A prep work approach for Clotrizole Option, consisting of action one and also step 2. The total response flow formula is:
Action 1: Chlorine (2-chlorophenyl) diphenylmethanol right into (2-chlorophenyl) diphenylmethane. The specific operation is as adheres to:
Include 1L toluene and also 100g (2-chlorophenyl) diphenylmethanol right into a 2L three-necked flask, stir and also liquify, add 5ml N,N-dimethylformamide and 10g thionyl chloride, and raise the temperature to 60 ~ 65 ° C to initiate, start adding 91g of thionyl chloride dropwise after initiation, as well as manage the temperature not to exceed 65 ° C throughout the procedure. After the dropwise addition is completed, maintain the temperature level at 60-65 ° C and also mix for 2 hrs.
After the response is completed, raise the temperature to 90-95 ° C, start purification under typical pressure, and also continue distillation for 2 hours after no obvious portion drains. Cool the temperature to 30-35 ° C, distill under decreased stress at this temperature, as well as collect 130 mL of fraction. The response service was warmed to 40-45 ° C, and also distilled under reduced pressure at this temperature to accumulate 390 mL of portion. The deposit is cooled to 20-30 ° C to obtain a toluene service of( 2-chlorophenyl) diphenylmethane chloride. Action 2: Condensate (2-chlorophenyl) diphenylmethane chloride and imidazole to create clotrimazole. The details operation is as complies with:
Under nitrogen defense, add 35g of imidazole to the toluene option of the above intermediate (2-chlorophenyl)diphenylmethane chloride, and also include 51mL of triethylamine dropwise. Throughout the dropwise enhancement, the temperature must not exceed 35 ° C. After the dropwise addition is finished, proceed stirring at 20-30 ° C for 1 hour, then raise the temperature of the reaction solution to 40-50 ° C, as well as maintain the temperature for 2 hrs.
After the reaction is finished, change the hot water with cold water, include 330g saturated liquid sodium bicarbonate option (30g sodium bicarbonate dissolved in 300 mL) to the reaction option, continue mixing for 0.5 h, and also separate the liquids. The natural stage was cleaned three times with 300 mL cleansed water as well as soon as with 300 L saturated salt water. Distill under reduced stress at 55-65 ° C up until no noticeable portion flows out. Add 200mL isopropyl alcohol to the deposit, heat to 65 ~ 75 ° C, stir to liquify, add 5g activated carbon, keep mixed for 0.5 h, warmth, cool down the filtrate to -5 ~ 5 ° C, add a small amount of seed crystal, keep mixed for 12h, filter and also completely dry to acquire clotrimazole.
Take 4 mmol of 2-chlorotrityl chloride, 8 mmol of imidazole as well as 8 mmol of sodium carbonate, include 20 mL of hexafluoroisopropanol (HFIP), and also mix at space temperature (25 ° C) for 2 days. After the response is finished, the reaction standing is figured out by tender loving care, concentrated, as well as separated by column chromatography. The response return was evaluated to be 92%. 1HNMR(500MHz, CDCl3)δ& delta; 7.46(s,1 H),7.41(d, J ＝ 7.7 Hz,1 H),7.34(d, J ＝ 1.2 Hz,7 H ),7.24 (d, J ＝ 8.0 Hz,1 H), 7.20 (d, J = 1.3 Hz, 4H), 7.06 (s, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.75 (s, 1H). 13CNMR (125MHz, CDCl3) & delta; 140.90,140.38,139.13,135.59,132.23,130.42,130.19,129.87,128.43,128.17,128.03,127.04,121.59,75.10.
