Using lincomycin hydrochloride as raw material, selective chlorination without separation of Vilsmeier reagent, and precipitation of clindamycin alcoholate in ethanol-saturated hydrogen chloride solution, and then using triethyl orthoformate as hydroxyl group Protecting agent, and finally using phosphorus oxychloride (POCl3) as a phosphorylating reagent, after hydrolysis reaction, recrystallization to obtain the product clindamycin phosphate.
Synthetic route of Clindamycin Phosphate Gel Price
Fig. 1 is the synthetic route of Clindamycin Phosphate Gel Price
The operation steps are as follows:
1. Synthesis of clindamycin 2 in a dry 250ml three-necked flask, pass N2 protection, add 20ml DMF and 100ml 1,2-dichloroethane, cool to 0°C, add 20ml POCl dropwise with stirring, and place in an ice bath after dropping. After keeping the temperature for about 30min, add 20g lincomycin hydrochloride 1 in batches, after adding, control the temperature to react at about 10°C for 1h, and react at room temperature for 1h, and then increase the temperature at 5-6°C every hour under the oil bath until it reaches 65-70°C, The reaction was incubated for 10h, and there was no raw material detected by thin layer chromatography (TLC). Cool to room temperature.
2. Synthesis of clindamycin alcoholate 3 The above reaction solution was transferred to a 500ml beaker, cooled in an ice bath, and 18% NaOH solution was added dropwise with stirring to pH 10-11. Transferred to a separatory funnel, The lower organic phase was separated, the aqueous phase was extracted with ethyl acetate (40ml×3), the organic phases were combined, washed with saturated brine until neutral, and dried over anhydrous Na2SO4. The organic phase was concentrated to dryness, and 70ml of ethyl acetate was added to make it Dissolve, add dropwise 25ml of ethanol solution saturated with hydrogen chloride under cooling, and separate out a white solid. Filter with suction, wash twice with ethyl acetate, and dry at 70 ° C to obtain white clindamycin alcoholate 321g, yield 92%, Meltpoint (mp) 142～144℃.
3. Synthesis of cyclic orthoester 4 In a 500ml three-necked flask, add 200ml of acetone and 20g of clindamycin alcoholate 3 respectively, and after stirring for 30min, slowly add 40ml of triethyl orthoformate dropwise to the system, at room temperature. The reaction was stirred for 18-24 hours, and no raw material was detected by TLC. Filtration, the filter cake was dissolved in 10 ml of dichloromethane and 150 ml of water, left to stand for stratification, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 ml × 3). Combined The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure.
4. Synthesis of phosphoryl compound 5 In a dry 500ml three-neck flask, pass N2 protection, add 350ml dichloromethane, 40ml triethylamine respectively, stir at room temperature for 30min, cool with ice water to below 10 ℃, slowly add dropwise 8.5ml of phosphorus oxychloride (POCl3) was added dropwise and kept at room temperature for 1h, then the above-mentioned cyclic orthoester 4 dissolved in dichloromethane was added dropwise, and the reaction was carried out at room temperature for 4h. TLC detected no raw materials. The reaction solution was slowly cooled under an ice bath. It was added dropwise to a 10% Na2CO3 solution for neutralization, the organic phase was separated, the aqueous phase was extracted with dichloromethane (100ml×3), the organic phases were combined, dried with Na2SO4, and the organic phase was concentrated under reduced pressure to a viscous state. .
5. Synthesis of Clindamycin Phosphate 6 The above-mentioned viscous substance was dissolved in dichloromethane, dropped into cold water at 10°C, and adjusted to pH 2 to 3 with dilute hydrochloric acid, and then heated to 25 to 30°C for thermal insulation and hydrolysis. 4h, TLC tracked the reaction. After the hydrolysis was completed, the reaction solution was concentrated under reduced pressure, and then 50ml of absolute ethanol was added to azeotrope. Then 100ml of absolute ethanol was added, stirred, left to stand for cooling and crystallization, filtered, washed with a small amount of ethanol, and dried at 70°C. Dry to give 6 as a white solid.