CN104086542A - Preparation method of pyrroloquinolinone compound - Google Patents

Preparation method of pyrroloquinolinone compound Download PDF

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CN104086542A
CN104086542A CN201410213978.6A CN201410213978A CN104086542A CN 104086542 A CN104086542 A CN 104086542A CN 201410213978 A CN201410213978 A CN 201410213978A CN 104086542 A CN104086542 A CN 104086542A
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王治永
薛丽俊
贺依依
翁礼丛
付立磊
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Chongqing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the technical field of the organic chemistry, and concretely relates to a preparation method of a pyrroloquinolinone compound. The structure of the compound is characterized through <1>H NMR, <13>C NMR, HRMS and the like, and is confirmed. The pyrroloquinolinone compound is efficiently prepared through a serial coupling cyclization reaction of various substituted 3-bromo-4-alkynylquinolinone and primary amine in N,N-dimethyl acetamide. The method has the advantages of mild reaction conditions, simple operation, low cost, few side reactions, high product purity, convenient separation and purification, and suitableness for large scale preparation. The compound of like compounds has a broad range bioactivity, and has a very good application prospect in the research and development of new drugs.

Description

A kind of preparation method of pyrroloquinoline ketone compounds
Technical field
The invention belongs to technical field of organic chemistry, be specifically related to a kind of preparation method of pyrroloquinoline ketone compounds.
Background technology
As a kind of structural framework of wide spectrum, quinolinone is one of modal heterocycle structure, is extensively present among the multiple natural product and drug molecule with notable biological activity.As quinolinones compound is widely used in pharmaceutical chemistry, as anticancer ((a) Ferrer, P.; c.; m.Liebigs Ann.1995,1895. (b) Angibaud, P.R.; Venet, M.G.; Filliers, W.; Broeckx, R.; Ligny, Y.A.; Muller, P.; Poncelet, V.S.; End, D.W.Eur.J.Org.Chem.2004,479. (c) Andresen, B.M.; Couturier, M.; Cronin, B.; D ' Occhio, M.; Ewing, M.D.; Guinn, M.; Hawkins, J.M.; Jasys, V.J.; LaGreca, S.D.; Lyssikatos, J.P.; Moraski, G.; Ng, K.; Raggon, J.W.; Stewart, A.M.; Tickner, D.L.; Tucker, J.L.; Urban, F.J.; Vazquez, E.; Wei, L.Org.Process Res.Dev.2004,8,643.), anti-virus and antihypertensive drug ((a) Hopkins, A.L.; Ren, J.; Milton, J.; Hazen, R.J.; Chan, J.H.; Stuart, D.I.; Stammers, D.K.J.Med.Chem.2004,47,5912. (b) Freeman, G.A.; Andrews III, C.W.; Hopkins, A.L.; Lowell, G.S.; Schaller, L.T.; Cowan, J.R.; Gonzales, S.S.; Koszalka, G.W.; Hazen, R.J.; Boone, L.R.; Ferris, R.G.; Creech, K.L.; Roberts, G.B.; Short, S.A.; Weaver, K.; Reynolds, D.J.; Milton, J.; Ren, J.; Stuart, D.I.; Stammers, D.K.; Chan, J.H.J.Med.Chem.2004,47,5923.) receive for a long time numerous scientists' concern always.In addition, quinolinone is also a kind of important intermediate in organic synthesis, because it can be converted into 2-chlorine and the amino quinoline replacing of 2-easily.Therefore chemist constantly makes great efforts the novel texture of exploitation based on quinolinone skeleton and brand-new synthetic method thereof.
Cascade reaction is a kind of efficient, green synthesis strategy, and in order to obtain the various types of natural framework compound with potential source biomolecule activity, the synthetic method by cascade reaction " one kettle way " is current study hotspot.Based on this, the present invention is based on the basis of intermolecular coupling and intramolecular cyclization reaction, the efficiently new technology of synthetic pyrroloquinoline ketone compounds of a kind of warp " one kettle way " is provided.
Summary of the invention
The object of the present invention is to provide a kind of easy, method of efficiently obtaining pyrroloquinoline ketone compounds.
The coupling cyclization that the present invention uses primary amine to connect in the solution of N,N-dimethylacetamide with the bromo-4-alkynyl of the 3-quinolinone of various replacements, thus efficiently prepare pyrroloquinoline ketone compounds.Its reaction formula is:
Concrete steps are as follows:
(1) primary amine (1.0-1.5 equivalent) is added to the bromo-4-alkynyl of 3-quinolinone (1.0 equivalent), the K of various replacements 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(3-6%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (6-12%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end;
(2) wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone compounds.This reaction yield reaches 99%, and the inventive method reaction conditions is gentle, wide application range of substrates (R wherein 1the simple group such as=Me, Et or Ph, R 2the simple group such as=H, 6-Me or 6-Cl, R 3=Ph or 4-Me-C 6h 4, 4-MeO-C 6h 4deng the aromatic substituent that contains various electron-donating groups, or 3-Cl-C 6h 4, 4-F-C 6h 4deng the aromatic substituent that contains various electron-withdrawing groups, also can be various aliphatic chain groups, as: butyl, the tertiary butyl and cyclopropyl etc., primary amine is: aniline, to monomethylaniline, P-nethoxyaniline, para-fluoroaniline, m-chloro aniline, Ortho-Chloro aniline, benzylamine, NSC 158269 or hexahydroaniline etc.), side reaction is few, product purity is high, is convenient to separating-purifying; Easy and simple to handle, cost is lower, applicable to fairly large preparation, has extraordinary application prospect.
Optimum reaction condition of the present invention is:
(1) molar ratio of the 3-of various replacements bromo-4-alkynyl quinolinone and primary amine is 1: 1-1.5;
(2) organic solvent that reaction system is used is N,N-dimethylacetamide;
(3) temperature of reaction is 120 ℃ to 130 ℃;
(4) Pd (OAc) in reaction system 2consumption be 3-6%; Preferably 5%;
(5) in reaction system, the consumption of part R-(+)-BINAP is 6-12%; Preferably 10%;
(6) alkali K in reaction system 3pO 4consumption be 2.5-3.5 equivalent (the bromo-4-alkynyl of the 3-quinolinones of relatively various replacements);
(7) reaction times is 8-24 hour.
The inventive method reaction conditions is gentle, easy and simple to handle, cost compared with low, side reaction is few, product purity is high, be convenient to separating-purifying, applicable to fairly large preparation, and this compounds skeleton has the biological activity of wide spectrum, has extraordinary application prospect in new drug development.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described:
Embodiment 1
The bromo-4-alkynyl of the 3-quinolinone (1.0 equivalent), the K that aniline (1.0-1.5 equivalent) are added to replacement 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(5%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (10%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end; Wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone derivatives a, white solid, and yield reaches 99%.
1H?NMR(400MHz，CDCl3)δ8.02-8.00(m，1H)，7.50-7.46(m，1H)，7.42-7.37(m，4H)，7.33-7.29(m，3H)，7.23(s，5H)，7.01(s，1H)，3.73(s，3H)； 13C?NMR(125MHz，CDCl3)δ155.2，143.1，138.6，137.0，131.6，129.2，128.9，128.2，128.1，128.0，127.8，127.2，123.5，123.1，122.0，118.0，114.9，102.6，29.0；HRMS(ESI)calcd?for?C 24H 19N 2O[M+H] +351.1492，found351.1508.
Embodiment 2
The bromo-4-alkynyl of the 3-quinolinone (1.0 equivalent), the K that P-nethoxyaniline (1.0-1.5 equivalent) are added to replacement 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(5%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (10%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end; Wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone derivatives b, white solid, and yield reaches 96%.
1H?NMR(400MHz，CDCl3)δ8.01-7.99(m，1H)，7.48-7.44(m，1H)，7.41-7.39(m，1H)，7.32-7.20(m，8H)，6.99(s，1H)，6.88(d，J＝8.8Hz，2H)，3.82(s，3H)，3.72(s，3H)； 13C?NMR(150MHz，CDCl3)δ159.0，155.3，143.2，136.9，131.7，131.5，129.7，129.2，128.2，127.9，127.7，127.2，123.5，123.2，122.0，118.0，114.9，113.5，102.3，55.3，29.0；HRMS(ESI)calcd?for?C 25H 21N 2O 2[M+H] +381.1598，found381.1592.
Embodiment 3
The bromo-4-alkynyl of the 3-quinolinone (1.0 equivalent), the K that benzylamine (1.0-1.5 equivalent) are added to replacement 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(5%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (10%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end; Wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone derivatives c, white solid, and yield reaches 84%.
1H?NMR(400MHz，CDCl3)δ7.95-7.93(m，1H)，7.46-7.39(m，7H)，7.29-7.26(m，1H)，7.21-7.12(m，3H)，6.89(d，J＝6.9Hz，2H)，6.84(s，1H)，5.91(s，2H)，3.76(s，3H)； 13C?NMR(100MHz，CDCl3)δ155.9，143.7，139.5，136.9，131.8，129.6，128.6，128.5，128.4，127.9，127.0，126.8，126.0，123.4，122.0，118.2，114.8，102.4，49.0，29.1；HRMS(ESI)calcd?for?C 25H 21N 2O[M+H] +365.1648，found365.1644.
Embodiment 4
The bromo-4-alkynyl of the 3-quinolinone (1.0 equivalent), the K that aniline (1.0-1.5 equivalent) are added to replacement 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(5%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (10%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end; Wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone derivatives d, brown solid, and yield reaches 95%.
1H?NMR(400MHz，CDCl 3)δ7.98-7.95(m，1H)，7.53-7.41(m，6H)，7.37-7.35(m，1H)，7.30-7.26(m，1H)，6.75(s，1H)，3.65(s，3H)，1.27(s，9H)； 13C?NMR(100MHz，CDCl 3)δ155.1，152.2，140.6，136.9，129.8，128.7，128.0，126.8，126.6，123.6，123.2，121.7，118.1，114.7，99.3，33.6，31.1，28.8；HRMS(ESI)calcd?for?C 22H 23N 2O[M+H] +331.1805，found331.1798.
Embodiment 5
The bromo-4-alkynyl of the 3-quinolinone (1.0 equivalent), the K that aniline (1.0-1.5 equivalent) are added to replacement 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(5%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (10%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end; Wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone derivatives e, yellow solid, and yield reaches 63%.
1H?NMR(400MHz，CDCl3)δ8.01(d，J＝7.5Hz，1H)，7.53-7.50(m，2H)，7.44-7.41(m，1H)，7.29-7.15(m，11H)，7.01(s，1H)，6.77(d，J＝7.4Hz，2H)，6.64(d，J＝8.1Hz，1H)，3.77(s，3H)； 13C?NMR(150MHz，CDCl3)δ159.3，155.2，143.5，138.5，138.4，138.3，130.4，129.9，129.6，128.9，128.7，128.3，128.2，127.8，126.7，124.1，123.1，122.6，122.0，117.6，116.7，113.7，102.2，55.2；HRMS(ESI)calcd?for?C 30H 23N 2O 2[M+H] +443.1754，found443.1774.
Embodiment 6
The bromo-4-alkynyl of the 3-quinolinone (1.0 equivalent), the K that aniline (1.0-1.5 equivalent) are added to replacement 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(5%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (10%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end; Wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone derivatives f, beige solid, and yield reaches 88%.
1H?NMR(400MHz，CDCl 3)δ7.80(s，1H)，7.38-7.36(m，3H)，7.31-7.26(m，4H)，7.23(s，5H)，7.00(s，1H)，3.70(s，3H)，2.49(s，3H)； 13C?NMR(150MHz，CDCl 3)δ155.1，143.0，138.7，134.9，131.7，131.4，129.2，128.9，128.4，128.2，128.1，128.0，127.9，127.7，123.5，123.2，117.8，114.8，102.5，29.0，20.8；HRMS(ESI)calcd?for?C 25H 21N 2O[M+H] +365.1648，found365.1665.
Embodiment 7
The bromo-4-alkynyl of the 3-quinolinone (1.0 equivalent), the K that aniline (1.0-1.5 equivalent) are added to replacement 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(5%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (10%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end; Wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone derivatives g, dark brown solid, and yield reaches 55%.
1H?NMR(400MHz，CDCl 3)δ7.90(d，J＝7.8Hz，1H)，7.53-7.41(m，6H)，7.38-7.36(m，1H)，?7.28-7.24(m，1H)，6.41(s，1H)，3.69(s，3H)，1.62-1.55(m，1H)，0.89-0.84(m，2H)，0.82-0.78(m，2H)； 13C?NMR(100MHz，CDCl 3)δ154.7，146.5，138.7，136.9，128.5，128.3，128.1，127.7，126.9，123.3，122.2，121.8，118.1，114.8，96.6，28.8，8.5，8.1；HRMS(ESI)calcd?for?C 21H 19N 2O[M+H] +315.1492，found315.1484.
Embodiment 8
The bromo-4-alkynyl of the 3-quinolinone (1.0 equivalent), the K that aniline (1.0-1.5 equivalent) are added to replacement 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(5%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (10%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end; Wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone derivatives h, Off-white solid, and yield reaches 97%.
1H?NMR(400MHz，CDCl 3)δ7.99-7.97(m，1H)，7.53-7.44(m，4H)，7.41-7.38(m，3H)，7.30(t，J＝7.4Hz，1H)，7.19(d，J＝5.0Hz，1H)，7.09(s，1H)，6.89(m，1H)，6.76-6.75(m，1H)，3.70(s，3H)； 13C?NMR(150MHz，CDCl 3)δ155.0，138.6，137.0，136.6，133.2，129.0，128.9，128.7，127.8，127.3，127.2，126.6，126.2，123.6，123.5，122.0，117.8，114.9，101.9，28.9；HRMS(ESI)calcd?for?C 22H 17N 2OS[M+H] +357.1056，found357.1064.
Embodiment 9
The bromo-4-alkynyl of the 3-quinolinone (1.0 equivalent), the K that aniline (1.0-1.5 equivalent) are added to replacement 3pO 4(2.5-3.5 equivalent), Pd (OAc) 2(5%) and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP (10%), and stir 8-24 hour at 120-130 ℃ of temperature, TLC monitors end; Wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated and column chromatography for separation obtains corresponding pyrroloquinoline ketone derivatives i, light yellow solid, and yield reaches 45%.
1H?NMR(400MHz，CDCl 3)δ8.00-7.98(m，1H)，7.50-7.46(m，1H)，7.42-7.37(m，4H)，7.33-7.28(m，3H)，7.23-7.19(m，2H)，7.16-7.14(m，2H)，6.99(s，1H)，3.72(s，3H)； 13C?NMR(150MHz，CDCl 3)δ155.1，141.7，138.4，137.0，133.9，130.3，130.1，128.8，128.4，128.3，128.2，128.0，127.4，123.5，123.3，122.1，117.8，114.9，102.8，29.0；HRMS(ESI)calcd?for?C 24H 18ClN 2O[M+H] +385.1102，found385.1093。

Claims (2)

1. a preparation method for pyrroloquinoline ketone compounds, is characterized in that concrete steps are as follows:
(1) primary amine of 1-1.5 equivalent is added to the bromo-4-alkynyl of the 3-quinolinone of the various replacements of 1 equivalent, the K of 2.5-3.5 equivalent 3pO 4, Pd (OAc) 2and in the solution of the N,N-dimethylacetamide of R-(+)-BINAP, at 120-130 ℃ of temperature, stirring 8-24 hour, TLC monitors end; Wherein, Pd (OAc) 2consumption be whole reaction system 3-6%, the 6-12% that the consumption of R-(+)-BINAP is whole reaction system
(2) wash reaction solution with water, be extracted with ethyl acetate, dry, concentrated, and column chromatography for separation, obtain pyrroloquinoline ketone compounds.
2. preparation method as claimed in claim 1, is characterized in that described primary amine is: aniline, to monomethylaniline, P-nethoxyaniline, para-fluoroaniline, m-chloro aniline, Ortho-Chloro aniline, benzylamine, NSC 158269 or hexahydroaniline.
CN201410213978.6A 2014-05-21 2014-05-21 Preparation method of pyrroloquinolinone compound Pending CN104086542A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112759553A (en) * 2019-11-01 2021-05-07 重庆大学 Synthesis and application of water-soluble pyridazine derivative

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COLIN A. LEACH,ET AL: "《Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 2.l-Arylpyrrolo[3,2-c ]quinolines: Effect of the 4-Substituent》", 《J. MED. CHEM》 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112759553A (en) * 2019-11-01 2021-05-07 重庆大学 Synthesis and application of water-soluble pyridazine derivative
CN112759553B (en) * 2019-11-01 2022-10-04 重庆大学 Synthesis and application of water-soluble pyridazine derivative

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Application publication date: 20141008