CN102643245A - Linezolid crystal form and preparation method thereof - Google Patents
Linezolid crystal form and preparation method thereof Download PDFInfo
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- CN102643245A CN102643245A CN2012101018520A CN201210101852A CN102643245A CN 102643245 A CN102643245 A CN 102643245A CN 2012101018520 A CN2012101018520 A CN 2012101018520A CN 201210101852 A CN201210101852 A CN 201210101852A CN 102643245 A CN102643245 A CN 102643245A
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Abstract
The invention relates to a linezolid crystal form IV. The linezolid crystal form IV has characteristic peaks when the reflection angle 2 theta of X-ray powder diffraction is approximately 7.04, 7.33, 9.34, 13.50, 14.70, 18.00, 21.01, 22.10 and 25.40. The invention discloses a preparation method for the linezolid crystal form IV. A crude linezolid product is re-crystallized and then directly dried in vacuum to form the crystal form IV. Any solvent is not introduced into the preparation process of the production method, and only heating is required, so that the technical defects of organic residue, complex process, high cost and the like in the linezolid production process are overcome. The production method is easy to operate, low in cost and very suitable for industrialized production.
Description
Technical field
The present invention relates to chemosynthesis technical field, be specifically related to the preparation method of a kind of Linezolid (linezolid) crystal formation.
Background technology
Linezolid, chemical name (S)-N [[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide;
Structural formula is:
U.S. Pat 5688792, US5837870 discloses the preparation method of Linezolid, also has many other to relate to the open source literature of this compound; Like West China pharmaceutical journal (W C J.PS) 2007,22 (2) 179-181), medical chemistry magazine (J.Med; Chem) 39 (3), 673-679 (1996), tetrahedron communication (Tetrahedron Lett) .40 (26; 4855 (1999), PCT/US98/20934, WO99/24393 also successively disclose the preparation method of Linezolid.
In the preparation method of above-mentioned open source literature, relate to this compound purified method and mostly used ETHYLE ACETATE, sherwood oil, normal hexane; Methyl alcohol, acetone, acetonitrile, octane-iso equal solvent or mixed system; The non-common solvent of octane-iso and so on costs an arm and a leg, and cost is higher, and the low boiling point solvent of ethers is inflammable and explosive, acetonitrile; The solvent toxicity of methyl alcohol and so on is bigger, and ETHYLE ACETATE is bad to the solvability of this compound, and usage quantity is bigger, and is not suitable for suitability for industrialized production.
About the report of the crystal formation of Linezolid just like, WO 2005/035530, US 2008/0319191, US 2006/0111350; Mainly included the common I crystal formation of this compound, II crystal formation, III crystal formation, the preparation method of IV crystal formation or the like; Be mainly concerned with and propyl carbinol toluene, YLENE, DMF; DMEA, the pyridine equal solvent mixes, and under the temperature near boiling point, the crystal seed that adds the target crystal formation carries out the crystal formation conversion; These said solvent toxicity are bigger, and solvent-oil ratio is also big, and the molten residual problem of finished product is difficult to solve.
Linezolid I crystal formation fusing point is 181.5 ℃-182.5, ℃, IR absorption peak data are: 3284,3092,1753,1728,1649,1565,1519,1447, and 1435cm
-1, but research shows this compound the most stable with the II crystal formation below 80 ℃, II crystal form X RPD data are: 7.10,9.54,13.88,14.23,16.18; 16.79,17.69,19.41,19.69,19.93,21.63; 22.39,23.52,24.16,25.28,26.66,27.77.The Linezolid that is used for clinical trial at present and has gone on the market is all the II crystal formation, but this crystal formation patent protection, the brilliant raw material of II can not be used in the home market.
Through the controlled trial (US2008/0319191) under the condition of different temperatures, IV crystal formation Linezolid also can stable existence, and especially easy storing under the normal temperature is difficult for taking place to change brilliant; Detect through XRPD, this crystalline 2-θ angular data is: 7.04,7.33,9.34; 13.50,14.70,18.00; 21.01,22.10,25.40.
In the preparation process of IV crystal formation Linezolid, exist organic solvent residual, complex process, cost high-technology defective in the prior art.
Summary of the invention
The objective of the invention is to overcome the technological deficiency of problems such as organic residual, complex process, cost height in the existing technological process, a kind of stable, simple to operate, with low cost, preparation technology efficiently is provided, to be fit to industrialized production.
From the angle of suitability for industrialized production, the invention provides a kind of preparation method of Linezolid IV crystal formation.This method with Linezolid bullion recrystallization after convection drying promptly get the IV crystal formation, only need heating, do not introduce any solvent, simple to operate, with low cost, be fit to very much suitability for industrialized production.Specifically may further comprise the steps:
A, Linezolid bullion use volumetric concentration to be the dissolving of the aqueous ethanolic solution of 40-95% (v/v) ,-10-10 ℃ crystallization 4-24 hour, separate obtaining midbody;
B, midbody are under vacuum environment, prior to 40-60 ℃ of dry 1-3 hour; Be warming up to 120-160 ℃ then, dry 2-4 hour, promptly get.
Wherein said Linezolid bullion can shine the document preparation, also can buy commercially available article;
Wherein said aqueous ethanolic solution is preferably 50% (v/v);
Recrystallization temperature is preferred 0 ℃-5 ℃ in the wherein said steps A;
Preferred 20 hours of the crystallization time in the wherein said steps A;
Preferred 50 ℃ of the temperature of wherein said step B mid-early stage; Preferred 2 hours of time of drying;
The temperature of wherein said step B middle and later periods is 155 ℃; Preferred 3 hours of time of drying.
This technology gained finished product is white or off-white color; To the gained finished product; Adopt Cu K alpha-ray, carry out the X-ray powder diffraction analysis (Japan's (Rigaku D/Max-2550pc type X ray polycrystalline diffractometer) of science, measured power is 40kV * 250mA; 5 °/min of sweep velocity, the step wide 0.02 °; θ-2 θ the continuous sweep of sweep limit 3-40 ° (2 θ), through contrast, the conclusive evidence products therefrom is the IV crystal formation.
Finished product is with reference to two appendix VD of Chinese Pharmacopoeia version in 2010 HPLC method (Tianjin, island LC-20AT; Agilent XDB C18 150*4.6mm chromatographic column detects wavelength 254nm) detect, its enantiomorph content is all greater than 99.5%; Presentation of results, the repeatability of this technology is fine with stability.
Technique effect of the present invention is mainly reflected in:
1) select the alcohol-water solvent systems in the technology for use, cheap, safety non-toxic; The three wastes are handled easy; Decolorizing effect is fine, once refining can the bullion purity of normalizing content more than 90% being brought up to more than 99.5%, and yield is higher than 80%; The mother liquor recovery set is highly suitable for suitability for industrialized production with also simple and feasible.
2 Linezolid bullions gained midbody drying-free after making with extra care is handled, and directly gets into IV crystal formation Linezolid finished product and prepares link, has both avoided dust pollution; Shortened the production cycle again, practiced thrift cost, the most outstanding advantage is; Need not to introduce any solvent, be breakthrough optimization aspect labour protection and the three wastes processing, and practicing thrift cost greatly; Simple possible extremely is applicable to suitability for industrialized production.Evidence repeatedly, IV crystal formation Linezolid finished product prepares in the process, and the color of finished product and normalization method content almost do not have change, and the repeatability of this technology is fine with stability, and the finished product enantiomorph content that obtains is greater than 99.5%.
Description of drawings
Fig. 1 is the X-ray powder diffraction spectrum of embodiment 3.1 finished products.
Specific embodiment
Through specific embodiment given below, can further clearly understand the present invention, but they not to qualification of the present invention.
Embodiment 1: the preparation of bullion
Under the nitrogen protection, with 9.8kg N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline and 2kg methyl alcohol, 19kgDMF, the 75kg THF adds in the reaction kettle, and mixture is cooled to 0 ℃ and stirs 15min; Add 10kg trimethyl carbinol lithium, be cooled to adding (s)-N-[2-acetoxy-3-chloropropyl] ethanamide 11kg about 0 ℃, temperature is raised to 20-25 ℃, stopped reaction behind the reaction 20hr; Add 200kg water and 160kg methylene dichloride, layering, water layer is used the 50kg*2 dichloromethane extraction, merges organic layer; Be concentrated into driedly, add 80kg YLENE, in-5 ℃ of left and right sides stirring and crystallizing 20hr; Centrifugal, the filter cake forced air drying obtains 6.2kg linwzolid bullion.
Embodiment 2.1: the preparation of midbody
6.2kg embodiment 1 gained Linezolid bullion is dropped in the reaction kettle, add absolute ethyl alcohol 31kg, pure water 40kg (50% ethanol (v/v)); Add gac 500g after the heating for dissolving, reflux, decolouring; Filter, mother liquor naturally cools to the room temperature postcooling to 0-5 ℃, insulated and stirred 12h; Centrifugal, get 6.8kg white solid powder (without oven dry).
Embodiment 2.2: the preparation of midbody
6.2kg embodiment 1 gained Linezolid bullion is dropped in the reaction kettle, add absolute ethyl alcohol 25kg, pure water 2kg (95% ethanol (v/v)); Add gac 500g after the heating for dissolving, reflux, decolouring; Filter, mother liquor naturally cools to the room temperature postcooling to-10 ℃, insulated and stirred 4h; Centrifugal, get 5.6kg off-white color pressed powder (without oven dry).
Embodiment 2.3: the preparation of midbody
6.2kg embodiment 1 gained Linezolid bullion is dropped in the reaction kettle, add absolute ethyl alcohol 42kg, pure water 36kg (60% ethanol (v/v)); Add gac 500g after the heating for dissolving, reflux, decolouring; Filter, mother liquor naturally cools to the room temperature postcooling to-5 ℃, insulated and stirred 24h; Centrifugal, get 6.5kg white solid powder (without oven dry).
Embodiment 2.4: the preparation of midbody
6.2kg embodiment 1 gained Linezolid bullion is dropped in the reaction kettle, add absolute ethyl alcohol 22kg, pure water 42kg (40% ethanol (v/v)); Add gac 500g after the heating for dissolving, reflux, decolouring; Filter, mother liquor naturally cools to room temperature postcooling to 10 ℃, insulated and stirred 20h; Centrifugal, get 7.1kg white solid powder (without oven dry).
Embodiment 3.1: the preparation of IV crystal formation finished product
Gained midbody among the embodiment 2.1 is directly dropped into bipyramid, be steam heated to 50 ℃, dry 3h; Be warming up to 155 ℃ then, dry 4h is cooled to room temperature under the nitrogen protection; Discharging obtains white Linezolid finished product 5kg, with reference to two appendix V of Chinese Pharmacopoeia version in 2010 D HPLC method (Tianjin, island LC-20AT; Agilent XDB C18 150*4.6mm chromatographic column detects wavelength 254nm) detect, normalization method content is 99.8%.Detect (employing Cu K alpha-ray through XRD; Carry out X-ray powder diffraction analysis (Japan's (Rigaku D/Max-2550pc type X ray polycrystalline diffractometer) of science; Measured power is 40kV * 250mA; 5 °/min of sweep velocity, the step wide 0.02 °, the θ-2 θ continuous sweep of sweep limit 3-40 ° (2 θ)), this crystalline 2-θ angular data is:
7.339,13.462,14.702,17.978,19.840,20.944,22.177,25.419,27.683,29.661 (seeing accompanying drawing 1).
Through contrast, conclusive evidence gained crystal is an IV crystal formation Linezolid.
Embodiment 3.2: the preparation of IV crystal formation finished product
Gained midbody among the embodiment 2.2 is directly dropped into vacuum drying oven, be steam heated to 40 ℃, dry 2h; Be warming up to 120 ℃ then; Dry 3h is cooled to room temperature under the nitrogen protection, discharging; Obtain white Linezolid finished product 4.5kg, normalization method content is 99.9% (detection method is with reference to embodiment 3.1).Detect (detection method is with reference to embodiment 3.1) through XRD, it is similar with figure 01 that it detects collection of illustrative plates, and this crystalline 2-θ angular data is:
7.339,9.340,13.481,16.802,18.000,18.740,21.019,22.180,25.401，27.701,28.341?。
Through contrast, the conclusive evidence products therefrom is an IV crystal formation Linezolid.
Embodiment 3.3: the preparation of IV crystal formation finished product
Gained midbody among the embodiment 2.3 is directly dropped into bipyramid, be steam heated to 50 ℃, dry 2h; Be warming up to 120 ℃ then, dry 4h is cooled to room temperature under the nitrogen protection; Discharging obtains white Linezolid finished product 4.8kg, and normalization method content is 99.5% (detection method is with reference to embodiment 3.1).Detect (detection method is with reference to embodiment 3.1) through XRD, it is similar with figure 01 that it detects collection of illustrative plates, and this crystalline 2-θ angular data is:
7.338,9.339,13.481,14.699,16.821,18.720,20.999,22.178,25.382,27.681,?28.320?。
Through contrast, the conclusive evidence products therefrom is an IV crystal formation Linezolid.
Embodiment 3.4: the preparation of IV crystal formation finished product
Gained midbody among the embodiment 2.4 is directly dropped into bipyramid, be steam heated to 60 ℃, dry 1h; Be warming up to 160 ℃ then, dry 2h is cooled to room temperature under the nitrogen protection; Discharging obtains off-white color Linezolid finished product 5kg, and normalization method content is 99.6% (detection method is with reference to embodiment 3.1).Detect (detection method is with reference to embodiment 3.1) through XRD, it is similar with figure 01 that it detects collection of illustrative plates, and this crystalline 2-θ angular data is: 7.340,13.500,14.719,18.001,21.020,22.164,25.420.
Through contrast, the conclusive evidence products therefrom is an IV crystal formation Linezolid.
Claims (8)
1. Linezolid IV crystal formation, reflection angle 2 θ of its X-ray powder diffraction are near 7.04,7.33, and 9.34,13.50,14.70,18.00,21.01,22.10,25.40 have characteristic peak, and its preparation method comprises:
A, Linezolid bullion use volumetric concentration to be the dissolving of the aqueous ethanolic solution of 40-95% ,-10-10 ℃ crystallization 4-24 hour, separate obtaining midbody;
B, midbody are under vacuum environment, prior to 40-60 ℃ of dry 1-3 hour; Be warming up to 120-160 ℃ then, dry 2-4 hour, promptly get.
2. preparation method as claimed in claim 1, the ethanol volumetric concentration that it is characterized in that said aqueous ethanolic solution is 50%.
3. preparation method as claimed in claim 1 is characterized in that recrystallization temperature is 0-5 ℃ in the said steps A.
4. preparation method as claimed in claim 1 is characterized in that the crystallization time is 20 hours in the said steps A.
5. preparation method as claimed in claim 1 is characterized in that the temperature of said step B mid-early stage is 50 ℃.
6. preparation method as claimed in claim 1, the temperature that it is characterized in that the said step B middle and later periods is 155 ℃.
7. preparation method as claimed in claim 1 is characterized in that said step B mid-early stage drying 2 hours.
8. preparation method as claimed in claim 1 is characterized in that dry 3 hours of said step B middle and later periods.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103099792A (en) * | 2012-12-10 | 2013-05-15 | 成都欣捷高新技术开发有限公司 | Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving |
| CN104370846A (en) * | 2013-08-15 | 2015-02-25 | 杭州华东医药集团生物工程研究所有限公司 | Method for preparing linezolid IV crystal form |
| CN109444294A (en) * | 2018-12-27 | 2019-03-08 | 南京盖斯夫医药科技有限公司 | A kind of efficient liquid-phase chromatography method separating Linezolid and its chiral isomer |
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 |
| CN102260222A (en) * | 2011-05-20 | 2011-11-30 | 上海医药工业研究院 | Linezolid crystal form V and preparation method thereof |
-
2012
- 2012-04-10 CN CN2012101018520A patent/CN102643245A/en active Pending
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 |
| CN102260222A (en) * | 2011-05-20 | 2011-11-30 | 上海医药工业研究院 | Linezolid crystal form V and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103099792A (en) * | 2012-12-10 | 2013-05-15 | 成都欣捷高新技术开发有限公司 | Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving |
| CN103099792B (en) * | 2012-12-10 | 2014-11-26 | 成都欣捷高新技术开发有限公司 | Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving |
| CN104370846A (en) * | 2013-08-15 | 2015-02-25 | 杭州华东医药集团生物工程研究所有限公司 | Method for preparing linezolid IV crystal form |
| CN104370846B (en) * | 2013-08-15 | 2017-04-12 | 杭州华东医药集团新药研究院有限公司 | Method for preparing linezolid IV crystal form |
| CN109444294A (en) * | 2018-12-27 | 2019-03-08 | 南京盖斯夫医药科技有限公司 | A kind of efficient liquid-phase chromatography method separating Linezolid and its chiral isomer |
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Application publication date: 20120822 |