CN108276403B - Method for synthesizing carbopol compounds - Google Patents
Method for synthesizing carbopol compounds Download PDFInfo
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Abstract
The invention discloses a synthesis method of a carbopol compound, which comprises the steps of carrying out coupling and reduction reaction on a pyridine derivative, o-nitroaniline and a derivative thereof, or directly carrying out coupling reaction with benzotriazole to convert the pyridine derivative into a diazotized triazole intermediate, and finally obtaining substituted carbopol under the action of a reagent from the intermediate obtained by the reaction. The process optimizes reaction raw materials, reaction reagents and conditions on the basis of the improved Graebe-Ullmann method, and has the characteristics of enhanced target product selectivity, shortened reaction time, reduced reaction temperature, less impurities, high yield and the like. Meanwhile, the method is suitable for synthesizing substituted alpha-carbopol and beta-carbopol, and provides a simple and reliable selection scheme for obtaining and utilizing the compounds.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a carbopol compound.
Background
Carbopoline (carboline), also known as carboline or diazafluorene, is a heterocyclic compound in which the pyridine ring is fused with the pyrrole ring of indole. At present, there are 4 isomers, wherein 2-carboline is also called alpha-carboline and alpha-carbopol forest, 3-carboline is also called beta-carbopol forest, and natural products thereof have a series of biological activities such as anti-inflammatory, bactericidal, cytotoxic, anticancer characteristic activity, central nervous system and cardiovascular system activity and the like.
Several synthetic routes to alpha-carbopol have been reported. In 1924 Robinson et al, the first report of improved Graebe-Ullmann method for synthesizing alpha-carbopol, namely, o-phenylenediamine and 2-chloropyridine are heated to 140 ℃ in ethanol for coupling, then the o-phenylenediamine and the 2-chloropyridine are reacted with nitrous acid under the acidic environment provided by hydrochloric acid to be converted into diazotized triazole intermediate, and finally the diazotized triazole intermediate is heated to 200 ℃ under the action of phosphoric acid to release N2And alpha-carbopol is formed (see scheme I), and the method is used for synthesizing alpha-carbopol for many times at present. However, the final cyclization to alpha-carbopol by the modified Graebe-Ullmann method is carried out at 200 ℃, the reaction conditions are severe, and the reaction yield of the step is only 35%.
In addition, since the modified Graebe-Ullmann method is disclosed, a series of synthetic strategies for alpha-carbopol have been gradually published, such as the Diels-Alder method, the transition metal catalysis method, and the like. The Diels-Alder method is a powerful aromatic heterocyclic system and a synthesis tool for the aromatic system to form carbon-carbon bonds, which has been incorporated as part of the strategy for the synthesis of alpha-carbopol; taking the synthesis of alpha-carbopol containing substituent groups by Molina et al as an example, the method takes carbodiimide as diene and diene to synthesize alpha-carbopol compounds, and the alpha-carbopol compounds are subjected to series intramolecular hetero Dielse-Alder addition/aromatization process (see a synthesis route II); this method has a few synthesis steps, but the reagents are expensive and the preparation of starting materials is difficult. The transition metal and the salt thereof have catalytic action on most coupling and cyclization reactions, and can be used for synthesizing alpha-carbopol by catalyzing the formation of carbon-carbon bonds and carbon-nitrogen bonds, namely a transition metal catalysis method; taking the synthesis of alpha-carbopol compound by Achab et al as an example, the synthesis scheme (see synthesis scheme III) of the method has the advantages of high yield, expensive raw materials and catalysts, large change of the reaction yield in the first step and difficult control of the reaction environment.
The synthesis, activity evaluation and molecular docking research of alpha-carboline GSK-3 beta inhibitors (Acta Chim. Sinica 2012,70,1974-1978) of Wangyi et al disclose that alpha-carboline compounds have various biological activities, and the synthesis method reported in the article is as follows: benzotriazole and 2-chloropyridine are used as raw materials, and are cyclized under the catalysis of polyphosphoric acid (PPA) through an improved Graebe-Ullmann reaction to obtain alpha-carboline; then adopting Buchwald-Hartwig coupling reaction, Pd2(dba)3As a catalyst, X-Phos is used as a ligand, and 9 4-substituted alpha-carboline amine derivatives are synthesized by adopting a weak base K2CO 3/tert-butyl alcohol base/solvent combination or a t-BuOK/toluene base/solvent combination. The synthesis method comprises the steps of firstly, synthesizing the alpha-carboline and the alpha-carboline amine derivative in a segmented manner, namely, firstly obtaining the alpha-carboline, then synthesizing the key intermediate 4-chloro-alpha-carboline, and then coupling to obtain the derivative, and has the advantages of complex operation, expensive raw materials, low yield, no environmental protection and longer whole reaction process.
Thus, although the current schemes for α -carbopol synthesis are numerous, there are some drawbacks such as low yield, expensive reagents, difficult preparation or availability of starting materials, or lack of flexibility, harsh reaction conditions, etc. The beta-carbopol is less in synthesis method, the target compound is generated by mainly using the 1-pyridyl benzotriazole intermediate under the action of ultraviolet rays or zinc chloride, the operation is difficult, the toxicity is high, and the large-scale synthesis is inconvenient. The synthesis method which has strong flexibility, high selectivity, low raw material cost, easy obtainment and mild reaction conditions is urgently needed, solves the existing problems and ensures that the synthesis of the carbopol compound is suitable for industrial mass production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for synthesizing a carbopol compound.
Specifically, the invention is realized by the following technical scheme:
a synthetic method of a carbopol compound comprises the following synthetic route:
R1、R2independently a mono-or polysubstituted proton, halogen, a linear or cyclic alkyl of different length, a phenyl or aralkyl group substituted with different substituents, preferably R1Is a proton, R2Is methyl; x is independently a halogen atom such as F, Br, I, etc., preferably X is a Br atom.
Wherein, the synthesis of the substituted alpha-carbopol is divided into four steps, and the route and the preparation process are as follows:
first step, synthesis of compound III:
the catalyst is Ni, Pd, Cu or CuI, preferably catalyzed with Pd/C palladium;
the base is selected from inorganic bases: na (Na)2CO3、K2CO3、Cs2CO3、NaOH、KOH、NaH、KH、NaNH2Or an organic base: methylamine, ethylamine, diethylamine, triethylamine, N-diisopropylethylamine, NaOCH3、KOCH3t-BuOK, t-BuONa, LDA, preferably t-BuOK;
second step, synthesis of compound IV:
the reducing agent is iron powder-amine chloride, sodium sulfide, palladium carbon-hydrogen, hydroiodic acid or hydrazine hydrate, and the iron powder-amine chloride is preferably used.
Thirdly, synthesizing a compound V:
the HX is an inorganic acid selected from hydrofluoric acid, hydrobromic acid, hydroiodic acid, hypoiodic acid, hypochlorous acid, hypobromic acid, hypophosphorous acid, hyposulfuric acid, iodic acid, fluoroboric acid, perchloric acid, permanganic acid, ferric acid, periodic acid, perbromic acid, sulfuric acid, phosphoric acid or nitric acid, preferably sulfuric acid is used.
Step four, synthesis of compound VI:
the acid is selected from phosphoric acid, pyrophosphoric acid, sulfuric acid, preferably pyrophosphoric acid is used.
The process steps of the synthetic route are as follows:
(1) coupling reaction: dissolving o-nitroaniline or derivatives thereof and pyridine derivatives in a reaction solvent, adding a catalyst and an acid scavenger, reacting the mixture at the temperature of 100-140 ℃ for 3-30 hours, cooling, adding water for dissolving, extracting by using an organic solvent, washing by using water, drying, concentrating and purifying to obtain an intermediate compound III;
(2) reduction reaction: dissolving the intermediate compound III in a reaction solvent, adding a reducing agent, reacting the mixture at 60-100 ℃ for 2-6 hours, cooling, adding water for dissolution, adjusting pH, filtering, extracting, drying, concentrating and purifying to obtain an intermediate compound IV;
(3) diazotization reaction: dissolving an intermediate compound IV in a reaction solvent at the temperature of-10-0 ℃, adding sodium nitrite and inorganic acid, reacting for 3-8 hours, adding water for dissolving, filtering, extracting, drying, concentrating and purifying to obtain an intermediate compound V;
(4) cyclization reaction: at the temperature of 100 ℃ and 180 ℃, acid is placed in a reactor, the compound V is added, the reaction is carried out for 0.5 to 5 hours, water is added for dissolution, and the target compound VI is obtained after filtration, extraction, drying, concentration and purification.
Preferably, in the synthesis process, the reaction solvent in step (1) is any one of DMF, DMSO and toluene; the molar ratio of the dosage of the catalyst to the o-nitroaniline or the derivative thereof is 1: 2-8; the molar ratio of the dosage of the acid scavenger, namely the inorganic base or the organic base to the o-nitroaniline or the derivatives thereof is 0.2-2.
Preferably, in the foregoing synthesis process, the reaction solvent in step (2) is any one of water, ethanol, methanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran, DMF, and DMSO; the molar ratio of the dosage of the reducing agent to the intermediate compound III is 3-8: 1.
Preferably, in the aforementioned synthesis process, the reaction solvent in step (3) is methanol, ethanol, propanol or acetonitrile;
preferably, in the aforementioned synthesis process, the molar ratio of the acid used in step (4) to the volume (mL) of intermediate compound V is 3-6: 1.
Wherein, the synthesis of the substituted beta-carbopol is divided into two steps, and the route and the preparation process are as follows:
step one, carbon-nitrogen coupling reaction:
the acid scavenger is potassium carbonate, cesium carbonate, sodium carbonate, calcium carbonate, sodium phosphate, triethanolamine, triethylamine, pyridine, preferably potassium carbonate.
Step two, cyclization reaction:
the reagent is pyrophosphoric acid, polyphosphoric acid, or zinc chloride, preferably zinc chloride.
The process steps of the synthetic route are as follows:
(1) carbon-nitrogen coupling reaction: mixing and dissolving a compound VI and a compound VIII in a reaction solvent at the temperature of 100 ℃ and 160 ℃, adding an acid scavenger, reacting for 20-40 hours, cooling, adding water for dissolving, extracting, backwashing with water, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain an intermediate compound IX;
(2) cyclization reaction: at the temperature of 150 ℃ and 350 ℃, the reagent is placed in a reactor, the compound IX is added, the reaction is carried out for 2 to 4 hours, the water is added for dissolution, the pH value is adjusted, and then the filtration, extraction, drying, concentration and purification are carried out, thus obtaining the target compound X.
Preferably, in the aforementioned synthesis process, the reaction solvent in step (1) is DMSO, DMF, DMAC, preferably DMSO;
preferably, in the aforementioned synthesis process, the extraction solvent is EtOAc.
Further, 2-methyl-3-bromo-9H-pyrido [2,3-b ] indole, a specific compound in the alpha-carbopol class, was prepared by the following steps:
(1) coupling reaction: dissolving o-nitroaniline and 2, 5-dibromo-6-methylpyridine in a reaction solvent DMF, adding a catalyst 5% Pd/C and an acid scavenger t-BuOK, stirring at 120 ℃ for reaction for 5 hours, cooling, adding water for dissolution, extracting with ethyl acetate (EtOAc), washing the extract with water and saturated salt water in turn, and adding anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain a reaction intermediate compound 2- (2-nitrophenylamino) -5-bromo-6-methylpyridine;
(2) reduction reaction: dissolving 2- (2-nitrophenylamino) -5-bromo-6-methylpyridine in ethyl acetate (EtOAc), adding reducing agent iron powder-amine chloride, stirring and refluxing the mixture at 80 deg.C for 3 hr, cooling, dissolving in water, dissolving with K2CO3Adjusting pH to 9, filtering, extracting the filtrate with ethyl acetate (EtOAc), and extracting with anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain intermediate compound 2- (2-amino group)Phenylamino) -5-bromo-6-methylpyridine;
(3) diazotization reaction: dissolving 2- (2-aminophenylamino) -5-bromo-6-methylpyridine in EtOH, adding NaNO2，H2SO4Stirring for reaction for 3 hr, dissolving in water, and adding K2CO3Adjusting pH to 9, filtering, extracting the filtrate with ethyl acetate (EtOAc), and extracting with anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain intermediate compound 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole;
(4) cyclization reaction: putting pyrophosphoric acid into a reactor at 160 ℃, adding 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole, stirring for reacting for 2 hours, heating to 180 ℃ for reacting for 3 hours, adding water for dissolving, and dissolving with K2CO3Adjusting pH to 9, filtering, extracting the filtrate with ethyl acetate (EtOAc), and extracting with anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain the target compound 2-methyl-3-bromo-9H-pyridine [2,3-b ]]Indole.
In the step (1), the mass ratio of the 2, 5-dibromo-6-methylpyridine to the o-nitroaniline is 1-3: 1; the volume mass ratio of the solvent DMF to the o-nitroaniline is 15-18: 1; the molar ratio of 5 percent Pd/C to o-nitroaniline is 0.2-0.5: 1; the molar ratio of the t-BuOK to the o-nitroaniline is 2-4: 1.
In the step (2), the volume (mL) molar ratio of the EtOAc to the 5-bromo-o-nitroanilino-6-methylpyridine is 20-40: 1; the molar ratio of the iron powder-amine chloride (1:3) to the 5-bromo-o-nitroanilino-6-methylpyridine is 4.5-6: 1.
In the step (3), the volume (mL) molar ratio of the solvent EtOH to the 5-bromo-o-aminophenylamino-6-methylpyridine is 20-40: 1; NaNO2The molar ratio of the compound to 5-bromo-o-aminophenylamino-6-methylpyridine is 3: 1; concentrated H2SO4The volume-mass ratio of the compound to the 5-bromo-o-aminophenylamino-6-methylpyridine is 1: 1.
In the step (4), the volume (mL) molar ratio of the pyrophosphoric acid to the 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole is 3-6: 1.
Further, 1-methyl-3-bromo-9H-pyrido [3,4-b ] indole, a specific compound in the beta-carbopol class, is prepared by the following steps:
(1) mixing 2, 5-dibromo-6-methylpyridine and benzotriazole at 150 ℃, dissolving in DMSO, and adding K2CO3Reacting at 100 ℃ for 24H, standing, cooling, adding water for dissolving, extracting with EtOAc, backwashing with water, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain an intermediate product 1- (6-bromine 2-methyl 3-pyridyl) -1H-benzotriazole;
(2) putting zinc chloride into a reaction bottle, reacting 1- (6-bromine 2-methyl 3-pyridyl) -1H-benzotriazole in the zinc chloride for 3H at 300 ℃, adding 50mL of water for dissolving after the reaction is finished, and dissolving with K2CO3Adjusting pH to 9, filtering, extracting the filtrate with EtOAc and extracting with anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain the target compound 1-methyl-3-bromo-9H-pyridine [3,4-b ]]Indole.
In the step (1), the molar ratio of the 2, 5-dibromo-6-methylpyridine to the benzotriazole is 1:2, K2CO3The dosage of the 2, 5-dibromo-6-methylpyridine is 6.5 to 7 times of the molar weight of the 2, 5-dibromo-6-methylpyridine;
in the step (2), the mass ratio of the zinc chloride to the intermediate product 1- (6-bromo-2-methyl-3-pyridyl) -1H-benzotriazole is 80: 1.
Compared with the prior art, in the process of synthesizing the alpha-carbopol compound, the o-nitroaniline or the derivative thereof is used as the starting material, the pyridine derivative is firstly synthesized into the intermediate compound containing the o-nitrobenzene, the reduction reaction is carried out under the action of the reducing agent, the intermediate compound is reacted with the nitrous acid in the presence of the inorganic acid to be converted into the diazotized triazole intermediate, and finally the intermediate obtained by the reaction is subjected to the action of pyrophosphoric acid or ferric chloride to obtain the target product substituted alpha-carbopol.
In the process of synthesizing the beta-carbopol compounds, pyridine derivatives and benzotriazole are taken as raw materials, and carbon-nitrogen coupling reaction is carried out in the presence of acid removing agents, such as potassium carbonate, cesium carbonate, sodium carbonate, calcium carbonate, sodium phosphate, triethanolamine, triethylamine, pyridine and the like; then cyclizing under the action of pyrophosphoric acid, polyphosphoric acid, zinc chloride and the like to obtain the target product.
Therefore, the invention has the following beneficial effects:
1. the invention can obtain alpha-carbopol and beta-carbopol containing different substituents by using the substituted pyridine compound, wherein part of the existing documents adopts quinoline rings, only tetracyclic compounds can be obtained, and the two are different carbo-quinoline rings.
2. In the synthesis process of the alpha-carbopol compounds, on the basis of an improved Graebe-Ullmann method, the o-nitroaniline or the derivatives thereof are used for replacing unstable o-phenylenediamine so as to facilitate the selective reaction of the substituent on the benzene ring in the later period, avoid the situation that the o-phenylenediamine containing the substituent generates isomers in the first step of reaction process, and enhance the selectivity of the target product of the substituted benzene ring. Meanwhile, a catalyst and an acid scavenger are added in the Ullmann C-N coupling reaction to reduce the reaction temperature, shorten the reaction time and improve the yield. Since the coupling reaction generates acidic HX, an alkaline substance is added as an acid scavenger to neutralize the acid generated by the coupling reaction, so that the reaction is carried out in the positive reaction direction.
3. In the synthesis process of the alpha-carbopol compound, a reductive amination process of nitro on a benzene ring is added, the reaction can be carried out at the temperature of 80-100 ℃ by using a reducing agent, the reaction condition is mild, the reaction time is only 1-2 hours, and the yield is improved by more than 90%. In the diazotization reaction process, the reaction temperature of the method is about 0 ℃, the reaction can be satisfied by ice water bath, the diazotization reaction temperature in the existing improved Graebe-Ullmann method is 10 ℃, and the temperature is required to be controlled by a corresponding device. In the reaction of cyclization to form alpha-carbopol, the invention replaces phosphoric acid with pyrophosphoric acid to reduce the reaction temperature and increase the yield to about 30 percent to 76 percent.
4. Gradient heating is used in the process of synthesizing the carboline ring, namely, the reaction is carried out at 160 ℃, when no bubble is generated in the reaction, the temperature is raised to 180 ℃, and the yield of the link is generally raised to more than 50%.
5. Meanwhile, the invention also uses iron chloride to cyclize to form beta-carbopol, thereby avoiding using zinc chloride with high toxicity.
In conclusion, the method optimizes reaction raw materials, reagents and condition parameters of each step in the synthesis process, uses raw materials which are low in cost and easy to obtain, is more environment-friendly and adapts to the requirements of ecological development; the reaction conditions are controlled well in the early stage, and the occurrence of isomers is avoided. From the whole view, the method has the advantages of strong flexibility, low raw material cost, mild reaction conditions, high yield, less impurities, simple and convenient operation, environmental protection and the like, can be used for large-scale production, and is easy for industrial production of the carbopol compound.
Detailed Description
Example 1: preparation of 2-methyl-3-bromo-9H-pyrido [2,3-b ] indole
The synthesis process comprises the following steps: (1) the compound 2, 5-dibromo-6 methylpyridine (2.70g,10.76mmol) and o-nitroaniline (1.78g, 12.91mmol) were dissolved in DMF (30mL), t-BuOK (3.62g, 32.28mmol), 5% Pd/C (474.68mg, 2.96mmol) were added, the mixture was evacuated and protected with nitrogen, the mixture was stirred at 120 ℃ for 5h, cooled, dissolved in 20mL of water, extracted with EtOAc, the extracts were washed with water and saturated brine, and anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain a product 5-bromo-o-nitroanilino-6-methylpyridine with a yield of 66%;
(2) 5-bromo-o-nitroanilino-6-methylpyridine (2.41g, 6.8mmol) was dissolved in EtOAc (20mL) and SnCl was added2(6.46g, 34.08mmol), the mixture is stirred at 80 ℃ under reflux for 3h, cooled, dissolved in 20mL of water and dissolved with K2CO3Adjusting pH to 9, filtering, extracting the filtrate with EtOAc and extracting with anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain 5-bromo-o-aminophenylamino-6-methylpyridine with a yield of 92.6%;
(3) the compound 5-bromo-o-aminophenylamino-6-methylpyridine (2.01g, 7.2mmol) was dissolved in EtOH (20mL) at 0 deg.C, NaNO was added2(1.49g, 21.6mmol) and concentrated sulfuric acid (2mL) are stirred for reaction for 3h, and 20mL of water is added for dissolving, and K is used2CO3Adjusting pH to 9, filtering, extracting the filtrate with EtOAc and extracting with anhydrous Na2SO4Drying, concentrating under reduced pressureCondensing, purifying the residue by silica gel column chromatography to obtain a product 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole with the yield of 97.3%;
(4) taking pyrophosphoric acid (80mL) at 160 ℃, putting the pyrophosphoric acid (2.03g, 7.0mmol) in a reaction bottle, stirring for reacting for 2h, raising the temperature to 180 ℃ after no bubbles exist in the reaction, reacting for 3h, adding 50mL of water for dissolving, and dissolving with K2CO3Adjusting pH to 9, filtering, extracting the filtrate with EtOAc and extracting with anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain alpha-carbopol compound 2-methyl-3-bromo-9H-pyridine [2,3-b]Indole, yield 62%.
Examples 1 to 1
In the step (1), the mass ratio of 2, 5-dibromo-6 methylpyridine to o-nitroaniline is selected to be 1: 1. 2:1, 3: 1; the volume mass ratio of the DMF solvent to the o-nitroaniline is 15: 1. 16:1, 17:1, 18: 1; the molar ratio of 5% Pd/C to o-nitroaniline is 0.2: 1. 0.3:1, 0.4:1, 0.5: 1; the molar ratio of the t-BuOK to the o-nitroaniline is 2: 1. 3:1 and 4: 1. The product 5-bromo-o-nitroanilino-6-methylpyridine is obtained, and the average yield is 64.8%; but selecting the molar ratio of the acid scavenger t-BuOK to the o-nitroaniline as 1:1, the average yield of the obtained product is 42.5%, which is not ideal.
Examples 1 to 2
In the step (2), the volume (mL) molar ratio of EtOAc to 5-bromo-o-nitroanilino-6-methylpyridine is selected to be 20:1, 30:1 and 40: 1; the molar ratio of the iron powder-amine chloride (1:3) to the 5-bromo-o-nitroanilino-6-methylpyridine is 4.5:1, 5:1, 5.5:1, and 6: 1. The average yield of the obtained product 5-bromo-o-aminophenylamino-6-methylpyridine is over 90 percent.
Examples 1 to 3
In the step (3), the volume (mL) molar ratio of the solvent EtOH to the 5-bromo-o-aminophenylamino-6-methylpyridine is 20:1, 30:1 and 40:1, and the average yield of the product 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole is more than 95%.
Examples 1 to 4
In the step (4), the volume (mL) molar ratio of pyrophosphoric acid to 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole is selected to be 3:1, 4:1, 5:1 and 6:1, and the average yield of the target compound is 61-65%.
Examples 1 to 5
The steps (1) - (3) are the same as example 1, wherein the reaction temperature in step (4) is not increased to 180 ℃ after 2 hours of reaction, i.e. the reaction is maintained at 160 ℃ for 5 hours, and the rest is the same, so that the yield of the target compound is 51.7%, which is not ideal.
Examples 1 to 6
The steps (1) - (3) are the same as example 1, wherein the reaction temperature in step (4) is selected from (i) 140 ℃ for 2 hours, then raising the temperature to 180 ℃ for 3 hours, then raising the temperature to 200 ℃ for 3 hours after 2 hours, then raising the temperature to 180 ℃ for 2 hours after 3 hours, and then obtaining the target compounds with the same yield of 53.5%, 57.2% and 55.3% respectively, which is not ideal.
Example 2
The reaction temperature in the step (1) is 100 ℃, the reaction time is 10h, the reaction solvent is DMSO, CuI is a catalyst, and t-BuONa is an acid scavenger, so that the yield of the 5-bromo-o-nitroanilino-6-methylpyridine is 64.7%.
The reaction temperature of the step (2) is 100 ℃, the reaction time is 2 hours, the reaction solvent is tetrahydrofuran, and the iron powder-amine chloride is a reducing agent, so that the yield of the 5-bromo-o-aminophenylamino-6-methylpyridine is 91%.
The reaction temperature in the step (3) is-10 ℃, the reaction time is 3 hours, the solvent is propanol, the concentrated sulfuric acid is changed into sulfenic acid, and the yield of the 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole is 96.1 percent.
The reaction temperature of the step (4) is 160 ℃ and 180 ℃, the reaction time is 3H and 1H, and the yield of the 2-methyl-3-bromo-9H-pyridine [2,3-b ] indole is 65 percent by changing the pyrophosphoric acid into sulfuric acid.
The other steps are the same as in example 1.
Example 3
The reaction temperature in the step (1) is 140 ℃, the reaction time is 3h, the reaction solvent is toluene, Ni is a catalyst, and t-BuONa is an acid scavenger, so that the yield of the 5-bromo-o-nitroanilino-6-methylpyridine is 62.8%.
The reaction temperature in the step (2) is 60 ℃, the reaction time is 6 hours, the reaction solvent is acetone, the sodium carbide is a reducing agent, and the yield of the 5-bromo-o-aminophenylamino-6-methylpyridine is 91%.
The reaction temperature in the step (3) is-10 ℃, the reaction time is 3 hours, the solvent is methanol, and the concentrated sulfuric acid is changed into concentrated hydrochloric acid, so that the yield of the 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole is 96.1 percent.
The reaction temperature of the step (4) is 150 ℃, the reaction time is 5 hours, and the yield of the 2-methyl-3-bromo-9H-pyridine [2,3-b ] indole is 64.8 percent.
Example 4
The reaction temperature in the step (1) is 130 ℃, the reaction time is 8h, the reaction solvent is DMF, Pd is a catalyst, NaH is an acid scavenger, and the yield of the 5-bromo-o-nitroanilino-6-methylpyridine is 63.4%.
The reaction temperature in the step (2) is 80 ℃, the reaction time is 4 hours, the reaction solvent is acetonitrile, palladium carbon-hydrogen is a reducing agent, and the yield of the 5-bromine-o-aminophenylamino-6-methylpyridine is 92.8 percent.
And (3) reacting at-5 ℃ for 5H in the presence of ethanol as a solvent and hydrobromic acid as concentrated sulfuric acid to obtain the 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole with a yield of 97.7%.
The reaction temperature in the step (4) is 150 ℃, the reaction time is 1H and 2H, and the yield of the 2-methyl-3-bromo-9H-pyridine [2,3-b ] indole is 59.3 percent by changing the pyrophosphoric acid into phosphoric acid.
Example 5
The reaction temperature in the step (1) is 110 ℃, the reaction time is 7 hours, the reaction solvent is DMSOF, CuI is a catalyst, KOBu-t is an acid scavenger, and the yield of the 5-bromo-o-nitroanilino-6-methylpyridine is 66.3%.
The reaction temperature in the step (2) is 90 ℃, the reaction time is 3.5 hours, the reaction solvent is methanol, hydroiodic acid is a reducing agent, and the yield of the 5-bromo-o-aminophenylamino-6-methylpyridine is 93.2%.
The reaction temperature in the step (3) is-2 ℃, the reaction time is 6H, the solvent is methanol, and the concentrated sulfuric acid is changed into ferric acid, so that the yield of the 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole is 96.8%.
The reaction temperature in the step (4) is 160 ℃, the reaction time is 45min and 90min, and the yield of the 2-methyl-3-bromo-9H-pyridine [2,3-b ] indole is 66.4%.
Example 6
The reaction temperature in the step (1) is 120 ℃, the reaction time is 10 hours, and the rest is not changed, so that the yield of the 5-bromo-o-nitroanilino-6-methylpyridine is 64%.
The reaction temperature in the step (2) is 90 ℃, the reaction time is 3 hours, the reaction solvent is DMF, sodium sulfide is reducing agent, and the yield of the 5-bromo-o-aminophenylamino-6-methylpyridine is 92.5%.
The reaction temperature in the step (3) is-8 ℃, the reaction time is 3 hours, the solvent is propanol, concentrated HCl is changed into concentrated sulfuric acid, and the yield of the 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole is 96.4%.
The reaction temperature in the step (4) is 150 ℃, 180 ℃, the reaction time is 1.5H and 3H, and pyrophosphoric acid is changed into pyrosulfuric acid, so that the yield of the 2-methyl-3-bromo-9H-pyridine [2,3-b ] indole is 67.5%.
In addition, the invention has carried on the limited collocation to the choice of reaction condition, solvent and raw materials described, the result shows that the yield range to obtain alpha-carbopol compound is 53-70%.
Example 7 preparation of 1-methyl-3-bromo-9H-pyrido [3,4-b ] indole
The synthesis process comprises the following steps: (1) 2, 5-dibromo-6-methylpyridine (3.0g, 11.96mmol) and benzotriazole (2.85g, 23.91mmol) were mixed and dissolved in DMSO (100mL) at 150 ℃, and K was added2CO3(11.26g,81.47mmol), reacting at 100 ℃ for 24H, standing, cooling, adding water for dissolving, extracting with EtOAc, backwashing with water, concentrating under reduced pressure, purifying the residue by silica gel column chromatography to obtain a product 1- (6-bromo-2-methyl-3-pyridyl) -1H-benzotriazole with a yield of 55.1%;
(2) putting zinc chloride (80g) into a reaction bottle, reacting a compound 1- (6-bromo-2-methyl-3-pyridyl) -1H-benzotriazole (1.02g, 3.5mmol) in the zinc chloride for 3H at 300 ℃, adding 50mL of water for dissolving after the reaction is finished, and dissolving with K2CO3Adjusting pH to 9, filtering, extracting the filtrate with EtOAc and extracting with anhydrous Na2SO4Drying, concentrating under reduced pressure, and collecting the residue silica gelPurifying by column chromatography to obtain 1-methyl-3-bromo-9H-pyridine [3,4-b ]]Indole, yield 28%.
Example 7-1
In the step (1), K is selected respectively2CO3The dosage of the 1- (6-bromo-2-methyl-3-pyridyl) -1H-benzotriazole is 6.5 times and 7 times of the molar weight of the 2, 5-dibromo-6-methylpyridine, and the yield of the 1- (6-bromo-2-methyl-3-pyridyl) -1H-benzotriazole is 54.8 percent and 55.7 percent.
Example 8
The reaction temperature in the step (1) is 130 ℃, the reaction time is 30H, the reaction solvent is DMF, sodium carbonate is an acid scavenger, and the yield of the 1-methyl-3-bromine-9H-pyridine [3,4-b ] indole is 64.7%.
The reaction temperature in the step (2) is 250 ℃, the reaction time is 4 hours, the reaction reagent is pyrophosphoric acid, and the yield of the 1-methyl-3-bromo-9H-pyridine [3,4-b ] indole is 27.3%.
The other steps were the same as in example 7.
Example 9
The reaction temperature in the step (1) is 150 ℃, the reaction time is 20 hours, the reaction solvent is DMAC, calcium carbonate is used as an acid scavenger, and the yield of the 1-methyl-3-bromo-9H-pyridine [3,4-b ] indole is 62.3%.
The reaction temperature in the step (2) is 250 ℃, the reaction time is 4 hours, the reaction reagent is polyphosphoric acid, and the yield of the 1-methyl-3-bromine-9H-pyridine [3,4-b ] indole is 26.8%.
The other steps were the same as in example 7.
Example 10
The reaction temperature in the step (1) is 100 ℃, the reaction time is 28H, the reaction solvent is DMSO, triethanolamine is used as an acid scavenger, and the yield of the 1-methyl-3-bromo-9H-pyridine [3,4-b ] indole is 61.73%.
The reaction temperature in the step (2) is 350 ℃, the reaction time is 2 hours, the reaction reagent is zinc chloride, and the yield of the 1-methyl-3-bromine-9H-pyridine [3,4-b ] indole is 25.4%.
The other steps were the same as in example 7.
Comparative test example 1: preparation of intermediate 5-bromo-o-nitroanilino-6-methylpyridine
The compound o-nitroaniline (1.00g, 3.99mmol) was dissolved in t-BuOH: 1:1(30mL) in DCM, cooled to 5 ℃, addInto ZnBr2(2.69g, 11.96mmol), stirred at 5 ℃ for 30min, then added with 2, 5-dibromo-6 methylpyridine (0.50mg,3.59mmol), followed by Et3N (5.52mL, 39.85mmol) and the temperature was raised to 25 ℃ and the reaction stirred for 64h without proceeding.
Comparative test example 2: preparation of intermediate 1- (5 bromo-6-methyl-2-pyridyl) -1H-benzotriazole
2, 5-dibromo-6-methylpyridine (3.0g, 11.96mmol) and benzotriazole (2.85g, 23.91mmol) are mixed and dissolved in DMSO (100mL) at 120 ℃, K2CO3(11.26g,81.47mmol) is added, the mixture reacts for 48 hours at 120 ℃, the mixture is placed and cooled, 300mL of water is added for dissolution, the mixture is extracted by EtOAc, water backwashing is carried out again, reduced pressure concentration is carried out, and the residue is purified by silica gel column chromatography to obtain the product, wherein the yield is 35.7%.
Comparative test example 3: preparation of 2-methyl-3-bromo-9H-pyrido [2,3-b ] indole
The synthesis process steps are the same as example 1, wherein the reduction reaction in the step (2) is eliminated, and the yield of the 1- (5-bromo-6-methyl-2-pyridyl) -1H-benzotriazole is 84.2%, and the yield of the 2-methyl-3-bromo-9H-pyridine [2,3-b ] indole is 52.3%.
Although the invention has been described in detail hereinabove with respect to specific embodiments thereof, it will be apparent to those skilled in the art that modifications and improvements can be made thereto without departing from the scope of the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (3)
1. The synthetic method of the carbopol compound is characterized in that the synthetic route of the alpha-carbopol compound is as follows:
wherein R is1Is a proton, R2Is methyl, X is Br atom;
the synthesis of the substituted alpha-carbopol is divided into four steps, and the route and the preparation process are as follows:
the catalyst is Pd/C palladium catalyst; the alkali is t-BuOK;
and step two, synthesizing a compound IV:
the reducing agent is iron powder-amine chloride;
thirdly, synthesizing a compound V:
the HX is sulfuric acid;
fourthly, synthesizing a compound VI:
the acid is pyrophosphoric acid.
2. The synthesis method according to claim 1, characterized by comprising the following process steps:
(1) coupling reaction: dissolving o-nitroaniline or derivatives thereof and pyridine derivatives in a reaction solvent, adding a catalyst and alkali, reacting the mixture at the temperature of 100 ℃ and 140 ℃ for 3-30 hours, cooling, adding water for dissolving, extracting by using an organic solvent, washing by using water, drying, concentrating and purifying to obtain an intermediate compound III;
(2) reduction reaction: dissolving an intermediate compound III in a reaction solvent, adding a reducing agent, reacting the mixture at the temperature of 60-100 ℃ for 2-6 hours, cooling, adding water for dissolution, adjusting the pH, filtering, extracting, drying, concentrating and purifying to obtain an intermediate compound IV;
(3) diazotization reaction: dissolving an intermediate compound IV in a reaction solvent at the temperature of-10-0 ℃, adding sodium nitrite and inorganic acid, reacting for 3-8 hours, adding water for dissolving, filtering, extracting, drying, concentrating and purifying to obtain an intermediate compound V;
(4) cyclization reaction: at the temperature of 100 ℃ and 180 ℃, acid is placed in a reactor, the compound V is added, the reaction lasts for 0.5 to 1 hour, water is added for dissolution, and the target compound VI is obtained after filtration, extraction, drying, concentration and purification.
3. The method of synthesis of claim 2, wherein:
the reaction solvent in the step (1) is any one of DMF, DMSO and toluene; the molar ratio of the dosage of the catalyst to the o-nitroaniline or the derivative thereof is 1: 2-8; the molar ratio of the used amount of the alkali to the o-nitroaniline or the derivative thereof is 0.2-2;
the reaction solvent in the step (2) is any one of water, ethanol, methanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran, DMF and DMSO; the molar ratio of the dosage of the reducing agent to the intermediate compound III is 3-8: 1;
the reaction solvent in the step (3) is methanol, ethanol, propanol or acetonitrile;
the molar ratio of the dosage of the acid in the step (4) to the volume (mL) of the intermediate compound V is 3-6: 1.
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| US4154943A (en) * | 1977-12-29 | 1979-05-15 | University Of Vermont | Preparation of vincadifformine |
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| Synthesis and Structure-Activity Relationship of Methyl-Substituted Indolo[2,3-b]quinolines: Novel Cytotoxic, DNA Topoisomerase II Inhibitors;Wanda Peczyńska-Czoch等;《J. Med. Chem.》;19941231;第37卷;3503-3510 * |
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