Cephalosporin compositions and methods of manufacture
View Patent ↗Provided herein is a method for the synthesis of cephalosporin antibiotic compounds comprising the conversion of a protected 7-amino group into a 7-carboxamide moiety in a single step.
1. A method for preparing a compound of formula (II), or a salt thereof,
comprising the step of reacting a compound of formula (III), or a salt thereof,
with a compound of formula (IV), or a salt thereof,
in a mixture comprising an organic solvent and water, to form a compound of formula (II), or a salt thereof;
wherein:
R 1 is selected from the group consisting of:
wherein Z′ is independently hydrogen or an oxygen protecting group;
Y is selected from the group consisting of:
wherein R′ is selected from the group consisting of hydrogen and an oxygen protecting group;
R 2 is hydrogen;
R 3 is selected from the group consisting of hydrogen and an oxygen protecting group; and
R 4 and R 4 , are each independently selected from the group consisting of:
and —CH═CH 2 , wherein each occurrence of A is independently an anion, and
X is —OSO 2 R 8 , wherein R 8 is methyl.
2. The method of claim 1 , wherein R 3 is an oxygen protecting group that is a benzyl ether.
3. The method of claim 1 , wherein the compound of formula (III) is the compound of formula (III-1):
the compound of formula (II) is the compound of formula (II-1):
and the compound of formula (IV) is the compound of formula (IV-1):
4. The method of claim 3 , wherein the compound of formula (IV-1) is prepared from the compound of formula (IVa):
by a process comprising the steps of:
(a) forming a mixture comprising potassium carbonate and the compound of formula (IVa); and
(b) adding methanesulfonyl chloride to the mixture of step (a) such that the compound of formula (IV-1) is formed.
5. The method of claim 1 , further comprising the step of reacting the compound of formula (II), or a salt thereof, with a strong acid to form a compound of formula (V), or a salt thereof, wherein the compound of formula (V) is selected from the compounds of Table 2.
6. The method of claim 5 wherein the compound of formula (III) has the structure:
the compound of formula (II) has the structure:
and
the compound of formula (V) has the structure:
7. The method of claim 5 , wherein the compound of formula (III) has the structure:
the compound of formula (II) has the structure:
and
the compound of formula (V) has the structure:
8. The method of claim 5 , wherein the compound of formula (III) has the structure:
the compound of formula (II) has the structure:
and
the compound of formula (V) has the structure:
9. The method of claim 5 , wherein the compound of formula (III) has the structure:
the compound of formula (II) has the structure:
and
the compound of formula (V) has the structure:
10. The method of claim 5 , wherein the compound of formula (III) has the structure:
the compound of formula (II) has the structure:
and
the compound of formula (V) has the structure:
11. The method of claim 5 , wherein the compound of formula (III) has the structure:
the compound of formula (II) has the structure:
and
the compound of formula (V) has the structure:
12. The method of claim 5 , wherein the compound of formula (III) has the structure:
the compound of formula (II) has the structure:
and
the compound of formula (V) has the structure:
13. The method of claim 5 , wherein the compound of formula (III) has the structure:
the compound of formula (II) has the structure:
and
the compound of formula (V) has the structure:
14. The method of claim 3 , wherein the weight ratio of the compound of formula (III-1) to the compound of formula (IV-1) is 150 g:60 g.
15. The method of claim 3 , wherein the organic solvent is dichloromethane; wherein the compound of formula (IV-1) is prepared from the compound of formula (IVa):
by a process comprising the steps of:
(a) forming a mixture comprising potassium carbonate and the compound of formula (IVa); and
(b) adding methanesulfonyl chloride to the mixture of step (a) such that the compound of formula (IV-1) is formed;
wherein the method further comprises the step of reacting the compound of formula (II-1), or a salt thereof, with a strong acid to form a compound of the formula:
or a salt thereof.
16. The method of claim 1 , wherein the compounds of formula (II), formula (III) and formula (IV) are selected from the compounds in Table 1:
TABLE 1
Formula (II)
Formula (III)
Formula (IV)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32