CN117069717A - 2, 6-naphthyridine micromolecule derivative and preparation method thereof - Google Patents

2, 6-naphthyridine micromolecule derivative and preparation method thereof Download PDF

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CN117069717A
CN117069717A CN202310964304.9A CN202310964304A CN117069717A CN 117069717 A CN117069717 A CN 117069717A CN 202310964304 A CN202310964304 A CN 202310964304A CN 117069717 A CN117069717 A CN 117069717A
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naphthyridine
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万晓波
汪文健
穆有炳
曾祥飞
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Jianghan University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention relates to a 2, 6-naphthyridine small molecule derivative and a preparation method thereof, wherein the structural formula of the derivative is shown as the following formula 1 and/or formula 2; the novel 2, 6-naphthyridine micromolecule derivative designed and synthesized by the invention has relatively simple synthesis steps, various derivative structures including aromatic heterocycle, straight chain or branched chain alkyl and the like, and is beneficial to large-scale popularization and application of the 2, 6-naphthyridine derivative structure.

Description

2, 6-naphthyridine micromolecule derivative and preparation method thereof
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a 2, 6-naphthyridine micromolecule derivative and a preparation method thereof.
Background
Naphthyridine compounds are isomerism heterocyclic ring systems formed by fusing two pyridine rings, also called diaminonaphthalene and pyridopyridine, and have certain aromaticity. With one sp per N atom not participating in the bond formation 2 The hybridization orbit contains a pair of lone pair electrons, so that the hybridization orbit has certain alkalinity and is a good electron donor.
The synthetic method of naphthyridine compounds mainly adopts a preparation method of quinoline, and comprises Friedlasender reaction, combes reaction and Gould-Jacobs reaction. Friedlasender has mild reaction conditions, high yield and stability and good regionality and selectivity, and has been widely applied to the construction of various naphthyridine compounds with novel structures; the Combes reaction is a common method for synthesizing quinoline compounds, and is commonly used for preparing naphthyridine derivatives by reacting pyridinamine with 1, 3-dicarbonyl compounds; the Gould-Jacobs reaction is one of the classical strategies for modern synthesis of hydroxyquinolines, such as condensation of diethyl 2- (1-ethoxyethyl) malonate with aniline to form enamine intermediates, which can be used to synthesize various highly functionalized hydroxy-substituted naphthyridine compounds via intramolecular Gould-Jacobs ring closure reactions to give 4-hydroxy-2-methyl-1, 6-naphthyridine-3-carboxylic acid. However, the above method is mainly widely applied to 1, 8-naphthyridine derivatives and 1, 6-naphthyridine derivatives, and is very rare for the synthesis of 2, 6-naphthyridine.
The Montreal has completely proposed the synthesis of 2, 6-naphthyridine, 3-ethyl acetate pyridine is used as a reactant, and the target compound is obtained by ring closure and hydrogenation of a product after oxidation, cyanation, amidation and cyanation, but the reaction process is complicated, the synthesis is easy to be limited by batches, and the toxicity of the used reagent is strong. In 2010, 2, 6-naphthyridine is synthesized by taking 2-methyl pyrazine as a starting material through condensation, elimination, double bond addition, amino protection, cycloaddition/elimination and deprotection reactions, and the method uses more easily available reaction raw materials in the reaction, improves the yield and does not use cyanide with great toxicity in the process. Alfred taurines starts from 4-cyano-3-pyridylacetonitrile, and 4-methyl-2, 6-naphthyridine is obtained after coupling, ring closure and hydrogenation, but cyanide is still involved in the reaction, and the derivative structure is simple.
At present, the synthesis method of the 2, 6-naphthyridine derivative has less research, and the existing 2, 6-naphthyridine derivative structure is less and simpler, so that the 2, 6-naphthyridine derivative is difficult to popularize and apply in various fields in a large scale.
Disclosure of Invention
The invention aims to overcome the technical defects, and provides a 2, 6-naphthyridine small molecule derivative and a preparation method thereof, which solve the technical problems that the 2, 6-naphthyridine derivative structure is less and cyanide with strong toxicity is usually required to be adopted in the synthesis process in the prior art.
In order to achieve the technical purpose, the technical scheme provided by the invention is as follows:
in a first aspect, the invention provides a 2, 6-naphthyridine small molecule derivative, wherein the structural formula of the derivative is shown in the following formula 1 and/or formula 2:
wherein Ar is selected from
X 2 Is any one of halogen atoms;
R 1 is a mono-or polysubstituted functional group, wherein the functional group is: any one of a C1-C20 linear alkyl group, a C1-C20 branched alkyl group, a C5-C20 aralkyl group, and a C5-C20 aromatic ether group;
R 2 is a mono-or polysubstituted functional group, wherein the functional group is: any one of a C1-C20 straight chain alkyl group, a C1-C20 branched chain alkyl group, a C1-C20 alkoxy group, and a C5-C10 aralkyl group.
In a second aspect, the invention provides a preparation method of a 2, 6-naphthyridine small molecule derivative, which comprises the following steps:
1) Compound 3 and compound 4 are subjected to coupling reaction to generate compound 5;
2) The compound 5 and N1, N4-dimethyl fumaramide are subjected to a coupling reaction to generate a compound 6;
3) Compound 6 and PO (X) 2 ) 3 Demethylation gives compound 7;
4) Compound 7 and PO (X) 2 ) 3 Reacting in a pressure-resistant pipe to obtain a compound 1;
and/or, further comprising the steps of:
5) Coupling the compound 1 with an organometallic reagent through metal catalysis to obtain a compound 2;
the synthetic route of the reaction is shown below:
wherein R is 2 M in MBr is any one of Mg, cu, fe, zn and Li.
Compared with the prior art, the invention has the beneficial effects that:
the invention synthesizes a novel 2, 6-naphthyridine derivative by adopting a very simple method and adopting reactions such as coupling, demethylation and the like, closing a ring and then aromatizing, does not need to adopt virulent cyanide as a raw material, has simple and convenient synthesis method, and the obtained compound has better solubility (can be dissolved in common solvents such as dichloromethane, chloroform and the like) and absorption energy level, and compared with other polymer materials, the small molecular compound has the advantages of definite structure, high product purity (more than 98 percent) and higher yield. The novel 2, 6-naphthyridine micromolecule derivative designed and synthesized by the invention has relatively simple synthesis steps, various derivative structures including aromatic heterocycle, straight chain or branched chain alkyl and the like, and is beneficial to large-scale popularization and application of the 2, 6-naphthyridine derivative structure.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of compound 6a in example 1 of the present invention; in FIG. 1, (a) is a hydrogen spectrum and (b) is a carbon spectrum.
FIG. 2 is a nuclear magnetic resonance spectrum of compound 7a in example 1 of the present invention; in fig. 2, (a) is a hydrogen spectrum and (b) is a carbon spectrum.
FIG. 3 is a nuclear magnetic resonance spectrum of compound 1a in example 1 of the present invention; in FIG. 3, (a) is a hydrogen spectrum and (b) is a carbon spectrum.
FIG. 4 is a nuclear magnetic resonance spectrum of compound 2a-1 in example 1 of the present invention; in fig. 4, (a) is a hydrogen spectrum and (b) is a carbon spectrum.
FIG. 5 (a) is an ultraviolet absorption diagram of the compound 2a-1 of example 1 in toluene solvent; FIG. 5 (b) is an ultraviolet absorbance graph of compound 2a-1 of example 1 in different solvents.
FIG. 6 is a CV diagram; wherein FIG. 6 (a) is the oxidation curve of ferrocene in methylene chloride, (b) is the oxidation curve of ferrocene in tetrahydrofuran, (c) is the complete redox curve of compound 2a-1 of example 1, (d) is the oxidation curve of compound 2a-1 of example 1 in methylene chloride, and (e) is the reduction curve of compound 2a-1 of example 1 in tetrahydrofuran.
FIG. 7 (a) is a hydrogen spectrum of the compound 6b in the example 2 of the present invention, and FIG. 7 (b) is a carbon spectrum of the compound 6b in the example 2 of the present invention.
FIG. 8 (a) is a hydrogen spectrum of the compound 1b in the example 2 of the present invention; FIG. 8 (b) is a carbon spectrum of the compound 1b in example 2 of the present invention.
FIG. 9 (a) is a hydrogen spectrum of the compound 2b in the example 2 of the present invention; FIG. 9 (b) is a carbon spectrum of the compound 2b in the example 2 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Abbreviation interpretation
Pd(PPh 3 ) 2 Cl 2 : bis (triphenylphosphine) palladium dichloride
NEt 3 : triethylamine
PO(X 2 ) 3 : phosphorus oxytrihalide
DCM: dichloromethane (dichloromethane)
THF: tetrahydrofuran (THF)
The invention provides a 2, 6-naphthyridine small molecule derivative, which has a structural formula shown in the following formula 1 and/or formula 2:
wherein Ar is selected from
X 2 Is any one of halogen atoms;
R 1 is a mono-or polysubstituted functional group, wherein the functional group is: any one of a C1-C20 linear alkyl group, a C1-C20 branched alkyl group, a C5-C20 aralkyl group, and a C5-C20 aromatic ether group;
R 2 is a mono-or polysubstituted functional group, wherein the functional group is: any one of a C1-C20 straight chain alkyl group, a C1-C20 branched chain alkyl group, a C1-C20 alkoxy group, and a C5-C10 aralkyl group.
The invention provides a preparation method of the 2, 6-naphthyridine small molecule derivative, which comprises the following steps:
1) Compound 3 and compound 4 are subjected to coupling reaction to generate compound 5;
2) The compound 5 and N1, N4-dimethyl fumaramide are subjected to a coupling reaction to generate a compound 6;
3) Compound 6 and PO (X) 2 ) 3 Demethylation gives compound 7;
4) Compound 7 and PO (X) 2 ) 3 Reacting in a pressure-resistant pipe to obtain a compound 1;
5) Coupling the compound 1 with an organometallic reagent through metal catalysis to obtain a compound 2;
the synthetic route of the reaction is shown below:
in the above process, ar is selected from
R 1 Is a mono-or polysubstituted functional group, wherein the functional group is: any one of a C1-C20 linear alkyl group, a C1-C20 branched alkyl group, a C5-C20 aralkyl group, and a C5-C20 aromatic ether group;
R 2 is a mono-or polysubstituted functional group, wherein the functional group is: any one of a C1-C20 linear alkyl group, a C1-C20 branched alkyl group, a C1-C20 alkoxy group, and a C5-C10 aralkyl group;
PO(X 2 ) 3 and X in Compound 3 2 Is any one of halogen atoms;
R 2 m in MBr is any one of Mg, cu, fe, zn and Li.
Compounds 3, 4 and PO (X) 2 ) 3 The product can be purchased directly from the common market or can be prepared according to literature methods. Compounds 1 and 2 were both yellow solids. All have good solubility and can be dissolved in common organic solvents such as dichloromethane, chloroform, tetrahydrofuran and the like.
Preferably, in the preparation method, in the step 1), the compound 3 and the compound 4 undergo a coupling reaction under the action of a catalyst a and CuI, wherein the catalyst a is a palladium catalyst, and is at least one selected from tetra (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, bis (1, 4-biphosphine) butylpalladium dichloride, palladium acetate and bis (triphenylphosphine) palladium dichloride.
It is further preferred that the molar ratio of compound 3 to compound 4 in step 1) is from 1:1 to 1.5.
Further preferably, the molar ratio of compound 3 to catalyst a in step 1) is 1:0.01 to 0.1; the molar ratio of compound 3 to CuI is 1:0.01 to 0.05, more preferably 1:0.02 to 0.04.
Preferably, step 2) is a coupling reaction by adding compound 5, N1, N4-dimethylfumaramide, copper acetate, catalyst B and a base.
Further preferably, the catalyst B is a ruthenium catalyst selected from at least one of p-cymene ruthenium dichloride dimer, diiodide (p-cymene) ruthenium (II) dimer, (p-cymene) tricyclohexylphosphine ruthenium (II) chloride and (p-cymene) bis (mesityl) ruthenium (II);
further preferably, the base is at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate, and sodium acetate;
it is further preferred that the molar ratio of compound 5 to N1, N4-dimethyl fumaramide in step 2) is from 2 to 2.5:1, the molar ratio of compound 5 to catalyst B is 1:0.001 to 0.1, the molar ratio of the compound 5 to the alkali is 1:1 to 10; the molar ratio of the compound 5 to the copper acetate is 2-2.5: 4, a step of;
preferably, the starting materials for the demethylation reaction in step 3) and step 4) further comprise tetrabutylammonium halides and organic solvents; the molar ratio of the compound 6 or the compound 7 to the tetrabutylammonium halide is 1:5-10; the ratio of compound 6 or compound 7 to the organic solvent is (3-10) mmol: (100-150) mL;
PO(X 2 ) 3 comprising phosphorus oxychloride or phosphorus oxybromide;
when phosphorus oxychloride is adopted, the phosphorus oxychloride is liquid and serves as a reactant and a solvent, and the volume ratio of the phosphorus oxychloride to the organic solvent is 1:1-100, and more preferably 1:1.1 to 100, more preferably 1:1.9 to 2.1;
when the phosphorus oxybromide is adopted, the molar ratio of the compound 6 or the compound 7 to the phosphorus oxybromide is 1:1-100;
preferably, in the demethylation reaction in step 3) and step 4), the halogen atom and PO (X) in the tetrabutylammonium halide 2 ) 3 The halogen atoms in the two are the same, so that the mixed products with different halogenated conditions are avoided.
Preferably, compounds 1 and R in step 5) 2 The molar ratio of MBr is 1:2-48;
preferably, compounds 1 and R in step 5) 2 The MBr solution is subjected to coupling reaction under the action of a catalyst C.
Further preferably, catalyst C is selected from at least one of tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, bis (1, 4-biphosphine) butylpalladium dichloride, palladium acetate, and bis (triphenylphosphine) palladium dichloride; the molar ratio of compound 1 to catalyst C is 1:0.01 to 0.15.
Preferably, the reaction temperature of all the reactions is 0-160 ℃ and the reaction time is 4-120 h; and the demethylation temperature of step 3) is lower than the demethylation temperature of step 4).
Further preferably, the demethylation reaction of step 3) is carried out at 80-120 ℃ for 2.5-3.5 h under normal pressure;
more preferably, the demethylation reaction in step 4) is carried out in a pressure-resistant tube at 150 to 160℃for 3 to 5 days.
Further preferably, the coupling reaction in step 1) and step 5) is carried out at 15-45 ℃ for 10-36 h; in the step 2), the coupling reaction is carried out at the temperature of 110-140 ℃ for 15-25 h.
All reactions are carried out in organic solvents;
the organic solvent in the step 1) is at least one selected from triethylamine, ethylenediamine and diisopropylamine;
the organic solvent in the steps 2), 3), 4) and 5) is at least one selected from toluene, diethyl ether, N-dimethylformamide, N-methylpyrrolidone, 1, 2-dichloroethane, tetrahydrofuran, dichloromethane, carbon tetrachloride and chloroform.
The invention provides a novel conjugated 2, 6-naphthyridine derivative with good solubility and simple synthesis method, which designs and synthesizes different aromatic heterocyclic ring end-capped and different alkyl chain modified 2, 6-naphthyridine derivatives, flexibly introduces different aromatic heterocyclic ring end-caps into molecules, changes LUMO and HOMO energy levels of the molecules, and changes the photoelectric properties of the molecules to a certain extent. Simultaneously, alkyl chains with different lengths are introduced, so that the solubility of molecules is improved, and the molecules are easily dissolved in most organic solvents, so that the purification is convenient. Meanwhile, the synthesis method of the target molecule is simple, and is beneficial to mass accumulation of products.
In the preparation method, the compound 3 and the compound 4 are adopted as the starting materials, so that the source is wide; the end group of the compound 4 is alkynyl, the compound 5 is obtained in a coupling reaction catalyzed by transition metals such as cuprous salt, pd and the like, and the reaction is carried out at room temperature and is mild; then, the coupling reaction is carried out with N1, N4-dimethyl fumaramide to generate a compound 6, and the reaction is carried out at a slightly high temperature and a slightly high pressure in a pressure-resistant pipe; by reacting compound 6 with a lower temperature in a shorter reaction timePO(X 2 ) 3 The demethylation reaction is carried out to obtain the compound 7, and then the compound 1 is produced under the conditions of higher temperature and higher pressure by prolonging the reaction time, so that the purity and the yield of the product are high.
The special structure of the 2,6 naphthyridine derivative has certain research and application in the aspects of biomedical research, photochemistry, electrochemistry, luminescent materials and the like, has complex and various synthetic structures and potential pharmacological activity, and can play an increasingly large role in friendly ecological environment construction and human society development in the near future.
The invention is further illustrated by the following specific examples.
The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials and reagents used in the following examples are commercially available from conventional commercial sources unless otherwise specified.
Example 1
1) Synthesis of Compound 5a
Weighing Pd (PPh) 3 ) 2 Cl 2 (1.6 mmol,0.04 eq) and CuI (0.8 mmol,0.02 eq) in a dry 500mL two-necked flask, add 2-iodothiophene (40 mmol,1 eq) with NEt 3 After (120 mL), 4a (40 mmol,1 eq) was added after argon substitution and stirred overnight at room temperature. After the reaction is finished, the solvent in the system is rotationally evaporated after the diatomite is used for assisting filtration, and the compound 5a is obtained through purification of a silica gel chromatographic column, wherein the yield is 60%, the purity of the product is 98.13%, and the molecular weight is 122.02.
2) Synthesis of Compound 6a
N1, N4-dimethylfumaramide (22.3 mmol,1 eq), copper acetate hydrate (89.2 mmol,4 eq), potassium carbonate (89.2 mmol,4 eq) and p-cymene ruthenium dichloride dimer (2.2 mmol,0.1 eq) were weighed in sequence in a pressure-resistant tube. Compound 5a (49.1 mmol,2.2 eq) was added and reacted with 1, 2-dichloroethane (240 mL) at 120℃for 20h. After the reaction is finished, diatomite is used for assisting filtration, the solvent in the system is rotationally evaporated, and the compound 6a is obtained through purification of a silica gel chromatographic column, wherein the yield is 53%, the purity of the product is 99.02%, and the molecular weight is 382.08.
The nuclear magnetic resonance spectrum of the compound 6a is shown in FIG. 1, specifically 1H NMR (400 MHz, chloroform-d) δ7.51 (d, J=5.1 Hz, 2H), 7.15 (t, J=4.4 Hz, 2H), 7.01 (d, J=4.5 Hz, 2H), 3.30 (s, 6H), 2.39 (s, 6H) 13C NMR (101 MHz, chloroform-d) δ 161.58,135.97,135.75,131.03,129.17,127.97,127.55,116.93,34.97,18.85.
3) Synthesis of Compound 7a
Compound 6a (7.8 mmol,1 eq) and tetrabutylammonium chloride (54.6 mmol,7 eq) were charged to a round bottom flask. 1, 2-dichloroethane (120 mL) and phosphorus oxychloride (60 mL) were added and the mixture was refluxed at 110℃for 3h. When medicines are added, the water content in the container is controlled, the water content is increased, the reaction byproducts are obviously increased, and the product yield is obviously reduced. Phosphorus oxychloride is used as both reactant and solvent in a 1:1.9 to 2.1 volume ratio to 1, 2-dichloroethane, and decreasing the amount of phosphorus oxychloride used will result in a reduced product yield (the yield is reduced to 60% when the phosphorus oxychloride to 1, 2-dichloroethane volume ratio is 1:1). After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system is rotationally evaporated after extraction, and the compound 7a is obtained through purification of a silica gel chromatographic column, the yield is 80 percent, the purity of the product is 99.23 percent, and the molecular weight is 386.03.
The nuclear magnetic resonance spectrum of the compound 7a is shown in FIG. 2, specifically 1H NMR (400 MHz, chloroform-d) delta 7.54 (d, J=6.4 Hz, 1H), 7.45 (t, J=4.8 Hz, 2H), 7.19-7.16 (m, 1H), 7.12 (t, J=4.4 Hz, 1H), 7.06 (d, J=3.2 Hz, 1H), 3.28 (s, 3H), 3.05 (s, 3H), 2.36 (s, 3H) 13C NMR (101 MHz, chloroform-d) delta 160.67,147.94,143.52,141.36,135.37,134.41,132.83,129.29,129.15,128.44,127.69,127.24,126.87,126.61,126.47,111.08,33.93,19.27,18.61.
4) Synthesis of Compound 1a
Compound 7a (3.87 mmol,1 eq) and tetrabutylammonium chloride (38.7 mmol,10 eq) were charged into a dry pressure-resistant tube. After the addition of 1, 2-dichloroethane (150 mL) and phosphorus oxychloride (75 mL) and reaction at 150℃for 4d, the reaction solution should be sufficiently stirred and should be completely immersed in the heating medium, otherwise the yield of the target product would be reduced (from 55% to 35%) for at least 4d, otherwise the raw materials would not be completely reacted. After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system is rotationally evaporated after extraction, and the compound 1a is obtained through purification of a silica gel chromatographic column, the yield is 55 percent, the purity of the product is 98.53 percent, and the molecular weight is 389.98.
The nuclear magnetic resonance spectrum of the compound 1a is shown in FIG. 3, specifically 1H NMR (400 MHz, chloroform-d) delta 7.51 (d, J=4.9 Hz, 4H), 7.20-7.15 (m, 2H), 3.07 (s, 6H), 13CNMR (101 MHz, chloroform-d) delta 147.68,146.16,142.25,132.51,129.31,128.58,127.81,123.51,21.88.
5) Synthesis of Compound 2a-1
Compound 1a (2.56 mmol,1 eq) was reacted with Pd (PPh) 3 ) 2 Cl 2 (0.384 mmol,0.15 eq) was placed in a 250mL single neck flask. 100mL of dry toluene was added to the flask after argon substitution, and since methylmagnesium bromide is extremely moisture sensitive, it was necessary to ensure that the moisture content was kept at trace levels before methylmagnesium bromide was added. A solution of methyl magnesium bromide (40.96 mmol,16 eq) was slowly added at 40℃and the reaction solution was sufficiently preheated before the addition of methyl magnesium bromide, while slowly dropwise adding methyl magnesium bromide, which might otherwise be sprayed out due to rapid expansion of the gas volume at too fast a reaction rate, and reacted overnight. After the reaction is finished, the reaction is quenched by saturated ammonium chloride solution, saturated saline and dichloromethane are used for extraction, the solvent in the system is rotationally evaporated from an organic phase, and the compound 2a-1 is obtained through purification of a silica gel chromatographic column, wherein the yield is 70%, the purity of the product is 98.21%, and the molecular weight is 350.09.
The nuclear magnetic resonance spectrum of the compound 2a-1 is shown in FIG. 4, specifically 1H NMR (400 MHz, chloroform-d) δ7.44 (dd, J=8.1, 4.4Hz, 1H), 3.08 (s, 1H), 2.91 (s, 1H), 13CNMR (101 MHz, chloroform-d) δ 155.35,146.28,144.80,132.71,128.04,127.65,127.43,121.73,29.48,21.67.
Synthesis of Compound 2a-2
Compound 1a [ ]2.56mmol,1 eq) with Pd (PPh 3 ) 2 Cl 2 (0.384 mmol,0.15 eq) was placed in a 250mL single neck flask. 100mL of dry toluene was added to the flask after argon substitution. A solution of phenylmagnesium bromide (40.96 mmol,16 eq) was slowly added at 40℃and reacted overnight. After the reaction, the reaction is quenched by saturated ammonium chloride solution, saturated saline and dichloromethane are used for extraction, the solvent in the system is rotationally evaporated from the organic phase, and the compound 2a-2 is obtained through purification of a silica gel chromatographic column, wherein the yield is 63%, the purity of the product is 99.15%, and the molecular weight is 474.12.
Synthesis of Compound 2a-3
Compound 1a (2.56 mmol,1 eq) was reacted with Pd (PPh) 3 ) 2 Cl 2 (0.384 mmol,0.15 eq) was placed in a 250mL single neck flask. 100mL of dry toluene was added to the flask after argon substitution. A solution of 2-methoxyphenyl magnesium bromide (40.96 mmol,16 eq) was slowly added at 40℃and reacted overnight. After the reaction is finished, the reaction is quenched by saturated ammonium chloride solution, saturated saline and dichloromethane are used for extraction, the solvent in the system is rotationally evaporated from an organic phase, and the compound 2a-3 is obtained through purification of a silica gel chromatographic column, wherein the yield is 45%, the purity of the product is 99.01%, and the molecular weight is 534.69.
Performance testing
Optical and electrochemical measurements were carried out on the compound 2a-1 of the above example 1, specifically as follows.
Optical testing: an ultraviolet-visible absorption spectrometer was used to test the optical band gap of compound 2 a-1. 10 was prepared using N-Hexane (HEX), toluene (Tol), chloroform (TCM), dichloromethane (DCM), tetrahydrofuran (THF) and N, N-Dimethylformamide (DMF) as solvents, respectively, and compound 2a-1 as solute -3 5mL of a mol/L sample solution, adopting a quartz cuvette with the wavelength of 250-800 nm with the wavelength of 1X 1cm as a sample cell, and respectively placing the quartz cuvette into an ultraviolet absorption spectrometer for formal test.
Analysis of results: as shown in FIG. 5 (a), by making a tangent to the absorption curve of Compound 2a-1 in toluene solution, the wavelength of Compound 2a-1 in toluene was known, and Compound 2a-1 exhibited a strongest absorption peak around 350nm, corresponding to pi-pi of the molecular skeleton* And (5) transition. The band gap of the compound was estimated from the maximum absorption peak cut-off position of the ultraviolet spectrum. The optical bandgap of 3.042cm can be calculated from the formula eg=1240/X -1 . As shown in fig. 5 (b), as the polarity of the solvent increases, the polar orientation between the solvent and the molecule increases, the absorption spectrum shifts red, and the absorption peak of chloroform as the solvent is weaker, probably due to the quenching of fluorescence that occurs due to the solvent polarity being too strong.
TABLE 1 optical data for Compounds 2a-1
Solvent(s) HEX Tol TCM DCM THF DMF
Ultraviolet absorption peak/nm 345 350 None 344 348 349
Electrochemical testing: the Cyclic Voltammetry (CV) test was performed on the compound 2a-1 on a standard commercial electrochemical analyzer (Shanghai Chen Hua instruments Co., ltd., CHI 520E), and the three electrode system consisted of a cylindrical platinum working electrode, a platinum wire counter electrode and an Ag/AgCl reference electrode whose potential was internally calibrated according to ferrocene. Preparing a deoxidized dichloromethane solution and a deoxidized tetrahydrofuran solution of 0.1M tetrabutylammonium hexafluorophosphate (TBAPF 6) respectively as electrolyte solutions, adding a sample into the electrolyte solutions, filling into a dried container, plugging a three-hole plug, connecting a working electrode and a reference electrode with a wire respectively, inserting the counter electrode into the three-hole plug, replacing argon gas, exhausting air, starting a test, setting a range to 0-2.0V, and testing oxidation curves and reduction curves of all solvents respectively.
Analysis of results: the redox peak position of the compound is calibrated by using a ferrocene/ferrocene cation (Foc/Foc +) redox system as an internal standard, and the LUMO and HOMO energy levels of the compound are estimated by the initial reduction peak and the initial oxidation peak potential. FIGS. 6 (a) and 6 (b) are oxidation curves of ferrocene in DCM and THF, respectively, and the corresponding X values can be obtained by making a tangent line. FIG. 6 (c) shows the complete redox profile of compound 2a-1, and FIGS. 6 (c) and 6 (d) show the oxidation profile of compound 2a-1 in DCM and the reduction profile in THF, respectively, with corresponding X values obtained by making a tangent line.
According to the formula:
E HOMO ＝-[4.8-X FocDCM +X (2a-1)DCM ]
E LUMO ＝-[4.8-X FocTHF +X (2a-1)THF ]
the LUMO level was finally calculated to be-3.503 eV and the HOMO level was calculated to be-5.345 eV. Electrochemical band gap of 1.842cm -1 . Compound 2a-1 has two pairs of redox peaks and has good reversibility. The LUMO level of compound 2a-1 was lower than-3.4 eV, indicating that it has a higher electron affinity.
From the results of CV and UV tests, it was found that the optical bandgap of Compound 2a-1 was 3.042cm -1 Electrochemical band gap of 1.842cm -1 Can be used as donor materials in photoelectric materials and semiconductor materials.
Example 2
1) Synthesis of Compound 5b
Weighing Pd (PPh) 3 ) 2 Cl 2 (0.8 mmol,0.02 eq) and CuI (1.6 mmol,0.04 eq) in a dry 500mL two-necked flask, 2-iodobenzene (40 mmol,1 eq) and NEt were added 3 After replacing argon (120 mL), 4b (60 mmol,1.5 eq) was added and stirred overnight at room temperature. After the reaction, the solvent in the system is rotationally evaporated after the kieselguhr is used for assisting filtration, and the compound 5b is purified by a silica gel chromatographic column, so that the yield is 78%, the purity of the product is 98.10%, and the molecular weight is 116.06.
2) Synthesis of Compound 6b
N1, N4-dimethylfumaramide (12 mmol,1 eq), copper acetate hydrate (48 mmol,4 eq), potassium carbonate (48 mmol,4 eq) and p-cymene ruthenium dichloride dimer (0.6 mmol,0.05 eq) were weighed in sequence in a pressure-resistant tube. Compound 5b (26.4 mmol,2.2 eq) was added and reacted with 1, 2-dichloroethane (240 mL) at 135℃for 20h. After the reaction is finished, diatomite is used for assisting filtration, the solvent in the system is rotationally evaporated, and the compound 6b is obtained through purification of a silica gel chromatographic column, wherein the yield is 50%, the purity of the product is 99.31%, and the molecular weight is 370.17.
The nuclear magnetic resonance spectrum of the compound 6b is shown in FIG. 7, specifically 1H NMR (400 MHz, chloroform-d) δ7.46 (dq, J=14.3, 7.9,7.2Hz, 6H), 7.22 (d, J=7.5 Hz, 4H), 3.18 (s, 6H), 2.30 (s, 6H) 13C NMR (101 MHz, chloroform-d) δ 161.85,143.07,135.89,130.68,129.24,128.84,113.31,35.33,18.65.
3) Synthesis of Compound 7b
Compound 6b (8.0 mmol,1 eq) and tetrabutylammonium bromide (56.1 mmol,7 eq) were charged to a round bottom flask. 1, 2-dichloroethane (120 mL) and phosphorus oxybromide (80.0 mmol,10 eq) were added and then refluxed at 105℃for 3h. After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system is rotationally evaporated after extraction, and the compound 7b is obtained through purification of a silica gel chromatographic column, the yield is 75 percent, the purity of the product is 98.20 percent, and the molecular weight is 418.07.
4) Synthesis of Compound 1b
Compound 7b (3.87 mmol,1 eq) and tetrabutylammonium bromide (38.7 mmol,10 eq) were placed in a dry pressure-resistant tube. 1, 2-dichloroethane (150 mL) and phosphorus oxybromide (38.7 mmol,10 eq) were added and reacted at 150℃for 4.5d. After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system is rotationally evaporated after extraction, and the compound 1b is obtained through purification of a silica gel chromatographic column, the yield is 45 percent, the purity of the product is 98.89 percent, and the molecular weight is 467.97.
The nuclear magnetic resonance spectrum of the compound 1b is shown in FIG. 8, specifically 1H NMR (400 MHz, chloroform-d) δ7.65 (d, J=7.7 Hz, 4H), 7.49 (dt, J=13.4, 6.9Hz, 6H), 2.92 (s, 6H) 13C NMR (101 MHz, chloroform-d) δ 154.78,146.89,139.14,132.70,130.08,128.85,128.53,124.91,21.96.
5) Synthesis of Compound 2b-1
Compound 1b (2.63 mmol,1 eq) was reacted with Pd (PPh) 3 ) 2 Cl 2 (0.399mmol, 0.15 eq) was placed in a 250mL single neck flask. After argon was replaced, 50mL of dry toluene was added to the flask. Methyl magnesium bromide solution (21.0 mmol,8 eq) was slowly added at 45℃and reacted overnight. After the reaction is finished, the reaction is quenched by saturated ammonium chloride solution, saturated saline and dichloromethane are used for extraction, the solvent in the system is rotationally evaporated from an organic phase, and the compound 2b-1 is obtained through purification of a silica gel chromatographic column, wherein the yield is 60%, the purity of the product is 99.01%, and the molecular weight is 338.18.
The nuclear magnetic resonance spectrum of the compound 2b is shown in FIG. 9, specifically 1H NMR (400 MHz, chloroform-d) δ7.64 (d, J=7.5 Hz, 4H), 7.49 (t, J=7.5 Hz, 4H), 7.42 (t, J=7.5 Hz, 2H), 3.13 (s, 6H), 2.75 (s, 6H) 13C NMR (101 MHz, chloroform-d) δ 155.54,153.33,141.31,132.54,130.03,128.41,128.00,122.58,29.84,21.57.
Synthesis of Compound 2b-2
Compound 1b (2.63 mmol,1 eq) was reacted with Pd (PPh) 3 ) 2 Cl 2 (0.399mmol, 0.15 eq) was placed in a 250mL single neck flask. After argon was replaced, 50mL of dry toluene was added to the flaskIs a kind of medium. 4-methyl-1-naphthylmagnesium bromide solution (21.0 mmol,8 eq) was slowly added at 45℃and reacted overnight. After the reaction, the reaction is quenched by saturated ammonium chloride solution, saturated saline and dichloromethane are used for extraction, the solvent in the system is rotationally evaporated from the organic phase, and the compound 2b-2 is obtained through purification of a silica gel chromatographic column, wherein the yield is 37%, the purity of the product is 98.45%, and the molecular weight is 590.27.
Synthesis of Compound 2b-3
Compound 1b (2.63 mmol,1 eq) was reacted with Pd (PPh) 3 ) 2 Cl 2 (0.399mmol, 0.15 eq) was placed in a 250mL single neck flask. After argon was replaced, 50mL of dry toluene was added to the flask. A solution of 6-methoxy-2-naphthylmagnesium bromide (21.0 mmol,8 eq) was slowly added at 45℃and reacted overnight. After the reaction is finished, the reaction is quenched by saturated ammonium chloride solution, saturated saline and dichloromethane are used for extraction, the solvent in the system is rotationally evaporated from an organic phase, and the compound 2b is obtained through purification of a silica gel chromatographic column, wherein the yield is 60%, the purity of the product is 99.36%, and the molecular weight is 622.26.
Example 3
1) Synthesis of Compound 5c
Weighing Pd (PPh) 3 ) 4 (0.4 mmol,0.01 eq) and CuI (0.8 mmol,0.02 eq) were placed in a dry 500mL two-necked flask, 2-bromoselenol (40 mmol,1 eq) and diisopropylamine (120 mL) were added, argon was replaced, and 4c (40 mmol,1 eq) was added and stirred overnight at 40 ℃. After the reaction is finished, the solvent in the system is rotationally evaporated after the diatomite is used for assisting filtration, and the compound 5c is obtained through purification of a silica gel chromatographic column, wherein the yield is 45%, the purity of the product is 98.01%, and the molecular weight is 436.26.
2) Synthesis of Compound 6c
N1, N4-dimethylfumaramide (22.3 mmol,1 eq), copper acetate hydrate (89.2 mmol,4 eq), potassium acetate (89.2 mmol,4 eq), (p-cymene) bis (mesitylene) ruthenium (II) (0.22 mmol,0.01 eq) were weighed in sequence in a pressure-resistant tube. Compound 5c (46.8 mmol,2.1 eq) was added and reacted with 1, 2-dichloroethane (240 mL) at 110℃for 20h. After the reaction is finished, diatomite is used for assisting filtration, the solvent in the system is rotationally evaporated, and the compound 6c is obtained through purification of a silica gel chromatographic column, wherein the yield is 37%, the purity of the product is 99.06%, and the molecular weight is 1008.57.
3) Synthesis of Compound 7c
Compound 6c (7.8 mmol,1 eq) and tetrabutylammonium bromide (54.6 mmol,7 eq) were charged to a round bottom flask. 1, 2-dichloroethane (120 mL) and phosphorus oxybromide (117 mmol,15 eq) were added and the mixture was refluxed at 115℃for 3h. After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system was rotary evaporated after extraction and purified by silica gel column chromatography to give compound 7c in 53% yield, 99.21% purity and 1058.46 molecular weight.
4) Synthesis of Compound 1c
Compound 7c (3.87 mmol,1 eq) and tetrabutylammonium bromide (19.35 mmol,5 eq) were charged into a dry pressure-resistant tube. 1, 2-dichloroethane (150 mL) and phosphorus oxybromide (58.05 mmol,15 eq) were added and reacted at 160℃for 3.5d. After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system is rotationally evaporated after extraction, and the compound 1c is obtained by purifying by a silica gel chromatographic column, the yield is 42 percent, the purity of the product is 98.51 percent, and the molecular weight is 1106.36.
5) Synthesis of Compound 2c
Compound 1c (2.56 mmol,1 eq) was reacted with Pd (PPh) 3 ) 2 Cl 2 (0.384 mmol,0.15 eq) was placed in a 250mL single neck flask. 100mL of dry toluene was added to the flask after argon substitution. A solution of ethyl magnesium bromide (81.92 mmol,32 eq) was slowly added at 40℃and the reaction was allowed to proceed overnight. After the reaction, the reaction is quenched by saturated ammonium chloride solution, saturated saline and dichloromethane are used for extraction, the solvent in the system is rotationally evaporated from the organic phase, and the compound 2c is obtained through purification of a silica gel chromatographic column, wherein the yield is 56%, the purity of the product is 98.64%, and the molecular weight is 1006.41.
Example 4
1) Synthesis of Compound 5d
Weighing Pd (O) 2 CCH 3 ) 2 (4.0 mmol,0.1 eq) and CuI (0.8 mmol,0.02 eq) in a dry 500mL two-necked flask, 2-iodofuran (40 mmol,1 eq) and NEt were added 3 After (120 mL), argon was replaced, 4d (40 mmol,1 eq) was added and stirred overnight at room temperature. After the reaction, the solvent in the system is rotationally evaporated after the kieselguhr is used for assisting filtration, and the compound 5d is obtained through purification of a silica gel chromatographic column, wherein the yield is 57%, the purity of the product is 98.24%, and the molecular weight is 232.18.
2) Synthesis of Compound 6d
N, N-dimethyl N1, N4-dimethyl fumaramide (22.3 mmol,1 eq), copper acetate hydrate (89.2 mmol,4 eq), cesium carbonate (89.2 mmol,4 eq), diiodide (p-cymene) ruthenium (II) dimer (1.1 mmol,0.05 eq) were weighed in sequence in a pressure-resistant tube. Compound 5d (49.1 mmol,2.5 eq) was added and reacted with 1, 2-dichloroethane (240 mL) at 120℃for 20h. After the reaction is finished, diatomite is used for assisting filtration, the solvent in the system is rotationally evaporated, and the compound 6d is obtained through purification of a silica gel chromatographic column, the yield is 48%, the purity of the product is 98.31%, and the molecular weight is 602.41.
3) Synthesis of Compound 7d
Compound 6d (7.8 mmol,1 eq) and tetrabutylammonium chloride (54.6 mmol,7 eq) were charged to a round bottom flask. 1, 2-dichloroethane (120 mL) and phosphorus oxychloride (60 mL) were added and the mixture was refluxed at 110℃for 3h. After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system is rotationally evaporated after extraction, and the compound 7d is obtained through purification of a silica gel chromatographic column, the yield is 75 percent, the purity of the product is 99.21 percent, and the molecular weight is 606.36.
4) Synthesis of Compound 1d
Compound 7d (3.87 mmol,1 eq) and tetrabutylammonium chloride (38.7 mmol,10 eq) were charged into a dry pressure-resistant tube. 1, 2-dichloroethane (150 mL) and phosphorus oxychloride (75 mL) were added and reacted at 150℃for 4d. After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system is rotationally evaporated after extraction, and the compound 1d is obtained through purification of a silica gel chromatographic column, the yield is 45 percent, the purity of the product is 99.05 percent, and the molecular weight is 610.31.
5) Synthesis of Compound 2d
Compound 1d (2.56 mmol,1 eq) was reacted with Pd (PPh) 3 ) 2 Cl 2 (0.384 mmol,0.15 eq) was placed in a 250mL single neck flask. 100mL of dry toluene was added to the flask after argon substitution. Slowly adding C at 40deg.C 20 H 41 MgBr solution (40.96 mmol,16 eq) was reacted overnight. After the reaction, the reaction is quenched by saturated ammonium chloride solution, saturated saline and dichloromethane are used for extraction, the solvent in the system is rotationally evaporated from the organic phase, and the compound 2d is obtained through purification of a silica gel chromatographic column, wherein the yield is 63%, the purity of the product is 99.12%, and the molecular weight is 1103.01.
Example 5
1) Synthesis of Compound 5e
Weighing Pd (O) 2 CCH 3 ) 2 (4.0 mmol,0.1 eq) and CuI (0.8 mmol,0.02 eq) in a dry 500mL two-necked flask, 5-iodothiazole (40 mmol,1 eq) and NEt were added 3 After replacing argon (120 mL), 4e (60 mmol,1.5 eq) was added and stirred overnight at room temperature. After the reaction, the solvent in the system is rotationally evaporated after the kieselguhr is used for assisting filtration, and the compound 5e is purified by a silica gel chromatographic column, so that the yield is 43%, the purity of the product is 98.36%, and the molecular weight is 213.06.
2) Synthesis of Compound 6e
N1, N4-dimethylfumaramide (22.3 mmol,1 eq), copper acetate hydrate (89.2 mmol,4 eq), cesium carbonate (89.2 mmol,4 eq), diiodide (p-cymene) ruthenium (II) dimer (1.1 mmol,0.05 eq) were weighed in order in a pressure-resistant tube. Compound 5e (49.1 mmol,2.5 eq) was added and reacted with 1, 2-dichloroethane (240 mL) at 120℃for 20h. After the reaction is finished, diatomite is used for assisting filtration, the solvent in the system is rotationally evaporated, and the compound 6e is obtained through purification of a silica gel chromatographic column, wherein the yield is 37%, the purity of the product is 98.62%, and the molecular weight is 564.72.
3) Synthesis of Compound 7e
Compound 6e (7.8 mmol,1 eq) and tetrabutylammonium chloride (54.6 mmol,7 eq) were charged to a round bottom flask. 1, 2-dichloroethane (120 mL) and phosphorus oxychloride (60 mL) were added and the mixture was refluxed at 110℃for 3h. After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system is rotationally evaporated after extraction, and the compound 7e is obtained through purification of a silica gel chromatographic column, the yield is 53 percent, the purity of the product is 98.62 percent, and the molecular weight is 567.12.
4) Synthesis of Compound 1e
Compound 7e (3.87 mmol,1 eq) and tetrabutylammonium chloride (38.7 mmol,10 eq) were charged into a dry pressure-resistant tube. 1, 2-dichloroethane (150 mL) and phosphorus oxychloride (75 mL) were added and reacted at 150℃for 5d. After the reaction, the solvent in the system was removed by rotary evaporation, and the mixture was dissolved in methylene chloride, quenched with saturated sodium bicarbonate solution, and extracted 3 times with saturated brine and methylene chloride. The solvent in the system is rotationally evaporated after extraction, and the compound 1e is obtained through purification of a silica gel chromatographic column, the yield is 21 percent, the purity of the product is 98.21 percent, and the molecular weight is 572.01.
5) Synthesis of Compound 2e
Compound 1e (2.56 mmol,1 eq) was reacted with Pd (PPh) 3 ) 2 Cl 2 (0.384 mmol,0.15 eq) was placed in a 250mL single neck flask. 100mL of dry toluene was added to the flask after argon substitution. Slowly adding C at 40deg.C 20 H 41 MgBr solution (40.96 mmol,16 eq) was reacted overnight. Quenching the reaction with saturated ammonium chloride solution after the reaction is finished, extracting with saturated saline and dichloromethane, rotationally evaporating the organic phase to remove the solvent in the system, purifying the organic phase by a silica gel chromatographic column to obtain the compound 2e with the yield of 63 percent and the purity of the product98.47% and a molecular weight of 1064.77.
Comparative example 1
The only difference from example 1 is that: the synthesis step of the compound 7a is removed, the compound 6a is adopted to directly react in a pressure-resistant pipe to obtain the compound 1a, the compound 7a is filled in the pressure-resistant pipe and then reacts for 3 hours at 110 ℃, and then the temperature is raised to 150 ℃ to react for 4 days.
As a result, it was found that obtaining compound 1a at one time resulted in a decrease in yield, 45% of the total yield of the two-step reaction, only 35% of the yield after the one-step reaction, and that a small amount of isomerized product was present when compound 6a produced compound 7a, and the polarity of the by-product was close to that of compound 1a, resulting in difficulty in separation of compound 1a after the one-step reaction.
Comparative example 2
The only difference from example 1 is that: the tetrabutylammonium chloride in step 3) was removed, and the other steps and conditions were the same as in example 1.
As a result, it was found that removal of tetrabutylammonium chloride resulted in a decrease in the yield of compound 7a to 40 to 50%, and similarly, removal of tetrabutylammonium chloride in step 4) resulted in a decrease in the yield, thereby indicating that addition of an appropriate amount of tetrabutylammonium chloride in the demethylation reaction is advantageous in promoting the increase in the yield.
The invention relates to a novel 2, 6-naphthyridine micromolecule derivative, which is characterized in that different aromatic heterocycles and different alkyl chain modified 2, 6-naphthyridine micromolecule derivatives are designed and synthesized, different aromatic heterocycles are introduced into molecules, LUMO and HOMO energy levels of the 2, 6-naphthyridine micromolecule derivatives are changed to a certain extent, photoelectric properties of the derivatives are regulated and controlled to a certain extent, and alkyl chains with different lengths are flexibly introduced into the molecules, so that the solubility of the molecules is improved, and the derivatives are easily dissolved in most organic solvents to facilitate purification; the effect of substituents on the nature of the compounds can also be investigated. The synthesis method provided by the invention has relatively simple synthesis steps through ring closure and aromatization, and is beneficial to large-scale popularization and application of the 2, 6-naphthyridine derivative structure.
The above-described embodiments of the present invention do not limit the scope of the present invention. Any other corresponding changes and modifications made in accordance with the technical idea of the present invention shall be included in the scope of the claims of the present invention.

Claims (10)

1. The 2, 6-naphthyridine small molecule derivative is characterized in that the structural formula of the derivative is shown as the following formula 1 and/or formula 2:
wherein Ar is selected from
X 2 Is any one of halogen atoms;
R 1 is a mono-or polysubstituted functional group, wherein the functional group is: any one of a C1-C20 linear alkyl group, a C1-C20 branched alkyl group, a C5-C20 aralkyl group, and a C5-C20 aromatic ether group;
R 2 is a mono-or polysubstituted functional group, wherein the functional group is: any one of a C1-C20 straight chain alkyl group, a C1-C20 branched chain alkyl group, a C1-C20 alkoxy group, and a C5-C10 aralkyl group.
2. The method for preparing the 2, 6-naphthyridine type small molecule derivative according to claim 1, comprising the steps of:
1) Compound 3 and compound 4 are subjected to coupling reaction to generate compound 5;
2) The compound 5 and N1, N4-dimethyl fumaramide are subjected to a coupling reaction to generate a compound 6;
3) Compound 6 and PO (X) 2 ) 3 Demethylation gives compound 7;
4) Compound 7 and PO (X) 2 ) 3 Reacting in a pressure-resistant pipe to obtain a compound 1;
and/or, further comprising the steps of:
5) Coupling the compound 1 with an organometallic reagent through metal catalysis to obtain a compound 2;
the synthetic route of the reaction is shown below:
wherein R is 2 M in MBr is any one of Mg, cu, fe, zn and Li.
3. The preparation method of the 2, 6-naphthyridine small molecule derivative according to claim 2, wherein in the step 1), the compound 3 and the compound 4 undergo a coupling reaction under the action of a catalyst A and a CuI, and the catalyst A is a palladium catalyst; the molar ratio of the compound 3 to the compound 4 is 1:1-1.5; the molar ratio of the compound 3 to the CuI is 1:0.01 to 0.05.
4. The method for preparing a 2, 6-naphthyridine-based small molecule derivative according to claim 3, wherein in the step 1), the catalyst a is at least one selected from the group consisting of tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, bis (1, 4 biphenylphosphine) butylpalladium dichloride, palladium acetate and bis (triphenylphosphine) palladium dichloride; the molar ratio of the compound 3 to the catalyst A is 1:0.01 to 0.1.
5. The method for preparing the 2, 6-naphthyridine small molecule derivative according to claim 2, wherein in the step 2), a compound 5, N1, N4-dimethyl fumaramide, copper acetate, a catalyst B and alkali are added for coupling reaction; the catalyst B is a ruthenium catalyst; the molar ratio of the compound 5 to the N1, N4-dimethyl fumaramide is 2-2.5: 1.
6. the method for preparing 2, 6-naphthyridine small molecule derivatives according to claim 5, wherein the catalyst B is at least one selected from a paracymene ruthenium dichloride dimer, a diiodide (paracymene) ruthenium (II) dimer, a (paracymene) tricyclohexylphosphine ruthenium (II) chloride and a (p-cymene) bis (mesitylene) ruthenium (II), and the molar ratio of the compound 5 to the catalyst B is 1:0.001 to 0.1; the alkali is at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate and sodium acetate, and the molar ratio of the compound 5 to the alkali is 1:1 to 10; the molar ratio of the compound 5 to the copper acetate is 2-2.5: 4.
7. the method for preparing 2, 6-naphthyridine small molecule derivatives according to claim 2, wherein the reaction temperature is 0-160 ℃ and the reaction time is 4-120 h in the steps 1) to 5); and the demethylation temperature of step 3) is lower than the demethylation temperature of step 4).
8. The method for preparing 2, 6-naphthyridine small molecule derivatives according to claim 2 or 7, characterized in that the demethylation reaction of step 3) is carried out for 2.5-3.5 hours at 80-120 ℃ under normal pressure; the demethylation reaction of the step 4) is carried out in a pressure-resistant pipe at 150-160 ℃ for 3-5 days;
in the step 3) and the step 4), the raw materials of the demethylation reaction further comprise tetrabutylammonium halide and an organic solvent; the molar ratio of the compound 6 or the compound 7 to the tetrabutylammonium halide is 1:5-10; the ratio of compound 6 or compound 7 to the organic solvent is (3-10) mmol: (100-150) mL;
PO(X 2 ) 3 comprising phosphorus oxychloride or phosphorus oxybromide; the volume ratio of the phosphorus oxychloride to the organic solvent is 1:1-100; alternatively, the molar ratio of the compound 6 or the compound 7 to the phosphorus oxybromide is 1:1-100.
9. The method for preparing 2, 6-naphthyridine type small molecule derivatives according to claim 2, wherein in step 5), the compound 1 and R are as follows 2 MBr solution action on catalyst CThe coupling reaction is carried out under the condition that the compound 1 and R 2 The molar ratio of MBr is 1:2-48; the molar ratio of compound 1 to catalyst C is 1:0.01 to 0.15; the catalyst C is a palladium catalyst.
10. The method for producing a 2, 6-naphthyridine type small molecule derivative according to claim 2, wherein the reactions in steps 1) to 5) are all carried out in the presence of an organic solvent; and the organic solvent in the step 1) is selected from at least one of triethylamine, ethylenediamine and diisopropylamine, and the organic solvent in the steps 2) to 5) is selected from at least one of toluene, diethyl ether, N-dimethylformamide, N-methylpyrrolidone, 1, 2-dichloroethane, tetrahydrofuran, dichloromethane, carbon tetrachloride and chloroform.
CN202310964304.9A 2023-07-31 2023-07-31 2, 6-naphthyridine micromolecule derivative and preparation method thereof Pending CN117069717A (en)

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