Conazole, like the traditional imidazole anti-bacterial product ketoconazole, is a brand-new imidazole broad-spectrum antifungal item that can prevent fungal ergosterol biosynthesis as well as transform the composition of various other lipid compounds in the cell membrane layer. It has hostile effects against Candida fungus, Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides. Nonetheless, compared with ketoconazole, the latter can not be utilized in individual treatment items, while neoconazole It has far better water solubility than ketoconazole and is suitable for use in the field of personal treatment products. It has actually been included in the extent of European individual care products and also has a really broad market possibility.
The synthesis of Conazole is based on cis- [2-( 2,4-dichlorophenyl) -2-( 1H-imidazole-1-ylmethyl) -1,3- dioxolane- 4-yl] Methanol p-toluenesulfonate (III, active ester form) is used as basic material, as well as is obtained by condensation with 4-( 4-hydroxyphenyl) -1- piperazine carboxylic acid ethyl ester (IV).
In US4335125, neoconazole is recrystallized from 2-methyl-2-pentanone, and also the melting point of the neoconazole acquired is 112.2 ° C. In world license WO93/18743, the synthesis of neoconazole begins with ketoconazole. The raw materials are hydrolyzed, acylated, fine-tuned and also changed to acquire Kind I neoconazole.
The filtration technique is to utilize 2-methyl-2-pentanone to crystallize, the response as well as crystallization yield is 84.9%, and then utilize acetone to transform to type I, the makeover return is 82.1%, and the complete return of kind I is 69.7%. The melting point of type I neoconazole is 127.6 ° C
. In WO93/18743, the buildings of Conazole Type I as well as Type II are likewise pointed out. The optimum DSC height of Type I with high melting point goes to 127.6 ° C, while the optimum DSC height of Kind II with reduced melting point goes to 110.9 ° C. Kind I is smaller sized than II. It is much more steady and is favored for use in cosmetics for the body. In the above two patents, 2-methyl-2-pentanone is used for recrystallization, which is not just costly and also expensive, yet also ketone chemicals continue to be in the item, which is hazardous to human wellness. In the Chinese patent disclosure spec CN101665490A, it is stated that recrystallization with ethyl acetate is utilized, and the recrystallization yield is 69.8% to 84.5%. Ethyl acetate is used for recrystallization of organic matter, yet the yield is low, and the melting point of the product is not discussed.
CN201210075893.7 provides a brand-new approach for purifying Conazole. The technological option actions are as complies with:
Action (1 ). Make use of a combined service of water and lower alkanol to dissolve the unrefined neoconazole at a temperature of 5085 ° C. The ratio of water to lower alkanol in the mixed solution is 3/71/19;
The lower alkanols in the action (1) consist of methanol, ethanol, propanol, and also isopropyl alcohol; the weight ratio of the combined remedy of water and reduced alkanols to the crude new conazole is 10/ 12/1;
Step (2 ). In the mixed service in which the unrefined neoconazole is liquified, add triggered carbon for decolorization. After filtering system to get rid of the carbon, awesome to -515 ° C for condensation; after that filter and dry again. The web content of the improved neoconazole gotten is above 99.0%., HPLC pureness is above 99.5%, melting point is in between 127.6 ~ 130 ℃.
The useful effects of today development are as follows:
Today creation is used to purify Conazole. The technique is basic as well as inexpensive. The pureness of the product acquired after filtration is more than 99.5%, the content is more than 99.0%, the melting point is 127.6-130 ° C, the stability of the acquired product is good, and the complete molar return of the response is 89 ~ 91%.
Certain instances of purification operations are as follows:
Action (1 ). In the reaction kettle, placed 100KG of ketoconazole and also 110KG of 10% hydrochloric acid, react at 85 ° C for 20 hrs, as well as trendy to space temperature level; then include 400L of toluene, and then slowly include 96.5 KG of 50% hydroxide. Salt remedy, speed up crystalline solid, centrifuge, laundry with 40KG of water, filter and combine, spin dry, as well as completely dry to get 92.1 KG of hydrolyzate, with HPLC purity of greater than 99.5% and also yield of 100%.
Step (2 ). Place the 92.1 KG hydrolyzate obtained symphonious (1) right into the reaction kettle, then include 520KG methylene chloride and 36KG potassium carbonate, include 25KG ethyl chloroformate dropwise at area temperature, then mix for 3 hours as well as include 300KG water., take the organic phase by layering, boil down under minimized stress to recuperate methylene chloride to dry skin, and obtain crude new conazole.
Action (3 ). Add the gotten unrefined neoconazole into 400KG of water-ethanol blended service (weight proportion 25:75), heat to 75 ° C to liquify, include carbon to filter, cool, crystallize, filter, and also drain. After drying, 95.6 KG of new conazole was gotten, with HPLC purity of 99.6%, chemical titration material of 99.4%, melting point of 127.6 ~ 128.5 ° C, and total return of 90.5%.
