CN106478659A - Crystal formation C of benzoxazoles oxazines ketone compounds WA1-089 and preparation method thereof - Google Patents
Crystal formation C of benzoxazoles oxazines ketone compounds WA1-089 and preparation method thereof Download PDFInfo
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- CN106478659A CN106478659A CN201510522375.9A CN201510522375A CN106478659A CN 106478659 A CN106478659 A CN 106478659A CN 201510522375 A CN201510522375 A CN 201510522375A CN 106478659 A CN106478659 A CN 106478659A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- 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
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to a kind of new Xa factor inhibitor benzoxazoles the novel crystal forms of oxazines ketone compounds WA1-089 and preparation method are and in particular to novel crystal forms C and preparation method thereof.At 2 θ are 5.35,11.00,16.00,16.24,16.89,17.95,18.64,18.89,19.35,20.71,21.01,22.91,23.39,23.85,24.63,25.68,27.00,29.69,30.19,30.81,32.07,32.92 and 34.24 ± 0.2 °, there is X-ray powder diffraction peak in the X-ray powder diffraction figure of described crystal formation C.Crystal formation C is obtained by the method for fusion-crystallization, the method has that product purity is high, energy consumption low it is not necessary to add other solvents, the features such as environmental pollution is little.
Description
Technical field
The present invention relates to a kind of new Xa factor inhibitor benzoxazoles novel crystal forms of oxazines ketone compounds WA1-089 and preparation method are and in particular to 5- is chloro-N-(((3S,3aS) -1- ketone -7- (3- ketone morpholine) -1,3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [1,4] oxazines -3- base) methyl) thiophene-2-carboxamide derivatives novel crystal forms and preparation method thereof.
Background technology
A kind of brand-new Xa factor inhibitor benzoxazoles oxazines ketone compounds（Abbreviation WA1-089）By structural formula（I）Represent, chemical name is that 5- is chloro-N-(((3S,3aS) -1- ketone -7- (3- ketone morpholine) -1,3,3a, 4- tetrahydro benzo [b] oxazole simultaneously [3,4-d] [Isosorbide-5-Nitrae] oxazines -3- base) methyl) thiophene-2-carboxamide derivatives, can be used for prevention of postoperative venous thrombosis（DVT）And pulmonary infarction（PE）, the apoplexy in atrial fibrillation for the prevention, treat acute coronary syndrome（ACS）Deng.
Crystal formation is an important physicochemical property of compound, and the different crystal formation of same medicine may have significant difference due to the difference of crystal formation type and purity, some of physicochemical property, thus affecting the performance of the stability of medicine, bioavailability and curative effect.The crystal formation of compound can by ripe technology such as：X-ray diffraction spectrum method, infrared spectrometry, differential scanning calorimetry, thermogravimetric analysiss and melting point analysis are being distinguished by and to characterize.
WO2015/043364A1 " benzoxazoles as thrombin Xa factor inhibitor oxazines ketone compounds " discloses structural formula（I）Shown compound, but it is not directed to the research of its crystal formation.
Content of the invention
An object of the present invention is to provide a kind of formula of good stability（I）The crystal formation C of compound.
The second object of the present invention is to provide previously described formula（I）The preparation method of the crystal formation C of compound.
An object of the present invention is realized in：
Formula disclosed by the invention（I）The crystal formation C of compound has following feature：
Crystal formation C can be by comprising the X-ray powder diffraction that 2 θ angles are about 5.35,11.00,16.00,16.24,16.89,17.95,18.64,18.89,19.35,20.71,21.01,22.91,23.39,23.85,24.63,25.68,27.00,29.69,30.19,30.81,32.07,32.92,34.24（XRPD）Collection of illustrative plates is described, and the general precision of 2 θ values is about in the range of ± 0.2 °.
Preferably, described XRPD figure is substantially consistent with Fig. 1.
Crystal formation C also can pass through to include at about 190 DEG C ~ 205 DEG C, preferably at about 201.6 DEG C further（All ± 2 DEG C）The means of differential scanning calorimetry of the endothermic peak at place（DSC）Trace is characterizing.
Preferably, the figure of described DSC is substantially consistent with Fig. 2.
Or, crystal formation C also can be further by having thermogravimetric analysiss as shown in Figure 3（TGA）Trace, to characterize, shows that this crystal formation does not contain water of crystallization.
Or, crystal formation C also can be characterized by the total reflection infrared spectrum of decay further, including the absorption band in about following wave number：636th, 715,807,881,994,1024,1039,1113,1151,1185,1235,1342,1383,1424,1506,1558,1623,1669 and 1760
cm-1.The general precision of wave number value is about ± 2cm-1In the range of.
Preferably, the total reflection infrared spectrogram of described decay is that Fourier is infrared（FT-IR）Collection of illustrative plates, substantially consistent with Fig. 4.
The second object of the present invention is realized in：
Prepare described formula（I）The method of the crystal formation C of compound, comprises the following steps：
1）By formula（I）Compound is warming up to molten condition；
2）Maintain molten condition for a period of time；
3）It is cooled to room temperature again and can get crystalline solid.
Described formula（I）The preparation method of compound crystal form C, wherein step（1）Between described molten condition temperature is 190 DEG C ~ 205 DEG C.
Described formula（I）The preparation method of compound crystal form C, wherein step（2）The described time maintaining molten condition is 3 ~ 10min.
Described formula（I）The preparation method of compound crystal form C, wherein step（3）Described room temperature is 10 DEG C ~ 30 DEG C.
Beneficial effects of the present invention：
Crystal formation C disclosed by the invention has good performance, such as good water solubility, good stability, not hygroscopic deliquescence the features such as；In addition, this crystal formation is obtained by the method for fusion-crystallization, the method has that product purity is high, energy consumption low it is not necessary to add other solvents, the features such as environmental pollution is little.
Brief description
Fig. 1 is the powder diffraction of WA1-089 crystal formation C（XRPD）Collection of illustrative plates
Fig. 2. it is the means of differential scanning calorimetry of WA1-089 crystal formation C（DSC）Collection of illustrative plates
Fig. 3. it is the thermogravimetric analysiss of WA1-089 crystal formation C（TGA）Collection of illustrative plates
Fig. 4. be WA1-089 crystal formation C Fourier infrared（FT-IR）Collection of illustrative plates
Fig. 5. it is the dynamic water absorption collection of illustrative plates of WA1-089 crystal formation C
Fig. 6. it is the adsorption isothermal curve of WA1-089 crystal formation C.
Specific embodiment
Following embodiments are used merely to explain realizes the method for the present invention, should not be construed as limitation of the present invention.
Formula used in the present invention（Ⅰ）Compound（WA1-089）From North China Pharmacuetical Group New Drug Research ＆ Development Co., Ltd, content is 99%.The high performance liquid chromatography that the present invention uses（HPLC）For 996 type detectors, 515 pumps（Waters company）.Powder diffractometer model used in the present invention is Bruker D8 Advance diffractometer, is the K α radiation of 1.54nm using copper target wavelength（40Kv, 40mA）, θ -2 θ clinometer, Mo monochromator and Lynxeye detector.Instrument was detected with corundum before use.Acquisition software is Diffrac Plus XRD Commander, and analysis software shows MDI Jade 6.Sample is tested at ambient temperature, and the sample needing detection is placed on areflexia piece.Testing conditions in detail are as follows, angular range：3-40 ° of 2 θ, step-length：0.02 ° of 2 θ, speed：0.2 s.step-1.Except special instruction, sample is not ground before detection.Differential thermal analyses data is picked up from TA Instruments Q200 DSC, and instrument control software is Thermal Advantage, and analysis software is Universal
Analysis.Thermogravimetric analysis data picks up from TA Instruments Q500TGA, and instrument control software is Thermal Advantage, and analysis software is Universal
Analysis.Fourier is infrared（FT-IR）Data acquisition is in Bruker
Tensor 27, instrument control software data analysis software is all OPUS.Dynamic water is adsorbed（DVS）Analytical data picks up from TA Instruments
Q500TGA, instrument control software is Thermal Advantage, and analysis software is Universal Analysis.Unless stated otherwise, the usual testing conditions of sample are as shown in the table.
Table 1 DSV experiment parameter
Embodiment 1
10mg WA1-089 is placed on DSC instrument, is warming up to 190 DEG C with 10 DEG C/min, maintain 10min, then be cooled to 10 DEG C with 10 DEG C/min and can obtain solid crystal.
XRPD and dsc analysis data confirm that, the product of acquisition is the crystal formation C of WA1-089, its yield 99%, chemical purity ＞ 99%（Recorded by HPLC）.
Its X-ray powder diffraction figure（XRPD）As shown in figure 1, means of differential scanning calorimetry figure（DSC）As shown in Fig. 2 thermogravimetric analysis figure is as shown in figure 3, the total reflection infrared spectrogram of decay is as shown in Figure 4.
Embodiment 2
10mg WA1-089 is placed on DSC instrument, is warming up to 205 DEG C with 20 DEG C/min, maintain 3min, then be cooled to 30 DEG C with 10 DEG C/min and can obtain solid crystal.
XRPD and dsc analysis data confirm that, the product of acquisition is the crystal formation C of WA1-089, its yield 99%, chemical purity ＞ 99%（Recorded by HPLC）.
Its XRPD collection of illustrative plates is basically identical with Fig. 1, and DSC trace collection of illustrative plates is basically identical with Fig. 2, and TGA trace collection of illustrative plates is basically identical with Fig. 3, and FT-IR collection of illustrative plates is basically identical with Fig. 4.
Embodiment 3
10mg WA1-089 is placed on DSC instrument, is warming up to 200 DEG C with 20 DEG C/min, maintain 7min, then be cooled to 20 DEG C with 10 DEG C/min and can obtain solid crystal.
XRPD and dsc analysis data confirm that, the product of acquisition is the crystal formation C of WA1-089, its yield 99%, chemical purity ＞ 99%（Recorded by HPLC）.
Its XRPD collection of illustrative plates is basically identical with Fig. 1, and DSC trace collection of illustrative plates is basically identical with Fig. 2, and TGA trace collection of illustrative plates is basically identical with Fig. 3, and FT-IR collection of illustrative plates is basically identical with Fig. 4.
Embodiment 4
The crystal formation C taking the WA1-089 of 10mg is positioned in the platinum crucible of TGA, weight change in humidity change procedure for the TA software records sample, as shown in figure 5, Fig. 6 is crystalline product weight change in 20% ~ 80% RH range is 0.67%, result display crystal formation C is difficult moisture absorption.
Embodiment
5
Product 10.28mg in Example 1, adds in 37 DEG C of water of 3 mL, and constant temperature 10 minutes filters to obtain clear liquid.Clear liquid carries out assay using HPLC, and recording dissolubility is 22.56
µg/ml.
Claims (10)
1. a kind of formula（I）Shown benzoxazoles the crystal formation C of oxazines ketone compounds WA1-089, it is characterized in that, at 2 θ are 5.35,11.00,16.00,16.24,16.89,17.95,18.64,18.89,19.35,20.71,21.01,22.91,23.39,23.85,24.63,25.68,27.00,29.69,30.19,30.81,32.07,32.92 and 34.24 ± 0.2 °, there is X-ray powder diffraction peak in the X-ray powder diffraction figure of described crystal formation C.
2. crystal formation C as claimed in claim 1 is it is characterised in that described X-ray powder diffraction figure is basically identical with Fig. 1.
3. crystal formation C as claimed in claim 1, it is characterized by means of differential scanning calorimetry trace, and described means of differential scanning calorimetry trace includes having an endothermic peak between 190 DEG C ~ 205 DEG C.
4. crystal formation C as claimed in claim 3 is it is characterised in that the figure of described means of differential scanning calorimetry is basically identical with Fig. 2.
5. crystal formation C as claimed in claim 1 is it is characterised in that its thermogravimetric analysis figure is basically identical with Fig. 3.
6. crystal formation C as claimed in claim 1, it is characterized in that, the total reflection infrared spectrum of its decay is in about 636,715,807,881,994,1024,1039,1113,1151,1185,1235,1342,1383,1424,1506,1558,1623,1669 and 1760 ± 2cm-1Wave number comprises absorption band.
7. crystal formation C as claimed in claim 6 is it is characterised in that the total reflection infrared spectrogram of described decay is basically identical with Fig. 4.
8. a kind of method for preparing crystal formation C any one of claim 1-7, comprises the steps of：
1）By described formula（I）Compound is heated to molten condition；
2）Maintain molten condition 3 ~ 10min；
3）It is cooled to room temperature again and can get crystalline solid.
9. preparation method as claimed in claim 8, wherein step 1) described in molten condition temperature be 190 DEG C ~ 205 DEG C between.
10. preparation method as claimed in claim 8, wherein step 3) described in room temperature be 10 DEG C ~ 30 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114685529A (en) * | 2020-12-29 | 2022-07-01 | 中国科学院上海药物研究所 | Amorphous substance of oxazolidinone compound and preparation method and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114685529A (en) * | 2020-12-29 | 2022-07-01 | 中国科学院上海药物研究所 | Amorphous substance of oxazolidinone compound and preparation method and application thereof |
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Application publication date: 20170308 |