CN105254580A - Linezolid crystal form preparation method - Google Patents
Linezolid crystal form preparation method Download PDFInfo
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- CN105254580A CN105254580A CN201410164535.2A CN201410164535A CN105254580A CN 105254580 A CN105254580 A CN 105254580A CN 201410164535 A CN201410164535 A CN 201410164535A CN 105254580 A CN105254580 A CN 105254580A
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- crystal form
- form iii
- ethyl acetate
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- linezolid
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Abstract
The present invention discloses a linezolid crystal form preparation method, and particularly relates to a preparation method of the crystal form III of a compound (S)-N-[[3-(3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide represented by a formula (1), ie., the linezolid crystal form III preparation method, wherein the method comprises adding linezolid to a composite solvent, carrying out recrystallization, and drying to obtain the target crystal form. According to the present invention, the prepared crystal form III has characteristics of stable characteristics and good repeatability, and is suitable for drug development. The formula (1) is defined in the specification.
Description
Technical field
The present invention relates to the preparation method of Linezolid (S)-N-[[3-(the fluoro-4-of 3-(4-morpholinyl) phenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide crystalline form III.
Background technology
Linezolid (1inezolid, trade(brand)name Zyvox) be by the novel oxazolidinone class synthetic antibacterial drug of Pharmacia & Upjohn company of the U.S. (then purchased by Pfizer) development and production, U.S. FDA ratifies the listing of this medicine on April 18th, 2000.This product is U.S.'s medicine that over 40 years, first is approved for treatment methicillin resistance staphylococcus aureus and infects.
Current patent report, Linezolid has 14 kinds of crystal formations.Pharmacia & Upjohn discloses Linezolid crystallization, crystalline form I at 1998-10-13 in CN101353313A first time; CN1221547C (Pharmacia & Upjohn) reports crystal form II; WO2005035530A1 (SYMEDLABSLIMRRED) reports crystalline form III; WO2006110155A (Teva) reports crystalline form V to crystal form X VIII, and amorphous crystal formation.
Wherein crystal form II (crystal formation is declared by Yuan Yan company) and crystalline form III possess that preparation technology is simple, crystal formation solvability and good stability, be well suited for as pharmaceutical developments crystal formation.
The preparation method of the linezolid form III of document patent report commonly uses high boiling point reagent toluene as solvent, because toluene is two kind solvents, so toluene prepares solvent used as crystal formation in pharmaceutical developments certain risk.In addition, also have in prior art and use ethyl acetate to be crystallization solvent, but when preparing crystal form II I with this solvent, reaction process is complicated, and need there is rigors to reaction conditionss such as temperature, be difficult to industrial applications.
Summary of the invention
The object of the invention is to solve the problems of the technologies described above, provide structure to be the preparation method of the linezolid form III of formula (1), comprise and Linezolid is added crystallization in double solvents, dry, obtain target crystal formation.
Preferably, described double solvents is selected from ethyl acetate, butylacetate or isopropyl acetate and normal heptane, normal hexane, isohexane, hexanaphthene, iso-pentane, the combination of octane or octane-iso.
Preferred further, described double solvents is selected from following combination: ethyl acetate/normal heptane, ethyl acetate/normal hexane, ethyl acetate/octane or ethyl acetate/octane-iso.
Preferably, in described double solvents, the volume ratio of each solvent is 1:0.5 ~ 1:10.
Preferred, in described double solvents, the volume ratio of each solvent is 1:1 ~ 1:5.
Preferred further, in described double solvents, the volume ratio of each solvent is 1:1 ~ 1:3, particularly preferably 1:1.
Preferably, in described preparation method, the temperature of crystallization is that room temperature is to 80 DEG C.
Preferred, recrystallization temperature is 30 ~ 60 DEG C.
Preferred further, recrystallization temperature is 40 ~ 55 DEG C, particularly preferably 50 DEG C.
Applicant is surprised to find through great many of experiments, prepare crystal form II I by double solvents and acquisition can make us unexpected technique effect, gained crystal form II I has very large improvement on product yield and purity, greatly reduce production cost, and improve the quality of production of bulk drug, and, enormously simplify production technique by double solvents, and do not need cooling low especially or higher temperature of reaction, thus make the preparation technology of this invention be more suitable for suitability for industrialized production application.In addition, contriver is investigated the character such as solvability, stability being obtained crystal formation by the inventive method, and result shows, the crystalline form III stable in properties obtained by the present invention, favorable repeatability, is applicable to drug development.
Accompanying drawing explanation
Fig. 1 is the x-ray diffraction pattern of formula (1) compound linezolid form III.
Embodiment
To specifically set forth content of the present invention by drawings and Examples below, but protection content of the present invention is not defined in specific embodiment.
Embodiment 1 uses ethyl acetate/normal heptane to prepare the crystalline form III of Linezolid
Compound 1 (500g, 1.48mol) is added in ethyl acetate (15L), heating for dissolving, then solution is poured into cooling and stirring 1h crystallization in normal heptane (15L).Filter, at gained solid 50 DEG C, drying under reduced pressure is to constant weight.Obtain target product (468g, off-white color solid), productive rate 93.6%, HPLC:99.8%.After testing, its XRPD collection of illustrative plates as shown in Figure 1.
Embodiment 2 linezolid form III preparation condition shaker test
Contriver has carried out conditional filtering test for the optimum preparating condition of crystal form II I further, except solvent species in following table is distinct, all the other test conditionss are all identical with embodiment 1, and after having tested, yield and the product purity result of crystal form II I are as shown in the table:
| Solvent | Yield/% | HPLC/％ |
| Ethyl acetate/normal heptane | 93.6 | 99.8 |
| Ethyl acetate/normal hexane | 89.4 | 99.5 |
| Ethyl acetate/isohexane | 88.6 | 99.3 |
| Ethyl acetate/hexanaphthene | 84.8 | 95.9 |
| Ethyl acetate/Skellysolve A | 88.1 | 98.7 |
| Ethyl acetate/iso-pentane | 87.4 | 98.2 |
| Ethyl acetate/octane | 91.5 | 99.0 |
| Ethyl acetate/octane-iso | 90.2 | 99.1 |
| Isopropyl acetate/normal heptane | 86.6 | 97.7 |
| Butylacetate/normal heptane | 88.4 | 97.1 |
| Ethyl acetate | 74.9 | 77.1 |
| Toluene | 67.2 | 88.6 |
As can be seen from preparation condition screening, double solvents is all better than single solvent crystallization on product yield and purity.
Experimental example 1 stability experiment
INSTRUMENT MODEL: D/Max-RA Japan RigakuX-ray powder diffractometer
Ray: monochromatic Cu-K alpha-ray
Scan mode: θ/2 θ, sweep limit: 3-45 °
Temperature range: 294K voltage: 40KV
X-ray diffraction Data Comparison is in table 1.
The X-ray diffraction Data Comparison table of table 1 accelerated stability laboratory sample
Experiment conclusion: after 6 months Acceleration study, x-ray diffraction pattern is consistent with primary data, does not occur to turn brilliant phenomenon, shows that stability of crystal form provided by the present invention is good.
Experimental example 2 stability experiment
Table 2
Experiment conclusion: stability of crystal form provided by the present invention is good.
Claims (9)
1. a method for preparation formula (1) compound crystal form III,
Comprise and Linezolid is added crystallization in double solvents, dry, obtain target crystal formation.
2. the method for preparation formula according to claim 1 (1) compound crystal form III, is characterized in that, described double solvents is selected from ethyl acetate, butylacetate or isopropyl acetate and normal heptane, normal hexane, isohexane, hexanaphthene, iso-pentane, the combination of octane or octane-iso.
3. the method for preparation formula according to claim 1 (1) compound crystal form III, it is characterized in that, described double solvents is selected from following combination: ethyl acetate/normal heptane, ethyl acetate/normal hexane, ethyl acetate/octane or ethyl acetate/octane-iso.
4. the method for preparation formula according to claim 3 (1) compound crystal form III, is characterized in that, in described double solvents, the volume ratio of each solvent is 1:0.5 ~ 1:10.
5. the method for preparation formula according to claim 4 (1) compound crystal form III, is characterized in that, in described double solvents, the volume ratio of each solvent is 1:1 ~ 1:5.
6. the method for preparation formula according to claim 5 (1) compound crystal form III, is characterized in that, in described double solvents, the volume ratio of each solvent is 1:1 ~ 1:3.
7. the method for preparation formula according to claim 1 (1) compound crystal form III, is characterized in that, the temperature of crystallization is that room temperature is to 80 DEG C.
8. the method for preparation formula according to claim 7 (1) compound crystal form III, is characterized in that, recrystallization temperature is 30 ~ 60 DEG C.
9. the method for preparation formula according to claim 7 (1) compound crystal form III, is characterized in that, recrystallization temperature is 40 ~ 55 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410164535.2A CN105254580B (en) | 2014-04-22 | 2014-04-22 | The preparation method of linezolid form |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410164535.2A CN105254580B (en) | 2014-04-22 | 2014-04-22 | The preparation method of linezolid form |
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| CN105254580A true CN105254580A (en) | 2016-01-20 |
| CN105254580B CN105254580B (en) | 2018-01-02 |
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| CN201410164535.2A Active CN105254580B (en) | 2014-04-22 | 2014-04-22 | The preparation method of linezolid form |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005035530A1 (en) * | 2003-10-16 | 2005-04-21 | Symed Labs Limited | A novel crystalline form of linezolid |
| CN101948442A (en) * | 2009-07-10 | 2011-01-19 | 符健 | Preparation method of linezolid and preparation thereof |
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2014
- 2014-04-22 CN CN201410164535.2A patent/CN105254580B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005035530A1 (en) * | 2003-10-16 | 2005-04-21 | Symed Labs Limited | A novel crystalline form of linezolid |
| CN101948442A (en) * | 2009-07-10 | 2011-01-19 | 符健 | Preparation method of linezolid and preparation thereof |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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Effective date of registration: 20160323 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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