7-aminocephem derivative compounds

1. A process for making a compound of the formula (II):

comprising the steps of:

(a) forming a reaction mixture comprising phosphorous pentachloride (PCl 5 ) and pyridine;

(b) adding a compound of the formula (IIa) to the reaction mixture:

(c) adding isobutyl alcohol;

(d) adding a solvent comprising water;

(e) adding ethyl acetate; and

(f) obtaining the compound of the formula (II).

2. The process of claim 1 , wherein step (a) comprises:

(1) combining PCl 5 and dichloromethane; and

(2) adding pyridine.

3. The process of claim 2 , wherein step (1) comprises:

(i) combining 2.0 equivalents PCl 5 and 6.0 volumes dichloromethane while maintaining the temperature below 30° C.; and

(ii) adjusting the temperature to 10 to 30° C. and agitating.

4. The process of claim 2 , wherein step (2) comprises:

(i) adjusting the temperature to −10 to −5° C.;

(ii) adding 2.0 equivalents of pyridine while maintaining the temperature at −10 to 5° C.; and

(iii) adjusting the temperature to −5 to 0° C. and agitating.

5. The process of claim 1 , wherein step (b) comprises:

(1) adding 1.0 equivalent compound (IIa) to the reaction mixture of step (a) while maintaining the temperature of the mixture at −10 to 0° C.; and

(2) stirring the mixture at −10 to 0° C.

6. The process of claim 5 , wherein the mixture of step (2) comprises ≤5.0% compound (IIa) relative to compound (II)+compound (IIa).

7. The process of claim 1 , wherein step (c) comprises:

(1) adjusting the temperature of the mixture to −20 to −10° C.;

(2) adding 2.0 volumes of isobutyl alcohol dropwise while maintaining the temperature of the mixture at −20 to 5° C.; and

(3) agitating the mixture at −10 to 0° C.

8. The process of claim 1 , wherein step (d) comprises:

(1) adding a solvent comprising water to the mixture of step (c) while maintaining the temperature of the mixture at −10 to 5° C.;

(2) agitating the mixture at −5 to 5° C.; and

(3) separating a lower organic phase from the mixture and collecting the lower organic phase.

9. The process of claim 8 , wherein the solvent comprising water is a mixture of ethanol and water.

10. The process of claim 8 , which further comprises:

(4) adding dichloromethane to the mixture at −10 to 0° C.;

(5) agitating the mixture at −10 to 0° C.; and

(6) separating a lower organic phase from the mixture and collecting the lower organic phase.

11. The process of claim 1 , wherein step (e) comprises:

(1) concentrating the organic phase to 4 to 5 volumes;

(2) adjusting the temperature to −10 to −5° C.;

(3) adding 2.1 volumes of ethyl acetate dropwise while maintaining the temperature of the mixture at −10 to −5° C.; and

(4) agitating the mixture at −10 to 5° C.

12. The process of claim 11 , wherein step (e) further comprises:

(5) observing the formation of a precipitate;

(6) concentrating the organic phase to 4 to 5 volumes;

(7) adjusting the temperature of the mixture to −10 to −5° C.;

(8) adding 2.1 volumes of ethyl acetate while maintaining the temperature of the mixture at −10 to −8° C.; and

(9) agitating the mixture at −10 to −5° C.

13. The process of claim 1 , wherein step (f) comprises:

(1) centrifuging the mixture to produce a cake; and

(2) collecting the cake.

14. The process of claim 13 , wherein step (f) further comprises:

(3) adding 2.2 volumes of ethyl acetate;

(4) adjusting the temperature to −10 to −5° C.;

(5) agitating at −10 to −5° C.;

(6) centrifuging to produce a cake;

(7) collecting the cake; and

(8) drying the cake at 5 to 20° C.