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The preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline

A technology of hydroxyquinoline and methoxyphenyl, which is applied in the field of organic compound synthesis, can solve the problems of long reaction time, high energy consumption, and high requirements for production equipment, and achieves the effects of simple operation, high yield and no special requirements.

Inactive Publication Date: 2019-08-09
JIAXING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The nitration step of the method uses highly corrosive concentrated nitric acid as a nitration reagent, which requires high production equipment; and the reaction time is long and the energy consumption is high

Method used

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  • The preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline
  • The preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline
  • The preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Preparation of 3-benzyloxy-4-methoxynitrobenzene

[0052] Add 2-methoxyl-5-nitrophenol (10.0g, 59.2mmol), anhydrous potassium carbonate (12.2g, 88.4mmol) and N,N-dimethylformamide 100ml successively in a 250ml three-necked flask, Benzyl bromide (11.1g, 64.9mmol) was added dropwise under stirring, and the temperature was raised to 40°C for 4 hours after the drop, during which the reaction was detected by thin layer chromatography (ethyl acetate:petroleum ether (V:V)=2:1) completely. After the reaction was completed, after cooling to room temperature, the reaction solution was poured into 500 ml of ice water, stirred, filtered with suction, and dried to obtain 14.1 g of a light yellow solid with a yield of 93.1%.

[0053] 1 H-NMR(400MHz,DMSO-d6)δ:3.88(s,3H,-CH 3 ); 5.18(s,2H,-CH 2 ); 7.13~7.15(d,1H,ArH); 7.33~7.46(m,5H,ArH); 7,81~7,82(d,1H,ArH); 7.87~7.90(dd,1H,ArH)) .

[0054] Preparation of 3-benzyloxy-4-methoxyaniline

[0055] Add 3-benzyloxy-4-methoxynitrobenz...

Embodiment 2

[0062] The preparation of 3-benzyloxy-4-methoxynitrobenzene and 3-benzyloxy-4-methoxyaniline is according to Example 1.

[0063] Preparation of 7-benzyloxy-6-methoxy-4-hydroxyquinoline

[0064] First add 3,3-diethoxy ethyl propionate (4.84ml, 25.0mmol) and 0.57g of anhydrous p-toluenesulfonic acid into a 100ml three-necked flask, stir at room temperature for 15 minutes, then add 3-benzyl Oxy-4-methoxyaniline (5.73g, 25.0mmol) was heated to 60°C for 5 hours, during which the reaction was detected by thin layer chromatography (ethyl acetate:petroleum ether (V:V)=1:2) . Cool to room temperature to obtain ethyl 3-(3-benzyloxy-4-methoxyphenyl)iminopropionate, which can be directly subjected to ring closure without separation and purification.

[0065] Add 49ml of diphenyl ether to the above reaction product, slowly heat to 180°C for a ring closure reaction for 6 hours, thin layer chromatography (ethyl acetate:petroleum ether (V:V)=2:1) ​​detects that the reaction is complete, c...

Embodiment 3

[0067] The preparation of 3-benzyloxy-4-methoxynitrobenzene and 3-benzyloxy-4-methoxyaniline is according to Example 1.

[0068] Preparation of 7-benzyloxy-6-methoxy-4-hydroxyquinoline

[0069] First add 3,3-diethoxy ethyl propionate (4.84ml, 25.0mmol) and 0.1g of anhydrous p-toluenesulfonic acid into a 100ml three-necked flask, stir at room temperature for 15 minutes, then add 3-benzyl Oxy-4-methoxyaniline (5.73g, 25.0mmol) was heated to 95°C for 5 hours, during which the reaction was detected by thin layer chromatography (ethyl acetate:petroleum ether (V:V)=1:2) . Cool to room temperature to obtain ethyl 3-(3-benzyloxy-4-methoxyphenyl)iminopropionate, which can be directly subjected to ring closure without separation and purification.

[0070] Add 25ml of diphenyl ether to the above reaction product, slowly heat to 180°C for a ring closure reaction for 6 hours, thin layer chromatography (ethyl acetate:petroleum ether (V:V)=2:1) ​​detects that the reaction is complete, co...

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Abstract

The invention discloses a preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline. The method comprises the following steps: under the action of anhydrous p-methylbenzenesulfonic acid, carrying out condensation reaction on 3-benzyloxy-4-methoxyaniline and ethyl 3,3-diethoxypropionate to obtain ethyl 3-(3-benzyloxy-4-methoxyphenyl)imino propionate; and without the need for separation and purification, directly adding a high-boiling-point non-protonic solvent to perform cyclization reaction, thereby obtaining the 7-benzyloxy-6-methoxy-4-hydroxyquinoline. The reaction formula is disclosed in the specification. The whole process is simple to operate, and saves the separation and purification link in the intermediate step. The preparation method is simple to operate, has the advantages of high safety, mild reaction conditions, high yield and low requirements for reactors, and can easily implement industrial production. The 3-benzyloxy-4-methoxyaniline can be obtained by carrying out oxygen atom alkylation and nitro reduction on the initial raw material 2-methoxy-5-nitrophenol; and the initial raw material 2-methoxy-5-nitrophenol is cheap and accessible.

Description

technical field [0001] The invention belongs to the field of organic compound synthesis, and more specifically relates to a preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline. Background technique [0002] The structure of 7-benzyloxy-6-methoxy-4-hydroxyquinoline is shown in the following formula I, wherein Bn is benzyl. It is an important intermediate in the preparation of various antitumor drugs and antibacterial drugs. [0003] [0004] At present, the preparation method of 7-benzyloxy group-6-methoxyl group-4-hydroxyquinoline mainly contains following several kinds: [0005] The first preparation method: patent documents CN104817497, CN102675282 and WO2006108059 disclose the preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline, using 4-hydroxyl-3-methoxyacetophenone as The starting material is subjected to benzylation, nitration, reduction, and condensation with formate to obtain the target product. The nitration step of the method uses highly...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 张洋吴建一周盛梅缪程平屠晓华
Owner JIAXING UNIV
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