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A kind of preparation method of 1h-indazole derivatives

A -5-R-1H-, indazole technology, applied in the field of preparation of 1H-indazole derivatives, can solve the problems of high cost of 2-fluoro-5-substituted acetophenone, potential safety hazards, unfavorable amplification and the like , to achieve the effect of saving time and operating costs, improving yield, and improving safety factor

Active Publication Date: 2016-03-23
上海毕得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

However, there are many disadvantages in this method: first, the cost of obtaining 2-fluoro-5-substituted acetophenone as a raw material or intermediate is relatively high, and the reaction involves the reflux heating reaction of hydrazine hydrate. It is known that hydrazine hydrate is about 100 degrees It will decompose into nitrogen, ammonia and hydrogen, so there are certain safety hazards
In addition, in the purification process of the product, it is necessary to go through the column, which is not conducive to amplification, and the yield is low, only about 60%.

Method used

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  • A kind of preparation method of 1h-indazole derivatives
  • A kind of preparation method of 1h-indazole derivatives
  • A kind of preparation method of 1h-indazole derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Synthesis of 3-methyl-5-bromo-1H-indazole

[0028] The reaction principle is as figure 1 shown.

[0029] The first step: the synthesis of 2-nitro-5-bromoacetophenone

[0030] Slowly drop 100 g of m-bromoacetophenone into 500 ml of sulfuric acid and nitric acid mixture (volume ratio 1:7, minus 20 degrees), and keep stirring at this temperature overnight. The reaction solution was added into ice water and filtered to obtain 107 g of yellow solid 2-nitro-5-bromoacetophenone with a yield of 87%.

[0031] The second step: the synthesis of 2-amino-5-bromoacetophenone

[0032] 107g of 2-nitro-5-bromoacetophenone was dissolved in 1LH 2 In O / MeOH (1:1) mixed solution, add 75g of iron powder and 380g of ammonium chloride, and stir overnight at 60°C. Filter, add water, extract with ethyl acetate, spin dry, and recrystallize with EA / PE (ethyl acetate / petroleum ether) to obtain 80 g of yellow solid 2-amino-5-bromoacetophenone with a yield of 85%.

[0033] The thir...

Embodiment 2

[0035] Example 2: Synthesis of 3-methyl-5-chloro-1H-indazole

[0036] The reaction principle is as Figure 4 shown.

[0037] The first step: the synthesis of 2-nitro-5-chloroacetophenone

[0038] Slowly drop 100 g of m-chloroacetophenone into 500 ml of sulfuric acid and nitric acid mixture (volume ratio 1:6.5, minus 18 degrees), and keep stirring at this temperature overnight. Add ice water and filter to obtain 110 g of yellow solid 2-nitro-5-chloroacetophenone with a yield of 85%.

[0039] The second step: the synthesis of 2-amino-5-chloroacetophenone

[0040] 110g of 2-nitro-5-chloroacetophenone was dissolved in 1LH 2 In O / MeOH (1:1) mixed solution, add 75g of iron powder and 380g of ammonium chloride, and stir overnight at 60°C. After filtering and adding water, it was extracted with ethyl acetate, spin-dried, and recrystallized with EA / PE to obtain 79 g of yellow solid 2-amino-5-chloroacetophenone, with a yield of 84%.

[0041] The third step: the synthesis of 3-meth...

Embodiment 3

[0043] Example 3: Synthesis of 3-methyl-1H-indazole

[0044] The reaction principle is as Figure 5 shown.

[0045] The first step: the synthesis of 2-nitroacetophenone

[0046] Slowly drop 100 g of acetophenone into 500 ml of sulfuric acid and nitric acid mixture (volume ratio 1:7, minus 15 degrees), and keep stirring at this temperature overnight. Add ice water and filter to obtain 110 g of yellow solid 2-nitroacetophenone with a yield of 80%.

[0047] The second step: the synthesis of 2-aminoacetophenone

[0048] 110g of 2-nitroacetophenone was dissolved in 1LH 2 In O / MeOH (1:1) mixed solution, add 75g of iron powder and 380g of ammonium chloride, and stir overnight at 60°C. After filtering and adding water, it was extracted with ethyl acetate, spin-dried, and recrystallized with EA / PE to obtain 81 g of yellow solid 2-aminoacetophenone with a yield of 90%.

[0049] The third step: the synthesis of 3-methyl-1H-indazole

[0050] Add 81g of 2-aminoacetophenone to 600m...

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Abstract

The invention provides a method for preparing 3-methyl-5-R-1H-indazole easily, safely and efficiently without performing any hydrazine hydrate reflux heating reaction or purifying a product and making the product pass through a column. The method at least comprises the following steps of: a, performing a diazo-reaction on 2-amino-5-R-hypnone serving as a raw material or an intermediate under the condition of an acid solution to generate a diazo salt; b, slowly adding a stannous chloride-hydrate hydrochloric acid solution into the diazo salt obtained in the step a for reacting to generate a 3-methyl-5-R-1H-indazole solution; and c, cooling the solution obtained in the step b under the condition that the pH value is 8-9, and precipitating a product out, wherein R in the steps above represents H or a halogen element.

Description

technical field [0001] The invention relates to a preparation method of 1H-indazole derivatives, in particular to a preparation method of 3-methyl-5-R-1H-indazole as an important intermediate of phosphodiesterase type IV inhibitor. Background technique [0002] Phosphodiesterase inhibitors (phosphodiesteras, PDEs) are drugs that inhibit the activity of phosphodiesterases. Selective phosphodiesterase type IV inhibitors have broad application prospects in the treatment of heart failure, asthma, impotence and other diseases. The principle is to inhibit cAMP by inhibiting the action of phosphodiesterase F-III, which cracks cAMP Cleavage, thereby increasing intracellular cAMP concentration, increasing Ca++ influx, and producing positive inotropic effect. In addition to the positive inotropic effect, phosphodiesterase type IV inhibitors also have a vasodilatory effect by increasing the cAMP content in vascular smooth muscle cells. [0003] In view of the important value of phosp...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/56
Inventor 王超郦荣浩黄冬瑞刘汉
Owner 上海毕得医药科技股份有限公司