Background and overview[1]
4-Chloromethylbiphenyl is an important biphenyl derivative and is widely used in medicine, polymer liquid crystals, dyes, etc. For example, it can be used to synthesize non-steroidal anti-inflammatory drugs biphenylacetic acid, fenbufen, anti-inflammatory and analgesic drugs ethyl biphenylacetate, etc. If 4-chloromethylbiphenyl is inhaled, please move the patient to fresh air; if there is skin contact, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical treatment if you feel uncomfortable; if there is eye contact , you should separate your eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse your mouth immediately, do not induce vomiting, and seek medical attention immediately.
Application [2-3]
4-Chloromethylbiphenyl is an important biphenyl derivative and is widely used in medicine, polymer liquid crystals, dyes, etc. Examples of its application are as follows: Preparation of 4-biphenyl acetic acid. The molecular formula of 4-biphenylacetic acid is C14H12O2, molecular weight 212.24, white flaky crystals. 4-Diphenylacetic acid is a non-steroidal anti-inflammatory drug and an effective metabolite of fenbufen, which has anti-inflammatory and analgesic activity similar to fenbufen. Indications include degenerative arthritis, frozen shoulder, tenosynovitis, peritendinitis, myalgia, trauma swelling, pain, etc. Its derivative, ethyl biphenylacetate, is also an anti-inflammatory and analgesic. It is used to treat rheumatoid arthritis, low back pain, periarthritis of the shoulder, traumatic pain, and post-operative pain. It has good effects, especially in the treatment of cancer pain. Excellent. The preparation method is as follows: using 4-chloromethylbiphenyl as raw material, in the presence of catalyst palladium dichloride, ligand triphenylphosphine, alkali, and solvent, undergo a carbonylation reaction with carbon monoxide, and then undergo acidification and separation to obtain 4-biphenylacetic acid. This method can be realized under the conditions of reaction temperature of 50-100°C and pressure of 0.3-1.0MPa. The reaction yield is high, the three waste emissions are small, and it is suitable for industrial production.
Preparation[1]
Method 1: The preparation method of 4-chloromethylbiphenyl includes the following steps:
1) Weigh 2kg of chlorobenzene, and add 1.2kg of anhydrous AlCl3, 0.1kg of CuCl and 1kg of biphenyl while stirring;
2) Under the condition of 33℃, first introduce hydrogen chloride gas for 10 minutes, and the weight of the introduced hydrogen chloride gas is 1g; then pass in the mixed gas of carbon monoxide and hydrogen chloride for 24 hours, in which the carbon monoxide in the introduced mixed gas 90g of gas, the weight of hydrogen chloride gas in the mixed gas is 14g; the reaction end point is when the biphenyl content of the raw material is ≤1% as detected by gas chromatography.
3) Add 0.12kg of 35% hydrochloric acid and 4kg of crushed ice to the reaction product obtained in step 2 at a temperature of 3°C for ice-lysis. Maintain the temperature at 6°C until the solid is completely dissolved and stir for 30 minutes. , let stand for 90 minutes and then separate the aqueous layer; wash the organic phase with dilute hydrochloric acid with a mass percentage concentration of 10%; separate the aqueous phase, and then wash the organic phase with 5kg of water until neutral; take the organic phase and wash it with anhydrous sulfuric acid Dry over sodium, filter out the desiccant, recover the solvent under reduced pressure, and collect the 183-185°C/11mmIIg fraction to obtain crude 4-formylbiphenyl.
4) Add the crude 4-formylbiphenyl obtained in step 3 to toluene. The weight ratio of the crude 4-formylbiphenyl to toluene is 8:1. Recrystallize, filter, and wash the crystal with 100g petroleum ether and dry. , 4-formylbiphenyl was obtained; the yield was 94%, and the gas chromatography analysis content was ≥99.5%.
5) Put 20g Raney Nickel and 280g ethanol into the reaction bottle, add 60g 4-formylbiphenyl while stirring; heat to 30°C, vent hydrogen gas under the liquid surface; start sampling and analysis after 3 hours of ventilation, and gas phase The reaction end point is when the 4-formylbiphenyl content is less than 0.5% measured by chromatography. After the reaction was completed, the Raney nickel was removed by filtration at 30°C. 210g of ethanol is recovered under normal pressure, crystallized by cooling, and filtered to obtain 4-hydroxymethylbiphenyl. The mother liquor is concentrated, recrystallized, filtered, and the crystals are combined. After drying, 58g of 4-hydroxymethylbiphenyl is obtained. The gas chromatography analysis content is ≥98.7%.
6) Weigh 264g of concentrated hydrochloric acid with a mass percentage of 35%, add 80g of 4-hydroxymethylbiphenyl while stirring, and heat to 75°C for 5 hours. Gas chromatography analysis shows that the 4-chloromethylbiphenyl content ≥97% is the reaction end point; cool down to 0°C and separate the aqueous layer, add 300g water and 80g petroleum ether, stir and raise the temperature to 70°C to separate the aqueous layer; take the organic phase and wash it with water until the pH is 7. Cool to -5°C to crystallize and filter. After drying the solid, 88g of 4-chloromethylbiphenyl was obtained, and the content was ≥98% according to gas chromatography analysis.
Method 2: In the reaction bottle, add 15.4g biphenyl (100mmol), 6.0g paraformaldehyde (200mmol), and add 48.5g ferric chloride (300mmol), and connect the air tube to the four ports At the bottom of the bottle, open the HCl gas generating device, slowly introduce dry HCl gas (100mmol), control the temperature at 70-80°C, and react for 18 hours. Cool, add the reaction solution to ice water, extract three times with ethyl acetate, combine the organic layers, wash with saturated NaHCO3 solution and water until neutral, distill off the ethyl acetate, and obtain a white solid, which is washed with ethanol. After crystallization, 16.2g of off-white or white powder 4-chloromethylbiphenyl was obtained (yield 80.2%, m.p: 71-73°C).
Main reference materials
[1] CN200810239871.3 A preparation method of 4-formylbiphenyl, 4-hydroxymethylbiphenyl and 4-chloromethylbiphenyl
[2] CN201210488221.9 Palladium-catalyzed carbonylation to prepare 4-biphenylacetic acid
[3] CN201710013415.6 Preparation method of 2-amino-3-biphenylpropionic acid ethyl ester derivative hydrochloride
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