WO1999002492A1 - Crystalline forms of antibiotic side chain intermediates - Google Patents

Crystalline forms of antibiotic side chain intermediates Download PDF

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Publication number
WO1999002492A1
WO1999002492A1 PCT/US1998/014036 US9814036W WO9902492A1 WO 1999002492 A1 WO1999002492 A1 WO 1999002492A1 US 9814036 W US9814036 W US 9814036W WO 9902492 A1 WO9902492 A1 WO 9902492A1
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WO
WIPO (PCT)
Prior art keywords
crystalline
pyrrolidinyl
mercapto
cis
carbonyl
Prior art date
Application number
PCT/US1998/014036
Other languages
French (fr)
Inventor
Karel M. J. Brands
Ronald B. Jobson
Original Assignee
Merck & 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
Priority claimed from GBGB9800463.3A external-priority patent/GB9800463D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP50883899A priority Critical patent/JP3378021B2/en
Priority to EP98933212A priority patent/EP0998457A4/en
Priority to CA002294341A priority patent/CA2294341C/en
Priority to AU82920/98A priority patent/AU736136B2/en
Publication of WO1999002492A1 publication Critical patent/WO1999002492A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • 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.
  • crystalline forms of the compound 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino] benzoic acid have been discovered and characterized.
  • Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino]benzoic acid and pharmaceutically acceptable salts and solvates thereof are disclosed.
  • the compounds can generally be synthesized taking into account the disclosure of U. S. Patent No. 5,478,820 granted on December 26, 1995. This patent does not disclose the side chain in crystalline form.
  • Figure 1 is an X-Ray Powder Diffraction pattern of Compound I, in unsolvated form
  • Figure 2 is an X-Ray Powder Diffraction pattern of Compound I as the 1-butanol solvate
  • Figure 3 is an X-Ray Powder Diffraction pattern of Compound I, as the acetic acid solvate.
  • the compound has the following structural formula:
  • the salt form of the compound can be protonated as shown in the following:
  • X represents a negatively charged counterion.
  • the salt forms can also be present in the form of a solvate.
  • 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 APD 3720 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°C.
  • the hydrochloride salt of the compound (unsolvated material) was characterized as having an XRPD pattern at 5.5, 5.3, 4.9, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.3, 3.2, 2.9, 2.6 and 2.3 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 1.
  • Step size sample time 0.015 deg, 0.20 s, 0.075 deg/s
  • the hydrochloride salt 1-butanol solvate was shown to exhibit patterns such as the ERPD pattern shown as Figure 2. Characteristic D-spacings are 14.6, 7.3, 5.6, 4.9, 4.2, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.3, 3.0 and 2.9 Ang. More complete XRPD data pertaining to the solvate is shown below in Table 2.
  • Step size sample time 0.015 deg, 0.20 s, 0.075 deg/s
  • Solid material which was exposed to acetic acid was characterized as having an XRPD pattern at 5.4, 5.3, 5.1, 4.2, 3.8, 3.6, 3.4, 3.1, 2.7 and 2.6 angstroms. More complete XRPD data pertaining to the solvate is shown below in Table 3.
  • Peak position criterion Top of smoothed data Cryst peak width range 0.00-2.00 deg
  • the crystalline compound of the present invention is useful in various pharmaceutically acceptable salt forms, for the synthesis of carbapenem compounds that are in turn useful for the treatment of bacterial infections in animal and human subjects.
  • pharmaceutically acceptable salt refers to those salt forms which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
  • Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.
  • the intermediate compound is protonated, and is found in association with a negatively charged counterion, represented by the generic X".
  • a negatively charged counterion represented by the generic X.
  • charge balancing counterion X Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bicarbonate, bisulfate, bromide, citrate, camphorate, camphorsulfonate, carbonate, chloride, digluconate, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolate, hydroxynaphthoate, 2-hydroxyethanesulfonate, iodide, lactate, lactobionate, malate, maleate, man
  • the preferred form of the crystalline compound is the hydrochloride salt form.
  • the compound can be produced in accordance with the following non-limiting examples.
  • the BOC protected sidechain 1 (prepared according to the teachings of PCT WO97/06154 published on February 20, 1997) was dissolved in 1.5 L of a 1 N solution of dry hydrogen chloride in acetic acid (30 min). Gas evolution was observed and the reaction product slowly crystallized. After filtering, washing (with acetic acid and hexane) and drying 137 g of product was obtained. The crystals contain acetic acid but are not a solvate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino]benzoic acid and salts and solvates thereof are disclosed. Three different crystalline types are 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 the compound 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino] benzoic acid have been discovered and characterized. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino]benzoic acid and pharmaceutically acceptable salts and solvates thereof are disclosed. The compounds can generally be synthesized taking into account the disclosure of U. S. Patent No. 5,478,820 granted on December 26, 1995. This patent does not disclose the side chain in crystalline form.
SUMMARY OF THE INVENTION Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl) carbonyl]-amino]benzoic acid as well as pharmaceutically acceptable salts and solvates thereof are disclosed.
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, in unsolvated form;
Figure 2 is an X-Ray Powder Diffraction pattern of Compound I as the 1-butanol solvate, and
Figure 3 is an X-Ray Powder Diffraction pattern of Compound I, as the acetic acid solvate. DETAILED DESCRIPTION OF THE INVENTION
The compound has the following structural formula:
Figure imgf000004_0001
wherein P represents H or a protecting group.
The salt form of the compound can be protonated as shown in the following:
Figure imgf000004_0002
wherein X represents a negatively charged counterion. The salt forms can also be present in the form of a solvate.
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 APD 3720 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°C. The hydrochloride salt of the compound (unsolvated material) was characterized as having an XRPD pattern at 5.5, 5.3, 4.9, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.3, 3.2, 2.9, 2.6 and 2.3 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 1.
Figure imgf000005_0001
Notes:
Generator settings: 45kV, 40 mA
Cu alphal, 2 wave lengths 1.54060, 1.54439 Ang
Step size, sample time 0.015 deg, 0.20 s, 0.075 deg/s
Monochromator used
Divergence slit Automatic (irradiated sample length 12.5 mm)
Peak angle range 2.007-40.002 deg Monochromator used
Divergence slit Automatic (irradiated sample length 12.5 mm)
Peak angle range 2.007-40.002 deg
Range in D spacing 2.25207-43.9723 Ang
Peak position criterion Top of smoothed data
Cry st peak width range 0.00-2.00 deg
Minim peak significance 0.75
Number of peaks in file 33 (alpha 1: 33, amorphous: 0)
Maximum intensity 437. cts, 2184.1 cps
The XRPD pattern corresponding to Table I is shown as Figure 1.
The hydrochloride salt 1-butanol solvate was shown to exhibit patterns such as the ERPD pattern shown as Figure 2. Characteristic D-spacings are 14.6, 7.3, 5.6, 4.9, 4.2, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.3, 3.0 and 2.9 Ang. More complete XRPD data pertaining to the solvate is shown below in Table 2.
Figure imgf000007_0001
Notes:
Generator settings: 45k V, 40 mA
Cu alphal , 2 wavelengths 1.54060, 1.54439 Ang
Step size, sample time 0.015 deg, 0.20 s, 0.075 deg/s
Monochromator used Divergence slit Automatic (irradiated sample length 12.5 mm)
Peak angle range 2.007 - 40.002 deg
Range in D spacing 2.25207 - 43.9723 Ang
Peak position criterion Top of smoothed data
Cryst peak width range 0.00-2.00 deg Minim peak significance 0.75
Number of peaks in file 33 (alphal: 33, amorphous: 0)
Maximum intensity 437. cts, 2184.1 cps
The XRPD pattern corresponding to Table 2 is shown as
Figure 2.
Solid material which was exposed to acetic acid was characterized as having an XRPD pattern at 5.4, 5.3, 5.1, 4.2, 3.8, 3.6, 3.4, 3.1, 2.7 and 2.6 angstroms. More complete XRPD data pertaining to the solvate is shown below in Table 3.
Figure imgf000009_0001
Notes:
Generator settings: 45kV, 40 mA Cu alphal, 2 wavelengths 1.54060, 1.54439 Ang Step size, sample time 0.015 deg, 0.20 s, 0.075 deg/s Monochromator used Divergence slit Automatic (irradiated sample length 12.5 mm)
Peak angle range 2.007-40.002 deg
Range in D spacing 2.25207-43.9723 Ang
Peak position criterion Top of smoothed data Cryst peak width range 0.00-2.00 deg
Minim peak significance 0.75
Number of peaks in file 33 (alphal: 33, amorphous: 0)
Maximum intensity 437. cts, 2184.1 cps
The XRPD pattern corresponding to Table 3 is shown as
Figure 3.
The crystalline compound of the present invention is useful in various pharmaceutically acceptable salt forms, for the synthesis of carbapenem compounds that are in turn useful for the treatment of bacterial infections in animal and human subjects. The term "pharmaceutically acceptable salt" refers to those salt forms which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.
Typically the intermediate compound is protonated, and is found in association with a negatively charged counterion, represented by the generic X". There are various possibilities for the charge balancing counterion X" Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bicarbonate, bisulfate, bromide, citrate, camphorate, camphorsulfonate, carbonate, chloride, digluconate, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolate, hydroxynaphthoate, 2-hydroxyethanesulfonate, iodide, lactate, lactobionate, malate, maleate, mandelate, methylenebis(salicylate), mucate, methanesulfonate, napadisylate, napsylate, pamoate, pantothenate, pectinate, phosphate/ diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, triflate, tosylate and undecanoate. Other anionic species will be apparent to the ordinarily skilled chemist.
The preferred form of the crystalline compound is the hydrochloride salt form.
The compound can be produced in accordance with the following non-limiting examples.
EXAMPLE ONE
A. Synthesis
Figure imgf000011_0001
The BOC protected sidechain 1 (prepared according to the teachings of PCT WO97/06154 published on February 20, 1997) was dissolved in 1.5 L of a 1 N solution of dry hydrogen chloride in acetic acid (30 min). Gas evolution was observed and the reaction product slowly crystallized. After filtering, washing (with acetic acid and hexane) and drying 137 g of product was obtained. The crystals contain acetic acid but are not a solvate.
B. Recrystallization procedures
1-Propanol Solvate
The above product (25 g) was dissolved in 1-propanol (500 mL) at 100°C. Upon cooling the product crystallized out. After filtering, washing (with 1-propanol and hexane) and drying 20 g of the 1-propanol solvate was obtained. 1-Butanol Solvate
The above product (25 g) was dissolved in a mixture of 1-butanol (225 mL) and water (25 mL) at RT. The resulting solution was concentrated in vacuo to a total volume of 125 mL and seeded with authentic 1-butanol solvate. The crystals were filtered, washed (with 1-butanol and hexane) and dried at RT to give 25 g of the 1-butanol solvate.
Acetic Acid Solvate
The above product was slurried overnight in a 95/5 mixture of acetic acid and water at RT and then partially concentrated via distillation in vacuo. The crystals were filtered, washed (with acetic acid and hexane) and dried to give the acetic acid solvate.

Claims

WHAT IS CLAIMED IS:
1. Crystalline 2S-cis-3-[[(4-mercapto-2- pyrrolidinyl)carbonyl]amino]benzoic acid or a pharmaceutically acceptable salt or solvate thereof.
2. Crystalline 2S-cis-3-[[(4-mercapto-2- pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 1, having an X-ray powder diffraction pattern in accordance with Figure 1, 2 or 3.
3. Crystalline 2S-cis-3-[[(4-mercapto-2- pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 1 as the hydrochloride salt.
4. Crystalline 2S-cis-3-[[(4-mercapto-2- pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 3 as the hydrochloride salt unsolvated form.
5. Crystalline 2S-cis-3-[[(4-mercapto-2- pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 3 as the hydrochloride salt 1-butanol solvate.
6. Crystalline 2S-cis-3-[[(4-mercapto-2- pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 3 as the hydrochloride salt acetic acid solvate.
7. Crystalline 2S-cis-3-[[(4-mercapto-2- pyrrolidinyl)carbonyl]aminolbenzoic acid in accordance with claim 1, having one of the following X-ray powder diffraction patterns:
Figure imgf000014_0001
PCT/US1998/014036 1997-07-10 1998-07-07 Crystalline forms of antibiotic side chain intermediates WO1999002492A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP50883899A JP3378021B2 (en) 1997-07-10 1998-07-07 Antibacterial side chain intermediate in crystalline form
EP98933212A EP0998457A4 (en) 1997-07-10 1998-07-07 Crystalline forms of antibiotic side chain intermediates
CA002294341A CA2294341C (en) 1997-07-10 1998-07-07 Crystalline forms of antibiotic side chain intermediates
AU82920/98A AU736136B2 (en) 1997-07-10 1998-07-07 Crystalline forms of antibiotic side chain intermediates

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US5219797P 1997-07-10 1997-07-10
US60/052,197 1997-07-10
GBGB9800463.3A GB9800463D0 (en) 1998-01-09 1998-01-09 Crystalline forms of antibiotic side chain intermediates
GB9800463.3 1998-01-09

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006222A1 (en) * 2000-07-19 2002-01-24 F. Hoffmann-La Roche Ag Pyrrolidine derivatives as inhibitors of endothelin-converting enzyme
WO2010073706A1 (en) * 2008-12-25 2010-07-01 株式会社カネカ Improved process for producing intermediate for side chain of carbapenem

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478820A (en) * 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2294342C (en) * 1997-07-09 2006-03-14 Merck & Co., Inc. Process for synthesizing carbapenem side chain intermediates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478820A (en) * 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0998457A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006222A1 (en) * 2000-07-19 2002-01-24 F. Hoffmann-La Roche Ag Pyrrolidine derivatives as inhibitors of endothelin-converting enzyme
US6541638B2 (en) 2000-07-19 2003-04-01 Hoffman-La Roche Inc. Pyrrolidine derivatives
WO2010073706A1 (en) * 2008-12-25 2010-07-01 株式会社カネカ Improved process for producing intermediate for side chain of carbapenem
CN102264744A (en) * 2008-12-25 2011-11-30 株式会社钟化 Improved process for producing intermediate for side chain of carbapenem

Also Published As

Publication number Publication date
CA2294341A1 (en) 1999-01-21
EP0998457A4 (en) 2010-03-10
EP0998457A1 (en) 2000-05-10
AU736136B2 (en) 2001-07-26
CA2294341C (en) 2007-09-25
JP2002504157A (en) 2002-02-05
AU8292098A (en) 1999-02-08
JP3378021B2 (en) 2003-02-17

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