CN105461648B - Crystal formation of Linezolid and preparation method thereof - Google Patents
Crystal formation of Linezolid and preparation method thereof Download PDFInfo
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- CN105461648B CN105461648B CN201610004353.8A CN201610004353A CN105461648B CN 105461648 B CN105461648 B CN 105461648B CN 201610004353 A CN201610004353 A CN 201610004353A CN 105461648 B CN105461648 B CN 105461648B
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- crystal formation
- linezolid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to novel crystal forms of Linezolid and preparation method thereof.The present invention relates to the crystal formation of (S) N formula (1) Suo Shi [[the oxazole alkyl of 3 (3 fluorine 4 (4 morpholinyl) phenyl) 2 oxo 5] methyl] acetamide, and preparation method thereof.
Description
The application is that Chinese Patent Application No. is 201210122882.X, entitled " novel crystal forms of Linezolid and
Its preparation method ", the applying date are the divisional application of the Chinese invention patent application on April 24th, 2012.
Technical field
The present invention relates to Linezolid (S)-N- [[3- (the fluoro- 4- of 3- (4- morpholinyls) phenyl) -2- oxo -5- oxazolidines
Base] methyl] acetamide crystal formation and preparation method thereof.
Background technology
Linezolid (1inezolid, trade name Zyvox) be by Pharmacia＆Upjohn companies of the U.S. (after by Pfizer
Corporate buyout) development and production novel oxazolidinone class synthetic antibacterial drug, U.S. FDA ratifies on the medicine on April 18th, 2000
City.This product is that the U.S. is approved for treating the medicine that methicillin resistance staphylococcus aureus infects for first over 40 years.
Linezolid has a variety of crystal formations.Pharmacia＆Upjohn is in 1998-10-13 in CN101353313A first
Secondary open Linezolid crystallization, alpha-crystal form；CN1221547C (Pharmacia＆Upjohn) reports beta crystal；
WO2006004922A (Teva) reports γ crystal formations；WO2006110155A (Teva) reports crystal formation IV to crystal formation XVIII, with
And amorphous crystal formation.
The content of the invention
Novel crystal forms it is an object of the invention to provide structure for the Linezolid of formula 1.
Wherein,
Formula (1) compound is crystal formation A：
Its θ of the angle of diffraction 2 be 13.4 ° of (a), 20.9 ° of (b), 22.0 ° of (c), show X-ray diffraction peak at 25.3 ° of (d)；
It is to show X-ray diffraction peak at 13.4 ° of (a) in the θ of the angle of diffraction 2, and the relative line intensity that the peak has is
37；It is that 20.9 ° of (b) place shows X-ray diffraction peak in the θ of the angle of diffraction 2, the relative line intensity that the peak has is 43；In diffraction
The θ of angle 2 is that 22.0 ° of (c) place shows X- ray diffraction peaks, and the relative line intensity that the peak has is 100；It is in the θ of the angle of diffraction 2
(d) X-ray diffraction peak is shown at 25.3 °, the relative line intensity that the peak has is 22；
It is shown at the θ of the angle of diffraction 2 with X-ray diffraction spectral line (the intensity of spectral line that relative line intensity is 20 or more
Provided in bracket)：13.4°(37)、20.9°(43)、22.0°(100)、 25.3°(22)；
It is shown at the θ of the angle of diffraction 2 with X-ray diffraction spectral line (the intensity of spectral line that relative line intensity is 10 or more
Provided in bracket)：7.3°(12)、13.4°(37)、14.6°(10)、 17.9°(19)、18.4°(10)、18.7°(10)、
20.9°(43)、22.0°(100)、25.3° (22)、27.6°(10)；Preferably, it is each in crystal formation A x-ray diffraction pattern
The relative peak intensities at peak correspond to more than the 20% of peak relative peak intensities without departing from above-mentioned.
It exists in the form of relevant material is more than 99.5%.
Our the primary studies dissolubility of the crystal formation, stability etc., with prior art disclosed in crystal formation compare,
As a result show, crystal formation A properties are stable, favorable repeatability, are adapted to drug development.
Brief description of the drawings
Fig. 1 is the crystal formation A of the compound Linezolid of formula 1 x-ray diffraction pattern.
Embodiment
Present disclosure will be specifically described by drawings and examples below, but be not meant to that the present invention only includes
Following content.
Embodiment 1 prepares the crystal formation A of Linezolid using toluene
Compound 1 (500g, 1.48mol) is added in toluene (15L), is heated to reflux making flow back after dissolving 3h, Ran Houleng
But 12h crystallizations are stirred.Filter, be dried under reduced pressure at 50 DEG C of gained solid to constant weight.Target product (494g, off-white powder) is obtained,
Yield 98.8%.
The stability experiment of experimental example 1
INSTRUMENT MODEL：D/Max-RA Japan RigakuX- ray powder diffractometers
Ray：Monochromatic Cu-K alpha rays
Scan mode：The θ of θ/2, scanning range：3-45 °
Temperature range：294K voltages：40KV
X-ray diffraction data comparison is shown in Table 1.
The X-ray diffraction data comparison table of the accelerated stability laboratory sample of table 1
Experiment conclusion：After 6 months Acceleration studies, x-ray diffraction pattern is consistent with primary data, does not occur to turn brilliant existing
As showing that stability of crystal form provided by the present invention is good.
The stability experiment of experimental example 2
Table 2
Experiment conclusion：Stability of crystal form provided by the present invention is good.
Claims (6)
- The crystal formation A of formula 1. (1) compound preparation method, comprises the following steps：Formula (1) compound is dissolved in organic solvent, is heated to reflux dissolving, cooling crystallization, is dried under reduced pressure, obtain target product crystal form A, The crystal formation A the θ of the angle of diffraction 2 be 7.3 °, 13.4 °, 14.6 °, 17.9 °, 18.4 °, 18.7 °, 20.9 °, 22.0 °, 25.3 °, There is diffraction maximum at 27.6 °；The organic solvent is toluene；The w/v of formula (1) compound and organic solvent is 1: 30kg/L；
- 2. preparation method as claimed in claim 1, it is characterised in that it is 1~5h to be heated to reflux the time.
- 3. preparation method as claimed in claim 2, it is characterised in that it is 3h to be heated to reflux the time.
- 4. preparation method as claimed in claim 1, it is characterised in that the cooling crystallization time is 10~15h.
- 5. preparation method as claimed in claim 4, it is characterised in that the cooling crystallization time is 12h.
- 6. preparation method as claimed in claim 1, it is characterised in that form of the crystal formation A relevant material more than 99.5% In the presence of.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610004353.8A CN105461648B (en) | 2011-05-03 | 2012-04-24 | Crystal formation of Linezolid and preparation method thereof |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110115784 | 2011-05-03 | ||
| CN2011101157849 | 2011-05-03 | ||
| CN201610004353.8A CN105461648B (en) | 2011-05-03 | 2012-04-24 | Crystal formation of Linezolid and preparation method thereof |
| CN201210122882XA CN102766106A (en) | 2011-05-03 | 2012-04-24 | Novel crystal form of linezolid and preparation method thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210122882XA Division CN102766106A (en) | 2011-05-03 | 2012-04-24 | Novel crystal form of linezolid and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105461648A CN105461648A (en) | 2016-04-06 |
| CN105461648B true CN105461648B (en) | 2018-01-12 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210122882XA Pending CN102766106A (en) | 2011-05-03 | 2012-04-24 | Novel crystal form of linezolid and preparation method thereof |
| CN201610004353.8A Active CN105461648B (en) | 2011-05-03 | 2012-04-24 | Crystal formation of Linezolid and preparation method thereof |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210122882XA Pending CN102766106A (en) | 2011-05-03 | 2012-04-24 | Novel crystal form of linezolid and preparation method thereof |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503764B (en) * | 2016-01-12 | 2017-09-19 | 江苏豪森药业集团有限公司 | Linezolid form B and its production and use |
| CN110194750A (en) * | 2019-06-19 | 2019-09-03 | 四川美大康华康药业有限公司 | A kind of preparation method and refining methd of Linezolid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1394207A (en) * | 2000-02-02 | 2003-01-29 | 法玛西雅厄普约翰美国公司 | Linezolid-crystal form II |
| WO2005035530A1 (en) * | 2003-10-16 | 2005-04-21 | Symed Labs Limited | A novel crystalline form of linezolid |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1658275A1 (en) * | 2004-06-29 | 2006-05-24 | Teva Pharmaceutical Industries Ltd | Crystalline form iv of linezolid |
| WO2009063505A2 (en) * | 2007-10-08 | 2009-05-22 | Usv Limited | Process for preparation of (s) (n-[[3-[3-fluoro-4-(4-morpholinyl) hen l -2-oxo-5-oxazolidin l methyl]acetamide |
| CN102174027B (en) * | 2010-03-11 | 2014-04-02 | 四川美大康佳乐药业有限公司 | New crystal form of linezolid and preparation method and application thereof |
-
2012
- 2012-04-24 CN CN201210122882XA patent/CN102766106A/en active Pending
- 2012-04-24 CN CN201610004353.8A patent/CN105461648B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1394207A (en) * | 2000-02-02 | 2003-01-29 | 法玛西雅厄普约翰美国公司 | Linezolid-crystal form II |
| WO2005035530A1 (en) * | 2003-10-16 | 2005-04-21 | Symed Labs Limited | A novel crystalline form of linezolid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105461648A (en) | 2016-04-06 |
| CN102766106A (en) | 2012-11-07 |
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