CN106608884A - Tedizolid system intermediate crystal form - Google Patents
Tedizolid system intermediate crystal form Download PDFInfo
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- CN106608884A CN106608884A CN201510706581.5A CN201510706581A CN106608884A CN 106608884 A CN106608884 A CN 106608884A CN 201510706581 A CN201510706581 A CN 201510706581A CN 106608884 A CN106608884 A CN 106608884A
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Abstract
The present invention discloses a crystal form of a compound represented by a formula (415b) defined in the specification, wherein the characteristic absorption peaks exist at 2[theta]+/-0.2 of 9.54, 14.28, 19.12, 19.48, 20.86 and 28.77 in the X-ray powder diffraction pattern, and the determination results of the crystal through the differential scanning calorimetry method show that the initial endothermic temperature is about 177.9 DEG C and the endothermic peak value is about 179.4 DEG C.
Description
Technical field
The invention belongs to medicinal chemistry art, is related to synthesize the intermediate of safe ground azoles amine, and in particular to the crystal formation of the intermediate of synthesis safe ground azoles amine.
Background technology
Safe ground azoles amine（Tedizolid）It is a kind of novel oxazolidinone antibiotics, its phosphate（tedizolid
phosphate）FDA is obtained
Ratify for treating staphylococcus aureuses（Including methicillin resistant strains, methicillin sensitive strain）The acute bacterial skin caused with the gram-positive bacterium such as various Streptococcus and enterococcus faecalis and skin structure infection（ABSSSI）.Entitled (R) -3- (4- (2- (the 2- methyl tetrazolium -5- of chemistry
Base) pyridine -5- bases) -3- fluorophenyls) -5- Qiang Jia Ji Evil oxazolidine -2-
Ketone.
CN104496979 discloses a kind of preparation method of safe ground azoles amine, wherein intermediate used just includes following compounds 416b：
416b
Polymorph in pharmaceuticals is the common phenomenon in medicament research and development, is the key factor for affecting drug quality.The different crystal forms of same drug molecule might have significant difference in properties such as outward appearance, dissolubility, fusing point, dissolution, biological effectivenesses, so as to directly affect stability, bioavailability and the curative effect of medicine.Therefore, the polymorphic problem of medicine in drug research and development, should be considered comprehensively, crystal formation screening is carried out comprehensive system, crystal formation is furtherd investigate, so as to find the crystal formation of most suitable exploitation.
Accordingly, it would be desirable to the crystal formation of 416b is studied, to develop most stable of crystal formation, so as to be conducive to the industrialized production of safe ground azoles amine.
The content of the invention
The present invention provides a kind of novel crystal forms of 416b, and the stability of crystal form preferably, is conducive to the industrialized production of safe ground azoles amine.
Another aspect of the present invention, there is provided the preparation method of the crystal formation.
Third method of the present invention, there is provided application of the crystal formation in terms of safe ground azoles amine is prepared.
416b
There is following characteristic absorption peak in 2 θ ± 0.2 in its X-ray powder diffraction figure：9.54、14.28、19.12、19.48、20.86.
Furtherly, there is following characteristic absorption peak in 2 θ ± 0.2 in its X-ray powder diffraction figure：9.54、14.28、19.12、19.48、20.86、28.77.
Its X-ray powder diffraction figure has following characteristics：
Table 1：X-ray powder diffraction
| Sequence number | Peak position（°） | Interplanar distance D（Å） | Peak intensity (%) |
| 1 | 9.54 | 9.26886 | 90.30 |
| 2 | 14.28 | 6.20240 | 42.11 |
| 3 | 19.12 | 4.64118 | 55.38 |
| 4 | 19.48 | 4.55607 | 34.92 |
| 5 | 20.86 | 4.25840 | 100.00 |
| 6 | 28.77 | 3.10303 | 26.51 |
Its X-ray powder diffraction figure is as shown in Figure 1.
Its differential scanning calorimetry determines the crystal formation, about 177.9 DEG C of initial endothermic temperature, endotherm peak about at 179.4 DEG C, as shown in Figure 2.
It should be noted that; for the X- ray powder diffractions peak of the above crystal formation; between a machine and another machine and between a sample and another sample; 2 θ of X- ray powder diffractions may be slightly changed; its numerical value may differ by about 1 unit; or about 0.8 unit of difference; or about 0.5 unit of difference; or about 0.3 unit of difference; or about 0.2 unit of difference; or difference about 0.1 unit, therefore given numerical value can not be considered as it is absolute, in the scope of the present invention.
For the value of the DSC of the above crystal formation; between a machine and another machine and between a sample and another sample; fusing point may be slightly changed; its numerical value may differ by and approximately less than be equal to 5 DEG C; or difference is approximately less than equal to 4 DEG C, or difference is approximately less than equal to 3 DEG C, or difference is approximately less than equal to 2 DEG C; therefore given numerical value can not be considered as it is absolute, in the scope of the present invention.
Present invention also offers the preparation method of the crystal formation：416b crude products are added into dichloromethane, it is warming up to backflow, and keep entirely molten to solid, then slow cooling is to 30 DEG C or so, being slowly added dropwise normal heptane makes solid separate out in a large number, then 5 ~ 10 DEG C are cooled in 1-2h, filter after keeping crystallize 1-2h, filter cake is obtained into white solid in 40 ~ 45 DEG C of decompression dryings.
Also using the 416b of the crystal formation provided by the present invention, safe ground azoles amine is prepared according to the method for CN104496979：
Relational language is defined：
Term " crystal formation " refers to because intramolecular or intermolecular bonding mode are different, causes molecule different in lattice vacancy arrangement, form different crystal structures.
The crystal formation that the present invention is obtained is essentially pure, term " essentially pure " refers to that a kind of crystal formation is essentially free of one or more other crystal formation, its crystal form purity at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, except this main crystal formation, other a small amount of crystal formations can also be mixed, the percentage by weight of other crystal formations is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
In the context of the present invention, 2 θ values in X- ray powder diffraction patterns are to spend (°) as unit.
416b of the present invention can be prepared according to the method reported in published patent or document,
The method as disclosed according to CN104496979 embodiments 1 is prepared.
Under the high temperature conditions, crystal formation is not changed in crystal formation of the present invention, and relevant material is not also significantly increased, and in long term test, crystal formation is also not changed in, and relevant material is not also significantly increased.Illustrate that crystal formation of the present invention is relatively stable, be conducive to the industrialized production of safe ground azoles amine.
Description of the drawings
Fig. 1：The X-ray powder diffraction figure of 416b；
Fig. 2：The means of differential scanning calorimetry of 416b（DSC）Figure.
Specific embodiment
In order that those skilled in the art is better understood from technical scheme, the present invention is described in further detail to disclose some non-limiting embodiments further below.
Reagent used in the present invention can be buied from the market or can be prepared by method described in the invention.
Instrument parameter
Except making separate stipulations in nonparametric, all analyses are all carried out at ambient temperature.
X- ray powder diffractions (XRPD)
XRPD tests use Panalytical（PANalytical）The XPERT-3 type X-ray diffractometers of company.Will be about 10 milligrams of samples evenly laid out on monocrystal silicon sample disk, XRPD tests are carried out with parameter described below：
Table 2：XRPD sweep parameters
| Start Position [°2Th.]：3.0056 | End Position [°2Th.]：39.9906 |
| Step Size [°2Th.]：0.0130 | Scan Step Time [s]：23.9700 |
| K-Alphal [Å]：1.54060 | K-Alphal2 [Å]：1.54443 |
| Generator Settings：40 mA, 45kV |
Differential scanning calorimetry (DSC)
DSC collection of illustrative plates is gathered on TA Q200 differential scanning calorimeters, and following table lists test parameterss：
Table 3：DSC test parameterss
| Specimen disc | Aluminium dish, gland |
| Temperature range/DEG C | 25-250℃ |
| Sweep speed/（℃/min） | 10 |
| Protective gas | Nitrogen |
The preparation of 1 416b crystal formations of embodiment：
100g crude products are added in 2L there-necked flasks, add 500ml dichloromethane, it is warming up to backflow, and keep entirely molten to solid, then to 30 DEG C or so, be slowly added dropwise 500ml normal heptane makes solid separate out in a large number to slow cooling, is then cooled to 5 ~ 10 DEG C in 1-2h, filter after keeping crystallize 1-2h, filter cake is obtained into white solid 85.7g in 40 ~ 45 DEG C of decompression dryings.
Embodiment 2
Stability experiment
（1）Accelerated test
Instrument：Constant temperature and humidity incubator
Condition：Temperature 50 C ± 2 DEG C, relative humidity RH75% ± 5%
The 416b crystal formations prepared in embodiment 1 are put in constant temperature and humidity incubator, the crystal formation and relevant material of sample is measured by sampling respectively at the 1st day, the 2nd day, the 5th day, the 10th day.As seen from the experiment, under the high temperature conditions, crystal formation is not changed in this crystal formation, and relevant material is not also significantly increased.
（2）Long term test
Instrument：Constant temperature and humidity incubator
Condition：25 DEG C ± 2 DEG C of temperature, relative humidity RH60% ± 5%
The 416b crystal formations prepared in embodiment 1 are put in constant temperature and humidity incubator, the crystal formation and relevant material of sample is measured by sampling respectively at 1st month, the 3rd month, the 6th month.As seen from the experiment, in long term test, crystal formation is not changed in this crystal formation, and relevant material is not also significantly increased.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that：These embodiments can be carried out with various changes, modification, replacement and modification in the case of the principle and objective without departing from the present invention, the scope of the present invention is limited by claim and its equivalent.
Claims (5)
1. a kind of formula（416b）The crystal formation of shown compound：
（416b）
There is following characteristic absorption peak in 2 θ ± 0.2 in its X-ray powder diffraction figure：9.54、14.28、19.12、19.48、20.86.
2. crystal formation according to claim 1, it is characterised in that there is following characteristic absorption peak in 2 θ ± 0.2 in its X-ray powder diffraction figure：9.54、14.28、19.12、19.48、20.86、28.77.
3. crystal formation according to claim 1 and 2, it is characterised in that its differential scanning calorimetry determines the crystal formation, about 177.9 DEG C of initial endothermic temperature, and endotherm peak is about at 179.4 DEG C.
4. crystal formation according to claim 1 and 2, the preparation method of the crystal formation is：By formula（416b）Dichloromethane is added in crude compound, it is warming up to backflow, and keep entirely molten to solid, then slow cooling is to 30 DEG C or so, being slowly added dropwise normal heptane makes solid separate out in a large number, then 5 ~ 10 DEG C are cooled in 1-2h, filter after keeping crystallize 1-2h, filter cake is obtained into white solid in 40 ~ 45 DEG C of decompression dryings。
5. application of the crystal formation according to claim 1 and 2 in terms of safe ground azoles amine is prepared：
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201510706581.5A CN106608884A (en) | 2015-10-27 | 2015-10-27 | Tedizolid system intermediate crystal form |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679454A (en) * | 2007-03-02 | 2010-03-24 | 盟科医药有限公司 | Antimicrobial heterocyclic compounds for treatment of bacterial infections |
| WO2010047737A2 (en) * | 2008-09-02 | 2010-04-29 | Micurx Pharmaceuticals, Inc. | Antimicrobial indoline compounds for treatment of bacterial infections |
| CN104327119A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tedizolid phosphate |
-
2015
- 2015-10-27 CN CN201510706581.5A patent/CN106608884A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679454A (en) * | 2007-03-02 | 2010-03-24 | 盟科医药有限公司 | Antimicrobial heterocyclic compounds for treatment of bacterial infections |
| WO2010047737A2 (en) * | 2008-09-02 | 2010-04-29 | Micurx Pharmaceuticals, Inc. | Antimicrobial indoline compounds for treatment of bacterial infections |
| CN104327119A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tedizolid phosphate |
Non-Patent Citations (1)
| Title |
|---|
| GANG LI ET AL.: ""An Improved Efficient Synthesis of the Antibacterial Agent Torezolid"", 《CHEM. PHARM. BULL》 * |
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Application publication date: 20170503 |