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Preparation process of benzofuran with amide side chain

A preparation process, benzofuran technology, applied in the field of benzofuran preparation process, can solve the problems of difficult separation, high cost, difficult to scale up production of synthesis process, etc.

Inactive Publication Date: 2015-05-20
NANTONG HENGSHENG FINE CHEM
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0003] Among the above preparation methods, method (1) is mainly used for the preparation of 2,3-disubstituted benzofuran. The main disadvantage is that the dehydration reaction often produces two kinds of ring-closing products, which are difficult to separate and low in yield, and the 2-halogenated Ketone raw materials are not easy to obtain
The main disadvantage of method (2) is that 2-(2'-hydroxyphenyl) ketone (i.e. benzyl ketone) is difficult to prepare, and the acid-catalyzed dehydration ring-closing yield is very low
However, the disadvantage of this method is that it needs to be divided into three steps, and the operation cost is high.
The shortcoming of method (4) will use precious palladium catalyst, and needs raw material o-bromo or iodophenol, the cost is high
[0004] 2-Alkylbenzofuran is a popular structure for drug research and development. The existing synthetic methods use some expensive catalysts, but their disadvantages are low yield and high cost, and the synthetic process is difficult to scale up.
This method is currently the main production method used to prepare 2-methyl-6-methoxybenzofuran, but its disadvantages are low yield, high cost and poor process controllability
[0008] In addition, in the preparation of 2-methyl-3-formyl chloride-6-methoxybenzofuran, in the U.S. Patent Publication No. US2005137395A1 patent and the World Patent Publication No. WO03106462A1 patent, etc., the direct use of oxalyl chloride and acid chloride However, acid chlorides are easily reacted in water to form carboxylic acids, resulting in low recovery and low purity of crude products
In a series of preparation reactions, in the process of preparing 6-methoxy-N,2-dimethylbenzofuran-3-carboxamide, in US Patent Publication No. US2005137395A1 and World Patent Publication No. WO03106462A1 The monomethylamine used in patents and other reports is a gas, and the state of the solution formed after dissolving in tetrahydrofuran is extremely unstable, which increases the difficulty of the process and brings hidden dangers

Method used

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  • Preparation process of benzofuran with amide side chain
  • Preparation process of benzofuran with amide side chain
  • Preparation process of benzofuran with amide side chain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Embodiment 1: preparation 2-(2-formyl-5-methoxyphenoxy)-propionic acid ethyl ester

[0015]

[0016] Add 92.1 g of 2-hydroxyl-4-methoxybenzaldehyde, 120.7 g of ethyl 2-bromopropionate, 92 g of potassium carbonate and 900 ml of dimethylformamide (DMF, Dimethylformamide) in a 2L reaction flask, and the reaction temperature Raise the temperature to 60°C-90°C, preferably 70°C-90°C, preferably 80°C-90°C, the best implementation temperature is 90°C, and keep at this temperature for 2 hours until the reaction is complete. Then, the reaction intermediate was diluted into 2700ml of water, and the reaction intermediate was extracted three times with 1000ml ethyl acetate, and then the extracts obtained after three extractions with ethyl acetate solution were combined, and then saturated with Wash with brine, and dry with anhydrous sodium sulfate, use distillation to remove the ethyl acetate contained in the reaction intermediate to obtain the first product, 2-(2-formyl-5-methox...

Embodiment 2

[0017] Embodiment 2: prepare 2-methyl-6-methoxybenzofuran

[0018]

[0019] In a 1L reaction flask, add the first product prepared in Example 1, 100.8 g of ethyl 2-(2-formyl-5-methoxyphenoxy)-propionate and 500 ml of dioxane, and mix them in Stir at room temperature and slowly add 14.4g of sodium chloride into the reaction flask, and react with the solution in the reaction flask. After the addition is complete, keep the temperature at 50°C and keep it warm for 1 hour. Dilute to 1000ml of water, and use mineral acid, such as hydrochloric acid (HCl) or concentrated sulfuric acid (H 2 SO 4 ), the acid-base value (p H value) of this reaction solution is adjusted to 3. Next, use 1000ml of ethyl acetate to extract the reaction intermediate after pH adjustment three times, combine the extracts obtained after three extractions with ethyl acetate solution, wash with saturated brine, and wash with anhydrous Sodium sulfate is dried, and the ethyl acetate in the extract is removed b...

Embodiment 3

[0020] Embodiment 3: prepare 2-methyl-3-carboxy-6-methoxybenzofuran

[0021]

[0022]Add 1250ml of dichloromethane and 80.9g of aluminum chloride into a 2L reaction flask, stir in an ice bath, and cool the temperature of the reaction solution to a temperature ranging from 0°C to minus 15°C. Next, 77 g of oxalyl chloride was added to the reaction solution in the reaction flask, and after stirring for 30 minutes, the second product obtained in the aforementioned Example 2, 30 g of 2-methyl-6-methoxybenzofuran, was started to be added dropwise to the reaction flask. In the liquid, after the dropwise addition is completed, a reaction intermediate is formed, remove the ice bath, and increase the reaction temperature to 25°C-30°C, the optimal reaction temperature is 30°C, and keep the reaction intermediate at this temperature 2 hours. After the reaction, dichloromethane contained in the reaction intermediate was removed by distillation. Next, add 200 ml of water to the reaction...

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Abstract

The invention relates to a preparation process of benzofuran with amide side chain. The preparation process comprises the following steps: reacting adjacent hydroxyl compound, 2-halogen substituendum, solvent and alkali to obtain 2-(2-formyl-5-methoxy-phenoxyl)-ethyl propionate; reacting a first product, dioxane and sodium salt to obtain 2-methyl-6-methoxy benzofuran; mixing dichloromethane, aluminium chloride, oxalyl chloride and a second product to obtain 2-methyl-3-carboxyl-6-methoxy benzofuran; carrying out backflow on a third product, dichloromethane, thionyl chloride and dimethyl formamide to obtain 2-methyl-3-chloroformy-6-methoxy benzofuran; reacting a first product, tetrahydrofuran, methylamine hydrochloride and alkali to obtain 6-methoxyl-N,2-dimethyl benzofuran-3-formamide; and reacting a fifth product, dichloromethane and boron tribromide to obtain the benzofuran with amide side chain. The yield reaches 97%.

Description

technical field [0001] The invention relates to a preparation process of benzofuran, more specifically a preparation process of benzofuran with amide side chain. Background technique [0002] Benzofuran is an important pharmaceutical and chemical intermediate, the main structure of many natural products and drugs, and the core structure of many medicines and many new drugs currently under development. In the published literature, the synthetic method of benzofuran can be simply divided into four kinds: (1) generate phenoxyalkanone with phenol and 2-halogenated ketone reaction, acid catalyzed direct dehydration and obtain benzofuran product ( Bull Soc.Chem.Jpn, 1971,44,749); (2) first prepare 2-(2'-hydroxyphenyl) ketone, and dehydrate under acidic conditions to obtain benzofuran (Tetrahedron Lett, 1980,21,4391); ( 3) Reaction of salicylaldehyde or 2-hydroxyphenyl ketone with substituted bromoacetate to form phenol ether, decarboxylation under basic catalysis to obtain benzof...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/84
CPCC07D307/84
Inventor 钟天桂申伟成陈均鸿
Owner NANTONG HENGSHENG FINE CHEM
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