阅读说明：本技术 一种吡喃并[4,3-b]吡啶-2,7-二酮化合物的合成方法 (Synthesis method of pyrano [4,3-b ] pyridine-2, 7-dione compound ) 是由 胡居吾 韩晓丹 王慧宾 于 2021-08-05 设计创作，主要内容包括：本发明公开一种吡喃并[4,3-b]吡啶-2,7-二酮化合物的合成方法,其以4-胺基-2-吡喃酮化合物和炔酸酯类化合物为原料,铜盐为催化剂,溶于有机溶剂中,进行环合反应,得到吡喃并[4,3-b]吡啶-2,7-二酮化合物。本发明反应步骤少,产物结构单一,副反应少,产率高,具有良好的市场前景。(The invention discloses a synthesis method of a pyrano [4,3-b ] pyridine-2, 7-dione compound, which takes a 4-amino-2-pyranone compound and an alkynoate compound as raw materials, takes copper salt as a catalyst, dissolves in an organic solvent, and carries out a cyclization reaction to obtain the pyrano [4,3-b ] pyridine-2, 7-dione compound. The method has the advantages of few reaction steps, single product structure, few side reactions, high yield and good market prospect.)

1. A synthetic method of a pyrano [4,3-b ] pyridine-2, 7-dione compound is characterized by comprising the following steps: dissolving a 4-amino-2-pyrone compound A and an alkynoate compound B serving as raw materials and a copper salt serving as a catalyst in an organic solvent to perform a cyclization reaction to obtain a pyrano [4,3-B ] pyridine-2, 7-dione compound C;

the reaction route is as follows:

wherein R is¹Is selected from C₁～C₅In straight or branched alkanes, phenylOne kind of (1); r²Is selected from C₁～C₂One of straight-chain alkane and phenyl; r³One selected from methyl, ethyl, benzyl, n-butyl, cyclohexyl, phenyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl and p-trifluoromethylphenylpyridyl; r⁴One selected from hydrogen, methyl, phenyl, COOMe and COOEt; r⁵One selected from methyl, ethyl, tert-butyl, phenyl, naphthyl and benzyl.

2. Pyrano [4,3-b ] according to claim 1]The synthesis method of the pyridine-2, 7-diketone compound is characterized by comprising the following steps: r of which¹Is one of methyl, ethyl, propyl or phenyl.

3. The method for synthesizing a pyrano [4,3-b ] pyridine-2, 7-dione compound according to claim 1, wherein: the mol ratio of the 4-amido-2-pyrone compound to the alkynoate compound is 1: 1.2 to 2.0, the ratio of the amounts of the 4-amino-2-pyrone compound, the organic solvent and the copper salt is 1 mmol: 5-8 mL: 0.1 to 0.25 mmol.

4. Pyrano [4,3-b ] according to claim 1]The synthesis method of the pyridine-2, 7-diketone compound is characterized by comprising the following steps: the copper salt is cupric bromide, cupric chloride, cuprous iodide, cupric acetate, cupric trifluoroacetate, copper trifluoromethanesulfonate, or copper complex Cu (dppp) Cl₂Or Cu (MeCN)₂Cl₂One kind of (1).

5. The method for synthesizing a pyrano [4,3-b ] pyridine-2, 7-dione compound according to claim 1, wherein: the organic solvent is one of toluene, xylene, tetrahydrofuran, acetonitrile, 1, 4-dioxane, 1, 2-dichloroethane, nitrogen-nitrogen dimethylformamide and dimethyl sulfoxide.

6. The method for synthesizing a pyrano [4,3-b ] pyridine-2, 7-dione compound according to claim 1, wherein: the heating reaction temperature is 70-110 ℃, and the reaction time is 6-10 h.

7. The method for synthesizing a pyrano [4,3-b ] pyridine-2, 7-dione compound according to claim 1, wherein: monitoring the reaction process by thin layer chromatography TLC, adding saturated salt solution into the reaction system after the reactant A completely disappears, extracting by using an extracting agent, and combining organic phases; drying the organic phase by a drying agent, filtering, concentrating, and carrying out column chromatography to obtain the pyrano [4,3-b ] pyridine-2, 7-dione compound C.

8. A pyrano [4,3-b ] pyridine-2, 7-dione compound characterized by: the synthetic method of any one of claims 1-7, wherein the synthetic method is represented by the following structural formula:

wherein R is¹Is selected from C₁～C₅One of the straight chain or branched chain alkane and phenyl; r²Is selected from C₁～C₂One of straight-chain alkane and phenyl; r³One selected from methyl, ethyl, benzyl, n-butyl, cyclohexyl, phenyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl and p-trifluoromethylphenylpyridyl; r⁴One selected from hydrogen, methyl, phenyl, COOMe and COOEt; r⁵One selected from methyl, ethyl, tert-butyl, phenyl, naphthyl and benzyl.

9. Pyrano [4,3-b ] according to claim 8]A pyridine-2, 7-dione compound characterized by: r of which¹Is one of methyl, ethyl, propyl or phenyl.

Technical Field

The invention belongs to the technical field of compound synthesis, and particularly relates to a synthetic method of a pyrano [4,3-b ] pyridine-2, 7-dione compound.

Background

The pyranopyridine derivatives are important heterocyclic structural units, and various molecules containing the structural units show important biological and pharmacological activities, such as antifungal activity, antitumor activity, antiviral activity, antimycobacterial activity, antiangiogenic activity, neurotropic activity, antiangiogenic activity and the like, so that the pyranopyridine derivatives have wide application in the fields of medicine and other related fields. In view of the importance of the compounds, the synthesis research of the compounds also receives extensive attention, and a plurality of synthesis methods are developed secondarily.

Selvam et al, using SnCl in the absence of solvent₂·2H₂O catalyzes 2-amino-3-nitrile-4H-pyran to have Friedlander reaction with cyclopentanone or cyclohexanone to synthesize pyran [2,3-b]Pyridines (Tetrahedron,2009,65(41), 8524); the group of the Mamedov, V.A. uses diethyl 2,4, 6-trioxoheptadicarboxylate and salicylaldehyde and its derivatives in ammonium acetateThe pyran [4,3-b ] is synthesized by the condensation reaction of the three components under the action]Pyridine compounds (Russ Chem Bull,2009,58(7), 1452.); rostamizadeh et al synthesized a series of pyranopyridine derivatives by sulfonic acid catalyzed reaction of malononitrile and 3, 5-diarylmethylene-N-methylpyridin-4-one in 2012 (j.chi.chem.soc.2012, 59,866). Further, the method for producing the pyranopyridine derivative further comprises: [4+2 ] using amino acid and unsaturated alcohol as raw materials]Cycloaddition reaction (org. lett.2012,14,1604); reaction of 3-oxo-3-phenyl-N- (3-pyridyl) propionamide with enaminonitrile (j.chem.sci.2012,124, 647); solvent reaction of aldehyde, pyridone and malononitrile catalyzed by triethylamine (j.med.chem.2008,51,2561); in ionic liquids, three-component reactions of aromatic aldehydes, malononitrile or cyanoacetate and tert-butyl 2, 4-dioxopyridine-1-carboxylate (Chin.J.org.chem.2013,33,1728) etc. However, the method reported in the prior published literature has the defects that the sources of reaction raw materials are limited to a certain extent (especially in multi-component reaction), the number of steps is large, the number of by-products is increased, the yield is not high, the operation is complicated, and the method is not suitable for large-scale production. Therefore, the method for searching a new method for synthesizing the pyranopyridone compound more efficiently, simply and quickly has important significance.

Disclosure of Invention

In order to solve the problems, the invention aims to provide a simple and efficient synthesis method of a pyrano [4,3-b ] pyridine-2, 7-dione compound.

In order to achieve the purpose, the invention adopts the following technical scheme:

a synthetic method of a pyrano [4,3-B ] pyridine-2, 7-dione compound comprises the steps of dissolving a 4-amino-2-pyranone compound A and an alkynoate compound B serving as raw materials in an organic solvent by using a copper salt as a catalyst, and carrying out a cyclization reaction to obtain a pyrano [4,3-B ] pyridine-2, 7-dione compound C;

the reaction route is as follows:

wherein R is¹Is selected from C₁～C₅One of the straight chain or branched chain alkane and phenyl; r²Is selected from C₁～C₂One of straight-chain alkane and phenyl; r³One selected from methyl, ethyl, benzyl, n-butyl, cyclohexyl, phenyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl and p-trifluoromethylphenylpyridyl; r⁴One selected from hydrogen, methyl, phenyl, COOMe and COOEt; r⁵One selected from methyl, ethyl, tert-butyl, phenyl, naphthyl and benzyl.

Further, R is as defined above¹Is one of methyl, ethyl, propyl or phenyl.

Further, the molar ratio of the 4-amino-2-pyrone compound to the alkynoate compound is 1: 1.2 to 2.0, the ratio of the amounts of the 4-amino-2-pyrone compound, the organic solvent and the copper salt is 1 mmol: 5-8 mL: 0.1 to 0.25 mmol.

Further, the copper salt is cupric bromide, cupric chloride, cuprous iodide, cupric acetate, cupric trifluoroacetate, cupric trifluoromethanesulfonate, or copper complex Cu (dppp) Cl₂Or Cu (MeCN)₂Cl₂One kind of (1).

Further, the organic solvent is one of toluene, xylene, tetrahydrofuran, acetonitrile, 1, 4-dioxane, 1, 2-dichloroethane, nitrogen-nitrogen dimethylformamide and dimethylsulfoxide.

Further, the temperature of the heating reaction is 70-110 ℃, and the reaction time is 6-10 h.

The synthesis method of the pyrano [4,3-b ] pyridine-2, 7-dione compound comprises the steps of monitoring the reaction process by thin layer chromatography TLC, adding saturated salt solution into the reaction system after the reactant A completely disappears, extracting by using an extracting agent, and combining organic phases; drying the organic phase by a drying agent, filtering, concentrating, and carrying out column chromatography to obtain the pyrano [4,3-b ] pyridine-2, 7-dione compound C.

Further, the extractant is dichloromethane, ethyl acetate, diethyl ether or chloroform.

Further, the drying agent is anhydrous sodium sulfate, anhydrous calcium chloride, anhydrous magnesium sulfate or a molecular sieve.

Further, the organic phase is dried for 6 to 8 hours by a drying agent.

Another object of the present invention is to provide a pyrano [4,3-b ] pyridine-2, 7-dione compound, prepared according to the synthesis method described above, of the formula:

wherein R is¹Is selected from C₁～C₅One of the straight chain or branched chain alkane and phenyl; r²Is selected from C₁～C₂One of straight-chain alkane and phenyl; r³One selected from methyl, ethyl, benzyl, n-butyl, cyclohexyl, phenyl, p-methylphenyl, p-chlorophenyl, p-methoxyphenyl and p-trifluoromethylphenylpyridyl; r⁴One selected from hydrogen, methyl, phenyl, COOMe and COOEt; r⁵One selected from methyl, ethyl, tert-butyl, phenyl, naphthyl and benzyl.

Further, R is as defined above¹Is one of methyl, ethyl, propyl or phenyl.

Due to the adoption of the technical scheme, the invention has the following advantages:

the synthetic method of the pyrano [4,3-b ] pyridine-2, 7-dione compound utilizes the aminolysis reaction of the 4-site amino substituent of the 4-amino-2-pyranone compound and the alkynoate compound and the coupling reaction of the 5-site alkene carbon in the 4-amino-2-pyranone compound and the alkyne carbon in the alkynoate compound to quickly construct the pyrano [4,3-b ] pyridine-2, 7-dione compound, and has the advantages of wide raw material source, less reaction steps, single product structure, less side reactions, high yield, yield reaching 75-89%, simple and convenient operation, strong universality, time saving, high efficiency and good market prospect.

Detailed Description

The present invention will be further described in detail with reference to the following examples; however, the following examples are merely illustrative, and the present invention is not limited to these examples.

Example 1

The compound 4-amino-2-pyrone compound A₁(1mmol, 0.26g), Butynedioic acid dimethyl ester B₁(1.5mmol, 0.18mL) and 0.1-fold amount of copper trifluoromethanesulfonate (0.1mmol, 0.03g) were placed in a 25mL round-bottomed flask, dissolved in toluene (8mL), stirred, reacted at 80 ℃ for 6 hours, monitored by TLC until the reaction substrate A₁Disappearance; after the reaction is finished, pouring the reaction solution into 20mL of saturated sodium chloride solution, stirring, extracting three times (3X 20mL) by using dichloromethane, separating the solution, and combining organic phases; the organic phase was over anhydrous MgSO₄Drying, evaporating the solvent under reduced pressure, and separating by column chromatography, wherein the eluent is petroleum ether/acetone, and the volume ratio of petroleum ether to acetone is 5:1, to obtain white solid target compound C₁The yield was 87%.

The specific reaction formula is as follows:

for compound C₁Performing nuclear magnetic hydrogen spectrum detection: white solid; m.p.133-135 ℃;¹HNMR(CDCl₃,400MHz)δ：1.34(t,J＝7.5Hz,3H),1.47(s,3H),2.75(q,J＝7.5Hz,2H),3.85(s,3H),3.86(s,3H),6.50(s,1H),7.00(d,J＝8.5Hz,2H),7.16(d,J＝8.5Hz,2H)。

example 2

The compound 4-amino-2-pyrone compound A₂(1mmol, 0.17g), Butynedioic acid dimethyl ester B₁(1.5mmol, 0.18mL) and 0.1 times the amount of copper acetate (0.1mmol, 0.02g) in a 25mL round-bottom flask, adding xylene (6mL) to dissolve, stirring, reacting at 100 deg.C for 5 hours, and monitoring by TLC until the reaction substrate A₂Disappearance; after the reaction is finished, pouring the reaction solution into 20mL of saturated sodium chloride solution, stirring, extracting three times (3X 20mL) by using dichloromethane, separating the solution, and combining organic phases; anhydrous NaSO for organic phase₄Drying, evaporating under reduced pressure to remove solvent, separating by column chromatography, eluting with petroleum ether/acetone at a volume ratio of 5:2 to obtain white pigmentTarget Compound C as a colored solid₂The yield was 83%.

The specific reaction formula is as follows:

for compound C₂Performing nuclear magnetic hydrogen spectrum detection: white solid; m.p.95-97 deg.c;¹HNMR(CDCl₃,400MHz)δ：1.31(t,J＝7.5Hz,3H),1.42(s,3H),2.63(q,J＝7.5Hz,2H),2.78(s,3H),3.76(s,3H),6.54(s,1H)。

example 3

The compound 4-amino-2-pyrone compound A₃(1mmol, 0.24g), methyl 2-butynoate B₂(1.2mmol, 0.12mL) and 0.13 times the amount of cupric bromide (0.13mmol, 0.03g) were placed in a 25mL round-bottomed flask, dissolved by adding 1, 2-dichloroethane (5mL), stirred, reacted at 90 ℃ for 7 hours, monitored by TLC until the reaction substrate A was reacted₃Disappearance; after the reaction is finished, pouring the reaction solution into 20mL of saturated sodium chloride solution, stirring, extracting three times (3X 20mL) by using dichloromethane, separating the solution, and combining organic phases; anhydrous NaSO for organic phase₄Drying, evaporating the solvent under reduced pressure, and separating by column chromatography, wherein the eluent is petroleum ether/ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 6:1, to obtain a white solid target compound C₃The yield was 79%.

The specific reaction formula is as follows:

for compound C₃Performing nuclear magnetic hydrogen spectrum detection: white solid; m.p.103-105 ℃;¹HNMR(CDCl₃,400MHz)δ：1.23(t,J＝7.5Hz,3H),1.68(s,3H),1.86(s,3H)，2.74(q,J＝7.5Hz,2H),4.01(s,2H),6.24(s,1H),7.27-7.37(m,5H)。

example 4

The compound 4-amino-2-pyrone compound A₄(1mmol, 0.24g), ethyl phenyl propiolate B₃(1.8mmol, 0.3mL) and 0.25 times the amount of cupric chloride (0.25mmol, 0.03g) in a 25mL round-bottomed flask, dissolved in N-dimethylformamide (6mL), stirred, reacted at 70 ℃ for 8 hours, monitored by TLC until the reaction substrate A₄Disappearance; after the reaction is finished, pouring the reaction solution into 20mL of saturated sodium chloride solution, stirring, extracting three times (3X 20mL) by using dichloromethane, separating the solution, and combining organic phases; anhydrous CaCl for organic phase₂Drying, evaporating under reduced pressure to remove solvent, separating by column chromatography, eluting with petroleum ether/diethyl ether at a volume ratio of petroleum ether to diethyl ether of 3:1 to obtain white solid target compound C₄The yield was 82%.

The specific reaction formula is as follows:

for compound C₄Performing nuclear magnetic hydrogen spectrum detection: white solid; m.p.141-143 ℃;¹HNMR(CDCl₃,400MHz)δ：1.93(s,3H),1.98(s,3H),6.77(s,1H),7.11-7.16(m,2H),7.20-7.29(m,1H),7.38-7.41(m,3H),7.41-7.47(m,2H),7.49-7.57(m,2H)。

example 5

The compound 4-amino-2-pyrone compound A₅(1mmol, 0.24g) benzyl propiolate B₄(1.5mmol, 0.21mL) and 0.10 times the amount of Cu (dppp) Cl₂(0.10mmol, 0.07g) in a 25mL round-bottomed flask, dissolved by addition of acetonitrile (7mL), stirred, reacted at 80 ℃ for 8 hours, monitored by TLC until substrate A was reacted₅Disappearance; after the reaction is finished, pouring the reaction solution into 20mL of saturated sodium chloride solution, stirring, extracting three times (3X 20mL) by using dichloromethane, separating the solution, and combining organic phases; anhydrous CaCl for organic phase₂Drying, evaporating under reduced pressure to remove solvent, separating by column chromatography, eluting with n-hexane/diethyl ether at a volume ratio of n-hexane to diethyl ether of 4:1 to obtain white solid target compound C₅The yield was 78%.

The specific reaction formula is as follows:

for compound C₅Performing nuclear magnetic hydrogen spectrum detection: white solid; m.p.117-119 deg.c;¹HNMR(CDCl₃,400MHz)δ：1.23(t,J＝8.0Hz,3H),1.38-1.47(m,5H),1.58-1.65(m,5H),1.87(s,3H),2.50(q,J＝8.0Hz,2H),3.26(m,1H),5.80(d,J＝12Hz,1H),6.42(d,J＝12Hz,1H)。

example 6

The compound 4-amino-2-pyrone compound A₆(1mmol, 0.23g), tert-butyl propiolate B₅(2.0mmol, 0.27mL) and 0.20 times of cuprous iodide (0.20mmol, 0.04g) were placed in a 25mL round bottom flask, dissolved in dimethylsulfoxide (5mL), stirred, reacted at 90 ℃ for 6 hours, monitored by TLC until substrate A was reacted₆Disappearance; after the reaction is finished, pouring the reaction solution into 20mL of saturated sodium chloride solution, stirring, extracting three times (3X 20mL) by using dichloromethane, separating the solution, and combining organic phases; drying the organic phase with molecular sieve, evaporating the solvent under reduced pressure, separating by column chromatography, eluting with petroleum ether/acetone at a volume ratio of petroleum ether to acetone of 2:1 to obtain white solid target compound C₆The yield was 88%.

The specific reaction formula is as follows:

for compound C₆Performing nuclear magnetic hydrogen spectrum detection: white solid; m.p.154-156 ℃;¹HNMR(CDCl₃,400MHz)δ：1.24(t,J＝8.0Hz,3H),2.15(s,3H),2.54(q,J＝6.5Hz,2H),6.43(d,J＝12.0Hz,1H),6.60(d,J＝12.0Hz,1H),6.92(t,J＝12.0Hz,1H),7.01(t,J＝4.0Hz,1H),7.69(t,J＝8.0Hz,1H),8.35(s,1H)。

example 7

The compound 4-amino-2-pyrone compound A₇(1mmol, 0.28g) but-yne diacid diethyl ester B₆(1.6mmol,0.26mL) and 0.15 times the amount of Cu (MeCN)₂Cl₂(0.15mmol, 0.03g) was placed in a 25mL round bottom flask and addedXylene (7mL) was dissolved, homogenized, reacted at 110 ℃ for 6 hours, monitored by TLC until substrate A was reacted₇Disappearance; after the reaction is finished, pouring the reaction solution into 20mL of saturated sodium chloride solution, stirring, extracting three times (3X 20mL) by using dichloromethane, separating the solution, and combining organic phases; drying the organic phase with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, separating by column chromatography, eluting with n-hexane/acetone at a volume ratio of n-hexane to acetone of 3:1 to obtain white solid target compound C₇The yield was 75%.

The specific reaction formula is as follows:

for compound C₇Performing nuclear magnetic hydrogen spectrum detection: white solid; m.p.151-153 ℃;¹HNMR(CDCl₃,400MHz)δ：1.27(t,J＝8.0Hz,3H)，1.67(s,3H)，2.63(q,J＝7.0Hz,2H),6.61(s,1H),6.95(d,J＝8.0Hz,2H),7.20(d,J＝12.0Hz,2H),7.26-7.30(m,4H),7.51(d,J＝8.0Hz,2H)。

the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.