Synthesis of cephalosporin compounds

Patent metadata

Field	Value
Publication number	US-10662202-B2
Application number	US-201816181884-A
Country	US
Kind code	B2
Filing date	Nov 6, 2018
Priority date	Aug 15, 2014
Publication date	May 26, 2020
Grant date	May 26, 2020

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), or a salt thereof:

comprising the step of admixing a compound of the formula (IIIa), or a salt thereof,

with a nucleophile having the structure of formula (X):

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, wherein the palladium-binding ligand is a phosphite ligand of formula (VI):

wherein
R 7 is, at each occurrence, independently selected from phenyl, heteroaryl, heterocyclyl, and C 1-6 alkyl, wherein said phenyl, heteroaryl, heterocyclyl, and C 1-6 alkyl are optionally substituted with one or more of halo, C 1-6 alkyl, C 1-6 alkoxy, or N(R 9 ) 2 , and wherein said phenyl and heteroaryl are optionally further substituted with a fused C 3-6 cycloalkyl or C 3-6 heterocyclyl;
R 8 is selected from phenyl, heteroaryl, heterocyclyl, and C 1-6 alkyl, wherein said phenyl, heteroaryl, heterocyclyl, and C 1-6 alkyl are optionally substituted with one or more of halo, C 1-6 alkyl, C 1-6 alkoxy, or N(R 9 ) 2 , and wherein said phenyl and heteroaryl are optionally substituted with a fused C 3-6 cycloalkyl or C 3-6 heterocyclyl, or
R 8 is

wherein
L is selected from the group consisting of —(CH 2 ) n —,

R 8 is optionally connected by a bond or —(CH 2 ) n — to one R 7 to form a ring, or to each R 7 to form two rings;
each R 9 is C 1-6 alkyl, or two R 9 can combine to form a 3-10 membered heterocyclyl, wherein heterocyclyl comprises 1-3 nitrogen atoms and is optionally substituted by C 1-6 alkyl or C(O)—(C 1-6 alkyl); and n is 1, 2, or 3;

to form a compound of formula (IIa), or a salt thereof;
wherein:
is a pharmaceutically acceptable anion;
LG is halo or —OC(O)R 18 , wherein R 18 is selected from the group consisting of C 1-6 alkyl and haloalkyl;
R 3 is an oxygen protecting group, wherein the oxygen protecting group is selected from the group consisting of an ethyl ether, a substituted methyl ether, a substituted ethyl ether, a substituted benzyl ether, a silyl ethers, an ester, a carbonates, a cyclic acetal and a ketal;
R′ is an oxygen protecting group, wherein the oxygen protecting group is selected from the group consisting of an ethyl ether, a substituted methyl ether, a substituted ethyl ether, a substituted benzyl ether, a silyl ethers, an ester, a carbonates, a cyclic acetal and a ketal;
R 5 is a nitrogen protecting group, wherein the nitrogen protecting group is selected from the group consisting of a carbamate, an amides, a cyclic imide derivative, a N-alkyl amine, a N-aryl amine, a benzyl amine, a substituted benzyl amine, a trityl amine, an imine derivative, and a enamine derivative; and
R 6 is a nitrogen protecting group, wherein the nitrogen protecting group is selected from the group consisting of a carbamate, an amides, a cyclic imide derivative, a N-alkyl amine, a N-aryl amine, a benzyl amine, a substituted benzyl amine, a trityl amine, an imine derivative, and a enamine derivative.

2. The process of claim 1 , wherein the oxygen protecting group is selected from the group consisting of methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, trimethylsilyl ether, triethylsilylether, triisopropylsilyl ether, t-butyldimethylsilyl ether, tribenzyl silyl ether, t-butyldiphenyl silyl ether, formate, acetate, benzoate, trifluoroacetate, dichloroacetate.

3. The process of claim 1 , wherein the oxygen protecting group is selected from the group consisting of tert-butyl, 4-methoxybenzyl, triphenylmethyl, benzyl ether, t-butyldimethylsilyl ether, triisopropylsilyl ether, and triethylsilylether.

4. The process of claim 1 , wherein R 3 and R′ are each independently tert-butyldimethylsilyl, tert-butyl, 4-methoxybenzyl, 2-methoxybenzyl, or triphenylmethyl.

5. The process of claim 1 , wherein the nitrogen protecting group is selected from the group consisting of methyl carbamate, ethyl carbamate, triphenylmethyl, tert-butyl, tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, and 4-methoxybenzyloxycarbonyl.

6. The process of claim 1 , wherein the nitrogen protecting group is selected from the group consisting of 9-fluorenylmethyl carbamate, triphenylmethyl, tert-butyl, tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 4-methoxybenzyloxycarbonyl, and benzyl.

7. The process of claim 1 , wherein the nitrogen protecting group is selected from the group consisting of tert-butyloxycarbonyl, and triphenylmethyl.

8. The process of claim 1 , wherein R 5 and R 6 are each independently triphenylmethyl, tert-butyl, tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or 4-methoxybenzyloxycarbonyl.

9. The process of claim 1 , wherein:
R′ is tert-butyl;
R 3 is 4-methoxybenzyl;
R 5 is tert-butyloxycarbonyl; and
R 6 is triphenylmethyl.

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

11. 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).

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

13. 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

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohm Corp

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