内容SUMMARY OF THE INVENTION

针对背景技术中提到的问题，本发明提供四氢萘并呋喃酮螺吡咯烷酮化合物及其制备方法。In view of the problems mentioned in the background art, the present invention provides a tetrahydronaphthofuranone spiropyrrolidone compound and a preparation method thereof.

本发明提供的四氢萘并呋喃酮螺吡咯烷酮化合物，具有如式3所示的结构：The tetrahydronaphthofuranone spiropyrrolidone compound provided by the present invention has the structure shown in formula 3:

Figure BDA0002370852880000051
Figure BDA0002370852880000051

其中，R1、R2、R3独立地选自氢、卤素、C1～C4的烷基、苯基、萘基、硝基、酯基、甲砜基等基团，R4选自C1～C4的烷基、含有取代基的C1～C4的烷基等基团。Wherein, R 1 , R 2 , R 3 are independently selected from hydrogen, halogen, C 1 -C 4 alkyl, phenyl, naphthyl, nitro, ester, methylsulfonyl and other groups, and R 4 is selected from Groups such as a C 1 -C 4 alkyl group and a C 1 -C 4 alkyl group containing a substituent.

优选的，R1、R2、R3独立地选自H、Me、Et、Ph、F、Cl、Br、-NO2、-CO2Me、-SO2Me，R4选自Me、Et、-CH2CH2Ph。Preferably, R 1 , R 2 and R 3 are independently selected from H, Me, Et, Ph, F, Cl, Br, -NO 2 , -CO 2 Me, -SO 2 Me, and R 4 is selected from Me, Et , -CH 2 CH 2 Ph.

更优选的，所述的四氢萘并呋喃酮螺吡咯烷酮化合物具有如式3a～3s中任一所示的结构：More preferably, the tetrahydronaphthofuranone spiropyrrolidone compound has the structure shown in any one of formulas 3a to 3s:

Figure BDA0002370852880000052
Figure BDA0002370852880000052

Figure BDA0002370852880000061
Figure BDA0002370852880000061

所述的四氢萘并呋喃酮螺吡咯烷酮化合物的制备方法，包括以下步骤：在有机溶剂中，在催化剂参与的条件下，使式1所示的化合物(邻位吡咯烷酮取代的苯甲醛或其衍生物)与式2所示的化合物(2(5H)-呋喃酮)反应，得到所述的四氢萘并呋喃酮螺吡咯烷酮化合物；The preparation method of the described tetrahydronaphthofuranone spiropyrrolidone compound, comprises the following steps: in an organic solvent, under the condition that a catalyst participates, make the compound shown in formula 1 (the ortho-pyrrolidone-substituted benzaldehyde or its derivative). compound) reacts with the compound (2(5H)-furanone) shown in formula 2 to obtain the tetrahydronaphthofuranone spiropyrrolidone compound;

Figure BDA0002370852880000062
Figure BDA0002370852880000062

其中，R1、R2、R3、R4的定义与上文相同。Here, R 1 , R 2 , R 3 , and R 4 have the same definitions as above.

上述方法中，式1所示的化合物与式2所示的化合物的摩尔比例可以为1:1.5、1:1.2或1:1。In the above method, the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 may be 1:1.5, 1:1.2 or 1:1.

上述方法中，有机溶剂可以为二氯甲烷、1,2-二氯乙烷、丙酮、甲醇或二甲亚砜。In the above method, the organic solvent can be dichloromethane, 1,2-dichloroethane, acetone, methanol or dimethyl sulfoxide.

上述方法中，催化剂可以为碳酸钾、碳酸铯或1,8-二氮杂二环十一碳-7-烯(DBU)。In the above method, the catalyst may be potassium carbonate, cesium carbonate or 1,8-diazabicycloundec-7-ene (DBU).

上述方法中，反应温度可以为室温、60℃或100℃，反应时间可以为4到24小时。In the above method, the reaction temperature may be room temperature, 60° C. or 100° C., and the reaction time may be 4 to 24 hours.

所述的四氢萘并呋喃酮螺吡咯烷酮化合物可以应用于抗肿瘤或抗疟疾等药物中。The tetrahydronaphthofuranone spiropyrrolidone compound can be used in medicines such as anti-tumor or anti-malarial.

本发明的技术效果是：本发明利用有机催化直接区域选择性插烯羟醛缩合-迈克尔加成串联反应，制得四氢萘并呋喃酮螺吡咯烷酮化合物；从邻位吡咯烷酮取代的苯甲醛和2(5H)-呋喃酮出发，在温和的条件下高效率、高选择性地合成四氢萘并呋喃酮螺吡咯烷酮化合物。本发明方法的反应收率可达到中等到优秀，反应的化学选择性高，条件温和，底物适用范围广，操作简便，成本较低，副反应少，产品纯度高，便于分离提纯和可适用于较大规模的制备。本方法所得产物具有潜在的生物和药物活性，因此可应用于生物医药领域，具有非常好的应用前景。The technical effects of the present invention are: the present invention utilizes organic catalytic direct regioselective vinylaldol condensation-Michael addition series reaction to prepare tetrahydronaphthofuranone spiropyrrolidone compound; Starting from (5H)-furanone, the tetrahydronaphthofuranone spiropyrrolidone compound was synthesized with high efficiency and high selectivity under mild conditions. The reaction yield of the method of the invention can reach medium to excellent, the chemical selectivity of the reaction is high, the conditions are mild, the substrate application range is wide, the operation is simple, the cost is low, the side reactions are few, the product purity is high, and the separation and purification is convenient and applicable. for larger scale preparations. The product obtained by the method has potential biological and pharmaceutical activities, so it can be applied in the field of biomedicine and has a very good application prospect.

附图说明Description of drawings

图1为四氢萘并呋喃酮螺吡咯烷酮化合物3a的X-单晶衍射结构图。FIG. 1 is an X-single crystal diffraction structure diagram of the tetrahydronaphthofuranone spiropyrrolidone compound 3a.

图2为四氢萘并呋喃酮螺吡咯烷酮化合物3a的分子结构图。Figure 2 is a molecular structure diagram of the tetrahydronaphthofuranone spiropyrrolidone compound 3a.

具体实施方式Detailed ways

下面将结合附图实施例详细说明本发明所具有的有益效果，旨在帮助阅读者更好地理解本发明的实质，但不能对本发明的实施和保护范围构成任何限定。The beneficial effects of the present invention will be described in detail below with reference to the embodiments of the accompanying drawings, which are intended to help readers better understand the essence of the present invention, but cannot constitute any limitation to the implementation and protection scope of the present invention.

本发明方法的具体操作为：向反应试管中分别依次加入邻位吡咯烷酮取代的苯甲醛或其衍生物、2(5H)-呋喃酮、催化剂，再加入有机溶剂，用橡胶塞密封反应试管；把试管置于一定温度的油浴中搅拌加热一段时间，反应过程中用TLC检测至完全反应；后处理时先将溶剂旋干，再直接上硅胶柱层析分离得纯净的产物四氢萘并呋喃酮螺吡咯烷酮化合物3。The specific operation of the method of the invention is as follows: adding ortho-pyrrolidone-substituted benzaldehyde or its derivative, 2(5H)-furanone, and a catalyst into the reaction test tube in sequence, then adding an organic solvent, and sealing the reaction test tube with a rubber stopper; The test tube was stirred and heated for a period of time in an oil bath at a certain temperature. During the reaction, TLC was used to detect the complete reaction; during post-processing, the solvent was spin-dried, and then directly separated by silica gel column chromatography to obtain the pure product tetrahydronaphthofuran Ketospiropyrrolidone compound 3.

实施例1Example 1

Figure BDA0002370852880000081
Figure BDA0002370852880000081

向反应试管中分别依次加入邻位吡咯烷酮取代的苯甲醛1a(0.2mmol)、2(5H)-呋喃酮(1.5equiv)、1,8-二氮杂二环十一碳-7-烯(DBU，20mol％)，再加入二甲亚砜(2mL)，用橡胶塞密封反应试管。把反应试管置于60℃油浴中搅拌加热4小时左右，反应过程中用TLC检测至完全反应。然后将溶剂旋干，用硅胶柱层析分离得纯净的四氢萘并呋喃酮螺吡咯烷酮化合物3a。The ortho-pyrrolidone-substituted benzaldehyde 1a (0.2 mmol), 2(5H)-furanone (1.5 equiv), 1,8-diazabicycloundec-7-ene (DBU) were added to the reaction test tube in sequence. , 20 mol%), then dimethyl sulfoxide (2 mL) was added, and the reaction tube was sealed with a rubber stopper. The reaction test tube was placed in an oil bath at 60° C. and heated with stirring for about 4 hours. During the reaction, TLC was used to detect the complete reaction. Then the solvent was spin-dried, and purified tetrahydronaphthofuranone spiropyrrolidone compound 3a was isolated by silica gel column chromatography.

化合物3a，产率:90％。1H NMR(500MHz,CDCl3)δ7.10(s,1H),6.75(s,1H),5.39(d,J＝9.0Hz,1H),4.96(d,J＝12.0Hz,1H),4.76(d,J＝12.5Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H),3.42(dd,J＝20.0,10.0Hz,1H),3.34(d,J＝18.0Hz,1H),2.78(d,J＝18.5Hz,1H),2.51(dd,J＝18.0,9.5Hz,1H),2.46(s,3H),2.31(s,3H),2.17(dd,J＝17.5,11.0Hz,1H),1.12(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ180.6,173.9,173.6,140.8,139.2,133.3,132.9,130.8,123.3,84.0,67.2,50.3,41.7,41.5,34.6,31.1,21.3,19.2,12.7.HRMS(pos.ESI):m/z[M+H]+for C19H22NO5 calcd:344.1492,found:344.1499。Compound 3a, yield: 90%. 1 H NMR (500 MHz, CDCl 3 ) δ 7.10 (s, 1H), 6.75 (s, 1H), 5.39 (d, J=9.0 Hz, 1H), 4.96 (d, J=12.0 Hz, 1H), 4.76 (d, J=12.5Hz, 1H), 3.54 (dtt, J=20.5, 14.0, 7.0Hz, 2H), 3.42 (dd, J=20.0, 10.0Hz, 1H), 3.34 (d, J=18.0Hz, 1H), 2.78(d, J=18.5Hz, 1H), 2.51(dd, J=18.0, 9.5Hz, 1H), 2.46(s, 3H), 2.31(s, 3H), 2.17(dd, J=17.5 , 11.0Hz, 1H), 1.12 (t, J=7.0Hz, 3H); 13 C NMR (125MHz, CDCl 3 ) δ 180.6, 173.9, 173.6, 140.8, 139.2, 133.3, 132.9, 130.8, 123.3, 84.0, 67.2, 50.3, 41.7, 41.5, 34.6, 31.1, 21.3, 19.2, 12.7. HRMS(pos.ESI): m/z[M+H] + for C 19 H 22 NO 5 calcd: 344.1492, found: 344.1499.

仅改变相应的反应物，用同样的方法得到实施例2-19。Examples 2-19 were obtained in the same manner, only changing the corresponding reactants.

实施例2Example 2

Figure BDA0002370852880000082
Figure BDA0002370852880000082

化合物3b，产率:75％；6:1dr。Major isomer:1H NMR(500MHz,CDCl3)δ7.01(dd,J＝9.0,2.0Hz,1H),6.71(dd,J＝9.5,2.5Hz,1H),5.37(d,J＝9.0Hz,1H),4.95(d,J＝11.5Hz,1H),4.82–4.78(m,1H),3.55(dd,J＝9.0,7.5Hz,2H),3.47(q,J＝9.5Hz,1H),3.28(d,J＝18.0Hz,1H),2.85(d,J＝18.5Hz,1H),2.56(dd,J＝17.5,9.5Hz,1H),2.51(s,3H),2.15(dd,J＝18.0,7.0Hz,1H),1.12(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ180.0,173.4,173.3,162.4(d,JC-F＝247.9Hz),144.1(d,JC-F＝8.1Hz),133.2(d,JC-F＝7.3Hz),132.4(d,JC-F＝3.3Hz),118.9(d,JC-F＝20.4Hz),109.9(d,JC-F＝22.8Hz),83.7,67.0,50.5(d,JC-F＝1.6Hz),41.4,41.3,34.7,31.0,19.6(d,JC-F＝1.4Hz),12.6.Minor isomer:1H NMR(500MHz,CDCl3)δ6.93(dd,J＝9.0,2.0Hz,1H),6.53(dd,J＝9.0,2.5Hz,1H),5.38(d,J＝9.0Hz,1H),4.82–4.78(m,1H),3.71(qd,J＝7.5,2.0Hz,2H),3.47(q,J＝9.5Hz,1H),3.13(d,J＝20.0Hz,1H),2.75(d,J＝18.5Hz,1H),2.47(s,3H),1.28(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ179.9,175.2,174.7,162.6(d,JC-F＝247.9Hz),141.1(d,JC-F＝8.4Hz),140.9(d,JC-F＝7.6Hz),128.7(d,JC-F＝3.1Hz),117.2(d,JC-F＝20.9Hz),110.2(d,JC-F＝22.9Hz),78.5,63.2,50.7(d,JC-F＝1.6Hz),42.5,37.0,34.5,30.4,19.3(d,JC-F＝1.1Hz),13.2.HRMS(pos.ESI):m/z[M+H]+for C18H19FNO5 calcd:348.1242,found:348.1250。Compound 3b, yield: 75%; 6: 1 dr. Major isomer: 1 H NMR (500 MHz, CDCl 3 ) δ 7.01 (dd, J=9.0, 2.0 Hz, 1H), 6.71 (dd, J=9.5, 2.5 Hz, 1H), 5.37 (d, J=9.0 Hz) ,1H),4.95(d,J＝11.5Hz,1H),4.82–4.78(m,1H),3.55(dd,J＝9.0,7.5Hz,2H),3.47(q,J＝9.5Hz,1H) ,3.28(d,J＝18.0Hz,1H),2.85(d,J＝18.5Hz,1H),2.56(dd,J＝17.5,9.5Hz,1H),2.51(s,3H),2.15(dd, J=18.0, 7.0 Hz, 1H), 1.12 (t, J=7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 180.0, 173.4, 173.3, 162.4 (d, J CF =247.9 Hz), 144.1 ( d, J CF = 8.1 Hz), 133.2 (d, J CF = 7.3 Hz), 132.4 (d, J CF = 3.3 Hz), 118.9 (d, J CF = 20.4 Hz), 109.9 (d, J CF = 22.8 Hz), 83.7, 67.0, 50.5 (d, J CF = 1.6 Hz), 41.4, 41.3, 34.7, 31.0, 19.6 (d, J CF = 1.4 Hz), 12.6. Minor isomer: 1 H NMR (500 MHz, CDCl 3 )δ6.93(dd,J＝9.0,2.0Hz,1H),6.53(dd,J＝9.0,2.5Hz,1H),5.38(d,J＝9.0Hz,1H),4.82–4.78(m,1H ), 3.71(qd, J＝7.5, 2.0Hz, 2H), 3.47(q, J＝9.5Hz, 1H), 3.13(d, J＝20.0Hz, 1H), 2.75(d, J＝18.5Hz, 1H) ), 2.47(s, 3H), 1.28(t, J=7.0Hz, 3H); 13 C NMR(125MHz, CDCl 3 ) δ 179.9, 175.2, 174.7, 162.6(d, J CF =247.9Hz), 141.1(d , J CF = 8.4 Hz), 140.9 (d, J CF = 7.6 Hz), 128.7 (d, J CF = 3.1 Hz), 117.2 (d, J CF = 20.9 Hz), 110.2 (d, J CF = 22.9 Hz) ), 78.5, 63.2, 50.7 (d, J CF = 1.6 Hz), 42.5, 37.0 , 34.5, 30.4, 19.3 (d, J CF = 1.1 Hz), 13.2. HRMS (pos. ESI): m/z [M+H] + for C 18 H 19 FNO 5 calcd: 348.1242, found: 348.1250.

实施例3Example 3

Figure BDA0002370852880000091
Figure BDA0002370852880000091

化合物3c，产率:80％。1H NMR(500MHz,CDCl3)δ7.29(s,1H),6.98(d,J＝1.5Hz,1H),5.37(d,J＝9.0Hz,1H),4.94(d,J＝12.5Hz,1H),4.80(d,J＝12.5Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H),3.46(dd,J＝20.0 9.5Hz,1H),3.32(d,J＝18.0Hz,1H),2.85(d,J＝18.0Hz,1H),2.56(dd,J＝17.5,9.5Hz,1H),2.50(s,3H),2.15(dd,J＝17.5,11.0Hz,1H),1.14(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ179.9,173.3,143.1,135.0,134.9,132.8,131.9,123.0,83.6,67.1,50.3,41.5,41.3,34.7,30.9,19.3,12.7.HRMS(pos.ESI):m/z[M+H]+for C18H19ClNO5 calcd:364.0946,found:364.0955。Compound 3c, yield: 80%. 1 H NMR (500MHz, CDCl 3 ) δ 7.29 (s, 1H), 6.98 (d, J=1.5Hz, 1H), 5.37 (d, J=9.0Hz, 1H), 4.94 (d, J=12.5Hz) ,1H),4.80(d,J＝12.5Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H),3.46(dd,J＝20.0 9.5Hz,1H),3.32(d,J ＝18.0Hz, 1H), 2.85(d, J＝18.0Hz, 1H), 2.56(dd, J＝17.5, 9.5Hz, 1H), 2.50(s, 3H), 2.15(dd, J＝17.5, 11.0Hz) , 1H), 1.14 (t, J=7.0Hz, 3H); 13 C NMR (125MHz, CDCl 3 ) δ 179.9, 173.3, 143.1, 135.0, 134.9, 132.8, 131.9, 123.0, 83.6, 67.1, 50.3, 41.5, 41.3 , 34.7, 30.9, 19.3, 12.7. HRMS(pos.ESI): m/z[M+H] + for C 18 H 19 ClNO 5 calcd: 364.0946, found: 364.0955.

实施例4Example 4

Figure BDA0002370852880000101
Figure BDA0002370852880000101

化合物3d，产率:79％；19:1dr。Major isomer:1H NMR(500MHz,CDCl3)δ7.44(d,J＝1.0Hz,1H),7.12(d,J＝1.0Hz,1H),5.35(d,J＝9.0Hz,1H),4.93(d,J＝12.0Hz,1H),4.83(d,J＝12.0Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H),3.46(dd,J＝20.0,9.0Hz,1H),3.33(d,J＝18.5Hz,1H),2.85(d,J＝18.5Hz,1H),2.56(dd,J＝17.5,9.5Hz,1H),2.49(s,3H),2.16(dd,J＝18.0,11.0Hz,1H),1.14(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ180.0,173.34,173.3,143.3,135.5,134.9,133.0,125.9,123.2,83.5,67.1,50.2,41.5,41.2,34.7,30.9,19.2,12.7.Minor isomer:1H NMR(500MHz,CDCl3)δ7.38(d,J＝1.0Hz,1H),6.94(d,J＝1.0Hz,1H),4.93(d,J＝12.0Hz,2H),3.71(qd,J＝7.5,1.0Hz,2H),3.12(d,J＝19.5Hz,1H),2.79(d,J＝19.5Hz,1H),2.73(dd,J＝18.0,11.0Hz,1H),2.45(s,3H),1.28(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ179.8,175.2,174.6,140.7,140.4,133.4,131.9,126.1,123.5,78.3,63.3,50.6,42.5,37.1,34.5,30.4,19.0,13.2.HRMS(pos.ESI):m/z[M+H]+for C18H19BrNO5 calcd:408.0441,found:408.0451。Compound 3d, yield: 79%; 19: 1 dr. Major isomer: 1 H NMR (500MHz, CDCl 3 )δ7.44(d,J=1.0Hz,1H),7.12(d,J=1.0Hz,1H),5.35(d,J=9.0Hz,1H), 4.93(d,J＝12.0Hz,1H),4.83(d,J＝12.0Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H),3.46(dd,J＝20.0,9.0Hz ,1H),3.33(d,J＝18.5Hz,1H),2.85(d,J＝18.5Hz,1H),2.56(dd,J＝17.5,9.5Hz,1H),2.49(s,3H),2.16 (dd, J=18.0, 11.0 Hz, 1H), 1.14 (t, J=7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 180.0, 173.34, 173.3, 143.3, 135.5, 134.9, 133.0, 125.9, 123.2, 83.5, 67.1, 50.2, 41.5, 41.2, 34.7, 30.9, 19.2, 12.7. Minor isomer: 1 H NMR (500 MHz, CDCl 3 ) δ 7.38 (d, J=1.0 Hz, 1 H), 6.94 (d, J=1.0Hz, 1H), 4.93(d, J=12.0Hz, 2H), 3.71(qd, J=7.5, 1.0Hz, 2H), 3.12(d, J=19.5Hz, 1H), 2.79(d, J=19.5Hz, 1H), 2.73 (dd, J=18.0, 11.0Hz, 1H), 2.45 (s, 3H), 1.28 (t, J=7.0Hz, 3H); 13 C NMR (125MHz, CDCl 3 ) δ179.8,175.2,174.6,140.7,140.4,133.4,131.9,126.1,123.5,78.3,63.3,50.6,42.5,37.1,34.5,30.4,19.0,13.2.HRMS(pos.ESI):m/z[M+H ] + for C 18 H 19 BrNO 5 calcd: 408.0441, found: 408.0451.

实施例5Example 5

Figure BDA0002370852880000102
Figure BDA0002370852880000102

化合物3e，产率:87％。1H NMR(500MHz,CDCl3)δ7.17(d,J＝8.0Hz,1H),6.89(d,J＝8.5Hz,1H),5.41(d,J＝9.5Hz,1H),5.07(d,J＝12.5Hz,1H),4.88(d,J＝12.5Hz,1H),3.52(dtt,J＝20.5,14.0,7.0Hz,2H),3.43(dd,J＝20.0,9.5Hz,1H),3.32(d,J＝18.0Hz,1H),2.81(d,J＝18.0Hz,1H),2.53(dd,J＝18.0,9.5Hz,1H),2.40(s,3H),2.31(s,3H),2.17(dd,J＝18.0,11.0Hz,1H),1.09(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ180.8,173.9,173.7,139.5,139.1,135.9,130.9,128.4,122.2,84.1,67.5,50.4,41.6,41.0,34.5,31.1,20.8,15.1,12.6.HRMS(pos.ESI):m/z[M+H]+for C19H22NO5 calcd:344.1492,found:344.1496。Compound 3e, yield: 87%. 1 H NMR (500 MHz, CDCl 3 ) δ 7.17 (d, J=8.0 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.41 (d, J=9.5 Hz, 1H), 5.07 (d , J=12.5Hz, 1H), 4.88 (d, J=12.5Hz, 1H), 3.52 (dtt, J=20.5, 14.0, 7.0Hz, 2H), 3.43 (dd, J=20.0, 9.5Hz, 1H) ,3.32(d,J＝18.0Hz,1H),2.81(d,J＝18.0Hz,1H),2.53(dd,J＝18.0,9.5Hz,1H),2.40(s,3H),2.31(s, 3H), 2.17 (dd, J=18.0, 11.0 Hz, 1H), 1.09 (t, J=7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 180.8, 173.9, 173.7, 139.5, 139.1, 135.9, 130.9,128.4,122.2,84.1,67.5,50.4,41.6,41.0,34.5,31.1,20.8,15.1,12.6.HRMS(pos.ESI):m/z[M+H] + for C 19 H 22 NO 5 calcd :344.1492,found:344.1496.

实施例6Example 6

Figure BDA0002370852880000111
Figure BDA0002370852880000111

化合物3f，产率:70％。1H NMR(500MHz,CDCl3)δ7.28(s,2H),6.99(d,J＝4.5Hz,1H),5.40(d,J＝9.0Hz,1H),5.00(d,J＝12.5Hz,1H),4.81(d,J＝12.5Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H),3.45(dd,J＝20.0,10.0Hz,1H),3.33(d,J＝18.0Hz,1H),2.81(d,J＝18.0Hz,1H),2.53(dd,J＝17.5,9.5Hz,1H),2.51(s,3H),2.17(dd,J＝17.5,11.0Hz,1H),1.10(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ180.5,173.8,173.6,141.0,136.3,132.1,131.0,129.2,122.8,83.9,67.3,50.4,41.7,41.3,34.5,31.5,19.3,12.6.HRMS(pos.ESI):m/z[M+H]+for C18H20NO5 calcd:330.1336,found:330.1345。Compound 3f, yield: 70%. 1 H NMR (500MHz, CDCl 3 ) δ 7.28 (s, 2H), 6.99 (d, J=4.5Hz, 1H), 5.40 (d, J=9.0Hz, 1H), 5.00 (d, J=12.5Hz ,1H),4.81(d,J＝12.5Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H),3.45(dd,J＝20.0,10.0Hz,1H),3.33(d, J=18.0Hz, 1H), 2.81 (d, J=18.0Hz, 1H), 2.53 (dd, J=17.5, 9.5Hz, 1H), 2.51 (s, 3H), 2.17 (dd, J=17.5, 11.0 Hz, 1H), 1.10 (t, J=7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 180.5, 173.8, 173.6, 141.0, 136.3, 132.1, 131.0, 129.2, 122.8, 83.9, 67.3, 50.4, 41.7, 41.3, 34.5, 31.5, 19.3, 12.6. HRMS(pos.ESI): m/z[M+H] + for C 18 H 20 NO 5 calcd: 330.1336, found: 330.1345.

实施例7Example 7

Figure BDA0002370852880000112
Figure BDA0002370852880000112

化合物3g，产率:83％。1H NMR(500MHz,CDCl3)δ7.35(dd,J＝14.0,8.0Hz,1H),7.10(t,J＝9.0Hz,1H),6.78(d,J＝7.5Hz,1H),5.56(s,1H),4.82(dd,J＝9.5,4.5Hz,1H),3.70(q,J＝7.0Hz,2H),3.50(dd,J＝17.5,10.0Hz,1H),3.13(d,J＝20.0Hz,2H),2.86(d,J＝19.5Hz,1H),2.75(dd,J＝18.5,11.0Hz,1H),2.45(dd,J＝18.0,7.0Hz,1H),1.27(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ179.6,175.1,174.7,160.9(d,JC-F＝249Hz),140.8(d,JC-F＝3.1Hz),131.5(d,JC-F＝9.0Hz),122.1(d,JC-F＝16.1Hz),120.7(d,JC-F＝3.4Hz),115.6(d,JC-F＝22.1Hz),77.8,60.1(d,JC-F＝5.0Hz),50.3(d,JC-F＝2.1Hz),42.3,37.4,34.5,30.4,13.2.HRMS(pos.ESI):m/z[M+H]+for C17H17FNO5 calcd:334.1085,found:334.1076。Compound 3g, yield: 83%. 1 H NMR (500 MHz, CDCl 3 ) δ 7.35 (dd, J=14.0, 8.0 Hz, 1H), 7.10 (t, J=9.0 Hz, 1H), 6.78 (d, J=7.5 Hz, 1H), 5.56 (s, 1H), 4.82 (dd, J=9.5, 4.5Hz, 1H), 3.70 (q, J=7.0Hz, 2H), 3.50 (dd, J=17.5, 10.0Hz, 1H), 3.13 (d, J＝20.0Hz, 2H), 2.86(d, J＝19.5Hz, 1H), 2.75(dd, J＝18.5, 11.0Hz, 1H), 2.45(dd, J＝18.0, 7.0Hz, 1H), 1.27( t, J=7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 179.6, 175.1, 174.7, 160.9 (d, J CF =249 Hz), 140.8 (d, J CF =3.1 Hz), 131.5 (d, J CF = 9.0 Hz), 122.1 (d, J CF = 16.1 Hz), 120.7 (d, J CF = 3.4 Hz), 115.6 (d, J CF = 22.1 Hz), 77.8, 60.1 (d, J CF = 5.0 Hz), 50.3 (d, J CF = 2.1 Hz), 42.3, 37.4, 34.5, 30.4, 13.2. HRMS (pos. ESI): m/z[M+H] + for C 17 H 17 FNO 5 calcd: 334.1085 , found: 334.1076.

实施例8Example 8

Figure BDA0002370852880000121
Figure BDA0002370852880000121

化合物3h，产率:86％。1H NMR(500MHz,CDCl3)δ7.52(dd,J＝8.0,0.5Hz,1H),7.35(t,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),5.41(d,J＝9.0Hz,1H),5.29(d,J＝12.5Hz,1H),4.96(d,J＝12.0Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H),3.45(dd,J＝20.0,10.0Hz,1H),3.32(d,J＝18.0Hz,1H),2.87(d,J＝18.0Hz,1H),2.57(dd,J＝17.5,9.5Hz,1H),2.14(dd,J＝17.5,11.0Hz,1H),1.11(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ179.8,173.3,173.1,138.2,135.9,133.4,131.4,130.3,123.8,83.1,67.4,50.6,41.6,41.3,34.7,30.9,12.6.HRMS(pos.ESI):m/z[M+H]+for C17H17ClNO5 calcd:350.0790,found:350.0781。Compound 3h, yield: 86%. 1 H NMR (500 MHz, CDCl 3 ) δ 7.52 (dd, J=8.0, 0.5 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.41 (d, J=9.0Hz, 1H), 5.29 (d, J=12.5Hz, 1H), 4.96 (d, J=12.0Hz, 1H), 3.54 (dtt, J=20.5, 14.0, 7.0Hz, 2H) ,3.45(dd,J＝20.0,10.0Hz,1H),3.32(d,J＝18.0Hz,1H),2.87(d,J＝18.0Hz,1H),2.57(dd,J＝17.5,9.5Hz, 1H), 2.14 (dd, J=17.5, 11.0 Hz, 1H), 1.11 (t, J=7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 179.8, 173.3, 173.1, 138.2, 135.9, 133.4, 131.4,130.3,123.8,83.1,67.4,50.6,41.6,41.3,34.7,30.9,12.6.HRMS(pos.ESI): m/z[M+H] + for C 17 H 17 ClNO 5 calcd:350.0790,found : 350.0781.

实施例9Example 9

Figure BDA0002370852880000122
Figure BDA0002370852880000122

化合物3i，产率:81％；9:1dr。Major isomer:1H NMR(500MHz,CDCl3)δ7.72(d,J＝8.0Hz,1H),7.26(t,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),5.42(d,J＝9.0Hz,1H),5.26(d,J＝12.5Hz,1H),4.97(d,J＝12.5Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H),3.47(dd,J＝20.0,9.5Hz,1H),3.32(d,J＝18.0Hz,1H),2.87(d,J＝18.0Hz,1H),2.56(dd,J＝18.0,9.5Hz,1H),2.15(dd,J＝18.0,11.0Hz,1H),1.11(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ179.9,173.2,173.0,137.5,134.9,133.5,130.6,129.0,124.4,83.2,70.0,50.8,41.6,41.4,34.7,31.0,12.6.Minor isomer:1H NMR(500MHz,CDCl3)δ7.60(d,J＝8.0Hz,1H),7.21(t,J＝8.0Hz,1H),6.88(d,J＝7.5Hz,1H),5.29(d,J＝9.0Hz,1H),5.05(d,J＝2.0Hz,1H),4.32(d,J＝2.5Hz,1H),3.70(dd,J＝14.5,7.0Hz,2H),2.80(s,1H),2.69(dd,J＝18.0,8.5Hz,1H),2.29(d,J＝2.5,Hz,1H),1.27(t,J＝8.5Hz,3H)；13C NMR(125MHz,CDCl3)δ179.4,175.2,174.6,140.8,140.5,133.2,130.7,127.7,124.7,71.3,64.4,55,2,41.7,41.2,35.0,29.7,12.8.HRMS(pos.ESI):m/z[M+H]+for C17H17BrNO5 calcd:394.0285,found:394.0301。Compound 3i, yield: 81%; 9: 1 dr. Major isomer: 1 H NMR (500MHz, CDCl 3 )δ7.72(d,J=8.0Hz,1H),7.26(t,J=8.0Hz,1H),7.11(d,J=8.0Hz,1H), 5.42(d,J＝9.0Hz,1H),5.26(d,J＝12.5Hz,1H),4.97(d,J＝12.5Hz,1H),3.54(dtt,J＝20.5,14.0,7.0Hz,2H ),3.47(dd,J＝20.0,9.5Hz,1H),3.32(d,J＝18.0Hz,1H),2.87(d,J＝18.0Hz,1H),2.56(dd,J＝18.0,9.5Hz , 1H), 2.15 (dd, J=18.0, 11.0 Hz, 1H), 1.11 (t, J=7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 179.9, 173.2, 173.0, 137.5, 134.9, 133.5 , 130.6, 129.0, 124.4, 83.2, 70.0, 50.8, 41.6, 41.4, 34.7, 31.0, 12.6. Minor isomer: 1 H NMR (500MHz, CDCl 3 )δ7.60(d, J=8.0Hz, 1H), 7.21 (t,J=8.0Hz,1H),6.88(d,J=7.5Hz,1H),5.29(d,J=9.0Hz,1H),5.05(d,J=2.0Hz,1H),4.32(d , J=2.5Hz, 1H), 3.70(dd, J=14.5, 7.0Hz, 2H), 2.80(s, 1H), 2.69(dd, J=18.0, 8.5Hz, 1H), 2.29(d, J= 2.5, Hz, 1H), 1.27 (t, J=8.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 179.4, 175.2, 174.6, 140.8, 140.5, 133.2, 130.7, 127.7, 124.7, 71.3, 64.4, 55, 2, 41.7, 41.2, 35.0, 29.7, 12.8. HRMS(pos. ESI): m/z[M+H] + for C 17 H 17 BrNO 5 calcd: 394.0285, found: 394.0301.

实施例10Example 10

Figure BDA0002370852880000131
Figure BDA0002370852880000131

化合物3j，产率:77％。1H NMR(500MHz,CDCl3)δ7.87(dd,J＝8.0,1.0Hz,1H),7.56(t,J＝8.0Hz,1H),7.28(d,J＝8.0Hz,1H),5.60(d,J＝2.5Hz,1H),4.79(dd,J＝10.0,4.5Hz,1H),3.76–3.72(m,2H),3.58–3.52(m,1H),3.28(d,J＝19.5Hz,1H),3.30(brs,1H),2.81(d,J＝19.5Hz,1H),2.775(dd,J＝18.0,11.0Hz,1H),2.52(dd,J＝18.0,8.0Hz,1H),1.30(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ179.4,174.4,174.0,150.5,141.3,130.8,130.0,129.3,124.1,62.9,50.6,42.7,36.9,34.7,30.2,13.2.HRMS(pos.ESI):m/z[M+H]+for C17H17N2O7 calcd:361.1030,found:361.1041。Compound 3j, yield: 77%. 1 H NMR (500 MHz, CDCl 3 ) δ 7.87 (dd, J=8.0, 1.0 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 5.60 (d, J=2.5Hz, 1H), 4.79 (dd, J=10.0, 4.5Hz, 1H), 3.76–3.72 (m, 2H), 3.58–3.52 (m, 1H), 3.28 (d, J=19.5 Hz, 1H), 3.30 (brs, 1H), 2.81 (d, J=19.5Hz, 1H), 2.775 (dd, J=18.0, 11.0Hz, 1H), 2.52 (dd, J=18.0, 8.0Hz, 1H) ), 1.30 (t, J=7.0 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 179.4, 174.4, 174.0, 150.5, 141.3, 130.8, 130.0, 129.3, 124.1, 62.9, 50.6, 42.7, 36.9, 34.7 , 30.2, 13.2.HRMS(pos.ESI): m/z[M+H] + for C 17 H 17 N 2 O 7 calcd: 361.1030, found: 361.1041.

实施例11Example 11

Figure BDA0002370852880000132
Figure BDA0002370852880000132

化合物3k，产率:82％。1H NMR(500MHz,DMSO-d6)δ7.63(d,J＝1.0Hz,1H),7.48(dd,J＝8.5,2.0Hz,1H),7.01(d,J＝8.5Hz,1H),5.91(d,J＝6.5Hz,1H),5.48(t,J＝5.0Hz,1H),5.10(dd,J＝9.0,4.5Hz,1H),3.46(ddd,J＝11.0,9.0,6.0Hz,1H),3.27(q,J＝7.5Hz,2H),3.15(d,J＝18.0Hz,1H),3.06(d,J＝18.0Hz,1H),2.79(dd,J＝18.5,11.0Hz,1H),2.13(dd,J＝18.5,5.5Hz,1H),0.89(t,J＝7.0Hz,3H)；13C NMR(125MHz,DMSO-d6)δ184.0,180.6,179.7,146.8,138.4,135.9,134.8,132.4,127.0,85.5,71.2,55.5,45.4,42.1,38.5,37.1,17.6.HRMS(pos.ESI):m/z[M+H]+for C17H17BrNO5 calcd:394.0285,found:394.0299。Compound 3k, yield: 82%. 1 H NMR (500MHz, DMSO-d6) δ 7.63 (d, J=1.0Hz, 1H), 7.48 (dd, J=8.5, 2.0Hz, 1H), 7.01 (d, J=8.5Hz, 1H), 5.91(d,J＝6.5Hz,1H),5.48(t,J＝5.0Hz,1H),5.10(dd,J＝9.0,4.5Hz,1H),3.46(ddd,J＝11.0,9.0,6.0Hz ,1H),3.27(q,J＝7.5Hz,2H),3.15(d,J＝18.0Hz,1H),3.06(d,J＝18.0Hz,1H),2.79(dd,J＝18.5,11.0Hz , 1H), 2.13 (dd, J=18.5, 5.5Hz, 1H), 0.89 (t, J=7.0Hz, 3H); 13 C NMR (125MHz, DMSO-d6) δ 184.0, 180.6, 179.7, 146.8, 138.4, 135.9,134.8,132.4,127.0,85.5,71.2,55.5,45.4,42.1,38.5,37.1,17.6.HRMS(pos.ESI): m/z[M+H] + for C 17 H 17 BrNO 5 calcd:394.0285 ,found:394.0299.

实施例12Example 12

Figure BDA0002370852880000141
Figure BDA0002370852880000141

化合物3l，产率:63％；5:1dr。Major isomer:1H NMR(500MHz,CDCl3)δ7.57(dd,J＝8.5,6.0Hz,1H),7.09(td,J＝10.5,2.5Hz,1H),6.80(dd,J＝9.5,2.5Hz,1H),5.42(d,J＝5.0Hz,1H),5.13(dd,J＝9.5,5.0Hz,1H),3.59(q,J＝7.0Hz,2H),3.49(ddd,J＝11.0,9.5,7.0Hz,1H),3.00(s,2H),2.80(dd,J＝18.5,11.0Hz,1H),2.25(dd,J＝18.5,7.0Hz,1H),2.09(d,J＝21.0Hz,1H),1.17(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ178.7,174.7,174.0,163.0(d,JC-F＝247.6Hz),137.3(d,JC-F＝7.1Hz),132.3(d,JC-F＝3.0Hz),130.7(d,JC-F＝8.4Hz),115.8(d,JC-F＝20.9Hz),112.5(d,JC-F＝23.4Hz),79.5,67.2,50.6(d,JC-F＝1.3Hz),41.4,37.6,34.4,31.1,12.9.Minor isomer:1H NMR(500MHz,CDCl3)δ7.57(dd,J＝8.5,6.0Hz,1H),7.09(td,J＝10.5,2.5Hz,1H),6.86(dd,J＝9.5,2.5Hz,1H),5.24(d,J＝3.5Hz,1H),4.93(dd,J＝8.0,3.5Hz,1H),3.59(q,J＝7.0Hz,2H),2.99(s,2H),2.75(dd,J＝19.0,11.0Hz,1H),2.48(dd,J＝18.5,7.0Hz,1H),1.17(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ177.5,175.0,174.2,162.8(d,JC-F＝247.4Hz),136.9(d,JC-F＝7.4Hz),132.3(d,JC-F＝3.3Hz),130.7(d,JC-F＝8.4Hz),115.9(d,JC-F＝20.9Hz),113.1(d,JC-F＝23.5Hz),82.9,70.2,50.4(d,JC-F＝1.3Hz),42.6,40.3,34.4,30.8,12.9.HRMS(pos.ESI):m/z[M+H]+for C17H17FNO5 calcd:334.1085,found:334.1096。Compound 31, yield: 63%; 5: 1 dr. Major isomer: 1 H NMR (500 MHz, CDCl 3 ) δ 7.57 (dd, J=8.5, 6.0 Hz, 1H), 7.09 (td, J=10.5, 2.5 Hz, 1H), 6.80 (dd, J=9.5, 2.5Hz, 1H), 5.42 (d, J=5.0Hz, 1H), 5.13 (dd, J=9.5, 5.0Hz, 1H), 3.59 (q, J=7.0Hz, 2H), 3.49 (ddd, J= 11.0,9.5,7.0Hz,1H),3.00(s,2H),2.80(dd,J=18.5,11.0Hz,1H),2.25(dd,J=18.5,7.0Hz,1H),2.09(d,J =21.0Hz, 1H), 1.17 (t, J=7.0Hz, 3H); 13 C NMR (125MHz, CDCl 3 ) δ 178.7, 174.7, 174.0, 163.0 (d, J CF =247.6Hz), 137.3 (d, J CF = 7.1 Hz), 132.3 (d, J CF = 3.0 Hz), 130.7 (d, J CF = 8.4 Hz), 115.8 (d, J CF = 20.9 Hz), 112.5 (d, J CF = 23.4 Hz), 79.5, 67.2, 50.6 (d, J CF = 1.3 Hz), 41.4, 37.6, 34.4, 31.1, 12.9. Minor isomer: 1 H NMR (500 MHz, CDCl 3 ) δ 7.57 (dd, J = 8.5, 6.0 Hz, 1H), 7.09 (td, J=10.5, 2.5Hz, 1H), 6.86 (dd, J=9.5, 2.5Hz, 1H), 5.24 (d, J=3.5Hz, 1H), 4.93 (dd, J=8.0 ,3.5Hz,1H),3.59(q,J=7.0Hz,2H),2.99(s,2H),2.75(dd,J=19.0,11.0Hz,1H),2.48(dd,J=18.5,7.0Hz , 1H), 1.17 (t, J=7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 177.5, 175.0, 174.2, 162.8 (d, J CF =247.4 Hz), 136.9 (d, J CF =7.4 Hz), 132.3 (d, J CF = 3.3 Hz), 130.7 (d, J CF = 8.4 Hz), 115.9 (d, J CF = 20.9 Hz), 113.1 (d, J CF = 23.5 Hz), 82.9, 70.2 , 50.4 (d, J CF = 1.3 Hz), 42.6, 40.3 , 34.4, 30.8, 12.9. HRMS(pos.ESI): m/z[M+H] + for C 17 H 17 FNO 5 calcd: 334.1085, found: 334.1096.

实施例13Example 13

Figure BDA0002370852880000142
Figure BDA0002370852880000142

化合物3m，产率:76％。1H NMR(500MHz,Acetone-d6)δ7.67(d,J＝8.5Hz,1H),7.43(dd,J＝8.0,2.0Hz,1H),7.21(d,J＝2.0Hz,1H),5.62–5.59(m,1H),5.18(dd,J＝9.0,4.5Hz,1H),4.84(d,J＝7.0Hz,1H),3.66(ddd,J＝11.0,9.0,7.0Hz,1H),3.50(dt,J＝13.5,7.0Hz,2H),3.24(s,2H),2.88(dd,J＝18.5,11.0Hz,1H),2.32(dd,J＝18.5,7.0Hz,1H),1.08(t,J＝7.0Hz,3H)；13C NMR(125MHz,Acetone-d6)δ178.9,174.5,173.9,137.6,137.2,133.6,129.5,128.3,125.2,79.8,67.1,50.8,40.8,37.7,33.6,31.2,12.1.HRMS(pos.ESI):m/z[M+H]+for C17H17ClNO5calcd:350.0790,found:350.0785。Compound 3m, yield: 76%. 1 H NMR (500MHz, Acetone-d6) δ 7.67 (d, J=8.5Hz, 1H), 7.43 (dd, J=8.0, 2.0Hz, 1H), 7.21 (d, J=2.0Hz, 1H), 5.62–5.59 (m, 1H), 5.18 (dd, J=9.0, 4.5Hz, 1H), 4.84 (d, J=7.0Hz, 1H), 3.66 (ddd, J=11.0, 9.0, 7.0Hz, 1H) ,3.50(dt,J＝13.5,7.0Hz,2H),3.24(s,2H),2.88(dd,J＝18.5,11.0Hz,1H),2.32(dd,J＝18.5,7.0Hz,1H), 1.08 (t, J=7.0Hz, 3H); 13 C NMR (125MHz, Acetone-d6) δ 178.9, 174.5, 173.9, 137.6, 137.2, 133.6, 129.5, 128.3, 125.2, 79.8, 67.1, 50.8, 40.8, 37.7, 33.6, 31.2, 12.1. HRMS (pos. ESI): m/z [M+H] + for C 17 H 17 ClNO 5 calcd: 350.0790, found: 350.0785.

实施例14Example 14

Figure BDA0002370852880000151
Figure BDA0002370852880000151

化合物3n，产率:66％。1H NMR(500MHz,CDCl3)δ8.10(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),7.66(s,1H),4.88(t,J＝6.0Hz,1H),4.82(s,1H),4.32(s,1H),3.91(s,3H),3.74(q,J＝7.0Hz,2H),3.39(dd,J＝9.0,6.0Hz,1H),2.88(dd,J＝18.0,7.0Hz,2H),2.68(d,J＝18.0Hz,1H),2.16(dd,J＝18.5,4.0Hz,1H),1.30(t,J＝7.2Hz,3H)；13C NMR(125MHz,CDCl3)δ178.3,174.3,173.3,166.1,140.5,136.4,130.4,130.2,127.4,125.1,84.2,71.4,52.5,50.7,38.8,38.3,34.9,30.2,13.2.HRMS(pos.ESI):m/z[M+H]+for C19H20NO7 calcd:374.1234,found:374.1245。Compound 3n, yield: 66%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.10 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.66 (s, 1H), 4.88 (t, J=6.0 Hz ,1H),4.82(s,1H),4.32(s,1H),3.91(s,3H),3.74(q,J=7.0Hz,2H),3.39(dd,J=9.0,6.0Hz,1H) ,2.88(dd,J＝18.0,7.0Hz,2H),2.68(d,J＝18.0Hz,1H),2.16(dd,J＝18.5,4.0Hz,1H),1.30(t,J＝7.2Hz, 3H); 13 C NMR (125MHz, CDCl 3 ) δ 178.3, 174.3, 173.3, 166.1, 140.5, 136.4, 130.4, 130.2, 127.4, 125.1, 84.2, 71.4, 52.5, 50.7, 38.8, 38.3, 34.9, 30.2, 13 HRMS(pos.ESI): m/z[M+H] + for C 19 H 20 NO 7 calcd: 374.1234, found: 374.1245.

实施例15Example 15

Figure BDA0002370852880000152
Figure BDA0002370852880000152

化合物3o，产率:51％。1H NMR(500MHz,DMSO-d6)δ7.97(dd,J＝8.0,1.5Hz,1H),7.84(dd,J＝8.0,1.0Hz,1H),7.62(d,J＝2.0Hz,1H),6.11(d,J＝6.0Hz,1H),5.64(t,J＝5.0Hz,1H),5.21(dd,J＝9.0,4.5Hz,1H),3.58(ddd,J＝11.0,8.8,6.0Hz,1H),3.41(d,J＝3.0Hz,1H),3.38(q,J＝7.0Hz,2H),3.23(s,3H),3.18(d,J＝18.0Hz,1H),2.88(dd,J＝18.5,11.0Hz,1H),2.22(dd,J＝18.5,6.0Hz,1H),0.98(t,J＝7.0Hz,3H)；13C NMR(125MHz,DMSO-d6)δ179.1,175.8,174.8,145.4,140.7,135.6,128.5,127.6,124.0,80.5,66.8,51.0,44.0,40.9,37.6,33.8,32.3,12.9.HRMS(pos.ESI):m/z[M+H]+for C18H20NO7S calcd:394.0955,found:394.0958。Compound 3o, yield: 51%. 1 H NMR (500MHz, DMSO-d6) δ 7.97 (dd, J=8.0, 1.5Hz, 1H), 7.84 (dd, J=8.0, 1.0Hz, 1H), 7.62 (d, J=2.0Hz, 1H) ),6.11(d,J＝6.0Hz,1H),5.64(t,J＝5.0Hz,1H),5.21(dd,J＝9.0,4.5Hz,1H),3.58(ddd,J＝11.0,8.8, 6.0Hz, 1H), 3.41 (d, J=3.0Hz, 1H), 3.38 (q, J=7.0Hz, 2H), 3.23 (s, 3H), 3.18 (d, J=18.0Hz, 1H), 2.88 (dd, J=18.5, 11.0 Hz, 1H), 2.22 (dd, J=18.5, 6.0 Hz, 1H), 0.98 (t, J=7.0 Hz, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 179 .1,175.8,174.8,145.4,140.7,135.6,128.5,127.6,124.0,80.5,66.8,51.0,44.0,40.9,37.6,33.8,32.3,12.9.HRMS(pos.ESI):m/z[M+H] + for C 18 H 20 NO 7 S calcd: 394.0955, found: 394.0958.

实施例16Example 16

Figure BDA0002370852880000161
Figure BDA0002370852880000161

化合物3p，产率:75％。1H NMR(500MHz,CDCl3)δ7.69(d,J＝8.0Hz,1H),7.62(d,J＝7.5Hz,1H),7.50(d,J＝7.5Hz,2H),7.45(t,J＝7.5Hz,2H),7.38(t,J＝7.2Hz,1H),7.25(s,1H),5.56(t,J＝6.0Hz,1H),5.25(dd,J＝9.0,5.0Hz,1H),3.60(q,J＝7.0Hz,2H),3.52(dd,J＝17.0,10.0Hz,1H),3.17(d,J＝18.0Hz,1H),2.95(d,J＝18.5Hz,1H),2.82(dd,J＝18.5,11.0Hz,1H),2.67(d,J＝7.0Hz,1H),2.26(dd,J＝18.5,7.0Hz,1H),1.17(t,J＝7.0Hz,3H)；13C NMR(125MHz,CDCl3)δ178.9,174.2,174.0,142.6,139.9,135.5,135.1,129.1,129.0,128.0,127.9,127.2,123.6,79.5,67.6,50.7,41.4,37.9,34.3,31.4,13.0.HRMS(pos.ESI):m/z[M+H]+for C23H22NO5 calcd:392.1492,found:392.1505。Compound 3p, yield: 75%. 1 H NMR (500 MHz, CDCl 3 ) δ 7.69 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.50 (d, J=7.5 Hz, 2H), 7.45 (t , J＝7.5Hz, 2H), 7.38(t, J＝7.2Hz, 1H), 7.25(s, 1H), 5.56(t, J＝6.0Hz, 1H), 5.25(dd, J＝9.0, 5.0Hz ,1H),3.60(q,J＝7.0Hz,2H),3.52(dd,J＝17.0,10.0Hz,1H),3.17(d,J＝18.0Hz,1H),2.95(d,J＝18.5Hz ,1H),2.82(dd,J＝18.5,11.0Hz,1H),2.67(d,J＝7.0Hz,1H),2.26(dd,J＝18.5,7.0Hz,1H),1.17(t,J＝ 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 178.9, 174.2, 174.0, 142.6, 139.9, 135.5, 135.1, 129.1, 129.0, 128.0, 127.9, 127.2, 123.6, 79.5, 67.6, 50.7, 41.4 , 34.3, 31.4, 13.0.HRMS(pos.ESI): m/z[M+H] + for C 23 H 22 NO 5 calcd: 392.1492, found: 392.1505.

实施例17Example 17

Figure BDA0002370852880000162
Figure BDA0002370852880000162

化合物3q，产率:68％。1H NMR(500MHz,CDCl3)δ7.28–7.25(m,2H),7.00(d,J＝6.5Hz,1H),5.40(d,J＝9.0Hz,1H),5.00(d,J＝12.5Hz,1H),4.81(d,J＝12.5Hz,1H),3.45(q,J＝10.0Hz,1H),3.37(d,J＝18.0Hz,1H),2.98(s,3H),2.84(d,J＝18.0Hz,1H),2.56–2.53(m,1H),2.51(s,3H),2.17(dd,J＝17.65,11.0Hz,1H)；13C NMR(125MHz,CDCl3)δ180.7,174.0,173.6,141.1,136.3,132.1,130.9,129.2,122.9,83.9,67.4,50.5,41.6,41.4,31.0,25.6,19.3.HRMS(pos.ESI):m/z[M+H]+for C17H18NO5 calcd:316.1179,found:316.1185。Compound 3q, yield: 68%. 1 H NMR (500 MHz, CDCl 3 ) δ 7.28-7.25 (m, 2H), 7.00 (d, J=6.5 Hz, 1H), 5.40 (d, J=9.0 Hz, 1H), 5.00 (d, J= 12.5Hz, 1H), 4.81 (d, J=12.5Hz, 1H), 3.45 (q, J=10.0Hz, 1H), 3.37 (d, J=18.0Hz, 1H), 2.98 (s, 3H), 2.84 (d, J=18.0 Hz, 1H), 2.56-2.53 (m, 1H), 2.51 (s, 3H), 2.17 (dd, J=17.65, 11.0 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ180.7,174.0,173.6,141.1,136.3,132.1,130.9,129.2,122.9,83.9,67.4,50.5,41.6,41.4,31.0,25.6,19.3.HRMS(pos.ESI):m/z[M+H] + for C 17 H 18 NO 5 calcd: 316.1179, found: 316.1185.

实施例18Example 18

Figure BDA0002370852880000171
Figure BDA0002370852880000171

化合物3r，产率:65％。1H NMR(500MHz,CDCl3)δ7.27(s,2H),7.20(s,3H),7.06(s,2H),6.89(d,J＝7.5Hz,1H),5.26(d,J＝9.0Hz,1H),4.95(d,J＝12.0Hz,1H),4.67(d,J＝12.5Hz,1H),3.75(t,J＝7.0Hz,2H),3.27(d,J＝18.0Hz,1H),3.19(q,J＝9.5Hz,1H),2.90–2.79(m,2H),2.66(d,J＝18.0Hz,1H),2.50(s,3H),2.46–2.43(m,1H),2.11(dd,J＝17.5,11.0Hz,1H)；13C NMR(125MHz,CDCl3)δ180.5,173.8,173.6,140.9,136.9,136.3,132.0,130.7,129.1,128.9,128.5,127.0,123.0,83.9,67.4,50.2,41.6,41.3,40.3,33.0,30.9,19.3.HRMS(pos.ESI):m/z[M+H]+for C24H24NO5 calcd:406.1649,found:406.1659。Compound 3r, yield: 65%. 1 H NMR (500 MHz, CDCl 3 ) δ 7.27 (s, 2H), 7.20 (s, 3H), 7.06 (s, 2H), 6.89 (d, J=7.5 Hz, 1H), 5.26 (d, J= 9.0Hz, 1H), 4.95(d, J＝12.0Hz, 1H), 4.67(d, J＝12.5Hz, 1H), 3.75(t, J＝7.0Hz, 2H), 3.27(d, J＝18.0Hz ,1H),3.19(q,J=9.5Hz,1H),2.90–2.79(m,2H),2.66(d,J=18.0Hz,1H),2.50(s,3H),2.46–2.43(m, 1H), 2.11 (dd, J=17.5, 11.0 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 180.5, 173.8, 173.6, 140.9, 136.9, 136.3, 132.0, 130.7, 129.1, 128.9, 128.5, 127.0, 123.0,83.9,67.4,50.2,41.6,41.3,40.3,33.0,30.9,19.3.HRMS(pos.ESI): m/z[M+H] + for C 24 H 24 NO 5 calcd:406.1649,found:406.1659 .

实施例19Example 19

Figure BDA0002370852880000172
Figure BDA0002370852880000172

化合物3s，产率:72％。1H NMR(500MHz,CDCl3)δ7.20(s,3H),7.08(s,2H),7.06(s,1H),6.66(s,1H),5.24(d,J＝9.0Hz,1H),4.90(d,J＝12.0Hz,1H),4.61(d,J＝12.5Hz,1H),3.76(t,J＝7.0Hz,2H),3.27(d,J＝18.0Hz,1H),3.14(q,J＝10.0Hz,1H),2.92–2.82(m,2H),2.62(d,J＝18.0Hz,1H),2.45(s,3H),2.42(t,J＝9.0Hz,1H),2.30(s,3H),2.10(dd,J＝17.5,11.0Hz,1H)；13C NMR(125MHz,CDCl3)δ180.5,173.9,173.6,140.8,139.0,136.9,133.4,132.9,130.6,128.9,128.5,126.9,123.5,84.1,67.3,50.1,41.8,41.3,40.3,33.0,30.9,21.3,19.3.HRMS(pos.ESI):m/z[M+H]+for C25H26NO5 calcd:420.1805,found:420.1818。Compound 3s, yield: 72%. 1 H NMR (500MHz, CDCl 3 ) δ 7.20(s, 3H), 7.08(s, 2H), 7.06(s, 1H), 6.66(s, 1H), 5.24(d, J=9.0Hz, 1H) ,4.90(d,J＝12.0Hz,1H),4.61(d,J＝12.5Hz,1H),3.76(t,J＝7.0Hz,2H),3.27(d,J＝18.0Hz,1H),3.14 (q, J=10.0Hz, 1H), 2.92–2.82 (m, 2H), 2.62 (d, J=18.0Hz, 1H), 2.45 (s, 3H), 2.42 (t, J=9.0Hz, 1H) , 2.30 (s, 3H), 2.10 (dd, J=17.5, 11.0 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 180.5, 173.9, 173.6, 140.8, 139.0, 136.9, 133.4, 132.9, 130.6, 128.9 ,128.5,126.9,123.5,84.1,67.3,50.1,41.8,41.3,40.3,33.0,30.9,21.3,19.3.HRMS(pos.ESI):m/z[M+H] + for C 25 H 26 NO 5 calcd: 420.1805, found: 420.1818.

综上所述，本发明采用邻位吡咯烷酮取代的苯甲醛及其衍生物作为反应底物，使其与2(5H)-呋喃酮在1,8-二氮杂二环十一碳-7-烯(DBU)催化下，通过一个直接区域选择性插烯羟醛缩合-迈克尔加成串联反应，制得四氢萘并呋喃酮螺吡咯烷酮化合物。所述邻位吡咯烷酮取代的苯甲醛的苯环上可以有各种取代基团。使用廉价易得有机小分子1,8-二氮杂二环十一碳-7-烯(DBU)为催化剂，避免使用金属催化剂和添加剂。反应具有百分之百的原子经济性和区域选择性，反应条件温和，在室温到100℃均可反应良好，底物官能团兼容性好，操作简便，反应不需要除水除氧，因此有巨大的优势，适合医药合成工业化放大生产。To sum up, the present invention uses ortho-pyrrolidone-substituted benzaldehyde and its derivatives as reaction substrates to make it react with 2(5H)-furanone in 1,8-diazabicycloundec-7- The tetrahydronaphthofuranone spiropyrrolidone compound was prepared via a direct regioselective vinylogous aldol condensation-Michael addition tandem reaction under the catalysis of alkene (DBU). The benzene ring of the ortho-pyrrolidone-substituted benzaldehyde may have various substituent groups. The inexpensive and readily available small organic molecule 1,8-diazabicycloundec-7-ene (DBU) was used as the catalyst and metal catalysts and additives were avoided. The reaction has 100% atom economy and regioselectivity, mild reaction conditions, good reaction at room temperature to 100 °C, good substrate functional group compatibility, easy operation, and the reaction does not require water and oxygen removal, so it has huge advantages. It is suitable for industrial scale-up production of pharmaceutical synthesis.

以上所述的实施例仅仅是对本发明的优选实施方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案作出的各种变形和改进，均应落入本发明权利要求书确定的保护范围内。The above-mentioned embodiments merely describe the preferred embodiments of the present invention, and do not limit the scope of the present invention. Without departing from the design spirit of the present invention, those of ordinary skill in the art can make various modifications to the technical solutions of the present invention. Variations and improvements should fall within the protection scope determined by the claims of the present invention.

Claims (10)

1.式3所示的化合物：1. The compound represented by formula 3:
Figure FDA0002370852870000011
Figure FDA0002370852870000011
 其中，R1、R2、R3独立地选自氢、卤素、C1～C4的烷基、苯基、萘基、硝基、酯基、甲砜基，R4选自C1～C4的烷基、含有取代基的C1～C4的烷基。Wherein, R 1 , R 2 and R 3 are independently selected from hydrogen, halogen, alkyl of C 1 -C 4 , phenyl, naphthyl, nitro, ester group and methylsulfonyl, and R 4 is selected from C 1 -C 4 A C 4 alkyl group, a C 1 -C 4 alkyl group containing a substituent. 2.根据权利要求1所述的化合物，其特征在于：R1、R2、R3独立地选自H、Me、Et、Ph、F、Cl、Br、-NO2、-CO2Me、-SO2Me，R4选自Me、Et、-CH2CH2Ph。2. The compound according to claim 1, wherein: R 1 , R 2 , R 3 are independently selected from H, Me, Et, Ph, F, Cl, Br, -NO 2 , -CO 2 Me, -SO 2 Me, R 4 is selected from Me, Et, -CH 2 CH 2 Ph. 3.根据权利要求2所述的化合物，其特征在于：所述的化合物具有如式3a～3s中任一所示的结构：3. The compound according to claim 2, characterized in that: the compound has a structure as shown in any one of formulae 3a to 3s:
Figure FDA0002370852870000012
Figure FDA0002370852870000012
Figure FDA0002370852870000021
Figure FDA0002370852870000021
 4.根据权利要求1所述的化合物的制备方法，包括以下步骤：在有机溶剂中，在催化剂参与的条件下，使式1所示的化合物与式2所示的化合物反应，得到所述的四氢萘并呋喃酮螺吡咯烷酮化合物；4. the preparation method of compound according to claim 1, comprises the following steps: in organic solvent, under the condition that catalyzer participates, make the compound shown in formula 1 react with the compound shown in formula 2, obtain described tetrahydronaphthofuranone spiropyrrolidone compounds;
Figure FDA0002370852870000022
Figure FDA0002370852870000022
 其中，R1、R2、R3、R4的定义与权利要求1中相同。Wherein, the definitions of R 1 , R 2 , R 3 and R 4 are the same as in claim 1 . 5.根据权利要求4所述的方法，其特征在于：式1所示的化合物与式2所示的化合物的摩尔比例为1:1.5、1:1.2或1:1。5 . The method according to claim 4 , wherein the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 is 1:1.5, 1:1.2 or 1:1. 6 . 6.根据权利要求4所述的方法，其特征在于：有机溶剂为二氯甲烷、1,2-二氯乙烷、丙酮、甲醇或二甲亚砜。6. The method according to claim 4, wherein the organic solvent is dichloromethane, 1,2-dichloroethane, acetone, methanol or dimethyl sulfoxide. 7.根据权利要求4所述的方法，其特征在于：催化剂为碳酸钾、碳酸铯或1,8-二氮杂二环十一碳-7-烯。7. The method according to claim 4, wherein the catalyst is potassium carbonate, cesium carbonate or 1,8-diazabicycloundec-7-ene. 8.根据权利要求4所述的方法，其特征在于：反应温度为室温、60℃或100℃，反应时间为4到24小时。8 . The method according to claim 4 , wherein the reaction temperature is room temperature, 60° C. or 100° C., and the reaction time is 4 to 24 hours. 9 . 9.根据权利要求1所述的化合物的应用。9. Use of a compound according to claim 1. 10.根据权利要求9所述的应用，其特征在于：所述的化合物用于制备抗肿瘤或抗疟疾药物。10. The use according to claim 9, wherein the compound is used for preparing antitumor or antimalarial drugs.
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