CN114560814B - Synthesis method of substituted 2, 3-naphthyridine ketone compound - Google Patents
Synthesis method of substituted 2, 3-naphthyridine ketone compound Download PDFInfo
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- CN114560814B CN114560814B CN202210208080.4A CN202210208080A CN114560814B CN 114560814 B CN114560814 B CN 114560814B CN 202210208080 A CN202210208080 A CN 202210208080A CN 114560814 B CN114560814 B CN 114560814B
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- C07—ORGANIC CHEMISTRY
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- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a synthesis method of a substituted 2, 3-naphthyridine ketone compound, which comprises the following steps: adding solvent and titanocene dichloride into a reaction container respectively, continuously adding substituted hydrazine and substituted o-carboxybenzaldehyde, and carrying out heat preservation reaction under mechanical mixing; and (3) detecting the reaction by TLC, cooling to 0 ℃ after the reaction is finished, and filtering to obtain a crystalline solid. The method develops a novel method for synthesizing the 2, 3-naphthyridine ketone compound by using the dichloro-titanocene as a catalyst in the reaction process, and the product can be separated and obtained only by recrystallization, so that the separation and purification process of the product becomes easy to carry out, the operation is simple, the applicability is wide, and the application potential is large. The reaction process shortens the reaction time, improves the product yield, has the yield reaching 90% -98%, has the purity reaching 99%, has low toxicity and no harm, has small use amount, can be recycled, accords with the green economic principle, and has wide application prospect.
Description
Technical Field
The invention belongs to the technical field of compound preparation, and in particular relates to a synthetic method of a substituted 2, 3-naphthyridine ketone compound.
Background
The nitrogen-containing heterocycle is the core part of an active compound widely existing in medicines, pesticides and functional materials, and is a large class of active compounds in the field of medical research at present, wherein the phthalazinone compounds are nitrogen-containing heterocycle compounds with remarkable biological activity, have various medicinal characteristics of resisting cancer, inflammation, bacteria, oxidization, nerve degeneration and the like, and can be used for treating various diseases such as diabetes, asthma, hepatitis B, vascular hypertension, arrhythmia and the like. In addition, some naphthyridones have been found to act as inhibitors of phosphodiesterase IV and phosphodiesterase V, the latter having a potential therapeutic effect on pulmonary hypertension and erectile dysfunction.
The synthesis of naphthyridones has been the focus of research. Various methods for synthesizing phthalazinones are reported in the literature, including cycloaddition, reduction, cyclocondensation, and biotechnology. The current common method for synthesizing the phthalazinone compounds is mainly divided into the following steps according to different raw materials: (1) Condensing and ring-closing by taking substituted benzaldehyde or benzyl ester and substituted hydrazine as raw materials; (2) Condensing and ring-closing by using substituted phthalic anhydride or phthalide as raw material.
The traditional method for synthesizing the naphthyridine ketone generally needs strong acid, strong alkali, strong reducing agent, long-time reaction, high temperature or multiple steps and the like, and palladium and TiO are utilized in recent years 2 The method for synthesizing the phthalazinone by catalyzing with the catalyst such as solid acid can enlarge the reaction substrate, improve the reaction rate and increase the product yield, but the heavy metal residue exists in the process of using the catalyst in a large amount, and the production cost and the labor intensity are increased. The applicant of the present invention has proposed a solvent-free and catalysis-free method for synthesizing phthalazinone compounds with high efficiency, but the solvent-free method has the disadvantages that the reaction can not be sufficiently stirred at high temperature and is not suitable for the amplification reaction. Therefore, development of efficient, simple, and mild-condition methods for synthesizing phthalazinone is still the focus of research.
By searching, no patent publication related to the present patent application has been found.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a synthesis method of a substituted 2, 3-naphthyridine ketone compound.
The technical scheme adopted for solving the technical problems is as follows:
a substituted 2, 3-naphthyridine ketone compound comprises the following steps:
(1) Adding solvent and titanocene dichloride into a reaction container respectively, continuously adding substituted hydrazine and substituted o-carboxybenzaldehyde, controlling the reaction temperature at 40-160 ℃, and carrying out heat preservation reaction under mechanical mixing;
(2) TLC detection reaction, cooling to 0 ℃ after the reaction is finished, filtering, and drying to obtain a crystalline solid, namely the substituted 2, 3-naphthyridine ketone compound which has the structural formula shown in formula (I):
wherein R is hydrogen atom, alkyl and aryl.
Further, the aryl group is an alkyl substitution, a phenyl substitution, a substituted phenyl substitution, or a hydroxy substitution.
Further, the substituted 2, 3-naphthyridones are one or more of the following compounds:
further, the substituted hydrazine in the step (1) is phenylhydrazine, hydrazine hydrate, methyl hydrazine, isopropyl hydrazine, 2-hydrazinoethanol, 2-chlorophenylhydrazine, 3-chlorophenylhydrazine, 4-fluorophenylhydrazine, 4-nitrophenylhydrazine, o-methylphenylhydrazine hydrochloride, 3-methylphenylhydrazine hydrochloride, p-methylphenylhydrazine, 2-hydrazinopyridine, 4-bromophenylhydrazine, 4-iodophenylhydrazine or 2, 5-dichlorophenylhydrazine.
Further, the molar ratio of the substituted hydrazine to the o-carboxybenzaldehyde in the step (1) is 0.9-1.5: 1, the condensation temperature is 40-160 ℃.
Further, the molar amount of the dichloro-titanocene in the step (1) is 0.2% -1% of the molar amount of the substituted hydrazine.
Further, the heat preservation time in the step (1) is 20-120min.
Further, the mechanical mixing in the step (1) is mechanical stirring or grinding stirring.
Further, the solvent in the step (1) is one or more of methanol, ethanol, toluene, ethyl acetate and diethyl ether.
Further, the preparation method of the substituted 2, 3-naphthyridine ketone compound comprises the following process routes:
the invention has the advantages and positive effects that:
1. the synthesis method of the phthalazinone compounds develops a new method for synthesizing the 2, 3-phthalazinone compounds by using the titanocene dichloride as a catalyst in the reaction process, and the products can be separated and obtained only by recrystallization, so that the separation and purification process of the products becomes easy to carry out, the operation is simple, and the method has potential of industrial production. The reaction process shortens the reaction time, improves the product yield, has the yield reaching 90% -98%, has the purity reaching 99%, has less catalyst consumption, can be recycled, accords with the principle of green economy, and has wide application prospect.
2. The preparation method of the invention starts from cheap and easily available raw materials, and prepares a series of 2, 3-naphthyridine ketone compounds with high activity with high efficiency in a yield of 90% -98% and a purity of more than 99% by taking the dichloro-titanocene as a catalyst.
3. Compared with the prior melting method of the subject group, the method has the advantages of mild conditions and capability of carrying out amplification experiments, and has industrial production significance.
4. The raw material solvent, the dichloro-titanocene, the substituted hydrazine and the dichloro-titanocene synergistic solvent in the substituted o-carboxybenzaldehyde can jointly catalyze the reaction, so that the reaction rate is improved, and the product yield is increased (specifically shown in comparative example 1).
Drawings
FIG. 1 shows nuclear magnetic resonance of the target compound 1 of the present invention 1 H spectrogram;
FIG. 2 shows nuclear magnetic resonance of the target compound 1 of the present invention 1 C, spectrogram;
FIG. 3 shows nuclear magnetic resonance of the target compound 2 of the present invention 1 H spectrogram;
FIG. 4 shows nuclear magnetic resonance of the target compound 2 of the present invention 1 C, spectrogram;
FIG. 5 shows nuclear magnetic resonance of the target compound 3 of the present invention 1 H spectrogram;
FIG. 6 shows nuclear magnetic resonance of the target compound 3 of the present invention 1 C, spectrogram;
FIG. 7 shows nuclear magnetic resonance of the target compound 4 of the present invention 1 H spectrogram;
FIG. 8 shows nuclear magnetic resonance of the target compound 4 of the present invention 1 C, spectrogram;
FIG. 9 shows nuclear magnetic resonance of target compound 5 of the present invention 1 H spectrogram;
FIG. 10 shows nuclear magnetic resonance of target compound 5 of the present invention 1 C, spectrogram;
FIG. 11 shows nuclear magnetic resonance of the target compound 6 of the present invention 1 H spectrogram;
FIG. 12 shows nuclear magnetic resonance of target compound 6 of the present invention 1 C, spectrogram;
FIG. 13 shows nuclear magnetic resonance of target compound 7 of the present invention 1 H spectrogram;
FIG. 14 shows nuclear magnetic resonance of target compound 7 of the present invention 1 C, spectrogram;
FIG. 15 shows nuclear magnetic resonance of target compound 8 of the present invention 1 H spectrogram;
FIG. 16 shows nuclear magnetic resonance of target compound 8 of the present invention 1 C, spectrogram;
FIG. 17 shows nuclear magnetic resonance of the target compound 9 of the present invention 1 H spectrogram;
FIG. 18 shows nuclear magnetic resonance of the target compound 9 of the present invention 1 C, spectrogram;
FIG. 19 shows nuclear magnetic resonance of the target compound 10 of the present invention 1 H spectrogram;
FIG. 20 shows nuclear magnetic resonance of the target compound 10 of the present invention 1 C, spectrogram;
FIG. 21 shows nuclear magnetic resonance of the target compound 11 of the present invention 1 H spectrogram;
FIG. 22 shows nuclear magnetic resonance of the target compound 11 according to the present invention 1 C, spectrogram;
FIG. 23 shows nuclear magnetic resonance of target compound 12 according to the present invention 1 H spectrogram;
FIG. 24 shows nuclear magnetic resonance of the target compound 12 of the present invention 1 C, spectrogram;
FIG. 25 shows nuclear magnetic resonance of target compound 13 according to the present invention 1 H spectrogram;
FIG. 26 shows nuclear magnetic resonance of target compound 13 according to the present invention 1 C, spectrogram;
FIG. 27 shows nuclear magnetic resonance of target compound 14 according to the present invention 1 H spectrogram;
FIG. 28 shows nuclear magnetic resonance of target compound 14 according to the present invention 1 C, spectrogram;
FIG. 29 shows nuclear magnetic resonance of target compound 15 according to the present invention 1 H spectrogram;
FIG. 30 shows nuclear magnetic resonance of target compound 15 according to the present invention 1 C, spectrogram;
FIG. 31 shows the nuclear magnetic resonance of the target compound 16 according to the present invention 1 H spectrogram;
FIG. 32 shows nuclear magnetic resonance of target compound 16 according to the present invention 1 C, spectrogram;
FIG. 33 shows nuclear magnetic resonance of target compound 17 according to the present invention 1 H spectrogram;
FIG. 34 shows nuclear magnetic resonance of target compound 17 according to the present invention 1 C spectrogram.
Detailed Description
The following describes the embodiments of the present invention in detail, but the present embodiments are illustrative and not limitative, and are not intended to limit the scope of the present invention.
The raw materials used in the invention are conventional commercial products unless specified; the methods used in the present invention are conventional in the art unless otherwise specified.
A substituted 2, 3-naphthyridine ketone compound comprises the following steps:
(1) Adding solvent and titanocene dichloride into a reaction container respectively, continuously adding substituted hydrazine and substituted o-carboxybenzaldehyde, controlling the reaction temperature at 40-160 ℃, and carrying out heat preservation reaction under mechanical mixing;
(2) TLC detection reaction, cooling to 0 ℃ after the reaction is finished, standing, filtering and drying to obtain a crystalline solid, namely the substituted 2, 3-naphthyridones compound which has the structural formula shown in formula (I):
wherein R is hydrogen atom, alkyl and aryl.
Further, the aryl group is one of a plurality of substituents such as alkyl substitution, phenyl substitution, substituted phenyl substitution or hydroxy substitution.
Further, the substituted 2, 3-naphthyridones are one or more of the following compounds:
preferably, the substituted hydrazine in the step (1) is phenylhydrazine, hydrazine hydrate, methyl hydrazine, isopropyl hydrazine, 2-hydrazinoethanol, 2-chlorophenylhydrazine, 3-chlorophenylhydrazine, 4-fluorophenylhydrazine, 4-nitrophenylhydrazine, o-methylphenylhydrazine hydrochloride, 3-methylphenylhydrazine hydrochloride, p-methylphenylhydrazine, 2-hydrazinopyridine, 4-bromophenylhydrazine, 4-iodophenylhydrazine or 2, 5-dichlorophenylhydrazine.
Preferably, the molar ratio of the substituted hydrazine to the o-carboxybenzaldehyde in the step (1) is 0.9-1.5: 1, the condensation temperature is 40-160 ℃.
Preferably, the molar amount of the titanocene dichloride in the step (1) is 0.2% -1% of the molar amount of the substituted hydrazine.
Preferably, the heat preservation time in the step (1) is 20-120min.
Preferably, the mechanical mixing in the step (1) is mechanical stirring or grinding stirring.
Preferably, the solvent in the step (1) is one or more of methanol, ethanol, toluene, ethyl acetate and diethyl ether.
Preferably, the preparation method of the substituted 2, 3-naphthyridine ketone compound comprises the following process routes:
specifically, the relevant preparation and detection examples are as follows:
example 1
Preparation of 2-phenyl-2, 3-naphthyridin-1-one of the formula
In a 25mL round bottom flask, 15mL of methanol was added at room temperature, 0.02g of titanocene dichloride was added, which could not be completely dissolved, then 1g (9 mmol,1 eq) of phenylhydrazine was added, the red color of titanocene dichloride itself was lost to become a yellowish brown clear solution, presumably a catalytic intermediate was formed at this time, and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde was continuously added, the system became a yellow solid soon, and it was judged that the reaction had started at this time. Slowly gradient warmed to 60℃by TLC (V) Petroleum ether ：V Acetic acid ethyl ester =3:1) detecting that the raw material point disappears soon to generate a single ultraviolet point, and judging that the point is the product point. The reaction is carried out for 20min under mechanical mixing, TLC detection reaction is carried out, the reaction is finished (preferably, part of solvent can be distilled off), the reaction bottle is put into a refrigerator to be cooled to 0 ℃, and the yellow crystalline solid with the product yield of 95.6 percent and the purity of 99.91 percent is obtained through filtering and drying in a system (preferably, recrystallization can be carried out).
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown as m.p. as shown in figure 1 and figure 2, wherein the temperature is 104-105 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.54(dd,J＝7.6,1.6Hz,1H),8.32(s,1H),7.86(td,J＝10.3,7.4,1.7Hz,2H),7.78(dd,J＝7.3,1.7Hz,1H),7.72-7.65(m,2H),7.53(dd,J＝8.6,7.1Hz,2H),7.42(d,J＝7.4Hz,1H)； 13 C NMR(101MHz,Chloroform-d)δ159.22,141.92,138.49,133.53,132.02,129.54,128.81,128.61,127.80,127.31,126.15,125.76.
comparative example 1
In example 1, no solvent (e.g., one or more of methanol, ethanol, toluene, ethyl acetate, and diethyl ether) was added, and no 2-phenyl-2, 3-naphthyridin-1-one could be obtained in the same manner as in example 1.
Comparative example 2
In example 1, except that titanocene dichloride was not added, the procedure was the same as in example 1, except that 2-phenyl-2, 3-naphthyridin-1-one was obtained in a yield of 32%.
As can be seen from comparative examples 1 and 2, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 2
Preparation of 2, 3-naphthyridones as follows
To a 25mL round bottom flask, 6mL of ethanol was added, 0.015g of titanocene dichloride was added, 0.26g (8.1 mmol,0.9 eq) of hydrazine hydrate and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, the temperature was raised to 40℃and the reaction was allowed to proceed for 30min with mechanical mixing, and the progress of the reaction was detected by TLC. And after the reaction is completed, cooling the temperature to 0 ℃, filtering, separating and drying to obtain pale yellow 2, 3-naphthyridine ketone solid. The yield was 98.8% and the purity was 99.99%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is as shown in the figure 3 and the figure 4, wherein the m.p. is 181-183 ℃; 1 H NMR(400MHz,Chloroform-d)δ11.00(s,1H),8.47(dd,J＝7.7,1.4Hz,1H),8.23(s,1H),7.91-7.79(m,2H),7.76(dd,J＝7.5,1.5Hz,1H)； 13 C NMR(101MHz,Chloroform-d)δ160.87,139.11,133.75,131.86,130.25,128.03,126.51,126.30.
comparative example 3
In example 2, the other steps were the same as in example 2 except that titanocene dichloride was not added, and only 2, 3-naphthyridine ketone was obtained in a yield of 28%.
As can be seen from comparative examples 1 and 3, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 3
Preparation of 2-methyl-2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 9mL of toluene was added, 0.022g of titanocene dichloride was added, 0.46g (9.9 mmol,1.1 eq) of methylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, the temperature was raised to 45℃and the reaction was carried out for 35min with mechanical mixing, and the progress of the reaction was detected by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the mixture is filtered, separated and dried to obtain pale yellow 2-methyl-2, 3-naphthyridine-1-one powder. The yield was 96.4% and the purity was 99.71%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 5 and figure 6, wherein m.p. is 112-114 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.49-8.42(m,1H),8.20-8.15(m,1H),7.81(td,J＝7.3,1.7Hz,2H),7.72(dd,J＝7.6,1.5Hz,1H),3.88(s,3H)； 13 C NMR(101MHz,Chloroform-d)δ159.73,137.63,132.99,131.67,129.82,127.79,126.55,126.00,39.46.
comparative example 4
In example 3, except that titanocene dichloride was not added, the procedure was the same as in example 3, except that 2-methyl-2, 3-naphthyridin-1-one was obtained in a yield of 22%.
As can be seen from comparative examples 1 and 4, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 4
Preparation of 2-isopropyl-2, 3-naphthyridin-1-one as follows
To a 25mL round bottom flask, 10mL of ethyl acetate was added, 0.023g of titanocene dichloride was added, 0.73g (9.9 mmol,1.1 eq) of isopropyl hydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, the temperature was raised to 70℃and the reaction was carried out with mechanical mixing for 50min with open mouth, and the progress of the reaction was detected by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, the mixture is separated by a column, and orange-colored 2-isopropyl-2, 3-naphthyridine-1-ketone liquid is obtained after drying. The yield was 98.5% and the purity was 99.93%.
The products are detected by nuclear magnetism, and the nuclear magnetism results are shown in fig. 7 and 8: 1 H NMR(400MHz,Chloroform-d)δ8.37(d,J＝5.8Hz,1H),8.16(s,1H),7.80-7.63(m,2H),7.63-7.40(m,1H),5.39(p,J＝6.6Hz,1H),1.35(d,J＝6.7Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ158.85,137.50,132.84,131.31,129.25,127.77,126.72,125.73,48.37,20.98.
comparative example 5
In example 4, except that titanocene dichloride was not added, the procedure was the same as in example 4, except that 2-isopropyl-2, 3-naphthyridin-1-one was obtained in a yield of 19%.
As can be seen from comparative examples 1 and 5, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 5
Preparation of 2-hydroxyethyl-2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 5mL of ethanol was added, 0.025g of titanocene dichloride was added, 0.62g (8.1 mmol,0.9 eq) of 2-hydrazinoethanol and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, the temperature was raised to 55℃and the reaction was carried out with mechanical mixing for 25min with open reaction, and the progress of the reaction was detected by TLC. And after the reaction is completed, cooling the temperature to 0 ℃, filtering, separating and drying to obtain white 2-hydroxyethyl-2, 3-naphthyridine-1-ketone solid. The yield was 96.6% and the purity was 99.55%.
The product passes through a melting point instrumentAnd nuclear magnetic detection, wherein the nuclear magnetic results are shown in FIG. 9 and FIG. 10, and the magnetic results are shown as m.p. 116-118 ℃. 1 H NMR(400MHz,Chloroform-d)δ8.46(d,J＝7.3Hz,1H),8.23(s,1H),8.06-7.78(m,2H),7.75(d,J＝7.2Hz,1H),4.63-4.32(m,2H),4.19-3.99(m,2H),3.17(s,1H)； 13 C NMR(101MHz,Chloroform-d)δ160.57,138.39,133.40,131.98,129.61,127.76,126.75,126.15,62.01,54.04.
Comparative example 6
In example 5, except that titanocene dichloride was not added, the procedure was the same as in example 5, except that 2-hydroxyethyl-2, 3-naphthyridin-1-one was obtained in a yield of 35%.
As can be seen from comparative examples 1 and 6, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 6
Preparation of 2- (2-chlorophenyl) -2, 3-naphthyridin-1-one as follows
To a 25mL round bottom flask, 15mL of diethyl ether was added, 0.04g of titanocene dichloride was added, and 1.54g (10.8 mmol,1.2 eq) of 2-chlorophenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, and the reaction was allowed to proceed with mechanical mixing at 65℃for 40min with open reaction by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the orange 2- (2, -chlorphenyl) -2, 3-naphthyridine-1-ketone solid is obtained by filtering, separating and drying. The yield was 90.1% and the purity was 99.35%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 11 and figure 12, wherein m.p. is 125-126 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.53(d,J＝7.7Hz,1H),8.32(s,1H),7.96-7.88(m,1H),7.86(td,J＝7.6,1.4Hz,1H),7.81(d,J＝7.0Hz,1H),7.65-7.57(m,1H),7.52(dt,J＝7.3,3.0Hz,1H),7.49-7.38(m,2H)； 13 C NMR(101MHz,Chloroform-d)δ159.04,139.48,138.77,133.77,132.15,130.41,130.19,129.81,129.38,128.29,127.83,127.27,126.41.
comparative example 7
In example 6, except that titanocene dichloride was not added, the procedure was the same as in example 6, except that 2- (2-chlorophenyl) -2, 3-naphthyridin-1-one was obtained in a yield of 20%.
As can be seen from comparative examples 1 and 7, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 7
Preparation of 2- (3-chlorophenyl) -2, 3-naphthyridin-1-one as follows
To a 25mL round bottom flask, 10mL of ethanol was added, 0.03g of titanocene dichloride was added, 1.54g (10.8 mmol,1.2 eq) of 3-chlorophenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, the temperature was raised to 50℃and the reaction was allowed to proceed with mechanical mixing for 45min and the progress of the reaction was detected by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the orange 2- (3, -chlorophenyl) -2, 3-naphthyridin-1-one solid is obtained after filtration, separation and drying. The yield was 89.5% and the purity was 99.76%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 13 and figure 14, wherein m.p. is 134-136 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.52(d,J＝7.6Hz,1H),8.32(s,1H),8.04-7.82(m,2H),7.82-7.67(m,2H),7.65(d,J＝7.3Hz,1H),7.44(t,J＝8.0Hz,1H),7.38(d,J＝8.1Hz,1H)； 13 C NMR(101MHz,Chloroform-d)δ159.10,142.82,138.87,134.31,133.77,132.23,129.66,129.42,128.45,127.83,127.35,126.28,126.01,123.84.
comparative example 8
In example 7, except that titanocene dichloride was not added, the same procedure as in example 7 was conducted, except that 2- (3-chlorophenyl) -2, 3-naphthyridin-1-one was prepared in the following yield of 39%.
As can be seen from comparative examples 1 and 8, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 8
Preparation of 2- (4-chlorophenyl) -2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 10mL of methanol was added, 0.03g of titanocene dichloride was added, and 1.54g (10.8 mmol,1.2 eq) of 4-chlorophenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, and the reaction was allowed to proceed with mechanical mixing at a temperature of 70℃for 35min with open reaction, and the progress of the reaction was detected by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the orange 2- (4, -chlorophenyl) -2, 3-naphthyridin-1-one solid is obtained after filtration, separation and drying. The yield was 94.4% and the purity was 99.77%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 15 and figure 16, wherein m.p. is 139-141 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.61-8.41(m,1H),8.32(d,J＝0.7Hz,1H),7.98-7.82(m,2H),7.80-7.71(m,1H),7.68(d,J＝2.1Hz,1H),7.66(d,J＝2.1Hz,1H),7.49(d,J＝2.2Hz,1H),7.47(d,J＝2.0Hz,1H)； 13 C NMR(101MHz,Chloroform-d)δ159.14,140.36,138.78,133.70,133.30,132.18,129.45,128.86,128.47,127.34,126.93,126.24.
comparative example 9
Other steps than adding no titanocene dichloride in example 8 were carried out in the same manner as in example 8, except that 2- (4-chlorophenyl) -2, 3-naphthyridin-1-one was prepared in the following yield of 40%.
As can be seen from comparative examples 1 and 9, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 9
Preparation of 2- (4-fluorophenyl) -2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 15mL of toluene was added, 0.03g of titanocene dichloride was added, and 1.48g (11.7 mmol,1.3 eq) of 4-chlorophenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, and the temperature was raised to 70℃and the reaction was allowed to proceed for 55 minutes with mechanical mixing, followed by detection of the progress of the reaction by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the white 2- (4-fluorophenyl) -2, 3-naphthyridin-1-one solid is obtained after filtration, separation and drying. The yield was 95.1% and the purity was 99.38%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 17 and figure 18, wherein m.p. is 140-142 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.53(d,J＝7.5Hz,1H),8.32(s,1H),7.98-7.82(m,2H),7.82-7.72(m,1H),7.67(dd,J＝9.0,4.9Hz,2H),7.21(t,J＝8.7Hz,2H)； 13 C NMR(101MHz,Chloroform-d)δ162.95,160.49,159.24,138.63,137.91,133.65,132.15,129.51,128.49,127.60,127.51,127.31,126.23,115.53.
comparative example 10
In example 9, except that titanocene dichloride was not added, the same procedure as in example 9 was conducted, except that 2- (4-fluorophenyl) -2, 3-naphthyridin-1-one was prepared in the following yield of 18%.
As can be seen from comparative examples 1 and 10, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 10
Preparation of 2- (4-nitrophenyl) -2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 8mL of ethyl acetate was added, 0.05g of titanocene dichloride was added, 1.65g (10.8 mmol,1.2 eq) of 4-nitrophenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, the temperature was raised to 80℃and the reaction was carried out with mechanical mixing for 70min with open mouth, and the progress of the reaction was detected by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the white 2- (4-nitrophenyl) -2, 3-naphthyridine-1-ketone flocculent solid is obtained after filtration, separation and drying. The yield was 97.5% and the purity was 99.83%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 19 and figure 20, wherein m.p. is 271-273 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.54(dd,J＝7.7,1.5Hz,1H),8.39(d,J＝1.9Hz,1H),8.37(d,J＝1.7Hz,2H),8.19-8.00(m,2H),8.00-7.84(m,2H),7.84-7.70(m,1H)； 13 C NMR(101MHz,Chloroform-d)δ159.18,146.93,146.14,139.57,134.16,132.56,129.26,128.35,127.52,126.46,125.80,124.09.
comparative example 11
The procedure of example 10 was otherwise repeated except that titanocene dichloride was not added, to give a yield of 25% of 2- (4-nitrophenyl) -2, 3-naphthyridin-1-one prepared as follows.
As can be seen from comparative example 1 and comparative example 11, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 11
Preparation of 2- (2-methylphenyl) -2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 10mL of ethanol was added, 0.03g of titanocene dichloride was added, and 1.32g (10.8 mmol,1.1 eq) of 2-methylphenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, and the temperature was raised to 75℃and the reaction was allowed to proceed for 80 minutes with mechanical mixing, followed by detection by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the white 2- (2-methylphenyl) -2, 3-naphthyridin-1-one solid is obtained after filtration, separation and drying. The yield was 91.7% and the purity was 99.61%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 21 and figure 22, wherein m.p. is 136-138 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.53(dd,J＝7.6,1.5Hz,1H),8.31(s,1H),7.88(td,J＝7.4,1.5Hz,1H),7.84(td,J＝7.5,1.5Hz,1H),7.79(dd,J＝7.6,1.5Hz,1H),7.38(d,J＝4.0Hz,2H),7.37(d,J＝3.5Hz,2H),2.23(s,3H)； 13 C NMR(101MHz,Chloroform-d)δ159.12,140.99,138.36,135.25,133.55,132.00,131.07,129.79,128.99,128.45,127.41,127.21,126.93,126.26,17.69.
comparative example 12
Other steps than adding no titanocene dichloride in example 11 were carried out in the same manner as in example 11, except that the following 2- (2-methylphenyl) -2, 3-naphthyridin-1-one was prepared in a yield of 27%.
As can be seen from comparative examples 1 and 12, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 12
Preparation of 2- (3-methylphenyl) -2, 3-naphthyridin-1-one as follows
To a 25mL round bottom flask, 15mL of ethyl acetate was added, 0.03g of titanocene dichloride was added, and 1.32g (10.8 mmol,1.1 eq) of 3-methylphenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, and the reaction was allowed to proceed through an open reaction with mechanical mixing at 75℃for 90min and the progress of the reaction was examined by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the white 2- (3-methylphenyl) -2, 3-naphthyridin-1-one solid is obtained after filtration, separation and drying. The yield was 90.8% and the purity was 99.95%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 23 and figure 24, wherein m.p. is 140-142 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.53(dd,J＝7.5,1.6Hz,1H),8.30(s,1H),7.93-7.79(m,2H),7.79-7.70(m,1H),7.60-7.43(m,2H),7.40(t,J＝7.6Hz,1H),7.23(d,J＝7.5Hz,1H),2.45(s,3H)； 13 C NMR(101MHz,Chloroform-d)δ159.24,141.84,138.82,138.37,133.48,131.99,129.54,128.69,128.67,128.61,127.28,126.40,126.14,122.90,21.45.
comparative example 13
Other steps than adding no titanocene dichloride in example 12 were carried out in the same manner as in example 12, except that 2- (3-methylphenyl) -2, 3-naphthyridin-1-one was prepared in a yield of 20%.
As can be seen from comparative examples 1 and 13, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 13
Preparation of 2- (4-methylphenyl) -2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 15mL of methanol was added, 0.03g of titanocene dichloride was added, and 1.10g (9 mmol,1 eq) of 4-methylphenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, and the temperature was raised to 70℃and the reaction was allowed to proceed with mechanical mixing for 85min with open reaction, and the progress of the reaction was detected by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the orange 2- (4-methylphenyl) -2, 3-naphthyridin-1-one solid is obtained after filtration, separation and drying. The yield was 95.5% and the purity was 99.91%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 25 and figure 26, wherein m.p. is 144-146 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.53(dd,J＝7.6,1.5Hz,1H),8.33-8.28(m,1H),7.92-7.80(m,2H),7.77(dd,J＝7.8,1.4Hz,1H),7.59-7.51(m,2H),7.32(d,J＝8.2Hz,2H),2.44(s,3H)； 13 C NMR(101MHz,Chloroform-d)δ159.25,139.45,138.33,137.71,133.43,131.93,129.55,129.42,128.60,127.29,126.11,125.54,21.21.
comparative example 14
Other steps than adding no titanocene dichloride in example 13 were carried out in the same manner as in example 13, except that 2- (4-methylphenyl) -2, 3-naphthyridin-1-one was prepared in a yield of 20%.
As can be seen from comparative examples 1 and 14, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 14
Preparation of 2-pyridinyl-2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 20mL of methanol was added, 0.06g of titanocene dichloride was added, and 1.37g (12.6 mmol,1.4 eq) of 2-hydrazinopyridine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, and the temperature was raised to 100℃and the reaction was allowed to proceed for 120min with mechanical mixing, and the progress of the reaction was detected by TLC. And after the reaction is completed, cooling the temperature to 0 ℃, filtering, separating and drying to obtain white 2-pyridyl-2, 3-naphthyridine-1-ketone solid. The yield was 97.5% and the purity was 99.53%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 27 and figure 28, wherein m.p.:269 ℃; 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.16-8.04(m,2H),7.82(d,J＝7.8Hz,1H),7.64(td,J＝8.8,7.2,1.9Hz,1H),7.57(td,J＝7.7,1.5Hz,1H),7.41(td,J＝7.6,1.3Hz,1H),7.26(d,J＝8.4Hz,1H),6.78(td,J＝7.2,4.9,1.0Hz,1H)； 13 C NMR(101MHz,DMSO-d6)δ168.98,157.46,148.20,138.39,138.03,135.93,132.08,130.55,130.09,128.45,126.39,115.60,107.01.
comparative example 15
Other than adding no titanocene dichloride in example 14, the same procedure as in example 14 was conducted to obtain only 31% of the yield of 2-pyridyl-2, 3-naphthyridin-1-one prepared as follows.
As can be seen from comparative examples 1 and 15, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 15
Preparation of 2- (4-bromophenyl) -2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 10mL of ethyl acetate was added, 0.04g of titanocene dichloride was added, and 1.52g (8.1 mmol,0.9 eq) of 4-bromophenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, and the reaction was allowed to proceed with mechanical mixing at a temperature of 90℃for 45min and progress of the reaction was detected by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the white 2- (4-bromophenyl) -2, 3-naphthyridine-1-ketone is obtained after filtration, separation and drying. The yield was 95.2% and the purity was 99.63%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 29 and figure 30, wherein the m.p. is 170 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.53(dd,J＝7.6,1.5Hz,1H),8.36-8.27(m,1H),7.94-7.82(m,2H),7.79(dd,J＝7.9,1.4Hz,1H),7.69-7.63(m,2H),7.63-7.58(m,2H)； 13 C NMR(101MHz,Chloroform-d)δ159.09,140.88,138.81,133.71,132.19,131.83,129.44,128.47,127.34,127.24,126.25,121.31.
comparative example 16
Other steps than adding no titanocene dichloride in example 15 were carried out in the same manner as in example 15, except that 2- (4-bromophenyl) -2, 3-naphthyridin-1-one was prepared in the following yield of 22%.
As can be seen from comparative examples 1 and 16, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 16
Preparation of 2- (4-iodophenyl) -2, 3-naphthyridin-1-one as follows
To a 25mL round bottom flask, 15mL of ethanol was added, 0.04g of titanocene dichloride was added, 2.10g (9 mmol,1 eq) of 4-iodophenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, the temperature was raised to 95℃and the reaction was allowed to proceed with mechanical mixing for 80min with open reaction, and the progress of the reaction was checked by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the mixture is filtered, separated and dried to obtain pale yellow 2- (4-iodophenyl) -2, 3-naphthyridine-1-ketone. The yield was 93.7% and the purity was 99.57%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 31 and figure 32, wherein m.p. is 112-113 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.53(dd,J＝7.7,1.6Hz,1H),8.37-8.27(m,1H),7.89(dd,J＝7.4,1.6Hz,1H),7.87-7.83(m,2H),7.83-7.70(m,2H),7.50(d,J＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H)； 13 C NMR(101MHz,Chloroform-d)δ159.05,141.62,138.85,137.81,133.71,132.19,129.42,128.46,127.44,127.34,126.26,92.77.
comparative example 17
Other than adding no titanocene dichloride in example 16, the same procedure as in example 16 was conducted to obtain only the following 2- (4-iodophenyl) -2, 3-naphthyridin-1-one in 40% yield.
As can be seen from comparative examples 1 and 17, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 17
Preparation of 2- (2, 5, -2-chlorophenyl) -2, 3-naphthyridin-1-one as follows
Into a 25mL round bottom flask, 20mL of methanol was added, 0.05g of titanocene dichloride was added, 2.38g (13.5 mmol,1.5 eq) of 2,5-2 chlorophenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde were continuously added, the temperature was raised to 140℃and the reaction was allowed to proceed with mechanical mixing for 110min and the progress of the reaction was detected by TLC. After the reaction is completed, the temperature is reduced to 0 ℃ after the reaction is completed, and the mixture is filtered, separated and dried to obtain pale yellow 2- (2, 5-2-chlorophenyl) -2, 3-naphthyridin-1-one crystalline solid. The yield was 89.9% and the purity was 99.46%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 33 and figure 34, wherein m.p. is 154-158 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.53(dd,J＝7.8,1.4Hz,1H),8.32(s,1H),7.97-7.85(m,2H),7.81(dd,J＝8.0,1.2Hz,1H),7.60-7.47(m,2H),7.42(dd,J＝8.7,2.4Hz,1H)； 13 C NMR(101MHz,Chloroform-d)δ158.85,140.25,139.08,133.96,133.18,132.32,131.17,130.74,130.27,129.73,128.15,127.30,126.50.
comparative example 18
Other steps than adding no titanocene dichloride in example 17 were conducted in the same manner as in example 17, except that 2- (2, 5, -2-chlorophenyl) -2, 3-naphthyridin-1-one was prepared in the following yield of 15%.
As can be seen from comparative examples 1 and 18, the titanocene dichloride can be used for the co-catalytic reaction with the solvent, the single use effect is far less than that of the co-catalytic reaction with the solvent, the reaction rate can be improved, and the product yield can be increased.
Example 18
Preparation of the following 2-phenyl-2, 3-naphthyridin-1-one by one recovery of the catalytic intermediate
In a 25mL round bottom flask, the mother liquor containing the intermediate was recovered, a methanol solvent was added additionally, followed by 1g (9 mmol,1 eq) of phenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde, and the mixture was heated to 60℃and reacted for 20-30min with mechanical mixing under thermal insulation. And detecting by TLC, cooling to 0 ℃ after the reaction is finished, filtering, separating and drying to obtain yellow 2-phenyl-2, 3-naphthyridine-1-ketone crystalline solid, wherein the product yield is 94.3% and the purity is 99.65%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 1 and figure 2, wherein m.p. is 104-105 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.54(dd,J＝7.6,1.6Hz,1H),8.32(s,1H),7.86(td,J＝10.3,7.4,1.7Hz,2H),7.78(dd,J＝7.3,1.7Hz,1H),7.72-7.65(m,2H),7.53(dd,J＝8.6,7.1Hz,2H),7.42(d,J＝7.4Hz,1H)； 13 C NMR(101MHz,Chloroform-d)δ159.22,141.92,138.49,133.53,132.02,129.54,128.81,128.61,127.80,127.31,126.15,125.76.
example 19
Preparation of 2-phenyl-2, 3-naphthyridin-1-one by Secondary recovery of catalytic intermediate
Into a 25mL round bottom flask, a mother liquor containing the intermediate recovered secondarily was added, methanol as a solvent was added, followed by 1g (9 mmol,1 eq) of phenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde, and the mixture was heated to 60℃and reacted under mechanical mixing with thermal insulation and mechanical mixing for 20-30min. And detecting by TLC, cooling to 0 ℃ after the reaction is finished, filtering, separating and drying to obtain yellow 2-phenyl-2, 3-naphthyridine-1-ketone crystalline solid, wherein the product yield is 94.5%, and the purity is 99.58%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 1 and figure 2, wherein m.p. is 104-105 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.54(dd,J＝7.6,1.6Hz,1H),8.32(s,1H),7.86(td,J＝10.3,7.4,1.7Hz,2H),7.78(dd,J＝7.3,1.7Hz,1H),7.72-7.65(m,2H),7.53(dd,J＝8.6,7.1Hz,2H),7.42(d,J＝7.4Hz,1H)； 13 C NMR(101MHz,Chloroform-d)δ159.22,141.92,138.49,133.53,132.02,129.54,128.81,128.61,127.80,127.31,126.15,125.76.
example 20
Preparation of 2-phenyl-2, 3-naphthyridin-1-one from three recovery of catalytic intermediate
In a 25mL round bottom flask, three recovered mother liquor containing the intermediate was added, methanol as a solvent was added, followed by 1g (9 mmol,1 eq) of phenylhydrazine and 1.39g (9 mmol,1 eq) of o-carboxybenzaldehyde, and the mixture was heated to 60℃and reacted for 20-30min under mechanical mixing with thermal insulation. And detecting by TLC, cooling to 0 ℃ after the reaction is finished, filtering, separating and drying to obtain yellow 2-phenyl-2, 3-naphthyridine-1-ketone crystalline solid, wherein the product yield is 95.1%, and the purity is 99.49%.
The product is detected by a melting point instrument and nuclear magnetism, and the nuclear magnetism result is shown in figure 1 and figure 2, wherein m.p. is 104-105 ℃; 1 H NMR(400MHz,Chloroform-d)δ8.54(dd,J＝7.6,1.6Hz,1H),8.32(s,1H),7.86(td,J＝10.3,7.4,1.7Hz,2H),7.78(dd,J＝7.3,1.7Hz,1H),7.72-7.65(m,2H),7.53(dd,J＝8.6,7.1Hz,2H),7.42(d,J＝7.4Hz,1H)； 13 C NMR(101MHz,Chloroform-d)δ159.22,141.92,138.49,133.53,132.02,129.54,128.81,128.61,127.80,127.31,126.15,125.76.
the structural formula of each corresponding compound of the target compounds in the above examples 1 to 17 (the last three examples are catalyst recycling, and the products are the same as those in example 1) is shown in the following table 1:
TABLE 1 structural formulas corresponding to the respective target compounds in examples 1-17
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Although embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that: various substitutions, changes and modifications are possible without departing from the spirit and scope of the invention and the appended claims, and therefore the scope of the invention is not limited to the disclosure of the embodiments.
Claims (5)
1. A synthetic method of substituted 2, 3-naphthyridine ketone compounds is characterized in that: the method comprises the following steps:
(1) Adding solvent and titanocene dichloride into a reaction container respectively, continuously adding substituted hydrazine and o-carboxybenzaldehyde, controlling the reaction temperature at 40-160 ℃, and carrying out heat preservation reaction under mechanical mixing;
(2) TLC detection reaction, cooling to 0 ℃ after the reaction is finished, filtering, and drying to obtain crystalline solid, namely the substituted 2, 3-naphthyridine ketone compound, wherein the substituted 2, 3-naphthyridine ketone compound is one or more of the following compounds:
the solvent in the step (1) is one or more of methanol, ethanol, toluene, ethyl acetate and diethyl ether;
the substituted hydrazine in the step (1) is phenylhydrazine, hydrazine hydrate, methyl hydrazine, isopropyl hydrazine, 2-hydrazinoethanol, 2-chlorophenylhydrazine, 3-chlorophenylhydrazine, 4-fluorophenylhydrazine, 4-nitrophenylhydrazine, o-methylphenylhydrazine hydrochloride, 3-methylphenylhydrazine hydrochloride, p-methylphenylhydrazine, 2-hydrazinopyridine, 4-bromophenylhydrazine, 4-iodophenylhydrazine or 2, 5-dichlorobenzene.
2. The substituted 2, 3-naphthyridones according to claim 1, characterized in that: the molar ratio of the substituted hydrazine to the o-carboxybenzaldehyde in the step (1) is 0.9-1.5: 1, the condensation temperature is 40-160 ℃.
3. The substituted 2, 3-naphthyridones according to claim 1, characterized in that: the molar amount of the dichloro-titanocene in the step (1) is 0.2-1% of the molar amount of the substituted hydrazine.
4. The substituted 2, 3-naphthyridones according to claim 1, characterized in that: the heat preservation time in the step (1) is 20-120min.
5. The substituted 2, 3-naphthyridones according to claim 1, characterized in that: the mechanical mixing in the step (1) is mechanical stirring or grinding stirring.
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