Main preparation of p-octyl acetophenone_Kain Industrial Additive

Background and overview^[1]

P-Octyl acetophenone can be used as a pharmaceutical synthesis intermediate. If p-octyl acetophenone is inhaled, move the patient to fresh air; if there is skin contact, take off contaminated clothing, wash the skin thoroughly with soap and water, and seek medical treatment if you feel uncomfortable; if there is eye contact, remove The eyelids should be separated, rinsed with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Preparation^[1]

Step A: n-octanoylbenzene

Place 6.843g (47.5mmol) n-octanoic acid and 2.740g (19mmol) phosphine trichloride in a three-necked flask, stir and heat to 55-60°C for 3 hours. Stop heating, allow to cool to room temperature, pour off the supernatant, and wash the residue with 20 mL of benzene. Combine benzene and the decanted upper liquid, place it in another three-necked flask, stir, and slowly add 7.600g (57mmol) aluminum trichloride in batches. The reaction is carried out at room temperature for 4 hours. Stop stirring, pour the reaction mixture into a mixture of ice and dilute hydrochloric acid and stir continuously. The layers were separated, the organic layer was separated, the aqueous layer was extracted three times with benzene, and the organic layers were combined. The organic layer was washed successively with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 8.237g of n-octanoylbenzene, an oily product, with a yield of 84%.

MS: 204(M+), 133, 120, 105, 77.

NMR (CDCl3δ): 0.884 (t, 3H, -CH3), 1.362-1.392 (m, 10H, 5CH2), 1.719-1.773 (m, 2H, CH2), 2.964 (t, 2H, 2CH2), 7.458 (t, J＝5.7Hz, 2H, 2ArH), 7.552 (t, J＝5.7Hz, 1H, ArH), 7.458 (d, J＝5.7Hz, 2H, 2ArH).

Step B: n-octylbenzene

45g (220mmol) n-octanoylbenzene was dissolved in 120mL 95% ethanol, and 2mL 70% perchloric acid was added. Hydrogenate at medium pressure (3bar) until hydrogen is no longer consumed. The reaction solution was filtered and concentrated, and the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and washed with saturated sodium chloride solution. The organic layer was dried, filtered, and concentrated to obtain 35 g of n-octylbenzene, with a yield of 83.7%.

NMR (CDCl3δ): 0.889 (t, 3H, -CH3), 1.279-1.315 (m, 10H, 5CH2), 1.583-1.656 (m, 2H, CH2), 2.608 (t, 2H, 2CH2), 7.177 (t, J＝5.7Hz, 3H, 3ArH), 7.279 (t, J＝5.7Hz, 2H, 2ArH).

Step C: 4-n-Octylacetophenone

1.217g (6.4mmol) n-octylbenzene and 0.628g (8mmol) acetyl chloride are placed in a three-necked flask, stir at room temperature, add 1.175g (8.8mmol) aluminum trichloride in batches, and continue stirring after the addition. 1 hour. Stop stirring, pour the reaction mixture into a mixture of ice and dilute hydrochloric acid and stir continuously. The layers were separated, the organic layer was separated, the aqueous layer was extracted three times with benzene, and the organic layers were combined. The organic layer was washed successively with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 1.375g of oily product, with a yield of 93%.

MS: 232(M+), 217.

NMR (CDCl3δ): 0.886 (t, 3H, -CH3), 1.273-1.322 (m, 10H, 5CH2), 1.634 (m, 2H, CH2), 2.590 (s, 3H, CH3), 2.665 (t , 2H, 2CH2), 7.269 (d, J＝6.3Hz, 2H, 2ArH), 7.876 (d, J＝6.3Hz, 2H, 2ArH).

Main reference materials

[1]CN201710075350.8 A production process of amodiaquine and amodiaquine hydrochloride