CN101555248B - Method for preparing poly-substituted 1, 5-naphthyridine compound - Google Patents
Method for preparing poly-substituted 1, 5-naphthyridine compound Download PDFInfo
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- CN101555248B CN101555248B CN2009100847360A CN200910084736A CN101555248B CN 101555248 B CN101555248 B CN 101555248B CN 2009100847360 A CN2009100847360 A CN 2009100847360A CN 200910084736 A CN200910084736 A CN 200910084736A CN 101555248 B CN101555248 B CN 101555248B
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- -1 1, 5-naphthyridine compound Chemical class 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 239000000706 filtrate Substances 0.000 claims abstract description 11
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims abstract description 11
- 238000010992 reflux Methods 0.000 claims abstract description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007670 refining Methods 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 230000007935 neutral effect Effects 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- 238000002360 preparation method Methods 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 238000000605 extraction Methods 0.000 claims description 10
- 239000011790 ferrous sulphate Substances 0.000 claims description 10
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 10
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 238000002386 leaching Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 150000003927 aminopyridines Chemical class 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 5
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 claims description 5
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical group C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical group CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 claims description 4
- MMFCJPPRCYDLLZ-UHFFFAOYSA-N dec-2-enal Chemical compound CCCCCCCC=CC=O MMFCJPPRCYDLLZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 3
- SNOFKGQEUYMNCE-UHFFFAOYSA-N 2,2,2-trifluoro-1-$l^{1}-oxidanylethanone Chemical compound [O]C(=O)C(F)(F)F SNOFKGQEUYMNCE-UHFFFAOYSA-N 0.000 claims description 2
- IDEYZABHVQLHAF-UHFFFAOYSA-N 2-methylpent-2-enal Chemical class CCC=C(C)C=O IDEYZABHVQLHAF-UHFFFAOYSA-N 0.000 claims description 2
- DTCCTIQRPGSLPT-UHFFFAOYSA-N 2-pentenal Chemical class CCC=CC=O DTCCTIQRPGSLPT-UHFFFAOYSA-N 0.000 claims description 2
- 150000003929 3-aminopyridines Chemical class 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000000758 substrate Substances 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 230000001105 regulatory effect Effects 0.000 abstract 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 abstract 1
- 239000000376 reactant Substances 0.000 abstract 1
- 235000011149 sulphuric acid Nutrition 0.000 abstract 1
- 239000001117 sulphuric acid Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000005055 1,5-naphthyridines Chemical class 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VMLKTERJLVWEJJ-UHFFFAOYSA-N 1,5-naphthyridine Chemical group C1=CC=NC2=CC=CN=C21 VMLKTERJLVWEJJ-UHFFFAOYSA-N 0.000 description 1
- DHBZSUSBPQEFPV-UHFFFAOYSA-N 2-hydroxy-4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C(O)=C1C(O)=O DHBZSUSBPQEFPV-UHFFFAOYSA-N 0.000 description 1
- GDOIKKMNCIMDAO-UHFFFAOYSA-N 5-amino-1h-pyridin-2-one Chemical compound NC1=CC=C(O)N=C1 GDOIKKMNCIMDAO-UHFFFAOYSA-N 0.000 description 1
- SDWJADNJUJDELC-UHFFFAOYSA-N 6,7-dimethyl-1,5-naphthyridine-4-carboxylic acid Chemical class C1=CC(C(O)=O)=C2N=C(C)C(C)=CC2=N1 SDWJADNJUJDELC-UHFFFAOYSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- VVEGURRPTDBLHJ-UHFFFAOYSA-N 6-methyl-1h-1,5-naphthyridin-2-one Chemical class N1C(=O)C=CC2=NC(C)=CC=C21 VVEGURRPTDBLHJ-UHFFFAOYSA-N 0.000 description 1
- MHPFNLJRODSRMR-UHFFFAOYSA-N 7-fluoro-2-methyl-1,5-naphthyridine Chemical class N1=CC(F)=CC2=NC(C)=CC=C21 MHPFNLJRODSRMR-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 238000007108 Doebner-von Miller reaction Methods 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a method for preparing a poly-substituted 1, 5-naphthyridine compound. The method comprises the steps of: mixing 3-aminopyridines compound shown in constitutional formula (II), (III) or (IV) with 2-alkenyl aldehyde or 2-alkenyl ketone; adding green vitriol as a catalyst; carrying out heating reflux reaction in sulphuric acid for 2 to 20 hours; cooling a reaction system till the temperature of the reaction system reaches room temperature and then regulating pH value to be neutral; filtering the reactants and extracting, concentrating, separating and refining the filtrate to obtain the poly-substituted 1, 5-naphthyridine compound shown in constitutional formula (I). The method can be applied to various substrates and materials are highly available; poly-substituted 1, 5-naphthyridine compound banks with diverse structures can be synthesized by optimizing and regulating substrates involved in the reaction, and the compounds can be widely applied to the fields suchas pharmacochemistry, biomedicine, materials science and the like.
Description
Technical field
The invention belongs to the field of chemical synthesis, specifically, relate to a kind of polysubstituted 1, the preparation method of 5-naphthyridine compounds.
Background technology
1,5-naphthyridines compounds is a kind of important heterogeneous ring compound, and they are widely distributed at occurring in nature, all contain 1 in the structure of many natural products, 5-naphthyridines ring.1,5-naphthyridines compounds also is the important intermediate of multiple synthetic drugs.Have been found that 1,5-naphthyridines compounds has anti-malarial, anti-inflammatory, sterilization, antiviral, anticancer, anti-virus, control and pant and biological activity such as antiemetic.Pharmaceutical Chemist is for 1, and the utilization of 5-naphthyridines compounds is also underway always for the research of acceptor inhibitor such as transforming growth factor acceptor inhibitor.New functional materials such as many new dyes that development in recent years is got up and advanced luminescent material all contains 1 in its structure, 5-naphthyridines ring.Therefore, find, development is novel 1 that 5-naphthyridines compounds and novel preparation method thereof will produce significance for them in Application for Field researchs such as pharmaceutical chemistry, biomedicine and Materials science.
Because 1, the extensive use that 5-naphthyridines compounds is had has developed multiple synthetic method for many years.Mainly contain synthetic method (Org.Lett.2000 such as Skraup, Doebner-von Miller, Combes, Conrad-Limpach-Knorr and Pfitzinger, 2,875-878 and WO06040052 and WO02062794 and J.Med.Chem.2004,47,4494-4506) etc.
These 1, the method for 5-naphthyridines compounds often has the characteristics such as active reaction substrate, temperature of reaction height, reaction yield are low that need.For the arylamine of the substituting group that is connected with strong sucting electronic effect such as fluorine, nitro or trifluoromethyl, reaction is difficult to carry out.Most widely used in these methods is Skraup1,5-naphthyridines synthesis method.Because the substrate form of this method is fixed, so the synthetic product has limitation, the handiness of replacement form shortage; Simultaneously, this method is substituent 1 for all having on synthetic two rings, and 5-naphthyridines compounds is powerless.Thereby development can synthesize novel structure, have a plurality of substituently 1, and the method for 5-naphthyridines compounds seems and is even more important.
Summary of the invention
The purpose of this invention is to provide a kind of polysubstituted 1, the preparation method of 5-naphthyridine compounds.
Of the present invention polysubstituted 1, the preparation method of 5-naphthyridine compounds is with structural formula (II), (III) or the 3-aminopyridines (IV),
After 2-thiazolinyl aldehyde or 2-alkenyl ketone mix, add the catalyzer ferrous sulfate, in sulfuric acid heating reflux reaction 2-20 hour, after reaction system is cooled to room temperature, regulate the pH value to neutral, filter, filtrate is extracted, concentrates, separates and makes with extra care, make the polysubstituted 1 of structural formula (I), the 5-naphthyridine compounds.
Wherein, substituent R
1Be hydrogen, methyl, ethyl, propyl group or hexyl; R
2Be hydrogen or methyl; R
3Be hydrogen or methyl; R
4For hydrogen, to contain carbon number be C
1-C
7Saturated straight or branched aliphatic alkyl, to contain carbon number be C
1-C
7Saturated straight or branched aliphatics alkoxyl group, halogen, phenyl, hydroxyl, carboxyl, methylene radical carboxyl, 2-methyl carboxyl methylene radical, methoxycarbonyl methylene radical, ethoxycarbonyl methylene radical, 2-methyl methoxy carbonyl methylene radical, 2-methyl ethoxycarbonyl methylene radical, trifluoroacetyl oxygen base, nitro, cyano group, trifluoromethyl.
Preferably, R
1Be hydrogen or methyl, R
2Be hydrogen or methyl, R
3Be hydrogen or methyl, R
4Be hydrogen, methyl, hydroxyl, fluorine, bromine, methoxyl group, cyano group, trifluoromethyl, carboxyl or methylene radical carboxyl.
More preferably, R
1, R
2Be methyl, R
3Be hydrogen, R
4Be the 8-carboxyl; R
1Be methyl, R
2, R
3Be hydrogen, R
4Be the 7-fluorine; R
1, R
2, R
3Be methyl, R
4Be 1 of 6-cyano group, the 5-naphthyridine compounds.
The described carbon number that contains is C
1-C
7Saturated straight or branched aliphatic alkyl be methyl, ethyl, the tertiary butyl; The described carbon number that contains is C
1-C
7Saturated straight or branched aliphatics alkoxyl group be methoxy or ethoxy; Described halogen is fluorine, chlorine or bromine.
Described 2-thiazolinyl aldehyde is propenal, crotonic aldehyde, 2-methyl-2-butene aldehyde, 2-pentenals, 2-hexenoic aldehyde, 2-methyl-2-pentenals or 2-decenal; Described 2-alkenyl ketone is ethenyl methyl ketone or 3-methyl-3-amylene-2-ketone etc.
Polysubstituted 1, in the preparation process of 5-naphthyridine compounds, described extraction, to concentrate be with ethyl acetate washing leaching cake, extraction filtrate, and the combined ethyl acetate phase is revolved to steam and reclaimed ethyl acetate, makes enriched material.
Described separation and refining be after concentrating, to enriched material in order to sherwood oil: ethyl acetate=0-50: 1 mixed solution is an eluent, carries out silica gel column chromatography, obtain polysubstituted 1, the 5-naphthyridine compounds; Also can be after concentrating, enriched material is obtained with the method for underpressure distillation polysubstituted 1, the 5-naphthyridine compounds.
In above-mentioned preparation process, described aminopyridines and 2-thiazolinyl aldehyde or 2-alkenyl ketone are by 1: 1.5-5.0, preferred 1: 3.5 mixed in molar ratio.
The mol ratio of described catalyzer ferrous sulfate and aminopyridines is 0.01-0.09: 1.
Because this type of reaction is suitable for multiple substrate, and raw material obtains easily, through optimization and adjusting to reaction substrate, can synthesize polysubstituted, structure is various 1,5-naphthyridines compounds combinatorial libraries, simultaneously, can be with this method synthetic 1 through the organic chemistry method of routine, 5-naphthyridines compounds is converted into a series of 7-naphthyridine derivatives.Compound might be used widely in fields such as pharmaceutical chemistry, biomedicine and Materials science.
The productive rate of the target product that the present invention obtains through separating after purifying is 50%-75%.Gained compound process nmr spectrum (
1Determine that H NMR) structure is errorless.
The present invention with before this 1, the synthetic method of 5-naphthyridines compounds is compared, biggest advantage be to provide all have on two rings substituent polysubstituted 1,5-naphthyridines compounds.Shown in structural formula (I).Can only obtain R by before this method
1, R
2, R
3Be 1 of hydrogen, 5-naphthyridines ring; And adopt the present invention can obtain R
1, R
2, R
3, R
4For substituent 1,5-naphthyridines ring.
Embodiment
Following examples further specify content of the present invention, but should not be construed as limitation of the present invention.
Embodiment 1 2-methyl isophthalic acid, the preparation (R of 5-naphthyridines
1, R
2, R
3Be hydrogen, R
4Be the 6-methyl)
Add the 0.129mol ferrous sulfate in reactor successively, 1.59mol 3-aminopyridine and 5.56mol crotonic aldehyde slowly add the 2.8mol vitriol oil, reflux 12 hours.Be cooled to room temperature, be neutralized to neutrality, filter, use 1L ethyl acetate washing leaching cake, extraction filtrate three times with sodium hydroxide solution, the combined ethyl acetate phase is revolved to steam and is reclaimed ethyl acetate, makes enriched material, underpressure distillation obtains the 2-methyl isophthalic acid to enriched material, and 5-naphthyridines 112.5g, productive rate are 50%.Clear crystal, 64 ℃-65 ℃ of fusing points.Proton nmr spectra (
1H NMR, 300MHz, CDCl
3) δ 8.90-8.89 (m, 1H), 8.31-8.25 (m, 2H), 7.60-7.49 (m, 2H), 2.76 (s, 3H).
Embodiment 2 2-1, the preparation (R of 5-naphthyridines methyl acetate
1, R
2, R
3Be hydrogen, R
4Be 6-methylene radical carbonyl oxygen methyl)
In reactor, add 69mmol 2-methyl 1, the 5-naphthyridines, under the anhydrous and oxygen-free condition, add and heavily steam tetrahydrofuran (THF), be warming up to 50 ℃, drip the 208mmol lithium diisopropyl amido, dropwise the back and stir 30min down, continue to drip the 76mmol methylcarbonate, dropwise the back and stir 2h down at 50 ℃ at 50 ℃, saturated ammonium chloride solution cancellation reaction with 20ml30%, with 50ml ethyl acetate extraction three times, merge organic phase, concentrate, underpressure distillation, obtain 2-1,5-naphthyridines methyl acetate 7.8g, productive rate is 56%, clear crystal, fusing point are 68 ℃-70 ℃.Proton nmr spectra (
1H NMR, 300MHz, CDCl
3) δ 8.95-8.93 (m, 1H), 8.37-8.33 (m, 2H), 7.66-7.59 (m, 2H), 4.06 (s, 2H), 3.72 (s, 3H).
Embodiment 3 2-hydroxyl-6-methyl isophthalic acid, the preparation (R of 5-naphthyridines
1Be methyl, R
2, R
3Be hydrogen, R
4Be the 6-hydroxyl)
In reactor, add the 1.8mmol ferrous sulfate successively, 145mmol 2-hydroxyl-5-aminopyridine and 290mmol crotonic aldehyde, slowly add the 110mmol vitriol oil, after the reflux 2 hours, reaction system is cooled to room temperature, is neutralized to neutrality, filter with the sodium hydroxide solution of 88ml 10%, use 150ml ethyl acetate washing leaching cake, extraction filtrate three times, the combined ethyl acetate phase is revolved to steam and is removed ethyl acetate, makes enriched material, to enriched material is leacheate with the ethyl acetate, carry out silica gel column chromatography, obtain 2-hydroxyl-6-methyl 1,5-naphthyridines 13.9g, productive rate 60%, colorless solid.Proton nmr spectra (
1H NMR, 300MHz, CDCl
3) δ 8.04-8.01 (dd, 1H), 7.67 (d, 1H), 7.36-7.26 (d, 1H), 6.92-6.89 (d, 1H), 2.67-2.58 (s, 3H).
Embodiment 4 2-methoxyl group-8-methyl isophthalic acid, the preparation (R of 5-naphthyridines
1, R
2Be hydrogen, R
3Be methyl, R
4Be the 6-methoxyl group)
Add the 6.45mmol ferrous sulfate in reactor successively, 80mmol-amino-6-methoxypyridine and 278mmol methyl vinyl ketone slowly add the 140mmol vitriol oil, reflux 6 hours.Be cooled to room temperature, be neutralized to neutrality with sodium hydroxide solution, filter, use 500ml ethyl acetate washing leaching cake, extraction filtrate three times, the combined ethyl acetate phase is revolved to steam and is reclaimed ethyl acetate, make enriched material, underpressure distillation obtains 2-methoxyl group-8-methyl isophthalic acid to enriched material, and 5-naphthyridines 7.5g, productive rate are 54%.Proton nmr spectra (
1H NMR, 300MHz, CDCl
3) δ 9.02 (d, J=7.34Hz, 1H), 8.43 (d, J=7.28Hz, 1H) 7.54 (d, J=7.34Hz, 1H), 6.90 (d, J=7.28Hz, 1H), 3.76 (s, 3H), 2.40 (s, 3H)
Embodiment 52,3-dimethyl-8-carboxyl-1, the preparation (R of 5-naphthyridines
1, R
2Be methyl, R
3Be hydrogen, R
4Be the 8-carboxyl)
Add the 11.61mmol ferrous sulfate in reactor successively, 144mmol3-amino-4-pyridine carboxylic acid and 720mmol 2-methyl-2-butene aldehyde slowly add the 252mmol vitriol oil, reflux 8 hours.Be cooled to room temperature, be neutralized to neutrality, filter with sodium hydroxide solution, use 900ml ethyl acetate washing leaching cake, extraction filtrate three times, the combined ethyl acetate phase is revolved to steam and is reclaimed ethyl acetate, makes enriched material, to enriched material is leacheate with the ethyl acetate, silica gel column chromatography obtains 2,3-dimethyl-8-carboxyl-1,5-naphthyridines 16.3g, productive rate are 56%.Proton nmr spectra (
1H NMR, 300MHz, CDCl
3) δ 9.57 (d, J=7.62Hz, 1H), 8.34 (s, 1H), 8.18 (d, J=7.62Hz, 1H), 2.53 (s, 3H), 2.31 (s, 3H)
Embodiment 6 2-methyl-7-fluoro-1, the preparation (R of 5-naphthyridines
1Be methyl, R
2, R
3Be hydrogen, R
4Be the 7-fluorine)
Add the 3.87mmol ferrous sulfate in reactor successively, 48mmol3-amino-5-fluorine pyridine and 167mmol crotonic aldehyde slowly add the 84mmol vitriol oil, reflux 16 hours.Be cooled to room temperature, be neutralized to neutrality with sodium hydroxide solution, filter, use 300ml ethyl acetate washing leaching cake, extraction filtrate three times, the combined ethyl acetate phase, revolve and steam to reclaim ethyl acetate, make enriched material, to enriched material with sherwood oil: the mixed solution of ethyl acetate=20: 1 is a leacheate, silica gel column chromatography, obtain 2-methyl-7-fluoro-1,5-naphthyridines 4.67g, productive rate are 60%.Proton nmr spectra (
1H NMR, 300MHz, CDCl
3) δ 8.70 (s, 1H), 8.49 (d, J=7.62Hz, 1H), 8.12 (s, 1H), 7.49 (d, J=7.62Hz, 1H), 2.55 (s, 3H)
Embodiment 72, and 3,4-trimethylammonium-6-cyano group-1, the preparation (R of 5-naphthyridines
1, R
2, R
3Be methyl,, R
4Be 6-cyano group)
Add the 1.29mmol ferrous sulfate in reactor successively, 16mmol 3-amino-6-fluorine pyridine and 55.7mmol3-methyl-3-amylene-2-ketone slowly adds the 28mmol vitriol oil, reflux 16 hours.Be cooled to room temperature, be neutralized to neutrality, filter with sodium hydroxide solution, use 100ml ethyl acetate washing leaching cake, extraction filtrate three times, the combined ethyl acetate phase is revolved to steam and is reclaimed ethyl acetate, make enriched material, to enriched material with sherwood oil: the mixed solution of ethyl acetate=15: 1 is a leacheate, and silica gel column chromatography obtains 2,3,4-trimethylammonium-6-cyano group-1,5-naphthyridines 1.64g, productive rate are 52%.Proton nmr spectra (
1H NMR, 300MHz, CDCl
3) δ 8.88 (d, J=8.02Hz, 1H), 8.48 (d, J=8.02Hz, 1H), 7.51-7.48 (m, 2H), 2.57 (s, 3H), 2.49 (s, 3H), 2.33 (s, 3H)
Claims (9)
- One kind polysubstituted 1, the preparation method of 5-naphthyridine compounds is characterized in that, with structural formula (II), (III) or the 3-aminopyridines (IV), with 2-thiazolinyl aldehyde
Or after the mixing of 2-alkenyl ketone, add the catalyzer ferrous sulfate, in sulfuric acid heating reflux reaction 2-20 hour, after reaction system is cooled to room temperature, regulate the pH value to neutral, filter, filtrate is extracted, concentrates, separates and makes with extra care, make the polysubstituted 1 of structural formula (I), the 5-naphthyridine compounds;
Wherein, substituent R 1Be hydrogen, methyl, ethyl, propyl group or hexyl; R 2Be hydrogen or methyl; R 3Be hydrogen or methyl; R 4For hydrogen, to contain carbon number be C 1-C 7Saturated straight or branched aliphatic alkyl, to contain carbon number be C 1-C 7Saturated straight or branched aliphatics alkoxyl group, halogen, phenyl, hydroxyl, carboxyl, methylene radical carboxyl, 2-methyl carboxyl methylene radical, methoxycarbonyl methylene radical, ethoxycarbonyl methylene radical, 2-methyl methoxy carbonyl methylene radical, 2-methyl ethoxycarbonyl methylene radical, trifluoroacetyl oxygen base, nitro, cyano group, trifluoromethyl. - 2. preparation method as claimed in claim 1 is characterized in that, the described carbon number that contains is C 1-C 7Saturated straight or branched aliphatic alkyl be methyl, ethyl, the tertiary butyl; The described carbon number that contains is C 1-C 7Saturated straight or branched aliphatics alkoxyl group be methoxy or ethoxy; Described halogen is fluorine, chlorine or bromine.
- 3. preparation method as claimed in claim 1 is characterized in that, described 2-thiazolinyl aldehyde is propenal, crotonic aldehyde, 2-methyl-2-butene aldehyde, 2-pentenals, 2-hexenoic aldehyde, 2-methyl-2-pentenals or 2-decenal; Described 2-alkenyl ketone is ethenyl methyl ketone or 3-methyl-3-amylene-2-ketone.
- 4. as the arbitrary described preparation method of claim 1-3, it is characterized in that described extraction, to concentrate be that the combined ethyl acetate phase is revolved to steam and reclaimed ethyl acetate, makes enriched material with ethyl acetate washing leaching cake, extraction filtrate three times.
- 5. as the arbitrary described preparation method of claim 1-4, it is characterized in that, described separation and the refining silica gel column chromatography that adopts, with sherwood oil: ethyl acetate=0-50: 1 mixed solution is an eluent.
- 6. as the arbitrary described preparation method of claim 1-4, it is characterized in that described separation and the refining distillation under vacuum that adopts.
- 7. as the arbitrary described preparation method of claim 1-6, it is characterized in that described aminopyridines and 2-thiazolinyl aldehyde or 2-alkenyl ketone are by 1: the 1.5-5.0 mixed in molar ratio.
- 8. preparation method as claimed in claim 7 is characterized in that, described aminopyridines and 2-thiazolinyl aldehyde or 2-alkenyl ketone were by 1: 3.5 mixed in molar ratio.
- 9. as the arbitrary described preparation method of claim 1-6, it is characterized in that the mol ratio of described catalyzer ferrous sulfate and aminopyridines is 0.01-0.09: 1.
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