CN110627785B - A kind of preparation method of 1,5-tetrahydronaphthyridine derivative - Google Patents
A kind of preparation method of 1,5-tetrahydronaphthyridine derivative Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052761 rare earth metal Inorganic materials 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 150000002910 rare earth metals Chemical class 0.000 claims abstract description 10
- 238000010499 C–H functionalization reaction Methods 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 239000012298 atmosphere Substances 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical group C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- -1 alkene butylamino pyridine compound Chemical class 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 3
- 238000003780 insertion Methods 0.000 claims description 3
- 230000037431 insertion Effects 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- 230000001681 protective effect Effects 0.000 abstract 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- BLKXRUFSALITIZ-UHFFFAOYSA-N 1-benzyl-4-methyl-3,4-dihydro-2H-1,5-naphthyridine Chemical compound C(C1=CC=CC=C1)N1CCC(C2=NC=CC=C12)C BLKXRUFSALITIZ-UHFFFAOYSA-N 0.000 description 1
- FTVVJYKITVYBCC-UHFFFAOYSA-N 1-benzyl-4-methyl-3,4-dihydro-2H-benzo[b][1,5]naphthyridine Chemical compound CC1CCN(C2=CC3=C(N=C12)C=CC=C3)CC3=CC=CC=C3 FTVVJYKITVYBCC-UHFFFAOYSA-N 0.000 description 1
- JXQRTYMSAACGNJ-UHFFFAOYSA-N 4,6-dimethyl-1-phenyl-3,4-dihydro-2H-1,5-naphthyridine Chemical compound CC1CCN(C2=CC=C(N=C12)C)C1=CC=CC=C1 JXQRTYMSAACGNJ-UHFFFAOYSA-N 0.000 description 1
- ISRBFPXRDYAZJJ-UHFFFAOYSA-N 4-methyl-1-phenyl-3,4-dihydro-2H-1,5-naphthyridine Chemical compound CC1CCN(C2=CC=CN=C12)C1=CC=CC=C1 ISRBFPXRDYAZJJ-UHFFFAOYSA-N 0.000 description 1
- HRYQKLMMVNQBDP-UHFFFAOYSA-N 6-chloro-4-methyl-1-phenyl-3,4-dihydro-2H-1,5-naphthyridine Chemical compound ClC=1N=C2C(CCN(C2=CC1)C1=CC=CC=C1)C HRYQKLMMVNQBDP-UHFFFAOYSA-N 0.000 description 1
- YOHYGUIDHSOVLE-UHFFFAOYSA-N C1(=CC=CC=C1)C(C)N1CCC(C2=NC=CC=C12)C Chemical compound C1(=CC=CC=C1)C(C)N1CCC(C2=NC=CC=C12)C YOHYGUIDHSOVLE-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VAWGQHXJMFVQKR-UHFFFAOYSA-N N-benzyl-2-butylpyridin-3-amine Chemical compound C(CCC)C1=NC=CC=C1NCC1=CC=CC=C1 VAWGQHXJMFVQKR-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- CUYKNJBYIJFRCU-UHFFFAOYSA-N pyridine-3-amine Natural products NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910052706 scandium Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- 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
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开了一种1,5‑四氢萘啶衍生物的制备方法，本发明通过稀土催化吡啶碳氢键活化/官能团化从而实现结构多样化的1,5‑四氢萘啶衍生物的合成。具体是在稀土催化体系下，氮气保护氛围下，以各种3‑烯丁氨基吡啶为原料，制备1,5‑四氢萘啶衍生物。本发明方法原料来源广泛或易于制备，操作简便、选择性可控，收率高，条件温和，普适性广。The invention discloses a preparation method of 1,5-tetrahydronaphthyridine derivatives. The invention realizes the preparation of 1,5-tetrahydronaphthyridine derivatives with diversified structures through rare earth-catalyzed pyridine carbon-hydrogen bond activation/functionalization. synthesis. Specifically, 1,5-tetrahydronaphthyridine derivatives are prepared by using various 3-enbutyaminopyridines as raw materials under a rare earth catalytic system and a nitrogen protective atmosphere. The method of the invention has wide raw material sources or easy preparation, simple operation, controllable selectivity, high yield, mild conditions and wide applicability.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 1, 5-tetrahydronaphthyridine derivative for realizing structural diversification by pyridine carbon-hydrogen bond activation and intramolecular cyclization reaction.
Background
The 1, 5-tetrahydronaphthyridine derivatives are important organic compounds, which are important components of natural products and medicines. Therefore, the development of new and diversified and efficient methods for synthesizing 1, 5-tetrahydronaphthyridine derivatives has been an important issue in organic synthetic chemistry.
In the existing technology for preparing 1, 5-tetrahydronaphthyridine derivatives, the synthesis of the 1, 5-tetrahydronaphthyridine derivatives is always realized by adopting a catalytic hydrogenation or hydrogen transfer reduction method. The literature (org. Lett.2016,18,2730-2733) reports a process for preparing 1, 5-tetrahydronaphthyridine derivatives using ruthenium as a catalyst, hydrogen as a reducing agent and isopropanol or n-butanol as a solvent. This type of reaction presents a narrow substrate range and is difficult to derivatize with functional groups. And moreover, hydrogen which is flammable and has potential safety hazards is used as a hydrogen source, so that the operation is inconvenient and has certain limitations. The literature (Organometallics 2016,35,943-949) reports a process for the synthesis of 1, 5-tetrahydronaphthyridine derivatives by means of a hydrogen transfer reaction reduction strategy, which, although not requiring the direct use of hydrogen as the hydrogen source, utilizes an alcohol via a hydrogen transfer process. In the actual process, hydrogen is released to achieve the aim of transfer hydrogenation, so that the method has certain limitation, certain potential safety hazard and generally moderate yield.
Disclosure of Invention
In order to solve the problems and the defects in the prior art, the invention aims to provide the preparation method of the 1, 5-tetrahydronaphthyridine derivative, which avoids using hydrogen, improves the safety of the preparation process, and has wide raw material source and simple and convenient operation.
In order to achieve the purpose, the technical scheme of the invention comprises the following steps:
under the existence of inert atmosphere and rare earth catalyst, taking an alkene butylamino pyridine compound shown in a formula (I) as a raw material, and preparing a 1, 5-tetrahydronaphthyridine derivative shown in a formula (II) through carbon-hydrogen bond activation and intramolecular insertion cyclization reaction; the reaction formula is as follows:
in the above formula, R1Is hydrogen, methyl or halogen; r2Is hydrogen or methyl; r3Is methyl, phenyl or benzyl;
R4is hydrogen;
the rare earth catalyst is selected from Ln [ N (SiMe)3)2]3Ln ═ Sc, Y, La-Lu and rare earth alkyl complexes;
the solvent is toluene or n-hexane or tetrahydrofuran.
The additive is dibenzylamine, and the yield of the reaction can be greatly improved by using catalytic amount of dibenzylamine.
It is further provided that the inert atmosphere is nitrogen.
It is further provided that the molar ratio of the enamino pyridine compound/rare earth catalyst is 1.0/0.1.
The reaction temperature is further set to be 80-100 ℃, and the reaction time is 24-48 h.
Through intensive research, the inventor discovers that the synthesis of the 1, 5-tetrahydronaphthyridine derivative with diversified structures is realized by catalyzing carbon-hydrogen bond activation/intramolecular insertion cyclization reaction of pyridine under a rare earth catalytic system, and the method has the advantages of high atom economy, relatively mild reaction conditions and safe and simple operation. Compared with the prior method, the method has the advantages that the reaction conditions and the substrate universality are obviously improved, and no chemical reagents such as hydrogen and the like with potential safety hazards are adopted, which is difficult to realize by other methods. The invention has the following advantages and innovations:
(1) the reaction universality is good, the yield is high, most of the reaction yield is over 80 percent, and the atom economy is high;
(2) the method is an important supplement of carbon-hydrogen bond activation/functionalization of pyridine catalyzed by rare earth, and provides an important idea for constructing a nitrogen-containing heterocyclic compound;
(3) the reaction condition is mild, a large amount of complex additives are not needed, and compared with a plurality of transition metal catalyzed pyridine carbon-hydrogen bond activation reactions, the reaction only needs to add dibenzylamine with a catalytic amount and a simple structure, so that the cost is reduced, and the dibenzylamine is easy to recover.
(4) The method does not need hydrogen which is inflammable and inconvenient to store and transport as a chemical raw material;
(5) the rare earth silicon amino complex catalyst is simple, moderate in price and commercially available;
compared with the prior art, the invention has the following beneficial effects:
the 1, 5-tetrahydronaphthyridine derivative prepared by the method has high quality and high yield; the reaction universality is good, the reaction atom economy is high, and the post-treatment is convenient; the method realizes the activation of carbon-hydrogen bond of pyridine catalyzed by rare earth metal complex to construct the pyridine-fused ring compound for the first time, and provides important reference for the construction of 1, 5-tetrahydronaphthyridine derivatives and other heterocyclic compounds.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the following examples.
Example 1
Preparation of 4-methyl-1-phenyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine, structural formula as follows:
under the protection of nitrogen, adding raw material N-alkenyl butyl-N-phenylpyridine-3-amine (0.5mmol) and catalyst Y [ N (SiMe)3)2]3(10 mol%), dibenzylamine (10 mol%), toluene (3mL) and reacted at 100 ℃ for 24h, and the isolated yield of the product is 93%.
1H NMR(CDCl3,500MHz,ppm):δ7.96(dd,J＝1.3,4.6Hz,1H),7.37(t,J＝8.2Hz,2H),7.21(d,J＝8.3Hz,2H),7.14(t,J＝7.4Hz,1H),6.97(dd,J＝1.2,8.3Hz,1H),6.83(dd,J＝4.6,8.3Hz,1H),3.69-3.56(m,2H),3.17-3.09(m,1H),2.24-2.17(m,1H),1.90-1.83(m,1H),1.43(d,J＝7.0Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ148.8,147.2,140.6,138.5,129.9,125.2,124.8,121.6,121.5,47.9,33.9,29.7,20.9。
Example 2
Preparation of 4, 6-dimethyl-1-phenyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine, structural formula:
under the protection of nitrogen, raw material N-alkenyl butyl-N-phenyl-6-methylpyridine-3-amine (0.5mmol) and catalyst Y [ N (SiMe) are added3)2]3(10 mol%), toluene (3mL), dibenzylamine (10 mol%), reacted at 100 ℃ for 24h, and the isolated yield was 91%.
1H NMR(CDCl3,500MHz,ppm):δ7.35(t,J＝8.2Hz,2H),7.18(d,J＝7.5Hz,2H),7.10(t,J＝7.4Hz,1H),6.98(d,J＝8.4Hz,1H),6.72(d,J＝8.4Hz,1H),3.66-3.56(m,2H),3.16-3.10(m,1H),2.45(s,3H),2.22-2.16(m,1H),1.87-1.82(m,1H),1.41(d,J＝7.1Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ148.5,147.8,147.2,137.7,129.7,124.4,124.1,123.3,121.1,47.4,33.8,29.6,23.4,21.4。
Example 3
Preparation of 6-chloro-4-methyl-1-phenyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine, structural formula as follows:
under the protection of nitrogen, raw material N-alkene butyl-6-chlorine-N-methylpyridine-3-amine (0.5mmol), dibenzylamine (10 mol%) and catalyst Y [ N (SiMe) are added3)2]3(10 mol%) and toluene (3mL) were reacted at 100 ℃ for 24h, and the product was isolated in 86% yield.
1H NMR(CDCl3,500MHz,ppm):δ7.38(t,J＝7.6Hz,2H),7.20-7.15(m,3H),6.92(d,J＝8.6Hz,1H),6.82(d,J＝8.6Hz,1H),3.66-3.56(m,2H),3.13-3.06(m,1H),2.21-2.15(m,1H),1.88-1.82(m,1H),1.41(d,J＝7.1Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ148.9,147.0,139.6,138.7,129.9,125.2,125.1,124.6,121.6,47.8,33.8,29.4,21.0。
Example 4
The preparation of 1-benzyl-4-methyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine has the following structural formula:
under the protection of nitrogen, raw material N-alkene butyl-N-benzyl pyridine-3-amine (0.5mmol), dibenzylamine (10 mol%) and catalyst Y [ N (SiMe) are added3)2]3(10 mol%) and toluene (3mL) at 100 deg.C for 24h, the product was isolated in 93% yield.
1H NMR(CDCl3,500MHz,ppm):δ7.85(d,J＝4.5Hz,1H),7.33(t,J＝7.4Hz,2H),7.26-7.22(m,3H),6.87(dd,J＝4.6,8.2Hz,1H),6.71(d,J＝7.8Hz,1H),4.47(d,J＝4.7Hz,2H),3.48-3.43(m,1H),3.38-3.33(m,1H),3.14-3.07(m,1H),2.19-2.13(m,1H),1.88-1.82(m,1H),1.40(d,J＝7.0Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ147.4,141.3,138.0,136.3,128.9,127.2,126.6,122.1,117.1,54.7,46.6,34.1,29.2,20.7。
Example 5
Preparation of 1-phenethyl-4-methyl-1, 2,3, 4-tetrahydro-1, 5-naphthyridine, structural formula is as follows:
under the protection of nitrogen, raw material N-allyl-N-phenethyl pyridine-3-amine (0.5mmol), dibenzylamine (10 mol%) and catalyst Y [ N (SiMe)3)2]3(10 mol%) and toluene (3mL) at 100 deg.C for 24h, with an isolated yield of 94%.
1H NMR(CDCl3,500MHz,ppm):δ7.84(dd,J＝1.3,4.6Hz,1H),7.31(t,J＝6.9Hz,2H),7.25-7.20(m,3H),6.97(dd,J＝4.6,8.3Hz,1H),6.85(dd,J＝1.1,8.3Hz,1H),3.56-3.43(m,2H),3.26-3.20(m,1H),3.15-3.09(m,1H),3.04-2.96(m,1H),2.85(t,J＝7.6Hz,2H),2.04-1.97(m,1H),1.74-1.67(m,1H),1.32(d,J＝7.1Hz,3H).13C NMR(CDCl3,125MHz,ppm):δ147.7,140.6,139.6,135.9,128.9,128.7,126.5,122.1,116.3,52.8,46.1,34.0,32.3,28.9,20.8。
Example 6
4-methyl-1-benzyl-1, 2,3, 4-tetrahydro-1, 5-benzonaphthyridine, the structural formula of which is as follows:
under the protection of nitrogen, adding raw material N-alkenyl butyl-N-benzyl quinoline-3-amine (0.5mmol), dibenzyl amine (10 mol%) and catalyst Y [ N (SiMe)3)2]3(10 mol%) and toluene (3mL) at 100 deg.C for 24h, the product isolated in 91% yield.
1H NMR(CDCl3,500MHz,ppm):δ7.88(d,J＝4.8Hz,1H),7.23(d,J＝8.0Hz,1H),7.17(d,J＝8.3Hz,2H),7.10(d,J＝8.4Hz,2H),6.93(dd,J＝5.1,7.8Hz,1H),4.09(t,J＝9.0Hz,1H),3.57(t,J＝8.7Hz,1H),3.52-3.46(m,1H),2.33(s,3H),1.46(d,J＝6.8Hz,3H),.13C NMR(CDCl3,125MHz,ppm):δ157.7,141.2,141.1,138.6,131.5,130.0,121.7,117.7,113.2,58.5,36.2,20.8,18.1。
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (5)
1. A preparation method of a 1, 5-tetrahydronaphthyridine derivative is characterized by comprising the following steps:
under the existence of inert atmosphere and rare earth catalyst, taking an alkene butylamino pyridine compound shown in a formula (I) as a raw material, and preparing a 1, 5-tetrahydronaphthyridine derivative shown in a formula (II) through carbon-hydrogen bond activation and intramolecular insertion cyclization reaction; the reaction formula is as follows:
in the above formula, R1Is hydrogen, methyl or halogen; r2Is hydrogen or methyl; r3Is methyl, phenyl or benzyl;
R4is hydrogen;
the rare earth catalyst is Y [ N (SiMe)3)2]3
The solvent is toluene;
the additive is dibenzylamine.
2. The method for preparing a 1, 5-tetrahydronaphthyridine derivative according to claim 1, wherein: the inert atmosphere is nitrogen.
3. The method for preparing a 1, 5-tetrahydronaphthyridine derivative according to claim 1, wherein: the mol ratio of the alkene butylamino pyridine compound shown in the formula (I) to the rare earth catalyst is 1.0/0.1.
4. The method for preparing a 1, 5-tetrahydronaphthyridine derivative according to claim 1, wherein: the reaction temperature is 80-100 ℃, and the reaction time is 24-48 h.
5. The method for preparing a 1, 5-tetrahydronaphthyridine derivative according to claim 1, wherein: the amount of dibenzylamine added was the same as the amount of the catalyst.
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| GB201218862D0 (en) * | 2012-10-19 | 2012-12-05 | Astex Therapeutics Ltd | Bicyclic heterocycle compounds and their uses in therapy |
| AR112463A1 (en) * | 2017-07-27 | 2019-10-30 | Esteve Pharmaceuticals Sa | PROPANAMINE DERIVATIVES TO TREAT PAIN AND PAIN RELATED STATES |
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