CRYSTALLINE FORMS OF ANTIBIOTIC SIDE CHAIN INTERMEDIATES

Abstract: Crystalline DIPP thiolactone and solvates thereof are disclosed. A crystalline type is described.

Description: TITLE OF THE INVENTION CRYSTALLINE FORMS OF ANTIBIOTIC SIDE CHAIN INTERMEDIATES BACKGROUND OF THE INVENTION Crystalline forms of intermediates for carbapenem antibiotics are desirable from a stability and purity standpoint. These compounds facilitate the synthesis of carbapenem antibiotics on a commercial scale. In the present invention, crystalline forms of diisoproprylphosphoryl (DIPP) thiolactone 1 have been discovered and characterized. Crystalline 1 and solvates thereof and the process of making said compounds are disclosed. The compounds can generally be synthesized taking into account the disclosure of U. S. serial number 09/106297, field June 29, 1998 (incorporated herein by reference). SUMMARY OF THE INVENTION Crystalline DIPP thiolactone and solvates thereof are disclosed. Also disclosed is a process for crystallizing said compounds. BRIEF DESCRIPTION OF THE DRAWINGS The invention is described in connection with the following drawings, of which: Figure 1 is an X-Ray Powder Diffraction pattern of Compound I, as the DIPP thiolactone. DETAILED DESCRIPTION OF THE INVENTION The compound, (lS)-3-oxo-2-thia-5-azabicyclo[2.2.1]hept-5- yl)phosphonic acid bis(l-methylethyl) ester, has the following structural formula 1: wherein DIPP represents diisopropylphosphoryl. The crystalline forms of the compound are characterized below by virtue of their X-Ray Powder Diffraction (XRPD) patterns. The XRPD patterns were collected on a Philips PW 3710 MPD control automated powder diffractometer. The x-ray generator employed a copper target, an accelerating potential of 45 kV and a filament emission of 40 mA. Diffraction patterns were collected from 2°C to 40°. The DIPP thiolactone was characterized as having an XRPD pattern at 9.405, 23.638 and 28.585 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 1. Notes: Generator settings: 45kV, 40 mA Cu alphal , 2 wave lengths 1.54060, 1.54439 Ang The XRPD pattern corresponding to Table I is shown as Figure 1. The crystalline compound of the present invention is useful for the synthesis of carbapenem compounds that are in turn useful for the treatment of bacterial infections in animal and human subjects. The invention also relates to a process for synthesizing a compound of the formula 1: wherein P is diisopropylphosphoryl, comprising (a) reacting a compound of formula 2: wherein P is as previously defined with diphenylphosphinic chloride to produce a compound of formula 3: (b) reacting compound 3 with methanesulfonyl chloride to produce a compound of formula 4: - A - and (c) combining compound 4 with an alkali metal sulfide or non-alkali metal sulfide in water to produce a compound of formula 1, which is subsequently isolated and crystallized via standard techniques. The compounds of this invention can be produced in accordance with the following non-limiting examples. EXAMPLE ONE A. Synthesis A solution of DIPP protected trans-4-hydroxy-L-proline (46.7 g; prepared acccording to the teachings of US 5,877,328 filed October 2, 1997 or USSN 09/106,294, filed 6/29/98; both incorporated herein) in dichloromethane (1 L) was cooled to -20°C and diisopropylethylamine (48.1 g) followed by a solution of diphenylphosphinic chloride (39.3 g) in dichloromethane (75 mL) were added at such a rate that the temperature was maintained below -18°C. After 40 min, pyridine (13.4 g) followed by a solution of methanesulfonyl chloride (20.0 g) in dichloromethane (110 mL) were added at such a rate that the temperature was maintained below -18°C. The mixture was aged for 30 min before a solution of sodium sulfide trihydrate (25.1 g) in water (360 mL) was added rapidly. The mixture was warmed to 25°C and agitated for 2 h. The layers were separated. The organic layer was washed with dilute hydrochloric acid, a sodium bicarbonate solution and water. B. Crystallization The above solution was dried and concentrated to dryness. The residue was dissolved in hot ethylacetate (100 mL). After cooling and adding heptane (100 mL) DIPP- thiolactone 1 crystallized. The product was filtered and dried.

Claims: WHAT IS CLAIMED IS: 1. Crystalline (lS)-3-oxo-2-thia-5-azabicyclo[2.2.1]-hept-5- yl)phosphonic acid bis(l-methylethyl) ester. 2. Crystalline (lS)-3-oxo-2-thia-5-azabicyclo[2.2.1]-hept-5- yl)phosphonic acid bis(l-methylethyl) ester in accordance with claim 1, having an X- ray powder diffraction pattern in accordance with Figure 1. 3. Crystalline (lS)-3-oxo-2-thia-5-azabicyclo[2.2.1]-hept-5- yl)phosphonic acid bis(l-methylethyl) ester acid in accordance with claim 1, having an X-ray powder diffraction pattern: 2.3296 2.2987

Inventors: BRANDS KAREL J M, JOBSON RONALD J, BRANDS, KAREL, J., M., JOBSON, RONALD, J.
Applicants: BRANDS KAREL J M, JOBSON RONALD J, MERCK & CO INC, BRANDS, KAREL, J., M., JOBSON, RONALD, J., MERCK & CO., INC.
Application year: 2001
Main classification: C07D495
IPC codes: C07F9