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Improved preparation method of nicergoline

A technique for nicergoline and ergoline, applied in the field of improved preparation of nicergoline, can solve the problems of high activity of 5-bromonicotinyl chloride, difficult recycling of organic bases, unfavorable industrialized production, etc., achieves good impurity removal effect, labor The effect of reduced strength and easy recycling

Active Publication Date: 2020-05-08
SHANGHAI INST OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] 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
[0015] In the improved preparation method of nicergoline disclosed above, there are insufficient factors, which are unfavorable for suitability for suitability for industrialized production

Method used

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  • Improved preparation method of nicergoline

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Experimental program
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Effect test

Embodiment 1

[0047] Add ergot alcohol (50.8g, 0.2mol) into the mixed solution of 98% sulfuric acid (20.0g, 0.2mol) and anhydrous methanol (500mL) prepared in advance, turn on the ultraviolet lamp irradiation (wavelength 254nm, power 125W), control the internal temperature Stir and react at 30-40°C for about 48 hours, TLC detection (UV254, methanol / chloroform / ammonia = 1:8:0.1) the reaction is complete. Add pre-cooled sodium methoxide-methanol (0.4mol) dropwise to the reaction solution, control the rate of addition so that the internal temperature of the reaction solution does not exceed 10°C, after the addition is complete, remove the sodium sulfate generated by filtration, and decolorize the mother liquor with activated carbon (10-15%) , filtered, concentrated under reduced pressure to recover methanol, and the residue was recrystallized with acetonitrile to obtain 49.7 g of 10α-methoxy phoergodol, with a HPLC purity of 95.1%.

[0048] 10α-methoxy phoergodol (42.9g, 0.15mol) was dissolved...

Embodiment 2

[0051] Add ergot alcohol (50.8g, 0.2mol) into pre-configured 98% sulfuric acid (60.0g, 0.6mol) mixed solution of anhydrous methanol (750mL), cool the reaction solution to about 20°C, turn on the ultraviolet lamp irradiation (wavelength 365nm, power 250W), control the internal temperature at 20-30°C and stir the reaction for about 24 hours, TLC detection (UV254, methanol / chloroform / ammonia=1:8:0.1) the reaction is complete. Cool the reaction liquid to 0-5°C, add pre-cooled sodium hydroxide-methanol (1.2mol) dropwise to the reaction liquid while stirring, control the drop rate so that the internal temperature of the reaction liquid does not exceed 20°C, after the addition is complete, filter to remove the sulfuric acid formed Sodium, the mother liquor is decolorized with activated carbon (10-15%), filtered, concentrated under reduced pressure to recover methanol, the residue is slurried with acetonitrile-methanol (10:1, V / V), filtered, and dried to obtain 10α-methoxyphotoergot A...

Embodiment 3

[0055] Add ergot alcohol (50.8g, 0.2mol) into the mixed solution of 98% sulfuric acid (100g, 1.0mol) and anhydrous methanol (750mL) prepared in advance, cool the reaction solution to about 10°C, turn on the ultraviolet lamp irradiation (wavelength 365nm , power 500W), control the temperature at 10-20°C and stir the reaction for about 9 hours, TLC detection (UV254, methanol / chloroform / ammonia = 1:8:0.1) the reaction is complete. Cool the reaction liquid to 0-5°C, add pre-cooled sodium hydroxide-methanol (2.0mol) dropwise to the reaction liquid while stirring, control the drop rate so that the internal temperature of the reaction liquid does not exceed 20°C, after the addition is complete, filter to remove the sulfuric acid formed Sodium, the mother liquor is decolorized with activated carbon (10-15%), filtered, concentrated under reduced pressure to recover most of the methanol, and the residue is recrystallized with acetonitrile-methanol (5:1, V / V) to obtain 10α-methoxy glaucol...

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Abstract

The invention relates to an improved preparation method of nicergoline. The method comprises the following steps: (1) carrying out a photoreaction on ergosterol and methanol under the conditions of catalysis of a proper amount of concentrated sulfuric acid and ultraviolet irradiation to obtain 10alpha-methoxyergosterol; (2) adding an inorganic base into an amide aprotic solvent, and carrying out amethylation reaction on the 10alpha-methoxyergosterol and methyl iodide to generate 1-methyl-10alpha-methoxyergosterol; and (3) reacting 5-bromonicotinic acid with oxalyl chloride in a solvent with organic amine as an acid-binding agent to prepare a 5-bromonicotinyl chloride intermediate, and then carrying out a condensation reaction on the 5-bromonicotinyl chloride intermediate and 1-methyl-10alpha-methoxyergosterol to prepare the nicergoline. Compared with the prior art, the method of the invention has the advantages of no inert gas shielding in the reaction, small acid dosage, and easinessin recycling of reaction byproducts, makes the final yield of the product reach 50% or above and the purity of the product reach 99% or above, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to an improved 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 tr...

Claims

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Application Information

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