Hydrochloric Acid → Ceftolozane Impurity 15

Temperature

3.5 °C

A 5.0 liter reactor was charged with N,N-dimethylacetamide (1.4 L). Solid (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetic acid (250 g, 1 eq., prepared according to the method disclosed in U.S. Pat. No. 7,129,232) was added to the reactor at ambient temperature and the mixture was stirred until the solid was dissolved. The solution was cooled to about 4° C. (target: 2-5° C.) and stirred for another 10-15 minutes. Potassium carbonate (106.7 g, 184.9 mmol, 1.1 eq.) was added to the reactor in one portion. Methanesulfonyl chloride (118.0 mL, 2.2 eq.) was added to the reactor at a rate of about 5 mL/min while maintaining the batch temperature <10° C. The reaction was stirred for 1-2 hours at about 6° C., then cooled to about 0-5° C. Ethyl acetate (2.5 L, 10 volumes) was added to the reactor while maintaining a temperature of about 0-5° C. 1.6% HCl (aq) (1.35 L) was added to the reactor, maintaining a temperature of about 10-15° C. The biphasic mixture was agitated and the layers were then separated. The organic layer was washed with sodium chloride solution, dried with sodium sulfate and concentrated under reduced pressure to obtain crude material. The crude material was dissolved in ethyl acetate (150 mL) and filtered over silica gel. The filtrate was concentrated under reduced pressure to yield the title compound (299 g, 96.7%) as a colorless solid. Exact Mass: 408.08. HRMS: 409.0846 (M+1).

1. addition7,129,232) was added to the reactor at ambient temperature
2. dissolutionwas dissolved
3. stirringstirred for another 10-15 minutes
4. temperaturewhile maintaining the batch temperature <10° C
5. stirringThe reaction was stirred for 1-2 hours at about 6° C.
6. temperaturecooled to about 0-5° C
7. temperaturewhile maintaining a temperature of about 0-5° C
8. temperaturemaintaining a temperature of about 10-15° C
9. stirringThe biphasic mixture was agitated
10. customthe layers were then separated
11. washThe organic layer was washed with sodium chloride solution
12. dry with materialdried with sodium sulfate
13. concentrationconcentrated under reduced pressure
14. customto obtain crude material
15. filtrationfiltered over silica gel
16. concentrationThe filtrate was concentrated under reduced pressure

ORD record

ord-6c59921d4f184e54aba171e61f703244

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09006421B2