Preparation and application of benzophenone oxime_Kain Industrial Additive

Background and overview^[1]

Parecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), a prodrug of valdecoxib, and a coxib analgesic among anti-arthritic drugs. . Parecoxib is used for the short-term treatment of postoperative pain. The sodium salt of parecoxib is used clinically as an injection. Benzophenone oxime is an intermediate in the preparation of parecoxib.

Preparation^[1]

Preparation of benzophenone oxime

Add 200g 1,2-benzophenone (purchased from Tianjin Guangfu Fine Chemical Research Institute), 92.2g hydroxylamine hydrochloride (1.3mol) (purchased from Tianjin Guangfu Fine Chemical Research Institute) and 400ml ethanol into the reaction bottle, stir. Add 134g triethylamine (1.3mol) (purchased from Tianjin Guangfu Fine Chemical Research Institute), raise the temperature to 70-75°C and keep stirring for 4 hours, then lower the temperature to 50-60°C, distill the ethanol under reduced pressure to obtain an oily substance, add 500ml Water, the oily substance is solidified, stir vigorously for 30 minutes to disperse, filter, wash with water (300ml×1), and wash with solvent (water: ethanol = 2:1, 300ml×2). Dry at 50°C for 4-6 hours to obtain 194g of white solid, with a yield of 90%.

Apply^[1]

1. Preparation of 4,5-dihydro-5-methyl-5-hydroxy-3,4-diphenylisoxazole

Under nitrogen protection, add 120g benzophenone oxime and 500ml tetrahydrofuran to the reaction flask, stir and dissolve completely, cool down to -10℃~-20℃ in the ice-salt bath, and then start to drop 500ml of diisopropyl Lithium amide/tetrahydrofuran solution (purchased from Chengdu Hongsheng Technology Development Co., Ltd.), control the temperature to ‑5℃～‑20℃, add it within 1 to 2h, after adding, keep the temperature at ‑5～‑20℃ and stir for 15min , add 240ml of ethyl acetate at one time, naturally raise the temperature to about 15°C, and keep stirring for 1 hour. Then add 240ml of ethyl acetate, stir the ice-salt bath and cool it to -10~0℃, quickly add the quenching solution (a mixed solution of 100ml saturated sodium chloride aqueous solution + 100ml water + 73.4g acetic acid, and cool it to 0~5 in advance °C), control the temperature at 15-20 °C, stir for 5 minutes, place to separate layers, and wash the organic phase with 100 ml of saturated sodium chloride aqueous solution. Take the organic phase and evaporate to dryness under reduced pressure to obtain a solid. Add 240 ml of n-hexane, raise the temperature to reflux, stir under reflux for 5 minutes, filter, cool down, keep stirring at 0-10°C for 3 hours, precipitate the solid, filter, wash with n-hexane, and dry the filter residue at 50°C to obtain 70g of white solid, yield 47 %.

2. Preparation of valdecoxib

Add 70.0g 4,5-dihydro-5-methyl-5-hydroxy-3,4-diphenylisoxazole and 210ml methylene chloride into the reaction bottle, stir, and cool to 0~-5℃ , start adding 315g chlorosulfonic acid (purchased from Tianjin Guangfu Fine Chemical Research Institute) dropwise, and control the temperature at ‑5~10°C. After the addition is completed, raise the temperature to reflux, keep it warm and stir for 5 hours, stir and cool down to ‑5~0°C, and slowly pour Pour into ice water, stir for 5 minutes, let stand for layering, collect the lower layer, extract the aqueous phase with dichloromethane (210ml×1), and combine the organic phases.

Measure 175ml of ammonia water, stir and cool, add the above organic phase to the ammonia water, control the temperature at 15-25°C, after adding, keep stirring at 23-27°C for 1 hour, raise the temperature and reflux, stir for 1 hour, and evaporate under reduced pressure. Methyl chloride, add 700ml water to the residue, stir and disperse, filter, wash with 140ml water, wash with 140ml isopropyl alcohol, no need to dry, add a mixture of isopropyl alcohol, water and butanone with a volume ratio of 1:1:1 Solvent, heat and reflux until completely dissolved, cool down and stir to crystallize, filter, and dry at 50°C for 4-6 hours to obtain 70g of white powder solid with a yield of 80.6%. The melting point of the product is 172-174℃.

3. Preparation of parecoxib

Add 35.0g of valdecoxib prepared in the previous step, 24.3g of propionic anhydride (1.6mol) (purchased from Sinopharm Chemical Reagent Company), and 14.6g (1.3mol) of triethylamine (purchased from Tianjin) into the reaction bottle. Guangfu Fine Chemical Research Institute), 35ml tetrahydrofuran and 0.35g 4-dimethylaminopyridine (DMAP) (Aladdin’s reagent), stir and raise the temperature to reflux, keep stirring for 7 hours, evaporate the solvent to dryness under reduced pressure, add water to the residue, stir and disperse, and filter , washed with water (70ml Recoxib 31.0g, total yield 75.0%. productThe melting point is 147-149°C. Elemental analysis shows that the theoretical values ​​are: C61.61, H4.90, N7.56; the measured values ​​are: C61.59, H4.92, N7.55.

Main reference materials

[1] CN201310072508.8 A method of preparing parecoxib