Merck + Co., Inc.

Joseph Kukura, Ii

Louis S Crocker

Andrew S Thompson

Steven D Young

Christine Stelmach

John M Williams

Ulf H Dolling

Raymond Cvetovich

Daniel Richard Sidler

Robert Wenslow

Hsien-Hsin Tung

Brian K Johnson

The present invention relates to a process for reducing the levels of organic solvents to pharmaceutically acceptable levels in thermally unstable crystalline carbapenem solids represented by formula I:or a salt thereof, wherein Rand R, are the same or different, and are selected from H, alkyl, aryl, and heteroaryl, comprising washing a carbapenem solid containing organic solvent with an organic solvent containing water; and using vacuum and/or inert gas (hydrated or dry) at low temperature to produce a compound of formula I containing pharmaceutically acceptable levels of organic solvents, wherein the water content of the crystalline carbapenem solid, correcting for organic solvents, is maintained at about 13% to about 25% during the process.

Process for making carbapenem compounds

The instant invention describes a method for crystallizing (&#x2212;)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one from a solvent and anti-solvent solvent system and producing the crystalline product. The desired final crystal form, Form I, can be produced when using methanol or ethanol. Form II is isolated from 2-propanol and can be converted to the desired crystal form at low drying temperatures, such as between about a temperature of 40&#xb0; C. and 50&#xb0; C.

Crystal forms of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

The instant invention describes a method for crystallizing (&minus;)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one from a solvent and anti-solvent system and producing the crystalline product. The desired final crystal form, Form I, can be produced when using methanol or ethanol. Form II is isolated from 2-propanol and can be converted to the desired crystal form at low drying temperatures, such as between about a temperature of 40&deg; C. and 50&deg; C.

Crystal Forms of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

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Somerset, NJ, United States of America

Joseph Kukura, Ii