A kind of preparation method of pimecrolimus
A technology of pimecrolimus and pyridine, which is applied in the field of medicinal chemistry, can solve the problems of low HPLC purity, decreased yield, and difficulty in removing ascomycin, etc., and achieves improved reaction yield, improved conversion rate and yield, and simplified Effect of Treatment Purification Methods
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Embodiment 1
[0063] Example 1: Comparative example based on Example 1 in EP1817317B1 (only using chloride ion source A)
[0064] A solution of 3.0 g (3.79 mmol) of ascomycin in 25 ml of anhydrous dichloromethane was slowly passed through the solution with a stream of dry nitrogen, and cooled to -15°C. Then 24 ml of a 5% by weight solution of trifluoromethanesulfonic anhydride in anhydrous dichloromethane were added to the above solution together with 1.8 g of 2,6-lutidine. After the addition was complete, 28 g of a 10% by weight solution of lithium chloride (66.05 mmol, corresponding to 17.4 molar equivalents of ascomycin) in dichloromethane was added to the above reaction mixture. The reaction mixture was warmed to about 21 °C and stirred at this temperature for 4 days. The reaction mixture was diluted with a mixture of 200ml ethyl acetate and 25ml water, the organic layer was extracted, and then the solvent was evaporated to obtain 3.4g of crude product of pimecrolimus, yield (110.8%), ...
Embodiment 2
[0065] Example 2: Comparative example based on Example 2 in EP1817317B1 (only using chloride ion source B)
[0066]Dissolve 2.9 g (3.66 mmol) of ascomycin in 20 ml of toluene. The solution was concentrated to dryness at 40 °C. Under the protection of nitrogen, the obtained residue was dissolved in 23 ml of anhydrous toluene, and then 28 ml of anhydrous acetonitrile was added. The resulting solution was cooled to -15°C, and 1.13 g of diisopropylethylamine was added to the reaction mixture. 32 ml of anhydrous toluene solution of 1.39 g of trifluoromethanesulfonic anhydride previously cooled to -15°C was added to the above reaction mixture. After the addition was complete, the reaction temperature was raised to 0°C and 30 g of a 12.5% by weight solution of benzyltriethylammonium chloride (16.46 mmol, corresponding to 4.5 molar equivalents of ascomycin) in anhydrous acetonitrile was added. Then the reaction temperature was raised to about 25°C, stirred at 24-25°C for 45min, a...
Embodiment 3
[0067] Embodiment 3: Prepare pimecrolimus according to the method of the present invention
[0068] 2.9 g (3.66 mmol) of ascomycin were dissolved in 20 ml of toluene, and the solution was concentrated to dryness at 40°C. Under the protection of nitrogen, the obtained residue was dissolved in 23 ml of anhydrous toluene, and then 28 ml of anhydrous acetonitrile was added. The resulting solution was cooled to -15°C, and 1.13 g of diisopropylethylamine was added to the reaction mixture. 32 ml of anhydrous toluene solution of 1.39 g of trifluoromethanesulfonic anhydride previously cooled to -15°C was added to the above reaction mixture. After the addition was complete, the reaction temperature was raised to 0°C, and then 1.90 g (8.34 mmol) of benzyltriethylammonium chloride and 0.34 g (8.02 mmol) of LiCl were added (the total amount of chloride ions was 16.36 mmol, equivalent to 4.5 moles equivalent of ascomycin) in anhydrous acetonitrile. Then the reaction temperature was raise...
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