Method for synthesizing pharmaceutical intermediate nitrogen heterocyclic bromo-compound

A technology for intermediates and compounds, applied in the field of pharmaceutical intermediates, can solve problems such as inability to popularize, and achieve the effects of saving synthesis steps, high yield and high yield

Active Publication Date: 2018-05-29
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

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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...

Method used

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  • Method for synthesizing pharmaceutical intermediate nitrogen heterocyclic bromo-compound
  • Method for synthesizing pharmaceutical intermediate nitrogen heterocyclic bromo-compound
  • Method for synthesizing pharmaceutical intermediate nitrogen heterocyclic bromo-compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] S1: Raw material preparation 200 grams of 6-bromoisoquinoline, 1.5 L of dichloromethane and 300 grams of m-chloroperoxybenzoic acid with an effective content of 80%, select a 4 L four-necked bottle with a water separator, add the aforementioned two After methyl chloride, keep stirring at 25-30°C, slowly add 6-bromoisoquinoline, and then add m-chloroperoxybenzoic acid with an effective content of 80%, keep stirring at 25-30°C overnight , after TLC showed that the reaction was complete during the day, the system was filtered with suction, and the filter cake was slowly dried and collected carefully to obtain a product mixture of step S1 containing 6-bromoisoquinoline nitrogen oxide.

[0022] S2: Take 150 g of the product mixture of the S1 step, select a 4L four-necked bottle with a water separator, add 400 ml of phosphorus oxychloride and stir, slowly add the product mixture of the S1 step into 400 ml of phosphorus oxychloride in batches, three After the phosphorus oxychl...

Embodiment 2

[0028] S1: Raw material preparation 250 grams of 6-bromoisoquinoline, 2 L of dichloromethane and 350 grams of m-chloroperoxybenzoic acid with an effective content of 85%, select a 4 L four-necked bottle with a water separator, add the aforementioned dichloro After methane, keep stirring at 25-30°C, slowly add 6-bromoisoquinoline, then add m-chloroperoxybenzoic acid with an effective content of 85%, keep stirring at 25-30°C overnight, After TLC showed that the reaction was complete during the day, the system was filtered with suction, and the filter cake was slowly dried and collected carefully to obtain the product mixture of step S1, 6-bromoisoquinoline nitrogen oxide.

[0029] S2: Take 200 g of the product mixture 6-bromoisoquinoline nitrogen oxide of step S1, select a 4L four-necked bottle with a water separator, add 500ml of phosphorus oxychloride and stir, and mix the mixture 6-bromoisoquinoline Nitrogen oxides were slowly added to 500ml of phosphorus oxychloride in batch...

Embodiment 3

[0035] S1: Raw material preparation 250 grams of 6-bromoisoquinoline, 2 L of dichloromethane and 350 grams of m-chloroperoxybenzoic acid with an effective content of 85%, select a 4 L four-necked bottle with a water separator, add the aforementioned dichloro After methane, keep stirring at 25-30°C, slowly add 6-bromoisoquinoline, then add m-chloroperoxybenzoic acid with an effective content of 85%, keep stirring at 25-30°C overnight, After TLC showed that the reaction was complete during the day, the system was filtered with suction, and the filter cake was slowly dried and collected carefully to obtain the product mixture of step S1, 6-bromoisoquinoline nitrogen oxide.

[0036] S2: Take 200 g of the product mixture 6-bromoisoquinoline nitrogen oxide of step S1, select a 4L four-necked bottle with a water separator, add 500ml of phosphorus oxychloride and stir, and mix the mixture 6-bromoisoquinoline Nitrogen oxides were slowly added to 500ml of phosphorus oxychloride in batch...

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Abstract

The invention relates to a method for synthesizing a pharmaceutical intermediate nitrogen heterocyclic bromo-compound. The method comprises that 6-bromoisoquinoline, dichloromethane and m-chloroperoxybenzoic acid as raw materials undergo a reaction to produce a mixture 6-bromoisoquine oxynitride, phosphorus oxychloride is added into the mixture so that solid and water phase products are obtained,the solid products are dried, the water phase products are repeatedly washed and are extracted multiple times, the organic phase is spin-dried, the solid and water phases are treated so that 6-bromo-1-chloroisoquinoline is obtained, the solid crude product and the water crude product are mixed, the mixture is treated through a silica gel column of 100-200 meshes, the mixture is eluted through a petroleum ether PE: ethyl acetate EA eluent A to form a pure product 6-bromo-1-chloroisoquinoline, trimethylbromosilane, acetonitrile and 6-bromo-1-chloroisoquinoline undergo a reaction, pH of the reaction product is adjusted to 7 so that 1, 6-dibromoisoquinoline is obtained, and the 1, 6-dibromoisoquinoline is added into dichloroditriphenyl phosphine and a homemade Grignard reagent so that a finalproduct 6-bromo-1-methylisoquinoline is obtained. The method has the advantages of clear processes, less waste, high yield, raw material saving and operation easiness.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a method for synthesizing brominated compounds of nitrogen-containing heterocycles as pharmaceutical intermediates. 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-bromo-1-methyl The application of isoquinoline as a pharmaceutical i...

Claims

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Application Information

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IPC IPC(8): C07D217/02
CPCC07D217/02
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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