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The synthetic method of felodipine intermediate 2,3-dichlorobenzaldehyde

A technology of dichlorobenzaldehyde and felodipine, applied in chemical instruments and methods, preparation of carbon-based compounds, preparation of organic compounds, etc., can solve the problems of high production cost, complex process, environmental pollution, etc., and achieve less discharge of three wastes , high reaction yield and cost reduction effect

Active Publication Date: 2022-04-01
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

2,3-dichlorotoluene is prepared by chlorination under light to obtain benzyl chloride, which is hydrolyzed to obtain 2,3-dichlorobenzyl alcohol, and then oxidized with nitric acid to obtain 2,3-dichlorobenzaldehyde, or deep chlorination To obtain benzylidene dichloride, hydrolyze to obtain 2,3-dichlorobenzaldehyde; another method is to use 2,3-dichlorotoluene as raw material to synthesize 2,3-dichlorophenylnitromethane, through permanganic acid Potassium oxidation produces 2,3-dichlorobenzaldehyde. From the actual production point of view, the production control of the above-mentioned process is difficult, the selectivity is difficult to control, the conditions are harsh, the process is complicated, the utilization rate of raw materials is low, and the production cost is high, and the product quality is difficult. Meet the requirements, and there are serious environmental pollution problems

Method used

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  • The synthetic method of felodipine intermediate 2,3-dichlorobenzaldehyde
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  • The synthetic method of felodipine intermediate 2,3-dichlorobenzaldehyde

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Experimental program
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Effect test

Embodiment 1

[0031] The synthetic method of 2,3-dichlorobenzaldehyde comprises the following steps:

[0032] 1) Slowly add o-dichlorobenzene and the catalyst into concentrated sulfuric acid with a mass fraction of 98% and mix well. Stir the reaction at 85° C. for 6 hours. After cooling to room temperature, pour into ice water and filter to obtain solid R1.

[0033] The molar ratio of o-dichlorobenzene and sulfuric acid is 1:6; the catalyst is a mixture of aluminum chloride and zinc chloride, and the molar ratio of aluminum chloride and zinc chloride is 1:0.61; The molar ratio of aluminum chloride is 1:0.08.

[0034] 2) Under the protection of argon, mix the solid R1 and the solvent DMSO, control the reaction temperature to 130 ° C, and the reaction pressure to 3.5 atmospheres. After stirring for 25 minutes, add the mixture of hexamethylenetetramine and acid A1 dropwise to control The dropwise addition time is 40min. After the dropwise addition, control the reaction temperature to 155°C an...

Embodiment 2

[0039] 1) Slowly add o-dichlorobenzene and the catalyst into concentrated sulfuric acid with a mass fraction of 98% and mix well. Stir the reaction at 75°C for 5 hours. After cooling to room temperature, pour into ice water and filter to obtain solid R1.

[0040] The molar ratio of o-dichlorobenzene and sulfuric acid is 1:5; the catalyst is a mixture of aluminum chloride and zinc chloride, and the molar ratio of aluminum chloride and zinc chloride is 1:0.55; The molar ratio of aluminum chloride is 1:0.05.

[0041] 2) Under the protection of nitrogen, mix the solid R1 and the solvent DMSO, control the reaction temperature to 120°C, and the reaction pressure to 2 atmospheres. After stirring for 20 minutes, add the mixture of hexamethylenetetramine and acid A1 dropwise, and control the dropwise Adding time is 30min. After the dropwise addition, the reaction temperature is controlled to be 145°C and the reaction pressure is 5 atmospheres. After the reaction is finished for 6h, it ...

Embodiment 3

[0046] The synthetic method of 2,3-dichlorobenzaldehyde comprises the following steps:

[0047] 1) Slowly add o-dichlorobenzene and the catalyst into concentrated sulfuric acid with a mass fraction of 98% and mix well. Stir the reaction at 90° C. for 7 hours. After cooling to room temperature, pour into ice water and filter to obtain solid R1.

[0048] The molar ratio of o-dichlorobenzene and sulfuric acid is 1:8; the catalyst is a mixture of aluminum chloride and zinc chloride, and the molar ratio of aluminum chloride and zinc chloride is 1:0.65; The molar ratio of aluminum oxide is 1:0.1.

[0049] 2) Under the protection of protective gas, mix the solid R1 and the solvent DMSO, control the reaction temperature to 135 ° C, and the reaction pressure to 4 atmospheres. After stirring for 30 minutes, add the mixture of hexamethylenetetramine and acid A1 dropwise to control The dropwise addition time is 50min. After the dropwise addition, control the reaction temperature to 160°C...

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Abstract

The invention discloses a method for synthesizing 2,3-dichlorobenzaldehyde as a felodipine intermediate. Ortho-dichlorobenzene is subjected to sulfonation, aldylation and desulfonation to generate 2,3-dichlorobenzaldehyde. Under protonic acid conditions, urotropine is protonated and broken to generate iminium ions; the iminium ions undergo electrophilic aromatic substitution on the aromatic ring, and through tautomerization, a benzylamine derivative is generated; next, urotropine The remaining part undergoes a second protonation and fragmentation to generate iminium ions, and then undergoes an intramolecular redox reaction, and the benzylamine is partially oxidized to benzylidene iminium ions; after hydrolysis, the aldehyde is obtained. The method has high selectivity, less pollution discharge and low cost.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to a method for synthesizing felodipine intermediate 2,3-dichlorobenzaldehyde. Background technique [0002] The chemical name of felodipine is 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl ethyl ester, Its structure is as follows: [0003] [0004] Felodipine is a second-generation dihydropyridine calcium channel blocker antihypertensive drug developed by Astra Company in Switzerland. It has the effect of selectively relaxing the high activity of peripheral arterioles and weakening the contraction force. It was launched in 1988 . The drug is mainly used for the treatment of hypertension, ischemic heart disease, angina pectoris and other diseases, and has an excellent effect on the treatment of heart failure symptoms. Felodipine, a selective calcium antagonist, mainly inhibits the inflow of extracellular calcium in arteriole smooth muscle, selecti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C45/00C07C47/55
CPCC07C303/06C07C303/22C07C45/00C07C309/39C07C309/44C07C47/55
Inventor 谭回李维平
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN