Preparation of 4-pyridinecarboxaldehyde_Industrial additives

Preparation background and overview of 4-pyridinecarboxaldehyde

As an important pharmaceutical intermediate and fine chemical raw material, 4-pyridinecarboxaldehyde has a wide range of applications and broad market prospects. In medicine, 4-pyridinecarboxaldehyde, as an important pharmaceutical intermediate, can be used to synthesize the laxative bisacodyl and is also a raw material for the synthesis of the organophosphate antidote pralidoxime. Recently, it has been reported that 4-pyridinecarboxaldehyde can also be used to synthesize the laxative bisacodyl. Raw material for anti-HIV protease inhibitors; in agriculture, 4-pyridinecarboxaldehyde is a necessary intermediate for the synthesis of some acaricides; in the photosensitive industry, 4-pyridinecarboxaldehyde can be used to synthesize nitrogen-containing heterocyclic color photographic materials.

Preparation of 4-pyridinecarboxaldehyde

Preparation Report 1 of 4-Pyridinecarboxaldehyde

1. Preparation of Cu‑Ni catalyst

Add 900L purified water to the 1000L reactor, stir, add 9kg copper sulfate pentahydrate, then add 30kg Raney-Ni catalyst (containing 50% water), stir for 30 minutes, let it stand, and draw out the supernatant; add 600L for purification Stir the water for 30 minutes, let it stand, and extract the supernatant; repeat washing 4 to 6 times until the washing water is checked with barium chloride test solution and there is no precipitation; put the washed catalyst into a bucket, add purified water, seal and soak for 25 days, and prepare Obtain Cu‑Ni catalyst.

2. The preparation method of 4-pyridinecarboxaldehyde includes the following steps:

(1) In a 1000L dissolution reaction kettle, add 300kg of purified water, stir, and slowly add 130kg of concentrated sulfuric acid (mass fraction of more than 97%) while cooling with brine, and add 50.0kg of 4-cyanopyridine below 30°C. Continue stirring for 30 to 60 minutes to completely dissolve 4-cyanopyridine.

Transfer the above 4-cyanopyridine sulfuric acid solution to a 1000L hydrogenation reactor, stir, and transfer 15kg (50% water) Cu-Ni catalyst and 80kg purified water to the hydrogenation reactor. Use 0.7MPaN2 to test for leaks, and then replace N₂ with 0.5MPaH₂ three times. Charge H₂ to 0.5MPa, raise the temperature to 70°C, and hydrogenate at 0.6MPa until the reaction system absorbs 0.01-0.03MPa hydrogen for 20 minutes, then cool down to normal temperature. Discharge H₂ and replace H₂ with 0.3MPaN₂ three times.

(2) Filtration: Filter to remove the catalyst, and wash the hydrogenation reactor and filter with 50L purified water.

(3) Transfer the filtrate and washing liquid from step (2) to a 1000L neutralization reaction kettle, stir, cool down, and neutralize to pH 5 with 30% sodium hydroxide at 20°C.

(4) Separation and purification of 4-pyridinecarboxaldehyde: Use a pump to pump in 300kg methylene chloride at 25°C, stir for 30 minutes, let stand for 50 minutes, and separate into layers; the water layer is extracted with 200kg, 150kg, and 150kg methylene chloride in sequence. ; Transfer the combined methylene chloride hydrated samarium carbonate layer to a 1000L dry reaction kettle, stir, add 30kg anhydrous sodium sulfate, and dry for 5 hours; filter, remove the desiccant, distill to 60°C under normal pressure, recover methylene chloride, and apply ; The residue was distilled under reduced pressure, and the fractions with a vacuum of 0.095MPa or above and a temperature of 90 to 120°C were collected to obtain 25.7kg of product, with a yield of 50% and a GC purity of 99.3%.

Preparation Report 2 of 4-pyridinecarboxaldehyde

4-methylpyridine reacts with glacial acetic acid and hydrogen peroxide. The reaction temperature is 61°C and the reaction time is 18h. The molar ratio of 4-methylpyridine, glacial acetic acid and hydrogen peroxide is 1:3.6:3.2 to obtain 4-methylpyridine. Pyridine nitrogen oxide; 4-pyridine nitrogen oxide reacts with acetic anhydride, the reaction temperature is 91°C, the reaction time is 4h, the molar ratio of the 4-pyridine nitrogen oxide and acetic anhydride is 1:2.4, and acetic acid-4 is obtained -Pyridine methyl ester; 4-pyridine methyl acetate reacts with potassium hydroxide solution, the reaction time is 6 hours, the molar ratio of 4-pyridine methyl acetate and potassium hydroxide is 1:1.6, the reaction obtains 4-pyridine Methanol; 4-pyridinemethanol is cooled with ice water and PCC is added. The molar ratio of 4-pyridinemethanol to PCC is 1:2.4, and the temperature is 3°C; then the reaction is carried out at room temperature, the temperature is 22°C, and monitored by thin layer chromatography. Complete response.

Preparation Report 3 of 4-Pyridinecarboxaldehyde

A new synthesis method of 4-pyridinecarboxaldehyde, which includes the following steps:

Step 1: In a 500ml three-neck bottle with stirring, reflux and drying device, add 50.5g of isonicotinic acid, 120ml of absolute ethanol, dropwise add concentrated sulfuric acid, heat and reflux for 3 hours with stirring, recover 95% under normal pressure Ethanol, after cooling, add 50 ml of absolute ethanol to potassium trifluoroborate, continue the reflux reaction for 2 hours, pour into ml of ice water after cooling, neutralize with sodium bicarbonate to pH 7, then adjust the pH with concentrated ammonia, and extract three times with EtOAc , combine the organic layers, wash with water until neutral, wash with saturated brine, dry with anhydrous sodium sulfate, recover the solvent under reduced pressure, and distill under reduced pressure to obtain 53.2g of colorless oily liquid ethyl isonicotinate, with a yield of 88.5%;

Step 2: Dissolve 30g of ethyl isonicotinate in 95% ethanol, add 80% hydrazine hydrate, after the addition is completed, heat to reflux for 8 hours, TLC detects that the reaction is complete, cool, concentrate under reduced pressure, and freeze in the refrigerator , precipitate colorless needle-like crystals, filter, wash twice, and dry to obtain 21.8g of white crystal isoniazid, with a yield of 79.8%; Step 3: Add 13.7g of isoniazid, ml of water, and 50ml of concentrated ammonia to a three-neck bottle , use an external ice-water bath to cool to 0℃, slowly add 300ml of 20% K₃[Fe(CN)]₆ aqueous solution dropwise, and let it naturally rise to room temperature after the addition. , react for 3-4 hours. After TLC detects that the reaction is complete, extract it with CH₂Cl₂ three times, wash the organic layer with water until neutral, and dry it with anhydrous sodium sulfate. The solvent was evaporated, distilled under reduced pressure and the 82-83°C/16mmHg fraction was collected to obtain 7.5g of product, with a yield of 71.3%.

References

[1][China invention] CN201210108087.5 a 4-�Preparation method of cycloformaldehyde

[2][China Invention] CN201710496578.4 A synthesis method of 4-pyridinecarboxaldehyde

[3][Invented in China] CN201711030836.6 A new method for the synthesis of 4-pyridinecarboxaldehyde