USRE40794E1 - Crystalline forms of carbapenem antibiotics and methods of preparation - Google Patents

Crystalline forms of carbapenem antibiotics and methods of preparation Download PDF

Info

Publication number
USRE40794E1
USRE40794E1 US11/999,720 US99972002A USRE40794E US RE40794 E1 USRE40794 E1 US RE40794E1 US 99972002 A US99972002 A US 99972002A US RE40794 E USRE40794 E US RE40794E
Authority
US
United States
Prior art keywords
formula iia
propanol
carbapenem
acid
crystals
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime, expires
Application number
US11/999,720
Inventor
Karel M. J. Brands
Raymond Cvetovich
Louis S. Crocker
Michael D. Ward
Amar J. Mahajan
Robert M. Wenslow
John M. Williams
Daniel R. Sidler
Charles Orella
Elizabeth S. Fisher
Ronald Jobson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to US11/999,720 priority Critical patent/USRE40794E1/en
Application granted granted Critical
Publication of USRE40794E1 publication Critical patent/USRE40794E1/en
Assigned to MERCK SHARP & DOHME CORP. reassignment MERCK SHARP & DOHME CORP. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: MERCK & CO., INC.
Assigned to MERCK SHARP & DOHME CORP. reassignment MERCK SHARP & DOHME CORP. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: MERCK & CO., INC.
Assigned to MERCK SHARP & DOHME CORP. reassignment MERCK SHARP & DOHME CORP. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: SCHERING CORPORATION
Assigned to SCHERING CORPORATION reassignment SCHERING CORPORATION MERGER (SEE DOCUMENT FOR DETAILS). Assignors: MERCK SHARP & DOHME CORP.
Assigned to MERCK SHARP & DOHME LLC reassignment MERCK SHARP & DOHME LLC MERGER (SEE DOCUMENT FOR DETAILS). Assignors: MERCK SHARP & DOHME CORP.
Adjusted expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • Carbapenems are a broad class of antibiotic compounds useful for the treatment of infectious diseases, including gram positive and negative, aerobic and anaerobic bacteria.
  • U.S. Pat. No. 5,478,820 to Betts et al, issued Dec. 26, 1995, now assigned to Zeneca Ltd. teaches carbapenem compounds, salts and hydrolysable esters thereof, of the general formula I: wherein R 1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl, R 2 and R 3 are hydrogen or C 1-4 alkyl, and R 4 and R 5 are hydrogen, halo, cyano, nitro, hydroxy, alkylamino, aminosulphonyl, or carbamoyl.
  • Crystalline forms of carbapenem antibiotics are desirable for improved purity and stability compared with amorphous forms. Crystallization allows isolation of a compound with rejection of impurities, and crystalline forms tend to be more stable than amorphous forms of the same compound.
  • crystalline forms of the carbapenem (4R, 5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl) amino]carbonyl]pyrrolidin-4-yl]thio]-4-methyl-6-(1-hydroxyethyl)-7-oxo1-azabicyclo [3.2.0]hept-2-en-2-carboxylic acid have been discovered and characterized and the processes for making said forms are disclosed.
  • the compounds of formula I can generally be synthesized taking into account the disclosure of U.S. Pat. No. 6,063,931 granted May 16, 2000, U.S. Pat. No. 5,648,501 granted Jul. 15, 1997, U.S. Pat. No. 5,478,820 granted Dec. 26, 1995, U.S. Pat. No. 6,180,783 granted Jan. 30, 2001, U.S. Pat. No. 5,872,250 granted Feb. 16, 1999 and U.S. Pat. No. 5,965,747, granted Oct. 12, 1999 (all incorporated herein by reference). See also Bugay, D. E., Pharm. Res., 1993, 10, 317; Harris, R. K., et al., Spectrochimica Acta, 1989, 45A, 465; Byrn, S. R., et al., J. Pharmaceutical Sciences, 1985, 74, 565.
  • crystalline forms which are solvates and hydrates or mixed solvates/hydrates of the monosodium salt IIa, are disclosed. These crystalline forms are useful in the isolation and purification of the carbapenem of formula IIa in the manufacture of an antibiotic product for the treatment of serious infections.
  • FIGS. 1, 2, 3, 4, and 5 display the 13C CP/MAS solid-state NMR spectra for the A, B, C, D and E solvates, respectively.
  • FIGS. 1, 2 and 3 display solvates containing methanol.
  • FIGS. 4 and 5 display solvates containing n-propanol (NPA) and isopropanol, respectively.
  • NPA n-propanol
  • FIGS. 6 and 7 display the unique spectral characteristice of each solvate, A, B, C, D, and E.
  • FIG. 1 is the X-ray Powder Diffraction pattern of Compound IIa crystallized from a mixture of water, methanol, and 1 -propanol.
  • FIG. 2 is the solid-state NMR spectrum of Compound IIa crystallized from a mixture of water, methanol, and 1 -propanol.
  • FIG. 3 is the X-Ray Powder diffraction pattern of Compound IIa after contacting 2 -propanol containing 15 % water.
  • FIG. 4 is the solid-state NMR spectrum of Compound IIa after contacting 2 -propanol containing 15 % water.
  • a carbapenem of formula I can be prepared according to several methods known in the art. Generally, these carbapenems can be prepared according to U.S. Pat. No. 4,888,344 to M. Sunagawa, issued Dec. 19, 1989, as well as U.S. Pat. No. 4,943,569 to M. Sunagawa, issued Jul. 24, 1990, as well as U.S. Pat. No. 5,478,820 to Betts et al., issued Dec. 26, 1995, all incorporated herein by reference thereto. Additional starting compounds and methods of preparation are taught in U.S. Pat. No. 5,641,770 to Kwak et al., issued Jun. 24, 1997 and U.S. Pat. No. 5,756,765 to Kwak et al., issued May 26, 1998, incorporated herein by reference hereto.
  • the compound having the structural formula II: can be isolated by crystallization as the monosodium salt which is represented by the structural formula IIa:
  • the crystalline forms of this invention are not thermally stable, and do not exhibit distinct, well-defined melting points, but rather undergo decomposition upon heating.
  • the compound of formula IIa readily converts from one crystalline form to another or from amorphous material to a crystalline form depending upon the composition of the solvent that the compound contacts.
  • crystalline forms of the compound of formula IIa arising by contact of the compound with mixtures of water and certain alcohols are also disclosed herein. These forms are useful in maintaining crystallinity through washing operations intended to remove impurities and in producing seed that can be used to improve performance of the crystallization.
  • the crystalline compound of formula IIa losses crystallinity thereby producing amorphous material under dehydrating conditions as when the solid is contacted by dry gas or dry water miscible solvent such as ethanol each of which can result in reducing the water content of the solid to less than about 13%, correcting for residual organic solvent.
  • the crystalline solids are characterized below by virtue of their X-Ray Powder Diffraction (XRPD) patterns and solid-state nuclear magnetic resonance (NMR) spectra, which are useful in unambiguous identification of the unique forms disclosed herein.
  • XRPD X-Ray Powder Diffraction
  • NMR nuclear magnetic resonance
  • the XRPD patterns were collected on a Philips automated powder diffractometer with XRG 3100 control and PW3710 mpd control using CuK ⁇ radiation with an accelerating potential of 45 kV and a filament emission of 40 mA. Diffraction patterns were collected from about 2 to about 40 °2Theta.
  • the solid-state NMR spectra were generated using a Bruker DSX 400WB NMR system operating a 100.6 MHz for 13 C and 400.1 MHz for 1 H using a Bruker MAS 400WB BL7 double-resonance probe with a spinning module housing a 7 mm zirconia rotor with either KEL-F® end caps with a liquid seal plug or zirconia endcaps.
  • the solid-state 13 C NMR spectra were acquired using cross polarization (CP), magic-angle spinning (MAS), and high-power decoupling. Proton and carbon 90° pulse widths were ⁇ 4 ⁇ sec with a contact time of 2.0 msec.
  • the sample was spun at 7.0 kHz and a total of 600-800 scans were collected with a recycle delay of 7.0 sec. Sample temperature between ⁇ 20 and ⁇ 5° C. A line broadening of 10 Hz was applied before FT was performed. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.03) as a secondary reference.
  • the crystalline Form A is formed through crystallization from a solution containing a compound of formula IIa or by contact of a solid of formula IIa with a mixture of water, methanol, and 1-propanol.
  • This form is unambiguously characterized as having the XRPD pattern 18.44, 13.09, 8.43, 7.58, 6.48, 6.16, 5.55, 5.14, 4.81, 4.50, 4.26, 4.11, 4.02, 3.85, 3.69, 3.41, 3.35, 3.03, 3.25, 3.12, and 2.87 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 1.
  • the XRPD pattern corresponding to Table 1 is shown in FIG. 1.
  • the solid-state NMR pattern corresponding to Form A is shown in FIG. 2.
  • the crystalline Form B of the compound of formula IIa is formed through contact of the compound of formula IIa with a mixture of water and 2-propanol and is unambiguously characterized as having the XRPD pattern 18.48, 13.02, 11.27, 8.50, 7.51, 6.51, 6.13, 5.82, 5.13, 4.78, 4.67, 4.50, 4.24, 4.06, 3.85, 3.69, 3.63, 3.41, 3.36, 3.31, 3.22, 3.11, 2.98, 2.87, and 2.77 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 2.
  • the XRPD pattern corresponding to Table 1 2 is shown in FIG. 3.
  • the solid-state NMR pattern corresponding to Form B is shown in FIG. 4.
  • This invention also relates to a process for producing a crystalline carbapenem salt of formula IIa: comprising adding about 10 to 30% of an organic solvent including but not limited to C 1 to C 5 alcohols to an aqueous solution containing a compound of formula II, its carbamate form (e.g., structural formula 4) and/or salt forms thereof, cooling the resulting solution to below ⁇ 5° C., adjusting the pH using a solution of an acid such as formic acid, acetic acid, propionic acid, or hydrochloric acid, preferably acetic acid, in an organic solvent including but not limited to C 1 to C 4 alcohols, preferably methanol, to give the pH required for crystallization of the compound of formula IIa (pH of about 5 to about 6).
  • an organic solvent including but not limited to C 1 to C 5 alcohols
  • the solution is seeded with a slurry containing Compound IIa (up to about 0.5% relative to Compound IIa going into the crystallization) in a mixture of water, methanol, and 1-propanol (10-30, 5-15, and 3-7 mL/g of Compound IIa charged to make the slurry, respectively).
  • the carbamate form of the compound of formula II is formed at the pyrrolidinone nitrogen.
  • the compound is crystallized by adding from 0.5 to 2 volumes of methanol relative to the aqueous volume, and a C 2-5 alcohol (from 0.5 to 2.5 volumes relative to the aqueous volume), preferably 1-propanol, at between ⁇ 5 and ⁇ 25° C. to give crystalline Form A.
  • the solid is then washed with a mixture of water and 2-propanol (from 5 to 30 mL/g of the compound of formula IIa) with said mixture containing from 5 to 20% water (v/v) to give crystalline Form B.
  • the crystalline form of formula IIa as crystallized from a solution containing formula IIa in a mixture of water/methanol/1-propanol is also referred to herein as (4R,5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl)amino]carbonyl]-pyrrolidin-4-yl]thio]4-methyl-6-(1-hydroxyethyl)-7-oxo1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid monosodium salt.
  • the crystalline compound of the present invention is used in the manufacture of a drug product that is useful for the treatment of bacterial infections in animal and human subjects.
  • the crystalline forms can be produced in accordance with the following non-limiting examples.
  • a hydrogenator is charged with 63 g of 5% Pd on carbon catalyst (dry weight) in 1.8 L of water. The vessel is placed under hydrogen then vented and placed under nitrogen. Sodium hydroxide (68 g, 50%) is charged adjusting the pH to about 7.5 with carbon dioxide.
  • the enol phosphate (170 g) and the thiol (86 g) are dissolved in 1.3 L of N-ethylpyrrolidinone (NEP).
  • NEP N-ethylpyrrolidinone
  • the mixture is cooled to below ⁇ 40° C. and 1,1,3,3-tetramethylguanidine (109 g) is added.
  • the reaction mixture is quenched into the hydrogenator at below 15° C. adjusting the pH to about 8 with carbon dioxide.
  • the vessel is placed under hydrogen. When the reaction is complete, the hydrogen is vented and the reaction mixture is treated with activated carbon and filtered.
  • the filtrate is extracted with iso-amyl alcohol containing diphenylphosphoric acid (240 g) and 50% NaOH (44 g).
  • the resulting aqueous solution is further extracted with iso-amyl alcohol to give an aqueous solution containing at least 90 mg/mL of the compound of formula II (predominantly in the stabilized form, 4).
  • Both extractions are performed using two CINC (Costner Industries Nevada Corporation) centrifugal separators set in series for countercurrent extraction.
  • 1-Propanol is added (20% by volume) and the resulting solution is cooled to below ⁇ 5° C.
  • the pH is adjusted to 5.5 at below ⁇ 5° C. using a solution of acetic acid in methanol (3 M). Methanol and 1-propanol are respectively added to 0.5 and 0.25 volumes total relative to the aqueous solution from the extraction.
  • the resulting solution is seeded with a slurry containing 0.1 g of the compound of formula IIa in a mixture of water, methanol, and 1-propanol (2, 1, and 0.5 mL, respectively) prepared at ⁇ 10° C.
  • the product is then crystallized at below ⁇ 5° C. by adding methanol and 1-propanol to bring the total of each to one volume relative to the aqueous solution from the extraction and isolated by filtration to give the compound of formula IIa as a crystalline solid (Form A).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process for preparing a crystalline, carbapenem monosodium salt of formula IIa:
Figure USRE040794-20090623-C00001
characterized by the steps a) adding about 10 to 30% of an organic solvent to an aqueous solution of the carbapenem, b) cooling the resulting solution to less than −5° C., c) adjusting the pH using a solution containing an acid in an organic solvent to give the appropriate pH for crystallization, and d) crystallizing the compound by adding methanol, and a C2-5 alcohol at between −5 and −25° C.

Description

CROSS REFERENCE TO RELATED APPLICATIONS
This application is the National Stage of International Application No. PCT/US02/30002 filed on Sep. 20, 2002 which claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 60/325,127 filed on Sep. 26, 2001.
BACKGROUND OF THE INVENTION
Carbapenems are a broad class of antibiotic compounds useful for the treatment of infectious diseases, including gram positive and negative, aerobic and anaerobic bacteria. U.S. Pat. No. 5,478,820 to Betts et al, issued Dec. 26, 1995, now assigned to Zeneca Ltd. (incorporated herein by reference thereto), teaches carbapenem compounds, salts and hydrolysable esters thereof, of the general formula I:
Figure USRE040794-20090623-C00002
wherein R1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl, R2 and R3 are hydrogen or C1-4 alkyl, and R4 and R5 are hydrogen, halo, cyano, nitro, hydroxy, alkylamino, aminosulphonyl, or carbamoyl.
Crystalline forms of carbapenem antibiotics are desirable for improved purity and stability compared with amorphous forms. Crystallization allows isolation of a compound with rejection of impurities, and crystalline forms tend to be more stable than amorphous forms of the same compound. In the present invention, crystalline forms of the carbapenem (4R, 5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl) amino]carbonyl]pyrrolidin-4-yl]thio]-4-methyl-6-(1-hydroxyethyl)-7-oxo1-azabicyclo [3.2.0]hept-2-en-2-carboxylic acid have been discovered and characterized and the processes for making said forms are disclosed.
The compounds of formula I can generally be synthesized taking into account the disclosure of U.S. Pat. No. 6,063,931 granted May 16, 2000, U.S. Pat. No. 5,648,501 granted Jul. 15, 1997, U.S. Pat. No. 5,478,820 granted Dec. 26, 1995, U.S. Pat. No. 6,180,783 granted Jan. 30, 2001, U.S. Pat. No. 5,872,250 granted Feb. 16, 1999 and U.S. Pat. No. 5,965,747, granted Oct. 12, 1999 (all incorporated herein by reference). See also Bugay, D. E., Pharm. Res., 1993, 10, 317; Harris, R. K., et al., Spectrochimica Acta, 1989, 45A, 465; Byrn, S. R., et al., J. Pharmaceutical Sciences, 1985, 74, 565.
SUMMARY OF INVENTION
Crystalline forms of the carbapenem (4R,5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl)amino]carbonyl]pyrrolidin-4-yl]thio]-4-methyl-6-(1-hydroxyethyl)-7-oxo1-azabicyclo [3.2.0]hept-2-en-2-carboxylic acid (formula II) and processes for making said forms are disclosed:
Figure USRE040794-20090623-C00003
Specifically, crystalline forms, which are solvates and hydrates or mixed solvates/hydrates of the monosodium salt IIa, are disclosed. These crystalline forms are useful in the isolation and purification of the carbapenem of formula IIa in the manufacture of an antibiotic product for the treatment of serious infections.
Figure USRE040794-20090623-C00004
BRIEF DESCRIPTION OF DRAWINGS
The invention is described in connection with the following pages, of which:
FIGS. 1, 2, 3, 4, and 5 display the 13C CP/MAS solid-state NMR spectra for the A, B, C, D and E solvates, respectively. FIGS. 1, 2 and 3 display solvates containing methanol. FIGS. 4 and 5 display solvates containing n-propanol (NPA) and isopropanol, respectively.
FIGS. 6 and 7 display the unique spectral characteristice of each solvate, A, B, C, D, and E.
The invention is described in connection with the following figures, of which:
FIG. 1 is the X-ray Powder Diffraction pattern of Compound IIa crystallized from a mixture of water, methanol, and 1-propanol.
FIG. 2 is the solid-state NMR spectrum of Compound IIa crystallized from a mixture of water, methanol, and 1-propanol.
FIG. 3 is the X-Ray Powder diffraction pattern of Compound IIa after contacting 2-propanol containing 15 % water.
FIG. 4 is the solid-state NMR spectrum of Compound IIa after contacting 2-propanol containing 15% water.
 DETAILED DESCRIPTION OF THE INVENTION
A carbapenem of formula I can be prepared according to several methods known in the art. Generally, these carbapenems can be prepared according to U.S. Pat. No. 4,888,344 to M. Sunagawa, issued Dec. 19, 1989, as well as U.S. Pat. No. 4,943,569 to M. Sunagawa, issued Jul. 24, 1990, as well as U.S. Pat. No. 5,478,820 to Betts et al., issued Dec. 26, 1995, all incorporated herein by reference thereto. Additional starting compounds and methods of preparation are taught in U.S. Pat. No. 5,641,770 to Kwak et al., issued Jun. 24, 1997 and U.S. Pat. No. 5,756,765 to Kwak et al., issued May 26, 1998, incorporated herein by reference hereto.
The compound having the structural formula II:
Figure USRE040794-20090623-C00005
can be isolated by crystallization as the monosodium salt which is represented by the structural formula IIa:
Figure USRE040794-20090623-C00006
The crystalline forms of this invention are not thermally stable, and do not exhibit distinct, well-defined melting points, but rather undergo decomposition upon heating.
The compound of formula IIa readily converts from one crystalline form to another or from amorphous material to a crystalline form depending upon the composition of the solvent that the compound contacts. In addition to the crystalline forms derived by crystallization, crystalline forms of the compound of formula IIa arising by contact of the compound with mixtures of water and certain alcohols are also disclosed herein. These forms are useful in maintaining crystallinity through washing operations intended to remove impurities and in producing seed that can be used to improve performance of the crystallization.
The crystalline compound of formula IIa losses crystallinity thereby producing amorphous material under dehydrating conditions as when the solid is contacted by dry gas or dry water miscible solvent such as ethanol each of which can result in reducing the water content of the solid to less than about 13%, correcting for residual organic solvent.
The crystalline solids are characterized below by virtue of their X-Ray Powder Diffraction (XRPD) patterns and solid-state nuclear magnetic resonance (NMR) spectra, which are useful in unambiguous identification of the unique forms disclosed herein. The XRPD patterns were collected on a Philips automated powder diffractometer with XRG 3100 control and PW3710 mpd control using CuKα radiation with an accelerating potential of 45 kV and a filament emission of 40 mA. Diffraction patterns were collected from about 2 to about 40 °2Theta. The solid-state NMR spectra were generated using a Bruker DSX 400WB NMR system operating a 100.6 MHz for 13C and 400.1 MHz for 1H using a Bruker MAS 400WB BL7 double-resonance probe with a spinning module housing a 7 mm zirconia rotor with either KEL-F® end caps with a liquid seal plug or zirconia endcaps. The solid-state 13C NMR spectra were acquired using cross polarization (CP), magic-angle spinning (MAS), and high-power decoupling. Proton and carbon 90° pulse widths were ˜4 μsec with a contact time of 2.0 msec. The sample was spun at 7.0 kHz and a total of 600-800 scans were collected with a recycle delay of 7.0 sec. Sample temperature between −20 and −5° C. A line broadening of 10 Hz was applied before FT was performed. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.03) as a secondary reference.
Form A:
The crystalline Form A is formed through crystallization from a solution containing a compound of formula IIa or by contact of a solid of formula IIa with a mixture of water, methanol, and 1-propanol. This form is unambiguously characterized as having the XRPD pattern 18.44, 13.09, 8.43, 7.58, 6.48, 6.16, 5.55, 5.14, 4.81, 4.50, 4.26, 4.11, 4.02, 3.85, 3.69, 3.41, 3.35, 3.03, 3.25, 3.12, and 2.87 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 1.
TABLE 1
XRPD pattern for the compound of formula IIa (Form A) crystallized
from a mixture of water, methanol, and 1-propanol
Angle D Spacing I/Imax
(°2Theta) (angstroms) (%)
4.8 18.44 100
6.7 13.09 41
10.5 8.43 38
11.7 7.58 41
13.6 6.48 72
14.4 6.16 62
16.0 5.55 39
17.2 5.14 44
18.4 4.81 63
19.7 4.50 60
20.8 4.26 64
21.6 4.11 59
22.1 4.02 66
23.1 3.85 63
24.1 3.69 93
26.1 3.41 83
26.6 3.35 67
27.0 3.03 71
27.4 3.25 71
28.6 3.12 63
31.1 2.87 83
The XRPD pattern corresponding to Table 1 is shown in FIG. 1. The solid-state NMR pattern corresponding to Form A is shown in FIG. 2.
Form B:
The crystalline Form B of the compound of formula IIa is formed through contact of the compound of formula IIa with a mixture of water and 2-propanol and is unambiguously characterized as having the XRPD pattern 18.48, 13.02, 11.27, 8.50, 7.51, 6.51, 6.13, 5.82, 5.13, 4.78, 4.67, 4.50, 4.24, 4.06, 3.85, 3.69, 3.63, 3.41, 3.36, 3.31, 3.22, 3.11, 2.98, 2.87, and 2.77 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 2.
TABLE 2
XRPD pattern for the compound of formula IIa (Form B)
contacted with a mixture of water and 2-propanol.
Angle D Spacing I/Imax
(°2Theta) (angstroms) (%)
4.8 18.48 59
6.8 13.02 24
7.8 11.27 21
10.4 8.50 49
11.8 7.51 34
13.6 6.51 55
14.4 6.13 51
15.2 5.82 27
17.3 5.13 32
18.5 4.78 58
19.0 4.67 64
19.7 4.50 62
20.9 4.24 58
21.9 4.06 100
23.1 3.85 39
24.1 3.69 46
24.5 3.63 65
26.1 3.41 51
26.5 3.36 37
26.9 3.31 34
27.7 3.22 75
28.7 3.11 32
30.0 2.98 33
31.1 2.87 47
32.3 2.77 49
The XRPD pattern corresponding to Table 1 2 is shown in FIG. 3. The solid-state NMR pattern corresponding to Form B is shown in FIG. 4.
This invention also relates to a process for producing a crystalline carbapenem salt of formula IIa:
Figure USRE040794-20090623-C00007
comprising adding about 10 to 30% of an organic solvent including but not limited to C1 to C5 alcohols to an aqueous solution containing a compound of formula II, its carbamate form (e.g., structural formula 4) and/or salt forms thereof, cooling the resulting solution to below −5° C., adjusting the pH using a solution of an acid such as formic acid, acetic acid, propionic acid, or hydrochloric acid, preferably acetic acid, in an organic solvent including but not limited to C1 to C4 alcohols, preferably methanol, to give the pH required for crystallization of the compound of formula IIa (pH of about 5 to about 6). The solution is seeded with a slurry containing Compound IIa (up to about 0.5% relative to Compound IIa going into the crystallization) in a mixture of water, methanol, and 1-propanol (10-30, 5-15, and 3-7 mL/g of Compound IIa charged to make the slurry, respectively). The carbamate form of the compound of formula II is formed at the pyrrolidinone nitrogen.
The compound is crystallized by adding from 0.5 to 2 volumes of methanol relative to the aqueous volume, and a C2-5 alcohol (from 0.5 to 2.5 volumes relative to the aqueous volume), preferably 1-propanol, at between −5 and −25° C. to give crystalline Form A. The solid is then washed with a mixture of water and 2-propanol (from 5 to 30 mL/g of the compound of formula IIa) with said mixture containing from 5 to 20% water (v/v) to give crystalline Form B.
The crystalline form of formula IIa as crystallized from a solution containing formula IIa in a mixture of water/methanol/1-propanol is also referred to herein as (4R,5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl)amino]carbonyl]-pyrrolidin-4-yl]thio]4-methyl-6-(1-hydroxyethyl)-7-oxo1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid monosodium salt.
The crystalline compound of the present invention is used in the manufacture of a drug product that is useful for the treatment of bacterial infections in animal and human subjects.
Figure USRE040794-20090623-C00008
The crystalline forms can be produced in accordance with the following non-limiting examples.
EXAMPLE ONE
A hydrogenator is charged with 63 g of 5% Pd on carbon catalyst (dry weight) in 1.8 L of water. The vessel is placed under hydrogen then vented and placed under nitrogen. Sodium hydroxide (68 g, 50%) is charged adjusting the pH to about 7.5 with carbon dioxide.
The enol phosphate (170 g) and the thiol (86 g) are dissolved in 1.3 L of N-ethylpyrrolidinone (NEP). The mixture is cooled to below −40° C. and 1,1,3,3-tetramethylguanidine (109 g) is added. After 3 hours, the reaction mixture is quenched into the hydrogenator at below 15° C. adjusting the pH to about 8 with carbon dioxide. The vessel is placed under hydrogen. When the reaction is complete, the hydrogen is vented and the reaction mixture is treated with activated carbon and filtered. The filtrate is extracted with iso-amyl alcohol containing diphenylphosphoric acid (240 g) and 50% NaOH (44 g). The resulting aqueous solution is further extracted with iso-amyl alcohol to give an aqueous solution containing at least 90 mg/mL of the compound of formula II (predominantly in the stabilized form, 4). Both extractions are performed using two CINC (Costner Industries Nevada Corporation) centrifugal separators set in series for countercurrent extraction. 1-Propanol is added (20% by volume) and the resulting solution is cooled to below −5° C. The pH is adjusted to 5.5 at below −5° C. using a solution of acetic acid in methanol (3 M). Methanol and 1-propanol are respectively added to 0.5 and 0.25 volumes total relative to the aqueous solution from the extraction. The resulting solution is seeded with a slurry containing 0.1 g of the compound of formula IIa in a mixture of water, methanol, and 1-propanol (2, 1, and 0.5 mL, respectively) prepared at −10° C. The product is then crystallized at below −5° C. by adding methanol and 1-propanol to bring the total of each to one volume relative to the aqueous solution from the extraction and isolated by filtration to give the compound of formula IIa as a crystalline solid (Form A).
EXAMPLE TWO
The solid derived by crystallization from a mixture of water, methanol, and 1-propanol (Form A) is washed with a mixture of water and 2-propanol (15:85 v/v, 10 mL/assay g of compound IIa) at below 10° C. to give the compound of formula IIa as a crystalline solid (Form B).

Claims (6)

1. Crystalline solvate (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, formula IIa, having an X-ray powder diffraction pattern of Form B in accordance with FIG. 3.
2. A process for preparing a crystalline solvate carbapenem monosodium salt of formula IIa:
Figure USRE040794-20090623-C00009
comprising the steps of:
a) adding an organic solvent selected from the group consisting of methanol and/or 1-propanol to an aqueous solution containing carbapenems of formula II and 4:
Figure USRE040794-20090623-C00010
and/or salt forms thereof,
b) cooling the solution to below −5° C.;
c) adjusting the pH to between about 6 and about 5 utilizing an acid;
d) crystallizing by adding to the solution from about 0.5 to about 3.0 volumes of methanol relative to the aqueous solution volume, and optionally, from about 0.5 to about 3.0 volumes of [a C1-5 alcohol] 1-propanol relative to the aqueous solution volume, thereby producing a slurry of formula IIa carbapenem crystals; and
e) [washing the formula IIa carbapenem crystals with methanol and 1-propanol and] isolating the formula IIa carbapenem crystals of Form A; and
f) washing the formula IIa carbapenem crystals of Form A with water and 2-propanol and isolating the formula IIa carbapenem crystals of Form B.
3. The process according to claim 2, wherein the C1-5 alcohol is selected from the group consisting of methanol, 1-propanol, 2-propanol, isopropyl alcohol, ethanol, 1-butanol, 2-butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol, 2-pentanol, 3-pentanol, isopentyl alcohol and mixtures thereof.
4. A process according to claim 2 which is conducted at a temperature of about −5° C. to about −25° C. and wherein the acid is selected from a group consisting of formic acid, acetic acid, propionic acid, and butyric acid.
5. A process according to claim 4 wherein the acid is acetic acid.
6. A process for preparing a crystalline solvate carbapenem monosodium salt of general formula IIa, Form B:
Figure USRE040794-20090623-C00011
wherein Form B has an X-ray powder diffraction patter pattern 18.48, 13.02, 11.27, 8.50, 7.51, 6.51, 6.13, 5.82, 5.13, 4.78, 4.67, 4.50, 4.24, 4.06, 3.85, 3.69, 3.63, 3.41, 3.36, 3.31, 3.22, 3.11, 2.98, 2.87, and 2.77 angstroms;
comprising:
a) adding 1-propanol to an aqueous solution containing carbapenems of formula II and 4:
Figure USRE040794-20090623-C00012
and/or salt forms thereof,
b) cooling the solution to below −5° C.;
c) adjusting the pH to between about 6 and about 5 utilizing an acid;
d) crystallizing by adding to the solution from about 0.5 to about 3.0 volumes of methanol relative to the aqueous volume, and from about 0.5 to a bout about 3.0 volumes of 1-propanol relative to the aqueous solution volume; and
e) isolating the formula IIa Form A carbapenem crystals
Figure USRE040794-20090623-C00013
wherein Form A has an X-ray powder diffraction pattern 18.44, 13.09, 8.43, 7.58, 6.48, 6.16, 5.55, 5.14, 4.81, 4.50, 4.26, 4.11, 4.02, 3.85, 3.69, 3.41, 3,35, 3.35, 3.03, 3.25, 3.12 and 2.87 angstroms; and
f) washing solids containing formula IIa Form A crystals with a mixture of water and 2-propanol to give the compound of formula IIa, Form B, wherein said mixture contains from about 5% to about 25% water (v/v).
US11/999,720 2001-09-26 2002-09-20 Crystalline forms of carbapenem antibiotics and methods of preparation Expired - Lifetime USRE40794E1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/999,720 USRE40794E1 (en) 2001-09-26 2002-09-20 Crystalline forms of carbapenem antibiotics and methods of preparation

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US32512701P 2001-09-26 2001-09-26
PCT/US2002/030002 WO2003026572A2 (en) 2001-09-26 2002-09-20 Crystalline forms of ertapenem sodium
US10/485,319 US7145002B2 (en) 2001-09-26 2002-09-20 Crystalline forms of carbapenem antibiotics and methods of preparation
US11/999,720 USRE40794E1 (en) 2001-09-26 2002-09-20 Crystalline forms of carbapenem antibiotics and methods of preparation

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/485,319 Reissue US7145002B2 (en) 2001-09-26 2002-09-20 Crystalline forms of carbapenem antibiotics and methods of preparation

Publications (1)

Publication Number Publication Date
USRE40794E1 true USRE40794E1 (en) 2009-06-23

Family

ID=23266545

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/999,720 Expired - Lifetime USRE40794E1 (en) 2001-09-26 2002-09-20 Crystalline forms of carbapenem antibiotics and methods of preparation
US10/485,319 Ceased US7145002B2 (en) 2001-09-26 2002-09-20 Crystalline forms of carbapenem antibiotics and methods of preparation

Family Applications After (1)

Application Number Title Priority Date Filing Date
US10/485,319 Ceased US7145002B2 (en) 2001-09-26 2002-09-20 Crystalline forms of carbapenem antibiotics and methods of preparation

Country Status (6)

Country Link
US (2) USRE40794E1 (en)
EP (1) EP1442038A4 (en)
JP (1) JP2005508321A (en)
AU (1) AU2002331885B2 (en)
CA (1) CA2457642C (en)
WO (1) WO2003026572A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090312539A1 (en) * 2006-11-20 2009-12-17 Orchid Chemicals & Pharmaceuticals Limited An improved process for the preparation of carbapenem antibiotic

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002341747B2 (en) * 2001-09-26 2007-10-18 Merck Sharp & Dohme Corp. Process for making carbapenem compounds
CN1608066A (en) * 2001-11-16 2005-04-20 兰贝克赛实验室有限公司 Process for the preparation of crystalline imipenem
PT1606293E (en) * 2003-03-27 2009-10-14 Basilea Pharmaceutica Ag Cephalosporin in crystalline form
KR20090007572A (en) * 2006-04-28 2009-01-19 카네카 코포레이션 Improved Crystallization Method of Carbapenem Antibiotic Intermediates
DK2045244T3 (en) * 2006-07-20 2013-04-15 Asahi Kasei Pharma Corp Hitherto crystal of substituted phenylalkanoic acid and method of preparation
AU2008290329B2 (en) 2007-08-22 2011-12-22 Astrazeneca Ab Cyclopropyl amide derivatives
EP2505191A1 (en) * 2008-06-11 2012-10-03 Ranbaxy Laboratories Limited Lyophilized Carbapenem antibiotic composition
CA2747252C (en) 2008-12-19 2018-09-18 Vertex Pharmaceuticals Incorporated Pyrazine derivatives useful as inhibitors of atr kinase
MY161598A (en) * 2009-01-30 2017-04-28 Glaxosmithkline Llc Crystalline n-{ (1s)-2-amino-1-[(3-fluorophenyl)methyl]ethyl} -5-chloro-4-(4-chloro-1-methyl-1h-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride
TW201039825A (en) 2009-02-20 2010-11-16 Astrazeneca Ab Cyclopropyl amide derivatives 983
EP2426131B1 (en) * 2009-04-30 2016-08-17 CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Intermediates of carbapenem, compositions containing them and preparation methods thereof
AU2011218490B9 (en) * 2010-02-18 2014-12-18 Astrazeneca Ab Solid forms comprising a cyclopropyl amide derivative
CA2788444A1 (en) * 2010-02-18 2011-08-25 Astrazeneca Ab New crystalline form of a cyclopropyl benzamide derivative
CA2798763A1 (en) 2010-05-12 2011-11-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
CN102260264A (en) * 2010-05-25 2011-11-30 浙江海翔药业股份有限公司 Method for preparing ertapenem through non-palladium system
WO2012038979A2 (en) * 2010-09-24 2012-03-29 Sequent Anti Biotics Private Limited A process for preparation of ertapenem
CN102558182B (en) * 2010-12-31 2015-02-11 石药集团中奇制药技术（石家庄）有限公司 Ertapenem sodium crystal form E and preparation method thereof
CN102731506B (en) * 2011-04-13 2015-08-12 石药集团中奇制药技术（石家庄）有限公司 The preparation method of a kind of ertapenem and sodium salt thereof
CN102731502B (en) * 2011-04-13 2016-08-03 石药集团中奇制药技术（石家庄）有限公司 A kind of preparation method of carbapenem antibiotics
EP3878851A1 (en) * 2011-09-30 2021-09-15 Vertex Pharmaceuticals Incorporated Process for making compounds useful as inhibitors of atr kinase
SG11201401095YA (en) 2011-09-30 2014-04-28 Vertex Pharma Treating pancreatic cancer and non-small cell lung cancer with atr inhibitors
US20150038726A1 (en) * 2012-04-04 2015-02-05 Hospira, Inc. Process for the preparation of carbapenem antibiotic
NZ726671A (en) 2012-04-05 2018-04-27 Vertex Pharma Compounds useful as inhibitors of atr kinase and combination therapies thereof
DK2904406T3 (en) 2012-10-04 2018-06-18 Vertex Pharma METHOD OF DETERMINING THE ATR INHIBITION, INCREASED DNA DAMAGE
JP2015533142A (en) 2012-10-12 2015-11-19 サンド・アクチエンゲゼルシヤフト Production of ertapenem intermediate
WO2014087972A1 (en) * 2012-12-03 2014-06-12 株式会社カネカ Reduced coenzyme q10 derivative and method for producing same
EP2950803A1 (en) * 2013-01-30 2015-12-09 Sandoz AG Crystalline form of linaclotide
CN105517992B (en) * 2013-09-05 2018-06-22 田边三菱制药株式会社 Novel crystalline aralkylamine compound and its production method
IN2013MU03862A (en) 2013-12-11 2015-07-31 Unimark Remedies Ltd
CA2965169C (en) 2014-10-21 2021-11-16 Ariad Pharmaceuticals, Inc. Crystalline forms of 5-chloro-n4-[2-(dimethylphosphoryl)phenyl]-n2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]pyrimidine-2,4-diamine
KR20170014842A (en) * 2015-07-31 2017-02-08 주식회사 대웅제약 Manufacuring method of improved ertapenem injection
HK1258570A1 (en) 2015-09-30 2019-11-15 Vertex Pharmaceuticals Inc. Method for treating cancer using a combination of dna damaging agents and atr inhibitors
WO2017125557A1 (en) * 2016-01-22 2017-07-27 Sandoz Ag Crystalline eravacycline bis-hydrochloride
MA45588A (en) * 2016-07-07 2019-05-15 Ironwood Pharmaceuticals Inc SOLID FORMS OF A GCS STIMULATOR
CN110698480B (en) * 2018-07-09 2023-09-08 武汉启瑞药业有限公司 Synthesis and purification method of ertapenem intermediate
US11186556B1 (en) * 2018-10-16 2021-11-30 Celgene Corporation Salts of a thiazolidinone compound, solid forms, compositions and methods of use thereof
UA119735C2 (en) 2018-12-20 2019-07-25 Анатолій Семенович Редер PHARMACEUTICAL COMPOUND, METHOD OF PREPARATION AND APPLICATION AS A MEDICINAL PRODUCT
CN113416193B (en) * 2021-08-23 2021-12-17 凯莱英医药集团（天津）股份有限公司 New crystal form of ertapenem sodium and preparation method thereof

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4888344A (en) 1986-07-30 1989-12-19 Sumitomo Pharmaceuticals Company, Limited Carbapenem compound in crystalline form, and its production and use
US4943569A (en) 1983-05-09 1990-07-24 Sumitomo Pharmaceuticals Co., Ltd. B-lactam compounds
US5478820A (en) 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds
US5641770A (en) 1992-12-21 1997-06-24 Chong Kun Dang Corp. 2-(2-substituted pyrrolidin-4-yl) thio-carbapenem derivatives
US5648501A (en) 1995-08-04 1997-07-15 Merck & Co., Inc. Process for synthesizing carbapenem side chain intermediates
US5872250A (en) 1997-07-30 1999-02-16 Merck & Co., Inc. Process for synthesizing carbapenem antibiotics
WO1999045010A1 (en) 1998-03-02 1999-09-10 Merck & Co., Inc. Process for synthesizing carbapenem antibiotics
US5965747A (en) 1997-07-10 1999-10-12 Merck & Co., Inc. Crystalline forms of antibiotic side chain intermediates
US6063931A (en) 1997-07-09 2000-05-16 Merck & Co., Inc. Process for synthesizing carbapenem side chain intermediates
US6180783B1 (en) 1997-06-16 2001-01-30 Merck & Co., Inc. Stabilized carbapenem intermediates and improved process for carbapenem synthesis
WO2002057266A1 (en) 2001-01-16 2002-07-25 Merck & Co., Inc. Improved process for carbapenem synthesis
US20040176351A1 (en) 2001-09-26 2004-09-09 Raymond Cvetovich Process for making carbapenem compounds

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4943569A (en) 1983-05-09 1990-07-24 Sumitomo Pharmaceuticals Co., Ltd. B-lactam compounds
US4888344A (en) 1986-07-30 1989-12-19 Sumitomo Pharmaceuticals Company, Limited Carbapenem compound in crystalline form, and its production and use
US5478820A (en) 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds
EP0579826B1 (en) 1992-02-04 1998-11-11 Zeneca Limited Carbapenems containing a carboxy substituted phenyl group, processes for their preparation, intermediates and use as antibiotics
US5641770A (en) 1992-12-21 1997-06-24 Chong Kun Dang Corp. 2-(2-substituted pyrrolidin-4-yl) thio-carbapenem derivatives
US5756765A (en) 1992-12-21 1998-05-26 Chong Kun Dang Corp. 2- (2-Substituted pyrrolidin-4-yl) thio-carbapenem derivatives
US5648501A (en) 1995-08-04 1997-07-15 Merck & Co., Inc. Process for synthesizing carbapenem side chain intermediates
US6180783B1 (en) 1997-06-16 2001-01-30 Merck & Co., Inc. Stabilized carbapenem intermediates and improved process for carbapenem synthesis
US6063931A (en) 1997-07-09 2000-05-16 Merck & Co., Inc. Process for synthesizing carbapenem side chain intermediates
US5965747A (en) 1997-07-10 1999-10-12 Merck & Co., Inc. Crystalline forms of antibiotic side chain intermediates
US5872250A (en) 1997-07-30 1999-02-16 Merck & Co., Inc. Process for synthesizing carbapenem antibiotics
WO1999045010A1 (en) 1998-03-02 1999-09-10 Merck & Co., Inc. Process for synthesizing carbapenem antibiotics
WO2002057266A1 (en) 2001-01-16 2002-07-25 Merck & Co., Inc. Improved process for carbapenem synthesis
US20040063931A1 (en) * 2001-01-16 2004-04-01 William John M. Process for carbapenem synthesis
US7071330B2 (en) 2001-01-16 2006-07-04 Williams John M Process for carbapenem synthesis
US20040176351A1 (en) 2001-09-26 2004-09-09 Raymond Cvetovich Process for making carbapenem compounds

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Bugay "Solid-State Nuclear Magnetic Resonance Spectroscopy: Theory and Pharmaceutical Applications", Pharmaceutical Research, 1993, vol. 10, pp. 317-327.
Byrn et al. "Analsyis of Solid-State Carbon-13 NMR Spectra of Polymorphs (Benoxaprofen and Nabilone) and Pseudopolymorphs (Cefazolin)", Journal of Pharmaceutical Sciences, 1985, vol. 74, pp. 565-568.
Harris et al. "Cross-polarization/magic-angle spinning NMR studies of polymorphism: androstanolone", Spectrochimica Acta, 1989, vol. 45A, pp. 465-469.
Natishan et al. "Residual solvents determination in the antibiotic L-749,345 by static headspace gas chromatography", Journal of Chromatography, 1998, vol. 800, pp. 275-281.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090312539A1 (en) * 2006-11-20 2009-12-17 Orchid Chemicals & Pharmaceuticals Limited An improved process for the preparation of carbapenem antibiotic
US8293894B2 (en) * 2006-11-20 2012-10-23 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of carbapenem antibiotic

Also Published As

Publication number Publication date
WO2003026572A3 (en) 2003-06-19
JP2005508321A (en) 2005-03-31
EP1442038A4 (en) 2005-01-05
AU2002331885B2 (en) 2007-07-26
CA2457642A1 (en) 2003-04-03
CA2457642C (en) 2009-01-06
US7145002B2 (en) 2006-12-05
EP1442038A2 (en) 2004-08-04
US20040235817A1 (en) 2004-11-25
WO2003026572A2 (en) 2003-04-03

Similar Documents

Publication Publication Date Title
USRE40794E1 (en) Crystalline forms of carbapenem antibiotics and methods of preparation
AU2002331885A1 (en) Crystalline forms of ertapenem sodium
US8097719B2 (en) Meropenem intermediate in novel crystalline form and a method of manufacture of meropenem
US8729260B2 (en) Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem
US7071330B2 (en) Process for carbapenem synthesis
US9233963B2 (en) Method for preparing meropenem using zinc powder
US7022841B2 (en) Process for making carbapenem compounds
AU2002234240A1 (en) Improved process for carbapenem synthesis
AU2002341747A1 (en) Process for making carbapenem compounds
US8293924B2 (en) Process for the preparation of carbapenem antibiotic
US20150038726A1 (en) Process for the preparation of carbapenem antibiotic
US20110288289A1 (en) Preparation of Carbapenem Intermediate and Their Use
WO2007104221A1 (en) A process for the preparation of meropenem
HRP20040264A2 (en) Process for making carbapenem compounds

Legal Events

Date Code Title Description
AS Assignment

Owner name: MERCK SHARP & DOHME CORP.,NEW JERSEY

Free format text: CHANGE OF NAME;ASSIGNOR:MERCK & CO., INC.;REEL/FRAME:023870/0001

Effective date: 20091102

Owner name: MERCK SHARP & DOHME CORP., NEW JERSEY

Free format text: CHANGE OF NAME;ASSIGNOR:MERCK & CO., INC.;REEL/FRAME:023870/0001

Effective date: 20091102

FPAY Fee payment

Year of fee payment: 4

AS Assignment

Owner name: MERCK SHARP & DOHME CORP., NEW JERSEY

Free format text: CHANGE OF NAME;ASSIGNOR:MERCK & CO., INC.;REEL/FRAME:030089/0409

Effective date: 20091102

AS Assignment

Owner name: MERCK SHARP & DOHME CORP., NEW JERSEY

Free format text: CHANGE OF NAME;ASSIGNOR:SCHERING CORPORATION;REEL/FRAME:030137/0837

Effective date: 20120502

Owner name: SCHERING CORPORATION, NEW JERSEY

Free format text: MERGER;ASSIGNOR:MERCK SHARP & DOHME CORP.;REEL/FRAME:030133/0200

Effective date: 20120426

FPAY Fee payment

Year of fee payment: 8

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 12TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1553)

Year of fee payment: 12

AS Assignment

Owner name: MERCK SHARP & DOHME LLC, NEW JERSEY

Free format text: MERGER;ASSIGNOR:MERCK SHARP & DOHME CORP.;REEL/FRAME:061102/0145

Effective date: 20220407