CN114560814B - Synthesis method of substituted 2, 3-naphthyridine ketone compound - Google Patents

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

A method for synthesizing substituted 2,3-phthalazinone compounds

Technical Field

The invention belongs to the technical field of compound preparation, in particular to a method for synthesizing substituted 2,3-phthalazinone compounds.

Background Art

Nitrogen-containing heterocycles are the core part of active compounds widely found in drugs, pesticides and functional materials. They have become a major class of active compounds in the field of medical research. Among them, phthalazinone compounds are a class of nitrogen-containing heterocyclic compounds with significant biological activity. They have various drug properties such as anti-cancer, anti-inflammatory, antibacterial, antioxidant, and anti-neurodegeneration, and can be used to treat diabetes, asthma, hepatitis B, vascular hypertension, arrhythmia and other diseases. In addition, some phthalazinone compounds have been found to be inhibitors of phosphodiesterase IV and phosphodiesterase V, the latter of which has a certain potential therapeutic effect on pulmonary hypertension and erectile dysfunction.

The synthesis of phthalazinone compounds has always been the focus of research. Various methods for synthesizing phthalazinone compounds have been reported in the literature, including cycloaddition, reduction, cyclocondensation and biotechnology. The common methods for synthesizing phthalazinone compounds are mainly divided into the following categories according to the raw materials: (1) condensation ring closure using substituted benzaldehyde or benzyl ester and substituted hydrazine as raw materials; (2) condensation ring closure using substituted phthalic anhydride or phthalide as raw materials.

Traditional methods for synthesizing phthalazinone usually require strong acids and bases, strong reducing agents, long reaction times, high temperatures or multiple steps. In recent years, methods for synthesizing phthalazinone using catalysts such as palladium, _TiO2 , and solid acids can expand the reaction substrate, increase the reaction rate, and increase the product yield. However, the use of a large amount of catalysts results in heavy metal residues, increased production costs, and labor intensity. The research group of the applicant of the present invention previously proposed a solvent-free and catalytic-free method that can efficiently synthesize phthalazinone compounds. However, the solvent-free method has the disadvantage that the reaction cannot be fully stirred at high temperatures and is not suitable for amplifying the reaction. Therefore, the development of an efficient, simple, and mild method for synthesizing phthalazinone remains a research focus.

Through searching, no patent publication documents related to the patent application of the present invention have been found.

Summary of the invention

The present invention aims to overcome the deficiencies in the prior art and provide a method for synthesizing substituted 2,3-phthalazinone compounds.

The technical solution adopted by the present invention to solve the technical problem is:

A substituted 2,3-phthalazinone compound, the steps are as follows:

(1) Adding a solvent and titanocene dichloride into a reaction vessel respectively, and then adding substituted hydrazine and substituted o-carboxybenzaldehyde, the reaction temperature is controlled at 40° C. to 160° C., and the reaction is carried out under mechanical mixing;

(2) The reaction was detected by TLC. After the reaction was completed, the temperature was lowered to 0° C., filtered, and dried to obtain a crystalline solid, which was a substituted 2,3-diazinone compound having the structural formula (I):

Wherein, R is a hydrogen atom, an alkyl group, or an aryl group.

Furthermore, the aryl group is alkyl substituted, phenyl substituted, substituted phenyl substituted or hydroxy substituted.

Furthermore, the substituted 2,3-phthalazinone compound is one or more of the following compounds:

Furthermore, in the step (1), the substituted hydrazine is phenylhydrazine, hydrazine hydrate, methylhydrazine, isopropylhydrazine, 2-hydrazineethanol, 2-chlorophenylhydrazine, 3-chlorophenylhydrazine, 4-chlorophenylhydrazine, 4-fluorophenylhydrazine, 4-nitrophenylhydrazine, o-methylphenylhydrazine hydrochloride, 3-methylphenylhydrazine hydrochloride, p-methylphenylhydrazine, 2-hydrazinepyridine, 4-bromophenylhydrazine, 4-iodophenylhydrazine or 2,5-dichlorophenylhydrazine.

Furthermore, in the step (1), the molar ratio of substituted hydrazine to o-carboxybenzaldehyde is 0.9-1.5:1, and the condensation temperature is 40°C-160°C.

Furthermore, in the step (1), the molar amount of titanocene dichloride is 0.2%-1% of the molar amount of the substituted hydrazine.

Furthermore, the insulation time in step (1) is 20-120 minutes.

Furthermore, the mechanical mixing in step (1) is mechanical stirring or grinding stirring.

Furthermore, the solvent in step (1) is one or more of methanol, ethanol, toluene, ethyl acetate and ether.

Furthermore, the process route for preparing the substituted 2,3-phthalazinone compounds is as follows:

The advantages and positive effects achieved by the present invention are:

1. The synthesis method of phthalazinone compounds of the present invention has developed a new method for synthesizing 2,3-phthalazinone compounds by catalyzing dichlorotitacenes. During the reaction process, dichlorotitacenes are used as catalysts, and the products can be separated only by recrystallization, making the separation and purification process of the products easy to carry out, simple to operate, and having the potential for industrial production. The reaction process not only shortens the reaction time, but also improves the product yield, the yield can reach 90%-98%, the purity can reach 99%, the catalyst usage is small, and it can be repeatedly recycled, which conforms to the principle of green economy and has broad application prospects.

2. The preparation method of the present invention starts from cheap and readily available raw materials, and uses dichlorodiphenylphosphine as a catalyst to efficiently prepare a series of highly active 2,3-diazinone compounds with a yield of 90%-98% and a purity greater than 99%. The method has a wide range of substrate applicability, mild conditions, extremely high product yield and purity, a small amount of catalyst used, and can be repeatedly recycled (specifically embodied in Examples 18-20), which complies with the principles of green economy and has potential for industrial production.

3. Compared with the previous melting method of our research group, the present invention has the advantages of milder conditions and can be used for scale-up experiments, which has the significance of industrial production.

4. The raw material solvent, dichlorotitanocene, substituted hydrazine and dichlorotitanocene synergistic solvent in the substituted o-carboxybenzaldehyde of the present invention can jointly catalyze the reaction, increase the reaction rate, and increase the product yield (as specifically shown in Comparative Example 1).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a nuclear magnetic resonance ¹ H spectrum of the target compound 1 in the present invention;

FIG2 is a nuclear magnetic resonance ¹ C spectrum of the target compound 1 in the present invention;

FIG3 is a nuclear magnetic resonance ¹ H spectrum of the target compound 2 in the present invention;

FIG4 is a nuclear magnetic resonance ¹ C spectrum of the target compound 2 in the present invention;

FIG5 is a nuclear magnetic resonance ¹ H spectrum of the target compound 3 in the present invention;

FIG6 is a nuclear magnetic resonance ¹ C spectrum of the target compound 3 in the present invention;

FIG7 is a nuclear magnetic resonance ¹ H spectrum of target compound 4 in the present invention;

FIG8 is a nuclear magnetic resonance ¹ C spectrum of target compound 4 in the present invention;

FIG9 is a nuclear magnetic resonance ¹ H spectrum of the target compound 5 in the present invention;

FIG10 is a nuclear magnetic resonance ¹ C spectrum of the target compound 5 in the present invention;

FIG11 is a nuclear magnetic resonance ¹ H spectrum of the target compound 6 in the present invention;

FIG12 is a nuclear magnetic resonance ¹ C spectrum of the target compound 6 in the present invention;

FIG13 is a nuclear magnetic resonance ¹ H spectrum of target compound 7 in the present invention;

FIG14 is a nuclear magnetic resonance ¹ C spectrum of target compound 7 in the present invention;

FIG15 is a nuclear magnetic resonance ¹ H spectrum of target compound 8 in the present invention;

FIG16 is a nuclear magnetic resonance ¹ C spectrum of the target compound 8 in the present invention;

FIG17 is a nuclear magnetic resonance ¹ H spectrum of the target compound 9 in the present invention;

FIG18 is a nuclear magnetic resonance ¹ C spectrum of the target compound 9 in the present invention;

FIG19 is a nuclear magnetic resonance ¹ H spectrum of the target compound 10 in the present invention;

FIG20 is a nuclear magnetic resonance ¹ C spectrum of the target compound 10 in the present invention;

FIG21 is a nuclear magnetic resonance ¹ H spectrum of the target compound 11 in the present invention;

FIG22 is a nuclear magnetic resonance ¹ C spectrum of the target compound 11 in the present invention;

FIG23 is a nuclear magnetic resonance ¹ H spectrum of the target compound 12 in the present invention;

FIG24 is a nuclear magnetic resonance ¹ C spectrum of the target compound 12 in the present invention;

FIG25 is a nuclear magnetic resonance ¹ H spectrum of the target compound 13 in the present invention;

FIG26 is a nuclear magnetic resonance ¹ C spectrum of the target compound 13 in the present invention;

FIG27 is a nuclear magnetic resonance ¹ H spectrum of the target compound 14 in the present invention;

FIG28 is a nuclear magnetic resonance ¹ C spectrum of target compound 14 in the present invention;

FIG29 is a nuclear magnetic resonance ¹ H spectrum of target compound 15 in the present invention;

FIG30 is a nuclear magnetic resonance ¹ C spectrum of target compound 15 in the present invention;

FIG31 is a nuclear magnetic resonance ¹ H spectrum of the target compound 16 in the present invention;

FIG32 is a nuclear magnetic resonance ¹ C spectrum of the target compound 16 in the present invention;

FIG33 is a nuclear magnetic resonance ¹ H spectrum of the target compound 17 in the present invention;

FIG34 is a nuclear magnetic resonance ¹ C spectrum of the target compound 17 in the present invention.

DETAILED DESCRIPTION

The embodiments of the present invention are described in detail below. It should be noted that the embodiments are descriptive rather than restrictive and cannot be used to limit the protection scope of the present invention.

The raw materials used in the present invention, unless otherwise specified, are conventional commercially available products; the methods used in the present invention, unless otherwise specified, are conventional methods in the art.

A substituted 2,3-phthalazinone compound, the steps are as follows:

(1) Adding a solvent and titanocene dichloride into a reaction vessel respectively, and then adding substituted hydrazine and substituted o-carboxybenzaldehyde, the reaction temperature is controlled at 40° C. to 160° C., and the reaction is carried out under mechanical mixing;

(2) The reaction was detected by TLC. After the reaction was completed, the temperature was lowered to 0° C., the mixture was allowed to stand, filtered, and dried to obtain a crystalline solid, which was a substituted 2,3-phthalazinone compound having the structural formula (I):

Wherein, R is a hydrogen atom, an alkyl group, or an aryl group.

Furthermore, the aryl group is one of various substituents such as alkyl substitution, phenyl substitution, substituted phenyl substitution or hydroxyl substitution.

Furthermore, the substituted 2,3-phthalazinone compound is one or more of the following compounds:

Preferably, the substituted hydrazine in step (1) is phenylhydrazine, hydrazine hydrate, methylhydrazine, isopropylhydrazine, 2-hydrazineethanol, 2-chlorophenylhydrazine, 3-chlorophenylhydrazine, 4-chlorophenylhydrazine, 4-fluorophenylhydrazine, 4-nitrophenylhydrazine, o-methylphenylhydrazine hydrochloride, 3-methylphenylhydrazine hydrochloride, p-methylphenylhydrazine, 2-hydrazinepyridine, 4-bromophenylhydrazine, 4-iodophenylhydrazine or 2,5-dichlorophenylhydrazine.

Preferably, in step (1), the molar ratio of substituted hydrazine to o-carboxybenzaldehyde is 0.9-1.5:1, and the condensation temperature is 40°C-160°C.

Preferably, the molar amount of titanocene dichloride in step (1) is 0.2%-1% of the molar amount of the substituted hydrazine.

Preferably, the insulation time in step (1) is 20-120 min.

Preferably, the mechanical mixing in step (1) is mechanical stirring or grinding stirring.

Preferably, the solvent in step (1) is one or more of methanol, ethanol, toluene, ethyl acetate and ether.

Preferably, the process route for preparing the substituted 2,3-phthalazinone compounds is as follows:

Specifically, the relevant preparation and detection examples are as follows:

Example 1

Preparation of 2-phenyl-2,3-naphthyridin-1-one having the following structural formula

In a 25mL round-bottom flask, 15mL of methanol was first added at room temperature, and 0.02g of dichlorotitanocene was added. The dichlorotitanocene could not be completely dissolved. Then 1g (9mmol, 1eq) of phenylhydrazine was added. The red color of dichlorotitanocene itself disappeared and turned into a yellow-brown clear solution. It was speculated that a catalytic intermediate was generated at this time. 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde was continued to be added. The system quickly turned into a yellow solid, and it was judged that the reaction had begun at this time. The temperature was slowly increased to 60°C. The raw material point quickly disappeared and a single ultraviolet point was generated by TLC (V _{petroleum ether} : V _{ethyl acetate} = 3:1). This point was judged to be the product point. The reaction was carried out for 20 minutes under mechanical mixing, and the reaction was detected by TLC. The reaction was completed (preferably, part of the solvent could be evaporated by rotary evaporation). The reaction bottle was placed in a refrigerator and cooled to 0°C. The product yield was 95.6% and the purity was 99.91% yellow crystalline solid with filtration and drying in the system (preferably, recrystallization could be performed first).

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 1 and 2. mp: 104-105°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.54 (dd, J = 7.6, 1.6 Hz, 1H), 8.32 (s, 1H), 7.86 (td, J = 10.3, 7.4, 1.7 Hz, 2H), 7.78 (dd, J = 7.3, 1.7 Hz, 1H), 7.72-7.65 (m, 2H), 7.53 (dd, J = 8.6, 7.1 Hz, 2H), 7.42 (d, J = 7.4 Hz, 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 (such as one or more of methanol, ethanol, toluene, ethyl acetate, and ether) was added, and the other steps were the same as in Example 1, but 2-phenyl-2,3-naphthyridin-1-one could not be obtained.

Comparative Example 2

In Example 1, titanocene dichloride was not added, and the other steps were the same as in Example 1, only the yield of 2-phenyl-2,3-naphthyridin-1-one was 32%.

It can be seen from Comparative Examples 1 and 2 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far inferior to the coordinated use of the two solvents. The reaction rate can be increased and the product yield can be increased.

Example 2

Prepare the following 2,3-phthalazinone

In a 25mL round-bottom flask, add 6mL of ethanol, add 0.015g of dichlorotantalum, continue to add 0.26g (8.1mmol, 0.9eq) of hydrazine hydrate and 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, heat to 40℃, and react in an open state for 30min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain a light yellow 2,3-diazinone solid. The yield is 98.8% and the purity is 99.99%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 3 and 4. mp: 181–183°C; ¹ H NMR (400 MHz, Chloroform-d) δ11.00 (s, 1H), 8.47 (dd, J=7.7, 1.4 Hz, 1H), 8.23 (s, 1H), 7.91-7.79 (m, 2H), 7.76 (dd, J=7.5, 1.5 Hz, 1H); ¹³ C NMR (101 MHz, Chloroform-d) δ160.87, 139.11, 133.75, 131.86, 130.25, 128.03, 126.51, 126.30.

Comparative Example 3

In Example 2, no titanocene dichloride was added, and the other steps were the same as in Example 2, only the yield of 2,3-phthalazinone was 28%.

It can be seen from Comparative Examples 1 and 3 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far inferior to the coordinated use of the two solvents. The reaction rate can be increased and the product yield can be increased.

Example 3

Prepare 2-methyl-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 9mL of toluene, add 0.022g of dichlorotantalum, continue to add 0.46g (9.9mmol, 1.1eq) of methylhydrazine, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, raise the temperature to 45°C, and react in an open state for 35min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0°C, filter and separate, and dry to obtain a light yellow 2-methyl-2,3-naphthyridin-1-one powder. The yield is 96.4% and the purity is 99.71%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 5 and 6: mp: 112-114°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.49-8.42 (m, 1H), 8.20-8.15 (m, 1H), 7.81 (td, J = 7.3, 1.7 Hz, 2H), 7.72 (dd, J = 7.6, 1.5 Hz, 1H), 3.88 (s, 3H); ¹³ C NMR (101 MHz, 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, titanocene dichloride was not added, and the other steps were the same as in Example 3, only the yield of 2-methyl-2,3-naphthyridin-1-one was 22%.

It can be seen from Comparative Examples 1 and 4 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far inferior to the coordinated use of the two solvents. The reaction rate can be increased and the product yield can be increased.

Example 4

Prepare 2-isopropyl-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 10mL of ethyl acetate, add 0.023g of dichlorotantalum, continue to add 0.73g (9.9mmol, 1.1eq) of isopropylhydrazine, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, raise the temperature to 70℃, and react in an open state for 50min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, separate through a column, and dry to obtain an orange-yellow 2-isopropyl-2,3-naphthyridin-1-one liquid. The yield is 98.5% and the purity is 99.93%.

The product was detected by NMR, and the results are shown in Figures 7 and 8: ¹ H NMR (400 MHz, Chloroform-d) δ8.37 (d, J = 5.8 Hz, 1H), 8.16 (s, 1H), 7.80-7.63 (m, 2H), 7.63-7.40 (m, 1H), 5.39 (p, J = 6.6 Hz, 1H), 1.35 (d, J = 6.7 Hz, 6H). ¹³ C NMR (101 MHz, 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, titanocene dichloride was not added, and the other steps were the same as in Example 4, only the yield of 2-isopropyl-2,3-naphthyridin-1-one was 19%.

It can be seen from Comparative Examples 1 and 5 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far less than that of using the two solvents in combination. The reaction rate can be increased and the product yield can be increased.

Example 5

Prepare 2-hydroxyethyl-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 5mL of ethanol, add 0.025g of dichlorotantalum, continue to add 0.62g (8.1mmol, 0.9eq) of 2-hydrazinoethanol, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, raise the temperature to 55℃, and react in an open state for 25min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain a white 2-hydroxyethyl-2,3-naphthyridin-1-one solid. The yield is 96.6% and the purity is 99.55%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 9 and 10: mp: 116-118°C. ¹ H NMR (400 MHz, Chloroform-d) δ8.46 (d, J = 7.3 Hz, 1H), 8.23 (s, 1H), 8.06-7.78 (m, 2H), 7.75 (d, J = 7.2 Hz, 1H), 4.63-4.32 (m, 2H), 4.19-3.99 (m, 2H), 3.17 (s, 1H); ¹³ C NMR (101 MHz, 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, titanocene dichloride was not added, and the other steps were the same as in Example 5, only the yield of 2-hydroxyethyl-2,3-naphthyridin-1-one was 35%.

It can be seen from Comparative Examples 1 and 6 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far less than that of using the two solvents in combination. The reaction rate can be increased and the product yield can be increased.

Example 6

Prepare 2-(2,-chlorophenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 15mL of ether, add 0.04g of dichlorotantalum, continue to add 1.54g (10.8mmol, 1.2eq) of 2-chlorophenylhydrazine, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, raise the temperature to 65℃, and react in an open state for 40min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain an orange 2-(2,-chlorophenyl)-2,3-naphthyridin-1-one solid. The yield is 90.1% and the purity is 99.35%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 11 and 12: mp: 125-126°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.53 (d, J = 7.7 Hz, 1H), 8.32 (s, 1H), 7.96-7.88 (m, 1H), 7.86 (td, J = 7.6, 1.4 Hz, 1H), 7.81 (d, J = 7.0 Hz, 1H), 7.65-7.57 (m, 1H), 7.52 (dt, J = 7.3, 3.0 Hz, 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, no titanocene dichloride was added, and the other steps were the same as in Example 6, only the yield of 2-(2,-chlorophenyl)-2,3-naphthyridin-1-one was 20%.

It can be seen from Comparative Examples 1 and 7 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far less than that of using the two solvents in combination. The reaction rate can be increased and the product yield can be increased.

Example 7

Prepare 2-(3,-chlorophenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 10mL of ethanol, add 0.03g of dichlorotantalum, continue to add 1.54g (10.8mmol, 1.2eq) of 3-chlorophenylhydrazine, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, raise the temperature to 50℃, and react in an open state for 45min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain an orange 2-(3,-chlorophenyl)-2,3-naphthyridin-1-one solid. The yield is 89.5% and the purity is 99.76%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 13 and 14: mp: 134-136°C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.52 (d, J = 7.6 Hz, 1H), 8.32 (s, 1H), 8.04-7.82 (m, 2H), 7.82-7.67 (m, 2H), 7.65 (d, J = 7.3 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.1 Hz, 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, no titanocene dichloride was added, and the other steps were the same as in Example 7, only the yield of 2-(3,-chlorophenyl)-2,3-naphthyridin-1-one prepared as follows was 39%.

It can be seen from Comparative Examples 1 and 8 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far inferior to the coordinated use of the two. It can improve the reaction rate and increase the product yield.

Example 8

Prepare 2-(4,-chlorophenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 10mL of methanol, add 0.03g of dichlorotantalum, continue to add 1.54g (10.8mmol, 1.2eq) of 4-chlorophenylhydrazine, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, heat to 70℃, and react in an open state for 35min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain an orange 2-(4,-chlorophenyl)-2,3-naphthyridin-1-one solid. The yield is 94.4% and the purity is 99.77%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 15 and 16: mp: 139-141°C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.61-8.41 (m, 1H), 8.32 (d, J = 0.7 Hz, 1H), 7.98-7.82 (m, 2H), 7.80-7.71 (m, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 2.0 Hz, 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

In Example 8, no titanocene dichloride was added, and the other steps were the same as in Example 8, only the yield of 2-(4,-chlorophenyl)-2,3-naphthyridin-1-one prepared as follows was 40%.

It can be seen from Comparative Examples 1 and 9 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far less than that of using the two solvents in combination. The reaction rate can be increased and the product yield can be increased.

Example 9

Prepare 2-(4,-fluorophenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 15mL of toluene, add 0.03g of dichlorotantalum, continue to add 4-chlorophenylhydrazine 1.48g (11.7mmol, 1.3eq), o-carboxybenzaldehyde 1.39g (9mmol, 1eq), heat to 70℃, and react in an open state for 55min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain a white 2-(4,-fluorophenyl)-2,3-naphthyridin-1-one solid. The yield is 95.1% and the purity is 99.38%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 17 and 18: mp: 140-142°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.53 (d, J = 7.5 Hz, 1H), 8.32 (s, 1H), 7.98-7.82 (m, 2H), 7.82-7.72 (m, 1H), 7.67 (dd, J = 9.0, 4.9 Hz, 2H), 7.21 (t, J = 8.7 Hz, 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, titanocene dichloride was not added, and the other steps were the same as in Example 9, only the yield of 2-(4,-fluorophenyl)-2,3-naphthyridin-1-one prepared as follows was 18%.

It can be seen from Comparative Examples 1 and 10 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far less than that of using the two solvents in combination. The reaction rate can be increased and the product yield can be increased.

Example 10

Prepare 2-(4,-nitrophenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 8mL of ethyl acetate, add 0.05g of dichlorotantalum, continue to add 4-nitrophenylhydrazine 1.65g (10.8mmol, 1.2eq), o-carboxybenzaldehyde 1.39g (9mmol, 1eq), heat to 80℃, and react in an open state for 70min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain a white 2-(4,-nitrophenyl)-2,3-naphthyridin-1-one flocculent solid. The yield is 97.5% and the purity is 99.83%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 19 and 20: mp: 271-273°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.54 (dd, J=7.7, 1.5 Hz, 1H), 8.39 (d, J=1.9 Hz, 1H), 8.37 (d, J=1.7 Hz, 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

In Example 10, titanocene dichloride was not added, and the other steps were the same as in Example 10, only the yield of 2-(4,-nitrophenyl)-2,3-naphthyridin-1-one prepared as follows was 25%.

It can be seen from Comparative Examples 1 and 11 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far inferior to the coordinated use of the two solvents. The reaction rate can be increased and the product yield can be increased.

Embodiment 11

Prepare 2-(2,-methylphenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 10mL of ethanol, add 0.03g of dichlorotantalum, continue to add 1.32g (10.8mmol, 1.1eq) of 2-methylphenylhydrazine, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, raise the temperature to 75℃, and carry out open reaction for 80min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, the temperature is lowered to 0℃, filtered and separated, and dried to obtain a white 2-(2,-methylphenyl)-2,3-naphthyridin-1-one solid. The yield is 91.7% and the purity is 99.61%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 21 and 22: mp: 136-138°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.53 (dd, J = 7.6, 1.5 Hz, 1H), 8.31 (s, 1H), 7.88 (td, J = 7.4, 1.5 Hz, 1H), 7.84 (td, J = 7.5, 1.5 Hz, 1H), 7.79 (dd, J = 7.6, 1.5 Hz, 1H), 7.38 (d, J = 4.0 Hz, 2H), 7.37 (d, J = 3.5 Hz, 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

In Example 11, titanocene dichloride was not added, and the other steps were the same as in Example 11, only the yield of 2-(2,-methylphenyl)-2,3-naphthyridin-1-one prepared as follows was 27%.

It can be seen from Comparative Examples 1 and 12 that titanocene dichloride can cooperate with the solvent to jointly catalyze the reaction. The effect of using a single solvent is far inferior to the coordinated use of the two solvents. The reaction rate can be increased and the product yield can be increased.

Example 12

Prepare 2-(3,-methylphenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 15mL of ethyl acetate, add 0.03g of dichlorotantalum, continue to add 1.32g (10.8mmol, 1.1eq) of 3-methylphenylhydrazine, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, heat to 75℃, and react in an open state for 90min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain a white 2-(3,-methylphenyl)-2,3-naphthyridin-1-one solid. The yield is 90.8% and the purity is 99.95%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 23 and 24: mp: 140-142°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.53 (dd, J = 7.5, 1.6 Hz, 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 = 7.6 Hz, 1H), 7.23 (d, J = 7.5 Hz, 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

In Example 12, titanocene dichloride was not added, and the other steps were the same as in Example 12, only the yield of 2-(3,-methylphenyl)-2,3-naphthyridin-1-one prepared as follows was 20%.

It can be seen from Comparative Examples 1 and 13 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far inferior to the coordinated use of the two solvents. The reaction rate can be increased and the product yield can be increased.

Example 13

Prepare 2-(4,-methylphenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 15mL of methanol, add 0.03g of dichlorotantalum, continue to add 1.10g (9mmol, 1eq) of 4-methylphenylhydrazine, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, raise the temperature to 70℃, and carry out open reaction for 85min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain an orange 2-(4,-methylphenyl)-2,3-naphthyridin-1-one solid. The yield is 95.5% and the purity is 99.91%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 25 and 26: mp: 144-146°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.53 (dd, J=7.6, 1.5 Hz, 1H), 8.33-8.28 (m, 1H), 7.92-7.80 (m, 2H), 7.77 (dd, J=7.8, 1.4 Hz, 1H), 7.59-7.51 (m, 2H), 7.32 (d, J=8.2 Hz, 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

In Example 13, no titanocene dichloride was added, and the other steps were the same as in Example 13, only the yield of 2-(4,-methylphenyl)-2,3-naphthyridin-1-one prepared as follows was 20%.

It can be seen from Comparative Example 1 and Comparative Example 14 that dichlorotitanocene can cooperate with the solvent to jointly catalyze the reaction. The effect of using a single solvent is far less than that of using the two solvents in combination. The reaction rate can be increased and the product yield can be increased.

Embodiment 14

Prepare 2-pyridyl-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 20mL of methanol, add 0.06g of dichlorotantalum, continue to add 1.37g (12.6mmol, 1.4eq) of 2-hydrazinopyridine, 1.39g (9mmol, 1eq) of o-carboxybenzaldehyde, heat to 100℃, and carry out open reaction for 120min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, the temperature is cooled to 0℃, filtered and separated, and dried to obtain a white 2-pyridyl-2,3-naphthyridin-1-one solid. The yield is 97.5% and the purity is 99.53%.

The product was detected by melting point instrument and NMR. The NMR results are shown in Figures 27 and 28: mp: 269°C; ¹ H NMR (400 MHz, DMSO-d6) δ8.74 (s, 1H), 8.16-8.04 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.64 (td, J = 8.8, 7.2, 1.9 Hz, 1H), 7.57 (td, J = 7.7, 1.5 Hz, 1H), 7.41 (td, J = 7.6, 1.3 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.78 (td, J = 7.2, 4.9, 1.0 Hz, 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

In Example 14, titanocene dichloride was not added, and the other steps were the same as in Example 14, only the yield of 2-pyridyl-2,3-naphthyridin-1-one prepared as follows was 31%.

It can be seen from Comparative Examples 1 and 15 that titanocene dichloride can cooperate with the solvent to catalyze the reaction. The effect of using a single solvent is far inferior to the coordinated use of the two solvents. The reaction rate can be increased and the product yield can be increased.

Embodiment 15

Prepare 2-(4,-bromophenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 10mL of ethyl acetate, add 0.04g of dichlorotantalum, continue to add 4-bromophenylhydrazine 1.52g (8.1mmol, 0.9eq), o-carboxybenzaldehyde 1.39g (9mmol, 1eq), heat to 90℃, and react in an open state for 45min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain white 2-(4,-bromophenyl)-2,3-naphthyridin-1-one. The yield is 95.2% and the purity is 99.63%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 29 and 30: mp: 170°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.53 (dd, J=7.6, 1.5 Hz, 1H), 8.36-8.27 (m, 1H), 7.94-7.82 (m, 2H), 7.79 (dd, J=7.9, 1.4 Hz, 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

In Example 15, titanocene dichloride was not added, and the other steps were the same as in Example 15, only the yield of 2-(4,-bromophenyl)-2,3-naphthyridin-1-one prepared as follows was 22%.

It can be seen from Comparative Example 1 and Comparative Example 16 that dichlorotitanocene can cooperate with the solvent to jointly catalyze the reaction. The effect of using a single solvent is far less than that of using the two solvents in combination. The reaction rate can be increased and the product yield can be increased.

Example 16

Prepare 2-(4,-iodophenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 15mL of ethanol, add 0.04g of dichlorotantalum, continue to add 4-iodophenylhydrazine 2.10g (9mmol, 1eq), o-carboxybenzaldehyde 1.39g (9mmol, 1eq), heat to 95℃, and react in an open state for 80min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain light yellow 2-(4,-iodophenyl)-2,3-naphthyridin-1-one. The yield is 93.7% and the purity is 99.57%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 31 and 32: mp: 112-113°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.53 (dd, J = 7.7, 1.6 Hz, 1H), 8.37-8.27 (m, 1H), 7.89 (dd, J = 7.4, 1.6 Hz, 1H), 7.87-7.83 (m, 2H), 7.83-7.70 (m, 2H), 7.50 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 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

In Example 16, no titanocene dichloride was added, and the other steps were the same as in Example 16, only the yield of 2-(4,-iodophenyl)-2,3-naphthyridin-1-one prepared as follows was 40%.

It can be seen from Comparative Example 1 and Comparative Example 17 that dichlorotitanocene can cooperate with the solvent to jointly catalyze the reaction. The effect of using a single solvent is far less than that of using the two solvents in combination. The reaction rate can be increased and the product yield can be increased.

Embodiment 17

Prepare 2-(2,5,-2-chlorophenyl)-2,3-naphthyridin-1-one as follows

In a 25mL round-bottom flask, add 20mL of methanol, add 0.05g of dichlorotantalum, continue to add 2,5-2-chlorophenylhydrazine 2.38g (13.5mmol, 1.5eq), o-carboxybenzaldehyde 1.39g (9mmol, 1eq), heat to 140℃, and react in an open state for 110min under mechanical mixing. Use TLC to monitor the reaction progress. After the reaction is complete, cool the temperature to 0℃, filter and separate, and dry to obtain a light yellow crystalline solid of 2-(2,5,-2-chlorophenyl)-2,3-naphthyridin-1-one. The yield is 89.9% and the purity is 99.46%.

The product was tested by melting point instrument and NMR. The NMR results are shown in Figures 33 and 34: mp: 154-158°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.53 (dd, J=7.8, 1.4 Hz, 1H), 8.32 (s, 1H), 7.97-7.85 (m, 2H), 7.81 (dd, J=8.0, 1.2 Hz, 1H), 7.60-7.47 (m, 2H), 7.42 (dd, J=8.7, 2.4 Hz, 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

In Example 17, no titanocene dichloride was added, and the other steps were the same as in Example 17, only the yield of 2-(2,5,-2-chlorophenyl)-2,3-naphthyridin-1-one prepared as follows was 15%.

It can be seen from Comparative Example 1 and Comparative Example 18 that dichlorotitanocene can cooperate with the solvent to jointly catalyze the reaction. The effect of using a single solvent is far inferior to the coordinated use of the two solvents. The reaction rate can be increased and the product yield can be increased.

Embodiment 18

The catalytic intermediate is recovered once to prepare the following 2-phenyl-2,3-naphthyridin-1-one

In a 25mL round-bottom flask, the mother liquor containing the intermediate was recovered, methanol solvent was added, and then 1g (9mmol, 1eq) phenylhydrazine and 1.39g (9mmol, 1eq) o-carboxybenzaldehyde were added, and the temperature was raised to 60°C, and the reaction was carried out under mechanical mixing for 20-30min. After the reaction was completed, the temperature was lowered to 0°C, filtered and separated, and dried to obtain a yellow crystalline solid of 2-phenyl-2,3-naphthyridin-1-one, with a product yield of 94.3% and a purity of 99.65%.

The product was detected by melting point instrument and NMR. The NMR results are shown in Figures 1 and 2: mp: 104-105°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.54 (dd, J = 7.6, 1.6 Hz, 1H), 8.32 (s, 1H), 7.86 (td, J = 10.3, 7.4, 1.7 Hz, 2H), 7.78 (dd, J = 7.3, 1.7 Hz, 1H), 7.72-7.65 (m, 2H), 7.53 (dd, J = 8.6, 7.1 Hz, 2H), 7.42 (d, J = 7.4 Hz, 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.

Embodiment 19

The secondary recovery of the catalytic intermediate is used to prepare the following 2-phenyl-2,3-naphthyridin-1-one

In a 25mL round-bottom flask, add the secondary recovered mother liquor containing the intermediate, add the solvent methanol, then add 1g (9mmol, 1eq) phenylhydrazine and 1.39g (9mmol, 1eq) o-carboxybenzaldehyde, heat to 60°C, and keep warm for reaction under mechanical mixing. The reaction is carried out for 20-30min under mechanical mixing. After the reaction is completed, the temperature is cooled to 0°C, filtered and separated, and dried to obtain a yellow crystalline solid of 2-phenyl-2,3-naphthyridin-1-one, with a product yield of 94.5% and a purity of 99.58%.

The product was detected by melting point instrument and NMR. The NMR results are shown in Figures 1 and 2: mp: 104-105°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.54 (dd, J = 7.6, 1.6 Hz, 1H), 8.32 (s, 1H), 7.86 (td, J = 10.3, 7.4, 1.7 Hz, 2H), 7.78 (dd, J = 7.3, 1.7 Hz, 1H), 7.72-7.65 (m, 2H), 7.53 (dd, J = 8.6, 7.1 Hz, 2H), 7.42 (d, J = 7.4 Hz, 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.

Embodiment 20

The catalytic intermediate was recovered three times to prepare the following 2-phenyl-2,3-naphthyridin-1-one

In a 25mL round-bottom flask, add the mother liquor containing the intermediate recovered three times, add the solvent methanol, then add 1g (9mmol, 1eq) phenylhydrazine and 1.39g (9mmol, 1eq) o-carboxybenzaldehyde, heat to 60°C, and keep warm for reaction under mechanical mixing. The reaction is carried out for 20-30min under mechanical mixing. After the reaction is completed, the temperature is cooled to 0°C, filtered and separated, and dried to obtain a yellow 2-phenyl-2,3-diazine-1-one crystalline solid, with a product yield of 95.1% and a purity of 99.49%.

The product was detected by melting point instrument and NMR. The NMR results are shown in Figures 1 and 2: mp: 104-105°C; ¹ H NMR (400 MHz, Chloroform-d) δ8.54 (dd, J = 7.6, 1.6 Hz, 1H), 8.32 (s, 1H), 7.86 (td, J = 10.3, 7.4, 1.7 Hz, 2H), 7.78 (dd, J = 7.3, 1.7 Hz, 1H), 7.72-7.65 (m, 2H), 7.53 (dd, J = 8.6, 7.1 Hz, 2H), 7.42 (d, J = 7.4 Hz, 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 corresponding compound structural formulas of the target compounds in the above Examples 1-17 (the last three Examples are catalyst recycling, and the products are the same as those in Example 1) are shown in Table 1 below:

Table 1 Corresponding compound structures of target compounds in Examples 1-17

Although the embodiments of the present invention are 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 present invention and the appended claims. Therefore, the scope of the present invention is not limited to the contents disclosed in the embodiments.

Claims (5)

1. A synthetic method for substituted 2,3-naphthyridone compounds, which is characterized in that: the steps are as follows: (1) Add solvent and titanocene dichloride to the reaction vessel respectively, continue to add substituted hydrazine and o-carboxybenzaldehyde, control the reaction temperature at 40°C-160°C, and perform the insulation reaction under mechanical mixing; (2) TLC detects the reaction. After the reaction is completed, the temperature is lowered to 0°C, filtered, and dried to obtain a crystalline solid, which is a substituted 2,3-naphthyridinone compound. The substituted 2,3-naphthyridine compound is Ketone compounds are one or more of the following compounds: The solvent in step (1) is one or more of methanol, ethanol, toluene, ethyl acetate, and diethyl ether; In the step (1), the substituted hydrazine is phenylhydrazine, hydrazine hydrate, methylhydrazine, isopropylhydrazine, 2-hydrazinoethanol, 2-chlorophenylhydrazine, 3-chlorophenylhydrazine, 4-chlorophenylhydrazine, 4 -Fluorophenylhydrazine, 4-nitrophenylhydrazine, o-methylphenylhydrazine hydrochloride, 3-methylphenylhydrazine hydrochloride, p-methylphenylhydrazine, 2-hydrazopyridine, 4-bromophenylhydrazine, 4- Iodophenylhydrazine or 2,5-dichlorophenylhydrazine. 2. The substituted 2,3-naphthyridone compounds according to claim 1, characterized in that: the molar ratio of substituted hydrazine and o-carboxybenzaldehyde in the step (1) is 0.9~1.5:1, The condensation temperature is 40℃-160℃. 3. Substituted 2,3-naphthyridone compounds according to claim 1, characterized in that: the molar amount of titanium dichloride in the step (1) is 0.2% of the molar amount of substituted hydrazines. -1%. 4. The substituted 2,3-naphthyridinone compound according to claim 1, characterized in that: the holding time in step (1) is 20-120 min. 5. The substituted 2,3-naphthyridone compounds according to claim 1, wherein the mechanical mixing in step (1) is mechanical stirring or grinding and stirring.