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The synthetic method of ropinirole hydrochloride intermediate 2-methyl-3-nitrophenylacetic acid

A technology for ropinirole hydrochloride and nitrophenylacetic acid, which is applied in the field of synthesis of ropinirole hydrochloride intermediate 2-methyl-3-nitrophenylacetic acid, can solve drainage pollution, low overall yield and pollution Large and other problems, to achieve the effect of less pollution discharge

Active Publication Date: 2022-04-01
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The overall yield of this method is low (only 10%), because the steps such as nitrification, oxidation, chlorination pollute greatly, and operation is also extremely unsafe; Cyanogenation and hydrolysis part need to use highly toxic substances such as potassium cyanide, and it is easy to Problems such as drainage pollution
Therefore, this method is not conducive to practical production application

Method used

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  • The synthetic method of ropinirole hydrochloride intermediate 2-methyl-3-nitrophenylacetic acid
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  • The synthetic method of ropinirole hydrochloride intermediate 2-methyl-3-nitrophenylacetic acid

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Experimental program
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Effect test

Embodiment 1

[0032] The synthetic method of 2-methyl-3-nitrophenylacetic acid comprises the following steps:

[0033] 1) Under argon protection, mix ethyl iodoacetate, magnesium ethoxide, catalyst and anhydrous tetrahydrofuran, control the reaction temperature to rise to 112°C, and the pressure to 4.5 atmospheres, dropwise add 6-iodo-2- The mixture composed of nitrotoluene and anhydrous isopropanol is controlled to be added for 50 minutes. After the addition is completed, the temperature is controlled to rise to 140°C and the pressure is raised to 8 atmospheres. After continuing to react for 3 hours, cool to room temperature and drop Add a 12% sodium hydroxide aqueous solution, and control the temperature not to exceed 90°C. After the sodium hydroxide aqueous solution is added dropwise, control the temperature to rise to 132°C, and the pressure is 2.6 atmospheres, and the reaction is completed for 1.5 hours.

[0034] The preparation method of the catalyst is as follows: the nanometer molec...

Embodiment 2

[0038] The synthetic method of 2-methyl-3-nitrophenylacetic acid comprises the following steps:

[0039] 1) Under nitrogen protection, mix ethyl bromoacetate, magnesium ethoxide, catalyst and absolute ethanol, control the reaction temperature to rise to 100°C, and the pressure to 3 atmospheres, dropwise add 6-chloro-2-nitrate The mixture composed of methyl toluene and anhydrous isopropanol is controlled to be added for 30 minutes. After the addition is completed, the temperature is increased to 130°C and the pressure is increased to 7 atmospheres. After continuing the reaction for 2 hours, cool to room temperature and add dropwise The mass fraction of potassium hydroxide aqueous solution is 12%, and the temperature is controlled not to exceed 90°C. After the potassium hydroxide aqueous solution is added dropwise, the temperature is controlled to rise to 120°C, the pressure is 2 atmospheres, and the reaction is completed for 1 hour.

[0040] The preparation method of the cataly...

Embodiment 3

[0044] The synthetic method of 2-methyl-3-nitrophenylacetic acid comprises the following steps:

[0045]1) Under argon protection, mix ethyl iodoacetate, magnesium ethoxide, catalyst and anhydrous tetrahydrofuran, control the reaction temperature to rise to 120°C, and the pressure to 5 atmospheres, dropwise add 6-bromo-2- The mixture composed of nitrotoluene and anhydrous isopropanol is controlled to drop for 60 minutes. After the drop is completed, the temperature is controlled to rise to 155 ° C, and the pressure is raised to 9 atmospheres. After continuing to react for 4 hours, cool to room temperature and drop Add 12% sodium hydroxide aqueous solution, control the temperature not to exceed 90°C, after the sodium hydroxide aqueous solution is added dropwise, control the temperature to rise to 140°C, and the pressure is 3 atmospheres, and the reaction is completed for 2 hours.

[0046] The preparation method of the catalyst is as follows: the nanometer molecular sieve is soa...

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Abstract

The invention discloses a method for synthesizing ropinirole hydrochloride intermediate 2-methyl-3-nitrophenylacetic acid, in which 6-halo-2-nitrotoluene and ethyl haloacetate are combined under the action of a catalyst Reaction to obtain 2-methyl-3-nitrophenylacetic acid, 1) under protective gas, ethyl haloacetate, organic base, catalyst and solvent S1 are mixed, the temperature is raised to 100-120 ° C, and the pressure is raised to 3- At 5 atmospheres, add dropwise a mixture of 6-halogenated-2-nitrotoluene and solvent S2 for 30-60 minutes, increase the temperature to 130-155 °C, increase the pressure to 7-9 atmospheres, and react for 2-4 hours After cooling to room temperature, drip alkaline water, control the temperature not to exceed 90°C, after the dropwise addition, control the temperature to 120-140°C, pressure 2-3 atmospheres, and finish the reaction for 1-2 hours; 2) Filter and remove the precipitate after cooling , the filtrate was adjusted to pH 1 with acid water, added solvent S3 for extraction, layered, the organic layer was washed with water, dried, concentrated and evaporated to remove the solvent to obtain the product. The method has short steps, high yield and less pollution discharge.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to a method for synthesizing ropinirole hydrochloride intermediate 2-methyl-3-nitrophenylacetic acid. Background technique [0002] Parkinson's disease is a common neurodegenerative disease, more common in the elderly, the average age of onset is about 60 years old, young people under the age of 40 with onset Parkinson's disease are rare. The main pathological change of Parkinson's disease is the degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain, which leads to a significant decrease in the content of DA in the striatum and causes the disease. The exact cause of this pathological change is still unclear. Genetic factors, environmental factors, aging and oxidative stress may all be involved in the degeneration and death of dopaminergic neurons in PD. [0003] Drug therapy is the most important treatment for Parkinson's disease. It is an early-stage Parkin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C201/12C07C205/56
Inventor 谭回李维平黄国栋
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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