CN111393440B - Method for preparing pharmaceutical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative - Google Patents
Method for preparing pharmaceutical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative Download PDFInfo
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Abstract
The invention discloses a method for preparing a medical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative, and belongs to the technical field of biological medicine preparation. The method for preparing the medical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative under the catalysis of the acidic ionic liquid takes aromatic aldehyde, amine and 2, 4-piperidedione as reaction raw materials, takes ethanol-dimethylformamide-water mixed liquor as a reaction solvent, and prepares the 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative under the catalysis of the acidic ionic liquid catalyst. The preparation process has the advantages of high product yield, recyclable catalytic system, short reaction time, simple and convenient product purification process and the like.
Description
Technical Field
The invention belongs to the technical field of biological medicine preparation, and particularly relates to a method for preparing a medical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative by catalysis of an acidic ionic liquid.
Background
Naphthyridine compounds are fused bicyclic heterocyclic compounds having two nitrogen atoms and having excellent biological and pharmacological activities, and for example, naphthyridine acid, which is the first-generation quinolone antibacterial agent, has antibacterial activity against klebsiella, shigella, enterobacter, escherichia coli, salmonella, haemophilus influenzae, and the like. As one of the naphthyridine compounds, [1,6] naphthyridine derivatives have recently received much attention in the fields of drug synthesis and medicine due to their structural diversity and various biological and pharmacological activities.
The ionic liquid consists of organic cation and inorganic or organic anion, is in a liquid state at room temperature and has certain fluidity. The physicochemical properties of the ionic liquid can be effectively regulated and controlled through the change of anions and cations, so that the ionic liquid can be used as a green reaction solvent to be applied to the process of preparing the [1,6] naphthyridine derivative. For example, Wanxiangshan of Jiangsu university and the like can obtain a series of 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivatives by taking aldehyde, aromatic amine and 2, 4-piperiddione as raw materials, taking ionic liquid [ Bmim ] Br (4-butyl-1-methylimidazolium bromide) as a green solvent and p-methylbenzenesulfonic acid as a catalyst and reacting at 80 ℃. The reaction has the advantages of high yield, environmental friendliness, mild reaction conditions and the like (One-pot four-component synthesis of 5,10-diarylpyrido [4,3-b ] [1,6] naphthyridine derivatives in ionic lipids captured by TsOH [ J ], multicyclic Aromatic Compounds, 2018, 38 (3): 236-243).
However, the preparation method has many disadvantages in the industrial large-scale production process, for example, the catalyst p-toluenesulfonic acid can not be recycled, and a large amount of waste liquid generated can pollute the environment; the preparation cost of the imidazole ionic liquid [ Bmim ] Br is higher, the usage amount of the imidazole ionic liquid [ Bmim ] Br as a reaction solvent is larger, and the economy is poorer. In addition, ionic liquids containing imidazole ring structures are not susceptible to microbial degradation. Finally, the reaction time in the whole preparation process is long, the yield is low and the purification process of the product is complex.
Disclosure of Invention
1. Problems to be solved
The invention aims to overcome the defects of the existing [1,6] naphthyridine derivative preparation process and provides a method for preparing a medical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative. The invention takes ethanol-dimethylformamide-water mixed solution as a reaction solvent and a recrystallization solvent, takes non-imidazolyl acidic ionic liquid as a catalyst to catalyze the reaction of aromatic aldehyde, 2, 4-piperidione and aromatic amine, so as to prepare the 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative, and the preparation process has the advantages of high product yield, recyclable catalytic system, short reaction time, simple and convenient product purification process and the like.
2. Technical scheme
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the invention relates to a method for preparing a medical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative under the catalysis of an acidic ionic liquid, which is characterized in that aromatic aldehyde, amine and 2, 4-piperiddione are used as reaction raw materials, an ethanol-dimethylformamide-water mixed solution is used as a reaction solvent, and the 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative is prepared under the catalysis of the acidic ionic liquid catalyst:
the chemical reaction formula is as follows:
the molar ratio of aromatic aldehyde, amine and 2, 4-piperiddione in the reaction is 1: 1-1.3: 2, the molar weight of the acidic ionic liquid catalyst is 5-9% of the molar weight of the aromatic aldehyde, the volume of the ethanol-dimethylformamide-water mixed solvent in milliliters is 7-11 times of the molar weight of the aromatic aldehyde in millimoles, and the volume ratio of the ethanol-dimethylformamide-water is 2: 4-7: 1, the reaction pressure is one atmosphere, the reflux reaction time is 75-96 min, after the reaction is finished, the reaction liquid is cooled to room temperature, a large amount of solid is separated out, the mixture is stood, filtered, washed by water, and dried in vacuum at 80 ℃ for 48 hours to obtain the 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative. Aromatic aldehyde, amine and 2, 4-piperiddione are directly added into the filtrate obtained by suction filtration, and the filtrate can be reused.
The aromatic aldehyde is any one of p-chlorobenzaldehyde, p-bromobenzaldehyde, p-cyanobenzaldehyde, p-fluorobenzaldehyde and 2, 4-dichlorobenzaldehyde, and the amine is any one of aniline, p-chloroaniline, p-bromoaniline, p-methylaniline and 3-amino-9-ethyl carbazole. The preparation of the acidic ionic liquid catalyst is described in the literature (Design, preparation, and catalysis of novel IL-based catalyst, [ (Et)3N)2SO][HSO4]2，as an efficient and recyclable catalyst in Biginelli reaction under solvent-free conditions[J]，Polycyclic Aromatic Compounds，2019，DOI:https://doi.org/10.1080/10406638.2019.1653943)。
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) the method for preparing the medical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative takes aromatic aldehyde, 2, 4-piperiddione and aromatic amine as reaction raw materials, and selects specific acidic ionic liquid as a catalyst, so that the catalyst has high catalytic activity and selectivity and short reaction time, and can effectively reduce side reactions, thereby improving the yield and purity of the obtained 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative. And using the mixed solution of ethanol-dimethyl formamide-water as a reaction solvent,
(2) according to the method for preparing the medical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative, the catalyst is good in recycling performance and can be directly reused without being treated. Meanwhile, the ethanol-dimethylformamide-water mixed solution is used as a reaction solvent and a recrystallization solvent, and technological parameters such as the addition proportion of each component in the reaction solvent, the addition amount of the reaction solvent, the reaction temperature, the reaction time and the like are optimally designed, so that the side reaction is further reduced, the catalytic activity of the catalyst is best exerted, the reaction solvent can be reused, the energy conservation and emission reduction are facilitated, and the economic benefit is high.
(3) The method for preparing the medical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative has the advantages that the whole preparation process is environment-friendly, the discharge amount of waste liquid is extremely low, the purification process of the product is simple, and a recrystallization process is not required to be independently arranged.
Drawings
FIG. 1 is a schematic representation of the effect of the number of catalyst system cycles on the yield and purity of the product obtained in example 1;
FIG. 2 is a graphical representation of the effect of the number of catalyst system cycles on the yield and purity of the product obtained in example 3.
Detailed Description
The present invention will be further described in the following detailed description, which shows the essential features and significant effects of the present invention, but they do not limit the present invention in any way, and those skilled in the art can make modifications and variations which are not essential to the present invention, and fall within the scope of the present invention. Wherein the IR spectroscopy of the reaction products of the examples is characterized by the EQUINOX 55 IR spectrometer (KBr pellet) from Bruker, Germany; the hydrogen nuclear magnetic resonance characterization adopts a nuclear magnetic resonance instrument with the model of AVANCE 400MHz of Germany Bruker company.
Example 1
To a 50ml single-neck flask containing 7ml of a mixed solvent (ethanol-dimethylformamide-water volume ratio of 2: 5: 1) with a spherical condenser and a stirrer were added 1.0mmol of p-bromobenzaldehyde, 1.2mmol of aniline, 2.0mmol of 2, 4-piperidinedione and 0.07mmol of an acidic ionic liquid catalyst, and the mixture was stirred at room temperature. Heating to reflux (solvent vapor does not exceed the second ball of the spherical condenser tube), keeping reflux for 81min, detecting by TLC (thin-plate chromatography), eliminating the raw material point, cooling the reaction liquid to room temperature, separating out a large amount of solid, standing, filtering, washing filter residue by water (5ml multiplied by 3), and drying in vacuum at 80 ℃ for 48H to obtain 0.43g of 10- (4-bromophenyl) -5-phenyl-3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -dione, wherein the purity is 98.5% by high performance liquid chromatography, and the calculated yield is 93%. P-bromobenzaldehyde, aniline and 2, 4-piperiddione are directly added into the filtrate for reuse.
The product obtained in this example, 10- (4-bromophenyl) -5-phenyl-3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ]][1，6]The performance parameters of naphthyridine-1, 9(2H, 5H) -dione are as follows: ir (kbr) v: 3413, 3052, 2924, 2860, 1678, 1626, 1599, 1475, 1411, 1373, 1269, 1237, 1144, 1008, 846, 825, 782, 694cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.77～1.84(m，2H，CH2)，2.18～2.31(m，2H，CH2)，2.94～3.01(m，4H，CH2)，5.13(s，1H，CH)，7.08(brs，2H，NH)，7.26(d，J＝8.6Hz，2H，ArH)，7.35(d，J＝6.4Hz，2H，ArH)，7.41(d，J＝8.2Hz，2H，ArH)，7.48～7.54(m，3H，ArH)。
Example 2
To a 50ml single neck flask containing 9ml of a mixed solvent (ethanol-dimethylformamide-water volume ratio of 2: 6: 1) with a spherical condenser and a stirrer were added 1.0mmol of p-bromobenzaldehyde, 1.2mmol of p-bromoaniline, 2.0mmol of 2, 4-piperidinedione and 0.07mmol of an acidic ionic liquid catalyst, and the mixture was stirred at room temperature. Uniformly heating to reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the reflux for 88min, detecting by TLC (thin-plate chromatography), eliminating the raw material point, cooling the reaction liquid to room temperature, separating out a large amount of solid, standing, performing suction filtration, washing filter residues by water (5ml multiplied by 3), and performing vacuum drying at 80 ℃ for 48H to obtain 0.47g of 5, 10-bis (4-bromophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -diketone, wherein the purity is 98.3% by high performance liquid chromatography, and the calculated yield is 88%. Adding p-bromobenzaldehyde, p-bromoaniline and 2, 4-piperidedione into the filtrate for reuse.
The product obtained in this example was 5, 10-bis (4-bromophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ]][1，6]The performance parameters of naphthyridine-1, 9(2H, 5H) -dione are as follows: ir (kbr) v: 3444, 3389, 1672, 1625, 1469, 1370, 1264, 1238, 1207, 1007, 836, 781cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.83～1.88(m，2H，CH2)，2.19～2.30(m，2H，CH2)，2.97～3.04(m，4H，CH2)，5.17(s，1H，CH)，7.12(brs，2H，NH)，7.28(d，J＝8.2Hz，2H，ArH)，7.38(d，J＝8.2Hz，2H，ArH)，7.45(d，J＝8.2Hz，2H，ArH)，7.74(d，J＝8.6Hz，2H，ArH)。
Example 3
To a 50ml single neck flask containing 8ml of a mixed solvent (ethanol-dimethylformamide-water volume ratio of 2: 6: 1) with a spherical condenser and a stirrer were added 1.0mmol of p-chlorobenzaldehyde, 1.1mmol of p-chloroaniline, 2.0mmol of 2, 4-piperidinedione and 0.06mmol of an acidic ionic liquid catalyst, and the mixture was stirred at room temperature. Heating to reflux (solvent vapor does not exceed the second ball of the spherical condenser tube), keeping reflux for 84min, detecting by TLC (thin-plate chromatography), eliminating raw material points, cooling the reaction liquid to room temperature, separating out a large amount of solid, standing, performing suction filtration, washing filter residue by water (5ml multiplied by 3), and performing vacuum drying at 80 ℃ for 48H to obtain 0.38g of 5, 10-bis (4-chlorophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -diketone, wherein the purity is 98.8% by high performance liquid chromatography, and the calculated yield is 86%. Adding p-chlorobenzaldehyde, p-chloroaniline and 2, 4-piperidedione into the filtrate for reuse.
The product obtained in this example was 5, 10-bis (4-chlorophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ]][1，6]The performance parameters of naphthyridine-1, 9(2H, 5H) -dione are as follows: ir (kbr) v: 3363, 3039, 2864, 1674, 1619, 1593, 1474, 1369, 1338, 1266, 1239, 1213, 1130, 1085, 1008, 922, 839, 784cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.84～1.94(m，2H，CH2)，2.23～2.35(m，2H，CH2)，3.03(s，4H，CH2)，5.19(s，1H，CH)，7.11(brs，2H，NH)，7.29(d，J＝8.0Hz，2H，ArH)，7.36(d，J＝8.2Hz，2H，ArH)，7.44(d，J＝7.8Hz，2H，ArH)，7.61(d，J＝8.0Hz，2H，ArH)。
The mixed solvent and acidic ionic liquid of example 1 and this example are recycled for several times, and the effect of the number of times on the purity and yield of the product is examined, and the results are shown in fig. 1 and fig. 2, which show that the yield and purity of the product obtained by recycling the mixed solvent and acidic ionic liquid of example 1 and this example for several times are still relatively high.
Comparative example 1
To a 50ml single-neck flask containing 7ml of a mixed solvent (ethanol-dimethylformamide-water volume ratio of 2: 4: 1) with a spherical condenser and a stirrer were added 1.0mmol of p-bromobenzaldehyde, 1.2mmol of aniline, 2.0mmol of 2, 4-piperidinedione and 0.07mmol of an acidic ionic liquid catalyst, and the mixture was stirred at room temperature. Heating to reflux (solvent vapor does not exceed the second ball of the spherical condenser), maintaining reflux for 81min, detecting by TLC (thin-plate chromatography), and finding that both the raw material and the product are present in the solvent. The reaction solution is cooled to room temperature, a large amount of solid is separated out, the reaction solution is kept stand and filtered, filter residues are washed by water (5ml multiplied by 3), vacuum drying is carried out at 80 ℃ for 48 hours, 0.40g of 10- (4-bromophenyl) -5-phenyl-3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -dione is obtained, the purity is 92.6% by high performance liquid chromatography, and the calculated yield is 82%.
Comparative example 2
To a 50ml single neck flask containing 7ml of a mixed solvent (ethanol-dimethylformamide in a volume ratio of 2: 5) with a spherical condenser and a stirrer were added 1.0mmol of p-bromobenzaldehyde, 1.2mmol of aniline, 2.0mmol of 2, 4-piperidinedione and 0.07mmol of an acidic ionic liquid catalyst, and the mixture was stirred at room temperature. Heating to reflux (solvent vapor does not exceed the second ball of the spherical condenser), maintaining reflux for 81min, detecting by TLC (thin-plate chromatography), and finding that a large amount of raw materials and a small amount of product spots are present in the solvent. Cooling the reaction liquid to room temperature, precipitating a large amount of solid, standing, performing suction filtration, washing filter residues by water (5ml multiplied by 3), and performing vacuum drying at 80 ℃ for 48 hours to obtain a large amount of solid, wherein the purity of the product 10- (4-bromophenyl) -5-phenyl-3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -dione is 28.4% by high performance liquid chromatography, and the calculated yield is 37%.
Comparative example 3
To a 50ml single neck flask containing 7ml of a mixed solvent (dimethylformamide-water volume ratio of 5: 1) with a spherical condenser and a stirrer were added 1.0mmol of p-bromobenzaldehyde, 1.2mmol of aniline, 2.0mmol of 2, 4-piperidinedione and 0.07mmol of acidic ionic liquid catalyst, and the mixture was stirred at room temperature. Heating to reflux (solvent vapor does not exceed the second ball of the spherical condenser), maintaining reflux for 81min, detecting by TLC (thin-plate chromatography), and finding that both the raw material and the product are present in the solvent. Cooling the reaction liquid to room temperature, precipitating a large amount of solid, standing, performing suction filtration, washing filter residues by water (5ml multiplied by 3), and performing vacuum drying at 80 ℃ for 48 hours to obtain a large amount of solid, wherein the purity of the product 10- (4-bromophenyl) -5-phenyl-3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -diketone is 74.1% by high performance liquid chromatography, and the calculated yield is 64%.
Example 4
To a 50ml single neck flask containing 8ml of a mixed solvent (ethanol-dimethylformamide-water volume ratio of 2: 5: 1) with a spherical condenser and a stirrer were added 1.0mmol of p-chlorobenzaldehyde, 1.2mmol of p-bromoaniline, 2.0mmol of 2, 4-piperidinedione and 0.07mmol of an acidic ionic liquid catalyst, and the mixture was stirred at room temperature. Heating to reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping reflux for 83min, detecting by TLC (thin-plate chromatography), eliminating the raw material point, cooling the reaction liquid to room temperature, separating out a large amount of solid, standing, filtering, washing filter residue by water (5ml multiplied by 3), and drying in vacuum at 80 ℃ for 48H to obtain 0.43g of 5- (4-bromophenyl) -10- (4-chlorophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -dione, wherein the purity is 98.2% by high performance liquid chromatography and the calculated yield is 88%. Adding p-chlorobenzaldehyde, p-bromoaniline and 2, 4-piperiddione into the filtrate for reuse.
The product obtained in this example was 5- (4-bromophenyl) -10- (4-chlorophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ]][1，6]The performance parameters of naphthyridine-1, 9(2H, 5H) -dione are as follows: ir (kbr) v: 3421, 3040, 2865, 1679, 1622, 1478, 1375, 1270, 1246, 1213, 1139, 1073, 1019, 847, 791cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.86～1.92(m，2H，CH2)，2.25～2.37(m，2H，CH2)，2.96～3.03(m，4H，CH2)，5.14(s，1H，CH)，7.14(brs，2H，NH)，7.32(d，J＝8.6Hz，2H，ArH)，7.35～7.40(m，4H，ArH)，7.69(d，J＝8.6Hz，2H，ArH)。
Example 5
To a 50ml single neck flask containing 10ml of a mixed solvent (ethanol-dimethylformamide-water volume ratio of 2: 5: 1) with a spherical condenser and a stirrer were added 1.0mmol of p-bromobenzaldehyde, 1.1mmol of p-chloroaniline, 2.0mmol of 2, 4-piperidinedione and 0.07mmol of an acidic ionic liquid catalyst, and the mixture was stirred at room temperature. Heating to reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping reflux for 86min, detecting by TLC (thin-plate chromatography), eliminating the raw material point, cooling the reaction liquid to room temperature, separating out a large amount of solid, standing, filtering, washing filter residue by water (5ml multiplied by 3), and drying in vacuum at 80 ℃ for 48H to obtain 0.43g of 10- (4-bromophenyl) -5- (4-chlorophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -dione, wherein the purity is 98.6% by high performance liquid chromatography, and the calculated yield is 87%. Adding p-bromobenzaldehyde, p-chloroaniline and 2, 4-piperidedione into the filtrate for reuse.
The product obtained in this example is 10- (4-bromophenyl) -5- (4-chlorophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ]][1，6]The performance parameters of naphthyridine-1, 9(2H, 5H) -dione are as follows: ir (kbr) v: 3404, 3071, 2862, 1674, 1625, 1616, 1475, 1373, 1340, 1268, 1243, 1212, 1092, 844, 787cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.80～1.87(m，2H，CH2)，2.21～2.34(m，2H，CH2)，2.94～3.03(m，4H，CH2)，5.17(s，1H，CH)，7.11(brs，2H，NH)，7.30(d，J＝8.4Hz，2H，ArH)，7.42(d，J＝8.4Hz，4H，ArH)，7.63(d，J＝8.8Hz，2H，ArH)。
Example 6
To a 50ml single neck flask containing 10ml of a mixed solvent (ethanol-dimethylformamide-water volume ratio of 2: 4: 1) with a spherical condenser and a stirrer were added 1.0mmol of p-chlorobenzaldehyde, 1.0mmol of p-methylaniline, 2.0mmol of 2, 4-piperidinedione and 0.05mmol of an acidic ionic liquid catalyst, and the mixture was stirred at room temperature. Heating to reflux (solvent vapor does not exceed the second ball of the spherical condenser), keeping reflux for 75min, detecting by TLC (thin-plate chromatography), eliminating raw material spots, cooling the reaction liquid to room temperature, separating out a large amount of solid, standing, performing suction filtration, washing filter residue by water (5ml multiplied by 3), and performing vacuum drying at 80 ℃ for 48H to obtain 0.38g of 10- (4-chlorophenyl) -5- (4-methylphenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -dione, wherein the purity is 98.2% by high performance liquid chromatography and the calculated yield is 90%. P-chlorobenzaldehyde, p-methylaniline and 2, 4-piperidedione are directly added into the filtrate for reuse.
The product obtained in this example, 10- (4-chlorophenyl) -5- (4-methylphenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ]][1，6]The performance parameters of naphthyridine-1, 9(2H, 5H) -dione are as follows: ir (kbr) v: 3378, 3046, 2911, 2854, 1668, 1625, 1593, 1510, 1470, 1369, 1265, 1239, 1207, 1141, 1085, 986, 841, 784, 731, 690cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.83～1.87(m，2H，CH2)，2.18～2.31(m，2H，CH2)，2.34(s，3H，CH3)，2.92～2.99(m，4H，CH2)，5.13(s，1H，CH)，7.07(brs，2H，NH)，7.24(d，J＝6.6Hz，2H，ArH)，7.28(d，J＝8.4Hz，3H，ArH)，7.36(d，J＝8.4Hz，3H，ArH)。
Example 7
1.0mmol of p-cyanobenzaldehyde, 1.3mmol of 3-amino-9-ethylcarbazole, 2.0mmol of 2, 4-piperidinedione and 0.09mmol of acidic ionic liquid catalyst are added into a 50ml single-neck flask with a spherical condenser and a stirrer, which contains 7ml of mixed solvent (the volume ratio of ethanol-dimethylformamide-water is 2: 7: 1), and the mixture is stirred uniformly at room temperature. Uniformly heating until refluxing (solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 96min, detecting by TLC (thin-plate chromatography), eliminating the raw material point, cooling the reaction liquid to room temperature, separating out a large amount of solid, standing, performing suction filtration, washing filter residue by water (5ml multiplied by 3), and performing vacuum drying at 80 ℃ for 48H to obtain 0.44g of 4- (5- (9-ethyl-9H-carbazole-3-yl) -1, 9-dioxo-1, 2, 3, 4, 5, 6, 7, 8, 9, 10-decahydropyrido [4,3-b ] [1,6] naphthyridin-10-yl) benzonitrile, wherein the purity of the benzonitrile is 99.0% as determined by high performance liquid chromatography, and the calculated yield is 84%. P-cyanobenzaldehyde, 3-amino-9-ethyl carbazole and 2, 4-piperidedione are directly added into the filtrate for reuse.
The product obtained in this example, 4- (5- (9-ethyl-9H-carbazol-3-yl) -1, 9-dioxo-1, 2, 3, 4, 5, 6, 7, 8, 9, 10-decahydropyrido [4,3-b ]][1，6]The performance parameters of naphthyridin-10-yl) benzonitrile are as follows: ir (kbr) v: 3423, 2981, 2937, 2874, 2226, 1673, 1629, 1478, 1380, 1346, 1279, 1235, 1208, 855, 792, 774cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.32(t，J＝6.4Hz，3H，CH3)，1.93～1.97(m，2H，CH2)，2.24～2.37(m，2H，CH2)，3.06(s，4H，CH2)，4.47～4.50(q，J＝6.4Hz，2H，CH2)，5.34(s，1H，CH)，7.12(brs，2H，NH)，7.28(s，1H，ArH)，7.36～7.52(m，2H，ArH)，8.15～8.19(m，1H，ArH)，8.25～8.31(m，1H，ArH)。
Example 8
Adding 1.0mmol of p-fluorobenzaldehyde, 1.2mmol of 3-amino-9-ethyl carbazole, 2.0mmol of 2, 4-piperiddione and 0.08mmol of acidic ionic liquid catalyst into a 50ml single-neck bottle with a spherical condenser tube and a stirrer, which contains 8ml of mixed solvent (the volume ratio of ethanol-dimethylformamide-water is 2: 6: 1), and uniformly stirring at room temperature. Heating to reflux (solvent vapor does not exceed the second ball of the spherical condenser tube), keeping reflux for 91min, detecting by TLC (thin-plate chromatography), eliminating the raw material point, cooling the reaction liquid to room temperature, separating out a large amount of solid, standing, filtering, washing filter residue by water (5ml multiplied by 3), and drying in vacuum at 80 ℃ for 48H to obtain 0.46g of 5- (9-ethyl-9H-carbazole-3-yl) -10- (4-fluorophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -dione, wherein the purity of the product is 98.6% by high performance liquid chromatography, and the calculated yield is 89%. P-fluorobenzaldehyde, 3-amino-9-ethyl carbazole and 2, 4-piperiddione are directly added into the filtrate for repeated use.
The product obtained in this example, 5- (9-ethyl-9H-carbazol-3-yl) -10- (4-fluorophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ]][1，6]The performance parameters of naphthyridine-1, 9(2H, 5H) -dione are as follows: ir (kbr) v: 3398, 3380, 3061, 2964, 1668, 1616, 1469, 1372, 1343, 1272, 1229, 1154, 1142, 852, 788, 743, 729cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.37(t，J＝7.0Hz，3H，CH3)，1.84～1.90(m，2H，CH2)，2.28～2.41(m，2H，CH2)，3.00～3.04(m，4H，CH2)，4.48(q，J＝7.0Hz，2H，CH2)，5.23(s，1H，CH)，7.03(brs，2H，NH)，7.07～7.11(m，2H，ArH)，7.20～7.25(m，1H，ArH)，7.34～7.42(m，3H，ArH)，7.48～7.51(m，1H，ArH)，7.64(d，J＝8.0Hz，1H，ArH)，7.69～7.75(m，1H，ArH)，8.16～8.18(m，1H，ArH)，8.22～8.28(m，1H，ArH)。
Example 9
Adding 1.0mmol of 2, 4-dichlorobenzaldehyde, 1.3mmol of 3-amino-9-ethylcarbazole, 2.0mmol of 2, 4-piperiddione and 0.09mmol of acidic ionic liquid catalyst into a 50ml single-neck bottle with a spherical condenser tube and a stirrer, which contains 11ml of mixed solvent (the volume ratio of ethanol-dimethylformamide-water is 2: 4: 1), and uniformly stirring at room temperature. Uniformly heating until refluxing (solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 93min, detecting by TLC (thin-plate chromatography), eliminating the raw material point, cooling the reaction liquid to room temperature, separating out a large amount of solid, standing, performing suction filtration, washing filter residue by water (5ml multiplied by 3), and performing vacuum drying at 80 ℃ for 48H to obtain 0.49g of 10- (2, 4-dichlorophenyl) 5- (9-ethyl-9H-carbazole-3-yl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ] [1,6] naphthyridine-1, 9(2H, 5H) -dione, wherein the purity of the product is 99.2% as determined by high performance liquid chromatography, and the calculated yield is 87%. 2, 4-dichlorobenzaldehyde, 3-amino-9-ethyl carbazole and 2, 4-piperiddione are directly added into the filtrate for reuse.
The product obtained in this example, 10- (2, 4-dichlorophenyl) 5- (9-ethyl-9H-carbazol-3-yl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4,3-b ]][1，6]The performance parameters of naphthyridine-1, 9(2H, 5H) -dione are as follows: ir (kbr) v: 3403, 3376, 3070, 2979, 1676, 1627, 1472, 1380, 1346, 1276, 1234, 1146, 858, 794, 775, 751cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.34(t，J＝6.6Hz，3H，CH3)，1.82～1.91(m，2H，CH2)，2.15～2.51(m，2H，CH2)，2.88～2.95(m，4H，CH2)，4.47(q，J＝6.6Hz，2H，CH2)，5.45(s，1H，CH)，6.94(brs，2H，NH)，7.20～7.26(m，1H，ArH)，7.32～7.45(m，3H，ArH)，7.49～7.60(m，2H，ArH)，7.63(d，J＝7.8Hz，1H，ArH)，7.70～7.75(m，1H，ArH)，8.14～8.19(m，1H，ArH)，8.25～8.30(m，1H，ArH)。
Claims (6)
1. A process for preparing a pharmaceutical intermediate 5,10-diarylpyrido [4,3-b ] [1,6] naphthyridine derivative, characterized by: the method takes aromatic aldehyde, amine and 2, 4-piperiddione as reaction raw materials, takes ethanol-dimethylformamide-water mixed solution as a reaction solvent, and prepares the 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative under the catalysis of an acidic ionic liquid catalyst as follows:
the volume of the ethanol-dimethylformamide-water mixed solution in milliliters is 7-11 times of the mole of the aromatic aldehyde in millimole, and the volume ratio of ethanol, dimethylformamide and water in the ethanol-dimethylformamide-water mixed solution is 2: 4-7: 1; the aromatic aldehyde is any one of p-chlorobenzaldehyde, p-bromobenzaldehyde, p-cyanobenzaldehyde, p-fluorobenzaldehyde and 2, 4-dichlorobenzaldehyde; the amine is any one of aniline, parachloroaniline, para-bromoaniline, para-methylaniline and 3-amino-9-ethyl carbazole.
2. The method for preparing the pharmaceutical intermediate 5,10-diarylpyrido [4,3-b ] [1,6] naphthyridine derivative according to claim 1, wherein: the molar ratio of the aromatic aldehyde, the amine and the 2, 4-piperiddione as the raw materials for the reaction is 1: 1-1.3: 2, the molar weight of the acidic ionic liquid catalyst is 5-9% of the molar weight of the aromatic aldehyde.
3. The method for preparing the 5,10-diarylpyrido [4,3-b ] [1,6] naphthyridine derivative as the pharmaceutical intermediate according to claim 1 or 2, which is carried out by: adding the reaction raw materials and a catalyst into a reaction solvent, uniformly stirring, heating to a reflux state for reaction, cooling reaction liquid to room temperature after the reaction is finished, precipitating a large amount of solid, standing, performing suction filtration, washing filter residues, and drying in vacuum to obtain the medical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative.
4. A process for preparing a pharmaceutical intermediate 5,10-diarylpyrido [4,3-b ] [1,6] naphthyridine derivative according to claim 3, characterized in that: controlling the reaction pressure to be one atmosphere, and controlling the reflux reaction time to be 75-96 min.
5. A process for preparing a pharmaceutical intermediate 5,10-diarylpyrido [4,3-b ] [1,6] naphthyridine derivative according to claim 3, characterized in that: the temperature of vacuum drying is 75-80 ℃, and the drying time is 45-48 h.
6. A process for preparing a pharmaceutical intermediate 5,10-diarylpyrido [4,3-b ] [1,6] naphthyridine derivative according to claim 3, characterized in that: and (3) directly adding aromatic aldehyde, amine and 2, 4-piperidedione into the filtrate obtained by suction filtration for reuse.
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