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Preparation method of 3-chloro(bromo)-6-nitroisoquinoline

A technology of nitroisoquinoline and nitrobenzoic acid, which is applied in the field of preparation of 3-chloro-6-nitroisoquinoline, can solve problems such as inability to promote

Active Publication Date: 2015-11-04
烟台宁远药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the properties of the isoquinoline molecule, this method cannot be extended to the synthesis of other similar structures

Method used

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  • Preparation method of 3-chloro(bromo)-6-nitroisoquinoline
  • Preparation method of 3-chloro(bromo)-6-nitroisoquinoline
  • Preparation method of 3-chloro(bromo)-6-nitroisoquinoline

Examples

Experimental program
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Effect test

Embodiment 1

[0039] The 3-chloro-6-nitroisoquinoline of the present embodiment is prepared by the following method:

[0040] A kind of 3-chloro-6-nitroisoquinoline preparation method is characterized in that comprising the steps:

[0041]S1. First add 200g of 2-chloro-4-nitrobenzoic acid into 2000ml of dimethyl malonate, then inject nitrogen into the liquid surface for about 1 hour, then add 2g of cuprous bromide and 117g of sodium methoxide, Keep nitrogen, then raise the temperature to 90-100°C and react for 16 hours. After TLC monitors the reaction is complete, cool to room temperature, add 2L water and 2L petroleum ether, wash the water phase with 500ml petroleum ether and 500ml toluene respectively, and then wash the water phase with 2N HCl Adjust the pH to 2-3, filter the precipitated solid with suction, and obtain most of the product, about 160 g. The aqueous phase was further extracted with 500 mL of petroleum ether, and the organic phases were combined, washed with saturated NaCl,...

Embodiment 2

[0052] The 3-bromo-6-nitroisoquinoline of the present embodiment is prepared by the following method:

[0053] A kind of 3-bromo-6-nitroisoquinoline preparation method is characterized in that comprising the steps:

[0054] S5. 50 g of 6-nitroisoquinoline-1,3(2H,4H)-dione prepared in step S4 of Example 1 was dissolved in 250 ml of 1,4-dioxane, and 348 g of phosphorus oxybromide was added , react at 105-110°C for 3.5 hours, cool, pour into a beaker, add water dropwise to quench the reaction, and complete the addition in about 30 minutes; adjust the pH to 10 with ammonia water, solids precipitate, filter with suction, and dry the filter cake. The filtrate is extracted with ethyl acetate, and the extract is spin-dried and the dried solid is purified with a silica gel column. The silica gel column uses a mixed solution of petroleum ether and ethyl acetate as the eluent, and the volume ratio of the two is petroleum ether: ethyl acetate Ester=3:1, the product 1,3-dibromo-6-nitroiso...

Embodiment 3

[0059] The 3-chloro-6-nitroisoquinoline of the present embodiment is prepared by the following method:

[0060] A kind of 3-chloro-6-nitroisoquinoline preparation method is characterized in that comprising the steps:

[0061] S1. First add 100g of 2-chloro-4-nitrobenzoic acid to 1000ml of dimethyl malonate, then let the nitrogen gas go deep into the liquid surface for about 2 hours, then add 1g of cuprous bromide and 58.5g of sodium methoxide , keep nitrogen, then raise the temperature to 90-100°C for 12 hours, after TLC monitors the reaction is complete, cool to room temperature, add 1L of water and 1L of petroleum ether, wash the water phase with 250ml of petroleum ether and 250ml of toluene respectively, and then wash the water phase with Adjust the pH to 2-3 with 2N HCl, and filter the precipitated solid with suction to obtain most of the product, about 80 g. The aqueous phase was further extracted with 250 mL of petroleum ether, the organic phases were combined, washed w...

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Abstract

The invention relates to a preparation method of 3-chloro(bromo)-6-nitroisoquinoline. The preparation method comprises that 2-chloro-4-nitrobenzoic acid as a raw material undergoes a nucleophilic substitution reaction to produce 2-(2-methoxy-2-oxoethyl)-4-nitrobenzoic acid, the 2-(2-methoxy-2-oxoethyl)-4-nitrobenzoic acid is hydrolyzed to form 2-(carboxymethyl)-4-nitrobenzoic acid, the 2-(carboxymethyl)-4-nitrobenzoic acid, acetyl chloride and ammonium hydroxide undergo a reaction to produce 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid, the 2-(2-amino-2-oxoethyl)-4-nitrobenzoic acid undergoes a cyclization reaction to produce 6-nitroisoquinolin-1,3(2H,4H)-dione, the 6-nitroisoquinolin-1,3(2H,4H)-dione undergoes a chlorination (bromination) reaction to produce 1,3-dichloro(bromo)-6-nitroisoquinoline, because of activity of isoquinoline at the first site, chlorine(bromine) at the first site is replaced by methoxybenzylamine so that 3-chloro(bromo)-N-(4-methoxybenzyl)-6-nitroisoquinolin-1-amine is formed, the p-methoxybenzyl group is removed by trifluoroacetic acid so that 3-chloro(bromo)-6-nitroisoquinolin-1-amine is formed, 1-amine is subjected to diazotization, and the hydrogen produced by diazotization is removed by heating so that a product is obtained. The preparation method is convenient for operation and has a high yield in each process.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates, in particular to a preparation method of 3-chloro(bromo)-6-nitroisoquinoline. Background technique [0002] Isoquinoline and its derivatives are an important class of alkaloids with important biological activities, widely used in medicine, pesticides and other fields, so the synthesis of isoquinoline derivatives has received extensive attention. [0003] The structural formula of isoquinoline: [0004] [0005] Derivatives of isoquinoline have a wide range of applications, especially in pharmaceutical intermediates. The literature has reported the synthetic method of 3-chloro-5-nitroisoquinoline, and its method is: use 1,3-dichloroisoquinoline to hydrogenate to obtain 3-chloroisoquinoline, and 3-chloroisoquinoline to obtain 3-Chloro-5-nitroisoquinoline. Due to the properties of isoquinoline molecules, this method cannot be extended to the synthesis of other similar structures. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/22
CPCC07D217/22
Inventor 刘波
Owner 烟台宁远药业有限公司
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