CN108570036A - A kind of polymorph and preparation method thereof of BTK inhibitor - Google Patents
A kind of polymorph and preparation method thereof of BTK inhibitor Download PDFInfo
- Publication number
- CN108570036A CN108570036A CN201710135109.XA CN201710135109A CN108570036A CN 108570036 A CN108570036 A CN 108570036A CN 201710135109 A CN201710135109 A CN 201710135109A CN 108570036 A CN108570036 A CN 108570036A
- Authority
- CN
- China
- Prior art keywords
- polymorph
- pyrroles
- pyrazoles
- benzene
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Abstract
The present invention relates to a kind of polymorphs and preparation method thereof of BTK inhibitor
Description
Technical field
The present invention relates to the polymorphics of medical compounds, and in particular to (R, E) -5- amino -1- (1- (4- methoxyl group butyl- 2-
Ketenes base) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides polymorph and preparation method thereof.
Background technology
(R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -
1H- pyrazoles -4- amides are highly selective irreversible small molecule bruton's tyrosine kinase (BTK) inhibitor, in cell
Level has BTK the inhibiting effect of nanomole grade action intensity, in animal body for chronic leaching caused by BTK overexpressions
The tumour growth of bar cell leukemia and lymphoma mantle cell has complete inhibiting effect.Structural formula is as follows:
The synthetic method of the compound discloses in WO2014082598, but is not directed to the crystal form situation of compound, and nothing
Other document report (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxo benzene
Base) -1H- pyrazoles -4- amides crystal form.And the polymorphic of drug is to the physical property of drug, bioavilability, the quality of preparation
Significant with technique, between the different crystal forms of polymorph medicine, the stability of the differentia influence drug of physicochemical property is same
The crystal form of drug is different, and bioavilability might have significant difference.Different crystal forms influences the dissolution rate of drug, also,
The difference of different crystal forms surface free energy can cause the binding force between crystalline particle different, influence mobility, the particle of drug
The uniformity, uniformity of dosage units and physical stability.Therefore, it is necessary to study its crystal form.
Description of the drawings
Fig. 1 is the X-ray powder diffraction pattern of polymorphic A
Fig. 2 is the X-ray powder diffraction pattern of polymorph b
Fig. 3 is the X-ray powder diffraction pattern of polymorphic C
Fig. 4 is the X-ray powder diffraction pattern of polymorphic D
Fig. 5 is the X-ray powder diffraction pattern of polymorphic E
Fig. 6 is the DSC collection of illustrative plates of polymorphic A
Fig. 7 is the DSC collection of illustrative plates of polymorph b.
Fig. 8 is the DSC collection of illustrative plates of polymorphic C
Fig. 9 is the DSC collection of illustrative plates of polymorphic D
Figure 10 is the TGA collection of illustrative plates of polymorphic A
Invention content
The present invention relates to (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxygen
For phenyl) polymorph A, B, C, D, E and preparation method thereof of -1H- pyrazoles -4- amides.
The present invention relates to (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxygen
For phenyl) the polymorphic A of -1H- pyrazoles -4- amides, crystal type (R, the E) -5- amino -1- (1- (4- methoxyl group but-2-ene ketone
Base) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides have X-ray powder diffraction figure as shown in Figure 1
Spectrum, measurement error ± 0.10 degree of 2 θ are as shown in table 1 containing multiple characteristic peaks between 0~50 degree.
Table 1:The d- values of polymorphic A and 2 angles θ
d- | 2 angles θ | Relative intensity |
10.227 | 8.646 | 31.62 |
9.655 | 9.160 | 21.30 |
8.308 | 10.648 | 21.75 |
5.012 | 17.696 | 21.82 |
4.943 | 17.947 | 32.83 |
4.699 | 18.885 | 56.27 |
4.624 | 19.197 | 43.59 |
4.380 | 20.275 | 100.00 |
4.288 | 20.715 | 17.64 |
4.207 | 21.118 | 44.25 |
3.926 | 22.648 | 44.53 |
3.816 | 23.313 | 62.92 |
3.758 | 23.676 | 30.25 |
3.672 | 24.237 | 28.91 |
3.578 | 24.887 | 16.97 |
3.482 | 25.581 | 26.70 |
3.386 | 26.319 | 22.63 |
3.298 | 27.039 | 32.55 |
3.082 | 28.969 | 10.16 |
2.879 | 31.067 | 13.33 |
The present invention relates to (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxygen
For phenyl) polymorph bs of -1H- pyrazoles -4- amides, crystal type (R, the E) -5- amino -1- (1- (4- methoxyl group but-2-ene ketone
Base) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides have X-ray powder diffraction figure as shown in Figure 2
Spectrum, measurement error ± 0.10 degree of 2 θ are as shown in table 2 containing multiple characteristic peaks between 0~50 degree.
Table 2:The d- values of polymorph b and 2 angles θ
d- | 2 angles θ | Relative intensity |
10.860 | 8.142 | 47.98 |
10.026 | 8.820 | 23.31 |
8.218 | 10.766 | 20.13 |
6.501 | 13.621 | 10.13 |
4.999 | 17.742 | 41.10 |
4.905 | 18.086 | 41.08 |
4.672 | 18.994 | 100.00 |
4.633 | 19.156 | 71.76 |
4.437 | 20.010 | 83.57 |
4.296 | 20.676 | 63.87 |
4.237 | 20.967 | 85.18 |
3.903 | 22.786 | 25.97 |
3.820 | 23.285 | 61.19 |
3.776 | 23.562 | 59.85 |
3.737 | 23.811 | 41.74 |
3.605 | 24.697 | 14.22 |
3.537 | 25.177 | 21.37 |
3.471 | 25.666 | 30.99 |
3.425 | 26.017 | 32.45 |
3.382 | 26.350 | 40.85 |
3.098 | 28.819 | 15.72 |
3.051 | 29.274 | 11.64 |
2.902 | 30.814 | 17.07 |
2.868 | 31.181 | 10.46 |
The present invention relates to (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxygen
For phenyl) the polymorphic C of -1H- pyrazoles -4- amides, crystal type (R, the E) -5- amino -1- (1- (4- methoxyl group but-2-ene ketone
Base) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides have X-ray powder diffraction figure as shown in Figure 3
Spectrum, measurement error ± 0.10 degree of 2 θ are as shown in table 3 containing multiple characteristic peaks between 0~50 degree.
Table 3:The d- values of polymorphic C and 2 angles θ
d- | 2 angles θ | Relative intensity |
10.859 | 8.143 | 70.57 |
9.969 | 8.870 | 19.16 |
8.346 | 10.600 | 18.29 |
6.610 | 13.396 | 10.81 |
4.970 | 17.846 | 12.48 |
4.808 | 18.453 | 100.00 |
4.646 | 19.102 | 64.71 |
4.410 | 20.135 | 52.66 |
4.346 | 20.437 | 34.36 |
4.230 | 21.004 | 15.98 |
4.159 | 21.367 | 35.61 |
4.058 | 21.904 | 16.29 |
3.985 | 22.311 | 23.86 |
3.838 | 23.173 | 13.06 |
3.764 | 23.640 | 15.74 |
3.712 | 23.972 | 48.15 |
3.636 | 24.484 | 50.10 |
3.558 | 25.030 | 24.13 |
3.497 | 25.469 | 15.43 |
3.425 | 26.017 | 20.92 |
3.339 | 26.695 | 12.47 |
3.216 | 27.737 | 11.16 |
3.094 | 28.857 | 10.09 |
3.068 | 29.103 | 17.14 |
2.878 | 31.078 | 12.69 |
2.804 | 31.916 | 10.77 |
The present invention relates to (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxygen
For phenyl) the polymorphic D of -1H- pyrazoles -4- amides, crystal type (R, the E) -5- amino -1- (1- (4- methoxyl group but-2-ene ketone
Base) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides have X-ray powder diffraction figure as shown in Figure 4
Spectrum, measurement error ± 0.10 degree of 2 θ are as shown in table 4 containing multiple characteristic peaks between 0~50 degree.
Table 4:The d- values of polymorphic D and 2 angles θ
d- | 2 angles θ | Relative intensity |
10.222 | 8.651 | 44.02 |
9.741 | 9.079 | 16.14 |
8.078 | 10.952 | 35.95 |
6.331 | 13.988 | 11.41 |
5.094 | 17.410 | 13.36 |
5.003 | 17.730 | 26.01 |
4.859 | 18.260 | 29.55 |
4.815 | 18.426 | 34.62 |
4.657 | 19.060 | 100.00 |
4.492 | 19.764 | 98.10 |
4.369 | 20.325 | 74.67 |
4.202 | 21.143 | 14.45 |
4.126 | 21.539 | 36.79 |
4.073 | 21.822 | 36.74 |
4.016 | 22.135 | 23.42 |
3.921 | 22.677 | 14.12 |
3.782 | 23.522 | 65.73 |
3.623 | 24.572 | 77.81 |
3.548 | 25.098 | 48.58 |
3.479 | 25.606 | 10.86 |
3.392 | 26.273 | 11.88 |
3.340 | 26.694 | 15.82 |
3.313 | 26.916 | 17.27 |
3.287 | 27.126 | 14.31 |
3.151 | 28.325 | 23.22 |
2.966 | 30.136 | 10.23 |
2.869 | 31.170 | 21.35 |
Umerical relative intensity according to the form below definition in aforementioned four table:
Relative intensity | Definition |
80-100 | VS (very strong) |
60-80 | S (strong) |
40-60 | M (medium) |
10-40 | W (weak) |
The present invention also provides (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4-
Benzene oxo phenyl) -1H- pyrazoles -4- amide polymorphics A, B, C, D, E preparation method, (R, E) -5- amino -1- (1- (4- methoxies
Base but-2-ene ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides are according to patent WO2014082598
Method synthesis gained, five kinds of polymorphous preparation methods are by (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes
Ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides recrystallized in different solvents or water in plus
Heat turns crystalline substance.
The preparation method of polymorphic A is by (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3-
Base) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides dissolve by heating in ethyl acetate and dichloromethane, second alcohol and water, take advantage of
Heat filters, at room temperature stirring and crystallizing.
The preparation method of polymorph b is by (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3-
Base) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides crystal form A heat in water turn crystalline substance.
The preparation method of polymorphic C is by (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3-
Base) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides dissolve by heating in ethyl acetate, stirring and crystallizing at room temperature.
The preparation method of polymorphic D is by (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3-
Base) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides crystal form C heat in water turn crystalline substance.
The preparation method of polymorph E is by (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3-
Base) concentration removing solvent obtains polymorph E to the dissolving of -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides in methylene chloride.
Polymorph A, B, the C are filtered after crystallization in the preparation method of D, E, and are dried in vacuo and are removed solvent and moisture.
Above-mentioned polymorphic A can be by being recrystallized to give, to two kinds of solvent bodies in ethyl acetate and dichloromethane, second alcohol and water
It is that the product being recrystallized to give carries out X-ray powder diffraction figure analysis, 2 angles θ difference numbers are less than one third, and all include table
Listed characteristic peak in 1, it is thus regarded that (R, E) -5- amino -1- (1- (4- methoxyl groups that two kinds of solvent systems are recrystallized to give
But-2-ene ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides belong to same crystal form.
(R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases)-is found through experiments that in the present invention
There are polymorph A, B, C, D, E for -1H- pyrazoles -4- amides by 3- (4- benzene oxos phenyl).Five kinds of polymorphs carry out crystal form
Transformation experiment, display polymorph A has good stability, and other several polymorph stability are poor.
Embodiment With reference to embodiment is described in further details the present invention.
Embodiment 1, (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amide polymorphs A preparation
By compound (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amides (55.0g), ethyl acetate (200mL) and dichloromethane (10mL) be added to the single port of 1000mL
In flask, 85 DEG C are heated to, solid all dissolves, and filters while hot, and filtrate is added in the single-necked flask of another 1000mL, cooling
To room temperature, it is slowly stirred crystallization, is filtered, 50 DEG C are dried in vacuum overnight, and obtain off-white powder 40.8g, yield:74.2%.
DSC detection figures (25 DEG C of initial temperature, 250 DEG C of final temperature, 10 DEG C/min of the rate of heat addition) are as shown in Figure 6.
Embodiment 2, (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amide polymorph bs preparation
By compound (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amides (polymorph A:10.5g) and pure water (20mL) is added in the single-necked flask of 50mL, is added
Heat stirs 4 days to 50 DEG C, filters, 50 DEG C are dried in vacuum overnight, and obtain off-white powder 10.2g, yield:97.0%.
DSC detection figures (25 DEG C of initial temperature, 250 DEG C of final temperature, 10 DEG C/min of the rate of heat addition)) as shown in Figure 7.
Embodiment 3, (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amide polymorphs C preparation
By compound (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amides (15.0g) and ethyl acetate (100mL) is added in the single-necked flask of 500mL, is heated to back
Stream, solid are all dissolved, are filtered while hot, filtrate is added in the single-necked flask of another 500mL, is cooled to room temperature, and is slowly stirred
Crystallization, filtering, 50 DEG C are dried in vacuum overnight, and obtain off-white powder 13.5g, yield:90.0%.
DSC detection figures (25 DEG C of initial temperature, 250 DEG C of final temperature, 10 DEG C/min of the rate of heat addition) are as shown in Figure 8.
Embodiment 4, (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amide polymorphs D preparation
By compound (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amides (polymorph C:6.0g) and pure water (15mL) is added in the single-necked flask of 50mL, heating
It to 50 DEG C, stirs 4 days, filters, 50 DEG C are dried in vacuum overnight, and obtain off-white powder 5.5g, yield:92.0%.
DSC detection figures (25 DEG C of initial temperature, 250 DEG C of final temperature, 10 DEG C/min of the rate of heat addition) are as shown in Figure 9.
Embodiment 5, (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amide polymorphs E preparation
By compound (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amides (5.0g) and dichloromethane (15mL) be added in the single-necked flask of 50mL, 50 DEG C are heated to,
Until completely dissolved, it is concentrated under reduced pressure, 50 DEG C are dried in vacuum overnight, and obtain light yellow solid 5.0g, yield:100.0%.
Embodiment 6, (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amide polymorph A, B crystal form transformation experiment.
By compound (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) each 2g of polymorph A and B of -1H- pyrazoles -4- amides carries out micronizing crushing respectively, send X-ray powder respectively after the completion
Last diffraction, the results showed that polymorph A is converted into after polymorph b micro mist, and crystal form is unconverted after polymorph A micro mists.
Embodiment 7, (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) -1H- pyrazoles -4- amide polymorph C, form D transformation experiment.
By compound (R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos
Phenyl) each 2g of polymorph C and D of -1H- pyrazoles -4- amides carries out micronizing crushing respectively, send X-ray powder respectively after the completion
Last diffraction, the results showed that polymorph D is converted into after polymorph C micro mists, crystal form is unconverted after polymorph D micro mists, still,
D types are unstable, and the room temperature time is longer or heating can be partially converted into c-type.
The above result shows that polymorphic A has good stability, other several stability of crystal form are poor.
Claims (15)
- (1. R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- The polymorph A of pyrazoles -4- amides, which is characterized in that it is melted at 132 ± 3 DEG C.
- 2. polymorph A according to claim 1, which is characterized in that X-ray powder diffraction figure is indicating following with 2 θ There is characteristic peak in position:8.646,9.160,10.648,17.947,18.885,19.197,20.275,21.118,22.648, 23.313 27.039.
- 3. polymorph A according to claim 1 or 2, which is characterized in that X-ray powder diffraction figure, as shown in Figure 1.
- 4. the preparation method of the polymorph A of claim 1,2 or 3, which is characterized in that (R, E) -5- amino -1- (1- (4- first Oxygroup but-2-ene ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides are in ethyl acetate and dichloromethane It is recrystallized to give polymorph A in alkane, second alcohol and water.
- (5. R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- The polymorph b of pyrazoles -4- amides, which is characterized in that X-ray powder diffraction figure has feature in the following position indicated with 2 θ Peak:8.142,8.820,10.766,17.742,18.086,18.994,19.156,20.010,20.676,20.967, 23.285 23.562.
- 6. polymorph b according to claim 5, which is characterized in that X-ray powder diffraction figure, as shown in Figure 2.
- 7. the preparation method of the polymorph b of claim 5 or 6, which is characterized in that (R, E) -5- amino -1- (1- (4- methoxies Base but-2-ene ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides crystal form A heat in water turn crystalline substance Obtain polymorph b.
- (8. R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- The polymorph C of pyrazoles -4- amides, which is characterized in that X-ray powder diffraction figure has feature in the following position indicated with 2 θ Peak:8.143,8.870,10.600,18.453,19.102,20.135,23.972,24.484.
- 9. polymorph C according to claim 8, which is characterized in that X-ray powder diffraction figure, as shown in Figure 3.
- 10. the preparation method of the polymorph C of claim 8 or 9, which is characterized in that (R, E) -5- amino -1- (1- (4- methoxies Base but-2-ene ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides dissolve by heating in ethyl acetate, room The lower stirring and crystallizing of temperature, obtains polymorph C.
- (11. R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- The polymorph D of pyrazoles -4- amides, which is characterized in that X-ray powder diffraction figure has feature in the following position indicated with 2 θ Peak:8.651,9.079,10.952,19.060,19.764,20.325,23.522,24.572,25.098.
- 12. polymorph D according to claim 11, which is characterized in that X-ray powder diffraction figure, as shown in Figure 4.
- 13. the preparation method of the polymorph D of claim 11 or 12, which is characterized in that (R, E) -5- amino -1- (1- (4- first Oxygroup but-2-ene ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides crystal form C heat in water turn Crystalline substance obtains polymorph D.
- (14. R, E) -5- amino -1- (1- (4- methoxyl group but-2-enes ketone group) pyrroles -3- bases) -3- (4- benzene oxos phenyl) -1H- The polymorph E of pyrazoles -4- amides, which is characterized in that X-ray powder diffraction figure is amorphous article, such as Fig. 5 institutes without characteristic peak Show.
- 15. the preparation method of the polymorph E of claim 14, which is characterized in that (R, E) -5- amino -1- (1- (4- methoxyl groups But-2-ene ketone group) pyrroles -3- bases) concentration removes the dissolving of -3- (4- benzene oxos phenyl) -1H- pyrazoles -4- amides in methylene chloride Solvent is gone to obtain polymorph E.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710135109.XA CN108570036A (en) | 2017-03-09 | 2017-03-09 | A kind of polymorph and preparation method thereof of BTK inhibitor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710135109.XA CN108570036A (en) | 2017-03-09 | 2017-03-09 | A kind of polymorph and preparation method thereof of BTK inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108570036A true CN108570036A (en) | 2018-09-25 |
Family
ID=63577795
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710135109.XA Pending CN108570036A (en) | 2017-03-09 | 2017-03-09 | A kind of polymorph and preparation method thereof of BTK inhibitor |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108570036A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021004401A1 (en) * | 2019-07-09 | 2021-01-14 | 上海再启生物技术有限公司 | Crystal form of key intermediate of btk kinase inhibitor and preparation method therefor |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101805341A (en) * | 2006-09-22 | 2010-08-18 | 药品循环公司 | The inhibitor of bruton's tyrosine kinase |
CN103848810A (en) * | 2012-11-30 | 2014-06-11 | 北京赛林泰医药技术有限公司 | Bruton's tyrosine kinases inhibitor |
CN105085474A (en) * | 2014-05-07 | 2015-11-25 | 北京赛林泰医药技术有限公司 | Bruton tyrosine kinase inhibitor |
CN105764896A (en) * | 2013-09-30 | 2016-07-13 | 药品循环有限责任公司 | Inhibitors of Bruton's tyrosine kinase |
CN105884747A (en) * | 2014-08-28 | 2016-08-24 | 北京赛林泰医药技术有限公司 | Preparation method for preparing Bruton's tyrosine kinase (BTK) inhibitor |
-
2017
- 2017-03-09 CN CN201710135109.XA patent/CN108570036A/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101805341A (en) * | 2006-09-22 | 2010-08-18 | 药品循环公司 | The inhibitor of bruton's tyrosine kinase |
US20170007611A1 (en) * | 2006-09-22 | 2017-01-12 | Pharmacyclics Llc | Inhibitors of bruton's tyrosine kinase |
CN103848810A (en) * | 2012-11-30 | 2014-06-11 | 北京赛林泰医药技术有限公司 | Bruton's tyrosine kinases inhibitor |
CN104837825A (en) * | 2012-11-30 | 2015-08-12 | 北京赛林泰医药技术有限公司 | Inhibitors of bruton's tyrosine kinase |
CN105764896A (en) * | 2013-09-30 | 2016-07-13 | 药品循环有限责任公司 | Inhibitors of Bruton's tyrosine kinase |
CN105085474A (en) * | 2014-05-07 | 2015-11-25 | 北京赛林泰医药技术有限公司 | Bruton tyrosine kinase inhibitor |
CN105884747A (en) * | 2014-08-28 | 2016-08-24 | 北京赛林泰医药技术有限公司 | Preparation method for preparing Bruton's tyrosine kinase (BTK) inhibitor |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021004401A1 (en) * | 2019-07-09 | 2021-01-14 | 上海再启生物技术有限公司 | Crystal form of key intermediate of btk kinase inhibitor and preparation method therefor |
US11180449B2 (en) | 2019-07-09 | 2021-11-23 | Shanghai Zaiqi Bio-Tech Co., Ltd. | Crystal form of key intermediate of bruton tyrosine kinase (BTK) inhibitor and preparation method thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106661025B (en) | A kind of isethionate of cyclin dependent kinase inhibitor, its crystal form and preparation method | |
WO2006024863A1 (en) | Stable crystal form of imatinib mesylate and process for the preparation thereof | |
JP6378844B2 (en) | Method for preparing sixth crystalline form of sofosbuvir | |
CN106687470A (en) | Sofosbuvir in crystalline form and process for its preparation | |
TWI745289B (en) | A crystalline form of cyclin-dependent protein kinase inhibitor and preparation methods thereof | |
CN108570036A (en) | A kind of polymorph and preparation method thereof of BTK inhibitor | |
CN104926872B (en) | Tenofovir Chinese mugwort draws the tartrate of phenol amine half | |
EP4046687A1 (en) | Method for producing centanafadine | |
CN105503854A (en) | New crystal form substance of Dasatinib anhydrous substance and preparation method thereof | |
CN108976234B (en) | Co-amorphous substance of ibrutinib and saccharin and preparation method thereof | |
CN112351986B (en) | Crystals of benzoxazole derivative | |
WO2017118447A1 (en) | A preparation method of amorphous apremilast | |
CN110526914B (en) | Polymorphic substance of ALK inhibitor and preparation method thereof | |
CN108456210A (en) | A kind of polymorph and preparation method thereof of alk tyrosine kinase inhibitor | |
JP2022520629A (en) | FGFR inhibitor compound in solid form and method for producing the same | |
CN106065016B (en) | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor | |
CN107698563B (en) | Method for preparing neratinib maleate crystal form | |
CN104788435A (en) | I-type crystal of dibenzenesulfonate of inhibitor of protein tyrosine kinase | |
CN105777651A (en) | Crystal form of poly adenosinediphosphate-ribose polymerase (PARP) inhibitor, preparation method for crystal form and medicinal use of crystal form | |
WO2017152858A1 (en) | Crystal form of ceritinib and preparation method thereof | |
WO2013120496A1 (en) | Process for the preparation of linezolid in crystalline form and salts thereof | |
CN106432197B (en) | Ledipasvir intermediate mono-p-toluenesulfonate, crystal form and preparation method thereof | |
CN106432253A (en) | New crystal form of Velpatasvir and preparation method of new crystal form | |
WO2015123801A1 (en) | Preparation method for polymorphic 6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine and use thereof | |
CN107162965A (en) | A kind of toluene fulfonate amorphous forms of Sorafenib half and preparation method thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20190516 Address after: 100176 Beijing Economic and Technological Development Zone, No. 99 Kechuang 14th Street, 33 Building D, 2213 on the second floor (centralized office area) Applicant after: Capital Pharmaceutical Holdings (Beijing) Co., Ltd. Address before: 100195 No. 15 Building, Yuquan Huigu, No. 3 Minzhuang Road, Haidian District, Beijing Applicant before: Beijing Centaurus Biopharma Technology Co., Ltd. |
|
TA01 | Transfer of patent application right | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180925 |
|
RJ01 | Rejection of invention patent application after publication |