Synthesis of cephalosporin compounds

Patent metadata

Field	Value
Publication number	US-11059835-B2
Application number	US-202016880223-A
Country	US
Kind code	B2
Filing date	May 21, 2020
Priority date	Aug 15, 2014
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

Provided herein is a method for the synthesis of cephalosporin antibiotic compounds comprising a palladium-catalyzed coupling reaction.

First claim

What is claimed is:

1. A process for preparing a compound of the formula (IIa):

wherein A Θ is a pharmaceutically acceptable anion, selected from the group consisting of chloride, bromide, iodide, sulfate, bisulfate, toluenesulfonate, methanesulfonate, edisylate, maleate, monophosphate, biphosphate, ketoglutarate, trifluoroacetate, and trifluoromethanesulfonate;
comprising the step of admixing a compound of the formula (IIIa), or a salt thereof,

with a compound of the formula (X):

wherein:
R′ is tert-butyldimethylsilyl, tert-butyl, 4-methoxybenzyl, 2-methoxybenzyl, or triphenylmethyl;
R 3 is tert-butyldimethylsilyl, tert-butyl, 4-methoxybenzyl, 2-methoxybenzyl, or triphenylmethyl;
R 5 is triphenylmethyl, tert-butyl, tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or 4-methoxybenzyloxycarbonyl;
R 6 is triphenylmethyl, tert-butyl, tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or 4-methoxybenzyloxycarbonyl; and
LG is halo or —OC(O)R 18 , wherein R 18 is selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl;
in the presence of reagents comprising:
(a) a palladium source, wherein the palladium source is selected from the group consisting of: bis(acetonitrile)dichloropalladium(II), bis(acetylacetonate)palladium(II), bis(benzonitrile)palladium(II) chloride, bis(dibenzylideneacetone)palladium, allylpalladium(II) chloride dimer, palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) chloride, palladium(II) bromide, tetrakis(acetonitrile)-palladium(II)tetrafluoroborate, tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, [1,2-bis(diphenylphosphinoethane] dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct, bis(tricyclohexylphosphine)palladium(0), bis(triethylphosphine)palladium(II) chloride, bis(triphenylphosphine)palladium(II) acetate, bis(triphenylphosphine)palladium(II) chloride, bis(tri-t-butylphosphine)palladium(0), bis[1,2-bis(diphenylphosphino)ethane]palladium(0), bis[tri(o-tolyl)phosphine]palladium(II) chloride, dichlorobis(tricyclohexylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), and trans-benzyl(chloro)bis(triphenylphosphine)palladium(II); and
(b) a palladium-binding ligand selected from the group consisting of:

to provide the compound of formula (IIa), or a salt thereof.

2. The process of claim 1 , wherein:
R′ is tert-butyl; and
R 3 is 4-methoxybenzyl.

3. The process of claim 1 , wherein:
R 5 is tert-butyloxycarbonyl; and
R 6 is triphenylmethyl.

4. The process of claim 1 , wherein LG is chloro or —OC(O)CF 3 .

5. The process of claim 1 , wherein A Θ is selected from chloride, acetate, trifluoroacetate and bisulfate.

6. The process of claim 1 , wherein A Θ is trifluoroacetate or bisulfate.

7. The process of claim 1 , wherein A Θ is trifluoroacetate.

8. The process of claim 1 , wherein the palladium source is selected from the group consisting of: tris(dibenzylideneacetone) dipalladium(0), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, tetrakis(triphenylphosphine)palladium, palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) chloride, palladium(II) bromide, and bis(acetonitrile)dichloropalladium(II).

9. The process of claim 1 , wherein the palladium source is tris(dibenzylideneacetone)dipalladium(0).

10. The process of claim 1 , wherein the palladium-binding ligand is selected from the group consisting of:

11. The process of claim 1 , wherein the palladium-binding ligand is:

12. The process of claim 1 , wherein the step of admixing a compound of formula (IIa) in the presence of reagents comprising (a) a palladium source and (b) a palladium-binding ligand forms a pi-allyl intermediate.

13. The process of claim 1 , wherein the palladium-binding ligand is present in a molar ratio of between about 1:1 to about 10:1 with respect to the molar amount of palladium in the palladium source.

14. The process of claim 1 , wherein the palladium-binding ligand is present in a molar ratio of between about 3:1 and about 10:1 with respect to the molar amount of palladium in the palladium source.

15. The process of claim 1 , wherein the palladium-binding ligand is present in a molar ratio of between about 4:1 and about 10:1 with respect to the molar amount of palladium in the palladium source.

16. The process of claim 1 , wherein the palladium-binding ligand is present in a molar ratio of between about 5:1 and about 10:1 with respect to the molar amount of palladium in the palladium source.

17. The process of claim 1 , wherein the palladium-binding ligand is present in a molar ratio of between about 6:1 and about 10:1 with respect to the molar amount of palladium in the palladium source.

18. The process of claim 1 , wherein the palladium source is present in an amount of from about 0.2 mole % to about 5 mole % with respect to the compound of formula (IIIa).

19. The process of claim 1 , wherein the palladium source is present in an amount of from about 0.5 mole % to about 5 mole % with respect to the compound of formula (IIIa).

20. The process of claim 1 , further comprising the step of removing the palladium by washing with an aqueous acidic solution after forming the compound of formula (II).

21. The process of claim 20 , further comprising the step of recovering the palladium, after the step of removing the palladium, by increasing the pH of the aqueous acidic solution and adding an oxidant to the aqueous acidic solution, thereby recovering the palladium.

22. The process of claim 1 , wherein the reagents further comprise (c) a salt additive which is selected from the group consisting of potassium trifluoroacetate, sodium trifluoroacetate, lithium trifluoroacetate, potassium triflate, sodium triflate, lithium triflate, silver triflate and copper sulfate.

23. The process of claim 1 , wherein the reagents further comprise (c) a salt additive which is potassium trifluoroacetate.

24. The process of claim 1 , further comprising the step of admixing the compound of formula (IIa):

wherein A Θ is a pharmaceutically acceptable a

Assignees

• Merck Sharp & Dohme

Inventors

• Waller David
• Gazda Gregory
• Minden Zachary
• Barton Lisa
• Leigh Clifton

Classifications

• C07D501/04

  from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents · CPC title

• C07D501/56 Primary

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