Synthesis of cephalosporin compounds

Patent metadata

Field	Value
Publication number	US-10214543-B2
Application number	US-201515540283-A
Country	US
Kind code	B2
Filing date	Dec 18, 2015
Priority date	Dec 30, 2014
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

Described herein are methods for the manufacture of ceftolozane and related compounds, as well as compositions comprising the same.

First claim

What is claimed is:

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.

Assignees

• Merck Sharp & Dohme

Inventors

• Moshos Kristos Adrian
• Jurkauskas Valdas
• Fogliato Giovanni
• Scanu Manuel
• Benotti Michele

Classifications

• C07D501/56 Primary

  with the 7-amino radical acylated by carboxylic acids containing hetero rings · CPC title

• C07B43/06

  of amide groups · CPC title

• C07B43/04

  of amino groups · CPC title

• C07B51/00

  Introduction of protecting groups or activating groups, not provided for in the preceding groups · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title