Patent ID: 7078534

Claim:
A process for the preparation and isolation of highly pure crystalline N-formimidoyl thienamycin monohydrate (imipenem) of Formula I having the X-ray diffraction pattern having characteristic d-spacing values at about 9.11, 7.79, 5.05, 4.14, 4.08, 3.90, 3.88, 3.65, 3.31, and 3.10, directly from a reaction mixture without any need to prepare lyophilized imipenem first, the process comprising: (a) activating a keto ester compound of Formula II wherein p is hydrogen or a protecting group, in the presence of a suitable secondary amine, in a suitable N-substituted lactam or N,N-disubstituted amide as a solvent, optionally in combination with an inert organic solvent to obtain a compound of Formula III wherein x is OP(O)(OR) 2 or OS(O) 2 R and R is C 16 alkyl, C 1-6 alkaryl, aryl or perfluoro C 1-6 alkyl; the term alkyl refers to a straight or branched chain and when of sufficient size, may be cyclic, preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl, preferred cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl and cyclopropyl methyl; the term aryl refers to aromatic rings including phenyl, substituted phenyl and naphthyl, aryl groups may be substituted with one to three substituents independently selected from halogen, alkyl and halogenated lower alkyl group, wherein alkyl has the same meaning as defined above, (b) reacting the activated keto ester of Formula III in situ with 2-aminoethanethiol (cysteamine) or its salt in the presence of a secondary amine, in a N-substituted lactam or N,N-disubstituted amide as a solvent to get thienamycin ester of Formula IV wherein p,n-substituted lactam and N,N-disubstituted amine, have the same meaning as defined above, (c) reacting thienamycin ester of Formula IV, in situ with benzyl formimidate hydrochloride (C 6 H 5 CH 2 OCH═NH 2 30 Cl − ) in the presence of a secondary amine in (d) a N-substituted lactam or N,N-disubstituted amide to get amidine carboxylate ester (blocked N-formimidoyl thienamycin) of Formula V wherein p,N-substituted lactam and N,N-disubstituted amine, have the same meaning as defined above, and (e) hydrogenating the blocked N-formimidoyl thienamycin of Formula V, to yield N-formimidoyl thienamycin (imipenem) in a solution and subjecting the solution containing the imipenem to dianion chromatography followed by crystallization in the presence of an alcohol or a ketone co-solvent, and isolating the highly pure crystalline N-formimidoyl monohydrate (imipenem monohydrate) of Formula I, by filtration.