Intermediates in the synthesis of c3-substituted cephalosporins
AssigneeNorbrook Laboratories Limited
InventorKarolina MADELA
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Abstract
Disclosed herein are novel and inventive methods for preparing intermediates in the synthesis of C3-substituted cephalosporins. One preferred C3-substituted cephalosporin of clinical interest is Cefovecin. Accordingly, the present invention provides for methods of preparing reactive halogen intermediates for use in the synthesis of C3-substituted cephalosporins, such as Cefovecin. In the case of Cefovecin the reactive intermediates are of the formula:
Claims23
A method of synthesising a C3-substituted cephalosporin comprising the steps of:
- (i) generating a compound of the formula (II) from a compound of the formula (I)
- (ii) reacting the compound of formula (II) with a thiol of the formula (III-1) or (III-2) to yield a compound of the formula (IV-1) or (IV-2), and
- (iii) further processing the compound of formula (IV-1) or (IV-2) to yield a C3-substituted cephalosporin, wherein
- Z is selected from the group consisting of C1-C20 aliphatic, C3-C20 cycloaliphatic, C2-C20 heteroaliphatic, C2-C20 heterocycloaliphatic, C6-C20 aryl, C2-C20 heteroaryl, and combinations thereof;
- X is selected from the group consisting of Cl, Br, and I;
- and
- R11, R12, R13 are the same or different and are independently selected from the group consisting of H, C1-C20 aliphatic, C3-C20 cycloaliphatic, C2-C20 heteroaliphatic, C2-C20 heterocycloaliphatic, C6-C20 aryl, C2-C20 heteroaryl, and combinations thereof.
The method of any preceding claim wherein Z is selected from the group consisting of tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydropyrrolyl.
The method of any preceding claim wherein Z is 2-tetrahydrofuranyl.
The method of any preceding claim wherein Z is 2-tetrahydrofuranyl and C2 on the tetrahydrofuran ring has the (S) stereochemical configuration.
The method of any preceding claim wherein R11 is C1-C20 aliphatic.
The method of any preceding claim wherein R11 is tertiary-butyl.
The method of any preceding claim wherein R12 is selected from the group consisting of C1-C20 aliphatic, C6-C20 aryl, C2-C20 heteroaryl, and combinations thereof.
The method of any preceding claim wherein R12 is para-nitrobenzyl.
The method of any preceding claim wherein R13 is selected from the group consisting of C1-C20 aliphatic, C6-C20 aryl, C2-C20 heteroaryl, and combinations thereof.
The method of any preceding claim wherein R13 is benzyl.
Use of a compound of the formula (I) in the synthesis of a C3-substituted cephalosporin, wherein the compound of formula (I) is processed to yield a reactive intermediate of formula (II)
- and further wherein
- Z is selected from the group consisting of C1-C20 aliphatic, C3-C20 cycloaliphatic, C2-C20 heteroaliphatic, C2-C20 heterocycloaliphatic, C6-C20 aryl, C2-C20 heteroaryl, and combinations thereof;
- X is selected from the group consisting of Cl, Br, and I;
- and
- R11 is selected from the group consisting of H, C1-C20 aliphatic, C3-C20 cycloaliphatic, C2-C20 heteroaliphatic, C2-C20 heterocycloaliphatic, C6-C20 aryl, C2-C20 heteroaryl, and combinations thereof.
A compound of the formula (V), wherein
- W is selected from the group consisting of O, S, and N, preferably W is selected from the group consisting of O, S and NH;
- X is selected from the group consisting of Cl, Br, and I;
- and
- R11 is selected from the group consisting of H, C1-C20 aliphatic, C3-C20 cycloaliphatic, C2-C20 heteroaliphatic, C2-C20 heterocycloaliphatic, C6-C20 aryl, C2-C20 heteroaryl, and combinations thereof.
Dependencies are inferred from the claim text.