Hydrogen iodide → 111390-01-3

Temperature

37 °C

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).

1. temperatureThe thick product slurry was then cooled to about 5° C.
2. custombelow 10° C
3. stirringAfter agitating the mixture for 15 minutes with continued cooling
4. customto rise to 20° C.
5. stirringthe two-liquid phase mixture was agitated for 15 minutes at about 20° C
6. customThe rich aqueous phase was separated
7. washthe spent cyclohexane phase was washed with water (10 ml)
8. extractionThe combined aqueous extract
9. additionwas treated with diatomaceous earth (3 g)
10. stirringagitated for 5 minutes at 20°-25° C.
11. additionthen treated with decolorizing carbon (4 g)
12. stirringAfter agitating for 30 minutes at 20°-25° C.
13. filtrationthe mixture was filtered
14. washthe spent cake was washed with water (40 ml)
15. additionThe filtrate was diluted with 2-propanol (500 ml)
16. customto crystallize the product
17. temperatureThe resulting product slurry was cooled to 0°-5° C.
18. stirringwas agitated for 1 hour
19. filtrationThe slurry was filtered
20. washwashed with 80 ml of 2-propanol:water (4:1) and 80 ml of 2-propanol
21. customFurther drying in vacuo at 45° C.

ORD record

ord-cda9922dacb1491e9cd9054f5db2da17

Source dataset

uspto-grants-1997_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05594131