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Method for synthesizing 4-bromo-7-fluoroisoquinoline

A synthetic method, the technology of isoquinoline, applied in the direction of organic chemistry, etc., can solve the problems of complex operation and post-processing steps, inconvenient large-scale production, complex synthetic route, etc., and achieve convenient operation and post-processing, low raw material cost, and Easy to get effect

Inactive Publication Date: 2018-07-24
SUZHOU KANGRUN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The existing synthetic methods of 4-bromo-7-fluoroisoquinoline usually have the disadvantages of complicated synthetic route, high raw material cost, complex operation and post-treatment steps, low overall yield, and inconvenient large-scale production.

Method used

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  • Method for synthesizing 4-bromo-7-fluoroisoquinoline
  • Method for synthesizing 4-bromo-7-fluoroisoquinoline
  • Method for synthesizing 4-bromo-7-fluoroisoquinoline

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preparation example Construction

[0038] Such as figure 1 As shown, according to the formula VII provided by the present invention: the synthetic method of 4-bromo-7-fluoroisoquinoline comprises the following steps:

[0039] The synthesis of step (1) 5-fluoro-2-methylbenzamide:

[0040] The raw material 5-fluoro-2-methyl-benzoic acid (formula I) is subjected to carboxylic acid amination reaction to generate 5-fluoro-2-methylbenzamide (formula II);

[0041] Step (2) Synthesis of (E)-N-((dimethylamino)methyl)-5-fluoro-2-methylbenzamide:

[0042] 5-fluoro-2-methylbenzamide (formula II) is subjected to condensation reaction to obtain (E)-N-((dimethylamino)methyl)-5-fluoro-2-methylbenzamide (formula III);

[0043] Synthesis of step (3) 1-hydroxyl-7-fluoroisoquinoline:

[0044] (E)-N-((dimethylamino)methyl)-5-fluoro-2-methylbenzamide (formula III) is subjected to ring closure reaction to obtain 1-hydroxyl-7-fluoroisoquinoline (formula IV);

[0045] Synthesis of step (4) 1-chloro-7-fluoroisoquinoline:

[0046]...

Embodiment 1

[0065] The first step reaction is to use the reactant as 5-fluoro-2-methyl-benzoic acid, the reaction solvent is dichloromethane, and carry out carboxylic acid amination under the action of condensing agent N'N-carbonyldiimidazole (CDI) and ammonia water Reaction, the reaction temperature is 35°C, the reaction time is 3h, and 5-fluoro-2-methylbenzamide is obtained.

[0066] The second step reaction is the condensation reaction of the obtained 5-fluoro-2-methylbenzamide with the reagent N,N-dimethylformamide dimethyl acetal (DMF-DMA), and the reaction solvent is tetrahydrofuran (THF ), the reaction condition was reflux for 2h to obtain (E)-N-((dimethylamino)methyl)-5-fluoro-2-methylbenzamide.

[0067] The third step reaction is to carry out the ring closure reaction of the obtained (E)-N-((dimethylamino)methyl)-5-fluoro-2-methylbenzamide and potassium tert-butoxide (t-BuOK) , the reaction solvent is N,N-dimethylformamide (DMF), and the reaction condition is to react at 120° C....

Embodiment 2

[0072] Synthesis of 5-fluoro-2-methylbenzamide

[0073] Dissolve 5-fluoro-2-methyl-benzoic acid (153g, 0.99mol) in 1500mL of dichloromethane, heat to 35°C, and then add N'N-carbonyldiimidazole (CDI) (193g, 1.2 mol), after reacting for 1 hour, add ammonia water 500mL, react at 35°C for 2 hours, cool to room temperature and separate layers, wherein the aqueous phase is extracted with dichloromethane, then the organic phases are combined, dried and spin-dried to obtain 118g of the product (5 -fluoro-2-methylbenzamide).

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Abstract

The invention provides a method for synthesizing 4-bromo-7-fluoroisoquinoline. The method is characterized in that 5-fluoro-2-methyl-benzoic acid is taken as a starting material and is subjected to areaction to generate 7-fluoroisoquinoline, and lastly the 7-fluoroisoquinoline is subjected to a bromination reaction to obtain the 4-bromo-7-fluoroisoquinoline. The method for synthesizing the 4-bromo-7-fluoroisoquinoline provided by the invention has the advantages of simple synthesizing route, reasonable process selection, low raw material cost, adoption of readily-available raw material, convenience in operation and posttreatment, high yield, no use of highly-toxic reagents, easiness in performing scale-up experiments, realization of large-scale production and the like.

Description

technical field [0001] The present invention relates to a synthesis method of a pharmaceutical intermediate, in particular to a synthesis method of 4-bromo-7-fluoroisoquinoline. Background technique [0002] Isoquinoline compounds are a very important class of azacyclic alkaloids, which have remarkable physiological activities and broad application prospects. Studies have found that isoquinoline alkaloids can exert anti-tumor effects through different mechanisms such as alkylation, receptor regulation, inhibition of anti-apoptotic genes, and inhibition of angiogenesis. At present, isoquinoline has played a huge role in drugs: anesthetics (dimethylisoquinoline), antihypertensive drugs (quinapril hydrochloride), antifungal drugs (1,2,3,4-tetrahydroquinone) Azolines), vasodilators (papaverine), and isoquinolines are also used in the manufacture of dyes, paints, insecticides, preservatives and disinfectants. In the process of drug design, fluorine atoms are usually introduced ...

Claims

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Application Information

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IPC IPC(8): C07D217/22
CPCC07D217/22
Inventor 赵啸颖徐卫良徐炜政
Owner SUZHOU KANGRUN PHARMA
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