Preparation method of amiodarone hydrochloride intermittent

A technology for amiodarone hydrochloride and intermediates, which is applied in the preparation of amiodarone hydrochloride intermediates for antiarrhythmic drugs and the field of preparation of 2-butyl-3-benzofuran, which can solve the problems of low reaction yield and cyclization Low reaction conversion rate, cost increase and other problems, to achieve the effect of simple operation and high reaction conversion rate

Inactive Publication Date: 2018-12-21
BEIJING SHENLANHAI BIO PHARM TECH
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Problems solved by technology

[0005] This synthetic route has the following disadvantages: Compound 3 can be directly obtained without hydrolysis under the condition of sodium methoxide as alkali and toluene as solvent, but the difficulty of demethylation is much greater than that of decarboxylation, resulting in the formation of compound 5 The conversion rate of the cyclization reaction is low, the by-products are many, and the separation is difficult; thus resulting in low overall yield and increased cost
[0008] This route has the following disadvantages: when compound 3 is used to prepare compound 5, trimethyl orthoformate is added to protect the aldehyde group, then the ester group is hydrolyzed to acid, and then the protective group of the aldehyde group is removed; although it can reduce the side reaction of the aldehyde group, the The reaction steps are added, and trimethyl orthoformate is highly flammable and has potential safety hazards
The reaction yield of compound 4 in p-toluenesulfonyl chloride catalyzed to generate compound 5 is low, and it also increases the cost

Method used

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  • Preparation method of amiodarone hydrochloride intermittent
  • Preparation method of amiodarone hydrochloride intermittent
  • Preparation method of amiodarone hydrochloride intermittent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]15.00kg (122.8mol, 1eq) of compound 1 and 30.82kg (147.4mol, 1.2eq) of compound 2 were added to 120.00kg (8w / w) of ethyl acetate, and 24.00kg (73.7mol, 0.6eq) of cesium carbonate was added, 1.00kg (2.5mol, 0.02eq) of methyl trioctyl ammonium chloride, stirred and heated to 75-85°C, reacted for 1-2 hours. Suction filtration after the reaction was completed, the filtrate was washed with 60.00kg (4w / w) purified water, and the organic phase was concentrated to dryness at 40°C under reduced pressure to obtain 30.21kg (120.7mol) of compound 3 with a yield of about 98.3%.

[0055] Add 30.00kg (120.0mol, 1eq) of compound 3 to 14.40kg (360.0mol, 3eq) of 150.00kg (5w / w) aqueous solution of sodium hydroxide, and stir at 20-30°C. After the reaction, add 1N dilute hydrochloric acid to adjust the pH to 4, add 30.00kg (1w / w) ethyl acetate for extraction, add 30.00kg (1w / w) purified water to the organic phase to wash once, add 30.00kg (1w / w) to the organic phase Wash with saturated sod...

Embodiment 2

[0063] 15.00kg (122.8mol, 1eq) of compound 1 and 30.82kg (147.4mol, 1.2eq) of compound 2 were added to 120.00kg (8w / w) of ethyl acetate, and 10.19kg (73.7mol, 0.6eq) of potassium carbonate was added, 1.00kg (2.5mol, 0.02eq) of methyl trioctyl ammonium chloride, stirred and heated to 75-85°C, reacted for 1-2 hours. Suction filtration after the reaction was completed, the filtrate was washed with 60.00 kg (4w / w) purified water, and the organic phase was concentrated to dryness at 40°C under reduced pressure. 26.21kg (104.7mol) of compound 3 were obtained, the yield was about 85.3%.

[0064] Add 26.00kg (103.9mol, 1eq) of compound 3 to 12.47kg (311.7mol, 3eq) of sodium hydroxide in 130.00kg (5w / w) methanol solution, and stir at 20-30°C. After the reaction was completed, it was concentrated to dryness under reduced pressure at 40°C. Add 130.00kg (5w / w) aqueous solution to dissolve, add 1N dilute hydrochloric acid to adjust the pH to 4, add 26.00kg (1w / w) ethyl acetate for extrac...

Embodiment 3

[0071]15.00kg (122.8mol, 1eq) of compound 1 and 30.82kg (147.4mol, 1.2eq) of compound 2 were added to 120.00kg (8w / w) of toluene, and 24.00kg (73.7mol, 0.6eq) of cesium carbonate was added, 1.00kg (2.5mol, 0.02eq) methyl trioctyl ammonium chloride, stir and heat up to 75-85°C, react for 1-2 hours. Suction filtration after the reaction was completed, the filtrate was washed with 60.00 kg (4w / w) purified water, and the organic phase was concentrated to dryness under reduced pressure at 40°C. 30.36 kg (121.3 mol) of compound 3 were obtained, with a yield of about 98.8%.

[0072] Add 30.00kg (120.0mol, 1eq) of compound 3 to 20.20kg (360.0mol, 3eq) of potassium hydroxide in 150.00kg (5w / w) aqueous solution, and stir at 20-30°C. After the reaction, add 1N dilute hydrochloric acid to adjust the pH to 4, add 30.00kg (1w / w) ethyl acetate for extraction, add 30.00kg (1w / w) purified water to the organic phase to wash once, add 30.00kg (1w / w) to the organic phase Wash with saturated sod...

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Abstract

The invention belongs to the field of medicine synthesis, and relates to a preparation method of an amiodarone hydrochloride intermittent. The method is characterized by including the following stepsthat 1, under an alkaline condition, in the presence of a phase transfer catalyst, a compound 1 and a compound 2 are subjected to nucleophilic substitution reaction to obtain a compound 3; 2, under analkaline condition, the compound 3 is hydrolyzed to generate a compound 4; 3, the compound 4 is subjected to intramolecular aldol condensation, decarboxylation and dehydration to obtain a compound 5;4, a compound 6 and thionyl chloride are subjected to heating reaction to obtain a compound 7; 5, under the presence of lewis acid, the compound 5 and the compound 7 are subjected to friede-crafts acylation reaction to obtain a compound 8; 6, under the presence of lewis acid, the compound 8 is subjected to demethylation to generate a compound 9, namely the amiodarone hydrochloride intermittent 2-butyl-3-(4-hydroxybenzoyl)benzofuran. The preparation method of the amiodarone hydrochloride intermittent has the advantages of being short in reaction time, high in product purity and high in yield,and the amiodarone hydrochloride intermittent is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of an antiarrhythmic drug amiodarone hydrochloride intermediate, in particular to a preparation method of 2-butyl-3-(4-hydroxybenzoyl)benzofuran, belonging to the field of drug synthesis. Background technique [0002] Amiodarone hydrochloride is the most widely used antiarrhythmic drug in clinical practice. In addition, amiodarone hydrochloride has become the preferred long-term medication for patients with arrhythmia due to its stable curative effect and relatively small side effects. In today's society, people's work rhythm is constantly increasing, the pressure they are facing is increasing, and the number of patients with cardiovascular diseases is increasing. The demand for antiarrhythmic drugs has increased significantly, and the market share of amiodarone hydrochloride will continue to increase. [0003] 2-Butyl-3-(4-hydroxybenzoyl)benzofuran is an important intermediate of amiodarone hydrochloride....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/80
CPCC07D307/80
Inventor 李培姜爱斌胡卫东王辉
Owner BEIJING SHENLANHAI BIO PHARM TECH
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