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)