Pimecrolimus synthesis

Yield:-

Reaction Conditions:

with lithium chloride in dichloromethane at -15 - 21; for 96 h;Product distribution / selectivity;

Steps:

1

Example 1[00047] A 3.0 g sample of crude ascomycin was purified by passing it through a short silica column. The 3.0 g of syrup obtained was dissolved in 25 ml of anhydrous dichloromethane. The solution was cooled to -15°C with a slow stream of dried nitrogen gas bubbling through the solution.[00048] A 5 percent by weight solution of trifluoromethanesulfonic anhydride in anhydrous dichloromethane was added to the above solution in 6 ml parts, together with 0.3 g parts of 2,6-lutidine. After the addition of a total of 24 ml trifluoromethanesulfonic anhydride solution, 28 g of a 10 percent by weight lithium chloride solution was added to the reaction mixture, and the reaction mixture was allowed to warm to room temperature, i.e., about 21⁰C. The reaction mixture was then stirred for 4 days.[00049] The reaction mixture was diluted with a mixture of 200 ml ethyl acetate and 25 ml of water, and poured into a separating funnel, and shaken. After extraction, 25 ml of a 10 percent by weight aqueous solution OfKHSO₄ was added. Following additional shaking, the aqueous layer was removed, and the organic phase was washed three times with 25 ml of a 10 percent by weight aqueous ICHSO₄ solution, twice with 25 ml of a saturated aqueous NaHCO₃ solution, and twice with 25 ml of brine. The organic phase was dried over anhydrous MgSO₄. After filtration, it was concentrated in vacuum, and, then, finally, under high vacuum to completely remove the solvent. The yield was 2.94 g of crude amorphous pimecrolimus.[00050] The product was purified by flash chromatography using n- hexane/acetone (2:1, VAO ^{as an} eluent. The yield was 2.54 g of amorphous pimecrolimus.

References:

WO2006/60614,2006,A1 Location in patent:Page/Page column 13