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Novel preparation method of nicergoline

A technology of nicergoline and ergot alcohol, which is applied in the field of new preparation of nicergoline, can solve the problems of unfavorable industrial production, difficult recycling, easy decomposition, etc., to avoid harmful substances and useless by-products, easy recycling, recycling high rate effect

Pending Publication Date: 2020-04-14
SHANGHAI INST OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method can avoid the problem of DCU residues and has a good reaction yield, but there are problems with the production of sulfur dioxide waste gas during the preparation of acid chlorides, the high activity of 5-bromonicotinoyl chloride, which is easily decomposed, and the organic bases such as triethylamine used in ester bonds. Problems such as difficulty in recycling
[0012] In the new preparation method of above-disclosed nicergoline, all have some insufficient factors, are unfavorable for suitability for suitability for industrialized production

Method used

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  • Novel preparation method of nicergoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Dissolve ergot alcohol (50.8g, 0.2mol) in dimethyl sulfoxide (150mL), add potassium hydroxide (11.2g, 0.2mol), stir at room temperature for 45 minutes, then add dropwise methyl iodide (28.4g, 0.2mol) The dimethyl sulfoxide (50mL) solution was added dropwise in about 1h, and continued for 1h after the addition. TLC detection (UV254, methanol / chloroform / ammonia = 1:8:0.1) had a complete reaction, and the reaction solution was poured into ice water. The solid precipitated, was filtered and washed with water, and the solid was recrystallized with methanol, filtered, and dried to obtain 41.3 g of 1-methylergot alcohol with a HPLC purity of 99.1%.

[0050] Add 1-methylergot alcohol (40.2g, 0.15mol) into a pre-prepared mixed solution of 98% sulfuric acid (15.0g, 0.15mol) anhydrous methanol (500mL), cool the reaction solution to 0-5°C, and turn on UV lamp irradiation (wavelength 254nm, power 250W), control internal temperature 0-5 ℃ stirring reaction for 48 hours, TLC detection...

Embodiment 2

[0054] Dissolve ergot alcohol (50.8g, 0.2mol) in N,N-dimethylformamide (150mL), add sodium hydroxide (9.6g, 0.24mol), stir at room temperature for 45 minutes, then add dimethyl sulfate dropwise (27.7g, 0.22mol) of N,N-dimethylformamide (50mL) solution, the dropwise addition was completed in about 1h, and continued for 1h after the addition, and TLC detection (UV254, methanol / chloroform / ammonia water=1:8:0.1) After the reaction was complete, the reaction solution was poured into ice water, and solids were precipitated, filtered and washed with water, and the solids were slurried with methanol, filtered, and dried to obtain 45.2 g of 1-methylergodol with an HPLC purity of 99.5%.

[0055] Add 1-methylergot alcohol (40.2g, 0.15mol) into the pre-configured 98% sulfuric acid (45.0g, 0.45mol) mixed solution of anhydrous methanol (750mL), turn on the ultraviolet lamp irradiation (wavelength 365nm, power 750W) , control the internal temperature at 10-20°C and stir for 12 hours, TLC det...

Embodiment 3

[0058] Dissolve ergot alcohol (50.8g, 0.2mol) in N,N-dimethylacetamide (150mL), add potassium hydroxide (16.8g, 0.3mol), stir at room temperature for 45 minutes, then add dropwise dimethyl carbonate (21.6g, 0.24mol) of N,N-dimethylacetamide (50mL) solution, the dropwise addition was completed in about 1h, and the addition was continued for 1h, and TLC detection (UV254, methanol / chloroform / ammonia water=1:8:0.1) After the reaction was complete, the reaction solution was poured into ice water, and solids were precipitated, filtered and washed with water, and the solids were washed with a small amount of methanol-water, filtered, and dried to obtain 50.1 g of 1-methylergodol with a HPLC purity of 98.5%.

[0059] Add 1-methylergot alcohol (40.2g, 0.15mol) into the pre-configured 98% sulfuric acid (75.0g, 0.75mol) anhydrous methanol (750mL) mixed solution, turn on the ultraviolet lamp irradiation (wavelength 365nm, power 500W) , control the temperature at 10-20°C and stir for 12 ho...

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Abstract

The invention relates to a new preparation method of nicergoline. The method comprises the following steps: (1) adding an inorganic alkali into a polar aprotic solvent, and carrying out a methylationreaction on lysergol (II) and a methylation reagent to generate 1-methyl lysergol (III); (2) carrying out a light reaction on the 1-methyl lysergol (III) and methanol under the catalysis of concentrated sulfuric acid to prepare 1-methyl-10 alpha-methoxy dihydrolysergol (IV); and (3) in a polar aprotic organic solvent, carrying out a reaction on 5-bromonicotinic acid (V) and N,N'-carbonyl diimidazole by taking the N,N'-carbonyl diimidazole as a condensing agent to prepare a 5-bromo nicotinyl imidazole (VI) intermediate, and then carrying out a condensation reaction on the 5-bromo nicotinyl imidazole (VI) intermediate and the 1-methyl-10 alpha-methoxy dihydrolysergol (IV) to prepare nicergoline (I). Compared with the method in the prior art, the method of the invention does not require inertgas protection, is small in acid consumption, good in product quality, high in yield, easy in reaction byproduct recovery and utilization and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a new preparation method of Nicergoline. Background technique [0002] Nicergoline, the chemical name is 10α-methoxy-1,6-dimethylergoline-8-methanyl-5-bromonicotinate, which was first listed in Italy in 1972. It can strengthen the energy metabolism of brain cells, increase the utilization of oxygen and glucose, promote the conversion of neurotransmitter dopamine to enhance nerve conduction, strengthen the biosynthesis of brain proteins, and improve brain function. It is suitable for acute and chronic cerebral palsy. Vascular and peripheral circulation disorders, cerebral metabolic dysfunction and headache; also used for adjuvant treatment of chronic brain insufficiency syndrome, inconvenient movement, language disorder syndrome, etc. It is mainly used clinically for cognitive, emotional and behavioral disorders of the elderly It is especially suitable for the treatmen...

Claims

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Application Information

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IPC IPC(8): C07D457/02
CPCC07D457/02
Inventor 黄金文胡建刘运立夏郅唐慧聂辉刘烨城吴范宏舒海英
Owner SHANGHAI INST OF TECH
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