Synthesis of cephalosporin compounds

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
• R7 is, at each occurrence, independently selected from phenyl, heteroaryl, heterocyclyl, and C1-6 alkyl, wherein said phenyl, heteroaryl, heterocyclyl, and C1-6 alkyl are optionally substituted with one or more of halo, C1-6 alkyl, C1-6 alkoxy, or N(R9)2, and wherein said phenyl and heteroaryl are optionally further substituted with a fused C3-6 cycloalkyl or C3-6 heterocyclyl;
• R8 is selected from phenyl, heteroaryl, heterocyclyl, and C1-6 alkyl, wherein said phenyl, heteroaryl, heterocyclyl, and C1-6 alkyl are optionally substituted with one or more of halo, C1-6 alkyl, C1-6 alkoxy, or N(R9)2, and wherein said phenyl and heteroaryl are optionally substituted with a fused C3-6 cycloalkyl or C3-6 heterocyclyl, or
• R8 is
• wherein
• L is selected from the group consisting of —(CH2)n—,
• R8 is optionally connected by a bond or —(CH2)n— to one R7 to form a ring, or to each R7 to form two rings;
• each R9 is C1-6 alkyl, or two R9 can combine to form a 3-10 membered heterocyclyl, wherein heterocyclyl comprises 1-3 nitrogen atoms and is optionally substituted by C1-6 alkyl or C(O)—(C1-6 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)R18, wherein R18 is selected from the group consisting of C1-6 alkyl and haloalkyl;
• R3 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;
• R5 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
• R6 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.