Hydrogen iodide → (6R,7R)-7-amino-3-(1-methyl-1-pyrrolidinio)methylceph-3-em-4-carboxylate monohydroiodide

Participants

Reaction Conditions

Reaction Steps

The silylated 7-ACA slurry was added to the TMSI/NMP slurry and the mixture was agitated for 30 minutes at 15°-20° C. Next, iodotrimethylsilane (TMSI, 4.2 ml, 29.5 mmol) was added and the reaction mixture was warmed to about 37° C. for 40 hours under a slight stream of nitrogen. The thick product slurry was then cooled to about 5° C. and 2-propanol (10 ml) was added dropwise keeping the temperature at or below 10° C. After agitating the mixture for 15 minutes with continued cooling, a solution of hydriodic acid (20 ml of 57% HI in 30 ml of water) was added. The temperature was allowed to rise to 20° C. and the two-liquid phase mixture was agitated for 15 minutes at about 20° C. The rich aqueous phase was separated and the spent cyclohexane phase was washed with water (10 ml). The combined aqueous extract was treated with diatomaceous earth (3 g), agitated for 5 minutes at 20°-25° C. then treated with decolorizing carbon (4 g). After agitating for 30 minutes at 20°-25° C., the mixture was filtered and the spent cake was washed with water (40 ml). The filtrate was diluted with 2-propanol (500 ml) to crystallize the product. The resulting product slurry was cooled to 0°-5° C. and was agitated for 1 hour. The slurry was filtered and washed with 80 ml of 2-propanol:water (4:1) and 80 ml of 2-propanol. Further drying in vacuo at 45° C. afforded 18.5 g (59.2%) of crystalline (6R, 7R)-7-amino-3-[(1-methyl-1-pyrrolidinio)methyl]ceph-3-em-4-carboxylate monohydriodide. Purity as determined by HPLC was 97.3%. The 1H NMR spectrum observed with the title compound is the same as an authentic sample prepared by the method in the art using Freon TF (U.S. Pat. No. 4,714,760): 1H NMR (D2O, 360 MHz) δ: 2.14-2.32 (envelope, 4H, --N(CH3)CH2CH2 --), 3.00 (s, 3H, NCH3), 3.46-3.67 (m, 5H, --N(CH3)CH2CH2 ; SCH2), 3.96 (d, 1H, J=16.9 Hz, --SCH2), 4.09 (d, 1H, J=13.9 Hz, =CCH2N--), 4.73 (d, 1H, J=13.9 Hz, =CCH2N--), 5.21 (d, 1H, J=5.1 Hz, --COCHCHS--), 5.41 (d, 1H, J=5.1 Hz, --COCHCHS).

Provenance & Evidence