Process for preparing ceftolozane from 7-aminocephalosporanic acid (7-ACA)

A method for preparing a compound of formula

• wherein R6′ is hydrogen or a negative charge, and
• A⊖ an anion, with the condition that n is zero when R6′ is a negative charge, and n is one when R6′ is hydrogen,
• comprising the steps of
• a) preparing a compound of formula
• wherein
• R1, R2, R3 and R4 are independently an amino protecting group or hydrogen with the condition that R4 is not hydrogen if R3 is hydrogen, or R1 and R2, and/or R3 and R4 are bound together by a cyclic amino protecting group,
• R5 is trialkylsilyl or hydrogen,
• R6 is trialkylsilyl, hydrogen or a negative charge, and
• A1⊖ is an anion, with the condition that n is zero when R6 is a negative charge, and n is one when R6 is trialkylsilyl or hydrogen,
• which comprises the steps of
• a-i) reacting a compound of formula
• with a silylating agent, optionally in presence of a catalyst, and
• with iodotrialkylsilane,
• a-ii) providing a compound of formula
• wherein
• R1-R4 are as defined above, and
• optionally reacting this compound of formula IV with a silylating agent,
• a-iii) reacting the products of steps a-i) and a-ii),
• a-iv) and optionally desilylating the product of step a-iii) to produce the compound of formula II
• b) preparing a compound of formula
• wherein
• R1-R4 and R6′ are as defined above,
• R7 is hydrogen or an amino protecting group,
• R10 is an ester protecting group, and
• A2⊖ is an anion, with the condition that n is zero when R6′ is a negative charge, and n is one when R6′ is hydrogen,
• which comprises the step of
• reacting the compound of formula II with a compound of formula
• wherein R7 and R10 are as defined above,
• R8 is Cl or SR9, wherein R9 is C1-C6 straight or branched alkyl, C3-C6 cycloalkyl, or a substituted or unsubstituted mono- or bicyclic aryl or heteroaryl ring system of 5 to 12 atoms and where each monocyclic ring contains 0 to 3 hetero atoms, and each bicyclic ring contains 0 to 4 hetero atoms selected from N, O and S, and
• c) removing any protecting groups from the compound of formula V to produce a compound of formula I,
• d) if in the compound of formula I produced in step c) R6′ is a negative charge and n is zero optionally treating the compound of formula I produced in step c) with an acid to produce a compound of formula I, wherein R6′ is hydrogen and n is one,
• e) optionally exchanging the anion by a different anion in the compound of formula I produced in step d) or in the compound of formula I produced in step c) if R6′ is hydrogen and n is one.