CN104961688A - Phosphate of epidermal growth factor receptor kinase inhibitor and preparation method thereof - Google Patents
Phosphate of epidermal growth factor receptor kinase inhibitor and preparation method thereof Download PDFInfo
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- CN104961688A CN104961688A CN201410821405.1A CN201410821405A CN104961688A CN 104961688 A CN104961688 A CN 104961688A CN 201410821405 A CN201410821405 A CN 201410821405A CN 104961688 A CN104961688 A CN 104961688A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/48—Two nitrogen atoms
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Abstract
The invention relates to phosphate of N-(3-(2-(4-(4-acetylpiperazine-1-yl)-2-methoxyphenylamino)-5-(trifluoromethyl)pyrimidine-4-yl-amino)phenyl)acrylamide), and a crystal form and a preparation method thereof. The phosphate of the compound as shown in a formula (I) which is described in the specification has favorable performance like good stability, low hygroscopicity and process developability and manageability; and the preparation method is simple and has low cost, so the method has an important value to optimization and development of the phosphate of the compound as a drug in the future.
Description
Technical field
The present invention relates to chemical medicine, particularly relate to N-(3-(2-(4-(4-Acetylpiperazine-1-base)-2-Methoxyphenylamino)-5-(trifluoromethyl) pyrimidine-4-yl amino) phenyl) acrylamide) phosphoric acid salt and preparation method thereof.
Background technology
N-(3-(2-(4-(4-Acetylpiperazine-1-base)-2-Methoxyphenylamino)-5-(trifluoromethyl) pyrimidine-4-yl is amino) phenyl) acrylamide) (having another name called CO1686); first researched and developed by Clovis tumour company (Clovis Oncology); a kind of oral, target covalency (third generation EGF-R ELISA (EGFR) inhibitor of irreversible saltant type of novelty; crucial activated mutant and T790 medicament-resistant mutation can be suppressed, Wild type EGFR signal is left unused.The exploitation of this medicine is for carrying the treatment of the NSCLC patient of initial activation EGFR sudden change and key resistance mutations T790M.On May 20th, 2014, FDA has authorized the breakthrough therapy identification of experimental drug CO1686, as one list pharmacotherapy, for carrying the treatment of two wires EGFR sudden change nonsmall-cell lung cancer (NSCLC) of T790M.CO1686 is in clinical II stage phase at present, and its structure is as shown in formula I:
At present, patent WO2013138495 discloses the crystal formation of the multiple free alkali of CO1686; Patent WO2013138502 discloses the multiple crystal formation of its hydrobromate and the crystal formation of other salt.
Research finds, early stage research uses the free alkali form of CO1686, but can improve pharmaceutical utility, reduce variability because of its form of hydrobromide, clinically use its hydrobromate instead, but its dosage is still continuing to climb in August, 2013.
Therefore be necessary to develop further that dosage is low, good stability, draw moist low, be applicable to storing and the new salt of suitability for industrialized production and the crystal formation of salt, thus meet the subsequent development needs of medicine.
Summary of the invention
The invention provides the phosphoric acid salt of formula I compound, phosphoric acid salt new crystal and preparation method thereof.Phosphoric acid salt provided by the invention and new crystal thereof are suitable for drug research and suitability for industrialized production.
An object of the present invention is to provide the phosphoric acid salt of formula I compound, it is characterized in that, described phosphoric acid salt is crystallized form.
Particularly, the phosphatic crystallized form of formula I compound provided by the invention, called after crystal form A in the present invention.
Crystal form A provided by the invention, is characterized in that, its X-ray powder diffraction figure is that 7.9 ° ± 0.2 °, 22.4 ° ± 0.2 °, 25.6 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 12.7 ° ± 0.2 °, 15.4 ° ± 0.2 °, 21.3 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 18.3 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.7 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form A provided by the invention, is characterized in that, its X-ray powder diffraction figure substantially as shown in Figure 1.
Crystal form A provided by the invention, is characterized in that, starts to occur endotherm(ic)peak near being heated to 192.4 DEG C, and its differential scanning calorimetric thermogram substantially as shown in Figure 2.
Crystal form A provided by the invention, is characterized in that, when being heated to 175 DEG C, have the weight loss gradient of about 0.9%, its thermogravimetric analysis figure substantially as shown in Figure 3.
Another object of the present invention is to provide formula I compound method for production of phosphate salt, it is characterized in that, its preparation method comprises makes formula I compound and phosphoric acid react in ketone or ether solvent, and stirring and crystallizing obtains.
Further, the preferred acetone of described ketones solvent, the preferred tetrahydrofuran (THF) of described ether solvent.
Further, the reaction mol ratio of described formula I compound and phosphoric acid is between 1:0.8 to 1:2.
Phosphatic crystal form A provided by the invention has and lower draws moist, without the need to special drying conditions in preparation process, simplifies preparation and the aftertreatment technology of medicine, is easy to suitability for industrialized production.Compared with patent WO2013138502 hydrobromate crystal formation I, the phosphatic crystal form A solubleness in the present invention is higher, is conducive to the bioavailability and the curative effect of medication that improve medicine, has very strong economic worth.
The phosphatic crystal form A of formula I compound provided by the invention can be used for the preparation of Therapeutic cancer medicine, especially for the preparation for the treatment of non-small cell lung cancer drug.
Medicinal compositions is with the phosphatic crystal form A of formula I compound for activeconstituents, and interpolation medicine is commonly used auxiliary material and is prepared from.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of phosphoric acid salt crystal form A
Fig. 2 is the DSC figure of phosphoric acid salt crystal form A
Fig. 3 is the TGA figure of phosphoric acid salt crystal form A
Fig. 4 is phosphoric acid salt crystal form A
1h NMR schemes
Fig. 5 is the DVS figure of phosphoric acid salt crystal form A
Fig. 6 is the DVS figure of WO2013138502 hydrobromate crystal formation I
Embodiment
Below will set forth the present invention further by specific embodiment, but be not limited to protection scope of the present invention.Those skilled in the art can make improvements preparation method and use instrument in right, and these improvement also should be considered as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
DVS: dynamic water is adsorbed
1h NMR: proton nmr spectra
X-ray powder diffraction figure of the present invention gathers on Panalytical Empyrean x-ray powder diffraction instrument.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K α
Kα1(
)：1.540598；Kα2(
)：1.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliampere(mA)s (mA)
Sweep limit: from 3.0 to 40.0 degree
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TA Q2000.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Thermogravimetric analysis of the present invention (TGA) figure gathers on TA Q5000.The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Dynamic water absorption (DVS) figure of the present invention gathers on the Intrinsic dynamic water adsorption instrument produced by SMS company (Surface MeasurementSystems Ltd.).The method parameter of described dynamic water adsorption instrument is as follows:
Temperature: 25 DEG C
Carrier gas, flow velocity: N
2, 200 ml/min
Unit time quality change: 0.002%/minute
RH range: 0%RH-95%RH
Embodiment 1
Formula I compound method for production of phosphate salt:
The formula I compound getting 10.2mg is dissolved in the acetone of 0.9mL, dropwise adds the phosphoric acid solution of 0.09mL 0.2mol/L, stirring reaction 24 hours under 50 DEG C of conditions, and collecting solid can obtain.
The phosphate product that aforesaid method prepares, its
1h NMR appraising datum is as follows:
1H NMR(400MHz,DMSO)δ10.17(s,1H),8.67(s,1H),8.28(s,1H),8.10(s,1H),7.74(s,1H),7.51(dd,J＝16.7,8.3Hz,2H),7.26(t,J＝8.1Hz,2H),6.61(d,J＝2.0Hz,1H),6.44(dd,J＝17.0,10.1Hz,1H),6.26(dd,J＝17.0,1.8Hz,2H),5.76(dd,J＝10.1,1.9Hz,1H),3.77(s,3H),3.56(d,J＝4.7Hz,4H),3.03(d,J＝25.7Hz,4H),2.07(d,J＝15.7Hz,3H).
After testing, it is crystal form A that the present embodiment obtains solid, and its X-ray powder diffraction data are as shown in table 1.Its XRPD schemes as Fig. 1, and its DSC schemes as Fig. 2, and its TGA schemes as Fig. 3, its
1h NMR schemes as shown in Figure 4.
Table 1
| 2theta | D interval | Intensity % |
| 7.93 | 11.15 | 53.24 |
| 9.68 | 9.14 | 33.02 |
| 12.70 | 6.97 | 50.26 |
| 15.44 | 5.74 | 45.82 |
| 15.98 | 5.55 | 10.65 |
| 17.99 | 4.93 | 23.67 |
| 18.31 | 4.84 | 44.26 |
| 19.87 | 4.47 | 19.25 |
| 20.84 | 4.26 | 45.33 |
| 21.26 | 4.18 | 53.86 |
| 21.71 | 4.09 | 50.39 |
| 22.43 | 3.96 | 100.00 |
| 23.04 | 3.86 | 29.01 |
| 23.55 | 3.78 | 18.24 |
| 23.83 | 3.73 | 20.45 |
| 24.09 | 3.69 | 19.36 |
| 24.74 | 3.60 | 11.21 |
| 25.63 | 3.48 | 64.96 |
| 26.46 | 3.37 | 18.59 |
| 27.72 | 3.22 | 13.16 |
| 28.27 | 3.16 | 18.97 |
| 28.87 | 3.09 | 11.13 |
| 32.99 | 2.71 | 6.37 |
Embodiment 2
Formula I compound method for production of phosphate salt:
The formula I compound getting 10.2mg obtains free alkali and is dissolved in the tetrahydrofuran (THF) of 0.9mL, dropwise adds the phosphoric acid solution of 0.09mL 0.2mol/L, stirring reaction 24 hours at 50 DEG C, and collecting solid can obtain.
After testing, it is crystal form A that the present embodiment obtains solid, and its X-ray powder diffraction data are as shown in table 2.
Table 2
| 2theta | D interval | Intensity % |
| 4.54 | 19.48 | 6.08 |
| 7.95 | 11.12 | 63.41 |
| 9.68 | 9.14 | 17.18 |
| 12.70 | 6.97 | 42.80 |
| 15.45 | 5.73 | 31.58 |
| 15.98 | 5.54 | 11.75 |
| 18.34 | 4.84 | 32.52 |
| 19.87 | 4.47 | 13.69 |
| 20.04 | 4.43 | 7.38 |
| 20.87 | 4.26 | 38.51 |
| 21.28 | 4.18 | 52.62 |
| 21.75 | 4.09 | 63.19 |
| 22.44 | 3.96 | 100.00 |
| 23.05 | 3.86 | 24.63 |
| 23.56 | 3.78 | 18.32 |
| 24.75 | 3.60 | 22.53 |
| 25.63 | 3.48 | 54.25 |
| 26.44 | 3.37 | 14.20 |
| 26.97 | 3.31 | 17.94 |
| 27.71 | 3.22 | 14.12 |
| 28.30 | 3.15 | 22.45 |
| 28.93 | 3.09 | 12.19 |
| 30.52 | 2.93 | 3.20 |
| 31.26 | 2.86 | 3.48 |
| 32.96 | 2.72 | 7.08 |
Embodiment 3
Phosphoric acid salt and the comparative study of patent WO2013138502 hydrobromate solubleness:
FeSSIF (under full abdomen state simulated intestinal fluid) and water phosphoric acid salt of the present invention and patent hydrobromate sample is used to be mixed with saturated solution, after 1 hour, by the content of sample in high-performance liquid chromatogram determination saturated solution after 4 hours respectively.Experimental result is as shown in table 3.
Table 3
Can be found out by above-mentioned comparing result, place after 1 hour in FeSSIF and water, after 4 hours, phosphoric acid salt of the present invention is compared with patent hydrobromate, and solubleness is higher.
Embodiment 4
Phosphoric acid salt crystal form A and patent WO2013138502 hydrobromate crystal formation I draw moist comparative study:
Get 10mg phosphoric acid salt crystal form A of the present invention and patent hydrobromate crystal formation I respectively to carry out dynamic water absorption (DVS) and test.Result is as shown in table 4, and as shown in Figure 5, the DVS of patent hydrobromate crystal formation I as shown in Figure 6 for the DVS of phosphoric acid salt crystal form A.
Table 4
Result shows, phosphoric acid salt crystal form A draws moist all low than patent hydrobromate crystal formation I under 80% and 95% humidity.
Claims (10)
1. formula I compound N-(3-(2-(4-(4-Acetylpiperazine-1-base)-2-Methoxyphenylamino)-5-(trifluoromethyl) pyrimidine-4-yl amino) phenyl) acrylamide) phosphoric acid salt.
2. the phosphoric acid salt of formula I compound according to claim 1, is characterized in that, described salt is crystallized form, called after phosphoric acid salt crystal form A.
3. the phosphoric acid salt crystal form A of formula I compound according to claim 2, is characterized in that, its X-ray powder diffraction figure is that 7.9 ° ± 0.2 °, 22.4 ° ± 0.2 °, 25.6 ° ± 0.2 ° place has characteristic peak in 2theta value.
4. formula I compound phosphoric acid salt crystal form A according to claim 3, is further characterized in that, its X-ray powder diffraction figure is that 12.7 ° ± 0.2 °, 15.4 ° ± 0.2 °, 21.3 ° ± 0.2 ° place has characteristic peak in 2theta value.
5. formula I compound phosphoric acid salt crystal form A according to claim 4, is further characterized in that, its X-ray powder diffraction figure is that 18.3 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.7 ° ± 0.2 ° place has characteristic peak in 2theta value.
6. formula I compound phosphoric acid salt crystal form A according to claim 3, it is characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 1.
7. prepare a phosphatic method for formula I compound, it is characterized in that, comprise and formula I compound and phosphoric acid are reacted in ketone or ether solvent, stirring and crystallizing obtains.
8. method according to claim 6, the preferred acetone of described ketones solvent, the preferred tetrahydrofuran (THF) of described ether solvent; The reaction mol ratio of described formula I compound and phosphoric acid is between 1:0.8 to 1:2.
9. a pharmaceutical composition, its phosphoric acid salt crystal form A containing the formula I compound described in good grounds claim 2 to 5 any one and pharmaceutically acceptable carrier.
10. the phosphoric acid salt crystal form A of the formula I compound according to claim 2 to 5 any one or pharmaceutical composition according to claim 9 are preparing the purposes in Therapeutic cancer medicine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410821405.1A CN104961688A (en) | 2014-12-25 | 2014-12-25 | Phosphate of epidermal growth factor receptor kinase inhibitor and preparation method thereof |
| PCT/CN2015/098901 WO2016101912A1 (en) | 2014-12-25 | 2015-12-25 | Crystal form of salt of epidermal growth factor receptor kinase inhibitor and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410821405.1A CN104961688A (en) | 2014-12-25 | 2014-12-25 | Phosphate of epidermal growth factor receptor kinase inhibitor and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and uses thereof |
| WO2013138495A1 (en) * | 2012-03-15 | 2013-09-19 | Celgene Avilomics Research, Inc. | Solid forms of an epidermal growth factor receptor kinase inhibitor |
| WO2013138502A1 (en) * | 2012-03-15 | 2013-09-19 | Celgene Avilomics Research, Inc. | Salts of an epidermal growth factor receptor kinase inhibitor |
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- 2014-12-25 CN CN201410821405.1A patent/CN104961688A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and uses thereof |
| WO2013138495A1 (en) * | 2012-03-15 | 2013-09-19 | Celgene Avilomics Research, Inc. | Solid forms of an epidermal growth factor receptor kinase inhibitor |
| WO2013138502A1 (en) * | 2012-03-15 | 2013-09-19 | Celgene Avilomics Research, Inc. | Salts of an epidermal growth factor receptor kinase inhibitor |
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