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Preparation method of 2-cyanobenzaldehyde and derivatives thereof

A technology of derivatives and cyanobenzene, which is applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as low reaction yields, hidden safety hazards, and harsh reaction conditions, and achieve high reaction yields, high utilization rates, and mild reaction conditions. Effect

Active Publication Date: 2022-04-26
SHANDONG WEIFANG PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0011] This method has a short route, but the cyanation reagent zinc cyanide (reacts with carbon dioxide in humid air to release highly toxic hydrogen cyanide gas) used in the reaction process is a highly toxic control product, and there are huge risks in the production and use process. Potential safety hazard, and the reaction yield is not high
[0012] From the perspective of prior art, route 1 uses reagents such as chlorine gas and phosphorus trichloride with high toxicity, and the reaction conditions are harsh, and there are potential safety hazards; the bromination reaction in route 2 is a free radical reaction, and the reaction in the initiation stage is violent. There are potential safety hazards, and carbon tetrachloride is used as a solvent at the same time, which is not environmentally friendly
The cyanide used in route 3 is used as a reactant, and there are potential safety hazards in the scale-up production process

Method used

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  • Preparation method of 2-cyanobenzaldehyde and derivatives thereof
  • Preparation method of 2-cyanobenzaldehyde and derivatives thereof
  • Preparation method of 2-cyanobenzaldehyde and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: a kind of preparation method of 2-cyanobenzaldehyde

[0038] Add 600ml of toluene to a 1L three-necked reaction flask, start stirring, and then add Pd(TFA) 2 1.99g (0.006mol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene 5.79g (0.01mol) and potassium carbonate 41.46g (0.30mol), 2-bromobenzonitrile 36.40 g (0.2 mol), paraformaldehyde 12.00 g (0.4 mol); the reaction mixture was heated to 100°C, and reacted for 12 hours. After the reaction is completed, cool down to room temperature and filter; the filtrate is extracted and washed with saturated saline for 3 times (the amount of saturated saline is 60ml / time), and 4.0g of activated carbon is added to the extracted and washed filtrate to decolorize at room temperature for 1.5h. Filter through the funnel, remove the activated carbon, and remove the toluene with a rotary evaporator to obtain crude 2-cyanobenzaldehyde as a brownish-yellow solid. The crude product is recrystallized with toluene and dried to obta...

Embodiment 2

[0040] Embodiment 2: a kind of preparation method of 2-cyanobenzaldehyde

[0041] Add 600ml of toluene to a 1L three-necked reaction flask, start stirring, and then add Pd(TFA) 2 0.66g (0.002mol), 1,2-bis(diphenylphosphine)ethane 1.59g (0.004mol) and potassium bicarbonate 20.02g (0.20mol), 2-chlorobenzonitrile 27.51g (0.2mol) , 6.00 g (0.2 mol) of paraformaldehyde; the reaction mixture was heated to 80° C., and kept for 6 hours. After the reaction is completed, cool down to room temperature and filter; the filtrate is extracted and washed twice with saturated saline (the amount of saturated saline is 50ml / time), and 3.0g of activated carbon is added to the extracted and washed filtrate to decolorize at room temperature for 1 hour. Filtrate, remove the activated carbon, and remove the toluene with a rotary evaporator to obtain crude 2-cyanobenzaldehyde as a brownish-yellow solid. The crude product is recrystallized with toluene and dried to obtain high-purity 2-cyanobenzaldehy...

Embodiment 3

[0043] Embodiment 3: a kind of preparation method of 2-cyanobenzaldehyde

[0044]Add 600ml of toluene to a 1L three-neck reaction flask, start stirring, and then add Pd(OAC) 2 2.25g (0.01mol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene 11.57g (0.02mol) and potassium carbonate 55.28g (0.40mol), 2-bromobenzonitrile 36.40g (0.2mol), paraformaldehyde 18.0g (0.6mol); the reaction mixture was heated up to 110°C, and kept for 24h. After the reaction is completed, cool down to room temperature and filter; the filtrate is extracted and washed with saturated saline for 3 times (the amount of saturated saline is 80ml / time), and 6.0g of activated carbon is added to the extracted and washed filtrate to decolorize at room temperature for 2 hours. Filtrate, remove the activated carbon, and remove the toluene with a rotary evaporator to obtain crude 2-cyanobenzaldehyde as a brownish-yellow solid. The crude product is recrystallized with toluene and dried to obtain high-purity 2-cyanobenza...

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Abstract

A preparation method of 2-cyanobenzaldehyde and derivatives thereof belongs to the field of preparation of drug intermediates, and comprises the following steps: sequentially adding a palladium catalyst, a ligand and an acid-binding agent into a reaction solvent, then adding o-halogenated cyanobenzene and derivatives thereof, and paraformaldehyde, stirring and heating to 80-110 DEG C, reacting for 6-24 hours, filtering, washing, and drying to obtain 2-cyanobenzaldehyde. And carrying out post-treatment to obtain the high-purity 2-cyanobenzaldehyde and the derivative thereof. The preparation method disclosed by the invention is green and environment-friendly, the utilization rate of initial raw materials is relatively high, the reaction yield is relatively high, and the reaction conditions are mild; the use of high-toxicity and high-risk reaction materials such as chlorine and cyanide used in the prior art is avoided; according to the 2-cyanobenzaldehyde and the derivative thereof prepared by the method disclosed by the invention, the yield can reach 74.2%-91.9% in terms of o-halogenated benzonitrile and the derivative thereof, and the purity can reach 97.54%-99.45%.

Description

technical field [0001] The invention specifically relates to a preparation method of a pharmaceutical intermediate 2-cyanobenzaldehyde and derivatives thereof, and belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] 2-cyanobenzaldehyde is an important intermediate for the treatment of hypertension drug hydralazine hydrochloride, and the synthetic methods of o-cyanobenzaldehyde in existing domestic and foreign literature reports mainly contain the following types: [0003] Method 1: Using 2-methylbenzonitrile as a raw material, a double substitution reaction occurs in the presence of chlorine gas to generate o-cyanodichlorobenzyl; then react with an organic base sodium methoxide to generate 2-cyanobenzaldehyde dimethyl acetal Aldehyde, and finally hydrochloric acid hydrolysis to obtain o-cyanobenzaldehyde. This method is discussed in "Fine Petrochemical Industry" vol.25(2), 2008, 32-34, and its synthesis process is roughly as foll...

Claims

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Application Information

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IPC IPC(8): C07C253/30C07C255/56
CPCC07C253/30C07C255/56Y02P20/584
Inventor 谭新李金姑步雁冰周青青赵娜孙园园
Owner SHANDONG WEIFANG PHARMA FACTORY
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