Preparation method of 6-methyl-4-bromo-isoquinoline

A technology of isoquinoline and methyl, which is applied in the field of pharmaceutical intermediates, can solve problems such as inability to promote, and achieve the effects of saving synthesis steps, saving raw materials, and high yield

Inactive Publication Date: 2018-05-15
北京六合宁远医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A kind of preparation method of 8-nitro-1,2,3,4-tetrahydroisoquinoline is given in CN2016100987718, and a kind of synthesis of 4-hydroxyl-8-bromoisoquinoline is given in CN201610042580.X Method, a preparation method of 7-bromoisoquinoline is given in CN201210340505.3, which are examples of the application and synthesis of isoquinoline derivatives, but the 6-methyl-4-bromo -Isoquinoline is rarely used as a pharmaceutical intermediate, or there are literature or information published
Due to the properties of this molecule, the method cannot be extended to the synthesis of other similar structures

Method used

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  • Preparation method of 6-methyl-4-bromo-isoquinoline
  • Preparation method of 6-methyl-4-bromo-isoquinoline
  • Preparation method of 6-methyl-4-bromo-isoquinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] S1. Raw material preparation: 90 grams of amino acetal dimethyl acetal, 0.8 L of toluene and 100 grams of p-toluene, select a 2 L four-necked bottle with a water separator, first put 0.8 L of toluene, and add it under stirring Amino acetal dimethyl acetal 90 grams, after being completely dissolved by naked eyes, then add 100 grams of p-tolualdehyde, then increase the temperature, use the condenser tube to reflux and separate water for 3 hours, until no water is separated, end step S1 ;

[0023] S2. Distill the mixture in the four-necked flask obtained in S1 to remove most of the toluene, then add 50ml of toluene, and repeat the rotary distillation twice to obtain the crude product of step S2, 2,2-methyl-N-(4-methoxy phenylalkenyl) ethylamine;

[0024] S3. Take another four-necked bottle, put 0.8L tetrahydrofuran in it and stir in the four-necked bottle, take 160 grams of the crude product of step S2 2,2-methyl-N-(4-methoxyphenylenyl)ethyl Add the amine into the 0.8L t...

Embodiment 2

[0030] S1. Raw material preparation: 102 grams of amino acetal dimethyl acetal, 1 L of toluene and 105 grams of p-toluene, select a 2 L four-necked bottle with a water separator, first put 1 L of toluene, and add amino ethyl under stirring 102 grams of acetal dimethyl acetal, after being completely dissolved by naked eyes, then add 105 grams of p-tolualdehyde, then increase the temperature, use the condenser to reflux and separate water for 3 hours, until no water is separated, and step S1 is ended;

[0031] S2. Distill the mixture in the four-neck flask obtained in S1, remove most of the toluene, then add 100ml of toluene, and repeat the rotary steaming 3 times to obtain the crude product 2,2-methyl-N-(4-methoxy phenylalkenyl) ethylamine;

[0032] S3. Take another four-necked bottle, put 1L tetrahydrofuran inside and stir in the four-necked bottle, take 185 grams of the crude product of step S2, 2,2-methyl-N-(4-methoxyphenylenyl)ethylamine , into the 1L tetrahydrofuran, and ...

Embodiment 3

[0038] S1. Raw material preparation: 110 grams of amino acetal dimethyl acetal, 1.2 L of toluene and 110 grams of p-toluene aldehyde, select a 2 L four-necked bottle with a water separator, first put 1.2 L of toluene, and add it under stirring Amino acetal dimethyl acetal 110 grams, after being completely dissolved by naked eyes, then add 110 grams of p-tolualdehyde, then increase the temperature, use the condenser tube to reflux and separate water for 3 hours, until no water is separated, end step S1 ;

[0039] S2. Distill the mixture in the four-necked flask obtained in S1 to remove most of the toluene, then add 150ml of toluene, and repeat the rotary steaming 4 times to obtain the crude product 2,2-methyl-N-(4-methoxy phenylalkenyl) ethylamine;

[0040] S3. Take another four-necked bottle, put 1.2L tetrahydrofuran inside and stir in the four-necked bottle, take 200 grams of the crude product of step S2 2,2-methyl-N-(4-methoxyphenylenyl)ethyl Add the amine into the 1.2L te...

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Abstract

The present invention relates to a synthesis method of 6-methyl-4-bromo-isoquinoline. The synthesis method comprises the following steps: using amino acetaldehyde dimethyl acetal and p-tolualdehyde asraw materials, and carrying out a reaction for forming 2,2-methyl-N-(4-methoxy phenyl alkenyl)ethylamine; then adding methyl chloroacetate and trimethyl phosphite to obtain 2,2-dimethoxyethyl((dimethoxyphosphoryl)(p-methylphenyl)methyl)ethyl carbamate; further adding titanium tetrachloride for a reaction, after the reaction traced by a TLC method is completed, further adding a 2N sodium hydroxidewater solution for reaction, then adding diatomite, carrying out stirring and suction filtration, carrying out extraction on the water phase and the filter cake with ethyl acetate, carrying out drying and rotary evaporateion, and carrying out column chromatography purification by using a sufficient amount of silica gel columns of 100-200 meshes to obtain 6-methyl isoquinoline; and adding the 6-methyl isoquinoline into carbon tetrachloride, then adding N-bromo-succinimide, carrying out heating and refluxing for 2-5 hours, concentrating the reaction mixture, carrying out column chromatography with silica gel columns of 100-200 meshes, using petroleum ether PE and ethyl acetate EA as eluants, and carrying out recrystallization with excess petroleum ether to obtain the final product 4-bromo-6-methyl-isoquinoline. The method has the advantages of clear steps, less waste, high yield, raw material conservation and easy operation.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a preparation method of 6-methyl-4-bromo-isoquinoline. Background technique [0002] Isoquinoline and its derivatives are an important class of compounds with strong biological activity and are widely used in medicine, pesticides and other fields. Therefore, the synthesis of pyrazole derivatives has received extensive attention, especially in pharmaceutical intermediates is widely used. A kind of preparation method of 8-nitro-1,2,3,4-tetrahydroisoquinoline is given in CN2016100987718, and a kind of synthesis of 4-hydroxyl-8-bromoisoquinoline is given in CN201610042580.X Method, a preparation method of 7-bromoisoquinoline is given in CN201210340505.3, which are examples of the application and synthesis of isoquinoline derivatives, but the 6-methyl-4-bromo -The application of isoquinoline as a pharmaceutical intermediate rarely appears, or there are literature or infor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/22
CPCC07D217/22
Inventor 邢立新
Owner 北京六合宁远医药科技股份有限公司
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