CN112679426B - Intermediate compound for synthesizing nitrogen-containing heterocycle and preparation method and application thereof - Google Patents
Intermediate compound for synthesizing nitrogen-containing heterocycle and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an intermediate compound for synthesizing nitrogen-containing heterocycles, a preparation method and application thereof, wherein the chemical structural formula of the intermediate compound is as follows:
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to an intermediate compound for synthesizing nitrogen-containing heterocycles, and a preparation method and application thereof.
Background
The nitrogenous heterocyclic compounds are very important compounds, widely exist in various natural products and active drug molecules, such as morphine and derivatives thereof in alkaloid, are main drugs for clinical analgesia, are powerful analgesics with the largest use amount all over the world, such as indole reserpine, are used for treating hypertension and psychosis, such as quinolone antibiotics, have wide antibacterial spectrum and strong antibacterial activity, and are widely used for treating human and animal diseases.
The nitrogen-containing heterocyclic compound has a wide application range, and the existing preparation methods are more, but generally one method can only synthesize one type of nitrogen-containing heterocyclic ring, for example, a method for synthesizing thienopyridine nitrogen-containing heterocyclic compound is disclosed in patent CN101845051A, and a method for synthesizing nitrogen-containing heterocyclic quaternary salt is disclosed in patent CN 201910112334.0. Therefore, the invention provides a universal method for synthesizing a plurality of heterocyclic compounds, and has important research significance.
Disclosure of Invention
The invention aims to solve the problems and provide an intermediate compound for synthesizing nitrogen-containing heterocycles, a preparation method and application thereof.
The invention provides a high-efficiency carbon-hydrogen bond nitrogen-oxygen double functionalization method, on the basis, a series of novel nitrogen-oxygen functional group-containing compounds are synthesized, and various nitrogen-containing heterocyclic compounds can be obtained through further derivation.
The purpose of the invention is realized by the following technical scheme:
an intermediate compound for use in the synthesis of a nitrogen-containing heterocycle, the intermediate compound having the chemical formula:
in the formula (I), the compound is shown in the specification,
R 1 、R 2 、R 3 selected from hydrogen, alkyl, branched alkyl, cycloalkyl, methoxy, siloxy, amide, halogen, aryl with various substituents, heterocyclic radical or heterocyclic radical with various substituents;
R 4 selected from hydrogen, alkyl, branched alkyl, aryl or substituted amino;
R 5 selected from hydrogen, alkyl, branched alkyl, cycloalkyl, alkenyl, aryl or aryl with various substituents, heteroaryl;
R 6 selected from the group consisting of formate groups.
Furthermore, the intermediate compound is prepared by taking amide, azodicarboxylate and carboxylic acid as raw materials and performing direct carbon-hydrogen bond bifunctional synthesis under the action of a catalyst.
Further, the chemical structural formula of the amide is as follows:
in the formula: r 1 、R 2 、R 3 Selected from hydrogen, alkyl, branched alkyl, cycloalkyl, methoxy, siloxy, amide, halogen, aryl with various substituents, heterocyclic radical or heterocyclic radical with various substituents
R 4 Selected from hydrogen, alkyl, branched alkyl, aryl or substituted amino;
the carboxylic acid has the formula R 5 -COOH, wherein: r is 5 Selected from hydrogen, alkyl, branched alkyl, cycloalkyl, alkenyl, aryl or heteroaryl with various substituents;
the chemical structural formula of the azodicarbonic ester is as follows: r 6 -N＝N-R 6 In the formula: r 6 Is a formate group.
Further, the azodicarboxylate is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate.
The preparation process of intermediate compound for synthesizing nitrogen-containing heterocycle includes direct carbon-hydrogen bond double functionalization reaction of amide, carboxylic acid and azodicarboxylate in the presence of catalyst and solvent A to synthesize intermediate compound I.
Further, the catalyst is palladium acetate or palladium pivalate;
the solvent A is 2-methyl-2-butanol, toluene, tetrahydrofuran or dioxane;
the molar ratio of the catalyst to the amide is 5-10:100, the molar ratio of the amide, the carboxylic acid and the azodicarbonic ester is 1:1-2:1-2, the temperature of the double functionalization reaction is 80-150 ℃, the reaction time is 4-48h, preferably, the reaction temperature is 100-120 ℃, the reaction time is 3-5h, most preferably, the reaction time is 4h at 110 ℃, and the product is obtained by purification after cooling to room temperature.
The intermediate compound is used for synthesizing a nitrogen-containing heterocyclic compound.
Stirring the intermediate compound I for 0.5-2.5 h at normal temperature under the action of boron trifluoride diethyl etherate and dichloromethane, neutralizing, extracting and drying to obtain an intermediate product, further reacting for 12h at 80 ℃ in tetrahydrofuran, and performing column chromatography to obtain a nitrogen-containing heterocyclic compound A, wherein the chemical structural formula of the nitrogen-containing heterocyclic compound A is as follows:
stirring the intermediate compound for 1-4 h at 70 ℃ under the action of 4-dimethylaminopyridine, di-tert-butyl dicarbonate and acetonitrile, washing, extracting and drying to obtain a crude product, further dissolving the crude product in alcohol, adding corresponding sodium alkoxide, reacting for 12h at 100 ℃ and 120 ℃, washing, extracting, drying and carrying out column chromatography to obtain an intermediate product, refluxing the intermediate product for 2-8h in ferrous chloride, polymethylhydrosiloxane and ethanol, removing a solvent, and carrying out column chromatography to obtain an intermediate compound II, wherein the chemical structural formula of the intermediate compound II is as follows:
stirring the intermediate compound II for 0.5-2.5 h at normal temperature under the action of boron trifluoride diethyl ether and dichloromethane, neutralizing, extracting and drying to obtain an intermediate product, further reacting in toluene at 100 ℃ for 12-24h under the action of N, N-dimethylformamide dimethyl acetal, filtering, washing and drying to obtain a nitrogen-containing heterocyclic compound B, wherein the chemical structural formula of the nitrogen-containing heterocyclic compound B is as follows:
and stirring the intermediate compound II for 2-5 h at normal temperature under the action of ceric ammonium nitrate, 2,6, 6-tetramethylpiperidine oxide and acetonitrile, and filtering and carrying out column chromatography to obtain a nitrogen-containing heterocyclic compound C, wherein the nitrogen-containing heterocyclic compound C has a chemical structural formula as follows:
in the nitrogen-containing heterocyclic compound A, B, C: r 1 、R 2 、R 3 Selected from hydrogen, alkyl, branched alkyl, cycloalkyl, methoxy, siloxy, amide, halogen, aryl with various substituents, heterocyclic radical or heterocyclic radical with various substituents; r 4 Selected from the group consisting of hydrogen, alkyl, branched alkyl, aryl, substituted amino; r 5 From hydrogen, alkyl, branched alkyl, cycloalkyl, alkenyl, aryl with various substituents, heteroaryl; r 6 Is alkoxycarbonyl; r 7 Is a formate group.
The synthetic process route of the invention is specifically as follows:
compared with the prior art, the method synthesizes the intermediate compound I through the direct carbon-hydrogen bond double functionalization process, can expand the substrate in a large range, can obtain different nitrogen-containing heterocycles through different subsequent treatments, has structural diversity, and provides a new method for the industrial production of the nitrogen-containing heterocycles.
Detailed Description
The present invention will be described in detail with reference to specific examples.
In the present embodiment, the hydrogen nuclear magnetic resonance spectrum of the compound (b) ((b)) 1 H NMR) by Bruker AVANCE III HD 400; mass Spectrometry (ESI-MS) was determined by SolariX-70 FT-MS; all reagents used were commercially available reagents.
Example 1
Intermediate compound I: preparation of 1- (2- ((tert-butoxycarbonyl) amino) phenyl) -3-oxo-3- (quinolin-8-ylamino) propyl pivalate
Adding 0.1mmol of 3-phenyl-N- (quinoline-8-yl) propionamide, 0.01mmol of palladium pivalate, 0.2mmol of di-tert-butyl azodicarboxylate, 0.15mmol of pivalic acid and 1mL of anhydrous toluene into a reaction bottle, sealing, heating to 110 ℃, reacting for 4 hours, cooling to room temperature, and purifying to obtain the intermediate (I) with the yield of 81%.
The intermediate compound I is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ9.87(s,1H),8.80-8.73(m,2H),8.16(dd,J＝1.6Hz,J＝8.4Hz,1H),7.93(s,1H),7.79(d,J＝8.4Hz,1H),7.55-7.50(m,2H),7.47-7.41(m,2H),7.29(t,J＝7.6Hz,1H),7.11(t,J＝7.6Hz,1H),6.40(dd,J＝4.8Hz,J＝8.8Hz,1H),3.37(dd,J＝8.8Hz,J＝15.2Hz,1H),3.02(dd,J＝5.2Hz,J＝15.2Hz,1H),1.56(s,9H),1.13(s,9H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ177.6,167.7,153.8,148.2,138.2,136.4,136.2,134.1,129.8,129.1,127.9,127.4,127.2,124.3,123.7,121.8,121.7,116.7,80.3,68.9,43.6,38.7,28.4,26.9；HRMS:calculated for C 28 H 34 N 3 O 5 [M+H + ]:492.2498；found:492.2504.
example 2
Intermediate compound II: preparation of ethyl 3- (2- ((tert-butoxycarbonyl) amino) phenyl) -3-oxopropanoate
Adding 2mmol of intermediate compound I into 10mL of acetonitrile, adding 1.6mmol of 4-dimethylaminopyridine and 6.0mmol of di-tert-butyl dicarbonate, stirring for 1h at 70 ℃, washing with water, extracting and drying to obtain a crude product, further dissolving the crude product in 10mL of absolute ethanol, adding 6.0mmol of sodium ethoxide, reacting at 120 ℃ for 12 hours, washing with water, extracting, drying and carrying out column chromatography to obtain a compound X with the yield of 53%; adding 1.0mmol of compound X, 0.1mmol of ferrous chloride and 3.0mmol of polymethylhydrosiloxane into 5.0mL of ethanol, refluxing for 4h, cooling to room temperature, removing the solvent, and performing column chromatography to obtain an intermediate compound II with the yield of 55%.
The compound X is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ7.83(d,J＝15.6Hz,1H),7.76-7.74(m,1H),7.51-7.49(m,1H),7.37-7.32(m,1H),7.13-7.08(m,1H),6.55(s,1H),6.37(d,J＝15.6Hz,1H),4.26(q,J＝7.2Hz,2H),1.51(s,9H),1.33(t,J＝6.8Hz,3H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ166.8,153.0,139.4,136.6,130.8,127.2,126.3,124.5,123.0,120.5,81.0,60.7,28.3,14.3；HRMS:calculated for C 16 H 21 NNaO 4 [M+Na + ]:314.1368；found:314.1375.
intermediate compound II is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ10.74(s,1H),8.52-8.50(m,1H),7.77-7.75(m,1H),7.56-7.51(m,1H),7.05-7.01(m,1H),4.23(q,J＝7.2Hz,2H),4.02(s,2H),1.52(s,9H),1.27(t,J＝7.2Hz,3H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ196.2,167.4,153.0,142.5,135.6,131.2,121.1,120.3,119.4,80.8,61.7,47.4,28.3,14.1；HRMS:calculated for C 16 H 21 NNaO 5 [M+Na + ]:330.1317；found:330.1327.
example 3
Preparation of heterocyclic 2-oxo-1, 2,3, 4-tetrahydroquinoline-4-pentanoate of type A
Dissolving 0.2mmol of intermediate compound I in 5mL of dichloromethane, adding 1.0mmol of boron trifluoride diethyl etherate, stirring at normal temperature for 1h, neutralizing, extracting and drying to obtain an intermediate crude product, adding the intermediate crude product into 5mL of tetrahydrofuran, reacting at 80 ℃ for 12h, and performing column chromatography to obtain 2-oxo-1, 2,3, 4-tetrahydroquinoline-4-pentanoate with the yield of 62%.
The obtained A-type heterocycle is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ9.06(s,1H),7.38(d,J＝7.6Hz,1H),7.32-7.28(m,1H),7.07-7.02(m,1H),6.94-6.89(m,1H),6.01(t,J＝4.4Hz,1H),2.91-2.89(m,1H),1.13(s,9H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ177.7,169.0,137.3,130.2,129.3,123.4,121.1,115.9,67.6,38.9,36.8,26.9；HRMS:calculated for C 14 H 17 NNaO 3 [M+Na + ]:270.1106；found:270.1110.
example 4
Preparation of heterocyclic 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester of class B
0.5mmol of intermediate compound II was added to 4mL of dichloromethane, 2.5mmol of boron trifluoride diethyl etherate was added at 0 ℃ and stirred at room temperature for 2 hours, neutralized with saturated aqueous sodium bicarbonate solution, extracted with DCM, dried, the solvent was removed, the resulting crude product was further dissolved in 2mL of toluene, 0.8mmol of N, N-dimethylformamide dimethyl acetal was added and reacted at 100 ℃ for 12 hours. Cooled to room temperature, filtered, and the resulting solid washed with 50% ethanol/water (5mL x 2) and dried under vacuum at 60 ℃ to give class B heterocyclic 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester in 46% yield.
The obtained B heterocyclic ring is:
1 H NMR(DMSO-d 6 ,400MHz,ppm):δ12.32(s,1H),8.55(s,1H),8.18-8.15(m,1H),7.73-7.68(m,1H),7.63-7.61(m,1H),7.44-7.39(m,1H),4.22(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H)； 13 C NMR(DMSO-d 6 ,100MHz,ppm)δ173.9,165.3,145.4,139.5,132.8,127.7,126.1,125.1,119.3,110.3,60.0,14.8；HRMS:calculated for C 12 H 11 NNaO 3 [M+Na + ]:240.0637；found:240.0647.
example 5
Preparation of heterocyclic 1- (tert-butyl) -2-ethyl-2-hydroxy-3-oxaindoline-1, 2-dicarboxylate of group C
1.9mmol of intermediate compound II was added to 20mL of acetonitrile, 3.8mmol of ceric ammonium nitrate and 2.28mmol of tetramethylpiperidine nitroxide were added, and the mixture was stirred at room temperature for 2 hours. The acetonitrile was removed, 40mL of dichloromethane was added, stirring was continued at room temperature for 30 minutes, and the filtrate was collected by filtration. The solvent of the obtained filtrate is removed, and C heterocyclic 1- (tert-butyl) -2-ethyl-2-hydroxy-3-oxaindoline-1, 2-dicarboxylic ester is obtained by column chromatography, with the yield of 90%.
The obtained C-type heterocycle is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ8.26-8.22(m,1H),7.73-7.71(m,1H),7.68-7.64(m,1H),7.19-7.15(m,1H),4.84(s,1H),4.32-4.20(m,2H),1.53(s,9H),1.23(t,J＝7.2Hz,3H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ196.8,167.3,153.5,149.4,138.2,125.2,123.7,120.2,116.3,85.8,83.9,63.7,28.2,14.0；HRMS:calculated for C 16 H 19 NNaO 6 [M+Na + ]:344.1110；found:344.1101.
examples 6-8 are the syntheses of intermediate compounds (I) starting from amides of different substituents.
Example 6
Intermediate compound I: preparation of 1- (2- ((tert-butoxycarbonyl) amino) -4-methylphenyl) -3-oxo-3- (quinolin-8-ylamino) propyl pivalate
0.1mmol of N- (quinolin-8-yl) -3-p-tolylpropanamide, 0.01mmol of palladium pivalate, 0.2mmol of di-tert-butyl azodicarboxylate, 0.15mmol of pivalic acid and 1mL of anhydrous toluene were charged into a reaction flask, and after sealing, the reaction flask was heated to 110 ℃ for 4 hours, cooled to room temperature, and purified to obtain intermediate (I) with a yield of 76%.
The intermediate compound I is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ9.86(s,1H),8.80-8.73(m,2H),8.15(dd,J＝2.0Hz,J＝8.4Hz,1H),7.91(s,1H),7.63(s,1H),7.54-7.49(m,2H),7.47-7.43(m,1H),7.30(d,J＝8.0Hz,1H),6.92(d,J＝7.6Hz,1H),6.35(dd,J＝4.8Hz,J＝8.8Hz,1H),3.35(dd,J＝9.2Hz,J＝15.2Hz,1H),3.00(dd,J＝4.8Hz,J＝15.2Hz,1H),2.32(s,3H),1.56(s,9H),1.12(s,9H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ177.7,167.7,153.8,148.2,139.2,138.2,136.4,136.0,134.1,127.9,127.4,127.1,126.7,125.2,123.9,121.8,121.7,116.7,80.2,68.9,43.6,38.7,28.4,26.9,21.3；HRMS:calculated for C 29 H 36 N 3 O 5 [M+H + ]:506.2655；found:506.2646.
example 7
Intermediate compound I: preparation of 1- (2- ((tert-butoxycarbonyl) amino) -5-methoxyphenyl) -3-oxo-3- (quinolin-8-ylamino) propyl pivalate
Adding 0.1mmol of 3- (3-methoxyphenyl) -N- (quinolin-8-yl) propionamide, 0.01mmol of palladium pivalate, 0.2mmol of di-tert-butyl azodicarboxylate, 0.15mmol of pivalic acid and 1mL of anhydrous toluene into a reaction bottle, sealing, heating to 110 ℃ for reaction for 4 hours, cooling to room temperature, and purifying to obtain intermediate (I) with the yield of 90%.
The intermediate compound I is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ9.86(s,1H),8.81-8.73(m,2H),8.16(dd,J＝1.6Hz,J＝8.0Hz,1H),7.58-7.49(m,4H),7.47-7.44(m,1H),6.96(d,J＝3.2Hz,1H),6.85(dd,J＝3.2Hz,J＝8.4Hz,1H),6.37(dd,J＝4.8Hz,J＝8.8Hz,1H),3.79(s,3H),3.31(dd,J＝8.8Hz,J＝15.2Hz,1H),3.04(dd,J＝4.8Hz,J＝15.2Hz,1H),1.55(s,9H),1.14(s,9H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ177.5,167.6,156.8,154.3,148.2,138.2,136.4,134.1,132.8,128.8,127.9,127.4,126.3,121.8,121.7,116.7,114.2,112.3,80.1,68.6,55.5,43.7,38.6,28.4,26.9；HRMS:calculated for C 29 H 36 N 3 O 6 [M+H + ]:522.2604；found:522.2610.
example 8
Intermediate compound I: preparation of 1- (2- ((tert-butoxycarbonyl) amino) phenyl) -2-methyl-3-oxo-3- (quinolin-8-ylamino) propyl pivalate
Adding 0.1mmol of 2-methyl-3-phenyl-N- (quinolin-8-yl) propionamide, 0.01mmol of palladium pivalate, 0.2mmol of di-tert-butyl azodicarboxylate, 0.15mmol of pivalic acid and 1mL of anhydrous toluene into a reaction bottle, sealing, heating to 110 ℃ for reaction for 24 hours, cooling to room temperature, and purifying to obtain an intermediate (I) with the yield of 70%.
The intermediate compound I is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ10.04-9.70(m,1H),8.85-8.60(m,2H),8.19-8.07(m,1H),7.84-7.71(m,2H),7.57-6.98(m,6H),6.22-5.96(m,1H),3.33-3.22(m,1H),1.56-1.44(m,12H),1.22-0.99(m,9H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ
176.7,171.7,153.5,148.1,138.2,136.4,136.3,133.8,129.2,128.7,127.7,127.4,127.2,124.3,123.9,121.8,121.6,116.7,80.3,72.5,48.9,38.8,28.4,27.1,15.7；HRMS:calculated for C 29 H 36 N 3 O 5 [M+H + ]:506.2655；found:506.2664.
examples 9 to 10 were conducted to synthesize the compound (I) using different azodicarboxylic acid esters as starting materials.
Example 9
Intermediate compound I: preparation of 1- (2- ((ethoxycarbonyl) amino) phenyl) -3-oxy-3- (quinoline-8-amino) propyl pivalate
Adding 0.1mmol of 3-phenyl-N- (quinolin-8-yl) propionamide, 0.01mmol of palladium pivalate, 0.2mmol of diethyl azodicarboxylate, 0.15mmol of pivalic acid and 1mL of anhydrous toluene into a reaction bottle, sealing, heating to 110 ℃, reacting for 4 hours, cooling to room temperature, and purifying to obtain intermediate (I) with the yield of 48%.
The intermediate compound I is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ9.86(s,1H),8.79-8.70(m,2H),8.25(s,1H),8.15(dd,J＝1.6Hz,J＝8.0Hz,1H),7.77(d,J＝8.4Hz,1H),7.54-7.49(m,2H),7.46-7.43(m,2H),7.31(t,J＝7.6Hz,1H),7.14(t,J＝7.6Hz,1H),6.42(dd,J＝5.2Hz,J＝8.0Hz,1H),4.29-4.23(m,2H),3.39(dd,J＝8.4Hz,J＝15.6Hz,1H),3.03(dd,J＝5.6Hz,J＝15.2Hz,1H),1.35(t,J＝6.8Hz,3H),1.13(s,9H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ177.7,167.7,154.6,148.2,138.2,136.4,135.9,134.0,130.2,129.2,127.9,127.4,127.1,124.6,123.8,121.8,121.7,116.7,68.4,61.2,43.6,38.7,26.9,14.6；HRMS:calculated for C 26 H 30 N 3 O 5 [M+H + ]:464.2185；found:464.2180.
example 10
Intermediate compound I: preparation of 1- (2- ((benzyloxycarbonyl) amino) phenyl) -3-oxo-3- (quinoline-8-amino) propyl pivalate
Adding 0.1mmol of 3-phenyl-N- (quinolin-8-yl) propionamide, 0.01mmol of palladium pivalate, 0.2mmol of dibenzyl azodicarboxylate, 0.15mmol of pivalic acid and 1mL of anhydrous toluene into a reaction bottle, sealing, heating to 110 ℃, reacting for 4 hours, cooling to room temperature, and purifying to obtain an intermediate (I) with the yield of 41%.
The intermediate compound I is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ9.86(s,1H),8.78-8.71(m,2H),8.39(s,1H),8.15(dd,J＝1.6Hz,J＝8.4Hz,1H),7.79(d,J＝8.0Hz,1H),7.52-7.50(m,2H),7.48-7.44(m,3H),7.43-7.37(m,2H),7.36-7.30(m,3H),7.16(t,J＝7.6Hz,1H),6.43(dd,J＝5.2Hz,J＝8.0Hz,1H),5.27(s,2H),3.39(dd,J＝8.0Hz,J＝15.2Hz,1H),3.04(dd,J＝5.6Hz,J＝15.6Hz,1H),1.13(s,9H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ177.7,167.7,154.5,148.2,138.2,136.5,136.4,135.8,134.0,130.3,129.2,128.6,128.5,128.2,128.1,127.9,127.4,127.1,124.8,123.8,121.9,121.7,116.8,68.3,66.9,43.6,38.7,26.9；HRMS:calculated for C 31 H 32 N 3 O 5 [M+H + ]:526.2342；found:526.2349.
examples 11-12 are directed to the synthesis of compound (I) starting from different carboxylic acids.
Example 11
Intermediate compound I: preparation of 1- (2- ((tert-butoxycarbonyl) amino) -5-methoxyphenyl) -3-oxo-3- (quinolin-8-ylamino) propyl acetate
Adding 0.1mmol of 3- (3-methoxyphenyl) -N- (quinolin-8-yl) propionamide, 0.01mmol of palladium pivalate, 0.2mmol of di-tert-butyl azodicarboxylate, 0.15mmol of acetic acid and 1mL of anhydrous toluene into a reaction bottle, sealing, heating to 110 ℃ for reaction for 4 hours, cooling to room temperature, and purifying to obtain an intermediate (I) with the yield of 82%.
The intermediate compound I is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ9.90(s,1H),8.79-8.72(m,2H),8.15(d,J＝8.4Hz,1H),7.58-7.48(m,4H),7.46-7.43(m,1H),6.96(d,J＝2.8Hz,1H),6.85(dd,J＝2.8Hz,J＝8.8Hz,1H),6.41(dd,J＝4.8Hz,J＝8.8Hz,1H),3.79(s,3H),3.36(dd,J＝8.8Hz,J＝15.6Hz,1H),3.01(dd,J＝4.8Hz,J＝15.6Hz,1H),2.06(s,3H),1.53(s,9H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ170.6,167.7,156.9,154.4,148.2,138.2,136.4,134.1,132.8,128.8,127.9,127.4,126.7,121.8,121.7,116.7,114.3,112.5,80.1,68.2,55.5,43.4,28.4,21.1；HRMS:calculated for C 26 H 30 N 3 O 6 [M+H + ]:480.2135；found:480.2128.
example 12
Intermediate compound I: preparation of 1- (2- ((tert-butoxycarbonyl) amino) -5-methoxyphenyl) -3-oxo-3- (quinolin-8-ylamino) propylfuran-3-carboxylate
Adding 0.1mmol of 3- (3-methoxyphenyl) -N- (quinolin-8-yl) propionamide, 0.01mmol of palladium pivalate, 0.2mmol of di-tert-butyl azodicarboxylate, 0.15mmol of 3-furancarboxylic acid and 1mL of anhydrous toluene into a reaction bottle, sealing, heating to 110 ℃ for reaction for 4 hours, cooling to room temperature, and purifying to obtain intermediate (I) with the yield of 85%.
The intermediate compound I is:
1 H NMR(CDCl 3 ,400MHz,ppm):δ9.94(s,1H),8.73-8.71(m,2H),8.12(d,J＝8.4Hz,1H),8.06(s,1H),7.65-7.47(m,4H),7.44-7.41(m,1H),7.34(d,J＝2.0Hz,1H),7.02(d,J＝3.2Hz,1H),6.86(dd,J＝2.8Hz,J＝8.8Hz,1H),6.71(d,J＝2.0Hz,1H),6.57(dd,J＝4.8Hz,J＝8.8Hz,1H),3.78(s,3H),3.46(dd,J＝8.4Hz,J＝15.2Hz,1H),3.11(dd,J＝4.8Hz,J＝15.6Hz,1H),1.55(s,9H)； 13 C NMR(CDCl 3 ,100MHz,ppm)δ167.6,162.3,156.9,154.3,148.2,148.1,143.7,138.2,136.4,134.0,132.8,128.8,127.9,127.3,126.7,121.8,121.7,118.9,116.7,114.2,112.6,109.8,80.1,68.6,55.5,43.6,28.4；HRMS:calculated for C 29 H 30 N 3 O 7 [M+H + ]:532.2084；found:532.2080.
the embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make modifications and alterations without departing from the scope of the present invention.
Claims (7)
1. A synthetic method of a nitrogen-containing heterocyclic compound A is characterized in that an intermediate compound I is stirred for 0.5-2.5 h at normal temperature under the action of boron trifluoride diethyl etherate and dichloromethane, and is subjected to neutralization, extraction and drying to prepare an intermediate product, the intermediate product is further subjected to reaction for 12h at 80 ℃ in tetrahydrofuran, and column chromatography is performed to obtain the nitrogen-containing heterocyclic compound A, wherein the chemical structural formula of the nitrogen-containing heterocyclic compound A is as follows:
wherein the chemical structural formula of the intermediate compound I is as follows:
in the formula (I), the compound is shown in the specification,
R 1 、R 2 、R 3 selected from hydrogen, alkyl, cycloalkyl, methoxy, siloxy, amide, halogen, aryl with various substituents, heterocyclic radical or heterocyclic radical with various substituents;
R 4 selected from hydrogen, alkyl, aryl or substituted amino;
R 5 selected from hydrogen, alkyl, cycloalkyl, alkenyl, aryl or aryl with various stituents;
R 6 selected from the group consisting of formate groups.
2. The method for synthesizing the nitrogen-containing heterocyclic compound A according to claim 1, characterized in that the intermediate compound I is synthesized by taking amide, azodicarboxylate and carboxylic acid as raw materials and performing direct carbon-hydrogen bond bifunctional synthesis under the action of a catalyst, wherein the catalyst is palladium pivalate;
the chemical structural formula of the amide is as follows:
in the formula: r 1 、R 2 、R 3 Selected from hydrogen, alkyl, cycloalkyl, methoxy, siloxy, amide, halogen, aryl with various substituents, heterocyclic radical or heterocyclic radical with various substituents;
R 4 selected from hydrogen, alkyl, aryl or substituted amino;
the carboxylic acid has the formula R 5 -COOH, wherein: r 5 Selected from hydrogen, alkyl, cycloalkyl, alkenyl, aryl or heteroaryl with various substituents;
the chemical structural formula of the azodicarbonic acid ester is as follows: r 6 -N＝N-R 6 In the formula: r 6 Is a formate group.
3. The method for synthesizing the nitrogen-containing heterocyclic compound A according to claim 2, characterized in that the azodicarboxylic acid ester is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate.
4. The method for synthesizing a nitrogen-containing heterocyclic compound A according to claim 2,
for the specific preparation of intermediate compound I: amide, carboxylic acid and azodicarbonic acid ester are subjected to direct carbon-hydrogen bond bifunctional reaction under the action of a catalyst and a solvent A to synthesize an intermediate compound I.
5. The method for synthesizing a nitrogen-containing heterocyclic compound according to claim 4,
the solvent A is 2-methyl-2-butanol, toluene, tetrahydrofuran or dioxane;
the molar ratio of the catalyst to the amide is 5-10:100, the molar ratio of the amide to the carboxylic acid to the azodicarboxylate is 1:1-2:1-2, the temperature of the bifunctional reaction is 80-150 ℃, and the reaction time is 4-48 h.
6. A synthetic method of a nitrogen-containing heterocyclic compound B is characterized in that an intermediate compound I is stirred for 1-4 hours at 70 ℃ under the action of 4-dimethylaminopyridine, di-tert-butyl dicarbonate and acetonitrile, the mixture is washed, extracted and dried, an obtained crude product is further dissolved in alcohol, corresponding sodium alkoxide is added, the reaction is carried out for 12 hours at the temperature of 100 ℃ and 120 ℃, an intermediate product is obtained through washing, extraction, drying and column chromatography, the intermediate product is refluxed for 2-8 hours in ferrous chloride, polymethylhydrosiloxane and ethanol, a solvent is removed, and an intermediate compound II is obtained through column chromatography, wherein the chemical structural formula of the intermediate compound II is as follows:
stirring the intermediate compound II for 0.5-2.5 h at normal temperature under the action of boron trifluoride diethyl ether and dichloromethane, neutralizing, extracting and drying to obtain an intermediate product, further reacting in toluene at 100 ℃ for 12-24h under the action of N, N-dimethylformamide dimethyl acetal, filtering, washing and drying to obtain a nitrogen-containing heterocyclic compound B, wherein the chemical structural formula of the nitrogen-containing heterocyclic compound B is as follows:
wherein R is 7 Is a formate group;
wherein, the chemical structural formula of the intermediate compound I is as follows:
in the formula (I), the compound is shown in the specification,
R 1 、R 2 、R 3 selected from hydrogen, alkyl, cycloalkyl, methoxy, siloxy, amide, halogen, aryl with various substituents, heterocyclic radical or heterocyclic radical with various substituents;
R 4 selected from hydrogen, alkyl, aryl or substituted amino;
R 5 selected from hydrogen, alkyl, cycloalkyl, alkenyl, aryl or aryl with various stituents;
R 6 selected from the group consisting of formate groups.
7. A synthetic method of a nitrogen-containing heterocyclic compound C is characterized in that an intermediate compound I is stirred for 1-4 hours at 70 ℃ under the action of 4-dimethylaminopyridine, di-tert-butyl dicarbonate and acetonitrile, the mixture is washed, extracted and dried, an obtained crude product is further dissolved in alcohol, corresponding sodium alkoxide is added, the reaction is carried out for 12 hours at the temperature of 100 ℃ and 120 ℃, an intermediate product is obtained through washing, extraction, drying and column chromatography, the intermediate product is refluxed for 2-8 hours in ferrous chloride, polymethylhydrosiloxane and ethanol, a solvent is removed, and an intermediate compound II is obtained through column chromatography, wherein the chemical structural formula of the intermediate compound II is as follows:
and stirring the intermediate compound II for 2-5 h at normal temperature under the action of ceric ammonium nitrate, 2,6, 6-tetramethylpiperidine oxide and acetonitrile, and filtering and carrying out column chromatography to obtain a nitrogen-containing heterocyclic compound C, wherein the nitrogen-containing heterocyclic compound C has a chemical structural formula as follows:
wherein R is 7 Is a formate group;
wherein the chemical structural formula of the intermediate compound I is as follows:
in the formula (I), the compound is shown in the specification,
R 1 、R 2 、R 3 selected from hydrogen, alkyl, cycloalkyl, methoxy, siloxy, amide, halogen, aryl with various substituents, heterocyclic radical or heterocyclic radical with various substituents;
R 4 selected from hydrogen, alkyl, aryl or substituted amino;
R 5 selected from hydrogen, alkyl, cycloalkyl, alkenyl, aryl or aryl with various stituents;
R 6 selected from the group consisting of formate groups.
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