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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 PDF

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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
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China
Prior art keywords
polymorph
pyrroles
pyrazoles
benzene
amino
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Inventor
杨利民
孙德广
冀冲
杨嘉铭
张传玉
张晓军
刘洋健
李毅
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Capital Pharmaceutical Holdings (Beijing) Co., Ltd.
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Centaurus Biopharma Co Ltd
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    • 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

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of polymorphs and preparation method thereof of BTK inhibitor

Description

A kind of polymorph and preparation method thereof of BTK inhibitor
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. (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. 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. 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. 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. (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. 6. polymorph b according to claim 5, which is characterized in that X-ray powder diffraction figure, as shown in Figure 2.
  7. 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. (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. 9. polymorph C according to claim 8, which is characterized in that X-ray powder diffraction figure, as shown in Figure 3.
  10. 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. (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. 12. polymorph D according to claim 11, which is characterized in that X-ray powder diffraction figure, as shown in Figure 4.
  13. 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. (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. 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.
CN201710135109.XA 2017-03-09 2017-03-09 A kind of polymorph and preparation method thereof of BTK inhibitor Pending CN108570036A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101805341A (en) * 2006-09-22 2010-08-18 药品循环公司 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
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

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101805341A (en) * 2006-09-22 2010-08-18 药品循环公司 Inhibitors 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)

* Cited by examiner, † Cited by third party
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

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