Synthesis of cephalosporin compounds

1. A process of making a compound of formula (V′):

comprising admixing a compound of formula (III′):

and a compound of formula (IV′):

in a solvent to provide the compound of formula (V′),

wherein:

P 1 and P 2 are each independently an acid-labile nitrogen protecting group,

P 3 and P 4 are each independently an acid-labile oxygen protecting group,

X − is a pharmaceutically acceptable salt,

Y is Cl or Br;

the molar ratio of the compound of formula (IV′) to the compound of formula (III′) is from 1.0:1 to 1.3:1; and

the solvent is purged with nitrogen at from 0.2 m 3 /h to 1.2 m 3 /h per kilogram of the compound of formula (III′).

2. A process of making a compound of formula (V′):

comprising admixing a compound of formula (III′):

and a compound of formula (IV′):

in a solvent to provide the compound of formula (V′),

wherein:

P 1 and P 2 are each independently an acid-labile nitrogen protecting group,

P 3 and P 4 are each independently an acid-labile oxygen protecting group,

X − is a pharmaceutically acceptable salt,

Y is Cl, Br or I;

the temperature of the admixture is from 25° C. to 32° C.; and

the solvent is purged with nitrogen at from 0.2 m 3 /h to 1.2 m 3 /h per kilogram of the compound of formula (III′).

3. A process of making a compound of formula (V′):

comprising admixing a compound of formula (III′):

and a compound of formula (IV′):

in a solvent to provide the compound of formula (V′),

wherein:

P 1 and P 2 are each independently an acid-labile nitrogen protecting group,

P 3 and P 4 are each independently an acid-labile oxygen protecting group,

X − is a pharmaceutically acceptable salt,

Y is Cl, Br or I; and

the solvent is purged with nitrogen at from 0.2 m 3 /h to 1.2 m 3 /h per kilogram of the compound of formula (III′).

4. The process of claim 1 , 2 or 3 , wherein P 1 is tert-butoxycarbonyl.

5. The process of claim 1 , 2 or 3 , wherein P 2 is triphenylmethyl.

6. The process of claim 1 , 2 or 3 , wherein P 3 is 4-methoxybenzyl.

7. The process of claim 1 , 2 or 3 , wherein P 4 is tert-butyl.

8. The process of claim 1 , 2 or 3 , wherein X − is trifluoroacetate, bromide, chloride, iodide, or methanesulfonate.

9. The process of claim 1 , 2 or 3 , wherein Y is Cl.

10. The process of claim 1 , 2 or 3 , wherein the admixture further comprises 1, 3-bis(trimethylsilyl)urea.

11. The process of claim 1 , 2 or 3 , wherein the admixture further comprises potassium iodide.

12. The process of claim 1 , 2 or 3 , wherein the temperature is from 27° C. to 30° C.

13. The process of claim 1 , 2 or 3 , wherein the solvent is a polar aprotic solvent.

14. The process of claim 1 , 2 or 3 , wherein the solvent comprises N-methylpyrrolidinone.

15. The process of claim 1 , 2 or 3 , wherein the solvent is purged with nitrogen at from 0.3 m 3 /h to 1.2 m 3 /h per kilogram of the compound of formula (III′).

16. The process of claim 1 , 2 or 3 , wherein the molar ratio of the compound of formula (IV′) to the compound of formula (III′) is 1.2:1.

17. The process of claim 1 , 2 or 3 , wherein the compound of formula (V′) has the structure of compound (V):

the compound of formula (III′) has the structure of compound (III):

and the compound of formula (IV′) has the structure of compound (IV):

18. The process of claim 1 , 2 or 3 , further comprising making a compound of formula (Vb′):

comprising contacting the compound of formula (V′) with an acid of formula HX,

at a temperature of from 18° C. to 22° C.,

to provide the compound of formula (Vb′),

wherein

HX is trifluoroacetic acid, hydrogen bromide, hydrogen chloride, hydrogen iodide, or methanesulfonic acid; and

X′ is trifluoroacetate, bromide, chloride, iodide, or methanesulfonate.

19. The process of claim 18 , wherein the amount of the acid is from 4.5 L to 6.0 L per kilogram of the compound of formula (V′).

20. The process of claim 18 , further comprising separating the compound of formula (Vb′) at a temperature of from −40° C. to −30° C.