Preparation method for nicergoline

A kind of technology of nicergoline and ergot alcohol, which is applied in the field of preparation of nicergoline, can solve the problems of high toxicity and troublesome post-processing, and achieve the effects of low toxicity, simple equipment and low energy consumption

Inactive Publication Date: 2012-10-10
珠海润都制药股份有限公司
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  • Abstract
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Problems solved by technology

[0011] Based on this, it is necessary to provide a new nicergoline preparation method for the problem that the organic reagents used in the traditional nicergoline synthesis process have high toxicity and troublesome aftertreatment. The nicergoline preparation method of the present invention adopts toxic Reagents with low cost and simple post-treatment, more in line with the requirements of environmentally friendly production

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  • Preparation method for nicergoline
  • Preparation method for nicergoline
  • Preparation method for nicergoline

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Example 1: Preparation of 5-bromonicotinoyl chloride

[0035]

[0036] Dissolve 8.65kg of 5-bromonicotinic acid in 175kg of dichloromethane, add 0.5%~1% mass equivalent of N,N-dimethylformamide (DMF), add 7.5kg of thionyl chloride under stirring, and dissolve the mixture Stir and reflux for 5 hours. After the raw materials were completely reacted, methylene chloride was removed by distillation under reduced pressure, and 1.5 kg of anhydrous toluene was added to the resulting solid to remove residual thionyl chloride, and then the toluene was removed by distillation under reduced pressure to obtain 5-bromonicotinoyl chloride as a white powdery solid. The yield was 92.6%.

Embodiment 2

[0037] Example 2: Preparation of 10α-methoxy-photoergool (Compound IV)

[0038]Add 50kg of methanol and 5kg of concentrated sulfuric acid into the photocatalytic reactor to prepare methanol-concentrated sulfuric acid mixed solution, add 2.0kg of ergot alcohol (compound VI) under stirring, turn on the ultraviolet high-pressure mercury lamp with a wavelength range of 280nm~350nm and a power of 1500W , under the protection of nitrogen, the temperature was controlled below 25°C, and the reaction was continued with stirring for 48 hours. After the raw materials are completely reacted, pour the reaction solution into 1000kg of ice water, add concentrated ammonia water under stirring, and adjust the pH to 9~10 to neutralize the sulfuric acid in the reaction system. Extracted with dichloromethane (20kg×3 times), the extract was washed with 100kg of saturated brine, and then the solvent was distilled off under reduced pressure at 35°C to obtain 2.0kg of a crude red powder solid. The c...

Embodiment 3

[0039] Example 3: Preparation of 1-methyl-10α-methoxy-photoergool (Compound VII)

[0040] Add 4.8kg powdered potassium hydroxide to 40kg dimethyl sulfoxide, stir for 15 minutes, add 12.3kg 10α-methoxyl-photoergool (compound IV), continue stirring at room temperature for 30 minutes, and control the temperature at At 15°C to 20°C, slowly add 7.92 kg of iodomethane in dimethyl sulfoxide solution dropwise, and stir for 1 hour to react. After the raw materials were completely reacted, the reaction solution was poured into 400 kg of ice water and stirred for 10 minutes. Extract with dichloromethane (100kg x 3 times), wash the extract with 200kg of saturated brine, and distill off the solvent under reduced pressure at 35°C to obtain a crude red powder solid. The crude product was recrystallized with 530kg of acetone to obtain 8.2kg of light red crystal 1-methyl-10α-methoxyl-photoergool with a yield of 60%.

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Abstract

The invention discloses a preparation method for nicergoline. The preparation method for the nicergoline comprises the following steps: 1) reacting ergot alcohol in a methanol-sulfuric acid system under photocatalysis to prepare 10alpha-methoxyl-light ergot alcohol; 2) performing methylation on the 10alpha-methoxyl-light ergot alcohol and a methylated reagent in an aprotic polar solvent under the catalytic action of strong alkali to prepare 1-methyl-10alpha-methyl-light ergot alcohol; and 3) performing acylation reaction on the1-methyl-10alpha-methyl-light ergot alcohol and 5-bromine nicotinoyl halide in an aprotic hydrophobic solvent under the catalytic action of weak alkali to prepare the nicergoline. The solvents and catalysts adopted by the method have the advantages of low toxicity, low price, simple aftertreament and the like, so that the reaction residues of the products can be reduced, the quality of the product can be improved, and the requirement of environment-friendly production can be met.

Description

technical field [0001] The present invention relates to a kind of preparation method of nicergoline. Background technique [0002] With the continuous development of medical technology and the continuous improvement of living conditions, the proportion of the elderly in society is increasing. In the world, 6.1% of the elderly over 65 years old suffer from Alzheimer's disease. Due to the problem of population aging, forecasts show that the prevalence of Alzheimer's will continue to rise worldwide, from 25 million patients in 2000 to 63 million in 2030. The degeneration of the cerebral cortex of Alzheimer's patients leads to the loss of normal activity functions, including memory, judgment, abstract thinking, reasoning ability and spatial relationship, etc., and finally even the simplest tasks cannot be completed. Therefore, the understanding and treatment of senile dementia have important medical and social significance. The treatment of senile dementia is a major problem i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D457/02
Inventor 关东周爱新陈新民郭欣李桂铤
Owner 珠海润都制药股份有限公司
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