Process for making carbapenem compounds

A process for reducing the levels of organic solvents in a carbapenem solid of formula I:

• or salts thereof, wherein R1 and R2 are the same or different and are selected from H, alkyl, aryl, and heteroaryl, said alkyl, aryl and heteroaryl optionally substituted, comprising the steps of:
• a) washing the carbapenem solid containing organic solvent with an organic solvent containing water to produce a washed carbapenem solid containing residual organic solvent;
• and
• b) evaporating the residual organic solvent in the washed carbapenem solid using vacuum and/or an inert gas stream at low temperature to produce a carbapenem solid of formula I containing pharmaceutically acceptable levels of organic solvents, wherein the organic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, methyl acetate, ethyl acetate, isopropyl acetate, acetone, and methyl ethyl ketone or mixture thereof and the organic solvent containing water is selected from the group consisting of methyl acetate, acetonitrile, tetrahydrofuran, and acetone or a mixture thereof.

A process for reducing the levels of residual organic solvents to pharmaceutically acceptable levels in a carbapenem solid of formula II:

• wherein X+ is selected from Na+, K+, and Li+, comprising the steps of:
• a) washing the carbapenem solid of formula II containing organic solvent with an organic solvent containing water selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, methyl acetate or a mixture thereof;
• said organic solvent containing about 1% to about 5% (w/v) water to produce a washed carbapenem solid of formula II containing residual organic solvent;
• and
• b) evaporating the residual organic solvent in the washed carbapenem solid of formula II using vacuum and/or inert gas at a temperature of about −15° C. to about 20° C. to produce a carbapenem solid of formula II containing pharmaceutically acceptable levels of residual organic solvent.

A process for reducing the levels of organic solvents in a carbapenem solid of(4R, 5S, 6S, 8R, 2′S, 4′S)-3-[[2-[[3-carboxyphenyl)amino]-carbonyl]pyrrolidin-4-yl]thio]-4-methyl-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid monosodium salt represented by formula IIa:

• comprising the steps of:
• a) washing the carbapenem solid of formula IIa containing organic solvent with methyl acetate containing 1–5% (w/v) water to produce a washed carbapenem solid of formula IIa containing residual organic solvent;
• and
• b) evaporating the residual organic solvent in the washed carbapenem solid of formula IIa under vacuum using a hydrated nitrogen stream at a nitrogen flow rate of about 0.3 to about 30 SLPH (standard liters/hour)/assay gram of the compound and a temperature of about 10° C. or below to produce a carbapenem solid of formula IIa containing pharmaceutically acceptable levels of residual organic solvents.

A process for reducing the levels of organic solvents in carbapenem solids of formula I:

• or salts thereof, wherein R1 and R2 are the same or different and are selected from H, alkyl, aryl, and heteroaryl, said alkyl, aryl and heteroaryl optionally substituted, comprising the steps of:
• a) washing the carbapenem solid containing organic solvent with an anhydrous organic solvent to produce a washed carbapenem solid containing residual organic solvents;
• and
• b) evaporating the residual organic solvents in the washed carbapenem solid using vacuum and a hydrated inert gas stream at a temperature of about 20° C. or below to produce a carbapenem solid of formula I containing pharmaceutically acceptable levels of organic solvents, said inert gas stream hydrated in such a way to achieve the water content of the solids to a level of about 13 to about 25% throughout the washing and evaporating steps;
• wherein the organic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, methyl acetate, ethyl acetate, isopropyl acetate, acetone, and methyl ethyl ketone or mixture thereof;
• and the anhydrous organic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, methyl acetate, and acetone or a mixture thereof.