According to the method of the present invention, bacteriostatic ester (±) cis-4-[4-[[2-(2,4-dichlorophenyl)-2-(1-H-imidazolemethyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinecarboxylic acid ethyl ester is prepared, comprising the following steps:
1. Condensation reaction
In a dry 500ml three-necked flask, add 473g of dimethyl sulfoxide, 130g of active lipid, 50g of N-(4-hydroxyphenyl)piperazine, and 21g of potassium hydroxide. Control the temperature at 30℃ and keep the reaction for 24 hours. After the reaction, add 520g of purified water. After the addition is completed, cool to 5℃, stir and keep warm for 2h, and filter to obtain the antibacterial ester condensate. The condensation yield is about 85%.
2. Esterification reaction
In a three-necked flask, 322g of dichloromethane, 50g of antibacterial ester condensate, and 52g of potassium carbonate were added, and then 11.9g of ethyl chloroformate was slowly added. After the addition was completed, the temperature was controlled at 25°C and the reaction was kept warm for 4 hours. After the reaction was completed, 108g of purified water was slowly added. After the addition was completed, stirring was continued for 2h. The organic layer was washed three times with purified water until the pH reached 7. After washing, dichloromethane was evaporated under reduced pressure. After evaporation, 60ml of methyl isobutyl ketone was added and the temperature was kept at 0-5°C for 2-4h. The antibacterial ester was obtained by suction filtration, and the esterification yield was about 80%.
Heat the antibacterial ester and dissolve it in 8 times the amount of acetone, add 0.5 times the amount of activated carbon, reflux and keep warm for 0.5 hours, cool down to no reflux, filter and remove the activated carbon, concentrate the filtrate to 5 times the weight of the antibacterial ester, add water and cool down to 0-5°C after concentration, keep warm for 1-3 hours under stirring, and filter to obtain an off-white crystalline powder. After analysis, the antibacterial ester content is greater than 97%.
In a 1000ml reaction bottle, under nitrogen protection, add 500g of water, 178.5g of dichloroethylamine hydrochloride and 109g of p-hydroxyaniline, heat to 100°C, add 160g of 50% sodium hydroxide solution (80g of sodium hydroxide dissolved in 80g of water), reflux for 10 hours. Then cool to 35°C, add 400g of methanol, adjust the pH value to 8 with ammonia water, filter, and dry the filter cake in vacuum at 40°C to obtain 128g of 4-(4-hydroxyphenyl)piperazine (HPLC content greater than 98%), with a yield of 71.9%.
Example 2
In a 1000ml reaction bottle, under nitrogen protection, add 500g of water, 178.5g of dichloroethylamine hydrochloride and 218g of p-hydroxyaniline, heat to 70°C, add 112g of 50% potassium hydroxide solution (56g of potassium hydroxide dissolved in 56g of water), and react for 5 hours. Then cool to 35°C, add 400g of methanol, adjust the pH value to 8 with ammonia water, filter, and dry the filter cake in vacuum at 40°C to obtain 112g of 4-(4-hydroxyphenyl)piperazine (HPLC content greater than 98%), with a yield of 62.9%.
Example 3
In a 1000ml reaction bottle, under nitrogen protection, add 500g of water, 312g of dichloroethylamine hydrobromide and 150g of p-hydroxyaniline, stir at room temperature (25°C), add 200g of 50% potassium bicarbonate solution (100g of potassium bicarbonate dissolved in 100g of water), react for 1 hour, then cool to 35°C, add 400g of methanol, adjust the pH value to 8 with ammonia water, filter, and dry the filter cake in vacuum at 40°C to obtain 87g of 4-(4-hydroxyphenyl)piperazine (HPLC content greater than 98%), with a yield of 48.8%.
Example 4
In a 1000ml reaction bottle, under nitrogen protection, add 500g of water, 452g of dichloroethylamine hydroiodide and 327g of p-hydroxyaniline, heat to 100°C, add 480g of 50% sodium hydroxide solution (240g of sodium hydroxide dissolved in 240g of water), reflux for 10 hours. Then cool to 35°C, add 600g of methanol, adjust the pH value to 8 with ammonia water, filter, and dry the filter cake in vacuum at 40°C to obtain 154g of 4-(4-hydroxyphenyl)piperazine (HPLC content greater than 98%), with a yield of 86.5%.
Synthesis of Ethyl [4-(4-Hydroxyphenyl)]-1-piperazinecarboxylate
Example 5
In a 2000 ml reaction bottle, add 178 g of 4-(4-hydroxyphenyl)piperazine, 150 g of sodium bicarbonate and 500 g of acetone, cool to -20°C with ice brine, add 110 g of ethyl chloroformate dropwise, and keep the temperature in the bottle not higher than zero degrees. After the addition is complete, heat to room temperature and react for 5 hours;
Add 700g of water, stir for 1 hour and filter. Add the filter cake obtained by filtration to a 1000ml reaction bottle, add 300g of 75% ethanol solution by volume, heat to dissolve, cool to zero degrees with ice brine, filter, and dry the filter cake in vacuum at 40°C to obtain 146g of [4-(4-hydroxyphenyl)]-1-piperazinecarboxylic acid ethyl ester (HPLC content greater than 99%), 58.4%.
Example 6
In a 2000ml reaction bottle, add 178g of 4-(4-hydroxyphenyl)piperazine, 180g of sodium carbonate and 500g of acetone, cool to -10°C with ice brine, add 165g of ethyl chloroformate dropwise, and keep the temperature in the bottle not higher than zero degrees. After the addition is complete, heat to 50 degrees and react for 1 hour;
Add 700g of water, stir for 1 hour and filter. Add the filter cake obtained by filtration to a 1000ml reaction bottle, add 300g of 75% ethanol solution by volume, heat to dissolve, cool to zero degrees with ice brine, filter, and dry the filter cake in vacuum at 40°C to obtain 156g of [4-(4-hydroxyphenyl)]-1-piperazinecarboxylic acid ethyl ester (HPLC content greater than 99%), 62.4%.
Example 7
In a 2000ml reaction bottle, add 178g of 4-(4-hydroxyphenyl)piperazine, 400g of potassium bicarbonate and 1000g of acetone, cool to 0°C with ice brine, add 440g of ethyl chloroformate dropwise, and keep the temperature in the bottle not higher than zero degrees. After the addition is completed, react at about 0°C for 10 hours;
Add 1000g of water, stir for 1 hour and filter. Add the filter cake obtained by filtration to a 1000ml reaction bottle, add 500g of 75% ethanol solution by volume, heat to dissolve, cool to zero degrees with ice brine, filter, and dry the filter cake in vacuum at 40°C to obtain 216g of [4-(4-hydroxyphenyl)]-1-piperazinecarboxylic acid ethyl ester (HPLC content greater than 99%), 86.4%.
Example 8
In a 2000ml reaction bottle, add 178g of 4-(4-hydroxyphenyl)piperazine, 140g of triethylamine, and 500g of acetone; cool to -10°C with ice brine, add 110g of ethyl chloroformate dropwise, and keep the temperature in the bottle not higher than zero degrees. After the addition is complete, react at -10°C for 10 hours;
Add 700g of water, stir for 1 hour and filter. Add the filter cake obtained by filtration to a 1000ml reaction bottle, add 300g of 75% ethanol solution by volume, heat to dissolve, cool to zero degrees with ice brine, filter, and dry the filter cake in vacuum at 40°C to obtain 126g of [4-(4-hydroxyphenyl)]-1-piperazinecarboxylic acid ethyl ester (HPLC content greater than 99%), 50.4%.
Synthesis of Ketoconazole Derivatives:
Example 9
In a 1000ml reaction bottle, add 45g of cis-[2-(2,4-dichlorophenyl)-2(1H-imidazol-1-yl-methyl)-1,3-dioxopentyl]-4-methyl-p-toluenesulfonate, 25g of ethyl [4-(4-hydroxyphenyl)]-1-piperazinecarboxylate, 5.6g of potassium hydroxide and 180g of dimethyl sulfoxide; react at 25°C for 20 hours. After the reaction, add 450g of ice water to the reaction bottle to reduce the temperature in the reaction bottle to 10°C, and filter; wash the filter cake with water until it is neutral and dry; obtain 42g of crude ketoconazole derivative (HPLC content is 94%).
In a 1000ml reaction bottle, add 42g of crude ketoconazole derivative and 350g of ethyl acetate, heat to dissolve, add 0.5g of activated carbon, reflux for half an hour, filter, wash the filter cake with hot ethyl acetate, combine the ethyl acetate, and concentrate to 230g; cool naturally to room temperature, then continue to cool to 0°C with ice water, and keep warm for 1 hour, filter, and vacuum dry to obtain 39g of white powder (HPLC content greater than 99%), with a yield of 73.6%.
Example 10
In a 1000 ml reaction bottle, add 45 g of cis-[2-(2,4-dichlorophenyl)-2(1H-imidazol-1-yl-methyl)-1,3-dioxolane]-4-methyl-p-toluenesulfonate, 50 g of ethyl [4-(4-hydroxyphenyl)]-1-piperazinecarboxylate, 11.2 g of sodium hydroxide and 200 g of dioxane; react at 50° C. for 10 hours. After the reaction, add 450 g of ice water to the reaction bottle to reduce the temperature in the reaction bottle to 10° C. and filter; wash the filter cake with water until it is neutral and dry; obtain 41 g of crude ketoconazole derivative (HPLC content is 94%).
In a 1000ml reaction bottle, add 41g of crude ketoconazole derivative and 340g of ethyl acetate, heat to dissolve, add 0.5g of activated carbon, reflux for half an hour; filter, wash the filter cake with hot ethyl acetate, combine ethyl acetate, and concentrate to 230g; cool naturally to room temperature, then continue to cool to 0°C with ice water, and keep warm for 1 hour, filter, and vacuum dry to obtain 37g of white powder (HPLC content greater than 99%), with a yield of 69.8%.
Embodiment 11
In a 1000ml reaction bottle, add 45g of cis-[2-(2,4-dichlorophenyl)-2(1H-imidazol-1-yl-methyl)-1,3-dioxopentyl]-4-methyl-p-toluenesulfonate, 100g of ethyl [4-(4-hydroxyphenyl)]-1-piperazinecarboxylate, 22.4g of sodium methoxide and 300g of tetrahydrofuran; react at 0°C for 50 hours. After the reaction, add 500g of ice water to the reaction bottle to reduce the temperature in the reaction bottle to 10°C, filter; wash the filter cake with water until neutral and dry; obtain 49g of crude ketoconazole derivative (HPLC content is 94%).
In a 1000ml reaction bottle, add 49g of crude ketoconazole derivative and 350g of ethyl acetate, heat to dissolve, add 0.5g of activated carbon, reflux for half an hour; filter, wash the filter cake with hot ethyl acetate, combine ethyl acetate, and concentrate to 250g; cool naturally to room temperature, then continue to cool to 0°C with ice water, and keep warm for 1 hour, filter, and vacuum dry to obtain 43.9g of white powder (HPLC content greater than 99%), with a yield of 82.8%.
Example 12
In a 1000ml reaction bottle, add 45g of cis-[2-(2,4-dichlorophenyl)-2(1H-imidazol-1-yl-methyl)-1,3-dioxopentyl]-4-methyl-p-toluenesulfonate, 42g of ethyl [4-(4-hydroxyphenyl)]-1-piperazinecarboxylate, 15g of sodium ethoxide and 300g of N,N-dimethylformamide; react at 10°C for 30 hours. After the reaction, add 500g of ice water to the reaction bottle to reduce the temperature in the reaction bottle to 10°C, and filter; wash the filter cake with water until it is neutral and dry; obtain 51.2g of crude ketoconazole derivative (HPLC content is 94%).
In a 1000ml reaction bottle, add 51.2g of crude ketoconazole derivative and 400g of ethyl acetate, heat to dissolve, add 0.5g of activated carbon, reflux for half an hour; filter, wash the filter cake with hot ethyl acetate, combine ethyl acetate, and concentrate to 250g; cool naturally to room temperature, then continue to cool to 0°C with ice water, and keep warm for 1 hour, filter, and vacuum dry to obtain 44.8g of white powder (HPLC content greater than 99%), with a yield of 84.5%.
