CN110963967B - Preparation method of 2-methyl-4-aminoquinoline - Google Patents
Preparation method of 2-methyl-4-aminoquinoline Download PDFInfo
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- CN110963967B CN110963967B CN201911162308.5A CN201911162308A CN110963967B CN 110963967 B CN110963967 B CN 110963967B CN 201911162308 A CN201911162308 A CN 201911162308A CN 110963967 B CN110963967 B CN 110963967B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
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Abstract
The invention relates to a preparation method of 2-methyl-4-aminoquinoline, which comprises the following steps: (1) dissolving 2-methyl-4-chloroquinoline in a solvent, and then adding substituted benzylamine or benzylamine and alkali to perform an ammoniation reaction to obtain 2-methyl-4-aminated quinoline; (2) and carrying out debenzylation reaction on the 2-methyl-4-aminated quinoline to obtain the 2-methyl-4-aminoquinoline. The preparation method of the 2-methyl-4-aminoquinoline takes the 2-methyl-4-chloroquinoline as a starting material, adds substituted benzylamine or benzylamine to carry out an ammoniation reaction under an alkaline condition, and obtains a target product after debenzylation reaction.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a preparation method of 2-methyl-4-aminoquinoline.
Background
Because of good pharmacological activity, the quinoline compound is widely used as an intermediate of medicaments for resisting tumors, inflammation and bacteria, cardiovascular diseases and the like. The 2-methyl-4-aminoquinoline has certain antitumor activity and strong anti-inflammatory bactericidal activity, and is a main functional group of an anti-inflammatory drug dequalinium chloride. The synthesis of 2-methyl-4-aminoquinoline is therefore of great interest, the formula of 2-methyl-4-aminoquinoline being shown below:
the existing method for synthesizing 2-methyl-4-aminoquinoline is obtained by directly ammoniating 2-methyl-4-chloroquinoline, needs a noble metal catalyst and high pressure conditions, has high requirements on reaction equipment, and also reports that 2-hydroxy-4-chloroquinoline is used as a raw material to react with N, N-diethyl chloroformamide to obtain an esterified product which reacts with ammonia gas to obtain a product.
The present invention has been made in view of the above circumstances.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides the preparation method of the 2-methyl-4-aminoquinoline, the preparation method has simple reaction conditions, does not need noble metal catalysts and high pressure conditions, and has high purity and yield of the obtained product and reduced production cost.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of 2-methyl-4-aminoquinoline comprises the following steps:
(1) dissolving 2-methyl-4-chloroquinoline in a solvent, adding substituted benzylamine or benzylamine and alkali to perform ammoniation reaction to obtain 2-methyl-4-aminated quinoline, wherein the reaction route is as follows:
(2) the 2-methyl-4-amino quinoline is obtained by debenzylation reaction of 2-methyl-4-amino quinoline, and the reaction route is as follows:
further, R1Is one of-H, 4-methoxyl, 4-methylsulfonyl, sulfonyl substituted by 4-2-6 carbon ring hydrocarbon or chain hydrocarbon, 4-nitro and 2, 4-dimethoxy.
Further, the substituted benzylamine in the step (1) is one of p-methoxybenzylamine, p-methylsulfonyl benzylamine, p-nitrobenzylamine, sulfonyl benzylamine substituted by 2-6 carbon cyclic hydrocarbon or chain hydrocarbon, and 2, 4-dimethoxybenzylamine.
Further, the substituted benzylamine described in the step (1) is p-methoxybenzylamine, 2, 4-dimethoxybenzylamine or p-methylsulfonylbenzylamine.
Further, the solvent in the step (1) is one of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide and substituted benzylamine.
Further, the base in the step (1) is one of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine and piperidine.
Further, the debenzylation reagent in the debenzylation reaction in the step (2) is one or more of palladium carbon, hydrogen, formic acid, methanol, ammonium cerium nitrate and acetonitrile.
Furthermore, the temperature of the amination reaction in the step (1) is 80-160 ℃, and the reaction time is 1-12 h.
Further, the temperature of the amination reaction in the step (1) is 120-.
Further, the temperature of the debenzylation reaction in the step (2) is 40-120 ℃, and the reaction time is 1-12 h.
Further, the temperature of the debenzylation reaction in the step (2) is 50 ℃, and the reaction time is 6 hours.
Further, after the debenzylation reaction in the step (2) is completed, water and dichloromethane are added for extraction, and drying is carried out to obtain the 2-methyl-4-aminoquinoline.
Further, the specific reaction process in the step (1) is as follows: dissolving 2-methyl-4-chloroquinoline in a solvent, adding substituted benzylamine or benzylamine and alkali, reacting at any constant temperature of 80-160 ℃ for 1-12h, cooling, adding water to obtain a white precipitate, performing suction filtration, and performing vacuum drying on a filter cake to obtain the 2-methyl-4-aminated quinoline.
Further, the specific reaction process in the step (2) is as follows: dissolving 2-methyl-4-amino quinoline in a solvent, adding a debenzylation reagent, reacting at any constant temperature of 40-120 ℃ for 1-12h, cooling, spin-drying, adding water and dichloromethane for extraction, and drying an organic phase to obtain the 2-methyl-4-amino quinoline.
Compared with the prior art, the invention has the following beneficial effects:
(1) the preparation method of the 2-methyl-4-aminoquinoline takes the 2-methyl-4-chloroquinoline as a starting material, adds substituted benzylamine or benzylamine to carry out an ammoniation reaction under an alkaline condition, and obtains a target product after debenzylation reaction;
(2) the method of the invention has more reagents in the ammonification reaction and the debenzylation reaction, can be selected according to the actual requirement, and solves the problem that the reaction for synthesizing amino compounds from chloro compounds requires high pressure.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
The purity of the commercially available reagents used in the examples of the present invention, such as 2-methyl-4-chloroquinoline, 4-methoxybenzylamine, 2, 4-dimethoxybenzylamine, 4-benzenesulfonylbenzylamine, was > 98%. Organic solvents N, N-dimethylformamide, dimethyl sulfoxide, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, formic acid, methanol and the like were purchased from Shanghai Tantake technologies, Ltd.
The route for the synthesis of 2-methyl-4-aminoquinoline is shown below in the following examples:
example 1
The preparation method of 2-methyl-4-aminoquinoline of this embodiment includes the following steps:
(1) dissolving 2-methyl-4-chloroquinoline (5.31g, 0.03mol) in 30mL of N, N-dimethylformamide, adding p-oxybenzylamine (4.52g, 0.033mol) and triethylamine (3.10g, 0.03mol), heating to 120 ℃ for reaction for 4h, cooling, pouring the reaction solution into water, separating out an off-white precipitate, performing suction filtration, washing a filter cake for three times, and drying the filter cake to obtain 7.19g of the product 2-methyl-4-N- (4-methoxy) benzylaminoquinoline, wherein the yield is 86.1 percent and the HPLC purity is 96.2 percent;
(2) dissolving 2-methyl-4-N- (4-methoxy) benzylamine quinoline (5.6g, 002mol) in methanol, adding 0.5g of palladium carbon, introducing hydrogen, heating to 50 ℃, reacting for 6h, cooling, filtering, and spin-drying to obtain 2-methyl-4-aminoquinoline 2.82g, wherein the yield is 89.6% (calculated by the amount of 2-methyl-4-N- (4-methoxy) benzylamine quinoline substance) and the HPLC purity is 99.5%.
Example 2
The preparation method of 2-methyl-4-aminoquinoline of this embodiment includes the following steps:
(1) dissolving 2-methyl-4-chloroquinoline (5.31g, 0.03mol) in 30mL of dimethyl sulfoxide, adding p-oxybenzylamine (13.56g, 0.1mol) and N, N-diisopropylethylamine (3.87g, 0.03mol), heating to 140 ℃, reacting for 2h, cooling, pouring the reaction solution into water, separating out a white-like precipitate, performing suction filtration, washing a filter cake for three times, and drying the filter cake to obtain 6.84g of the product 2-methyl-4-N- (4-methoxy) benzylamine quinoline, wherein the yield is 85.3 percent, and the HPLC purity is 97.4 percent;
(2) dissolving 2-methyl-4-N- (4-methoxy) benzylamine quinoline (5.6g, 0.02mol) in formic acid, adding 0.5g of palladium carbon, introducing hydrogen, heating to 50 ℃, reacting for 6h, cooling, filtering, and spin-drying to obtain 2-methyl-4-aminoquinoline 2.76g, wherein the yield is 88.7% (calculated by the amount of 2-methyl-4-N- (4-methoxy) benzylamine quinoline substance) and the HPLC purity is 99.6%.
Example 3
The preparation method of 2-methyl-4-aminoquinoline of this embodiment includes the following steps:
(1) dissolving 2-methyl-4-chloroquinoline (5.31g, 0.03mol) in 30mLN, N-dimethylformamide, then adding 2, 4-dimethoxybenzylamine (5.01g, 0.033mol) and potassium carbonate (4.14g, 0.03mol), heating to 120 ℃ for reaction for 4h, cooling, pouring the reaction solution into water, separating out a white-like precipitate, carrying out suction filtration, washing a filter cake for three times, and drying the filter cake to obtain 7.11g of the product 2-methyl-4-N- (2, 4-dimethoxy) benzylamine quinoline, wherein the yield is 86% and the HPLC purity is 96.5%;
(2) dissolving 2-methyl-4-N- (2, 4-dimethoxy) benzylamine quinoline (6.16g, 0.02mol) in acetonitrile, adding ceric ammonium nitrate (10.96g, 0.02mol), heating to 40 ℃, reacting for 5h, cooling, filtering, drying, adding water and dichloromethane for extraction, extracting for three times, combining organic phases, drying and desolventizing to obtain 2-methyl-4-aminoquinoline 2.79g with the yield of 89.5% (calculated by the amount of 2-methyl-4-N- (4-methoxy) benzylamine quinoline substance) and the HPLC purity of 99.3%.
Example 4
The preparation method of 2-methyl-4-aminoquinoline of this embodiment includes the following steps:
(1) dissolving 2-methyl-4-chloroquinoline (5.31g, 0.03mol) in 30mL of dimethyl sulfoxide, adding 4-tosylbenzylamine (5.65g, 0.033mol) and cesium carbonate (9.77g, 0.03mol), heating to 120 ℃ for reaction for 4h, cooling, pouring the reaction solution into water, separating out a white-like precipitate, carrying out suction filtration, washing a filter cake for three times, and drying the filter cake to obtain 7.24g of the product 2-methyl-4-N- (4-tosyl) benzylamine quinoline, wherein the yield is 87.1%, and the HPLC purity is 96.2%;
(2) dissolving 2-methyl-4-N- (4-tosyl) benzylamine quinoline (6.53g, 0.02mol) in acetonitrile, adding ceric ammonium nitrate (10.96g, 0.02mol), heating to 120 ℃, reacting for 5h, cooling, filtering, spin-drying, adding water and dichloromethane for extraction, extracting for three times, combining organic phases, drying and desolventizing to obtain 2.79g of 2-methyl-4-aminoquinoline product with the yield of 89.5% (calculated by the amount of 2-methyl-4-N- (4-methoxy) benzylamine quinoline substance) and the HPLC purity of 99.3%.
Example 5
The preparation method of 2-methyl-4-aminoquinoline of this embodiment includes the following steps:
(1) dissolving 2-methyl-4-chloroquinoline (5.31g, 0.03mol) in 30mL tetrahydrofuran, adding p-4-nitrobenzylamine (4.76g, 0.033mol) and piperidine (2.55g, 0.03mol), heating to 120 ℃ for reaction for 4h, cooling, pouring the reaction solution into water, separating out a white-like precipitate, performing suction filtration, washing a filter cake for three times, and drying the filter cake to obtain 7.03g of the product 2-methyl-4-N- (4-nitro) benzylamine quinoline, wherein the yield is 85.9 percent and the HPLC purity is 97.1 percent;
(2) dissolving 2-methyl-4-N- (4-nitro) benzylamine quinoline (3.86g, 0.02mol) in acetonitrile, adding ceric ammonium nitrate (10.96g, 0.02mol), heating to 80 ℃, reacting for 5h, cooling, filtering, spin-drying, adding water and dichloromethane for extraction, extracting for three times, combining organic phases, drying and desolventizing to obtain 2-methyl-4-aminoquinoline 2.65g, wherein the yield is 89.2% (calculated by the amount of 2-methyl-4-N- (4-methoxy) benzylamine quinoline substance), and the HPLC purity is 99.5%.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (6)
1. The preparation method of the 2-methyl-4-aminoquinoline is characterized by comprising the following steps:
(1) dissolving 2-methyl-4-chloroquinoline in a solvent, adding substituted benzylamine or benzylamine and alkali to perform ammoniation reaction to obtain 2-methyl-4-aminated quinoline, wherein the reaction route is as follows:
(2) the 2-methyl-4-amino quinoline is obtained by debenzylation reaction of 2-methyl-4-amino quinoline, and the reaction route is as follows:
wherein R is1Is one of-H, 4-methoxyl, 4-methylsulfonyl, sulfonyl substituted by para-2-6-membered carbocyclic hydrocarbon or chain hydrocarbon, 4-nitryl and 2, 4-dimethoxy;
wherein, the debenzylation reagent in the debenzylation reaction in the step (2) is one or more of palladium carbon, hydrogen, formic acid, methanol, ammonium ceric nitrate and acetonitrile;
the temperature of amination reaction in the step (1) is 80-160 ℃, and the reaction time is 1-12 h;
the temperature of the debenzylation reaction in the step (2) is 40-120 ℃, and the reaction time is 1-12 h.
2. The process according to claim 1, wherein the substituted benzylamine in the step (1) is one of p-methoxybenzylamine, p-methylsulfonylbenzylamine, p-nitrobenzylamine, 2-6 carbon ring hydrocarbon or chain hydrocarbon substituted sulfonylbenzylamine, and 2, 4-dimethoxybenzylamine.
3. The process according to claim 1, wherein the substituted benzylamine in the step (1) is p-methoxybenzylamine, 2, 4-dimethoxybenzylamine or p-methylsulfonylbenzylamine.
4. The process according to claim 1, wherein the solvent used in step (1) is one selected from the group consisting of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, 1, 4-dioxane, N-dimethylformamide, dimethylsulfoxide, and substituted benzylamine.
5. The method for preparing 2-methyl-4-aminoquinoline according to claim 1, wherein the base in step (1) is one of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine, and piperidine.
6. The process according to claim 1, wherein the 2-methyl-4-aminoquinoline is obtained by adding water and dichloromethane to the mixture after the debenzylation reaction in the step (2) is completed, and then drying the mixture.
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