EP1261612A1 - Crystalline forms of antibiotic side chain intermediates - Google Patents
Crystalline forms of antibiotic side chain intermediatesInfo
- Publication number
- EP1261612A1 EP1261612A1 EP01920152A EP01920152A EP1261612A1 EP 1261612 A1 EP1261612 A1 EP 1261612A1 EP 01920152 A EP01920152 A EP 01920152A EP 01920152 A EP01920152 A EP 01920152A EP 1261612 A1 EP1261612 A1 EP 1261612A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- crystalline forms
- side chain
- compound
- crystalline
- dipp
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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.
- DIPP diisoproprylphosphoryl
- 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).
- Crystalline DIPP thiolactone and solvates thereof are disclosed. Also disclosed is a process for crystallizing said compounds.
- Figure 1 is an X-Ray Powder Diffraction pattern of Compound I, as the DIPP thiolactone.
- DIPP diisopropylphosphoryl
- the crystalline forms of the compound are characterized below by virtue of their X-Ray Powder Diffraction (XRPD) patterns.
- XRPD X-Ray Powder Diffraction
- 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.
- 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:
- the compounds of this invention can be produced in accordance with the following non-limiting examples.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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
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
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18603900P | 2000-03-01 | 2000-03-01 | |
| US186039P | 2000-03-01 | ||
| PCT/US2001/006179 WO2001064684A1 (en) | 2000-03-01 | 2001-02-27 | Crystalline forms of antibiotic side chain intermediates |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP1261612A1 true EP1261612A1 (en) | 2002-12-04 |
| EP1261612A4 EP1261612A4 (en) | 2003-04-02 |
Family
ID=22683405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP01920152A Withdrawn EP1261612A4 (en) | 2000-03-01 | 2001-02-27 | CRYSTALLINE SHAPES OF SIDE CHAIN CONTAINING ANTIBIOTIC INTERMEDIATES |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1261612A4 (en) |
| JP (1) | JP2003525297A (en) |
| AU (1) | AU4723501A (en) |
| CA (1) | CA2401578A1 (en) |
| WO (1) | WO2001064684A1 (en) |
Family Cites Families (1)
| 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 |
-
2001
- 2001-02-27 WO PCT/US2001/006179 patent/WO2001064684A1/en not_active Ceased
- 2001-02-27 AU AU47235/01A patent/AU4723501A/en not_active Abandoned
- 2001-02-27 JP JP2001564180A patent/JP2003525297A/en not_active Withdrawn
- 2001-02-27 CA CA002401578A patent/CA2401578A1/en not_active Abandoned
- 2001-02-27 EP EP01920152A patent/EP1261612A4/en not_active Withdrawn
Non-Patent Citations (2)
| Title |
|---|
| No further relevant documents disclosed * |
| See also references of WO0164684A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2401578A1 (en) | 2001-09-07 |
| JP2003525297A (en) | 2003-08-26 |
| WO2001064684A1 (en) | 2001-09-07 |
| EP1261612A4 (en) | 2003-04-02 |
| AU4723501A (en) | 2001-09-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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| 17P | Request for examination filed |
Effective date: 20021001 |
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| AK | Designated contracting states |
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| AX | Request for extension of the european patent |
Free format text: AL PAYMENT 20021001;LT PAYMENT 20021001;LV PAYMENT 20021001;MK PAYMENT 20021001;RO PAYMENT 20021001;SI PAYMENT 20021001 |
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| A4 | Supplementary search report drawn up and despatched |
Effective date: 20030217 |
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| RIC1 | Information provided on ipc code assigned before grant |
Ipc: 7C 07F 9/6561 B Ipc: 7C 07D 495/08 A |
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| 17Q | First examination report despatched |
Effective date: 20030616 |
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| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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| 18D | Application deemed to be withdrawn |
Effective date: 20031028 |